公开(公告)号：US11247991B2

公开(公告)日：2022-02-15

申请号：US17083940

申请日：2020-10-29

申请人： DANA-FARBER CANCER INSTITUTE, INC.

发明人： Nathanael S. Gray ,  Tinghu Zhang ,  Calla M. Olson ,  Yanke Liang ,  Nicholas Kwiatkowski

IPC分类号： C07D471/04 ,  C07D471/10 ,  C07D401/14 ,  A61K47/54 ,  A61K47/18 ,  A61P35/00

摘要： The present application provides bifunctional compounds of Formula (Ia) or (Ib): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which act as protein degradation inducing moieties for cyclin-dependent kinase 8 (CDK8). The present application also relates to methods for the targeted degradation of CDK8 through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to CDK8 which can be utilized in the treatment of disorders modulated by CDK8.

公开(公告)号：US10954242B2

公开(公告)日：2021-03-23

申请号：US16315438

申请日：2017-07-05

申请人： The Broad Institute, Inc. ,  Dana-Farber Cancer Institute, Inc. ,  The General Hospital Corporation

发明人： Nathanael S. Gray ,  Yanke Liang ,  Hwan Geun Choi ,  Thomas Sundberg ,  Alykhan Shamji ,  Ramnik Xavier ,  David E. Fisher ,  Nisma Mujahid

IPC分类号： C07D487/04 ,  A61K45/06

摘要： The present disclosure provides compounds of Formula (I), (II), and (III). The provided compounds are able to bind protein kinases (e.g., SIK) and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., SIK, (e.g., SIK1, SIK2, or SIK3)) in a subject or cell. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein.

公开(公告)号：US10532103B2

公开(公告)日：2020-01-14

申请号：US16094102

申请日：2017-04-21

申请人： Dana-Farber Cancer Institute, Inc.

发明人： Nathanael S. Gray ,  Tinghu Zhang ,  Calla M. Olson ,  Yanke Liang ,  Nicholas Kwiatkowski

IPC分类号： A61K47/55 ,  A61K31/427 ,  A61K31/4523 ,  C07D417/14

摘要： The present application provides bifunctional compounds of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which act as protein degradation inducing moieties for cyclin-dependent kinase 9 (CDK9), the present application also relates to methods for the targeted degradation of CDK9 through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to CDK9 which can be utilized in the treatment of disorders modulated by CDK9.

公开(公告)号：US10287268B2

公开(公告)日：2019-05-14

申请号：US15327705

申请日：2015-07-21

申请人： Dana-Farber Cancer Institute, Inc.

发明人： Nathanael S. Gray ,  Hwan Geun Choi ,  Yanke Liang

IPC分类号： C07D403/04 ,  C07D403/14

摘要： The present disclosure provides imidazolyl compounds of Formula (I) and methods of preparing the compounds. The provided compounds are able to bind protein kinases and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase in a subject or cell and/or in treating or preventing a disease (e.g., proliferative disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein.

公开(公告)号：US10265321B2

公开(公告)日：2019-04-23

申请号：US15847856

申请日：2017-12-19

申请人： Dana-Farber Cancer Institute, Inc. ,  The Broad Institute, Inc. ,  President and Fellows of Harvard College ,  The General Hospital Corporation

发明人： Alykhan Shamji ,  Thomas Sundberg ,  Nathanael S. Gray ,  Ramnik Xavier ,  Stuart L. Schreiber ,  Hwan Geun Choi ,  Yanke Liang

IPC分类号： A61K31/5377 ,  A61K31/519 ,  A61K45/06 ,  A61K31/506

摘要： The present disclosure provides methods of treating and/or preventing inflammatory bowel disease (IBD) and graft-versus-host disease (GVHD) using salt-inducible kinase (SIK) inhibitors, such as macrocyclic SIK inhibitors of Formula (I), imidazolyl SIK inhibitors of Formula (II), and urea and carbamate SIK inhibitors of Formula (III-A) (e.g., urea and carbamate SIK inhibitors of Formula (III)).

公开(公告)号：US20170204082A1

公开(公告)日：2017-07-20

申请号：US15327705

申请日：2015-07-21

申请人： Dana-Farber Cancer Institute, Inc.

