US20070173483A1 - Pyrrolopyrimidines and Related Analogs as HSP90-Inhibitors - Google Patents

Pyrrolopyrimidines and Related Analogs as HSP90-Inhibitors Download PDF

Info

Publication number
US20070173483A1
US20070173483A1 US11/531,218 US53121806A US2007173483A1 US 20070173483 A1 US20070173483 A1 US 20070173483A1 US 53121806 A US53121806 A US 53121806A US 2007173483 A1 US2007173483 A1 US 2007173483A1
Authority
US
United States
Prior art keywords
dimethyl
aryl
heteroaryl
group
chloro
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
US11/531,218
Inventor
Srinivas Kasibhatla
Jiandong Shi
Jean-Yves Le Brazidec
Marco Biamonte
Kevin Hong
Marcus Boehm
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.)
Conforma Therapeutics Corp
Original Assignee
Conforma Therapeutics Corp
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
Priority claimed from PCT/US2002/035069 external-priority patent/WO2003037860A2/en
Application filed by Conforma Therapeutics Corp filed Critical Conforma Therapeutics Corp
Priority to US11/531,218 priority Critical patent/US20070173483A1/en
Publication of US20070173483A1 publication Critical patent/US20070173483A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/24—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one nitrogen and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom

Abstract

Pyrrolopyrimidines and related analogs are described and demonstrated to have utility as Heat Shock Protein 90 (HSP90) inhibiting agents used in the treatment and prevention of various HSP90 mediated disorders, e.g., proliferative disorders. Methods of synthesis and use of such compounds are also described and claimed.

