RAF INHIBITOR COMPOUNDS AND METHODS OF USE THEREOFCompounds of Formula (I) are useful for inhibiting Raf kinase and for treating disorders mediated thereby. Methods of using compounds of Formula (I), and stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof, 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 of Formula I, include stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof, I wherein:X is NR5, CH2 or CO;R1 is C1-CiO alkyl, C2-CiO alkenyl, C2-Ci0 alkynyl, cycloalkyl, heterocycloalkyl, Zn-aryl, heteroaryl, -C(=O)R12, -C(=O)OR12, -C(=O)NR12R13, - NR12R13, -N(R13)C(=O)R12, -N(R13)C(=O)OR12, -N(R12)C(=O)NR13R14, -S(O)R14, - S(O)2R14 or -S(O)2NR12R13, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl portions are optionally substituted with one or more groups independently selected from F, Cl, Br, I, NO2, oxo (with the proviso that it is not on said aryl or heteroaryl) alkyl, Zn-aryl, Zn-heterocycloalkyl, Zn- heteroaryl, Zn-CN, Zn-OR12, Zn-C(O)R12, Zn-C(O)OR12, Zn-C(O)-heterocycloalkyl, Zn-NR15R15, Zn-NR12C(O)R13, Zn-NR12C(O)OR13, Zn-SR12, Zn-SOR12, Zn-SO2R12, Zn-O-(Ci-C6 alkyl)-C(O)NR12R13, Zn-O-(Cj-C6 alkyl)-C(O)OR12, Zn-O-(Cj-C6 alkyl)-heterocycloalkyl, Zn-O-(CpC6 alkyl)-C(O)-heterocycloalkyl, Zn- C(O)NR12R13, Zn-NR12-(Ci-C6 alkyl)-C(O)NR12R13, Zn-NR12-(Ci-C6 alkyl)- C(O)OR12, Zn-NR12-(C2-C6 alkyl)-OC(O)NR12R13, Zn-NR12C(=O)NR13 Zn-R16, and Zn-NR12-(C2-C6 alkyl)-NR12C(O)NR12R13;R2, R3 and R4 are independently selected from H, F, Cl, Br, I, -C(=O)R12, - C(=O)OR12, -C(=O)NR12R13, -NR12R14, -OR12, -OC(^O)R12, -0C(=0)0R12, -OC(= O)NR12R13, -NR12C(O)-R13, -NR12-C(O)NR13R14 and -NR12-C(O)OR13;R5 is H, Ci-Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C6-C20 cycloalkyl, C6-C20 heterocycloalkyl, -C(O)R12 or -C(O)OR12, wherein said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl portions are optionally substituted with one or more groups independently selected from halogen, OH, O-alkyl, and amino; R6 is , wherein(i) R7 and R8 form a 5 or 6 membered fused carbocyclic ring substituted with =Y, and R9, R10 and R11 are independently selected from H,F, Cl, Br, and I, or(ii) R8 and R9 form a 5 or 6 membered fused carbocyclic ring substituted with =Y, and R7, R10 and R11 are independently selected from