公开(公告)号：US09868738B2

公开(公告)日：2018-01-16

申请号：US15512081

申请日：2015-09-14

申请人： Merck Sharp & Dohme Corp. ,  Kun Liu ,  Shuwen He ,  Jared N. Cumming ,  Andrew W. Stamford

发明人： Kun Liu ,  Shuwen He ,  Jared N. Cumming ,  Andrew W. Stamford

IPC分类号： C07D471/04

CPC分类号： C07D471/04 ,  A61K45/06 ,  A61P25/00

摘要： In its many embodiments, the present invention provides certain C-6 spirocarbocyclic iminothiadiazine compounds, including compounds Formula (I) or a tautomer thereof, and pharmaceutically acceptable salts of said compounds and said tautomers, wherein R1A, R1B, R2, RA, ring A, RA, m, L1, RL, ring C, RC, and p are as defined herein. The novel compounds of the invention are useful as BACE inhibitors and/or for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including for the possible treatment of Alzheimer's disease, are also disclosed.

公开(公告)号：US09181236B2

公开(公告)日：2015-11-10

申请号：US14240215

申请日：2012-08-21

申请人： Wen-Lian Wu ,  Duane A. Burnett ,  Andrew W. Stamford ,  Jared N. Cumming ,  Theodros Asberom ,  Chad Bennett ,  Thavalakulamgara K. Sasiskumar ,  Jack D. Scott

发明人： Wen-Lian Wu ,  Duane A. Burnett ,  Andrew W. Stamford ,  Jared N. Cumming ,  Theodros Asberom ,  Chad Bennett ,  Thavalakulamgara K. Sasiskumar ,  Jack D. Scott

IPC分类号： C07D417/14 ,  C07D417/12 ,  C07D513/04 ,  C07D513/10 ,  A61K45/06 ,  C07D417/04 ,  C07D417/10 ,  C07D279/34 ,  C07D519/00

CPC分类号： C07D417/14 ,  A61K45/06 ,  C07D279/34 ,  C07D417/04 ,  C07D417/10 ,  C07D417/12 ,  C07D513/04 ,  C07D513/10 ,  C07D519/00

摘要： In its many embodiments, the present invention provides certain iminothiazine dioxide compounds, including compounds Formula (I): and tautomers and stereoisomers thereof, and pharmaceutically acceptable salts of said compounds, said tautomeros and said stereoisomers, wherein each of the variables shown in the formula are as defined herein. The novel compounds of the invention are useful as BACE inhibitors and/or for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including Alzheimer's disease, are also disclosed.

摘要翻译： 在其许多实施方案中，本发明提供了某些亚氨基噻嗪二氧化物化合物，包括式（I）化合物及其互变异构体和立体异构体，以及所述化合物，所述互变异构体和所述立体异构体的药学上可接受的盐，其中式 如本文所定义。 本发明的新化合物可用作BACE抑制剂和/或用于治疗和预防与其相关的各种病症。 还公开了包含一种或多种这样的化合物（单独和与一种或多种其它活性剂组合）的药物组合物及其制备和使用方法，包括阿尔茨海默氏病。

公开(公告)号：US08829036B2

公开(公告)日：2014-09-09

申请号：US13420007

申请日：2012-03-14

申请人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voight ,  Corey O. Strickland ,  Elizabeth M. Smith ,  Andrew W. Stamford ,  William J. Greenlee ,  Robert D. Mazzola, Jr. ,  John P. Caldwell ,  Jared N. Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Xiaoiang Liu ,  Tao Guo ,  Thuy X. E. Le ,  Kurt W. Saionz ,  Suresh D. Babu ,  Rachael C. Hunter ,  Michelle L. Morris ,  Huizhong Gu ,  Gang Qian ,  Dawit Tadesse ,  Ying Huang ,  Guoqing Li ,  Jianping Pan ,  Jeffrey A. Misiaszek ,  Gaifa Lai ,  Jingqi Duo ,  Chuanxing Qu ,  Yuefei Shao

发明人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voight ,  Corey O. Strickland ,  Elizabeth M. Smith ,  Andrew W. Stamford ,  William J. Greenlee ,  Robert D. Mazzola, Jr. ,  John P. Caldwell ,  Jared N. Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Xiaoiang Liu ,  Tao Guo ,  Thuy X. E. Le ,  Kurt W. Saionz ,  Suresh D. Babu ,  Rachael C. Hunter ,  Michelle L. Morris ,  Huizhong Gu ,  Gang Qian ,  Dawit Tadesse ,  Ying Huang ,  Guoqing Li ,  Jianping Pan ,  Jeffrey A. Misiaszek ,  Gaifa Lai ,  Jingqi Duo ,  Chuanxing Qu ,  Yuefei Shao