Description

  • This application relates and claims priority to U.S. application Ser. No. 10/945,851 filed Sep. 20, 2004 and U.S. Provisional Application Ser. No. 60/504,135, filed Sep. 18, 2003, and U.S. Provisional Application Ser. No. 60/591,467, filed Jul. 26, 2004. This application also relates to three other U.S. Utility Applications Ser. No. 10/946,645 filed Sep 20, 2004 (now Publication No. 20050113340; 10/946,637 filed Sep. 20, 2004 (now Publication No. 2005-119282) and 10/946,628 filed Sep. 20, 2004 (now Publication No. This application further relates to International Application PCT/US02/35069, filed Oct. 30, 2002 (now Publication No. WO03/37860. All the above cited U.S. utility applications, provisional applications and international application are expressly incorporated herein by reference in their entirety.
    • FIELD OF THE INVENTION
  • The invention relates in general to pyrrolopyrimidines and their broad-spectrum utility, e.g., in inhibiting heat shock protein 90 (HSP90) to thereby treat or prevent HSP90-mediated diseases.
    • BACKGROUND
  • HSP90s are ubiquitous chaperone proteins that are involved in folding, activation and assembly of a wide range of proteins, including key proteins involved in signal transduction, cell cycle control and transcriptional regulation. Researchers have reported that HSP90 chaperone proteins are associated with important signaling proteins, such as steroid hormone receptors and protein kinases, including, e.g., Raf-1, EGFR, v-Src family kinases, Cdk4, and ErbB-2 (Buchner J. TIBS 1999, 24, 136-141; Stepanova, L. et al. Genes Dev. 1996, 10, 1491-502; Dai, K. et al. J. Biol. Chem. 1996, 271, 22030-4). Studies further indicate that certain co-chaperones, e.g., HSP70, p60/Hop/Sti1, Hip, Bag1, HSP40/Hdj2/Hsj1, immunophilins, p23, and p50, may assist HSP90 in its function (see, e.g., Caplan, A. Trends in Cell Biol. 1999, 9, 262-68).
  • Ansamycin antibiotics, e.g., herbimycin A (HA), geldanamycin (GM), and 17-allylamninogeldanamycin (17-AAG) are thought to exert their anticancerous effects by tight binding of the N-terminus pocket of HSP90, thereby destabilizing substrates that normally interact with HSP90 (Stebbins, C. et al. Cell 1997, 89, 239-250). This pocket is highly conserved and has weak homology to the ATP-binding site of DNA gyrase (Stebbins, C. et al., supra; Grenert, J. P. et al. J. Biol. Chem. 1997, 272, 23843-50). Further, ATP and ADP have both been shown to bind this pocket with low affinity and to have weak ATPase activity (Proromou, C. et al. Cell 1997, 90, 65-75; Panaretou, B. et al. EMBO J. 1998, 17, 4829-36). In vitro and in vivo studies have demonstrated that occupancy of this N-terminal pocket by ansamycins and other HSP90 inhibitors alters HSP90 function and inhibits protein folding. At high concentrations, ansamycins and other HSP90 inhibitors have been shown to prevent binding of protein substrates to HSP90 (Scheibel, T. H. et al. Proc. Natl. Acad. Sci. USA 1999, 96, 1297-302; Schulte, T. W. et al. J. Biol. Chem. 1995, 270, 24585-8; Whitesell, L., et al. Proc. Natl. Acad. Sci. USA 1994, 91, 8324-8328). Ansamycins have also been demonstrated to inhibit the ATP-dependent release of chaperone-associated protein substrates (Schneider, C. L. et al. Proc. Natl. Acad. Sci., USA 1996, 93, 14536-41; Sepp-Lorenzino et al. J. Biol. Chem. 1995, 270, 16580-16587). In either event, the substrates are degraded by a ubiquitin-dependent process in the proteasome (Schneider, C. L., supra; Sepp-Lorenzino, L., et al. J. Biol. Chem. 1995, 270, 16580-16587; Whitesell, L. et al. Proc. Natl. Acad. Sci. USA 1994, 91, 8324-8328).
  • HSP90 substrate destabilization occurs in tumor and non-transformed cells alike and has been shown to be especially effective on a subset of signaling regulators, e.g., Raf (Schulte, T. W. et al. Biochem. Biophys. Res. Commun. 1997, 239, 655-9; Schulte, T. W., et al. J. Biol. Chem. 1995, 270, 24585-8), nuclear steroid receptors (Segnitz, B.; U. Gehring J. Biol. Chem. 1997, 272, 18694-18701; Smith, D. F. et al. Mol. Cell. Biol. 1995, 15, 6804-12), v-Src (Whitesell, L., et al. Proc. Natl. Acad. Sci. USA 1994, 91, 8324-8328) and certain transmembrane tyrosine kinases (Sepp-Lorenzino, L. et al. J. Biol. Chem. 1995, 270, 16580-16587) such as EGF receptor (EGFR) and HER2/Neu (Hartmann, F., et al. Int. J. Cancer 1997, 70, 221-9; Miller, P. et al. Cancer Res. 1994, 54, 2724-2730; Mimnaugh, E. G., et al. J. Biol. Chem. 1996, 271, 22796-801; Schnur, R. et al. J. Med. Chem. 1995, 38, 3806-3812), CDK4, and mutant p53. Erlichman et al. Proc. AACR 2001, 42, abstract 4474. The ansamycin-induced loss of these proteins leads to the selective disruption of certain regulatory pathways and results in growth arrest at specific phases of the cell cycle (Muise-Heimericks, R. C. et al. J. Biol. Chem. 1998, 273, 29864-72), and apoptosis, and/or differentiation of cells so treated (Vasilevskaya, A. et al. Cancer Res., 1999, 59, 3935-40). Ansamycins thus hold great promise for the treatment and/or prevention of many types of cancers and proliferative disorders, and also hold promise as traditional antibiotics. However, their relative insolubility makes them difficult to formulate and administer, and they are not easily synthesized and currently must, at least in part, be generated through fermentation. Further, the hepatic toxicity of ansamyins is dose limiting.
  • In addition to anti-cancer and antitumorgenic activity, HSP90 inhibitors have also been implicated in a wide variety of other utilities, including use as anti-inflammation agents, anti-infectious disease agents, agents for treating autoimmunity, agents for treating stroke, ischemia, multiple sclerosis, cardiac disorders, central nervous system related disorders and agents useful in promoting nerve regeneration (See, e.g., Rosen et al. WO 02/09696 (PCT/US01/23640); Degranco et al. WO 99/51223 (PCT/US99/07242); Gold, U.S. Pat. No. 6,210,974 B1; DeFranco et al., U.S. Pat. No. 6,174,875. Overlapping somewhat with the above, there are reports in the literature that fibrogenetic disorders including but not limited to scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis, and pulmonary fibrosis also may be treatable with HSP90 inhibitors. Strehlow, WO 02/02123 (PCT/US01/20578). Still further HSP90 modulation, modulators and uses thereof are reported in Application Nos. PCT/US03/04283, PCT/US02/35938, PCT/US02/16287, PCT/US02/06518, PCT/US98/09805, PCT/US00/09512, PCT/US01/09512, PCT/US01/23640, PCT/US01/46303, PCT/US01/46304, PCT/US02/06518, PCT/US02/29715, PCT/US02/35069, PCT/US02/35938, PCT/US02/39993, 60/293,246, 60/371,668, 60/335,391, 60/128,593, 60/337,919, 60/340,762, 60/359,484 and 60/331,893.
  • Recently, purine derivatives showing HSP90 inhibitory activity have been reported, e.g., in PCT/US02/35069; PCT/US02/36075. Purine moieties are well accepted bioisosteres for a variety of ATP-dependent molecular targets, see, JP 10025294; U.S. Pat. No. 4,748,177; U.S. Pat. No. 4,772,606; U.S. Pat. No. 6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO 02/055083; European Patent 0178178; Eur. J. Med. Chem. 1994, 29(1), 3-9; and J. Het. Chem. 1990, 27(5), 1409. However, compounds having the desired potency, selectivity and pharmaceutical properties required for effective HSP90 inhibition in vivo have not been reported. Therefore, a need remains for additional novel and potent HSP90 inhibitors that meet the demanding biological and pharmaceutical criteria required to proceed towards human clinical trials.
    • SUMMARY OF THE INVENTION
  • The present invention is directed towards heterocyclic compounds, in particular, pyrrolopyrimidines and related compounds that show broad utility, e.g., by inhibiting HSP90 and treating diseases that are HSP90-dependent.
  • In one aspect, the invention comprises heterocyclic compounds as specified below in Formulae A, I, II, III and IV. Also included in the scope of the present invention are stereoisomic forms, including the individual enantiomers and diastereomers, racemic mixtures, and diasteromeric mixtures, and combinations thereof, where appropriate, as well as polymorphs, specific racemates and stereoisomers, solvates, esters, tautomers, pharmaceutically acceptable salts and prodrugs of these compounds. Stereoisomers of the compounds of the present invention may be isolated by standard resolution techniques such as, for example, fractional crystallization and chiral column chromatography.
  • In one embodiment, the invention provides compounds of Formula A, or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, which show utility by inhibiting HSP90 and treating and preventing diseases that are HSP90-dependent.
    Figure US20070173483A1-20070726-C00001
    wherein:
      • X1 and X2 are the same or different and each is nitrogen or —CR6;
      • X3 is nitrogen or —CR3 wherein R3 is hydrogen, OH, a keto tautomer, —OR8, —CN, halogen, lower alkyl, or —C(O)R9;
      • X4 is nitrogen or —CR6 when X3 is nitrogen, and X4 is —CR6R7 when X3 is —CR3;
      • R1 is halogen, —OR8, —SR8, or lower alkyl;
      • R2 is —NR8R10;
      • R4 is —(CH2)n— wherein n=0-3, —C(O), —C(S), —SO2—, or —SO2N—; and
      • R5 is alkyl, aromatic, heteroaromatic, alicyclic, or heterocyclic, each of which is optionally bi- or tri-cyclic, and optionally substituted with H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, —N3, —SR8, —OR8, —CN, —CO2R9, —NO2, or —NR8R10.
  • In certain embodiments, there are exclusionary provisos with respect to compounds disclosed in JP 10025294; U.S. Pat. No. 4,748,177; U.S. Pat. No. 4,748,177; U.S. Pat. No. 6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO 02/055083; Eur. J. Med. Chem. 1994, 29(1), 3-9; and J. Het. Chem. 1990, 27(5), 1409, which disclose compounds with, -R4R5 comprising ribose or a derivative thereof, or a sugar or derivative thereof; and compounds where -R4R5 is a phosphonate or phosphonic acid, or is substituted with a phosphonate or phosphonic acid; or compounds connected where R4 is —CH2— or —(CH2)n— that are connected through an oxygen atom to another group.
  • In another embodiment, the invention features compounds of Formulae I, II, III, & IV:
    Figure US20070173483A1-20070726-C00002
    or a polymorph, solvate, ester, diastereomer, enantiomer, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
      • R0 is selected from hydrogen, halogen, lower alkyl, —SR8, —OR8, —CN, and —NHR8,
      • R1 is halogen, —OR11, —SR11 or lower alkyl;
      • R2 is —NHR8;
      • R3 is selected from the group consisting of hydrogen, halogen, —SR8, —OR8, —CN, —C(O)R9, —C(O)OH, —NO2, —NR8R10, lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic, and heterocyclic, all optionally substituted, wherein:
        • the aryl, heteroaryl, alicyclic and heterocyclic groups are optionally mono-, bi- or tri-cyclic;
        • R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N; and
        • the optional substituents on R3 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR8, —OR8, —CN, —C(O)OH, —C(O)R9, —NO2, —NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
      • when R0 or R3 is —OH or —SH, the compound may exist as the corresponding (thio)keto tautomer or a mixture of keto-enol tautomers;
      • R4 is —CHR12—, —C(O)—, —C(S)—, —S(O)— or —SO2—;
      • R5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein:
        • the aryl group is substituted with 3 to 5 substituents,
        • the heteroaryl group is substituted with 2 to 5 substituents,
        • the alicyclic group is substituted with 3 to 5 substituents,
        • the heterocyclic group is substituted with 3 to 5 substituents, and
        • the substituents are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR8, —OR8, —CN, —C(O)OH, —C(O)R9, —NO2, —NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylarnino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
      • R8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R9;
      • R9 is H, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, —NR10R10, or —OR11, wherein R10 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
      • R10 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
      • R11 is lower alkyl, lower alkenyl, lower alkynyl, lower heteroaryl or lower aryl;
      • R12 is hydrogen or lower alkyl;
      • R0 and R10 taken together optionally form an exocyclic double bond which is optionally substituted, or optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N; and
      • R3 and R10 taken together optionally form an exocyclic double bond which is optionally substituted, or optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N.
  • In another aspect, the invention features pharmaceutical compositions comprising the compounds of the invention, in particular, the compounds of Formulae A, I, II, III or IV, or a polymorph, solvate, ester, tautomer, diastereoisomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, and one or more pharmaceutical excipients, for use in treatment or prevention of diseases that are HSP90-dependent.
  • In another aspect, the invention features a method of treating an individual having an HSP90-mediated disorder by administering to the individual a pharmaceutical composition that comprises a pharmaceutically effective amount of a compound of Formula A, I, II, III or IV, or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof.
  • In one embodiment, the invention provides a method for treating an individual having a disorder selected from the group of inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorders, neurological disorders, fibrogenetic disorders, proliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases, and malignant diseases.
  • In another embodiment, the invention provides a method for treating an individual having a fibrogenetic disorder, such as, for example, scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.
  • In another embodiment, the invention provides a combination therapy comprising the administration of a pharmaceutically effective amount of a compound of Formula I, II, III, or IV, or a solvate, tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt, polymorph, or prodrug thereof according to any of the preceding aspects or embodiments, and at least one therapeutic agent selected from the group of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents. The anti-neoplastic agent may be selected from the group of alkylating agents, anti-metabolites, epidophyllotoxins antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.
  • Any of the above described aspects and embodiments of the invention can be combined where practical.
  • The individual compounds, methods and compositions prescribed do not preclude the utilization of other, unspecified steps and agents, and those of ordinary skill in the art will appreciate that additional steps and compounds may also be combined usefully within the spirit of various aspects and embodiments of the invention.
  • Advantages of the invention depend on the specific aspect and embodiment and may include one or more of: ease of synthesis and/or formulation, solubility, and IC50 relative to previously existing compounds in the same or different classes of HSP90 inhibitors.
    • DETAILED DESCRIPTION OF THE INVENTION
  • I. Definitions
  • A “pharmaceutically acceptable derivative or prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention, which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or a pharmaceutically active metabolite or residue thereof. Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing orally administered compound to be more readily absorbed into blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system).
  • A “pharmaceutically acceptable salt” may be prepared for any compound of the invention having a functionality capable of forming a salt, for example, an acid or base functionality. Pharmaceutically acceptable salts may be derived from organic or inorganic acids and bases. Compounds of the invention that contain one or more basic functional groups, e.g., amino or alkylamino, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable organic and inorganic acids. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. See, e.g., Berge et al. “Pharmaceutical Salts”, J. Pharm. Sci. 1977, 66:1-19.
  • Compounds of the present invention that contain one or more acidic functional groups are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative pharmaceutically acceptable cations include alkali or alkaline earth salts such as the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Illustrative examples of some of the bases that can be used include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. This invention also envisions the quatemization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. See, for example, Berge et al., supra.
  • Pharmaceutically acceptable prodrugs of the compounds of this invention include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, aminoacid conjugates, phosphate esters, metal salts and sulfonate esters.
  • Suitable positions for derivatization of the compounds of the invention to create “prodrugs” include but are not limited, to, 2-amino substitution. Those of ordinary skill in the art have the knowledge and means to accomplish this without undue experimentation. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see, e.g.,
  • a) Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p.309-396;
  • b) Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and
  • c) Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38.
  • Each of which is incorporated herein by reference.
  • The tenn “prodrugs” as employed herein includes, but is not limited to, the following groups and combinations of these groups:
  • Amine Prodrugs:
    Figure US20070173483A1-20070726-C00003
  • Hydroxy Prodrugs:
      • Acyloxyalkyl esters;
      • Alkoxycarbonyloxyalkyl esters;
      • Alkyl esters;
      • Aryl esters; and
      • Disulfide containing esters.
  • The term “alkyl,” alone or in combination, refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon radical having from one to thirty carbons, more preferably one to twelve carbons. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like. The term “cycloalkyl” embraces cyclic alkyl radicals which include monocyclic, bicyclic, tricyclic, and higher multicyclic alkyl radicals wherein each cyclic moiety has from three to eight carbon atoms. Examples of cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. A “lower alkyl” is a shorter alkyl, e.g., one containing from one to six carbon atoms.
  • The term “alkenyl,” alone or in combination, refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds and having from two to thirty carbon atoms, more preferably two to eighteen carbons. Examples of alkenyl radicals include ethenyl, propenyl, butenyl, 1,3-butadienyl and the like. The term “cycloalkenyl” refers to cyclic alkenyl radicals which include monocyclic, bicyclic, tricyclic, and higher multicyclic alkenyl radicals wherein each cyclic moiety has from three to eight carbon atoms. A “lower alkenyl” refers to an alkenyl having from two to six carbons.
  • The term “alkynyl,” alone or in combination, refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon radical having one or more carbon-carbon triple-bonds and having from two to thirty carbon atoms, more preferably from two to twelve carbon atoms, or from two to six carbon atoms, as well as those having from two to four carbon atoms. Examples of alkynyl radicals include ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. The term “cycloalkynyl” refers to cyclic alkynyl radicals which include monocyclic, bicyclic, tricyclic, and higher multicyclic alkynyl radicals wherein each cyclic moiety has from three to eight carbon atoms. A “lower alkynyl” refers to an alkynyl having from two to six carbons.
  • The terms “heteroalkyl, heteroalkenyl and heteroalkynyl” include optionally substituted alkyl, alkenyl and alkynyl structures, as described above, and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorous or combinations thereof.
  • The term “carbon chain” embraces any alkyl, alkenyl, alkynyl, or heteroalkyl, heteroalkenyl, or heteroalkynyl group, which are linear, cyclic, or any combination thereof. If the chain is part of a linker and that linker comprises one or more rings as part of the core backbone, for purposes of calculating chain length, the “chain” only includes those carbon atoms that compose the bottom or top of a given ring and not both, and where the top and bottom of the ring(s) are not equivalent in length, the shorter distance shall be used in determining the chain length. If the chain contains heteroatoms as part of the backbone, those atoms are not calculated as part of the carbon chain length.
  • The term “membered ring” can embrace any cyclic structure, including aromatic, heteroaromatic, alicyclic, heterocyclic and polycyclic fused ring systems as described below. The term “membered” is meant to denote the number of skeletal atoms that constitute the ring. Thus, for example, pyridine, pyran, and pyrimidine are six-membered rings and pyrrole, tetrahydrofuran, and thiophene are five-membered rings.
  • The term “aryl,” alone or in combination, refers to an optionally substituted aromatic hydrocarbon radical of six to twenty ring atoms, and includes mono-aromatic rings and fused aromatic rings. A fuised aromatic ring radical contains from two to four fused rings where the ring of attachment is an aromatic ring, and the other individual rings within the fused ring may be aromatic, heteroaromatic, alicyclic or heterocyclic. Further, the term aryl includes mono-aromatic rings and fused aromatic rings containing from six to twelve carbon atoms, as well as those containing from six to ten carbon atoms. Examples of aryl groups include, without limitation, phenyl, naphthyl, anthryl, chrysenyl, and benzopyrenyl ring systems. The term “lower aryl” refers to an aryl having six to ten skeletal ring carbons, e.g., phenyl and naphthyl ring systems.
  • The term “heteroaryl” refers to optionally substituted aromatic radicals containing from five to twenty skeletal ring atoms and where one or more of the ring atoms is a heteroatom such as, for example, oxygen, nitrogen, sulfur, selenium or phosphorus. The term heteroaryl includes optionally substituted mono-heteroaryl radicals and fused heteroaryl radicals having at least one heteroatom (e.g., quinoline, benzothiazole). A fused heteroaryl radical may contain from two to four fused rings where the ring of attachment is a heteroaromatic ring, the other individual rings within the fused ring system may be aromatic, heteroaromatic, alicyclic or heterocyclic. The term heteroaryl also includes mono-heteroaryls or fused heteroaryls having from five to twelve skeletal ring atoms, as well as those having from five to ten skeletal ring atoms. Examples of heteroaryls include, without limitation, furanyl, benzofuranyl, chromenyl, pyridyl, pyrrolyl, indolyl, quinolinyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, benzothiozole, benzimidazole, benzoxazoles, benzothiadiazole, benzoxadiazole, benzotriazole, quinolines, isoquinolines, indoles, purinyl, indolizinyl, thienyl and the like and their oxides. The term “lower heteroaryl” refers to a heteroaryl having five to ten skeletal ring atoms, e.g., pyridyl, thienyl, pyrimidyl, pyrazinyl, pyrrolyl, or furanyl.
  • The term “alicyclic” alone or in combination, refers to an optionally substituted saturated or unsaturated nonaromatic hydrocarbon ring system containing from three to twenty ring atoms. The term alicyclic includes mono-alicyclic and fused alicyclic radicals. A fused alicyclic may contain from two to four fused rings where the ring of attachment is an alicyclic ring, and the other individual rings within the fused-alicyclic radical may be aromatic, heteroaromatic, alicyclic and heterocyclic. The term alicyclic also includes mono-alicyclic and fuised alicyclic radicals containing from three to twelve carbon atoms, as well as those containing from three to ten carbon atoms. Examples of alicyclics include, without limitation, cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, cyclodecyl, cyclododecyl, cyclopentadienyl, indanyl, and cyclooctatetraenyl ring systems. The term “lower alicyclic” refers to an alicyclic having three to ten skeletal ring carbons, e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, decalinyl, and cyclohexyl.
  • The term “heterocyclic” refers to optionally substituted saturated or unsaturated nonaromatic ring radicals containing from five to twenty ring atoms where one or more of the ring atoms are heteroatoms such as, for example, oxygen, nitrogen, sulfur, and phosphorus. The term alicyclic includes mono-heterocyclic and fused heterocyclic ring radicals. A fused heterocyclic radical may contain from two to four fused rings where the attaching ring is a heterocyclic, and the other individual rings within the fused heterocyclic radical may be aromatic, heteroaromatic, alicyclic or heterocyclic. The term heterocyclic also includes mono-heterocyclic and fused alicyclic radicals having from five to twelve skeletal ring atoms, as well as those having from five to ten skeletal ring atoms. Example of heterocyclics include without limitation, tetrahydrofuranyl, benzodiazepinyl, tetrahydroindazolyl, dihyroquinolinyl, and the like. The term “lower heterocyclic” refers to a heterocyclic ring system having five to ten skeletal ring atoms, e.g., dihydropyranyl, pyrrolidinyl, dioxolanyl, piperidinyl, piperazinyl, and the like.
  • The term “alkylaryl,” or “araalkyl,” alone or in combination, refers to an aryl radical as defined above in which at least one H atom is replaced by an alkyl radical as defined above, such as, for example, tolyl, xylyl and the like.
  • The term “arylalkyl,” alone or in combination, refers to an alkyl radical as defined above in which at least one H atom is replaced by an aryl radical as defined above, such as, for example, benzyl, 2-phenylethyl and the like.
  • The termn “heteroarylalkyl” refers to an alkyl radical as defined above in which at least one H atom is replaced by a heteroaryl radical as defined above, each of which may be optionally substituted.
  • The term “alkoxy,” alone or in combination, refers to an alkyl ether radical, alkyl-O—, wherein the term alkyl is defined as above. Examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
  • The term “aryloxy,” alone or in combination, refers to an aryl ether radical wherein the term aryl is defined as above. Examples of aryloxy radicals include phenoxy, thienyloxy and the like.
  • The term “alkylthio,” alone or in combination, refers to an alkyl thio radical, alkyl-S—, wherein the term alkyl is as defined above.
  • The term “arylthio,” alone or in combination, refers to an aryl thio radical, aryl-S—, wherein the term aryl is as defined above.
  • The term “heteroarylthio” refers to the group heteroaryl-S—, wherein the term heteroaryl is as defined above.
  • The term “acyl” refers to a radical —C(O)R where R includes alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroarylalkyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroaryl alkyl groups may be optionally substituted.
  • The term “acyloxy” refers to the ester group —OC(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl, or heteroarylalkyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroarylalkyl may be optionally substituted.
  • The term “carboxy esters” refers to —C(O)OR where R is alkyl, aryl or arylalkyl, wherein the alkyl, aryl and arylalkyl groups may be optionally substituted.
  • The term “carboxamido” refers to
    Figure US20070173483A1-20070726-C00004
  • where each of R and R′ are independently selected from the group consisting of H, alkyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl and heteroarylalkyl, wherein the alkyl, aryl, heteroaryl, alicyclic, heterocyclic, or arylalkyl groups may be optionally substituted.
  • The term “oxo” refers to ═O.
  • The term “halogen” includes F, Cl, Br and I.
  • The terms “haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures, as described above, that are substituted with one or more fluorines, chlorines, bromines or iodines, or with combinations thereof.
  • The terms “perhaloalkyl, perhaloalkyloxy and perhaloacyl” refer to alkyl, alkyloxy and acyl radicals as described above, in which all the H atoms are replaced by fluorines, chlorines, bromines or iodines, or combinations thereof.
  • The terms “cycloalkyl, arylalkyl, aryl, heteroaryl, alicyclic, heterocyclic, alkyl, alkynyl, alkenyl, haloalkyl, and heteroalkyl” include optionally substituted cycloalkyl, arylalkyl, aryl, heteroaryl, alicyclic, heterocyclic, alkyl, alkynyl, alkenyl, haloalkyl and heteroalkyl groups.
  • The terms “alkylamino”, refers to the group —NHR where R is alkyl.
  • The terms “dialkylamino”, refers to the group —NRR′ where R and R′ are alkyls.
  • The term “sulfide” refers to a sulfur atom covalently linked to two atoms; the formal oxidation state of said sulfur is (II). The term “thioether” may be used interchangeably with the term “sulfide.”
  • The term “sulfoxide” refers to a sulfur atom covalently linked to three atoms, at least one of which is an oxygen atom; the formal oxidation state of said sulfur atom is (IV).
  • The term “sulfone” refers to a sulfur atom covalently linked to four atoms, at least two of which are oxygen atoms; the formal oxidation state of said sulfur atom is (VI).
  • The terms “optional” or “optionally” mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “aryl optionally mono- or di-substituted with an alkyl” means that the alkyl may but need not be present, or either one alkyl or two may be present, and the description includes situations where the aryl is substituted with one or two alkyls and situations where the aryl is not substituted with an alkyl.
  • “Optionally substituted” groups may be substituted or unsubstituted. The substituents of an “optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or designated subsets thereof: lower alkyl, lower alkenyl, lower alkynyl, lower aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl, heteroarylalkyl, lower alkoxy, lower aryloxy, amino, alkylamino, dialkylamino, diarylalkylamino, alkylthio, arylthio, heteroarylthio, oxo, oxa, acyl (—C(O)R), (—C(O)), carboxyesters (—C(O)OR), carboxamido (—C(O)NH2), carboxy, acyloxy, —H, halo, —CN, —NO2, —N3, —SH, —OH, —C(O)CH3, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, esters, amides, phosphonates, phosphonic acid, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas, thioamides and thioalkyls. An optionally substituted group may be unsubstituted (e.g., —CH2CH3), fully substituted (e.g., —CF2CF3), monosubstituted (e.g., —CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., —CH2CF3).
  • The term “pyridine-1-oxy” also means “pyridine-N-oxy.”
  • Some of the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms. The scope of the present invention is intended to cover all isomers per se, as well as mixtures of cis and trans isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers) as well. Further, it is possible using well known techniques to separate the various forms, and some embodiments of the invention may feature purified or enriched species of a given enantiomer or diastereomer.
  • A “pharmacological composition” refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, with other chemical components, such as pharmaceutically acceptable carriers and/or excipients. The purpose of a pharmacological composition is to facilitate administration of a compound to an organism.
  • The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. A physiologically acceptable carrier should not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • An “excipient” refers to an inert substance added to a pharmacological composition to further facilitate administration of a compound. Examples of excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • A “pharmaceutically effective amount” means an amount which is capable of providing a therapeutic and/or prophylactic effect. The specific dose of compound administered according to this invention to obtain therapeutic and/or prophylactic effect will, of course, be determined by the particular circumstances surrounding the case, including, for example, the specific compound administered, the route of administration, the condition being treated, and the individual being treated. A typical daily dose (administered in single or divided doses) will contain a dosage level of from about 0.01 mg/kg to about 50-100 mg/kg of body weight of an active compound of the invention. Preferred daily doses generally will be from about 0.05 mg/kg to about 20 mg/kg and ideally from about 0.1 mg/kg to about 10 mg/kg. Factors such as clearance rate, half-life and maximum tolerated dose (MTD) have yet to be determined but one of ordinary skill in the art can determine these using standard procedures.
  • In some method embodiments, the preferred therapeutic effect is the inhibition, to some extent, of the growth of cells characteristic of a proliferative disorder, e.g., breast cancer. A therapeutic effect will also normally, but need not, relieve to some extent one or more of the symptoms other than cell growth or size of cell mass. A therapeutic effect may include, for example, one or more of 1) a reduction in the number of cells; 2) a reduction in cell size; 3) inhibition (i.e., slowing to some extent, preferably stopping) of cell infiltration into peripheral organs, e.g., in the instance of cancer metastasis; 3) inhibition (i.e., slowing to some extent, preferably stopping) of tumor metastasis; 4) inhibition, to some extent, of cell growth; and/or 5) relieving to some extent one or more of the symptoms associated with the disorder.
  • As used herein, the term IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response. In some method embodiments of the invention, the “IC50” value of a compound of the invention can be greater for normal cells than for cells exhibiting a proliferative disorder, e.g., breast cancer cells. The value depends on the assay used.
  • By a “standard” is meant a positive or negative control. A negative control in the context of HER2 expression levels is, e.g., a sample possessing an amount of HER2 protein that correlates with a normal cell. A negative control may also include a sample that contains no HER2 protein. By contrast, a positive control does contain HER2 protein, preferably of an amount that correlates with overexpression as found in proliferative disorders, e.g., breast cancers. The controls may be from cell or tissue samples, or else contain purified ligand (or absent ligand), immobilized or otherwise. In some embodiments, one or more of the controls may be in the form of a diagnostic “dipstick.”By “selectively targeting” is meant affecting one type of cell to a greater extent than another, e.g., in the case of cells with high as opposed to relatively low or normal HER2 levels.
  • II. Compounds of the Invention
  • Compounds of the invention and their polymorphs, solvates, esters, tautomers, diastereomers, enantiomers, pharmaceutically acceptable salts or prodrugs show utility for inhibiting HSP90 and treating and preventing diseases that are HSP90-dependent.
  • One embodiment of the compounds of the invention is of Formula A:
    Figure US20070173483A1-20070726-C00005
    or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
      • X1 and X2 are the same or different and each is nitrogen or —CR6;
      • X3 is nitrogen or —CR3 wherein R3 is hydrogen, OH, a keto tautomer, —OR8, —CN, halogen, lower alkyl, or —C(O)R9;
      • X4 is nitrogen or a group CR6 when X3 is nitrogen, and X4 is —CR6R7 when X3 is —CR3;
      • R1 is halogen, —OR8, —SR8, or lower alkyl;
      • R2 is —NR8R10;
      • R4 is —(CH2)n— wherein n=0-3, —C(O), —C(S), —SO2—, or —SO2N—; and
  • R5 is alkyl, aryl, heteroaryl, alicyclic, or heterocyclic, each of which is optionally bi- or tricyclic, and optionally substituted with H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, araalkyl, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, —N3, —SR8, —OR8, —CN, —CO2R9, —NO2, or —NR8R10;
  • with the provisos that:
  • the compound is not one found or described in one or more of JP 10025294; U.S. Pat. No. 4,748,177; U.S. Pat. No. 4,748,177; U.S. Pat. No. 6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO 02/055083; Eur. J. Med. Chem., 1994, 29(1), 3-9; and J. Het. Chem. 1990, 27(5), 1409;
  • -R4R5 is not a ribose or derivative thereof, or a sugar or derivative thereof;
  • -R4R5 is not a phosphonate or phosphonic acid, or a group substituted with a phosphonate or phosphonic acid; and
  • when R4 is (CH2)n where n=0 or 1, then R4 and R5 are not connected with ‘O’, e.g., —CH2—O—CH2— or —CH2—CH2—O—CH2—.
  • In one embodiment of, the compound, tautomer, pharmaceutically acceptable salt thereof, or prodrug thereof of Formula A, X1 and X2 are the same or different and each is nitrogen or —CR6; R1 is halogen, —OR8, —SR8, or lower alkyl; R2 is —NR8R10; R3 is hydrogen, —OH or keto tautomer, —OR8, halogen, —CN, lower alkyl, or —C(O)R9; R4 is —(CH2)n— wherein n=0-3, —C(O), —C(S), —SO2—, or —SO2N—; and R5 is alkyl, aromatic, heteroaromatic, alicyclic, heterocyclic, each of which is optionally bi- or tricyclic, and optionally substituted with H, halogen, lower alkyl, —SR8, —OR8, —CN, —CO2R9, —NO2 or —NR8R10; R8 is hydrogen, lower alkyl, lower aryl or —(CO)R9; R9 is lower alkyl, lower aryl, lower heteroaryl, —NR8R10 or OR11; R11 is lower alkyl or lower aryl; and R10 is hydrogen or lower alkyl.
  • In one embodiment, the compound, tautomer, pharmaceutically acceptable salt thereof, or prodrug thereof of Formula A, R1 is selected from halogen, hydroxyl, lower alkoxy, lower thioalkyl and C1-4 alkyl; and R2 is —NH2.
  • In another embodiment, R4 is —(CH2)n—, wherein n=0-3.
  • In another embodiment, R1 is selected from halogen, hydroxyl, lower alkoxy, lower thioalkyl or C1-4 alkyl; optionally wherein R2 is NH2.
  • In another embodiment, R4 is —(CH2)n—, wherein n=0-3.
  • In another embodiment, R4 is —(CH2)n—, wherein n=0-3, R1 is selected from halogen, hydroxyl, lower alkoxy, lower thioalkyl, and C1-4 alkyl, and R2 is optionally NH2.
  • In another embodiment, R1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R2 is optionally NH2, R4 is —(CH2)—, and R5 is phenyl, benzyl, or pyridyl, all optionally substituted with H, halogen, lower alkyl, —SR8, —OR8 (or cyclic ethers such as methylenedioxy), —CN, —C02R9, —NO2, or —NR8R10; R8 is hydrogen, lower alkyl, lower aryl or —(CO)R9; R9 is lower alkyl, lower aryl, lower heteroaryl, —NR8R10 or —OR11; R11 is lower alkyl or lower aryl; and R10 is hydrogen or lower alkyl.
  • In another embodiment R1 is halogen, R2 is —NH2, R4 is —CH2—, R6 is H or halogen, and R5 is phenyl optionally substituted with H, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, perhaloalkyl, perhaloalkyloxy, —CN, —NO2, —NH2 or —CO2R11.
  • In another embodiment, R1 is halogen, R2 is —NH2, R4 is —CH2—, R6 is H, and R5 is 2-halo-3, 5-dimethoxyphenyl optionally substituted with H, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, perhaloalkyl, perhaloalkyloxy, —CN, —NO2, —NH2, or —CO2R11 at the para (4-) position.
  • In another embodiment, R1 is chloro, R2 is —NH2, R4 is —CH2—, R6 is H and R5 is 2-chloro-3, 4,5-trimethoxyphenyl.
  • In another embodiment, R1 is chloro, R2 is —NH2, R4 is —CH2—, R6 is H and R5 is 2-bromo-3, 4,5-trimethoxyphenyl. In other embodiments, R5 is selected from 2-iodo-3,4,5-trimethoxyphenyl, 2-fluoro-3,4,5-trimethoxyphenyl, and 2-bromo-3,4,5-trimethoxyphenyl.
  • Any of the foregoing embodiments can be combined where feasible and appropriate.
  • In another embodiment, the invention provides compounds of Formula A1:
    Figure US20070173483A1-20070726-C00006
    or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein:
      • X1 and X2 are the same or different and each is nitrogen or a group —CR6;
      • R1 is halogen, —OR8, —SR8, or lower alkyl;
      • R2 is —NR8R10;
      • R4 is —(CH2)n— where n=0-3, —C(O), —C(S), —SO2— or —SO2N—;
      • R5 is alkyl, aromatic, heteroaromatic, alicyclic, heterocyclic, all optionally bi- or tricyclic, and all optionally substituted with H, halogen, lower alkyl, —SR8, —OR8, —CN, —CO2R9, —NO2, or —NR8R10;
      • R6 is hydrogen, halogen, lower alkyl, —SR8, —OR8, —NR8R10, —N3, —CN, —C(O)R9, or taken together with R7 is carbonyl (C═O);
      • R7 is independently selected from hydrogen, lower alkyl or taken together with R6 is —C(O);
      • R8 is hydrogen, lower alkyl, lower aryl, or —(CO)R9;
      • R9 is lower alkyl, lower aryl, lower heteroaryl, —NR8R10 or —OR11;
      • R10 is hydrogen or lower alkyl, and
      • R11 is lower alkyl or lower aryl.
  • In one embodiment of the compounds of Formula A1, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R2 is NH2.
  • In another embodiment of the compounds of Formula A1, or a tautomer, pharmaceutically acceptable salt thereof, or prodrug thereof, R4 is —(CH2)n—, where n=0-3.
  • In another embodiment of the compounds of Formula A1, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R2 is NH2; R4 is —(CH2)n—, and wherein n=0-3.
  • In another embodiment of the compounds of Formula A1, or a tautomer, pharmaceutically acceptable salt thereof, R1 is halogen; R2 is NH2, R4 is —CH2—.
  • In another embodiment, the invention provides compounds of Formula A2.
    Figure US20070173483A1-20070726-C00007
    or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein:
  • X1 and X2 are the same or different and each is nitrogen or —CR6;
  • R1 is halogen, —OR8, —SR8 or lower alkyl;
  • R2 is —NR8R10;
  • R3 is hydrogen, OH or a keto tautomer, —OR8, halogen, —CN, lower alkyl or —C(O)R9;
  • R4 is —(CH2)n— where n=0-3, —C(O), —C(S), —SO2— or —SO2N—;
  • R6 is hydrogen, halogen, lower alkyl, —SR8, —OR8, —NR8R10, —N3, or —C(O)R9;
  • R5 is alkyl, aromatic, heteroaromatic, alicyclic, heterocyclic, all optionally bi- or tricyclic, and all optionally substituted with H, halogen, lower alkyl, —SR8, —OR8, —CN, —CO2R9, —NO2, or —NR8R10;
  • R8 is hydrogen, lower alkyl, lower aryl, or —(CO)R9;
  • R9 is lower alkyl, lower aryl, lower heteroaryl, —NR8R10 or —OR11;
  • R11 is lower alkyl or lower aryl; and
  • R10 is hydrogen or lower alkyl.
  • In another embodiment of the compounds of Formula A2, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl or C1-4 alkyl; and wherein R2 is NH2.
  • In another embodiment of the compounds of Formula A2, or a tautomer, pharmaceutically acceptable salt or prodrug thereof, R4 is —(CH2)n—, wherein n=0-3.
  • In another embodiment of the compounds of Formula A2, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R4 is —(CH2)—.
  • In another embodiment of the compounds of Formula A2, or a tautomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl or C1-4 alkyl; R2 is NH2, R4 is —(CH2)—.
  • Another embodiment of the invention is compounds of Formula I:
    Figure US20070173483A1-20070726-C00008
    or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
      • R0 is selected from hydrogen, halogen, lower alkyl, —SR8, —OR8, —CN, and —NHR8,
      • R1 is halogen, —OR11, —SR11 or lower alkyl;
      • R2 is —NHR8;
      • R3 is selected from the group consisting of hydrogen, halogen, —SR8, —OR8, —CN, —C(O)R9, —C(O)OH, —NO2, —NR8R10, lower alkyl, lower alkenyl, lower alkynyl, aryl, lower perhaloalkyl, heteroaryl, alicyclic, heterocyclic, all optionally substituted, wherein:
        • the aryl, heteroaryl, alicyclic and heterocyclic groups are optionally mono-, bi- or tri-cyclic,
        • R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N, and
        • the optional substituents on R3 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR8, —OR8, —CN, —C(O)OH, —C(O)R9, —NO2, —NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
      • R0 or R3 is —OH or —SH, the compound may exist as the corresponding (thio)keto tautomer or a mixture of keto-enol tautomers;
      • R4 is —CHR12—, —C(O)—, —C(S)—, —S(O)— or —SO2—;
      • R5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
        • the aryl group is substituted with 3 to 5 substituents,
        • the heteroaryl group is substituted with 2 to 5 substituents,
        • the alicyclic group is substituted with 3 to 5 substituents,
        • the heterocyclic group is substituted with 3 to 5 substituents, and
        • the substituents are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR8, —OR8, —CN, —C(O)OH, —C(O)R9, —NO2, —NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
      • R8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R9;
      • R9 is H, lower alkyl, lower alkenyl, or lower alkynyl, lower aryl, lower heteroaryl, —NR10R10, or —OR11, wherein R10 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
      • R10 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
      • R11 is lower alkyl, lower alkenyl, or lower alkynyl, lower heteroaryl or lower aryl; and
      • R12 is hydrogen or lower alkyl.
  • In one embodiment of the compounds of Formula I, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, each of the aryl, heteroaryl, alicyclic or heterocyclic group is monocyclic or bicyclic.
  • In another embodiment of the compounds of Formula I, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R0 is hydrogen, halogen, —SH, —OH, or —CN; R1 is halogen; and R2 is —NHR8, where R8 is hydrogen or —C(O)R9.
  • In another embodiment of the compounds of Formula I, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is chloro or bromo, R2 is —NHR8, where R8 is hydrogen or —C(O)R9; R3is hydrogen, halogen, OR8, SR8, NR8R10, lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower aryl, or lower heteroaryl.
  • In another embodiment of the compounds of Formula I, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R0 is hydrogen, halogen or —CN; R2 is —NHR8, where R8 is hydrogen or —C(O)R9; and R4 is —CH2—.
  • In another embodiment of the compounds of Formula I, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R0 is hydrogen, halogen, —SH, —OH or —CN; R1 is halogen; R2 is —NH2, R3 is hydrogen, halogen, —OR8, —SR8, —NR8R10, lower alkyl, lower alkenyl, lower alkynyl, perhaloalkyl, lower aryl, or lower heteroaryl, wherein R8 is hydrogen, lower alkyl, lower aryl, or —C(O)R9; R4 is —CH2—; and R5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents.
  • In another embodiment of the compounds of Formula I, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is chloro or bromo, R2 is —NH2, and R5 is a phenyl having at least three substituents.
  • In another embodiment of the compounds of Formula I, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is chloro or bromo, R2 is —NH2 and R5 is a pyridyl having at least two substituents.
  • In another embodiment of the compounds of Formula I, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is chloro or bromo, R2 is —NH2, and R5 is 1-oxy-pyridyl (N-oxy-pyridyl) having at least two substituents.
  • Another embodiment of the invention is a compound of Formula II:
    Figure US20070173483A1-20070726-C00009
    or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
      • R0 is hydrogen, halogen, lower alkyl, —SR8, —OR8, —CN or —NHR8,
      • R1 is halogen, —OR11, —SR11 or lower alkyl;
      • R2 is —NH2;
      • R4 is —CHR12—, —C(O)—, —C(S)—, —S(O)— or —SO2—;
      • R5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein:
        • the aryl group is substituted with 3 to 5 substituents,
        • the heteroaryl group is substituted with 2 to 5 substituents,
        • the alicyclic group is substituted with 3 to 5 substituents,
        • the heterocyclic group is substituted with 3 to 5 substituents, and
        • the substituents on R5 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR8, —OR8, —CN, —C(O)OH, —C(O)R9, —NO2, —NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
      • R8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R9;
      • R9 is H, lower alkyl, lower aryl, lower heteroaryl, —NR10R10, or —OR11, wherein R10 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
      • R10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl,
      • R11 is lower alkyl, lower alkenyl, lower alkynyl, lower heteroaryl or lower aryl;
      • R12 is hydrogen or lower alkyl; and
      • R0 and R10 taken together optionally form an exocyclic double bond which is optionally substituted, or optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N.
  • In one embodiment of the compounds of Formula II, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen or lower alkyl; R4 is —CHR12—; R5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents.
  • In another embodiment of the compounds of Formula II, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R0 is hydrogen or —NHR 8, R1 is halogen, —OR11, —SR11 or lower alkyl; R10 is hydrogen or lower alkyl.
  • In another embodiment of the compounds of Formula II, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R0 is hydrogen; R1 is halogen; R4 is —CH2—; and R5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents; and R10 is hydrogen.
  • In another embodiment of the compounds of Formula II, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is chloro or bromo, R5is phenyl, pyridyl or 1-oxy-pyridyl (N-oxy-pyridyl) each of which has at least two substituents.
  • Another embodiment of the invention is a compound represented by Formula III:
    Figure US20070173483A1-20070726-C00010
    or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
      • R1 is halogen, —OR11, —SR11 or lower alkyl;
      • R2 is —NH2;
      • R3 is selected from the group consisting of hydrogen, halogen, —SR8, —OR8, —CN, —C(O)R9, —C(O)OH, —NO2, —NR8R10, lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic, heterocyclic, all optionally substituted, wherein:
        • the aryl, heteroaryl, alicyclic and heterocyclic groups are optionally mono-, bi- or tri-cyclic,
        • R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N, and
        • the optional substituents on R3 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR8, —OR8, —CN, —C(O)OH, —C(O)R9, —NO2, —NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
      • R4 is —CHR12—, —C(O)—, —C(S)—, —S(O)— or —SO2—;
      • R5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
        • the aryl group is substituted with 3 to 5 substituents,
        • the heteroaryl group is substituted with 2 to 5 substituents,
        • the alicyclic group is substituted with 3 to 5 substituents,
        • the heterocyclic group is substituted with 3 to 5 substituents, and
        • the substituents on R5 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR8, —OR8, —CN, —C(O)OH, —C(O)R9, —NO2, —NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
      • R8 is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R9;
      • R9 is H, lower alkyl, lower aryl, lower heteroaryl, —NR10R10, or —OR11, wherein R10 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
      • R10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl,
      • R11 is lower alkyl, lower alkenyl, lower alkynyl, lower heteroaryl or lower aryl;
      • R12 is hydrogen or lower alkyl; and
      • R3 and R10 taken together optionally form an exocyclic double bond which is optionally substituted, or optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N.
  • In one embodiment of the compounds of Formula III, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen; R3 is hydrogen, halogen, —OR8, —SR8, —NR8R10, lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower aryl, or lower heteroaryl, wherein R8 is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R9; R4 is —CH2—; R5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents; and R10 is hydrogen or lower alkyl.
  • In another embodiment of the compounds of Formula III, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen; R4 is —CH2—; R5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents; and R10 is hydrogen.
  • In another embodiment of the compounds of Formula III, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen; R3 is hydrogen; R4 is —CH2—; R5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents; and R10 is hydrogen.
  • In another embodiment of the compounds of Formula III, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein R1 is chloro or bromo, R5 is phenyl, pyridyl or 1-oxy-pyridyl (N-oxy-pyridyl), each of which has at least two substituents.
  • Another embodiment of the invention is compounds represented by Formula IV:
    Figure US20070173483A1-20070726-C00011
    or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
      • R1 is halogen, —OR11, —SR11 or lower alkyl;
      • R2 is —NH2;
      • R4 is —CHR12—, —C(O)—, —C(S)—, —S(O)— or —SO2—;
      • R5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
        • the aryl group is substituted with 3 to 5 substituents,
        • the heteroaryl group is substituted with 2 to 5 substituents,
        • the alicyclic group is substituted with 3 to 5 substituents,
        • the heterocyclic group is substituted with 3 to 5 substituents, and
        • the substituents on R5 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR8, —OR8, —CN, —C(O)OH, —C(O)R9, —NO2, —NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
      • R8 is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R9;
      • R9 is H, lower alkyl, lower aryl, lower heteroaryl, —NR10R10, or —OR11, wherein R10 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
      • R10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl,
      • R11 is lower alkyl, lower alkenyl, or lower alkynyl, lower heteroaryl lower aryl; and
      • R12 is hydrogen or lower alkyl.
  • In one embodiment of the compounds of Formula IV, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen; R4 is —CH2—; R5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents.
  • In another embodiment of the compounds of Formula IV, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is chloro or bromo, and R5 is phenyl, pyridyl or 1-oxy-pyridyl (N-oxy-pyridyl), each of which has at least two substituents.
  • It should be understood that any of the foregoing embodiments can be combined where feasible and appropriate.
  • Illustrative species of the compounds of the invention that are based on Formula I are described in TABLE 1. Prodrugs which can be employed with the compound of the invention include, but are not limited to, those listed in the Definition section above.
    TABLE 1
    Exemplary Compounds based on Formula I
    I
    Figure US20070173483A1-20070726-C00012
    No. Ex R1 R2 R3 R4 R5 R0
    1 9 Cl NH2 H CH2 3,4,5-Trimethoxyphenyl H
    2 Cl NH2 H CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    3 6 Cl NH2 H CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    4 7 Cl NH2 H CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    5 Cl NH2 H CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    6 Cl NH2 H CH2 3,4,5-Trimethylphenyl H
    7 Cl NH2 H CH2 2-Chloro-3,4,5-trimethylphenyl H
    8 Cl NH2 H CH2 2-Bromo-3,4,5-trimethylphenyl H
    9 Cl NH2 H CH2 2-Iodo-3,4,5-trimethylphenyl H
    10 Cl NH2 H CH2 2-Fluoro-3,4,5-trimethylphenyl H
    11 Cl NH2 H CH2 3,5-Dimethoxy-4-methylphenyl H
    12 Cl NH2 H CH2 2-Chloro-3,5-dimethoxy-4-methylphenyl H
    13 Cl NH2 H CH2 2-Bromo-3,5-dimethoxy-4-methylphenyl H
    14 Cl NH2 H CH2 2-Iodo-3,5-dimethoxy-4-methylphenyl H
    15 Cl NH2 H CH2 2-Fluoro-3,5-dimethoxy-4-methylphenyl H
    16 Cl NH2 i-pr CH2 3,4,5-Trimethoxyphenyl H
    17 Cl NH2 i-pr CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    18 Cl NH2 i-pr CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    19 Cl NH2 i-pr CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    20 Cl NH2 i-pr CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    21 Cl NH2 i-pr CH2 3,4,5-Trimethylphenyl H
    22 Cl NH2 i-pr CH2 2-Chloro-3,4,5-trimethylphenyl H
    23 Cl NH2 i-pr CH2 2-Bromo-3,4,5-trimethylphenyl H
