8-fluorophthalazin-1 (2h) - one compounds as inhibitors of btk activity8-Fluorophthalazin-1(2h)-one compounds of Formula (II) where one or two of X1, X2, and X3 are N, are provided, including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula (II) for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.Be selected from compound or its steric isomer of formula ii, tautomer or pharmacologically acceptable salt:wherein:x 1for cr 1or n; x 2for cr 2or n; x 3for cr 3or n; x wherein 1, x 2and x 3in one or two be n; y 1and y 2independently selected from ch and n, wherein y 1and y 2not all n; r 1, r 2and r 3independently selected from h, f, cl, cn ,-ch 3,-ch 2ch 3,-ch 2oh ,-ch 2f ,-chf 2,-cf 3,-ch 2ch 2oh ,-nh 2,-nhch 3,-n (ch 3) 2,-oh ,-och 3,-och 2ch 3with-och 2ch 2oh; r 4be selected from h, f, cl, cn ,-ch 2oh ,-ch (ch 3) oh ,-c (ch 3) 2oh ,-ch (cf 3) oh ,-ch 2f ,-chf 2,-ch 2chf 2,-cf 3,-c (o) nh 2,-c (o) nhch 3,-c (o) n (ch 3) 2,-nh 2,-nhch 3,-n (ch 3) 2,-nhc (o) ch 3,-oh ,-och 3,-och 2ch 3,-och 2ch 2oh ,-op (o) are (oh) 2, cyclopropyl, cyclopropyl methyl, 1-hydroxyl cyclopropyl, imidazolyl, pyrazolyl, 3-hydroxyl-trimethylene oxide-3-base, trimethylene oxide-3-base and azetidine-1-base; r 6be selected from h ,-ch 3,-ch 2ch 3,-ch 2ch 2oh ,-ch 2f ,-chf 2,-cf 3,-nh 2,-nhch 3,-n (ch 3) 2,-oh ,-och 3,-och 2ch 3with-och 2ch 2oh; r 8be selected from c 6-c 20aryl, c 3-c 12carbocylic radical, c 2-c 20heterocyclic radical, c 1-c 20heteroaryl ,-(c 6-c 20aryl)-(c 2-c 20heterocyclic radical) ,-(c 1-c 20heteroaryl)-(c 2-c 20heterocyclic radical) ,-(c 1-c 20heteroaryl)-(c 2-c 20heterocyclic radical)-(c 2-c 20heterocyclic radical) ,-(c 1-c 20heteroaryl)-(c 2-c 20heterocyclic radical)-(c 1-c 6alkyl) ,-(c 1-c 20heteroaryl)-(c 1-c 6alkyl) and-(c 1-c 20heteroaryl)-c (=o)-(c 2-c 20heterocyclic radical); wherein aryl, carbocylic radical, heterocyclic radical and heteroaryl are optionally independently selected from following group and replace by one or more: f, cl, br, i, cn ,-ch 3,-ch 2ch 3,-ch (ch 3) 2,-ch 2ch (ch 3) 2,-ch 2oh ,-ch 2och 3,-ch 2ch 2oh ,-c (ch 3) 2oh ,-ch (oh) ch (ch 3) 2,-c (ch 3) 2ch 2oh ,-ch 2ch 2so 2ch 3,-ch 2op (o) (oh) 2,-c (ch 3) 2conh 2,-ch 2och 3,-ch 2ch 2oh ,-ch 2ch 2och 3,-ch 2f ,-chf 2,-cf 3,-ch 2cf 3,-ch 2chf 2,-ch (ch 3) cn ,-c (ch 3) 2cn ,-ch 2cn ,-co 2h ,-c (o) ch 3,-co 2ch 3,-co 2c (ch 3) 3,-coch (oh) ch 3,-c (o) ch 2ch 3,-c (o) ch (ch 3) 2,-c (o) nh 2,-c (o) nhch 3,-c (o) n (ch 3) 2,-nh 2,-nhch 3,-n (ch 3) 2,-nhc (o) ch 3,-n (ch 3) coch 3,-nhs (o) 2ch 3,-n (ch 3) c (ch 3) 2conh 2,-n (ch 3) ch 2ch 2s (o) 2ch 3,-no 2,=o ,-oh ,-och 3,-och 2ch 3,-och 2ch 2och 3,-och 2ch 2oh ,-och 2ch 2n (ch 3) 2,-op (o) (oh) 2,-s (o) 2n (ch 3) 2,-sch 3,-s (o) 2ch 3,-s (o) 3h, cyclopropyl, oxetanyl, azetidinyl, 1-methyl azetidine-3-yl) oxygen base, n-methyl-n-trimethylene oxide-3-base are amino, azetidine-1-ylmethyl and morpholino.
