Tricyclic protein kinase inhibitors

A pharmaceutical composition comprising a compound of Formula (I)

• wherein:
• Z is —NH—, —O—, —S(O)a—, 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 of 1 to 6 carbon atom groups;
• or
• X is pyridinyl, pyrimidinyl, or an aryl ring;
• wherein the pyridinyl, pyrimidinyl or aryl ring may be optionally mono-, di-, or tri-substituted with a substituent independently selected from the group consisiting 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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 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 independently 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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
• E is pyridinyl, pyrimidinyl, or an aryl ring;
• wherein the pyridinyl, pyrimidinyl or aryl ring may be optionally mono-, di-, or tri-substituted with a substituent selected from the group consisiting 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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;
• T is substituted on E at a carbon and is
• —NH(CH2)m—, —O(CH2)m—, —S(O)a—(CH2)m—, NR(CH2)m—, (CH2)m—, —(CH2)mNH —, —(CH2)mO —, —(CH2)mS(O)a—, or —(CH2)mNR—;
• L is an aryl ring;
• that is 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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
• 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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;
• A″ is a moiety selected from the group
• G1, G2, G3 and G4 are independently selected from the group consisting of hydrogen, and alkyl of 1 to 6 carbon atoms;
• R1 is —H, R11—CH2—, —R12,
• R11 is —H, alkyl of 1 to 5 carbon atoms, aryl, or R13—(C(R6)2)k—;
• R13 is
• R7—R7(C(R6)2)p—M— or Het-(C(R6)2)q—W—;
• R7 is —H, —NR6R6, —OR6, —J, —N(R6)3+, or —NR6(OR6);
• or 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, optionally mono- or di-substituted on carbon by —R6, hydroxy, —N(R6)2, —OR6 —(C(R6)2)sOR6, or —(C(R6)2)sN(R6)2;
• or
• 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 independently selected from —H, 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 6 carbon atoms, carboalkyl of 2 to 7 carbon atoms, carboxyalkyl of 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 1-3 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, hydroxy, carboxyl, carboalkoxy of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, and alkyl of 1 to 6 carbon atoms;
• R12 is alkylsulphonyl of 1 to 6 carbon atoms, carboalkoxy of 2 to 7 carbon atoms, or carboalkyl of 2 to 7 carbon atoms;
• R5 is hydrogen, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, aryl, carboalkyl of 2 to 7 carbon atoms,
• 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 —H, —F, or —J′;
• J′ is independently chlorine, bromine, iodine, tosylate (p-toluenesulfonate), or mesylate (methanesulfonate);
• Q is Q′, alkoxy of 1 to 6 carbon atoms, hydroxy, or hydrogen;
• Q′ is alkyl of 1 to 6 carbon atoms;
• R2 is selected from the group consisting of
• R3 is independently selected from —H, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, aryl, carboalkyl of 2 to 7 carbon atoms, and R3a—(C(R6)2)s—;
• R3a is
• R7—, R7—(C(R6)2)p—M—, R8R9—CH—M—, or Het-(C(R6)2)q—W—,
• a is 0-2;
• k is 1, 3-5;
• n is 0-1;
• m is 0-3;
• p is 2-4;
• q is 0-4;
• r is 1-4;
• s is 1 to 6;
• u is 0-4 and v is 0-4, wherein the sum of u+v is 2-4;
• provided that:
• a. when —R6 is alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms, said alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• b. when R3 is bound to sulfur, R3 is not —H, carboxy, carboalkoxy, or carboalkyl;
• c. when M is —O—, and R7 is —OR6, then p is 1-4;
• d. when M is —O—, then k is 1 to 5;
• e. when W is —O—, then k is 1 to 5;
• f. when R7 is —OR6, then k is 1 to 5;
• g. when W is not a bond with Het bonded through a nitrogen atom, q is 2-4, and when W is a bond, q is 0;
• or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

A method of treating, inhibiting the growth of, or eradicating a neoplasm in a mammal in need thereof which comprises providing to said mammal an effective amount of a compound of Formula (I)

