3-Cyanoquinolines,3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors

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) having the structure:

• 41
• wherein:
• X is —NH—, —NR5—, —O—, or —S(O)m—;
• n is an integer of 0 or 1;
• m is an integer of 0 to 2;
• q is an integer of 0 to 5;
• p is an integer of 2 to 5;
• s is an integer of 0 to 5;
• r is an integer of 0 to 5;
• J is halogen;
• A is —(C(R9)2)r—, —C(O)—, —C(O)(C(R9)2)r—, —(C(R9)2)rC(O)—, -cycloalkyl- or is absent;
• T and Z are each independently carbon or N, provided that both T and Z are not simultaneously N;
• R1 is selected from a cycloalkyl ring of 3 to 10 carbon atoms, optionally substituted with one or more independently selected alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R5OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon, atoms;
• a heteroaryl rilig having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R5OH, —R6OR5, —R6NH2, —R5NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —R7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —R6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6C(O)R5, —R6C(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein
• Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• a bicyclic heteroaryl ling system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein
• Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q, —NR10(C(R9)2)q, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• and a moiety of the formula
• 42
• E is —NH—, —NR5—, —O—, —S(O)m—, —C(O)—, —CH2—, —CHR5— or —CR5R5—;
• Q is —NR5R5 and further provided that when each R5 is independently selected from alkyl and alkenyl, R5R5 may optionally be taken together with the nitrogen atom to which they are attached forming a heterocyclyl ring of 3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms which may be the same or different selected from N,O and S;
• R1a, R1b, R1c, R1d and R1e are each, independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —R11, —OR11, —NHR11 and —R6OC(O)Q;
• R2a, R2b, and R2c, are each, independently selected from —H, -aryl, —CH2aryl, —Oaryl, —S(O)maryl, —J, —NO2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —S(O)mR5, —NHSO2R5, —R11, —OR11, —R6OH, —R6OR5, —R6SH, —R6S(O)mR5, —OR7OH, —OR7OR5, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q, —G—(C(R9)2)p—R12, —(C(R9)2)q—R12, R18—CONH(CH2)r—, R18≡CONH(CH2)r—,
• 43
• G is —NH—, —NR10—, —O— or —S(O)m—;
• R3 is selected from alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteratoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S where the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R4 is selected from —(C(R9)2)2H, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, ——CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR 10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, ——(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R5 is a monovalent group independently selected from alkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R6 is a divalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R7 is a divalent alkyl group of 2 to 6 carbon atoms;
• R8 is a cycloalkyl ring of 3 to 10 carbon atoms that may optionally be substituted with one or more alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —H,-aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R)R7OH, —R6R12, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R5S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —R6R12, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH,—R6R12, —R6S(O)mR5, —NHR7OH5, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• R9 is independently —H, —F or —R5;
• R10 is an alkyl group of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms;
• R11 is a cycloalkyl group of 3 to 10 carbon atoms;
• R12 is —N(O)n R13R14 or —N+(R10R13R14)J−;
• provided that when R12 is N(O)n R13R14 and n is 1, R13 or R14 are not H;
• R13 and R14 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl-R15, —(C(R9)2)qheteroaryl-R15, —(C(R9)2)qheterocyclyl-R15, —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, —(C(R9)2)pS(O)mR16, —(C(R9)2R16, —(C(R9)2)pC(O)NHR16 and —(C(R9)2)pC(O)R15;
• further provided that R13 and R14 may optionally be taken together with the nitrogen to which they are attached forming a heterocyclyl, heteroaryl or bicyclyl heteroaryl ring optionally substituted on either nitrogen or carbon by one or more selected from the group, —R5, —R11, —(C(R9)2)qarylR15, —(C(R9)2)qheteroarylR15, —(C(R9)2)qheterocyclylR15, —(C(R9)2)qCO2R16, —(C(R9)2)qC(O)NHR16, and —(C(R9)2)qC(O)R15;
• or optionally substituted on carbon by —F, —(C(R7)2)qOR16, —(C(R7)2)qNR16R17, and —(C(R9)2)qS(O)mR16;
• or optionally substituted on nitrogen by —(C(R9)2)pOR16, —(C(R9)2)NR16R17, and —(C(R9)2)mS(O)mR16;
• R15 is independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNH2, —(C(R9)2)qNHR10, —(C(R9)2)qR10, —(C(R9)2)qS(O)mR10, —(C(R9)2)qCO2R10, —(C(R9)2)qCONHR10, —(C(R9)2)qCONR10R10, —(C(R9)2)qCOR10, —(C(R9)2)qCO2H, and —(C(R9)2)qCONH2;
• R16 and R17 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)pOH, —(C(R9)2)pOR10, —(C(R9)2)pNH2, —(C(R9)2)pNHR10, —(C(R9)2)pNR10R10, —(C(R9)2)pS(O)mR10, —(C(R9)2)pCO2R10, —(C(R9)2)pCONHR10, —(C(R9)2)pCONR10OR10, —(C(R9)2)pCOR10, —(C(R9)2)pCO2H, and —(C(R9)2)pCONH2;
• R18 is independently selected from the group consisting of —H, -aryl, —R5, —R6NH2, —R6NHR5 and —R6Q;
• provided that, when T and Z are carbon, A is absent, r is 0 and R4 is —(C(R9)2)rH, then,
• a. R3 is not unsubstituted thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, phenyl, alkenyl or alkynyl;
• or
• b. R3 is not monosubstituted by —R10, —(C(R9)2)qOH, or —(C(R9)2)qOR10 when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• c. R13 and R14 are not alkyl of 1 to 6 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine when R3 is substituted by —(C(R))2)sR12 and R12 is —NR13R14;
• further provided that, when T and Z are carbon, A is absent and R4 is phenyl, then,
• a. R4 is not substituted by —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —(C(R9)2)qOH, —(C(R7)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ or —(C(R9)2)qNH2 or unsubstituted when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• b. R13 and R14 are not independently alkyl of 1 to 3 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine, wherein R4 is substituted by —(C(R9)2)sR12 and s is 0 and R12 is —NR13R14;
• additionally provided that, when T and Z are carbon, then,
• a. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR10 when carbon-5 is substituted by an imidazole, oxazole or thiazole ring that is fused to a 6-membered aryl or heteroaryl ring having 0 to 2 nitrogen atoms and wherein the fused bicyclic heteroaryl ring is attached to carbon-5 of Formula (I) via carbon-2 of the imidazole, oxazole or thiazole ring;
• and
• b. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when X is —O— and carbon-5 is substituted by aryl or heteroaryl;
• further provided that when either T or Z are N, then R2c is absent;
• 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) having the structure:

• 44
• wherein:
• X is —NH—, —NR5—, —O—, or —S(O)m—;
• n is an integer of 0 or 1;
• m is all integer of 0 to 2;
• q is an integer of 0 to 5;
• p is an integer of 2 to 5;
• s is an integer of 0 to 5;
• r is an integer of 0 to 5;
• J is halogen;
• A is —(C(R9)2)r—, —C(O)—, —C(O)(C(R9)2)r—, —(C(R9)2)rC(O)—, -cycloalkyl- or is absent;
• T and Z are each independently carbon or N, provided that both T and Z are not simultaneously N;
• R1 is selected from a cycloalkyl ring of 3 to 10 carbon atoms, optionally substituted with one or more independently selected alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(Om(C(R9)2)q—, —NH(C(R9)2)q—,—NR10(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —R7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —R6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein
• Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, (C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein
• Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q, —NR10(C(R9)2)q, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• and a moiety of the formula
• 45
• E is —NH—, —NR5—, —O—, —S(O)m—, —C(O)—, —CH2—, —CHR5— or —CR5R5—;
• Q is —NR5R5 and further provided that when each R5 is independently selected from alkyl and alkenyl, R5R5 may optionally be taken together with the nitrogen atom to which they are attached forming a heterocyclyl ling of 3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms which may be the same or different selected from N, O and S;
• R1a, R1b, R1c, R1d and R1e are each, independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, -aryl, —CH2aryl, —Oaryl, —S(O)maryl, —R11, —OR11, —NHR11 and —R6OC(O)Q;
• R2a, R2b, and R2c, are each, independently selected from —H, -aryl, —CH2aryl, —Oaryl, —S(O)maryl, —J, —NO2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —S(O)mR5, —NHSO2R5, —R11, —OR11, R6OH, —R6OR5, —R6SH, —R6S(O)mR5, —OR7OR5, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q, —G—(C(R9)2)p—R12, —(C(R9)2)q—R12, —R18CONH(CH2)r—, R18≡CONH(CH2)r—,
• 46
• G is —NH—, —NR10—, —O— or —S(O)m—;
