Substituted 3-cyano-[1.7], [1.5], and [1.8] naphthyridine inhibitors of tyrosine kinases

A method of inhibiting the biological effects of a deregulated protein tyrosine kinase in a mammal in need thereof which comprises administering to said mammal a compound of formula 1 having the structure

• 58
• wherein:
• X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups;
• or
• X is pyridinyl, pyrimidinyl, or Ph;
• or
• X is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms, where the bicyclic heteroaryl ring contains 1 to 4 heteroatoms selected from N, O, and S;
• wherein the bicyclic aryl or bicyclic heteroaryl ring may be optionally mono-, di-, tri-, or tetra-substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymnethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
• or
• X is the radical
• 59
• ;
• E is pyridinyl, pyrimidinyl, or Ph;
• T is substituted on E at carbon and is
• —NH(CH2)m—, —O(CH2)m—, —S(CH2)m—, —NR(CH2)m—, —(CH2)m—(CH2)mNH—, —(CH2)mO—, —(CH2)mS—, or —(CH2)mNR—;
• L is a Ph;
• or
• L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatoms selected from N, O, and S;
• wherein the heteroaryl ring may be optionally mono- or di-substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
• Pyridinyl, pyrimidinyl, or Ph are pyridinyl, pyrimidinyl, or phenyl radicals, respectively, which may be optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
• Z is —NH—, —O—, —S—, or —NR—;
• R is alkyl of 1-6 carbon atoms, or carboalkyl of 2-7 carbon atoms;
• A″ is a diavalent moiety selected from the group
• 60
• G1, G2, G3, and G4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 2-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkynoyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulphpnyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, R2NH,
• 61
• ,
• R7—(C(R6)2)g—Y—, R7—(C(R6)2)p—M—(C(R6)2)k—Y—, Het-(C)(R6)2)q—W—(C(R6)2)k—Y—, with the proviso that G3 and G4 are not R2NH;
• Y is a divalent radical selected from the group consisting of
• 62
• R7 is —NR6R6, —OR6, —J, —N(R6)3+, or —NR6(OR6);
• M is >NR6, —O—, >N—(C(R6)2)pNR6R6, or >N—(C(R6)2)p—OR6;
• W is >NR6, —O— or is a bond;
• Het is a heterocyclic radical selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine , tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran, and
• 63
• which may be optionally mono- or di-substituted on carbon with R6, hydroxy, —N(R6)2, —OR6—(C(R6)2)sOR6 or —(C(R6)2)sN(R6)2;
• optionally mono-substituted on nitrogen with R6;
• and
• optionally mono or di-substituted on a saturated carbon with divalent radicals —O— or —O(C(R6)2)sO—;
• R6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl 2-7 carbon atoms, phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms;
• with the proviso that the alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• R2, is selected from the group consisting of
• 64
• R3 is hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms,
• 65
• R7—(C(R6)2)s—, R7—(C(R6)2)p—M—(C(R6)2)r—, R8R9—CH—M—(C(R6)2)r—, or Het-(C(R6)2)q—W—(C(R6)2)r—;
• R5 is hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms,
• 66
• R7—(C(R6)2)s—, R7—(C(R6)2)p—M—(C(R6)2)r—, R8R9—CH—M—(C(R6)2)r—, or Het-(C(R6)2)q—W—(C(R6)2)r—;
• R8, and R9 are each, independently, —(C(R6)2)rNR6R6, or —(C(R6)2)rOR6;
• J is independently hydrogen, chlorine, fluorine, or bromine;
• Q is alkyl of 1-6 carbon atoms or hydrogen;
• a=0-1;
• g=1-6;
• k=0-4;
• n is 1;
• m is 0-3;
• p=2-4;
• q=0-4;
• r=1-4;
• s=1-6;
• u=0-4 and v=0-4, wherein the sum of u+v is 2-4;
• or a pharmaceutically acceptable salt thereof,
• provided that
• when R6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• and provided that
• when R3 is bound to sulfur, it cannot be hydrogen, carboxy, carboalkoxy, or carboalkyl;
• and provided that
• when Y is —NR6— and R7 is —NR6R6, —N(R6)3+, or —NR6(OR6), then g=2-6;
• when M is —O— and R7 is —OR6 then p=1-4;
• when Y is —NR6— then k=2-4;
• when Y is —O— and M or W is —O— then k=1-4
• when W is not a bond with Het bonded through a nitrogen atom then q=2-4
• and when W is a bond with Het bonded through a nitrogen atom and Y is —O— or —NR6— then k=2-4;
• and finally provided that
• when A″ is the moiety
• 67
• n=0,
• Z is NH,
• G1 is hydrogen, halogen, alkyl alkoxy, hydroxy, alkanoyloxy of 2-6 carbon atoms, or phenoxy, and
• G2 is hydrogen, halogen, alkyl, hydroxy, carboxyalkyl, carboalkoxyalkyl, hydroxyalkyl, alkoxy,halomethyl, carboxyl, carboalkoxy, alkanoylamino, or alkenoylamino,
• then X can not be a pyridinyl, pyrimidinyl, or phenyl ring that is substituted with a hydroxy or alkoxy group.

