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US 5,965,578 AGranted
Inhibitors of farnesyl-protein transferase
AssigneeMerck & Co., Inc.
InventorsSamuel L. Graham, Theresa M. Williams, John S. Wai
Life of this patent
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Abstract
The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
Claims20
A compound which inhibits farnesyl-protein transferase of the formula A:
- ##STR64## wherein:
- R.sup.1a and R.sup.1b are independently selected from:
- a) hydrogen,
- b) aryl, 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 N--C(O)--, CN, NO.sub.2, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
- 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, 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 N--C(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 -C.sub.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 ##STR65## wherein the substituted group is substituted with one or more of:
- 1) aryl or unsubstituted or substituted with:
- a) C.sub.1-4 alkyl,
- b) (CH.sub.2).sub.p OR.sup.6,
- c) (CH.sub.2).sub.p NR.sup.6 R.sup.7,
- d) halogen,
- e) CN,
- f) aryl,
- g) perfluoro-C.sub.1-4 alkyl,
- h) SR.sup.6a, S(O)R.sup.6a, SO.sub.2 R.sup.6a,
- 2) C.sub.3-6 cycloalkyl,
- 3) OR.sup.6,
- 4) SR.sup.6a, S(O)R.sup.6a, or SO.sub.2 R.sup.6a,
- 5) --N R.sup.6 R.sup.7,
- 6) ##STR66## 7) ##STR67## 8) ##STR68## 9) ##STR69## 10) ##STR70## 11) --SO.sub.2 --NR.sup.6 R.sup.7, 12) ##STR71## 13) ##STR72## 14) ##STR73## 15) N.sub.3, 16) F, or
- 17) perfluoro-C.sub.1-4 -alkyl;
- or
- R.sup.2 and R.sup.3 are attached to the same C atom and are combined to form --(CH.sub.2).sub.u --;
- R.sup.4 and R.sup.5 are independently selected from H and CH.sub.3 ;
- and any two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are optionally attached to the same carbon atom;
- R.sup.6, R.sup.7 and R.sup.7a are independently selected from:
- H;
- C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, aryl, aroyl, and arylsulfonyl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) aryl,
- c) halogen,
- d) HO,
- e) ##STR74## f) --SO.sub.2 R.sup.11, or g) N(R.sup.10).sub.2 ;
- or
- R.sup.6a is selected from:
- C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl and aryl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) aryl,
- c) halogen,
- d) HO,
- e) ##STR75## 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, 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.10).sub.2, or R.sup.11 OC(O)NH--, and
- c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cyanophenyl, 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--;
- R.sup.9 is selected from:
- a) hydrogen,
- b) 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.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
- c) 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 and aryl;
- R.sup.11 is independently selected from C.sub.1-C.sub.6 alkyl and 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 -- and S(O).sub.m ;
- G.sup.1 and G.sup.2 are independently oxygen or absent, provided that at least one of G.sup.1 and G.sup.2 is oxygen;
- G.sup.3 is oxygen or H.sub.2 ;
- V is selected from:
- a) hydrogen,
- b) aryl,
- c) 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, and
- d) 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 imidazolyl or pyridyl;
- X is a bond, --CH.sub.2 --, --C(.dbd.O)--, or --S(.dbd.O).sub.m --;
- Y is unsubstituted or substituted aryl, wherein the substituted aryl is substituted with one or more of:
- 1) C.sub.1-4 alkyl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) NR.sup.6 R.sup.7,
- c) C.sub.3-6 cycloalkyl,
- d) aryl,
- e) HO,
- f) --S(O).sub.m R.sup.6a, or
- g) --C(O)NR.sup.6 R.sup.7,
- 2) aryl,
- 3) halogen,
- 4) OR.sup.6,
- 5) NR.sup.6 R.sup.7,
- 6) CN,
- 7) NO.sub.2,
- 8) CF.sub.3 ;
- 9) --S(O).sub.m R.sup.6a,
- 10) --C(O)NR.sup.6 R.sup.7, or
- 11) C.sub.3 -C.sub.6 cycloalkyl;
- 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 to 5, provided that r is 0 when V is hydrogen;
- s is 0;
- t is 0 or 1;
- and
- u is 4 or 5;
- or an optical isomer or pharmaceutically acceptable salt thereof.
