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

University of Pennsylvania

Vanderbilt University

The UAB Research Foundation (the University of Alabama at Birmingham)

University of California

Thomas Jefferson University

Eastern Virginia Medical School

Convergene, LLC

Other

The United States of America As Represented by the Department of Health

University of Virginia Patent Foundation

Washington University

Yale University

University of Delaware

Children's Hospital

David Joseph Maloney

Ajit Jadhav

Anton Simeonov

Shyh Ming Yang

Daniel Jason Urban

Diane K Luci

Alex Gregory Waterson

William J Moore

Gary Allen Sulikowski

Kwangho Kim

Xin Hu

Leonard M Neckers

Plamen P Christov

Kyle Ryan Brimacombe

Victor M Darley-Usmar

Somnath Jana

Chi V Dang

Bryan T Mott

Jennifer L Kouznetsova

Adam Yasgar

Ganesh Rai Bantukallu

Theodore Holman

Thomas S Dexheimer

David A Taylor-Fishwick

Michael Holinstat

Makoto Yoshioka

Steven McKenzie

Jerry L Nadler

Elias Set Jenö Arnér

William Chester Stafford

Nathan Patrick Coussens

Sidney M Hecht

Jeffrey William Strovel

Natalia Martinez

Ganesha Rai Bantukallu

Elias Set Arner

Diane Karen Luci

Matthew E Hall

Shyh-Ming Yang

Fumihiko Urano

Thomas Kristie

Yu Liang

Zhihao Zhuang

Jodi Vogel

Deborah A Lannigan-Macara

Jeffrey Allan Smith

Jana Mahadevan

Vasilis Vasiliou

Mark Henderson

Brandon Harvey

Amy Clark

Andrew S Rosenthal

Klaus Joachin Van Leyen

Ganesha Rai

Qin Liang

Nathan Coussens

Matthew Hall

Brian T Mott

The present invention relates to compounds that bind to and otherwise modulate the activity of bromodomain-containing proteins, including BRD4, to processes for preparing these compounds, to pharmaceutical compositions containing these compounds, and to methods of using these compounds for treating a wide variety of conditions and disorders. In particular, this disclosure provides certain BRD4 inhibitors for the treatment of fibrotic diseases or conditions.

Small molecule bromodomain inhibitors and uses therof

Provided is a compound of formula (I) in which Ar, R, U, V, W, X, and p are as described herein. Also provided are methods of using a compound of formula (I), including a method of treating cancer, a method of treating a patient with cancer cells resistant to an anti-cancer agent, and a method of inhibiting lactate dehydrogenase A (LDHA) and/or lactate dehydrogenase B (LDHB) activity in a cell.

Small molecule inhibitors of lactate dehydrogenase and methods of use thereof

The disclosure provides compounds of Formula I, which may be useful as aldehyde dehydrogenase inhibitors and the pharmaceutically acceptable salts thereof. The variables, J, R, G, Q, and ring A are defined herein. Aldehyde dehydrogenase inhibitors of Formula I are useful for treating a variety of conditions including cancer and inflammation. The disclosure includes methods for using compounds and salts of Formula I to treat colon cancer, pancreatic cancer, nasopharyngeal carcinoma, thyroid cancer, prostate cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, hepatocellular carcinoma, leukemia, brain tumors breast cancer, atherosclerosis, ischaemic heart disease, acne vulgaris, asthma, autoimmune diseases, autoinflammatory diseases, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, and interstitial cystitis. The disclosure also includes pharmaceutical compositions containing a compound or salt of Formula I.

