WO2001019798A2 - INHIBITORS OF FACTOR Xa - Google Patents

INHIBITORS OF FACTOR Xa Download PDF

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Publication number
WO2001019798A2
WO2001019798A2 PCT/US2000/025195 US0025195W WO0119798A2 WO 2001019798 A2 WO2001019798 A2 WO 2001019798A2 US 0025195 W US0025195 W US 0025195W WO 0119798 A2 WO0119798 A2 WO 0119798A2
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Prior art keywords
group
alkyl
substituted
cycloalkyl
conh
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PCT/US2000/025195
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French (fr)
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WO2001019798A3 (en
Inventor
Bing-Yan Zhu
Zhaozhong Jon Jia
Wenrong Huang
Yonghong Song
James Kanter
Robert M. Scarborough
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Cor Therapeutics Inc.
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Priority to AU74866/00A priority Critical patent/AU781880B2/en
Priority to EP00963451A priority patent/EP1216231A2/en
Priority to CA002385589A priority patent/CA2385589A1/en
Priority to JP2001523378A priority patent/JP2003509412A/en
Priority to NZ517828A priority patent/NZ517828A/en
Priority to HU0203954A priority patent/HUP0203954A2/en
Application filed by Cor Therapeutics Inc. filed Critical Cor Therapeutics Inc.
Priority to IL14869800A priority patent/IL148698A0/en
Priority to MXPA02002762 priority patent/MX228790B/en
Priority to BR0014078-3A priority patent/BR0014078A/en
Publication of WO2001019798A2 publication Critical patent/WO2001019798A2/en
Publication of WO2001019798A3 publication Critical patent/WO2001019798A3/en
Priority to NO20021230A priority patent/NO20021230L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
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    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to novel compounds which are potent and highly selective inhibitors of isolated factor Xa or when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa versus other proteases of the coagulation (e.g. thrombin, fVIIa, flXa) or the fibrinolytic cascades (e.g. plasminogen activators, plasmin).
  • the present invention relates to novel non-amidino-containing compounds, their pharmaceutically acceptable salts, and pharmaceutically acceptable compositions thereof which are useful as potent and specific inhibitors of blood coagulation in mammals.
  • the invention relates to methods for using these inhibitors as therapeutic agents for disease states in mammals characterized by coagulation disorders.
  • Hemostasis the control of bleeding, occurs by surgical means, or by the physiological properties of vasoconstriction and coagulation.
  • This invention is particularly concerned with blood coagulation and ways in which it assists in maintaining the integrity of mammalian circulation after injury, inflammation, disease, congenital defect, dysfunction or other disruption.
  • platelets and blood coagulation are both involved in thrombus formation, certain components of the coagulation cascade are primarily responsible for the amplification or acceleration of the processes involved in platelet aggregation and fibrin deposition.
  • Thrombin is a key enzyme in the coagulation cascade as well as in hemostasis. Thrombin plays a central role in thrombosis through its ability to catalyze the conversion of fibrinogen into fibrin and through its potent platelet activation activity. Direct or indirect inhibition of thrombin activity has been the focus of a variety of recent anticoagulant strategies as reviewed by Claeson, G., "Synthetic Peptides and Peptidomimetics as Substrates and Inhibitors of Thrombin and Other Proteases in the Blood Coagulation System", Blood Coag. Fibrinol. 5_, 411-436 (1994).
  • Several classes of anticoagulants currently used in the clinic directly or indirectly affect thrombin (i.e. heparins, low-molecular weight heparins, heparin-like compounds and coumarins).
  • a prothrombinase complex including Factor Xa (a serine protease, the activated form of its Factor X precursor and a member of the calcium ion binding, gamma carboxyglutamyl (Gla)-containing, vitamin K dependent, blood coagulation glycoprotein family), converts the zymogen prothrombin into the active procoagulant thrombin.
  • Factor Xa a serine protease, the activated form of its Factor X precursor and a member of the calcium ion binding, gamma carboxyglutamyl (Gla)-containing, vitamin K dependent, blood coagulation glycoprotein family
  • Ga carboxyglutamyl
  • Polypeptides derived from hematophagous organisms have been reported which are highly potent and specific inhibitors of factor Xa.
  • United States Patent 4,588,587 describes anticoagulant activity in the saliva of the Mexican leech, Haementeria officinalis. A principal component of this saliva was shown to be the polypeptide factor Xa inhibitor, antistasin (ATS), by Nutt, E. et al, "The Amino Acid Sequence of Antistasin, a Potent Inhibitor of Factor Xa Reveals a Repeated Internal Structure", J. Biol. Chem., 263, 10162-10167 (1988).
  • ATS antistasin
  • tick anticoagulant peptide Another potent and highly specific inhibitor of Factor Xa, called tick anticoagulant peptide (TAP), has been isolated from the whole body extract of the soft tick Ornithidoros moubata, as reported by Waxman, L., et al, "Tick Anticoagulant Peptide (TAP) is a Novel Inhibitor of Blood Coagulation Factor Xa" Science, 24g, 593-596 (1990).
  • Factor Xa inhibitory compounds which are not large polypeptide-type inhibitors have also been reported including: Tidwell, R.R. et al, "Strategies for Anticoagulation With Synthetic Protease Inhibitors. Xa Inhibitors Versus Thrombin Inhibitors", Thromb. Res., 19_, 339-349 (1980); Turner, A.D. et al, "p-Amidino Esters as Irreversible Inhibitors of Factor IXa and Xa and Thrombin", Biochemistry, 25, 4929-4935 (1986); Hitomi, Y.
  • Factor Xa inhibitors which are small molecule organic compounds, such as nitrogen containing heterocyclic compounds which have amidino substituent groups, wherein two functional groups of the compounds can bind to Factor Xa at two of its active sites.
  • WO 99/10316 describes compounds having a 4-phenyl-N-alkylamidino-piperidine and 4-phenoxy-N- alkylamidino-piperidine group connected to a 3-amidinophenyl group via a carboxamidealkyleneamino bridge
  • EP 798295 describes compounds having a 4-phenoxy-N-alkylamidino-piperidine
  • the present invention relates to novel compounds which inhibit factor Xa, their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, and pharmaceutically acceptable compositions thereof which have particular biological properties and are useful as potent and specific inhibitors of blood coagulation in mammals.
  • the invention relates to methods of using these inhibitors as diagnostic reagents or as therapeutic agents for disease states in mammals characterized by undesired thrombosis which have coagulation disorders, such as in the treatment or prevention of any thrombotically mediated acute coronary or cerebro vascular syndrome, any thrombotic syndrome occurring in the venous system, any coagulopathy, and any thrombotic complications associated with extracorporeal circulation or instrumentation, and for the inhibition of coagulation in biological samples.
  • coagulation disorders such as in the treatment or prevention of any thrombotically mediated acute coronary or cerebro vascular syndrome, any thrombotic syndrome occurring in the venous system, any coagulopathy, and any thrombotic complications associated with extracorporeal circulation or instrumentation, and for the inhibition of coagulation in biological samples.
  • this invention relates to novel compounds which are potent and highly selective inhibitors of isolated factor Xa when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa versus other proteases of the coagulation cascade (e.g. thrombin, etc.) or the fibrinolytic cascade, and are useful as diagnostic reagents as well as antithrombotic agents.
  • coagulation cascade e.g. thrombin, etc.
  • the present invention provides compounds comprising a five- membered heterocyclic ring structure having from 1-4 hetero atoms selected from the group consisting of N, O and S or a bicyclic ring system comprising the 5-membered heterocyclic ring structure wherein the bicyclic ring structure may have 1-5 hetero atoms selected from the group consisting of N, O and S, and wherein the overall compound has an essentially neutral pH.
  • the compounds according to the invention are potent and selective inhibitors of factor Xa versus other proteases of the coagulation cascade (e.g.
  • the compounds of the present invention are set forth below as preferred embodiments and include all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
  • compounds are provided which are useful as diagnostic reagents.
  • the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier.
  • the present invention includes methods comprising using the above compounds and pharmaceutical compositions for preventing or treating disease states characterized by undesired thrombosis or disorders of the blood coagulation process in mammals, or for preventing coagulation in stored blood products and samples.
  • the methods of this invention comprise administering the pharmaceutical composition in combination with an additional therapeutic agent such as an antithrombotic and/or a thrombolytic agent and/or an anticoagulant.
  • the preferred compounds also include their pharmaceutically acceptable isomers, hydrates, solvates, salts and prodrug derivatives.
  • alkenyl refers to a trivalent straight chain or branched chain unsaturated aliphatic radical.
  • alkinyl (or “alkynyl”) refers to a straight or branched chain aliphatic radical that includes at least two carbons joined by a triple bond. If no number of carbons is specified alkenyl and alkinyl each refer to radicals having from 2-12 carbon atoms.
  • alkyl refers to saturated aliphatic groups including straight-chain, branched-chain and cyclic groups having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms.
  • cycloalkyl refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms and preferably 3 to 7 carbon atoms.
  • the terms "carbocyclic ring structure " and " C 3- ⁇ 6 carbocyclic mono, bicyclic or tricyclic ring structure” or the like are each intended to mean stable ring structures having only carbon atoms as ring atoms wherein the ring structure is a substituted or unsubstituted member selected from the group consisting of: a stable monocyclic ring which is an aromatic ring ("aryl") having six ring atoms; a stable monocyclic non-aromatic ring having from 3 to 7 ring atoms in the ring; a stable bicyclic ring structure having a total of from 7 to 12 ring atoms in the two rings wherein the bicyclic ring structure is selected from the group consisting of ring structures in which both of the rings are aromatic, ring structures in which one of the rings is aromatic and ring structures in which both of the rings are non-aromatic; and a stable tricyclic ring structure having a total of from 10 to 16 atoms in the three
  • non-aromatic rings when present in the monocyclic, bicyclic or tricyclic ring structure may independently be saturated, partially saturated or fully saturated.
  • carbocyclic ring structures include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
  • the ring structures described herein may be attached to one or more indicated pendant groups via any carbon atom which results in a stable structure.
  • substituted as used in conjunction with carbocyclic ring structures means that hydrogen atoms attached to the ring carbon atoms of ring structures described herein may be substituted by one or more of the substituents indicated for that structure if such substitution(s) would result in a stable compound.
  • aryl which is included with the term “carbocyclic ring structure” refers to an unsubstituted or substituted aromatic ring, substituted with one, two or three substituents selected from loweralkoxy, loweralkyl, loweralkylamino, hydroxy, aminoloweralkyl, hydroxyloweralkyl, halogen, cyano, hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl, carboalkoxy and carboxamide, including but not limited to carbocyclic aryl, heterocyclic aryl, and biaryl groups and the like, all of which may be optionally substituted.
  • Preferred aryl groups include phenyl, halophenyl, loweralkylphenyl, napthyl, biphenyl, phenanthrenyl and naphthacenyl.
  • arylalkyl which is included with the term “carbocyclic aryl” refers to one, two, or three aryl groups having the number of carbon atoms designated, appended to an alkyl group having the number of carbon atoms designated. Suitable arylalkyl groups include, but are not limited to, benzyl, picolyl, naphthylmethyl, phenethyl, benzyhydryl, trityl, and the like, all of which may be optionally substituted.
  • heterocyclic ring or “heterocyclic ring system” is intended to mean a substituted or unsubstituted member selected from the group consisting of stable monocyclic ring having from 5-7 members in the ring itself and having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S; a stable bicyclic ring structure having a total of from 7 to 12 atoms in the two rings wherein at least one of the two rings has from 1 to 4 hetero atoms selected from N, O and S, including bicyclic ring structures wherein any of the described stable monocyclic heterocyclic rings is fused to a hexane or benzene ring; and a stable tricyclic heterocyclic ring structure having a total of from 10 to 16 atoms in the three rings wherein at least one of the three rings has from 1 to 4 hetero atoms selected from the group consisting of N, O and S.
  • heterocyclic ring or “heterocyclic ring system” include aromatic rings, as well as non-aromatic rings which can be saturated, partially saturated or fully saturated non-aromatic rings.
  • heterocyclic ring system includes ring structures wherein all of the rings contain at least one hetero atom as well as structures having less than all of the rings in the ring structure containing at least one hetero atom, for example bicyclic ring structures wherein one ring is a benzene ring and one of the rings has one or more hetero atoms are included within the term "heterocyclic ring systems” as well as bicyclic ring structures wherein each of the two rings has at least one hetero atom.
  • the ring structures described herein may be attached to one or more indicated pendant groups via any hetero atom or carbon atom which results in a stable structure.
  • substituted means that one or more of the hydrogen atoms on the ring carbon atom(s) or nitrogen atom(s) of the each of the rings in the ring structures described herein may be replaced by one or more of the indicated substituents if such replacement(s) would result in a stable compound.
  • Nitrogen atoms in a ring structure may be quaternized, but such compounds are specifically indicated or are included within the term "a pharmaceutically acceptable salt” for a particular compound.
  • the total number of O and S atoms in a single heterocyclic ring is greater than 1, it is preferred that such atoms not be adjacent to one another. Preferably, there are no more that 1 O or S ring atoms in the same ring of a given heterocyclic ring structure.
  • Examples of monocylic and bicyclic heterocylic ring systems, in alphabetical order, are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H- 1,5,2- dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolin
  • Preferred heterocyclic ring structures include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, IH-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocylic ring structures.
  • aromatic heterocyclic ring system has essentially the same definition as for the monocyclic and bicyclic ring systems except that at least one ring of the ring system is an aromatic heterocyclic ring or the bicyclic ring has an aromatic or non-aromatic heterocyclic ring fused to an aromatic carbocyclic ring structure.
  • halo or halogen as used herein refer to CI, Br, F or I substituents.
  • haloalkyl refers to an aliphatic carbon radicals having at least one hydrogen atom replaced by a CI, Br, F or I atom, including mixtures of different halo atoms.
  • Trihaloalkyl includes trifluoromethyl and the like as preferred radicals, for example.
  • methylene refers to -CH2-.
  • salts includes salts of compounds derived from the combination of a compound and an organic or inorganic acid. These compounds are useful in both free base and salt form. In practice, the use of the salt form amounts to use of the base form; both acid and base addition salts are within the scope of the present invention.
  • “Pharmaceutically acceptable acid addition salt” refers to salts retaining the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, trifluoroacetic
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.
  • Bio property for the purposes herein means an in vivo effector or antigenic function or activity that is directly or indirectly performed by a compound of this invention that are often shown by in vitro assays. Effector functions include receptor or ligand binding, any enzyme activity or enzyme modulatory activity, any carrier binding activity, any hormonal activity, any activity in promoting or inhibiting adhesion of cells to an extracellular matrix or cell surface molecules, or any structural role. Antigenic functions include possession of an epitope or antigenic site that is capable of reacting with antibodies raised against it.
  • carbon atoms bonded to four non-identical substituents are asymmetric. Accordingly, the compounds may exist as diastereoisomers, enantiomers or mixtures thereof.
  • the syntheses described herein may employ racemates, enantiomers or diastereomers as starting materials or intermediates. Diastereomeric products resulting from such syntheses may be separated by chromatographic or crystallization methods, or by other methods known in the art. Likewise, enantiomeric product mixtures may be separated using the same techniques or by other methods known in the art.
  • Each of the asymmetric carbon atoms when present in the compounds of this invention, may be in one of two configurations (R or S) and both are within the scope of the present invention.
  • the invention provides a compound of the formula (I): A-Q-D-E-G-J-X
  • A is selected from:
  • R 1 is selected from:
  • R 2 and R 3 are independently selected from the group consisting of: -H, -OR a , -N(-R a , -R b ), -C M alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -Co ⁇ alkylC ⁇ cycloalkyl, -Co- alkylphenyl and -Co ⁇ alkylnaphthyl, wherein from 1- 4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C alkyl-CN,
  • R 2 and R 3 taken together can form a 3-8 membered cycloalkyl or a heterocyclic ring system, wherein the heterocyclic ring system may have from 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo, Ci ⁇ alkyl-CN, -Cj. 4 alkyl, -C 2 . 6 alkenyl, -C 2-6 alkynyl, -C - 8 cycloalkyl, -Co ⁇ alkylC ⁇ scycloalkyl and -NO 2 ;
  • R a and R b are independently selected from the group consisting of -C M alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -Co- alkylC 3-8 cycloalkyl, or R a and R b can be taken together with a nitrogen atom to which they are attached to form a 3-8 heterocyclic ring sytem containing 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo, -CN, -C alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl,
  • n is an integer of 0-2;
  • Q is selected from the group consisting of:
  • R 4 is selected from the group consisting of: -H, -CF 3 , gcycloalkyl, -Co ⁇ alkylphenyl and -Co ⁇ alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, -C alkyl, -C ⁇ - ⁇ alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -Co ⁇ alkylC ⁇ scycloalkyl, -
  • D is selected from the group consisting of:
  • R la is selected from the group consisting of:
  • R 2a and R 3a are independently selected from the group consisting of:
  • Co ⁇ alkylphenyl and Co ⁇ alkylnaphthyl wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C ⁇ aHcyl, C 2- 6alkenyl, C 2-6 alkynyl, C 3- gcycloalkyl, Co ⁇ alkylC ⁇ scycloalkyl, -CN and -NO 2 ;
  • n is an integer of 0-2;
  • E is selected from the group consisting of:
  • q and x are independently an integer of 0-2;
  • R s and R 6 are independently selected from the group consisting of:
  • G is selected from the group consisting of:
  • R lb is independently selected from the group consisting of:
  • R lb when two R lb may be present on adjacent ring atoms of G and combine to form a benzene ring substituted with 0-4 R lb groups or a 5-6 membered aromatic or non-aromatic heterocyclic ring having 1-3 heteroatoms selected from N, O and S substituted with 0-4 R lb' groups;
  • R 2b and R 3b are independently selected from the group consisting of:
  • R lb is independently selected from the group consisting of:
  • R 2b and R 3b are independently selected from the group consisting of:
  • J is selected from the group consisting of:
  • y is an integer of 0-2;
  • R 7 is selected from the group consisting of:
  • X is selected from the group consisting of:
  • a fused heterobicyclic ring system wherein the ring system contains 1-3 heteroatoms selected from N, O and S and is substituted with 0-3 R lc groups;
  • z is an integer of 0-4;
  • R 2c and R 3c are independently selected from the group consisting of:
  • -Co- 6 alkylC 3-8 cycloalkyl and -Co- 6 alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety may be independently replaced with a member selected from the group consisting of halo, - S( O) 2 -OH, -CN, -CF 3 and -NO 2 ;
  • the invention also provides a compound of the formula (I):
  • A is selected from the group consisting of:
  • a 5-10 membered aromatic or non-aromatic heterocyclic ring system which may be a monocyclic ring system or a fused bicyclic ring system, wherein the heterocyclic ring system contains 1-4 heteroatoms selected from N, O and S and is substituted with 0-2 R 1 groups;
  • R 1 is independently selected from the group consisting of:
  • R 2 and R 3 are independently selected from the group consisting of:
  • R 2 and R 3 taken together can form a 3-8 membered cycloalkyl or a heterocyclic ring system, wherein the heterocyclic ring system may have from 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo, C ⁇ -C -alkyl-CN, -C M alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C -8 cycloalkyl, and -NO 2 ;
  • n is an integer of 0-2;
  • Q is selected from the group consisting of:
  • R 4 is selected from the group consisting of:
  • D is selected from the group consisting of: a direct link
  • a 5-10 membered aromatic or non-aromatic heterocyclic ring system which may be a monocyclic ring system or a fused bicyclic ring system, wherein the heterocyclic ring system contains 1-4 heteroatoms selected from N, O and S and the ring system is substituted with 0-2 R la groups;
  • R la is independently selected from the group consisting of:
  • n is an integer of 0-2;
  • R 2a and R 3a are independently selected from the group consisting of:
  • E is selected from the group consisting of:
  • R 5 and R 6 are each H, -C M alkyl, -C 2 . 6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, or -C 0- alkylC 3 .gcycloalkyl;
  • q and x are independently an integer of 0-2;
  • G is selected from the group consisting of:
  • phenyl which is substituted with 0-2 R lb groups; and a 5-6 membered aromatic and non-aromatic heterocyclic ring containing 1-4 hetero atoms selected from O, S and N, wherein the heterocyclic ring is substituted with 0-2 R lb groups;
  • R lb is independently selected from the group consisting of:
  • R lb when two R lb may be present on adjacent ring atoms of G and combine to form a benzene ring substituted with 0-4 R lb groups or a 5-6 membered aromatic or non-aromatic heterocyclic ring having 1-3 heteroatoms selected from N, O and S substituted with 0-4 R lb groups;
  • R 2b and R 3b are independently selected from the group consisting of:
  • R lb' is independently selected from the group consisting of:
  • R 2b and R 3b are independently selected from the group consisting of: -H, -C M alkyl and -C alkyl-(carbocyclic aryl);
  • J is selected from the group consisting of:
  • y is an integer of 0-2;
  • R 7 is selected from the group consisting of:
  • X is selected from the group consisting of:
  • a fused heterobicyclic ring system wherein the ring system contains 1-3 heteroatoms selected from N, O and S and is substituted with 0-3 R lc groups;
  • R Ic is independently selected from the group consisting of:
  • R >2c a. n .d r R>3c are independently selected from the group consisting of:
  • the present invention also provides compounds of the formula (I):
  • A is selected from the group consisting of:
  • Q is selected from the group consisting of:
  • D is selected from the group consisting of:
  • G is selected from the group consisting of:
  • R , 1b is independently selected from the group consisting of:
  • J is selected from the group consisting of:
  • X is selected from the group consisting of:
  • R is selected from the group consisting of-H, -CH and -CF 3 .
  • R and R are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lb is selected from the group consisting of-H, -CH 3 and CF 3 ;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 and -NH 2 .
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 and -NH 2
  • R i lal and J D Rla2 are independently selected from the group consisting of -H, -F, -CI and -Br;
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R and R are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lb is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lal and R la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lb is selected from the group consisting of -H, -CH 3 , -CF 3 , -CH 2 CH 3 , -CF 2 CF 3 , -CH 2 NH 2 , -CONH 2 , -SO 2 CH 3 , -SO 2 NH 2 , -NH 2 COCH 3 and -NH 2 COCF 3 ;
  • R lc2 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 ;
  • R lc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 .
  • R 1 is selected from the group consisting of -H, -NH 2 , -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , -CONH(CH 3 ), -CON(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R u is selected from the group consisting of -H, -NH 2 , -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , -CONH(CH 3 ), -CON(CH 3 ) 2) -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R and R , la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lb is selected from the group consisting of -H, -CH 3 , -CF 3 , -CH 2 CH 3 , -CF 2 CF 3 , -CH 2 NH 2 , -CONH 2 , -SO 2 CH 3 , -SO 2 NH 2 , -NH 2 COCH 3 and -NH 2 COCF 3 ;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 ;
  • R Ic3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 .
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , -CONH(CH 3 ), -CON(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R is selected from the group consisting of-H, -CH and -CF 3 ;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 ;
  • R is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 .
  • A is selected from the group consisting of:
  • R lal and R la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lb is selected from the group consisting of -H, -CH 3 , -CF 3 , -CH 2 CH 3 , -CF 2 CF 3 , -CH 2 NH 2 , -CONH 2 , -SO 2 CH 3 , -SO 2 NH 2 , -NH 2 COCH 3 and -NH 2 COCF 3 ;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH , and -NH 2 ;
  • R l 3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 .
  • A-Q is selected from the group consisting of:
  • R lal and R la2 are independently selected from the group consisting of -H, -F, -CI and -Br;
  • R lb is selected from the group consisting of -H, -CH 3 , -CF 3 , -CH 2 CH 3 , -CF 2 CF 3 , -CH 2 NH 2 , -CONH 2 , -SO 2 CH 3 , -SO 2 NH 2 , -NH 2 COCH 3 and -NH 2 COCF 3 ;
  • R lc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 .
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , -CONH(CH 3 ), -CON(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R l ib is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lal and R la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 ;
  • R lc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH , and -NH 2 ;
  • G is selected from the group consisting of:
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R , lb2 is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R , lb3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • A is selected from the group consisting of:
  • R lb is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lal and R la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 ;
  • R lc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 ;
  • G is selected from the group consisting of:
  • R lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb2 is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • A-Q is selected from the group consisting of:
  • R lb is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lal and R la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 ;
  • R lc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 ; and G is selected from the group consisting of:
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb2 is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , -CONH(CH 3 ), -CON(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R lb is selected from the group consisting of-H, -CH , -CF 3 ;
  • R ,c2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 ;
  • R lc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH , and -NH 2 .
  • A is selected from the group consisting of:
  • R lb is selected from the group consisting of-H, -CH and -CF 3 ;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH , and -NH 2 ;
  • R lc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 .
  • A-Q is selected from the group consisting of:
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 ;
  • R lc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 .
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , -CONH(CH 3 ), -CON(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R and R , la2 are independently selected from the group consisting of-H, -F, -CI and Br;
  • R lb is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R and R , la2 are independently selected from the group consisting of-H, -F, -CI and Br;
  • R , 1b is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 ;
  • R 1CJ is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 .
  • Table 19
  • R lal and R la2 are independently selected from the group consisting of-H, -F, -CI and Br;
  • R lb is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH , and -NH 2 ;
  • R lc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH , and -NH 2 .
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2) -CONH(CH 3 ), -CON(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R lal and R la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 ;
  • G is selected from the group consisting of:
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , -CONH(CH 3 ), -CON(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R and R , la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lc2 is selected from the group consisting of-CH 2 -, -O-, -NH-, -N(CH 3 )-, -CH 2 CH 2 -, -O- CH 2 -, -NH-CH 2 -, and -N(CH 3 )-CH 2 -;
  • R lc3 is selected from the group consisting of-CH 2 -, -O-, -NH-, -N(CH 3 )-, and -CH(NH 2 )- ;
  • G is selected from the group consisting of:
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ; and R . Ib3 ; is selected from the group consisting 6f-Cl, -NH 2 , -CH 3 and -CF 3 .
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , -CONH(CH 3 ), -CON(CH 3 ) 2> -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R and R , 132 are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R , lc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 ;
  • G is selected from the group consisting of:
  • R , lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF .
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , -CONH(CH 3 ), -CON(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R a and R are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lc2 and R lc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 ;
  • R , lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , -CONH(CH 3 ), -CON(CH 3 ) 2) -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R lal and R la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R . l , c C l 1 i • s selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH 2 NH 2 , -CH 2 OH, CONH 2 , -C( NH)NH 2 , -CO 2 H, -CO 2 Me, -SO 2 Me, -SO 2 NH 2 , -OH, -NH 2 , and -NO 2 ;
  • R lc2 is selected from the group consisting of-CH-, and -N-;
  • R lc3 is selected from the group consisting of -NH-, and -O-;
  • G is selected from the group consisting of:
  • R , lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R , lb2 is selected from the group consisting of-H, -CH and -CF 3 ;
  • R is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , -CONH(CH 3 ), -CON(CH 3 ) 2 ,-CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R and R , la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lc2 is selected from the group consisting of -CH 2 -, -O- and -NH-;
  • R lc3 is selected from the group consisting of-CH-, -C(NH 2 )- and -N-;
  • G is selected from the group consisting of:
  • R , lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R , lb2 is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • A is selected from the group consisting of:
  • R and R are independently selected from the group consisting of -H, -F, -CI and -Br;
  • R is selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 ;
  • G is selected from the group consisting of:
  • R lbl is selected from the group consisting of-H, -CH 3 and -CF 3
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb3 is selected from the group consisting of-Cl, -NH , -CH 3 and -CF 3 .
  • A-Q is selected from the group consisting of: ⁇ _r_ ⁇ -y ⁇ _ ⁇ - QT- ⁇ -T CM"- CM S -
  • R and R are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 ;
  • R lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R Ib2 is selected from the group consisting of-H, -CH and -CF 3 ;
  • R lb3 is selected from the group consisting of-Cl, -NH 2 , -CH and -CF 3 .
  • A is selected from the group consisting of:
  • R and R , la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 ;
  • G is selected from the group consisting of:
  • R lb2 is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • A-Q is selected from the group consisting of:
  • R lal and R l 2 are independently selected from the group consisting of -H, -F, -CI and -Br;
  • R lc2 is selected from the group consisting of-CH 2 -, -O-, -NH-, -N(CH 3 )-, -CH 2 CH 2 -, -O- CH 2 -, -NH-CH2-, and -N(CH 3 )-CH 2 -;
  • R lc3 is selected from the group consisting of -CH 2 -, -O-, -NH-, -N(CH 3 )-, and -CH(NH 2 )- ; and G is selected from the group consisting of:
  • R lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb2 is selected from the group consisting of-H, -CH and -CF 3 ;
  • R , lb3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • A is selected from the group consisting of:
  • R and R are independently selected from the group consisting of -H, -F, -CI and -Br;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH ;
  • G is selected from the group consisting of:
  • R lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb2 is selected from the group consisting of-H, -CH 3 and -CF 3 ; and R is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • R lal and R la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH2;
  • R lc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH 3 , and -NH 2 ; and G is selected from the group consisting of:
  • R lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb2 is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • A is selected from the group consisting of:
  • R and R are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 ;
  • G is selected from the group consisting of:
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R , lb3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • A is selected from the group consisting of:
  • R a and R , la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R is selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 ;
  • G is selected from the group consisting of:
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • A-Q is selected from the group consisting of:
  • R and R are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 ; and G is selected from the group consisting of:
  • R lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb2 is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • A-Q is selected from the group consisting of:
  • A is selected from the group consisting of:
  • R and R are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lc2 and R lc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 ;
  • G is selected from the group consisting of:
  • R lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb2 is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • A-Q is selected from the group consisting of:
  • A is selected from the group consisting of:
  • R and R , la2 are independently selected from the group consisting of -H, -F, -CI and -Br;
  • R lc3 is selected from the group consisting of-CH-, -C(NH 2 )- and -N-;
  • G is selected from the group consisting of:
  • R lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb2 is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF . Table 37
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , CONH(CH 3 ), -CON(CH 3 ) 2> -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R la is selected from the group consisting of-H, -F, -CI and -Br;
  • R Ibl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb2 is selected from the group consisting of-Cl, -NH 2 , -CH and -CF ;
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , CONH(CH 3 ), -CON(CH 3 ) 2, -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R la is selected from the group consisting of-H, -F, -CI and -Br;
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb2 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 ;
  • R lc2 is selected from the group consisting of-H, -F, -CI and -Br; and R lc3 is selected from the group consisting of-H and -NH2.
  • A-Q is selected from the group consisting of:
  • A is selected from the group consisting of:
  • R l is selected from the group consisting of-H, -F, -CI and -Br;
  • R , lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF ;
  • R is selected from the group consisting of-H, -F, -CI and -Br;
  • A-Q is selected from the group consisting of:
  • A is selected from the group consisting of: H . H _ H _ Me
  • R is selected from the group consisting of-H, -F, -CI and -Br;
  • R lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb2 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 ;
  • R lc3 is selected from the group consisting of-H and -NH 2 .