    24 Cl NH2 i-pr CH2 2-Iodo-3,4,5-trimethylphenyl H
    25 Cl NH2 i-pr CH2 2-Fluoro-3,4,5-trimethylphenyl H
    26 Cl NH2 i-pr CH2 3,5-Dimethoxy-4-methylphenyl H
    27 Cl NH2 i-pr CH2 2-Chloro-3,5-dimethoxy-4-methylphenyl H
    28 Cl NH2 i-pr CU2 2-Bromo-3,5-dimethoxy-4-methylphenyl H
    29 Cl NH2 i-pr CU2 2-Iodo-3,5-dimethoxy-4-methylphenyl H
    30 Cl NH2 i-pr CU2 2-Fluoro-3,5-dimethoxy-4-methylphenyl H
    31 Cl NH2 Et CH2 3,4,5-Trimethoxyphenyl H
    32 Cl NH2 Et CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    33 Cl NH2 Et CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    34 Cl NH2 Et CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    35 Cl NH2 Et CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    36 Cl NH2 Et CH2 3,4,5-Trimethylphenyl H
    37 Cl NH2 Et CH2 2-Chloro-3,4,5-trimethylphenyl H
    38 Cl NH2 Et CH2 2-Bromo-3,4,5-trimethylphenyl H
    39 Cl NH2 Et CH2 2-Iodo-3,4,5-trimethylphenyl H
    40 Cl NH2 Et CH2 2-Fluoro-3,4,5-trimethylphenyl H
    41 Cl NH2 Et CH2 3,5-Dimethoxy-4-methylphenyl H
    42 Cl NH2 Et CH2 2-Chloro-3,5-dimethoxy-4-methylphenyl H
    43 Cl NH2 Et CH2 2-Bromo-3,5-dimethoxy-4-methylphenyl H
    44 Cl NH2 Et CH2 2-Iodo-3,5-dimethoxy-4-methylphenyl H
    45 Cl NH2 Et CH2 2-Fluoro-3,5-dimethoxy-4-methylphenyl H
    46 Cl NH2 Me CH2 3,4,5-Trimethoxyphenyl H
    47 Cl NH2 Me CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    48 Cl NH2 Me CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    49 Cl NH2 Me CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    50 Cl NH2 Me CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    51 Cl NH2 Me CH2 3,4,5-Trimethylphenyl H
    52 Cl NH2 Me CH2 2-Chloro-3,4,5-trimethylphenyl H
    53 Cl NH2 Me CH2 2-Bromo-3,4,5-trimethylphenyl H
    54 Cl NH2 Me CH2 2-Iodo-3,4,5-trimethylphenyl H
    55 Cl NH2 Me CH2 2-Fluoro-3,4,5-trimethylphenyl H
    56 Cl NH2 Me CH2 3,5-Dimethoxy-4-methylphenyl H
    57 Cl NH2 Me CH2 2-Chloro-3,5-dimethoxy-4-methylphenyl H
    58 Cl NH2 Me CH2 2-Bromo-3,5-dimethoxy-4-methylphenyl H
    59 Cl NH2 Me CH2 2-Iodo-3,5-dimethoxy-4-methylphenyl H
    60 Cl NH2 Me CH2 2-Fluoro-3,5-dimethoxy-4-methylphenyl H
    61 Cl NH2 Ph CH2 3,4,5-Trimethoxyphenyl H
    62 Cl NH2 Ph CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    63 Cl NH2 Ph CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    64 Cl NH2 Ph CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    65 Cl NH2 Ph CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    66 Cl NH2 Ph CH2 3,4,5-Trimethylphenyl H
    67 Cl NH2 Ph CH2 2-Chloro-3,4,5-trimethylphenyl H
    68 Cl NH2 Ph CH2 2-Bromo-3,4,5-trimethylphenyl H
    69 Cl NH2 Ph CH2 2-Iodo-3,4,5-trimethylphenyl H
    70 Cl NH2 Ph CH2 2-Fluoro-3,4,5-trimethylphenyl H
    71 Cl NH2 Ph CH2 3,5-Dimethoxy-4-methylphenyl H
    72 Cl NH2 Ph CH2 2-Chloro-3,5-dimethoxy-4-methylphenyl H
    73 Cl NH2 Ph CH2 2-Bromo-3,5-dimethoxy-4-methylphenyl H
    74 Cl NH2 Ph CH2 2-Iodo-3,5-dimethoxy-4-methylphenyl H
    75 Cl NH2 Ph CH2 2-Fluoro-3,5-dimethoxy-4-methylphenyl H
    76 Cl NH2 2-Py CH2 3,4,5-Trimethoxyphenyl H
    77 Cl NH2 2-Py CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    78 Cl NH2 2-Py CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    79 Cl NH2 2-Py CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    80 Cl NH2 2-Py CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    81 Cl NH2 2-Py CH2 3,4,5-Trimethylphenyl H
    82 Cl NH2 2-Py CH2 2-Chloro-3,4,5-trimethylphenyl H
    83 Cl NH2 2-Py CH2 2-Bromo-3,4,5-trimethylphenyl H
    84 Cl NH2 2-Py CH2 2-Iodo-3,4,5-trimethylphenyl H
    85 Cl NH2 2-Py CH2 2-Fluoro-3,4,5-trimethylphenyl H
    86 Cl NH2 2-Py CH2 3,5-Dimethoxy-4-methylphenyl H
    87 Cl NH2 2-Py CH2 2-Chloro-3,5-dimethoxy-4-methylphenyl H
    88 Cl NH2 2-Py CH2 2-Bromo-3,5-dimethoxy-4-methylphenyl H
    89 Cl NH2 2-Py CH2 2-Iodo-3,5-dimethoxy-4-methylphenyl H
    90 Cl NH2 2-Py CU2 2-Fluoro-3,5-dimethoxy-4-methylphenyl H
    91 Cl NH2 4-Py CH2 3,4,5-Trimethoxyphenyl H
    92 Cl NH2 4-Py CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    93 Cl NH2 4-Py CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    94 Cl NH2 4-Py CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    95 Cl NH2 4-Py CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    96 Cl NH2 Ph CH2 3,4,5-Trimethylphenyl H
    97 Cl NH2 Ph CH2 2-Chloro-3,4,5-trimethylphenyl H
    98 Cl NH2 Ph CH2 2-Bromo-3,4,5-trimethylphenyl H
    99 Cl NH2 Ph CH2 2-Iodo-3,4,5-trimethylphenyl H
    100 Cl NH2 Ph CH2 2-Fluoro-3,4,5-trimethylphenyl H
    101 Cl NH2 Ph CH2 3,5-Dimethoxy-4-methylphenyl H
    102 Cl NH2 Ph CH2 2-Chloro-3,5-dimethoxy-4-methylphenyl H
    103 Cl NH2 Ph CH2 2-Bromo-3,5-dimethoxy-4-methylphenyl H
    104 Cl NH2 Ph CH2 2-Iodo-3,5-dimethoxy-4-methylphenyl H
    105 Cl NH2 Pr CH2 2-Fluoro-3,5-dimethoxy-4-methylphenyl H
    106 Cl NH2 Pr CH2 3,5-Dimethoxy-4-methylphenyl H
    107 Cl NH2 Pr CH2 2-Chloro-3,5-dimethoxy-4-methylphenyl H
    108 Cl NH2 Pr CH2 2-Bromo-3,5-dimethoxy-4-methylphenyl H
    109 Cl NH2 Pr CH2 2-Iodo-3,5-dimethoxy-4-methylphenyl H
    110 Cl NH2 Pr CH2 2-Fluoro-3,5-dimethoxy-4-methylphenyl H
    111 Cl NH2 Pr CH2 3,4,5-Trimethoxyphenyl H
    112 Cl NH2 Pr CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    113 Cl NH2 Pr CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    114 Cl NH2 Pr CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    115 Cl NH2 Pr CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    116 Cl NH2 Pr CH2 3,4,5-Trimethylphenyl H
    117 Cl NH2 Pr CH2 2-Chloro-3,4,5-trimethylphenyl H
    118 Cl NH2 Pr CH2 2-Bromo-3,4,5-trimethylphenyl H
    119 Cl NH2 Pr CH2 2-Iodo-3,4,5-trimethylphenyl H
    120 Cl NH2 Pr CH2 2-Fluoro-3,4,5-trimethylphenyl H
    121 Cl NH2 Pr CH2 3,5-Dimethoxy-4-methylphenyl H
    122 Cl NH2 Pr CH2 2-Chloro-3,5-dimethoxy-4-methylphenyl H
    123 Cl NH2 Pr CH2 2-Bromo-3,5-dimethoxy-4-methylphenyl H
    124 Cl NH2 Pr CH2 2-Iodo-3,5-dimethoxy-4-methylphenyl H
    125 Cl NH2 Pr CH2 2-Fluoro-3,5-dimethoxy-4-methylphenyl H
    126 Br NH2 H CH2 3,4,5-Trimethoxyphenyl H
    127 Br NH2 H CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    128 Br NH2 H CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    129 Br NH2 H CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    130 Br NH2 H CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    131 Br NH2 H CH2 3,4,5-Trimethylphenyl H
    132 Br NH2 H CH2 2-Chloro-3,4,5-trimethylphenyl H
    133 Br NH2 H CH2 2-Bromo-3,4,5-trimethylphenyl H
    134 Br NH2 H CH2 2-Iodo-3,4,5-trimethylphenyl H
    135 Br NH2 H CH2 2-Fluoro-3,4,5-trimethylphenyl H
    136 Br NH2 H CH2 3,5-Dimethoxy-4-methylphenyl H
    137 Br NH2 H CH2 2-Chloro-3,5-dimethoxy-4-methylphenyl H
    138 Br NH2 H CH2 2-Bromo-3,5-dimethoxy-4-methylphenyl H
    139 Br NH2 H CH2 2-Iodo-3,5-dimethoxy-4-methylphenyl H
    140 Br NH2 H CH2 2-Fluoro-3,5-dimethoxy-4-methylphenyl H
    141 Cl NH2 i-Bu CH2 3,4,5-Trimethoxyphenyl H
    142 Cl NH2 i-Bu CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    143 Cl NH2 i-Bu CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    144 Cl NH2 i-Bu CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    145 Cl NH2 i-Bu CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    146 Cl NH2 i-Bu CH2 3,4,5-Trimethylphenyl H
    147 Cl NH2 i-Bu CH2 2-Chloro-3,4,5-trimethylphenyl H
    148 Cl NH2 i-Bu CH2 2-Bromo-3,4,5-trimethylphenyl H
    149 Cl NH2 i-Bu CH2 2-Iodo-3,4,5-trimethylphenyl H
    150 Cl NH2 i-Bu CH2 2-Fluoro-3,4,5-trimethylphenyl H
    151 Cl NH2 i-Bu CH2 3,5-Dimethoxy-4-methylphenyl H
    152 Cl NH2 i-Bu CH2 2-Chloro-3,5-dimethoxy-4-methylphenyl H
    153 Cl NH2 i-Bu CH2 2-Bromo-3,5-dimethoxy-4-methylphenyl H
    154 Cl NH2 i-Bu CH2 2-Iodo-3,5-dimethoxy-4-methylphenyl H
    155 Cl NH2 i-Bu CH2 2-Fluoro-3,5-dimethoxy-4-methylphenyl H
    156 Cl NH2 CN CH2 3,4,5-Trimethoxyphenyl H
    157 Cl NH2 CN CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    158 Cl NH2 CN CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    159 Cl NH2 CN CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    160 Cl NH2 CN CH2 3,4,5-Trimethoxyphenyl H
    161 Cl NH2 CN CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    162 Cl NH2 CN CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    163 Cl NH2 CN CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    164 Cl NH2 CN CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    165 Cl NH2 CN CH2 3,4,5-Trimethylphenyl H
    166 Cl NH2 CN CH2 2-Chloro-3,4,5-trimethylphenyl H
    167 Cl NH2 CN CH2 2-Bromo-3,4,5-trimethylphenyl H
    168 Cl NH2 CN CH2 2-Iodo-3,4,5-trimethylphenyl H
    169 Cl NH2 CN CH2 2-Fluoro-3,4,5-trimethylphenyl H
    170 Cl NH2 CN CH2 3,5-Dimethoxy-4-methylphenyl H
    171 Cl NH2 CN CH2 2-Chloro-3,5-dimethoxy-4-methylphenyl H
    172 Cl NH2 CN CH2 2-Bromo-3,5-dimethoxy-4-methylphenyl H
    173 Cl NH2 CN CH2 2-Iodo-3,5-dimethoxy-4-methylphenyl H
    174 Cl NH2 CN CH2 2-Fluoro-3,5-dimethoxy-4-methylphenyl H
    175 Cl NH2 Cl CH2 3,4,5-Trimethoxyphenyl H
    176 Cl NH2 Cl CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    177 Cl NH2 Cl CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    178 Cl NH2 Cl CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    179 Cl NH2 Cl CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    180 Cl NH2 Cl CH2 3,4,5-Trimethylphenyl H
    181 Cl NH2 Cl CH2 2-Chloro-3,4,5-trimethylphenyl H
    182 Cl NH2 Cl CH2 2-Bromo-3,4,5-trimethylphenyl H
    183 Cl NH2 Cl CH2 2-Iodo-3,4,5-trimethylphenyl H
    184 Cl NH2 Cl CH2 2-Fluoro-3,4,5-trimethylphenyl H
    185 Cl NH2 Cl CH2 3,5-Dimethoxy-4-methylphenyl H
    186 Cl NH2 Cl CH2 2-Chloro-3,5-dimethoxy-4-methylphenyl H
    187 Cl NH2 Cl CH2 2-Bromo-3,5-dimethoxy-4-methylphenyl H
    188 Cl NH2 Cl CH2 2-Iodo-3,5-dimethoxy-4-methylphenyl H
    189 Cl NH2 Cl CH2 2-Fluoro-3,5-dimethoxy-4-methylphenyl H
    190 Cl NH2 Br CH2 3,4,5-Trimethoxyphenyl H
    191 Cl NH2 Br CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    192 Cl NH2 Br CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    193 Cl NH2 Br CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    194 Cl NH2 Br CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    195 Cl NH2 Br CH2 3,4,5-Trimethylphenyl H
    196 Cl NH2 Br CH2 2-Chloro-3,4,5-trimethylphenyl H
    197 Cl NH2 Br CH2 2-Bromo-3,4,5-trimethylphenyl H
    198 Cl NH2 Br CH2 2-Iodo-3,4,5-trimethylphenyl H
    199 Cl NH2 Br CH2 2-Fluoro-3,4,5-trimethylphenyl H
    200 Cl NH2 Br CH2 3,5-Dimethoxy-4-methylphenyl H
    201 Cl NH2 Br CH2 2-Chloro-3,5-dimethoxy-4-methylphenyl H
    202 Cl NH2 Br CH2 2-Bromo-3,5-dimethoxy-4-methylphenyl H
    203 Cl NH2 Br CH2 2-Iodo-3,5-dimethoxy-4-methylphenyl H
    204 Cl NH2 Br CH2 2-Fluoro-3,5-dimethoxy-4-methylphenyl H
    205 Cl NH2 I CH2 3,4,5-Trimethoxyphenyl H
    206 Cl NH2 I CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    207 Cl NH2 I CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    208 Cl NH2 I CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    209 Cl NH2 I CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    210 Cl NH2 I CH2 3,4,5-Trimethylphenyl H
    211 Cl NH2 I CH2 2-Chloro-3,4,5-trimethylphenyl H
    212 Cl NH2 I CH2 2-Bromo-3,4,5-trimethylphenyl H
    213 Cl NH2 I CH2 2-Iodo-3,4,5-trimethylphenyl H
    214 Cl NH2 I CH2 2-Fluoro-3,4,5-trimethylphenyl H
    215 Cl NH2 I CH2 3,5-Dimethoxy-4-methylphenyl H
    216 Cl NH2 I CH2 2-Chloro-3,5-dimethoxy-4-methylphenyl H
    217 Cl NH2 I CH2 2-Bromo-3,5-dimethoxy-4-methylphenyl H
    218 Cl NH2 I CH2 2-Iodo-3,5-dimethoxy-4-methylphenyl H
    219 Cl NH2 I CH2 2-Fluoro-3,5-dimethoxy-4-methylphenyl H
    220 Cl NH2 CH2—NMe2 CH2 3,4,5-Trimethoxyphenyl H
    221 Cl NH2 CH2—NMe2 CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    222 Cl NH2 CH2—NMe2 CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    223 Cl NH2 CH2—NMe2 CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    224 Cl NH2 CH2—NMe2 CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    225 Cl NH2 CH2—NMe2 CH2 3,4,5-Trimethylphenyl H
    226 Cl NH2 CH2—NMe2 CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    227 Cl NH2 CH2—NMe2 CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    228 Cl NH2 CH2—NMe2 CH2 2-Iodo-3,4,5-trimethylphenyl H
    229 Cl NH2 CH2—NMe2 CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    230 Cl NH2 CH2—NMe2 CH2 3,5-Dimethoxy-4-methylphenyl H
    231 Cl NH2 CH2—NMe2 CH2 2-Chloro-3,5-dimethoxy-4-methylphenyl H
    232 Cl NH2 CH2—NMe2 CH2 2-Bromo-3,5-dimethoxy-4-methylphenyl H
    233 Cl NH2 CH2—NMe2 CH2 2-Iodo-3,5-dimethoxy-4-methylphenyl H
    234 Cl NH2 CH2—NMe2 CH2 2-Fluoro-3,5-dimethoxy-4-methylphenyl H
    235 Cl NH2 3-Py CH2 3,4,5-Trimethoxyphenyl H
    236 Cl NH2 3-Py CH2 2-Chloro-3,4,5-trimethoxyphenyl H
    237 Cl NH2 3-Py CH2 2-Bromo-3,4,5-trimethoxyphenyl H
    238 Cl NH2 3-Py CH2 2-Iodo-3,4,5-trimethoxyphenyl H
    239 Cl NH2 3-Py CH2 2-Fluoro-3,4,5-trimethoxyphenyl H
    240 5 Cl NH2 H CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    241 8 Cl NH2 H CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    242 Cl NH2 H CH2 6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl H
    243 10 Cl NH2 H CH2 6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl H
    244 13 Cl NH2 H CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    245 15 Cl NH2 H CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    246 11 Cl NH2 H CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    247 14 Cl NH2 H CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    248 Cl NH2 H CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    249 Cl NH2 H CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    250 Cl NH2 H CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    251 Cl NH2 H CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    252 Cl NH2 H CH2 3,4,5-Trimethyl-pyridin-2-yl H
    253 Cl NH2 H CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    254 Cl NH2 H CH2 4,5,6-Trimethoxypyridin-2-yl H
    255 Cl NH2 H CH2 4,5,6-Trimethoxy-1-oxypyridin-2-yl H
    256 Cl NH2 H CH2 3-Bromo-4,5,6-trimethoxypyridin-2-yl H
    257 Cl NH2 H CH2 3-Chloro-4,5,6-trimethoxypyridin-2-yl H
    258 Cl NH2 H CH2 3,4,5-Trimethoxy-pyridin-2-yl H
    259 Cl NH2 H CH2 3,4,5-Trimethoxy-1-oxypyridin-2-yl H
    260 Cl NH2 H CH2 3-Bromo-3,4,5-trimethoxy-pyridin-2-yl H
    261 Cl NH2 H CH2 3-Chloro-3,4,5-trimethoxy-pyridin-2-yl H
    262 Cl NH2 H CH2 4,5,6-Trimethyl-pyridin-2-yl H
    263 Cl NH2 H CH2 4,5,6-Trimethyl-1-oxypyridin-2-yl H
    264 Cl NH2 H CH2 4,6-Dimethyl-5-methoxy-pyridin-2-yl H
    265 Cl NH2 H CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    266 Cl NH2 H CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    267 Cl NH2 H CH2 4,6-Dimethyl-5-bromopyridin-3-yl H
    268 Cl NH2 H CH2 4,6-Dimethyl-5-chloropyridin-3-yl H
    269 Cl NH2 H CH2 5,6-Dimethyl-4-bromopyridin-3-yl H
    270 Cl NH2 H CH2 5,6-Dimethyl-4-chloropyridin-3-yl H
    271 Cl NH2 H CH2 2,6-Dimethyl-3-methoxypyridin-4-yl H
    272 Cl NH2 H CH2 2,6-Dimethyl-pyridin-4-yl H
    273 Cl NH2 H CH2 2,3,6-Trimethyl-pyridin-4-yl H
    274 Cl NH2 H CH2 2,3,6-Trimethoxy-pyridin-4-yl H
    275 Cl NH2 H CH2 2,6-Dimethyl-3-bromopyridin-4-yl H
    276 Cl NH2 H CH2 2,6-Dimethyl-3-chloropyridin-4-yl H
    277 Cl NH2 H CH2 2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl H
    278 Cl NH2 H CH2 2,6-Dimethyl-1-oxy-pyridin-4-yl H
    279 Cl NH2 H CH2 2,3,6-Trimethyl-1-oxy-pyridin-4-yl H
    280 Cl NH2 H CH2 2,3,6-Trimethoxy-1-oxy-pyridin-4-yl H
    281 Cl NH2 H CH2 2,6-Dimethyl-3-bromo1-oxy-pyridin-4-yl H
    282 Cl NH2 H CH2 2,6-Dimethyl-3-chloro1-oxy-pyridin-4-yl H
    283 Cl NH2 H CH2 4,6-Dimethyl-5-iodopyridin-3-yl H
    284 Cl NH2 H CH2 3,5-Dimethyl-4-aminopyridin-2-yl H
    285 Cl NH2 i-pr CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    286 Cl NH2 i-pr CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    287 Cl NH2 i-pr CH2 6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl H
    288 Cl NH2 i-pr CH2 6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl H
    289 Cl NH2 i-pr CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    290 Cl NH2 i-pr CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    291 Cl NH2 i-pr CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    292 Cl NH2 i-pr CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    293 Cl NH2 i-pr CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    294 Cl NH2 i-pr CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    295 Cl NH2 i-pr CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    296 Cl NH2 i-pr CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    297 Cl NH2 i-pr CH2 3,4,5-Trimethyl-pyridin-2-yl H
    298 Cl NH2 i-pr CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    299 Cl NH2 i-pr CH2 4,5,6-Trimethoxypyridin-2-yl H
    300 Cl NH2 i-pr CH2 4,5,6-Trimethoxy-1-oxypyridin-2-yl H
    301 Cl NH2 i-pr CH2 3-Bromo-4,5,6-trimethoxypyridin-2-yl H
    302 Cl NH2 i-pr CH2 3-Chloro-4,5,6-trimethoxypyridin-2-yl H
    303 Cl NH2 i-pr CH2 3,4,5-Trimethoxy-pyridin-2-yl H
    304 Cl NH2 i-pr CH2 3,4,5-Trimethoxy-1-oxypyridin-2-yl H
    305 Cl NH2 i-pr CH2 3-Bromo-3,4,5-trimethoxy-pyridin-2-yl H
    306 Cl NH2 i-pr CH2 3-Chloro-3,4,5-trimethoxy-pyridin-2-yl H
    307 Cl NH2 i-pr CH2 4,5,6-Trimethyl-pyridin-2-yl H
    308 Cl NH2 i-pr CH2 4,5,6-Trimethyl-1-oxypyridin-2-yl H
    309 Cl NH2 i-pr CH2 4,6-Dimethyl-5-methoxy-pyridin-2-yl H
    310 Cl NH2 i-pr CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    311 Cl NH2 i-pr CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    312 Cl NH2 i-pr CH2 4,6-Dimethyl-5-bromopyridin-3-yl H
    313 Cl NH2 i-pr CH2 4,6-Dimethyl-5-chloropyridin-3-yl H
    314 Cl NH2 i-pr CH2 5,6-Dimethyl-4-bromopyridin-3-yl H
    315 Cl NH2 i-pr CH2 5,6-Dimethyl-4-chloropyridin-3-yl H
    316 Cl NH2 i-pr CH2 2,6-Dimethyl-3-methoxypyridin-4-yl H
    317 Cl NH2 i-pr CH2 2,6-Dimethyl-pyridin-4-yl H
    318 Cl NH2 i-pr CH2 2,3,6-Trimethyl-pyridin-4-yl H
    319 Cl NH2 i-pr CH2 2,3,6-Trimethoxy-pyridin-4-yl H
    320 Cl NH2 i-pr CH2 2,6-Dimethyl-3-bromopyridin-4-yl H
    321 Cl NH2 i-pr CH2 2,6-Dimethyl-3-chloropyridin-4-yl H
    322 Cl NH2 i-pr CH2 2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl H
    323 Cl NH2 i-pr CH2 2,6-Dimethyl-1-oxy-pyridin-4-yl H
    324 Cl NH2 i-pr CH2 2,3,6-Trimethyl-1-oxy-pyridin-4-yl H
    325 Cl NH2 i-pr CH2 2,3,6-Trimethoxy-1-oxy-pyridin-4-yl H
    326 Cl NH2 i-pr CH2 2,6-Dimethyl-3-bromo1-oxy-pyridin-4-yl H
    327 Cl NH2 i-pr CH2 2,6-Dimethyl-3-chloro1-oxy-pyridin-4-yl H
    328 Cl NH2 i-pr CH2 4,6-Dimethyl-5-iodopyridin-3-yl H
    329 Cl NH2 i-pr CH2 3,5-Dimethyl-4-aminopyridin-2-yl H
    330 Cl NH2 Me CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    331 Cl NH2 Me CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    332 Cl NH2 Me CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    333 Cl NH2 Me CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    334 Cl NH2 Me CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    335 Cl NH2 Me CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    336 Cl NH2 Me CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    337 Cl NH2 Me CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    338 Cl NH2 Me CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    339 Cl NH2 Me CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    340 Cl NH2 Me CH2 3,4,5-Trimethyl-pyridin-2-yl H
    341 Cl NH2 Me CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    342 Cl NH2 Me CH2 4,5,6-Trimethoxypyridin-2-yl H
    343 Cl NH2 Me CH2 4,5,6-Trimethoxy-1-oxypyridin-2-yl H
    344 Cl NH2 Me CH2 3,4,5-Trimethoxy-pyridin-2-yl H
    345 Cl NH2 Me CH2 3,4,5-Trimethoxy-1-oxypyridin-2-yl H
    346 Cl NH2 Me CH2 4,5,6-Trimethyl-pyridin-2-yl H
    347 Cl NH2 Me CH2 4,5,6-Trimethyl-1-oxypyridin-2-yl H
    348 Cl NH2 Me CH2 4,6-Dimethyl-5-methoxy-pyridin-2-yl H
    349 Cl NH2 Me CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    350 Cl NH2 Me CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    351 Cl NH2 Me CH2 4,6-Dimethyl-5-bromopyridin-3-yl H
    352 Cl NH2 Me CH2 4,6-Dimethyl-5-chloropyridin-3-yl H
    353 Cl NH2 Me CH2 5,6-Dimethyl-4-bromopyridin-3-yl H
    354 Cl NH2 Me CH2 5,6-Dimethyl-4-chloropyridin-3-yl H
    355 Cl NH2 Me CH2 2,6-Dimethyl-3-methoxypyridin-4-yl H
    356 Cl NH2 Me CH2 2,6-Dimethyl-pyridin-4-yl H
    357 Cl NH2 Me CH2 2,3,6-Trimethyl-pyridin-4-yl H
    358 Cl NH2 Me CH2 2,3,6-Trimethoxy-pyridin-4-yl H
    359 Cl NH2 Me CH2 2,6-Dimethyl-3-bromopyridin-4-yl H
    360 Cl NH2 Me CH2 2,6-Dimethyl-3-chloropyridin-4-yl H
    361 Cl NH2 Me CH2 4,6-Dimethyl-5-iodopyridin-3-yl H
    362 Cl NH2 Me CH2 3,5-Dimethyl-4-aminopyridin-2-yl H
    363 Cl NH2 Et CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    364 Cl NH2 Et CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    365 Cl NH2 Et CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    366 Cl NH2 Et CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    367 Cl NH2 Et CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    368 Cl NH2 Et CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    369 Cl NH2 Et CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    370 Cl NH2 Et CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    371 Cl NH2 Ef CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    372 Cl NH2 Et CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    373 Cl NH2 Et CH2 3,4,5-Trimethyl-pyridin-2-yl H
    374 Cl NH2 Et CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    375 Cl NH2 Et CH2 4,5,6-Trimethoxypyridin-2-yl H
    376 Cl NH2 Et CH2 4,5,6-Trimethoxy-1-oxypyridin-2-yl H
    377 Cl NH2 Et CH2 3,4,5-Trimethoxy-pyridin-2-yl H
    378 Cl NH2 Et CH2 3,4,5-Trimethoxy-1-oxypyridin-2-yl H
    379 Cl NH2 Et CH2 4,5,6-Trimethyl-pyridin-2-yl H
    380 Cl NH2 Et CH2 4,5,6-Trimethyl-1-oxypyridin-2-yl H
    381 Cl NH2 Et CH2 4,6-Dimethyl-5-methoxy-pyridin-2-yl H
    382 Cl NH2 Et CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    383 Cl NH2 Et CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    384 Cl NH2 Et CH2 4,6-Dimethyl-5-bromopyridin-3-yl H
    385 Cl NH2 Et CH2 4,6-Dimethyl-5-chloropyridin-3-yl H
    386 Cl NH2 Et CH2 5,6-Dimethyl-4-bromopyridin-3-yl H
    387 Cl NH2 Et CH2 5,6-Dimethyl-4-chloropyridin-3-yl H
    388 Cl NH2 Et CH2 2,6-Dimethyl-3-methoxypyridin-4-yl H
    389 Cl NH2 Et CH2 2,6-Dimethyl-pyridin-4-yl H
    390 Cl NH2 Et CH2 2,3,6-Trimethyl-pyridin-4-yl H
    391 Cl NH2 Et CH2 2,3,6-Trimethoxy-pyridin-4-yl H
    392 Cl NH2 Et CH2 2,6-Dimethyl-3-bromopyridin-4-yl H
    393 Cl NH2 Et CH2 2,6-Dimethyl-3-chloropyridin-4-yl H
    394 Cl NH2 Et CH2 4,6-Dimethyl-5-iodopyridin-3-yl H
    395 Cl NH2 Et CH2 3,5-Dimethyl-4-aminopyridin-2-yl H
    396 Cl NH2 2-Py CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    397 Cl NH2 2-Py CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    398 Cl NH2 2-Py CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    399 Cl NH2 2-Py CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    400 Cl NH2 2-Py CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    401 Cl NH2 2-Py CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    402 Cl NH2 2-Py CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    403 Cl NH2 2-Py CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    404 Cl NH2 2-Py CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    405 Cl NH2 2-Py CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    406 Cl NH2 2-Py CH2 3,4,5-Trimethyl-pyridin-2-yl H
    407 Cl NH2 2-Py CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    408 Cl NH2 2-Py CH2 4,5,6-Trimethoxypyridin-2-yl H
    409 Cl NH2 2-Py CH2 4,5,6-Trimethoxy-1-oxypyridin-2-yl H
    410 Cl NH2 2-Py CH2 3,4,5-Trimethoxy-pyridin-2-yl H
    411 Cl NH2 2-Py CH2 3,4,5-Trimethoxy-1-oxypyridin-2-yl H
    412 Cl NH2 2-Py CH2 4,5,6-Trimethyl-pyridin-2-yl H
    413 Cl NH2 2-Py CH2 4,5,6-Trimethyl-1-oxypyridin-2-yl H
    414 Cl NH2 2-Py CH2 4,6-Dimethyl-5-methoxy-pyridin-2-yl H
    415 Cl NH2 2-Py CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    416 Cl NH2 2-Py CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    417 Cl NH2 2-Py CH2 4,6-Dimethyl-5-bromopyridin-3-yl H
    418 Cl NH2 2-Py CH2 4,6-Dimethyl-5-chloropyridin-3-yl H
    419 Cl NH2 2-Py CH2 5,6-Dimethyl-4-bromopyridin-3-yl H
    420 Cl NH2 2-Py CH2 5,6-Dimethyl-4-chloropyridin-3-yl H
    421 Cl NH2 2-Py CH2 2,6-Dimethyl-3-methoxypyridin-4-yl H
    422 Cl NH2 2-Py CH2 2,6-Dimethyl-pyridin-4-yl H
    423 Cl NH2 2-Py CH2 2,3,6-Trimethyl-pyridin-4-yl H
    424 Cl NH2 2-Py CH2 2,3,6-Trimethoxy-pyridin-4-yl H
    425 Cl NH2 2-Py CH2 2,6-Dimethyl-3-bromopyridin-4-yl H
    426 Cl NH2 2-Py CH2 2,6-Dimethyl-3-chloropyridin-4-yl H
    427 Cl NH2 2-Py CH2 4,6-Dimethyl-5-iodopyridin-3-yl H
    428 Cl NH2 2-Py CH2 3,5-Dimethyl-4-aminopyridin-2-yl H
    429 Cl NH2 Ph CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    430 Cl NH2 Ph CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    431 Cl NH2 Ph CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    432 Cl NH2 Ph CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    433 Cl NH2 Ph CH2 3,5-Dmethyl-4-chloropyridin-2-yl H
    434 Cl NH2 Ph CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    435 Cl NH2 Ph CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    436 Cl NH2 Ph CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    437 Cl NH2 Ph CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    438 Cl NH2 Ph CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    439 Cl NH2 Ph CH2 3,4,5-Trimethyl-pyridin-2-yl H
    440 Cl NH2 Ph CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    441 Cl NH2 Ph CH2 4,5,6-Trimethoxypyridin-2-yl H
    442 Cl NH2 Ph CH2 4,5,6-Trimethoxy-1-oxypyridin-2-yl H
    443 Cl NH2 Ph CH2 3,4,5-Trimethoxy-pyridin-2-yl H
    444 Cl NH2 Ph CH2 3,4,5-Trimethoxy-1-oxypyridin-2-yl H
    445 Cl NH2 Ph CH2 4,5,6-Trimethyl-pyridin-2-yl H
    446 Cl NH2 Ph CH2 4,5,6-Trimethyl-1-oxypyridin-2-yl H
    447 Cl NH2 Ph CH2 4,6-Dimethyl-5-methoxy-pyridin-2-yl H
    448 Cl NH2 Ph CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    449 Cl NH2 Ph CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    450 Cl NH2 Ph CH2 4,6-Dimethyl-5-bromopyridin-3-yl H
    451 Cl NH2 Ph CH2 4,6-Dimethyl-5-chloropyridin-3-yl H
    452 Cl NH2 Ph CH2 5,6-Dimethyl-4-bromopyridin-3-yl H
    453 Cl NH2 Ph CH2 5,6-Dimethyl-4-chloropyridin-3-yl H
    454 Cl NH2 Ph CH2 2,6-Dimethyl-3-methoxypyridin-4-yl H
    455 Cl NH2 Ph CH2 2,6-Dimethyl-pyridin-4-yl H
    456 Cl NH2 Ph CH2 2,3,6-Trimethyl-pyridin-4-yl H
    457 Cl NH2 Ph CH2 2,3,6-Trimethoxy-pyridin-4-yl H
    458 Cl NH2 Ph CH2 2,6-Dimethyl-3-bromopyridin-4-yl H
    459 Cl NH2 Ph CH2 2,6-Dimethyl-3-chloropyridin-4-yl H
    460 Cl NH2 Ph CH2 4,6-Dimethyl-5-iodopyridin-3-yl H
    461 Cl NH2 Ph CH2 3,5-Dimethyl-4-aminopyridin-2-yl H
    462 Cl NH2 3-Py CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    463 Cl NH2 3-Py CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    464 Cl NH2 3-Py CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    465 Cl NH2 3-Py CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    466 Cl NH2 3-Py CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    467 Cl NH2 3-Py CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    468 Cl NH2 3-Py CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    469 Cl NH2 3-Py CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    470 Cl NH2 3-Py CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    471 Cl NH2 3-Py CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    472 Cl NH2 3-Py CH2 3,4,5-Trimethyl-pyridin-2-yl H
    473 Cl NH2 3-Py CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    474 Cl NH2 3-Py CH2 4,5,6-Trimethoxypyridin-2-yl H
    475 Cl NH2 3-Py CH2 4,5,6-Trimethoxy-1-oxypyridin-2-yl H
    476 Cl NH2 3-Py CH2 3,4,5-Trimethoxy-pyridin-2-yl H
    477 Cl NH2 3-Py CH2 3,4,5-Trimethoxy-1-oxypyridin-2-yl H
    478 Cl NH2 3-Py CH2 4,5,6-Trimethyl-pyridin-2-yl H
    479 Cl NH2 3-Py CH2 4,5,6-Trimethyl-1-oxypyridin-2-yl H
    480 Cl NH2 3-Py CH2 4,6-Dimethyl-5-methoxy-pyridin-2-yl H
    481 Cl NH2 3-Py CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    482 Cl NH2 3-Py CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    483 Cl NH2 3-Py CH2 4,6-Dimethyl-5-bromopyridin-3-yl H
    484 Cl NH2 3-Py CH2 4,6-Dimethyl-5-chloropyridin-3-yl H
    485 Cl NH2 3-Py CH2 5,6-Dimethyl-4-bromopyridin-3-yl H
    486 Cl NH2 3-Py CH2 5,6-Dimethyl-4-chloropyridin-3-yl H
    487 Cl NH2 3-Py CH2 2,6-Dimethyl-3-methoxypyridin-4-yl H
    488 Cl NH2 3-Py CH2 2,6-Dimethyl-pyridin-4-yl H
    489 Cl NH2 3-Py CH2 2,3,6-Trimethyl-pyridin-4-yl H
    490 Cl NH2 3-Py CH2 2,3,6-Trimethoxy-pyridin-4-yl H
    491 Cl NH2 3-Py CH2 2,6-Dimethyl-3-bromopyridin-4-yl H
    492 Cl NH2 3-Py CH2 2,6-Dimethyl-3-chloropyridin-4-yl H
    493 Cl NH2 3-Py CH2 4,6-Dimethyl-5-iodopyridin-3-yl H
    494 Cl NH2 3-Py CH2 3,5-Dimethyl-4-aminopyridin-2-yl H
    495 Cl NH2 CH2—NMe2 CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    496 Cl NH2 CH2—NMe2 CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    497 Cl NH2 CH2—NMe2 CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    498 Cl NH2 CH2—NMe2 CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    499 Cl NH2 CH2—NMe2 CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    500 Cl NH2 CH2—NMe2 CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    501 Cl NH2 CH2—NMe2 CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    502 Cl NH2 CH2—NMe2 CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    503 Cl NH2 CH2—NMe2 CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    504 Cl NH2 CH2—NMe2 CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    505 Cl NH2 CH2—NMe2 CH2 3,4,5-Trimethyl-pyridin-2-yl H
    506 Cl NH2 CH2—NMe2 CH2 3,4,5-Trimethyl-pyridin-2-yl H
    507 Cl NH2 CH2—NMe2 CH2 4,5,6-Trimethoxypyridin-2-yl H
    508 Cl NH2 CH2—NMe2 CH2 4,5,6-Trimethoxy-1-oxypyridin-2-yl H
    509 Cl NH2 CH2—NMe2 CH2 3,4,5-Trimethoxy-pyridin-2-yl H
    510 Cl NH2 CH2—NMe2 CH2 3,4,5-Trimethoxy-1-oxypyridin-2-yl H
    511 Cl NH2 CH2—NMe2 CH2 4,5,6-Trimethyl-pyridin-2-yl H
    512 Cl NH2 CH2—NMe2 CH2 4,5,6-Trimethyl-1-oxypyridin-2-yl H
    513 Cl NH2 CH2—NMe2 CH2 4,6-Dimethyl-5-methoxy-pyridin-2-yl H
    514 Cl NH2 CH2—NMe2 CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    515 Cl NH2 CH2—NMe2 CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    516 Cl NH2 CH2—NMe2 CH2 4,6-Dimethyl-5-bromopyridin-3-yl H
    517 Cl NH2 CH2—NMe2 CH2 4,6-Dimethyl-5-chloropyridin-3-yl H
    518 Cl NH2 CH2—NMe2 CH2 5,6-Dimethyl-4-bromopyridin-3-yl H
    519 Cl NH2 CH2—NMe2 CH2 5,6-Dimethyl-4-chloropyridin-3-yl H
    520 Cl NH2 CH2—NMe2 CH2 2,6-Dimethyl-3-methoxypyridin-4-yl H
    521 Cl NH2 CH2—NMe2 CH2 2,6-Dimethyl-pyridin-4-yl H
    522 Cl NH2 CH2—NMe2 CH2 2,3,6-Trimethyl-pyridin-4-yl H
    523 Cl NH2 CH2—NMe2 CH2 2,3,6-Trimethoxy-pyridin-4-yl H
    524 Cl NH2 CH2—NMe2 CH2 2,6-Dimethyl-3-bromopyridin-4-yl H
    525 Cl NH2 CH2—NMe2 CH2 2,6-Dimethyl-3-chloropyridin-4-yl H
    526 Cl NH2 CH2—NMe2 CH2 4,6-Dimethyl-5-iodopyridin-3-yl H
    527 Cl NH2 CH2—NMe2 CH2 3,5-Dimethyl-4-aminopyridin-2-yl H
    528 Cl NH2 2-furanyl CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    529 Cl NH2 2-furanyl CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    530 Cl NH2 2-furanyl CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    531 Cl NH2 2-furanyl CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    532 Cl NH2 2-furanyl CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    533 Cl NH2 2-furanyl CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    534 Cl NH2 2-furanyl CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    535 Cl NH2 2-furanyl CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    536 Cl NH2 2-furanyl CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    537 Cl NH2 2-furanyl CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    538 Cl NH2 2-furanyl CH2 3,4,5-Trimethyl-pyridin-2-yl H
    539 Cl NH2 2-furanyl CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    540 Cl NH2 2-furanyl CH2 4,5,6-Trimethoxypyridin-2-yl H
    541 Cl NH2 2-furanyl CH2 4,5,6-Trimethoxy-1-oxypyridin-2-yl H
    542 Cl NH2 2-furanyl CH2 3,4,5-Trimethoxy-pyridin-2-yl H
    543 Cl NH2 2-furanyl CH2 3,4,5-Trimethoxy-1-oxypyridin-2-yl H
    544 Cl NH2 2-furanyl CH2 4,5,6-Trimethyl-pyridin-2-yl H
    545 Cl NH2 2-furanyl CH2 4,5,6-Trimethyl-1-oxypyridin-2-yl H
    546 Cl NH2 2-furanyl CH2 4,6-Dimethyl-5-methoxy-pyridin-2-yl H
    547 Cl NH2 2-furanyl CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    548 Cl NH2 2-furanyl CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    549 Cl NH2 2-furanyl CH2 4,6-Dimethyl-5-bromopyridin-3-yl H
    550 Cl NH2 2-furanyl CH2 4,6-Dimethyl-5-chloropyridin-3-yl H
    551 Cl NH2 2-furanyl CH2 5,6-Dimethyl-4-bromopyridin-3-yl H
    552 Cl NH2 2-furanyl CH2 5,6-Dimethyl-4-chloropyridin-3-yl H
    553 Cl NH2 2-furanyl CH2 2,6-Dimethyl-3-methoxypyridin-4-yl H
    554 Cl NH2 2-furanyl CH2 2,6-Dimethyl-pyridin-4-yl H
    555 Cl NH2 2-furanyl CH2 2,3,6-Trimethyl-pyridin-4-yl H
    556 Cl NH2 2-furanyl CH2 2,3,6-Trimethoxy-pyridin-4-yl H
    557 Cl NH2 2-furanyl CH2 2,6-Dimethyl-3-bromopyridin-4-yl H
    558 Cl NH2 2-furanyl CH2 2,6-Dimethyl-3-chloropyridin-4-yl H
    559 Cl NH2 2-furanyl CH2 3,5-Dimethyl-4-aminopyridin-2-yl H
    560 Cl NH2 Cl CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    561 Cl NH2 Cl CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    562 Cl NH2 Cl CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    563 Cl NH2 Cl CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    564 Cl NH2 Cl CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    565 Cl NH2 Cl CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    566 Cl NH2 Cl CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    567 Cl NH2 Cl CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    568 Cl NH2 Cl CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    569 Cl NH2 Cl CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    570 Cl NH2 Cl CH2 3,4,5-Trimethyl-pyridin-2-yl H
    571 Cl NH2 Cl CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    572 Cl NH2 Cl CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    573 Cl NH2 Cl CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    574 Cl NH2 Cl CH2 3,5-Dimethyl-4-aminopyridin-2-yl H
    575 Cl NH2 Br CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    576 Cl NH2 Br CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    577 Cl NH2 Br CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    578 Br NH2 Br CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    579 Cl NH2 Br CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    580 Br NH2 Br CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    581 Cl NH2 Br CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    582 Br NH2 Br CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    583 Cl NH2 Br CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    584 Br NH2 Br CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    585 Cl NH2 Br CH2 3,4,5-Trimethyl-pyridin-2-yl H
    586 Br NH2 Br CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    587 Cl NH2 Br CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    588 Cl NH2 Br CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    589 Cl NH2 Br CH2 3,5-Dimethyl-4-aminopyridin-2-yl H
    590 Cl NH2 I CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    591 Cl NH2 I CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    592 Cl NH2 I CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    593 Cl NH2 I CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    594 Cl NH2 I CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    595 Cl NH2 I CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    596 Cl NH2 I CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    597 Cl NH2 I CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    598 Cl NH2 I CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    599 Cl NH2 I CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    600 Cl NH2 I CH2 3,4,5-Trimethyl-pyridin-2-yl H
    601 Cl NH2 I CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    602 Cl NH2 I CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    603 Cl NH2 I CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    604 Cl NH2 I CH2 3,5-Dimethyl-4-aminopyridin-2-yl H
    605 Cl NH2 CN CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    606 Cl NH2 CN CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    607 Cl NH2 CN CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    608 Cl NH2 CN CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    609 Cl NH2 CN CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    610 Cl NH2 CN CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    611 Cl NH2 CN CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    612 Cl NH2 CN CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    613 Cl NH2 CN CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    614 Cl NH2 CN CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    615 Cl NH2 CN CH2 3,4,5-Trimethyl-pyridin-2-yl H
    616 Cl NH2 CN CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    617 Cl NH2 CN CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    618 Cl NH2 CN CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    619 Cl NH2 CN CH2 3,5-Dimethyl-4-aminopyridin-2-yl H
    620 Cl NH2 H C(O) 3,5-Dimethyl-4-methoxypyridin-2-yl H
    621 Cl NH2 H C(O) 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    622 Cl NH2 H C(O) 3,5-Dimethyl-4-bromopyridin-2-yl H
    623 Cl NH2 H C(O) 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    624 Cl NH2 H C(O) 3,5-Dimethyl-4-chloropyridin-2-yl H
    625 Cl NH2 H C(O) 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    626 Cl NH2 H C(O) 3,5-Dimethyl-4-iodopyridin-2-yl H
    627 Cl NH2 H C(O) 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    628 Cl NH2 H C(O) 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    629 Cl NH2 H C(O) 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    630 Cl NH2 H C(O) 3,4,5-Trimethyl-pyridin-2-yl H
    631 Cl NH2 H C(O) 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    632 Cl NH2 H C(O) 4,6-Dimethyl-5-methoxypyridin-3-yl H
    633 Cl NH2 H C(O) 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    634 Cl NH2 H C(O) 3,5-Dimethyl-4-aminopyridin-2-yl H
    635 Cl NH2 H S(O) 3,5-Dimethyl-4-methoxypyridin-2-yl H
    636 Cl NH2 H S(O) 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    637 Cl NH2 H S(O) 3,5-Dimethyl-4-bromopyridin-2-yl H
    638 Cl NH2 H S(O) 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    639 Cl NH2 H S(O) 3,5-Dimethyl-4-chloropyridin-2-yl H
    640 Cl NH2 H S(O) 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    641 Cl NH2 H S(O) 3,5-Dimethyl-4-iodopyridin-2-yl H
    642 Cl NH2 H S(O) 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    643 Cl NH2 H S(O) 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    644 Cl NH2 H S(O) 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    645 Cl NH2 Br S(O) 3,4,5-Trimethyl-pyridin-2-yl H
    646 Cl NH2 H S(O) 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    647 Cl NH2 Br S(O) 4,6-Dimethyl-5-methoxypyridin-3-yl H
    648 Cl NH2 H S(O) 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    649 Cl NH2 H SO2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    650 Cl NH2 H SO2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    651 Cl NH2 H SO2 3,5-Dimethyl-4-bromopyridin-2-yl H
    652 Cl NH2 H SO2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    653 Cl NH2 Br SO2 3,5-Dimethyl-4-chloropyridin-2-yl H
    654 Cl NH2 H SO2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    655 Cl NH2 H SO2 3,5-Dimethyl-4-iodopyridin-2-yl H
    656 Cl NH2 H SO2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    657 Cl NH2 H SO2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    658 Cl NH2 H SO2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    659 Cl NH2 H SO2 3,4,5-Trimethyl-pyridin-2-yl H
    660 Cl NH2 H SO2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    661 Cl NH2 H SO2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    662 Cl NH2 H SO2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    663 Cl NH2 i-pr C(O) 3,5-Dimethyl-4-methoxypyridin-2-yl H
    664 Cl NH2 i-pr C(O) 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    665 Cl NH2 i-pr C(O) 3,5-Dimethyl-4-bromopyridin-2-yl H
    666 Cl NH2 i-pr C(O) 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    667 Cl NH2 i-pr C(O) 3,5-Dimethyl-4-chloropyridin-2-yl H
    668 Cl NH2 i-pr C(O) 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    669 Cl NH2 i-pr C(O) 3,5-Dimethyl-4-iodopyridin-2-yl H
    670 Cl NH2 i-pr C(O) 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    671 Cl NH2 i-pr C(O) 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    672 Cl NH2 i-pr C(O) 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    673 Cl NH2 i-pr C(O) 3,4,5-Trimethyl-pyridin-2-yl H
    674 Cl NH2 i-pr C(O) 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    675 Cl NH2 i-pr C(O) 4,6-Dimethyl-5-methoxypyridin-3-yl H
    676 Cl NH2 i-pr C(O) 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    677 Cl NH2 i-pr C(O) 3,5-Dimethyl-4-aminopyridin-2-yl H
    678 Cl NH2 i-pr S(O) 3,5-Dimethyl-4-methoxypyridin-2-yl H
    679 Cl NH2 i-pr S(O) 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    680 Cl NH2 i-pr S(O) 3,5-Dimethyl-4-bromopyridin-2-yl H
    681 Cl NH2 i-pr S(O) 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    682 Cl NH2 i-pr S(O) 3,5-Dimethyl-4-chloropyridin-2-yl H
    683 Cl NH2 i-pr S(O) 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    684 Cl NH2 i-pr S(O) 3,5-Dimethyl-4-iodopyridin-2-yl H
    685 Cl NH2 i-pr S(O) 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    686 Cl NH2 i-pr S(O) 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    687 Cl NH2 i-pr S(O) 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    688 Cl NH2 i-pr S(O) 3,4,5-Trimethyl-pyridin-2-yl H
    689 Cl NH2 i-pr S(O) 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    690 Cl NH2 i-pr S(O) 4,6-Dimethyl-5-methoxypyridin-3-yl H
    691 Cl NH2 i-pr S(O) 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    692 Cl NH2 i-pr SO2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    693 Cl NH2 i-pr SO2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    694 Cl NH2 i-pr SO2 3,5-Dimethyl-4-bromopyridin-2-yl H
    695 Cl NH2 i-pr SO2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    696 Cl NH2 i-pr SO2 3,5-Dimethyl-4-chloropyridin-2-yl H
    697 Cl NH2 i-pr SO2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    698 Cl NH2 i-pr SO2 3,5-Dimethyl-4-iodopyridin-2-yl H
    699 Cl NH2 i-pr SO2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    700 Cl NH2 i-pr SO2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    701 Cl NH2 i-pr SO2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    702 Cl NH2 i-pr SO2 3,4,5-Trimethyl-pyridin-2-yl H
    703 Cl NH2 i-pr SO2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    704 Cl NH2 i-pr SO2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    705 Cl NH2 i-pr SO2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    706 Cl NH2 H C(O) 3,4,5-Trimethoxyphenyl H
    707 Cl NH2 H C(O) 2-Chloro-3,4,5-trimethoxyphenyl H
    708 Cl NH2 H C(O) 2-Bromo-3,4,5-trimethoxyphenyl H
    709 Cl NH2 H C(O) 3,5-Dimethyl-4-methoxyphenyl H
    710 Cl NH2 H C(O) 2-Chloro-3,5-Dimethyl-4-methoxyphenyl H
    711 Cl NH2 H C(O) 2-Bromo-3,5-Dimethyl-4-methoxyphenyl H
    712 Cl NH2 H SO2 3,4,5-Trimethoxyphenyl H
    713 Cl NH2 H SO2 2-Chloro-3,4,5-trimethoxyphenyl H
    714 Cl NH2 H SO2 2-Bromo-3,4,5-trimethoxyphenyl H
    715 Cl NH2 H SO2 3,5-Dimethyl-4-methoxyphenyl H
    716 Cl NH2 H SO2 2-Chloro-3,5-Dimethyl-4-methoxyphenyl H
    717 Cl NH2 H SO2 2-Bromo-3,5-Dimethyl-4-methoxyphenyl H
    718 Cl NH2 H CH2 3,5-Dimethyl-4-methoxypyridin-2-yl Br
    719 Cl NH2 H CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl Br
    720 Cl NH2 H CH2 3,5-Dimethyl-4-bromopyridin-2-yl Br
    721 Cl NH2 H CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl Br
    722 Cl NH2 H CH2 3,5-Dimethyl-4-chloropyridin-2-yl Br
    723 Cl NH2 H CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl Br
    724 Cl NH2 H CH2 3,5-Dimethyl-4-iodopyridin-2-yl Br
    725 Cl NH2 H CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl Br
    726 Cl NH2 H CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl Br
    727 Cl NH2 H CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl Br
    728 Cl NH2 H CH2 3,4,5-Trimethyl-pyridin-2-yl Br
    729 Cl NH2 H CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl Br
    730 Cl NH2 H CH2 4,6-Dimethyl-5-methoxypyridin-3-yl Br
    731 Cl NH2 H CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl Br
    732 Cl NH2 H CH2 3,5-Dimethyl-4-methoxypyridin-2-yl Cl
    733 Cl NH2 H CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl Cl
    734 Cl NH2 H CH2 3,5-Dimethyl-4-bromopyridin-2-yl Cl
    735 Cl NH2 H CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl Cl
    736 Cl NH2 H CH2 3,5-Dimethyl-4-chloropyridin-2-yl Cl
    737 Cl NH2 H CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl Cl
    738 Cl NH2 H CH2 3,5-Dimethyl-4-iodopyridin-2-yl Cl
    739 Cl NH2 H CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl Cl
    740 Cl NH2 H CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl Cl
    741 Cl NH2 H CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl Cl
    742 Cl NH2 H CH2 3,4,5-Trimethyl-pyridin-2-yl Cl
    743 Cl NH2 H CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl Cl
    744 Cl NH2 H CH2 4,6-Dimethyl-5-methoxypyridin-3-yl Cl
    745 Cl NH2 H CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl Cl
    746 Cl NH2 H CH2 3,5-Dimethyl-4-methoxypyridin-2-yl CN
    747 Cl NH2 H CH2 3, 5-Dimethyl-4-methoxy- 1 -oxypyridin-2-yl CN
    748 Cl NH2 H CH2 3,5-Dimethyl-4-bromopyridin-2-yl CN
    749 Cl NH2 H CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl CN
    750 Cl NH2 H CH2 3,5-Dimethyl-4-chloropyridin-2-yl CN
    751 Cl NH2 H CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl CN
    752 Cl NH2 H CH2 3,5-Dimethyl-4-iodopyridin-2-yl CN
    753 25 Br NH2 H CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    754 20 Br NH2 H CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    755 Br NH2 H CH2 6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl H
    756 Br NH2 H CH2 6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl H
    757 23 Br NH2 H CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    758 24 Br NH2 H CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    759 21 Br NH2 H CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    760 22 Br NH2 H CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    761 Br NH2 H CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    762 Br NH2 H CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    763 Br NH2 H CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    764 Br NH2 H CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    765 Br NH2 H CH2 3,4,5-Trimethyl-pyridin-2-yl H
    766 Br NH2 H CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    767 Br NH2 H CH2 4,5,6-Trimethoxypyridin-2-yl H
    768 Br NH2 H CH2 4,5,6-Trimethoxy-1-oxypyridin-2-yl H
    769 Br NH2 H CH2 3-Bromo-4,5,6-trimethoxypyridin-2-yl H
    770 Br NH2 H CH2 3-Chloro-4,5,6-trimethoxypyridin-2-yl H
    771 Br NH2 H CH2 3,4,5-Trimethoxy-pyridin-2-yl H
    772 Br NH2 H CH2 3,4,5-Trimethoxy-1-oxypyridin-2-yl H
    773 Br NH2 H CH2 3-Bromo-3,4,5-trimethoxy-pyridin-2-yl H
    774 Br NH2 H CH2 3-Chloro-3,4,5-trimethoxy-pyridin-2-yl H
    775 Br NH2 H CH2 4,5,6-Trimethyl-pyridin-2-yl H
    776 Br NH2 H CH2 4,5,6-Trimethyl-1-oxypyridin-2-yl H
    777 Br NH2 H CH2 4,6-Dimethyl-5-methoxy-pyridin-2-yl H
    778 Br NH2 H CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    779 Br NH2 H CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    780 Br NH2 H CH2 4,6-Dimethyl-5-bromopyridin-3-yl H
    781 Br NH2 H CH2 4,6-Dimethyl-5-chloropyridin-3-yl H
    782 Br NH2 H CH2 5,6-Dimethyl-4-bromopyridin-3-yl H
    783 Br NH2 H CH2 5,6-Dimethyl-4-chloropyridin-3-yl H
    784 Br NH2 H CH2 2,6-Dimethyl-3-methoxypyridin-4-yl H
    785 Br NH2 H CH2 2,6-Dimethyl-pyridin-4-yl H
    786 Br NH2 H CH2 2,3,6-Trimethyl-pyridin-4-yl H
    787 Br NH2 H CH2 2,3,6-Trimethoxy-pyridin-4-yl H
    788 Br NH2 H CH2 2,6-Dimethyl-3-bromopyridin-4-yl H
    789 Br NH2 H CH2 2,6-Dimethyl-3-chloropyridin-4-yl H
    790 Br NH2 H CH2 2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl H
    791 Br NH2 H CH2 2,6-Dimethyl-1-oxy-pyridin-4-yl H
    792 Br NH2 H CH2 2,3,6-Trimethyl-1-oxy-pyridin-4-yl H
    793 Br NH2 H CH2 2,3,6-Trimethoxy-1-oxy-pyridin-4-yl H
    794 Br NH2 H CH2 2,6-Dimethyl-3-bromo1-oxy-pyridin-4-yl H
    795 Br NH2 H CH2 2,6-Dimethyl-3-chloro1-oxy-pyridin-4-yl H
    796 Br NH2 H CH2 4,6-Dimethyl-5-iodopyridin-3-yl H
    797 Br NH2 H CH2 3,5-Dimethyl-4-aminopyridin-2-yl H
    798 Br NH2 i-pr CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    799 Br NH2 i-pr CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    800 Br NH2 i-pr CH2 6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl H
    801 Br NH2 i-pr CH2 6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl H
    802 Br NH2 i-pr CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    803 Br NH2 i-pr CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    804 Br NH2 i-pr CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    805 Br NH2 i-pr CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    806 Br NH2 i-pr CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    807 Br NH2 i-pr CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    808 Br NH2 i-pr CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    809 Br NH2 i-pr CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    810 Br NH2 i-pr CH2 3,4,5-Trimethyl-pyridin-2-yl H
    811 Br NH2 i-pr CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    812 Br NH2 i-pr CH2 4,5,6-Trimethoxypyridin-2-yl H
    813 Br NH2 i-pr CH2 4,5,6-Trimethoxy-1-oxypyridin-2-yl H
    814 Br NH2 i-pr CH2 3-Bromo-4,5,6-trimethoxypyridin-2-yl H
    815 Br NH2 i-pr CH2 3-Chloro-4,5,6-trimethoxypyridin-2-yl H
    816 Br NH2 i-pr CH2 3,4,5-Trimethoxy-pyridin-2-yl H
    817 Br NH2 i-pr CH2 3,4,5-Trimethoxy-1-oxypyridin-2-yl H
    818 Br NH2 i-pr CH2 3-Bromo-3,4,5-trimethoxy-pyridin-2-yl H
    819 Br NH2 i-pr CH2 3-Chloro-3,4,5-trimethoxy-pyridin-2-yl H
    820 Br NH2 i-pr CH2 4,5,6-Trimethyl-pyridin-2-yl H
    821 Br NH2 i-pr CH2 4,5,6-Trimethyl-1-oxypyridin-2-yl H
    822 Br NH2 i-pr CH2 4,6-Dimethyl-5-methoxy-pyridin-2-yl H
    823 Br NH2 i-pr CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    824 Br NH2 i-pr CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    825 Br NH2 i-pr CH2 4,6-Dimethyl-5-bromopyridin-3-yl H
    826 Br NH2 i-pr CH2 4,6-Dimethyl-5-chloropyridin-3-yl H
    827 Br NH2 i-pr CH2 5,6-Dimethyl-4-bromopyridin-3-yl H
    828 Br NH2 i-pr CH2 5,6-Dimethyl-4-chloropyridin-3-yl H
    829 Br NH2 i-pr CH2 2,6-Dimethyl-3-methoxypyridin-4-yl H
    830 Br NH2 i-pr CH2 2,6-Dimethyl-pyridin-4-yl H
    831 Br NH2 i-pr CH2 2,3,6-Trimethyl-pyridin-4-yl H
    832 Br NH2 i-pr CH2 2,3,6-Trimethoxy-pyridin-4-yl H
    833 Br NH2 i-pr CH2 2,6-Dimethyl-3-bromopyridin-4-yl H
    834 Br NH2 i-pr CH2 2,6-Dimethyl-3-chloropyridin-4-yl H
    835 Br NH2 i-pr CH2 2,6-Dimethyl-3-methoxy-1-oxypyridin-4-yl H
    836 Br NH2 i-pr CH2 2,6-Dimethyl-1-oxy-pyridin-4-yl H
    837 Br NH2 i-pr CH2 2,3,6-Trimethyl-1-oxypyridin-4-yl H
    838 Br NH2 i-pr CH2 2,3,6-Trimethoxy-1-oxypyridin-4-yl H
    839 Br NH2 i-pr CH2 2,6-Dimethyl-3-bromo1-oxypyridin-4-yl H
    840 Br NH2 i-pr CH2 2,6-Dimethyl-3-chloro1-oxypyridin-4-yl H
    841 Br NH2 i-pr CH2 4,6-Dimethyl-5-iodopyridin-3-yl H
    842 Br NH2 i-pr CH2 3,5-Dimethyl-4-aminopyridin-2-yl H
    843 Br NH2 Ph CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    844 Br NH2 Ph CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    845 Br NH2 Ph CH2 6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl H
    846 Br NH2 Ph CH2 6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl H
    847 Br NH2 Ph CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    848 Br NH2 Ph CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    849 Br NH2 Ph CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    850 Br NH2 Ph CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    851 Br NH2 Ph CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    852 Br NH2 Ph CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    853 Br NH2 Ph CH2 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl H
    854 Br NH2 Ph CH2 3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl H
    855 Br NH2 Ph CH2 3,4,5-Trimethyl-pyridin-2-yl H
    856 Br NH2 Ph CH2 3,4,5-Trimethyl-1-oxypyridin-2-yl H
    857 Br NH2 Ph CH2 4,5,6-Trimethoxypyridin-2-yl H
    858 Br NH2 Ph CH2 4,5,6-Trimethoxy-1-oxypyridin-2-yl H
    859 Br NH2 Ph CH2 3-Bromo-4,5,6-trimethoxypyridin-2-yl H
    860 Br NH2 Ph CH2 3-Chloro-4,5,6-trimethoxypyridin-2-yl H
    861 Br NH2 Ph CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    862 Br NH2 Ph CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    863 Br NH2 Me CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    864 Br NH2 Me CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    865 Br NH2 Me CH2 6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl H
    866 Br NH2 Me CH2 6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl H
    867 Br NH2 Me CH2 3,5-Dimethyl-4-bromopyridin-2-yl H
    868 Br NH2 Me CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    869 Br NH2 Me CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    870 Br NH2 Me CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    871 Br NH2 Me CH2 3,5-Dimethyl-4-iodopyridin-2-yl H
    872 Br NH2 Me CH2 3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl H
    873 Br NH2 Me CH2 4,6-Dimethyl-5-methoxypyridin-3-yl H
    874 Br NH2 Me CH2 4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl H
    875 39 Cl NH2 CH2(Bn)2 CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    876 12 Cl NH2 H CH2 2-Chloro-4,5-dimethoxylphenyl H
    877 16 Cl NH2 H CH2 2-Nitro-4,5-dimethoxylphenyl H
    878 17 Cl NH2 H CH2 3,4-Dichlorophenyl H
    879 18 Cl NH2 H CH2 3,5-DIMETHOXYLPHENYL H
    880 19 Cl NH2 H CH2 2,5-DIMETHOXYLPHENYL H
    881 26 Br NH2 H CH2 3,5-DIMETHOXYLPHENYL H
    882 27 Cl NH2 H CH2 3-METHOXYLPHENYL H
    883 28 Cl NH2 H CH2 4-METHOXYLPIENYL H
    884 29 Cl
    Figure US20070173483A1-20070726-C00013
         		I CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    885 30 Cl
    Figure US20070173483A1-20070726-C00014
         		I CH2 3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl H
    886 31 Cl
    Figure US20070173483A1-20070726-C00015
         		I CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    887 32 Cl
    Figure US20070173483A1-20070726-C00016
         		H CH2 3,5-DIMETHYL-4-BROMO-1-OXYPYRIDIN-2-YL H
    888 33 Cl
    Figure US20070173483A1-20070726-C00017
         		H CH2 3,5-Dimethyl-4-methoxypyridin-2-yl H
    889 34 Cl
    Figure US20070173483A1-20070726-C00018
         		H CH2 3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl H
    890 35 Cl
    Figure US20070173483A1-20070726-C00019
         		H CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    891 36 Cl
    Figure US20070173483A1-20070726-C00020
         		I CH2 3,5-Dimethyl-4-chloropyridin-2-yl H
    892 37 Cl
    Figure US20070173483A1-20070726-C00021
         		H CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H
    893 38 Cl
    Figure US20070173483A1-20070726-C00022
         		I CH2 3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl H

