公开(公告)号：US11981683B2

公开(公告)日：2024-05-14

申请号：US17699082

申请日：2022-03-19

Applicant: Arvinas Operations, Inc.

Inventor： Erika Marina Vieira Araujo ,  Michael Berlin ,  Hanqing Dong ,  Steven M. Sparks ,  Jing Wang ,  Wei Zhang

IPC: C07D401/14 ,  A61K45/06 ,  C07D413/14 ,  C07D417/14 ,  C07D471/04 ,  C07D471/10 ,  C07D487/08 ,  C07D487/10 ,  C07D498/10

CPC classification number: C07D498/10 ,  A61K45/06 ,  C07D401/14 ,  C07D413/14 ,  C07D417/14 ,  C07D471/04 ,  C07D471/10 ,  C07D487/08 ,  C07D487/10

Abstract: Bifunctional compounds, which find utility as modulators of leucine-rich repeat kinase 2 (LRRK2), are described herein. In particular, the hetero-bifunctional compounds of the present disclosure contain on one end a moiety that binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds LRRK2, 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：US20240131023A1

公开(公告)日：2024-04-25

申请号：US18460063

申请日：2023-09-01

Applicant: Arvinas Operations, Inc.

Inventor： LAWRENCE B. Snyder ,  Andrew P. Crew ,  Jing Wang ,  Hanqing Dong

IPC: A61K31/496 ,  A61K31/167 ,  A61K31/277 ,  A61K31/337 ,  A61K31/417 ,  A61K31/4523 ,  A61K31/4545 ,  A61K31/497 ,  A61K31/501 ,  A61K31/506 ,  A61K31/5377 ,  A61K31/5386 ,  A61K31/57 ,  A61K31/661 ,  A61K31/663 ,  A61K31/675 ,  A61K38/09 ,  A61K47/54 ,  C07D401/12 ,  C07D401/14 ,  C07D413/12 ,  C07D413/14 ,  C07D498/10

CPC classification number: A61K31/496 ,  A61K31/167 ,  A61K31/277 ,  A61K31/337 ,  A61K31/417 ,  A61K31/4523 ,  A61K31/4545 ,  A61K31/497 ,  A61K31/501 ,  A61K31/506 ,  A61K31/5377 ,  A61K31/5386 ,  A61K31/57 ,  A61K31/661 ,  A61K31/663 ,  A61K31/675 ,  A61K38/09 ,  A61K47/545 ,  C07D401/12 ,  C07D401/14 ,  C07D413/12 ,  C07D413/14 ,  C07D498/10

Abstract: This disclosure pertains to compounds, the preparation thereof, and the use of these compounds in the treatment of prostate cancer, including metastatic and/or castrate-resistant prostate cancer, in subjects in need thereof.

公开(公告)号：US20240091204A1

公开(公告)日：2024-03-21

申请号：US18309867

申请日：2023-09-18

Applicant: Arvinas Operations, Inc.

Inventor： Andrew P. Crew ,  Hanqing Dong ,  Michael Berlin ,  Steven M. Sparks

IPC: A61K31/427 ,  A61K31/4035 ,  A61K31/4245 ,  A61K31/437 ,  A61K31/4439 ,  A61K31/496 ,  A61K31/541 ,  A61K47/54

CPC classification number: A61K31/427 ,  A61K31/4035 ,  A61K31/4245 ,  A61K31/437 ,  A61K31/4439 ,  A61K31/496 ,  A61K31/541 ,  A61K47/555

Abstract: The present disclosure relates to bifunctional compounds, which find utility as modulators of α-synuclein (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：US11707452B2

公开(公告)日：2023-07-25

申请号：US16545983

申请日：2019-08-20

Applicant: Arvinas Operations, Inc.

Inventor： Andrew P. Crew ,  Hanqing Dong ,  Michael Berlin ,  Steven M. Sparks

IPC: A61K31/427 ,  A61K47/54 ,  A61K31/4035 ,  A61K31/4245 ,  A61K31/437 ,  A61K31/4439 ,  A61K31/496 ,  A61K31/541

CPC classification number: A61K31/427 ,  A61K31/4035 ,  A61K31/4245 ,  A61K31/437 ,  A61K31/4439 ,  A61K31/496 ,  A61K31/541 ,  A61K47/555

Abstract: The present disclosure relates to bifunctional compounds, which find utility as modulators of α-synuclein (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：US20230203030A1

公开(公告)日：2023-06-29

申请号：US17931814

申请日：2022-09-13

Applicant: Arvinas Operations, Inc. ,  Yale University

Inventor： 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: C07D471/04 ,  C07D417/14 ,  A61K45/06 ,  C07D417/12 ,  C07D403/06 ,  C07D403/14 ,  C07D401/14 ,  C07D413/14 ,  C07D405/14 ,  C07D495/04

CPC classification number: C07D471/04 ,  A61K45/06 ,  C07D401/14 ,  C07D403/06 ,  C07D403/14 ,  C07D405/14 ,  C07D413/14 ,  C07D417/12 ,  C07D417/14 ,  C07D495/04

Abstract: 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：US20220267305A1

公开(公告)日：2022-08-25

申请号：US17727386

申请日：2022-04-22

Applicant: Arvinas Operations, Inc.

Inventor： Andrew P. Crew ,  Hanqing Dong ,  Keith R. Hornberger ,  Yimin Qian ,  Jing Wang

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

Abstract: 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：US20190192514A1

公开(公告)日：2019-06-27

申请号：US16284790

申请日：2019-02-25

Applicant: Arvinas Operations, Inc.

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

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

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

Abstract: 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：US12239711B2

公开(公告)日：2025-03-04

申请号：US17571018

申请日：2022-01-07

Applicant: Arvinas Operations, Inc.

Inventor： Andrew P. Crew ,  Craig M. Crews ,  Hanqing Dong ,  Keith R. Hornberger ,  Yimin Qian ,  Lawrence B. Snyder ,  Jing Wang

IPC: C07D401/04 ,  A61K31/437 ,  A61K31/496 ,  A61K31/497 ,  A61K31/501 ,  A61K31/506 ,  A61K31/551 ,  A61K45/06 ,  A61K47/54 ,  A61K47/55 ,  A61P35/00 ,  C07D401/14 ,  C07D471/04

Abstract: 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.

公开(公告)号：US12172981B2

公开(公告)日：2024-12-24

申请号：US17359424

申请日：2021-06-25

Applicant: Arvinas Operations, Inc.

Inventor： Andrew P. Crew ,  Hanqing Dong ,  Keith R. Hornberger ,  Yimin Qian ,  Jing Wang

IPC: 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 ,  A61P15/00 ,  A61P35/00 ,  C07D401/04 ,  C07D471/04 ,  C07D471/10 ,  C07D487/04 ,  C07D487/08 ,  C07D487/10 ,  C07D498/10 ,  C07K5/078 ,  C07K5/083 ,  C07K5/062

Abstract: 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：US12043612B2

公开(公告)日：2024-07-23

申请号：US17313679

申请日：2021-05-06

Applicant: Arvinas Operations, Inc.

Inventor： Laura E. N. Allan ,  Chungpin Herman Chen ,  Hanqing Dong ,  John A. Grosso ,  Royal J. Haskell, III ,  Rhys LLoyd ,  Hayley Reece

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

CPC classification number: C07D401/14 ,  A61K9/0053 ,  A61K9/2009 ,  A61K9/2018 ,  A61K9/2054 ,  A61K45/06 ,  C07B2200/13

Abstract: 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.