公开(公告)号：US10723717B2

公开(公告)日：2020-07-28

申请号：US15853166

申请日：2017-12-22

申请人： Arvinas, Inc. ,  Yale University

发明人： Andrew P. Crew ,  Keith R. Hornberger ,  Jing Wang ,  Hanqing Dong ,  Yimin Qian ,  Craig M. Crews ,  Saul Jaime-Figueroa

IPC分类号： C07D519/00 ,  C07D401/14 ,  C07D401/04 ,  A61K31/4439 ,  C07D417/14 ,  A61K31/4545 ,  C07D487/04 ,  A61P9/00 ,  C07D471/04 ,  A61K31/437 ,  A61K45/06 ,  A61P35/00 ,  A61P43/00 ,  A61P25/00 ,  A61K31/4188 ,  A61K47/54 ,  A61K47/55

摘要： The present disclosure relates to bifunctional compounds, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A-RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.

公开(公告)号：US20180155322A1

公开(公告)日：2018-06-07

申请号：US15829541

申请日：2017-12-01

申请人： Arvinas, Inc.

发明人： Andrew P. Crew ,  Yimin Qian ,  Hanqing Dong ,  Jing Wang ,  Keith R. Hornberger ,  Craig M. Crews

IPC分类号： C07D401/14 ,  C07K5/083 ,  A61K38/06 ,  C07D401/04 ,  C07D487/08 ,  A61K31/4725 ,  A61K31/454 ,  C07D487/10 ,  A61K31/4545 ,  A61K31/551 ,  A61K31/497 ,  C07D498/10 ,  A61K31/5386 ,  A61K31/501 ,  C07D471/04 ,  C07D471/10 ,  C07D487/04 ,  A61K31/519 ,  A61K45/06 ,  A61K31/496 ,  C07K5/078 ,  A61K38/05 ,  A61P35/00 ,  A61P15/00

CPC分类号： C07D401/14 ,  A61K31/454 ,  A61K31/4545 ,  A61K31/4725 ,  A61K31/496 ,  A61K31/497 ,  A61K31/501 ,  A61K31/519 ,  A61K31/5386 ,  A61K31/551 ,  A61K38/05 ,  A61K38/06 ,  A61K45/06 ,  A61K47/54 ,  A61K47/545 ,  A61P15/00 ,  A61P35/00 ,  C07D401/04 ,  C07D471/04 ,  C07D471/10 ,  C07D487/04 ,  C07D487/08 ,  C07D487/10 ,  C07D498/10 ,  C07K5/06034 ,  C07K5/06165 ,  C07K5/0806

摘要： The present disclosure relates to bifunctional compounds, which find utility as modulators of estrogen receptor (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end at least one of a Von Hippel-Lindau ligand, a cereblon ligand, Inhibitors of Apoptosis Proteins ligand, mouse double-minute homolog 2 ligand, or a combination thereof, which binds to the respective E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

公开(公告)号：US20180147202A1

公开(公告)日：2018-05-31

申请号：US15574770

申请日：2016-06-06

申请人： Arvinas, Inc.

发明人： Andrew P. Crew ,  Jing Wang ,  Hanqing Dong ,  Yimin Qian ,  Craig M Crews

IPC分类号： A61K31/506 ,  C07K5/062 ,  C07D417/04 ,  A61K47/66 ,  C07D413/04 ,  A61K45/06

CPC分类号： A61K31/506 ,  A61K45/06 ,  A61K47/665 ,  A61K2300/00 ,  C07D413/04 ,  C07D417/04 ,  C07K5/06034

摘要： The present invention relates to bifunctional compounds, which find utility to degrade and (inhibit) TBK 1. In particular, the present invention is directed to compounds, which contain on one end an E3 ubiquitin ligase binding moiety which binds to an E3 ubiquitin ligase and on the other end a moiety which binds TBK1 such that TBK1 is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of TBK1. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of TBK1.

公开(公告)号：US20180099940A1

公开(公告)日：2018-04-12

申请号：US15730728

申请日：2017-10-11

申请人： Arvinas, Inc.

发明人： Andrew P. Crew ,  Keith R. Hornberger ,  Lawrence B. Snyder ,  Kurt Zimmermann ,  Jing Wang ,  Michael Berlin ,  Craig M. Crews ,  Hanqing Dong

IPC分类号： C07D233/42 ,  C07D209/48 ,  C07D211/76 ,  C07D241/04 ,  C07D231/12 ,  C07D213/72 ,  C07D205/04 ,  C07D237/08 ,  C07D239/24 ,  C07D221/20 ,  A61K31/277 ,  A61K47/10 ,  A61K31/02 ,  A61K31/497 ,  A61K31/166

摘要： The present disclosure relates to bifunctional compounds, which find utility to degrade and (inhibit) Androgen Receptor. In particular, the present disclosure is directed to compounds, which contain on one end a cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds Androgen Receptor, such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present disclosure exhibits a broad range of pharmacological activities associated with compounds according to the present disclosure, consistent with the degradation/inhibition of Androgen Receptor.

公开(公告)号：US20180237418A1

公开(公告)日：2018-08-23

申请号：US15881318

申请日：2018-01-26

申请人： Arvinas, Inc.

