JP7297871B2 - Ｐｔｐｎ１１の置換されたヘテロ環式インヒビター - Google Patents
Ｐｔｐｎ１１の置換されたヘテロ環式インヒビター Download PDFInfo
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- JP7297871B2 JP7297871B2 JP2021510272A JP2021510272A JP7297871B2 JP 7297871 B2 JP7297871 B2 JP 7297871B2 JP 2021510272 A JP2021510272 A JP 2021510272A JP 2021510272 A JP2021510272 A JP 2021510272A JP 7297871 B2 JP7297871 B2 JP 7297871B2
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- 101001087416 Homo sapiens Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 title claims description 51
- 125000000623 heterocyclic group Chemical group 0.000 title claims description 51
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 title claims description 50
- 239000003112 inhibitor Substances 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims description 296
- 239000000203 mixture Substances 0.000 claims description 239
- 125000000217 alkyl group Chemical group 0.000 claims description 165
- -1 hydroxy, amino Chemical group 0.000 claims description 159
- 125000005843 halogen group Chemical group 0.000 claims description 125
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 111
- 125000001072 heteroaryl group Chemical group 0.000 claims description 79
- 229910052760 oxygen Inorganic materials 0.000 claims description 76
- 125000005842 heteroatom Chemical group 0.000 claims description 69
- 229910052799 carbon Inorganic materials 0.000 claims description 65
- 229910052717 sulfur Inorganic materials 0.000 claims description 61
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 60
- 125000003545 alkoxy group Chemical group 0.000 claims description 59
- 150000003839 salts Chemical class 0.000 claims description 59
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 54
- 229910052757 nitrogen Inorganic materials 0.000 claims description 54
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 52
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 47
- 229910052736 halogen Inorganic materials 0.000 claims description 43
- 125000003282 alkyl amino group Chemical group 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 39
- 239000001257 hydrogen Substances 0.000 claims description 38
- 229920006395 saturated elastomer Polymers 0.000 claims description 38
- 206010028980 Neoplasm Diseases 0.000 claims description 36
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 34
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical group FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 34
- 201000010099 disease Diseases 0.000 claims description 33
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 30
- 201000011510 cancer Diseases 0.000 claims description 27
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 27
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 26
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- 125000004990 dihydroxyalkyl group Chemical group 0.000 claims description 22
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 22
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 19
- 230000001404 mediated effect Effects 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 150000001721 carbon Chemical group 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 9
- 208000032839 leukemia Diseases 0.000 claims description 9
- 201000001441 melanoma Diseases 0.000 claims description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 300
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 163
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 161
- 235000019439 ethyl acetate Nutrition 0.000 description 149
- 239000000243 solution Substances 0.000 description 127
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 114
- 230000002829 reductive effect Effects 0.000 description 106
- 239000007787 solid Substances 0.000 description 102
- 125000003118 aryl group Chemical group 0.000 description 86
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 83
- 238000010898 silica gel chromatography Methods 0.000 description 71
- 239000011541 reaction mixture Substances 0.000 description 66
- 238000000034 method Methods 0.000 description 64
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 62
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 57
- 239000012044 organic layer Substances 0.000 description 49
- 239000000047 product Substances 0.000 description 48
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 47
- 239000012267 brine Substances 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 44
- 239000003039 volatile agent Substances 0.000 description 44
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 42
- 239000000460 chlorine Substances 0.000 description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 38
- 238000005481 NMR spectroscopy Methods 0.000 description 37
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 37
- 239000007832 Na2SO4 Substances 0.000 description 36
- 229910052938 sodium sulfate Inorganic materials 0.000 description 36
- 235000011152 sodium sulphate Nutrition 0.000 description 36
- 239000011734 sodium Substances 0.000 description 35
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000000543 intermediate Substances 0.000 description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 29
- 239000010410 layer Substances 0.000 description 29
- 239000003208 petroleum Substances 0.000 description 28
- 239000003814 drug Substances 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- 150000002431 hydrogen Chemical class 0.000 description 25
- 239000000741 silica gel Substances 0.000 description 25
- 229910002027 silica gel Inorganic materials 0.000 description 25
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 description 24
- 239000007788 liquid Substances 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 23
- 238000000746 purification Methods 0.000 description 23
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000012230 colorless oil Substances 0.000 description 21
- 238000009472 formulation Methods 0.000 description 21
- 229910052698 phosphorus Inorganic materials 0.000 description 21
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- 239000003921 oil Substances 0.000 description 20
- 235000019198 oils Nutrition 0.000 description 19
- 238000011282 treatment Methods 0.000 description 19
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 18
- 239000012071 phase Substances 0.000 description 18
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 18
- 230000000694 effects Effects 0.000 description 17
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- 125000004043 oxo group Chemical group O=* 0.000 description 17
- 239000004480 active ingredient Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 15
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- 239000000651 prodrug Substances 0.000 description 15
- 208000035475 disorder Diseases 0.000 description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
- 239000004698 Polyethylene Substances 0.000 description 13
- 239000008346 aqueous phase Substances 0.000 description 13
- 239000012458 free base Substances 0.000 description 13
- 238000002953 preparative HPLC Methods 0.000 description 13
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 229940124597 therapeutic agent Drugs 0.000 description 12
- 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 11
- 150000001412 amines Chemical class 0.000 description 11
- 229910052796 boron Inorganic materials 0.000 description 11
- 239000000463 material Substances 0.000 description 11
- LSEAAPGIZCDEEH-UHFFFAOYSA-N 2,6-dichloropyrazine Chemical compound ClC1=CN=CC(Cl)=N1 LSEAAPGIZCDEEH-UHFFFAOYSA-N 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 10
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 9
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- 125000001188 haloalkyl group Chemical group 0.000 description 9
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- DDZGQYREBDXECY-UHFFFAOYSA-N 1h-pyrazolo[3,4-b]pyrazine Chemical compound C1=CN=C2C=NNC2=N1 DDZGQYREBDXECY-UHFFFAOYSA-N 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
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- 239000002775 capsule Substances 0.000 description 8
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 8
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- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 7
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- 125000003342 alkenyl group Chemical group 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
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- 235000009518 sodium iodide Nutrition 0.000 description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 5
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical class C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
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- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 4
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- 125000000304 alkynyl group Chemical group 0.000 description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 4
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- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 4
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- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- C07—ORGANIC CHEMISTRY
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
-
- 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
Landscapes
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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| US62/773,915 | 2018-11-30 | ||
| PCT/US2019/030277 WO2019213318A1 (en) | 2018-05-02 | 2019-05-01 | Substituted heterocyclic inhibitors of ptpn11 |
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| AU2017274199B2 (en) | 2016-05-31 | 2021-09-23 | Board Of Regents, The University Of Texas System | Heterocyclic inhibitors of PTPN11 |
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| US10954243B2 (en) | 2021-03-23 |
| IL278297B2 (en) | 2023-12-01 |
| EP3787627A1 (en) | 2021-03-10 |
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| MX2020011528A (es) | 2021-02-09 |
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| AU2019263294B2 (en) | 2024-03-21 |
| KR20210003901A (ko) | 2021-01-12 |
| NZ770260A (en) | 2024-12-20 |
| CN112351780A (zh) | 2021-02-09 |
| IL278297A (https=) | 2020-12-31 |
| KR102611661B1 (ko) | 2023-12-08 |
| JP2021523221A (ja) | 2021-09-02 |
| CA3099151A1 (en) | 2019-11-07 |
| AU2019263294A1 (en) | 2020-12-17 |
| EP3787627A4 (en) | 2021-12-01 |
| SG11202010822SA (en) | 2020-11-27 |
| CN112351780B (zh) | 2023-12-01 |
| WO2019213318A1 (en) | 2019-11-07 |
| US20190389867A1 (en) | 2019-12-26 |
| US11932643B2 (en) | 2024-03-19 |
| US20210317122A1 (en) | 2021-10-14 |
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