H,F, Cl, Br, and I;Y is O or N-OH;R12, R13 and R14 are independently selected from H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, OH, O- alkyl, amino, alkylamino and dialkylamino;R15 is H, -SO2-alkyl, -SO2NR13R14, (Cj-C6 alkyl)-OH, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl portions are optionally substituted with one or more groups independently selected from halogen, OH, O-alkyl, amino, alkylamino and dialkylamino;R16, is heteroaryl that is substituted with one or more alkyl, alkenyl, or alkynyl;Z is alkylene having from 1 to 4 carbons, or alkenylene or alkynylene each having from 2 to 4 carbons, wherein said alkylene, alkenylene and alkynylene are optionally substituted with one or more groups independently selected from halogen, OH, O-alkyl, and amino; and n is 0, 1, 2, 3 or 4. 2. The compound of claim 1 wherein:R1 is Ci-C10 alkyl, C2-Ci0 alkenyl, C2-C10 alkynyl, cycloalkyl, heterocycloalkyl, Zn-aryl, heteroaryl, -C(=O)R12, -C(=O)OR12, -C(=O)NR12R13, - NR12R13, -N(R13)C(=O)R12, -N(R13)C(=O)OR12, -N(R12)C(=O)NR13R14, -S(O)R14, - S(O)2R14 or -S(O)2NR12R13, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl portions are optionally substituted with one or more groups independently selected from F, Cl, Br, I, NO2, oxo (with the proviso that it is not on said aryl or heteroaryl) alkyl, Zn-aryl, Zn-heterocycloalkyl, Zn- heteroaryl, Zn-CN, Zn-OR12, Zn-C(O)R12, Zn-C(O)OR12, Zn-C(O)-heterocycloalkyl, Zn-NR12R15, Zn-NR12C(O)R13, Zn-NR12C(O)OR13, Zn-SR12, Zn-SOR12, Zn-SO2R12, Zn-O-(Ci-C6 alkyl)-C(O)NR12R13, Zn-O-(Ci-C6 alkyl)-C(O)OR12, Zn-O-(Cj-C6 alkyl)-heterocycloalkyl, Zn-C(O)NR12R13, Zn-NR12-(CrC6 alkyl)-C(O)NR12R13, Zn- NR12-(Ci-C6 alkyl)-C(O)OR12, Zn-NR12-(C2-C6 alkyl)-OC(O)NR12R13, Zn- NR12C(=O)NR13 and Zn-NR12-(C2-C6 alkyl)-NR12C(O)NR12R13; andR15 is H, -SO2-alkyl, -SO2NR13R14, (Ci-C6 alkyl)-OH, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl portions are optionally substituted with one or more groups independently selected from halogen, OH, O-alkyl, and amino.
