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AU7486600A - Inhibitors of factor xa - Google Patents

Inhibitors of factor xa Download PDF

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Publication number
AU7486600A
AU7486600A AU74866/00A AU7486600A AU7486600A AU 7486600 A AU7486600 A AU 7486600A AU 74866/00 A AU74866/00 A AU 74866/00A AU 7486600 A AU7486600 A AU 7486600A AU 7486600 A AU7486600 A AU 7486600A
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Australia
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group
rib
ric
usoo
pct
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AU74866/00A
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AU781880B2 (en
Inventor
Wenrong Huang
Zhaozhong Jon Jia
James Kanter
Robert M. Scarborough
Yonghong Song
Bing-Yan Zhu
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Millennium Pharmaceuticals Inc
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Millennium Pharmaceuticals Inc
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Publication of AU7486600A publication Critical patent/AU7486600A/en
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Assigned to MILLENNIUM PHARMACEUTICALS, INC. reassignment MILLENNIUM PHARMACEUTICALS, INC. Amend patent request/document other than specification (104) Assignors: COR THERAPEUTICS, INC.
Anticipated expiration legal-status Critical
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • 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
    • C—CHEMISTRY; METALLURGY
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • 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
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • 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
    • C07C317/40—Y being a hydrogen or a carbon atom
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    • C07C317/00—Sulfones; Sulfoxides
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    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • 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
    • C07D213/78—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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    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • 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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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • 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
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—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
    • 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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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—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
    • 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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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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WO 01/19798 PCT/USOO/25195 1 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 5 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. 10 thrombin, fVIIa, fIXa) 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 15 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 20 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 25 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 WO 01/19798 PCT/USOO/25195 2 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 5 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 seine 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 10 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 15 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 20 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. 25 Chem., 26, 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, 248, 593-596 (1990). 30 Factor Xa inhibitory compounds which are not large polypeptide-type inhibitors have also been reported including: Tidwell, R.R. et al., "Strategies for Anticoagulation WO 01/19798 PCT/USOO/25195 3 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 5 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, C.M. et al., "Mechanism Based Isocoumarin Inhibitors for Trypsin and Blood Coagulation Serind Proteases: New Anticoagulants", Biochemistry, 27, 2547-2557 (1988); Hauptmann, J. et al., "Comparison of the 10 Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors", Thromb. Haemost., fa, 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 15 Xa at two of its active sites. For example, WO 98/28269 describes pyrazole compounds having a terminal C(=NH)-NH 2 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 20 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 25 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 30 Factor Xa than to thrombin are desired, especially those compounds having good bioavailability or other pharmacologically desirable properties.
WO 01/19798 PCT/USOO/25195 4 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 5 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 cerebrovascular syndrome, 10 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 15 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 20 group consisting of N, 0 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, 0 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 25 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 30 thereof.
WO 01/19798 PCT/USOO/25195 5 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 5 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 10 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. 15 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 20 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, 25 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.
WO 01/19798 PCT/USOO/25195 6 As used herein, the terms "carbocyclic ring structure " and " C 3 16 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 5 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 10 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 15 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, 20 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 25 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 "caibocyclic ring structure" refers to an unsubstituted or substituted aromatic ring, substituted with one, two or three substituents selected from loweralkoxy, loweralkyl, loweralkylamino, hydroxy, 30 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 WO 01/19798 PCT/USOO/25195 7 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 5 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 10 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, 0 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, 0 and S, including bicyclic ring structures wherein any of the described stable monocyclic 15 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, 0 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" 20 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 25 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 30 "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 WO 01/19798 PCT/USOO/25195 8 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 0 and S atoms in a 5 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 0 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, 10 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, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, 15 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, 20 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 25 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, 30 1 H-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocylic ring structures.
WO 01/19798 PCT/USOO/25195 9 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 5 structure. The terms "halo" or "halogen" as used herein refer to Cl, 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 Cl, Br, F or I atom, including mixtures of different halo atoms. Trihaloalkyl includes trifluoromethyl and the like as preferred radicals, for 10 example. The term "methylene" refers to -CH 2 -. 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 15 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, 20 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. 25 "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, WO 01/19798 PCT/USOO/25195 10 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, 5 hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the liked. 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 10 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 15 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, 20 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 25 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): WO 01/19798 PCT/USOO/25195 11 A-Q-D-E-G-J-X wherein: A is selected from: (a) CI-C 6 -alkyl; 5 (b) C 3
-C
8 -cycloalkyl; (c) -N(R 2
,R
3 ), -C(=NR 2
)-R
3 , -C(=NR 2
)N(R
2
,R
3 ), -N(R 3
)-C(=NR
2
)N(R
2 , R 3 )-, and -N(R 2
)C(=NR)-R
2 (d) phenyl, which is independently substituted with 0-2 R' substituents; (e) naphthyl, which is independently substituted with 0-2 R' substituents; and 10 (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, 0 and S, and wherein the ring system may be substituted with 0-2 R' substituents; R' is selected from: 15 Halo, -CN, -C(=0)-N(R 2 , R), -NO 2 , -SO 2
N(R
2 , RW), -S0 2
R
2 , -(CH 2 )mNR 2
R
3 , (CH 2 )m-C(=NR 3
)-R
2 , -(CH 2 )m-C(=NR 2
)-N(R
2
,R
3 ), -(CH 2 )m-N(R 2
)-C(=NR
2
N(R
2
,R
3 ), -(CH 2 )mNR 2
-C
3
.
6 heterocyclics, CI.4alkyl, C2- 6 alkenyl, C 2
.
6 alkynyl, C 3 . 8 cycloalkyl, Co4alkylC 3 .scycloalkyl, -CF 3 , -OR 2 , and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from N, 0 and S, wherein from 20 1-4 hydrogen atoms on the heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C1.
4 alkyl-CN, C1.4alkyl, C 2
-
6 alkenyl, C 2
.
6 alkynyl, C 3 .scycloalkyl, Co.4alkylC 3 -scycloalkyl and NO 2 ; R2 and R3 are independently selected from the group consisting of: WO 01/19798 PCT/USOO/25195 12 -H, -ORa, -N(-Ra, -Rb), -C.4alkyl, -C 2
-
6 alkenyl, -C 2
-
6 alkynyl, -C 3
.
8 cycloalkyl, -Co4alkylC 3 .gcycloalkyl, -CO4alkylphenyl and -Co4alkylnaphthyl, 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, 5 CI.
4 alkyl-CN, -CI.
4 alkyl, -C2- 6 alkenyl, -C 2
-
6 alkynyl, -C 3 .scycloalkyl, -Co.4alkylC 3 . 8 cycloalkyl, -CN, and -NO 2 ; 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 10 selected from N, 0 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 1 .4alkyl-CN, -C 1
.
4 alkyl, -C 2
-
6 alkenyl, -C 2
-
6 alkynyl, -C 3 . scycloalkyl, -Co4alkylC 3
.
8 cycloalkyl and -NO 2 ; Ra and Rb are independently selected from the group consisting of -CI.4alkyl, -C 2
-
6 alkenyl, 15 -C 2 -6alkynyl, -C 3
.
8 cycloalkyl, -Co4alkylC 3 .scycloalkyl, 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, 0 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, 20 -CN, -C 14 alkyl, -C 2 .salkenyl, -C 2
-
6 alkynyl, -C 3 .scycloalkyl, -Co4alkylC 3 .scycloalkyl and -NO 2 ; m is an integer of 0-2; Q is selected from the group consisting of: a direct link, divalent -Ci- 4 alkyl, divalent -C 2
-
4 alkenyl, divalent -C2-4alkynyl, 25 -C(=O)-, -C(=NH)-, -C(=NMe)-, -N(-R 4 )-, -N(-R 4
)-CH
2 -, -C(=0)-N(-R 4 )-,
-N(-R
4 )-C(=0)-, -S(=0) 2 -, -0-, -S(=0) 2
-N(-R
4 )- and -N(-R 4 )-S(=0) 2 -, wherein one or more hydrogens on each of the divalent C 1
-
4 alkyl, divalent C 2
-
4 alkenyl and divalent C 2 -4alkynyl moieties can be replaced with a -R 4 group; R4 is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 13 -H, -CF 3 , -CI.4alkyl, -C 2
-
6 alkenyl, -C 2
-
6 alkynyl, -C 3
.
8 cycloalkyl, -Co-alkylC 3 . scycloalkyl, -Co.
4 alkylphenyl and -Co.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, 5 -C 1
.
4 alkyl, -C 2
-
6 alkenyl, -C 2
-
6 alkynyl, -C 3
-
8 cycloalkyl, -C 04 alkylC 3
.
8 cycloalkyl, CN, -CF 3 , and -NO 2 ; D is selected from the group consisting of: (a) a direct link; (b) phenyl, which is independently substituted with 0-2 Rla substituents; 10 (c) naphthyl, which is independently substituted with 0-2 R 1 la 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, 0 and S, and wherein the ring system may be subsituted from 0-2 Ria 15 substituents; Ria is selected from the group consisting of: halo, C14alkyl, C 2
-
6 alkenyl, C 2
.
6 alkynyl, C 3
.
8 cycloalkyl, Co.4alkylC 3 .scycloalkyl, CN, -NO 2 , (CH 2 )nNR 2 aR 3 a, SO 2
NR
2 aR 3 a, SO 2
R
2 a, CF 3 , OR 2 a, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, 0 20 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 1 4alkyl, C 2
.
6 alkenyl, C 2
.
6 alkynyl, C 3
.
8 cycloalkyl, Co4alkylC 3 scycloalkyl, -CN and -NO 2 ;
R
2 a and R3a are independently selected from the group consisting of: 25 -H, C 1
.
4 alkyl, C 2
-
6 alkenyl, C 2
-
6 alkynyl, C 3
.
8 cycloalkyl, Co4alkylC 3 -scycloalkyl, Co.4alkylphenyl and Co4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced WO 01/19798 PCT/USOO/25195 14 with a member selected from the group consisting of halo, CI-alkyl, C 2
-
6 alkenyl,
C
2
-
6 alkynyl, C 3 .scycloalkyl, Co-alkylC 3 .scycloalkyl, -CN and -NO 2 ; n is an integer of 0-2; E is selected from the group consisting of: 5 a direct link, -(CH 2 )q-C(=O)-, -(CH 2 )q-N(-R 5
)-C(=O)-(CH
2 )x-,
-(CH
2 )q-C(=O)-N(-R)-(CH 2 )x-, -(CH 2 )q-N(-R 5
)-(CH
2 )x-, , -(CH 2 )q-N(R)CO
NR
6
(CH
2 )x and -S02-; q and x are independently an integer of 0-2; Ri and R are independently selected from the group consisting of: 10 H, -CI-6alkyl, -CI- 6 alkyloxy, -C 2
-
6 alkenyl, -C 2
-
6 alkynyl, -C 3
.
8 cycloalkyl, -Co- 6 alkylC 3
.
8 cycloalkyl, -Ci4alkyl-C(=0)-OH, -Co- 6 alkyl-(carbocyclic aryl), -Co4alkyl-(monocyclic heteroaryl) and -C 1 i4alkyl-C(=O)-O-Ci alkyl, 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 15 selected from the group consisting of halo, -Ci 4 alkyl, -C 2
-
6 alkenyl, -C 2
-
6 alkynyl, C 3
.
8 cycloalkyl, -Co4alkylC 3
.
8 cycloalkyl, -S(=0) 2 -OH, -CN, -CF 3 and -NO 2 ; G is selected from the group consisting of: phenyl, which is substituted with 0-2 RIb groups; and a 5-6 membered aromatic and non-aromatic heterocyclic ring containing 1-4 20 hetero atoms selected from N, 0 and S wherein the heterocyclic ring is substituted with 0-2 RIb groups; RIb is independently selected from the group consisting of: halo, -CI 6 alkyl, -C 2
.
6 alkenyl, -C 2
-
6 alkynyl, -C 3 .scycloalkyl, -Co- 6 alkylC 3
.
8 cycloalkyl, -Cialkyl-C(=O)-OH, -CN, -COOR 2 b, -CONR 2 bRab, 25 NO 2 , -S(=0) 2 -OH, -N(-R 2 b, -R 3 b), -C(=O)-N(-R 2 b, -R 3 b), -S(=O) 2
-N(-R
2 b, -R 3 b), S(=0) 2
-R
2 , -CF 3 , -O-R 2 b, -O-CH2-CH2-0-R26 -O-CH2-C(=0)-O-R2, WO 01/19798 PCT/USOO/25195 15 -N(-R2b)-CH2-CH2-0-Rb, -N(-CH2-CH2-0-R2b)2, -N(-R 2 b)-C(=O)-R 3 b,
-N(-R
2 b)-S(=0) 2
-R
3 b, and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, 0 and S substituted with 0-4 Rib' groups; alternatively, when two Rib may be present on adjacent ring atoms of G and 5 combine to form a benzene ring substituted with 0-4 RI' groups or a 5-6 membered aromatic or non-aromatic heterocyclic ring having 1-3 heteroatoms selected from N, 0 and S substituted with 0-4 RIb' groups; in a second alternative, one of the RIb groups of G can cylize with the -N-R 5 group of E to form a 5-7 membered heterocyclic ring containing 1-4 heteroatoms 10 selected from N, 0 and S, which is subtituted with 0-4 Rib' groups, wherein two of the Rib' groups attached to the same ring carbon may form a (=0) group;
R
2 b and R 3 b are independently selected from the group consisting of: -H, -Ci- 6 alkyl, -Ci-6alkyloxy, -C 2
-
6 alkenyl, -C 2
-
6 alkynyl, -C 3 .scycloalkyl,
-CO.
6 alkylC 3 .scycloalkyl and -Co.
6 alkyl-(carbocyclic aryl), wherein from 0-4 15 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,
-CI
4 alkyl, -C 2
-
6 alkenyl, -C 2
-
6 alkynyl, -C 3 .scycloalkyl, -CowalkylC 3 .scycloalkyl, S(=0)2-OH, -CN, -CF 3 and -NO 2 ; Ri' is independently selected from the group consisting of: 20 halo, -C 1
-
6 alkyl, -C 2
.
6 alkenyl, -C 2
-
6 alkynyl, -C 3 -scycloalkyl,
-CO.
6 alkylC 3
.
8 cycloalkyl, -Cialkyl-C(=O)-OH, -CN, -NO 2 , -S(=0) 2 -OH, -N(-R 2 b'
-R
3 b'), -C(=0)-N(-R 2 ', -R 3 b'), -S(=0) 2
N(-R
2 b', -R 3 '), -S(=0) 2
-R
2 b', -CF 3 , -- R 2 b' -O-CH2-CH2-O-R2', -O-CH2-C(=0)-O-R2b', -N(-R2b')-CH2-CH2-0-R2b' -N(-CH2-CH2-0-Rb)2, -N(-R 2 b')-C(=0)-R 3 b' and -N(-R 2 b')-S(=0) 2
-R
3 b; 25 R 2 b' and R 3 b' are independently selected from the group consisting of: -H, -Ci_ 6 alkyl, -CI- 6 alkoxy, -C 2
-
6 alkenyl, -C 2
-
6 alkynyl, -C 3 .scycloalkyl, -Co- 6 alkylC 3 .scycloalkyl and -Co.
6 alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety may be WO 01/19798 PCT/USOO/25195 16 independently replaced with a member selected from the group consisting of halo,
-C
1 .4alkyl, -C 2
-
6 alkenyl, -C 2
-
6 alkynyl, -C 3 -scycloakyl, -Co.
4 alkylC 3 .scycloalkyl, S(=0) 2 -OH, -CN, -CF 3 and -NO 2 ; J is selected from the group consisting of: 5 a direct link, -S(=0) 2 -, -C(=O)-, -N(-R)-S(=0) 2 -, -C(=0)-N(-R 7 )-S(=0) 2 -, -C(=0)-N(-R 7
)-(CH
2 )y-, -S(=0) 2
-N(-R
7 ) -(CH 2 )y-, and -N(-R 7
)-C(=O)-(CH
2 )y-; y is an integer of 0-2;
R
7 is selected from the group consisting of: -H, -C 2 -4alkyl, -C 2 -6alkenyl, -C 2
-
6 alkynyl, -C 3
.
8 cycloalkyl, -Co- 6 alkylC 3 .scycloalkyl, 10 -CI- 6 alkyl-C(=O)-OH, -C 1
.
6 alkyl-OH, -C 1
-
6 alkyl-O-CI.4alkyl, -CO. 4 alkyl-(carbocyclic aryl), -Co.4alkyl-(monocyclic or bicyclic heterocyclic ring system having from 0-4 heteroatoms selected from the group consisting of N, 0 and S), -CH 2 -C(=O)-O-C1.4alkyl and -CH 2 -C(=O)-O-C1.4alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl 15 moiety or the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo, -CI-4alkyl, -C 2
-
6 alkenyl, -C 2 6 alkynyl, -C 3 -gCycloalkyl, -Co 4 alkylC 3 -8cycloalkyl, -S(=0) 2 -OH, -CN, -CF 3 and
-NO
2 ; X is selected from the group consisting of: 20 phenyl, which is substituted with 0-3 R'* groups; naphthyl, which is substituted with 0-3 RI* groups; a 6-membered heteroaromatic ring containing from 1-2 nitrogen atoms, wherein the ring is substituted with 0-3 RIc groups; and a fused heterobicyclic ring system, wherein the ring system contains 1-3 25 heteroatoms selected from N, 0 and S and is substituted with 0-3 R'C groups; RIC is independently selected from the group consisting of: WO 01/19798 PCT/USOO/25195 17 halo, -CF 3 , -CI- 6 alkyl, -C 2
-
6 alkenyl, -C 2
-
6 alkynyl, -C 3 .scycloalkyl, -Co- 6 alkylC 3
.
8 cycloalkyl, -C l4alkyl-C(=O)-OH, -CF 3 , -CN, -NO 2 , -(CH 2 )z-N(-R 2 c,
-R
3 ), -C(=O)-N(-R 2 c, -R 3 ), -C(=NH)-N(-R 2 c, -R 3 ) -C(=NMe)-N(-R 2 c, -R 3 *), -S(=0) 2
-N(-R
2 c, -R 3 ) -S(=0) 2
-R
2 c, -S(=0) 2 -0 H, -CF 3 , -O-R 2 c, -0(-CH 2 )z-0-R 2 c, 5 -O(-CH 2 )z-C(=0)-O-R 2 c, -N(-R 2 c), -0(-CH 2 )z-0-R 2 c, -N[(-CH 2 )z-O-R 2 c] 2 ,
-(CH
2 )z-N(-R 2 c)-C(=O)-R 3 C, -(CH 2 )z-N(-R 2 c)-S(=0) 2
-R
3 , and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, 0 and S; z is an integer of 0-4;
R
2 e and R 3 C are independently selected from the group consisting of: 10 -H, -CI- 6 alkyl, -CI- 6 alkyloxy, -C 2
-
6 alkenyl, -C 2
-
6 alkynyl, -C 3
-
8 cycloalkyl,
-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,
-CI.
4 alkyl, -C 2 -6alkenyl, -C 2
-
6 alkynyl, -C 3
-
8 cycloalkyl, -Co.4alkylC 3
-
8 cycloalkyl, 15 S(=0) 2 -OH, -CN, -CF 3 and -NO 2 ; 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 20 wherein: A is selected from the group consisting of:
-C
1 .-alkyl and -C 3 .scycloalkyl; phenyl, which is substituted with 0-2 R' groups; naphthyl, which is substituted with 0-2 R' groups; and WO 01/19798 PCT/USOO/25195 18 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, 0 and S and is substituted with 0-2 R' groups; 5 R' is independently selected from the group consisting of: halo, -C 1
.
4 alkyl, -CN, -N0 2 , -(CH 2 )m-N(-R 2
,-R
3 ), -C(=0)-N(-R 2
,-R
3 ), -S(=0) 2
-N(
R
2
,-R
3 ), -S(=0) 2
-R
2 , -(CH 2 )m-C(=NR 3
)-R
2 , -(CH 2 )m-C(=NR 2
)-N(R
2 ,R), -(CH 2 )m
N(R
2
)-C(=NR
2
)-N(R
2
,R
3 ), -CF 3 , -(CH 2 )m0-R 2 and a 5-6 membered aromatic heterocyclic ring containing 1-4 heteroatoms selected from N, 0 and S; 10 R2 and R3 are independently selected from the group consisting of: -H, -C14alkyl, or R 2 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 15 selected from N, 0 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 1
-C
4 -alkyl-CN, -Cl 14 alkyl, -C 2
-
6 alkenyl, -C 2
-
6 alkynyl,
-C
3 .scycloalkyl, -Co.4alkylC 3 .scycloalkyl and -NO 2 ; m is an integer of 0-2; 20 Q is selected from the group consisting of: a direct link, -CI- 4 alkyl, -C 2
-
4 alkenyl, -C 2 -4alkynyl, -C(=O)-, -C(=NH)-, C(=NMe)-, -N(-R 4 )-, -N(-R 4
)-CH
2 -, -C(=O)-N(-R 4 )-, -N(-R 4 )-C(=O)-, -S(=0)2-, 0-, -S(=0) 2
-N(-R
4 )- and -N(-R 4 )-S(=0) 2 -; RW is selected from the group consisting of: 25 -H, -CF 3 , -C 1
.
4 alkyl, D is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 19 a direct link; phenyl, which is substituted with 0-2 Ra 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 5 heterocyclic ring system contains 1-4 heteroatoms selected from N, 0 and S and the ring system is substituted with 0-2 R 1 la groups; Rla is independently selected from the group consisting of: halo, -ClAalkyl, -CN, -NO 2 , -(CH 2 )n-N(-R 2 a, -Ra), -S(=O) 2
-N(-R
2 a, -R 3 a)
-S(=O)
2
-R
2 a, -CF 3 , -(CH 2 )n-OR 2 a, -C(=O)-O-R 2 a, -C(=O)-N(-R 2 a, R 3 a) and a 5-6 10 membered aromatic heterocyclic ring containing 1-4 heteroatoms selected from N, 0 and S; n is an integer of 0-2;
R
2 a and R3a are independently selected from the group consisting of: -H, -CF 3 and -CI 4 alkyl, 15 E is selected from the group consisting of: a direct link, -(CH2)q-C(=O)-, -(CH2)q-N(-R)-C(=0)-(CH2)x-,
-(CH
2 )q-C(=O)-N(-R 5
)-(CH
2 )x-, -(CH 2 )q-N(-R 5
)-(CH
2 )x-, -(CH 2 )q-N(R 5
)CO
NR
6
(CH
2 )x- and -SO 2 -; R5 and R 6 are each H, -CI-alkyl, -C 2
-
6 alkenyl, -C 2
-
6 alkynyl, -C 3 .scycloalkyl, or 20 -Co-alkylC 3 .scycloalkyl; 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 RIb groups; and WO 01/19798 PCT/USOO/25195 20 a 5-6 membered aromatic and non-aromatic heterocyclic ring containing 1-4 hetero atoms selected from 0, S and N, wherein the heterocyclic ring is substituted with 0-2 RIb groups; R"b is independently selected from the group consisting of: 5 halo, -Ci 4 alkyl, -CN, -NO 2 , -N(-R 2 b, -R 3 b), -C(=O)-N(-R 2 b, -R 3 b), -S(=O) 2
-N(-R
2 b,
-R
3 b), -S(=0) 2
-R
2 b, -CF 3 , -O-R 2 b, -O-CH2-CH2-0-R26 -O-CH2-C(=0)-O-R b -N(-R2b)-CH2-CH2-0-R2, -N(-CH2-CH2-0-R2)2, -N(-R 2 b)-C(=O)-R 3 b,
-N(-R
2 b)-S(=O) 2
-R
3 b and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, 0 and S; 10 alternatively, when two RIb may be present on adjacent ring atoms of G and combine to form a benzene ring substituted with 0-4 Rib' groups or a 5-6 membered aromatic or non-aromatic heterocyclic ring having 1-3 heteroatoms selected from N, 0 and S substituted with 0-4 Rib' groups; in a second alternative, one of the RIb groups of G can cylize with the -N-R 15 group of E to form a 5-7 membered saturated, unsaturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from N, 0 and S, which is substituted with 0-4 Rib' groups, wherein two of the Ri'b' groups attached to the same ring carbon may form a (=0) group;
R
2 b and R 3 b are independently selected from the group consisting of: 20 -H, -CF 3 , -C Ialkyl and -Ci4alkyl-(carbocyclic aryl); Ri' is independently selected from the group consisting of: halo, -Cigalkyl, -CN, -NO2, -N(-R2b', -R31'), -C(=0)-N(-R26', -RWb'), -S(=0)2-N( R2b', R 3 b'), -S(=O) 2
-R
2 b', -CF 3 , -O-R 2 b', -O-CH2-CH2-0-R2b' -O-CH2-C(=0)-O-R2"', -N(-R2b')-CH2-CH2-0-R2V, -N(-CH2-CH2-0-R2V')2, 25 -N(-R 2
')-C(=O)-R
3 b, -N(-R 2 b')-S(=0) 2
-R
3 b;
R
2 b' and R 3 b' are independently selected from the group consisting of: WO 01/19798 PCT/USOO/25195 21 -H, -C IAalkyl and -C I alkyl-(carbocyclic aryl); J is selected from the group consisting of: a direct link, -S(=0)2-, -C(=0)-, -N(-R 7 )-S(=0) 2 -, -C(=O)-N(-R 7 )-S(=0) 2 -,
-C(=O)-N(-R
7
)-(CH
2 )y-, -S(=0) 2
-N(-R
7 )-, -(CH 2 )y- and -N(-R 7
)-C(=O)-(CH
2 )y-; 5 y is an integer of 0-2; R7 is selected from the group consisting of: -H, -CI-4alkyl, -C 2
-
6 alkenyl, -C 2
-
6 alkynyl, -Co 4 alkyl-(carbocyclic aryl), -Co 4 alkyl-(heterocyclic ring system), -CH 2 -C(=O)-O-Ci 4 alkyl and
-CH
2 -C(=O)-O-CI-alkyl-(carbocyclic aryl); 10 X is selected from the group consisting of: phenyl, which is substituted with 0-3 RIC groups; naphthyl, which is substituted with 0-3 RIC groups; a 6-membered heteroaromatic ring containing from 1-2 nitrogen atoms, wherein the ring is substituted with 0-3 RIC groups; and 15 a fused heterobicyclic ring system, wherein the ring system contains 1-3 heteroatoms selected from N, 0 and S and is substituted with 0-3 RIC groups; RIc is independently selected from the group consisting of: halo, -Ci-alkyl, -CN, -NO 2 , -(CH 2 )z-N(-R 2 c, -R 3 ), -C(=0)-N(-R 2 c, -R 3 c)
-C(=NH)-N(-R
2 c, -R 3 c), -C(=NMe)-N(-R 2 c, -R 3 C), -S(=0) 2
-N(-R
2 c, -R 3 C), -S(=O)2 20 R 2 c, -S(=0)2-O-, -CF 3 , -O-R 2 C, -O-CH2-CH2-0-Rc, -0-CH 2 -C(=0)-O-R 2 C
-N(-R
2 c)-CH 2
-CH
2 -0-R 2 C, -N(-CH 2
-CH
2 -0-R 2
C)
2 , -(CH 2 )z-N(-R 2 c)-C(=O)-R 3 C,
-(CH
2 )z-N(-R 2 c)-S(=0) 2
-R
3 c, and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, 0 and S; z is an integer of 0-2; WO 01/19798 PCT/USOO/25195 22
R
2 e and R 3 ' are independently selected from the group consisting of: -H, -C 1 .4alkyl and -Ci4alkyl-(carbocyclic aryl); and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. 5 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: H S N1 N0M Me H
SO
2
NH
2
SO
2 NHMe SO 2 Me CH 2
NH
2 Nme Me
CONH
2 CN SO 2
NH
2
SO
2
NH
2
SO
2
NH
2
SO
2 Me SO 2 Me SO 2 Me N F ci Br F ci Br F / / N N NC H 2 NOC H 2
NH
2 C NC H 2 NOC Nl\N N Y N D Cl Br
H
2
NH
2 C Me 2
NH
2 C Me 2 N H 2 N NH 2
CH
2
NH
2 CN NMe 2 N N N N N N N N
CH
2 NMe 2
SO
2
NH
2
SO
2 Me CONH 2
H
2 N H 2
NH
2 C N N)NNN N N HN N N N H2Et N N N/
H
2 N NH 2
CH
2
NH
2
/NH
2
CH
2
NH
2 CN N=N /Y N" \ \N N N, =N N N, N / \~-N ~ N EtO 'NNN
SO
2 Me NH 2
H
2 N Me 2 N H 2
NH
2 C H 2 NOC NC N N N N N N NN N N N N N N EN 10 WO 01/19798 PCT/USOO/25195 23 N N Me-N' HN O S 0 2 S N IN H2N N N- N- N- N- N
NH
2 H H C N- Me-N N- Me-N HN N- HN N- O N- S N N-Me, Et* Et, Me, 02S N- N N- N <N- rN- N- mN- mN- EN-M N Me Me Me H E - N- [ N- \N- M N-M /[ N-- 0 E HNN-N O Me Me H Me Me S N N N N H Me Et NH NH N O' -- '. H 2 N H 2 N )NH- me ANH- H 2 N H Me Et NH 0 Me Me Me Me H Me Me 2 N Me 2 N H 2
N-CH
2 - N-CH 2 - N-CH2- Me-N-CH 2 - Me- -N- Me-#-O H Me Me Me Me Q is selected from the group consisting of: a direct link, -C(=NH), -C(=NMe)-, -C(=O)-, -CH 2 -, -NH-, -N(-CH 3 )-, -0-, -NH
CH
2 -, -CH 2 -NH-, -N(-CH 3
)-CH
2 -, and -CH 2
-N(-CH
3 )-; 5 D is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 24 -N F C Br CN -NN
CH
2
NH
2 MeFF FCI Br F F -ND - N- -N N M e Me HN) NH N N MQ Me H NN N N N N N E is selected from the group consisting of: a direct link, -NH-C(=0)-, -N(-CH 3 )-C(=0)-, -N(-CH 2
CO
2 H)-C(=0)-, C(=O)-NH-, -C(=O)-N(-CH 3 )-, -NH-CH 2 - and -CH 2 -NH-; 5 G is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 25 lb Rib Rib RiR b R R Rb R ib R RRib 'RN Rlb )/ R NRib R R Rb i ib R1=Rb Rb1 N R N R 0bN N IN IN N N N I R R is indpedetl lb R lb lb of: - e S HN andN-CO2H R Ib Rl ib Sk R ib Rib nb 0RlIb Rlb N/ N 10 yN N _ 5 J is 2 s fromlb lb go c si R Rib R Rib _V "' R ib lb bR lb R i lb lb lb R\ i i R R Rib Ri R ib l b a diect ink, - - -O- S=)- -S(=)2 lb -S=)- lb =0 R-ib =O a -N.RCb \/R \ l b lb l R b lb I R Rlb R b R i ) b R Rib l N- lb - lb Rib N * RbR Rlb RbRi NR RibN N N R ib is independently selected from the group consisting of: -H, -Me, -CF 3 , -F, -Cl, -Br, -SO 2 Me, -CN,. -CON1I 2 , -CONMe 2 , -NH 2 , -NO 2 , -NHCOMe, -NHSO 2 Me, -CH 2
NH-
2 and -CO2H; 5 J is selected from the group consisting of: a direct link, -NH-, -0-, -S(=0) 2 -, -S(=0) 2 '-N-H, -NH-S(=0) 2 -, -C(=0)-, -NH-C(0O)- and -C(=0)-NH-; WO 01/19798 PCT/USOO/25195 26 X is selected from the group consisting of: MeO 2 S H 2
NO
2 S 0 2 N
H
2
NH
2 C H 2 N HO H2N H2N Y o HO MeO), H2ND~ 0 0 0 N 'C F CBr£ F CI Br CI Br F CI CI Br Br PA F F CI F Br Br FrC Br F C Br F -Kcir -$' F Br 02 02 02 rF CI Br 020 02 F H H H WO 01/19798 PCT/USOO/25195 27 -<ix , "c Br S cF S l Br 4S"'F 02 S) c4 SN Br N aF N"' Cl N"' Br SF 02 cl 2 H H Hs N Nq I >F N Ci N Br / AN
/H
2
N
2 S> Me0 2 S 0 2 N~ F N"' NN~ N "N (-Kk)/\ H H H
H
2 NOC NC FN C -&F BrB '~M -a oN NN N HN0 NeO 0N: N F HN N H 2 N Me0 2 Me 2 0 2 N F H N N _0 H 2 0 2 M O 2 F H 2 N C H 2 NH H 2 N Me 2 S 0 2 N clB cl c ObBr O Br 'RO BrMe'~M F OH 2 NO
H
2 N0 2 F CI Br OMe F Meo 2 0 2 N F H 2 NO
H
2
NH
2 q F F F F F F WO 01/19798 PCT/USOO/25195 28
H
2 N0 2 MeO! 2 0 2 N F H 2 NO Nq H 2
NH
2 C CCI CI CI CI CI CI
H
2 N0 2 q MeOA 0 2 N F H 2 NO Nq H 2
NH
2 q Br Br Br Br Br Br Br F CI Br F CI Br F ~Br ~Br ~OMe 'OMe ~OMe 2O CI Br F CI Br
H
2 N MeO 2 0 2 N F H 2 NO N H 2
NH
2 C
H
2 N H 2 N H 2 N H 2 N H 2 N H 2 N F-C cl CI - Br N F CI Br /\ Me
H
2 N H 2 N H 2 N H 2 N H 2 N H 2 N H 2 N MeO H 2 N0 H 2 NO -N -NH DN -ND -NN
H
2 N H 2 N H 2 N H 2 N H 2 N H 2 N
H
2 NH.CNF0N e 2 N \/ \ \/\ .! \ ' -N -N -N -N NH NH \/-NH
H
2 N H 2 N H 2 N H 2 N H 2 N H 2 N H 2 N
H
2
NO
2 S
H
2 NOC
H
2
NH
2 CF 2 -N NN H H -NH - N H
H
2 N H 2 N H 2 N H 2 N H 2 N H 2
N
WO 01/19798 PCT/USOO/25195 29 MeO 2 S H 2
NO
2
H
2 NO H 2
NH
2 C NC F 0 -0 - o -o -o -o
H
2 N H 2 N H 2 N H 2 N H 2 N H 2 N
O
2 N ON (7N ~ Me O,(Me o -N N N
H
2 N N l -Q -r -(Q K N1 /7) \ N N \CI \/r-I ,N CI Br NH 0
H
2 N H 2 N H 2 N MeO 2 S F MeO 2 S CI MeO 2 S Br MeO 2 SF >X CI ~fBr MeO 2 S CMeO 2 S H 2
NO
2 S F H 2
NO
2 S CI H 2 N 0 2 'CK'B 1 - F 2 2 B H2NO2S Br H 2
NO
2 S H2NO2 IH2NO2sB 02N F O2N CI 02N LBr O2N
O
2 N BrN NC0 2 F NBr CI N CB r N yF N C I N B r
H
2 NOC F H 2 NOC)M CI H 2 NOC Br H2NOF
H
2 NOC CI H 2 NO & Br H 2
NH
2 cF H 2
NH
2 CCI
H
2
NH
2 C Br H 2
NH
2 F H 2
NH
2 w cI H 2
NH
2 ;ca Br WO 01/19798 PCT/USOO/25195 30 HO F HO M CI HO M, Br HO F HO HO MeO F MeO m Cl ~ ~ ~ ~ Q~C yyIy zFI'Z :zc zBr MeO Br MeO MeO MeO
H
2 N F H 2 N CI H 2 N Br H 2 Ny F H2 Br MeO2SFMeO 2 S M2Ww Br MeO a MeO 2 S FMeO2 MeO 2 S BrF MeO 2 S MeO 2 S CH2O 2 S F FI clBrF MeO 2 s Br MeO 2 S CaBr Me0 2 1=~"Br H 2
NO
2 Sa F
H
2
NO
2 S F H 2
NO
2 S F H 2
NO
2 S CI H 2
NO
2 S= CI Br F Cl Br H2NO2S C1 H 2
NO
2 S Br H 2
NO
2 S Br H 2
N
2 S Br F Ncl BrF 02N 0 2 N F 0 2 N F O 2 N CI 0 2 N CI 0 2 N CI 0 2 N Br O 2 N Br 02 NC F .N N)= Br 0 2 N)= Br N -~F .NC -- = F NC ~F WO 01/19798 PCT/USOO/25195 31 FCI BrF NC C NC C NC ' C NC Br NCr NC H2NOC F H 2 NOC=F
H
2 NOC Br H 2 NOC CI H 2 NOC I H 2 NOC B 2NOC Br H 2 NOC B OH2NH HN Br 2NH 2 NBr H 2
NH
2 C F
H
2 NHC F ' N" Cr H 2
NH
2 O' C 2
N
2 CB'C clBr F .>-lC
NH
2 Cxa~C H 2
NH
2 C~K Br H 2
NH
2 CA)=Br H 2
NH
2 C B ~ F ""M l NBr N F
H
2 N F H 2 N F H 2 N Br H 2 N rMCl NH fH AH NH
H
2 N CI H 2 N B H 2 N H 2 N Br H FH FH H N NBr NH 2
NH
2
NH
2
H
2 N Y aBr ~ F N: ~Cl ~Br hH
NH
2
NH
2
NH
2
NH
2 F F F F ~CI F Br WO 01/19798 PCT/USOO/25195 32
NH
2
NH
2
NH
2
NH
2 N- N F N H 2
NO
2 S MeO2S
NH
2
NH
2
NH
2
NH
2 "'"N" N " N "N
H
2 NOC
H
2NH2 HO2 O 2 N - F CI Br F CI F F F C1 CI - Br F _P CI - Br CI Br Br Br and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. 5 The compounds listed in the following 53 tables are an embodiment of the present invention: WO 01/19798 PCT/USOO/25195 33 Table 1
SO
2
NH
2 IbSO 2
CH
3 I H H H H - NI S0 2
NH
2 lbS0 2 0H 3 I H b H wherein:N \N H So 2
NH
2 o Sc 2 CH3 - -N N ' wherein: Rib is selected from the group consisting of -H, -CH 3 and -CF 3 . Table 2
SO
2
NH
2 Rial Rlb SO 2
CH
3
IR
1 ' Rlb NN N 5 wherein: R I a' and R' a are independently selected from the group consisting of -H, -F, -CI and -Br; WO 01/19798 PCT/USOO/25195 34 Rib is selected from the group consisting of -H, -CH 3 and CF 3 ; and Ric 2 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 and -NH 2 . Table 3 SONlb lSO3 0 Rb H H N~ N' R1e2 R 1.2
SO
2
NH
2 lbSO 2
CH
3 ,Rib H 1 H N- N N CK- N -NN R1c2 RIC2 5 wherein: RIb is selected from the group consisting of -H, -CH 3 and -CF 3 ; and Ric 2 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 and -NH 2
.
WO 01/19798 PCT/USOO/25195 35 Table 4 lb Hl R R
SO
2
NH
2 lb S0 2 0H 3 181 H 0 H - NI- CN Rid
R
12 R'C* l0NH b Zlb HI\H NN wherein: R lal and R ia2 are independently selected from the group consisting of -H, -F, -Cl and -Br; R I is selected from the group consisting of -H, -CH3 and -CF3; and 5 R' is selected from the group consisting of -F, -Cl, -Br, -CN, -CH2NH2, -CH2 H,
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
.
WO 01/19798 PCT/USOO/25195 36 Table 5 lbH RaNH 2 1 SO 2 CH3 R 1 1 Rib H 1N N N R1 3 R 40 So 2
NH
2 c oCH3 n 0 0 H _/ N \N -N
-
N', 1 Rilal Rlal R'c 3 "' R'C 3 S0 2
NH
2 Ib 2
CH
3 R I NN N N Rio 3
R
1 C3 wherein: " l 1 and R'a2 are independently selected from the group consisting of -H, -F,. -CI and -Br; R ib is selected from the group consisting of -H, -CH 3 and -CF 3 ; and 5 R 1, 3 is selected from the group consisting of -H, -F7, -Cl, -Br, -OH, -OCH 3 and -NH 2
.
WO 01/19798 PCT/USOO/25195 37 Table 6
S
2
NH
2 R'l I S0 2 0H 3 R R 1 H H_ N - N N N N" Rla R'c R 12R'C R1c 3 R 1 3
R
1 c 2 R1.
2 S1 2
NH
2 RH 1 l 2
'H
3 111 lb R RH - NNN N' NN N R Rc i R R 1.2 R1c2 S0N2lb Z3lb H 10 H 10 -- N N N N
RR
3 Rica R1c2 R 1c2 wherein: Ra 1 and Ria2 are independently selected from the group consisting of -H, -F, -Cl and -Br; R I 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 ; 5 RIC is selected from the group consisting of -H, -F, -Cl, -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 ; Ric2 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; and Rid 3 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2
.
WO 01/19798 PCT/USOO/25195 38 Table 7 R R1a2 RR11 RR Rib R I R HH , 0 N~ ~ H, 7\ RIGIRc3 RRdR43 NN N R1a2 R Ra R R R R 4Ric RIc 2 R U 2 RiC 2 Ri I sel e R R 1 Rib Rgo c f , CN N H/\N Nj'~ \I ONH, -3 - NH N N N N N
RIU
3 I OR 1 0 R' 3
RIU
2
RIG
2 Rc wherein: R' 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
NIH
2 , -CH 2
NII(CH
3 ), -CH 2
N(CH
3
)
2 ; 5 R" is selected from the group consisting of -H, -NH 2 , -SO 2
NH
2 , -SO 2
CH
3 , -CN,
-CONH
2 , -CONH(CHA) -CON(CH 3
)
2 , -CH 2 NII1 2 , -CH 2 NH(CHA) -CH 2
N(CH
3
)
2 ; Ral and Ria 2 are independently selected from the group consisting of -H, -F, -Cl and -Br; R I 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 ; 10 RI' is selected from the group consisting of -H, -F, -Cl, -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 ; Ric 2 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NiH 2 ; and Ric 3 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2
.
WO 01/19798 PCT/USOO/25195 39 Table 8 R1lb 1 b lb 1 N H2 -L N &ON IL( N R" R'c RW* R 1 3 R1 3 , RU 3
R
1 c 2
RU
2 R1.
2 lb 2R Ib N NZ R io 3
RIU
3
RIU
2 RI1C 2 wherein: R' 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 ; Rib is selected from the group consisting of -H, -CH 3 and -CF 3 ; 5 RI'c is selected from the group consisting of -H, -F, -Cl, -Br, -CN, -CH 2
NH
2 , -CH 2 OH, CONH 2 , -C(=NH)NH 2 , -C02H, -CO 2 Me, -SO 2 Me, -SO 2
NH
2 , -OH, -NH 2 , and -NO 2 ; Ric 2 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; and Ric 3 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2
.
WO 01/19798 PCT/USOO/25195 40 Table 9 l. b lb 1.1 Rib H H H AH A-/H 'N' 1 ,N A NJ-N R1a2 RiR
R
1 Rid RIc 3
RO
3 RIca R1c 2 Rc2 R c2 l~b CH 3 1.1 RlIb lb NH H A H 0 N- , A- N N N NL N N R'c Rc R'c*
R
1 c3 R1e3 RiU 2
R
1 c2 R1c2 NH0lb l/C , b b AJL~g 'N A.J~\\0N \Nl-g~ H 1 N RRio RRio RRIO Rc X0 R1c3 R 10 R1c 2 R1 2 RIc 2 wherein: A is selected from the group consisting of: M N EN-EN- N Me\N- ON- N H H H Me Me Et Me-&N- N- N- N- QN- (N MeQN N- N- N- OI2N- HQN- MehN C N_ 020 _ H
M-NN'-
WO 01/19798 PCT/USOO/25195 41 Ria 1 and Ria 2 are independently selected from the group consisting of -H, -F, -Cl and -Br; RIb 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 ; RiC is selected from the group consisting of -H, -F, -Cl, -Br, -CN, -CH 2
NH
2 , -CH 2 OH, 5 CONH 2 , -C(=NH)NH 2 , -CO 2 H, -CO 2 Me, -SO 2 Me, -SO 2
NH
2 , -OH, -NiH 2 , and -NO 2 ; RIc 2 is selected from the group consisting of-H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; and RIc 3 is selected from the group consisting of-H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 Table 10 lb Rib lb ANQ 1b A-Q \H 16 A- H 1I R2 R R"' Re RIca R 1 c 3 R 1 3 R'c2 R U 2 R1c2 wherein: 10 A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 42 H Me Et Me Et MM Me C H HC2 0 S Me M M H H2 SMe Me me3 Me Me HC H Me HTo 02H H 2 2 22 C H22 N-0- N- N H- N-N- - N Me MeMe N eN N M N 0 2
NH
2 8 2 H H ~ 2 M 2 Me jO H
N
2
C
2 H 2 H\_ JN Me- N- H\ - - 2 NN N- N N N N> Me CONH 2
CH
2
NH
2 Rial and Ria 2 are independently selected from the group consisting of -H, -F, -Cl and -Br; Rib 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 ; Ri'd is selected from the group consisting of--H, -F, -Cl, -Br, -CN, -CH 2
NH
2 , -CH 2 OH, 5 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 ; Ric 2 is selected from the group consisting of--H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; and Ri4 3 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2
.
WO 01/19798 PCT/USOO/25195 43 Table 11 1 lal R' Rla 1 H G H OH G H O G R2 R R R''
R'
3 R1e 3 Rica Rc2 R1c 2 Ric 2 wherein: R' 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 ; 5 RIb is selected from the group consisting of-H, -CH 3 and -CF 3 ; Rial and Ria 2 are independently selected from the group consisting of -H, -F, -Cl and -Br; RiC is selected from the group consisting of -H, -F, -Cl, -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 ; Ric 2 is selected from the group consisting of-H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; 10 R14 3 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; and G is selected from the group consisting of: / \ 'bI Rib2
RIO
3 I P ::N /N \\)N \N N' N N wherein: RIbI is selected from the group consisting of -H, -CH 3 and -CF 3 ; RIb 2 is selected from the group consisting of -H, -CH 3 and -CF 3 ; and WO 01/19798 PCT/USOO/25195 44 Table 12 ,CH 3 a A G A H G A H G R'a2 R'C R1.2 R R1.2 R"* Ric 3 RIc 3 RIc 3 R1c 2 Ric 2 Rce 2 AH O GHO GH O G R R R Rio 3 Rica RIO Rio 2 Ric 2 Rio 2 CHa NH0 0 0H G H G H G
N
R'c R'c R'' R1.
3 Rio 3 R1 3 Ric 2 Ric 2 Ric2 Rib is selected from the group consisting of-Cl, -NHl 2 , -CH 3 and -CF 3 . wherein: A is selected from the group consisting of: Me H H M Me M N Me Me ->)N- N- - N-CN bN- Me QQO2Q H N - MU2N RN R I3 s elctd ro te gou cnsstngofQC, NH QJ3 n C3 WO 01/19798 PCT/USOO/25195 45 Rib is selected from the group consisting of -H, -CH 3 and -CF 3 ; RIal and Ria 2 are independently selected from the group consisting of-H, -F, -Cl and -Br; RiC is selected from the group consisting of -H, -F, -Cl, -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 ; 5 R 1
,
2 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; RiC 3 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; and G is selected from the group consisting of:
R
1 '' Rib2 Rib 3 / ~ ~/N~ /- NN N ,-N V' wherein: Ribi is selected from the group consisting of -H, -CH 3 and -CF 3 ; 10 Rib 2 is selected from the group consisting of-H, -CH 3 and -CF 3 ; and Rib 3 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 . Table 13 A- H G A- G A-,- _H G R2 R'd R1 R* RIc3 R1c 3 Rc3
R
1 'c 2
R
1 ,2 RIC 2 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 46 CN>- cc>- cc- oc- cc>- 0 -0C- - C> HN Me Et Me Et T Me -- H - M N- H N- H NM N 0-N H MMe Me M e N H 2 - M z - e C Me aM eM MMe C ~Me NHe"'CC eM
H
2 22 OH H2 C 2 H2
H
2 /N- N- HN C- N- N- N - N N M N N M N N M N N M N NQ N NN- N N- N
CH
2
NH
2 Rib is selected from the group consisting of -H, -GCH 3 and -CF 3 ; Rial and Ria 2 are independently selected from the group consisting of -H, -F, -Cl and -Br; 5 RICd is selected from the group consisting of -H, -F, -Cl, -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 ; Ric 2 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; Ric 3 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; and WO 01/19798 PCT/USOO/25195 47 G is selected from the group consisting of:
R
1 W RIb 2 R ib 3 ~ ~N N ' N ..- ,N
'
N N"N N' wherein: 5 RIbI is selected from the group consisting of -H, -CH 3 and -CF 3 ; RIb 2 is selected from the group consisting of -H, -CH 3 and -CF 3 ; and R Ib 3 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 . Table 14 RR, RR R
R
1 c 3 Ric 3 Rica R1.2 R1.2 RU2 Me
CF
3 R N N R"I Ric 3 Ric 3 R1c2 Ric2 10 wherein: WO 01/19798 PCT/USOO/25195 48 R' 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 ; RIb is selected from the group consisting of -H, --CH 3 , -CF 3 ; Ri'l is selected from the group consisting of -H, -F, -Cl, -Br, -CN, -CH 2
NH
2 , -CH 2 OH, 5 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 ; Ric 2 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; and Ri" 3 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 . 10 WO 01/19798 PCT/USOO/25195 49 Table 15 l Rb l ~b A Rib H R OH 3 R R * A~ H \N N--L~j AI/ \, NII~' A Rica RcaIRic A N A N N
RR
3 R'c RRI* R Rc3 Rica R R o R lC2 R lc2 R bc2 N H - o R b t 1 O 3 - , . lb.< N L I R I A HN A N R/ N 1N A N J A N -- b m N N N" N" R'c R'c R'
RIO
3
RIO
3 RI1 3 R'c 2
R
1 c2 R1c2 A NRb H NRib Ab N NNN RRIO R/RO RRIO Rica R c3 R c3 Rc2 N 12 Ri2 S1b A e R A RIb
RO
1
RIO
1 Rid RIc 3 Rica R1c 3 R1,2 R1 2 R1 2
CF
3 b
CF
3 lb
CF
3 NH 0 NI' 000 A I'N I > A N A N -N NI N1N R io 3
/RIO
3
RIO
3 R IO 2
R
1
'
2 RIc 2 wherein: WO 01/19798 PCT/USOO/25195 50 A is selected from the group consisting of: Me N- M EN- N- N-N- N H H ( M Md Et/ Me Me Me-(N- ON- N N- N- Me QN N- N- O 2 N- H - Me-N N QN- O - 0 2 , ' H/-\ Me-N/s \ N N-
-
UN
N
Rib is selected from the group consisting of-H, -CH 3 and -CF 3 ; R"' is selected from the group consisting of -H, -F, -Cl, -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 ; 5 R1c 2 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; and Ric 3 is selected from the group consisting of-H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2
.
WO 01/19798 PCT/USOO/25195 51 Table 16 AQ N- NR~N A-Q/" N N~bA--Nb R Cb Rb Rib RIca Rlc, R'c3 Rc2 ic2 RRi R2 R ' RN N-Me Rib ~ CF 3 RlIb A-Q NR\, A-Q NR/ N' N , RIO R * RIc 2 Rc2 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 52 CS-C> C- Co- C>- C-Qa-Co-C> HN Me Et Me Et MH2 L Me Me Me N N- N---M- N H - HHC eHC H C -MS eNM Me Me M0e NM MMe HNN TN C N ~M a v-' Mem
O
2 I HH 2
NH
2 R ssletdfomtegop ossinHf-, -,-1 -Br, -CN, -eC H 2N 2,-C 2O _N- f N C- -NN M mM Me a~N N- Me N o -l 2Me
COH
2
(H
2 H
CONH
2 , -C(=NHNH 2 , -CO 2 H, -CO 2 Me, -SO 2 Me, -SO 2
NH
2 , -OH, -NH 2 , and -NO 2 ; 5 RIc 2 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and --NH 2 ; and
RIC
3 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2
.
WO 01/19798 PCT/USOO/25195 53 Table 17 RIb R Rib RO Rib N N N N IN N' IN
'N
O~2 R'c R'c O R' R1c 3 Rica R1i3 R1c2 RIc2 RIC2 1 IR ib I aRilb 0 Rilb NN N N\ NR N NR N Ol2 R'c O R'c R'c R1.3 Ri Rc3 Ric2 RIc2 R 1 2 O Rib a Rib Rib -N N N Rica 1
R
1 ~c3R R N NR R2o R'c O R'C R'
R
1 0c Ric3 Ric3 Ric 2 R ic2 Ri2 R RRilb Rib Rib N N N NI 'N v'N Ri.3 R io 3 R io 3 , RiII b llb R ib "'/ NN NN R'2R" 0 Rio 1 Rio' R io 3 Rio? Rio0 3 Rio2 R 1 2 Rio WO 01/19798 PCT/USOO/25195 54 Table 17 (continued)
R
1 ' PH /l ' Ra Rib0H l N NR N N 0 Rio 1
R
1 c 1 0 Rio 1 Rio 3
R
1
'
3 Rica Rie 2 Ric 2 RIc2 wherein: R' 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 ; 5 Rlal and Ria2 are independently selected from the group consisting of-H, -F, -Cl and Br; RIb is selected from the group consisting of-H, -CH 3 and -CF 3 ; Ridc is selected from the group consisting of-H, -F, -Cl, -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 ; Ric 2 is selected from the group consisting of-H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; and 10 Rid 3 is selected from the group consisting of-H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2
.
WO 01/19798 PCT/USOO/25195 55 Table 18 RR .3CH 3 Rb Rib RAc R-Lc2 R N NH0 RA NN R AN N N N R R'c R' Rc RR.3 RRO, RRio R1c2 RiU 2 Ric2 Rib CH 3 1b Rib R~a O R'C ''0RC R~3 ~c2Rc A NR A 'A A C\N A- I> N NNN N R1a2 ORR A N R R i 3 Rio 3 Rio 3 , 1c2 R 1 c2 Ri 2 RRc R1c2 Rlb C 3 _ R ib R ib N A NN Rioi RidRRca A NR Ri0 3 Rio0 R R~~ NR,3 1c1,R 0 RIo 2 Ric 2 Ric2 H N R 1 b CH3 R. ib R ib A INi A ANi N N 'N N NI N N I Ric 3
RO
3
RIO
3 RiU 2 Ric 2 Riw 2 WO 01/19798 PCT/USOO/25195 56 Table 18 (continued) R"' PH Ri HI CH 3 R8 RbH Rl A NN A N N N N~ ~N N 101ic Rc Ri0d
OR
3 RI Rica R 1 R'c R~c R1c2 R1.2 wherein: A is selected from the group consisting of: Me N- M N- M E N- Et N MN--KN H H H Md Md Et Me Me N- [N- - ON- QN- HN- Me-N MaQN- QN- N-N- HN-N- Me-F N RIal and R 1 a2 are independently selected from the group consisting of -H, -F, -Cl and Br; RIb is selected from the group consisting of -H, -CH 3 and -CF 3 ; 5 RI' is selected from the group consisting of -H, -F, -Cl, -Br, -CN, -CH 2
NH
2 , -CH 2 OH, CONH 2 , -C(=NH)NH 2 , -C02H, -CO 2 Me, -SO 2 Me, -SO 2
NH
2 , -OH, -NH 2 , and -NO 2 ; Ric 2 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; and Ri 3 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2
.
WO 01/19798 PCT/USOO/25195 57 Table 19 Ol Ri R 1 1 R ib R ib A- A-Q N'N A-Q N AQ\/ IN N oRx Ri R 1 ~ 4O RIO Q-N- NI N R i0 R'c 3
R
1 c3 R1c 2
R
1 c2 Rc2 Rio 1 Rib "i lb R ib RA_ 18 A-Q N A- NQ N N N R~1c1 R R"o c2i 1 o N- N N R1- O R' 0R'0R"
RIO
3 R1c 3
R
1
'
3
RI.
2
R
1 A-Q 16.11 Ri O Rib Rib A-Q IN A- N A-Q- N v N N'/ N N' RicO R SN NA-QNR Rio 3 io R O R R02 Rc2 O Ric 0 Ric O Ric R U3R c3 R 1c3 "
RIU
2 R1c 2 RIc2
R
1 Rib R ib R ib N'N N .- 1N NI N N Ri 0 Ric' 0 RicIOic 1023 RiO 2 - RIO
R
1 R lb R lb R ib WO 01/19798 PCT/USOO/25195 58 Table 19 (continued) R11 O H R1ib R O' H OH Ib -RA-Qib A-N NN -N N R a W / N NN N RRRc R R* R U3 R1c3 R103 Ric 2 R1c 2 102 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 59 N NH Me Et Me Et Me SH MeMe N Me 02NH O2NH 02Me I2M COH ONH H2NH2 j H2H ~N- My'- N - N- N- N -M N M M NN Me N--- N\ ,N N Me me
I
2 C H C I H 2 C IN H2 1N2 R/ssletdfo th.ru cnitngo H -H n -CF3
H
2 Ne MeN me 3 N M~ Me MeN HN M Ne R C_ is selected frmtegopcnitig-H Q -F,-C-Br -N,-CH2NH2,-CO MMe C N H 2 = NH 2 -ONH 2-OH -N NH - 2 0O M Me~e N ~N MNC N N Me- N N Me H N_N MeN M NyN NQ MeN N~( CH 2
NH
2 lj 5 CO NH 2 -C( N NH 2 , 0C 2 M" 0C 2 e, O 2 e O 2
NH
2 , -O H, -N H n -N 2 ; H Ric 2 is selected from the group consisting of-H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; and
RIC
3 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2
.
WO 01/19798 PCT/USOO/25195 60 Table 20 R RR H HO G HO0 G NG RI3 iR Rlc3 RIc 2 Ri_ 2 1c2 wherein: R' 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 ; 5 Rlal and R'a2 are independently selected from the group consisting of -H, -F, -Cl and -Br; Ridc is selected from the group consisting of-H, -F, -Cl, -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 ; R1c2 is selected from the group consisting of-H, -F, -Cl, -Br, and -OCH 3 ;
RC
3 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , -NH 2 , 10 CONH 2 , -CH 2
NH
2 , -CH 2
NHCH
3 , -CH 2
N(CH
3
)
2 , -C(=NH)NH 2 ; and G is selected from the group consisting of:
R
1 bt Rib 2 Rib 3 N -CN N NINN N NN NV wherein: RibI is selected from the group consisting of-H, -CH 3 and -CF 3 ; Rib 2 is selected from the group consisting of.-H, -CH 3 and -CF 3 ; 15 RIb 3 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3
.
WO 01/19798 PCT/USOO/25195 61 Table 21 H G H G H 0 G Ra2 R' - R' R' R
R
1 0 ~3 3 \~R RRc3 Rl Rc2 R1.R 2 Rl Rc2 wherein: R' 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 ; 5 Rial and Ria2 are independently selected from the group consisting of -H, -F, -Cl and -Br; Ric is selected from the group consisting of -H, -F, -Cl, -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 ; Ric 2 is selected from the group consisting of -CH 2 -, -0-, -NH-, -N(CH 3 )-, -CH 2
CH
2 -, -0
CH
2 -, -NH-CH 2 -, and -N(CH 3
)-CH
2 -; 10 R'4 3 is selected from the group consisting of -CH 2 -, -0-, -NH-, -N(CH 3 )-, and -CH(NH 2
)
; and G is selected from the group consisting of: RIM Rib RIb 2 Rb 3 / N N N N N wherein: 15 RIbl is selected from the group consisting of--H, -CH 3 and -CF 3 ; Rib 2 is selected from the group consisting of -H, -CH 3 and -CF 3 ; and WO 01/19798 PCT/USOO/25195 62 R Ib 3 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 . Table 22 H G G H G R N Ric1 R' RN- R N" R*c' Rc 3 Rc 3 R1 3 RIc 2 RIc 2
RU
2 H O G G Ri1 R1.1 RRIi Ri R1a2 R'"' R"' R N R - N Rc 3 RIc 3 RIc 3 Ric 2 Ric 2 Ric2 wherein: R' is selected from the group consisting of -SO 2
NH
2 , -SO 2
CH
3 , -CN, -CONH 2 , 5 -CONH(CH 3 ), -CON(CH 3
)
2 , -CH 2
NH
2 , -CH 2
NH(CH
3 ), -CH 2
N(CH
3
)
2 ; R jal and Ria 2 are independently selected from the group consisting of -H, -F, -Cl and -Br; R' is selected from the group consisting of -H, -F, -Cl, -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 ; Ric 2 is selected from the group consisting of -H, -F, -Cl, -Br, and -OCH 3 ; 10 R'c 3 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , -NH 2 ,
-CONH
2 , -CH 2
NH
2 , -CH 2
NHCH
3 , -CH 2
N(CH
3
)
2 , -C(=NH)NH 2 ; and G is selected from the group consisting of: RibW R'bI Rib 2 RIbO N N N N wherein: WO 01/19798 PCT/USOO/25195 63 RibI is selected from the group consisting of-H, -CH 3 and -CF 3 ; Rib 2 is selected from the group consisting of-H, -CH 3 and -CF 3 ; and Rib 3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 . Table 23 H G HO G H G -L 1 N R'a2 R"* R l R'C R'C' H2N H 2 N HN R Ic2 R 1.2 R1.2 I RI8 0 0 0 H G H G H G R132 RC * Rla1 Rc R'c* H2N H2N H2N N N N R Ic2 R'c2 R1.2 0 H G H G H G N R"N
R
1 '2 R1.1 Rica R17 R17
R
c 2 RIc2 5 wherein: R' 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 al and Ria2 are independently selected from the group consisting of -H, -F, -Cl and -Br; WO 01/19798 PCT/USOO/25195 64 Ri* is selected from the group consisting of -H, -F, -Cl, -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 ; Ric 2 and R1,3 are independently selected from the group consisting of -H, -F, -Cl, -Br, and
-OCH
3 ; and 5 G is selected from the group consisting of: b I b 2 R ib 3 N N - N -- N N N" N N' N N, I I I II wherein: RIbI is selected from the group consisting of -H, -CH 3 and -CF 3 ; R Ib 2 is selected from the group consisting of -H, -CH 3 and -CF 3 ; and Rib 3 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 . Table 24 R' Rla' R1 R' H G H G H G - - N R12 Ra2 R 1 t R R R0 4Rc3 Rc3 2R 2 R R' R"* R1 R' H O G R H O G R*H\O G R R R Rid 3 R13 Rc3 N= N R 1 'c 2
N=RC
2 10 wherein: WO 01/19798 PCT/USOO/25195 65 R' 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 ; Ri' and Ria2 are independently selected from the group consisting of -H, -F, -Cl and -Br; Rild is selected from the group consisting of -H, -F, -Cl, -Br, -CN, -CH 2
NH
2 , -CH 2 OH, 5 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 ; R1c2 is selected from the group consisting of--CH-, and -N-; Ric0 is selected from the group consisting of -NH-, and -N-; and G is selected from the group consisting of: RIbI IbI RIb 2 RIbN / N 1 N 1b N > (J N 'A N N- N ' wherein: 10 RIbI is selected from the group consisting of-H, -CH 3 and -CF 3 ; Rib 2 is selected from the group consisting of -H, -CH 3 and -CF 3 ; and RIb 3 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3
.
