Tyrosine kinase inhibitorsThe present invention is directed to low molecular weight and orally bioavailable 3H-[1,2,3]triazolo[4,5-d]pyrimidine derivatives, that are useful for treating cellular proliferative diseases, for treating disorders associated with MET activity, and for inhibiting the tyrosine kinase MET. The invention is also directed to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.The formula i compound of formula i compound or part deuterate or its pharmaceutically acceptable salt:wherein:r 1be independently selected from :-o (ch 2) nor 11,-c (o) r 11,-c (o) or 11,-c (o) nr 11r 12, c 3-c 8cyclic hydrocarbon radical, 3-8 unit heterolipid cyclic group, 3-8 unit heterolipid cyclic group-(3-8 unit heterolipid cyclic group), the assorted bicyclic group of 8-10 unit, 5-7 unit heteroaryl, c 6-c 10aryl, c 2-c 6thiazolinyl and c 2-c 6alkynyl, wherein c 3-c 8cyclic hydrocarbon radical, 3-8 unit heterolipid cyclic group, the assorted bicyclic group of 8-10 unit, 5-7 unit heteroaryl, c 6-c10 aryl, c 2-c 6thiazolinyl and c 2-c 6alkynyl randomly replaces with one or more parts of being selected from by the following group of forming: br, cl, f ,-(ch 2) nch (or 11) ch 3,-(ch 2) nor 11,-(ch 2) nc (ch 3) 2or 11,-c (o) r 11,-c (o) or 11,-(cr 11r 12) nc (o) or 11,-c (o) nr 11r 12,-(cr 11r 12) nc (o) nr 11r 12,-(ch 2) nnr 11r 12,-s (o) 2r 11,-s (o) r 11,-s (o) 2nr 11r 12,-cf 3,-cf 2h ,-(ch 2) nnr 11c (o) nr 11r 12,-(ch 2) nnr 11c (o) or 12,-nr 11c (o) r 12,-nr 11c (o) or 12,-nr 11s (o) 2r 12,-cn ,-no 2, oxo, c 1-c 6alkyl, c 3-c 8cyclic hydrocarbon radical ,-(ch 2) n(3-8 unit heterolipid cyclic group) ,-(ch 2) n(5-7 unit heteroaryl) ,-(ch) n(c 6-c 10aryl), c 2-c 6thiazolinyl and c 2-c 6alkynyl; r 2be h; r 3and r 4be independently selected from: h, f, cf 3, c 1-c 6alkyl; or r 3and r 4can form c together 3-c 5the cyclic hydrocarbon basic ring; r 5be the part of following formula: r wherein 6, r 7, r 8, r 9and r 10be independently selected from hydrogen, br, cl, f ,-(ch 2) nor 11,-c (o) r 11,-c (o) or 11,-c (o) nr 11r 12,-nr 11r 12,-s (o) 2r 11,-s (o) r 11,-s (o) 2nr 11r 12,-cf 3,-cf 2h ,-nr 11c (o) nr 11r 12,-nr 11c (o) r 12,-nr 11so 2r 12,-cn ,-no 2, c 1-c 6alkyl, c 3-c 8cyclic hydrocarbon