Inhibitors of farnesyl-protein transferase

• US 6,127,366 A
• Filed: 10/05/1998
• Issued: 10/03/2000
• Est. Priority Date: 11/22/1995
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Kim, Byeong M., Graham, Samuel L., Shaw, Anthony W., deSolms, S. Jane, Ciccarone, Terrence M.
• Primary Examiner(s): FAN, JANE T
• Application Number:
  US09/166,271
• Time in Patent Office: 729 Days
• Field of Search: 514/235.5, 544/130
• US Class Current: 514/235.5
• CPC Class Codes: C07D 233/24 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

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 famesylation of the oncogene protein Ras.

Claims

1. A compound which inhibits farnesyl-protein transferase of the formula A:

##STR65## wherein;

R^1a, R^1b and R^1c are independently selected from;

a) hydrogen,

b) unsubstituted or substituted aryl, C₃ -C₁₀ cycloalkyl, F, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R⁸ O--, R⁹ S(O)_m --, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --,

c) C₁ -C₆ alkyl unsubstituted or substituted by unsubstituted or substituted aryl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R⁸ O--, R⁹ S(O)_m --, R⁸ C(O)NR⁸ --, CN, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, --N(R⁸)₂, or R⁹ OC(O)--NR⁸ --;

R² is selected from;

H;

unsubstituted or substituted C_1-8 alkyl, unsubstituted or substituted C_2-8 alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted morpholinyl, ##STR66## and --S(O)₂ R⁶, wherein the substituted group is substituted with one or more of;

1) aryl or morpholinyl, unsubstituted or substituted with one or two groups selected from;

a) C_1-4 alkyl,

b) (CH₂)_p OR⁶,

c) (CH₂)_p NR⁶ R⁷,

d) halogen,

e) C_1-4 perfluoroalkyl,

2) C_3-6 cycloalkyl,

3) OR⁶,

4) SR⁶, S(O)R⁶, SO₂ R⁶, ##STR67##

     15) C_1-8 alkyl, or

     16) C_1-8 perfluoroalkyl,

provided R² comprises a morpholinyl group if R³ does not comprise a morpholinyl group;

R³ is selected from;

H, ##STR68## provided R³ comprises a morpholinyl group if R² does not comprise a morpholinyl group;

R⁴ is independently selected from;

a) hydrogen,

b) unsubstituted or substituted aryl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R⁸ O--, R⁹ S(O)_m --, R⁸ C(O)NR⁸ --, CN, NO₂, R⁸₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R⁸ O--, R⁹ S(O)_m --, R⁸ C(O)NH--, CN, H₂ N--C(NH)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, --N(R⁸)₂, or R⁸ OC(O)NH--;

R⁵ is independently selected from;

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, perfluoroalkyl, F, Cl, Br, R⁸ O--, R⁹ S(O)_m --, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C-(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --, and

c) C₁ -C₆ alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R⁸ O--, R⁹ S(O)_m --, R⁸ C(O)NR⁸ --, CN, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --;

R⁶, R⁷ and R^7a are independently selected from;

H;

C_1-4 alkyl, C_3-6 cycloalkyl, morpholinyl, aryl, C_1-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) substituted or unsubstituted aryl or substituted or unsubstituted morpholinyl,

c) halogen,

d) HO, ##STR69## h) N(R⁸)₂ ;

or R⁶ and R⁷ may be joined in a ring to form a carbocycle or a morpholine;

R⁷ and R^7a may be joined in a ring to form a carbocycle or a morpholine;

R⁸ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;

R⁹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹⁰ is selected from;

H;

R⁸ C(O)--;

R⁹ S(O)_m --;

unsubstituted or substituted C_1-4 alkyl, unsubstituted or substituted C_3-6 cycloalkyl, unsubstituted or substituted aryl, substituted aroyl, substituted arylsulfonyl, wherein the substituted group is substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR70## h) N(R⁸)₂, or i) C_3-6 cycloalkyl;

A¹ is selected from;

a bond, --CH═

CH--, --C.tbd.C--, --C(O)--, --C(O)NR⁸ --, O, --N(R⁸)--, and S(O)_m ;

