Cancer Research Technology Limited

The Institute of Cancer Research

Vernalis &r&d) Ltd.

Cyclacel Limited

Vernalis (cambridge) Limited

Bristol-myers Squibb Compnay

Pharmacopeia Inc.

Pharmacopeia Drug Discovery, Inc.

Other

Ludwig Institute for Cancer Research Limited

Astellas Pharma Gmbh

Daiichi Pharmaceutical Co., Ltd.

F. Hoffmann-la Roche Ag

The Institute of Cancer Research: Royal Cancer Hospital

Institute of Cancer Research of Royal Cancer Hospital

Edward McDonald

Brian William Dymock

Martin James Drysdale

Kwai Ming Cheung

Paul Webb

Thomas Peter Matthews

Harry Finch

Karen Elizabeth James

John J Baldwin

Paul Workman

Kevin Joseph Moriarty

Peter Martin Fischer

Michael Jarman

Florence Irene Raynaud

Bernard Paul Nutley

Stuart Wilson

Katerina Leftheris

Alaric J Dyckman

Koc-Kan Ho

Stephen T Wrobleski

Tao Guo

Shawn David Erickson

Wei Li

Atsushi Nakayama

Christopher Ronald Sarko

Jeffrey John Letourneau

Ian Henderson

Axel Metzger

Steven G Kultgen

Yvonne Class Shimshock

Gulzar Ahmed

Nobuo Machinaga

Jun Chiba

Yoshiyuki Yoneda

Zahid Hussain

James Wen

Junjun Wu

Roland Ellwood Dolle

Kurt William Saionz

Julian Blagg

Peter William Sheldrake

Simon Richard Green

Robert A Horlick

Vassilios Bavetsias

Stephen Joseph Shuttleworth

Guizhen Dong

Butrus Atrash

Shin Iimura

John Richard Morphy

Ruiyan Liu

Adolph C Bohnstedt

Mandy Christine Beswick

Peng Geng

Anton Egbert Peter Adang

Spyridon Linardopoulos

Xavier Barril-Alonso

Simon Ross Crumpler

Laurence Pearl

Nicole Corine Renee Van Straten

Sheelagh Frame

Kenneth C Appell

Chrisostomos Prodromou

Mark Pichowicz

Jonathan M Large

Iimura Shin

Zoran Rankovic

Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: wherein R, is a group of formula (IA): &#x2014;Ar-(Alk)-(Z)-(Alk)-Q, wherein in any compatible combination Aris an optionally substituted aryl or heteroaryl radical, Alkand Alkare optionally substituted divalent C-Calkylene or C-Calkenylene radicals, p, r and s are independently 0 or 1, Z is -0-, &#x2014;S&#x2014;, &#x2014;(C&#x2550;O)&#x2014;, &#x2014;(C&#x2550;S)&#x2014;, &#x2014;SO.sub.2-, &#x2014;C(&#x2550;O)O&#x2014;, &#x2014;C(&#x2550;O)NR&#x2014;, &#x2014;C(&#x2550;S) NR&#x2014;, &#x2014;SONR&#x2014;, &#x2014;NRC(&#x2550;O)&#x2014;, &#x2014;NRSO&#x2014; or &#x2014;NR&#x2014; wherein Ris hydrogen or C-Calkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; Ris (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk)p-(Z)-(Alk)-Q wherein Q, Alk, Alk, Z, p, r and s are as defined above in relation to group (IA); and Ris hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C-Calkyl, C-Calkenyl, or C-Calkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

Isoxazole compounds as inhibitors of heat shock proteins

Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: wherein R, is a group of formula (IA): &#x2014;Ar-(Alk)-(Z)-(Alk)-Q, wherein in any compatible combination Aris an optionally substituted aryl or heteroaryl radical, Alkand Alkare optionally substituted divalent C-Calkylene or C-Calkenylene radicals, p, r and s are independently 0 or 1, Z is &#x2014;O&#x2014;, &#x2014;S&#x2014;, &#x2014;(C&#x2550;O)&#x2014;, &#x2014;(C&#x2550;S)&#x2014;, &#x2014;SO.sub.2-, &#x2014;C(&#x2550;O)O&#x2014;, &#x2014;C(&#x2550;O)NR&#x2014;, &#x2014;C(&#x2550;S)NR&#x2014;, &#x2014;SONR&#x2014;, &#x2014;NRC(&#x2550;O)&#x2014;, &#x2014;NRSO&#x2014; or &#x2014;NR&#x2014; wherein Ris hydrogen or C-Calkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; Ris (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk)p-(Z)-(Alk)-Q wherein Q, Alk, Alk, Z, p, r and s are as defined above in relation to group (IA); and Ris hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C-Calkyl, C-Calkenyl, or C-Calkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

The present invention relates to compounds of formula 1  A further aspect of the invention relates to pharmaceutical compositions comprising compounds of formula 1, and the use of said compounds in treating proliferative disorders, viral disorders, stroke, alopecia, CNS disorders, neurodegenerative disorders, or diabetes.