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , CONH(CH 3 ), -CON(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R la is selected from the group consisting of-H, -F, -CI and -Br;
  • R lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R , lb2 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 ;
  • R lcl is selected from the group consisting of-H, -F, -CN, -CH 2 NH 2 , -CONH 2 , -SO 2 Me, - SO 2 NH 2 and -NO 2 ;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br and -OCH 3 ;
  • Table 42
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , CONH(CH 3 ), -CON(CH 3 ) 2) -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R la is selected from the group consisting of-H, -F, -CI and -Br;
  • R lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb2 is selected from the group consisting of-Cl, -NH 2 , -CH and -CF 3 ;
  • R ,cl is selected from the group consisting of-H, -F, -CN, -CH 2 NH 2 , -CONH 2 , -SO 2 Me, - SO 2 NH 2 and -NO 2 ;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br and -OCH 3 ;
  • A-Q is selected from the group consisting of: c ⁇ c ⁇ Me cv Et cy cy cy c ⁇ c ⁇ Me c ⁇ Et
  • A is selected from the group consisting of:
  • R la is selected from the group consisting of -H, -F, -CI and -Br;
  • R lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb2 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF ;
  • R lcl is selected from the group consisting of-H, -F, -CN, -CH 2 NH 2 , -CONH 2 , -SO 2 Me, - SO 2 NH 2 and -NO 2 ;
  • R lc2 is selected from the group consisting of-H, -F, -CI, -Br and -OCH 3 ;
  • A-Q is selected from the group consisting of:
  • A is selected from the group consisting of:
  • R la is selected from the group consisting of-H, -F, -CI and -Br;
  • R Ibl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb2 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF ;
  • R lcl is selected from the group consisting of-H, -F, -CN, -CH 2 NH 2 , -CONH 2 , -SO 2 Me, - SO 2 NH 2 and -NO 2 ;
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , CONH(CH 3 ), -CON(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R and R are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R !c2 and R lc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 ;
  • G is selected from the group consisting of: wherein:
  • R , lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R , lb3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , - CONH(CH 3 ), -CON(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R and R are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lc2 and R lc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 ;
  • G is selected from the group consisting of: wherein:
  • R lb2 is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lb3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • A-Q is selected from the group consisting of: c ⁇ c ⁇ Me cy Et cy c ⁇ c ⁇ c ⁇ Me
  • A is selected from the group consisting of:
  • R and R , la a 2 2 are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lc2 and R lc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 ;
  • G is selected from the group consisting of:
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R is selected from the group consisting of-H, -CH and -CF 3 ;
  • A-Q is selected from the group consisting of:
  • A is selected from the group consisting of:
  • H r- H V H V M >i- Mi V- Ef >- O N - O N - C N - C N -
  • R and R , la2 are independently selected from the group consisting of -H, -F, -CI and -Br;
  • R lc2 and R Ic3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 ;
  • G is selected from the group consisting of:
  • R , lb2 is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • A-Q is selected from the group consisting of:
  • A is selected from the group consisting of:
  • R and R , la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
  • R lc2 and R lc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 ;
  • G is selected from the group consisting of:
  • R , lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 .
  • R 1 is selected from the group consisting of -SO 2 NH 2 , -SO 2 CH 3 , -CN, -CONH 2 , - CONH(CH 3 ), -CON(CH 3 ) 2j -CH 2 NH 2 , -CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ;
  • R , 1a is selected from the group consisting of-H, -F, -CI and -Br;
  • R is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lc2 and R lc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 .
  • Table 51
  • R l is selected from the group consisting of-H, -F, -CI and -Br;
  • R lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lc2 and R lc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH 3 .
  • Table 52
  • A-Q is selected from the group consisting of:
  • N > — N— C — H HN. — ⁇ /— .NN — MM ⁇ —— N N. ,NN — ..X — Ni fl HNI N I — MMee— N N — Nl ⁇ N
  • A is selected from the group consisting of:
  • R la is selected from the group consisting of-H, -F, -CI and -Br;
  • R lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R Ic2 and R lc3 are independently selected from the group consisting of-H, -F, -CI, -Br and -OCH 3 .
  • A-Q is selected from the group consisting of:
  • R lbl is selected from the group consisting of-H, -CH 3 and -CF 3 ;
  • R lc2 and R lc3 are independently selected from the group consisting of-H, -F, -CI, -Br and -OCH 3 .
  • R is selected from the group consisting of:
  • R a is selected from the group consisting of: -H, -F, -CI and -Br;
  • R lb is selected from the group consisting of:
  • R lcl is selected from the group consisting of:
  • R lc2 is selected from the group consisting of:
  • R lc3 is selected from the group consisting of:
  • R 1 is selected from the group consisting of:
  • R la is selected from the group consisting of:
  • R lb is selected from the group consisting of:
  • R lcl is selected from the group consisting of:
  • R is selected from the group consisting of:
  • R is selected from the group consisting of:
  • R is selected from the group consisting of:
  • R la is selected from the group consisting of: -H, -F, -CI and -Br;
  • R is selected from the group consisting of:
  • R lcl is selected from the group consisting of:
  • R lc2 is selected from the group consisting of:
  • R lc3 is selected from the group consisting of:
  • R is selected from the group consisting of:
  • R la is selected from the group consisting of:
  • R lb is selected from the group consisting of:
  • R lc is selected from the group consisting of:
  • R 1 is selected from the group consisting of:
  • R la is selected from the group consisting of:
  • R lb is selected from the group consisting of: -CH 3 , -CF 3 , -CH 2 CH 3 , -SO 2 Me, -CONH 2 and -NHSO 2 Me;
  • R lcl is selected from the group consisting of:
  • R lc2 and R lc3 are independently selected from the group consisting of:
  • A-Q is selected from the group consisting of:
  • A is selected from the group consisting of:
  • R la is selected from the group consisting of-H, -F, -CI and -Br;
  • R lb is selected from the group consisting of:
  • R lcl is selected from the group consisting of:
  • R lc2 is selected from the group consisting of:
  • A-Q is selected from the group consisting of:
  • A is selected from the group consisting of:
  • R la is selected from the group consisting of:
  • R lb is selected from the group consisting of:
  • R lcl is selected from the group consisting of:
  • R lc2 is selected from the group consisting of:
  • R lc3 is selected from the group consisting of:
  • R la is selected from the group consisting of:
  • R is selected from the group consisting of:
  • R lcl is selected from the group consisting of:
  • R is selected from the group consisting of:
  • R , lc3 is selected from the group consisting of:
  • R la is selected from the group consisting of:
  • R lb is selected from the group consisting of:
  • R lcl is selected from the group consisting of:
  • R lc2 is selected from the group consisting of:
  • R lc3 is selected from the group consisting of:

Abstract

Compounds of formula A Q D E G J X in which D is a direct link, a substituted or unsubsituted phenyl or naphtyl gourp or a heterocyclic ring system; G is substituted or unsubstituted phenyl or a heterocyclic ring system; X is a substituted or unsubstituted phenyl or naphtyl group or a heterocyclic ring system; and the other variables are as defined in the claims, their salts and compositions related thereto having activity against mammalian factor Xa are disclosed, The compounds are useful in vitro or in vivo for preventing or treating coagulation disorders.

Description

INHIBITORS OF FACTOR Xa
Cross Reference to Related Applications
This application claims benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 60/154,332 filed on September 17, 1999, which is herein incorporated in its entirety by reference.
Field of the Invention
This invention relates to novel compounds which are potent and highly selective inhibitors of isolated factor Xa or when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa versus other proteases of the coagulation (e.g. thrombin, fVIIa, flXa) or the fibrinolytic cascades (e.g. plasminogen activators, plasmin). In another aspect, the present invention relates to novel non-amidino-containing compounds, their pharmaceutically acceptable salts, and pharmaceutically acceptable compositions thereof which are useful as potent and specific inhibitors of blood coagulation in mammals. In yet another aspect, the invention relates to methods for using these inhibitors as therapeutic agents for disease states in mammals characterized by coagulation disorders.
Background of the Invention
Hemostasis, the control of bleeding, occurs by surgical means, or by the physiological properties of vasoconstriction and coagulation. This invention is particularly concerned with blood coagulation and ways in which it assists in maintaining the integrity of mammalian circulation after injury, inflammation, disease, congenital defect, dysfunction or other disruption. Although platelets and blood coagulation are both involved in thrombus formation, certain components of the coagulation cascade are primarily responsible for the amplification or acceleration of the processes involved in platelet aggregation and fibrin deposition.
Thrombin is a key enzyme in the coagulation cascade as well as in hemostasis. Thrombin plays a central role in thrombosis through its ability to catalyze the conversion of fibrinogen into fibrin and through its potent platelet activation activity. Direct or indirect inhibition of thrombin activity has been the focus of a variety of recent anticoagulant strategies as reviewed by Claeson, G., "Synthetic Peptides and Peptidomimetics as Substrates and Inhibitors of Thrombin and Other Proteases in the Blood Coagulation System", Blood Coag. Fibrinol. 5_, 411-436 (1994). Several classes of anticoagulants currently used in the clinic directly or indirectly affect thrombin (i.e. heparins, low-molecular weight heparins, heparin-like compounds and coumarins).
A prothrombinase complex, including Factor Xa (a serine protease, the activated form of its Factor X precursor and a member of the calcium ion binding, gamma carboxyglutamyl (Gla)-containing, vitamin K dependent, blood coagulation glycoprotein family), converts the zymogen prothrombin into the active procoagulant thrombin. Unlike thrombin, which acts on a variety of protein substrates as well as at a specific receptor, factor Xa appears to have a single physiologic substrate, namely prothrombin. Since one molecule of factor Xa may be able to generate up to 138 molecules of thrombin (Elodi et al., Thromb. Res. 15, 617-619 (1979)), direct inhibition of factor Xa as a way of indirectly inhibiting the formation of thrombin may be an efficient anticoagulant strategy. Therefore, it has been suggested that compounds which selectively inhibit factor Xa may be useful as in vitro diagnostic agents, or for therapeutic administration in certain thrombotic disorders, see e.g., WO 94/13693.
Polypeptides derived from hematophagous organisms have been reported which are highly potent and specific inhibitors of factor Xa. United States Patent 4,588,587 describes anticoagulant activity in the saliva of the Mexican leech, Haementeria officinalis. A principal component of this saliva was shown to be the polypeptide factor Xa inhibitor, antistasin (ATS), by Nutt, E. et al, "The Amino Acid Sequence of Antistasin, a Potent Inhibitor of Factor Xa Reveals a Repeated Internal Structure", J. Biol. Chem., 263, 10162-10167 (1988). Another potent and highly specific inhibitor of Factor Xa, called tick anticoagulant peptide (TAP), has been isolated from the whole body extract of the soft tick Ornithidoros moubata, as reported by Waxman, L., et al, "Tick Anticoagulant Peptide (TAP) is a Novel Inhibitor of Blood Coagulation Factor Xa" Science, 24g, 593-596 (1990).
Factor Xa inhibitory compounds which are not large polypeptide-type inhibitors have also been reported including: Tidwell, R.R. et al, "Strategies for Anticoagulation With Synthetic Protease Inhibitors. Xa Inhibitors Versus Thrombin Inhibitors", Thromb. Res., 19_, 339-349 (1980); Turner, A.D. et al, "p-Amidino Esters as Irreversible Inhibitors of Factor IXa and Xa and Thrombin", Biochemistry, 25, 4929-4935 (1986); Hitomi, Y. et al, "Inhibitory Effect of New Synthetic Protease Inhibitor (FUT-175) on the Coagulation System", Haemostasis, 15, 164-168 (1985); Sturzebecher, J. et al, "Synthetic Inhibitors of Bovine Factor Xa and Thrombin. Comparison of Their Anticoagulant Efficiency", Thromb. Res., 54, 245-252 (1989); Kam, CM. et al, "Mechanism Based Isocoumarin Inhibitors for Trypsin and Blood Coagulation Serine Proteases: New Anticoagulants", Biochemistry, 22, 2547-2557 (1988); Hauptmann, J. et al, "Comparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors", Thromb. Haemost., £3_, 220-223 (1990); and the like.
Others have reported Factor Xa inhibitors which are small molecule organic compounds, such as nitrogen containing heterocyclic compounds which have amidino substituent groups, wherein two functional groups of the compounds can bind to Factor Xa at two of its active sites. For example, WO 98/28269 describes pyrazole compounds having a terminal C(=NH)-NH2 group; WO 97/21437 describes benzimidazole compounds substituted by a basic radical which are connected to a naphthyl group via a straight or branched chain alkylene,-C(=O) or -S(=O)2 bridging group; WO 99/10316 describes compounds having a 4-phenyl-N-alkylamidino-piperidine and 4-phenoxy-N- alkylamidino-piperidine group connected to a 3-amidinophenyl group via a carboxamidealkyleneamino bridge; and EP 798295 describes compounds having a 4-phenoxy-N-alkylamidino-piperidine group connected to an amidinonaphthyl group via a substituted or unsubstituted sulfonamide or carboxamide bridging group.
There exists a need for effective therapeutic agents for the regulation of hemostasis, and for the prevention and treatment of thrombus formation and other pathological processes in the vasculature induced by thrombin such as restenosis and inflammation. In particular, there continues to be a need for compounds which selectively inhibit factor Xa or its precursors. Compounds are needed which selectively or preferentially bind to Factor Xa. Compounds with a higher affinity for binding to Factor Xa than to thrombin are desired, especially those compounds having good bioavailability or other pharmacologically desirable properties. Summary of the Invention
The present invention relates to novel compounds which inhibit factor Xa, their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, and pharmaceutically acceptable compositions thereof which have particular biological properties and are useful as potent and specific inhibitors of blood coagulation in mammals. In another aspect, the invention relates to methods of using these inhibitors as diagnostic reagents or as therapeutic agents for disease states in mammals characterized by undesired thrombosis which have coagulation disorders, such as in the treatment or prevention of any thrombotically mediated acute coronary or cerebro vascular syndrome, any thrombotic syndrome occurring in the venous system, any coagulopathy, and any thrombotic complications associated with extracorporeal circulation or instrumentation, and for the inhibition of coagulation in biological samples.
In certain embodiments, this invention relates to novel compounds which are potent and highly selective inhibitors of isolated factor Xa when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa versus other proteases of the coagulation cascade (e.g. thrombin, etc.) or the fibrinolytic cascade, and are useful as diagnostic reagents as well as antithrombotic agents.
In one embodiment, the present invention provides compounds comprising a five- membered heterocyclic ring structure having from 1-4 hetero atoms selected from the group consisting of N, O and S or a bicyclic ring system comprising the 5-membered heterocyclic ring structure wherein the bicyclic ring structure may have 1-5 hetero atoms selected from the group consisting of N, O and S, and wherein the overall compound has an essentially neutral pH. Preferably, a pH of about pH 5-8, more preferably, about pH 6-7.5 and most preferably, about pH 7.0. The compounds according to the invention are potent and selective inhibitors of factor Xa versus other proteases of the coagulation cascade (e.g. thrombin, etc.) or the fibrinolytic cascade, and are useful as diagnostic reagents as well as antithrombotic agents. Particular embodiments of the compounds of the present invention are set forth below as preferred embodiments and include all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof. In certain aspects of this invention, compounds are provided which are useful as diagnostic reagents. In another aspect, the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier. In yet another aspect, the present invention includes methods comprising using the above compounds and pharmaceutical compositions for preventing or treating disease states characterized by undesired thrombosis or disorders of the blood coagulation process in mammals, or for preventing coagulation in stored blood products and samples. Optionally, the methods of this invention comprise administering the pharmaceutical composition in combination with an additional therapeutic agent such as an antithrombotic and/or a thrombolytic agent and/or an anticoagulant.
The preferred compounds also include their pharmaceutically acceptable isomers, hydrates, solvates, salts and prodrug derivatives.
Detailed Description of the Invention
Definitions
In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
The term "alkenyl" refers to a trivalent straight chain or branched chain unsaturated aliphatic radical. The term "alkinyl" (or "alkynyl") refers to a straight or branched chain aliphatic radical that includes at least two carbons joined by a triple bond. If no number of carbons is specified alkenyl and alkinyl each refer to radicals having from 2-12 carbon atoms.
The term "alkyl" refers to saturated aliphatic groups including straight-chain, branched-chain and cyclic groups having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms. The term "cycloalkyl" as used herein refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms and preferably 3 to 7 carbon atoms. As used herein, the terms "carbocyclic ring structure " and " C3-ι6 carbocyclic mono, bicyclic or tricyclic ring structure" or the like are each intended to mean stable ring structures having only carbon atoms as ring atoms wherein the ring structure is a substituted or unsubstituted member selected from the group consisting of: a stable monocyclic ring which is an aromatic ring ("aryl") having six ring atoms; a stable monocyclic non-aromatic ring having from 3 to 7 ring atoms in the ring; a stable bicyclic ring structure having a total of from 7 to 12 ring atoms in the two rings wherein the bicyclic ring structure is selected from the group consisting of ring structures in which both of the rings are aromatic, ring structures in which one of the rings is aromatic and ring structures in which both of the rings are non-aromatic; and a stable tricyclic ring structure having a total of from 10 to 16 atoms in the three rings wherein the tricyclic ring structure is selected from the group consisting of: ring structures in which three of the rings are aromatic, ring structures in which two of the rings are aromatic and ring structures in which three of the rings are non-aromatic. In each case, the non-aromatic rings when present in the monocyclic, bicyclic or tricyclic ring structure may independently be saturated, partially saturated or fully saturated. Examples of such carbocyclic ring structures include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Moreover, the ring structures described herein may be attached to one or more indicated pendant groups via any carbon atom which results in a stable structure. The term "substituted" as used in conjunction with carbocyclic ring structures means that hydrogen atoms attached to the ring carbon atoms of ring structures described herein may be substituted by one or more of the substituents indicated for that structure if such substitution(s) would result in a stable compound.
The term "aryl" which is included with the term "carbocyclic ring structure" refers to an unsubstituted or substituted aromatic ring, substituted with one, two or three substituents selected from loweralkoxy, loweralkyl, loweralkylamino, hydroxy, aminoloweralkyl, hydroxyloweralkyl, halogen, cyano, hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl, carboalkoxy and carboxamide, including but not limited to carbocyclic aryl, heterocyclic aryl, and biaryl groups and the like, all of which may be optionally substituted. Preferred aryl groups include phenyl, halophenyl, loweralkylphenyl, napthyl, biphenyl, phenanthrenyl and naphthacenyl.
The term "arylalkyl" which is included with the term "carbocyclic aryl" refers to one, two, or three aryl groups having the number of carbon atoms designated, appended to an alkyl group having the number of carbon atoms designated. Suitable arylalkyl groups include, but are not limited to, benzyl, picolyl, naphthylmethyl, phenethyl, benzyhydryl, trityl, and the like, all of which may be optionally substituted.
As used herein, the term "heterocyclic ring" or "heterocyclic ring system" is intended to mean a substituted or unsubstituted member selected from the group consisting of stable monocyclic ring having from 5-7 members in the ring itself and having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S; a stable bicyclic ring structure having a total of from 7 to 12 atoms in the two rings wherein at least one of the two rings has from 1 to 4 hetero atoms selected from N, O and S, including bicyclic ring structures wherein any of the described stable monocyclic heterocyclic rings is fused to a hexane or benzene ring; and a stable tricyclic heterocyclic ring structure having a total of from 10 to 16 atoms in the three rings wherein at least one of the three rings has from 1 to 4 hetero atoms selected from the group consisting of N, O and S. Any nitrogen and sulfur atoms present in a heterocyclic ring of such a heterocyclic ring structure may be oxidized. Unless indicated otherwise the terms "heterocyclic ring" or "heterocyclic ring system" include aromatic rings, as well as non-aromatic rings which can be saturated, partially saturated or fully saturated non-aromatic rings. Also, unless indicated otherwise the term "heterocyclic ring system" includes ring structures wherein all of the rings contain at least one hetero atom as well as structures having less than all of the rings in the ring structure containing at least one hetero atom, for example bicyclic ring structures wherein one ring is a benzene ring and one of the rings has one or more hetero atoms are included within the term "heterocyclic ring systems" as well as bicyclic ring structures wherein each of the two rings has at least one hetero atom. Moreover, the ring structures described herein may be attached to one or more indicated pendant groups via any hetero atom or carbon atom which results in a stable structure. Further, the term "substituted" means that one or more of the hydrogen atoms on the ring carbon atom(s) or nitrogen atom(s) of the each of the rings in the ring structures described herein may be replaced by one or more of the indicated substituents if such replacement(s) would result in a stable compound. Nitrogen atoms in a ring structure may be quaternized, but such compounds are specifically indicated or are included within the term "a pharmaceutically acceptable salt" for a particular compound. When the total number of O and S atoms in a single heterocyclic ring is greater than 1, it is preferred that such atoms not be adjacent to one another. Preferably, there are no more that 1 O or S ring atoms in the same ring of a given heterocyclic ring structure.
Examples of monocylic and bicyclic heterocylic ring systems, in alphabetical order, are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H- 1,5,2- dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H- 1,2,5- thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. Preferred heterocyclic ring structures include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, IH-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocylic ring structures. As used herein the term "aromatic heterocyclic ring system" has essentially the same definition as for the monocyclic and bicyclic ring systems except that at least one ring of the ring system is an aromatic heterocyclic ring or the bicyclic ring has an aromatic or non-aromatic heterocyclic ring fused to an aromatic carbocyclic ring structure.
The terms "halo" or "halogen" as used herein refer to CI, Br, F or I substituents. The term "haloalkyl", and the like, refer to an aliphatic carbon radicals having at least one hydrogen atom replaced by a CI, Br, F or I atom, including mixtures of different halo atoms. Trihaloalkyl includes trifluoromethyl and the like as preferred radicals, for example.
The term "methylene" refers to -CH2-.
The term "pharmaceutically acceptable salts" includes salts of compounds derived from the combination of a compound and an organic or inorganic acid. These compounds are useful in both free base and salt form. In practice, the use of the salt form amounts to use of the base form; both acid and base addition salts are within the scope of the present invention.
"Pharmaceutically acceptable acid addition salt" refers to salts retaining the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.
"Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.
"Biological property" for the purposes herein means an in vivo effector or antigenic function or activity that is directly or indirectly performed by a compound of this invention that are often shown by in vitro assays. Effector functions include receptor or ligand binding, any enzyme activity or enzyme modulatory activity, any carrier binding activity, any hormonal activity, any activity in promoting or inhibiting adhesion of cells to an extracellular matrix or cell surface molecules, or any structural role. Antigenic functions include possession of an epitope or antigenic site that is capable of reacting with antibodies raised against it.
In the compounds of this invention, carbon atoms bonded to four non-identical substituents are asymmetric. Accordingly, the compounds may exist as diastereoisomers, enantiomers or mixtures thereof. The syntheses described herein may employ racemates, enantiomers or diastereomers as starting materials or intermediates. Diastereomeric products resulting from such syntheses may be separated by chromatographic or crystallization methods, or by other methods known in the art. Likewise, enantiomeric product mixtures may be separated using the same techniques or by other methods known in the art. Each of the asymmetric carbon atoms, when present in the compounds of this invention, may be in one of two configurations (R or S) and both are within the scope of the present invention.
Preferred Embodiments
The invention provides a compound of the formula (I): A-Q-D-E-G-J-X
wherein:
A is selected from:
(a) C.-Ce-alkyl;
(b) C3-C8-cycloalkyl;
(c) -N(R2,R3), -C(=NR2)-R3, -C(=NR2)N(R2,R3), -N(R3)-C(=NR2)N(R2, R3)-, and -N(R2)C(=NR3)-R2
(d) phenyl, which is independently substituted with 0-2 R1 substituents;
(e) naphthyl, which is independently substituted with 0-2 R1 substituents; and
(f) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to
10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R1 substituents;
R1 is selected from:
Halo, -CN, -C(=O)-N(R2, R3), -NO2, -SO2N(R2, R3), -SO2R2, -(CH2)mNR2R3, -
(CH2)m-C(=NR3)-R2, -(CH2)m-C(=NR2)-N(R2,R3), -(CH2)m-N(R2)-C(=NR2)- N(R2,R3), -(CH2)mNR2-C3-6heterocyclics,
Figure imgf000012_0001
C2-6alkenyl, C2-6alkynyl, C3- gcycloalkyl, Co^alkylC^scycloalkyl, -CF3, -OR2, and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic system may be independently replaced with a member selected from the group consisting of halo,
Figure imgf000012_0002
C1- alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, Co^alkylC3-8cycloalkyl and - NO2;
R2 and R3 are independently selected from the group consisting of: -H, -ORa, -N(-Ra, -Rb), -CMalkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -Co^alkylC^cycloalkyl, -Co- alkylphenyl and -Co^alkylnaphthyl, wherein from 1- 4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C alkyl-CN,
Figure imgf000013_0001
8cycloalkyl, -CN, and -NO2;
or R2 and R3 taken together can form a 3-8 membered cycloalkyl or a heterocyclic ring system, wherein the heterocyclic ring system may have from 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo, Ci^alkyl-CN, -Cj.4alkyl, -C2.6alkenyl, -C2-6alkynyl, -C - 8cycloalkyl, -Co^alkylC^scycloalkyl and -NO2;
Ra and Rb are independently selected from the group consisting of -CMalkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -Co- alkylC3-8cycloalkyl, or Ra and Rb can be taken together with a nitrogen atom to which they are attached to form a 3-8 heterocyclic ring sytem containing 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo, -CN, -C alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl,
Figure imgf000013_0002
m is an integer of 0-2;
Q is selected from the group consisting of:
a direct link, divalent -Cι- alkyl, divalent -C2-4alkenyl, divalent -C2-4alkynyl, -C(=O)-, -C(=NH)-, -C(=NMe)-, -N(-R4)-, -N(-R4)-CH2-, -C(=O)-N(-R4)-,
-N(-R4)-C(=O)-, -S(=O)2-, -O-, -S(=O)2-N(-R4)- and -N(-R4)-S(=O)2-, wherein one or more hydrogens on each of the divalent d- alkyl, divalent C2- alkenyl and divalent C2^alkynyl moieties can be replaced with a -R4 group;
R4 is selected from the group consisting of: -H, -CF3,
Figure imgf000014_0001
gcycloalkyl, -Co^alkylphenyl and -Co^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, -C alkyl, -C∑-βalkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -Co^alkylC^scycloalkyl, -
CN, -CF3, and -NO2;
D is selected from the group consisting of:
(a) a direct link;
(b) phenyl, which is independently substituted with 0-2 Rla substituents;
(c) naphthyl, which is independently substituted with 0-2 Rla substituents; and
(d) monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be subsituted from 0-2 Rla substituents;
Rla is selected from the group consisting of:
halo, Chalky!, C2-6alkenyl, C2.6alkynyl, C -8cycloalkyl, Co^alkylC^cycloalkyl, - CN, -NO2, (CH2)nNR2aR3a, SO2NR2aR3a, SO2R2a, CF3, OR2a, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, d^alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, Co^ lkyld. gcycloalkyl, -CN and -NO2;
R2a and R3a are independently selected from the group consisting of:
-H, C alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, Co- alkylC3-8cycloalkyl,
Co^alkylphenyl and Co^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C^aHcyl, C2-6alkenyl, C2-6alkynyl, C3-gcycloalkyl, Co^alkylC^scycloalkyl, -CN and -NO2;
n is an integer of 0-2;
E is selected from the group consisting of:
a direct link, -(CH2)q-C(=O)-, -(CH2)q-N(-R5)-C(=O)-(CH2)x-,
-(CH2)q-C(=O)-N(-R5)-(CH2)x-, -(CH2)q-N(-R5)-(CH2)x-, , -(CH2)q-N(R5)CO- NR6(CH2)X and -SO2-;
q and x are independently an integer of 0-2;
Rs and R6 are independently selected from the group consisting of:
H, -Cι-6alkyl, -Ci-βalkyloxy, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl,
-Co-6alkylC3-8cycloalkyl, -Cι-4alkyl-C(=O)-OH, -Co-6alkyl-(carbocyclic aryl), -Co- alkyl-(monocyclic heteroaryl) and -C alkyl-C(=O)-O-Cι-4alkyl, wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety and the monocyclic heteroaryl moieties may be independently replaced with a member selected from the group consisting of halo,
Figure imgf000015_0001
-C2-6alkenyl, -C2-6alkynyl, -
C3-8cycloalkyl, -C0- alkylC3.8cycloalkyl, -S(=O)2-OH, -CN, -CF3 and -NO2;
G is selected from the group consisting of:
phenyl, which is substituted with 0-2 Rlb groups; and
a 5-6 membered aromatic and non-aromatic heterocyclic ring containing 1-4 hetero atoms selected from N, O and S wherein the heterocyclic ring is substituted with 0-2 Rlb groups;
Rlb is independently selected from the group consisting of:
halo, -Ci-βalkyl, -C2-6alkenyl, -C2-6alkynyl, -C -8cycloalkyl,
-Co-6alkylC3-8cycloalkyl, -C alkyl-C(=O)-OH, -CN, -COOR2b, -CONR2bR3b, - NO2, -S(=O)2-OH, -N(-R2b, -R3b), -C(=O)-N(-R2b, -R3b), -S(=O)2-N(-R2b, -R3b), -
S(=O)2-R2b, -CF3, -O-R2b, -O-CH2-CH2-O-R2b, -O-CH2-C(=O)-O-R2b, -N(-R2b)-CH2-CH2-O-R2b, -N(-CH2-CH2-O-R2b)2, -N(-R2b)-C(=O)-R3b,
-N(-R2b)-S(=O)2-R3b, and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S substituted with 0-4 Rlb groups;
alternatively, when two Rlb may be present on adjacent ring atoms of G and combine to form a benzene ring substituted with 0-4 Rlb groups or a 5-6 membered aromatic or non-aromatic heterocyclic ring having 1-3 heteroatoms selected from N, O and S substituted with 0-4 Rlb' groups;
