Dihydro-2H-naphthalene-1-one inhibitors of ras farnesyl transferase

A compound of formula

• 77
• and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof,
• wherein:
• R1 and R2 are independently hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl, O-alkyl, S-alkyl, OH, SH, —CN, halogen, 1,3-dioxolanyl, CF3, NO2, NH2, NHCH3, N(CH3)2, NHCO-alkyl, (CH2)mCO2H, —(CH2)mCO2-alkyl, —(CH2)mSO3H, —NH-alkyl, —N(alkyl)2, —(CH2)mPO3H2, —(CH2)mPO3(alkyl)2, (CH2)mSO2NH2, —(CH2)m-heteroaryl, —(CH2)mS-aryl, —(CH2)mS-heteroaryl, —(CH2)mSO2-aryl, —(CH2)mSO2-heteroaryl, and —(CH2)mSO2NH-alkyl, wherein m is 0, 1, 2, or 3;
• and wherein each of the R1 and R2 groups can be attached through a linker, or through a lower alkyl optionally interrupted by a linker, said linker selected from the group consisting of
• 78
• S, SO, SO2, O, and NRc;
• Rc is hydrogen, (C1-C6)-alkyl, or aryl;
• q is 1 or 2;
• R4 is hydrogen, heteroaryl, or aryl, wherein the aryl or heteroaryl is optionally substituted with up to three groups selected from the group consisting of halogen, (C1-C6)-alkyl, amino, (C1-C6)-alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, (C1-C6)-thioalkoxy, cyano, nitro, 1,3-dioxolanyl, NHCO(C1-C6)-alkyl, (CH2)mCO2H, (CH2)mCO2(C1-C6)-alkyl, (CH2)mSO3H, —(CH2)mPO3H2, (CH2)mPO3 [(C1-C6)-alkyl]2, (CH2)mSO2NH2, and (CH2)mSO2NH(C1-C6)-alkyl, wherein m is 0, 1, 2, or 3;
• and
• R3 is aryl, heteroarylalkyl, or arylalkyl, wherein the aryl, heteroaryl or arylalkyl is optionally substituted with up to three groups selected from the group consisting of halogen, (C1-C6)-alkyl, amino, (C1-C6)-alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, (C1-C6)-thioalkoxy, cyano, nitro, 1,3-dioxolanyl, NHCO(C1-C6)-alkyl, (CH2)mCO2H, (CH2)mCO2(C1-C6)-alkyl, (CH2)mSO3H, —(CH2)mPO3H2, (CH2)mPO3 [(C1-C6)-alkyl]2, (CH2)mSO2NH2, and (CH2)mSO2NH(C1-C6)-alkyl, wherein m is 0, 1, 2, or 3.

A compound of formula

• 79
• and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof,
• wherein:
• R1 and R2 are independently hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl, O-alkyl, S-alkyl, OH, SH, —CN, halogen, 1,3-dioxolanyl, CF3, NO2, NH2, NHCH3, N(CH3)2, NHCO-alkyl, —(CH2)mCO2H, —(CH2)mCO2-alkyl, —(CH2)mSO3H, —NH-alkyl, —N(alkyl)2, —(CH2)mPO3H2, —(CH2)mPO3(alkyl)2, (CH2)mSO2NH2, —(CH2)m-heteroaryl, —(CH2)mS-aryl, —(CH2)mS-heteroaryl, —(CH2)mSO2-aryl, —(CH2)mSO2-heteroaryl, and —(CH2)mSO2NH-alkyl, wherein m is 0, 1, 2, or 3;
• and wherein each of the R1 and R2 groups can be attached through a linker, or through a lower alkyl optionally interrupted by a linker, said linker selected from the group consisting of
• 80
• S, SO, SO2, O, and NRc;
• Rc is hydrogen, (C1-C6)-alkyl, or aryl;
• q is 1 or 2;
• R4 is hydrogen, heteroaryl, or aryl, wherein the aryl or heteroaryl is optionally substituted with up to three groups selected from the group consisting of halogen, (C1-C6)-alkyl, amino, (C1-C6)-alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, (C1-C6)-thioalkoxy, cyano, nitro, 1,3-dioxolanyl, NHCO(C1-C6)-alkyl, (CH2)mCO2H, (CH2)mCO2(C1-C6)-alkyl, (CH2)mSO3H, (CH2)mPO3H2, (CH2)mPO3 [(C1-C6)-alkyl]2, (CH2)mSO2NH2, and (CH2)mSO2NH(C1-C6)-alkyl, wherein m is 0, 1, 2, or 3;
• and
• R5 is aryl optionally substituted with up to three groups selected from the group consisting of halogen, (C1-C6)-alkyl, amino, (C1-C6)-alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, (C1-C6)-thioalkoxy, cyano, nitro, 1,3-dioxolanyl, NHCO(C1-C6)-alkyl, (CH2)mCO2H, (CH2)mCO2(C1-C6)-alkyl, (CH2)mSO3H, —(CH2)mPO3H2, (CH2)mPO3 [(C1-C6)-alkyl]2, (CH2)mSO2NH2, and (CH2)mSO2NH(C1-C6)-alkyl, wherein m is 0, 1, 2, or 3.

