WO2023125846A1 - Composé pour prévenir et traiter une infection à coronavirus, conjugué de celui-ci et méthode associée - Google Patents
Composé pour prévenir et traiter une infection à coronavirus, conjugué de celui-ci et méthode associée Download PDFInfo
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- WO2023125846A1 WO2023125846A1 PCT/CN2022/143566 CN2022143566W WO2023125846A1 WO 2023125846 A1 WO2023125846 A1 WO 2023125846A1 CN 2022143566 W CN2022143566 W CN 2022143566W WO 2023125846 A1 WO2023125846 A1 WO 2023125846A1
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- WIPO (PCT)
- Prior art keywords
- alkyl
- hydrogen
- cycloalkyl
- deuterium
- halogen
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 196
- 238000000034 method Methods 0.000 title claims description 13
- 208000001528 Coronaviridae Infections Diseases 0.000 title abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 57
- 239000000651 prodrug Substances 0.000 claims abstract description 47
- 229940002612 prodrug Drugs 0.000 claims abstract description 47
- 239000012453 solvate Substances 0.000 claims abstract description 47
- 241001678559 COVID-19 virus Species 0.000 claims abstract description 32
- 230000000694 effects Effects 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 9
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 435
- 229910052739 hydrogen Inorganic materials 0.000 claims description 354
- 239000001257 hydrogen Substances 0.000 claims description 354
- 150000002431 hydrogen Chemical class 0.000 claims description 249
- 229910052805 deuterium Inorganic materials 0.000 claims description 237
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 236
- -1 amino, hydroxyl Chemical group 0.000 claims description 229
- 229910052736 halogen Inorganic materials 0.000 claims description 222
- 150000002367 halogens Chemical class 0.000 claims description 222
- 125000003118 aryl group Chemical group 0.000 claims description 151
- 125000003545 alkoxy group Chemical group 0.000 claims description 142
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 127
- 125000001424 substituent group Chemical group 0.000 claims description 112
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 107
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 92
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 91
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 88
- 125000004432 carbon atom Chemical group C* 0.000 claims description 86
- 238000002360 preparation method Methods 0.000 claims description 82
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 80
- 238000006467 substitution reaction Methods 0.000 claims description 75
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 73
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 65
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 49
- 125000000623 heterocyclic group Chemical group 0.000 claims description 38
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 35
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 29
- 150000004677 hydrates Chemical class 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 21
- 241000700605 Viruses Species 0.000 claims description 20
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 241000711573 Coronaviridae Species 0.000 claims description 11
- 208000025721 COVID-19 Diseases 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000003386 piperidinyl group Chemical group 0.000 claims description 9
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000001425 triazolyl group Chemical group 0.000 claims description 7
- 230000029812 viral genome replication Effects 0.000 claims description 7
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 101800000504 3C-like protease Proteins 0.000 claims description 4
- 101800001016 Picornain 3C-like protease Proteins 0.000 claims description 4
- 101800000596 Probable picornain 3C-like protease Proteins 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 4
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 3
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 3
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 2
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 108091005804 Peptidases Proteins 0.000 abstract description 12
- 239000004365 Protease Substances 0.000 abstract description 12
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 6
- 206010035664 Pneumonia Diseases 0.000 abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 221
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 77
- 238000006243 chemical reaction Methods 0.000 description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 53
- 239000000243 solution Substances 0.000 description 46
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 33
- 239000012043 crude product Substances 0.000 description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 31
- 239000007787 solid Substances 0.000 description 31
- 230000002829 reductive effect Effects 0.000 description 30
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 29
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 28
- 239000000203 mixture Substances 0.000 description 28
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 26
- 239000012074 organic phase Substances 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 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 23
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 22
- ZRLFRWNYFMYZEG-UHFFFAOYSA-N 2-methylhexanamide Chemical compound CCCCC(C)C(N)=O ZRLFRWNYFMYZEG-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000007821 HATU Substances 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 125000001246 bromo group Chemical group Br* 0.000 description 12
- 125000001309 chloro group Chemical group Cl* 0.000 description 12
- KWAIYQAHLXWVKC-UHFFFAOYSA-N 3-azabicyclo[3.1.0]hexane-2-carboxamide Chemical compound NC(=O)C1NCC2CC12 KWAIYQAHLXWVKC-UHFFFAOYSA-N 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- LIENCHBZNNMNKG-OJFNHCPVSA-N nirmatrelvir Chemical compound CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F)C(=O)N[C@@H](C[C@@H]3CCNC3=O)C#N)C LIENCHBZNNMNKG-OJFNHCPVSA-N 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 239000012267 brine Substances 0.000 description 10
- 150000001721 carbon Chemical group 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
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- 125000001072 heteroaryl group Chemical group 0.000 description 9
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- JZYXJKBNUJJIKU-DTWKUNHWSA-N (1r,2r)-2-(4-chlorophenyl)cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C1=CC=C(Cl)C=C1 JZYXJKBNUJJIKU-DTWKUNHWSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 229940125674 nirmatrelvir Drugs 0.000 description 8
- 125000006413 ring segment Chemical group 0.000 description 8
- QJJWMUZHTDQZDW-DTWKUNHWSA-N (1r,2r)-2-(4-fluorophenyl)cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C1=CC=C(F)C=C1 QJJWMUZHTDQZDW-DTWKUNHWSA-N 0.000 description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 125000002619 bicyclic group Chemical group 0.000 description 7
- 239000012230 colorless oil Substances 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 7
- 125000003367 polycyclic group Chemical group 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000011593 sulfur Chemical group 0.000 description 7
- FXRZNBPQNVOJTP-JGVFFNPUSA-N (1r,2r)-2-(2-chlorophenyl)cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C1=CC=CC=C1Cl FXRZNBPQNVOJTP-JGVFFNPUSA-N 0.000 description 6
- CSLVZAGSOJLXCT-NKWVEPMBSA-N (1r,2r)-2-(3,4-difluorophenyl)cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C1=CC=C(F)C(F)=C1 CSLVZAGSOJLXCT-NKWVEPMBSA-N 0.000 description 6
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000003937 drug carrier Substances 0.000 description 6
- WKJJNMWERMSARF-DTWKUNHWSA-N ethyl (1r,2r)-2-(3,4-difluorophenyl)cyclopropane-1-carboxylate Chemical compound CCOC(=O)[C@@H]1C[C@H]1C1=CC=C(F)C(F)=C1 WKJJNMWERMSARF-DTWKUNHWSA-N 0.000 description 6
- KIKIJDKRTQXILG-GQCTYLIASA-N ethyl (E)-3-(3,4-difluorophenyl)prop-2-enoate Chemical compound FC=1C=C(C=CC=1F)/C=C/C(=O)OCC KIKIJDKRTQXILG-GQCTYLIASA-N 0.000 description 6
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 6
- 125000000168 pyrrolyl group Chemical group 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
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- 239000000725 suspension Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- SJXGNJABBYVEHY-JGVFFNPUSA-N (1r,2r)-2-(2-bromophenyl)cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C1=CC=CC=C1Br SJXGNJABBYVEHY-JGVFFNPUSA-N 0.000 description 4
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- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 description 4
- 229940125673 3C-like protease inhibitor Drugs 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
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Classifications
-
- 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
- A61K31/40—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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D403/14—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 three or more hetero rings
Definitions
- the present invention relates to the field of medicine, in particular to a compound and its conjugate and method for preventing and treating coronavirus infection.
- the present invention relates to compounds and methods for inhibiting viral replication activity, comprising contacting a SARS-CoV-2 related 3C-like (3CL) protease with a therapeutically effective amount of a SARS-CoV-2 related 3C-like protease inhibitor.
- the present invention also relates to methods of treating coronavirus disease 2019 (COVID-19) in patients by providing them with a therapeutically effective amount of a SARS-CoV-2-associated 3C-like protease inhibitor.
- the present invention also relates to a method of treating COVID-19 in a patient comprising administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a SARS-CoV-2 associated 3C-like protease inhibitor agent.
- SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
- SARS-CoV-2 has 79% homology with SARS-CoV (Severe Acute Respiratory Syndrome Coronavirus), the causative agent of the SARS epidemic in 2002-2003, and with Middle East Respiratory Syndrome Coronavirus (MERS-CoV) There is 50% homology.
- Symptoms of COVID-19 include fever, cough, shortness of breath, fatigue, headache, loss of smell, nasal congestion, sore throat, expectoration, muscle or joint pain, chills, nausea, vomiting and diarrhea.