IPC分类号： A61K31/4168 ,  A61K31/4178 ,  C07D403/06 ,  C07D233/88

CPC分类号： C07D233/88 ,  A61K31/4168 ,  A61K31/4178 ,  C07D239/22 ,  C07D401/06 ,  C07D401/10 ,  C07D403/06 ,  C07D409/04 ,  C07D409/14 ,  C07D413/04 ,  C07D417/10 ,  C07D417/14 ,  C07D495/10

摘要： Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein each variable in Formula 1 are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I. Also disclosed are methods of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes. Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic m1 agonist or m2 antagonist.

公开(公告)号：US20140057893A1

公开(公告)日：2014-02-27

申请号：US14110332

申请日：2012-04-05

申请人： Scott Edmondson ,  Zhiqiang Guo ,  Harold B. Wood ,  Andrew W. Stamford ,  Michael W. Miller ,  Duane E. DeMong ,  Gregori J. Morriello ,  Rajan Anand ,  Vincent J. Colandrea ,  Megan Macala ,  Milana Maletic ,  Cheng Zhu ,  Yuping Zhu ,  Wanying Sun ,  Kake Zhao ,  Yong Huang ,  Joel M. Harris ,  Lehua Chang ,  Nam Fung Kar ,  Zhiyong Hu ,  Liping Wang ,  Bowei Wang ,  Ping Liu ,  Jason W. Szewczyk ,  William B. Geiss

发明人： Scott Edmondson ,  Zhiqiang Guo ,  Harold B. Wood ,  Andrew W. Stamford ,  Michael W. Miller ,  Duane E. DeMong ,  Gregori J. Morriello ,  Rajan Anand ,  Vincent J. Colandrea ,  Megan Macala ,  Milana Maletic ,  Cheng Zhu ,  Yuping Zhu ,  Wanying Sun ,  Kake Zhao ,  Yong Huang ,  Joel M. Harris ,  Lehua Chang ,  Nam Fung Kar ,  Zhiyong Hu ,  Liping Wang ,  Bowei Wang ,  Ping Liu ,  Jason W. Szewczyk ,  William B. Geiss

IPC分类号： C07D513/04 ,  C07D413/14 ,  C07D413/04 ,  C07D498/04 ,  C07D405/04 ,  C07D471/04 ,  C07D487/04 ,  C07D401/12 ,  C07D211/22

CPC分类号： C07D513/04 ,  A61K9/4858 ,  C07D211/22 ,  C07D401/12 ,  C07D405/04 ,  C07D413/04 ,  C07D413/14 ,  C07D417/14 ,  C07D471/04 ,  C07D487/04 ,  C07D495/04 ,  C07D498/04

摘要： Substituted cyclopropyl compounds of the formula I: and pharmaceutically acceptable salts thereof are disclosed as useful for treating or preventing type 2 diabetes and similar conditions. The compounds are useful as agonists of the G-protein coupled receptor GPR-119. Pharmaceutical compositions and methods of treatment are also included

摘要翻译： 公开了取代的式I的环丙基化合物及其药学上可接受的盐可用于治疗或预防2型糖尿病和类似病状。 该化合物可用作G蛋白偶联受体GPR-119的激动剂。 还包括药物组合物和治疗方法

公开(公告)号：US20140023668A1

公开(公告)日：2014-01-23

申请号：US14009883

申请日：2012-04-04

申请人： Jared N. Cumming ,  Eric J. Gilbert ,  Andrew W. Stamford

发明人： Jared N. Cumming ,  Eric J. Gilbert ,  Andrew W. Stamford

IPC分类号： C07D513/04 ,  A61K45/06 ,  A61K31/549

CPC分类号： C07D513/04 ,  A61K31/54 ,  A61K31/549 ,  A61K45/06 ,  A61K2300/00

摘要： In its many embodiments, the present invention provides certain iminothiadiazine dioxide compounds, including compounds Formula: (I) and tautomers and stereoisomers thereof, and pharmaceutically acceptable salts of said compounds, said tautomeros and said stereoisomers, wherein each of ring A, ring B, ring C, R2, R3, R4, m, n, p, and -L1- is as defined herein. The novel compounds of the invention may be useful as BACE inhibitors and/or for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including Alzheimer's disease, are also disclosed.

