EA024824B1 - Соединения-ингибиторы raf - Google Patents
Соединения-ингибиторы raf Download PDFInfo
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- EA024824B1 EA024824B1 EA201491456A EA201491456A EA024824B1 EA 024824 B1 EA024824 B1 EA 024824B1 EA 201491456 A EA201491456 A EA 201491456A EA 201491456 A EA201491456 A EA 201491456A EA 024824 B1 EA024824 B1 EA 024824B1
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- EA
- Eurasian Patent Office
- Prior art keywords
- cancer
- methyl
- atcc
- cat
- compound
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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- Chemical & Material Sciences (AREA)
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- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
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- Engineering & Computer Science (AREA)
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261607702P | 2012-03-07 | 2012-03-07 | |
| PCT/US2013/029084 WO2013134243A1 (en) | 2012-03-07 | 2013-03-05 | 2-amino, 6-phenyl substituted pyrido [2, 3 - d] pyrimidine derivatives useful as raf kinase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA201491456A1 EA201491456A1 (ru) | 2014-12-30 |
| EA024824B1 true EA024824B1 (ru) | 2016-10-31 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA201491456A EA024824B1 (ru) | 2012-03-07 | 2013-03-05 | Соединения-ингибиторы raf |
Country Status (39)
Families Citing this family (59)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR090151A1 (es) * | 2012-03-07 | 2014-10-22 | Lilly Co Eli | Compuestos inhibidores de raf |
| US8461179B1 (en) | 2012-06-07 | 2013-06-11 | Deciphera Pharmaceuticals, Llc | Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases |
| TWI704151B (zh) | 2014-12-22 | 2020-09-11 | 美商美國禮來大藥廠 | Ｅｒｋ抑制劑 |
| MX2018015353A (es) * | 2016-06-10 | 2019-09-09 | Novartis Ag | Usos terapeuticos de un inhibidor de c-raf. |
| WO2018115380A1 (en) | 2016-12-22 | 2018-06-28 | Boehringer Ingelheim International Gmbh | Novel benzylamino substituted quinazolines and derivatives as sos1 inhibitors |
| CN110545853A (zh) * | 2017-04-28 | 2019-12-06 | 石英治疗有限公司 | Raf降解偶联化合物 |
| PE20210163A1 (es) | 2017-12-21 | 2021-01-26 | Boehringer Ingelheim Int | Nuevas piridopirimidinonas sustituidas con bencilamino y derivados como inhibidores de sos1 |
| JP7161849B2 (ja) * | 2018-01-24 | 2022-10-27 | 株式会社クラレ | 第一級アミンの製造方法 |
| KR102708050B1 (ko) | 2018-01-31 | 2024-09-24 | 데시페라 파마슈티칼스, 엘엘씨. | 비만 세포증의 치료를 위한 병용 요법 |
| WO2019152711A1 (en) | 2018-01-31 | 2019-08-08 | Diciphera Pharmaceuticals Llc. | Combination therapy for the treatment of gastrointestinal stromal tumors |
| WO2020055760A1 (en) | 2018-09-10 | 2020-03-19 | Mirati Therapeutics, Inc. | Combination therapies |
| SMT202500389T1 (it) | 2018-12-28 | 2025-11-10 | Deciphera Pharmaceuticals Llc | Inibitori di csf1r per l'uso nel trattamento di tumori tenosinoviali a cellule giganti |
| LT3921030T (lt) | 2019-02-06 | 2024-01-25 | Eli Lilly And Company | 1-((2-(2,2,2-trifluoroetoksi)piridin-4-il)metil)karbamido dariniai, kaip kcnq stiprikliai |
| AR118119A1 (es) * | 2019-02-18 | 2021-09-22 | Genentech Inc | Compuestos de pirido-pirimidinilo y métodos de uso |
| AU2020268814A1 (en) | 2019-05-03 | 2021-12-16 | Kinnate Biopharma Inc. | Inhibitors of RAF kinases |
| PE20220592A1 (es) | 2019-05-10 | 2022-04-22 | Deciphera Pharmaceuticals Llc | Inhibidores de la autofagia de heteroarilaminopirimidina amida y metodos de uso de estos |
| HUE065486T2 (hu) | 2019-05-10 | 2024-05-28 | Deciphera Pharmaceuticals Llc | Fenilaminopirimidinamid autophágia inhibitorok és azok felhasználási eljárásai |
