公开(公告)号：US09096582B2

公开(公告)日：2015-08-04

申请号：US14354992

申请日：2012-10-26

申请人： William Greenlee ,  Dmitri Pissarnitski ,  Zhiqiang Zhao ,  Zhaoning Zhu

发明人： William Greenlee ,  Dmitri Pissarnitski ,  Zhiqiang Zhao ,  Zhaoning Zhu

IPC分类号： C07D413/10

CPC分类号： C07D413/10 ,  C07D413/14

摘要： Disclosed herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein each of the substituents is given the definition as set forth in the specification and claims. Also disclosed are pharmaceutical compositions containing compounds of Formula (I) and use of the compounds in the treatment of neurodegenerative diseases or conditions such as Alzheimer's disease.

摘要翻译： 本文公开了式（I）的化合物及其药学上可接受的盐，其中每个取代基被给出如说明书和权利要求书中所阐述的定义。 还公开了含有式（I）化合物的药物组合物和该化合物在治疗神经变性疾病或病症如阿尔茨海默病中的用途。

公开(公告)号：US08450343B2

公开(公告)日：2013-05-28

申请号：US12746041

申请日：2008-12-04

申请人： Xianhai Huang ,  Anandan Palani ,  Jun Qin ,  Robert G. Aslanian ,  Zhaoning Zhu ,  William Greenlee ,  Hubert Josien ,  Wei Zhou ,  Xiaohong Zhu ,  Chad E. Bennett ,  Dmitri Pissarnitski ,  Mihirbaran Mandal ,  Pawan Dhondi ,  Troy McCracken ,  Thomas Bara ,  Zhiqiang Zhao ,  Duane Burnett ,  John Clader

发明人： Xianhai Huang ,  Anandan Palani ,  Jun Qin ,  Robert G. Aslanian ,  Zhaoning Zhu ,  William Greenlee ,  Hubert Josien ,  Wei Zhou ,  Xiaohong Zhu ,  Chad E. Bennett ,  Dmitri Pissarnitski ,  Mihirbaran Mandal ,  Pawan Dhondi ,  Troy McCracken ,  Thomas Bara ,  Zhiqiang Zhao ,  Duane Burnett ,  John Clader

IPC分类号： A01N43/42 ,  A61K31/44 ,  C07D471/02 ,  C07D491/02 ,  C07D498/02 ,  C07D513/02 ,  C07D515/02

CPC分类号： C07D471/04 ,  C07D403/10 ,  C07D487/04 ,  C07D498/04 ,  C07D513/04

摘要： This invention provides novel compounds that are modulators of gamma secretase. The compounds have the formula (I) wherein R2 is a fused bicyclic ring of the formula (II). Also disclosed are methods of modulating gamma secretase activity and methods of treating Alzheimer's disease using the compounds of formula (I).

摘要翻译： 本发明提供了作为γ分泌酶调节剂的新型化合物。 所述化合物具有式（I），其中R 2是式（II）的稠合双环。 还公开了使用式（I）的化合物调节γ-分泌酶活性和治疗阿尔茨海默病的方法的方法。

公开(公告)号：US20110015190A1

公开(公告)日：2011-01-20

申请号：US12746041

申请日：2008-12-04

申请人： Xianhai Huang ,  Anandan Palani ,  Jun Qin ,  Robert Aslanian ,  Zhaoning Zhu ,  William Greenlee ,  Hubert Josien ,  Wei Zhou ,  Xiaohong Zhou ,  Chad E. Bennett ,  Dmitri Pissarnitski ,  Mihirbaran Mandal ,  Pawan Dhondi ,  Troy McCracken ,  Thomas Bara ,  Zhiqiang Zhao ,  Duane Burnett ,  John Clader

发明人： Xianhai Huang ,  Anandan Palani ,  Jun Qin ,  Robert Aslanian ,  Zhaoning Zhu ,  William Greenlee ,  Hubert Josien ,  Wei Zhou ,  Xiaohong Zhou ,  Chad E. Bennett ,  Dmitri Pissarnitski ,  Mihirbaran Mandal ,  Pawan Dhondi ,  Troy McCracken ,  Thomas Bara ,  Zhiqiang Zhao ,  Duane Burnett ,  John Clader

IPC分类号： A61K31/5383 ,  C07D471/04 ,  A61K31/437 ,  C07D487/04 ,  A61K31/519 ,  A61K31/5377 ,  C07D498/04 ,  C07D403/02 ,  A61K31/4178 ,  A61P25/28

CPC分类号： C07D471/04 ,  C07D403/10 ,  C07D487/04 ,  C07D498/04 ,  C07D513/04

摘要： This invention provides novel compounds that are modulators of gamma secretase. The compounds have the formula (I) wherein R2 is a fused bicyclic ring of the formula (II). Also disclosed are methods of modulating gamma secretase activity and methods of treating Alzheimer's disease using the compounds of formula (I).