A method of treating, inhibiting the growth of, or eradicating neoplasms in a mammal in need thereof which comprises administering to said mammal a compound of formula i having the structure

• 68
• wherein:
• X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups;
• or
• X is pyridinyl, pyrimidinyl, or Ph;
• or
• X is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms, where the bicyclic heteroaryl ring contains 1 to 4 heteroatoms selected from N, O, and S;
• wherein the bicyclic aryl or bicyclic heteroaryl ring may be optionally mono-, di-, tri-, or tetra-substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkykninoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
• or
• X is the radical
• 69
• E is pyridinyl, pyrimidinyl, or Ph;
• T is substituted on E at carbon and is
• —NH(CH2)m—, —O(CH2)m—, —S(CH2)m—, —NR(CH2)m—, —(CH2)m—(CH2)mNH—, —(CH2)mO—, —(CH2)mS—, or —(CH2)mNR—;
• L is a Ph;
• or
• L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatoms selected from N, O, and S;
• wherein the heteroaryl ring may be optionally mono- or di-substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
• Pyridinyl, pyrimidinyl, or Ph are pyridinyl, pyrimidinyl, or phenyl radicals, respectively, which may be optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, 5 alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
• Z is —NH—, —O—, —S—, or —NR—;
• R is alkyl of 1-6 carbon atoms, or carboalkyl of 2-7 carbon atoms;
• A″ is a diavalent moiety selected from the group
• 70
• G1, G2, G3, and G4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 2-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkynoyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulphonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 14 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, R2NH,
• 71
• R7—(C(R6)2)g—Y—, R7—(C(R6)2)p—M—(C(R6)2)k—Y—, Het-(C(R6)2)q—W—(C(R6)2)k—Y—, with the proviso that G3 and G4 are not R2NH;
• Y is a divalent radical selected from the group consisting of
• 72
• R7 is —NR6R6, —OR6, —J, —N(R6)3+ or —NR6(OR6);
• M is >NR6, —O—, >N—(C(R6)2)pNR6R6, or >N—(C(R6)2)p—OR6;
• W is >NR6, —O— or is a bond;
• Het is a heterocyclic radical selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3triazole, 1,2,4-triazole, thiazole, thiazolidine , tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran, and
• 73
• which may be optionally mono- or di-substituted on carbon with R6, hydroxy, —N(R6)2, —OR6—(C(R6)2)sOR6 or —(C(R6)2)sN(R6)2;
• optionally mono-substituted on nitrogen with R6;
• and
• optionally mono or di-substituted on a saturated carbon with divalent radicals —O— or —O(C(R6)2)sO—;
• R6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, ayl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl 2-7 carbon atoms, phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms;
• with the proviso that the alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• R2, is selected from the group consisting of
• 74
• R3 is hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms,
• 75
• R7—(C(R6)2)s—, R7—(C(R6)2)p—M—C(R6)2)r—, R8R9—CH—M—(C(R6)2)r—, or Het-(C(R6)2)q—W—(C(R6)2)r—;
• R5 is hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms,
• 76
• R7—(C(R6)2)s—, R7—(C(R6)2)p—M—(C(R6)2)r, R8R9—CH—M—(C(R6)2)r—, or Het-(C(R6)2)q—W—(C(R6)2)r—;
• R8, and R9 are each, independently, —(C(R6)2)rNR6R6, or —(C(R)2)rOR6;
• J is independently hydrogen, chlorine, fluorine, or bromine;
• Q is alkyl of 1-6 carbon atoms or hydrogen;
• a=0-1;
• g=1-6;
• k=0-4;
• n is 0-1;
• m is 0-3;
• p=2-4;
