Kinase inhibitors as therapeutic agents

A compound of Formula (I), the racemic-diastereomeric mixtures, optical isomers or pharmaceutically-acceptable salts thereof,

• wherein:
• where Z100 is
• or a group optionally substituted with Rb selected from the group consisting of cycloalkyl, naphthyl, tetrahydronaphthyl, benzothienyl, furanyl, thienyl, benzoxazolyl, benzothiazolyl,
• thiazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, indolyl, isoxazolyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrazolyl, pyrrolyl, oxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, indolinyl, indazolyl, benzoisothiazolyl, pyrido-oxazolyl, pyrido-thiazolyl, pyrimido-oxazolyl, pyrimido-thiazolyl and benzimidazolyl;
• Z110 is a covalent bond, or an optionally substituted straight chained, branched or cyclic hydrocarbon which is completely saturated or which contains one or more units of unsaturation, which is optionally substituted with one or more substituents selected from the group consisting of alkyl, CN, OH, halogen, NO2, COOH, substituted or unsubstituted amino and substituted or unsubstituted phenyl;
• Z111 is a covalent bond, an optionally substituted straight chained, branched or cyclic hydrocarbon which is completely saturated or which contains one or more units of unsaturation or an optionally substituted —(CH2)n-cycloalkyl-(CH2)n—;
• where the optionally substituted groups are optionally substituted with one or more substituents selected from the group consisting of alkyl, CN, OH, halogen, NO2, COOH, substituted or unsubstituted amino and substituted or unsubstituted phenyl;
• Ra and Rb each represent one or more substituents for each occurrence independently selected from the group consisting of hydrogen, halogen, —CN, —NO2, —C(O)OH, —C(O)H, —OH, —C(O)O-alkyl, substituted or unsubstituted carboxamido, tetrazolyl, trifluoromethylcarbonylamino, trifluoromethylsulfonamido, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted amido groups, substituted or unsubstituted heteroarylthio, substituted or unsubstituted arylthio, -Z105-C(O)N(R)2, -Z105-N(R)—C(O)-Z200, -Z105-N(R)—S(O)2-Z200, -Z105-N(R)—C(O)—N(R)-Z200, Rc and CH2ORc;
• where Rc for each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, —CH2—NRdRe, —W—(CH2)t—NRdRe, —W—(CH2)t—O-alkyl, —W—(CH2)t—S-alkyl, or —W—(CH2)t—OH;
• Z105 for each occurrence is independently a covalent bond or straight chained, branched or cyclic hydrocarbon which is completely saturated or which contains one or more units of unsaturation;
• Z200 for each occurrence is independently a substituted or unsubstituted straight chained, branched or cyclic hydrocarbon which is completely saturated or which contains one or more units of unsaturation, substituted or unsubstituted phenyl or substituted or unsubstituted (straight chained, branched or cyclic hydrocarbon which is completely saturated or which contains one or more units of unsaturation)-phenyl;
• Rd and Re for each occurrence are independently H, alkyl, alkanoyl or SO2-alkyl;
• or Rd, Re and the nitrogen atom to which they are attached together form pyridyl, pyrazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyrimidinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl or tetrazolyl ring;
• t for each occurrence is independently an integer from 2 to 6;
• W for each occurrence is independently a direct bond or O, S, S(O), S(O)2, or NRf, wherein Rf for each occurrence is independently H or alkyl;
• or R1 is a substituted or unsubstituted carbocyclic, thienyl, pyridyl, pyrazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, indazolyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyrimidinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, tetrazolyl, benzo[b]thienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzodiazolyl, indolyl, tetrahydroindolyl, azaindolyl, indazolyl, quinolinyl, imidazopyridinyl, quinazoline purinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl or their N-oxides fused with ring 2;