radical, 3-8 unit heterolipid cyclic group, the assorted bicyclic group of 8-10 unit, 5-7 unit heteroaryl, c 6-c 10aryl, c 2-c 6thiazolinyl and c 2-c 6alkynyl, c wherein 1-c 6alkyl, c 3-c 8cyclic hydrocarbon radical, 3-8 unit heterolipid cyclic group, the assorted bicyclic group of 8-10 unit, 5-7 unit heteroaryl, c 6-c 10aryl, c 2-c 6thiazolinyl and c 2-c 6alkynyl randomly replaces with one or more parts of being selected from by the following group of forming: br, cl, f ,-(ch 2) nor 11,-c (o) r 11,-c (o) or 11,-c (o) nr 11r 12,-nr 11r 12,-s (o) 2r 11,-s (o) r 11,-s (o) 2nr 11r 12,-cf 3,-cf 2h ,-nr 11c (o) nr 11r 12,-nr 11c (o) r 12,-nr 11s (o) 2r 12,-cn ,-no 2, oxo, c 1-c 6alkyl, c 3-c 8cyclic hydrocarbon radical, c 3-c 8heterolipid cyclic group, 5-7 unit heteroaryl, c 6-c 10aryl, c 2-c 6thiazolinyl and c 2-c 6alkynyl; or r 8and r 9, or r 9and r 10be combined to form and be selected from following ring: saturated c 4-c 8cyclic hydrocarbon radical, undersaturated c 5-c 8cyclic hydrocarbon radical, 3-8 unit heterolipid cyclic group, 5-7 unit's heteroaryl and c 6-c 10aryl, wherein said ring randomly replaces with the one or more parts that are selected from by the following group of forming: br, cl, f ,-(ch 2) nor 11,-c (o) r 11,-c (o) or 11,-c (o) nr 11r 12,-nr 11r 12,-s (o) 2r 11,-s (o) r 11,-s (o) 2nr 11r 12,-cf 3,-cf 2h ,-nr 11c (o) nr 11r 12,-nr 11c (o) r 12,-nr 11s (o) 2r 12,-cn ,-no 2, oxo, c 1-c 6alkyl, c 3-c 8cyclic hydrocarbon radical, c 3-c 8heterolipid cyclic group, 5-7 unit heteroaryl, c 6-c 10aryl, c 2-c 6thiazolinyl and c 2-c 6alkynyl; r 11and r 12be independently selected from: h ,-(ch 2) nor 13,-(ch 2) nc (ch 3) 2or 13,-chr 13(ch 2) nor 14,-c (o) or 13,-(ch 2) nchr 13or 14,-c (ch 3) 2(ch 2) nor 13,-ch 2cf 2h ,-(ch 2) nc (ch 3) 2nr 13r 14,-(ch 2) nnr 13r 14,-(ch 2) nchor 13(ch 2) nor 14,-(ch 2) n(nr 13r 14) c (o) nr 13r 14,-(ch 2) ns (o) 2r 13,-(ch 2) nc (o) nr 13r 14,-nr 13(ch 2) n(5-7 unit heteroaryl) ,-nr 13(ch 2) n(3-8 unit heterocycle) ,-(ch 2) n(the assorted bicyclic group of 8-10 unit) ,-(ch 2) n(3-8 unit heterolipid cyclic group), c 1-c 6alkyl, c 3-c 8cyclic hydrocarbon radical, c 6-c 10aryl, c 2-c 6thiazolinyl and c 2-c 6alkynyl, the first heteroaryl of wherein