• R3 is selected from alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S where the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2—CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —N2, —CN, —CO2H, —CONH2—CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R4 is selected from —(C(R9)2)rH, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, ——CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12 and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R5 is a monovalent group independently selected from alkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkenyl of 2 to 6 carbon atoms;
• R6 is a divalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R7 is a divalent alkyl group of 2 to 6 carbon atoms;
• R8 is a cycloalkyl ring of 3 to 10 carbon atoms that may optionally be substituted with one or more alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —R6R12, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR , —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6R12, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6R12, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• R9 is independently —H, —F or —R5;
• R10 is an alkyl group of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms;
• R11 is a cycloalkyl group of 3 to 10 carbon atoms;
• R12 is —N(O)n R13R14 or —N+(R10R13R14)J−;
• provided that when R12 is N(O)n R13R14 and n is 1, R13 or R14 are not H;
• R13 and R14 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl-R15, —(C(R))2)qheteroaryl-R15, —(C(R9)2)qheterocyclyl-R15, —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, —(C(R9)2)pS(O)mR16, —(C(R9)2)pCO2R16, —(C(R9)2)pC(O)NHR16 and —(C(R9)2)pC(O)R15;
• further provided that R13 and R14 may optionally be taken together with the nitrogen to which they are attached forming a heterocyclyl, heteroaryl or bicyclyl heteroaryl ring optionally substituted on either nitrogen or carbon by one or more selected from the group, —R5, —R11, —(C(R9)2)qarylR15, —(C(R9)2)qheteroarylR15, —(C(R9)2)qheterocyclylR15, —(C(R9)2)qCO2R16, —(C(R9)2)q(C(O)NHR16, and —(C(R9)2)qC(O)R15;
• or optionally substituted on carbon by —F, —(C(R7)2)qOR16, —(C(R7)2)qNR16R17, and —(C(R9)2)qS(O)mR16;
• or optionally substituted on nitrogen by —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, and —(C(R9)2)pS(O)mR16;
• R15 is independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNH2, —(C(R9)2)qNHR10, —(C(R9)2)qR10, —(C(R9)2)qS(O)mR10, —(C(R9)2)qCO2R10, —(C(R9)2)qCONHR10, —(C(R9)2)qCONR10R10, —(C(R9)2)qCOR10, —(C(R9)2)qCO2H, and —(C(R9)2)qCONH2;
• R16 and R17 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)pOH, —(C(R9)2)pOR10, —(C(R9)2)pNH2, —(C(R9)pNHR10, —(C(R9)2)pNR10OR10, —(C(R9)2)pS(O)mR10, —(C(R9)2)pCO2R10, —(C(R9)2) pCONHR10, —(C(R9)2)pCONR10R10, —(C(R9)2)pCOR10, —(C(R9)2)pCO2H, and —(C(R9)2)pCONH2;
• R18 is independently selected from the group consisting of —H, -aryl, —R5, —R6NH2, —R6NHR5 and —R6Q;
• provided that, when T and Z are carbon, A is absent, r is 0 and R4 is —(C(R9)2)rH, then,
• a. R3 is not unsubstituted thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, phenyl, alkenyl or alkynyl;
• or
• b. R3 is not monosubstituted by —R10, —(C(R9)2)qOH, or —(C(R9)2)qOR10 when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• c. R13 and R14 are not alkyl of 1 to 6 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine when R3 is substituted by —(C(R9)2)sR12 and R12 is —NR13R14;
• further provided that, when T and Z are carbon, A is absent and R4 is phenyl, then,
• a. R4 is not substituted by —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —(C(R9)2)qOH, —(C(R7)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ or —(C(R9)2)qNH2 or unsubstituted when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• b. R13 and R14 are not independently alkyl of 1 to 3 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine, wherein R4 is substituted by —(C(R9)2)sR12 and s is 0 and R12 is —NR13R14;
• additionally provided that, when T and Z are carbon, then,
• a. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when carbon-5 is substituted by an imidazole, oxazole or thiazole ring that is fused to a 6-membered aryl or heteroaryl ring having 0 to 2 nitrogen atoms and wherein the fused bicyclic heteroaryl ring is attached to carbon-5 of Formula (I) via carbon-2 of the imidazole, oxazole or thiazole ring;
• and
• b. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when X is —O— and carbon-5 is substituted by aryl or heteroaryl;
• further provided that when either T or Z are N, then R2c is absent;
• 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) having the structure.

• 47
• wherein:
• X is —NH—, —NR5—, —O—, or —S(O)m—;
• n is an integer of 0 or 1;
• m is an integer of 0 to 2;
• q is an integer of 0 to 5;
• p is an integer of 2 to 5;
• s is an integer of 0 to 5;
• r is an integer of 0 to 5;
• J is halogen;
• A is —(C(R9)2)r—, —C(O)—, —C(O)(C(R9)2)r—, —(C(R9)2)rC(O)—, -cycloalkyl- or is absent;
• T and Z are each independently carbon or N, provided that both T and Z are not simultaneously N;
• R1 is selected from a cycloalkyl ring of 3 to 10 carbon atoms, optionally substituted with one or more independently selected alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R7NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5—R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —R7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —R6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR6, —R6OC(O)Q and YR8 groups wherein
• Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ling system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R51, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q, —NR10(C(R9)2)q, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• and a moiety of the formula
• 48
• E is —NH—, —NR5—, —O—, —S(O)m—, —C(O)—, —CH2—, —CHR5— or —CR5R5—;
• Q is —NR5R5 and further provided that when each R5 is independently selected from alkyl and alkenyl, R5R5 may optionally be taken together with the nitrogen atom to which they are attached forming a heterocyclyl ring of 3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms which may be the same or different selected from N, O and S;
• R1a, R1b, R1c, R1d and R1e are each, independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —R11, —OR11, —NHR11 and —R6OC(O)Q;
• R2a, R2b, and R2c, are each, independently selected from —H, -aryl, —CH2aryl, —Oaryl, —S(O)maryl, —J, —NO2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —S(O)mR5, —NHSO2R5, —R11, —OR11, —R6OH, —R6OR5, —R6SH, —R6S(O)mR5, —OR7OH, —OR7OR5, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q, —G—(C(R9)2)p—R12, —(C(R9)2)q—R12, —R18—CONH(CH2)r—, R18≡CONH(CH2)r—,
• 49
• G is —NH—, —NR10—, —O— or —S(O)m—;
• R3 is selected from alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)pOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12 and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S where the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R4 is selected from —(C(R9)2)rH, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)q10, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)pOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2—(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR10, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R 9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R5 is a monovalent group independently selected from alkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R6 is a divalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R7 is a divalent alkyl group of 2 to 6 carbon atoms;
• R8 is a cycloalkyl ring of 3 to 10 carbon atoms that may optionally be substituted with one or more alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —R6R12, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5—, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —R6R12, —NHC(O)NHR5, —OR6C(O)R5, —NHR C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6R12, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• R9 is independently —H, —F or —R5;
• R10 is an alkyl group of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms;
• R11 is a cycloalkyl group of 3 to 10 carbon atoms;
• R12 is —N(O)n R13R14 or —N+(R10R13R14)J−;
• provided that when R12 is N(O)n R13R14 and n is 1, R13 or R14 are not H;
• R13 and R14 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl-R15, —(C(R9)2)qheteroaryl-R15, —(C(R9)2)qheterocyclyl-R15, —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, —(C(R9)2)pS(O)mR16, —(C(R9)2)pCO2R16, —(C(R9)2)pC(O)NHR16and —(C(R9)2)pC(O)R15;
• further provided that R13 and R14 may optionally be taken together with the nitrogen to which they are attached forming a heterocyclyl, heteroaryl or bicyclyl heteroaryl ring optionally substituted on either nitrogen or carbon by one or more selected from the group, —R5, —R11, —(C(R9)2)qarylR15, —(C(R9)2)qheteoarylR15, —(C(R9)2)qheterocyclylR15, —(C(R9)2)qCO2R16, —(C(R9)2)qC(O)NHR16, and —(C(R9)2)qC(O)R15;
• or optionally substituted on carbon by —F, —(C(R7)2)qOR6, —(C(R7)2)qNR16R17, and —(C(R9)2)qS(O)mR16;
• or optionally substituted on nitrogen by —(C(R9)2)pOR16, —(C(R9)2)pNR16R17R, and —(C(R9)2)pS(O)mR16;
