Pyrrolopyrimidine compounds as kinase inhibitors

摘要

Disclosed herein are pyrrolo[2,3-d]pyrimidine 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 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 halogen, —CN, —OH, —NH2, —SH, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C4alkoxy, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted C3-C8cycloalkyl; G is substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C1-C4alkoxy, substituted or unsubstituted C1-C4heteroalkyl, substituted or unsubstituted C2-C7heterocycloalkyl, halogen, —CN, —NO2, —OH, —OCF3, —OCH2F, —OCF2H, —CF3, —SCH3, —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), —C(═O)N(R21)(R22), —N(R21)C(═O)R23, N(R21)C(═O)OR22, N(R21)C(═O)N(R21)(R22), or La-Ar; La is a bond, —CH2—, —CH(OH)—, —C(O)—, —CH2O—, —OCH2—, —SCH2, —CH2S—, —N(R21)—, —N(R21)C(O)—, —C(O)N(R21)—, —N(R21)C(O)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 R24 is independently halogen, —CN, —NO2, —OH, —OCF3, —OCH2F, —OCF2H, —CF3, —SCH3, —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), —C(═O)N(R21)(R22), —N(R21)C(═O)R23, N(R21)C(═O)OR22, N(R21)C(═O)N(R21)(R22), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted cycloalkyl; each R21 and R22 is independently H, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C3-C8cycloalkyl; each R23 is each independently substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C3-C8cycloalkyl; n is 0-4; Y is an optionally substituted group selected from among C1-C6alkylene, C1-C6heteroalkylene, C6-C12arylene, C3-C12heteroarylene, C1-C6alkyleneC6-C12arylene, C1-C6alkyleneC3-C12heteroarylene, C1-C6alkyleneC3-C8cycloalkylene, C1-C6alkyleneC2-C7heterocycloalkylene, C3-C8cycloalkylene, C2-C7heterocycloalkylene, fused C3-C8cycloalkyleneC2-C7heterocycloalkylene, and spiro C3-C8cycloalkyleneC2-C7heterocycloalkylene; Z is —C(═O)—, —N(Ra)C(═O)—, or —N(Ra)S(═O)x—, where x is 1 or 2, and Ra is H, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C3-C8cycloalkyl; R6 is H or L-J-W; R7 and R8 are independently H or L-J-W; or R7 and R8 taken together form a bond; L and J are each independently a bond, substituted or unsubstituted C1-C6alkylene, substituted or unsubstituted C3-C8cycloalkylene, substituted or unsubstituted C1-C6heteroalkylene, substituted or unsubstituted C2-C7heterocycloalkylene, substituted or unsubstituted C6-C12arylene, substituted or unsubstituted C3-C12heteroarylene, —CO—, —O—, or —S—; W is H, or NR25R26; and R25 and R26 are each independently H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C2-C7heterocycloalkyl, substituted or unsubstituted C6-C12aryl, or substituted or unsubstituted C3-C12heteroaryl; or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt thereof.