CN114630820A - 3-硝基-n-(2,2,2-三氟乙基)-4-吡啶胺的合成 - Google Patents
3-硝基-n-(2,2,2-三氟乙基)-4-吡啶胺的合成 Download PDFInfo
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- CIQUARQQVOVOGH-UHFFFAOYSA-N 3-nitro-N-(2,2,2-trifluoroethyl)pyridin-4-amine Chemical compound [O-][N+](=O)C1=CN=CC=C1NCC(F)(F)F CIQUARQQVOVOGH-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 title abstract description 8
- 230000015572 biosynthetic process Effects 0.000 title abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 150000007524 organic acids Chemical class 0.000 claims description 9
- KIPSRYDSZQRPEA-UHFFFAOYSA-N 2,2,2-trifluoroethanamine Chemical compound NCC(F)(F)F KIPSRYDSZQRPEA-UHFFFAOYSA-N 0.000 claims description 7
- BZPVREXVOZITPF-UHFFFAOYSA-N 4-methoxy-3-nitropyridine Chemical compound COC1=CC=NC=C1[N+]([O-])=O BZPVREXVOZITPF-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 150000005232 imidazopyridines Chemical class 0.000 abstract description 3
- 150000005237 imidazopyrimidines Chemical class 0.000 abstract description 3
- 230000005764 inhibitory process Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000725643 Respiratory syncytial virus Species 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 229960002303 citric acid monohydrate Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- 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
- A61K31/435—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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Health & Medical Sciences (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
Abstract
本发明涉及用于制备3‑硝基‑N‑(2,2,2‑三氟乙基)‑4‑吡啶胺(b)的化学合成途径，该化合物可以在抑制RSV的咪唑并吡啶类或咪唑并嘧啶类的合成中用作中间体化合物。
Description
本发明涉及用于制备3-硝基-N-(2,2,2-三氟乙基)-4-吡啶胺的化学合成途径，该化合物可以在抑制RSV的咪唑并吡啶类或咪唑并嘧啶类的合成中用作中间体化合物。
背景技术
呼吸道合胞病毒是引起幼儿、免疫功能受损的成人和老年人急性下呼吸道感染的主要原因。使用对呼吸道合胞病毒具有特异性的小分子抗病毒药物的干预提供了重要的治疗机会，但目前还没有此类化合物被批准。
3-硝基-N-(2,2,2-三氟乙基)-4-吡啶胺是一种可在抑制RSV的咪唑并吡啶类或咪唑并嘧啶类(如WO-01/95910中所披露的那些)的合成中用作结构单元的化合物。
现有技术
WO-01/95910在65页披露了3-硝基-N-(2,2,2-三氟乙基)-4-吡啶胺的盐酸盐，其由4-甲氧基-3-硝基-吡啶制备，如下所示：
发明内容
现已发现，可以通过在包含酸的水溶液存在下、在加热下，用2,2,2-三氟乙胺处理4-甲氧基-3-硝基-吡啶来方便地制备3-硝基-N-(2,2,2-三氟乙基)-4-吡啶胺。
对于大规模生产，这种新的合成方法避免了高压反应容器(即密封管的升级版本)的使用并将反应时间从2天减少到小于1天(典型地在10到16小时之间)。
本发明提供了制备具有式(b)的3-硝基-N-(2,2,2-三氟乙基)-4-吡啶胺的方法，该方法通过在包含酸的水溶液存在下、在加热下，用2,2,2-三氟乙胺处理具有式(a)的4-甲氧基-3-硝基-吡啶。
使用的酸可以是任何无机酸或有机酸，该无机酸或有机酸可溶于水并且能够使吡啶部分进行质子化以活化吡啶环来亲核取代。无机酸选自盐酸、氢溴酸、硫酸、磷酸、硼酸、硝酸等。有机酸优选地为羧酸，这些羧酸选自甲酸、乙酸、对甲苯磺酸、柠檬酸、草酸、丙二酸、琥珀酸、乳酸等。适合的有机酸为柠檬酸或柠檬酸一水合物，其成本低、毒性低并且易于处理。相对于4-甲氧基-3-硝基-吡啶的量，有机酸的量可以是1摩尔至5摩尔之间的任何量。在实践中，有机酸的量的范围为从1.2至3摩尔，并且优选的范围是1.2至1.5。
相对于4-甲氧基-3-硝基-吡啶的量，2,2,2-三氟乙胺的量可以是1摩尔至5摩尔之间的任何量。在实践中，2,2,2-三氟乙胺的量的范围为从1.1至3摩尔。
反应可以方便地在范围为室温与反应混合物的回流温度之间的温度下进行。在实践中，温度的范围可以为从室温至90℃、或从30℃至80℃、或从40℃至70℃。
反应完成后，可以通过用有机溶剂萃取来从反应混合物中分离希望的3-硝基-N-(2,2,2-三氟乙基)-4-吡啶胺。
实例：3-硝基-N-(2,2,2-三氟乙基)-4吡啶胺的合成
将柠檬酸一水合物(295.0g)溶解在水(370.0g)中，并且然后添加4-甲氧基-3-硝基吡啶(179.0g)，随后添加2,2,2-三氟乙胺(348.0g)。将混合物在50℃下搅拌直至完全转化(10-16小时)。在冷却至室温后，添加2-MeTHF(1250mL)，并将混合物搅拌1小时，并且然后分离各相。将水相用2-MeTHF(530mL)再萃取。将合并的有机层用7％NaHCO3水溶液(890g)、并且最后用水(903g)洗涤。将有机层蒸发至干燥，产生3-硝基-N-(2,2,2-三氟乙基)-4-吡啶胺(233.7g，91％产率)。
1H NMR(400MHz,DMSO-d6)δppm 4.28-4.47(m,2H)；7.28(d,J＝6.27Hz,1H)；8.38(d,J＝6.02Hz,1H)；8.63(br t,J＝6.65Hz,1H)；9.08(s,1H)
13C NMR(101MHz,DMSO-d6)δppm 43.15(q,J＝33.0Hz)；109.30124.05；126.84；130.70；148.55(d,J＝4.4Hz)；153.68
Claims (9)
1.一种用于制备具有式(b)的3-硝基-N-(2,2,2-三氟乙基)-4-吡啶胺的方法，
该方法通过在包含酸的水溶液中、在加热下，用2,2,2-三氟乙胺处理具有式(a)的4-甲氧基-3-硝基-吡啶。
2.如权利要求1所述的方法，其中该酸是无机酸或有机酸。
3.如权利要求2所述的方法，其中该无机酸选自由以下组成的列表：盐酸、氢溴酸、硫酸、磷酸、硼酸、和硝酸。
4.如权利要求2所述的方法，其中该有机酸选自由以下组成的列表：甲酸、乙酸、对甲苯磺酸、柠檬酸、草酸、丙二酸、琥珀酸、和乳酸。
5.如权利要求4所述的方法，其中该有机酸是柠檬酸。
6.如权利要求1至5中任一项所述的方法，其中将该反应混合物加热至范围为从室温至该反应混合物的回流温度的温度。
7.如权利要求6所述的方法，其中该温度的范围是从30℃至80℃。
8.如权利要求7所述的方法，其中该温度的范围是从40℃至70℃。
9.如前述权利要求中任一项所述的方法，其中该有机酸的量的范围为从1摩尔至5摩尔，并且2,2,2-三氟乙胺的量的范围为从1摩尔至3摩尔。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2019114253 | 2019-10-30 | ||
| CNPCT/CN2019/114253 | 2019-10-30 | ||
| PCT/EP2020/080379 WO2021083996A1 (en) | 2019-10-30 | 2020-10-29 | Synthesis of 3-nitro-n-(2,2,2-trifluoroethyl)-4-pyridinamine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114630820A true CN114630820A (zh) | 2022-06-14 |
| CN114630820B CN114630820B (zh) | 2023-10-31 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN202080073794.8A Active CN114630820B (zh) | 2019-10-30 | 2020-10-29 | 3-硝基-n-(2,2,2-三氟乙基)-4-吡啶胺的合成 |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US20240101515A1 (zh) |
| EP (1) | EP4051663B1 (zh) |
| JP (1) | JP2023500213A (zh) |
| KR (1) | KR20220097385A (zh) |
| CN (1) | CN114630820B (zh) |
| AU (1) | AU2020372712A1 (zh) |
| BR (1) | BR112022007208A2 (zh) |
| CA (1) | CA3151904A1 (zh) |
| WO (1) | WO2021083996A1 (zh) |
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| US20020016309A1 (en) * | 2000-06-13 | 2002-02-07 | Kuo-Long Yu | Imidazopyridine and imidazopyrimidine antiviral agents |
| US20060069116A1 (en) * | 2003-01-17 | 2006-03-30 | Ashton Wallace T | 3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| CN104540816A (zh) * | 2012-06-15 | 2015-04-22 | 爱尔兰詹森研发公司 | 作为呼吸道合胞病毒抗病毒剂的被杂环取代的1,3-二氢-2h-苯并咪唑-2-酮衍生物 |
| CN104955824A (zh) * | 2012-11-20 | 2015-09-30 | 基因泰克公司 | 作为含t790m的egfr突变体的抑制剂的氨基嘧啶化合物 |
| CN107709322A (zh) * | 2015-05-12 | 2018-02-16 | 百时美施贵宝公司 | 作为抗癌剂的三环化合物 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018187480A1 (en) * | 2017-04-04 | 2018-10-11 | Praxis Precision Medicines, Inc. | Compounds and their methods of use |
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2020
- 2020-10-29 WO PCT/EP2020/080379 patent/WO2021083996A1/en active Application Filing
- 2020-10-29 AU AU2020372712A patent/AU2020372712A1/en not_active Abandoned
- 2020-10-29 CA CA3151904A patent/CA3151904A1/en active Pending
- 2020-10-29 CN CN202080073794.8A patent/CN114630820B/zh active Active
- 2020-10-29 BR BR112022007208A patent/BR112022007208A2/pt not_active Application Discontinuation
- 2020-10-29 US US17/754,588 patent/US20240101515A1/en active Pending
- 2020-10-29 JP JP2022522041A patent/JP2023500213A/ja active Pending
- 2020-10-29 KR KR1020227011028A patent/KR20220097385A/ko unknown
- 2020-10-29 EP EP20800097.6A patent/EP4051663B1/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020016309A1 (en) * | 2000-06-13 | 2002-02-07 | Kuo-Long Yu | Imidazopyridine and imidazopyrimidine antiviral agents |
| CN1436079A (zh) * | 2000-06-13 | 2003-08-13 | 布里斯托尔-迈尔斯斯奎布公司 | 咪唑并吡啶和咪唑并嘧啶抗病毒剂 |
| US20060069116A1 (en) * | 2003-01-17 | 2006-03-30 | Ashton Wallace T | 3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| CN104540816A (zh) * | 2012-06-15 | 2015-04-22 | 爱尔兰詹森研发公司 | 作为呼吸道合胞病毒抗病毒剂的被杂环取代的1,3-二氢-2h-苯并咪唑-2-酮衍生物 |
| CN104955824A (zh) * | 2012-11-20 | 2015-09-30 | 基因泰克公司 | 作为含t790m的egfr突变体的抑制剂的氨基嘧啶化合物 |
| US20160016948A1 (en) * | 2012-11-20 | 2016-01-21 | Genentech, Inc. | Aminopyrimidine compounds as inhibitors of t790m containing egfr mutants |
| CN107709322A (zh) * | 2015-05-12 | 2018-02-16 | 百时美施贵宝公司 | 作为抗癌剂的三环化合物 |
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| BR112022007208A2 (pt) | 2022-07-26 |
| KR20220097385A (ko) | 2022-07-07 |
| CN114630820B (zh) | 2023-10-31 |
| AU2020372712A1 (en) | 2022-06-16 |
| JP2023500213A (ja) | 2023-01-05 |
| EP4051663B1 (en) | 2024-02-21 |
| EP4051663A1 (en) | 2022-09-07 |
| CA3151904A1 (en) | 2021-05-06 |
| US20240101515A1 (en) | 2024-03-28 |
| WO2021083996A1 (en) | 2021-05-06 |
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