3-cyanoquinolines as inhibitors of EGF-R and HER2 kinases

A method of treating, inhibiting the growth of, or eradicating neoplasms in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I) represented by the structure

• 25
• wherein:
• Z is —NH—, —O—, —S—, or —NR—;
• R is alkyl of 1 to 6 carbon atoms, or carboalkyl of 2 to 7 carbon atoms;
• X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms;
• or
• X is pyridinyl, pyrimidinyl, or aryl which may optionally be mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• 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 independently 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 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5S—), benzoyl, benzyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1 to 5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• or
• X is the radical
• 26
• E is pyridinyl, pyrimidinyl, or aryl optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• 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 an aryl ring optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• or
• L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatoms independently 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 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5S—), benzoyl, benzyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1 to 5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• Pyridinyl, pyrimidinyl, or aryl are pyridinyl, pyrimidinyl, or aryl radicals, respectively, optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• G1, G2, G3, and G4 are each, independently, hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkenyloxy of 2 to 6 carbon atoms, alkynyloxy of 2 to 6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 2 to 6 carbon atoms, alkenoyloxy of 3 to 8 carbon atoms, alkynoyloxy of 3 to 8 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkenoyloxymethyl of 4 to 9 carbon atoms, alkynoyloxymethyl of 4 to 9 carbon atoms, alkoxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, alkylsulphinyl of 1 to 6 carbon atoms, alkylsulphonyl of 1 to 6 carbon atoms, alkylsulfonamido of 1 to 6 carbon atoms, alkenylsulfonamido of 2 to 6 carbon atoms, alkynylsulfonamido of 2 to 6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5S—), benzyl, amino, hydroxyamino, alkoxyamino of 1 to 4 carbon atoms, alkylamino of 1 to 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 to 12 carbon atoms, phenylamino, benzylamino, R2NH,
• 27
• R8R9—CH-M-(C(R6)2)k—Y—;
• R7—(C(R6)2)g—Y—, R7—(C(R6)2)p-M-(C(R6)2)k—Y—,
• or
• Het-(C(R6)2)q—W—(C(R6)2)k—Y—,
• provided that either G2 or G3 or both G2 and G3 are R2NH;
• Y is a divalent radical selected from the group consisting of
• 28
• R7 is —NR6R6, —OR6, -J, —N(R6)3 +Q−, 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
• 29
• 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 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, carboxyalkyl 2 to 7 carbon atoms, phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, amino, alkylamino of 1 to 3 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, carboxyl, carboalkoxy of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5S—), benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms;
• provided 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
• 30
• R3 is hydrogen, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, phenyl, carboalkyl of 2 to 7 carbon atoms,
• 31
• 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—;
• R4 is —NR6R6, —OR6, —SR6, R7-(C(R6)2)p—S—, R7-(C(R6)2)p—N(R6)—, R7-(C(R6)2)p—O—, R8R9—CH—N(R6)—, R8R9—CH—S—, R8R9—CH—O—, Het-(C(R6)2)q—N(R6)—, Het-(C(R6)2)q—S—, Het-(C(R6)2)q—O—,
• 32
• cysteine, or a peptide comprised of 2 to 10 native amino acid residues containing at least one unoxidized cysteine residue wherein R4 is bound to the rest of the molecule through the sulfur atom of one or more of the cysteine residues;
• R8 and R9 are each, independently, —(C(R6)2)rNR6R6, or —(C(R6)2)rOR6;
• J is independently hydrogen, chlorine, fluorine, or bromine;
• a is an integer of 0-1;
• g is an integer of 1-6;
• k is an integer of 0-4;
• n is an integer of 0-1;
• m is an integer of 0-3;
• p is an integer of 2-4;
• q is an integer of 0-4;
• r is an integer of 1-4;
• s is an integer of 1-6
• u is an integer of 2-6;
• Q− is a counterion selected from salts formed from organic and inorganic acids;
• provided that:
• a. when R6 is alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• b. when Y is —NR6— and R7 is —NR6R6, —N(R6)3 +Q−, or —NR6(OR6), then g is an integer of 2 to 6;
• c. when M is —O— and R7 is —OR6 then p is an integer of 1 to 4;
• d. when Y is —NR6— then k is an integer of 2 to 4;
• e. when Y is —O— and M or W is —O— then k is an integer of 1 to 4;
• f. when W is not a bond with Het bonded through a nitrogen atom then q is an integer of 2 to 4 and when W is a bond with Het bonded through a nitrogen atom and Y is —O— or —NR613 then k is an integer of 2 to 4;
• or a pharmaceutically acceptable salt thereof.