| CA3143489A1 (en) | 2019-06-17 | 2020-12-24 | Deciphera Pharmaceuticals, Llc | Aminopyrimidine amide autophagy inhibitors and methods of use thereof |
| CA3150433A1 (en) | 2019-08-12 | 2021-02-18 | Deciphera Pharmaceuticals, Llc | Ripretinib for treating gastrointestinal stromal tumors |
| TWI878335B (zh) | 2019-08-12 | 2025-04-01 | 美商迪賽孚爾製藥有限公司 | 治療胃腸道基質瘤方法 |
| BR112022007612A2 (pt) | 2019-10-24 | 2022-09-20 | Kinnate Biopharma Inc | Inibidores de raf quinases |
| CN115243681B (zh) | 2019-12-30 | 2024-08-16 | 德西费拉制药有限责任公司 | 1-(4-溴-5-(1-乙基-7-(甲氨基)-2-侧氧基-1,2-二氢-1,6-萘啶-3-基)-2-氟苯基)-3-苯基脲的组合物 |
| FI4084778T3 (fi) | 2019-12-30 | 2023-12-18 | Deciphera Pharmaceuticals Llc | Amorfisia kinaasi-inhibiittoriformulaatioita ja menetelmiä niiden käyttämiseksi |
| AU2021285032A1 (en) | 2020-06-02 | 2022-12-08 | Boehringer Ingelheim International Gmbh | Annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer |
| WO2022060996A1 (en) | 2020-09-18 | 2022-03-24 | Kinnate Biopharma Inc. | Inhibitors of raf kinases |
| WO2022081469A1 (en) | 2020-10-12 | 2022-04-21 | Kinnate Biopharma Inc. | Inhibitors of raf kinases |
| CN116507627A (zh) | 2020-11-02 | 2023-07-28 | 勃林格殷格翰国际有限公司 | 作为egfr抑制剂的经取代1h-吡唑并[4,3-c]吡啶及衍生物 |
| JP2023549540A (ja) | 2020-11-18 | 2023-11-27 | デシフェラ・ファーマシューティカルズ，エルエルシー | Ｇｃｎ２およびｐｅｒｋキナーゼ阻害剤およびその使用方法 |
| JP2024501280A (ja) | 2020-12-22 | 2024-01-11 | キル・レガー・セラピューティクス・インコーポレーテッド | Ｓｏｓ１阻害剤およびその使用 |
| IL307908A (en) | 2021-04-23 | 2023-12-01 | Kinnate Biopharma Inc | Cancer treatment with a RAF inhibitor |
| US12065427B2 (en) | 2021-04-29 | 2024-08-20 | Boehringer Ingelheim International Gmbh | Heterocyclic compounds capable of activating STING |
| IL312905A (en) | 2021-12-01 | 2024-07-01 | Boehringer Ingelheim Int | Annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer |
| EP4441056A1 (en) | 2021-12-01 | 2024-10-09 | Boehringer Ingelheim International GmbH | Annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer |
| US20250145608A1 (en) | 2021-12-01 | 2025-05-08 | Boehringer Ingelheim Int'l GmbH Corp. | Kras degrading compounds comprising annulated 2-amino-3-cyano thiophenes |
| WO2023099612A1 (en) | 2021-12-01 | 2023-06-08 | Boehringer Ingelheim International Gmbh | Annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer |
| WO2023099623A1 (en) | 2021-12-01 | 2023-06-08 | Boehringer Ingelheim International Gmbh | Annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer |
| US20250313553A1 (en) | 2021-12-01 | 2025-10-09 | Boehringer Ingelheim Int'l GmbH Corp. | Annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer |
| KR20240133793A (ko) | 2021-12-09 | 2024-09-04 | 데시페라 파마슈티칼스, 엘엘씨. | Raf 키나아제 억제제 및 그 사용 방법 |
| US20230357179A1 (en) | 2021-12-09 | 2023-11-09 | Deciphera Pharmaceuticals, Llc | Raf kinase inhibitors and methods of use thereof |
| US20250382288A1 (en) | 2021-12-23 | 2025-12-18 | Boehringer Ingelheim International Gmbh | 8-aza quinazolines as brain-penetrant sos1-inhibitors |
| WO2023173017A1 (en) * | 2022-03-09 | 2023-09-14 | Blossomhill Therapeutics, Inc. | Kras inhibitors for treating disease |
| US11779572B1 (en) | 2022-09-02 | 2023-10-10 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
| CA3266173A1 (en) | 2022-10-26 | 2024-05-02 | Boehringer Ingelheim International Gmbh | HETEROCYCLIC COMPOUNDS CAPABLE OF ACTIVATING STING |
| AR130848A1 (es) | 2022-10-26 | 2025-01-22 | Boehringer Ingelheim Int | Compuestos heterocíclicos con capacidad para activar el receptor sting |
| KR20250092268A (ko) | 2022-10-26 | 2025-06-23 | 베링거 인겔하임 인터내셔날 게엠베하 | Sting을 활성화시킬 수 있는 헤테로사이클릭 화합물 |
| AU2024265078A1 (en) | 2023-05-04 | 2025-12-11 | Revolution Medicines, Inc. | Combination therapy for a ras related disease or disorder |
