Inhibitors of farnesyl protein transferase

Claim 2

A compound of Claim 1, wherein G¹ is G² is and A¹ and A² are each, independently, H or D-, L- or D,L- -CH₃, -CH(CH₃)₂, -CH₂CH(CH₃)₂, -CH(CH₃)CH₂CH₃, -C(CH₃)₃, -CH₂OH, -CH₂CH₂OH, -CH₂CH₂CH₂OH, -CH(OH)CH₃, -CH₂CH₂CH₂CH₂NH₂, -CH₂C(O)OH, -CH₂CH₂C(O)OH, -CH₂C(O)NH₂, -CH₂CH₂C(O)NH₂, -CH₂CH₂OCH₃, -CH₂CH₂CONR¹⁵R¹⁶, -CH₂SH, -CH₂CH₂SH, -CH₂CH₂SOCH₃, -CH₂CH₂SO₂CH₃ or -CH₂CH₂SCH₃, where R¹⁵ and R¹⁶ are each, independently, hydrogen or alkyl, or R¹⁵ and R¹⁶, taken together, form a 5- to 7-membered, optionally substituted, saturated ring with the N-atom to which they are attached.

Claim 3

A compound of Claim 1, wherein G² is -NR⁶CH(Q¹)- and Q¹ is

Claim 4

A compound of Claim 1, wherein A¹ and A² are each, independently, H or D-, L- or D,L- -CH₃, -CH(CH₃)₂, -CH₂CH(CH₃)₂, -CH(CH₃)CH₂CH₃, -C(CH₃)₃, -CH₂OH, -CH₂CH₂OH,-CH₂CH₂CH₂OH, -CH(OH)CH₃, -CH₂CH₂CH₂CH₂NH₂, -CH₂C(O)OH, -CH₂CH₂C(O)OH, -CH₂C(O)NH₂, -CH₂CH₂C(O)NH₂, -CH₂CH₂OCH₃, -CH₂CH₂CONR¹⁵R¹⁶, -CH₂SH, -CH₂CH₂SH, -CH₂CH₂SOCH₃, -CH₂CH₂SO₂CH₃ or -CH₂CH₂SCH₃, where R¹⁵ and R¹⁶ are each, independently, hydrogen or alkyl, or R¹⁵ and R¹⁶, taken together, form a 5- to 7-membered, optionally substituted, saturated ring with the N-atom to which they are attached.

Claim 5

A compound of Claim 1, wherein A¹ is L--CH₃, -CH(CH₃)₂, -CH₂CH(CH₃)₂, -C(CH₃)₃, -CH(CH₃)CH₂CH₃, -CH₂OH or -CH(OH)CH₃.

Claim 6

A compound of Claim 1, wherein A² is L--CH₂CH₂SCH₃, -CH₂CH₂OH, -CH₂CH₂CH₂OH, -CH₂CH₂OCH₃, -CH₂CH₂CONR¹²R¹³, -CH₂CH₂SH, -CH₂CH₂SOCH₃ or -CH₂CH₂SO₂CH₃.

Claim 7

A compound of Claim 1, wherein G² is and the fused five-membered optionally substituted heteroring is

Claim 8

A compound of Claim 1, wherein G¹ is

Claim 9

A compound of Claim 1, wherein G² is

Claim 10

A compound of Claim 1, wherein G¹ is G² is G³ is -C(O)OH, -C(O)OR⁸ or -C(O)NHSO₂R¹¹; A¹ is L--CH₃, -CH(CH₃)₂, -CH₂CH(CH₃)₂, -C(CH₃)₃, -CH(CH₃)CH₂CH₃, -CH₂OH or -CH(OH)CH₃; A² is L--CH₂CH₂SCH₃, -CH₂CH₂OH, -CH₂CH₂CH₂OH, -CH₂CH₂C(O)NH₂, -CH₂CH₂OCH₃, -CH₂CH₂CONR¹⁵R¹⁶, -CH₂CH₂SH, -CH₂CH₂SOCH₃ or -CH₂CH₂SO₂CH₃; and R¹, R², R³ and R⁴ are H.