- symptoms include difficulty waking up, confusion, bluish face or lips, coughing up blood, decreased white blood cells, and kidney failure.
- Complications include pneumonia, viral sepsis, acute respiratory distress syndrome, and renal failure.
- the SARS-CoV-2 coronavirus belongs to the Coronaviridae family and is a single-stranded positive-sense RNA virus with an envelope. Similar to other known coronaviruses, the SARS-CoV-2 coronavirus also undergoes several processes such as adsorption, penetration, shelling, biosynthesis, assembly and release of progeny viruses to complete the proliferation of progeny viruses.
- SARS-CoV-2 coronavirus infection of host cells begins with the binding of the spike glycoprotein on the surface of the virus envelope to the receptors on the surface of the host cell, followed by membrane fusion, and the virus enters the host cell under the action of cell organelles such as lysosomes , to release the genetic material of the virus, single-stranded positive-sense RNA, which is translated into a polyprotein under the action of protein synthesis elements such as mitochondria and ribosomes of the host cell, and necessary raw materials.
- cell organelles such as lysosomes
- the two major components of the SARS-CoV-2 coronavirus Essential cysteine proteases papain-like protease (PL pro) and 3C-like protease (3C-like protease, 3CL pro) cut and process polyprotein precursors at specific sites, resulting in multiple pairs of viral life Periodically important nonstructural proteins. Under the action of these non-structural proteins, viral RNA replicates progeny viral nucleic acid substances, and translates a large amount of required structural proteins to complete the assembly and release of progeny viruses.
- Any link or key enzyme in the life cycle of SARS-CoV-2 coronavirus-infected cells can be used as a research target for antiviral drugs, such as cysteine proteases PL pro and 3CL pro, which hydrolyze and cut polyprotein precursors, are responsible for RNA polymerase that completes the replication of the genetic material of progeny viruses, etc.
- antiviral drugs such as cysteine proteases PL pro and 3CL pro, which hydrolyze and cut polyprotein precursors, are responsible for RNA polymerase that completes the replication of the genetic material of progeny viruses, etc.
- 3CL protease (3chymotrypsin-like protease, 3CL pro), also known as the main protease (M pro), is the key protease in the process of hydrolyzing the polyproteins pp1a and pp1ab after the translation of coronavirus RNA to produce multiple non-structural proteins. Replication and infection are very important. Inhibiting the catalytic function of 3CL protease can effectively inhibit the cleavage of viral polyprotein precursors, block virus replication, and inhibit the generation of progeny viruses.
- 3CL pro belongs to cysteine protease, which is a key protease that catalyzes the proteolysis of single positive-strand RNA virus precursor, and plays an important role in the replication activity of coronaviruses such as SARS-CoV-2. Therefore, 3CL pro is currently recognized as an ideal target for the development of anti-coronavirus drugs.
- the threat to public health is particularly serious.
- the coronavirus is highly contagious, and current research suggests that it can be spread by asymptomatic carriers or pre-symptomatic people.
- the early development of the disease is very slow, and carriers are often unaware that they are infected, leading them to expose many people to the virus.
- the combination of the ease with which COVID-19 spreads and the high rates of hospitalization and mortality among patients make viral infection a significant public health risk, especially in those without the healthcare system to provide supportive care for patients at pandemic levels nation.
- Pfizer's oral drug Paxlovid has been authorized by the FDA for emergency use.
- 3CLpro inhibitor nirmatrelvir
- CYP3A inhibitor ritonavir
- SARS-CoV-2 coronavirus 3CL pro an oral antiviral drug with novel structure, low toxicity and high efficiency, more stable and independent intellectual property rights has been developed to meet the clinical needs of patients infected with SARS-CoV-2 coronavirus at home and abroad. great social significance.
- SARS-CoV-2 coronavirus 3CL protease for the prevention and treatment of pneumonia caused by SARS-CoV-2 coronavirus infection.
- the present invention provides a class of inhibitors against SARS-CoV-2 coronavirus 3CL protease, which can be used to prevent and treat pneumonia caused by SARS-CoV-2 coronavirus infection.
- the present invention provides the following technical solutions:
- the present invention provides a compound represented by formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, conjugates and pharmaceutically acceptable salts:
- the compound provided by the invention has good activity of inhibiting SARS-CoV-2 coronavirus 3CL protease, and can be used for preventing and treating pneumonia caused by SARS-CoV-2 coronavirus infection.
- the present invention provides a compound represented by formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, conjugates and pharmaceutically acceptable salts:
- n are each independently any integer from 0 to 4.
- R 3 is selected from cyano, aldehyde, -(CO)CH 3 and -(CO)CF 3 ;
- Each R is independently selected from hydrogen, deuterium, unsubstituted or selected from cyano, amino, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl and C 1-6 alkyl, C 3-7 cycloalkyl and 3-7 heterocycloalkyl substituted by substituents of 5-10 membered heteroaryl;
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- any R 4 and R 5 and their connected C atoms and N atoms form a substituted or unsubstituted 5-7 membered ring
- the replacement is 1-4 selected from hydrogen, deuterium, cyano, halogen, trifluoro Substituents of methyl, trifluoromethoxy, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl and 5-10 membered heteroaryl, or 5-7 membered ring
- the substituent and the 5-7 membered ring form a ring;
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- any R 4 and R 6 and their connected C atoms and N atoms form a substituted or unsubstituted 5-7 membered ring, and the substitution is 1-4 selected from hydrogen, deuterium, cyano, halogen, tri Substituents of fluoromethyl, trifluoromethoxy, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl and 5-10 membered heteroaryl, or the 5-
- the two substituents of the 7-membered ring form the same carbon atom or two adjacent carbon atoms and are deuterated by hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 deuterated alkyl
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- R 7 and R 8 and their connected C atoms and N atoms form unsubstituted or are selected from hydrogen, deuterium, cyano, amino, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl , C 1-6 alkoxyl, C 6-10 aryl and 5-10 membered heteroaryl substituents substituted 5-7 membered rings;
- R 9 is selected from substituted or unsubstituted C 1-6 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 3-7 cycloalkoxy, C 3-7 cycloalkylamino, 3-7 heterocycloalkoxy, C 3-7 heterocycloalkylamino, C 6-10 aryl, C 6-10 aryl Baseoxy, 5-10 membered heteroaryl, 6-14 membered spiroheterocyclic group, 5-11 membered bridged heterocyclic group, -NH-C(O)-C 1-6 alkyl, -NH-C( O)-NH-C 1-6 alkyl and 4-11 membered fused heterocyclic groups, the replacement is 1-4 selected from hydrogen, deuterium, cyano, amino, hydroxyl, halogen, trifluoromethyl , trifluoromethoxy, by 1-4 selected from hydrogen, deuterium,
- each R 1 is independently selected from hydrogen, deuterium, halogen, and C 1-6 alkyl.
- each R 1 is independently selected from hydrogen, halogen, and C 1-3 alkyl.
- each R 1 is independently selected from hydrogen.
- each R 2 is independently selected from hydrogen, deuterium, halogen, and C 1-6 alkyl.
- each R 2 is independently selected from hydrogen, halogen, and C 1-3 alkyl.
- each R2 is independently selected from hydrogen.
- R 3 is selected from cyano, aldehyde, -(CO)CH 3 and -(CO)CF 3 .
- R3 is selected from cyano and -(CO) CH3 .
- R is selected from cyano.
- any of R 4 and R 6 and their attached C and N atoms form a substituted or unsubstituted 5-6 membered ring.
- any of R 4 and R 6 and their attached C and N atoms form substituted or unsubstituted pyrrolidinyl and piperidinyl groups.
- the substitution is by 1-4 selected from hydrogen, deuterium, cyano, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl, C 1-6 alkane Oxygen, C 6-10 aryl and 5-10 membered heteroaryl substituents are substituted.
- the substitution is substituted by 1-4 substituents selected from halogen, trifluoromethyl and C 1-6 alkyl.
- the substitution is by 1-4 substituents selected from fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, n-propyl and isopropyl.
- the two substituents of the 5-6 membered ring form the same carbon atom or two adjacent carbon atoms by hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy A C 3-7 cycloalkyl group substituted by a C 1-6 deuterated alkyl substituent.
- the two substituents of the 5-6 membered ring form the same carbon atom or two adjacent carbon atoms by hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy A C 3-5 cycloalkyl group substituted by a C 1-6 deuterated alkyl substituent.
- the two substituents of the 5-6 membered ring form the same carbon atom or two adjacent carbon atoms by hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy Cyclopropyl and cyclobutyl substituted by C 1-6 deuterated alkyl substituents.
