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1. 发明申请

WO2007014925A1 MACROCYLIC INHIBITORS OF HEPATITIS C VIRUS 审中-公开
标题翻译： HEPATITIS C病毒的大肠抑制剂
公开(公告)号：WO2007014925A1
公开(公告)日：2007-02-08
申请号：PCT/EP2006/064819
申请日：2006-07-28
申请人： TIBOTEC PHARMACEUTICALS LTD. , MEDIVIR AB , RABOISSON, Pierre, Jean-Marie, Bernard , DE KOCK, Herman, Augustinus , HU, Lili , SURLERAUX, Dominique, Louis, Nestor, Ghislain , SIMMEN, Kenneth, Alan , SALVADOR ODÉN, Lourdes , NILSSON, Karl, Magnus , ROSENQUIST, Åsa, Annica, Kristina , SAMUELSSON, Bengt, Bertil
发明人： RABOISSON, Pierre, Jean-Marie, Bernard , DE KOCK, Herman, Augustinus , HU, Lili , SURLERAUX, Dominique, Louis, Nestor, Ghislain , SIMMEN, Kenneth, Alan , SALVADOR ODÉN, Lourdes , NILSSON, Karl, Magnus , ROSENQUIST, Åsa, Annica, Kristina , SAMUELSSON, Bengt, Bertil
IPC分类号： C07D487/04 , C07D245/04 , C07K5/078 , A61K38/05 , A61K31/33 , A61P31/14 , C07K5/06
CPC分类号： C07D487/04 , C07D245/04 , C07K5/06139
摘要： Inhibitors of HCV replication of formula (I), and the N -oxides, salts, and stereoisomers thereof, wherein each dashed line represents an optional double bond; X is Ν, CH and where X bears a double bond it is C; R 1a and R 1b are hydrogen, C 3-7 cycloalkyl, aryl, Het, C 1-6 alkoxy, C 1-6 alkyl optionally substituted with halo, C 1-6 alkoxy, cyano, polyhaloC1 1-6 alkoxy, C 3-7 cycloalkyl, aryl, or with Het; or R 1a and R 1b together with the nitrogen to which they are attached form a 4 to 6 membered heterocyclic ring which may be optionally substituted; L is a direct bond, -O- , -O-C 1-4 alkanediyl-, -O-CO-, -O-C(=O)-ΝR 5a - or -O -C(=O)-NR 5a -C 1-4 alkanediyl-; R 2 is hydrogen, and where X is C or CH, R 2 may also be C 1-6 alkyl; R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, C 3-7 cycloalkyl, amino, mono- or diC 1-6 alkylamino; R 4 is aryl or a saturated, a partially unsaturated or completely unsaturated 5 or 6 membered monocyclic or 9 to 12 membered bicyclic heterocyclic ring system wherein said ring system contains one nitrogen, and optionally one to three additional heteroatoms selected from O, S and N, and wherein the remaining ring members are carbon atoms; wherein said ring system may be optionally substituted; n is 3, 4, 5, or 6; p is 1 or 2; aryl is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydronaphthyl, each of which may be optionally substituted with one, two or three substituents; and Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from N, O and S , being optionally condensed with a benzene ring, and wherein Het may be optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I).
摘要翻译：式（I）的HCV复制抑制剂及其N-氧化物，盐和立体异构体，其中每个虚线表示任选的双键; X为α，CH，X为双键，为C; R 1a和R 1b是氢，C 3-7环烷基，芳基，Het，C 1-6烷基，烷氧基，任选被卤素取代的C 1-6烷基，C 1-6烷氧基，氰基，多卤代C 1-6烷氧基，C <亚<！ - SIPO