90 more elements
A compound which inhibits farnesyl-protein transferase of the formula B:
- ##STR76## wherein:
- R.sup.1a and R.sup.1b are independently selected from:
- a) hydrogen,
- b) aryl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10)--, 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 --, and
- 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, 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.2 and R.sup.3 are independently selected from:
- H;
- unsubstituted or substituted C.sub.1 -C.sub.8 alkyl, unsubstituted or substituted C.sub.2 -.sub.8 alkenyl, unsubstituted or substituted C.sub.2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted ##STR77## wherein the substituted group is substituted with one or more of:
- 1) aryl, unsubstituted or substituted with:
- a) C.sub.1-4 alkyl,
- b) (CH.sub.2).sub.p OR.sup.6,
- c) (CH.sub.2).sub.p NR.sup.6 R.sup.7,
- d) halogen,
- e) CN,
- f) aryl,
- g) perfluoro-C.sub.1-4 alkyl,
- h) SR.sup.6a, S(O)R.sup.6a, S(O)R.sup.6a,
- 2) C.sub.3-6 cycloalkyl,
- 3) OR.sup.6,
- 4) SR.sup.6a, S(O)R.sup.6a, or SO.sub.2 R.sup.6a,
- 5) --NR.sup.6 R.sup.7,
- 6) ##STR78## 7) ##STR79## 8) ##STR80## 9) ##STR81## 10) ##STR82## 11)--SO.sub.2 --NR.sup.6 R.sup.7, 12) ##STR83## 13) ##STR84## 14) ##STR85## 15) N.sub.3, 16) F, or
- 17) perfluoro-C.sub.1-4 -alkyl;
- or
- R.sup.2 and R.sup.3 are attached to the same C atom and are combined to form --(CH.sub.2).sub.u --;
- R.sup.4 is selected from H and CH.sub.3 ;
- and any two of R.sup.2, R.sup.3 and R.sup.4 are optionally attached to the same carbon atom;
- R.sup.6, R.sup.7 and R.sup.7a are independently selected from:
- H;
- C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, aryl, aroyl and arylsulfonyl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) aryl,
- c) halogen,
- d) HO,
- e) ##STR86## f) --SO.sub.2 R.sup.11, or g) N(R.sup.10).sub.2 ;
- or
- R.sup.6a is selected from:
- C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl and aryl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) aryl,
- c) halogen,
- d) HO,
- e) ##STR87## 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, 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.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
- c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cyanophenyl, 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 O C(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 --, and
- c) 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 and aryl;
- R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and 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 -- and S(O).sub.m ;
- G.sup.1 and G.sup.2 are independently oxygen or absent provided that at least one of G.sup.1 and G2 is oxygen;
- V is selected from:
- a) hydrogen,
- b) aryl,
- c) 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, and
- d) 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 imidazolyl or pyridyl;
- X is a bond, --CH.sub.2 --, --C(.dbd.O)--, or --S(.dbd.O).sub.m --;
- Z is selected from:
- 1) a unsubstituted or substituted group selected from aryl, arylmethyl, and arylsulfonyl, wherein the substituted group is substituted with one or more of the following:
- a) C.sub.1-4 alkyl, unsubstituted or substituted with:
- C.sub.1-4 alkoxy, NR.sup.6 R.sup.7, C.sub.3-6 cycloalkyl, aryl, HO, --S(O).sub.m R.sup.6a, or --C(O)NR.sup.6 R.sup.7,
- b) aryl,
- c) halogen,
- d) OR.sup.6,
- e) NR.sup.6 R.sup.7,
- f) CN,
- g) NO.sub.2,
- h) CF.sub.3 ;
- i) --S(O).sub.m R.sup.6a,
- j) --C(O)NR.sup.6 R.sup.7, or
- k) C.sub.3 -C.sub.6 cycloalkyl;
- and
- 2) unsubstituted C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, unsubstituted C.sub.3 -C.sub.6 cycloalkyl or substituted C.sub.3 -C.sub.6 cycloalkyl, wherein the substituted C.sub.1 -C.sub.6 alkyl and substituted C.sub.3 -C.sub.6 cycloalkyl is substituted with one or two of the following:
- a) C.sub.1-4 alkoxy,
- b) NR.sup.6 R.sup.7,
- c) C.sub.3-6 cycloalkyl,
- d) --NR.sup.6 C(O)R.sup.7,
- e) HO,
- f) --S(O).sub.m R.sup.6a,
- g) halogen, or
- h) 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 to 5, provided that r is 0 when V is hydrogen;
- s is 0;
- t is 0 or 1;
- and
- u is 4 or 5;
- or a pharmaceutically acceptable salt thereof.
