KINASE INHIBITORS USEFUL FOR THE TREATMENT OF MYLEOPROLIFIC DISEASES AND OTHER PROLIFERATIVE DISEASES

1 . Compounds of the formula Ia

and wherein the pyrimidine ring may be optionally substituted with one or more R20 moieties;

each D is individually taken from the group consisting of C, CH, C—R20, N-Z3, N, O and S, such that the resultant ring is taken from the group consisting of pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxazolyl, imidazoyl, and thiadiazolyl;

wherein E is selected from the group consisting phenyl, pyridyl, and pyrimidinyl;

E may be optionally substituted with one or two R16 moieties;

wherein A is a ring system selected from the group consisting of cyclopentyl, cyclohexyl, G1, G2, and G3;

G1 is a heteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazol-4-yl, isoxazol-5-yl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl;

G2 is a fused bicyclic heteroaryl taken from the group consisting of indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, pyrazolopyridinyl, imidazolonopyridinyl, thiazolopyridinyl, thiazolonopyridinyl, oxazolopyridinyl, oxazolonopyridinyl, isoxazolopyridinyl, isothiazolopyridinyl, triazolopyridinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, imidazolonopyrimidinyl, thiazolopyridiminyl, thiazolonopyrimidinyl, oxazolopyridiminyl, oxazolonopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, triazolopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, and benzoxazepinyl;

G3 is a heterocyclyl taken from the group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;

the A ring may be optionally substituted with-one or two R2 moieties;

X is selected from the group consisting of —O—, —S(CH 2 ) n —, —N(R3)(CH 2 ) n —, —(CH 2 ) p —, and wherein the carbon atoms of —(CH 2 ) n —, —(CH 2 ) p —, of X may be further substituted by oxo or one or more C1-C6alkyl moieties;

when A, G1, G2 or G3 has one or more substitutable sp2-hybridized carbon atoms, each respective sp2 hybridized carbon atom may be optionally substituted with a Z1 substituent;

when A, G1, G2 or G3 has one or more substitutable sp3-hybridized carbon atoms, each respective sp3 hybridized carbon atom may be optionally substituted with a Z2 substituent;

when A, G1, G2 or G3 has one or more substitutable nitrogen atoms, each respective nitrogen atom may be optionally substituted with a Z4 substituent;

each Z1 is independently and individually selected from the group consisting of C1-6alkyl, branched C3-C7alkyl, C3-C8cycloalkyl, halogen, fluoroC1-C6alkyl wherein the alkyl moiety can be partially or fully fluorinated, cyano, C1-C6alkoxy, fluoroC1-C6alkoxy wherein the alkyl moiety can be partially or fully fluorinated, —(CH 2 ) n OH, oxo, C1-C6alkoxyC1-C6alkyl, (R4) 2 N(CH 2 ) n —, (R3) 2 N(CH 2 ) n —, (R4) 2 N(CH 2 ) q N(R4)(CH 2 ) n —, (R4) 2 N(CH 2 ) q O(CH 2 ) n —, (R3) 2 NC(O)—, (R4) 2 NC(O)—, (R4) 2 NC(O)C1-C6alkyl-, —(R4)NC(O)R8, C1-C6alkoxycarbonyl-, -carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl-, (R3) 2 NSO 2 —, —SOR3, (R4) 2 NSO 2 —, —N(R4)SO 2 R8, —O(CH2) q OC1-C6alkyl, —SO 3 R3, —SOR4, —C(O)R8, —C(O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, —N(R3)(CH 2 ) q O-alkyl, —N(R3)(CH 2 ) q N(R4) 2 , nitro, —CH(OH)CH(OH)R4, —C(═NH)N(R4) 2 , —C(═NOR3)N(R4) 2 , and —NHC(═NH)R8, R17 substituted G3, R17 substituted pyrazolyl and R17 substituted imidazolyl;

in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;

