WO2016015638A1 - Inhibiteur du virus de l'hépatite c et ses utilisations - Google Patents
Inhibiteur du virus de l'hépatite c et ses utilisations Download PDFInfo
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- WO2016015638A1 WO2016015638A1 PCT/CN2015/085380 CN2015085380W WO2016015638A1 WO 2016015638 A1 WO2016015638 A1 WO 2016015638A1 CN 2015085380 W CN2015085380 W CN 2015085380W WO 2016015638 A1 WO2016015638 A1 WO 2016015638A1
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- WIPO (PCT)
- Prior art keywords
- group
- alkyl
- amino
- acyl
- hydroxy
- Prior art date
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- 241000711549 Hepacivirus C Species 0.000 title abstract description 42
- 239000003112 inhibitor Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 228
- 238000002360 preparation method Methods 0.000 claims abstract description 91
- 239000003814 drug Substances 0.000 claims abstract description 12
- -1 hydroxy, amino Chemical group 0.000 claims description 211
- 125000000217 alkyl group Chemical group 0.000 claims description 209
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 163
- 125000003545 alkoxy group Chemical group 0.000 claims description 146
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 126
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 120
- 125000001072 heteroaryl group Chemical group 0.000 claims description 104
- IJMWOMHMDSDKGK-UHFFFAOYSA-N Isopropyl propionate Chemical compound CCC(=O)OC(C)C IJMWOMHMDSDKGK-UHFFFAOYSA-N 0.000 claims description 98
- 229910052736 halogen Inorganic materials 0.000 claims description 97
- 150000002367 halogens Chemical class 0.000 claims description 97
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 91
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 87
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 86
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 84
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 82
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 81
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 74
- 229910052739 hydrogen Inorganic materials 0.000 claims description 67
- 150000003839 salts Chemical class 0.000 claims description 55
- 239000012453 solvate Substances 0.000 claims description 54
- 125000003118 aryl group Chemical group 0.000 claims description 51
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 51
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 49
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 47
- 239000013078 crystal Substances 0.000 claims description 40
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 39
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 39
- 125000000304 alkynyl group Chemical group 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 36
- 125000003342 alkenyl group Chemical group 0.000 claims description 35
- 125000002252 acyl group Chemical group 0.000 claims description 33
- 125000005256 alkoxyacyl group Chemical group 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 229910052799 carbon Inorganic materials 0.000 claims description 31
- 150000002431 hydrogen Chemical class 0.000 claims description 28
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 28
- 125000003282 alkyl amino group Chemical group 0.000 claims description 27
- FHGWEHGZBUBQKL-UHFFFAOYSA-N 1,2-benzothiazepine Chemical compound S1N=CC=CC2=CC=CC=C12 FHGWEHGZBUBQKL-UHFFFAOYSA-N 0.000 claims description 26
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 19
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 15
- 150000001721 carbon Chemical group 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 229940049706 benzodiazepine Drugs 0.000 claims description 13
- 230000009385 viral infection Effects 0.000 claims description 13
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical group C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 claims description 12
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 12
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000001188 haloalkyl group Chemical group 0.000 claims description 12
- 125000002883 imidazolyl group Chemical group 0.000 claims description 12
- 125000002971 oxazolyl group Chemical group 0.000 claims description 12
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 12
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 12
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 12
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 11
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical group C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 11
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 11
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 11
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 11
- ZCXLTWVZYXBHJS-UHFFFAOYSA-N 1,2-benzoxazepine Chemical compound O1N=CC=CC2=CC=CC=C12 ZCXLTWVZYXBHJS-UHFFFAOYSA-N 0.000 claims description 10
- 125000004442 acylamino group Chemical group 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 10
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 8
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 8
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 229910052698 phosphorus Inorganic materials 0.000 claims description 5
- 239000011574 phosphorus Substances 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- SNYGEZDJPPMIEK-BHPVSCQASA-N propan-2-yl (2s)-2-[[[(2r,3r,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-quinoxalin-5-yloxyphosphoryl]amino]propanoate Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)COP(=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C3=NC=CN=C3C=CC=2)C=CC(=O)NC1=O SNYGEZDJPPMIEK-BHPVSCQASA-N 0.000 claims description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 3
