Patent ID: 6218537
Filing Date: 2001-04-17
Classification: A61P,C07D

Abstract:
A process for preparing a compound of Formula (A) ##STR19##whereinR.sub.1 is 4-pyridyl, pyrimidinyl, quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl, which heteroaryl ring is substituted with NHR.sub.a and optionally with an additional independent substituent selected from C.sub.1-4 alkyl, halogen, hydroxyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfinyl, CH.sub.2 OR.sub.12, amino, mono and di-C.sub.1-6 alkyl substituted amino, N(R.sub.10)C(O)R.sub.b or NHR.sub.a ;R.sub.a is C.sub.1-6 alkyl substituted one or more times, independently by halogen; hydroxy; C.sub.1-10 alkoxy; S(O)m alkyl, amino, mono & di-C.sub.1-4 alkyl substituted amino; C.sub.3-7 cycloalkyl; C.sub.3-7 cycloalkyloxy; or a moiety having the formula A.sub.1 --B.sub.1 --D.sub.1 :wherein A.sub.1 is CR.sub.10 R.sub.20, oxygen, sulfur, or NR.sub.10 R.sub.20 ;B.sub.1 is C(O) or S(O).sub.2 ;D.sub.1 is E.sub.1 or E.sub.2 ; E.sub.1 is C.sub.1-10 alkyl, aryl, aryl C.sub.1-6 alkyl, heteroaryl, heteroaryl C.sub.2-6 alkenyl, heterocyclic, or heterocyclic C.sub.1-6 alkyl; and E.sub.2 is O--E.sub.1 or N--E.sub.1 ;R.sub.b is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, aryl, arylC.sub.1-4 alkyl, heteroaryl, heteroarylC.sub.1-4 alkyl, heterocyclyl, or heterocyclylC.sub.1-4 alkyl;R.sub.4 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)NR.sub.7 R.sub.17, C(Z)OR.sub.16, (CR.sub.10 R.sub.20).sub.v COR.sub.12, SR.sub.5, SOR.sub.5, OR.sub.12, halo-substituted-C.sub.1-4 alkyl, C.sub.1-4 alkyl, ZC(Z)R.sub.12, NR.sub.10 C(Z)R.sub.16, or (CR.sub.10 R.sub.20).sub.v NR.sub.10 R.sub.20 and which, for other positions of substitution, is halogen, cyano, C(Z)NR.sub.13 R.sub.14, C(Z)OR.sub.3, (CR.sub.10 R.sub.20).sub.m"" COR.sub.3, S(O).sub.m R.sub.3, OR.sub.3, halo-substituted-C.sub.1-4 alkyl, C.sub.1-4 alkyl, (CR.sub.10 R.sub.20).sub.m"" NR.sub.10 C(Z)R.sub.3, NR.sub.10 S(O).sub.m' R.sub.8, NR.sub.10 S(O).sub.m' NR.sub.7 R.sub.17, ZC(Z)R.sub.3 or (CR.sub.10 R.sub.20).sub.m"" NR.sub.13 R.sub.14;v is 0, or an integer having a value of 1 or 2;m is 0, or the integer 1 or 2;m' is an integer having a value of 1 or 2,m"" is 0, or an integer having a value of 1 to 5;R.sub.2 is C.sub.1-10 alkyl N.sub.3, --(CR.sub.10 R.sub.20).sub.n' OR.sub.9, heterocyclyl, heterocyclylC.sub.1-10 alkyl, C.sub.1-10 alkyl, halo-substituted C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-10 alkyl, C.sub.5-7 cycloalkenyl, C.sub.5-7 cycloalkenyl-C.sub.1-10 -alkyl, aryl, arylC.sub.1-10 alkyl, heteroaryl, heteroaryl-C.sub.1-10 -alkyl, (CR.sub.10 R.sub.20).sub.n OR.sub.11, (CR.sub.10 R.sub.20).sub.n S(O).sub.m R.sub.18, (CR.sub.10 R.sub.20).sub.n NHS(O).sub.2 R.sub.18, (CR.sub.10 R.sub.20).sub.n NR.sub.13 R.sub.14, (CR.sub.10 R.sub.20).sub.n NO.sub.2, (CR.sub.10 R.sub.20).sub.n CN, (CR.sub.10 R.sub.20).sub.n' SO.sub.2 R.sub.18, (CR.sub.10 R.sub.20).sub.n S(O).sub.m' NR.sub.13 R.sub.14, (CR.sub.10 R.sub.20).sub.n C(Z)R.sub.11, (CR.sub.10 R.sub.20).sub.n OC(Z)R.sub.11, (CR.sub.10 R.sub.20).sub.n C(Z)OR.sub.11, (CR.sub.10 R.sub.20).sub.n C(Z)NR.sub.13 R.sub.14, (CR.sub.10 R.sub.20).sub.n C(Z)NR.sub.11 OR.sub.9, (CR.sub.10 R.sub.20).sub.n NR.sub.10 C(Z)R.sub.11, (CR.sub.10 R.sub.20).sub.n NR.sub.10 C(Z)NR.sub.13 R.sub.14, (CR.sub.10 R.sub.20).sub.n N(OR.sub.6)C(Z)NR.sub.13 R.sub.14, (CR.sub.10 R.sub.20).sub.n N(OR.sub.6)C(Z)R.sub.11, (CR.sub.10 