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

1 . Compounds of the formula Ia

wherein Q1 and Q2 are each individually and independently selected from the group consisting of N and CH and wherein at least one of Q1 and Q2 is N;

and wherein the ring containing Q1 and Q2 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, and thiadiazolyl;

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

when Q1 and Q2 are both N, the A ring is selected from the group consisting of cyclopentyl, cyclohexyl, G1, G2, and G3;

when only one of Q1 and Q2 is N, the A ring is selected from the group consisting of cyclopentyl, cyclohexyl, G1, G2, G3 and G4;

G1 is a heteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl-4-yl, isoxazolyl-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, plithalazinyl, benzodioxyl, benizisothiazoline-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, morpholiniyl, tiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;

G4 is selected from the group consisting of phenyl, naphthyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl;

the A ring is substituted with one —(X1-A1) moiety or one A1 moiety, and may be optionally substituted with one or two R2 moieties;

when A is phenyl and E is phenyl, then Z1 cannot be —O(CH 2 ) q R5, —(CH 2 ) p -G33, or —(CH 2 ) p R5;

A1 is selected from the group consisting of phenyl, G1, G3 and G4;

X1 is selected from the group consisting of a direct bond linking the A and A1 rings, —(CH 2 ) n )(O) r (CH 2 ) n —, —(CH 2 ) n NR3) r (CH 2 ) n —, —(CH 2 ) n (S) r (CH 2 ) n —, —(CH 2 ) n (C(O)) r (CH 2 ) n —, —(CH 2 ) n (C(O)NR3) r (CH 2 ) n —, and —(CH 2 ) n (SO 2 NR3) r (CH 2 ) n —, wherein any of the alkylenes may be straight or branched chain;

when X1 is a direct bond, E is substituted with one or two R16 moieties;

when X1 is not a direct bond, then E is optionally substituted with one or two R16 moieties;

X2 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 X2 may be further substituted by oxo or one or more C 1 -C 6 alkyl moieties;

when A, A1, G1, G2 G3 or G4 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, A1, 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, A1, 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) n —, (R3) 2 N(CH) 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 R5, —N(R4)SO 2 R8, —O(CH 2 ) q OC1-C6alkyl, —O(CH 2 ) q R5, —SO 2 R3, —SOR4, —S(O) 2 R5, —(CH 2 ) n C(O)R5, —C(O)R8, —C(O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH2) n N(R4)C(O)R8, —(CH 2 ) n -G1, —(CH 2 ) n -G4, phenoxy, —(CH 2 ) n O(CH 2 ) n -G1, —(CH 2 ) p O(CH 2 ) n -G4, —N(R3)(CH 2 ) q O-alkyl, —N(R3)(CH 2 ) q N(R4) 2 , —N(R3)(CH 2 ) q R5, —(CH 2 ) n N(R3)(CH 2 ) n -aryl, —(CH 2 ) n N(R3)(CH 2 ) n —G1, —(CH 2 ) n N(R3)(CH 2 ) n -G4, nitro, —(CH 2 ) n NHC(O)(CH 2 ) n R5, —(CH 2 ) n NHS(O) 2 (CH 2 ) n R5, —(CH 2 ) n C(O)NH(CH 2 ) q R5, —(CH 2 ) n OC(O)R5, —CH(OH)(CH 2 ) p R5, —CH(OH)CH(OH)R4, —(CH 2 ) n R5, —C(═NH)R5, —C(═NH)N(R4) 2 , —C(═NOR3)R5, —C(═NOR3)N(R4) 2 , and —NHC(═NH)R8;

in the event mat Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C 1 -C 6 alkyls;