- WHGMHGPIJZTKTI-UHFFFAOYSA-N 3h-1,2-benzodithiole Chemical compound C1=CC=C2CSSC2=C1 WHGMHGPIJZTKTI-UHFFFAOYSA-N 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 14
- 150000001336 alkenes Chemical class 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 208000006454 hepatitis Diseases 0.000 claims 1
- 231100000283 hepatitis Toxicity 0.000 claims 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 25
- 230000000694 effects Effects 0.000 abstract description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 5
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- 102000004506 Blood Proteins Human genes 0.000 abstract description 2
- 108010017384 Blood Proteins Proteins 0.000 abstract description 2
- 230000002155 anti-virotic effect Effects 0.000 abstract 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 118
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 89
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 84
- 238000000034 method Methods 0.000 description 77
- 239000007858 starting material Substances 0.000 description 63
- 125000005843 halogen group Chemical group 0.000 description 62
- 239000000047 product Substances 0.000 description 59
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 58
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 58
- 238000005481 NMR spectroscopy Methods 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- YAQKNCSWDMGPOY-JEDNCBNOSA-N propan-2-yl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.CC(C)OC(=O)[C@H](C)N YAQKNCSWDMGPOY-JEDNCBNOSA-N 0.000 description 41
- 238000006243 chemical reaction Methods 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 29
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 26
- COIQUVGFTILYGA-UHFFFAOYSA-N (4-hydroxyphenyl)boronic acid Chemical compound OB(O)C1=CC=C(O)C=C1 COIQUVGFTILYGA-UHFFFAOYSA-N 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 23
- ARKKGZQTGXJVKW-VPCXQMTMSA-N 1-[(2r,3r,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidine-2,4-dione Chemical compound C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 ARKKGZQTGXJVKW-VPCXQMTMSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 18
- 235000019439 ethyl acetate Nutrition 0.000 description 15
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- 125000004434 sulfur atom Chemical group 0.000 description 13
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- 241000700605 Viruses Species 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical compound C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
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- 239000000243 solution Substances 0.000 description 11
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
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- 125000005842 heteroatom Chemical group 0.000 description 10
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- 238000006392 deoxygenation reaction Methods 0.000 description 9
- 208000015181 infectious disease Diseases 0.000 description 9
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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 8
- 241000710781 Flaviviridae Species 0.000 description 8
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- 102000014150 Interferons Human genes 0.000 description 8
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 8
- 150000002430 hydrocarbons Chemical group 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 125000000355 1,3-benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 7
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- 238000000746 purification Methods 0.000 description 7
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- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
Definitions
- the invention belongs to the field of medical chemistry, and particularly relates to a compound having a good hepatitis C virus inhibitory effect, a preparation method thereof, a composition containing the same, and the compound or composition as a therapeutic drug for hepatitis C virus infectious diseases. the use of.
- Hepatitis C virus (HCV) infection is a worldwide disease. The number of chronically infected people worldwide has exceeded 200 million, and the infection rate in China is 3.2%, ranking the top three in the world.
- the clinical manifestations of hepatitis C virus infection are diverse, ranging from inflammation to cirrhosis and liver cancer.
- Chronic hepatitis C can also be associated with certain extrahepatic manifestations, including rheumatoid arthritis, dry conjunctival keratitis, lichen planus, glomerulonephritis, mixed cryoglobulinemia, B-cell lymphoma, and delayed onset Skin porphyria, etc., may be caused by abnormal immune response in the body.
- Hepatitis C cirrhosis decompensation there may be various complications, such as ascites abdominal infection, upper gastrointestinal bleeding, hepatic encephalopathy, liver and kidney syndrome, liver failure and other performance.
- HCV belongs to the Flaviviridae virus, which is similar in gene structure to the other two genera of the Flaviviridae, the genus Pestivirus and Flavivirus.
- standard methods of treating HCV infection are interferon and a combination of interferon and ribavirin.
- interferons had significant side effects such as pan-like symptoms, weight loss, and fatigue, while interferon and ribavirin combination therapy produced considerable Side effects, including hemolysis, anemia, and fatigue.