WO 01/19798 PCT/USOO/25195 66 Table 25 R1 Rla1 R R' HO G H G G -N R02 Re R1.1 R c7 R' R R 2RR1c3 R 2 R~3107l3 RR R' R R HO G H G H G - - N R ~a2 R " R ~a1 R 'C' R ' R 1 R19% N-Ro 2 N-Rc 2 wherein: R' 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 ; 5 R 1 and Ria2 are independently selected from the group consisting of -H, -F, -Cl and -Br; R14d is selected from the group consisting of -H, -F, -Cl, -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 ; Ric 2 is selected from the group consisting of -CH 2 -, -0- and -NH-; R'c 3 is selected from the group consisting of-CH-, -C(NH 2 )- and -N-; and 10 G is selected from the group consisting of: Ribi Rib Ri 2 Rib 3 N N-N N NN N N /N w h N wherein: WO 01/19798 PCT/USOO/25195 67 RIbI is selected from the group consisting of-H, -CH 3 and -CF 3 ; R Ib 2 is selected from the group consisting of -H, -CH 3 and -CF 3 ; and R Ib 3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 . Table 26 R"'1 CH 3 R"'~ Rla1 N0N00 0 A O G A I/ H G A / H O G RR R 1 a2 R 1 2 RO 1 R'4: RIc 3
R
1 c 3 RIc 2
RU
2 Rc2 R"'1 CH3 R 1 1 R"' A \ HO G Al /\ H G A H O G R4c R'C R4' I ~II R ca R'c3 R'c3 RRc2 Rc2 R U2 NH 0 N/ CH3 000 A H O G AH 0 G H 0 G R1c3 R1c3 Ries R1.2 Rc2 R c2 wherein: 5 A is selected from the group consisting of: Me H - Me\ Et Mq Et\ Et-M\ - /N- /N- /N- / N-
N-
H H H Me Me Et MeC N <DNN- N2 N- H Me-N N M M CN- 0N- N- 02 - H N- Me-N yo - QN-- 02Q_ HM- WO 01/19798 PCT/USOO/25195 68 Ra 1 and R'a2 are independently selected from the group consisting of -H, -F, -Cl and -Br; Ridc is selected from the group consisting of -H, -F, -Cl, -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 ; Ric 2 is selected from the group consisting of -H, -F, -Cl, -Br, and -OCH 3 ; 5 R 1
,
3 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , -NH 2 ,
-CONH
2 , -CH 2
NH
2 , -CH 2
NHCH
3 , -CH 2
N(CH
3
)
2 , -C(=NH)NH 2 ; and G is selected from the group consisting of: RibI RIb1 RIb 2 Rba N N' NN N N wherein: RibI is selected from the group consisting of -H, -CH 3 and -CF 3 ; 10 Rib 2 is selected from the group consisting of -H, -CH 3 and -CF 3 ; and Rib 3 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 . Table 27 N HN' A- \ G A- G A- 0-H O-- G R2 R
R
1 c' Rid Rid 3 R1c 3 Ri 3 R1c2 R1c2 R'c2 wherein: A-Q is selected from the group consisting of: 15 WO 01/19798 PCT/USOO/25195 69 N>- 0- 0- C>- C> Q- 3- c> HO Me Et Me Et Me MeMe H2 MeH2e C> NC H N- M N- HL N-e-- N MMeM H N - 2 C - )M 2H- 0M s M aH -e O -- N - Me MMe Hea H 2 N 2 2 O e M H2 N-- Me MC- N - N N- Me H> 2 N- N N-N N-- NeN N Mo COHH2 C H2H 2 M -N-C-C -_ Q - MN--- t -NNC 0~N N< NyN 0~ 0~A MeNH 2
C
2 H
R
1 al and Ria 2 are independently selected from the group consisting of -H, -F, -Cl and -Br; Rici is selected from the group consisting of -H, -F, -Cl, -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 ; 5 Ric 2 is selected from the group consisting of -H, -F, -Cl, -Br, and -OCH 3 ; RIc 3 is selected from the group consisting of -H, -F, '-Cl, -Br, -OH, -OCH 3 , -NH 2 ,
-CONH
2 , -C H 2 , -CH 2
NHCH
3 , -CH 2
N(CH
3
)
2 , -C(=NH)NH 2 ; and WO 01/19798 PCT/USOO/25195 70 G is selected from the group consisting of: Ribi Rib RIb 2 R b N" ~N ' N-N N ~i NNN N wherein: RIbI is selected from the group consisting of -H, -CH 3 and -CF 3 ; R Ib 2 is selected from the group consisting of-H, -CH 3 and -CF 3 ; and 5 R Ib 3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 . Table 28 Rla1 CH 3 R181 R"' NH0 0 0 A N G A' N G A N G H L H1A-0 H R U2 R R12 R R1a2 Rid RIe RI RIc R " 3 RI' RC R1c2 R c2 R~c
R"
1
,CH
3
R
1 1 RIa1 NH0 N 0 00 A N G N' N O G A N G N N H N H R"' R"' R*' R103 R1e3 R'c3 RRIC2 R12 RRc2
,CH
3 NH N 0 N 00 N A o G A NO G A/ N G R'c R R* R 1.R c3_ R 101 R'c 2 RIc2 R U2 wherein: WO 01/19798 PCT/USOO/25195 71 A is selected from the group consisting of: Me N- M E N- MN- E EtN N- N - ON- N H d Md Md Et Me Me Me-KN- N- bN- CN N-MeK N >O-Z~ <§O- O7- O27- H(JN-M-N OMeOHMe m N- <N- N--N- N--" R'ia and Ria2 are independently selected from the group consisting of -H, -F, -Cl and -Br; Ri' is selected from the group consisting of -H, -F, -Cl, -Br, -CN, -CH 2
NH
2 , -CH 2 OH, 5 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 ; Ric 2 is selected from the group consisting of -H, -F, -Cl, -Br, and -OCH 3 ; Rica is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , -NH 2 ,
-CONH
2 , -CH 2
NH
2 , -CH 2
NHCH
3 , -CH 2
N(CH
3
)
2 , -C(=NH)NH 2 ; G is selected from the group consisting of: R1b1 R b1 Rib2 Rib 3 N NN N N N 10 wherein: Ribl is selected from the group consisting of-H, -CH 3 and -CF 3 ; Rib 2 is selected from the group consisting of -H, -CH 3 and -CF 3 ; and RIb 3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3
.
WO 01/19798 PCT/USOO/25195 72 Table 29 NA N G GG NJ NN R182 R'c* R' R'c* RIdai 3 R10Rc VR*c2 \-Rc2 R Rc2 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 73 Me Et Me Et Mee Me_ Me H2_ H2 Me NN- M/ H N Me Me Me H 2 NH2 N- \>N- N - N- N - TN- C M NN M NN HNMe NI N0 N N Me me 2N H2C LC e Mee CONH 2 H2NH2 N- C M NNNH N N 0
R
1
M
1 and R 1 2 are independently selected from the group consisting of -H, -F, -Cl and -Br; Ri'd is selected from the group consisting of -H, -F, -Cl, -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 ; 5Ric 2 is selected from the group consisting of -CH 2 -, -0-, -NH-, -N(CH 3 )-, -CH 2
CH
2 -, -0
CH
2 -, -NH-CH 2 -, and -N(CH 3
)-CH
2 Ri* 3 is selected from the group consisting of -CH 2 -, -0-, -NH-, -N(CH 3 )-, and -CH(NH 2
)
; and2N\ WO 01/19798 PCT/USOO/25195 74 G is selected from the group consisting of: RibI RW RIb 2 RIb 3 / \ N '~'N N-N N N N N N N wherein: RibI is selected from the group consisting of -H, -CH 3 and -CF 3 ; 5 RIb 2 is selected from the group consisting of -H, -CH 3 and -CF 3 ; and RIb 3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3
.
WO 01/19798 PCT/USOO/25195 75 Table 30 H G H G A G A N A R N A R N R I~c IRc RRi3 Rc3 RIOR RIc2 2 R1c2 Rio 1
,CH
3 101 Ris 1 H0 N0 0 0 A /\ H G A H G A H G N RN RN Ri II Ric 3 Rio 3 RI .3 Rc2 R 2 R1c 2 "CH3 A j H G G AH G N Ri NN Ri N R Rio 3 RIc 3
R
1 c3 Ric2 .Rc 2 Ric2 H G/\H GH A G A N OG A G R1I2 R'C R1.2 RWe R'2 R'C R1 RIO
R
1 R R* N Ric N Ric N R1c2
R
1 2 Rc2 1CH 3 NH 0 N ~ 00 0 H G H G H G A A 1AL N Ri N Ric 1
R
1 C' R N N Rica Rc R1c2 RIc2 RIc2 Re Rii R 0H 0H-N00 A-IL H> G A-I / >4H G H-L(~\t G N N Rio t Rid' Rid R Rbc 3 NRio 3 N Rio 2 Rio 2 Rio 2 wherein: WO 01/19798 PCT/USOO/25195 76 A is selected from the group consisting of: Me N- me E N- M N- E N- EtN- N- M\N- ON- (N H H M Md Et Me Me Me -N- CN- 6N- GN- CN-- -M SON- O 2 -SN- H N- Me-N N N- N- N-- N- N- N Ria' and Ria 2 are independently selected from the group consisting of -H, -F, -Cl and -Br; Ri' is selected from the group consisting of -H, -F, -Cl, -Br, -CN, -CH 2
NH
2 , -CH 2 OH, 5 CONH 2 , -C(=NH)NH 2 , -C02H, -CO 2 Me, -SO 2 Me, -SO 2
NH
2 , -OH, -NH 2 , and -NO 2 ; Ric 2 is selected from the group consisting of -H, -F, -Cl, -Br, and -OCH 3 ; R1, 3 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , -NH 2 ,
-CONH
2 , -CH 2
NH
2 , -CH 2
NHCH
3 , -CH 2
N(CH
3
)
2 , -C(=NH)NH 2 , -C(=NH)NH(CH 3 ),
-C(=NH)NH(CH
3
)
2 ; and 10 G is selected from the group consisting of: RibW Rib W ib 2 RIb 3 / \ / ~N / 'N >~N 'N/ N b N i N N N wherein: RIbI is selected from the group consisting of -H, -CH 3 and -CF 3 ; Rib 2 is selected from the group consisting of -H, -CH 3 and -CF 3 ; and WO 01/19798 PCT/USOO/25195 77 R Ib 3 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 . Table 31 A-Q H G A- /\ H G AQ_( _H G R~a2 N- Re N- Rc N- R'c Rica Rlc3 R103 R1c2 Rc2
R
1 ' c2 0 0 0 A- / H O G A- H G A-H G RIa2 R'c Rd R
R
1 c 3 . R Ric 3 R1c 2 R1c 2 R'c2 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 78 cc>- Cc>- 0c- cc- cc>- c>Q-C3-0 HN Me Et Me Et e e Me MeMe H2
M
e Me S ~ ~ ~ ~ ~ IH N-C H -M M -H N-M- N H\ N - H2 C - M2C-M3HC e - e O - -M C N C N N- N- N- N YN N Me me cselc f e go co of H H2,2 O a M H, C To C T CO N2-C(=NH N -C 2 ,O M -- SO Me -O N 2 -OH, -N 2ad-NO2; H Me o H,,-, - NC,, ,- and---NH2; Me H 2 N\ H 2 -\ r ' r N- C H~-HC- HN /-N- N- /N Me\/ H 2 N Me 2 N Me 3 N Me 3 eC N N / cf2NH2 S 2
NH
2 & 4 OMe 2 Me ON 2CONH 2
CH
2
NH
2
CH
2
NH
2 N M N N~N M NN ~ N NN- NVN- NyN-Q m1e CONH 2
CH
2
NH
2
R
1
"
1 and R I 2 are independently selected from the group consisting of -H, -F, -Cl and -Br; Rid is selected from the group consisting of -H, -F, -Cl, -Br, -CN, -CH 2
NII
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 ; 5 R' 2 is selected from the group consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; R1, is selected frmtegroup consisting of -H, -F, -Cl, -Br, -OH, -OCH 3 , and -NH 2 ; and WO 01/19798 PCT/USOO/25195 79 G is selected from the group consisting of: R'bW RIbl Rib 2 Rib 3 N NN I I IN' wherein: RibI is selected from the group consisting of-H, -CH 3 and -CF 3 ; Rib 2 is selected from the group consisting of -H, -CH 3 and -CF 3 ; and 5 R Ib 3 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 . wherein: Table 32 H G A H G AH O G A AA N R112 R R"' Ri RO 1
H
2 N H 2 N H 2 N R1 2 Ric 2 R1c2 CH Ri CHa C0 A H G _H G H G A- A-1 A- \/ N Ria2 R10 R1 R R'ci
H
2
H
2 N H 2 N Ric 2 RiU 2 RiU 2 000 A H G A H G -LC/ N R1.R R 1
.
1 Rio Rid
H
2 N H 2 N H 2 N Ric 2 Rc 2 Ric2 WO 01/19798 PCT/USOO/25195 80 A is selected from the group consisting of: I1 _ Mc E\_ M Et\ N /N- M N- M E N-ON- M H H H Me Me Et Me N- ON- j N- Me- tN M N- N\2 N-_ O N-- H%_N- Me--N- C N- 02 _ H -- MeN
N/
Ria and R'a are independently selected from the group consisting of -H, -F, -Cl and -Br; 5 R' is selected from the group consisting of -H, -F, -Cl, -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 ; Ric 2 is selected from the group consisting of -H, -F, -Cl, -Br, and -OCH 3 ; and G is selected from the group consisting of: RIMl R b1 R1b 2 RIb 3 -A \\_N NN N P/ \NNN N" VN NNN wherein: 10 RIbI is selected from the group consisting of -H, -CH 3 and -CF 3 ; Rib 2 is selected from the group consisting of-H, -CH 3 and -CF 3 ; and Rib 3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3
.
WO 01/19798 PCT/USOO/25195 81 wherein: Table 33 NHH _ 0 NHN 0 A H G H G A H G R'a2 R'* Rla Re'N R'
H
2 N H 2 N H 2 N N N N
R
1 c 2
R
1 c2 Rc2 AG A H G A- HI G R1a2 Rlc We RN R'c'
H
2 N H 2 N H 2 N N N N Ric 2 Ric 2 R1c2 0 _ 0 0, 0 A G\R/ H G A HO G R I/AH G \/N RRid Rial Rid 1
H
2 N H 2 N H 2 N N N N
R
1 c 2 Ric 2 R1c 2 A is selected from the group consisting of: Me H MeN Et N- Me Et N Et N- M N N- N- N-- N- N H H H Me Me Et Me Me Me>KON- SN- N- N- N- N- MeH -N ON- N- N 0 2 N N - Me-N N NN- - N- OU N_ H_ N- Me N N- WO 01/19798 PCT/USOO/25195 82 Rial and R'a are independently selected from the group consisting of -H, -F, -Cl and -Br; Ri' is selected from the group consisting of -H, -F, -Cl, -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 ; Ri 2 is selected from the group consisting of-H, -F, -Cl, -Br, and -OCH 3 ; and 5 G is selected from the group consisting of: RIbI RIb1 Rib 2 Rib / NNN N N N -- I ( INN wherein: RibI is selected from the group consisting of -H, -CH 3 and -CF 3 ; Rib 2 is selected from the group consisting of -H, -CH 3 and -CF 3 ; and Rib 3 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 . 10 WO 01/19798 PCT/USOO/25195 83 Table 34 A- G H G A--H G RIa2 R * ca R'C N R * R R'd
H
2 N N H 2 N H 2 N Ric 2 R1c 2 1c2 Ri 1 1 H G A__ H 0 G -N\H 0 G A-Q A - G A- HNO G R'Q Rid RI 1 M R'd Rid*
H
2 N I, H 2 N H 2 N N / N , N 1.2 R1c2 Ric2 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 84 Me Et Me Et Me M eM C: -C C
-
- - C--:,. H Me CN Me He - H N- M N Me e - Me MeO N- -- N N- N NN N- N N N Me m e CONH 2 mH 2
NH
2 RIal and Ria2 are independently selected from the group consisting of-H, -F, -C and -Br; RiCd is selected from the group consisting of -H, -F, -Cl, -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 ; 5 Ric 2 is selected from the group consisting of -H, -F, -Cl, -Br, and -OCH 3 ; and WO 01/19798 PCT/USOO/25195 85 G is selected from the group consisting of: RIM R1bI Ri b 2 Ri b 3 / \ __>1 1N ' N NR N N NN N wherein: RibI is selected from the group consisting of -H, -CH 3 and -CF 3 ; Rib 2 is selected from the group consisting of -H, -CH 3 and -CF 3 ; and 5 Rib 3 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 . Table 35
R
1 1 o -N 0 N 0 A--Q G A G A G N Ri* R 1 1 Rc Rc1 R1.3 RIc3 R1c3 RiU2 RR12 Rc2 Rial A-QO R~1 OA- N O G ' o N 0N 0 RR Ri 1 Rid Rid 1 R 1.3 R .31 R103 N - N RRi. RC2 RRi2 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 86 K>- C>- >- C>- - C C-C>- C> H % Me Et Me Et me Mee Me N Me em eem -C N-- MN H - N- Me -C N-C HH QaSNN Me Me He N - H OH2 O2M e 2 H2 o H2 C CH2N N- Me N- N N- N M N N - - H 2 N - N N \ A Me CONH CHNH N-C- M EN- M E N - EtM N- N-- N HS H H Mme Et/ Me Me H M N H - H 2 C- N H 2 C HN- 0 _N/- CM 2 N- M ONN- Me 3 C N-M- N- Me . 5 N me N 1 0 2
NH
2 S O 2 NH- & M e N 2 Me ?ON H 2
CONH
2 CH2NH2 CH2NH2 /N_ Me>-N N_ N_ N- /N_ ~N Nej NkM N- N,"N- N NNN-N N- D2 A-"- A--11- A- Me CONH 2
CH
2
NH
2 wherein: A is selected from the group consisting of: _ Ny Me N- N - _ E\ e N- E N- EtN-
<'N
H H H Md me/ Et/ Me Me Me-K>- ON- bN- ON- QN- KjN- Me-QN <N W CN- HN'IN- Me-N'N >ON- QN-QN-
O'
WO 01/19798 PCT/USOO/25195 87 Ral and R 1 ia 2 are independently selected from the group consisting of -H, -F, -Cl and -Br; Ri4 is selected from the group consisting of -H, -F, -Cl, -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 ; RIc 2 and Ric 3 are independently selected from the group consisting of -H, -F, -Cl, -Br, and 5 -OCH 3 ; and G is selected from the group consisting of: RIbI RibI N b 2 RIb 3 N N -N N N )' KN N wherein: RibI is selected from the group consisting of -H, -CH 3 and -CF 3 ; Rib 2 is selected from the group consisting of-H, -CH 3 and -CF 3 ; and 10 RIb 3 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3
.
WO 01/19798 PCT/USOO/25195 88 Table 36 0 H G H G A-Q- A-Q H G G N R182 Rc1 R''1.1c I I R RlC 3
R
1 ' R'c 3 \ H GH G H G A-N- G A-Q- N --- j- R2Rid' R101 R"o Ri',\ R3 NN12 +Ro 2
N-RIC
2 wherein: WO 01/19798 PCT/USOO/25195 89 A-Q is selected from the group consisting of: HO Me Et Me Et Me me)- Me Me C H e N- M0 He- H - e Me MeH Me NM Me M M M N-MeN NH CN N H% me Me N Me Me Me Me ee C H w n :Me 3 M HNH 2 CN
M
3 N' Hec N em
SO
2
NH
2 SoO 2 ONH OMe CONH - e 2
NH
2 02OMd NSOM 2N 2 N H CN N- N N- N_ elMl M N/', NyN N N NH h( CH 0 N---A~L~ A-iL Me CONH 2 HNH, wherein: WO 01/19798 PCT/USOO/25195 90 A is selected from the group consisting of: Me N- MN- N- MN- N- EtN- NN- N H H H Md Md Et Me me Me- - N-NN- ON- Me G QN b : Me QN- N- N- OC N- HN N- Me-N N-- iN- N- N-- N- N R'ia and Ra 2 are independently selected from the group consisting of -H, -F, -Cl and -Br; RiC is selected from the group consisting of -H, -F, -Cl, -Br, -CN, -CH 2
NH
2 , -CH 2 OH, 5 CONHI 2 , -C(=NH)NH 2 , -CO 2 H, -CO 2 Me, -SO 2 Me, -SO 2
NH
2 , -OH, -NH 2 , and -NO 2 ; Ric 2 is selected from the group consisting of-CH 2 -, -0- and -NH-; Ric 3 is selected from the group consisting of-CH-, -C(NH 2 )- and -N-; and G is selected from the group consisting of: RIbI RibI R1b 2 Rib 3 N N N N N N" N" N wherein: 10 RIbI is selected from the group consisting of -H, -CH 3 and -CF 3 ; Rib 2 is selected from the group consisting of-H, -CH 3 and -CF 3 ; and RIb 3 is selected from the group consisting of-Cl, -NiH 2 , -CH 3 and -CF 3
.
WO 01/19798 PCT/USOO/25195 91 Table 37 RRb RIM R' R NH NH NH R'c R'c R4 RIO3 R3 Rc R1c2 R c2 RRI 2 R Rla R' Ria N-- S R1b2 \ / \ / \ N 0 0 NH NH
RIO
3
RIO
3 R1c2 Rl cz
RIO
3 IO wherein: R' is selected from the group consisting of -SO 2
NH
2 , -S0 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 ; Ria is selected from the group consisting of -H, -F, -Cl and -Br; 5 RIbI is selected from the group consisting of -H, -CH 3 and -CF 3 ; Rib 2 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 ; Ri' is selected from the group consisting of -H, -F, -Cl, -Br, -CN, -CH 2
NIH
2 , -CH 2 OH, CONH 2 , -C(=NH)NH 2 , -CO2H, -CO 2 Me, -SO 2 Me, -SO 2
NH
2 , -OH, -NH 2 , and -NO 2 ; Ric 2 is selected from the group consisting of -H, -F, -Cl and -Br; and WO 01/19798 PCT/USOO/25195 92
RI'
3 is selected from the group consisting of -H, -F, -Cl and -Br. Table 38 RIO RI 0 NH NH NH R'c Ric1 R * I 3~ 1c R 1 c N N Ric 2 Ric 2 RiU 2 R Rla R Ria Rib 2 - N~ N 0 0 NH NH R'c' R *' R R1c3 N / N / R1 2 - R c 2 wherein: R' is selected from the group consisting of -SO 2
NH
2 , -SO 2
CH
3 , -CN, -CONH1 2 , 5 CONH(CH 3 ), -CON(CH 3
)
2 , -CH 2
NH
2 , -CH 2
NH(CH
3 ), -CH 2
N(CH
3
)
2 ; Ra is selected from the group consisting of -H, -F, -Cl and -Br; RibI is selected from the group consisting of -H, -CH 3 and -CF 3 ; RIb 2 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 ; Ri" is selected from the group consisting of -H, -F, -Cl, -Br, -CN, -CH 2
NH
2 , -CH 2 OH, 10 CONHI 2 , -C(=NH)NH 2 , -CO 2 H, -CO 2 Me, -SO 2 Me, -SO 2
NH
2 , -OH, -NH 2 , and -NO 2 ; Ric 2 is selected from the group consisting of -H, -F, -Cl and -Br; and WO 01/19798 PCT/USOO/25195 93
RIC
3 is selected from the group consisting of -H and -NH 2 . Table 39 Ri" Rla Ri* A-Q R A-Q N A-Q NH NH NH R R' Rie Rica Rica R 1 0 3 c2 RU2 R1c2 Ri1a Ri aR Rio R Rb A-Q NO A-Q Y, RIb 2 0 0 NH NH R'c1 R'c* R1e3 R Ric 2 Ric2 wherein: 5 A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 94 H N Me Et Me Et Me e r J Me N C HC Ce CMC Me - N Me Me HMe N He Me N C N-\-I QQ - N- Q-N- CUN H N Me Me H N M M e M e CM e Mma M e N NH CH \ Me 0 MeHHN\ N-C- HN- EN-M / N HN - N- N Me Me
H
2 N N H 2 C- H 2 -- H 2 - HN > - H N Me 2 NCN- HN N- M- N Me 2 /NMdC'
SO
2
NH
2
SO
2
NH
2
SO
2 Me SO 2 Me CONH 2
CONH
2
OH
2
NH
2
CH
2
NH
2 W K - N- / I+- le N O H MerN N, N- NN - N - N- / N N Y1 N Me CONH 2 Y2H wherein: A is selected from the group consisting of: Me 1 N- Me\N- Et\N M\_ E N Et \ N- - M\ - ON N H H i' Md Md Et Me Me Me-(& N- CN- 63N- CN- QN- K~M4N >QN- CN-Gt- OCN- HN N- Me-N \N CN- I- SK>N- Y>-- KJN--- WO 01/19798 PCT/USOO/25195 95 Ria is selected from the group consisting of -H, -F, -Cl and -Br; R ibi is selected from the group consisting of-H, -CH 3 and -CF 3 ; Rib 2 is selected from the group consisting of-Cl, -NH 2 , -CH 3 and -CF 3 ; Ri" is selected from the group consisting of -H, -F, -Cl, -Br, -CN, -CH 2
NH
2 , -CH 2 OH, 5 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 ; R1c2 is selected from the group consisting of -H, -F, -Cl and -Br; and R1c3 is selected from the group consisting of -H, -F, -Cl and -Br. Table 40 Rla R'a Rio A-Q \R A-Q O A- NH NH NH R" R" R'c I 1c3 .31I Ric R R143 N N N RIc 2 RIc 2 RiU 2 Ria R - S Rib 2 A-Q A- Jr\I 0 0 NH NH
RO
1 RiC R1c3 Rc3 N / N RIc 2 R1c2 10 wherein: WO 01/19798 PCT/USOO/25195 96 A-Q is selected from the group consisting of: Hk% Me Et Me Et MeM Me C2 H-C 0-C-- C M C H Me CeH CH2 S --- N- M-MMN- H N-M- N Me M Me Me Me Me e O2NH O2H I2M O2M ON2O H2 CHNH H2H Me m H Me HLN- HN HN- H2H \N- N N -NNHN - A- A Me Me me COH2 C 2
N
2
I
2 H H2 -, M- C N MN_ HN e N N- _ H~ N - N H N- N" 0 MeN2 2N2 & e 02e OH CONH 2
CH
2
NH
2 H22 wherein: A is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 97 Me N- E N--e\ N- E/ N- E V N- N- ON- IN H H H Me Me Et Me Me Me-N-N- CN- N ON- QN- jN--Me N-N M N- N- 0 2 \N-- H N- Me-N N e- CN-- ~ ~ 04 N_ HNU M NU R" is selected from the group consisting of -H, -F, -Cl and -Br; RibI is selected from the group consisting of -H, -CH 3 and -CF 3 ; Rib 2 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 ; 5 RI' is selected from the group consisting of -H, -F, -Cl, -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 ; Ric 2 is selected from the group consisting of -H, -F, -Cl and -Br; and Rc 3 is selected from the group consisting of -H and -NH 2 . 10 WO 01/19798 PCT/USOO/25195 98 Table 41 1 R 1 RI Ri, R' Rio R~b1 N -0 O NH NH NH Rio 1 Rilc Ri'c Rc3 Rica Ric 3 R1c 2
R
1 c 2 Rio 2 1 1. R 1 1. - /b2 / N \.Y 0 0 NH NH RiaRi* oe Ri 1 1 Rio 3 ' R1.
3 # 1.2 Rio 2 Ric 2 wherein: R' 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 ; Ria is selected from the group consisting of -H, -F, -Cl and -Br; 5 R 1 IbI is selected from the group consisting of-H, -CH 3 and -CF 3 ; RIb 2 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 ; Ri'd 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 ; Ric 2 is selected from the group consisting of-H, -F, -Cl, -Br and -OCH 3 ; and 10 RIC 3 is selected from the group consisting of -H, -F, -Cl, Br, -OCH 3 , -CH 2
NH
2 , -CONH 2 and -C(N=H)NH 2
.
WO 01/19798 PCT/USOO/25195 99 Table 42 RRR RR1 R Ke3 Rib * R R NH NH NH RI R 1 ~ Nc R'c 1 Rio 3 'N . RI.