BTK 활성 억제제로서의 8-플루오로프탈라진-1(2H)-온 화합물본 발명은 키나제를 억제하고, 면역 장애, 예컨대 Btk 키나제로 매개되는 염증을 억제하는데 유용한 하기 화학식 II의 8-플루오로프탈라진-1(2H)-온 화합물, 이의 입체이성질체, 호변체, 및 약학적으로 허용가능한 염을 제공한다. 시험관내, 동일 반응계내 및 생체내 진단, 및 포유동물 세포 내의 상기 질환 또는 관련된 병리학적 병태의 치료를 위한 화학식 II의 화합물의 사용 방법이 기술되어 있다: II 상기 식에서, X1, X2, 및 X3 중 1개 또는 2개가 N이다. 하기 화학식 II로부터 선택된 화합물 또는 이의 입체이성질체(stereoisomer), 호변체(tautomer), 또는 약학적으로 허용가능한 염:[이미지]상기 식에서,X1은 CR1 또는 N이고;X2는 CR2 또는 N이고;X3은 CR3 또는 N이고;이때 X1, X2, 및 X3 중 1개 또는 2개는 N이고;Y1 및 Y2는 CH 및 N으로부터 독립적으로 선택되되, 이때 Y1 및 Y2는 각각 N은 아니고;R1, R2 및 R3은 H, F, Cl, CN, -CH3, -CH2CH3, -CH2OH, -CH2F, -CHF2, -CF3, -CH2CH2OH, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -OCH2CH3, 및 -OCH2CH2OH로부터 독립적으로 선택되고;R4는 H, F, Cl, CN, -CH2OH, -CH(CH3)OH, -C(CH3)2OH, -CH(CF3)OH, -CH2F, -CHF2, -CH2CHF2, -CF3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -NHC(O)CH3, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OP(O)(OH)2, 사이클로프로필, 사이클로프로필메틸, 1-하이드록시사이클로프로필, 이미다졸릴, 피라졸릴, 3-하이드록시-옥세탄-3-일, 옥세탄-3-일, 및 아제티딘-1-일로부터 선택되고;R6은 H, -CH3, -CH2CH3, -CH2CH2OH, -CH2F, -CHF2, -CF3, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -OCH2CH3, 및 -OCH2CH2OH로부터 선택되고;R8은 C6-C20 아릴, C3-C12 카보사이클릴, C2-C20 헤테로사이클릴, C1-C20 헤테로아릴, -(C6-C20 아릴)-(C2-C20 헤테로사이클릴), -(C1-C20 헤테로아릴)-(C2-C20 헤테로사이클릴), -(C1-C20 헤테로아릴)-(C2-C20 헤테로사이클릴)-(C2-C20 헤테로사이클릴), -(C1-C20 헤테로아릴)-(C2-C20 헤테로사이클릴)-(C1-C6 알킬), -(C1-C20 헤테로아릴)-(C1-C6 알킬), 및 -(C1-C20 헤테로아릴)-C(=O)-(C2-C20 헤테로사이클릴)로부터 선택되고; 이때 아릴, 카보사이클릴, 헤테로사이클릴, 및 헤테로아릴은 임의적으로, F, Cl, Br, I, CN, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, -CH2OP(O)(OH)2, -C(CH3)2CONH2, -CH2OCH3, -CH2CH2OH, -CH2CH2OCH3, -CH2F, -CHF2, -CF3, -CH2CF3, -CH2CHF2, -CH(CH3)CN, -C(CH3)2CN, -CH2CN, -CO2H, -C(O)CH3, -CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3, -C(O)CH2CH3, -C(O)CH(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -NHC(O)CH3, -N(CH3)COCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, -NO2, =O, -OH, -OCH3, -OCH2CH3, -OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, -OP(O)(OH)2, -S(O)2N(CH3)2, -SCH3, -S(O)2CH3, -S(O)3H, 사이클로프로필, 옥세탄일, 아제티딘일, 1-메틸아제티딘-3-일)옥시, N-메틸-N-옥세탄-3-일아미노, 아제티딘-1-일메틸, 및 모폴리노로부터 독립적으로 선택된 1개 이상의 기로 치환된다.