Inhibitors of bruton's tyrosine kinase

摘要

Disclosed herein are compounds of Formula (A) that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.;

主权项

1. A method of treating a B-cell malignancy, comprising administering to a patient in need thereof a therapeutically effective amount of a compound that irreversibly inhibits EGFR, wherein the irreversible inhibitor is a compound having the structure of Formula (A): wherein: A is N; R1 is L2-(substituted or unsubstituted heteroaryl) or L2-(substituted or unsubstituted aryl), where L2 is a bond, O, S, —S(═O), —S(═O)2, C(═O), -(substituted or unsubstituted C1-C6alkyl), or -(substituted or unsubstituted C2-C6-alkenyl); R2 and R3 are independently H or lower alkyl; R4 is L3-X-L4-G, wherein,
L3 is optional, and when present is an optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, or optionally substituted or unsubstituted alkynyl;X is optional, and when present is O, —C(═O), S, —S(═O), —S(═O)2, —NH, —NR9, —NHC(O), —C(O)NH, —NR9C(O), —C(O)NR9, —S(═O)2NH, —NHS(═O)2, —S(═O)2NR9—, —NR9S(═O)2, —OC(O)NH—, —NHC(O)O—, —OC(O)NR9—, —NR9C(O)O—, —CH═NO—, —ON═CH—, —NR10C(O)NR10—, heteroaryl, aryl, —NR10C(═NR11)NR10—, —NR10C(═NR11)—, —C(═NR11)NR10—, —OC(═NR11)—, or —C(═NR11)O—;L4 is optional, and when present is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycle;or L3, X and L4 taken together form a nitrogen containing heterocyclic ring;G is  wherein,
R6, R7 and R8 are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl; R9 is selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl; each R10 is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or two R10 groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or R10 and R11 can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; and each R11 is independently selected from H, —S(═O)2R8, —S(═O)2NH2, —C(O)R8, —CN, —NO2, heteroaryl, or heteroalkyl; or a pharmaceutically acceptable solvate, hydrate, or salts thereof.