• R15 is independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNH2, —(C(R9)2)qNHR10, —(C(R9)2)qR10, —(C(R9)2)qS(O)mR10, —(C(R9)2)qCO2R10, —(C(R9)2)qCONHR10, —(C(R9)2)qR10, —(C(R9)2)COR10, —(C(R9)2)qCO2H, and —(C(R9)2)qCONH2;
• R16 and R17 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)pOH, —(C(R9)2)pOR10, —(C(R9)2)pNH2, —(C(R9)2)pNHR10, —(C(R9)2)pNR10R10, —(C(R9)2)pS(O)mR10, —(C(R9)2)pCO2R10, —(C(R9)2)pCONHR10, —(C(R9)2)pCONR10R10, —(C(R9)2)pCOR10, —(C(R9)2)pCO2H, and —(C(R9)2)pCONH2;
• R18 is independently selected from the group consisting of —H, -aryl, —R5, —R6NH2, —R6NHR5 and —R6Q;
• provided that, when T and Z are carbon, A is absent, r is 0 and R4 is —(C(R9)2)rH, then,
• a. R3 is not unsubstituted thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, phenyl, alkenyl or alkynyl;
• or
• b. R3 is not monosubstituted by —R10, —(C(R9)2)qOH, or —(C(R9)2)qOR10 when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• c. R13 and R14 are not alkyl of 1 to 6 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine when R3 is substituted by —(C(R9)2)sR12 and R12 is —NR13R14;
• further provided that, when T and Z are carbon, A is absent and R4 is phenyl, then,
• a. R4 is not substituted by —NO2, —CN, —CO2H, —CONH2—CO2R10, —CONHR10, —(C(R9)2)qOH, —(C(R7)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ or —(C(R9)2)qNH2 or unsubstituted when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• b. R13 and R14 are not independently alkyl of 1 to 3 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine, wherein R4 is substituted by —(C(R9)2)sR2 and s is 0 and R12 is —NR13R14;
• additionally provided that, when T and Z are carbon, then,
• a. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when carbon-5 is substituted by an imidazole, oxazole or thiazole ring that is fused to a 6-membered aryl or heteroaryl ring having 0 to 2 nitrogen atoms and wherein the fused bicyclic heteroaryl ring is attached to carbon-5 of Formula (I) via carbon-2 of the imidazole, oxazole or thiazole ring;
• and
• b. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when X is —O— and carbon-5 is substituted by aryl or heteroaryl;
• further provided that when either T or Z are N, then R2c is absent;
• or a pharmaceutically acceptable salt thereof.

A method of treating a disease or inhibiting a disease state whose etiology is at least in part caused by a defect in a signaling pathway upstream from a protein kinase;

• by overexpression of a protein kinase;
• or by a dysregulated protein kinase in a mammal in need thereof which comprises providing said mammal an effective amount of a compound of Formula (I),
• 50
• wherein:
• X is —NH—, —NR5—, —O—, or —S(O)m—;
• n is an integer of 0 or 1;
• m is an integer of 0 to 2;
• q is an integer of 0 to 5;
• p is an integer of 2 to 5;
• s is an integer of 0 to 5;
• r is an integer of 0 to 5;
• J is halogen;
• A is —(C(R9)2)r—, —C(O)—, —C(O)(C(R9)2)r—, —(C(R9)2)rC(O)—, -cycloalkyl- or is absent;
• T and Z are each independently carbon or N, provided that both T and Z are not simultaneously N;
• R1 is selected from a cycloalkyl ring of 3 to 10 carbon atoms, optionally substituted with one or more independently selected alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein Y is independently selected from —C(O)—, —C(O)Q—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or 1 particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —R7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —R6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q, —NR10(C(R9)2)q, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• and a moiety of the formula
• 51
• E is —NH—, —NR5—, —O—, —S(O)m—, —C(O)—, —CH2—, —CHR5— or —CR5R5—;
• Q is —NR5R5 and further provided that when each R5 is independently selected from alkyl and alkenyl, R5R5 may optionally be taken together with the nitrogen atom to which they are attached forming a heterocyclyl ring of 3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms which may be the same or different selected from N, O and S;
• R1a, R1b, R1c, R1d and R1e are each, independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)m R5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6C(O)NH2, —R6OC(O)NHR5, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —R11, —OR11, —NHR11 and —R6OC(O)Q;
• R2a, R2b, and R2c, are each, independently selected from —H, -aryl, —CH2aryl, —Oaryl, —S(O)maryl, —J, —NO2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —S(O)mR5, —NHSO2R5, —R11, —OR11, —R6OH, —R6OR5, —R6SH, —R6S(O)mR5, —OR7OH, —OR7OR5, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q, —G—(C(R9)2)p—R12, —(C(R9)2)q—R12, R18—CONH(CH2)r—, R18≡CONH(CH2)r—,
• 52
• G is —NH—, —NR10—, —O— or —S(O)m—;
• R3 is selected from alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, (C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S where the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9) 2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10—G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R4 is selected from —(C(R9)2)rH, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R5 is a monovalent group independently selected from alkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R6 is a divalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R7 is a divalent alkyl group of 2 to 6 carbon atoms;
• R8 is a cycloalkyl ring of 3 to 10 carbon atoms that may optionally be substituted with one or more alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6R12, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5—NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6R12, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6R12, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5—OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• R9 is independently —H, —F or —R5;
• R10 is an alkyl group of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms;
• R11 is a cycloalkyl group of 3 to 10 carbon atoms;
• R12 is —N(O)nR13R14 or —N30 (R10R13R14)J31 ;
• provided that when R12 is N(O)nR13R14 and n is 1, R13 or R14 are not H;
• R13 and R14 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl-R15, —(C(R9)2)qheteroaryl-R15, —(C(R9)2)qheterocyclyl-R15, —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, —(C(R9)2)pS(O)mR16, —(C(R9)2)pCO2R16, —(C(R9)2)pC(O)NHR16 and —(C(R9)2)pC(O)R15;
• further provided that R13 and R14 may optionally be taken together with the nitrogen to which they are attached forming a heterocyclyl, heteroaryl or bicyclyl heteroaryl ring optionally substituted on either nitrogen or carbon by one or more selected from the group, —R5, —R11, —(C(R9)2)qarylR15, —(C(R9)2)qheteroarylR15, —(C(R9)2)qheterocyclylR15, —(C(R9)2)qCO2R16, —(C(R9)2)qC(O)NHR16, and —(C(R9)2)qC(O)R15;
• or optionally substituted on carbon by —F, —(C(R7)2)qOR16, —(C(R7)2)qNR16R7, and —(C(R9)2)qS(O)mR16;
• or optionally substituted on nitrogen by —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, and —(C(R9)2)pS(O)mR16;
• R15 is independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNH2, —(C(R9)2)qNHR10, —(C(R9)2)qR10, —(C(R9)2)qS(O)mR10, —(C(R9)2)qCO2R10, —(C(R9)2)qCONHR10, —(C(R9)2)qCONR10OR10, —(C(R9)2)qCOR10, —(C(R9)2)qCO2H, and —(C(R9)2)qCONH2;
• R16 and R17 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)pOH, —(C(R9)2)pOR10, —(C(R9)2)pNH2, —(C(R9)2)pNHR10, —(C(R9)2)pNR10R10, —(C(R9)2)pS(O)mR10, —(C(R9)2)pCO2R10, —(C(R9)2)pCONHR10, —(C(R9)2)pCONR10R10, —(C(R9)2)pCOR10, —(C(R9)2)pCO2H, and —(C(R9)2)pCONH2;
• R18 is independently selected from the group consisting of —H, -aryl, —R5, —R6NH2, —R6NHR5 and —R6Q;
• provided that, when T and Z are carbon, A is absent, r is 0 and R4 is —(C(R9)2)rH, then,
• a. R3 is not unsubstituted thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, phenyl, alkenyl or alkynyl;
• or
• b. R3 is not monosubstituted by —R10, —(C(R9)2)qOH, or —(C(R9)2)qOR10 when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• c. R13 and R14 are not alkyl of 1 to 6 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine when R3 is substituted by —(C(R9)2)sR12 and R12 is —NR13R14;
• further provided that, when T and Z are carbon, A is absent and R4 is phenyl, then,
• a R4 is not substituted by —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —(C(R9)2)qOH, —(C(R7)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ or —(C(R9)2)qNH2 or unsubstituted when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• b. R13 and R14 are not independently alkyl of 1 to 3 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine, wherein R4 is substituted by —(C(R9)2)sR12 and s is 0 and R12 is —NR13R14;
• additionally provided that, when T and Z are carbon, then,
• a. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when carbon-5 is substituted by an imidazole, oxazole or thiazole ring that is fused to a 6-membered aryl or heteroaryl ring having 0 to 2 nitrogen atoms and wherein the fused bicyclic heteroaryl ring is attached to carbon-5 of Formula (I) via carbon-2 of the imidazole, oxazole or thiazole ring;
• and
• b. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when X is —O— and carbon-5 is substituted by aryl or heteroaryl;
• further provided that when either T or Z are N, then R2c is absent;
• or a pharmaceutically acceptable salt thereof.

