Patent ID: 6051574
Filing Date: 2000-04-18
Classification: C07D

Abstract:
A compound which inhibits farnesyl-protein transferase of the formula A: ##STR27## wherein: a is C;at least one of b, c, d and e is S, and the remaining b, c, d and e atoms are independently selected from CH, S, and O;of f(s) are independently N or N->O, and the remaining f's are CH; R.sup.1 and R.sup.2 are independently selected from:a) hydrogen,b) aryl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m -, R.sup.10 C(O)NR.sup.10 -, R.sup.11 C(O)O--, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)-, CN, NO.sub.2, R.sup.1 .degree. C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 -,c) unsubstituted or 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, heterocyclic, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m -, R.sup.10 C(O)NR.sup.10 -, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)-, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, and R.sup.11 OC(O)--NR.sup.10 -;R.sup.3, R.sup.4 and R.sup.5 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, halogen, C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.12 O--, R.sup.11 S(O).sub.m -, R.sup.10 C(O)NR.sup.10 -, (R.sup.10).sub.2 NC(O)--, R.sup.11 C(O)O--, R.sup.10.sub.2 N--C(NR.sup.10)-, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 -,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.12 O--, R.sup.11 S(O).sub.m -, R.sup.10 C(O)NR.sup.10 -, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)-, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, and R.sup.11 OC(O)--NR.sup.10 -;provided that when R.sup.3, R.sup.4 or R.sup.5 is unsubstituted or substituted heterocycle, attachment of R.sup.3, R.sup.4 or R.sup.5 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;R.sup.6a, R.sup.6b, R.sup.6c and R.sup.6d 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, halogen, C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.10 -, R.sup.11 S(O).sub.m -, R.sup.10 C(O)NR.sup.10 -, (R.sup.10).sub.2 NC(O)--, R.sup.11 C(O)O--, R.sup.10.sub.2 N--C(NR.sup.10)-, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 -,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.12 O--, R.sup.11 S(O).sub.m -, R.sup.10 C(O)NR.sup.10 -, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)-, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, and R.sup.11 OC(O)--NR.sup.10 -;R.sup.7 is selected from: H; C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:a) C.sub.1-4 alkoxy,b) aryl or heterocycle,c) halogen,d) HO, ##STR28## f) --SO.sub.2 R.sup.11 g) N(R.sup.10).sub.2 orh) C.sub.1-4 perfluoroalkyl;R.sup.8 is independently selected from:a) hydrogen,b) aryl, substituted 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.10 O--, R.sup.11 S(O).sub.m -, R.sup.10 C(O)NR.sup.10 -, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)-, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.11).sub.2, or R.sup.11 OC(O)NR.sup.10 -, andc) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cyanophenyl, 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.10 O--, R.sup.11 S(O).sub.m -, R.sup.10 C(O)NH--, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)-, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.10 OC(O)NH--;provided that when R.sup.8 is heterocycle, attachment of R.sup.8 to V is through a substitutable ring carbon;R.sup.9 is independently selected from:a) hydrogen,b) C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, Br, R.sup.11 O--, R.sup.11 S(O).sub.m -, R.sup.10 C(O)NR.sup.10 -, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)-, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 -, andc) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R .sup.10 O--, R.sup.11 S(O).sub.m -, R.sup.10 C(O)NR.sup.10 -, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)-, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 -;R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;R.sup.12 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 aralkyl, C.sub.1 -C.sub.6 substituted aralkyl, C.sub.1 -C.sub.6 heteroaralkyl, C.sub.1 -C.sub.6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C.sub.1 -C.sub.6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;A.sup.1 and A.sup.2 are independently selected from: a bond, --CH.dbd.CH--, --C.ident.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 ;V is aryl;W is imidazole;X is a bond, --CH.dbd.CH--, O, --C(.dbd.O)--, --C(O)NR.sup.7 -, --NR.sup.7 C(O)--, --C(O)O--, --OC(O)--, --C(O)NR.sup.7 C(O)--, --NR.sup.7 -, --S(O).sub.2 N(R.sup.10)-, --N(R.sup.10)S(O).sub.2 - or --S(.dbd.O).sub.m -;m is 0, 1 or 2;n is independently 0, 1, 2, 3 or 4;p is independently 0, 1, 2, 3 or 4;q is 0, 1,2or 3;r is 0 to 5, provided that r is 0 when V is hydrogen; andt is 0 or 1;or a pharmaceutically acceptable salt thereof.