• wherein:
• Z is —NH—, —O—, —S(O)a—, 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 of 1 to 6 carbon atom groups;
• or
• X is pyridinyl, pyrimidinyl, or an aryl ring;
• wherein the pyridinyl, pyrimidinyl or aryl ring may be optionally mono-, di-, or tri-substituted with a substituent independently 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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 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 independently 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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, methylmercapto, and benzoylamino;
• or
• X is the radical
• E is pyridinyl, pyrimidinyl, or an aryl ring;
• wherein the pyridinyl, pyrimidinyl or aryl ring may be optionally mono-, di-, or tri-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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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;
• T is substituted on E at a carbon and is
• —NH(CH2)m—, —O(CH2)m—, —S(O)a—(CH2)m—, —NR(CH2)m—, —(CH2)m—, —(CH2)mNH—, —(CH2)mO—, —(CH2)mS(O)a—, or —(CH2)mNR—;
• L is an aryl ring;
• that is 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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
• 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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;
• A″ is a moiety selected from the group
• G1, G2, G3 and G4 are independently selected from the group consisting of hydrogen, and alkyl of 1 to 6 carbon atoms;
• R1 is —H, R11—CH2—, —R12,
• R11, is —H, alkyl of 1 to 5 carbon atoms, aryl, or R13—(C(R6)2)k—;
• R13 is
• R7—, R7—(C(R6)2)p—M—, or Het-(C(R6)2)q—W—;
• R7 is —H, —NR6R6, —OR6, —J, —N(R6)3+or —NR6(OR6);
• or 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, and tetrahydropyran, optionally mono- or di-substituted on carbon by —R6, hydroxy, —N(R6)2, —OR6, —(C(R6)2)sOR6, or —(C(R6)2)sN(R6)2;
• or
• 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 independently selected from —H, 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 6 carbon atoms, carboalkyl of 2 to 7 carbon atoms, carboxyalkyl of 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, hydroxy, carboxyl, carboalkoxy of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, and alkyl of 1 to 6 carbon atoms;
• R12 is alkylsulphonyl of 1 to 6 carbon atoms, carboalkoxy of 2 to 7 carbon atoms, or carboalkyl of 2 to 7 carbon atoms;
• R5 is hydrogen, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, aryl, carboalkyl of 2 to 7 carbon atoms,
• 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)r OR6;
• J is independently —H, —F, or —J′;
• J′ is independently chlorine, bromine, iodine, tosylate (p-toluenesulfonate), or mesylate (methanesulfonate);
• Q is Q′, alkoxy of 1 to 6 carbon atoms, hydroxy, or hydrogen;
• Q′ is alkyl of 1 to 6 carbon atoms;
• R2 is selected from the group consisting of
• R3 is independently selected from —H, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, aryl, carboalkyl of 2 to 7 carbon atoms, and R3a—(C(R6)2)s—;
• R3a is
• R7—, R7—(C(R6)2)p—M—, R8R9—CH—M—, or Het-(C(R6)2)q—W—;
• k is 1,3 to 5;
• n is 0 to;
• m is 0 to 3;
• p is 2 to 4;
• q is 0 to 4;
• r is 1 to 4;
• s is 1 to 6;
• u is 0 to 4 and v is 0 to 4, wherein the sum of u+v is 2 to 4;
• provided that:
• a. when —R6 is alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms, said alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• b. when R3 is bound to sulfur, R3 is not —H, carboxy, carboalkoxy, or carboalkyl;
• c. when M is —O—, and R7 is —OR6, then p is 1 to 4;
• d. when M is —O—, then k is 1 to 5;
• e. when W is —O—, then k is 1 to 5;
• f. when R7 is —OR6, then k is 1 to 5;
• g. when W is not a bond with Het bonded through a nitrogen atom, q is 2 to 4, and when W is a bond, q is 0;
• or a pharmaceutically acceptable salt thereof, wherein the neoplasm is selected from the group consisting of breast, kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary, lung, pancreas, liver, prostate, brain, and skin.

