PYRROLOPYRIMIDINE COMPOUNDS AS KINASE INHIBITORSDisclosed 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.A compound having the structure of Formula (I):Formula (I);wherein:Ri is halogen, -CN, -OR21, -N(R21)(R22), -SR21, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-C4alkoxy, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted C3-Cgcycloalkyl;G is substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C3-Cgcycloalkyl, substituted or unsubstituted Ci-C4alkoxy, substituted or unsubstituted Ci-C4heteroalkyl, substituted or unsubstituted C2- C7heterocycloalkyl, halogen, -CN, -N02, -OR2i, -OCF3, -OCH2F, -OCF2H, -CF3, -SCH3, - N(R2i)S(=0)2R23, S(=0)2N(R2i)(R22), -S(=0)R23, -S(=0)2R23, -C(=0)R23, -OC(=0)R23, - CO2R21, N(R2i)(R22), -C(=0)N(R2i)(R22), -N(R2i)C(=0)R23, N(R2i)C(=0)OR22,N(R2i)C(=0)N(R2i)(R22), or La-A;La is a bond, -C(R2i)(R22)-, -CR2i(OR2i)-, -C(O)-, -CO-, -0(R2i)(R22)-, -S(R2i)(R22)-, - C(R2i)(R22)S-, -N(R2i)-, -N(R2i)C(0)-, -C(0)N(R2i)-, -N(R2i)C(0)N(R2i)-, -0-, -S-, -S(O)-, -S(0)2-, -N(R2i)S(0)2-, or -S(0)2N(R2i)-;A 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, -N02, -OH, -OCF3, -OCH2F, -OCF2H, -CF3, -SCH3, -N(R2i)S(=0)2R23, S(=0)2N(R2i)(R22), -S(=0)R23, -S(=0)2R23, -C(=0)R23, -OC(=0)R23, - CO2R21, N(R2i)(R22), -C(=0)N(R2i)(R22), -N(R2i)C(=0)R23, N(R2i)C(=0)OR22,N(R2i)C(=0)N(R2i)(R22), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstitutedheterocycloalkyl, or substituted or unsubstituted cycloalkyl; each R2i and R22 is independently H, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted C3-Cgcycloalkyl;each R23 is each independently substituted or unsubstituted Ci-C6alkyl, or substituted or unsubstituted C3-Cgcycloalkyl;n is 0-4;Y is an optionally substituted group selected from among Ci-Cealkylene, Ci- Ceheteroalkylene, C6-Ci2arylene, C3-Ci2heteroarylene, Ci-C6alkyleneC6-Ci2arylene, Ci- C6alkyleneC3-Ci2heteroarylene, Ci-C6alkyleneC3-Cgcycloalkylene, Ci-C6alkyleneC2- C7heterocycloalkylene, C3-Cgcycloalkylene, C2-C7heterocycloalkylene, fused C3- CgcycloalkyleneC2-C7heterocycloalkylene, and spiro C3-CgcycloalkyleneC2- C7heterocycloalkylene;Z is -C(=0), -N(Ra)C(=0), -S(=0)x, or -N(Ra)S(=0)x, where x is 1 or 2, and Ra is H, substituted or unsubstituted Ci-C6alkyl, or substituted or unsubstituted C3-Cgcycloalkyl; R6 is H, -CN, halogen, or L-J-W;R7 and Rg are independently H, -CN, halogen, or L-J-W; or R7 and Rg taken together form a bond;L and J are each independently a bond, substituted or unsubstituted Ci-Cealkylene, substituted or unsubstituted C3-Cgcycloalkylene, substituted or unsubstituted Ci- Ceheteroalkylene, substituted or unsubstituted C2-C7heterocycloalkylene, substituted or unsubstituted C6-Ci2arylene, substituted or unsubstituted C3-Ci2heteroarylene, -CO-, -0-, or -S-;R25 and R26 are each independently H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C3-Cgcycloalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C2-C7heterocycloalkyl, substituted or unsubstituted C6-C12aryl, or substituted or unsubstituted C3-Ci2heteroaryl; ora pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof.