- R 5 is selected from hydrogen and C 1-3 alkyl.
- R is selected from hydrogen
- R is selected from hydrogen, deuterium and C 1-6 alkyl.
- R 7 is selected from hydrogen and C 1-3 alkyl.
- R7 is selected from hydrogen
- R 8 is selected from hydrogen and C 1-3 alkyl.
- R is selected from hydrogen
- m is any integer from 0 to 3.
- n is any integer from 0-2.
- n is any integer from 0-1.
- m is 0.
- n is any integer from 0 to 3.
- n is any integer from 0-2.
- n is any integer from 0-1.
- n 1
- the present invention provides a compound represented by formula I-1 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, conjugates and pharmaceutically acceptable salts:
- n are each independently any integer from 0 to 4.
- R 3 is selected from cyano, aldehyde, -(CO)CH 3 and -(CO)CF 3 ;
- Each R is independently selected from hydrogen, deuterium, unsubstituted or selected from cyano, amino, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl and C 1-6 alkyl, C 3-7 cycloalkyl and 3-7 heterocycloalkyl substituted by substituents of 5-10 membered heteroaryl;
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- any R 4 and R 5 and their connected C atoms and N atoms form a substituted or unsubstituted 5-7 membered ring
- the replacement is 1-4 selected from hydrogen, deuterium, cyano, halogen, trifluoro Substituents of methyl, trifluoromethoxy, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl and 5-10 membered heteroaryl, or 5-7 membered ring
- the substituent and the 5-7 membered ring form a ring;
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- any R 4 and R 6 and their connected C atoms and N atoms form a substituted or unsubstituted 5-7 membered ring, and the substitution is 1-4 selected from hydrogen, deuterium, cyano, halogen, tri Substituents of fluoromethyl, trifluoromethoxy, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl and 5-10 membered heteroaryl, or the 5-
- the two substituents of the 7-membered ring form the same carbon atom or two adjacent carbon atoms and are deuterated by hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 deuterated alkyl
- R 8 is selected from hydrogen, deuterium, C 1-6 alkyl
- R 7 and R 8 and their connected C atoms and N atoms form unsubstituted or are selected from hydrogen, deuterium, cyano, amino, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl , C 1-6 alkoxyl, C 6-10 aryl and 5-10 membered heteroaryl substituents substituted 5-7 membered rings;
- Ring A and ring B are each independently selected from substituted or unsubstituted C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 6-14 Member spiroheterocyclyl, 5-11 member bridging heterocyclyl and 4-11 member condensed heterocyclyl; the replacement is 1-4 selected from hydrogen, deuterium, cyano, amino, hydroxyl, halogen, trifluoro Substituents of methyl, trifluoromethoxy, C 1-6 alkyl and C 6-10 aryl.
- each R 1 is independently selected from hydrogen, deuterium, halogen, and C 1-6 alkyl.
- each R 1 is independently selected from hydrogen, halogen, and C 1-3 alkyl.
- each R 1 is independently selected from hydrogen.
- each R 2 is independently selected from hydrogen, deuterium, halogen, and C 1-6 alkyl.
- each R 2 is independently selected from hydrogen, halogen, and C 1-3 alkyl.
- each R2 is independently selected from hydrogen.
- R 3 is selected from cyano, aldehyde, -(CO)CH 3 and -(CO)CF 3 .
- R3 is selected from cyano and -(CO) CH3 .
- R is selected from cyano.
- any of R 4 and R 6 and their attached C and N atoms form a substituted or unsubstituted 5-6 membered ring.
- any of R 4 and R 6 and their attached C and N atoms form substituted or unsubstituted pyrrolidinyl and piperidinyl groups.
- the substitution is by 1-4 selected from hydrogen, deuterium, cyano, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl, C 1-6 alkane Oxygen, C 6-10 aryl and 5-10 membered heteroaryl substituents are substituted.
- the substitution is substituted by 1-4 substituents selected from halogen, trifluoromethyl and C 1-6 alkyl.
- the substitution is by 1-4 substituents selected from fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, n-propyl and isopropyl.
- the two substituents of the 5-6 membered ring form the same carbon atom or two adjacent carbon atoms by hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy A C 3-7 cycloalkyl group substituted by a C 1-6 deuterated alkyl substituent.
- the two substituents of the 5-6 membered ring form the same carbon atom or two adjacent carbon atoms by hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy A C 3-5 cycloalkyl group substituted by a C 1-6 deuterated alkyl substituent.
- the two substituents of the 5-6 membered ring form the same carbon atom or two adjacent carbon atoms by hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy Cyclopropyl and cyclobutyl substituted by C 1-6 deuterated alkyl substituents.
- R 5 is selected from hydrogen and C 1-3 alkyl.
- R is selected from hydrogen
- R is selected from hydrogen, deuterium and C 1-6 alkyl.
- R 7 is selected from hydrogen and C 1-3 alkyl.
- R7 is selected from hydrogen
- R 8 is selected from hydrogen and C 1-3 alkyl.
- R is selected from hydrogen
- m is any integer from 0 to 3.
- n is any integer from 0-2.
- n is any integer from 0-1.
- m is 0.
- n is any integer from 0 to 3.
- n is any integer from 0-2.
- n is any integer from 0-1.
- n 1
- Ring A is selected from substituted or unsubstituted C 3-7 cycloalkyl and 3-7 membered heterocycloalkyl.
- ring A is selected from substituted or unsubstituted C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl.
- Ring A is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl.
- the substitution is 1-4 selected from deuterium, cyano, amino, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl and C 6- 10 aryl substituents are substituted.
- the substitution is substituted by 1-4 substituents selected from halogen, trifluoromethyl and C 1-6 alkyl.
- the substitution is by 1-4 substituents selected from fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, n-propyl and isopropyl.
- ring B is selected from substituted or unsubstituted C 6-10 aryl and 5-10 membered heteroaryl.
- ring B is selected from substituted or unsubstituted C 6-10 aryl and 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S.
- Ring B is selected from substituted or unsubstituted phenyl, furyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, tri Azolyl and tetrazolyl.
- the substitution is 1-4 selected from deuterium, cyano, amino, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl and C 6- 10 aryl substituents are substituted.
- the substitution is substituted by 1-4 substituents selected from halogen, trifluoromethyl, C 1-6 alkyl.
- the substitution is by 1-4 substituents selected from fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, n-propyl and isopropyl.
- the present invention provides a compound represented by formula I-2 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, conjugates and pharmaceutically acceptable salts:
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- R 7 and R 8 and their connected C atoms and N atoms form unsubstituted or are selected from hydrogen, deuterium, cyano, amino, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl , C 1-6 alkoxyl, C 6-10 aryl and 5-10 membered heteroaryl substituents substituted 5-7 membered rings;
- Ring A and ring B are each independently selected from substituted or unsubstituted C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 6-14 Member spiroheterocyclyl, 5-11 member bridging heterocyclyl and 4-11 member condensed heterocyclyl; the replacement is 1-4 selected from hydrogen, deuterium, cyano, amino, hydroxyl, halogen, trifluoro Substituents of methyl, trifluoromethoxy, C 1-6 alkyl and C 6-10 aryl.
- each R 1 is independently selected from hydrogen, deuterium, halogen, and C 1-6 alkyl.
- each R 1 is independently selected from hydrogen, halogen, and C 1-3 alkyl.
- each R 1 is independently selected from hydrogen.
- each R 2 is independently selected from hydrogen, deuterium, halogen, and C 1-6 alkyl.
- each R 2 is independently selected from hydrogen, halogen, and C 1-3 alkyl.
- each R2 is independently selected from hydrogen.
- R 5 is selected from hydrogen and C 1-3 alkyl.
- R is selected from hydrogen
- R is selected from hydrogen, deuterium and C 1-6 alkyl.
- R 7 is selected from hydrogen and C 1-3 alkyl.
- R7 is selected from hydrogen
- R 8 is selected from hydrogen and C 1-3 alkyl.
- R is selected from hydrogen
- Ring A is selected from substituted or unsubstituted C 3-7 cycloalkyl and 3-7 membered heterocycloalkyl.
- ring A is selected from substituted or unsubstituted C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl.
- Ring A is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl.
- the substitution is 1-4 selected from deuterium, cyano, amino, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl and C 6- 10 aryl substituents are substituted.
- the substitution is substituted by 1-4 substituents selected from halogen, trifluoromethyl and C 1-6 alkyl.
