Cancer Research Technology Limited

The Institute of Cancer Research

Vernalis &r&d) Ltd.

Vernalis (cambridge) Limited

Thomas Peter Matthews

Ian James Collins

Kwai Ming Cheung

Edward McDonald

Brian William Dymock

Martin James Drysdale

Michael Lainchbury

Paul Webb

Harry Finch

Karen Elizabeth James

John Charles Reader

James Daniel Osborne

Michelle Dawn Garrett

Michael Ian Walton

Tatiana Faria Da Fonseca Mchardy

Michael Cherry

Sukhbinder Singh Klair

David Hugh Williams

Jane Elizabeth Scanlon

Nelly Piton

Glynn Jonathan Addison

Nicolas Proisy

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

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 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 certain pyridyl-amino-pyrazine carbonitrile compounds that, 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 thymidylate synthase (TS) inhibitor; (d) a microtubule targeted agent; and (e) ionizing radiation. 

5-(Pyridin-2-yl-amino)-pyrazine-2-carbonitrile compounds and their therapeutic use

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 certain pyridyl-amino-pyrazine carbonitrile compounds that, 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 thymidylate synthase (TS) inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation. 

5-(pyridin-2-yl-amino)-pyrazine-2-carbonitrile compounds and their therapeutic use

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.

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain biarylamine compounds (referred to herein as BAA compounds), and especially certain pyrazin-2-yl-pyridin-2-yl-amine and pyrazine-2-yl-pyrimidin-4-yl-amine 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 TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Pyrazin-2-yl-pyridin-2-yl-amine and pyrazin-2-yl-pyrimidin-4-yl-amine compounds and their use

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain biarylamine compounds (referred to herein as BAA compounds), and especially certain pyrazin-2-yl-pyridin-2-yl-amine and pyrazine-2-yl-pyrimidin-4-yl-amine compounds of formula (I), 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 TS inhibitor; (d) a microtubule targeted agent; and (e) ionisi&#x3c0;q radiation, wherein: &#x2014;X&#x2550; is independently &#x2014;CR&#x2550; or &#x2014;N&#x2550;; and the rest of the substituents are as specified in the claims.

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. 

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Sutton, United Kingdom

Thomas Peter Matthews