The United States of America, As Represented by the Secretary, Department of Health and Human Services

Beth Israel Deaconess Medical Center, Inc.

University of Utah Research Foundation

The University of North Carolina at Chapel Hill

Dana-farber-cancer Institute Inc.

Whitehead Institute for Biomedical Research

Matthew Brian Boxer

Min Shen

Douglas S Auld

Craig J Thomas

Li Liu

Anton Simeonov

Mindy Irene Emily Davis

Rajan Pragani

James Inglese

Jian-kang Jiang

Amanda P Skoumbourdis

Kun Ping Lu

Xiao Zhen Zhou

Martin J Walsh

Kyle Ryan Brimacombe

Shuo Wei

Jason Matthew Rohde

Xiaodong Wang

Ajit Jadhav

Andrew Louis McIver

Kent Lai

Manshu Tang

Cordelle D Tanega

Surendra Karavadhi

David Sabatini

Matthew E Hall

Daniel Jason Urban

Ganesha Rai Bantukallu

Natalia Martinez

Michael Pacold

Wei Zhao

Yuhong Fang

Andrew Louis Mciver

Mindy Irene Davis

Matthew Hall

Anton Momtchilov Simeonov

The present invention provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, pro-drugs, and compositions thereof. Also provided are methods and kits involving the compounds of Formula (I), (II) or (III) for treating diseases associated with the over-expression of phosphoglycerate dehydrogenase (PHGDH) in a subject, such as proliferative diseases (e.g., cancers (e.g., breast cancer, ER negative breast cancer, melanoma, cervical cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases). Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the activity of PHGDH or inhibit the serine biosynthetic pathway, or both.

Inhibitors of phosphoglycerate dehydrogenase (PHGDH) and uses thereof

The invention features compositions and methods for inhibiting the Pin1 protein, and the treatment of disorders characterized by elevated Pin1 levels.

Methods and compositions for the inhibition of PIN1

A compound of Formula II or a pharmaceutically acceptable salt thereof, wherein CyN is a cyclic amine group bound via a nitrogen atom; X is C or N; Rand Rare each independently a halogen, CN, CF, CHF, CHF, a C-C10alkyl group, a C1-Calkoxy group, a di(C-Calkyl)amino; m and n are each independently 1, 2, or 3, and represents either a single bond or a double bond, wherein the racemic mixture of 3-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-ethyl-5-methoxyphenyl)-6-(2-methylprop-1-en-1-yl)-5-(piperazine-1-carbonyl)pyridin-2(1H)-one atropisomers is excluded.

Thiazole derivatives useful as mutant IDH1 inhibitors for treating cancer

Compounds of Formula I and Formula II and the pharmaceutically acceptable salts thereof are disclosed The variables A, B, Y, Z, X, X, Rand Rare disclosed herein. The compounds are useful for treating cancer disorders, especially those involving mutant IDH1 enzymes. Pharmaceutical compositions containing compounds of Formula I or Formula II and methods of treatment comprising administering compounds of Formula I and Formula II are also disclosed. 

Mutant IDH1 inhibitors useful for treating cancer

Disclosed are inhibitors of human galactokinase of formula (I) that are useful in treating or preventing a galactokinase mediated disease or disorder, e.g., galactosemia. Also disclosed are a composition comprising a pharmaceutically acceptable carrier and at least one inhibitor of the invention, and a method of treating or preventing such disease or disorder in a mammal. Formula (I). 

Galactokinase inhibitors for the treatment and prevention of associated diseases and disorders

Methods and compositions for the inhibition of Pin1

Disclosed are pyruvate kinase M2 activators, which are, bis sulfonamide piperazinyl compounds of Formula (I) and 2,4-disubstituted 4H-thieno[3,2-b]pyrrole-2-(substituted benzyl)pyridazin-3(2H)ones of Formula (II), wherein L and Rto Rare as defined herein, that are useful in treating a number of diseases that are treatable by the activation of PKM2, for example, cancer and anemia, 

Activators of human pyruvate kinase

Disclosed are pyruvate kinase M2 activators which are compounds of Formula (I), including those of Formula (II), wherein A, A, L, R, Rto R, Xto X, k, n, and m are as defined herein, that are useful in treating a number of diseases that are treatable by the activation of PKM2, for example, cancer. A-NR-L-A(I). 

Disclosed are inhibitors of human galactokinase of formula (1) that are useful in treating or preventing a galactokinase mediated disease or disorder, e.g., galactosemia. Also disclosed are a composition comprising a pharmaceutically acceptable carrier and at least one inhibitor of the invention, and a method of treating or preventing such disease or disorder in a mammal. Formula (I). 

A compound, or a pharmaceutically acceptable salt or ester thereof, of formula I:X&#x2014;Wwherein X is a caspase-selective structure and W has the structure of&#x2014;NH&#x2014;CH(Y)(Z)wherein Y is a structure that can form a reversible covalent bond with a caspase; andZ is selected from a carboxyl moiety or a carboxylic acid mimetic.

Caspase inhibitors

Disclosed are pyruvate kinase M2 activators, which are, bis sulfonamide piperazinyl compounds of Formula (I) and 2,4-disubstituted 4H-thieno[3,2-b]pyrrole-2-(substituted benzyl)pyridazin-3(2H)ones of Formula (II), wherein L and Rto Rare as defined herein, that are useful in treating a number of diseases that are treatable by the activation of PKM2, for example, cancer and anemia, Formulas (I); (II). 

Disclosed are pyruvate kinase M2 activators, which are bis sulfonamide piperazinyl and piperidinyl compounds of Formula (I), 2,4-disubstituted 4H-thieno[3,2-c]pyrrole-2-(substituted benzyl)pyridazin-3(2H)-ones of Formula (II) and 6-(3,4-dimethylphenylaminosulfonyl)-3,4-dihydro-1H-quinolin-2-one of formula (III), wherein L, R, R, Rto R, Rand Rare as defined herein, that are useful in treating a number of diseases that are treatable by the activation of PKM2, for example, cancer and anemia. 

Activators of the human pyruvate kinase M2 receptor

Growing community of inventors

New Market, MD, United States of America

Matthew Brian Boxer