A² is selected from;

a bond, --CH═

CH--, --C.tbd.C--, --C(O)--, --C(O)NR⁸ --, --NR⁸ C(O)--, O, --N(R⁸), --S(O)₂ N(R⁸)--, --N(R⁸)S(O)₂ --, and S(O)_m ;

V is aryl;

W is a imidazolyl;

X is a bond, --C(═

O)NR¹⁰, --NR¹⁰ C(═

O)--, --S(O)_m --, or --NR¹⁰ --;

space="preserve" listing-type="tabular">______________________________________ m is 0, 1 or 2;

n is 0 or 1;

p is 0, 1, 2, 3 or 4;

q is 0, 1, 2, 3 or 4;

r is 0 to 5, s is 1 or 2; and

t is 1;

______________________________________

or an optical isomer or pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, which inhibits farnesyl-protein transferase, of the formula A:

##STR71## wherein;

R^1a and R^1c are independently selected from;

hydrogen, C₃ -C₁₀ cycloalkyl, R⁸ O--, --N(R⁸)₂, F or C₁ -C₆ alkyl;

R^1b is independently selected from;

a) hydrogen,

b) unsubstituted or substituted aryl, C₃ -C₆ cycloalkyl, R⁸ O--, --N(R⁸)₂ or C₂ -C₆ alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by unsubstituted or substituted aryl, C₃ -C₆ cycloalkyl, C₂ -C₆ alkenyl, R⁸ O--, or --N(R⁸)₂ ;

R² is selected from;

a) C_1-8 alkyl, unsubstituted or substituted with one or more of;

1) aryl or morpholinyl, unsubstituted or substituted with;

i) C_1-4 alkyl,

ii) (CH₂)_p OR⁶,

iii) (CH₂)_p NR⁶ R⁷,

iv) halogen,

v) C_1-4 perfluoroalkyl,

2) OR⁶,

3) SR⁶, SO₂ R⁶, or ##STR72## c) aryl, substituted or substituted with one or more of;

     1) C_1-8 alkyl,

2) C_1-8 perfluoroalkyl,

3) OR⁶,

4) SR⁶, SO₂ R⁶, or ##STR73## d) --SO₂ R⁶, provided R² comprises a morpholinyl group if R³ does not comprise a morpholinyl group;

R³ is selected from H;

##STR74## provided R³ comprises a morpholinyl group if R³ does not comprise a morpholinyl group;

R⁴ is independently selected from;

a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R⁸ O--, R⁸ C(O)NR⁸ --, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, --N(R⁸)₂, or R⁹ 0C(O)NR⁸ --;

R⁵ is selected from;

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁹ S(O)_m --, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁹ S(O)_m --, R⁸ C(O)NR⁸ --, CN, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --;

R⁶, R⁷ and R^7a are independently selected from;

H, C_1-4 alkyl, C_3-6 cycloalkyl, aryl, morpholinyl, unsubstituted or substituted with;

a) C_1-4 alkoxy,

b) halogen, or

c) substituted or unsubstituted aryl or substituted or unsubstituted morpholinyl;

R⁶ and R⁷ may be joined in a ring to form a carbocycle or a morpholine;

R⁷ and R^7a may be joined in a ring to form a carbocycle or a morpholine;

R⁸ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;

R⁹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹⁰ is selected from;

H;

R⁸ C(O)--;

R⁹ S(O)_m --;

unsubstituted or substituted C_1-4 alkyl, unsubstituted or substituted C_3-6 cycloalkyl, unsubstituted or substituted aryl, substituted aroyl, substituted arylsulfonyl, wherein the substituted group is substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR75## h) N(R⁸)₂, or i) C_3-6 cycloalkyl;

A¹ and A² are independently selected from;

a bond, --CH═

CH--, --C.tbd.C--, --C(O)--, --C(O)NR⁸ --, O, --N(R⁸)--, or S(O)_m ;

V is aryl;

W is imidazolyl;

X is a bond, --C(═

O)NR¹⁰ --, NR¹⁰ C(═

O)--, --S(O)_m -- or --NR¹⁰ --;

space="preserve" listing-type="tabular">______________________________________ m is 0, 1 or 2;

n is 0 or 1;

p is 1, 2 or 3;

q is 0 or 1;

r is 0 or 5;

s is 1 or 2; and

t is 1;

______________________________________

or an optical isomer or pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, which inhibits farnesyl-protein transferase, of the formula B:

##STR76## wherein;

R^1a and R^1c are independently selected from;

hydrogen, C₃ -C₁₀ cycloalkyl, R⁸ O--, --N(R⁸)₂, F or C₁ -C₆ alkyl;

R^1b is independently selected from;

a) hydrogen,

b) aryl, C₃ -C₁₀ cycloalkyl, R⁸ O--, --N(R⁸)₂, F or C₂ -C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁ -C₆ alkyl is selected from unsubstituted or substituted aryl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R⁸ O-- and --N(R⁸)₂ ;

R² is selected from;

H;

unsubstituted or substituted C_1-8 alkyl, unsubstituted or substituted C_2-8 alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted morpholinyl, ##STR77## and --S(O)₂ R⁶, wherein the substituted group is substituted with one or more of;

1) aryl or morpholinyl, unsubstituted or substituted with one or two groups selected from;

a) C_1-4 alkyl,

b) (CH₂)_p OR⁶,

c) (CH₂)_p NR⁶ R⁷,

d) halogen,

e) C_1-4 perfluoroalkyl,

2) C_3-6 cycloalkyl,

3) OR⁶,

4) SR⁶, S(O)R⁶, SO₂ R⁶, ##STR78##

     15) C_1-8 alkyl, or

     16) C_1-8 perfluoroalkyl,

provided R² comprises a morpholinyl group if R³ does not comprise a morpholinyl group;

R³ is selected from;

H;

##STR79## provided R³ comprises a morpholinyl group if R² does not comprise a morpholinyl group;

R⁴ is independently selected from;

a) hydrogen,

b) aryl, substituted aryl, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R⁸ O--, R⁸ C(O)NR⁸ --, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --;

R^5a and R^5b are independently hydrogen, C₁ -C₆ alkyl, cyclopropyl, trifluoromethyl and halogen;

R⁶, R⁷ and R^7a are independently selected from;

H;

C₁₄ alkyl, C_3-6 cycloalkyl, aryl, morpholinyl, unsubstituted or substituted with;

a) C_1-4 alkoxy,

b) halogen, or

c) substituted or unsubstituted aryl or substituted or unsubstituted morpholinyl;

R⁶ and R⁷ may be joined in a ring to form a carbocycle or a morpholine;

R⁷ and R^7a may be joined in a ring to form a carbocycle or a morpholine;

R⁸ is independently selected from hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

R⁹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹⁰ is selected from;

H;

R⁸ C(O)--;

R⁹ S(O)_m --;

unsubstituted or substituted C_1-4 alkyl, unsubstituted or substituted C_3-6 cycloalkyl, or substituted heteroaroyl, substituted arylsulfonyl, wherein the substituted group is substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR80## h) N(R⁸)₂, or i) C_3-6 cycloalkyl;

A¹ and A² are independently selected from;

a bond, --CH═

CH--, --C.tbd.C--, --C(O)--, --C(O)NR⁸ --, O, --N(R⁸)--, or S(O)_m ;

V is aryl;

X is a bond, --C(═

O)NR¹⁰ --, --NR¹⁰ C(═

O)--, --S(O)_m -- or --NR¹⁰ --;

space="preserve" listing-type="tabular">______________________________________ m is 0, 1 or 2;

n is 0 or 1;

p is 0, 1, 2, 3 or 4;

q is 0 or 1; and

r is 0 to 5;

______________________________________

or an optical isomer or pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, which inhibits farnesyl-protein transferase, of the formula C:

##STR81## wherein;

R^1a and R^1c are independently selected from;

hydrogen, C₃ -C₁₀ cycloalkyl, R⁸ O--, --N(R⁸)₂, F or C₁ -C₆ alkyl;