in a second alternative, one of the Rlb groups of G can cylize with the -N-R5 group of E to form a 5-7 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, which is subtituted with 0-4 Rlb groups, wherein two of the Rlb groups attached to the same ring carbon may form a (=O) group;
R2b and R3b are independently selected from the group consisting of:
-H, -Cι.6alkyl,
Figure imgf000016_0001
-C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -Co-6alkylC3-8cycloalkyl and -Co-6alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety may be independently replaced with a member selected from the group consisting of halo,
Figure imgf000016_0002
-C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -Co- alkylC3-8cycloalkyl, - S(=O)2-OH, -CN, -CF3 and -NO2;
Rlb is independently selected from the group consisting of:
halo, -Cι.6alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-gcycloalkyl,
-C0-6alkylC3-8cycloalkyl, -C alkyl-C(=O)-OH, -CN, -NO2, -S(=O)2-OH, -N(-R2b', -R3b'), -C(=O)-N(-R2b', -R3b'), -S(=O)2-N(-R2b', -R3b'), -S(=O)2-R2b', -CF3, -O-R2b', -O-CH2-CH2-O-R2b', -O-CH2-C(=O)-O-R2b', -N(-R2b')-CH2-CH2-O-R2b',
-N(-CH2-CH2-O-R2b')2, -N(-R b')-C(=O)-R3b' and -N(-R2b')-S(=O)2-R3b';
R2b and R3b are independently selected from the group consisting of:
-H, -Cι-6alkyl, -Cι-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -C3-gcycloalkyl, -Co-6alkylC3-8cycloalkyl and -Co-6alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety may be independently replaced with a member selected from the group consisting of halo, -C^aU yl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloakyl, -Co^alkylC3-8cycloalkyl, - S(=O)2-OH, -CN, -CF3 and -NO2;
J is selected from the group consisting of:
a direct link, -S(=O)2-, -C(=O)-, -N(-R7)-S(=O)2-, -C(=O)-N(-R7)-S(=O)2-,
-C(=O)-N(-R7)-(CH2)y-, -S(=O)2-N(-R7) -(CH2)y-, and -N(-R7)-C(=O)-(CH2)y-;
y is an integer of 0-2;
R7 is selected from the group consisting of:
-H, -C^alkyl, -C2-6alkenyl, -C2-6alkynyl, -C -8cycloalkyl, -Co-6alkylC -gcycloalkyl, -Cι-6alkyl-C(=O)-OH, -Cι-6alkyl-OH, -Cι-6alkyl-O-CMalkyl, -C0- 4alkyl-(carbocyclic aryl), -Co^alkyHmonocyclic or bicyclic heterocyclic ring system having from 0-4 heteroatoms selected from the group consisting of N, O and S), -CH2-C(=O)-O-C1-4alkyl and -CH2-C(=O)-O-Cι-4alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety or the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo, -C^aH yl, -C2-6alkenyl, -C2- 6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3-8cycloalkyl, -S(=O)2-OH, -CN, -CF3 and -NO2;
X is selected from the group consisting of:
phenyl, which is substituted with 0-3 Rlc groups;
naphthyl, which is substituted with 0-3 Rlc groups;
a 6-membered heteroaromatie ring containing from 1-2 nitrogen atoms, wherein the ring is substituted with 0-3 Rlc groups; and
a fused heterobicyclic ring system, wherein the ring system contains 1-3 heteroatoms selected from N, O and S and is substituted with 0-3 Rlc groups;
Rlc is independently selected from the group consisting of: halo, -CF3, -Cι-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-6alkylC3-gcycloalkyl, -CMalkyl-C(=O)-OH, -CF3, -CN, -NO2, -(CH2)Z-N(-R2c, -R3c), -C(=O)-N(-R2c, -R3c), -C(=NH)-N(-R2c, -R3c), -C(=NMe)-N(-R2c, -R3c), -S(=O)2-N(-R2c, -R3c), -S(=O)2-R2c, -S(=O)2-OH, -CF3, -O-R2c, -O(-CH2)z-O-R2c, -O(-CH2)z-C(=O)-O-R2c, -N(-R2c), -O(-CH2)z-O-R2c, -N[(-CH2)z-O-R2c]2,
-(CH2)z-N(-R2c)-C(=O)-R3c, -(CH2)z-N(-R2c)-S(=O)2-R3c, and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from , O and S;
z is an integer of 0-4;
R2c and R3c are independently selected from the group consisting of:
-H, -Cι-6alkyl, -Cuβalkyloxy, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl,
-Co-6alkylC3-8cycloalkyl and -Co-6alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety may be independently replaced with a member selected from the group consisting of halo,
Figure imgf000018_0001
- S(=O)2-OH, -CN, -CF3 and -NO2;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
The invention also provides a compound of the formula (I):
A-Q-D-E-G-J-X
wherein:
A is selected from the group consisting of:
-Ci-ealkyl and -C -8cycloalkyl;
phenyl, which is substituted with 0-2 R1 groups;
naphthyl, which is substituted with 0-2 R1 groups; and a 5-10 membered aromatic or non-aromatic heterocyclic ring system which may be a monocyclic ring system or a fused bicyclic ring system, wherein the heterocyclic ring system contains 1-4 heteroatoms selected from N, O and S and is substituted with 0-2 R1 groups;
R1 is independently selected from the group consisting of:
halo, -C alkyl, -CN, -NO2, -(CH2)m-N(-R2,-R3), -C(=O)-N(-R2,-R3), -S(=O)2-N(- R2,-R3), -S(=O)2-R2, -(CH2)m-C(=NR3)-R2, -(CH2)m-C(=NR2)-N(R2,R3), -(CH2)m- N(R2)-C(=NR2)-N(R2,R3), -CF3, -(CH2)m-O-R2 and a 5-6 membered aromatic heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;
R2 and R3 are independently selected from the group consisting of:
-H, -C alkyl,
or R2 and R3 taken together can form a 3-8 membered cycloalkyl or a heterocyclic ring system, wherein the heterocyclic ring system may have from 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo, Cι-C -alkyl-CN, -CMalkyl, -C2-6alkenyl, -C2-6alkynyl, -C -8cycloalkyl,
Figure imgf000019_0001
and -NO2;
m is an integer of 0-2;
Q is selected from the group consisting of:
a direct link, -Cι-4alkyl, -C2-4alkenyl, -C2-4alkynyl, -C(=O)-, -C(=NH)-, - C(=NMe)-, -N(-R4)-, -N(-R4)-CH2-, -C(=O)-N(-R4)-, -N(-R4)-C(=O)-, -S(=O)2-, - O-, -S(=O)2-N(-R4)- and -N(-R4)-S(=O)2-;
R4 is selected from the group consisting of:
-H, -CF3, -C alkyl,
D is selected from the group consisting of: a direct link;
phenyl, which is substituted with 0-2 Rla groups; and
a 5-10 membered aromatic or non-aromatic heterocyclic ring system which may be a monocyclic ring system or a fused bicyclic ring system, wherein the heterocyclic ring system contains 1-4 heteroatoms selected from N, O and S and the ring system is substituted with 0-2 Rla groups;
Rla is independently selected from the group consisting of:
halo, -CMalkyl, -CN, -NO2, -(CH2)„-N(-R2a, -R3a), -S(=O)2-N(-R2a, -R3a), -S(=O)2-R2a, -CF3, -(CH2)n-OR2a, -C(=O)-O-R2a, -C(=O)-N(-R2a, -R3a) and a 5-6 membered aromatic heterocyclic ring containing 1-4 heteroatoms selected from
N, O and S;
n is an integer of 0-2;
R2a and R3a are independently selected from the group consisting of:
-H, -CF3 and -CMalkyl,
E is selected from the group consisting of:
direct link, -(CH2)q-C(=O)-, -(CH2)q-N(-R5)-C(=O)-(CH2)x
-(CH2 V)q-C(=O)-N(-R5)-(CH2)x -(CH2)q-N(-R5)-(CH2)x-, -(CH2)q-N(R5)CO-
NR6(CH2)X- and -SO2-;
R5 and R6 are each H, -CMalkyl, -C2.6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, or -C0- alkylC3.gcycloalkyl;
q and x are independently an integer of 0-2;
G is selected from the group consisting of:
phenyl, which is substituted with 0-2 Rlb groups; and a 5-6 membered aromatic and non-aromatic heterocyclic ring containing 1-4 hetero atoms selected from O, S and N, wherein the heterocyclic ring is substituted with 0-2 Rlb groups;
Rlb is independently selected from the group consisting of:
halo, -CMalkyl, -CN, -NO2, -N(-R2b, -R3b), -C(=O)-N(-R2b, -R3b), -S(=O)2-N(-R2b,
-R3b), -S(=O)2-R2b, -CF3, -O-R2b, -O-CH2-CH2-O-R2b, -O-CH2-C(=O)-O-R2b, -N(-R2b)-CH2-CH2-O-R2b, -N(-CH2-CH2-O-R2b)2, -N(-R2b)-C(=O)-R3b,
-N(-R2b)-S(=O)2-R3b and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;
alternatively, when two Rlb may be present on adjacent ring atoms of G and combine to form a benzene ring substituted with 0-4 Rlb groups or a 5-6 membered aromatic or non-aromatic heterocyclic ring having 1-3 heteroatoms selected from N, O and S substituted with 0-4 Rlb groups;
in a second alternative, one of the Rlb groups of G can cylize with the -N-R5 group of E to form a 5-7 membered saturated, unsaturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, which is substituted with 0-4 Rlb' groups, wherein two of the Rlb groups attached to the same ring carbon may form a (=O) group;
R2b and R3b are independently selected from the group consisting of:
-H, -CF3, -CMalkyl and -C1- alkyl-(carbocyclic aryl);
Rlb' is independently selected from the group consisting of:
halo, -C alkyl, -CN, -NO2, -N(-R2b', -R3b'), -C(=O)-N(-R2b', -R3b'), -S(=O)2-N(- R2b', -R3b), -S(=O)2-R2b', -CF3, -O-R2b', -O-CH2-CH2-O-R2b', -O-CH2-C(=O)-O-R2b', -N(-R2b')-CH2-CH2-O-R2 ', -N(-CH2-CH2-O-R2b')2, -N(-R2b')-C(=O)-R3b', -N(-R2b')-S(=O)2-R3b';
R2b and R3b are independently selected from the group consisting of: -H, -CMalkyl and -C alkyl-(carbocyclic aryl);
J is selected from the group consisting of:
a direct link, -S(=O)2-, -C(=O)-, -N(-R7)-S(=O)2-, -C(=O)-N(-R7)-S(=O)2-, -C(=O)-N(-R7)-(CH2)y-, -S(=O)2-N(-R7)-, -(CH2)y- and -N(-R7)-C(=O)-(CH2)y-;
y is an integer of 0-2;
R7 is selected from the group consisting of:
-H, -CM lkyl, -C2-6alkenyl, -C2-6alkynyl, -Co- alkyl-(carbocyclic aryl), -Co^alkyl-^eterocyclic ring system), -CH2-C(=O)-O-Cι-4alkyl and -CH2-C(=O)-O-C alkyl-(carbocyclic aryl);
X is selected from the group consisting of:
phenyl, which is substituted with 0-3 Rlc groups; ,
naphthyl, which is substituted with 0-3 Rlc groups;
a 6-membered heteroaromatie ring containing from 1-2 nitrogen atoms, wherein the ring is substituted with 0-3 Rlc groups; and
a fused heterobicyclic ring system, wherein the ring system contains 1-3 heteroatoms selected from N, O and S and is substituted with 0-3 Rlc groups;
RIc is independently selected from the group consisting of:
halo, -CMalkyl, -CN, -NO2) -(CH2)Z-N(-R2c, -R3c), -C(=O)-N(-R2c, -R3c), -C(=NH)-N(-R2c, -R3c), -C(=NMe)-N(-R2c, -R3c), -S(=O)2-N(-R2c, -R3c), -S(=O)2- R2c, -S(=O)2-O\ -CF3, -O-R2c, -O-CH2-CH2-O-R2c, -O-CH2-C(=O)-O-R c,
-N(-R2c)-CH2-CH2-O-R2c, -N(-CH2-CH2-O-R2c)2, -(CH2)z-N(-R2c)-C(=O)-R3c, -(CH2)z-N(-R2c)-S(=O)2-R3c, and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;
z is an integer of 0-2; R >2c a. n .d r R>3c are independently selected from the group consisting of:
-H, -CMalkyl and -CMalkyl-(carbocyclic aryl);
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
The present invention also provides compounds of the formula (I):
A-Q-D-E-G-J-X
wherein:
A is selected from the group consisting of:
Figure imgf000023_0001
C e2NH2C Mβ2N H2N
•b- - - to- to-
Figure imgf000023_0002
Figure imgf000023_0003
o°'MN- s'MN-
Figure imgf000024_0001
Figure imgf000024_0002
f N— Me-N N— Mθ-N > — HN N— H
Figure imgf000024_0003
Et, Et, Me,
°^CN- N" Q" N" <γN- [ " N ~ N— N— ,N—
Me' Et' H
Me Me Mβ -
Figure imgf000024_0004
D- Q- Me - Me J ό- - ό- iV
Figure imgf000024_0005
Q is selected from the group consisting of:
a direct link, -C(=NH), -C(=NMe)-, -C(=O)-, -CH2-, -NH-, -N(-CH3)-, -O-, -NH- CH2-, -CH2-NH-, -N(-CH3)-CH2-, and -CH2-N(-CH3)-;
D is selected from the group consisting of:
Figure imgf000025_0001
Me. Me
— y~ S — - - ~~ M- -M^- " NI — — N "N ~~
Figure imgf000025_0002
E is selected from the group consisting of:
a direct link, -NH-C(=O)-, -N(-CH3)-C(=O)-, -N(-CH2CO2H)-C(=O)-, C(=O)-NH-, -C(=O)-N(-CH3)-, -NH-CH2- and-CH2-NH-;
G is selected from the group consisting of:
Figure imgf000026_0001
R , 1b is independently selected from the group consisting of:
-H, -Me, -CF3, -F, -CI, -Br, -SO2Me, -CN, -CONH2, -CONMe2, -NH2, -NO2, -NHCOMe, -NHSO2Me, -CH2NH2 and -CO2H;
J is selected from the group consisting of:
a direct link, -NH-, -O-, -S(=O)2-, -S(=O)2-NH, -NH-S(=O)2-, -C(=O)-, -NH-C(=O)- and -C(=O)-NH-; X is selected from the group consisting of:
J J Me02S H2N02S" ^-^ 0,N
Figure imgf000027_0001
Br F CI Br ^ ^ CI ^* ^ Br ^ ^
Figure imgf000027_0002
^αcl-αBr ^xxF -iαcι π xBr -< o2o
Figure imgf000028_0001
*N
- too, -£αB, -W ^σcι ^σBr N-
Figure imgf000028_0002
H2NOC NC
-O -O -^O O* "O01 ^O6' " ^O e
Figure imgf000028_0003
N N N H2N02S Me02S Q2N cι Br 0Me - F -O ^ F
Figure imgf000028_0004
H2N0C
- -CI -Q-c,
Figure imgf000028_0005
Figure imgf000028_0006
Figure imgf000029_0001
Figure imgf000030_0001
°2N>=\
~ >=o -Q -Q O - H Me OMe
N
H2N
Figure imgf000030_0002
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
The compounds listed in the following 53 tables are an embodiment of the present invention:
Table 1
Figure imgf000034_0001
wherein:
R is selected from the group consisting of-H, -CH and -CF3.
Table 2
Figure imgf000034_0002
wherein:
R and R are independently selected from the group consisting of-H, -F, -CI and -Br; Rlb is selected from the group consisting of-H, -CH3 and CF3; and
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3 and -NH2.
Table 3
Figure imgf000035_0001
wherein:
R is selected from the group consisting of-H, -CH3 and -CF3; and
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3 and -NH2
Table 4
Figure imgf000036_0001
wherein:
R i lal and J D Rla2 are independently selected from the group consisting of -H, -F, -CI and -Br;
R is selected from the group consisting of-H, -CH3 and -CF3; and
Rlcl is selected from the group consisting of -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2.
Table 5
Figure imgf000037_0001
wherein:
R and R are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlb is selected from the group consisting of-H, -CH3 and -CF3; and
Rlc3 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH3 and -NH2.
Table 6
Figure imgf000038_0001
wherein:
Rlal and Rla2 are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlb is selected from the group consisting of -H, -CH3, -CF3, -CH2CH3, -CF2CF3, -CH2NH2, -CONH2, -SO2CH3, -SO2NH2, -NH2COCH3 and -NH2COCF3;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and
Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2. Table 7
Figure imgf000039_0001
wherein:
R1 is selected from the group consisting of -H, -NH2, -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
Ru is selected from the group consisting of -H, -NH2, -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2) -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
R and R , la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlb is selected from the group consisting of -H, -CH3, -CF3, -CH2CH3, -CF2CF3, -CH2NH2, -CONH2, -SO2CH3, -SO2NH2, -NH2COCH3 and -NH2COCF3;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and
RIc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2. Table 8
Figure imgf000040_0001
wherein:
R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
R is selected from the group consisting of-H, -CH and -CF3;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and
R is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2.
Table 9
Figure imgf000041_0001
wherein:
A is selected from the group consisting of:
Figure imgf000041_0002
Rlal and Rla2 are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlb is selected from the group consisting of -H, -CH3, -CF3, -CH2CH3, -CF2CF3, -CH2NH2, -CONH2, -SO2CH3, -SO2NH2, -NH2COCH3 and -NH2COCF3;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH , and -NH2; and
Rl 3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2.
Table 10
Figure imgf000042_0001
wherein:
A-Q is selected from the group consisting of:
Figure imgf000043_0001
r t±. o_r»- o-c*. < NH-τ*. < ' — 1^ ^ Q-E*-
Me
( /-\ —_T—H C* — HN r" ^ N — Me— N" -\ N — "\ V> — /" -\ N — HN rI λ N — Me— ri r Λ N-
Figure imgf000043_0002
02NH2 S02Me CONH2
Figure imgf000043_0005
Figure imgf000043_0004
Figure imgf000043_0006
Rlal and Rla2 are independently selected from the group consisting of -H, -F, -CI and -Br;
Rlb is selected from the group consisting of -H, -CH3, -CF3, -CH2CH3, -CF2CF3, -CH2NH2, -CONH2, -SO2CH3, -SO2NH2, -NH2COCH3 and -NH2COCF3;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and
Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2. Table 11
Figure imgf000044_0001
wherein:
R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
R l ib is selected from the group consisting of-H, -CH3 and -CF3;
Rlal and Rla2 are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2;
Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH , and -NH2; and
G is selected from the group consisting of:
Figure imgf000044_0002
wherein:
R is selected from the group consisting of-H, -CH3 and -CF3;
R , lb2 is selected from the group consisting of-H, -CH3 and -CF3; and
Figure imgf000045_0001
R , lb3 is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
wherein:
A is selected from the group consisting of:
Figure imgf000045_0002
Me Me
Figure imgf000045_0003
- CN- ~ C/~ Mβ DN
Figure imgf000045_0004
Rlb is selected from the group consisting of-H, -CH3 and -CF3;
Rlal and Rla2 are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2;
Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and
G is selected from the group consisting of:
Figure imgf000046_0001
wherein:
Rlbl is selected from the group consisting of-H, -CH3 and -CF3;
Rlb2 is selected from the group consisting of-H, -CH3 and -CF3; and
Rlb3 is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
Table 13
Figure imgf000046_0002
wherein:
A-Q is selected from the group consisting of:
Figure imgf000047_0001
/ ( "Λ — T—β H C2 — HN Γ N — Me—
Figure imgf000047_0002
Figure imgf000047_0003
Rlb is selected from the group consisting of-H, -CH3 and -CF3;
Rlal and Rla2 are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2;
Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and G is selected from the group consisting of:
Figure imgf000048_0001
wherein:
R is selected from the group consisting of-H, -CH3 and -CF3;
Rlb2 is selected from the group consisting of-H, -CH3 and -CF3; and
Rlb3 is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
Table 14
Figure imgf000048_0002
wherein: R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
Rlb is selected from the group consisting of-H, -CH , -CF3;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
R,c2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and
Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH , and -NH2.
Table 15
Figure imgf000050_0001
wherein: A is selected from the group consisting of:
Me
*V Me, — V4— <
\6 M Vi V Et I^N- t>:N —- <> ,N- < V NN —
Me'
Figure imgf000051_0001
D^- ~ ~ °2 ~ H ~ Mβ~NQ^
Figure imgf000051_0002
Rlb is selected from the group consisting of-H, -CH and -CF3;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH , and -NH2; and
Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2.
Table 16
Figure imgf000052_0001
wherein:
A-Q is selected from the group consisting of:
Figure imgf000053_0001
r C Mβ^ O*- O*- O*- c - } MeJte-
o-rM C>J-"-- ox*. r- Me - μ--
< \ y — N—β" C> — HN /~^ N — Me— N ^~\ N — H2 > — /^ N Ht ^i N — Me— h ^i N —
Figure imgf000053_0003
H * HN'c_ Mβ * HN*c~
Figure imgf000053_0002
Figure imgf000053_0004
R is selected from the group consisting of-H, -CH3 and -CF3;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and
Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2. Table 17
Figure imgf000054_0001
Table 17 (continued)
Figure imgf000055_0001
wherein:
R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
R and R , la2 are independently selected from the group consisting of-H, -F, -CI and Br;
Rlb is selected from the group consisting of-H, -CH3 and -CF3;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, CONHz, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
R is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and
Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2.
Table 18
Figure imgf000056_0001
Table 18 (continued)
Figure imgf000057_0001
wherein:
A is selected from the group consisting of:
Figure imgf000057_0002
R and R , la2 are independently selected from the group consisting of-H, -F, -CI and Br;
R , 1b is selected from the group consisting of-H, -CH3 and -CF3;
R,cI is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and
R1CJ is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2. Table 19
Figure imgf000058_0001
Table 19 (continued)
Figure imgf000059_0001
wherein:
A-Q is selected from the group consisting of:
Figure imgf000060_0001
Q- Q- - Me- ---
Figure imgf000060_0002
Figure imgf000060_0003
r t- - r x$- ry "^- ς x . -T-5- Q-Ts-
1 ~Λ y —7 N—" c, — H HNN N — Me— Λ .NN —— ..Γ y —Λ r N —~ HHCN — Me— N N —
Figure imgf000060_0004
Rlal and Rla2 are independently selected from the group consisting of-H, -F, -CI and Br;
Rlb is selected from the group consisting of-H, -CH3 and -CF3;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONHz, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH , and -NH2; and
Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH , and -NH2. Table 20
Figure imgf000061_0001
wherein:
R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2) -CONH(CH3), -CON(CH3)2, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
Rlal and Rla2 are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH3;
RIc3 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH3, -NH2, - CONH2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -C(=NH)NH2; and
G is selected from the group consisting of:
Figure imgf000061_0002
wherein:
Rlbl is selected from the group consisting of-H, -CH3 and -CF3;
R is selected from the group consisting of-H, -CH3 and -CF3;
Rlb3 is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3. Table 21
Figure imgf000062_0001
wherein:
R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
R and R , la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
R'cl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-CH2-, -O-, -NH-, -N(CH3)-, -CH2CH2-, -O- CH2-, -NH-CH2-, and -N(CH3)-CH2-;
Rlc3 is selected from the group consisting of-CH2-, -O-, -NH-, -N(CH3)-, and -CH(NH2)- ; and
G is selected from the group consisting of:
Figure imgf000062_0002
wherein:
R is selected from the group consisting of-H, -CH3 and -CF3;
R is selected from the group consisting of-H, -CH3 and -CF3; and R . Ib3 ; is selected from the group consisting 6f-Cl, -NH2, -CH3 and -CF3.
Table 22
Figure imgf000063_0001
wherein:
R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2> -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
R and R , 132 are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
R , lc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH3;
Rlc3 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH3, -NH2, -CONH2, -CH2NH2, -CH2NHCH3>-CH2N(CH3)2, -C(=NH)NH2; and
G is selected from the group consisting of:
Figure imgf000063_0002
wherein: R , lbl ; is selected from the group consisting of-H, -CH3 and -CF3;
R is selected from the group consisting of-H, -CH3 and -CF3; and
Rlb3 is selected from the group consisting of-Cl, -NH2, -CH3 and -CF .
Table 23
Figure imgf000064_0001
wherein:
R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
R a and R are independently selected from the group consisting of-H, -F, -CI and -Br; R'cl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 and Rlc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and
G is selected from the group consisting of:
Figure imgf000065_0001
wherein:
R , lbl is selected from the group consisting of-H, -CH3 and -CF3;
R is selected from the group consisting of-H, -CH3 and -CF3; and
R is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
Table 24
Figure imgf000065_0002
wherein: R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2) -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
Rlal and Rla2 are independently selected from the group consisting of-H, -F, -CI and -Br;
R . l,cCl1 i •s selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-CH-, and -N-;
Rlc3 is selected from the group consisting of -NH-, and -O-; and
G is selected from the group consisting of:
Figure imgf000066_0001
wherein:
R , lbl is selected from the group consisting of-H, -CH3 and -CF3;
R , lb2 is selected from the group consisting of-H, -CH and -CF3; and
R is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
Table 25
Figure imgf000067_0001
wherein:
R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2,-CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
R and R , la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
R'cl is selected from the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of -CH2-, -O- and -NH-;
Rlc3 is selected from the group consisting of-CH-, -C(NH2)- and -N-; and
G is selected from the group consisting of:
Figure imgf000067_0002
wherein: R , lbl is selected from the group consisting of-H, -CH3 and -CF3;
R , lb2 is selected from the group consisting of-H, -CH3 and -CF3; and
R is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
Table 26
Figure imgf000068_0001
wherein:
A is selected from the group consisting of:
Me ^ Me Et Me Et Et "\ /\ i
/N_ /N_ /N- N N-- NN-- V N-- [>- [>- <^N- <^N
Me Me Et
Figure imgf000068_0002
R and R are independently selected from the group consisting of -H, -F, -CI and -Br;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2) and -NO2;
R is selected from the group consisting of-H, -F, -CI, -Br, and -OCH3;
Rlc3 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH3, -NH2, -CONH2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -C(=NH)NH2; and
G is selected from the group consisting of:
Figure imgf000069_0001
wherein:
Rlbl is selected from the group consisting of-H, -CH3 and -CF3
R is selected from the group consisting of-H, -CH3 and -CF3; and
Rlb3 is selected from the group consisting of-Cl, -NH , -CH3 and -CF3.
Figure imgf000069_0002
wherein:
A-Q is selected from the group consisting of:
Figure imgf000070_0001
ζ _r_ ζ-yτ_ ς - QT- < -T CM"- CMS-
Me Me
Figure imgf000070_0002
/ < - —_ Nι—β H C —2 Hhi ^Λ — Me— N N — J — N /" - N — H I N — Me— ri
Me
Figure imgf000070_0003
R and R are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH3;
Rlc3 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH3, -NH2, -CONH2, -CH2NH2, -CH2NHCH3> -CH2N(CH3)2, -C(=NH)NH2; and G is selected from the group consisting of:
Figure imgf000071_0001
wherein:
Rlbl is selected from the group consisting of-H, -CH3 and -CF3;
RIb2 is selected from the group consisting of-H, -CH and -CF3; and
Rlb3 is selected from the group consisting of-Cl, -NH2, -CH and -CF3.
Table 28
Figure imgf000071_0002
wherein: A is selected from the group consisting of:
Figure imgf000072_0001
R and R , la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH3;
Rlc3 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH , -NH2, -CONH2, -CH2NH2, -CH2NHCH3> -CH2N(CH3)2, -C(=NH)NH2;
G is selected from the group consisting of:
Figure imgf000072_0002
wherein:
R is selected from the group consisting of-H, -CH and -CF3;
Rlb2 is selected from the group consisting of-H, -CH3 and -CF3; and
Rlb3 is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3. Table 29
Figure imgf000073_0001
wherein:
A-Q is selected from the group consisting of:
Figure imgf000074_0001
Vπiπ- »gy- M HN M .NN. — MM ..ee—— M Nti M N —
Figure imgf000074_0002
Figure imgf000074_0003
Rlal and Rl 2 are independently selected from the group consisting of -H, -F, -CI and -Br;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONHz, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-CH2-, -O-, -NH-, -N(CH3)-, -CH2CH2-, -O- CH2-, -NH-CH2-, and -N(CH3)-CH2-;
Rlc3 is selected from the group consisting of -CH2-, -O-, -NH-, -N(CH3)-, and -CH(NH2)- ; and G is selected from the group consisting of:
Figure imgf000075_0001
wherein:
Rlbl is selected from the group consisting of-H, -CH3 and -CF3;
Rlb2 is selected from the group consisting of-H, -CH and -CF3; and
R , lb3 is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
Table 30
Figure imgf000076_0001
wherein: A is selected from the group consisting of:
Figure imgf000077_0001
R and R are independently selected from the group consisting of -H, -F, -CI and -Br;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONHz, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH ;
Rlc3 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH3, -NH2, -CONH2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -C(=NH)NH2, -C(=NH)NH(CH3), -C(=NH)NH(CH3)2; and
G is selected from the group consisting of:
Figure imgf000077_0002
wherein:
Rlbl is selected from the group consisting of-H, -CH3 and -CF3;
Rlb2 is selected from the group consisting of-H, -CH3 and -CF3; and R is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
Table 31
Figure imgf000078_0001
wherein:
A-Q is selected from the group consisting of:
cy Et Q- cy c Qr Cr Me Ct Et-
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000079_0003
- rN—β H C2 — HN /^ N — Me— Ni -Λ N — J — NΪ ^ N — HN rI "^ N — Me— i ^\ N-
Figure imgf000079_0004
Rlal and Rla2 are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2;
Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and G is selected from the group consisting of:
Figure imgf000080_0001
wherein:
Rlbl is selected from the group consisting of-H, -CH3 and -CF3;
Rlb2 is selected from the group consisting of-H, -CH3 and -CF3; and
R is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
wherein:
Table 32
Figure imgf000080_0002
A is selected from the group consisting of:
Figure imgf000081_0001
R and R are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and
G is selected from the group consisting of:
Figure imgf000081_0002
wherein:
R is selected from the group consisting of-H, -CH3 and -CF3;
R is selected from the group consisting of-H, -CH3 and -CF3; and
R , lb3 ; is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3. wherein:
Table 33
Figure imgf000082_0001
A is selected from the group consisting of:
Figure imgf000082_0002
Me Me
Me→0N- O*- - CN- - CN~ "- -
MM ON- °GN- - o " Me— N N-
Figure imgf000082_0003
Figure imgf000082_0004
R a and R , la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
R is selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and
G is selected from the group consisting of:
Figure imgf000083_0001
wherein:
R is selected from the group consisting of-H, -CH3 and -CF3;
R is selected from the group consisting of-H, -CH3 and -CF3; and
R is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
Table 34
Figure imgf000084_0001
wherein:
A-Q is selected from the group consisting of:
Figure imgf000085_0001
y Me cy Et cy cy Qr Cr Me C Et
Figure imgf000085_0002
( ^ — N— C — HN N — Me— N N — f — " ft — HNI N — Me— N —
Figure imgf000085_0004
">" "*>" MβN Me3<? Me
S02NH2 S02NH2 S02Mθ S02Me CONH2
Figure imgf000085_0003
Figure imgf000085_0005
R and R are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and G is selected from the group consisting of:
Figure imgf000086_0001
wherein:
Rlbl is selected from the group consisting of-H, -CH3 and -CF3;
Rlb2 is selected from the group consisting of-H, -CH3 and -CF3; and
R is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
Table 35
Figure imgf000086_0002
wherein:
A-Q is selected from the group consisting of:
Figure imgf000087_0001
( z. ry - Qjf QC- r t- cμ*- cμ*-
Me Me
Figure imgf000087_0002
( / V y ——_ NN '—— CC " —> — HHNt{ ^ , NN —— MMee—— N N, N , NN —— H2 JJ ——_ h Ii N — HNI N — Me—i K
Me
Figure imgf000087_0003
wherein:
A is selected from the group consisting of:
H Me Et Me Et Et \ /\ A
H- H H >- M< /5- Me >- Et >- ϊ>- N- 0N- CN-
Me Me
Mβ→0N- ex- CN- ON- cx~ *- M°^ ~
D*- ~ *~ °ON~ H ~ *- *~
Figure imgf000087_0004
R and R are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, - CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 and Rlc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and
G is selected from the group consisting of:
Figure imgf000088_0001
wherein:
Rlbl is selected from the group consisting of-H, -CH3 and -CF3;
Rlb2 is selected from the group consisting of-H, -CH3 and -CF3; and
Rlb3 is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
Table 36
Figure imgf000089_0001
wherein:
A-Q is selected from the group consisting of:
y H
Figure imgf000090_0001
CrCrO c
Figure imgf000090_0002
αMe — Me N Mβ , — N Me /— N Me M Mee H
.... *- cμ Me cμ CM CM- cμ-
Figure imgf000090_0003
c *. *. c *- cμ*. c Me*- cμ-
Figure imgf000090_0004
wherein:
A is selected from the group consisting of:
Figure imgf000091_0001
Mβ-0N- CN- ό- O- CX~ - Mβ→G'
Figure imgf000091_0002
R and R , la2 are independently selected from the group consisting of -H, -F, -CI and -Br;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-CH2-, -O- and -NH-;
Rlc3 is selected from the group consisting of-CH-, -C(NH2)- and -N-; and
G is selected from the group consisting of:
Figure imgf000091_0003
wherein:
Rlbl is selected from the group consisting of-H, -CH3 and -CF3;
Rlb2 is selected from the group consisting of-H, -CH3 and -CF3; and
R is selected from the group consisting of-Cl, -NH2, -CH3 and -CF . Table 37
Figure imgf000092_0001
wherein:
R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, CONH(CH3), -CON(CH3)2> -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
Rla is selected from the group consisting of-H, -F, -CI and -Br;
RIbl is selected from the group consisting of-H, -CH3 and -CF3;
Rlb2 is selected from the group consisting of-Cl, -NH2, -CH and -CF ;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
R is selected from the group consisting of-H, -F, -CI and -Br; and R is selected from the group consisting of-H, -F, -CI and -Br.
Table 38
Figure imgf000093_0001
wherein:
R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, CONH(CH3), -CON(CH3)2,-CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
Rla is selected from the group consisting of-H, -F, -CI and -Br;
R is selected from the group consisting of-H, -CH3 and -CF3;
Rlb2 is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI and -Br; and Rlc3 is selected from the group consisting of-H and -NH2.
Table 39
Figure imgf000094_0001
wherein:
A-Q is selected from the group consisting of:
cr cμ Me c Et cy cyc cy Me
Figure imgf000095_0001
Figure imgf000095_0002
( N) — — C — HN N — Me— N N — ϊ — — HN , — Me— N N —
Figure imgf000095_0003
T A—" A— * — A-
M Mee- O T CCOONNHH-,j I CCHH22IN-H2 O N= - "H ^ Q
wherein:
A is selected from the group consisting of:
Figure imgf000095_0004
Me Me
MΘ N- CN_ CX- O4- C - ~ Mβ~0N~
M M>CX~ O"- ~ ^ HNCX~ Mθ→θ~
Figure imgf000095_0005
Rl is selected from the group consisting of-H, -F, -CI and -Br;
R , lbl is selected from the group consisting of-H, -CH3 and -CF3;
R is selected from the group consisting of-Cl, -NH2, -CH3 and -CF ;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
R is selected from the group consisting of-H, -F, -CI and -Br; and
R , lc3 is selected from the group consisting of-H, -F, -CI and -Br.
