HRP20241581T1 - Fuzionirani prstenasti spojevi - Google Patents
Fuzionirani prstenasti spojevi Download PDFInfo
- Publication number
- HRP20241581T1 HRP20241581T1 HRP20241581TT HRP20241581T HRP20241581T1 HR P20241581 T1 HRP20241581 T1 HR P20241581T1 HR P20241581T T HRP20241581T T HR P20241581TT HR P20241581 T HRP20241581 T HR P20241581T HR P20241581 T1 HRP20241581 T1 HR P20241581T1
- Authority
- HR
- Croatia
- Prior art keywords
- pharmaceutically acceptable
- acceptable salt
- compound
- cancer
- image
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims 19
- 150000003839 salts Chemical class 0.000 claims 16
- 238000000034 method Methods 0.000 claims 9
- 239000008194 pharmaceutical composition Substances 0.000 claims 7
- 101710113436 GTPase KRas Proteins 0.000 claims 5
- 206010028980 Neoplasm Diseases 0.000 claims 5
- 102000004169 proteins and genes Human genes 0.000 claims 5
- 108090000623 proteins and genes Proteins 0.000 claims 5
- 102200006538 rs121913530 Human genes 0.000 claims 5
- 201000011510 cancer Diseases 0.000 claims 4
- 230000035772 mutation Effects 0.000 claims 4
- 229910052736 halogen Inorganic materials 0.000 claims 3
- 150000002367 halogens Chemical group 0.000 claims 3
- 238000000338 in vitro Methods 0.000 claims 3
- 206010009944 Colon cancer Diseases 0.000 claims 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 claims 2
- 201000005202 lung cancer Diseases 0.000 claims 2
- 208000020816 lung neoplasm Diseases 0.000 claims 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 2
- 201000002528 pancreatic cancer Diseases 0.000 claims 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 2
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims 1
- 206010073360 Appendix cancer Diseases 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 206010027476 Metastases Diseases 0.000 claims 1
- 208000021780 appendiceal neoplasm Diseases 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 230000002489 hematologic effect Effects 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- 201000005249 lung adenocarcinoma Diseases 0.000 claims 1
- 230000001404 mediated effect Effects 0.000 claims 1
- 230000009401 metastasis Effects 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 208000015768 polyposis Diseases 0.000 claims 1
- 230000035755 proliferation Effects 0.000 claims 1
- 230000001105 regulatory effect Effects 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
Classifications
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
- C07D471/02—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Peptides Or Proteins (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2018114788 | 2018-11-09 | ||
| EP19842848.4A EP3735299B1 (en) | 2018-11-09 | 2019-11-08 | Fused ring compounds |
| PCT/US2019/060578 WO2020097537A2 (en) | 2018-11-09 | 2019-11-08 | Fused ring compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20241581T1 true HRP20241581T1 (hr) | 2025-01-31 |
Family
ID=69232886