R.sub.20).sub.n C(.dbd.NOR.sub.6)R.sub.11, (CR.sub.10 R.sub.20).sub.n NR.sub.10 C(.dbd.NR.sub.19)NR.sub.13 R.sub.14, (CR.sub.10 R.sub.20).sub.n OC(Z)NR.sub.13 R.sub.14, (CR.sub.10 R.sub.20).sub.n NR.sub.10 C(Z)NR.sub.13 R.sub.14, (CR.sub.10 R.sub.20).sub.n NR.sub.10 C(Z)OR.sub.10, 5-(R.sub.18)-1,2,4-oxadizaol-3-yl or 4-(R.sub.12)-5-(R.sub.18 R.sub.19)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, cycloalkyl, cycloalkylalkyl, heterocyclic and heterocyclic alkyl groups are unsubstituted or substituted;n is an integer having a value of 1 to 10;n' is 0, or an integer having a value of 1 to 10;Z is oxygen or sulfur;R.sub.3 is heterocyclyl, heterocyclylC.sub.1-10 alkyl or R.sub.8;R.sub.5 is hydrogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl or NR.sub.7 R.sub.17, excluding the moieties SR.sub.5 being SNR.sub.7 R.sub.17 and SOR.sub.5 being SOH;R.sub.6 is hydrogen, a pharmaceutically acceptable cation, C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, aryl, arylC.sub.1-4 alkyl, heteroaryl, heteroarylC.sub.1-4 alkyl, heterocyclic, aroyl, or C.sub.1-10 alkanoyl;R.sub.7 and R.sub.17 is each independently selected from hydrogen or C.sub.1-4 alkyl or R.sub.7 and R.sub.17 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 NR.sub.15 ;R.sub.8 is C.sub.1-10 alkyl, halo-substituted C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7 cycloalkenyl, aryl, arylC.sub.1-10 alkyl, heteroaryl, heteroarylC.sub.1-10 alkyl, (CR.sub.10 R.sub.20).sub.n OR.sub.11, (CR.sub.10 R.sub.20).sub.n S(O).sub.m R.sub.18, (CR.sub.10 R.sub.20).sub.n NHS(O).sub.2 R.sub.18, (CR.sub.10 R.sub.20).sub.n NR.sub.13 R.sub.14 ; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl are unsubstituted or substituted;R.sub.9 is hydrogen, --C(Z)R.sub.11 or optionally substituted C.sub.1-10 alkyl, S(O).sub.2 R.sub.18, unsubstituted or substituted aryl, unsubstituted or substituted aryl-C.sub.1-4 alkyl;R.sub.10 and R.sub.20 is each independently selected from hydrogen or C.sub.1-4 alkyl;R.sub.11 is hydrogen, C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, heterocyclyl, heterocyclyl C.sub.1-10 alkyl, aryl, arylC.sub.1-10 alkyl, heteroaryl or heteroarylC.sub.1-10 alkyl;R.sub.12 is hydrogen or R.sub.16 ;R.sub.13 and R.sub.14 is each independently selected from hydrogen, unsubstituted or substituted C.sub.1-4 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-C.sub.1-4 alkyl, or R.sub.13 and R.sub.14 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 NR.sub.9 ;R.sub.15 is R.sub.10 or C(Z)--C.sub.1-4 alkyl;R.sub.16 is C.sub.1-4 alkyl, halo-substituted-C.sub.1-4 alkyl, or C.sub.3-7 cycloalkyl;R.sub.18 is C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C.sub.1-10 alkyl, heteroaryl or heteroarylalkyl;R.sub.19 is hydrogen, cyano, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or aryl;or a pharmaceutically acceptable salt thereof;which process comprises reacting a compound of the Formula (II): ##STR20##with a compound of the Formula (III): ##STR21##wherein p is 0 or 2; and a base strong enough to deprotonate the isonitrile moiety of Formula (II); and R.sub.1, R.sub.2 and R.sub.4 are as defined above or are precursors of the groups R.sub.1, R.sub.2 and R.sub.4 and Ar is an optionally substituted phenyl napthyl or heteroaryl group, and thereafter if necessary, converting a precursor of R.sub.1, R.sub.2 and R.sub.4 to a group R.sub.1, R.sub.2 and R.sub.4.