公开(公告)号：US11234987B2

公开(公告)日：2022-02-01

申请号：US16528278

申请日：2019-07-31

Applicant: Vernalis (R&D) Ltd. ,  The Institute of Cancer Research ,  Cancer Research Technology Limited

Inventor： Martin James Drysdale ,  Brian William Dymock ,  Harry Finch ,  Paul Webb ,  Edward McDonald ,  Karen Elizabeth James ,  Kwai Ming Cheung ,  Thomas Peter Matthews

IPC: A61P25/14 ,  A61P25/28 ,  A61P17/06 ,  A61P17/00 ,  A61P9/10 ,  A61P15/00 ,  A61P43/00 ,  A61P25/00 ,  A61P3/10 ,  A61P35/00 ,  A61P19/02 ,  A61P29/00 ,  A61P27/02 ,  A61P11/06 ,  A61P1/00 ,  C07D495/04 ,  C07D261/10 ,  C07D261/08 ,  C07D417/04 ,  C07D413/04 ,  C07D413/10 ,  A61K31/42 ,  A61K31/4439 ,  A61K31/427 ,  A61K31/541 ,  A61K31/4709 ,  A61K31/496 ,  A61K31/5377 ,  A61K31/454 ,  A61K31/422 ,  A61P31/12

Abstract: Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: wherein R1, is a group of formula (IA): —Ar1-(Alk1)p-(Z)r-(Alk2)s-Q, wherein in any compatible combination Ar1 is an optionally substituted aryl or heteroaryl radical, Alk1 and Alk2 are optionally substituted divalent C1-C6 alkylene or C2-C6 alkenylene radicals, p, r and s are independently 0 or 1, Z is -0-, —S—, —(C═O)—, —(C═S)—, —SO.sub.2-, —C(═O)O—, —C(═O)NRA—, —C(═S) NRA—, —SO2NRA—, —NRAC(═O)—, —NRASO2— or —NRA— wherein RA is hydrogen or C1-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R2 is (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 -(Alk1)p-(Z)r-(Alk2)s-Q wherein Q, Alk1, Alk2, Z, p, r and s are as defined above in relation to group (IA); and R3 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

公开(公告)号：US11787792B2

公开(公告)日：2023-10-17

申请号：US17124606

申请日：2020-12-17

Applicant: Cancer Research Technology Limited

Inventor： Ian Collins ,  Thomas Peter Matthews ,  Tatiana Faria Da Fonseca McHardy ,  James Osborne ,  Michael Lainchbury ,  Michael Ian Walton ,  Michelle Dawn Garrett

IPC: C07D413/14 ,  A61P35/00 ,  A61P35/02 ,  A61K31/5377 ,  C07D413/02 ,  C07D401/12 ,  A61K9/00 ,  A61K31/4745 ,  A61K31/7068 ,  A61K45/06

CPC classification number: C07D413/14 ,  A61K9/0053 ,  A61K31/4745 ,  A61K31/5377 ,  A61K31/7068 ,  A61K45/06 ,  A61P35/00 ,  A61P35/02 ,  C07D401/12 ,  C07D413/02

Abstract: 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.

公开(公告)号：US20210276990A1

公开(公告)日：2021-09-09

申请号：US17124606

申请日：2020-12-17

Applicant: Cancer Research Technology Limited

Inventor： Ian Collins ,  Thomas Peter Matthews ,  Tatiana Faria Da Fonseca McHardy ,  James Osborne ,  Michael Lainchbury ,  Michael Ian Walton ,  Michelle Dawn Garrett

IPC: C07D413/14 ,  A61K31/4745 ,  C07D401/12 ,  C07D413/02 ,  A61K31/5377 ,  A61K9/00 ,  A61K45/06 ,  A61K31/7068

Abstract: 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.