• R3 is hydrogen, hydroxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy;
• A is —O—;
• —S—;
• —S(O)p—;
• —N(R)—;
• —N(C(O)OR)—;
• —N(C(O)R)—;
• —N(SO2R)—;
• —CH2O—;
• —CH2S—;
• —CH2N(R)—;
• —CH(NR)—;
• —CH2N(C(O)R))—;
• —CH2N(C(O)OR)—;
• —CH2N(SO2R)—;
• —CH(NHR)—;
• —CH(NHC(O)R)—;
• —CH(NHSO2R)—;
• —CH(NHC(O)OR)—;
• —CH(OC(O)R)—;
• —CH(OC(O)NHR);
• —CH═CH—;
• —C(═NOR)—;
• —C(O)—;
• —CH(OR)—;
• —C(O)N(R)—;
• —N(R)C(O)—;
• —N(R)S(O)p—;
• —OC(O)N(R)—;;
• —N(R)—C(O)—(CH2)n—N(R)—, —N(R)C(O)O—;
• —N(R)—(CH2)n+1—C(O)—, —S(O)pN(R)—;
• —O—(CR2)n+1—C(O)—, —O—(CR2)n+1—O—, —N(C(O)R)S(O)p—;
• —N(R)S(O)pN(R)—;
• —N(R)—C(O)—(CH2)n—O—, —C(O)N(R)C(O)—;
• —S(O)pN(R)C(O)—;
• —OS(O)pN(R)—;
• —N(R)S(O)pO—;
• —N(R)S(O)pC(O)—;
• —SOpN(C(O)R)—;
• —N(R)SOpN(R)—;
• —C(O)O—;
• —N(R)P(ORg)O—;
• —N(R)P(ORg)—;
• —N(R)P(O)(ORg)O—;
• —N(R)P(O)(ORg)—;
• —N(C(O)R)P(ORg)O—;
• —N(C(O)R)P(ORg)—;
• —N(C(O)R)P(O)(ORg)O—, or —N(C(O)R)P(ORg)—;
• where R for each occurrence is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl or substituted or unsubstituted aryl;
• Rg for each occurrence is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl;
• p is 1 or 2;
• or in a phosphorus containing group, the nitrogen atom, the phosphorus atom, R and Rg together form a pyridyl, pyrazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyrimidinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl or tetrazolyl ring;
• or
• A is NRSO2 and R, Ra and the nitrogen atom together form a substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxazolyl or substituted or unsubstituted tetrazolyl ring fused to ring 1;
• R2 is -Z101-Z102;
• Z101 is a covalent bond, straight chained, branched or cyclic hydrocarbon which is completely saturated or which contains one or more units of unsaturation, straight chained, branched or cyclic hydrocarbon which is completely saturated or which contains one or more units of unsaturation-O—, straight chained, branched or cyclic hydrocarbon which is completely saturated or which contains one or more units of unsaturation-C(O)—, straight chained, branched or cyclic hydrocarbon which is completely saturated or which contains one or more units of unsaturation-C(O)O—, straight chained, branched or cyclic hydrocarbon which is completely saturated or which contains one or more units of unsaturation-C(O)—NH—, (straight chained, branched or cyclic hydrocarbon which is completely saturated or which contains one or more units of unsaturation)-C(O)—N (straight chained, branched or cyclic hydrocarbon which is completely saturated or which contains one or more units of unsaturation) or a substituted or unsubstituted phenyl group;
• Z102 is hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted, thienyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted benzo[b]thienyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzothiadiazolyl, substituted or unsubstituted benzodiazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted tetrahydroindolyl, substituted or unsubstituted azaindolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted imidazopyridinyl, substituted or unsubstituted quinazoline substituted or unsubstituted purinyl, substituted or unsubstituted pyrrolo[2,3-d]pyrimidinyl, substituted or unsubstituted pyrazolo[3,4-d]pyrimidinyl or their N-oxides, or a substituted or unsubstituted, saturated or unsaturated heterobicyclic group;