Table 40
Figure imgf000096_0001
wherein: A-Q is selected from the group consisting of:
cμ cμ Me cv Et cy cyc o- cμ Me cμ Et
Figure imgf000097_0001
jf c Me*1 cμv- cμ cμ cμ*-
Figure imgf000097_0002
Figure imgf000097_0003
/ ( Λ y — V—H C —. HN ^-\ N — Me—ti-\ N — H J — 1 /-\ N — HN rI^\ N — Me— N rl^ l>
Me
Figure imgf000097_0004
wherein:
A is selected from the group consisting of: H . H _ H _ Me
Figure imgf000098_0001
Figure imgf000098_0002
R is selected from the group consisting of-H, -F, -CI and -Br;
Rlbl is selected from the group consisting of-H, -CH3 and -CF3;
Rlb2 is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3;
Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, CONH2, -C(=NH)NH2, -CO2H, -CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI and -Br; and
Rlc3 is selected from the group consisting of-H and -NH2.
Table 41
Figure imgf000099_0001
wherein:
R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, CONH(CH3), -CON(CH3)2, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
Rla is selected from the group consisting of-H, -F, -CI and -Br;
Rlbl is selected from the group consisting of-H, -CH3 and -CF3;
R , lb2 is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3;
Rlcl is selected from the group consisting of-H, -F, -CN, -CH2NH2, -CONH2, -SO2Me, - SO2NH2 and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br and -OCH3; and
Rlc3 is selected from the group consisting of -H, -F, -CI, Br, -OCH3, -CH2NH2, -CONH2 and -C(N=H)NH2. Table 42
Figure imgf000100_0001
wherein:
R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, CONH(CH3), -CON(CH3)2)-CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
Rla is selected from the group consisting of-H, -F, -CI and -Br; Rlbl is selected from the group consisting of-H, -CH3 and -CF3;
Rlb2 is selected from the group consisting of-Cl, -NH2, -CH and -CF3;
R,cl is selected from the group consisting of-H, -F, -CN, -CH2NH2, -CONH2, -SO2Me, - SO2NH2 and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br and -OCH3; and
Rlc3 is selected from the group consisting of-H, -F, -CI, Br, -OCH3, -CH2NH2, -CONH2 and -C(N=H)NH2.
Figure imgf000101_0001
wherein:
A-Q is selected from the group consisting of: cμ cμ Me cv Et cy cy cy cμ cμ Me cμ Et
Figure imgf000102_0001
f z. ς Met- ςyz- c cμ- cμ*- cμ Me -
cμ*. c *- cμ- cμ- cμ Me1*- cμ-
( y — N— C — HN N — Me— N" N — J — N" N — Hti N — Me— Ki —
Figure imgf000102_0002
wherein:
A is selected from the group consisting of:
N — N-
H M Mi M Vi V Et ON- ON- O- <>
Figure imgf000103_0001
Figure imgf000103_0002
Figure imgf000103_0003
Rla is selected from the group consisting of -H, -F, -CI and -Br;
Rlbl is selected from the group consisting of-H, -CH3 and -CF3;
Rlb2 is selected from the group consisting of-Cl, -NH2, -CH3 and -CF ;
Rlcl is selected from the group consisting of-H, -F, -CN, -CH2NH2, -CONH2, -SO2Me, - SO2NH2 and -NO2;
Rlc2 is selected from the group consisting of-H, -F, -CI, -Br and -OCH3; and
Rlc3 is selected from the group consisting of-H, -F, -CI, Br, -OCH3, -CH2NH2, -CONH2 and -C(N=H)NH2.
Table 44
Figure imgf000104_0001
wherein: A-Q is selected from the group consisting of:
c^ cμ Mθ cμ Et cy cy cy cμ cμ Me cμ Et
Figure imgf000105_0001
( r y T N—ΘH C2 — HN /-^ N Mθ— hi N y —i f N HNI ^ N Me— N fi^Λ N
Figure imgf000105_0002
wherein:
A is selected from the group consisting of:
Figure imgf000106_0001
*-o- CN- X- CN- CX~ - Mβ~ N yy N — 0^ N — N — 02 N — HN N — Me— Nl N-
yr M yy yf- yy -
Rla is selected from the group consisting of-H, -F, -CI and -Br;
RIbl is selected from the group consisting of-H, -CH3 and -CF3;
Rlb2 is selected from the group consisting of-Cl, -NH2, -CH3 and -CF ;
Rlcl is selected from the group consisting of-H, -F, -CN, -CH2NH2, -CONH2, -SO2Me, - SO2NH2 and -NO2;
RIc2 is selected from the group consisting of-H, -F, -CI, -Br and -OCH3; and
Rlc3 is selected from the group consisting of-H, -F, -CI, Br, -OCH3, -CH2NH2, -CONH2 and -C(N=H)NH2.
Table 45
Figure imgf000107_0001
wherein:
R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, CONH(CH3), -CON(CH3)2, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
R and R are independently selected from the group consisting of-H, -F, -CI and -Br;
R!c2 and Rlc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and
G is selected from the group consisting of:
Figure imgf000108_0001
wherein:
R , lbl is selected from the group consisting of-H, -CH3 and -CF3;
R is selected from the group consisting of-H, -CH3 and -CF3; and
R , lb3 is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
Table 46
Figure imgf000109_0001
wherein:
R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, - CONH(CH3), -CON(CH3)2, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
R and R are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlc2 and Rlc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and
G is selected from the group consisting of:
Figure imgf000110_0001
wherein:
Rlbl is selected from the group consisting of-H, -CH3 and -CF3;
Rlb2 is selected from the group consisting of-H, -CH3 and -CF3; and
Rlb3 is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
Table 47
Figure imgf000110_0002
wherein:
A-Q is selected from the group consisting of: cμ cμ Me cy Et cy cμ cμ cμ cμ Me
Figure imgf000111_0001
Figure imgf000111_0002
ζy_ ryr. ryfL QX. c cμ*- cμr-
Me Me
Figure imgf000111_0003
Mβ— N Γl Λ N-
Figure imgf000111_0004
Figure imgf000111_0005
A is selected from the group consisting of:
H Me Et Me
N — N — N — I
Λ H H ' H 1 Me / M vi v Et ON- V- O- <6N-
Me
Me→C- CN- O*- 0- ON_ - Me→ N~
M M> "~ - ~ o ~ H ~ Mβ→CX
Figure imgf000111_0006
R and R , laa22 are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlc2 and Rlc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and
G is selected from the group consisting of:
Figure imgf000112_0001
wherein:
R is selected from the group consisting of-H, -CH3 and -CF3;
R is selected from the group consisting of-H, -CH and -CF3; and
Rlb3 is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
Table 48
Figure imgf000113_0001
wherein:
A-Q is selected from the group consisting of:
cμ cμ Me cμt cμ cμ cμ cμ c Me cμ Et
Figure imgf000114_0001
r t. ( z. ry - Q-t- ry Me- - cμ M«θ
Me Me cμ*. cμ*- cμ- cμ- cμ
Figure imgf000114_0002
Me*-
( X y —J N—*" C* — H HN ΓI Λ N — Me— Ni Λ N —
Figure imgf000114_0003
Figure imgf000114_0004
wherein:
A is selected from the group consisting of:
Me H. Me Et Me Et Et \ S X.
H r- H V H V M >i- Mi V- Ef >- ON- ON- CN- CN-
Mβ→0N_ N—
Figure imgf000114_0005
MΘ~ _/
Figure imgf000114_0006
R and R , la2 are independently selected from the group consisting of -H, -F, -CI and -Br;
Rlc2 and RIc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and
G is selected from the group consisting of:
Figure imgf000115_0001
wherein:
R , lbl is selected from the group consisting of-H, -CH and -CF3;
R , lb2 is selected from the group consisting of-H, -CH3 and -CF3; and
R is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
Table 49
Figure imgf000116_0001
wherein:
A-Q is selected from the group consisting of:
Figure imgf000117_0001
cμ Me cμ Et cy cy cy cμ cμ Me cμ Et
Figure imgf000117_0002
Mθ-t- c cμr c cμr- μ Me -
cμ*. cμ*- cμ*- cμ*1- cμ Me- cμ*-
y — N— C — ti N — Me— Ni N — y — Ni N — HNI N — Me— 1^ N —
Figure imgf000117_0003
wherein:
A is selected from the group consisting of:
Figure imgf000117_0004
Me Me
Λ — <X- CX- CX- CX- - - MA ~
I " N~ *- °2CN- HON_ X
Figure imgf000117_0005
R and R , la2 are independently selected from the group consisting of-H, -F, -CI and -Br;
Rlc2 and Rlc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and
G is selected from the group consisting of:
Figure imgf000118_0001
wherein:
R , lbl is selected from the group consisting of-H, -CH3 and -CF3;
R , lb2 i •s selected from the group consisting of-H, -CH3 and -CF3; and
R is selected from the group consisting of-Cl, -NH2, -CH3 and -CF3.
Table 50
Figure imgf000119_0001
wherein:
R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, - CONH(CH3), -CON(CH3)2j -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
R , 1a ; is selected from the group consisting of-H, -F, -CI and -Br;
R is selected from the group consisting of-H, -CH3 and -CF3; and
Rlc2 and Rlc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH3. Table 51
Figure imgf000120_0001
wherein:
R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, - CONH(CH3), -CON(CH3)2> -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2;
Rl is selected from the group consisting of-H, -F, -CI and -Br;
Rlbl is selected from the group consisting of-H, -CH3 and -CF3; and
Rlc2 and Rlc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH3. Table 52
Figure imgf000121_0001
wherein:
A-Q is selected from the group consisting of:
cμ cμ Me cμ Et cμ cμ cμ cμ cμ Mβ cμ Et
Figure imgf000122_0001
f t_ ς z. ft_ ςt. c cμ Me*- Cμ11-
Me Me
cμ*- cμ*. cμ*- cμ- cμ11*- cμ-
\
N> — N— C — H HN. — \ /— .NN — MMθθ—— N N. ,NN — ..X — Ni fl HNI N I — MMee— N N — Nl Λ N
Me w- HV_
Figure imgf000122_0002
wherein:
A is selected from the group consisting of:
Figure imgf000123_0001
M M>C>- "- X 02 ~ H ~ Mβ-NQ^
Figure imgf000123_0002
Rla is selected from the group consisting of-H, -F, -CI and -Br;
Rlbl is selected from the group consisting of-H, -CH3 and -CF3; and
RIc2 and Rlc3 are independently selected from the group consisting of-H, -F, -CI, -Br and -OCH3.
Table 53
Figure imgf000124_0001
wherein:
A-Q is selected from the group consisting of:
cμ cμ Me cμ Et cμ cμ cμ cμ cμ Mθ cμ Et
Figure imgf000125_0001
( y — N— C — HN N — Me— N" — f — Nl N — HNI N — Me— Ni N —
HJNΛ
/
Figure imgf000125_0002
Figure imgf000125_0003
wherein:
A is selected from the group consisting of:
N
Figure imgf000126_0001
M Vi - V Et - ON- bN- CN- VN_
Figure imgf000126_0002
! D"- N- 0~ θ2CX H ~ AIX-
Figure imgf000126_0003
Rla is selected from the group consisting of-H, -F, -CI and -Br;
Rlbl is selected from the group consisting of-H, -CH3 and -CF3; and
Rlc2 and Rlc3 are independently selected from the group consisting of-H, -F, -CI, -Br and -OCH3.
The following compounds are an embodiment of the present invention:
Figure imgf000126_0004
wherein:
R is selected from the group consisting of:
-SO2NH2, -SO2Me, -CH2NH2 and -CH2NMe2;
R a is selected from the group consisting of: -H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-CH3, -CF3, -CH2CH3, -SO2Me, -CONH2 and -NHSO2Me;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -NH2, -OH, -SO2Me, -SO2Et, -SO2NH2, -NO2, -CH2NH2, -CN,
CONH2, -CH2OH;
Rlc2 is selected from the group consisting of:
-H, -F, -CI and -Br; and
Rlc3 is selected from the group consisting of:
-H, -F, -Cl and -Br.
The following compounds are an embodiment of the present invention:
Figure imgf000127_0001
wherein :
R1 is selected from the group consisting of:
-SO2NH2, -SO2Me, -CH2NH2 and -CH2NMe2;
Rla is selected from the group consisting of:
-H, -F, -CI and -Br; Rlb is selected from the group consisting of:
-CH3, -CF3, -CH2CH3, -SO2Me, -CONH2 and -NHSO2Me;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -NH2, -OH, -SO2Me, -SO2Et, -SO2NH2, -NO2, -CH2NH2, -CN, CONH2, -CH2OH;
R is selected from the group consisting of:
-H, -F, -CI, -Br and -OMe; and
R is selected from the group consisting of:
-H, -F, -CI, -Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2.
The following compounds are an embodiment of the present invention:
Figure imgf000128_0001
wherein:
R is selected from the group consisting of:
-SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2l -CH2NH2, CH2NH(CH3), -CH2N(CH3)2;
Rlais selected from the group consisting of: -H, -F, -CI and -Br;
R is selected from the group consisting of:
-CH3 and -CF3;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of:
-H, -F, -CI, -Br, and -OCH3; and
Rlc3 is selected from the group consisting of:
-H, -F, -CI, -Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2.
The following compounds are an embodiment of the present invention:
Figure imgf000129_0001
wherein:
R is selected from the group consisting of:
-SO2NH2, -SO2Me, -CH2NH2 and -CH2NMe2; Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-CH3, -CF3, -CH2CH3, -SO2Me, -CONH2 and -NHSO2Me; and
Rlc is selected from the group consisting of:
-H, -F, -CI, -Br, -NH2, -OH, -SO2Me, -SO2Et, -SO2NH2, -NO2, -CH2NH2, -CN, CONH2, -CH2OH;
The following compounds are an embodiment of the present invention:
Figure imgf000131_0001
wherein:
R1 is selected from the group consisting of:
-SO2NH2, -SO2Me, -CH2NH2 and -CH2NMe2;
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of: -CH3, -CF3, -CH2CH3, -SO2Me, -CONH2 and -NHSO2Me;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -NH2, -OH, -SO Me, -SO2Et, -SO2NH2, -NO2, -CH2NH2, -CN, CONH2, -CH2OH; and
Rlc2 and Rlc3 are independently selected from the group consisting of:
-H, -F, -Cl and -Br.
The following compounds are an embodiment of the present invention:
Figure imgf000132_0001
wherein:
A-Q is selected from the group consisting of:
cμ cμ Me cμ Et c^ cμ cμ cμ cμ Me Et
Figure imgf000133_0001
ζ-_ι_ c c cμ- cμ cμ- cμ*-
cμc*. c *- cμ*- r- cμ Me*1*- cμ-
( y — N— C — HN N — Mθ— Ni — — Ni N — HNI N — Mβ— Nl N
Me
Figure imgf000133_0002
!302NH2
/--
Figure imgf000133_0003
Figure imgf000133_0004
wherein:
A is selected from the group consisting of:
H H . v H M Mθ M vi y Et . ON- ON- O- <6N-
Figure imgf000133_0005
M M> - N~ CA °2 ~ H ~ "- -
Figure imgf000133_0006
Rla is selected from the group consisting of-H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-Me, -CF3, -Et, -SO2Me, -CONH2 and -NHSO2Me;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -NH2, -OH, -SO2Me, -SO2Et, -SO2NH2, -NO2, -CH2NH2, -CN,
CONH2) -CH2OH;
Rlc2 is selected from the group consisting of:
-H, -F, -CI and -Br; and
Rlc3 is selected from the group consisting of:
-H, -F, -CI and -Br.
The following compounds are an embodiment of the present invention:
Figure imgf000134_0001
wherein:
A-Q is selected from the group consisting of:
cμ cμ Me cyt cμ cμ cμ cμ cμ Me cμ Et
Figure imgf000135_0001
c cμ cμr- cμr- cμ Me *-
Figure imgf000135_0002
wherein:
A is selected from the group consisting of:
Figure imgf000135_0003
Me Me
Mβ→ N- CA CX- CN- ON- - M°A -
CX- - CX- o ~ H ~ *- ~
Figure imgf000135_0004
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-CH3, -CF3, -CH2CH3, -SO2Me, -CONH2 and -NHSO2Me;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -NH2, -OH, -SO2Me, -SO2Et, -SO2NH2, -NO2, -CH2NH2, -CN, CONH2, -CH2OH;
Rlc2 is selected from the group consisting of:
-H, -F, -CI, -Br and -OMe; and
Rlc3 is selected from the group consisting of:
-H, -F, -CI, -Br, -OH, -OCH3, -NH2, -CONH2, -CH2NH2.
The following compounds are an embodiment of the present invention:
Figure imgf000137_0001
Figure imgf000138_0001
wherein:
R1 is selected from the group consisting of:
-SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2, -CH2NH2, CH2NH(CH3), -CH2N(CH3)2;
Rla is selected from the group consisting of:
-H, -F, -CI and Br;
R is selected from the group consisting of:
-CH3 and -CF3;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
R is selected from the group consisting of:
-H, -F, -CI and -Br; and
R , lc3 is selected from the group consisting of:
-H, -F, -CI and -Br.
The following compounds are an embodiment of the present invention: 138
Figure imgf000139_0001
wherein:
R1 is selected from the group consisting of: -CN, -CH2NH2, -CONH2, -C(=NH)NH2„ SO2Me, -SO2NH2, and -NH2;
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-CH3, -CF3, -CH2CH3, -SO2Me, -CONH2 and -NHSO2Me;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -NH2, -OH, -SO2Me, -SO2Et, -SO2NH2, -NO2, -CH2NH2, -CN, CONH2, -CH2OH;
Rlc2 is selected from the group consisting of:
-H, -F, -CI, -Br and -OCH3;
Rlc3 is selected from the group consisting of:
-H, -F, -CI, -Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2.
The following compounds are an embodiment of the present invention:
Figure imgf000140_0001
wherein:
A-Q is selected from the group consisting of:
cμ cμ Me cμ Et cμ cμ cμ cμ cμ Mβ cμ Et
Figure imgf000141_0001
c yy Me- c c r cμ- cμ*- cμ Mβ11*-
Figure imgf000141_0002
Hrw — Ni N — HNI N — Me "W
Figure imgf000141_0003
wherein:
A is selected from the group consisting of: N-
Figure imgf000142_0001
Mθ We
Mβ-θN- CX- A- - ~ O1- ΑD1" Mβ / — \ / \ / — \ / \ / \ / \
Figure imgf000142_0002
Rlal is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-CH3 and -CF3;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of:
-H, -F, -CI, -Br, and -OCH3; and
Rlc3 is selected from the group consisting of:
-H, -F, -CI, -Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2.
The following compounds are an embodiment of the present invention:
Figure imgf000143_0001
wherein:
R1 is selected from the group consisting of:
-SO2NH2, -SO2CH3, -ON, -CONH2, -CONH(CH3), -CON(CH3)2, -CH2NH2, CH2NH(CH3), -CH2N(CH3)2;
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of: -H, -CH3 and -CF3;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of:
-H, -F, -CI and -Br; and
Rlc3 is selected from the group consisting of:
-H, -F, -Cl and -Br.
The following compounds are an embodiment of the present invention:
Figure imgf000145_0001
wherein:
R1 is selected from the group consisting of:
-SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2, -CH2NH2, CH2NH(CH3), -CH2N(CH3)2;
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
R is selected from the group consisting of:
-H, -CH3 and -CF3;
Rlcl is selected from the group consisting of: -H, -F, -CN, -CH2NH2, -CONH2, -SO2Me, -SO2NH2 and -NO2;
R is selected from the group consisting of:
-H, -F, -CI, -Br and -OCH3; and
Rlc3 is selected from the group consisting of:
-H, -F, -CI, -Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2.
The following compounds are an embodiment of the present invention:
Figure imgf000146_0001
wherein:
Figure imgf000147_0001
Q-t- < M-eτ c cμr cμ cμ*- cμ Me *-
Figure imgf000147_0002
( ^ — N— C — HNi N — Mβ— N" N — \ — s Ni -\ N. — . H.NrI y N. — . M.e— J NTl I
Figure imgf000147_0003
A-Q is selected from the group consisting of:
wherein:
A is selected from the group consisting of: Mθ
H _ M H _ E H _ Mθ M vθ E Ett>- ON- t>- o- <>-
Me Me
M A^N- CA CX- CX- CX ~ MAIX~
Figure imgf000148_0001
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-H, -CH3 and -CF3;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of:
-H, -F, -CI and -Br; and
Rlc3 is selected from the group consisting of:
-H, -F, -Cl and -Br.
The following compounds are an embodiment of the present invention:
Figure imgf000149_0001
wherein:
A-Q is selected from the group consisting of:
cμ cμ Mβ cμ Et c cμ cμ cμ cμ Mθ cμ Et
Figure imgf000150_0001
y — — C — HN N — Me— N Nl — f — N — HNI N — Me— Nl N-
Figure imgf000150_0002
wherein:
A is selected from the group consisting of:
Figure imgf000151_0001
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-H, -CH3 and -CF3;
Rlcl is selected from the group consisting of:
-H, -F, -CN, -CH2NH2, -CONH2, -SO2Me, -SO2NH2 and -NO2;
Rlc2 is selected from the group consisting of:
-H, -F, -CI, -Br and -OCH3; and
Rlc3 is selected from the group consisting of:
-H, -F, -CI, -Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2.
The following compounds are an embodiment of the present invention:
Figure imgf000152_0001
wherein:
R is selected from the group consisting of:
-SO2NH2, -SO2Me, -CH2NH2 and -CH2NMe2;
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
R , 1b is selected from the group consisting of:
-CH3, -CF3, -CH2CH3, -SO2Me, -CONH2 and -NHSO2Me;
R c and R c are independently selected from the group consisting of:
-H, -F, -CI and -Br. The following compounds are an embodiment of the present invention:
Figure imgf000153_0001
wherein:
R1 is selected from the group consisting of:
-SO2NH2, -SO2Me, -CH2NH2 and -CH2NMe2;
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
R , 1b ; is selected from the group consisting of:
-CH3, -CF3, -CH2CH3, -SO2Me, -CONH2 and -NHSO2Me;
R c and R c are independently selected from the group consisting of: -H, -F, -Cl and -Br.
This invention also encompasses all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives of the compounds of the formula (I). In addition, the compounds of formula (I) can exist in various isomeric and tautomeric forms, and all such forms are meant to be included in the invention, along with pharmaceutically acceptable salts, hydrates, solvates and prodrug derivatives of such isomers and tautomers.
The compounds of this invention may be isolated as the free acid or base or converted to salts of various inorganic and organic acids and bases. Such salts are within the scope of this invention. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the processes of isolation and purification.
A number of methods are useful for the preparation of the salts described above and are known to those skilled in the art. For example, the free acid or free base form of a compound of one of the formulas above can be reacted with one or more molar equivalents of the desired acid or base in a solvent or solvent mixture in which the salt is insoluble, or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying. Alternatively, the free acid or base form of the product may be passed over an ion exchange resin to form the desired salt or one salt form of the product may be converted to another using the same general process.
Preparation of Compounds
The compounds of the present invention may be synthesized by standard organic chemical synthetic methods as described and referenced in standard textbooks. These methods are well known in the art. See, e.g., March, "Advanced Organic Chemistry", John Wiley & Sons, New York,, 1992; Joule, Mills and Smith, "Heterocyclic Chemistry", Chapman & Hall, London, 1995, et seq.
Starting materials used in any of these methods are commercially available from chemical vendors such as Aldrich, Fluka, Lancaster, TCI, Maybridge, Frontier, Fluorochem, Alfa Aesar, and the like, or may be readily synthesized by known procedures.
Reactions are carried out in standard laboratory glassware and reaction vessels under reaction conditions of standard temperature and pressure, except where otherwise indicated.
During the syntheses of these compounds, the functional groups of the substitutents are optionally protected by blocking groups to prevent cross reaction. Examples of suitable protective groups and their use are described in Kocienski, "Protecting Groups", Thieme, Stuttgart, 1994; Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York, 1999, and the disclosures of which are incorporated herein by reference.
Non-limiting exemplary synthesis schemes are outlined directly below, and specific steps are described in the Examples. The reaction products are isolated and purified by conventional methods, typically by solvent extraction into a compatible solvent. The products may be further purified by any means known in the art such as, for example, flash column chromatography, reverse-phase preparative high performance liquid chromatography (HPLC) with high purity water and acetonitrile, or other appropriate methods.
General Synthesis
General synthesis for compounds with a N-linked G ring is outlined in Scheme 1 below. In Scheme 1, A', Q', D', E', J' and X' are protected functional structures which can be converted to A, Q, D, E, J and X respectively by methods known in the art (e.g. deprotection methods). For formation of the N-linked G ring, the appropriate aromatic amine precursor is treated under conditions described in Joule, Mills and Smith, "Heterocyclic Chemistry", Chapman & Hall, London, 1995, or the references cited therein, or as described later in the preparation section to give the G ring. Scheme 1 -linked heterocycle G
Figure imgf000156_0001
heterocycle E' formation y$ coupling
Figure imgf000156_0003
Figure imgf000156_0002
Figure imgf000156_0004
d jepro .tec -»t•ion A— Q — 6,, D // /) NL G
Scheme 2
For pyrazole-linked compounds
Figure imgf000157_0001
deprotection
Figure imgf000157_0002
Scheme 2 above shows the general synthesis of compounds with a N-linked pyrazole G ring. Appropriately protected aromatic amines are converted to aromatic hydrazines by reduction of their diazonium salts. The hydrazines are condensed with 1,3- diketones to yield the pyrazole structures.
Scheme 3 shows the general synthesis of compounds with a N-linked triazole G ring. An appropriately protected aromatic amine is converted to aromatic azide from its diazonium salt. The azide is condensed with an alkyne to yield the triazole structure.
Scheme 3 or triazole-linked compounds
Figure imgf000159_0001
couPling . A-Q-D-N-Lf}N deprotection
Figure imgf000159_0002
Figure imgf000159_0003
deprotection
Figure imgf000159_0004
Scheme 4 or tetrazole-linked compounds
Figure imgf000160_0001
coupling deprotection »
Figure imgf000160_0002
Figure imgf000160_0003
Figure imgf000160_0004
deprotection
Figure imgf000160_0005
Scheme 4 shows the general synthesis of compounds with a N-linked tetrazole G ring. An appropriately protected aromatic amine is acylated with ethyl chlorooxoacetate. The resulting amide can be converted to the tetrazole by methods known in the art. See e.g. Journal of Organic Chemistry, 56, 2395 (1991); Synthesis, 767 (1993); Journal of Organic Chemistry, 5£, 32 (1993); Bioorganic & Medicinal Chemistry Letters, 6, 1015 (1996)).
General synthesis for compounds with a C-linked G ring is outlined in Scheme 5. A', Q', D', E', J' and X' are protected functional structures which can be converted to A, Q, D, E, J and X respectively. For formation of the C-linked G ring, the appropriate aromatic aldehyde precursor is treated under conditions described in Joule, Mills and Smith, "Heterocyclic Chemistry", Chapman & Hall, London, 1995, or the references cited therein, or as described later in the preparation section to give the G ring. The C-linked G ring can also be connected to aromatic X or aromatic D using Suzuki cross-coupling method (Chemical Reviews, 25, 2457 (1995)).
Scheme 5
For carbon-linked heterocycle G
coupling
Figure imgf000162_0002
Figure imgf000162_0001
Figure imgf000162_0003
Scheme 6 shows the general synthesis of compounds with a C-linked isoxazole G ring. A substituted aromatic aldehyde is reacted with hydroxylamine and then chlorinated to yield the hydroximinoyl choride (Journal of Organic Chemistry, 45, 3916 (1980)). It is treated with triethylamine to generate nitrile oxide in situ, which is reacted with methyl trαws-3-mthoxyacrylate or methyl propiolate to give the isoxazole structure (Chemical Letters, !, 85 (1987)). Scheme 6 For isoxazole-l inked hetereocycle compounds
coupling
Figure imgf000163_0001
Figure imgf000163_0002
Scheme 7 shows the general synthesis of compounds with a C-linked thiozole G ring. A substituted aromatic aldehyde is reacted with ethyl diazoacetate in presence of tin(II) chloride to afford the beta-ketoester. It is then converted to thiazole. Scheme 7 For thiazole-linked hetereocycle compounds
Figure imgf000164_0001
Compositions and Formulations
The compounds of this invention may be isolated as the free acid or base or converted to salts of various inorganic and organic acids and bases. Such salts are within the scope of this invention. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the processes of isolation and purification. A number of methods are useful for the preparation of the salts described above and are known to those skilled in the art. For example, reaction of the free acid or free base form of a compound of the structures recited above with one or more molar equivalents of the desired acid or base in a solvent or solvent mixture in which the salt is insoluble, or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying. Alternatively, the free acid or base form of the product may be passed over an ion exchange resin to form the desired salt or one salt form of the product may be converted to another using the same general process.
This invention also encompasses prodrug derivatives of the compounds contained herein. The term "prodrug" refers to a pharmacologically inactive derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug. Prodrugs are variations or derivatives of the compounds of this invention which have groups cleavable under metabolic conditions. Prodrugs become the compounds of the invention which are pharmaceutically active in vivo, when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. Prodrug compounds of this invention may be called single, double, triple etc., depending on the number of biotransformation steps required to release the active drug within the organism, and indicating the number of functionalities present in a precursor-type form. Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, CA, 1992). Prodrugs commonly known in the art include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, or amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative. Moreover, the prodrug derivatives of this invention may be combined with other features herein taught to enhance bioavailability.
Diagnostic applications of the compounds of this invention will typically utilize formulations such as solution or suspension. In the management of thrombotic disorders the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions or injectable administration, and the like, or incoφorated into shaped articles. Subjects in need of treatment (typically mammalian) using the compounds of this invention can be administered dosages that will provide optimal efficacy. The dose and method of administration will vary from subject to subject and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet, concurrent medication, overall clinical condition, the particular compounds employed, the specific use for which these compounds are employed, and other factors which those skilled in the medical arts will recognize.
Formulations of the compounds of this invention are prepared for storage or administration by mixing the compound having a desired degree of purity with physiologically acceptable carriers, excipients, stabilizers etc., and may be provided in sustained release or timed release formulations. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remington 's Pharmaceutical Sciences, Mack Publishing Co., (A.R. Gennaro edit. 1985). Such materials are nontoxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinalpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium and/or nonionic surfactants such as Tween, Pluronics or polyethyleneglycol.
Dosage formulations of the compounds of this invention to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods. Formulations typically will be stored in lyophilized form or as an aqueous solution. The pH of the preparations of this invention typically will be between about 3 and about 11, more preferably from about 5 to about 9 and most preferably from about 7 to about 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of cyclic polypeptide salts. While the preferred route of administration is by injection, other methods of administration are also anticipated such as intravenously (bolus and/or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally or intraperitoneally, employing a variety of dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches. The compounds of this invention are desirably incorporated into shaped articles such as implants which may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers commercially available.
The compounds of this invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines.
The compounds of this invention may also be delivered by the use of antibodies, antibody fragments, growth factors, hormones, or other targeting moieties, to which the compound molecules are coupled. The compounds of this invention may also be coupled with suitable polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-rnethacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the factor Xa inhibitors of this invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels. Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.
Therapeutic compound liquid formulations generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by hypodermic injection needle. Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular compound of the present invention, individual determinations may be made to determine the optimal dosage required. The range of therapeutically effective dosages will naturally be influenced by the route of administration, the therapeutic objectives, and the condition of the patient. For injection by hypodermic needle, it may be assumed the dosage is delivered into the body's fluids. For other routes of administration, the absorption efficiency must be individually determined for each inhibitor by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. The determination of effective dosage levels, that is, the dosage levels necessary to achieve the desired result, will be within the ambit of one skilled in the art. Typically, applications of compound are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved.
A typical dosage might range from about 0.001 mg/kg to about 1000 mg/kg, preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferably from about 0.10 mg/kg to about 20 mg/kg. Advantageously, the compounds of this invention may be administered several times daily, and other dosage regimens may also be useful.
Typically, about 0.5 to about 500 mg of a compound or mixture of compounds of this invention, as the free acid or base form or as a pharmaceutically acceptable salt, is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor etc., as called for by accepted pharmaceutical practice. The amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained.
