Heterocyclic compounds as protein kinase inhibitors

摘要

The present invention provides a heterocyclic compound of formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof or a hydrate thereof, wherein A, A′ B, D, R1, R2 and R3 are as defined herein, a pharmaceutical composition comprising a compound of formula (I) as an active ingredient, methods of production, and methods of use thereof. Particularly, the present invention provides a compound of formula (I) useful for treating or preventing a disease, condition or disorder associated with protein kinases, preferably Janus Kinase family.

主权项

1. A method for inhibiting JAK1, JAK2, JAK3, or TYK2 in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure of formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, or a hydrate thereof, wherein: A represents CR and B represents N; R and R′ independently represent H, (C1-C6) alkyl, halogen, —CN, —NRaRb, —NRaCORb or —CONRaRb; R″ represents H, halogen or —NRaCORb; R1 represents H or (C1-C3) alkyl; R2 represents H, (C1-C3) alkyl, halo or —CN; R3 represents —COR4; R4 represents R7, R8, and R9 independently represent H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, halo, —NO2, —(CH2)qC(O)NRcRd, —(CH2)qNRcCORd, —(CH2)qNRcCONRcRd, —(CH2)qNRcC(O)ORd, —(CH2)qNRcRd, —(CH═CH)—(CH2)sC(O)ORe, —(CH═CH)—(CH2)sCONRcRd, —(CH═CH)—(CH2)sCN, —(CH═CH)—(CH2)sRe, —(CH2)sC(O)ORe, —(CH)rCN, —(CH2)rORe, —(CH2)rRe, —(CH2)rC(O)ORe, —(CH)rhalo, —S(O)pRe, —S(O)pNRcRd, —NRcS(O)pRd, and wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl heterocyclyl are optionally substituted; Rc and Rd independently represent H, (C1-C8) alkyl, (C3-C8) cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, —(CH2)rORe, —(CH2)rSRe, —(CH2)rCN, —(CH2)rhalo, —(CH2)rC(O)ORe, —(CH2)rNRcRd, —CORe, —S(O)pRe, or —(CH2)rRe, wherein alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted; or Rc and Rd are taken together with the N atom to which they are attached to form 3-8 membered heterocyclyl, optionally containing additional heteroatom(s) selected from N, O, or S, wherein heterocyclyl is optionally substituted; Re represents H, (C1-C6) alkyl, —CF3, (C3-C8) cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted; p represents an integer of 1 or 2; q represents an integer of 0, 1, 2 or 3; r represents an integer of 0, 1, 2, 3 or 4; and s represents an integer of 0, 1 or 2; Ra and Rb independently represent H, (C1-C8) alkyl, (C3-C8) cycloalkyl or OR′″; or Ra and Rb are taken together with the N atom to which they are attached to form 3-8 membered heterocyclyl, optionally containing additional heteroatom(s) selected from N, O or S, wherein heterocyclyl is optionally substituted; and R′″ represents H or (C1-C3) alkyl.