摘要翻译： 本发明提供了作为γ分泌酶调节剂的新型化合物。 所述化合物具有式（I），其中R 2是式（II）的稠合双环。 还公开了使用式（I）的化合物调节γ-分泌酶活性和治疗阿尔茨海默病的方法的方法。

公开(公告)号：US20080200445A1

公开(公告)日：2008-08-21

申请号：US11710582

申请日：2007-02-23

申请人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan Ye ,  Johannes Voigt ,  Corey Strickland ,  Elizabeth Smith ,  Andrew Stamford ,  William Greenlee ,  Robert Mazzola ,  John Caldwell ,  Jared Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Xiaoxiang Liu ,  Tao Guo ,  Thuy Le ,  Kurt Saionz ,  Suresh Babu ,  Rachael Hunter ,  Michelle Morris ,  Huizhong Gu ,  Gang Qian ,  Dawit Tadesse ,  Ying Huang ,  Guoqing Li ,  Jianping Pan ,  Jeffrey Misiaszek ,  Gaifa Lai ,  Jingqi Duo ,  Chuanxing Qu ,  Yuefei Shao

发明人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan Ye ,  Johannes Voigt ,  Corey Strickland ,  Elizabeth Smith ,  Andrew Stamford ,  William Greenlee ,  Robert Mazzola ,  John Caldwell ,  Jared Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Xiaoxiang Liu ,  Tao Guo ,  Thuy Le ,  Kurt Saionz ,  Suresh Babu ,  Rachael Hunter ,  Michelle Morris ,  Huizhong Gu ,  Gang Qian ,  Dawit Tadesse ,  Ying Huang ,  Guoqing Li ,  Jianping Pan ,  Jeffrey Misiaszek ,  Gaifa Lai ,  Jingqi Duo ,  Chuanxing Qu ,  Yuefei Shao

IPC分类号： A61K31/506 ,  A61K31/4178 ,  A61K31/4245 ,  A61K31/4439 ,  A61K31/454 ,  A61K31/541 ,  A61P31/00 ,  C07D233/02 ,  C07D271/00 ,  C07D413/14 ,  C07D409/14 ,  C07D409/04 ,  C07D403/06 ,  C07D401/14 ,  C07D401/12 ,  C07D401/10 ,  C07D401/06 ,  C07D239/04 ,  A61P9/00 ,  A61P25/00 ,  A61K31/5377 ,  A61K31/4545 ,  A61K31/4709 ,  A61K31/498

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 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 1. 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：US20060089351A1

公开(公告)日：2006-04-27

申请号：US11117584

申请日：2005-04-28

申请人： Zhaoning Zhu ,  Zhong-Yue Sun ,  Yuanzan Ye ,  Deborra Mullins ,  Brian McKitrtick ,  Andrew Stamford ,  William Greenlee

发明人： Zhaoning Zhu ,  Zhong-Yue Sun ,  Yuanzan Ye ,  Deborra Mullins ,  Brian McKitrtick ,  Andrew Stamford ,  William Greenlee

IPC分类号： A61K31/541 ,  A61K31/4709 ,  A61K31/506 ,  A61K31/4439 ,  A61K31/427 ,  C07D417/02

CPC分类号： C07D487/04 ,  C07D417/12 ,  C07D513/04

摘要： The present invention discloses compounds, which are novel receptor antagonists for NPY Y1 as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such NPY Y1 receptor antagonists as well as methods of using them to treat obesity, metabolic disorders, eating disorders such as hyperphagia, and diabetes. The compounds are represented by the structural Formula 1, a prodrug thereof, or any pharmaceutically acceptable salt, solvate, isomer or racemic mixture of the compound or said prodrug wherein R1 is heteroaryl, N-arylaminocarbonyl, N-heteroarylaminocarbonyl, benzimidazolyl or benzothiazolyl; R15 is present or not and if present is H, aryl, alkyl, arylalky or heteroarylalkyl; A is aryl, heteroaryl, cycloalkyl, cycloalkylidene, heterocycloalkylidene or heterocycloalkyl wherein said aryl, heteroaryl, cycloalkyl, cycloalkylidene, heterocycloalkylidene and heterocycloalkyl moieties may be substituted or unsubstituted; and B, L, X and R18 are defined herein.