A compound of formula

• 81
• and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof,
• wherein:
• R1 and R2 are independently hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with one, two, or three groups independently selected from the group consisting of alkyl, O-alkyl, S-alkyl, OH, SH, —CN, halogen, 1,3-dioxolanyl, CF3, NO2, NH2, NHCH3, N(CH3)2, NHCO-alkyl, —(CH2)mCO2H, —(CH2)mCO2-alkyl, —(CH2)mSO3H, —NH-alkyl, —N(alkyl)2, —(CH2)mPO3H2, —(CH2)mPO3(alkyl)2, (CH2)mSO2NH2, —(CH2)m-heteroaryl, —(CH2)mS-aryl, —(CH2)mS-heteroaryl, —(CH2)mSO2-aryl, —(CH2)mSO2-heteroaryl, and —(CH2)mSO2NH-alkyl, wherein m is 0, 1, 2, or 3;
• and wherein each of the R1 and R2 groups can be attached through a linker, or through a lower alkyl optionally interrupted by a linker, said linker selected from the group consisting of
• 82
• S, SO, SO2, O, and NRc;
• Rc is hydrogen, (C1-C6)-alkyl, or aryl;
• q is 1 or 2;
• R4 is hydrogen, heteroaryl, or aryl, wherein the aryl or heteroaryl is optionally substituted with up to three groups selected from the group consisting of halogen, (C1-C6)-alkyl, amino, (C1-C6)-alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, (C1-C6)-thioalkoxy, cyano, nitro, 1,3-dioxolanyl, NHCO(C1-C6)-alkyl, (CH2)mCO2H, (CH2)mCO2(C1-C6)-alkyl, (CH2)mSO3H, —(CH2)mPO3H2, (CH2)mPO3 [(C1-C6)-alkyl]2, (CH2)mSO2NH2, and (CH2)mSO2NH(C1-C6)-alkyl, wherein m is 0, 1, 2, or 3;
• and
• R5 is aryl optionally substituted with up to three groups selected from the group consisting of halogen, (C1-C6)-alkyl, amino, (C1-C6)-alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, (C1-C6)-thioalkoxy, cyano, nitro, 1,3-dioxolanyl, NHCO(C1-C6)-alkyl, (CH2)mCO2H, (CH2)mCO2(C1-C6)-alkyl, (CH2)mSO3H, —(CH2)mPO3H2, (CH2)mPO3 [(C1-C6)-alkyl]2, (CH2)mSO2NH2, and (CH2)mSO2NH(C1-C6)-alkyl, wherein m is 0, 1, 2, or 3.

A compound of formula

• 83
• and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof,
• wherein:
• R2 is hydrogen, (C1-C6)-alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl, or heteroarylalkyl is optionally substituted with a group independently selected from the group consisting of alkyl, O-alkyl, S-alkyl, OH, SH, —CN, halogen, 1,3-dioxolanyl, CF3, NO2, NH2, NHCH3, N(CH3)2, NHCO-alkyl, —(CH2)mCO2H, —(CH2)mCO2-alkyl, —(CH2)mSO3H, —NH-alkyl, —N(alkyl)2, —(CH2)mPO3H2, —(CH2)mPO3(alkyl)2, —(CH2)mSO2NH2, —(CH2)m-heteroaryl, —(CH2)mS-aryl, —(CH2)mS-heteroaryl, —(CH2)mSO2-aryl, —(CH2)mSO2-heteroaryl, and —(CH2)mSO2NH-alkyl, wherein m is 0, 1, 2, or 3, and wherein each of the R1 and R2 groups can be attached through a linker, or through a lower alkyl optionally interrupted by a linker, said linker selected from the group consisting of
• 84
• S, SO, SO2, O, and NH;
• R4 is hydrogen or phenyl;
• and
• R5 is aryl optionally substituted by (C1-C6)-alkyl, (C1-C6)-alkoxy, or cyano.

A compound of formula

• 85
• and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof,
• wherein:
• R2 is hydrogen, (C1-C6)-alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl, or heteroarylalkyl is optionally substituted with a group independently selected from the group consisting of alkyl, O-alkyl, S-alkyl, OH, SH, —CN, halogen, 1,3-dioxolanyl, CF3, NO2, NH2, NHCH3, N(CH3)2, NHCO-alkyl, —(CH2)mCO2H, —(CH2)mCO2-alkyl, —(CH2)mSO3H, —NH-alkyl, —N(alkyl)2, —(CH2)mPO3H2, —(CH2)mPO3(alkyl)2, —(CH2)mSO2NH2, —(CH2)m-heteroaryl, —(CH2)mS-aryl, —(CH2)mS-heteroaryl, —(CH2)mSO2-aryl, —(CH2)mSO2-heteroaryl, and —(CH2)mSO2NH-alkyl, wherein m is 0, 1, 2, or 3, and wherein each of the R1 and R2 groups can be attached through a linker, or through a lower alkyl optionally interrupted by a linker, said linker selected from the group consisting of
• 86
• S, SO, SO2, O, and NH;
• R4 is hydrogen or phenyl;
• and
• R5 is aryl optionally substituted by (C1-C6)-alkyl, (C1-C6)-alkoxy, or cyano.