• q=0-4;
• r=1-4;
• s=1-6;
• u =0-4 and v=0-4, wherein the sum of u+v is 2-4;
• or a pharmaceutically acceptable salt thereof,
• provided that
• when R6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• and provided that
• when R3 is bound to sulfur, it cannot be hydrogen, carboxy, carboalkoxy, or carboalkyl;
• and provided that
• when Y is —NR6— and R7 is —NR6R6, —N(R6)3+ or —NR6(OR6), then g=2-6;
• when M is —O— and R7 is —OR6 then p=1-4;
• when Y is —NR6— then k=2-4;
• when Y is —O— and M or W is —O— then k=1-4
• when W is not a bond with Het bonded through a nitrogen atom then q=2-4
• and when W is a bond with Het bonded through a nitrogen atom and Y is —O— or —NR6— then k=2-4;
• and finally provided that
• when A″ is the moiety
• 77
• n=0,
• Z is NH,
• G1 is hydrogen, halogen, alkyl, alkoxy, hydroxy, alkanoyloxy of 2-6 carbon atoms, or phenoxy, and
• G2 is hydrogen, halogen, alkyl, hydroxy, carboxyalkyl, carboalkoxyalkyL hydroxyalkyl, alkoxy,halomethyl, carboxyl, carboalkoxy, alkanoylamino, or alkenoylamino,
• then X can not be a pyridinyl, pyrimidinyl, or phenyl ring that is substituted with a hydroxy or alkoxy group.

A method of treating, inhibiting the progression of, or eradicating polycystic kidney disease in a mammal in need thereof which comprises administering to said mammal a compound of formula I having the structure

• 78
• wherein:
• X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups;
• or
• X is pyridinyl pyrimidinyl, or Ph;
• or
• X is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms, where the bicyclic heteroaryl ring contains 1 to 4 heteroatoms selected from N, O, and S;
• wherein the bicyclic aryl or bicyclic heteroaryl ring may be optionally mono-, di-, tri-, or tetra-substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy qf 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
• or
• X is the radical
• 79
• ;
• E is pyridinyl, pyrimidinyl, or Ph;
• T is substituted on E at carbon and is
• —NH(CH2)m—, —O(CH2)m, —S(CH2)m—, —NR(CH2)m—, —(CH2)m—(CH2)mNH—, —(CH2)mO—, —(CH2)mS—, or —(CH2)mNR—;
• L is a Ph;
• or
• L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatoms selected from N, O, and S;
• wherein the heteroaryl ring may be optionally mono- or di-substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
• Pyridinyl, pyrimidinyl, or Ph are pyridinyl, pyrimidinyl, or phenyl radicals, respectively, which may be optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, -alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
• Z is —NH—, —O—, —S—, or —NR—;
• R is alkyl of 1-6 carbon atoms, or carboalkyl of 2-7 carbon atoms;
• A″ is a diavalent moiety selected from the group
• 80
• G1, G2, G3, and G4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 2-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkynoyloxymethyl of 4-9 carbon 5 atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulphonyl of 1-6 carbon atoms, akylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, R2NH,
• 81
• R7—(C(R6)2)g—Y—, R7—(C(R6)2)p—M—(C(R6)2)k—Y—, Het-(C(R6)2)q—W—(C(R6)2)k—Y—, with the proviso that G3 and G4 are not R2NH;
• Y is a divalent radical selected from the group consisting of
• 82
• ;
• R7 is —NR6R6, —OR6, —J, —N(R6)3+, or —NR6(OR6);
• M is >NR6, —O—, >N—(C(R6)2)pNR6R6, or >N—(C(R6)2)p—OR6;
• W is >NR6, —O— or is a bond;
• Het is a heterocyclic radical selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine , tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran, and
• 83
