ES2916549T3 - Compuestos heteroarilo como inhibidores de necrosis y composición relacionada - Google Patents
Compuestos heteroarilo como inhibidores de necrosis y composición relacionada Download PDFInfo
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- ES2916549T3 ES2916549T3 ES18819803T ES18819803T ES2916549T3 ES 2916549 T3 ES2916549 T3 ES 2916549T3 ES 18819803 T ES18819803 T ES 18819803T ES 18819803 T ES18819803 T ES 18819803T ES 2916549 T3 ES2916549 T3 ES 2916549T3
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- alkyl
- cycloalkyl
- heteroatoms
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- 230000017074 necrotic cell death Effects 0.000 title claims description 33
- 239000000203 mixture Substances 0.000 title description 150
- 125000001072 heteroaryl group Chemical group 0.000 title description 10
- 239000003112 inhibitor Substances 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 211
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 82
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 51
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 50
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 46
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 41
- 150000004820 halides Chemical class 0.000 claims abstract description 35
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims abstract description 34
- 229910052805 deuterium Inorganic materials 0.000 claims abstract description 34
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 33
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 31
- -1 C6-12 spirocycle Chemical group 0.000 claims abstract description 31
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 27
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims abstract description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 19
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 14
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 14
- 125000004429 atom Chemical group 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 7
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims abstract description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 6
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
- 239000012453 solvate Substances 0.000 claims abstract description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 3
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- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 230000004770 neurodegeneration Effects 0.000 claims description 4
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- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
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- 238000000034 method Methods 0.000 description 76
- 238000005160 1H NMR spectroscopy Methods 0.000 description 61
- 239000000243 solution Substances 0.000 description 59
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 58
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 56
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 239000007832 Na2SO4 Substances 0.000 description 35
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 35
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- 235000011152 sodium sulphate Nutrition 0.000 description 35
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 16
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 10
- 125000000753 cycloalkyl group Chemical group 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
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- 125000006239 protecting group Chemical group 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 101710156256 Myosin phosphatase Rho-interacting protein Proteins 0.000 description 7
- 102100033729 Receptor-interacting serine/threonine-protein kinase 3 Human genes 0.000 description 7
- 102100040247 Tumor necrosis factor Human genes 0.000 description 7
- 230000033228 biological regulation Effects 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- WWQQPSDIIVXFOX-UHFFFAOYSA-N 5-bromo-2-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC(Br)=CN=C1Cl WWQQPSDIIVXFOX-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
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- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 5
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- QOMPZPDKILKUGG-UHFFFAOYSA-N 7-bromo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine Chemical class N1CCNC2=CC(Br)=CN=C21 QOMPZPDKILKUGG-UHFFFAOYSA-N 0.000 description 4
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
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- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- General Health & Medical Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
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- Neurology (AREA)
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- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710483983 | 2017-06-23 | ||
| CN201810575869.7A CN109111464B (zh) | 2017-06-23 | 2018-06-06 | 一种具有细胞坏死抑制活性的杂环化合物 |
| PCT/US2018/039180 WO2018237370A1 (en) | 2017-06-23 | 2018-06-23 | Heteroaryl compounds as inhibitors of necrosis, composition and method using the same |
Publications (1)
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| ES2916549T3 true ES2916549T3 (es) | 2022-07-01 |
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| ES18819803T Active ES2916549T3 (es) | 2017-06-23 | 2018-06-23 | Compuestos heteroarilo como inhibidores de necrosis y composición relacionada |
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| EP (1) | EP3642193B1 (https=) |
| JP (1) | JP6950006B2 (https=) |
| KR (1) | KR102367257B1 (https=) |
| CN (1) | CN109111464B (https=) |
| ES (1) | ES2916549T3 (https=) |
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| TW202116771A (zh) * | 2019-07-17 | 2021-05-01 | 英屬開曼群島商百濟神州有限公司 | 作為ｈｐｋ１抑制劑之三環化合物及其用途 |
| CN115894489A (zh) * | 2021-09-22 | 2023-04-04 | 中国药科大学 | 一种受体相互作用蛋白激酶1的抑制剂及其制备方法、应用 |
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| MY155517A (en) * | 2008-03-31 | 2015-10-30 | C&C Res Lab | Heterocyclic derivatives |
| WO2010008847A2 (en) * | 2008-06-24 | 2010-01-21 | Takeda Pharmaceutical Company Limited | Pi3k/m tor inhibitors |
| US20110172217A1 (en) * | 2008-09-05 | 2011-07-14 | Shionogi & Co., Ltd. | Ring-fused morpholine derivative having pi3k-inhibiting activity |
| WO2010100144A1 (en) * | 2009-03-04 | 2010-09-10 | Merck Serono S.A. | Fused bicyclic compounds as inhibitors for pi3 kinase |
| US9295673B2 (en) * | 2011-02-23 | 2016-03-29 | Intellikine Llc | Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof |
| US20160256458A1 (en) * | 2013-11-18 | 2016-09-08 | Forma Therapeutics, Inc. | Benzopiperazine compositions as bet bromodomain inhibitors |
| CN106029076B (zh) * | 2013-11-18 | 2019-06-07 | 福马疗法公司 | 作为bet溴域抑制剂的苯并哌嗪组合物 |
| WO2018017435A1 (en) * | 2016-07-22 | 2018-01-25 | Accro Bioscience Inc. | Heteroaryl compounds as inhibitors of necrosis, composition and application thereof |
| CN107641118B (zh) | 2016-07-22 | 2020-11-06 | 爱科诺生物医药股份有限公司 | 具有细胞坏死抑制活性的化合物及其组合物和应用 |
| RU2019133646A (ru) * | 2017-03-30 | 2021-04-30 | Ф. Хоффманн-Ля Рош Аг | Изохинолины в качестве ингибиторов hpk1 |
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- 2018-06-23 JP JP2019569828A patent/JP6950006B2/ja active Active
- 2018-06-23 EP EP18819803.0A patent/EP3642193B1/en active Active
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- 2018-06-23 KR KR1020197036806A patent/KR102367257B1/ko active Active
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Also Published As
| Publication number | Publication date |
|---|---|
| JP6950006B2 (ja) | 2021-10-13 |
| JP2020525417A (ja) | 2020-08-27 |
| EP3642193B1 (en) | 2022-04-27 |
| EP3642193A1 (en) | 2020-04-29 |
| US20210155635A1 (en) | 2021-05-27 |
| CN109111464A (zh) | 2019-01-01 |
| KR102367257B1 (ko) | 2022-02-24 |
| KR20200017411A (ko) | 2020-02-18 |
| CN109111464B (zh) | 2021-02-26 |
| EP3642193A4 (en) | 2021-03-10 |
| US11339177B2 (en) | 2022-05-24 |
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