A method of inhibiting the biological effects of a dysregulated protein kinase in a mammal which comprises administering to said mammal an effective amount of a compound of Formula (I)

• 53
• wherein:
• X is —NH—, —NR5—, —O—, or —S(O)m—;
• n is an integer of 0 or 1;
• m is an integer of 0 to 2;
• q is an integer of 0 to 5;
• p is an integer of 2 to 5;
• s is an integer of 0 to 5;
• r is an integer of 0 to 5;
• J is halogen;
• A is —(C(R9)2)r—, —C(O)—, —C(O)(C(R9)2)r—, —(C(R9)2)rC(O)—, -cycloalkyl- or is absent;
• T and Z are each independently carbon or N, provided that both T and Z are not simultaneously N;
• R1 is selected from a cycloalkyl ring of 3 to 10 carbon atoms, optionally substituted with one or more independently selected alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R5NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9))2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R9)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —R7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —R6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5—N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9))2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q, —NR10(C(R9)2)q, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• and a moiety of the formula
• 54
• E is —NH—, —NR5—, —O—, —S(O)m—, —C(O)—, —CH2—, —CHR5— or —CR5R5—;
• Q is —NR5R5 and further provided that when each R5 is independently selected from alkyl and alkenyl, R5R5 may optionally be taken together with the nitrogen atom to which they are attached forming a heterocyclyl ring of 3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms which may be the same or different selected from N, O and S;
• R1a, R1b, R1c, R1d and R1e are each, independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —R11, —OR11, —NHR11 and —R6OC(O)Q;
• R2a, R2b, and R2c, are each, independently selected from —H, -aryl, —CH2aryl, —Oaryl, —S(O)maryl, —J, —NO2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —S(O)mR5, —NHSO2R5, —R11, —OR11, —R6OH, —R6OR5, —R6SH, —R6S(O)mR5, —OR7OH, —OR7OR5, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q, —G—(C(R9)2)p—R12, —(C(R9)2)q—R12, R18—CONH(CH2)r—, R18≡CONH(CH2)r—,
• 55
• G is —NH—, —NR10—, —O— or —S(O)m—;
• R3 is selected from alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S where the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R4 is selected from —(C(R9)2)rH, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3dioxolane, —NO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• at heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R5 is a monovalent group independently selected from alkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R6 is a divalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R7 is a divalent alkyl group of 2 to 6 carbon atoms;
• R8 is a cycloalkyl ring of 3 to 10 carbon atoms that may optionally be substituted with one or more alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —H,-aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6R12, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6R12, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6R12, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• R9 is independently —H, —F or —R5;
• R10 is an alkyl group of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms;
• R11 is a cycloalkyl group of 3 to 10 carbon atoms;
• R12 is —N(O)n R13R14 or —N+(R10R13R14)J−;
• provided that when R12 is N(O)n R13 R14 and n is 1, R13 or R14 are not H;
• R13 and R14 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl-R15, —(C(R9)2)qheteroaryl-R15, —(C(R9)2)qheterocyclyl-R15, —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, —(C(R9)2)pS(O)mR16, —(C(R9)2)pCO2R16, —(C(R9)2)pC(O)NHR16 and —(C(R9)2)pC(O)R15;
• further provided that R13 and R14 may optionally be taken together with the nitrogen to which they are attached forming a heterocyclyl, heteroaryl or bicyclyl heteroaryl ring optionally substituted on either nitrogen or carbon by one or more selected from the group, —R5, —R11, —(C(R9)2)qarylR15, —(C(R9)2)qheteroarylR15, —(C(R9)2)qheterocyclylR15, —(C(R9)2)qCO2R16, —(C(R9)2)qC(O)NHR16, and —(C(R9)2)qC(O)R15;
• or optionally substituted on carbon by —F, —(C(R7)2)qOR16, —(C(R9)2)qNR16R17, and —(C(R9)2)qS(O)m R16;
• or optionally substituted on nitrogen by —(C(R9)2)pR16, —(C(R9)2)pNR16R17, and —(C(R9)2)pS(O)mR16;
• R15 is independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)qOH, —C(R9)2)qOR10, —(C(R9)2)qNH2, —(C(R9)2)qNHR10, —(C(R9)2),R10, —(C(R9)2)qS(O)mR10, —(C(R9)2)qCO2R10, —(C(R9)2)qCONHR10, —(C(R9)2)qCONR10R10, —(C(R9)2)qCOR10, —(C(R9)2)qCO2H, and —(C(R9)2)qCONH2;
• R16 and R17 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)pOH, —(C(R9)2)pOR10, —(C(R9)2)pNH2, —(C(R9)2)pNHR10, —(C(R9)2)pNR10R10, —(C(R9)2)pS(O)mR10, —(C(R9)2)pCO2R10, —(C(R9)2)pCONHR10, —(C(R9)2)pCONR10R10, —(C(R9)2)pCOR10, —(C(R9)2)pCO2H, and —(C(R9)2)pCONH2;
• R18 is independently selected from the group consisting of —H, -aryl, —R5, —R6NH2, —R6NHR5 and —R6Q;
• provided that, when T and Z are carbon, A is absent, r is 0 and R4 is —(C(R9)2)rH, then,
• a. R3 is not unsubstituted thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, phenyl, alkenyl or alkynyl;
• or
• b. R3 is not monosubstituted by —R10, —(C(R9)2)qOH, or —(C(R9)2)qOR10 when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• c. R13 and R14 are not alkyl of 1 to 6 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, triazole or pyridine when R3 is substituted by —(C(R9)2)sR12 and R12 is —NR13R14;
• further provided that, when T and Z are carbon, A is absent and R4 is phenyl, then,
• a. R4 is not substituted by —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —(C(R9)2)qOH, —(C(R7)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ or —(C(R9)2)qNH2 or unsubstituted when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• b. R13 and R14 are not independently alkyl of 1 to 3 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine, wherein R4 is substituted by —(C(R9)2)sR12 and s is 0 and R12 is —NR13R14;
• additionally provided that, when T and Z are carbon, then,
• a. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when carbon-5 is substituted by an imidazole, oxazole or thiazole ring that is fused to a6-membered aryl or heteroaryl ring having 0 to 2 nitrogen atoms and wherein the fused bicyclic heteroaryl ring is attached to carbon-5-of Formula (I) via carbon-2 of the imidazole, oxazole or thiazole ring;
• and
• b. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when X is —O— and carbon-5 is substituted by aryl or heteroaryl;
• further provided that when either T or Z are N, then R2c is absent;
• or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition for treating or inhibiting disease in a mammal characterized by abnormal growth of cells which comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I) having the structure:

• 56
• wherein:
• X is —NH—, —NR5—, —O—, or —S(O)m—;
• n is an integer of 0 or 1;
• m is an integer of 0 to 2;
• q is an integer of 0 to 5;
• p is an integer of 2 to 5;
• s is an integer of 0 to 5;
• r is an integer of 0 to 5;
• J is halogen;
• A is —(C(R9)2)r—, —C(O)—, —C(O)(C(R9)2)r—, —(C(R9)2)rC(O)—, -cycloalkyl- or is absent;
• T and Z are each independently carbon or N, provided that both T and Z are not simultaneously N;
• R1 is selected from a cycloalkyl ring of 3 to 10 carbon atoms, optionally substituted with one or more independently selected alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R9)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NH5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6C(O)NHR5, —R6OC(O)Q and YR8 groups wherein Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R9)R7NHR5, —N(R5)R7Q, —OR7OH, —R7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —R6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6C(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein
• Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q, —NR10(C(R9)2)q, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• and a moiety of the formula
• 57
• E is —NH—, —NR5—, —O—, —S(O)m—, —C(O)—, —CH2—, —CHR5— or —CR5R5—;