- the substitution is by 1-4 substituents selected from fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, n-propyl and isopropyl.
- ring B is selected from substituted or unsubstituted C 6-10 aryl and 5-10 membered heteroaryl.
- ring B is selected from substituted or unsubstituted C 6-10 aryl and 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S.
- Ring B is selected from substituted or unsubstituted phenyl, furyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, tri Azolyl and tetrazolyl.
- the substitution is 1-4 selected from deuterium, cyano, amino, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl and C 6- 10 aryl substituents are substituted.
- the substitution is substituted by 1-4 substituents selected from halogen, trifluoromethyl, C 1-6 alkyl.
- the substitution is by 1-4 substituents selected from fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, n-propyl and isopropyl.
- the present invention provides a compound represented by formula I-2-1 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable Salt:
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- R 7 and R 8 and their connected C atoms and N atoms form unsubstituted or are selected from hydrogen, deuterium, cyano, amino, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl , C 1-6 alkoxyl, C 6-10 aryl and 5-10 membered heteroaryl substituents substituted 5-7 membered rings;
- Ring A and ring B are each independently selected from substituted or unsubstituted C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 6-14 Member spiroheterocyclyl, 5-11 member bridging heterocyclyl and 4-11 member condensed heterocyclyl; the replacement is 1-4 selected from hydrogen, deuterium, cyano, amino, hydroxyl, halogen, trifluoro Substituents of methyl, trifluoromethoxy, C 1-6 alkyl and C 6-10 aryl.
- each R 1 is independently selected from hydrogen, deuterium, halogen, and C 1-6 alkyl.
- each R 1 is independently selected from hydrogen, halogen, and C 1-3 alkyl.
- each R 1 is independently selected from hydrogen.
- each R 2 is independently selected from hydrogen, deuterium, halogen, and C 1-6 alkyl.
- each R 2 is independently selected from hydrogen, halogen, and C 1-3 alkyl.
- each R2 is independently selected from hydrogen.
- R 5 is selected from hydrogen and C 1-3 alkyl.
- R is selected from hydrogen
- R is selected from hydrogen, deuterium and C 1-6 alkyl.
- R 7 is selected from hydrogen and C 1-3 alkyl.
- R7 is selected from hydrogen
- R 8 is selected from hydrogen and C 1-3 alkyl.
- R is selected from hydrogen
- Ring A is selected from substituted or unsubstituted C 3-7 cycloalkyl and 3-7 membered heterocycloalkyl.
- ring A is selected from substituted or unsubstituted C 3-5 cycloalkyl and 3-5 membered heterocycloalkyl.
- Ring A is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl.
- the substitution is 1-4 selected from deuterium, cyano, amino, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl and C 6- 10 aryl substituents are substituted.
- the substitution is substituted by 1-4 substituents selected from halogen, trifluoromethyl and C 1-6 alkyl.
- the substitution is by 1-4 substituents selected from fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, n-propyl and isopropyl.
- ring B is selected from substituted or unsubstituted C 6-10 aryl and 5-10 membered heteroaryl.
- ring B is selected from substituted or unsubstituted C 6-10 aryl and 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S.
- Ring B is selected from substituted or unsubstituted phenyl, furyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, tri Azolyl and tetrazolyl.
- the substitution is 1-4 selected from deuterium, cyano, amino, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl and C 6- 10 aryl substituents are substituted.
- the substitution is substituted by 1-4 substituents selected from halogen, trifluoromethyl, C 1-6 alkyl.
- the substitution is by 1-4 substituents selected from fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, n-propyl and isopropyl.
- the present invention provides a compound represented by formula I-3 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, conjugates and pharmaceutically acceptable salts:
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- R 7 and R 8 and their connected C atoms and N atoms form unsubstituted or are selected from hydrogen, deuterium, cyano, amino, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl , C 1-6 alkoxyl, C 6-10 aryl and 5-10 membered heteroaryl substituents substituted 5-7 membered rings;
- Ring B is selected from substituted or unsubstituted C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 6-14 membered spiroheterocyclyl, 5-11 member bridged heterocyclic group and 4-11 membered condensed heterocyclic group; the replacement is 1-4 selected from hydrogen, deuterium, cyano, amino, hydroxyl, halogen, trifluoromethyl, trifluoromethyl Oxygen, C 1-6 alkyl and C 6-10 aryl substituents are substituted.
- each R 1 is independently selected from hydrogen, deuterium, halogen, and C 1-6 alkyl.
- each R 1 is independently selected from hydrogen, halogen, and C 1-3 alkyl.
- each R 1 is independently selected from hydrogen.
- each R 2 is independently selected from hydrogen, deuterium, halogen, and C 1-6 alkyl.
- each R 2 is independently selected from hydrogen, halogen, and C 1-3 alkyl.
- each R2 is independently selected from hydrogen.
- R 5 is selected from hydrogen and C 1-3 alkyl.
- R is selected from hydrogen
- R is selected from hydrogen, deuterium and C 1-6 alkyl.
- R 7 is selected from hydrogen and C 1-3 alkyl.
- R7 is selected from hydrogen
- R 8 is selected from hydrogen and C 1-3 alkyl.
- R is selected from hydrogen
- R 10 is selected from hydrogen, deuterium and C 1-6 alkyl.
- R 10 is selected from hydrogen and C 1-3 alkyl.
- R 10 is selected from hydrogen and methyl.
- R 11 is selected from hydrogen, deuterium and C 1-6 alkyl.
- R 11 is selected from hydrogen and C 1-3 alkyl.
- R 11 is selected from hydrogen and methyl.
- each R 12 is independently selected from hydrogen, deuterium, and C 1-6 alkyl.
- each R 12 is independently selected from hydrogen and C 1-3 alkyl.
- each R 12 is independently selected from hydrogen and methyl.
- ring B is selected from substituted or unsubstituted C 6-10 aryl and 5-10 membered heteroaryl.
- ring B is selected from substituted or unsubstituted C 6-10 aryl and 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S.
- Ring B is selected from substituted or unsubstituted phenyl, furyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, tri Azolyl and tetrazolyl.
- the substitution is 1-4 selected from deuterium, cyano, amino, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl and C 6- 10 aryl substituents are substituted.
- the substitution is substituted by 1-4 substituents selected from halogen, trifluoromethyl, C 1-6 alkyl.
- the substitution is by 1-4 substituents selected from fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, n-propyl and isopropyl.
- the present invention provides a compound represented by formula I-3-1 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable Salt:
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- R 7 and R 8 and their connected C atoms and N atoms form unsubstituted or are selected from hydrogen, deuterium, cyano, amino, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl , C 1-6 alkoxyl, C 6-10 aryl and 5-10 membered heteroaryl substituents substituted 5-7 membered rings;
- Ring B is selected from substituted or unsubstituted C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 6-14 membered spiroheterocyclyl, 5-11 member bridged heterocyclic group and 4-11 membered condensed heterocyclic group; the replacement is 1-4 selected from hydrogen, deuterium, cyano, amino, hydroxyl, halogen, trifluoromethyl, trifluoromethyl Oxygen, C 1-6 alkyl and C 6-10 aryl substituents are substituted.
- each R 1 is independently selected from hydrogen, deuterium, halogen, and C 1-6 alkyl.
- each R 1 is independently selected from hydrogen, halogen, and C 1-3 alkyl.
- each R 1 is independently selected from hydrogen.
- each R 2 is independently selected from hydrogen, deuterium, halogen, and C 1-6 alkyl.
- each R 2 is independently selected from hydrogen, halogen, and C 1-3 alkyl.
- each R2 is independently selected from hydrogen.
- R 5 is selected from hydrogen and C 1-3 alkyl.
- R is selected from hydrogen
- R is selected from hydrogen, deuterium and C 1-6 alkyl.
- R 7 is selected from hydrogen and C 1-3 alkyl.
- R7 is selected from hydrogen
- R 8 is selected from hydrogen and C 1-3 alkyl.
- R is selected from hydrogen
- R 10 is selected from hydrogen, deuterium and C 1-6 alkyl.
- R 10 is selected from hydrogen and C 1-3 alkyl.
- R 10 is selected from hydrogen and methyl.
- R 11 is selected from hydrogen, deuterium and C 1-6 alkyl.
- R 11 is selected from hydrogen and C 1-3 alkyl.
- R 11 is selected from hydrogen and methyl.
- each R 12 is independently selected from hydrogen, deuterium, and C 1-6 alkyl.
- each R 12 is independently selected from hydrogen and C 1-3 alkyl.
- each R 12 is independently selected from hydrogen and methyl.
- ring B is selected from substituted or unsubstituted C 6-10 aryl and 5-10 membered heteroaryl.
- ring B is selected from substituted or unsubstituted C 6-10 aryl and 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S.
- ring B is selected from substituted or unsubstituted phenyl, furyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, tri Azolyl and tetrazolyl.
- the substitution is 1-4 selected from deuterium, cyano, amino, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl and C 6- 10 aryl substituents are substituted.
- the substitution is substituted by 1-4 substituents selected from halogen, trifluoromethyl, C 1-6 alkyl.
- the substitution is by 1-4 substituents selected from fluoro, chloro, bromo, trifluoromethyl, methyl, ethyl, n-propyl and isopropyl.
- the present invention provides a compound represented by formula I-4 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, conjugates and pharmaceutically acceptable salts:
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- R 7 and R 8 and their connected C atoms and N atoms form unsubstituted or are selected from hydrogen, deuterium, cyano, amino, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl , C 1-6 alkoxyl, C 6-10 aryl and 5-10 membered heteroaryl substituents substituted 5-7 membered rings;
- R 13 is selected from hydrogen, deuterium, cyano, halogen, amino, hydroxyl, -NO 2 , C 1-6 alkylamino, C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkyl, C 3-7 cycloalkyl and 3-7 membered heterocycloalkyl; the substitution is by one or more selected from cyano, amino, hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy replaced by substituents;
- q is any integer of 0 to 4.
- each R 1 is independently selected from hydrogen, deuterium, halogen, and C 1-6 alkyl.
- each R 1 is independently selected from hydrogen, halogen, and C 1-3 alkyl.
- each R 1 is independently selected from hydrogen.
- each R 2 is independently selected from hydrogen, deuterium, halogen, and C 1-6 alkyl.
- each R 2 is independently selected from hydrogen, halogen, and C 1-3 alkyl.
- each R2 is independently selected from hydrogen.
- R 5 is selected from hydrogen and C 1-3 alkyl.
- R is selected from hydrogen
- R is selected from hydrogen, deuterium and C 1-6 alkyl.
- R 7 is selected from hydrogen and C 1-3 alkyl.
- R7 is selected from hydrogen
- R 8 is selected from hydrogen and C 1-3 alkyl.
- R is selected from hydrogen
- R 10 is selected from hydrogen, deuterium and C 1-6 alkyl.
- R 10 is selected from hydrogen and C 1-3 alkyl.
- R 10 is selected from hydrogen and methyl.
- R 11 is selected from hydrogen, deuterium and C 1-6 alkyl.
- R 11 is selected from hydrogen and C 1-3 alkyl.
- R 11 is selected from hydrogen and methyl.
- each R 12 is independently selected from hydrogen, deuterium, and C 1-6 alkyl.
- each R 12 is independently selected from hydrogen and C 1-3 alkyl.
- each R 12 is independently selected from hydrogen and methyl.
- R 13 is selected from hydrogen, deuterium, cyano, halogen, amino, hydroxyl, -NO 2 , C 1-3 alkylamino, C 1-3 alkoxy, substituted or unsubstituted C 1-3 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl.
- R 13 is selected from hydrogen, halogen, amino, hydroxyl, -NO 2 and substituted or unsubstituted C 1-3 alkyl.
- R 13 is selected from hydrogen, fluoro, chloro, bromo, substituted or unsubstituted methyl, ethyl, n-propyl and isopropyl.
- the substitution is substituted by one or more substituents selected from cyano, amino, hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy.
- the substitution is substituted by one or more substituents selected from halogen, C 1-3 alkyl and C 1-3 alkoxy.
- the substitution is with one or more substituents selected from fluoro, chloro, bromo, methyl, ethyl, n-propyl, and isopropyl.
- q is any integer from 0 to 3.
- q is any integer from 0-2.
- q is 1 or 2.
- the present invention provides a compound represented by formula I-4-1 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable Salt:
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- R is selected from hydrogen, deuterium and C 1-6 alkyl
- R 7 and R 8 and their connected C atoms and N atoms form unsubstituted or are selected from hydrogen, deuterium, cyano, amino, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl , C 1-6 alkoxyl, C 6-10 aryl and 5-10 membered heteroaryl substituents substituted 5-7 membered rings;
- R 13 is selected from hydrogen, deuterium, cyano, halogen, amino, hydroxyl, -NO 2 , C 1-6 alkylamino, C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkyl, C 3-7 cycloalkyl and 3-7 membered heterocycloalkyl; the substitution is by one or more selected from cyano, amino, hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy replaced by substituents;
- q is any integer of 0 to 4.
- each R 1 is independently selected from hydrogen, deuterium, halogen, and C 1-6 alkyl.
- each R 1 is independently selected from hydrogen, halogen, and C 1-3 alkyl.
- each R 1 is independently selected from hydrogen.
- each R 2 is independently selected from hydrogen, deuterium, halogen, and C 1-6 alkyl.
- each R 2 is independently selected from hydrogen, halogen, and C 1-3 alkyl.
- each R2 is independently selected from hydrogen.
- R 5 is selected from hydrogen and C 1-3 alkyl.
- R is selected from hydrogen
- R is selected from hydrogen, deuterium and C 1-6 alkyl.
- R 7 is selected from hydrogen and C 1-3 alkyl.
- R7 is selected from hydrogen
- R 8 is selected from hydrogen and C 1-3 alkyl.
- R is selected from hydrogen
- R 10 is selected from hydrogen, deuterium and C 1-6 alkyl.
- R 10 is selected from hydrogen and C 1-3 alkyl.
- R 10 is selected from hydrogen and methyl.
- R 11 is selected from hydrogen, deuterium and C 1-6 alkyl.
- R 11 is selected from hydrogen and C 1-3 alkyl.
- R 11 is selected from hydrogen and methyl.
- each R 12 is independently selected from hydrogen, deuterium, and C 1-6 alkyl.
- each R 12 is independently selected from hydrogen and C 1-3 alkyl.
- each R 12 is independently selected from hydrogen and methyl.
- R 13 is selected from hydrogen, deuterium, cyano, halogen, amino, hydroxyl, -NO 2 , C 1-3 alkylamino, C 1-3 alkoxy, substituted or unsubstituted C 1-3 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl.
- R 13 is selected from hydrogen, halogen, amino, hydroxyl, -NO 2 and substituted or unsubstituted C 1-3 alkyl.
- R 13 is selected from hydrogen, fluoro, chloro, bromo, substituted or unsubstituted methyl, ethyl, n-propyl and isopropyl.
- the substitution is substituted by one or more substituents selected from cyano, amino, hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy.
- the substitution is substituted by one or more substituents selected from halogen, C 1-3 alkyl and C 1-3 alkoxy.
- the substitution is with one or more substituents selected from fluoro, chloro, bromo, methyl, ethyl, n-propyl, and isopropyl.
- q is any integer from 0 to 3.
- q is any integer from 0-2.
- q is 1 or 2.
- the present invention provides a compound or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable salt thereof, the compound is any of the following kind:
- the present invention provides a compound or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable salt thereof, the compound is any of the following kind:
- the present invention also provides a preparation method of the compound shown in formula I, specifically as follows:
- Step 1 Compound I-2-1 undergoes a condensation reaction with I-2-2 to obtain Compound I-2-3;
- Step 2 compound 1-2-3 ester group is hydrolyzed under alkaline conditions to obtain compound 1-2-4;
- Step 3 compound I-2-4 undergoes a condensation reaction with compound I-2-5 to obtain compound I-2-6;
- Step 4 Compound I-2-6 undergoes removal of the amino protecting group to obtain Compound I-2-7;
- Step 5 Compound I-2-7 undergoes a condensation reaction with Compound I-2-8 to obtain a compound of formula I;
- PG is the protecting group of amino, including tert-butoxycarbonyl (t-Boc), benzyloxycarbonyl (CBz), 2-biphenyl-2-propoxycarbonyl (BPoc), phthalimide ( Pht), p-toluenesulfonyl (Tos), trityl (Trt), formyl, trifluoroacetyl, Watt methoxycarbonyl (Fmoc), p-methoxybenzyl (PMB), benzyl (Bn) , Allyloxycarbonyl (Alloc), etc.
- PG is preferably t-butoxycarbonyl (t-Boc).
- the present invention also provides a pharmaceutical composition, comprising at least one of the aforementioned compounds or their stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, and pharmaceutically acceptable acceptable carrier, diluent or excipient.
- the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
- the pharmaceutical composition contains 0.01%-99.99% of the aforementioned compound based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned compounds. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compounds. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compounds. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compounds.
- the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable carrier, diluent or excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of pharmaceutically acceptable carriers, diluents or excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% of pharmaceutically acceptable carriers, diluents or excipients.
- All the compounds of the present invention and mixtures, compositions, etc. containing the compounds of the present invention can be administered to a living body through any route of administration.
- the route of administration can be oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual administration, nasal cavity inhalation, oral inhalation, eye drops, and local or systemic transdermal administration.
- All the compounds involved in the present invention and mixtures, compositions, etc. containing the compounds of the present invention can be formulated into a single dose, which contains the active compound of the present invention and carriers, excipients, etc., and the dosage form can be tablets, capsules , injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, lotions, etc.
- These dosage forms may contain ingredients commonly used in pharmaceutical preparations, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH regulators, antioxidants, bacteriostats, isotonic regulators, Anti-sticking agent, etc.
- Suitable formulations of the above-mentioned various dosage forms can be obtained from public sources, such as Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins published in 2006 and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press in 2005 Published in 2010. Therefore, those skilled in the art can easily prepare.
- the dosage of the compound of the present invention can be 0.01 to 500 mg/kg per day , the preferred daily dose is 1-100 mg/kg, which can be administered in single or multiple doses.
- Inhibit virus replication activity preferably inhibit coronavirus activity, particularly preferably inhibit SARS-CoV-2 virus activity;
- the present invention also provides a method for inhibiting viral replication activity, comprising administering to a subject a therapeutically effective amount of any one of the compounds described above or its stereoisomers, solvates, hydrates, prodrugs, stable isotopes Derivatives, conjugates and pharmaceutically acceptable salts, and/or any of the aforementioned drug conjugates or their stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salt.
- the virus is a coronavirus, preferably SARS-CoV-2.
- C 1-6 alkyl alone or in combination means a saturated linear or branched alkyl group containing 1-6, especially 1-4 carbon atoms, including methyl, ethyl, propyl, Isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2- Butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2 -Pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3 ,-Dimethyl-2-butyl and so on.
- C 1-6 alkyl is any one of methyl, ethyl, isopropyl and tert-butyl.
- Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
- C 3-7 cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which means a saturated cycloalkyl group having 3 to 7, especially 3-6 carbon atoms, including Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
- Particular “C 3-7 cycloalkyl” is cyclopropyl, cyclopentyl, cyclohexyl and the like.
- C 3-5 cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which represents a saturated cycloalkyl group with 3 to 5 carbon atoms, including cyclopropyl, cyclobutyl , cyclopentyl, etc.
- C 1-6 alkoxy alone or in combination denotes the group C 1-6 alkyl-O-, wherein “C 1-6 alkyl” denotes as defined above.
- C 1-6 alkylamino alone or in combination denotes the group C 1-6 alkyl-NH-, wherein “C 1-6 alkyl” denotes as defined above.
- heterocycloalkyl refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) non-aromatic cyclic group composed of carbon atoms and heteroatoms such as nitrogen, oxygen or sulfur, which can be It is a monocyclic or bicyclic group.
- the number of heteroatoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl group can be optionally oxidized.
- the hydrogen atoms on the "heterocycloalkyl” are independently optionally substituted with one or more substituents described herein.
- a “heterocycloalkyl” may be attached to the parent molecule through any ring atom in the ring.
- 3-7 membered heterocycloalkyl refers to a monocyclic heterocycloalkyl group containing 3-7 carbon atoms and heteroatoms; for example, aziridinyl, azetidinyl, oxetanyl, pyrrole Alkyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl.
- 5-6 membered heterocycloalkyl refers to a monocyclic heterocycloalkyl group containing 5-6 carbon atoms and heteroatoms; for example, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholine thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl.
- 6-14 membered spiroheterocyclic group refers to 6 to 14 members, a polycyclic heterocyclic group sharing one atom (called spiro atom) between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen and sulfur heteroatoms, said sulfur optionally being oxo-substituted (ie to form sulfoxides or sulfones), with the remaining ring atoms being carbon. It may contain one or more double bonds. More preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
- the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclic group.
- spiroheterocyclyls include:
- 4-11 membered fused heterocyclic group refers to a 4 to 11-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain One or more double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, said sulfur optionally being oxo-substituted (i.e. to form sulfoxides or sulfones), and the remaining ring atoms being carbon . More preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
- bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan 5-membered and 6-membered/6-membered bicyclic condensed heterocyclic groups.
- fused heterocyclic groups include:
- 5-11 membered bridged heterocyclic group refers to a 5 to 11-membered polycyclic heterocyclic group that any two rings share two atoms that are not directly connected, which may contain one or more double bonds, one or A number of ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, said sulfur being optionally substituted with oxo (ie to form sulfoxides or sulfones), and the remainder of the ring atoms being carbon.
- it is 6 to 11 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
- bridged heterocyclyl groups include:
- C 6-10 aryl refers to a 6 to 10 membered all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group with a conjugated ⁇ -electron system, such as benzene base and naphthyl.
- the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include :
- Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from halogen, alkyl, alkoxy, haloalkane one of radical, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or multiple substituents.
- 5-10 membered heteroaryl refers to a heteroaromatic system containing 1 to 4 (eg 1, 2, 3 and 4) heteroatoms, 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen, (for example 5, 6, 7, 8, 9 or 10 members), more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl , pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
- 1 to 4 eg 1, 2, 3 and 4
- heteroatoms selected from oxygen, sulfur and nitrogen, (for example 5, 6, 7, 8, 9 or 10 members), more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl ,
- the heteroaryl ring includes a heteroaryl as described above fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include :
- Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from halogen, alkyl, alkoxy, One of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl or multiple substituents.
- benzo C 5-7 cycloalkyl means that a phenyl group and a C 5-7 cycloalkyl group form a ring, and the structure is: Wherein, n is 1, 2 or 3, meanwhile, benzo C 5-7 cycloalkyl can be that phenyl is connected with connection position, also can be that C 5-7 cycloalkyl is connected with connection position; and benzene And the C 5-7 cycloalkyl can be either substituted by phenyl or C 5-7 cycloalkyl.
- amino alone or in combination denotes a primary (-NH 2 ), secondary (-NH-) or tertiary amino group
- halogen alone or in combination means fluorine, chlorine, bromine or iodine. Especially fluorine, chlorine or bromine.
- cyano alone or in combination refers to the group -CN.
- hydroxyl alone or in combination refers to the group -OH.
- aldehyde alone or in combination refers to the group -CHO.
- substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
- the bond configuration is not specified, i.e. the key can be or or both and Two configurations.
- stereoisomer refers to compounds that have the same chemical structure but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis/trans) isomers, atropisomers, and the like.
- isotopically derivative refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms.
- hydrogen is replaced by "deuterium” or “tritium”, or 18 F-fluorine label ( 18 F isotope) is used instead of fluorine, or 11 C-, 13 C-, or 14 C-enriched
- carbon atoms 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes
- Such compounds are useful, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.
- the various deuterated forms of the compounds of the present invention mean that each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound.
- deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including but not limited to deuterated borane, trideuterioborane in tetrahydrofuran , deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
- Deuterated compounds generally retain comparable activity to undeuterated compounds, and can achieve better metabolic stability when deuterated at certain sites, thereby gaining certain therapeutic advantages.
- pharmaceutically acceptable salt means that the compounds of the present invention exist in the form of their pharmaceutically acceptable salts, including acid addition salts and base addition salts.
- Pharmaceutically acceptable salts are described in pharmaceutically salts by SM Berge in J. Pharmaceutical Sciences (Vol. 66: 1-19, 1977).
- the pharmaceutically acceptable non-toxic acid addition salt means the salt formed by the compound in the present invention and organic or inorganic acid
- organic or inorganic acid includes but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydrogen iodide Acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc.
- Non-toxic base addition salts refer to salts formed by the compounds of the present invention with organic or inorganic bases, including but not limited to alkali metal salts such as lithium, sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; organic base salts, such as ammonium salts or N + (C 1-6 alkyl) 4 salts formed by organic bases containing N groups.
- alkali metal salts such as lithium, sodium or potassium salts
- alkaline earth metal salts such as calcium or magnesium salts
- organic base salts such as ammonium salts or N + (C 1-6 alkyl) 4 salts formed by organic bases containing N groups.
- solvate refers to the physical association of a compound of the present invention with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated in the crystal lattice of a crystalline solid, solvates will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
- prodrug refers to a compound that can be transformed in vivo under physiological conditions, for example by hydrolysis in blood, to yield the active prodrug.
- pharmaceutical composition means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof and other chemical components, and other components such as physiologically/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.
- Example 1 Intermediate tert-butyl ((S)-1-((1R,2S,5S)-2-((S)-1-amino-1-oxo-3-((S)-2- Oxypyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-yl)-3,3-di Preparation of methyl-1-oxobutan-2-yl) carbamate (intermediate A)
- Step 1 tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (intermediate Preparation of body 2-2)
- Step 2 Preparation of (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propionamide hydrochloride (intermediate 2-3)
- Step 3 Methyl(1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyryl)-6,6-dimethyl Preparation of methyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (intermediate 2-5)
- Step 4 (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyryl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (intermediate 2-6)
- Step 5 tert-butyl ((S)-1-((1R,2S,5S)-2-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrole Alkyl-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl Preparation of -1-oxobutan-2-yl) carbamate (intermediate 2-7)
- Step 6 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl )-3-((S)-2-amino-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide salt
- (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl )-3-((S)-2-amino-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide salt Preparation of acid salt (intermediate A)
- Step 1 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl )-3-((S)-2-((1R,2R)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxamide)-3,3-dimethylbutyryl)
- Preparation of -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 3-1)
- Step 2 (1R,2S,5S)-3-(2-((1R,2R)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxamide)-3,3- Dimethylbutyryl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-
- azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride compound 3
- Step 1 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl )-3-((S)-2-(cyclopropanylamino)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-
- 2-formamide compound 4-1
- Step 2 (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S )-2-(cyclopropanecarboxamide)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 4 ) preparation.
- Step 1 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl )-3-((S)-2-((1S,2S)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxamide)-3,3-dimethylbutyryl)
- Preparation of -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 5-1)
- Step 2 (1R,2S,5S)-3-(2-((1S,2S)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxamide)-3,3- Dimethylbutyryl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-
- Step 1 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl )-3-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[ 3.1.0]
- hexane-2-carboxamide compound 7-2
- Step 2 (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S )-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-
- 2-formamide compound 7
- Step 1 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl )-3-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[ 3.1.0]
- hexane-2-carboxamide compound 8-1)
- Step 2 (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S )-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-
- 2-formamide compound 8
- Step 1 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl )-3-((R)-3,3-Dimethyl-2-(1-(trifluoromethyl)cyclopropane-1-carboxamido)butyryl)-6,6-dimethyl-3 -Preparation of azabicyclo[3.1.0]hexane-2-carboxamide (compound 9-1)
- Step 2 (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S )-3,3-Dimethyl-2-(1-(trifluoromethyl)cyclopropane-1-carboxamido)butyryl)-6,6-dimethyl-3-azabicyclo[3.1. 0]
- hexane-2-carboxamide compound 9
- Step 1 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl )-3-((S)-3,3-Dimethyl-2-((1R,2R)-2-phenylcyclopropane-1-carboxamido)butyryl)-6,6-dimethyl -
- Step 1 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl )-3-((S)-3,3-Dimethyl-2-((1R,2R)-2-phenylcyclopropane-1-carboxamido)butyryl)-6,6-dimethyl -
- 3-azabicyclo[3.1.0]hexane-2-carboxamide compound 10-1
- Step 2 (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S )-3,3-dimethyl-2-((1R,2R)-2-phenylcyclopropane-1-carboxamido)butyryl)-6,6-dimethyl-3-azabicyclo[ 3.1.0]
- hexane-2-carboxamide compound 10
- Step 1 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl )-3-((S)-3,3-dimethyl-2-((1R,2S)-2-phenylcyclopropane-1-carboxamido)butyryl)-6,6-dimethyl -
- Step 1 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl )-3-((S)-3,3-dimethyl-2-((1R,2S)-2-phenylcyclopropane-1-carboxamido)butyryl)-6,6-dimethyl -
- 3-azabicyclo[3.1.0]hexane-2-carboxamide compound 11-1)
- Step 2 (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S )-3,3-dimethyl-2-((1R,2S)-2-phenylcyclopropane-1-carboxamido)butyryl)-6,6-dimethyl-3-azabicyclo[ 3.1.0]
- Preparation of hexane-2-carboxamide (compound 11)
- Step 2 Preparation of ethyl (1S,2S) or (1R,2R)-2-(4-fluorophenyl)cyclopropane-1-carboxylate (compound 12-3)
- Step 3 Preparation of (1S,2S) or (1R,2R)-2-(4-fluorophenyl)cyclopropane-1-carboxylic acid (compound 12-4)
- Step 4 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2- Base)-3-((S)-2-((1R,2R) or (1S,2S)-2-(4-fluorophenyl)cyclopropane-1-carboxamido)-3,3-dimethyl Preparation of butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 12-4)
- Step 5 (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-(( S)-2-((1R,2R)-2-(4-fluorophenyl)cyclopropane-1-carboxamido)-3,3-dimethylbutyryl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 12)
- Step 2 Preparation of ethyl (1R,2R)-2-(2-chlorophenyl)cyclopropane-1-carboxylate (compound 14-3)
- Step 5 (1R,2S,5S)-3-((S)-2-((1R,2R)-2-(2-chlorophenyl)cyclopropane-1-carboxamido)-3,3 -Dimethylbutyryl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 14)
- Step 2 Preparation of ethyl (1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-carboxylate (compound 15-3)
- Step 3 Preparation of (1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-carboxylic acid (compound 15-4)
- Step 4 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2- Base)-3-((S)-2-((1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-carboxamido)-3,3-dimethylbutyryl )-6,6-Dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide (compound 15-5)
- Step 2 Preparation of ethyl (1S,2S) or (1R,2R)-2-(4-chlorophenyl)cyclopropane-1-carboxylate (compound 16-3)
- Step 3 Preparation of (1S,2S) or (1R,2R)-2-(4-chlorophenyl)cyclopropane-1-carboxylic acid (compound 16-4)
- Step 4 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2- Base)-3-((S)-2-((1R,2R) or (1S,2S)-2-(4-chlorophenyl)cyclopropane-1-carboxamido)-3,3-dimethyl Preparation of butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 16-4)
- Step 5 (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-(( S)-2-((1R,2R)-2-(4-chlorophenyl)cyclopropane-1-carboxamido)-3,3-dimethylbutyryl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 16)
- Step 2 Preparation of (1S,2S) or (1R,2R)-2-(2-bromophenyl)cyclopropane-1-carboxylic acid ethyl ester (compound 17-3)
- Step 3 Preparation of (1S,2S) or (1R,2R)-2-(2-bromophenyl)cyclopropane-1-carboxylic acid (compound 17-4)
- Step 4 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2- Base)-3-((S)-2-((1R,2R) or (1S,2S)-2-(2-bromophenyl)cyclopropane-1-carboxamido)-3,3-dimethyl Preparation of butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 17-4)
- Step 5 (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-(( S)-2-((1R,2R)-2-(2-bromophenyl)cyclopropane-1-carboxamido)-3,3-dimethylbutyryl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 17)
- Step 1 (S)-2-((1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyryl)-6 , the preparation of 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido) (compound 18-1)
- Step 2 (S)-2-((1R,2S,5S)-3-((S)-2-Amino-3,3-dimethylbutyryl)-6,6-dimethyl-3 -
- Step 3 (S)-2-((1R,2S,5S)-3-((R)-3,3-Dimethyl-2-(1R,2R)-2-phenylcyclopropane-1 Preparation of -formamido)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide) (compound 18-3)
- Step 4 (1R,2S,5S)-3-((R)-3,3-Dimethyl-2-((1R,2R)-2-phenylcyclopropane-1-carboxamido)butyl Acyl)-N-((S)-1-hydroxy-3-(S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-aza Preparation of bicyclo[3.1.0]hexane-2-carboxamide (compound 18-4)
- triethyl phosphoroacetate (10.05 g, 44.83 mmol) was added to a solution of sodium hydride (1.66 g, 41.38 mmol) in toluene (80 ml) and vigorously stirred for 10 min, followed by addition of S-propylene oxide (2.00 g , 34.48mmol) and stirred at room temperature for 6h. Then 30% sodium hydroxide (30ml) was added and stirred at reflux for 2h. After completion, it was cooled to room temperature, the aqueous phase was taken out by separation, and the mixture was quenched by adjusting the pH of the solution to 2-3 with HCl, and extracted three times with EA (100 mL).
- Step 2 (2S)-2-((1R,2S,5S)-3-((2S,3,3-Dimethyl-2-(2R)-2-methylcyclopropane-1-carboxamide Preparation of butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 19-3)
- Step 3 (1R,2S,5S)-3-((2S)-3,3-Dimethyl-2-((2R)-2-methylcyclopropane-1-carboxamido)butyryl) -N-((S)-1-hydroxy-3-(S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[ 3.1.0]
- Preparation of hexane-2-carboxamide compound 19-4)
- Step 4 1R,2S,5S)-3-((S)-3,3-Dimethyl-2-((1R,2R)-2-methylcyclopropane-1-carboxamido)butyryl )-6,6-Dimethyl-N-((R)-1-oxo-3-(S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-aza Preparation of bicyclo[3.1.0]hexane-2-carboxamide (compound 19)
- Step 1 Methyl (S)-2-((1R,2S,5S)-3-(S)-2-((1R,2R)-2-(4-bromo-3-fluorophenyl) ring Propane-1-carboxamido)-3,3-dimethylbutanol)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)- Preparation of 3-((S)-2-oxopyrrolidin-3-yl)propionate
- Step 2 (1R,2S,5S)-3-((S)-2-((1R,2R)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxamide)- 3,3-Dimethylbutyryl)-n-(S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- Preparation of Dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
- Step 3 (1R,2S,5S)-3-((S)-2-((1R,2R)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxamide)- 3,3-Dimethylbutyryl)-6,6-dimethyl-n-(S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propane- Preparation of 2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
- Embodiment 19 SARS-CoV-2 3CL enzyme inhibition experiment
- the wavelength of excitation light is 340nm, and the wavelength of emission light is 490nm.
- the calculated inhibition rate was used to fit the inhibition curve with log (inhibitor) vs. response-Variable slope (four parameters) in the Nonlinear regression (curve fit) function of GraphPad Prism 8 software, and calculate the IC 50 value.
- the compounds in the list all show good inhibitory activity of SARS-CoV-2 3CL enzyme, all at nM level. Among them, compounds 3, 4, 14, 16, and 18 had better activities than PF-07321332; compounds 7, 8, 9, 17, and 19 had comparable enzyme inhibitory activities to PF-07321332.
- Coronavirus OC43 coronavirus OC43, CoV-OC43
- SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
- MRC-5 cells were digested, diluted with DME medium containing 2% FBS and 1% P/S to 2 ⁇ 10 5 /mL, 50 ⁇ L per well was inoculated in a 96-well plate, and cultured overnight in an incubator.
- Inhibition rate (measured sample value-average value of virus control group)/(average value of cell control group-average value of virus control group).
- the calculated inhibition rate was used to fit the inhibition curve with log(inhibitor)vs.response--Variable slope(four parameters) in the Nonlinear regression(curve fit) function of GraphPad Prism 8 software, and the EC 50 value was calculated.
- the compounds in the list all exhibit excellent anti-OC43 coronavirus activity in MDCK cells, and the compound activities are all at the nM level.
- Compounds 3, 10, 14, 16, and 17 all have better antiviral activity than the reference positive molecule PF-07321332.
- mice information Purchase ICR (CD-1) female mice from Zhejiang VT-River Company, weighing between 20-30g.
- test compound was administered PO to 3 mice, and blood was collected at 0.083, 0.25, 0.5, 1, 2, 4 and 8 hours for testing.
- test compound was administered at 10 mg/kg.
- HPLC Pump Shimadzu LC-30AD; Kinetex 2.6 ⁇ m C18 100A column(50mm*2.1mm);
- Mobile phase mobile phase A: W water (0.1% FA), mobile phase B: acetonitrile (0.1% FA);
- K2EDTA is used as an anticoagulant; add 2 ⁇ L of methanol to all samples, add 200 ⁇ L of acetonitrile containing 100 ng/mL IS (Tolbutamide), vortex for 1 minute, and centrifuge at 4000 rpm for 15 minutes. Take the supernatant.
- IS Tolbutamide
- the positive molecule PF-07321332 (CAS: 2628280-40-8) was purchased from Shanghai Xingmo (lot number: XM211031-1).
- the drug concentrations of the test compounds in plasma were as follows:
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Abstract
La présente invention concerne un composé représenté par la formule I ou un stéréoisomère, un solvate, un hydrate, un promédicament, un dérivé isotopique stable, un conjugué et un sel pharmaceutiquement acceptable de celui-ci. Le composé et le conjugué de médicament ont une excellente activité dans l'inhibition de la protéase 3CL du coronavirus SARS-CoV-2 et peuvent être utilisés pour prévenir et traiter la pneumonie provoquée par une infection à coronavirus SARS-CoV-2.
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US11851422B2 (en) | 2021-07-09 | 2023-12-26 | Aligos Therapeutics, Inc. | Anti-viral compounds |
US12065428B2 (en) | 2021-09-17 | 2024-08-20 | Aligos Therapeutics, Inc. | Anti-viral compounds |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006061714A2 (fr) * | 2004-12-09 | 2006-06-15 | Pfizer Inc. | Compositions et composes anti-coronaviraux, leur utilisation pharmaceutique et materiaux destines a leur synthese |
WO2021252644A1 (fr) * | 2020-06-09 | 2021-12-16 | Pardes Biosciences, Inc. | Inhibiteurs de cystéine protéases et leurs procédés d'utilisation |
WO2021250648A1 (fr) * | 2020-09-03 | 2021-12-16 | Pfizer Inc. | Composés antiviraux contenant du nitrile |
WO2022020242A1 (fr) * | 2020-07-20 | 2022-01-27 | Enanta Pharmaceuticals, Inc. | Peptides fonctionnalisés en tant qu'agents antiviraux |
CN114149415A (zh) * | 2021-07-26 | 2022-03-08 | 中国药科大学 | 一种拟肽类化合物及其衍生物、制备方法、药物组合物和应用 |
WO2022251615A1 (fr) * | 2021-05-28 | 2022-12-01 | Arun K Ghosh | Composés pour le traitement du sras |
WO2022256434A1 (fr) * | 2021-06-02 | 2022-12-08 | ACEA Therapeutics, Inc. | Inhibiteurs de protéase utilisés comme antiviraux |
WO2023283256A1 (fr) * | 2021-07-09 | 2023-01-12 | Aligos Therapeutics, Inc. | Composés anti-viraux |
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Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006061714A2 (fr) * | 2004-12-09 | 2006-06-15 | Pfizer Inc. | Compositions et composes anti-coronaviraux, leur utilisation pharmaceutique et materiaux destines a leur synthese |
WO2021252644A1 (fr) * | 2020-06-09 | 2021-12-16 | Pardes Biosciences, Inc. | Inhibiteurs de cystéine protéases et leurs procédés d'utilisation |
WO2022020242A1 (fr) * | 2020-07-20 | 2022-01-27 | Enanta Pharmaceuticals, Inc. | Peptides fonctionnalisés en tant qu'agents antiviraux |
WO2021250648A1 (fr) * | 2020-09-03 | 2021-12-16 | Pfizer Inc. | Composés antiviraux contenant du nitrile |
WO2022251615A1 (fr) * | 2021-05-28 | 2022-12-01 | Arun K Ghosh | Composés pour le traitement du sras |
WO2022256434A1 (fr) * | 2021-06-02 | 2022-12-08 | ACEA Therapeutics, Inc. | Inhibiteurs de protéase utilisés comme antiviraux |
WO2023283256A1 (fr) * | 2021-07-09 | 2023-01-12 | Aligos Therapeutics, Inc. | Composés anti-viraux |
CN114149415A (zh) * | 2021-07-26 | 2022-03-08 | 中国药科大学 | 一种拟肽类化合物及其衍生物、制备方法、药物组合物和应用 |
Non-Patent Citations (1)
Title |
---|
CITARELLA ANDREA, SCALA ANGELA, PIPERNO ANNA, MICALE NICOLA: "SARS-CoV-2 Mpro: A Potential Target for Peptidomimetics and Small-Molecule Inhibitors", BIOMOLECULES, M D P I AG, CH, vol. 11, no. 4, 19 April 2021 (2021-04-19), CH , pages 607, XP055869885, ISSN: 2218-273X, DOI: 10.3390/biom11040607 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11851422B2 (en) | 2021-07-09 | 2023-12-26 | Aligos Therapeutics, Inc. | Anti-viral compounds |
US12065428B2 (en) | 2021-09-17 | 2024-08-20 | Aligos Therapeutics, Inc. | Anti-viral compounds |
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