ＲＡＦ 억제제 화합물 및 그의 사용 방법화학식 I의 화합물은 Raf 키나제를 억제하는데 유용하며, 그로 인해 매개되는 장애를 치료하는데 유용하다. 포유동물 세포의 그러한 장애 또는 관련된 병리학적 상태를 시험관내(in vitro), 원위치(in situ) 및 생체내(in vivo)에서 진단, 예방 또는 치료하기 위해 화학식 I의 화합물, 및 그의 입체이성질체, 호변이성질체, 용매화물 및 제약학적으로 허용되는 염을 사용하는 방법이 개시된다. <화학식 I> 하기 화학식 I의 화합물 또는 그의 입체이성질체, 호변이성질체, 용매화물 또는 제약학적으로 허용되는 염. <화학식 I>  상기 식 중, X는 NR5, CH2 또는 CO이고; R1은 C1-C10 알킬, C2-C10 알케닐, C2-C10 알키닐, 시클로알킬, 헤테로시클로알킬, Zn-아릴, 헤테로아릴, -C(=O)R12, -C(=O)OR12, -C(=O)NR12R13, -NR12R13, -N(R13)C(=O)R12, -N(R13)C(=O)OR12, -N(R12)C(=O)NR13R14, -S(O)R14, -S(O)2R14 또는 -S(O)2NR12R13이고, 여기서 상기 알킬, 알케닐, 알키닐, 시클로알킬, 헤테로시클로알킬, 아릴 및 헤테로아릴 부분은 F, Cl, Br, I, NO2, 옥소(다만, 상기 아릴 또는 헤테로아릴 상에는 존재하지 않음), 알킬, Zn-아릴, Zn-헤테로시클로알킬, Zn-헤테로아릴, Zn-CN, Zn-OR12, Zn-C(O)R12, Zn-C(O)OR12, Zn-C(O)-헤테로시클로알킬, Zn-NR15R15, Zn-NR12C(O)R13, Zn-NR12C(O)OR13, Zn-SR12, Zn-SOR12, Zn-SO2R12, Zn-O-(C1-C6 알킬)-C(O)NR12R13, Zn-O-(C1-C6 알킬)-C(O)OR12, Zn-O-(C1-C6 알킬)-헤테로시클로알킬, Zn-O-(C1-C6 알킬)-C(O)-헤테로시클로알킬, Zn-C(O)NR12R13, Zn-NR12-(C1-C6 알킬)-C(O)NR12R13, Zn-NR12-(C1-C6 알킬)-C(O)OR12, Zn-NR12-(C2-C6 알킬)-OC(O)NR12R13, Zn-NR12C(=O)NR13, Zn-R16, 및 Zn-NR12-(C2-C6 알킬)-NR12C(O)NR12R13로부터 독립적으로 선택되는 하나 이상의 기로 임의적으로 치환되고; R2, R3 및 R4는 독립적으로, H, F, Cl, Br, I, -C(=O)R12, -C(=O)OR12, -C(O)NR12R13, -NR12R14, -OR12, -OC(=O)R12, -OC(=O)OR12, -OC(=O)NR12R13, -NR12C(O)-R13, -NR12-C(O)NR13R14 및 -NR12-C(O)OR13으로부터 선택되고; R5는 H, C1-C10 알킬, C2-C10 알케닐, C2-C10 알키닐, C6-C20 시클로알킬, C6-C20 헤테로시클로알킬, -C(O)R12 또는 -C(O)OR12이고, 여기서 상기 알킬, 알케닐, 알키닐, 시클로알킬 및 헤테로시클로알킬 부분은 할로겐, OH, O-알킬, 및 아미노로부터 독립적으로 선택되는 하나 이상의 기로 임의적으로 치환되고; R6은 이고, 상기 식 중, (i) R7 및 R8은 =Y로 치환된 5 또는 6원 융합 카르보시클릭 고리를 형성하고, R9, R10 및 R11은 독립적으로 H, F, Cl, Br, 및 I로부터 선택되거나, 또는 (ii) R8 및 R9는 =Y로 치환된 5 또는 6원 융합 카르보시클릭 고리를 형성하고, R7, R10 및 R11은 독립적으로 H, F, Cl, Br, 및 I로부터 선택되고; Y는 O 또는 N-OH이고; R12, R13 및 R14는 독립적으로, H, 알킬, 알케닐, 알키닐, 헤테로알킬, 헤테로알케닐, 헤테로알키닐, 시클로알킬, 헤테로시클로알킬, 아릴 및 헤테로아릴로부터 선택되고, 여기서 상기 알킬, 알케닐, 알키닐, 헤테로알킬, 헤테로알케닐, 헤테로알키닐, 시클로알킬, 헤테로시클로알킬, 아릴 및 헤테로아릴은 할로겐, OH, O-알킬, 아미노, 알킬아미노 및 디알킬아미노로부터 독립적으로 선택되는 하나 이상의 기로 임의적으로 치환되고; R15는 H, -SO2-알킬, -SO2NR13R14, (C1-C6 알킬)-OH, -C(O)O-알킬, 알킬, 알케닐, 알키닐, 헤테로알킬, 헤테로알케닐, 헤테로알키닐, 시클로알킬, 헤테로시클로알킬, 아릴 또는 헤테로아릴이고, 여기서 상기 알킬, 알케닐, 알키닐, 헤테로알킬, 헤테로알케닐, 헤테로알키닐, 시클로알킬, 헤테로시클로알킬, 아릴 및 헤테로아릴 부분은 할로겐, OH, O-알킬, 아미노, 알킬아미노 및 디알킬아미노로부터 독립적으로 선택되는 하나 이상의 기로 임의적으로 치환되고; R16은 하나 이상의 알킬, 알케닐, 또는 알키닐로 치환된 헤테로아릴이고; Z는 1 내지 4개의 탄소를 갖는 알킬렌, 또는 각각 2 내지 4개의 탄소를 갖는 알케닐렌 또는 알키닐렌이고, 여기서 상기 알킬렌, 알케닐렌 및 알키닐렌은 할로겐, OH, O-알킬, 및 아미노로부터 독립적으로 선택되는 하나 이상의 기로 임의적으로 치환되며; n은 0, 1, 2, 3 또는 4이다.