INHIBITORS OF IRAK4 ACTIVITY

摘要

The present invention relates to compounds which modulate interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK4) and are useful in the prevention or treatment of inflammatory, cell proliferative and immune-related conditions and diseases. Specifically, provided herein are inhibitors of IRAK4 of Formula I and pharmaceutical compositions comprising such inhibitors, as well as methods therewith for treating IRAK4-mediated or -associated conditions or diseases.

主权项

1. A method for treating an inflammatory disease which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to Formula I: wherein: X is independently CH or N; Y is H or methyl; a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; Ring A is (C3-C8)cycloalkenyl, aryl or heterocycle optionally substituted with one to three substituents independently selected from R1; R1 is selected from: H, oxo, (C═O)aOb(C1-C10)alkyl, (C═O)aOb-aryl, (C═O)aOb(C2-C10)alkenyl, (C═O)aOb(C2-C10)alkynyl, CO2H, halo, OH, Ob(C1-C6)fluoroalkyl, (C═O)aNR5R6, CN, (C═O)aOb(C3-C8)cycloalkyl, S(O)mNR5R6, SH, S(O)m—(C1-C10)alkyl and (C═O)aOb-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents selected from Ra; R2 and R3 are independently selected from: H, (C═O)aObC1-C10 alkyl, (C═O)aObaryl, C2-C10 alkenyl, C2-C10 alkynyl, (C═O)aOb heterocyclyl, CO2H, CN, ObC1-C6fluoroalkyl, Oa(C═O)bNR5R6, CHO, (N═O)R5R6, S(O)mNR5R6, SH, S(O)m—(C1-C10)alkyl, (C═O)aObC3-C8 cycloalkyl, optionally substituted with one or more substituents selected from R1; or R2 and R3 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R1; R4 is independently selected from: (C1-C6)alkyl, OH, methoxy, CF3 and F, said alkyl optionally substituted with OH; R5 and R6 are independently selected from: H, (C═O)aOb(C1-C10)alkyl, (C═O)aOb-aryl, (C═O)aOb(C2-C10)alkenyl, (C═O)aOb(C2-C10)alkynyl, CO2H, Ob(C1-C6)fluoroalkyl, (C═O)aN(Ra)2, CN, (C═O)aOb(C3-C8)cycloalkyl, S(O)mN(Ra)2, SH, S(O)m—(C1-C10)alkyl and (C═O)aOb-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents selected from Ra; Ra is independently selected from Rb, OH, (C1-C6)alkoxy, halogen, cyclopropyl, CO2H, CN, Oa(C═O)b(C1-C6)alkyl, oxo, and N(Rb)2; and Rb is independently selected from H and (C1-C6)alkyl; or a pharmaceutically acceptable salt or a stereoisomer thereof.