A method of treating, inhibiting the progression of, or eradicating polycystic kidney disease in a mammal in need thereof which comprises providing to said mammal an effective amount of a compound of Formula (I)

• wherein:
• Z is —NH—, —O—, —S(O)a—, or —N—;
• 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 of 1 to 6 carbon atom groups;
• or
• X is pyridinyl, pyrimidinyl, or an aryl ring;
• wherein the pyridinyl, pyrimidinyl or aryl ring may be optionally mono-, di-, or tri-substituted with a substituent independently 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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 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, 0, and S;
• wherein the bicyclic aryl or bicyclic heteroaryl ring may be optionally mono-, di-, tri-, or tetra-substituted with a substituent independently 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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
• E is pyridinyl, pyrimidinyl, or an aryl ring;
• wherein the pyridinyl, pyrimidinyl or aryl ring may be optionally mono-, di-, or tri-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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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;
• T is substituted on E at a carbon and is
• —NH(CH2)m—, —O(CH2)m—, —S(O)a—(CH2)m—, —NR(CH2)m—, —(CH2)m—;
• —(CH2)mNH—, —(CH2)mO—, —(CH2)mS(O)a—, or —(CH2)mNR—;
• L is an aryl ring;
• that is 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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, alkenoylaraino 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
• 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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;
• A″ is a moiety selected from the group
• G1, G2, G3 and G4 are independently selected from the group consisting of hydrogen, and alkyl of 1 to 6 carbon atoms;
• R1 is —H, R11—CH2—, —R12,
• R11 is —H, alkyl of 1 to 5 carbon atoms, aryl, or R13—(C(R6)2)k—;
• R13 is
• R7—, R7—(C(R6)2)p—M—, or Het-(C(R6)2)q—W—;
• R7 is —H, —NR6R6, —OR6, —J, —N(R6)3+, or —NR6(OR6);
• or 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, and tetrahydropyran,
• optionally mono- or di-substituted on carbon by —R6, hydroxy, —N(R6)2, —OR6, —(C(R6)2)sOR6, or —(C(R6)2)sN(R6)2;
• or
• 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 independently selected from —H, 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 6 carbon atoms, carboalkyl of 2 to 7 carbon atoms, carboxyalkyl of 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, hydroxy, carboxyl, carboalkoxy of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, and alkyl of 1 to 6 carbon atoms;
• R12 is alkylsulphonyl of 1 to 6 carbon atoms, carboalkoxy of 2 to 7 carbon atoms, or carboalkyl of 2 to 7 carbon atoms;
• R5 is hydrogen, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, aryl, carboalkyl of 2 to 7 carbon atoms,
• 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 —H, —F, or —J′;
• J′ is independently chlorine, bromine, iodine, tosylate (p-toluenesulfonate), or mesylate (methanesulfonate);
• Q is Q′, alkoxy of 1 to 6 carbon atoms, hydroxy, or hydrogen;
• Q′ is alkyl of 1 to 6 carbon atoms;
• R2 is selected from the group consisting of
• R3 is independently selected from —H, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, aryl, carboalkyl of 2 to 7 carbon atoms, and R3a—(C(R6)2)s—;
• R3a is
• R7—, R7—(C(R6)2)p—M—, R8R9—CH—M—, or Het-(C(R6)2) q—W—;
• a is 0 to 2;
• k is 1,3 to 5;
• n is 0 to 1;
• m is 0 to 3;
• p is 2 to 4;
• q is 0 to 4;
• r is 1 to 4;
• s is 1 to 6;
• u is 0 to 4 and v is 0 to 4, wherein the sum of u+v is 2 to 4;
• provided that:
• a. when —R6 is alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms, said alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• b. when R3 is bound to sulfur, R3 is not —H, carboxy, carboalkoxy, or carboalkyl;
• c. when M is —O—, and R7 is —OR6, then p is 1 to 4;
• d. when M is —O—, then k is 1 to 5;
• e. when W is —O—, then k is 1 to 5;
• f. when R7 is —OR6, then k is 1 to 5;
• g. when W is not a bond with Het bonded through a nitrogen atom, q is 2 to 4, and when W is a bond, q is 0;
• or a pharmaceutically acceptable salt thereof.

