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：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：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：US20180179183A1

公开(公告)日：2018-06-28

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： C07D401/14 ,  C07D401/04 ,  A61K31/4439 ,  C07D417/14 ,  A61K31/4545 ,  C07D487/04 ,  A61K31/4188 ,  C07D471/04 ,  A61K31/437 ,  A61K45/06 ,  A61P35/00 ,  A61P43/00 ,  A61P25/00 ,  A61P9/00

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：US20170065719A1

公开(公告)日：2017-03-09

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： A61K47/48 ,  A61K45/06 ,  A61K31/422 ,  A61K31/437 ,  A61K31/551 ,  A61K31/427

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.

摘要翻译： 本发明涉及双官能化合物，其可用作靶向泛素化的调节剂，特别是根据本发明的双官能化合物降解和/或以其它方式抑制的多种多肽和其它蛋白质的抑制剂。 特别地，本发明涉及化合物，其一端含有与泛素连接酶结合的VHL配体，另一端含有结合靶蛋白的部分，使得靶蛋白置于接近泛素连接酶 以实现该蛋白质的降解（和抑制）。 与靶向多肽的降解/抑制一致，本发明表现出与根据本发明的化合物相关的广泛的药理学活性。

公开(公告)号：US20160272639A1

公开(公告)日：2016-09-22

申请号：US15074820

申请日：2016-03-18

申请人： Arvinas, Inc. ,  Yale University

发明人： Andrew P. Crew ,  Craig M. Crews ,  Xin Chen ,  Hanqing Dong ,  Caterina Ferraro ,  Yimin Qian ,  Kam Siu ,  Jing Wang ,  Meizhong Jin ,  Michael Berlin ,  Kurt Zimmermann ,  Lawrence Snyder

IPC分类号： C07D471/04 ,  A61K31/427 ,  A61K45/06 ,  C07D417/12 ,  C07D403/06 ,  A61K31/4035 ,  C07D403/14 ,  A61K31/4155 ,  C07D401/14 ,  A61K31/454 ,  A61K31/4439 ,  A61K31/5377 ,  A61K31/437 ,  C07D413/14 ,  A61K31/4245 ,  C07D405/14 ,  A61K31/422 ,  A61K31/501 ,  A61K31/497 ,  A61K31/53 ,  C07D417/14

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.

摘要翻译： 本发明涉及双官能化合物，其可用作靶向泛素化的调节剂，特别是根据本发明的双官能化合物降解和/或以其它方式抑制的多种多肽和其它蛋白质的抑制剂。 特别地，本发明涉及化合物，其一端含有与泛素连接酶结合的VHL配体，另一端含有结合靶蛋白的部分，使得靶蛋白置于接近泛素连接酶 以实现该蛋白质的降解（和抑制）。 与靶向多肽的降解/抑制一致，本发明表现出与根据本发明的化合物相关的广泛的药理学活性。

公开(公告)号：US10730870B2

公开(公告)日：2020-08-04

申请号：US15074820

申请日：2016-03-18

申请人： Arvinas, Inc. ,  Yale University

发明人： Andrew P. Crew ,  Craig M. Crews ,  Xin Chen ,  Hanqing Dong ,  Caterina Ferraro ,  Yimin Qian ,  Kam Siu ,  Jing Wang ,  Meizhong Jin ,  Michael Berlin ,  Kurt Zimmermann ,  Lawrence Snyder

IPC分类号： C07D521/00 ,  C07D471/04 ,  C07D417/14 ,  A61K45/06 ,  C07D417/12 ,  C07D403/06 ,  C07D403/14 ,  C07D401/14 ,  C07D413/14 ,  C07D405/14 ,  C07D495/04

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：US20180256586A1

公开(公告)日：2018-09-13

申请号：US15840950

申请日：2017-12-13

申请人： Arvinas, Inc. ,  Yale University

发明人： Andrew P. Crew ,  Keith R. Hornberger ,  Craig M. Crews ,  George Burslem

IPC分类号： A61K31/529 ,  A61K31/429 ,  A61K31/454 ,  A61K45/06 ,  A61P35/02

摘要： The present disclosure relates to bifunctional compounds, which find utility as modulators of FLT3 (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hppel-Lindau, cereblon, ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds the target protein FLT3, 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 the 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：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.