said 5-7, the assorted bicyclic group of 3-8 unit's heterocycle and 8-10 unit randomly replace with the one or more parts that are selected from by the following group of forming :-(ch 2) nor 13, c 1-c 6alkyl, c 3-c 8cyclic hydrocarbon radical, c 6-c 10aryl, c 2-c 6thiazolinyl, 3-8 unit's heterolipid cyclic group and c 2-c 6alkynyl, or work as r 11and r 12be connected to the same atomic time, r 11and r 12randomly be combined to form 3-8 unit heterolipid cyclic group ring; r 13and r 14be independently selected from: h, c 1-c 6alkyl ,-c (o) ch 3, c 3-c 8cyclic hydrocarbon radical, c 6-c 10aryl, c 2-c 6thiazolinyl, 5-7 unit's heteroaryl and c 2-c 6alkynyl, the first heteroaryl of wherein said 5-7 randomly replaces with the one or more parts that are selected from by the following group of forming: c 1-c 6alkyl, c 3-c 8cyclic hydrocarbon radical, c 6-c 10aryl, c 2-c 6thiazolinyl and c 2-c 6alkynyl, or work as r 13and r 14be connected to the...
티로신 키나아제 억제제 본 발명은 세포 증식 질병 치료, MET 활성 관련 질환 치료 및 티로신 키나아제 MET 억제에 유용한 저분자량 및 경구적으로 생체이용가능한 3H-[1,2,3]트리아졸로[4,5-d]피리미딘(3H-[1,2,3]triazolo[4,5-d]pyrimidine) 유도체에 관한 것이다. 또한, 본 발명은 이러한 화합물을 포함하는 조성물 및 포유류 암 치료에 이를 사용하는 사용방법에 관한 것이다.식 I 또는 부분적으로 중수소화된(deuterated) 식 I의 화합물:[이미지]또는 그 약학적으로 허용가능한 염으로서,R1은 -O(CH2)nOR11, -C(O)R11, -C(O)OR11, -C(O)NR11R12, C3-C8 시클로알킬, 3-8 원(membered) 헤테로알리사이클릭(heteroalicylic), 3-8 원 헤테로알리사이클릭-(3-8 원 헤테로알리사이클릭), 8-10 원 헤테로비사이클릭(heterobicyclic), 5-7 원 헤테로아릴, C6-C10 아릴, C2-C6 알케닐 및 C2-C6 알키닐로부터 독립적으로 선택되며, C3-C8 시클로알킬, 3-8 원 헤테로알리사이클릭, 8-10 원 헤테로비사이클릭, 5-7 원 헤테로아릴, C6-C10 아릴, C2-C6 알케닐 및 C2-C6 알키닐은 Br, Cl, F, -(CH2)nCH(OR11)CH3, -(CH2)nOR11, -(CH2)nC(CH3)2OR11, -C(O)R11, -C(O)OR11, -(CR11R12)nC(O)OR11, -C(O)NR11R12, -(CR11R12)nC(O)NR11R12, -(CH2)nNR11R12, -S(O)2R11, -S(O)R11, -S(O)2NR11R12, -CF3, -CF2H, -(CH2)nNR11C(O)NR11R12, -(CH2)nNR11C(O)OR12, -NR11C(O)R12, -NR11C(O)OR12, -NR11S(O)2R12, -CN, -NO2, 옥소(oxo), C1-C6 알킬, C3-C8 시클로알킬, -(CH2)n(3-8 원 헤테로알리사이클릭), -(CH2)n(5-7 원 헤테로아릴), -(CH)n(C6-C10 아릴), C2-C6 알케닐 및 C2-C6 알키닐로 이루어진 그룹으로부터 선택된 하나 이상의 모이어티들에 의하여 선택적으로 치환되며;R2는 H이며;R3 및 R4는: H, F, CF3, C1-C6 알킬로부터 독립적으로 선택되며;또는 R3 및 R4는 함께 C3-C5 시클로알킬 고리를 형성할 수 있으며;R5는 하기 식의 모이어티이며:[이미지]여기서, R6, R7, R8, R9 및 R10은 