SUBSTITUTED AMINOPYRIMIDINE COMPOUNDS AND METHODS OF USEThe invention relates to the preparation and use of new aminopyrimidine derivatives as drug candidates in free form or in pharmaceutically acceptable salt form and formulations thereof for the modulation of a disorder or disease which is mediated by the activity of the PI3K enzymes. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of disorders or diseases, such as disorders of immunity and inflammation in which PI3K enzymes play a role in leukocyte function, and hyperproliferative disorders associated with PI3K activity, including but not restricted to leukemias and solid tumors, in mammals, especially humans.A compound of Formula (I):or a stereoisomer, a geometric isomer, a tautomer, an L'-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein:each R1 and R2 is independently H, D, F, CN, N02, -C(=0)Ra, -C(=0)0Ra, -C(=0)NRaRb, - (Ci-C4)alkylene-C(=0)NRaRb, -(Ci-C4)alkylene-N(Rc)C(=0)NRaRb, -(Ci-C4)alkylene- N(Rc)C(=0)0Ra, -(Ci-C4)alkylene-OC(=0)NRaRb, -(Ci-C4)alkylene-S(=0)2NRaRb, -(C C4)alkylene-N(Rc)S(=0)2Rb, -(Ci-C4)alkylene-ORa, -(Ci-C4)alkylene-NRaRb, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (Ci-C8)cycloalkyl, -(Ci-C4)alkylene-(C3-C8)cycloalkyl, 3-8 membered heterocyclyl, -(Ci-C4)alkylene-(3-8 membered heterocyclyl), (C6-Cio)aryl, -(Ci-C4)alkylene-(C6- C |o)aryl, 5-10 membered heteroaryl, or -(Ci-C4)alkylene-(5-l0 membered heteroaryl), wherein each of the (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, -(Ci-C4)alkylene-(C3- C8)cycloalkyl, 3-8 membered heterocyclyl, -(Ci-C4)alkylene-(3-8 membered heterocyclyl), (C6- C io)aryl, -(Ci-C4)alkylene-(C6-Cio)aryl, 5-10 membered heteroaryl and -(Ci-C4)alkylene-(5-l0 membered heteroaryl) is optionally substituted with 1 , 2, 3 or 4 substitutents independently selected from D, F, Cl, Br, oxo (=0), CN, Ra, ORa, NRaRb, (Ci-C6)alkyl, -(Ci-C4)alkylene-ORa and -(Ci- C4)alkylene-NRaRb; or R1 and R2, together with the carbon atom they are attached to, form an optionally substituted 3-8 membered carbocyclic or heterocyclic ring;X is 3-8 membered heterocyclyl, (C6-Cio)aryl or 5-10 membered heteroaryl, wherein X is optionally substituted by 1, 2, 3, 4 or 5 R groups;m is 