Heterocyclic inhibitors of farnesyl protein transferase

Claim 2

A compound of Claim 1, wherein A₁ and A₂ are each independently H or D-, L- or DL- -CH₃, -CH(CH₃)₂, -CH₂CH(CH₃)₂, -CH(CH₃)CH₂CH₃, -C(CH₃)₃, -CH₂OH, -CH₂CH₂OH, -CH₂CH₂CH₂OH, -CH(OH)CH₃, -CH₂ CH₂ CH₂ CH₂ NH₂, -CH₂C(O)OH, -CH₂CH₂C(O)OH, -CH₂C(O)NH₂, -CH₂CH₂C(O)NR₁₁R₁₂ where R₁₁ and R₁₂ are each independently H, alkyl or phenyl, and R₁₁ and R₁₂ taken together may be -(CH₂) o - where o is 2 to 6, -CH₂CH₂C(O)NHOH, -CH₂SH, -CH₂CH₂SH, -CH₂CH₂S(O)₂NH₂, -CH₂CH₂OCH₃ or -CH₂CH₂SCH₃.

Claim 3

A compound of Claim 2, wherein A₁ and A₂ are each independently H or L- -CH₃, -CH(CH₃)₂, -CH₂CH(CH₃)₂, -CH(CH₃)CH₂CH₃, -C(CH₃)₃, -CH₂OH, -CH₂CH₂OH, -CH₂CH₂CH₂OH, -CH(OH)CH₃, -CH₂ CH₂ CH₂ CH₂ NH₂, -CH₂C(O)OH, -CH₂CH₂C(O)OH, -CH₂C(O)NH₂, -CH₂CH₂C(O)NR₁₁R₁₂ where R₁₁ and R₁₂ are each independently H, alkyl or phenyl, and R₁₁ and R₁₂ taken together may be -(CH₂) o - where o is 2 to 6, -CH₂CH₂C(O)NHOH, -CH₂SH, -CH₂CH₂SH, -CH₂CH₂S(O)₂NH₂, -CH₂CH₂OCH₃ or -CH₂CH₂SCH₃.

Claim 4

A compound of Claim 3, wherein A₁ is L- -CH₃, -CH(CH₃)₂, -CH₂CH(CH₃)₂, -C(CH₃)₃, -CH(CH₃)CH₂CH₃, -CH₂OH or -CH(OH)CH₃; and A₂ is L- -CH₂CH₂SCH₃, -CH₂CH₂OH, -CH₂CH₂CH₂OH, -CH₂CH₂C(O)NR₁₁R₁₂ where R₁₁ and R₁₂ are each independently H, alkyl or phenyl, and R₁₁ and R₁₂ taken together may be -(CH₂) o - where o is 2 to 6, -CH₂CH₂OCH₃ or -CH₂CH₂SH.

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; A₂ is L- -CH₂CH₂SCH₃, -CH₂CH₂OH, -CH₂CH₂CH₂OH, -CH₂CH₂C(O)NR₁₁R₁₂ where R₁₁ and R₁₂ are each independently H, alkyl or phenyl, and R₁₁ and R₁₂ taken together may be -(CH₂) o - where o is 2 to 6, -CH₂CH₂OCH₃ or -CH₂CH₂SH; G₁ is S; G₂ is -C(O)OH; X is R₈N; Y is -CH₂-; R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are each H; n is 1; and p is 1.

Claim 6

A compound of any preceding claim, wherein n is 1.

Claim 7

A compound of any preceding claim, wherein R₈ is H.

Claim 8

A compound of Claim 1 of the formula or an enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: A₁ and A₂ are each independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, phenyl or substituted phenyl; G₁ is S or O; G₂ is H, -C(O)OH, -C(O)NH₂, -C(O)N(R₇)OH or -CH₂OH; X is O or R₈N; R₁, R₂, R₃, R₄ and R₇ are each independently H or alkyl; R₁ may also be alkanoyl; R₁ and A₁ taken together may be -(CH₂) m ; R₈ is H, alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl or -C(O)R₉; R₉ is H, alkyl, phenyl, phenylalkyl, substituted phenyl or (substituted phenyl)alkyl; m is 3 or 4; n is 0, 1 or 2; p is 0, 1 or 2; and q is 0 or 1, with the proviso that when p is 0, q is also 0.