Typical adjuvants which may be incorporated into tablets, capsules and the like are a binder such as acacia, corn starch or gelatin, and excipient such as microcrystalline cellulose, a disintegrating agent like corn starch or alginic acid, a lubricant such as magnesium stearate, a sweetening agent such as sucrose or lactose, or a flavoring agent. When a dosage form is a capsule, in addition to the above materials it may also contain a liquid carrier such as water, saline, a fatty oil. Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired. Buffers, preservatives, antioxidants and the like can be incoφorated according to accepted pharmaceutical practice.
In practicing the methods of this invention, the compounds of this invention may be used alone or in combination, or in combination with other therapeutic or diagnostic agents. In certain preferred embodiments, the compounds of this inventions may be coadministered along with other compounds typically prescribed for these conditions according to generally accepted medical practice, such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin. The compounds of this invention can be utilized in vivo, ordinarily in mammals such as primates, such as humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
The preferred compounds of the present invention are characterized by their ability to inhibit thrombus formation with acceptable effects on classical measures of coagulation parameters, platelets and platelet function, and acceptable levels of bleeding complications associated with their use. Conditions characterized by undesired thrombosis would include those involving the arterial and venous vasculature.
With respect to the coronary arterial vasculature, abnormal thrombus formation characterizes the rupture of an established atherosclerotic plaque which is the major cause of acute myocardial infarction and unstable angina, as well as also characterizing the occlusive coronary thrombus formation resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA).
With respect to the venous vasculature, abnormal thrombus formation characterizes the condition observed in patients undergoing major surgery in the lower extremities or the abdominal area who often suffer from thrombus formation in the venous vasculature resulting in reduced blood flow to the affected extremity and a predisposition to pulmonary embolism. Abnormal thrombus formation further characterizes disseminated intravascular coagulopathy commonly occurs within both vascular systems during septic shock, certain viral infections and cancer, a condition wherein there is rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the microvasculature leading to widespread organ failure.
The compounds of this present invention, selected and used as disclosed herein, are believed to be useful for preventing or treating a condition characterized by undesired thrombosis, such as (a) the treatment or prevention of any thrombotically mediated acute coronary syndrome including myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post-coronary angioplasty, (b) the treatment or prevention of any thrombotically mediated cerebrovascular syndrome including embolic stroke, thrombotic stroke or transient ischemic attacks, (c) the treatment or prevention of any thrombotic syndrome occurring in the venous system including deep venous thrombosis or pulmonary embolus occurring either spontaneously or in the setting of malignancy, surgery or trauma, (d) the treatment or prevention of any coagulopathy including disseminated intravascular coagulation (including the setting of septic shock or other infection, surgery, pregnancy, trauma or malignancy and whether associated with multi-organ failure or not), thrombotic thrombocytopenic puφura, thromboangiitis obliterans, or thrombotic disease associated with heparin induced thrombocytopenia, (e) the treatment or prevention of thrombotic complications associated with extracoφoreal circulation (e.g. renal dialysis, cardiopulmonary bypass or other oxygenation procedure, plasmapheresis), (f) the treatment or prevention of thrombotic complications associated with instrumentation (e.g. cardiac or other intravascular catheterization, intra-aortic balloon pump, coronary stent or cardiac valve), and (g) those involved with the fitting of prosthetic devices.
Anticoagulant therapy is also useful to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage. Thus the compounds of this invention can be added to or contacted with any medium containing or suspected to contain factor Xa and in which it is desired that blood coagulation be inhibited, e.g., when contacting the mammal's blood with material such as vascular grafts, stents, orthopedic prostheses, cardiac stents, valves and prostheses, extra coφoreal circulation systems and the like.
Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following working examples therefore, specifically point out preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.
Examples
Example 1.
Figure imgf000171_0001
Step 1. To the solution of 2-naphthylboronic acid (5.00 g, 29.1 mmol) and ethyl 3- methylpyrazole-5-carboxylate (4.48 g, 29.1 mmol) in 100 mL dry dichloromethane (DCM) were added pyridine (4.7 mL, 58.2 mmol) and anhydrous powder of copper(II) acetate (7.94 g, 43.7 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was stirred for 2 days under argon. The mixture was diluted with DCM. It was filtered through a celite bed. The blue filtrate was washed with water (X2), dried over MgSO4, concentrated, purified by silica column to yield ethyl 3- methyl-l-(2-naphthyl)-lH-pyrazole-5-carboxylate and its regioisomer in a 1:1 ratio in 70% yield. Rf 0.59 (1:2 EtOAc: hexane), M+H 281; regioisomer, ethyl 5-methyl-l-(2- naphthyl)-lH-pyrazole-3-carboxylate, Rf 0.44 (1:2 EtOAc: hexane). ES-MS: (M+H)+ 281.
Step 2. To a solution of 2'-N-tert-butylaminosulfonyl-[l, ]-biphenyl-4-ylamine (50 mg, 0.16 mmol) in 1 mL DCM was added trimethylaluminum (2.0M in hexane, 0.41 mL, 0.82 mmol) under argon at room temperature. After being stirred for 30 minutes, to the mixture was added the above-prepared ester (46 mg, 0.16 mmol) in 1 mL DCM. The resulting mixture was stirred overnight. The reaction was quenched using 5 mL saturated Rochelle salt aq solution. The mixture was extracted using DCM (X3). The organic phases were combined, dried, rotovaped and subjected on flash column to give the coupled product in 52% yield (46 mg). Rf 0.46 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 539.
Step 3. The above-prepared compound (42 mg, 0.078 mmol) was placed in 3 mL trifluoroacetic acid (TFA). The solution was stirred in 60°C bath for 30 minutes. TFA was removed on rotovap. The residue was dissolved in methanol and purified by preparative HPLC to afford the title compound in 95% yield. ES-MS: (M+H)+ 483.
Example 2.
Figure imgf000172_0001
Stepl. A mixture of tin(II) chloride (2.08 g, 10.96 mmol) and ethyl diazoacetate (2.76 mL, 26.28 mmol) in 50 mL DCM was stirred for 2 hours. Naphthalene-2-carbaldehyde was added. After stirred at room temperature for 18 hours, the mixture was concentrated, dissolved in EtOAc, washed with water (X3), dried and evaporated. The crude material was purified to give product ethyl 3-(2-naphthyl)-3-oxopφpionate. Rf 0.61 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 243.
Step 2. To a solution of the above-prepared ester (240 mg, 1 mmol) in 15 mL MeCN at 65°C was added hydroxy(tosyloxy)iodobenzene (430 mg, 1.1 mmol). After stirred for 1 hour, to the mixture was added thiourea (83 mg, 1.1 mmol). The resulting mixture was stirred overnight at 65°C. The solution was cooled and concentrated. The residue was dissolved in EtOAc, washed with brine, dried over MgSO , and evaporated to give crude 2-methyl-4-(2-naphthyl)-5-(carboethoxy)thiazole. Rf 0.64 (1:3 EtOAc: hexane). ES-MS: (M+H)+ 298. Step 3. To a solution of the above-prepared product (148 mg, 0.50 mmol) and 2'-N-tert- butylaminosulfonyl-[l,l']-biphenyl-4-ylamine (152 mg, 0.50 mmol) in 3 mL DCM was added trimethylaluminum (2.0M in hexane, 0.75 mL, 1.5 mmol), and the mixture was stirred at room temperature for 20 hours. The reaction was neutralized with 4 mL IN HCI and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO , and concentrated to give the coupling product (170 mg, 61%). Rf 0.25 (1:3 EtOAc: hexane). ES-MS: (M+H)+ 556.
Step 4. The above-prepared product (100 mg) was placed in 3 mL TFA. The solution was stirred in 80°C bath for 60 minutes. TFA was removed on rotovap. The residue was dissolved in methanol and purified by preparative HPLC to afford the title compound in over 90% yield. ES-MS: (M+H)+ 500.
Example 3.
Figure imgf000173_0001
Step 1. 3-Amino-2-naphthoic acid (40.4 g, 216 mmol) was placed in 200 mL concentrated HCI. At 0°C, the slurry was stirred vigorously using a mechanical stirring blade. To it was added a cold solution of sodium nitrite (29.8 g, 432 mmol) in 70 mL water. After completion, the cold slurry was stirred for 30 minutes at 0°C. To it was added cold tetrafluoroboric acid (48 wt. % in water, 56 mL, 432 mmol). After stirred at 0°C for 30 minutes, the solid was filtered using a Buchner funnel. The soild cake was carefully rinsed with cold water (10 mL X2), cold tetrafluoroboric acid (10 mL X2) and cold ethanol (5 mL X2). The solid was dried in vacuuo. It was then placed in 300 mL xylene and refluxed overnight. Xylene was removed on rotovap. The residue was acidified to pHl with aq HCI and taken into EtOAc. It was washed with brine (X2), dried, evaporated to give 3-fluoro-2-naphthoic acid (32.6 g, 78%). ES-MS: (M+H)+ 191.
Step 2. The above-prepared acid (14.7 g, 77 mmol) was dissolved in 200 mL CHC13. To it was added 0.5 mL dry DMF. Then at room temperature, oxalyl chloride (20 mL, 232 mmol) was added dropwise. The reaction solution was stirred for overnight. All solvent was removed in vacuuo. The residue was pumped till dryness. It was dissolved in 150 mL dry dioxane, chilled to 0°C and vigorously stirred. To it, at the cold tempareture, was added the cold solution of sodium azide (10 g, 155 mmol, in 30 mL water and 15 mL dioxane) in small portions. The reaction was allowed for 2 hours at 0°C. The solvent was removed in vacuuo. The residue was taken into EtOAc and washed with brine (X3). The organic phase was dried and evaporated to dryness in vacuuo to give 3-fluoro-2- naphthoyl azide. Rf 0.83 (1:1 EtOAc: hexane). It was dissolved in 80 mL DMF. To it was added 40 mL water. The milky mixture was refluxed overnight. The solvent was removed in vacuuo. The residue was taken into EtOAc, and washed with brine (X2). The organic phase was dried, concentrated and purified with flash silica column to yield 3-fluoro-2- naphthylamine (8.1 g, 65%). Rf 0.40 (1:3 EtOAc: hexane). ES-MS: (M+H)+ 162.
Step 3. The above-prepared compound (7.5 g, 46 mmol) was placed in 50 mL concentrate HCI. The mixture was vigorously stirred in ice bath. To it was dropwise added cold sodium nitrite ( 3.8 g, 55 mmol) solution in 10 mL water. After completion, the mixture was stirred at 0°C for half an hour. At 0°C, to it was dropwise added cold SnCl2.2H2O (26.3 g, 116 mmol) solution in 20 mL concentrate HCI. The slurry was stirred for half an hour at 0°C, chilled, and filtered through a Buchner funnel to isolate the solid hydrazine. It was dried in vacuuo. The solid hydrazine was dissolved in 100 mL glacial acetic acid. To it were added ethyl 2-N-(methoxy)imino-4-oxopentanoate (10.4 g, 56 mmol, prepared from ethyl 2,4-dioxovalerate and methoxylamine hydrogen chloride in ethanol) and 50 mL THF. The mixture was refluxed for 2 hours. The solvent was removed in vacuuo. The residue was taken into EtOAc, washed with brine and water. The organic phase was dried, concentrated and purified with flash column to yield ethyl 3-methyl-l-(3-fluoro-2- naphthyl)-lH-pyrazole-5-carboxylate (9.0 g, 65%). Rf 0.52 (1:2 EtOAc: hexane). ES-MS: (M+H)+ 299. Step 4. To a solution of 2'-N-tert-butylaminosulfonyl-[l,l']-biphenyl-4-ylamine (77mg, 0.25 mmol) in 1 mL dry DCM was added trimethylaluminum (2.0M in hexane, 0.51 mL, 1.0 mmol). The mixture was stirred for 20 minutes. The above-prepared ester (50 mg, 0.17 mmol) was dissolved in 3 mL dry DCM and added into the aluminum mixture. The reaction was stirred at room temperature for overnight and quenched using saturated Rochelle's salt aq solution. It was extracted with CHC13 (X3). The organic phases were combined, dried, concentrated and purified with flash column to yield the coupling product (85 mg, 90%). Rf 0.45 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 557.
Step 5. The above-prepared product was placed into 3 mL TFA. The mixture was stirred overnight at room temperature. It was evaporated, dissolved in methanol, purified with prep HPLC to afford the title compound in over 90% yield. ). ES-MS: (M+H)+ 501.
Example 4.
Figure imgf000175_0001
Step 1. The preparation of ethyl 3-methyl-l-(3-fluoro-2-naphthyl)-lH-pyrazole-5- carboxylate was the same as that in Step 3 for Example 3. This ester (13.2 g, 44 mmol) was dissolved in 80 mL methanol. To it were added LiOH.H2O (3.7 g, 49 mmol) and 40 mL water. The mixture was stirred for overnight at room temperature. It was evaporated in vacuuo to remove methanol. The residue was acidified with IN HCI till pH 1. The mixture was extracted with EtOAc (X4). The organic extracts were combined, dried, evaporated and pumped to dryness to afford 3-methyl-l-(3-fluoro-2-naphthyl)-lH- pyrazolecarboxylic acid in over 90% yield. ES-MS: (M+H)+ 271.
Step 2. The above-prepared acid (33 mg, 0.12 mmol), 2'-N-tert-butylaminosulfonyl-3- fluoro-[l,l']-biphenyl-4-ylamine (77 mg, 0.24 mmol) and catalytic amount of DMAP (5 mg) were dissolved in 2 mL pyridine. The solution was stirred at 0°C. To it was added POCl3 (45 μL, 0.48 mmol). The mixture was stirred for 1 hour and quenched with ice chips. To it was added EtOAc. It was washed with brine (X2), dried, and concentrated. To the residue was added 3 mL TFA. The mixture was stirred at 60°C for 1 hour, concentrated, dissolved in methanol and subjected on prep HPLC to afford the title compound in 50% yield (31 mg). ES-MS: (M+H)+ 519.
Example 5.
Figure imgf000176_0001
This compound was prepared by the same methodology described for Example 4 with 2'- N-tert-butylaminosulfonyl-3-chloro-[l,l']-biphenyl-4-ylamine substituted for 2'-N-tert- butylaminosulfonyl-3-fluoro-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 535.
Example 6.
Figure imgf000176_0002
This compound was prepared by the same methodology described for Example 4 with 2'- N-tert-butylaminosulfonyl-3-bromo-[l,l']-biphenyl-4-ylamine substituted for 2'-N-tert- butylaminosulfonyl-3-fluoro-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 579, 581 (Br pattern). Example 7.
Figure imgf000177_0001
This compound was prepared by the same methodology described for Example 4 with 2- amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyridine substituted for 2'-N-tert- butylaminosulfonyl-3-fluoro-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 502.
Example 8.
Figure imgf000177_0002
This compound was prepared by the same methodology described for Example 4 with 2- amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyrimidine substituted for 2'-N-tert- butylaminosulfonyl-3-fluoro-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 503.
Example 9.
Figure imgf000178_0001
This compound was prepared by the same methodology described for Example 4 with 2'- cyano-[l,l ']-biphenyl-4-ylamine substituted 2'-N-tert-butylaminosulfonyl-3-fluoro- [l,l']-biphenyl-4-ylamine, without the TFA treatment. ES-MS: (M+H)+ 447.
Example 10.
Figure imgf000178_0002
The title compound (40 mg, 0.09 mmol) of Example 9 was dissolved in 2 mL dry DMF. At 0°C, to it were added sodium borohydride (27 mg, 0.72 mmol) and anhydrous Co(II) chloride (23 mg, 0.18 mmol). The mixture was stined for 2 hours and quenched with 1 mL acetic acid. The mixture was evaporated, dissolved in methanol, filtered, loaded on prep HPLC to afford the title compound in 60% yield. ES-MS: (M+H)+ 451.
Example 11.
Figure imgf000179_0001
The title compound (40 mg, 0.09 mmol) of Example 9 was dissolved in 2 mL dry DMF. At 0°C, to it were added sodium borohydride (27 mg, 0.72 mmol) and anhydrous Co(II) chloride (23 mg, 0.18 mmol). The mixture was stirred for 2 hours. To it was added 10 mL acetone. The mixture was stirred for 1 hour at room temperature. The reaction was quenched with 1 mL acetic acid. The mixture was evaporated, dissolved in methanol, filtered, loaded on prep HPLC to afford the title compound in 50% yield. ES-MS: (M+H)+ 493.
Example 12.
Figure imgf000179_0002
This compound was prepared by the same methodology described for Example 4 with 2'- (N-dimethylamino)methyl-[l,l']-biphenyl-4-ylamine substituted for 2'-N-tert- butylaminosulfonyl-3-fluoro-[l , 1 ']-biphenyl-4-ylamine, without the TFA treatment. ES- MS: (M+H)+ 479. Example 13.
Figure imgf000180_0001
Step 1. The preparation of 3-methyl-l-(3-fluoro-2-naphthyl)-lH-pyrazolecarboxylic acid was the same as that in Step 1 of Example 4.
Step2. This acid (65 mg, 0.24 mmol), 4-aminobenzonitrile (57 mg, 0.48 mmol) and DMAP (5 mg) were dissolved in 3 mL pyridine. The solution was stirred at 0°C. To it was added POCl3 (90 μL, 0.96 mmol). The mixture was stirred for 1 hour. The reaction was then quenched with ice chips. It was diluted with EtOAc. The organic phase was washed with brine (X2). It was dried, concentrated and purified with flash column to afford the coupling product (60 mg, 68%). Rf 0.40 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 371.
Step 3. The above-prepared nitrile was dissolved in 10 mL dry methanol. It was chilled and stined in an ice bath. To this solution was bubbled dry HCI gas via a long needle till saturation reached (indicated by a bl own-up balloon attached on the top of the reaction flask). The resulting solution was stirred overnight. ES-MS: (M+H)+ 403. The solvent was removed in vacuuo. The residue was pumped to dryness. The solid was dissolved in 5 mL dry methanol. To it was added anhydrous N-methylethylenediamine (0.5 mL). The mixture was refluxed for 1 hour, concentrated and loaded on prep HPLC to afford the title compound in 80% yield. ES-MS: (M+H)+ 428.
Example 14.
Figure imgf000181_0001
This compound was prepared by the same methodology described for Example 13 with pyrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 442.
Example 15.
Figure imgf000181_0002
This compound was prepared by the same methodology described for Example 13 with piperidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 456.
Example 16.
Figure imgf000181_0003
This compound was prepared by the same methodology described for Example 13 with dimethylamine (commercial 2M solution in THF) substituted for N- methylethylenediamine. ES-MS: (M+H)+ 416. Example 17.
Figure imgf000182_0001
This compound was prepared by the same methodology described for Example 13 with thiomoφholine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 474.
Example 18.
Figure imgf000182_0002
This compound was prepared by the same methodology described for Example 13 with moφholine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 458.
Example 19.
Figure imgf000182_0003
This compound was prepared by the same methodology described for Example 13 with piperazine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 457. Example 20.
Figure imgf000183_0001
This compound was prepared by the same methodology described for Example 13 with N-methylpiperazine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 471.
Example 21.
Figure imgf000183_0002
This compound was prepared by the same methodology described for Example 13 with ammonium acetate substituted for N-methylethylenediamine. ES-MS: (M+H)+ 388.
Example 22.
Figure imgf000183_0003
Step 1. 2-Fluoro-4-iodoaniline (5.0 g, 21 mmol) was dissolved in 20 mL dry DMF. To it were added CuCN (3.8 g, 42 mmol) and catalytic amount of Cul (200 mg). The slurry was refluxed for 1 hour. Diluted with EtOAc. Filtered through celite. Concentrated in vacuuo to yield solid 4-amino-3-fluorobenzonitrile (2.9 g, 100%). ES-MS: (M+H)+ 137. Step 2. The preparation of 3-methyl-l-(3-fluoro-2-naphthyl)-lH-pyrazolecarboxylic acid was the same as that in Step 1 of Example 4. This acid (270 mg, 1.0 mmol), 4-amino-3- fluorobenzonitrile (272 mg, 2.0 mmol) and DMAP (10 mg) were dissolved in 15 mL pyridine. The solution was stirred at 0°C. To it was added POCl3 (380 μL, 4.0 mmol). The mixture was stirred for 1 hour. The reaction was then quenched with ice chips. It was diluted with EtOAc. The organic phase was washed with brine (X2). It was dried, concentrated and purified with flash column to afford the coupling product (350 mg, 97%). Rf 0.77 (7:3 EtOAc: hexane). ES-MS: (M+H)+ 389.
Step 3. The above-prepared nitrile (30 mg, 0.077 mmol) was dissolved in 10 mL dry methanol. It was chilled and stirred in an ice bath. To this solution was bubbled dry HCI gas via a long needle till saturation reached (indicated by a blown-up balloon attached on the top of the reaction flask). The resulting solution was stined overnight. ES-MS: (M+H)+ 421. The solvent was removed in vacuuo. The residue was pumped to dryness. The solid was dissolved in 5 mL dry methanol. To it was added anhydrous N- methylethylenediamine (0.5 mL). The mixture was refluxed for 1 hour, concentrated and loaded on prep HPLC to afford the title compound in 80% yield. ES-MS: (M+H)+ 446.
Example 23
Figure imgf000184_0001
This compound was prepared by the same methodology described for Example 22 with pyrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 460.
Example 24.
Figure imgf000184_0002
This compound was prepared by the same methodology described for Example 22 with piperidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 474.
Example 25.
Figure imgf000185_0001
This compound was prepared by the same methodology described for Example 22 with hexamethyleneimine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 488.
Example 26.
Figure imgf000185_0002
This compound was prepared by the same methodology described for Example 22 with moφholine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 476.
Example 27.
Figure imgf000185_0003
This compound was prepared by the same methodology described for Example 22 with ammonium acetate substituted for N-methylethylenediamine. ES-MS: (M+H)+ 406.
Example 28.
Figure imgf000186_0001
Step 1. The preparation of 3-methyl-l-(3rfluoro-2-naphthyl)-lH-pyrazolecarboxylic acid was the same as that in Step 1 of Example 4. This acid (50 mg, 0.18 mmol), 4-amino-2,5- difluorobenzonitrile (57 mg, 0.36 mmol) and DMAP (5 mg) were dissolved in 8 mL pyridine. The solution was stirred at 0°C. To it was added POCl3 (70 μL, 0.74 mmol). The mixture was stured for 1 hour. The reaction was then quenched with ice chips. It was diluted with EtOAc. The organic phase was washed with brine (X2). It was dried, concentrated and purified with flash column to afford the coupling product (70 mg, 93%). Rf 0.69 (7:3 EtOAc: hexane). ES-MS: (M+H)+ 407.
Step 2. The above-prepared nitrile (30 mg, 0.074 mmol) was dissolved in 10 mL dry methanol. It was chilled and stined in an ice bath. To this solution was bubbled dry HCI gas via a long needle till saturation reached (indicated by a blown-up balloon attached on the top of the reaction flask). The resulting solution was stirred overnight. ES-MS: (M+H)+ 439. The solvent was removed in vacuuo. The residue was pumped to dryness. The solid was dissolved in 5 mL dry methanol. To it was added anhydrous N- methylethylenediamine (0.5 mL). The mixture was refluxed for 1 hour, concentrated and loaded on prep HPLC to afford the title compound in 80% yield. ES-MS: (M+H)+ 464.
Example 29
Figure imgf000187_0001
This compound was prepared by the same methodology described for Example 28 with pyrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 478.
Example 30.
Figure imgf000187_0002
This compound was prepared by the same methodology described for Example 28 with ammonium acetate substituted for N-methylethylenediamine. ES-MS: (M+H)+ 424.
Example 31.
Figure imgf000187_0003
This compound was prepared by the same methodology from Step 3 to Step 5 described for Example 3 with 3-chloro-2-naphthylamine substituted for 3-fluoro-2-naphthylamine. ES-MS: (M+H)+ 517. Example 32.
Figure imgf000188_0001
This compound was prepared by the same methodology from Step 3 to Step 5 described for Example 3 with 3-bromo-2-naphthylamine substituted for 3-fluoro-2-naphthylamine. ES-MS: (M+H)+ 561 , 563 (Br pattern).
Example 33.
Figure imgf000188_0002
This compound was prepared by the same methodology from Step 3 to Step 5 described for Example 3 with 3-hydroxy-2-naphthylamine substituted for 3-fluoro-2- naphthylamine. ES-MS: (M+H)+ 499.
Example 34.
Figure imgf000188_0003
Step 1. The synthesis of ethyl 3 -methyl- l-(3-bromo-2-naphthyl)-lH-pyrazole-carboxylate followed the same methodology described for Step 3 of Example 3 with commercial with 3-bromo-2-naphthylamine substituted for 3-fluoro-2-naphthylamine. Yield 60%. Rf 0.42 (1:3 EtOAc: hexane). ES-MS: (M+H)+ 359, 361 (Br pattern).
Step 2. The above-prepared bromide (370 mg, 1.0 mmol) was dissolved in 3 mL dry DMF. To it were added CuCN (180 mg, 2.0 mmol) and Cul (20 mg). The slurry mixture was refluxed for 2 hours. It was diluted with EtOAc. Filtered through celite. Concentrated and purified by flash column to yield of ethyl 3-methyl-l-(3-cyano-2-naphthyl)-lH- pyrazole-carboxylate (220 mg, 70%). Rf 0.48 (1:2 EtOAc: hexane). ). ES-MS: (M+H)+ 306.
Step 3. To a solution of 2'-N-tert-butylaminosulfonyl-[l,l']-biphenyl-4-ylamine (164 mg, 0.54 mmol) in 2 mL dry DCM was added trimethylaluminum (2.0M in hexane, 1.1 mL, 2.2 mmol). The mixture was stirred for 20 minutes. The above-prepared ester (137 mg, 0.45 mmol) was dissolved in 6 mL dry DCM and added into the aluminum mixture. The reaction was stirred at room temperature for overnight and quenched using saturated Rochelle's salt aq solution. It was extracted with CHC13 (X3). The organic phases were combined, dried, concentrated and purified with flash column to yield 3 -methyl- 1 -(3- cyano-2-naphthyl)- 1 H-pyrazole-5-(N-(2'-N-tert-butylaminosulfonyl-[ 1 , 1 ']-biphen-4- yl))carboxyamide (170 mg, 67%). Rf 0.40 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 564.
Step 4. The above-prepared compound (30 mg, 0.05 mmol) was dissolved in 5 mL dry DCM. At 0°C, to it was added BF3.OEt2 (62 μL, 0.5 mmol) dropwise. The mixture was stirred overnight. Extra 1.0 mmol BF3.OEt2 was added in small portions at room temperature the next day. After another overnight, deprotection was about 70% complete. The mixture was loaded on a short flash column for separation. The title product was purified using prep HPLC (55% yield). ES-MS: (M+H)+ 508.
Example 35.
Figure imgf000190_0001
Step 1. The synthesis of 3-methyl-l-(3-cyano-2-naphthyl)-lH-pyrazole-5-(N-(2'-N-tert- butylaminosulfonyl-[l,l']-biphen-4-yl))carboxyamide followed the same procedure of Step 3 for Example 34.
Step 2. The above-prepared compound (30 mg, 0.05 mmol) was placed in 3 mL TFA and refluxed for 1 hour. After concentration, it was purified with prep HPLC to yield the title compound (85%). ES-MS: (M+H)+ 526.
Example 36
Figure imgf000190_0002
This compound was prepared by the same methodology described for Example 34 with 2'-N-tert-butylaminosulfonyl-3-fluoro-[l,l']-biphenyl-4-ylamine substituted for 2'-N- tert-butylaminosulfonyl-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 526. Example 37.
Figure imgf000191_0001
This compound was prepared by the same methodology described for Example 35 with 2'-N-tert-butylaminosulfonyl-3-fluoro-[l, ]-biphenyl-4-ylamine substituted for 2'-N- tert-butylaminosulfonyl-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 544.
Example 38
Figure imgf000191_0002
Step 1. The synthesis of ethyl 3-methyl-l-(3-cyano-2-naphthyl)-lH-pyrazole-carboxylate followed the same procedure of Step 2 for Example 34.
Step 2. The above-prepared ester (930 mg, 3.0 mmol) was dissolved in 20 mL methanol. To it were added LiOH.H2O (256 mg, 6.0 mmol) and 10 mL water. The mixture was stined for 3 hours at room temperature. Methanol was removed in vacuuo. The residue was carefully acidified with IN HCI till pH 1. It was extracted with EtOAc (X4). The organic phases were combined, dried and evaporated in vacuuo till dryness to give 3- methyl-l-(3-cyano-2-naphthyl)-lH-pyrazole-5-carboxylic acid (720 mg, 85%). ES-MS: (M+H)+ 278. Step 3. The mixture of the above-prepared acid (110 mg, 0.40 mmol), 2'-N-tert- butylaminosulfonyl-3-chloro-[l,l']-biphenyl-4-ylamine (0.21 g, 0.60 mmol), DMAP (5 mg) were dissolved in 5 mL pyridine and stiπed at 0°C. To it was added POCl3 (120 μL, 1.2 mmol). The mixture was stirred for 2.5 hours and quenched with ice chips. It was diluted with EtOAc, washed with brine (X2), dried, concentrated and purified with flash column to give 3-methyl-l-(3-cyano-2-naphthyl)-lH-pyrazole-5-(N-(2'-N-tert- butylaminosulfonyl-3-chloro-[l,l']-biphen-4-yl))carboxyamide (240 mg, 95%). Rf 0.65 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 598.
Step 4. The above-prepared compound (30 mg, 0.05 mmol) was dissolved in 5 mL dry DCM. At 0°C, to it was added BF3.OEt2 (62 μL, 0.5 mmol) dropwise. The mixture was stirred overnight. Extra 1.0 mmol BF3.OEt2 was added in small portions at room temperature the next day. After another overnight, deprotection was about 70% complete. The mixture was loaded on a short flash column for separation. The title product was purified using prep HPLC (52% yield). ES-MS: (M+H)+ 542.
Example 39.
Figure imgf000192_0001
Step 1. The synthesis of 3-methyl-l-(3-cyano-2-naphthyl)-lH-pyrazole-5-(N-(2'-N-tert- butylaminosulfonyl-3-chloro-[l,l']-biphen-4-yl))carboxyamide followed the same procedure of Step 3 for Example 38.
Step 2. The above-prepared compound (30 mg, 0.05 mmol) was placed in 3 mL TFA and refluxed for 1 hour. After concentration, it was purified with prep HPLC to yield the title compound (85%). ES-MS: (M+H)+ 560. Example 40
Figure imgf000193_0001
This compound was prepared by the same methodology described for Example 38 with 2'-N-tert-butylaminosulfonyl-3-bromo-[l,l']-biphenyl-4-ylamine substituted for 2'-N- tert-butylaminosulfonyl-3-chloro-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 586, 588 (Br pattern).
Example 41.
Figure imgf000193_0002
This compound was prepared by the same methodology described for Example 39 with 2'-N-tert-butylaminosulfonyl-3-bromo-[l,l ']-biphenyl-4-ylamine substituted for 2'-N- tert-butylaminosulfonyl-3-chloro-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 604, 606 (Br pattern).
Example 42
Figure imgf000194_0001
This compound was prepared by the same methodology described for Example 38 with 2- amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyridine substituted for 2'-N-tert- butylaminosulfonyl-3-chloro-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 509.
Example 43.
Figure imgf000194_0002
This compound was prepared by the same methodology described for Example 39 with 2- amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyridine substituted for 2'-N-tert- butylaminosulfonyl-3-chloro-[l,l ']-biphenyl-4-ylamine. ES-MS: (M+H)+ 527.
Example 44
Figure imgf000195_0001
This compound was prepared by the same methodology described for Example 38 with 2- amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyrimidine substituted for 2'-N-tert- butylaminosulfonyl-3-chloro-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 510.
Example 45.
Figure imgf000195_0002
This compound was prepared by the same methodology described for Example 39 with 2- amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyrimidine substituted for 2'-N-tert- butylaminosulfonyl-3-chloro-[l,l ']-biphenyl-4-ylamine. ES-MS: (M+H)+ 528.
Example 46.
