Astex Therapeutics Limited

Cancer Research Technology Limited

The Institute of Cancer Research : the Royal Cancer Hospital

Martyn Frederickson

Gianni Chessari

Alison Jo-Anne Woolford

Miles Stuart Congreve

Christopher William Murray

Andrew James Woodhead

Eva Figueroa Navarro

Michael Alistair O'Brien

Maria Grazia Carr

Brian John Williams

Robert Downham

Theresa Rachel Phillips

Charlotte Mary Griffiths-Jones

Christopher Norbert Johnson

Steven Howard

Ildiko Maria Buck

Thomas Daniel Heightman

James Edward Harvey Day

Emiliano Tamanini

Elisabetta Chiarparin

Neil Thomas Thompson

John Francis Lyons

Mladen Vinkovic

Patrick René Angibaud

Andrew Madin

Eddy Jean Edgard Freyne

Valerio Berdini

Gordon Saxty

David Charles Rees

Steven John Woodhead

Christopher Charles Frederick Hamlett

Emma Vickerstaffe

Tom Cornelis Hortense Govaerts

Michael Alistair O'brien

Rajdeep Kaur Benning

Kyla Merriom Grimshaw

Lynsey Helen Fazal

Charlotte Mary Griffiths-jones

Alison Jo-Ann Woolford

The invention relates to bicyclic heterocycle compounds of formula (I): or tautomeric or stereochemically isomeric forms, N-oxides, pharmaceutically acceptable salts or the solvates thereof; wherein R, R, R, R, R, R, R, R, R, R, p and E are as defined herein; to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

Bicyclic heterocycle compounds and their uses in therapy

The invention provides compounds of the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein Ris hydroxy or hydrogen; Ris hydroxy; methoxy or hydrogen; provided that at least one of Rand Ris hydroxy; Ris selected from hydrogen; halogen; cyano; optionally substituted Chydrocarbyl and optionally substituted Chydrocarbyloxy; Ris selected from hydrogen; a group &#x2014;(O)&#x2014;Rwhere n is 0 or 1 and Ris an optionally substituted acyclic Chydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-Chydrocarbyl-amino; or Rand Rtogether form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NRRforms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur. The compounds have activity as Hsp90 inhibitors.

Hydroxybenzamide derivatives and their use as inhibitors of HSP90

The invention provides an acid addition salt of a compound of the formula (1). Also provided by the invention are processes for preparing the compound of formula (1) and alkyl analogs thereof, novel intermediates for use in the process and methods for preparing the intermediates. The invention also provides new medical uses of compounds of the formula (1) and its ethyl analog.

Hydrobenzamide derivatives as inhibitors of Hsp90

The invention relates to bicyclic heterocycle compounds of formula (I): or tautomeric or stereochemically isomeric forms, N-oxides, pharmaceutically acceptable salts or the solvates thereof; wherein R, R, R, R, R, R, R, R, R, R, p and E are as defined herein; to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer. 

The invention provides compounds of the general formula (I) which have activity as Hsp90 inhibitors.

Hydroxybenzamide derivatives and their use as inhibitors of Hsp90

The invention relates to new bicyclic heterocyclic derivative compounds, to pharmaceutical compositions comprising the compounds and to the use of the compounds in the treatment of diseases, e.g. cancer.

Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases

The invention provides a compound for use in medicine, the compound being a compound of the formula (VI) or a salt, solvate, tautomer or N-oxide thereof: wherein the bicyclic group: is selected from the structures C1, C5 and C6: wherein n is 0, 1, 2 or 3; Ris hydrogen, hydroxy, or O&#x2014;R; Ris hydroxy, methoxy or O&#x2014;R; provided that at least one of Rand Ris O&#x2014;R; Ris L-R; SOH; a glucuronide residue; a mono-, di- or tripeptide residue; or Lis a bond, C&#x2550;O, (C&#x2550;O)O, (C&#x2550;O)NRor S(O)NR; x is 1 or 2; Ris hydrogen or a an optionally substituted Chydrocarbyl group containing 0, 1 or 2 carbocyclic rings and 0, 1, 2, 3, 4, 5 or 6 carbon-carbon multiple bonds, provided that Ris not hydrogen when Lis a bond, C&#x2550;O or (C&#x2550;O)O; and provided also that O&#x2014;Rdoes not contain an O&#x2014;O moiety; and excluding compounds wherein Ris hydroxy and Ris methoxy; Rand Rare the same or different and each is a group R; and R, R, Rand Rare defined in the claims. The compounds of formula (VI) are pro-drugs of parent compounds wherein Rand/or Rare hydroxy, wherein the parent compounds have Hsp90 inhibiting activity.

