RU2764523C2 - Соединение аминопиразолопиримидина, используемое в качестве ингибитора тирозинкиназного рецептора нейротрофического фактора - Google Patents
Соединение аминопиразолопиримидина, используемое в качестве ингибитора тирозинкиназного рецептора нейротрофического фактора Download PDFInfo
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- RU2764523C2 RU2764523C2 RU2019114600A RU2019114600A RU2764523C2 RU 2764523 C2 RU2764523 C2 RU 2764523C2 RU 2019114600 A RU2019114600 A RU 2019114600A RU 2019114600 A RU2019114600 A RU 2019114600A RU 2764523 C2 RU2764523 C2 RU 2764523C2
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- phenyl
- substituted
- independently selected
- hydrogen
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- -1 Aminopyrazolopyrimidine compound Chemical class 0.000 title claims abstract description 183
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 title claims abstract description 14
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 title claims abstract 6
- 108010025020 Nerve Growth Factor Proteins 0.000 title description 6
- 102000007072 Nerve Growth Factors Human genes 0.000 title description 4
- 239000003900 neurotrophic factor Substances 0.000 title description 4
- 239000003112 inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 211
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 125
- 125000001424 substituent group Chemical group 0.000 claims abstract description 99
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 97
- 239000001257 hydrogen Substances 0.000 claims abstract description 97
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 77
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 53
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 41
- 150000002367 halogens Chemical class 0.000 claims abstract description 41
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 35
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 25
- 201000010099 disease Diseases 0.000 claims abstract description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000001404 mediated effect Effects 0.000 claims abstract description 14
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 13
- 230000002265 prevention Effects 0.000 claims abstract description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims abstract description 4
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 4
- 239000001301 oxygen Chemical group 0.000 claims abstract description 4
- 239000011593 sulfur Substances 0.000 claims abstract description 4
- 229910052757 nitrogen Chemical group 0.000 claims abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 91
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 84
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 55
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 39
- 229910052731 fluorine Inorganic materials 0.000 claims description 39
- 239000011737 fluorine Substances 0.000 claims description 39
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 39
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 33
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 31
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 31
- 229910052794 bromium Inorganic materials 0.000 claims description 31
- 239000000460 chlorine Substances 0.000 claims description 31
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 30
- 229910052801 chlorine Inorganic materials 0.000 claims description 30
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 29
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 25
- 125000002971 oxazolyl group Chemical group 0.000 claims description 25
- 125000000335 thiazolyl group Chemical group 0.000 claims description 24
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 23
- 125000001153 fluoro group Chemical group F* 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 20
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 20
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 20
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 19
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 16
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 16
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 14
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 14
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 14
- 229910052740 iodine Inorganic materials 0.000 claims description 14
- 239000011630 iodine Substances 0.000 claims description 14
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 125000004193 piperazinyl group Chemical group 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 10
- 241000124008 Mammalia Species 0.000 claims description 9
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 7
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 7
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 5
- 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 claims description 5
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 11
- 239000000126 substance Substances 0.000 abstract description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 117
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
- 239000000243 solution Substances 0.000 description 89
- 239000000203 mixture Substances 0.000 description 77
- 238000006243 chemical reaction Methods 0.000 description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 230000002829 reductive effect Effects 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 238000010898 silica gel chromatography Methods 0.000 description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 30
