US20120122860A1 - Solid forms of sulfonamides and amino acids - Google Patents

Solid forms of sulfonamides and amino acids Download PDF

Info

Publication number
US20120122860A1
US20120122860A1 US13/318,760 US201013318760A US2012122860A1 US 20120122860 A1 US20120122860 A1 US 20120122860A1 US 201013318760 A US201013318760 A US 201013318760A US 2012122860 A1 US2012122860 A1 US 2012122860A1
Authority
US
United States
Prior art keywords
phenyl
pyrrolo
pyridine
carbonyl
difluoro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13/318,760
Inventor
Gary Conard Visor
Prabha N. Ibrahim
Wayne Spevak
Hanna Cho
Songyuan Shi
Guoxian Wu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Plexxikon Inc
Original Assignee
Plexxikon Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=42236712&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20120122860(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Plexxikon Inc filed Critical Plexxikon Inc
Priority to US13/318,760 priority Critical patent/US20120122860A1/en
Publication of US20120122860A1 publication Critical patent/US20120122860A1/en
Assigned to PLEXXIKON INC. reassignment PLEXXIKON INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHO, HANNA, IBRAHIM, PRABHA N., SHI, SONGYUAN, SPEVAK, WAYNE, WU, GUOXIAN
Assigned to PLEXXIKON INC. reassignment PLEXXIKON INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: VISOR, GARY
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • novel compounds and novel solid forms, formulations, and uses thereof.
  • disclosed compounds are kinase inhibitors.
  • solid forms of phenyl sulfonamide compounds preferably an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compounds.
  • solid forms comprising a phenyl sulfonamide compound, preferably an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound and a basic amino acid, wherein the solid form provides improved biopharmaceutical properties.
  • Solid forms and related compositions in treating diseases and conditions associated with regulation of the activity of one or more protein kinases, including, but not limited to Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • the solid forms that can be used for therapeutic methods involving modulation of one or more Raf protein kinases including treatment of a variety of indications, including, but not limited to, melanoma, colorectal cancer, thyroid cancer, ovarian cancer, cholangiocarcinoma, pain and/or polycystic kidney disease.
  • a solid form comprising a phenyl sulfonamide compound, preferably an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound, and a basic amino acid
  • the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound and the basic amino acid provides improved biopharmaceutical properties of the phenyl sulfonamide compound relative to the free base, salt or other solid form of the compound.
  • the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound and the basic amino acid provides improved pharmacokinetics of the phenyl sulfonamide compound relative to the free base, salt or other solid form of the compound, wherein said improvement is an increase in the Cmax and/or AUC for a given dose of the compound in a suitable animal model, such as a mouse, rat, dog or monkey model.
  • a composition comprising the solid form is provided.
  • the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound and the basic amino acid is provided in a formulation that further improves the biopharmaceutical properties of the N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound.
  • a solid form comprising a phenyl sulfonamide compound, preferably an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound, and arginine is provided.
  • the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound and arginine provides improved biopharmaceutical properties of the phenyl sulfonamide compound relative to the free base, salt or other solid form of the compound.
  • the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound and arginine provides improved pharmacokinetics of the phenyl sulfonamide compound relative to the free base, salt or other solid form of the compound, wherein said improvement is an increase in the Cmax and/or AUC for a given dose of the compound in a suitable animal model, such as a mouse, rat, dog or monkey model.
  • a composition comprising the solid form is provided.
  • the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound and arginine is provided in a formulation that further improves the biopharmaceutical properties of the N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound.
  • a solid form comprising a phenyl sulfonamide compound, preferably an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound and lysine is provided.
  • the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound and lysine provides with improved biopharmaceutical properties of the phenyl sulfonamide compound relative to the free base, salt or other solid form of the compound.
  • the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound and lysine provides improved pharmacokinetics of the phenyl sulfonamide compound relative to the free base, salt or other solid form of the compound, wherein said improvement is an increase in the Cmax and/or AUC for a given dose of the compound in a suitable animal model, such as a mouse, rat, dog or monkey model.
  • a composition comprising the solid form is provided.
  • the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound and lysine is provided in a formulation that further improves the biopharmaceutical properties of the N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound.
  • a solid form comprising a basic amino acid and a phenyl sulfonamide compound of Formula I, wherein Formula I is as follows:
  • each R 7 when present, is independently fluoro, chloro, —CN, —OH, lower alkyl, lower alkenyl, —C(O)—O—R 16 substituted lower alkenyl, lower alkoxy, lower alkoxy substituted lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, —S(O) 2 R 20 , —N(H)—S(O) 2 —R 20 , —N(H)—C(O)—R 20 , —C(O)—N(R 21 )—R 22 , or —S(O) 2 —N(R 23 )R 24 , wherein lower alkyl is optionally substituted with —C(O)—O—R 16 , mono-alkylamino, di-alkylamino, or cycloalkylamino;
  • a solid form comprising a basic amino acid and an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound of Formula Ia, wherein Formula Ia is as follows:
  • R 28 is selected from the group consisting of hydrogen, chloro, methyl, methoxy, —CN, and —C ⁇ CH;
  • each R 35 when present, is independently fluoro, chloro, —OH, —NH 2 , lower alkyl, lower alkynyl, di-alkylamino substituted lower alkynyl, lower alkoxy, lower alkylthio, monoalkylamino, di-alkylamino, cycloalkylamino, phenyl, —C(O)—N(R 52 )—R 53 , or —N(H)—C(O)—R 47 , wherein lower alkyl is optionally substituted with one or more fluoro, alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or phenyl, and wherein lower alkoxy is optionally substituted with —OH, lower alkoxy, mono-alkylamino, di-alkylamino or cycloalkylamino;
  • U and V are C—H
  • W is C—R 27
  • R 27 is selected from the group consisting of hydrogen, chloro, lower alkyl, phenyl, heteroaryl, —CN, —C ⁇ CH, —O—R 38 , —N(R 39 )—R 40 , —C(O)—N(R 41 )—R 42 , —C(O)—O—R 43 , —S(O) 2 —R 44 , and —N(H)—C(O)—R 45 , wherein lower alkyl is optionally substituted with one or more R 32 , phenyl is optionally substituted with one or more R 34 , and heteroaryl is optionally substituted with one or more R 35 .
  • R 27 is selected from the group consisting of hydrogen, chloro, lower alkyl, phenyl, heteroaryl, —CN, —C ⁇ CH, —O—R 38 , —N(R 39 )—R 40 , —C(O)—N(R 41 )—R 42 , —C(O)—O—R 43 , —S(O) 2 —R 44 , and —N(H)—C(O)—R 45 , wherein lower alkyl is optionally substituted with one or more R 32 , phenyl is optionally substituted with one or more R 34 , and heteroaryl is optionally substituted with one or more R 35 and R 31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl.
  • R 27 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 31 is lower alkyl, dialkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl.
  • R 27 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 31 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl.
  • R 27 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluorophenyl, 2,5-di-fluoro-phenyl, 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethylphenyl.
  • R 27 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl.
  • R 27 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl.
  • R 27 is chloro, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluorophenyl, or 2,5-di-fluoro-phenyl.
  • R 27 is chloro, methyl, or —CN
  • R 31 is 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl.
  • U and W are C—H
  • V is C—R 28
  • R 28 is selected from the group consisting of hydrogen, chloro, methyl, methoxy, —CN, and —C ⁇ CH.
  • R 28 is selected from the group consisting of hydrogen, chloro, methyl, methoxy, —CN, and —C ⁇ CH and R 31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl.
  • R 28 is —CN, or —C ⁇ CH
  • R 31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl.
  • R 28 is —CN, or —C ⁇ CH
  • R 31 is n-propyl, dimethylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl.
  • R 28 is —CN, or —C ⁇ CH
  • R 31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl.
  • R 28 is —CN, or —C ⁇ CH
  • R 31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl.
  • R 28 is —CN, or —C ⁇ CH
  • R 31 is 4-trifluoromethyl-phenyl.
  • U is C—H
  • V is N
  • W is C—R 27
  • R 27 is selected from the group consisting of hydrogen, chloro, lower alkyl, phenyl, heteroaryl, —CN, —C ⁇ CH, —O—R 38 , —N(R 39 )—R 40 , —C(O)—N(R 41 )—R 42 , —C(O)—O—R 43 , —S(O) 2 —R 44 , and —N(H)—C(O)—R 45 , wherein lower alkyl is optionally substituted with one or more R 32 , phenyl is optionally substituted with one or more R 34 , and heteroaryl is optionally substituted with one or more R 35 .
  • R 27 is selected from the group consisting of hydrogen, chloro, lower alkyl, phenyl, heteroaryl, —CN, —C ⁇ CH, —O—R 38 , —N(R 39 )—R 40 , —C(O)—N(R 41 )—R 42 , —C(O)—O—R 43 , C(O)—O—R 43 , —S(O) 2 —R 44 , and —N(H)—C(O)—R 45 , wherein lower alkyl is optionally substituted with one or more R 32 , phenyl is optionally substituted with one or more R 34 , and heteroaryl is optionally substituted with one or more R 35 and R 31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl.
  • R 27 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl.
  • R 27 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl.
  • R 27 is hydrogen and R 31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl.
  • R 27 is hydrogen and R 31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl.
  • R 27 is hydrogen and R 31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl.
  • R 27 is hydrogen and R 31 is 4-trifluoromethyl-phenyl.
  • U is C—H
  • W is N
  • V is C—R 28
  • R 28 is selected from the group consisting of hydrogen, chloro, methyl, methoxy, —CN, and —C ⁇ CH.
  • R 28 is selected from the group consisting of hydrogen, chloro, methyl, methoxy, —CN, and —C ⁇ CH and R 31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl.
  • R 28 is hydrogen, chloro, methyl, methoxy, —CN, or —C ⁇ CH and R 31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl.
  • R 28 is hydrogen, chloro, methyl, methoxy, —CN, or —C ⁇ CH
  • R 31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl.
  • R 28 is hydrogen or methoxy
  • R 31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl.
  • R 28 is hydrogen or methoxy
  • R 31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl.
  • R 28 is hydrogen or methoxy
  • R 31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl.
  • R 28 is hydrogen or methoxy
  • R 31 is 4-t-butyl-phenyl or 4-trifluoromethyl-phenyl.
  • U is N
  • V is —CH
  • W is C—R 27
  • R 27 is selected from the group consisting of hydrogen, chloro, lower alkyl, phenyl, heteroaryl, —CN, —C ⁇ CH, —O—R 38 , —N(R 39 )—R 40 , —C(O)—N(R 41 )—R 42 , —C(O)—O—R 43 , —S(O) 2 —R 44 , and —N(H)—C(O)—R 45 , wherein lower alkyl is optionally substituted with one or more R 32 , phenyl is optionally substituted with one or more R 34 , and heteroaryl is optionally substituted with one or more R 35 .
  • R 27 is selected from the group consisting of hydrogen, chloro, lower alkyl, phenyl, heteroaryl, —CN, —C ⁇ CH, —O—R 38 , —N(R 39 )—R 40 , —C(O)—N(R 41 )—R 42 , —C(O)—O—R 43 , —S(O) 2 —R 44 , and —N(H)—C(O)—R 45 , wherein lower alkyl is optionally substituted with one or more R 32 , phenyl is optionally substituted with one or more R 34 , and heteroaryl is optionally substituted with one or more R 35 and R 31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl.
  • R 27 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl.
  • R 27 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl.
  • U is N
  • W is —CH
  • V is C—R 28
  • R 28 is selected from the group consisting of hydrogen, chloro, methyl, methoxy, —CN, and —C ⁇ CH.
  • R 28 is selected from the group consisting of hydrogen, chloro, methyl, methoxy, —CN, and —C ⁇ CH and R 31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl.
  • R 28 is hydrogen, chloro, methyl, methoxy, —CN, or —C ⁇ CH and R 31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl.
  • R 28 is hydrogen, chloro, methyl, methoxy, —CN, or —C ⁇ CH
  • R 31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl.
  • U and V are C—H
  • W is C—R 27 , R 27 is chloro, methyl or —CN
  • R 29 is fluoro
  • R 30 is fluoro
  • R 31 is 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl
  • U and W are C—H
  • V is C—R 28 , R 28 is —CN or —C ⁇ CH
  • R 29 is fluoro
  • R 30 is fluoro
  • R 31 is 4-trifluoromethyl phenyl
  • U is C—H
  • W is N
  • R 29 is fluoro
  • R 30 is fluoro
  • R 31 is 4-t-butyl-phenyl or 4-trifluoromethyl phenyl
  • U is C—H, V is N
  • R 29 is fluoro
  • R 30 is fluoro
  • U and V are C—H
  • W is C—R 27
  • R 27 is chloro, —CN, 4-chloro-phenyl, or 2-methoxy-pyrimidin-5-yl
  • R 29 is hydrogen or fluoro
  • R 30 is fluoro
  • R 31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, 2,5-di-fluoro-phenyl.
  • a solid form comprising a basic amino acid and an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound of Formula Ib, wherein Formula Ib is as follows:
  • each R 58 when present, is independently fluoro, chloro, —CN, —OH, lower alkyl, lower alkenyl, —C(O)—O—R 67 substituted lower alkenyl, lower alkoxy, lower alkoxy substituted lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, —S(O) 2 R 71 , —N(H)—S(O) 2 —R 71 , —N(H)—C(O)—R 71 , —C(O)—N(R 72 )—R 73 , or —S(O) 2 —N(R 74 )—R 75 , wherein lower alkyl is optionally substituted with —C(O)—O—R 67 , mono-alkylamino, di-alkylamino, or cycloalkylamino;
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl.
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl and R 55 is fluoro.
  • R 54 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl.
  • R 54 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl
  • R 55 is fluoro.
  • R 54 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl.
  • R 54 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl
  • R 55 is fluoro.
  • R 54 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl.
  • R 54 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl.
  • R 54 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl
  • R 55 is fluoro.
  • R 54 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl
  • R 55 is fluoro.
  • R 54 is chloro, methyl or —CN
  • R 56 is 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl
  • R 55 is fluoro.
  • R 54 is chloro, —CN, 4-chloro-phenyl, or 2-methoxy-pyrimidin-5-yl
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, or 3-fluoro-phenyl, 2,5-di-fluoro-phenyl
  • R 55 is fluoro.
  • a solid form comprising a basic amino acid and an N-[3-(5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-phenyl]-sulfonamide compound of Formula Ic, wherein Formula Ic is as follows:
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl.
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl and R 55 is fluoro.
  • R 78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl.
  • R 78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl
  • R 55 is fluoro.
  • R 78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl.
  • R 78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl
  • R 55 is fluoro.
  • R 78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl
  • R 78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl.
  • R 78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl
  • R 55 is fluoro.
  • R 78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl
  • R 55 is fluoro.
  • R 78 is hydrogen, R 56 is 4-trifluoromethyl phenyl, and R 55 is fluoro.
  • a solid form comprising a basic amino acid and an N-[3-(1H-Pyrazolo[3,4-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound of Formula Id, wherein Formula Id is as follows:
  • R 54 , R 55 , and R 56 are as defined for Formula Ib and R 78 is as defined for Formula Ic.
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl.
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl and R 55 is fluoro.
  • R 78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl.
  • R 78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl
  • R 55 is fluoro.
  • R 78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl.
  • R 78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl
  • R 55 is fluoro.
  • R 78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl
  • R 78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl.
  • R 78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl
  • R 55 is fluoro.
  • R 78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl
  • R 56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl
  • R 55 is fluoro.
  • R 78 is hydrogen or —CN
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl.
  • R 78 is hydrogen or —CN and R 56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl.
  • R 78 is hydrogen or —CN
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl
  • R 55 is fluoro.
  • R 78 is hydrogen or —CN
  • R 56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl
  • R 55 is fluoro.
  • R 78 is hydrogen or —CN and R 56 is n-propyl.
  • R 78 is hydrogen or —CN, R 56 is n-propyl, and R 55 is fluoro.
  • a solid form comprising a basic amino acid and an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound of Formula Ie, wherein Formula Ie is as follows:
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl.
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl and R 55 is fluoro.
  • R 79 is —CN, or —C ⁇ CH
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl.
  • R 79 is —CN, or —C ⁇ CH
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl
  • R 55 is fluoro.
  • R 79 is —CN, or —C ⁇ CH
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl.
  • R 79 is —CN, or —C ⁇ CH
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl and R 55 is fluoro.
  • R 79 is —CN, or —C ⁇ CH
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl.
  • R 79 is —CN, or —C ⁇ CH
  • R 56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl
  • R 55 is fluoro.
  • R 79 is —CN, or —C ⁇ CH
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl
  • R 55 is fluoro.
  • R 79 is —CN, or —C ⁇ CH
  • R 56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl.
  • R 79 is —CN, or —C ⁇ CH
  • R 56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl
  • R 55 is fluoro.
  • R 79 is —CN, or —C ⁇ CH
  • R 56 is 4-trifluoromethyl phenyl.
  • R 79 is —CN, or —C ⁇ CH
  • R 56 is 4-trifluoromethyl phenyl and R 55 is fluoro.
  • a solid form comprising a basic amino acid and an N-[3-(7H-Pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-sulfonamide compound of Formula If, wherein Formula If is as follows:
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl.
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl and R 55 is fluoro.
  • R 80 is hydrogen or methoxy and R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl.
  • R 80 is hydrogen or methoxy, and R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl and R 55 is fluoro.
  • R 80 is hydrogen or methoxy
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl.
  • R 80 is hydrogen or methoxy
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl and R 55 is fluoro.
  • R 80 is hydrogen or methoxy
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl.
  • R 80 is hydrogen or methoxy
  • R 56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl.
  • R 80 is hydrogen or methoxy
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl
  • R 55 is fluoro.
  • R 80 is hydrogen or methoxy
  • R 56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl and R 55 is fluoro.
  • R 80 is hydrogen or methoxy
  • R 56 is 4-t-butyl-phenyl or 4-trifluoromethyl phenyl.
  • R 80 is hydrogen or methoxy
  • R 56 is 4-t-butyl-phenyl or 4-trifluoromethyl phenyl and R 55 is fluoro.
  • a solid form comprising a basic amino acid and an N-[3-(1H-Pyrazolo[3,4-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound of Formula Ig, wherein Formula Ig is as follows:
  • R 55 , and R 56 are as defined for Formula Ib, and R 80 is as defined in Formula If.
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl.
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl and R 55 is fluoro.
  • R 80 is hydrogen, methoxy, —CN, or —C ⁇ CH
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl.
  • R 80 is hydrogen, methoxy, —CN, or —C ⁇ CH
  • R 56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl and R 55 is fluoro.
  • R 80 is hydrogen, methoxy, —CN, or —C ⁇ CH
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl.
  • R 80 is hydrogen, methoxy, —CN, or —C ⁇ CH
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl and R 55 is fluoro.
  • R 80 is hydrogen, methoxy, —CN, or —C ⁇ CH
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl.
  • R 80 is hydrogen, methoxy, —CN, or —C ⁇ CH
  • R 56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl.
  • R 80 is hydrogen, methoxy, —CN, or —C ⁇ CH
  • R 56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl
  • R 55 is fluoro.
  • R 80 is hydrogen, methoxy, —CN, or —C ⁇ CH
  • R 56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl
  • R 55 is fluoro
  • a solid form comprising arginine and a compound of Formula I, Ia, Ib, Ic, Id, Ie, If or Ig, or any embodiment herein above.
  • a solid form comprising lysine and a compound of Formula I, Ia, Ib, Ic, Id, Ie, If or Ig, or any embodiment herein above.
  • a solid form comprising a basic amino acid and a compound of Formula Ib, Ic, Id, Ie, If or Ig, or any embodiments herein above.
  • the solid form comprises arginine and a compound of Formula Ib, Ic, Id, Ie, If or Ig, or any embodiment herein above.
  • the solid form comprises lysine and a compound of Formula Ib, Ic, Id, Ie, If or Ig, or any embodiment herein above.
  • a solid form comprising a complex of arginine and a compound of any of Formula I, Ia, Ib, Ic, Id, Ie, If, or Ig.
  • a composition comprising said complex.
  • the composition is effective as a pharmaceutical, for example in the treatment of pain or polycystic kidney disease.
  • the composition is effective as a pharmaceutical, for example in the treatment of melanoma, thyroid cancer, ovarian cancer, cholangiocarcinoma or colorectal cancer.
  • the complex is an amorphous solid.
  • the composition comprises an amorphous complex of arginine and the compound, and further comprises a crystalline form of the compound, preferably crystalline free base of the compound. In one embodiment, the composition comprises the amorphous complex and 0-80% crystalline compound, also 0-50%, 0-20%, 0-10%, 0-5%, or 0-2% crystalline compound.
  • a solid form comprising a complex of lysine and a compound of any of Formula I, Ia, Ib, Ic, Id, Ie, If, or Ig.
  • a composition comprising said complex.
  • the composition is effective as a pharmaceutical, for example in the treatment of pain or polycystic kidney disease.
  • the composition is effective as a pharmaceutical, for example in the treatment of melanoma, thyroid cancer, ovarian cancer, cholangiocarcinoma or colorectal cancer.
  • the complex is an amorphous solid.
  • the composition comprises an amorphous complex of lysine and the compound, and further comprises a crystalline form of the compound, preferably crystalline free base of the compound. In one embodiment, the composition comprises the amorphous complex and 0-80% crystalline compound, also 0-50%, 0-20%, 0-10%, 0-5%, or 0-2% crystalline compound.
  • a solid form comprising a ternary complex of arginine, a strong acid, and a compound of any of Formula I, Ia, Ib, Ic, Id, Ie, If or Ig.
  • the strong acid is hydrochloric acid.
  • the ternary complex is an amorphous solid.
  • the ternary complex is a ternary co-crystal.
  • a composition is provided comprising said complex.
  • the composition is effective as a pharmaceutical, for example in the treatment of pain or polycystic kidney disease.
  • the composition is effective as a pharmaceutical, for example in the treatment of melanoma, thyroid cancer, ovarian cancer, cholangiocarcinoma or colorectal cancer.
  • a solid form comprising a ternary complex of lysine, a strong acid, and a compound of any of Formula I, Ia, Ib, Ic, Id, Ie, If or Ig.
  • the strong acid is hydrochloric acid.
  • the ternary complex is an amorphous solid.
  • the ternary complex is a ternary co-crystal.
  • a composition is provided comprising said complex.
  • the composition is effective as a pharmaceutical, for example in the treatment of pain or polycystic kidney disease.
  • the composition is effective as a pharmaceutical, for example in the treatment of melanoma, thyroid cancer, ovarian cancer, cholangiocarcinoma or colorectal cancer.
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • Pentane-2-sulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1478).
  • the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of: 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-amide (P-1362),
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a solid form comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • a complex of arginine and N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1021) is provided.
  • a composition comprising said complex.
  • the composition is effective as a pharmaceutical, for example in the treatment of pain or polycystic kidney disease.
  • the complex is an amorphous solid.
  • a complex of lysine and N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1021) is provided.
  • a composition is provided comprising said complex.
  • the composition is effective as a pharmaceutical, for example in the treatment of pain or polycystic kidney disease.
  • the complex is an amorphous solid.
  • a complex of arginine and N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1092) is provided.
  • a composition is provided comprising said complex.
  • the composition is effective as a pharmaceutical, for example in the treatment of pain or polycystic kidney disease.
  • the complex is an amorphous solid.
  • a complex of lysine and N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1092) is provided.
  • a composition comprising said complex.
  • the composition is effective as a pharmaceutical, for example in the treatment of pain or polycystic kidney disease.
  • the complex is an amorphous solid.
  • a complex of arginine and Propane-1-sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl ⁇ -amide (P-1167) is provided.
  • a composition is provided comprising said complex.
  • the composition is effective as a pharmaceutical, for example in the treatment of melanoma or colorectal cancer.
  • the complex is an amorphous solid.
  • a complex of lysine and Propane-1-sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl ⁇ -amide (P-1167) is provided.
  • a composition is provided comprising said complex.
  • the composition is effective as a pharmaceutical, for example in the treatment of melanoma or colorectal cancer.
  • the complex is an amorphous solid.
  • a complex of arginine and N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-1497) is provided.
  • a composition is provided comprising said complex.
  • the composition is effective as a pharmaceutical, for example in the treatment of melanoma or colorectal cancer.
  • the complex is an amorphous solid.
  • a complex of lysine and N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-1497) is provided.
  • a composition is provided comprising said complex.
  • the composition is effective as a pharmaceutical, for example in the treatment of melanoma or colorectal cancer.
  • the complex is an amorphous solid.
  • a complex of arginine and Propane-1-sulfonic acid ⁇ 2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl ⁇ -amide P-1496 is provided.
  • a composition is provided comprising said complex.
  • the composition is effective as a pharmaceutical, for example in the treatment of melanoma or colorectal cancer.
  • the complex is an amorphous solid.
  • a complex of lysine and Propane-1-sulfonic acid ⁇ 2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl ⁇ -amide (P-1496) is provided.
  • a composition is provided comprising said complex.
  • the composition is effective as a pharmaceutical, for example in the treatment of melanoma or colorectal cancer.
  • the complex is an amorphous solid.
  • a composition comprising an amorphous complex of arginine and any of the above-referenced specific compounds, and further comprises a crystalline form of the compound, preferably crystalline free base of the compound.
  • the composition comprises the amorphous complex and 0-80% crystalline compound, also 0-50%, 0-20%, 0-10%, 0-5%, or 0-2% crystalline compound.
  • a composition comprising an amorphous complex of lysine and any of the above-referenced specific compounds, and further comprises a crystalline form of the compound, preferably crystalline free base of the compound.
  • the composition comprises the amorphous complex and 0-80% crystalline compound, also 0-50%, 0-20%, 0-10%, 0-5%, or 0-2% crystalline compound.
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • a compound is provided, where the compound is selected from the group consisting of:
  • the compound 5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic acid [5-(3- ⁇ 3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -propionylamino)-pentyl]-amide (P-2008) is provided.
  • P-2008 may be used as a probe for binding to one or more of A-Raf, B-Raf, and c-Raf-1, including any mutations of these kinases, in order to assess whether such kinase is present in a biological sample, and in some instances, to assess the amounts of such kinase in a biological sample.
  • a compound or group of compounds includes salts or solid forms of such compound(s) (including pharmaceutically acceptable salts and solid forms), formulations of such compound(s) (including pharmaceutically acceptable formulations), conjugates thereof, derivatives thereof, prodrugs thereof, and all stereoisomers thereof.
  • a compound of Formula I includes all sub-embodiments thereof (e.g. including Formulae Ia-Ig, and all embodiments as described above).
  • methods for treating a protein kinase mediated disease or condition in an animal subject, wherein the method involves administering to the subject an effective amount of any one or more compound(s) of the invention as described herein.
  • the terms “treat,” “therapy,” and like terms refer to the administration of material, e.g., one or more compound(s) of the invention as described herein in an amount effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or condition, i.e., indication, and/or to prolong the survival of the subject being treated.
  • protein kinase mediated disease or condition refers to a disease or condition in which the biological function of a protein kinase affects the development, course, and/or symptoms of the disease or condition, and/or in which modulation of the protein kinase alters the development, course, and/or symptoms of the disease or condition.
  • a protein kinase mediated disease or condition includes a disease or condition for which modulation provides a therapeutic benefit, e.g. wherein treatment with protein kinase inhibitors, including compounds of the invention as described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition.
  • the method involves administering to the subject an effective amount of a compound of the invention as described herein in combination with one or more other therapies for the disease or condition.
  • the invention provides methods for treating a Raf protein kinase mediated disease or condition in an animal subject, wherein the method involves administering to the subject an effective amount of any one or more compound(s) of the invention as described herein.
  • the terms “Raf protein kinase mediated disease or condition,” “Raf kinase mediated disease or condition,” “Raf mediated disease or condition,” and the like refer to a disease or condition in which the biological function of a Raf protein kinase, including any mutations thereof, affects the development, course, and/or symptoms of the disease or condition, and/or in which modulation of the Raf protein kinase alters the development, course, and/or symptoms of the disease or condition.
  • the Raf protein kinase includes, but is not limited to, A-Raf, mutations of A-Raf, B-Raf, mutations of B-Raf, c-Raf-1 and mutations of c-Raf-1.
  • the Raf protein kinase is B-Raf mutation V600E.
  • the Raf protein kinase is B-Raf mutation V600E/T5291.
  • the disease or condition is a cancer that is amenable to treatment by an inhibitor of the V600E mutant B-Raf.
  • the disease or condition is a cancer that is amenable to treatment by an inhibitor of the V600E/T5291 mutant B-Raf.
  • the Raf protein kinase mediated disease or condition includes a disease or condition for which Raf inhibition provides a therapeutic benefit, e.g. wherein treatment with Raf inhibitors, including compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition.
  • the method involves administering to the subject an effective amount of any one or more compound(s) of the invention as described herein in combination with one or more other therapies for the disease or condition.
  • A-Raf, B-Raf or c-Raf-1 protein kinase mediated disease or condition refers to a disease or condition in which the biological function of an A-Raf, B-Raf or c-Raf-1 kinase, respectively, including any mutations thereof, affects the development, course and/or symptoms of the disease or condition, and/or in which modulation of the A-Raf, B-Raf or c-Raf-1 protein kinase, respectively, alters the development, course, and/or symptoms of the disease or condition.
  • a compound of the invention as described herein is an inhibitor of a Raf kinase and has an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Raf kinase activity assay.
  • the compound will have an IC 50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM with respect to one or more of A-Raf, B-Raf, c-Raf-1, B-Raf V600E mutant, or B-Raf V600E/T529I mutant.
  • the compound will selectively inhibit one Raf kinase relative to one or more other Raf kinases.
  • the compound will selectively inhibit a mutation of the Raf kinase relative to the wild type kinase, for example B-Raf V600E mutant relative to wild type B-Raf.
  • a compound of the invention as described herein may selectively inhibit one kinase relative to one or more other kinases, where preferably inhibition is selective with respect to any of the other kinases, whether a kinase discussed herein, or other kinases.
  • the compound may selectively inhibit the effects of a mutation of the kinase relative to the wild type kinase, for example B-Raf V600E mutant relative to wild type B-Raf.
  • the compound may selectively inhibit Fms relative to Kit.
  • IC 50 for the one kinase may be at least about 2-fold, also 5-fold, also 10-fold, also 20-fold, also 50-fold, or at least about 100-fold less than the IC 50 for any of the other kinases as determined in a generally accepted kinase activity assay.
  • compositions include a therapeutically effective amount of any one or more compound(s) of the invention as described herein and at least one pharmaceutically acceptable carrier, excipient, and/or diluent.
  • the composition can include any one or more compound(s) of the invention as described herein along with one or more compounds that are therapeutically effective for the same disease indication.
  • the composition includes any one or more compound(s) of the invention as described herein along with one or more compounds that are therapeutically effective for the same disease indication, wherein the compounds have a synergistic effect on the disease indication.
  • the composition includes any one or more compound(s) of the invention as described herein effective in treating a cancer and one or more other compounds that are effective in treating the same cancer, further wherein the compounds are synergistically effective in treating the cancer.
  • the invention provides methods for treating a disease or condition mediated by A-Raf, B-Raf, c-Raf-1, B-Raf V600E mutant, or B-Raf V600E/T529I mutant by administering to the subject an effective amount of a composition including any one or more compound(s) of the invention as described herein.
  • the invention provides methods for treating a disease or condition mediated by A-Raf, B-Raf, c-Raf-1, B-Raf V600E mutant, or B-Raf V600E/T529I mutant by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein in combination with one or more other suitable therapies for treating the disease.
  • the invention provides methods for treating a cancer mediated by B-Raf V600E mutant or B-Raf V600E/T529I mutant by administering to the subject an effective amount of a composition including any one or more compound(s) of the invention as described herein in combination with one or more suitable anticancer therapies, such as one or more chemotherapeutic drugs.
  • the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including any one or more compound(s) of the invention as described herein, in combination with one or more other therapies or medical procedures effective in treating the cancer.
  • Other therapies or medical procedures include suitable anticancer therapy (e.g. drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedure (e.g. surgery, radiation treatment, hyperthermia heating, bone marrow or stem cell transplant).
  • the one or more suitable anticancer therapies or medical procedures is selected from treatment with a chemotherapeutic agent (e.g. chemotherapeutic drug), radiation treatment (e.g.
  • x-ray, ⁇ -ray, or electron, proton, neutron, or ⁇ particle beam hyperthermia heating (e.g. microwave, ultrasound, radiofrequency ablation),
  • Vaccine therapy e.g. AFP gene hepatocellular carcinoma vaccine, AFP adenoviral vector vaccine, AG-858, allogeneic GM-CSF-secretion breast cancer vaccine, dendritic cell peptide vaccines
  • gene therapy e.g. Ad5CMV-p53 vector, adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha
  • photodynamic therapy e.g. aminolevulinic acid, motexafin lutetium
  • the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including any one or more compound(s) of the invention as described herein, in combination with one or more suitable chemotherapeutic agents.
  • the one or more suitable chemotherapeutic agents is selected from an alkylating agent, including, but not limited to, adozelesin, altretamine, bendamustine, bizelesin, busulfan, carboplatin, carboquone, carmofur, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, etoglucid, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mannosulfan, mechlorethamine, melphalan, mitobronitol, nedaplatin, nimustine, oxaliplatin, piposulfan, prednimustine, procarbazine, ranimustine, satraplatin, semustine, streptozocin, temozolomide, thiotepa, tre
  • PI3K inhibitors e.g. BEZ235, GDC-0941, XL147, XL765
  • Cdk4 inhibitors e.g. PD-332991
  • Akt inhibitors e.g. Akt inhibitors
  • Hsp90 inhibitors e.g. tanespimycin
  • farnesyltransferase inhibitors e.g. tipifarnib
  • the method of treating a cancer involves administering to the subject an effective amount of a composition including any one or more compound(s) of the invention as described herein in combination with a chemotherapeutic agent selected from capecitabine, 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab, interferon- ⁇ , interleukin-2, or erlotinib.
  • a chemotherapeutic agent selected from capecitabine, 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab, interferon- ⁇ , interleukin-2, or erlotinib.
  • the invention provides a method of treating or prophylaxis of a disease or condition in a mammal, by administering to the mammal a therapeutically effective amount of any one or more compound(s) of the invention as described herein, a prodrug of such compound, or a pharmaceutically acceptable salt of such compound or prodrug.
  • the compound can be alone or can be part of a composition.
  • the invention provides a method of treating or prophylaxis of a disease or condition in a mammal, by administering to the mammal a therapeutically effective amount of one or more compounds as described herein, a prodrug of such compound, or a pharmaceutically acceptable salt of such compound or prodrug in combination with one or more other suitable therapies for the disease or condition.
  • kits that include any one or more compound(s) or the invention or composition thereof as described herein.
  • the composition is packaged, e.g., in a vial, bottle, flask, which may be further packaged, e.g., within a box, envelope, or bag; the composition is approved by the U.S.
  • the composition is approved for administration to a mammal, e.g., a human, for a protein kinase mediated disease or condition;
  • the invention kit includes written instructions for use and/or other indication that the composition is suitable or approved for administration to a mammal, e.g., a human, for a protein kinase-mediated disease or condition; and the composition is packaged in unit dose or single dose form, e.g., single dose pills, capsules, or the like.
  • the invention provides methods for treating an A-Raf-mediated, B-Raf-mediated and/or c-Raf-1-mediated disease or condition in an animal subject (e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), e.g., a disease or condition characterized by abnormal A-Raf, B-Raf, and/or c-Raf-1 activity (e.g. kinase activity).
  • an animal subject e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats
  • a disease or condition characterized by abnormal A-Raf, B-Raf, and/or c-Raf-1 activity e.g. kinase activity.
  • invention methods may involve administering to the subject suffering from or at risk of an A-Raf-mediated, B-Raf-mediated and/or c-Raf-1-mediated disease or condition an effective amount of compounds as described herein.
  • the A-Raf-mediated, B-Raf-mediated, and/or c-Raf-1-mediated disease is selected from the group consisting of neurologic diseases, including, but not limited to, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, seizures and epilepsy; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g.
  • lymphoma e.g. histiocytic lymphoma
  • neurofibromatosis acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer, Kaposi's sarcoma, and pheochromocytoma
  • pain of neuropathic or inflammatory origin including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine
  • cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g.
  • inflammation and/or proliferation including, but not limited to, psoriasis, eczema, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiency diseases, including, but not limited to, organ transplant rejection, graft versus host disease, and Kaposi's sarcoma associated with HIV; renal, cystic, or prostatic diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, polycystic liver disease, tuberous sclerosis, Von Hippel Lindau disease, medullary cystic kidney disease, nephronophthisis, and cystic fibrosis; metabolic disorders, including, but not limited to, obesity
  • the disease or condition is selected from the group consisting of melanoma, glioma, sarcoma, gastrointestinal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, lung cancer, breast cancer, pancreatic cancer, thyroid cancer, renal cancer, ovarian cancer, prostate cancer, histiocytic lymphoma, neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, medullary thyroid cancer, carcinoid, small cell lung cancer, Kaposi's sarcoma, pheochromocytoma, pain, and polycystic kidney disease.
  • the disease or condition is selected from the group consisting of melanoma, colorectal cancer, thyroid cancer, ovarian cancer, cholangiocarcinoma, pain, and polycystic kidney disease.
  • compounds as described herein can be used in the preparation of a medicament for the treatment of an A-Raf-mediated, B-Raf-mediated or c-Raf-1-mediated disease or condition selected from the group consisting of neurologic diseases, including, but not limited to, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, seizures and epilepsy; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g.
  • lymphoma e.g. histiocytic lymphoma
  • neurofibromatosis acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer, Kaposi's sarcoma, and pheochromocytoma
  • pain of neuropathic or inflammatory origin including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine
  • cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g.
  • inflammation and/or proliferation including, but not limited to, psoriasis, eczema, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiency diseases, including, but not limited to, organ transplant rejection, graft versus host disease, and Kaposi's sarcoma associated with HIV; renal, cystic, or prostatic diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, polycystic liver disease, tuberous sclerosis, Von Hippel Lindau disease, medullary cystic kidney disease, nephronophthisis, and cystic fibrosis; metabolic disorders, including, but not limited to, obesity
  • the disease or condition is selected from the group consisting of melanoma, glioma, sarcoma, gastrointestinal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, lung cancer, breast cancer, pancreatic cancer, thyroid cancer, renal cancer, ovarian cancer, prostate cancer, histiocytic lymphoma, neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, medullary thyroid cancer, carcinoid, small cell lung cancer, Kaposi's sarcoma, pheochromocytoma, pain, and polycystic kidney disease.
  • the disease or condition is selected from the group consisting of melanoma, colorectal cancer, thyroid cancer, ovarian cancer, cholangiocarcinoma, pain, and polycystic kidney disease.
  • hydrogen includes for example 1 H, 2 H, 3 H; carbon includes for example 11 C, 12 C, 14 C; oxygen includes for example 16 O, 17 O, 18 O, nitrogen includes for example 13 N, 14 N, 15 N; sulfur includes for example 32 S, 33 S, 34 S, 35 S, 36 S, 37 S, 38 S; fluoro includes for example 17 F, 18 F, 19 F; chloro includes for example 35 Cl, 36 Cl, 37 Cl, 38 Cl, 39 Cl; and the like.
  • Halogen refer to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo (I).
  • Haldroxyl or “hydroxy” refer to the group —OH.
  • Thiol refers to the group —SH.
  • “Lower alkyl” alone or in combination means an alkane-derived radical containing from 1 to 6 carbon atoms (unless specifically defined) that includes a straight chain alkyl or branched alkyl.
  • the straight chain or branched lower alkyl group is chemically feasible and attached at any available point to provide a stable compound.
  • a lower alkyl is a straight or branched alkyl group containing from 1-6, 1-4, or 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like.
  • substituted lower alkyl denotes lower alkyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents.
  • fluoro substituted lower alkyl denotes a lower alkyl group substituted with one or more fluoro atoms, such as perfluoroalkyl, where preferably the lower alkyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
  • “Lower alkenyl” alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) and at least one, preferably I-3, more preferably I-2, most preferably one, carbon to carbon double bond. Carbon to carbon double bonds may be either contained within a straight chain or branched portion.
  • the straight chain or branched lower alkenyl group is chemically feasible and attached at any available point to provide a stable compound. Examples of lower alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and the like.
  • substituted lower alkenyl denotes lower alkenyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents.
  • fluoro substituted lower alkenyl denotes a lower alkenyl group substituted with one or more fluoro atoms, where preferably the lower alkenyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
  • “Lower alkynyl” alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) containing at least one, preferably one, carbon to carbon triple bond.
  • the straight chain or branched lower alkynyl group is chemically feasible and attached at any available point to provide a stable compound.
  • alkynyl groups include ethynyl, propynyl, butynyl, and the like.
  • a “substituted lower alkynyl” denotes lower alkynyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents.
  • fluoro substituted lower alkynyl denotes a lower alkynyl group substituted with one or more fluoro atoms, where preferably the lower alkynyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound
  • Cycloalkyl refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems of 3-10, also 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
  • a “substituted cycloalkyl” is a cycloalkyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
  • Heterocycloalkyl refers to a saturated or unsaturated non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally fused with benzo or heteroaryl of 5-6 ring members. Heterocycloalkyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. Heterocycloalkyl is also intended to include compounds in which a ring carbon may be oxo substituted, i.e.
  • the ring carbon is a carbonyl group, such as lactones and lactams.
  • the point of attachment of the heterocycloalkyl ring is at a carbon or nitrogen atom such that a stable ring is retained.
  • heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl.
  • a “substituted heterocycloalkyl” is a heterocycloalkyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
  • Aryl alone or in combination refers to a monocyclic or bicyclic ring system containing aromatic hydrocarbons such as phenyl or naphthyl, which may be optionally fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members.
  • a “substituted aryl” is an aryl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
  • Heteroaryl alone or in combination refers to a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, even more preferably 1-2, heteroatoms independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound is provided.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl.
  • a “substituted heteroaryl” is a heteroaryl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
  • “Lower alkoxy” denotes the group —OR a , where R a is lower alkyl.
  • “Substituted lower alkoxy” denotes lower alkoxy in which R a is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I, including descriptions of substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl, attached at any available atom to provide a stable compound.
  • substitution of lower alkoxy is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents.
  • fluoro substituted lower alkoxy denotes lower alkoxy in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that substitutions on alkoxy are chemically feasible and attached at any available atom to provide a stable compound.
  • Lower alkylthio denotes the group —SR b , where R b is lower alkyl.
  • Substituted lower alkylthio denotes lower alkylthio in which R b is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I, including descriptions of substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl, attached at any available atom to provide a stable compound.
  • substitution of lower alkylthio is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents.
  • fluoro substituted lower alkylthio denotes lower alkylthio in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkylthio is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that substitutions on alkylthio are chemically feasible and attached at any available atom to provide a stable compound.
  • “Amino” or “amine” denotes the group —NH 2 .
  • “Mono-alkylamino” denotes the group —NHR c where R c is lower alkyl.
  • “Di-alkylamino” denotes the group —NR c R d , where R c and R d are independently lower alkyl.
  • “Cycloalkylamino” denotes the group —NR e R f , where R e and R f combine with the nitrogen to form a 5-7 membered heterocycloalkyl, where the heterocycloalkyl may contain an additional heteroatom within the ring, such as O, N, or S, and may also be further substituted with one or more lower alkyl.
  • Examples of 5-7 membered heterocycloalkyl include, but are not limited to, piperidine, piperazine, 4-methylpiperazine, morpholine, and thiomorpholine. It is understood that when mono-alkylamino, di-alkylamino, or cycloalkylamino are substituents on other moieties, these are chemically feasible and attached at any available atom to provide a stable compound.
  • solid form refers to a solid preparation (i.e. a preparation that is neither gas nor liquid) of a pharmaceutically active compound that is suitable for administration to an intended animal subject for therapeutic purposes.
  • the solid form includes any complex, such as a salt, co-crystal or an amorphous complex, as well as any polymorph of the compound.
  • the solid form may be substantially crystalline, semi-crystalline or substantially amorphous.
  • the solid form may be administered directly or used in the preparation of a suitable composition having improved pharmaceutical properties.
  • the solid form may be used in a formulation comprising at least one pharmaceutically acceptable carrier or excipient.
  • substantially crystalline material embraces material which has greater than about 90% crystallinity; and “crystalline” material embraces material which has greater than about 98% crystallinity.
  • substantially amorphous material embraces material which has no more than about 10% crystallinity; and “amorphous” material embraces material which has no more than about 2% crystallinity.
  • the term “semi-crystalline” material embraces material which is greater than 10% crystallinity, but no greater than 90% crystallinity; preferably “semi-crystalline” material embraces material which is greater than 20% crystallinity, but no greater than 80% crystallinity.
  • a mixture of solid forms of a compound may be prepared, for example, a mixture of amorphous and crystalline solid forms, e.g. to provide a “semi-crystalline” solid form.
  • Such a “semi-crystalline” solid form may be prepared by methods known in the art, for example by mixing an amorphous solid form with a crystalline solid form in the desired ratio.
  • the complex of the compound and arginine or lysine may be prepared with an amount of compound component in excess of the stoichiometry of the complex, thereby resulting in an amount of the complex that is based on the stoichiometry of the complex, with excess compound in a crystalline form.
  • the amount of excess compound used in the preparation of the complex can be adjusted to provide the desired ratio of amorphous complex to crystalline compound in the resulting mixture of solid forms. For example, where the amorphous complex of arginine and compound has a 1:1 stoichiometry, preparing said complex with a 2:1 mole ratio of compound to arginine will result in a solid form of 50% amorphous complex and 50% crystalline compound.
  • Such a mixture of solid forms may be beneficial as a drug product, for example, by providing an amorphous component having improved biopharmaceutical properties along with the crystalline component.
  • the amorphous component would be more readily bioavailable while the crystalline component would have a delayed bioavailablity.
  • Such a mixture may provide both rapid and extended exposure to the active compound.
  • the term “complex” refers to a combination of a pharmaceutically active compound and an additional molecular species that forms or produces a new chemical species in a solid form.
  • the complex may be a salt, i.e. where the additional molecular species provides an acid/base counter ion to an acid/base group of the compound resulting in an acid:base interaction that forms a typical salt. While such salt forms are typically substantially crystalline, they can also be partially crystalline, substantially amorphous, or amorphous forms.
  • the additional molecular species, in combination with the pharmaceutically active compound forms a non-salt co-crystal, i.e.
  • the compound and molecular species do not interact by way of a typical acid:base interaction, but still form a substantially crystalline structure.
  • the pharmaceutically active compound and two additional molecular species may form a ternary complex, where the ternary complex could be amorphous, partially amorphous, or crystalline, such as a co-crystal.
  • co-crystals may be formed from a salt of the compound and an additional molecular species.
  • the complex is a substantially amorphous complex, which may contain salt-like acid:base interactions that do not form typical salt crystals, but instead form a substantially amorphous solid, i.e. a solid whose X-ray powder diffraction pattern exhibits no sharp peaks (e.g. exhibits an amorphous halo).
  • the term “stoichiometry” refers to the molar ratio of two or more reactants that combine to form a complex, for example, the molar ratio of arginine to compound that form an amorphous complex.
  • a 1:1 mixture of arginine with compound i.e. 1 mole arginine per mole of compound
  • amorphous solid form has a 1:1 stoichiometry.
  • composition refers to a pharmaceutical preparation suitable for administration to an intended animal subject for therapeutic purposes that contains at least one pharmaceutically active compound, including any solid form thereof.
  • the composition may include at least one pharmaceutically acceptable component to provide an improved formulation of the compound, such as a suitable carrier or excipient.
  • biopharmaceutical properties refers to the pharmacokinetic action of a pharmaceutical (e.g. a compound or complex of the present invention), including the dissolution, absorption and distribution of the compound on administration to an animal.
  • a pharmaceutical e.g. a compound or complex of the present invention
  • the amorphous complexes of compounds of the invention are intended to provide improved dissolution and absorption of the active compound, which is typically reflected in improved C max (i.e. the maximum achieved concentration in the plasma after administration of the drug) and improved AUC (i.e. area under the curve of drug plasma concentration vs. time after administration of the drug).
  • pharmaceutically acceptable indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectibles.
  • the term “therapeutically effective” or “effective amount” indicates that the materials or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated.
  • the terms “synergistically effective” or “synergistic effect” indicate that two or more compounds that are therapeutically effective, when used in combination, provide improved therapeutic effects greater than the additive effect that would be expected based on the effect of each compound used by itself.
  • the term “modulating” or “modulate” refers to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule such as a protein kinase.
  • a biological activity associated with a particular biomolecule such as a protein kinase.
  • an agonist or antagonist of a particular biomolecule modulates the activity of that biomolecule, e.g., an enzyme, by either increasing (e.g. agonist, activator), or decreasing (e.g. antagonist, inhibitor) the activity of the biomolecule, such as an enzyme.
  • Such activity is typically indicated in terms of an inhibitory concentration (IC 50 ) or excitation concentration (EC 50 ) of the compound for an inhibitor or activator, respectively, with respect to, for example, an enzyme.
  • IC 50 inhibitory concentration
  • EC 50 excitation concentration
  • “Pain” or a “pain condition” can be acute and/or chronic pain, including, without limitation, arachnoiditis; arthritis (e.g. osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout); back pain (e.g. sciatica, ruptured disc, spondylolisthesis, radiculopathy); burn pain; cancer pain; dysmenorrhea; headaches (e.g. migraine, cluster headaches, tension headaches); head and facial pain (e.g. cranial neuralgia, trigeminal neuralgia); hyperalgesia; hyperpathia; inflammatory pain (e.g.
  • irritable bowel syndrome pain associated with irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, cystitis, pain from bacterial, fungal or viral infection); keloid or scar tissue formation; labor or delivery pain; muscle pain (e.g. as a result of polymyositis, dermatomyositis, inclusion body myositis, repetitive stress injury (e.g. writer's cramp, carpal tunnel syndrome, tendonitis, tenosynovitis)); myofascial pain syndromes (e.g. fibromyalgia); neuropathic pain (e.g.
  • diabetic neuropathy causalgia, entrapment neuropathy, brachial plexus avulsion, occipital neuralgia, gout, reflex sympathetic dystrophy syndrome, phantom limb or post-amputation pain, postherpetic neuralgia, central pain syndrome, or nerve pain resulting from trauma (e.g. nerve injury), disease (e.g. diabetes, multiple sclerosis, Guillan-Barre Syndrome, myasthenia gravis, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, or cancer treatment); pain associated with skin disorders (e.g. shingles, herpes simplex, skin tumors, cysts, neurofibromatosis); sports injuries (e.g.
  • vascular disease or injury e.g. vasculitis, coronary artery disease, reperfusion injury (e.g. following ischemia, stroke, or myocardial infarcts)
  • other specific organ or tissue pain e.g. ocular pain, corneal pain, bone pain, heart pain, visceral pain (e.g. kidney, gall bladder, gastrointestinal), joint pain, dental pain, pelvic hypersensitivity, pelvic pain, renal colic, urinary incontinence
  • other disease associated pain e.g.
  • sickle cell anemia AIDS, herpes zoster, psoriasis, endometriosis, asthma, chronic obstructive pulmonary disease (COPD), silicosis, pulmonary sarcoidosis, esophagitis, heart burn, gastroesophageal reflux disorder, stomach and duodenal ulcers, functional dyspepsia, bone resorption disease, osteoporosis, cerebral malaria, bacterial meningitis); or pain due to graft v. host rejection or allograft rejections.
  • COPD chronic obstructive pulmonary disease
  • the present invention concerns compounds and compositions as disclosed herein that are modulators of protein kinases, for example without limitation, the compounds are modulators, preferably inhibitors, of at least one of the kinases selected from the group consisting of Ab1, Akt1, Akt2, Akt3, ALK, Alk5, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3 ⁇ , Gsk3 ⁇ , HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP
  • the compounds of the invention with kinase inhibitory activity IC 50 less than 10 ⁇ M as determined in a standard assay known in the art can be used to treat protein kinase mediated diseases and conditions related to the following protein kinases, including any mutations thereof, for example without limitation:
  • Protein kinases play key roles in propagating biochemical signals in diverse biological pathways. More than 500 kinases have been described, and specific kinases have been implicated in a wide range of diseases or conditions (i.e., indications), including for example without limitation, cancer, cardiovascular disease, inflammatory disease, neurological disease, and other diseases. As such, kinases represent important control points for small molecule therapeutic intervention.
  • Specific target protein kinases contemplated by the present invention are described in the art, including, without limitation, protein kinases as described in U.S. patent application Ser. No. 11/473,347 (see also, PCT publication WO2007002433), the disclosure of which is hereby incorporated by reference in regards to such target protein kinases. Additional description of Raf target protein kinases contemplated by the present invention follow:
  • A-Raf Target kinase
  • A-Raf i.e., v-raf murine sarcoma 3611 viral oncogene homolog I
  • ARAF ARAF
  • the mature protein comprises RBD (i.e., Ras binding domain) and phorbol-ester/DAG-type zinc finger domain and is involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
  • A-Raf inhibitors may be useful in treating neurologic diseases such as multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g.
  • neurologic diseases such as multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease
  • neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g.
  • muscle regeneration or degeneration including, but not limited to, vascular restenosis, sarcopenia, muscular dystrophies (including, but not limited to, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies), motor neuron diseases (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myos
  • B-Raf Target kinase B-Raf (i.e., v-raf murine sarcoma viral oncogene homolog BI) is a 84.4 kDa serine/threonine kinase encoded by chromosome 7q34 (symbol: BRAF).
  • the mature protein comprises RBD (i.e., Ras binding domain), Cl (i.e., protein kinase C conserved region 1) and STK (i.e., serine/threonine kinase) domains.
  • Target kinase B-Raf is involved in the transduction of mitogenic signals from the cell membrane to the nucleus and may play a role in the postsynaptic responses of hippocampal neurons.
  • genes of the RAF family encode kinases that are regulated by Ras and mediate cellular responses to growth signals.
  • B-Raf kinase is a key component of the RAS->Raf->MEK->ERK/MAP kinase signaling pathway, which plays a fundamental role in the regulation of cell growth, division and proliferation, and, when constitutively activated, causes tumorigenesis.
  • the B-type, or B-Raf is the strongest activator of the downstream MAP kinase signaling.
  • the BRAF gene is frequently mutated in a variety of human tumors, especially in malignant melanoma and colon carcinoma.
  • the most common reported mutation was a missense thymine (T) to adenine (A) transversion at nucleotide 1796 (T1796A; amino acid change in the B-Raf protein is Val ⁇ 600> to Glu ⁇ 600>) observed in 80% of malignant melanoma tumors.
  • T1796A missense thymine
  • A adenine transversion at nucleotide 1796
  • Functional analysis reveals that this transversion is the only detected mutation that causes constitutive activation of B-Raf kinase activity, independent of RAS activation, by converting B-Raf into a dominant transforming protein.
  • Niihori et al. report that in 43 individuals with cardio-facio-cutaneous (CFC) syndrome, they identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders (Niihori et al., Nat. Genet. 2006, 38(3):294-6).
  • c-Raf-1 Target kinase c-Raf-1 (i.e., v-raf murine sarcoma viral oncogene homolog 1) is a 73.0 kDa STK encoded by chromosome 3p25 (symbol: RAF1).
  • c-Raf-1 can be targeted to the mitochondria by BCL2 (i.e., oncogene B-cell leukemia 2) which is a regulator of apoptotic cell death. Active c-Raf-1 improves BCL2-mediated resistance to apoptosis, and c-Raf-1 phosphorylates BAD (i.e., BCL2-binding protein).
  • BAD i.e., BCL2-binding protein
  • c-Raf-1 is implicated in carcinomas, including colorectal, ovarian, lung and renal cell carcinoma. C-Raf-1 is also implicated as an important mediator of tumor angiogenesis (Hood, J. D. et al., 2002, Science 296, 2404). C-Raf-1 inhibitors may also be useful for the treatment of acute myeloid leukemia and myelodysplastic syndromes (Crump, Curr Pharm Des 2002, 8(25):2243-8).
  • Raf-1 activators may be useful as treatment for neuroendocrine tumors, such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma (Kunnimalaiyaan et al., Anticancer Drugs 2006, 17(2):139-42).
  • Raf inhibitors may be useful in treating A-Raf-mediated, B-Raf-mediated or c-Raf-1-mediated disease or condition selected from the group consisting of neurologic diseases, including, but not limited to, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g.
  • histiocytic lymphoma neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma
  • pain of neuropathic or inflammatory origin including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine
  • cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g.
  • inflammation including, but not limited to, psoriasis, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiency diseases, including, but not limited to, organ transplant rejection, graft versus host disease; renal or prostatic diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia; metabolic disorders, including, but not limited to, obesity; infection, including, but not limited to, Helicobacter pylori, Hepatitis and Influenza viruses, fever, and sepsis; pulmonary diseases, including, but not limited to, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental diseases, including, but not limited to, COPD) and chronic respiratory distress syndrome (ARDS); genetic developmental diseases, including
  • a number of different assays for kinase activity can be utilized for assaying for active modulators and/or determining specificity of a modulator for a particular kinase or group or kinases.
  • assays for kinase activity can be utilized for assaying for active modulators and/or determining specificity of a modulator for a particular kinase or group or kinases.
  • one of ordinary skill in the art will know of other assays that can be utilized and can modify an assay for a particular application. For example, numerous papers concerning kinases describe assays that can be used.
  • Additional alternative assays can employ binding determinations.
  • this sort of assay can be formatted either in a fluorescence resonance energy transfer (FRET) format, or using an AlphaScreen (amplified luminescent proximity homogeneous assay) format by varying the donor and acceptor reagents that are attached to streptavidin or the phosphor-specific antibody.
  • FRET fluorescence resonance energy transfer
  • AlphaScreen amplified luminescent proximity homogeneous assay
  • invention compounds may exist in a number of different forms or derivatives, all within the scope of the present invention.
  • Alternative forms or derivatives include, for example, (a) prodrugs, and active metabolites (b) tautomers, isomers (including stereoisomers and regioisomers), and racemic mixtures (c) pharmaceutically acceptable salts and (d) solid forms, including different crystal forms, polymorphic or amorphous solids, including hydrates and solvates thereof, and other forms.
  • the invention also includes prodrugs (generally pharmaceutically acceptable prodrugs), active metabolic derivatives (active metabolites), and their pharmaceutically acceptable salts.
  • Prodrugs are compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by solvolysis, yield the desired active compound.
  • Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound.
  • the prodrug is inactive, or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties.
  • some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug.
  • Esters include, for example, esters of a carboxylic acid group, or S-acyl or O-acyl derivatives of thiol, alcohol, or phenol groups.
  • Prodrugs may also include variants wherein an —NH group of the compound has undergone acylation, such as the 1-position of the pyrrolo[2,3-b]pyridine ring or the nitrogen of the sulfonamide group of compounds of the present invention, where cleavage of the acyl group provides the free —NH group of the active drug.
  • Some prodrugs are activated enzymatically to yield the active compound, or a compound may undergo further chemical reaction to yield the active compound.
  • Prodrugs may proceed from prodrug form to active form in a single step or may have one or more intermediate forms which may themselves have activity or may be inactive.
  • bioprecursor prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs.
  • bioprecursor prodrugs are compounds that are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity.
  • the formation of active drug compound involves a metabolic process or reaction that is one of the following types:
  • Oxidative reactions are exemplified without limitation by reactions such as oxidation of alcohol, carbonyl, and acid functionalities, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N-dealkylation, oxidative O- and S-dealkylation, oxidative deamination, as well as other oxidative reactions.
  • Reductive reactions are exemplified without limitation by reactions such as reduction of carbonyl functionalitites, reduction of alcohol functionalities and carbon-carbon double bonds, reduction of nitrogen-containing functional groups, and other reduction reactions.
  • Reactions without change in the state of oxidation are exemplified without limitation to reactions such as hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration at multiple bonds, new atomic linkages resulting from dehydration reactions, hydrolytic dehalogenation, removal of hydrogen halide molecule, and other such reactions.
  • Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improves uptake and/or localized delivery to a site(s) of action.
  • a transport moiety e.g., that improves uptake and/or localized delivery to a site(s) of action.
  • the linkage between the drug moiety and the transport moiety is a covalent bond
  • the prodrug is inactive or less active than the drug compound
  • the prodrug and any release transport moiety are acceptably non-toxic.
  • the transport moiety is intended to enhance uptake
  • the release of the transport moiety should be rapid.
  • it is desirable to utilize a moiety that provides slow release e.g., certain polymers or other moieties, such as cyclodextrins.
  • carrier prodrugs are often advantageous for orally administered drugs.
  • the transport moiety provides targeted delivery of the drug, for example the drug maybe conjugated to an antibody or antibody fragment.
  • Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property).
  • lipophilicity can be increased by esterification of hydroxyl groups with lipophilic carboxylic acids, or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols. Wermuth, supra.
  • Metabolites e.g., active metabolites
  • prodrugs as described above, e.g., bioprecursor prodrugs.
  • metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic processes in the body of a subject.
  • active metabolites are such pharmacologically active derivative compounds.
  • the prodrug compound is generally inactive or of lower activity than the metabolic product.
  • the parent compound may be either an active compound or may be an inactive prodrug.
  • one or more alkoxy groups can be metabolized to hydroxyl groups while retaining pharmacologic activity and/or carboxyl groups can be esterified, e.g., glucuronidation.
  • carboxyl groups can be esterified, e.g., glucuronidation.
  • there can be more than one metabolite where an intermediate metabolite(s) is further metabolized to provide an active metabolite.
  • a derivative compound resulting from metabolic glucuronidation may be inactive or of low activity, and can be further metabolized to provide an active metabolite.
  • Metabolites of a compound may be identified using routine techniques known in the art, and their activities determined using tests such as those described herein. See, e.g., Bertolini et al., 1997 , J Med. Chem., 40:2011-2016; Shan et al., 1997 , J Pharm Sci 86(7):756-757; Bagshawe, 1995 , Drug Dev. Res., 34:220-230; Wermuth, supra.
  • some of the compounds according to the present invention may exist as stereoisomers, i.e. having the same atomic connectivity of covalently bonded atoms yet differing in the spatial orientation of the atoms.
  • compounds may be optical stereoisomers, which contain one or more chiral centers, and therefore, may exist in two or more stereoisomeric forms (e.g. enantiomers or diastereomers).
  • stereoisomers i.e., essentially free of other stereoisomers
  • racemates i.e., essentially free of other stereoisomers
  • stereoisomers include geometric isomers, such as cis- or trans-orientation of substituents on adjacent carbons of a double bond. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Unless specified to the contrary, all such steroisomeric forms are included within the formulae provided herein.
  • a chiral compound of the present invention is in a form that contains at least 80% of a single isomer (60% enantiomeric excess (“e.e.”) or diastereomeric excess (“d.e.”)), or at least 85% (70% e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5% (95% e.e. or d.e.), or 99% (98% e.e. or d.e.).
  • 60% enantiomeric excess (“e.e.”) or diastereomeric excess (“d.e.”) or at least 85% (70% e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5% (95% e.e. or d.e.), or 99% (98% e.e. or d.e
  • an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
  • the compound is present in optically pure form, such optically pure form being prepared and/or isolated by methods known in the art (e.g. by recrystallization techniques, chiral synthetic techniques (including synthesis from optically pure starting materials), and chromatographic separation using a chiral column.
  • compositions of the invention can be in the form of pharmaceutically acceptable salts, or can be formulated as pharmaceutically acceptable salts.
  • Contemplated pharmaceutically acceptable salt forms include, without limitation, mono, bis, tris, tetrakis, and so on.
  • Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.
  • a compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly can react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing chloride, bromide, iodide, hydrochloride, acetate, phenylacetate, acrylate, ascorbate, aspartate, benzoate, 2-phenoxybenzoate, 2-acetoxybenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, bicarbonate, butyne-1,4 dioate, hexyne-1,6-dioate, caproate, caprylate, chlorobenzoate, cinnamate, citrate, decanoate, formate, fumarate, glycolate, gluconate, glucarate, glucuronate, glucose-6-phosphate, glutamate, heptanoate, hexanoate, isethionate, isobutyrate, gamma-hydroxybutyrate, phenylbutyrate, lactate, malate, maleate, hydroxymaleate, methyl
  • pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, ethanolamine, diethanolamine, triethanolamine, t-butylamine, dicyclohexylamine, ethylenediamine, N,N′-dibenzylethylenediamine, meglumine, hydroxyethylpyrrolidine, piperidine, morpholine, piperazine, procaine, aluminum, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, ammonium, and mono-, di-, or tri-alkylamines (e.g.
  • diethylamine or salts derived from amino acids such as L-histidine, L-glycine, L-lysine, and L-arginine.
  • L-histidine amino acids
  • L-glycine amino acids
  • L-lysine amino acids
  • L-arginine amino acids
  • salts can be prepared by standard techniques.
  • the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution.
  • a salt can be prepared by reacting the free base and acid in an organic solvent. If the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an appropriate inorganic or organic base.
  • the compounds and salts may exist in different crystal or polymorphic forms, or may be formulated as co-crystals, or may be in an amorphous form, or may be any combination thereof (e.g. partially crystalline, partially amorphous, or mixtures of polymorphs) all of which are intended to be within the scope of the present invention and specified formulae.
  • salts are formed by acid/base addition, i.e.
  • co-crystals are a new chemical species that is formed between neutral compounds, resulting in the compound and an additional molecular species in the same crystal structure.
  • compounds of the invention are complexed with a basic amino acid, such as L-histidine, L-lysine, or L-arginine, preferably L-lysine or L-arginine.
  • the complex of the compound and basic amino acid further comprises a strong acid, such as hydrochloric acid.
  • the resulting ternary complex can be amorphous, partially amorphous, or crystalline (e.g. a co-crystal).
  • an amorphous complex is preferably formed rather than a crystalline material such as a typical salt or co-crystal.
  • the amorphous form of the complex is facilitated by additional processing, such as by spray-drying, mechanochemical methods such as roller compaction, or microwave irradiation of the parent compound mixed with the basic amino acid.
  • additional processing such as by spray-drying, mechanochemical methods such as roller compaction, or microwave irradiation of the parent compound mixed with the basic amino acid.
  • additional processing such as hot melt extrusion, to further improve the biopharmaceutical properties of the compound.
  • the amorphous complex is readily friable, which provides improved compression for loading of the solid into capsule or tablet form.
  • the formulae are intended to cover hydrated or solvated as well as unhydrated or unsolvated forms of the identified structures.
  • the indicated compounds include both hydrated and non-hydrated forms.
  • Other examples of solvates include the structures in combination with a suitable solvent, such as isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
  • the methods and compounds will typically be used in therapy for human subjects. However, they may also be used to treat similar or identical indications in other animal subjects.
  • Compounds of the invention can be administered by different routes, including injection (i.e. parenteral, including intravenous, intraperitoneal, subcutaneous, and intramuscular), oral, transdermal, transmucosal, rectal, or inhalant. Such dosage forms should allow the compound to reach target cells. Other factors are well known in the art, and include considerations such as toxicity and dosage forms that retard the compound or composition from exerting its effects. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy, 21 st edition, Lippincott, Williams and Wilkins, Philadelphia, Pa., 2005 (hereby incorporated by reference herein).
  • compositions will comprise pharmaceutically acceptable carriers or excipients, such as fillers, binders, disintegrants, glidants, lubricants, complexing agents, solubilizers, and surfactants, which may be chosen to facilitate administration of the compound by a particular route.
  • carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, and the like.
  • Carriers also include physiologically compatible liquids as solvents or for suspensions, including, for example, sterile solutions of water for injection (WFI), saline solution, dextrose solution, Hank's solution, Ringer's solution, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, and the like.
  • WFI water for injection
  • Excipients may also include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethyl cellulose, cross-linked sodium carboxymethylcellulose, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated cotton seed oil, castor seed oil mineral oil, polyethylene glycol (e.g.
  • PEG 4000-8000 polyoxyethylene glycol
  • poloxamers povidone
  • crospovidone croscarmellose sodium
  • alginic acid casein
  • methacrylic acid divinylbenzene copolymer sodium docusate
  • cyclodextrins e.g. 2-hydroxypropyl-.delta.-cyclodextrin
  • polysorbates e.g.
  • polysorbate 80 cetrimide
  • TPGS d-alpha-tocopheryl polyethylene glycol 1000 succinate
  • magnesium lauryl sulfate sodium lauryl sulfate
  • polyethylene glycol ethers di-fatty acid ester of polyethylene glycols
  • a polyoxyalkylene sorbitan fatty acid ester e.g., polyoxyethylene sorbitan ester Tween®
  • polyoxyethylene sorbitan fatty acid esters sorbitan fatty acid ester, e.g.
  • a fatty acid such as oleic, stearic or palmitic acid
  • mannitol xylitol
  • sorbitol maltose
  • oral administration may be used.
  • Pharmaceutical preparations for oral use can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops.
  • Compounds of the invention may be combined with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e.g. aqueous, alcoholic, or oily solutions) and the like.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone); oily excipients, including vegetable and animal oils, such as sunflower oil, olive oil, or codliver oil.
  • fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol
  • cellulose preparations for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP: povid
  • the oral dosage formulations may also contain disintegrating agents, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate; a lubricant, such as talc or magnesium stearate; a plasticizer, such as glycerol or sorbitol; a sweetening such as sucrose, fructose, lactose, or aspartame; a natural or artificial flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring; or dye-stuffs or pigments, which may be used for identification or characterization of different doses or combinations. Also provided are dragee cores with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, poly-vinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • compositions that can be used orally include push-fit capsules made of gelatin (“gelcaps”), as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • injection parenteral administration
  • Compounds of Formula I for injection may be formulated in sterile liquid solutions, preferably in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • Dispersions may also be prepared in non-aqueous solutions, such as glycerol, propylene glycol, ethanol, liquid polyethylene glycols, triacetin, and vegetable oils. Solutions may also contain a preservative, such as methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • the compounds may be formulated in solid form, including, for example, lyophilized forms, and redissolved or suspended prior to use.
  • transmucosal, topical or transdermal administration may be used.
  • penetrants appropriate to the barrier to be permeated are used.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.
  • detergents may be used to facilitate permeation.
  • Transmucosal administration for example, may be through nasal sprays or suppositories (rectal or vaginal).
  • Compositions of compounds of Formula I for topical administration may be formulated as oils, creams, lotions, ointments, and the like by choice of appropriate carriers known in the art.
  • Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C 12 ). In some embodiments, carriers are selected such that the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Creams for topical application are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of solvent (e.g., an oil), is admixed.
  • solvent e.g., an oil
  • administration by transdermal means may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents known in the art.
  • a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents known in the art.
  • the dosage administration will be continuous rather than intermittent throughout the dosage regimen.
  • compounds are administered as inhalants.
  • Compounds of Formula I may be formulated as dry powder or a suitable solution, suspension, or aerosol.
  • Powders and solutions may be formulated with suitable additives known in the art.
  • powders may include a suitable powder base such as lactose or starch, and solutions may comprise propylene glycol, sterile water, ethanol, sodium chloride and other additives, such as acid, alkali and buffer salts.
  • Such solutions or suspensions may be administered by inhaling via spray, pump, atomizer, or nebulizer, and the like.
  • the compounds of Formula I may also be used in combination with other inhaled therapies, for example corticosteroids such as fluticasone proprionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone furoate; beta agonists such as albuterol, salmeterol, and formoterol; anticholinergic agents such as ipratroprium bromide or tiotropium; vasodilators such as treprostinal and iloprost; enzymes such as DNAase; therapeutic proteins; immunoglobulin antibodies; an oligonucleotide, such as single or double stranded DNA or RNA, siRNA; antibiotics such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; cromolyn sodium; nedocril sodium; and sodium cromoglycate.
  • corticosteroids such as
  • the amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound activity (in vitro, e.g. the compound IC 50 vs. target, or in vivo activity in animal efficacy models), pharmacokinetic results in animal models (e.g. biological half-life or bioavailability), the age, size, and weight of the subject, and the disorder associated with the subject. The importance of these and other factors are well known to those of ordinary skill in the art. Generally, a dose will be in the range of about 0.01 to 50 mg/kg, also about 0.1 to 20 mg/kg of the subject being treated. Multiple doses may be used.
  • the compounds of Formula I may also be used in combination with other therapies for treating the same disease.
  • Such combination use includes administration of the compounds and one or more other therapeutics at different times, or co-administration of the compound and one or more other therapies.
  • dosage may be modified for one or more of the compounds of the invention or other therapeutics used in combination, e.g., reduction in the amount dosed relative to a compound or therapy used alone, by methods well known to those of ordinary skill in the art.
  • use in combination includes use with other therapies, drugs, medical procedures etc., where the other therapy or procedure may be administered at different times (e.g. within a short time, such as within hours (e.g. 1, 2, 3, 4-24 hours), or within a longer time (e.g. I-2 days, 2-4 days, 4-7 days, I-4 weeks)) than a compound of Formula I, or at the same time as a compound of Formula I.
  • Use in combination also includes use with a therapy or medical procedure that is administered once or infrequently, such as surgery, along with a compound of Formula I administered within a short time or longer time before or after the other therapy or procedure.
  • the present invention provides for delivery of a compound of Formula I and one or more other drug therapeutics delivered by a different route of administration or by the same route of administration.
  • the use in combination for any route of administration includes delivery of a compound of Formula I and one or more other drug therapeutics delivered by the same route of administration together in any formulation, including formulations where the two compounds are chemically linked in such a way that they maintain their therapeutic activity when administered.
  • the other drug therapy may be co-administered with a compound of Formula I.
  • Use in combination by co-administration includes administration of co-formulations or formulations of chemically joined compounds, or administration of two or more compounds in separate formulations within a short time of each other (e.g.
  • Co-administration of separate formulations includes co-administration by delivery via one device, for example the same inhalant device, the same syringe, etc., or administration from separate devices within a short time of each other.
  • Co-formulations of a compound of Formula I and one or more additional drug therapies delivered by the same route includes preparation of the materials together such that they can be administered by one device, including the separate compounds combined in one formulation, or compounds that are modified such that they are chemically joined, yet still maintain their biological activity.
  • Such chemically joined compounds may have a linkage that is substantially maintained in vivo, or the linkage may break down in vivo, separating the two active components.
  • the mass spectrometry result indicated for a compound may have more than one value due to the isotope distribution of an atom in the molecule, such as a compound having a bromo or chloro substituent.
  • reaction mixture was poured into water and extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum and crystallized from ether to give the desired compound (4, 3.0 g, 71%).
  • Step 3 Preparation of ⁇ 3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methy]-2,4-difluoro-phenyl ⁇ -carbamic acid benzyl ester (6):
  • Step 5 Preparation of (3-amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (8):
  • Step 5a was prepared similarly, replacing 5-chloro-1H-pyrrolo[2,3-b]pyridine 5 with 1H-pyrrolo[2,3-b]pyridine-4-carbonitrile in Step 3, resulting in the methyl ester of the carbamic acid along with the benzyl ester.
  • the methyl ester is carried through Step 4 and the resulting [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-carbamic acid methyl ester (12) was reacted by the following Step 5a:
  • Step 5a Preparation of 3-(3-amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (13):
  • Step 3 Preparation of (3-amino-2-fluoro-phenyl)-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (70):
  • the suspension was degassed by bubbling with argon and zinc powder (0.032 g, 0.48 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.0568 g, 0.102 mmol), zinc cyanide (0.223 g, 1.90 mmol), and tris(dibenzylideneacetone)dipalladium (0) (0.053 g, 0.052 mmol) were added at room temperature under argon.
  • the mixture was heated to 120° C., resulting in most of the solid dissolving, and the mixture was heated at 120° C. for 2 hours, then cooled to 100° C. and 8 mL of water was added and the reaction mixture cooled to room temperature.
  • Step 3a Preparation of (3-amino-2,6-difluoro-phenyl)-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone (21):
  • the ethyl acetate layer was dried over sodium sulfate, filtered and the filtrate was concentrated under vacuum.
  • the desired compound was purified with preparative TLC plate eluting with 5% methanol/dichloromethane with some triethylamine drops added.
  • the desired band was extracted to provide the desired compound (25, 14.3 mg) of white solid after lyophilization.
  • Step 1 Preparation of benzo[b]thiophene-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1117):
  • the reaction mixture was irradiated in a microwave at 160° C. for 5 minutes.
  • the solution was neutralized with 100 ⁇ L of acetic acid and all material was transferred to a 4 mL vial and the solvents were removed under vacuum.
  • the crude material was dissolved in 400 ⁇ L of dimtheylsulfoxide and purified by reverse phase HPLC, eluting with 0.1% trifluoroacetic acid in water and 0.1% trifluoroacetic acid in acetonitrile, 20-100% acetonitrile over 16 minutes at 6 mL per minute. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound.
  • MS (ESI)[M+H + ] 487.9.
  • Step 1 Preparation of propane-1-sulfonic acid ⁇ 2,4-difluoro-3-[hydroxy-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methy]-phenyl ⁇ -amide (P-2473):
  • Step 1 Preparation of 5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic acid [5-(3- ⁇ 3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -propionylamino)-pentyl]-amide (P-2008):
  • N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (175 mg, 0.913 mmol) was added and the reaction was stirred at room temperature overnight. This resulted in a solid material to which 10 mL of dimethylformamide was added in order to dissolve most of the solid, and the reaction was stirred at room temperature for another 24 hours.
  • the reaction mixture was extracted with ethyl acetate and saturated sodium chloride in water. The organic layer was washed with water and brine, then dried with magnesium sulfate.
  • Step 1 Preparation of 3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (2-hydroxy-ethyl)-amide (P-2217):
  • Propane-1-sulfonic acid ⁇ 2,4-difluoro-3-[5-(6-propyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl ⁇ -amide P-2224 was synthesized in one step from propane-1-sulfonic acid (3- ⁇ 5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl ⁇ -2,4-difluoro-phenyl)-amide P-2222 as shown in Scheme 9.
  • Propane-1-sulfonic acid (3- ⁇ 5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl ⁇ -2,4-difluoro-phenyl)-amide (P-2222, 20.3 mg, 0.0359 mmol) was dissolved in 0.14 mL of methanol. Platinum dioxide (0.81 mg, 0.0036 mmol) was added and the resulting mixture was stirred under an atmosphere of hydrogen for 1 hour. The mixture was filtered through a bed of celite and the filtrate was concentrated.
  • Step 1 Preparation of propane-1-sulfonic acid ⁇ 2,4-difluoro-3-[5-(2H-tetrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl ⁇ -amide (P-2242):
  • Step 1 Preparation of 2,2,2-trifluoro-ethanesulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2334):
  • 5-chloro-1H-pyrrolo[2,3-b]pyridine Into a round bottom flask, 5-chloro-1H-pyrrolo[2,3-b]pyridine (5, 0.200 g, 1.31 mmol) was dissolved in 10 mL of N,N-dimethylformamide at 0° C. and sodium hydride (63 mg, 1.6 mmol) was added to the flask in one portion. The reaction was allowed to stir for 15 minutes, then 3-nitrophenyl disulfide (56, 490 mg, 1.6 mmol) was added in one portion to the flask. The reaction was stirred at room temperature overnight. The reaction was diluted with 3 volumes of water, and extracted 3 ⁇ with ethyl acetate.
  • N-(6-Acetylamino-pyridin-3-yl)-3-amino-2,6-difluoro-benzamide 64 was synthesized in two steps from N-(5-amino-pyridin-2-yl)-acetamide 61 as shown in Scheme 13.
  • 6-Acetylamino-N-(3-amino-2,6-difluoro-phenyl)-nicotinamide 68 was synthesized in two steps from 6-acetylamino-nicotinic acid 65 as shown in Scheme 14.
  • 6-acetylamino-nicotinic acid 65, 0.362 g, 2.01 mmol
  • cyanuric chloride 0.371 g, 2.01 mmol
  • the reaction mixture was stirred at room temperature for 5 hours, after which 2,6-difluoro-3-nitro-phenylamine (66, 0.200 g, 1.15 mmol) in 2 mL of tetrahydrofuran and pyridine (320 ⁇ L, 4.0 mmol) were added and the reaction stirred at room temperature for 4 days.
  • Step 2 Preparation of 6-acetylamino-N-(3-amino-2,6-difluoro-phenyl)-nicotinamide (68):
  • 5-Ethynyl-1H-pyrrolo[2,3-b]pyridine 72 was synthesized in two steps from 5-iodo-1H-pyrrolo[2,3-b]pyridine 69 as shown in Scheme 15.
  • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester 74 was synthesized in one step from 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 73 as shown in Scheme 16.
  • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid methylamide 75 was synthesized in one step from 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 73 as shown in Scheme 17.
  • N,N-Diethyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propionamide 87 was synthesized in three steps from (E)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-acrylic acid methyl ester 83 as shown in Scheme 19.
  • 3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propionic acid methyl ester (84, 4.21 g, 20.6 mmol) was dissolved in 150 mL of tetrahydrofuran and a solution of lithium hydroxide (3550 mg, 0.0845 mol, dissolved in 84 mL of deionized water) was added. The mixture was heated at 50° C. for 2 hours, then the reaction mixture was acidified to pH-1-2 with 6 N hydrochloric acid and extracted with ethyl acetate and water.
  • the aqueous layer was adjusted pH ⁇ 3-4 resulting in a precipitate, which was collected with filtration to provided 1.051 g of the desired compound.
  • MS (ESI) [M+H + ] + 191.4.
  • the aqueous layer was then extracted with ethyl acetate and the combined organic layers was washed with water and brine, and dried with magnesium sulfate and filtered. The filtrate was concentrated under vacuum to provide an additional 1.67 g of the desired compound.
  • 5-Methanesulfonyl-1H-pyrrolo[2,3-b]pyridine 93 was synthesized in one step from 5-bromo-1H-pyrrolo[2,3-b]pyridine 54 as shown in Scheme 20.
  • the aqueous layer was washed with ethyl acetate and the combined organic layers were washed with 1M aqueous sodium bicarbonate followed by water.
  • the organic layer was washed with brine and dried over anhydrous sodium sulfate, then filtered and the filtrate concentrated.
  • the crude material was purified by silica gel flash chromatography eluting with ethyl acetate and dichloromethane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (95, 0.702 g).
  • the triethylamine was removed under vacuum and 30 mL of water was added to the residue, and extracted with 2 ⁇ 20 mL of ether. The combined organic layers were washed with brine and dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was purified by silica gel flash chromatography eluting with ethyl acetate and dichloromethane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound.
  • the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate, then filtered and the filtrate concentrated under vacuum.
  • the crude material was purified by silica gel flash chromatography eluting with ethyl acetate and dichloromethane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (98, 0.215 g).
  • Step 1 Preparation of 5-bromo-pyridine-2-carboxylic acid ethylamide (101): 5-Bromo-pyridine-2-carboxylic acid (99, 0.417 g, 2.06 mmol) was dissolved in 19 mL of tetrahydrofuran.
  • N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.633 g, 3.30 mmol), N,N-diisopropylethylamine (1.81 mL, 10.4 mmol), and 1-hydroxybenzotriazole (0.363 g, 2.68 mmol) were added, followed by 2.00 Methylamine in tetrahydrofuran (100, 1.20 mL, 2.40 mmol).
  • the reaction mixture was stirred for overnight at room temperature, after which 1.5 mL of dimethylformamide was added and stirred for another 4 hours.
  • the resulting mixture was poured into water and extracted with ethyl acetate.
  • the organic layer was dried with anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum.
  • the crude material was purified by silica gel flash chromatography eluting with ethyl acetate and hexane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (108, 2.64 g).
  • Step 2 Preparation of dimethyl- ⁇ 3-[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrimidin-2-yloxy]-propyl ⁇ -amine (115):
  • Propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide 124 was synthesized in seven steps from 4-chloro-2-fluoro-phenylamine 116 as shown in Scheme 25.
  • the reaction was stirred at 78° C. for 20 minutes and then allowed to warm to room temperature over 60 minutes.
  • the reaction was cooled to 78° C., followed by addition of n-butyllithium (2.50 M in hexane, 26.0 mL) slowly.
  • benzyl chloroformate (117, 10.0 mL, 70.0 mmol) was added to the reaction.
  • the reaction mixture was stirred at 78° C. overnight followed by addition of 80 mL of water and 25 mL of concentrated hydrochloric acid.
  • the reaction was allowed to warm to room temperature for 2 hours.
  • the organic layer was separated.
  • the aqueous layer was basified with potassium carbonate and extracted with ethyl acetate.
  • reaction was concentrated under vacuum and purified with silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the desired compound as a crude white solid (122, 4.0 g), used in the next step without further purification.
  • N,N-diisopropylamin (2.74 mL, 19.6 mmol) in 51 mL of tetrahydrofuran, n-butyllithium (7.83 mL, 2.50 M in hexane, 19.6 mmol) was added at 78° C. under an atmosphere of nitrogen. After 30 minutes, propane-1-sulfonic acid (2-chloro-4-fluoro-phenyl)-amide (127, 1.59 g, 6.32 mmol) was added under nitrogen, maintaining the temperature at 78° C. After 1 hour, N,N-dimethylformamide (1.7 mL, 22 mmol) was added under nitrogen, maintaining the temperature at 78° C.
  • 5-Cyclopropyl-1H-pyrrolo[2,3-b]pyridine 136 was synthesized in one step from 5-iodo-1H-pyrrolo[2,3-b]pyridine 69 as shown in Scheme 27.
  • Propane-1-sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl ⁇ -amide may be prepared according to methods known in the art, for example, using methods described in U.S. patent application Ser. No. 11/473,347 (see also, PCT publication WO2007002433), the disclosure of which is hereby incorporated by reference.
  • Compound P-1167 can exist in polymorphic forms, for example as polymorphic forms 1 or 2, where such polymorphic forms may be isolated as the substantially pure polymorph.
  • the desired polymorphic form may be prepared, for example, by using appropriate crystallization conditions.
  • Form 1 was isolated by recrystallization from acetone/absolute ethanol (e.g. 1:1 to 5:1, preferably 2:1 by volume).
  • Form 2 is the more stable polymorph, and can be formed under a variety of recrystallization conditions, for example, recrystallization from methyl-t-butyl ether/tetrahydrofuran, ethyl acetate, or acetone, or may be formed by heating/melting and re-solidifying.
  • the substantially pure isolated polymorphic forms were characterized by X-Ray Powder Diffraction (XRPD), differential scanning calorimetry (DSC) and infrared spectroscopy.
  • Form 1 was also prepared treating a sample with acetone:ethanol (1:1 by volume) at reflux, then filtering hot and removing solvent from the filtrate under vacuum until solid precipitates out.
  • the propane-1-sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl ⁇ -amide polymorphic form 1 and form 2 were characterized by X-ray powder diffraction, infra-red spectrometry, and differential scanning calorimetry. Samples were analyzed by X-ray powder diffraction (XRPD) using a ShimadzuXRD-6000 X-ray powder diffractometer using Cu K ⁇ radiation. The tube voltage and amperage were set to 40 kV and 40 mA, respectively.
  • the divergence and scattering slits were set at 1° and the receiving slit was set at 0.15 mm. Diffracted radiation was detected by a NaI scintillation detector. A ⁇ -2 ⁇ continuous scan at 3°/min (0.4 sec/0.02° step) from 2.5° to 40° 2 ⁇ was used. A silicon standard was analyzed to check the instrument alignment. Data were collected and analyzed using XRD-6100/7000 v.5.0. Sample was prepared for analysis by placing it in an aluminum holder with silicon insert. The results are provided in the following Table 1.
  • the propane-1-sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl ⁇ -amide polymorphic form 1 and form 2 were analyzed by differential scanning calorimetry, scanning at 10.00° C. per minute.
  • the DSC thermogram for form 1 shows an exothermic shift at approximately 152-164° C. and an endothermic peak at 268.0° C.
  • the DSC thermogram for form 2 shows an endothermic peak at 271.2° C.
  • N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]sulfonamide and related compounds, such as compounds of Formula I are characterized as having functionalities providing both weakly basic and weakly acidic centers which can form organic salt complexes, resulting in improved solubility.
  • the N-7 of the azaindole portion is weakly basic (pKa approximately 4-5) while the sulfonamide nitrogen is weakly acidic (pKa approximately 7).
  • An organic salt complex reflects the potential for multiple sites of interaction between the guest and host. Attempts to make inorganic salts, e.g. using sodium or potassium, resulted in material that was difficult to isolate and was hygroscopic in some instances.
  • the material may be non-hygroscopic
  • isolated material may exhibit multiple polymorphic forms.
  • the basic amino acids arginine and lysine were found to form non-crystalline complexes readily in a stoichiometric manner, and the resulting materials demonstrated enhanced solubility and bioavailability (exposure in pharmacokinetic analysis) relative to the free base form as well as other standard salt forms. Demonstrating additional unexpected advantages, such complexes were isolated as amorphous forms rather than typical crystalline salt forms, were non-hygroscopic, and chemically stable.
  • Organic base complexes including arginine, nicotinamide and lysine complexes are typically formed by dissolving N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]sulfonamide and related compounds in 20-50 solvent volumes of an alcohol, preferably methanol, with moderate heating (30-35° C.).
  • the milky suspension is stirred, and 1 equivalent of the L-form of arginine or lysine that has been triturated in a separate portion of the alcohol is added.
  • the mixture is stirred under an inert atmosphere until a clear yellowish solution is formed.
  • the solution is filtered and the solvent removed from the filtrate under reduced pressure.
  • the resulting yellow film forms a friable solid upon vacuum drying.
  • the complex may be precipitated by addition of cold solvent such as heptane, methyl t-butyl ether, ethyl acetate or the like to the alcohol solution, the resulting solid filtered and vacuum dried to isolate the friable solid.
  • the resulting solid is typically amorphous with some degree ( ⁇ 30%) of crystallinity, preferably the complex is substantially amorphous, and is less than 10%, also less than 5%, also less than 1% crystalline.
  • the resulting solid may be prepared to have some degree of crystalline material, where the method above is modified by using an excess amount of the N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]sulfonamide relative to the arginine or lysine.
  • an excess amount of the N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]sulfonamide relative to the arginine or lysine.
  • 0.5 equivalent of the L-form of arginine or lysine may be added to the suspension of compound in methanol.
  • the resulting solid that is isolated will comprise a mixture of the amorphous complex and crystalline compound.
  • the amount of L-arginine or L-lysine used may be adjusted appropriately to provide a solid that has any level of crystalline material, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% crystalline, with 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10% amorphous solid, respectively.
  • the relative amount of crystalline material and amorphous material in a solid can be readily determined by one skilled in the art, for example as described in Shah et al., J Pharm Sci 2006, 95:1641-1665.
  • Acid addition salts including sulfonic acid series of organic anions such as tosylate, besylate or mesylate, of N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide and related compounds are preferably formed using acetone, which provides solubility of the free base and is a non-solvent once the salt is formed.
  • N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide is added to 20-50 solvent volumes of acetone with stirring and heating (30-35° C.), followed by the addition of 1 equivalent of the desired acid counter ion.
  • the solution is slowly cooled to 2-8° C. and the solid is isolated by either filtration or centrifugation, followed by vacuum drying.
  • the resulting solid may be amorphous, partially amorphous or crystalline, and can be recrystallized as needed from alcohol:acetone:ethyl acetate or alcohol alone to obtain the desired solid in crystalline form.
  • Organic acid complexes including citric acid, tartaric acid, succinic acid, glutaric acid and acetylsalicylic acid complexes of N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide and related compounds are preferably formed in 1:1 or 1:2 compound:acid ratios in a suitable solvent such as methanol.
  • a suitable solvent such as methanol.
  • N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide is added to 15-20 solvent volumes of methanol, with the desired solid isolated by either spray drying or by addition of non-solvent such as heptane followed by filtration and vacuum drying.
  • the resulting solid is preferably an amorphous complex.
  • Mineral acids including sulfate, phosphate and hydrochloric acid salts of N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide and related compounds are prepared from methanol or ethyl acetate solutions.
  • the resulting complexes or salts may also be processed through spray-drying techniques to provide the preferred form directly, or with suitable excipient materials to provide for a directly compressible or encapsulated dosage form.
  • Salts or complexes may also be achieved by mechanochemical (e.g. roller compaction) or microwave irradiation of the parent compound with the appropriate selection of charge transfer partner.
  • mechanochemical e.g. roller compaction
  • microwave irradiation e.g. microwave irradiation of the parent compound with the appropriate selection of charge transfer partner.
  • the arginine complex of N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide P-1021 was prepared by suspending 5 g (9.7 mmol) of the free base in 100 mL of methanol, mixing with heating 30-35° C. L-arginine (1.70 g, 9.7 mmol) as a triturated dispersion in 5.1 mL of methanol. The milky white suspension is stirred with heating until a clear yellowish solution is formed. The solution was filtered and the solvent removed from the filtrate under reduced pressure, or processed by spray-drying to provide the complex as a friable yellow solid.
  • any of these arginine or lysine complexes may be prepared as a ternary complex comprising a strong acid, such as hydrochloric acid, for example by addition of 1 equivalent of hydrochloric acid (or other suitable acid) to the suspension of compound in methanol and mixing with the L-arginine or L-lysine.
  • a strong acid such as hydrochloric acid
  • the mesylate salt of N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide P-1021 was prepared by suspending 5 g (9.7 mmol) in 100 mL of acetone, mixing with heating 30-35° C. Methanesulfonic acid (0.63 mL, 9.7 mmol) was added and the solution cooled to 5° C. over 30 minutes. The resulting solid was isolated by filtration, washed and dried under vacuum to provide the desired salt.
  • the lysine complex is amorphous, with the lack of any clear structure in the XRPD sprecta and the intensity of the peaks corresponding to the two largest peaks in form 2 (20 values of about 9.2 and 15.0) reduced to less than 5% of the form 2 intensity.
  • the arginine complex is substantially amorphous, showing some residual level of crystallinity in the XRPD spectra, with the intensity of these peaks at less than 30% of the form 2 intensity.
  • the amount of crystalline material in such complexes can be readily reduced further in processing, for example, by spray drying techniques such that an amorphous complex with arginine or lysine is provided.
  • the DSC of these samples shows that the arginine and lysine complexes lack a characteristic transition and have completely melted before the free base crystalline transition at 271° C., further supporting that these complexes are amorphous.
  • the intrinsic dissolution rate of a similarly prepared substantially amorphous arginine complex of P-1167 was compared to that of the form 2 polymorph in simulated gastric fluid (SGF) without enzyme and in simulated intestinal fluid (SIF).
  • SGF gastric fluid
  • SIF simulated intestinal fluid
  • a pellet of test sample was dissolved in the appropriate fluid, and the UV absorbance as a function of time was measured at 254 nm (SGF) or 310 nm (SIF) and plotted.
  • SGF gastric fluid
  • SIF 310 nm
  • the DSC shows that the arginine complex has a very broad transition from about 56° C. to about 120° C. and lacks the characteristic transition of the free base at approximately 275° C.
  • the spectra were acquired with phase modulated SPINAL-64 high power 1 H decoupling during the acquisition time using a 1 H pulse width of 2.2 ⁇ s(90°), a ramped amplitude cross polarization contact time of 3-8 ms, a 30 ms acquisition time, a 10-30 second delay between scans, a spectral width of 45 kHz with 2700 data points, and 100 or 400 co-added scans.
  • Each free induction decay was processed using Varian VNMR 6.1C software3 with 32768 points and an exponential line broadening factor of 10 or 100 Hz to improve the signal-to-noise ratio.
  • the first three data points of the free induction decay were back predicted using VNMR linear prediction algorithm to produce a flat baseline.
  • Pharmacokinetic properties of various compositions prepared from the complexes may be assessed in male Sprague Dawley rats or male Beagle dogs, and compared to the properties of the free base compound. Rats are dosed daily with compound either by IV injections via surgically implanted jugular catheters or by oral gavage (PO). Each compound is prepared as a 20 mg/mL stock solution in dimethyl sulfoxide, which is further diluted to provide the dosing stock at the desired concentration for the IV or PO formulations. For IV dosing, the dosing stock is diluted into a 1:1:8 mixture of Solutol®:ethanol:water. For PO dosing, the dosing stock is diluted into 1% methylcellulose.
  • 5 compounds are diluted to 0.5 mg/mL each for IV dosing and 0.4 mg/mL each for PO dosing and dosed at 1 mg/kg (2 mL/kg) or 2 mg/kg (5 mL/kg), respectively.
  • IV dosed animals tail vein blood samples are collected with lithium heparin anticoagulant at 5, 15, 30, and 60 minutes and 4, 8, and 24 hours post dosing each day.
  • PO dosed animals tail vein blood samples are collected with lithium heparin anticoagulant at 30 minutes, 1, 2, 4, 8 and 24 hours post dosing each day.
  • Dogs are dosed daily by oral capsules in a suitable formulation at 50 mg/mL.
  • Cephalic vein blood samples are collected with lithium heparin anticoagulant at 30 minutes, 1, 2, 4, 8 and 24 hours post dosing each day. All samples are processed to plasma and frozen for later analysis of each compound by LC/MS/MS. Plasma levels as a function of time are plotted to assess the AUC (ng*hr/mL).
  • the arginine complex of N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide P-1021 was analyzed in a number of dog PK studies following the above or similar protocols. These were done primarily at Bridge Laboratories, Beijing, China, with one study done at Seventh Wave Laboratories LLC, Chesterfield, Mo. Plasma samples were analyzed to determine the plasma concentration (PPD Development, Madison, Wis.) at each time point from which the Cmax and AUC ⁇ were determined. The dosing formulations and results for these studies are given in the following tables.
  • the materials are combined in the solvents indicated, and the solvent is removed by evaporation, or by spray drying where indicated.
  • the dose is mg/dog
  • the Cmax/dose ((ng/mL)/(mg/kg)) and the AUC ⁇ /dose ((ng*hr/mL)/(mg/kg)) are calculated assuming a 10 kg weight for the dogs.
  • P-1021 arginine complex Amoung (g) per 10 gram Component batch W/W % P-1021 arginine complex 5.00 free base 50.0 1.70 L-arginine 17.0 Mannitol 1.70 17.0 Polyplasdone XL 0.40 4.0 Mg-Al-silicate 1.00 10.0 Poloxamer F127 0.40 4.0 In methanol solvent ( ⁇ 50 mg/mL) removed during processing P-1021 free base Amoung (g) per 7.4 gram Component batch W/W % Micronized P-1021 free base 5.00 50.0 Mannitol 2.22 22.0 D-Sorbitol 2.00 20.0 Polyplasdone XL 0.40 4.0 Poloxamer F127 0.40 4.0 Dry blended with simulation of roller compaction P-1021 amorphous free base Amoung (g)
  • a PK study was carried out in Sprague-Dawley rats on the arginine or lysine complex of propane-1-sulfonic acid ⁇ 2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl ⁇ -amide P-1496 (Murigenics, Berkeley, Calif.), dosing via tail vein injection, with sampling of approximately 250 ⁇ L of blood via jugular veing in Lithium heparin tubes at 30 minutes, 1, 3, 6, 8, 12, 24, 36 and 48 hours. Blood samples were centrifuged at 4° C. for 10 minutes at RCF of 1,000, plasma was stored at 80° C.
  • Raf kinases including, but not limited to, B-Raf, B-Raf V600E, B-Raf V600E/T529I and c-Raf-1, as well as for other kinases are known in the art, for example as described in U.S. patent application Ser. No. 11/473,347 (see also, PCT publication WO2007002433), the disclosure of which is hereby incorporated by reference in its entirety.
  • the activity of compounds for Raf kinases and other kinases is summarized in the following tables.
  • TrkA TABLE 11k Compounds with activity toward kinase TrkA with IC 50 ⁇ 10 ⁇ M. TrkA P-2060, P-2061, P-2105, P-2168, P-2174, P-2176, P-2239, P-2240, P-2301, P-2302, P-2344, P-2345, P-2407
  • Flt1 P-2099, P-2100, P-2105, P-2150, P-2151, P-2162, P-2193, P-2196, P-2199, P-2200, P-2201, P-2203, P-2210, P-2213, P-2214, P-2215, P-2216, P-2217, P-2218, P-2299, P-2302, P-2404, P-2430, P-2432, P-2434, P-2457
  • any of the terms “comprising”, “consisting essentially of” and “consisting of” may be replaced with either of the other two terms.
  • the invention also includes another embodiment wherein one of these terms is replaced with another of these terms.
  • the terms have their established meaning.
  • one embodiment may encompass a method “comprising” a series of steps, another embodiment would encompass a method “consisting essentially of” the same steps, and a third embodiment would encompass a method “consisting of” the same steps.

