Patent ID: 6015817
Filing Date: 2000-01-18
Classification: C07D

Abstract:
A compound which inhibits farnesyl-protein transferase of the formula I: ##STR44## wherein: R.sup.1a, R.sup.1b and R.sup.1c are independently selected from:a) hydrogen,b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --,c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocyclic, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)--NR.sup.8 --,provided that R.sup.1a is not unsubstituted or substituted imidazolyl;R.sup.2a, R.sup.2b ' and R.sup.2b "" are independently hydrogen or --(CR.sup.11.sub.2).sub.v A.sup.3 (CR.sup.12.sub.2).sub.w R.sup.13 ; orR.sup.2b ' and R.sup.2b "" are combined as O;R.sup.3a and R.sup.3b are independently selected from:a) hydrogen,b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C.sub.3 -C.sub.10 cycloalkyl, unsubstituted or substituted C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, halogen, C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.9 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, (R.sup.8).sub.2 NC(O)--, R.sup.9 C(O)O--, R.sup.8.sub.2 N--C(NR.sup.8)--, CN, NO.sub.2, R.sup.8 C(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --,c) unsubstituted C.sub.1 -C.sub.6 alkyl,d) substituted C.sub.1 -C.sub.6 alkyl wherein the substituent on the substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.9 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, (R.sup.8).sub.2 NC(O)--, R.sup.8.sub.2 N--C(NR.sup.8)--, CN, R.sup.8 C(O)--, N.sub.3, --N(R.sup.8).sub.2, and R.sup.9 OC(O)--NR.sup.8 --;R.sup.4 is independently selected from:a) hydrogen,b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, R.sup.8.sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --, andc) C.sub.1 -C.sub.6 alkyl urisubstituted or substituted by aryl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NH--, CN, H.sub.2 N--C(NH)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.8 OC(O)NH--,provided that R.sup.4 is not unsubstituted or substituted imidazolyl;R.sup.5 is independently selected from:a) hydrogen,b) C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8).sub.2 N--C--(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --, andc) C.sub.1 -C.sub.6 alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --;R.sup.8 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;R.sup.9 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;R.sup.10 is selected from: H; R.sup.8 C(O)--; R.sup.9 S(O).sub.m --; unsubstituted or substituted C.sub.1-4 alkyl, unsubstituted or substituted C.sub.1-6 cycloalkyl, unsubstituted or substituted heterocycle, unsubstituted or substituted aryl, substituted aroyl, unsubstituted or substituted heteroaroyl, substituted arylsulfonyl, unsubstituted or substituted heteroarylsulfonyl, wherein the substituted group is substituted with one or two substituents selected from:a) C.sub.1-4, alkoxy,b) aryl or heterocycle,c) halogen,d) HO, ##STR45## h) N(R.sup.8).sub.2, or i) C.sub.3-6 cycloalkyl;R.sup.11 and R.sup.12 are independently selected from:a) hydrogen,b) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by C.sub.2 -C.sub.20 alkenyl, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, N.sub.3, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --,c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.20 alkenyl, halogen, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --, andd) C.sub.1 -C.sub.6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C.sub.3 -C.sub.10 cycloalkyl;R.sup.13 is selected from:a) hydrogen,b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl, C.sub.1 -C.sub.20 perfluoroalkyl, allyloxy, F, Cl, Br, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, R.sup.8.sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, N.sub.3, --N(R.sup.8).sub.2, (R.sup.9).sub.2 NC(O)-- or R.sup.9 OC(O)NR.sup.8 --, andc) C.sub.1 -C.sub.6 alkyl urisubstituted or substituted by substituted or unsubstituted aryl, substituted or tnsubstituted heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl, C.sub.2 -C.sub.20 perfluoroalkyl, F, Cl, Br, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NH--, CN, H.sub.2 N--C(NH)--, R.sup.8 C(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NH--;A.sup.1 and A.sup.2 are independently selected from: a bond, --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(O)NR.sup.8 --, --NR.sup.8 C(O)--, O, --N(R.sup.8)--, --S(O).sub.2 N(R.sup.8)--, --N(R.sup.8)S(O).sub.2 --, or --S(O).sub.m ;A.sup.3 are independently selected from: a bond, --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(O)NR.sup.10 --, --NR.sup.10 C(O)--, O, --N(R.sup.10)--, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 --, or --S(O).sub.m ;J-K-L represents CH.dbd.CH--S;V is selected from:a) hydrogen,b) heterocycle,c) aryl,d) C.sub.1 -C.sub.20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, ande) C.sub.2 -C.sub.20 alkenyl,provided that V is not hydrogen if A.sup.1 is --S(O).sub.m and V is not hydrogen if A.sup.1 is a bond, n is 0 and A.sup.2 is --S(O).sub.m ;and provided that V is not imidazolyl;W is imidazolyl;X is a bond, --S(O).sub.m --, O or --C(.dbd.O)--;m is 0, 1 or 2;n is 0, 1, 2, 3 or 4;p is 0, 1, 2, 3 or 4;q is 0, 1, 2, 3 or 4, provided that q is not 0 or 1 if X is O;r is 0 to 5, provided that r is 0 when V is hydrogen;s is 1 or 2;t is 1;u is independently 0,1 or 2; provided that the sum of the u variables is equal to 2;v is 0, 1, 2, 3 or 4, provided that v is not 0 when A.sup.3 is --NR.sup.10 C(O)--, O, --N(R.sup.10)--, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 --, or S(O).sub.m ;w is 0, 1, 2, 3 or 4; andthe dashed lines represent optional double bonds;or an optical isomer or a pharmiaceutically acceptable salt thereof.