3 RN c RIO 3 , RROc3 Ri R1.2 R1 R"RI Rla R1 Rla - ~0 ~0 NH NH NH R' Rlc, R sN R1.2 102 I R"R' Rla R Ra
R
1 b IR R NH NH NH NH R'dc Ri 1 c N Rio Ic N
R'RIO
3 R
RIO
2 Ric 2 R Ri R 1 b 2 0 NH Rio wherein: R1 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 ; 5 Ria is selected from the group consisting of -H, -F, -CI and -Br; WO 01/19798 PCT/USOO/25195 100 R Ib is selected from the group consisting of -H, -CH3 and -CF3; Rib2 is selected from the group consisting of -Cl, -NH2, -CH 3 and -CF 3 ; RiC is selected from the group consisting of -H, -F, -CN, -CH 2
NH
2 , -CONH 2 , -SO 2 Me, S0 2
NH
2 and -NO 2 ; 5 Ric 2 is selected from the group consisting of -H, -F, -Cl, -Br and -OCH 3 ; and Ric 3 is selected from the group consisting of -H, -F, -Cl, Br, -OCH 3 , -CH 2
NH
2 , -CONH 2 and -C(N=H)NH 2 . Table 43 Rla Rla R"e -R1b 1 NH NH NH RR RR RC R 3 Rc2
R
1 ' 2 Rla .R"a R O R12 A-o
A
0 0 NH NH R'3 , R'o R c q R io 1 Ric 3 R iRo 3 R* 10 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 101 CN>- 0c- cc>- 0c- cc- 0c- Q-C3- Co H NN Me Et Me Et me M Me C N MNH- H N- Me - N H H 2 H C - M 2 - 3C - M C M e C M H N CNa HH Me Me me Me Me M _J Me N / - N - - N N A N N NH Me0S Me me
H
2 C - C - - C- - - _N- N N-C
H
2 N M 2 N MeN MMe Me C NH 2 2
CH
2
NH
2 OiIII- N Me\- Me H\N- NM Me N N N N- N- N A is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 102 Me N- me\N E N- Mq N- E N Et\N MO- N- N H H H Md M E Me Me Me-4N- 6N- bN- CN- QN- N- MeQN N- N- N- 02 N- HN N > N- N-N/ MN- N-N Ria is selected from the group consisting of -H, -F, -Cl and -Br; RibI is selected from the group consisting of -H, -CH 3 and -CF 3 ; RIb 2 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 ; 5 RIdc 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 ; RIc 2 is selected from the group consisting of -H, -F, -Cl, -Br and -OCH 3 ; and Rid 3 is selected from the group consisting of -H, -F, -Cl, Br, -OCH 3 , -CH 2
NH
2 , -CONH2 and -C(N=H)NH 2 . 10 WO 01/19798 PCT/USOO/25195 103 Table 44 Ra Ri Rla A- Rib 1 A-Q O A-Q I NH NH NH R R R R3 R Ri 2
R
3 a Rc2 R1 R ia R i A-Q O A-Q SYRb 2 A-Q / K R W1 0 0 NH NH NH Rio 3 R R 3 R R 3 Rio 2 RIo2 Rc2 RIa Rio Ria A -Q N A -Q I A - QO H 0 H NH NH Reo I N Ri cl IN Ri ~N 103 1 l34 W03 RR R c R~tc2 Rfc2 Ria R ib 2 A- RI/ 0 NH RiRc R I Rio 2 wherein: 5 WO 01/19798 PCT/USOO/25195 104 A-Q is selected from the group consisting of: oC- cC>- C>- o- C - C1-0-0C- C> H Me Et Me Et C N e e Me Me Me M e M2 S N- C HN-- Me- Me N- H N-M- N-eM C Me Me C me N- M SOT 2N I H 2N 2 I2M H 2 M ONH2 ON H CH NH H 2N 2 M \,,N- M -NM-- M N- (N- Me CN N N N - N\ A0 S Me " Me Me Me H1N H 2 - H 2 C- H 2 C- HN H2/ 2 N - /N Me/ 3 N MCN
SO
2
NH
2 '0 2
NH
2 gO2Me O 2 Me ONH _ 11N2_ 2H HN N MeM N N MeNM
,CH
3 N- N,, N- NY -0 Me CONH 2
CH
2
NH
2 wherein: 5 A is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 105 Me M N- m EN Mq\ E Et N--N N- N- N--N H H H Md Md Et Me Me Me.-K$N- rN- tlN- IN- GN- jN- Me-:N-
"XC
1 \ CN- C*- O/CN- HN/-- Me I S O2S H Me \ N- N--N- j Ria is selected from the group consisting of -H, -F, -Cl and -Br; 5 RIbI is selected from the group consisting of -H, -CH 3 and -CF 3 ; Rib2 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 ; Ridc 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 ; Rie 2 is selected from the group consisting of -H, -F, -Cl, -Br and -OCH 3 ; and 10 Ri' 3 is selected from the group consisting of -H, -F, -Cl, Br, -OCH3, -CH 2
NH
2 , -CONH 2 and -C(N=H)NH 2
.
WO 01/19798 PCT/USOO/25195 106 Table 45 H G HO G H 0 G - - N 2NH RNH NH R1c 3 RIc 2 RI* Ric 2 R.3 3 Ric2 RIO I'2R \ G H G H G R2 Ral Ric 3 R1c 2 Ric 3 Ric 2 R 1 3 R1c2 HO0 G G c - H GG - N N S RH H Ric 3 Rio 2 Rio 3 Ric 2 Rio 3 Ric2 wherein: R' 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 al and R 1 a2 are independently selected from the group consisting of -H, -F, -Cl and -Br; 5 Ric 2 and RIC 3 are independently selected from the group consisting of -H, -F, -Cl, -Br, and
-OCH
3 ; and G is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 107 Rib RIbl R Ib 2 Rib 3 / \ N1 N N N NR N" N N"N N N" wherein: RibI is selected from the group consisting of -H, -CH 3 and -CF 3 ; RIb 2 is selected from the group consisting of -H, -CH 3 and -CF 3 ; and Rib 3 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 . 5 WO 01/19798 PCT/USOO/25195 108 Table 46 H G H O G H O G Rla2 NH Ria 1 NH NH N N N Rica Rc 2
RC
3
R
1 .2 R 1 .3 Rie 2 G H 0 OG G R102 H 1a1NHH RR4 RR*R'c O G H 0 G H0 G R 72 H R1.1 NH 7 H \N 02 RH RiO 1 NH N H N NX Rie 2 Ric 2 Ric 2 wherein: R' is selected from the group consisting of -SO 2
NH
2 , -SO 2
CH
3 , -CN, -CONH 2 , CONH(CH1 3 ), -CON(CH 3
)
2 , -CH 2
NH
2 , -CH 2
NH(CH
3 ), -CH 2
N(CH
3
)
2 ;
R
1 a 1 and Ria 2 are independently selected from the group consisting of -H, -F, -Cl and -Br; 5 R"c 2 and RI* 3 are independently selected from the group consisting of-H, -F, -Cl, -Br, and
-OCH
3 ; and G is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 109 R b1 Rib1 R1b2 Rib 3 N N "A N N N N N wherein: RIbl is selected from the group consisting of -H, -CH 3 and -CF 3 ; R Ib 2 is selected from the group consisting of -H, -CH 3 and -CF 3 ; and RIb 3 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 . 5 Table 47 A-Q G H O G Q H 0 G A-- ON A-Q G R'-' -C/ N ~ R1a2 N N R 3.7R 10R1c3 R12 R2 R __ 0 A-Q N / A-Q N A-Q-~C >-N G 0 2 NN R1 c2 IR2 . wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 110 H Me Et Me Et Se Me C - CC- C N- N- C- -C C0 VS H S Me e H2 2e N- N - N- N N M N\NN N M N Me Me
SH
2 C H 2 NH -H 2 2 HN I N N- M EN M MN E E N N- N- /N H HMH Me MNEt M Me Me N- - N- N- N- - Me N _ NN- N O N- N-N / M M 0N 2 N M e N N ONH 2
CH
2
NH
2 N - N-N N- N- N /N= /- /- - /J H H H me Md E/ M<CN- QNN- Me - QN-b e-N Me -C N-C + A N- HN N- Me-N N Z>N- 0)- QN- o2 N 7
J/'-
WO 01/19798 PCT/USOO/25195 111
R
1 ca and R'a 2 are independently selected from the group consisting of -H, -F, -Cl and -Br; Ric 2 and Rica are independently selected from the group consisting of -H, -F, -Cl, -Br, and
-OCH
3 ; and G is selected from the group consisting of: Ribi Rib1 Rib 2 R1b 3 NN N.N N N NN N 5 wherein: Ribi is selected from the group consisting of -H, -CH 3 and -CF 3 ; Rib2 is selected from the group consisting of-H, -CH 3 and -CF 3 ; and Rib 3 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 . 10 WO 01/19798 PCT/USOO/25195 112 Table 48 Rla1 0_ N 0 'N H0 A G H G A-Q HO G A- N A-0 A- X/> R2 NH R'a1 NH NH R i3 Ric2 R'"3 Ric2 Rica Ric 2 R" o0_ 0 ,N 0 A- O G A-Q \ H G A G
RR
1 a1 A- Q N A- Q A- Q- N S RI4 3 R12 Ric 3 Ric2 R1c3 R1c2 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 113 HO Me Et Me Et C / C- C 11 C- Me C --r2 Me e Me M Me- Me M MH H 2 2 2H2 MNC Me Me N- N e N N -N N A A N N Me C-I Me
SCH
2 H2N HH 2 2H 2 I H 2 N- - N- M - N-- ML - N-- N H- H M M5 Et 0 2 H (NH . N Me Me 0 Me NN :>-c- HtC N _ 0e %N- HN\N- Me-N\_.
N- Nx N - N - - HON- - NN Me 0ONH 2
CH
2
NH
2 N Me"Me N-_N--N- N- N-NN Nil MjN- QN Me N -M Ny - N-N NyN N- e- N \ N A -1- -.
WO 01/19798 PCT/USOO/25195 114 Rial and R 1 a are independently selected from the group consisting of -H, -F, -Cl and -Br;
RIC
2 and R C 3 are independently selected from the group consisting of -H, -F, -Cl, -Br, and
-OCH
3 ; and G is selected from the group consisting of: R b1 Rib RIb 2 Rb 3 /1b N N N N N N N N N N 5 wherein: Ribi is selected from the group consisting of-H, -CH 3 and -CF 3 ; RIb 2 is selected from the group consisting of -H, -CH 3 and -CF 3 ; and Rib 3 is selected from the group consisting of -- Cl, -NH 2 , -CH 3 and -CF 3
.
WO 01/19798 PCT/USOO/25195 115 Table 49 R11.1 _0 00 A-H G H G Ao H G A-0- A- Q\/Q \Z N R1.2 NH R H H N N N RIc 3 R1 RIO 4C Rc2 3 R R 0 G H G RH_ 1 N N N N N A- H GH A-Q H\ G RNH R H NH N Ric 2 - RR 2
RI
2 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 116 HO Me Et Me Et Me Me TeeMM M e
-
C- - N- - - C C5 -N C0 S H Me Me Me M Me M~Ne Me M I H2 H2 I HI H S-N- C---H N- Mrl Me N- HN- MeN- ON- C H N H H Cm e N- MeM Me m MMe
H
2 H C N N - N N--N A A A M e ONH 2 H 2 N H 2\ " N-M- M ENN MH Et EtMN- MeN- N Me Me M \ - H- HNC- H 2 C- HN- - NN
H
2 N Me 2 N M03 Mee' 3' me Me 3 N MN 3 N Me CN O2H 2H M 2 Me ON2ONH 2
CH
2
NH
2
CH
2
NH
2 N-N- N- N- N MN- N M N N M N N M NM NCH3 NN-NyN- N- N-
N
Me OONH 2
YH
2
NH
2 N= - A wherein: A is selected from the group consisting of:. Me N-\ Me\ Et\ Me\ Et\ Et\ H H H Md Md E/ MeAN ON M 6N ON CNNd+- Me-QN OM Q QeoN Q M
~
WO 01/19798 PCT/USOO/25195 117
R
1 a' and Ria 2 are independently selected from the group consisting of -H, -F, -Cl and -Br;
R
1 c 2 and R 1 c 3 are independently selected from the group consisting of -H, -F, -Cl, -Br, and -OCH3; and G is selected from the group consisting of: R IbI IbI RIb 2 R1 b 3 / \ NR NR1 N N N 5 wherein: RibI is selected from the group consisting of -H, -CH 3 and -CF 3 ; Rib 2 is selected from the group consisting of-H, -CH 3 and -CF 3 ; and Rib 3 is selected from the group consisting of -Cl, -NH 2 , -CH 3 and -CF 3 . 10 15 WO 01/19798 PCT/USOO/25195 118 Table 50 I la 1 1a Rb Rb R b NH NH NH NH R R 3
R
1 2 3 R"" R R R 1 Ric 2 R1bI R W R bI NH NH NH H S R 3 RiU 2 RIc 3 RIc 2 Ric 3 Rc2 1RRR 0 N R1.
3 Rc 2 R1e RO 2 wherein: R' 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, -F, -Cl and -Br; 5 RIbI is selected from the group consisting of -H, -CH 3 and -CF 3 ; and Ric 2 and R 1
C
3 are independently selected from the group consisting of -H, -F, -Cl, -Br, and
-OCH
3
.
WO 01/19798 PCT/USOO/25195 119 Table 51 1 1R RR R1 R b0 RIb RIbI 00 NH NH NH H NH NH N R1c3 R1c2 Rl43 R U2 R143 R Rb1 R NH N NH 7 NHH H N N-\N
R
1 c 3
R
1 . R1c2 wherein: R' is selected from the group consisting of -SO 2
NH
2 , -SO 2
CH
3 , -CN, -CONH2, 5 CONH(CH 3 ), -CON(CH 3
)
2 , -CH 2
NH{
2 , -CH 2
NH(CH
3 ), -CH 2
N(CH
3
)
2 ; R a is selected from the group consisting of -H, -F, -Cl and -Br; Rib is selected from the group consisting of -H, -CH 3 and -CF 3 ; and
RIC
2 and R 1 c 3 are independently selected from the group consisting of -H, -F, -Cl, -Br, and
-OCH
3 . 10 WO 01/19798 PCT/USOO/25195 120 Table 52 - RIM Rb RIbI A-Q A-Q- Ri1 A-Q Rb1 p NH NH NH NH
RO
3
R
1
.
3 RIc 2
R
1 2
R
1 c Rio 2 A- A-R- Ribt o o NH NH NH NH S R10 1.2 R1c3 R1.2 R1c3 R1c2 1Y A- R ' A-Q \R/b NH NH N)'S NK R1c3 RIc 2 Rc 3
RIU
2 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 121 Hk Me Et Me Et 0MeC - MeS~ Me C C- H3 - M) H -- - N- H N HMH2 C-->- -~ MeHCeeHC- eC M3
H
2 H Me Me Me Me MeN Me M MN- Me N\U~ 3 N 'N N A A H3 H SOMeH M 2 H ~ 2 e MeeLO H CN 2
C
2 H Me CONH 2
CH
2
NH
2 wherein: A is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 122 Me N- N-- M EN Et N- N H H H MI M E Me Me Me-<CN- ON- bN- N- QN ( N- MeQN N- N- N- OC N- HN JN- Me-N N 0O~r HC Me-N/' yN- -- N- N- N- N Ria is selected from the group consisting of -H, -F, -Cl and -Br; RibI is selected from the group consisting of -H, -CH 3 and -CF 3 ; and Ric 2 and Rc 3 are independently selected from the group consisting of -H, -F, -Cl, -Br and 5 -OCH 3
.
WO 01/19798 PCT/USOO/25195 123 Table 53 Ri0 RIa A- Q - R bi A- Q\ / R ibA Rbl NH NH NH N H NH NH N NN
R
1
'
3 Rlc 2
RIO
3 RIc 2
R
1
'
3 A-Q RM A- / Rib1 R1b1 A-0 OX O A NH NH H NH $ NH H N RIc 3 RIc2 R1.2 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 124 NN H N Me Et Me Et C _M Me N Me M Ci0- 0- CN- N- N- CN Me e N N M e N me N Me N 'NH N\H me Me SHMe2H C Me H C - Me - N M N SONH SO N2 - SO2Me SO2MCNH CONH CH2 CH2H Me Me-C __\_ N Me-N ,N >4ON- HNy,,N- Me-N.-/N Me me
H
2 N _ H 2 C- H 2 C- H 2 C- HN- Ma- N'
H
2 N Me 2 N MeN /e e Mee 3 Nd c MC
SO
2
NH
2
SO
2
NH
2
SO
2 Me SO 2 Me CONH 2
CONH
2
CH
2
NH
2
CH
2
NH
2 M M M N- M N _ /-\ CH3 N N- N N- NNN A-- A I3 A-I1 Me CONH 2
CH
2
NH
2 wherein: A is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 125 Me IN- MeN Et Mq N- E t N- N N- N-- N- N H H H Md Md E Me me Me-KIN- ON- N- N- N- N- Me N MeQN- CN QN- OC N- H - Ma-QN4 He O O H M -N / \ N-N- N-- -N Ria is selected from the group consisting of -H, -F, -Cl and -Br; RibI is selected from the group consisting of-H, -CH 3 and -CF 3 ; and
R
1 c 2 and R 1 c 3 are independently selected from the group consisting of -H, -F, -Cl, -Br and 5 -OCH 3 . The following compounds are an embodiment of the present invention: 1 l lb lb lb 0 H H RW 4 R\R -NN-N- N N R'C R'ca R'ca R1. 2 R 1
R
3 R R2 wherein: R' is selected from the group consisting of: 10 -SO 2
NH
2 , -SO 2 Me, -CH 2
NH
2 and -CH 2 NMe 2 ; Ra is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 126 -H, -F, -Cl and -Br; Rib is selected from the group consisting of:
-CH
3 , -CF 3 , -CH 2
CH
3 , -SO 2 Me, -CONH 2 and -NHSO 2 Me; RiC is selected from the group consisting of: 5 -H, -F, -Cl, -Br, -NH 2 , -OH, -SO 2 Me, -SO 2 Et, -SO 2
NH
2 , -NO 2 , -CH 2
NH
2 , -CN, CONH 2 , -CH 2 OH; Ric 2 is selected from the group consisting of: -H, -F, -Cl and -Br; and Rid 3 is selected from the group consisting of: 10 -H, -F, -Cl and -Br. The following compounds are an embodiment of the present invention: R Ria Rib l'Rb lb H N R& H 1b H - -N N N R'c" R' Rie Rlc3 RIO 3
R
1 c3 Ricz RIc 2
R
1
'
2 wherein: R' is selected from the group consisting of: 15 -SO 2
NH
2 , -SO 2 Me, -CH 2
NH
2 and -CH 2 NMe 2 ; Ria is selected from the group consisting of: -H, -F, -Cl and -Br; WO 01/19798 PCT/USOO/25195 127 Rib 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'id is selected from the group consisting of: -H, -F, -Cl, -Br, -NH 2 , -OH, -SO 2 Me, -SO 2 Et, -SO 2
NH
2 , -NO 2 , -CH 2
NH
2 , -CN, 5 CONH 2 , -CH 2 OH; Ric 2 is selected from the group consisting of: -H, -F, -Cl, -Br and -OMe; and Rd 3 is selected from the group consisting of: -H, -F, -Cl, -Br, -OCH 3 , -NH 2 , -CH 2
NH
2 , -CONIH 2 , -CONHMe, -CONMe 2 . 10 The following compounds are an embodiment of the present invention: R Rla R ib Rib R1 RIb H O N H N H N *I fN - - N N NR N N" R R1c 3
R.
3 Ric 3 Ric 2
R
1 2 Ric 2 R Rla R'b RIb R' RIb 0 0 HI N H N H N N N Ri N
R
1 c 3 Ric0 R1c3 Rc 2 102 Rc 2 wherein: R1 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 ; 15 Riais selected from the group consisting of: WO 01/19798 PCT/USOO/25195 128 -H, -F, -Cl and -Br; RIb is selected from the group consisting of:
-CH
3 and -CF 3 ; RiC is selected from the group consisting of: 5 -H, -F, -Cl, -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 ; Ric 2 is selected from the group consisting of: -H, -F, -Cl, -Br, and -OCH 3 ; and Ri" 3 is selected from the group consisting of: 10 -H, -F, -Cl, -Br, -OCH 3 , -NH 2 , -CH 2
NH
2 , -CONH 2 , -CONHMe, -CONMe 2 . The following compounds are an embodiment of the present invention: R HN R * HN R H R N N ~N /_\ N) N N/ N' N N HN R HN H R Rl ib lb 1 R Ib -SO2H2 -S2N - 2 N - N N N RcR 1 ' Rio H HN HN wherein: R1 is selected ftrm the group consisting of:
-SO
2
NH
2 , -SO 2 Me, -CH 2
NH
2 and -CH 2 NMe 2
;
WO 01/19798 PCT/USOO/25195 129 Ria is selected from the group consisting of: -H, -F, -Cl and -Br; RIb is selected from the group consisting of:
-CH
3 , -CF 3 , -CH 2
CH
3 , -SO 2 Me, -CONH 2 and -NHSO 2 Me; and 5 Ric is selected from the group consisting of: -H, -F, -Cl, -Br, -NH 2 , -OH, -SO 2 Me, -SO 2 Et, -SO 2
NH
2 , -NO 2 , -CH 2
NH
2 , -CN, CONH 2 , -CH 2
OH;
WO 01/19798 PCT/USOO/25195 130 The following compounds are an embodiment of the present invention: R Ris Rib R Rib R1 Rib H NN N N
H
2 N H 2 N H 2 N Ric 2 Ric 2 Ric 2 N N H N - N -O N - -CN eRie R
H
2 N H 2 N H 2 N N -'N .- N R1c 2 RIc2 Rc2 N Rib RN Rib RH Rib N' H I~ /\ N \yN NN N N N RiRc RR 3 Ric 1c2 Ric 2
RI
2 wherein: 5 RR is selected from the group consisting of:
-SO
2
NH
2 , -SO 2 Me, -CH 2
NH
2 and -CH 2 NMe 2 ; Ria is selected from the group consisting of: -H, -F, -Cl and -Br; Rib is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 131
-CH
3 , -CF 3 , -CH 2
CH
3 , -SO 2 Me, -CONH 2 and -NHSO 2 Me; Ri' is selected from the group consisting of: -H, -F, -Cl, -Br, -NH 2 , -OH, -SO 2 Me, -SO 2 Et, -SO 2
NH
2 , -NO 2 , -CH 2
NH
2 , -CN, CONH 2 , -CH 2 OH; and 5 Ric 2 and RI, 3 are independently selected from the group consisting of: -H, -F, -Cl and -Br. The following compounds are an embodiment of the present invention: l1bbl1b A- / H NR A- N 'N A-Q 1bN R' R R R'c 3
R
1 c 3
R
1 3 Rlc2 R C R 1c2 wherein: 10 A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 132 0c- c- 0c- cc- 0c- C )Q-Co- C> HO Me Et Me Et Me MM e -- C- C N - C N Me Me HMe M N-C-e Me Me H H 2 C - M e 2 H C - e 3H - M 3 C M aMM Mee e Me
HAH
2 C- H 2 C- MeH 2 C- HN- 'P-61
S
2
NH
2 0 2
NH
2 H 2 Me 2 Me CONH 2
CONH
2
H
2
NH
2
CH
2
NH
2 - ~ N NNN N-- ,N_ N NM N N/CH3 N N- NN N- /y N \- N'- Me CONH 2
CH
2
NH
2 wherein: A is selected from the group consisting of: Me N- MN- E N- MN E EtN N- ON- N H H H Md Md Et Me Me 0-- HN N- Me-N
N
N- N
-
N N-
N-
WO 01/19798 PCT/USOO/25195 133 Ria is selected from the group consisting of -H, -F, -CI and -Br; R I is selected from the group consisting of: -Me, -CF 3 , -Et, -SO 2 Me, -CONH 2 and -NHSO 2 Me; RIC is selected from the group consisting of: 5 -H, -F, -Cl, -Br, -NH 2 , -OH, -SO 2 Me, -SO 2 Et, -SO 2
NH
2 , -NO 2 , -CH 2
NH
2 , -CN, CONH 2 , -CH 2 OH; Ric 2 is selected from the group consisting of: -H, -F, -Cl and -Br; and
RIC
3 is selected from the group consisting of: 10 -H, -F, -Cl and -Br. The following compounds are an embodiment of the present invention: Ria Rib Rib Rib A- N A-Q N N A-QK H N R'c' R 1 clR" RRic3 R 4 R 1 c3 R Ric 2
R
1 c 2 Ric2 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 134 cc> o- > c- cc>- 0 -0C--C HN Me Et Me Et Me Me C -C C2\ HC2 HC HS Me MeeH2Me SMe MC e- Me H - M M N C MeH N-NN- - N- - N-N N - N-C Me me' me eMeMeT me H2N H 2 I H 2
H
2 C N-H2 /CL IeC~ K - -N-C M N NN MN M 3 N NN N M N N N - N0 MMe 0 Me CN2 2 NN- -N- N Et- IN - M N- N N _\ _ N- H2N /eN eN e( ~ ?6 Me N N M e N I-' 2H %M 2e N2 N2 C2H CH2NH M -d/ ON-H N - M N- N--N- N N - N -N Nj N- AJL A--[- A-i Me CONH 2
CH
2
NH
2 wherein: A is selected from the group consisting of: Me / N e E N- E N t N- N-> ON- <SN H H H 1 Md Md t Me Me Me-{&ON- ON- cci% ON- QN- jN- M-QN &e\_ \JC__j> ~~\ WO 01/19798 PCT/USOO/25195 135 Ria is selected from the group consisting of: -H, -F, -Cl and -Br; Rib is selected from the group consisting of:
-CH
3 , -CF 3 , -CH 2
CH
3 , -SO 2 Me, -CONH 2 and -NHSO 2 Me; 5 RIC is selected from the group consisting of: -H, -F, -Cl, -Br, -NH 2 , -OH, -SO 2 Me, -SO 2 Et, -SO 2
NH
2 , -NO 2 , -CH 2
NH
2 , -CN, CONH 2 , -CH 2 OH; Ric 2 is selected from the group consisting of: -H, -F, -Cl, -Br and -OMe; and 10 RIC 3 is selected from the group consisting of: -H, -F, -Cl, -Br, -OH, -OCH 3 , -NH 2 , -CONH 2 , -CH 2
NH
2
.
WO 01/19798 PCT/USOO/25195 136 The following compounds are an embodiment of the present invention: 18 R ib R 1 Rib R 1 Rib N\/ I~ N N N R N N R R 0 R'c O R'c O ' RiO RiU 3 Ric3 x RiU 2 RIc 2 R1c2 R R Rb Rlb R lb N N N NV-N VN NV Ri1R R 10 RIOR RRc3 RRI3 2 R'e2 R1.2 RU2 S Rlb Rb Rib NN NN N1 V N V 0 R'C O R'c R'c Ri.
3 R1.
3 R1 3 R'c2 RIc 2 Ric 2 R I- Rib x ~ lbI N N N Rio 3 xRio0 x Ri.
3 x Ric 2 Ri 2 Ri 2 RI Ria Rilb Rib R ib N'N N~ N V V N NV Rio 3 xRio 3 xRic 3 lo R12Rio 2 Rio 2 WO 01/19798 PCT/USOO/25195 137 RQR H Ib R 1 O H OH lb0 RRb R bIc - N' - N W N - N 0 ~ R'"' R"' Rc R U 3 , R' lc 3 ' - ' R' 3 R c 2 1c2 1-2 wherein: R' is selected from the group consisting of: -S0 2
NH
2 , -SO 2
CH
3 , -CN, -CONH 2 , -CONH(CH 3 ), -CON(CH 3
)
2 , -CH 2
NH
2 , 5 CH 2
NH(CH
3 ), -CH 2
N(CH
3
)
2 ; Ra is selected from the group consisting of: -H, -F, -Cl and Br; R I is selected from the group consisting of
-CH
3 and -CF 3 ; 10 RI'd is selected from the group consisting of: -H, -F, -Cl, -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 ; Ric2 is selected from the group consisting of: -H, -F, -Cl and -Br; and 15 RIC 3 is selected from the group consisting of: -H, -F, -Cl and -Br. The following compounds are an embodiment of the present invention: WO 01/19798 PCT/USOO/25195 138 RR Rib R Rib R R N> : \ \o: - / N N N N O Rlc O Rlc* O Rl I I lb R ~ i R RRlb Ro 3 'N R ' 3 # Ro 3 #. Rc 2 Ric 2 Rc2 R R b R lb Rlb 1N N N~i Ri - R O N R N N NR NN Ri 3 0 R R 3 R Ri30 Ro Ric 2 Rio 2 Rio 2 NN RRc3 RRc RR Ric 2 R1o2 RIc2 Ri -l lb Rib Rlb NN N N N cN NNR Ri3 2 Ri 2 Ri 2 R' Ro R~ Rib R l H Rb R lb N N - c a0 . Rio 1 Rlcl 0 , Rio Rio 3 1R1 l3 'N N Rio 'N NRiN, WO 01/19798 PCT/USOO/25195 139 wherein: R' is selected from the group consisting of: -CN, -CH 2
NH
2 , -CONH 2 , -C(=NH)NH 2 ,, SO 2 Me, -SO 2
NH
2 , and -NH 2 ; Ria is selected from the group consisting of: 5 -H, -F, -Cl and -Br; RIb is selected from the group consisting of:
-CH
3 , -CF 3 , -CH 2
CH
3 , -SO 2 Me, -CONH 2 and -NHSO 2 Me; Ri'd is selected from the group consisting of: -H, -F, -Cl, -Br, -NH 2 , -OH, -SO 2 Me, -SO 2 Et, -SO 2
NH
2 , -NO 2 , -CH 2
NH
2 , -CN, 10 CONH 2 , -CH 2 OH; Ric 2 is selected from the group consisting of: -H, -F, -Cl, -Br and -OCH 3 ; Ric 3 is selected from the group consisting of: -H, -F, -Cl, -Br, -OCH 3 , -NH 2 , -CH 2
NH
2 , -CONH 2 , -CONHMe, -CONMe 2 . 15 The following compounds are an embodiment of the present invention: 101 Rib 101 Rib Rb A-Q H ONA- H N A-QC N N N' N'N RIO N~ RioN RiR 3 RIca R" 3 R'c2
R
1 c2 Ric2 1l Rib 11 Rib Rib A- HiO N A- _ H N A- H O N N N N N AQ0 N Ric0 R * Ri Rica R 1 c3 R1c3 R1c 2 Rio2 Rio2 WO 01/19798 PCT/USOO/25195 140 wherein: A-Q is selected from the group consisting of: Me Et Me Et Me O Me Me Me Me C _- C N Me Me S N-CN M- Me - HNN-N - Me- N S- MeS N Me Me HH 2 C - M e 2 C - M H 2 C - M e C M e aC N - N M
H
2 NT Meme Me aNm
O
2
NH
2 2 H I HLIH 2 CO H 2
CH
2
NH
2
H
2
NH
2 NN- N- N N M N N M N N M ~N N N' N 0 N - NNH AA H 3 0 0 Me CON 2
C
2 NH wherein: 5 A is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 141 Me M E N- N- NN- - CN- N / / /M /N / H H H Me Me Et Me N- N- N-Ne MeN Me-KN- ON- ON- ON- N- bN- Me-QN Me~l- N_ 02"\_ H_2 M N -/ Ral is selected from the group consisting of: -H, -F, -Cl and -Br; RIb is selected from the group consisting of: 5 -CH 3 and -CF 3 ; RidC is selected from the group consisting of: -H, -F, -Cl, -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 ; Ric 2 is selected from the group consisting of: 10 -H, -F, -Cl, -Br, and -OCH 3 ; and RiC 3 is selected from the group consisting of: -H, -F, -Cl, -Br, -OCH 3 , -NH 2 , -CH 2
NH
2 , -CONH 2 , -CONHMe, -CONMe 2 . 15 The following compounds are an embodiment of the present invention: WO 01/19798 PCT/USOO/25195 142 - Rib - N~Rib / > Ri RRR R bR~b R l N N - N o 0 NH NH NH Rio 1 R'c 1 R'c Rc2 RUc2 Ric2 Rb Rb NN R RR R NH NH NH
H
2 N N*H 2 N N.H 2 N RIc 2
R
1 2 Ric2 Rilb R ib R Rib S- S- N CON NH NH NH N R 3 Rl 3 Rft o n g RiU 2
R
1
.
