公开(公告)号：US09108955B2

公开(公告)日：2015-08-18

申请号：US14152703

申请日：2014-01-10

申请人： President and Fellows of Harvard College ,  Tufts University ,  THE BRIGHAM AND WOMEN'S HOSPITAL, INC. ,  TRUSTEES OF BOSTON UNIVERSITY

发明人： Gregory D. Cuny ,  Xin Teng ,  Junying Yuan ,  Alexei Degterev ,  John A. Porco, Jr.

IPC分类号： C07D285/06 ,  C07D417/12 ,  C07D207/34 ,  C07D241/24 ,  C07D263/34 ,  C07D277/56 ,  C07D307/84 ,  C07D333/38 ,  C07D231/14 ,  C07D307/68

CPC分类号： C07D417/12 ,  C07D207/34 ,  C07D231/14 ,  C07D241/24 ,  C07D263/34 ,  C07D277/56 ,  C07D285/06 ,  C07D307/68 ,  C07D307/84 ,  C07D333/38

摘要： The invention features a series of heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-α) induced necroptosis. The heterocyclic compounds of the invention are described by Formulas (I) and (Ia)-(Ie) and are shown to inhibit TNF-α induced necroptosis in FADD-deficient variant of human Jurkat T cells. The invention further features pharmaceutical compositions featuring the compounds of the invention. The compounds and compositions of the invention may also be used to treat disorders where necroptosis is likely to play a substantial role.

摘要翻译： 本发明具有一系列抑制肿瘤坏死因子α（TNF-α）诱导的人工坏死的杂环衍生物。 本发明的杂环化合物由式（I）和（Ia） - （Ie）描述，并且显示出抑制人Jurkat T细胞的FADD缺陷型变体中的TNF-α诱导的人工死亡。 本发明还涉及以本发明化合物为特征的药物组合物。 本发明的化合物和组合物也可以用于治疗棘球菌根可能起重要作用的病症。

公开(公告)号：US20140128437A1

公开(公告)日：2014-05-08

申请号：US14152703

申请日：2014-01-10

申请人： President and Fellows of Harvard College ,  TRUSTEES OF BOSTON UNIVERSITY ,  THE BRIGHAM AND WOMEN'S HOSPITAL, INC. ,  Tufts University

发明人： Gregory D. Cuny ,  Xin Teng ,  Junying Yuan ,  Alexei Degterrev ,  John A. Proco, JR.

IPC分类号： C07D333/38 ,  C07D207/34 ,  C07D307/68 ,  C07D263/34 ,  C07D231/14 ,  C07D285/06 ,  C07D277/56

CPC分类号： C07D417/12 ,  C07D207/34 ,  C07D231/14 ,  C07D241/24 ,  C07D263/34 ,  C07D277/56 ,  C07D285/06 ,  C07D307/68 ,  C07D307/84 ,  C07D333/38

摘要： The invention features a series of heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-α) induced necroptosis. The heterocyclic compounds of the invention are described by Formulas (I) and (Ia)-(Ie) and are shown to inhibit TNF-α induced necroptosis in FADD-deficient variant of human Jurkat T cells. The invention further features pharmaceutical compositions featuring the compounds of the invention. The compounds and compositions of the invention may also be used to treat disorders where necroptosis is likely to play a substantial role.

摘要翻译： 本发明具有一系列抑制肿瘤坏死因子α（TNF-α）诱导的人工坏死的杂环衍生物。 本发明的杂环化合物由式（I）和（Ia） - （Ie）描述，并且显示出抑制人Jurkat T细胞的FADD缺陷型变体中的TNF-α诱导的人工死亡。 本发明还涉及以本发明化合物为特征的药物组合物。 本发明的化合物和组合物也可以用于治疗棘球菌根可能起重要作用的病症。

公开(公告)号：US09725452B2

公开(公告)日：2017-08-08

申请号：US14214360

申请日：2014-03-14

申请人： President and Fellows of Harvard College ,  Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences ,  Tufts University ,  University of Houston

发明人： Junying Yuan ,  Alexei Degterev ,  Gregory D. Cuny

IPC分类号： A61K31/4025 ,  A61K31/404 ,  C07D207/30 ,  C07D209/04 ,  C07D487/04 ,  C07D401/14 ,  C07D471/04

CPC分类号： C07D487/04 ,  C07D401/14 ,  C07D471/04

摘要： The present invention relates to heterocyclic compounds (e.g., compounds described by Formula (I)) and pharmaceutically acceptable salts thereof. The invention also features pharmaceutical compositions that include these compounds and their use in therapy for treating conditions in which necroptosis is likely to play a substantial role. The heterocyclic compounds described herein can also achieve improved activity and selectivity towards RIP1 and/or RIP3.