• Q is —NR5R5 and further provided that when each R5 is independently selected from alkyl and alkenyl, R5R5 may optionally be taken together with the nitrogen atom to which they are attached forming a heterocyclyl ring of 3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms which may be the same or different selected from N, O and S;
• R1a, R1b, R1c, R1d and R1c are each, independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —R11, —OR11, —NHR11 and —R6OC(O)Q;
• R2a, R2b, and R2c, are each, independently selected from —H, -aryl, —CH2aryl, —Oaryl, —S(O)maryl, —J, —NO2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —S(O)mR5, —NHSO2R5, —R11, —OR11, —R6OH, —R6OR5, —R6SH, —R6S(O)mR5, —OR7OH, —OR7OR5, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q, —G—(C(R9)2)p—R12, —(C(R9)2)q—R12, R18≡CONH(CH2)r—, R18≡CONH(CH2)r—,
• 58
• G is —NH—, —NR10—, —O— or —S(O)m—;
• R3 is selected from alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S where the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R4 is selected from —(C(R9)2)rH, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3—dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ling system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R5 is a monovalent group independently selected from alkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R6 is a divalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R7 is a divalent alkyl group of 2 to 6 carbon atoms;
• R8 is a cycloalkyl ring of 3 to 10 carbon atoms that may optionally be substituted with one or more alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —R6R12, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —R6R12, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6R12, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• R9 is independently —H, —F or —R5;
• R10 is an alkyl group of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms;
• R11 is a cycloalkyl group of 3 to 10 carbon atoms;
• R12 is —N(O)n R13R14 or —N+(R10R13R14)J−;
• provided that when R12 is N(O)n R13R14 and n is 1, R13 or R14 are not H;
• R13 and R14 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl-R15, —(C(R9)2)qheteroaryl-R15, —(C(R9)2)qheterocyclyl-R15, —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, —(C(R9)2)pS(O)mR16, —(C(R9)2)pCO2R16, —(C(R9)2)pC(O)NHR16 and —(C(R9)2)pC(O)R15;
• further provided that R13 and R14 may optionally be taken together with the nitrogen to which they are attached forming a heterocyclyl, heteroaryl or bicyclyl heteroaryl ring optionally substituted on either nitrogen or carbon by one or more selected from the group, —R5, —R11, —(C(R9)2)qarylR15, —(C(R9)2)qheteroarylR15, —(C(R9)2)qheterocyclylR15, —(C(R9)2)qCO2R16, —(C(R9)2)qC(O)NHR16, and —(C(R9)2)qC(O)R15;
• or optionally substituted on carbon by —F, —(C(R7)2)qOR16, —(C(R7)2)qNR16R17, and —(C(R9)2)qS(O)mR16;
• or optionally substituted on nitrogen by —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, and —(C(R9)2)pS(O)mR16;
• R15 is independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNH2, —(C(R9)2)qNHR10, —(C(R9)2)qR10, —(C(R9)2)qS(O)mR10, —(C(R9)2)qCO2R10, —(C(R9)2)qCONHR10, —(C(R9)2)qCONR10R10, —(C(R9)2)qCOR10, —(C(R9)2)qCO2H, and —(C(R9)2)qCONH2;
• R16 and R17 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)pOH, —(C(R9)2)pOR10, —(C(R9)2)pNH2, —(C(R9)2)pNHR10, —(C(R9)2)pNR10R10, —(C(R9)2)pS(O)mR10, —(C(R9)2)pCO2R10, —(C(R9)2pCONHR10, —(C(R9)2)pCONR10R10, —(C(R9)2)pCOR10, —(C(R9)2)pCO2H, and —(C(R9)2)pCONH2;
• R18 is independently selected from the group consisting of —H, -aryl, —R5, —R6NH2, —R6NHR5 and —R6Q;
• provided that, when T and Z are carbon, A is absent, r is 0 and R4 is —(C(R9)2)rH, then,
• a. R3 is not unsubstituted thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, phenyl, alkenyl or alkynyl;
• or
• b. R3 is not monosubstituted by —R10, —(C(R9)2)(qOH, or —(C(R9)2)qOR10 when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• c. R13 and R14 are not alkyl of 1 to 6 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine when R3 is substituted by —(C(R9)2)sR12 and R12 is —NR13R14;
• further provided that, when T and Z are carbon, A is absent and R4 is phenyl, then,
• a. R4 is not substituted by —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10—(C(R9)2)qOH, —(C(R7)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ or —(C(R9)2)qNH2 or unsubstituted when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• b. R13 and R14 are not independently alkyl of 1 to 3 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine, wherein R4 is substituted by —(C(R9)2)sR12 and s is 0 and R12 is —NR13R14;
• additionally provided that, when T and Z are carbon, then,
• a. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when carbon-5 is substituted by an imidazole, oxazole or thiazole ring that is fused to a 6-membered aryl or heteroaryl ring halving 0 to 2 nitrogen atoms and wherein the fused bicyclic heteroaryl ring is attached to carbon-5 of Formula (I) via carbon-2 of the imidazole, oxazole or thiazole ring;
• and
• b. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when X is —O— and carbon-5 is substituted by aryl or heteroaryl;
• further provided that when either T or Z are N, then R2c is absent;
• or a pharmaceutically acceptable salt thereof.

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

• 59
• wherein:
• X is —NH—, —NR5—, —O—, or —S(O)m—;
• n is an integer of 0 or 1;
• m is an integer of 0 to 2;
• q is an integer of 0 to 5;
• p is an integer of 2 to 5;
• s is an integer of 0 to 5;
• r is an integer of 0 to 5;
• J is halogen;
• A is —(C(R9)2)r—, —C(O)—, —C(O)(C(R9)2)r—, —(C(R9)2)rC(O)—, -cycloalkyl- or is absent;
• T and Z are each independently carbon or N, provided that both T and Z are not simultaneously N;
• R1 is selected from a cycloalkyl ring of 3 to 10 carbon atoms, optionally substituted with one or more independently selected alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—,—(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroayl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q , —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —R7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —R6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, (C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6C(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein
• Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q, —NR10(C(R9)2)q, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• and a moiety of the formula
• 60
• E is —NH—, —NR5—, —O—, —S(O)m—, —C(O)—, —CH2—, —CHR5— or —CR5R5—;
• Q is —NR5R5 and further provided that when each R5 is independently selected from alkyl and alkenyl, R5R5 may optionally be taken together with the nitrogen atom to which they are attached forming a heterocyclyl ring of 3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms which may be the same or different selected from N, O and S;
• R1a, R1b, R1c, R1d and R1e are each, independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —R11, —OR11, —NHR11 and —R6OC(O)Q;
• R2a, R2b, and R2c, are each, independently selected from —H, -aryl, —CH2aryl, —Oaryl, —S(O)maryl, —J, —NO2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —S(O)mR5, —NHSO2R5, —R11, —OR11, —R6OH, —R6OR5, —R6SH, —R6S(O)mR5, —OR7OH, —OR7OR5, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q, —G—(C(R9)2)p—R12, —(C(R9)2)q—R12, R18—CONH(CH2)r—, R18≡CONH(CH2)r—,
• 61
• G is —NH—, —NR10—, —O— or —S(O)m—;
• R3 is selected from alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S where the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R4 is selected from —(C(R9)2)2H, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ling system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R5 is a monovalent group independently selected from alkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R6 is a divalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R7 is a divalent alkyl group of 2 to 6 carbon atoms;
• R8 is a cycloalkyl ring of 3 to 10 carbon atoms that may optionally be substituted with one or more alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —R6R12, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3;
• —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6R12, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• R9 is independently —H, —F or —R5;
• R10 is an alkyl group of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms;
• R11 is a cycloalkyl group of 3 to 10 carbon atoms;
• R12 is —N(O)n R13R14 or —N+(R10R13R14)J−;
• provided that when R12 is N(O)nR13R14 and n is 1, R13 or R14 are not H;
• R13 and R14 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl-R15, —(C(R9)2)qheteroaryl-R15, —(C(R9)2)qheterocyclyl-R15, —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, —(C(R9)2)pS(O)mR16, —(C(R9)2)pCO2R16, —(C(R9)2)pC(O)NHR16 and —(C(R9)2)pC(O)R15;
• further provided that R13 and R14 may optionally be taken together with the nitrogen to which they are attached forming a heterocyclyl, heteroaryl or bicyclyl heteroaryl ring optionally substituted on either nitrogen or carbon by one or more selected from the group, —R5, —R11, —(C(R9)2)qarylR15, —(C(R9)2)qheteroarylR15, —(C(R9)2)qheterocyclylR15, —(C(R9)2)qCO2R16, —(C(R9)2)qC(O)NHR16, and —(C(R9)2)qC(O)R15;
• or optionally substituted on carbon by —F, —(C(R7)2)qOR16, —(C(R7)2)qNR16R17, and —(C(R9)2)qS(O)mR16;
• or optionally substituted on nitrogen by —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, and —(C(R9)2)pS(O)mR16;
• R15 is independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNH2, —(C(R9)2)qNHR10, —(C(R9)2)qR10, —(C(R9)2)qS(O)mR10, —(C(R9)2)qCO2R10, —(C(R9)2)qCONHR10, —(C(R9)2)qCONR10R10, —(C(R9)2)qCOR10, —(C(R9)2)qCO2H, and —(C(R9)2)qCONH2;
• R16 and R17 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)pOH, —(C(R9)2)pOR10, —(C(R9)2)pNH2, —(C(R9)2)pNHR10, —(C(R9)2)pNR10R10, —(C(R9)2)pS(O)mR10, —(C(R9)2)pCO2R10, —(C(R9)2pCONHR10, —(C(R9)2)pCONR10R10, —(C(R9)2)pCOR10, —(C(R9)2)pCO2H, and —(C(R9)2)pCONH2;
• R18 is independently selected from the group consisting of —H, -aryl, —R5, —R6NH2, —R6NHR5 and —R6Q;
• provided that, when T and Z are carbon, A is absent, r is 0 and R4 is —(C(R9)2)rH, then,
• a. R3 is not unsubstituted thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, phenyl, alkenyl or alkynyl;
• or
• b. R3 is not monosubstituted by —R10, —(C(R9)2)qOH, or —(C(R9)2)qOR10 when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• c. R13 and R14 are not alkyl of 1 to 6 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine when R3 is substituted by —(C(R9)2)sR12 and R12 is —NR13R14;
• further provided that, when T and Z are carbon, A is absent and R4 is phenyl, then,
• a. R4 is not substituted by —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —(C(R9)2)qOH, —(C(R7)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ or —(C(R9)2)qNH2 or unsubstituted when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• b. R13 and R14 are not independently alkyl of 1 to 3 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine, wherein R4 is substituted by —(C(R9)2)sR12 and s is 0 and R12 is —NR13R14;
• additionally provided that, when T and Z are carbon, then,
• a. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when carbon-5 is substituted by an imidazole, oxazole or thiazole ring that is fused to a 6-membered aryl or heteroaryl ring halving 0 to 2 nitrogen atoms and wherein the fused bicyclic heteroaryl ring is attached to carbon-5 of Formula (I) via carbon-2 of the imidazole, oxazole or thiazole ring;
• and
• b. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when X is —O— and carbon-5 is substituted by aryl or heteroaryl;
• further provided that when either T or Z are N, then R2c is absent;
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting or eradicating autoimmune diseases which include rheumatoid arthritis, sepsis and transplant rejection 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), having the structure

• 62
• wherein:
• X is —NH—, —NR5—, —O—, or —S(O)m—;
• n is an integer of 0 or 1;
• m is an integer of 0 to 2;
• q is an integer of 0 to 5;
• p is an integer of 2 to 5;
• s is an integer of 0 to 5;
• r is an integer of 0 to 5;
• J is halogen;
• A is —(C(R9)2)r—, —C(O)—, —C(O)(C(R9)2)r—, —(C(R9)2)rC(O)—, -cycloalkyl- or is absent;
• T and Z are each independently carbon or N, provided that both T and Z are not simultaneously N;
• R1 is selected from a cycloalkyl ring of 3 to 10 carbon atoms, optionally substituted with one or more independently selected alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or—different, selected from N, O and S wherein the heteroayl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q , —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —R7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)N—NHR5, —R6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein
• Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6C(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein
• Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q, —NR10(C(R9)2)q, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• and a moiety of the formula
• 63
• E is —NH—, —NR5—, —O—, —S(O)m—, —C(O)—, —CH2—, —CHR5— or —CR5R5—;
• Q is —NR5R5 and further provided that when each R5 is independently selected from alkyl and alkenyl, R5R5 may optionally be taken together with the nitrogen atom to which they are attached forming a heterocyclyl ring of 3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms which may be the same or different selected from N, O and S;
• R1a, R1b, R1c, R1d and R1e are each, independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —R11, —OR11, —NHR11 and —R6OC(O)Q;
• R2a, R2b, and R2c, are each, independently selected from —H, -aryl, —CH2aryl, —Oaryl, —S(O)maryl, —J, —NO2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —S(O)mR5, —NHSO2R5, —R11, —OR11, —R6OH, —R6OR5, —R6SH, —R6S(O)mR5, —OR7OH, —OR7OR5, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q, —G—(C(R9)2)p—R12, —(C(R9)2)q—R12, R18—CONH(CH2)r—, R18≡CONH(CH2)r—,
• 64
• G is —NH—, —NR10—, —O— or —S(O)m—;
• R3 is selected from alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S where the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R4 is selected from —(C(R9)2)rH, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ling system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R5 is a monovalent group independently selected from alkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R6 is a divalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R7 is a divalent alkyl group of 2 to 6 carbon atoms;
• R8 is a cycloalkyl ring of 3 to 10 carbon atoms that may optionally be substituted with one or more alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —R6R12, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6R12, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6R12, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• R9 is independently —H, —F or —R5;
• R10 is an alkyl group of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms;
• R11 is a cycloalkyl group of 3 to 10 carbon atoms;
• R12 is —N(O)n R13R14 or —N+(R10R13R14)J−;
• provided that when R12 is N(O)nR13R14 and n is 1, R13 or R14 are not H;
• R13 and R14 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl-R15, —(C(R9)2)qheteroaryl-R15, —(C(R9)2)qheterocyclyl-R15, —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, —(C(R9)2)pS(O)mR16, —(C(R9)2)pCO2R16, —(C(R9)2)pC(O)NHR16 and —(C(R9)2)pC(O)R15;
• further provided that R13 and R14 may optionally be taken together with the nitrogen to which they are attached forming a heterocyclyl, heteroaryl or bicyclyl heteroaryl ring optionally substituted on either nitrogen or carbon by one or more selected from the group, —R5, —R11, —(C(R9)2)qarylR15, —(C(R9)2)qheteroarylR15, —(C(R9)2)qheterocyclylR15, —(C(R9)2)qCO2R16, —(C(R9)2)qC(O)NHR16, and —(C(R9)2)qC(O)R15;
• or optionally substituted on carbon by —F, —(C(R7)2)qOR16, —(C(R7)2)qNR16R17, and —(C(R9)2)qS(O)mR16;
• or optionally substituted on nitrogen by —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, and —(C(R9)2)pS(O)mR16;
• R15 is independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNH2, —(C(R9)2)qNHR10, —(C(R9)2)qR10, —(C(R9)2)qS(O)mR10, —(C(R9)2)qCO2R10, —(C(R9)2)qCONHR10, —(C(R9)2)qCONR10R10, —(C(R9)2)qCOR10, —(C(R9)2)qCO2H, and —(C(R9)2)qCONH2;
• R16 and R17 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)pOH, —(C(R9)2)pOR10, —(C(R9)2)pNH2, —(C(R9)2)pNHR10, —(C(R9)2)pNR10R10, —(C(R9)2)pS(O)mR10, —(C(R9)2)pCO2R10, —(C(R9)2pCONHR10, —(C(R9)2)pCONR10R10, —(C(R9)2)pCOR10, —(C(R9)2)pCO2H, and —(C(R9)2)pCONH2;
• R18 is independently selected from the group consisting of —H, -aryl, —R5, —R6NH2, —R6NHR5 and —R6Q;