    Compounds of interest in Table 1 are compounds 2, 3, 17, 18, 27, 28, 62, 63, 77, 78, 92, 93, 129, 130, 238, 239, 242, 243, 245, 246, 247, 248, 249, 250, 251, 252, 253, 267, 268, 287, 288, 291, 292, 293, 294, 295, 296, 297, 298, 312,313, 332,333, 334, 335, 336, 337, 338, 339, 351, 352, 365, 366, 384, 385, 398, 399, 400, 401, 402, 403, 404, 405, 417, 418, 431, 432, 433, 434, 435, 436, 437, 438, 450, 451, 464, 465, 483, 484, 497, 498, 530, 531, 549, 550, 562, 563,574, 575, 577, 578, 589, 590, 592, 593, 604, 605, 607, 608, 619, 620, 755, 756, 759, 760, 761, 762, 763, 764, 765, 766, 780, 781, 800, 801, 804, 805, 806, 807, 808, 809, 810, 811, 825, 826, 845, 846, 863, 864, 865, 866, 875, and 876 with the selected ones being 17, 18, 27, 28, 62, 63, 77, 78, 242, 243, 245, 246, 247, 248, 249, 250, 251, 252, 253, 267, 268, 287, 288, 291, 292, 293, 294, 295, 296, 312,313, 431, 432, 755, 756, 759, 760, 761, 762, 763, 764, 800, and 801.
    III. Synthesis of the Compounds of the Invention
  • The compounds of Formula I of the present invention may be synthesized by various methods known in the art. The general strategy is outlined in Scheme 1 and consists of three parts: (1) constructing the bicyclic system, starting from either a pyridine or a pyrrole, or an acyclic precursor (2) appending the R5-R4-group, and (3) further elaborating the ring systems.
  • Importantly, one skilled in the art will recognize that the sequence of events is not necessarily (1)-(2)-(3), and that these events may be interchanged, provided there be no incompatibility between the reagents and the functional groups specific to the case in point.
    Figure US20070173483A1-20070726-C00023
  • Also, the starting materials or the intermediates of Formula 1, 4, 5, and I can exist in tautomeric forms as shown in FIG. 1 Scheme 1-B, and both forms are indiscriminately used in this patent.
    Figure US20070173483A1-20070726-C00024
    1. Assembly of the pyrrolo[2,3-d]pyrimidine
  • 1.1. Assembly of the pyrrolo[2,3-d]pyrimidine starting from a pyrimidine
  • The compounds of Formula 4 can be prepared from pyrimidines as outlined in Scheme 2. For instance:
    Figure US20070173483A1-20070726-C00025
    Figure US20070173483A1-20070726-C00026
  • Method 1.1.1:
  • The compounds of Formula 4 can be made by intramolecular cyclization of an aldehyde or ketone, possibly protected, as in Formula 6. (See, J. Davoll, J. Chem. Soc. 1960, 131; J. A. Montgomery, J. Chem. Soc. 1967, 665; G. Cristalli, J. Med. Chem. 1988, 31, 390; T. Miwa, J. Org. Chem. 1993,58, 1696; D. M. Williams, J. Chem. Soc., Perkin Trans 1, 1997, 1171).
  • Method 1.1.2
  • The compounds of Formula 4, wherein R3 is H, R6 is Cl, and R7 is NH2 can be prepared by treating compounds of Formula 7 wherein R is a halogen or a leaving group with ammonia. Similarly, compounds of Formula I wherein R3 is H, R1 is Cl, R2 is NH2 can be prepared by treating the compound of Formula 7 wherein R is a halogen or leaving group with R5-R4—NH2 in butanol at reflux in presence of a base such as K2CO3, Cs2CO3 or iPrNEt2. (A. B. Reitz J. Med. Chem. 1994, 37, 3561). Compounds of Formula 7 can in turn be prepared as taught by G. W. Craig, J. Prakt. Chem. 2000, 342, 504 and M. Semonsky, Coll. Czech. Chem. Commun. 1980, 45, 3583).
  • Method 1.1.3:
  • The compounds of Formula 4 can be obtained by treatment of a α-haloketone of Formula 8 wherein X is a halogen with ammonia or a synthetic equivalent thereof.
  • Method 1.1.4:
  • The compounds of Formula 4 wherein R0 is methyl can be obtained by a tandem Pd-mediated intramolecular cyclization/double-bond migration of alkenes of Formula 9 (S. E. Watson, Synth. Commun. 1998, 28, 3885).
  • Method 1.1.5:
  • The compounds of Formula 4 wherein R3 is H can be obtained by Pd-mediated intramolecular cyclization of alkynes of Formula 10, wherein Z in as electron-withdrawing group such as, e.g., tosyl-, or —CO2Et.
  • Method 1.1.6:
  • The compounds of Formula 4 wherein R3 is AcO— can be obtained by intramolecular Friedel-Crafts acylation of precursors of Formula 11 (E. D. Edstrom, J. Org. Chem. 1993, 58, 403).
  • Method 1.1.7:
  • The compound of Formula 4, wherein R0 is H, R6 is OH, and R7 is NH2, can be prepared by treating the compound of Formula 12 with an α-haloaldehyde of the formula R3—CHX-CHO. See, D. M. Williams, J. Chem. Soc., Perkin Trans 1, 1997, 1171; C. J. Barnett, Org. Proc. Res. Devop. 1999, 3, 184; A. Gangjee, J. Med. Chem. 2001, 44, 1993.
  • Method 1.1.8:
  • The compounds of Formula 4, wherein R6 is OH and R7 is NH2 can be obtained by treating the compound of Formula 13 with an aldehyde of the formula R3—CHO. See, A. Gangjee, J. Med. Chem. 2003, 46, 591; E. C. Taylor, Heterocycles 1996, 43, 323.
  • 1.2: Assembly of the pyrrolo[2,3-d]pyrimidine starting from a pyrrole
  • The compounds of Formula 4 can also be made from pyrroles of Formula 2. There is a variety of methods by which the 6-membered ring can be formed (e.g. R. J. Bontems, J. Med. Chem, 1990, 33, 2174 and references therein). For instance:
    Figure US20070173483A1-20070726-C00027
  • Compounds of Formula 2 wherein R13 is —CN and R14 is R—NH—CR7═N— can be cyclized and rearranged to give compounds of Formula 4 where R6 is R—NH—. See, E. C. Taylor, J. Am. Chem. Soc. 1965, 87,1995.
  • Compounds of Formula 2 wherein R13 is —CN and R14 is NH2 can be treated with thiourea, guanidine, or chloroformamidine to give compounds of Formula 4 in which R6 is —NH2 and R7 is —NH2. See, H. Kosaku, Heterocycles, 2001, 55, 2279; A. Gangjee, U.S. Pat. No. 5,939,420 (1999).
  • Compounds of Formula 2 wherein R13 is —CN and R14 is NH2 can be treated with formamidine acetate to give compounds of Formula 4 wherein R6 is NH2 and R7 is H (J. A. Montgomery, J. Chem. Soc. 1967, 665). The same transformation can be accomplished by treatment with DMF-DMA or an orthoester such as (EtO)3CH, followed by treatment with ammonia. See, E. C. Taylor, J. Am. Chem. Soc, 1965, 87, 1995.
  • Compounds of Formula 2 wherein R13 is —CN and R14 is NH2 can be treated with formic acid to give compounds of Formula 4 wherein R6 is OH and R7 is H (K. A. M. El-Bayouki, J. Chem. Res. Miniprint, 1995, 1901).
  • Compounds of Formula 2 wherein R13 is —CO2NH2 and R14 is —NH2 can be treated under Vilsmeyer-Haack conditions (DMF/POCl3) to give compounds of Formula 4 wherein R6 is OH or Cl and R7 is H. See, K. A. M. El-Bayouki, J. Chem. Res. Miniprint, 1995, 1901.
  • Compounds of Formula 2 wherein R13 is —CONH2 and R14 is —NH2 can be treated with CS2 or EtOCS2K to give compounds of Formula 4 in which R6 is —OH and R7 is —SH. See, S. M. Bennett, J. Med. Chem. 1990, 33, 2162.
  • 1.3. Assembly of the pyrrolo[2,3-d]pyrimidine starting from an acyclic precursor
  • The compounds of Formula 14 can be prepared from an acyclic precursor as outlined in Scheme 4 (T. Miwa, J. Med. Chem. 1991, 34,555).
    Figure US20070173483A1-20070726-C00028
    2. Incorporation of the -R4-R5 fragment.
  • 2.1. Alkylation of compounds of Formula 4.
  • Compounds of Formula 4 can be alkylated in the presence of a base such as K2CO3, NaH, Cs2CO3, DBU etc. with/without the presence of a catalyst such as NaI, KI, (Bu)4NI etc., and in a polar solvent such as DMF, THF, DMSO etc. using electrophiles such as L1-R-R5 where L1 is a leaving group. See Scheme 5. Leaving groups include but are not limited to, e.g., halogen, triflate, tosylate, mesylate, triphenylphosphonium (generated under Mitsunobu conditions, e.g. PPh3/DEAD) etc. See Kasibhatla, PCT publication number WO 03/037860.
    Figure US20070173483A1-20070726-C00029
    2.2. Preparation of electrophiles L1-R4-R5 wherein L1 is a leaving group
  • 2.2.1. Synthesis of benzyl type electrophile:
    Figure US20070173483A1-20070726-C00030
  • The electrophiles can be prepared from the substituted benzene derivatives using various methods reported in the literature, see Jerry March, Advanced Organic Chemistry, 4th edition; Larock, Comprehensive Organic Transformations, 1989, VCH, New York. For example the compounds wherein L1 is Br can be prepared by reduction of the corresponding benzoic acid or benzaldehyde, followed by halogenation. These benzyl derivatives can also be prepared by benzylic oxidation or benzylic halogenation. Further modification of the benzyl ring can be done before or after the pyrrolo[2,3-d]pyrimidine alkylation step.
    Figure US20070173483A1-20070726-C00031
  • These compounds can be prepared by many methods reported in the literature.
  • Morisawa, J. Med. Chem. 1974, 17, 1083; Klaus, W., J. Med. Chem. 1992, 35, 438; Abramovitch, R. A.; Smith, E. M. “Pyridine-1-oxide in Pyridine and its Derivatives,” in The Chemistry of Heterocyclic Compounds; Weissberger, A., Taylor, E. C., Eds.; John Wiley, New York, 1974, Pt. 2, pp 1-261; Jeromin, G. E., Chem. Ber. 1987, 120, 649. Blanz, E. J., J. Med. Chem. 1970, 13, 1124; Smith, Kline and French, EP Application EP 0184322, 1986; Abblard, J., Bull. Soc. Chim. Fr. 1972, 2466; Fisher, B. E., The Structure of Isomaltol. J. Org. Chem. 1964, 29, 776. De Cat, A., Bull. Soc. Chim. Belg. 1965, 74, 270; Looker, J. H., J. Org. Chem. 1979, 44, 3407. Ackerman, J. F. Ph.D. Dissertation, University of Notre Dame, June, 1949. These methods can be applied to the synthesis of quinoline and isoquinoline type compounds.
  • 2.3. Incorporation of the -R4-R5 fragment by nucleophilic substitution.
  • In some cases, the -R4-R5 group can be appended before the bicyclic pyrrolo[2,3-d]pyrimidine bicyclic ring is constructed, and this is further detailed below (paragraph 4, schemes 8 and 9). In these cases the -R4-R5 group can be appended by an aromatic nucleophilic substitution using NH2—R4-R5. The compound NH2—R4—R5 is obtained by treating L1-R4-R5 with ammonia at temperatures of 20-160° C. in a pressure vessel. The corresponding amines where L1 is —NH2 can be prepared by a variety of methods, for instance from compounds where L1 is leaving group such as chloride, bromide, tosylate, mesylate etc. using ammonia, or with sodium azide followed by hydrogenation.
  • 3. Further Elaboration of the Ring Systems.
  • 3.1. Functional Group Interconversions of R0:
  • Compounds of Formula I, wherein R0 is H can be oxidized to compounds of Formula I wherein R0 is OH with pyridinium tribromide or polymer supported pyridinium tribromide in tert-butanol/acetic acid mixture followed by zinc reduction. See, C. Liang, U.S. Pat No. 6,610,688 (2000); L. Sun, Bioorg. Med. Chem Lett., 2002, 12, 2153.
  • Compounds of Formula I, wherein R0 is H can be treated under Mannich conditions (HCHO+HNRR′) to give compounds Formula I wherein R0 is —CH—NRR′. See, F. Seela, Synthesis, 1997, 1067.
  • Compounds of Formula I, wherein R0 is H can be lithiated and treated with electrophiles (e.g., I2, ArCHO) to provide compounds of Formula I wherein R0 is, e.g. —I or —CH(OH)Ar. See, E. Bisagni, Tetrahedron, 1983, 39, 1777; T, Sakamoto, Tetrahedron Lett. 1994, 35, 2919; T. Sakamoto, J. Chem. Soc., Perkin Trans 1, 1996, 459.
  • 3.2. Functional group interconversions of R1:
  • Compounds of Formula I, wherein R1 is OH, can be converted to halides using standard conditions POCl3, POBr3 etc. with/without a base such as Et3N, N,N-dimethylaniline, (iPr)2NEt etc. and with/without a catalyst such as BnEt3N+Cl−, in polar solvents such as CH3CN, CH2Cl2 etc. Related methods include, but are not limited to, SOCl2/DMF (M. J. Robins, Can. J. Chem. 1973, 12, 3161), PPh3 /CCl4 (L. De Napoli, J. Chem. Soc. Perkin Trans 1, 1994, 923), HMPT/CCl4 or HMPT/NBS (E. A. Veliz, Tetrahedron Lett, 2000, 41, 1695) or PPh3/I2 (X. Lin, Org. Letters, 2000, 2, 3497).
  • Compounds of Formula I, wherein R1 is NH2, can be converted to halides by a Balz-Schiemann (F) or Sandmeyer reaction (Cl, Br, I) by means of a nitrosylating agent (NaNO2/H+, NOBF4, RONO) and a halogen donor (BF4 −, CuX2, SbX3).
  • Compounds of Formula I, wherein R1 is alkyl can be prepared from compounds of Formula 4 where R1 is halogen and trialkyl aluminum or dialkyl zinc (A. Holy, J. Med. Chem. 1999, 42, 2064).
  • Compounds of Formula I, wherein R1 is a halide can be converted to compounds wherein R1 is —NH2, —OH, —SH, —OR8 , —SR8 with standard reagents, e.g., NH3, NaOH, thiourea, R8O−, R8S−, with or without a catalyst (e.g. Pd, Ni, Cu, Lewis acid, H+) (e.g., B. G. Ugarkar, J. Med. Chem. 2000, 43, 2883-2893 and 2894-2905).
  • Compounds of Formula I, wherein R1 is halogen or another leaving group can be treated with ammonia to provide compounds of Formula I wherein R1 is NH2 (F. Seela, Liebigs. Ann. Chem. 1985, 315).
  • 3.2. Functional group interconversions of R2:
  • Compounds of Formula I, wherein R2 is NH2 can be temporarily protected, e.g. as an amide (Ac2O, PivCl), a carbamate (tBoc)2O) or amidine (DMF-DMA).
  • Compounds of Formula I, wherein R2 is NH2 can be converted to halides by a Balz-Schiemann (F) or Sandmeyer reaction (Cl, Br, I) by means of a nitrosylating agent (NaNO2/H+, NOBF4, RONO) and a halogen donor (BF4−, CuX2, SbX3).
  • Compounds of Formula I, wherein R2 is a halide can be converted to compounds wherein R2 is NH2, OH, SH, OR8, SR8 with standard reagents, e.g. NH3, NaOH, thiourea, R8O−, R8S−, with or without a catalyst (e.g. Pd, Ni, Cu, Lewis acid, H+).
  • Compounds of Formula I, wherein R2 is SH can be converted to halides (Br2). They can also be oxidized (e.g., H2O2) and treated with ammonia to give a NH2 group (S. M. Bennett, J. Med. Chem. 1990, 33, 2162).
  • Compounds of Formula I, wherein R2 is a sulfide, e.g., MeS—, can be converted to a sulfone, e.g MeSO2—, and displaced with a nucleophile, e.g. NH3 or NH2—NH2, N3—, CN—.
  • 3.3. Functional group interconversions of R3:
  • Compounds of Formula I, wherein R3 is H can be halogenated (J. F. Gerster, J. Chem. Soc. 1969, 207) and further functionalized by Pd-catalyzed reactions ((a) Sonogashira coupling: E. C. Taylor et al, Tetrahedron, 1992, 48, 8089; (b) carboxylation: J. W. Pawlik, J. Heterocycl. Chem. 1992, 29, 1357; (c) Suzuki coupling: T. Y. I Wu, Org. Lett., 2003,5, 3587) or by addition of nucleophiles (e.g. hydrazine, B. M. Lynch, Can. J. Chem. 1988, 66, 420).
  • Compounds of Formula I wherein R3 is —CHO can be sujected to a Bayer-Villiger oxidation to provide compounds of Formula I wherein R3 is —O—CHO. The latter can be hydrolyzed to R3 is —OH. (A. S. Bourlot, E. Desarbre, J. Y. Mérour Synthesis 1994, 411)
  • Compounds of Formula I, wherein R3is H can be treated under Mannich condition (HCHO+HNRR′) to give compounds Formula I wherein R3 is —CH—NRR′ (F. Seela, Synthesis, 1997, 10-67)
  • Compounds of Formula I, wherein R3 is —CH2—NBn2 can be obtained by Mannich reaction and further treated with an aniline of Formula NH2—Ar to give compounds of Formula I wherein R3 is —CH2—NH—Ar (D. C. Miller, J. Med. Chem. 2002, 45, 90).
  • Compounds of Formula I, wherein R3 is Br can be metallated with BuLi, and treated with an electrophile such as MeI to give a compound of Formula I, wherein R3 is Me. Compounds of Formula I, wherein R1 is Cl and R3 is Br can undergo selective metallation at R3 (J. S. Pudlo, J. Med. Chem. 1990, 33, 1984).
  • Compounds of Formula I, wherein R0 is OH and R3 is H can be be monalkylated or bis-alkylated to give compounds of Formula III, wherein R1 is an alkyl group. The alkylation can be effected in the presence of a base such as KHMDS, LHMDS, LDA etc. with/without the presence of a catalyst such as NaI, KI, (Bu)4NI etc., and in a polar solvent such as THF, DMSO etc. using electrophiles such as L1-R3 where L1 is a leaving group. Leaving groups include but are not limited to, e.g., halogen, triflate, tosylate or mesylate.
    Figure US20070173483A1-20070726-C00032
  • Compounds of Formula I, wherein R0 is H and R3 is H can be oxidized to compounds of Formula 16/IV, with an oxidizing reagent such as ruthenium tetroxide in a binary solvent such as acetonitrile/water. (G. W. Gribble Org. Prep. Proced. Int. 2001, 33(6), 615).
  • Compounds of Formula I, wherein R0 is OH and R3 is H can be oxidized to compounds of Formula II, (wherein R3, R3 is an oxo group) with an oxidizing reagent such as selenium dioxide or oxygen in presence of a cobalt (III) catalyst. (SeO2 oxidation: Romeo Helv. Chim. Acta. 1955, 38, 463, 465. Oxygen oxidation: A. Inada Heterocycles 1982, 19, 2139).
  • 3.4. Further elaboration of R5:
  • R5, especially when it is aryl or heteroaryl, can be further modified as needed, for example by halogenation, nitration, palladium coupling of halogen, Friedel-Crafts alkylation/acylation, etc. or these modifications can also be done before alkylation, see Jerry March, Advanced Organic Chemistry. The heteroaromatic rings can also be oxidized to their corresponding N-oxides using various oxidizing agents such as H2O2, O3, MCPBA etc. in polar solvents such as CH2Cl2, CHCl3, CF3COOH etc. See Jerry March, Advanced Organic Chemistry, 4th edition, Chapter 19. Examples of modifications are suggested in Scheme 6.
    Figure US20070173483A1-20070726-C00033
    Figure US20070173483A1-20070726-C00034
    4. Permutations of the order of events
  • As mentioned above, the events (1) assembly of the bicyclic system (2) appendage of the R5-R4-moiety, and (3) further elaboration of the ring systems do not necessarily have to be made in the sequence (1)-(2)-(3), and it may be beneficial to proceed in a different sequence.
  • Method 4.1.
  • Scheme 8 shows a synthesis in which the order of events is not (1)-(2)-(3), but is (2)-(1)-(3). First R5 is appended via an aromatic nucleophilic substitution, then the bicyclic system is constructed, and finally it is elaborated.
    Figure US20070173483A1-20070726-C00035
  • Method 4.1.1
  • The compound of Formula 18, wherein R1 is Cl and R2 is NH2, can be prepared by treating the compound of Formula 17 wherein R2═NH2, and R1═X═Cl, with R5-R4—NH2 in butanol at reflux in presence of a base such as K2CO3, Cs2CO3 or iPrNEt2. (A. B. Reitz J. Med. Chem. 1994, 37, 3561).
  • Method 4.1.2
  • The compound of Formula 19, wherein R1 is Cl and R2 is NH2 and L1=Br on I, can be prepared by refluxing the compound of Formula 18 in chloroform or dichloroethane in presence of an halogenating reagent such as bromine, N-bromosuccinimide, iodine or N-iodosuccinimide and an acid such as acetic acid or p-toluenesulfonic acid. (A. P. Phillips J. Am. Chem. Soc. 1952, 74, 3922).
  • Method 4.1.3
  • The compound of Formula 20, wherein R1 is Cl and R2 is NH2, can be prepared by coupling the compound of Formula 19 with trimethylsilylacetylene under Sonogashira conditions followed by hydroboration using dicylohexylborane and oxidation using hydrogen peroxide in presence of sodium hydroxide. (Sonogashira coupling: E. C. Taylor Tetrahedron, 1992, 48, 8089. Hydroboration/oxidation: G. Zweifel J. Am. Chem. Soc. 1976, 98, 3184).
  • Method 4.1.4
  • The compound of Formula 21, wherein R1 is Cl and R2 is NH2, can be prepared by heating the compound of Formula 20 in a polar aprotic solvent such as THF, DME or dioxane in presence of oxalyl chloride, thionyl chloride, mesyl chloride or alkyl chloroformate and a base such as iPrNEt2 or pyridine. It can also be prepared by treating the compound of Formula 20 with coupling reagents such DCC/HOBt, DCC/DMAP or EDCI/HOBt. (R. C. Larock Comprehensive Organic Transformations, Second Edition, p. 1870).
  • Method 4.2
  • Again, as mentioned above, the events (1) assembly of the bicyclic system (2) appendage of the R5-R4-moiety, and (3) further elaboration of the ring systems do not necessarily have to be made in the sequence (1)-(2)-(3), and it may be beneficial to proceed in a different sequence. For illustrative purposes, Scheme 9 shows a putative synthesis in which the order of events is not (1)-(2)-(3), but is (2)-(1)-(3). First R5 is appended via an aromatic nucleophilic substitution, then the bicyclic system is constructed, and finally it is elaborated.
    Figure US20070173483A1-20070726-C00036
  • Method 4.3
  • For illustrative purposes, Scheme 10 shows a putative synthesis in which the order of events is not (1)-(2)-(3), but is (1)-(3)-(2)-(3). First the bicyclic ring is constructed, then it is elaborated, then the R4-R5 moiety is appended, and finally the bicyclic ring system is further elaborated (deprotection).
    Figure US20070173483A1-20070726-C00037
  • Also, if R5 is for instance a pyridine, it can be converted to a N-oxide either before or after alkylation.
  • IV. Pharmaceutical Compositions, Dosaging, and Modes of Administration
  • The present invention is directed to the clinical use of the heterocyclics, in particular, the pyrazolopyrimidines and their related analogs of Formulae A, I, II, III and IV, and their polymorphs, solvates, esters, tautomers, diastereomers, enantiomers, pharmaceutically acceptable salts and prodrugs thereof, for use in treatment or prevention of diseases that are HSP90-dependent. Examples of such diseases include disorders such as inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorder, neurological disorders, fibrogenetic disorders, proliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases, and malignant disease. The fibrogenetic disorders include but are not limited to scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis.
  • The present invention features pharmaceutical compositions comprising the compound of Formulae A, I, II, III and IV, or a polymorph, solvate, ester, tautomer, enantiomer, diastereomer, pharmaceutically acceptable salt thereof, or prodrug thereof, of any of the preceding aspects and embodiments and one or more pharmaceutical excipients.
  • Those of ordinary skill in the art are familiar with formulation and administration techniques that can be employed with the compounds and methods of the invention, e.g., as discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.
  • The compounds utilized in the methods of the instant invention may be administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • For example, the therapeutic or pharmaceutical compositions of the invention can be administered locally to the area in need of treatment. This may be achieved by, for example, but not limited to, local infuision during surgery, topical application, e.g., cream, ointment, injection, catheter, or implant, said implant made, e.g., out of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. The administration can also be by direct injection at the site (or former site) of a tumor or neoplastic or pre-neoplastic tissue.
  • Still further, the compounds or compositions of the invention can be delivered in a vesicle, e.g., a liposome (see, for example, Langer, Science 1990, 249,1527-1533; Treat et al., Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Bernstein and Fidler, Ed., Liss, N.Y., pp. 353-365, 1989).
  • The compounds and pharmaceutical compositions used in the methods of the present invention can also be delivered in a controlled release system. In one embodiment, a pump may be used (see, Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al. Surgery, 1980 88, 507; Saudek et al. N. Engl. J. Med. 1989, 321, (574). Additionally, a controlled release system can be placed in proximity of the therapeutic target. (See, Goodson, Medical Applications of Controlled Release, 1984, Vol. 2, pp. 115-138).
  • The pharmaceutical compositions used in the methods of the instant invention can also contain the active ingredient in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be un-coated or coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, or cellulose acetate butyrate may be employed as appropriate.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • The compounds and pharmaceutical compositions used in the methods of the instant invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution may then be introduced into a water and glycerol mixture and processed to form a microemulsion.
  • The injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.
  • The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
  • The compounds of the present invention used in the methods of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the inhibitors with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing a compound or composition of the invention can be used. As used herein, topical application can include mouth washes and gargles.
  • The compounds used in the methods of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • The methods, compounds and compositions of the instant invention may also be used in conjunction with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents. Further, the instant methods and compounds may also be usefuil in combination with other inhibitors of parts of the signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
  • The methods of the present invention may also be useful with other agents that inhibit angiogenesis and thereby inhibit the growth and invasiveness of tumor cells, including, but not limited to VEGF receptor inhibitors, including ribozymes and antisense targeted to VEGF receptors, angiostatin and endostatin.
  • Examples of antineoplastic agents that can be used in combination with the compounds and methods of the present invention include, in general, and as appropriate, alkylating agents, anti-metabolites, epidophyllotoxins, an antineoplastic enzyme, a topoisomerase inhibitor, procarbazine, mitoxantrone, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors. Exemplary classes of antineoplastic include the anthracyclines, vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, epothilones, discodermolide, pteridines, diynenes and podophyllotoxins. Particularly usefuil members of those classes include, for example, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like. Other useful antineoplastic agents include estramustine, carboplatin, cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
  • When a compound or composition of the invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer, for example, breast cancer. Administration typically occurs in an amount of between about 0.01 mg/kg of body weight to about 100 mg/kg of body weight per day (administered in single or divided doses), more preferably at least about 0.1 mg/kg of body weight per day. A particular therapeutic dosage can include, e.g., from about 0.01 mg to about 1000 mg of compound, and preferably includes, e.g., from about 1 mg to about 1000 mg. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, preferably from about 1 mg to 300 mg, more preferably 10 mg to 200 mg, according to the particular application. The amount administered will vary depending on the particular IC50 value of the compound used and the judgment of the attending clinician taking into consideration factors such as health, weight, and age. In combinational applications in which the compound is not the sole active ingredient, it may be possible to administer lesser amounts of compound and still have therapeutic or prophylactic effect.
  • Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • The amount and frequency of administration of the compounds and compositions of the present invention used in the methods of the present invention, and if applicable other chemotherapeutic agents and/or radiation therapy, will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition and size of the patient as well as severity of the disease being treated.
  • The chemotherapeutic agent and/or radiation therapy can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent and/or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent and/or radiation therapy on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents (i.e., antineoplastic agent or radiation) on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.
  • Also, in general, the compounds of the invention need not be administered in the same pharmaceutical composition as a chemotherapeutic agent, and may, because of different physical and chemical characteristics, be administered by a different route. For example, the compounds/compositions may be administered orally to generate and maintain good blood levels thereof, while the chemotherapeutic agent may be administered intravenously. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
  • The particular choice of compound (and where appropriate, chemotherapeutic agent and/or radiation) will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol.
  • The compounds/compositions of the invention (and where appropriate chemotherapeutic agent and/or radiation) may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the proliferative disease, the condition of the patient, and the actual choice of chemotherapeutic agent and/or radiation to be administered in conjunction (i.e., within a single treatment protocol) with the compound/composition.
  • In combinational applications and uses, the compound/composition and the chemotherapeutic agent and/or radiation need not be administered simultaneously or essentially simultaneously, and the initial order of administration of the compound/composition, and the chemotherapeutic agent and/or radiation, may not be important. Thus, the compounds/compositions of the invention may be administered first followed by the administration of the chemotherapeutic agent and/or radiation; or the chemotherapeutic agent and/or radiation may be administered first followed by the administration of the compounds/compositions of the invention. This alternate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient. For example, the chemotherapeutic agent and/or radiation may be administered first, especially if it is a cytotoxic agent, and then the treatment continued with the administration of the compounds/compositions of the invention followed, where determined advantageous, by the administration of the chemotherapeutic agent and/or radiation, and so on until the treatment protocol is complete.
  • Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of a compound/composition for treatment according to the individual patient's needs, as the treatment proceeds.
  • The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.
  • V. Assays for Determining HSP90 Binding and Downstream Effect
  • A variety of in vitro and in vivo assays are available to test the effect of the compounds of the invention on HSP90. HSP90 competitive binding assays and functional assays can be performed as known in the art by substituting in the compounds of the invention. Chiosis et al. Chemistry & Biology 2001, 8, 289-299, describe some of the known ways in which this can be done. For example, competition binding assays using, e.g., geldanamycin or 17-AAG as a competitive binding inhibitor of HSP90 can be used to determine relative HSP90 affinity of the compounds of the invention by immobilizing the compound of interest or other competitive inhibitor on a gel or solid matrix, preincubating HSP90 with the other inhibitor, passing the preincubated mix over the gel or matrix, and then measuring the amount of HSP90 that retains or does not retain on the gel or matrix.
  • Downstream effects can also be evaluated based on the known effect of HSP90 inhibition on function and stability of various steroid receptors and signaling proteins including, e.g., Raf1 and HER2. Compounds of the present invention induce dose-dependent degradation of these molecules, which can be measured using standard techniques. Inhibition of HSP90 also results in up-regulation of HSP90 and related chaperone proteins that can similarly be measured. Antiproliferative activity on various cancer cell lines can also be measured, as can morphological and functional differentiation related to HSP90 inhibition.
  • Many different types of methods are known in the art for determining protein concentrations and measuring or predicting the level of proteins within cells and in fluid samples. Indirect techniques include nucleic acid hybridization and amplification using, e.g., polymerase chain reaction (PCR). These techniques are known to the person of skill and are discussed, e.g., in Sambrook, Fritsch & Maniatis Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., 1989; Ausubel, et al. Current Protocols in Molecular Biology, John Wiley & Sons, N.Y., 1994, and, as specifically applied to the quantification, detection, and relative activity of HER2/Neu in patient samples, e.g., in U.S. Pat. Nos. 4,699,877, 4,918,162, 4,968,603, and 5,846,749. A brief discussion of two generic techniques that can be used follows.
  • The determination of whether cells overexpress or contain elevated levels of HER2 can be determined using well known antibody techniques such as immunoblotting, radioimmunoassays, western blotting, immunoprecipitation, enzyme-linked immunosorbant assays (ELISA), and derivative techniques that make use of antibodies directed against HER2. As an example, HER2 expression in breast cancer cells can be determined with the use of an immunohistochemical assay, such as the Dako Hercep™ test (Dako Corp., Carpinteria, Calif. The Hercep™ test is an antibody staining assay designed to detect HER2 overexpression in tumor tissue specimens. This particular assay grades HER2 expression into four levels: 0, 1, 2, and 3, with level 3 representing the highest level of HER2 expression. Accurate quantitation can be enhanced by employing an Automated Cellular Imaging System (ACIS) as described, e.g., by Press, M. et al. Modern Pathology 2000, 13, 225A.
  • Antibodies, polyclonal or monoclonal, can be purchased from a variety of commercial suppliers, or may be manufactured using well-known methods, e.g., as described in Harlow et al. Antibodies: A Laboratory Manual, 2nd ed; Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., 1988.
  • HER2 overexpression can also be determined at the nucleic acid level since there is a reported high correlation between overexpression of the HER2 protein and amplification of the gene that codes for it. One way to test this is by using RT-PCR. The genomic and cDNA sequences for HER2 are known. Specific DNA primers can be generated using standard, well-known techniques, and can then be used to amplify template already present in the cell. An example of this is described in Kurokawa, H. et al. Cancer Res. 2000, 60, 5887-5894. PCR can be standardized such that quantitative differences are observed as between normal and abnormal cells, e.g., cancerous and noncancerous cells. Well known methods employing, e.g., densitometry, can be used to quantitate and/or compare nucleic acid levels amplified using PCR.
  • Similarly, fluorescent in situ hybridization (FISH) assays and other assays can be used, e.g., Northern and/or Southern blotting. These rely on nucleic acid hybridization between the HER2 gene or mRNA and a corresponding nucleic acid probe that can be designed in the same or a similar way as for PCR primers, above. See, e.g., Mitchell M S, and Press M. F. Oncol., Suppl. 1999, 12, 108-116. For FISH, this nucleic acid probe can be conjugated to a fluorescent molecule, e.g., fluorescein and/or rhodamine, that preferably does not interfere with hybridization, and which fluorescence can later be measured following hybridization. See, e.g., Kurokawa, H et al, Cancer Res. 2000, 60, 5887-5894 (describing a specific nucleic acid probe having sequence 5′-FAM-NucleicAcid-TAMRA-p-3′ sequence). ACIS-based approaches as described above can be employed to make the assay more quantitative (de la Torre-Bueno, J., et al. Modern Pathology 2000, 13, 221A).
  • Immuno and nucleic acid detection can also be directed against proteins other than HSP90 and HER2, which proteins are nevertheless affected in response to HSP90 inhibition.
  • The following examples are offered by way of illustration only and are not intended to be limiting of the full scope and spirit of the invention.
    • EXAMPLES
  • I. Materials and Methods
  • The chemical reagents used to create the novel products of the invention below are all available commercially, e.g., from Aldrich Chemical Co., Milwaukee, Wis., USA. Otherwise their preparation is facile and known to one of ordinary skill in the art, or it is referenced or described herein.
  • The final compounds were usually purified by preparative TLC (silica gel 60 Å, Whatman Partisil PK6F) or flash chromatography (silica gel 60 Å, EMD Chemicals) using EtOAc/hexane or MeOH/CH2Cl2 as eluents. Rf's were measured using silica gel TLC plates (silica gel 60 Å, EMD Chemicals). Analytical HPLC chromatograms were obtained using a C18 column (Agilent Zorbax 300SB-C18; 5 microns; 4.6 mm×150 mm). A gradient was applied between solvent A (0.1% TFA in H2O) and solvent B (0.5% TFA in CH3CN) increasing the proportion of A linearly from 5% (t=0) to 100% (t=7.00 min), with a constant flow rate of 1 mL/min. The samples were diluted to typically 0.1-1 mg/mL in MeOH or CH3CN and the injection volumes were typically 10 μL. The column was not heated, and UV detection was effected at 254 nm. 1H-NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer.
  • The chemical names were generated using the Beilstein Autonom 2.1 software.
  • II. General Procedures
  • 1. General Procedures to Prepare and Manipulate the pyrrolo[2,3-d]pyrimidine Ring
  • General Procedure 1.1: Preparation of pyrrolo[2,3-d]pyrimidines (R0≠OH)
    Figure US20070173483A1-20070726-C00038
  • A suspension of 4-diamino-6-hydroxypyrimidine (6 mmol), AcONa (12 mmol) and α-haloaldehyde (6 mmol ) in CH3CN (20 mL) and H2O (20 mL) was stirred at 22-40° C. overnight whereupon the starting materials gradually dissolved and the desired pyrrolo[2,3-d]pyrimidine precipitated. The precipitate was collected by filtration and washed (water, acetontrile, ether) and air-dried ((a) C. J. Barnett, Org. Proc. Res. Develop. 1999, 3, 184. (b) F. Seela, Liebigs Ann. Chem. 1987, 15).
  • General Procedure 1.2: Preparation of pyrrolo[2,3-d]pyrimidines (R0═OH)
    Figure US20070173483A1-20070726-C00039
  • A suspension of (2-amino-4,6-dichloro-pyrimidin-5-yl)-acetic acid ethyl ester, R5—R4—NH2 and EtN(i-Pr)2 in BuOH was heated at reflux for 24 h whereupon the solvent was removed under reduced pressure. The residue was then dissolved in CH2Cl2 and washed with sat. NaHCO3 solution and dried with Na2SO4. The crude material was purified by preparative TLC or flash chromatography (EtOAc/hexane or MeOH/CH2Cl2) to give the pure pyrrolo[3,4-d]pyrimidin-6-one.
  • General Procedure 1.3: Alkylation of pyrrolo[2,3-d]pyrimidines at N-7
    Figure US20070173483A1-20070726-C00040
  • A suspension of the 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (1 mmol), benzyl halide (1 mmol) and K2CO3 or Cs2CO3 (1-5 mmol) in dry DMF (5 mL) was heated to 40° C. for 3 to 10 h. Work-up (EtOAc) and purification by preparative TLC or flash chromatography (EtOAc/hexane or MeOH/CH2Cl2) yielded the pure N-7 alkylated product.
  • General Procedure 1.4: Aminomethylation of pyrrolo[2,3-d]pyrimidines at C-5
    Figure US20070173483A1-20070726-C00041
  • A solution of 2-amino-7H-pyrrolo[2,3-d]pyrimidin-4-ol, formaldehyde (2-5 equiv.) and HNR9R9 (2-5 equiv.) in 80% aq. acetic acid was heated in a sealed tube at 60° C. overnight, concentrated, extracted in MeOH:CH2Cl2 (1:10), washed with sat. NaHCO3 and concentrated. See H. Akimoto, J. Chem. Soc. Perkin Trans 1. 1998, 1637.
  • General Procedure 1.5: Alkylation of pyrrolo[2,3-d]pyrimidin-6-one at C-5
    Figure US20070173483A1-20070726-C00042
  • To a solution of pyrrolo[2,3-d]pyrimidin-6-one in THF at −78° C. was added a base such as LDA, LHMDS or KHMDS and after 30 min, the alkyl halide was further added to give monoalkylated and bisalkylated pyrrolo[2,3-d]pyrimidin-6-ones which were purified by preparative TLC or flash chromatography (EtOAc/hexane or MeOH/CH2Cl2).
  • General Procedure 1.6: Oxidation of pyrrolo[2,3-d]pyrimidines at C-5
    Figure US20070173483A1-20070726-C00043
  • A solution of 2-amino-4-chloro-pyrrolo[3,4-d]pyrimidin-6-one and SeO2 in dioxane was heated at reflux until completion of the reaction, (1 h) whereupon the solvent was removed under reduced pressure. The crude was purified by preparative TLC or flash chromatography (EtOAc/hexane or MeOH/CH2Cl2) to give the pure 4-chloro-5-hydroxy-2-imino-2,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one.
  • 2. General Procedures to Manipulate the Pyridine Ring
  • General Procedure 2.1: Preparation of Pyridine N-oxides
  • A solution of the pyridine derivative (1 mmol) in dichloromethane or chloroform (5 mL) was cooled by means of an ice-bath, treated with m-CPBA (1.1 to 3 mmol) in three portions, and allowed to warm to r.t. The mixture was extracted with dichloromethane and washed with aqueous NaOH, followed by water. Drying (Na2SO4) and concentration afforded the pyridine N-oxide.
  • General Procedure 2.2: Preparation of 2-(acetoxymethyl)-piridines
  • A solution of the 2-methylpyridine N-oxide (1.0 mmol) in acetic anhydride (5 mL) was heated to reflux for 0.5 h. Work-up (EtOAc), drying (MgSO4), evaporation and purification by preparative TLC or flash chromatography afforded the 2-(acetoxymethyl) pyridine.
  • General Procedure 2.3: Preparation of 2-(hydroxymethyl)-pyridines
  • A suspension of 2-acetoxymethyl-pyridine derivative and solid K2CO3 in methanol was heated to 50° C. for 5-30 min. Evaporation, work-up (EtOAc), and drying (MgSO4) afforded the 2-(hydroxymethyl)-pyridine.
  • General Procedure 2.4: Preparation of 2-(bromomethyl)-pyridines
  • A solution of 2-(hydroxymethyl)-pyridine (1.0 mmol) and triphenyl phosphine (1.2 mmol) in dichloromethane or chloroform (5 mL) was cooled to 0° C. A solution of CBr4 (1.5 mmol) in dichloromethane or chlorofornm was added dopwise, and the resulting mixture was stirred at 0° C. for 0.5-1 h. Work-up and purification by flash chromatography afforded the 2-(bromomethyl)-pyridine.
  • General Procedure 2.5: Preparation of 2-(aminomethyl)-pyridines
  • The 2-(chloromethyl)-pyridine derivative in a solution of ammonia in MeOH was heated at 100° C. overnight whereupon it was concentrated under reduced pressure and purified by flash chromatography (MeOH/CH2Cl2) to afford the 2-(aminomethyl)-pyridine derivative.
  • General Procedure 2.6: Preparation of 2-chloropyridines
  • A suspension of 2-(hydroxymethyl)-pyridine (10 g) in POCl3 (30 mL) was stirred at 110° C. for 1.5 h. The resulting viscous oil was cooled to r.t. and poured onto ice water (500 g). The pH was adjusted to 10 with solid KOH. Work-up (CHCl3), drying (MgSO4) and evaporation gave the 2-chloropyridine, which was used without purification.
  • General Procedure 2.7: Preparation of pyridinium salts.
  • A solution of the pyridine was heated in MeOH until it dissolved. A methanolic solution of acid (1.0 equiv of e.g. HCl, MsOH) was added, and the solvent was evaporated to give the pyridinium salt.
  • 3. General Procedure to Manipulate Benzene Rings
  • General Procedure 3.1: Halogenation of Benzene Rings.
  • Variant 1: A solution of the aromatic compound in MeOH/THF/acetate buffer (1N in each AcOH and AcONa) was treated with Br2 (1.3-equiv) at r.t. for 5 min. The excess bromine and solvent were removed on a rotary evaporator. Work-up (CHCl3) and flash chromatography afforded the desired bromobenzene.
  • Variant 2: A solution of the aromatic compound (7 mmol) and N-halosuccinimide (NCS, NBS, or NIS, 1.06 equiv) in acetic acid (40 mL) was heated to 4-90° C. for 0.3-1 h. Evaporation, work-up (EtOAc) and flash chromatography afforded the desired halogenated benzene.
  • Preparation of Intermediates
    • Example 1 2-Chloro-1-chloromethyl-3,4,5-trimethoxy-benzene
  • Figure US20070173483A1-20070726-C00044
  • The title compound was obtained by chlorination of 5-chloromethyl-1,2,3-trimethoxy-benzene with NCS according to the general procedure 3.1.
  • 1H-NMR (CDCl3): δ 6.82 (s, 1H), 4.70 (s, 1H), 3.93 (s, 3H), 3.90 (s, 3H) 3.87 (s, 3H).
    • Example 2 2-Chloro-6-chloromethyl-4-methoxy-3,5-dimethyl-pyridine
  • Figure US20070173483A1-20070726-C00045
    • Step 1: 2-Chloromethyl-4-methoxy-3,5-dimethylpyridine-1-oxide
  • The title compound was obtained by oxidation of 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to the general procedure 2.1. HPLC Rt: 4.46 min. 1H-NMR (CDCl3): δ 8.05 (s, 1H), 4.93 (s, 2H), 3.77 (s, 3H), 2.37 (s, 3H), 2.24 (s, 3H).
    • Step 2: 2-Chloro-6-chloromethyl-4-methoxy-3,5-dimethylpyridine
  • The title compound was obtained by treating 2-chloromethyl-4-methoxy-3,5-dimethylpyridine-1-oxide with POCl3 according to the general procedure 2.6. HPLC Rt: 6.757 min. 1H-NMR (CDCl3): δ 4.64 (s, 2H), 3.79 (s, 3H), 2.35 (s, 3H), 2.33 (s, 3H).
    • Example 3 4-Chloro-2-chloromethyl-3,5-dimethyl-pyridine
  • Figure US20070173483A1-20070726-C00046
  • The title compound was obtained by treating 2-chloromethyl-3,5-dimethyl-pyridin-4-ol (Tarbit, et al. WO 99/10326) with POCl3 in the same manner as in the general procedure 2.6 (74% yield). HPLC Rt: 5.54 min. 1H-NMR (CDCl3): 8.24 (s, 1H), 4.71 (s, 2H), 2.48 (s, 3H), 2.36 (s, 3H).
    • Example 4 4-Bromo-2-bromomethyl-3,5-dimethyl-pyridine
  • 4-Bromo-2-bromomethyl-3,5-dimethyl-pyridine was prepared by any of the following three methods:
    Figure US20070173483A1-20070726-C00047
    • Step 1: 2,3,5-Collidine-N-oxide
  • 2,3,5-Collidine-N-oxide was obtained by oxidation of 2,3,5-collidine according to the general procedure 2.1 in 70% yield. HPLC Rt: 3.96 min. 1H-NMR (CDCl3): δ 8.03 (s, 1H), 6.90 (s, 1H), 2.47 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H). m/z (%) 138.2 (M+1, 100%). Rf (20% MeOH/EtOAc): 0.35.
    • Step 2: 4-Bromo-2,3,5-collidine-N-oxide
  • 2,3,5-collidine-N-oxide (1.3 g, 10 mmol) and K2CO3 (2.9 g, 20 mmol) were suspended in 10 mL of CCl4. Bromine (1 mL, 20 mmol) was added dropwise, and the reaction mixture was heated to reflux for 2 h. Work-up (EtOAc) and flash chromatography (10% MeOH/EtOAc) afforded the title compound as a solid (1.05 g, 51% yield). HPLC Rt: 5.24 min. 1H-NMR (CDCl3): δ 8.06 (s, 1H), 2.56 (s, 3H), 2.43 (s, 3H), 2.31 (s, 3H). m/z (%) 216.2 (M+1, 100%), 218.2 (M+3, 100%). Rf (20% MeOH/EtOAc): 0.45.
    • Step 3: Acetic acid 4-bromo-3,5-dimethyl-pyridin-2-yl methyl ester
  • 4-Bromo-2,3,5-collidine-N-oxide (0.25 g, 11 mmol) was dissolved in acetic anhydride (5 mL) and the solution was heated to reflux for 30 min. Work-up and flash chromatography (50% Hexane/EtOAc) afforded the title compound (0.27 g, 96% yield). Rf (50% Hexane/EtOAc): 0.70. HPLC Rt: 4.76 min. 1H-NMR (CDCl3): δ 8.26 (s, 1H), 5.27 (s, 2H), 2.46 (s, 3H), 2.41 (s, 3H), 2.14 (s, 3H).
    • Step 4: 4-Bromo-3,5-dimethyl-pyridin-2-yl methanol
  • A suspension of acetic acid 4-bromo-3,5-dimethyl-pyridin-2-yl methyl ester (0.26 g, 1.0 mmol) and K2CO3 (excess) in MeOH (5 mL) was heated to 50° C. for 15 min. Work-up (CHCl3), evaporation, and filtration through a silica gel pad (eluent: 100% EtOAc) gave the title compound as a white solid (0.19 g, 88% yield). Rf (50% Hexane/EtOAc): 0.5. HPLC Rt: 3.80 min. 1H-NMR (CDCl3): δ 8.23 (s, 1H), 4.70 (s, 2H), 2.46 (s, 3H), 2.30 (s, 3H).
    • Step 5: 4-Bromo-2-bromomethyl-3,5-dimethyl-pyridine
  • The title compound was obtained from 4-bromo-3,5-dimethyl-pyridin-2-yl methanol according to the general procedure 2.4. HPLC Rt: 6.32 min. 1H-NMR (CDCl3): δ 8.22 (s, 1H), 4.63 (s, 2H), 2.52 (s, 3H), 2.40 (s, 3H).
    Figure US20070173483A1-20070726-C00048
    • Step 1: 2-chloromethyl-3,5-dimethyl-pyridin-4-ol
  • The title compound was obtained by heating 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine hydrochloride in toluene as described in the patent by Tarbit, et al. WO 99/10326.
    • Step 2: 4-bromo-2-chloromethyl-3,5-dimethylpyridine
  • A mixture of 2-chloromethyl-3,5-dimethyl-pyridin-4-ol (8.2 g, 47.8 mmol) and POBr3 (60 g, 209 mmol) was stirred at 130° C. for 3 h. The resulting viscous oil was cooled to r.t. and poured onto ice water. The pH was adjusted to 10 with solid KOH. Work-up (CHCl3), drying (MgSO4) and evaporation afforded the title compound as a purple solid (8.7 g, 78% yield) which was used without purification. HPLC Rt: 6.03 min. 1H-NMR (CDCl3): 8.20 (s, 1H), 4.62 (s, 2H), 2.50 (s, 3H), 2.38 (s, 3H).
    Figure US20070173483A1-20070726-C00049
    • Step 1: 4-bromo-2-chloromethyl-3,5-dimethylpyridine
  • A suspension of 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (3.24 g, 14.6 mmol) in PBr3 (8.0 mL, 85.1 mmol, 5.8 equiv.) was heated to 80° C. under nitrogen. A catalytic amount of DMF (0.50 mL, 6.4 mmol, 0.44 equiv.) was added, whereupon the suspension rapidly turned into an orange solution. After 40 min., the reaction was still incomplete as judged by HPLC. The temperature was raised to 110° C. and the reaction was prolonged for 30 min, at which point it was complete. The mixture was poured over ice, made basic with conc. aq. NH4OH and extracted into EtOAc. Washing with water, drying (brine, MgSO4) and concentration gave the title compound as a pink solid (1.51 g, 44%) containing 10% of an impurity by 1H-NMR. The crude was used without further purification. 1H-NMR (CDCl3) δ 8.19 (s, 1H), 4.59 (s, 2H), 2.48 (s, 3H), 2.37 (s, 3H).
  • Preparation of Final Compounds
    • Example 5 4-Chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00050
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (F. Seela,Liebigs Ann. Chem. 1987, 15) with 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine hydrochloride according to the general procedure 1.3. HPLC Rt: 4.709 min. 1H-NMR (CDCl3): δ 8.23 (s, 1H), 6.90 (m, 1H), 6.38 (m 1H), 5.35 (s, 2H), 4.99 (s, 2H), 3.75 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H).
    • Example 6 7-(2-Bromo-3,4,5-trimethoxy-benzyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00051
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 2-bromo-1-chloromethyl-3,4,5-trimethoxy-benzene according to the general procedure 1.3. HPLC Rt: 6.937 min. 1H-NMR (DMSO-d6): δ 7.11 (m 1H), 6.73(s, 2H), 6.42 (s, 1H), 6.37 (m 1H), 5.23 (s, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.61 (s, 3H).
    • Example 7 4-Chloro-7-(2-iodo-3,4,5-trimethoxy-benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00052
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 1-chloromethyl-2-iodo-3,4,5-trimethoxy-benzene according to the general procedure 1.3. HPLC Rt: 7.069 min. 1H-NMR (DMSO-d6): δ 7.08 (m 1H), 6.74 (s, 2H), 6.38 (m 1H), 6.36 (s, 1H), 5.19 (s, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.60 (s, 3H).
    • Example 8 4-Chloro-7-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00053
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine I-oxide according to the general procedure 1.3. HPLC Rt: 5.079 min. 1H-NMR (DMSO-d6): δ 8.18 (s, 1H), 7.29 (m, 1H), 6.68(s, 2H), 6.24 (m, 1H), 5.38 (s, 2H), 3.70 (s, 3H), 2.42 (s, 3H), 2.17 (s, 3H). ESI-MS 334.2 (M+1).
    • Example 9 4-Chloro-7-(3,4,5-trimethoxy-benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00054
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 5-chloromethyl-1,2,3-trimethoxy-benzene according to the general procedure 1.3. HPLC Rt: 6.036 min. 1H-NMR (CDCl3): δ 6.82 (m, 1H), 6.41(s, 2H), 6.40 (m, 1H), 5.36 (s, 2H), 5.16 (s, 2H), 3.81 (s, 3H), 3.78 (s, 6H).
    • Example 10 4-Chloro-7-(6-chloro-4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00055
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 2-chloro-6-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 6.880 min. 1H-NMR (DMSO-d6): δ 7.06 (m, 1H), 6.63(s, 2H), 6.32 (m, 1H), 5.29 (s, 2H), 3.74 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H).
    • Example 11 4-Chloro-7-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00056
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 5.878 min. 1H-NMR (CDCl3): δ 8.27 (s, 1H), 6.89 (m, 1H), 6.40 (m, 1H), 5.40 (s, 2H), 4.94 (s, 2H), 2.39 (s, 3H), 2.37 (s, 3H).
    • Example 12 4-Chloro-7-(2-chloro-4,5-dimethoxy-benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00057
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 1-bromomethyl-2-chloro-4,5-dimethoxy-benzene according to the general procedure 1.3. HPLC Rt: 6.635 min. 1H-NMR (CDCl3): δ 6.91 (m, 1H), 6.90 (s, 1H), 6.71 (s, 1H), 6.42 (m, 1H), 5.30 (s, 2H), 4.97 (s, 2H), 3.88 (s, 3H), 3.75 (s, 3H).
    • Example 13 7-(4-Bromo-3,5-dimethyl-pyridin-2-ylmethyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00058
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 6.072 min. 1H-NMR (DMSO-d6): δ 8.15 (s, 1H), 7.10 (m, 1H), 6.60(s, 1H), 6.30 (m, 1H), 5.40(s, 2H), 2.46 (s, 3H), 2.30 (s, 3H).
    • Example 14 4-Chloro-7-(4-chloro-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00059
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide according to the general procedure 1.3. HPLC Rt: 5.610 min. 1H-NMR (DMSO-d6): δ 8.36 (s, 1H), 7.26 (m, 1H), 6.69(s, 1H), 6.21 (m, 1H), 5.43(s, 2H), 2.60 (s, 3H), 2.27 (s, 3H).
    • Example 15 7-(4-Bromo-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00060
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide according to the general procedure 1.3. HPLC Rt: 5.734 min. 1H-NMR (DMSO-d6): δ 8.33 (s, 1H), 7.24 (m, 1H), 6.69 (s, 1H), 6.25 (m, 1H), 5.47(s, 2H), 2.65 (s, 3H), 2.29 (s, 3H).
    • Example 16 4-Chloro-7-(3,5-dimethoxy-2-nitro-benzyl)-7H1-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00061
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 1-bromomethyl-4,5-dimethoxy-2-nitro-benzene according to the general procedure 1.3. HPLC Rt: 6.345 min. 1H-NMR (DMSO-d6): δ 7.73 (s, 1H), 7.16 (in, 1H), 6.72 (s, 2H), 6.41 (s, 1H), 6.40 (m, 1H), 5.58(s, 2H), 3.92 (s, 3H), 3.62 (s, 3H).
    • Example 17 4-Chloro-7-(3,4-dichloro-benzyl)-7H-pyrrolo [2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00062
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 4-bromomethyl-1,2-dichloro-benzene according to the general procedure 1.3. HPLC Rt: 7.148 min. 1H-NMR (DMSO-d6): δ 7.60 (m, 1H), 7.59 (in, 1H), 7.25(q, 1H), 7.12(m, 1H), 6.71 (s, 2H), 6.37 (q, 1H), 5.26(s, 2H).
    • Example 18 4-Chloro-7-(3,5-dimethoxy-benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00063
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 1-chloromethyl-3,5-dimethoxy-benzene according to the general procedure 1.3. HPLC Rt: 6.423 min. 1H-NMR (DMSO-d6): δ 7.21(m, 1H), 6.69 (s, 2H), 6.40 (m,3H), 6.34 (m, 1H), 5.34 (s, 2H), 3.68 (s, 6H).
    • Example 19 4-Chloro-7-(2,5-dimethoxy-benzy1)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00064
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 2-chloromethyl-1,4-dimethoxy-benzene according to the general procedure 1.3. HPLC Rt: 6.537 min. 1H-NMR (DMSO-d6): δ 7.13 (m, 1H), 6.85 (d, 1H), 6.82 (m, 1H), 6.68 (s, 2H), 6.35 (m, 1H), 6.22 (d, 1H), 3.78 (s, 3H), 3.60 (s, 3H).
    • Example 20 4-Bromo-7-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00065
  • The title compound was obtained by alkylation of 4-bromo-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (obtained as described in F. Seela, Liebigs Ann. Chem. 1987, 15 for 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine, but replacing POCl3 with POBr3) with 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine-1-oxide according to the general procedure 1.3. HPLC Rt: 5.158 min. 1H-NMR (DMSO-d6): δ 8.18 (s, 1H), 7.29 (m, 1H), 6.69 (s, 2H), 6.15 (m, 1H), 5.37(s, 2H), 3.70 (s, 3H), 2.42 (s, 3H), 2.17 (s, 3H).
    • Example 21 4-Bromo-7-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00066
  • The title compound was obtained by alkylation of 4-bromo-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 5.803 min. 1H-NMR (DMSO-d6): δ 8.20 (s, 1H), 7.04 (m, 11H), 6.61 (s, 2H), 6.21 (m, 1H), 5.38(s, 2H), 2.42 (s, 3H), 2.28 (s, 3H).
    • Example 22 4-Bromo-7-(4-chloro-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00067
  • The title compound was obtained by alkylation of 4-bromo-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine-1-oxide according to the general procedure 1.3. HPLC Rt: 5.688 min. 1H-NMR (DMSO-d6): δ 8.35 (s, 1H), 7.25 (m, 1H), 6.70 (s, 2H), 6.15 (m, 1H), 5.43 (s, 2H), 2.60 (s, 3H), 2.27 (s, 3H).
    • Example 23 4-Bromo-7-(4-bromo-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo [2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00068
  • The title compound was obtained by alkylation of 4-bromo-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 5.996 min. 1H-NMR (DMSO-d6): δ 8.15 (s, 1H), 7.05 (m, 1H), 6.61 (s, 2H), 6.21 (m, 1H), 5.43 (s, 2H), 2.46 (s, 3H), 2.30 (s, 3H).
    • Example 24 4-Bromo-7-(4-bromo-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00069
  • The title compound was obtained by alkylation of 4-bromo-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine-1-oxide according to the general procedure 1.3. HPLC Rt: 5.798 min. 1H-NMR (DMSO-d6): δ 8.33 (s, 1H), 7.24 (m, 1H), 6.71 (s, 2H), 6.15 (m, 1H), 5.46 (s, 2H), 2.64 (s, 3H), 2.29 (s, 3H).
    • Example 25 4-Bromo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00070
  • The title compound was obtained by alkylation of 4-bromo-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 4.847 min. 1H-NMR (DMSO-d6): δ 8.07 (s, 1H), 7.03 (m, 1H), 6.60 (s, 2H), 6.20 (m, 1H), 5.29 (s, 2H), 3.72 (s, 3H), 2.24 (s, 3H), 2.17 (s, 3H).
    • Example 26 4-Bromo-7-(3,5-dimethoxy-benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00071
  • The title compound was obtained by alkylation of 4-bromo-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 1-cloromethyl-3,5-dimethoxy-benzene according to the general procedure 1.3. HPLC Rt: 6.490 min. 1H-NMR (CDCl3): δ 7.20 (m, 1H), 6.70 (s, 2H), 6.40 (s, 1H), 6.34 (s, 2H), 6.23 (m, 1H), 5.16 (s, 2H), 3.69 (s, 6H).
    • Example 27 4-Chloro-7-(3-methoxy-benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00072
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 1-chloromethyl-3-methoxy-benzene according to the general procedure 1.3. HPLC Rt: 7.177 min. 1H-NMR (DMSO-d6): δ 7.26-7.18 (m, 2H), 6.82-6.80 (m, 1H), 6.67 (s, 1H), 6.70-6.67 (m, 3H), 6.32-6.30 (m, 1H), 5.20 (s, 2H), 3.68 (s, 3H).
    • Example 28 4-Chloro-7-(4-methoxy-benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00073
  • The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 1-chloromethyl-4-methoxy-benzene according to the general procedure 1.3. HPLC Rt: 6.889 min. H-NMR (DMSO-d6): δ 7.19-7.16 (m, 3H), 6.90-6.88 (m, 2H), 6.69 (s, 2H), 6.32-6.30 (m, 1H), 5.18 (s, 2H), 3.71 (s, 3H).
    • Example 29 N-[4-Chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide
  • Figure US20070173483A1-20070726-C00074
  • The title compound was obtained by alkylation of N-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionamide with 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine-1-oxide according to the general procedure 1.3. HPLC Rt: 6.812min. 1H-NMR (DMSO-d6): δ 10.20 (s, 1H), 8.13(s, 1H), 7.97 (s, 1H), 5.50 (s, 2H), 3.72 (s, 3H), 2.50 (s, 3H), 2.16 (s, 3H), 1.22 (s, 9H).
    • Example 30 N-[7-(4-Bromo-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide
  • Figure US20070173483A1-20070726-C00075
  • The title compound was obtained by alkylation of N-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionamide with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine-1-oxide according to the general procedure 1.3. HPLC Rt: 7.630 min. H-NMR (DMSO-d6): δ 10.21 (s, 1H), 8.30(s, 1H), 7.91 (s, 1H), 5.59 (s, 2H), 2.72 (s, 3H), 2.28 (s, 3H), 1.22 (s, 9H).
    • Example 31 N-[4-Chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide
  • Figure US20070173483A1-20070726-C00076
  • The title compound was obtained by alkylation of N-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionamide (A. Gangjee, J. Med. Chem. 2003, 46, 591) with 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 6.627 min. 1H-NMR (DMSO-d6): δ 10.15 (s, 1H), 8.05(s, 1H), 7.73 (s, 1H), 5.46 (s, 2H), 3.74 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H), 1.21 (s, 9H).
    • Example 32 N-[7-(4-Bromo-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide
  • Figure US20070173483A1-20070726-C00077
  • The title compound was obtained by alkylation of N-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionamide with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine-1-oxide according to the general procedure 1.3. HPLC Rt: 6.806 min. 1H-NMR (DMSO-d6): δ 10.13 (s, 1H), 8.30(s, 1H), 7.74 (m, 1H), 6.52 (m, 1H), 5.62 (s, 2H), 2.73 (s, 3H), 2.28 (s, 3H), 1.23 (s, 9H).
    • Example 33 N-[4-Chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide
  • Figure US20070173483A1-20070726-C00078
  • The title compound was obtained by alkylation of N-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionamide with 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 6.087 min. 1H-NMR (CDCl3): δ 8.18 (s, 1H), 8.13(s, 1H), 7.18 (m, 1H), 6.49 (m, 1H), 5.50 (s, 2H), 3.72 (s, 3H), 2.26 (s, 3H), 2.22 (s, 3H), 1.34 (s, 9H).
    • Example 34 N-[4-Chloro-7-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide
  • Figure US20070173483A1-20070726-C00079
  • The title compound was obtained by alkylation of N-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionamide with 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine-1-oxide according to the general procedure 1.3. HPLC Rt: 6.115 min. 1H-NMR (CDCl3): δ 8.12 (s, 1H), 8.02(s, 1H), 7.93 (m, 1H), 6.49 (m, 1H), 5.71 (s, 2H), 3.76 (s, 3H), 2.70 (s, 3H), 2.22 (s, 3H), 1.36 (s, 9H).
    • Example 35 N-[4-Chloro-7-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide
  • Figure US20070173483A1-20070726-C00080
  • The title compound was obtained by alkylation of N-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionamide with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 6.761 min. 1H-NMR (CDCl3): δ 8.23 (s, 1H), 8.11(s, 1H), 7.15 (m, 1H), 6.50 (m, 1H), 5.71 (s, 2H), 2.43 (s, 3H), 2.33 (s, 3H), 1.35 (s, 9H).
    • Example 36 N-[4-Chloro-7-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide
  • Figure US20070173483A1-20070726-C00081
  • The title compound was obtained by alkylation of N-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionamide with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 7.508 min. 1H-NMR (CDCl3): δ 8.17 (s, 1H), 8.11 (s, 1H), 8.07 (s, 1H), 5.77 (s, 2H), 2.81 (s, 3H), 2.33 (s, 3H), 1.37 (s, 9H).
    • Example 37 N-[4-Chloro-7-(4-chloro-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide
  • Figure US20070173483A1-20070726-C00082
  • The title compound was obtained by alkylation of N-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionamide with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine-1-oxide according to the general procedure 1.3. HPLC Rt: 6.688 min. 1H-NMR (CDCl3): δ 8.15 (s, 1H), 8.09 (s, 1H), 7.87 (m, 1H), 6.47 (m, 1H), 5.77 (s, 2H), 2.84 (s, 3H), 2.31 (s, 3H), 1.37(s,9H).
    • Example 38 N-[4-Chloro-7-(4-chloro-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide
  • Figure US20070173483A1-20070726-C00083
  • The title compound was obtained by alkylation of N-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionamide with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine-1-oxide according to the general procedure 1.3. HPLC Rt: 7.619 min. 1H-NMR (CDCl3): δ 8.25 (s, 1H), 8.13 (s, 1H), 7.33 (s, 1H), 5.55 (s, 2H), 2.47 (s, 3H), 2.36 (s, 3H), 1.36 (s, 9H).
    • Example 39 4-Chloro-5-[(dibenzylamino)-methyl]-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00084
    • Step 1. Octanoic acid {4-chloro-5-[(dibenzylamino)-methyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-amide
  • A solution of octanoic acid {5-[(dibenzylamino)-methyl]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl}-amide (1.0 g, 2 mmol; J. Chem. Soc. Perkin Trans. 1 1998, 1637), BnNEt3Cl (1.4 g, 4 mmol), PhNMe2 (0.5 mL) and POCl3 (1.73 mL, 12 mmol) in CH3CN (9.2 mL) was heated to 100° C. for 40 min and concentrated. The residue was poured into ice water and neutralized with 2N NaOH, extracted with EtOAc (50 mL×3), and evaporated, to give the title compound (0.80 g, 76%). HPLC Rt: 6.868 min. 1H-NMR (DMSO-d6): δ 12.19 (s, 1H), 10.49 (s, 1H), 1.45-7.21 (m, 11H), 3.80 (s, 2H), 3.59 (s, 4H), 2.41 (t, 2H), 1,56 (m, 2H), 1.27 (br s 8H), 0.85 (t, 3H).
    • Step 2. 4-Chloro-5-[(dibenzylamino)-methyl]-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • A suspension of octanoic acid {4-chloro-5-[(dibenzylamino)-methyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-amide (150 mg, 0.30 mmol), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (56 mg, 0.30 mmol) and K2CO3 (84 mg, 0.60 mmol) in dry DMF (1 mL) was heated to 45° C. overnight. After work-up (EtOAc) and evaporation, the residue was taken up in methanolic 4N HCl (1 mL), stirred at room temperature for 1 h, and neutralized to pH 7 with 2N NaOH. Extraction with EtOAc (10 mL×3), evaporation and purification by preparative TLC (MeOH/CH2Cl2 10:1) gave the title compound (70.5 mg, 45%). HPLC Rt: 5.362 min. 1H-NMR (DMSO-d6): δ 8.05 (s, 1H), 7.30-7.22 (m, 10H), 6.99(s, 1H), 6.57s, 2H), 5.27 (s 2H), 3.70 (s, 2H), 3.65 (s, 3H), 3.54 (s, 4H), 2.17 (s, 3H), 2.15 (s, 3H).
    • Example 40 4-Chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5-phenylaminomethyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00085
    • Step 1. Octanoic acid (4-chloro-5-phenylaminomethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide
  • A solution of octanoic acid {5-[(dibenzylamino)-methyl]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl}-amide (2.42 g, 3 mmol) and aniline (10 mL) was heated to 90° C. in a sealed tube overnight, concentrated, filtered, and washed with MeOH (2 mL×3) to give the title compound (1.1 g, 57%). HPLC Rt: 6.327 min. 1H-NMR (DMSO-d6): δ 11.77 (s, 1H), 11.47 (s, 1H), 11.37 (s, 1H), 7.05 (m, 2H), 6.85 (s, 1H), 6.62 (m, 2H), 6.52 (m, 1H), 5.58 (t, 1H), 4.31 (d, 2H), 2.43 (t, 2H), 1.58 (m, 2H), 1.27 (m, 8H), 0.86 (t, 3H).
    • Step 2. 4-Chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5-phenylaminomethyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • A solution of octanoic acid (4-chloro-5-phenylaminomethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide (270 mg, 0.68 mmol), BnNEt3Cl (0.48 g, 1.36 mmol), PhNMe2 (0.17 mL) and POCl3 (0.59 mL, 4.08 mmol) in CH3CN (3 mL) was heated to 100° C. for 40 min and concentrated. The residue was poured into ice water and neutralized with 2N NaOH, extracted with EtOAc (20 mL×3), evaporated, to give 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine as a crude oil (282 mg) which was used without purification. A suspension of this crude (282 mg, 0.68 mmol), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (140 mg, 0.68 mmol) and Cs2CO3 (266 mg, 0.68 mmol) in dry DMF (1 mL) was heated to 45° C. overnight. After work-up (EtOAc) and evaporation, the residue was taken up in methanolic 4N HCl (1 mL), stirred at room temperature for 1 h, and neutralized to pH 7 with 2N NaOH. Extraction with EtOAc (10 mL×3), evaporation and purification by preparative TLC (MeOH/CH2Cl2 10: 1) gave the title compound (4.8 mg, 1.6%). HPLC Rt: 4.785 min. 1H-NMR (CDCl3): δ 8.12 (s, 1H), 7.18(m, 2H), 6.75(m, 2H), 6.60 (s, 1H), 5.26(s, 2H), 4.93 (s, 2H), 4.74 (s, 2H), 3.70 (s, 3H), 3.00 (s, 3H), 2.23 (s, 3H), 2.16 (s, 3H).
    • Example 41 4-Chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5-[(methyl-phenyl-amino)-methyl]-7H-pyrrolo [2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00086
    • Step 1: Octanoic acid (4-chloro-5-[(methyl-phenyl-amino)-methyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide
  • The title compound was obtained by treating octanoic acid {5-[(dibenzylamino)-methyl]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl}-amide (2.42 g, 3 mmol) and N-methylaniline (10 mL) as in step 1 of the previous example. HPLC Rt: 6.325 min. 1H-NMR (DMSO-d6): δ 11.73 (s, 1H), 11.47 (s, 1H), 11.35 (s, 1H), 7.13 (m, 2H), 6.78 (s, 2H), 6.60 (m, 2H), 4.64(s, 2H), 2.98 (s, 3H), 2.43 (t, 2H), 1.58 (m, 2H), 1.27 (m, 8H), 0.86 (t, 3H).
    • Step 2: 4-Chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5-[(methyl-phenyl-amino)-methyl]-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • The title compound was obtained by alkylation of octanoic acid {4-chloro-5-[(methyl-phenyl-amino)-methyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-amide with 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine and deprotection with 4N HCl as in step 2 of the previous example. HPLC 4.844 min. 1H-NMR (CDCl3): δ 8.20 (s, 1H), 7.16 (m, 2H), 6.87 (s, 1H), 6.70-6.64 (m, 2H), 5.28 (s, 2H), 5.13 (s, 2H), 4.46 (s, 2H), 4.15 (br s, 1H), 3.73 (s, 3H), 2.25 (s, 3H), 2.18 (s, 3H).
    • Example 42 4-Chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-6-pyrrolidin-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00087
    • Step 1. Octanoic acid (4-chloro-6-pyrrolidin-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide
  • A solution of octanoic acid (4-oxo-6-pyrrolidin-1-ylmethyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide (0.36 g 1 mmol; J. Chem. Soc. Perkin Trans. 1 1998, 1637), BnNEt3Cl (0.70 g, 2 mmol), PhNMe2 (0.25 mL) and POCl3 (0.86 mL, 6 mmol) in CH3CN (5 mL) was heated to 100° C. for 40 min and concentrated. The residue was poured into ice water and neutralized with 2N NaOH, extracted with EtOAc (50 mL ×3), and evaporated to give octanoic acid (4-chloro-6-pyrrolidin-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide as a crude (0.33 g) which was used without purification. HPLC Rt: 6.737 min. 1H-NMR (CDCl3): δ 11.60 (br s, 1H), 10.20 (br s, 1H), 6.38 (s, 1H), 3.86 (s, 2H), 2.90 (m, 2H), 2.70 9s, 4H), 1.86 (s, 4H), 1.78 (t, 2H), 1.32-1.29 (m, 8H), 0.90 (t, 3H).
  • Step 2. 4-Chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-6-pyrrolidin-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • A suspension of the crude octanoic acid (4-chloro-6-pyrrolidin-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide (330 mg, 0.87 mmol), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (162 mg, 0.87 mmol) and K2CO3 (121 mg, 0.87 mmol) in dry DMF (1 mL) was heated to 45° C. overnight. After work-up (EtOAc) and evaporation, the residue was taken up in 6N methanolic HCl (1 mL), stirred at room temperature for 1 h, and neutralized to pH 7 with 2N NaOH. Extraction with EtOAc (10 mL×3), evaporation and purification by preparative TLC (MeOH/CH2Cl2 10:1) yielded 4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-6-pyrrolidin-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (4.1 mg, yield 1.0%). HPLC Rt: 6.092 min. 1H-NMR (CDCl3): δ 8.09 (s, 1H), 6.31(s, 1H), 5.55(s, 2H), 4.85(s, 2H), 3.77 (s, 3H), 3.52(brs, 2H), 2.43 (m, 4H), 1.76-1.71(m, 4H).
    • Example 43 4-Chloro-5-isopropyl-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00088
    • Step 1. 3-Bromo-4-methyl-pentanal
  • A mixture of 4-methyl-pentanal (8.60 g, 0.10 mol), 5,5-dibromobarbituric acid (DBBA, 17.15 g, 0.06 mol), 40% HBr (2 mL) and HOAc (1 mL) in CH2Cl2 (180 mL) was stirred at 25° C. for 5 h. after filtration, the filtrate was washed with 1N Na2SO3, Na2CO3, and brine, dried with Na2SO4, and evaporated to give 3-bromo-4-methyl-pentanal (8.76 g, 53%). 1H-NMR (CDCl3): δ 9.40 (s, 1H), 4.40 (t, 1H), 2.10 (m, 1H), 1.06 (s, 3H), 1.05 (s, 3H).
    • Step 2. 2-Amino-5-isopropyl-3, 7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one
  • A suspension of 2,4-diamino-6-hydroxypyrimidine (6.68 g, 50 mmol), AcONa (8.3 g 100 mmol) and 3-bromo-4-methyl-pentanal (8.76 g, 50 mmol) in CH3CN (100 mL) and H2O (100 mL) was stirred at 25° C. overnight whereupon the starting materials gradually dissolved and the desired pyrrolo[2,3-d]pyrimidine precipitated. The precipitate was collected by filtration and washed with MeOH to give 2-amino-5-isopropyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (3.80 g, 40%). HPLC Rt: 4.408 min. 1H-NMR (DMSO-d6): δ 10.58 (s, 1H), 10.10 (s, 1H), 6.30 (s, 1H), 5.97 (s, 2H), 3.03 (7, 1H), 1.20 (s, 3H), 1.19 (s, 3H).
    • Step 3. 4-Chloro-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • A mixture of 2-amino-5-isopropyl-3,7-dihydro-pyrrolo [2,3-d]pyrimidin-4-one and acetic anhydride (20 mL) was heated to reflux for 3 h and evaporated. The residue was treated with BnNEt3Cl (8.99 g, 40 mmol), PhNMe2 (4.9 mL) and POCl3 (17 mL, 120 mmol) in CH3CN (100 mL) at 100° C. for 40 min and concentrated. The residue was poured into ice water and neutralized with 2N NaOH, extracted with EtOAc (80 mL×3), and evaporated to give an oil which was digested with methanolic 4N HCl (50 mL) at 50° C. for 2 h. After cooling, and neutralization to pH 7 with 2N NaOH, the solid was collected by filtration and dried to give 4-chloro-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (1.88 g, 45%). HPLC Rt: 5.796 min. 1H-NMR (DMSO-d6): δ 11.170 (s, 1H), 6.82 (s, 1H), 6.42 (s, 2H), 3.24 (7, 1H), 1.25 (s, 3H), 1.23 (s, 3H).
    • Step 4. 4-Chloro-5-isopropyl-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • A suspension of 4-chloro-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (105 mg, 0.5 mmol), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (93 mg, 0.5 mmol) and K2CO3 (85 mg, 0.6 mmol) in dry DMF (1 mL) was heated to 45° C. overnight, Work-up (EtOAc), evaporation, and purification by preparative TLC (MeOH/CH2Cl2 10:1) gave 4-chloro-5-isopropyl-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (36 mg). HPLC Rt: 5.867 min. 1H-NMR (DMSO-d6): δ 8.07 (s, 1H), 6.74(s, 1H), 6.51(s, 2H), 5.22 (s, 2H), 3.70 0s, 3H), 3.23 (7, 1H), 2.21 (s, 3H), 2.15 (s, 3H).
    • Example 44 4-chloro-7-(4-chloro-3-methyl-pyridin-2-ylmethyl)-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00089
  • The title compound was obtained by alkylation of 4-chloro-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 6.997 min. 1H-NMR (CDCl3): δ 8.27 (s, 1H), 6.61 (s, 1H), 5.33 (s, 2H), 5.09 (s, 2H), 3.35 (7, 1H), 2.35 (s, 6H), 1.25 (s, 3H), 1.23 (s, 3H).
    • Example 45 4-Chloro-7-(4-chloro-3-methyl-1-oxy-pyridin-2-ylmethyl)-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00090
  • The title compound was obtained by alkylation of 4-chloro-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 2-chloromethyl-3,5-dimethyl-pyridine-1-oxide according to the general procedure 1.3. HPLC Rt: 6.753 min. 1H-NMR (DMSO-d6): δ 8.37 (s, 1H), 7.03 (s, 1H), 6.63 (s, 2H), 5.40 (s, 2H), 3.20 (7, 1H), 2.59 (s, 3H), 2.27 (s, 3H), 1.20 (s, 3H), 1.19 (s, 3H).
    • Example 46 4-Chloro-5-(2-isobutylamino-ethyl)-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • Figure US20070173483A1-20070726-C00091
    Figure US20070173483A1-20070726-C00092
    • Step 1. 4-(tert-Butyl-diphenyl-silanyloxy)-butan-1-ol
  • A mixture of tBuPh2SiCl (25 mL, 98 mmol), 1,4-butanediol (25 mL, 281 mmol), iPrNEt2 (50 mL, 303 mmol) and CH2Cl2 (50 mL) was stirred at rt for 14 h, concentrated, diluted with diethyl ether, washed with water (3×) and brine. Drying (Na2SO4) and concentration afforded the title compound as a clear oil (29.8 g, 93%) which was used without further purification. Rf (EtOAc:hexane 1:4) 0.3. 1H-NMR (CDCl3): δ 7.71 (dd, 4H), 7.43 (m, 6H), 3.74 (t, 2H), 3.70 (q, 2H), 2.10 (br. t, 1H), 1.69 (m, 4H), 1.08 (s, 9H).
    • Step 2. 4-(tert-Butyl-diphenyl-silanyloxy)-butyraldehyde
  • A solution of 4-(tert-butyl-diphenyl-silanyloxy)-butan-1-ol (29.8 g, 91 mmol) in CH2Cl2 (70 mL) was added to a slurry of PCC (21.5 g, 100 mmol), celite (50 g) and CH2Cl2 (300 mL). The mixture was stirred for 2 h at rt, and the celite was removed by filtration and washed with CH2Cl2 (300 mL). Concentration and chromatography (EtOAc/hexane 1:4) afforded the title compound as a clear oil (22.2 g, 75%). Rf (EtOAc:hexane 1:4) 0.7. 1H-NMR (CDCl3): δ 9.82 (t, 1H), 7.68 (dd, 4H), 7.41 (m, 6H), 3.71 (t, 2H), 2.57 (t, 2H), 1.91 (q, 2H), 1.07 (s, 9H).
    • Step 3. 2-Bromo-4-(tert-butyl-diphenyl-silanyloxy)-butyraldehyde
  • A mixture of 4-(tert-butyl-diphenyl-silanyloxy)-butyraldehyde (22.2 g, 68 mmol), 5,5-dibromobarbituric acid (12.1 g, 43 mmol) and CH2Cl2 (80 mL) was treated with 70% aq HBr (1 mL, 14 mmol) and stirred at rt for 1 h. The by-product (barbituric acid) was removed by filtration and washed with CH2Cl2 (100 mL). The combined organic layers were washed (1N Na2S2O3, 5% NaHCO3, half-sat. brine) and dried (Na2SO4). Concentration gave the title compound as a clear oil (25.3 g, 92%) which was used without further purification. Rf (EtOAc:hexane 1:4) 0.7. 1H-NMR (CDCl3): δ 9.55 (d, 1H), 7.68 (dd, 4H), 7.41 (m, 6H), 4.60 (ddd, 1H), 3.84 (m, 2H), 2.35 (m, 1H), 2.10 (m, 1H), 1.07 (s, 9H).
    • Step 4. 2-Amino-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-3, 7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one
  • The title compound was obtained by treating 2-bromo-4-(tert-butyl-diphenyl-silanyloxy)-butyraldehyde (25.3 g, 62 mmol) with 2,4-diamino-6-hydroxypyrimidine (10.2 g, 124 mmol) according to the general procedure 1.1 (23.4 g, 87%). HPLC Rt: 6.981 min. H-NMR (CDCl3): δ 10.67 (s, 1H), 10.14 (s, 1H), 7.55 (m, 4H), 7.38 (m, 6H), 6.37 (s, 1H), 5.98 (s, 2H), 3.86 (t, 2H), 2.86 (t, 2H), 0.95 (s, 9H).
    • Step 5. N-{7-Acetyl-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl}-acetamide
  • A solution of 2-amino-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (22.7 g, 52 mmol) in Ac2O (200 mL) was heated to 110° C. for 2.5 h, concentrated, diluted with toluene (300 mL) and concentrated again to afford the title compound to afford the title compound as a crude brown oil (27 g) which was used without further purification. An aliquot was purified by chromatography for characterization. HPLC Rt: 8.349 min. 1H-NMR (CDCl3): δ 11.77 (s, 1H), 8.81 (s, 1H), 7.61 (dd, 4H), 7.30 (m, 7H), 6.37 (s, 1H), 4.00 (t, 2H), 3.02 (t, 2H), 2.70 (s, 3H), 2.23 (s, 3H), 1.04 (s, 9H).
    • Step 6. N-{7-Acetyl-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-acetamide
  • A solution of crude N-{7-acetyl-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl}-acetamide (26.4 g, 51 mmol), BnNEt3Cl (23.2 g, 102 mmol), PhNMe2 (19.6 mL, 153 mmol) and POCl3 (9.3 mL, 77 mmol) in CH3CN (100 mL) was heated to 80° C. for 1.5 h. The mixture was diluted with EtOAc (800 mL), washed (sat. NaHCO3, brine) and concentrated to afford the title compound as an oil (46 g) which was used without further purification. An aliquot was purified by chromatography for characterization. HPLC Rt: 8.562 min. 1H-NMR (CDCl3): δ 8.05 (s, 1H), 7.68 (s, 1H), 7.57 (dd, 4H), 7.40 (m, 6H), 3.99 (t, 2H), 3.06 (t, 2H), 2.98 (s, 3H), 2.52 (s, 3H), 1.04 (s, 9H).
    • Step 7. N-{5-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-acetamide
  • A solution of crude N-{7-acetyl-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-acetamide (46 g) in MeOH (150 mL) was treated with K2CO3 (8.0 g, 58 mmol) at rt for 15 min. Filtration, concentration, and chromatography (EtOAc/hexane 1:1) afforded the title compound as an oil contaminated with residual PhNMe2 from step 6. The oil was diluted with EtOAc (40 mL) and treated with hexane (40 mL) to obtained the desired product as a pale yellow precipitate (4.2 g, 16% over 3 steps). HPLC Rt: 8.558 min. 1H-NMR (CDCl3): δ 11.75 (br. s, 1H), 11.35 (br. s, 1H), 7.60 (dd, 4H), 7.37 (m, 6H), 3.97 (t, 2H), 3.10 (t, 2H), 2.57 (s, 3H), 1.06 (s, 9H).
    • Step 8. N-[5-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-acetamide
  • A mixture of N-{5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-acetamide (344 mg, 0.70 mmol), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine hydrochloride (175 mg, 0.77 mmol), K2CO3 (516 mg, 3.7 mmol) and DMF (3.0 mL) was stirred at rt overnight. Work-up (EtOAc/water; brine) afforded the title compound as an off-white solid which was used without further purification (516 mg, “115%”). HPLC Rt: 8.419 min. 1H-NMR (CDCl3): δ 8.20 (s, 1H), 7.95 (s, 1H), 7.55 (dd, 4H), 7.32 (m, 6H), 7.04 (s, 1H), 5.37 (s, 2H), 3.91 (t, 2H), 3.73 (s, 3H), 3.06 (t, 2H), 2.57 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H), 0.97 (s, 9H).
    • Step 9. 5-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • A solution of N-[5-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-acetamide (511 mg) in THF (3 mL) and MeOH (3 mL) was treated with NaOH 2M (3 mL) at 45° C. for 1.5 h. Work-up and chromatography (EtOAc/hexane 1:1) afforded the title compound as a white powder (290 mg, 69% over 2 steps). HPLC Rt: 8.198 min. 1H-NMR (CDCl3): δ 8.20 (s, 1H), 7.57 (dd, 4H), 7.40 (m, 2H), 7.32 (m, 4H), 6.69 (s, 1H), 5.26 (s, 2H), 4.90 (s, 2H), 3.98 (t, 2H), 3.66 (s, 3H), 3.00 (t, 2H), 2.24 (s, 3H), 2.18 (s, 3H), 0.96 (s, 9H).
    • Step 10. 2-[2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-ethanol
  • A solution of 5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (246 mg, 0.41 mmol) in THF (5 mL) was treated with TBAF (1N in THF, 0.5 mL, 0.50 mmol) at rt for 1 h. Work-up (EtOAc/water, brine) gave the crude product as an oil, which was diluted with diethyl ether (15 mL) whereupon the desired product precipitated out of solution as a white powder (110 mg, 74%). HPLC Rt: 4.474 min. 1H-NMR (CDCl3): δ 8.21 (s, 1H), 6.78 (s, 1H), 5.30 (s, 2H), 4.93 (s, 2H), 3.87 (t, 2H), 3.76 (s, 3H), 3.03 (t, 2H), 2.26 (s, 3H), 2.23 (s, 3H).
    • Step 11. Methanesulfonic acid 2-[2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-ethyl ester
  • A solution of 2-[2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-ethanol (11.6 mg, 0.031 mmol) and Et3N (30 ul, 0.22 mmol) in THF (2 mL) was treated with MsCl (11 uL, 0.14 mmol) at rt for 15 min to give a solution of the title compound which was used without further purification. In a separate experiment, the material was purified by preparative TLC (EtOAc 100%). HPLC Rt: 4.765 min. 1H-NMR (CDCl3): δ 8.22 (s, 1H), 6.80 (s, 1H), 5.31 (s, 2H), 4.93 (s, 2H), 4.42 (t, 2H), 3.77 (s, 3H), 2.98 (t, 2H), 2.85 (s, 3H), 2.23 (s, 3H), 2.07 (s, 3H).
    • Step 12. 4-Chloro-5-(2-isobutylamino-ethyl)-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
  • The solution of methanesulfonic acid 2-[2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-ethyl ester in THF obtained from step 11 was diluted with i-BuNH2 (4 mL) and heated to 50° C. for 15 h. Concentration, work-up (EtOAc/NaHCO3 sat.; brine) and preparative TLC (MeOH:Et3N:CCH2Cl2 7:3:100) gave the title compound as a colorless oil (6 mg, 50%). HPLC Rt: 4.263 min. 1H-NMR (CDCl3): δ 8.20 (s, 1H), 6.79 (s, 1H), 5.29 (s, 2H), 4.97 (s, 2H), 3.76 (s, 3H), 3.04 (t, 2H), 2.96 (t, 2H), 2.53 (d, 2H), 2.26 (s, 3H), 2.22 (s, 3H), 1.85 (oct., 1H), 0.90 (d, 6H).
    • Example 47 2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one
  • Figure US20070173483A1-20070726-C00093
  • The title compound was obtained by condensation between (2-amino-4,6-dichloro-pyrimidin-5-yl)-acetic acid ethyl ester and (4-methoxy-3,5-dimethyl-pyridin-2-yl)-methylamine according to the general procedure 1.2. HPLC Rt: 4.893 min. 1H-NMR (CDCl3): δ 8.07 (s, 1H), 5.03 (s, 2H), 4.92 (s, 2H), 3.77 (s, 3H), 3.57 (s, 2H), 2.31 (s, 3H), 2.20 (s, 3H).
    • Example 48 2-Amino-4-chloro-7-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one
  • Figure US20070173483A1-20070726-C00094
  • The title compound was obtained by alkylation of 4-chloro-pyrrolo[2,3-d]pyrimidin-6-one with 2-chloromethyl-4-chloro-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 5.367 min. 1H-NMR (CDCl3): δ 8.09 (s, 1H), 5.02 (s, 2H), 4.96 (s, 2H), 3.57 (s, 2H), 2.45 (s, 3H), 2.29 (s, 3H).
    • Example 49 2-Amino-4-chloro-7-(3,5-dimethyl-4-methoxy-.-oxy-pyridin-2-ylmethyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one
  • Figure US20070173483A1-20070726-C00095
  • The title compound was obtained by oxidation of 2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one with m-CPBA according to the general procedure 2.1. HPLC Rt: 4.763 min. 1H-NMR (DMSO-d6): δ 8.01 (s, 1H), 7.01 (s, 2H), 4.93 (s, 2H), 3.73 (s, 3H), 3.46 (s, 2H), 2.40 (s, 3H), 2.19 (s, 3H).
    • Example 50 2-Amino-4-chloro-7-(4-chloro-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one
  • Figure US20070173483A1-20070726-C00096
  • The title compound was obtained by oxidation of 2-amino-4-chloro-7-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one with m-CPBA according to the general procedure 2.1. HPLC Rt: 4.90 min. 1H-NMR (CDCl3/CD3OD): δ 7.96 (s, 1H), 5.12 (s, 2H), 3.38 (s, 2H), 2.47 (s, 3H), 2.27 (s, 3H).
    • Example 51 2-Amino-4-chloro-7-(3,4,5-trimethoxy-benzyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one
  • Figure US20070173483A1-20070726-C00097
  • The title compound was obtained by condensation between (2-Amino-4,6-dichloro-pyrimidin-5-yl)-acetic acid ethyl ester and 3,4,5-Trimethoxy-benzylamine according to the general procedure 1.2. HPLC Rt: 6.391 min. 1H-NMR (CDCl3): δ 6.70 (s, 2H), 5.14 (s, 2H), 4.77 (s, 2H), 3.84 (s, 6H), 3.81 (s, 3H), 3.47 (s, 2H).
    • Example 52 2-Amino-4-chloro-7-(2-bromo-3,4,5-trimethoxy-benzyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one
  • Figure US20070173483A1-20070726-C00098
  • The title compound was obtained by treating 2-amino-4-chloro-7-(3,4,5-trimethoxy-benzyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one with bromine in acetic acid according to the general procedure 3.1. HPLC Rt: 7.150 min. 1H-NMR (CDCl3): δ 6.49 (s, 1H), 5.14 (s, 2H), 4.94 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 3.75 (s, 3H), 3.55 (s, 2H).
    • Example 53 2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5-methyl-5,7-dihydro-pyrrolo[2,3-d] pyrimidin-6-one
  • Figure US20070173483A1-20070726-C00099
  • The title compound was obtained by alkylation of 2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one with iodomethane according to the general procedure 1.5. HPLC Rt: 4.091 min. 1H-NMR (CDCl3): δ 8.01 (s, 1H), 5.15 (s, 2H), 4.93 (d, 1H), 4.87 (d, 1H), 3.76 (s, 3H), 3.51 (s, 1H), 2.29 (s, 3H), 2.20 (s, 3H), 1.78 (s, 3H).
    • Example 54 2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5,5-dimethyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one
  • Figure US20070173483A1-20070726-C00100
  • The title compound was obtained by alkylation of 2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one with iodomethane according to the general procedure 1.5. HPLC Rt: 5.002 min. 1H-NMR (CDCl3): δ 8.02 (s, 1H), 5.02 (s, 2H), 4.90 (s, 2H), 3.75 (s, 3H), 2.29 (s, 3H), 2.18 (s, 3H), 1.53 (s, 6H).
    • Example 55 2-Amino-4-chloro-7-(2-bromo-3,4,5-trimethoxy-benzy1)-5,5-dimethyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one
  • Figure US20070173483A1-20070726-C00101
  • The title compound was obtained by alkylation of 2-amino-4-chloro-7-(3,4,5-trimethoxy-benzyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one with iodomethane according to the general procedure 1.5. HPLC Rt: 6.944 min. 1H-NMR (CDCl3): δ 6.34 (s, 1H), 5.09 (s, 2H), 4.93 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 3.71 (s, 3H), 1.52 (s, 6H).
    • Example 56 4-Chloro-5-hydroxy-2-imino-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-2,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one
  • Figure US20070173483A1-20070726-C00102
  • The title compound was obtained by oxidation of 2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one with selenium dioxide according to the general procedure 1.6. HPLC Rt: 4.294 min. 1H-NMR (CDCl3): δ 8.04 (s, 1H), 5.93 (s, 1H), 5.76 (s, 1H), 4.97 (s, 2H), 3.765 (s, 3H), 2.29 (s, 3H), 2.20 (s, 3H).
    • Example 57 4-Chloro-5-hydroxy-2-imino-7-(3,4,5-trimethoxy-benzyl)-2,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one
  • Figure US20070173483A1-20070726-C00103
  • The title compound was obtained by oxidation of 2-amino-4-chloro-7-(3,4,5-trimethoxy-benzyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one with selenium dioxide according to the general procedure 1.6. HPLC Rt: 6.156 min. 1H-NMR (CDCl3): δ 6.68 (s, 2H), 6.12 (s, 1H), 5.93 (s, 1H), 4.84 (s, 2H), 3.86 (s, 6H), 3.83 (s, 3H).
    • Example 58 4-Chloro-5-hydroxy-2-imino-7-(2-bromo-3,4,5-trimethoxy-benzyl)-2,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one
  • Figure US20070173483A1-20070726-C00104
  • The title compound was obtained by oxidation of 4-chloro-5-hydroxy-2-imino-7-(2-bromo-3,4,5-trimethoxy-benzyl)-2,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one according to the general procedure 1.6. HPLC Rt: 6.230 min. 1H-NMR (CDCl3): δ 6.57 (s, 1H), 6.14 (s, 1H), 5.91 (s, 1H), 5.01 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.78 (s, 3H).
    • BIOLOGY EXAMPLES Example A rHSP90 Competitive Binding Assay
  • Five microgram of purified rHSP90 protein (Stressgen, BC, Canada, #SPP-770) in phosphate buffered saline (PBS) was coated on 96 well plates by incubating overnight at 4° C. Unbound protein was removed and the coated wells were washed twice with 200 μL PBS. DMSO controls (considered as untreated samples) or test compounds were then added at 100-30-10-3-1-0.3 μM dilutions (in PBS), the plates mixed for 30 seconds on the plate shaker, and then incubated for 60 min. at 37° C. The wells were washed twice with 200 μL PBS, and 10 μM biotinylated-geldanamycin (biotin-GM) was added and incubated for 60 min. at 37° C. The wells were washed again twice with 200 μL PBS, before the addition of 20 μg/mL streptavidin-phycoerythrin (streptavidin-PE) (Molecular Probes, Eugene, Oreg.) and incubation for 60 min. at 37° C. The wells were washed again twice with 200 μL PBS. Relative fluorescence units (RFU) was measured using a SpectraMax Gemini XS Spectrofluorometer (Molecular Devices, Sunnyvale, Calif.) with an excitation at 485 nm and emission at 580 nm; data was acquired using SOFTmax®PRO software (Molecular Devices Corporation, Sunnyvale, Calif.). The background was defined as the RFU generated from wells that were not coated with HSP90 but were treated with the biotin-GM and streptavidin-PE. The background measurements were subtracted from each sample treated with biotin-GM and streptavidin-PE measurements before other computation. Percent inhibition of binding for each sample was calculated from the background subtracted values as follows:
    % binding inhibition=[(RFU untreated−RFU treated)/RFU untreated]×100.
    • Example B Cell Lysate Binding Assay
  • MCF7 breast carcinoma cell lysates were prepared by douncing in lysing buffer (20 mM HEPES, pH 7.3, 1 mM EDTA, 5 mM MgCl2, 100 mM KCl), and then incubated with or without test compound for 30 mins at 4° C., followed by incubation with biotin-GM linked to BioMag™ streptavidin magnetic beads (Qiagen) for 1 hr at 4° C. The tubes were placed on a magnetic rack, and the unbound supernatant removed. The magnetic beads were washed three times in lysis buffer and boiled for 5 mins at 95° C. in SDS-PAGE sample buffer. Samples were analyzed on SDS protein gels, and Western blots were done for rHSP90. Bands in the Western Blots were quantitated using the Bio-rad Fluor-S MultiImager, and the % inhibition of binding of rHSP90 to the biotin-GM was calculated.
  • The lysate binding ability of selected compounds of the invention based on the above assay is summarized in Table 2. The IC50 reported is the concentration of test compound needed to achieve 50% inhibition of the biotin-GM binding to rHSP90 in the MCF7 cell lysates.
    • Example C HER2 Degradation Assay
  • MCF7 breast carcinoma cells (ATCC) were grown in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS) and 10 mM HEPES, and plated in 24 well plates (50% confluent). Twenty-four hrs later (cells are 65-70% confluent), test compounds were added and incubated overnight for 16 h. For the less potent compounds, the amounts added were 100 μM, 30 μM, 10 μM and 1 μM, and for more potent compounds, the amounts added were 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM and 0.003 μM. The wells were washed with 1 mL phosphate buffered saline (PBS), and 200 μL trypsin was added to each well. After trypsinization was complete, 50 μL of FBS was added to each well. Then 200 μL cells was transferred to 96 well plates. The cells were pipetted up and down to obtain a single cell suspension. The plates were centrifuiged at 2,500 rpm for 1 min using a Sorvall Legend RT™ tabletop centrifuge (Kendro Laboratory Products, Asheville, N.C.). The cells were then washed once in PBS containing 0.2% BSA and 0.2% sodium azide (BA buffer). Phycoerythrin (PE) conjugated anti HER2/Neu antibody (Becton Dickinson, #340552), or PE conjugated anti-keyhole limpet hemocyanin [KLH] (Becton Dickinson, #340761) control antibody was added at a dilution of 1:20 and 1:40 respectively (final concentration was 1 μg/mL) and the cells were pipeted up and down to form a single cell suspension, and incubated for 15 mins. The cells were washed twice with 200 μL BA buffer, and resuspended in 200 μL BA buffer, and transferred to FACSCAN tubes with an additional 250 μL BA buffer. Samples were analyzed using a FACSCalibur™ flow cytometer (Becton Dickinson, San Jose, Calif.) equipped with Argon-ion laser that emits 15 mW of 488 nm light for excitation of the PE fluorochrome. 10,000 events were collected per sample. A fluorescence histogram was generated and the mean fluorescence intensity (MFI) of each sample was determined using Cellquest software. The background was defined as the MFI generated from cells incubated with control IgG-PE, and was subtracted from each sample stained with the HER2/Neu antibody. Cells incubated with DMSO were used as untreated controls since the compounds were resuspended in DMSO. Percent degradation of HER2 was calculated as follows:
    % HER2 degraded=[(MF1 untreated cells−MF1 treated cells)/MF1 untreated cell]×100
  • The HER2 degradation ability of selected compounds of the invention based on this assay is summarized in Table 2. IC50 is defined as the concentration at which there was 50% degradation of the HER2/Neu protein.
    • Example D MTS Assay
  • MTS assays measure the cytotoxicity of geldanamycin derivatives. MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) is a tetrazolium dye that is converted to a formazan product by dehydrogenase enzymes of metabolically active cells (Corey, A. et al. “Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture,” Cancer Commun. 1991, 3, 207-212). Cells were seeded in 96 well plates at 2000 cells/well and allowed to adhere overnight in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum. The final culture volume was 100 μl. Viable cell number was determined by using the Celltiter 96 AQueous Non-radioactive Cell Proliferation Assay (Promega, Madison Wis.). The MTS/PMS (phenazine methosulfate) solution was mixed at a ratio of 20:1, and 20 μL was added per well to 100 μl of culture medium. After 2-4 hours, the formation of the formazan product was measured at 490 nm absorbance using a multiwell plate spectrophotometer. Background was determined by measuring the Abs 490 nm of cell culture medium and MTS-PMS in the absence of cells and was subtracted from all values. Percent viable cells was calculated as follows:
    % viable cells=(Abs at 490 nm treated cells/Abs at 490 nm untreated cells)×100
  • The effect of selected compounds of the invention on MCF7 breast carcinoma cells according to the MTS assay is summarized in Table 2. IC50 was defined as the concentration of the compound which gave rise to 50% reduction in viable cell number.
    TABLE 2
    Biological Activities of Selected Compounds of the Invention
    Lysate HER2 MIS
    binding IC50 IC50
    S. No. Ex # Structure (μM) (μM) (μM)
    1 8
    Figure US20070173483A1-20070726-C00105
         		ND 0.023 0.1
    2 10
    Figure US20070173483A1-20070726-C00106
         		ND 0.25 0.6
    3 11
    Figure US20070173483A1-20070726-C00107
         		0.09 0.08 0.2
    4 5
    Figure US20070173483A1-20070726-C00108
         		0.15 0.095 0.3
    5 13
    Figure US20070173483A1-20070726-C00109
         		0.09 0.05 1.0
    6 14
    Figure US20070173483A1-20070726-C00110
         		0.05 0.038 1.0
    7 15
    Figure US20070173483A1-20070726-C00111
         		0.03 0.015 0.023
    8 20
    Figure US20070173483A1-20070726-C00112
         		ND 0.042 1.0
    9 21
    Figure US20070173483A1-20070726-C00113
         		ND 0.17 >10.0
    10 22
    Figure US20070173483A1-20070726-C00114
         		ND 0.065 1.0
    11 23
    Figure US20070173483A1-20070726-C00115
         		ND 0.13 >10.0
    12 24
    Figure US20070173483A1-20070726-C00116
         		ND 0.025 0.3
    13 25
    Figure US20070173483A1-20070726-C00117
         		ND 0.15 >10.0
    14 46
    Figure US20070173483A1-20070726-C00118
         		ND 0.07 ND
    16 45
    Figure US20070173483A1-20070726-C00119
         		ND 0.02 ND
    17 43
    Figure US20070173483A1-20070726-C00120
         		ND 0.13 ND
    18 47
    Figure US20070173483A1-20070726-C00121
         		ND 0.45 ND
    19 48
    Figure US20070173483A1-20070726-C00122
         		ND 1.5 ND
    20 52
    Figure US20070173483A1-20070726-C00123
         		ND 0.4 10.0
    21 49
    Figure US20070173483A1-20070726-C00124
         		ND 0.18 0.9