Claim 9

A compound of Claim 1 of the formula or an enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: A₁ and A₂ are each independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, phenyl or substituted phenyl; X is O or R₈N; Y and Z are independently -CH₂- or -C(O)-; R₁, R₂, R₃, R4 , R₅, R₆ and R₇ are each independently H or alkyl; R₁ may also be alkanoyl; R₁ and A₁ taken together may be -(CH₂) m ; R₈ is H, alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl or -C(O)R₉; R₉ is H, alkyl, phenyl, phenylalkyl, substituted phenyl or (substituted phenyl)alkyl; m is 3 or 4; n is 0, 1 or 2; p is 0, 1 or 2; and q is 0 or 1, with the proviso that when p is 0, q is also 0.

Claim 10

A compound of Claim 9, wherein A₁ is L- -CH₃, -CH(CH₃)₂, -CH₂CH(CH₃)₂, -C(CH₃)₃, -CH(CH₃)CH₂CH₃, -CH₂OH or -CH(OH)CH₃; A₂ is L- -(CH₂)₂SCH₃, -CH₂CH₂OH, -CH₂CH₂CH₂OH, -CH₂CH₂C(O)NR₁₁R₁₂ where R₁₁ and R₁₂ are each independently H, alkyl or phenyl, and R₁₁ and R₁₂ taken together may be -(CH₂) o - where o is 2 to 6, -CH₂CH₂OCH₃ or -CH₂CH₂SH; Y is -CH₂-; Z is -C(O)-; X is R₈N; R₁, R₂, R₃, R₄, R₅, R₆ and R₈ are H; n is 1; and p is 1.