R^1b is independently selected from;

a) hydrogen,

b) aryl, C₃ -C₁₀ cycloalkyl, R⁸ O--, --N(R⁸)₂, F or C₂ -C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁ -C₆ alkyl is selected from unsubstituted or substituted aryl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R⁸ O-- and --N(R⁸)₂ ;

R² is selected from;

H;

unsubstituted or substituted CI -8 alkyl, unsubstituted or substituted C_2-8 alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted morpholinyl, ##STR82## and --S(O)₂ R⁶, wherein the substituted group is substituted with one or more of;

1) aryl or morpholinyl, unsubstituted or substituted with one or two groups selected from;

a) C_1-4 alkyl,

b) (CH₂)_p OR⁶,

c) (CH₂)_p NR⁶ R⁷,

d) halogen,

e) C_1-4 perfluoroalkyl,

2) C_3-6 cycloalkyl,

3) OR⁶,

4) SR⁶, S(O)R⁶, SO₂ R⁶, ##STR83##

     15) C_1-8 alkyl, or

     16) C_1-8 perfluoroalkyl,

provided R² comprises a morpholinyl group if R³ does not comprise a morpholinyl group;

R³ is selected from;

H;

##STR84## provided R³ comprises a morpholinyl group if R² does not comprise a morpholinyl group;

R⁴ is independently selected from;

a) hydrogen,

b) aryl, substituted aryl, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R⁸ O--, R⁸ C(O)NR⁸ --, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --;

R^5a and R^5b are independently hydrogen, C₁ -C₆ alkyl, cyclopropyl, trifluoromethyl and halogen;

R⁶, R⁷ and R^7a are independently selected from;

H;

C_1-4 alkyl, C_3-6 cycloalkyl, aryl, morpholinyl, unsubstituted or substituted with;

a) C_1-4 alkoxy,

b) halogen, or

c) substituted or unsubstituted aryl or substituted or unsubstituted morpholinyl;

R⁶ and R⁷ may be joined in a ring to form a carbocycle or a morpholine;

R⁷ and R^7a may be joined in a ring to form a carbocycle or a morpholine;

R⁸ is independently selected from hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

R⁹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹⁰ is selected from;

H;

R⁸ C(O)--;

R⁹ S(O)_m --;

unsubstituted or substituted C_1-4 alkyl, unsubstituted or substituted C_3-6 cycloalkyl, unsubstituted or substituted aryl, substituted aroyl, substituted arylsulfonyl, wherein the substituted group is substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR85## h) N(R⁸)₂, or i) C_3-6 cycloalkyl;

A¹ and A² are independently selected from;

a bond, --CH═

CH--, --C.tbd.C--, --C(O)--, --C(O)NR⁸ --, O, --N(R⁸)--, or S(O)_m ;

V is aryl;

X is a bond, --C(═

O)NR¹⁰ --, --NR¹⁰ C(═

O)--, --S(O)_m -- or --NR¹⁰ --;

space="preserve" listing-type="tabular">______________________________________ m is 0, 1 or 2;

n is 0 or 1;

p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or --NR.sup.10 --. q is 0 or 1; and

r is 0 to 5;

______________________________________

or an optical isomer or pharmaceutically acceptable salt thereof.

5. The compound according to claim 3, which inhibits farnesyl-protein transferase, of the formula D:

##STR86## wherein;

R^1a and R^1c are independently selected from;

hydrogen, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl;

R^1b is independently selected from;

a) hydrogen,

b) aryl, C₃ -C₁₀ cycloalkyl, R⁸ O--, --N(R⁸)₂, F or C₂ -C₆ alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R⁸ O--, or --N(R⁸)₂ ;

R² is selected from;

H;

unsubstituted or substituted C_1-8 alkyl, unsubstituted or substituted aryl, ##STR87## and --S(O)₂ R⁶, wherein the substituted group is substituted with one or more of;

