Biogen Ma Inc.

Millennium Pharmaceuticals Limited

Sunesis Pharmaceuticals, Inc.

Biogen Idec Ma Inc.

University of South Florida

Yale University

Max-planck-gesellschaft Zur F&#xf6;rderung Der Wissenschaften E. V.

Hairuo Peng

Gnanasambandam Kumaravel

Zhili Xin

Arthur G Taveras

Kevin Guckian

Bin Ma

Lihong Sun

Jeffrey Vessels

Alexey Alexandrovich Lugovskoy

Hiroko Tanaka

Sha Mi

Lei Zhang

John Howard Jones

Bing Guan

Noel Aaron Powell

Brian Raimundo

Zhaohui Shao

Jennifer Cossrow

Thomas Wynn

Weirong Chen

Benjamin Lane

Russell Colyn Petter

Deping Wang

Timothy Raymond Chan

Gang Yao

Adam Littke

Lloyd Franklin

Said M Sebti

John Michael McCall

Andrew D Hamilton

Eddine Saiah

Edward Yin-Shiang Lin

Jianhua Chao

Heather Tye

Xiaogao Liu

Kai Peter Johnsson

Alexey V Ishchenko

Mark Joseph Tebbe

Holly Atton

Mark Peter Ridgill

Mirco Meniconi

James E Dowling

Mark Anthony Kerry

Adrian Kotey

Steven Mark Bromidge

Hexi Chang

Katarzyna Irena Gorska

Nathaniel J Monck

Craig Avery

Mark Kerry

Adrian Kotei Kotey

Lioyd Franklin

Compounds of formula (I) can modulate the activity of autotaxin (ATX). 

ATX modulating agents

Disclosed are bicyclic aryl compounds of formula (I), that can modulate the activity of the autotaxin (ATX) enzyme. This invention further relates to compounds that are ATX inhibitors, and methods of making and using such compounds in the treatment of demyelination due to injury or disease, as well as for treating proliferative disorders such as cancer.

Inhibitors of sepiapterin reductase and uses of sepiapterin reductase inhibitors in analgesia, treatment of acute and chronic pain, anti-inflammation, and immune cell regulation are disclosed.

Sepiapterin reductase inhibitors

Compounds of formula (I) can modulate the activity of one or more SIP receptors and/or the activity of autotaxin (ATX). 

Compounds that are S1P modulating agents and/or ATX modulating agents

The present invention provides methods of inhibiting Raf kinase activity in a patient, the method comprising administering to the patient a compound having formula I: or a pharmaceutically acceptable salt thereof, wherein R, R, R, L, L, Cy, and Cyare as defined as set forth in the specification.

Substituted pyrimidines for inhibiting Raf kinase activity

Compounds of formula (I) wherein: X is &#x2014;O&#x2014;, &#x2014;S(O)&#x2014;, &#x2014;CH&#x2014;, or &#x2014;NR&#x2014;, wherein r is 0, 1, or 2; X, X, and Xare each independently CRor N; one of Xor Xis C and is attached by a single bond to -L-, and the other is CRor N, provided that no more than three of X, X, X, X or Xare N; Ring A is monocyclic Cscycloalkyl or a 5- to 6-membered monocyclic heterocyclyl comprising from 1 to 5 heteroatoms independently selected from N, S, or O; wherein Ring A is further optionally substituted with from 1 to 3 R; provided that Ring A is not morpholinyl, thiomorpholinyl or tetrahydro-2H-pyranyl; L is a bond, &#x2014;O&#x2014;, &#x2014;NR&#x2014;, &#x2014;S(O)&#x2014;, &#x2014;CH&#x2014;, or &#x2014;C(O)&#x2014;, wherein n is 0, 1, or 2; 1 2 Lis an Calkylene, Ccycloalkylene, &#x2014;CH-L-, or a 3- to 8-membered heterocyclylene comprising 1 to 5; Ris Calkyl or a monocyclic Ccycloalkyl; wherein said Ccycloalkyl is substituted with at least one Rand may be optionally substituted with from 1 to 5 additional Rsubstituents, wherein Rfor each occurrence is independently selected; and Ris &#x2014;C(O)OR, &#x2014;C(O)N(R)&#x2014;S(O)R, &#x2014;S(O)OR, &#x2014;C(O)NHC(O)R, &#x2014;Si(O)OH, &#x2014;B(OH), &#x2014;N(R)S(O)R, &#x2014;S(O)N(R), &#x2014;O&#x2014;P(O)(OR), or &#x2014;P(O)(OR), &#x2014;CN, &#x2014;S(O)NHC(O)R, &#x2014;C(O)NHS(O)R3, &#x2014;C(O)NHOH, &#x2014;C(O)NHCN, &#x2014;CH(CF)OH, &#x2014;C(CF)OH, or a selected heteroaryl or heterocyclyl; and pharmaceutically acceptable salts thereof, can modulate the activity of one or more SIP receptors and/or the activity of autotaxin (ATX). 

S1P and/or ATX modulating agents

Compounds of formula (I), and pharmaceutically acceptable salts thereof, can modulate the activity of one or more SIP receptors and/or the activity of autotaxin (ATX).

Compounds of formula (I) can modulate the activity of one or more S 1P receptors. Sphingosine 1-phosphate (S IP) is a lysophospholipid mediator that evokes a variety of cellular responses by stimulation of five members of the endothelial cell differentiation gene (EDG) receptor family, namely S1P1, S1P2, S1P3, S1P4, and S1P5 (formerly EDG1, EDG5, EDG3, EDG6 and EDG8). The EDG receptors are G-protein coupled receptors (GPCRs) and on stimulation propagate second messenger signals via activation of heterotrimeric G-protein alpha (Ga.) subunits and beta-gamma (G( )y) dimers.

S1P modulating agents

The present disclosure provides compounds having Formula II-vi-a: wherein Cy, Cy, and Aare defined as set forth in the specification. These compounds are synthetic intermediates used to prepare inhibitors of Raf protein kinase.

Substituted 1,3-thiazoles as synthetic intermediates for preparation of Raf kinase inhibitors

The present invention provides compounds useful as inhibitors of Raf protein kinase. The present invention also provides compositions thereof, and methods of treating Raf-mediated diseases.

Compounds useful as Raf kinase inhibitors

The present invention provides compounds useful as inhibitors of protein kinase. The present invention also provides compositions thereof, and methods of treating Raf-mediated diseases.

Heterocyclic compounds useful as RAF kinase inhibitors

The invention is based on the discovery that compounds of formula (I) possess unexpectedly high affinity for the Aadenosine receptor, and can be useful as antagonists thereof for preventing and/or treating numerous diseases, including Parkinson's disease. In one embodiment, the invention features a compound of formula (I). 

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Needham, MA, United States of America

Hairuo Peng