A method of treating, inhibiting, or eradicating colonic polyps in a mammal in need thereof which comprises providing to said mammal an effective amount of a compound of Formula (I)

• wherein:
• Z is —NH—, —O—, —S(O)a—, 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 of 1 to 6 carbon atom groups;
• or
• X is pyridinyl, pyrimidinyl, or an aryl ring;
• wherein the pyridinyl, pyrimidinyl or aryl ring may be optionally mono-, di-, or tri-substituted with a substituent independently 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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 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 independently 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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
• E is pyridinyl, pyrimidinyl, or an aryl ring;
• wherein the pyridinyl, pyrimidinyl or aryl ring may be optionally mono-, di-, or tri-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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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;
• T is substituted on E at a carbon and is
• —NH(CH2)m—, —O(CH2)m, —S(O)a—(CH2)m—, —NR(CH2)m—, —(CH2)m—, —(CH2)mNH—, —(CH2)mO—, —(CH2)mS(O)a—, or —(CH2)mNR—;
• L is an aryl ring;
• that is 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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
• L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatoms independently selected from N, 0, 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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;
• A′ is a moiety selected from the group
• G1, G2, G3 and G4 are independently selected from the group consisting of hydrogen, and alkyl of 1 to 6 carbon atoms;
• R1 is —H, R11—CH2—, —R12,
• R11 is —H, alkyl of 1 to 5 carbon atoms, aryl, or R13—(C(R6)2)k—;
• R13 is
• R7—,R7—(C(R7(R6)2)p—M—, or Het-(C(R6)2)q—W—;
• R7 is —H, —NR6R6, —OR6, —J, —N(R6)3+, or —NR6(OR6);
• or 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, optionally mono- or di-substituted on carbon by —R6, hydroxy, —N(R6)2, —OR6, —(C(R6)2)sOR6, or —(C(R6)2)sN(R6)2;
• or
• 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 independently selected from —H, 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 6 carbon atoms, carboalkyl of 2 to 7 carbon atoms, carboxyalkyl of 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, hydroxy, carboxyl, carboalkoxy of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, and alkyl of 1 to 6 carbon atoms;
• R12 is alkylsulphonyl of 1 to 6 carbon atoms, carboalkoxy of 2 to 7 carbon atoms, or carboalkyl of 2 to 7 carbon atoms;
• R5 is hydrogen, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, aryl, carboalkyl of 2 to 7 carbon atoms,
• 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 —H, —F, or —J′;
• J′ is independently chlorine, bromine, iodine, tosylate (p-toluenesulfonate), or mesylate (methanesulfonate);
• Q is Q′, alkoxy of 1 to 6 carbon atoms, hydroxy, or hydrogen;
• Q′ is alkyl of 1 to 6 carbon atoms;
• R2 is selected from the group consisting of
• R3 is independently selected from —H, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, aryl, carboalkyl of 2 to 7 carbon atoms, and R3a—(C(R6)2)s—;
• R3a is
• R7—, R7—(C(R6)2)p—M—, R8R9—CH—M—, or Het-(C(R6)2)q—W—;
• a is 0 to 2;
• l is 1,3 to 5;
• n is 0 to 1;
• m is 0 to 3;
• p is 2 to 4;
• q is to 4;
• r is 1 to 4;
• s is 1 to 6;
• u is 0 to 4 and v is 0 to 4, wherein the sum of u+v is 2 to 4;
• provided that:
• a. when —R6 is alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms, said alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• b. when R3 is bound to sulfur, R3 is not —H, carboxy, carboalkoxy, or carboalkyl;
• c. when M is —O—, and R7 is —OR6, then p is 1 to 4;
• d. when M is —O—, then k is 1 to 5;
• e. when W is —O—, then k is 1 to 5;
• f. when R7 is —OR6, then k is 1 to 5;
• g. when W is not a bond with Het bonded through a nitrogen atom, q is 2 to 4, and when W is a bond, q is 0;