1) aryl or morpholinyl, unsubstituted or substituted with one or two groups selected from;

a) C_1-4 alkyl,

b) (CH₂)_p OR⁶,

c) (CH₂)_p NR⁶ R⁷,

d) halogen,

e) C_1-4 perfluoroalkyl,

2) C_3-6 cycloalkyl,

3) OR⁶,

4) SR⁶, S(O)R⁶, SO₂ R⁶, ##STR88##

     15) C_1-8 alkyl, or

     16) C_1-8 perfluoroalkyl,

provided R² comprises a morpholinyl group if R³ does not comprise a morpholinyl group;

R³ is selected from;

H;

##STR89## provided R³ comprises a morpholinyl group if R² does not comprise a morpholinyl group;

R⁴ is independently selected from;

a) hydrogen,

b) aryl, substituted aryl, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R⁸ O--, R⁸ C(O)NR⁸ --, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --;

R^5a and R^5b are independently hydrogen, ethyl, cyclopropyl or methyl;

R⁶, R⁷ and R^7a are independently selected from;

H;

C_1-4 alkyl, C_3-6 cycloalkyl, aryl, morpholinyl, unsubstituted or substituted with;

a) C_1-4 alkoxy,

b) halogen, or

c) substituted or unsubstituted aryl or substituted or unsubstituted morpholinyl;

R⁶ and R⁷ may be joined in a ring to form a carbocycle or a morpholine;

R⁷ and R^7a may be joined in a ring to form a carbocycle or a morpholine;

R⁸ is independently selected from hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

R⁹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹⁰ is selected from;

H;

R⁸ C(O)--;

R⁹ S(O)_m --;

unsubstituted or substituted C_1-4 alkyl, wherein the substituted alkyl group is substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR90## h) N(R⁸)₂, or i) C_3-6 cycloalkyl;

A¹ is selected from;

a bond, --C(O)--, O, --N(R⁸)--, or S(O)_m ;

X is a bond, --C(═

O)NR¹⁰ --, --NR¹⁰ C(═

O)--, --S(O)_m -- or --NR¹⁰ --;

space="preserve" listing-type="tabular">______________________________________ n is 0 or 1;

provided that n is not 0 if A.sup.1 is a bond, O, --N(R.sup.8)--, or S(O).sub.m ;

m is 0, 1 or 2;

p is 0, 1, 2, 3 or 4; and

q is 0 or 1;

______________________________________

or an optical isomer or pharmaceutically acceptable salt thereof.

6. The compound according to claim 4, which inhibits farnesyl-protein transferase, of the formula E:

##STR91## wherein;

R^1a and R^1c are independently selected from;

hydrogen, R⁸ O--, --N(R⁸)₂, F, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl;

R^1b is independently selected from;

a) hydrogen,

b) aryl, C₃ -C₁₀ cycloalkyl, R⁸ O--, --N(R⁸)₂, F or C₂ -C₆ alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, C₃ -C₁ O cycloalkyl, C₂ -C₆ alkenyl, R⁸ O--, or --N(R⁸)₂ ;

R² is selected from;

H;

unsubstituted or substituted C_1-8 alkyl, unsubstituted or substituted aryl, ##STR92## and --S(O)₂ R⁶, wherein the substituted group is substituted with one or more of;

1) aryl or morpholinyl, unsubstituted or substituted with one or two groups selected from;

a) C_1-4 alkyl,

b) (CH₂)_p OR⁶,

c) (CH₂)_p NR⁶ R⁷,

d) halogen,

e) C_1-4 perfluoroalkyl,

2) C_3-6 cycloalkyl,

3) OR⁶,

4) SR⁶, S(O)R⁶, SO₂ R⁶, ##STR93##

     15) C_1-8 alkyl, or

     16) C_1-8 perfluoroalkyl,

provided R² comprises a morpholinyl group if R³ does not comprise a morpholinyl group;

R³ is selected from;

H;

##STR94## provided R³ comprises a morpholinyl group if R² does not comprise a morpholinyl group;

R⁴ is independently selected from;

a) hydrogen,

b) aryl, substituted aryl, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R⁸ O--, R⁸ C(O)NR⁸ --, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --;

R^5a and R^5b are independently hydrogen, ethyl, cyclopropyl or methyl;

R⁶, R⁷ and R^7a are independently selected from;

H;