1, 2 or 3;W is N or CR5;A is H, D, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)hydroxyalkyl, (Ci-C6)aminoalkyl, (C3- C8)cycloalkyl or 3-8 membered heterocyclyl, wherein each (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci- C6)hydroxyalkyl, (Ci-C6)aminoalkyl, (C3-C8)cycloalkyl and 3-8 membered heterocyclyl is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from D, oxo, F, Cl, Br, OH, NH2, CN, N02, (Ci-C6)alkyl and (Ci-C6)alkoxy;B is (C3-C8)cycloalkyl, 3-8 membered heterocyclyl, (C6-Cio)aryl or 5-10 membered heteroaryl, wherein each of the (Ci-C8)cycloalkyl, 3-8 membered heterocyclyl, (C6-Cio)aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from D, oxo (=0), F, Cl, Br, CN, Ra, ORa, NRaRb, (Ci-C6)alkyl, -(Ci-C4)alkylene-ORa and -(Ci- C4)alkylene-NRaRb ;each R3, R4 and R5 is independently H, D, F, Cl, Br, CN, N02, oxo (=0), -C(=0)Ra, - C(=0)0Ra, -C(=0)NRaRb, -0C(=0)NRaRb, -0C(=0)0Ra, -N(Rc)C(=0)NRaRb, -N(Rc)C(=0)0Ra, - N(Rc)C(=0)Ra, -S(=0)2NRaRb, -S(=0)2Ra, -N(Rc)S(=0)2Ra, -N(Rc)-(Ci-C4)alkylene-S(=0)2Ra, - (Ci-C4)alkylene-C(=0)NRaRb, -(Ci-C4)alkylene-N(Rc)C(=0)NRaRb, -(Ci-C4)alkylene- N(Rc)C(=0)0Ra, -(Ci-C4)alkylene-OC(=0)NRaRb, -(Ci-C4)alkylene-S(=0)2NRaRb, -(Ci- C4)alkylene-N(Rc)S(=0)2Ra, ORa, NRaRb, -(Ci-C4)alkylene-ORa, -(Ci-C4)alkylene-NRaRb, (Ci- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, -(Ci-C4)alkylene-(C3-C8)cycloalkyl, 3- 8 membered heterocyclyl, -(Ci-C4)alkylene-(3-8 membered heterocyclyl), (C6-Cio)aryl, -(Ci- C4)alkylene-(C6-C!o)aryl, 5-10 membered heteroaryl, or -(Ci-C4)alkylene-(5-l0 membered heteroaryl), wherein each of the (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, - (Ci-C4)alkylene-(C3-C8)cycloalkyl, 3-8 membered heterocyclyl, -(Ci-C4)alkylene-(3-8 membered heterocyclyl), (C6-Cio)aryl, -(Ci-C4)alkylene-(C6-Cio)aryl, 5-10 membered heteroaryl and -(Ci- C4)alkylene-(5-l0 membered heteroaryl) is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from D, F, Cl, Br, CN, oxo (=0), Ra, ORa, NRaRb, (Ci-C6)alkyl, -(Ci- C4)alkylene-ORa and -(Ci-C4)alkylene-NRaRb; andeach Ra, Rb and Rc is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl, -(Ci-C4)alkylene-(C3-C6)cycloalkyl, 3-6 membered heterocyclyl, -(Ci-C4)alkylene- (3-6 