Pharmaceutical compounds

The invention provides a compound of the formula (1): or a salt, solvate, N-oxide or tautomer thereof.

The invention provides an acid addition salt of a compound of the formula (1) Also provided by the invention are processes for preparing the compound of formula (1) and alkyl analogues thereof, novel intermediates for use in the process and methods for preparing the intermediates. The invention also provides new medical uses of compounds of the formula (1) and its ethyl analogue.

The invention provides a combination comprising an Hsp90 inhibitor compound of the formula (VII): or tautomer or salt thereof and one or more therapeutic agents selected from topoisomerase I inhibitors; antimetabolites; tubulin targeting agents; DNA binder and topoisomerase II inhibitors; alkylating agents; monoclonal antibodies; anti-hormones; signal transduction inhibitors; proteasome inhibitors; DNA methyl transferases; cytokines; retinoids and HDAC or HAT modulators.

Therapeutic combinations of hydroxybenzamide derivatives as inhibitors of HSP90

The invention provides a compound of the formula (1): or a salt, solvate, N-oxide or tautomer thereof;wherein either Ris Rand Ris R; or Ris Rand Ris R; provided that in each case at least one of Rand Ris other than hydrogen;Rand Rare the same or different and each is selected from hydrogen, Calkyl, Calkenyl and Calkynyl wherein the Calkyl is optionally substituted by Calkoxy;Rand Rare the same or different and are selected from hydrogen, C(O)NRR, C(O)Rand C(O)ORwhere Ris Calkyl, Rand Rare both Calkyl, or NRRforms a 4 to 7 membered saturated heterocyclic ring optionally containing a second heteroatom ring member selected from O, N or S and oxidized forms of N and S, the heterocyclic ring being optionally substituted by one or two Calkyl groups and/or one or two oxo groups; andRis a group D: wherein the asterisk denotes the point of attachment to the isoindoline ring;but excluding acetic acid 5-acetoxy-4-isopropyl-2-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindole-2-carbonyl]-phenyl ester.

This invention provides methods for treating cancer, particularly hematopoietic tumors of lymphoid or myeloid lineage, prostate cancer, lung cancer, gastrointestinal stromal tumor, breast cancer and melanoma, which comprise administering to the mammal a compound, salt, hydrate, tautomer or N-oxide according to formula (I): and in particular, those of subgenus VIIa  These compounds inhibit or modulate the activity of the heat shock protein Hsp90.

Dihydroxyphenyl isoindolylmethanones

The invention provides compounds of the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein Ris hydrogen; Ris hydroxy or methoxy; Ris selected from hydrogen; halogen; cyano; optionally substituted Chydrocarbyl and optionally substituted Chydrocarbyloxy; Ris selected from hydrogen; a group &#x2014;(O)&#x2014;Rwhere n is 0 or 1 and Ris an optionally substituted acyclic Chydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-Chydrocarbyl-amino; or Rand Rtogether form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NRRforms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur. The compounds have activity as Hsp90 inhibitors.

Compounds having the formula (I): and in particular, those of subgenus VIIa are disclosed as inhibits or modulators of the activity of the heat shock protein Hsp90. As such they are useful for treating cancer, particularly hematopoietic tumors of lymphoid or myeloid lineage, prostate cancer, lung cancer, gastrointestinal stromal tumor, breast cancer and melanoma.

Growing community of inventors

Cambridge, United Kingdom

Martyn Frederickson