公开(公告)号：US11554171B2

公开(公告)日：2023-01-17

申请号：US16912329

申请日：2020-06-25

申请人： Arvinas Operations, Inc. ,  Yale University

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

IPC分类号： A61P35/00 ,  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：US20230012321A1

公开(公告)日：2023-01-12

申请号：US17313679

申请日：2021-05-06

申请人： Arvinas Operations, Inc.

发明人： Laura E.N. ALLAN ,  Chungpin Herman CHEN ,  Hanqing DONG ,  Robert J. DUGUID ,  John A. GROSSO ,  Royal J. HASKELL, III ,  Casey Keith JAGER ,  Venkata A. KATTUBOINA ,  Aditya Mohan KAUSHAL ,  Samuel Elliott KENNEDY ,  Rhys LLOYD ,  Miranda Annell NEESER ,  Yuping QIU ,  Hayley REECE ,  Maxwell Marco REEVE ,  Joseph P. REO ,  Jerod ROBERTSON ,  Mohammad Mehdi ZAHEDI

IPC分类号： C07D401/14 ,  A61K9/00 ,  A61K9/20 ,  A61K45/06

摘要： The present disclosure relates to ultra-pure forms, polymorphs, amorphous forms, and formulations of N-[(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]pyridazine-3-carboxamide, referred to herein as Compound A: The present disclosure also relates methods of manufacturing and purifying the same, as well as intermediates useful in the synthesis of Compound A. The ultra-pure forms, polymorphs, amorphous forms, and formulations of Compound A can be used as therapeutic agents for the treatment of various diseases and conditions such as cancer.

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：US20220370416A1

公开(公告)日：2022-11-24

申请号：US17223551

申请日：2021-04-06

申请人： Arvinas Operations, Inc. ,  Yale University

发明人： Ling Chu ,  Craig M. Crews ,  Hanqing Dong ,  Keith R. Hornberger ,  Jesus Raul Medina ,  Lawrence Snyder ,  Jing Wang

IPC分类号： A61K31/427 ,  A61K47/54 ,  A61K45/06 ,  A61K31/422 ,  A61K31/4155

摘要： Bifunctional compounds, which find utility as modulators of Kirsten ras sarcoma protein (KRas or KRAS), are described herein. In particular, the hetero-bifunctional compounds of the present disclosure contain on one end a moiety that binds to the Von Hippel-Lindau E3 ubiquitin ligase and on the other end a moiety which binds KRas, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The hetero-bifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aberrant regulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

公开(公告)号：US20220323457A1

公开(公告)日：2022-10-13

申请号：US17073135

申请日：2020-10-16

申请人： Arvinas Operations, Inc.

发明人： Michael Berlin ,  Hanqing Dong ,  Dan Sherman ,  Lawrence Snyder ,  Jing Wang ,  Wei Zhang

IPC分类号： A61K31/551 ,  A61K31/506 ,  C07D401/14 ,  C07D487/08 ,  A61K31/496 ,  C07D487/10 ,  C07D405/14 ,  C07D413/14 ,  A61K31/5355 ,  A61K31/5377 ,  A61K31/4985 ,  A61K31/55 ,  C07D487/04 ,  C07D417/14 ,  C07D471/10

摘要： Bifunctional compounds, which find utility as modulators of B-cell lymphoma 6 protein (BCL6; target protein), are described herein. In particular, the bifunctional compounds of the present disclosure contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand that 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 bifunctional compounds of the present disclosure exhibit 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：US20220089570A1

公开(公告)日：2022-03-24

申请号：US17484628

申请日：2021-09-24

申请人： Arvinas Operations, Inc.

发明人： Andrew P. CREW ,  Craig M. CREWS ,  Hanqing DONG ,  Meizhong JIN ,  Yimin QIAN ,  Jing WANG

IPC分类号： C07D401/14 ,  C12N9/12 ,  C12N9/18 ,  A61K45/06 ,  C12Q1/25 ,  A61K31/4439 ,  A61K31/519 ,  A61K31/513 ,  A61K47/54 ,  A61K47/66

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：US20210353621A1

公开(公告)日：2021-11-18

申请号：US17317235

申请日：2021-05-11

申请人： Arvinas Operations, Inc.

发明人： Ronald PECK ,  Yongqing HUANG ,  Chi Fung KEUNG

IPC分类号： A61K31/497 ,  A61K31/506 ,  A61K31/496 ,  A61K31/501 ,  A61P35/00

摘要： The present application relates to treating and/or preventing prostate cancer, including metastatic and/or castrate-resistant prostate cancer, in a subject in need of treatment, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein R1, R2, R3, X1, X2, X3, X4, and n are defined herein.

公开(公告)号：US20210139458A1

公开(公告)日：2021-05-13

申请号：US16889490

申请日：2020-06-01

申请人： Arvinas Operations, 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 ,  A61K31/4545 ,  A61K38/06 ,  C07D487/08 ,  C07D487/04 ,  A61P35/00 ,  A61K31/5386 ,  A61K38/05 ,  C07K5/083 ,  A61K31/497 ,  A61K47/54 ,  C07D498/10 ,  A61K45/06 ,  A61K31/454 ,  C07K5/078 ,  C07D487/10 ,  C07D401/04 ,  A61K31/501 ,  A61K31/519 ,  A61K31/4725 ,  C07D471/04 ,  C07D471/10 ,  A61K31/496 ,  A61P15/00 ,  A61K31/551

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：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：US20210113557A1

公开(公告)日：2021-04-22

申请号：US17075808

申请日：2020-10-21

申请人： Arvinas Operations, Inc.

发明人： Andrew P. CREW ,  Lawrence B. SNYDER ,  Jing WANG ,  Royal J. HASKELL, III ,  Marcia Dougan MOORE

IPC分类号： A61K31/501 ,  A61P35/00 ,  A61K9/00

摘要： The present application relates to treating and/or preventing prostate cancer, including metastatic and/or castrate-resistant prostate cancer, in a subject in need of treatment, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein R1, R2, R3, X1, X2, X3, X4 and n are defined herein.