Claim 11

A compound of Claim 1, selected from: (R*,S*)-N-[[2-[N-(2-Amino-3-mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (R*)-N-[[2-[N-(L-Cysteinyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl)carbonyl)-L-methionine, (R*)-N-[[2-[N-(L-Cysteinyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl)carbonyl]-L-methionine, methyl ester, (R*)-N-[[2-[N-(3-Mercapto-1-oxopropyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-1-methionine, (R*,R*)-N-[[2-[2-(L-Cysteinylamino)-3-methylbutyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (R*)-N-[[2-[N-(3-Mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (R*)-N-[[2-[N-(3-Mercaptopropyl)-L-alanyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (R*)-N-[[2-[N-(3-Mercaptopropyl)-N-methyl-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (R*,R*)-N-[[2-[2-[(3-Mercaptopropyl)amino]-3-methylbutyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (R*)-N-[[2-[N-(3-Mercaptopropyl)-L-propyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (R*)-N-[[2-[N-(2-Mercaptoethyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (R*)-N-[[2-[N-(3-Mercapto-1-oxopropyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, methyl ester, (R*,S*)-2-[N-(2-Amino-3-mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-N-[3-(methylthio)propyl]-3-isoquinolinecarboxamide, (R*)-2-[N-(3-Mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-N-[3-(methylthio)propyl]-3-isoquinolinecarboxamide, (R*)-N-[[2-[N-(L-Cysteinyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-alanine, (R*,R*)-N-[[2-[N-(2-Amino-4-hydroxy-1-oxobutyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (R*,R*)-2-[N-(L-Cysteinyl)-L-valyl]-1,2,3,4-tetrahydro-N-[1-(hydroxymethyl)-3-(methylthio)propyl]-3-isoquinolinecarboxamide, (R*)-N-[[2-(L-Cysteinyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-phenylalanine, (R*)-N-[[2-[N-(L-Cysteinyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-serine, (R*)-N²-[[2-[N-(L-Cysteinyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-N-hydroxy-L-methioninamide, (R*)-N-[[2-[N-(L-Cysteinyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-3-(2-thienyl)-DL-alanine, (R*)-N-[[2-[N-(L-Cysteinyl)glycyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (R*)-N²-[[2-[N-(L-Cysteinyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-glutamine, (R*)-N-[[2-[N-(L-Cysteinyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-histidine, (R*)-N-[[2-[N-(L-Cysteinyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-3-(phenylmethyl)-L-alanine, (R*)-N-[[2-[N-(L-Seryl)-L-valyl]-1,2,3,4- tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (R*,R*)-2-[N-(3-Mercapto-1-oxopropyl)-L-valyl]-1,2,3,4-tetrahydro-N-[3-(methylthio)-1-(1H-tetrazol-5-yl)propyl]-3-isoquinolinecarboxamide, (R*,S*)-N-[[2-[N-(2-Amino-3-mercaptopropyl)-N-methyl-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (R*,R*,S*)-N-[[2-[2-[(2-Amino-3-mercaptopropyl)amino]-3-methylbutyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (R*)-N-[[1-[N-(L-Cysteinyl)-L-valyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]-L-methionine, (S*,R*)-N-[[2-[N-(2-Amino-3-mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, methyl ester, [3S-[2[R*(S*)],3R*(R*)]]-2-[N-(2-Amino-3-mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-N-(tetrahydro-2-oxo-3-furanyl)-3-isoquinolinecarboxamide, (S*,R*)-N²-[[2-[N-(2-Amino-3-mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-N-hydroxy-L-methioninamide, [R-(R*,S*)]-N²-[[2-[N-(2-Amino-3-mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-glutamine, [R-(R*,S*)]-2-[N-(2-Amino-3-mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-N-(tetrahydro-2-oxo-3-thienyl)-3-isoquinolinecarboxamide, (S*,R*)-N²-[[2-[N-(2-Amino-3-mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-asparagine, (S*,R*)-N-[[2-[(2-Amino-3-mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-norleucine, (S*,R*)-N-[(2-[N-(2-Amino-3-mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-γ-(aminosulphonyl)-L-α-amino-butyric acid, (S*,R*)-N-[[2[N-(2-Amino-3-mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-glutamic acid, (S*,R*)-N²-[[2-[N-(2-Amino-3-mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]-carbonyl]-N⁵-hydroxy-L-glutamine, [R-(R*,S*)]-N²-[[2-[N-(2-Amino-3-mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methioninamide, N-[[(S)-2-[N-[(R)-2-Amino-3-mercaptopropyl]-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-2-methyl-DL-methionine, (S*,R*)-N-[[2-[N-(2-Amino-3-mercaptopropyl)-L-alanyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (S*,R*)-N-[[2-[N-(2-Amino-3-mercaptopropyl)-L-leucyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, [R*[R*(S*)]]-N-[[2-[2-[(2-Amino-3-mercaptopropyl)amino]-1-oxobutyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (S*,R*)-N-[[2-[2-[(2-Amino-3-mercapto-propyl)amino]-4-methylpentyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (R)-N-[[2-[1-[(2-amino-3-mercaptopropyl)-L-prolyl]-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyl]-L-methionine, [R*[S*(S*)]]-N-[[2-[[1-(2-Amino-3-mercaptopropyl)-2-methyl-2-pyrrolidinyl]carbonyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (S*,R*)-N-[[2-[N-(2-Amino-3-mercaptopropyl)-3-methyl-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, [R*[R*(S*)]]-N-[(2-[[(2-Amino-3-mercaptopropyl)amino)phenylacetyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, [R*[R*(S*)]]-N-[[2-[2-[(2-Amino-3-mercaptopropyl)amino]-2-cyclohexylacetyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (S*,R*)-N-[[2-[N-(2-Amino-3-mercaptopropyl)-3-methyl-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, methyl ester, (S*,R*)-N²-[[2-[N-(2-Amino-3-mercaptopropyl)-3-methyl-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-N⁵-methyl-L-glutamine, (S*,R*)-N²-[[2-[N-(2-Amino-3-mercaptopropyl)-3-methyl-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-glutamine, (S*,R*)-N²-[[2-[N-(2-Amino-3-mercaptopropyl)-3-methyl-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-glutamine, methyl ester, [R*[R*(S*)]]-N-[[2-[2-[(2-Amino-3-mercaptopropyl)amino]-3-methylbutyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-N-methyl-L-methionine, (S*,R*)-N-[[2-[2-[N-(2-Amino-3-mercaptopropyl)methylamino]-3-methylbutyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (S*,R*)-N-[[2-[N-Acetyl-N-(2-amino-3-mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (S*,R*)-N-[[2-[N-[3-Mercapto-2-(methylamino)propyl]-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (S*,R*)-N-[[1,2,3,4-Tetrahydro-2-[N-[3-mercapto-2-[(phenylmethyl)amino]propyl]-L-valyl]-3-isoquinolinyl]carbonyl]-L-methionine, (S*,R*)-N-[[2-[N-[2-(Acetylamino)-3-mercaptopropyl]-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, [R*[S*(S*)]]-N-[[2-[N-[2-amino-3-[(2-amino-2-carboxyethyl)dithio]propyl]-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, (S*,R*)-N,N'-Dithiobis(2-amino-3,1-propanediyl)bis-[N-[[2-(L-valyl)-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine], (S*,R*)-N-[[2-[N-[2-Amino-3-(methyldithio)propyl]-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, N-[[(S)-1,2,3,4-Tetrahydro-2-[N-[[(4R)-2-methyl-4-thiazolidinyl]methyl]-L-valyl]-3-isoquinolinyl]carbonyl]-L-methionine, (S*,R*)-N-[[1,2,3,4-Tetrahydro-2-[N-(4-thiazolidinylmethyl)-L-valyl]-3-isoquinolinyl]carbonyl]-L-methionine, (S*,R*)-N-[[2-[N-[2-(Acetylamino)-3-(acetylthio)propyl]-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine, N-[[(S)-1,2,3,4-Tetrahydro-2-[N-(2-hydroxy-3-mercaptopropyl)-L-vaIyl]-3-isoquinolinyl]carbonyl]-L-methionine, (S*,R*)-N-[[1,2,3,4-Tetrahydro-2-[N-[3-mercapto-2-[(3-phenylpropyl)amino]propyl] L-valyl]-3-isoquinolinyl]carbonyl]-L-methionine, (S*,R*)-N²-[[2-[N-(2-Amino-3-mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-N-hydroxy-N-methyl-L-methioninamide, and (S*,R*)-N-[[2-[N-(2-Amino-3-mercaptopropyl)-L-valyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]carbonyl]-O-methyl-L-homoserine.