Abstract

Solid forms of phenyl sulfonamide compounds of formula (I) active on protein kinases, including Raf protein kinases, are described, as well as methods of using such solid forms to treat diseases and conditions associated with activity of protein kinases, e.g. Raf protein kinases, including pain, polycystic kidney disease, melanoma and colorectal cancer.
Figure US20120122860A1-20120517-C00001

Description

    FIELD OF THE INVENTION
  • Disclosed are novel compounds, and novel solid forms, formulations, and uses thereof. In certain embodiments disclosed compounds are kinase inhibitors.
    • SUMMARY OF THE INVENTION
  • In one aspect, solid forms of phenyl sulfonamide compounds, preferably an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compounds, are provided. Also contemplated in accordance with the present invention are solid forms comprising a phenyl sulfonamide compound, preferably an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound and a basic amino acid, wherein the solid form provides improved biopharmaceutical properties. Also contemplated in accordance with the present invention are methods for the use of the above-described solid forms and related compositions in treating diseases and conditions associated with regulation of the activity of one or more protein kinases, including, but not limited to Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof. In certain embodiments, the solid forms that can be used for therapeutic methods involving modulation of one or more Raf protein kinases, including treatment of a variety of indications, including, but not limited to, melanoma, colorectal cancer, thyroid cancer, ovarian cancer, cholangiocarcinoma, pain and/or polycystic kidney disease.
  • In a second aspect, a solid form comprising a phenyl sulfonamide compound, preferably an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound, and a basic amino acid is provided. In one embodiment, the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound and the basic amino acid provides improved biopharmaceutical properties of the phenyl sulfonamide compound relative to the free base, salt or other solid form of the compound.
  • In one embodiment, the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound and the basic amino acid provides improved pharmacokinetics of the phenyl sulfonamide compound relative to the free base, salt or other solid form of the compound, wherein said improvement is an increase in the Cmax and/or AUC for a given dose of the compound in a suitable animal model, such as a mouse, rat, dog or monkey model. In one embodiment, a composition comprising the solid form is provided. In one embodiment, the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound and the basic amino acid is provided in a formulation that further improves the biopharmaceutical properties of the N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound.
  • In a third aspect, a solid form comprising a phenyl sulfonamide compound, preferably an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound, and arginine is provided. In one embodiment, the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound and arginine provides improved biopharmaceutical properties of the phenyl sulfonamide compound relative to the free base, salt or other solid form of the compound. In one embodiment, the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound and arginine provides improved pharmacokinetics of the phenyl sulfonamide compound relative to the free base, salt or other solid form of the compound, wherein said improvement is an increase in the Cmax and/or AUC for a given dose of the compound in a suitable animal model, such as a mouse, rat, dog or monkey model. In one embodiment, a composition comprising the solid form is provided. In one embodiment, the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound and arginine is provided in a formulation that further improves the biopharmaceutical properties of the N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound.
  • In a fourth aspect, a solid form comprising a phenyl sulfonamide compound, preferably an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound and lysine is provided. In one embodiment, the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound and lysine provides with improved biopharmaceutical properties of the phenyl sulfonamide compound relative to the free base, salt or other solid form of the compound. In one embodiment, the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound and lysine provides improved pharmacokinetics of the phenyl sulfonamide compound relative to the free base, salt or other solid form of the compound, wherein said improvement is an increase in the Cmax and/or AUC for a given dose of the compound in a suitable animal model, such as a mouse, rat, dog or monkey model. In one embodiment, a composition comprising the solid form is provided. In one embodiment, the solid form comprising an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound and lysine is provided in a formulation that further improves the biopharmaceutical properties of the N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound.
  • In a fifth aspect, a solid form is provided comprising a basic amino acid and a phenyl sulfonamide compound of Formula I, wherein Formula I is as follows:
  • Figure US20120122860A1-20120517-C00002
  • wherein:
      • Ar is heteroaryl;
      • each R1, when present, is independently selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, —CN, —NO2, —O—R11, —N(R12)—R13, —C(O)—N(R14)—R15, —C(O)—O—R16, —S(O)2—R17, and —N(H)—C(O)—R18, wherein lower alkyl is optionally substituted with one or more R5, lower alkenyl and lower alkynyl are optionally substituted with one or more R6, heterocycloalkyl is optionally substituted with one or more lower alkyl, phenyl is optionally substituted with one or more R7, and heteroaryl is optionally substituted with one or more R8;
      • m is 0, 1, 2, or 3;
      • R2 is hydrogen, fluoro or chloro;
      • R3 is hydrogen, fluoro, chloro, or methyl;
      • R4 is selected from the group consisting of lower alkyl, fluoro substituted lower alkyl, mono-alkylamino, di-alkylamino, cycloalkylamino, cycloalkyl, phenyl, and heteroaryl, wherein cycloalkyl is optionally substituted with —C(O)OR16, phenyl is optionally substituted with one or more R9, and heteroaryl is optionally substituted with one or more R10;
      • L is selected from the group consisting of —NH—, —CH2—, —C(OH)H—, —C(O)—, —S(O)2—, —O—CH2—, —CH2—NH—, —NH—CH2—, —C(O)—NH—, and —NH—C(O)—;
      • each R5, when present, is independently fluoro, —OH, lower alkoxy, heteroaryl, chloro substituted heteroaryl, phenyl, chloro substituted phenyl, mono-alkylamino, dialkylamino, cycloalkylamino, —C(O)—N(R14)—R19, or —C(O)—O—R16;
      • each R6, when present, is independently —C(O)—O—R16, lower alkoxy, mono-alkylamino or dialkylamino;
  • each R7, when present, is independently fluoro, chloro, —CN, —OH, lower alkyl, lower alkenyl, —C(O)—O—R16 substituted lower alkenyl, lower alkoxy, lower alkoxy substituted lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, —S(O)2R20, —N(H)—S(O)2—R20, —N(H)—C(O)—R20, —C(O)—N(R21)—R22, or —S(O)2—N(R23)R24, wherein lower alkyl is optionally substituted with —C(O)—O—R16, mono-alkylamino, di-alkylamino, or cycloalkylamino;
      • each R8, when present, is independently fluoro, chloro, —OH, —NH2, lower alkyl, lower alkynyl, di-alkylamino substituted lower alkynyl, lower alkoxy, lower alkylthio, monoalkylamino, di-alkylamino, cycloalkylamino, phenyl, —C(O)—N(R25)—R26, or —N(H)—C(O)—R20, wherein lower alkyl is optionally substituted with one or more fluoro, alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or phenyl, and wherein lower alkoxy is optionally substituted with —OH, lower alkoxy, mono-alkylamino, di-alkylamino or cycloalkylamino;
      • each R9, when present, is independently fluoro, chloro, —CN, —NO2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, —C(O)—O—R16, —N(H)—C(O)—R26, heteroaryl optionally substituted with one or more lower alkyl, or two R9 on adjacent carbons combine to form a fused heterocycloalkyl optionally substituted with one or more lower alkyl;
      • each R10, when present, is independently lower alkyl, fluoro substituted lower alkyl, lower alkoxy, —C(O)—O—R16, or heteroaryl optionally substituted with one or more lower alkyl;
      • each R11, when present, is independently hydrogen, lower alkyl, cycloalkyl, or heterocycloalkyl, wherein lower alkyl is optionally substituted with —OH, lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, phenyl, or heteroaryl;
      • each R12, R14, and R16, when present, are independently hydrogen or lower alkyl;
      • each R11, when present, is independently hydrogen, lower alkyl, cycloalkyl, phenyl, heteroaryl or combined with the nitrogen and R11 form cycloalkylamino, wherein lower alkyl is optionally substituted with cycloalkylamino, phenyl, heteroaryl or lower alkyl substituted heteroaryl;
      • each R15, when present, is independently hydrogen, lower alkyl, —OH substituted lower alkyl, cycloalkyl or lower alkoxy;
      • each R17, when present, is independently lower alkyl, phenyl or lower alkyl substituted phenyl;
      • each R18, when present, is independently lower alkyl or cycloalkylamino;
      • each R19, when present, is independently hydrogen, lower alkyl, or lower alkoxy;
      • each R20, when present, is independently lower alkyl;
      • each R21 and R22, when present, are independently hydrogen, lower alkyl, or combine with the nitrogen to form cycloalkylamino;
      • each R23 and R24, when present, are independently hydrogen, lower alkyl optionally substituted with —OH, cycloalkyl, or combine with the nitrogen to form cycloalkylamino; and
      • each R25 and R26, when present, are independently hydrogen, lower alkyl, or cycloalkyl.
  • In a sixth aspect, a solid form is provided comprising a basic amino acid and an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide or similar sulfonamide compound of Formula Ia, wherein Formula Ia is as follows:
  • Figure US20120122860A1-20120517-C00003
  • wherein:
      • U and V are C—H, and W is C—R27;
      • or U and W are C—H, and V is C—R28;
      • or U is N, V is C—H, and W is C—R27;
      • or U is N, V is C—R28, and W is C—H;
      • or U is C—H, V is N, and W is C—R27;
      • or U is C—H, V is C—R28, and W is N;
      • L1 is —CH2—, —C(OH)H—, or —C(O)—;
      • R27 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, —CN, —O—R38, —N(R39)—R40, —C(O)—N(R41)—R42, —C(O)—O—R43, —S(O)2—R44, and —N(H)—C(O)—R45, wherein lower alkyl is optionally substituted with one or more R32, lower alkenyl and lower alkynyl are optionally substituted with one or more R33, heterocycloalkyl is optionally substituted with one or more lower alkyl, phenyl is optionally substituted with one or more R34, and heteroaryl is optionally substituted with one or more R35;
  • R28 is selected from the group consisting of hydrogen, chloro, methyl, methoxy, —CN, and —C≡CH;
      • R29 is hydrogen, fluoro or chloro;
      • R30 is hydrogen, fluoro, chloro, or methyl;
      • R31 is selected from the group consisting of lower alkyl, fluoro substituted lower alkyl, mono-alkylamino, di-alkylamino, cycloalkylamino, cycloalkyl, phenyl, and heteroaryl, wherein cycloalkyl is optionally substituted with —C(O)OR43, phenyl is optionally substituted with one or more R36, and heteroaryl is optionally substituted with one or more R37;
      • each R32, when present, is independently fluoro, —OH, lower alkoxy, heteroaryl, chloro substituted heteroaryl, phenyl, chloro substituted phenyl, mono-alkylamino, dialkylamino, cycloalkylamino, —C(O)—N(R41)—R46, or —C(O)—O—R43;
      • each R33, when present, is independently —C(O)—O—R43, lower alkoxy, mono-alkylamino or dialkylamino;
      • each R34, when present, is independently fluoro, chloro, —CN, —OH, lower alkyl, lower alkenyl, —C(O)—O—R43 substituted lower alkenyl, lower alkoxy, lower alkoxy substituted lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, —S(O)2R47, —N(H)—S(O)2—R47, —N(H)—C(O)—R47, —C(O)—N(R48)—R49, or —S(O)2—N(R50)—R51, wherein lower alkyl is optionally substituted with —C(O)—O—R43, mono-alkylamino, di-alkylamino, or cycloalkylamino;
  • each R35, when present, is independently fluoro, chloro, —OH, —NH2, lower alkyl, lower alkynyl, di-alkylamino substituted lower alkynyl, lower alkoxy, lower alkylthio, monoalkylamino, di-alkylamino, cycloalkylamino, phenyl, —C(O)—N(R52)—R53, or —N(H)—C(O)—R47, wherein lower alkyl is optionally substituted with one or more fluoro, alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or phenyl, and wherein lower alkoxy is optionally substituted with —OH, lower alkoxy, mono-alkylamino, di-alkylamino or cycloalkylamino;
      • each R36, when present, is independently fluoro, chloro, —CN, —NO2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, —C(O)—O—R43, —N(H)—C(O)—R47, heteroaryl optionally substituted with one or more lower alkyl, or two R36 on adjacent carbons combine to form a fused heterocycloalkyl optionally substituted with one or more lower alkyl;
      • each R37, when present, is independently lower alkyl, fluoro substituted lower alkyl, lower alkoxy, —C(O)—O—R43, or heteroaryl optionally substituted with one or more lower alkyl;
      • R38 is hydrogen, lower alkyl, cycloalkyl, or heterocycloalkyl, wherein lower alkyl is optionally substituted with —OH, lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, phenyl, or heteroaryl;
      • each R39, R41, and R43, when present, are independently hydrogen or lower alkyl;
      • R40 is hydrogen, lower alkyl, cycloalkyl, phenyl, heteroaryl or combined with the nitrogen and R39 form cycloalkylamino, wherein lower alkyl is optionally substituted with cycloalkylamino, phenyl, heteroaryl or lower alkyl substituted heteroaryl;
      • R42 is hydrogen, lower alkyl, —OH substituted lower alkyl, cycloalkyl or lower alkoxy;
      • R44 is lower alkyl, phenyl or lower alkyl substituted phenyl;
      • R45 is lower alkyl or cycloalkylamino;
      • each R46, when present, is independently hydrogen, lower alkyl, or lower alkoxy;
      • each R47, when present, is independently lower alkyl;
      • each R48 and R49, when present, are independently hydrogen, lower alkyl, or combine with the nitrogen to form cycloalkylamino;
      • each R50 and R51, when present, are independently hydrogen, lower alkyl optionally substituted with —OH, cycloalkyl, or combine with the nitrogen to form cycloalkylamino; and
      • each R52 and R53, when present, are independently hydrogen, lower alkyl, or cycloalkyl.
  • In one embodiment of a solid form comprising a basic amino acid and a compound of Formula Ia, U and V are C—H, W is C—R27, and R27 is selected from the group consisting of hydrogen, chloro, lower alkyl, phenyl, heteroaryl, —CN, —C≡CH, —O—R38, —N(R39)—R40, —C(O)—N(R41)—R42, —C(O)—O—R43, —S(O)2—R44, and —N(H)—C(O)—R45, wherein lower alkyl is optionally substituted with one or more R32, phenyl is optionally substituted with one or more R34, and heteroaryl is optionally substituted with one or more R35. In one embodiment, R27 is selected from the group consisting of hydrogen, chloro, lower alkyl, phenyl, heteroaryl, —CN, —C≡CH, —O—R38, —N(R39)—R40, —C(O)—N(R41)—R42, —C(O)—O—R43, —S(O)2—R44, and —N(H)—C(O)—R45, wherein lower alkyl is optionally substituted with one or more R32, phenyl is optionally substituted with one or more R34, and heteroaryl is optionally substituted with one or more R35 and R31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one embodiment, R27 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R31 is lower alkyl, dialkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl. In one embodiment, R27 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R31 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl. In one embodiment, R27 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluorophenyl, 2,5-di-fluoro-phenyl, 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethylphenyl. In one embodiment, R27 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl. In one embodiment, R27 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl. In one embodiment, R27 is chloro, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluorophenyl, or 2,5-di-fluoro-phenyl. In one embodiment, R27 is chloro, methyl, or —CN, and R31 is 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl.
  • In one embodiment of a solid form comprising a basic amino acid and a compound of Formula Ia, U and W are C—H, V is C—R28, and R28 is selected from the group consisting of hydrogen, chloro, methyl, methoxy, —CN, and —C≡CH. In one embodiment, R28 is selected from the group consisting of hydrogen, chloro, methyl, methoxy, —CN, and —C≡CH and R31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one embodiment, R28 is —CN, or —C≡CH, and R31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl. In one embodiment, R28 is —CN, or —C≡CH, and R31 is n-propyl, dimethylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl. In one embodiment, R28 is —CN, or —C≡CH, and R31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl. In one embodiment, R28 is —CN, or —C≡CH, and R31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl. In one embodiment, R28 is —CN, or —C≡CH, and R31 is 4-trifluoromethyl-phenyl.
  • In one embodiment of a solid form comprising a basic amino acid and a compound of Formula Ia, U is C—H, V is N, W is C—R27, and R27 is selected from the group consisting of hydrogen, chloro, lower alkyl, phenyl, heteroaryl, —CN, —C≡CH, —O—R38, —N(R39)—R40, —C(O)—N(R41)—R42, —C(O)—O—R43, —S(O)2—R44, and —N(H)—C(O)—R45, wherein lower alkyl is optionally substituted with one or more R32, phenyl is optionally substituted with one or more R34, and heteroaryl is optionally substituted with one or more R35. In one embodiment, R27 is selected from the group consisting of hydrogen, chloro, lower alkyl, phenyl, heteroaryl, —CN, —C≡CH, —O—R38, —N(R39)—R40, —C(O)—N(R41)—R42, —C(O)—O—R43, C(O)—O—R43, —S(O)2—R44, and —N(H)—C(O)—R45, wherein lower alkyl is optionally substituted with one or more R32, phenyl is optionally substituted with one or more R34, and heteroaryl is optionally substituted with one or more R35 and R31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one embodiment, R27 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl. In one embodiment, R27 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl. In one embodiment, R27 is hydrogen and R31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl. In one embodiment, R27 is hydrogen and R31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl. In one embodiment, R27 is hydrogen and R31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl. In one embodiment, R27 is hydrogen and R31 is 4-trifluoromethyl-phenyl.
  • In one embodiment of a solid form comprising a basic amino acid and a compound of Formula Ia, U is C—H, W is N, V is C—R28, and R28 is selected from the group consisting of hydrogen, chloro, methyl, methoxy, —CN, and —C≡CH. In one embodiment, R28 is selected from the group consisting of hydrogen, chloro, methyl, methoxy, —CN, and —C≡CH and R31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one embodiment, R28 is hydrogen, chloro, methyl, methoxy, —CN, or —C≡CH and R31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl. In one embodiment, R28 is hydrogen, chloro, methyl, methoxy, —CN, or —C≡CH, and R31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl. In one embodiment, R28 is hydrogen or methoxy, and R31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl. In one embodiment, R28 is hydrogen or methoxy, and R31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl. In one embodiment, R28 is hydrogen or methoxy, and R31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl. In one embodiment, R28 is hydrogen or methoxy, and R31 is 4-t-butyl-phenyl or 4-trifluoromethyl-phenyl.
  • In one embodiment of a solid form comprising a basic amino acid and a compound of Formula Ia, U is N, V is —CH, W is C—R27, and R27 is selected from the group consisting of hydrogen, chloro, lower alkyl, phenyl, heteroaryl, —CN, —C≡CH, —O—R38, —N(R39)—R40, —C(O)—N(R41)—R42, —C(O)—O—R43, —S(O)2—R44, and —N(H)—C(O)—R45, wherein lower alkyl is optionally substituted with one or more R32, phenyl is optionally substituted with one or more R34, and heteroaryl is optionally substituted with one or more R35. In one embodiment, R27 is selected from the group consisting of hydrogen, chloro, lower alkyl, phenyl, heteroaryl, —CN, —C≡CH, —O—R38, —N(R39)—R40, —C(O)—N(R41)—R42, —C(O)—O—R43, —S(O)2—R44, and —N(H)—C(O)—R45, wherein lower alkyl is optionally substituted with one or more R32, phenyl is optionally substituted with one or more R34, and heteroaryl is optionally substituted with one or more R35 and R31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one embodiment, R27 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl. In one embodiment, R27 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl.
  • In one embodiment of a solid form comprising a basic amino acid and a compound of Formula Ia, U is N, W is —CH, V is C—R28, and R28 is selected from the group consisting of hydrogen, chloro, methyl, methoxy, —CN, and —C≡CH. In one embodiment, R28 is selected from the group consisting of hydrogen, chloro, methyl, methoxy, —CN, and —C≡CH and R31 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one embodiment, R28 is hydrogen, chloro, methyl, methoxy, —CN, or —C≡CH and R31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, or 2,5-di-fluoro-phenyl. In one embodiment, R28 is hydrogen, chloro, methyl, methoxy, —CN, or —C≡CH, and R31 is 4-t-butyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl.
  • In one embodiment of a solid form comprising a basic amino acid and a compound of Formula Ia, U and V are C—H, W is C—R27, R27 is chloro, methyl or —CN, R29 is fluoro, R30 is fluoro, and R31 is 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl; or U and W are C—H, V is C—R28, R28 is —CN or —C≡CH, R29 is fluoro, R30 is fluoro, and R31 is 4-trifluoromethyl phenyl; or U is C—H, W is N, V is C—R28, R28 is hydrogen or methoxy, R29 is fluoro, R30 is fluoro, and R31 is 4-t-butyl-phenyl or 4-trifluoromethyl phenyl; or U is C—H, V is N, W is C—R27, R27 is hydrogen, R29 is fluoro, R30 is fluoro, and R31 is 4-trifluoromethyl-phenyl.
  • In one embodiment of a solid form comprising a basic amino acid and a compound of Formula Ia, U and V are C—H, W is C—R27, R27 is chloro, —CN, 4-chloro-phenyl, or 2-methoxy-pyrimidin-5-yl, R29 is hydrogen or fluoro, R30 is fluoro, and R31 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro-phenyl, 2,5-di-fluoro-phenyl.
  • In a seventh aspect, a solid form is provided comprising a basic amino acid and an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound of Formula Ib, wherein Formula Ib is as follows:
  • Figure US20120122860A1-20120517-C00004
  • wherein:
      • R54 is selected from the group consisting of chloro, lower alkyl, phenyl, heteroaryl, —CN, —C≡CH, —O—R62, —N(R63)—R64, —C(O)—N(R65)—R66, —C(O)—O—R67, —S(O)2—R68, and —N(H)—C(O)—R69, wherein lower alkyl is optionally substituted with one or more R57, phenyl is optionally substituted with one or more R58, and heteroaryl is optionally substituted with one or more R59;
      • R55 is hydrogen or fluoro;
      • R56 is selected from the group consisting of lower alkyl, fluoro substituted lower alkyl, mono-alkylamino, di-alkylamino, cycloalkylamino, cycloalkyl, phenyl, and heteroaryl, wherein phenyl is optionally substituted with one or more R60, and heteroaryl is optionally substituted with one or more R61;
      • each R57, when present, is independently fluoro, —OH, lower alkoxy, heteroaryl, chloro substituted heteroaryl, phenyl, chloro substituted phenyl, mono-alkylamino, di-alkylamino, cycloalkylamino, —C(O)—N(R65)—R70, or —C(O)—O—R67;
  • each R58, when present, is independently fluoro, chloro, —CN, —OH, lower alkyl, lower alkenyl, —C(O)—O—R67 substituted lower alkenyl, lower alkoxy, lower alkoxy substituted lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, —S(O)2R71, —N(H)—S(O)2—R71, —N(H)—C(O)—R71, —C(O)—N(R72)—R73, or —S(O)2—N(R74)—R75, wherein lower alkyl is optionally substituted with —C(O)—O—R67, mono-alkylamino, di-alkylamino, or cycloalkylamino;
      • each R59, when present, is independently fluoro, chloro, —OH, —NH2, lower alkyl, lower alkynyl, di-alkylamino substituted lower alkynyl, lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkylamino, phenyl, —C(O)—N(R76)—R77, or —N(H)—C(O)—R71, wherein lower alkyl is optionally substituted with one or more fluoro, alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or phenyl, and wherein lower alkoxy is optionally substituted with —OH, lower alkoxy, mono-alkylamino, di-alkylamino or cycloalkylamino;
      • each R60, when present, is independently fluoro, chloro, —CN, —NO2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, —C(O)—O—R67, —N(H)—C(O)—R71, heteroaryl optionally substituted with one or more lower alkyl, or two R60 on adjacent carbons combine to form a fused heterocycloalkyl optionally substituted with one or more lower alkyl;
      • each R61, when present, is independently lower alkyl, fluoro substituted lower alkyl, lower alkoxy, —C(O)—O—R67, or heteroaryl optionally substituted with one or more lower alkyl;
      • R62 is hydrogen, lower alkyl, cycloalkyl, or heterocycloalkyl, wherein lower alkyl is optionally substituted with —OH, lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, phenyl, or heteroaryl;
      • each R63, R65, and R67, when present, are independently hydrogen or lower alkyl;
      • R64 is hydrogen, lower alkyl, cycloalkyl, phenyl, heteroaryl or combined with the nitrogen and R63 form cycloalkylamino, wherein lower alkyl is optionally substituted with cycloalkylamino, phenyl, heteroaryl or lower alkyl substituted heteroaryl;
      • R66 is hydrogen, lower alkyl, —OH substituted lower alkyl, cycloalkyl or lower alkoxy;
      • R68 is lower alkyl, phenyl or lower alkyl substituted phenyl;
      • R69 is lower alkyl or cycloalkylamino;
      • each R70, when present, is independently hydrogen, lower alkyl, or lower alkoxy;
      • each R71, when present, is independently lower alkyl;
      • each R72 and R73, when present, are independently hydrogen, lower alkyl, or combine with the nitrogen to form cycloalkylamino;
      • each R74 and R75, when present, are independently hydrogen, lower alkyl optionally substituted with —OH, cycloalkyl, or combine with the nitrogen to form cycloalkylamino; and
      • each R76 and R77, when present, are independently hydrogen, lower alkyl, or cycloalkyl.
  • In one embodiment of a solid form comprising a basic amino acid and a compound of Formula Ib, R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one embodiment, R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl and R55 is fluoro. In one embodiment, R54 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl. In one embodiment, R54 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl and R55 is fluoro. In one embodiment, R54 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl. In one embodiment, R54 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl, and R55 is fluoro. In one embodiment, R54 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl. In one embodiment, R54 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl. In one embodiment, R54 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl, and R55 is fluoro. In one embodiment, R54 is chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, R56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl, and R55 is fluoro. In one embodiment, R54 is chloro, methyl or —CN, R56 is 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl, and R55 is fluoro. In one embodiment, R54 is chloro, —CN, 4-chloro-phenyl, or 2-methoxy-pyrimidin-5-yl, R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, or 3-fluoro-phenyl, 2,5-di-fluoro-phenyl, and R55 is fluoro.
  • In an eighth aspect, a solid form is provided comprising a basic amino acid and an N-[3-(5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-phenyl]-sulfonamide compound of Formula Ic, wherein Formula Ic is as follows:
  • Figure US20120122860A1-20120517-C00005
  • wherein
      • R78 is selected from the group consisting of hydrogen, lower alkyl, phenyl, heteroaryl, —CN, —C≡CH, —O—R62, —N(R63)—R64, —C(O)—N(R65)—R66, —C(O)—O—R67, C(O)—O—R67, —S(O)2—R68, and —N(H)—C(O)—R69, wherein lower alkyl is optionally substituted with one or more R57, phenyl is optionally substituted with one or more R58, and heteroaryl is optionally substituted with one or more R59; and
      • R55, R56, R57, R58, R59, R62, R63, R64, R65, R66, R67, R68, and R69, are as defined for Formula Ib.
  • In one embodiment of a solid form comprising a basic amino acid and a compound of Formula Ic, R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one embodiment, R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl and R55 is fluoro. In one embodiment, R78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl. In one embodiment, R78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl and R55 is fluoro. In one embodiment, R78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl. In one embodiment, R78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl, and R55 is fluoro. In one embodiment, R78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl. In one embodiment, R78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl. In one embodiment, R78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl, and R55 is fluoro. In one embodiment, R78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, R56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl, and R55 is fluoro. In one embodiment, R78 is hydrogen, R56 is 4-trifluoromethyl phenyl, and R55 is fluoro.
  • In a ninth aspect, a solid form is provided comprising a basic amino acid and an N-[3-(1H-Pyrazolo[3,4-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound of Formula Id, wherein Formula Id is as follows:
  • Figure US20120122860A1-20120517-C00006
  • wherein R54, R55, and R56 are as defined for Formula Ib and R78 is as defined for Formula Ic.
  • In one embodiment of a solid form comprising a basic amino acid and a compound of Formula Id, R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one embodiment, R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl and R55 is fluoro. In one embodiment, R78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl. In one embodiment, R78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl and R55 is fluoro. In one embodiment, R78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl. In one embodiment, R78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl, and R55 is fluoro. In one embodiment, R78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl. In one embodiment, R78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, and R56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl. In one embodiment, R78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl, and R55 is fluoro. In one embodiment, R78 is hydrogen, chloro, methyl, —CN, chloro substituted phenyl, or methoxy substituted pyrimidinyl, R56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl, and R55 is fluoro. In one embodiment, R78 is hydrogen or —CN, and R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl. In one embodiment, R78 is hydrogen or —CN and R56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl. In one embodiment, R78 is hydrogen or —CN, R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl, and R55 is fluoro. In one embodiment, R78 is hydrogen or —CN, R56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl, and R55 is fluoro. In one embodiment, R78 is hydrogen or —CN and R56 is n-propyl. In one embodiment, R78 is hydrogen or —CN, R56 is n-propyl, and R55 is fluoro.
  • In a tenth aspect, a solid form is provided comprising a basic amino acid and an N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound of Formula Ie, wherein Formula Ie is as follows:
  • Figure US20120122860A1-20120517-C00007
  • wherein:
      • R79 is selected from the group consisting of chloro, methyl, methoxy, —CN, and —C≡CH;
      • R55 is hydrogen or fluoro;
      • R56 is selected from the group consisting of lower alkyl, fluoro substituted lower alkyl, mono-alkylamino, di-alkylamino, cycloalkylamino, cycloalkyl, phenyl, and heteroaryl, wherein phenyl is optionally substituted with one or more R60, and heteroaryl is optionally substituted with one or more R61;
      • R60 is fluoro, chloro, —CN, —NO2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, heteroaryl optionally substituted with lower alkyl, —C(O)—O—R67, —N(H)—C(O)—R71, or two R60 on adjacent carbons combine to form a fused heterocycloalkyl optionally substituted with lower alkyl;
      • R61 is lower alkyl, fluoro substituted lower alkyl, lower alkoxy, heteroaryl optionally substituted with lower alkyl, or —C(O)—O—R67;
      • R67 is hydrogen or lower alkyl; and
      • R71 is lower alkyl.
  • In one embodiment of a solid form comprising a basic amino acid and a compound of Formula Ie, R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one embodiment, R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl and R55 is fluoro. In one embodiment, R79 is —CN, or —C≡CH, and R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl. In one embodiment, R79 is —CN, or —C≡CH, R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl and R55 is fluoro. In one embodiment, R79 is —CN, or —C≡CH, and R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl. In one embodiment, R79 is —CN, or —C≡CH, R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl and R55 is fluoro. In one embodiment, R79 is —CN, or —C≡CH, and R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl. In one embodiment, R79 is —CN, or —C≡CH, R56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl, and R55 is fluoro. In one embodiment, R79 is —CN, or —C≡CH, R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl, and R55 is fluoro. In one embodiment, R79 is —CN, or —C≡CH, and R56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl. In one embodiment, R79 is —CN, or —C≡CH, R56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl, and R55 is fluoro. In one embodiment, R79 is —CN, or —C≡CH, and R56 is 4-trifluoromethyl phenyl. In one embodiment, R79 is —CN, or —C≡CH, R56 is 4-trifluoromethyl phenyl and R55 is fluoro.
  • In an eleventh aspect, a solid form is provided comprising a basic amino acid and an N-[3-(7H-Pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-sulfonamide compound of Formula If, wherein Formula If is as follows:
  • Figure US20120122860A1-20120517-C00008
  • wherein:
      • R8° is hydrogen, methyl, methoxy, —CN, or —C≡CH; and
      • R55 and R56 are as defined for Formula Ib.
  • In one embodiment of a solid form comprising a basic amino acid and a compound of Formula If, R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one embodiment, R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl and R55 is fluoro. In one embodiment, R80 is hydrogen or methoxy and R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl. In one embodiment, R80 is hydrogen or methoxy, and R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl and R55 is fluoro. In one embodiment, R80 is hydrogen or methoxy, and R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl. In one embodiment, R80 is hydrogen or methoxy, R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl and R55 is fluoro. In one embodiment, R80 is hydrogen or methoxy, and R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl. In one embodiment, R80 is hydrogen or methoxy, and R56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl. In one embodiment, R80 is hydrogen or methoxy, R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl, and R55 is fluoro. In one embodiment, R80 is hydrogen or methoxy, R56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl and R55 is fluoro. In one embodiment, R80 is hydrogen or methoxy, and R56 is 4-t-butyl-phenyl or 4-trifluoromethyl phenyl. In one embodiment, R80 is hydrogen or methoxy, R56 is 4-t-butyl-phenyl or 4-trifluoromethyl phenyl and R55 is fluoro.
  • In a twelfth aspect, a solid form is provided comprising a basic amino acid and an N-[3-(1H-Pyrazolo[3,4-b]pyridine-3-carbonyl)-phenyl]-sulfonamide compound of Formula Ig, wherein Formula Ig is as follows:
  • Figure US20120122860A1-20120517-C00009
  • wherein:
  • R55, and R56 are as defined for Formula Ib, and R80 is as defined in Formula If.
  • In one embodiment of a solid form comprising a basic amino acid and a compound of Formula Ig, R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl. In one embodiment, R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl and R55 is fluoro. In one embodiment, R80 is hydrogen, methoxy, —CN, or —C≡CH, and R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl. In one embodiment, R80 is hydrogen, methoxy, —CN, or —C≡CH, and R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or trifluoromethyl and R55 is fluoro. In one embodiment, R80 is hydrogen, methoxy, —CN, or —C≡CH, and R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl. In one embodiment, R80 is hydrogen, methoxy, —CN, or —C≡CH, R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, fluoro substituted phenyl, di-fluoro substituted phenyl, t-butyl substituted phenyl or trifluoromethyl substituted phenyl and R55 is fluoro. In one embodiment, R80 is hydrogen, methoxy, —CN, or —C≡CH, and R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl. In one embodiment, R80 is hydrogen, methoxy, —CN, or —C≡CH, and R56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl. In one embodiment, R80 is hydrogen, methoxy, —CN, or —C≡CH, R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl, and R55 is fluoro. In one embodiment, R80 is hydrogen, methoxy, —CN, or —C≡CH, R56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl, and R55 is fluoro.
  • In a thirteenth aspect, a solid form is provided comprising arginine and a compound of Formula I, Ia, Ib, Ic, Id, Ie, If or Ig, or any embodiment herein above.
  • In a fourteenth aspect, a solid form is provided comprising lysine and a compound of Formula I, Ia, Ib, Ic, Id, Ie, If or Ig, or any embodiment herein above.
  • In a fifteenth aspect, a solid form is provided comprising a basic amino acid and a compound of Formula Ib, Ic, Id, Ie, If or Ig, or any embodiments herein above. In certain embodiments, the solid form comprises arginine and a compound of Formula Ib, Ic, Id, Ie, If or Ig, or any embodiment herein above. In certain embodiments, the solid form comprises lysine and a compound of Formula Ib, Ic, Id, Ie, If or Ig, or any embodiment herein above.
  • In a sixteenth aspect, a solid form is provided comprising a complex of arginine and a compound of any of Formula I, Ia, Ib, Ic, Id, Ie, If, or Ig. In one embodiment, a composition is provided comprising said complex. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of pain or polycystic kidney disease. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of melanoma, thyroid cancer, ovarian cancer, cholangiocarcinoma or colorectal cancer. In one embodiment, the complex is an amorphous solid. In one embodiment, the composition comprises an amorphous complex of arginine and the compound, and further comprises a crystalline form of the compound, preferably crystalline free base of the compound. In one embodiment, the composition comprises the amorphous complex and 0-80% crystalline compound, also 0-50%, 0-20%, 0-10%, 0-5%, or 0-2% crystalline compound.
  • In a seventeenth aspect, a solid form is provided comprising a complex of lysine and a compound of any of Formula I, Ia, Ib, Ic, Id, Ie, If, or Ig. In one embodiment, a composition is provided comprising said complex. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of pain or polycystic kidney disease. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of melanoma, thyroid cancer, ovarian cancer, cholangiocarcinoma or colorectal cancer. In one embodiment, the complex is an amorphous solid. In one embodiment, the composition comprises an amorphous complex of lysine and the compound, and further comprises a crystalline form of the compound, preferably crystalline free base of the compound. In one embodiment, the composition comprises the amorphous complex and 0-80% crystalline compound, also 0-50%, 0-20%, 0-10%, 0-5%, or 0-2% crystalline compound.
  • In an eighteenth aspect, a solid form is provided comprising a ternary complex of arginine, a strong acid, and a compound of any of Formula I, Ia, Ib, Ic, Id, Ie, If or Ig. In one embodiment, the strong acid is hydrochloric acid. In one embodiment, the ternary complex is an amorphous solid. In one embodiment, the ternary complex is a ternary co-crystal. In one embodiment, a composition is provided comprising said complex. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of pain or polycystic kidney disease. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of melanoma, thyroid cancer, ovarian cancer, cholangiocarcinoma or colorectal cancer.
  • In a nineteenth aspect, a solid form is provided comprising a ternary complex of lysine, a strong acid, and a compound of any of Formula I, Ia, Ib, Ic, Id, Ie, If or Ig. In one embodiment, the strong acid is hydrochloric acid. In one embodiment, the ternary complex is an amorphous solid. In one embodiment, the ternary complex is a ternary co-crystal. In one embodiment, a composition is provided comprising said complex. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of pain or polycystic kidney disease. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of melanoma, thyroid cancer, ovarian cancer, cholangiocarcinoma or colorectal cancer.
  • In a twentieth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide (P-1001),
    • N-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-1002),
    • N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-1003),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide (P-1012),
    • N-[2,4-Difluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-1013),
    • N-{3-[(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-benzenesulfonamide (P-1014),
    • N-{2,4-Difluoro-3-[(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-phenyl}-benzenesulfonamide (P-1015),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide (P-1017),
    • N-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-benzenesulfonamide (P-1018), and
    • N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]benzenesulfonamide (P-1097).
  • In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a twenty-first aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide (P-1004),
    • N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1005),
    • 4-Butoxy-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-1006),
    • 4-Chloro-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-1007),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-methoxy-benzenesulfonamide (P-1016),
    • N-{3-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-1019),
    • N-{2,4-Difluoro-3-[hydroxy-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-1020),
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1022),
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro-benzenesulfonamide (P-1024),
    • N-{3-[5-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-1030),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-ethyl-benzenesulfonamide (P-1031),
    • N-[3-(5-Ethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1032),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-cyano-benzenesulfonamide (P-1033),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-isopropyl-benzenesulfonamide (P-1035),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-fluoro-benzenesulfonamide (P-1036),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-methyl-benzenesulfonamide (P-1038),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-oxazol-5-yl-benzenesulfonamide (P-1039),
    • N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro-benzenesulfonamide (P-1040),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-fluoro-benzenesulfonamide (P-1042),
    • N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-1043),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-1045),
    • N-{4-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-phenyl}-acetamide (P-1047),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-difluoromethoxy-benzenesulfonamide (P-1049),
    • N-{4-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}-acetamide (P-1060),
    • N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonamide (P-1066),
    • N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-isopropyl-benzenesulfonamide (P-1069),
    • N-(2,4-Difluoro-3-{5-[4-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-4-trifluoromethyl-benzenesulfonamide (P-1071),
    • 4-Butoxy-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide (P-1073),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-pyrazol-1-yl-benzenesulfonamide (P-1074),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-isopropoxy-benzenesulfonamide (P-1075),
    • 4-tert-Butyl-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide (P-1076),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-propyl-benzenesulfonamide (P-1077),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide (P-1079),
    • N-{2,4-Difluoro-3-[5-(4-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide (P-1080),
    • 3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-1081),
    • N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide (P-1082),
    • N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide (P-1083),
    • N-{2,4-Difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide (P-1084),
    • N-{2,4-Difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-1086),
    • N-{2,4-Difluoro-3-[5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide (P-1087),
    • N-{3-[5-(1,5-Dimethyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-4-propyl-benzenesulfonamide (P-1088),
    • N-{2,4-Difluoro-3-[hydroxy-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-1090),
    • (E)-3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acrylic acid methyl ester (P-1093),
    • 3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid methyl ester (P-1094),
    • 3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid (P-1095),
    • 3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-propionamide (P-1096),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-fluoro-benzenesulfonamide (P-2026),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro-benzenesulfonamide (P-2027),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-fluoro-benzenesulfonamide (P-2028),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-fluoro-benzenesulfonamide (P-2035),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-fluoro-benzenesulfonamide (P-2040),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2047),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-fluoro-benzenesulfonamide (P-2050),
    • N-[2-Fluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2060),
    • N-[2,4-Difluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2482),
    • N-[3-(5-Cyclopropyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2483),
    • N-[3-(5-Ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2484),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-propyl-benzenesulfonamide (P-2486), and
    • N-[3-(4-Ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2487).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a twenty-second aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]-3-methoxy-benzenesulfonamide (P-1008),
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-1023),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide (P-1025),
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide (P-1026),
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide (P-1027),
    • N-[2,4-Difluoro-3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide (P-1029),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide (P-1041),
    • N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide (P-1044),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-methoxy-benzenesulfonamide (P-1046),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-methyl-benzenesulfonamide (P-1055),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-cyano-benzenesulfonamide (P-1058),
    • N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-nitro-benzenesulfonamide (P-1059),
    • N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-methyl-benzenesulfonamide (P-1065),
    • 3-Cyano-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-1068),
    • N-{2,4-Difluoro-3-[5-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide (P-1070),
    • 3-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-benzoic acid (P-1072),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-difluoromethoxy-benzenesulfonamide (P-1078),
    • 3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-1085),
    • N-(2,4-Difluoro-3-{hydroxy-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methyl}-phenyl)-3-fluoro-benzenesulfonamide (P-1089),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-2016),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide (P-2019),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-2023),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide (P-2039),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide (P-2045), and
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-fluoro-benzenesulfonamide (P-2053).
  • In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a twenty-third aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3,4-dimethoxy-benzenesulfonamide (P-1009),
    • 3,4-Dichloro-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-1010),
    • N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-dimethoxy-benzenesulfonamide (P-1011),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-4-methyl-benzenesulfonamide (P-1034),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3,5-difluoro-benzenesulfonamide (P-1037),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide (P-1048),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,4-dimethoxy-benzenesulfonamide (P-1050),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-methyl-benzenesulfonamide (P-1051),
    • 2,3-Dihydro-benzo[1,4]dioxine-6-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1052),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,4-difluoro-benzenesulfonamide (P-1053),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-5-fluoro-2-methyl-benzenesulfonamide (P-1054),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-dimethoxy-benzenesulfonamide (P-1056),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-cyano-benzenesulfonamide (P-1057),
    • N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,4-dimethoxy-benzenesulfonamide (P-1061),
    • N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-methyl-benzenesulfonamide (P-1062),
    • 2,3-Dihydro-benzo[1,4]dioxine-6-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1063),
    • N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-5-fluoro-2-methyl-benzenesulfonamide (P-1064),
    • 2-Cyano-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-1067),
    • 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2001),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2002),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2003),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3,5-dimethyl-benzenesulfonamide (P-2004),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-4-methoxy-benzenesulfonamide (P-2005),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-fluoro-2-methyl-benzenesulfonamide (P-2006),
    • 2,3-Dihydro-benzofuran-5-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2007),
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-fluoro-benzenesulfonamide (P-2009),
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-2010),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2011),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-fluoro-benzenesulfonamide (P-2014),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-2015),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2017),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2018),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2020),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-fluoro-benzenesulfonamide (P-2021),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-2022),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,6-difluoro-benzenesulfonamide (P-2024),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,4-difluoro-benzenesulfonamide (P-2025),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2029),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,4-difluoro-benzenesulfonamide (P-2030),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,6-difluoro-benzenesulfonamide (P-2031),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,4-difluoro-benzenesulfonamide (P-2032),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2033),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,4-difluoro-benzenesulfonamide (P-2034),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2036),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2037),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,4-difluoro-benzenesulfonamide (P-2038),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2-fluoro-benzenesulfonamide (P-2041),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-2042),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,6-difluoro-benzenesulfonamide (P-2043),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,4-difluoro-benzenesulfonamide (P-2044),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide (P-2046),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2051),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2052),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2054),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,4-difluoro-benzenesulfonamide (P-2055), and
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-benzenesulfonamide (P-2056).
  • In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a twenty-fourth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1098),
    • Thiophene-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1099),
    • Thiophene-3-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1100),
    • Benzo[b]thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1101),
    • 5-Pyridin-2-yl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1102),
    • 5-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-furan-2-carboxylic acid methyl ester (P-1103),
    • 5-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-2-methyl-furan-3-carboxylic acid methyl ester (P-1104),
    • 1,2-Dimethyl-1H-imidazole-4-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1105),
    • 2,5-Dimethyl-thiophene-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1106),
    • 2,5-Dimethyl-furan-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1107),
    • 2,4-Dimethyl-thiazole-5-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1108),
    • 5-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenylsulfamoyl]-furan-2-carboxylic acid methyl ester (P-1109),
    • 5-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenylsulfamoyl]-2-methyl-furan-3-carboxylic acid methyl ester (P-1110),
    • 5-Oxazol-5-yl-thiophene-2-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1111),
    • 5-Isoxazol-5-yl-thiophene-2-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1112),
    • 2,5-Dimethyl-thiophene-3-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1113),
    • 2,5-Dimethyl-furan-3-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1114),
    • 2,4-Dimethyl-thiazole-5-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1115),
    • Benzothiazole-6-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1116),
    • Benzo[b]thiophene-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1117),
    • 5-Methyl-2-trifluoromethyl-furan-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1118),
    • 5-Oxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1119),
    • 2-Oxo-2H-chromene-6-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1120),
    • 5-Isoxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1121),
    • Benzothiazole-6-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1122),
    • 1-Methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1123),
    • Benzo[1,2,5]thiadiazole-5-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1124),
    • 5-Methyl-benzo[b]thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1125),
    • 5-Methyl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1126),
    • 1-Methyl-1H-pyrazole-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1127),
    • Pyridine-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1128),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2061),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2062),
    • Pyridine-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2063),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2064),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2065),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2066),
    • Pyridine-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2067),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2068),
    • Pyridine-3-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2069),
    • Pyridine-2-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2070),
    • Pyridine-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2071),
    • Pyridine-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2072),
    • Pyridine-3-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2073),
    • Pyridine-3-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2074),
    • Pyridine-2-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2075),
    • Pyridine-2-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2076),
    • Pyridine-3-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2077),
    • Pyridine-2-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2078),
    • Pyridine-2-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2079),
    • 2H-[1,2,4]Triazole-3-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2080),
    • 5-Methyl-isoxazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2081),
    • 1,5-Dimethyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2082),
    • 1-Ethyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2083),
    • 1-Methyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2084),
    • 6-Methoxy-pyridine-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2085),
    • Pyridine-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2086),
    • Pyridine-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2087),
    • 5-Methyl-isoxazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2088),
    • 1-Ethyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2089),
    • 1-Methyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2090),
    • 1,5-Dimethyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2091),
    • 6-Methoxy-pyridine-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2092),
    • 6-Trifluoromethyl-pyridine-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2481), and
    • 5-Trifluoromethyl-pyridine-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2485).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a twenty-fifth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-C-pyridin-2-yl-methanesulfonamide (P-2093),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-C-pyridin-3-yl-methanesulfonamide (P-2094),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-C-pyridin-4-yl-methanesulfonamide (P-2095),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-pyridin-3-yl-methanesulfonamide (P-2096),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-pyridin-4-yl-methanesulfonamide (P-2097), and
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-pyridin-2-yl-methanesulfonamide (P-2098).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a twenty-sixth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • 4-Fluoro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2100),
    • N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-2104),
    • 4-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-benzenesulfonamide (P-2106),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-fluoro-benzenesulfonamide (P-2107),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-trifluoromethoxy-benzenesulfonamide (P-2109),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2112),
    • 4-Chloro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2113), 4-Fluoro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2114),
    • N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide (P-2116),
    • N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2119),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro-benzenesulfonamide (P-2121),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide (P-2123),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2126),
    • 4-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2128),
    • 4-Chloro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2129),
    • 4-Fluoro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2130),
    • N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethoxy-benzenesulfonamide (P-2132), and
    • N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-2135).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a twenty-seventh aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-[4-Chloro-3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-1129),
    • N-[4-Chloro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-1130),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-fluoro-benzenesulfonamide (P-1131),
    • 4-Cyano-N-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-1132),
    • N-[3-(1H-Pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1133),
    • N-{2-Chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-difluoromethoxy-benzenesulfonamide (P-2099),
    • N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-trifluoromethyl-benzenesulfonamide (P-2101),
    • N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-trifluoromethoxy-benzenesulfonamide (P-2102),
    • 3-Chloro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2103),
    • 3-Fluoro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2105),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-trifluoromethyl-benzenesulfonamide (P-2108),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-trifluoromethoxy-benzenesulfonamide (P-2110),
    • 3-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-benzenesulfonamide (P-2111),
    • N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide (P-2115),
    • N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluoromethoxy-benzenesulfonamide (P-2117),
    • 3-Chloro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2118),
    • 3-Fluoro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2120),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide (P-2122),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluoromethoxy-benzenesulfonamide (P-2124),
    • 3-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2125),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-2127),
    • N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-trifluoromethyl-benzenesulfonamide (P-2131),
    • N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-trifluoromethoxy-benzenesulfonamide (P-2133),
    • 3-Chloro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2134), and
    • 3-Fluoro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2136).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a twenty-eighth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Pyridine-3-sulfonic acid [4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2137),
    • Pyridine-3-sulfonic acid {4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2138),
    • Pyridine-3-sulfonic acid {4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2139),
    • Pyridine-3-sulfonic acid{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2140),
    • Pyridine-3-sulfonic acid [3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2141),
    • Pyridine-3-sulfonic acid [3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2142),
    • Pyridine-3-sulfonic acid [3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2143),
    • Pyridine-3-sulfonic acid {3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2144),
    • Pyridine-3-sulfonic acid {3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2145),
    • Pyridine-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2146),
    • 3-{3-[3-(Pyridine-3-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzamide (P-2147),
    • 3-(3-{3-[3-(Pyridine-3-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-phenyl)-propionic acid (P-2148),
    • Pyridine-3-sulfonic acid {3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2149), and
    • N-(6-Acetylamino-pyridin-3-yl)-3-benzenesulfonylamino-2,6-difluoro-benzamide (P-2472).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a twenty-ninth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-1134),
    • N-{2,4-Difluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-methanesulfonamide (P-1135),
    • N-{2,4-Difluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-methanesulfonamide (P-1136),
    • N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-methanesulfonamide (P-1137), 3-[3-(2,6-Difluoro-3-methanesulfonylamino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide (P-1138),
    • N-[2,4-Difluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-1139),
    • N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-1140),
    • N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-methanesulfonamide (P-1141),
    • N-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-methanesulfonamide (P-1142),
    • N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-chloro-2-fluoro-phenyl]-methanesulfonamide (P-1249),
    • N-{4-Chloro-2-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-methanesulfonamide (P-1250),
    • N-[4-Chloro-2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-1251),
    • N-{4-Chloro-2-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-methanesulfonamide (P-1252),
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-2288),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-2289),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-methanesulfonamide (P-2290),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-methanesulfonamide (P-2291),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-methanesulfonamide (P-2292),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-2293),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-methanesulfonamide (P-2294), and
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-methanesulfonamide (P-2295).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a thirtieth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Ethanesulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1143),
    • Propane-2-sulfonic acid {3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-amide (P-1144),
    • Propane-2-sulfonic acid {3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methoxy-methyl]-2,4-difluoro-phenyl}-amide (P-1145),
    • Propane-2-sulfonic acid {2,4-difluoro-3-[methoxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (P-1146),
    • Propane-2-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-amide (P-1147),
    • Propane-2-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1148),
    • Propane-2-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amide (P-1149),
    • Ethanesulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2268),
    • Ethanesulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2269),
    • Ethanesulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2270),
    • Ethanesulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2271),
    • Ethanesulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2272),
    • Propane-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2273),
    • Ethanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2274),
    • Propane-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2275),
    • Ethanesulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2276),
    • Ethanesulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2277),
    • Propane-2-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2278),
    • Ethanesulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2279),
    • Propane-2-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2280),
    • Ethanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2281),
    • Propane-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2282),
    • Ethanesulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2283),
    • Propane-2-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2284),
    • Propane-2-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2285),
    • Ethanesulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2286),
    • Propane-2-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2287),
    • Ethanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2410), and
    • Propane-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2411).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a thirty-first aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1150),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1151),
    • Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1152),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1153),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1154),
    • Propane-1-sulfonic acid {3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-amide (P-1155),
    • Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-amide (P-1156),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-phenylamino-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amide (P-1157),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-phenylamino-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1158),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methyl-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1159),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1160),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(5-phenylamino-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (P-1161),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(5-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (P-1162),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (P-1163),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[methoxy-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (P-1164),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amide (P-1165),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amide (P-1166),
    • Propane-1-sulfonic acid {3-[5-(4-dimethylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-1168),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1169),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1170),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1171),
    • Propane-1-sulfonic acid {3-[5-(3-dimethylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-1172),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methyl-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-phenyl}-amide (P-1173),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1175),
    • Propane-1-sulfonic acid {3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methoxy-methyl]-2,4-difluoro-phenyl}-amide (P-1176),
    • Propane-1-sulfonic acid {3-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-amide (P-1177),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (P-1178),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(5-isopropenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (P-1179),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-isopropenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1180),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-isopropyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1181),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(5-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (P-1182),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (P-1183),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1184),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[methoxy-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (P-1185),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amide (P-1186),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (P-1187),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[methoxy-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (P-1188),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{hydroxy-[5-(4-methyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methyl}-phenyl)-amide (P-1189),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amide (P-1190),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1191),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[2-(4-methyl-piperazin-1-yl)-ethylamino]-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl}-phenyl)-amide (P-1192),
    • Propane-1-sulfonic acid [3-(5-ethoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1193),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1194),
    • Propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-amide (P-1195),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amide (P-1196),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1197),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1198),
    • Propane-1-sulfonic acid [2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1199),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-pyridin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1200),
    • 3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzoic acid (P-1204),
    • 3-3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-acrylic acid (P-1205),
    • 3-3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-propionic acid (P-1206),
    • 3-[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-hydroxy-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (P-1207),
    • 4{-3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzamide (P-1208),
    • 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N,N-dimethyl-benzamide (P-1209),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(morpholine-4-carbonyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-1210),
    • 3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzamide (P-1211),
    • 3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (P-1212),
    • 3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (P-1213),
    • 3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethylamide (P-1214),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1215),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-morpholin-4-yl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1216),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-morpholin-4-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1217),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1218),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-morpholin-4-yl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1219),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-1220),
    • Propane-1-sulfonic acid {3-[5-(4-cyano-3,5-dimethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-1221),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-1222),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1223),
    • 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2,N,N-trimethyl-benzamide (P-1224),
    • Propane-1-sulfonic acid [3-(5-benzyloxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1225),
    • Propane-1-sulfonic acid [3-(5-cyclopentyloxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1226),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1227),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(tetrahydro-pyran-4-yloxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1228),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1229),
    • 5-(3-{[2,6-Difluoro-3-(propane-1-sulfonylamino)-phenyl]-hydroxy-methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid ethylamide (P-2150),
    • 5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridine-2-carboxylic acid ethylamide (P-2151),
    • Propane-1-sulfonic acid {3-[5-(1,5-dimethyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2152),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2153),
    • Propane-1-sulfonic acid {3-[5-(6-chloro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2154),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-fluoro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2155),
    • Propane-1-sulfonic acid {3-[5-(3,5-dimethyl-isoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2156),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(I-isobutyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2157),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2158),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-3-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2159),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-3-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2160),
    • N-(4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-phenyl)-acetamide (P-2161),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2162),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-fluoro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2164),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2165),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(morpholine-4-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2166),
    • 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2167),
    • N-Cyclopropyl-4-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzenesulfonamide (P-2168),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2169),
    • 3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2170),
    • Propane-1-sulfonic acid {3-[5-(4-chloro-3-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2171),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-fluoro-6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2172),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2173),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2174),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2175),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2176),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[I-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2177),
    • Propane-1-sulfonic acid (3-{5-[6-(3-dimethylamino-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2178),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-hydroxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2179),
    • 5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridine-2-carboxylic acid methylamide (P-2180),
    • 5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridine-2-carboxylic acid cyclopropylamide (P-2181),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2182),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (P-2473),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2183),
    • Propane-1-sulfonic acid {3-[5-(2,6-dimethoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2184),
    • 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N,N-dimethyl-benzenesulfonamide (P-2185),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(piperidine-1-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2186),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-methylsulfanyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2187),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(5-methanesulfonyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2188),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methylsulfanyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2189),
    • Propane-1-sulfonic acid {3-[5-(1-benzyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2190),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2191),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-fluoro-pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2192),
    • N-(5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridin-2-yl)-acetamide (P-2193),
    • 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzenesulfonamide (P-2194),
    • Propane-1-sulfonic acid {3-[5-(2,5-dimethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2195),
    • Propane-1-sulfonic acid {3-[5-(2-dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2196),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-morpholin-4-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2197),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-hydroxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2198),
    • Propane-1-sulfonic acid {3-[5-(2,4-dimethoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2199),
    • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methylamide (P-2200),
    • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid cyclopropylamide (P-2201),
    • Propane-1-sulfonic acid (3-{5-[2-(3-dimethylamino-propoxy)-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2203),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-hydroxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2204),
    • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (P-2207),
    • Propane-1-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2208),
    • Propane-1-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2209),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2210),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2211),
    • Propane-1-sulfonic acid {3-[5-(2-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2212),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2213),
    • Propane-1-sulfonic acid {3-[5-(6-amino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2214),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(2-hydroxy-ethoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2215),
    • Propane-1-sulfonic acid (3-{5-[6-(3-diethylamino-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2216),
    • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (2-hydroxy-ethyl)-amide (P-2217),
    • Propane-1-sulfonic acid {3-[5-(4-ethanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2218),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2219),
    • 5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridine-2-carboxylic acid amide (P-2220),
    • 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-(2-hydroxy-ethyl)-benzenesulfonamide (P-2221),
    • Propane-1-sulfonic acid (3-{5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2222),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(propane-2-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2223),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-propyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2224),
    • (E)-3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acrylic acid methyl ester (P-2225),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(3-methoxy-propyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2226),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2227),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2228),
    • Propane-1-sulfonic acid {3-[5-(6-dimethylamino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2229),
    • 3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid methyl ester (P-2230),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-pyrrolidin-1-yl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2231),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(2-morpholin-4-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2232),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(2-pyrrolidin-1-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2233),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-hydroxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2234),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(3-pyrrolidin-1-yl-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2235),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(3-morpholin-4-yl-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2236),
    • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid dimethyl amide (P-2237),
    • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methoxy-amide (P-2238),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2239),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-methoxy-propyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2240),
    • Propane-1-sulfonic acid {3-[5-(3-diethylamino-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2241), Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2H-tetrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2242),
    • 3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-methoxy-propionamide (P-2243),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-morpholin-4-ylmethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2244),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-morpholin-4-yl-propyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2247),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-pyrrolidin-1-yl-propyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2248),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-hydroxymethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2250),
    • 3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N,N-diethyl-propionamide (P-2255),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2257),
    • Propane-1-sulfonic acid [3-(5-diethylaminomethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2258),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-pyrrolidin-1-ylmethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2259),
    • Propane-1-sulfonic acid [3-(5-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2260), and
    • Propane-1-sulfonic acid [3-(4-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2261).
  • In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a thirty-second aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-1240),
    • Propane-1-sulfonic acid [2-fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1241),
    • Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl}-amide (P-1242),
    • Propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-1243),
    • Propane-1-sulfonic acid [2-fluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1244),
    • Propane-1-sulfonic acid [2-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1245),
    • Propane-1-sulfonic acid [2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1247),
    • Propane-1-sulfonic acid [2-fluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1248),
    • Propane-1-sulfonic acid [2-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2403),
    • 3-[2-Fluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (P-2404),
    • 3-[2-Fluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (P-2406),
    • Propane-1-sulfonic acid {2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2407),
    • Propane-1-sulfonic acid {3-[5-(2-dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl}-amide (P-2408),
    • Propane-1-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2409), and
    • Propane-1-sulfonic acid [2-fluoro-3-(5-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2480).
  • In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a thirty-third aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Butane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1201),
    • Butane-1-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1202),
    • Butane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1203),
    • Butane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-1246),
    • 2-Methyl-propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2296),
    • 2-Methyl-propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2297),
    • 2-Methyl-propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2298),
    • 2-Methyl-propane-1-sulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2299),
    • Butane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2300),
    • Butane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2301),
    • Butane-1-sulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2302),
    • 2-Methyl-propane-1-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2303),
    • 2-Methyl-propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2304),
    • 2-Methyl-propane-1-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2305),
    • 2-Methyl-propane-1-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2306),
    • 2-Methyl-propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2307),
    • Butane-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2308),
    • Pentane-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2309),
    • Butane-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2310),
    • Pentane-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2311),
    • Butane-2-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2312),
    • Butane-2-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2313),
    • Pentane-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2314),
    • Pentane-2-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2315),
    • Pentane-2-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2316),
    • Butane-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2317),
    • 2-Methyl-propane-1-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2318),
    • Butane-2-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2319),
    • 2-Methyl-propane-1-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2320),
    • Butane-2-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2321),
    • 2-Methyl-propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2322),
    • Butane-2-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2323),
    • 2-Methyl-propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2412), and
    • Butane-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2413).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a thirty-fourth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2324),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2325),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2326),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2327),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2328),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2329),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2330),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2331),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2332),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2333),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2415), and
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2478).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a thirty-fifth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2334),
    • 2,2,2-Trifluoro-ethanesulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2335),
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2336),
    • 2,2,2-Trifluoro-ethanesulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2337),
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2338),
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2339),
    • 2,2,2-Trifluoro-ethanesulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2340),
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2341),
    • 2,2,2-Trifluoro-ethanesulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2342),
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2414).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a thirty-sixth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-{3-[5-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2343),
    • N-{2,4-Difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2344),
    • N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2345),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-C,C,C-trifluoro-methanesulfonamide (P-2346),
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-C,C,C-trifluoro-methanesulfonamide (P-2347), and
    • N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-C,C,C-trifluoro-methanesulfonamide (P-2479).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a thirty-seventh aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
  • Cyclopropanesulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2348),
    • 1-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-cyclopropanecarboxylic acid (P-2349),
    • Cyclopropanesulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2350),
    • Cyclopropanesulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2351),
    • Cyclopropanesulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2352),
    • Cyclobutanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2353),
    • Cyclobutanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2354),
    • Cyclohexanesulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2355),
    • Cyclopentanesulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2356),
    • Cyclohexanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2357),
    • Cyclopentanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2358),
    • Cyclopentanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2359),
    • Cyclohexanesulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2360),
    • Cyclohexanesulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2361),
    • Cyclobutanesulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2362),
    • Cyclobutanesulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2363),
    • Cyclobutanesulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2364),
    • Cyclopentanesulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2365),
    • Cyclohexanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2366),
    • Cyclohexanesulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2367),
    • Cyclopentanesulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2368),
    • Cyclohexanesulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2369),
    • Cyclobutanesulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2370),
    • Cyclohexanesulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2371),
    • Cyclopentanesulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2372),
    • Cyclobutanesulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2373),
    • Cyclohexanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2416),
    • Cyclopentanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2417), and
    • Cyclobutanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2418).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a thirty-eighth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Dimethylamino-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (P-1230),
    • N,N-dimethylamino-1-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amide (P-1231),
    • N,N-diemethylamino-1-sulfonic acid [3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1232),
    • N,N-diemethylamino-1-sulfonic acid [3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1233),
    • N,N-diemethylamino-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1234),
    • N,N-diemethylamino-sulfonic acid [2,4-difluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1235),
    • Piperidine-1-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1236),
    • Piperidine-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1237),
    • Dimethylamine-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-1238),
    • Dimethylamine-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1239),
    • Pyrrolidine-1-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2374),
    • Pyrrolidine-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2375),
    • N,N-dimethylamino-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2376),
    • Pyrrolidine-1-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2377),
    • N,N-diethylamino-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2378),
    • Pyrrolidine-1-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2379),
    • N,N-dimethylamino-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2382),
    • N,N-dimethylamino-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2383),
    • N,N-diethylamino-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2384),
    • N,N-diethylamino-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2385),
    • N,N-diethylamino-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2386),
    • N,N-diethylamino-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2387),
    • N,N-diethylamino-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2388),
    • N,N-diethylamino-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2389),
    • Morpholine-4-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2390),
    • Morpholine-4-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2391),
    • Morpholine-4-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2392),
    • Morpholine-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2393),
    • Pyrrolidine-1-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2394),
    • Morpholine-4-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2395),
    • Morpholine-4-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2396),
    • Morpholine-4-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2397),
    • Pyrrolidine-1-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2398),
    • N,N-dimethylamino-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2399),
    • Pyrrolidine-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2400),
    • N,N-diethylamino-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2401),
    • Morpholine-4-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2402),
    • N,N-dimethylamino-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2419),
    • Pyrrolidine-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2420),
    • Morpholine-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2421),
    • Pyrrolidine-1-sulfonic acid {2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2422),
    • N,N-dimethylamino-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl}-amide (P-2423),
    • N,N-dimethylamino-sulfonic acid {2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2424),
    • Pyrrolidine-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl}-amide (P-2425),
    • Pyrrolidine-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2476), and
    • N,N-dimethylamino-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2477).
  • In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a thirty-ninth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-chloro-2-fluoro-phenyl]-amide (P-1253),
    • Propane-1-sulfonic acid [4-chloro-2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1254),
    • Propane-1-sulfonic acid [4-chloro-2-fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1255),
    • Propane-1-sulfonic acid [4-chloro-2-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1256),
    • Propane-1-sulfonic acid [4-chloro-3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-1257), and
    • Propane-1-sulfonic acid {4-chloro-3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2-fluoro-phenyl}-amide (P-1258).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a fortieth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide (P-1269),
    • Propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide (P-1270),
    • Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-4-fluoro-phenyl}-amide (P-1271),
    • Propane-1-sulfonic acid [4-fluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1272),
    • Propane-1-sulfonic acid [3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1273),
    • Propane-1-sulfonic acid {3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1274),
    • Propane-1-sulfonic acid [3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1275),
    • Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1276),
    • Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-chloro-4-fluoro-phenyl]-amide (P-2426),
    • Propane-1-sulfonic acid {2-chloro-3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-4-fluoro-phenyl}-amide (P-2427),
    • Propane-1-sulfonic acid {2-chloro-4-fluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2428),
    • Propane-1-sulfonic acid {2-chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2429),
    • Propane-1-sulfonic acid {4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2431),
    • Propane-1-sulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2437),
    • Propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2449),
    • Propane-1-sulfonic acid {3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2454), and
    • Propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl)-phenyl]-amide (P-2467).
  • In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a forty-first aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-[3-(1H-Pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-1259),
    • N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-1260),
    • N-[4-Fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-1261),
    • N-[4-Fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-1262),
    • N-{4-Fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-methane sulfonamide (P-1263),
    • N-{4-Fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-methanesulfonamide (P-1264),
    • N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-methanesulfonamide (P-1265),
    • 3-[3-(2-Fluoro-5-methanesulfonylamino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide (P-1266),
    • (E)-3-{3-[3-(3-Methanesulfonylamino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acrylic acid methyl ester (P-1267), and
    • N-[3-(1H-Pyrrolo[2,3-b]pyridin-3-ylamino)-phenyl]-methanesulfonamide (P-1268).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a forty-second aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Butane-1-sulfonic acid {2-chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2430),
    • Butane-1-sulfonic acid {4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2432),
    • Butane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide (P-2435),
    • Butane-1-sulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2438),
    • Butane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2450), and
    • Butane-1-sulfonic acid {3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2455).
  • In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a forty-third aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Cyclopropanesulfonic acid {4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2433),
    • Cyclohexanesulfonic acid {4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2434),
    • Cyclopropanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide (P-2436),
    • Cyclopropanesulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2439),
    • Cyclohexanesulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2441),
    • Cyclopentanesulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2442),
    • Cyclohexanesulfonic acid [4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2443),
    • Cyclohexanesulfonic acid {4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2444),
    • Cyclopentanesulfonic acid {4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2445),
    • Cyclohexanesulfonic acid {4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2446),
    • Cyclopentanesulfonic acid {4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2447),
    • Cyclopentanesulfonic acid [4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2448),
    • Cyclopropanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2451),
    • Cyclohexanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2452),
    • Cyclopentanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2453),
    • Cyclopropanesulfonic acid {3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2456),
    • Cyclohexanesulfonic acid {3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2457),
    • Cyclohexanesulfonic acid [3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2458),
    • Cyclopentanesulfonic acid [3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2459),
    • Cyclohexanesulfonic acid [3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2460),
    • Cyclohexanesulfonic acid {3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2461),
    • Cyclohexanesulfonic acid [3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2462),
    • Cyclopentanesulfonic acid [3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2463),
    • Cyclopentanesulfonic acid [3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2464),
    • 3-{3-[3-(3-Cyclohexanesulfonyl amino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-propionic acid (P-2465), and
    • 3-{3-[3-(3-Cyclopentanesulfonylamino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-propionic acid (P-2466).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a forty-fourth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Piperidine-1-sulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2440),
    • Piperidine-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide (P-2468),
    • N,N-dimethylamino-sulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2469),
    • N,N-dimethylamino-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2470), and
    • Piperidine-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2471).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a forty-fifth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-methyl-phenyl]-methanesulfonamide (P-1277),
    • N-[2-Methyl-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-1278),
    • N-[2-Methyl-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-1279),
    • Propane-1-sulfonic acid {3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2-methyl-phenyl}-amide (P-1280),
    • Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-methyl-phenyl]-amide (P-1281),
    • N,N-demethylamino-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-methyl-phenyl]-amide (P-1282),
    • Propane-1-sulfonic acid [2-methyl-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1283), and
    • Propane-1-sulfonic acid [2-methyl-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1284).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a forty-sixth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-2,4-difluoro-3-[hydroxy-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-phenyl-4-trifluoromethyl-benzenesulfonamide (P-1426),
    • N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-2-fluoro-benzenesulfonamide (P-1448),
    • N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-1449),
    • N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-1450),
    • N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-benzenesulfonamide (P-1451),
    • N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-4-isopropyl-benzenesulfonamide (P-1452),
    • N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-4-propyl-benzenesulfonamide (P-1453),
    • 3-Difluoromethoxy-N-[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-benzenesulfonamide (P-1454),
    • 4-Difluoromethoxy-N-[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-benzenesulfonamide (P-1455),
    • N-{2-Fluoro-3-[hydroxy-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-1457),
    • N-[2-Fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1458),
    • 4-Fluoro-N-[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-benzenesulfonamide (P-1460),
    • 2,5-Difluoro-N-[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-benzenesulfonamide (P-1463),
    • 2,6-Difluoro-N-[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-benzenesulfonamide (P-1464),
    • 2,4-Difluoro-N-[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-benzenesulfonamide (P-1465),
    • 3-Fluoro-N-[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-benzenesulfonamide (P-1467),
    • 2-Fluoro-N-[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-benzenesulfonamide (P-1475),
    • N-[2-Fluoro-3-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1481),
    • N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-4-fluoro-benzenesulfonamide (P-1495), and
    • N-[3-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1505).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a forty-seventh aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • 2H-[1,2,4]Triazole-3-sulfonic acid [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1445),
    • Thiazole-2-sulfonic acid [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1446),
    • Pyridine-2-sulfonic acid [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1447), and
    • Pyridine-3-sulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1462).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a forty-eighth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Propane-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-phenyl}-amide (P-1424),
    • Propane-1-sulfonic acid {2-fluoro-3-[hydroxy-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-phenyl}-amide (P-1428),
    • Propane-1-sulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1429),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1479),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1480),
    • Propane-1-sulfonic acid [2-fluoro-3-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1482), and
    • Propane-1-sulfonic acid [3-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4-difluoro-phenyl]-amide (P-1506).
  • In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a forty-ninth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-methanesulfonamide (P-1430),
    • Ethanesulfonic acid [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1431),
    • Propane-2-sulfonic acid [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1432),
    • Butane-2-sulfonic acid [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1433),
    • 2-Methyl-propane-1-sulfonic acid [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1434),
    • Pentane-2-sulfonic acid [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1435),
    • Ethanesulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1459),
  • Propane-2-sulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1466),
    • 2-Methyl-propane-1-sulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1470),
    • Butane-2-sulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1471),
    • Pentane-2-sulfonic acid [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1474), and
  • Pentane-2-sulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1478).
  • In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a fiftieth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Cyclopentanesulfonic acid [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1436),
    • Cyclohexanesulfonic acid [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1437),
    • Cyclobutanesulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1472),
    • Cyclohexanesulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1476), and
    • Cyclopentanesulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1477).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a fifty-first aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-C,C,C-trifluoro-methanesulfonamide (P-1438),
    • 2,2,2-Trifluoro-ethanesulfonic acid [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1439),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1440), and
    • 2,2,2-Trifluoro-ethanesulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1461).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a fifty-second aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Dimethylamine-1-sulfonic acid [3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4-difluoro-phenyl]-amide (P-1441),
    • Diethylamine-1-sulfonic acid [3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4-difluoro-phenyl]-amide (P-1442),
    • Pyrrolidine-1-sulfonic acid [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1443),
    • Morpholine-4-sulfonic acid [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1444),
    • N,N-Dimethylamino-sulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1468),
    • Pyrrolidine-1-sulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1469), and
    • Morpholine-4-sulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1473).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a fifty-third aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-phenyl]-amide (P-1484),
    • Propane-1-sulfonic acid [3-(2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-2,4-difluoro-phenyl]-amide (P-1485),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[2-(2-methoxy-pyrimidin-5-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-phenyl}-amide (P-1486),
    • Propane-1-sulfonic acid {3-[2-(4-chloro-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-2,4-difluoro-phenyl}-amide (P-1487),
    • Propane-1-sulfonic acid [3-(2-cyano-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-2,4-difluoro-phenyl]-amide (P-1488),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-phenyl}-amide (P-1489),
    • Propane-1-sulfonic acid [2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-phenyl]-amide (P-1490), and
    • N-[2-Fluoro-3-(5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1492).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a fifty-fourth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Propane-1-sulfonic acid [2,4-difluoro-3-(1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-phenyl]-amide (P-1493), and
    • Propane-1-sulfonic acid [3-(5-cyano-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1494).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a fifty-fifth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • 6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-pyridin-3-yl-benzamide (P-1285), 6-Chloro-2-fluoro-N-(6-methoxy-pyridin-3-yl)-3-(propane-1-sulfonylamino)-benzamide (P-1287),
    • N-(2-Acetylamino-pyrimidin-5-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamide (P-1288),
    • 6-Chloro-2-fluoro-N-(6-isopropylamino-pyridin-3-yl)-3-(propane-1-sulfonylamino)-benzamide (P-1289),
    • Pyrrolidine-1-carboxylic acid {5-[6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylamino]-pyridin-2-yl}-amide (P-1290),
    • 6-Chloro-N-(3,5-dimethyl-isoxazol-4-yl)-2-fluoro-3-(propane-1-sulfonylamino)-benzamide (P-1291),
    • 6-Chloro-N-(6-cyclopentylamino-pyridin-3-yl)-2-fluoro-3-(propane-1-sulfonylamino)-benzamide (P-1292),
    • 6-Chloro-N-[5-(4-chloro-phenyl)-2H-pyrazol-3-yl]-2-fluoro-3-(propane-1-sulfonylamino)-benzamide (P-1293),
    • 6-Chloro-2-fluoro-N-[6-(5-methyl-thiazol-2-ylamino)-pyridin-3-yl]-3-(propane-1-sulfonylamino)-benzamide (P-1294),
    • 6-Chloro-N-[5-(4-chloro-benzyl)-[1,3,4]thiadiazol-2-yl]-2-fluoro-3-(propane-1-sulfonylamino)-benzamide (P-1295),
    • 6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide (P-1296),
    • 6-Chloro-N-(6-cyclopropylamino-pyridin-3-yl)-2-fluoro-3-(propane-1-sulfonylamino)-benzamide (P-1298),
    • 6-Chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-{6-[(thiophen-2-ylmethyl)-amino]-pyridin-3-yl}-benzamide (P-1299),
    • N-(6-Benzylamino-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamide (P-1300),
    • 6-Chloro-2-fluoro-N-imidazo[1,2-a]pyridin-3-yl-3-(propane-1-sulfonylamino)-benzamide (P-1301), and
    • 2,6-Difluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide (P-1312).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a fifty-sixth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-(6-Acetylamino-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamide (P-1286),
    • N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(propane-1-sulfonylamino)-benzamide (P-1315),
    • N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-benzamide (P-1340),
    • N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-benzamide (P-1341),
    • N-(6-Acetylamino-pyridin-3-yl)-3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-benzamide (P-1342),
    • N-(6-Acetylamino-pyridin-3-yl)-3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-benzamide (P-1343),
    • N-(6-Acetylamino-pyridin-3-yl)-3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-benzamide (P-1344),
    • 6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-nicotinamide (P-1345),
    • N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzamide (P-1346),
    • N-(6-Acetylamino-pyridin-3-yl)-3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-benzamide (P-1347),
    • N-(6-Acetylamino-pyridin-3-yl)-3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-benzamide (P-1348),
    • N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-benzamide (P-1349),
    • N-(6-Acetylamino-pyridin-3-yl)-3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-benzamide (P-1350),
    • N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-benzamide (P-1351),
    • N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyridine-2-sulfonylamino)-benzamide (P-1352),
    • N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyridine-3-sulfonylamino)-benzamide (P-1353),
    • N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(dimethylaminosulfonylamino)-benzamide (P-1354),
    • N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(piperidine-1-sulfonylamino)-benzamide (P-1355),
    • N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(morpholine-4-sulfonylamino)-benzamide (P-1356),
    • N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-benzamide (P-1357),
    • N-(6-Acetylamino-pyridin-3-yl)-3-cyclopentanesulfonylamino-2,6-difluoro-benzamide (P-1358),
    • N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-benzamide (P-1359),
    • N-(6-Acetylamino-pyridin-3-yl)-2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-benzamide (P-1360),
    • N-(6-Acetylamino-pyridin-3-yl)-3-benzenesulfonylamino-2,6-difluoro-benzamide (P-2474), and
    • 6-Acetylamino-N-(3-benzenesulfonylamino-2,6-difluoro-phenyl)-nicotinamide (P-2475).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a fifty-seventh aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Quinoline-3-carboxylic acid [2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-1309),
    • 6-Acetylamino-N-[2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-nicotinamide (P-1317),
    • 6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-nicotinamide (P-1318),
    • 6-Acetylamino-N-[3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide (P-1319),
    • 6-Acetylamino-N-[3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide (P-1320),
    • 6-Acetylamino-N-[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide (P-1321),
    • 6-Acetylamino-N-[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-nicotinamide (P-1322),
    • 6-Acetylamino-N-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-nicotinamide (P-1323),
    • 6-Acetylamino-N-[3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide (P-1324),
    • 6-Acetylamino-N-[3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide (P-1325),
    • 6-Acetylamino-N-[2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-nicotinamide (P-1326),
    • 6-Acetylamino-N-[3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide (P-1327),
    • 6-Acetylamino-N-[2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-nicotinamide (P-1328),
    • 6-Acetylamino-N-[2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-nicotinamide (P-1329),
    • 6-Acetylamino-N-[2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-nicotinamide (P-1330),
    • 6-Acetylamino-N-[2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-nicotinamide (P-1331),
    • 6-Acetylamino-N-[2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-nicotinamide (P-1332),
    • 6-Acetylamino-N-[2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-nicotinamide (P-1333),
    • 6-Acetylamino-N-[2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-nicotinamide (P-1334),
    • 6-Acetylamino-N-(3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-nicotinamide (P-1335),