2 R U 2 wherein: R1 is selected from the group consisting of:
-SO
2
NH
2 , -SO 2
CH
3 , -- CN, -CONH 2 , -CONH(CHA) -CON(CH 3
)
2 , -CH 2
NH
2
,
5 CH 2 NII(CHA) -CH 2
N(CH
3
)
2 ; R'" is selected from the group consisting of: -H, -F, -Cl and -Br; R ib is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 143 -H, -CH 3 and -CF 3 ; R4 is selected from the group consisting of: -H, -F, -Cl, -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 ; 5 Ric 2 is selected from the group consisting of: -H, -F, -Cl and -Br; and Ri* 3 is selected from the group consisting of: -H, -F, -Cl and -Br. 10 The following compounds are an embodiment of the present invention: WO 01/19798 PCT/USOO/25195 144 RRib RRb RR N _R lb -R b Rlb NH NH NH RicaNoR 3 R * 3
R
1 '* R1c R1c Rc Rib Rib Rlb R- N R N-C R 1 i RN.2 RIc 2 Ric 2 Ric 2 1Ii eetdfo h gropon istn of - i N, -Ob - -) -RHRib N -CN NH NH NH 5~~Rc Ria isslctdfo tegou osstn f Ri- F- RiiandRiBr RE is selected from the group consisting of: CHN NHH) NHHN(CNH 2 5 ~ ~ll R'' isl seetdfoNh ro pc nitn f Rib is selected from the group consisting of: -H, -CH 3 and -CF 3 ; RI' is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 145 -H, -F, -CN, -CH 2
NH
2 , -CONH 2 , -SO 2 Me, -SO 2
NH
2 and -NO 2 ; RIc 2 is selected from the group consisting of: -H, -F, -Cl, -Br and -OCH 3 ; and
R'C
3 is selected from the group consisting of: 5 -H, -F, -Cl, -Br, -OCH 3 , -NH 2 , -CH 2
NH
2 , -CONH 2 , -CONHMe, -CONMe 2 . The following compounds are an embodiment of the present invention: A- R ib'A-eRbC - A Rib NH NH NH Rc Ri R
R
1 c 3 Rica RIc 3 RIC2 Ric2 Rc2 A-Q R/b A- Rb A-Q KR-b NH NH NH Ric1 Ri*. R'
H
2 N H 2
H
2 N N N R1.2 R1c2 R~c2 R id -t RIOb Ribd R A- Rib A-Q Rb A- (Rib NH NH NH RIOc Ric R1c3 1c2R RU22 WO 01/19798 PCT/USOO/25195 146 wherein: oC- oC-c> ->- C--~ > H Me Et Me Et Me MMeH2Me Me MeC- N- eM N- H N-M [ H2H 0 -C- e- M HHH Mee NH N N - A\ A A Me Me Mem er e N e
H
2 M NC- H 2 - C- MeC- Me/ - - -N N- N- 0N M NM Me CONH 2
CH
2
NH
2 A-Q is selected from the group consisting of: wherein: A is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 147 Me ~MR, E\ Me Et\ N--E N- N-MN-- N IN W N- / N- N H H H me me Et MM Me-KN- Q N- N- O N- H iN- Me- N N_ OC N HN
M
Ra is selected from the group consisting of: -H, -F, -Cl and -Br; R I is selected from the group consisting of: 5 -H, -CH 3 and -CF 3 ; RiC is selected from the group consisting of: -H, -F, -Cl, -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 ; Ric 2 is selected from the group consisting of: 10 -H, -F, -Cl and -Br; and Ric 3 is selected from the group consisting of: -H, -F, -Cl and -Br.
WO 01/19798 PCT/USOO/25195 148 The following compounds are an embodiment of the present invention: Rl R ib Rb Rib A- Rb A-0 R AR NH NH NH R1c 3 R4 RiR 3 R1 3 ,
RIO
2 Ri 2
RIO
2 Rib Rib R b A- RZ A- R/Y A-0R 0 0 NH NH NH R10 iR
RIO
1 Rc2 R1.2 Rc2 RRio _Rib - N-Rib NR ib A- ~ /A N 000 NH NH N Cl j'N NI Rio 3 yR' R Rioc 2 Ri. R2 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 149 HI Me Et Me Et e HMe e Me Mee ee 2 H 2 N eC H N- M - Me N- HN- M MMe H Me a -M e M SO2NH2~ O2NH 02M O2M CN2O H2 CHNH H2H N- +C NHN 0e 2 Me 3 Ne N HCH3 Ny N- N N- N-A A 0 Me CONH 2
CH
2
NH
2 wherein: A is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 150 N- M Et N- MN E N- EtN- N- N- N- N H H H Me Me Et Me- N- ON- -- N- RN- QN-MN MM M -N-- F- C N- O2 N- H N- Me- N NKN/O2KHNM R"a is selected from the group consisting of: -H, -F, -Cl and -Br; RIb is selected from the group consisting of: 5 -H, -CH 3 and -CF 3 ; Ri" 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 ; Ric 2 is selected from the group consisting of: -H, -F, -Cl, -Br and -OCH 3 ; and 10 RIc 3 is selected from the group consisting of: -H, -F, -Cl, -Br, -OCH 3 , -NH 2 , -CH 2
NH
2 , -CONH 2 , -CONHMe, -CONMe 2
.
WO 01/19798 PCT/USOO/25195 151 The following compounds are an embodiment of the present invention: laRlb R lb l'Rb H H 0 N H I> H H NH
RI.
3 R' 32 0 2 03 1c2 Ra R R" R HRb N Rb I NRib 0 Nf\ /\ / - N"-~ N N" 'S RIca R1 2
R
2 Rc3 R1c2 H Rib Rib lb N~ H\ H Ri* 3 Ric 2 R 43 R1.2 R *3 R1c2 wherein: R' is selected from the group consisting of:
-SO
2
NH
2 , -SO 2 Me, -CH 2
NH
2 and -CH 2 NMe 2 ; 5 Rla is selected from the group consisting of: -H, -F, -Cl and -Br; R ib is selected from the group consisting of:
-CH
3 , -CF 3 , -CH 2
CH
3 , -SO 2 Me, -CONH 2 and -NHSO 2 Me; RiC 2 and RIC 3 are independently selected from the group consisting of: 10 -H, -F, -Cl and -Br.
WO 01/19798 PCT/USOO/25195 152 The following compounds are an embodiment of the present invention: Rib H Rib H Rib H H NH /NN - N H NRb L& N RN Ni NH NH NH NN N R1 R2 R Rc2 R1 3 c2 R' R8Rib l b ,Rlb N N N N 5r" NH" NH N R' is selected from the group consisting of: 5 -SO 2
NH
2 , -SO 2 Me, -CH 2
NH
2 and -CH 2 NMe 2 ; Ria is selected from the group consisting of: -H, -F, -Cl and -Br; Rib is selected from the group consisting of:
-CH
3 , -CF 3 , -CH 2
CH
3 , -SO 2 Me, -CONH 2 and -NHSO 2 Me; 10 R 1 c 2 and R'c 3 are independently selected from the group consisting of: WO 01/19798 PCT/USOO/25195 153 -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 5 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 10 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 15 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 20 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", 25 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 WO 01/19798 PCT/USOO/25195 154 procedures. Reactions are carried out in standard laboratory glassware and reaction vessels under reaction conditions of standard temperature and pressure, except where otherwise indicated. 5 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 10 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 15 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 20 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, Londoni, 1995, or the references cited 25 therein, or as described later in the preparation section to give the G ring.
WO 01/19798 PCT/USOO/25195 155 Scheme 1 For nitrogen-linked heterocycle G 6 NH2 heterocycle AQD-A-Q-D-E
NH
2 formation coupling deprotection A-Q ND heterocycle A'--Q'ui formation A-Q' N coupling XX deprotectionA WO 01/19798 PCT/USOO/25195 156 Scheme 2 For pyrazole-linked compounds Rib A- H N Rib Rib
H
2 1) NaNO 2
HNH
2 O N NOH T N HCI, 0*C Rib CO 2 Et water0T-I, O 2) SnC 2 HOAc, THF 6 HCI, 0"C reflux 6 Rib Rib coupling H ? N deprotection H A--D R -C-b _ _ 6 Rlb NH x 1) NaNO 2 1b AQ/ HG!, OC RibM C0 2 Et Rl A'-Q o NH 2 H,0" A -Q--D-NHNH 2 R H A'-Q R - 2) SnCI 2 HOAc, THEF HCI, 0 0 C reflux CO 2 Et LiOH lb 1b water coupling deprotection
CO
2 H NH A-CRi NH x Scheme 2 above shows the general synthesis of compounds with a N-linked pyrazole G ring. Appropriately protected aromatic amines are converted to aromatic WO 01/19798 PCT/USOO/25195 157 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 5 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. 10 WO 01/19798 PCT/USOO/25195 158 Scheme 3 For triazole-linked compounds A-Q-D-H N OO NH 6 1)N0 NaNO2HF LiOHH I TFA, 0 0 C jCO 2 Et EtO 2 waHOter KI2)NaN 3 tuee heat coupling A'- , deprotectionde 0 LY-N---- N ~ .A-Q-DN NN A-A- //DN NH x 1) NaN0 2 / ~ TFA, 0 0 C C0 2 Et A-Q-F0" NH 2 -' A'-Q.-K'D\)-N 3 -- '-D\/
R
- 2) NaN 3 toluene, heat Y
CO
2 Et LiOH waerH THF, A*' -/-N Q.pn 0 ~ deprotection C0 2 H NH A-Q /D NH x WO 01/19798 PCT/USOO/25195 159 Scheme 4 For tetrazole-linked compounds N A-Q-D-N NH C C2E N C2E P3P DADEt2 " LOH, THH2 N N
N
2 NH- CO2Et EtO C" "N' MeOH, THF, HO 2 1, NI CI CO 2 Et P 3 ,DEAD water Et3N coupling A deprotection A- -D N\ N' ~ N' A-Q ~ I~ N NH X x CI CO 2 Et Ph 3 P, DEAD A \ I A-Q'_ NH 2 - A-Q' -NH CO 2 Et -- N - Et 3 N CO 2 Et LiOH MeOH, THF,_ water A_ N coupling A'-,N deprotection NH NH x WO 01/19798 PCT/USOO/25195 160 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, 5-, 2395 (1991); Synthesis, 767 (1993); Journal of 5 Organic Chemistry, a, 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, 10 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 15 method (Chemical Reviews, 95, 2457 (1995)).
WO 01/19798 PCT/USOO/25195 161 Scheme 5 For carbon-linked heterocycle G G A-Q-D-E X| CHO heterocycle formation G G G E' A'-Q'-D'-E
A-Q-D
coupling deprotection B(OH)2 E') X X X Br, Pd catalyst A-QG heterocycle AQHformation A'- A-Q' \ D/ coupling A-Q' Br J A'-Q' B(OH)2 BrX Pd catalyst deprotection X 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 5 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 trans-3-mthoxyacrylate or methyl propiolate to give the isoxazole structure (Chemical Letters, 1, 85 (1987)).
WO 01/19798 PCT/USOO/25195 162 Scheme 6 For isoxazole-linked hetereocycle compounds A-Q-D-E , N xl C COM MeO 2 CHO 1) NH 2 OH C -N\ MeO coupling 2) NCS Et 3 N x A'-Q'-D'-E N deprotection A-Q-D-E N N A- Q NH x
CO
2 Me 1) NH 2 0H -OH Me /\ CHO -'- QO e3 A-Q' __ 2) NCS C1 Et 3
N
CO
2 Et LiOH NA'-Q /A-0 MeOH, THE, / N 0 /D /D water A-Q D / coupling A Qdeprotection
CO
2 H NH NH X x Scheme 7 shows the general synthesis of compounds with a C-linked thiozole G 5 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.
WO 01/19798 PCT/USOO/25195 163 Scheme 7 For thiazole-linked hetereocycle compounds R'b A-Q-D-E X Rib S_ 0 MeO 2 g CHO N2CH 2
CO
2 Et 1) NBS coupling SnCX 2 , DCM CO 2 Et 2) RlbC(=S)NH 2 X Rib Rib A - N deprotection A-Q-D-E A-Q-D'-E A0D A-Q- Rib 0 NH X 1) NBS /R ~ N2CH2CO2Et A'-Q. 1)DNBSQR A'-Q CHO SnCl 2 , DCM E 2 2) RibC(=S)NH 2 A'-Q SnC12 DCMEtO2
CO
2 Et LOH Rib A-Q'- lb A-Q N~Rb MeOH, THF, _ N pin Ik A' -Q' ouplingA deprotection
-
0 0
CO
2 H NH NH X X 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 5 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.
WO 01/19798 PCT/USOO/25195 164 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 5 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 10 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 15 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 20 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. 352-40 1, 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 25 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 30 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 WO 01/19798 PCT/USOO/25195 165 or elixirs for oral administration, suppositories, sterile solutions or suspensions or injectable administration, and the like, or incorporated 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 5 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. 10 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 15 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, 20 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, 25 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 30 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 WO 01/19798 PCT/USOO/25195 166 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, 5 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 10 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. 15 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-methacrylamide-phenol, 20 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, 25 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 30 stopper pierceable by hypodermic injection needle.
WO 01/19798 PCT/USOO/25195 167 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 5 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 10 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. 15 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 20 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. 25 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 30 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 WO 01/19798 PCT/USOO/25195 168 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 incorporated according to 5 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 10 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 15 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 20 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 25 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 30 predisposition to pulmonary embolism. Abnormal thrombus. formation further WO 01/19798 PCT/USOO/25195 169 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 5 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, 10 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 15 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 purpura, thromboangiitis obliterans, or thrombotic disease associated 20 with heparin induced thrombocytopenia, (e) the treatment or prevention of thrombotic complications associated with extracorporeal 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 25 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 30 inhibited, e.g., when contacting the mammal's blood with material such as vascular WO 01/19798 PCT/USOO/25195 170 grafts, stents, orthopedic prostheses, cardiac stents, valves and prostheses, extra corporeal 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 5 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 10 Example 1. SO,NH, H N ~N/ 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 15 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 MgSO 4 , concentrated, purified by silica column to yield ethyl 3 methyl-1-(2-naphthyl)-1H-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-1-(2 20 naphthyl)-1H-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-[1,1']-biphenyl-4-ylamine (50 mg, 0.16 mmol) in 1 mL DCM was added trimethylaluminum (2.OM in hexane, 0.41 mL, 0.82 mmol) under argon at room temperature. After being stirred for 30 minutes, to the 25 mixture was added the above-prepared ester (46 mg, 0.16 mmol) in 1 mL DCM. The WO 01/19798 PCT/USOO/25195 171 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)* 5 539. 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. 10 Example 2.
SO
2
NH
2 H O Step 1. 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, 15 dissolved in EtOAc, washed with water (X3), dried and evaporated. The crude material was purified to give product ethyl 3-(2-naphthyl)-3-oxoprppionate. 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 20 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 4 , 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.
WO 01/19798 PCT/USOO/25195 172 Step 3. To a solution of the above-prepared product (148 mg, 0.50 mmol) and 2'-N-tert butylaminosulfonyl-[1, 1']-biphenyl-4-ylamine (152 mg, 0.50 mmol) in 3 mL DCM was added trimethylaluminum (2.OM 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 5 HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO 4 , 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 10 dissolved in methanol and purified by preparative HPLC to afford the title compound in over 90% yield. ES-MS: (M+H)* 500. Example 3.
SO
2
NH
2 N N F 15 Step 1. 3-Amino-2-naphthoic acid (40.4 g, 216 mmol) was placed in 200 mL concentrated HCl. At 0 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 20 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 WO 01/19798 PCT/USOO/25195 173 pH1 with aq HCl 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 CHCl 3 . To it was added 0.5 mL dry DMF. Then at room temperature, oxalyl chloride (20 mL, 232 5 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 10 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 15 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 HCL. 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 20 was stirred at 0*C for half an hour. At 0*C, to it was dropwise added cold SnCl 2 .2H 2 0 (26.3 g, 116 mmol) solution in 20 mL concentrate HCl. The slurry was stirred for half an hour at 0 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 25 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-1-(3-fluoro-2 naphthyl)-1H-pyrazole-5-carboxylate (9.0 g, 65%). Rf 0.52 (1:2 EtOAc: hexane). ES-MS: 30 (M+H)* 299.
WO 01/19798 PCT/USOO/25195 174 Step 4. To a solution of 2'-N-tert-butylaminosulfonyl-[1,1']-biphenyl-4-ylamine (77mg, 0.25 mmol) in 1 mL dry DCM was added trimethylaluminum (2.OM 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 5 reaction was stirred at room temperature for overnight and quenched using saturated Rochelle's salt aq solution. It was extracted with CHC1 3 (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 10 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.
SO
2
NH
2 F N N F Step 1. The preparation of ethyl 3-methyl-l-(3-fluoro-2-naphthyl)-1H-pyrazole-5 15 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.H 2 0 (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 1N HCI till pH 1. The mixture was extracted with EtOAc (X4). The organic extracts were combined, dried, 20 evaporated and pumped to dryness to afford 3-methyl-1-(3-fluoro-2-naphthyl)-1H 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-[ 1,1 ']-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 0 C. To it was added WO 01/19798 PCT/USOO/25195 175 POCl3 (45 ptL, 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 5 compound in 50% yield (31 mg). ES-MS: (M+H)* 519. Example 5.
SO
2
,NH
2 CI __ 0 H N F This compound was prepared by the same methodology described for Example 4 with 2' N-tert-butylaminosulfonyl-3-chloro-[1,1']-biphenyl-4-ylamine substituted for 2'-N-tert 10 butylaminosulfonyl-3-fluoro-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 535. Example 6.
SO
2
NH
2 Br H N N F This compound was prepared by the same methodology described for Example 4 with 2' N-tert-butylaminosulfonyl-3-bromo-[ 1,1 ']-biphenyl-4-ylamine substituted for 2'-N-tert 15 butylaminosulfonyl-3-fluoro-[1, 1']-biphenyl-4-ylamine. ES-MS: (M+H)* 579, 581 (Br pattern).
WO 01/19798 PCT/USOO/25195 176 Example 7.
SO
2
NH
2 __ 0 H-N F 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-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 502. 5 Example 8.
SO
2
NH
2 H N N F 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-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 503. 10 WO 01/19798 PCT/USOO/25195 177 Example 9. ON H N F This compound was prepared by the same methodology described for Example 4 with 2' cyano-[1,1']-biphenyl-4-ylamine substituted 2'-N-tert-butylaminosulfonyl-3-fluoro [1,1']-biphenyl-4-ylamine, without the TFA treatment. ES-MS: (M+H)* 447. 5 Example 10. N _ 0 H H N F 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 and quenched with 1 10 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.
WO 01/19798 PCT/USOO/25195 178 Example 11. N H N F The title compound (40 mg, 0.09 mmol) of Example 9 was dissolved in 2 mL dry DMF. At 0 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 5 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. 10 Example 12. H N F N This compound was prepared by the same methodology described for Example 4 with 2' (N-dimethylamino)methyl-[1,1']-biphenyl-4-ylamine substituted for 2'-N-tert butylaminosulfonyl-3-fluoro-[1,1']-biphenyl-4-ylamine, without the TFA treatment. ES MS: (M+H)* 479. 15 WO 01/19798 PCT/USOO/25195 179 Example 13, H _ N N F Step 1. The preparation of 3-methyl-1-(3-fluoro-2-naphthyl)-1H-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 5 DMAP (5 mg) were dissolved in 3 mL pyridine. The solution was stirred at 0*C. To it was added POC1 3 (90 pL, 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)* 10 371. Step 3. The above-prepared nitrile was dissolved in 10 mL dry methanol. It was chilled and stirred in an ice bath. To this solution was bubbled dry HCl 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)* 403. The solvent 15 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.
WO 01/19798 PCT/USOO/25195 180 Example 14. NH N F This compound was prepared by the same methodology described for Example 13 with pyrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)* 442. 5 Example 15, C N NH H N F 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. H N F 10 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.
WO 01/19798 PCT/USOO/25195 181 Example 17. CMHN N F This compound was prepared by the same methodology described for Example 13 with thiomorpholine substituted for N-methylethylenediamine. ES-MS: (M+H)* 474. 5 Example 18, F This compound was prepared by the same methodology described for Example 13 with morpholine substituted for N-methylethylenediamine. ES-MS: (M+H)* 458. Example 19. N F 10 This compound was prepared by the same methodology described for Example 13 with piperazine substituted for N-methylethylenediamine. ES-MS: (M+H)* 457.
WO 01/19798 PCT/USOO/25195 182 Example 20, N F This compound was prepared by the same methodology described for Example 13 with N-methylpiperazine substituted for N-methylethylenediamine. ES-MS: (M+H)* 471. 5 Example 21, H N F 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. F NN N F 10 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 CuI (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.
WO 01/19798 PCT/USOO/25195 183 Step 2. The preparation of 3-methyl-1-(3-fluoro-2-naphthyl)-1H-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 0 C. To it was added POC13 (380 IL, 4.0 mmol). 5 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 10 methanol. It was chilled and stirred in an ice bath. To this solution was bubbled dry HCl 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)* 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 15 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 F H4 H N F This compound was prepared by the same methodology described for Example 22 with 20 pyrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)* 460. Example 24, NH _ CH >N
F
WO 01/19798 PCT/USOO/25195 184 This compound was prepared by the same methodology described for Example 22 with piperidine substituted for N-methylethylenediamine. ES-MS: (M+H)* 474. 5 Example 25. F NH\ Hj N/,t NH N F 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. NH H O N /H N F 10 This compound was prepared by the same methodology described for Example 22 with morpholine substituted for N-methylethylenediamine. ES-MS: (M+H)* 476. Example 27. F NH H H2H HN-L / NZ WO 01/19798 PCT/USOO/25195 185 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. F H0 F NI N F 5 Step 1. The preparation of 3-methyl-1-(3-fluoro-2-naphthyl)- IH-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 POCl 3 (70 pL, 0.74 mmol). The mixture was stirred for 1 hour. The reaction was then quenched with ice chips. It was 10 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 stirred in an ice bath. To this solution was bubbled dry HCl 15 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 20 loaded on prep HPLC to afford the title compound in 80% yield. ES-MS: (M+H)* 464.
WO 01/19798 PCT/USOO/25195 186 Example 29 F [IDN H. H F F This compound was prepared by the same methodology described for Example 28 with pyrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)* 478. 5 Example 30. F F 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 3 1, SNH2_ H N N 10 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.
WO 01/19798 PCT/USOO/25195 187 Example 32. S0 2
NH
2 N N Br 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. 5 ES-MS: (M+H)* 561, 563 (Br pattern). Example 33. S0 2
NH
2 - HN OH 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 10 naphthylamine. ES-MS: (M+H)* 499. Example 34. S0 2
NH
2 CN
CN
WO 01/19798 PCT/USOO/25195 188 Step 1. The synthesis of ethyl 3-methyl-1-(3-bromo-2-naphthyl)-1H-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). 5 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-1-(3-cyano-2-naphthyl)-1H pyrazole-carboxylate (220 mg, 70%). Rf 0.48 (1:2 EtOAc: hexane). ). ES-MS: (M+H)* 10 306. Step 3. To a solution of 2'-N-tert-butylaminosulfonyl-[1,1']-biphenyl-4-ylamine (164 mg, 0.54 mmol) in 2 mL dry DCM was added trimethylaluminum (2.OM 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 15 reaction was stirred at room temperature for overnight and quenched using saturated Rochelle's salt aq solution. It was extracted with CHCl 3 (X3). The organic phases were combined, dried, concentrated and purified with flash column to yield 3-methyl-1-(3 cyano-2-naphthyl)-1H-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. 20 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 BF 3 .OEt 2 (62 pL, 0.5 mmol) dropwise. The mixture was stirred overnight. Extra 1.0 mmol BF 3 .OEt 2 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 25 purified using prep HPLC (55% yield). ES-MS: (M+H)* 508.
WO 01/19798 PCT/USOO/25195 189 Example 35, H-N
CONH
2 Step 1. The synthesis of 3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-5-(N-(2'-N-tert butylaminosulfonyl-[1,1']-biphen-4-yl))carboxyamide followed the same procedure of Step 3 for Example 34. 5 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
SO
2
NH
2 F __ 0 H N CN 10 This compound was prepared by the same methodology described for Example 34 with 2'-N-tert-butylaminosulfonyl-3-fluoro-[1,1 ']-biphenyl-4-ylamine substituted for 2'-N tert-butylaminosulfonyl-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 526.
WO 01/19798 PCT/USOO/25195 190 Example 37. SO0 2
NH
2 F - H I - N
CONH
2 This compound was prepared by the same methodology described for Example 35 with 2'-N-tert-butylaminosulfonyl-3-fluoro-[ 1,1 ']-biphenyl-4-ylamine substituted for 2'-N 5 tert-butylaminosulfonyl-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 544. Example 38
SO
2
NH
2 C1 N H N ON NI Step 1. The synthesis of ethyl 3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-carboxylate followed the same procedure of Step 2 for Example 34. 10 Step 2. The above-prepared ester (930 mg, 3.0 mmol) was dissolved in 20 mL methanol. To it were added LiOH.H 2 0 (256 mg, 6.0 mmol) and 10 mL water. The mixture was stirred for 3 hours at room temperature. Methanol was removed in vacuuo. The residue was carefully acidified with 1N HCl till pH 1. It was extracted with EtOAc (X4). The organic phases were combined, dried and evaporated in vacuuo till dryness to give 3 15 methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-5-carboxylic acid (720 mg, 85%). ES-MS: (M+H)* 278.
WO 01/19798 PCT/USOO/25195 191 Step 3. The mixture of the above-prepared acid (110 mg, 0.40 mmol), 2'-N-tert butylaminosulfonyl-3-chloro-[I,1']-biphenyl-4-ylamine (0.21 g, 0.60 mmol), DMAP (5 mg) were dissolved in 5 mL pyridine and stirred at 0*C. To it was added POCl 3 (120 pL, 1.2 mmol). The mixture was stirred for 2.5 hours and quenched with ice chips. It was 5 diluted with EtOAc, washed with brine (X2), dried, concentrated and purified with flash column to give 3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-5-(N-(2'-N-tert butylaminosulfonyl-3-chloro-[1,1']-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 10 DCM. At 0*C, to it was added BF 3 .OEt 2 (62 ptL, 0.5 mmol) dropwise. The mixture was stirred overnight. Extra 1.0 mmol BF 3 .OEt 2 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. 15 Example 39.
SO
2
NH
2 a 0 H N
CONH
2 Step 1. The synthesis of 3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-5-(N-(2'-N-tert butylaminosulfonyl-3-chloro-[ 1,1 ']-biphen-4-yl))carboxyamide followed the same procedure of Step 3 for Example 38. 20 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.
WO 01/19798 PCT/USOO/25195 192 Example 40
SO
2
NH
2 Br H 7 \N H N CN This compound was prepared by the same methodology described for Example 38 with 2'-N-tert-butylaminosulfonyl-3-bromo-[1,1']-biphenyl-4-ylamine substituted for 2'-N 5 tert-butylaminosulfonyl-3-chloro-[1,1 ']-biphenyl-4-ylamine. ES-MS: (M+H)* 586, 588 (Br pattern). Example 41. SO0 2
NH
2 Br H N
CONH
2 This compound was prepared by the same methodology described for Example 39 with 10 2'-N-tert-butylaminosulfonyl-3-bromo-[ 1,1 ']-biphenyl-4-ylamine substituted for 2'-N tert-butylaminosulfonyl-3-chloro-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 604, 606 (Br pattern).
WO 01/19798 PCT/USOO/25195 193 Example 42 SONH, -Hj -H N CN 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 5 butylaminosulfonyl-3-chloro-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 509. Example 43.
SO
2
NH
2 -H H N
CONH
2 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 10 butylaminosulfonyl-3-chloro-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 527. 15 WO 01/19798 PCT/USOO/25195 194 Example 44 SON H 2 H 0 CN 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 5 butylaminosulfonyl-3-chloro-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 510. Example 45. S0 2
NH
2 HN N CONH 2 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 10 butylaminosulfonyl-3-chloro-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 528. Example 46. NN N \ CN WO 01/19798 PCT/USOO/25195 195 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 HCl gas via a long needle till saturation reached. The resulting solution was stirred 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 5 N-methylethylenediamine. The mixture was refluxed for 1 hour and evaporated in vacuuo to give the 1-methyl-2-(4-nitrophenyl)-2-imidazoline HCl 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 HCl and 50 mL methanol was added 10% Pd/C (50 mg). The mixture was stirred for 2 10 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-1-(3 cyano-2-naphthyl)-lH-pyrazole-5-carboxylic acid (15 mg, 0.054 mmol, see Step 2, 15 Example 38), DMAP (2 mg) in 2 mL pyridine at 0*C was added POCl 3 (20 ptL, 0.22 mmol). The mixture was stirred 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. N> Q N N \ CONH2 20 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.
WO 01/19798 PCT/USOO/25195 196 Example 48. F H N% \ ~ CN 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 HCl gas via a long needle till saturation reached. The resulting solution was stirred overnight. The solvent was removed in vacuuo. The residue 5 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 1-methyl-2-(2-fluoro-4-nitrophenyl)-2-imidazoline HCl salt in 90% yield. ES-MS: (M+H)* 224. Step 2. To a solution of the above-prepared nitro compound in 2 mL 4N HCl and 25 mL 10 methanol was added 10% Pd/C (20 mg). The mixture was stirred 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 HCl 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.OM in hexane, 2 mL, 4.0 mmol). The mixture was 15 stirred for 20 minutes. Ethyl 3-methyl-1-(3-cyano-2-naphthyl)-1H-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 stirred for 2 days at room temperature. It was quenched with saturated Rochelle's salt aq solution and extracted with CHC1 3 (X4). The organic phases were combined, dried, concentrated and purifed with prep HPLC to yield 20 the title compound (55%). ES-MS: (M+H)* 453.
WO 01/19798 PCT/USOO/25195 197 Example 49. F NN N
CONI-
2 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. 5 Example 50.
SO
2
NH
2 H N NH 2 Step 1. Compound 3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-5-(N-(2'-N-tert butylaminosulfonyl- [1, 1']-biphen-4-yl))carboxyamide was prepared by the same 10 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 0 C, to it were added sodium borohydride (36 mg, 0.96 mmol) and CoC1 2 (32 mg, 0.24 mmol). It was stirred for 2 days. Diluted with EtOAc and stirred for 1 hour. The mixture was filtered through celite. The filtrate was evaporated to give crude 3-methyl-1 15 (3-aminomethyl-2-naphthyl)-1H-pyrazole-5-(N-(2'-N-tert-butylaminosulfonyl-[1,1 '] biphen-4-yl))carboxyamide. ES-MS: (M+H)* 568.
