Title:
6-6 FUSED BICYCLIC HETEROARYL COMPOUNDS AND THEIR USE AS LATS INHIBITORS
Document Type and Number:
WIPO Patent Application WO/2018/198077
Kind Code:
A3
Abstract:
The present invention is related to 6-6 Fused Bicyclic Heteroaryl Compounds of the Formula A2 or A1 and their Use as LATS Inhibitors, or a salt, stereoisomer or pharmaceutical composition thereof; wherein the variables are as defined herein (A1 & A2). The present invention further relates to a method of LATS inhibition in a cell population using a compound of Formula A1, or a salt, stereoisomer or pharmaceutical composition thereof. The present invention further provides a method for manufacturing compounds of the invention, and its therapeutic uses. The invention further provides methods to their preparation, to their medical use, their use in the treatment and management of diseases or disorders.
Inventors:
BEHNKE DIRK (CH)
BERENSHTEYN FRADA (US)
HAO XUESHI (US)
HOFFMAN TIMOTHY (US)
JIN QIHUI (US)
LACOSTE ARNAUD (US)
LEE CAMERON (US)
LIU JUN (US)
LIU YAHU (US)
MAIBAUM JUERGEN KLAUS (CH)
MO TINGTING (US)
PAN JIANFENG (US)
QU XIN (US)
TCHORZ JAN (CH)
XIE YUN FENG (US)
YAN SHANSHAN (US)
ZOU YEFEN (US)
BERENSHTEYN FRADA (US)
HAO XUESHI (US)
HOFFMAN TIMOTHY (US)
JIN QIHUI (US)
LACOSTE ARNAUD (US)
LEE CAMERON (US)
LIU JUN (US)
LIU YAHU (US)
MAIBAUM JUERGEN KLAUS (CH)
MO TINGTING (US)
PAN JIANFENG (US)
QU XIN (US)
TCHORZ JAN (CH)
XIE YUN FENG (US)
YAN SHANSHAN (US)
ZOU YEFEN (US)
Application Number:
PCT/IB2018/052919
Publication Date:
February 14, 2019
Filing Date:
April 26, 2018
Export Citation:
Assignee:
NOVARTIS AG (CH)
International Classes:
C07D487/04; A61K35/30; A61P17/02; C07D519/00; C12N5/079
Domestic Patent References:
| WO2015148597A1 | 2015-10-01 |
Foreign References:
| EP2733201A1 | 2014-05-21 | |||
| US20110319409A1 | 2011-12-29 |
Other References:
YAWEI HAO ET AL: "Tumor Suppressor LATS1 Is a Negative Regulator of Oncogene YAP", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 283, no. 9, 29 February 2008 (2008-02-29), US, pages 5496 - 5509, XP055485512, ISSN: 0021-9258, DOI: 10.1074/jbc.M709037200
WANG PENG ET AL: "Selective inhibition of ROCK kinase isoforms to promote neuroregeneration after brain surgery", MEDICINAL CHEMISTRY RESEARCH, BIRKHAEUSER, BOSTON, US, vol. 25, no. 1, 21 September 2015 (2015-09-21), pages 40 - 50, XP035802888, ISSN: 1054-2523, [retrieved on 20150921], DOI: 10.1007/S00044-015-1463-0
PAOLO RAMA ET AL: "Limbal Stem-Cell Therapy and Long-Term Corneal Regeneration", THE NEW ENGLAND JOURNAL OF MEDICINE, 8 July 2010 (2010-07-08), United States, pages 147 - 155, XP055291854, Retrieved from the Internet DOI: 10.1056/NEJMoa0905955
RENATA RUOCO LOUREIRO: "Comparison of culture media for ex vivo cultivation of limbal epithelial progenitor cells", MOLECULAR VISION 2013; 19, 17 January 2013 (2013-01-17), pages 69 - 77, XP055488414, Retrieved from the Internet [retrieved on 20180627]
MOHIT PAREKH ET AL: "Concise Review: An Update on the Culture of Human Corneal Endothelial Cells for Transplantation : Corneal Endothelial Cell Culture", STEM CELLS TRANSLATIONAL MEDICINE, vol. 5, no. 2, 23 December 2015 (2015-12-23), pages 258 - 264, XP055489663, ISSN: 2157-6564, DOI: 10.5966/sctm.2015-0181
MATTHIAS FUEST ET AL: "Advances in corneal cell therapy", REGENERATIVE MEDICINE, vol. 11, no. 6, 1 September 2016 (2016-09-01), GB, pages 601 - 615, XP055489738, ISSN: 1746-0751, DOI: 10.2217/rme-2016-0054
R?KA ALBERT ET AL: "Cultivation and Characterization of Cornea Limbal Epithelial Stem Cells on Lens Capsule in Animal Material-Free Medium", PLOS ONE, vol. 7, no. 10, 9 October 2012 (2012-10-09), pages e47187, XP055345741, DOI: 10.1371/journal.pone.0047187
BAKIAH SHAHARUDDIN ET AL: "A Human Corneal Epithelial Cell Line Model for Limbal Stem Cell Biology and Limbal Immunobiology : Immunobiology of a Corneal Cell Line", STEM CELLS TRANSLATIONAL MEDICINE, vol. 6, no. 3, 14 October 2016 (2016-10-14), pages 761 - 766, XP055519839, ISSN: 2157-6564, DOI: 10.5966/sctm.2016-0175