membered heterocyclyl), (C6-Cio)aryl, -(Ci-C4)alkylene-(C6-Cio)aryl, 5-10 membered heteroaryl, or -(Ci-C4)alkylene-(5-l0 membered heteroaryl), wherein each of the (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, -(Ci-C4)alkylene-(C3-C6)cycloalkyl, 3-6 membered heterocyclyl, -(Ci-C4)alkylene-(3-6 membered heterocyclyl), (C6-Cio)aryl, -(Ci-C4)alkylene-(C6- C |o)aryl, 5-10 membered heteroaryl and -(Ci-C4)alkylene-(5-l0 membered heteroaryl) is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from D, F, Cl, Br, CN, N02, N3, OH, NH2, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)alkoxy and (Ci-C6)alkylamino; or Ra and Rb, together with the nitrogen atom they are attached to, form an optionally substituted 3-8 membered heterocyclic ring. 
치환된 아미노피리미딘 화합물 및 이의 사용 방법본 발명은 PI3K 효소의 활성에 의해 매개되는 장애 또는 질병의 조절을 위한, 유리 형태 또는 약학적으로 허용되는 염 형태의 약물 후보자로서 새로운 아미노피리미딘 유도체, 및 이의 제형의 제조 및 용도에 관한 것이다. 또한, 본 발명은 상기 화합물을 포함하는 약학적으로 허용되는 조성물, 및 포유동물, 특히 인간에서 장애 또는 질병, 예컨대 PI3K 효소가 백혈구 기능에서 역할을 하는 면역력 및 염증의 장애, 및 백혈병 및 고형 종양을 포함하나 이에 제한되지 않는 PI3K 활성과 관련된 과증식성 장애의 치료에서 상기 조성물을 사용하는 방법을 제공한다.하기 화학식 I의 화합물, 또는 이의 입체 이성질체, 기하 이성질체, 호변 이성질체, N-옥사이드, 수화물, 용매화물, 대사물, 약학적으로 허용되는 염 또는 전구약물:[화학식 I]상기 식에서,R1 및 R2 각각은 독립적으로 H, D, F, CN, NO2, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -(C1-C4)알킬렌-C(=O)NRaRb, -(C1-C4)알킬렌-N(Rc)C(=O)NRaRb, -(C1-C4)알킬렌-N(Rc)C(=O)ORa, -(C1-C4)알킬렌-OC(=O)NRaRb, -(C1-C4)알킬렌-S(=O)2NRaRb, -(C1-C4)알킬렌-N(Rc)S(=O)2Rb, -(C1-C4)알킬렌-ORa, -(C1-C4)알킬렌-NRaRb, (C1-C6)알킬, (C2-C6)알켄일, (C2-C6)알킨일, (C3-C8)사이클로알킬, -(C1-C4)알킬렌-(C3-C8)사이클로알킬, 3 내지 8원 헤테로사이클릴, -(C1-C4)알킬렌-(3 내지 8원 헤테로사이클릴), (C6-C10)아릴, -(C1-C4)알킬렌-(C6-C10)아릴, 5 내지 10원 헤테로아릴 또는 -(C1-C4)알킬렌-(5 내지 10원 헤테로아릴)이되, 상기 (C1-C6)알킬, (C2-C6)알켄일, (C2-C6)알킨일, (C3-C8)사이클로알킬, -(C1-C4)알킬렌-(C3-C8)사이클로알킬, 3 내지 8원 헤테로사이클릴, -(C1-C4)알킬렌-(3 내지 8원 헤테로사이클릴), (C6-C10)아릴, -(C1-C4)알킬렌-(C6-C10)아릴, 5 내지 10원 헤테로아릴 및 -(C1-C4)알킬렌-(5 내지 10원 헤테로아릴) 각각은 D, F, Cl, Br, 옥소(=O), CN, Ra, ORa, NRaRb, (C1-C6)알킬, -(C1-C4)알킬렌-ORa 및 -(C1-C4)알킬렌-NRaRb로부터 독립적으로 선택된 1, 2, 3 또는 4개의 치환기로 임의적으로 치환되거나; R1 및 R2는, 이들이 부착된 탄소 원자와 함께, 임의적으로 치환된 3 내지 8원 탄소환형 또는 헤테로환형 고리를 형성하고; X는 3 내지 8원 헤테로사이클릴, (C6-C10)아릴 또는 5 내지 10원 헤테로아릴이되, 상기 X는 1, 2, 3, 4 또는 5개의 R3 기로 임의적으로 치환되고;m은 1, 2 또는 3이고;W는 