Chroma Therapeutics Limited

Macrophage Pharma Limited

Glaxosmithkline Intellectual Property Development Limited

Vernalis &r&d) Ltd.

Laboratoires Serono S.a.

Laboratories Serono Sa

Vernalis (oxford) Limited

Stephen John Davies

David Festus Charles Moffat

Alan Hornsby Davidson

Alan Hastings Drummond

David Festus Moffat

Sanjay Ratilal Patel

Francesca Ann Mazzei

Stéphane Pintat

Kenneth William John Baker

Alistair David Donald

Stuart Thomas Onions

Simon Christopher Hirst

Alastair David Graham Donald

Alistair David Graham Donald

David Charles Festus Moffat

Gilles Pain

Michael Hugh Charlton

Agnes Bombrun

Jonathan Gareth Williams

Carl Leslie North

Jonathon Gareth Williams

Andrew Paul Ayscough

Jean-Yves Gillon

Kenneth William Baker

Stephane Pintat

Oliver James Philps

David Festus C Moffat

The present invention provides a compound which is: tert-butyl N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl)-L-alaninate or a salt, hydrate or solvate thereof. The present invention also provides a pharmaceutical composition comprising the compound together with one or more pharmaceutically acceptable carriers and/or excipients. The compound and composition are useful for inhibiting the activity of a p38 MAP kinase enzyme. As such they may be used in the treatment of a autoimmune or inflammatory disease, or a cell proliferative disease. In addition, the invention provides an acid produced by hydrolysis of the ester group of the compound of the invention. The acid is N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl)-L-alanine.

Tert-butyl N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-YL]-3,5-difluorophenyl}ethyl]-L-alaninate or a salt, hydrate or solvate thereof

Tert-butyl N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl]-L-alaninate or a salt,hydrate or solvate thereof

Covalent conjugates of an &#x3b1;,&#x3b1;-disubstituted glycine ester and a modulator of the activity of a target intracellular enzyme or receptor, wherein the ester group of the conjugate is hydrolysable by one or more intracellular carboxylesterase enzymes to the corresponding acid and the &#x3b1;,&#x3b1;-disubstituted glycine ester is conjugated to the modulator at a position remote from the binding interface between the inhibitor and the target enzyme or receptor pass into cells and the active acid hydrolysis product accumulates within the cells, as in the following compound: 

Enzyme and receptor modulation using covalent conjugates of alpha,alpha-disubstituted glycine esters

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof: wherein: ring A, R, R, n, X, V, W, Z, ring B, [Linker] and R areas defined herein. The compounds are useful as inhibitors of CSF-1R kinase. The compounds can thus be used in medicine. 

2-aminopyrazine derivatives as CSF-1R kinase inhibitors

Tert-butyl N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl]-L-alaninate or a salt, hydrate or solvate thereof

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

Compounds of formula (I) are p38 MAP kinase inhibitors useful for the treatment of autoimmune and inflammatory diseases: wherein: G is &#x2014;N&#x2550; or &#x2014;CH&#x2550;; D is an optionally substituted divalent mono- or bi-cyclic aryl or heteroaryl radical having 5-13 ring members; R6 is hydrogen or optionally substituted CrC3 alkyl; P represents hydrogen and U represents a radical of formula (IA); or U represents hydrogen and P represents a radical of formula (IA); wherein A represents an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members; z is O or 1; &#x2014;X-L-Y&#x2014; is a linker radical or bond; Ris a carboxylic acid group (&#x2014;COOH), or an ester group which is hydrolysable by one or more intracellular esterase enzymes to a carboxylic acid group; and Rand Rare as defined in the claims. 

Inhibitors of P38 map kinase

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

Compounds of formula (IA) or (IB), are inhibitors of aurora kinase activity: Formula (IA), (IB) wherein -L1Y1-[CH2]z- is a linker radical wherein Y, Land z are as defined in the claims; Ris C-Calkoxy, hydrogen or halo; W represents a bond, &#x2014;CH&#x2014;, &#x2014;O&#x2014;, &#x2014;S&#x2014;, &#x2014;S(&#x2550;O)&#x2014;, or &#x2014;NR&#x2014; where Ris hydrogen or C-Calkyl; Q is &#x2550;N&#x2014;, &#x2550;CH&#x2014; or &#x2550;C(X)&#x2014; wherein Xis cyano, cyclopropyl or halo; linker radicals Lare as defined in the claims; R is a radical of formula (X) or (Y): wherein Ris a carboxylic acid group (&#x2014;COOH), or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group; Ris hydrogen; or optionally substituted C-Calkyl, C-Ccycloalkyl, aryl, aryl(C-Calkyl)-, heteroaryl, heteroaryl(C-Calkyl)-, &#x2014;(C&#x2550;O)R, &#x2014;(C&#x2550;O)OR, or &#x2014;(C&#x2550;O)NRwherein Ris hydrogen or optionally substituted (C-C)alkyl, C-Ccycloalkyl, aryl, aryl(C-Calkyl)-, heteroaryl, or heteroaryl(C-Calkyl)-; Ris hydrogen or optionally substituted C-Calkyl; and D is a mono-cyclic heterocyclic ring of 5 or 6 ring atoms. 

