Heterocyclic compounds useful as inhibitors of tyrosine kinases

A Compound of the formula(I):

• 75
• wherein:
• Ar1 is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle;
• wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more R1, R2 and R3;
• X is NH, N—C1-3alkyl, N-cyclopropyl, S or O;
• Y is NR15, S or O;
• Ra is H, C1-10alkyl, C2-10alkenyl or C2-10alkynyl, each of which may be branched or cyclic;
• or Ra is aryl or heteroaryl;
• wherein each Ra is independently optionally substituted with one or more C1-6alkyl, C1-6 alkoxy, halogen, OH, oxo, NR10R11, aryl or heteroaryl each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, C1-3alkyl, C1-3alkoxy, hydroxyC1-3alkyl and (CH2)mNR10R11;
• and wherein Ra is attached at the 4- or 5- position;
• R1 and R2 are the same or different and selected from H, halogen, CN, NO2, C1-10 branched or unbranched saturated or unsaturated alkyl, C1-10 branched or unbranched alkoxy, C1-10 branched or unbranehed acyl, C1-10 branched or unbranched acyloxy, C1-10 branched or unbranched alkylthio, aminosulfonyl, di-(C1-3)alkylaminosulfonyl, NR10R11, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy;
• wherein the abovementioned R1 and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NR10R11, C1-6 branched or unbranched alkyl, C3-7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C1-3)alkylaminocarbonyl;
• R3 is H, halogen, OH, (CH2)nNR10R11, CONR10R11, (CH2)nCO2R12;
• C1-3alkyl optionally substituted with OH, C1-3 alkoxy optionally halogenated or C1-3 alkylthio;
• R4 and R5 together with the atoms to which they are attached complete a fused ring system of the formulas A or B:
• 76
• R6 IS C1-3alkyl or H;
• R7 is C1-6alkyl branched or unbranched or H;
• R8 is H, C1-6alkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or C1-3alkoxy;
• or R8 is (CH2)mNR10R11, (CH2)mNR10COR12, (CH2)nCO2R12, (CH2)nCONR10R11;
• or R8 is phenyl or heteroaryl, each being optionally substituted with C1-3alkyl, C1-3alkoxy, OH, —SO3H or halogen;
• R9 is H, CN or CONR10R11;
• or R9 is C1-10alkyl branched or unbranched, C3-10cycloalkyl, C5-7cycloalkenyl, C2-6 alkenyl, C2-6 alkynyl each being optionally substituted with one or more C3-10cycloalkyl, C3-10cycloalkylidene, C5-7cycloalkenyl, halogen, OH, oxo, CN, C1-3alkoxy, C1-3acyloxy, NR10R11, NR10CONR10R11, NR10C(═NR10)NR10R11, NR10COR12, NR10S(O)pR12, SR12, CONR10R11, CO2R12, C(R10)═NNR10R11, C(R10)═NNR10CONR10R11, aryloxy, arylthio, aryl or heteroaryl;
• wherein each aryloxy, arylthio, aryl or heteroaryl is optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, (CH2)nNR10R11 or O(CH2)24NR10R11;
• or R9 is aryl, heteroaryl, or heterocycle, wherein each aryl, heteroaryl or heterocycle is optionally substituted with one to three groups selected from C1-3alkyl optionally substituted with phenyl or NR10C(═NR10)NR10R11, C1-3alkoxy, halogen, CN, oxo, (CH2)nNR10R11, (CH2)nCO2R12;
• (CH2)nCONR10R11 and O(CH2)2-4NR10R11;
• or R8 and R9 together form a saturated or unsaturated 5 or 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by one or two C1-3alkyl, OH, oxo or (CH2)nNR10R11, or optionally spiro-fused to a 1,3 dioxolane group or 1,3 dithiolane group, each 1,3 dioxolane group or 1,3 dithiolane group optionally substituted by C1-6alkyl, C1-6alkoxy, OH or (CH2)nNR10R11;
• R10 and R11 may be the same or different and are each independently selected from H, OH, C1-3alkoxy, C1-6alkyl branched or unbranched, C3-8cycloalkyl, aryl, arylC1-3alkyl and heteroaryl;
• wherein said alkyl, cycloalkyl, aryl, arylC1-3alkyl or heteroaryl are optionally substituted with OH, C1-3alkoxy, CN, NO2, C1-3acyloxy, CO2R12, NR13R14, O(CH2)2-4NR13R14, aryl or heteroaryl;
• or R10 and R11 together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached;
• wherein said alkylene chain is optionally interrupted by O, S(O)p, and NR13;
• and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, OH, —(CH2)nNR13R14, CONR13R14 or NR13COR14;
• R12 is H, C1-6alkyl or C3-8cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C1-3alkoxy or NR13R14;
• or R12 is phenyl or heterocycle, optionally substituted with one to three groups selected from C1-3alkyl, C1-3alkoxy, halogen, (CH2)mNR10R11, (CH2)nCONR10R11 and O(CH2)2-4NR10R11;
• R13 and R14 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3alkoxy, OH or phenyl;
• or R13 and R14 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2;
• R15 is H or C1-3 alkyl;
• m is 1-4;
• n is 0-3 and p is 0-2;
• and
• the pharmaceutically acceptable acid or salt derivatives thereof.