each Z2 is independently and individually selected from the group consisting of aryl, C1-C6alkyl, C3-C8cycloalkyl, branched C3-C7alkyl, hydroxyl, hydroxyC1-C6alkyl-, cyano, (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl-, (R4) 2 NC2-C6alkylN(R4)(CH 2 ) n —, (R4) 2 NC2-C6alkylO(CH 2 ) n —, (R4) 2 NC(O)—, (R4) 2 NC(O)—, (R4) 2 NC(O)-C1-C6alkyl-, carboxyl, -carboxyC1-C6alkyl, C1-C6alkoxycarbonyl-, C1-C6alkoxycarbonylC1-C6alkyl-, (R3) 2 NSO 2 —, (R4) 2 NSO 2 —, —SO 2 R8, —(CH 2 ) n N(R4)C(O)R8, —C(O)R8, ═O, ═NOH, and ═N(OR6);

in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;

each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C8cycloalkyl, fluoroC1-C6alkyl wherein the alkyl moiety can be partially or fully fluorinated, hydroxyC2-C6alkyl-, C1-C6alkoxycarbonyl-, —C(O)R8, R5C(O)(CH 2 ) n —, (R4) 2 NC(O)—, (R4) 2 NC(O)C1-C6alkyl-, R8C(O)N(R4)(CH 2 ) q —, (R3) 2 NSO 2 —, (R4) 2 NSO 2 —, —(CH 2 ) q N(R3) 2 , and —(CH 2 ) q N(R4) 2 ;

each Z4 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-7alkyl, hydroxyC2-C6alkyl-, C1-C6alkoxyC2-C6alkyl-, (R4) 2 N-C2-C6alkyl-, (R4) 2 N-C2-C6alkylN(R4)-C2-C6alkyl-, (R4) 2 N-C2-C6alkyl-O-C2-C6alkyl-, (R4) 2 NC(O)C1-C6alkyl-, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl-, -C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)—, —SO 2 R8, and —COR8;

in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;

each R2 is selected from the group consisting of H, C1-C6alkyl, branched C3-C8alkyl, R19 substituted C3-C8cycloalkyl-, fluoroC1-C6alkyl- wherein the alkyl is fully or partially fluorinated, halogen, cyano, C1-C6alkoxy-, and fluoroC1-C6alkoxy- wherein the alkyl group is fully or partially fluorinated, hydroxyl substituted C1-C6alkyl-, hydroxyl substituted branched C3-C8alkyl-, cyano substituted C1-C6alkyl-, cyano substituted branched C3-C8alkyl-, (R3) 2 NC(O)C1-C6alkyl- and (R3) 2 NC(O)C3-C8 branched alkyl-;

wherein each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, and C3-C8cycloalkyl;

each R4 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6alkyl-, dihydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-, branched C3-C7alkyl, branched hydroxyC1-C6alkyl-, branched C1-C6alkoxyC1-C6alkyl-, branched dihydroxyC1-C6alkyl-, —(CH 2 ) p N(R7) 2 , —(CH 2 ) p C(O)N(R7) 2 , —(CH 2 ) n C(C)OR3, and R19 substituted C3-C8cycloalkyl-;

each R5 is independently and individually selected from the group consisting of

and wherein the symbol (##) is the point of attachment to Z3;

each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, and R19 substituted C3-C8cycloalkyl-;

each R7 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl-, dihydroxyC2-C6alkyl-, C1-C6alkoxyC2-C6alkyl-, branched C3-C7alkyl, branched hydroxyC2-C6alkyl-, branched C1-C6alkoxyC2-C6alkyl-, branched dihydroxyC2-C6alkyl-, —(CH 2 ) n C(O)OR3, R19 substituted C3-C8cycloalkyl- and —(CH 2 ) n R17;

each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroC1-C6alkyl- wherein the alkyl moiety is partially or fully fluorinated, R19 substituted C3-C8cycloalkyl-, —OH, C1-C6alkoxy, —N(R3) 2 , and —N(R4) 2 ;

each R10 is independently and individually selected from the group consisting of —CO 2 H, —CO 2 C1-C6alkyl, —C(O)N(R4) 2 , OH, C1-C6alkoxy, and —N(R4) 2 ;

each R16 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, R19 substituted C3-C8cycloalkyl-, halogen, fluoroC1-C6alkyl- wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, C1-C6alkoxy, fluoroC1-C6alkoxy- wherein the alkyl moiety can be partially or fully fluorinated, —N(R3) 2 , —N(R4) 2 , R3 substituted C2-C3alkynyl- and nitro;

