BICYCLIC PYRIMIDINE PI3K INHIBITOR COMPOUNDS SELECTIVE FOR P110 DELTA, AND METHODS OF USEFormula (I) ((Ia) and (Ib)) compounds wherein (i) X1 is N and X2 is S, (ii) X1 is CR7 and X2 is S, (iii) X1 is N and X2 is NR2, or (iv) X1 is CR7 and X2 is O, including stereoisomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting the delta isoform of PI3K, and for treating disorders mediated by lipid kinases such as inflammation, immunological, and cancer. Methods of using compounds of Formula (I) for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed. A compound selected from Formulas Ia and Ib:Ia Ib and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein (i) X1 is N and X2 is S, (ii) X1 is CR7 and X2 is S, (iii) X1 is N and X2 is NR2, or (iv) X1 is CR7 and X2 is O;R1 is selected fromC1-C12 alkyl,C2-C8 alkenyl,C2-C8 alkynyl,C6-C20 aryl,C2-C20 heterocyclyl,C3-Ci2 carbocyclyl,Ci-C20 heteroaryl,-(Ci-Ci2 alkylene)-(C3-Ci2 carbocyclyl),-(Ci-Ci2 alkylene)-(C2-C20 heterocyclyl),-(Ci-Ci2 alkylene)-(C2-C20 heterocyclyl)-(C2-C20 heterocyclyl),-(Ci-Ci2 alkylene)-(C2-C20 heterocyclyl)-(C3-Ci2 carbocyclyl),-(Ci-Ci2 alkylene)-(C2-C20 heterocyclyl)-C(=O)-(C2-C20 heterocyclyl),-(Ci-Ci2 alkylene)-(Ci-C20 heteroaryl),-(Ci-Ci2 alkylene)-(C2-C20 heterocyclyl)-(Ci-Ci2 alkyl),-(Ci-Ci2 alkylene)-(C6-C20 MyI)-(C1-C12 alkyl),-(Ci-Ci2 alkylene)-(Ci-C20 heteroaryl)-(Ci-Ci2 alkyl),-(Ci-Ci2 alkylene)-C(=O)-(C2-C20 heterocyclyl),-(Ci-Ci2 alkylene)-NHR2',-(Ci-Ci2 alkylene)-NR2'-(Ci-Ci2 alkyl), -(Ci-Ci2 alkylene)-NR2'-(C3-Ci2 carbocyclyl),-(Ci-Ci2 alkylene)-NR2'-(C2-C20 heterocyclyl),-(Ci-Ci2 alkylene)-NR2'-(Ci-C20 heteroaryl),-(Ci-Ci2 alkylene)-NR2'-(C6-C20 aryl),-(Ci-Ci2 alkylene)-NR2'-(Ci-Ci2 alkylene)-(C3-Ci2 carbocyclyl),-(Ci-Ci2 alkylene)-NR2'-(Ci-Ci2 alkylene)-(Ci-C20 heteroaryl),-(Ci-Ci2 alkylene)-NR2'-(Ci-Ci2 alkylene)-(Ci-C20 heterocyclyl),-(Ci-Ci2 alkylene)-NR2'-(Ci-Ci2 alkylene)-(C6-C20 aryl),-(Ci-Ci2 alkylene)-NR2'-(Ci-Ci2 alkylene)-NHC(=O)-(Ci-C20 heteroaryl),-(Ci-Ci2 alkylene)-(C2-C20 heterocyclyl)-N(Ci-Ci2 alkyl)R2',-(Ci-Ci2 alkylene)-(C2-C20 heterocyclyl)-(Ci-Ci2 alkyl)-N(Ci-Ci2 alkyl)R2',-(C2-Ci2 alkenylene)-(C2-C2o heterocyclyl),-(Ci-C2O heteroaryl)-(C2-C2o heterocyclyl),-(Ci-C2O heteroaryl)-(C3-Ci2 carbocyclyl),-C(=O)-(C2-C20 heterocyclyl),-C(=O)-(Ci-C20 heteroaryl),-C(=O)-(C2-C20 heterocyclyl)-(C2-C20 heterocyclyl),-C(=O)-(C2-C20 heterocyclyl)-(Ci-C20 heteroaryl),-C(=O)-(Ci-Ci2 alkyl),-C(=O)-NR2'-(Ci-Ci2 alkyl), and-CR4=CR5R6 where R4 is selected from H, F, Cl, Br, I and Ci-Ci2 alkyl, and R5 and R6 form C2-C2O heterocyclyl, Ci-C2O heteroaryl, or C3-Ci2 