Inhibitors of bruton's tyrosine kinase

摘要

This application discloses 5-phenyl-1H-pyridin-2-one and 6-phenyl-2H-pyridazin-3-one derivatives according to generic Formulae I-IV:;
wherein, variables R, X, Y1, Y2, Y2′, Y3, Y4, n and m are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation such as rheumatoid arthritis. Also disclosed are compositions comprising compounds of Formulae I-IV and at least one carrier, diluent or excipient.

主权项

1. A compound of Formula IV, wherein: R is H, —R1, —R1—R2—R3, —R1—R3, or —R2—R3;
R1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with R1′;
R1′ is lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, heterocycloalkyl, cyano, or lower haloalkyl;R2 is —C(═O), —C(═O)O, —C(═O)N(R2′), —(CH2)q, or —S(═O)2;
R2′ is H or lower alkyl;q is 1, 2, or 3;R3 is H or R4;R4 is lower alkyl, lower alkoxy, lower heteroalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl; X is CH or N; Y1 is H or lower alkyl; Y2 is Y2a or Y2b;
Y2a is H or halogen;Y2b is lower alkyl, optionally substituted with one or more Y2b′;
Y2b′ is hydroxy, lower alkoxy, or halogen; each Y2′ is independently Y2′a or Y2′b;
Y2′a is halogen;Y2′b is lower alkyl, optionally substituted with one or more Y2′b′;
Y2′b′ is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3; Y3 is H, halogen, or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1; Y4 is Y4a, Y4b, Y4c, or Y4d;
Y4a is H or halogen;Y4b is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, cyano and lower alkoxy;Y4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; andY4d is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.