- 239000000706 filtrate Substances 0.000 description 29
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- 239000012074 organic phase Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 13
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- CMDGQQACQLVQAN-CQSZACIVSA-N ethyl 2-amino-5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate Chemical compound CCOC(=O)c1c(N)nn2ccc(nc12)N1CCC[C@@H]1c1cc(F)ccc1F CMDGQQACQLVQAN-CQSZACIVSA-N 0.000 description 8
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610970314.3 | 2016-10-28 | ||
| CN201610970314 | 2016-10-28 | ||
| CN201710044000.5 | 2017-01-21 | ||
| CN201710044000 | 2017-01-21 | ||
| PCT/CN2017/108100 WO2018077246A1 (zh) | 2016-10-28 | 2017-10-27 | 用作神经营养因子酪氨酸激酶受体抑制剂的氨基吡唑并嘧啶化合物 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| RU2019114600A RU2019114600A (ru) | 2020-11-30 |
| RU2019114600A3 RU2019114600A3 (enExample) | 2021-02-20 |
| RU2764523C2 true RU2764523C2 (ru) | 2022-01-18 |
Family
ID=62024344
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2019114600A RU2764523C2 (ru) | 2016-10-28 | 2017-10-27 | Соединение аминопиразолопиримидина, используемое в качестве ингибитора тирозинкиназного рецептора нейротрофического фактора |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US10829492B2 (enExample) |
| EP (1) | EP3533796B1 (enExample) |
| JP (1) | JP7046940B2 (enExample) |
| KR (1) | KR102616249B1 (enExample) |
| CN (1) | CN109890820B (enExample) |
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| CA (1) | CA3041942C (enExample) |
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| CN111182903A (zh) * | 2017-07-28 | 2020-05-19 | 特普医药公司 | 巨环化合物及其用途 |
| CA3071032A1 (en) * | 2017-08-23 | 2019-02-28 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Macrocycle containing aminopyrazole and pyrimidine and pharmaceutical composition and use thereof |
| CN108794370A (zh) * | 2018-07-31 | 2018-11-13 | 上海弈柯莱生物医药科技有限公司 | 一种拉罗替尼中间体的制备方法 |
| AU2019394520A1 (en) * | 2018-12-07 | 2021-07-01 | Betta Pharmaceuticals Co., Ltd | Tyrosine kinase inhibitors, compositions and methods there of |
| US20220177477A1 (en) | 2019-03-19 | 2022-06-09 | Central China Normal University | Pyrazolopyrimidine compound, pharmaceutical composition, and application therefor |
| CN112979654B (zh) * | 2019-12-16 | 2024-03-19 | 赛诺哈勃药业（成都）有限公司 | 杂芳基稠环化合物、其制备方法及应用 |
| WO2021249450A1 (zh) * | 2020-06-11 | 2021-12-16 | 贝达药业股份有限公司 | 酪氨酸激酶抑制剂的盐型、晶型、药物组合物及其用途 |
| CN111620881B (zh) * | 2020-07-08 | 2023-03-31 | 浙江合聚生物医药有限公司 | 拉罗替尼衍生物及其制备方法和应用 |
| CN113563343B (zh) * | 2020-07-27 | 2022-05-24 | 杭州邦顺制药有限公司 | 取代的吡唑并[1,5-a]嘧啶化合物及其用途 |
| CN112010860B (zh) * | 2020-08-05 | 2023-03-10 | 南京纳丁菲医药科技有限公司 | 苄氧基吡唑并嘧啶化合物和药物组合物及其应用 |
| CN114437075B (zh) * | 2020-11-03 | 2026-01-30 | 上海瑶琪生物科技有限公司 | 用作ntrk激酶抑制剂的化合物及其应用 |
| CN113200963A (zh) * | 2021-03-31 | 2021-08-03 | 广东石油化工学院 | N-(吡咯基)-3-吡唑基胺及其制备方法 |
| JP7840066B2 (ja) | 2021-05-03 | 2026-04-03 | ジェービーケーラボ カンパニー リミテッド | ２，６－ジクロロ－４－（４－（４－ヒドロキシシクロヘキシルアミノ）－７ｈ－ピロロ［２，３－ｄ］ピリミジン－５－イル）フェノールを活性成分として含有する、がんを予防、緩和、または処置するための医薬組成物 |
| WO2023006057A1 (zh) * | 2021-07-30 | 2023-02-02 | 正大天晴药业集团股份有限公司 | 氨基吡唑并嘧啶化合物的晶体 |
| CN117597129A (zh) * | 2021-08-06 | 2024-02-23 | 正大天晴药业集团股份有限公司 | 氨基吡唑并嘧啶化合物在治疗trk激酶介导的肿瘤中的用途 |
| CN117088800B (zh) * | 2023-08-18 | 2024-05-28 | 龙曦宁（上海）医药科技有限公司 | 一种5-甲基吡咯烷-3-醇盐酸盐的制备方法 |
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- 2017-10-27 PL PL17863410T patent/PL3533796T3/pl unknown
- 2017-10-27 CN CN201780064022.6A patent/CN109890820B/zh active Active
- 2017-10-27 RU RU2019114600A patent/RU2764523C2/ru active
- 2017-10-27 HU HUE17863410A patent/HUE057733T2/hu unknown
- 2017-10-27 KR KR1020197015241A patent/KR102616249B1/ko active Active
- 2017-10-27 DK DK17863410.1T patent/DK3533796T3/da active
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- 2017-10-27 US US16/345,679 patent/US10829492B2/en active Active
- 2017-10-27 PT PT178634101T patent/PT3533796T/pt unknown
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- 2017-10-27 AU AU2017348826A patent/AU2017348826B2/en active Active
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| RU2584157C2 (ru) * | 2009-07-09 | 2016-05-20 | Эррэй Биофарма Инк. | ЗАМЕЩЕННЫЕ СОЕДИНЕНИЯ ПИРАЗОЛО[1,5-a]ПИРИМИДИНА КАК ИНГИБИТОРЫ КИНАЗЫ TRK |
| WO2012034095A1 (en) * | 2010-09-09 | 2012-03-15 | Irm Llc | Compounds and compositions as trk inhibitors |
| CN104995172A (zh) * | 2013-02-19 | 2015-10-21 | 小野药品工业株式会社 | Trk抑制化合物 |
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| AU2017348826B2 (en) | 2021-12-02 |
| CN109890820B (zh) | 2020-11-03 |
| JP7046940B2 (ja) | 2022-04-04 |
| CA3041942A1 (en) | 2018-05-03 |
| CA3041942C (en) | 2023-03-14 |
| RU2019114600A (ru) | 2020-11-30 |
| JP2019537588A (ja) | 2019-12-26 |
| PL3533796T3 (pl) | 2022-01-17 |
| MX2019004847A (es) | 2019-08-29 |
| ES2896943T3 (es) | 2022-02-28 |
| EP3533796A4 (en) | 2020-06-03 |
| HUE057733T2 (hu) | 2022-06-28 |
| AU2017348826A1 (en) | 2019-05-23 |
| KR102616249B1 (ko) | 2023-12-21 |
| RU2019114600A3 (enExample) | 2021-02-20 |
| BR112019008656A8 (pt) | 2022-06-07 |
| WO2018077246A1 (zh) | 2018-05-03 |
| MX380283B (es) | 2025-03-12 |
| CN109890820A (zh) | 2019-06-14 |
| PT3533796T (pt) | 2021-11-18 |
| EP3533796A1 (en) | 2019-09-04 |
| DK3533796T3 (da) | 2021-11-08 |
| US10829492B2 (en) | 2020-11-10 |
| US20190352306A1 (en) | 2019-11-21 |
| KR20190067913A (ko) | 2019-06-17 |
| EP3533796B1 (en) | 2021-09-29 |
| BR112019008656A2 (pt) | 2019-07-09 |
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