WO 01/19798 PCT/USOO/25195 198 Step 3. The above-prepared crude compound was taken into 3 mL TFA. The mixture was stirred 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. 5 Example 51. S - 2
NH
2 F H I H N NH 2 NH Step 1. Compound 3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-5-(N-(2'-N-tert butylaminosulfonyl-3-fluoro-[1,1']-biphen-4-yl))carboxyamide was prepared by the same methodology shown in Step 3 of Example 34, with 2'-N-tert-butylaminosulfonyl-3 10 fluoro-[1, 1']-biphenyl-4-ylamine substituted for 2'-N-tert-butylaminosulfonyl-[1,1 '] 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 stirred for overnight. The solvent was 15 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.
WO 01/19798 PCT/USOO/25195 199 Example 52,
SO
2 NH2 -H -H N CO2H Step 1. 3-Amino-2-naphthoic acid (5.8 g, 31 mmol) was placed in 50 mL concentrate HCl. The slurry was vigorously stirred 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 5 stirred for 40 minutes at 0*C. Under vigorously stirring, a cold solution of SnC1 2 .2H 2 0 (21 g, 93 mmol, in 30 mL concentrate HCl) was added dropwise. The mixture was stirred 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 10 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-1-(3-carboxyl 2-naphthyl)-1H-pyrazole-5-carboxylate (4.1 g, 90%). Rf 0.15 (1:1 EtOAc: hexane). ES 15 MS: (M+H)* 325. Step 3. To a solution of 2'-N-tert-butylaminosulfonyl-[1,1']-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 stirred 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 20 reaction was stirred at room temperature for overnight and quenched using saturated Rochelle's salt aq solution. It was extracted with CHC1 3 (X3). The organic phases were combined, dried, concentrated and purified with flash column to yield the coupling product (60%). ES-MS: (M+H)* 583.
WO 01/19798 PCT/USOO/25195 200 Step 4. The above-prepared compound (15 mg) was placed in 3 mL TFA and stirred overnight. It was concentrated and purified with prep HPLC to afford the title compound in 90% yield. ES-MS: (M+H)* 527. 5 Example 53.
SO
2
NH
2 F __ 0 H N
CO
2 H This compound was prepared by the same methodology described for Example 52 with 2'-N-tert-butylaminosulfonyl-3-fluoro-[ 1,1']-biphenyl-4-ylamine substituted for 2'-N tert-butylaminosulfonyl-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 545. Step 1. The above-prepared crude acid was dissolved in 150 mL anhydrous ethanol. To it 10 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-1-(3-methylthio-2-naphthyl)-1H-pyrazole-5-carboxylate in over 80% yield. ES-MS: (M+H)* 327. 15 Step 2. The above-prepared ester (4.95 g, 15 mmol) was dissolved in 150 mL DCM. At 0*C, to the vigorously stirred solution was added MCPBA (11 g, 38 mmol) in small portions over 20 minutes. The reaction was allowed for 1 hour and diluted with CHCl 3 . It was washed with NaHCO 3 saturated aq solution (X3), dried, concentrated and purified with flash column to give ethyl 3-methyl-1-(3-methylsulfonyl-2-naphthyl)-1H-pyrazole 20 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-[1,1']-biphenyl-4-ylamine (21 mg, 0.068 mmol) in 1 mL dry DCM was added trimethylaluminum (2.OM in hexane, 0.14 mL, 0.28 mmol). The mixture was stirred 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 WO 01/19798 PCT/USOO/25195 201 mixture. The reaction was stirred at room temperature for overnight and quenched using saturated Rochelle's salt aq solution. It was extracted with CHC1 3 (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. 5 Step 4. The above-prepared compound was dissolved in 2 mL acetonitrile and 2 mL TFA. The mixture was stirred 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. SO NH 2 /5 - HL/ H N
SO
2 Me 10 Step 1. The synthesis of ethyl 3-methyl-1-(3-methylsulfonyl-2-naphthyl)-1H-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.H 2 0 (0.82 g, 19.5 mmol) and 10 mL water. The mixture was stirred 15 at room temperature for overnight. The solvent was evaporated. The residue was acidified with IN HCl till pH 1. The mixture was extracted with EtOAc (X4). The organic phases were combined, dried, evaporated to dryness to afford 3-methyl-1-(3-methylsulfonyl-2 naphthyl)-1H-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 20 fluoro-[1,l ']-biphenyl-4-ylamine (150 mg, 0.46 mmol), DMAP (10 mg) were dissolved in 3 mL pyridine. To this stirred solution at 0 0 C was added POC 3 (87 PL, 0.93 mmol). The mixture was stirred for 2 hours and quenched with ice chips. It was diluted with EtOAc, WO 01/19798 PCT/USOO/25195 202 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 5 HPLC to isolate the title compound (90%). MS: (M+H)* 579. Example 55.
SO
2
NH
2 CI 0 H N SO2Me This compound was prepared by the same methodology described for Example 54 with 2'-N-tert-butylaminosulfonyl-3-chloro-[ 1,1 ']-biphenyl-4-ylamine substituted for 2'-N 10 tert-butylaminosulfonyl-3-fluoro-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 595. Example 56.
SO
2 NH2 Br 0 H N
SO
2 Me This compound was prepared by the same methodology described for Example 54 with 15 2'-N-tert-butylaminosulfonyl-3-bromo-[1,1']-biphenyl-4-ylamine substituted for 2'-N- WO 01/19798 PCT/USOO/25195 203 tert-butylaminosulfonyl-3-fluoro-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 639, 641 (Br pattern). Example 57. -0. HH21 H N
SO
2 Me 5 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-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 562. Example 58.
SO
2
NH
2 H N
SO
2 Me 10 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-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 563. 15 WO 01/19798 PCT/USOO/25195 204 Example 59,
SO
2 Me H N
SO
2 Me This compound was prepared by the same methodology described for Example 54 with for 2'-methylsulfonyl-[1,1']-biphenyl-4-ylamine substituted for 2'-N-tert butylaminosulfonyl-3-fluoro-[1,1']-biphenyl-4-ylamine, without the final TFA treatment. 5 ES-MS: (M+H)* 560. Example 60. CN - H N
SO
2 Me This compound was prepared by the same methodology described for Example 54 with for 2'-cyano-[ 1,1 ']-biphenyl-4-ylamine substituted for 2'-N-tert-butylaminosulfonyl-3 10 fluoro-[1,1 ']-biphenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)* 507. 15 WO 01/19798 PCT/USOO/25195 205 Example 61.
INH
2 H 0 '
SO
2 Me The title compound of Example 60 (55 mg, 0.11 mmol) was dissolved in 2 mL anhydrous DMF. To this stirred solution at 0*C were added sodium borohydride (33 mg, 0.88 mmol) 5 and CoCl 2 (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 NaHCO 3 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. 10 Example 62. H N
SO
2 Me |. This compound was prepared by the same methodology described for Example 54 with for 2'-(N-dimethylaminomethyl)-[ 1,1 ']-biphenyl-4-ylamine substituted for 2'-N-tert butylaminosulfonyl-3-fluoro-[1,1']-biphenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)* 539. 15 WO 01/19798 PCT/USOO/25195 206 Example 63,
NH
2 H N
SO
2 Me This compound was prepared by the same methodology described for Example 54 with for 3'-(N-tert-Boc-aminomethyl)-[ 1,1 ']-biphenyl-4-ylamine substituted for 2'-N-tert butylaminosulfonyl-3-fluoro-[ 1, 1']-biphenyl-4-ylamine. ES-MS: (M+H)* 511. 5 Example 64. N SO2Me This compound was prepared by the same methodology described for Example 54 with for 1-(4-Aminophenyl)-4-methylpiperazine hydrochloride substituted for 2'-N-tert 10 butylaminosulfonyl-3-fluoro-[1,1']-biphenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)* 504. 15 WO 01/19798 PCT/USOO/25195 207 Example 65.
SO
2 Me This compound was prepared by the same methodology described for Example 54 with for 1-(N-methylpiperidin-4-yl)-piperazine substituted for 2'-N-tert-butylaminosulfonyl-3 5 fluoro-[ 1, 1']-biphenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)* 496. Example 66.
SO
2 Me 10 This compound was prepared by the same methodology described for Example 54 with for 1-(4-pyridyl)-piperazine substituted for 2'-N-tert-butylaminosulfonyl-3-fluoro-[ 1, 1'] biphenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)* 476. Example 67. _H<N N
SO
2 Me 15 WO 01/19798 PCT/USOO/25195 208 This compound was prepared by the same methodology described for Example 54 with for 4-(N-pyrrolidinylcarbonyl)-aniline substituted for 2'-N-tert-butylaminosulfonyl-3 fluoro-[1,l']-biphenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)* 503. 5 Example 68. H N
SO
2 Me Step 1. The synthesis of 3-methyl-1-(3-methylsulfonyl-2-naphthyl)-1H-pyrazole-5 carboxylic acid was the same as that described in Step 2 of Example 54. 10 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 stirred at 0 0 C. To it was added POC1 3 (170 p.L, 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 15 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 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 20 the top of the reaction flask). The resulting solution was stirred 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. 25 WO 01/19798 PCT/USOO/25195 209 Example 69, N N
SO
2 Me This compound was prepared by the same methodology described for Example 68 with pyrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)* 502. 5 Example 70. H 34Q < N NH--\N 0 N
SO
2 Me This compound was prepared by the same methodology described for Example 68 with morpholine substituted for N-methylethylenediamine. ES-MS: (M+H)* 518. 10 Example 71. NH N N
SO
2 Me This compound was prepared by the same methodology described for Example 68 with N-methylpiperazine substituted for N-methylethylenediamine. ES-MS: (M+H)* 531.
WO 01/19798 PCT/USOO/25195 210 Example 72. F i 0 H \N N
N
SO
2 Me This compound was prepared by the same methodology described for Example 68 with 4 5 amino-3-fluorobenzonitrile (preparation described in Step 1 of Example 22) substituted for 4-aminobenzonitrile. ES-MS: (M+H)* 506. Example 73. F HN So 2 Me 10 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.
WO 01/19798 PCT/USOO/25195 211 Example 74. F ON N- N P N"
SO
2 Me This compound was prepared by the same methodology described for Example 68 with 4 amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with pyrrolidine 5 substituted for N-methylethylenediamine. ES-MS: (M+H)* 520. Example 75. NH 0
SO
2 Me This compound was prepared by the same methodology described for Example 68 with 4 10 amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with piperidine substituted for N-methylethylenediamine. ES-MS: (M+H)* 534.
WO 01/19798 PCT/USOO/25195 212 Example 76 F N N N
SO
2 Me This compound was prepared by the same methodology described for Example 68 with 4 amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with dimethylamine 5 (2M solution in THF) substituted for N-methylethylenediamine. ES-MS: (M+H)* 494. Example 77. F NH H2N N N
SO
2 Me This compound was prepared by the same methodology described for Example 68 with 4 10 amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with ammonium acetate substituted for N-methylethylenediamine. ES-MS: (M+H)* 466. Example 78. SO0 2
NH
2 -H H N OMe WO 01/19798 PCT/USOO/25195 213 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 stirred 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 5 allowed to warm up to room temperature. After 15 hours, THF was mostly removed in vacuuo. To the residue was added 40 mL 3M HCL. The mixture was stirred 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: 10 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 15 slurry was stirred 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-1-(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-1 -(6-methoxy-2-naphthyl)- 1H-pyrazole-3-carboxylate 20 [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-[ 1, 1']-biphenyl-4-ylamine (44 mg, 0.14 mmol) in 1 mL DCM was added trimethylaluminum (2.OM in hexane, 0.35 mL, 0.70 mmol) at room temperature. The mixture was stirred for 30 minutes, and to it was added the above-prepared ethyl 3-methyl-i -(6-methoxy-2-naphthyl)- 1 H-pyrazole-5-carboxylate 25 (44 mg, 0.14 mmol) in 2 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, 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.
WO 01/19798 PCT/USOO/25195 214 Step 4. The above-prepared compound was placed in 3 mL TFA and stirred 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. 5 Example 79,
SO
2
NH
2 / H N OH Step 1. The preparation of ethyl 3-methyl-1-(6-methoxy-2-naphthyl)- 1 H-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 stirred solution was added boron tribromide (1.OM in DCM, 0.72 10 mL, 0.72 mmol). The mixture was stirred overnight at room temperature. It was directly subjected to flash column to afford ethyl 3-methyl-l-(6-hydroxy-2-naphthyl)-1H pyrazole-5-carboxylate (78 mg, 55%). Rf 0.73 (2:1 EtOAc: hexane). ES-MS: (M+H)* 297. Step 3. To a stirred solution of 2'-N-tert-butylaminosulfonyl-[ 1,1']-biphenyl-4-ylamine 15 (80 mg, 0.26 mmol) in 1 mL DCM was added trimethylaluminum (2.OM in hexane, 0.65 mL, 1.3 mmol) at room temperature. After 30 minutes, to the mixture was added ethyl 3 methyl-1-(6-hydroxy-2-naphthyl)-1H-pyrazole-5-carboxylate (78 mg, 0.26 mmol) in 3 mL DCM. The resulting mixture was stirred 4 hours. The reaction was quenched using 5 mL saturated Rochelle salt aq solution. The mixture was extracted using DCM (X3). The 20 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.
WO 01/19798 PCT/USOO/25195 215 Step 4. The above-prepared compound was placed in 3 mL TFA and stirred 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. 5 Example 80, SONH, H N - N" Br 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 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 10 stirred 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, 15 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 0 C to it was added a solution of sodium nitrite (0.37 g, 5.4 mmol) in 2 mL water 20 dropwise. The mixture was stirred for 30 minutes. At 0*C to the mixture was added a solution of SnCl 2 .2H 2 0 (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 transferred into a flask and pumped to dryness. To it WO 01/19798 PCT/USOO/25195 216 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-1-(6 5 bromo-2-naphthyl)-1H-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 stirred solution of 2'-N-tert-butylaminosulfonyl-[1,1']-biphenyl-4-ylamine (93 mg, 0.31 mmol) in 1 mL DCM was added trimethylaluminum (2.OM in hexane, 0.70 mL, 1.4 mmol) at room temperature. After 30 minutes, to the mixture was added the 10 above-prepared ethyl ester (100 mg, 0.28 mmol) in 3 mL DCM. The resulting mixture was stirred 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). 15 Step 5. The above-prepared compound was placed in 3 mL TFA and stirred 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).
WO 01/19798 PCT/USOO/25195 217 Example 81. 0 H N N Br This compound was prepared by the same methodology described for Example 80 with 2'-N-tert-butylaminosulfonyl-3-fluoro-[ 1,1 ']-biphenyl-4-ylamine substituted for 2'-N tert-butylaminosulfonyl-[ 1,1 ']-biphenyl-4-ylamine. ES-MS: (M+H)* 579, 581 (Br 5 pattern). Example 82.
SO
2
NH
2 C' H-N N Br This compound was prepared by the same methodology described for Example 80 with 2'-N-tert-butylaminosulfonyl-3-chloro-[1,1']-biphenyl-4-ylamine substituted for 2'-N 10 tert-butylaminosulfonyl-[ 1,1 ']-biphenyl-4-ylamine. ES-MS: (M+H)* 595, 597 (BrCl pattern).
WO 01/19798 PCT/USOO/25195 218 Example 83.
SO
2
NH
2 Br H N H N Br This compound was prepared by the same methodology described for Example 80 with 2'-N-tert-butylaminosulfonyl-3-bromo-[ 1,1 ']-biphenyl-4-ylamine substituted for 2'-N tert-butylaminosulfonyl-[1,1 ']-biphenyl-4-ylamine. ES-MS: (M+H)* 640, 642, 644 (Br 2 5 pattern). Example 84.
SO
2
NH
2 -N N c Br This compound was prepared by the same methodology described for Example 80 with 2'-N-tert-butylaminosulfonyl-5'-chloro-[ 1,1 ']-biphenyl-4-ylamine substituted for 2'-N 10 tert-butylaminosulfonyl-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 595, 597 (BrCl pattern).
WO 01/19798 PCT/USOO/25195 219 Example 85. SO NH 2 0 NI Br This compound was prepared by the same methodology described for Example 80 with 5 (2-N-tert-butylaminosulfonyl- 1 -phenyl)-2,3-dihydroindole substituted for 2'-N-tert butylaminosulfonyl-[1,l']-biphenyl-4-ylamine. ES-MS: (M+H)* 587, 589 (Br pattern). 5 Example 86.
SO
2
NH
2 H N Br Step 1. The synthesis of ethyl 3-methyl-1-(6-bromo-2-naphthyl)-1H-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 10 methanol. To the solution were added LiOH.H 2 0 (350 mg, 8.3 mmol) and 10 mL water. The mixture was stirred for overnight and evaporated in vacuuo. The residue was acidified with IN HCL. It was extracted with EtOAc (X4). The organic phases were combined, dried and concentrated in vacuuo to give 3-methyl-1-(6-bromo-2-naphthyl) 1H-pyrazole-5-carboxylic acid (0.97 g, 100%). ES-MS: (M+H)* 331, 333 (Br pattern). 15 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 stirred at 0*C. To it was added POCl 3 (55 PL, 0.6 mmol). The mixture was stirred for 2 hours and quenched with ice chips. It was diluted with EtOAc, WO 01/19798 PCT/USOO/25195 220 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 stirred at 65*C for 5 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.
SO
2
NH
2 H N Br 10 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).
WO 01/19798 PCT/USOO/25195 221 Exaple 88, NH N Br Step 1. The synthesis of 3-methyl-1-(6-bromo-2-naphthyl)- 1H-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 5 (700 mg, 5.8 mmol), DMAP (40 mg) were dissolved in 15 mL pyridine and stirred at 0*C. To it was added POCl 3 (1.1 mL, 12 mmol). The mixture was stirred 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). 10 Step 3. The above-prepared nitrile (40 mg, 0.09 mmol) was dissolved in 6 mL dry methanol. It was chilled and stirred in an ice bath. To this solution was bubbled dry HCl gas via a long needle till saturation reached. The resulting solution was stirred 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 15 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).
WO 01/19798 PCT/USOO/25195 222 Example 89. aH H N Br This compound was prepared by the same methodology described for Example 88 with pyrrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)* 502, 504 (Br pattern). 5 Example 90, HNN Br 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). 10 Example 91. NH 0 N Br WO 01/19798 PCT/USOO/25195 223 This compound was prepared by the same methodology described for Example 88 with morpholine substituted for N-methylethylenediamine. ES-MS: (M+H)* 518, 520 (Br pattern). 5 Example 92. N H\N / Br 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). 10 Example 93. F 0 H N Br 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).
WO 01/19798 PCT/USOO/25195 224 Example 94. F H_ 0 Br 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). 5 Example 95, H N N Br 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, 10 524 (BrCl pattern).
WO 01/19798 PCT/USOO/25195 225 Example 96. H N N" Br 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). 5 Example 97. 0 H N Br 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 10 ethylenediamine substituted for N-methylethylenediamine. ES-MS: (M+H)* 536, 538 (BrC1 pattern).
WO 01/19798 PCT/USOO/25195 226 Example 98, H 0 H Br 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 5 (BrCl pattern). Example 99. C N Br 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 10 propanediamine substituted for N-methylethylenediamine. ES-MS: (M+H)* 536, 538 (BrCl pattern).
WO 01/19798 PCT/USOO/25195 227 Example 100. H N CI NHH Br 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 5 (BrCI pattern). Example 101. F NH __ 0 H N Br This compound was prepared by the same methodology described for Example 88 with 4 amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with pyrrolidine 10 substituted for N-methylethylenediamine. ES-MS: (M+H)* 520, 522 (Br pattern).
WO 01/19798 PCT/USOO/25195 228 Example 102. NH H N qN-N Br This compound was prepared by the same methodology described for Example 88 with 4 amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with 2 5 methylpyrrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)* 534, 536 (Br pattern). Example 103. NH 0 H N F Br 10 This compound was prepared by the same methodology described for Example 88 with 4 amino-2,5-difluorobenzonitrile substituted for 4-aminobenzonitrile, and with pyrrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)* 538, 540 (Br pattern).
WO 01/19798 PCT/USOO/25195 229 Example 104. NH 0 0 KN N Br 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). 5 Example 105. ONNH H_ 0 N N N Br This compound was prepared by the same methodology described for Example 88 with 4 amino-2-chlorobenzonitrile substituted for 4-aminobenzonitrile, and with pyrrolidine 10 substituted for N-methylethylenediamine. ES-MS: (M+H)* 536, 538 (BrCI pattern).
WO 01/19798 PCT/USOO/25195 230 Example 106. F NH 0 N/ Br This compound was prepared by the same methodology described for Example 88 with 4 amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with thiomorpholine substituted for N-methylethylenediamine. ES-MS: (M+H)* 552, 554 (Br pattern). 5 Example 107. F NH H 0 N H2 H N Br 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). 10 WO 01/19798 PCT/USOO/25195 231 Example 108. F H F Br 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: 5 (M+H)* 498, 500 (Br pattern). Example 109. NH __ 0I ~N H N Br This compound was prepared by the same methodology described for Example 88 with 4 amino-3-chlorobenzonitrile substituted for 4-aminobenzonitrile, and with dimethylamine 10 (2M in THF) substituted for N-methylethylenediamine. ES-MS: (M+H)* 510, 512 (BrCI pattern).
WO 01/19798 PCT/USOO/25195 232 Example 110.
SO
2
NH
2 H N - N, Cl 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 CuI (0.2 g). The slurry was 5 refluxed for 1 hour. At room temperature it was diluted with 300 mL EtOAc and stirred 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. 10 ES-MS: (M+H)* 517. Example 111.
SO
2
NH
2 F 0 H \ - N' The title compound was prepared using the same methodology shown for Example 110, with 2'-N-tert-butylaminosulfonyl-3-fluoro-[1,1']-biphenyl-4-ylamine substituted for 2' 15 N-tert-butylaminosulfonyl- [1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 535.
WO 01/19798 PCT/USOO/25195 233 Example 112.
SO
2 Me F H N - - N CI The title compound was prepared using the same methodology shown for Example 110, with 2'-methylsulfonyl-3-fluoro-[ 1, 1']-biphenyl-4-ylamine substituted for 2'-N-tert butylaminosulfonyl-[1,1']-biphenyl-4-ylamine. ES-MS: (M+H)* 534. 5 Example 113. F H H N Cl 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. 10 Example 114. F NH H O N C4 WO 01/19798 PCT/US0/25195 234 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. 5 Example 115. __ NH _ CN H N C1 The title compound was prepared using the same methodology shown for Example 114, with piperidine substituted for N-methylethylenediamine. ES-MS: (M+H)* 490. 10 Example 116. F NH N - H NI C1 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. 15 WO 01/19798 PCT/USOO/25195 235 Example 117,
SO
2
NH
2 H0 N Step 1. The synthesis of 3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-5-(N-(2'-N-tert butylaminosulfonyl-[ 1,1 ']-biphen-4-yl))carboxyamide followed the same procedure shown in Step 3 of Example 34. 5 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 stirred 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 10 was concentrated in vacuuo. To the residue was added 3 mL TFA and the mixture was stirred 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.
SO
2
NH
2 H /N h(N NH 15 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.
WO 01/19798 PCT/USOO/25195 236 Example 119,
SO
2 NH-I HNH The title compound was prepared using the same methodology shown for Example 117, with pyrrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)* 579. 5 Example 120,
SO
2 NH2 H N
SO
2 NH2 The title compound was prepared using the same methodology shown for Example 1, with 2-N-tert-butylaminosulfonylphenylboronic acid substituted for 2-naphthylboronic 10 acid. ES-MS: (M+H)* 512. Example 121.
SO
2
NH
2 H N
SO
2 Me WO 01/19798 PCT/USOO/25195 237 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. 5 Example 122. S0 2
NH
2 H N
NO
2 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. 10 Example 123.
SO
2
NH
2 H N
SO
2 Me
H
2 NO 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 15 methylsulfonylbenzoic acid (>70%). ES-MS: (M+H)* 216. Step 2. The above-prepared aniline (2.2 g, 10 mmol) was stirred in 16 mL concentrate HC1 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 stirred for 30 minutes at 0*C. To it was added dropwise a cold solution of SnCl 2 .2H 2 0 (9.2 g, 40 mmol, in 14 mL WO 01/19798 PCT/USOO/25195 238 concentrate HCI). The mixture was stirred 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 5 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-1 -(5 carboxyl-2-methylsulfonylphenyl)- 1H-pyrazole-5-carboxylate (2.1 g, 60%). Rf 0.17 (pure EtOAc). ES-MS: (M+H)* 353. 10 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 stirred 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 15 flash column to isolate ethyl 3-methyl-i -(5-N-tert-butylaminocarbonyl-2 methylsulfonylphenyl)-1H-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-[I1,1']-biphenyl-4-ylamine (100 mg, 0.33 mmol) in 2 mL DCM was added trimethylaluminum (2.OM in hexane, 0.66 mL, 1.3 20 mmol) under argon at room temperature. After being stirred 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 stirred 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 25 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 stirred at 70*C for 1 hour and subjected on prep HPLC to isolate the title compound (90%) after evaporation. ES-MS: (M+H)* 554.
WO 01/19798 PCT/USOO/25195 239 Example 124. NH C1 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 5 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-1-(4-phenylphenyl)-1H-pyrazole-5-carboxylate 10 (26%), Rf 0.67 (1:2 EtOAc: hexane), ES-MS: (M+H)* 307; and its regioisomer, ethyl 5 methyl-1-(4-phenylphenyl)-1H-pyrazole-3-carboxylate (31%), Rf 0.50 (1:2 EtOAc: hexane), ES-MS: (M+H)* 307. Step 2. To a stirred solution of 4-chloroaniline (24 mg, 0.18 mmol) in 1 mL DCM was added trimethylaluminum (2.OM, 0.43 mL, 0.86 mmol) at room temperature. After 30 15 minutes, to the mixture was added ethyl 3-methyl-1-(4-phenylphenyl)-1H-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 20 EtOAc: hexane). ES-MS: (M+H)* 388.
WO 01/19798 PCT/USOO/25195 240 Example 125, NH OMe 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. 5 Example 126. S0 2
NH
2 N / 0 NH Br Step 1. 2'-N-tert-butylaminosulfonyl-[1,1']-biphenyl-4-ylamine (1.9 g, 6.2 mmol) was placed in 8 mL concentrate HCL. At 0*C to this stirred 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 10 added a cold solution of SnCl 2 .2H 2 0 (4.2 g, 18.4 mmol in 8 mL concentrate HCI). The mixture was stirred 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 15 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 WO 01/19798 PCT/USOO/25195 241 flash column to yield ethyl 3-methyl-i -(4-(2-aminosulfonylphenyl)-phenyl)- 1 H-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.H 2 0 (0.31 g, 7.4 mol) and 10 mL water. The mixture was stirred for 3 hours, 5 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 th6 organic product. The acetonitrile solutions were combined and evaporated in vacuuo to give yield 3-methyl-i (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. 10 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 pIL, 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). 15 Example 127,
SONH
2 0 NH OMe 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.
WO 01/19798 PCT/USOO/25195 242 Example 128, SONH2 0 NH
NO
2 OMe 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. 5 Example 129. S0 2
NH
2 0 NH Br 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). 10 WO 01/19798 PCT/USOO/25195 243 Example 130.
SO
2
NH
2 0 NH 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. 5 Example 131.
SO
2
NH
2 NH N / 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.
WO 01/19798 PCT/USOO/25195 244 Example 132.
S
2
NH
2 0 NH I N C1 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. 5 Example 133.
SO
2
NH
2 0 NH Br 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).
WO 01/19798 PCT/USOO/25195 245 Example 134. NH -N Br 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 5 500 mL EtOAc, which was washed with brine, dried and evaporated in vacuuo to afford ethyl 3-methyl-1-(4-cyanophenyl)-1H-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.H 2 0 (4.2 g, 100 mmol), 100 mL methanol and 50 mL water. The mixture was 10 stirred for 1 hour. It was acidified to pH 1 with IN HCL. 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-1-(4-cyanophenyl)-1H pyrazole-5-carboxylatic acid (95%). ES-MS: (M+i)* 228. Step 3. The above-prepared acid (1.4 g, 6.2 mmol) was dissolved in 20 mL pyridine. To it 15 were added 2-amino-5-bromopyridine (2.2 g, 13 mmol) and DMAP (100 mg). At 0*C to this mixture was added POCl 3 (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: 20 (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 0 C was bubbled dry HCI gas via a long needle till saturation reached. The mixture was stirred 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 WO 01/19798 PCT/USOO/25195 246 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). 5 Example 135. 0 NH Br 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). 10 Example 136. NH I N Br The title compound was prepared using the same methodology shown for Example 134, with pyrrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)* 453, 455 (Br pattern). 15 WO 01/19798 PCT/USOO/25195 247 Example 137. NH Br The title compound was prepared using the same methodology shown for Example 134, with 2-methylpyrrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)* 467, 469 (Br pattern). 5 Example 138. NH Br 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). 10 WO 01/19798 PCT/USOO/25195 248 Example 139. ON == Br The title compound was prepared using the same methodology shown for Example 134, with morpholine substituted for N-methylethylenediamine. ES-MS: (M+H)* 469, 471 (Br pattern). 5 Example 140. \,N-- Q NH Br The title compound was prepared using the same methodology shown for Example 134, with thiomorpholine substituted for N-methylethylenediamine. ES-MS: (M+H)* 485, 487 (Br pattern). 10 WO 01/19798 PCT/USOO/25195 249 Example 141. NH N Br 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). 5 Example 142, NH N Br 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). 10 WO 01/19798 PCT/USOO/25195 250 Example 143, NH Br 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). 5 Example 144. NH N Br 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). 10 WO 01/19798 PCT/USOO/25195 251 Example 145. H2N NH N Br 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). 5 Example 146, SO NH 2 H C1 2'-N-tert-butylaminosulfonyl-[1,1']-biphenyl-4-ylamine (50 mg, 0.16 mmol) was dissolved in 1 mL dry DCM. To this stirred solution was added Me 3 A1 (2.OM, 0.4 mL, 0.8 10 mmol). The mixture was stirred for 30 minutes. To it was added a solution of commercial ethyl 1-(6-chloro-1,3-benzothiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (50 mg, 0.16 mmol) in 2 mL DCM. The resulting mixture was stirred 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 15 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 (Cl pattern).