摘要翻译： 本发明公开了作为NPY Y1的新受体拮抗剂的化合物以及这些化合物的制备方法。 在另一个实施方案中，本发明公开了包含这种NPY Y1受体拮抗剂的药物组合物以及使用它们治疗肥胖，代谢紊乱，进食障碍如食欲过盛和糖尿病的方法。 化合物由结构式1表示，其前体药物或化合物或所述前体药物的任何药学上可接受的盐，溶剂合物，异构体或外消旋混合物，其中R 1是杂芳基，N-芳基氨基羰基，N - 杂芳基氨基羰基，苯并咪唑基或苯并噻唑基; R 15存在或不存在，如果存在，则为H，芳基，烷基，芳基烷基或杂芳基烷基; A是芳基，杂芳基，环烷基，环烷叉基，杂环亚烷基或杂环烷基，其中所述芳基，杂芳基，环烷基，亚环烷基，杂环亚烷基和杂环烷基部分可以是取代或未取代的; 和B，L，X和R 18在本文中定义。

公开(公告)号：US20100298359A1

公开(公告)日：2010-11-25

申请号：US12746313

申请日：2008-12-04

申请人： Xianhai Huang ,  Anandan Palani ,  Jun Qin ,  Robert Aslanian ,  Zhaoning Zhu ,  William Greenlee

发明人： Xianhai Huang ,  Anandan Palani ,  Jun Qin ,  Robert Aslanian ,  Zhaoning Zhu ,  William Greenlee

IPC分类号： A61K31/517 ,  C07D401/10 ,  A61K31/4725 ,  A61P29/00 ,  A61K39/395 ,  A61P25/28 ,  C07D403/10

CPC分类号： C07D471/04 ,  C07D401/10 ,  C07D403/10 ,  C07D491/04 ,  C07D498/04

摘要： This invention provides novel compounds that are modulators of gamma secretase. The compounds have the formula (I) wherein R2 is a fused bicyclic ring of the formula (II). Also disclosed are methods of modulating gamma secretase activity and methods of treating Alzheimer's disease using the compounds of formula (I).

摘要翻译： 本发明提供了作为γ分泌酶调节剂的新型化合物。 所述化合物具有式（I），其中R 2是式（II）的稠合双环。 还公开了使用式（I）的化合物调节γ-分泌酶活性和治疗阿尔茨海默病的方法的方法。

公开(公告)号：US20070072852A1

公开(公告)日：2007-03-29

申请号：US11010772

申请日：2004-12-13

申请人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan Ye ,  Johannes Voigt ,  Corey Strickland ,  Elizabeth Smith ,  Andrew Stamford ,  William Greenlee ,  Robert Mazzola ,  John Caldwell ,  Jared Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Tao Guo ,  Thuy Le ,  Kurt Saionz ,  Suresh Babu ,  Rachael Hunter

发明人： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan Ye ,  Johannes Voigt ,  Corey Strickland ,  Elizabeth Smith ,  Andrew Stamford ,  William Greenlee ,  Robert Mazzola ,  John Caldwell ,  Jared Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Tao Guo ,  Thuy Le ,  Kurt Saionz ,  Suresh Babu ,  Rachael Hunter

IPC分类号： A61K31/549 ,  A61K31/5395 ,  A61K31/513

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.

公开(公告)号：US20070060575A1

公开(公告)日：2007-03-15

申请号：US11451541

申请日：2006-06-12

申请人： Zhaoning Zhu ,  Brian McKittrick ,  Andrew Stamford ,  William Greenlee ,  Xiaoxiang Liu ,  Mihirbaran Mandal ,  Johannes Voigt ,  Corey Strickland

发明人： Zhaoning Zhu ,  Brian McKittrick ,  Andrew Stamford ,  William Greenlee ,  Xiaoxiang Liu ,  Mihirbaran Mandal ,  Johannes Voigt ,  Corey Strickland