N 또는 CR5이고;A는 H, D, (C1-C6)알킬, (C1-C6)할로알킬, (C1-C6)하이드록시알킬, (C1-C6)아미노알킬, (C3-C8)사이클로알킬 또는 3 내지 8원 헤테로사이클릴이되, 상기 (C1-C6)알킬, (C1-C6)할로알킬, (C1-C6)하이드록시알킬, (C1-C6)아미노알킬, (C3-C8)사이클로알킬 및 3 내지 8원 헤테로사이클릴 각각은 D, 옥소, F, Cl, Br, OH, NH2, CN, NO2, (C1-C6)알킬 및 (C1-C6)알콕시로부터 독립적으로 선택된 1, 2, 3 또는 4개의 치환기로 임의적으로 치환되고;B는 (C3-C8)사이클로알킬, 3 내지 8원 헤테로사이클릴, (C6-C10)아릴 또는 5 내지 10원 헤테로아릴이되, 상기 (C3-C8)사이클로알킬, 3 내지 8원 헤테로사이클릴, (C6-C10)아릴 및 5 내지 10원 헤테로아릴 각각은 D, 옥소(=O), F, Cl, Br, CN, Ra, ORa, NRaRb, (C1-C6)알킬, -(C1-C4)알킬렌-ORa 및 -(C1-C4)알킬렌-NRaRb로부터 독립적으로 선택된 1, 2, 3 또는 4개의 치환기로 임의적으로 치환되고;R3, R4 및 R5 각각은 독립적으로 H, D, F, Cl, Br, CN, NO2, 옥소(=O), -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -OC(=O)ORa, -N(Rc)C(=O)NRaRb, -N(Rc)C(=O)ORa, -N(Rc)C(=O)Ra, -S(=O)2NRaRb, -S(=O)2Ra, -N(Rc)S(=O)2Ra, -N(Rc)-(C1-C4)알킬렌-S(=O)2Ra, -(C1-C4)알킬렌-C(=O)NRaRb, -(C1-C4)알킬렌-N(Rc)C(=O)NRaRb, -(C1-C4)알킬렌-N(Rc)C(=O)ORa, -(C1-C4)알킬렌-OC(=O)NRaRb, -(C1-C4)알킬렌-S(=O)2NRaRb, -(C1-C4)알킬렌-N(Rc)S(=O)2Ra, ORa, NRaRb, -(C1-C4)알킬렌-ORa, -(C1-C4)알킬렌-NRaRb, (C1-C6)알킬, (C2-C6)알켄일, (C2-C6)알킨일, (C3-C8)사이클로알킬, -(C1-C4)알킬렌-(C3-C8)사이클로알킬, 3 내지 8원 헤테로사이클릴, -(C1-C4)알킬렌-(3 내지 8원 헤테로사이클릴), (C6-C10)아릴, -(C1-C4)알킬렌-(C6-C10)아릴, 5 내지 10원 헤테로아릴 또는 -(C1-C4)알킬렌-(5 내지 10원 헤테로아릴)이되, 상기 (C1-C6)알킬, (C2-C6)알켄일, (C2-C6)알킨일, (C3-C8)사이클로알킬, -(C1-C4)알킬렌-(C3-C8)사이클로알킬, 3 내지 8원 헤테로사이클릴, -(C1-C4)알킬렌-(3 내지 8원 헤테로사이클릴), (C6-C10)아릴, -(C1-C4)알킬렌-(C6-C10)아릴, 5 내지 10원 헤테로아릴 및 -(C1-C4)알킬렌-(5 내지 10원 헤테로아릴) 각각은 D, F, Cl, Br, CN, 옥소(=O), Ra, ORa, NRaRb, (C1-C6)알킬, -(C1-C4)알킬렌-ORa 및 -(C1-C4)알킬렌-NRaRb로부터 독립적으로 선택된 1, 2, 3 또는 4개의 치환기로 임의적으로 치환되고;Ra, Rb 및 Rc 각각은 독립적으로 H, (C1-C6)알킬, (C2-C6)알켄일, (C2-C6)알킨일, (C3-C6)사이클로알킬, -(C1-C4)알킬렌-(C3-C6)사이클로알킬, 3 내지 6원 헤테로사이클릴, -(C1-C4)알킬렌-(3 내지 6원 헤테로사이클릴), (C6-C10)아릴, -(C1-C4)알킬렌-(C6-C10)아릴, 5 내지 10원 헤테로아릴 또는 -(C1-C4)알킬렌-(5 내지 10원 헤테로아릴)이되, 상기 (C1-C6)알킬, (C2-C6)알켄일, (C2-C6)알킨일, (C3-C6)사이클로알킬, -(C1-C4)알킬렌-(C3-C6)사이클로알킬, 3 내지 6원 헤테로사이클릴, -(C1-C4)알킬렌-(3 내지 6원 헤테로사이클릴), (C6-C10)아릴, -(C1-C4)알킬렌-(C6-C10)아릴, 5 내지 10원 헤테로아릴 및 -(C1-C4)알킬렌-(5 내지 10원 헤테로아릴) 각각은 D, F, Cl, Br, CN, NO2, N3, OH, NH2, (C1-C6)알킬, (C1-C6)할로알킬, (C1-C6)알콕시 및 (C1-C6)알킬아미노로부터 독립적으로 선택된 1, 2, 3 또는 4개의 치환기로 임의적으로 치환되거나; Ra 및 Rb는, 이들이 부착된 질소 원자와 함께, 임의적으로 치환된 3 내지 8원 헤테로환형 고리를 형성한다.