公开(公告)号：US10413550B2

公开(公告)日：2019-09-17

申请号：US15631059

申请日：2017-06-23

Applicant: Vernalis (R&D) Ltd. ,  The Institute of Cancer Research ,  Cancer Research Technology Limited

Inventor： Martin James Drysdale ,  Brian William Dymock ,  Harry Finch ,  Paul Webb ,  Edward McDonald ,  Karen Elizabeth James ,  Kwai Ming Cheung ,  Thomas Peter Matthews

IPC: C07D261/08 ,  C07D261/10 ,  C07D495/04 ,  C07D417/04 ,  C07D413/04 ,  C07D413/10 ,  A61K31/454 ,  A61K31/42 ,  A61K31/496 ,  A61K31/541 ,  A61K31/427 ,  A61K31/422 ,  A61K31/4439 ,  A61K31/4709 ,  A61K31/5377

Abstract: Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: wherein R1, is a group of formula (IA): —Ar1-(Alk1)p-(Z)r-(Alk2)s-Q, wherein in any compatible combination Ar1 is an optionally substituted aryl or heteroaryl radical, Alk1 and Alk2 are optionally substituted divalent C1-C6 alkylene or C2-C6 alkenylene radicals, p, r and s are independently 0 or 1, Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO.sub.2-, —C(═O)O—, —C(═O)NRA—, —C(═S)NRA—, —SO2NRA—, —NRAC(═O)—, —NRASO2— or —NRA— wherein RA is hydrogen or C1-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R2 is (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 -(Alk1)p-(Z)r-(Alk2)s-Q wherein Q, Alk1, Alk2, Z, p, r and s are as defined above in relation to group (IA); and R3 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

公开(公告)号：US20160304493A1

公开(公告)日：2016-10-20

申请号：US15191967

申请日：2016-06-24

Applicant: Cancer Research Technology Limited

Inventor： Ian Collins ,  Michael Lainchbury ,  Thomas Peter Matthews ,  John Charles Reader

IPC: C07D401/14 ,  C07D401/12 ,  A61K45/06 ,  A61K31/497 ,  A61K9/00

CPC classification number: C07D401/14 ,  A61K9/0053 ,  A61K31/497 ,  A61K45/06 ,  A61N5/10 ,  A61N2005/1098 ,  C07D401/12

Abstract: 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.

公开(公告)号：US09040540B2

公开(公告)日：2015-05-26

申请号：US14356626

申请日：2012-11-09

Applicant: Cancer Research Technology Limited

Inventor： Ian Collins ,  Michael Lainchbury ,  Thomas Peter Matthews ,  John Charles Reader

IPC: A61K31/497 ,  C07D401/12 ,  C07D401/14

CPC classification number: C07D401/14 ,  A61K9/0053 ,  A61K31/497 ,  A61K45/06 ,  A61N5/10 ,  A61N2005/1098 ,  C07D401/12

Abstract: 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.

Abstract translation: 本发明一般涉及治疗化合物领域。 更具体地，本发明涉及特别是抑制检测点激酶1（CHK1）激酶功能的某些吡啶基 - 氨基 - 吡嗪腈化合物。 本发明还涉及包含这些化合物的药物组合物，以及这些化合物和组合物在体外和体内的用途，以抑制CHK1激酶功能，以及治疗由CHK1介导的疾病和病症，即 通过抑制CHK1激酶功能等改善，包括增殖条件如癌症等，任选地与另一种试剂组合，例如（a）DNA拓扑异构酶I或II抑制剂; （b）DNA损伤剂; （c）抗代谢物或胸苷酸合酶（TS）抑制剂; （d）微管靶向剂; 和（e）电离辐射。

公开(公告)号：US20180022739A1

公开(公告)日：2018-01-25

申请号：US15587270

申请日：2017-05-04

Applicant: Cancer Research Technology Limited

Inventor： Ian Collins ,  Thomas Peter Matthews ,  Tatiana Faria Da Fonseca Mchardy ,  James Osborne ,  Michael Lainchbury ,  Michael Ian Walton ,  Michelle Dawn Garrett

IPC: C07D413/14 ,  A61K31/7068 ,  A61K31/5377 ,  A61K31/4745 ,  A61K9/00 ,  A61K45/06 ,  C07D401/12

CPC classification number: C07D413/14 ,  A61K9/0053 ,  A61K31/4745 ,  A61K31/5377 ,  A61K31/7068 ,  A61K45/06 ,  C07D401/12 ,  C07D413/02

Abstract: 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.