IPC分类号： A61K31/5513 ,  A61K31/53 ,  A61K31/519 ,  C07D487/02

CPC分类号： C07D487/04

摘要： Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein j, k, U, W, R, R1, R2, R3, R4, R6, R7 and R7a are as described above in the specification. Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating 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 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j，k，U，W，R，R 1，R 2， R 3，R 4，R 4，R 6，R 7和R 7a， >如说明书中所述。 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。 还公开了使用式I化合物与胆碱酯酶抑制剂或毒蕈碱m 1激动剂或m 2 H 2拮抗剂组合治疗认知或神经变性疾病的方法。

公开(公告)号：US20050075325A1

公开(公告)日：2005-04-07

申请号：US10850530

申请日：2004-05-20

申请人： Duane Burnett ,  William Greenlee ,  Brian McKirtrick ,  Jing Su ,  Zhaoning Zhu ,  Thavalakulamgara Sasikumar ,  Robert Mazzola ,  Li Qiang ,  Yuanzan Ye

发明人： Duane Burnett ,  William Greenlee ,  Brian McKirtrick ,  Jing Su ,  Zhaoning Zhu ,  Thavalakulamgara Sasikumar ,  Robert Mazzola ,  Li Qiang ,  Yuanzan Ye

IPC分类号： C07D223/14 ,  C07D401/12 ,  C07D403/10 ,  C07D407/12 ,  A61K31/55 ,  C07D43/02

CPC分类号： C07D223/14

摘要： The present invention provides compounds, which, are novel antagonists for D1/D5 receptors as well as methods for preparing such compounds. In another embodiment, the invention provides pharmaceutical compositions comprising such D1/D5 receptor antagonists as well as methods of using them to treat CNS disorders, obesity, metabolic disorders, eating disorders such as hyperphagia, and diabetes.

摘要翻译： 本发明提供了作为D1 / D5受体的新型拮抗剂的化合物以及制备这些化合物的方法。 在另一个实施方案中，本发明提供包含这种D1 / D5受体拮抗剂的药物组合物以及使用它们治疗CNS障碍，肥胖，代谢紊乱，进食障碍如食欲过盛和糖尿病的方法。

公开(公告)号：US20140206715A1

公开(公告)日：2014-07-24

申请号：US14226338

申请日：2014-03-26

申请人： Andrew W. Stamford ,  Guoqing Li ,  William Greenlee ,  Zhaoning Zhu ,  Brian McKittrick ,  Robert Mazzola ,  Ying Huang ,  Tao Guo ,  Thuy X.E. Le ,  Gang Qian ,  Yuefei Shao

发明人： Andrew W. Stamford ,  Guoqing Li ,  William Greenlee ,  Zhaoning Zhu ,  Brian McKittrick ,  Robert Mazzola ,  Ying Huang ,  Tao Guo ,  Thuy X.E. Le ,  Gang Qian ,  Yuefei Shao

IPC分类号： C07D471/04

CPC分类号： C07D471/04 ,  C07D209/44 ,  C07D487/04

摘要： Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein Q is a bond or —N(R5)—; T is a bond, —O—, —C(O)—; S, —N(R5)—, or —C(R6′R7′); U is a bond or —C(R6)(R7)— Y is C or N; Z is C or N; ring A, including variables Y and Z, is a three to nine membered cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl ring having 0 to 4, preferably 0 to 2, heteroatoms independently selected from the group consisting of O, S, N and —N(R)—, wherein ring A is unsubstituted or substituted with 1 to 5 independently selected R1 moieties and/or oxo when ring A is cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl; and R, R1, R2, R3, R4, R5, R6, R6, R7 and R7′ are as defined in the specification; pharmaceutical compositions comprising the compounds of formula I and the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases.

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合物，其中Q是键或-N（R 5） - ; T是键，-O - ， - C（O） - ; S，-N（R 5） - 或-C（R 6'R 7'）; U是键或-C（R6）（R7）-Y是C或N; Z是C或N; 环A包括变量Y和Z是具有0至4个，优选0至2个杂原子的3至9元环烷基，环烯基，杂环基，杂环烯基，芳基和杂芳基环，其独立地选自O，S， N和-N（R） - ，其中当环A是环烷基，环烯基，杂环基或杂环烯基时，环A是未取代的或被1至5个独立选择的R 1部分和/或氧代取代。 并且R，R 1，R 2，R 3，R 4，R 5，R 6，R 6，R 7和R 7'如本说明书中所定义; 包含式I化合物的药物组合物和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。