Claim 11

A compound of Claim 1, selected from the group consisting of: N-[[(S)-1,2,3,4-Tetrahydro-2-[N-[[(2S-trans)-4-mercapto-2-pyrrolidinyl]methyl]-L-valyl]-3-isoquinolinyl]carbonyl]-L-methionine; N-[[(S)-1,2,3,4-Tetrahydro-2-[N-[[(2S-cis)-4-mercapto-2-pyrrolidinyl]methyl]-L-valyl]-3-isoquinolinyl]carbonyl]-L-methionine; N²-[[(S)-1,2,3,4-Tetrahydro-2-[N-[[(2S- cis )-4-mercapto-2-pyrrolidinyl]methyl]-3-methyl-L-valyl]-3-isoquinolinyl]carbonyl]-L-glutamine; 2-[2(S)-[[4(S)-Mercapto-2(S)-pyrrolidinyl)-methyl]amino]-3(S)-methyl-1-oxopentyl]-1,2,3,4-tetrahydroisoquinoline; [S-(R*,R*)]-N-[(2,3-Dichlorophenyl)methyl]-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; N²-[[(S)-1,2,3,4-Tetrahydro-2-[N-[[( cis )-3-mercaptocyclopentyl]methyl]-3-methyl-L-valyl]-3-isoquinolinyl]carbonyl]-L-glutamine; [S-(R*,R*)]-N-(2,3-Dihydro-1H-inden-5-yl)-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; [S-(R*,R*)]-N-(4-Cyclohexylphenyl)-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; N²[[(S)-2-[N-[[(2S-cis)-1-(2-Aminoethyl)-4-mercapto-2-pyrrolidinyl]methyl]-3-methyl-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-glutamine; N-2-[[(S)-1,2,3,4-Tetrahydro-2-[N-[(2-cis)-4-hydroxy-2-pyrrolidinyl]methyl]-3-methyl-L-valyl]-3-isoquinolinyl]carbonyl]-L-glutamine; N²-[[(S)-2-[N-[[(2S-trans)-4-Amino-2-pyrrolidinyl]methyl]-3-methyl-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-glutamine trifluoroacetate; (2S-cis)-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-N-[3-(1-methylethoxy)propyl]-L-isoleucinamide; (2S-cis)-N-(2,3-Dihydro-1H-inden-2-yl)-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; (2S-cis)-N²-[(4-Mercapto-2-pyrrolidinyl)methyl]-N-[[4-(trifluoromethyl)phenyl]methyl]-L-isoleucinamide; (2S-cis)-N-[[4-(Aminosulfonyl)phenyl]methyl]-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; (2S-cis)-N²-[(4-Mercapto-2-pyrrolidinyl)methyl]-N-[2-(2-pyridinyl)ethyl]-L-isoleucinamide; (2S-cis)-N-(3,3-Diphenylpropyl)-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; (2S-cis)-N-[4-(1,1-Dimethylethyl)phenyl]-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; (2S-cis)-N²-[(4-Mercapto-2-pyrrolidinyl)methyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-L-isoleucinamide; (2S-cis)-N²-[(4-Mercapto-2-pyrrolidinyl)methyl]-N-[[3-(trifluoromethyl)phenyl]methyl]-L-isoleucinamide; (2S-cis)-N-Ethyl-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-N-(phenylmethyl)-L-isoleucinamide; [2S-[2α(R*),4α]]-1,2,3,4-Tetrahydro-2-[2-[[(4-mercapto-2-pyrrolidinyl)methyl]amino]-3,3-dimethyl-1-oxobutyl]isoquinoline; (2S-cis-)-N²-[(4-Mercapto-2-pyrrolidinyl)methyl]-N-(1-phenylethyl)-L-isoleucinamide; (2S-cis)-N-(2,3-Dihydro-1H-inden-1-yl)-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; (2S-cis)-N-[(2-Ethoxyphenyl)methyl]-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; (2S-cis)-N-[2-(4-Hydroxyphenyl)ethyl]-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; (2S-cis)-N-[(2,6-Difluorophenyl)methyl]-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; N-[[(S)-1,2,3,4-Tetrahydro-2-[N-[[(2S-cis)-4-mercapto-2-pyrrolidinyl]methyl]-L-isoleucyl]-3-isoquinolinyl]carbonyl]glycine, methyl ester; (2S-cis)-N²-[(4-Mercapto-2-pyrrolidinyl)methyl]-N-(phenylmethyl)-L-isoleucinamide; [2S-[2α(2R*,3R*),4α]]-1,2,3,4-Tetrahydro-2-[2-[[(4-mercapto-2-pyrrolidinyl)methyl]amino]-3-methylpentyl]isoquinoline; (2S-cis)-N²-[(4-Mercapto-2-pyrrolidinyl)methyl]-N,N-bis(phenylmehyl)-L-isoleucinamide; (2S-cis)-N²-[(4-Mercapto-2-pyrrolidinyl)methyl]-N-(1-methylbutyl)-L-isoleucineamide; (2S-cis)-N-(Cyclohexylmethyl)-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; (2S-cis)-N-(1,3-Dimethylbutyl)-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; (2S-cis)-N-Hexyl-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-N-methyl-L-isoleucinamide; (2S-cis)-N²-[(4-Mercapto-2-pyrrolidinyl)methyl]-N-(2-methylpropyl)-L-isoleucinamide; (2S-cis)-N²-[(4-Mercapto-2-pyrrolidinyl)methyl]-N-(2-phenylethyl)-L-isoleucinamide; (2S-cis)-N-[(3-Hydroxyphenyl)methyl]-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; (2S-cis)-N-[(2,3-Dimethoxyphenyl)methyl]-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamde; (2S-cis)-N²-[(4-Mercapto-2-pyrrolidinyl)methyl]-N,N-bis(2-methylpropyl)-L-isoleucinamide; (2S-cis)-N-[(4-Hydroxyphenyl)methyl]-N²[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; (2S-cis)-N,N-Bis[(2-ethoxyphenyl)methyl]-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; (2S-cis)-N,N-Bis[(2,3-dimethoxyphenyl)methyl]-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; (2S-cis)-N-[(2-Hydroxyphenyl)methyl]-N²-[(4-mercapto-2-pyrrolidinyl)methyl]-L-isoleucinamide; cis-N-[(2,3-Dichlorophenyl)methyl]-N²-[(3-mercaptocyclopentyl)methyl]-L-isoleucinamide; cis-N²-[(3-Mercaptocyclopentyl)methyl]-N,N-bis(phenylmethyl)-L-isoleucinamide; [2S-[2α(R*),4α]]-N-Butyl-1,2,3,4-tetrahydro-2-[N-[[4-mercapto-2-pyrrolidinyl]-methyl]-L-isoleucyl]-3-isoquinolinecarboxamide; and (2S-cis)-N²-[(4-Mercapto-2-pyrrolidinyl)methyl]-N-(1-methylethyl)-N-(phenylmethyl)-L-isoleucinamide.