carbocyclyl,where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, - CH3, -CH2CH3, -CH2CH(CH3)2, -CH2NH2, -CH2N(CH3),, -CH2CH2NH2, - CH2CH2N(CH3)2, -CH2OH, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, - CH2C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, -CN, -CF3, - CO2H, -CHO, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH2OH, -COC(OH)(CH3)2, - COCH(OH)CH3, -CONH2, -CONHCH3, -CON(CH3)2, -CH2CONH2, -CH2CON(CH3)2, - C(CH3)2CONH2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, - NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, =0, -OH, -OCH3, - S(O)2N(CH3)2, -SCH3, -CH2OCH3, -S(O)2CH3, -C(O)-cyclopropyl, cyclopropyl, cyclobutyl, oxetanyl, and morpholino;R2 and R2 are independently selected from H, C1-C12 alkyl, C2-Cg alkenyl, C2-Cg alkynyl, -(Ci-Ci2 alkylene)-(C3-Ci2 carbocyclyl), -(Ci-Ci2 alkylene)-(C2-C20heterocyclyl), -(Ci-Ci2 alkylene)-C(=O)-(C2-C20 heterocyclyl), -(Ci-Ci2 alkylene)-(C6- C2o aryl), and -(Ci-Ci2 alkylene)-(Ci-C2o heteroaryl), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -COC(CH3)3, -COCF3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, - NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, - CH2OCH3, and -S(O)2CH3;R3 is a bicyclic heteroaryl group selected from:optionally substituted with one or more groups independently selected from C1-C12 alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C3-C12 carbocyclyl, C2-C2O heterocyclyl, C6-C2O aryl, Ci-C20 heteroaryl, -(Ci-Ci2 alkylene)-(C2-C20 heterocyclyl), -NH-(Ci-Ci2 alkylene)-(C2- C20 heterocyclyl), -N(Ci-Ci2 alkyl)-(Ci-Ci2 alkylene)-(C2-C20 heterocyclyl), -NH-(C2- C20 heterocyclyl), -0-(C2-C20 heterocyclyl), -NH-(C3-Ci2 carbocyclyl), -0-(C3-Ci2 carbocyclyl), F, Cl, Br, I, -CN, -CO2H, -CONH2, -CONH(Ci-Ci2 alkyl), -CON(Ci-Ci2 alkyl)2, -CO(Ci-Ci2 alkyl), -NO2, -NH2, -NH(Ci-Ci2 alkyl), -N(Ci-Ci2 alkyl)2, - NHCO(Ci-Ci2 alkyl), -NHS(O)2(Ci-Ci2 alkyl), -N(Ci-Ci2 alkyl)S(O)2(Ci-Ci2 alkyl), -OH, -0(Ci-Ci2 alkyl), -NHC(=0)NH(Ci-Ci2 alkyl), -SH, -S(Ci-Ci2 alkyl), -S(O)(Ci-Ci2 alkyl), -S(O)2(Ci-Ci2 alkyl), -S(O)2NH2, -S(O)2NH(Ci-Ci2 alkyl), and -S(O)2N(Ci-Ci2 alkyl)2, where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I,— CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, - NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, =0, -OH, -OCH3, -S(O)2N(CH3)2, -SH, - SCH3, -CH2OCH3, and -S(O)2CH3;R7 is selected from H, Ci-Ci2 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(Ci-Ci2 alkylene)-(C3-Ci2 carbocyclyl), -(Ci-Ci2 alkylene)-(C2-C20 heterocyclyl), -(Ci-Ci2 alkylene)-C(=O)-(C2-C20 heterocyclyl), -(Ci-Ci...