Figure imgf000195_0003
Step 1. To a solution of 4-nitroaniline (1.0 g, 6.7 mmol) in 50 mL anhydrous ethanol at 0°C was bubbled dry HCI gas via a long needle till saturation reached. The resulting solution was stined overnight. The solvent was removed in vacuuo. The residue was pumped to dryness. It was dissolved in 50 mL anhydrous ethanol. To it was added 2 mL N-methylethylenediamine. The mixture was refluxed for 1 hour and evaporated in vacuuo to give the l-methyl-2-(4-nitrophenyl)-2-imidazoline HCI salt in 90% yield. ES-MS: (M+H)+ 206.
Step 2. To a solution of the above-prepared nitro compound (500 mg, 2.4 mmol) in 4 mL 4N HCI and 50 mL methanol was added 10% Pd/C (50 mg). The mixture was stined for 2 hours under a hydrogen balloon. It was filtered through celite and concentrated in vacuuo to give the 4-(l-methyl-2-imidazolin-2-yl)aniline HCI salt in 90% yield. ES-MS: (M+H)+ 176.
Step 3. To a solution of the above-prepared amine (40 mg, 0.22 mmol), 3-methyl-l-(3- cyano-2-naphthyl)-lH-pyrazole-5-carboxylic acid (15 mg, 0.054 mmol, see Step 2, Example 38), DMAP (2 mg) in 2 mL pyridine at 0°C was added POCl3 (20 μL, 0.22 mmol). The mixture was stined for 2 hours. It was concentrated in vacuuo and loaded on prep HPLC to afford the title compound in 60% yield. ES-MS: (M+H)+ 435.
Example 47.
Figure imgf000196_0001
The title compound in Example 46 (10 mg) was placed in TFA. It was refluxed for 1 hour and subjected on prep HPLC purification to afford the title compound in 85% yield. ES- MS: (M+H)+ 453. Example 48.
Figure imgf000197_0001
Step 1. To a solution of 2-fluoro-4-nitroaniline (300 mg, 2.2 mmol) in 20 mL anhydrous methanol at 0°C was bubbled dry HCI gas via a long needle till saturation reached. The resulting solution was stined overnight. The solvent was removed in vacuuo. The residue was pumped to dryness. It was dissolved in 10 mL anhydrous methanol. To it was added 1 mL N-methylethylenediamine. The mixture was refluxed for 1 hour and evaporated in vacuuo to give the l-methyl-2-(2-fluoro-4-nitiOphenyl)-2-imidazoline HCI salt in 90% yield. ES-MS: (M+H)+ 224.
Step 2. To a solution of the above-prepared nitro compound in 2 mL 4N HCI and 25 mL methanol was added 10% Pd/C (20 mg). The mixture was stined for 2 hours under a hydrogen balloon. It was filtered through celite and concentrated in vacuuo to give the 2- fluoro-4-(l-methyl-2-imidazolin-2-yl)aniline HCI salt in 90% yield. ES-MS: (M+H)+ 194.
Step 3. To a solution of the above-prepared amine (100 mg, 0.51 mmol) in 2 mL DCM was added trimethylaluminum (2.0M in hexane, 2 mL, 4.0 mmol). The mixture was stined for 20 minutes. Ethyl 3-methyl-l-(3-cyano-2-naphthyl)-lH-pyrazole-carboxylate (76 mg, 0.25 mmol, see Step 2 of Example 34) was dissolved in 2 mL DCM and added into the reaction flask. The mixture was stined for 2 days at room temperature. It was quenched with saturated Rochelle's salt aq solution and extracted with CHC13 (X4). The organic phases were combined, dried, concentrated and purifed with prep HPLC to yield the title compound (55%). ES-MS: (M+H)+ 453. Example 49.
Figure imgf000198_0001
The title compound in Example 48 (10 mg) was placed in TFA. It was refluxed for 1 hour and subjected on prep HPLC purification to afford the title compound in 85% yield. ES- MS: (M+H)+ 471.
Example 50.
Figure imgf000198_0002
Step 1. Compound 3-methyl-l-(3-cyano-2-naphthyl)-lH-pyrazole-5-(N-(2'-N-tert- butylaminosulfonyl-[l,l']-biphen-4-yl))carboxyamide was prepared by the same procedure shown in Step 3 of Example 34.
Step 2. The above-prepared compound (70 mg, 0.12 mmol) was dissolved in 2 mL dry DMF. At 0°C, to it were added sodium borohydride (36 mg, 0.96 mmol) and CoCl2 (32 mg, 0.24 mmol). It was stined for 2 days. Diluted with EtOAc and stined for 1 hour. The mixture was filtered through celite. The filtrate was evaporated to give crude 3-methyl-l- (3-aminomethyl-2-naphthyl)-lH-pyrazole-5-(N-(2'-N-tert-butylaminosulfonyl-[l,l']- biphen-4-yl))carboxyamide. ES-MS: (M+H)+ 568. Step 3. The above-prepared crude compound was taken into 3 mL TFA. The mixture was stined for 1 hour at 60°C. The mixture was evaporated and subjected on prep HPLC to isolate the title compound (35% yield). ES-MS: (M+H)+ 512.
Example 51.
Figure imgf000199_0001
Step 1. Compound 3-methyl-l-(3-cyano-2-naphthyl)-lH-pyrazole-5-(N-(2'-N-tert- butylaminosulfonyl-3-fluoro-[l,l']-biphen-4-yl))carboxyamide was prepared by the same methodology shown in Step 3 of Example 34, with 2'-N-tert-butylaminosulfonyl-3- fluoro-[l,l']-biphenyl-4-ylamine substituted for 2'-N-tert-butylaminosulfonyl-[l,l']- biphenyl-4-ylamine. ES-MS: (M+H)+ 582.
Step 2. To a solution of the above-prepared compound (77 mg, 0.13 mmol) in 3 mL anhydrous methanol and 3 mL anhydrous EtOAc at -20°C was bubbled dry HCI gas via a long needle till saturation reached. The mixture was stined for overnight. The solvent was removed in vacuuo. The dry residue was dissolved in 5 mL anhydrous methanol. To it was added 50 mg ammonium acetate. The mixture was refluxed for 2.5 hours. It was subjected on prep HPLC to isolate the title compound (55% yield). ES-MS: (M+H)+ 543.
Example 52.
Figure imgf000200_0001
Step 1. 3-Amino-2-naphthoic acid (5.8 g, 31 mmol) was placed in 50 mL concentrate HCI. The slurry was vigorously stined at 0°C. To it was added dropwise a cold solution of sodium nitrite (2.35 g, 34 mmol, in 14 mL water). After completion, the mixture was stined for 40 minutes at 0°C. Under vigorously stirring, a cold solution of SnCl2.2H2O (21 g, 93 mmol, in 30 mL concentrate HCI) was added dropwise. The mixture was stined for 30 minutes and chilled in ice bath. The crude 3-carboxyl-2-naphthylhydrazine was collected with a Buchner funnel and pumped to dryness in vacuuo.
Step 2. The crude hydrazine prepared above was taken into 60 mL glacial acetic acid and 30 mL THF. To it was added ethyl 2-N-(methoxy)imino-4-oxopentanoate (2.6 g, 14 mmol). The mixture was refluxed for overnight. The solvent was removed in vacuuo. The residue was dissolved in EtOAc and washed with brine (X2). The organic phase was dried, concentrated and purified with flash column to yield ethyl 3-methyl-l-(3-carboxyl- 2-naphthyl)-lH-pyrazole-5-carboxylate (4.1 g, 90%). Rf 0.15 (1:1 EtOAc: hexane). ES- MS: (M+H)+ 325.
Step 3. To a solution of 2'-N-tert-butylaminosulfonyl-[l, ]-biphenyl-4-ylamine (36 mg, 0.12 mmol) in 1 mL dry DCM was added trimethylaluminum (2.0M in hexane, 0.5 mL, 1.0 mmol). The mixture was stined for 20 minutes. The above-prepared ester (38 mg, 0.12 mmol) was dissolved in 3 mL dry DCM and added into the aluminum mixture. The reaction was stined at room temperature for overnight and quenched using saturated Rochelle's salt aq solution. It was extracted with CHC13 (X3). The organic phases were combined, dried, concentrated and purified with flash column to yield the coupling product (60%). ES-MS: (M+H)+ 583. Step 4. The above-prepared compound (15 mg) was placed in 3 mL TFA and stined overnight. It was concentrated and purified with prep HPLC to afford the title compound in 90% yield. ES-MS: (M+H)+ 527.
Example 53.
Figure imgf000201_0001
This compound was prepared by the same methodology described for Example 52 with 2 '-N-tert-butylaminosulfonyl-3 -fluoro- [l,l']-biphenyl-4-ylamine substituted for 2'-N- tert-butylaminosulfonyl-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 545.
Step 1. The above-prepared crude acid was dissolved in 150 mL anhydrous ethanol. To it was added pTSA (3.3 g). The mixture was refluxed for 4 days till the esterification was over 95% complete. The solvent was removed in vacuuo. The residue was dissolved in EtOAc, washed with brine (X3), dried and purified by a short silica column to afford ethyl 3-methyl-l-(3-methylthio-2-naphthyl)-lH-pyrazole-5-carboxylate in over 80% yield. ES-MS: (M+H)+ 327.
Step 2. The above-prepared ester (4.95 g, 15 mmol) was dissolved in 150 mL DCM. At 0°C, to the vigorously stined solution was added MCPBA (11 g, 38 mmol) in small portions over 20 minutes. The reaction was allowed for 1 hour and diluted with CHC13. It was washed with NaHCO3 saturated aq solution (X3), dried, concentrated and purified with flash column to give ethyl 3-methyl-l-(3-methylsulfonyl-2-naphthyl)-lH-pyrazole- 5-carboxylate (3.49 g, 65%). Rf 0.52 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 359.
Step 3. To a solution of 2'-N-tert-butylaminosulfonyl-[l,l']-biphenyl-4-ylamine (21 mg, 0.068 mmol) in 1 mL dry DCM was added trimethylaluminum (2.0M in hexane, 0.14 mL, 0.28 mmol). The mixture was stined for 20 minutes. The above-prepared ester (16 mg, 0.045 mmol) in Step 4 was dissolved in 4 mL dry DCM and added into the aluminum mixture. The reaction was stined at room temperature for overnight and quenched using saturated Rochelle's salt aq solution. It was extracted with CHC13 (X3). The organic phases were combined, dried, concentrated and purified with flash column to yield the coupling product (52%). Rf 0.17 (1:1 EtOAc: Hexane). ES-MS: (M+H)+ 617.
Step 4. The above-prepared compound was dissolved in 2 mL acetonitrile and 2 mL TFA. The mixture was stined for 1 hour at 70°C. The mixture was evaporated and purified with prep HPLC to afford the title compound in 90% yield. ES-MS: (M+H)+ 561.
Example 54.
Figure imgf000202_0001
Step 1. The synthesis of ethyl 3-methyl-l-(3-methylsulfonyl-2-naphthyl)-lH-pyrazole-5- carboxylate was the same as that described in Step 4 of Example 53.
Step 2. The above-prepared ester (3.4 g, 9.7 mmol) was dissolved in 20 mL methanol. To it were added LiOH.H2O (0.82 g, 19.5 mmol) and 10 mL water. The mixture was stined at room temperature for overnight. The solvent was evaporated. The residue was acidified with IN HCI till pH 1. The mixture was extracted with EtOAc (X4). The organic phases were combined, dried, evaporated to dryness to afford 3-methyl-l-(3-methylsulfonyl-2- naphthyl)-lH-pyrazole-5-carboxylic acid (3.24 g, 99%). ES-MS: (M+H)+ 331.
Step 3. The above-prepared acid (102 mg, 0.31 mmol), 2'-N-tert-butylaminosulfonyl-3- fluoro-[l,l ']-biphenyl-4-ylamine (150 mg, 0.46 mmol), DMAP (10 mg) were dissolved in 3 mL pyridine. To this stirred solution at 0°C was added POCl3 (87 μL, 0.93 mmol). The mixture was stined for 2 hours and quenched with ice chips. It was diluted with EtOAc, washed with brine (X2), dried, concentrated and purified with flash column to give the coupling product (130 mg, 66%). Rf 0.29 (1:1 EtOAc: hexane). MS: (M+H)+ 635.
Step 4. The above-prepared compound (100 mg) was taken into 5 mL TFA and stirred at room temperature for overnight. After evaporation, the mixture was subjected on prep HPLC to isolate the title compound (90%). MS: (M+H)+ 579.
Example 55.
Figure imgf000203_0001
This compound was prepared by the same methodology described for Example 54 with 2'-N-tert-butylaminosulfonyl-3-chloro-[l,l']-biphenyl-4-ylamine substituted for 2'-N- tert-butylaminosulfonyl-3-fluoro-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 595.
Example 56.
Figure imgf000203_0002
This compound was prepared by the same methodology described for Example 54 with 2'-N-tert-butylaminosulfonyl-3-bromo-[l,l']-biphenyl-4-ylamine substituted for 2'-N- tert-butylaminosulfonyl-3-fluoro-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 639, 641 (Br pattern).
Example 57.
Figure imgf000204_0001
This compound was prepared by the same methodology described for Example 54 with 2- amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyridine substituted for 2'-N-tert- butylaminosulfonyl-3-fluoro-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 562.
Example 58.
Figure imgf000204_0002
This compound was prepared by the same methodology described for Example 54 with 2- amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyrimidine substituted for 2'-N-tert- butylaminosulfonyl-3-fluoro-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 563.
Example 59.
Figure imgf000205_0001
This compound was prepared by the same methodology described for Example 54 with for 2'-methylsulfonyl-[l,l']-biphenyl-4-ylamine substituted for 2'-N-tert- butylaminosulfonyl-3-fluoro-[l,l']-biphenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)+ 560.
Example 60.
Figure imgf000205_0002
This compound was prepared by the same methodology described for Example 54 with for 2'-cyano-[l,l']-biphenyl-4-ylamine substituted for 2'-N-tert-butylaminosulfonyl-3- fluoro-[l,l']-biphenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)+ 507.
Example 61.
Figure imgf000206_0001
The title compound of Example 60 (55 mg, 0.11 mmol) was dissolved in 2 mL anhydrous DMF. To this stined solution at 0°C were added sodium borohydride (33 mg, 0.88 mmol) and CoCl2 (30 mg, 0.22 mmol). The reaction was allowed for 2 hours and quenched with acetic acid. The mixture was evaporated, diluted with EtOAc, and washed with NaHCO3 aq solution. The organic phase was dried, evaporated and purified with prep HPLC to afford the title compound in 55% yield. ES-MS: (M+H)+ 511.
Example 62.
Figure imgf000206_0002
This compound was prepared by the same methodology described for Example 54 with for 2'-(N-dimethylaminomethyl)-[l,l']-biphenyl-4-ylamine substituted for 2'-N-tert- butylaminosulfonyl-3-fluoro-[l, ]-biphenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)+ 539. Example 63.
Figure imgf000207_0001
This compound was prepared by the same methodology described for Example 54 with for 3'-(N-tert-Boc-aminomethyl)-[l, ]-biphenyl-4-ylamine substituted for 2'-N-tert- butylaminosulfonyl-3-fluoro-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 511.
Example 64.
Figure imgf000207_0002
This compound was prepared by the same methodology described for Example 54 with for l-(4-Aminophenyl)-4-methylpiperazine hydrochloride substituted for 2'-N-tert- butylaminosulfonyl-3-fluoro-[l , 1 ']-biphenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)+ 504.
Example 65.
Figure imgf000208_0001
This compound was prepared by the same methodology described for Example 54 with for l-(N-methylpiperidin-4-yl)-piperazine substituted for 2'-N-tert-butylaminosulfonyl-3- fluoro-[l , 1 ']-biρhenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)+ 496.
Example 66.
Figure imgf000208_0002
This compound was prepared by the same methodology described for Example 54 with for l-(4-pyridyl)-piperazine substituted for 2'-N-tert-butylaminosulfonyl-3-fluoro-[l, ]- biphenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)+ 476.
Example 67.
Q Q This compound was prepared by the same methodology described for Example 54 with for 4-(N-pynolidinylcarbonyl)-aniline substituted for 2'-N-tert-butylaminosulfonyl-3- fluoro-[l,l']-biphenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)+ 503.
Example 68.
Figure imgf000209_0001
Step 1. The synthesis of 3-methyl-l-(3-methylsulfonyl-2-naphthyl)-lH-pyrazole-5- carboxylic acid was the same as that described in Step 2 of Example 54.
Step 2. The above-prepared acid (200 mg, 0.61 mmol), 4-aminobenzonitrile (108 mg, 0.91 mmol) and DMAP (10 mg) were dissolved in 6 mL pyridine. The solution was stined at 0°C. To it was added POCl (170 μL, 1.8 mmol). The mixture was stirred for 1 hour. The reaction was then quenched with ice chips. It was diluted with EtOAc. The organic phase was washed with brine (X2). It was dried, concentrated and purified with flash column to afford the coupling product (250 mg, 95%). Rf 0.20 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 431.
Step 3. The above-prepared nitrile (70 mg, 0.16 mmol) was dissolved in 6 mL dry methanol. It was chilled and stined in an ice bath. To this solution was bubbled dry HCI gas via a long needle till saturation reached (indicated by a blown-up balloon attached on the top of the reaction flask). The resulting solution was stined overnight. ES-MS:
(M+H)+ 463. The solvent was removed in vacuuo. The residue was pumped to dryness. The solid was dissolved in 6 mL dry methanol. To it was added anhydrous N- methylethylenediamine (0.5 mL). The mixture was refluxed for 1 hour, concentrated and loaded on prep HPLC to afford the title compound in 80% yield. ES-MS: (M+H)+ 488. Example 69.
Figure imgf000210_0001
This compound was prepared by the same methodology described for Example 68 with pyrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 502.
Example 70.
Figure imgf000210_0002
This compound was prepared by the same methodology described for Example 68 with moφholine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 518.
Example 71.
This compound was prepared by the same methodology described for Example 68 with N-methylpiperazine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 531. Example 72.
Figure imgf000211_0001
This compound was prepared by the same methodology described for Example 68 with 4- amino-3-fluorobenzonitrile (preparation described in Step 1 of Example 22) substituted for 4-aminobenzonitrile. ES-MS: (M+H)+ 506.
Example 73.
Figure imgf000211_0002
This compound was prepared by the same methodology described for Example 68 with 4- amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with N-methyl-1,3- propanediamine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 520.
Example 74.
Figure imgf000212_0001
This compound was prepared by the same methodology described for Example 68 with 4- amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with pynolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 520.
Example 75.
Figure imgf000212_0002
This compound was prepared by the same methodology described for Example 68 with 4- amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with piperidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 534.
Example 76,
Figure imgf000213_0001
This compound was prepared by the same methodology described for Example 68 with 4- amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with dimethylamine (2M solution in THF) substituted for N-methylethylenediamine. ES-MS: (M+H)+ 494.
Example 77.
Figure imgf000213_0002
This compound was prepared by the same methodology described for Example 68 with 4- amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with ammonium acetate substituted for N-methylethylenediamine. ES-MS: (M+H)+ 466.
Example 78.
Figure imgf000213_0003
Step 1. To a solution of 2-bromo-6-methoxynaphthalene (2.0 g, 8.4 mmol) in 20 mL anhydrous THF at -78°C was added BuLi (1.6M, 7.9 mL, 12.6 mmol) dropwise with a syringe. The mixture was stined for 30 minutes, then to it was added triisopropyl borane (2.34 mL, 10.1 mmol) dropwise. The dry ice bath was removed. The reaction mixture was allowed to warm up to room temperature. After 15 hours, THF was mostly removed in vacuuo. To the residue was added 40 mL 3M HCI. The mixture was stined at room temperature for 8 hours. Ether was used to extract the product (X3). The organic phases were combined, dried, concentrated in vacuuo and pumped to dryness to afford 6- methoxy-2-naphthylboronic acid (75% yield) as a white solid. Rf 0.34 (1: 1 EtOAc: hexane).
Step 2. To a solution of the above-prepared boronic acid (0.84 g, 3.2 mmol) and ethyl 3- methylpyrazole-5-carboxylate (0.49 g, 3.2 mmol) in 20 mL dry DCM were added pyridine (0.77 mL, 9.5 mmol) and anhydrous powder of copper(II) acetate (1.15 g, 6.3 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was stined for 4 days under argon. The mixture was diluted with DCM. It was filtered through celite. The blue filtrate was washed with water (X2), dried, concentrated and purified by flash column to separately afford ethyl 3 -methyl- l-(6-methoxy-2- naphthyl)-lH-pyrazole-5-carboxylate [37% yield. Rf 0.80 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 311] and ethyl 5-methyl-l-(6-methoxy-2-naphthyl)-lH-pyrazole-3-carboxylate [25% yield. Rf 0.69 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 311] in a 1.5:1 ratio.
Step 3. To a solution of 2'-N-tert-butylaminosulfonyl-[l, ]-biphenyl-4-ylamine (44 mg, 0.14 mmol) in 1 mL DCM was added trimethylaluminum (2.0M in hexane, 0.35 mL, 0.70 mmol) at room temperature. The mixture was stined for 30 minutes, and to it was added the above-prepared ethyl 3 -methyl- l-(6-methoxy-2-naphthyl)-lH-pyrazole-5 -carboxylate (44 mg, 0.14 mmol) in 2 mL DCM. The resulting mixture was stined overnight. The reaction was quenched using 5 mL saturated Rochelle salt aq solution. The mixture was extracted using DCM (X3). The organic phases were combined, dried, concentrated and subjected on flash column to afford the coupling product in 84% yield (67 mg). Rf 0.41 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 569. Step 4. The above-prepared compound was placed in 3 mL TFA and stined at 65°C for 30 minutes. After evaporation, the residue was dissolved in methanol and purified with prep HPLC to afford the title compound in 95% yield. ES-MS: (M+H)+ 513.
Example 79.
Figure imgf000215_0001
Step 1. The preparation of ethyl 3-methyl-l-(6-methoxy-2-naphthyl)-lH-pyrazole-5- carboxylate was the same as described in Step 2 of Example 83.
Step 2. The above-prepared compound (150 mg, 0.48 mmol) was dissolved in 2 mL DCM. At 0°C, to the stined solution was added boron tribromide (1.0M in DCM, 0.72 mL, 0.72 mmol). The mixture was stined overnight at room temperature. It was directly subjected to flash column to afford ethyl 3 -methyl- l-(6-hy droxy-2-naphthyl)-lH- pyrazole-5-carboxylate (78 mg, 55%). Rf 0.73 (2:1 EtOAc: hexane). ES-MS: (M+H)+ 297.
Step 3. To a stined solution of 2'-N-tert-butylaminosulfonyl-[l, ]-biphenyl-4-ylamine (80 mg, 0.26 mmol) in 1 mL DCM was added trimethylaluminum (2.0M in hexane, 0.65 mL, 1.3 mmol) at room temperature. After 30 minutes, to the mixture was added ethyl 3- methyl-l-(6-hydroxy-2-naphthyl)-lH-pyrazole-5-carboxylate (78 mg, 0.26 mmol) in 3 mL DCM. The resulting mixture was stined 4 hours. The reaction was quenched using 5 mL saturated Rochelle salt aq solution. The mixture was extracted using DCM (X3). The organic phases were combined, dried, concentrated and purified with flash column to afford the coupling product in 65% yield. Rf 0.32 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 555. Step 4. The above-prepared compound was placed in 3 mL TFA and stined at 70°C for 30 minutes. After evaporation, the residue was dissolved in methanol and purified with prep HPLC to afford the title compound in 95% yield. ES-MS: (M+H)+ 499.
Example 80.
Figure imgf000216_0001
Step 1. A mixture of 6-bromo-2-naphthoic acid (1.11 g, 4.4 mmol) and 2 mL thionyl chloride was refluxed for overnight. Thionyl chloride was removed in vacuuo. The dry acid chloride was dissolved in 5 mL dioxane. At 0°C to it was added a solution of sodium azide (0.52 g, 8.0 mmol) in 2.5 mL water and 2.5 mL dioxane dropwise. The mixture was stined for 2 hours. After evaporation in vacuuo to remove the solvent, the residue was dissolved in EtOAc, washed with brine, dried, concentrated in vacuuo to give the azidoketone (1.22 g, 99%). Rf 0.88 (1:1 EtOAc: hexane).
Step 2. The above-prepared compound was dissolved in 20 mL DMF. To it was added 10 mL water. The mixture was refluxed overnight. It was diluted with 500 mL EtOAc, washed with brine (X2), dried, concentrated in vacuuo to afford 6-bromo-2- naphthylamine (1.2 g, 99%). Rf 0.73 (1:1 EtOAc: hexane), ES-MS: (M+H)+ 222, 224 (Br pattern).
Step 3. The above-prepared compound (1.2 g, 5.4 mmol) was placed in 6 mL concentrate HCI. At 0°C to it was added a solution of sodium nitrite (0.37 g, 5.4 mmol) in 2 mL water dropwise. The mixture was stirred for 30 minutes. At 0°C to the mixture was added a solution of SnCl2.2H2O (3.66 g, 16.2 mmol) in 6 mL concentrate HCI dropwise. After stirring for 10 minutes, the mixture was placed in a freezer for overnight. The solid was collected on a cold Buchner funnel. It was washed by ice-cold brine (7 mL) and ice-cold hexane (7 mL). The solid cake was transfened into a flask and pumped to dryness. To it were added 30 mL acetic acid, 15 mL THF, and ethyl 2-N-(methoxy)imino-4- oxopentanoate (1.3 g, 7.0 mmol). The resulting mixture was refluxed for overnight. The solvent was removed in vacuuo. The residue was dissolved in EtOAc, washed with brine (X2), dried, concentrated and purified by flash column to yield ethyl 3-methyl-l-(6- bromo-2-naphthyl)- 1 H-pyrazole-5-carboxylate (0.64 g, 33%). Rf 0.71 ( 1 :2 EtOAc: hexane). ES-MS: (M+H)+ 359, 361 (Br pattern).
Step 4. To a stined solution of 2'-N-tert-butylaminosulfonyl-[l, ]-biphenyl-4-ylamine (93 mg, 0.31 mmol) in 1 mL DCM was added trimethylaluminum (2.0M in hexane, 0.70 mL, 1.4 mmol) at room temperature. After 30 minutes, to the mixture was added the above-prepared ethyl ester (100 mg, 0.28 mmol) in 3 mL DCM. The resulting mixture was stined overnight. The reaction was quenched using 5 mL saturated Rochelle's salt aq solution. The mixture was extracted using DCM (X3). The organic phases were combined, dried, evaporated and purified with flash column to yield the coupling product (146 mg, 85%). Rf 0.44 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 617, 619 (Br pattern).
Step 5. The above-prepared compound was placed in 3 mL TFA and stined at 65°C for 40 minutes. After evaporation, the residue was dissolved in methanol and purified with prep HPLC to afford the title compound in 95% yield. ES-MS: (M+H)+ 561, 563 (Br pattern).
Example 81.
Figure imgf000218_0001
This compound was prepared by the same methodology described for Example 80 with 2'-N-tert-butylaminosulfonyl-3-fluoro-[l, ]-biphenyl-4-ylamine substituted for 2'-N- tert-butylaminosulfonyl-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 579, 581 (Br pattern).
Example 82.
Figure imgf000218_0002
This compound was prepared by the same methodology described for Example 80 with 2'-N-tert-butylaminosulfonyl-3-chloro-[l,l']-biphenyl-4-ylamine substituted for 2'-N- tert-butylaminosulfonyl-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 595, 597 (BrCl pattern).
Example 83.
Figure imgf000219_0001
This compound was prepared by the same methodology described for Example 80 with 2'-N-tert-butylaminosulfonyl-3-bromo-[l, ]-biphenyl-4-ylamine substituted for 2'-N- tert-butylaminosulfonyl-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 640, 642, 644 (Br2 pattern).
Example 84.
Figure imgf000219_0002
This compound was prepared by the same methodology described for Example 80 with 2'-N-tert-butylaminosulfonyl-5'-chloro-[l,r]-biphenyl-4-ylamine substituted for 2'-N- tert-butylaminosulfonyl-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 595, 597 (BiCl pattern).
Example 85.
Figure imgf000220_0001
This compound was prepared by the same methodology described for Example 80 with 5- (2-N-tert-butylaminosulfonyl-l-phenyl)-2,3-dihydroindole substituted for 2'-N-tert- butylaminosulfonyl-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 587, 589 (Br pattern).
Example 86.
Figure imgf000220_0002
Step 1. The synthesis of ethyl 3-methyl-l-(6-bromo-2-naphthyl)-lH-pyrazole-5- carboxylate was the same as Step 3 of Example 80.
Step 2. The above-prepared ethyl ester (1.0 g, 2.8 mmol) was dissolved in 20 mL methanol. To the solution were added LiOH.H2O (350 mg, 8.3 mmol) and 10 mL water. The mixture was stined for overnight and evaporated in vacuuo. The residue was acidified with IN HCI. It was extracted with EtOAc (X4). The organic phases were combined, dried and concentrated in vacuuo to give 3-methyl-l-(6-bromo-2-naphthyl)- lH-pyrazole-5-carboxylic acid (0.97 g, 100%). ES-MS: (M+H)+ 331, 333 (Br pattern).
Step 3. A mixture of the above-prepared acid (33 mg, 0.10 mmol), 2-amino-5-(2-(N-tert- butylaminosulfonyl)phenyl)pyridine (61 mg, 0.20 mmol), DMAP (5 mg) were dissolved in 3 mL pyridine and stined at 0°C. To it was added POCl3 (55 μL, 0.6 mmol). The mixture was stined for 2 hours and quenched with ice chips. It was diluted with EtOAc, washed with brine (X2), dried, concentrated and purified with flash column to give the coupling product (34 mg, 55%). Rf 0.35 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 618, 620 (Br pattern).
Step 4. . The above-prepared compound was placed in 3 mL TFA and stined at 65°C for 40 minutes. After evaporation, the residue was dissolved in methanol and purified with prep HPLC to afford the title compound in 95% yield. ES-MS: (M+H)+ 562, 564 (Br pattern).
Example 87.
Figure imgf000221_0001
This compound was prepared by the same methodology described for Example 86 with 2- amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyrimidine substituted for 2-amino-5-(2- (N-tert-butylaminosulfonyl)phenyl)pyridine. ES-MS: (M+H)+ 563, 565 (Br pattern).
Example 88.
Figure imgf000222_0001
Step 1. The synthesis of 3-methyl-l-(6-bromo-2-naphthyl)-lH-pyrazole-5-carboxylic acid was the same as Step 2 of Example 86.
Step 2. A mixture of the above-prepared acid (970 mg, 2.9 mmol), 4-aminobenzonitrile (700 mg, 5.8 mmol), DMAP (40 mg) were dissolved in 15 mL pyridine and stined at 0°C. To it was added POCl3 (1.1 mL, 12 mmol). The mixture was stined for 1 hour and quenched with ice chips. It was diluted with EtOAc, washed with brine (X2), dried, concentrated and purified with flash column to give the coupling product (720 mg, 58%). Rf 0.30 (1: 1 EtOAc: hexane). ES-MS: (M+H)+ 431, 433 (Br pattern).
Step 3. The above-prepared nitrile (40 mg, 0.09 mmol) was dissolved in 6 mL dry methanol. It was chilled and stined in an ice bath. To this solution was bubbled dry HCI gas via a long needle till saturation reached. The resulting solution was stined overnight. ES-MS: (M+H)+ 463, 465 (Br pattern). The solvent was removed in vacuuo. The residue was pumped to dryness. The solid was dissolved in 6 mL dry methanol. To it was added anhydrous N-methylethylenediamine (0.5 mL). The mixture was refluxed for 1 hour, concentrated and loaded on prep HPLC to afford the title compound in 85% yield. ES- MS: (M+H)+ 488, 490 (Br pattern).
Example 89.
Figure imgf000223_0001
This compound was prepared by the same methodology described for Example 88 with pynolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 502, 504 (Br pattern).
Example 90.
Figure imgf000223_0002
This compound was prepared by the same methodology described for Example 88 with piperidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 516, 518 (Br pattern).
Example 91.