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting the recurrence of stenopsis after corrective surgery on the heart valve in a mammal in need thereof which comprises providing to said mammal an effective amount of a PDGFr kinase inhibitor of Formula (1),

• wherein:
• Z is —NH—, —O—, —S(O)a—, 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 of 1 to 6 carbon atom groups;
• or
• X is pyridinyl, pyrimidinyl, or an aryl ring;
• wherein the pyridinyl, pyrimidinyl or aryl ring may be optionally mono-, di-, or tri-substituted with a substituent independently 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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 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 independently 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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
• E is pyridinyl, pyrimidinyl, or an aryl ring;
• wherein the pyridinyl, pyrimidinyl or aryl ring may be optionally mono-, di-, or tri-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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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;
• T is substituted on E at a carbon and is
• —NH(CH2)m—, —O(CH2)m—, S(O)a—(CH2)a—, —NR(CH2)m—, —(CH2)m—, —(CH2)mNH—, —(CH2)mO—, —(CH2)mS(O)a—, or —(CH2)mNR—;
• L is an aryl ring;
• that is 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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
• 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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-dialkylaminoakyl 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;
• A′ is a moiety selected from the group
• G1, G2, G3 and G4 are independently selected from the group consisting of hydrogen, and alkyl of 1 to 6 carbon atoms;
• R1 is —H, R11—CH2—, —R12,
• R11, is —H, alkyl of 1 to 5 carbon atoms, aryl, or R13—(C(R6)2)k—;
• R13 is
• R7—, R7—(C(R6)2)p—M—, or Het-(C(R6)2)q—W—;
• R7 is —H, —NR6R6, —OR6, —J, —N(R6)3, or —NR6(OR6);
• or 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, and tetrahydropyran, optionally mono- or di-substituted on carbon by —R6, hydroxy, —N(R6)2, —OR6, —(C(R6)2)sOR6, or —(C(R6)2)sN(R6)2;
• or
• 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 independently selected from —H, 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 6 carbon atoms, carboalkyl of 2 to 7 carbon atoms, carboxyalkyl of 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, hydroxy, carboxyl, carboalkoxy of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, and alkyl of 1 to 6 carbon atoms;
• R12 is alkylsulphonyl of 1 to 6 carbon atoms, carboalkoxy of 2 to 7 carbon atoms, or carboalkyl of 2 to 7 carbon atoms;
• R5 is hydrogen, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, aryl, carboalkyl of 2 to 7 carbon atoms,
• 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)r—NR6R6, or —(C(R6)2)r OR6;
• J is independently —H, —F, or —J′;
• J′ is independently chlorine, bromine, iodine, tosylate (p-toluenesulfonate), or mesylate (methanesulfonate);
• Q is Q′, alkoxy of 1 to 6 carbon atoms, hydroxy, or hydrogen;
• Q′ is alkyl of 1 to 6 carbon atoms;
• R2 is selected from the group consisting of
• R3 is independently selected from —H, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, aryl, carboalkyl of 2 to 7 carbon atoms, and R3a—(C(R6)2)s—;
• R3a is
• R7—, R7—(C(R6)2)p—M—, R8R9—CH—M—, or Het-(C(R6)2)q—W—;
• a is 0 to 2;
• k is 1, 3 to 5;
• n is 0 to 1;
• m is 0 to 3;
• p is 2 to 4;
• q is 0 to 4;
• r is 1 to 4;
• s is 1 to 6;
• u is 0 to 4 and v is 0 to 4, wherein the sum of u+v is 2 to 4;
• provided that:
• a. when —R6 is alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms, said alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• b. when R3 is bound to sulfur, R3 is not —H, carboxy, carboalkoxy, or carboalkyl;
• c. when M is —O—, and R7 is —OR6, then p is 1 to 4;
• d. when M is —O—, then k is 1 to 5;
• e. when W is —O—, then k is 1 to 5;
• f. when R7 is —OR6, then k is 1 to 5;
• g. when W is not a bond with Het bonded through a nitrogen atom, q is 2 to 4, and when W is a bond, q is 0;
• or a pharmaceutically acceptable salt thereof.

