公开(公告)号：US20120189642A1

公开(公告)日：2012-07-26

申请号：US13392955

申请日：2010-10-06

申请人： Jack D. Scott ,  Andrew W. Stamford ,  Eric J. Gilbert ,  Jared N. Cumming ,  Ulrich Iserloh ,  Lingyan Wang ,  Wei Li

发明人： Jack D. Scott ,  Andrew W. Stamford ,  Eric J. Gilbert ,  Jared N. Cumming ,  Ulrich Iserloh ,  Lingyan Wang ,  Wei Li

IPC分类号： A61K31/549 ,  C07D417/10 ,  C07D417/04 ,  A61K31/55 ,  A61K39/00 ,  A61P25/24 ,  A61P25/16 ,  A61P25/00 ,  A61P29/00 ,  A61P9/00 ,  A61P7/04 ,  A61P27/06 ,  A61P3/10 ,  A61P7/00 ,  A61P37/04 ,  A61K39/395 ,  A61P31/04 ,  C07D285/18

CPC分类号： C07D417/04 ,  C07D285/18 ,  C07D417/10

摘要： In its many embodiments, the present invention provides certain iminothiadiazine dioxide compounds, including compounds Formula (a) and include tautomers, solvates, prodrugs, esters, and deuterates thereof, and pharmaceutically acceptable salts of said compounds, tautomers, solvates, prodrugs, esters, and deuterates, wherein each of R1, R2, R3, R4, R5, R9, ring A, ring B, ring C, m, n, p, q, -L1-, -L2-, L3-, and L4- is selected independently and as defined herein. The compounds of the invention have, surprisingly and advantageously, improved solution stability. 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，本发明提供某些亚氨基二嗪二氧化物化合物，包括式（a）化合物，并且包括其互变异构体，溶剂化物，前药，酯和氘代，以及所述化合物，互变异构体，溶剂合物，前药，酯， 氘代，其中R1，R2，R3，R4，R5，R9，环A，环B，环C，m，n，p，q，-L1-，-L2，L3-和L4- 独立选择和如本文所定义。 本发明的化合物令人惊奇地和有利地提高了溶液的稳定性。 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：US08563543B2

公开(公告)日：2013-10-22

申请号：US13392955

申请日：2010-10-06

申请人： Jack D. Scott ,  Andrew W. Stamford ,  Eric J. Gilbert ,  Jared N. Cumming ,  Ulrich Iserloh ,  Lingyan Wang ,  Wei Li

发明人： Jack D. Scott ,  Andrew W. Stamford ,  Eric J. Gilbert ,  Jared N. Cumming ,  Ulrich Iserloh ,  Lingyan Wang ,  Wei Li

IPC分类号： A61K31/54

CPC分类号： C07D417/04 ,  C07D285/18 ,  C07D417/10

摘要： In its many embodiments, the present invention provides certain iminothiadiazine dioxide compounds, including compounds Formula (a) and include tautomers, solvates, prodrugs, esters, and deuterates thereof, and pharmaceutically acceptable salts of said compounds, tautomers, solvates, prodrugs, esters, and deuterates, wherein each of R1, R2, R3, R4, R5, R9, ring A, ring B, ring C, m, n, p, q, -L1-, -L2-, L3-, and L4- is selected independently and as defined herein. The compounds of the invention have, surprisingly and advantageously, improved solution stability. 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，本发明提供某些亚氨基二嗪二氧化物化合物，包括式（a）化合物，并且包括其互变异构体，溶剂化物，前药，酯和氘代，以及所述化合物，互变异构体，溶剂合物，前药，酯， 氘代，其中R1，R2，R3，R4，R5，R9，环A，环B，环C，m，n，p，q，-L1-，-L2，L3-和L4- 独立选择和如本文所定义。 本发明的化合物令人惊奇地和有利地提高了溶液的稳定性。 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病在内的淀粉样蛋白β（Abeta）蛋白相关的病理学的方法。

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：US20140296222A1

公开(公告)日：2014-10-02

申请号：US14221644

申请日：2014-03-21

申请人： Jack D. Scott ,  Andrew W. Stamford ,  Eric J. Gilbert ,  Jared N. Cumming ,  Ulrich Iserloh

发明人： Jack D. Scott ,  Andrew W. Stamford ,  Eric J. Gilbert ,  Jared N. Cumming ,  Ulrich Iserloh

IPC分类号： C07D417/12 ,  C07C309/30

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): 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 Alzheimer's disease, are also disclosed.