Ｐ110 델타에 대해 선택적인 비시클릭 피리미딘 ＰＩ3Ｋ 억제제 화합물 및 사용 방법 하기 화학식 I (Ia 및 Ib)의 화합물 (그의 입체이성질체, 호변이성질체, 대사물 및 제약상 허용되는 염 포함)은 PI3K의 델타 이소형의 억제, 및 지질 키나제에 의해 매개되는 장애, 예컨대 염증, 면역장애 및 암의 치료에 유용하다. 포유동물 세포에서의 상기 장애 또는 연관된 병리 상태의 시험관내, 계내 및 생체내 진단, 예방 또는 치료를 위한 화학식 I의 화합물의 사용 방법이 개시되어 있다. <화학식 Ia> <화학식 Ib> 상기 식에서, (i) X1은 N이고, X2는 S이거나, (ii) X1은 CR7이고, X2는 S이거나, (iii) X1은 N이고, X2는 NR2거나, 또는 (iv) X1은 CR7이고, X2는 O이다. p110 델타에 대한 IC50 결합 활성이 p110 알파에 대한 결합 활성보다 10배 이상 낮은 하기 화학식 Ia 및 Ib로부터 선택된 화합물, 및 그의 입체이성질체, 호변이성질체 또는 제약상 허용되는 염.<화학식 Ia><화학식 Ib>상기 식에서,(i) X1은 N이고, X2는 S이거나, (ii) X1은 CR7이고, X2는 S이거나, (iii) X1은 N이고, X2는 NR2이거나, 또는 (iv) X1은 CR7이고, X2는 O이고;R1은C1-C12 알킬,C2-C8 알케닐,C2-C8 알키닐,C6-C20 아릴,C2-C20 헤테로시클릴,C3-C12 카르보시클릴,C1-C20 헤테로아릴,-(C1-C12 알킬렌)-(C3-C12 카르보시클릴),-(C1-C12 알킬렌)-(C2-C20 헤테로시클릴),-(C1-C12 알킬렌)-(C2-C20 헤테로시클릴)-(C2-C20 헤테로시클릴),-(C1-C12 알킬렌)-(C2-C20 헤테로시클릴)-(C3-C12 카르보시클릴),-(C1-C12 알킬렌)-(C2-C20 헤테로시클릴)-C(=O)-(C2-C20 헤테로시클릴),-(C1-C12 알킬렌)-(C1-C20 헤테로아릴),-(C1-C12 알킬렌)-(C2-C20 헤테로시클릴)-(C1-C12 알킬),-(C1-C12 알킬렌)-(C6-C20 아릴)-(C1-C12 알킬),-(C1-C12 알킬렌)-(C1-C20 헤테로아릴)-(C1-C12 알킬),-(C1-C12 알킬렌)-C(=O)-(C2-C20 헤테로시클릴),-(C1-C12 알킬렌)-NHR2',-(C1-C12 알킬렌)-NR2'-(C1-C12 알킬),-(C1-C12 알킬렌)-NR2'-(C3-C12 카르보시클릴),-(C1-C12 알킬렌)-NR2'-(C2-C20 헤테로시클릴),-(C1-C12 알킬렌)-NR2'-(C1-C20 헤테로아릴),-(C1-C12 알킬렌)-NR2'-(C6-C20 아릴),-(C1-C12 알킬렌)-NR2'-(C1-C12 알킬렌)-(C3-C12 카르보시클릴),-(C1-C12 알킬렌)-NR2'-(C1-C12 알킬렌)-(C1-C20 헤테로아릴),-(C1-C12 알킬렌)-NR2'-(C1-C12 알킬렌)-(C1-C20 헤테로시클릴),-(C1-C12 알킬렌)-NR2'-(C1-C12 알킬렌)-(C6-C20 아릴),-(C1-C12 알킬렌)-NR2'-(C1-C12 알킬렌)-NHC(=O)-(C1-C20 헤테로아릴),-(C1-C12 알킬렌)-(C2-C20 헤테로시클릴)-N(C1-C12 알킬)R2',-(C1-C12 알킬렌)-(C2-C20 헤테로시클릴)-(C1-C12 알킬)-N(C1-C12 알킬)R2',-(C2-C12 알케닐렌)-(C2-C20 헤테로시클릴),-(C1-C20 헤테로아릴)-(C2-C20 헤테로시클릴),-(C1-C20 헤테로아릴)-(C3-C12 카르보시클릴),-C(=O)-(C2-C20 헤테로시클릴),-C(=O)-(C1-C20 헤테로아릴),-C(=O)-(C2-C20 헤테로시클릴)-(C2-C20 헤테로시클릴),-C(=O)-(C2-C20 헤테로시클릴)-(C1-C20 헤테로아릴),-C(=O)-(C1-C12 알킬),-C(=O)-NR2'-(C1-C12 알킬) 및-CR4=CR5R6 (여기서, R4는 H, F, Cl, Br, I 및 C1-C12 알킬로부터 선택되고, R5 및 R6은 C2-C20 헤테로시클릴, C1-C20 헤테로아릴 또는 C3-C12 카르보시클릴을 형성함)으로부터 선택되고; 여기서알킬, 알케닐, 알키닐, 알킬렌, 카르보시클릴, 헤테로시클릴, 아릴 및 헤테로아릴은 F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH(CH3)2, -CH2NH2, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2N(CH3)2, -CH2OH, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, -CH2C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, -CN, -CF3, -CO2H, -CHO, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH2OH, -COC(OH)(CH3)2, -COCH(OH)CH3, -CONH2, -CONHCH3, -CON(CH3)2, -CH2CONH2, -CH2CON(CH3)2, -C(CH3)2CONH2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, =O, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, -S(O)2CH3, -C(O)-시클로프로필, 