Substituted quinoline analogs as aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors

The disclosure provides compounds of Formula I, which may be useful as aldehyde dehydrogenase inhibitors and the pharmaceutically acceptable salts thereof. The variables, J, R, G, Q, and ring A are defined herein. Aldehyde dehydrogenase inhibitors of Formula I are useful for treating a variety of conditions including cancer and inflammation. The disclosure includes methods for using compounds and salts of Formula I to treat colon cancer, pancreatic cancer, nasopharyngeal carcinoma, thyroid cancer, prostate cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, hepatocellular carcinoma, leukemia, brain tumors breast cancer, atherosclerosis, ischaemic heart disease, acne vulgaris, asthma, autoimmune diseases, autoinflammatory diseases, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, and interstitial cystitis. The disclosure also includes pharmaceutical compositions containing a compound or salt of Formula I. 

The present invention generally relates to compositions and methods for treating or preventing an endoplasmic reticulum stress disorder in subjects, including compositions and methods for treating or preventing Wolfram syndrome. The present invention also relates to methods for treating symptoms of neurodegenerative diseases.

Treatment for Wolfram syndrome and other endoplasmic reticulum stress disorders

Human lipoxygenases (LOXs) are a family of iron-containing enzymes involved in catalyzing the oxidation of polyunsaturated fatty acids to provide the corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites. These eicosanoid signaling molecules are involved in a number of physiologic responses such as platelet aggregation, inflammation, and cell proliferation. Platelet-type 12-(S)-LOX (12-LOX) is of particular interest because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. Disclosed herein is the identification and medicinal chemistry optimization of a 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide-based scaffold. The compounds display nM potency against 12-LOX and excellent selectivity over related lipoxygenases and cyclooxygenases. In addition to possessing favorable ADME properties, the compounds also inhibit PAR-4 induced aggregation and calcium mobilization in human platelets, and reduce 12-HETE in mouse/human beta cells. The compounds can also be used in methods for treating or preventing a 12-lipoxygenase mediated disease or disorder.

4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase

Provided is a compound of formula (I), in which Ar, R, U, V, W, X, and p are as described herein. Also provided are methods of using a compound of formula (I), including a method of treating cancer, a method of treating a patient with cancer cells resistant to an anti-cancer agent, and a method of inhibiting lactate dehydrogenase A (LDHA) and/or lactate dehydrogenase B (LDHB) activity in a cell.

There is provided compounds of formula (I) or pharmaceutically-acceptable salts thereof, wherein W, X, Y, Z, R, Rand Rhave meanings provided in the description, which compounds are useful in the treatment of cancers. 

Pyridazinones and their use in the treatment of cancer

The present invention relates to compounds that bind to and otherwise modulate the activity of bromodomain-containing proteins, to processes for preparing these compounds, to pharmaceutical compositions containing these compounds, and to methods of using these compounds for treating a wide variety of conditions and disorders.

Small molecule BET bromodomain inhibitors and uses thereof

The disclosure provides a compound of the formula (II) and pharmaceutically acceptable salts thereof. The variables, e.g. n, R, R, R, X, Y, and Z are defined herein. These compounds act as lactate dehydrogenase inhibitors and are useful for treating cancer and fibrosis. The compounds may be particularly useful for treating forms of cancer in which a metabolic switch from oxidative phosphorylation to glycolysis has occurred. The disclosure also provides pharmaceutical compositions containing a compound of this formula and method for treating patients having cancer, fibrosis, or other conditions in which a metabolic switch from oxidative phosphorylation to glycolysis has occurred. 

1 H-pyrazol-1-yl-thiazoles as inhibitors of lactate dehydrogenase and methods of use thereof

There is provided compounds of formula (I) or pharmaceutically-acceptable salts thereof, wherein L, R, R, R, Rand n have meanings provided in the description, which compounds are useful in the treatment of cancers. 

Pyridines and their use in the treatment of cancer

There is provided compounds of formula (I), or pharmaceutically-acceptable salts thereof, wherein X, Y, Z, Rand Rhave meanings provided in the description, which compounds are useful in the treatment of cancers. 

Tricyclic compounds and their use in the treatment of cancer

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Point of Rocks, MD, United States of America

David Joseph Maloney