Chroma Therapeutics Limited

Glaxosmithkline Intellectual Property Development Limited

Alan Hornsby Davidson

David Festus Charles Moffat

Sanjay Ratilal Patel

Stephen John Davies

Alan Hastings Drummond

Alastair David Graham Donald

Francesca Ann Day

Alistair David Graham Donald

Francesca Ann Mazzei

Kenneth William John Baker

Alistair David Donald

David Festus Moffat

David Charles Festus Moffat

Lindsey Ann Needham

Andrew James Belfield

David Festus C Moffat

Kenneth William Baker

Compounds of formula (I) inhibit HDAC activity: wherein A, B and D independently represent &#x2550;C&#x2014; or &#x2550;N&#x2014;; W is a divalent radical &#x2014;CH&#x2550;CH&#x2014; or CHCH&#x2014;; Ris an ester group; Ris the side chain of a natural or non-natural alpha-amino acid; z is 0 or 1; and Y, L, and Xare as defined in the claims.

HDAC inhibitors

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

Compounds of formula (I) inhibit HDAC activity: wherein A, B and D independently represent &#x2550;C&#x2014; or &#x2550;N&#x2014;; W is a divalent radical &#x2014;CH&#x2550;CH&#x2014; or CHCH&#x2014;; 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; z is 0 or 1; and Y, L, and Xare as defined in the claims.

Methods of treating lymphoma and rheumatoid arthritis with cyclopentyl (2S)-cyclohexyl[({6-[3-(hydroxyamino)-3-oxopropyl]pyridin-3-yl}methyl)amino]acetate

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), and salts, N-oxides, hydrates and solvates thereof are histone deacetylase inhibitors and are useful in the treatment of cell proliferative diseases, including cancers: wherein Q, V and W independently represent &#x2014;N&#x2550; or &#x2014;C&#x2550;; B is a divalent radical selected from (B1), (B2), (B3), (B4), (B5) and (B6). 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; -[Linker1]- and -[Linker2]- independently represent a bond, or a divalent linker radical; and R is (a) a radical of formula RRCHNH&#x2014;Y-L-X&#x2014;(CH)&#x2014; or (b) a radical of formula R-L-Y&#x2014;(CH)&#x2014;.

Hydroxamates as inhibitors of histone deacetylase

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

Compounds of formula (I) inhibit HDAC activity, wherein A, B and D independently represent &#x2550;C&#x2014; or &#x2550;N&#x2014;; W is a divalent radical &#x2014;CH&#x2550;CH&#x2014; or CHCH&#x2014;; 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; z is 0 or 1; and Y, L, and Xare as defined in the claims. 

Compounds which inhibit members of the histone deacetylase family of enzymes and their use in the treatment of cell proliferative diseases

Compounds of formula (I) or (II) are dihydrofolate reductase inhibitors, useful for the treatment of, for example, cell proliferative diseases: wherein A and D are independently &#x2014;CHR&#x2014; or &#x2014;NR&#x2014;; E and G are independently &#x2550;CR&#x2014; or &#x2550;N&#x2014;; each Rindependently represents hydrogen or &#x2014;OR; Ris hydrogen or C-Calkyl; 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 the side chain of a natural or non-natural alpha amino acid which does not contain a carboxyl, or carboxyl ester group; Y is a bond, &#x2014;C(&#x2550;O)&#x2014;, &#x2014;S(&#x2550;O)&#x2014;, &#x2014;C(&#x2550;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, and Q, Alkand Alkare as defined in the claims; 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; and z is 0 or 1.

DHFR enzyme inhibitors

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 (I) are inhibitors of histone deacetylase activity, and are useful in the treatment of, for example, cancers: wherein 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 radical of formula -(Alk)(Q)(Alk)wherein m, n, p, Alk, Alkand Q are as defined in the claims; z is 0 or 1; A represents an optionally substituted mono-, bi&#x2014; or tri-cyclic carbocyclic or heterocyclic ring system; -[Linker]- represents a divalent linker radical; 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 B is a monocyclic heterocyclic ring of 5 or 6 ring atoms wherein Ris linked to a ring carbon adjacent the ring nitrogen shown, and ring B is optionally fused to a second carbocyclic or heterocyclic ring of 5 or 6 ring atoms in which case the bond shown intersected by a wavy line may be from a ring atom in said second ring.

Hydroxamic acid derivatives as inhibitors of HDAC enzymatic activity

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

Growing community of inventors

Abingdon, United Kingdom

Alan Hornsby Davidson