키나제 억제제로서의 피롤로피리미딘 화합물브루톤 티로신 키나제 (Btk)와 공유 결합을 형성하는 화합물이 본원에 개시된다. 또한 Btk의 비가역적 억제제가 본원에 기재되어 있다. 게다가, Btk의 가역적 억제제도 기재되어 있다. 상기 화합물을 포함하는 약제학적 조성물도 개시된다. 자가 면역 질환 또는 상태, 이종 면역 질환 또는 상태, 림프종을 포함한 암, 및 염증성 질환 또는 상태의 치료를 위해, Btk 억제제를 단독으로 또는 다른 치료제와 병용하여 사용하는 방법이 개시된다.화학식 (I)의 구조를 갖는 화합물, 또는 이의 약제학적으로 허용가능한 용매화물, 약제학적으로 허용가능한 염 또는 약제학적으로 허용가능한 프로드러그:화학식 (I)상기 식에서,R1은 할로겐, -CN, -OR21, -N(R21)(R22), -SR21, 치환되거나 비치환된 C1-C6알킬, 치환되거나 비치환된 C1-C4알콕시, 치환되거나 비치환된 C1-C6헤테로알킬, 치환되거나 비치환된 페닐, 치환되거나 비치환된 헤테로아릴, 또는 치환되거나 비치환된 C3-C8사이클로알킬이고;G는 치환되거나 비치환된 C2-C4알케닐, 치환되거나 비치환된 C2-C4알키닐, 치환되거나 비치환된 C3-C8사이클로알킬, 치환되거나 비치환된 C1-C4알콕시, 치환되거나 비치환된 C1-C4헤테로알킬, 치환되거나 비치환된 C2-C7헤테로사이클로알킬, 할로겐, -CN, -NO2, -OR21, -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) 또는 La-A이며;La는 결합 (bond), -C(R21)(R22)-, -CR21(OR21)-, -C(O)-, -CO-, -O(R21)(R22)-, -S(R21)(R22)-, -C(R21)(R22)S-, -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- 또는 -S(O)2N(R21)-이고;A는 치환되거나 비치환된 사이클로알킬, 치환되거나 비치환된 헤테로사이클로알킬, 치환되거나 비치환된 아릴, 또는 치환되거나 비치환된 헤테로아릴이며;각 R24는 독립적으로 할로겐, -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), 치환되거나 비치환된 알킬, 치환되거나 비치환된 알콕시, 치환되거나 비치환된 헤테로알킬, 치환되거나 비치환된 헤테로사이클로알킬, 또는 치환되거나 비치환된 사이클로알킬이고;각 R21 및 R22는 독립적으로 H, 치환되거나 비치환된 C1-C6알킬, 또는 치환되거나 비치환된 C3-C8사이클로알킬이며;각 R23는 각각 독립적으로 치환되거나 비치환된 C1-C6알킬, 또는 치환되거나 비치환된 C3-C8사이클로알킬이고;n은 0 내지 4이며;Y는 C1-C6알킬렌, C1-C6헤테로알킬렌, C6-C12아릴렌, C3-C12헤테로아릴렌, C1-C6알킬렌C6-C12아릴렌, C1-C6알킬렌C3-C12헤테로아릴렌, C1-C6알킬렌C3-C8사이클로알킬렌, C1-C6알킬렌C2-C7헤테로사이클로알킬렌, C3-C8사이클로알킬렌, C2-C7헤테로사이클로알킬렌, 융합된 C3-C8사이클로알킬렌C2-C7헤테로사이클로알킬렌 및 스피로 C3-C8사이클로알킬렌C2-C7헤테로사이클로알킬렌 중에서 선택되는 임의로 치환된 기이고;Z는 -C(=O), -N(Ra)C(=O), -S(=O)x 또는 -N(Ra)S(=O)x이며, 여기서 x는 1 또는 2이고, Ra는 H, 치환되거나 비치환된 C1-C6알킬, 또는 치환되거나 비치환된 C3-C8사이클로알킬이며;R6는 H, -CN, 할로겐 또는 L-J-W이고;R7 및 R8은 독립적으로 H, -CN, 할로겐 또는 L-J-W이거나; R7 및 R8은 함께 결합을 형성하며;L 및 J는 각각 독립적으로 결합, 치환되거나 비치환된 C1-C6알킬렌, 치환되거나 비치환된 C3-C8사이클로알킬렌, 치환되거나 비치환된 C1-C6헤테로알킬렌, 치환되거나 비치환된 C2-C7헤테로사이클로알킬렌, 치환되거나 비치환된 C6-C12아릴렌, 치환되거나 비치환된 C3-C12헤테로아릴렌, -CO-, -O- 또는 -S-이고;W는 H 또는 NR25R26이며;R25 및 R26는 각각 독립적으로 H, 치환되거나 비치환된 C1-C6알킬, 치환되거나 비치환된 C3-C8사이클로알킬, 치환되거나 비치환된 C1-C6헤테로알킬, 치환되거나 비치환된 C2-C7헤테로사이클로알킬, 치환되거나 비치환된 C6-C12아릴, 또는 치환되거나 비치환된 C3-C12헤테로아릴이다.