Cancer Research Technology Limited

Institute of Cancer Research: Royal Cancer Hospital (the)

The Institute of Cancer Research: Royal Cancer Hospital

Astex Therapeutics Limited

Oxy Scientific Limited

Institute of Cancer Research: Royal Cancer Hosp. (the)

The Institute of Cancer Research : the Royal Cancer Hospital

Dan Niculescu-Duvaz

Caroline Joy Springer

Richard Marais

Alfonso Zambon

Ion Niculescu-Duvaz

Delphine Menard

Arnaud Nourry

Leo Leung

Deborah Smithen

Haoran Tang

Bartholomeus Marinus Josephus Marie Suijkerbuijk

Cedric Callens

Mohammed Aljarah

Michael Brown

Christopher Lord

Alan Ashworth

Trevor Robert Perrior

Rebekah Elisabeth Key

Harmen Dijkstra

Natalie Miller

Romina Girotti

Ashley Nicholas Jarvis

Stuart Firth-Clark

Melanie Jayne Bayford

Raymond John Boffey

Roderick Alan Porter

Richard Chubb

Adrian Liam Gill

Richard David Taylor

Kiri North

Rehan Aqil

Esteban Roman Vela

Anna Hopkins

Christopher James Lord

Philip Alan Skone

Ben Ayers

Lawrence Davies

Richard James Rowland Elliott

Steven Whittaker

Richard James Rowland Elliot

Catherine Gaulon

Richard Malcolm Marais

Whittaker Steven

Roderick Porter

Bartholomeus Marinus Suijkerbuijk

This invention relates to compounds useful as lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) family member (LOXL1, LOXL2, LOXL3, LOXL4) inhibitors. In addition there are contemplated pharmaceutical compositions comprising the compounds and the use of the compounds in the treatment of conditions mediated by LOX and LOXL, for example cancer. In particular a LOX inhibitor such as the present compounds may be for use in the treatment of a cancer associated with EGFR. The present invention also contemplates the identification of biomarkers that predict responsiveness to a LOX inhibitor.

Lysyl oxidase inhibitors

The disclosure relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof, wherein Xand Xis each selected from CRor N; X, Xand Xis each selected from CR, CRor N, provided at least one of X, Xand Xis CRand provided only one of X, X, X, Xand Xcan be N. R, R, R, R, R, L, Land Lare as defined herein. Compounds according to Formula (I) are pharmacologically effective as lysyl oxidase (LOX) inhibitors and are believed to be useful in the treatment of, for instance, cancer.

Hexahydropyrrolo[3,4-c]pyrrole derivatives useful as LOX inhibitors

Provided are compounds of the Formula (I), or a pharmaceutically acceptable salt thereof: wherein W, X, Y, Z, x, R, R, R, x and n are defined in the specification. The compounds are inhibitors of lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) family members (LOXL1, LOXL2, LOXL3, LOXL4) and are useful in therapy, particularly in the treatment of cancer. Also disclosed are LOX inhibitors for use in the treatment of a cancer associated with EGFR and biomarkers that predict responsiveness to a LOX inhibitor.

Methylamine derivatives as lysysl oxidase inhibitors for the treatment of cancer

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain 1-(5-tert-butyl-2-aryl-pyrazol-3-yl)-3-[2-fluoro-4-[(3-oxo-4H-pyrido[2,3-b]pyrazin-8-yl)oxy]phenyl]urea compounds (referred herein as 'TBAP compounds') that, inter alia, inhibit RAF (e.g., BRAF, CRAF, etc.). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit RAF (e.g., BRAF, CRAF, etc.); and to treat disorders including: proliferative disorders; cancer (including, e.g., malignant melanoma, colorectal carcinoma, pancreatic adenocarcinoma); inflammation; immunological disorders; viral infections; fibrotic disorders; disorders associated with a mutated form of RAF (e.g., BRAF, CRAF, etc.); disorders ameliorated by the inhibition of RAF (e.g., BRAF, CRAF, etc.); disorders ameliorated by the inhibition of mutant BRAF; disorders ameliorated by the inhibition of BRAF and CRAF; disorders associated with RAS mutations and/or MAPK pathway activation; disorders ameliorated by the inhibition of SRC, p38, FGFRA, VEGFR-2 (KDR), and/or LCK; etc. 

1-(5-tert-butyl-2-aryl-pyrazol-3-yl)-3-[2-fluoro-4-[(3-oxo-4H-pyrido [2, 3-B]pyrazin- 8-yl)oxy]phenyl]urea derivatives as RAF inhibitors for the treatment of cancer

The present invention pertains generally to the field of organic chemical synthesis, and in particular to certain methods for the synthesis of 8-(4-aminophenyoxy)-4H-pyrido[2,3-b]pyrazin-3-one and related compounds (denoted herein as (3)) from 4-(4-aminophenyoxy)pyridine-2,3-diamine and related compounds (denoted herein as (1)), by reaction with glyoxylic acid (denoted herein as (2)). The compounds (3) are useful in the synthesis of known anti-cancer agents, such as 1-(5-tert-butyl-2-(4-methyl-phenyl)-pyrazol-3-yl)-3-[2-fluoro-4-[(3-oxo-4H-pyrido[2,3-b]pyrazin-8-yl)oxy]phenyl]urea. 