| US20250019385A1 (en) | 2023-05-30 | 2025-01-16 | Boehringer Ingelheim International Gmbh | Spirocyclic annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer |
| GB2631397A (en) | 2023-06-28 | 2025-01-08 | Sevenless Therapeutics Ltd | New treatments for pain |
| WO2025034702A1 (en) | 2023-08-07 | 2025-02-13 | Revolution Medicines, Inc. | Rmc-6291 for use in the treatment of ras protein-related disease or disorder |
| GB2633813A (en) | 2023-09-21 | 2025-03-26 | Sevenless Therapeutics Ltd | New treatments for pain |
| WO2025080946A2 (en) | 2023-10-12 | 2025-04-17 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025083426A1 (en) | 2023-10-20 | 2025-04-24 | Sevenless Therapeutics Limited | New treatments for pain |
| US20250205161A1 (en) | 2023-12-08 | 2025-06-26 | Deciphera Pharmaceuticals, Llc | Formulations of vimseltinib |
| WO2025137507A1 (en) | 2023-12-22 | 2025-06-26 | Regor Pharmaceuticals, Inc. | Sos1 inhibitors and uses thereof |
| WO2025146548A1 (en) | 2024-01-04 | 2025-07-10 | Sevenless Therapeutics Limited | Sos1 inhibitors useful to treat pain and cancer |
| WO2025171296A1 (en) | 2024-02-09 | 2025-08-14 | Revolution Medicines, Inc. | Ras inhibitors |
| US20250313560A1 (en) | 2024-04-03 | 2025-10-09 | Boehringer Ingelheim International Gmbh | Novel bicyclic benzylamido pyridine derivatives as SOS1 inhibitors |
| WO2025240847A1 (en) | 2024-05-17 | 2025-11-20 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025255438A1 (en) | 2024-06-07 | 2025-12-11 | Revolution Medicines, Inc. | Methods of treating a ras protein-related disease or disorder |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008034008A2 (en) * | 2006-09-14 | 2008-03-20 | Deciphera Pharmaceuticals, Llc. | Kinase inhibitors useful for the treatment of proliferative diseases |
| WO2011100319A1 (en) * | 2010-02-09 | 2011-08-18 | Exelixis, Inc. | Methods of treating cancer using pyridopyrimidinone inhibitors of pi3k and mtor in combination with autophagy inhibitors |
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| WO2003033472A1 (en) * | 2001-10-17 | 2003-04-24 | Kirin Beer Kabushiki Kaisha | Quinoline or quinazoline derivatives inhibiting auto- phosphorylation of fibroblast growth factor receptors |
| EP1566379A4 (en) * | 2002-10-29 | 2005-11-09 | Kirin Brewery | CHINOLINE DERIVATIVES AND CHINAZOLINE DERIVATIVES AS INHIBITORS OF FLT3 AUTOPHOSPHORYLATION AND THE MEDICAL COMPOSITIONS CONTAINING THEREOF |
| US20070054916A1 (en) | 2004-10-01 | 2007-03-08 | Amgen Inc. | Aryl nitrogen-containing bicyclic compounds and methods of use |
| US7897762B2 (en) | 2006-09-14 | 2011-03-01 | Deciphera Pharmaceuticals, Llc | Kinase inhibitors useful for the treatment of proliferative diseases |
| AR090151A1 (es) * | 2012-03-07 | 2014-10-22 | Lilly Co Eli | Compuestos inhibidores de raf |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008034008A2 (en) * | 2006-09-14 | 2008-03-20 | Deciphera Pharmaceuticals, Llc. | Kinase inhibitors useful for the treatment of proliferative diseases |
| WO2011100319A1 (en) * | 2010-02-09 | 2011-08-18 | Exelixis, Inc. | Methods of treating cancer using pyridopyrimidinone inhibitors of pi3k and mtor in combination with autophagy inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| PALMER, B.D. ; SMAILL, J.B. ; REWCASTLE, G.W. ; DOBRUSIN, E.M. ; KRAKER, A. ; MOORE, C.W. ; STEINKAMPF, R.W. ; DENNY, W.A.: "Structure-activity relationships for 2-anilino-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-ones as inhibitors of the cellular checkpoint kinase Wee1", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 15, no. 7, 1 April 2005 (2005-04-01), AMSTERDAM, NL, pages 1931 - 1935, XP027800887, ISSN: 0960-894X * |
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