Purine derivatives

The present invention relates to pyridine and pyrimidine based compounds, pharmaceutical compositions comprising these compounds and their potential use as therapeutic agents for the treatment and/or prevention of cancer.

Pyridine and pyrimidine based compounds as Wnt signaling pathway inhibitors for the treatment of cancer

The present invention relates to compounds of formula (I) wherein: where one of X, Y and Z is N and the remainder are CR; A further aspect of the invention relates to pharmaceutical compositions comprising compounds of formula (I), and the use of said compounds in treating proliferative disorders, viral disorders, stroke, alopecia, CNS disorders, neurodegenerative disorders, or diabetes.

Trisubstituted purine derivatives

Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: wherein R, is a group of formula (IA): &#x2014;Ar-(Alk)-(Z)-(Alk)-Q, wherein in any compatible combination Aris an optionally substituted aryl or heteroaryl radical, Alkand Alkare optionally substituted divalent C-Calkylene or C-Calkenylene radicals, p, r and s are independently 0 or 1, Z is -0-, &#x2014;S&#x2014;, &#x2014;(C&#x2550;O)&#x2014;, &#x2014;(C&#x2550;S)&#x2014;, &#x2014;SO.sub.2-, &#x2014;C(&#x2550;O)O&#x2014;, &#x2014;C(&#x2550;O)NR&#x2014;, &#x2014;C(&#x2550;S)NR&#x2014;, &#x2014;SONR&#x2014;, &#x2014;NRC(&#x2550;O)&#x2014;, &#x2014;NRSO&#x2014;or &#x2014;NR&#x2014; wherein Ris hydrogen or C-Calkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; Ris (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk)-(Z)-(Alk)-Q wherein Q, Alk, Alk, Z, p, r and s are as defined above in relation to group (IA); and Ris hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C-Calkyl, C-Calkenyl, or C-Calkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

Isoxazoles of formula (A) or (B) wherein Ris a group of formula (IB)  The isoxazoles are inhibitors of HSP90 activity, and useful for the treatment of, for example, cancers.

Compounds of formula (I), are aurora kinase inhibitors: wherein X is &#x2014;N&#x2014;, &#x2014;CH2-N&#x2014;, &#x2014;CH2-CH&#x2014;, or &#x2014;CH&#x2014;; R1 is a radical of formula (IA) wherein Z is &#x2014;CH2-, &#x2014;NH&#x2014;, -0-, &#x2014;S(O)&#x2014; &#x2014;S&#x2014;, &#x2014;S(O)2 or a divalent monocyclic carbocyclic or heterocyclic radical having 3-7 ring atoms; Alk is an optionally substituted divalent C1-C6 alkylene radical; A is hydrogen or an optionally substituted monocyclic carbocyclic or heterocyclic ring having 5-7 ring atoms; r, s and t are independently 0 or 1, provided that when A is hydrogen then at least one of r and s is 1; R2 is halogen, &#x2014;CN, &#x2014;CF3, &#x2014;OCH3, or cyclopropyl; and R3 is a radical of formula (IB) wherein Q is hydrogen or an optionally substituted phenyl or monocyclic heterocyclic ring with 5 or 6 ring atoms; Z&It;1> is &#x2014;S&#x2014;, &#x2014;S(O)&#x2014;, &#x2014;S(O)2-, &#x2014;O&#x2014;, &#x2014;SO2NH&#x2014;, &#x2014;NHSO2-, NHC(&#x2550;O)NH, &#x2014;NH(C&#x2550;S)NH&#x2014;, Or &#x2014;N(R4)&#x2014; wherein R4 is hydrogen, C1-C3 alkyl, cycloalkyl, or benzyl; and Alk&It;1> and Alk&It;2> are, independently, optionally substituted divalent C1-C3 alkylene radicals; and m, n and p are independently 0 or 1.