• which may be optionally mono- or di-substituted on carbon with R6, hydroxy, —N(R6)2, —OR6—(C(R6)2)sOR6 or —(C(R6)2)sN(R6)2;
• optionally mono-substituted on nitrogen with R6;
• and
• optionally mono or di-substituted on a saturated carbon with divalent radicals —O— or —O(C(R6)2)sO—;
• R6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl 2-7 carbon atoms, phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms;
• with the proviso that the alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• R2, is selected from the group consisting of
• 84
• R3 is hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms,
• 85
• ,
• R7—(C(R6)2)s—, R7(C(R6)2)p—M—(C(R6)2)r—, R8R9—CH—M—(C(R6)2)r—, or Het-(C(R6)2)q—W—(C(R6)2)r—;
• R5 is hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms,
• 86
• ,
• R7—(C(R6)2)s—, R7—(C(R6)2)p—M—(C(R6)2)r—, R8R9—CH—M—(C(R6)2)r—, or Het-(C(R6)2)q—W—(C(R6)2)r—;
• R8, and R9 are each, independently, —(C(R6)2)rNR6R6, or —(C(R6)2)rOR6;
• J is independently hydrogen, chlorine, fluorine, or bromine;
• Q is alkyl of 1-6 carbon atoms or hydrogen;
• a=0-1;
• g=1-6;
• k=0-4;
• n is 0-1;
• m is 0-3;
• p=2-4;
• q=0-4;
• r=1-4;
• s=1-6;
• u=0-4 and v=0×4, wherein the sum of u+v is 2-4;
• or a pharmaceutically acceptable salt thereof,
• provided that
• when R6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• and provided that
• when R3 is bound to sulfur, it cannot be hydrogen, carboxy, carboalkoxy, or carboalkyl;
• and provided that
• when Y is —NR6— and R7 is —NR6R6, —N(R6)3+ or —NR6(OR6), then g=2-6;
• when M is —O— and R7 is —OR6 then p=1-4;
• when Y is —NR6— then k=2-4;
• when Y is —O— and M or W is —O— then k=1-4
• when W is not a bond with Het bonded through a nitrogen atom then q=2-4
• and when W is a bond with Het bonded through a nitrogen atom and Y is —O— or —NR6— then k=2-4;
• and finally provided that
• when A″ is the moiety
• 87
• n=0,
• Z is NH,
• G1 is hydrogen, halogen, alkyl, alkoxy, hydroxy, alkanoyloxy of 2-6 carbon atoms, or phenoxy, and
• G2 is hydrogen, halogen, alkyl, hydroxy, carboxyalkyl, carboalkoxyalkyl, hydroxyalkyl, alkoxy,halomethyl carboxyl, carboalkoxy, alkanoylamino, or alkenoylamino,
• then X can not be a pyridinyl, pyrimidinyl, or phenyl ring that is substituted with a hydroxy or alkoxy group.

A method of treating, inhibiting the progression of, or eradicating colonic polyps in a mammal in need thereof which comprises administering to said mammal a compound of formula I having the structure

• 88
• wherein:
• X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups;
• or
• X is pyridinyl, pyrmidinyl, or Ph;
• or
• X is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms, where the bicyclic heteroaryl ring contains 1 to 4 heteroatoms selected from N, O, and S;
• wherein the bicyclic aryl or bicyclic heteroaryl ring may be optionally mono-, di-, tri-, or tetra-substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylarrino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, allynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
• or
• X is the radical
• 89
• ;
• E is pyridinyl, pyrimidinyl, or Ph;
• T is substituted on E at carbon and is
• —NH(CH2)m—, —O(CH2)m, —S(CH2)m—, —NR(CH2)m—, —(CH2)m—(CH2)mNH—, —(CH2)mO—, —(CH2)mS—, or —(CH2)mNR—;
• L is a Ph;
• or
• L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatoms selected from N, O, and S;
• wherein the heteroaryl ring may be optionally mono- or di-substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylariino, benzylamino, alkanoylaiiino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