• provided that, when T and Z are carbon, A is absent, r is 0 and R4 is —(C(R9)2)rH, then,
• a. R3 is not unsubstituted thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, phenyl, alkenyl or alkynyl;
• or
• b. R3 is not monosubstituted by —R10, —(C(R9)2)qOH, or —(C(R9)2)qOR10 when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• c. R13 and R14 are not alkyl of 1 to 6 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine when R3 is substituted by —(C(R9)2)sR12 and R12 is —NR13R14;
• further provided that, when T and Z are carbon, A is absent and R4 is phenyl, then,
• a. R4 is not substituted by —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —(C(R9)2)qOH, —(C(R7)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ or —(C(R9)2)qNH2 or unsubstituted when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• b. R13 and R14 are not independently alkyl of 1 to 3 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine, wherein R4 is substituted by —(C(R9)2)sR12 and s is 0 and R12 is —NR13R14;
• additionally provided that, when T and Z are carbon, then,
• a. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when carbon-5 is substituted by an imidazole, oxazole or thiazole ring that is fused to a 6-membered aryl or heteroaryl ring halving 0 to 2 nitrogen atoms and wherein the fused bicyclic heteroaryl ring is attached to carbon-5 of Formula (I) via carbon-2 of the imidazole, oxazole or thiazole ring;
• and
• b. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when X is —O— and carbon-5 is substituted by aryl or heteroaryl;
• further provided that when either T or Z are N, then R2c is absent;
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting or eradication viral infections in a mammal in need thereof which comprises providing to said mammal an effective amount of a UL-97 kinase inhibitor of Formula (I), having the structure

• 65
• wherein:
• X is —NH—, —NR5—, —O—, or —S(O)m—;
• n is an integer of 0 or 1;
• m is an integer of 0 to 2;
• q is an integer of 0 to 5;
• p is an integer of 2 to 5;
• s is an integer of 0 to 5;
• r is an integer of 0 to 5;
• J is halogen;
• A is —(C(R9)2)r—, —C(O)—, —C(O)(C(R9)2)r—, —(C(R9)2)rC(O)—, -cycloalkyl- or is absent;
• T and Z are each independently carbon or N, provided that both T and Z are not simultaneously N;
• R1 is selected from a cycloalkyl ring of 3 to 10 carbon atoms, optionally substituted with one or more independently selected alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)m, R5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—,—(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or—different, selected from N, O and S wherein the heteroayl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q , —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —R7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —R6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR6, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein
• Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, (C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6C(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein
• Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q, —NR10(C(R9)2)q, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• and a moiety of the formula
• 66
• E is —NH—, —NR5—, —O—, —S(O)m—, —C(O)—, —CH2—, —CHR5— or —CR5R5—;
• Q is —NR5R5 and further provided that when each R5 is independently selected from alkyl and alkenyl, R5R5 may optionally be taken together with the nitrogen atom to which they are attached forming a heterocyclyl ring of 3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms which may be the same or different selected from N, O and S;
• R1a, R1b, R1c, R1d and R1e are each, independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —R11, —OR11, —NHR11 and —R6OC(O)Q;
• R2a, R2b, and R2c, are each, independently selected from —H, -aryl, —CH2aryl, —Oaryl, —S(O)maryl, —J, —NO2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —S(O)mR5, —NHSO2R5, —R11, —OR11, —R6OH, —R6OR5, —R6SH, —R6S(O)mR5, —OR7OH, —OR7OR5, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q, —G—(C(R9)2)p—R12, —(C(R9)2)q—R12, R18—CONH(CH2)r—, R18≡CONH(CH2)r—,
• 67
• G is —NH—, —NR10—, —O— or —S(O)m—;
• R3 is selected from alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S where the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R12, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R4 is selected from —(C(R9)2)2H, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3—dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ling system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R5 is a monovalent group independently selected from alkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R6 is a divalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R7 is a divalent alkyl group of 2 to 6 carbon atoms;
• R8 is a cycloalkyl ring of 3 to 10 carbon atoms that may optionally be substituted with one or more alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —H,-aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6R12, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6R12, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• R9 is independently —H, —F or —R5;
• R10 is an alkyl group of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms;
• R11 is a cycloalkyl group of 3 to 10 carbon atoms;
• R12 is —N(O)n R13R14 or —N+(R10R13R14)J−;
• provided that when R12 is N(O)n R13R14 and n is 1, R13 or R14 are not H;
• R13 and R14 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl-R15, —(C(R9)2)qheteroaryl-R15, —(C(R9)2)qheterocyclyl-R15, —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, —(C(R9)2)pS(O)mR16, —(C(R9)2)pCO2R16, —(C(R9)2)pC(O)NHR16 and —(C(R9)2)pC(O)R15;
• further provided that R13 and R14 may optionally be taken together with the nitrogen to which they are attached forming a heterocyclyl, heteroaryl or bicyclyl heteroaryl ring optionally substituted on either nitrogen or carbon by one or more selected from the group, —R5, —R11, —(C(R9)2)qarylR15, —(C(R9)2)qheteroarylR15, —(C(R9)2)qheterocyclylR15, —(C(R9)2)qCO2R16, —(C(R9)2)qC(O)NHR16, and —(C(R9)2)qC(O)R15;
• or optionally substituted on carbon by —F, —(C(R7)2)qOR16, —(C(R7)2)qNR16R17, and —(C(R9)2)qS(O)mR16;
• optionally substituted on nitrogen by —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, and —(C(R9)2)pS(O)mR16;
• R15 is independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNH2, —(C(R9)2)qNHR10, —(C(R9)2)qR10, —(C(R9)2)qS(O)mR10, —(C(R9)2)qCO2R10, —(C(R9)2)qCONHR10, —(C(R9)2)qCONR10R10, —(C(R9)2)qCOR10, —(C(R9)2)qCO2H, and —(C(R9)2)qCONH2;
• R16 and R17 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)pOH, —(C(R9)2)pOR10, —(C(R9)2)pNH2, —(C(R9)2)pNHR10, —(C(R9)2)pNR10R10, —(C(R9)2)pS(O)mR10, —(C(R9)2)pCO2R10, —(C(R9)2) pCONHR10, —(C(R9)2)pCONR10R10, —(C(R9)2)pCOR10, —(C(R9)2)pCO2H, and —(C(R9)2)pCONH2;
• R18 is independently selected from the group consisting of —H, -aryl, —R5, —R6NH2, —R6NHR5 and —R6Q;
• provided that, when T and Z are carbon, A is absent, r is 0 and R4 is —(C(R9)2)rH, then,
• a. R3 is not unsubstituted thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, phenyl, alkenyl or alkynyl;
• or
• b. R3 is not monosubstituted by —R10, —(C(R9)2)(qOH, or —(C(R9)2)qOR10 when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• c. R13 and R14 are not alkyl of 1 to 6 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine when R3 is substituted by —(C(R9)2)sR12 and R12 is —NR13R14;
• further provided that, when T and Z are carbon, A is absent and R4 is phenyl, then,
• a. R4 is not substituted by —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10—(C(R9)2)qOH, —(C(R7)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ or —(C(R9)2)qNH2 or unsubstituted when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• b. R13 and R14 are not independently alkyl of 1 to 3 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine, wherein R4 is substituted by —(C(R9)2)sR12 and s is 0 and R12 is —NR13R14;
• additionally provided that, when T and Z are carbon, then,
• a. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when carbon-5 is substituted by an imidazole, oxazole or thiazole ring that is fused to a 6-membered aryl or heteroaryl ring halving 0 to 2 nitrogen atoms and wherein the fused bicyclic heteroaryl ring is attached to carbon-5 of Formula (I) via carbon-2 of the imidazole, oxazole or thiazole ring;