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 —, (R3) 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 R5, —SO 2 R8, —(CH 2 ) n N(R4)C(O)R8, —C(O)R8, ═O, ═NOH, ═N(OR6), —(CH 2 ) n -G1, —(CH 2 ) n -G4, —(CH 2 ) n O(CH 2 ) n -G1, —(CH 2 ) n O(CH 2 ) n -G4, —(CH 2 ) n N(R3)(CH 2 ) n -aryl, —(CH 2 ) n N(R3)(CH 2 ) n -G1, —(CH 2 ) n N(R3)(CH 2 ) n -G4, —(CH 2 ) n NHC(O)(CH 2 ) n R5, —(CH 2 ) n NHS(O) 2 (CH 2 ) n R5, —(CH 2 ) n C(O)NH(CH 2 ) q R5, —(CH 2 ) n C(O)R5, —(CH 2 ) n OC(O)R5, and —(CH 2 ) n R5;

in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be ether 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, —COR8, —(CH 2 ) n -G1, —(CH 2 ) n -G4, —(CH 2 ) q O(CH 2 ) n -G1, —(CH 2 ) q O(CH 2 ) n -G4, —(CH 2 ) q NR1(CH 2 ) n -G1, —(CH 2 ) q NR3(CH 2 ) n -G4, —(CH 2 ) q NHC(O)(CH 2 ) n R5, —(CH 2 ) q C(O)NH(CH 2 ) q R5, —(CH 2 ) q C(O)R5, —(CH 2 ) q OC(O)R5. (CH 2 ) q R5, —(CH 2 ) q NR4(CH 2 ) q R5, and —(CH 2 ) q O(CH 2 ) q R5;

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, R17-substituted aryl-, R17-substituted G1, R17-substituted G4, C1-C6alkyl, branched C3-C8alkyl, R19 substituted C3-C8cycloalkyl-, fluoroC1-C6alkyl- wherein the alkyl is fully or partially fluorinated, halogen, cyano, C1-C 6 alkoxy-, 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-, (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-C 7 alkyl, branched hydroxyC1-C6alkyl-, branched C1-C6alkoxyC1-C6alkyl-, branched dihydroxyC1-C6alkyl-, —(CH 2 ) p N(R7) 2 , —(CH 2 ) p R5, —(CH 2 ) p C(O)N(R7) 2 , —(CH 2 ) n C(O)R5, —(CH 2 ) 2 C(O)OR3, 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 respective R4, R7, R8, Z2, Z3 or Z4 moieties containing a R5 moiety;

each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, R19 substituted C3-C8cycloalkyl-, phenyl, G1, and G3;

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 ) q R5, —(CH 2 ) n C(O)R5, —(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-, phenyl, phenylC1-C 6 alkyl-, G1, G1-C1-C6alkyl-, G4-(CH 2 ) n —, OH, C 1 -C 6 alkoxy, —N(R3) 2 , —N(R4) 2 , and R5;

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 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-C6allyl- 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;

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 or 2; x is 0-2;

stereo-, regioisomers and tautomers of such compounds;

and with the proviso if A1 is G3, imidazolyl or pyrazolyl then X1 is not a direct bond.

2 . Compounds of claim 1 wherein

is selected from the group consisting of

wherein the symbol (**) indicates the point of attachment to the aromatic 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 3 having formula Id

6 . Compounds of claim 3 having formula Ie

7 . Compounds of claim 2 having the formula If

wherein A is selected from the group consisting of any possible isomer of phenyl, pyridine and pyrimidine.

8 . Compounds of claim 7 having formula Ig

9 . Compounds of claim 7 having formula Ih

10 . Compounds of claim 7 having formula Ii

11 . 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, HER-1. HER-2, HER-3, HER-4, FGFR, c-Kit, Raf kinase, PDGFRα kinase and PDGFR, kinase, 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 .

12 . A method of claim 11 wherein said kinase is selected from the group consisting of bcr-Abl fusion protein kinases p210, bcr-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.

13 . The method of claim 12 , 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 TB315I 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.

14 . A method of claim 11 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.

15 . A method of claim 11 wherein said kinase is selected from the group consisting of B-Raf V600E protein kinase, and any fusion protein, mutation and polymorphs of any of the foregoing.

16 . A method of claim 11 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.

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

18 . 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 .

19 . The method of claim 18 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.