A method of treating, inhibiting or eradicating rheumatoid arthritis in a mammal in need thereof which comprises providing to said mammal an effective amount of a Zap-70 or Lck kinase inhibitor of Formula (I),

• wherein:
• Z is —NH—, —O—, —S(O)a—, 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 of 1 to 6 carbon atom groups;
• or
• X is pyridinyl, pyrimidinyl, or an aryl ring;
• wherein the pyridinyl, pyrimidinyl or aryl ring may be optionally mono-, di-, or tri-substituted with a substituent independently 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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 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 independently 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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
• E is pyridinyl, pyrimidinyl, or an aryl ring;
• wherein the pyridinyl, pyrimidinyl or aryl ring may be optionally mono-, di-, or tri-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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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;
• T is substituted on E at a carbon and is
• —NH(CH2)m—, —O(CH2)m—, —S(O)a—(CH2)m—, —NR(CH2)m—, —(CH2)m—, —(CH2)mNH—, —(CH2)mO—, —(CH2)mS(O)a—, or —(CH2)mNR—;
• L is an aryl ring;
• that is 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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
• 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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;
• A′ is a moiety selected from the group
• G1, G2, G3 and G4 are independently selected from the group consisting of hydrogen, and alkyl of 1 to 6 carbon atoms;
• R1 is —H, R11—CH2—, —R12,
• R11 is —H, alkyl of 1 to 5 carbon atoms, aryl, or R13—(C(R6)2)k—;
• R13 is
• R7—, R7—(C(R6)2)p—M—, or Het-(C(R6)2)q—W—;
• R7 is —H, —NR6R6, —OR6, —J, —N(R6)3+, or —NR6(OR6);
• or 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, and tetrahydropyran, optionally mono- or di-substituted on carbon by —R6, hydroxy, —N(R6)2, —OR6, —(C(R6)2)sOR6, or —(C(R6)2)sN(R6)2;
• or
• 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 independently selected from —H, 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 6 carbon atoms, carboalkyl of 2 to 7 carbon atoms, carboxyalkyl of 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, hydroxy, carboxyl, carboalkoxy of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, and alkyl of 1 to 6 carbon atoms;
• R12 is alkylsulphonyl of 1 to 6 carbon atoms, carboalkoxy of 2 to 7 carbon atoms, or carboalkyl of 2 to 7 carbon atoms;
• R5 is hydrogen, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, aryl, carboalkyl of 2 to 7 carbon atoms,
• 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)r OR6;
• J is independently —H, —F, or —J′;
• J′ is independently chlorine, bromine, iodine, tosylate (p-toluenesulfonate), or mesylate (methanesulfonate);
• Q is Q′, alkoxy of 1 to 6 carbon atoms, hydroxy, or hydrogen;
• Q′ is alkyl of 1 to 6 carbon atoms;
• R2 is selected from the group consisting of
• R3 is independently selected from —H, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, aryl, carboalkyl of 2 to 7 carbon atoms, and R3a—(C(R6)2)s—;
• R3ais
• a is 0 to 2;
• k is 1, 3 to 5;
• n is 0 to 1;
• m is 0 to 3;
• p is 2to 4;
• q is 0 to 4;
• r is 1 to 4;
• s is 1 to 6;
• u is 0 to 4 and v is 0 to 4, wherein the sum of u+v is 2 to 4;
• provided that:
• a. when —R6 is alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms, said alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• b. when R3 is bound to sulfur, R3 is not —H, carboxy, carboalkoxy, or carboalkyl;
• c. when M is —O—, and R7 is —OR6, then p is 1 to 4;
• d. when M is —O—, then k is 1 to 5;
• e. when W is —O—, then k is 1 to 5;
• f. when R7 is —OR6, then k is 1 to 5;
• g. when W is not a bond with Het bonded through a nitrogen atom, q is 2 to 4, and when W is a bond, q is 0;
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting the progression of osteoporosis in a mammal in need thereof which comprises providing to said mammal an effective amount of a Src kinase inhibitor of Formula (I),

