Cancer Research Technology Limited

Astex Therapeutics Limited

The Institute of Cancer Research: Royal Cancer Hospital

Michelle Dawn Garrett

Ian James Collins

Robert George Boyle

Michael Lainchbury

Thomas Peter Matthews

James Daniel Osborne

Tatiana Faria Da Fonseca Mchardy

Michael Ian Walton

Thomas Glanmor Davies

Neil Thomas Thompson

John Francis Lyons

Kyla Merriom Thompson

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to 5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2-pyridyl]amino]pyrazine-2-carbonitrile compounds (referred to herein as 'TFM compounds') which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function. 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 CHK1 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1, that are ameliorated by the inhibition of CHK1 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or a thymidylate synthase (TS) inhibitor; (d) a microtubule targeted agent; (e) ionising radiation; (f) an inhibitor of a mitosis regulator or a mitotic checkpoint regulator; (g) an inhibitor of a DNA damage signal transducer; or (h) an inhibitor of a DNA damage repair enzyme.

5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2 Pyridyl]Amino]Pyrazine-2-carbonitrile and therapeutic uses thereof

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to 5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2-pyridyl]amino]pyrazine-2-carbonitrile compounds (referred to herein as 'TFM compounds') which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function. 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 CHK1 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1, that are ameliorated by the inhibition of CHK1 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or a thymidylate synthase (TS) inhibitor; (d) a microtubule targeted agent; (e) ionizing radiation; (f) an inhibitor of a mitosis regulator or a mitotic checkpoint regulator; (g) an inhibitor of a DNA damage signal transducer; or (h) an inhibitor of a DNA damage repair enzyme. 

5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2 pyridyl]amino]pyrazine-2-carbonitrile and therapeutic uses thereof

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to 5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2-pyridyl]amino]pyrazine-2-carbonitrile compounds (referred to herein as 'TFM compounds') which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function. 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 CHK1 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1, that are ameliorated by the inhibition of CHK1 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or a thymidylate synthase (TS) inhibitor; (d) a microtubule targeted agent; (e) ionizing radiation; (f) an inhibitor of a mitosis regulator or a mitotic checkpoint regulator; (g) an inhibitor of a DNA damage signal transducer; or (h) an inhibitor of a DNA damage repair enzyme.

5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2-pyridyl]amino]pyrazine-2-carbonitrile and therapeutic uses thereof

The invention provides a compound of the formula (I) or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR; J-Jis N&#x2550;C(R), (R)C&#x2550;N, (R)N&#x2014;C(O), (R)C&#x2014;C(O), N&#x2550;N or (R)C&#x2550;C(R); E is a monocyclic carbocyclic or heterocyclic group of 5 or 6 ring members, the heterocyclic group containing up to 3 heteroatoms selected from O, N and S; Qis a bond or a saturated Chydrocarbon linker group, one of the carbon atoms in the linker group being optionally be replaced by an oxygen or nitrogen atom, or an adjacent pair of carbon atoms may be replaced by CONRor NRCO where Ris hydrogen or methyl, or Ris a Calkylene chain linked to Ror a carbon atom of Qto form a cyclic moiety; and wherein the carbon atoms of the linker group Qmay optionally bear one or more substituents selected from fluorine and hydroxy; Qis a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group may optionally bear one or more substituents selected from fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom &#x3b1; with respect to the G group; and provided that when E is aryl or heteroaryl, then Qis other than a bond; G is hydrogen, NRR, OH or SH provided that when E is aryl or heteroaryl and Qis a bond, then G is hydrogen; Ris hydrogen or an aryl or heteroaryl group, with the proviso that when Ris hydrogen and G is NRR, then Qis a bond; and R, RR, Rand Rare as defined in the claims, wherein the compound is for use in: (a) the treatment or prophylaxis of a disease or condition in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase P70S6K is indicated; and/or (b) the treatment of a subject or patient population in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase P70S6K is indicated. 

Purine and deazapurine derivatives as pharmaceutical compounds

The invention provides a combination comprising an ancillary compound (e.g. one, two or more ancillary compounds) and a compound of the formula (I) having protein kinase B inhibiting activity: wherein A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between Rand NRRand a maximum chain length of 4 atoms extending between E and NRR, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally bear one or more substituents selected from oxo, fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom &#x3b1; with respect to the NRRgroup and provided that the oxo group when present is located at a carbon atom &#x3b1; with respect to the NRRgroup; E is a monocyclic or bicyclic carbocyclic or heterocyclic group; Ris an aryl or heteroaryl group; and R, R, Rand Rare as defined in the claims. Also provided are patient packs, pharmaceutical kits and packs and compositions containing the combinations, methods for preparing the combinations and their use in combination therapy as anticancer agents. 

Pharmaceutical combinations comprising pyrazole derivatives as protein kinase modulators

The invention provides compounds of the formula (I) having ROCK kinase and/or protein kinase p70S6K inhibiting activity: wherein A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between R1 and NRRand a maximum chain length of 4 atoms extending between E and NRR, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally bear one or more substituents selected from oxo, fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom &#x3b1; with respect to the NRRgroup and provided that the oxo group when present is located at a carbon atom &#x3b1; with respect to the NRRgroup; E is a monocyclic or bicyclic carbocyclic or heterocyclic group; Ris an aryl or heteroaryl group; and R, R, Rand Rare as defined in the claims. 

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Walton-on-Thames, United Kingdom

Michelle Dawn Garrett