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20241581TT HRP20241581T1 (hr) | 2018-11-09 | 2019-11-08 | Fuzionirani prstenasti spojevi |
Country Status (33)
Families Citing this family (79)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3871673B1 (en) | 2018-10-26 | 2024-01-03 | Taiho Pharmaceutical Co., Ltd. | Novel indazole compound or salt thereof |
| CN112585129B (zh) | 2019-05-21 | 2022-03-01 | 益方生物科技(上海)股份有限公司 | 杂环化合物,其制备方法和用途 |
| US12122787B2 (en) | 2019-09-20 | 2024-10-22 | Shanghai Jemincare Pharmaceuticals Co., Ltd | Fused pyridone compound, and preparation method therefor and use thereof |
| US11697657B2 (en) | 2019-10-28 | 2023-07-11 | Merck Sharp & Dohme Llc | Small molecule inhibitors of KRAS G12C mutant |
| JP2023505100A (ja) | 2019-11-27 | 2023-02-08 | レボリューション メディシンズ インコーポレイテッド | 共有ras阻害剤及びその使用 |
| EP4067343A4 (en) | 2019-11-29 | 2024-01-03 | Taiho Pharmaceutical Co., Ltd. | NEW PHENOLIC COMPOUND OR SALT THEREOF |
| WO2021120045A1 (en) | 2019-12-18 | 2021-06-24 | InventisBio Co., Ltd. | Heterocyclic compounds, preparation methods and uses thereof |
| US12441707B2 (en) | 2019-12-30 | 2025-10-14 | Tyra Biosciences, Inc. | Indazole compounds |
| TW202214253A (zh) | 2020-06-18 | 2022-04-16 | 美商銳新醫藥公司 | 延遲、預防及治療對ras抑制劑之後天抗性之方法 |
| BR112023002591A2 (pt) * | 2020-08-12 | 2023-04-04 | Genentech Inc | Processo para a preparação de um composto e composto |
| JP2023538060A (ja) * | 2020-08-17 | 2023-09-06 | 貝達薬業股▲ふん▼有限公司 | 二環化合物、それを含む組成物、及びそれらの使用 |
| AU2021331492A1 (en) | 2020-08-28 | 2023-04-13 | Kumquat Biosciences Inc. | Heterocyclic compounds and uses thereof |
| IL301062A (en) | 2020-09-03 | 2023-05-01 | Revolution Medicines Inc | Use of sos1 inhibitors to treat malignancies with shp2 mutations |
| JP2023540809A (ja) | 2020-09-11 | 2023-09-26 | ミラティ セラピューティクス, インコーポレイテッド | Kras g12c阻害剤の結晶形態 |
| IL301524A (en) | 2020-09-23 | 2023-05-01 | Erasca Inc | Tricyclic pyridones and pyrimidones |
| US20230365563A1 (en) * | 2020-09-30 | 2023-11-16 | Shanghai Pharmaceuticals Holding Co., Ltd. | Quinazoline compound and application thereof |
| EP4240489A4 (en) * | 2020-11-03 | 2024-09-25 | Mirati Therapeutics, Inc. | KRAS-G12D INHIBITORS |
| AU2021377810B2 (en) * | 2020-11-13 | 2025-01-02 | Genentech, Inc. | Methods and compositions comprising a krasg12c inhibitor and a vegf inhibitor for treating solid tumors |
| MX2023005530A (es) * | 2020-11-13 | 2023-05-25 | Genentech Inc | Metodos y composiciones que comprenden un inhibidor de krasg12c y un antagonista de union a pd-l1 para tratar cancer de pulmon. |
| TW202229285A (zh) * | 2020-11-20 | 2022-08-01 | 大陸商北京加科思新藥研發有限公司 | Kras g12d抑制劑 |
| WO2022105855A1 (en) * | 2020-11-20 | 2022-05-27 | Jacobio Pharmaceuticals Co., Ltd. | Kras g12d inhibitors |
| US20220193077A1 (en) * | 2020-12-08 | 2022-06-23 | Genentech, Inc. | Methods and compositions comprising a krasg12c inhibitor and a egfr-inhibitor for treating solid tumors |
| IL303446A (en) | 2020-12-15 | 2023-08-01 | Mirati Therapeutics Inc | Azaquinazoline compounds as PAN-KRas inhibitors |
| WO2022133038A1 (en) | 2020-12-16 | 2022-06-23 | Mirati Therapeutics, Inc. | Tetrahydropyridopyrimidine pan-kras inhibitors |
| CN113999226B (zh) * | 2020-12-22 | 2023-01-06 | 上海科州药物研发有限公司 | 作为kras抑制剂的杂环化合物的制备及其应用方法 |
| TWI894413B (zh) * | 2020-12-22 | 2025-08-21 | 大陸商上海科州藥物股份有限公司 | 作為kras抑制劑的雜環化合物的製備及其應用方法 |
| CN114685532A (zh) * | 2020-12-31 | 2022-07-01 | 正大天晴药业集团股份有限公司 | 大环类化合物及其医药用途 |
| WO2022171018A1 (zh) * | 2021-02-09 | 2022-08-18 | 苏州泽璟生物制药股份有限公司 | 取代苯并或吡啶并嘧啶胺类抑制剂及其制备方法和应用 |
| WO2022171013A1 (zh) * | 2021-02-09 | 2022-08-18 | 南京明德新药研发有限公司 | 四氢喹唑啉类化合物 |
| CA3210167A1 (en) * | 2021-02-09 | 2022-08-18 | Genentech, Inc. | Tetracyclic oxazepine compounds and uses thereof |
| JP2024506329A (ja) * | 2021-02-09 | 2024-02-13 | カムクワット バイオサイエンシーズ インコーポレイテッド | 複素環式化合物およびその使用 |
| IL304986A (en) * | 2021-02-16 | 2023-10-01 | Theras Inc | Compositions and methods for inhibition of ras |
| WO2022214102A1 (zh) * | 2021-04-09 | 2022-10-13 | 杭州英创医药科技有限公司 | 作为kras g12d抑制剂的杂环化合物 |
| WO2022221386A1 (en) * | 2021-04-14 | 2022-10-20 | Erasca, Inc. | Selective kras inhibitors |
| US20240239788A1 (en) * | 2021-04-16 | 2024-07-18 | Merck Sharp & Dohme Llc | Small molecule inhibitors of kras g12d mutant |
| JP2024517695A (ja) * | 2021-04-29 | 2024-04-23 | アムジエン・インコーポレーテツド | 複素環式化合物及び使用方法 |
| CN117337193A (zh) * | 2021-05-19 | 2024-01-02 | 基因泰克公司 | 组合疗法 |
| WO2022247760A1 (zh) * | 2021-05-22 | 2022-12-01 | 上海科州药物研发有限公司 | 作为kras抑制剂的杂环化合物,及其制备和治疗用途 |
| US20240261444A1 (en) * | 2021-05-26 | 2024-08-08 | Cornell University | Rigidified macrocycles, complexes with radionuclides, and use in targeted radiotherapy of cancer |
| TW202325284A (zh) * | 2021-08-18 | 2023-07-01 | 大陸商北京加科思新藥研發有限公司 | N-環丙基吡啶并[4,3-d]嘧啶-4-胺衍生物及其用途 |
| TW202315626A (zh) * | 2021-08-31 | 2023-04-16 | 大陸商勁方醫藥科技(上海)有限公司 | 嘧啶并環類化合物及其製法和用途 |
| TW202327569A (zh) | 2021-09-01 | 2023-07-16 | 瑞士商諾華公司 | 包含tead抑制劑的藥物組合及其用於癌症治療之用途 |
| WO2023097194A2 (en) | 2021-11-24 | 2023-06-01 | Genentech, Inc. | Therapeutic compounds and methods of use |
| EP4436571A4 (en) * | 2021-11-24 | 2025-10-15 | Merck Sharp & Dohme Llc | SMALL MOLECULE INHIBITORS OF KRAS MUTATIONAL PROTEINS |
| JP2024541508A (ja) | 2021-11-24 | 2024-11-08 | ジェネンテック, インコーポレイテッド | 治療用インダゾール化合物およびがんの治療における使用方法 |
| JP2025500430A (ja) | 2021-12-22 | 2025-01-09 | ザ・リージエンツ・オブ・ザ・ユニバーシテイー・オブ・カリフオルニア | K-RAS GTPaseのG12S、G12D、及び/又はG12E変異体の共有結合阻害剤 |
| TW202334155A (zh) * | 2022-01-06 | 2023-09-01 | 美商德洛斯股份有限公司 | 用於抑制ras之組合物及方法 |
| US20250188085A1 (en) * | 2022-01-06 | 2025-06-12 | Theras, Inc. | Compositions and methods for inhibition of ras |
| CN118742544A (zh) * | 2022-02-07 | 2024-10-01 | 基因泰克公司 | 1-((s)-4-((r)-7-(6-氨基-4-甲基-3-(三氟甲基)吡啶-2-基)-6-氯-8-氟-2-(((s)-1-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3-甲基哌嗪-1-基)丙-2-烯-1-酮的固体形式 |
| JP7749857B2 (ja) * | 2022-02-07 | 2025-10-06 | ジェネンテック, インコーポレイテッド | キナゾリン化合物を合成するための方法 |
| KR20240163107A (ko) | 2022-03-11 | 2024-11-18 | 컴쿼트 바이오사이언시즈 인크. | 헤테로환 화합물 및 이의 용도 |
| US20250177406A1 (en) | 2022-03-31 | 2025-06-05 | Eisai R&D Management Co., Ltd. | Pharmaceutical composition for treating tumors |
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| CN115043729B (zh) * | 2022-07-04 | 2024-09-27 | 青岛大学 | 一种2,2’-二氟联芳基化合物的不对称合成方法 |
| IL318647A (en) | 2022-08-05 | 2025-03-01 | Kumquat Biosciences Inc | Heterocyclic compounds and their uses |
| KR20250048078A (ko) | 2022-08-11 | 2025-04-07 | 브리스톨-마이어스 스큅 컴퍼니 | Kras 억제제 |
| EP4573095A1 (en) | 2022-08-17 | 2025-06-25 | Treeline Biosciences, Inc. | Pyridopyrimidine kras inhibitors |
| WO2024081674A1 (en) | 2022-10-11 | 2024-04-18 | Aadi Bioscience, Inc. | Combination therapies for the treatment of cancer |
| KR20250109197A (ko) | 2022-11-21 | 2025-07-16 | 트리라인 바이오사이언시스, 인크. | 스피로환식 디하이드로피라노피리미딘 KRas 억제제 |
| CN115920658B (zh) * | 2023-01-15 | 2023-10-20 | 安徽科博瑞环境科技有限公司 | 低表面能抗污染中空纤维膜及其制备方法 |
| WO2024153119A1 (en) * | 2023-01-18 | 2024-07-25 | Suzhou Zanrong Pharma Limited | Kras g12d inhibitors and uses thereof |
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| KR20250151412A (ko) | 2023-01-26 | 2025-10-21 | 아비나스 오퍼레이션스, 인코포레이티드 | 세레블론계 kras 분해 단백질 및 이와 관련된 용도 |
| AU2024241633A1 (en) | 2023-03-30 | 2025-11-06 | Revolution Medicines, Inc. | Compositions for inducing ras gtp hydrolysis and uses thereof |
| WO2024209717A1 (ja) | 2023-04-06 | 2024-10-10 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 腫瘍治療用医薬組成物 |
| CN116396202A (zh) * | 2023-04-17 | 2023-07-07 | 南京优氟医药科技有限公司 | 一种(2s,4s)-4-氟代吡咯烷-2-羧酸的制备方法 |
| WO2024229406A1 (en) | 2023-05-04 | 2024-11-07 | Revolution Medicines, Inc. | Combination therapy for a ras related disease or disorder |
| US20250000802A1 (en) | 2023-06-09 | 2025-01-02 | Hoffmann-La Roche Inc. | Solid formulations comprising an inhibitor of the k-ras protein having a g12c mutation, and a process for preparing |
| WO2025010415A1 (en) * | 2023-07-05 | 2025-01-09 | The Regents Of The University Of California | Gtpase inhibitors and uses thereof |
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| TW202528315A (zh) | 2023-09-21 | 2025-07-16 | 美商樹線生物科學公司 | 螺環二氫哌喃并吡啶KRas抑制劑 |
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| TW202530228A (zh) | 2023-10-12 | 2025-08-01 | 美商銳新醫藥公司 | Ras抑制劑 |
| US12466840B2 (en) | 2023-10-20 | 2025-11-11 | Merck Sharp & Dohme Llc | Small molecule inhibitors of KRAS proteins |
| WO2025171296A1 (en) | 2024-02-09 | 2025-08-14 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025240847A1 (en) | 2024-05-17 | 2025-11-20 | Revolution Medicines, Inc. | Ras inhibitors |
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| WO2025255438A1 (en) | 2024-06-07 | 2025-12-11 | Revolution Medicines, Inc. | Methods of treating a ras protein-related disease or disorder |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1999002557A1 (en) | 1997-07-11 | 1999-01-21 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V | Novel pharmaceutically active compounds interacting with gtp-binding proteins |
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