    • 6-Acetylamino-N-[2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-nicotinamide (P-1336),
    • 6-Acetylamino-N-[2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-nicotinamide (P-1337), and
    • 6-Acetylamino-N-[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-nicotinamide (P-1361).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a fifty-eighth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of: 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-amide (P-1362),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-amide (P-1363),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide (P-1364),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide (P-1365),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide (P-1366),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-amide (P-1367),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-amide (P-1368),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide (P-1369),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide (P-1370),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-amide (P-1371),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide (P-1372),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-amide (P-1373),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-amide (P-1374),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-amide (P-1375),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-amide (P-1376),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-amide (P-1377),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-amide (P-1378),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-amide (P-1379),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid (3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-amide (P-1380),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-amide (P-1381),
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-amide (P-1382), and
    • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-1385).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a fifty-ninth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-amide (P-1386),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-amide (P-1387),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide (P-1388),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide (P-1389),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide (P-1390),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-amide (P-1391),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-amide (P-1392),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide (P-1393),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide (P-1394),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-amide (P-1395),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide (P-1396),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-amide (P-1397),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-amide (P-1398),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-amide (P-1399),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-amide (P-1400),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-amide (P-1401),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-amide (P-1402),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-amide (P-1403),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid (3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-amide (P-1404),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-amide (P-1405),
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-amide (P-1406), and
    • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide (P-1407).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a sixtieth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Propane-1-sulfonic acid (2,4-difluoro-3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-phenyl)-amide (P-1302),
    • Propane-1-sulfonic acid (3-{[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-2,4-difluoro-phenyl)-amide (P-1303),
    • Propane-1-sulfonic acid (2-fluoro-3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-phenyl)-amide (P-1304),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(quinolin-3-ylaminomethyl)-phenyl]-amide (P-1305),
    • Propane-1-sulfonic acid {3-[(6-chloro-pyridin-3-yl amino)-methyl]-2,4-difluoro-phenyl}-amide (P-1306),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[(6-methoxy-pyridin-3-ylamino)-methyl]-phenyl}-amide (P-1307),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[(5-methyl-isoxazol-3-ylamino)-methyl]-phenyl}-amide (P-1308),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[(quinolin-3-ylmethyl)-amino]-phenyl}-amide (P-1310),
      and
    • N-{5-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzyl amino]-pyridin-2-yl}-acetamide (P-1316)
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a sixty-first aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Propane-1-sulfonic acid [2,4-difluoro-3-(quinolin-3-yloxymethyl)-phenyl]-amide (P-1311),
    • Propane-1-sulfonic acid [3-(2-amino-pyridin-3-yloxymethyl)-2,4-difluoro-phenyl]-amide (P-1313),
    • N-[3-(2-Amino-pyridin-3-yloxymethyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1314),
    • N-{5-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzyloxy]-pyridin-2-yl}-acetamide (P-1338),
    • N-{5-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzyloxy]-pyridin-2-yl}-acetamide (P-1339),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yloxymethyl)-phenyl]-amide (P-1383), and
    • N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yloxymethyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1384).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a sixty-second aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2057),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2058), and
    • N-[2-Fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2059).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a sixty-third aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-trifluoromethyl-benzenesulfonamide (P-1028),
    • N-[2,4-Difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1427),
    • 4-tert-Butyl-N-[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-benzenesulfonamide (P-1456), and
    • N-[2,4-Difluoro-3-(5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1491).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a sixty-fourth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1091),
    • N-[2,4-Difluoro-3-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1483),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1503), and
    • N-[3-(4-Ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1504).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a sixty-fifth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1021), and
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1092).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a sixty-sixth aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1174),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide (P-1498),
    • Propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1499),
    • Pyrrolidine-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1500), and
    • N,N-dimethylamino-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1501).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a sixty-seventh aspect, a solid form is provided comprising a basic amino acid, preferably arginine or lysine, and a compound selected from the group consisting of:
    • Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-1167),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-1425),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1496),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-1497),
      and
    • Propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-1502).
      In one embodiment, the solid form is a complex of the compound and the basic amino acid. In one embodiment, the solid form is a complex of the compound and arginine. In one embodiment, the solid form is a complex of the compound and lysine. In one embodiment, the complex is an amorphous solid.
  • In a sixty-eighth aspect, a complex of arginine and N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1021) is provided. In one embodiment, a composition is provided comprising said complex. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of pain or polycystic kidney disease. In one embodiment, the complex is an amorphous solid.
  • In a sixty-ninth aspect, a complex of lysine and N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1021) is provided. In one embodiment, a composition is provided comprising said complex. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of pain or polycystic kidney disease. In one embodiment, the complex is an amorphous solid.
  • In a seventieth aspect, a complex of arginine and N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1092) is provided. In one embodiment, a composition is provided comprising said complex. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of pain or polycystic kidney disease. In one embodiment, the complex is an amorphous solid.
  • In a seventy-first aspect, a complex of lysine and N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1092) is provided. In one embodiment, a composition is provided comprising said complex. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of pain or polycystic kidney disease. In one embodiment, the complex is an amorphous solid.
  • In a seventy-second aspect, a complex of arginine and Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-1167) is provided. In one embodiment, a composition is provided comprising said complex. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of melanoma or colorectal cancer. In one embodiment, the complex is an amorphous solid.
  • In a seventy-third aspect, a complex of lysine and Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-1167) is provided. In one embodiment, a composition is provided comprising said complex. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of melanoma or colorectal cancer. In one embodiment, the complex is an amorphous solid.
  • In a seventy-fourth aspect, a complex of arginine and N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-1497) is provided. In one embodiment, a composition is provided comprising said complex. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of melanoma or colorectal cancer. In one embodiment, the complex is an amorphous solid.
  • In a seventy-fifth aspect, a complex of lysine and N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-1497) is provided. In one embodiment, a composition is provided comprising said complex. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of melanoma or colorectal cancer. In one embodiment, the complex is an amorphous solid.
  • In a seventy-sixth aspect, a complex of arginine and Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1496 is provided. In one embodiment, a composition is provided comprising said complex. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of melanoma or colorectal cancer. In one embodiment, the complex is an amorphous solid.
  • In a seventy-seventh aspect, a complex of lysine and Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1496) is provided. In one embodiment, a composition is provided comprising said complex. In one embodiment, the composition is effective as a pharmaceutical, for example in the treatment of melanoma or colorectal cancer. In one embodiment, the complex is an amorphous solid.
  • In a seventy-eighth aspect, a composition is provided comprising an amorphous complex of arginine and any of the above-referenced specific compounds, and further comprises a crystalline form of the compound, preferably crystalline free base of the compound. In one embodiment, the composition comprises the amorphous complex and 0-80% crystalline compound, also 0-50%, 0-20%, 0-10%, 0-5%, or 0-2% crystalline compound.
  • In a seventy-ninth aspect, a composition is provided comprising an amorphous complex of lysine and any of the above-referenced specific compounds, and further comprises a crystalline form of the compound, preferably crystalline free base of the compound. In one embodiment, the composition comprises the amorphous complex and 0-80% crystalline compound, also 0-50%, 0-20%, 0-10%, 0-5%, or 0-2% crystalline compound.
  • In an eightieth aspect, a compound is provided, where the compound is selected from the group consisting of:
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-fluoro-benzenesulfonamide (P-2026),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro-benzenesulfonamide (P-2027),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-fluoro-benzenesulfonamide (P-2028),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-fluoro-benzenesulfonamide (P-2035),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-fluoro-benzenesulfonamide (P-2040),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2047),
    • N-[2,4-Difluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2482),
    • N-[3-(5-Cyclopropyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2483),
    • N-[3-(5-Ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2484),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-propyl-benzenesulfonamide (P-2486),
    • N-[3-(4-Ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2487), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In an eighty-first aspect, a compound is provided, where the compound is selected from the group consisting of:
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-fluoro-benzenesulfonamide (P-2050),
  • N-[2-Fluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2060), and
  • a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In an eighty-second aspect, a compound is provided, where the compound is selected from the group consisting of:
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-2016),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide (P-2019),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-2023),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide (P-2039),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide (P-2045),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-fluoro-benzenesulfonamide (P-2053), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In an eighty-third aspect, a compound is provided, where the compound is selected from the group consisting of:
    • 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2001),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2002),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2003),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3,5-dimethyl-benzenesulfonamide (P-2004),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-4-methoxy-benzenesulfonamide (P-2005),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-fluoro-2-methyl-benzenesulfonamide (P-2006),
    • 2,3-Dihydro-benzofuran-5-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2007),
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-fluoro-benzenesulfonamide (P-2009),
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-2010),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2011),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-fluoro-benzenesulfonamide (P-2014),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-2015),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2017),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2018),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2020),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-fluoro-benzenesulfonamide (P-2021),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-2022),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,6-difluoro-benzenesulfonamide (P-2024),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,4-difluoro-benzenesulfonamide (P-2025),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2029),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,4-difluoro-benzenesulfonamide (P-2030),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,6-difluoro-benzenesulfonamide (P-2031),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,4-difluoro-benzenesulfonamide (P-2032),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2033),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,4-difluoro-benzenesulfonamide (P-2034),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2036),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2037),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,4-difluoro-benzenesulfonamide (P-2038),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2-fluoro-benzenesulfonamide (P-2041),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-2042),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,6-difluoro-benzenesulfonamide (P-2043),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,4-difluoro-benzenesulfonamide (P-2044),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide (P-2046),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2051),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2052),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2054),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,4-difluoro-benzenesulfonamide (P-2055),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-benzenesulfonamide (P-2056), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In an eighty-fourth aspect, a compound is provided, where the compound is selected from the group consisting of:
    • 2H-[1,2,4]Triazole-3-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2061),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2062),
    • Pyridine-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2063),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2064),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2065),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2066),
    • Pyridine-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2067),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2068),
    • Pyridine-3-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2069),
    • Pyridine-2-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2070),
    • Pyridine-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2071),
    • Pyridine-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2072),
    • Pyridine-3-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2073),
    • Pyridine-3-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2074),
    • Pyridine-2-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2075),
    • Pyridine-2-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2076),
    • Pyridine-3-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2077),
    • Pyridine-2-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2078),
    • Pyridine-2-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2079),
    • 2H-[1,2,4]Triazole-3-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2080),
    • 5-Methyl-isoxazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2081),
    • 1,5-Dimethyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2082),
    • 1-Ethyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2083),
    • 1-Methyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2084),
    • 6-Methoxy-pyridine-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2085),
    • Pyridine-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2086),
    • Pyridine-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2087),
    • 5-Methyl-isoxazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2088),
    • 1-Ethyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2089),
    • 1-Methyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2090),
    • 1,5-Dimethyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2091),
    • 6-Methoxy-pyridine-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2092),
    • 6-Trifluoromethyl-pyridine-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2481),
    • 5-Trifluoromethyl-pyridine-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2485), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In an eighty-fifth aspect, a compound is provided, where the compound is selected from the group consisting of:
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-C-pyridin-2-yl-methanesulfonamide (P-2093),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-C-pyridin-3-yl-methanesulfonamide (P-2094),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-C-pyridin-4-yl-methanesulfonamide (P-2095),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-pyridin-3-yl-methanesulfonamide (P-2096),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-pyridin-4-yl-methanesulfonamide (P-2097),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-pyridin-2-yl-methanesulfonamide (P-2098), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In an eighty-sixth aspect, a compound is provided, where the compound is selected from the group consisting of:
    • 4-Fluoro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2100),
    • N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-2104),
    • 4-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-benzenesulfonamide (P-2106),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-fluoro-benzenesulfonamide (P-2107),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-trifluoromethoxy-benzenesulfonamide (P-2109),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2112),
    • 4-Chloro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2113),
    • 4-Fluoro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2114),
    • N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide (P-2116),
    • N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2119),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro-benzenesulfonamide (P-2121),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide (P-2123),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2126),
    • 4-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2128),
    • 4-Chloro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2129),
    • 4-Fluoro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2130),
    • N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethoxy-benzenesulfonamide (P-2132), and
    • N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-2135), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In an eighty-seventh aspect, a compound is provided, where the compound is selected from the group consisting of:
    • N-{2-Chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-difluoromethoxy-benzenesulfonamide (P-2099),
    • N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-trifluoromethyl-benzenesulfonamide (P-2101),
    • N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-trifluoromethoxy-benzenesulfonamide (P-2102),
    • 3-Chloro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2103),
    • 3-Fluoro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2105),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-trifluoromethyl-benzenesulfonamide (P-2108),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-trifluoromethoxy-benzenesulfonamide (P-2110),
    • 3-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-benzenesulfonamide (P-2111),
    • N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide (P-2115),
    • N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluoromethoxy-benzenesulfonamide (P-2117),
    • 3-Chloro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2118),
    • 3-Fluoro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2120),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide (P-2122),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluoromethoxy-benzenesulfonamide (P-2124),
    • 3-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2125),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-2127),
    • N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-trifluoromethyl-benzenesulfonamide (P-2131),
    • N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-trifluoromethoxy-benzenesulfonamide (P-2133),
    • 3-Chloro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2134),
    • 3-Fluoro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2136), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In an eighty-eighth aspect, a compound is provided, where the compound is selected from the group consisting of:
    • Pyridine-3-sulfonic acid [4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2137),
    • Pyridine-3-sulfonic acid {4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2138),
    • Pyridine-3-sulfonic acid {4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2139),
    • Pyridine-3-sulfonic acid {4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2140),
    • Pyridine-3-sulfonic acid [3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2141),
    • Pyridine-3-sulfonic acid [3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2142),
    • Pyridine-3-sulfonic acid [3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2143),
    • Pyridine-3-sulfonic acid {3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2144),
    • Pyridine-3-sulfonic acid {3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2145),
    • Pyridine-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2146),
    • 3-{3-[3-(Pyridine-3-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzamide (P-2147),
    • 3-(3-{3-[3-(Pyridine-3-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-phenyl)-propionic acid (P-2148),
    • Pyridine-3-sulfonic acid {3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2149),
    • N-(6-Acetylamino-pyridin-3-yl)-3-benzenesulfonylamino-2,6-difluoro-benzamide (P-2472), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In an eighty-ninth aspect, a compound is provided, where the compound is selected from the group consisting of:
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-2288),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-2289),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-methanesulfonamide (P-2290),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-methanesulfonamide (P-2291),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-methanesulfonamide (P-2292),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-2293),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-methanesulfonamide (P-2294), and
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-methanesulfonamide (P-2295), and
  • a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In a ninetieth aspect, a compound is provided, where the compound is selected from the group consisting of:
    • Ethanesulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2268),
    • Ethanesulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2269),
    • Ethanesulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2270),
    • Ethanesulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2271),
    • Ethanesulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2272),
    • Propane-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2273),
    • Ethanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2274),
    • Propane-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2275),
    • Ethanesulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2276),
    • Ethanesulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2277),
    • Propane-2-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2278),
    • Ethanesulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2279),
    • Propane-2-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2280),
    • Ethanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2281),
    • Propane-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2282),
    • Ethanesulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2283),
    • Propane-2-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2284),
    • Propane-2-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2285),
    • Ethanesulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2286),
    • Propane-2-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2287),
    • Ethanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2410),
    • Propane-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2411), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In a ninety-first aspect, a compound is provided, where the compound is selected from the group consisting of:
    • 5-(3-{[2,6-Difluoro-3-(propane-1-sulfonylamino)-phenyl]-hydroxy-methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid ethylamide (P-2150),
    • 5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridine-2-carboxylic acid ethylamide (P-2151),
    • Propane-1-sulfonic acid {3-[5-(1,5-dimethyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2152),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2153),
    • Propane-1-sulfonic acid {3-[5-(6-chloro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2154),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-fluoro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2155),
    • Propane-1-sulfonic acid {3-[5-(3,5-dimethyl-isoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2156),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(I-isobutyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2157),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2158),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-3-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2159),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-3-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2160),
    • N-(4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-phenyl)-acetamide (P-2161),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2162),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-fluoro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2164),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2165),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(morpholine-4-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2166),
    • 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2167),
    • N-Cyclopropyl-4-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzenesulfonamide (P-2168),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2169),
    • 3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2170),
    • Propane-1-sulfonic acid {3-[5-(4-chloro-3-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2171),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-fluoro-6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2172),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2173),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2174),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2175),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2176),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[I-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2177),
    • Propane-1-sulfonic acid (3-{5-[6-(3-dimethylamino-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2178),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-hydroxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2179),
    • 5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridine-2-carboxylic acid methylamide (P-2180),
    • 5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridine-2-carboxylic acid cyclopropylamide (P-2181),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2182),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (P-2473),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2183),
    • Propane-1-sulfonic acid {3-[5-(2,6-dimethoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2184),
    • 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N,N-dimethyl-benzenesulfonamide (P-2185),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(piperidine-1-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2186),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-methylsulfanyl-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2187),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(5-methanesulfonyl-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2188),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methylsulfanyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2189),
    • Propane-1-sulfonic acid {3-[5-(1-benzyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2190),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2191),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-fluoro-pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2192),
    • N-(5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridin-2-yl)-acetamide (P-2193),
    • 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzenesulfonamide (P-2194),
    • Propane-1-sulfonic acid {3-[5-(2,5-dimethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2195),
    • Propane-1-sulfonic acid {3-[5-(2-dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2196),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-morpholin-4-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2197),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-hydroxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2198),
    • Propane-1-sulfonic acid {3-[5-(2,4-dimethoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2199),
    • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methylamide (P-2200),
    • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid cyclopropylamide (P-2201),
    • Propane-1-sulfonic acid (3-{5-[2-(3-dimethylamino-propoxy)-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2203),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-hydroxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2204),
    • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (P-2207),
    • Propane-1-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2208),
    • Propane-1-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2209),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2210),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2211),
    • Propane-1-sulfonic acid {3-[5-(2-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2212),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2213),
    • Propane-1-sulfonic acid {3-[5-(6-amino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2214),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(2-hydroxy-ethoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2215),
    • Propane-1-sulfonic acid (3-{5-[6-(3-diethylamino-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2216),
    • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (2-hydroxy-ethyl)-amide (P-2217),
    • Propane-1-sulfonic acid {3-[5-(4-ethanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2218),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2219),
    • 5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridine-2-carboxylic acid amide (P-2220),
    • 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-(2-hydroxy-ethyl)-benzenesulfonamide (P-2221),
    • Propane-1-sulfonic acid (3-{5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2222),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(propane-2-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2223),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-propyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2224),
    • (E)-3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acrylic acid methyl ester (P-2225),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(3-methoxy-propyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2226),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2227),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2228),
    • Propane-1-sulfonic acid {3-[5-(6-dimethylamino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2229),
    • 3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid methyl ester (P-2230),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-pyrrolidin-1-yl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2231),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(2-morpholin-4-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2232),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(2-pyrrolidin-1-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2233),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-hydroxy-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2234),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(3-pyrrolidin-1-yl-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2235),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(3-morpholin-4-yl-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2236),
    • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid dimethyl amide (P-2237),
    • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methoxy-amide (P-2238),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2239),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-methoxy-propyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2240),
    • Propane-1-sulfonic acid {3-[5-(3-diethylamino-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2241),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2H-tetrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2242),
    • 3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-methoxy-propionamide (P-2243),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-morpholin-4-ylmethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2244),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-morpholin-4-yl-propyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2247),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-pyrrolidin-1-yl-propyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2248),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-hydroxymethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2250),
    • 3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N,N-diethyl-propionamide (P-2255),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2257),
    • Propane-1-sulfonic acid [3-(5-diethylaminomethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2258),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-pyrrolidin-1-ylmethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2259),
    • Propane-1-sulfonic acid [3-(5-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2260),
    • Propane-1-sulfonic acid [3-(4-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2261), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In a ninety-second aspect, a compound is provided, where the compound is selected from the group consisting of:
    • Propane-1-sulfonic acid [2-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2403),
    • 3-[2-Fluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (P-2404),
    • 3-[2-Fluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (P-2406),
    • Propane-1-sulfonic acid {2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2407),
    • Propane-1-sulfonic acid {3-[5-(2-dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl}-amide (P-2408),
    • Propane-1-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2409),
    • Propane-1-sulfonic acid [2-fluoro-3-(5-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2480), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In a ninety-third aspect, a compound is provided, where the compound is selected from the group consisting of:
    • 2-Methyl-propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2296),
    • 2-Methyl-propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2297),
    • 2-Methyl-propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2298),
    • 2-Methyl-propane-1-sulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2299),
    • Butane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2300),
    • Butane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2301),
    • Butane-1-sulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2302),
    • 2-Methyl-propane-1-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2303),
    • 2-Methyl-propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2304),
    • 2-Methyl-propane-1-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2305),
    • 2-Methyl-propane-1-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2306),
    • 2-Methyl-propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2307),
    • Butane-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2308),
    • Pentane-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2309),
    • Butane-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2310),
    • Pentane-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2311),
    • Butane-2-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2312),
    • Butane-2-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2313),
    • Pentane-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2314),
    • Pentane-2-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2315),
    • Pentane-2-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2316),
    • Butane-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2317),
    • 2-Methyl-propane-1-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2318),
    • Butane-2-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2319),
    • 2-Methyl-propane-1-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2320),
    • Butane-2-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2321),
    • 2-Methyl-propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2322),
    • Butane-2-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2323),
    • 2-Methyl-propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2412),
    • Butane-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2413), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In a ninety-fourth aspect, a compound is provided, where the compound is selected from the group consisting of:
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2324),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2325),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2326),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2327),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2328),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2329),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2330),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2331),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2332),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2333),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2415),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2478), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In a ninety-fifth aspect, a compound is provided, where the compound is selected from the group consisting of:
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2334),
    • 2,2,2-Trifluoro-ethanesulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2335),
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2336),
    • 2,2,2-Trifluoro-ethanesulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2337),
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2338),
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2339),
    • 2,2,2-Trifluoro-ethanesulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2340),
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2341),
    • 2,2,2-Trifluoro-ethanesulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2342),
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2414), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In a ninety-sixth aspect, a compound is provided, where the compound is selected from the group consisting of:
    • N-{3-[5-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2343),
    • N-{2,4-Difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2344),
    • N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2345),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-C,C,C-trifluoro-methanesulfonamide (P-2346),
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-C,C,C-trifluoro-methanesulfonamide (P-2347),
    • N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-C,C,C-trifluoro-methanesulfonamide (P-2479), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In a ninety-seventh aspect, a compound is provided, where the compound is selected from the group consisting of:
    • Cyclopropanesulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2348),
    • I-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-cyclopropanecarboxylic acid (P-2349),
    • Cyclopropanesulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2350),
    • Cyclopropanesulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2351),
    • Cyclopropanesulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2352),
    • Cyclobutanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2353),
    • Cyclobutanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2354),
    • Cyclohexanesulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2355),
    • Cyclopentanesulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2356),
    • Cyclohexanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2357),
    • Cyclopentanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2358),
    • Cyclopentanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2359),
    • Cyclohexanesulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2360),
    • Cyclohexanesulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2361),
    • Cyclobutanesulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2362),
    • Cyclobutanesulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2363),
    • Cyclobutanesulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2364),
    • Cyclopentanesulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2365),
    • Cyclohexanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2366),
    • Cyclohexanesulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2367),
    • Cyclopentanesulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2368),
    • Cyclohexanesulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2369),
    • Cyclobutanesulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2370),
    • Cyclohexanesulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2371),
    • Cyclopentanesulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2372),
    • Cyclobutanesulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2373),
    • Cyclohexanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2416),
    • Cyclopentanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2417),
    • Cyclobutanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2418), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In a ninety-eighth aspect, a compound is provided, where the compound is selected from the group consisting of:
    • Pyrrolidine-1-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2374),
    • Pyrrolidine-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2375),
    • N,N-dimethylamino-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2376),
    • Pyrrolidine-1-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2377),
    • N,N-diethylamino-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2378),
    • Pyrrolidine-1-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2379),
    • N,N-dimethylamino-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2382),
    • N,N-dimethylamino-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2383),
    • N,N-diethylamino-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2384),
    • N,N-diethylamino-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2385),
    • N,N-diethylamino-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2386),
    • N,N-diethylamino-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2387),
    • N,N-diethylamino-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2388),
    • N,N-diethylamino-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2389),
    • Morpholine-4-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2390),
    • Morpholine-4-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2391),
    • Morpholine-4-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2392),
    • Morpholine-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2393),
    • Pyrrolidine-1-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2394),
    • Morpholine-4-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2395),
    • Morpholine-4-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2396),
    • Morpholine-4-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2397),
    • Pyrrolidine-1-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2398),
    • N,N-dimethylamino-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2399),
    • Pyrrolidine-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2400),
    • N,N-diethylamino-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2401),
    • Morpholine-4-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2402),
    • N,N-dimethylamino-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2419),
    • Pyrrolidine-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2420),
    • Morpholine-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2421),
    • Pyrrolidine-1-sulfonic acid {2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2422),
    • N,N-dimethylamino-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl}-amide (P-2423),
    • N,N-dimethylamino-sulfonic acid {2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2424),
    • Pyrrolidine-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl}-amide (P-2425),
    • Pyrrolidine-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2476),
    • N,N-dimethylamino-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2477), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In a ninety-ninth aspect, a compound is provided, where the compound is selected from the group consisting of:
    • Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-chloro-4-fluoro-phenyl]-amide (P-2426),
    • Propane-1-sulfonic acid {2-chloro-3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-4-fluoro-phenyl}-amide (P-2427),
    • Propane-1-sulfonic acid {2-chloro-4-fluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2428),
    • Propane-1-sulfonic acid {2-chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2429),
    • Propane-1-sulfonic acid {4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2431),
    • Propane-1-sulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2437),
    • Propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2449),
    • Propane-1-sulfonic acid {3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2454),
    • Propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl)-phenyl]-amide (P-2467), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In a one hundredth aspect, a compound is provided, where the compound is selected from the group consisting of:
    • Butane-1-sulfonic acid {2-chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2430),
    • Butane-1-sulfonic acid {4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2432),
    • Butane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide (P-2435),
    • Butane-1-sulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2438),
    • Butane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2450), Butane-1-sulfonic acid {3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2455), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In a one hundred and first aspect, a compound is provided, where the compound is selected from the group consisting of:
    • Cyclopropanesulfonic acid {4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2433),
    • Cyclohexanesulfonic acid {4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2434),
    • Cyclopropanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide (P-2436),
    • Cyclopropanesulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2439),
    • Cyclohexanesulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2441),
    • Cyclopentanesulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2442),
    • Cyclohexanesulfonic acid [4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2443),
    • Cyclohexanesulfonic acid {4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2444),
    • Cyclopentanesulfonic acid {4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2445),
    • Cyclohexanesulfonic acid {4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2446),
    • Cyclopentanesulfonic acid {4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2447),
    • Cyclopentanesulfonic acid [4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2448),
    • Cyclopropanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2451),
    • Cyclohexanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2452),
    • Cyclopentanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2453),
    • Cyclopropanesulfonic acid {3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2456),
    • Cyclohexanesulfonic acid {3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2457),
    • Cyclohexanesulfonic acid [3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2458),
    • Cyclopentanesulfonic acid [3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2459),
    • Cyclohexanesulfonic acid [3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2460),
    • Cyclohexanesulfonic acid {3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2461),
    • Cyclohexanesulfonic acid [3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2462),
    • Cyclopentanesulfonic acid [3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2463),
    • Cyclopentanesulfonic acid [3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2464),
    • 3-{3-[3-(3-Cyclohexanesulfonyl amino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-propionic acid (P-2465),
    • 3-{3-[3-(3-Cyclopentanesulfonylamino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-propionic acid (P-2466), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In a one hundred and second aspect, a compound is provided, where the compound is selected from the group consisting of:
    • Piperidine-1-sulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2440),
    • Piperidine-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide (P-2468),
    • N,N-dimethylamino-sulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2469),
    • N,N-dimethylamino-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2470),
    • Piperidine-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2471), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In a one hundred and third aspect, a compound is provided, where the compound is selected from the group consisting of:
    • N-(6-Acetylamino-pyridin-3-yl)-3-benzenesulfonylamino-2,6-difluoro-benzamide (P-2474), and
    • 6-Acetylamino-N-(3-benzenesulfonylamino-2,6-difluoro-phenyl)-nicotinamide (P-2475), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In a one hundred and fourth aspect, a compound is provided, where the compound is selected from the group consisting of:
    • 5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic acid [5-(3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionylamino)-pentyl]-amide (P-2008),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2057),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2058),
    • N-[2-Fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2059), and
      a salt, prodrug, tautomer, or stereoisomer thereof. In one embodiment, the compound is active on one or more Raf protein kinases, including A-Raf, B-Raf, c-Raf-1 and any mutations thereof.
  • In a one hundred and fifth aspect, the compound 5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic acid [5-(3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionylamino)-pentyl]-amide (P-2008) is provided. In one embodiment, P-2008 may be used as a probe for binding to one or more of A-Raf, B-Raf, and c-Raf-1, including any mutations of these kinases, in order to assess whether such kinase is present in a biological sample, and in some instances, to assess the amounts of such kinase in a biological sample.
  • In reference to compounds herein, unless clearly indicated to the contrary, specification of a compound or group of compounds includes salts or solid forms of such compound(s) (including pharmaceutically acceptable salts and solid forms), formulations of such compound(s) (including pharmaceutically acceptable formulations), conjugates thereof, derivatives thereof, prodrugs thereof, and all stereoisomers thereof. In reference to compositions, kits, methods of use, etc. of compounds of Formula I described herein, it is understood (unless indicated otherwise) that a compound of Formula I includes all sub-embodiments thereof (e.g. including Formulae Ia-Ig, and all embodiments as described above).
  • In a one hundred and sixth aspect, methods are provided for treating a protein kinase mediated disease or condition in an animal subject, wherein the method involves administering to the subject an effective amount of any one or more compound(s) of the invention as described herein. The terms “treat,” “therapy,” and like terms refer to the administration of material, e.g., one or more compound(s) of the invention as described herein in an amount effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or condition, i.e., indication, and/or to prolong the survival of the subject being treated. The term “protein kinase mediated disease or condition” “kinase mediated disease or condition” and the like refers to a disease or condition in which the biological function of a protein kinase affects the development, course, and/or symptoms of the disease or condition, and/or in which modulation of the protein kinase alters the development, course, and/or symptoms of the disease or condition. A protein kinase mediated disease or condition includes a disease or condition for which modulation provides a therapeutic benefit, e.g. wherein treatment with protein kinase inhibitors, including compounds of the invention as described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition. In certain embodiments, the method involves administering to the subject an effective amount of a compound of the invention as described herein in combination with one or more other therapies for the disease or condition.
  • In a one hundred and seventh aspect, the invention provides methods for treating a Raf protein kinase mediated disease or condition in an animal subject, wherein the method involves administering to the subject an effective amount of any one or more compound(s) of the invention as described herein. The terms “Raf protein kinase mediated disease or condition,” “Raf kinase mediated disease or condition,” “Raf mediated disease or condition,” and the like refer to a disease or condition in which the biological function of a Raf protein kinase, including any mutations thereof, affects the development, course, and/or symptoms of the disease or condition, and/or in which modulation of the Raf protein kinase alters the development, course, and/or symptoms of the disease or condition. The Raf protein kinase includes, but is not limited to, A-Raf, mutations of A-Raf, B-Raf, mutations of B-Raf, c-Raf-1 and mutations of c-Raf-1. In some embodiments, the Raf protein kinase is B-Raf mutation V600E. In some embodiments, the Raf protein kinase is B-Raf mutation V600E/T5291. In some embodiments, the disease or condition is a cancer that is amenable to treatment by an inhibitor of the V600E mutant B-Raf. In some embodiments, the disease or condition is a cancer that is amenable to treatment by an inhibitor of the V600E/T5291 mutant B-Raf. The Raf protein kinase mediated disease or condition includes a disease or condition for which Raf inhibition provides a therapeutic benefit, e.g. wherein treatment with Raf inhibitors, including compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition. In one embodiment, the method involves administering to the subject an effective amount of any one or more compound(s) of the invention as described herein in combination with one or more other therapies for the disease or condition. Similarly, the terms “A-Raf, B-Raf or c-Raf-1 protein kinase mediated disease or condition,” “A-Raf, B-Raf or c-Raf-1 kinase mediated disease or condition,” “A-Raf, B-Raf or c-Raf-1 mediated disease or condition,” and the like refer to a disease or condition in which the biological function of an A-Raf, B-Raf or c-Raf-1 kinase, respectively, including any mutations thereof, affects the development, course and/or symptoms of the disease or condition, and/or in which modulation of the A-Raf, B-Raf or c-Raf-1 protein kinase, respectively, alters the development, course, and/or symptoms of the disease or condition.
  • In a one hundred and eighth aspect, a compound of the invention as described herein is an inhibitor of a Raf kinase and has an IC50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Raf kinase activity assay. In some embodiments, the compound will have an IC50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM with respect to one or more of A-Raf, B-Raf, c-Raf-1, B-Raf V600E mutant, or B-Raf V600E/T529I mutant. In some embodiments, the compound will selectively inhibit one Raf kinase relative to one or more other Raf kinases. In some embodiments, the compound will selectively inhibit a mutation of the Raf kinase relative to the wild type kinase, for example B-Raf V600E mutant relative to wild type B-Raf.
  • Further to any of the above mentioned aspects and embodiments, a compound of the invention as described herein may selectively inhibit one kinase relative to one or more other kinases, where preferably inhibition is selective with respect to any of the other kinases, whether a kinase discussed herein, or other kinases. In some embodiments, the compound may selectively inhibit the effects of a mutation of the kinase relative to the wild type kinase, for example B-Raf V600E mutant relative to wild type B-Raf. In some embodiments, the compound may selectively inhibit Fms relative to Kit. Selective inhibition of one kinase relative to another is such that the IC50 for the one kinase may be at least about 2-fold, also 5-fold, also 10-fold, also 20-fold, also 50-fold, or at least about 100-fold less than the IC50 for any of the other kinases as determined in a generally accepted kinase activity assay.
  • In a one hundred and ninth aspect, compositions are provided that include a therapeutically effective amount of any one or more compound(s) of the invention as described herein and at least one pharmaceutically acceptable carrier, excipient, and/or diluent. In certain embodiments, the composition can include any one or more compound(s) of the invention as described herein along with one or more compounds that are therapeutically effective for the same disease indication. In one embodiment, the composition includes any one or more compound(s) of the invention as described herein along with one or more compounds that are therapeutically effective for the same disease indication, wherein the compounds have a synergistic effect on the disease indication. In one embodiment, the composition includes any one or more compound(s) of the invention as described herein effective in treating a cancer and one or more other compounds that are effective in treating the same cancer, further wherein the compounds are synergistically effective in treating the cancer.
  • In a one hundred and tenth aspect, the invention provides methods for treating a disease or condition mediated by A-Raf, B-Raf, c-Raf-1, B-Raf V600E mutant, or B-Raf V600E/T529I mutant by administering to the subject an effective amount of a composition including any one or more compound(s) of the invention as described herein. In one embodiment, the invention provides methods for treating a disease or condition mediated by A-Raf, B-Raf, c-Raf-1, B-Raf V600E mutant, or B-Raf V600E/T529I mutant by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein in combination with one or more other suitable therapies for treating the disease. In one embodiment, the invention provides methods for treating a cancer mediated by B-Raf V600E mutant or B-Raf V600E/T529I mutant by administering to the subject an effective amount of a composition including any one or more compound(s) of the invention as described herein in combination with one or more suitable anticancer therapies, such as one or more chemotherapeutic drugs.
  • In a one hundred and eleventh aspect, the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including any one or more compound(s) of the invention as described herein, in combination with one or more other therapies or medical procedures effective in treating the cancer. Other therapies or medical procedures include suitable anticancer therapy (e.g. drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedure (e.g. surgery, radiation treatment, hyperthermia heating, bone marrow or stem cell transplant). In one embodiment, the one or more suitable anticancer therapies or medical procedures is selected from treatment with a chemotherapeutic agent (e.g. chemotherapeutic drug), radiation treatment (e.g. x-ray, γ-ray, or electron, proton, neutron, or α particle beam), hyperthermia heating (e.g. microwave, ultrasound, radiofrequency ablation), Vaccine therapy (e.g. AFP gene hepatocellular carcinoma vaccine, AFP adenoviral vector vaccine, AG-858, allogeneic GM-CSF-secretion breast cancer vaccine, dendritic cell peptide vaccines), gene therapy (e.g. Ad5CMV-p53 vector, adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy (e.g. aminolevulinic acid, motexafin lutetium), surgery, or bone marrow and stem cell transplantation.
  • In a one hundred and twelfth aspect, the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including any one or more compound(s) of the invention as described herein, in combination with one or more suitable chemotherapeutic agents. In one embodiment, the one or more suitable chemotherapeutic agents is selected from an alkylating agent, including, but not limited to, adozelesin, altretamine, bendamustine, bizelesin, busulfan, carboplatin, carboquone, carmofur, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, etoglucid, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mannosulfan, mechlorethamine, melphalan, mitobronitol, nedaplatin, nimustine, oxaliplatin, piposulfan, prednimustine, procarbazine, ranimustine, satraplatin, semustine, streptozocin, temozolomide, thiotepa, treosulfan, triaziquone, triethylenemelamine, triplatin tetranitrate, trofosphamide, and uramustine; an antibiotic, including, but not limited to, aclarubicin, amrubicin, bleomycin, dactinomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, idarubicin, menogaril, mitomycin, neocarzinostatin, pentostatin, pirarubicin, plicamycin, valrubicin, and zorubicin; an antimetabolite, including, but not limited to, aminopterin, azacitidine, azathioprine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, azathioprine, raltitrexed, tegafur-uracil, thioguanine, trimethoprim, trimetrexate, and vidarabine; an immunotherapy, including, but not limited to, alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, panitumumab, pertuzumab, rituximab, tositumomab, trastuzumab, and 90 Y ibritumomab tiuxetan, ipilimumab, and tremelimumab; a hormone or hormone antagonist, including, but not limited to, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; a taxane, including, but not limited to, DJ-927, docetaxel, TPI 287, larotaxel, ortataxel, paclitaxel, DHA-paclitaxel, and tesetaxel; a retinoid, including, but not limited to, alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; an alkaloid, including, but not limited to, demecolcine, homoharringtonine, vinblastine, vincristine, vindesine, vinflunine, and vinorelbine; an antiangiogenic agent, including, but not limited to, AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; a topoisomerase inhibitor, including, but not limited to, amsacrine, belotecan, edotecarin, etoposide, etoposide phosphate, exatecan, irinotecan (also active metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin)), lucanthone, mitoxantrone, pixantrone, rubitecan, teniposide, topotecan, and 9-aminocamptothecin; a kinase inhibitor, including, but not limited to, axitinib (AG 013736), dasatinib (BMS 354825), erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, motesanib diphosphate (AMG 706), nilotinib (AMN107), seliciclib, sorafenib, sunitinib malate, AEE-788, BMS-599626, UCN-01(7-hydroxystaurosporine), and vatalanib; a targeted signal transduction inhibitor including, but not limited to bortezomib, geldanamycin, and rapamycin; a biological response modifier, including, but not limited to, imiquimod, interferon-α, and interleukin-2; and other chemotherapeutics, including, but not limited to 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors (e.g. temsirolimus, everolimus, deforolimus), PI3K inhibitors (e.g. BEZ235, GDC-0941, XL147, XL765), Cdk4 inhibitors (e.g. PD-332991), Akt inhibitors, Hsp90 inhibitors (e.g. tanespimycin) and farnesyltransferase inhibitors (e.g. tipifarnib). Preferably, the method of treating a cancer involves administering to the subject an effective amount of a composition including any one or more compound(s) of the invention as described herein in combination with a chemotherapeutic agent selected from capecitabine, 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab, interferon-α, interleukin-2, or erlotinib.
  • In a one hundred and thirteenth aspect, the invention provides a method of treating or prophylaxis of a disease or condition in a mammal, by administering to the mammal a therapeutically effective amount of any one or more compound(s) of the invention as described herein, a prodrug of such compound, or a pharmaceutically acceptable salt of such compound or prodrug. The compound can be alone or can be part of a composition. In another aspect, the invention provides a method of treating or prophylaxis of a disease or condition in a mammal, by administering to the mammal a therapeutically effective amount of one or more compounds as described herein, a prodrug of such compound, or a pharmaceutically acceptable salt of such compound or prodrug in combination with one or more other suitable therapies for the disease or condition.
  • In a one hundred and fourteenth aspect, the invention provides kits that include any one or more compound(s) or the invention or composition thereof as described herein. In some embodiments, the composition is packaged, e.g., in a vial, bottle, flask, which may be further packaged, e.g., within a box, envelope, or bag; the composition is approved by the U.S. Food and Drug Administration or similar regulatory agency for administration to a mammal, e.g., a human; the composition is approved for administration to a mammal, e.g., a human, for a protein kinase mediated disease or condition; the invention kit includes written instructions for use and/or other indication that the composition is suitable or approved for administration to a mammal, e.g., a human, for a protein kinase-mediated disease or condition; and the composition is packaged in unit dose or single dose form, e.g., single dose pills, capsules, or the like.
  • In aspects and embodiments involving treatment or prophylaxis of a disease or condition with the compounds as described herein, the invention provides methods for treating an A-Raf-mediated, B-Raf-mediated and/or c-Raf-1-mediated disease or condition in an animal subject (e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), e.g., a disease or condition characterized by abnormal A-Raf, B-Raf, and/or c-Raf-1 activity (e.g. kinase activity). In some embodiments, invention methods may involve administering to the subject suffering from or at risk of an A-Raf-mediated, B-Raf-mediated and/or c-Raf-1-mediated disease or condition an effective amount of compounds as described herein. In one embodiment, the A-Raf-mediated, B-Raf-mediated, and/or c-Raf-1-mediated disease is selected from the group consisting of neurologic diseases, including, but not limited to, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, seizures and epilepsy; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. gastrointestinal, liver, bile duct (cholangiocarcinoma), colorectal, lung, breast, pancreatic, thyroid, renal, ovarian, prostate), lymphoma (e.g. histiocytic lymphoma) neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer, Kaposi's sarcoma, and pheochromocytoma; pain of neuropathic or inflammatory origin, including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine; cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g. thrombotic microangiopathy syndromes), atherosclerosis, and reperfusion injury; inflammation and/or proliferation including, but not limited to, psoriasis, eczema, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiency diseases, including, but not limited to, organ transplant rejection, graft versus host disease, and Kaposi's sarcoma associated with HIV; renal, cystic, or prostatic diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, polycystic liver disease, tuberous sclerosis, Von Hippel Lindau disease, medullary cystic kidney disease, nephronophthisis, and cystic fibrosis; metabolic disorders, including, but not limited to, obesity; infection, including, but not limited to Helicobacter pylori, Hepatitis and Influenza viruses, fever, HIV and sepsis; pulmonary diseases including, but not limited to, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental diseases, including, but not limited to, Noonan's syndrome, Costello syndrome, (faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faciocutaneous syndrome (CFC), and neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases; and diseases associated with muscle regeneration or degeneration, including, but not limited to, sarcopenia, muscular dystrophies (including, but not limited to, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies), motor neuron diseases (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myositis), diseases of the neuromuscular junction (including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome), myopathies due to endocrine abnormalities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy) diseases of peripheral nerve (including, but not limited to, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, and periodic paralysis), and metabolic diseases of muscle (including, but not limited to, phosphorylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency). In one embodiment, the disease or condition is selected from the group consisting of melanoma, glioma, sarcoma, gastrointestinal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, lung cancer, breast cancer, pancreatic cancer, thyroid cancer, renal cancer, ovarian cancer, prostate cancer, histiocytic lymphoma, neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, medullary thyroid cancer, carcinoid, small cell lung cancer, Kaposi's sarcoma, pheochromocytoma, pain, and polycystic kidney disease. In a preferred embodiment, the disease or condition is selected from the group consisting of melanoma, colorectal cancer, thyroid cancer, ovarian cancer, cholangiocarcinoma, pain, and polycystic kidney disease.
  • In a one hundred and fifteenth aspect, compounds as described herein can be used in the preparation of a medicament for the treatment of an A-Raf-mediated, B-Raf-mediated or c-Raf-1-mediated disease or condition selected from the group consisting of neurologic diseases, including, but not limited to, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, seizures and epilepsy; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. gastrointestinal, liver, bile duct (cholangiocarcinoma), colorectal, lung, breast, pancreatic, thyroid, renal, ovarian, prostate), lymphoma (e.g. histiocytic lymphoma) neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer, Kaposi's sarcoma, and pheochromocytoma; pain of neuropathic or inflammatory origin, including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine; cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g. thrombotic microangiopathy syndromes), atherosclerosis, and reperfusion injury; inflammation and/or proliferation including, but not limited to, psoriasis, eczema, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiency diseases, including, but not limited to, organ transplant rejection, graft versus host disease, and Kaposi's sarcoma associated with HIV; renal, cystic, or prostatic diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, polycystic liver disease, tuberous sclerosis, Von Hippel Lindau disease, medullary cystic kidney disease, nephronophthisis, and cystic fibrosis; metabolic disorders, including, but not limited to, obesity; infection, including, but not limited to Helicobacter pylori, Hepatitis and Influenza viruses, fever, HIV and sepsis; pulmonary diseases including, but not limited to, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental diseases, including, but not limited to, Noonan's syndrome, Costello syndrome, (faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faciocutaneous syndrome (CFC), and neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases; and diseases associated with muscle regeneration or degeneration, including, but not limited to, sarcopenia, muscular dystrophies (including, but not limited to, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies), motor neuron diseases (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myositis), diseases of the neuromuscular junction (including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome), myopathies due to endocrine abnormalities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy) diseases of peripheral nerve (including, but not limited to, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, and periodic paralysis), and metabolic diseases of muscle (including, but not limited to, phosphorylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency). In one embodiment, the disease or condition is selected from the group consisting of melanoma, glioma, sarcoma, gastrointestinal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, lung cancer, breast cancer, pancreatic cancer, thyroid cancer, renal cancer, ovarian cancer, prostate cancer, histiocytic lymphoma, neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, medullary thyroid cancer, carcinoid, small cell lung cancer, Kaposi's sarcoma, pheochromocytoma, pain, and polycystic kidney disease. In a preferred embodiment, the disease or condition is selected from the group consisting of melanoma, colorectal cancer, thyroid cancer, ovarian cancer, cholangiocarcinoma, pain, and polycystic kidney disease.
  • Additional aspects and embodiments will be apparent from the following Detailed Description and from the claims.
    • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • As used herein the following definitions apply unless clearly indicated otherwise:
  • All atoms designated within a Formula or compound described herein, either within a structure provided, or within the definitions of variables related to the structure, is intended to include any isotope thereof, unless clearly indicated to the contrary. It is understood that for any given atom, the isotopes may be present essentially in ratios according to their natural occurrence, or one or more particular atoms may be enhanced with respect to one or more isotopes using synthetic methods known to one skilled in the art. Thus, hydrogen includes for example 1H, 2H, 3H; carbon includes for example 11C, 12C, 14C; oxygen includes for example 16O, 17O, 18O, nitrogen includes for example 13N, 14N, 15N; sulfur includes for example 32S, 33S, 34S, 35S, 36S, 37S, 38S; fluoro includes for example 17F, 18F, 19F; chloro includes for example 35Cl, 36Cl, 37Cl, 38Cl, 39Cl; and the like.
  • “Halogen” refer to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo (I).
  • “Hydroxyl” or “hydroxy” refer to the group —OH.
  • “Thiol” refers to the group —SH.
  • “Lower alkyl” alone or in combination means an alkane-derived radical containing from 1 to 6 carbon atoms (unless specifically defined) that includes a straight chain alkyl or branched alkyl. The straight chain or branched lower alkyl group is chemically feasible and attached at any available point to provide a stable compound. In many embodiments, a lower alkyl is a straight or branched alkyl group containing from 1-6, 1-4, or 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like. A “substituted lower alkyl” denotes lower alkyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents. For example “fluoro substituted lower alkyl” denotes a lower alkyl group substituted with one or more fluoro atoms, such as perfluoroalkyl, where preferably the lower alkyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
  • “Lower alkenyl” alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) and at least one, preferably I-3, more preferably I-2, most preferably one, carbon to carbon double bond. Carbon to carbon double bonds may be either contained within a straight chain or branched portion. The straight chain or branched lower alkenyl group is chemically feasible and attached at any available point to provide a stable compound. Examples of lower alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and the like. A “substituted lower alkenyl” denotes lower alkenyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents. For example “fluoro substituted lower alkenyl” denotes a lower alkenyl group substituted with one or more fluoro atoms, where preferably the lower alkenyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
  • “Lower alkynyl” alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) containing at least one, preferably one, carbon to carbon triple bond. The straight chain or branched lower alkynyl group is chemically feasible and attached at any available point to provide a stable compound. Examples of alkynyl groups include ethynyl, propynyl, butynyl, and the like. A “substituted lower alkynyl” denotes lower alkynyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents. For example “fluoro substituted lower alkynyl” denotes a lower alkynyl group substituted with one or more fluoro atoms, where preferably the lower alkynyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound
  • “Cycloalkyl” refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems of 3-10, also 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like. A “substituted cycloalkyl” is a cycloalkyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
  • “Heterocycloalkyl” refers to a saturated or unsaturated non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally fused with benzo or heteroaryl of 5-6 ring members. Heterocycloalkyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. Heterocycloalkyl is also intended to include compounds in which a ring carbon may be oxo substituted, i.e. the ring carbon is a carbonyl group, such as lactones and lactams. The point of attachment of the heterocycloalkyl ring is at a carbon or nitrogen atom such that a stable ring is retained. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl. A “substituted heterocycloalkyl” is a heterocycloalkyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
  • “Aryl” alone or in combination refers to a monocyclic or bicyclic ring system containing aromatic hydrocarbons such as phenyl or naphthyl, which may be optionally fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members. A “substituted aryl” is an aryl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
  • “Heteroaryl” alone or in combination refers to a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, even more preferably 1-2, heteroatoms independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound is provided. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl. A “substituted heteroaryl” is a heteroaryl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
  • “Lower alkoxy” denotes the group —ORa, where Ra is lower alkyl. “Substituted lower alkoxy” denotes lower alkoxy in which Ra is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I, including descriptions of substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl, attached at any available atom to provide a stable compound. Preferably, substitution of lower alkoxy is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents. For example “fluoro substituted lower alkoxy” denotes lower alkoxy in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that substitutions on alkoxy are chemically feasible and attached at any available atom to provide a stable compound.
  • “Lower alkylthio” denotes the group —SRb, where Rb is lower alkyl. “Substituted lower alkylthio” denotes lower alkylthio in which Rb is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I, including descriptions of substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl, attached at any available atom to provide a stable compound. Preferably, substitution of lower alkylthio is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents. For example “fluoro substituted lower alkylthio” denotes lower alkylthio in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkylthio is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that substitutions on alkylthio are chemically feasible and attached at any available atom to provide a stable compound.
  • “Amino” or “amine” denotes the group —NH2. “Mono-alkylamino” denotes the group —NHRc where Rc is lower alkyl. “Di-alkylamino” denotes the group —NRcRd, where Rc and Rd are independently lower alkyl. “Cycloalkylamino” denotes the group —NReRf, where Re and Rf combine with the nitrogen to form a 5-7 membered heterocycloalkyl, where the heterocycloalkyl may contain an additional heteroatom within the ring, such as O, N, or S, and may also be further substituted with one or more lower alkyl. Examples of 5-7 membered heterocycloalkyl include, but are not limited to, piperidine, piperazine, 4-methylpiperazine, morpholine, and thiomorpholine. It is understood that when mono-alkylamino, di-alkylamino, or cycloalkylamino are substituents on other moieties, these are chemically feasible and attached at any available atom to provide a stable compound.
  • As used herein, the term “solid form” refers to a solid preparation (i.e. a preparation that is neither gas nor liquid) of a pharmaceutically active compound that is suitable for administration to an intended animal subject for therapeutic purposes. The solid form includes any complex, such as a salt, co-crystal or an amorphous complex, as well as any polymorph of the compound. The solid form may be substantially crystalline, semi-crystalline or substantially amorphous. The solid form may be administered directly or used in the preparation of a suitable composition having improved pharmaceutical properties. For example, the solid form may be used in a formulation comprising at least one pharmaceutically acceptable carrier or excipient.
  • As used herein, the term “substantially crystalline” material embraces material which has greater than about 90% crystallinity; and “crystalline” material embraces material which has greater than about 98% crystallinity.
  • As used herein, the term “substantially amorphous” material embraces material which has no more than about 10% crystallinity; and “amorphous” material embraces material which has no more than about 2% crystallinity.
  • As used herein, the term “semi-crystalline” material embraces material which is greater than 10% crystallinity, but no greater than 90% crystallinity; preferably “semi-crystalline” material embraces material which is greater than 20% crystallinity, but no greater than 80% crystallinity. In one aspect of the present invention, a mixture of solid forms of a compound may be prepared, for example, a mixture of amorphous and crystalline solid forms, e.g. to provide a “semi-crystalline” solid form. Such a “semi-crystalline” solid form may be prepared by methods known in the art, for example by mixing an amorphous solid form with a crystalline solid form in the desired ratio. Alternatively, the complex of the compound and arginine or lysine may be prepared with an amount of compound component in excess of the stoichiometry of the complex, thereby resulting in an amount of the complex that is based on the stoichiometry of the complex, with excess compound in a crystalline form. The amount of excess compound used in the preparation of the complex can be adjusted to provide the desired ratio of amorphous complex to crystalline compound in the resulting mixture of solid forms. For example, where the amorphous complex of arginine and compound has a 1:1 stoichiometry, preparing said complex with a 2:1 mole ratio of compound to arginine will result in a solid form of 50% amorphous complex and 50% crystalline compound. Such a mixture of solid forms may be beneficial as a drug product, for example, by providing an amorphous component having improved biopharmaceutical properties along with the crystalline component. The amorphous component would be more readily bioavailable while the crystalline component would have a delayed bioavailablity. Such a mixture may provide both rapid and extended exposure to the active compound.
  • As used herein, the term “complex” refers to a combination of a pharmaceutically active compound and an additional molecular species that forms or produces a new chemical species in a solid form. In some instances, the complex may be a salt, i.e. where the additional molecular species provides an acid/base counter ion to an acid/base group of the compound resulting in an acid:base interaction that forms a typical salt. While such salt forms are typically substantially crystalline, they can also be partially crystalline, substantially amorphous, or amorphous forms. In some instances, the additional molecular species, in combination with the pharmaceutically active compound, forms a non-salt co-crystal, i.e. the compound and molecular species do not interact by way of a typical acid:base interaction, but still form a substantially crystalline structure. In some instances, the pharmaceutically active compound and two additional molecular species may form a ternary complex, where the ternary complex could be amorphous, partially amorphous, or crystalline, such as a co-crystal. For example, co-crystals may be formed from a salt of the compound and an additional molecular species. In some instances, the complex is a substantially amorphous complex, which may contain salt-like acid:base interactions that do not form typical salt crystals, but instead form a substantially amorphous solid, i.e. a solid whose X-ray powder diffraction pattern exhibits no sharp peaks (e.g. exhibits an amorphous halo).
  • As used herein, the term “stoichiometry” refers to the molar ratio of two or more reactants that combine to form a complex, for example, the molar ratio of arginine to compound that form an amorphous complex. For example, a 1:1 mixture of arginine with compound (i.e. 1 mole arginine per mole of compound) resulting in an amorphous solid form has a 1:1 stoichiometry.
  • As used herein, the term “composition” refers to a pharmaceutical preparation suitable for administration to an intended animal subject for therapeutic purposes that contains at least one pharmaceutically active compound, including any solid form thereof. The composition may include at least one pharmaceutically acceptable component to provide an improved formulation of the compound, such as a suitable carrier or excipient.
  • As used herein, the term “biopharmaceutical properties” refers to the pharmacokinetic action of a pharmaceutical (e.g. a compound or complex of the present invention), including the dissolution, absorption and distribution of the compound on administration to an animal. As such, the amorphous complexes of compounds of the invention are intended to provide improved dissolution and absorption of the active compound, which is typically reflected in improved Cmax (i.e. the maximum achieved concentration in the plasma after administration of the drug) and improved AUC (i.e. area under the curve of drug plasma concentration vs. time after administration of the drug).
  • The term “pharmaceutically acceptable” indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectibles.
  • In the present context, the term “therapeutically effective” or “effective amount” indicates that the materials or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated.
  • In the present context, the terms “synergistically effective” or “synergistic effect” indicate that two or more compounds that are therapeutically effective, when used in combination, provide improved therapeutic effects greater than the additive effect that would be expected based on the effect of each compound used by itself.
  • As used herein, the term “modulating” or “modulate” refers to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule such as a protein kinase. For example, an agonist or antagonist of a particular biomolecule modulates the activity of that biomolecule, e.g., an enzyme, by either increasing (e.g. agonist, activator), or decreasing (e.g. antagonist, inhibitor) the activity of the biomolecule, such as an enzyme. Such activity is typically indicated in terms of an inhibitory concentration (IC50) or excitation concentration (EC50) of the compound for an inhibitor or activator, respectively, with respect to, for example, an enzyme.
  • “Pain” or a “pain condition” can be acute and/or chronic pain, including, without limitation, arachnoiditis; arthritis (e.g. osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout); back pain (e.g. sciatica, ruptured disc, spondylolisthesis, radiculopathy); burn pain; cancer pain; dysmenorrhea; headaches (e.g. migraine, cluster headaches, tension headaches); head and facial pain (e.g. cranial neuralgia, trigeminal neuralgia); hyperalgesia; hyperpathia; inflammatory pain (e.g. pain associated with irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, cystitis, pain from bacterial, fungal or viral infection); keloid or scar tissue formation; labor or delivery pain; muscle pain (e.g. as a result of polymyositis, dermatomyositis, inclusion body myositis, repetitive stress injury (e.g. writer's cramp, carpal tunnel syndrome, tendonitis, tenosynovitis)); myofascial pain syndromes (e.g. fibromyalgia); neuropathic pain (e.g. diabetic neuropathy, causalgia, entrapment neuropathy, brachial plexus avulsion, occipital neuralgia, gout, reflex sympathetic dystrophy syndrome, phantom limb or post-amputation pain, postherpetic neuralgia, central pain syndrome, or nerve pain resulting from trauma (e.g. nerve injury), disease (e.g. diabetes, multiple sclerosis, Guillan-Barre Syndrome, myasthenia gravis, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, or cancer treatment); pain associated with skin disorders (e.g. shingles, herpes simplex, skin tumors, cysts, neurofibromatosis); sports injuries (e.g. cuts, sprains, strains, bruises, dislocations, fractures, spinal chord, head); spinal stenosis; surgical pain; tactile allodynia; temporomandibular disorders; vascular disease or injury (e.g. vasculitis, coronary artery disease, reperfusion injury (e.g. following ischemia, stroke, or myocardial infarcts)); other specific organ or tissue pain (e.g. ocular pain, corneal pain, bone pain, heart pain, visceral pain (e.g. kidney, gall bladder, gastrointestinal), joint pain, dental pain, pelvic hypersensitivity, pelvic pain, renal colic, urinary incontinence); other disease associated pain (e.g. sickle cell anemia, AIDS, herpes zoster, psoriasis, endometriosis, asthma, chronic obstructive pulmonary disease (COPD), silicosis, pulmonary sarcoidosis, esophagitis, heart burn, gastroesophageal reflux disorder, stomach and duodenal ulcers, functional dyspepsia, bone resorption disease, osteoporosis, cerebral malaria, bacterial meningitis); or pain due to graft v. host rejection or allograft rejections.
  • The present invention concerns compounds and compositions as disclosed herein that are modulators of protein kinases, for example without limitation, the compounds are modulators, preferably inhibitors, of at least one of the kinases selected from the group consisting of Ab1, Akt1, Akt2, Akt3, ALK, Alk5, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3α, Gsk3β, HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, mTOR, p38, PDGFRA, PDGFRB, PDPK1, PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ, Pim1, Pim2, Pim3, PKC alpha, PKC beta, PKC theta, Plk1, Pyk2, Ret, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, and Zap70, and the use of such compounds in the treatment of diseases or conditions.
  • The compounds of the invention with kinase inhibitory activity IC50 less than 10 μM as determined in a standard assay known in the art can be used to treat protein kinase mediated diseases and conditions related to the following protein kinases, including any mutations thereof, for example without limitation:
      • Ab1, related to chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML);
      • Akt1, related to gastric, prostate, colorectal, ovarian, pancreatic and breast cancer, glioblastoma and leukemia, as well as schizophrenia and bipolar disorders, and also use in combination with other chemotherapeutic drugs;
      • Akt2, related to hyperglycemia due to peripheral insulin resistance and nonsuppressible hepatic glucose production accompanied by inadequate compensatory hyperinsulinemia, also related to pancreatic, ovarian and breast cancer;
      • Akt3, related to melanoma, prostate and breast cancer;
      • ALK, related to non-Hodgkin lymphomas such as diffuse large B-cell lymphoma and anaplastic large cell lymphoma;
      • Alk5, related to pancreatic and biliary cancers, and cutaneous T-cell lymphoma;
      • A-Raf, related to neurologic diseases such as multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g. histiocytic lymphoma), neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis; pain of neuropathic or inflammatory origin, including acute pain, chronic pain, cancer-related pain and migraine; and diseases associated with muscle regeneration or degeneration, including, but not limited to, vascular restenosis, sarcopenia, muscular dystrophies (including, but not limited to, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies), motor neuron diseases (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myositis), diseases of the neuromuscular junction (including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome), myopathies due to endocrine abnormalities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy) diseases of peripheral nerve (including, but not limited to, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, and periodic paralysis), and metabolic diseases of muscle (including, but not limited to, phosphorylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency);
      • B-Raf or c-Raf-1, related to neurologic diseases, including, but not limited to, as multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g. histiocytic lymphoma) neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma; pain of neuropathic or inflammatory origin, including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine; cardiovascular diseases including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g. thrombotic microangiopathy syndromes), atherosclerosis, reperfusion injury; inflammation including, but not limited to, psoriasis, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiency diseases, including, but not limited to, organ transplant rejection, graft versus host disease; renal or prostatic diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia; metabolic disorders, including, but not limited to, obesity; infection, including, but not limited to, Helicobacter pylori, Hepatitis and Influenza viruses, fever, and sepsis; pulmonary diseases including, but not limited to, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental diseases, including, but not limited to, Noonan's syndrome, Costello syndrome, (faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faciocutaneous syndrome (CFC), and neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases;
      • Brk, related to breast and colon cancer, and head and neck squamous cell carcinoma;
      • Btk, related to X-linked agammaglobulinemia, acute lymphocytic leukemia, autoimmune diseases such as multiple sclerosis, systemic lupus erythematosis, rheumatoid arthritis, and Graves' disease, immune suppression in organ transplant, and drug sensitivity of B-lineage cells;
      • Cdk2, related to prostate, breast, colorectal and ovarian cancer;
      • Cdk4, related to glioblastoma (e.g. glioblastoma multiforme), anaplastic astrocytoma, and breast cancer;
      • Cdk5, related to Alzheimer's disease, amyotrophic lateral sclerosis and Lewy body disease;
      • Cdk6, related to glioblastoma multiforme, non-Hodgkin's lymphoma, splenic marginal zone lymphoma, T-cell lymphoblastic lymphoma (T-LBL) and T-cell acute lymphoblastic leukemia (T-ALL);
      • CHK1, related to DNA damage repair, sensitizes cells to chemotherapeutic agents;
      • Csk, related to colon and pancreatic carcinomas and autoimmune pathology such as type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus;
      • EGFR, related to breast, colorectal, bladder, prostate and non small cell lung cancer, squamous cell carcinomas of the head and neck cancer, oral cavity, and esophagus, and glioblastoma multiforme;
      • EphA1, related to head and neck squamous cell carcinoma, hepatoma and lung cancer;
      • EphA2, related to aberrant short-range contact-mediated axonal guidance, bladder, breast, prostate, colon, skin, cervical, ovarian, pancreatic and lung cancers, and metastatic melanoma;
      • EphB2, related to angiogenesis disorder (e.g. ocular angiogenesis disease such as retinopathy), and cancer (e.g. glioblastoma, breast and liver cancer);
      • EphB4, related to colorectal cancer (CRC), head and neck squamous cell carcinoma, and tumours of the prostate, breast, endometrium, and bladder;
      • Erk2, related to aberrant proliferation, differentiation, transcription regulation and development, and may be useful in treating inflammation, for example inflammation associated with Lyme neuroborreliosis, and in treating cancers, such as gastric cancer;
      • Fak, related to colon and breast tumors, and is also related to esophageal squamous cell carcinoma, melanoma, anaplastic astrocytoma, glioblastoma, ductal carcinoma in situ, prostate and hepatocellular carcinoma, and tumor metastases, and may also provide synergistic effects when used with other chemotherapeutic drugs;
      • FGFR1, related to 8 μl myeloproliferative syndrome;
      • FGFR2, related to Crouzon Syndrome, Jackson-Weiss Syndrome, Apert Syndrome, craniosynostosis, Pfeiffer Syndrome, acrocephalo syndactyl)-type V, and Beare-Stevenson Cutis Gyrata Syndrome;
      • FGFR3, related to angiogenesis, wound healing, achondroplasia, Muenke craniosynostosis, Crouzon syndrome, acanthosis nigricans, thanatophoric dysplasia, bladder carcinomas, and multiple myeloma;
      • FGFR4, related to cancer of the breast, lung, colon, medullary thyroid, pancreas, ovary, prostate, endometrium, and fallopian tube, head and neck squamous cell carcinomas and leiomyosarcoma;
      • Flt1, related to non-small cell lung carcinoma, prostate carcinoma, and colorectal cancer;
      • Flt3, related to acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia;
      • Flt4, related to primary lymphoedema;
      • Fms, related to immune disorders, including rheumatoid arthritis, systemic lupus erythematosis (SLE), and transplant rejection, inflammatory diseases including inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), emphysema, and atherosclerosis, metabolic disorders, including Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, and lipolysis, disorders of bone structure, mineralization and bone formation and resorption, including osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, and metastasis of cancer to bone, kidney diseases, including nephritis (e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes-associated renal complications (e.g. diabetic nephropathy), and hypertrophy, disorders of the central nervous system, including multiple sclerosis, stroke, Alzheimer's disease and Parkinson's disease; inflammatory and chronic pain, including bone pain; and cancers, including multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia (CML), prostate cancer, breast cancer, ovarian cancer, and metastasis of tumors to other tissues;
      • Frk, related to acute myeloid leukemia and type 1 diabetes;
      • Fyn, related to Alzheimer's disease, schizophrenia and prevention of metastases, e.g. in melanoma and squamous cell carcinoma;
      • GSK3 (Gsk3α and/or Gsk3β), related to CNS disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetes type II, bipolar disorders, stroke, cancer, chronic inflammatory disease, leucopenia, schizophrenia, chronic pain, neuropathic pain, and traumatic head injury;
      • HCK, related to chronic myelogenous leukemia and acute lymphocytic leukemia;
      • Her2/Erbb2, related to prostate and breast cancer;
      • Her4/Erbb4, related to childhood medulloblastoma;
      • IGF1R, related to prostate cancer, hepatocellular carcinoma;
      • IKK beta, related to leukemia of T-cells, necrosis, insulin resistance, and malignant neoplasms;
      • Irak4, related to bacterial infections, immunodeficiency syndrome, Crohn's disease, ulcerative colitis, asthma, chronic bronchitis, cardio hypertrophy, and kidney hypertension;
      • Itk, related to allergic asthma;
      • Jak1, related to Hepatitis C virus infection;
      • Jak2, related to myeloproliferative disorders such as polycythaemia vera, myelofibrosis, essential thrombocythemia, myeloid metaplasia and leukemias, including acute lymphoblastic leukemia, chronic neutrophilic leukemia, juvenile myelomonocytic leukemia, CMML, Philadelphia chromosome-negative CML, megakaryocytic leukemia, and acute erythroid leukemia;
      • Jak3, related to X-linked severe combined immunodeficiency, myeloproliferative disorders, transplant rejection and autoimmune diseases such as rheumatoid arthritis, inflammatory bowel syndrome, Crohn's disease, systemic lupus erythematosis, ulcerative colitis, psoriasis and multiple sclerosis;
      • Jnk (Jnk1, Jnk2, Jnk3), related to metabolic diseases including type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, and hepatic steatosis; cardiovascular diseases such as atherosclerosis, ischemia (e.g. cerebrovascular ischemia, liver ischemia), reperfusion injury, cardiac hypertrophy; renal diseases such as chronic renal failure; neoplastic diseases and associated complications, including chemotherapy-induced hypoxia, prostate tumors, myeloid leukemia and cancers of the liver, bone, skin, brain, pancreas, lung breast, colon, prostate and ovary; transplant rejection; pain of neuropathic or inflammatory origin including acute and chronic pain; inflammatory and autoimmune diseases including age-related macular degeneration, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosis, Sjogren's Syndrome, psoriasis, scleroderma, chronic thyroiditis, Grave's disease, myasthenia gravis, and multiple sclerosis, and inflammation in other organs including CNS inflammation, pancreatitis, nephritis, atopic dermatitis, and hepatitis; airway inflammatory diseases such as asthma, allergy, bronchitis, pulmonary fibrosis, chronic obstructive pulmonary disease; neurologic diseases such as stroke, cerebrovascular ischemia, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, dementia, senile chorea, head and spinal cord trauma, and Huntington's disease. More particularly, Jnk1 is related to type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity and hepatic steatosis, Jnk2 is related to atherosclerosis, and Jnk3 is related to inflammatory diseases including autoimmune diseases such as rheumatoid arthritis, inflammatory bowel syndrome, Crohn's disease, systemic lupus erythematosis, Sjogren's Syndrome, psoriasis and multiple sclerosis, airway inflammatory diseases such as asthma, allergy, pulmonary fibrosis, and chronic obstructive pulmonary disease, and inflammation in other organs, such as CNS inflammation, pancreatitis, nephritis, and hepatitis; neurologic diseases such as stroke, cerebrovascular ischemia, and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease; and neoplastic diseases such as prostate tumors and myeloid leukemia;
      • Kdr, related to anti-angiogenesis for treating solid tumor growth (e.g. ovarian, lung, breast, prancreatic, prostate, colon, gastrointestinal stromal tumor, non small cell lung cancer, and epidermoid cancer), metastasis, psoriasis, rheumatoid arthritis, diabetic retinopathy and age related macular degeneration;
      • Kit, related to malignancies, including mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GISTS), glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, mastocytosis, melanoma, and canine mast cell tumors, and inflammatory diseases, including asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, and hypereosinophilia;
      • Lck, related to acute lymphoblastic leukemia, T-cell lymphoma, lymphopenia, renal carcinoma, colon carcinoma, severe combined immunodeficiency, multiple sclerosis, inflammatory bowel and type I diabetes;
      • Lyn, related to
      • MAP2K1, related to acute myeloid leukemia, breast, ovarian and liver cancer;
      • MAP2K2, related to cancer and inflammation;
      • MAP4K4, related to metabolic indications, including re-sensitizing fat and muscle cells to insulin, ameliorating the pathology in adipocytes, ameliorating the pathology in muscle cells, metabolic syndrome, and type II diabetes; a broad range of oncology indications, including blocking the migration, invasion and metastasis in many different tumor types; and T-cell mediated autoimmune diseases;
      • MAPKAPK2, cancer (e.g. prostate, breast), stroke, menengitis, and inflammatory disorders;
      • Met, related to kidney, breast, bladder, non-small-cell lung, colorectal, and bladder cancers, and hepatocellular carcinoma;
      • Mnk1, related to conditions associated with heat shock, nutrient deprivation, oxidative or osmotic stress, and infection of mammalian cells (e.g. with viruses such as adenovirus (Ad) or influenza virus), and autoimmune diseases;
      • MLK1, related to neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, and inflammatory disorders;
      • mTOR, related to neuronal tumors, breast cancer, prostate cancer, acute myelogenous leukemia, lung cancer, pancreatic cancer, colon cancer, renal cancer and myeloma;
      • p38, related to acute coronary syndrome, stroke, atherosclerosis, and inflammatory autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and Crohn's disease;
      • PDGFR(PDGFRA, PDGFRB), related to idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, glioma, gastrointestinal stromal tumors (GISTS), juvenile myelomonocytic leukemia, metastatic medulloblastoma, atherogenesis, and restenosis. More particularly, PDGFRA related to idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, glioma, gastrointestinal stromal tumors (GISTS), juvenile myelomonocytic leukemia, metastatic medulloblastoma, atherogenesis, and restenosis, and PDGFRB related to idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, juvenile myelomonocytic leukemia, and metastatic medulloblastoma;
      • PDPK1, related to cancer and diabetes;
      • PI3K (including PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ), related to inflammatory disease, including asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, eosinophilia, lung fibrosis, osteoarthritis, ankylosing spondylitis, sepsis, septic shock, inflammatory myopathies, meningitis, encephalitis, lacrimal parotid gland syndrome, acute respiratory distress syndrome and pancreatitis, graft vs. host disease; allergies, including allergic rhinitis, type I hypersensitivity reactions, atopic dermatitis, contact dermatitis, and eczema; cardiovascular disease, including atherosclerosis, pulmonary hypertension, deep venous thrombosis, stroke, myocardial infarction, myocardial contractility disorders, ischemia, thromoemolism, pulmonary embolism, acute arterial ischemia, peripheral thrombotic occlusions, coronary artery disease and acute coronary syndrome; autoimmune disease, including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, glomerulonephritis, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, and Sjogren's syndrome; cancers, including ovarian cancer, cervical cancer, breast cancer, colorectal cancer, endometrial cancer, gastric carcinomas, hepatocellular carcinoma, pancreatic cancer, small and non-small cell lung cancer, thyroid carcinoma, lymphomas, multiple myelomas, leukemias (e.g. acute myelogenous leukemia, chronic myelogenous leukemia), neuroblastomas and glioblastomas;
      • Pim1, related to cancers such as hematopoietic (e.g. acute myeloid and acute lymphoid leukemias) and prostate cancers, and non-Hodgkin's lymphomas;
      • Pim2, related to lymphomas;
      • Pim3, related to hepatocellular carcinoma;
      • PKC alpha, related to pituitary tumors and prefrontal cortical dysfunction such as distractibility, impaired judgment, impulsivity, and thought disorder, also may be used to sensitize chemotherapy in breast, colon, and non small cell lung cancers;
      • PKC beta, related to diabetic retinopathy;
      • PKC-theta, related to insulin resistance, T-cell lymphoma;
      • Plk1, related to cancers (e.g. lymphoma of the thyroid, non-Hodgkin's lymphomas, colorectal cancers, leukemias and melanoma), also useful as sensitizer in chemotherapy;
      • Pyk2, related to inflammation (e.g. osteoporosis, polycystic kidney disease, rheumatoid arthritis and inflammatory bowel disease), CNS disease (e.g. Parkinson's disease and Alzheimer's disease), stroke and cancers (e.g. gliomas, breast cancer, and pancreatic cancer);
      • Ret, related to cancer of the thyroid, neuroblastoma, familial medullary thyroid carcinoma (FMTC), multiple endocrine neoplasia type IIA and IIB (MEN2A, MEN2B), and neurodegenerative disorders (e.g. Hirschsprung's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis);
      • ROCK (ROCK-1, ROCK-2), related to cancers (e.g. ovarian cancer, hepatocellular carcinoma, pancreatic cancer), ocular disease (e.g. glaucoma), cardiac hypertrophy, improved renal perfusion, transplant rejection, and acute respiratory distress syndrome;
      • Ron, related to cancer and inflammation;
      • Src, related to cancer and osteoporosis;
      • Stk6, related to gastric, bladder, breast, lung, CNS, ovarian, kidney, colon, prostate, pancreas, and cervical cancers, melanoma, leukemia, and neuroblastoma;
      • Syk, related to lymphomas (e.g. mantle cell lymphoma);
      • TEC, related to sepsis, septic shock, inflammation, rheumatoid arthritis, Crohn's disease, irritable bowel disease (IBD), and ulcerative colitis;
      • Tie2 (TEK), related to cancer, arthritis (e.g. rheumatoid arthritis), and atherosclerosis;
      • TrkA, related to pain (e.g. chronic pain, neuropathic pain), cancer (e.g. prostate cancer, lung cancer, pancreatic cancer), allergic disorders (e.g. asthma), arthritis, diabetic retinopathy, macular degeneration and psoriasis;
      • TrkB, related to obesity, hyperphagia, developmental delays, cancer (e.g. prostate cancer, lung cancer, Wilms tumors, neuroblastoma, pancreatic cancer), various neuropathies (e.g. stroke, multiple sclerosis, transverse myelitis, and encephalitis), and diabetes.
      • Yes, related to various cancers including esophageal squamous cell carcinoma; and
      • Zap70, related to AIDS, systemic lupus erythematosus, myasthenia gravis, atherosclerosis, rejection of transplanted organs or tissues, allograft rejection including acute and chronic allograft rejection, graft versus host disease, rheumathoid arthritis, psoriasis, systemic sclerosis, atopic dermatitis, eczematous dermatitis, alopecia, and inflammation of the nasal mucus membrane, including all forms of rhinitis.
    Kinase Targets and Indications of the Invention
  • Protein kinases play key roles in propagating biochemical signals in diverse biological pathways. More than 500 kinases have been described, and specific kinases have been implicated in a wide range of diseases or conditions (i.e., indications), including for example without limitation, cancer, cardiovascular disease, inflammatory disease, neurological disease, and other diseases. As such, kinases represent important control points for small molecule therapeutic intervention. Specific target protein kinases contemplated by the present invention are described in the art, including, without limitation, protein kinases as described in U.S. patent application Ser. No. 11/473,347 (see also, PCT publication WO2007002433), the disclosure of which is hereby incorporated by reference in regards to such target protein kinases. Additional description of Raf target protein kinases contemplated by the present invention follow:
  • A-Raf: Target kinase A-Raf (i.e., v-raf murine sarcoma 3611 viral oncogene homolog I) is a 67.6 kDa serine/threonine kinase encoded by chromosome Xp11.4-p11.2 (symbol: ARAF). The mature protein comprises RBD (i.e., Ras binding domain) and phorbol-ester/DAG-type zinc finger domain and is involved in the transduction of mitogenic signals from the cell membrane to the nucleus. A-Raf inhibitors may be useful in treating neurologic diseases such as multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g. histiocytic lymphoma), neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis; pain of neuropathic or inflammatory origin, including acute pain, chronic pain, cancer-related pain and migraine; and diseases associated with muscle regeneration or degeneration, including, but not limited to, vascular restenosis, sarcopenia, muscular dystrophies (including, but not limited to, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies), motor neuron diseases (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myositis), diseases of the neuromuscular junction (including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome), myopathies due to endocrine abnormalities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy) diseases of peripheral nerve (including, but not limited to, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, and periodic paralysis), and metabolic diseases of muscle (including, but not limited to, phosphorylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency).
  • B-Raf: Target kinase B-Raf (i.e., v-raf murine sarcoma viral oncogene homolog BI) is a 84.4 kDa serine/threonine kinase encoded by chromosome 7q34 (symbol: BRAF). The mature protein comprises RBD (i.e., Ras binding domain), Cl (i.e., protein kinase C conserved region 1) and STK (i.e., serine/threonine kinase) domains.
  • Target kinase B-Raf is involved in the transduction of mitogenic signals from the cell membrane to the nucleus and may play a role in the postsynaptic responses of hippocampal neurons. As such, genes of the RAF family encode kinases that are regulated by Ras and mediate cellular responses to growth signals. Indeed, B-Raf kinase is a key component of the RAS->Raf->MEK->ERK/MAP kinase signaling pathway, which plays a fundamental role in the regulation of cell growth, division and proliferation, and, when constitutively activated, causes tumorigenesis. Among several isoforms of Raf kinase, the B-type, or B-Raf, is the strongest activator of the downstream MAP kinase signaling.
  • The BRAF gene is frequently mutated in a variety of human tumors, especially in malignant melanoma and colon carcinoma. The most common reported mutation was a missense thymine (T) to adenine (A) transversion at nucleotide 1796 (T1796A; amino acid change in the B-Raf protein is Val<600> to Glu<600>) observed in 80% of malignant melanoma tumors. Functional analysis reveals that this transversion is the only detected mutation that causes constitutive activation of B-Raf kinase activity, independent of RAS activation, by converting B-Raf into a dominant transforming protein. Based on precedents, human tumors develop resistance to kinase inhibitors by mutating a specific amino acid in the catalytic domain as the “gatekeeper”. (Balak, et. al., Clin Cancer Res. 2006, 12:6494-501). Mutation of Thr-529 in BRAF to Ile is thus anticipated as a mechanism of resistance to BRAF inhibitors, and this can be envisioned as a transition in codon 529 from ACC to ATC.
  • Niihori et al., report that in 43 individuals with cardio-facio-cutaneous (CFC) syndrome, they identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders (Niihori et al., Nat. Genet. 2006, 38(3):294-6).