94 more elements
A compound which inhibits farnesyl-protein transferase of the formula C:
- ##STR88## wherein:
- R.sup.1a and R.sup.1b are independently selected from:
- a) hydrogen,
- b) aryl, 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, NO.sub.2, R.sup.10 C(O)--, R.sup.10 OC(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
- 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, 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)--, R.sup.10 OC(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 -C.sub.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 ##STR89## wherein the substituted group is substituted with one or more of:
- 1) aryl, unsubstituted or substituted with:
- a) C.sub.1-4 alkyl,
- b) (CH.sub.2).sub.p OR.sup.6,
- c) (CH.sub.2).sub.p NR.sup.6 R.sup.7,
- d) halogen,
- e) CN,
- f) aryl,
- g) perfluoro-C.sub.1-4 alkyl,
- h) SR.sup.6a, S(O)R.sup.6a, SO.sub.2 R.sup.6a,
- 2) C.sub.3-6 cycloalkyl,
- 3) OR.sup.6,
- 4) SR.sup.6a, S(O)R.sup.6a, or SO.sub.2 R.sup.6a,
- 5) --NR.sup.6 R.sup.7,
- 6) ##STR90## 7) ##STR91## 8) ##STR92## 9) ##STR93## 10) ##STR94## 11) --SO.sub.2 --NR.sup.6 R.sup.7, 12) ##STR95## 13) ##STR96## 14) ##STR97## 15) N.sub.3, 16) F, or
- 17) perfluoro-C.sub.1-4 -alkyl;
- or
- R.sup.2 and R.sup.3 are attached to the same C atom and are combined to form --(CH.sub.2).sub.u --;
- R.sup.4 is selected from H and CH.sub.3 ;
- and any two of R.sup.2, R.sup.3 and R.sup.4 are optionally attached to the same carbon atom;
- R.sup.6, R.sup.7 and R.sup.7a are independently selected from:
- H;
- C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, aryl, aroyl and arylsulfonyl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) aryl,
- c) halogen,
- d) HO,
- e) ##STR98## f) --SO.sub.2 R.sup.11, or g) N(R.sup.10).sub.2 ;
- or
- R.sup.6a is selected from:
- C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl and aryl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) aryl,
- c) halogen,
- d) HO,
- e) ##STR99## 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, 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.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
- c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cyanophenyl, 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--;
- R.sup.9 is selected from:
- a) hydrogen,
- b) 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.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
- c) 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)NR10--;
- R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, benzyl and aryl;
- R.sub.11 is independently selected from C.sub.1 -C.sub.6 alkyl and 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 -- and S(O).sub.m ;
- G.sup.1 and G.sup.2 are independently oxygen or absent, provided that if G.sup.1 is oxygen then G.sup.2 is absent and if s=0, G.sup.1 is oxygen;
- V is selected from:
- a) hydrogen,
- b) aryl,
- c) 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, and
- d) 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 imidazolyl or pyridyl;
- X is a bond, --CH.sub.2 --, --C(.dbd.O)--, or --S(.dbd.O).sub.m --;
- Z is selected from:
- 1) a unsubstituted or substituted group selected from aryl, arylmethyl, and arylsulfonyl, wherein the substituted group is substituted with one or more of the following:
- a) C.sub.1-4 alkyl, unsubstituted or substituted with:
- C.sub.1-4 alkoxy, NR.sup.6 R.sup.7, C.sub.3-6 cycloalkyl, aryl, HO, --S(O).sub.m R.sup.6a, or --C(O)NR.sup.6 R.sup.7,
- b) aryl,
- c) halogen,
- d) OR.sup.6,
- e) NR.sup.6 R.sup.7,
- f) CN,
- g) NO.sub.2,
- h) CF.sub.3 ;
- i) --S(O).sub.m R.sup.6a,
- j) --C(O)NR.sup.6 R.sup.7, or
- k) C.sub.3 -C.sub.6 cycloalkyl;
- and
- 2) unsubstituted C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, unsubstituted C.sub.3 -C.sub.6 cycloalkyl or substituted C.sub.3 -C.sub.6 cycloalkyl, wherein the substituted C.sub.1 -C.sub.6 alkyl and substituted C.sub.3 -C.sub.6 cycloalkyl is substituted with one or two of the following:
- a) C.sub.1-4 alkoxy,
- b) NR.sup.6 R.sup.7,
- c) C.sub.3-6 cycloalkyl,
- d) --NR.sup.6 C(O)R.sup.7,
- e) HO,
- f) --S(O).sub.m R.sup.6a,
- g) halogen, or
- h) 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 to 5, provided that r is 0 when V is hydrogen;
- s is 0;
- t is 0 or 1;
- and
- u is 4 or 5;
- or a pharmaceutically acceptable salt thereof.
94 more elements
A compound which inhibits farnesyl-protein transferase which is:
- 4-[5-(4-Cyanobenzyl)imidazol-1-ylmethyl]-1-phenyl-2-piperidinone
- 4-[2-{5-(4-Cyanobenzyl)imidazol-1-yl}ethyl]-1-phenyl-2-piperidinone
- 4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}ethyl]-1-phenyl-2-piperidinone
- (.+-.)cis-4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}ethyl]-3-methyl-1-phenyl-2-p iperidinone
- (.+-.)trans-4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}ethyl]-3-methyl-1-phenyl-2 -piperidinone
- 4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}carbonyl]-1-phenyl-2-piperidinone or
- Ethyl 1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-oxo-4-(3-methylbenzyl)piper idine-4-carboxylate or a pharmaceutically acceptable salt or optical isomer thereof.
4 more elements
Dependencies are inferred from the claim text.