摘要翻译： 在其许多实施方案中，本发明提供了某些亚氨基二嗪二氧化物化合物，包括式（I）化合物及其互变异构体和立体异构体，以及所述化合物，所述互变异构体和所述立体异构体的药学上可接受的盐，其中环A，环B， 环C，R 2，R 3，R 4，m，n，p和-L 1如本文所定义。 本发明的新化合物可用作BACE抑制剂和/或用于治疗和预防与其相关的各种病症。 还公开了包含一种或多种这样的化合物（单独和与一种或多种其它活性剂组合）的药物组合物及其制备和使用方法，包括阿尔茨海默氏病。

公开(公告)号：US20130072468A1

公开(公告)日：2013-03-21

申请号：US13616825

申请日：2012-09-14

申请人： Eric J. Gilbert ,  William J. Greenlee ,  Michael W. Miller ,  Jack D. Scott ,  Andrew W. Stamford

发明人： Eric J. Gilbert ,  William J. Greenlee ,  Michael W. Miller ,  Jack D. Scott ,  Andrew W. Stamford

IPC分类号： A61K31/496 ,  A61K31/495 ,  C07D401/04 ,  C07D401/06 ,  C07D401/14 ,  C07D403/06 ,  C07D413/06 ,  A61K31/5377 ,  C07D417/06 ,  A61K31/506 ,  C07D487/04 ,  A61K31/397 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  A61P25/30 ,  A61P25/32 ,  A61P25/34 ,  A61P25/00 ,  A61P25/06 ,  A61P25/08 ,  A61P25/14 ,  A61P25/16 ,  A61P25/28 ,  A61P3/04 ,  A61P3/10 ,  A61P1/00 ,  A61P1/08 ,  A61P1/12 ,  A61P13/00 ,  A61P15/08 ,  A61P29/00 ,  A61P9/10 ,  A61P31/00 ,  A61P35/00 ,  A61P3/00 ,  A61P1/16 ,  A61P9/00 ,  C07D241/04

CPC分类号： C07D403/10 ,  C07D241/04 ,  C07D401/04 ,  C07D401/06 ,  C07D401/12 ,  C07D401/14 ,  C07D403/06 ,  C07D407/04 ,  C07D413/06 ,  C07D417/06 ,  C07D487/04

摘要： Compounds of Formula (I): or pharmaceutically acceptable salts, solvates, or esters thereof, are useful in treating diseases or conditions mediated by CB1 receptors, such as metabolic syndrome and obesity, neuroinflammatory disorders, cognitive disorders and psychosis, addiction (e.g., smoking cessation), gastrointestinal disorders, and cardiovascular conditions.

摘要翻译： 式（I）化合物或其药学上可接受的盐，溶剂合物或酯可用于治疗由CB1受体介导的疾病或病症，例如代谢综合征和肥胖症，神经炎症性疾病，认知障碍和精神病，成瘾（例如吸烟 停止），胃肠道疾病和心血管疾病。

公开(公告)号：US08242112B2

公开(公告)日：2012-08-14

申请号：US13108454

申请日：2011-05-16

申请人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voigt ,  Corey Strickland ,  Elizabeth M. Smith ,  Andrew W. Stamford ,  William J. Greenlee ,  Robert D. Mazzola, Jr. ,  John P. Caldwell ,  Jared N. Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Tao Guo ,  Thuy X. H. Le ,  Kurt W. Saionz ,  Suresh D. Babu ,  Rachael C. Hunter ,  Michelle L. Morris ,  Huizhong Gu ,  Gang Qian ,  Dawit Tadesse

发明人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voigt ,  Corey Strickland ,  Elizabeth M. Smith ,  Andrew W. Stamford ,  William J. Greenlee ,  Robert D. Mazzola, Jr. ,  John P. Caldwell ,  Jared N. Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Tao Guo ,  Thuy X. H. Le ,  Kurt W. Saionz ,  Suresh D. Babu ,  Rachael C. Hunter ,  Michelle L. Morris ,  Huizhong Gu ,  Gang Qian ,  Dawit Tadesse

