Patent ID: 6103723
Filing Date: 2000-08-15
Classification: A61K,C07D

Abstract:
A compound which inhibits farnesyl-protein transferase of the formula A: ##STR37## wherein: R.sup.1a and R.sup.1b 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 --, CN(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 --,c) unsubstituted or substituted C.sub.1 -C.sub.6 alkyl wherein the substitutent 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)--, CN, (R.sup.10).sub.2 N--C(NR.sup.10)--, 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.2 and R.sup.3 are independently selected from: H, unsubstituted or substituted C.sub.1-8 alkyl, unsubstituted or substituted C.sub.2-8 alkenyl, unsubstituted or substituted C.sub.2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, ##STR38## wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with:a) C.sub.1-4 alkyl,b) (CH.sub.2).sub.p OR.sup.4,c) (CH.sub.2).sub.p NR.sup.4 R.sup.6,d) halogen,e) CN,2) C.sub.3-6 cycloalkyl,3) OR.sup.4,4) SR.sup.5, S(O)R.sup.5, SO.sub.2 R.sup.5,5) --NR.sup.4 R.sup.6, ##STR39## 15) N.sub.3, or 16) F;orR.sup.2 and R.sup.3 are attached to the same C atom and are combined to form --(CH.sub.2).sub.u -- wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O).sub.m, --NC(O)--, and --N(COR.sup.10)--;andR.sup.2 and R.sup.3 are optionally attached to the same carbon atom;R.sup.4 and R.sup.6 are independently 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,e) ##STR40## f) --SO.sub.2 R.sup.11, or g) N(R.sup.10).sub.2 ; orR.sup.4 and R.sup.6 may be joined in a ring;R.sup.5 is selected from: C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:a) C.sub.1-4 alkoxy,b) aryl or heterocycle,c) halogen,d) HOe) ##STR41## f) --SO.sub.2 R.sup.11, or g) N(R.sup.10).sub.2 ;R.sup.8 is 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, C.sub.1 -C.sub.6 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)--, (R10).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 aryl, cyanophenyl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, 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.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--;R.sup.9 is selected from:a) hydrogen,b) alkenyl, 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.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.14 alkyl, unsubstituted or substituted benzyl and unsubstituted or substituted aryl;R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and unsubstituted or substituted aryl;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.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 ;A.sup.3 is selected from:a) a bond,b) unsubstituted or substituted aryl, andc) unsubstituted or substituted heteroaryl;G.sup.1 and G.sup.2 are independently selected from: O or H.sub.2 ;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 ;W is a heterocycle;X is selected from a bond, --CH.sub.2 --, --C(.dbd.O)--, or --S(.dbd.O).sub.m ;Y is selected from: a bond, --CH.dbd.CH--, --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 ;Z is selected from:1) an unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of:a) C.sub.1-4 alkyl, unsubstituted or substituted with: C.sub.1-4 alkoxy, NR.sup.4 R.sup.6, C.sub.3-6 cycloalkyl, unsubstituted or substituted aryl, heterocycle, HO, --S(O).sub.m R.sup.5, or --C(O)NR.sup.4 R.sup.6,b) aryl or heterocycle,c) halogen,d) OR.sup.4,e) NR.sup.4 R.sup.6,f) CN,g) NO.sub.2,h) CF.sub.3,i) --S(O).sub.m R.sup.5,j) --C(O)NR.sup.4 R.sup.6, ork) C.sub.3 -C.sub.6 cycloalkyl; or2) an unsubstituted or substituted group selected from the group consisting of C.sub.1 -C.sub.6 alkyl and C.sub.3 -C.sub.6 cycloalkyl, wherein the substituted group is substituted with one or two of the following:a) C.sub.1-4 alkoxy,b) NR.sup.4 R.sup.6,c) C.sub.3-6 cycloalkyld) --NR.sup.4 C(O)R.sup.6,e) HO,f) --S(O).sub.m R.sup.5,g) halogen, orh) perfluoroalkyl;m is 0, 1 or 2;n is 0, 1, 2, 3 or 4;p is 0, 1, 2, 3 or 4;q is 1 or 2;r is 0, 1, 2, 3, 4 or 5; provided that r is 0 when V is hydrogen;t is 0 or 1; andu is 4 or 5;or the pharmaceutically acceptable salts thereof.