公开(公告)号：US20230219898A1

公开(公告)日：2023-07-13

申请号：US18010642

申请日：2021-06-16

申请人： President and Fellows of Harvard College

发明人： Junying Yuan ,  Heng Zhao ,  Daichao Xu ,  Mingzhi Jin ,  Hong Zhu ,  Gregory D. Cuny

IPC分类号： C07D233/42 ,  C07D233/26 ,  C07C335/32 ,  C07D401/12 ,  C07D295/195 ,  C07D207/08 ,  A61K31/4178 ,  A61K31/4184

CPC分类号： C07D233/42 ,  C07D233/26 ,  C07C335/32 ,  C07D401/12 ,  C07D295/195 ,  C07D207/08 ,  A61K31/4178 ,  A61K31/4184

摘要： Disclosed herein are small molecules that inhibit apoptosis and promote autophagy through the TRADD pathway, and their use for treatment of neurodegenerative diseases. Methods of preparing these small molecules and medicinal efficacy are described.

公开(公告)号：US20170088515A1

公开(公告)日：2017-03-30

申请号：US15144323

申请日：2016-05-02

申请人： AQUINNAH PHARMACEUTICALS, INC. ,  THE BRIGHAM AND WOMEN'S HOSPITAL, INC.

发明人： Benjamin Wolozin ,  Marcie Glicksman ,  Gregory D. Cuny ,  Justin Boyd

IPC分类号： C07D207/36 ,  C07D401/12 ,  C07D211/34 ,  C07D487/04 ,  C07D215/36 ,  G01N33/50 ,  C07D211/26 ,  C07D211/52 ,  C07D239/94 ,  C07D215/227 ,  C07D403/06 ,  C07D417/04 ,  C07D239/52

CPC分类号： C07D207/36 ,  A61K31/365 ,  A61K31/4025 ,  A61K31/445 ,  A61K31/454 ,  A61K31/4545 ,  A61K31/47 ,  A61K31/505 ,  A61K31/517 ,  A61K31/519 ,  A61K31/551 ,  A61K31/704 ,  C07D211/26 ,  C07D211/34 ,  C07D211/52 ,  C07D215/227 ,  C07D215/36 ,  C07D239/52 ,  C07D239/94 ,  C07D401/04 ,  C07D401/12 ,  C07D403/06 ,  C07D417/04 ,  C07D487/04 ,  G01N33/5058

摘要： Herein, compounds and compositions for use in treating diseases relating to inclusion formation and stress granules are described. Methods for screening for modulation of TDP-43 aggregation are also described.

公开(公告)号：US20160046633A1

公开(公告)日：2016-02-18

申请号：US14776302

申请日：2014-03-13

申请人： THE BRIGHAM AND WOMEN'S HOSPITAL, INC. ,  THE U.S.A., AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH & HUMAN SERVICES

发明人： Asaf Alimardanov ,  Gregory D. Cuny ,  Gurmit Singh Grewal ,  Arthur Lee ,  John C. McKew ,  Agustin H. Mohedas ,  Min Shen ,  Xin Xu ,  Paul B. Yu

IPC分类号： C07D487/04 ,  C07D519/00

CPC分类号： C07D487/04 ,  C07D519/00

摘要： The present invention provides small molecule inhibitors of BMP signaling. These compounds may be used to modulate cell growth, differentiation, proliferation, and apoptosis, and thus may be useful for treating diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders, as well as for modulating cellular differentiation and/or proliferation. These compounds may also be used to reduce circulating levels of ApoB-100 or LDL and treat or prevent acquired or congenital hypercholesterolemia or hyperlipoproteinemia; diseases, disorders, or syndromes associated with defects in lipid absorption or metabolism; or diseases, disorders, or syndromes caused by hyperlipidemia.

公开(公告)号：US09187421B2

公开(公告)日：2015-11-17

申请号：US14281149

申请日：2014-05-19

申请人： THE GENERAL HOSPITAL CORPORATION ,  THE BRIGHAM AND WOMEN'S HOSPITAL, INC.

发明人： Douglas E. Raines ,  Joseph F. Cotten ,  Stuart A. Forman ,  Keith W. Miller ,  Syed S. Husain ,  Gregory D. Cuny

IPC分类号： A61K31/40 ,  C07D207/34

CPC分类号： C07D207/34 ,  A61K31/40

摘要： The invention is directed to compounds according to formula (I): where R1 is L1C(O)OT or L1C(O)OL2C(O)OT; R2 is a substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl, or R1; n is an integer from 0 to 5; each R3 is independently halogen or R2; R4 and R5 are independently H, halogen, CN or CF3; L1 and L2 are each independently a bond, a substituted or unsubstituted C1-C10 alkylene, C2-C10 alkenylene, or C2-C10 alkynylene; and T is H, a substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl, nitrophenol, or cyclopropyl. The invention is also directed to a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier, and to methods for providing anesthesia in mammals by administering such a pharmaceutical composition.