C_1-4 alkyl, C_3-6 cycloalkyl, aryl, morpholinyl, unsubstituted or substituted with;

a) C_1-4 alkoxy,

b) halogen, or

c) substituted or unsubstituted aryl or substituted or unsubstituted morpholinyl;

R⁶ and R⁷ may be joined in a ring to form a carbocycle or a morpholine;

R⁷ and R^7a may be joined in a ring to form a carbocycle or a morpholine;

R⁸ is independently selected from hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

R⁹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹⁰ is selected from;

H;

R⁸ C(O)--;

R⁹ S(O)_m --;

unsubstituted or substituted C_1-4 alkyl, wherein the substituted alkyl group is substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR95## h) N(R⁸)₂, or i) C_3-6 cycloalkyl;

X is a bond, --C(═

O)NR¹⁰ --, --NR¹⁰ C(═

O)--, --S(O)_m -- or NR¹⁰ --;

space="preserve" listing-type="tabular">______________________________________ n is 0 or 1;

m is 0, 1 or 2;

p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or --NR.sup.10 --; and

q is 0 or 1;

______________________________________

or an optical isomer or pharmaceutically acceptable salt thereof.

7. The compound according to claim 5, which inhibits farnesyl-protein transferase, of the formula F:

##STR96## wherein;

R^1a and R^1c are independently selected from;

hydrogen, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl;

R^1b is independently selected from;

a) hydrogen,

b) aryl, C₃ -C₁₀ cycloalkyl, R⁸ O--, --N(R⁸)₂ or F,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, C₃ -C₁₀ cycloalkyl, R⁸ O--, or --N(R⁸)₂ ;

R² is selected from;

H;

unsubstituted or substituted C_1-8 alkyl, unsubstituted or substituted aryl, ##STR97## and --S(O)₂ R⁶, wherein the substituted group is substituted with one or more of;

1) aryl or morpholinyl, unsubstituted or substituted with one or two groups selected from;

a) C_1-4 alkyl,

b) (CH₂)_p OR⁶,

c) (CH₂)_p NR⁶ R⁷,

d) halogen,

e) C_1-4 perfluoroalkyl,

2) C_3-6 cycloalkyl,

3) OR⁶,

4) SR⁶, S(O)R⁶, SO₂ R⁶, ##STR98##

     15) C_1-8 alkyl, or

     16) C_1-8 perfluoroalkyl,

provided R² comprises a morpholinyl group if R³ does not comprise a morpholinyl group;

R³ is selected from;

H;

##STR99## provided R³ comprises a morpholinyl group if R² does not comprise a morpholinyl group;

R^5a and R^5b are independently hydrogen, ethyl, cyclopropyl or methyl;

R⁶, R⁷ and R^7a are independently selected from;

H;

C_1-4 alkyl, C_3-6 cycloalkyl, aryl, morpholinyl, unsubstituted or substituted with;

a) C_1-4 alkoxy,

b) halogen, or

c) substituted or unsubstituted aryl or substituted or unsubstituted morpholinyl,

R⁶ and R⁷ may be joined in a ring to form a carbocycle or a morpholine;

R⁷ and R^7a may be joined in a ring to form a carbocycle or a morpholine;

R⁸ is independently selected from hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

R⁹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹⁰ is selected from;

H;

R⁸ C(O)--;

R⁹ S(O)_m --;

unsubstituted or substituted C_1-4 alkyl, wherein the substituted alkyl group is substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR100## h) N(R⁸)₂, or i) C_3-6 cycloalkyl;

X is a bond, --C(═

O)NR¹⁰ --, --NR¹⁰ C(═

O)--, --S(O)_m -- or --NR¹⁰ --;

space="preserve" listing-type="tabular">______________________________________ m is 0, 1 or 2;

p is 0, 1, 2, 3 or 4; and

q is 0 or 1;

______________________________________

or an optical isomer or pharmaceutically acceptable salt thereof.

