EP1216231A2 - INHIBITORS OF FACTOR Xa - Google Patents

INHIBITORS OF FACTOR Xa

Info

Publication number
EP1216231A2
EP1216231A2 EP00963451A EP00963451A EP1216231A2 EP 1216231 A2 EP1216231 A2 EP 1216231A2 EP 00963451 A EP00963451 A EP 00963451A EP 00963451 A EP00963451 A EP 00963451A EP 1216231 A2 EP1216231 A2 EP 1216231A2
Authority
EP
European Patent Office
Prior art keywords
group
alkyl
substituted
cycloalkyl
conh
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00963451A
Other languages
German (de)
English (en)
French (fr)
Inventor
Bing-Yan Zhu
Zhaozhong Jon Jia
Wenrong Huang
Yonghong Song
James Kanter
Robert M. Scarborough
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Millennium Pharmaceuticals Inc
Original Assignee
Millennium Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Millennium Pharmaceuticals Inc filed Critical Millennium Pharmaceuticals Inc
Publication of EP1216231A2 publication Critical patent/EP1216231A2/en
Withdrawn legal-status Critical Current

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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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    • 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
    • C07C311/30—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
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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
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
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    • 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
    • C07D213/78—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
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • 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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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • 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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    • C07—ORGANIC CHEMISTRY
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • 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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    • C07D333/04—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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    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
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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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    • C07D487/04—Ortho-condensed systems

Definitions

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

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Hydrogenated Pyridines (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Facsimile Image Signal Circuits (AREA)
  • Controls And Circuits For Display Device (AREA)
  • Dot-Matrix Printers And Others (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
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CA2385589A1 (en) 2001-03-22
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JP2003509412A (ja) 2003-03-11
CN1390206A (zh) 2003-01-08
AU781880B2 (en) 2005-06-16
HUP0203954A2 (hu) 2003-03-28
NO20021230D0 (no) 2002-03-12
ZA200202117B (en) 2004-02-25
ZA200306488B (en) 2004-04-28
TR200201413T2 (tr) 2003-02-21
MXPA02002762A (es) 2003-10-14
CZ2002959A3 (cs) 2002-07-17
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MX228790B (es) 2005-06-30
BR0014078A (pt) 2002-12-31
WO2001019798A2 (en) 2001-03-22
ZA200202116B (en) 2004-02-10
IL148698A0 (en) 2002-09-12
RU2002110295A (ru) 2003-12-10
WO2001019798A3 (en) 2001-10-25

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