Quinoline and quinoxaline derivatives as inhibitors of kinase enzymatic activity

Compounds of formula (IA) or (IB) are inhibitors of IkB kinase (IKK) activity, and are useful in the treatment of autoimmune and inflammatory diseases: wherein Ris hydrogen or optionally substituted (C-C)alkyl; ring A is an optionally substituted aryl or heteroaryl ring of 5-13 ring atoms; Z is a radical of formula R-L-Y&#x2014;(CH)&#x2014;, wherein: z is 0 or 1; R is a radical of formula (X) or (Y) Ris a carboxylic acid group (&#x2014;COOH), or an ester group which is hydrolysable by one or more intracellular esterase enzymes to a carboxylic acid group; Ris hydrogen, or optionally substituted C-Calkyl, C-Ccycloalkyl, aryl or heteroaryl or &#x2014;(C&#x2550;O)R, &#x2014;(C&#x2550;O)OR, or &#x2014;(C&#x2550;O)NRwherein Ris hydrogen or optionally substituted (C-C)alkyl; Yis a bond, &#x2014;(C&#x2550;O)&#x2014;, &#x2014;S(O)&#x2014;, &#x2014;C(&#x2550;O)O&#x2014;, &#x2014;OC(&#x2550;O)&#x2014;, &#x2014;(C&#x2550;O)NR&#x2014;, &#x2014;NR(C&#x2550;O)&#x2014;, &#x2014;S(O)NR&#x2014;, &#x2014;NRS(O)&#x2014;, or &#x2014;NR(C&#x2550;O)NR&#x2014;, wherein Rand Rare independently hydrogen or optionally substituted (C-C)alkyl, Lis a divalent linker radical of formula -(Alk)(Q)(Alk)- wherein m, n, p, Q, Alkand Alkare as defined in the claims.

Inhibitors of IKK-beta serine-threonine protein kinase

Compounds of formula (I) are inhibitors of p38 MAP kinase, and are therefore of utility in the treatment of, inter alia, inflammatory conditions including rheumatoid arthritis and COPD: wherein: G is &#x2014;N&#x2550; or &#x2014;CH&#x2550;; D is an optionally substituted divalent mono- or bi-cyclic aryl or heteroaryl radical having 5-13 ring members; Ris hydrogen or optionally substituted C-Calkyl; P represents hydrogen and U represents a radical of formula (IA); or U represents hydrogen and P represents a radical of formula -A-(CH)&#x2014;X-L-Y&#x2014;NH&#x2014;CHRRwherein A represents an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members; z, Y, L, and Xare as defined in the specification; Ris a carboxylic acid group (&#x2014;COOH), or an ester group which is hydrolysable by one or more intracellular esterase enzymes to a carboxylic acid group; and Ris the side chain of a natural or non-natural alpha amino acid.

P38 MAP kinase inhibitors

Compounds of formula (IA) or (IB) are inhibitors of IkB kinase (IKK) activity, and are useful in the treatment of autoimmune and inflammatory diseases: Formula (A) and (B) wherein Ris hydrogen or optionally substituted (C-C)alkyl; ring A is an optionally substituted aryl or heteroaryl ring of 5-13 ring atoms; Z is (a) a radical of formula RRCHNH&#x2014;Y-L-X&#x2014;(CH)&#x2014; wherein: z is 0 or 1; R1 is a carboxylic acid group (&#x2014;COOH), or an ester group which is hydrolysable by one or more intracellular esterase enzymes to a carboxylic acid group; R2 is the side chain of a natural or non-natural alpha amino acid; Y is a bond, &#x2014;C(&#x2550;O)&#x2014;, &#x2014;S(&#x2550;P)2-, &#x2014;C(&#x2550;O)O&#x2014;, &#x2014;C(&#x2550;O)NR3-, &#x2014;C(&#x2550;S)&#x2014;NR, &#x2014;C(&#x2550;NH)&#x2014;NRor &#x2014;S(&#x2550;O)NR&#x2014; wherein Ris hydrogen or optionally substituted C-Calkyl; L is a divalent linker radical of formula -(Alk)(Q)(Alk)- wherein m, n, p, Q, AIkand AIkare as defined in the claims. 

IKK-beta serine-threonine protein kinase inhibitors

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

A compound of formula (I), or an enantiomer or diastereoisomer thereof, or a salt, hydrate or solvate thereof: for the treatment or prophylaxis of arthritis in mammals.

Derivatives of hydroxamic acid as metalloproteinase inhibitors

Compounds formula (IA) or (IB), wherein W represents HO(C&#x2550;O)&#x2014;, HONH(C&#x2550;O)&#x2014; or H(C&#x2550;O)N(OH)&#x2014;; X represents &#x2014;O&#x2014; or &#x2014;S&#x2014;; and R, R, and Rare as defined in the description and claims, are inhibitors of matrix metalloproteinases, in particular MMP9 and/or MMP12.

Growing community of inventors

Abingdon, United Kingdom

Stephen John Davies