8. The compound according to claim 6, which inhibits farnesyl-protein transferase, of the formula G:

##STR101## wherein;

R^1a and R^1c are independently selected from;

hydrogen, R⁸ O--, --N(R⁸)₂, F, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl;

R^1b is independently selected from;

a) hydrogen,

b) aryl or C₃ -C₁₀ cycloalkyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R⁸ O--, or --N(R⁸)₂ ;

R² is selected from;

H;

unsubstituted or substituted C_1-8 alkyl, unsubstituted or substituted aryl, ##STR102## and --S(O)₂ R⁶, wherein the substituted group is substituted with one or more of;

1) aryl or morpholinyl, unsubstituted or substituted with one or two groups selected from;

a) C_1-4 alkyl,

b) (CH₂)_p OR⁶,

c) (CH₂)_p NR⁶ R⁷,

d) halogen,

e) C_1-4 perfluoroalkyl,

2) C_3-6 cycloalkyl,

3) OR⁶,

4) SR⁶, S(O)R⁶, SO₂ R⁶, ##STR103##

     15) C_1-8 alkyl, or

     16) C_1-8 perfluoroalkyl,

provided R² comprises a morpholinyl group if R³ does not comprise a morpholinyl group;

R³ is selected from;

H;

##STR104## provided R³ comprises a morpholinyl group if R² does not comprise a morpholinyl group;

R^5a and R^5b are independently hydrogen, ethyl, cyclopropyl or methyl;

R⁶, R⁷ and R^7a are independently selected from;

H;

C_1-4 alkyl, C_3-6 cycloalkyl, aryl, morpholinyl, unsubstituted or substituted with;

a) C_1-4 alkoxy,

b) halogen, or

c) substituted or unsubstituted aryl or substituted or unsubstituted morpholinyl;

R⁶ and R⁷ may be joined in a ring to form a carbocycle or a morpholine;

R⁷ and R^7a may be joined in a ring to form a carbocycle or a morpholine;

R⁸ is independently selected from hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

R⁹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹⁰ is selected from;

H;

R⁸ C(O)--;

R⁹ S(O)_m --;

unsubstituted or substituted C_1-4 alkyl, wherein the substituted alkyl group is substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR105## h) N(R⁸)₂, or i) C_3-6 cycloalkyl;

A¹ is selected from;

a bond, --C(O)--, O, --N(R⁸)--, or S(O)_m ;

X is a bond, --C(═

O)NR¹⁰ --, --NR¹⁰ C(═

O)--, --S(O)_m -- or --NR¹⁰ ;

space="preserve" listing-type="tabular">______________________________________ m is 0, 1 or 2;

n is 0 or 1;

p is 1, 2 or 3; and

q is 0 or 1;

______________________________________

or an optical isomer or pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1.

14. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 5.

15. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 6.

17. A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier.

18. A process for making a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier.

19. A method for treating cancer by inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 13.

20. A method for treating cancer by inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 14.

21. A method for treating cancer by inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 15.

9. A compound which inhibits farnesyl-protein transferase which is:

1-Phenethyl-cis-3-[N-(1-morpholinyl)carbamyl]-5-[N-(1-(4-cyanobenzyl-1H-imidazol-5-ylethyl)carbamoyl]piperidine,

1-(2,2-Diphenylethyl)-cis-3-[N-(1-morpholinyl)carbamyl]-5-[N-(1-(4-cyanobenzyl-1H-imidazol-5-ylethyl)carbamoyl]piperidine, or

1-(2-(1-Morpholinyl)-2-phenylethyl)-3(S)-[N-(l -(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine,

or an optical isomer or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9 which is:

1-Phenethyl-cis-3-[N-(1 morpholinyl)carbamyl]-5-[N-(4-cyanobenzyl-1-imidazole-5-ylethyl)carbamyl]piperidine ##STR106## or an optical isomer or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 9 which is:

1-(2,2-Diphenylethyl)-cis-3-[N-(1-morpholinyl)carbamyl]-5-[N-(4-cyanobenzyl-1H-imidazole-5-ylethyl)carbamyl]piperidine ##STR107## or an optical isomer or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 9 which is:

1-(2-(1-Morpholinyl)-2-phenylethyl)-3(S)-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine ##STR108## or an optical isomer or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 9.

22. A method for treating cancer by inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 16.