    ND not determined.
  • The foregoing examples are not limiting and are merely illustrative of various aspects and embodiments of the present invention. All documents cited herein are indicative of the levels of skill in the art to which the invention pertains and are incorporated by reference herein in their entireties. None, however, is admitted to be prior art.
  • One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The methods and compositions described illustrate preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Certain modifications and other uses will occur to those skilled in the art, and are encompassed within the spirit of the invention, as defined by the scope of the 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. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described, or portions thereof. 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, optional features, modifications and variations 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 description and the appended claims.
  • In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, e.g., genuses, 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 subgenus, and exclusions of individual members as appropriate, e.g., by proviso.
  • Other embodiments are within the following claims.

Claims (17)

1-48. (canceled)
49. A method of treating an individual having an HSP90 mediated disorder comprising administering to said individual a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula I:
Figure US20070173483A1-20070726-C00125
or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R0 is selected from hydrogen, halogen, lower alkyl, —SR8, —OR8, —CN, and —NHR8,
R1 is halogen, —OR11, —SR11 or lower alkyl;
R2 is —NHR8;
R3is selected from the group consisting of hydrogen, halogen, —SR8, —OR8, —CN, —C(O)R9, —C(O)OH, —NO2, —NR8R10, lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic and heterocyclic, all optionally substituted, wherein:
the aryl, heteroaryl, alicyclic and heterocyclic groups are optionally mono-, bi- or tri-cyclic,
R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N, and
the optional substituents on R3 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR8, —OR8, —CN, —C(O)OH, —C(O)R9, —NO2, —NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R0 or R3 is —OH or —SH, the compound may exist as the corresponding (thio)keto tautomer or a mixture of keto-enol tautomers;
R4 is —CHR12—, —C(O)—, —C(S)—, —S(O)— or —SO2—;
R5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
the alicyclic group is substituted with 3 to 5 substituents,
the heterocyclic group is substituted with 3 to 5 substituents, and
the substituents are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR8, —OR8, —CN, —C(O)OH, —C(O)R, —NO2, —NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R8 is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R9;
R9 is H, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, —NR10R10, or —OR11, wherein R10 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R10 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
R11 is lower alkyl, lower alkenyl, or lower alkynyl, lower heteroaryl or lower aryl; and
R12 is hydrogen or lower alkyl.
50. The method of claim 49, wherein:
R0 is hydrogen, halogen, —SH, —OH, or —CN,
R1 is halogen; and
R2 is —NHR8, where R8 is hydrogen or —C(O)R9.
51. The method of claim 49, wherein:
R1 is chloro or bromo,
R2 is —NHR8, where R8 is hydrogen or —C(O)R9,
R3 is hydrogen, halogen, —OR8, —SR8, —NR8R10, lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower aryl, or lower heteroaryl.
52. The method of claim 49, wherein:
R0 is hydrogen, halogen or —CN,
R2 is —NHR8, where R8 is hydrogen or —C(O)R9; and
R4 is —CH2—.
53. The method of claim 49, wherein:
R0 is hydrogen, halogen, —SH, —OH or —CN;
R1 is halogen;
R2 is —NH2;
R3 is hydrogen, halogen, —OR8, —SR8, —NR8R8, lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower aryl, or lower heteroaryl, wherein R8 is hydrogen, lower alkyl, lower aryl, or —C(O)R9;
R4 is —CH2—; and
R5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents.
54. The method of claim 53, wherein:
R1 is chloro or bromo;
R2 is —NH2; and
R5 is a phenyl having at least three substituents, a pyridyl having at least two substituents, or 1-oxy-pyridyl (N-oxy-pyridyl) having at least two substituents.
55. The method of claim 49, wherein the HSP90 mediated disorder is selected from the group consisting of inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorders, neurological disorders, fibrogenetic disorders, proliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases, and malignant diseases.
56. The method of claim 55, wherein the fibrogenetic disorder is further selected from the group consisting of scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis.
57. The method of claim 49, further comprising administering at least one therapeutic agent selected from the group consisting of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents.
58. The method of claim 57, wherein the at least one anti-neoplastic agent is selected from the group consisting of alkylating agents, anti-metabolites, epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.
59-68. (canceled)
69. A method of treating an individual having an HSP90 mediated disorder comprising administering to said individual a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula II:
Figure US20070173483A1-20070726-C00126
wherein:
R0 is hydrogen, halogen, lower alkyl, —SR8, —OR8, —CN or —NHR8;
R1 is halogen, —OR11, —SR11 or lower alkyl;
R2 is —NH2;
R4 is —CHR12—, —C(O)—, —C(S)—, —S(O)— or —SO2—;
R5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein:
the aryl group is substituted with 3 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
the alicyclic group is substituted with 3 to 5 substituents,
the heterocyclic group is substituted with 3 to 5 substituents, and
the substituents on R5 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR8, —OR8, —CN, —C(O)OH, —C(O)R9, —NO2 and —NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R9;
R9 is H, lower alkyl, lower aryl, lower heteroaryl, —NR10R10, or —OR11, wherein R10 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl,
R11 is lower alkyl, lower alkenyl, lower alkynyl, lower heteroaryl or lower aryl;
R12 is hydrogen or lower alkyl; and
R0 and R10 taken together optionally form an exocyclic double bond which is optionally substituted, or optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N.
70-75. (canceled)
76. A method of treating an individual having an HSP90 mediated disorder comprising administering to said individual a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula III:
Figure US20070173483A1-20070726-C00127
or a polymorph, solvate, ester, tantomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is halogen, —OR11, —SR11 or lower alkyl;
R2 is —NH2;
R3 is selected from the group consisting of hydrogen, halogen, —SR8, —OR8, —CN, —C(O)R9, —C(O)OH, —NO2, —NR8R10, lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic, heterocyclic, all optionally substituted, wherein:
the aryl, heteroaryl, alicyclic and heterocyclic groups are optionally mono-, bi-or tri-cyclic;
R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N, and
the optional substituents on R3 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR8, —OR8, —CN, —C(O)OH, —C(O)R9, —NO2, —NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R4 is —CHR12—, —C(O)—, —C(S)—, —S(O)— or —SO2—;
R5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
the alicyclic group is substituted with 3 to 5 substituents,
the heterocyclic group is substituted with 3 to 5 substituents, and
the substituents on R5 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR8, —OR8, —CN, —C(O)OH, —C(O)R9, —NO2 and —NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, firanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R9;
R9 is H, lower alkyl, lower aryl, lower heteroaryl, —NR10R10, or —OR11, wherein R10 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl,
R11 is lower alkyl, lower alkenyl, lower alkynyl, lower heteroaryl or lower aryl;
R12 is hydrogen or lower alkyl; and
R3 and R10 taken together optionally form an exocyclic double bond which is optionally substituted, or optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N.
77-80. (canceled)
81. A method of treating an individual having an HSP90 mediated disorder comprising administering to said individual a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula IV:
Figure US20070173483A1-20070726-C00128
or a polymorph, solvate, ester, tantomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is halogen, —OR11, —SR11 or lower alkyl;
R2 is —NH2;
R4 is —CHR12—, —C(O)—, —C(S)—, —S(O)— or —SO2—;
R5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
the alicyclic group is substituted with 3 to 5 substituents,
the heterocyclic group is substituted with 3 to 5 substituents, and
the substituents on R5 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR8, —OR8, —CN, —C(O)OH, —C(O)R9, —NO2 and —NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R9;
R9 is H, lower alkyl, lower aryl, lower heteroaryl, —NR10R10, or —OR11, wherein R10 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl;
R11 is lower alkyl, lower alkenyl, lower alkynyl, lower heteroaryl or lower aryl; and
R12 is hydrogen or lower alkyl.
US11/531,218 2002-10-30 2006-09-12 Pyrrolopyrimidines and Related Analogs as HSP90-Inhibitors Abandoned US20070173483A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/531,218 US20070173483A1 (en) 2002-10-30 2006-09-12 Pyrrolopyrimidines and Related Analogs as HSP90-Inhibitors

