Patent ID: 6372741
Filing Date: 2002-04-16
Classification: A61K,A61P

Abstract:
A method of treating a chronic disease in a mammal in need thereof, which disease is characterized by excessive, undesired or inappropriate angiogenesis, with an effective amount of a compound of Formula (I) which inhibits the production, transcription or translation of a cytokine, which cytokine is inhibited by inhibition of the kinase CSBP/p38/RK: wherein:R1 is 4-pyridyl, pyrimidinyl, quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl ring, which ring is optionally substituted independently one to three times with Y, NHRa, optionally substituted C1-4 alkyl, halogen, hydroxyl, optionally substituted C1-4 alkoxy, optionally substituted C1-4 alkylthio, C1-4 alkylsulfinyl, CH2OR12, amnino, mono and di-C1-6 alkyl substituted amino, or N(R10)C(O)Rb; Y is ORa; R4 is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro, C(Z)NR7R17, C(Z)OR16, (CR10R20)vCOR12, SR5, SOR5, OR12, halo-substituted-C1-4 alkyl, C1-4 alkyl, ZC(Z)R12, NR10C(Z)R16, or (CR10R20)vNR10R20 and which, for other positions of substitution, is halogen, cyano, C(Z)NR13R14, C(Z)OR3, (CR10R20)mâ€³COR3, S(O)mR3, OR13, halo-substituted-C1-4 alkyl, C1-4 alkyl, (CR10R20)mâ€³NR10C(Z)3, NR10S(O)mâ€²R8, NR10S(O)mâ€²NR7R17, ZC(Z)3 or (CR10R20)mâ€³NR13R14; v is 0, or an integer having a value of 1 or 2; m is 0, or the integer 1 or 2; mâ€² is an integer having a value of 1 or 2, mâ€³ is 0, or an integer having a value of 1 to 5; R2 is (CR10R20)nâ€²OR9, heterocyclyl, heterocyclylC1-10 alkyl, C1-10alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylC1-10 alkyl, C5-7 cycloalkenyl, C5-7 cycloalkenylC1-10alkyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10alkyl, (CR10R20)nOR11, (CR10R20)nS(O)mR18, (CR10R20)nNHS(O)2R18, (CR10R20)nNR13R14, (CR10R20)nNO2, (CR10R20)nCN, (CR10R20)nâ€²SO2R18, (CR10R20)nS(O)mâ€²NR13R14, (CR10R20)nC(Z)R11, (CR10R20)nOC(Z)R11, (CR10R20)nC(Z)OR11, (CR10R20)nC(Z)NR13R14, (CR10R20)nC(Z)NR11OR9, (CR10R20)nNR10C(Z)R11, (CR10R20)nNR10C(Z)NR13R14, (CR10R20)nN(OR6)C(Z)NR13R14, (CR10R20)nN(OR6)C(Z)R11, (CR10R20)nC(&boxH;NOR6)R11, (CR10R20)nNR10C(&boxH;NR19)NR13R14, (CR10R20)nOC(Z)NR13R14, (CR10R20)nNR10C(Z)NR13R14, (CR10R20)nNR10C(Z)OR10, 5-(R18)-1,2,4-oxadizaol-3-yl or 4-(R12)-5-(R18R19)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted; n is an integer having a value of 1 to 10; nâ€² is 0, or an integer having a value of 1 to 10; Z is oxygen or sulfur; Ra is C1-6alkyl, aryl, arylC1-6alkyl, heterocyclic, heterocyclylC1-6 alkyl, heteroaryl, or heteroarylC1-6alkyl, wherein each of these moieties may be optionally substituted; Rb is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclyl, or heterocyclylC1-4 alkyl; R3 is heterocyclyl, heterocyclylC1-10 alkyl or R8; R5 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties â€”SR5 being â€”SNR7R17 and â€”SOR5 being â€”SOH; R6 is hydrogen, a pharmaceutically acceptable cation, C1-10 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4 alkyl, heterocyclic, aroyl, or C1-10 alkanoyl; R7 and R17 is each independently selected from hydrogen or C1-4 alkyl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; R8 is C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10 alkyl, (CR10R20)nOR11, (CR10R20)nS(O)mR18, (CR10R20)nNHS(O)2R18, (CR10R20)nNR13R14; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted; R9 is hydrogen, â€”C(Z)R11 or optionally substituted C1-10 alkyl, S(O)2R18, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl; R10 and R20 is each independently selected from hydrogen or C1-4 alkyl; R11 is hydrogen, C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl C1-10alkyl, aryl, arylC1-10 alkyl, heteroaryl or heteroarylC1-10 alkyl; R12 is hydrogen or R16; R13 and R14 is each independently selected from hydrogen or optionally substituted C1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9; R15 is R10 or C(Z)-C1-4 alkyl; R16 is C1-4 alkyl, halo-substituted-C1-4 alkyl, or C3-7 cycloalkyl; R18 is C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C1-10alkyl, heteroaryl or heteroarylalkyl; R19 is hydrogen, cyano, C1-4 alkyl, C3-7 cycloalkyl or aryl; or a pharmaceutically acceptable salt thereof.