IPC分类号： A61K31/535 ,  C07D273/04

CPC分类号： C07D233/46 ,  C07D233/70 ,  C07D233/88 ,  C07D239/22 ,  C07D239/70 ,  C07D271/07 ,  C07D273/00 ,  C07D401/04 ,  C07D401/08 ,  C07D401/10 ,  C07D401/12 ,  C07D403/04 ,  C07D403/06 ,  C07D403/08 ,  C07D403/10 ,  C07D403/12 ,  C07D405/10 ,  C07D409/04 ,  C07D409/10 ,  C07D409/14 ,  C07D413/10 ,  C07D413/12 ,  C07D417/06

摘要： Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein W is a bond, —C(═S)—, —S(O)—, —S(O)2—, —C(═O)—, —O—, —C(R6)(R7)—, —N(R5)— or —C(═N(R5))—; X is —O—, —N(R5)— or —C(R6)(R7)—; provided that when X is —O—, U is not —O—, —S(O)—, —S(O)2—, —C(═O)— or —C(═NR5)—; U is a bond, —S(O)—, —S(O)2—, —C(O)—, —O—, —P(O)(OR15)—, —C(═NR5)—, —(C(R6)(R7))b— or —N(R5)—; wherein b is 1 or 2; provided that when W is —S(O)—, —S(O)2—, —O—, or —N(R5)—, U is not —S(O)—, —S(O)2—, —O—, or —N(R5)—; provided that when X is —N(R5)— and W is —S(O)—, —S(O)2—, —O—, or —N(R5)—, then U is not a bond; and R1, R2, R3, R4, R5, R6, and R7 are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I. Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes.Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic m1 agonist or m2 antagonist.

公开(公告)号：US20120183563A1

公开(公告)日：2012-07-19

申请号：US13392297

申请日：2010-10-06

申请人： Jack D. Scott ,  Andrew W. Stamford ,  Eric J. Gilbert ,  Jared N. Cumming ,  Ulrich Iserloh ,  Jeffrey A. Misiaszek ,  Guoqing Li

发明人： Jack D. Scott ,  Andrew W. Stamford ,  Eric J. Gilbert ,  Jared N. Cumming ,  Ulrich Iserloh ,  Jeffrey A. Misiaszek ,  Guoqing Li

IPC分类号： A61K31/549 ,  C07D285/18 ,  C07D417/14 ,  C07D471/04 ,  C07D495/04 ,  A61K31/55 ,  A61K39/395 ,  A61K39/00 ,  A61P29/00 ,  A61P31/04 ,  A61P37/04 ,  A61P5/50 ,  A61P25/28 ,  A61P25/16 ,  A61P25/00 ,  A61P3/10 ,  C07D417/04 ,  A61P7/04 ,  A61P7/00 ,  C07D417/12

CPC分类号： A61K31/549 ,  A61K31/00 ,  A61K31/495 ,  A61K31/54 ,  A61K45/06 ,  C07C309/30 ,  C07D213/26 ,  C07D213/89 ,  C07D239/14 ,  C07D285/18 ,  C07D401/12 ,  C07D401/14 ,  C07D403/04 ,  C07D403/12 ,  C07D417/04 ,  C07D417/10 ,  C07D417/12 ,  C07D417/14 ,  C07D471/04 ,  C07D487/04 ,  C07D495/04 ,  A61K2300/00

摘要： In its many embodiments, the present invention provides certain iminothiadiazine dioxide compounds, including compounds Formula (I): (I) and include stereoisomers thereof, and pharmaceutically acceptable salts of said compounds stereoisomers, wherein each of R1, R2, R3, R4, R5, R9, ring A, ring B, m, n, p, -L1-,L2-, and L3- is selected independently and as defined herein. The novel iminothiadiazine dioxide compounds of the invention have surprisingly been found to exhibit properties which are expected to render them advantageous as BACE inhibitors and/or for the treatment and prevention of various pathologies related to β-amyloid (Aβ) production. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use in treating pathologies associated with amyloid beta (Aβ) protein, including Alzheimers disease, are also disclosed.

