Vertex Pharmaceuticals, Inc.

Chroma Therapeutics Limited

Francesca Ann Mazzei

Jean-Damien Charrier

Michael P Mortimore

David Kay

Juan-Miguel Jimenez

Sanjay Ratilal Patel

Stephen John Davies

Alan Hornsby Davidson

Kenneth William John Baker

Daniel Robinson

Hayley Marie Binch

Guy Brenchley

Andrew Miller

Alan Hastings Drummond

Simon Everitt

David Festus Charles Moffat

Alistair David Graham Donald

David Festus Moffat

Hayley Binch

Alastair David Graham Donald

Françoise Pierard

Andrew James Belfield

Sandra Van Meurs

Kenneth William Baker

Alistair David Donald

Ronald Kengtel

David Festus C Moffat

David F C Moffat

Compounds of formula (I) are inhibitors of histone deacetylase activity, and are useful in the treatment of, for example, cancers, wherein Ris a carboxylic acid group (&#x2014;COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group; Ris the side chain of a natural or non-natural alpha amino acid; Y is a bond, &#x2014;C(&#x2550;O), &#x2014;S(&#x2550;O)&#x2014;, &#x2014;C(&#x2550;O)O&#x2014;, &#x2014;C(O)NR&#x2014;, &#x2014;C(&#x2550;S)&#x2014;NR, &#x2014;C(&#x2550;NH)NRor &#x2014;S(&#x2550;O)NR&#x2014; wherein Ris hydrogen or optionally substituted C-Calkyl; Lis a divalent radical of formula -(Alk)(Q)(Alk)- wherein m, n and p are independently 0 or 1, Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, or (ii), in the case where both m and p are 0, a divalent radical of formula &#x2014;X-Q- or -Q-X&#x2014; wherein Xis &#x2014;O&#x2014;, S&#x2014; or NR&#x2014; wherein Ris hydrogen or optionally substituted C-Calkyl, and Qis an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, Alkand Alkindependently represent optionally substituted divalent C-Ccycloalkyl radicals, or optionally substituted straight or branched, C-Calkylene, C-Calkenylene, or C-Calkynylene radicals which may optionally contain or terminate in an ether (&#x2014;O&#x2014;), thioether (&#x2014;S&#x2014;) or amino (&#x2014;NR&#x2014;) link wherein Ris hydrogen or optionally substituted C-Calkyl; Xrepresents a bond; &#x2014;C(&#x2550;O); or &#x2014;S(&#x2550;O)&#x2014;; &#x2014;NRC(&#x2550;O)&#x2014;, &#x2014;C(&#x2550;O)NR&#x2014;, &#x2014;NRC(&#x2550;O)NR&#x2014;, &#x2014;NRS(&#x2550;O)&#x2014;, or &#x2014;S(&#x2550;O)NR&#x2014; wherein Rand Rare independently hydrogen or optionally substituted C-Calkyl; z is 0 or 1; A represents an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system wherein the radicals RRNH&#x2014;Y-L-X-[CH]&#x2014; and HONHCO-[LINKER]- are attached different ring atoms; and -[Linker]- represents a divalent linker radical linking a ring atom in A with the hydroxamic acid group CONIIOII, the length of the linker radical, from the terminal atom linked to the ring atom of A to the terminal atom linked to the hydroxamic acid group, is equivalent to that of an unbranched saturated hydrocarbon chain of from 3-10 carbon atoms. 

Enzyme inhibitors

The present invention provides a facile process for the preparation of tri- and tetra&#x2014;substituted pyrimidines. The process is useful for preparing inhibitors of protein kinases, especially Aurora kinase. These inhibitors are useful for treating or lessening the severity of Aurora&#x2014;mediated diseases or conditions.

Processes for preparing substituted pyrimidines

Compounds of formula (I) are inhibitors of histone deacetylase activity, and are useful in the treatment of, for example, cancers: 

The present invention provides compounds of formula I: or a pharmaceutically acceptable derivative thereof, wherein A, B, Q, R, and Rare as described in the specification. These compounds are inhibitors of protein kinase, particularly inhibitors of AKT or PDK1 kinase, mammalian protein kinases involved in proliferative and neurodegenerative disorders. The invention also provides pharmaceutical compositions comprising the compounds of the invention, processes for preparing the compounds, and methods of utilizing those compositions in the treatment of various disorders.

Compositions useful as inhibitors of protein kinases

The present invention provides a facile process for the preparation of tri- and tetra-substituted pyrimidines. The process is useful for preparing inhibitors of protein kinases, especially Aurora kinase. These inhibitors are useful for treating or lessening the severity of Aurora-mediated diseases or conditions.

Substituted pyrimidines useful as protein kinase inhibitors

Compounds of formula (I) are inhibitors of histone deacetylase activity, and are useful in the treatment of, for example, cancers. 

Compounds of formula: (I), and salts, N-oxides, hydrates and solvates thereof are histone deacetylase inhibitors and are useful in the treatment of cell proliferative diseases, including cancers: (I) wherein Q, V and W independently represent &#x2014;N&#x2550; or &#x2014;C&#x2550;; B is a divalent radical selected from: (IIA), (IIB), (IIC), (IID), and (IIE). Wherein the bond marked * is linked to the ring containing Q, V and W through -[Linker1]- and the bond marked ** is linked to A through -[Linker2]-; A is an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system; and -[Linker1]- and -[Linker2]- independently represent a bond, or a divalent linker radical. 

Histone deacetylase inhibitors

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Abingdon, United Kingdom

Francesca Ann Mazzei