Figure imgf000223_0003
This compound was prepared by the same methodology described for Example 88 with moφholine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 518, 520 (Br pattern).
Example 92.
Figure imgf000224_0001
This compound was prepared by the same methodology described for Example 88 with N-methylpiperazine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 531, 533 (Br pattern).
Example 93.
Figure imgf000224_0002
This compound was prepared by the same methodology described for Example 88 with 4- amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile. ES-MS: (M+H)+ 506, 508 (Br pattern). Example 94.
Figure imgf000225_0001
This compound was prepared by the same methodology described for Example 88 with 4- amino-2,5-difluorobenzonitrile substituted for 4-aminobenzonitrile. ES-MS: (M+H)+ 524, 526 (Br pattern).
Example 95.
Figure imgf000225_0002
This compound was prepared by the same methodology described for Example 88 with 4- amino-3-chlorobenzonitrile substituted for 4-aminobenzonitrile. ES-MS: (M+H)+ 522, 524 (BrCl pattern).
Example 96.
Figure imgf000226_0001
This compound was prepared by the same methodology described for Example 88 with 4- amino-2-chlorobenzonitrile substituted for 4-aminobenzonitrile. ES-MS: (M+H)+ 522, 524 (BrCl pattern).
Example 97.
Figure imgf000226_0002
This compound was prepared by the same methodology described for Example 88 with 4- amino-2-chlorobenzonitrile substituted for 4-aminobenzonitrile, and with N-ethyl ethylenediamine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 536, 538 (BrCl pattern).
Example 98.
Figure imgf000227_0001
This compound was prepared by the same methodology described for Example 88 with 4- amino-3-chlorobenzonitrile substituted for 4-aminobenzonitrile, and with ethylenediamine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 508, 510 (BrCl pattern).
Example 99.
Figure imgf000227_0002
This compound was prepared by the same methodology described for Example 88 with 4- amino-3-chlorobenzonitrile substituted for 4-aminobenzonitrile, and with N-methyl-1,3- propanediamine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 536, 538 (BrCl pattern).
Example 100.
Figure imgf000228_0001
This compound was prepared by the same methodology described for Example 88 with 4- amino-3-chlorobenzonitrile substituted for 4-aminobenzonitrile, and with 1,3- propanediamine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 522, 524 (BrCl pattern).
Example 101.
Figure imgf000228_0002
This compound was prepared by the same methodology described for Example 88 with 4- amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with pynolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 520, 522 (Br pattern).
Example 102.
Figure imgf000229_0001
This compound was prepared by the same methodology described for Example 88 with 4- amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with 2- methylpynolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 534, 536 (Br pattern).
Example 103.
Figure imgf000229_0002
This compound was prepared by the same methodology described for Example 88 with 4- amino-2,5-difluorobenzonitrile substituted for 4-aminobenzonitrile, and with pynolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 538, 540 (Br pattern). Example 104.
Figure imgf000230_0001
This compound was prepared by the same methodology described for Example 88 with 4- amino-3-chlorobenzonitrile substituted for 4-aminobenzonitrile, and with pyrrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 536, 538 (BrCl pattern).
Example 105.
Figure imgf000230_0002
This compound was prepared by the same methodology described for Example 88 with 4- amino-2-chlorobenzonitrile substituted for 4-aminobenzonitrile, and with pynolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 536, 538 (BrCl pattern).
Example 106.
Figure imgf000231_0001
This compound was prepared by the same methodology described for Example 88 with 4- amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with thiomoφholine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 552, 554 (Br pattern).
Example 107.
Figure imgf000231_0002
This compound was prepared by the same methodology described for Example 88 with 4- amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with ammonium acetate substituted for N-methylethylenediamine. ES-MS: (M+H)+ 466, 468 (Br pattern).
Example 108.
Figure imgf000232_0001
This compound was prepared by the same methodology described for Example 88 with 4- amino-2,5-difluorobenzonitrile substituted for 4-aminobenzonitrile, and with methylamine (2M in methanol) substituted for N-methylethylenediamine. ES-MS: (M+H)+ 498, 500 (Br pattern).
Example 109.
Figure imgf000232_0002
This compound was prepared by the same methodology described for Example 88 with 4- amino-3-chlorobenzonitrile substituted for 4-aminobenzonitrile, and with dimethylamine (2M in THF) substituted for N-methylethylenediamine. ES-MS: (M+H)+ 510, 512 (BrCl pattern).
Example 110.
Figure imgf000233_0001
Step 1. To a solution of 6-bromo-2-naphthoic acid (4.4 g, 17.5 mmol) in 50 mL anhydrous DMF were added CuCl (8.7 g, 87.5 mmol) and Cul (0.2 g). The slurry was refluxed for 1 hour. At room temperature it was diluted with 300 mL EtOAc and stined for 2 hours. It was filtered through celite. The filtrate was evaporated in vacuuo to afford 6-chloro-2-naphthoic acid (2.7 g, 75%). ES-MS: (M+H)+ 207.
Step 2. The title compound was prepared using the same methodology shown for Example 80, with 6-chloro-2-naphthoic acid substituted for 6-bromo-2-naphthoic acid. ES-MS: (M+H)+ 517.
Example 111.
Figure imgf000233_0002
The title compound was prepared using the same methodology shown for Example 110, with 2'-N-tert-butylaminosulfonyl-3-fluoro-[l, ]-biphenyl-4-ylamine substituted for 2'- N-tert-butylaminosulfonyl- [l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 535. Example 112.
Figure imgf000234_0001
The title compound was prepared using the same methodology shown for Example 110, with 2'-methylsulfonyl-3-fluoro-[l,l']-biphenyl-4-ylamine substituted for 2'-N-tert- butylaminosulfonyl-[l,l']-biphenyl-4-ylamine. ES-MS: (M+H)+ 534.
Example 113.
Figure imgf000234_0002
The title compound was prepared using the same methodology shown for Example 93, with 6-chloro-2-naphthoic acid substituted for 6-bromo-2-naphthoic acid. ES-MS: (M+H)+ 462.
Example 114.
Figure imgf000234_0003
The title compound was prepared using the same methodology shown for Example 101, with 6-chloro-2-naphthoic acid substituted for 6-bromo-2-naphthoic acid. ES-MS: (M+H)+ 476.
Example 115.
Figure imgf000235_0001
The title compound was prepared using the same methodology shown for Example 114, with piperidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 490.
Example 116.
Figure imgf000235_0002
The title compound was prepared using the same methodology shown for Example 114, with dimethylamine (2M in THF) substituted for N-methylethylenediamine. ES-MS: (M+H)+ 450. Example 117.
Figure imgf000236_0001
Step 1. The synthesis of 3-methyl-l-(3-cyano-2-naphthyl)-lH-pyrazole-5-(N-(2'-N-tert- butylaminosulfonyl-[l,l']-biphen-4-yl))carboxyamide followed the same procedure shown in Step 3 of Example 34.
Step 2. To a solution of the above-prepared compound (30 mg) in 10 mL anhydrous ethanol at 0°C was bubbled dry HCI gas via a long needle till saturation reached. The mixture was stined for overnight. The solvent was removed in vacuuo. The dry residue was dissolved in 5 mL anhydrous methanol. To it was added 0.5 mL N- methylethylenediamine. The mixture was refluxed for 2 hours. ES-MS: (M+H)+ 621. It was concentrated in vacuuo. To the residue was added 3 mL TFA and the mixture was stined at 70°C for 1 hour. After evaporation, the reaction mixture was subjected on prep HPLC to isolate the title compound (20% yield). ES-MS: (M+H)+ 565.
Example 118.
Figure imgf000236_0002
The title compound was prepared using the same methodology shown for Example 117, with dimethylamine (2M in THF) substituted for N-methylethylenediamine. ES-MS: (M+H)+ 553. Example 119.
Figure imgf000237_0001
The title compound was prepared using the same methodology shown for Example 117, with pynolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 579.
Example 120.
Figure imgf000237_0002
The title compound was prepared using the same methodology shown for Example 1, with 2-N-tert-butylaminosulfonylphenylboronic acid substituted for 2-naphthylboronic acid. ES-MS: (M+H)+ 512.
Example 121.
Figure imgf000237_0003
The title compound was prepared using the same methodology shown for Example 1, with 2-methylsulfonylphenylboronic acid substituted for 2-naphthylboronic acid. ES-MS: (M+H)+ 511.
Example 122.
Figure imgf000238_0001
The title compound was prepared using the same methodology shown for Example 52, with commercial 2-nitrophenylhydrazine substituted for 3-carboxyl-2-naphthylhydrazine. ES-MS: (M+H)+ 478.
Example 123.
Figure imgf000238_0002
Step 1. 4-methylsulfonyl-3-nitrobenzoic acid (0.90 g, 3.7 mmol) was dissolved in 10 mL ethanol. To it were added hydrazine monohydrate (0.46 mL, 15 mmol) and catalytic amount of 10% Pd/C. The mixture was refluxed for 1.5 hour, diluted with methanol, filtered through celite and concentrated in vacuuo to afford 3-amino-4- methylsulfonylbenzoic acid (>70%). ES-MS: (M+H)+ 216.
Step 2. The above-prepared aniline (2.2 g, 10 mmol) was stined in 16 mL concentrate HCI in ice bath. To it was dropwise added a cold solution of sodium nitrite (1.1 g, 15 mmol, in 7 mL water). After completion, the mixture was stined for 30 minutes at 0°C. To it was added dropwise a cold solution of SnCl2.2H2O (9.2 g, 40 mmol, in 14 mL concentrate HCI). The mixture was stined for 30 minutes and filtered through a Buchner funnel. The solid crude hydrazine was collected and dried.
Step 3. The crude hydrazine was dissolved in 40 mL acetic acid. To it were added 20 mL THF and ethyl 2-N-(methoxy)imino-4-oxopentanoate (2.8 g, 15 mmol). The mixture was refluxed for overnight. After removal of the solvent in vacuuo, the reaction mixture residue was dissolved in 800 mL ether. The organic solution was washed with brine (X2), dried, concentrated and purified with flash column to afford ethyl 3-methyl-l-(5- carboxyl-2-methylsulfonylphenyl)-lH-pyrazole-5-carboxylate (2.1 g, 60%). Rf 0.17 (pure EtOAc). ES-MS: (M+H)+ 353.
Step 4. The above-prepared acid (2.1 g, 6.5 mmol) was dissolved in 50 mL dry DMF. To it were added tert-butylamine (1.4 mL, 13 mmol), DIEA (9.2 mL, 52 mmol) and PyBOP (13 g, 26 mmol) in order. The resulting mixture was stined for overnight at room temperature. DMF was removed in vacuuo. The residue was taken into EtOAc and washed with brine (X2). The organic phase was dried, concentrated and subjected on flash column to isolate ethyl 3-methyl- 1 -(5-N-tert-butylaminocarbonyl-2- methylsulfonylphenyl)-lH-pyrazole-5-carboxylate (0.74 g, 30%). Rf 0.70 (pure EtOAc). ES-MS: (M+H)+ 408.
Step 5. To a solution of 2'-N-tert-butylaminosulfonyl-[l,l']-biphenyl-4-ylamine (100 mg, 0.33 mmol) in 2 mL DCM was added trimethylaluminum (2.0M in hexane, 0.66 mL, 1.3 mmol) under argon at room temperature. After being stined for 30 minutes, to the mixture was added the above-prepared ester (90 mg, 0.22 mmol) in 10 mL DCM. The resulting mixture was stined overnight. The reaction was quenched using 10 mL saturated Rochelle's salt aq solution. The mixture was extracted using DCM (X3). The organic phases were combined, dried, rotovaped and subjected on flash chromatography column to give the coupled product in 62% yield (90 mg). Rf 0.10 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 666.
Step 6. The above-prepared compound (20 mg) was placed in 5 mL TFA. It was stined at 70°C for 1 hour and subjected on prep HPLC to isolate the title compound (90%) after evaporation. ES-MS: (M+H)+ 554. Example 124.
Figure imgf000240_0001
Step 1. To a solution of 4-biphenylboronic acid (1.0 g, 5.1 mmol) and ethyl 3- methylpyrazole-5-carboxylate (0.78 g, 5.1 mmol) in 25 mL dry DCM were added pyridine (1.2 mL, 15 mmol) and anhydrous powder of copper(II) acetate (1.84 g, 10 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was refluxed for 2 days under argon. The mixture was diluted with DCM, filtered through celite. The blue filtrate was washed with water (X2), dried, concentrated, purified with flush column to yield ethyl 3-methyl-l-(4-phenylphenyl)-lH-pyrazole-5-carboxylate (26%), Rf 0.67 (1 :2 EtOAc: hexane), ES-MS: (M+H)+ 307; and its regioisomer, ethyl 5- methyl-l-(4-ρhenylphenyl)-lH-pyrazole-3-carboxylate (31%), Rf 0.50 (1:2 EtOAc: hexane), ES-MS: (M+H)+ 307.
Step 2. To a stined solution of 4-chloroaniline (24 mg, 0.18 mmol) in 1 mL DCM was added trimethylaluminum (2.0M, 0.43 mL, 0.86 mmol) at room temperature. After 30 minutes, to the mixture was added ethyl 3-methyl-l-(4-phenylphenyl)-lH-pyrazole-5- carboxylate (52 mg, 0.17 mmol) in 3 mL DCM. The resulting mixture was stirred for overnight. It was quenched using 5 mL saturated Rochelle's salt aq solution. The mixture was extracted using DCM (X3). The organic phases were combined, dried, concentrated and subjected on flash column to afford the title compound (46 mg, 70%). Rf 0.46 (1 : 1 EtOAc: hexane). ES-MS: (M+H)+ 388. Example 125.
Figure imgf000241_0001
The title compound was prepared using the same methodology shown for Example 124, with 4-methoxyaniline substituted for 4-chloroaniline. ES-MS: (M+H)+ 384.
Example 126.
Figure imgf000241_0002
Step 1. 2'-N-tert-butylaminosulfonyl-[l,l']-biphenyl-4-ylamine (1.9 g, 6.2 mmol) was placed in 8 mL concentrate HCI. At 0°C to this stined mixture was added a cold solution of sodium nitrite (0.43 g, 6.2 mmol in 2 mL water) dropwise. After 30 minutes, to it was added a cold solution of SnCl2.2H2O (4.2 g, 18.4 mmol in 8 mL concentrate HCI). The mixture was stined at 0°C for 1 hour and the solid was collected with a Buchner funnel. The crude solid hydrazine was dried.
Step 2. The above-prepared crude hydrazine was dissolved in 20 mL acetic acid. To it was added 10 mL THF and ethyl 2-N-(methoxy)imino-4-oxopentanoate (0.93 g, 5.0 mmol). The mixture was refluxed for 3 hours. The solvent was removed in vacuuo. The residue was taken into EtOAc, washed with brine, dried, concentrated and purified with flash column to yield ethyl 3-methyl-l-(4-(2-aminosulfonylphenyl)-phenyl)-lH-pyrazole- 5-carboxylate (0.95 g, 40%). Rf 0.51 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 386.
Step 3. The above-prepared ethyl ester was dissolved in 20 mL methanol. To it were added LiOH.H2O (0.31 g, 7.4 mol) and 10 mL water. The mixture was stined for 3 hours, acidifed till pH 5 with acetic acid, and evaporated in vacuuo. The residue was soaked with acetonitrile and decanted for several times to extract out the organic product. The acetonitrile solutions were combined and evaporated in vacuuo to give yield 3-methyl-l- (4-(2-aminosulfonylphenyl)-phenyl)-lH-pyrazole-5-carboxylic acid (0.81 g, 92%). ES- MS: (M+H)+ 358. It was further purified using prep HPLC.
Step 4. The above-prepared acid (20 mg, 0.056 mmol) was dissolved in 1 mL dry DMF. To it were added 4-bromoaniline (10 mg, 0.056 mmol), DIEA (30 μL, 0.17 mmol) and PyBOP (58 mg, 0.12 mmol) in order. The reaction mixture was directly loaded on prep HPLC to yield the title compound in 45% yield. ES-MS: (M+H)+ 511 , 513 (Br pattern).
Example 127.
Figure imgf000242_0001
The title compound was prepared using the same methodology shown for Example 126, with 4-methoxyaniline substituted for 4-bromoaniline. ES-MS: (M+H)+ 463.
Example 128.
Figure imgf000243_0001
The title compound was prepared using the same methodology shown for Example 126, with 4-methoxy-2-nitroaniline substituted for 4-bromoaniline. ES-MS: (M+H)+ 508.
Example 129.
The title compound was prepared using the same methodology shown for Example 126, with 6-bromo-2-naphthylamine substituted for 4-bromoaniline. ES-MS: (M+H)+ 562, 564 (Br pattern).
Example 130.
Figure imgf000244_0001
The title compound was prepared using the same methodology shown for Example 126, with 2-naphthylamine substituted for 4-bromoaniline. ES-MS: (M+H)+ 483.
Example 131.
Figure imgf000244_0002
The title compound was prepared using the same methodology shown for Example 126, with 7-aminoisoquinoline substituted for 4-bromoaniline. ES-MS: (M+H)+ 484.
Example 132.
Figure imgf000245_0001
The title compound was prepared using the same methodology shown for Example 126, with 2-amino-5-chloropyridine substituted for 4-bromoaniline. ES-MS: (M+H)+ 468.
Example 133.
Figure imgf000245_0002
The title compound was prepared using the same methodology shown for Example 126, with 2-amino-5-bromopyridine substituted for 4-bromoaniline. ES-MS: (M+H)+ 512, 154 (Br pattern).
Example 134.
Figure imgf000246_0001
Step 1. A mixture of 4-cyanophenylhydrazine hydrochloride (5.7 g, 33 mmol), ethyl 2-N- (methoxy)imino-4-oxopentanoate (7.5 g, 40 mmol), 100 mL acetic acid and 50 mL THF was refluxed for 2 hours. The solvent was removed in vacuuo. The residue was taken into 500 mL EtOAc, which was washed with brine, dried and evaporated in vacuuo to afford ethyl 3-methyl-l-(4-cyanophenyl)-lH-pyrazole-5-carboxylate (10 g, 99%). ES-MS: (M+H)+ 256.
Step 2. The above-prepared ester (10 g) was dissolved in 100 mL THF. To it were added LiOH.H2O (4.2 g, 100 mmol), 100 mL methanol and 50 mL water. The mixture was stined for 1 hour. It was acidified to pH 1 with IN HCI. It was evaporated to remove organic solvent. The residue was extracted with EtOAc (X4). The organic phases were combined, dried and evaporated to dryness to afford 3-methyl-l-(4-cyanophenyl)-lH- pyrazole-5-carboxylatic acid (95%). ES-MS: (M+H)+ 228.
Step 3. The above-prepared acid (1.4 g, 6.2 mmol) was dissolved in 20 mL pyridine. To it were added 2-amino-5-bromopyridine (2.2 g, 13 mmol) and DMAP (100 mg). At 0°C to this mixture was added POCl3 (2.3 mL, 25 mmol). The reaction was allowed for 1.5 hour and quenched with ice chips. After evaporation in vacuuo, the residue was taken into 300 mL EtOAc, which was washed with brine, dried, evaporated and purified with flash column to yield the coupling product (45%). Rf 0.52 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 382, 384 (Br pattern).
Step 4. To a solution of the above-prepared nitrile (30 mg) in 10 mL anhydrous methanol at 0°C was bubbled dry HCI gas via a long needle till saturation reached. The mixture was stined for overnight. The solvent was removed in vacuuo. The dry residue was dissolved in 5 mL anhydrous methanol. To it was added 0.5 mL N-methylethylenediamine. The mixture was refluxed for 1 hour. After evaporation, the reaction mixture was subjected on prep HPLC to isolate the title compound (80% yield). ES-MS: (M+H)+ 439, 441 (Br pattern).
Example 135.
Figure imgf000247_0001
The title compound was prepared using the same methodology shown for Example 134, with ethylenediamine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 425, 427 (Br pattern).
Example 136.
Figure imgf000247_0002
The title compound was prepared using the same methodology shown for Example 134, with pynolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 453, 455 (Br pattern). Example 137.
Figure imgf000248_0001
The title compound was prepared using the same methodology shown for Example 134, with 2-methylpynolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 467, 469 (Br pattern).
Example 138.
Figure imgf000248_0002
The title compound was prepared using the same methodology shown for Example 134, with piperidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 467, 469 (Br pattern).
Example 139.
Figure imgf000249_0001
The title compound was prepared using the same methodology shown for Example 134, with moφholine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 469, 471 (Br pattern).
Example 140.
Figure imgf000249_0002
The title compound was prepared using the same methodology shown for Example 134, with thiomoφholine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 485, 487 (Br pattern).
Example 141.
Figure imgf000250_0001
The title compound was prepared using the same methodology shown for Example 134, with N-methylpiperazine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 482, 484 (Br pattern).
Example 142.
Figure imgf000250_0002
The title compound was prepared using the same methodology shown for Example 134, with hexamethyleneimine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 481, 483 (Br pattern).
Example 143.
Figure imgf000251_0001
The title compound was prepared using the same methodology shown for Example 134, with 1-methylhomopiperazine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 496, 498 (Br pattern).
Example 144.
Figure imgf000251_0002
The title compound was prepared using the same methodology shown for Example 134, with dimethylamine (2M in THF) substituted for N-methylethylenediamine. ES-MS: (M+H)+ 427, 429 (Br pattern).
Example 145.
Figure imgf000252_0001
The title compound was prepared using the same methodology shown for Example 134, with ammonium acetate substituted for N-methylethylenediamine. ES-MS: (M+H)+ 399, 401 (Br pattern).
Example 146.
Figure imgf000252_0002
2'-N-tert-butylaminosulfonyl-[l,l']-biphenyl-4-ylamine (50 mg, 0.16 mmol) was dissolved in 1 mL dry DCM. To this stined solution was added Me3Al (2.0M, 0.4 mL, 0.8 mmol). The mixture was stined for 30 minutes. To it was added a solution of commercial ethyl l-(6-chloro-l,3-benzothiazol-2-yl)-3-methyl-lH-pyrazole-5-carboxylate (50 mg, 0.16 mmol) in 2 mL DCM. The resulting mixture was stined for 4 hours. After quenched with saturated Rochelle's salt aq solution, this reaction was diluted with DCM. The mixture was washed with brine (X2), dried, evaporated in vacuuo and exposed to 3 mL TFA. After stirring overnight, the reaction mixture was evaporated and purified with reverse-phase prep HPLC to afford the title compound in 55% yield. ES-MS: (M+H)+ 524 (CI pattern). BIOLOGICAL ACTIVITY EXAMPLES
Evaluation of the compounds of this invention is guided by in vitro protease activity assays (see below) and in vivo studies to evaluate antithrombotic efficacy, and effects on hemostasis and hematological parameters.
The compounds of the present invention are dissolved in buffer to give solutions containing concentrations such that assay concentrations range from 0 to 100 μM. In the assays for thrombin, prothrombinase and factor Xa, a synthetic chromogenic substrate is added to a solution containing test compound and the enzyme of interest and the residual catalytic activity of that enzyme is determined spectrophotometrically. The IC50 of a compound is determined from the substrate turnover. The IC50 is the concentration of test compound giving 50% inhibition of the substrate turnover. The compounds of the present invention desirably have an IC50 of less than 500 nM in the factor Xa assay, preferably less than 200 nM, and more prefened compounds have an IC50 of about 100 nM or less in the factor Xa assay. The compounds of the present invention desirably have an IC50 of less than 4.0 μM in the prothrombinase assay, preferably less than 200 nM, and more prefened compounds have an IC50 of about 10 nM or less in the prothrombinase assay. The compounds of the present invention desirably have an IC50 of greater than 1.0 μM in the thrombin assay, preferably greater than 10.0 μM, and more prefened compounds have an IC50 of greater than 100.0 μM in the thrombin assay.
Amidolytic Assays for determining protease inhibition activity
The factor Xa and thrombin assays are performed at room temperature, in 0.02 M Tris HCl buffer, pH 7.5, containing 0.15 M NaCl. The rates of hydrolysis of the para- nitroanilide substrate S-2765 (Chromogenix) for factor Xa, and the substrate Chromozym TH (Boehringer Mannheim) for thrombin following preincubation of the enzyme with inhibitor for 5 minutes at room temperature, and were determined using the Softmax 96- well plate reader (Molecular Devices), monitored at 405 nm to measure the time dependent appearance of p-nitroaniline. The prothrombinase inhibition assay is performed in a plasma free system with modifications to the method described by Sinha, U. et al, Thromb. Res., 25, 427-436 (1994). Specifically, the activity of the prothrombinase complex is determined by measuring the time course of thrombin generation using the p-nitroanilide substrate Chromozym TH. The assay consists of preincubation (5 minutes) of selected compounds to be tested as inhibitors with the complex formed from factor Xa (0.5 nM), factor Va (2 nM), phosphatidyl serine:phosphatidyl choline (25:75, 20 μM) in 20 mM TrisΗCl buffer, pH 7.5, containing 0.15 M NaCl, 5 mM CaCl2 and 0.1% bovine serum albumin. Aliquots from the complex-inhibitor mixture are added to prothrombin (1 nM) and Chromozym TH (0.1 mM). The rate of substrate cleavage is monitored at 405 nm for two minutes. Eight different concentrations of inhibitor are assayed in duplicate. A standard curve of thrombin generation by an equivalent amount of untreated complex are used for determination of percent inhibition.
Antithrombotic Efficacy in a Rabbit Model of Venous Thrombosis
A rabbit deep vein thrombosis model as described by Hollenbach, S. et al., Thromb. Haemost. 71, 357-362 (1994), is used to determine the in-vivo antithrombotic activity of the test compounds. Rabbits are anesthetized with I.M. injections of Ketamine, Xylazine, and Acepromazine cocktail. A standardized protocol consists of insertion of a thrombogenic cotton thread and copper wire apparatus into the abdominal vena cava of the anesthetized rabbit. A non-occlusive thrombus is allowed to develop in the central venous circulation and inhibition of thrombus growth is used as a measure of the antithrombotic activity of the studied compounds. Test agents or control saline are administered through a marginal ear vein catheter. A femoral vein catheter is used for blood sampling prior to and during steady state infusion of test compound. Initiation of thrombus formation begins immediately after advancement of the cotton thread apparatus into the central venous circulation. Test compounds are administered from time = 30 min to time = 150 min at which the experiment is terminated. The rabbits are euthanized and the thrombus excised by surgical dissection and characterized by weight and histology. Blood samples are analyzed for changes in hematological and coagulation parameters. Effects of Compounds in Rabbit Venous Thrombosis model
Administration of compounds in the rabbit venous thrombosis model demonstrates antithrombotic efficacy at the higher doses evaluated. There are no significant effects of the compound on the aPTT and PT prolongation with the highest dose (100 μg/kg + 2.57 μg/kg/min). Compounds have no significant effects on hematological parameters as compared to saline controls. All measurements are an average of all samples after steady state administration of vehicle or (D)-Arg-Gly-Arg-thiazole. Values are expressed as mean ± SD.
Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. It should be understood that the foregoing discussion and examples merely present a detailed description of certain prefened embodiments. It will be apparent to those of ordinary skill in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention. All the patents, journal articles and other documents discussed or cited above are herein incoφorated by reference.