2. 发明申请

WO2011070541A1 CYSTEINE PROTEASE INHIBITORS 审中-公开
标题翻译： CYSTEINE PROTEASE抑制剂
公开(公告)号：WO2011070541A1
公开(公告)日：2011-06-16
申请号：PCT/IB2010/055738
申请日：2010-12-10
申请人： MEDIVIR UK LIMITED , AYESA, Susana , CARLQUIST, Peter , ERSMARK, Karolina , GRABOWSKA, Urszula , HEWITT, Ellen , JÖNSSON, Daniel , KAHNBERG, Pia , KLASSON, Björn , LIND, Peter , ODÉN, Lourdes , PARKES, Kevin , WIKTELIUS, Daniel
发明人： AYESA, Susana , CARLQUIST, Peter , ERSMARK, Karolina , GRABOWSKA, Urszula , HEWITT, Ellen , JÖNSSON, Daniel , KAHNBERG, Pia , KLASSON, Björn , LIND, Peter , ODÉN, Lourdes , PARKES, Kevin , WIKTELIUS, Daniel
IPC分类号： C07D231/40 , A61K31/16 , A61K31/415 , A61K31/426 , A61P9/10 , A61P11/06 , A61P17/06 , A61P21/04 , A61P37/02 , A61P37/08 , C07C237/14 , C07D277/46
CPC分类号： C07K5/06078 , A61K38/05 , C07C271/22 , C07C2601/02 , C07C2601/04 , C07C2601/08 , C07D231/40 , C07D277/46 , C07D405/12 , C07K5/06034 , C07K5/0606 , C07K5/06139
摘要： Compounds of the formula (I) wherein R 1a is H; and R 1b is C 1 -C 6 alkyl, Carbocyclyl or Het; or R 1a and R 1b together define a saturated cyclic amine with 3-6 ring atoms; R 2a and R 2b are independently H, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 alkoxy, or R 2a and R 2b together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl; R 3 is a branched C 5 -C 10 alkyl chain, C 2 -C 4 haloalkyl or -CH 2 C 3 -C 7 cycloalkyl; R 4 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylamino or C 1 -C 6 dialkylamino; for use in the prophylaxis or treatment of a disorder characterised by inappropriate expression or activation of cathepsin S.
摘要翻译：式（I）的化合物，其中R 1a是H; 并且R 1b是C 1 -C 6烷基，碳环或Het; 或R 1a和R 1b一起限定具有3-6个环原子的饱和环胺; R2a和R2b独立地为H，卤素，C1-C4烷基，C1-C4卤代烷基或C1-C4烷氧基，或R2a和R2b与它们所连接的碳原子一起形成C 3 -C 6环烷基; R3是支链C 5 -C 10烷基链，C 2 -C 4卤代烷基或-CH 2 C 3 -C 7环烷基; R 4是C 1 -C 6烷基，C 1 -C 6卤代烷基，C 1 -C 6烷基氨基或C 1 -C 6二烷基氨基; 用于预防或治疗以组织蛋白酶S不适当表达或活化为特征的病症。

