Merck + Co., Inc.

Merck Sharp + Dohme Corp.

Burnham Institute for Medical Research

Nicholas D P Cosford

Nicholas D Smith

Mark T Bilodeau

Jeffrey Roger Roppe

Lida R Tehrani

Dehua Huang

Chixu Chen

Jun Liang

Brian Walter Eastman

Peter J Manley

Jacob M Hoffman

Ian A McDonald

Zhicai Wu

Mark E Layton

Johnny Yasuo Nagasawa

Thomas S Reger

Tony Siu

Essa H Hu

Lou Anne Neilson

Yiwei Li

Russell Dahl

Peter C Chua

John C Hartnett

Anindita Bhoumik

Craig William Lindsley

Jean-Michel Andre Vernier

Benito Munoz

Brian Andrew Stearns

Jeannie M Arruda

Philip E Sanderson

Bowei Wang

Zhijian Zhao

Brian T Campbell

Kevin J Rodzinak

Steve Fong Poon

Stephen D Hess

Ze'ev Ronai

Mark Andrew Varney

Ze′ev A Ronai

Steven F Poon

The present invention is directed to compounds which contain substituted pyridazines and pyrimidines moieties which inhibit the activity of Akt, a serine/threonine protein kinase. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for treating cancer comprising administration of the compounds of the invention.

Inhibitors of Akt activity

The present invention is directed to compounds which contain substituted naphthyridines which inhibit the activity of Akt, a serine/threonine protein kinase. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for treating cancer comprising administration of the compounds of the invention. These substituted naphthyridines have unexpected advantageous properties when compared to other naphthyridines reported in PCT publication WO2003/086394, such unexpected advantageous properties may include increased cellular potency/solubility, greater selectivity, enhanced pharmacokinetic properties, lack of off target activity and so on.

There are provided methods of inhibiting growth and metastasis of melanoma, methods of sensitizing melanoma cells to apoptosis, and methods of treating a subject having melanoma using acetyl isogambogic acid, celastrol, or a derivative thereof. There are further provided derivatives of celastrol and compositions comprising acetyl isogambogic acid, celastrol, or a derivative thereof.

Compositions and methods for inhibiting growth and metastasis of melanoma

The present invention is directed to compounds which contain substituted napthyridines which inhibit the activity of Akt, a serine/threonine protein kinase. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for treating cancer comprising administration of the compounds of the invention.

Tetrazole compounds substituted directly, or by a bridge, with i) a heteroaryl moiety containing N adjacent to the point of connection of the heteroaryl and ii) another heteroaryl or aryl ring, with at least one of the rings being further substituted with another ring, are mGluR5 modulators useful in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, panic, and bipolar disorder, as well as in the treatment of pain, Parkinson's disease, cognitive dysfunction, epilepsy, circadian rhythm disorders, drug addiction, drug abuse, drug withdrawal, obesity and other diseases.

Di-aryl substituted tetrazole modulators of metabotropic glutamate receptor-5

The instant invention provides for compounds that inhibit Akt activity. In particular, the compounds disclosed selectively inhibit one or two of the Akt isoforms. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting Akt activity by administering the compound to a patient in need of treatment of cancer.

Pyrazole compounds substituted directly, or by a bridge, with a heteroaryl moiety containing N adjacent to the point of connection of the heteroaryl, are mGluR5 modulators useful in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, bipolar disorder and panic, as well as in the treatment of pain, circadian rhythm disorders, and other diseases.

Heteroaryl substituted pyrazole modulators of metabotropic glutamate receptor-5

The present invention is directed to compounds which contain substituted 5-deazapteridine moieties which inhibit the activity of Akt, a serine/threonine protein kinase. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for treating cancer comprising administration of the compounds of the invention.

Pyrrole compounds of Formula (I): and pharmaceutically acceptable salts thereof (where A, B, R, R, R, W, X, Y and Z are as defined herein), which are substituted directly, or by a bridge, with i) a heteroaryl moiety containing N adjacent to the point of connection of the heteroaryl and ii) another heteroaryl or aryl ring, with at least one of the rings being further substituted with another ring, are mGluR5 modulators useful in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, panic, and bipolar disorder, as well as in the treatment of pain, Parkinson's disease, cognitive dysfunction, epilepsy, circadian rhythm disorders, drug addiction, drug abuse, drug withdrawal, obesity and other diseases 

Di-aryl substituted pyrrole modulators of metabotropic glutamate receptor-5

Pyrrole compounds substituted directly, or by a bridge, with a heteroaryl moiety containing N adjacent to the point of connection of the heteroaryl, are mGluR5 modulators useful in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, bipolar disorder and panic, as well as in the treatment of pain, circadian rhythm disorders, and other diseases.

Heteroaryl substituted pyrrole modulators of metabotropic glutamate receptor-5

Novel triazole compounds represented by Formula (1): (where A, A, A, A, A, A, B, R, W, X, Y and Z are as defined herein) in which the triazole is substituted directly, or by a bridge, with i) a heteroaryl moiety containing N adjacent to the point of connection of the heteroaryl and ii) another heteroaryl or aryl ring, with at least one of the rings being further substituted with another ring, are mGluR5 modulators useful in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, panic, and bipolar disorder, as well as in the treatment of pain, Parkinson's disease, cognitive dysfunction, epilepsy, circadian rhythm disorders, drug addiction, drug abuse, drug withdrawal, obesity and other diseases 

Di-aryl substituted triazole modulators of metabotropic glutamate receptor-5

Tetrazole compounds substituted directly, or by a bridge, with a heteroaryl moiety containing N adjacent to the point of connection of the heteroaryl, are mGluR5 modulators useful in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, and panic, as well as in the treatment of pain and other diseases.

Heteroaryl substituted tetrazole modulators of metabotrophic glutamate receptor-5

Triazole compounds substituted directly, or by a bridge, with a heteroaryl moiety containing N adjacent to the point of connection of the heteroaryl which are metabotropic glutamate receptor&#x2014;subtype 5 ('mGluR5') modulators useful in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, bipolar disorder and panic, as well as in the treatment of pain, Parkinson's disease, cognitive dysfunction, epilepsy, circadian rhythm disorders, drug addiction, drug abuse, drug withdrawal and other diseases.

Heteroaryl substituted triazole modulators of metabotropic glutamate receptor-5

Growing community of inventors

San Diego, CA, United States of America

Nicholas D P Cosford