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 an effective amount of a compound of Formula (I) represented by the structure:

• 33
• wherein:
• Z is —NH—, —O—, —S—, or —NR—;
• R is alkyl of 1 to 6 carbon atoms, or carboalkyl of 2 to 7 carbon atoms;
• X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms;
• or
• X is pyridinyl, pyrimidinyl, or aryl which may optionally be mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• 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 independently 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 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5S—), benzoyl, benzyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1 to 5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• or
• X is the radical
• 34
• E is pyridinyl, pyrimidinyl, or aryl optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• 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 an aryl ring optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• or
• L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatoms independently 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 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5S—), benzoyl, benzyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1 to 5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• Pyridinyl, pyrimidinyl, or aryl are pyridinyl, pyrimidinyl, or aryl radicals, respectively, optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto,), and benzoylamino;
• G1, G2, G3, and G4 are each, independently, hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkenyloxy of 2 to 6 carbon atoms, alkynyloxy of 2 to 6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 2 to 6 carbon atoms, alkenoyloxy of 3 to 8 carbon atoms, alkynoyloxy of 3 to 8 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkenoyloxymethyl of 4 to 9 carbon atoms, alkynoyloxymethyl of 4 to 9 carbon atoms, alkoxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, alkylsulphinyl of 1 to 6 carbon atoms, alkylsulphonyl of 1 to 6 carbon atoms, alkylsulfonamido of 1 to 6 carbon atoms, alkenylsulfonamido of 2 to 6 carbon atoms, alkynylsulfonamido of 2 to 6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5S—), benzyl, amino, hydroxyamino, alkoxyamino of 1 to 4 carbon atoms, alkylamino of 1 to 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 to 12 carbon atoms, phenylamino, benzylamino, R2NH,
• 35
• R8R9—CH-M-(C(R6)2)k—Y—, R7—(C(R6)2)g—Y—, R7—(C(R6)2)p-M-(C(R6)2)k—Y—,
• or
• Het-(C(R6)2)q—W—(C(R6)2)k—Y—,
• provided that either G2 or G3 or both G2 and G3 are R2NH;
• Y is a divalent radical selected from the group consisting of
• 36
• R7 is —NR6R6, —OR6, -J, —N(R6)3 +Q− 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
• 37
• 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 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, carboxyalkyl 2 to 7 carbon atoms, phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, amino, alkylamino of 1 to 3 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, carboxyl, carboalkoxy of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5S—), benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms;
• provided 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
• 38
• R3 is hydrogen, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, phenyl, carboalkyl of 2 to 7 carbon atoms,
• 39
• 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—;
• R4 is —NR6R6, —OR6, —SR6, R7-(C(R6)2)p—S—, R7-(C(R6)2)p—N(R6)—, R7-(C(R6)2)p—O—, R8R9—CH—N(R6)—, R8R9—CH—S—, R8R9—CH—O—, Het-(C(R6)2)q—N(R6)—, Het-(C(R6)2)q—S—, Het-(C(R6)2)q—O—,
• 40
• cysteine, or a peptide comprised of 2 to 10 native amino acid residues containing at least one unoxidized cysteine residue wherein R4 is bound to the rest of the molecule through the sulfur atom of one or more of the cysteine residues;
• R8 and R9 are each, independently, —(C(R6)2)rNR6R6, or —(C(R6)2)rOR6;
• J is independently hydrogen, chlorine, fluorine, or bromine;
• a is an integer of 0-1;
• g is an integer of 1-6;
• k is an integer of 0-4;
• n is an integer of 0-1;
• m is an integer of 0-3;
• p is an integer of 2-4;
• q is an integer of 0-4;
• r is an integer of 1-4;
• s is an integer of 1-6
• u is an integer of 2-6;
• Q− is a counterion selected from salts formed from organic and inorganic acids;
• provided that:
• a. when R6 is alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• b. when Y is —NR6— and R7 is —NR6R6, —N(R6)3 +Q−, or —NR6(OR6), then g is an integer of 2 to 6;
• c. when M is —O— and R7 is —OR6 then p is an integer of 1 to 4;
• d. when Y is —NR6— then k is an integer of 2 to 4;
• e. when Y is —O— and M or W is —O— then k is an integer of 1 to 4;
• f. when W is not a bond with Het bonded through a nitrogen atom then q is an integer of 2 to 4 and when W is a bond with Het bonded through a nitrogen atom and Y is —O— or —NR6— then k is an integer of 2 to 4;
• or a pharmaceutically acceptable salt thereof.

