Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases

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(CH2)n—, —N(R3)(CH2)n—, —(CH2)p—, and wherein the carbon atoms of —(CH2)n—, —(CH2)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, —(CH2)nOH, oxo, C1-C6alkoxyC1-C6alkyl, (R4)2N(CH2)n—, (R3)2N(CH2)n—, (R4)2N(CH2)qN(R4)(CH2)n—, (R4)2N(CH2)qO(CH2)n—, (R3)2NC(O)—, (R4)2NC(O)—, (R4)2NC(O)C1-C6alkyl-, —(R4)NC(O)R8, C1-C6alkoxycarbonyl-, -carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl-, (R3)2NSO2—, —SOR3, (R4)2NSO2—, —N(R4)SO2R8, —O(CH2)qOC1-C6alkyl, —SO3R3, —SOR4, —C(O)R8, —C(O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH2)nN(R4)C(O)R8, —N(R3)(CH2)qO-alkyl, —N(R3)(CH2)qN(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)2N—, (R4)2N—, (R4)2NC1-C6alkyl-, (R4)2NC2-C6alkylN(R4)(CH2)n—, (R4)2NC2-C6alkylO(CH2)n—, (R4)2NC(O)—, (R4)2NC(O)—, (R4)2NC(O)-C1-C6alkyl-, carboxyl, -carboxyC1-C6alkyl, C1-C6alkoxycarbonyl-, C1-C6alkoxycarbonylC1-C6alkyl-, (R3)2NSO2—, (R4)2NSO2—, —SO2R8, —(CH2)nN(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)(CH2)n—, (R4)2NC(O)—, (R4)2NC(O)C1-C6alkyl-, R8C(O)N(R4)(CH2)q—, (R3)2NSO2—, (R4)2NSO2—, —(CH2)qN(R3)2, and —(CH2)qN(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)2N-C2-C6alkyl-, (R4)2N-C2-C6alkylN(R4)-C2-C6alkyl-, (R4)2N-C2-C6alkyl-O-C2-C6alkyl-, (R4)2NC(O)C1-C6alkyl-, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl-, -C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)—, —SO2R8, 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)2NC(O)C1-C6alkyl- and (R3)2NC(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-, —(CH2)pN(R7)2, —(CH2)pC(O)N(R7)2, —(CH2)nC(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-, —(CH2)nC(O)OR3, R19 substituted C3-C8cycloalkyl- and —(CH2)nR17;
• 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 —CO2H, —CO2C1-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.