  • c-Raf-1: Target kinase c-Raf-1 (i.e., v-raf murine sarcoma viral oncogene homolog 1) is a 73.0 kDa STK encoded by chromosome 3p25 (symbol: RAF1). c-Raf-1 can be targeted to the mitochondria by BCL2 (i.e., oncogene B-cell leukemia 2) which is a regulator of apoptotic cell death. Active c-Raf-1 improves BCL2-mediated resistance to apoptosis, and c-Raf-1 phosphorylates BAD (i.e., BCL2-binding protein). c-Raf-1 is implicated in carcinomas, including colorectal, ovarian, lung and renal cell carcinoma. C-Raf-1 is also implicated as an important mediator of tumor angiogenesis (Hood, J. D. et al., 2002, Science 296, 2404). C-Raf-1 inhibitors may also be useful for the treatment of acute myeloid leukemia and myelodysplastic syndromes (Crump, Curr Pharm Des 2002, 8(25):2243-8). Raf-1 activators may be useful as treatment for neuroendocrine tumors, such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma (Kunnimalaiyaan et al., Anticancer Drugs 2006, 17(2):139-42).
  • Raf inhibitors (A-Raf and/or B-Raf and/or C-Raf-1, and/or mutations thereof) may be useful in treating A-Raf-mediated, B-Raf-mediated or c-Raf-1-mediated disease or condition selected from the group consisting of neurologic diseases, including, but not limited to, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g. histiocytic lymphoma) neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma; pain of neuropathic or inflammatory origin, including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine; cardiovascular diseases, including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g. thrombotic microangiopathy syndromes), atherosclerosis, and reperfusion injury; inflammation including, but not limited to, psoriasis, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiency diseases, including, but not limited to, organ transplant rejection, graft versus host disease; renal or prostatic diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia; metabolic disorders, including, but not limited to, obesity; infection, including, but not limited to, Helicobacter pylori, Hepatitis and Influenza viruses, fever, and sepsis; pulmonary diseases, including, but not limited to, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental diseases, including, but not limited to, Noonan's syndrome, Costello syndrome, (faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faciocutaneous syndrome (CFC), and neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases.
    • Kinase Activity Assays
  • A number of different assays for kinase activity can be utilized for assaying for active modulators and/or determining specificity of a modulator for a particular kinase or group or kinases. In addition to the assay mentioned in the Examples below, one of ordinary skill in the art will know of other assays that can be utilized and can modify an assay for a particular application. For example, numerous papers concerning kinases describe assays that can be used.
  • Additional alternative assays can employ binding determinations. For example, this sort of assay can be formatted either in a fluorescence resonance energy transfer (FRET) format, or using an AlphaScreen (amplified luminescent proximity homogeneous assay) format by varying the donor and acceptor reagents that are attached to streptavidin or the phosphor-specific antibody.
    • Organic Synthetic Techniques
  • A wide array of organic synthetic techniques exist in the art to facilitate the construction of potential modulators. Many of these organic synthetic methods are described in detail in standard reference sources utilized by those skilled in the art. One example of such a reference is March, 1994, Advanced Organic Chemistry; Reactions, Mechanisms and Structure, New York, McGraw Hill. Thus, the techniques useful to synthesize a potential modulator of kinase function are readily available to those skilled in the art of organic chemical synthesis.
    • Alternative Compound Forms or Derivatives
  • Compounds contemplated herein are described with reference to both generic formulae and specific compounds. In addition, invention compounds may exist in a number of different forms or derivatives, all within the scope of the present invention. Alternative forms or derivatives, include, for example, (a) prodrugs, and active metabolites (b) tautomers, isomers (including stereoisomers and regioisomers), and racemic mixtures (c) pharmaceutically acceptable salts and (d) solid forms, including different crystal forms, polymorphic or amorphous solids, including hydrates and solvates thereof, and other forms.
  • (a) Prodrugs and Metabolites
  • In addition to the present formulae and compounds described herein, the invention also includes prodrugs (generally pharmaceutically acceptable prodrugs), active metabolic derivatives (active metabolites), and their pharmaceutically acceptable salts.
  • Prodrugs are compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by solvolysis, yield the desired active compound. Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound. Typically, the prodrug is inactive, or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties. For example, some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug. Esters include, for example, esters of a carboxylic acid group, or S-acyl or O-acyl derivatives of thiol, alcohol, or phenol groups. In this context, a common example is an alkyl ester of a carboxylic acid. Prodrugs may also include variants wherein an —NH group of the compound has undergone acylation, such as the 1-position of the pyrrolo[2,3-b]pyridine ring or the nitrogen of the sulfonamide group of compounds of the present invention, where cleavage of the acyl group provides the free —NH group of the active drug. Some prodrugs are activated enzymatically to yield the active compound, or a compound may undergo further chemical reaction to yield the active compound. Prodrugs may proceed from prodrug form to active form in a single step or may have one or more intermediate forms which may themselves have activity or may be inactive.
  • As described in The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001), prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. Generally, bioprecursor prodrugs are compounds that are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity. Typically, the formation of active drug compound involves a metabolic process or reaction that is one of the following types:
  • Oxidative reactions: Oxidative reactions are exemplified without limitation by reactions such as oxidation of alcohol, carbonyl, and acid functionalities, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N-dealkylation, oxidative O- and S-dealkylation, oxidative deamination, as well as other oxidative reactions.
  • Reductive reactions: Reductive reactions are exemplified without limitation by reactions such as reduction of carbonyl functionalitites, reduction of alcohol functionalities and carbon-carbon double bonds, reduction of nitrogen-containing functional groups, and other reduction reactions.
  • Reactions without change in the oxidation state: Reactions without change in the state of oxidation are exemplified without limitation to reactions such as hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration at multiple bonds, new atomic linkages resulting from dehydration reactions, hydrolytic dehalogenation, removal of hydrogen halide molecule, and other such reactions.
  • Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improves uptake and/or localized delivery to a site(s) of action. Desirably for such a carrier prodrug, the linkage between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, the prodrug and any release transport moiety are acceptably non-toxic. For prodrugs where the transport moiety is intended to enhance uptake, typically the release of the transport moiety should be rapid. In other cases, it is desirable to utilize a moiety that provides slow release, e.g., certain polymers or other moieties, such as cyclodextrins. (See, e.g., Cheng et al., U.S. Patent Publ. No. 20040077595, application Ser. No. 10/656,838, incorporated herein by reference.) Such carrier prodrugs are often advantageous for orally administered drugs. In some instances, the transport moiety provides targeted delivery of the drug, for example the drug maybe conjugated to an antibody or antibody fragment. Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property). For example, lipophilicity can be increased by esterification of hydroxyl groups with lipophilic carboxylic acids, or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols. Wermuth, supra.
  • Metabolites, e.g., active metabolites, overlap with prodrugs as described above, e.g., bioprecursor prodrugs. Thus, such metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic processes in the body of a subject. Of these, active metabolites are such pharmacologically active derivative compounds. For prodrugs, the prodrug compound is generally inactive or of lower activity than the metabolic product. For active metabolites, the parent compound may be either an active compound or may be an inactive prodrug. For example, in some compounds, one or more alkoxy groups can be metabolized to hydroxyl groups while retaining pharmacologic activity and/or carboxyl groups can be esterified, e.g., glucuronidation. In some cases, there can be more than one metabolite, where an intermediate metabolite(s) is further metabolized to provide an active metabolite. For example, in some cases a derivative compound resulting from metabolic glucuronidation may be inactive or of low activity, and can be further metabolized to provide an active metabolite.
  • Metabolites of a compound may be identified using routine techniques known in the art, and their activities determined using tests such as those described herein. See, e.g., Bertolini et al., 1997, J Med. Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci 86(7):756-757; Bagshawe, 1995, Drug Dev. Res., 34:220-230; Wermuth, supra.
  • (b) Tautomers, Stereoisomers, and Regioisomers
  • It is understood that some compounds may exhibit tautomerism. In such cases, the formulae provided herein expressly depict only one of the possible tautomeric forms. It is therefore to be understood that the formulae provided herein are intended to represent any tautomeric form of the depicted compounds and are not to be limited merely to the specific tautomeric form depicted by the drawings of the formulae.
  • Likewise, some of the compounds according to the present invention may exist as stereoisomers, i.e. having the same atomic connectivity of covalently bonded atoms yet differing in the spatial orientation of the atoms. For example, compounds may be optical stereoisomers, which contain one or more chiral centers, and therefore, may exist in two or more stereoisomeric forms (e.g. enantiomers or diastereomers). Thus, such compounds may be present as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, and/or mixtures of enantiomers and/or diastereomers. As another example, stereoisomers include geometric isomers, such as cis- or trans-orientation of substituents on adjacent carbons of a double bond. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Unless specified to the contrary, all such steroisomeric forms are included within the formulae provided herein.
  • In some embodiments, a chiral compound of the present invention is in a form that contains at least 80% of a single isomer (60% enantiomeric excess (“e.e.”) or diastereomeric excess (“d.e.”)), or at least 85% (70% e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5% (95% e.e. or d.e.), or 99% (98% e.e. or d.e.). As generally understood by those skilled in the art, an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure. In some embodiments, the compound is present in optically pure form, such optically pure form being prepared and/or isolated by methods known in the art (e.g. by recrystallization techniques, chiral synthetic techniques (including synthesis from optically pure starting materials), and chromatographic separation using a chiral column.
  • (c) Pharmaceutically Acceptable Salts
  • Unless specified to the contrary, specification of a compound herein includes pharmaceutically acceptable salts of such compound. Thus, compounds of the invention can be in the form of pharmaceutically acceptable salts, or can be formulated as pharmaceutically acceptable salts. Contemplated pharmaceutically acceptable salt forms include, without limitation, mono, bis, tris, tetrakis, and so on. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug. A compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly can react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing chloride, bromide, iodide, hydrochloride, acetate, phenylacetate, acrylate, ascorbate, aspartate, benzoate, 2-phenoxybenzoate, 2-acetoxybenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, bicarbonate, butyne-1,4 dioate, hexyne-1,6-dioate, caproate, caprylate, chlorobenzoate, cinnamate, citrate, decanoate, formate, fumarate, glycolate, gluconate, glucarate, glucuronate, glucose-6-phosphate, glutamate, heptanoate, hexanoate, isethionate, isobutyrate, gamma-hydroxybutyrate, phenylbutyrate, lactate, malate, maleate, hydroxymaleate, methylmaleate, malonate, mandelate, nicotinate, nitrate, isonicotinate, octanoate, oleate, oxalate, pamoate, phosphate, monohydrogenphosphate, dihydrogenphosphate, orthophosphate, metaphosphate, pyrophosphate, 2-phosphoglycerate, 3-phosphoglycerate, phthalate, propionate, phenylpropionate, propiolate, pyruvate, quinate, salicylate, 4-aminosalicylate, sebacate, stearate, suberate, succinate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, sulfamate, sulfonate, benzenesulfonate (i.e. besylate), ethanesulfonate (i.e. esylate), ethane-1,2-disulfonate, 2-hydroxyethanesulfonate (i.e. isethionate), methanesulfonate (i.e. mesylate), naphthalene-1-sulfonate, naphthalene-2-sulfonate (i.e. napsylate), propanesulfonate, p-toluenesulfonate (i.e. tosylate), xylenesulfonates, cyclohexylsulfamate, tartrate, and trifluoroacetate. These pharmaceutically acceptable acid addition salts can be prepared using the appropriate corresponding acid.
  • When acidic functional groups, such as carboxylic acid or phenol are present, pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, ethanolamine, diethanolamine, triethanolamine, t-butylamine, dicyclohexylamine, ethylenediamine, N,N′-dibenzylethylenediamine, meglumine, hydroxyethylpyrrolidine, piperidine, morpholine, piperazine, procaine, aluminum, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, ammonium, and mono-, di-, or tri-alkylamines (e.g. diethylamine), or salts derived from amino acids such as L-histidine, L-glycine, L-lysine, and L-arginine. For example, see Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Co., Easton, Pa., Vol. 2, p. 1457, 1995. These pharmaceutically acceptable base addition salts can be prepared using the appropriate corresponding base.
  • Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution. In another example, a salt can be prepared by reacting the free base and acid in an organic solvent. If the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an appropriate inorganic or organic base.
  • (d) Other Compound Forms
  • In the case of agents that are solids, it is understood by those skilled in the art that the compounds and salts may exist in different crystal or polymorphic forms, or may be formulated as co-crystals, or may be in an amorphous form, or may be any combination thereof (e.g. partially crystalline, partially amorphous, or mixtures of polymorphs) all of which are intended to be within the scope of the present invention and specified formulae. Whereas salts are formed by acid/base addition, i.e. a free base or free acid of the compound of interest forms an acid/base reaction with a corresponding addition base or addition acid, respectively, resulting in an ionic charge interaction, co-crystals are a new chemical species that is formed between neutral compounds, resulting in the compound and an additional molecular species in the same crystal structure.
  • In some instances, compounds of the invention are complexed with a basic amino acid, such as L-histidine, L-lysine, or L-arginine, preferably L-lysine or L-arginine. In some instances, the complex of the compound and basic amino acid further comprises a strong acid, such as hydrochloric acid. In such instances, the resulting ternary complex can be amorphous, partially amorphous, or crystalline (e.g. a co-crystal). In combining the compound of the invention with the basic amino acid, an amorphous complex is preferably formed rather than a crystalline material such as a typical salt or co-crystal. In some instances, the amorphous form of the complex is facilitated by additional processing, such as by spray-drying, mechanochemical methods such as roller compaction, or microwave irradiation of the parent compound mixed with the basic amino acid. Such amorphous complexes provide several advantages. For example, lowering of the melting temperature relative to the free base facilitiates additional processing, such as hot melt extrusion, to further improve the biopharmaceutical properties of the compound. Also, the amorphous complex is readily friable, which provides improved compression for loading of the solid into capsule or tablet form.
  • Additionally, the formulae are intended to cover hydrated or solvated as well as unhydrated or unsolvated forms of the identified structures. For example, the indicated compounds include both hydrated and non-hydrated forms. Other examples of solvates include the structures in combination with a suitable solvent, such as isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
    • Formulations and Administration
  • The methods and compounds will typically be used in therapy for human subjects. However, they may also be used to treat similar or identical indications in other animal subjects. Compounds of the invention can be administered by different routes, including injection (i.e. parenteral, including intravenous, intraperitoneal, subcutaneous, and intramuscular), oral, transdermal, transmucosal, rectal, or inhalant. Such dosage forms should allow the compound to reach target cells. Other factors are well known in the art, and include considerations such as toxicity and dosage forms that retard the compound or composition from exerting its effects. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Philadelphia, Pa., 2005 (hereby incorporated by reference herein).
  • In some embodiments, compositions will comprise pharmaceutically acceptable carriers or excipients, such as fillers, binders, disintegrants, glidants, lubricants, complexing agents, solubilizers, and surfactants, which may be chosen to facilitate administration of the compound by a particular route. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, and the like. Carriers also include physiologically compatible liquids as solvents or for suspensions, including, for example, sterile solutions of water for injection (WFI), saline solution, dextrose solution, Hank's solution, Ringer's solution, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, and the like. Excipients may also include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethyl cellulose, cross-linked sodium carboxymethylcellulose, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated cotton seed oil, castor seed oil mineral oil, polyethylene glycol (e.g. PEG 4000-8000), polyoxyethylene glycol, poloxamers, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, methacrylic acid divinylbenzene copolymer, sodium docusate, cyclodextrins (e.g. 2-hydroxypropyl-.delta.-cyclodextrin), polysorbates (e.g. polysorbate 80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ethers, di-fatty acid ester of polyethylene glycols, or a polyoxyalkylene sorbitan fatty acid ester (e.g., polyoxyethylene sorbitan ester Tween®), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid ester, e.g. a sorbitan fatty acid ester from a fatty acid such as oleic, stearic or palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, lactose monohydrate or lactose spray dried, sucrose, fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrates, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, simethicone, polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl methyl celluloses), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, hypromellose, and the like.
  • In some embodiments, oral administration may be used. Pharmaceutical preparations for oral use can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops. Compounds of the invention may be combined with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e.g. aqueous, alcoholic, or oily solutions) and the like. Suitable excipients are, in particular, fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone); oily excipients, including vegetable and animal oils, such as sunflower oil, olive oil, or codliver oil. The oral dosage formulations may also contain disintegrating agents, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate; a lubricant, such as talc or magnesium stearate; a plasticizer, such as glycerol or sorbitol; a sweetening such as sucrose, fructose, lactose, or aspartame; a natural or artificial flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring; or dye-stuffs or pigments, which may be used for identification or characterization of different doses or combinations. Also provided are dragee cores with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, poly-vinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin (“gelcaps”), as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • In some embodiments, injection (parenteral administration) may be used, e.g., intramuscular, intravenous, intraperitoneal, and/or subcutaneous. Compounds of Formula I for injection may be formulated in sterile liquid solutions, preferably in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. Dispersions may also be prepared in non-aqueous solutions, such as glycerol, propylene glycol, ethanol, liquid polyethylene glycols, triacetin, and vegetable oils. Solutions may also contain a preservative, such as methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In addition, the compounds may be formulated in solid form, including, for example, lyophilized forms, and redissolved or suspended prior to use.
  • In some embodiments, transmucosal, topical or transdermal administration may be used. In such formulations of compounds of Formula I, penetrants appropriate to the barrier to be permeated are used. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays or suppositories (rectal or vaginal). Compositions of compounds of Formula I for topical administration may be formulated as oils, creams, lotions, ointments, and the like by choice of appropriate carriers known in the art. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C12). In some embodiments, carriers are selected such that the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Creams for topical application are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of solvent (e.g., an oil), is admixed. Additionally, administration by transdermal means may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents known in the art. To be administered in the form of a transdermal delivery system, the dosage administration will be continuous rather than intermittent throughout the dosage regimen.
  • In some embodiments, compounds are administered as inhalants. Compounds of Formula I may be formulated as dry powder or a suitable solution, suspension, or aerosol. Powders and solutions may be formulated with suitable additives known in the art. For example, powders may include a suitable powder base such as lactose or starch, and solutions may comprise propylene glycol, sterile water, ethanol, sodium chloride and other additives, such as acid, alkali and buffer salts. Such solutions or suspensions may be administered by inhaling via spray, pump, atomizer, or nebulizer, and the like. The compounds of Formula I may also be used in combination with other inhaled therapies, for example corticosteroids such as fluticasone proprionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone furoate; beta agonists such as albuterol, salmeterol, and formoterol; anticholinergic agents such as ipratroprium bromide or tiotropium; vasodilators such as treprostinal and iloprost; enzymes such as DNAase; therapeutic proteins; immunoglobulin antibodies; an oligonucleotide, such as single or double stranded DNA or RNA, siRNA; antibiotics such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; cromolyn sodium; nedocril sodium; and sodium cromoglycate.
  • The amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound activity (in vitro, e.g. the compound IC50 vs. target, or in vivo activity in animal efficacy models), pharmacokinetic results in animal models (e.g. biological half-life or bioavailability), the age, size, and weight of the subject, and the disorder associated with the subject. The importance of these and other factors are well known to those of ordinary skill in the art. Generally, a dose will be in the range of about 0.01 to 50 mg/kg, also about 0.1 to 20 mg/kg of the subject being treated. Multiple doses may be used.
  • The compounds of Formula I may also be used in combination with other therapies for treating the same disease. Such combination use includes administration of the compounds and one or more other therapeutics at different times, or co-administration of the compound and one or more other therapies. In some embodiments, dosage may be modified for one or more of the compounds of the invention or other therapeutics used in combination, e.g., reduction in the amount dosed relative to a compound or therapy used alone, by methods well known to those of ordinary skill in the art.
  • It is understood that use in combination includes use with other therapies, drugs, medical procedures etc., where the other therapy or procedure may be administered at different times (e.g. within a short time, such as within hours (e.g. 1, 2, 3, 4-24 hours), or within a longer time (e.g. I-2 days, 2-4 days, 4-7 days, I-4 weeks)) than a compound of Formula I, or at the same time as a compound of Formula I. Use in combination also includes use with a therapy or medical procedure that is administered once or infrequently, such as surgery, along with a compound of Formula I administered within a short time or longer time before or after the other therapy or procedure. In some embodiments, the present invention provides for delivery of a compound of Formula I and one or more other drug therapeutics delivered by a different route of administration or by the same route of administration. The use in combination for any route of administration includes delivery of a compound of Formula I and one or more other drug therapeutics delivered by the same route of administration together in any formulation, including formulations where the two compounds are chemically linked in such a way that they maintain their therapeutic activity when administered. In one aspect, the other drug therapy may be co-administered with a compound of Formula I. Use in combination by co-administration includes administration of co-formulations or formulations of chemically joined compounds, or administration of two or more compounds in separate formulations within a short time of each other (e.g. within an hour, 2 hours, 3 hours, up to 24 hours), administered by the same or different routes. Co-administration of separate formulations includes co-administration by delivery via one device, for example the same inhalant device, the same syringe, etc., or administration from separate devices within a short time of each other. Co-formulations of a compound of Formula I and one or more additional drug therapies delivered by the same route includes preparation of the materials together such that they can be administered by one device, including the separate compounds combined in one formulation, or compounds that are modified such that they are chemically joined, yet still maintain their biological activity. Such chemically joined compounds may have a linkage that is substantially maintained in vivo, or the linkage may break down in vivo, separating the two active components.
    • EXAMPLES
  • Examples related to the present invention are described below. In most cases, alternative techniques can be used. The examples are intended to be illustrative and are not limiting or restrictive to the scope of the invention. In some examples, the mass spectrometry result indicated for a compound may have more than one value due to the isotope distribution of an atom in the molecule, such as a compound having a bromo or chloro substituent. Synthesis of known starting materials in the following examples, or known compounds for formation of solid forms can be found, for example, in U.S. patent application Ser. No. 11/473,347 (see also, PCT publication WO2007002433), U.S. patent application Ser. No. 11/960,590 (Publication number 2008/0167338), U.S. patent application Ser. No. 11/961,901 (Publication number 2008/0188514), U.S. patent application Ser. No. 11/986,667 (see also, PCT publication WO2008064265), U.S. Provisional Patent Application Ser. No. 61/060,418, U.S. Provisional Patent Application Ser. No. 61/054,445, and PCT patent application PCT/US2008/070124, the disclosures of which are hereby incorporated by reference regarding methods of making compounds.
    • Example 1 Synthesis of (3-amino-2,6-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone compounds
  • (3-amino-2,6-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone compounds substituted at the 4 or 5 position were prepared by the following schemes.
  • Figure US20120122860A1-20120517-C00010
  • Step 1—Preparation of (2,4-difluoro-phenyl)-carbamic acid benzyl ester (3):
  • To 2,4-difluoro-phenylamine (1, 7.0 mL, 70.0 mmol) in 100 mL of dichloromethane, pyridine (11 mL, 140.0 mmol) and benzyl chloroformate (2, 11.9 mL, 83.4 mmol) were added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate and potassium bisulfate solution. The organic layer was dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum and crystallized from hexanes to give the desired compound (3, 15.6 g, 85%).
  • Step 2—Preparation of (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (4):
  • Into a round bottom flask was added (2,4-difluoro-phenyl)-carbamic acid benzyl ester (3, 3.83 g, 14.5 mmol) in 148 mL of tetrahydrofuran. The solution was chilled to 78° C. and n-butyllithium (1.60 M in hexane, 19.1 mL, 30.0 mmol) was added over 30 minutes followed by the addition of 1.12 mL of N,N-dimethylformamide. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum and crystallized from ether to give the desired compound (4, 3.0 g, 71%).
  • Step 3—Preparation of {3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methy]-2,4-difluoro-phenyl}-carbamic acid benzyl ester (6):
  • Into a round bottom flask was added 5-chloro-1H-pyrrolo[2,3-b]pyridine (5, 0.524 g, 3.43 mmol) in 5.00 mL of methanol. Potassium hydroxide (0.800 g, 14.2 mmol) and (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (4, 1.02 g, 3.5 mmol) were added and the reaction mixture was stirred overnight. The reaction mixture was poured into IN hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum and crystallized from ethyl acetate to give the desired compound (6, 710 mg, 46%). MS (ESI)[M+H]+=444.
  • Step 4—Preparation of [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-carbamic acid benzyl ester (7):
  • Into a round bottom flask was added {3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-carbamic acid benzyl ester (6, 1.01 g, 2.28 mmol) in 5.00 mL of tetrahydrofuran. Dess-Martin periodinane (1.20 g, 2.89 mmol) was added in portions. The reaction mixture was stirred at room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum and purified by silica gel chromatography to give the desired compound (7, 914 mg, 91%). MS (ESI)[M+H+]+=442.
  • Step 5—Preparation of (3-amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (8):
  • [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-carbamic acid benzyl ester (7,800 mg, 1.81 mmol) was added to 15.00 mL of 10 M sodium hydroxide and warmed to reflux overnight. The reaction mixture was diluted with 30 mL of water and extracted with ethyl acetate. The organic layer was separated, dried, filtered and the filtrate concentrated under vacuum to give the desired compound (8, 450 mg, 81%).
  • 3-(3-Amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 9, (3-amino-2,6-difluoro-phenyl)-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 10, and (3-amino-2,6-difluoro-phenyl)-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 11,
  • Figure US20120122860A1-20120517-C00011
  • were prepared similarly to the protocol of Scheme 1, replacing 5-chloro-1H-pyrrolo[2,3-b]pyridine 5 with 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile, 4-methoxy-1H-pyrrolo[2,3-b]pyridine, and 5-methoxy-1H-pyrrolo[2,3-b]pyridine, respectively, in Step 3.
  • 3-(3-Amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile 13
  • Figure US20120122860A1-20120517-C00012
  • was prepared similarly, replacing 5-chloro-1H-pyrrolo[2,3-b]pyridine 5 with 1H-pyrrolo[2,3-b]pyridine-4-carbonitrile in Step 3, resulting in the methyl ester of the carbamic acid along with the benzyl ester. The methyl ester is carried through Step 4 and the resulting [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-carbamic acid methyl ester (12) was reacted by the following Step 5a:
  • Figure US20120122860A1-20120517-C00013
  • Step 5a —Preparation of 3-(3-amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (13):
  • To [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-carbamic acid methyl ester (12, 0.290 g, 0.814 mmol) in 3.0 mL of acetonitrile at 25° C. under an atmosphere of nitrogen, iodotrimethylsilane (0.431 mL, 3.03 mmol) was added. The reaction was stirred at room temperature overnight, then concentrated and washed with ethyl acetate and hexane to give a brown solid, which was used without further purification (13, 245 mg, 79.1% purity) or further purified. MS (ESI) [M+H+]+=299.0.
  • (3-Amino-2-chloro-6-fluoro-phenyl)-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone 71
  • Figure US20120122860A1-20120517-C00014
  • was prepared similarly to the protocol used for 3-(3-Amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile 13, replacing 2,4-difluoro-phenylamine 1 with 2-chloro-4-fluoro-phenylamine in step 1 and replacing 5-chloro-1H-pyrrolo[2,3-b]pyridine 5 with 5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine in Step 3. MS (ESI) [M+H+]+=369.7 and 371.4.
  • Figure US20120122860A1-20120517-C00015
  • Step 1—Preparation of (2,6-difluoro-3-nitro-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (16):
  • To 5-methyl-1H-pyrrolo[2,3-b]pyridine (15, 2.00 g, 15.1 mmol) and aluminum trichloride (11.6 g, 87.2 mmol), nitromethane (63.1 mL, 1.16 mol) was added, followed by the addition of 2,6-difluoro-3-nitro-benzoyl chloride (14, 3.22 g, 14.5 mmol). The reaction was placed in an oil bath at 45° C. and stirred for 3 days, then cooled to room temperature and 30 mL of methanol was added. The reaction was then diluted with 200 mL of ethyl acetate and 100 mL each of water and IN hydrochloric acid, resulting in a precipitate that was collected to provide the desired compound (16, 2.761 g). Additonal compound was recovered from the organic layer, removing the solvent and purifying by silica gel column chromatography eluting with a gradient of 5 to 70% ethyl acetate in hexanes to provide another 126 mg of compound. MS (ESI) [M+H+]+=317.9.
  • Step 2—Preparation of (3-amino-2,6-difluoro-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (17):
  • To (2,6-difluoro-3-nitro-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (16, 1.165 g, 3.672 mmol), 80 mL of ethyl acetate was added, followed by stannous chloride, dihydrate (2.86 g, 12.6 mmol). The suspension was stirred in an oil bath at 65° C. for 18 hours, then poured into a beaker with 200 mL each of water and saturated bicarbonate. The resulting milky suspension was treated with celite, then vacuum filtered through a thin pad of celite. The resulting clear layers of the filtrate were separated and the solvents were removed from the ethyl acetate layer. The resulting material was purified by silica gel column chromatography eluting with a gradient from 30 to 100% ethyl acetate in hexanes to give the desired compound with some impurities. This material was re-purified by silica gel column chromatography eluting with a gradient from 1 to 60% methanol in dichloromethante to give the desired compound (17, 760 mg). 1H NMR was consistent with the desired compound structure. MS (ESI) [M+H+]+=288.5.
  • (3-Amino-2,6-difluoro-phenyl)-(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone
  • Figure US20120122860A1-20120517-C00016
  • was prepared similarly to the protocol of Scheme 2, replacing 5-methyl-1H-pyrrolo[2,3-b]pyridine 15 with 4-chloro-1H-pyrrolo[2,3-b]pyridine in Step 1, and in Step 2, the nitro compound is reduced in ethanol using iron instead of stannous chloride, and the reaction is carried out at 85° C. MS (ESI) [M+H+]+=308.4.
  • (3-Amino-2-fluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 69
  • Figure US20120122860A1-20120517-C00017
  • was prepared similarly to the protocol of Scheme 2, replacing 5-methyl-1H-pyrrolo[2,3-b]pyridine 15 with 5-bromo-1H-pyrrolo[2,3-b]pyridine and replacing 2,6-difluoro-3-nitro-benzoyl chloride 14 with 2-fluoro-3-nitro-benzoyl chloride in Step 1. MS (ESI) [M+H+]+=334.3 and 336.3. This was reacted further to provide (3-Amino-2-fluoro-phenyl)-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 70 as follows:
  • Figure US20120122860A1-20120517-C00018
  • Step 3—Preparation of (3-amino-2-fluoro-phenyl)-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (70):
  • To (3-amino-2-fluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (69, 1.080 g, 3.232 mmol) in a vial, N,N-dimethylacetamide (2.90 mL, 31.2 mmol) was added. The suspension was degassed by bubbling with argon and zinc powder (0.032 g, 0.48 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.0568 g, 0.102 mmol), zinc cyanide (0.223 g, 1.90 mmol), and tris(dibenzylideneacetone)dipalladium (0) (0.053 g, 0.052 mmol) were added at room temperature under argon. The mixture was heated to 120° C., resulting in most of the solid dissolving, and the mixture was heated at 120° C. for 2 hours, then cooled to 100° C. and 8 mL of water was added and the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate and saturated sodium chloride in water. The organic layer was washed with water and brine, then dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was suspended in acetonitrile and sonicated for 30 minutes, after which the precipitated material was collected by filtration to provide the desired compound as a tan solid (70, 613 mg). Additional material was recovered from the filtrate by silica gel chromatography eluting with ethyl acetate and hexanes, the appropriate fractions were combined and the solvent removed to provide an additional 42 mg. MS (ESI) [M+H+]+=280.9.
  • (3-Amino-2,6-difluoro-phenyl)-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 19
  • Figure US20120122860A1-20120517-C00019
  • was prepared similarly to the protocol of Scheme 2, replacing 5-methyl-1H-pyrrolo[2,3-b]pyridine 15 with 5-iodo-1H-pyrrolo[2,3-b]pyridine in Step 1. MS (ESI) [M+H+]+=399.9. This was reacted further to provide (3-amino-2,6-difluoro-phenyl)-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone 21 via the following Step 3a:
  • Figure US20120122860A1-20120517-C00020
  • Step 3a —Preparation of (3-amino-2,6-difluoro-phenyl)-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone (21):
  • In a microwave vial, (3-amino-2,6-difluoro-phenyl)-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (19, 1.36 g, 3.41 mmol), 2-methoxy-pyrimidine-5-boronic acid (20, 1.05 g, 6.81 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.25 g, 0.34 mmol) were mixed in 22 mL of 1.00 M potassium carbonate in water and 18 mL of acetonitrile. The resulting mixture was heated at 160° C. in the microwave for 15 minutes. The resulting mixture was filtered through a thin layer of celite, and the celite bed was washed with a mixture of water and ethyl acetate. The two layers of the filtrate were seperated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate concentrated under vacuum. The residue was purified by flash silica gel chromatography eluting with ethyl acetate and dichloromethane to provide the desired compound (21, 0.567 g). MS (ESI) [M+H+]+=382.1.
  • Figure US20120122860A1-20120517-C00021
  • Step 1—Preparation of (3-nitro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (24):
  • Into a round bottom flask under an atmosphere of nitrogen, aluminum trichloride (2.8 g, 21.0 mmol) was added to 40 mL of dichloromethane. 1H-Pyrrolo[2,3-b]pyridine (23, 0.5 g, 4.0 mmol) was then added and the solution was stirred under nitrogen at room temperature. After 1 hour, 3-nitro-benzoyl chloride (22, 2.0 g, 10.0 mmol) was added dropwise. The mixture was stirred at room temperature for 2.5 hours, then quenched with methanol. The solvents were removed under vacuum and ethyl acetate and water were added. The resulting solid was filtered out and stirred with hot methanol for 30 minutes, filtered and dried under vacuum to provide the desired compound (24, 150 mg).
  • Step 2—Preparation of (3-amino-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (25):
  • Into a round bottom flask, under an atmosphere of nitrogen, (3-nitro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (24, 26 mg, 0.097 mmol) was combined with 2 mL of 6 M hydrochloric acid in water and 0.44 mL of ethanol, resulting in a clear solution. Iron (95 mg, 1.7 mmol) was added to the mixture and the reaction was refluxed for 3.5 hours, then cooled and the solvents removed under vacuum. The resulting solid was dissolved into ethyl acetate and washed with sodium bicarbonate. The ethyl acetate layer was dried over sodium sulfate, filtered and the filtrate was concentrated under vacuum. The desired compound was purified with preparative TLC plate eluting with 5% methanol/dichloromethane with some triethylamine drops added. The desired band was extracted to provide the desired compound (25, 14.3 mg) of white solid after lyophilization.
  • (3-Amino-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 26, (3-amino-phenyl)-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone 27, (5-amino-2-fluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 28, (5-amino-2-fluoro-phenyl)-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone 29, and (5-amino-2-fluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 200,
  • Figure US20120122860A1-20120517-C00022
  • were prepared similarly to the protocol of Scheme 2a, where 1H-pyrrolo[2,3-b]pyridine 23 was replaced with 5-chloro-1H-pyrrolo[2,3-b]pyridine (26, 28) or 5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (27, 29) in Step 1 and optionally replacing 3-nitro-benzoyl chloride 22 with 2-fluoro-5-nitro-benzoyl chloride in Step 1 (28, 29, 200).
  • Figure US20120122860A1-20120517-C00023
  • Step 1—Preparation of (5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-nitro-phenyl)-methanone (31):
    • 5-Methyl-1H-pyrrolo[2,3-b]pyridine (30, 198 mg, 1.5 mmol) was dissolved in 2 mL of dichloromethane, followed by addition of aluminum trichloride (1.2 g, 9 mmol). After stirring at room temperature under nitrogen for 30 minutes, 3-nitro-benzoyl chloride (22, 555 mg, 3 mmol) was added. The reaction mixture was stirred at room temperature overnight, then poured into ice water and acetic acid was added to neutralize the pH. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum to provide the desired compound as an off white solid (31, 321 mg, 76%).
      Step 2—Preparation of (3-amino-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (32):
  • (5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-nitro-phenyl)-methanone (31, 321 mg, 1.14 mmol) was dissolved in 10 mL of ethanol and 1.5 mL of concentrated hydrochloric acid and iron dust (1.28 g, 23 mmol) was added. The reaction mixture was refluxed for 2 hours, the iron dust was filtered off and washed with ethanol. Combined filtrates were evaporated under vacuum and the residue was dissolved in ethyl acetate and washed with bicarbonate, then brine, and dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound as a yellow solid (32, 120 mg, 42%).
  • (5-Amino-2-fluoro-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 33, 3-[3-(5-amino-2-fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide 34, (5-amino-2-fluoro-phenyl)-[5-(3-methane sulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone 35, and N-{3-[3-(5-amino-2-fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide 36,
  • Figure US20120122860A1-20120517-C00024
  • were prepared similarly to the protocol of Scheme 2b, replacing 3-nitro-benzoyl chloride 22 with 2-fluoro-5-nitro-benzoyl chloride in Step 1 and optionally replacing 5-methyl-1H-pyrrolo[2,3-b]pyridine 30 with 3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-benzamide (34), 5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine (35), and N-[3-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-phenyl]-methanesulfonamide (36) in Step 1.
  • Figure US20120122860A1-20120517-C00025
  • Step 1—Preparation of (5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-nitro-phenyl)-methanol (39):
  • To a solution of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (38, 592 mg, 4 mmol) and 3-nitrobenzaldehyde (37, 1.2 g, 8 mmol) in 5 mL of dioxane, potassium hydroxide (448 mg, 8 mmol) was added. The reaction mixture was heated at 50° C. for 30 minutes. The resulting precipitate was isolated by filtration and washed with water. This solid was dissolved in ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound as a white solid (39, 938 mg, 78%).
  • Step 2—Preparation of (5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-nitro-phenyl)-methanone (40):
  • To a solution of (5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-nitro-phenyl)-methanol (39, 450 mg, 1.5 mmol) in 5 mL of dichloromethane, pyridinium chlorochromate (390 mg, 1.8 mmol) was added. The reaction mixture was stirred at room temperature overnight. The resulting precipitate was isolated by filtration and washed with dichloromethane and used in the next step without further purification.
  • Step 3—Preparation of (3-Amino-phenyl)-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (41):
  • The crude (5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-nitro-phenyl)-methanone (40) was treated according to the protocol of Scheme 2b Step 2 to provide the desired compound.
  • (3-Amino-phenyl)-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 42, (3-amino-phenyl)-[5-(3-methane sulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone 43, N-{3-[3-(3-amino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methane sulfonamide 44, and (3-amino-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 45,
  • Figure US20120122860A1-20120517-C00026
  • were prepared similarly to the protocol of Scheme 3, replacing 5-methoxy-1H-pyrrolo[2,3-b]pyridine 38 with 5-fluoro-1H-pyrrolo[2,3-b]pyridine (42), 5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine (43), N-[3-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-phenyl]-methanesulfonamide (44), and 5-bromo-1H-pyrrolo[2,3-b]pyridine (45), in Step 1.
    • Example 2 Synthesis of benzo[b]thiophene-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide P-1117
  • Benzo[b]thiophene-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide P-1117 was synthesized in one step from (3-amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 8 as shown in Scheme 4.
  • Figure US20120122860A1-20120517-C00027
  • Step 1—Preparation of benzo[b]thiophene-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1117):
  • To (3-amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (8, 10 mg, 0.033 mmol) and I-benzothiophene-3-sulfonyl chloride (46, 23 mg, 0.1 mmol) dissolved in 1 mL of tetrahydrofuran in a 2 mL microwave vial, 100 μL of pyridine was added and the solution was irradiated in microwave for 10 minutes at 130° C. The reaction mixture was transferred to a 5 mL vial and the solvents were removed under reduced pressure. The crude dry material was dissolved in 300 μL of dimethylsulfoxide and purified by reverse phase HPLC, eluting with 0.1% trifluoroacetic acid in water and 0.1% trifluoroacetic acid in acetonitrile, 20-100% acetonitrile over 16 minutes at 6 mL per minute. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound. MS (ESI)[M+H+]+=503.9.
  • N-(6-Acetyl amino-pyridin-3-yl)-3-benzenesulfonylamino-2,6-difluoro-benzamide P-2474 and 6-acetylamino-N-(3-benzenesulfonylamino-2,6-difluoro-phenyl)-nicotinamide P-2475,
  • Figure US20120122860A1-20120517-C00028
  • were prepared similarly to the protocol of Scheme 4, replacing (3-amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 8 with N-(6-acetylamino-pyridin-3-yl)-3-amino-2,6-difluoro-benzamide (64) and 6-acetylamino-N-(3-amino-2,6-difluoro-phenyl)-nicotinamide (68), respectively, and replacing I-benzothiophene-3-sulfonyl chloride 46 with benzenesulfonyl chloride. MS (ESI)[M+H+]+=447.1 (P-2474) and 447.1 (P-2475).
  • Additional compounds were prepared similarly to the protocol of Scheme 4, where optimal reaction conditions may have varied in terms of time and temperature of the reaction, and in chromatography conditions for purification of the desired compounds. The reactions were performed optionally replacing (3-amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 8 with 5-(2-methoxy-pyrimidin-5-yl), 5-methyl, 5-cyano, 5-methoxy, 4-methoxy, 4-cyano, or 4-chloro (3-amino-2,6-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (prepared as described in Example 1) and/or replacing 1-benzothiophene-3-sulfonyl chloride 46 with an appropriate sulfonyl chloride. The following compounds were prepared by this procedure:
    • 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2001),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2002),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2003),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3,5-dimethyl-benzenesulfonamide (P-2004),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-4-methoxy-benzenesulfonamide (P-2005),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-fluoro-2-methyl-benzenesulfonamide (P-2006),
    • 2,3-Dihydro-benzofuran-5-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2007),
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-fluoro-benzenesulfonamide (P-2009),
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-2010),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2011),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-1497),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide (P-1498),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-fluoro-benzenesulfonamide (P-2014),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-2015),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-2016),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2017),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2018),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide (P-2019),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2020),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-fluoro-benzenesulfonamide (P-2021),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-2022),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-2023),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,6-difluoro-benzenesulfonamide (P-2024),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,4-difluoro-benzenesulfonamide (P-2025),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-fluoro-benzenesulfonamide (P-2026),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro-benzenesulfonamide (P-2027),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-fluoro-benzenesulfonamide (P-2028),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2029),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,4-difluoro-benzenesulfonamide (P-2030),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,6-difluoro-benzenesulfonamide (P-2031),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,4-difluoro-benzenesulfonamide (P-2032),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2033),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,4-difluoro-benzenesulfonamide (P-2034),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-fluoro-benzenesulfonamide (P-2035),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2036),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2037),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,4-difluoro-benzenesulfonamide (P-2038),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide (P-2039),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-fluoro-benzenesulfonamide (P-2040),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2-fluoro-benzenesulfonamide (P-2041),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-2042),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,6-difluoro-benzenesulfonamide (P-2043),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,4-difluoro-benzenesulfonamide (P-2044),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide (P-2045),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide (P-2046),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2047),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-fluoro-benzenesulfonamide (P-2050),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2051),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2052),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-fluoro-benzenesulfonamide (P-2053),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2054),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,4-difluoro-benzenesulfonamide (P-2055),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-benzenesulfonamide (P-2056),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2061),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2062),
    • Pyridine-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2063),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2064),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2065),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2066),
    • Pyridine-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2067),
    • 2H-[1,2,4]Triazole-3-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2068),
    • Pyridine-3-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2069),
    • Pyridine-2-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2070),
    • Pyridine-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2071),
    • Pyridine-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2072),
    • Pyridine-3-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2073),
    • Pyridine-3-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2074),
    • Pyridine-2-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2075),
    • Pyridine-2-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2076),
    • Pyridine-3-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2077),
    • Pyridine-2-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2078),
    • Pyridine-2-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2079),
    • 2H-[1,2,4]Triazole-3-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2080),
    • 5-Methyl-isoxazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2081),
    • 1,5-Dimethyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2082),
    • 1-Ethyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2083),
    • 1-Methyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2084),
    • 6-Methoxy-pyridine-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2085),
    • Pyridine-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2086),
    • Pyridine-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2087),
    • 5-Methyl-isoxazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2088),
    • 1-Ethyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2089),
    • 1-Methyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2090),
    • 1,5-Dimethyl-1H-pyrazole-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2091),
    • 6-Methoxy-pyridine-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2092),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-C-pyridin-2-yl-methanesulfonamide (P-2093),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-C-pyridin-3-yl-methanesulfonamide (P-2094),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-C-pyridin-4-yl-methanesulfonamide (P-2095),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-pyridin-3-yl-methanesulfonamide (P-2096),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-pyridin-4-yl-methanesulfonamide (P-2097),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-C-pyridin-2-yl-methanesulfonamide (P-2098),
    • N-{2-Chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-difluoromethoxy-benzenesulfonamide (P-2099),
    • 4-Fluoro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2100),
    • N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-trifluoromethyl-benzenesulfonamide (P-2101),
    • N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-trifluoromethoxy-benzenesulfonamide (P-2102),
    • 3-Chloro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2103),
    • N-{4-Fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-2104),
    • 3-Fluoro-N-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2105),
    • 4-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-benzenesulfonamide (P-2106),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-fluoro-benzenesulfonamide (P-2107),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-trifluoromethyl-benzenesulfonamide (P-2108),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-trifluoromethoxy-benzenesulfonamide (P-2109),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-trifluoromethoxy-benzenesulfonamide (P-2110),
    • 3-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-benzenesulfonamide (P-2111),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2112),
    • 4-Chloro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2113),
    • 4-Fluoro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2114),
    • N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide (P-2115),
    • N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide (P-2116),
    • N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluoromethoxy-benzenesulfonamide (P-2117),
    • 3-Chloro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2118),
    • N-[4-Fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2119),
    • 3-Fluoro-N-[4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2120),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro-benzenesulfonamide (P-2121),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide (P-2122),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide (P-2123),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluoromethoxy-benzenesulfonamide (P-2124),
    • 3-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2125),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2126),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-2127),
    • 4-Chloro-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (P-2128),
    • 4-Chloro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2129),
    • 4-Fluoro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2130),
    • N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-trifluoromethyl-benzenesulfonamide (P-2131),
    • N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethoxy-benzenesulfonamide (P-2132),
    • N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-trifluoromethoxy-benzenesulfonamide (P-2133),
    • 3-Chloro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2134),
    • N-{3-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-2135),
    • 3-Fluoro-N-{3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-2136),
    • Pyridine-3-sulfonic acid [4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2137),
    • Pyridine-3-sulfonic acid {4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2138),
    • Pyridine-3-sulfonic acid {4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2139),
    • Pyridine-3-sulfonic acid {4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2140),
    • Pyridine-3-sulfonic acid [3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2141),
    • Pyridine-3-sulfonic acid [3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2142),
    • Pyridine-3-sulfonic acid [3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2143),
    • Pyridine-3-sulfonic acid {3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2144),
    • Pyridine-3-sulfonic acid {3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2145),
    • Pyridine-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2146),
    • Pyridine-3-sulfonic acid {3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2149),
    • Ethanesulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2272),
    • Propane-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2273),
    • Ethanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2274),
    • Propane-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2275),
    • Ethanesulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2276),
    • Ethanesulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2277),
    • Propane-2-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2278),
    • Ethanesulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2279),
    • Propane-2-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2280),
    • Ethanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2281),
    • Propane-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2282),
    • Ethanesulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2283),
    • Propane-2-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2284),
    • Propane-2-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2285),
    • Ethanesulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2286),
    • Propane-2-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2287),
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-2288),
    • N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-2289),
    • N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-methanesulfonamide (P-2290),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-methanesulfonamide (P-2291),
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-methanesulfonamide (P-2292),
    • N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide (P-2293),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-methanesulfonamide (P-2294),
    • N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-methanesulfonamide (P-2295),
    • 2-Methyl-propane-1-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2303),
    • 2-Methyl-propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2304),
    • 2-Methyl-propane-1-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2305),
    • 2-Methyl-propane-1-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2306),
    • 2-Methyl-propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2307),
    • Butane-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2308),
    • Pentane-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2309),
    • Butane-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2310),
    • Pentane-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2311),
    • Butane-2-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2312),
    • Butane-2-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2313),
    • Pentane-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2314),
    • Pentane-2-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2315),
    • Pentane-2-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2316),
    • Butane-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2317),
    • 2-Methyl-propane-1-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2318),
    • Butane-2-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2319),
    • 2-Methyl-propane-1-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2320),
    • Butane-2-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2321),
    • 2-Methyl-propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2322),
    • Butane-2-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2323),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2324),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2327),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2328),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2329),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2330),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2331),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2332),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2333),
    • 2,2,2-Trifluoro-ethanesulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2335),
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2336),
    • 2,2,2-Trifluoro-ethanesulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2337),
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2338),
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2339),
    • 2,2,2-Trifluoro-ethanesulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2340),
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2341),
    • 2,2,2-Trifluoro-ethanesulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2342),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-C,C,C-trifluoro-methanesulfonamide (P-2346),
    • N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-C,C,C-trifluoro-methanesulfonamide (P-2347),
    • Cyclobutanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2353),
    • Cyclobutanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2354),
    • Cyclohexanesulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2355),
    • Cyclopentanesulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2356),
    • Cyclohexanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2357),
    • Cyclopentanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2358),
    • Cyclopentanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2359),
    • Cyclohexanesulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2360),
    • Cyclohexanesulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2361),
    • Cyclobutanesulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2362),
    • Cyclobutanesulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2363),
    • Cyclobutanesulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2364),
    • Cyclopentanesulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2365),
    • Cyclohexanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2366),
    • Cyclohexanesulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2367),
    • Cyclopentanesulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2368),
    • Cyclohexanesulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2369),
    • Cyclobutanesulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2370),
    • Cyclohexanesulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2371),
    • Cyclopentanesulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2372),
    • Cyclobutanesulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2373),
    • Pyrrolidine-1-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2374),
    • Pyrrolidine-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2375),
    • N,N-dimethylamino-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2376),
    • Pyrrolidine-1-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2377),
    • N,N-diethylamino-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2378),
    • Pyrrolidine-1-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2379),
    • Pyrrolidine-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1500),
    • N,N-dimethylamino-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1501),
    • N,N-dimethylamino-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2382),
    • N,N-dimethylamino-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2383),
    • N,N-diethylamino-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2384),
    • N,N-diethylamino-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2385),
    • N,N-diethylamino-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2386),
    • N,N-diethylamino-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2387),
    • N,N-diethylamino-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2388),
    • N,N-diethylamino-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2389),
    • Morpholine-4-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2390),
    • Morpholine-4-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2391),
    • Morpholine-4-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2392),
    • Morpholine-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2393),
    • Pyrrolidine-1-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2394),
    • Morpholine-4-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2395),
    • Morpholine-4-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2396),
    • Morpholine-4-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2397),
    • Pyrrolidine-1-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2398),
    • N,N-dimethylamino-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2399),
    • Pyrrolidine-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2400),
    • N,N-diethylamino-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2401),
    • Morpholine-4-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2402),
    • Ethanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2410),
    • Propane-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2411),
    • 2-Methyl-propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2412),
    • Butane-2-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2413),
    • 2,2,2-Trifluoro-ethanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2414),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2415),
    • Cyclohexanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2416),
    • Cyclopentanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2417),
    • Cyclobutanesulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2418),
    • N,N-dimethylamino-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2419),
    • Pyrrolidine-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2420),
    • Morpholine-4-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2421),
    • Propane-1-sulfonic acid {4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2431),
    • Butane-1-sulfonic acid {4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2432),
    • Cyclopropanesulfonic acid {4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2433),
    • Cyclohexanesulfonic acid {4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2434),
    • Butane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide (P-2435),
    • Cyclopropanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide (P-2436),
    • Propane-1-sulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2437),
    • Butane-1-sulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2438),
    • Cyclopropanesulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2439),
    • Piperidine-1-sulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2440),
    • Cyclohexanesulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2441),
    • Cyclopentanesulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2442),
    • Cyclohexanesulfonic acid [4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2443),
    • Cyclohexanesulfonic acid {4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2444),
    • Cyclopentanesulfonic acid {4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2445),
    • Cyclohexanesulfonic acid {4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2446),
    • Cyclopentanesulfonic acid {4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2447),
    • Cyclopentanesulfonic acid [4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2448),
    • Propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2449),
    • Butane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2450),
    • Cyclopropanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2451),
    • Cyclohexanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2452),
    • Cyclopentanesulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2453),
    • Propane-1-sulfonic acid {3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2454),
    • Butane-1-sulfonic acid {3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2455),
    • Cyclopropanesulfonic acid {3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2456),
    • Cyclohexanesulfonic acid {3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2457),
    • Cyclohexanesulfonic acid [3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2458),
    • Cyclopentanesulfonic acid [3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2459),
    • Cyclohexanesulfonic acid [3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2460),
    • Cyclohexanesulfonic acid {3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2461),
    • Cyclohexanesulfonic acid [3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2462),
    • Cyclopentanesulfonic acid [3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2463),
    • Cyclopentanesulfonic acid [3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2464),
    • 3-{3-[3-(3-Cyclohexanesulfonylamino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-propionic acid (P-2465),
    • 3-{3-[3-(3-Cyclopentanesulfonylamino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-propionic acid (P-2466),
    • Piperidine-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide (P-2468),
    • N,N-dimethylamino-sulfonic acid [4-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2469),
    • N,N-dimethylamino-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2470),
    • Piperidine-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2471),
    • Pyridine-3-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]amide (P-2472),
    • Pyrrolidine-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2476),
    • N,N-dimethylamino-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2477),
    • 6-Trifluoromethyl-pyridine-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2481),
    • 5-Trifluoromethyl-pyridine-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2485), and
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-propyl-benzenesulfonamide (P-2486).
  • The following table indicates the 1H-pyrrolo[2,3-b]pyridine (column 2) and sulfonyl chloride (column 3) used to afford the desired compound (column 4). The compound number is provided in column 1, and the observed mass is in column 5.
  • MS(ESI)
    1H-pyrrolo[2,3- Sulfonyl [M + H+]+
    b]pyridine chloride Compound observed
    P-2001
    Figure US20120122860A1-20120517-C00029
    Figure US20120122860A1-20120517-C00030
    Figure US20120122860A1-20120517-C00031
         		519.1
    P-2002
    Figure US20120122860A1-20120517-C00032
    Figure US20120122860A1-20120517-C00033
    Figure US20120122860A1-20120517-C00034
         		483.9
    P-2003
    Figure US20120122860A1-20120517-C00035
    Figure US20120122860A1-20120517-C00036
    Figure US20120122860A1-20120517-C00037
         		483.9
    P-2004
    Figure US20120122860A1-20120517-C00038
    Figure US20120122860A1-20120517-C00039
    Figure US20120122860A1-20120517-C00040
         		475.9
    P-2005
    Figure US20120122860A1-20120517-C00041
    Figure US20120122860A1-20120517-C00042
    Figure US20120122860A1-20120517-C00043
         		495.9
    P-2006
    Figure US20120122860A1-20120517-C00044
    Figure US20120122860A1-20120517-C00045
    Figure US20120122860A1-20120517-C00046
         		479.9
    P-2007
    Figure US20120122860A1-20120517-C00047
    Figure US20120122860A1-20120517-C00048
    Figure US20120122860A1-20120517-C00049
         		490.3
    P-2009
    Figure US20120122860A1-20120517-C00050
    Figure US20120122860A1-20120517-C00051
    Figure US20120122860A1-20120517-C00052
         		461.9
    P-2010
    Figure US20120122860A1-20120517-C00053
    Figure US20120122860A1-20120517-C00054
    Figure US20120122860A1-20120517-C00055
         		479.9
    P-2011
    Figure US20120122860A1-20120517-C00056
    Figure US20120122860A1-20120517-C00057
    Figure US20120122860A1-20120517-C00058
         		457.1
    P-1497
    Figure US20120122860A1-20120517-C00059
    Figure US20120122860A1-20120517-C00060
    Figure US20120122860A1-20120517-C00061
         		475.1
    P-1498
    Figure US20120122860A1-20120517-C00062
    Figure US20120122860A1-20120517-C00063
    Figure US20120122860A1-20120517-C00064
         		457.1
    P-2014
    Figure US20120122860A1-20120517-C00065
    Figure US20120122860A1-20120517-C00066
    Figure US20120122860A1-20120517-C00067
         		445.9
    P-2015
    Figure US20120122860A1-20120517-C00068
    Figure US20120122860A1-20120517-C00069
    Figure US20120122860A1-20120517-C00070
         		463.9
    P-2016
    Figure US20120122860A1-20120517-C00071
    Figure US20120122860A1-20120517-C00072
    Figure US20120122860A1-20120517-C00073
         		445.9
    P-2017
    Figure US20120122860A1-20120517-C00074
    Figure US20120122860A1-20120517-C00075
    Figure US20120122860A1-20120517-C00076
         		465.9
    P-2018
    Figure US20120122860A1-20120517-C00077
    Figure US20120122860A1-20120517-C00078
    Figure US20120122860A1-20120517-C00079
         		483.9
    P-2019
    Figure US20120122860A1-20120517-C00080
    Figure US20120122860A1-20120517-C00081
    Figure US20120122860A1-20120517-C00082
         		465.9
    P-2020
    Figure US20120122860A1-20120517-C00083
    Figure US20120122860A1-20120517-C00084
    Figure US20120122860A1-20120517-C00085
         		457.1
    P-2021
    Figure US20120122860A1-20120517-C00086
    Figure US20120122860A1-20120517-C00087
    Figure US20120122860A1-20120517-C00088
         		461.9
    P-2022
    Figure US20120122860A1-20120517-C00089
    Figure US20120122860A1-20120517-C00090
    Figure US20120122860A1-20120517-C00091
         		479.9
    P-2023
    Figure US20120122860A1-20120517-C00092
    Figure US20120122860A1-20120517-C00093
    Figure US20120122860A1-20120517-C00094
         		461.9
    P-2024
    Figure US20120122860A1-20120517-C00095
    Figure US20120122860A1-20120517-C00096
    Figure US20120122860A1-20120517-C00097
         		463.9
    P-2025
    Figure US20120122860A1-20120517-C00098
    Figure US20120122860A1-20120517-C00099
    Figure US20120122860A1-20120517-C00100
         		463.9
    P-2026
    Figure US20120122860A1-20120517-C00101
    Figure US20120122860A1-20120517-C00102
    Figure US20120122860A1-20120517-C00103
         		465.9
    P-2027
    Figure US20120122860A1-20120517-C00104
    Figure US20120122860A1-20120517-C00105
    Figure US20120122860A1-20120517-C00106
         		461.9
    P-2028
    Figure US20120122860A1-20120517-C00107
    Figure US20120122860A1-20120517-C00108
    Figure US20120122860A1-20120517-C00109
         		457.1
    P-2029
    Figure US20120122860A1-20120517-C00110
    Figure US20120122860A1-20120517-C00111
    Figure US20120122860A1-20120517-C00112
         		474.7
    P-2030
    Figure US20120122860A1-20120517-C00113
    Figure US20120122860A1-20120517-C00114
    Figure US20120122860A1-20120517-C00115
         		475.1
    P-2031
    Figure US20120122860A1-20120517-C00116
    Figure US20120122860A1-20120517-C00117
    Figure US20120122860A1-20120517-C00118
         		479.9
    P-2032
    Figure US20120122860A1-20120517-C00119
    Figure US20120122860A1-20120517-C00120
    Figure US20120122860A1-20120517-C00121
         		479.9
    P-2033
    Figure US20120122860A1-20120517-C00122
    Figure US20120122860A1-20120517-C00123
    Figure US20120122860A1-20120517-C00124
         		483.9
    P-2034
    Figure US20120122860A1-20120517-C00125
    Figure US20120122860A1-20120517-C00126
    Figure US20120122860A1-20120517-C00127
         		483.9
    P-2035
    Figure US20120122860A1-20120517-C00128
    Figure US20120122860A1-20120517-C00129
    Figure US20120122860A1-20120517-C00130
         		457.1
    P-2036
    Figure US20120122860A1-20120517-C00131
    Figure US20120122860A1-20120517-C00132
    Figure US20120122860A1-20120517-C00133
         		475.1
    P-2037
    Figure US20120122860A1-20120517-C00134
    Figure US20120122860A1-20120517-C00135
    Figure US20120122860A1-20120517-C00136
         		474.7
    P-2038
    Figure US20120122860A1-20120517-C00137
    Figure US20120122860A1-20120517-C00138
    Figure US20120122860A1-20120517-C00139
         		475.1
    P-2039
    Figure US20120122860A1-20120517-C00140
    Figure US20120122860A1-20120517-C00141
    Figure US20120122860A1-20120517-C00142
         		457.1
    P-2040
    Figure US20120122860A1-20120517-C00143
    Figure US20120122860A1-20120517-C00144
    Figure US20120122860A1-20120517-C00145
         		540.3
    P-2041
    Figure US20120122860A1-20120517-C00146
    Figure US20120122860A1-20120517-C00147
    Figure US20120122860A1-20120517-C00148
         		539.9
    P-2042
    Figure US20120122860A1-20120517-C00149
    Figure US20120122860A1-20120517-C00150
    Figure US20120122860A1-20120517-C00151
         		558.0
    P-2043
    Figure US20120122860A1-20120517-C00152
    Figure US20120122860A1-20120517-C00153
    Figure US20120122860A1-20120517-C00154
         		558.0
    P-2044
    Figure US20120122860A1-20120517-C00155
    Figure US20120122860A1-20120517-C00156
    Figure US20120122860A1-20120517-C00157
         		558.0
    P-2045
    Figure US20120122860A1-20120517-C00158
    Figure US20120122860A1-20120517-C00159
    Figure US20120122860A1-20120517-C00160
         		539.9
    P-2046
    Figure US20120122860A1-20120517-C00161
    Figure US20120122860A1-20120517-C00162
    Figure US20120122860A1-20120517-C00163
         		437.5
    P-2047
    Figure US20120122860A1-20120517-C00164
    Figure US20120122860A1-20120517-C00165
    Figure US20120122860A1-20120517-C00166
         		512.4
    P-2050
    Figure US20120122860A1-20120517-C00167
    Figure US20120122860A1-20120517-C00168
    Figure US20120122860A1-20120517-C00169
         		439.1
    P-2051
    Figure US20120122860A1-20120517-C00170
    Figure US20120122860A1-20120517-C00171
    Figure US20120122860A1-20120517-C00172
         		439.1
    P-2052
    Figure US20120122860A1-20120517-C00173
    Figure US20120122860A1-20120517-C00174
    Figure US20120122860A1-20120517-C00175
         		457.1
    P-2053
    Figure US20120122860A1-20120517-C00176
    Figure US20120122860A1-20120517-C00177
    Figure US20120122860A1-20120517-C00178
         		438.7
    P-2054
    Figure US20120122860A1-20120517-C00179
    Figure US20120122860A1-20120517-C00180
    Figure US20120122860A1-20120517-C00181
         		457.7
    P-2055
    Figure US20120122860A1-20120517-C00182
    Figure US20120122860A1-20120517-C00183
    Figure US20120122860A1-20120517-C00184
         		457.1
    P-2056
    Figure US20120122860A1-20120517-C00185
    Figure US20120122860A1-20120517-C00186
    Figure US20120122860A1-20120517-C00187
         		420.9
    P-2061
    Figure US20120122860A1-20120517-C00188
    Figure US20120122860A1-20120517-C00189
    Figure US20120122860A1-20120517-C00190
         		435.1
    P-2062
    Figure US20120122860A1-20120517-C00191
    Figure US20120122860A1-20120517-C00192
    Figure US20120122860A1-20120517-C00193
         		439.1
    P-2063
    Figure US20120122860A1-20120517-C00194
    Figure US20120122860A1-20120517-C00195
    Figure US20120122860A1-20120517-C00196
         		439.9
    P-2064
    Figure US20120122860A1-20120517-C00197
    Figure US20120122860A1-20120517-C00198
    Figure US20120122860A1-20120517-C00199
         		429.9
    P-2065
    Figure US20120122860A1-20120517-C00200
    Figure US20120122860A1-20120517-C00201
    Figure US20120122860A1-20120517-C00202
         		419.1
    P-2066
    Figure US20120122860A1-20120517-C00203
    Figure US20120122860A1-20120517-C00204
    Figure US20120122860A1-20120517-C00205
         		439.1
    P-2067
    Figure US20120122860A1-20120517-C00206
    Figure US20120122860A1-20120517-C00207
    Figure US20120122860A1-20120517-C00208
         		448.7
    P-2068
    Figure US20120122860A1-20120517-C00209
    Figure US20120122860A1-20120517-C00210
    Figure US20120122860A1-20120517-C00211
         		435.1
    P-2069
    Figure US20120122860A1-20120517-C00212
    Figure US20120122860A1-20120517-C00213
    Figure US20120122860A1-20120517-C00214
         		429.1
    P-2070
    Figure US20120122860A1-20120517-C00215
    Figure US20120122860A1-20120517-C00216
    Figure US20120122860A1-20120517-C00217
         		429.1
    P-2071
    Figure US20120122860A1-20120517-C00218
    Figure US20120122860A1-20120517-C00219
    Figure US20120122860A1-20120517-C00220
         		448.8
    P-2072
    Figure US20120122860A1-20120517-C00221
    Figure US20120122860A1-20120517-C00222
    Figure US20120122860A1-20120517-C00223
         		439.9
    P-2073
    Figure US20120122860A1-20120517-C00224
    Figure US20120122860A1-20120517-C00225
    Figure US20120122860A1-20120517-C00226
         		445.1
    P-2074
    Figure US20120122860A1-20120517-C00227
    Figure US20120122860A1-20120517-C00228
    Figure US20120122860A1-20120517-C00229
         		448.7
    P-2075
    Figure US20120122860A1-20120517-C00230
    Figure US20120122860A1-20120517-C00231
    Figure US20120122860A1-20120517-C00232
         		448.7
    P-2076
    Figure US20120122860A1-20120517-C00233
    Figure US20120122860A1-20120517-C00234
    Figure US20120122860A1-20120517-C00235
         		445.1
    P-2077
    Figure US20120122860A1-20120517-C00236
    Figure US20120122860A1-20120517-C00237
    Figure US20120122860A1-20120517-C00238
         		439.9
    P-2078
    Figure US20120122860A1-20120517-C00239
    Figure US20120122860A1-20120517-C00240
    Figure US20120122860A1-20120517-C00241
         		439.9
    P-2079
    Figure US20120122860A1-20120517-C00242
    Figure US20120122860A1-20120517-C00243
    Figure US20120122860A1-20120517-C00244
    P-2080
    Figure US20120122860A1-20120517-C00245
    Figure US20120122860A1-20120517-C00246
    Figure US20120122860A1-20120517-C00247
         		513.1
    P-2081
    Figure US20120122860A1-20120517-C00248
    Figure US20120122860A1-20120517-C00249
    Figure US20120122860A1-20120517-C00250
         		444.3
    P-2082
    Figure US20120122860A1-20120517-C00251
    Figure US20120122860A1-20120517-C00252
    Figure US20120122860A1-20120517-C00253
         		457.1
    P-2083
    Figure US20120122860A1-20120517-C00254
    Figure US20120122860A1-20120517-C00255
    Figure US20120122860A1-20120517-C00256
         		457.1
    P-2084
    Figure US20120122860A1-20120517-C00257
    Figure US20120122860A1-20120517-C00258
    Figure US20120122860A1-20120517-C00259
         		443.1
    P-2085
    Figure US20120122860A1-20120517-C00260
    Figure US20120122860A1-20120517-C00261
    Figure US20120122860A1-20120517-C00262
         		469.9
    P-2086
    Figure US20120122860A1-20120517-C00263
    Figure US20120122860A1-20120517-C00264
    Figure US20120122860A1-20120517-C00265
         		421.9
    P-2087
    Figure US20120122860A1-20120517-C00266
    Figure US20120122860A1-20120517-C00267
    Figure US20120122860A1-20120517-C00268
         		421.9
    P-2088
    Figure US20120122860A1-20120517-C00269
    Figure US20120122860A1-20120517-C00270
    Figure US20120122860A1-20120517-C00271
         		425.8
    P-2089
    Figure US20120122860A1-20120517-C00272
    Figure US20120122860A1-20120517-C00273
    Figure US20120122860A1-20120517-C00274
         		439.0
    P-2090
    Figure US20120122860A1-20120517-C00275
    Figure US20120122860A1-20120517-C00276
    Figure US20120122860A1-20120517-C00277
         		425.1
    P-2091
    Figure US20120122860A1-20120517-C00278
    Figure US20120122860A1-20120517-C00279
    Figure US20120122860A1-20120517-C00280
         		439.1
    P-2092
    Figure US20120122860A1-20120517-C00281
    Figure US20120122860A1-20120517-C00282
    Figure US20120122860A1-20120517-C00283
         		451.9
    P-2093
    Figure US20120122860A1-20120517-C00284
    Figure US20120122860A1-20120517-C00285
    Figure US20120122860A1-20120517-C00286
         		453.9
    P-2094
    Figure US20120122860A1-20120517-C00287
    Figure US20120122860A1-20120517-C00288
    Figure US20120122860A1-20120517-C00289
         		453.9
    P-2095
    Figure US20120122860A1-20120517-C00290
    Figure US20120122860A1-20120517-C00291
    Figure US20120122860A1-20120517-C00292
         		453.9
    P-2096
    Figure US20120122860A1-20120517-C00293
    Figure US20120122860A1-20120517-C00294
    Figure US20120122860A1-20120517-C00295
         		436.0
    P-2097
    Figure US20120122860A1-20120517-C00296
    Figure US20120122860A1-20120517-C00297
    Figure US20120122860A1-20120517-C00298
         		436.0
    P-2098
    Figure US20120122860A1-20120517-C00299
    Figure US20120122860A1-20120517-C00300
    Figure US20120122860A1-20120517-C00301
         		436.3
    P-2098
    Figure US20120122860A1-20120517-C00302
    Figure US20120122860A1-20120517-C00303
    Figure US20120122860A1-20120517-C00304
         		436.3
    P-2099
    Figure US20120122860A1-20120517-C00305
    Figure US20120122860A1-20120517-C00306
    Figure US20120122860A1-20120517-C00307
         		575.7 577.5
    P-2101
    Figure US20120122860A1-20120517-C00308
    Figure US20120122860A1-20120517-C00309
    Figure US20120122860A1-20120517-C00310
         		544.3
    P-2102
    Figure US20120122860A1-20120517-C00311
    Figure US20120122860A1-20120517-C00312
    Figure US20120122860A1-20120517-C00313
         		560.0
    P-2103
    Figure US20120122860A1-20120517-C00314
    Figure US20120122860A1-20120517-C00315
    Figure US20120122860A1-20120517-C00316
         		510.3
    P-2104
    Figure US20120122860A1-20120517-C00317
    Figure US20120122860A1-20120517-C00318
    Figure US20120122860A1-20120517-C00319
         		544.3
    P-2105
    Figure US20120122860A1-20120517-C00320
    Figure US20120122860A1-20120517-C00321
    Figure US20120122860A1-20120517-C00322
         		493.9
    P-2106
    Figure US20120122860A1-20120517-C00323
    Figure US20120122860A1-20120517-C00324
    Figure US20120122860A1-20120517-C00325
         		463.9
    P-2107
    Figure US20120122860A1-20120517-C00326
    Figure US20120122860A1-20120517-C00327
    Figure US20120122860A1-20120517-C00328
         		447.9
    P-2108
    Figure US20120122860A1-20120517-C00329
    Figure US20120122860A1-20120517-C00330
    Figure US20120122860A1-20120517-C00331
         		498.3
    P-2109
    Figure US20120122860A1-20120517-C00332
    Figure US20120122860A1-20120517-C00333
    Figure US20120122860A1-20120517-C00334
         		514.3
    P-2110
    Figure US20120122860A1-20120517-C00335
    Figure US20120122860A1-20120517-C00336
    Figure US20120122860A1-20120517-C00337
         		513.9
    P-2111
    Figure US20120122860A1-20120517-C00338
    Figure US20120122860A1-20120517-C00339
    Figure US20120122860A1-20120517-C00340
         		563.9
    P-2112
    Figure US20120122860A1-20120517-C00341
    Figure US20120122860A1-20120517-C00342
    Figure US20120122860A1-20120517-C00343
         		498.3
    P-2113
    Figure US20120122860A1-20120517-C00344
    Figure US20120122860A1-20120517-C00345
    Figure US20120122860A1-20120517-C00346
         		430.3
    P-2114
    Figure US20120122860A1-20120517-C00347
    Figure US20120122860A1-20120517-C00348
    Figure US20120122860A1-20120517-C00349
         		414.3
    P-2115
    Figure US20120122860A1-20120517-C00350
    Figure US20120122860A1-20120517-C00351
    Figure US20120122860A1-20120517-C00352
         		463.9
    P-2116
    Figure US20120122860A1-20120517-C00353
    Figure US20120122860A1-20120517-C00354
    Figure US20120122860A1-20120517-C00355
         		479.9
    P-2117
    Figure US20120122860A1-20120517-C00356
    Figure US20120122860A1-20120517-C00357
    Figure US20120122860A1-20120517-C00358
         		479.9
    P-2118
    Figure US20120122860A1-20120517-C00359
    Figure US20120122860A1-20120517-C00360
    Figure US20120122860A1-20120517-C00361
         		430.3
    P-2119
    Figure US20120122860A1-20120517-C00362
    Figure US20120122860A1-20120517-C00363
    Figure US20120122860A1-20120517-C00364
         		463.9
    P-2120
    Figure US20120122860A1-20120517-C00365
    Figure US20120122860A1-20120517-C00366
    Figure US20120122860A1-20120517-C00367
         		413.9
    P-2121
    Figure US20120122860A1-20120517-C00368
    Figure US20120122860A1-20120517-C00369
    Figure US20120122860A1-20120517-C00370
         		430.3
    P-2122
    Figure US20120122860A1-20120517-C00371
    Figure US20120122860A1-20120517-C00372
    Figure US20120122860A1-20120517-C00373
         		479.9
    P-2123
    Figure US20120122860A1-20120517-C00374
    Figure US20120122860A1-20120517-C00375
    Figure US20120122860A1-20120517-C00376
         		496.3
    P-2124
    Figure US20120122860A1-20120517-C00377
    Figure US20120122860A1-20120517-C00378
    Figure US20120122860A1-20120517-C00379
         		496.3
    P-2125
    Figure US20120122860A1-20120517-C00380
    Figure US20120122860A1-20120517-C00381
    Figure US20120122860A1-20120517-C00382
         		445.9
    P-2126
    Figure US20120122860A1-20120517-C00383
    Figure US20120122860A1-20120517-C00384
    Figure US20120122860A1-20120517-C00385
         		479.9
    P-2127
    Figure US20120122860A1-20120517-C00386
    Figure US20120122860A1-20120517-C00387
    Figure US20120122860A1-20120517-C00388
         		430.3
    P-2128
    Figure US20120122860A1-20120517-C00389
    Figure US20120122860A1-20120517-C00390
    Figure US20120122860A1-20120517-C00391
         		445.9
    P-2129
    Figure US20120122860A1-20120517-C00392
    Figure US20120122860A1-20120517-C00393
    Figure US20120122860A1-20120517-C00394
         		491.9
    P-2130
    Figure US20120122860A1-20120517-C00395
    Figure US20120122860A1-20120517-C00396
    Figure US20120122860A1-20120517-C00397
         		475.9
    P-2131
    Figure US20120122860A1-20120517-C00398
    Figure US20120122860A1-20120517-C00399
    Figure US20120122860A1-20120517-C00400
         		526.3
    P-2132
    Figure US20120122860A1-20120517-C00401
    Figure US20120122860A1-20120517-C00402
    Figure US20120122860A1-20120517-C00403
         		541.9
    P-2133
    Figure US20120122860A1-20120517-C00404
    Figure US20120122860A1-20120517-C00405
    Figure US20120122860A1-20120517-C00406
         		542.3
    P-2134
    Figure US20120122860A1-20120517-C00407
    Figure US20120122860A1-20120517-C00408
    Figure US20120122860A1-20120517-C00409
         		492.3
    P-2135
    Figure US20120122860A1-20120517-C00410
    Figure US20120122860A1-20120517-C00411
    Figure US20120122860A1-20120517-C00412
         		525.9
    P-2136
    Figure US20120122860A1-20120517-C00413
    Figure US20120122860A1-20120517-C00414
    Figure US20120122860A1-20120517-C00415
         		475.9
    P-2137
    Figure US20120122860A1-20120517-C00416
    Figure US20120122860A1-20120517-C00417
    Figure US20120122860A1-20120517-C00418
         		411.1
    P-2138
    Figure US20120122860A1-20120517-C00419
    Figure US20120122860A1-20120517-C00420
    Figure US20120122860A1-20120517-C00421
         		551.1
    P-2139
    Figure US20120122860A1-20120517-C00422
    Figure US20120122860A1-20120517-C00423
    Figure US20120122860A1-20120517-C00424
         		566.4
    P-2140
    Figure US20120122860A1-20120517-C00425
    Figure US20120122860A1-20120517-C00426
    Figure US20120122860A1-20120517-C00427
         		477.1
    P-2141
    Figure US20120122860A1-20120517-C00428
    Figure US20120122860A1-20120517-C00429
    Figure US20120122860A1-20120517-C00430
         		393.1
    P-2142
    Figure US20120122860A1-20120517-C00431
    Figure US20120122860A1-20120517-C00432
    Figure US20120122860A1-20120517-C00433
         		409.1
    P-2143
    Figure US20120122860A1-20120517-C00434
    Figure US20120122860A1-20120517-C00435
    Figure US20120122860A1-20120517-C00436
         		397.1
    P-2144
    Figure US20120122860A1-20120517-C00437
    Figure US20120122860A1-20120517-C00438
    Figure US20120122860A1-20120517-C00439
         		459.1
    P-2145
    Figure US20120122860A1-20120517-C00440
    Figure US20120122860A1-20120517-C00441
    Figure US20120122860A1-20120517-C00442
         		547.9
    P-2146
    Figure US20120122860A1-20120517-C00443
    Figure US20120122860A1-20120517-C00444
    Figure US20120122860A1-20120517-C00445
         		413.1
    P-2149
    Figure US20120122860A1-20120517-C00446
    Figure US20120122860A1-20120517-C00447
    Figure US20120122860A1-20120517-C00448
         		533.1
    P-2272
    Figure US20120122860A1-20120517-C00449
    Figure US20120122860A1-20120517-C00450
    Figure US20120122860A1-20120517-C00451
         		395.9
    P-2273
    Figure US20120122860A1-20120517-C00452
    Figure US20120122860A1-20120517-C00453
    Figure US20120122860A1-20120517-C00454
         		410.3
    P-2274
    Figure US20120122860A1-20120517-C00455
    Figure US20120122860A1-20120517-C00456
    Figure US20120122860A1-20120517-C00457
         		399.9
    P-2275
    Figure US20120122860A1-20120517-C00458
    Figure US20120122860A1-20120517-C00459
    Figure US20120122860A1-20120517-C00460
         		413.9
    P-2276
    Figure US20120122860A1-20120517-C00461
    Figure US20120122860A1-20120517-C00462
    Figure US20120122860A1-20120517-C00463
         		399.9
    P-2277
    Figure US20120122860A1-20120517-C00464
    Figure US20120122860A1-20120517-C00465
    Figure US20120122860A1-20120517-C00466
         		379.9
    P-2278
    Figure US20120122860A1-20120517-C00467
    Figure US20120122860A1-20120517-C00468
    Figure US20120122860A1-20120517-C00469
         		393.9
    P-2279
    Figure US20120122860A1-20120517-C00470
    Figure US20120122860A1-20120517-C00471
    Figure US20120122860A1-20120517-C00472
         		395.9
    P-2280
    Figure US20120122860A1-20120517-C00473
    Figure US20120122860A1-20120517-C00474
    Figure US20120122860A1-20120517-C00475
         		409.9
    P-2281
    Figure US20120122860A1-20120517-C00476
    Figure US20120122860A1-20120517-C00477
    Figure US20120122860A1-20120517-C00478
         		391.1
    P-2282
    Figure US20120122860A1-20120517-C00479
    Figure US20120122860A1-20120517-C00480
    Figure US20120122860A1-20120517-C00481
         		405.1
    P-2283
    Figure US20120122860A1-20120517-C00482
    Figure US20120122860A1-20120517-C00483
    Figure US20120122860A1-20120517-C00484
         		391.1
    P-2284
    Figure US20120122860A1-20120517-C00485
    Figure US20120122860A1-20120517-C00486
    Figure US20120122860A1-20120517-C00487
         		413.9
    P-2285
    Figure US20120122860A1-20120517-C00488
    Figure US20120122860A1-20120517-C00489
    Figure US20120122860A1-20120517-C00490
         		405.1
    P-2286
    Figure US20120122860A1-20120517-C00491
    Figure US20120122860A1-20120517-C00492
    Figure US20120122860A1-20120517-C00493
         		474.6
    P-2287
    Figure US20120122860A1-20120517-C00494
    Figure US20120122860A1-20120517-C00495
    Figure US20120122860A1-20120517-C00496
         		487.9
    P-2288
    Figure US20120122860A1-20120517-C00497
    Figure US20120122860A1-20120517-C00498
    Figure US20120122860A1-20120517-C00499
         		381.9
    P-2289
    Figure US20120122860A1-20120517-C00500
    Figure US20120122860A1-20120517-C00501
    Figure US20120122860A1-20120517-C00502
         		365.9
    P-2290
    Figure US20120122860A1-20120517-C00503
    Figure US20120122860A1-20120517-C00504
    Figure US20120122860A1-20120517-C00505
         		385.9
    P-2291
    Figure US20120122860A1-20120517-C00506
    Figure US20120122860A1-20120517-C00507
    Figure US20120122860A1-20120517-C00508
         		385.9
    P-2292
    Figure US20120122860A1-20120517-C00509
    Figure US20120122860A1-20120517-C00510
    Figure US20120122860A1-20120517-C00511
         		377.1
    P-2293
    Figure US20120122860A1-20120517-C00512
    Figure US20120122860A1-20120517-C00513
    Figure US20120122860A1-20120517-C00514
         		381.9
    P-2294
    Figure US20120122860A1-20120517-C00515
    Figure US20120122860A1-20120517-C00516
    Figure US20120122860A1-20120517-C00517
         		377.1
    P-2295
    Figure US20120122860A1-20120517-C00518
    Figure US20120122860A1-20120517-C00519
    Figure US20120122860A1-20120517-C00520
         		459.9
    P-2303
    Figure US20120122860A1-20120517-C00521
    Figure US20120122860A1-20120517-C00522
    Figure US20120122860A1-20120517-C00523
         		423.9
    P-2304
    Figure US20120122860A1-20120517-C00524
    Figure US20120122860A1-20120517-C00525
    Figure US20120122860A1-20120517-C00526
         		427.9
    P-2305
    Figure US20120122860A1-20120517-C00527
    Figure US20120122860A1-20120517-C00528
    Figure US20120122860A1-20120517-C00529
         		408.3
    P-2306
    Figure US20120122860A1-20120517-C00530
    Figure US20120122860A1-20120517-C00531
    Figure US20120122860A1-20120517-C00532
         		423.9
    P-2307
    Figure US20120122860A1-20120517-C00533
    Figure US20120122860A1-20120517-C00534
    Figure US20120122860A1-20120517-C00535
         		419.1
    P-2308
    Figure US20120122860A1-20120517-C00536
    Figure US20120122860A1-20120517-C00537
    Figure US20120122860A1-20120517-C00538
         		423.9
    P-2309
    Figure US20120122860A1-20120517-C00539
    Figure US20120122860A1-20120517-C00540
    Figure US20120122860A1-20120517-C00541
         		438.3
    P-2310
    Figure US20120122860A1-20120517-C00542
    Figure US20120122860A1-20120517-C00543
    Figure US20120122860A1-20120517-C00544
         		427.9
    P-2311
    Figure US20120122860A1-20120517-C00545
    Figure US20120122860A1-20120517-C00546
    Figure US20120122860A1-20120517-C00547
         		442.3
    P-2312
    Figure US20120122860A1-20120517-C00548
    Figure US20120122860A1-20120517-C00549
    Figure US20120122860A1-20120517-C00550
         		409.1
    P-2313
    Figure US20120122860A1-20120517-C00551
    Figure US20120122860A1-20120517-C00552
    Figure US20120122860A1-20120517-C00553
         		423.9
    P-2314
    Figure US20120122860A1-20120517-C00554
    Figure US20120122860A1-20120517-C00555
    Figure US20120122860A1-20120517-C00556
         		433.1
    P-2315
    Figure US20120122860A1-20120517-C00557
    Figure US20120122860A1-20120517-C00558
    Figure US20120122860A1-20120517-C00559
         		421.9
    P-2316
    Figure US20120122860A1-20120517-C00560
    Figure US20120122860A1-20120517-C00561
    Figure US20120122860A1-20120517-C00562
         		437.9
    P-2317
    Figure US20120122860A1-20120517-C00563
    Figure US20120122860A1-20120517-C00564
    Figure US20120122860A1-20120517-C00565
         		419.1
    P-2318
    Figure US20120122860A1-20120517-C00566
    Figure US20120122860A1-20120517-C00567
    Figure US20120122860A1-20120517-C00568
         		427.9
    P-2319
    Figure US20120122860A1-20120517-C00569
    Figure US20120122860A1-20120517-C00570
    Figure US20120122860A1-20120517-C00571
         		427.9
    P-2320
    Figure US20120122860A1-20120517-C00572
    Figure US20120122860A1-20120517-C00573
    Figure US20120122860A1-20120517-C00574
         		419.1
    P-2321
    Figure US20120122860A1-20120517-C00575
    Figure US20120122860A1-20120517-C00576
    Figure US20120122860A1-20120517-C00577
         		419.1
    P-2322
    Figure US20120122860A1-20120517-C00578
    Figure US20120122860A1-20120517-C00579
    Figure US20120122860A1-20120517-C00580
         		501.9
    P-2323
    Figure US20120122860A1-20120517-C00581
    Figure US20120122860A1-20120517-C00582
    Figure US20120122860A1-20120517-C00583
         		501.9
    P-2324
    Figure US20120122860A1-20120517-C00584
    Figure US20120122860A1-20120517-C00585
    Figure US20120122860A1-20120517-C00586
         		467.9
    P-2327
    Figure US20120122860A1-20120517-C00587
    Figure US20120122860A1-20120517-C00588
    Figure US20120122860A1-20120517-C00589
         		463.9
    P-2328
    Figure US20120122860A1-20120517-C00590
    Figure US20120122860A1-20120517-C00591
    Figure US20120122860A1-20120517-C00592
         		447.9
    P-2329
    Figure US20120122860A1-20120517-C00593
    Figure US20120122860A1-20120517-C00594
    Figure US20120122860A1-20120517-C00595
         		467.9
    P-2330
    Figure US20120122860A1-20120517-C00596
    Figure US20120122860A1-20120517-C00597
    Figure US20120122860A1-20120517-C00598
         		463.9
    P-2331
    Figure US20120122860A1-20120517-C00599
    Figure US20120122860A1-20120517-C00600
    Figure US20120122860A1-20120517-C00601
         		459.1
    P-2332
    Figure US20120122860A1-20120517-C00602
    Figure US20120122860A1-20120517-C00603
    Figure US20120122860A1-20120517-C00604
         		459.1
    P-2333
    Figure US20120122860A1-20120517-C00605
    Figure US20120122860A1-20120517-C00606
    Figure US20120122860A1-20120517-C00607
    P-2335
    Figure US20120122860A1-20120517-C00608
    Figure US20120122860A1-20120517-C00609
    Figure US20120122860A1-20120517-C00610
         		449.9
    P-2336
    Figure US20120122860A1-20120517-C00611
    Figure US20120122860A1-20120517-C00612
    Figure US20120122860A1-20120517-C00613
         		445.1
    P-2337
    Figure US20120122860A1-20120517-C00614
    Figure US20120122860A1-20120517-C00615
    Figure US20120122860A1-20120517-C00616
         		433.9
    P-2338
    Figure US20120122860A1-20120517-C00617
    Figure US20120122860A1-20120517-C00618
    Figure US20120122860A1-20120517-C00619
         		453.9
    P-2339
    Figure US20120122860A1-20120517-C00620
    Figure US20120122860A1-20120517-C00621
    Figure US20120122860A1-20120517-C00622
         		453.9
    P-2340
    Figure US20120122860A1-20120517-C00623
    Figure US20120122860A1-20120517-C00624
    Figure US20120122860A1-20120517-C00625
         		449.9
    P-2341
    Figure US20120122860A1-20120517-C00626
    Figure US20120122860A1-20120517-C00627
    Figure US20120122860A1-20120517-C00628
         		445.1
    P-2342
    Figure US20120122860A1-20120517-C00629
    Figure US20120122860A1-20120517-C00630
    Figure US20120122860A1-20120517-C00631
    P-2346
    Figure US20120122860A1-20120517-C00632
    Figure US20120122860A1-20120517-C00633
    Figure US20120122860A1-20120517-C00634
         		439.9
    P-2347
    Figure US20120122860A1-20120517-C00635
    Figure US20120122860A1-20120517-C00636
    Figure US20120122860A1-20120517-C00637
         		435.9
    P-2353
    Figure US20120122860A1-20120517-C00638
    Figure US20120122860A1-20120517-C00639
    Figure US20120122860A1-20120517-C00640
         		417.1
    P-2354
    Figure US20120122860A1-20120517-C00641
    Figure US20120122860A1-20120517-C00642
    Figure US20120122860A1-20120517-C00643
         		426.7
    P-2355
    Figure US20120122860A1-20120517-C00644
    Figure US20120122860A1-20120517-C00645
    Figure US20120122860A1-20120517-C00646
         		449.9
    P-2356
    Figure US20120122860A1-20120517-C00647
    Figure US20120122860A1-20120517-C00648
    Figure US20120122860A1-20120517-C00649
         		436.3
    P-2357
    Figure US20120122860A1-20120517-C00650
    Figure US20120122860A1-20120517-C00651
    Figure US20120122860A1-20120517-C00652
         		453.9
    P-2358
    Figure US20120122860A1-20120517-C00653
    Figure US20120122860A1-20120517-C00654
    Figure US20120122860A1-20120517-C00655
         		439.9
    P-2359
    Figure US20120122860A1-20120517-C00656
    Figure US20120122860A1-20120517-C00657
    Figure US20120122860A1-20120517-C00658
         		431.1
    P-2360
    Figure US20120122860A1-20120517-C00659
    Figure US20120122860A1-20120517-C00660
    Figure US20120122860A1-20120517-C00661
         		433.9
    P-2361
    Figure US20120122860A1-20120517-C00662
    Figure US20120122860A1-20120517-C00663
    Figure US20120122860A1-20120517-C00664
         		449.9
    P-2362
    Figure US20120122860A1-20120517-C00665
    Figure US20120122860A1-20120517-C00666
    Figure US20120122860A1-20120517-C00667
         		406.3
    P-2363
    Figure US20120122860A1-20120517-C00668
    Figure US20120122860A1-20120517-C00669
    Figure US20120122860A1-20120517-C00670
         		425.9
    P-2364
    Figure US20120122860A1-20120517-C00671
    Figure US20120122860A1-20120517-C00672
    Figure US20120122860A1-20120517-C00673
         		421.9
    P-2365
    Figure US20120122860A1-20120517-C00674
    Figure US20120122860A1-20120517-C00675
    Figure US20120122860A1-20120517-C00676
         		419.9
    P-2366
    Figure US20120122860A1-20120517-C00677
    Figure US20120122860A1-20120517-C00678
    Figure US20120122860A1-20120517-C00679
         		445.1
    P-2367
    Figure US20120122860A1-20120517-C00680
    Figure US20120122860A1-20120517-C00681
    Figure US20120122860A1-20120517-C00682
         		453.9
    P-2368
    Figure US20120122860A1-20120517-C00683
    Figure US20120122860A1-20120517-C00684
    Figure US20120122860A1-20120517-C00685
         		439.9
    P-2369
    Figure US20120122860A1-20120517-C00686
    Figure US20120122860A1-20120517-C00687
    Figure US20120122860A1-20120517-C00688
         		445.1
    P-2370
    Figure US20120122860A1-20120517-C00689
    Figure US20120122860A1-20120517-C00690
    Figure US20120122860A1-20120517-C00691
         		417.5
    P-2371
    Figure US20120122860A1-20120517-C00692
    Figure US20120122860A1-20120517-C00693
    Figure US20120122860A1-20120517-C00694
         		527.9
    P-2372
    Figure US20120122860A1-20120517-C00695
    Figure US20120122860A1-20120517-C00696
    Figure US20120122860A1-20120517-C00697
    P-2373
    Figure US20120122860A1-20120517-C00698
    Figure US20120122860A1-20120517-C00699
    Figure US20120122860A1-20120517-C00700
         		499.9
    P-2374
    Figure US20120122860A1-20120517-C00701
    Figure US20120122860A1-20120517-C00702
    Figure US20120122860A1-20120517-C00703
         		437.1
    P-2375
    Figure US20120122860A1-20120517-C00704
    Figure US20120122860A1-20120517-C00705
    Figure US20120122860A1-20120517-C00706
         		441.1
    P-2376
    Figure US20120122860A1-20120517-C00707
    Figure US20120122860A1-20120517-C00708
    Figure US20120122860A1-20120517-C00709
         		411.1
    P-2377
    Figure US20120122860A1-20120517-C00710
    Figure US20120122860A1-20120517-C00711
    Figure US20120122860A1-20120517-C00712
         		437.1
    P-2378
    Figure US20120122860A1-20120517-C00713
    Figure US20120122860A1-20120517-C00714
    Figure US20120122860A1-20120517-C00715
         		439.1
    P-2379
    Figure US20120122860A1-20120517-C00716
    Figure US20120122860A1-20120517-C00717
    Figure US20120122860A1-20120517-C00718
         		421.1
    P-1500
    Figure US20120122860A1-20120517-C00719
    Figure US20120122860A1-20120517-C00720
    Figure US20120122860A1-20120517-C00721
         		432.3
    P-1501
    Figure US20120122860A1-20120517-C00722
    Figure US20120122860A1-20120517-C00723
    Figure US20120122860A1-20120517-C00724
         		407.1
    P-2382
    Figure US20120122860A1-20120517-C00725
    Figure US20120122860A1-20120517-C00726
    Figure US20120122860A1-20120517-C00727
         		395.1
    P-2383
    Figure US20120122860A1-20120517-C00728
    Figure US20120122860A1-20120517-C00729
    Figure US20120122860A1-20120517-C00730
         		415.1
    P-2384
    Figure US20120122860A1-20120517-C00731
    Figure US20120122860A1-20120517-C00732
    Figure US20120122860A1-20120517-C00733
         		443.1
    P-2385
    Figure US20120122860A1-20120517-C00734
    Figure US20120122860A1-20120517-C00735
    Figure US20120122860A1-20120517-C00736
         		433.9
    P-2386
    Figure US20120122860A1-20120517-C00737
    Figure US20120122860A1-20120517-C00738
    Figure US20120122860A1-20120517-C00739
         		422.7
    P-2387
    Figure US20120122860A1-20120517-C00740
    Figure US20120122860A1-20120517-C00741
    Figure US20120122860A1-20120517-C00742
         		443.1
    P-2388
    Figure US20120122860A1-20120517-C00743
    Figure US20120122860A1-20120517-C00744
    Figure US20120122860A1-20120517-C00745
         		433.9
    P-2389
    Figure US20120122860A1-20120517-C00746
    Figure US20120122860A1-20120517-C00747
    Figure US20120122860A1-20120517-C00748
         		439.1
    P-2390
    Figure US20120122860A1-20120517-C00749
    Figure US20120122860A1-20120517-C00750
    Figure US20120122860A1-20120517-C00751
         		457.1
    P-2391
    Figure US20120122860A1-20120517-C00752
    Figure US20120122860A1-20120517-C00753
    Figure US20120122860A1-20120517-C00754
         		452.7
    P-2392
    Figure US20120122860A1-20120517-C00755
    Figure US20120122860A1-20120517-C00756
    Figure US20120122860A1-20120517-C00757
         		437.1
    P-2393
    Figure US20120122860A1-20120517-C00758
    Figure US20120122860A1-20120517-C00759
    Figure US20120122860A1-20120517-C00760
         		447.9
    P-2394
    Figure US20120122860A1-20120517-C00761
    Figure US20120122860A1-20120517-C00762
    Figure US20120122860A1-20120517-C00763
         		431.9
    P-2395
    Figure US20120122860A1-20120517-C00764
    Figure US20120122860A1-20120517-C00765
    Figure US20120122860A1-20120517-C00766
         		447.9
    P-2396
    Figure US20120122860A1-20120517-C00767
    Figure US20120122860A1-20120517-C00768
    Figure US20120122860A1-20120517-C00769
         		453.1
    P-2397
    Figure US20120122860A1-20120517-C00770
    Figure US20120122860A1-20120517-C00771
    Figure US20120122860A1-20120517-C00772
         		457.1
    P-2398
    Figure US20120122860A1-20120517-C00773
    Figure US20120122860A1-20120517-C00774
    Figure US20120122860A1-20120517-C00775
         		441.1
    P-2399
    Figure US20120122860A1-20120517-C00776
    Figure US20120122860A1-20120517-C00777
    Figure US20120122860A1-20120517-C00778
         		489.1
    P-2400
    Figure US20120122860A1-20120517-C00779
    Figure US20120122860A1-20120517-C00780
    Figure US20120122860A1-20120517-C00781
         		515.1
    P-2401
    Figure US20120122860A1-20120517-C00782
    Figure US20120122860A1-20120517-C00783
    Figure US20120122860A1-20120517-C00784
         		517.1
    P-2402
    Figure US20120122860A1-20120517-C00785
    Figure US20120122860A1-20120517-C00786
    Figure US20120122860A1-20120517-C00787
         		531.1
    P-2410
    Figure US20120122860A1-20120517-C00788
    Figure US20120122860A1-20120517-C00789
    Figure US20120122860A1-20120517-C00790
         		373.1
    P-2411
    Figure US20120122860A1-20120517-C00791
    Figure US20120122860A1-20120517-C00792
    Figure US20120122860A1-20120517-C00793
         		387.1
    P-2412
    Figure US20120122860A1-20120517-C00794
    Figure US20120122860A1-20120517-C00795
    Figure US20120122860A1-20120517-C00796
         		401.1
    P-2413
    Figure US20120122860A1-20120517-C00797
    Figure US20120122860A1-20120517-C00798
    Figure US20120122860A1-20120517-C00799
         		401.1
    P-2414
    Figure US20120122860A1-20120517-C00800
    Figure US20120122860A1-20120517-C00801
    Figure US20120122860A1-20120517-C00802
         		427.1
    P-2415
    Figure US20120122860A1-20120517-C00803
    Figure US20120122860A1-20120517-C00804
    Figure US20120122860A1-20120517-C00805
         		441.1
    P-2416
    Figure US20120122860A1-20120517-C00806
    Figure US20120122860A1-20120517-C00807
    Figure US20120122860A1-20120517-C00808
         		427.1
    P-2417
    Figure US20120122860A1-20120517-C00809
    Figure US20120122860A1-20120517-C00810
    Figure US20120122860A1-20120517-C00811
         		413.1
    P-2418
    Figure US20120122860A1-20120517-C00812
    Figure US20120122860A1-20120517-C00813
    Figure US20120122860A1-20120517-C00814
         		399.1
    P-2419
    Figure US20120122860A1-20120517-C00815
    Figure US20120122860A1-20120517-C00816
    Figure US20120122860A1-20120517-C00817
         		388.3
    P-2420
    Figure US20120122860A1-20120517-C00818
    Figure US20120122860A1-20120517-C00819
    Figure US20120122860A1-20120517-C00820
         		413.9
    P-2421
    Figure US20120122860A1-20120517-C00821
    Figure US20120122860A1-20120517-C00822
    Figure US20120122860A1-20120517-C00823
         		429.9
    P-2431
    Figure US20120122860A1-20120517-C00824
    Figure US20120122860A1-20120517-C00825
    Figure US20120122860A1-20120517-C00826
         		442.3
    P-2432
    Figure US20120122860A1-20120517-C00827
    Figure US20120122860A1-20120517-C00828
    Figure US20120122860A1-20120517-C00829
         		455.9
    P-2433
    Figure US20120122860A1-20120517-C00830
    Figure US20120122860A1-20120517-C00831
    Figure US20120122860A1-20120517-C00832
         		440.3
    P-2434
    Figure US20120122860A1-20120517-C00833
    Figure US20120122860A1-20120517-C00834
    Figure US20120122860A1-20120517-C00835
         		481.9
    P-2435
    Figure US20120122860A1-20120517-C00836
    Figure US20120122860A1-20120517-C00837
    Figure US20120122860A1-20120517-C00838
         		410.3
    P-2436
    Figure US20120122860A1-20120517-C00839
    Figure US20120122860A1-20120517-C00840
    Figure US20120122860A1-20120517-C00841
         		393.9
    P-2437
    Figure US20120122860A1-20120517-C00842
    Figure US20120122860A1-20120517-C00843
    Figure US20120122860A1-20120517-C00844
         		362.3
    P-2438
    Figure US20120122860A1-20120517-C00845
    Figure US20120122860A1-20120517-C00846
    Figure US20120122860A1-20120517-C00847
         		376.3
    P-2439
    Figure US20120122860A1-20120517-C00848
    Figure US20120122860A1-20120517-C00849
    Figure US20120122860A1-20120517-C00850
         		359.9
    P-2440
    Figure US20120122860A1-20120517-C00851
    Figure US20120122860A1-20120517-C00852
    Figure US20120122860A1-20120517-C00853
         		403.1
    P-2441
    Figure US20120122860A1-20120517-C00854
    Figure US20120122860A1-20120517-C00855
    Figure US20120122860A1-20120517-C00856
         		402.3
    P-2442
    Figure US20120122860A1-20120517-C00857
    Figure US20120122860A1-20120517-C00858
    Figure US20120122860A1-20120517-C00859
         		388.3
    P-2443
    Figure US20120122860A1-20120517-C00860
    Figure US20120122860A1-20120517-C00861
    Figure US20120122860A1-20120517-C00862
         		416.3
    P-2444
    Figure US20120122860A1-20120517-C00863
    Figure US20120122860A1-20120517-C00864
    Figure US20120122860A1-20120517-C00865
         		556.0
    P-2445
    Figure US20120122860A1-20120517-C00866
    Figure US20120122860A1-20120517-C00867
    Figure US20120122860A1-20120517-C00868
         		542.3
    P-2446
    Figure US20120122860A1-20120517-C00869
    Figure US20120122860A1-20120517-C00870
    Figure US20120122860A1-20120517-C00871
         		571.2
    P-2447
    Figure US20120122860A1-20120517-C00872
    Figure US20120122860A1-20120517-C00873
    Figure US20120122860A1-20120517-C00874
         		557.2
    P-2448
    Figure US20120122860A1-20120517-C00875
    Figure US20120122860A1-20120517-C00876
    Figure US20120122860A1-20120517-C00877
         		402.3
    P-2449
    Figure US20120122860A1-20120517-C00878
    Figure US20120122860A1-20120517-C00879
    Figure US20120122860A1-20120517-C00880
         		378.3
    P-2450
    Figure US20120122860A1-20120517-C00881
    Figure US20120122860A1-20120517-C00882
    Figure US20120122860A1-20120517-C00883
         		391.9
    P-2451
    Figure US20120122860A1-20120517-C00884
    Figure US20120122860A1-20120517-C00885
    Figure US20120122860A1-20120517-C00886
         		376.3
    P-2452
    Figure US20120122860A1-20120517-C00887
    Figure US20120122860A1-20120517-C00888
    Figure US20120122860A1-20120517-C00889
         		418.3
    P-2453
    Figure US20120122860A1-20120517-C00890
    Figure US20120122860A1-20120517-C00891
    Figure US20120122860A1-20120517-C00892
         		404.3
    P-2454
    Figure US20120122860A1-20120517-C00893
    Figure US20120122860A1-20120517-C00894
    Figure US20120122860A1-20120517-C00895
         		423.9
    P-2455
    Figure US20120122860A1-20120517-C00896
    Figure US20120122860A1-20120517-C00897
    Figure US20120122860A1-20120517-C00898
         		438.3
    P-2456
    Figure US20120122860A1-20120517-C00899
    Figure US20120122860A1-20120517-C00900
    Figure US20120122860A1-20120517-C00901
         		421.9
    P-2457
    Figure US20120122860A1-20120517-C00902
    Figure US20120122860A1-20120517-C00903
    Figure US20120122860A1-20120517-C00904
         		463.9
    P-2458
    Figure US20120122860A1-20120517-C00905
