Bicyclic compounds as kinases inhibitors

摘要

The present invention is directed to novel bicyclic compounds, their derivatives, pharmaceutically acceptable salts, solvates and hydrates thereof. The compounds and compositions of the present invention have protein kinases inhibitory activities and are useful for the treatment of protein kinases mediated diseases and conditions. Novel bicyclic compounds disclosed herein include quinazolines shown in Formula I (X═N).;

主权项

1. A compound according to Formula I:or a pharmaceutically acceptable salt, solvate, stereoisomer or a tautomer thereof, wherein
X is N; Y is O, S, or NH; W is CHR3, O, S, NH, C(O), S(O), or S(O)2; Ar is C6-C12 aryl, 5-12 membered heteroaryl, C3-C12 cycloalkyl, or 3-12 membered heteroalicyclic, and Ar is optionally substituted by one or more R10) groups; R1 is hydrogen, —(CHR3)mN(O)R11R12, —(CHR3)mNR11R12, or —(CHR3)mR13; R2 is OCH3, or OCH2CH3; each R3 is independently hydrogen or C1-C6 alkyl; R4, R5, R6, R7, R8 and R9 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, F, Cl, CN, or CF3; each R10 is independently halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, NO2, —NR15R16, —(CR17R18)nOR15, CN, —C(O)R15, —O(CO)R15, —O(CR17R18)nR15, —OCR17R18(CR17R18)nNR15R16, —OCR17R18(CR17R18)nOR15, —NR15C(O)R16, —(CR17R18)nC(O)OR15, —(CR17R18)nNR15R16, —NR15(CO)—NR15R16, —NR15S(O)pR16, —S(O)tR15, or —S(O)2NR15R16, wherein two R10 groups on adjacent atoms of Ar may, together with the adjacent atoms to which two R10 groups are bound, be combined to form a C6-C12 aryl, 5-12 membered heteroaryl, C3-C12 cycloalkyl or 3-12 membered heteroalicyclic; R11 and R12 are independently hydrogen, C1-C6 alkyl, or —CR17R18(CR17R18)nOR15; R13 is morpholine, piperidine, piperazine, piperazine-N(C1-C6 alkyl), or pyrrolidine, and each hydrogen in R13 is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, OH, NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2; each R15, R16, R17, and R18 is independently hydrogen, C1-C6alkyl; C6-C12 aryl, 5-12 membered heteroaryl, C3-C12 cycloalkyl or 3-12 membered heteroalicyclic; or any two of R15, R16, R17, and R18 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from the group consisting of N, O, and S; or any two of R15, R16, R17, and R18 bound to the same carbon atom may, together with the carbon to which they are bound, be combined to form a C6-C12 aryl, 5-12 membered heteroaryl, C3-C12 cycloalkyl, or 3-12 membered heteroalicyclic group; each m is independently 1, 2, or 3; each n is independently 0, 1, 2, 3, or 4; each p is independently 1 or 2; and each t is independently 0, 1, or 2.