公开(公告)号：US09718793B2

公开(公告)日：2017-08-01

申请号：US13929098

申请日：2013-06-27

Applicant: Vernalis (R&D) Limited ,  Cancer Research Technology Limited ,  The Institute of Cancer Research

Inventor： Martin James Drysdale ,  Brian William Dymock ,  Harry Finch ,  Paul Webb ,  Edward McDonald ,  Karen Elizabeth James ,  Kwai Ming Cheung ,  Thomas Peter Matthews

IPC: C07D261/08 ,  C07D261/10 ,  C07D495/04 ,  C07D413/10 ,  C07D413/04 ,  C07D417/14 ,  C07D417/04

CPC classification number: A61K31/541 ,  A61K31/42 ,  A61K31/422 ,  A61K31/427 ,  A61K31/4439 ,  A61K31/454 ,  A61K31/4709 ,  A61K31/496 ,  A61K31/5377 ,  C07D261/08 ,  C07D261/10 ,  C07D413/04 ,  C07D413/10 ,  C07D417/04 ,  C07D495/04

Abstract: Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: wherein R1, is a group of formula (IA): —Ar1-(Alk1)p-(Z)r-(Alk2)s-Q, wherein in any compatible combination Ar1 is an optionally substituted aryl or heteroaryl radical, Alk1 and Alk2 are optionally substituted divalent C1-C6 alkylene or C2-C6 alkenylene radicals, p, r and s are independently 0 or 1, Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO.sub.2-, —C(═O)O—, —C(═O)NRA—, —C(═S)NRA—, —SO2NRA—, —NRAC(═O)—, —NRASO2— or —NRA— wherein RA is hydrogen or C1-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R2 is (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 -(Alk1)p-(Z)r-(Alk2)s-Q wherein Q, Alk1, Alk2, Z, p, r and s are as defined above in relation to group (IA); and R3 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

公开(公告)号：US09663503B2

公开(公告)日：2017-05-30

申请号：US14396338

申请日：2013-05-14

Applicant: Cancer Research Technology Limited

Inventor： Ian Collins ,  Thomas Peter Matthews ,  Tatiana Faria Da Fonseca Mchardy ,  James Osborne ,  Michael Lainchbury ,  Michael Ian Walton ,  Michelle Dawn Garrett

IPC: C07D413/14 ,  C07D401/12 ,  A61K9/00 ,  A61K31/4745 ,  A61K31/5377 ,  A61K31/7068 ,  A61K45/06

CPC classification number: C07D413/14 ,  A61K9/0053 ,  A61K31/4745 ,  A61K31/5377 ,  A61K31/7068 ,  A61K45/06 ,  C07D401/12

Abstract: 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.

公开(公告)号：US09403797B2

公开(公告)日：2016-08-02

申请号：US14693307

申请日：2015-04-22

Applicant: Cancer Research Technology Limited

Inventor： Ian Collins ,  Michael Lainchbury ,  Thomas Peter Matthews ,  John Charles Reader

IPC: A61K31/497 ,  C07D401/12 ,  C07D401/14 ,  A61K45/06 ,  A61N5/10

CPC classification number: C07D401/14 ,  A61K9/0053 ,  A61K31/497 ,  A61K45/06 ,  A61N5/10 ,  A61N2005/1098 ,  C07D401/12

Abstract: 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.

Abstract translation: 本发明一般涉及治疗化合物领域。 更具体地，本发明涉及特别是抑制检测点激酶1（CHK1）激酶功能的某些吡啶基 - 氨基 - 吡嗪腈化合物。 本发明还涉及包含这些化合物的药物组合物，以及这些化合物和组合物在体外和体内的用途，以抑制CHK1激酶功能，以及治疗由CHK1介导的疾病和病症，即 通过抑制CHK1激酶功能等改善，包括增殖条件如癌症等，任选地与另一种试剂组合，例如（a）DNA拓扑异构酶I或II抑制剂; （b）DNA损伤剂; （c）抗代谢物或胸苷酸合酶（TS）抑制剂; （d）微管靶向剂; 和（e）电离辐射。