Process for the preparation of 8-(4-aminophenoxy)-4H-pyrido[2,3-b]pyrazin-3-one derivatives

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain compounds of the following formula (for convenience, collectively referred to herein as 'IP compounds'), which, inter alia, are useful in the treatment of cancer, e.g., cancer characterized by (e.g., driven by) mutant RAS ('mutant RAS cancer'). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions in the treatment of cancer, e.g., mutant RAS cancer. 

1-(5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)-phenyl]-urea and related compounds and their use in therapy

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain 1-(5-tert-butyl-2-aryl-pyrazol-3-yl)-3-[2-fluoro-4-[(3-oxo-4H-pyrido[2,3-b]pyrazin-8-yl)oxy]phenyl]urea compounds (referred herein as 'TBAP compounds') that, inter alia, inhibit RAF (e.g., BRAF, CRAF, etc.). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit RAF (e.g., BRAF, CRAF, etc.); and to treat disorders including proliferative disorders; cancer (including, e.g., malignant melanoma, colorectal carcinoma, pancreatic adenocarcinoma); inflammation; immunological disorders; viral infections; fibrotic disorders; disorders associated with a mutated form of RAF (e.g. BRAF, CRAF, etc.); disorders ameliorated by the inhibition of RAF (e.g., BRAF. CRAF, etc.); disorders ameliorated by the inhibition of mutant BRAF; disorders ameliorated by the inhibition of BRAF and CRAF; disorders associated with RAS mutations and/or MAPK pathway activation; disorders ameliorated by the inhibition of SRC, p38, FGFRA, VEGFR-2 (KDR), and/or LCK; etc. 

1-(5-tert-butyl-2-aryl-pyrazol-3-yl)-3-[2-fluoro-4-[(3-oxo-4H-pyrido[2,3-b]pyrazin-8-yl)oxy]phenyl]urea derivatives as RAF inhibitors for the treatment of cancer

Process for the preparation of 8-(4-aminophenoxy)-4H-pyrido[2,3-B]pyrazin-3-one derivatives

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain 3-aryl-5-substituted-2/-/-isoquinolin-1-one compounds that, inter alia, inhibit PARP (e.g., PARP1, TNKS1, TNKS2, etc.) and/or Wnt signalling. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit PARP (e.g., PARP1, TNKS1, TNKS2, etc.); to inhibit Wnt signalling; to treat disorders that are ameliorated by the inhibition of PARP (e.g., PARP1, TNKS1, TNKS2, etc.); to treat disorders that are ameliorated by the inhibition of Wnt signalling; to treat proliferative conditions such as cancer, etc. 

3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use

The present invention pertains generally to the field of therapeutic compounds for treating proliferative disorders, cancer, etc., and more specifically to certain pyrido[2,3-b]pyrazin-8-substituted compounds, as described herein, which, inter alia, inhibit RAF (e.g.,B-RAF) activity. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit RAF (e.g., BRAF) activity, to inhibit receptor tyrosine kinase (RTK) activity, to inhibit cell proliferation, and in the treatment of diseases and disorders that are ameliorated by the inhibition of RAF, RTK, etc., proliferative disorders such as cancer (e.g., colorectal cancer, melanoma), etc.

Pyrido[2,3-b]pyrazin-8-substituted compounds and their use

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain compounds of the following formula (for convenience, collectively referred to herein as 'IP compounds'), which, inter alia, are useful in the treatment of cancer, e.g., cancer characterised by (e.g., driven by) mutant RAS ('mutant RAS cancer'). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions in the treatment of cancer, e.g., mutant RAS cancer. 

1-(5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-B]pyridin-7-yloxy)-phenyl]-urea and related compounds and their use in therapy

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain 3-aryl-5-substituted-2H-isoquinolin-1-one compounds that, inter alia, inhibit PARP (e.g., PARP1, TNKS1, TNKS2, etc.) and/or Wnt signalling. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit PARP (e.g., PARP1, TNKS1, TNKS2, etc.); to inhibit Wnt signalling; to treat disorders that are ameliorated by the inhibition of PARP (e.g., PARP1, TNKS1, TNKS2, etc.); to treat disorders that are ameliorated by the inhibition of Wnt signalling; to treat proliferative conditions such as cancer, etc. 

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Sutton, United Kingdom

Dan Niculescu-Duvaz