• Pyridinyl, pyrimidinyl, or Ph are pyridinyl, pyrimidinyl, or phenyl radicals, respectively, which may be optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, allynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
• Z is —NH—, —O—, —S—, or —NR—;
• R is alkyl of 1-6 carbon atoms, or carboalkyl of 2-7 carbon atoms;
• A″ is a diavalent moiety selected from the group
• 90
• G1, G2, G3, and G4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxyrnethyl, halomethyl, alkanoyloxy of 2-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkynoyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulphonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, R2NH,
• 91
• ,
• R7—(C(R6)2)g—Y—, R7—(C(R6)2)p—M—(C(R6)2)k—Y—, Het-(C(R6)2)q—W—(C(R6)2)k—Y—, with the proviso that G3 and G4 are not R2NH;
• Y is a divalent radical selected from the group consisting of
• 92
• ;
• R7 is —NR6R6, —OR6, —J, —N(R6)3+, or —NR6(OR6);
• M is >NR6, —O—, >N—(C(R6)2)pNR6R6, or >N—(C(R6)2)p—OR6;
• W is >NR6, —O— or is a bond;
• Het is a heterocyclic radical selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine , tetrazole, piperazifle, furan, thiophene, tetrahydrothiophene, tetrahydrofliran, dioxane, 1,3-dioxolane, tetrahydropyran, and
• 93
• which may be optionally mono- or di-substituted on carbon with R6, hydroxy, —N(R6)2, —OR6—(C(R6)2)sOR6 or —(C(R6)2)sN(R6)2;
• optionally mono-substituted on nitrogen with R6;
• and
• optionally mono or di-substituted on a saturated carbon with divalent radicals —O— or —O(C(R6)2)sO—;
• R6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl 2-7 carbon atoms, phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, anino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms;
• with the proviso that the alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• R2, is selected from the group consisting of
• 94
• R3 is hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms,
• 95
• R7-(C(R6)2)s—, R7—(C(R6)2)p—M—(C(R6)2)r—, R8R9—CH—M—(C(R6)2)r—, or Het-(C(R6)2)q—W—(C(R6)2)r—;
• R5 is hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms,
• 96
• ,
• R7—(C(R6)2)s—, R7—(C(R6)2)p—M—(C(R6)2)r—, R8R9—CH—M—(C(R6)2)r—, or Het-(C(R6)2)q—W—(C(R6)2)r—;
• R8, and R9 are each, independently, —(C(R6)2)rNR6R6, or —(C(R6)2)rOR6;
• J is independently hydrogen, chlorine, fluorine, or bromine;
• Q is alkyl of 1-6 carbon atoms or hydrogen;
• a=0-1;
• g=1-6;
• k=0-4;
• n is 0-1;
• m is 0-3;
• p=2-4;
• q=0-4;
• r=1-4;
• s=1-6;
• u=0-4 and v=0-4, wherein the sum of u+v is 2-4;
• or a pharmaceutically acceptable salt thereof,
• provided that
• when R6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• and provided that
• when R3 is bound to sulfur, it cannot be hydrogen, carboxy, carboalkoxy, or carboalkyl;
• and provided that
• when Y is —NR6— and R7 is —NR6R6, —N(R6)3+, or —(OR6), then g=2-6;
• when M is —O— and R7 is —OR6 then p=1-4;
• when Y is —NR6— then k=2-4;
• when Y is —O— and M or W is —O— then k=1-4
• when W is not a bond with Het bonded through a nitrogen atom then q=2-4
• and when W is a bond with Het bonded through a nitrogen atom and Y is —O— or —NR6— then k=2-4;
• and finally provided that
• when A″ is the moiety
• 97
• n=0,
• Z is NH,
• G1 is hydrogen, halogen, alkyl, alkoxy, hydroxy, alkanoyloxy of 2-6 carbon atoms, or phenoxy, and
• G2 is hydrogen, halogen, alkyl, hydroxy, carboxyalkyl, carboalkoxyalkyl, hydroxyalkyl, alkoxyhalomethyl, carboxyl, carboalkoxy, alkanoylamino, or alkenoylamino,
• then X can not be a pyridinyl, pyrimidinyl, or phenyl ring that is substituted with a hydroxy or alkoxy group.