- drugs developed for the treatment of HCV infection include protease inhibitors, thiazolidine derivatives, thiazolidine and n-benzoanilide, phenanthrenequinone, helicase inhibitor, nucleoside polymerase inhibitor and colloidal Toxins, antisense phosphorothioate oligonucleotides, inhibitors of IRES-dependent translation, ribozymes, and nucleoside analogs, and the like.
- nucleoside phosphate compounds for the treatment of Flaviviridae viruses, especially HCV infections, is an important research and development direction in the field.
- WO 2006/065335 discloses a fluorinated pyrrolo[2,3,d]pyrimidine nucleoside compound which inhibits HCV virus.
- US 2006/0241064 discloses nucleoside compounds for the treatment of viral infections caused by Flaviviridae family viruses such as HCV.
- WO 2008/121634 discloses nucleoside phosphoramidate compounds for use in the treatment of viral infections in mammals.
- Another object of the invention is to provide a process for the preparation of a compound of formula I of the invention, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof.
- a further object of the present invention is to provide a composition comprising a compound of the formula I according to the invention, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline and pharmaceutically acceptable carrier thereof, and A compound of the formula I according to the invention, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate thereof or a combination of crystals and another antiviral agent.
- a further object of the present invention is to provide a compound of the formula I according to the invention, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystallization thereof, and a method for the treatment and/or prevention of hepatitis C virus infection and Use of a compound of formula I according to the invention, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, for the manufacture of a medicament for the treatment and/or prevention of a viral infection.
- the present invention provides the following technical solutions:
- the invention provides a compound of Formula I, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof:
- R 1 is selected from the group consisting of H, alkyl and haloalkyl
- R 2 is selected from the group consisting of H and halogen
- R 3 is selected from the group consisting of H, OH, and alkoxy
- R 4 is selected from the group consisting of H and alkyl, wherein the alkyl group is optionally selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, halogen, hydroxy, amino, nitro, cyano Substituting one or more groups of an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a sulfonyl group, a sulfinyl group, a fluorenyl group, an aryl group, and a heteroaryl group;
- R 5 is selected from the group consisting of H, alkyl, cycloalkyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl are optionally selected from alkyl, cycloalkyl, heterocycle Alkyl, alkoxy, alkylamino, halogen, hydroxy, amino, nitro, cyano, alkyl acyl, amino acyl, alkylamino acyl, sulfonyl, sulfinyl, decyl, aryl and heteroaryl Substituted by one or more groups;
- Cy 1 is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl are optionally selected from the group consisting of halogen, hydroxy, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, Substituting one or more groups of an alkylamino group, an alkyl acylamino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a nitro group, a cyano group;
- Cy 2 is selected from the group consisting of hydrogen, aryl, heteroaryl, heterocycloalkyl and heterocycloalkenyl, wherein said aryl, heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from halogen, Hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, nitrate Substituting one or more groups in the cyano group;
- Cy 1 is an aryl group
- Cy 2 is not hydrogen or an aryl group
- the compound of the formula I of the present invention is not the following compound:
- R 1 is selected from H, C 1-6 alkyl, halo C 1-6 alkyl, R 2 is selected from H, fluoro, chloro, bromo, and R 3 is selected from H, OH.
- R 1 is selected from H, C 1-3 alkyl
- R 2 is selected from fluoro, chloro
- R 3 is selected from H, OH.
- R 4 is selected from H, C 1-6 alkyl
- R 5 is selected from C 1-6 alkyl and C 3-8 cycloalkyl, wherein said alkyl and cycloalkyl Optionally selected from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, halo, hydroxy, amino, nitro, cyano, alkyl acyl, amino acyl, alkylamino acyl, sulfonyl Substituting one or more groups of a sulfinyl group, a fluorenyl group, an aryl group, and a heteroaryl group.
- R 4 is selected from H, C 1-3 alkyl
- R 5 is selected from C 1-6 alkyl and C 3-6 cycloalkyl, wherein said alkyl and naphthenic
- the group may be selected from a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 3-8 heterocycloalkyl group, a C 1-6 alkoxy group, a C 1-6 alkylamino group, a halogen, a hydroxyl group, an amino group.
