Patent ID: 6528512
Filing Date: 2003-03-04
Classification: A61K,A61P,C07D,Y02A

Abstract:
A method of treating a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (III) wherein:R1 is 4-pyridyl, 4-pyrimidinyl, 4-quinazolinyl, 4-quinolyl, or 6-isoquinolinyl ring, which ring is optionally substituted with one or two substituents, each of which is independently selected from Y, NHRa, optionally substituted C1-4 alkyl, halogen, hydroxyl, optionally substituted C1-4 alkoxy, optionally substituted C1-4 alkylthio, C1-4 alkylsulfinyl, CH2OR12, amino, mono and di-C1-6 alkyl substituted amino, or N(R10)C(O)Rb; Y is X1â€”Ra; X1 is oxygen or sulfur; Ra is C1-6alkyl, aryl, arylC1-6alkyl, heterocyclic, heterocyclylC1-6 alkyl, heteroaryl, 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, wherein each of these moieties may be optionally substituted; R2 is an optionally substituted aryl or optionally substituted heteroaryl group, provided that both R1 and R2 are not the same heteroaryl group; wherein when one R2 is an optionally substituted aryl ring, the ring is substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl or 5-naphth-2-yl substituent, is halo, cyano, C(Z)NR13R14, C(Z)OR23, (CR10R20)n COR36, SR15, S(O)R15, OR36, halo-substituted-C1-4 alkyl, C1-4 alkyl, ZC(Z)R36, NR10C(Z)R23, or (CR10R20)n NR10R20 and which, for other positions of substitution, is halo, cyano, C(Z)NR16R26, C(Z)OR8, (CR10R20)n COR8, S(O)mR8, OR8, halo-substituted-C1-4 alkyl, C1-4 alkyl, (CR10R20)nNR10C(Z)R8, NHS(O)mR7, NHS(O)mNR13R14, NR7S(O)mR7, NR7S(O)mâ€²NR13R14, ZC(Z)R8 or (CR10R20)n NR16R26; and when R2 is an optionally substituted heteroaryl group, the substituent groups include one or two substituents each of which is independently selected from C1-4 alkyl, halo, C1-4 alkoxy, C1-4 alkylthio, NR10R20, or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR12; m is 0 or an integer of 1 or 2; mâ€² is an integer of 1 or 2; mâ€³ is an integer having a value of 1 to 10; n is 0 or an integer of 1 or 2; nâ€² is 0 or an integer having a value of 1 to 10; nâ€³ is an integer having a value of 1 to 10 R3 is hydrogen, C1-10 alkyl, halosubstituted C1-10 alkyl, (CR10R20)nâ€²Q-(Y1)t, (CR10R20)nâ€²(Y2)p, (CR10R20)nâ€³(Y3)p, or (CR10R20)mâ€³(Y4)p; p is 0 or an integer of 1 or 2; t is an integer of 1, 2, or 3; Q is an aryl or heteroaryl group; Y1 is independently selected from hydrogen, halogen, C1-5 alkyl, halo-substituted C1-5 alkyl, (CR10R20)nâ€²(Y2)p, (CR10R20)nâ€³(Y3)p, or (CR10R20)mâ€³(Y4)p; Y2 is halogen, OR8, S(O)mâ€²R18, SR8, S(O)mâ€²OR8, S(O)mNR8R9, or O(CR10R20)nNR8R9, ZC(O)R8, or OC(Z)NR8R9; Y3 is NR8R9, NR10C(Z)R8, NR10C(Z)NR8R9, NR10S(O)mR18, N(OR21)C(Z)NR8R9, N(OR21)C(Z)R8, NR10C(&boxH;NR11)SR18, NR10C(&boxH;NR11)NR8R9, NR10C(&boxH;CR14R24)SR18, NR10C(&boxH;C(R24)2)NR8R9, NR10C(O)C(O)NR8R9, NR10C(O)C(O)OR10, NR10S(O)mCF3, or NR10C(Z)OR10O; Y4 is C(O)R8, CO2R8, CO2(CR10R20)mâ€³CONR8R9, CN, C(Z)NR8R9, C(Z)NR8OR9, C(&boxH;NOR21)R8, C(&boxH;NR19)NR8R9, C(&boxH;NOR19)NR8R9, C(&boxH;NR19)ZR18, NR10S(O)mCF3, or NR10OC(Z)OR10O; R4 is hydrogen, NR5R6, NHS(O)2R7, NR10C(Z)R8, NR10C(Z)NR5R6, NR10C(&boxH;NR11)NR5R6, or NR10C(Z)OR10; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl moieties of R7, and R8 may be optionally substituted; R5 and R6 are 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 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 NR17; Z is oxygen or sulfur; R7 is C1-10 alkyl, C3-7 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C1-10alkyl, heteroaryl or heteroarylalkyl; R8 is hydrogen, C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl C1-10alkyl, aryl, arylC1-10 alkyl, heteroaryl or heteroarylC1-10 alkyl; R9 is hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or R8 and R9 may 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 NR17; R10 and R20 is each independently selected from hydrogen or C1-4 alkyl; R11 is hydrogen, cyano, C1-4 alkyl, C3-7 cycloalkyl or aryl; R12 is R10 or C(Z)â€”C1-4 alkyl; R13 and R14 is each independently selected from hydrogen or C1-4 alkyl or R13 and R14 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 NR22; R15 is hydrogen, C1-4 aikyl, C2-4 alkenyl, C2-4 alkynyl or NR13R14, provided that the moiety SR15 is not SNR13R14and the moiety S(O)R15 is not â€”SOH; R16 and R26 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 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 NR17; R17 is hydrogen, C(Z)R8 or optionally substituted C1-10 alkyl, S(O)2R7, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl; R18 is C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R19 is hydrogen, C1-10 alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R21 is hydrogen, a pharmaceutically acceptable cation, C1-10 alkyl, C3-7 cycloalkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or C1-10 alkanoyl; R22 is R10 or C(Z)â€”C1-4 alkyl; R23 is C1-4 alkyl, halo-substituted-C1-4 alkyl, or C3-5 cycloalkyl; R24 is independently selected from hydrogen, alkyl, nitro or cyano; R36 is hydrogen or R23; provided that R3 and R4 are not both hydrogen; or a pharmaceutically acceptable salt thereof.