    Figure US20120122860A1-20120517-C00906
    Figure US20120122860A1-20120517-C00907
         		398.3
    P-2459
    Figure US20120122860A1-20120517-C00908
    Figure US20120122860A1-20120517-C00909
    Figure US20120122860A1-20120517-C00910
         		384.3
    P-2460
    Figure US20120122860A1-20120517-C00911
    Figure US20120122860A1-20120517-C00912
    Figure US20120122860A1-20120517-C00913
         		414.3
    P-2461
    Figure US20120122860A1-20120517-C00914
    Figure US20120122860A1-20120517-C00915
    Figure US20120122860A1-20120517-C00916
         		538.3
    P-2462
    Figure US20120122860A1-20120517-C00917
    Figure US20120122860A1-20120517-C00918
    Figure US20120122860A1-20120517-C00919
         		402.3
    P-2463
    Figure US20120122860A1-20120517-C00920
    Figure US20120122860A1-20120517-C00921
    Figure US20120122860A1-20120517-C00922
         		388.3
    P-2464
    Figure US20120122860A1-20120517-C00923
    Figure US20120122860A1-20120517-C00924
    Figure US20120122860A1-20120517-C00925
         		399.9
    P-2465
    Figure US20120122860A1-20120517-C00926
    Figure US20120122860A1-20120517-C00927
    Figure US20120122860A1-20120517-C00928
         		531.9
    P-2466
    Figure US20120122860A1-20120517-C00929
    Figure US20120122860A1-20120517-C00930
    Figure US20120122860A1-20120517-C00931
         		518.3
    P-2468
    Figure US20120122860A1-20120517-C00932
    Figure US20120122860A1-20120517-C00933
    Figure US20120122860A1-20120517-C00934
         		437.1
    P-2469
    Figure US20120122860A1-20120517-C00935
    Figure US20120122860A1-20120517-C00936
    Figure US20120122860A1-20120517-C00937
         		363.1
    P-2470
    Figure US20120122860A1-20120517-C00938
    Figure US20120122860A1-20120517-C00939
    Figure US20120122860A1-20120517-C00940
         		379.1
    P-2471
    Figure US20120122860A1-20120517-C00941
    Figure US20120122860A1-20120517-C00942
    Figure US20120122860A1-20120517-C00943
         		419.1
    P-2472
    Figure US20120122860A1-20120517-C00944
    Figure US20120122860A1-20120517-C00945
    Figure US20120122860A1-20120517-C00946
    P-2476
    Figure US20120122860A1-20120517-C00947
    Figure US20120122860A1-20120517-C00948
    Figure US20120122860A1-20120517-C00949
         		465.5 467.4 [M − H+]−
    P-2477
    Figure US20120122860A1-20120517-C00950
    Figure US20120122860A1-20120517-C00951
    Figure US20120122860A1-20120517-C00952
         		439.4 441.4 [M − H+]−
    P-2481
    Figure US20120122860A1-20120517-C00953
    Figure US20120122860A1-20120517-C00954
    Figure US20120122860A1-20120517-C00955
         		517   519  
    P-2485
    Figure US20120122860A1-20120517-C00956
    Figure US20120122860A1-20120517-C00957
    Figure US20120122860A1-20120517-C00958
         		516.9
    P-2486
    Figure US20120122860A1-20120517-C00959
    Figure US20120122860A1-20120517-C00960
    Figure US20120122860A1-20120517-C00961
         		481.2
  • Figure US20120122860A1-20120517-C00962
  • Figure US20120122860A1-20120517-C00963
    • Example 3 Synthesis of propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide P-1496
  • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide P-1496 was synthesized in one step from propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide 47 as shown in Scheme 5.
  • Figure US20120122860A1-20120517-C00964
  • Step 1—Preparation of propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1496):
  • Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (47, 10 mg, 0.022 mmol) was weighed into a 5 mL microwave vial and combined with 2-methoxypyrimidine-5-boronic acid (48, 4.4 mg, 0.028 mmol), followed by the addition of 600 μL of acetonitrile and 500 μL of 1M potassium carbonate and a spatula tip (≈1 mg) of [1,1″-bis(diphenylphosphino)-ferrocene]dichloropalladium(II). The reaction mixture was irradiated in a microwave at 160° C. for 5 minutes. The solution was neutralized with 100 μL of acetic acid and all material was transferred to a 4 mL vial and the solvents were removed under vacuum. The crude material was dissolved in 400 μL of dimtheylsulfoxide and purified by reverse phase HPLC, eluting with 0.1% trifluoroacetic acid in water and 0.1% trifluoroacetic acid in acetonitrile, 20-100% acetonitrile over 16 minutes at 6 mL per minute. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound. MS (ESI)[M+H+]=487.9.
  • Additional compounds were prepared similarly to the protocol of Scheme 5, where optimal reaction conditions may have varied in terms of time and temperature of the reaction, or alternatively, tetrakis(triphenylphosphine)palladium(0) was used as a catalyst, and in chromatography conditions for purification of the desired compounds. The reactions were performed optionally substituting 2-methoxypyrimidine-5-boronic acid 48 with an appropriate boronic acid and/or propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide 47 with an appropriate 5-bromo-1H-pyrrolo[2,3-b]pyridine derivative. The following compounds were prepared by this procedure:
    • 3-{3-[3-(Pyridine-3-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzamide (P-2147),
    • 3-(3-{3-[3-(Pyridine-3-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-phenyl)-propionic acid (P-2148),
    • Propane-1-sulfonic acid {3-[5-(6-chloro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2154),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-fluoro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2155),
    • Propane-1-sulfonic acid {3-[5-(3,5-dimethyl-isoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2156),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1-isobutyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2157),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2158),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-3-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2159),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-3-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2160),
    • N-(4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-phenyl)-acetamide (P-2161),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2162),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-fluoro-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2164),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2165),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(morpholine-4-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2166),
    • 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2167),
    • N-Cyclopropyl-4-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzenesulfonamide (P-2168),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2169),
    • 3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-methyl-benzenesulfonamide (P-2170),
    • Propane-1-sulfonic acid {3-[5-(4-chloro-3-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2171),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-fluoro-6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2172),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2174),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2175),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2H-pyrazol-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2176),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2177),
    • Propane-1-sulfonic acid (3-{5-[6-(3-dimethylamino-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2178),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-hydroxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2179),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2183),
    • Propane-1-sulfonic acid {3-[5-(2,6-dimethoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2184),
    • 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N,N-dimethyl-benzenesulfonamide (P-2185),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(piperidine-1-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2186),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-methylsulfanyl-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2187),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(5-methanesulfonyl-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2188),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methylsulfanyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2189),
    • Propane-1-sulfonic acid {3-[5-(1-benzyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2190),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2191),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-fluoro-pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2192),
    • N-(5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridin-2-yl)-acetamide (P-2193),
    • 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzenesulfonamide (P-2194),
    • Propane-1-sulfonic acid {3-[5-(2,5-dimethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2195),
    • Propane-1-sulfonic acid {3-[5-(2-dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2196),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-morpholin-4-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2197),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-hydroxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2198),
    • Propane-1-sulfonic acid {3-[5-(2,4-dimethoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2199),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2211),
    • Propane-1-sulfonic acid {3-[5-(2-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2212),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2213),
    • Propane-1-sulfonic acid {3-[5-(6-amino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2214),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(2-hydroxy-ethoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2215),
    • Propane-1-sulfonic acid (3-{5-[6-(3-diethylamino-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2216),
    • Propane-1-sulfonic acid {3-[5-(4-ethanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2218),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2219),
    • 5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridine-2-carboxylic acid amide (P-2220),
    • 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-(2-hydroxy-ethyl)-benzenesulfonamide (P-2221),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(propane-2-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2223),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2227),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2228),
    • Propane-1-sulfonic acid {3-[5-(6-dimethylamino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2229),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-pyrrolidin-1-yl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2231),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(2-morpholin-4-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2232),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(2-pyrrolidin-1-yl-ethoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2233),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-hydroxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2234),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(3-pyrrolidin-1-yl-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2235),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(3-morpholin-4-yl-propoxy)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2236),
    • Ethanesulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2269),
    • Ethanesulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2270),
    • Ethanesulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2271),
    • 2-Methyl-propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2297),
    • 2-Methyl-propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2298),
    • 2-Methyl-propane-1-sulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2299),
    • Butane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2300),
    • Butane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2301),
    • Butane-1-sulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2302),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2325),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2326),
    • N-{3-[5-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2343),
    • N-{2,4-Difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2344),
    • N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide (P-2345),
    • Cyclopropanesulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2350),
    • Cyclopropanesulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2351),
    • Cyclopropanesulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2352),
    • Propane-1-sulfonic acid {2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2407),
    • Propane-1-sulfonic acid {3-[5-(2-dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl}-amide (P-2408),
    • Pyrrolidine-1-sulfonic acid {2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2422),
    • N,N-dimethylamino-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl}-amide (P-2423),
    • N,N-dimethylamino-sulfonic acid {2-fluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2424),
    • Pyrrolidine-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl}-amide (P-2425),
    • Propane-1-sulfonic acid {2-chloro-3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-4-fluoro-phenyl}-amide (P-2427),
    • Propane-1-sulfonic acid {2-chloro-4-fluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2428), and
    • Propane-1-sulfonic acid {2-chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2429).
  • The following table indicates the 1H-pyrrolo[2,3-b]pyridine (column 2) and boronic acid (column 3) used to afford the desired compound (column 4). The compound number is provided in column 1, and the observed mass is in column 5.
  • MS
    (ESI)
    [M +
    H+]+
    1H-pyrrolo[2,3- Boronic ob-
    b]pyridine acid Compound served
    P- 2147
    Figure US20120122860A1-20120517-C00965
    Figure US20120122860A1-20120517-C00966
    Figure US20120122860A1-20120517-C00967
         		498.3
    P- 2148
    Figure US20120122860A1-20120517-C00968
    Figure US20120122860A1-20120517-C00969
    Figure US20120122860A1-20120517-C00970
         		527.1
    P- 2154
    Figure US20120122860A1-20120517-C00971
    Figure US20120122860A1-20120517-C00972
    Figure US20120122860A1-20120517-C00973
         		491.1
    P- 2155
    Figure US20120122860A1-20120517-C00974
    Figure US20120122860A1-20120517-C00975
    Figure US20120122860A1-20120517-C00976
         		475.1
    P- 2156
    Figure US20120122860A1-20120517-C00977
    Figure US20120122860A1-20120517-C00978
    Figure US20120122860A1-20120517-C00979
         		475.1
    P- 2157
    Figure US20120122860A1-20120517-C00980
    Figure US20120122860A1-20120517-C00981
    Figure US20120122860A1-20120517-C00982
         		502.3
    P- 2158
    Figure US20120122860A1-20120517-C00983
    Figure US20120122860A1-20120517-C00984
    Figure US20120122860A1-20120517-C00985
         		488.3
    P- 2159
    Figure US20120122860A1-20120517-C00986
    Figure US20120122860A1-20120517-C00987
    Figure US20120122860A1-20120517-C00988
         		503.9
    P- 2160
    Figure US20120122860A1-20120517-C00989
    Figure US20120122860A1-20120517-C00990
    Figure US20120122860A1-20120517-C00991
         		541.9
    P- 2161
    Figure US20120122860A1-20120517-C00992
    Figure US20120122860A1-20120517-C00993
    Figure US20120122860A1-20120517-C00994
         		513.1
    P- 2162
    Figure US20120122860A1-20120517-C00995
    Figure US20120122860A1-20120517-C00996
    Figure US20120122860A1-20120517-C00997
         		458.3
    P- 2164
    Figure US20120122860A1-20120517-C00998
    Figure US20120122860A1-20120517-C00999
    Figure US20120122860A1-20120517-C01000
         		475.1
    P- 2165
    Figure US20120122860A1-20120517-C01001
    Figure US20120122860A1-20120517-C01002
    Figure US20120122860A1-20120517-C01003
         		549.1
    P- 2166
    Figure US20120122860A1-20120517-C01004
    Figure US20120122860A1-20120517-C01005
    Figure US20120122860A1-20120517-C01006
         		605.2
    P- 2167
    Figure US20120122860A1-20120517-C01007
    Figure US20120122860A1-20120517-C01008
    Figure US20120122860A1-20120517-C01009
         		549.1
    P- 2168
    Figure US20120122860A1-20120517-C01010
    Figure US20120122860A1-20120517-C01011
    Figure US20120122860A1-20120517-C01012
         		575.2
    P- 2169
    Figure US20120122860A1-20120517-C01013
    Figure US20120122860A1-20120517-C01014
    Figure US20120122860A1-20120517-C01015
         		549.1
    P- 2170
    Figure US20120122860A1-20120517-C01016
    Figure US20120122860A1-20120517-C01017
    Figure US20120122860A1-20120517-C01018
         		549.1
    P- 2171
    Figure US20120122860A1-20120517-C01019
    Figure US20120122860A1-20120517-C01020
    Figure US20120122860A1-20120517-C01021
    P- 2172
    Figure US20120122860A1-20120517-C01022
    Figure US20120122860A1-20120517-C01023
    Figure US20120122860A1-20120517-C01024
    P- 2174
    Figure US20120122860A1-20120517-C01025
    Figure US20120122860A1-20120517-C01026
    Figure US20120122860A1-20120517-C01027
         		446.0
    P- 2175
    Figure US20120122860A1-20120517-C01028
    Figure US20120122860A1-20120517-C01029
    Figure US20120122860A1-20120517-C01030
         		460.4
    P- 2176
    Figure US20120122860A1-20120517-C01031
    Figure US20120122860A1-20120517-C01032
    Figure US20120122860A1-20120517-C01033
         		446.0
    P- 2177
    Figure US20120122860A1-20120517-C01034
    Figure US20120122860A1-20120517-C01035
    Figure US20120122860A1-20120517-C01036
         		459.0
    P- 2178
    Figure US20120122860A1-20120517-C01037
    Figure US20120122860A1-20120517-C01038
    Figure US20120122860A1-20120517-C01039
         		458.2
    P- 2179
    Figure US20120122860A1-20120517-C01040
    Figure US20120122860A1-20120517-C01041
    Figure US20120122860A1-20120517-C01042
         		472.1
    P- 2183
    Figure US20120122860A1-20120517-C01043
    Figure US20120122860A1-20120517-C01044
    Figure US20120122860A1-20120517-C01045
         		533.9
    P- 2184
    Figure US20120122860A1-20120517-C01046
    Figure US20120122860A1-20120517-C01047
    Figure US20120122860A1-20120517-C01048
         		517.1
    P- 2185
    Figure US20120122860A1-20120517-C01049
    Figure US20120122860A1-20120517-C01050
    Figure US20120122860A1-20120517-C01051
         		563.2
    P- 2186
    Figure US20120122860A1-20120517-C01052
    Figure US20120122860A1-20120517-C01053
    Figure US20120122860A1-20120517-C01054
         		603.2
    P- 2187
    Figure US20120122860A1-20120517-C01055
    Figure US20120122860A1-20120517-C01056
    Figure US20120122860A1-20120517-C01057
         		503.1
    P- 2188
    Figure US20120122860A1-20120517-C01058
    Figure US20120122860A1-20120517-C01059
    Figure US20120122860A1-20120517-C01060
         		535.1
    P- 2189
    Figure US20120122860A1-20120517-C01061
    Figure US20120122860A1-20120517-C01062
    Figure US20120122860A1-20120517-C01063
         		503.9
    P- 2190
    Figure US20120122860A1-20120517-C01064
    Figure US20120122860A1-20120517-C01065
    Figure US20120122860A1-20120517-C01066
         		536.3
    P- 2191
    Figure US20120122860A1-20120517-C01067
    Figure US20120122860A1-20120517-C01068
    Figure US20120122860A1-20120517-C01069
         		537.5
    P- 2192
    Figure US20120122860A1-20120517-C01070
    Figure US20120122860A1-20120517-C01071
    Figure US20120122860A1-20120517-C01072
         		475.1
    P- 2193
    Figure US20120122860A1-20120517-C01073
    Figure US20120122860A1-20120517-C01074
    Figure US20120122860A1-20120517-C01075
         		514.3
    P- 2194
    Figure US20120122860A1-20120517-C01076
    Figure US20120122860A1-20120517-C01077
    Figure US20120122860A1-20120517-C01078
         		535.1
    P- 2195
    Figure US20120122860A1-20120517-C01079
    Figure US20120122860A1-20120517-C01080
    Figure US20120122860A1-20120517-C01081
         		474.3
    P- 2196
    Figure US20120122860A1-20120517-C01082
    Figure US20120122860A1-20120517-C01083
    Figure US20120122860A1-20120517-C01084
         		501.1
    P- 2197
    Figure US20120122860A1-20120517-C01085
    Figure US20120122860A1-20120517-C01086
    Figure US20120122860A1-20120517-C01087
         		543.1
    P- 2198
    Figure US20120122860A1-20120517-C01088
    Figure US20120122860A1-20120517-C01089
    Figure US20120122860A1-20120517-C01090
         		472.1
    P- 2199
    Figure US20120122860A1-20120517-C01091
    Figure US20120122860A1-20120517-C01092
    Figure US20120122860A1-20120517-C01093
         		517.9
    P- 2211
    Figure US20120122860A1-20120517-C01094
    Figure US20120122860A1-20120517-C01095
    Figure US20120122860A1-20120517-C01096
         		472.0
    P- 2212
    Figure US20120122860A1-20120517-C01097
    Figure US20120122860A1-20120517-C01098
    Figure US20120122860A1-20120517-C01099
         		490.0 492.0
    P- 2213
    Figure US20120122860A1-20120517-C01100
    Figure US20120122860A1-20120517-C01101
    Figure US20120122860A1-20120517-C01102
         		471.0
    P- 2214
    Figure US20120122860A1-20120517-C01103
    Figure US20120122860A1-20120517-C01104
    Figure US20120122860A1-20120517-C01105
         		472.5
    P- 2215
    Figure US20120122860A1-20120517-C01106
    Figure US20120122860A1-20120517-C01107
    Figure US20120122860A1-20120517-C01108
         		517.0
    P- 2216
    Figure US20120122860A1-20120517-C01109
    Figure US20120122860A1-20120517-C01110
    Figure US20120122860A1-20120517-C01111
         		586.5
    P- 2218
    Figure US20120122860A1-20120517-C01112
    Figure US20120122860A1-20120517-C01113
    Figure US20120122860A1-20120517-C01114
         		546.5 [M − H+]−
    P- 2219
    Figure US20120122860A1-20120517-C01115
    Figure US20120122860A1-20120517-C01116
    Figure US20120122860A1-20120517-C01117
         		527.7
    P- 2220
    Figure US20120122860A1-20120517-C01118
    Figure US20120122860A1-20120517-C01119
    Figure US20120122860A1-20120517-C01120
         		500.2
    P- 2221
    Figure US20120122860A1-20120517-C01121
    Figure US20120122860A1-20120517-C01122
    Figure US20120122860A1-20120517-C01123
         		579.6
    P- 2223
    Figure US20120122860A1-20120517-C01124
    Figure US20120122860A1-20120517-C01125
    Figure US20120122860A1-20120517-C01126
         		562.3
    P- 2227
    Figure US20120122860A1-20120517-C01127
    Figure US20120122860A1-20120517-C01128
    Figure US20120122860A1-20120517-C01129
         		589.6
    P- 2228
    Figure US20120122860A1-20120517-C01130
    Figure US20120122860A1-20120517-C01131
    Figure US20120122860A1-20120517-C01132
         		532.3 [M − H+]−
    P- 2229
    Figure US20120122860A1-20120517-C01133
    Figure US20120122860A1-20120517-C01134
    Figure US20120122860A1-20120517-C01135
         		500.4
    P- 2231
    Figure US20120122860A1-20120517-C01136
    Figure US20120122860A1-20120517-C01137
    Figure US20120122860A1-20120517-C01138
         		526.4
    P- 2232
    Figure US20120122860A1-20120517-C01139
    Figure US20120122860A1-20120517-C01140
    Figure US20120122860A1-20120517-C01141
         		586.1
    P- 2233
    Figure US20120122860A1-20120517-C01142
    Figure US20120122860A1-20120517-C01143
    Figure US20120122860A1-20120517-C01144
         		570.5
    P- 2234
    Figure US20120122860A1-20120517-C01145
    Figure US20120122860A1-20120517-C01146
    Figure US20120122860A1-20120517-C01147
         		473.1
    P- 2235
    Figure US20120122860A1-20120517-C01148
    Figure US20120122860A1-20120517-C01149
    Figure US20120122860A1-20120517-C01150
         		584.1
    P- 2236
    Figure US20120122860A1-20120517-C01151
    Figure US20120122860A1-20120517-C01152
    Figure US20120122860A1-20120517-C01153
         		600.1
    P- 2269
    Figure US20120122860A1-20120517-C01154
    Figure US20120122860A1-20120517-C01155
    Figure US20120122860A1-20120517-C01156
    P- 2270
    Figure US20120122860A1-20120517-C01157
    Figure US20120122860A1-20120517-C01158
    Figure US20120122860A1-20120517-C01159
    P- 2271
    Figure US20120122860A1-20120517-C01160
    Figure US20120122860A1-20120517-C01161
    Figure US20120122860A1-20120517-C01162
    P- 2297
    Figure US20120122860A1-20120517-C01163
    Figure US20120122860A1-20120517-C01164
    Figure US20120122860A1-20120517-C01165
    P- 2298
    Figure US20120122860A1-20120517-C01166
    Figure US20120122860A1-20120517-C01167
    Figure US20120122860A1-20120517-C01168
    P- 2299
    Figure US20120122860A1-20120517-C01169
    Figure US20120122860A1-20120517-C01170
    Figure US20120122860A1-20120517-C01171
    P- 2300
    Figure US20120122860A1-20120517-C01172
    Figure US20120122860A1-20120517-C01173
    Figure US20120122860A1-20120517-C01174
         		503.9
    P- 2301
    Figure US20120122860A1-20120517-C01175
    Figure US20120122860A1-20120517-C01176
    Figure US20120122860A1-20120517-C01177
         		488.3
    P- 2302
    Figure US20120122860A1-20120517-C01178
    Figure US20120122860A1-20120517-C01179
    Figure US20120122860A1-20120517-C01180
         		474.3
    P- 2325
    Figure US20120122860A1-20120517-C01181
    Figure US20120122860A1-20120517-C01182
    Figure US20120122860A1-20120517-C01183
         		544.3
    P- 2326
    Figure US20120122860A1-20120517-C01184
    Figure US20120122860A1-20120517-C01185
    Figure US20120122860A1-20120517-C01186
         		529.1
    P- 2343
    Figure US20120122860A1-20120517-C01187
    Figure US20120122860A1-20120517-C01188
    Figure US20120122860A1-20120517-C01189
         		516.3
    P- 2344
    Figure US20120122860A1-20120517-C01190
    Figure US20120122860A1-20120517-C01191
    Figure US20120122860A1-20120517-C01192
         		500.3
    P- 2345
    Figure US20120122860A1-20120517-C01193
    Figure US20120122860A1-20120517-C01194
    Figure US20120122860A1-20120517-C01195
         		486.3
    P- 2350
    Figure US20120122860A1-20120517-C01196
    Figure US20120122860A1-20120517-C01197
    Figure US20120122860A1-20120517-C01198
    P- 2351
    Figure US20120122860A1-20120517-C01199
    Figure US20120122860A1-20120517-C01200
    Figure US20120122860A1-20120517-C01201
    P- 2352
    Figure US20120122860A1-20120517-C01202
    Figure US20120122860A1-20120517-C01203
    Figure US20120122860A1-20120517-C01204
    P- 2407
    Figure US20120122860A1-20120517-C01205
    Figure US20120122860A1-20120517-C01206
    Figure US20120122860A1-20120517-C01207
         		470.1
    P- 2408
    Figure US20120122860A1-20120517-C01208
    Figure US20120122860A1-20120517-C01209
    Figure US20120122860A1-20120517-C01210
         		483.6
    P- 2422
    Figure US20120122860A1-20120517-C01211
    Figure US20120122860A1-20120517-C01212
    Figure US20120122860A1-20120517-C01213
         		597.1
    P- 2423
    Figure US20120122860A1-20120517-C01214
    Figure US20120122860A1-20120517-C01215
    Figure US20120122860A1-20120517-C01216
         		471.5 473.5 [M − H+]−
    P- 2424
    Figure US20120122860A1-20120517-C01217
    Figure US20120122860A1-20120517-C01218
    Figure US20120122860A1-20120517-C01219
         		469.6 [M − H+]−
    P- 2425
    Figure US20120122860A1-20120517-C01220
    Figure US20120122860A1-20120517-C01221
    Figure US20120122860A1-20120517-C01222
         		499.1 501.1
    P- 2427
    Figure US20120122860A1-20120517-C01223
    Figure US20120122860A1-20120517-C01224
    Figure US20120122860A1-20120517-C01225
    P- 2428
    Figure US20120122860A1-20120517-C01226
    Figure US20120122860A1-20120517-C01227
    Figure US20120122860A1-20120517-C01228
    P- 2429
    Figure US20120122860A1-20120517-C01229
    Figure US20120122860A1-20120517-C01230
    Figure US20120122860A1-20120517-C01231
    P- 1496
    Figure US20120122860A1-20120517-C01232
    Figure US20120122860A1-20120517-C01233
    Figure US20120122860A1-20120517-C01234
         		487.9
    • Example 4 Synthesis of propane-1-sulfonic acid [2,4-difluoro-3-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide P-2182
  • Propane-1-sulfonic acid [2,4-difluoro-3-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide P-2182 was synthesized in two steps from 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine 49 as shown in Scheme 6.
  • Figure US20120122860A1-20120517-C01235
  • Step 1—Preparation of propane-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methy]-phenyl}-amide (P-2473):
  • 5-Trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (49, 100 mg, 0.537 mmol), propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (50, 170 mg, 0.645 mmol) and potassium hydroxide (90.4 mg, 1.61 mmol), were combined in a vial with 2 mL of methanol. The reaction was stirred for 3 hours at room temperature. The reaction solution was extracted with 20 mL of ethyl acetate and 20 mL water (with 1N hydrochloric acid added to pH˜1). The organic layer was separated and the solvents removed under vacuum, and the resulting residue was taken up in 4:1 acetonitrile:water with 5% TFA. This was allowed to stir over the weekend at room temperature, then extracted with ethyl acetate and water. The organic layer was washed with brine and then dried over magnesium sulfate, filtered, and the solvents were removed from the filtrate under vacuum. The resulting material was purified by silica gel column chromatography eluting with a gradient of ethyl acetate in hexanes to provide the desired compound (P-2473, 135 mg). MS (ESI) [M+H+]+=449.9.
  • Step 2—Preparation of propane-1-sulfonic acid [2,4-difluoro-3-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2182):
  • To propane-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (P-2473, 135 mg, 0.300 mmol) dissolved in 2 mL of dichloromethane and 2 mL of tetrahydrofuran, Dess-Martin periodinane (127 mg, 0.300 mmol) was added as a solid. The reaction was a suspension, which was allowed to stir at room temperature for 15 minutes, then quenched with 60 mL of 5:1 saturated sodium bicarbonate:saturated sodium bisulfite and 20 mL of ethyl acetate. The mixture was stirred for 10 minutes, and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvents were removed from the filtrate under vacuum, and the resulting residue was purified by silica gel column chromatography eluting with a gradient from 1% to 5% methanol in dichloromethane to provide the desired compound (P-2182, 53 mg). MS (ESI) [M−H+]−=446.0.
  • Additional compounds were prepared similarly to the protocol of Scheme 6, where optimal reaction conditions may have varied in terms of time and temperature of the reaction, and in chromatography conditions for purification of the desired compounds. The reactions were performed optionally substituting 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine 49 with an appropriate 1H-pyrrolo[2,3-b]pyridine and/or propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 50 with an appropriate aldehyde in step 1. The following compounds were prepared by this procedure:
    • N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1503),
    • N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2057),
    • N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2058),
    • N-[2-Fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2059),
    • N-[2-Fluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2060),
    • 5-(3-{[2,6-Difluoro-3-(propane-1-sulfonylamino)-phenyl]-hydroxy-methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid ethylamide (P-2150),
    • 5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridine-2-carboxylic acid ethylamide (P-2151),
    • Propane-1-sulfonic acid {3-[5-(1,5-dimethyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2152),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2153),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2173),
    • 5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridine-2-carboxylic acid methylamide (P-2180),
    • 5-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridine-2-carboxylic acid cyclopropylamide (P-2181),
    • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methylamide (P-2200),
    • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid cyclopropylamide (P-2201),
    • Propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1499),
    • Propane-1-sulfonic acid (3-{5-[2-(3-dimethylamino-propoxy)-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2203),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-hydroxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2204),
    • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (P-2207),
    • Propane-1-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2208),
    • Propane-1-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2209),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2210),
    • Propane-1-sulfonic acid (3-{5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2222),
    • (E)-3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acrylic acid methyl ester (P-2225),
    • Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(3-methoxy-propyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-2226),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2239),
    • Propane-1-sulfonic acid {3-[5-(3-diethylamino-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-2241),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-morpholin-4-ylmethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2244),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-morpholin-4-yl-propyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2247),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-pyrrolidin-1-yl-propyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2248),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-hydroxymethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2250),
    • 3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N,N-diethyl-propionamide (P-2255),
    • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2257),
    • Propane-1-sulfonic acid [3-(5-diethylaminomethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2258),
    • Propane-1-sulfonic acid [2,4-difluoro-3-(5-pyrrolidin-1-ylmethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2259),
    • Propane-1-sulfonic acid [3-(5-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2260),
    • Propane-1-sulfonic acid [3-(4-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2261),
    • Ethanesulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2268),
    • 2-Methyl-propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2296),
    • Cyclopropanesulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2348),
    • 1-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-cyclopropanecarboxylic acid (P-2349),
    • Propane-1-sulfonic acid [2-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2403),
    • 3-[2-Fluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (P-2404),
    • Propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-1502),
    • 3-[2-Fluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (P-2406),
    • Propane-1-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2409),
    • Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-chloro-4-fluoro-phenyl]-amide (P-2426),
    • Butane-1-sulfonic acid {2-chloro-4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2430),
    • N-[3-(4-Ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1504),
    • 3,3,3-Trifluoro-propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2478),
    • N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-C,C,C-tri fluoro-methanesulfonamide (P-2479), and
    • Propane-1-sulfonic acid [2-fluoro-3-(5-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2480),
    • N-[2,4-Difluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2482),
    • N-[3-(5-Cyclopropyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2483),
    • N-[3-(5-Ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2484), and
    • N-[3-(4-Ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-2487).
      The following table indicates the 1H-pyrrolo[2,3-b]pyridine (column 2) and aldehyde (column 3) used to afford the desired compound (column 4). The compound number is provided in column 1, and the observed mass is in column 5.
  • MS
    (ESI)
    [M +
    1H- H+]+
    pyrrolo[2,3- ob-
    b]pyridine Aldehyde Compound served
    P- 1503 
    Figure US20120122860A1-20120517-C01236
    Figure US20120122860A1-20120517-C01237
    Figure US20120122860A1-20120517-C01238
         		505.5 ([M − H+]−)
    P- 2057 
    Figure US20120122860A1-20120517-C01239
    Figure US20120122860A1-20120517-C01240
    Figure US20120122860A1-20120517-C01241
         		487.7 ([M − H+]−)
    P- 2058 
    Figure US20120122860A1-20120517-C01242
    Figure US20120122860A1-20120517-C01243
    Figure US20120122860A1-20120517-C01244
         		496.4 498.4 ([M − H+]−)
    P- 2059 
    Figure US20120122860A1-20120517-C01245
    Figure US20120122860A1-20120517-C01246
    Figure US20120122860A1-20120517-C01247
         		478.2
    P- 2060 
    Figure US20120122860A1-20120517-C01248
    Figure US20120122860A1-20120517-C01249
    Figure US20120122860A1-20120517-C01250
         		494.1
    P- 2150  Iso- late after step 1
    Figure US20120122860A1-20120517-C01251
    Figure US20120122860A1-20120517-C01252
    Figure US20120122860A1-20120517-C01253
         		530.1
    P- 2151 
    Figure US20120122860A1-20120517-C01254
    Figure US20120122860A1-20120517-C01255
    Figure US20120122860A1-20120517-C01256
         		528.2
    P- 2152 
    Figure US20120122860A1-20120517-C01257
    Figure US20120122860A1-20120517-C01258
    Figure US20120122860A1-20120517-C01259
         		474.2
    P- 2153 
    Figure US20120122860A1-20120517-C01260
    Figure US20120122860A1-20120517-C01261
    Figure US20120122860A1-20120517-C01262
         		460.2
    P- 2173 
    Figure US20120122860A1-20120517-C01263
    Figure US20120122860A1-20120517-C01264
    Figure US20120122860A1-20120517-C01265
         		456.0 ([M − H+]−)
    P- 2180 
    Figure US20120122860A1-20120517-C01266
    Figure US20120122860A1-20120517-C01267
    Figure US20120122860A1-20120517-C01268
         		512.1 ([M − H+]−)
    P- 2181 
    Figure US20120122860A1-20120517-C01269
    Figure US20120122860A1-20120517-C01270
    Figure US20120122860A1-20120517-C01271
         		538.1 ([M − H+]−)
    P- 2200 
    Figure US20120122860A1-20120517-C01272
    Figure US20120122860A1-20120517-C01273
    Figure US20120122860A1-20120517-C01274
         		437.1
    P- 2201 
    Figure US20120122860A1-20120517-C01275
    Figure US20120122860A1-20120517-C01276
    Figure US20120122860A1-20120517-C01277
         		462.8
    P- 1499 
    Figure US20120122860A1-20120517-C01278
    Figure US20120122860A1-20120517-C01279
    Figure US20120122860A1-20120517-C01280
         		403.2 ([M − H+]−)
    P- 2203 
    Figure US20120122860A1-20120517-C01281
    Figure US20120122860A1-20120517-C01282
    Figure US20120122860A1-20120517-C01283
         		559.1
    P- 2204 
    Figure US20120122860A1-20120517-C01284
    Figure US20120122860A1-20120517-C01285
    Figure US20120122860A1-20120517-C01286
         		396.3
    P- 2207 
    Figure US20120122860A1-20120517-C01287
    Figure US20120122860A1-20120517-C01288
    Figure US20120122860A1-20120517-C01289
         		450.3 ([M − H+]−)
    P- 2208 
    Figure US20120122860A1-20120517-C01290
    Figure US20120122860A1-20120517-C01291
    Figure US20120122860A1-20120517-C01292
         		414.1
    P- 2209 
    Figure US20120122860A1-20120517-C01293
    Figure US20120122860A1-20120517-C01294
    Figure US20120122860A1-20120517-C01295
         		403.3 ([M − H+]−)
    P- 2210 
    Figure US20120122860A1-20120517-C01296
    Figure US20120122860A1-20120517-C01297
    Figure US20120122860A1-20120517-C01298
         		410.2 ([M − H+]−)
    P- 2222 
    Figure US20120122860A1-20120517-C01299
    Figure US20120122860A1-20120517-C01300
    Figure US20120122860A1-20120517-C01301
         		566.7
    P- 2225 
    Figure US20120122860A1-20120517-C01302
    Figure US20120122860A1-20120517-C01303
    Figure US20120122860A1-20120517-C01304
         		464.2
    P- 2226 
    Figure US20120122860A1-20120517-C01305
    Figure US20120122860A1-20120517-C01306
    Figure US20120122860A1-20120517-C01307
         		529.6
    P- 2239 
    Figure US20120122860A1-20120517-C01308
    Figure US20120122860A1-20120517-C01309
    Figure US20120122860A1-20120517-C01310
         		448.1
    P- 2241 
    Figure US20120122860A1-20120517-C01311
    Figure US20120122860A1-20120517-C01312
    Figure US20120122860A1-20120517-C01313
         		489.3
    P- 2244 
    Figure US20120122860A1-20120517-C01314
    Figure US20120122860A1-20120517-C01315
    Figure US20120122860A1-20120517-C01316
         		479.7
    P- 2247 
    Figure US20120122860A1-20120517-C01317
    Figure US20120122860A1-20120517-C01318
    Figure US20120122860A1-20120517-C01319
         		507.1
    P- 2248 
    Figure US20120122860A1-20120517-C01320
    Figure US20120122860A1-20120517-C01321
    Figure US20120122860A1-20120517-C01322
         		491.4
    P- 2250 
    Figure US20120122860A1-20120517-C01323
    Figure US20120122860A1-20120517-C01324
    Figure US20120122860A1-20120517-C01325
         		410.0
    P- 2255 
    Figure US20120122860A1-20120517-C01326
    Figure US20120122860A1-20120517-C01327
    Figure US20120122860A1-20120517-C01328
         		507.0
    P- 2257 
    Figure US20120122860A1-20120517-C01329
    Figure US20120122860A1-20120517-C01330
    Figure US20120122860A1-20120517-C01331
         		492.5
    P- 2258 
    Figure US20120122860A1-20120517-C01332
    Figure US20120122860A1-20120517-C01333
    Figure US20120122860A1-20120517-C01334
    P- 2259 
    Figure US20120122860A1-20120517-C01335
    Figure US20120122860A1-20120517-C01336
    Figure US20120122860A1-20120517-C01337
         		463.1
    P- 2260 
    Figure US20120122860A1-20120517-C01338
    Figure US20120122860A1-20120517-C01339
    Figure US20120122860A1-20120517-C01340
         		404.2
    P- 2261 
    Figure US20120122860A1-20120517-C01341
    Figure US20120122860A1-20120517-C01342
    Figure US20120122860A1-20120517-C01343
         		404.0
    P- 2268 
    Figure US20120122860A1-20120517-C01344
    Figure US20120122860A1-20120517-C01345
    Figure US20120122860A1-20120517-C01346
         		441.9 443.9 [M − H+]−
    P- 2296 
    Figure US20120122860A1-20120517-C01347
    Figure US20120122860A1-20120517-C01348
    Figure US20120122860A1-20120517-C01349
         		469.9 471.9 [M − H+]−
    P- 2348 
    Figure US20120122860A1-20120517-C01350
    Figure US20120122860A1-20120517-C01351
    Figure US20120122860A1-20120517-C01352
         		453.9 455.9 [M − H+]−
    P- 2349*
    Figure US20120122860A1-20120517-C01353
    Figure US20120122860A1-20120517-C01354
    Figure US20120122860A1-20120517-C01355
         		497.9 499.9 [M − H+]−
    P- 2403 
    Figure US20120122860A1-20120517-C01356
    Figure US20120122860A1-20120517-C01357
    Figure US20120122860A1-20120517-C01358
         		376.2
    P- 2404 
    Figure US20120122860A1-20120517-C01359
    Figure US20120122860A1-20120517-C01360
    Figure US20120122860A1-20120517-C01361
         		418.4 [M − H+]−
    P- 1502 
    Figure US20120122860A1-20120517-C01362
    Figure US20120122860A1-20120517-C01363
    Figure US20120122860A1-20120517-C01364
         		385.4 [M − H+]−
    P- 2406 
    Figure US20120122860A1-20120517-C01365
    Figure US20120122860A1-20120517-C01366
    Figure US20120122860A1-20120517-C01367
         		432.3 [M − H+]−
    P- 2409 
    Figure US20120122860A1-20120517-C01368
    Figure US20120122860A1-20120517-C01369
    Figure US20120122860A1-20120517-C01370
         		387.2
    P- 2426 
    Figure US20120122860A1-20120517-C01371
    Figure US20120122860A1-20120517-C01372
    Figure US20120122860A1-20120517-C01373
         		474.0 [M − H+]−
    P- 2430 
    Figure US20120122860A1-20120517-C01374
    Figure US20120122860A1-20120517-C01375
    Figure US20120122860A1-20120517-C01376
         		490.7
    P- 1504 
    Figure US20120122860A1-20120517-C01377
    Figure US20120122860A1-20120517-C01378
    Figure US20120122860A1-20120517-C01379
         		506  
    P- 2478 
    Figure US20120122860A1-20120517-C01380
    Figure US20120122860A1-20120517-C01381
    Figure US20120122860A1-20120517-C01382
    P- 2479 
    Figure US20120122860A1-20120517-C01383
    Figure US20120122860A1-20120517-C01384
    Figure US20120122860A1-20120517-C01385
    P- 2480 
    Figure US20120122860A1-20120517-C01386
    Figure US20120122860A1-20120517-C01387
    Figure US20120122860A1-20120517-C01388
         		486.4 [M − H+]−
    P- 2482 
    Figure US20120122860A1-20120517-C01389
    Figure US20120122860A1-20120517-C01390
    Figure US20120122860A1-20120517-C01391
         		499.6
    P- 2483 
    Figure US20120122860A1-20120517-C01392
    Figure US20120122860A1-20120517-C01393
    Figure US20120122860A1-20120517-C01394
         		522.4
    P- 2484 
    Figure US20120122860A1-20120517-C01395
    Figure US20120122860A1-20120517-C01396
    Figure US20120122860A1-20120517-C01397
         		506.0
    P- 2487 
    Figure US20120122860A1-20120517-C01398
    Figure US20120122860A1-20120517-C01399
    Figure US20120122860A1-20120517-C01400
         		487.9
    *isolated by-product of reaction for P-2348.
    • Example 5 Synthesis of 5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic acid [5-(3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzene sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionylamino)-pentyl]-amide P-2008
  • 5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic acid [5-(3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionylamino)-pentyl]-amide P-2008 was synthesized in one step from 3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid P-1095 as shown in Scheme 7.
  • Figure US20120122860A1-20120517-C01401
  • Step 1—Preparation of 5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic acid [5-(3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionylamino)-pentyl]-amide (P-2008):
  • In a vial, 3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid (P-1095, 278 mg, 0.502 mmol) was dissolved in 20 mL of tetrahydrofuran, followed by the addition of 5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic acid (5-amino-pentyl)-amide (150.0 mg, 0.457 mmol). To the resulting suspension, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (175 mg, 0.913 mmol) was added and the reaction was stirred at room temperature overnight. This resulted in a solid material to which 10 mL of dimethylformamide was added in order to dissolve most of the solid, and the reaction was stirred at room temperature for another 24 hours. The reaction mixture was extracted with ethyl acetate and saturated sodium chloride in water. The organic layer was washed with water and brine, then dried with magnesium sulfate. The solvents were removed under vacuum and the resulting crude material was purified by silica gel chromatography eluting with ethyl acetate with 4% acetic acid, gradient of 0-15% with methanol in dichloromethane. The appropriate fractions were combined and concentrated under vacuum. This was found to have some impurity, and was further purified by preparitive HPLC. Lyophilization of the appropriate fractions provided the desired compound as a white fluffy solid (P-2008, 57 mg). MS (ESI) [M+H+]+=864.3.
    • Example 6 Synthesis of 3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1,1-pyrrolo[2,3-b]pyridine-5-carboxylic acid (2-hydroxy-ethyl)-amide P-2217
  • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (2-hydroxy-ethyl)-amide P-2217 was synthesized in one step from 3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid P-1213 as shown in Scheme 8.
  • Figure US20120122860A1-20120517-C01402
  • Step 1—Preparation of 3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (2-hydroxy-ethyl)-amide (P-2217):
  • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (P-1213, 0.206 g, 0.486 mmol) was dissolved in 3.9 mL of tetrahydrofuran and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.149 g, 0.778 mmol), N,N-diisopropylethylamine (0.426 mL, 2.44 mmol), and 1-hydroxybenzotriazole (0.0855 g, 0.632 mmol) were added, followed by addition of ethanolamine (52, 0.0341 mL, 0.564 mmol). The reaction mixture was stirred overnight at room temperature, then poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum and the crude material was purified by silica gel flash chromatography to provide the desired compound (P-2217, 6 mg). MS (ESI) [M+H+]+=467.5.
  • 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid dimethyl amide P-2237, P-2238, and P-2243,
  • Figure US20120122860A1-20120517-C01403
  • were prepared following the protocol of Scheme 8, replacing ethanolamine 52 with dimethylamine (P-2237), replacing ethanolamine 52 with methoxylamine hydrochloride, using N,N-dimethylformamide in place of tetrahydrofuran, and using 1-methylpyrrolidine in place of N,N-diisopropylethylamine (P-2238), or replacing ethanolamine 52 with methoxylamine hydrochloride, using N,N-dimethylformamide in place of tetrahydrofuran, using 1-methylpyrrolidine in place of N,N-diisopropylethylamine and replacing 3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid P-1213 with 3-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid P-1206 (P-2243). P-2237 MS (ESI) [M+H+]+=451.2, P-2238 MS (ESI) [M+H+]+=453.2, and P-2243 MS (ESI) [M+H+]30 =481.8.
    • Example 7 Synthesis of propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-propyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide P-2224
  • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-propyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide P-2224 was synthesized in one step from propane-1-sulfonic acid (3-{5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide P-2222 as shown in Scheme 9.
  • Figure US20120122860A1-20120517-C01404
  • Step 1—Preparation of propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-propyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2224):
  • Propane-1-sulfonic acid (3-{5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2222, 20.3 mg, 0.0359 mmol) was dissolved in 0.14 mL of methanol. Platinum dioxide (0.81 mg, 0.0036 mmol) was added and the resulting mixture was stirred under an atmosphere of hydrogen for 1 hour. The mixture was filtered through a bed of celite and the filtrate was concentrated. The crude material was purified by flash silica gel chromatography, eluting with a gradient of 15% methanol in dichloromethane to 1% methanol in dichloromethane. The appropriate fractions were combined and concentrated to provide the desired compound as a solid. MS (ESI) [M+H+]+=499.4.
  • 3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid methyl ester P-2230, and propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-methoxy-propyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide P-2240,
  • Figure US20120122860A1-20120517-C01405
  • were prepared similarly by hydrogenation following the protocol of Scheme 9, using palladium hydroxide 20% on carbon in place of platinum dioxide and replacing propane-1-sulfonic acid (3-{5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide P-2222 with either (E)-3-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acrylic acid methyl ester P-2225 or propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide P-2239, respectively. P-2230 MS (ESI) [M+H+]+=466.0, P-2240 MS (ESI) [M+H+]+=452.2.
    • Example 8 Synthesis of propane-1-sulfonic acid {2,4-difluoro-3-[5-(2H-tetrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide P-2242
  • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2H-tetrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide P-2242 was synthesized in one step from propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide P-1499 as shown in Scheme 10.
  • Figure US20120122860A1-20120517-C01406
  • Step 1—Preparation of propane-1-sulfonic acid {2,4-difluoro-3-[5-(2H-tetrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-2242):
  • In a vial, propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-1499, 0.217 g, 0.537 mmol) was combined with azidotrimethylsilane (53, 356 μL, 2.68 mmol) and dibutyloxostannane (24 mg, 0.096 mmol) in 1.5 mL of toluene. The mixture was heated at 110° C. for 24 hours, and remained as a suspension. The reaction mixture was extracted with ethyl acetate and saturated sodium chloride in water. The organic layer was washed with water and brine, then dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was suspended in some acetonitrile and sonicated for 10 minutes. The precipitated material was collected by filtration and dried under vacuum to provide the desired compound as an off-white solid (P-2242, 98 mg). 1H-NMR (dmso-d6) was consistent with the desired compound structure. MS (ESI) [M+H+]+=448.0.
    • Example 9 Synthesis of 2,2,2-trifluoro-ethanesulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide P-2334
  • 2,2,2-Trifluoro-ethanesulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide P-2334 was synthesized in one step from 5-bromo-1H-pyrrolo[2,3-b]pyridine 54 as shown in Scheme 11.
  • Figure US20120122860A1-20120517-C01407
  • Step 1—Preparation of 2,2,2-trifluoro-ethanesulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2334):
  • To 2,6-difluoro-3-(2,2,2-trifluoro-ethanesulfonylamino)-benzoic acid (55, 0.520 g, 1.63 mmol) 2 mL of dichloromethane and 2 mL of tetrahydrofuran were added, followed by thionyl chloride (297 μL, 4.07 mmol). The reaction was placed in a 50° C. oil bath. After 45 minutes, the reaction had turned clear and solvent was removed and the solid dried under vacuum for 1 hour. In a separate reaction flask, 5-bromo-1H-pyrrolo[2,3-b]pyridine (54, 0.267 g, 1.36 mmol) and aluminum trichloride (0.905 g, 6.79 mmol) in 10 mL of dichloromethane was stirred at room temperature for 1 hour, becoming a cloudy orange colored solution. The dried acid chloride reaction was added to this reaction as a solution in dichloromethane and the reaction was allowed to stir overnight. The reaction was quenched with methanol, providing a clear solution. Solvent was removed under vacuum to reduce the volume, and the crude reaction mixture was purified by silica gel column chromatography. Appropriate fractions were combined and the solvents removed to provide the desired compound as a solid (P-2334, 6 mg). MS (ESI) [M−H+]−=496.0, 498.0.
    • Example 10 Synthesis of propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl)-phenyl]-amide P-2467
  • Propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl)-phenyl]-amide P-2467 was synthesized in four steps from 5-chloro-1H-pyrrolo[2,3-b]pyridine 5 as shown in Scheme 12.
  • Figure US20120122860A1-20120517-C01408
  • Step 1—Preparation of 5-chloro-3-(3-nitro-phenylsulfanyl)-1H-pyrrolo[2,3-b]pyridine (57):
  • Into a round bottom flask, 5-chloro-1H-pyrrolo[2,3-b]pyridine (5, 0.200 g, 1.31 mmol) was dissolved in 10 mL of N,N-dimethylformamide at 0° C. and sodium hydride (63 mg, 1.6 mmol) was added to the flask in one portion. The reaction was allowed to stir for 15 minutes, then 3-nitrophenyl disulfide (56, 490 mg, 1.6 mmol) was added in one portion to the flask. The reaction was stirred at room temperature overnight. The reaction was diluted with 3 volumes of water, and extracted 3× with ethyl acetate. The combined organic layers were washed 2× with water, 2× with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide an orange solid. The solid was triturated with dichloromethane and collected by filtration to provide the desired compound as a yellow solid. MS (ESI) [M−H+]−=305.9.
  • Step 2—Preparation of 5-chloro-3-(3-nitro-benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (58):
  • Into a round bottom flask, 5-chloro-3-(3-nitro-phenylsulfanyl)-1H-pyrrolo[2,3-b]pyridine (57, 0.100 g, 0.326 mmol) was dissolved in 3 mL of N,N-dimethylformamide, m-chloroperbenzoic acid (0.1 g, 0.6 mmol) was added, and the reaction was stirred at room temperature for 3 hours, after which an additional 100 mg of m-chloroperbenzoic acid was added and the reaction stirred for another 16 hours. The reaction was diluted with water: saturated sodium bicarbonate solution (1:1), and extracted 4× with ethyl acetate. The combined organic layers were washed 3× with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. This crude material was taken on to the next step without further purification (approximately 50% purity by MS analysis).
  • Step 3—Preparation of 3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl)-phenylamine (59):
  • To 5-chloro-3-(3-nitro-benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (58, 0.14 g, 0.41 mmol), 30 mL of ethanol was added, followed by tin dichloride (0.39 g, 2.1 mmol). The reaction was stirred at 58° C. overnight, then diluted with brine, and extracted 3× with ethyl acetate. The combined organic layers were washed 3× with brine, dried over sodium sulfate, and evaporated under reduced pressure to provide a yellow solid. This was treated further with 50 mL of water and 50 mL of saturated sodium bicarbonate, 100 mL of ethyl acetate was added and the milky suspension was treated with celite and mixed well before filtering. Brine was added to give clear layers that were separated and the organic layer was dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel chromatography eluting with ethyl acetate/hexane. The appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a yellow solid (59, 466 mg). 1H-NMR (dmso-d6) was consistent with the desired compound structure. MS (ESI) [M−H+]−=306.5 and 308.5.
  • Step 4—Preparation of propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl)-phenyl]-amide (P-2467):
  • Into a round bottom flask, 3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl)-phenylamine (59, 0.1 g, 0.2 mmol) was dissolved in 1 mL of tetrahydrofuran and 1 mL of pyridine. Propane-1-sulfonyl chloride (60, 0.044 mL, 0.39 mmol) was added in one portion, and the reaction was allowed to stir at room temperature for 3 days, after which the reaction was warmed at 35° C. overnight. The reaction was diluted with water, and extracted 3× with ethyl acetate. The combined organic layers were washed with 2× brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide a solid. The solid was purified using reverse phase chromatography to provide the desired compound (P-2467, 15 mg),along with an impurity that runs close to the product (difficult to isolate). 1H-NMR was consistent with the desired compound structure. MS (ESI) [M−H+]−=412.38.
    • Example 11 Synthesis of N-(6-acetylamino-pyridin-3-yl)-3-amino-2,6-difluoro-benzamide 64
  • N-(6-Acetylamino-pyridin-3-yl)-3-amino-2,6-difluoro-benzamide 64 was synthesized in two steps from N-(5-amino-pyridin-2-yl)-acetamide 61 as shown in Scheme 13.
  • Figure US20120122860A1-20120517-C01409
  • Step 1—Preparation of N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-nitro-benzamide (63):
  • To N-(5-amino-pyridin-2-yl)-acetamide (61, 1.53 g, 10.1 mmol), 20 mL of tetrahydrofuran was added followed by pyridine (0.900 mL, 11.1 mmol). To this suspension a solution of 2,6-difluoro-3-nitro-benzoyl chloride (62, 2.24 g, 10.1 mmol) in 10 mL of tetrahydrofuran was added, the reaction was stirred at room temperature overnight, then extracted with addition of ethyl acetate and water (with added hydrochloric acid). The organic layer was washed with brine, and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under vacuum and this material was purified by silica gel column chromatography eluting with a gradient of 1 to 6% methanol in dichloromethane to provide the desired compound (63, 1.527 g). MS (ESI) [M+H+]+=336.9.
  • Step 2—Preparation of N-(6-acetylamino-pyridin-3-yl)-3-amino-2,6-difluoro-benzamide (64):
  • To N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-nitro-benzamide (63, 0.500 g, 1.49 mmol) in 30 mL of ethanol and 85 mL of tetrahydrofuran, ˜3 cc of raney nickle slurry in water was added. Then, the reaction was placed in a parr hydrogenator under hydrogen (0.0718 g, 35.5 mmol) at 35 psi. The reaction was left over the weekend, after which it was filtered through celite and all volatile solvents removed from the filtrate to give crude material that was purified by silica gel column chromatography eluting with 1 to 6% methanol in dichloromethane to provide the desired product (64, 345 mg). MS (ESI) [M+H+]+=306.9.
    • Example 12 Synthesis of 6-acetylamino-N-(3-amino-2,6-difluoro-phenyl)-nicotinamide 68
  • 6-Acetylamino-N-(3-amino-2,6-difluoro-phenyl)-nicotinamide 68 was synthesized in two steps from 6-acetylamino-nicotinic acid 65 as shown in Scheme 14.
  • Figure US20120122860A1-20120517-C01410
  • Step 1—Preparation of 6-acetylamino-N-(2,6-difluoro-3-nitro-phenyl)-nicotinamide (67):
  • In a vial, 6-acetylamino-nicotinic acid (65, 0.362 g, 2.01 mmol) and cyanuric chloride (0.371 g, 2.01 mmol) were mixed in 10 mL of tetrahydrofuran, followed by the addition of pyridine (162 μL, 2.01 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 5 hours, after which 2,6-difluoro-3-nitro-phenylamine (66, 0.200 g, 1.15 mmol) in 2 mL of tetrahydrofuran and pyridine (320 μL, 4.0 mmol) were added and the reaction stirred at room temperature for 4 days. Water (with 1N hydrochloric acid) was added the mixture extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. The volatile solvents were removed under vacuum and the residue was purified by silica gel chromatography eluting with ethyl acetate/hexane. The appropriate fractions were combined and concentrated under vacuum to provide the desired compound (67, 225 mg). 1H-NMR (dmso-d6) was consistent with the desired compound. MS (ESI) [M+H+]+=337.1.
  • Step 2—Preparation of 6-acetylamino-N-(3-amino-2,6-difluoro-phenyl)-nicotinamide (68):
  • To 6-acetylamino-N-(2,6-difluoro-3-nitro-phenyl)-nicotinamide (67, 0.431 g, 1.28 mmol) in 20 mL of ethanol and 75 mL of tetrahydrofuran, ˜3 cc of raney nickle slurry in water. The reaction was placed in a flask under hydrogen (0.0619 g, 30.6 mmol) with a balloon. After 4 hours, the reaction was filtered through celite and all volatile solvents removed from the filtrate to give crude material that was purified by silica gel chromatography eluting with ethyl acetate/hexane. The appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a white solid (68, 310 mg). 1H-NMR (dmso-d6) was consistent with the desired compound. MS (ESI) [M+H+]+=307.1.
    • Example 13 Synthesis of 5-ethynyl-1H-pyrrolo[2,3-b]pyridine 72
  • 5-Ethynyl-1H-pyrrolo[2,3-b]pyridine 72 was synthesized in two steps from 5-iodo-1H-pyrrolo[2,3-b]pyridine 69 as shown in Scheme 15.
  • Figure US20120122860A1-20120517-C01411
  • Step 1—Preparation of 5-trimethylsilanylethynyl-1,1-pyrrolo[2,3-b]pyridine (71):
  • 5-Iodo-1H-pyrrolo[2,3-b]pyridine (69, 0.303 g, 1.22 mmol), (trimethylsilyl)acetylene (70, 0.210 mL, 1.46 mmol), bis(triphenylphosphine)palladium(II) chloride (0.039 g, 0.055 mmol), and copper(I) iodide (0.0019 g, 0.010 mmol) were dissolved in triethylamine (19 mL, 0.14 mol) under an atmosphere of nitrogen. The resulting mixture was heated to 60° C. and stirred under an atmosphere of nitrogen for 16 hours. The triethylamine was removed under vacuum, 30 mL of water was added to the residue, and it was extracted with 2×20 mL with ether. The combined organic layers were washed with brine and dried over sodium sulfate. Solids were filtered out and the filtrate was concentrated under vacuum. The crude material was purified by silica gel flash chromatography, eluting with ethyl acetate and dichloromethane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound as a solid (71, 0.237 g). MS (ESI) [M+H+]+=215.3.
  • Step 2—Preparation of 5-ethynyl-1H-pyrrolo[2,3-b]pyridine (72):
  • 5-Trimethylsilanylethynyl-1H-pyrrolo[2,3-b]pyridine (71, 0.235 g, 1.10 mmol) was dissolved in 16 mL of methanol, and potassium carbonate (0.0152 g, 0.110 mmol) was added. The reaction was stirred for 2 hours at room temperature, then concentrated under vacuum, and the residue was dissolve in dichloromethane, dried over sodium sulfate. Solids were filtered out and the filtrate was concentrated under vacuum. The crude material was purified by silica gel flash chromatography, eluting with ethyl acetate and hexane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound as a solid (72, 0.155 g). MS (ESI) [M+H+]+=143.3.
    • Example 14 Synthesis of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester 74
  • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester 74 was synthesized in one step from 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 73 as shown in Scheme 16.
  • Figure US20120122860A1-20120517-C01412
  • Step 1—Preparation of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (74):
  • To 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (73, 0.511 g, 3.15 mmol) in 18 mL of ethanol, sulfuric acid (2.5 mL, 0.047 mol) was added. The resulting mixture was refluxed overnight. The solvents were reduced under vacuum, and the residue was poured into 5% aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and the crude material was purified by silica gel flash chromatography. The appropriate fractions were combined to provide the desired compound as a white solid. MS (ESI) [M+H+]+=191.2.
    • Example 15 Synthesis of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methylamide 75
  • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid methylamide 75 was synthesized in one step from 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 73 as shown in Scheme 17.
  • Figure US20120122860A1-20120517-C01413
  • Step 1—Preparation of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methylamide (75):
  • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid (73, 0.441 g, 2.72 mmol) was dissolved in 22 mL of tetrahydrofuran. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.834 g, 4.35 mmol), N,N-diisopropylethylamine (2.37 mL, 13.6 mmol), and 1-hydroxybenzotriazole (0.478 g, 3.54 mmol) were added, followed by a mixture of methylammonium chloride (0.213 g, 3.15 mmol) and triethylamine (0.455 mL, 3.26 mmol) in 2 mL of tetrahydrofuran. The resulting mixture was very cloudy, and 1.5 ml of dimethylformamide was added. The reaction was stirred overnight at room temperature. The resulting mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum and the crude material was purified by silica gel flash chromatography. The appropriate fractions were combined and solvents removed under vacuum to provide the desired compound as a white solid (75, 198 mg). MS (ESI) [M+H+]+=176.0.
  • 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid cyclopropylamide 76,
  • Figure US20120122860A1-20120517-C01414
  • was prepared following the protocol of Scheme 17, replacing methylammonium chloride and triethylamine with cyclopropylamine. MS (ESI) [M+H+]+=202.0.
    • Example 16 Synthesis of 5-morpholin-4-ylmethyl-1H-pyrrolo[2,3-b]pyridine 79
  • 5-Morpholin-4-ylmethyl-1H-pyrrolo[2,3-b]pyridine-79 was synthesized in one step from 1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde 77 as shown in Scheme 18.
  • Figure US20120122860A1-20120517-C01415
  • Step 1—Preparation of 5-morpholin-4-ylmethyl-1H-pyrrolo[2,3-b]pyridine (79):
  • To 1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (77, 0.303 g, 2.07 mmol), 20 mL of dichloromethane was added followed by morpholine (78, 181 μL, 2.07 mmol) and then acetic acid (354 μL, 6.22 mmol). This suspension was stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (1.32 g, 6.22 mmol) was added. The reaction was stirred over the weekend, then was quenched with methanol and all volatile solvents were removed under vacuum. The solid was treated with ˜50 mL of tetrahydrofuran and the white precipitate was removed by filtration. Solvents were removed under vacuum from the filtrate to give crude solid that was purified by silica gel column chromatography eluting with a gradient of 1 to 10% methanol in dichloromethane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (79, 395 mg). MS (ESI) [M+H+]+=218.1.
  • 5-Pyrrolidin-1-ylmethyl-1H-pyrrolo[2,3-b]pyridine 80, 5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine 81, and diethyl-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amine 82,
  • Figure US20120122860A1-20120517-C01416
  • were prepared following the protocol of Scheme 18, replacing morpholine 78 with pyrrolidine, 1-methyl-piperazine and diethyl-amine, respectively. MS (ESI) [M+H+]+=202.4 (80), 231.2 (81), and 204.9 (82).
    • Example 17 Synthesis of N,N-diethyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propionamide 87
  • N,N-Diethyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propionamide 87 was synthesized in three steps from (E)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-acrylic acid methyl ester 83 as shown in Scheme 19.
  • Figure US20120122860A1-20120517-C01417
  • Step 1—Preparation of 3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propionic acid methyl ester (84):
  • Into a 1-neck round-bottom flask, (E)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-acrylic acid methyl ester (4.615 g, 22.82 mmol) was dissolved in 150 mL of methanol and 200 mL of tetrahydrofuran. This solution was degassed with nitrogen gas for 5 minutes and 465 mg of 10% Pd/C was added to the solution. The mixture was hydrogenation with a hydrogen balloon and stirred at room temperature overnight. The Pd/C was removed by filtration and solvents removed from the filtrates under vacuum to provide the desired compound 84. MS (ESI) [M+H+]+=205.2.
  • Step 2—Preparation of 3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propionic acid (85):
  • Into a round bottom flask, 3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propionic acid methyl ester (84, 4.21 g, 20.6 mmol) was dissolved in 150 mL of tetrahydrofuran and a solution of lithium hydroxide (3550 mg, 0.0845 mol, dissolved in 84 mL of deionized water) was added. The mixture was heated at 50° C. for 2 hours, then the reaction mixture was acidified to pH-1-2 with 6 N hydrochloric acid and extracted with ethyl acetate and water. The aqueous layer was adjusted pH˜3-4 resulting in a precipitate, which was collected with filtration to provided 1.051 g of the desired compound. MS (ESI) [M+H+]+=191.4. The aqueous layer was then extracted with ethyl acetate and the combined organic layers was washed with water and brine, and dried with magnesium sulfate and filtered. The filtrate was concentrated under vacuum to provide an additional 1.67 g of the desired compound.
  • Step 3—Preparation of N,N-diethyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propionamide (87):
  • In a vial, 3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propionic acid (85, 401 mg, 2.11 mmol) was dissolved in 20 mL of tetrahydrofuran and diethyl-amine (86, 436 μL, 4.22 mmol) was added. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (808 mg, 4.22 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and water saturated with sodium chloride. The organic layer was washed with water and brine, then dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the crude material was purified by silica gel column chromatography eluting with methanol/dichloromethane. The appropriate fractions were combined and solvents removed under vacuum to provide the desired compound as an oily material (87, 267 mg). MS (ESI) [M+H+]+=246.5.
  • 1-Pyrrolidin-1-yl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propan-1-one 88, and 1-morpholin-4-yl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propan-1-one 89,
  • Figure US20120122860A1-20120517-C01418
  • were prepared following the protocol of Scheme 19, replacing diethyl-amine 86 with pyrrolidine, and morpholine, respectively in Step 3. MS (ESI) [M+H+]+=244.5 (88), and 260.5 (89).
  • 1-Pyrrolidin-1-yl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propan-1-one 88 was reacted according to the following step 4 to provide 5-(3-pyrrolidin-1-yl-propyl)-1H-pyrrolo[2,3-b]pyridine 90:
  • Figure US20120122860A1-20120517-C01419
  • Step 4—Preparation of 5-(3-pyrrolidin-1-yl-propyl)-1H-pyrrolo[2,3-b]pyridine (90):
  • To 1.0 M lithium tetrahydroaluminate in tetrahydrofuran (2.65 mL, 2.66 mmol) 50 mL of tetrahydrofuran was added and the mixture cooled to 0° C. in an ice-water bath. A solution of 1-pyrrolidin-1-yl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propan-1-one (88, 431 mg, 1.77 mmol) in 10 mL of tetrahydrofuran was added dropwise and kept at 0° C. for 15 minutes. The reaction mixture was allowed to warm to room temperature. After 2 hours, the reaction mixture was diluted with 20 mL of tetrahydrofuran and added ˜4 grams of sodium sulfate and stirred at room temperature for 30 minutes. The reaction was filtered to remove solid material and the filtrate was concentrated under vacuum. The crude material was purified by silica gel chromatography eluting with ethyl acetate and hexanes. The appropriate fractions were combined and concentrated under vacuum to provide the desired compound (90, 235 mg). MS (ESI) [M+H+]+=230.5.
  • 5-(3-Morpholin-4-yl-propyl)-1H-pyrrolo[2,3-b]pyridine 91
  • Figure US20120122860A1-20120517-C01420
  • was prepared following the protocol of Scheme 19, step 4, replacing 1-pyrrolidin-1-yl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propan-1-one 88 with 1-morpholin-4-yl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-propan-1-one 89. MS (ESI) [M+H+]+=246.5.
    • Example 18 Synthesis of 5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine 93
  • 5-Methanesulfonyl-1H-pyrrolo[2,3-b]pyridine 93 was synthesized in one step from 5-bromo-1H-pyrrolo[2,3-b]pyridine 54 as shown in Scheme 20.
  • Figure US20120122860A1-20120517-C01421
  • Step 1—Preparation of 5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine (93):
  • To 5-bromo-1H-pyrrolo[2,3-b]pyridine (54, 1.00 g, 5.08 mmol) in 15 mL of dimethyl sulfoxide, sodium methanesulfinate (92, 0.6218 g, 6.090 mmol), L-proline (0.117 g, 1.02 mmol), copper(I) iodide (0.200 g, 1.05 mmol) and sodium hydroxide (0.0406 g, 1.02 mmol) were added. The reaction was stirred at 120° C. overnight, then poured into aqueous ammonia and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, then filtered and the filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to provide the desired compound as a white solid (93, 0.50 g). MS (ESI) [M−H+]−=195.1.
    • Example 19 Synthesis of 5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine 98
  • 5-(3-Methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine 98 was synthesized in three steps from 5-iodo-1H-pyrrolo[2,3-b]pyridine 69 as shown in Scheme 21.
  • Figure US20120122860A1-20120517-C01422
  • Step 1—Preparation of 1-benzenesulfonyl-5-iodo-1H-pyrrolo[2,3-b]pyridine (95):
  • 5-Iodo-1H-pyrrolo[2,3-b]pyridine (69, 0.521 g, 2.13 mmol), tetra-N-butylammonium bromide (0.0689 g, 0.214 mmol), and 5.00 M sodium hydroxide in water (5.50 mL, 0.0275 mol) were combined in a round bottom flask. Benzenesulfonyl chloride (94, 0.327 mL, 2.56 mmol) in 5.0 mL of tetrahydrofuran was added dropwise at room temperature. The reaction was stirred at room temperature overnight and the two layers were seperated. The aqueous layer was washed with ethyl acetate and the combined organic layers were washed with 1M aqueous sodium bicarbonate followed by water. The organic layer was washed with brine and dried over anhydrous sodium sulfate, then filtered and the filtrate concentrated. The crude material was purified by silica gel flash chromatography eluting with ethyl acetate and dichloromethane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (95, 0.702 g).
  • Step 2—Preparation of 1-benzenesulfonyl-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine (97):
  • 1-Benzenesulfonyl-5-iodo-1H-pyrrolo[2,3-b]pyridine (95, 0.482 g, 1.23 mmol), 3-methoxy-propyne (96, 0.127 mL, 1.48 mmol), bis(triphenylphosphine)palladium(II) chloride (0.039 g, 0.056 mmol), and copper(I) iodide (0.0020 g, 0.010 mmol) were dissolved in 19 mL of triethylamine under an atmosphere of nitrogen. The resulting mixture was heated to 60° C. and stirred under an atmosphere of nitrogen for 16 hours. The triethylamine was removed under vacuum and 30 mL of water was added to the residue, and extracted with 2×20 mL of ether. The combined organic layers were washed with brine and dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was purified by silica gel flash chromatography eluting with ethyl acetate and dichloromethane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound.
  • Step 3—Preparation of 5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine (98):
  • Under an atmosphere of nitrogen 1-benzenesulfonyl-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine (97, 0.541 g, 1.66 mmol) was dissolved in 13 mL of tetrahydrofuran and 1.00 M tetra-n-butylammonium fluoride in 9.12 mL of tetrahydrofuran was added. The resulting solution was stirred for three hours at room temperature under an atmosphere of nitrogen. The reaction was quenched with water and the two layers were seperated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate, then filtered and the filtrate concentrated under vacuum. The crude material was purified by silica gel flash chromatography eluting with ethyl acetate and dichloromethane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (98, 0.215 g).
    • Example 20 Synthesis of 5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid ethylamide 101
  • 5-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid ethylamide 101 was synthesized in two steps from 5-bromo-pyridine-2-carboxylic acid 99 as shown in Scheme 22.
  • Figure US20120122860A1-20120517-C01423
  • Step 1—Preparation of 5-bromo-pyridine-2-carboxylic acid ethylamide (101): 5-Bromo-pyridine-2-carboxylic acid (99, 0.417 g, 2.06 mmol) was dissolved in 19 mL of tetrahydrofuran. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.633 g, 3.30 mmol), N,N-diisopropylethylamine (1.81 mL, 10.4 mmol), and 1-hydroxybenzotriazole (0.363 g, 2.68 mmol) were added, followed by 2.00 Methylamine in tetrahydrofuran (100, 1.20 mL, 2.40 mmol). The reaction mixture was stirred for overnight at room temperature, after which 1.5 mL of dimethylformamide was added and stirred for another 4 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The crude material was purified by silica gel flash chromatography. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (101, 163 mg). MS (ESI) [M+H+]+=229.29, 231.3.
    Step 2—Preparation of 5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid ethylamide (103):
  • 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (102, 0.424 g, 1.74 mmol), 5-bromo-pyridine-2-carboxylic acid ethylamide (101, 0.159 g, 0.694 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.016 g, 0.014 mmol) were mixed in 1.00 M potassium carbonate in water (4.2 mL, 4.2 mmol). The reaction mixture was heated at 80° C. overnight. The two layers were seperated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The crude material was purified by silica gel flash chromatography. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (103, 200 mg). MS (ESI) [M+H+]+=267.2.
  • 5-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid methylamide 104, and 5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid cyclopropylamide 105,
  • Figure US20120122860A1-20120517-C01424
  • were prepared following the protocol of Scheme 22, replacing ethylamine 100 with methylammonium chloride and cycloalkylamine, respectively in Step 1. MS (ESI) [M+H+]+=253.1 (104), and 279.1 (105).
    • Example 21 Synthesis of 5-[6-(3-methoxy-propyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine 110
  • 5-[6-(3-Methoxy-propyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine 110 was synthesized in three steps from 2,5-dibromo-pyridine 106 as shown in Scheme 23.
  • Figure US20120122860A1-20120517-C01425
  • Step 1—Preparation of 5-bromo-2-(3-methoxy-prop-1-ynyl)-pyridine (108):
  • A solution of 2,5-dibromo-pyridine (106, 4.64 g, 19.6 mmol), 3-methoxy-propyne (107, 1.66 mL, 19.7 mmol), and copper(I) iodide (0.084 g, 0.44 mmol) in 61.6 mL of triethylamine was purged with nitrogen, and bis(triphenylphosphine)palladium(II) chloride (0.31 g, 0.44 mmol) was added at 0° C. The resulting mixture was stirred at 0° C. for 1 hour, then at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, then washed with water and brine. The organic layer was dried with anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was purified by silica gel flash chromatography eluting with ethyl acetate and hexane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (108, 2.64 g).
  • Step 2—Preparation of 5-[6-(3-methoxy-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine (109):
  • 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (102, 0.998 g, 4.09 mmol), 5-bromo-2-(3-methoxy-prop-1-ynyl)-pyridine (108, 0.616 g, 2.72 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.157 g, 0.136 mmol) were mixed in 8.2 mL of 1.00 M potassium carbonate in water (8.2 mmol) and 22 mL of tetrahydrofuran. The resulting mixture was heated at 80° C. Ethyl acetate and water were added, and the two layers were seperated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate concentrated under vacuum. The crude material was purified by silica gel flash chromatography. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (109, 565 mg). MS (ESI) [M+H+]+=264.3.
  • Step 3—Preparation of 5-[6-(3-methoxy-propyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine (110):
  • 5-[6-(3-Methoxy-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine (109, 0.534 g, 2.03 mmol) was dissolved in 8.1 mL of methanol. Palladium hydroxide (0.028 g, 0.20 mmol) was added, and the resulting mixture was stirred under an atmosphere of hydrogen for a few hours, then filtered through a bed of celite. The filtrate was concentrated under vacuum. The crude material was purified by silica gel flash chromatography eluting with ethyl acetate and hexane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (110, 419 g). MS (ESI) [M+H+]+=268.3.
  • Diethyl-{3-[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridin-2-yl]-prop-2-ynyl}-amine 111
  • Figure US20120122860A1-20120517-C01426
  • was prepared following the protocol of Scheme 23, steps 1 and 2, replacing 3-methoxy-propyne 107 with diethyl-prop-2-ynyl-amine in step 1. MS (ESI) [M+H+]+=305.3.
    • Example 22 Synthesis of dimethyl-{3-[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrimidin-2-yloxy]-propyl}-amine 115
  • Dimethyl-{3-[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrimidin-2-yloxy]-propyl}-amine-115 was synthesized in two steps from 5-bromo-2-chloro-pyrimidine 112 as shown in Scheme 24.
  • Figure US20120122860A1-20120517-C01427
  • Step 1—Preparation of [3-(5-bromo-pyrimidin-2-yloxy)-propyl]-dimethyl-amine (114):
  • To a solution of 3-(dimethylamino)-1-propanol (113, 3.45 mL, 2.84 mmol) in 10 mL of dry tetrahydrofuran, sodium hydride (0.0784 g, 3.10 mmol) was added at room temperature. After 15 minutes, 5-bromo-2-chloro-pyrimidine (112, 0.500 g, 2.58 mmol) was added and the mixture was stirred at room temperature for 16 hours. To this, ˜500 μL of saturated ammonium chloride was added and the reaction was treated with ethyl acetate and filtered. The solvents were removed from the filtrate under vacuum, then added diethyl ether, removed solvent under vacuum and repeated twice. The resulting residue was taken up with tetrahydrofuran/acetonitrile and filtered. Silica gel was added to the filtrate and solvents removed under vacuum, then purified by silica gel chromatography eluting with 1 to 6% methanol in dichloromethane, followed with 20% methanol in dichloromethane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (113, 259 mg). MS (ESI) [M+H+]+=261.9.
  • Step 2—Preparation of dimethyl-{3-[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrimidin-2-yloxy]-propyl}-amine (115):
  • Into a round bottom flask, [3-(5-bromo-pyrimidin-2-yloxy)-propyl]-dimethyl-amine (114, 259 mg, 0.996 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (102, 364 mg, 1.49 mmol), tetrakis(triphenylphosphine)palladium(0) (57.5 mg, 0.0498 mmol), and tetra-n-butylammonium iodide (37 mg, 0.10 mmol) were mixed in 6 mL of 1.00 M potassium carbonate in water (6.0 mmol) and 12 mL of tetrahydrofuran. The resulting mixture was heated at 70° C. overnight. The two layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were washed with saturated aqueous sodium bicarbonate, water, and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under vacuum. The crude material was purified by silica gel chromatography, eluting with up to 30% methanol in dichloromethane. The appropriate fractions were combined and concentrated under vacuum, then further purified on a new column eluting with 15% methanol in ethyl acetate with 8% triethylamine. The appropriate fractions were combined and concentrated under vacuum to provide the desired compound as an off-white solid (115, 76 mg). MS (ESI) [M+H+]+=298.0.
    • Example 23 Synthesis of Aldehyde Reactants
  • Propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide 124, was synthesized in seven steps from 4-chloro-2-fluoro-phenylamine 116 as shown in Scheme 25.
  • Figure US20120122860A1-20120517-C01428
    Figure US20120122860A1-20120517-C01429
  • Step 1—Preparation of 3-amino-6-chloro-2-fluoro-benzoic acid benzyl ester (118):
  • To 4-chloro-2-fluoro-phenylamine (116, 6.30 mL, 57.0 mmol) in 300 mL of tetrahydrofuran cooled with dry ice/acetone bath under an atmosphere of nitrogen, n-butyllithium (2.50 M in hexane, 24.4 mL) was added slowly. After 20 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (12.9 g, 60.0 mmol) dissolved in tetrahydrofuran (40.0 mL) was added slowly to the reaction. After 1 hour, n-butyllithium (2.50 M in hexane, 25.0 mL) was added slowly to the reaction. The reaction was stirred at 78° C. for 20 minutes and then allowed to warm to room temperature over 60 minutes. The reaction was cooled to 78° C., followed by addition of n-butyllithium (2.50 M in hexane, 26.0 mL) slowly. After 80 minutes, benzyl chloroformate (117, 10.0 mL, 70.0 mmol) was added to the reaction. The reaction mixture was stirred at 78° C. overnight followed by addition of 80 mL of water and 25 mL of concentrated hydrochloric acid. The reaction was allowed to warm to room temperature for 2 hours. The organic layer was separated. The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The desired compound was isolated by silica gel column chromatography (ethyl acetate/hexane 20%) to give a colorless oil (3, 12.5 g, 78.3%). MS (ESI) [M+H+]+=280.0.
  • Step 2—Preparation of 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid benzyl ester (119):
  • To 3-amino-6-chloro-2-fluoro-benzoic acid benzyl ester (118, 1.20 g, 4.3 mmol) in 28 mL of dichloromethane, pyridine (0.52 mL, 6.4 mmol) and propane-1-sulfonyl chloride (60, 0.685 g, 4.8 mmol) were added. The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The desired compound was isolated with silica gel column chromatography to give a colorless oil (119, 960 mg, 58.0%). MS (ESI) [M−H+]−=384.1.
  • Step 3—Preparation of 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (120):
  • To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid benzyl ester (119, 6.00 g, 15.6 mmol) in 100 mL of tetrahydrofuran, 100 mL of 1.0 M aqueous potassium hydroxide was added. The reaction was heated to reflux overnight, then poured into water, acidified to pH 2 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic portion was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum to give the desired compound as a white solid (120, 3.95 g, 85.8%).
  • Step 4—Preparation of 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (121):
  • To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (120, 0.69 g, 2.3 mmol) in 10 mL of methanol, 20% palladium hydroxide on carbon (200 mg) was added. The reaction was stirred under hydrogen at 50 psi for 2 hours. The reaction was filtered and the filtrate concentrated under vacuum to give the desired compound (121) as a white solid that was used in the next step without further purification. MS (ESI) [M−H+]−=260.1.
  • Step 5—Preparation of 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid methyl ester (122):
  • To a 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (121, 5.05 g, 19.3 mmol) in 100 mL of dichloromethane, N,N-dimethylformamide (0.075 mL, 0.97 mmol) was added under an atmosphere of nitrogen. The reaction was cooled with ice/water, followed by slow addition of oxalyl chloride (2.00 M in dichloromethane, 10.8 mL, 21.6 mmol). The reaction mixture was stirred at room temperature for 3.0 hours. The reaction was cooled with ice/water, followed by addition of methanol (36.0 mL, 0.89 mol) slowly. The reaction was stirred at room temperature overnight. The reaction was concentrated under vacuum and purified with silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the desired compound as a crude white solid (122, 4.0 g), used in the next step without further purification.
  • Step 6—Preparation of propane-1-sulfonic acid (2-fluoro-3-hydroxymethyl-phenyl)-amide (123):
  • To 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid methyl ester (122, 3.80 g, 13.8 mmol) in 133 mL of tetrahydrofuran, lithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 20.0 mL, 20.0 mmol) was added under an atmosphere of nitrogen at room temperature. The reaction was stirred at room temperature for 8 hours, followed by addition of 10 g of sodium sulfate decahydrate. After 12 hours, the reaction was filtered, the filtrate concentrated under vacuum and purified with silica gel column chromatography eluting with 5% methanol in dichloromethane to give the desired compound as a white solid (123, 3.0 g, 87.9%).
  • Step 7—Preparation of propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide (124):
  • To propane-1-sulfonic acid (2-fluoro-3-hydroxymethyl-phenyl)-amide (123, 0.20 g, 0.81 mmol) in 5.0 mL of tetrahydrofuran, Dess-Martin periodinane (0.377 g, 0.89 mmol) was added. The reaction was stirred at room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuume and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the desired compound as a white solid (124, 100 mg, 50.0%). MS (ESI) [M−H+]−=244.1.
  • N-(2-Fluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide 125
  • Figure US20120122860A1-20120517-C01430
  • was prepared following the protocol of scheme 25, replacing propane-1-sulfonyl chloride 60 with 4-trifluoromethyl-benzenesulfonyl chloride in step 2. MS (ESI) [M−H+]−=346.4.
  • Propane-1-sulfonic acid (2-chloro-4-fluoro-3-formyl-phenyl)-amide (127) was synthesized in two steps from 2-chloro-4-fluoro-phenylamine 125 as shown in Scheme 26.
  • Figure US20120122860A1-20120517-C01431
  • Step 1—Preparation of propane-1-sulfonic acid (2-chloro-4-fluoro-phenyl)-amide (127):
  • To 2-chloro-4-fluoro-phenylamine (126, 1.226 g, 8.422 mmol) in 10 mL of dichloromethane, pyridine (0.759 mL, 9.26 mmol) and propane-1-sulfonyl chloride (60, 1.04 mL, 9.26 mmol) were added and the reaction was stirred at room temperature for 3-4 hours. The reaction was quenched with 1M aqueous hydrochloric acid, the aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was purified by silica gel column chromatography to provide the desired compound (127, 1.59 g). MS (ESI) [M−H+]−=250.03, 252.03.
  • Step 2—Preparation of propane-1-sulfonic acid (2-chloro-4-fluoro-3-formyl-phenyl)-amide (128):
  • To N,N-diisopropylamin (2.74 mL, 19.6 mmol) in 51 mL of tetrahydrofuran, n-butyllithium (7.83 mL, 2.50 M in hexane, 19.6 mmol) was added at 78° C. under an atmosphere of nitrogen. After 30 minutes, propane-1-sulfonic acid (2-chloro-4-fluoro-phenyl)-amide (127, 1.59 g, 6.32 mmol) was added under nitrogen, maintaining the temperature at 78° C. After 1 hour, N,N-dimethylformamide (1.7 mL, 22 mmol) was added under nitrogen, maintaining the temperature at 78° C. with stirring for 30 minutes, then allowing to warm to room temperature for one hour. The reaction was quenched with saturated aqueous ammonium chloride, the aqueous layer separated and extracted 3× with ethyl acetate. All organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was purified by silica gel column chromatography to provide the desired compound (127, 398 mg). MS (ESI) [M−H+]−=278.1.
  • Butane-1-sulfonic acid (2-chloro-4-fluoro-3-formyl-phenyl)-amide 129
  • Figure US20120122860A1-20120517-C01432
  • was prepared following the protocol of scheme 26, replacing propane-1-sulfonyl chloride 60 with butane-1-sulfonyl chloride in step 1. MS (ESI) [M−H+]−=291.9.
  • Ethanesulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 130, 2-methyl-propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 131, 3,3,3-tri fluoro-propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 132, N-(2,4-difluoro-3-formyl-phenyl)-C,C,C-trifluoro-methanesulfonamide 133, and cyclopropanesulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 134,
  • Figure US20120122860A1-20120517-C01433
  • were prepared following the protocol of scheme 26, replacing 2-chloro-4-fluoro-phenylamine 126 with 2,4-difluoro-phenylamine and propane-1-sulfonyl chloride 60 with ethanesulfonyl chloride, 2-methyl-propane-1-sulfonyl chloride, 3,3,3-trifluoro-propane-1-sulfonyl chloride, trifluoro-methanesulfonyl chloride, and cyclopropanesulfonyl chloride, respectively, in step 1. MS (ESI) [M−H+]+=248.1 (130), 276.1 (131), 288.0 (133).
    • Example 24 Synthesis of 5-cyclopropyl-1H-pyrrolo[2,3-b]pyridine 136
  • 5-Cyclopropyl-1H-pyrrolo[2,3-b]pyridine 136 was synthesized in one step from 5-iodo-1H-pyrrolo[2,3-b]pyridine 69 as shown in Scheme 27.
  • Figure US20120122860A1-20120517-C01434
  • Step 2—Preparation of 5-Cyclopropyl-1H-pyrrolo[2,3-b]pyridine (136):
  • In a reaction vessel, 5-Iodo-1H-pyrrolo[2,3-b]pyridine (69, 0.343 g, 1.40 mmol), cyclopropylzinc bromide (135, 12.6 mL of 0.500 M in tetrahydrofuran, 6.32 mmol), and [1,3-bis(diphenylphosphino)propane]nickel(II) chloride (0.0762 g, 0.140 mmol) were combined with 5.37 mL of 1,4-dioxane. The reaction was heated at 100° C. overnight. Methanol was added, and the mixture was concentrated under vacuum. Ethyl acetate and water were added to the residue, and the resulting mixture was filtered through a bed of celite. The celite bed was washed with ethyl acetate. The combined filtrate was separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate and hexane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound. MS (ESI) [M+H+]+=159.0.
    • Example 25 Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-1167) polymorphs
  • Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-1167) may be prepared according to methods known in the art, for example, using methods described in U.S. patent application Ser. No. 11/473,347 (see also, PCT publication WO2007002433), the disclosure of which is hereby incorporated by reference. Compound P-1167 can exist in polymorphic forms, for example as polymorphic forms 1 or 2, where such polymorphic forms may be isolated as the substantially pure polymorph. The desired polymorphic form may be prepared, for example, by using appropriate crystallization conditions. For example, Form 1 was isolated by recrystallization from acetone/absolute ethanol (e.g. 1:1 to 5:1, preferably 2:1 by volume). Form 2 is the more stable polymorph, and can be formed under a variety of recrystallization conditions, for example, recrystallization from methyl-t-butyl ether/tetrahydrofuran, ethyl acetate, or acetone, or may be formed by heating/melting and re-solidifying. The substantially pure isolated polymorphic forms were characterized by X-Ray Powder Diffraction (XRPD), differential scanning calorimetry (DSC) and infrared spectroscopy.
  • To demonstrate the formation of polymorphic form 1, propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-1167) was treated with about 2.4 w/w of an acetone:absolute ethanol mixture (1:4 by volume) and agitated at 20° C. 5° C. for at least 6 hours. The contents were filtered and the solids were washed with acetone:absolute ethanol (1:4 by volume) mixture. Solids were treated with about 3.4 w/w tetrahydrofuran, and the suspension was heated to 60° C. 5° C. for at least 30 minutes and agitated. The mixture was cooled to 55° C. 5° C. and about 11.8 w/w methyl-t-butyl ether was added. The resulting suspension was cooled to 20° C. 5° C. for at least 1 hour. The contents were filtered and the solids were washed with methyl-t-butyl ether and dried. The solid was treated with acetone:absolute ethanol (2:1 by volume). The contents were agitated and the suspension was heated at 60° C. until a solution was achieved. The solution was filtered through a polish filter to remove any residual solid from the methyl-t-butyl ether treatment step. The filtrate was concentrated under vacuum, stirred at 20° C. 5° C. for at least 30 minutes and filtered. The solids were washed with pre-cooled (0° C. to 5° C.) ethanol and dried at 45° C. followed by drying at 75° C. under vacuum until a constant weight was achieved, to provide pure P-1167 polymorphic form 1. Form 1 was also prepared treating a sample with acetone:ethanol (1:1 by volume) at reflux, then filtering hot and removing solvent from the filtrate under vacuum until solid precipitates out.
  • The propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide polymorphic form 1 and form 2 were characterized by X-ray powder diffraction, infra-red spectrometry, and differential scanning calorimetry. Samples were analyzed by X-ray powder diffraction (XRPD) using a ShimadzuXRD-6000 X-ray powder diffractometer using Cu Kα radiation. The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The divergence and scattering slits were set at 1° and the receiving slit was set at 0.15 mm. Diffracted radiation was detected by a NaI scintillation detector. A θ-2θ continuous scan at 3°/min (0.4 sec/0.02° step) from 2.5° to 40° 2θ was used. A silicon standard was analyzed to check the instrument alignment. Data were collected and analyzed using XRD-6100/7000 v.5.0. Sample was prepared for analysis by placing it in an aluminum holder with silicon insert. The results are provided in the following Table 1.
  • TABLE 1
    XRPD 2θ values for P-1167 polymorphic Form 1 and Form 2.
    2θ value (+/−0.2)
    Form 1 Form 2
    4.7
    6.7
    8.8
    9.4 9.2
    10.0
    11.0
    12.5
    13.5
    14.2 14.1
    14.5
    14.9 15.0
    15.4
    16.1 16.2
    17.0
    17.3 17.7
    18.6 18.3
    19.0 19.1
    19.7
    20.6
    20.0 20.9
    21.2 21.4
    21.6 22.0
    22.2 22.2
    23.2
    23.9 23.8
    24.1
    24.4
    25.1
    25.7
    26.1 26.6
    26.8 28.1
    28.8
    29.2 29.3
    30.1
    31.1
    31.7
    34.5
    34.9
    35.9
    39.2
    41.3
  • The propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide polymorphic form 1 and form 2 were analyzed by infra-red spectrometry. The results are provided in the following Table 2, which provides the characteristic wavenumbers observed for each sample.
  • TABLE 2
    IR absorption spectrum wavenumber values for P-1167
    polymorphic Form 1 and Form 2.
    Wavenumber cm−1
    Form 1 Form 2
    3238 3266
    3121
    2969
    2879 2880
    1709
    1645 1639
    1590 1589
    1519 1519
    1485 1487
    1417 1417
    1331 1322
    1305 1306
    1280 1287
    1246 1246
    1211 1215
    1149 1143
    1102 1096
    1022 1027
    1013 1012
    965 968
    915 916
    891 893
    857
    825 825
    796 798
    773 767
    717
    685 683
    651 662
    631
    607
    587 585
    564 558
    550
    532 532
    516 508
    503
  • The propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide polymorphic form 1 and form 2 were analyzed by differential scanning calorimetry, scanning at 10.00° C. per minute. The DSC thermogram for form 1 shows an exothermic shift at approximately 152-164° C. and an endothermic peak at 268.0° C. The DSC thermogram for form 2 shows an endothermic peak at 271.2° C.
    • Example 26 N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]sulfonamide and related compounds, acidic and basic addition salts and complexes
  • N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]sulfonamide and related compounds, such as compounds of Formula I are characterized as having functionalities providing both weakly basic and weakly acidic centers which can form organic salt complexes, resulting in improved solubility. For example, the N-7 of the azaindole portion is weakly basic (pKa approximately 4-5) while the sulfonamide nitrogen is weakly acidic (pKa approximately 7). An organic salt complex reflects the potential for multiple sites of interaction between the guest and host. Attempts to make inorganic salts, e.g. using sodium or potassium, resulted in material that was difficult to isolate and was hygroscopic in some instances. In other instances, while the material may be non-hygroscopic, isolated material may exhibit multiple polymorphic forms. In contrast, the basic amino acids arginine and lysine were found to form non-crystalline complexes readily in a stoichiometric manner, and the resulting materials demonstrated enhanced solubility and bioavailability (exposure in pharmacokinetic analysis) relative to the free base form as well as other standard salt forms. Demonstrating additional unexpected advantages, such complexes were isolated as amorphous forms rather than typical crystalline salt forms, were non-hygroscopic, and chemically stable.
  • Organic base complexes, including arginine, nicotinamide and lysine complexes are typically formed by dissolving N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]sulfonamide and related compounds in 20-50 solvent volumes of an alcohol, preferably methanol, with moderate heating (30-35° C.). The milky suspension is stirred, and 1 equivalent of the L-form of arginine or lysine that has been triturated in a separate portion of the alcohol is added. The mixture is stirred under an inert atmosphere until a clear yellowish solution is formed. The solution is filtered and the solvent removed from the filtrate under reduced pressure. The resulting yellow film forms a friable solid upon vacuum drying. Alternatively, the complex may be precipitated by addition of cold solvent such as heptane, methyl t-butyl ether, ethyl acetate or the like to the alcohol solution, the resulting solid filtered and vacuum dried to isolate the friable solid. The resulting solid is typically amorphous with some degree (<30%) of crystallinity, preferably the complex is substantially amorphous, and is less than 10%, also less than 5%, also less than 1% crystalline. In some instances, the resulting solid may be prepared to have some degree of crystalline material, where the method above is modified by using an excess amount of the N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]sulfonamide relative to the arginine or lysine. For example, 0.5 equivalent of the L-form of arginine or lysine may be added to the suspension of compound in methanol. The resulting solid that is isolated will comprise a mixture of the amorphous complex and crystalline compound. The amount of L-arginine or L-lysine used may be adjusted appropriately to provide a solid that has any level of crystalline material, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% crystalline, with 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10% amorphous solid, respectively. The relative amount of crystalline material and amorphous material in a solid can be readily determined by one skilled in the art, for example as described in Shah et al., J Pharm Sci 2006, 95:1641-1665.
  • Acid addition salts, including sulfonic acid series of organic anions such as tosylate, besylate or mesylate, of N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide and related compounds are preferably formed using acetone, which provides solubility of the free base and is a non-solvent once the salt is formed. Typically, N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide is added to 20-50 solvent volumes of acetone with stirring and heating (30-35° C.), followed by the addition of 1 equivalent of the desired acid counter ion. The solution is slowly cooled to 2-8° C. and the solid is isolated by either filtration or centrifugation, followed by vacuum drying. The resulting solid may be amorphous, partially amorphous or crystalline, and can be recrystallized as needed from alcohol:acetone:ethyl acetate or alcohol alone to obtain the desired solid in crystalline form.
  • Organic acid complexes, including citric acid, tartaric acid, succinic acid, glutaric acid and acetylsalicylic acid complexes of N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide and related compounds are preferably formed in 1:1 or 1:2 compound:acid ratios in a suitable solvent such as methanol. Typically, N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide is added to 15-20 solvent volumes of methanol, with the desired solid isolated by either spray drying or by addition of non-solvent such as heptane followed by filtration and vacuum drying. The resulting solid is preferably an amorphous complex.
  • Mineral acids, including sulfate, phosphate and hydrochloric acid salts of N-[3-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-sulfonamide and related compounds are prepared from methanol or ethyl acetate solutions.
  • The resulting complexes or salts may also be processed through spray-drying techniques to provide the preferred form directly, or with suitable excipient materials to provide for a directly compressible or encapsulated dosage form. Salts or complexes may also be achieved by mechanochemical (e.g. roller compaction) or microwave irradiation of the parent compound with the appropriate selection of charge transfer partner. Such an approach is used to minimize solvent utilization, increase yield, purity and throughput, as well as achieve constructs not attainable using conventional solvent techniques.
  • The arginine complex of N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide P-1021 was prepared by suspending 5 g (9.7 mmol) of the free base in 100 mL of methanol, mixing with heating 30-35° C. L-arginine (1.70 g, 9.7 mmol) as a triturated dispersion in 5.1 mL of methanol. The milky white suspension is stirred with heating until a clear yellowish solution is formed. The solution was filtered and the solvent removed from the filtrate under reduced pressure, or processed by spray-drying to provide the complex as a friable yellow solid.
  • The arginine complexes of N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide P-1092, propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide P-1167, and propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide P-1496 were prepared similarly, as were the lysine or nicotinamide complexes of N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide P-1021 and the lysine complex of propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide P-1167.
  • Any of these arginine or lysine complexes may be prepared as a ternary complex comprising a strong acid, such as hydrochloric acid, for example by addition of 1 equivalent of hydrochloric acid (or other suitable acid) to the suspension of compound in methanol and mixing with the L-arginine or L-lysine.
  • The mesylate salt of N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide P-1021 was prepared by suspending 5 g (9.7 mmol) in 100 mL of acetone, mixing with heating 30-35° C. Methanesulfonic acid (0.63 mL, 9.7 mmol) was added and the solution cooled to 5° C. over 30 minutes. The resulting solid was isolated by filtration, washed and dried under vacuum to provide the desired salt.
  • The besylate and tosylate salts of N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide P-1021 were prepared similarly.
    • Example 27 Physical Properties of Solid Forms
  • Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide P-1167 complexed with either lysine or arginine was compared to the free base polymorph form 2 from which the complexes were formed. The XRPD comparison of these materials indicate that the lysine complex is essentially amorphous (some peaks associated with the free base having much reduced intensity), and the arginine complex is substantially amorphous (no clear peaks associated with the free base). The 2-theta values and intensities are provide in the following Table 3.
  • TABLE 3
    XRPD 2θ values for P-1167 polymorphic Form 2 and the lysine or
    arginine complex thereof.
    Peak intensity (cps)
    Arginine Lysine
    2θ value (+/−0.2) Form 2 complex complex
    6.7 240 48.3 39.6
    8.8 229 119 27.4
    9.2 2141 564 66.3
    13.5 341 103 22
    14.1 185 64.6 14.1
    14.5 272 101 18
    15.0 887 218 37.1
    17.7 106 43.5 17
    18.3 253 220 20.1
    19.1 442 267 72.4
    19.7 310 96.7 47.5
    20.9 165 79.6 16.5
    21.4 205 181 20.8
    24.1 200 149 43.4
    24.4 591 373 78.1
    25.1 163 115 34.1
    28.1 121 97.4 32.7
    30.1 116 68.9 22.2
  • It is clear from this data that the lysine complex is amorphous, with the lack of any clear structure in the XRPD sprecta and the intensity of the peaks corresponding to the two largest peaks in form 2 (20 values of about 9.2 and 15.0) reduced to less than 5% of the form 2 intensity. The arginine complex is substantially amorphous, showing some residual level of crystallinity in the XRPD spectra, with the intensity of these peaks at less than 30% of the form 2 intensity. The amount of crystalline material in such complexes can be readily reduced further in processing, for example, by spray drying techniques such that an amorphous complex with arginine or lysine is provided.
  • The DSC of these samples shows that the arginine and lysine complexes lack a characteristic transition and have completely melted before the free base crystalline transition at 271° C., further supporting that these complexes are amorphous.
  • The intrinsic dissolution rate of a similarly prepared substantially amorphous arginine complex of P-1167 was compared to that of the form 2 polymorph in simulated gastric fluid (SGF) without enzyme and in simulated intestinal fluid (SIF). A pellet of test sample was dissolved in the appropriate fluid, and the UV absorbance as a function of time was measured at 254 nm (SGF) or 310 nm (SIF) and plotted. The results demonstrate a maximum absorbance in SGF at approximately 200 minutes that is substantially greater than the free base, and a substantially higher absorbance in SIF than the free base. As such, significant improvement of dissolution of the arginine complex is shown, which is likely to be improved further by processing the complex to a completely amorphous form.
  • Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide P-1496 complexed with arginine was compared to the free base from which the complex was formed. The XRPD comparison of these materials indicate that the arginine complex is amorphous, demonstrating the characteristic amorphous halo.
  • Similarly, the DSC shows that the arginine complex has a very broad transition from about 56° C. to about 120° C. and lacks the characteristic transition of the free base at approximately 275° C.
  • N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide P-1021 lot number 14 complexed with arginine was compared to the free base from which the complex was formed. The XRPD comparison of these materials indicate that the arginine complex is amorphous, demonstrating essentially the characteristic amorphous halo with some minor peaks associated with the free base. Similarly, the DSCshows that the arginine complex has a broad transition at lower temperatures and a very minor transition at about 140° C. and lacks the characteristic transition of the free base at approximately 276° C. Finally, the solid state NMR was also compared, where 13C cross polarization magic angle spinning was acquired at room temperature using a Varian UnityINOVA-400 spectrometer (Larmor frequencies: 13C=100.542 MHz, 1H=399.790 MHz). Samples were packed into 4 mm PENCIL type zirconia rotors and rotated at 12 kHz at the magic angle. The spectra were acquired with phase modulated SPINAL-64 high power 1H decoupling during the acquisition time using a 1H pulse width of 2.2 μs(90°), a ramped amplitude cross polarization contact time of 3-8 ms, a 30 ms acquisition time, a 10-30 second delay between scans, a spectral width of 45 kHz with 2700 data points, and 100 or 400 co-added scans. Each free induction decay was processed using Varian VNMR 6.1C software3 with 32768 points and an exponential line broadening factor of 10 or 100 Hz to improve the signal-to-noise ratio. The first three data points of the free induction decay were back predicted using VNMR linear prediction algorithm to produce a flat baseline. The chemical shifts of the spectral peaks were externally referenced to the carbonyl carbon resonance of glycine at 176.5 ppm. The results show that the complex has no ordered structure as compared to either the free base or L-arginine, clearly demonstrating the amorphous nature of the complex. This amorphous complex, in addition to providing preferable biopharmaceutical properties, is readily friable and compressible, and therefor is advantageous in preparation of solid capsules, as more material can be compressed into a tablet than with the free base.
  • N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide P-1092 lot number 2 complexed with arginine was compared to the free base from which the complex was formed. The XRPD comparison of these materials indicate that the arginine complex is amorphous, demonstrating essentially the characteristic amorphous halo. Similarly, the DSC show that the arginine complex has a broad transition at lower temperatures and a very minor transition at about 140° C. and lacks the characteristic transition of the free base at approximately 276° C.
    • Example 28 Pharmacokinetic Evaluation of Solid Forms
  • Pharmacokinetic properties of various compositions prepared from the complexes may be assessed in male Sprague Dawley rats or male Beagle dogs, and compared to the properties of the free base compound. Rats are dosed daily with compound either by IV injections via surgically implanted jugular catheters or by oral gavage (PO). Each compound is prepared as a 20 mg/mL stock solution in dimethyl sulfoxide, which is further diluted to provide the dosing stock at the desired concentration for the IV or PO formulations. For IV dosing, the dosing stock is diluted into a 1:1:8 mixture of Solutol®:ethanol:water. For PO dosing, the dosing stock is diluted into 1% methylcellulose. In a cassette format, 5 compounds are diluted to 0.5 mg/mL each for IV dosing and 0.4 mg/mL each for PO dosing and dosed at 1 mg/kg (2 mL/kg) or 2 mg/kg (5 mL/kg), respectively. For IV dosed animals, tail vein blood samples are collected with lithium heparin anticoagulant at 5, 15, 30, and 60 minutes and 4, 8, and 24 hours post dosing each day. For PO dosed animals, tail vein blood samples are collected with lithium heparin anticoagulant at 30 minutes, 1, 2, 4, 8 and 24 hours post dosing each day. Dogs are dosed daily by oral capsules in a suitable formulation at 50 mg/mL. Cephalic vein blood samples are collected with lithium heparin anticoagulant at 30 minutes, 1, 2, 4, 8 and 24 hours post dosing each day. All samples are processed to plasma and frozen for later analysis of each compound by LC/MS/MS. Plasma levels as a function of time are plotted to assess the AUC (ng*hr/mL).
  • The arginine complex of N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide P-1021 was analyzed in a number of dog PK studies following the above or similar protocols. These were done primarily at Bridge Laboratories, Beijing, China, with one study done at Seventh Wave Laboratories LLC, Chesterfield, Mo. Plasma samples were analyzed to determine the plasma concentration (PPD Development, Madison, Wis.) at each time point from which the Cmax and AUC∞ were determined. The dosing formulations and results for these studies are given in the following tables. In some instances, the materials are combined in the solvents indicated, and the solvent is removed by evaporation, or by spray drying where indicated. In these tables, unless indicated otherwise, the dose is mg/dog, and the Cmax/dose ((ng/mL)/(mg/kg)) and the AUC∞/dose ((ng*hr/mL)/(mg/kg)) are calculated assuming a 10 kg weight for the dogs.
  • TABLE 4A
    Solid forms and formulations for dog PK study comparing P-1021 arginine
    complex to the free base, a sulfate salt or a nicotinamide complex.
    Amoung (g) per
    Component 7.4 gram batch W/W%
    P-1021 arginine complex
    Micronized P-1021 free base 2.68 36.2
    Crystalline spray dried 2.32 31.4
    mannitol
    Polyplasdone XL 0.400 5.40
    Poloxamer F-68 2.00 27.0
    P-1021 free base
    P-1021 arginine complex 2.00 27.0
    Crystalline spray dried 3.00 40.5
    mannitol
    Polyplasdone XL 0.400 5.40
    Poloxamer F-68 2.00 27.0
    P-1021 sulfate salt
    P-1021 sulfate salt 2.38 32.2
    Crystalline spray dried 2.62 35.4
    mannitol
    Polyplasdone XL 0.400 5.40
    Poloxamer F-68 2.00 27.0
    P-1021 nicotinamide complex
    P-1021 nicotinamide 1:2 2.31 39.0
    Polyplasdone XL 0.20 6.25
    Poloxamer F-68 1.00 15.6
  • TABLE 4B
    Cmax/dose and AUC∞/dose comparing P-1021 arginine
    complex to free base, sulfate salt and nicotinamide complex.
    Dose
    Test article (mg/dog) Cmax/dose AUC∞/dose
    Arginine complex 100 830.5 16,850
    Free base 100 581.3 8,031
    Sulfate 100 181.5 5,067
    Nicotinamide 100 110.7 2,043
  • TABLE 5A
    Solid forms and formulations for dog PK study comparing P-1021 arginine
    complex to the free base, an amorphous form of the free base, or mesylate salt.
    P-1021 arginine complex
    Amoung (g) per 10 gram
    Component batch W/W %
    P-1021 arginine complex 5.00 free base 50.0
    1.70 L-arginine 17.0
    Mannitol 1.70 17.0
    Polyplasdone XL 0.40 4.0
    Mg-Al-silicate 1.00 10.0
    Poloxamer F127 0.40 4.0
    In methanol solvent (~50 mg/mL) removed during processing
    P-1021 free base
    Amoung (g) per 7.4 gram
    Component batch W/W %
    Micronized P-1021 free base 5.00 50.0
    Mannitol 2.22 22.0
    D-Sorbitol 2.00 20.0
    Polyplasdone XL 0.40 4.0
    Poloxamer F127 0.40 4.0
    Dry blended with simulation of roller compaction
    P-1021 amorphous free base
    Amoung (g) per 7.4 gram
    Component batch W/W %
    P-1021 amorphous free base 5.00 50.0
    Mannitol 1.20 12.0
    D-Sorbitol 2.00 20.0
    Polyplasdone XL 0.40 4.0
    Mg-Al-silicate 1.00 10.0
    Poloxamer F127 0.40 4.0
    In acetone solvent (~100 mg/mL) removed during processing
    P-1021 mesylate salt
    Amoung (g) per 10 gram
    Component batch W/W %
    Micronized P-1021 free base 5.00 50.0
    Methane-sulfonic acid 1.00 10.0
    Mannitol 0.70 7.0
    D-Sorbitol 1.50 15.0
    Polyplasdone XL 0.40 4.0
    Mg-Al-Silicate 1.00 10.0
    Poloxamer F127 0.40 4.0
  • TABLE 5B
    Cmax/dose and AUC∞/dose comparing P-1021 arginine
    complex to free base, amorphous free base and mesylate salt.
    Dose
    Test article (mg/dog) Cmax/dose AUC∞/dose
    Arginine complex 150 810 34,693
    Free base 150 482 5,270
    Amorphous free base 150 33 482
    Mesylate 150 116 2,849
  • TABLE 6A
    Solid forms and formulations for dog PK study comparing arginine
    complex of P-1021, mixed formulation vs. spray dried formulation.
    Component W/W %
    P-1021 Arginine complex P-10
    P-1021 arginine complex 30.0
    PEG400 55.0
    Propylene Glycol 5.00
    Polysorbate 20 5.00
    TPGS 5.00
    P-1021 arginine complex spray dried P-11*
    P-1021 arginine complex 50.0
    Poloxamer 188 40.0
    Mannitol 10.0
    In acetone: ethanol 80:20, removed on spray drying onto Poloxamer F68
    P-1021 arginine complex P-18
    P-1021 arginine complex 26.8
    Propylene Glycol 25.0
    Polysorbate 20 5.00
    TPGS 5.00
    Capryol 90 38.2
    In acetone: ethanol 80:20, removed during processing
  • TABLE 6B
    Cmax/dose and AUC∞/dose comparing various formulations.
    Dose
    Test article (mg/dog) Cmax/dose AUC∞/dose
    P-10 400 808 13,787
    P-10 800 824 16,881
    P-11 200 1,525 37,211
    P-18 200 1,030 18,324
  • TABLE 7A
    Solid forms and formulations for dog PK study comparing
    arginine complex at 200 or 400 mg per dog dose.
    P-1021 arginine complex spray dried P-11
    Component W/W %
    P-1021 arginine complex 50.0
    Poloxamer 407 35.0
    Mannitol 15.0
    Methanol removed during processing
  • TABLE 7B
    Cmax/dose and AUC∞/dose for P-1021 arginine complex
    dosed at 200 or 400 mg perdog.
    Dose AUC∞/
    Test article (mg/dog) Cmax/dose dose
    Arginine complex 200 960 22,480
    Arginine complex 400 455 12,120
  • TABLE 8A
    Solid forms and formulations for dog PK study comparing
    arginine complex at increasesing doses (mg/kg).
    P-1021 arginine complex
    Component W/W %
    P-1021 arginine complex 54.3% P-1021
    18.5% L-arginine
    Poloxamer 407 27.2