摘要翻译： 在其许多实施方案中，本发明提供了某些亚氨基二嗪二氧化物化合物，包括式（I）：（I）的化合物并包括其立体异构体，以及所述化合物立体异构体的药学上可接受的盐，其中R1，R2，R3，R4，R5 ，R9，环A，环B，m，n，p，-L1-，L2-和L3-是独立选择和如本文所定义的。 令人惊奇地发现本发明的新型亚氨基二嗪二氧化物化合物表现出预期使其作为BACE抑制剂和/或用于治疗和预防与β-淀粉样蛋白（A＆bgr）生产相关的各种病症的优点的性质。 还公开了包含一种或多种这样的化合物（单独和与一种或多种其它活性剂组合）的药物组合物及其制备和用于治疗与包括阿尔茨海默氏病在内的淀粉样蛋白β（A＆bgr））蛋白相关的病理学的方法。

公开(公告)号：US20120148603A1

公开(公告)日：2012-06-14

申请号：US13390856

申请日：2010-10-06

申请人： Andrew W. Stamford ,  Jared N Cumming

发明人： Andrew W. Stamford ,  Jared N Cumming

IPC分类号： A61K31/505 ,  C07D409/04 ,  A61K31/506 ,  A61K31/55 ,  A61P7/00 ,  A61P25/28 ,  A61P25/16 ,  A61P25/00 ,  A61P3/10 ,  C07D239/04 ,  A61K39/395

CPC分类号： C07D239/22 ,  C07D409/04

摘要： In its many embodiments, the present invention provides provides certain pentafluorosulfur imino heterocyclic compounds, including compounds Formula (I): and tautomers thereof, and solvates, prodrugs, esters, and deuterates of said compounds and said tautomers, and pharmaceutically acceptable salts of said compounds, tautomers, solvates, prodrugs, esters, and deuterates, wherein each of R1, R2, R3, R4, R5, R9, R11, ring A, ring B, m, n, p, q, r, -L1-, L2-, and L3- is selected independently and as defined herein. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use in treating pathologies associated with amyloid beta (Aβ) protein, including Alzheimers Disease, are also disclosed.

摘要翻译： 在其许多实施方案中，本发明提供了某些五氟硫亚胺杂环化合物，包括式（I）化合物及其互变异构体，以及所述化合物和所述互变异构体的溶剂化物，前药，酯和氘代，以及所述化合物的药学上可接受的盐 ，互变异构体，溶剂合物，前药，酯和氘代，其中R1，R2，R3，R4，R5，R9，R11，环A，环B，m，n，p，q，r，-L1， - 和L3-是独立选择的，如本文所定义。 还公开了包含一种或多种这样的化合物（单独并与一种或多种其它活性剂组合）的药物组合物及其制备和用于治疗与包括阿尔茨海默病在内的淀粉样蛋白β（A＆bgr））蛋白相关的病理学的方法。

公开(公告)号：US20110110957A1

公开(公告)日：2011-05-12

申请号：US12988461

申请日：2009-04-21

申请人： Andrew W. Stamford ,  Zhaoning Zhu ,  Mihirbaran Mandal ,  Yusheng Wu ,  Jared N. Cumming ,  Xiaoxiang Liu ,  Guoqing Li ,  Ulrich Iserloh

发明人： Andrew W. Stamford ,  Zhaoning Zhu ,  Mihirbaran Mandal ,  Yusheng Wu ,  Jared N. Cumming ,  Xiaoxiang Liu ,  Guoqing Li ,  Ulrich Iserloh

IPC分类号： A61K31/519 ,  C07D487/04 ,  A61K31/55 ,  A61K39/395 ,  A61K39/00 ,  A61P25/28 ,  A61P25/16 ,  A61P25/00 ,  A61P27/00 ,  A61P27/06 ,  A61P3/10 ,  A61P13/12

CPC分类号： C07D487/04

摘要： In its many embodiments, the present invention provides certain 2-imino-3-methyl pyrrolo pyrimidone compounds, including compounds Formula (II): and include tautomers, steroisomers, or pharmaceutically acceptable salts or solvates of said compounds, stereoisomers, or said tautomers, wherein R2, R3, R4, R5, R6, R7, R8, and R9 are each selected independently and as defined herein. Pharmaceutical compositions comprising one or more such compounds, and methods for their preparation and use in treating pathologies associated with amyloid beta (Aβ) protein, including Alzheimer's Disease, are also disclosed.

摘要翻译： 在其许多实施方案中，本发明提供某些2-亚氨基-3-甲基吡咯烷酮化合物，包括式（II）化合物：并且包括所述化合物，立体异构体或所述互变异构体的互变异构体，立体异构体或药学上可接受的盐或溶剂化物， 其中R2，R3，R4，R5，R6，R7，R8和R9各自独立地并如本文所定义。 还公开了包含一种或多种这样的化合物的药物组合物，及其制备和用于治疗与淀粉样蛋白β（A＆bgr））蛋白质（包括阿尔茨海默氏病）相关的病理学的方法。