发明人： Andrew P. Crew ,  Keith R. Hornberger ,  Hanqing Dong ,  Jing Wang ,  Yimin Qian ,  Craig M. Crews

IPC分类号： C07D401/14 ,  C07D471/04 ,  C07D409/12 ,  C07D403/06 ,  C07D403/14 ,  C07D405/14 ,  C07D413/14 ,  C07D417/12 ,  C07D417/14 ,  A61P35/00

CPC分类号： C07D401/14 ,  A61P35/00 ,  C07D403/06 ,  C07D403/14 ,  C07D405/14 ,  C07D409/12 ,  C07D413/14 ,  C07D417/12 ,  C07D417/14 ,  C07D471/04

摘要： The present disclosure relates to bifunctional compounds, which find utility as modulators of estrogen receptor (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a cereblon, Von Hippel-Lindau ligase-binding moiety, Inhibitors of Apotosis Proteins, or mouse double-minute homolog 2 ligand, which binds to the respective E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

公开(公告)号：US20180193470A1

公开(公告)日：2018-07-12

申请号：US15852854

申请日：2017-12-22

申请人： Arvinas, Inc. ,  Yale University

发明人： Andrew P. Crew ,  Kurt Zimmermann ,  Jing Wang ,  Michael Berlin ,  Hanqing Dong ,  Alexey Ishchenko ,  Yimin Qian ,  Craig M. Crews ,  Saul Jaime-Figueroa ,  George Burslem

IPC分类号： A61K47/54 ,  A61K47/55 ,  A61K31/519 ,  A61K31/427 ,  A61K31/454 ,  A61K31/517 ,  A61K31/506 ,  A61K31/496 ,  A61K31/551 ,  A61K45/06 ,  A61K38/07 ,  A61K31/52 ,  A61K31/55

摘要： The present disclosure relates to bifunctional compounds, which find utility as modulators of receptor tyrosine kinase (RTK) proteins. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand which binds to an E3 ubiquitin ligase and on the other end a moiety which binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effectuate ubiquitination, and therefore, degradation (and inhibition) of the target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

公开(公告)号：US20170327469A1

公开(公告)日：2017-11-16

申请号：US15663273

申请日：2017-07-28

申请人： Arvinas, Inc.

发明人： Andrew P. Crew ,  Hanqing Dong ,  Jing Wang ,  Caterina Ferraro ,  Xin Chen ,  Yimin Qian

IPC分类号： C07D233/86 ,  C07D471/10 ,  C07D401/08 ,  C07D401/04 ,  C07D241/28 ,  C07D239/42 ,  C07D237/24 ,  C07D235/02 ,  C07D231/14 ,  C07D213/82 ,  C07C271/24 ,  C07C255/54 ,  A61K45/06 ,  A61K31/454 ,  A61K31/4439 ,  A61K31/435 ,  A61K31/4188 ,  A61K31/4184 ,  A61K31/4166 ,  A61K31/277 ,  A61K47/54 ,  C07D491/107 ,  C07C2601/04

CPC分类号： C07D233/86 ,  A61K31/277 ,  A61K31/4166 ,  A61K31/4184 ,  A61K31/4188 ,  A61K31/435 ,  A61K31/4439 ,  A61K31/454 ,  A61K45/06 ,  A61K47/545 ,  C07C255/54 ,  C07C271/24 ,  C07C2601/04 ,  C07D213/82 ,  C07D231/14 ,  C07D235/02 ,  C07D237/24 ,  C07D239/42 ,  C07D241/28 ,  C07D401/04 ,  C07D401/08 ,  C07D413/12 ,  C07D413/14 ,  C07D417/12 ,  C07D417/14 ,  C07D471/10 ,  C07D491/107

摘要： The present disclosure relates to bifunctional compounds, which find utility to degrade (and inhibit) Androgen Receptor. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds Androgen Receptor such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of Androgen Receptor.

公开(公告)号：US10772962B2

公开(公告)日：2020-09-15

申请号：US15230354

申请日：2016-08-05

申请人： Arvinas, Inc. ,  Yale University

发明人： Yimin Qian ,  Hanqing Dong ,  Jing Wang ,  Michael Berlin ,  Andrew P. Crew ,  Craig M. Crews

IPC分类号： C07D521/00 ,  A61K45/06 ,  C07D519/00 ,  C07D417/14 ,  C07D495/14 ,  A61K47/55

摘要： The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.

公开(公告)号：US20180353501A1

公开(公告)日：2018-12-13

申请号：US15996151

申请日：2018-06-01

申请人： Arvinas, Inc. ,  Yale University

发明人： Andrew P. Crew ,  Hanqing Dong ,  Jing Wang ,  Craig M. Crews ,  Saul Jaime-Figueroa

IPC分类号： A61K31/47 ,  A61K45/06 ,  A61K47/54 ,  A61K31/427 ,  A61K31/454 ,  A61K31/5025 ,  A61K47/60

CPC分类号： A61K31/47 ,  A61K31/427 ,  A61K31/454 ,  A61K31/5025 ,  A61K45/06 ,  A61K47/54 ,  A61K47/60

摘要： The present disclosure relates to bifunctional compounds, which find utility as modulators of c-Met and/or p38 (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

公开(公告)号：US20180228907A1

公开(公告)日：2018-08-16

申请号：US15953108

申请日：2018-04-13

申请人： Arvinas, Inc.

发明人： Andrew P. Crew ,  Craig M. Crews ,  Hanqing Dong ,  Keith R. Hornberger ,  Jing Wang ,  Yimin Qian ,  Kurt Zimmermann ,  Michael Berlin ,  Lawrence B. Snyder

IPC分类号： A61K47/55 ,  C07D401/04 ,  C07D401/14 ,  C07D471/04 ,  A61K31/437 ,  A61K31/496 ,  A61K31/551 ,  A61K45/06 ,  A61K31/501 ,  A61K31/506 ,  A61K31/497

CPC分类号： A61K47/55 ,  A61K31/437 ,  A61K31/496 ,  A61K31/497 ,  A61K31/501 ,  A61K31/506 ,  A61K31/551 ,  A61K45/06 ,  A61K47/545 ,  A61P35/00 ,  C07D401/04 ,  C07D401/14 ,  C07D471/04

摘要： The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.