WO 01/19798 PCT/USOO/25195 252 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. 5 The compounds of the present invention are dissolved in buffer to give solutions containing concentrations such that assay concentrations range from 0 to 100 pM. 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 IC 5 0 of a 10 compound is determined from the substrate turnover. The IC 50 is the concentration of test compound giving 50% inhibition of the substrate turnover. The compounds of the present invention desirably have an IC 50 of less than 500 nM in the factor Xa assay, preferably less than 200 nM, and more preferred compounds have an IC 50 of about 100 nM or less in the factor Xa assay. The compounds of the present invention desirably have 15 an IC 5 0 of less than 4.0 gM in the prothrombinase assay, preferably less than 200 nM, and more preferred compounds have an IC 50 of about 10 nM or less in the prothrombinase assay. The compounds of the present invention desirably have an IC 5 0 of greater than 1.0 gM in the thrombin assay, preferably greater than 10.0 pLM, and more preferred compounds have an IC 50 of greater than 100.0 pM in the thrombin assay. 20 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 25 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.
WO 01/19798 PCT/USOO/25195 253 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 5 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 pM) in 20 mM Tris-HCl buffer, pH 7.5, containing 0.15 M NaCl, 5 mM CaCI2 and 0.1% bovine serum albumin. Aliquots from the complex-inhibitor mixture are added to prothrombin (1 nM) and Chromozym 10 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. 15 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 20 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 25 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 30 parameters.
WO 01/19798 PCT/USOO/25195 254 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 5 compound on the aPTT and PT prolongation with the highest dose (100 pg/kg + 2.57 pg/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 10 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 preferred 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 15 the patents, journal articles and other documents discussed or cited above are herein incorporated by reference.

Claims (36)

1. A compound of the formula (I): A-Q-D-E-G-J-X Wherein: 5 A is selected from: (a) Cl-C 6 -alkyl; (b) C 3 -Cs-cycloalkyl; (c) -N(R 2 ,R 3 ), -C(=NR 2 )-R 3 , -C(=NR 2 )N(R 2 ,R 3 ), -N(R 3 )-C(=NR 2 )N(R 2 , Rs)-, and -N(R 2 )C(=NR 3 )-R 2 10 (d) phenyl, which is independently substituted with 0-2 R' substituents; (e) naphthyl, which is independently substituted with 0-2 R' 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, 0 and S, and wherein the ring system may be substituted with 0-2 R' substituents; 15 R' is selected from: Halo, -CN, -C(=0)-N(R 2 , R), -N0 2 , -SO 2 N(R 2 , R'), -S0 2 R 2 , -(CH 2 )mNR 2 R 3 , (CH 2 )m-C(=NR 3 )-R 2 , -(CH 2 )m-C(=NR 2 )-N(R 2 ,R 3 ), -(CH 2 )m-N(R 2 )-C(=NR 2 )_ N(R 2 ,R 3 ), -(CH 2 )mNR 2 -C 3 . 6 heterocyclics, CI-alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 . scycloalkyl, CoAalkylC 3 .scycloalkyl, -CF 3 , -OR 2 , and a 5-6 membered heterocyclic 20 system containing from 1-4 heteroatoms selected from N, 0 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, Ci alkyl-CN, C 1 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, CowalkylC 3 .scycloalkyl and NO 2 ; WO 01/19798 PCT/USOO/25195 256 R2 and R3 are independently selected from the group consisting of: -H, -ORa, -N(-Ra, -R), -C.4alkyl, -C 2 - 6 alkenyl, -C 2 - 6 alkynyl, -C 3 .scycloalkyl, -CO. 4 alkylC 3 .scycloalkyl, -Co-alkylphenyl and -Co-alkylnaphthyl, wherein from 1 4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be 5 independently replaced with a member selected from the group consisting of halo, C 1 .4alkyl-CN, -C 1 . 4 alkyl, -C 2 . 6 alkenyl, -C 2 - 6 alkynyl, -C 3 .scycloalkyl, -Co4alkylC 3 . scycloalkyl, -CN, and -NO 2 ; 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, 10 with 1 to 2 rings being in the ring system and contain from 1-4 heteroatoms selected from N, 0 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 1 . 4 alkyl-CN, -Cialkyl, -C 2 . 6 alkenyl, -C 2 - 6 alkynyl, -C 3 . 8 cycloalkyl, -CoaalkylC 3 -scycloalkyl and -NO 2 ; 15 Ra and Rb are independently selected from the group consisting of -CI4alkyl, -C 2 - 6 alkenyl, -C 2 - 6 alkynyl, -C 3 . 8 cycloalkyl, -Co4alkylC 3 .scycloalkyl, 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, 0 and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring system may be 20 independently replaced with a member selected from the group consisting of halo, -CN, -C 1 .4alkyl, -C 2 .salkenyl, -C 2 - 6 alkynyl, -C3-scycloalkyl, -CO. 4 alkylC 3 . 8 cycloalkyl and -NO 2 ; m is an integer of 0-2; Q is selected from the group consisting of: 25 a direct link, divalent -CI- 4 alkyl, divalent -C 2 - 4 alkenyl, divalent -C 2 4alkynyl, -C(=O)-, -C(=NH)-, -C(=NMe)-, -N(-R 4 )-, -N(-R 4 )-CH 2 -, -C(=O)-N(-R 4 )-, -N(-R 4 )-C(=O)-, -S(=0) 2 -, -0-, -S(=0) 2 -N(-R 4 )- and -N(-R 4 )-S(=0) 2 -, wherein one or more hydrogens on each of the divalent CI- 4 alkyl, divalent C 2 - 4 alkenyl and divalent C 2 4alkynyl moieties can be replaced with a -R4 group; WO 01/19798 PCT/USOO/25195 257 R 4 is selected from the group consisting of: -H, -CF 3 , -C.4alkyl, -C 2 - 6 alkenyl, -C 2 . 6 alkynyl, -C 3 . 8 cycloalkyl, -Co.4alkylC 3 . scycloalkyl, -Co4alkylphenyl and -Co.4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be 5 independently replaced with a member selected from the group consisting of halo, -Cl_4alkyl, -C 2 . 6 alkenyl, -C 2 - 6 alkynyl, -C 3 . 8 cycloalkyl, -Co.4alkylC 3 -scycloalkyl, CN, -CF 3 , and -NO 2 ; D is selected from the group consisting of: (a) a direct link; 10 (b) phenyl, which is independently substituted with 0-2 Rila 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, 15 0 and S, and wherein the ring system may be subsituted from 0-2 Ria substituents; R"a is selected from the group consisting of: halo, CI.4alkyl, C 2 - 6 alkenyl, C 2 . 6 alkynyl, C 3 - 8 cycloalkyl, Co.4alkylC 3 .scycloalkyl, CN, -NO 2 , (CH 2 )nNR 2 aR 3 a, SO 2 NR 2 aR 3 a, SO 2 R 2 a, CF 3 , OR 2 a, and a 5-6 membered 20 aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, 0 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 1 . 4 alkyl, C 2 . 6 alkenyl, C 2 - 6 alkynyl, C 3 .scycloalkyl, Co.4alkylC 3 . scycloalkyl, -CN and -NO 2 ; 25 R 2 a and R 3a are independently selected from the group consisting of: WO 01/19798 PCT/USOO/25195 258 -H, C 1 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 . 8 cycloalkyl, Co0alkylC 3 -scycloalkyl, Coalkylphenyl and Co0alkylnaphthyl, 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, CIalkyl, C 2 - 6 alkenyl, 5 C 2 - 6 alkynyl, C 3 . 8 cycloalkyl, CowalkylC 3 .scycloalkyl, -CN and -NO 2 ; n is an integer of 0-2; E is selected from the group consisting of: a direct link, -(CH2)q-C(=O)-, -(CH 2 )q-N(-R 5 )-C(=0)-(CH 2 )x-, -(CH 2 )q-C(=0)-N(-R)-(CH 2 )x-, -(CH 2 )q-N(-R 5 )-(CH 2 )x-, , -(CH 2 )q-N(R 5 )CO 10 NR 6 (CH 2 )x and -SO 2 -; q and x are independently an integer of 0-2; R 5 and R6 are independently selected from the group consisting of: H, -C 1 .alkyl, -C 1 .-alkyloxy, -C 2 . 6 alkenyl, -C 2 - 6 alkynyl, -C 3 .scycloalkyl, -Co- 6 alkylC 3 . 8 cycloalkyl, -Ci4alkyl-C(=O)-OH, -Co- 6 alkyl-(carbocyclic aryl), 15 -Co4alkyl-(monocyclic heteroaryl) and -Ci4alkyl-C(=O)-O-Cilalkyl, wherein from 0-4 hydrogen atoms on the iing 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, -Ci-alkyl, -C 2 - 6 alkenyl, -C 2 - 6 alkynyl, C 3 . 8 cycloalkyl, -Co-alkylC 3 .scycloalkyl, -S(=O)2-OH, -CN, -CF 3 and -NO 2 ; 20 G is selected from the group consisting of: phenyl, which is substituted with 0-2 R Ib groups; and a 5-6 membered aromatic and non-aromatic heterocyclic ring containing 1-4 hetero atoms selected from N, 0 and S wherein the heterocyclic ring is substituted with 0-2 R groups; 25 R Ib is independently selected from the group consisting of: WO 01/19798 PCT/USOO/25195 259 halo, -C 1 . 6 alkyl, -C 2 - 6 alkenyl, -C 2 - 6 alkynyl, -C 3 .scycloalkyl, -CO 6 alkylC 3 . 8 cycloalkyl, -CI.4alkyl-C(=O)-OH, -CN, -COOR 2 b, -CONR 2 bR 3 b, NO 2 , -S(=0) 2 -OH, -N(-R 2 b, -R 3 b), -C(=O)-N(-R 2 b, -R 3 b), -S(=0) 2 -N(-R 2 b, -R 3 b) _ S(=0) 2 -R 2 b, -CF 3 , -O-R 2 b, -O-CH2-CH2-0-R2b, -O-CH2-C(=0)-O-R2b, 5 -N(-R2)-CH2-CH2-0-Rb, -N(-CH2-CH2-0-R2b)2, -N(-R 2 b)-C(=O)-R 3 b, -N(-R 2 b)-S(=0)2-R 3 b, and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, 0 and S substituted with 0-4 RIb' groups; alternatively, when two RIb may be present on adjacent ring atoms of G and combine to form a benzene ring substituted with 0-4 RI' groups or a 5-6 10 membered aromatic or non-aromatic heterocyclic ring having 1-3 heteroatoms selected from N, 0 and S substituted with 0-4 RIb' groups; in a second alternative, one of the RIb groups of G can cylize with the -N-R 5 group of E to form a 5-7 membered heterocyclic ring containing 1-4 heteroatoms selected from N, 0 and S, which is subtituted with 0-4 RIb' groups, wherein two of 15 the Rib' groups attached to the same ring carbon may form a (=O) group; R 2 b and R 3 b are independently selected from the group consisting of: -H, -C 1 . 6 alkyl, -CI-6alkyloxy, -C 2 - 6 alkenyl, -C 2 - 6 alkynyl, -C 3 . 8 cycloalkyl, -Co- 6 alkylC 3 .scycloalkyl and -Co- 6 alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety may be 20 independently replaced with a member selected from the group consisting of halo, -C 1 .4alkyl, -C 2 - 6 alkenyl, -C 2 - 6 alkynyl, -C 3 . 8 cycloalkyl, -Co. 4 alkylC 3 -scycloalkyl, S(=0) 2 -OH, -CN, -CF 3 and -NO 2 ; R is independently selected from the group consisting of: halo, -C 1 .salkyl, -C 2 -6alkenyl, --C 2 . 6 alkynyl, -C 3 . 8 cycloalkyl, 25 -Co- 6 alkylC 3 - 8 cycloalkyl, -C 1 . 4 alkyl-C(=O)-OH, -CN, -NO 2 , -S(=0) 2 -OH, -N(-R 2 b', -R3b'), -C(=0)-N(-Rb' -R3b'), -S(=0)2N(Rb', -R3b'), -S(=0) 2 -R2', -CF3, -O-R2' -O-CH2-CH2-0-R2', -O-CH2-C(=0)-O-Rb', -N(-R2b')-CH2-CH2-0-R2V' -N(-CH2-CH2-O-RWb' )2, -N(-R2b')-C(=0)-R3b' and -N(-Rb')-S(=O)2-R 3b'. WO 01/19798 PCT/USOO/25195 260 R 2 b' and Rb' are independently selected from the group consisting of: -H, -CI- 6 alkyl, -CI- 6 alkoxy, -C 2 - 6 alkenyl, -- C 2 - 6 alkynyl, -C 3 . 8 cycloalkyl, -Co- 6 alkylC 3 .scycloalkyl and -Co- 6 alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety may be 5 independently replaced with a member selected from the group consisting of halo, -CI.4alkyl, -C 2 - 6 alkenyl, -C 2 . 6 alkynyl, -C 3 - 8 cycloakyl, -Co.4alkylC 3 -scycloalkyl, S(=0) 2 -OH, -CN, -CF 3 and -NO 2 ; J is selected from the group consisting of: a direct link, -S(=0) 2 -, -C(=0)-, -N(-R)-S(=0) 2 -, -C(=O)-N(-R)-S(=0) 2 -, 10 -C(=O)-N(-R 7 )-(CH 2 )y-, -S(=0) 2 -N(-R 7 ) -(CH 2 )y-, and -N(-R 7 )-C(=O)-(CH 2 )y-; y is an integer of 0-2; R 7 is selected from the group consisting of: -H, -C2-4alkyl, -C 2 - 6 alkenyl, -C 2 - 6 alkynyl, -C 3 .scycloalkyl, -Co- 6 alkylC 3 -scycloalkyl, -C 1 . 6 alkyl-C(=O)-OH, -C i* 6 alkyl-OH, -CI 6 alkyl-O-C I4alkyl, -CO. 15 4 alkyl-(carbocyclic aryl), -Co.4alkyl-(monocyclic or bicyclic heterocyclic ring system having from 0-4 heteroatoms selected from the group consisting of N, 0 and S), -CH 2 -C(=O)-O-CI_4alkyl and -CH 2 -C(=O)-O-C4alkyl-(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 20 member selected from the group consisting of halo, -C1.4alkyl, -C 2 . 6 alkenyl, -C 2 6 alkynyl, -C 3 - 8 cycloalkyl, -Co-4alkylC 3 -8cycloalkyl, -S(=0) 2 -OH, -CN, -CF 3 and -NO 2 ; X is selected from the group consisting of: phenyl, which is substituted with 0-3 RIc groups; 25 naphthyl, which is substituted with 0-3 RIC groups; WO 01/19798 PCT/USOO/25195 261 a 6-membered heteroaromatic ring containing from 1-2 nitrogen atoms, wherein the ring is substituted with 0-3 RIC groups; and a fused heterobicyclic ring system, wherein the ring system contains 1-3 heteroatoms selected from N, 0 and S and is substituted with 0-3 RIC groups; 5 R" is independently selected from the group consisting of: halo, -CF 3 , -C I- 6 alkyl, -C 2 - 6 alkenyl, -C 2 - 6 alkynyl, -C3.scycloalkyl, -Co. 6 alkylC 3 -scycloalkyl, -Ci alkyl-C(=O)-OH, -CF 3 , -CN, -NO 2 , -(CH 2 )z-N(-R 2 , -R 3 c), -C(=O)-N(-R 2 c, -R 3 c), -C(=NH)-N(-R 2 c, -RSc), -C(=NMe)-N(-R 2 c, -R 3 %) -S(=0) 2 -N(-R 2 c, -R 3 c), -S(=0) 2 -R 2 c, -S(=0)2-0 H, -CF 3 , -0-R 2 c, -0(-CH 2 )z-O-R 2 c, 10 -0(-CH 2 )z-C(=O)-O-R 2 c, -N(-R 2 c), -0(-CH 2 )z-O-R 2 c, -N[(-CH 2 )z-O-R 2 c] 2 , -(CH 2 )z-N(-R 2 c)-C(=0)-R 3 , -(CH 2 )z-N(-R 2 c)-S(=0) 2 -R 3 , and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, 0 and S; z is an integer of 0-4; R 2 c and R 3 C are independently selected from the group consisting of: 15 -H, -C 1 .6alkyl, -C 1 . 6 alkyloxy, -C 2 - 6 alkenyl, -C 2 - 6 alkynyl, -C 3 .scycloalkyl, -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, -CiG-alkyl, -C 2 -6alkenyl, -C 2 - 6 alkynyl, -C 3 .scycloalkyl, -Co-alkylC 3 .scycloalkyl, 20 S(=0) 2 -OH, -CN, -CF 3 and -NO 2 ; and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
2. A compound of claim 1, wherein: 25 A is selected from the group consisting of: -C 1 . 6 alkyl and -C 3 .scycloalkyl; WO 01/19798 PCT/USOO/25195 262 phenyl, which is substituted with 0-2 R' groups; naphthyl, which is substituted with 0-2 R' 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 5 heterocyclic ring system contains 1-4 heteroatoms selected from N, 0 and S and is substituted with 0-2 R 1 groups; R1 is independently selected from the group consisting of: halo, -C 1 .4alkyl, -CN, -NO 2 , -(CH 2 )m-N(-R 2 ,-R 3 ), -C(=0)-N(-R 2 ,-R 3 ), -S(=0) 2 -N( R 2 ,-R 3 ), -S(=0) 2 -R 2 , -(CH 2 )m-C(=NR 3 )-R 2 , -(CH 2 )m-C(=NR 2 )-N(R 2 ,R 3 ), -(CH 2 )m 10 N(R 2 )-C(=NR 2 )-N(R 2 ,R 3 ), -CF 3 , -(CH 2 )m-O-R 2 and a 5-6 membered aromatic heterocyclic ring containing 1-4 heteroatoms selected from N, 0 and S; R2 and R3 are independently selected from the group consisting of: -H, -CI4alkyl, or R2 and RW taken together can form a 3-8 membered cycloalkyl or a heterocyclic ring 15 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, 0 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-C 4 -alkyl-CN, -C.4alkyl, -C2- 6 alkenyl, -C 2 - 6 alkynyl, 20 -C 3 . 8 cycloalkyl, -CowalkylC 3 .scycloalkyl and -NO 2 ; m is an integer of 0-2; Q is selected from the group consisting of: a direct link, -Ci- 4 alkyl, -C 2 - 4 alkenyl, -C 2 .4alkynyl, -C(=O)-, -C(=NH)-, C(=NMe)-, -N(-R 4 )-, -N(-R 4 )-CH 2 -, -C(=O)-N(-R 4 )-, -N(-R 4 )-C(=O)-, -S(=0)2-, 25 0-, -S(=0) 2 -N(-R 4 )- and -N(-R 4 )-S(=0) 2 -; R 4 is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 263 -H, -CF 3 , -Ci 4 alkyl, D is selected from the group consisting of: a direct link; phenyl, which is substituted with 0-2 R"a groups; and 5 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, 0 and S and the ring system is substituted with 0-2 Ria groups; Ra is independently selected from the group consisting of: 10 halo, -Ci-alkyl, -CN, -NO 2 , -(CH 2 )n-N(-R 2 a, -R 3 a), -S(=0) 2 -N(-R 2 a, -R 3 a), -S(=0) 2 -R 2 a, -CF 3 , -(CH 2 )n-OR 2 a, -C(=O)-O-R 2 a, -C(=O)-N(-R 2 a, -R 3 a) and a 5-6 membered aromatic heterocyclic ring containing 1-4 heteroatoms selected from N, 0 and S; n is an integer of 0-2; 15 R 2 a and R3a are independently selected from the group consisting of: -H, -CF 3 and -CI alkyl, E is selected from the group consisting of: a direct link, -(CH2)q-C(=O)-, -(CH 2 )q-N(-R 5 )-C(=O)-(CH 2 )x-, -(CH 2 )q-C(=0)-N(-Rs)-(CH 2 )x-, -(CH 2 )q-N(-R 5 )-(CH 2 )x-, -(CH 2 )q-N(R)CO 20 NR 6 (CH 2 )x- and -SO 2 -; R 5 and R6 are each H, -CI-alkyl, -C 2 - 6 alkenyl, -C 2 - 6 alkynyl, -C 3 - 8 cycloalkyl, or -CO-alkylC 3 .scycloalkyl; q and x are independently an integer of 0-2; G is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 264 phenyl, which is substituted with 0-2 Rib groups; and a 5-6 membered aromatic and non-aromatic heterocyclic ring containing 1-4 hetero atoms selected from 0, S and N, wherein the heterocyclic ring is substituted with 0-2 RIb groups; 5 R I is independently selected from the group consisting of: halo, -Cigalkyl, -CN, -NO 2 , -N(-R 2 b, -R 3 b), -C(=O)-N(-R 2 b, -R 3 b), -S(=O) 2 -N(-R 2 b, -R 3 b), -S(=0) 2 R 2 b, -CF 3 , -O-R 2 b, -O-CH2-CH2-0-R26 -O-CH2-C(=0)-O-R2b -N(-R2b)-CH2-CH2-0-R2, -N(-CH2-CH2-0-R2 )2, -N(-R 2 b)-C(=O)-R 3 b, -N(-R 2 b)-S(=O) 2 -R 3 b and a 5-6 membered heterocyclic ring containing 1-4 10 heteroatoms selected from N, 0 and S; alternatively, when two RIb may be present on adjacent ring atoms of G and combine to form a benzene ring substituted with 0-4 Rib' groups or a 5-6 menibered aromatic or non-aromatic heterocyclic ring having 1-3 heteroatoms selected from N, 0 and S substituted with 0-4 RIb' groups; 15 in a second alternative, one of the Rib groups of G can cylize with the -N-R group of E to form a 5-7 membered saturated, unsaturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected from N, 0 and S, which is substituted with 0-4 RIb' groups, wherein two of the RIb' groups attached to the same ring carbon may form a (=0) group; 20 R 2 b and R 3 b are independently selected from the group consisting of: -H, -CF 3 , -C,4alkyl and -C 1 alkyl-(carbocyclic aryl); Ri' is independently selected from the group consisting of halo, -Cigalkyl, -CN, -NO2, -N(-R26', -R3b'), -C(=0)-N(-R2b', -R3b'), -S(=0)2-N( Rb' -Rlb'), -S(=0) 2 -R 2 ', -CF 3 , -O-R 2 ', -O-CH2-CH2-0-R2' 25 -O-CH2-C(=O)-Rb', -N(-R2b')-CH2-CH2-0-R2, -N(-CH2-CH2-0-R2b')2, -N(-R2b')-C(=0)-RWb',-N(-R2b')-S(=0)2-R3b; WO 01/19798 PCT/USOO/25195 265 R 2 b' and R 3 b' are independently selected from the group consisting of: -H, -Cigalkyl and -Clalkyl-(carbocyclic aryl); J is selected from the group consisting of: a direct link, -S(=0) 2 -, -C(=0)-, -N(-R 7 )-S(=0) 2 -, -C(=O)-N(-R 7 )-S(=0) 2 -, 5 -C(=O)-N(-R 7 )-(CH 2 )y-, -S(=0) 2 -N(-R 7 )-, -(CH 2 )y- and -N(-R 7 )-C(=O)-(CH 2 )y-; y is an integer of 0-2; R 7 is selected from the group consisting of: -H, -C 1 alkyl, -C 2 - 6 alkenyl, -C 2 - 6 alkynyl, -Co4alkyl-(carbocyclic aryl), -Co4alkyl-(heterocyclic ring system), -CH 2 -C(=O)-O-Ci4alkyl and 10 -CH 2 -C(=O)-O-CIgalkyl-(carbocyclic aryl); X is selected from the group consisting of: phenyl, which is substituted with 0-3 R* groups; naphthyl, which is substituted with 0-3 RI groups; a 6-membered heteroaromatic ring containing from 1-2 nitrogen atoms, wherein 15 the ring is substituted with 0-3 RiC groups; and a fused heterobicyclic ring system, wherein the ring system contains 1-3 heteroatoms selected from N, 0 and S and is substituted with 0-3 RIC groups; RIC is independently selected from the group consisting of: halo, -Clalkyl, -CN, -NO 2 , -(CH 2 )z-N(-R 2 c, -R 3 ), -C(=0)-N(-R 2 c, -R 3 *) 20 -C(=NH)-N(-R 2 c, -R 3 ), -C(=NMe)-N(-R 2 c, -R 3 c), -S(=0) 2 -N(-R 2 c, -R 3 ), -S(=0)2 R 2 C, -S(=0) 2 -O-, -CF 3 , -O-R 2 c, -O-CH2-CH2-0-Rc, -O-CH2-C(=0)-O-R2e -N(-R2c)-CH 2 -CH 2 -0-R 2 C, -N(-CH 2 -CH 2 -0-R 2 C) 2 , -(CH 2 )z-N(-R 2 )-C(=O)-R 3 C, -(CH 2 )z-N(-R 2 C)-S(=O) 2 -R 3 c, and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, 0 and S; WO 01/19798 PCT/USOO/25195 266 z is an integer of 0-2; R 2 e and R 3 " are independently selected from the group consisting of: -H, -C 1 . 4 alkyl and -C 1 . 4 alkyl-(carbocyclic aryl); and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug 5 derivatives, thereof.