    This study was done at Seventh Wave, containers were provided with 13.259 g, 39.776 g or 66.301 g of this formulation and suspended in 360 mL of 1.5% Polysorbate 20 vehicle and dosed by oral gavage.
  • TABLE 8B
    Cmax/dose and AUC∞/dose for P-1021 arginine complex
    dosed at the indicated mg/kg.
    Dose AUC∞/
    Test article (mg/kg) Cmax/dose dose
    Arginine complex 249 208 11,247
    Arginine complex 795 107 7,457
    Arginine complex 965 178 3,883
  • N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide P-1021 was analyzed in a dog PK study wherein the arginine complex of N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide P-1092 was also assessed. Formulations and results are provided in the following Tables 9A and 9B.
  • TABLE 9A
    Solid forms and formulations for dog PK study of P-1021 arginine mixed
    in formulation (non-complex) and P-1092 arginine complex.
    P-1092 arginine complex
    Component Amoung (g) per 5.00 g batch W/W %
    P-1092 arginine complex 2.50 50.0
    Poloxamer 407 1.75 35.0
    Mannitol 0.75 15.0
    P-1021 non-complex arginine formulation
    Component Amoung (g) per 15.00 g batch W/W %
    P-1021 5.00 33.33
    L-arginine 3.38 22.53
    Poloxamer 407 5.25 35.0
    Mannitol 1.37 9.13
  • TABLE 9B
    Cmax/dose and AUC∞/dose for P-1021 non-complexed
    with arginine, or P-1092 arginine complex.
    Dose Cmax/
    Test article (mg/dog) dose AUC∞/dose
    P-1021 non-complex 400 392.5 8,092
    P-1092 arginine complex 200 550 11,720
    P-1092 arginine complex 400 617.5 12,580
  • These dog PK studies demonstrate favorable biopharmaceutical properties of the compounds as an arginine complex. For example, P-1021 shows favorable Cmax and AUC compared to free base and other formulations (Table 4B, Table 5B), and Table 6B demonstrates further improvement of these properties with spray drying of the formulations. The arginine complex, and not just the presence of an equivalent amount of arginine, is favorable, as typically, the AUC/dose of the complex dosed at 400 mg per dog is greater than 12,000 (Table 6B, Table 7B), whereas the AUC/dose for a non-complexed formulation with arginine is approximately 8,000 (Table 9B). The P-1092 arginine complex shows similar exposure as the P-1021 complex (Table 9B).
  • A PK study was carried out in Sprague-Dawley rats on the arginine or lysine complex of propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide P-1496 (Murigenics, Berkeley, Calif.), dosing via tail vein injection, with sampling of approximately 250 μL of blood via jugular veing in Lithium heparin tubes at 30 minutes, 1, 3, 6, 8, 12, 24, 36 and 48 hours. Blood samples were centrifuged at 4° C. for 10 minutes at RCF of 1,000, plasma was stored at 80° C. and shipped frozen for analytical analysis (Integrated Analytical Solutions, Inc., Berkeley, Calif.). The results demonstrate improved biopharmaceutical properties for either the arginine or the lysine comples. The solid form and formulations are provided in Table 10A, with the results provided in Table 10B.
  • TABLE 10A
    Solid forms and formulations for rat PK study of
    P-1496 arginine or lysine complex.
    Amoung (g) per 2.00 g
    Component batch W/W %
    P-1496 free base
    P-1496 free base 1.00 50.0
    Poloxamer 407 1.00 50.0
    Methanol removed in processing
    P-1496 arginine complex
    P-1496 1.00 50.00
    L-arginine 0.36 18.00
    Poloxamer 407 0.64 32.0
    Acetone removed in processing
    P-1496 lysine complex
    P-1496 1.00 50.00
    L-lysine 0.30 15.00
    Poloxamer 407 0.70 35.0
    Acetone removed in processing