• wherein:
• Z is —NH—, —O—, —S(O)a—, 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 of 1 to 6 carbon atom groups;
• or
• X is pyridinyl, pyrimidinyl, or an aryl ring;
• wherein the pyridinyl, pyrimidinyl or aryl ring may be optionally mono-, di-, or tri-substituted with a substituent independently selected from the group consisiting 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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 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 independently 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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
• E is pyridinyl, pyrimidinyl, or an aryl ring;
• wherein the pyridinyl, pyrimidinyl or aryl ring may be optionally mono-, di-, or tri-substituted with a substituent selected from the group consisiting 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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;
• T is substituted on E at a carbon and is
• —NH(CH2)m—, —O(CH2)m—, —S(O)a—(CH2)m—, —NR(CH2)m—, —(CH2)m—, —(CH2)mNH—, —(CH2)mO—, —(CH2)mS(O)a—, or —(CH2)mNR—;
• L is an aryl ring;
• that is 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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
• 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, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, 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;
• A″ is a moiety selected from the group
• G1, G2, G3 and G4 are independently selected from the group consisting of hydrogen, and alkyl of 1 to 6 carbon atoms;
• R1 is —H, R11—CH2—, —R12,
• R11 is —H, alkyl of 1 to 5 carbon atoms, aryl, or R13—(C(R6)2)k—;
• R13 is
• R7—, R7—(C(R6)2)p—M—, or Het-(C(R6)2)q—W—;
• R7 is —H, —NR6R6, —OR6, —J, —N(R6)3+, or —NR6(OR6);
• or 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, and tetrahydropyran, optionally mono- or di-substituted on carbon by —R6, hydroxy, —N(R6)2, —OR6, —(C(R6)2)sOR6, or —(C(R6)2)sN(R6)2;
• or
• 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 independently selected from —H, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2- to carbon atoms, cycloalkyl of 3 to 6 carbon atoms, carboalkyl of 2 to 7 carbon atoms, carboxyalkyl of 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, hydroxy, carboxyl, carboalkoxy of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, and alkyl of 1 to 6 carbon atoms;
• R12 is alkylsulphonyl of 1 to 6 carbon atoms, carboalkoxy of 2 to 7 carbon atoms, or carboalkyl of 2 to 7 carbon atoms;
• R5 is hydrogen, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, aryl, carboalkyl of 2 to 7 carbon atoms,
• 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)r OR6;
• J is independently —H, —F, or —J′;
• J′ is independently chlorine, bromine, iodine, tosylate (p-toluenesulfonate), or mesylate (methanesulfonate);
• Q is Q′, alkoxy of 1 to 6 carbon atoms, hydroxy, or hydrogen;
• Q′ is alkyl of 1 to 6 carbon atoms;
• R2 is selected from the group consisting of
• R3 is independently selected from —H, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, aryl, carboalkyl of 2 to 7 carbon atoms, and R3a—(C(R6)2)s—;
• R3a is
• R7—,R7—(C(R6)2)p—M—, R8R9—CH—M—, or Het-(C(R6)2)q—W—;
• a is 0 to 2;
• k is 1, 3 to 5;
• n is 0 to 1;
• m is 0 to 3;
• p is 2 to 4;
• q is 0 to 4;
• r is 1 to 4;
• s is 1 to 6;
• u is 0 to 4 and v is 0 to 4, wherein the sum of u+v is 2 to 4;
• provided that:
• a. when —R6 is alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms, said alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms is bound to a nitrogen or oxygen atom through a saturated carbon atom;
• b. when R3 is bound to sulfur, R3 is not —H, carboxy, carboalkoxy, or carboalkyl;
• c. when M is —O—, and R7 is —OR6, then p is 1 to 4;
• d. when M is —O—, then k is 1 to 5;
• e. when W is —O—, then k is 1 to 5;
• f. when R7 is —OR6, then k is 1 to 5;
• g. when W is not a bond with Het bonded through a nitrogen atom, q is 2 to 4, and when W is a bond, q is 0;
• or a pharmaceutically acceptable salt thereof.