3. A compound of claim 1, wherein: A is selected from the group consisting of: SO 2 NH 2 SO 2 NHMe SO 2 Me CH 2 NH 2 NMe Me CONH 2 CN SO 2 NH 2 SO 2 NH 2 SO 2 NH 2 SO 2 Me SO 2 Me SO 2 Me N F ci Br F CI Br F / / N N NC H 2 NOC H 2 NH 2 C NC H 2 NOC N/N NND2 Cl Br H 2 NH 2 C Me 2 NH 2 C Me 2 N H 2 N NH 2 CH 2 NH 2 CN NMe 2 N N N N N N N N CH 2 NMe 2 SO 2 NH 2 SO 2 Me CONH 2 H 2 N H 2 NH 2 C N N N N N N N - NL$N N\/ N\/ N\ H 2 N NH 2 CH 2 NH 2 NH 2 CH2NH2 CN N= N)/ rlN N\ N\ N N EtO N N N SO 2 Me NH 2 H 2 N Me 2 N H 2 NH 2 C H 2 NOC NC N N N NI/ N N N N N N N N N N N 10 WO 01/19798 PCT/USOO/25195 267 N N- Me'N"- HN'\ O,- Sz-- 02S-- NH-- ( N N> N - N - N - N NH 2 HH C N- Me-N N- Me-N HN N- HN }- CN- ON- SN 0 2 SN- N- NS- N- N-N 02 I\- EN N-C - N r -me I-me /-Et'N H N Me Me Me H Et, ,0 N - N - N - N - M e N -N H Me Me H Me MeN S N N N N H Me EN S NH 2 N H 2 N NH- Me NH- H 2 N H Me Et H O Me Me Me Me Me SH 2 N-CH 2 - N-H 2 - N-CH 2 - Me-N-OH 2 - Me N- Me - O MN MeN H Me Me' Me Me Q is selected from the group consisting of: a direct link, -C(=NH), -C(=NMe)-, -C(=0)-, -CH 2 -, -NH-, -N(-CH 3 )-, -0-, -NH CH 2 -, -CH 2 -NH-, -N(-CH 3 )-CH 2 -, and -CH 2 -N(-CH 3 )-; 5 D is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 268 / -N F CI Br CN -NN CH 2 NH 2 Me F F F CI Br F F N N- -N N Me PMe 4NN N N me Me N N N N E is selected from the group consisting of: a direct link, -NH-C(=0)-, -N(-CH 3 )-C(=0)-, -N(-CH 2 CO 2 H)-C(=0)-, C(=O)-NH-, -C(=0)-N(-CH 3 )-, -NH-CH 2 - and -CH 2 -NH-; 5 WO 01/19798 PCT/USOO/25195 269 G is a member selected from the group consisting of: Rb Rib Rb R ib Rb R lb R Rb R~bR~b N b R ) N- R N-Rb -Rb N N N NN N - N R RN Rib R~N Rib R N NR b RR R R, R b 1 Rib lbb lb b R Rib Rib Nx RR N r -KN 'N *Z NN N N -H -e,-C3 -, Cl-r -SO2e,N ,-CN 2 -CN e -- N,-N O2 R ib R ib S\Rlb N-R blb 0S\Rl l N Rlb NN 'N 'NS2 5 NHCe NHS2e -C2N2anCOH lbRbRib Rib Rlb l1b. R V2 R- Ri1b / R Rib Rlb R Rib R Rib lb RI lb R R llb 1 b RI lb R R b Rb R R Rbb Rl R lbR Rb DO lb R (,lb lbRl R R R Ri l b lb~i lb N- lb R ib R b Rb R
4 R ib ' N-Rl lb N lb- Rb N N Rb _R \NR lb ib ibs ineednl eete rmtegopcnsitn f J is selected from the group consisting of: a direct link, -N-H-, -O-, -S(=0)2-, -S(=0)2-NH, -NH-S(=0)2-, -C(=0)-, NH-C(=0)- and -C(=0)-NH-; WO 01/19798 PCT/USOO/25195 270 X is selected from the group consisting of: -O MeO 2 S H 2 NO 2 S 02N H2NH2 H 2 N HO H 2 N H 2 N HOI1 MeOOK H 2 N&I O 0 0 F CI Brr CI Br F C F C Br F F CFBr OH K OMe K~''NH 2 F CBr / F /CI Br 1*:z /N z/ 02 02 02 / rF CBr N0 NN SN0 H- H HC r -~ WO 01/19798 PCT/USOO/25195 271 ~ICI:IaBr-M Br§S <0 M C / 02 S:~c -m Na F NaC 4iN Br s 02 02 H H H N N _Nl>F N >CI N ?Br N ~CI S -Br S-< H--, /H 2 N 2 S Me0 2 ~ 0 2 N~ F NNN 'N -~-~ = H H H H 2 NOC Nq No -&Fi ' &Br -- &Br 4 4 }.F N N N- H 2 N0 MeO 0 2 N .- < C < -r-K'_9-Ole F IF /"F F H 2 NO H 2 NH 2 2 0 MeO F H 2 NO N 1- 2 NH 2 H 2 NO 2 S Me0 2 0 2 N F H 2 NO H 2 NH 2 C H 2 N0 2 S Meo 2 2 'Br "~Br ~Br ' Me OMe 0 Me F H 2 NOb _ H 2 NO 2 S OMe ~Me F Cl Br OMe IF Me0 2 q 0 2 N F H 2 NO NC H 2 NH 2 q F F F F F IF WO 01/19798 PCT/USOO/25195 272 H 2 NO 2 S MeO 2 0 2 N F H 2 NO NC H 2 NH 2 C C C| CI C1 CI CI CI H 2 NO2S MeO 2 0 2 N F H 2 NO NC H 2 NH 2 Br Br Br Br Br Br Br -Q F -Q F - -F Q CI -Q CI -Q CI - Br F CI Br F CI Br F H 2 NO 2 -Q Br -Q Br -QOMe _QOMe -Q OMe CI Br F Cl Br H 2 N MeO 2 0 2 N R H 2 NO N H 2 NH 2 H 2 N H 2 N H 2 N H 2 N H 2 N H 2 N NN\ N\ N\\N F C - Br F F CI Br H\ Me - Q ;) -: -, _, NH , MeN H 2 N H 2 N H 2 N H 2 N H 2 N H 2 N H 2 N MeO 2 S H 2 NO 2 H 2 NO O NH \ -N -N N HN H2N H -N H 2 N H 2 N H 2 N H 2 N H 2 N H 2 N H 2 NH 2 CNF0NMO -N -N -N -N =NH NH \ -NH H 2 N H 2 N H 2 N H 2 N H 2 N H 2 N H 2 N H 2 NO 2 S H 2 NOC H 2 NH 2 F O 2 N NH NH -NH -NH -NH O H 2 N H 2 N H 2 N H 2 N H 2 N H 2 N WO 01/19798 PCT/USOO/25195 273 MeO H 2 NO H 2 NO H 2 NH NC F 0i = -_-0o o H 2 N H 2 N H 2 N H 2 N H 2 N H 2 N 0 2 N O<N:N Me OMe -o N0 N N N H 2 N N NN CI Br NH 0 H 2 N H 2 N H 2 N MeO 2 S F MeO 2 S CI MeO 2 S Br MeO 2 S MeO 2 S MeO 2 S H 2 NO 2 S F H 2 NO 2 S;CI F CI Br H 2 NO 2 S Br H 2 NO 2 S H 2 NO 2 S H 2 NO 2 S 0 2 N F 0 2 N CI 0 2 N Br 0 2 N 0 2 N 0 2 N Br NCF NC"M C NCBr NCF N C NBr ': Br NcWIr N~ 2 C y H 2 NOC F H 2 NOCIX CI H 2 NOC IBr H2NO 'Yl YBr H 2 NOCC H 2 NO w Br H 2 NH 2 C= F H 2 NH 2 CCI H 2 NH 2 C Br H 2 NH 2 C F H 2 NH 2 C H 2 NH 2 CB WO 01/19798 PCT/USOO/25195 274 >~yF HO F HO Br HO HO HO MeO F MeO m Cl MeO Br MeO F MeO MeO B H2N F H 2 N CI H 2 N Br H 2 N >X CI ~ Br FycF H 2 N H 2 N MeO 2 S F MeO 2 S F Br F lB BMeO 2 S CI MeO 2 S CI MeO 2 S C F CI B r F MeO 2 S Br MeO 2 S Br MeO 2 S Br H 2 NO 2 S F H 2 NO 2 S F H 2 NO 2 S F H 2 NO 2 S CI H 2 NO 2 Sc aCI Br F . Cl Br H2NO2S CI H 2 NO 2 S Br H 2 NO 2 S Br H 2 NO 2 S Br O 2 N F O 2 N F 0 2 N F O 2 N CI CI Br F CI O 2 N CI 0 2 N CI O 2 N Br O 2 N Br O 2 N Br NCF NC NC F WO 01/19798 PCT/USOO/25195 275 CNC NC NC Br N H2NBr F H 2 NO I H 2 NOC B H 2 NOC CI 2NOC NOC r H 2 NOC H 2NHF H 2 NH 2 C ~FH 2 NH 2 C BrF H 2 NH 2 C.'' CI H 2 NH 2 C C Br F ~ -CI Br H 2 NH 2 C H 2 NH 2 C Br H 2 NH 2 Cl H 2 NH 2 CA -)=~F ~ C Br F H 2 N B H 2 N H 2 N Br H 2 N Ci HNH= H2N2= H-2I1 C Hqm c Br 0 F I BrBr N C H 2 N F H 2 N = H 2 N l Br H 2 N MBr fH AH H hH H2N F Br NH N NH Fr NF NC N H2 NH 2 NH 2 NH- 2 NH 2 F F F F ~CI F Br WO 01/19798 PCT/USOO/25195 276 NH 2 NH 2 NH 2 NH 2 F N H 2 NO 2 S MeO 2 S NH 2 NH 2 NH 2 NH 2 'NN L N"' ' H 2 NOC H 2 NH 2 C HO 2 02N F CI Br F C F F F CI Ci N\ N N Br F C - Br CI Br Br Br and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. 5 4. A compound of claim 1, wherein: A is selected from the group consisting of: phenyl, which is substituted with 0-2 R' groups; naphthyl, which is substituted with 1 R' group; and a 5-7 membered aromatic or non-aromatic monocyclic heterocyclic ring, wherein 10 the heterocyclic ring contains 1-2 heteroatoms selected from N, 0 and S and is substituted with 0-1 R' groups; R 1 is selected from the group consisting of: -S(=0) 2 -N(-R 2 , -R), -S(=0) 2 -R 2 , -CH 2 N(-R 2 , -R), -CN and halo. WO 01/19798 PCT/USOO/25195 277 R 2 and R 3 are independently selected from the group consisting of: -H and -C14alkyl; Q is selected from the group consisting of: a direct link, -C(=NH), -C(=NMe)-, -C(=O)-, -CH 2 -, -NH-, and -N(-CH 3 )-; 5 D is selected from the group consisting of: a direct link; phenyl, which is substituted with 0-2 Ria 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 RI a 10 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-; 15 G is selected from the group consisting of: Pyrazole, pyrazoline, triazole and tertrazole, which are substituted with 0-2 RIb groups; and a 5-membered aromatic heterocyclic ring, wherein the heterocyclic ring contains 2 heteroatoms selected from N, 0 and S and is substituted with 0-1 R 1 " groups 20 and; Rib is selected from the group consisting of: -Me, -Et, -CF 3 , -C(=O)-NH 2 , -NH 2 , -NH-C(=O)-Me, -NH-S(=0) 2 -Me, -SMe, -S(=0) 2 -Me and halo; WO 01/19798 PCT/USOO/25195 278 alternatively, when two Rib 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 5 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(=0)- and -C(=0)-NH-; X is selected from the group consisting of: phenyl, which is substituted with 1-3 RI" groups; 10 naphthyl, which is substituted with 0-3 RIC groups; pyridinyl, which is substituted with 1-3 RiC groups; and a 9-10 membered fused bicyclic aromatic ring, wherein the aromatic ring contains 0-2 heteroatoms selected from N and 0 and is substituted with 0-3 RIc groups; R1c is independently selected from the group consisting of: 15 -H, halo, -Me, -CF 3 , -OH, -OMe, -NH 2 , -CN, -NO 2 , -CH 2 -R 2 c, -C(=O)-N(-R 2 c, R 3 ), -S(=0) 2 -R 2 c, -S(=O) 2 -N(-R 2 c, -R 3 C), -S(=0) 2 -OH, -C(=NH)-N(-R 2 c, -R 3 ), 2 imidazolin-2-yl and 1-methyl-2-imidazolin-2-yl; R 2 c and R 3 C are independently selected from the group consisting of: -H, -OH, -NH 2 and -CI-alkyl; 20 and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
5. A compound of claim 1 selected from the group consisting of: WO 01/19798 PCT/USOO/25195 279 R Rib b H \\N NH~ -NN N - N Rica RIO3 RRc3 Ric 2 R1c 2 Ri. 2 wherein: R' is selected from the group consisting of: 5 -SO 2 NH 2 , -SO 2 Me, -CH 2 NH 2 and -CH 2 NMe 2 ; Ri a is selected from the group consisting of: -H, -F, -Cl and -Br; RIb is selected from the group consisting of: -CH 3 , -CF 3 , -CH 2 CH 3 , -SO 2 Me, -CONH 2 and -NHSO 2 Me; 10 RI'd is selected from the group consisting of: -H, -F, -Cl, -Br, -NH 2 , -OH, -SO 2 Me, -SO 2 Et, -SO 2 NH 2 , -NO 2 , -CH 2 NH 2 , -CN, CONH 2 , -CH 2 OH; Ric 2 is selected from the group consisting of: -H, -F, -Cl and -Br; and 15 R"c 3 is selected from the group consisting of: -H, -F, -Cl and -Br and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. WO 01/19798 PCT/USOO/25195 280
6. A compound of claim 1 selected from the group consisting of: R R1.Rib RI RIb 1 l H Ni N N NH N R 1 ' / Ri* R R 1 RR R4 3 Rio 3 R 1 c 2 R1. 2 RIc2 wherein: R' is selected from the group consisting of: 5 -SO 2 NH 2 , -SO 2 Me, -CH 2 NH 2 and -CH 2 NMe 2 ; Ra is selected from the group consisting of: -H, -F, -Cl and -Br; RIb is selected from the group consisting of: -CH 3 , -CF 3 , -CH 2 CH 3 , -SO 2 Me, -CONH 2 and -NHSO 2 Me; 10 R'4d is selected from the group consisting of: -H, -F, -Cl, -Br, -NH 2 , -OH, -SO 2 Me, -SO 2 Et, -SO 2 NH 2 , -NO 2 , -CH 2 NH 2 , -CN, CONH 2 , -CH 2 OH; Ric2 is selected from the group consisting of: -H, -F, -Cl, -Br and -OMe; and 15 RIC 3 is selected from the group consisting of: -H, -F, -Cl, -Br, -OCH 3 , -NH 2 , -CH 2 NH 2 , -CONH 2 , -CONHMe, -CONMe 2 and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. WO 01/19798 PCT/USOO/25195 281
7. A compound of claim 1 selected from the group consisting of: 1 3a Rib RR Rib RR Rb 00 H H HNR N N N I> N R R N Ric 3 Rica Rio 3 R0 23 Rjc2 R R 1 c 2 R Rib Ri Rd m t gIb HH~ H_ > 5CH2 NH(H) -CH2N(CH3)2 -Hi-F,-C andh-Br RiHa Rd 3 R-C 3 Rio 2 Ric 2 Rio 2 wherein: R' is selected from the group consisting of: -SO 2 N-H 2 , -S 2 CH 3 , -CN, -CONH 2 , -CONH(COH, -CON(CH 3 ) 2 , -CH 2 NH 2 , 5 CO- 2 NH(CHe, -CH 2 N(CH 3 ) 2 ; R"i is selected from the group consisting of: -H, -F, -Cl and -Br; RIb is selected from the group consisting of: -CH 3 and -CF 3 ; 10 R"' is selected from the group consisting of: -H, -F, -Cl, -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 , -01H, -NH 2 , and -NO 2 ; R 1 2 is selected from the group consisting of: -H, -F, -Cl, -Br, and -OCH 3 ; and 15 R' 3 is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 282 -H, -F, -Cl, -Br, -OCH 3 , -NH 2 , -CH 2 NH 2 , -CONH 2 , -CONHMe, -CONMe 2 and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. 5
8. A compound of claim 1 selected from the group consisting of: R Rla R R 1 R R' R H 0 0 H 0 N N N - H N HN H R RaR R1 R R1 R HN HN H N H Ri R R RH Ri 1 -S - 2 n NCH2N e2 N N N H H H wherein: R' is selected from the group consisting of: 10 -S 2 NH 2 , -S 2 Me, -CH 2 NH 2 and -CH 2 NMe 2 ; Rl is selected from the group consisting of: -H, -F, -Cl and -Br; S RIb is selected from the group consisting of: -CH 3 , -CF 3 , -CH 2 CH 3 , -SO 2 Me, -CONH 2 and -NHSO 2 Me; and 15 Ric is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 283 -H, -F, -Cl, -Br, -NH 2 , -OH, -SO 2 Me, -SO 2 Et, -SO 2 NH 2 , -NO 2 , -CH 2 NH 2 , -CN, CONH 2 , -CH 2 OH and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. 5
9. A compound of claim 1 selected from the group consisting of: 1 la R Ib RI Rib R1 lb H 0 N H\ H 2 N '.H 2 N ' H 2 N Ric 2 Ric 2 Rc H N N - N N1 RIO 1 R' R H 2 N H 2 N I" H 2 N N -N ,-N R U2 R1c2 Ri1c2 R' R2R ib RIb lb H N NR NN R'ca RRca R'ca N N N R1.2 R1c2 R U 10 whereRI 10 wheein WO 01/19798 PCT/USOO/25195 284 R' is selected from the group consisting of: -SO 2 NH 2 , -SO 2 Me, -CH 2 NH 2 and -CH 2 NMe 2 ; Ria is selected from the group consisting of: -H, -F, -Cl and -Br; 5 R"' is selected from the group consisting of: -CH 3 , -CF 3 , -CH 2 CH 3 , -SO 2 Me, -CONH 2 and -NHSO 2 Me; Ri' is selected from the group consisting of: -H, -F, -Cl, -Br, -NH 2 , -OH, -SO 2 Me, -SO 2 Et, -SO 2 NH 2 , -NO 2 , -CH 2 NH 2 , -CN, CONH 2 , -CH 2 OH; and
10 Ric 2 and RiC 3 are independently selected from the group consisting of: -H, -F, -Cl and -Br, and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. 15 10. A compound of claim 1 selected from the group consisting of: Ra Rlb Rlb RIb N H0 \ 0 AH N AQ H 0N A- H R 4' RI'" R' R1c 3 RIc 3 RIc 3 ! RIc 2 Ric2 RIc 2 wherein: WO 01/19798 PCT/USOO/25195 285 A-Q is selected from the group consisting of: 0- 0- K0-> K>- K- Q-C0-C3 HN Me Et Me Et Me_ MeNZ C MeT C- CN- C- - oSH 0 $ Me Me , e Me Me H2 H2H Q N- CHN-- M&Me N H N-- ON-C NHN H\0 N Me Me H Me2HeCmMe H C-Me Me Me 2 H SO2 H O2M 0MCOH2 ONH 2 H2H CH2NH Me C>me H2M IH 2 2 ~ N- C- HN,- MeN\,,N- Me Hly,,N- MeN\,,NL H 2 C- HC- H C-. PN- CQ N- MeN Me Me H 2 NI Me 2 N/ Me 3 N Me e3 N ['d'ee 0N2 S 2 NH 2 J2MG 2 Me CONH 2 ONH 2 fH2NH2 CH 2 NH 2 bN N - M- N N - N _ M N N - Nx N- N A H3 Me CONH 2 CH 2 NH 2 wherein: A is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 286 Me 1 m\ E me, E t MgN KIN- K&N N- N- N- E N- E N- NN H H H me Me Et Me N- - eNMe N Me-KN N- QN- C N- N- QN- N- Me- QN M>0 1-~qj H'_ e\_l" soN__ HN Me R"a is selected from the group consisting of -H, -F, -Cl and -Br; RIb is selected from the group consisting of: -Me, -CF 3 , -Et, -SO 2 Me, -CONH 2 and -NHSO 2 Me; 5 RI' is selected from the group consisting of: -H, -F, -Cl, -Br, -NH 2 , -OH, -SO 2 Me, -SO 2 Et, -SO 2 NH 2 , -NO 2 , -CH 2 NH 2 , -CN, CONH 2 , -CH 2 OH; Ric 2 is selected from the group consisting of: -H, -F, -Cl and -Br; and 10 RI'0 is selected from the group consisting of: -H, -F, -Cl and -Br and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. WO 01/19798 PCT/USOO/25195 287
11. A compound of claim 1 selected from the group consisting of: a Rlb Rib Rb A-Q N N A-Q N H A-Q H N Rid 3 R' R I 1 3 Ric1 R 1 2 R 1 2c2 wherein: A-Q is selected from the group consisting of: 5 Nc-c> c> c-c> \-Q-C - HN Me Et Me Et Me C > Me e Me Mel H - -N H Me- N HH MMe Me Mee H N 2 - M - m ea H N - M N H A M M e m e M e M e /-M W SO 2 NH 2 0 2 NH 2 SO 2 Me SO 2 Me CONH 2 CONH 2 CH 2 NH 2 CH 2 NH 2 MN M M N M M NH C/H3 0 NN- ONH N- N A A NMe OH2 CH2NH2 WO 01/19798 PCT/USOO/25195 288 wherein: A is selected from the group consisting of: Me M N- M N- M E NN- N H H H Me Me Et * me Me7 N- ON- - N- N- N-- MejN N- N-2N- H\_ N- Me-\_ Q N_ Q - Q N_ 02Q H( N- Me.N/-\ Ra is selected from the group consisting of: 5 -H, -F, -Cl and -Br; Rib is selected from the group consisting of: -CH 3 , -CF 3 , -CH 2 CH 3 , -SO 2 Me, -CONH 2 and -NHSO 2 Me; Ri is selected from the group consisting of: -H, -F, -Cl, -Br, -NH 2 , -OH, -SO 2 Me, -SO 2 Et, -SO 2 NH 2 , -NO 2 , -CH 2 NH 2 , -CN, 10 CONH 2 , -CH 2 OH; Rie 2 is selected from the group consisting of: -H, -F, -Cl, -Br and -OMe; and Rid 3 is selected from the group consisting of: -H, -F, -Cl, -Br, -OH, -OCH 3 , -NH 2 , -CONH 2 , -CH 2 NH 2 , WO 01/19798 PCT/USOO/25195 289 and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. WO 01/19798 PCT/USOO/25195 290
12. A compound of claim 1 selected from the group consisting of: R b R Rib R' Rib N N N / N N N N 0 R'c R'c R' R1 3 R1 3 RI 3 RIc 2 RiU 2 R1c2 R RIa Rb R ib R Ib N N N R R O R R1c3 R U3 Rica, R Ri 1 1 b 1N Rib RIb RO Rb NN RRI3 RcRiRic N N NR Ri 3 R RR 3 RR 3 Ri U2 c 1 2 Ric 2 R Rib Rib Rib N N N Rio0 RIG 3 RIO 3 RIU 2 Ri. 2 R Ic 2 R a Rib ib Rib RIG Rio R Ck (N N N, Rio 3 RiG 3 RiU 3 Ri 2 RU 2 RU2 WO 01/19798 PCT/USOO/25195 291 Is P H R N H R ib 1 1H R ib - N N' NN O R'c' o R'c 1 o R Ric 3 Ri1 3 RI. 3 R 4C2 R Ic2 R 1.2 wherein: R' 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 , 5 CH 2 NH(CH 3 ), -CH 2 N(CH 3 ) 2 ; Ria is selected from the group consisting of: -H, -F, -Cl and Br; RIb is selected from the group consisting of: -CH 3 and -CF 3 ; 10 RI'd is selected from the group consisting of: -H, -F, -Cl, -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 ; RIc 2 is selected from the group consisting of: -H, -F, -Cl and -Br; and 15 R 3 is selected from the group consisting of: -H, -F, -Cl and -Br, WO 01/19798 PCT/USOO/25195 292 and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. WO 01/19798 PCT/USOO/25195 293
13. A compound of claim 1 selected from the group consisting of: R RR i b R ib R Rib N N N Rico Ric Ric' R 1 3 1 Rc 3 R iR 3 1 2 R1 2 N2 RlO Rib Rb RR 0 Rlb NN NR NRN o Ric 3 RiioR 3 R'c3 R Rc3O R R"3 R Ric 2 Ric 2 R1c 2 RR Riba R 1 Rib R' Rib N N N N' Ri 0 RicR Ric4 Rio 3 0 Rio 3 NRio 3 N R1c 2 Ric 2 Ric2 RR R18 b R' Rib R 1 Rib R N NR 0 Ric0 Ric' 0 R'C' Ri 3 1 Ric 3 N RiC 3 R Rio 2 R io 2 Rio 2 RI RIO Rib R' Rib R 1 Rlb 1b N N' N o0~ Ric' 0 Ric' R'c Rio 3 RN R1c 3 N Ric 3 R R1c 2 R 1 C2 R U2 R' Rio OH Rlb R' O H l1b R 1 ONH lb N N N N N 0Ric' Ric' R'C' Rio 10 Rio 3 NRio N0 Ric 2 R io 2 Rio 2 WO 01/19798 PCT/USOO/25195 294 wherein: R' 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 ; 5 Ria is selected from the group consisting of: -H, -F, -Cl and -Br; RIb is selected from the group consisting of: -CH 3 , -CF 3 , -CH 2 CH 3 , -SO 2 Me, -CONH 2 and -NHSO 2 Me; RiC is selected from the group consisting of: 10 -H, -F, -Cl, -Br, -NH 2 , -OH, -SO 2 Me, -SO 2 Et, -SO 2 NH 2 , -NO 2 , -CH 2 NH 2 , -CN, CONH 2 , -CH 2 OH; Ric2 is selected from the group consisting of: -H, -F, -Cl, -Br and -OCH 3 ; and RiC 3 is selected from the group consisting of: 15 -H, -F, -Cl, -Br, -OCH 3 , -NH 2 , -CH 2 NH 2 , -CONH 2 , -CONHMe, -CONMe 2 , and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. WO 01/19798 PCT/USOO/25195 295
14. A compound of claim 1 selected from the group consisting of: Ho lb 1H I lb \ A-Q H N\ A- N NRt A- H NR NRi NN R Ric3 R 1 'c 3 R R RIc 2 R 2 R2 1c1 Rl*Rb R Rib 1 Rib R 00 0 7\ Ric 2 Ric 2 Ric 2 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 296 HO Me Et Me Et H 0 s Me MeH2MH H e Me M e Me CN-Me C me NH ONH2 2 I2 OH OH 2NH2 H H2 /N- N-C Me Me N M N Me N NmMe M N M e-NN0N - HN H A \ Me Me\ ONH2 CHN we H 2 C- H 2 C- H 2 C- HN- e // N- /N- N HN Me 2 N' Me 3 N Me e 3C C Me 3 eC N N M6I N' 50NH2 J NH2 {M e 0Me ONH2 ' H H 2 NH 2 5 H2 N Me N N e N N M NN M N /CH3 NN- NN N- NN N- N' 0 MeCONH 2 CH 2 NH 2 wherein: WO 01/19798 PCT/USOO/25195 297 A is selected from the group consisting of: M / t / N- / -N- N- - N- N H H H Me Me Et Me-<N- ON- ON- QN- N- MN M N- C N,_- O2 N-2- H N- M-- N" 2- HN -MN N Ral is selected from the group consisting of: -H, -F, -Cl and -Br; 5 RIb is selected from the group consisting of: -CH 3 and -CF 3 ; Ri'd is selected from the group consisting of: -H, -F, -Cl, -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 ; 10 Ric 2 is selected from the group consisting of: -H, -F, -Cl, -Br, and -OCH 3 ; and R 1 0 is selected from the group consisting of: -H, -F, -Cl, -Br, -OCH 3 , -NH 2 , -CH 2 NH 2 , -CONH 2 , -CONHMe, -CONMe 2 , and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug 15 derivatives, thereof. WO 01/19798 PCT/USOO/25195 298
15. A compound of claim 1 selected from the group consisting of: Ra R RicaRRbc3 RRib R Rb R RbRI N N NH NH NH R'c' R' R"4 N N N R 1 R 3 R 1 R R 3 R R R NN NH NH NH H 2 N NH 2 * H 2 N N N -N ).-N$, R3 2 Uc 2 RR c 2 R R 1 c2 RR Rilb Rib -IRb - H - N C NH NH NH -~N R 1 . 3 R'c 3 Rid" R ic 2 U~ 2 R 1.2 wherein: R 1 is selected from the group consisting of: 5 -SO 2 NH1 2 -S- 2 FH 3 , -CN, -ONH 2 , -CONH(CnB -CrN(;H 3 ) 2 , -CI 2 NH 2 , CH 2 NH(CHA) -CH 2 N(CH 3 ) 2 ; R 1 " is selected from the group consisting of: -H, -F, -Cl and -Br; WO 01/19798 PCT/USOO/25195 299 RIb is selected from the group consisting of: -H, -CH 3 and -CF 3 ; Ri" is selected from the group consisting of: -H, -F, -Cl, -Br, -CN, -CH 2 NH 2 , -CH 2 OH, -CONH 2 , -C(=NH)NH 2 , -CO 2 H, 5 CO 2 Me, -SO 2 Me, -SO 2 NH 2 , -OH, -NH 2 , and -NO 2 ; Ric 2 is selected from the group consisting of: -H, -F, -Cl and -Br; and RIC 3 is selected from the group consisting of: -H, -F, -Cl and -Br 10 and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. WO 01/19798 PCT/USOO/25195 300
16. A compound of claim 1 selected from the group consisting of: R R Rl Rlb RiO 1 R -- Ni N~R NH NH NH Rio 3 R Ric 3 N Ric 3 R RR12 RO 2 Rc 2 1 la Rib R b Rb R NRN N R N N 0 0 NH NH NH R13' R1c3 N R RR Ri N_-RIO N- RIO 3 N_- RI N - N YO0 0 NH NH NH Rid-14 R'Io Rio R 3 N ic3 -- N R i0o3 N Rio 2 Rio 2 R1c2 wherein: R' is selected from the group consisting of: 5 -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 ; Ra is selected from the group consisting of:. -H, -F, -Cl and -Br; Rib is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 301 -H, -CH 3 and -CF 3 ; R' 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 ; Ric 2 is selected from the group consisting of: 5 -H, -F, -Cl, -Br and -OCH 3 ; and R14 3 is selected from the group consisting of: -H, -F, -Cl, -Br, -OCH 3 , -NH 2 , -CH 2 NH 2 , -CONH 2 , -CONHMe, -CONMe 2 and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. 10
17. A compound of claim 1 selected from the group consisting of: WO 01/19798 PCT/USOO/25195 302 Rla A- - N/ Rib A-Q R A Rib 0 ~NN NH NH NH RR' RRco RRi' R c i R1R3 R i3 RU2 R Ic2 RU2 Ris A - Q /R b A - Q R ib A - Q R b NH NH NH R' R'C1 RRc1 H 2 N N H 2 N H 2 N N / N N Ric 2 RUc2 R A-Q / ,,Rib A-a Rb A_>N, Rib A- R & A-Q R /) NH NH NH RIo 3 Ric3 Ric 3 RiU 2 ~Ri 2 R1c2 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 303 Hk Me Et Me Et e mMme C- C- 0 S MM - M H HMe H 2 H 2 N e n\HH Me Me HH 2 HC - M 2 HC- MH C- Me C MeN - N - M N Me Me m 0 2 NI H 2 NH 2 0M O 2 Me CONH 2 ONH 2 CH 2 NH 2 H 2 NH 2 0 N-- -NC-C N-- N - O N-C - Q N N M N Me N 7N M N MNN MMe H/CH3 N2 N- N N - H A Me CONH 2 H2 NH2 A wherein: A is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 304 Me - - Me Et N - M Et\ Et N 1 ~ / O -~- )- N- K,,N HPl HN H me Me Er y e Me Me-IN- ON- ON- ON- QN-- N- Me-QN M N-- - 2- H - Me O N-' N_ OUH - M N R 1 a is selected from the group consisting of: -H, -F, -Cl and -Br; RIb is selected from the group consisting of: 5 -H, -CH 3 and -CF 3 ; Ridc is selected from the group consisting of: -H, -F, -Cl, -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 ; Ric 2 is selected from the group consisting of: 10 -H, -F, -Cl and -Br; and Ric 3 is selected from the group consisting of: -H, -F, -Cl and -Br, and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. 15
18. A compound of claim 1 selected from the group consisting of: WO 01/19798 PCT/USOO/25195 305 R"a A- / Rib A-Q R A-Q Rb NH NH NH RR R"ca Ric RIO 3 Rio 3 RIO Ro 2 R 1 c 2 Ri 2 R~3 R'c' RR R"'R R1.2 Rjc2 Rjc2 R1a l Rb -Rib Rib A-Q R A-Q R AQ N \ 0 0 T NH NH NH Ric1 R 1 ' 101l I R c N R4 NI N Ric 3 RIc 3 R 1 ' 3 Ric 2 RI 2 R wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 306 0C-C- -C- C>-C -- Q-KZ>- <I> HN Me Et Me Et MeM C >~ o -N c-"- c -N- H MMeH2MH 0 M- e H N MMe H H2 -Me me C- M M o H 2 22 e H OH2N2 H2 N-- N- N- N- N N- CN Me Me IHH2- H 2 C I- L H 2 C HNLo N N Me 2 N M 3 N N-MC MN- NNM N Me 3 C Ne N N - N N- N AN- A MN N- MN MN N N N- HN eN- A-"- Ae3C C Me Mej Nj N4-e Me CONH 2 CH 2 NH 2 wherein: A is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 307 N- Me E\ M, E Et\(N IN-- M N- / N- E- E N- N- N N- N H H H me me Et Me-KN- CN- N-N- QN- (jN- Me QN S\_ 02,\2 Hl\2 M-N_2 QN_ Q- - C- HN- M eN\j Ria is selected from the group consisting of: -H, -F, -Cl and -Br; Rib is selected from the group consisting of: 5 -H, -CH 3 and -CF 3 ; R'c' 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 ; Ric 2 is selected from the group consisting of: -H, -F, -Cl, -Br and -OCH 3 ; and 10 RI' 3 is selected from the group consisting of: -H, -F, -Cl, -Br, -OCH 3 , -NH 2 , -CH 2 NH 2 , -CONH 2 , -CONHMe, -CONMe 2 , and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof. 15 WO 01/19798 PCT/USOO/25195 308
19. A compound of claim 1 selected from the group consisting of: i lbR lb RRib H NNR H NR N I~N /N H H NH Ric 3 RiU 2 Rica R1e2 Ric 3 R1c2 Ria Rib Rlb NRlb /-C H INHN /I \ / R 1 c 3 R1. Ri10 Rc2 R4 3 R1c2 R "Rib Rilb ilb H NR N NR H 1 Ric 3 R. R1c3 R1c2 R *0 Ricz wherein: 5 R1 is selected from the group consisting of: -SO 2 NH 2 , -SO 2 Me, -CH 2 NH 2 and -CH 2 NMe 2 ; Ria is selected from the group consisting of: -H, -F, -Cl and -Br; RIb is selected from the group consisting of: 10 -CH 3 , -CF 3 , -CH 2 CH 3 , -SO 2 Me, -CONH 2 and -NIISO 2 Me; and Ric 2 and R 1 c 3 are independently selected from the group consisting of: WO 01/19798 PCT/USOO/25195 309 -H, -F, -Cl 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: 1 lH Rib N Rib R Rib H H NH \LO /N NN H NRN NH NH NH NH H Ri1 R1i 2 R1ca RIO 2 RiO Ri 2 RI Ri" Rib Rib Rlb H N N N NH NH H N NN R i R 3 R2 3 Rio 3 aRilb R ib 1,l _/\W/ H !~ \ j H/ N N N 6N H NH 7 NH R io 2 RIG 2 Rio 2 5 wherein: R' is selected from the group consisting of: -SO 2 NH 2 , -SO 2 Me, -CH 2 NH 2 and -CH 2 NMe 2 ; Ria is selected from the group consisting of: 10 -H, -F, -Cl and -Br; RIb is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 310 -CH 3 , -CF 3 , -CH 2 CH 3 , -SO 2 Me, -CONH 2 and -NHSO 2 Me; and Ric 2 and RI' 3 are independently selected from the group consisting of: -H, -F, -CI and -Br, and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug 5 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. 10
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. 15
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, 20 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 25 complications associated with instrumentation, and thrombotic complications associated with the fitting of prosthetic devices. WO 01/19798 PCT/USOO/25195 311
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 5 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 10 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 15 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 20 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. 25
28. A method for inhibiting the coagulation of biological samples, comprising the step of administering a compound of claim 2. WO 01/19798 PCT/USOO/25195 312
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. 5
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. 10
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, 15 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 20 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. 25 WO 01/19798 PCT/USOO/25195 313
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. 5
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 10 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, 15 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 20 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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