    Solid formulations were taken up in PEG400:water at 200 mg/cc for free base, arginine, and lysine complexes, and also at 400 mg/cc for lysine complex and dosed by oral gavage 10 mL/kg to provide the P-1496 doses indicated in Table 10B.
  • TABLE 10B
    Cmax/dose and AUC∞/dose for P-1496 free base, arginine
    complex and lysine complex in rats.
    Cmax/dose AUC∞/
    Test article Dose (mg/kg) dose
    P-1496 free base 100 106 1,970
    P-1496 arginine complex 100 159 3,620
    P-1496 lysine complex 100 283 3,210
    P-1496 lysine complex 200 155 2,750
    • Example 29 Kinase Activity Assays
  • Assays for the activity of Raf kinases, including, but not limited to, B-Raf, B-Raf V600E, B-Raf V600E/T529I and c-Raf-1, as well as for other kinases are known in the art, for example as described in U.S. patent application Ser. No. 11/473,347 (see also, PCT publication WO2007002433), the disclosure of which is hereby incorporated by reference in its entirety. The activity of compounds for Raf kinases and other kinases is summarized in the following tables. Compounds having IC50 of less than 10 μM with respect to the indicated kinase are shown in tables 11a (A-Raf), 11b (B-Raf), 11c (B-Raf V600E), 11d (C-Raf), 11e (Btk), 11f (Fms), 11 g (Kdr), 11 h (Kit), 11i (Src), 11j (TEC), 11k (TrkA), 11m (MAP4K4), 11n (Flt1), 11o (PI3Kα), 11p (PI3Kδ), and 11q (PI3Kγ).
  • TABLE 11a
    Compounds with activity toward kinase A-Raf with IC50 ≦ 10 μM.
    A-Raf P-2002, P-2009, P-2010, P-2011, P-2014, P-2015, P-2016, P-2017,
    P-2018, P-2019, P-2020, P-2022, P-2035, P-2036, P-2037, P-2038,
    P-2039, P-2046, P-2047, P-2056, P-2057, P-2061, P-2062, P-2063,
    P-2064, P-2065, P-2066, P-2067, P-2069, P-2071, P-2075, P-2076,
    P-2077, P-2078, P-2113, P-2115, P-2116, P-2117, P-2119, P-2165,
    P-2182, P-2196, P-2208, P-2209, P-2210, P-2220, P-2224, P-2230,
    P-2231, P-2232, P-2233, P-2234, P-2235, P-2236, P-2238, P-2239,
    P-2240, P-2243, P-2244, P-2247, P-2248, P-2250, P-2255, P-2257,
    P-2258, P-2259, P-2260, P-2261, P-2272, P-2273, P-2274, P-2275,
    P-2276, P-2277, P-2278, P-2283, P-2284, P-2285, P-2288, P-2289,
    P-2290, P-2291, P-2292, P-2297, P-2303, P-2304, P-2305, P-2314,
    P-2315, P-2316, P-2317, P-2318, P-2319, P-2320, P-2321, P-2327,
    P-2328, P-2329, P-2332, P-2335, P-2336, P-2337, P-2338, P-2339,
    P-2341, P-2343, P-2346, P-2347, P-2353, P-2354, P-2362, P-2363,
    P-2364, P-2365, P-2366, P-2367, P-2368, P-2369, P-2370, P-2374,
    P-2375, P-2379, P-2384, P-2385, P-2386, P-2387, P-2388, P-2389,
    P-2390, P-2391, P-2392, P-2393, P-2394, P-2395, P-2396, P-2397,
    P-2398, P-2407, P-2408, P-2420, P-2437
  • TABLE 11b
    Compounds with activity toward kinase B-Raf with IC50 ≦ 10 μM.
    B-Raf P-2001, P-2002, P-2003, P-2004, P-2005, P-2006, P-2007, P-2008,
    P-2009, P-2010, P-2011, P-2014, P-2015, P-2016, P-2017, P-2018,
    P-2019, P-2020, P-2021, P-2022, P-2023, P-2024, P-2025, P-2026,
    P-2027, P-2028, P-2029, P-2030, P-2031, P-2032, P-2033, P-2034,
    P-2035, P-2036, P-2037, P-2038, P-2039, P-2040, P-2041, P-2042,
    P-2043, P-2044, P-2045, P-2046, P-2047, P-2050, P-2051, P-2052,
    P-2053, P-2054, P-2055, P-2056, P-2057, P-2058, P-2059, P-2060,
    P-2063, P-2066, P-2067, P-2069, P-2070, P-2071, P-2072, P-2073,
    P-2074, P-2075, P-2076, P-2077, P-2078, P-2079, P-2080, P-2084,
    P-2085, P-2086, P-2087, P-2090, P-2099, P-2101, P-2102, P-2103,
    P-2104, P-2105, P-2106, P-2108, P-2109, P-2110, P-2112, P-2113,
    P-2116, P-2117, P-2119, P-2123, P-2126, P-2127, P-2128, P-2139,
    P-2140, P-2142, P-2144, P-2145, P-2147, P-2148, P-2149, P-2150,
    P-2151, P-2152, P-2153, P-2154, P-2155, P-2162, P-2165, P-2166,
    P-2167, P-2168, P-2171, P-2172, P-2173, P-2174, P-2175, P-2176,
    P-2177, P-2178, P-2179, P-2180, P-2181, P-2182, P-2183, P-2184,
    P-2185, P-2186, P-2187, P-2188, P-2189, P-2190, P-2191, P-2192,
    P-2193, P-2194, P-2195, P-2196, P-2197, P-2198, P-2199, P-2200,
    P-2201, P-2203, P-2204, P-2207, P-2208, P-2209, P-2210, P-2211,
    P-2212, P-2213, P-2214, P-2215, P-2216, P-2217, P-2218, P-2219,
    P-2220, P-2222, P-2223, P-2224, P-2225, P-2226, P-2227, P-2228,
    P-2229, P-2230, P-2231, P-2232, P-2233, P-2234, P-2235, P-2236,
    P-2237, P-2238, P-2239, P-2240, P-2243, P-2244, P-2247, P-2248,
    P-2250, P-2255, P-2257, P-2258, P-2259, P-2260, P-2261, P-2268,
    P-2269, P-2270, P-2271, P-2272, P-2273, P-2274, P-2275, P-2276,
    P-2277, P-2278, P-2279, P-2280, P-2281, P-2282, P-2283, P-2285,
    P-2286, P-2287, P-2290, P-2295, P-2297, P-2298, P-2299, P-2300,
    P-2301, P-2302, P-2303, P-2304, P-2305, P-2306, P-2307, P-2310,
    P-2313, P-2317, P-2318, P-2320, P-2321, P-2322, P-2323, P-2324,
    P-2325, P-2326, P-2327, P-2328, P-2329, P-2330, P-2331, P-2332,
    P-2333, P-2334, P-2335, P-2336, P-2338, P-2339, P-2340, P-2341,
    P-2342, P-2343, P-2344, P-2345, P-2346, P-2347, P-2350, P-2351,
    P-2352, P-2353, P-2354, P-2355, P-2356, P-2357, P-2358, P-2359,
    P-2360, P-2361, P-2363, P-2364, P-2366, P-2367, P-2368, P-2369,
    P-2370, P-2371, P-2372, P-2373, P-2374, P-2375, P-2376, P-2377,
    P-2379, P-2382, P-2383, P-2393, P-2394, P-2395, P-2396, P-2397,
    P-2398, P-2399, P-2400, P-2402, P-2403, P-2404, P-2406, P-2407,
    P-2408, P-2409, P-2412, P-2413, P-2414, P-2415, P-2416, P-2417,
    P-2418, P-2420, P-2422, P-2425, P-2430, P-2431, P-2432, P-2434,
    P-2444, P-2445, P-2447, P-2465, P-2481
  • TABLE 11c
    Compounds with activity toward kinase B-Raf V600E with IC50 ≦ 10 μM.
    B-Raf P-2002, P-2003, P-2004, P-2005, P-2006, P-2007, P-2008, P-2009,
    V600E P-2010, P-2011, P-2014, P-2015, P-2016, P-2017, P-2018, P-2019,
    P-2020, P-2021, P-2022, P-2023, P-2024, P-2025, P-2026, P-2027,
    P-2028, P-2029, P-2030, P-2031, P-2032, P-2033, P-2034, P-2035,
    P-2036, P-2037, P-2038, P-2039, P-2040, P-2041, P-2042, P-2043,
    P-2044, P-2045, P-2046, P-2047, P-2050, P-2051, P-2052, P-2053,
    P-2054, P-2055, P-2056, P-2057, P-2058, P-2059, P-2060, P-2061,
    P-2062, P-2063, P-2064, P-2065, P-2066, P-2067, P-2068, P-2069,
    P-2070, P-2071, P-2072, P-2073, P-2074, P-2075, P-2076, P-2077,
    P-2078, P-2079, P-2080, P-2081, P-2082, P-2083, P-2084, P-2085,
    P-2086, P-2087, P-2088, P-2089, P-2090, P-2091, P-2092, P-2093,
    P-2094, P-2095, P-2096, P-2097, P-2098, P-2099, P-2100, P-2101,
    P-2102, P-2103, P-2104, P-2105, P-2108, P-2110, P-2111, P-2120,
    P-2127, P-2129, P-2130, P-2131, P-2132, P-2133, P-2134, P-2135,
    P-2136, P-2139, P-2140, P-2147, P-2150, P-2151, P-2152, P-2153,
    P-2154, P-2155, P-2156, P-2157, P-2158, P-2159, P-2160, P-2161,
    P-2162, P-2164, P-2165, P-2166, P-2167, P-2168, P-2169, P-2170,
    P-2171, P-2172, P-2173, P-2174, P-2175, P-2176, P-2177, P-2178,
    P-2179, P-2180, P-2181, P-2182, P-2183, P-2184, P-2185, P-2186,
    P-2187, P-2188, P-2189, P-2190, P-2191, P-2192, P-2193, P-2194,
    P-2195, P-2196, P-2197, P-2198, P-2199, P-2200, P-2201, P-2203,
    P-2204, P-2207, P-2208, P-2209, P-2210, P-2211, P-2212, P-2213,
    P-2214, P-2215, P-2216, P-2217, P-2218, P-2219, P-2220, P-2222,
    P-2223, P-2224, P-2225, P-2226, P-2227, P-2228, P-2229, P-2230,
    P-2231, P-2232, P-2233, P-2234, P-2235, P-2236, P-2238, P-2239,
    P-2240, P-2243, P-2244, P-2247, P-2248, P-2250, P-2255, P-2257,
    P-2258, P-2259, P-2260, P-2261, P-2268, P-2269, P-2270, P-2271,
    P-2272, P-2273, P-2274, P-2275, P-2276, P-2277, P-2278, P-2279,
    P-2280, P-2281, P-2282, P-2283, P-2284, P-2285, P-2286, P-2287,
    P-2288, P-2289, P-2290, P-2291, P-2292, P-2293, P-2294, P-2295,
    P-2296, P-2297, P-2298, P-2299, P-2300, P-2301, P-2302, P-2303,
    P-2304, P-2305, P-2306, P-2307, P-2308, P-2309, P-2310, P-2311,
    P-2312, P-2313, P-2314, P-2315, P-2316, P-2317, P-2318, P-2319,
    P-2320, P-2321, P-2322, P-2323, P-2324, P-2325, P-2326, P-2327,
    P-2328, P-2329, P-2330, P-2331, P-2332, P-2333, P-2334, P-2335,
    P-2336, P-2337, P-2338, P-2339, P-2340, P-2341, P-2342, P-2343,
    P-2344, P-2345, P-2346, P-2347, P-2348, P-2350, P-2351, P-2352,
    P-2353, P-2354, P-2355, P-2356, P-2357, P-2358, P-2359, P-2360,
    P-2361, P-2362, P-2363, P-2364, P-2365, P-2366, P-2367, P-2368,
    P-2369, P-2370, P-2371, P-2372, P-2373, P-2374, P-2375, P-2376,
    P-2377, P-2378, P-2379, P-2382, P-2383, P-2384, P-2385, P-2386,
    P-2387, P-2388, P-2389, P-2390, P-2391, P-2392, P-2393, P-2394,
    P-2395, P-2396, P-2397, P-2398, P-2399, P-2400, P-2401, P-2402,
    P-2403, P-2404, P-2406, P-2407, P-2408, P-2409, P-2410, P-2411,
    P-2412, P-2413, P-2414, P-2415, P-2416, P-2417, P-2418, P-2419,
    P-2420, P-2421, P-2422, P-2423, P-2424, P-2425, P-2429, P-2430,
    P-2431, P-2432, P-2433, P-2434, P-2435, P-2436, P-2437, P-2442,
    P-2444, P-2445, P-2446, P-2447, P-2449, P-2450, P-2452, P-2453,
    P-2454, P-2455, P-2456, P-2457, P-2464, P-2465, P-2466, P-2467,
    P-2468
  • TABLE 11d
    Compounds with activity toward kinase C-Raf with IC50 ≦ 10 μM.
    C-Raf P-2001, P-2002, P-2003, P-2004, P-2005, P-2006, P-2007, P-2008,
    P-2009, P-2010, P-2011, P-2014, P-2015, P-2016, P-2017, P-2018,
    P-2019, P-2020, P-2021, P-2022, P-2023, P-2024, P-2025, P-2026,
    P-2027, P-2028, P-2029, P-2030, P-2031, P-2032, P-2033, P-2034,
    P-2035, P-2036, P-2037, P-2038, P-2039, P-2040, P-2041, P-2042,
    P-2043, P-2044, P-2045, P-2046, P-2047, P-2050, P-2051, P-2052,
    P-2053, P-2054, P-2055, P-2056, P-2057, P-2058, P-2059, P-2060,
    P-2061, P-2062, P-2063, P-2064, P-2065, P-2066, P-2067, P-2068,
    P-2069, P-2070, P-2071, P-2072, P-2073, P-2074, P-2075, P-2076,
    P-2077, P-2078, P-2079, P-2080, P-2081, P-2083, P-2084, P-2085,
    P-2086, P-2087, P-2088, P-2089, P-2090, P-2092, P-2101, P-2105,
    P-2116, P-2117, P-2119, P-2139, P-2140, P-2143, P-2147, P-2150,
    P-2151, P-2154, P-2155, P-2162, P-2165, P-2166, P-2167, P-2168,
    P-2178, P-2179, P-2182, P-2185, P-2193, P-2196, P-2199, P-2200,
    P-2201, P-2208, P-2209, P-2210, P-2211, P-2213, P-2214, P-2215,
    P-2216, P-2217, P-2218, P-2219, P-2220, P-2222, P-2223, P-2224,
    P-2225, P-2226, P-2227, P-2228, P-2229, P-2230, P-2231, P-2232,
    P-2233, P-2234, P-2235, P-2236, P-2238, P-2239, P-2240, P-2243,
    P-2244, P-2247, P-2248, P-2250, P-2255, P-2257, P-2258, P-2259,
    P-2260, P-2261, P-2272, P-2273, P-2274, P-2275, P-2276, P-2277,
    P-2278, P-2279, P-2280, P-2281, P-2282, P-2283, P-2284, P-2285,
    P-2286, P-2287, P-2288, P-2289, P-2290, P-2291, P-2292, P-2293,
    P-2294, P-2295, P-2297, P-2303, P-2304, P-2305, P-2306, P-2307,
    P-2308, P-2310, P-2311, P-2312, P-2313, P-2314, P-2317, P-2318,
    P-2319, P-2320, P-2321, P-2322, P-2323, P-2324, P-2327, P-2328,
    P-2329, P-2330, P-2331, P-2332, P-2333, P-2335, P-2336, P-2337,
    P-2338, P-2339, P-2340, P-2341, P-2342, P-2343, P-2346, P-2347,
    P-2350, P-2353, P-2354, P-2355, P-2356, P-2357, P-2358, P-2359,
    P-2360, P-2361, P-2362, P-2363, P-2364, P-2365, P-2366, P-2367,
    P-2368, P-2369, P-2370, P-2371, P-2372, P-2373, P-2374, P-2375,
    P-2376, P-2377, P-2379, P-2382, P-2383, P-2391, P-2392, P-2393,
    P-2394, P-2395, P-2396, P-2397, P-2398, P-2399, P-2400, P-2401,
    P-2402, P-2403, P-2404, P-2407, P-2408, P-2409, P-2410, P-2411,
    P-2412, P-2413, P-2414, P-2415, P-2416, P-2417, P-2418, P-2420,
    P-2421, P-2422, P-2424, P-2425, P-2430, P-2431, P-2432, P-2434,
    P-2444, P-2445, P-2446, P-2447, P-2467, P-2481, P-2483
  • TABLE 11e
    Compounds with activity toward kinase Btk with IC50 ≦ 10 μM.
    Btk P-2022, P-2041, P-2042, P-2043, P-2044, P-2045, P-2051, P-2052,
    P-2053, P-2054, P-2079, P-2080, P-2086, P-2087, P-2099, P-2100,
    P-2101, P-2102, P-2103, P-2105, P-2114, P-2120, P-2129, P-2130,
    P-2131, P-2134, P-2136, P-2138, P-2139, P-2140, P-2142, P-2144,
    P-2145, P-2147, P-2157, P-2158, P-2159, P-2160, P-2161, P-2165,
    P-2168, P-2174, P-2176, P-2177, P-2178, P-2184, P-2190, P-2194,
    P-2199, P-2214, P-2222, P-2229, P-2235, P-2260, P-2270, P-2271,
    P-2286, P-2287, P-2295, P-2299, P-2302, P-2308, P-2322, P-2323,
    P-2345, P-2350, P-2351, P-2352, P-2371, P-2372, P-2379, P-2383,
    P-2394, P-2399, P-2400, P-2401, P-2402, P-2410, P-2414, P-2420,
    P-2429, P-2431, P-2432, P-2433, P-2434, P-2440, P-2444, P-2446,
    P-2447, P-2448, P-2449, P-2454, P-2455, P-2456, P-2457, P-2460,
    P-2461, P-2462, P-2464, P-2468, P-2469, P-2471
  • TABLE 11f
    Compounds with activity toward kinase Fms with IC50 ≦ 10 μM.
    Fms P-2001, P-2002, P-2003, P-2004, P-2005, P-2006, P-2007, P-2008,
    P-2010, P-2015, P-2017, P-2018, P-2022, P-2042, P-2043, P-2044,
    P-2088, P-2099, P-2100, P-2101, P-2102, P-2103, P-2104, P-2105,
    P-2106, P-2107, P-2108, P-2110, P-2111, P-2112, P-2113, P-2114,
    P-2115, P-2116, P-2117, P-2118, P-2120, P-2121, P-2122, P-2123,
    P-2124, P-2125, P-2127, P-2128, P-2129, P-2130, P-2131, P-2132,
    P-2133, P-2134, P-2135, P-2136, P-2137, P-2138, P-2139, P-2140,
    P-2141, P-2142, P-2143, P-2144, P-2145, P-2148, P-2149, P-2151,
    P-2152, P-2153, P-2155, P-2157, P-2158, P-2159, P-2161, P-2164,
    P-2165, P-2166, P-2167, P-2168, P-2169, P-2170, P-2172, P-2174,
    P-2175, P-2176, P-2177, P-2178, P-2179, P-2180, P-2181, P-2183,
    P-2184, P-2185, P-2187, P-2190, P-2192, P-2193, P-2194, P-2198,
    P-2199, P-2200, P-2201, P-2203, P-2204, P-2207, P-2211, P-2212,
    P-2213, P-2214, P-2215, P-2216, P-2218, P-2221, P-2222, P-2224,
    P-2226, P-2228, P-2230, P-2232, P-2233, P-2234, P-2235, P-2236,
    P-2239, P-2241, P-2242, P-2260, P-2268, P-2270, P-2271, P-2273,
    P-2296, P-2297, P-2298, P-2299, P-2300, P-2301, P-2302, P-2304,
    P-2322, P-2324, P-2326, P-2331, P-2334, P-2339, P-2343, P-2344,
    P-2348, P-2350, P-2351, P-2352, P-2371, P-2383, P-2390, P-2404,
    P-2406, P-2423, P-2425, P-2429, P-2430, P-2431, P-2432, P-2433,
    P-2434, P-2435, P-2436, P-2437, P-2438, P-2439, P-2440, P-2441,
    P-2442, P-2443, P-2444, P-2445, P-2446, P-2447, P-2448, P-2449,
    P-2450, P-2451, P-2452, P-2453, P-2454, P-2455, P-2456, P-2457,
    P-2458, P-2460, P-2461, P-2464, P-2465, P-2468, P-2469, P-2471
  • TABLE 11g
    Compounds with activity toward kinase Kdr with IC50 ≦ 10 μM.
    Kdr P-2001, P-2002, P-2003, P-2004, P-2005, P-2006, P-2008, P-2009,
    P-2010, P-2011, P-2014, P-2015, P-2016, P-2017, P-2018, P-2019,
    P-2020, P-2021, P-2022, P-2023, P-2024, P-2025, P-2026, P-2027,
    P-2029, P-2030, P-2031, P-2032, P-2033, P-2034, P-2036, P-2037,
    P-2038, P-2041, P-2042, P-2043, P-2044, P-2051, P-2052, P-2054,
    P-2055, P-2058, P-2059, P-2060, P-2061, P-2062, P-2064, P-2065,
    P-2066, P-2067, P-2070, P-2075, P-2079, P-2080, P-2081, P-2082,
    P-2088, P-2089, P-2093, P-2094, P-2095, P-2096, P-2097, P-2099,
    P-2100, P-2101, P-2102, P-2103, P-2104, P-2105, P-2106, P-2107,
    P-2108, P-2109, P-2110, P-2111, P-2113, P-2114, P-2115, P-2117,
    P-2118, P-2120, P-2121, P-2122, P-2124, P-2125, P-2126, P-2127,
    P-2128, P-2129, P-2130, P-2131, P-2132, P-2133, P-2134, P-2135,
    P-2136, P-2137, P-2138, P-2139, P-2140, P-2141, P-2142, P-2143,
    P-2144, P-2145, P-2146, P-2147, P-2148, P-2149, P-2150, P-2151,
    P-2152, P-2153, P-2154, P-2155, P-2156, P-2157, P-2158, P-2159,
    P-2160, P-2161, P-2162, P-2164, P-2165, P-2166, P-2167, P-2168,
    P-2169, P-2170, P-2171, P-2172, P-2174, P-2175, P-2176, P-2177,
    P-2178, P-2179, P-2180, P-2181, P-2182, P-2183, P-2184, P-2185,
    P-2186, P-2187, P-2188, P-2189, P-2190, P-2191, P-2192, P-2193,
    P-2194, P-2195, P-2196, P-2197, P-2199, P-2200, P-2201, P-2203,
    P-2204, P-2207, P-2208, P-2209, P-2210, P-2211, P-2212, P-2213,
    P-2214, P-2215, P-2216, P-2217, P-2218, P-2219, P-2220, P-2221,
    P-2222, P-2223, P-2224, P-2225, P-2226, P-2227, P-2228, P-2229,
    P-2230, P-2231, P-2232, P-2233, P-2234, P-2235, P-2236, P-2237,
    P-2238, P-2239, P-2240, P-2241, P-2242, P-2243, P-2247, P-2248,
    P-2250, P-2255, P-2260, P-2261, P-2268, P-2269, P-2270, P-2271,
    P-2272, P-2273, P-2274, P-2275, P-2276, P-2277, P-2278, P-2279,
    P-2280, P-2281, P-2286, P-2287, P-2288, P-2289, P-2290, P-2291,
    P-2292, P-2293, P-2294, P-2295, P-2296, P-2298, P-2299, P-2300,
    P-2301, P-2302, P-2303, P-2304, P-2305, P-2308, P-2309, P-2310,
    P-2311, P-2312, P-2313, P-2315, P-2319, P-2320, P-2321, P-2322,
    P-2323, P-2324, P-2326, P-2327, P-2328, P-2329, P-2331, P-2333,
    P-2334, P-2335, P-2337, P-2338, P-2339, P-2343, P-2344, P-2345,
    P-2346, P-2347, P-2348, P-2349, P-2350, P-2351, P-2352, P-2353,
    P-2354, P-2355, P-2356, P-2357, P-2358, P-2359, P-2360, P-2362,
    P-2363, P-2364, P-2365, P-2370, P-2371, P-2372, P-2373, P-2374,
    P-2375, P-2376, P-2377, P-2378, P-2379, P-2382, P-2383, P-2384,
    P-2385, P-2386, P-2387, P-2389, P-2390, P-2394, P-2398, P-2399,
    P-2400, P-2401, P-2403, P-2404, P-2406, P-2408, P-2409, P-2417,
    P-2422, P-2423, P-2424, P-2425, P-2430, P-2431, P-2432, P-2433,
    P-2434, P-2435, P-2436, P-2437, P-2438, P-2439, P-2442, P-2443,
    P-2444, P-2445, P-2446, P-2447, P-2448, P-2449, P-2450, P-2451,
    P-2452, P-2453, P-2454, P-2455, P-2456, P-2457, P-2458, P-2459,
    P-2460, P-2461, P-2463, P-2464, P-2465, P-2466, P-2468, P-2469,
    P-2470, P-2471, P-2481, P-2483
  • TABLE 11h
    Compounds with activity toward kinase Kit with IC50 ≦ 10 μM.
    Kit P-2001, P-2002, P-2003, P-2004, P-2005, P-2006, P-2007, P-2008,
    P-2009, P-2010, P-2011, P-2014, P-2015, P-2016, P-2017, P-2018,
    P-2019, P-2020, P-2021, P-2022, P-2023, P-2024, P-2025, P-2026,
    P-2027, P-2029, P-2030, P-2031, P-2032, P-2033, P-2034, P-2035,
    P-2036, P-2037, P-2038, P-2039, P-2041, P-2042, P-2043, P-2044,
    P-2046, P-2047, P-2051, P-2052, P-2054, P-2055, P-2058, P-2071,
    P-2088, P-2094, P-2099, P-2100, P-2101, P-2102, P-2103, P-2104,
    P-2105, P-2106, P-2107, P-2108, P-2109, P-2110, P-2111, P-2112,
    P-2113, P-2114, P-2115, P-2116, P-2117, P-2118, P-2120, P-2121,
    P-2122, P-2123, P-2124, P-2125, P-2126, P-2127, P-2128, P-2129,
    P-2130, P-2131, P-2132, P-2133, P-2134, P-2135, P-2136, P-2138,
    P-2139, P-2140, P-2141, P-2142, P-2144, P-2145, P-2147, P-2148,
    P-2149, P-2151, P-2152, P-2153, P-2155, P-2157, P-2158, P-2159,
    P-2161, P-2164, P-2165, P-2166, P-2167, P-2168, P-2169, P-2170,
    P-2172, P-2174, P-2175, P-2176, P-2177, P-2178, P-2179, P-2180,
    P-2181, P-2182, P-2183, P-2184, P-2185, P-2187, P-2190, P-2192,
    P-2193, P-2194, P-2195, P-2199, P-2200, P-2201, P-2203, P-2204,
    P-2207, P-2209, P-2213, P-2214, P-2215, P-2216, P-2218, P-2220,
    P-2221, P-2222, P-2223, P-2224, P-2226, P-2228, P-2229, P-2230,
    P-2231, P-2232, P-2233, P-2234, P-2235, P-2236, P-2238, P-2239,
    P-2240, P-2241, P-2242, P-2260, P-2268, P-2270, P-2271, P-2272,
    P-2273, P-2274, P-2275, P-2282, P-2288, P-2289, P-2290, P-2291,
    P-2293, P-2296, P-2297, P-2298, P-2299, P-2300, P-2301, P-2302,
    P-2303, P-2304, P-2305, P-2306, P-2307, P-2309, P-2310, P-2311,
    P-2314, P-2315, P-2317, P-2318, P-2319, P-2322, P-2324, P-2325,
    P-2326, P-2327, P-2328, P-2329, P-2331, P-2333, P-2334, P-2335,
    P-2338, P-2341, P-2343, P-2344, P-2345, P-2347, P-2348, P-2350,
    P-2351, P-2352, P-2353, P-2354, P-2355, P-2356, P-2357, P-2358,
    P-2359, P-2360, P-2361, P-2365, P-2366, P-2367, P-2369, P-2371,
    P-2372, P-2374, P-2375, P-2379, P-2383, P-2384, P-2389, P-2390,
    P-2391, P-2392, P-2393, P-2398, P-2400, P-2401, P-2406, P-2419,
    P-2430, P-2431, P-2432, P-2433, P-2434, P-2435, P-2436, P-2438,
    P-2441, P-2443, P-2444, P-2445, P-2446, P-2447, P-2448, P-2449,
    P-2450, P-2451, P-2452, P-2453, P-2454, P-2455, P-2456, P-2457,
    P-2458, P-2459, P-2460, P-2461, P-2464, P-2465, P-2466, P-2468,
    P-2471
  • TABLE 11i
    Compounds with activity toward kinase Src with IC50 ≦ 10 μM.
    Src P-2001, P-2002, P-2003, P-2004, P-2005, P-2006, P-2007, P-2009,
    P-2010, P-2011, P-2014, P-2015, P-2016, P-2017, P-2018, P-2019,
    P-2020, P-2021, P-2022, P-2023, P-2024, P-2025, P-2026, P-2027,
    P-2029, P-2030, P-2031, P-2032, P-2033, P-2034, P-2036, P-2037,
    P-2038, P-2039, P-2040, P-2041, P-2042, P-2043, P-2044, P-2045,
    P-2046, P-2047, P-2051, P-2052, P-2053, P-2054, P-2055, P-2056,
    P-2057, P-2059, P-2060, P-2061, P-2062, P-2063, P-2065, P-2067,
    P-2069, P-2070, P-2071, P-2073, P-2074, P-2075, P-2076, P-2078,
    P-2079, P-2080, P-2087, P-2100, P-2101, P-2102, P-2103, P-2104,
    P-2105, P-2137, P-2138, P-2139, P-2140, P-2142, P-2144, P-2145,
    P-2147, P-2148, P-2149, P-2150, P-2151, P-2153, P-2154, P-2155,
    P-2156, P-2157, P-2158, P-2159, P-2161, P-2162, P-2164, P-2165,
    P-2166, P-2167, P-2168, P-2169, P-2170, P-2171, P-2172, P-2174,
    P-2175, P-2176, P-2177, P-2178, P-2179, P-2180, P-2181, P-2184,
    P-2185, P-2187, P-2190, P-2191, P-2192, P-2193, P-2194, P-2195,
    P-2196, P-2204, P-2209, P-2210, P-2211, P-2213, P-2214, P-2215,
    P-2216, P-2217, P-2219, P-2220, P-2222, P-2223, P-2224, P-2225,
    P-2226, P-2228, P-2229, P-2230, P-2231, P-2232, P-2233, P-2234,
    P-2235, P-2236, P-2237, P-2238, P-2239, P-2240, P-2242, P-2260,
    P-2261, P-2268, P-2270, P-2271, P-2272, P-2273, P-2275, P-2276,
    P-2277, P-2280, P-2284, P-2286, P-2287, P-2290, P-2296, P-2298,
    P-2299, P-2300, P-2301, P-2302, P-2303, P-2304, P-2305, P-2306,
    P-2308, P-2309, P-2310, P-2311, P-2312, P-2313, P-2315, P-2316,
    P-2318, P-2319, P-2321, P-2322, P-2323, P-2324, P-2325, P-2326,
    P-2327, P-2328, P-2329, P-2330, P-2331, P-2332, P-2333, P-2334,
    P-2335, P-2336, P-2337, P-2338, P-2339, P-2340, P-2341, P-2342,
    P-2343, P-2344, P-2345, P-2346, P-2347, P-2350, P-2351, P-2352,
    P-2354, P-2355, P-2356, P-2357, P-2358, P-2359, P-2360, P-2361,
    P-2364, P-2365, P-2367, P-2368, P-2369, P-2371, P-2372, P-2373,
    P-2374, P-2375, P-2376, P-2377, P-2378, P-2379, P-2382, P-2383,
    P-2384, P-2389, P-2390, P-2391, P-2392, P-2393, P-2394, P-2396,
    P-2397, P-2398, P-2399, P-2400, P-2401, P-2402, P-2408, P-2414,
    P-2429, P-2431, P-2432, P-2433, P-2434, P-2444, P-2445, P-2446,
    P-2447, P-2448, P-2457, P-2460, P-2465, P-2466, P-2481
  • TABLE 11j
    Compounds with activity toward kinase TEC with IC50 ≦ 10 μM.
    TEC P-2003, P-2020, P-2021, P-2022, P-2023, P-2024, P-2027, P-2029,
    P-2030, P-2031, P-2040, P-2041, P-2042, P-2043, P-2044, P-2045,
    P-2046, P-2047, P-2051, P-2052, P-2053, P-2054, P-2067, P-2070,
    P-2071, P-2072, P-2079, P-2080, P-2087, P-2099, P-2105, P-2111,
    P-2118, P-2120, P-2129, P-2130, P-2131, P-2132, P-2133, P-2134,
    P-2135, P-2136, P-2138, P-2139, P-2140, P-2142, P-2144, P-2145,
    P-2161, P-2174, P-2177, P-2198, P-2199, P-2207, P-2212, P-2214,
    P-2247, P-2248, P-2250, P-2257, P-2260, P-2261, P-2271, P-2278,
    P-2282, P-2287, P-2292, P-2299, P-2302, P-2306, P-2307, P-2308,
    P-2309, P-2310, P-2312, P-2313, P-2322, P-2323, P-2330, P-2333,
    P-2342, P-2352, P-2353, P-2354, P-2355, P-2356, P-2357, P-2358,
    P-2359, P-2361, P-2371, P-2372, P-2373, P-2376, P-2377, P-2378,
    P-2379, P-2382, P-2383, P-2394, P-2399, P-2400, P-2401, P-2402,
    P-2414, P-2417, P-2430, P-2432, P-2434, P-2440, P-2441, P-2442,
    P-2443, P-2444, P-2445, P-2446, P-2447, P-2448, P-2454, P-2455,
    P-2457, P-2460, P-2461, P-2464, P-2467, P-2468, P-2471
  • TABLE 11k
    Compounds with activity toward kinase TrkA with IC50 ≦ 10 μM.
    TrkA P-2060, P-2061, P-2105, P-2168, P-2174, P-2176, P-2239, P-2240,
    P-2301, P-2302, P-2344, P-2345, P-2407
  • TABLE 11m
    Compounds with activity toward kinase MAP4K4 with IC50 ≦ 10 μM.
    MAP4K4 P-2002, P-2003, P-2008, P-2009, P-2010, P-2011, P-2014,
    P-2015, P-2016, P-2017, P-2018, P-2019, P-2021, P-2022,
    P-2023, P-2024, P-2025, P-2026, P-2029, P-2030, P-2031,
    P-2033, P-2034, P-2036, P-2061, P-2062, P-2063, P-2064,
    P-2065, P-2066, P-2067, P-2069, P-2070, P-2071, P-2074,
    P-2075, P-2076, P-2099, P-2105, P-2137, P-2138, P-2139,
    P-2140, P-2141, P-2142, P-2143, P-2144, P-2145, P-2146,
    P-2147, P-2148, P-2149, P-2176, P-2182, P-2193, P-2199,
    P-2211, P-2214, P-2215, P-2219, P-2220, P-2221, P-2222,
    P-2223, P-2224, P-2226, P-2228, P-2229, P-2230, P-2231,
    P-2232, P-2233, P-2234, P-2235, P-2236, P-2239, P-2240,
    P-2242, P-2244, P-2247, P-2269, P-2270, P-2272, P-2274,
    P-2275, P-2276, P-2277, P-2278, P-2279, P-2288, P-2289,
    P-2290, P-2291, P-2300, P-2301, P-2308, P-2309, P-2310,
    P-2312, P-2315, P-2324, P-2327, P-2328, P-2329, P-2331,
    P-2335, P-2337, P-2338, P-2339, P-2346, P-2347, P-2353,
    P-2354, P-2355, P-2356, P-2357, P-2360, P-2362, P-2366,
    P-2367, P-2375, P-2382, P-2383, P-2407, P-2408, P-2430,
    P-2432, P-2434, P-2443, P-2444, P-2445, P-2446, P-2447,
    P-2448, P-2452, P-2453, P-2457, P-2458, P-2459, P-2460,
    P-2461, P-2462, P-2464, P-2465, P-2466, P-2467
  • TABLE 11n
    Compounds with activity toward kinase Flt1 with IC50 ≦ 10 μM.
    Flt1 P-2099, P-2100, P-2105, P-2150, P-2151, P-2162, P-2193, P-2196,
    P-2199, P-2200, P-2201, P-2203, P-2210, P-2213, P-2214, P-2215,
    P-2216, P-2217, P-2218, P-2299, P-2302, P-2404, P-2430, P-2432,
    P-2434, P-2457
  • TABLE 11o
    Compounds with activity toward kinase PI3Kα with IC50 ≦ 10 μM.
    PI3Kα P-2040, P-2041, P-2042, P-2043, P-2044, P-2045, P-2079, P-2080,
    P-2139, P-2145, P-2147, P-2149, P-2170, P-2174, P-2188, P-2193,
    P-2214, P-2220, P-2234, P-2286, P-2287, P-2295, P-2322, P-2323,
    P-2333, P-2342, P-2371, P-2372, P-2373, P-2399, P-2401, P-2402,
    P-2407
  • TABLE 11p
    Compounds with activity toward kinase PI3Kδ with IC50 ≦ 10 μM.
    PI3Kδ P-2170, P-2188
  • TABLE 11q
    Compounds with activity toward kinase PI3Kγ with IC50 ≦ 10 μM.
    PI3Kγ P-2188, P-2220, P-2407
  • Additional examples of certain methods contemplated by the present invention may be found in the following applications: U.S. Patent Publ. No. 2006/058339, application Ser. No. 11/154,287; U.S. Patent Publ. No. 2006/058340, application Ser. No. 11/154,988; U.S. Prov. App. No. 60/682,076, filed May 17, 2005; U.S. Prov. App. No. 60/682,058, filed May 17, 2005; U.S. Prov. App. No. 60/682,063, filed May 17, 2005; U.S. Prov. App. No. 60/682,051, filed May 17, 2005; U.S. Prov. App. No. 60/682,042, filed May 17, 2005; U.S. Prov. App. No. 60/692,750, filed Jun. 22, 2005; and U.S. Prov. App. No. 60/692,960, filed Jun. 22, 2005; U.S. Prov. App. No. 60/731,528, filed Oct. 28, 2005, U.S. patent application Ser. No. 11/435,381, filed May 16, 2006, and U.S. patent application Ser. No. 11/473,347, filed Jun. 21, 2006, each of which are hereby incorporated by reference herein in their entireties including all specifications, figures, and tables, and for all purposes.
  • All patents and other references cited in the specification are indicative of the level of skill of those skilled in the art to which the invention pertains, and are incorporated by reference in their entireties, including any tables and figures, to the same extent as if each reference had been incorporated by reference in its entirety individually.
  • One skilled in the art would readily appreciate that the present invention is well adapted to obtain the ends and advantages mentioned, as well as those inherent therein. The methods, variances, and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims.
  • It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. For example, variations can be made to crystallization or co-crystallization conditions for Ret and Ret surrogate proteins and/or various kinase domain sequences can be used. Thus, such additional embodiments are within the scope of the present invention and the following claims.
  • The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising”, “consisting essentially of” and “consisting of” may be replaced with either of the other two terms. Thus, for an embodiment of the invention using one of the terms, the invention also includes another embodiment wherein one of these terms is replaced with another of these terms. In each embodiment, the terms have their established meaning. Thus, for example, one embodiment may encompass a method “comprising” a series of steps, another embodiment would encompass a method “consisting essentially of” the same steps, and a third embodiment would encompass a method “consisting of” the same steps. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.
  • In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group.
  • Also, unless indicated to the contrary, where various numerical values are provided for embodiments, additional embodiments are described by taking any 2 different values as the endpoints of a range. Such ranges are also within the scope of the described invention.
  • Thus, additional embodiments are within the scope of the invention and within the following claims.