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：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：US08691831B2

公开(公告)日：2014-04-08

申请号：US13416140

申请日：2012-03-09

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 ,  Xiaoxiang 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 ,  Xiaoxiang 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： A01N43/54 ,  A61K31/505

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 I 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.

摘要翻译： 公开了式I化合物或其立体异构体，互变异构体或其药学上可接受的盐或溶剂化物，其中式I中的每个变量如说明书中所定义; 以及包含式I化合物的药物组合物。还公开了抑制天冬氨酰蛋白酶的方法，特别是治疗心血管疾病，认知和神经退行性疾病的方法，以及抑制人类免疫缺陷病毒，plasmepins，组织蛋白酶D和 原生动物酶。 还公开了使用式I化合物与胆碱酯酶抑制剂或毒蕈碱m1激动剂或m2拮抗剂组合治疗认知或神经变性疾病的方法。

公开(公告)号：US08178513B2

公开(公告)日：2012-05-15

申请号：US12480391

申请日：2009-06-08

申请人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voigt ,  Corey O. Strickland ,  Elizabeth M. Smith ,  Andrew W. Stamford ,  William J. Greenlee ,  Robert D. Mazzola, Jr. ,  John 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

发明人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voigt ,  Corey O. Strickland ,  Elizabeth M. Smith ,  Andrew W. Stamford ,  William J. Greenlee ,  Robert D. Mazzola, Jr. ,  John 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

IPC分类号： A01N57/00 ,  A01N43/54 ,  A01N43/40 ,  A61K31/675 ,  A61K31/44 ,  A61K31/445 ,  C07D239/02 ,  C07D233/00 ,  C07D239/24 ,  C07D401/00

CPC分类号： C07D233/88 ,  A61K31/4168 ,  A61K31/4178 ,  A61K31/4184 ,  A61K31/4439 ,  A61K31/454 ,  A61K31/4545 ,  A61K31/4725 ,  A61K31/5377 ,  A61K31/655 ,  A61K45/06 ,  C07D233/46 ,  C07D233/70 ,  C07D235/02 ,  C07D239/22 ,  C07D239/70 ,  C07D271/07 ,  C07D273/00 ,  C07D295/15 ,  C07D401/04 ,  C07D401/06 ,  C07D401/08 ,  C07D401/10 ,  C07D401/12 ,  C07D401/14 ,  C07D403/04 ,  C07D403/06 ,  C07D403/08 ,  C07D403/10 ,  C07D403/12 ,  C07D405/06 ,  C07D405/10 ,  C07D405/14 ,  C07D407/06 ,  C07D409/04 ,  C07D409/06 ,  C07D409/10 ,  C07D409/14 ,  C07D413/10 ,  C07D413/12 ,  C07D417/06 ,  Y02A50/411

摘要： Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein W, U, X, R1, R2, R3, and R4 are as defined herein, and pharmaceutical compositions comprising the compounds of formula I. Also disclosed are methods of using such compounds to inhibit aspartyl protease and to treat a variety of disease or disorders, including cardiovascular diseases, cognitive and neurodegenerative diseases. 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 antagonist

摘要翻译： 公开了式I化合物或其立体异构体，互变异构体或其药学上可接受的盐或溶剂化物，其中W，U，X，R 1，R 2，R 3和R 4如本文所定义，并且药物组合物包含式I化合物 还公开了使用这些化合物抑制天冬氨酰蛋白酶和治疗各种疾病或病症（包括心血管疾病，认知和神经变性疾病）的方法。 还公开了使用式I化合物与胆碱酯酶抑制剂或毒蕈碱拮抗剂组合治疗认知或神经变性疾病的方法

公开(公告)号：US08691833B2

公开(公告)日：2014-04-08

申请号：US13415404

申请日：2012-03-08

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： A01N43/54 ,  A61K31/505 ,  C07D239/02

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.