Claim 12

A compound of any preceding claim for use as an active pharmaceutical substance.

Claim 13

Use of a compound of any one of claims 1-11 for the manufacture of a medicament for treatment of conditions requiring inhibition of farnesyl protein transferase in a mammalian subject.

Claim 14

Use of a compound of any one of claims 1-11 for the manufacture of a medicament for treatment of conditions requiring inhibition of prenyl transferases in a mammalian subject.

Claim 15

Use of a compound of any one of claims 1-11 for the manufacture of a medicament for treatment of conditions requiring inhibition of tumors in a mammalian subject.

Claim 16

Use of a compound of any one of claims 1-11 for the manufacture of a medicament for treatment of diseases associated with signal transduction pathways operating through Ras in a mammalian subject.

Claim 17

Use of a compound of any one of claims 1-11 for the manufacture of a medicament for treatment of diseases associated with proteins that are post-translationally modified by the enzyme farnesyl protein transferase, in a mammalian subject.

Claim 18

A compound of the formula its enantiomers and diastereomers, and pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein: A₁ and A₂ are each independently H or any of the natural D-, L- or DL-amino acid side chains; W is CH-R₄; X is O or R₅N; Y is S or O; Z is H, C(O)OH, tetrazolyl, C(O)N(R₇)OH or C(O)CH₂OH; R₁, R₂, R₃, R₄ and R₇ are each independently H or alkyl; R₁ and A₁ taken together may be (CH₂) m ; R₅ is H, alkyl, phenyl, phenylalkyl, or C(O)R₆, where the phenyl and phenylalkyl may be optionally substituted on the phenyl ring; R₆ is H, alkyl, phenyl or phenylalkyl, where the phenyl and phenylalkyl may be optionally substituted on the phenyl ring; m is 3 or 4; n is 0, 1 or 2; p is 1 or 2; and q is 0 or 1.

Claim 19

A compound of the formula or its enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs or solvates thereof, wherein: A₁ and A₂ are each independently H, alkyl, substituted alkyl, phenyl or substituted phenyl; G₁ is S or O; G₂ is H, -C(O)OH, -C(O)NH₂, 5-tetrazolyl, -C(O)N(R₇)OH or -CH₂OH; X is O or R₈N; Y and Z are each independently -CH₂- or -C(O)-; R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are each independently H or alkyl; R₁ and A₁ taken together may be -(CH₂) m ; R₈ is H, alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl or -C(O)R₉; R₉ is H, alkyl, phenyl, phenylalkyl, substituted phenyl or (substituted phenyl)alkyl; m is 3 or 4; n is 0, 1 or 2; p is 0, 1 or 2; and q is 0 or 1, with the proviso that when p is 0, q is also 0.