Claim 12

A compound as defined in any one of claims 1-11 for use as an pharmaceutically active ingredient.

Claim 13

Use of a compound as defined in any one of claims 1-11 for the preparation of a pharmaceutical composition for inhibiting farnesyl protein transferase.

Claim 14

Use of a compound as defined in any one of claims 1-11 for the preparation of a pharmaceutical composition for inhibiting prenyl transferase.

Claim 15

Use of a compound as defined in any one of claims 1-11 for the preparation of a pharmaceutical composition for inhibiting tumors.

Claim 16

Use of a compound as defined in any one of claims 1-11 for the preparation of a pharmaceutical composition for treating diseases associated with signal transduction pathways operating through Ras.

Claim 17

Use of a compound as defined in any one of claims 1-11 for the preparation of a pharmaceutical composition for treating diseases associated with proteins that are post-translationally modified by the enzyme farnesyl protein transferase.

Claim 18

Use of a compound as defined in any one of claims 1-11 for the preparation of a pharmaceutical composition for treating diseases associated with proteins that are post-translationally modified by the enzymes geranylgeranyl protein transferase.

Claim 19

A compound of the formula or an enantiomer, diastereomer, pharmaceutically acceptable salt or solvate thereof, wherein: G is when G is it is optionally substituted, at any available position or positions, with halo, alkyl or substituted alkyl having 1 to 20 carbon atoms, alkoxy, or a combination of these groups; G¹ is optionally substituted, at any of the available position or positions on the ring, with halo, alkyl or substituted alkyl having 1 to 20 carbon atoms, alkoxy, aryl, aralkyl, hydroxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, N-hydroxycarbamyl, N-alkylcarbamyl, N-dialkylcarbamyl, alkoxycarbonyl, phenyl, substituted phenyl, or a combination of these groups; G² is or -NR⁶-CH(Q¹)-; J, K and L are each, independently, N, NR⁷, O, S or CR⁶ with the provisos that only one of the groups J, K and L can be O or S, and at least one of the groups J or L must be N, NR⁷, O or S to form a fused five-membered heteroring; the bond between J and K or K and L may also form one side of a phenyl ring fused to the fused five-membered heteroring; Q is aryl; Q¹, A¹ and A² are each, independently, H, alkyl, substituted alkyl, phenyl or substituted phenyl; G³ is R⁸, -C(O)OR⁸, -C(O)NR⁸R⁹, -C(O)N(R¹⁰)OR⁸, -C(O)NHSO₂R¹¹ or -CH₂OR¹¹; X is -SH, -OH or NHR¹²; X¹ is -NR¹³-, -CH₂- or -CH(NHR¹⁴)-; Y and Z are each, independently, -CH₂- or -C(O)-; R¹ - R¹⁴ are each, independently, H or alkyl having 1 to 20 carbon atoms; R⁴, R⁵ and R¹¹ may also be aryl or aralkyl; R⁷, R⁸, R⁹ and R¹⁰ may also be aralkyl; and R¹², R¹³ and R¹⁴ may also be substituted alkyl or aralkyl; m is 0 or an integer from 1 to 2; q is 0 or an integer from 1 to 3; t is an integer from 1 to 2; and the dotted line represents an optional double bond.