3. 发明申请

WO2010070615A1 CYSTEINE PROTEASE INHIBITORS 审中-公开
标题翻译： CYSTEINE PROTEASE抑制剂
公开(公告)号：WO2010070615A1
公开(公告)日：2010-06-24
申请号：PCT/IB2009/055839
申请日：2009-12-18
申请人： MEDIVIR UK LTD , AYESA, Susana , BELFRAGE, Anna, Karin , CLASSON, Björn , GRABOWSKA, Urszula , HEWITT, Ellen , IVANOV, Vladimir , Jönsson, Daniel , KAHNBERG, Pia , LIND, Peter , NILSSON, Magnus , ODÉN, Lourdes , PELCMAN, Mikael , WÄHLING, Horst
发明人： AYESA, Susana , BELFRAGE, Anna, Karin , CLASSON, Björn , GRABOWSKA, Urszula , HEWITT, Ellen , IVANOV, Vladimir , Jönsson, Daniel , KAHNBERG, Pia , LIND, Peter , NILSSON, Magnus , ODÉN, Lourdes , PELCMAN, Mikael , WÄHLING, Horst
IPC分类号： C07D295/20 , A61K31/145 , A61K31/16 , A61K31/341 , A61K31/343 , A61K31/415 , A61K31/4965 , A61K31/5375 , A61P11/00 , A61P17/06 , A61P37/00 , C07C215/20 , C07C235/74 , C07C311/21 , C07D213/71 , C07D215/20 , C07D231/12 , C07D231/40 , C07D233/64 , C07D239/80 , C07D241/12 , C07D275/00 , C07D275/03 , C07D307/46 , C07D307/80
CPC分类号： C07C311/21 , C07C237/24 , C07C271/24 , C07C2601/02 , C07C2601/04 , C07C2601/06 , C07C2601/08 , C07D207/34 , C07D213/40 , C07D213/71 , C07D231/14 , C07D231/40 , C07D239/80 , C07D241/24 , C07D277/36 , C07D277/56 , C07D295/215 , C07D307/68 , C07D307/85 , C07D401/12 , C07D403/12 , C07D405/12 , C07D417/12
摘要： Compounds of the formula I wherein R 1a is H; and R 1b is C 1 -C 6 alkyl, Carbocyclyl or Het; or R 1a and R 1b together define a saturated cyclic amine with 3-6 ring atoms; R 2a and R 2b are H, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy; or R 2a and R 2b together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl; R is a branched C 5 -C 10 alkyl chain, C 2 -C 4 haloalkyl or C 3 -C 7 cycloalkylmethyl, R 4 is Het, Carbocyclyl, optionally substituted as defined in the specification and pharmaceutically acceptable salts, hydrates and N-oxides thereof; are inhibitors of cathepsin S and have utility in the treatment of psoriasis, autoimmune disorders and other disorders such as asthma, arteriosclerosis, COPD and chronic pain
摘要翻译：式Ⅰ化合物，其中R1a是H; 并且R 1b是C 1 -C 6烷基，碳环或Het; 或R 1a和R 1b一起限定具有3-6个环原子的饱和环胺; R2a和R2b是H，卤素，C1-C4烷基，C1-C4卤代烷基，C1-C4烷氧基; 或R 2a和R 2b与它们所连接的碳原子一起形成C 3 -C 6环烷基; R是支链C 5 -C 10烷基链，C 2 -C 4卤代烷基或C 3 -C 7环烷基甲基，R 4是Het，碳环基，如说明书中所定义的任选取代，以及其药学上可接受的盐，水合物和N-氧化物; 是组织蛋白酶S的抑制剂，并且可用于治疗牛皮癣，自身免疫性疾病和其它疾病如哮喘，动脉硬化，COPD和慢性疼痛