A method of treating, inhibiting, or eradicating colonic polyps in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I) represented by the structure:

• 41
• wherein:
• Z is —NH—, —O—, —S—, or —NR—;
• R is alkyl of 1 to 6 carbon atoms, or carboalkyl of 2 to 7 carbon atoms;
• X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms;
• or
• X is pyridinyl, pyrimidinyl, or aryl which may optionally be mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• 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 independently 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 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5S—), benzoyl, benzyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1 to 5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• or
• X is the radical
• 42
• E is pyridinyl, pyrimidinyl, or aryl optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• 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 an aryl ring optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• or
• L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatoms independently 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 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5S—), benzoyl, benzyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1 to 5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• Pyridinyl, pyrimidinyl, or aryl are pyridinyl, pyrimidinyl, or aryl radicals, respectively, optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• G1, G2, G3, and G4 are each, independently, hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkenyloxy of 2 to 6 carbon atoms, alkynyloxy of 2 to 6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 2 to 6 carbon atoms, alkenoyloxy of 3 to 8 carbon atoms, alkynoyloxy of 3 to 8 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkenoyloxymethyl of 4 to 9 carbon atoms, alkynoyloxymethyl of 4 to 9 carbon atoms, alkoxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, alkylsulphinyl of 1 to 6 carbon atoms, alkylsulphonyl of 1 to 6 carbon atoms, alkylsulfonamido of 1 to 6 carbon atoms, alkenylsulfonamido of 2 to 6 carbon atoms, alkynylsulfonamido of 2 to 6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5S—), benzyl, amino, hydroxyamino, alkoxyamino of 1 to 4 carbon atoms, alkylamino of 1 to 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 to 12 carbon atoms, phenylamino, benzylamino, R2NH,
• 43
• R8R9—CH-M-(C(R6)2)k—Y—, R7—(C(R6)2)g—Y—, R7—(C(R6)2)p-M-(C(R6)2)k—Y—,
• or
• Het-(C(R6)2)q—W—(C(R6)2)k—Y—,
• provided that either G2 or G3 or both G2 and G3 are R2NH;
• Y is a divalent radical selected from the group consisting of
• 44
• R7 is —NR6R6, —OR6, -J, —N(R6)3 +Q−, 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
• 45
• 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 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, carboxyalkyl 2 to 7 carbon atoms, phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, amino, alkylamino of 1 to 3 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, carboxyl, carboalkoxy of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5S—), benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms;
• provided 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
• 46
• R3 is hydrogen, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, phenyl, carboalkyl of 2 to 7 carbon atoms,
• 47
• 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—;
• R4 is —NR6R6, —OR6, —SR6, R7—(C(R6)2)p—S—, R7-(C(R6)2)p—N(R6)—, R7-(C(R6)2)p—O—, R8R9—CH—N(R6)—, R8R9—CH—S—, R8R9—CH—O—, Het-(C(R6)2)q—N(R6)—, Het-(C(R6)2)q—S—, Het-(C(R6)2)q—O—,
• 48
• cysteine, or a peptide comprised of 2 to 10 native amino acid residues containing at least one unoxidized cysteine residue wherein R4 is bound to the rest of the molecule through the sulfur atom of one or more of the cysteine residues;
• R8 and R9 are each, independently, —(C(R6)2)rNR6R6, or —(C(R6)2)rOR6;
• J is independently hydrogen, chlorine, fluorine, or bromine;
• a is an integer of 0-1;
• g is an integer of 1-6;
• k is an integer of 0-4;
• n is an integer of 0-1;
• m is an integer of 0-3;
• p is an integer of 2-4;
• q is an integer of 0-4;
• r is an integer of 1-4;
• s is an integer of 1-6
• u is an integer of 2-6;
• Q− is a counterion selected from salts formed from organic and inorganic acids;
• provided that:
• a. when R6 is alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• b. when Y is —NR6— and R7 is —NR6R6, —N(R6)3 +Q−, or —NR6(OR6), then g is an integer of 2 to 6;
• c. when M is —O— and R7 is —OR6 then p is an integer of 1 to 4;
• d. when Y is —NR6— then k is an integer of 2 to 4;
• e. when Y is —O— and M or W is —O— then k is an integer of 1 to 4;
• f. when W is not a bond with Het bonded through a nitrogen atom then q is an integer of 2 to 4 and when W is a bond with Het bonded through a nitrogen atom and Y is —O— or —NR6— then k is an integer of 2 to 4;
• or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition which comprises a compound of Formula (I) represented by the structure

