公开(公告)号：US11986531B2

公开(公告)日：2024-05-21

申请号：US17387621

申请日：2021-07-28

申请人： ARVINAS OPERATIONS, INC. ,  YALE UNIVERSITY

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

IPC分类号： C07D401/14 ,  A61K31/437 ,  A61K47/55 ,  A61P35/00 ,  C07D413/14 ,  C07D417/14 ,  C07D471/04 ,  C07D519/00

CPC分类号： A61K47/55 ,  C07D413/14 ,  C07D417/14 ,  C07D471/04 ,  C07D519/00

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：US20230000994A1

公开(公告)日：2023-01-05

申请号：US17387621

申请日：2021-07-28

申请人： ARVINAS OPERATIONS, INC. ,  YALE UNIVERSITY

发明人： Andrew P. Crew ,  Keith R. Hornberger ,  Jing Wang ,  Saul Jaime-Figueroa ,  Hanqing Dong ,  Lawrence B. Snyder

IPC分类号： A61K47/55 ,  C07D471/04 ,  C07D519/00 ,  C07D417/14 ,  C07D413/14

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：US10994015B2

公开(公告)日：2021-05-04

申请号：US15852854

申请日：2017-12-22

申请人： Arvinas Operations, Inc. ,  Yale University

发明人： Andrew P. Crew ,  Kurt Zimmermann ,  Jing Wang ,  Craig M. Crews ,  Saul Jaime-Figueroa ,  George Burslem

IPC分类号： C07D471/04 ,  A61P35/00 ,  A61K31/506 ,  A61K47/54 ,  A61K47/55 ,  A61K31/519 ,  A61K31/427 ,  A61K31/454 ,  A61K31/517 ,  A61K31/55 ,  A61K31/496 ,  A61K31/551 ,  A61K45/06 ,  A61K38/07 ,  A61K31/52

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：US20210220475A1

公开(公告)日：2021-07-22

申请号：US17192083

申请日：2021-03-04

申请人： Arvinas Operations, Inc. ,  Yale University

发明人： Andrew P. Crew ,  Kurt Zimmermann ,  Jing Wang ,  Craig M. Crews ,  Saul Jaime-Figueroa ,  George Burslem

IPC分类号： A61K47/54 ,  A61K47/55 ,  A61K31/519 ,  A61K31/427 ,  A61K31/454 ,  A61K31/517 ,  A61K31/55 ,  A61K31/496 ,  A61K31/551 ,  A61K45/06 ,  A61K38/07 ,  A61K31/52 ,  A61K31/506 ,  C07D471/04

摘要： The present invention relates to bifunctional compounds, which find utility to degrade and (inhibit) TBK1. 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：US11173211B2

公开(公告)日：2021-11-16

申请号：US16563842

申请日：2019-09-07

申请人： ARVINAS OPERATIONS, INC. ,  YALE UNIVERSITY

发明人： Andrew P. Crew ,  Keith R. Hornberger ,  Jing Wang ,  Saul Jaime-Figueroa ,  Hanqing Dong

IPC分类号： C07D401/14 ,  C07D471/04 ,  A61K31/437 ,  A61P35/00 ,  A61K47/55 ,  C07D519/00 ,  C07D417/14 ,  C07D413/14

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：US11220515B2

公开(公告)日：2022-01-11

申请号：US16258563

申请日：2019-01-26

申请人： YALE UNIVERSITY

发明人： Craig M. Crews ,  George Burslem ,  Philipp M. Cromm ,  Saul Jaime-Figueroa ,  Momar Toure

IPC分类号： C07D495/14 ,  C07D261/08 ,  A61P35/00 ,  C07D417/14 ,  C07D413/14

摘要： The description relates to imide-based 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 invention. 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.

公开(公告)号：US20190276459A1

公开(公告)日：2019-09-12

申请号：US16297282

申请日：2019-03-08

申请人： Yale University

发明人： Craig M. Crews ,  Saul Jaime-Figueroa ,  Momar Toure

IPC分类号： C07D487/04 ,  A61K47/54 ,  A61K47/14 ,  A61K47/10 ,  C07D401/14 ,  A61P35/02

摘要： The present disclosure relates to bifunctional compounds, which find utility as modulators of Burton's Tyrosine Kinase (BTK). In particular, the present disclosure is directed to bifunctional compounds. One end of a bifunctional compound includes a Von Hippel-Lindau, Cereblon, Inhibitors of Apotosis Proteins, or Mouse Double-Minute Homolog 2 ligand that binds to the respective E3 ubiquitin ligase. The other end of a bifunctional compound includes a moiety that binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. Diseases or disorders that result from aggregation, accumulation, and/or overactivation of the target protein can be 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：US11834460B2

公开(公告)日：2023-12-05

申请号：US17554831

申请日：2021-12-17

申请人： YALE UNIVERSITY

发明人： Craig M. Crews ,  George Burslem ,  Philipp M. Cromm ,  Saul Jaime-Figueroa ,  Momar Toure

IPC分类号： C07D495/14 ,  C07D261/08 ,  C07D413/14 ,  C07D417/14 ,  A61P35/00

CPC分类号： C07D495/14 ,  A61P35/00 ,  C07D261/08

摘要： The description relates to imide-based 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 invention. 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.

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.