4. 发明申请

WO2007014922A1 MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS 审中-公开
标题翻译：丙型肝炎病毒大肠杆菌抑制剂
公开(公告)号：WO2007014922A1
公开(公告)日：2007-02-08
申请号：PCT/EP2006/064816
申请日：2006-07-28
申请人： TIBOTEC PHARMACEUTICALS LTD. , MEDIVIR AB , RABOISSON, Pierre Jean-Marie Bernard , DE KOCK, Herman Augustinus , SIMMEN, Kenneth Alan , JÖNSSON, Carl Erik Daniel , NILSSON, Karl Magnus , ROSENQUIST, Åsa Annica Kristina , SAMUELSSON, Bengt Bertil , ANTONOV, Dmitry , SALVADOR ODÉN, Lourdes , AYESA ALVAREZ, Susana , CLASSON, Björn Olof
发明人： RABOISSON, Pierre Jean-Marie Bernard , DE KOCK, Herman Augustinus , SIMMEN, Kenneth Alan , JÖNSSON, Carl Erik Daniel , NILSSON, Karl Magnus , ROSENQUIST, Åsa Annica Kristina , SAMUELSSON, Bengt Bertil , ANTONOV, Dmitry , SALVADOR ODÉN, Lourdes , AYESA ALVAREZ, Susana , CLASSON, Björn Olof
IPC分类号： C07D401/12 , C07D403/12 , C07D245/04 , A61K31/4523 , A61P31/14
CPC分类号： C07D401/12 , C07D225/04 , C07D245/04 , C07D403/12 , C07D413/12 , C07D417/12 , C07D487/04
摘要： Inhibitors of HCV replication of formula (I) and the N -oxides, salts, or stereoisomers thereof, wherein each dashed line (represented by ------) represents an optional double bond; X is N, CH and where X bears a double bond it is C; R 1 is -OR 6 , -NH-SO 2 R 7 ; R 2 is hydrogen, and where X is C or CH, R 2 may also be C 1-6 alkyl; R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, or C 3-7 cycloalkyl; n is 3, 4, 5, or 6; R 4 and R 5 independently from one another are hydrogen, halo, hydroxy, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy- carbonyl, amino, azido, mercapto, C 1-6 alkylthio, polyhaloC 1-6 alkyl, aryl or Het; W is aryl or Het; R 6 is hydrogen; aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; R 7 is aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; aryl is phenyl or naphthyl, each optionally substituted with 1-3 substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 - 4 heteroatoms each independently selected from N, O or S, and optionally substituted with 1 -3 substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.
摘要翻译：式（I）的HCV复制抑制剂及其N-氧化物，盐或立体异构体，其中每个虚线（由 - 表示）表示任选的双键; X为N，CH，X为双键，C为C; R 1是-OR 6，-NH-SO 2 R 7， R 2是氢，并且其中X是C或CH，R 2也可以是C 1-6烷基; R 3是氢，C 1-6烷基，C 1-6烷氧基C 1-6烷基，或 ç_{3-7 环烷基; n为3,4,5或6; R 4和R 5彼此独立地是氢，卤素，羟基，硝基，氰基，羧基，C 1-6烷基，C C 1-6烷氧基，C 1-6烷氧基C 1-6烷基，C 1-6烷基羰基，C 烷基 - 羰基，氨基，叠氮基，巯基，C 1-6烷基硫基，多卤代C 1-6烷基，芳基或Het; W是芳基或Het; R 6是氢; 芳基; HET; 任选被C 1-6烷基取代的C 3-7环烷基; 或任选被C 3-7环烷基，芳基或与Het取代的C 1-6烷基; R 7是芳基; HET; 任选被C 1-6烷基取代的C 3-7环烷基; 或任选被C 3-7环烷基，芳基或与Het取代的C 1-6烷基; 芳基是苯基或萘基，各自任选被1-3个取代基取代; Het是含有1-4个杂原子的5或6元饱和，部分不饱和或完全不饱和的杂环，各自独立地选自N，O或S，并且任选被1-3取代基取代; 含有化合物（I）的药物组合物和制备化合物（I）的方法。还提供了式（I）的HCV抑制剂与利托那韦的生物可利用组合。}