수소, Br, Cl, F, -(CH2)nOR11, -C(O)R11, -C(O)OR11, -C(O)NR11R12, -NR11R12, -S(O)2R11, -S(O)R11, -S(O)2NR11R12, -CF3, -CF2H, -NR11C(O)NR11R12, -NR11C(O)R12, -NR11SO2R12, -CN, -NO2, C1-C6 알킬, -N(CH2)n(C3-C8 시클로알킬), -CN, -NO2, C1-C6 알킬, C3-C8 시클로알킬, 3-8 원 헤테로알리사이클릭, 8-10 원 헤테로비사이클릭, 5-7 원 헤테로아릴, C6-C10 아릴, C2-C6 알케닐 및 C2-C6 알키닐로부터 독립적으로 선택되며, C1-C6 알킬, C3-C8 시클로알킬, 3-8 원 헤테로알리사이클릭, 8-10 원 헤테로비사이클릭, 5-7 원 헤테로아릴, C6-C10 아릴, C2-C6 알케닐 및 C2-C6 알키닐은 Br, Cl, F, -(CH2)nOR11, -C(O)R11, -C(O)OR11, -C(O)NR11R12, -NR11R12, -S(O)2R11, -S(O)R11, -S(O)2NR11R12, -CF3, -CF2H, -NR11C(O)NR11R12, -NR11C(O)R12, -NR11S(O)2R12, -CN, -NO2, 옥소, C1-C6 알킬, C3-C8 시클로알킬, C3-C8 헤테로알리사이클릭, 5-7 원 헤테로아릴, C6-C10 아릴, C2-C6 알케닐 및 C2-C6 알키닐로 이루어진 그룹으로부터 선택된 하나 이상의 모이어티들에 의하여 선택적으로 치환되며; 또는R8 및 R9 또는 R9 및 R10은 조합하여 포화 C4-C8 시클로알킬, 불포화 C5-C8 시클로알킬, 3-8 원 헤테로알리사이클릭, 5-7 원 헤테로아릴 및 C6-C10 아릴로부터 선택된 고리를 형성하고, 상기 고리는 Br, Cl, F, -(CH2)nOR11, -C(O)R11, -C(O)OR11, -C(O)NR11R12, -NR11R12, -S(O)2R11, -S(O)R11, -S(O)2NR11R12, -CF3, -CF2H, -NR11C(O)NR11R12, -NR11C(O)R12, -NR11S(O)2R12, -CN, -NO2, 옥소, C1-C6 알킬, C3-C8 시클로알킬, C3-C8 헤테로알리사이클릭, 5-7 원 헤테로아릴, C6-C10 아릴, C2-C6 알케닐 및 C2-C6 알키닐로 이루어진 그룹으로부터 선택된 하나 이상의 모이어티들로 선택적으로 치환되며;R11 및 R12는 H, -(CH2)nOR13, -(CH2)nC(CH3)2OR13, -CHR13(CH2)nOR14, -C(O)OR13, -(CH2)nCHR13OR14, -C(CH3)2(CH2)nOR13, -CH2CF2H, -(CH2)nC(CH3)2NR13R14, -(CH2)nNR13R14, -(CH2)nCHOR13(CH2)nOR14, -(CH2)n(NR13R14)C(O)NR13R14, -(CH2)nS(O)2R13, -(CH2)nC(O)NR13R14, -NR13(CH2)n(5-7 원 헤테로아릴), -NR13(CH2)n(3-8 원 헤테로사이클), -(CH2)n(8-10 원 헤테로비사이클릭), -(CH2)n(3-8 원 헤테로알리사이클릭), C1-C6 알킬, C3-C8 시클로알킬, C6-C10 아릴, C2-C6 알케닐 및 C2-C6 알키닐로부터 독립적으로 선택되며, 상기 5-7 원 헤테로아릴, 3-8 원 헤테로사이클 및 8-10 원 헤테로비사이클릭은 -(CH2)nOR13, C1-C6 알킬, C3-C8 시클로알킬, C6-C10 아릴, C2-C6 알케닐, 3-8 원 헤테로알리사이클릭 및 C2-C6 알키닐로 이루어진 그룹으로부터 선택된 하나 이상의 모이어티들에 의하여 선택적으로 치환되며; 또는 R11 및 R12가 동일한 원자에 부착되는 경우, R11 및 R12는 선택적으로 조합하여 3-8 원 헤테로알리사이클릭 고리를 형성하며;R13 및 R14는 H, C1-C6 알킬, -C(O)CH3, C3-C8 시클로알킬, C6-C10 아릴, C2-C6 알케닐, 5-7 원 헤테로아릴 및 C2-C6 알키닐로부터 독립적으로 선택되며, 상기 5-7 원 헤테로아릴은 C1-C6 알킬, C3-C8 시클로알킬, C6-C10 아릴, C2-C6 알케닐 및 C2-C6 알키닐로 이루어진 그룹으로부터 선택된 하나 이상의 모이어티들에 의하여 선택적으로 치환되며; 또는 R13 및 R14는 동일한 원자에 부착되는 경우, R13 및 R14는 선택적으로 조합하여 3-8 원 헤테로알리사이클릭 고리를 형성하며;각각의 n은 독립적으로 0, 1, 2, 3 또는 4인 것을 특징으로 하는 화합물 또는 그 약학적으로 허용가능한 염.