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
PCT/US2002/035069 WO2003037860A2 (en) 2001-10-30 2002-10-30 Purine analogs having hsp90-inhibiting activity
USPCT/US02/35069 2002-10-30
US50413503P 2003-09-18 2003-09-18
US59146704P 2004-07-26 2004-07-26
US10/945,851 US7138402B2 (en) 2003-09-18 2004-09-20 Pyrrolopyrimidines and related analogs as HSP90-inhibitors
US11/531,218 US20070173483A1 (en) 2002-10-30 2006-09-12 Pyrrolopyrimidines and Related Analogs as HSP90-Inhibitors

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/945,851 Continuation US7138402B2 (en) 2002-10-30 2004-09-20 Pyrrolopyrimidines and related analogs as HSP90-inhibitors

Publications (1)

Publication Number Publication Date
US20070173483A1 true US20070173483A1 (en) 2007-07-26

Family

ID=34381103

Family Applications (8)

Application Number Title Priority Date Filing Date
US10/946,645 Active 2024-10-13 US7138401B2 (en) 2003-09-18 2004-09-20 2-aminopurine analogs having HSP90-inhibiting activity
US10/946,628 Active US7129244B2 (en) 2003-09-18 2004-09-20 Triazolopyrimidines and related analogs as HSP90-inhibitors
US10/946,637 Active US7148228B2 (en) 2003-09-18 2004-09-20 Pyrazolopyrimidines and related analogs as HSP90-inhibitors
US10/945,851 Active 2024-11-17 US7138402B2 (en) 2002-10-30 2004-09-20 Pyrrolopyrimidines and related analogs as HSP90-inhibitors
US11/531,221 Abandoned US20070185064A1 (en) 2003-09-18 2006-09-12 2-Aminopurine Analogs Having HSP90-Inhibiting Activity
US11/531,218 Abandoned US20070173483A1 (en) 2002-10-30 2006-09-12 Pyrrolopyrimidines and Related Analogs as HSP90-Inhibitors
US11/537,002 Abandoned US20070111996A1 (en) 2003-09-18 2006-09-29 Pyrazolopyrimidines and related analogs as HSP90-inhibitors
US11/537,017 Abandoned US20070111997A1 (en) 2003-09-18 2006-09-29 Triazolopyrimidines and related analogs as HSP90-inhibitors

Family Applications Before (5)

Application Number Title Priority Date Filing Date
US10/946,645 Active 2024-10-13 US7138401B2 (en) 2003-09-18 2004-09-20 2-aminopurine analogs having HSP90-inhibiting activity
US10/946,628 Active US7129244B2 (en) 2003-09-18 2004-09-20 Triazolopyrimidines and related analogs as HSP90-inhibitors
US10/946,637 Active US7148228B2 (en) 2003-09-18 2004-09-20 Pyrazolopyrimidines and related analogs as HSP90-inhibitors
US10/945,851 Active 2024-11-17 US7138402B2 (en) 2002-10-30 2004-09-20 Pyrrolopyrimidines and related analogs as HSP90-inhibitors
US11/531,221 Abandoned US20070185064A1 (en) 2003-09-18 2006-09-12 2-Aminopurine Analogs Having HSP90-Inhibiting Activity

Family Applications After (2)

Application Number Title Priority Date Filing Date
US11/537,002 Abandoned US20070111996A1 (en) 2003-09-18 2006-09-29 Pyrazolopyrimidines and related analogs as HSP90-inhibitors
US11/537,017 Abandoned US20070111997A1 (en) 2003-09-18 2006-09-29 Triazolopyrimidines and related analogs as HSP90-inhibitors

Country Status (14)

Country Link
US (8) US7138401B2 (en)
EP (2) EP2145888A1 (en)
JP (1) JP2007505933A (en)
KR (1) KR20060070572A (en)
CN (1) CN101906106A (en)
AU (2) AU2004274507B2 (en)
BR (1) BRPI0414533A (en)
CA (1) CA2539548A1 (en)
EA (1) EA010160B1 (en)
IL (1) IL174375A0 (en)
MX (1) MXPA06002997A (en)
NO (1) NO20061396L (en)
NZ (1) NZ546611A (en)
WO (1) WO2005028434A2 (en)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060223797A1 (en) * 2005-03-30 2006-10-05 Conforma Therapeutics Corporation Alkynyl pyrrolopyrimidines and related analogs as hsp90-inhibitors
US20090202626A1 (en) * 2008-02-07 2009-08-13 Carson Dennis A Treatment of bladder diseases with a tlr7 activator
WO2009139834A1 (en) * 2008-05-13 2009-11-19 Poniard Pharmaceuticals, Inc. Bioactive compounds for treatment of cancer and neurodegenerative diseases
US20090324551A1 (en) * 2005-08-22 2009-12-31 The Regents Of The University Of California Office Of Technology Transfer Tlr agonists
US20100210598A1 (en) * 2009-02-11 2010-08-19 Regents Of The University Of California, San Diego Toll-like receptor modulators and treatment of diseases
WO2010117425A1 (en) * 2009-03-31 2010-10-14 Biogen Idec Ma Inc. Certain substituted pyrimidines, pharmaceutical compositions thereof, and methods for their use
US20110098294A1 (en) * 2006-05-31 2011-04-28 Carson Dennis A Purine analogs
US8357374B2 (en) 2007-02-07 2013-01-22 The Regents Of The University Of California Conjugates of synthetic TLR agonists and uses therefor
US9050319B2 (en) 2010-04-30 2015-06-09 Telormedix, Sa Phospholipid drug analogs
US9066940B2 (en) 2009-02-06 2015-06-30 Telormedix, Sa Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration
US9173936B2 (en) 2010-04-30 2015-11-03 Telormedix Sa Phospholipid drug analogs
US11697851B2 (en) 2016-05-24 2023-07-11 The Regents Of The University Of California Early ovarian cancer detection diagnostic test based on mRNA isoforms

Families Citing this family (168)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6992188B1 (en) * 1995-12-08 2006-01-31 Pfizer, Inc. Substituted heterocyclic derivatives
CN1501928A (en) * 2000-11-02 2004-06-02 斯隆-凯特林癌症研究所 Small molecule compositions for binding to hsp90
US20030114467A1 (en) * 2001-06-21 2003-06-19 Shakespeare William C. Novel pyrazolo- and pyrrolo-pyrimidines and uses thereof
US20070129334A1 (en) * 2001-10-30 2007-06-07 Conforma Therapeutics Corporation Orally Active Purine-Based Inhibitors of Heat Shock Protein 90
EP1440072A4 (en) * 2001-10-30 2005-02-02 Conforma Therapeutic Corp Purine analogs having hsp90-inhibiting activity
BRPI0414533A (en) * 2003-09-18 2006-11-07 Conforma Therapeutics Corp compound, pharmaceutical composition, and methods for inhibiting an hsp90 and treating an individual having an hsp90 mediated disorder
US20080280878A1 (en) * 2004-11-02 2008-11-13 Castro Januario E Methods and Compositions for Treating Chronic Lymphocytic Leukemia
WO2006050333A2 (en) * 2004-11-02 2006-05-11 The Regents Of The University Of California Methods and compositions for modulating apoptosis
US9120774B2 (en) 2004-11-03 2015-09-01 University Of Kansas Novobiocin analogues having modified sugar moieties
US8212012B2 (en) * 2004-11-03 2012-07-03 University Of Kansas Novobiocin analogues having modified sugar moieties
MX2007012659A (en) * 2005-04-13 2008-01-11 Astex Therapeutics Ltd Hydroxybenzamide derivatives and their use as inhibitors of hsp90.
WO2006113498A2 (en) * 2005-04-14 2006-10-26 Novartis Vaccines And Diagnostics Inc. 2-amino-quinaz0lin-5-ones as hsp90 inhibitors useful in treating proliferation diseases
WO2006124897A2 (en) * 2005-05-13 2006-11-23 Lexicon Genetics Incorporated Methods and compositions for improving cognition
CA2615946A1 (en) * 2005-07-22 2007-02-01 Sunesis Pharmaceuticals, Inc. Pyrazolo pyrimidines useful as aurora kinase inhibitors
EP1926734A1 (en) 2005-08-22 2008-06-04 Amgen Inc. Pyrazolopyridine and pyrazolopyrimidine compounds useful as kinase enzymes modulators
JP2009506036A (en) * 2005-08-24 2009-02-12 レキシコン・ファーマシューティカルズ・インコーポレーテッド Pyrrolopyridine, pyrrolopyrimidine and pyrazolopyridine compounds, compositions containing them, and methods of their use
US20070105874A1 (en) * 2005-09-23 2007-05-10 Conforma Therapeutics Corporation Anti-Tumor Methods Using Multi Drug Resistance Independent Synthetic HSP90 Inhibitors
US20080269131A1 (en) * 2005-11-10 2008-10-30 Smithkline Beecham Corporation Inhibitors of Akt Activity
EP1948185A4 (en) * 2005-11-10 2010-04-21 Glaxosmithkline Llc Inhibitors of akt activity
JP2009521446A (en) * 2005-12-22 2009-06-04 コンフォーマ・セラピューティクス・コーポレイション Orally active purine-based inhibitors of heat shock protein 90
US20070253896A1 (en) * 2006-02-07 2007-11-01 Conforma Therapeutics Corporation 7,9-Dihydro-Purin-8-One and Related Analogs as HSP90-Inhibitors
US8658633B2 (en) * 2006-02-16 2014-02-25 Massachusetts Eye And Ear Infirmary Methods and compositions for treating conditions of the eye
AU2007249194B2 (en) 2006-05-12 2012-11-22 Myrexis, Inc. Therapeutic compounds and their use in cancer
EP3305297A1 (en) * 2006-06-30 2018-04-11 Sloan-Kettering Institute for Cancer Research Treatment of neurodegenerative diseases through inhibition of hsp90
US20080009508A1 (en) * 2006-07-10 2008-01-10 Lucie Szucova 6,9-Disubstituted Purine Derivatives And Their Use For Treating Skin
ATE414281T1 (en) * 2006-08-03 2008-11-15 Cellzome Ag METHOD FOR IDENTIFYING MOLECULES THAT INTERACT WITH PI3K AND METHOD FOR PURIFYING PI3K
CA2663965C (en) 2006-09-19 2012-06-12 Daiichi Sankyo Company, Limited Pyrazolopyrimidine derivative and use thereof as an anticancer agent
WO2008045529A1 (en) * 2006-10-12 2008-04-17 Serenex, Inc. Purine and pyrimidine derivatives for treatment of cancer and inflammatory diseases
CL2007002994A1 (en) * 2006-10-19 2008-02-08 Wyeth Corp HETEROCICLIC DERIVATIVE COMPOUNDS CONTAINING SULFAMOIL, INHIBITORS OF HSP90; PHARMACEUTICAL COMPOSITION; AND USE FOR THE TREATMENT OF CANCER, SUCH AS CANCER OF BREAST, COLON AND PROSTATE, BETWEEN OTHERS.
FR2907453B1 (en) 2006-10-24 2008-12-26 Sanofi Aventis Sa NOVEL FLUORENE DERIVATIVES, COMPOSITIONS CONTAINING SAME AND USE THEREOF
GB0622084D0 (en) * 2006-11-06 2006-12-13 Chroma Therapeutics Ltd Inhibitors of HSP90
US20110281821A9 (en) * 2007-01-30 2011-11-17 Biogen Idec Ma Inc. Modulators of Mitotic Kinases
CA2675677A1 (en) * 2007-02-01 2008-08-07 Astrazeneca Ab 5,6,7,8-tetrahydropteridine derivatives as hsp90 inhibitors
MX2009009936A (en) * 2007-03-20 2010-02-11 Curis Inc Fused amino pyridine as hsp90 inhibitors.
BRPI0810178A2 (en) 2007-04-12 2014-09-23 Joyant Pharmaceuticals Inc SMAC MIME DIMERS AND THERMALS USEFUL AS ANTICCAN AGENTS
US8143265B2 (en) * 2007-04-16 2012-03-27 Meharry Medical College Method of treating atherosclerosis
US7960353B2 (en) * 2007-05-10 2011-06-14 University Of Kansas Novobiocin analogues as neuroprotective agents and in the treatment of autoimmune disorders
DE102007028521A1 (en) * 2007-06-21 2008-12-24 Merck Patent Gmbh Indazolamidderivate
US8119616B2 (en) * 2007-09-10 2012-02-21 Curis, Inc. Formulation of quinazoline based EGFR inhibitors containing a zinc binding moiety
CN101854955B (en) * 2007-09-10 2012-07-18 马萨诸塞大学 Mitochondria-targeted anti-tumor agents
WO2009046448A1 (en) 2007-10-04 2009-04-09 Intellikine, Inc. Chemical entities and therapeutic uses thereof
US7960420B2 (en) 2007-12-21 2011-06-14 Joyant Pharmaceuticals, Inc Diazonamide analogs with improved solubility
US8895701B2 (en) 2008-01-05 2014-11-25 Sloan-Kettering Institute For Cancer Research Peptide-conjugated oligonucleotide therapeutic and method of making and using same
US8190543B2 (en) * 2008-03-08 2012-05-29 Tokyo Electron Limited Autonomous biologically based learning tool
WO2009114470A2 (en) * 2008-03-10 2009-09-17 Curis, Inc. Tetrahydroindole and tetrahdyroindazole as hsp90 inhibitors containing a zinc binding moiety
US8993580B2 (en) 2008-03-14 2015-03-31 Intellikine Llc Benzothiazole kinase inhibitors and methods of use
US8637542B2 (en) 2008-03-14 2014-01-28 Intellikine, Inc. Kinase inhibitors and methods of use
CA2720516C (en) 2008-04-29 2013-10-01 Joyant Pharmaceuticals, Inc. Indoline anti-cancer agents
LT5623B (en) 2008-04-30 2010-01-25 Biotechnologijos Institutas, , 5-aryl-4-(5-substituted 2,4-dihydroxyfenil)-1,2,3-thiadiazoles as inhibitors of hsp90 chaperone and the intermediates for production thereof
US8153619B2 (en) 2008-05-22 2012-04-10 Joyant Pharmaceuticals, Inc. Diazonamide analogs
WO2010006086A2 (en) 2008-07-08 2010-01-14 Intellikine, Inc. Kinase inhibitors and methods of use
US20100022635A1 (en) * 2008-07-28 2010-01-28 University Of Kansas Heat shock protein 90 inhibitor dosing methods
GB0819102D0 (en) * 2008-10-17 2008-11-26 Chroma Therapeutics Ltd Pyrrolo-pyrimidine compounds
US8476431B2 (en) 2008-11-03 2013-07-02 Itellikine LLC Benzoxazole kinase inhibitors and methods of use
WO2010065275A1 (en) * 2008-11-25 2010-06-10 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
NZ594414A (en) 2009-01-16 2013-08-30 Curis Inc Fused amino pyridines for the treatment of brain tumors
AU2010218853A1 (en) * 2009-02-25 2011-10-06 Daiichi Sankyo Company, Limited Tricyclic pyrazolopyrimidine derivative
WO2010115749A2 (en) * 2009-03-30 2010-10-14 Nordic Bioscience A/S Fibrosis biomarker assay
AR077280A1 (en) 2009-06-29 2011-08-17 Incyte Corp PYRIMIDINONES AS PI3K INHIBITORS, AND PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND THEM
JP5227456B2 (en) * 2009-07-10 2013-07-03 大鵬薬品工業株式会社 Azabicyclic compound or salt thereof
JP5819831B2 (en) 2009-08-17 2015-11-24 インテリカイン， エルエルシー Heterocyclic compounds and their use
WO2011041593A1 (en) * 2009-09-30 2011-04-07 University Of Kansas Novobiocin analogues and treatment of polycystic kidney disease
WO2011044394A1 (en) 2009-10-07 2011-04-14 Sloan-Kettering Institute For Cancer Research Purine derivatives useful as hsp90 inhibitors
WO2011059763A2 (en) 2009-10-28 2011-05-19 Joyant Pharmaceuticals, Inc. Dimeric smac mimetics
US20110130711A1 (en) * 2009-11-19 2011-06-02 Follica, Inc. Hair growth treatment
WO2011075630A1 (en) * 2009-12-18 2011-06-23 Incyte Corporation Substituted fused aryl and heteroaryl derivatives as pi3k inhibitors
WO2011075643A1 (en) 2009-12-18 2011-06-23 Incyte Corporation Substituted heteroaryl fused derivatives as pi3k inhibitors
AR079545A1 (en) 2009-12-21 2012-02-01 Bayer Cropscience Ag TIENILPIRI (MI) DINILAZOL
EP2558463A1 (en) 2010-04-14 2013-02-20 Incyte Corporation Fused derivatives as i3 inhibitors
EP2571361A4 (en) * 2010-05-19 2013-11-13 Univ North Carolina Pyrazolopyrimidine compounds for the treatment of cancer
US9062055B2 (en) 2010-06-21 2015-06-23 Incyte Corporation Fused pyrrole derivatives as PI3K inhibitors
JPWO2012026433A1 (en) 2010-08-23 2013-10-28 第一三共株式会社 Free crystals of tricyclic pyrazolopyrimidine derivatives
JP5701884B2 (en) 2010-08-23 2015-04-15 第一三共株式会社 Crystals of tricyclic pyrazolopyrimidine derivatives
JP6063870B2 (en) 2010-11-08 2017-01-18 ライセラ・コーポレイション Treatment of N-sulfonylated tetrahydroquinolines and related bicyclic compounds and diseases for inhibition of RORγ activity
WO2012083181A1 (en) * 2010-12-16 2012-06-21 Indiana University Research And Technology Corporation Alpha helix mimetics and methods for using
AR084312A1 (en) 2010-12-16 2013-05-08 Genentech Inc INHIBITING TRICICLIC COMPOUNDS OF THE PI3K AND PHARMACEUTICAL COMPOSITIONS
TW201249844A (en) 2010-12-20 2012-12-16 Incyte Corp N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
WO2012088266A2 (en) 2010-12-22 2012-06-28 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of fgfr3
US8362023B2 (en) 2011-01-19 2013-01-29 Hoffmann-La Roche Inc. Pyrazolo pyrimidines
BR112013020329A2 (en) 2011-02-09 2016-08-02 Hoffmann La Roche heterocyclic compounds as pi3 kinase inhibitors
TWI592411B (en) 2011-02-23 2017-07-21 英特爾立秦有限責任公司 Combination of kinase inhibitors and uses thereof
WO2012125629A1 (en) 2011-03-14 2012-09-20 Incyte Corporation Substituted diamino-pyrimidine and diamino-pyridine derivatives as pi3k inhibitors
WO2012135009A1 (en) 2011-03-25 2012-10-04 Incyte Corporation Pyrimidine-4,6-diamine derivatives as pi3k inhibitors
JP5961683B2 (en) 2011-04-05 2016-08-02 スローン − ケッタリング インスティチュート フォー キャンサー リサーチ HSP90 inhibitor
US9346808B2 (en) 2011-04-05 2016-05-24 Sloan-Kettering Institute For Cancer Research Hsp90 inhibitors
AU2012245702B2 (en) 2011-04-22 2016-09-29 Joyant Pharmaceuticals, Inc. Diazonamide analogs
JP2014515368A (en) 2011-05-26 2014-06-30 第一三共株式会社 Heterocyclic compounds as protein kinase inhibitors
JP2014517079A (en) 2011-06-22 2014-07-17 バーテックス ファーマシューティカルズ インコーポレイテッド Compounds useful as ATR kinase inhibitors
ITTO20110652A1 (en) * 2011-07-20 2013-01-21 Medestea Res & Production S P A COMPOUND DERIVED FROM THE ADENINE HAVING IMMUNO-MODULATING ACTION, ANTI-INFLAMMATORY AND ANTI-DOLUTION ACTION
SI2751109T1 (en) 2011-09-02 2017-03-31 Incyte Holdings Corporation Heterocyclylamines as pi3k inhibitors
CN103958510B (en) 2011-10-03 2016-10-19 北卡罗来纳大学教堂山分校 For treating the Pyrrolopyrimidine compounds of cancer
AR090548A1 (en) 2012-04-02 2014-11-19 Incyte Corp BICYCLIC AZAHETEROCICLOBENCILAMINS AS PI3K INHIBITORS
US9394315B2 (en) 2012-05-08 2016-07-19 Lycera Corporation Tetrahydro[1,8]naphthyridine sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease
US9657033B2 (en) 2012-05-08 2017-05-23 Lycera Corporation Tetrahydronaphthyridine and related bicyclic compounds for inhibition of RORγ activity and the treatment of disease
JP2015516464A (en) * 2012-05-15 2015-06-11 カルアジア ファーマシューティカルズ，インコーポレイテッド Pyrimidinediamine derivatives as inhibitors of cytoplasmic Hsp90
CN104302627A (en) 2012-05-22 2015-01-21 北卡罗来纳大学教堂山分校 Pyrimidine compounds for the treatment of cancer
PT3176170T (en) 2012-06-13 2019-02-05 Incyte Holdings Corp Substituted tricyclic compounds as fgfr inhibitors
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
WO2014055624A1 (en) 2012-10-02 2014-04-10 The General Hospital Corporation D/B/A Massachusetts General Hospital Methods relating to dna-sensing pathway related conditions
JP2015531395A (en) 2012-10-04 2015-11-02 ファイザー・リミテッドＰｆｉｚｅｒ Ｌｉｍｉｔｅｄ Pyrrolo [3,2-C] pyridine tropomyosin-related kinase inhibitor
CN103724269B (en) * 2012-10-11 2016-12-21 中国科学院上海药物研究所 Phenyl 1,2-isoxazole or phenyl 1,2-pyrazole compound and application thereof
US9562047B2 (en) 2012-10-17 2017-02-07 The University Of North Carolina At Chapel Hill Pyrazolopyrimidine compounds for the treatment of cancer
EP2925752A4 (en) 2012-11-27 2016-06-01 Univ North Carolina Pyrimidine compounds for the treatment of cancer
ES2842876T3 (en) 2012-12-07 2021-07-15 Vertex Pharma Pyrazolo [1,5-a] pyrimidines useful as ATR kinase inhibitors for the treatment of cancer diseases
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
WO2014145576A2 (en) 2013-03-15 2014-09-18 Northwestern University Substituted pyrrolo(2,3-d)pyrimidines for the treatment of cancer
JP2016512816A (en) 2013-03-15 2016-05-09 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ Compounds useful as inhibitors of ATR kinase
EP2970289A1 (en) 2013-03-15 2016-01-20 Vertex Pharmaceuticals Inc. Compounds useful as inhibitors of atr kinase
JP2016512815A (en) 2013-03-15 2016-05-09 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ Condensed pyrazolopyrimidine derivatives useful as inhibitors of ATR kinase
AU2014228822A1 (en) 2013-03-15 2015-10-01 Memorial Sloan-Kettering Cancer Center HSP90-targeted cardiac imaging and therapy
CN105209042B (en) 2013-03-22 2019-03-08 米伦纽姆医药公司 The combination of 1/2 inhibitor of catalytic MTORC and selective aurora A kinase inhibitor
PE20152033A1 (en) 2013-04-19 2016-01-21 Incyte Holdings Corp BICYCLE HETEROCYCLES AS FGFR INHIBITORS
CN105764501A (en) 2013-07-26 2016-07-13 现代化制药公司 Compositions to improve the therapeutic benefit of bisantrene
SG11201601542SA (en) 2013-08-16 2016-04-28 Sloan Kettering Inst Cancer Selective grp94 inhibitors and uses thereof
DK3077397T3 (en) 2013-12-06 2019-12-16 Vertex Pharma 2-AMINO-6-FLUOR-N- [5-FLUOR-PYRIDIN-3-YL] PYRAZOLO [1,5-A] PYRIMIDIN-3-CARBOXAMIDE COMPOUND USED AS AN AT-KINASE INHIBITOR, DIFFERENTLY DIFFERENTLY DERIVATIVES THEREOF
US9663502B2 (en) 2013-12-20 2017-05-30 Lycera Corporation 2-Acylamidomethyl and sulfonylamidomethyl benzoxazine carbamates for inhibition of RORgamma activity and the treatment of disease
US9809561B2 (en) 2013-12-20 2017-11-07 Merck Sharp & Dohme Corp. Tetrahydronaphthyridine, benzoxazine, aza-benzoxazine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease
WO2015095792A1 (en) 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. Carbamate benzoxaxine propionic acids and acid derivatives for modulation of rorgamma activity and the treatment of disease
US10532088B2 (en) 2014-02-27 2020-01-14 Lycera Corporation Adoptive cellular therapy using an agonist of retinoic acid receptor-related orphan receptor gamma and related therapeutic methods
ES2548927B1 (en) * 2014-03-21 2016-08-11 Universidad De Granada Purine derivatives as Dapk-1 inhibitors
US20150291606A1 (en) * 2014-04-11 2015-10-15 The University Of North Carolina At Chapel Hill Mertk-specific pyrrolopyrimidine compounds
US10189777B2 (en) 2014-05-05 2019-01-29 Lycera Corporation Benzenesulfonamido and related compounds for use as agonists of RORγ and the treatment of disease
AU2015256190B2 (en) 2014-05-05 2019-08-15 Lycera Corporation Tetrahydroquinoline sulfonamide and related compounds for use as agonists of rory and the treatment of disease
BR112016028273B1 (en) 2014-06-05 2022-06-28 Vertex Pharmaceuticals Incorporated FORMULA I-A COMPOUND, SOLID FORM OF A FORMULA I-1 COMPOUND AND ITS PREPARATION PROCESS
WO2015191677A1 (en) 2014-06-11 2015-12-17 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as pi3k inhibitors
DK3157566T3 (en) 2014-06-17 2019-07-22 Vertex Pharma METHOD OF TREATING CANCER USING A COMBINATION CHK1 AND ATR INHIBITORS
MX2017003513A (en) 2014-09-17 2017-07-28 Memorial Sloan Kettering Cancer Center Hsp90-targeted inflammation and infection imaging and therapy.
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
KR101713638B1 (en) * 2014-11-18 2017-03-08 한국과학기술연구원 Novel pyrrolo pyrimidine derivatives and composition for preventing or treating cancer comprising the same
CA2975997A1 (en) 2015-02-11 2016-08-18 Merck Sharp & Dohme Corp. Substituted pyrazole compounds as rorgammat inhibitors and uses thereof
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
MA41551A (en) 2015-02-20 2017-12-26 Incyte Corp BICYCLIC HETEROCYCLES USED AS FGFR4 INHIBITORS
EP3617205B1 (en) 2015-02-20 2021-08-04 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
CN117800973A (en) 2015-02-27 2024-04-02 因赛特控股公司 Salts of PI3K inhibitors and methods of making the same
CA2982847A1 (en) 2015-05-05 2016-11-10 Lycera Corporation Dihydro-2h-benzo[b][1,4]oxazine sulfonamide and related compounds for use as agonists of ror.gamma. and the treatment of disease
US9988401B2 (en) 2015-05-11 2018-06-05 Incyte Corporation Crystalline forms of a PI3K inhibitor
WO2016183060A1 (en) 2015-05-11 2016-11-17 Incyte Corporation Process for the synthesis of a phosphoinositide 3-kinase inhibitor
KR20180025894A (en) 2015-06-11 2018-03-09 라이세라 코퍼레이션 Benzo [B] [1,4] oxazinesulfonamides and related compounds for use as agonists of RORY and the treatment of diseases
CA3217238A1 (en) * 2015-07-20 2017-01-26 Genzyme Corporation Colony stimulating factor-1 receptor (csf-1r) inhibitors
EP3355926A4 (en) 2015-09-30 2019-08-21 Vertex Pharmaceuticals Inc. Method for treating cancer using a combination of dna damaging agents and atr inhibitors
EP3368535B1 (en) 2015-10-27 2020-12-02 Merck Sharp & Dohme Corp. Heteroaryl substituted benzoic acids as rorgammat inhibitors and uses thereof
MX2018005004A (en) 2015-10-27 2018-09-12 Merck Sharp & Dohme Substituted indazole compounds as rorgammat inhibitors and uses thereof.
JP2018531957A (en) 2015-10-27 2018-11-01 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． Substituted bicyclic pyrazole compounds and their use as RORγT inhibitors
US10709708B2 (en) 2016-03-17 2020-07-14 The University Of North Carolina At Chapel Hill Method of treating cancer with a combination of MER tyrosine kinase inhibitor and an epidermal growth factor receptor (EGFR) inhibitor
KR101896616B1 (en) * 2016-10-11 2018-09-07 한국과학기술연구원 2-Amino-purine derivative compound, preparing method and use thereof
KR102053933B1 (en) * 2016-10-26 2019-12-11 울산과학기술원 Compound as TRAP1 inhibitor and pharmaceutical composition for anticancer comprising the same
EA201992215A1 (en) 2017-03-20 2020-02-06 Форма Терапьютикс, Инк. Pyrrolopyrrole Compositions as Pyruvate Kinase Activators (PKR)
AR111960A1 (en) 2017-05-26 2019-09-04 Incyte Corp CRYSTALLINE FORMS OF A FGFR INHIBITOR AND PROCESSES FOR ITS PREPARATION
US10472361B2 (en) 2017-08-16 2019-11-12 Bristol-Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having a benzotriazole moiety, conjugates thereof, and methods and uses therefor
KR20190043437A (en) 2017-10-18 2019-04-26 씨제이헬스케어 주식회사 Heterocylic compound as a protein kinase inhibitor
CN107857763A (en) * 2017-11-28 2018-03-30 江苏杏睿生物科技有限公司 A kind of adjacent nitro aroylation derivatives quasi-compound, preparation method and applications
FR3075795A1 (en) 2017-12-21 2019-06-28 Galderma Research & Development NEW MTOR INHIBITOR COMPOUNDS
FR3075794A1 (en) * 2017-12-21 2019-06-28 Galderma Research & Development NEW MTOR INHIBITOR COMPOUNDS
EP3762385A4 (en) 2018-03-09 2021-11-24 Recurium IP Holdings, LLC Substituted 1,2-dihydro-3h-pyrazolo[3,4-d]pyrimidin-3-ones
CA3099116A1 (en) 2018-05-04 2019-11-07 Incyte Corporation Salts of an fgfr inhibitor
CN112867716A (en) 2018-05-04 2021-05-28 因赛特公司 Solid forms of FGFR inhibitors and methods for their preparation
US20220031671A1 (en) 2018-09-19 2022-02-03 Forma Therapeutics, Inc. Treating sickle cell disease with a pyruvate kinase r activating compound
EP3852791A4 (en) 2018-09-19 2022-06-15 Forma Therapeutics, Inc. Activating pyruvate kinase r
WO2020185532A1 (en) 2019-03-08 2020-09-17 Incyte Corporation Methods of treating cancer with an fgfr inhibitor
WO2021007269A1 (en) 2019-07-09 2021-01-14 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
JOP20220083A1 (en) 2019-10-14 2023-01-30 Incyte Corp Bicyclic heterocycles as fgfr inhibitors
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
CA3162010A1 (en) 2019-12-04 2021-06-10 Incyte Corporation Derivatives of an fgfr inhibitor
CA3163875A1 (en) 2019-12-04 2021-06-10 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors
KR102516260B1 (en) * 2020-07-10 2023-03-31 울산과학기술원 Compounds as a TRAP1 selective inhibitor, and composition for preventing or treating cancer comprising the same
EP4267573A1 (en) 2020-12-23 2023-11-01 Genzyme Corporation Deuterated colony stimulating factor-1 receptor (csf-1r) inhibitors
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
CN116332940A (en) * 2023-02-14 2023-06-27 广西民族大学 7-deazapurine derivative and preparation method and application thereof