5. 发明申请

WO2011070539A1 CYSTEINE PROTEASE INHIBITORS 审中-公开
公开(公告)号：WO2011070539A1
公开(公告)日：2011-06-16
申请号：PCT/IB2010/055732
申请日：2010-12-10
申请人： MEDIVIR UK LIMITED , AYESA, Susana , ERSMARK, Karolina , GRABOWSKA, Urszula , HEWITT, Ellen , JÖNSSON, Daniel , KAHNBERG, Pia , KLASSON, Björn , LIND, Peter , LUNDGREN, Stina , ODÉN, Lourdes , PARKES, Kevin , WIKTELIUS, Daniel
发明人： AYESA, Susana , ERSMARK, Karolina , GRABOWSKA, Urszula , HEWITT, Ellen , JÖNSSON, Daniel , KAHNBERG, Pia , KLASSON, Björn , LIND, Peter , LUNDGREN, Stina , ODÉN, Lourdes , PARKES, Kevin , WIKTELIUS, Daniel
IPC分类号： C07D231/40 , A61K31/27 , A61K31/415 , A61K31/4155 , A61K31/4164 , A61K31/42 , A61K31/426 , A61P9/10 , A61P11/06 , A61P17/06 , A61P21/04 , A61P37/02 , A61P37/08 , C07C271/20 , C07D233/88 , C07D261/14 , C07D277/46 , C07D405/12
CPC分类号： C07K5/06078 , A61K38/05 , C07C271/22 , C07C2601/02 , C07C2601/04 , C07C2601/08 , C07D231/40 , C07D277/46 , C07D405/12 , C07K5/06034 , C07K5/0606 , C07K5/06139
摘要： Compounds of Formula (II) wherein R 1a is H; and R 1b is C 1 -C 6 alkyl, Carbocyclyl or Het; or R 1a and R 1b together define a saturated cyclic amine with 3-6 ring atoms; R 2a and R 2b are independently H, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 alkoxy, or R 2a and R 2b together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl; R 3 is a branched C 5 -C 10 alkyl chain, C 2 -C 4 haloalkyl or -CH 2 C 3 -C 7 cycloalkyl; R 4' is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or oxetany-3-yl. for use in the prophylaxis or treatment of a disorder characterised by inappropriate expression or activation of cathepsin S.
摘要翻译：式（II）的化合物，其中R 1a是H; 并且R 1b是C 1 -C 6烷基，碳环或Het; 或R1a和R1b一起限定具有3-6个环原子的饱和环胺; R2a和R2b独立地为H，卤素，C1-C4烷基，C1-C4卤代烷基或C1-C4烷氧基，或R2a和R2b与它们所连接的碳原子一起形成C 3 -C 6环烷基; R3是支链C 5 -C 10烷基链，C 2 -C 4卤代烷基或-CH 2 C 3 -C 7环烷基; R 4'是C 1 -C 6烷基，C 1 -C 6卤代烷基或氧杂环丁烷-3-基。用于预防或治疗以组织蛋白酶S不适当表达或活化为特征的病症。

6. 发明申请

WO2010034790A1 PROTEASE INHIBITORS 审中-公开
标题翻译： PROTEASE抑制剂
公开(公告)号：WO2010034790A1
公开(公告)日：2010-04-01
申请号：PCT/EP2009/062408
申请日：2009-09-24
申请人： MEDIVIR AB , ODÉN, Lourdes, Salvadore , JOHANSSON, Per-Olof , KAHNBERG, Pia , NILSSON, Magnus , SAMUELSSON, Bertil , GRABOWSKA, Urszula
发明人： ODÉN, Lourdes, Salvadore , JOHANSSON, Per-Olof , KAHNBERG, Pia , NILSSON, Magnus , SAMUELSSON, Bertil , GRABOWSKA, Urszula
IPC分类号： C07D491/048 , A61K31/496 , A61P19/00
CPC分类号： C07D277/40 , C07D491/048 , C07D495/04
摘要： Compounds of the formula II: wherein R 1 forms an ethynyl bond and R 2 is H or C 3 -C 6 cycloalkyl which is optionally substituted with one or two substituents independently selected from methyl, CF 3 , OMe or halo; R 3 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, either of which is optionally substituted with one or two methyl and/or a fluoro, trifluoromethyl or methoxy, when R 3 is C 3 -C 6 cycloalkyl it may alternatively be gem subsituted with fluoro; R 4 is methyl or fluoro; m is 0, 1 or 2; E is a bond, A 1 is CH or N, A 2 is CR 6 R 7 or NR 6 , provided at least one of A 1 and A 2 comprises N; n is 0 or 1 such that the ring containing A 1 and A 2 is a saturated, nitrogen-containing ring of 5 or 6 ring atoms; R 6 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 3 alkyl-O-C 1 -C 3 alkyl, or when A 2 is C, R 6 can also be C 1 -C 4 alkoxy or F; R 7 is H, C 1 -C 4 alkyl or F or a pharmaceutically acceptable salt, N-oxide or hydrate thereof, have utility in the treatment of disorders characterized by inappropriate expression or activation of cathepsin K, such as osteoporosis, osteoarthritis, rheumatoid arthritis or bone metastases.
摘要翻译：式II化合物：其中R1形成乙炔基，R2是H或任选被一个或两个独立地选自甲基，CF 3，OMe或卤素的取代基取代的C 3 -C 6环烷基; R 3是C 1 -C 3烷基或C 3 -C 6环烷基，当R 3是C 3 -C 6环烷基时，它们任选被一个或两个甲基和/或氟，三氟甲基或甲氧基取代，也可以被氟取代; R4是甲基或氟; m为0,1或2; E是键，A1是CH或N，A2是CR6R7或NR6，条件是A1和A2中的至少一个包括N; n为0或1，使得含有A 1和A 2的环是5或6个环原子的饱和的含氮环; R6是H，C1-C4烷基，C1-C4卤代烷基，C1-C3烷基-O-C1-C3烷基，或当A2是C时，R6也可以是C1-C4烷氧基或F; R7是H，C1-C4烷基或F或其药学上可接受的盐，N-氧化物或其水合物，可用于治疗组织蛋白酶K不适当表达或活化的疾病，例如骨质疏松症，骨关节炎，类风湿性关节炎或骨骼转移。