Claims (26)

1. A solid form of a phenyl sulfonamide compound comprising a basic amino acid and the phenyl sulfonamide compound of Formula I
Figure US20120122860A1-20120517-C01435
wherein:
Ar is heteroaryl;
each R1, when present, is independently selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, —CN, —NO2, —O—R11, —N(R12)—R13, —C(O)—N(R14)—R15, —C(O)—O—R16, —S(O)2—R17, and —N(H)—C(O)—R18, wherein lower alkyl is optionally substituted with one or more R5, lower alkenyl and lower alkynyl are optionally substituted with one or more R6, heterocycloalkyl is optionally substituted with one or more lower alkyl, phenyl is optionally substituted with one or more R7, and heteroaryl is optionally substituted with one or more R8;
m is 0, 1, 2, or 3;
R2 is hydrogen, fluoro or chloro;
R3 is hydrogen, fluoro, chloro, or methyl;
R4 is selected from the group consisting of lower alkyl, fluoro substituted lower alkyl, mono-alkylamino, di-alkylamino, cycloalkylamino, cycloalkyl, phenyl, and heteroaryl, wherein cycloalkyl is optionally substituted with —C(O)OR16, phenyl is optionally substituted with one or more R9, and heteroaryl is optionally substituted with one or more R10;
L is selected from the group consisting of —NH—, —CH2—, —C(OH)H—, —C(O)—, —S(O)2—, —O—CH2—, —CH2—NH—, —NH—CH2—, —C(O)—NH—, and —NH—C(O)—;
each R5, when present, is independently fluoro, —OH, lower alkoxy, heteroaryl, chloro substituted heteroaryl, phenyl, chloro substituted phenyl, mono-alkylamino, di-alkylamino, cycloalkylamino, —C(O)—N(R14)—R19, or —C(O)—O—R16;
each R6, when present, is independently —C(O)—O—R16, lower alkoxy, mono-alkylamino or di-alkylamino;
each R7, when present, is independently fluoro, chloro, —CN, —OH, lower alkyl, lower alkenyl, —C(O)—O—R16 substituted lower alkenyl, lower alkoxy, lower alkoxy substituted lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, —S(O)2R20, —N(H)—S(O)2—R20, —N(H)—C(O)—R20, —C(O)—N(R21)—R22, or —S(O)2—N(R23), —R24, wherein lower alkyl is optionally substituted with —C(O)—O—R16, mono-alkylamino, di-alkylamino, or cycloalkylamino;
each R8, when present, is independently fluoro, chloro, —OH, —NH2, lower alkyl, lower alkynyl, di-alkylamino substituted lower alkynyl, lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkylamino, phenyl, —C(O)—N(R25)—R26, or —N(H)—C(O)—R20, wherein lower alkyl is optionally substituted with one or more fluoro, alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or phenyl, and wherein lower alkoxy is optionally substituted with —OH, lower alkoxy, mono-alkylamino, di-alkylamino or cycloalkylamino;
each R9, when present, is independently fluoro, chloro, —CN, —NO2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, —C(O)—O—R16, —N(H)—C(O)—R20, heteroaryl optionally substituted with one or more lower alkyl, or two R9 on adjacent carbons combine to form a fused heterocycloalkyl optionally substituted with one or more lower alkyl;
each R10, when present, is independently lower alkyl, fluoro substituted lower alkyl, lower alkoxy, —C(O)—O—R16, or heteroaryl optionally substituted with one or more lower alkyl;
each R11, when present, is independently hydrogen, lower alkyl, cycloalkyl, or heterocycloalkyl, wherein lower alkyl is optionally substituted with —OH, lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, phenyl, or heteroaryl;
each R12, R14, and R16, when present, are independently hydrogen or lower alkyl;
each R13, when present, is independently hydrogen, lower alkyl, cycloalkyl, phenyl, heteroaryl or combined with the nitrogen and R12 form cycloalkylamino, wherein lower alkyl is optionally substituted with cycloalkylamino, phenyl, heteroaryl or lower alkyl substituted heteroaryl;
each R15, when present, is independently hydrogen, lower alkyl, —OH substituted lower alkyl, cycloalkyl or lower alkoxy;
each R17, when present, is independently lower alkyl, phenyl or lower alkyl substituted phenyl;
each R18, when present, is independently lower alkyl or cycloalkylamino;
each R19, when present, is independently hydrogen, lower alkyl, or lower alkoxy;
each R20, when present, is independently lower alkyl;
each R21 and R22, when present, are independently hydrogen, lower alkyl, or combine with the nitrogen to form cycloalkylamino;
each R23 and R24, when present, are independently hydrogen, lower alkyl optionally substituted with —OH, cycloalkyl, or combine with the nitrogen to form cycloalkylamino; and
each R25 and R26, when present, are independently hydrogen, lower alkyl, or cycloalkyl.
2. The solid form of claim 1, wherein the sulfonamide compound is a compound of Formula Ia
Figure US20120122860A1-20120517-C01436
wherein:
U and V are C—H, and W is C—R27;
or U and W are C—H, and V is C—R28;
or U is N, V is C—H, and W is C—R27;
or U is N, V is C—R28, and W is C—H;
or U is C—H, V is N, and W is C—R27;
or U is C—H, V is C—R28, and W is N;
L1 is —CH2—, —C(OH)H—, or —C(O)—;
R27 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, —CN, —O—R38, —N(R39)—R40, —C(O)—N(R41)—R42, —C(O)—O—R43, —S(O)2—R44, and —N(H)—C(O)—R45, wherein lower alkyl is optionally substituted with one or more R32, lower alkenyl and lower alkynyl are optionally substituted with one or more R33, heterocycloalkyl is optionally substituted with one or more lower alkyl, phenyl is optionally substituted with one or more R34, and heteroaryl is optionally substituted with one or more R35;
R28 is selected from the group consisting of hydrogen, chloro, methyl, methoxy, —CN, and —C≡CH;
R29 is hydrogen, fluoro or chloro;
R30 is hydrogen, fluoro, chloro, or methyl;
R31 is selected from the group consisting of lower alkyl, fluoro substituted lower alkyl, mono-alkylamino, di-alkylamino, cycloalkylamino, cycloalkyl, phenyl, and heteroaryl, wherein cycloalkyl is optionally substituted with —C(O)OR43, phenyl is optionally substituted with one or more R36, and heteroaryl is optionally substituted with one or more R37;
each R32, when present, is independently fluoro, —OH, lower alkoxy, heteroaryl, chloro substituted heteroaryl, phenyl, chloro substituted phenyl, mono-alkylamino, di-alkylamino, cycloalkylamino, —C(O)—N(R41)—R46, or —C(O)—O—R43;
each R33, when present, is independently —C(O)—O—R43, lower alkoxy, mono-alkylamino or di-alkylamino;
each R34, when present, is independently fluoro, chloro, —CN, —OH, lower alkyl, lower alkenyl, —C(O)—O—R43 substituted lower alkenyl, lower alkoxy, lower alkoxy substituted lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, —S(O)2R47, —N(H)—S(O)2—R47, —N(H)—C(O)—R47, —C(O)—N(R48)—R49, or —S(O)2—N(R50)—R51, wherein lower alkyl is optionally substituted with —C(O)—O—R43, mono-alkylamino, di-alkylamino, or cycloalkylamino;
each R35, when present, is independently fluoro, chloro, —OH, —NH2, lower alkyl, lower alkynyl, di-alkylamino substituted lower alkynyl, lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkylamino, phenyl, —C(O)—N(R52)—R53, or —N(H)—C(O)—R47, wherein lower alkyl is optionally substituted with one or more fluoro, alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or phenyl, and wherein lower alkoxy is optionally substituted with —OH, lower alkoxy, mono-alkylamino, di-alkylamino or cycloalkylamino;
each R36, when present, is independently fluoro, chloro, —CN, —NO2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, —C(O)—O—R43, —N(H)—C(O)—R47, heteroaryl optionally substituted with one or more lower alkyl, or two R36 on adjacent carbons combine to form a fused heterocycloalkyl optionally substituted with one or more lower alkyl;
each R37, when present, is independently lower alkyl, fluoro substituted lower alkyl, lower alkoxy, —C(O)—O—R43, or heteroaryl optionally substituted with one or more lower alkyl;
R38 is hydrogen, lower alkyl, cycloalkyl, or heterocycloalkyl, wherein lower alkyl is optionally substituted with —OH, lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, phenyl, or heteroaryl;
each R39, R41, and R43, when present, are independently hydrogen or lower alkyl;
R40 is hydrogen, lower alkyl, cycloalkyl, phenyl, heteroaryl or combined with the nitrogen and R39 form cycloalkylamino, wherein lower alkyl is optionally substituted with cycloalkylamino, phenyl, heteroaryl or lower alkyl substituted heteroaryl;
R42 is hydrogen, lower alkyl, —OH substituted lower alkyl, cycloalkyl or lower alkoxy;
R44 is lower alkyl, phenyl or lower alkyl substituted phenyl;
R45 is lower alkyl or cycloalkylamino;
each R46, when present, is independently hydrogen, lower alkyl, or lower alkoxy;
each R47, when present, is independently lower alkyl;
each R48 and R49, when present, are independently hydrogen, lower alkyl, or combine with the nitrogen to form cycloalkylamino;
each R50 and R51, when present, are independently hydrogen, lower alkyl optionally substituted with —OH, cycloalkyl, or combine with the nitrogen to form cycloalkylamino; and
each R52 and R53, when present, are independently hydrogen, lower alkyl, or cycloalkyl.
3. The solid form of claim 2, wherein the sulfonamide compound is a compound selected from the group consisting of
Figure US20120122860A1-20120517-C01437
wherein:
R54 is selected from the group consisting of chloro, lower alkyl, phenyl, heteroaryl, —CN, —C≡CH, —O—R62, —N(R63)—R64, —C(O)—N(R65)—R66, —C(O)—O—R67, —S(O)2—R68, and —N(H)—C(O)—R69, wherein lower alkyl is optionally substituted with one or more R57, phenyl is optionally substituted with one or more R58, and heteroaryl is optionally substituted with one or more R59;
R78 is selected from the group consisting of hydrogen, lower alkyl, phenyl, heteroaryl, —CN, —C≡CH, —O—R62, —N(R63)—R64, —C(O)—N(R65)—R66, —C(O)—O—R67, —S(O)2—R68, and —N(H)—C(O)—R69, wherein lower alkyl is optionally substituted with one or more R57, phenyl is optionally substituted with one or more R58, and heteroaryl is optionally substituted with one or more R59;
R79 is selected from the group consisting of chloro, methyl, methoxy, —CN, and —C≡H;
R80 is hydrogen, methyl, methoxy, —CN, or —C≡H;
R55 is hydrogen or fluoro;
R56 is selected from the group consisting of lower alkyl, fluoro substituted lower alkyl, mono-alkylamino, di-alkylamino, cycloalkylamino, cycloalkyl, phenyl, and heteroaryl, wherein phenyl is optionally substituted with one or more R60, and heteroaryl is optionally substituted with one or more R61;
each R57, when present, is independently fluoro, —OH, lower alkoxy, heteroaryl, chloro substituted heteroaryl, phenyl, chloro substituted phenyl, mono-alkylamino, di-alkylamino, cycloalkylamino, —C(O)—N(R65)—R70, or —C(O)—O—R67;
each R58, when present, is independently fluoro, chloro, —CN, —OH, lower alkyl, lower alkenyl, —C(O)—O—R67 substituted lower alkenyl, lower alkoxy, lower alkoxy substituted lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, —S(O)2R71, —N(H)—S(O)2—R71, —N(H)—C(O)—R71, —C(O)—N(R72)—R73, or —S(O)2—N(R74)—R75, wherein lower alkyl is optionally substituted with —C(O)—O—R67, mono-alkylamino, di-alkylamino, or cycloalkylamino;
each R59, when present, is independently fluoro, chloro, —OH, —NH2, lower alkyl, lower alkynyl, di-alkylamino substituted lower alkynyl, lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkylamino, phenyl, —C(O)—N(R76)—R77, or —N(H)—C(O)—R71, wherein lower alkyl is optionally substituted with one or more fluoro, alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or phenyl, and wherein lower alkoxy is optionally substituted with —OH, lower alkoxy, mono-alkylamino, di-alkylamino or cycloalkylamino;
each R60, when present, is independently fluoro, chloro, —CN, —NO2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, —C(O)—O—R67, —N(H)—C(O)—R71, heteroaryl optionally substituted with one or more lower alkyl, or two R60 on adjacent carbons combine to form a fused heterocycloalkyl optionally substituted with one or more lower alkyl;
each R61, when present, is independently lower alkyl, fluoro substituted lower alkyl, lower alkoxy, —C(O)—O—R67, or heteroaryl optionally substituted with one or more lower alkyl;
R62 is hydrogen, lower alkyl, cycloalkyl, or heterocycloalkyl, wherein lower alkyl is optionally substituted with —OH, lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, phenyl, or heteroaryl;
each R63, R65, and R67, when present, are independently hydrogen or lower alkyl;
R64 is hydrogen, lower alkyl, cycloalkyl, phenyl, heteroaryl or combined with the nitrogen and R63 form cycloalkylamino, wherein lower alkyl is optionally substituted with cycloalkylamino, phenyl, heteroaryl or lower alkyl substituted heteroaryl;
R66 is hydrogen, lower alkyl, —OH substituted lower alkyl, cycloalkyl or lower alkoxy;
R68 is lower alkyl, phenyl or lower alkyl substituted phenyl;
R69 is lower alkyl or cycloalkylamino;
each R70, when present, is independently hydrogen, lower alkyl, or lower alkoxy;
each R71, when present, is independently lower alkyl;
each R72 and R73, when present, are independently hydrogen, lower alkyl, or combine with the nitrogen to form cycloalkylamino;
each R74 and R75, when present, are independently hydrogen, lower alkyl optionally substituted with —OH, cycloalkyl, or combine with the nitrogen to form cycloalkylamino; and
each R76 and R77, when present, are independently hydrogen, lower alkyl, or cycloalkyl.
4. The solid form of claim 3, wherein the basic amino acid is L-lysine or L-arginine
5. The solid form of claim 3, wherein the solid form is an amorphous complex.
6. The solid form of claim 5, wherein R56 is lower alkyl, di-alkylamino, cycloalkylamino, or phenyl substituted with one or more fluoro, lower alkyl, or fluoro substituted lower alkyl.
7. The solid form of claim 6, wherein R56 is n-propyl, di-methylamino, pyrrolidin-1-yl, 3-fluoro phenyl, or 2,5-di-fluoro phenyl.
8. The solid form of claim 7, wherein the compound is propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide and the basic amino acid is L-lysine or L-arginine.
9. (canceled)
10. The solid form of claim 7, wherein the compound is propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide and the basic amino acid is L-lysine or L-arginine.
11. (canceled)
12. The solid form of claim 6, wherein R56 is 4-t-butyl phenyl, 3-trifluoromethyl phenyl or 4-trifluoromethyl phenyl.
13. The solid form of claim 12, wherein the compound is N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide and the basic amino acid is L-lysine or L-arginine.
14. (canceled)
15. The solid form of claim 12, wherein the compound is N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide and the basic amino acid is L-lysine or L-arginine.
16. (canceled)
17. A composition comprising the solid form of claim 1 and one or more pharmaceutically acceptable excipients.
18. A method of making an amorphous complex comprising propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide and, said method comprising contacting crystalline polymorph Form 1 of propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide with an amino acid selected from L-lysine or L-arginine under conditions sufficient for the preparation of said complex.
19. (canceled)
20. A method of making an amorphous complex comprising propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide and L-lysine, said method comprising contacting crystalline polymorph Form 2 of propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide with an amino acid selected from L-lysine or L-arginine under conditions sufficient for the preparation of said complex.
21. (canceled)
22. A composition comprising the solid form of claim 8 and one or more pharmaceutically acceptable excipients.
23. A composition comprising the solid form of claim 10 and one or more pharmaceutically acceptable excipients.
24. A composition comprising the solid form of claim 12 and one or more pharmaceutically acceptable excipients.
25. A composition comprising the solid form of claim 13 and one or more pharmaceutically acceptable excipients.
26. A composition comprising the solid form of claim 15 and one or more pharmaceutically acceptable excipients.
US13/318,760 2009-05-06 2010-05-04 Solid forms of sulfonamides and amino acids Abandoned US20120122860A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/318,760 US20120122860A1 (en) 2009-05-06 2010-05-04 Solid forms of sulfonamides and amino acids

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US17605409P 2009-05-06 2009-05-06
PCT/US2010/033576 WO2010129570A1 (en) 2009-05-06 2010-05-04 Solid forms of sulfonamides and amino acids
US13/318,760 US20120122860A1 (en) 2009-05-06 2010-05-04 Solid forms of sulfonamides and amino acids

Publications (1)

Publication Number Publication Date
US20120122860A1 true US20120122860A1 (en) 2012-05-17

Family

ID=42236712

Family Applications (3)

Application Number Title Priority Date Filing Date
US13/318,760 Abandoned US20120122860A1 (en) 2009-05-06 2010-05-04 Solid forms of sulfonamides and amino acids
US12/773,798 Active US8198273B2 (en) 2009-05-06 2010-05-04 Compounds and methods for kinase modulation, and indications therefor
US13/491,480 Abandoned US20120245174A1 (en) 2009-05-06 2012-06-07 Compounds and methods for kinase modulation, and indications therefor

Family Applications After (2)

Application Number Title Priority Date Filing Date
US12/773,798 Active US8198273B2 (en) 2009-05-06 2010-05-04 Compounds and methods for kinase modulation, and indications therefor
US13/491,480 Abandoned US20120245174A1 (en) 2009-05-06 2012-06-07 Compounds and methods for kinase modulation, and indications therefor

Country Status (23)

Country Link
US (3) US20120122860A1 (en)
EP (2) EP2427462A1 (en)
JP (2) JP2012526128A (en)
KR (1) KR20140014386A (en)
CN (1) CN102459262A (en)
AR (1) AR076749A1 (en)
AU (1) AU2010246005A1 (en)
BR (1) BRPI1013843A2 (en)
CA (1) CA2759997A1 (en)
CL (1) CL2011002739A1 (en)
CR (1) CR20110562A (en)
EC (1) ECSP11011437A (en)
IL (1) IL215908A0 (en)
MA (1) MA34042B1 (en)
MX (1) MX2011011737A (en)
NI (1) NI201100189A (en)
NO (1) NO20111508A1 (en)
PE (1) PE20120518A1 (en)
RU (1) RU2011149485A (en)
SG (1) SG175810A1 (en)
TW (1) TW201041888A (en)
WO (2) WO2010129570A1 (en)
ZA (1) ZA201108124B (en)

Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140094611A1 (en) * 2012-05-31 2014-04-03 Plexxikon Inc. Synthesis of heterocyclic compounds
US8741920B2 (en) 2009-08-03 2014-06-03 Hoffmann-La Roche, Inc. Process for the manufacture of pharmaceutically active compounds
US9249110B2 (en) 2011-09-21 2016-02-02 Neupharma, Inc. Substituted quinoxalines as B-raf kinase inhibitors
US9249111B2 (en) 2011-09-30 2016-02-02 Neupharma, Inc. Substituted quinoxalines as B-RAF kinase inhibitors
US9260437B2 (en) 2008-05-19 2016-02-16 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9295671B2 (en) 2011-08-26 2016-03-29 Neupharma, Inc. Benzenesulfonamide derivatives of quinoxaline, pharmaceutical compositions thereof, and their use in methods for treating cancer
US9358235B2 (en) 2012-03-19 2016-06-07 Plexxikon Inc. Kinase modulation, and indications therefor
US9399639B2 (en) 2012-08-27 2016-07-26 Calitor Sciences, Llc Substituted azaindole compounds, salts, pharmaceutical compositions thereof and methods of use
US9440969B2 (en) 2009-12-23 2016-09-13 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9469640B2 (en) 2007-07-17 2016-10-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9487515B2 (en) 2006-11-22 2016-11-08 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US9518029B2 (en) 2011-09-14 2016-12-13 Neupharma, Inc. Certain chemical entities, compositions, and methods
US9550768B2 (en) 2011-05-17 2017-01-24 Plexxikon Inc. Kinase modulation and indications therefor
US9617267B2 (en) 2009-11-18 2017-04-11 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9670180B2 (en) 2012-01-25 2017-06-06 Neupharma, Inc. Certain chemical entities, compositions, and methods
US9676748B2 (en) 2012-12-21 2017-06-13 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9682981B2 (en) 2010-04-21 2017-06-20 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9688635B2 (en) 2012-09-24 2017-06-27 Neupharma, Inc. Certain chemical entities, compositions, and methods
US9718847B2 (en) 2013-03-15 2017-08-01 Plexxikon Inc. Heterocyclic compounds and uses thereof
US9725421B2 (en) 2012-11-12 2017-08-08 Neupharma, Inc. Substituted quinoxalines as B-raf kinase inhibitors
US9771363B2 (en) 2015-09-21 2017-09-26 Plexxikon Inc. Heterocyclic compounds and uses thereof
US9771369B2 (en) 2014-03-04 2017-09-26 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9822109B2 (en) 2013-03-15 2017-11-21 Plexxikon Inc. Heterocyclic compounds and uses thereof
WO2017218544A1 (en) * 2016-06-13 2017-12-21 Chemocentryx, Inc. Methods of treating pancreatic cancer
US9856259B2 (en) 2014-09-15 2018-01-02 Plexxikon Inc. Heterocyclic compounds and uses thereof
US9873700B2 (en) 2013-05-30 2018-01-23 Plexxikon Inc. Compounds for kinase modulation, and indications therefor
US9938273B2 (en) 2015-12-07 2018-04-10 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10160755B2 (en) 2015-04-08 2018-12-25 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10160747B2 (en) 2016-03-16 2018-12-25 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10227357B2 (en) 2012-09-06 2019-03-12 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10428067B2 (en) 2017-06-07 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation
US10435404B2 (en) 2017-07-25 2019-10-08 Plexxikon Inc. Formulations of a compound modulating kinases
US10508085B2 (en) 2016-09-22 2019-12-17 Plexxikon Inc. Compounds and methods for IDO and TDO modulation, and indications therefor
US10577366B2 (en) 2017-03-20 2020-03-03 Plexxikon Inc. Crystalline forms of a compound that inhibits bromodomain
US10703757B2 (en) 2016-12-23 2020-07-07 Plexxikon Inc. Compounds and methods for CDK8 modulation and indications therefor
US10717735B2 (en) 2017-10-13 2020-07-21 Plexxikon Inc. Solid forms of a compound for modulating kinases
US10758540B2 (en) 2017-10-11 2020-09-01 Chemocentryx, Inc. Treatment of focal segmental glomerulosclerosis with CCR2 antagonists
US10829484B2 (en) 2015-07-28 2020-11-10 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10973809B2 (en) 2016-11-23 2021-04-13 Chemocentryx, Inc. Method of treating focal segmental glomerulosclerosis
US11103505B2 (en) 2017-10-27 2021-08-31 Plexxikon Inc. Formulations of a compound modulating kinases
US11116756B2 (en) 2016-06-13 2021-09-14 Chemocentryx, Inc. Methods of treating pancreatic cancer
US11149011B2 (en) 2018-03-20 2021-10-19 Plexxikon Inc. Compounds and methods for IDO and TDO modulation, and indications therefor

Families Citing this family (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3088400A1 (en) * 2005-06-22 2016-11-02 Plexxikon Inc. Pyrrolo[2,3-b]pyridine derivatives as protein kinase inhibitors
EA031116B1 (en) 2009-04-03 2018-11-30 Ф. Хоффманн-Ля Рош Аг PROPANE-1-SULFONIC ACID {3-[5-(4-CHLORO-PHENYL)-1H-PYRROLO[2,3-b]PYRIDINE-3-CARBONYL]-2,4-DIFLUORO-PHENYL}AMIDE CRYSTALLINE POLYMORPH FORMS
MX2012005284A (en) 2009-11-06 2012-06-28 Plexxikon Inc Compounds and methods for kinase modulation, and indications therefor.
GB201007286D0 (en) 2010-04-30 2010-06-16 Astex Therapeutics Ltd New compounds
GB201020179D0 (en) 2010-11-29 2011-01-12 Astex Therapeutics Ltd New compounds
US20140005160A1 (en) * 2010-12-01 2014-01-02 Hooshmand SHESHBARADARAN Method for Treating Refractory Cancer
US8889684B2 (en) * 2011-02-02 2014-11-18 Boehringer Ingelheim International Gmbh Azaindolylphenyl sulfonamides as serine/threonine kinase inhibitors
TWI558702B (en) * 2011-02-21 2016-11-21 普雷辛肯公司 Solid forms of a pharmaceutically active substance
ES2699965T3 (en) 2011-03-10 2019-02-13 Provectus Pharmatech Inc A combination of rose bengal and anti-CTLA4 antibody for use in the treatment of cancer
WO2012138809A1 (en) * 2011-04-05 2012-10-11 Dawei Zhang Heterocyclic compounds as kinase inhibitors
EP2670866A4 (en) * 2011-04-05 2015-09-02 Translational Genomics Res Inst Biomarkers and methods of use thereof
CN102993199A (en) * 2011-09-09 2013-03-27 山东轩竹医药科技有限公司 Heterocycle substituted pyrido-pyrrole kinase inhibitor
GB201118675D0 (en) 2011-10-28 2011-12-14 Astex Therapeutics Ltd New compounds
GB201118652D0 (en) 2011-10-28 2011-12-07 Astex Therapeutics Ltd New compounds
GB201118654D0 (en) 2011-10-28 2011-12-07 Astex Therapeutics Ltd New compounds
GB201118656D0 (en) 2011-10-28 2011-12-07 Astex Therapeutics Ltd New compounds
JP6013029B2 (en) * 2012-05-25 2016-10-25 千葉県 Anticancer drug
GB201209609D0 (en) 2012-05-30 2012-07-11 Astex Therapeutics Ltd New compounds
GB201209613D0 (en) 2012-05-30 2012-07-11 Astex Therapeutics Ltd New compounds
JO3407B1 (en) 2012-05-31 2019-10-20 Eisai R&D Man Co Ltd Tetrahydropyrazolopyrimidine Compounds
JP2015522037A (en) * 2012-07-03 2015-08-03 ラシオファルム ゲーエムベーハー Solid form of Vemurafenib choline salt
DE102012016908A1 (en) * 2012-08-17 2014-02-20 Aicuris Gmbh & Co. Kg Tris (hetero) aryl-pyrazoles and their use
CN103613591B (en) * 2012-09-29 2016-04-13 上海科州药物研发有限公司 As the compound and its production and use of cMet inhibitor
CN104853754A (en) 2012-11-20 2015-08-19 普林斯匹亚生物制药公司 Azaindole derivatives as jak3 inhibitors
JP6199991B2 (en) 2013-01-18 2017-09-20 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Trisubstituted pyrazoles and use as DLK inhibitors
CN105008356A (en) * 2013-03-14 2015-10-28 拉蒂奥法姆有限责任公司 Solid state forms of vemurafenib hydrochloride
GB201307577D0 (en) 2013-04-26 2013-06-12 Astex Therapeutics Ltd New compounds
WO2015075749A1 (en) * 2013-11-22 2015-05-28 Laurus Labs Private Limited Novel processes for the preparation of vemurafenib
CZ2013943A3 (en) 2013-11-27 2015-06-03 Zentiva, K.S. Vemurafenib crystalline forms
RU2715236C2 (en) 2014-03-26 2020-02-26 Астекс Терапьютикс Лтд Combinations
JO3512B1 (en) 2014-03-26 2020-07-05 Astex Therapeutics Ltd Quinoxaline derivatives useful as fgfr kinase modulators
EP3122359B1 (en) 2014-03-26 2020-12-16 Astex Therapeutics Ltd. Combinations of an fgfr inhibitor and an igf1r inhibitor
NO2714752T3 (en) * 2014-05-08 2018-04-21
JOP20200201A1 (en) 2015-02-10 2017-06-16 Astex Therapeutics Ltd Pharmaceutical compositions comprising n-(3,5-dimethoxyphenyl)-n'-(1-methylethyl)-n-[3-(1-methyl-1h-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine
US10478494B2 (en) 2015-04-03 2019-11-19 Astex Therapeutics Ltd FGFR/PD-1 combination therapy for the treatment of cancer
CZ2015250A3 (en) 2015-04-14 2016-10-26 Zentiva, K.S. Vemurafenib amorphous forms
GB201516504D0 (en) 2015-09-17 2015-11-04 Astrazeneca Ab Imadazo(4,5-c)quinolin-2-one Compounds and their use in treating cancer
RU2747644C2 (en) 2015-09-23 2021-05-11 Янссен Фармацевтика Нв Bigeteroaryl-substituted 1,4-benzodiazepines and ways of their use for cancer treatment
AU2016328692B2 (en) 2015-09-23 2021-03-11 Janssen Pharmaceutica Nv New compounds
CN107722013B (en) * 2016-08-11 2021-01-12 中国科学院上海药物研究所 Deazapurine compounds, pharmaceutical compositions, preparation method and uses thereof
ES2928773T3 (en) * 2017-01-17 2022-11-22 Heparegenix Gmbh Protein kinase inhibitors to promote liver regeneration or reduce or prevent hepatocyte death
WO2019139869A1 (en) 2018-01-10 2019-07-18 Cura Therapeutics Llc Pharmaceutical compositions comprising phenylsulfonamides, and their therapeutic applications
CN111788195B (en) 2018-01-31 2023-11-21 海帕瑞吉尼克斯股份有限公司 Protein kinase MKK4 inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US11731968B2 (en) 2018-06-21 2023-08-22 Heparegenix Gmbh Tricyclic protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US11912701B2 (en) 2018-07-16 2024-02-27 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007002325A1 (en) * 2005-06-22 2007-01-04 Plexxikon, Inc. Pyrrolo[2,3-b] pyridine derivatives as protein kinase inhibitors

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2497792C (en) * 2002-09-06 2014-08-05 Insert Therapeutics, Inc. Cyclodextrin-based polymers for therapeutics delivery
DE102005034406A1 (en) 2005-07-22 2007-02-01 Ratiopharm Gmbh New salts of rosiglitazone
WO2008063888A2 (en) 2006-11-22 2008-05-29 Plexxikon, Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
GB0624084D0 (en) * 2006-12-01 2007-01-10 Selamine Ltd Ramipril amino acid salts
PE20121126A1 (en) * 2006-12-21 2012-08-24 Plexxikon Inc PIRROLO [2,3-B] PYRIDINES COMPOUNDS AS KINASE MODULATORS
WO2008079909A1 (en) * 2006-12-21 2008-07-03 Plexxikon, Inc. Pyrrolo [2,3-b] pyridines as kinase modulators
NZ582772A (en) * 2007-07-17 2012-06-29 Plexxikon Inc Compounds and methods for kinase modulation, and indications therefor

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007002325A1 (en) * 2005-06-22 2007-01-04 Plexxikon, Inc. Pyrrolo[2,3-b] pyridine derivatives as protein kinase inhibitors

Cited By (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9487515B2 (en) 2006-11-22 2016-11-08 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US10426760B2 (en) 2007-07-17 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9844539B2 (en) 2007-07-17 2017-12-19 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9469640B2 (en) 2007-07-17 2016-10-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9260437B2 (en) 2008-05-19 2016-02-16 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US8741920B2 (en) 2009-08-03 2014-06-03 Hoffmann-La Roche, Inc. Process for the manufacture of pharmaceutically active compounds
US9617267B2 (en) 2009-11-18 2017-04-11 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9440969B2 (en) 2009-12-23 2016-09-13 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9682981B2 (en) 2010-04-21 2017-06-20 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US11337976B2 (en) 2011-02-07 2022-05-24 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9550768B2 (en) 2011-05-17 2017-01-24 Plexxikon Inc. Kinase modulation and indications therefor
US9295671B2 (en) 2011-08-26 2016-03-29 Neupharma, Inc. Benzenesulfonamide derivatives of quinoxaline, pharmaceutical compositions thereof, and their use in methods for treating cancer
US9572808B2 (en) 2011-08-26 2017-02-21 Neupharma, Inc. Benzenesulfonamide derivatives of quinoxaline, pharmaceutical compositions thereof, and their use in methods for treating cancer
US10137125B2 (en) 2011-08-26 2018-11-27 Neupharma, Inc. Benzenesulfonamide derivatives of quinoxaline, pharmaceutical compositions thereof, and their use in methods for treating cancer
US10561652B2 (en) 2011-08-26 2020-02-18 Neupharma, Inc. Benzenesulfonamide derivatives of quinoxaline, pharmaceutical compositions thereof, and their use in methods for treating cancer
US9518029B2 (en) 2011-09-14 2016-12-13 Neupharma, Inc. Certain chemical entities, compositions, and methods
US10065932B2 (en) 2011-09-14 2018-09-04 Neupharma, Inc. Certain chemical entities, compositions, and methods
US10759766B2 (en) 2011-09-14 2020-09-01 Neupharma, Inc. Certain chemical entities, compositions, and methods
US9822081B2 (en) 2011-09-14 2017-11-21 Neupharma, Inc. Certain chemical entities, compositions, and methods
US9249110B2 (en) 2011-09-21 2016-02-02 Neupharma, Inc. Substituted quinoxalines as B-raf kinase inhibitors
US9249111B2 (en) 2011-09-30 2016-02-02 Neupharma, Inc. Substituted quinoxalines as B-RAF kinase inhibitors
US9670180B2 (en) 2012-01-25 2017-06-06 Neupharma, Inc. Certain chemical entities, compositions, and methods
US10590106B2 (en) 2012-01-25 2020-03-17 Neupharma, Inc. Certain chemical entities, compositions, and methods
US9908866B2 (en) 2012-01-25 2018-03-06 Neupharma, Inc. Certain chemical entities, compositions, and methods
US9730918B2 (en) 2012-03-19 2017-08-15 Plexxikon Inc. Kinase modulation, and indications therefor
US9358235B2 (en) 2012-03-19 2016-06-07 Plexxikon Inc. Kinase modulation, and indications therefor
US10123998B2 (en) 2012-03-19 2018-11-13 Plexxikon Inc. Kinase modulation, and indications therefor
US20140094611A1 (en) * 2012-05-31 2014-04-03 Plexxikon Inc. Synthesis of heterocyclic compounds
US9695169B2 (en) 2012-05-31 2017-07-04 Plexxikon Inc. Synthesis of heterocyclic compounds
US9150570B2 (en) * 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
US9399639B2 (en) 2012-08-27 2016-07-26 Calitor Sciences, Llc Substituted azaindole compounds, salts, pharmaceutical compositions thereof and methods of use
US10227357B2 (en) 2012-09-06 2019-03-12 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10457641B2 (en) 2012-09-24 2019-10-29 Neupharma, Inc. Certain chemical entities, compositions, and methods
US9688635B2 (en) 2012-09-24 2017-06-27 Neupharma, Inc. Certain chemical entities, compositions, and methods
US10047059B2 (en) 2012-11-12 2018-08-14 Neupharma, Inc. Substituted quinoxalines for inhibiting kinase activity
US9725421B2 (en) 2012-11-12 2017-08-08 Neupharma, Inc. Substituted quinoxalines as B-raf kinase inhibitors
US9676748B2 (en) 2012-12-21 2017-06-13 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10301280B2 (en) 2012-12-21 2019-05-28 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9718847B2 (en) 2013-03-15 2017-08-01 Plexxikon Inc. Heterocyclic compounds and uses thereof
US9822109B2 (en) 2013-03-15 2017-11-21 Plexxikon Inc. Heterocyclic compounds and uses thereof
US9873700B2 (en) 2013-05-30 2018-01-23 Plexxikon Inc. Compounds for kinase modulation, and indications therefor
US10421761B2 (en) 2013-05-30 2019-09-24 Plexxikon Inc. Compounds for kinase modulation, and indications therefor
US9771369B2 (en) 2014-03-04 2017-09-26 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9856259B2 (en) 2014-09-15 2018-01-02 Plexxikon Inc. Heterocyclic compounds and uses thereof
US10160755B2 (en) 2015-04-08 2018-12-25 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10829484B2 (en) 2015-07-28 2020-11-10 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10899761B2 (en) 2015-09-21 2021-01-26 Plexxikon Inc. Heterocyclic compounds and uses thereof
US10647716B2 (en) 2015-09-21 2020-05-12 Plexxikon Inc. Heterocyclic compounds and uses thereof
US9771363B2 (en) 2015-09-21 2017-09-26 Plexxikon Inc. Heterocyclic compounds and uses thereof
US10370374B2 (en) 2015-09-21 2019-08-06 Plexxikon Inc. Heterocyclic compounds and uses thereof
US9975894B2 (en) 2015-09-21 2018-05-22 Plexxikon Inc. Heterocyclic compounds and uses thereof
US9938273B2 (en) 2015-12-07 2018-04-10 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10160747B2 (en) 2016-03-16 2018-12-25 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
WO2017218544A1 (en) * 2016-06-13 2017-12-21 Chemocentryx, Inc. Methods of treating pancreatic cancer
CN109562086A (en) * 2016-06-13 2019-04-02 坎莫森特里克斯公司 The method for treating cancer of pancreas
RU2768479C2 (en) * 2016-06-13 2022-03-24 Хемоцентрикс, Инк. Methods for treating pancreatic cancer
US11890276B2 (en) 2016-06-13 2024-02-06 Chemocentryx, Inc. Methods of treating pancreatic cancer
US11116756B2 (en) 2016-06-13 2021-09-14 Chemocentryx, Inc. Methods of treating pancreatic cancer
US10508085B2 (en) 2016-09-22 2019-12-17 Plexxikon Inc. Compounds and methods for IDO and TDO modulation, and indications therefor
US10973809B2 (en) 2016-11-23 2021-04-13 Chemocentryx, Inc. Method of treating focal segmental glomerulosclerosis
US10703757B2 (en) 2016-12-23 2020-07-07 Plexxikon Inc. Compounds and methods for CDK8 modulation and indications therefor
US10577366B2 (en) 2017-03-20 2020-03-03 Plexxikon Inc. Crystalline forms of a compound that inhibits bromodomain
US10428067B2 (en) 2017-06-07 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation
US10961240B2 (en) 2017-07-25 2021-03-30 Plexxikon Inc. Formulations of a compound modulating kinases
US10941142B2 (en) 2017-07-25 2021-03-09 Plexxikon Inc. Formulations of a compound modulating kinases
US10435404B2 (en) 2017-07-25 2019-10-08 Plexxikon Inc. Formulations of a compound modulating kinases
US10758540B2 (en) 2017-10-11 2020-09-01 Chemocentryx, Inc. Treatment of focal segmental glomerulosclerosis with CCR2 antagonists
US10717735B2 (en) 2017-10-13 2020-07-21 Plexxikon Inc. Solid forms of a compound for modulating kinases
US11103505B2 (en) 2017-10-27 2021-08-31 Plexxikon Inc. Formulations of a compound modulating kinases
US11149011B2 (en) 2018-03-20 2021-10-19 Plexxikon Inc. Compounds and methods for IDO and TDO modulation, and indications therefor

Also Published As

Publication number Publication date
WO2010129570A1 (en) 2010-11-11
AU2010246005A1 (en) 2011-12-01
ECSP11011437A (en) 2011-12-30
US20120245174A1 (en) 2012-09-27
WO2010129567A1 (en) 2010-11-11
EP2427433A1 (en) 2012-03-14
JP2012526127A (en) 2012-10-25
RU2011149485A (en) 2013-06-20
CL2011002739A1 (en) 2012-04-09
CN102459262A (en) 2012-05-16
US20100286142A1 (en) 2010-11-11
IL215908A0 (en) 2012-01-31
TW201041888A (en) 2010-12-01
MA34042B1 (en) 2013-03-05
AR076749A1 (en) 2011-07-06
BRPI1013843A2 (en) 2016-04-12
CR20110562A (en) 2012-02-09
SG175810A1 (en) 2011-12-29
KR20140014386A (en) 2014-02-06
MX2011011737A (en) 2011-12-08
PE20120518A1 (en) 2012-05-24
ZA201108124B (en) 2014-04-30
NI201100189A (en) 2012-01-11
CA2759997A1 (en) 2010-11-11
EP2427462A1 (en) 2012-03-14
JP2012526128A (en) 2012-10-25
NO20111508A1 (en) 2011-12-02
US8198273B2 (en) 2012-06-12

Similar Documents

Publication Publication Date Title
US10426760B2 (en) Compounds and methods for kinase modulation, and indications therefor
US20120122860A1 (en) Solid forms of sulfonamides and amino acids
US8153641B2 (en) Compounds and methods for kinase modulation, and indications therefor
US8110576B2 (en) Substituted pyrrolo[2,3b]pyrazines and methods for treatment of raf protein kinase-mediated indications
US9260437B2 (en) Compounds and methods for kinase modulation, and indications therefor
US8901301B2 (en) Pyrrolo[2,3-]pyridine kinase inhibitors
US9617267B2 (en) Compounds and methods for kinase modulation, and indications therefor
US8119637B2 (en) Substituted pyrrolo[2,3-b]pyrazines and methods for kinase modulation, and indications therefor
WO2010111527A1 (en) Pyrazolo [ 3, 4 -b] pyridines as kinase inhibitors and their medical use

Legal Events

Date Code Title Description
AS Assignment

Owner name: PLEXXIKON INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:IBRAHIM, PRABHA N.;SPEVAK, WAYNE;CHO, HANNA;AND OTHERS;REEL/FRAME:032297/0177

Effective date: 20100712

Owner name: PLEXXIKON INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:VISOR, GARY;REEL/FRAME:032297/0204

Effective date: 20111024

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION