WO2023036093A1 - 酮酰胺衍生物及其应用 - Google Patents
酮酰胺衍生物及其应用 Download PDFInfo
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- WO2023036093A1 WO2023036093A1 PCT/CN2022/117124 CN2022117124W WO2023036093A1 WO 2023036093 A1 WO2023036093 A1 WO 2023036093A1 CN 2022117124 W CN2022117124 W CN 2022117124W WO 2023036093 A1 WO2023036093 A1 WO 2023036093A1
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- WIPO (PCT)
- Prior art keywords
- compound
- pharmaceutically acceptable
- dichloromethane
- acceptable salt
- alkyl
- Prior art date
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- 150000004797 ketoamides Chemical class 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 268
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 12
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 7
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
- 229910005965 SO 2 Inorganic materials 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 208000001528 Coronaviridae Infections Diseases 0.000 claims description 6
- 239000003443 antiviral agent Substances 0.000 claims description 5
- 241000711573 Coronaviridae Species 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 241001678559 COVID-19 virus Species 0.000 claims description 3
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 claims description 3
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 claims description 3
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 claims description 3
- 229960001830 amprenavir Drugs 0.000 claims description 3
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 claims description 3
- 229960001936 indinavir Drugs 0.000 claims description 3
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 claims description 3
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- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 claims description 3
- 229960000311 ritonavir Drugs 0.000 claims description 3
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 claims description 3
- 241000711467 Human coronavirus 229E Species 0.000 claims description 2
- 241001109669 Human coronavirus HKU1 Species 0.000 claims description 2
- 241000482741 Human coronavirus NL63 Species 0.000 claims description 2
- 241001428935 Human coronavirus OC43 Species 0.000 claims description 2
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 claims description 2
- 241000315672 SARS coronavirus Species 0.000 claims description 2
- 229960001852 saquinavir Drugs 0.000 claims description 2
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 303
- 238000006243 chemical reaction Methods 0.000 description 153
- 239000000243 solution Substances 0.000 description 123
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 75
- 238000003786 synthesis reaction Methods 0.000 description 72
- 230000015572 biosynthetic process Effects 0.000 description 71
- 239000012074 organic phase Substances 0.000 description 61
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 52
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
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- 239000012043 crude product Substances 0.000 description 30
- -1 for example Chemical group 0.000 description 25
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- 239000012141 concentrate Substances 0.000 description 22
- 238000010898 silica gel chromatography Methods 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 125000001424 substituent group Chemical group 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 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 12
- 230000000694 effects Effects 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- 125000004429 atom Chemical group 0.000 description 11
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- 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 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 5
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- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 5
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- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 4
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- QMBQEXOLIRBNPN-UHFFFAOYSA-L zirconocene dichloride Chemical compound [Cl-].[Cl-].[Zr+4].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 QMBQEXOLIRBNPN-UHFFFAOYSA-L 0.000 description 1
Classifications
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- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61P31/14—Antivirals for RNA viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- 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
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
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- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
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Definitions
- the present invention relates to a class of ketoamide derivatives and applications thereof, in particular to compounds represented by formula (IV) and pharmaceutically acceptable salts thereof.
- SARS-Cov-2 coronavirus
- the main protease or 3CL protease of coronavirus is a key protein in virus replication, and its main function is to hydrolyze two polyproteins expressed by the virus. Sequence analysis indicated that 3CL protease may become one of the key targets for drug design. By developing its inhibitors and blocking the replication process of coronaviruses, it is of great value and significance for the prevention and treatment of coronavirus infections.
- PF-07321332 is a potent orally active SARS-CoV 3CL PRO inhibitor whose structure is shown below:
- the present invention provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, which is selected from:
- R3 is selected from and R4 ;
- Each R 1 is independently selected from F, Cl, Br, I, OR 11 , CN, CH 3 S(O) m -, and NHR 12 and C 1-3 alkyl, which C 1-3 alkyl is optionally 1, 2 or 3 F substitutions;
- R 11 is selected from H, C 1-3 alkyl, CH 3 (OCH 2 CH 2 ) p - and H(OCH 2 CH 2 ) q -, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 F replaced;
- R 12 is selected from C 1-3 alkyl, CH 3 CO- and CH 3 SO 2 -, said C 1-3 alkyl, CH 3 CO- and CH 3 SO 2 - are optionally independently represented by 1, 2 or 3 F replacements;
- n 0, 1 and 2;
- p and q are selected from 1, 2, 3, 4, 5 and 6;
- n is selected from 0, 1, 2, 3 and 4;
- R 2 is selected from C 1-4 alkyl, C 3-6 cycloalkyl and benzyl, and said C 1-4 alkyl, C 3-6 cycloalkyl and benzyl are optionally replaced by 1, 2 or 3 F replaces;
- R is selected from C 1-8 alkyl optionally substituted by 1, 2 or 3 F;
- Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl and phenyl;
- Ring B is selected from C 3-8 cycloalkyl and 5-membered heterocycloalkyl; said C 3-8 cycloalkyl and 5-membered heterocycloalkyl are optionally substituted by 1 or 2 R a ;
- R a is each independently selected from H and C 1-3 alkyl
- the "5-membered heterocycloalkyl” contains 1, 2 or 3 heteroatoms or atomic groups independently selected from O, S, SO 2 , N, P and Se.
- R 1 is selected from F and methyl, and other variables are as defined in the present invention.
- the above-mentioned ring A is selected from Other variables are as defined herein.
- R 4 is selected from tert-butyl, and other variables are as defined in the present invention.
- R a is selected from H and methyl, and other variables are as defined in the present invention.
- the above ring B is selected from Other variables are as defined herein.
- the present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof, which is selected from:
- Each R 1 is independently selected from F, Cl, Br, I, OR 11 , CN, CH 3 S(O) m -, and NHR 12 and C 1-3 alkyl, which C 1-3 alkyl is optionally 1, 2 or 3 F substitutions;
- R 11 is selected from H, C 1-3 alkyl, CH 3 (OCH 2 CH 2 ) p - and H(OCH 2 CH 2 ) q -, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 F replaced;
- R 12 is selected from C 1-3 alkyl, CH 3 CO- and CH 3 SO 2 -, the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F;
- n 0, 1 and 2;
- p and q are selected from 1, 2, 3, 4, 5 and 6;
- n is selected from 0, 1, 2, 3 and 4;
- R 2 is selected from C 1-4 alkyl, C 3-6 cycloalkyl and benzyl, and said C 1-4 alkyl, C 3-6 cycloalkyl and benzyl are optionally replaced by 1, 2 or 3 F replaces;
- Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl and phenyl;
- Ring B is selected from C 3-6 cycloalkyl and 5-membered heterocycloalkyl; said C 3-6 cycloalkyl and 5-membered heterocycloalkyl are optionally substituted by 1 or 2 R a ;
- R a is each independently selected from H and C 1-3 alkyl
- the "5-membered heterocycloalkyl” contains 1, 2 or 3 heteroatoms or atomic groups independently selected from O, S, SO 2 , N, P and Se.
- R 1 is selected from F and methyl, and other variables are as defined in the present invention.
- the above-mentioned ring A is selected from Other variables are as defined herein.
- R a is selected from H and methyl, and other variables are as defined in the present invention.
- R 1 , R 2 , R 3 , n and ring A are as defined in the present invention.
- R 1 , R 2 , R 3 , n and ring A are as defined in the present invention.
- the present invention also provides the following compounds or pharmaceutically acceptable salts thereof, which are selected from:
- the present invention also provides the following compounds or pharmaceutically acceptable salts thereof, which are selected from:
- the present invention provides a combined administration method, which comprises administering a therapeutically effective amount of the compound described in any one of the technical schemes of the present invention or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, and Therapeutically acceptable doses of other antiviral drugs.
- the present invention also provides a method for treating coronavirus infection, the method comprising administering a therapeutically effective amount of the compound described in any one of the technical schemes of the present invention or a pharmaceutically acceptable salt thereof to a subject in need of the treatment, and Therapeutically acceptable doses of other antiviral drugs.
- the above-mentioned other antiviral drugs are ritonavir, indinavir, nelfinavir, saquinavir, amprenavir or lopinavir.
- the aforementioned method for the treatment of coronavirus infection in which the compound described in any one of the technical schemes of the present invention or a pharmaceutically acceptable salt thereof, together with ritonavir, indinavir, nelfinavir, saqué
- the mass ratio of navir, amprenavir or lopinavir is 1:1 ⁇ 5:1, and the specific ratio can be 1:1, 2:1, 3:1, 4:1 or 5:1, etc., through Surprisingly found in the experiment: the two treatment components in this ratio range are conducive to realizing the synergistic effect of the two, and can achieve a better comprehensive treatment effect; further, the method can be given by the treatment components contained in the same unit preparation.
- Drugs that is, the administration of compound preparations, or the preparations containing different therapeutic components
- the aforementioned coronavirus infection is HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV or SARS-CoV-2 and variants thereof.
- the aforementioned coronavirus infection is SARS-CoV-2 and variants thereof.
- the present invention also provides following synthetic route:
- the compound of the present invention has better in vitro anti-new coronavirus Mpro protease activity; better in vitro anti-coronavirus activity at the cellular level, and has no cytotoxicity.
- the exposure of the compound in the plasma is significantly increased, the clearance rate is slower, the half-life is longer, and the pharmacokinetic properties are better.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
- base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
- acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
- such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
- “Pharmaceutical composition” means containing one or more compounds described in the present application, its isomers or pharmaceutically acceptable salts thereof, and other components such as physiological/pharmaceutically acceptable carriers and excipients.
- the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
- therapeutically effective amount is meant to include an amount of a compound which, when administered, is sufficient to prevent or slow the progression to some extent of one or more symptoms of a disease or condition.
- therapeutically effective amount also refers to an amount of a compound sufficient to detect a biological or pharmaceutical response in a (eg, protein, enzyme, RNA, or DNA) biomolecule, cell, tissue, system, animal, or human. This response is desired by the researcher, veterinarian, physician, or clinician.
- the compounds of the invention may exist in particular geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
- cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
- diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
- keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
- the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
- the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
- the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
- Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
- a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
- compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
- the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
- deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
- substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
- Oxygen substitution does not occur on aromatic groups.
- optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.
- any variable eg, R
- its definition is independent at each occurrence.
- said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
- substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- a substituent can be bonded to any atom on a ring when the bond of a substituent can cross-link two or more atoms on the ring, e.g., structural unit It means that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene. When the enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.
- linking group listed does not indicate its linking direction
- its linking direction is arbitrary, for example,
- the linking group L is -MW-, at this time -MW- can be connected to ring A and ring A in the same direction as the reading order from left to right to form It can also be formed by linking loop A and loop A in the opposite direction to the reading order from left to right
- Combinations of the described linking groups, substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
- any one or more sites of the group can be linked to other groups through chemical bonds.
- connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
- the chemical bonds that the site connects with other groups can use straight solid line bonds Straight dotted key or tilde express.
- the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
- the straight dotted line bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
- the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups.
- the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” means a “ring” with 5-7 atoms arranged around it.
- C n-n+m or C n -C n+m includes any specific instance of n to n+m carbons, for example C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 etc.; similarly, n to n +m means that the number of atoms on the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membere
- C 1-8 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 8 carbon atoms.
- the C 1-8 alkyl group includes C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 8 , C 7 , C 6 and C 5 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
- C 1-8 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, heptyl, octyl, etc.
- C 1-4 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
- the C 1-4 alkyl group includes C 1-2 , C 1-3 and C 2-3 alkyl groups, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
- Examples of C 1-4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl) and so on.
- C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
- the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
- Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- C 3-10 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 10 carbon atoms, which includes monocyclic, bicyclic and tricyclic systems, wherein bicyclic and tricyclic systems include Spiral, parallel and bridged rings.
- the C 3-10 cycloalkyl group includes C 3-8 , C 3-6 , C 3-5 , C 4-10 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 etc.; it may be monovalent, divalent or multivalent.
- C 3-10 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] bicyclooctane, [ 4.4.0] Bicyclodecane, etc.
- C 3-8 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 8 carbon atoms, which includes monocyclic, bicyclic and tricyclic systems, wherein bicyclic and tricyclic systems include Spiral, parallel and bridged rings.
- the C 3-8 cycloalkyl group includes C 3-8 , C 3-6 , C 3-5 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 etc. ; which may be monovalent, divalent or polyvalent.
- C 3-8 cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2.4]cyclohexane, and the like.
- C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which includes monocyclic, bicyclic and tricyclic systems, wherein bicyclic and tricyclic systems include Spiral, parallel and bridged rings.
- the C 3-6 cycloalkyl group includes C 3-4 , C 3-5 , C 4-5 , C 5-8 or C 5-6 ; it can be monovalent, divalent or multivalent.
- Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
- 3-10 membered heterocycloalkyl by itself or in combination with other terms denotes a saturated cyclic group consisting of 3 to 10 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, N, P, and Se, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen, sulfur, and phosphorus heteroatoms can be optionally oxidized (i.e., NO, S (O) p and P(O) p , where p is 1 or 2).
- the 3-10 membered heterocycloalkyl group includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, merged and bridged rings.
- a heteroatom may occupy the attachment position of the heterocycloalkyl group to the rest of the molecule.
- the 3-10 membered heterocycloalkyl includes 3-9, 3-8, 3-6, 5-9, 5, 6, 7, 8 and 9-membered heterocycloalkyl, etc. .
- 3-10 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidin,
- the term "5-membered heterocycloalkyl" by itself or in combination with other terms represents a saturated cyclic group consisting of 5 ring atoms, 1, 2 or 3 of which are independently selected from O, Heteroatoms of S, N, P, and Se, the remainder being carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen, sulfur, and phosphorus heteroatoms can be optionally oxidized (i.e., NO, S(O) p , and P (O) p , p is 1 or 2).
- 5-membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophene (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuran (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, etc.
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
- the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
- SXRD single crystal X-ray diffraction
- the solvent used in the present invention is commercially available.
- the present invention uses the following abbreviations:
- ACN stands for acetonitrile
- Boc stands for tert-butoxycarbonyl
- Bn stands for benzyl
- DCM stands for dichloromethane
- DMSO stands for dimethyl sulfoxide
- Ac represents acetyl
- Me represents methyl
- Et represents ethyl.
- the compound Boc-L-cyclohexylglycine (1g, 3.89mmol) was added to N,N-dimethylformamide (10mL), and 2-(7-azobenzotriazole)-N,N, N, N-tetramethyluronium hexafluorophosphate (1.77g, 4.66mmol), the reaction was stirred for 0.5hr, diisopropylethylamine (1.26g, 9.72mmol) was added, the hydrochloride of compound 1-3 (1.02 g, 4.66 mmol), the reaction was stirred at 20°C for 16 hours.
- Step 4 Synthesis of the hydrochloride salt of compound 2-4
- Dissolve compound 6-4 (10g, 36.71mmol) in methanol (100mL) and dichloromethane (100mL), cool to 0°C, add lead tetraacetate (13.56g, 27.53mmol), replace nitrogen three times, and react at 0°C Stir for 2h.
- [M+1] + 241.0.
- reaction solution was poured into 200 ml of 4M citric acid aqueous solution, extracted with dichloromethane (100 mL ⁇ 3), the organic phases were combined, and concentrated under reduced pressure.
- the resulting crude product was subjected to flash silica gel chromatography ( 12g Fast silica gel column, eluent 0-20% ethyl acetate/petroleum ether, flow rate 30mL/min) was purified to obtain compound 7-10.
- [M+Na] + 445.2.
- Chromatographic column ChromCore 120 C18 3 ⁇ m, 3.0*30mm; mobile phase: [A: water (trifluoroacetic acid)-B: acetonitrile]; acetonitrile %: 10%-80% within 6 minutes, then 80% keep 0.5 Minutes, flow rate 0.8mL/min.
- SARS-CoV-2 Mpro WuXi AppTec
- SpectraMax M2e microplate reader Molecular Devices
- the compound was dissolved in DMSO, and was diluted with Echo655 according to the 3-fold gradient according to the concentration to be tested, and 10 concentration points were added to the 384-well plate in duplicate wells for each concentration.
- Dilute Mpro protein and substrate with test buffer 100mM NaCl, 20mM Tris-HCL, 1mM EDTA
- add Mpro protein to a 384-well test plate and incubate with compound for 30min at room temperature, then add substrate, Mpro protein
- Inhibition rate% [(compound-BG compound )-(ZPE-BG ZPE )]/[(HPE-BG HPE )-(ZPE-BG ZPE )]*100%
- ZPE no inhibition control, containing 25nM Mpro protein + 25 ⁇ M substrate, no compound
- test compound well. Contains 25nM Mpro protein + 25 ⁇ M substrate + compound
- BG Background control well. Contains 25 ⁇ M substrate+compound without Mpro protein
- the compound of the present invention has better anti-new coronavirus Mpro protease activity in vitro.
- MEM medium Sigma
- L-Glutamine L-Glutamine: Gibco;
- Non-essential amino acids Gibco;
- DPBS Phosphate buffer saline
- MRC5 cells and coronavirus HCoV OC43 were purchased from ATCC.
- MRC5 cells were cultured in MEM (Sigma) medium supplemented with 10% fetal calf serum (Excell), 1% double antibody (Hyclone), 1% L-glutamine (Gibco) and 1% non-essential amino acids (Gibco).
- MEM (Sigma) culture medium supplemented with 5% fetal bovine serum (Excell), 1% double antibody (Hyclone), 1% L-glutamine (Gibco) and 1% non-essential amino acid (Gibco) was used as the experimental culture medium.
- Cells were seeded into 96 microwell plates at a certain density (Table 2) and cultured overnight in a 5% CO 2 , 37° C. incubator. On the second day, the compound after doubling dilution (8 concentration points, duplicate wells) was added, 50 ⁇ L per well. Then the diluted virus was added to the cells at 100 TCID 50 per well, 50 ⁇ L per well. Set up cell control (cells, no compound treatment or virus infection), virus control (cells infected with virus, no compound treatment) and culture medium control (only culture medium). The final volume of the experimental culture solution was 200 ⁇ L, and the final concentration of DMSO in the culture solution was 0.5%. The cells were cultured in a 5% CO 2 , 33°C incubator for 5 days. Cell viability was detected using the cell viability assay kit CellTiter Glo (Promega). Cytotoxicity experiments were performed under the same conditions as antiviral experiments, but without virus infection.
- the antiviral activity and cytotoxicity of the compound are represented by the inhibitory rate (%) and cell viability (%) of the compound on the cytopathic effect caused by the virus at different concentrations, respectively. Calculated as follows:
- Inhibition rate (%) (test hole reading value-virus control average value)/(cell control average value-virus control average value) ⁇ 100
- the compound of the present invention has good in vitro anti-coronavirus activity at the cellular level, and has no cytotoxicity.
- mice C57BL/6J male mice were selected as test animals, and the plasma concentrations of the test compounds given to mice by intravenous injection and gavage at different time points were quantitatively determined by LC/MS/MS method, so as to evaluate the effect of test drugs on mice. In vivo pharmacokinetic profile.
- Test compound solutions were administered orally and orally to mice (overnight fasted, 6-8 weeks old). After intravenous administration of animals, 40 ⁇ L of blood was collected from the saphenous vein of mice at 0.083h, 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 8.0h, and 24.0h, and placed in an anticoagulant tube added with EDTA-K2, at 4°C , 3200g centrifugation for 10min to get plasma. After the plasma samples were processed, the blood drug concentration was determined by LC-MS/MS method.
- ND means not detected
- NA means not detected
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Abstract
Description
化合物编号 | IC 50(nM) |
1 | 6 |
2 | 11 |
3 | 25 |
4 | 104 |
5 | 50 |
6 | 12 |
7A | 15 |
化合物编号 | EC 50(nM) | CC 50(nM) |
1 | 259 | >10000 |
2 | 368 | >10000 |
3 | 146 | >10000 |
4 | 823 | >10000 |
5 | 368 | >10000 |
7A | 410 | >10000 |
Claims (16)
- 式(IV)所示化合物或其药学上可接受的盐,其中,R 1各自独立地选自F、Cl、Br、I、OR 11、CN、CH 3S(O) m-和NHR 12和C 1-3烷基,所述C 1-3烷基任选被1、2或3个F取代;R 11选自H、C 1-3烷基、CH 3(OCH 2CH 2) p-和H(OCH 2CH 2) q-,所述C 1-3烷基任选被1、2或3个F取代;R 12选自C 1-3烷基、CH 3CO-和CH 3SO 2-,所述C 1-3烷基、CH 3CO-和CH 3SO 2-任选独立地被1、2或3个F取代;m选自0、1和2;p和q选自1、2、3、4、5和6;n选自0、1、2、3和4;R 2选自C 1-4烷基、C 3-6环烷基和苄基,所述C 1-4烷基、C 3-6环烷基和苄基任选被1、2或3个F取代;R 4选自任选独立地被1、2或3个F取代C 1-8烷基;环A选自C 3-10环烷基、3-10元杂环烷基和苯基;环B选自C 3-8环烷基和5元杂环烷基;所述C 3-8环烷基和5元杂环烷基任选被1或2个R a取代;R a各自独立地选自H和C 1-3烷基。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中,R 1选自F和甲基。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中,环A选自C 3-10环烷基。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中,R 4选自叔丁基。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中,R a选自H和甲基。
- 一种治疗冠状病毒感染的方法,该方法包括对需要该治疗的受试者给予治疗有效量的权利要求1~13任意一项所述的化合物或其药学上可接受的盐,和治疗可接受的其他抗病毒药物的剂量。
- 根据权利要求14所述的方法,其特征在于,所述冠状病毒是HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU1、SARS-CoV、MERS-CoV或SARS-CoV-2及其变种。
- 根据权利要求14所述的方法,其特征在于,所述其他抗病毒药物是利托那韦、茚地那韦、奈非那韦、沙奎那韦、安泼那韦或洛匹那韦。
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