시클로프로필, 시클로부틸, 옥세타닐 및 모르폴리노로부터 독립적으로 선택된 1개 이상의 기로 임의로 치환되고;R2 및 R2'는 H, C1-C12 알킬, C2-C8 알케닐, C2-C8 알키닐, -(C1-C12 알킬렌)-(C3-C12 카르보시클릴), -(C1-C12 알킬렌)-(C2-C20 헤테로시클릴), -(C1-C12 알킬렌)-C(=O)-(C2-C20 헤테로시클릴), -(C1-C12 알킬렌)-(C6-C20 아릴) 및 -(C1-C12 알킬렌)-(C1-C20 헤테로아릴)로부터 독립적으로 선택되고, 여기서 알킬, 알케닐, 알키닐, 알킬렌, 카르보시클릴, 헤테로시클릴, 아릴 및 헤테로아릴은 F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -COC(CH3)3, -COCF3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3 및 -S(O)2CH3으로부터 독립적으로 선택된 1개 이상의 기로 임의로 치환되고;R3은 C1-C12 알킬, C2-C8 알케닐, C2-C8 알키닐, C3-C12 카르보시클릴, C2-C20 헤테로시클릴, C6-C20 아릴, C1-C20 헤테로아릴, -(C1-C12 알킬렌)-(C2-C20 헤테로시클릴), -NH-(C1-C12 알킬렌)-(C2-C20 헤테로시클릴), -N(C1-C12 알킬)-(C1-C12 알킬렌)-(C2-C20 헤테로시클릴), -NH-(C2-C20 헤테로시클릴), -O-(C2-C20 헤테로시클릴), -NH-(C3-C12 카르보시클릴), -O-(C3-C12 카르보시클릴), F, Cl, Br, I, -CN, -CO2H, -CONH2, -CONH(C1-C12 알킬), -CON(C1-C12 알킬)2, -CO(C1-C12 알킬), -NO2, -NH2, -NH(C1-C12 알킬), -N(C1-C12 알킬)2, -NHCO(C1-C12 알킬), -NHS(O)2(C1-C12 알킬), -N(C1-C12 알킬)S(O)2(C1-C12 알킬), -OH, -O(C1-C12 알킬), -NHC(=O)NH(C1-C12 알킬), -SH, -S(C1-C12 알킬), -S(O)(C1-C12 알킬), -S(O)2(C1-C12 알킬), -S(O)2NH2, -S(O)2NH(C1-C12 알킬) 및 -S(O)2N(C1-C12 알킬)2로부터 독립적으로 선택된 1개 이상의 기로 임의로 치환된로부터 선택된 비시클릭 헤테로아릴 기이고, 여기서 알킬, 알케닐, 알키닐, 알킬렌, 카르보시클릴, 헤테로시클릴, 아릴 및 헤테로아릴은 F, Cl, Br, I, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, =O, -OH, -OCH3, -S(O)2N(CH3)2, -SH, -SCH3, -CH2OCH3 및 -S(O)2CH3으로부터 독립적으로 선택된 1개 이상의 기로 임의로 치환되고;R7은 H, C1-C12 알킬, C2-C8 알케닐, C2-C8 알키닐, -(C1-C12 알킬렌)-(C3-C12 카르보시클릴), -(C1-C12 알킬렌)-(C2-C20 헤테로시클릴), -(C1-C12 알킬렌)-C(=O)-(C2-C20 헤테로시클릴), -(C1-C12 알킬렌)-(C6-C20 아릴) 및 -(C1-C12 알킬렌)-(C1-C20 헤테로아릴)로부터 선택되고, 여기서 알킬, 알케닐, 알키닐, 알킬렌, 카르보시클릴, 헤테로시클릴, 아릴 및 헤테로아릴은 F, Cl, Br, I, -CH3, -CH2CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, =O, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3 및 -S(O)2CH3으로부터 독립적으로 선택된 1개 이상의 기로 임의로 치환되고;mor은 F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2OCH3, -CHF2, -CN, -CF3, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2C(CH3)2OH, -CH(CH3)OH, -CH(CH2CH3)OH, -CH2CH(OH)CH3, -C(CH3)2OH, -C(CH3)2OCH3, -CH(CH3)F, -C(CH3)F2, -CH(CH2CH3)F, -C(CH2CH3)2F, -CO2H, -CONH2, -CON(CH2CH3)2, -COCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH(CH3)2, -NHCH2CH2OH, -NHCH2CH2OCH3, -NHCOCH3, -NHCOCH2CH3, -NHCOCH2OH, -NHS(O)2CH3, -N(CH3)S(O)2CH3, =O, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -SH, -NHC(=O)NHCH3, -NHC(=O)NHCH2CH3, -S(O)CH3, -S(O)CH2CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2NHCH3, -S(O)2N(CH3)2, -CH2S(O)2CH3으로부터 선택된 1개 이상의 기로 임의로 치환된 로부터 선택된 모르폴린 기 또는 비시클릭 구조이고;단, (ii) X1이 CR7이고, X2가 S이고, R1이 -(C1-C12 ...