each R17 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, R19 substituted C3-C8cycloalkyl-, halogen, fluoroC1-C6alkyl- wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, C1-C6alkoxy, fluoroC1-C6alkoxy- wherein the alkyl moiety can be partially or fully fluorinated, —N(R3) 2 , —N(R4) 2 , and nitro;

each R19 is independently and individually selected from the group consisting of H, OH and C1-C6alkyl;

each R20 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, R19 substituted C3-C8cycloalkyl-, halogen, fluoroC1-C6alkyl- wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, C1-C6alkoxy, fluoroC1-C6alkoxy- wherein the alkyl moiety can be partially or fully fluorinated, —N(R3) 2 , —N(R4) 2 , —N(R3)C(O)R3, —C(O)N(R3) 2 and nitro and wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl-, and alkoxyalkyl and attached to the same nitrogen heteroatom may cyclize to form a C3-C7 heterocyclyl ring;

k is 0 or 1; n is 0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3; v is 1 or2; x is 0-2;

and stereo-, regioisomers and tautomers of such compounds.

2 . Compounds of claim 1 wherein

is selected from the group consisting of

wherein the symbol (**) indicates the point of attachment to the pyrimidine ring.

3 . Compounds of claim 2 having formula Ib

wherein A is any possible isomer of pyrazole.

4 . Compounds of claim 3 having formula Ic

5 . Compounds of claim having formula Id

6 . Compounds of claim 3 having formula Ie

7 . Compounds of claim 2 having formula If

8 . Compounds of claim 2 having formula Ig

9 . Compounds of claim 8 having formula Ih

10 . A method of treating mammalian disease wherein the disease etiology or progression is at least partially mediated by the kinase activity of c-Abl kinase, bcr-Abl kinase, Flt-3 kinase, VEGFR-2 kinase mutants, c-Met, PDGFR-alpha kinase, PDGFR-beta kinase, HER-1, HER-2, HER-3, HER-4, FGFR, c-Kit, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of administering to the mammal a compound of claim 1 .

11 . A method of claim 10 wherein said kinase is selected from the group consisting of bcr-Abl fusion protein kinases p210, ber-Abl fusion protein kinases p190, bcr-Abl fusion protein kinases bearing the T315I gatekeeper mutant in the Abl kinase domain of p210, bcr-Abl fusion protein kinases bearing the T315I gatekeeper mutant in the Abl kinase domain of p190, and other bcr-Abl polymorphs of any of the foregoing kinases.

12 . The method of claim 11 , wherein said bcr-Abl fusion protein kinases p210 having SEQ ID NO:3 & SEQ ID NO:4, wherein said bcr-Abl fusion protein kinase p190 has SEQ ID NO:5, wherein said bcr-Abl fusion protein kinases p210 bearing the T315I mutation in the Abl kinase domain has SEQ ID NO:6 & SEQ ID NO:7, and wherein said bcr-Abl fusion protein kinase p190 bearing the T315I mutation in the Abl kinase domain has SEQ ID NO:8.

13 . A method of claim 10 wherein said kinase is selected from the group consisting of cKit protein kinase, PDGFR-alpha kinase, and any fusion protein, mutation and polymorphs of any of the foregoing.

14 . A method of claim 10 wherein said kinase is selected from the group consisting of c-Met protein kinase, and any fusion protein, mutation and polymorphs of any of the foregoing.

15 . A pharmaceutical composition comprising a compound of claim 1 , together with a pharmaceutically acceptable carrier, optionally containing an additive selected from the group including adjuvants, excipients, diluents, and stabilizers.

16 . A method of treating an individual suffering from a condition selected from the group consisting of cancer, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, or diseases characterized by angiogenesis, such as solid tumors, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, renal cancers, hepatic cancers, cervical carcinomas, metastasis of primary tumor sites, myeloproliferative diseases, chronic myelogenous leukemia, leukemias, papillary thyroid carcinoma, non-small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colonic cancers, ocular diseases characterized by hyperproliferation leading to blindness including retinopathies, diabetic retinopathy, age-related macular degeneration and hypereosinophilic syndrome, rheumatoid arthritis, asthma, chronic obstructive pulmonary, mastocytosis, mast cell leukemia, or disease a disease caused by c-Kit kinase, oncogenic forms thereof; aberrant fusion proteins thereof and polymorphs thereof, comprising the step of administering to such individual a compound of claim 1 .

17 . The method of claim 16 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.