7. 发明申请

WO2010034788A1 PROTEASE INHIBITORS 审中-公开
标题翻译： PROTEASE抑制剂
公开(公告)号：WO2010034788A1
公开(公告)日：2010-04-01
申请号：PCT/EP2009/062406
申请日：2009-09-24
申请人： MEDIVIR AB , ODÉN, Lourdes Salvadore , NILSSON, Magnus , KAHNBERG, Pia , SAMUELSSON, Bertil , GRABOWSKA, Urszula
发明人： ODÉN, Lourdes Salvadore , NILSSON, Magnus , KAHNBERG, Pia , SAMUELSSON, Bertil , GRABOWSKA, Urszula
IPC分类号： C07D491/048 , A61K31/496 , A61P19/00
CPC分类号： C07D277/40 , C07D491/048 , C07D495/04
摘要： Compounds of the formula II: wherein R 1 and R 2 are independently H, F or CH 3 ; or R 1 forms an ethynyl bond and R 2 is H or C 3 -C 6 cycloalkyl which is optionally substituted with one or two substituents independently selected from methyl, CF 3 , OMe or halo; R 3 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, either of which is optionally substituted with one or two methyl and/or a fluoro, trifluoromethyl or methoxy, when R 3 is C 3 -C 6 cycloalkyl it may alternatively be gem subsituted with fluoro; R 4 is methyl or fluoro; m is 0, 1 or 2; E is a bond, or thiazolyl, optionally substituted with methyl or fluoro; A 1 is CH or N, A 2 is CR 6 R7 or NR 6 , provided at least one Of A 1 and A 2 comprises N; R 6 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 3 alkyl-O-C 1 -C 3 alkyl, or when A 2 is C, R 6 can also be C 1 -C 4 alkoxy or F; R 7 is H, C 1 -C 4 alkyl or F or a pharmaceutically acceptable salt, N-oxide or hydrate thereof, have utility in the treatment of disorders characterized by inappropriate expression or activation of cathepsin K, such as osteoporosis, osteoarthritis, rheumatoid arthritis or bone metastases.
摘要翻译：式II化合物：其中R 1和R 2独立地为H，F或CH 3; 或R1形成乙炔基，R2是H或C3-C6环烷基，其任选地被一个或两个独立地选自甲基，CF 3，OMe或卤素的取代基取代; R3是C1-C3烷基或C3-C6环烷基，当R 3是C 3 -C 6环烷基时，它们任选被一个或两个甲基和/或氟，三氟甲基或甲氧基取代，也可以被氟取代; R4是甲基或氟; m为0,1或2; E是任选被甲基或氟取代的键或噻唑基; A1是CH或N，A2是CR6R7或NR6，提供A1和A2中的至少一个包括N; R6是H，C1-C4烷基，C1-C4卤代烷基，C1-C3烷基-O-C1-C3烷基，或当A2是C时，R6也可以是C1-C4烷氧基或F; R 7是H，C 1 -C 4烷基或F或其药学上可接受的盐，N-氧化物或其水合物，可用于治疗组织蛋白酶K不适当表达或活化的疾病，例如骨质疏松症，骨关节炎，类风湿性关节炎或骨骼转移。

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