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula (I):
A-Q-D-E-G-J-X
Wherein:
A is selected from:
(a) Cι-C6-alkyl;
(b) C3-C8-cycloalkyl;
(c) -N(R2,R3), -C(=NR2)-R3, -C(=NR2)N(R2,R3), -N(R3)-C(=NR2)N(R2, R3)-, and -N(R2)C(=NR3)-R2
(d) phenyl, which is independently substituted with 0-2 R1 substituents;
(e) naphthyl, which is independently substituted with 0-2 R1 substituents; and
(f) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R1 substituents;
R1 is selected from:
Halo, -CN, -C(=O)-N(R2, R3), -NO2, -SO2N(R2, R3), -SO2R2, -(CH2)mNR2R3, - (CH2)m-C(=NR3)-R2, -(CH2)m-C(=NR2)-N(R2,R3), -(CH2)m-N(R2)-C(=NR2)- N(R2,R3), -(CH2)mNR2-C3-6heterocyclics, CMalkyl, C2-6alkenyl, C2-6alkynyl, C3- 8cycloalkyl, C0- alkylC3-8cycloalkyl, -CF3, -OR2, and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from
1-4 hydrogen atoms on the heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C^aHcyl-CN,
Figure imgf000256_0001
and - NO2; R2 and R3 are independently selected from the group consisting of:
-H, -ORa, -N(-Ra, -Rb), -CMalkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -Co- alkylC -8cycloalkyl, -Co^alkylphenyl and -Co^alkylnaphthyl, wherein from 1- 4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo,
C alkyl-CN, -CMalkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -Co-4alkylC3- 8cycloalkyl, -CN, and -NO2;
or R2 and R3 taken together can form a 3-8 membered cycloalkyl or a heterocyclic ring system, wherein the heterocyclic ring system may have from 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo,
Figure imgf000257_0001
-CMalkyl, -C2.6alkenyl, -C2-6alkynyl, -C3- 8cycloalkyl, -Co^alkylC -8cycloalkyl and -NO2;
Ra and Rb are independently selected from the group consisting of -CMalkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -Co^alkylC3-8cycloalkyl, or Ra and Rb can be taken together with a nitrogen atom to which they are attached to form a 3-8 heterocyclic ring sytem containing 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo,
-CN, -CMalkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl,
-Co- alkylC3-8cycloalkyl and -NO2;
m is an integer of 0-2;
Q is selected from the group consisting of:
a direct link, divalent -C1- alkyl, divalent -C2- alkenyl, divalent -C2- alkynyl,
-C(=O)-, -C(=NH , -C(=NMe)-, -N(-R4)-, -N(-R4)-CH2-, -C(=O)-N(-R4)-, -N(-R4)-C(=O)-, -S(=O)2-, -O-, -S(=O)2-N(-R4)- and -N(-R4)-S(=O)2-, wherein one or more hydrogens on each of the divalent Cj-4alkyl, divalent C2- alkenyl and divalent C2-4alkynyl moieties can be replaced with a -R4 group; R4 is selected from the group consisting of:
-H, -CF3, -CMalkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0- alkylC3- 8cycloalkyl, -Co^alkylphenyl and -Cu-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo,
-CM lkyl, -C2.6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -Co^alkyl -scycloalkyl, - CN, -CF3, and -NO2;
D is selected from the group consisting of:
(a) a direct link;
(b) phenyl, which is independently substituted with 0-2 Rla substituents;
(c) naphthyl, which is independently substituted with 0-2 Rla substituents; and
(d) monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be subsituted from 0-2 Rl substituents;
Rla is selected from the group consisting of:
halo, CMalkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, Co- alkylC3-8cycloalkyl, - CN, -NO2, (CH2)nNR2aR3a, SO2NR2aR3a, SO2R2a, CF3, OR2a, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C alkyl, C2.6alkenyl, C2-6alkynyl, C3-8cycloalkyl, Co^alkyl . 8cycloalkyl, -CN and -NO2;
R2a and R3a are independently selected from the group consisting of: -H, CMalkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0- alkylC3-8cycloalkyl, C0- alkylphenyl and Co^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, CMal yl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, Co- alkylC3-8cycloalkyl, -CN and -NO2;
n is an integer of 0-2;
E is selected from the group consisting of:
a direct link, -(CH2)q-C(=O)-, -(CH2)q-N(-R5)-C(=O)-(CH2)x-, -(CH2)q-C(=O)-N(-R5)-(CH2)x-, -(CH2)q-N(-R5)-(CH2)x-, , -(CH2)q-N(R5)CO- NR6(CH2)X and -SO2-;
q and x are independently an integer of 0-2;
R5 and R6 are independently selected from the group consisting of:
H,
Figure imgf000259_0001
-C2-6alkenyl, -C2-6alkynyl, -C -8cycloalkyl, -C0-6alkylC3-8cycloalkyl, -CMalkyl-C(=O)-OH, -Co-6alkyl-(carbocyclic aryl), -Co^alkyl^monocyclic heteroaryl) and -CMalkyl-C(=O)-O-CMalkyl, wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety and the monocyclic heteroaryl moieties may be independently replaced with a member selected from the group consisting of halo, -CMal yl, -C2-6alkenyl, -C2-6alkynyl, - C3-8cycloalkyl, -C0-4alkylC3.8cycloalkyl, -S(=O)2-OH, -CN, -CF3 and -NO2;
G is selected from the group consisting of:
phenyl, which is substituted with 0-2 Rlb groups; and
a 5-6 membered aromatic and non-aromatic heterocyclic ring containing 1-4 hetero atoms selected from N, O and S wherein the heterocyclic ring is substituted with 0-2 Rlb groups;
Rlb is independently selected from the group consisting of: halo, -Cι-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl,
-C0-6alkylC3-8cycloalkyl, -CMalkyl-C(=O)-OH, -CN, -COOR2b, -CONR2bR3b, - NO2, -S(=O)2-OH, -N(-R2b, -R3b), -C(=O)-N(-R2b, -R3b), -S(=O)2-N(-R2b, -R3b), - S(=O)2-R2b, -CF3, -O-R2b, -O-CH2-CH2-O-R2b, -O-CH2-C(=O)-O-R2b, -N(-R2b)-CH2-CH2-O-R2b, -N(-CH2-CH2-O-R2b)2, -N(-R2b)-C(=O)-R3b,
-N(-R2b)-S(=O)2-R3b, and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S substituted with 0-4 Rlb groups;
alternatively, when two Rlb may be present on adjacent ring atoms of G and combine to form a benzene ring substituted with 0-4 Rlb' groups or a 5-6 membered aromatic or non-aromatic heterocyclic ring having 1-3 heteroatoms selected from N, O and S substituted with 0-4 Rlb groups;
in a second alternative, one of the Rlb groups of G can cylize with the -N-R5 group of E to form a 5-7 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, which is subtituted with 0-4 Rlb' groups, wherein two of the Rlb groups attached to the same ring carbon may form a (=O) group;
R2b and R3b are independently selected from the group consisting of:
-H, -Cι-6alkyl, -C1-6alkyloxy, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -Co-6alkylC3.8cycloalkyl and -Co-6alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety may be independently replaced with a member selected from the group consisting of halo,
-CMalkyl, -C2-6alkenyl, -C2-6alkynyl, -C -8cycloalkyl, -C0-4alkylC3-8cycloalkyl, - S(=O)2-OH, -CN, -CF3 and -NO2;
RIb is independently selected from the group consisting of:
halo, -Cι-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-6alkylC3.8cycloalkyl, -C alkyl-C(=O)-OH, -CN, -NO2, -S(=O)2-OH, -N(-R2b',
-R3b'), -C(=O)-N(-R2b', -R3b'), -S(=O)2-N(-R2b', -R3b'), -S(=O)2-R2b', -CF3, -O-R2b', -O-CH2-CH2-O-R2b', -O-CH2-C(=O)-O-R2b', -N(-R2b')-CH2-CH2-O-R2b',
-N(-CH2-CH2-O-R2b')2, -N(-R2b')-C(=O)-R3b' and -N(-R2b')-S(=O)2-R3b'; R2b and R3b are independently selected from the group consisting of:
-H, -Cι-6alkyl, -Ci-όalkoxy, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -Co-6alkylC3.8cycloalkyl and -Co-6alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety may be independently replaced with a member selected from the group consisting of halo,
-CMalkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloakyl, -C0- alkylC3.8cycloalkyl, - S(=O)2-OH, -CN, -CF3 and -NO2;
J is selected from the group consisting of:
a direct link, -S(=O)2-, -C(=O)-, -N(-R7)-S(=O)2-, -C(=O)-N(-R7)-S(=O)2-, -C(=O)-N(-R7)-(CH2)y-, -S(=O)2-N(-R7) -(CH2)y-, and -N(-R7)-C(=O)-(CH2)y-;
y is an integer of 0-2;
R7 is selected from the group consisting of:
-H, -C2- alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -Co-6alkylC3-8cycloalkyl, -Cι-6alkyl-C(=O)-OH, -Cι-6alkyl-OH, -Cι-6alkyl-O-CMalkyl, -C0- 4alkyl-(carbocyclic aryl), -C0-4alkyl-(monocyclic or bicyclic heterocyclic ring system having from 0-4 heteroatoms selected from the group consisting of N, O and S), -CH2-C(=O)-O-C]-4alkyl and -CH2-C(=O)-O-CMalkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety or the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo, -CM lkyl, -C2.6alkenyl, -C2- 6alkynyl, -C3-8cycloalkyl, -C0- alkylC3.8cycloalkyl, -S(=O)2-OH, -CN, -CF3 and -NO2;
X is selected from the group consisting of:
phenyl, which is substituted with 0-3 Rlc groups;
naphthyl, which is substituted with 0-3 Rlc groups; a 6-membered heteroaromatie ring containing from 1-2 nitrogen atoms, wherein the ring is substituted with 0-3 Rlc groups; and
a fused heterobicyclic ring system, wherein the ring system contains 1-3 heteroatoms selected from N, O and S and is substituted with 0-3 Rlc groups;
Rlc is independently selected from the group consisting of:
halo, -CF3, -Ci-βalkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0.6alkylC3-8cycloalkyl, -CMalkyl-C(=O)-OH, -CF3, -CN, -NO2, -(CH2)Z-N(-R2c, -R3c), -C(=O)-N(-R2c, -R3c), -C(=NH)-N(-R2c, -R3c), -C(=NMe)-N(-R2c, -R3c), -S(=O)2-N(-R2c, -R3c), -S(=O)2-R2c, -S(=O)2-OH, -CF3, -O-R2c, -O(-CH2)z-O-R2c, -O(-CH2)z-C(=O)-O-R2c, -N(-R2c), -O(-CH2)z-O-R2c, -N[(-CH2)z-O-R2c]2,
-(CH2)z-N(-R2c)-C(=O)-R3c, -(CH2)z-N(-R2c)-S(=O)2-R3c, and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;
z is an integer of 0-4;
R2c and R3c are independently selected from the group consisting of:
-H, -C^aHcyl, -Cι.6alkyloxy, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl,
-Co-6alkylC3-8cycloalkyl and -Co-6alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety may be independently replaced with a member selected from the group consisting of halo, -CMalkyl, -C2-ealkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0- alkylC3-8cycloalkyl, - S(=O)2-OH, -CN, -CF3 and -NO2;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
2. A compound of claim 1, wherein:
A is selected from the group consisting of:
-Cι-6alkyl and -C3-8cycloalkyl; phenyl, which is substituted with 0-2 R1 groups;
naphthyl, which is substituted with 0-2 R1 groups; and
a 5-10 membered aromatic or non-aromatic heterocyclic ring system which may be a monocyclic ring system or a fused bicyclic ring system, wherein the heterocyclic ring system contains 1-4 heteroatoms selected from N, O and S and is substituted with 0-2 R1 groups;
R1 is independently selected from the group consisting of:
halo, -C alkyl, -CN, -NO2, -(CH2)m-N(-R2,-R3), -C(=O)-N(-R2,-R3), -S(=O)2-N(- R2,-R3), -S(=O)2-R2, -(CH2)m-C(=NR3)-R2, -(CH2)m-C(=NR2)-N(R2,R3), -(CH2)m- N(R2)-C(=NR2)-N(R2,R3), -CF3, -(CH2)m-O-R2 and a 5-6 membered aromatic heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;
R2 and R3 are independently selected from the group consisting of:
-H, -CMalkyl,
or R2 and R3 taken together can form a 3-8 membered cycloalkyl or a heterocyclic ring system, wherein the heterocyclic ring system may have from 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo, Cι-C -alkyl-CN, -CMalkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3-8cycloalkyl and -NO2;
m is an integer of 0-2;
Q is selected from the group consisting of:
a direct link, -CMalkyl, -C2-4alkenyl, -C2-4alkynyl, -C(=O)-, -C(=NH)-, - C(=NMe)-, -N(-R4)-, -N(-R4)-CH2-, -C(=O)-N(-R4)-, -N(-R4)-C(=O)-, -S(=O)2-, - O-, -S(=O)2-N(-R4)- and -N(-R4)-S(=O)2-;
R4 is selected from the group consisting of: -H, -CF3, -CMalkyl,
D is selected from the group consisting of:
a direct link;
phenyl, which is substituted with 0-2 Rla groups; and
a 5-10 membered aromatic or non-aromatic heterocyclic ring system which may be a monocyclic ring system or a fused bicyclic ring system, wherein the heterocyclic ring system contains 1-4 heteroatoms selected from N, O and S and the ring system is substituted with 0-2 Rla groups;
Rla is independently selected from the group consisting of:
halo, -CMalkyl, -CN, -NO2, -(CH2)n-N(-R2a, -R3a), -S(=O)2-N(-R2a, -R3a),
-S(=O)2-R2a, -CF3, -(CH2)n-OR2a, -C(=O)-O-R2a, -C(=O)-N(-R2a, -R3a) and a 5-6 membered aromatic heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;
n is an integer of 0-2;
R2a and R3a are independently selected from the group consisting of:
-H, -CF3 and -CMalkyl,
E is selected from the group consisting of:
a direct link, -(CH2)q-C(=O)-, -(CH2)q-N(-R5)-C(=O)-(CH2)x-, -(CH2)q-C(=O)-N(-R5)-(CH2)x-, -(CH2)q-N(-R5)-(CH2)x-, -(CH2)q-N(R5)CO- NR6(CH2)X- and -SO2-;
R5 and R6 are each H, -C1- alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, or -C0-4alkylC3-8cycloalkyl;
q and x are independently an integer of 0-2;
G is selected from the group consisting of: phenyl, which is substituted with 0-2 Rlb groups; and
a 5-6 membered aromatic and non-aromatic heterocyclic ring containing 1-4 hetero atoms selected from O, S and N, wherein the heterocyclic ring is substituted with 0-2 Rlb groups;
Rlb is independently selected from the group consisting of:
halo, -CMalkyl, -CN, -NO2, -N(-R2b, -R3b), -C(=O)-N(-R2b, -R3b), -S(=O)2-N(-R2b, -R3b), -S(=O)2-R2b, -CF3, -O-R2b, -O-CH2-CH2-O-R2b, -O-CH2-C(=O)-O-R2b, -N(-R2b)-CH2-CH2-O-R2b, -N(-CH2-CH2-O-R2b)2, -N(-R2b)-C(=O)-R3b,
-N(-R2b)-S(=O)2-R3b and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S;
alternatively, when two Rlb may be present on adjacent ring atoms of G and combine to form a benzene ring substituted with 0-4 Rlb groups or a 5-6 membered aromatic or non-aromatic heterocyclic ring having 1-3 heteroatoms selected from N, O and S substituted with 0-4 Rlb groups;
in a second alternative, one of the Rlb groups of G can cylize with the -N-R5 group of E to form a 5-7 membered saturated, unsaturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, which is substituted with 0-4 Rlb groups, wherein two of the Rlb groups attached to the same ring carbon may form a (=O) group;
R b and R3b are independently selected from the group consisting of:
-H, -CF3, -CMalkyl and -CMalkyl-(carbocyclic aryl);
Rlb' is independently selected from the group consisting of:
halo, -CMalkyl, -CN, -NO2, -N(-R2b', -R3b'), -C(=O)-N(-R2b', -R3b'), -S(=O)2-N(- R2b', -R3b), -S(=O)2-R2b', -CF3, -O-R2b', -O-CH2-CH2-O-R2b', -O-CH2-C(=O)-O-R2b', -N(-R2b')-CH2-CH2-O-R2b', -N(-CH2-CH2-O-R2b')2,
-N(-R2b')-C(=O)-R3b', -N(-R2b')-S(=O)2-R3b'; R2b and R3b are independently selected from the group consisting of:
-H, -CMal yl and -CMalkyl-(carbocyclic aryl);
J is selected from the group consisting of:
a direct link, -S(=O)2-, -C(=O)-, -N(-R7)-S(=O)2-, -C(=O)-N(-R7)-S(=O)2-, -C(=O)-N(-R7)-(CH2)y-, -S(=O)2-N(-R7)-, -(CH2)y- and -N(-R7)-C(=O)-(CH2)y-;
y is an integer of 0-2;
R7 is selected from the group consisting of:
-H, -CMalkyl, -C2-6alkenyl, -C2-6alkynyl, -Co^alkyl-^arbocyclic aryl), -Co^alkyl- eterocyclic ring system), -CH2-C(=O)-O-CMalkyl and -CH2-C(=O)-O-C alkyl-(carbocyclic aryl);
X is selected from the group consisting of:
phenyl, which is substituted with 0-3 Rlc groups;
naphthyl, which is substituted with 0-3 Rlc groups;
a 6-membered heteroaromatie ring containing from 1-2 nitrogen atoms, wherein the ring is substituted with 0-3 Rlc groups; and
a fused heterobicyclic ring system, wherein the ring system contains 1-3 heteroatoms selected from N, O and S and is substituted with 0-3 Rlc groups;
Rlc is independently selected from the group consisting of:
halo, -CMalkyl, -CN, -NO2, -(CH2)Z-N(-R2c, -R3c), -C(=O)-N(-R2c, -R3c), -C(=NH)-N(-R2c, -R3c), -C(=NMe)-N(-R2c, -R3c), -S(=O)2-N(-R2c, -R3c), -S(=O)2-
R2c, -S(=O)2-O -, -CF3, -O-R c, -O-CH2-CH2-O-R2c, -O-CH2-C(=O)-O-R2c, -N(-R2c)-CH2-CH2-O-R2c, -N(-CH2-CH2-O-R2c)2, -(CH2)z-N(-R2c)-C(=O)-R3c, -(CH2)z-N(-R2c)-S(=O)2-R3c, and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S; z is an integer of 0-2;
R >2cc and R ,3cc are independently selected from the group consisting of:
-H, -CMalkyl and -CMalkyl-(carbocyclic aryl);
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
3. A compound of claim 1, wherein:
A is selected from the group consisting of:
Figure imgf000267_0001
Figure imgf000268_0001
N— Me-N N— Me-N — HN N— HN — ( N— O N— S N—
02S N — C l_/N" C |_N" O N^ O- t " -N- M M e e - M E e ,^- Ef - H -
Me Me Me
E >t-
Figure imgf000268_0002
L> Q- Me J> Me J ό- - ό- 0-
Figure imgf000268_0003
α αααα NH NH NH O
H2N H2N Λ NH- Me A. NH- H2N A
Me Et
NH O
'»" f Me, Meλ Me, Me H Me
M kA H2N-CH2- N-CH2- N-CH2- Me-N-CH2- Me-V- N— Me — O —
Mβ N M Mee*->NN' H u M ..e' M ».e„' M ..e'/ M ..e/
Q is selected from the group consisting of:
a direct link, -C(=NH), -C(=NMe)-, -C(=O)-, -CH2-, -NH-, -N(-CH3)-, -O-, -NH- CH2-, -CH2-NH-, -N(-CH3)-CH2-, and -CH2-N(-CH3)-;
D is selected from the group consisting of:
Figure imgf000269_0001
M JΓS—-
Figure imgf000269_0002
Figure imgf000269_0003
E is selected from the group consisting of:
a direct link, -NH-C(=O)-, -N(-CH3)-C(=O)-, -N(-CH2CO2H)-C(=O)-, C(=O)-NH-, -C(=O)-N(-CH3)-, -NH-CH2- and -CH2-NH-;
G is a member selected from the group consisting of:
Figure imgf000270_0001
R is independently selected from the group consisting of:
-H, -Me, -CF3, -F, -CI, -Br, -SO2Me, -CN, -CONH2, -CONMe2, -NH2, -NO2, NHCOMe, -NHSO2Me, -CH2NH2 and -CO2H;
J is selected from the group consisting of:
a direct link, -NH-, -O-, -S(=O)2-, -S(=O)2-NH, -NH-S(=O)2-, -C(=O)-, NH-C(=O)- and -C(=O)-NH-; X is selected from the group consisting of:
Figure imgf000271_0001
v^ .Br F CI
*^*> vBr ^ ^ CI Br F
Figure imgf000271_0002
^
^•^SOH ^^> OMe ^= ^ NH, o-
Figure imgf000271_0003
Br CI Br
/ /
S s 02 02 o2
CI Br
/ / /
H H ^αF
Figure imgf000272_0001
N pac, ^αBr-£σF XCI - σBr - Ho
Figure imgf000272_0002
H2NOC NC
-O -O ^ -OF ^Oci -Oβr -CoMe
F
Figure imgf000272_0003
/K N^ N-. H2N02S Me02S Q2N_
- cι ^Br =~0 e O-F ^>F -T
Figure imgf000272_0004
Me02S 02N F» H2NOC NC H2NH2C
-to F -Q ^F to ^F -to ^F -to -to ^F
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
4. A compound of claim 1, wherein:
A is selected from the group consisting of:
phenyl, which is substituted with 0-2 R1 groups;
naphthyl, which is substituted with 1 R1 group; and
a 5-7 membered aromatic or non-aromatic monocyclic heterocyclic ring, wherein the heterocyclic ring contains 1-2 heteroatoms selected from N, O and S and is substituted with 0-1 R1 groups;
R is selected from the group consisting of:
-S(=O)2-N(-R , -RJ), -S(=O)2-R , -CH2N(-R 2, - ΓR3J)N, -CN and halo R2 and R3 are independently selected from the group consisting of:
-H and -CMalkyl;
Q is selected from the group consisting of:
a direct link, -C(=NH), -C(=NMe , -C(=O)-, -CH2-, -NH-, and -N(-CH3)-;
D is selected from the group consisting of:
a direct link;
phenyl, which is substituted with 0-2 Rl groups; and
a 5-6 membered aromatic heterocyclic ring, wherein the heterocyclic ring contains 1-2 heteroatoms selected from N and S and is substituted with 0-1 Rla groups;
Rla is selected from the group consisting of:
-H and halo;
E is selected from the group consisting of:
a direct link, -NH-C(=O)- and -C(=O)-NH-;
G is selected from the group consisting of:
Pyrazole, pyrazoline, triazole and tertrazole, which are substituted with 0-2 Rlb groups; and
a 5-membered aromatic heterocyclic ring, wherein the heterocyclic ring contains 2 heteroatoms selected from N, O and S and is substituted with 0-1 Rlb groups and;
Rlb is selected from the group consisting of:
-Me, -Et, -CF3, -C(=O)-NH2, -NH2, -NH-C(=O)-Me, -NH-S(=O)2-Me, -SMe -S(=O)2-Me and halo; alternatively, when two Rlb groups may be present on adjacent ring atoms of G and combine to form a benzene ring;
in a second alternative, one of the RIb groups of G can cyclize with the NH group of E to form a 5-6 membered non-aromatic heterocyclic ring containing 1-2 nitrogen atoms and which is substituted with 0-2 C=O groups;
J is selected from the group consisting of:
a direct link, -NH-C(=O)- and -C(=O)-NH-;
X is selected from the group consisting of:
phenyl, which is substituted with 1-3 Rlc groups;
naphthyl, which is substituted with 0-3 Rlc groups;
pyridinyl, which is substituted with 1-3 Rlc groups; and
a 9-10 membered fused bicyclic aromatic ring, wherein the aromatic ring contains 0-2 heteroatoms selected from N and O and is substituted with 0-3 Rlc groups;
Rlcis independently selected from the group consisting of:
-H, halo, -Me, -CF3, -OH, -OMe, -NH2, -CN, -NO2, -CH2-R c, -C(=O)-N(-R2c, -
R3c), -S(=O)2-R2c, -S(=O)2-N(-R2c, -R3c), -S(=O)2-OH, -C(=NH)-N(-R2c, -R3c), 2- imidazolin-2-yl and l-methyl-2-imidazolin-2-yl;
R2c and R3c are independently selected from the group consisting of:
-H, -OH, -NH2 and -CMalkyl;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
5. A compound of claim 1 selected from the group consisting of:
Figure imgf000280_0001
wherein:
R1 is selected from the group consisting of:
-SO2NH2, -SO2Me, -CH2NH2 and -CH2NMe2;
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
R is selected from the group consisting of:
-CH3, -CF3, -CH2CH3, -SO2Me, -CONH2 and -NHSO2Me;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -NH2, -OH, -SO2Me, -SO2Et, -SO2NH2, -NO2, -CH2NH2, -CN, CONH2, -CH2OH;
Rlc2 is selected from the group consisting of:
-H, -F, -CI and -Br; and
Rlc3 is selected from the group consisting of:
-H, -F, -CI and -Br
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
6. A compound of claim 1 selected from the group consisting of:
Figure imgf000281_0001
wherein :
R1 is selected from the group consisting of:
-SO2NH2, -SO2Me, -CH2NH2 and -CH2NMe2;
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-CH3, -CF3, -CH2CH3, -SO2Me, -CONH2 and -NHSO2Me;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -NH2, -OH, -SO2Me, -SO2Et, -SO2NH2, -NO2, -CH2NH2, -CN, CONH2, -CH2OH;
Rlc2 is selected from the group consisting of:
-H, -F, -CI, -Br and -OMe; and
Rlc3 is selected from the group consisting of:
-H, -F, -CI, -Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. A compound of claim 1 selected from the group consisting of:
Figure imgf000282_0001
wherein:
R1 is selected from the group consisting of:
-SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2, -CH2NH2, CH2NH(CH3), -CH2N(CH3)2;
RIais selected from the group consisting of:
-H, -F, -CI and -Br;
R is selected from the group consisting of:
-CH3 and -CF3;
R,cl is selected from the group consisting of:
-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
R , lc2 is selected from the group consisting of:
-H, -F, -CI, -Br, and -OCH3; and
R is selected from the group consisting of: -H, -F, -CI, -Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
A compound of claim 1 selected from the group consisting of:
Figure imgf000283_0001
wherein:
R is selected from the group consisting of:
-SO2NH2, -SO2Me, -CH2NH2 and -CH2NMe2
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-CH3, -CF3, -CH2CH3, -SO2Me, -CONH2 and -NHSO2Me; and
Rlc is selected from the group consisting of: -H, -F, -CI, -Br, -NH2, -OH, -SO2Me, -SO2Et, -SO2NH2, -NO2, -CH2NH2, -CN, CONH2, -CH2OH
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
A compound of claim 1 selected from the group consisting of:
Figure imgf000284_0001
wherein: R1 is selected from the group consisting of:
-SO2NH2, -SO2Me, -CH2NH2 and -CH2NMe2;
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-CH3, -CF3, -CH2CH3, -SO2Me, -CONH2 and -NHSO2Me;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -NH2, -OH, -SO2Me, -SO2Et, -SO2NH2, -NO2, -CH2NH2, -CN, CONH2, -CH2OH; and
Rlc2 and Rlc3 are independently selected from the group consisting of:
-H, -F, -CI and -Br,
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
10. A compound of claim 1 selected from the group consisting of:
Figure imgf000285_0001
wherein: A-Q is selected from the group consisting of: - c Me- cv Et- cy cy cyc c Mβ cy Et
Figure imgf000286_0001
r t- ( t- QL yyt- ryt- c x*- J
Figure imgf000286_0002
HN N Mβ— N" N J — U N HNI N Me—ti ti
Figure imgf000286_0003
Figure imgf000286_0004
CH3 - - y*- O- WH ^ O
N= A—" A — ■ A-
Me CONH2 CH2NH2
wherein:
A is selected from the group consisting of:
Figure imgf000287_0001
Rla is selected from the group consisting of-H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-Me, -CF3, -Et, -SO2Me, -CONH2 and -NHSO2Me;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -NH2, -OH, -SO2Me, -SO2Et, -SO2NH2, -NO2, -CH2NH2, -CN, CONH2, -CH2OH;
Rlc2 is selected from the group consisting of:
-H, -F, -CI and -Br; and
Rlc3 is selected from the group consisting of:
-H, -F, -CI and -Br
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
11. A compound of claim 1 selected from the group consisting of:
Figure imgf000288_0001
wherein:
A-Q is selected from the group consisting of:
Q- cy >
Me cy \ Et cy cy cyCrCr \ Mθ Cy \ Et
Figure imgf000288_0002
<- o→- &**- C - C Me- -
Figure imgf000288_0003
wherein:
A is selected from the group consisting of:
Figure imgf000289_0001
.Mθ
Λβ-0N- CN- C/N- CN- - - Mβ-
Figure imgf000289_0002
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-CH3, -CF3, -CH2CH3, -SO2Me, -CONH2 and -NHSO2Me;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -NH2, -OH, -SO2Me, -SO2Et, -SO2NH2, -NO2, -CH2NH2, -CN, CONH2, -CH2OH;
Rlc2 is selected from the group consisting of:
-H, -F, -CI, -Br and -OMe; and
Rlc3 is selected from the group consisting of:
-H, -F, -CI, -Br, -OH, -OCH3, -NH2, -CONH2, -CH2NH2, and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
2. A compound of claim 1 selected from the group consisting of:
Figure imgf000291_0001
Figure imgf000292_0001
wherein:
R1 is selected from the group consisting of:
-SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2; -CH2NH2, CH2NH(CH3), -CH2N(CH3)2;
Rla is selected from the group consisting of:
-H, -F, -CI and Br;
R is selected from the group consisting of:
-CH3 and -CF3;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
R is selected from the group consisting of:
-H, -F, -CI and -Br; and
R is selected from the group consisting of:
-H, -F, -Cl and -Br, and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
3. A compound of claim 1 selected from the group consisting of:
Figure imgf000294_0001
wherein:
R1 is selected from the group consisting of:
-SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2, -CH2NH2, CH2NH(CH3), -CH2N(CH3)2;
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-CH3, -CF3, -CH2CH3, -SO2Me, -CONH2 and -NHSO2Me;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -NH2, -OH, -SO2Me, -SO2Et, -SO2NH2, -NO2, -CH2NH2, -CN,
CONH2, -CH2OH;
Rlc2 is selected from the group consisting of:
-H, -F, -CI, -Br and -OCH3; and
Rlc3 is selected from the group consisting of:
-H, -F, -CI, -Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2,
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
14. A compound of claim 1 selected from the group consisting of:
Figure imgf000296_0001
wherein:
A-Q is selected from the group consisting of:
y cv Mβ- cy Et cy cy cy cy cy MMee cy Et
Figure imgf000297_0001
CJJC*- cμ v*,- ΓΛ_£_*_
Figure imgf000297_0002
Figure imgf000297_0003
wherein:
A is selected from the group consisting of:
Figure imgf000298_0001
Rlal is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-CH3 and -CF3;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of:
-H, -F, -CI, -Br, and -OCH3; and
RIc3 is selected from the group consisting of:
-H, -F, -CI, -Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2,
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
15. A compound of claim 1 selected from the group consisting of:
Figure imgf000299_0001
wherein:
R is selected from the group consisting of:
-SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2> -CH2NH2, CH2NH(CH3), -CH2N(CH3)2;
Rla is selected from the group consisting of:
-H, -F, -CI and -Br; Rlb is selected from the group consisting of:
-H, -CH3 and -CF3;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of:
-H, -F, -CI and -Br; and
Rlc3 is selected from the group consisting of:
-H, -F, -Cl and -Br
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
16. A compound of claim 1 selected from the group consisting of:
Figure imgf000301_0001
wherein:
R1 is selected from the group consisting of:
-SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2; -CH2NH2, CH2NH(CH3), -CH2N(CH3)2;
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
R is selected from the group consisting of: -H, -CH3 and -CF3;
Rlcl is selected from the group consisting of:
-H, -F, -CN, -CH2NH2, -CONH2, -SO2Me, -SO2NH2 and -NO2;
RIc2 is selected from the group consisting of:
-H, -F, -CI, -Br and -OCH3; and
Rlc3 is selected from the group consisting of:
-H, -F, -CI, -Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
17. A compound of claim 1 selected from the group consisting of:
Figure imgf000303_0001
wherein:
A-Q is selected from the group consisting of:
cr Q- cy cy cy cyOrO cy Et
Figure imgf000304_0001
r z. - J rμ. yy- cy- ryw-
Me Me
Figure imgf000304_0002
( y — N— C — HN N — Mβ—i N — — tf fi — HI N — Me—l N —
Figure imgf000304_0003
CH2NH2 CH: NH2 6 "- Me' -
Figure imgf000304_0004
wherein:
A is selected from the group consisting of:
Figure imgf000305_0001
Me— N Γ" N-
Figure imgf000305_0002
Figure imgf000305_0003
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-H, -CH3 and -CF3;
Rlcl is selected from the group consisting of:
-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, CO2Me, -SO2Me, -SO2NH2, -OH, -NH2, and -NO2;
Rlc2 is selected from the group consisting of:
-H, -F, -CI and -Br; and
Rlc3 is selected from the group consisting of:
-H, -F, -Cl and -Br,
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
18. A compound of claim 1 selected from the group consisting of:
Figure imgf000306_0001
wherein:
A-Q is selected from the group consisting of:
ζr- ty Mβ cy Et cy cy cyc
Figure imgf000307_0001
cy Et
Figure imgf000307_0002
( — N— C
Figure imgf000307_0003
Hj l \ H2C— H2 C— H2C— HN— o— [*M, Oκ>— 0^» -V/" ^ Mβ2N' M«N Mβ^ MΘ.C UA«
(S02NH2 θ2 θ
Figure imgf000307_0005
Figure imgf000307_0004
Figure imgf000307_0006
wherein:
A is selected from the group consisting of:
v H M Hy v H M M>β - M ve v Et o- V- o- <>-
Figure imgf000308_0001
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of:
-H, -CH3 and -CF3;
Rlcl is selected from the group consisting of:
-H, -F, -CN, -CH2NH2, -CONH2, -SO2Me, -SO2NH2 and -NO2;
Rlc2 is selected from the group consisting of:
-H, -F, -CI, -Br and -OCH3; and
Rlc3 is selected from the group consisting of:
-H, -F, -CI, -Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
19. A compound of claim 1 selected from the group consisting of:
Figure imgf000309_0001
wherein:
R is selected from the group consisting of:
-SO2NH2, -SO2Me, -CH2NH2 and -CH2NMe2;
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
R is selected from the group consisting of:
-CH3, -CF3, -CH2CH3, -SO2Me, -CONH2 and -NHSO2Me; and
R p lc2 a „„nd ϋ R lc3 are independently selected from the group consisting of: -H, -F, -CI and -Br,
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
20. A compound of claim 1 selected from the group consisting of:
Figure imgf000310_0001
wherein:
R is selected from the group consisting of:
-SO2NH2, -SO2Me, -CH2NH2 and -CH2NMe2;
Rla is selected from the group consisting of:
-H, -F, -CI and -Br;
Rlb is selected from the group consisting of: -CH3, -CF3, -CH2CH3, -SO2Me, -CONH2 and -NHSO2Me; and
Rlc2 and Rlc3 are independently selected from the group consisting of:
-H, -F, -CI and -Br,
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
21. A pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 1.
22. A method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising administering to said mammal a therapeutically effective amount of a compound of claim 1.
23. The method of claim 22, wherein the condition is selected from the group consisting of:
acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post- coronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparin-induced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation, and thrombotic complications associated with the fitting of prosthetic devices.
24. A method for inhibiting the coagulation of biological samples, comprising the step of administering a compound of claim 1.
25. A pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 2.
26. A method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising administering to said mammal a therapeutically effective amount of a compound of claim 2.
27. The method of claim 26, wherein the condition is selected from the group consisting of:
acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post- coronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparin-induced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation, and thrombotic complications associated with the fitting of prosthetic devices.
28. A method for inhibiting the coagulation of biological samples, comprising the step of administering a compound of claim 2.
29. A pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 3.
30. A method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising administering to said mammal a therapeutically effective amount of a compound of claim 3.
31. The method of claim 30, wherein the condition is selected from the group consisting of:
acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post- coronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparin-induced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation, and thrombotic complications associated with the fitting of prosthetic devices.
32. A method for inhibiting the coagulation of biological samples, comprising the step of administering a compound of claim 3.
33. A pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 4.
34. A method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising administering to said mammal a therapeutically effective amount of a compound of claim 4.
35. The method of claim 34, wherein the condition is selected from the group consisting of:
acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post- coronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparin-induced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation, and thrombotic complications associated with the fitting of prosthetic devices.
36. A method for inhibiting the coagulation of biological samples, comprising the step of administering a compound of claim 4.
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