A pharmaceutical composition which comprises a compound of formula I having the structure

• 98
• wherein:
• X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups;
• or
• X is pyridinyl, pyrimidinyl, or Ph;
• or
• X is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms, where the bicyclic heteroaryl ring contains 1 to 4 heteroatoms selected from N, O, and S;
• wherein the bicyclic aryl or bicyclic heteroaryl ring may be optionally mono-, di-, tri-, or tetra-substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
• or
• X is the radical
• 99
• E is pyridinyl, pyrimidinyl, or Ph;
• T is substituted on E at carbon and is
• —NH(CH2)m, —O(CH2)m—, —S(CH2)m—, —NR(CH2)m—, —(CH2)m—(CH2)mNH—, —(CH2)mO—, —(CH2)mS—, or —(CH2)mNR—;
• L is a Ph;
• or
• L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatoms selected from N, O, and S;
• wherein the heteroaryl ring may be optionally mono- or di-substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
• Pyridinyl, pyrimidinyl, or Ph are pyridinyl pyrimidinyl, or phenyl radicals, respectively, which may be optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, 5 alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
• Z is —NH—, —O—, —S—, or —NR—;
• R is alkyl of 1-6 carbon atoms, or carboalkyl of 2-7 carbon atoms;
• A″ is a diavalent moiety selected from the group
• 100
• G1, G2, G3, and G4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 2-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkynoyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulphonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, R2NH,
• 101
• R7-(C(R6)2)g—Y—, R7—(C(R6)2)p—M—(C(R6)2)k—Y—, Het-(C(R6)2)q—W—(G(R6)2)k—Y—, with the proviso that G3 and G4 are not R2NH;
• Y is a divalent radical selected from the group consisting of
• 102
• R7 is —NR6R6, —OR6, —J, —N(R6)3+, or —NR6(OR6);
• M is >NR6, —O—, >N—(C(R6)2)pNR6R6, or >N—(C(R6)2)p—OR6;
• W is >NR6, —O— or is a bond;
• Het is a heterocyclic radical selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran, and
• 103
• which may be optionally mono- or di-substituted on carbon with R6, hydroxy, —N(R6)2, —OR6—(C(R6)2)sOR6 or —(C(R6)2)sN(R6)2;
• optionally mono-substituted on nitrogen with R6;
• and
• optionally mono or di-substituted on a saturated carbon with divalent radicals —O— or —O(C(R6)2)sO—;
• R6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl 2-7 carbon atoms, phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amiino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, =thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylanino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms;
• with the proviso that the alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• R2, is selected from the group consisting of
• 104
• R3 is hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms,
• 105
• R7(C(R6)2)s—, R7—(C(R6)2)p—M—(C(R6)2)r—, R8R9CH—M—(C(R6)2)r—, or Het-(C(R6)2)q—W—(C(R6)2)r—;
• R5 is hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms,
• 106
• R7—(C(R6)2)s—, —R7(C(R6)2)p—M—(C(R6)2)r—, R8R9—CH—M—(C(R6)2)r—, or Het-(C(R6)2)q—W—(C(R6)2)r—;
• R8, and R9 are each, independently, —(C(R6)2)rNR6R6, or —(C(R6)2)rOR6;
• J is independently hydrogen, chlorine, fluorine, or bromine;
• Q is alkyl of 1-6 carbon atoms or hydrogen;
• a=0-1;
• g=1-6;
• k=0-4;
• n is 1;
• m is 0-3;
• p=2-4;
• q=0-4;
• r=1-4;
• s=1-6;
• u=0-4 and v=0-4, wherein the sum of u+v is 2-4;
• or a pharmaceutically acceptable salt thereof,
• provided that
• when R6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• and provided that
• when R3 is bound to sulfur, it cannot be hydrogen, carboxy, carboalkoxy, or carboalkyl;
• and provided that
• when Y is —NR6— and R7 is —NR6R6, —N(R6)3+, or —NR6(OR6), then g=2-6;
• when M is —O— and R7 is —OR6 then p=1-4;
• when Y is —NR6— then k=2-4;
• when Y is —O— and M or W is —O— then k=1-4
• when W is not a bond with Het bonded through a nitrogen atom then q=2-4
• and when W is a bond with Het bonded through a nitrogen atom and Y is —O— or —NR6— then k=2-4;
• and finally provided that
• when A″ is the moiety
• 107
• n=0,
• Z is NH,
• G1 is hydrogen, halogen, alkyl, alkoxy, hydroxy, alkanoyloxy of 2-6 carbon atoms, or phenoxy, and
• G2 is hydrogen, halogen, alkyl, hydroxy, carboxyalkyl, carboalkoxyalkyl, hydroxyalkyl, alkoxy, halomethyl, carboxyl, carboalkoxy, alkanoylamino, or alkenoylamino,
• then X can not be a pyridinyl, pyrimidinyl, or phenyl ring that is substituted with a hydroxy or alkoxy group;
• and a pharmaceutically acceptable carrier.