摘要翻译： 公开了式I化合物或其立体异构体，互变异构体或其药学上可接受的盐或溶剂化物，其中式1中的每个变量如说明书中所定义; 以及包含式I化合物的药物组合物。还公开了抑制天冬氨酰蛋白酶的方法，特别是治疗心血管疾病，认知和神经退行性疾病的方法，以及抑制人类免疫缺陷病毒，plasmepins，组织蛋白酶D和 原生动物酶。 还公开了使用式I化合物与胆碱酯酶抑制剂或毒蕈碱m1激动剂或m2拮抗剂组合治疗认知或神经变性疾病的方法。

公开(公告)号：US20140057910A1

公开(公告)日：2014-02-27

申请号：US13402521

申请日：2012-02-22

申请人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voight ,  Corey Strickland ,  Elizabeth M. Smith ,  Andrew W. Stamford ,  William J. Greenlee ,  Robert Mazzola ,  John 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

发明人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voight ,  Corey Strickland ,  Elizabeth M. Smith ,  Andrew W. Stamford ,  William J. Greenlee ,  Robert Mazzola ,  John 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

IPC分类号： A61K31/5377 ,  A61K31/4168 ,  C07D405/06 ,  A61K31/4178 ,  C07D401/04 ,  A61K45/06 ,  A61K31/454 ,  C07D409/06 ,  C07D401/06 ,  C07D295/15 ,  A61K31/4184 ,  C07D233/88 ,  A61K31/4439

CPC分类号： C07D233/88 ,  A61K31/4168 ,  A61K31/4178 ,  A61K31/4184 ,  A61K31/4439 ,  A61K31/454 ,  A61K31/4545 ,  A61K31/4725 ,  A61K31/5377 ,  A61K31/655 ,  A61K45/06 ,  C07D233/46 ,  C07D233/70 ,  C07D235/02 ,  C07D239/22 ,  C07D239/70 ,  C07D271/07 ,  C07D273/00 ,  C07D295/15 ,  C07D401/04 ,  C07D401/06 ,  C07D401/08 ,  C07D401/10 ,  C07D401/12 ,  C07D401/14 ,  C07D403/04 ,  C07D403/06 ,  C07D403/08 ,  C07D403/10 ,  C07D403/12 ,  C07D405/06 ,  C07D405/10 ,  C07D405/14 ,  C07D407/06 ,  C07D409/04 ,  C07D409/06 ,  C07D409/10 ,  C07D409/14 ,  C07D413/10 ,  C07D413/12 ,  C07D417/06 ,  Y02A50/411

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 antagonist.

摘要翻译： 公开了式I化合物或其立体异构体，互变异构体或其药学上可接受的盐或溶剂化物，其中W为键，-C（= S） - ， - S（O） - ， - S（O） -C（= O） - ， - O - ， - C（R6）（R7） - ， - N（R5） - 或-C（= N（R5） X是-O - ， - N（R 5） - 或-C（R 6）（R 7） - ; 条件是当X是-O-时，U不是-O-，-S（O） - ， - S（O）2 - ， - C（= O） - 或-C（= NR5） - ; U是一个键，-S（O） - ， - S（O）2 - ， - C（O） - ， - O - ， - O（OR） （C（R6）（R7））b-或-N（R5） - ; 其中b为1或2; 条件是当W是-S（O） - ， - S（O）2 - ， - O-或-N（R 5） - 时，U不是-S（O） - ， - S（O） -O-或-N（R 5） - ; 条件是当X为-N（R5） - 且W为-S（O） - ， - S（O）2 - ， - O-或-N（R5） - 时，则U不为键; 并且R1，R2，R3，R4，R5，R6和R7如说明书中所定义; 以及包含式I化合物的药物组合物。还公开了抑制天冬氨酰蛋白酶的方法，特别是治疗心血管疾病，认知和神经变性疾病的方法以及抑制人类免疫缺陷病毒，plasmepins，组织蛋白酶D 和原生动物酶。 还公开了使用式I化合物与胆碱酯酶抑制剂或毒蕈碱拮抗剂组合来治疗认知或神经变性疾病的方法。