发明人： Nathanael S. Gray ,  Hwan Geun Choi ,  Yanke Liang

IPC分类号： C07D403/04 ,  C07D403/14

CPC分类号： C07D403/04 ,  C07D403/14

摘要： The present disclosure provides imidazolyl compounds of Formula (I) and methods of preparing the compounds. The provided compounds are able to bind protein kinases and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase in a subject or cell and/or in treating or preventing a disease (e.g., proliferative disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein.

公开(公告)号：US11827636B2

公开(公告)日：2023-11-28

申请号：US17561032

申请日：2021-12-23

申请人： DANA-FARBER CANCER INSTITUTE, INC.

发明人： Nathanael S. Gray ,  Tinghu Zhang ,  Calla M. Olson ,  Yanke Liang ,  Nicholas Kwiatkowski

IPC分类号： C07D471/04 ,  C07D471/10 ,  A61K47/18 ,  A61K47/54 ,  A61P35/00

CPC分类号： C07D471/04 ,  A61K47/18 ,  A61K47/545 ,  C07D471/10 ,  A61P35/00

摘要： The present application provides bifunctional compounds of Formula (Ia) or (Ib):




or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which act as protein degradation inducing moieties for cyclin-dependent kinase 8 (CDK8). The present application also relates to methods for the targeted degradation of CDK8 through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to CDK8 which can be utilized in the treatment of disorders modulated by CDK8.

公开(公告)号：US20210147425A1

公开(公告)日：2021-05-20

申请号：US16953984

申请日：2020-11-20

申请人： The Broad Institute, Inc. ,  Dana-Farber Cancer Institute, Inc. ,  The General Hospital Corporation

发明人： Nathanael S. Gray ,  Yanke Liang ,  Hwan Geun Choi ,  Thomas Sundberg ,  Alykhan Shamji ,  Ramnik Xavier ,  David E. Fisher ,  Nisma Mujahid

IPC分类号： C07D487/04

摘要： The present disclosure provides compounds of Formula (I), (II), and (III). The provided compounds are able to bind C protein kinases (e.g., SIK) and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., SIK, (e.g., SIK1, SIK2, or SIK3)) in a subject or cell. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein.

公开(公告)号：US20180221379A1

公开(公告)日：2018-08-09

申请号：US15847856

申请日：2017-12-19

申请人： Dana-Farber Cancer Institute, Inc. ,  The Broad Institute, Inc. ,  President and Fellows of Harvard College ,  The General Hospital Corporation d/b/a Massachusetts General Hospital

发明人： Alykhan Shamji ,  Thomas Sundberg ,  Nathanael Gray ,  Ramnik Xavier ,  Stuart L. Schreiber ,  Hwan Geun Choi ,  Yanke Liang

IPC分类号： A61K31/5377 ,  A61K31/506 ,  A61K31/519

CPC分类号： A61K31/5377 ,  A61K31/506 ,  A61K31/519 ,  A61K45/06

摘要： The present disclosure provides methods of treating and/or preventing inflammatory bowel disease (IBD) and graft-versus-host disease (GVHD) using salt-inducible kinase (SIK) inhibitors, such as macrocyclic SIK inhibitors of Formula (I), imidazolyl SIK inhibitors of Formula (II), and urea and carbamate SIK inhibitors of Formula (III-A) (e.g., urea and carbamate SIK inhibitors of Formula (III)).

公开(公告)号：US20170224700A1

公开(公告)日：2017-08-10

申请号：US15502287

申请日：2015-08-08

申请人： Dana-Farber Cancer Institute, Inc. ,  The Broad Institute, Inc. ,  President and Fellows of Harvard College ,  The General Hospital Corporation d/b/a Massachusetts General Hospital

发明人： Alykhan Shamji ,  Thomas Sundberg ,  Nathanael S. Gray ,  Ramnik Xavier ,  Stuart L. Schreiber ,  Hwan Geun Choi ,  Yanke Liang

IPC分类号： A61K31/5377 ,  A61K31/506 ,  A61K31/519

CPC分类号： A61K31/5377 ,  A61K31/506 ,  A61K31/519 ,  A61K45/06 ,  A61P1/00 ,  A61P37/00

摘要： The present disclosure provides methods of treating and/or preventing inflammatory bowel disease (IBD) and graft-versus-host disease (GVHD) using salt-inducible kinase (SIK) inhibitors, such as macrocyclic SIK inhibitors of Formula (I), imidazolyl SIK inhibitors of Formula (II), and urea and carbamate SIK inhibitors of Formula (III-A) (e.g., urea and carbamate SIK inhibitors of Formula (III)).