• and
• b. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when X is —O— and carbon-5 is substituted by aryl or heteroaryl;
• further provided that when either T or Z are N, then R2c is absent;
• 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), having the structure

• 68
• wherein:
• X is —NH—, —NR5—, —O—, or —S(O)m—;
• n is an integer of 0 or 1;
• m is an integer of 0 to 2;
• q is an integer of 0 to 5;
• p is an integer of 2 to 5;
• s is an integer of 0 to 5;
• r is an integer of 0 to 5;
• J is halogen;
• A is —(C(R9)2)r—, —C(O)—, —C(O)(C(R9)2)r—, —(C(R9)2)rC(O)—, -cycloalkyl- or is absent;
• T and Z are each independently carbon or N, provided that both T and Z are not simultaneously N;
• R1 is selected from a cycloalkyl ring of 3 to 10 carbon atoms, optionally substituted with one or more independently selected alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—,—(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or—different, selected from N, O and S wherein the heteroayl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q , —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —R7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)N—NHR5, —R6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR6, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein
• Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q—, —NR10(C(R9)2)q—, —(C(R9)2)q, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6C(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q and YR8 groups wherein
• Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO2—, —SO2NH—, —C(OH)H—, —O(C(R9)2)q—, —S(O)m(C(R9)2)q—, —NH(C(R9)2)q, —NR10(C(R9)2)q, —(C(R9)2)q—, —(C(R9)2)qO—, —(C(R9)2)qS(O)m—, —(C(R9)2)qNH—, —(C(R9)2)qNR10—, —C≡C—, cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;
• and a moiety of the formula
• 69
• E is —NH—, —NR5—, —O—, —S(O)m—, —C(O)—, —CH2—, —CHR5— or —CR5R5—;
• Q is —NR5R5 and further provided that when each R5 is independently selected from alkyl and alkenyl, R5R5 may optionally be taken together with the nitrogen atom to which they are attached forming a heterocyclyl ring of 3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms which may be the same or different selected from N, O and S;
• R1a, R1b, R1c, R1d and R1e are each, independently selected from —H, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —R11, —OR11, —NHR11 and —R6OC(O)Q;
• R2a, R2b, and R2c, are each, independently selected from —H, -aryl, —CH2aryl, —Oaryl, —S(O)maryl, —J, —NO2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —S(O)mR5, —NHSO2R5, —R11, —OR11, —R6OH, —R6OR5, —R6SH, —R6S(O)mR5, —OR7OH, —OR7OR5, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5, —R6OC(O)Q, —G—(C(R9)2)p—R12, —(C(R9)2)q—R12, R18—CONH(CH2)r—, R18≡CONH(CH2)r—,
• 70
• G is —NH—, —NR10—, —O— or —S(O)m—;
• R3 is selected from alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S where the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10—, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R4 is selected from —(C(R9)2)rH, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ling system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —R10, —(C(R9)2)sR12, —CHO, 1,3-dioxolane, —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —COR10, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ, —(C(R9)2)qNH2, —(C(R9)2)rH, —G(C(R9)2)pOR10, —G(C(R9)2)pR12, and —G(C(R9)2)pOH;
• R5 is a monovalent group independently selected from alkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R6 is a divalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
• R7 is a divalent alkyl group of 2 to 6 carbon atoms;
• R8 is a cycloalkyl ring of 3 to 10 carbon atoms that may optionally be substituted with one or more alkyl groups of 1 to 6 carbon atoms;
• aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —R6R12, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6R12, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from —H, -aryl, —CH2aryl, —NHaryl, —Oaryl, —S(O)maryl, —J, —NO2, —NH2, —OH, —SH, —CN, —N3, —COOH, —CONH2, —NHC(O)NH2, —C(O)H, —CF3, —OCF3, —R5, —OR5, —NHR5, —Q, —S(O)mR5, —NHSO2R5, —R11, —OR11, —NHR11, —R6OH, —R6OR5, —R6NH2, —R6NHR5, —R6Q, —R6SH, —R6R12, —R6S(O)mR5, —NHR7OH, —NHR7OR5, —N(R5)R7OH, —N(R5)R7OR5, —NHR7NH2, —NHR7NHR5, —NHR7Q, —N(R5)R7NH2, —N(R5)R7NHR5, —N(R5)R7Q, —OR7OH, —OR7OR5, —OR7NH2, —OR7NHR5, —OR7Q, —OC(O)R5, —NHC(O)R5, —NHC(O)NHR5, —OR6C(O)R5, —NHR6C(O)R5, —C(O)R5, —C(O)OR5, —C(O)NHR5, —C(O)Q, —R6C(O)H, —R6C(O)R5, —R6C(O)OH, —R6C(O)OR5, —R6C(O)NH2, —R6C(O)NHR5, —R6C(O)Q, —R6OC(O)R5, —R6OC(O)NH2, —R6OC(O)NHR5 and —R6OC(O)Q;
• R9 is independently —H, —F or —R5;
• R10 is an alkyl group of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms;
• R11 is a cycloalkyl group of 3 to 10 carbon atoms;
• R12 is —N(O)n R13R14 or —N+(R10R13R14)J−;
• provided that when R12 is N(O)n R13R14 and n is 1, R13 or R14 are not H;
• R13 and R14 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl-R15, —(C(R9)2)qheteroaryl-R15, —(C(R9)2)qheterocyclyl-R15, —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, —(C(R9)2)pS(O)mR16, —(C(R9)2)pCO2R16, —(C(R9)2)pC(O)NHR16 and —(C(R9)2)pC(O)R15;
• further provided that R13 and R14 may optionally be taken together with the nitrogen to which they are attached forming a heterocyclyl, heteroaryl or bicyclyl heteroaryl ring optionally substituted on either nitrogen or carbon by one or more selected from the group, —R5, —R11, —(C(R9)2)qarylR15, —(C(R9)2)qheteroarylR15, —(C(R9)2)qheterocyclylR15, —(C(R9)2)qCO2R16, —(C(R9)2)qC(O)NHR16, and —(C(R9)2)qC(O)R15;
• or optionally substituted on carbon by —F, —(C(R7)2)qOR16, —(C(R7)2)qNR16R17, and —(C(R9)2)qS(O)mR16;
• or optionally substituted on nitrogen by —(C(R9)2)pOR16, —(C(R9)2)pNR16R17, and —(C(R9)2)pS(O)mR16;
• R15 is independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)qOH, —(C(R9)2)qOR10, —(C(R9)2)qNH2, —(C(R9)2)qNHR10, —(C(R9)2)qR10, —(C(R9)2)qS(O)mR10, —(C(R9)2)qCO2R10, —(C(R9)2)qCONHR10, —(C(R9)2)qCONR10R10, —(C(R9)2)qCOR10, —(C(R9)2)qCO2H, and —(C(R9)2)qCONH2;
• R16 and R17 are independently selected from a group consisting of —H, —R5, —R11, —(C(R9)2)qaryl, —(C(R9)2)qheteroaryl, —(C(R9)2)qheterocyclyl, —(C(R9)2)pOH, —(C(R9)2)pOR10, —(C(R9)2)pNH2, —(C(R9)2)pNHR10, —(C(R9)2)pNR10R10, —(C(R9)2)pS(O)mR10, —(C(R9)2)pCO2R10, —(C(R9)2pCONHR10, —(C(R9)2)pCONR10R10, —(C(R9)2)pCOR10, —(C(R9)2)pCO2H, and —(C(R9)2)pCONH2;
• R18 is independently selected from the group consisting of —H, -aryl, —R5, —R6NH2, —R6NHR5 and —R6Q;
• provided that, when T and Z are carbon, A is absent, r is 0 and R4 is —(C(R9)2)rH, then,
• a. R3 is not unsubstituted thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, phenyl, alkenyl or alkynyl;
• or
• b. R3 is not monosubstituted by —R10, —(C(R9)2)(qOH, or —(C(R9)2)qOR10 when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• c. R13 and R14 are not alkyl of 1 to 6 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine when R3 is substituted by —(C(R9)2)sR12 and R12 is —NR13R14;
• further provided that, when T and Z are carbon, A is absent and R4 is phenyl, then,
• a. R4 is not substituted by —NO2, —CN, —CO2H, —CONH2, —CO2R10, —CONHR10, —(C(R9)2)qOH, —(C(R7)2)qOR10, —(C(R9)2)qNHR10, —(C(R9)2)qJ or —(C(R9)2)qNH2 or unsubstituted when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine;
• and
• b. R13 and R14 are not independently alkyl of 1 to 3 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine, wherein R4 is substituted by —(C(R9)2)sR12 and s is 0 and R12 is —NR13R14;
• additionally provided that, when T and Z are carbon, then,
• a. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when carbon-5 is substituted by an imidazole, oxazole or thiazole ring that is fused to a 6-membered aryl or heteroaryl ring halving 0 to 2 nitrogen atoms and wherein the fused bicyclic heteroaryl ring is attached to carbon-5 of Formula (I) via carbon-2 of the imidazole, oxazole or thiazole ring;
• and
• b. carbon-8 is not substituted by —OH, —OR10, —SR10, or —OR11 when X is —O— and carbon-5 is substituted by aryl or heteroaryl;
• further provided that when either T or Z are N, then R2c is absent;
• or a pharmaceutically acceptable salt thereof.