Citations (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4495190A (en) * 1980-12-22 1985-01-22 Astra Lakemedel Aktiebolag Derivatives of guanine for combating herpes virus infections
US4547573A (en) * 1983-12-02 1985-10-15 Ici Pharma Process for preparing cephalosporin derivatives
US4617304A (en) * 1984-04-10 1986-10-14 Merck & Co., Inc. Purine derivatives
US4699877A (en) * 1982-11-04 1987-10-13 The Regents Of The University Of California Methods and compositions for detecting human tumors
US4748177A (en) * 1984-03-26 1988-05-31 Warner-Lambert Company Guanine derivatives
US4772606A (en) * 1985-08-22 1988-09-20 Warner-Lambert Company Purine derivatives
US4774325A (en) * 1984-09-20 1988-09-27 Pierrel Spa New 8-substituted nucleoside and purine derivatives, the process for the preparation thereof and the pharmaceutical compositions containing them
US4806642A (en) * 1984-10-05 1989-02-21 Warner-Lambert Company Purine derivatives
US4918162A (en) * 1986-05-06 1990-04-17 The Regents Of The University Of California Assays and antibodies for N-MYC proteins
US4921859A (en) * 1983-10-31 1990-05-01 Warner-Lambert Company Purine derivatives
US4923885A (en) * 1988-08-19 1990-05-08 Merck & Co., Inc. 5-amino-1-(4-naphthoylbenzyl)-1,2,3-triazole-4-carboxamides and analogs as antiproliferative agents
US4968603A (en) * 1986-12-31 1990-11-06 The Regents Of The University Of California Determination of status in neoplastic disease
US5002950A (en) * 1986-10-24 1991-03-26 Warner-Lambert Co. 7-deazaguanines as immunomodulators
US5098906A (en) * 1983-10-31 1992-03-24 Warner-Lambert Company Purine derivatives
US5110818A (en) * 1988-10-06 1992-05-05 Ciba-Geigy Corporation Anticonvulsive substituted-9-benzyl-9h-purines
US5204353A (en) * 1987-04-07 1993-04-20 Ciba-Geigy Corporation 3-benzyl-3H-1,2,3-triazolo[4,5-d]pyrimidines, compositions thereof, and method of treating epilepsy therewith
US5217866A (en) * 1985-03-15 1993-06-08 Anti-Gene Development Group Polynucleotide assay reagent and method
US5332744A (en) * 1989-05-30 1994-07-26 Merck & Co., Inc. Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
US5369008A (en) * 1991-05-24 1994-11-29 Board Of Regents, The University Of Texas System Methods for the detection of BCR-ABL and abnormal ABL proteins in leukemia patients
US5602156A (en) * 1993-09-17 1997-02-11 The United States Of America As Represented By The Department Of Health And Human Services Method for inhibiting metalloproteinase expression
US5656629A (en) * 1995-03-10 1997-08-12 Sanofi Winthrop, Inc. 6-substituted pyrazolo (3,4-d)pyrimidin-4-ones and compositions and methods of use thereof
US5789394A (en) * 1992-12-23 1998-08-04 Nguyen-Ba; Nghe Anti-viral compounds
US5846749A (en) * 1994-10-12 1998-12-08 The Regents Of The University Of California Quantitative measurement of tissue protein identified by immunohistochemistry and standardized protein determination
US5861503A (en) * 1997-04-30 1999-01-19 The Regents Of The University Of California Process for producing 8-fluoropurines
US5917042A (en) * 1994-02-04 1999-06-29 Glaxo Wellcome Inc. Process for the preparation of 2,5-diamino-4,6-dichloropyrimidine
US5932566A (en) * 1994-06-16 1999-08-03 Pfizer Inc. Ansamycin derivatives as antioncogene and anticancer agents
US5994361A (en) * 1994-06-22 1999-11-30 Biochem Pharma Substituted purinyl derivatives with immunomodulating activity
US6005107A (en) * 1992-12-23 1999-12-21 Biochem Pharma, Inc. Antiviral compounds
US6025126A (en) * 1991-10-28 2000-02-15 Arch Development Corporation Methods and compositions for the detection of chromosomal aberrations
US6143743A (en) * 1997-07-03 2000-11-07 Dupont Pharmaceuticals Company Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders
US6174875B1 (en) * 1999-04-01 2001-01-16 University Of Pittsburgh Benzoquinoid ansamycins for the treatment of cardiac arrest and stroke
US6177460B1 (en) * 1995-04-12 2001-01-23 The Procter & Gamble Company Method of treatment for cancer or viral infections
US6210974B1 (en) * 1997-10-24 2001-04-03 Oregon Health Sciences University Compositions and methods for promoting nerve regeneration
US6333331B1 (en) * 1994-08-01 2001-12-25 The United States Of America As Represented By The Department Of Health And Human Services Substituted O6-benzylguanines
US6369092B1 (en) * 1998-11-23 2002-04-09 Cell Pathways, Inc. Method for treating neoplasia by exposure to substituted benzimidazole derivatives
US6444656B1 (en) * 1992-12-23 2002-09-03 Biochem Pharma, Inc. Antiviral phosphonate nucleotides
US20020156277A1 (en) * 2001-04-20 2002-10-24 Fick David B. Synthesis and methods of use of purine analogues and derivatives
US20020161014A1 (en) * 2000-04-25 2002-10-31 Chanchal Sadhu Inhibitors of human phosphatidylinositol 3-kinase delta
US20030022864A1 (en) * 2001-04-24 2003-01-30 Ishaq Khalid S. 9-[(5-dihydroxyboryl)-pentyl] purines, useful as an inhibitor of inflammatory cytokines
US20030078413A1 (en) * 2001-09-12 2003-04-24 Epoch Biosciences, Inc. Process for the synthesis of pyrazolopyrimidines
US20030113331A1 (en) * 1999-01-06 2003-06-19 Brooks Peter C. Method and composition for angiogenesis inhibition
US20040063668A1 (en) * 2001-01-19 2004-04-01 Jong-Ryoo Choi Novel acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same
US6723727B1 (en) * 1996-12-20 2004-04-20 Hoechst Aktiengesellschaft Substituted purine derivatives, processes for their preparation, their use, and compositions comprising them
US20040097526A1 (en) * 2001-01-10 2004-05-20 Gillespie Roger John Triazolo[4,5-d]pyrimidine derivatives and their use as purinergic receptor antagonists
US20040102458A1 (en) * 2000-11-02 2004-05-27 Gabriela Chiosis Small molecule compositions for binding to hsp90
US20040242490A1 (en) * 2003-02-20 2004-12-02 Brooks Peter C. CLK-peptide and SLK-peptide
US20040241706A1 (en) * 2002-09-13 2004-12-02 Irm, Llc Highly specific modulators of GTPases for target validation
US20050043239A1 (en) * 2003-08-14 2005-02-24 Jason Douangpanya Methods of inhibiting immune responses stimulated by an endogenous factor
US20050049263A1 (en) * 2001-10-30 2005-03-03 Kasibhatla Srinivas Rao Purine analogs having hsp90-inhibiting activity
US20050113340A1 (en) * 2003-09-18 2005-05-26 Conforma Therapeutics Corporation 2-Aminopurine analogs having HSP90-inhibiting activity
US20050256183A1 (en) * 2001-11-09 2005-11-17 Kasibhatla Srinivas R Hsp90-inhibiting zearalanol compounds and methods of producing and using same
US20060035909A1 (en) * 2002-08-23 2006-02-16 Kveta Fuksova Azapurine derivatives
US7087754B2 (en) * 2001-01-10 2006-08-08 Vernalis Research Limited Pyrazolo[3,4-d]pyrimidine derivatives and their use as purinergic receptor antagonists

Family Cites Families (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB884151A (en) 1957-12-06 1961-12-06 Ciba Ltd New pyrazolo-pyrimidines substituted in the pyrazole nucleus, and process for their manufacture
DE3578499D1 (en) 1984-02-02 1990-08-09 Merck & Co Inc 5- (AMINO OR SUBSTITUTED AMINO) -1,2,3-TRIAZOLE.
ZA857647B (en) * 1984-10-12 1986-05-28 Warner Lambert Co Purine derivatives
IL76546A (en) 1984-10-12 1988-12-30 Warner Lambert Co 9-(heteroarylalkyl)-6-purine(thi)one derivatives,their preparation and pharmaceutical compositions containing them
JO1406B1 (en) 1984-11-02 1986-11-30 سميث كلاين اند فرينش لابوراتوريز ليمتد Chemical compounds
EP0215942B1 (en) 1985-03-15 1995-07-12 Antivirals Inc. Polynucleotide assay reagent and method
IL78643A0 (en) 1985-05-02 1986-08-31 Wellcome Found Purine derivatives,their preparation and pharmaceutical compositions containing them
GB8515934D0 (en) 1985-06-24 1985-07-24 Janssen Pharmaceutica Nv (4-piperidinomethyl and-hetero)purines
DE3623099C3 (en) * 1986-07-09 1998-08-13 Spoetzl Markus Dipl Ing Fh Blow molding machine
JPH0821101B2 (en) 1987-07-21 1996-03-04 三洋電機株式会社 Coin sorter
SE8801729D0 (en) 1988-05-06 1988-05-06 Astra Ab PURINE DERIVATIVES FOR USE IN THERAPY
DK0465297T3 (en) 1990-07-04 1996-02-19 Merrell Pharma Inc 9-Purinylphosphonsyre derivatives
GB9020931D0 (en) 1990-09-26 1990-11-07 Wellcome Found Heterocyclic compounds
ATE187173T1 (en) 1991-03-05 1999-12-15 Ajinomoto Kk CYCLOPROPANE DERIVATIVE
US5939420A (en) 1991-04-08 1999-08-17 Duquesne University Of The Holy Ghost Pyrrolo 2,3d!derivatives
CA2093403C (en) 1992-04-08 1999-08-10 Fumio Suzuki Therapeutic agent for parkinson's disease
JPH0680670A (en) 1992-09-03 1994-03-22 Ajinomoto Co Inc Cyclopropane derivative and its production
US5744492A (en) 1993-09-17 1998-04-28 United States Of America Method for inhibiting angiogenesis
JP3769737B2 (en) 1994-03-30 2006-04-26 味の素株式会社 Cyclopropane derivative and process for producing the same
JPH0841035A (en) 1994-08-05 1996-02-13 Ajinomoto Co Inc Cyclopropane derivative and its production
JPH08208687A (en) 1994-11-25 1996-08-13 Sankyo Co Ltd Glyceryl oligonucleotide
JPH0920776A (en) 1995-06-30 1997-01-21 Nippon Paper Ind Co Ltd New purine nucleoside derivative, its production and antiviral agent with the same as active ingredient
JPH09169758A (en) 1995-10-18 1997-06-30 Nippon Paper Ind Co Ltd New purine nucleoside derivative, its production and antivirus using the same
JPH1025294A (en) * 1996-03-26 1998-01-27 Akira Matsuda Condensed heterocyclic derivative, its production and malignant tumor therapeutic agent containing the same
ES2232871T3 (en) 1996-07-03 2005-06-01 Sumitomo Pharmaceuticals Company, Limited NEW DERIVATIVES OF PURINA.
AU6452098A (en) 1997-03-07 1998-09-22 Metabasis Therapeutics, Inc. Novel purine inhibitors of fructose-1,6-bisphosphatase
WO1998051702A1 (en) 1997-05-14 1998-11-19 Sloan-Kettering Institute For Cancer Research Methods and compositions for destruction of selected proteins
CA2294244A1 (en) 1997-07-12 1999-01-21 Cancer Research Campaign Technology Limited Cyclin dependent kinase inhibiting purine derivatives
GB9717849D0 (en) 1997-08-23 1997-10-29 Seal Sands Chemicals Limited Preparation of pyridene derivatives
AUPO912997A0 (en) 1997-09-11 1997-10-02 Commonwealth Scientific And Industrial Research Organisation Antiviral agents
CN1130363C (en) 1997-11-12 2003-12-10 三菱化学株式会社 Purine derivatives and medicine containing the same as the active ingredient
TW572758B (en) 1997-12-22 2004-01-21 Sumitomo Pharma Type 2 helper T cell-selective immune response inhibitors comprising purine derivatives
AU3378599A (en) 1998-04-03 1999-10-25 University Of Pittsburgh Benzoquinoid ansamycins for the treatment of cardiac arrest and stroke
US5985060A (en) 1998-07-25 1999-11-16 Breed Automotive Technology, Inc. Gas generant compositions containing guanidines
SI20022A (en) 1998-07-29 2000-02-29 Kemijski inštitut Alkyl substituted purine derivatives and their preparation
JP2000072773A (en) 1998-08-28 2000-03-07 Zeria Pharmaceut Co Ltd Purine derivative
CZ27399A3 (en) 1999-01-26 2000-08-16 Ústav Experimentální Botaniky Av Čr Substituted nitrogen heterocyclic derivatives process of their preparation, the derivatives employed as medicaments, pharmaceutical composition and a compound pharmaceutical preparation in which these derivatives are comprised as well as use of these derivatives for preparing medicaments
TR200102714T2 (en) 1999-02-01 2002-01-21 Cv Therapeutics, Inc. Purine inhibitors of cyclin dependent kinase 2 and IkB - &
FR2790702B1 (en) 1999-03-08 2001-07-20 Sidel Sa MOLDING UNIT AND EXTRUSION-BLOWING MACHINE PROVIDED WITH SUCH A UNIT
AU4589800A (en) 1999-05-05 2000-11-21 Darwin Discovery Limited 9-(1,2,3,4-tetrahydronaphthalen-1-yl)-1,9-dihydropurin-6-one derivatives as pde7inhibitors
US6660845B1 (en) 1999-11-23 2003-12-09 Epoch Biosciences, Inc. Non-aggregating, non-quenching oligomers comprising nucleotide analogues; methods of synthesis and use thereof
ES2245955T3 (en) 1999-12-21 2006-02-01 Sugen, Inc. 7-AZA-INDOLIN-2-ONAS 4-SUBSTITUTES AND THEIR USE AS PROTEIN-KINASE INHIBITORS.
AU3540101A (en) 2000-01-07 2001-07-16 Universitaire Instelling Antwerpen Purine derivatives, process for their preparation and use thereof
CA2429196A1 (en) 2000-03-24 2001-10-04 Duke University Characterization of grp94-ligand interactions and purification, screening, and therapeutic methods relating thereto
SI2223922T1 (en) 2000-04-25 2016-04-29 Icos Corporation Inhibitors of human phosphatidyl-inositol 3-kinase delta
US6887853B2 (en) 2000-06-29 2005-05-03 The Trustees Of Boston University Use of geldanamycin and related compounds for treatment of fibrogenic disorders
AU2001292548B2 (en) 2000-07-28 2005-06-16 Sloan-Kettering Institute For Cancer Research Methods for treating cell proliferative disorders and viral infections
US6613089B1 (en) 2000-10-25 2003-09-02 Sdgi Holdings, Inc. Laterally expanding intervertebral fusion device
EP2308515A1 (en) 2000-11-02 2011-04-13 Sloan-Kettering Institute For Cancer Research Methods for enhancing the efficacy of cytotoxic agents through the use of HSP90 inhibitors
GB0100623D0 (en) 2001-01-10 2001-02-21 Vernalis Res Ltd Chemical compounds IV
US20060079493A1 (en) 2001-03-01 2006-04-13 Lawrence Fritz Methods for treating genetically- defined proliferative disorders with hsp90 inhibitors
US6881567B2 (en) * 2001-03-16 2005-04-19 Her Majesty The Queen In Right Of Canada As Represented By The Minister Of Agricultural And Agri-Food Canada Pre-emergent biological control agents
CA2444130C (en) 2001-04-17 2010-12-21 Sumitomo Pharmaceuticals Company, Limited Adenine derivatives
WO2002088079A2 (en) 2001-05-01 2002-11-07 Bristol-Myers Squibb Company Dual inhibitors of pde 7 and pde 4
JP2004529188A (en) 2001-05-23 2004-09-24 スローン − ケッタリング インスティチュート フォー キャンサー リサーチ Treatment of cancer associated with elevation
PE20030008A1 (en) 2001-06-19 2003-01-22 Bristol Myers Squibb Co DUAL INHIBITORS OF PDE 7 AND PDE 4
BR0210594A (en) 2001-06-22 2005-11-01 Pharmasset Ltd (beta) -d or (beta) -1,3-halonucleoside
JP4381804B2 (en) 2001-06-27 2009-12-09 サイクラセル リミテッド 2,6,9-substituted purine derivatives and their use in the treatment of proliferative diseases
EP2050460A1 (en) 2001-09-24 2009-04-22 Imperial Innovations Limited PYY and agonists thereof for modification of feeding behaviour
CA2460498A1 (en) 2001-09-24 2003-04-03 Conforma Therapeutics Corporation Process for preparing 17-allyl amino geldanamycin (17-aag) and other ansamycins
JP2003113181A (en) 2001-10-04 2003-04-18 Sumika Fine Chemicals Co Ltd Method for producing 6-halopurine
WO2005012304A2 (en) * 2003-07-16 2005-02-10 Janssen Pharmaceutica N.V. Triazolopyrimidine derivatives as glycogen synthase kinase 3 inhibitors
CA2531333A1 (en) * 2003-07-16 2005-02-10 Janssen Pharmaceutica N.V. Triazolopyrimidine derivatives as glycogen synthase kinase 3 inhibitors
EP1772454A4 (en) * 2004-07-23 2009-02-25 Mitsubishi Tanabe Pharma Corp Nitrogenous fused bicyclic compound
US20070105874A1 (en) * 2005-09-23 2007-05-10 Conforma Therapeutics Corporation Anti-Tumor Methods Using Multi Drug Resistance Independent Synthetic HSP90 Inhibitors
CN107614533B (en) 2015-03-13 2021-12-21 朱宝麒 Zinc-conjugated glutathione S transferase and metallothionein fusion protein

Patent Citations (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4495190A (en) * 1980-12-22 1985-01-22 Astra Lakemedel Aktiebolag Derivatives of guanine for combating herpes virus infections
US4699877A (en) * 1982-11-04 1987-10-13 The Regents Of The University Of California Methods and compositions for detecting human tumors
US4921859A (en) * 1983-10-31 1990-05-01 Warner-Lambert Company Purine derivatives
US5098906A (en) * 1983-10-31 1992-03-24 Warner-Lambert Company Purine derivatives
US4547573A (en) * 1983-12-02 1985-10-15 Ici Pharma Process for preparing cephalosporin derivatives
US4748177A (en) * 1984-03-26 1988-05-31 Warner-Lambert Company Guanine derivatives
US4617304A (en) * 1984-04-10 1986-10-14 Merck & Co., Inc. Purine derivatives
US4774325A (en) * 1984-09-20 1988-09-27 Pierrel Spa New 8-substituted nucleoside and purine derivatives, the process for the preparation thereof and the pharmaceutical compositions containing them
US4806642A (en) * 1984-10-05 1989-02-21 Warner-Lambert Company Purine derivatives
US5217866A (en) * 1985-03-15 1993-06-08 Anti-Gene Development Group Polynucleotide assay reagent and method
US4772606A (en) * 1985-08-22 1988-09-20 Warner-Lambert Company Purine derivatives
US4918162A (en) * 1986-05-06 1990-04-17 The Regents Of The University Of California Assays and antibodies for N-MYC proteins
US5002950A (en) * 1986-10-24 1991-03-26 Warner-Lambert Co. 7-deazaguanines as immunomodulators
US4968603A (en) * 1986-12-31 1990-11-06 The Regents Of The University Of California Determination of status in neoplastic disease
US5204353A (en) * 1987-04-07 1993-04-20 Ciba-Geigy Corporation 3-benzyl-3H-1,2,3-triazolo[4,5-d]pyrimidines, compositions thereof, and method of treating epilepsy therewith
US4923885A (en) * 1988-08-19 1990-05-08 Merck & Co., Inc. 5-amino-1-(4-naphthoylbenzyl)-1,2,3-triazole-4-carboxamides and analogs as antiproliferative agents
US5110818A (en) * 1988-10-06 1992-05-05 Ciba-Geigy Corporation Anticonvulsive substituted-9-benzyl-9h-purines
US5332744A (en) * 1989-05-30 1994-07-26 Merck & Co., Inc. Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
US5369008A (en) * 1991-05-24 1994-11-29 Board Of Regents, The University Of Texas System Methods for the detection of BCR-ABL and abnormal ABL proteins in leukemia patients
US6025126A (en) * 1991-10-28 2000-02-15 Arch Development Corporation Methods and compositions for the detection of chromosomal aberrations
US6005107A (en) * 1992-12-23 1999-12-21 Biochem Pharma, Inc. Antiviral compounds
US5955610A (en) * 1992-12-23 1999-09-21 Biochem Pharma, Inc. Antiviral compounds
US5789394A (en) * 1992-12-23 1998-08-04 Nguyen-Ba; Nghe Anti-viral compounds
US6444656B1 (en) * 1992-12-23 2002-09-03 Biochem Pharma, Inc. Antiviral phosphonate nucleotides
US5602156A (en) * 1993-09-17 1997-02-11 The United States Of America As Represented By The Department Of Health And Human Services Method for inhibiting metalloproteinase expression
US5917042A (en) * 1994-02-04 1999-06-29 Glaxo Wellcome Inc. Process for the preparation of 2,5-diamino-4,6-dichloropyrimidine
US5932566A (en) * 1994-06-16 1999-08-03 Pfizer Inc. Ansamycin derivatives as antioncogene and anticancer agents
US5994361A (en) * 1994-06-22 1999-11-30 Biochem Pharma Substituted purinyl derivatives with immunomodulating activity
US6333331B1 (en) * 1994-08-01 2001-12-25 The United States Of America As Represented By The Department Of Health And Human Services Substituted O6-benzylguanines
US5846749A (en) * 1994-10-12 1998-12-08 The Regents Of The University Of California Quantitative measurement of tissue protein identified by immunohistochemistry and standardized protein determination
US5656629A (en) * 1995-03-10 1997-08-12 Sanofi Winthrop, Inc. 6-substituted pyrazolo (3,4-d)pyrimidin-4-ones and compositions and methods of use thereof
US6177460B1 (en) * 1995-04-12 2001-01-23 The Procter & Gamble Company Method of treatment for cancer or viral infections
US6723727B1 (en) * 1996-12-20 2004-04-20 Hoechst Aktiengesellschaft Substituted purine derivatives, processes for their preparation, their use, and compositions comprising them
US5861503A (en) * 1997-04-30 1999-01-19 The Regents Of The University Of California Process for producing 8-fluoropurines
US6262254B1 (en) * 1997-04-30 2001-07-17 The Regents Of Univ. Of California 8-fluoropurine compounds
US6143743A (en) * 1997-07-03 2000-11-07 Dupont Pharmaceuticals Company Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders
US6210974B1 (en) * 1997-10-24 2001-04-03 Oregon Health Sciences University Compositions and methods for promoting nerve regeneration
US6369092B1 (en) * 1998-11-23 2002-04-09 Cell Pathways, Inc. Method for treating neoplasia by exposure to substituted benzimidazole derivatives
US20030113331A1 (en) * 1999-01-06 2003-06-19 Brooks Peter C. Method and composition for angiogenesis inhibition
US6174875B1 (en) * 1999-04-01 2001-01-16 University Of Pittsburgh Benzoquinoid ansamycins for the treatment of cardiac arrest and stroke
US20020161014A1 (en) * 2000-04-25 2002-10-31 Chanchal Sadhu Inhibitors of human phosphatidylinositol 3-kinase delta
US20040102458A1 (en) * 2000-11-02 2004-05-27 Gabriela Chiosis Small molecule compositions for binding to hsp90
US20040097526A1 (en) * 2001-01-10 2004-05-20 Gillespie Roger John Triazolo[4,5-d]pyrimidine derivatives and their use as purinergic receptor antagonists
US7087754B2 (en) * 2001-01-10 2006-08-08 Vernalis Research Limited Pyrazolo[3,4-d]pyrimidine derivatives and their use as purinergic receptor antagonists
US20040063668A1 (en) * 2001-01-19 2004-04-01 Jong-Ryoo Choi Novel acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same
US20020156277A1 (en) * 2001-04-20 2002-10-24 Fick David B. Synthesis and methods of use of purine analogues and derivatives
US20030022864A1 (en) * 2001-04-24 2003-01-30 Ishaq Khalid S. 9-[(5-dihydroxyboryl)-pentyl] purines, useful as an inhibitor of inflammatory cytokines
US20030078413A1 (en) * 2001-09-12 2003-04-24 Epoch Biosciences, Inc. Process for the synthesis of pyrazolopyrimidines
US20050049263A1 (en) * 2001-10-30 2005-03-03 Kasibhatla Srinivas Rao Purine analogs having hsp90-inhibiting activity
US20050256183A1 (en) * 2001-11-09 2005-11-17 Kasibhatla Srinivas R Hsp90-inhibiting zearalanol compounds and methods of producing and using same
US20060035909A1 (en) * 2002-08-23 2006-02-16 Kveta Fuksova Azapurine derivatives
US20040241706A1 (en) * 2002-09-13 2004-12-02 Irm, Llc Highly specific modulators of GTPases for target validation
US20040242490A1 (en) * 2003-02-20 2004-12-02 Brooks Peter C. CLK-peptide and SLK-peptide
US20050043239A1 (en) * 2003-08-14 2005-02-24 Jason Douangpanya Methods of inhibiting immune responses stimulated by an endogenous factor
US20050119282A1 (en) * 2003-09-18 2005-06-02 Conforma Therapeutics Corporation Pyrazolopyrimidines and related analogs as HSP90-inhibitors
US20050113339A1 (en) * 2003-09-18 2005-05-26 Kasibhatla Srinivas R. Triazolopyrimidines and related analogs as HSP90-inhibitors
US20050113340A1 (en) * 2003-09-18 2005-05-26 Conforma Therapeutics Corporation 2-Aminopurine analogs having HSP90-inhibiting activity

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060223797A1 (en) * 2005-03-30 2006-10-05 Conforma Therapeutics Corporation Alkynyl pyrrolopyrimidines and related analogs as hsp90-inhibitors
US7544672B2 (en) 2005-03-30 2009-06-09 Conforma Therapeutics Corporation Alkynyl pyrrolo[2,3-d]pyrimidines and related analogs as HSP90-inhibitors
US8093229B2 (en) 2005-03-30 2012-01-10 Conforma Therapeutics Corporation Alkynyl pyrrolo[2,3-d]pyrimidines and related analogs as HSP90-inhibitors
US9359360B2 (en) 2005-08-22 2016-06-07 The Regents Of The University Of California TLR agonists
US20090324551A1 (en) * 2005-08-22 2009-12-31 The Regents Of The University Of California Office Of Technology Transfer Tlr agonists
US20110098294A1 (en) * 2006-05-31 2011-04-28 Carson Dennis A Purine analogs
US8846697B2 (en) 2006-05-31 2014-09-30 The Regents Of The University Of California Purine analogs
US8357374B2 (en) 2007-02-07 2013-01-22 The Regents Of The University Of California Conjugates of synthetic TLR agonists and uses therefor
US8790655B2 (en) 2007-02-07 2014-07-29 The Regents Of The University Of California Conjugates of synthetic TLR agonists and uses therefor
US9050376B2 (en) 2007-02-07 2015-06-09 The Regents Of The University Of California Conjugates of synthetic TLR agonists and uses therefor
US20090202626A1 (en) * 2008-02-07 2009-08-13 Carson Dennis A Treatment of bladder diseases with a tlr7 activator
WO2009139834A1 (en) * 2008-05-13 2009-11-19 Poniard Pharmaceuticals, Inc. Bioactive compounds for treatment of cancer and neurodegenerative diseases
US20110124634A1 (en) * 2008-05-13 2011-05-26 Poniard Pharmaceuticals, Inc. Bioactive compounds for treatment of cancer and neurodegenerative diseases
US9066940B2 (en) 2009-02-06 2015-06-30 Telormedix, Sa Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration
US9107919B2 (en) 2009-02-06 2015-08-18 Telormedix Sa Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration
US20100210598A1 (en) * 2009-02-11 2010-08-19 Regents Of The University Of California, San Diego Toll-like receptor modulators and treatment of diseases
US8729088B2 (en) 2009-02-11 2014-05-20 The Regents Of The University Of California Toll-like receptor modulators and treatment of diseases
WO2010117425A1 (en) * 2009-03-31 2010-10-14 Biogen Idec Ma Inc. Certain substituted pyrimidines, pharmaceutical compositions thereof, and methods for their use
US9050319B2 (en) 2010-04-30 2015-06-09 Telormedix, Sa Phospholipid drug analogs
US9173936B2 (en) 2010-04-30 2015-11-03 Telormedix Sa Phospholipid drug analogs
US9173935B2 (en) 2010-04-30 2015-11-03 Telormedix Sa Phospholipid drug analogs
US9180183B2 (en) 2010-04-30 2015-11-10 Telormedix Sa Phospholipid drug analogs
US11697851B2 (en) 2016-05-24 2023-07-11 The Regents Of The University Of California Early ovarian cancer detection diagnostic test based on mRNA isoforms

Also Published As

Publication number Publication date
AU2010202750B2 (en) 2011-09-01
CN101906106A (en) 2010-12-08
US20050113339A1 (en) 2005-05-26
EA200600594A1 (en) 2006-10-27
US7138402B2 (en) 2006-11-21
US20070185064A1 (en) 2007-08-09
US20070111996A1 (en) 2007-05-17
MXPA06002997A (en) 2007-02-08
JP2007505933A (en) 2007-03-15
EP2145888A1 (en) 2010-01-20
US20050107343A1 (en) 2005-05-19
EA010160B1 (en) 2008-06-30
AU2010202750A1 (en) 2010-07-22
US20070111997A1 (en) 2007-05-17
CA2539548A1 (en) 2005-03-31
AU2004274507B2 (en) 2010-08-19
US7129244B2 (en) 2006-10-31
BRPI0414533A (en) 2006-11-07
EP1670802A2 (en) 2006-06-21
US7148228B2 (en) 2006-12-12
US7138401B2 (en) 2006-11-21
EP1670802A4 (en) 2010-07-07
NZ546611A (en) 2010-02-26
WO2005028434A2 (en) 2005-03-31
NO20061396L (en) 2006-06-16
US20050113340A1 (en) 2005-05-26
KR20060070572A (en) 2006-06-23
WO2005028434A3 (en) 2006-03-23
AU2004274507A1 (en) 2005-03-31
US20050119282A1 (en) 2005-06-02
IL174375A0 (en) 2006-08-01

Similar Documents

Publication Publication Date Title
US7138402B2 (en) Pyrrolopyrimidines and related analogs as HSP90-inhibitors
US8093229B2 (en) Alkynyl pyrrolo[2,3-d]pyrimidines and related analogs as HSP90-inhibitors
US20210238183A1 (en) Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitors
US20080096903A1 (en) Sulfamoyl-containing derivatives and uses thereof
US20070253896A1 (en) 7,9-Dihydro-Purin-8-One and Related Analogs as HSP90-Inhibitors
SK3542002A3 (en) Pteridinones as kinase inhibitors
US20120058997A1 (en) Imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine derivatives and their use as protein kinase inhibitors
ZA200602786B (en) Novel heterocyclic compounds as HSP90-inhibitors

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

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