摘要翻译： 本发明涉及式（I）化合物：其中R1是L1C（O）OT或L1C（O）OL2C（O）OT; R2是取代或未取代的C1-C10烷基，C2-C10烯基或C2-C10炔基，或R1; n为0〜5的整数， 每个R 3独立地是卤素或R 2; R4和R5独立地为H，卤素，CN或CF3; L1和L2各自独立地为键，取代或未取代的C1-C10亚烷基，C2-C10亚烯基或C2-C10亚炔基; 和T是H，取代或未取代的C 1 -C 10烷基，C 2 -C 10烯基或C 2 -C 10炔基，硝基苯酚或环丙基。 本发明还涉及包含根据式（I）的化合物和药学上可接受的载体的药物组合物，以及通过施用这种药物组合物在哺乳动物中提供麻醉的方法。

公开(公告)号：US10017516B2

公开(公告)日：2018-07-10

申请号：US15598540

申请日：2017-05-18

申请人： The Brigham and Women's Hospital, Inc. ,  The United States of America, as represented by the Secretary, Department of Health and Human Services, National Institute of Health

发明人： Asaf Alimardanov ,  Gregory D. Cuny ,  Gurmit S. Grewal ,  Arthur Lee ,  John C. McKew ,  Agustin H. Mohedas ,  Min Shen ,  Xin Xu ,  Paul B. Yu

IPC分类号： C07D487/04 ,  C07D519/00

CPC分类号： C07D487/04 ,  C07D519/00

摘要： The present invention provides small molecule inhibitors of BMP signaling. These compounds may be used to modulate cell growth, differentiation, proliferation, and apoptosis, and thus may be useful for treating diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders, as well as for modulating cellular differentiation and/or proliferation. These compounds may also be used to reduce circulating levels of ApoB-100 or LDL and treat or prevent acquired or congenital hypercholesterolemia or hyperlipoproteinemia; diseases, disorders, or syndromes associated with defects in lipid absorption or metabolism; or diseases, disorders, or syndromes caused by hyperlipidemia.

公开(公告)号：US10125116B2

公开(公告)日：2018-11-13

申请号：US14571673

申请日：2014-12-16

申请人： Brandeis University ,  University of Georgia Research Foundation, Inc. ,  The Brigham and Women's Hospital, Inc.

发明人： Lizbeth K. Hedstrom ,  Gregory D. Cuny ,  Deviprasad R. Gollapalli ,  Sivapriya Kirubakaran ,  Sushil K. Maurya ,  Boris Striepen ,  Suresh K. Gorla ,  Corey R. Johnson ,  Mandapati Kavitha ,  Jihan Khan

IPC分类号： C07D401/12 ,  C07C233/15 ,  C07C235/24 ,  C07C235/38 ,  C07C237/20 ,  C07C255/60 ,  C07C275/28 ,  C07C275/30 ,  C07C275/42 ,  C07C309/15 ,  C07D209/08 ,  C07D209/12 ,  C07D209/30 ,  C07D215/38 ,  C07D235/26 ,  C07D237/32 ,  C07D263/56 ,  C07D263/57 ,  C07D295/192 ,  C07D401/04 ,  C07D401/14 ,  C07D409/04 ,  C07D413/04 ,  C07D417/04 ,  C07D417/14 ,  C07D471/08 ,  C07D491/052 ,  C07D249/06

摘要： Described herein are compounds, and pharmaceutically acceptable salts and prodrugs thereof, which are useful as inhibitors of IMPDH. In certain embodiments, a compound of the invention selectively inhibits a parasitic IMPDH versus a host IMPDH. Further, the invention provides pharmaceutical compositions comprising one or more compounds of the invention. The invention also relates to methods of treating various parasitic and bacterial infections in mammals. Moreover, the compounds may be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, anti-inflammatory agents, antimicrobials and immunosuppressants.

公开(公告)号：US09045484B2

公开(公告)日：2015-06-02

申请号：US13940641

申请日：2013-07-12

申请人： The Brigham and Women's Hospital, Inc. ,  The General Hospital Corporation

发明人： Paul B. Yu ,  Gregory D. Cuny ,  Kenneth D. Bloch ,  Randall T. Peterson ,  Charles C. Hong

IPC分类号： A01N43/90 ,  A61K31/519 ,  C07D487/00 ,  C07D487/04

CPC分类号： C07D487/04 ,  A61K31/519

摘要： The present invention provides pyridinyl-substituted pyrazolyl pyrimidine small molecule inhibitors of bone morphogenetic protein (BMP) signaling having the structure of formula (I), wherein variables A, B, E, F, X, Y, Z, Ar, L1, R4 and R15 are as defined in the specification. The compounds of the invention are useful in modulating cell growth, differentiation, proliferation, and apoptosis, and thus are useful for treating diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders, as well as for modulating cellular differentiation and/or proliferation.

摘要翻译： 本发明提供具有式（I）结构的吡啶基取代的吡唑基嘧啶小分子抑制剂骨形态发生蛋白（BMP）信号转导酶，其中变量A，B，E，F，X，Y，Z，Ar，L1，R4 和R 15如说明书中所定义。 本发明的化合物可用于调节细胞生长，分化，增殖和凋亡，因此可用于治疗与BMP信号相关的疾病或病症，包括炎症，心血管疾病，血液病，癌症和骨骼疾病 用于调节细胞分化和/或增殖。