• said substituted thienyl, substituted pyridyl, substituted pyrazolyl, substituted isoxazolyl, substituted thiadiazolyl, substituted oxadiazolyl, substituted indazolyl, substituted furanyl, substituted pyrrolyl, substituted imidazolyl, substituted pyrazolyl, substituted triazolyl, substituted pyrimidinyl, substituted pyrazinyl, substituted thiazolyl, substituted or isothiazolyl, substituted oxazolyl, substituted tetrazolyl, substituted benzo[b]thienyl, substituted benzimidazolyl, substituted benzoxazolyl, substituted benzothiazolyl, substituted benzothiadiazolyl, substituted benzodiazolyl, substituted indolyl, substituted tetrahydroindolyl, substituted azaindolyl, substituted indazolyl, substituted quinolinyl, substituted imidazopyridinyl, substituted quinazoline substituted purinyl, substituted pyrrolo[2,3-d]pyrimidinyl, substituted pyrazolo[3,4-d]pyrimidinyl or substituted heterobicyclic group having one or more substituents each independently selected from the group consisting of hydroxyl, cyano, substituted or unsubstituted alkoxy, substituted or unsubstituted sulfonamido, substituted or unsubstituted ureido, substituted or unsubstituted carboxamido;
• substituted or unsubstituted amino, oxo, a saturated, unsaturated or aromatic, substituted or unsubstituted thienyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted benzo[b]thienyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzothiadiazolyl, substituted or unsubstituted benzodiazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted tetrahydroindolyl, substituted or unsubstituted azaindolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted imidazopyridinyl, substituted or unsubstituted quinazoline purinyl, substituted or unsubstituted pyrrolo[2,3-d]pyrimidinyl, substituted or unsubstituted pyrazolo[3,4-d]pyrimidinyl or their N-oxides;
• wherein said nitrogen atoms are independently optionally substituted by a substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylalkyl group;
• or
• R2 is of the formula B-E, wherein B is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted azacycloalkyl, substituted or unsubstituted amino, substituted or unsubstituted aminoalkylsulfonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminoalklylcarbonyl, hydroxy, substituted or unsubstituted alkylene, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkylenecarbonyl or substituted or unsubstituted aminoalkylcarbonyl group;
• and E is substituted or unsubstituted azacycloalkyl, substituted or unsubstituted azacycloalkylcarbonyl, substituted or unsubstituted azacycloalkylsulfonyl, substituted or unsubstituted azacycloalkylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted azacycloalkylcarbonylamino, substituted or unsubstituted heteroarylcarbonylamino or substituted or unsubstituted aryl;
• a is 1 and D1, G1, J1, L1 and M1 are each independently selected from the group consisting of CRa and N, provided that at least two of D1, G1, J1, L1 and M1 are CRa;
• or
• a is 0, and one of D1, G1, L1 and M1 is NRa, one of D1, G1, L1 and M1 is CRa and the remainder are independently selected from the group consisting of CRa and N, wherein Ra is as defined above;
• b is 1 and D2, G2, J2, L2 and M2 are each independently selected from the group consisting of CRa and N, provided that at least two of D2, G2, J2, L2 and M2 are CRa;
• or
• b is 0, and one of D2, G2, L2 and M2 is NRa, one of D2, G2, L2 and M2 is CRa and the remainder are independently selected from the group consisting of CRa and N, wherein Ra is as defined above;
• and
• n for each occurrence is independently an integer from 0 to 6;
• wherein the substituents for Ra, Rb, Rc, Z200, R3, R1, Z101, Z102, B and E, are independently selected from the group consisting of alkyl, CF3, alkoxy, OCF3, halogen, hydroxyl, nitro, oxo, CN, COH, COOH, amino, N-alkylamino or N,N-dialkylamino, esters aryl, aryalkyl, alkyl-O—C(O), alkoxyalkyl, heterocycloalkyl, optionally substituted phenyl, nitro and optionally substituted amino.