INHIBITORS OF BRUTON'S TYROSINE KINASE

摘要

Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. In addition, reversible inhibitors of Btk are also described. 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 compound of Formula (I) having the structure:wherein:
R1 is optionally substituted heteroalkyl, —(C═O)C1-C6 alkyl, —(C═O)OR4, —(C═O)NR4R4, —(C═O)SR4, -G-X, or G is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, or optionally substituted aryl; X is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR4, —SR4, —NR4R4, or -L2-Ar; each R4 is each independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or C2-C6 heterocycloalkyl; Y is an optionally substituted group selected from among alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; Z is C(═O), OC(═O), N(R21)C(═O), C(═S), S(═O)p, OS(═O)p, or N(R21)S(═O)p, where p is 1 or 2; R2 is hydrogen, halogen, —CN, —NO2, —OH, —OR20, —OCF3, —OCH2F, —OCF2H, —CF3, —SR21, —N(R21)S(═O)2R23, —S(═O)2N(R21)(R22), —S(═O)R23, —S(═O)2R23, —C(═O)R23, —OC(═O)R23, —CO2R21, —N(R21)(R22), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkyl, or -L2-Ar; L2 is a bond, —CH2—, —CH(OH)—, —C(O)—, —CH2O—, —OCH2—, —SCH2, —CH2S—, —N(R21)—, —O—, —S—, —S(O)—, —S(O)2—, —N(R21)S(O)2—, or —S(O)2N(R21)—; Ar is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; each R3 is each independently halogen, —CN, —NO2, —OH, —OCF3, —OCH2F, —OCF2H, —CF3, —SR21, —N(R21)S(═O)2R23, —S(═O)2N(R21)(R22), —S(═O)R23, —S(═O)2R23, —C(═O)R23, —OC(═O)R23, —CO2R21, —N(R21)(R22), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted cycloalkyl; R20 is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C8heteroalkyl, or substituted or unsubstituted phenyl; each R21 and R22 are each independently H, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C3-C8cycloalkyl; R23 is each independently substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C3-C8cycloalkyl; n is 0-4; t is 0-2; R6 is H, halogen, —CN, or L3-J-W; R7 and R8 are independently H, halogen, —CN, or L3-J-W; or R7 and R8 taken together form a bond; each L3 and J are each independently a bond, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C3-C6 cycloalkylene, substituted or unsubstituted C1-C6 heteroalkylene, substituted or unsubstituted C2-C7 heterocycloalkylene, substituted or unsubstituted C6-C12 arylene, substituted or unsubstituted C3-C12 heteroarylene, —C(═O)—, —O—, or —S—; each W is H, —CN, or —NR25R26; R25 and R26 are each independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted C3-C12 heteroaryl; or a pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof.