CN115515947A - Shp2抑制剂及其组合物和应用 - Google Patents
Shp2抑制剂及其组合物和应用 Download PDFInfo
- Publication number
- CN115515947A CN115515947A CN202180033007.1A CN202180033007A CN115515947A CN 115515947 A CN115515947 A CN 115515947A CN 202180033007 A CN202180033007 A CN 202180033007A CN 115515947 A CN115515947 A CN 115515947A
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- Prior art keywords
- amino
- dihydrospiro
- pyrazin
- indene
- compound
- Prior art date
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- -1 non-covalent complex Substances 0.000 claims description 326
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 212
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 170
- 125000003118 aryl group Chemical group 0.000 claims description 93
- 239000001257 hydrogen Substances 0.000 claims description 88
- 229910052739 hydrogen Inorganic materials 0.000 claims description 88
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 84
- 125000000623 heterocyclic group Chemical group 0.000 claims description 82
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 72
- 229910052757 nitrogen Inorganic materials 0.000 claims description 71
- 125000000304 alkynyl group Chemical group 0.000 claims description 68
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- 150000002431 hydrogen Chemical class 0.000 claims description 65
- 125000001424 substituent group Chemical group 0.000 claims description 60
- 229910052736 halogen Inorganic materials 0.000 claims description 53
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 43
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 41
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- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 33
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- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 7
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- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
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- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
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- 208000010708 Noonan syndrome with multiple lentigines Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 4
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- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
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- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
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- SBVVTGMSNXGYJC-RUZDIDTESA-N 4-[3-[5-[(1S)-1-aminospiro[1,3-dihydroindene-2,4'-piperidine]-1'-yl]-6-(hydroxymethyl)pyrazin-2-yl]prop-2-ynoxy]-2-fluorobenzamide Chemical compound N[C@@H]1C2=CC=CC=C2CC1(CC1)CCN1C(N=C1)=C(CO)N=C1C#CCOC(C=C1)=CC(F)=C1C(N)=O SBVVTGMSNXGYJC-RUZDIDTESA-N 0.000 claims description 3
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- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 3
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- VYGVBJXOYXIYQC-OAQYLSRUSA-N [3-[(1S)-1-aminospiro[1,3-dihydroindene-2,4'-piperidine]-1'-yl]-6-[3-(1,3-oxazol-2-ylamino)prop-1-ynyl]pyrazin-2-yl]methanol Chemical compound N[C@@H]1C2=CC=CC=C2CC1(CC1)CCN1C(N=C1)=C(CO)N=C1C#CCNC1=NC=CO1 VYGVBJXOYXIYQC-OAQYLSRUSA-N 0.000 claims description 3
- NBCSYXKKXBSODM-RUZDIDTESA-N [3-[(1S)-1-aminospiro[1,3-dihydroindene-2,4'-piperidine]-1'-yl]-6-[3-(2-methoxypyridin-4-yl)oxyprop-1-ynyl]pyrazin-2-yl]methanol Chemical compound COC1=NC=CC(OCC#CC(N=C2CO)=CN=C2N(CC2)CCC2(CC2=CC=CC=C22)[C@@H]2N)=C1 NBCSYXKKXBSODM-RUZDIDTESA-N 0.000 claims description 3
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- 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
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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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
- C07D471/02—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
- C07D471/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C07—ORGANIC CHEMISTRY
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Abstract
本发明涉及一种作为含Src同源区2蛋白质酪氨酸磷酸酶2(SHP2)抑制剂的化合物(如式Ⅰ所示),及其药物组合物、制备方法,以及其在治疗SHP2介导的疾病中的用途。本发明的化合物通过参与调节细胞增殖、凋亡、迁移、新生血管生成等多个过程而发挥作用。
Description
PCT国内申请,说明书已公开。
Claims (32)
- PCT国内申请,权利要求书已公开。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNPCT/CN2020/104473 | 2020-07-24 | ||
CN2020104473 | 2020-07-24 | ||
CN2020119590 | 2020-09-30 | ||
CNPCT/CN2020/119590 | 2020-09-30 | ||
PCT/CN2021/107808 WO2022017444A1 (zh) | 2020-07-24 | 2021-07-22 | Shp2抑制剂及其组合物和应用 |
Publications (2)
Publication Number | Publication Date |
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CN115515947A true CN115515947A (zh) | 2022-12-23 |
CN115515947B CN115515947B (zh) | 2024-02-06 |
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US (1) | US20230339882A1 (zh) |
EP (1) | EP4186896A4 (zh) |
CN (1) | CN115515947B (zh) |
TW (1) | TW202214584A (zh) |
WO (1) | WO2022017444A1 (zh) |
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Publication number | Priority date | Publication date | Assignee | Title |
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WO2022235864A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors |
CN117616031A (zh) | 2021-05-05 | 2024-02-27 | 锐新医药公司 | 用于治疗癌症的ras抑制剂 |
WO2022235866A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
TW202319056A (zh) | 2021-07-09 | 2023-05-16 | 南韓商治納輔醫藥科技有限公司 | Shp2抑制劑及其用途 |
WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
TW202404581A (zh) | 2022-05-25 | 2024-02-01 | 美商醫肯納腫瘤學公司 | Mek抑制劑及其用途 |
WO2024206858A1 (en) | 2023-03-30 | 2024-10-03 | Revolution Medicines, Inc. | Compositions for inducing ras gtp hydrolysis and uses thereof |
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CN105916845A (zh) * | 2014-01-17 | 2016-08-31 | 诺华股份有限公司 | 用于抑制shp2活性的n-氮杂螺环烷取代的n-杂芳基化合物和组合物 |
WO2019118909A1 (en) * | 2017-12-15 | 2019-06-20 | Revolution Medicines, Inc. | Polycyclic compounds as allosteric shp2 inhibitors |
CN110143949A (zh) * | 2018-05-09 | 2019-08-20 | 北京加科思新药研发有限公司 | 可用作shp2抑制剂的新型杂环衍生物 |
WO2019183367A1 (en) * | 2018-03-21 | 2019-09-26 | Relay Therapeutics, Inc. | Shp2 phosphatase inhibitors and methods of use thereof |
WO2020063760A1 (en) * | 2018-09-26 | 2020-04-02 | Jacobio Pharmaceuticals Co., Ltd. | Novel heterocyclic derivatives useful as shp2 inhibitors |
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2021
- 2021-07-22 WO PCT/CN2021/107808 patent/WO2022017444A1/zh active Application Filing
- 2021-07-22 TW TW110126966A patent/TW202214584A/zh unknown
- 2021-07-22 US US18/016,144 patent/US20230339882A1/en active Pending
- 2021-07-22 EP EP21847300.7A patent/EP4186896A4/en active Pending
- 2021-07-22 CN CN202180033007.1A patent/CN115515947B/zh active Active
Patent Citations (5)
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CN105916845A (zh) * | 2014-01-17 | 2016-08-31 | 诺华股份有限公司 | 用于抑制shp2活性的n-氮杂螺环烷取代的n-杂芳基化合物和组合物 |
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