• 49
• wherein:
• Z is —NH—, —O—, —S—, or —NR—;
• R is alkyl of 1 to 6 carbon atoms, or carboalkyl of 2 to 7 carbon atoms;
• X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms;
• or
• X is pyridinyl, pyrimidinyl, or aryl which may optionally be mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• 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 independently 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 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5S—), benzoyl, benzyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1 to 5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• or
• X is the radical
• 50
• E is pyridinyl, pyrimidinyl, or aryl optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• T is substituted on E at carbon and is
• —NH(CH2)m—, —O(CH2)m—, —S(CH2)m—, —NR(CH2)m—, —(CH2)m—, —(CH2)m——(CH2)mNH—, —(CH2)mO—, —(CH2)mS—, or —(CH2)mNR—;
• L is an aryl ring optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• or
• L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatoms independently 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 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5S—), benzoyl, benzyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1 to 5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• Pyridinyl, pyrimidinyl, or aryl are pyridinyl, pyrimidinyl, or aryl radicals, respectively, optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
• G1, G2, G3, and G4 are each, independently, hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkenyloxy of 2 to 6 carbon atoms, alkynyloxy of 2 to 6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 2 to 6 carbon atoms, alkenoyloxy of 3 to 8 carbon atoms, alkynoyloxy of 3 to 8 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkenoyloxymethyl of 4 to 9 carbon atoms, alkynoyloxymethyl of 4 to 9 carbon atoms, alkoxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, alkylsulphinyl of 1 to 6 carbon atoms, alkylsulphonyl of 1 to 6 carbon atoms, alkylsulfonamido of 1 to 6 carbon atoms, alkenylsulfonamido of 2 to 6 carbon atoms, alkynylsulfonamido of 2 to 6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5S—), benzyl, amino, hydroxyamino, alkoxyamino of 1 to 4 carbon atoms, alkylamino of 1 to 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 to 12 carbon atoms, phenylamino, benzylamino, R2NH,
• 51
• R8R9—CH-M-(C(R6)2)k—Y—, R7—(C(R6)2)g—Y—, R7—(C(R6)2)p-M-(C(R6)2)k—Y—,
• or
• Het-(C(R6)2)q—W—(C(R6)2)k—Y—,
• provided that either G2 or G3 or both G2 and G3 are R2NH;
• Y is a divalent radical selected from the group consisting of
• 52
• R7 is —NR6R6, —OR6, -J, —N(R6)3 +Q−, 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
• 53
• 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 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, carboxyalkyl 2 to 7 carbon atoms, phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, amino, alkylamino of 1 to 3 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)S—, hydroxy, carboxyl, carboalkoxy of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5S—), benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms;
• provided 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
• 54
• R3 is hydrogen, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, phenyl, carboalkyl of 2 to 7 carbon atoms,
• 55
• 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—;
• R4 is —NR6R6, —OR6, —SR6,
• R7-(C(R6)2)p—S—, R7-(C(R6)2)p—N(R6)—, R7-(C(R6)2)p—O—, R8R9—CH—N(R6)—, R8R9—CH—S—, R8R9—CH—O—, Het-(C(R6)2)q—N(R6)—, Het-(C(R6)2)q—S—, Het-(C(R6)2)q—O—, 56
• cysteine, or a peptide comprised of 2 to 10 native amino acid residues containing at least one unoxidized cysteine residue wherein R4 is bound to the rest of the molecule through the sulfur atom of one or more of the cysteine residues;
• R8 and R9 are each, independently, —(C(R6)2)rNR6R6, or —(C(R6)2)rOR6;
• J is independently hydrogen, chlorine, fluorine, or bromine;
• a is an integer of 0-1;
• g is an integer of 1-6;
• k is an integer of 0-4;
• n is an integer of 0-1;
• m is an integer of 0-3;
• p is an integer of 2-4;
• q is an integer of 0-4;
• r is an integer of 1-4;
• s is an integer of 1-6
• u is an integer of 2-6;
• Q− is a counterion selected from salts formed from organic and inorganic acids;
• provided that:
• a. when R6 is alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• b. when Y is —NR6— and R7 is —NR6R6, —N(R6)3 +Q−, or —NR6(OR6), then g is an integer of 2 to 6;
• c. when M is —O— and R7 is —OR6 then p is an integer of 1 to 4;
• d. when Y is —NR6— then k is an integer of 2 to 4;
• e. when Y is —O— and M or W is —O— then k is an integer of 1 to 4;
• f. when W is not a bond with Het bonded through a nitrogen atom then q is an integer of 2 to 4 and when W is a bond with Het bonded through a nitrogen atom and Y is —O— or —NR6— then k is an integer of 2 to 4;
• or a pharmaceutically acceptable salt thereof in association with one or more pharmaceutically acceptable carriers.