Enzyme inhibitors

Compound of a compound of formula (I) or a salt, N-oxide, hydrate or solvate thereof, in the preparation of a composition for inhibition of HSP90 activity: wherein ring A is an aromatic or non-aromatic carbocyclic or heterocyclic ring having 5 ring atoms, for example 1,2,3-triazolyl or a 1,2,4-triazolyl or a tetrazolyl ring; and RRRare as defined in the specification are inhibitors of HSP90 and therefore of use in the treatment of, for example, cancers, viral disease, inflammatory diseases such as rheumatoid arthritis, asthma, multiple sclerosis, Type I diabetes, lupus, psoriasis and inflammatory bowel disease; cystic fibrosis angiogenesis-related disease such as diabetic retinopathy, haemangiomas, and endometriosis; or for protection of normal cells against chemotherapy-induced toxicity; or diseases where failure to undergo apoptosis is an underlying factor, or protection from hypoxia-ischemic injury due to elevation of Hsp70 in the heart and brain; scrapie/CJD, Huntingdon's and Alzheimer's disease. 

Substituted 5-membered ring compounds and their use

Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: (A), (B) wherein R, is a group of formula (IA): &#x2014;Ar-(Alk)p-(Z)-(Alk)-Q, wherein in any compatible combination Aris an optionally substituted aryl or heteroaryl radical, Alkand Alkare optionally substituted divalent C-Calkylene or C-Calkenylene radicals, p, r and s are independently 0 or 1, Z is &#x2014;O&#x2014;, &#x2014;S&#x2014;, &#x2014;(C&#x2550;O)&#x2014;, &#x2014;(C&#x2550;S)&#x2014;, &#x2014;SO&#x2014;, &#x2014;C(&#x2550;O)O&#x2014;, &#x2014;C(&#x2550;O)NR&#x2014;, &#x2014;C(&#x2550;S)NR&#x2014;, &#x2014;SONR&#x2014;, &#x2014;NRC(&#x2550;O)&#x2014;, &#x2014;NRSO&#x2014; or &#x2014;NR&#x2014; wherein Ris hydrogen or C-Calkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; Ris (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk)p-(Z)-(Alk)-Q wherein Q, Alk, Alk, Z, p, r and s are as defined above in relation to group (IA); and Ris hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C-Calkyl, C-Calkenyl, or C-Calkynyl; or a carboxyl, carboxamide, or carboxyl ester group. 

Pyrimidines of formula (I): wherein Rto R, X and Y are defined in the specification are inhibitors of P13K and may thus be used to treat diseases and disorders arising from abnormal cell growth, function or behavior associated with P13 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.

Pharmaceutical compounds

Compounds of formula (IA) or (IB) or a salt, N-oxide, hydrate or solvate thereof are inhibitors of HSP90, and are of value in the treatment of diseases responsive to HSP90 inhibition such as cancers. In the formulae, Ar is an aryl, aryl(C-Calkyl), aryl(C-Calkyl), heteroaryl, heteroarylaryl(C-Calkyl), or heteroarylaryl(C-Calkyl) group, any of which being optionally substituted in the aryl or heteroaryl part thereof; R, is hydrogen or optionally substituted C-Calkyl; Ris hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C-Calkyl, C-Calkenyl, or C-Calkynyl; or a carboxyl, carboxamide or carboxyl ester group; and ring A is a non aromatic carbocyclic or heterocyclic ring wherein (i) a ring carbon is optionally substituted, and/or (ii) a ring nitrogen is optionally substituted by a group of formula -(Alk)(Cyc)-(Alk)-(Z)r (Alk)Q where Alk, Alkand Alkare optionally substituted C-Calkyl, Cyc is an optionally substituted carbocyclic or heterocyclic radical; m, n, p, r and s are independently 0 or 1, Z is -0-, &#x2014;S&#x2014;, &#x2014;(C&#x2550;O)&#x2014;, &#x2014;S02-, &#x2014;C(&#x2550;O)O&#x2014;, &#x2014;OC(&#x2550;O)&#x2014;, &#x2014;NW&#x2014;, &#x2014;C(&#x2550;O)NRA-, &#x2014;NRC(&#x2550;O)&#x2014;, &#x2014;SONR&#x2014;, or &#x2014;NRSO&#x2014; wherein Ris hydrogen or C-Calkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical. 

Pyrazole compounds

The present invention relates to compounds of formula 1 or pharmaceutically acceptable salts thereof, wherein A further aspect of the invention relates to pharmaceutical compositions comprising compounds of formula 1, and the use of said compounds in treating proliferative disorders, viral disorders, stroke, alopecia, CNS disorders, neurodegenerative disorders, or diabetes.

The present invention relates to compounds of formula I or pharmaceutically acceptable salts thereof, wherein A further aspect of the invention relates to pharmaceutical compositions comprising compounds of formula 1, and the use of said compounds in treating proliferative disorders, viral disorders, CNS disorders, diabetes, stroke, alopecia or neurodegenerative disorders.

Growing community of inventors

Surrey, United Kingdom

Edward McDonald