MIRNA TOMINAC TRCIN ET AL: "Synthetic vs natural scaffolds for human limbal stem cells", CROATIAN MEDICAL JOURNAL, vol. 56, no. 3, 1 June 2015 (2015-06-01), CR, pages 246 - 256, XP055519842, ISSN: 0353-9504, DOI: 10.3325/cmj.2015.56.246
HIROKI TORIKAI ET AL: "Genetic editing of HLA expression in hematopoietic stem cells to broaden their human application", SCIENTIFIC REPORTS, vol. 6, 23 February 2016 (2016-02-23), pages 21757, XP055298744, DOI: 10.1038/srep21757
YUREEDA QAZI ET AL: "Gene Therapy in Corneal Transplantation", SEMINARS IN OPHTHALMOLOGY, vol. 28, no. 5-6, 1 September 2013 (2013-09-01), pages 287 - 300, XP055175574, ISSN: 0882-0538, DOI: 10.3109/08820538.2013.825297
ZARUHI KARABEKIAN ET AL: "HLA Class I Depleted hESC as a Source of Hypoimmunogenic Cells for Tissue Engineering Applications", TISSUE ENGINEERING PART A, vol. 21, no. 19-20, 1 October 2015 (2015-10-01), pages 2559 - 2571, XP055520166, ISSN: 1937-3341, DOI: 10.1089/ten.tea.2015.0105
WANG PENG ET AL: "Selective inhibition of ROCK kinase isoforms to promote neuroregeneration after brain surgery", MEDICINAL CHEMISTRY RESEARCH, BIRKHAEUSER, BOSTON, US, vol. 25, no. 1, 21 September 2015 (2015-09-21), pages 40 - 50, XP035802888, ISSN: 1054-2523, [retrieved on 20150921], DOI: 10.1007/S00044-015-1463-0
PAOLO RAMA ET AL: "Limbal Stem-Cell Therapy and Long-Term Corneal Regeneration", THE NEW ENGLAND JOURNAL OF MEDICINE, 8 July 2010 (2010-07-08), United States, pages 147 - 155, XP055291854, Retrieved from the Internet
RENATA RUOCO LOUREIRO: "Comparison of culture media for ex vivo cultivation of limbal epithelial progenitor cells", MOLECULAR VISION 2013; 19, 17 January 2013 (2013-01-17), pages 69 - 77, XP055488414, Retrieved from the Internet
MOHIT PAREKH ET AL: "Concise Review: An Update on the Culture of Human Corneal Endothelial Cells for Transplantation : Corneal Endothelial Cell Culture", STEM CELLS TRANSLATIONAL MEDICINE, vol. 5, no. 2, 23 December 2015 (2015-12-23), pages 258 - 264, XP055489663, ISSN: 2157-6564, DOI: 10.5966/sctm.2015-0181
MATTHIAS FUEST ET AL: "Advances in corneal cell therapy", REGENERATIVE MEDICINE, vol. 11, no. 6, 1 September 2016 (2016-09-01), GB, pages 601 - 615, XP055489738, ISSN: 1746-0751, DOI: 10.2217/rme-2016-0054
R?KA ALBERT ET AL: "Cultivation and Characterization of Cornea Limbal Epithelial Stem Cells on Lens Capsule in Animal Material-Free Medium", PLOS ONE, vol. 7, no. 10, 9 October 2012 (2012-10-09), pages e47187, XP055345741, DOI: 10.1371/journal.pone.0047187
BAKIAH SHAHARUDDIN ET AL: "A Human Corneal Epithelial Cell Line Model for Limbal Stem Cell Biology and Limbal Immunobiology : Immunobiology of a Corneal Cell Line", STEM CELLS TRANSLATIONAL MEDICINE, vol. 6, no. 3, 14 October 2016 (2016-10-14), pages 761 - 766, XP055519839, ISSN: 2157-6564, DOI: 10.5966/sctm.2016-0175
MIRNA TOMINAC TRCIN ET AL: "Synthetic vs natural scaffolds for human limbal stem cells", CROATIAN MEDICAL JOURNAL, vol. 56, no. 3, 1 June 2015 (2015-06-01), CR, pages 246 - 256, XP055519842, ISSN: 0353-9504, DOI: 10.3325/cmj.2015.56.246
HIROKI TORIKAI ET AL: "Genetic editing of HLA expression in hematopoietic stem cells to broaden their human application", SCIENTIFIC REPORTS, vol. 6, 23 February 2016 (2016-02-23), pages 21757, XP055298744, DOI: 10.1038/srep21757
YUREEDA QAZI ET AL: "Gene Therapy in Corneal Transplantation", SEMINARS IN OPHTHALMOLOGY, vol. 28, no. 5-6, 1 September 2013 (2013-09-01), pages 287 - 300, XP055175574, ISSN: 0882-0538, DOI: 10.3109/08820538.2013.825297
ZARUHI KARABEKIAN ET AL: "HLA Class I Depleted hESC as a Source of Hypoimmunogenic Cells for Tissue Engineering Applications", TISSUE ENGINEERING PART A, vol. 21, no. 19-20, 1 October 2015 (2015-10-01), pages 2559 - 2571, XP055520166, ISSN: 1937-3341, DOI: 10.1089/ten.tea.2015.0105
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