- R 4 is selected from H, C 1-3 alkyl
- R 5 is selected from C 1-3 alkyl and C 3-6 cycloalkyl, wherein said alkyl and naphthenic
- the group may be selected from C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 1-3 alkoxy, C 1-3 alkylamino, halogen, hydroxy, amino Substituting one or more groups of nitro, cyano, C 1-3 alkyl acyl, amino acyl, C 1-3 alkylamino acyl, sulfonyl, sulfinyl, decyl, phenyl and heteroaryl .
- Cy 1 is selected from the group consisting of a benzene ring
- Cy 2 is selected from the group consisting of a heteroaryl group, a heterocycloalkyl group, and a heterocycloalkenyl group, wherein the benzene ring, heteroaryl group, heterocycloalkyl group, and hetero
- the cycloalkenyl group is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1 Substituting one or more groups of the -6 alkylamino acyl group, the nitro group, and the cyano group.
- Cy 1 is selected from the group consisting of a benzene ring
- Cy 2 is selected from the group consisting of a heteroaryl group, a C 3-8 heterocycloalkyl group, and a C 3-8 heterocycloalkenyl group, wherein the benzene ring is hetero
- the aryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, Halogen C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, amino, C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 Substituting one or more groups of an alkyl acyl group, an amino acyl group, a C 1-3 alkylamino acyl group, a nitro group, and a
- Cy 1 is selected from the group consisting of a benzene ring
- Cy 2 is selected from the group consisting of a heteroaryl group, a C 3-6 heterocycloalkyl group, and a C 3-6 heterocycloalkenyl group, wherein the benzene ring is hetero
- the aryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, Halogen C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, amino, C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 Substituting one or more groups of an alkyl acyl group, an amino acyl group, a C 1-3 alkylamino acyl group, a nitro group, and a
- Cy 1 is selected from the group consisting of a benzene ring
- Cy 2 is selected from a five- or six-membered heteroaryl group, a heterocycloalkyl group, and a heterocycloalkenyl group having at least one N atom
- the benzene is The cyclo, 5- or 6-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkane Substituting one or more groups of a acylamino group, a C 1-6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamin
- Cy 1 is selected from the group consisting of benzene rings
- Cy 2 is selected from 5- or 6-membered heteroaryl, heterocycloalkyl, and heterocycloalkenyl groups having 1-3 N atoms
- a benzene ring, a five- or six-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkyne , C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-
- One or more groups of 6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, nitro, cyano are substituted.
- Cy 1 is selected from the group consisting of a benzene ring
- Cy 2 is selected from a five- or six-membered heteroaryl group, a heterocycloalkyl group, and a heterocycloalkenyl group having only one S atom
- the phenyl ring, five- or six-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 Substituting one or more groups of an alkyl acylamino group, a C 1-6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamino
- Cy 1 is selected from the group consisting of a benzene ring
- Cy 2 is selected from the group consisting of a six-membered heteroaryl group having 1 N atom, a heterocycloalkyl group, and a heterocycloalkenyl group, wherein the benzene ring and the heterocyclic group are Or a heterocycloalkyl or heterocycloalkenyl group is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkane Substituting one or more groups of a acyl group, an amino acyl group, a C 1-6 alkylamino acyl group,
- Cy 1 is selected from the group consisting of benzene rings
- Cy 2 is selected from the group consisting of a five-membered heteroaryl group having only one S atom, a heterocycloalkyl group, and a heterocycloalkenyl group, wherein the benzene ring
- the heteroaryl, heterocycloalkyl or heterocycloalkenyl group is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl , halogenated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1- Substituting one or more groups of a 6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamino acyl group, a nitro
- Cy 1 is selected from the group consisting of a benzene ring
- Cy 2 is selected from the group consisting of a 5-membered heteroaryl group having 2 N atoms, a heterocycloalkyl group, and a heterocycloalkenyl group, wherein the benzene ring is hetero
- the aryl, heterocycloalkyl or heterocycloalkenyl group is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, Halogenated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 Substituting one or more groups of an alkyl acyl group, an amino acyl group, a C 1-6 alkylamino acyl group, a nitro
- Cy 1 is selected from the group consisting of a benzene ring
- Cy 2 is selected from the group consisting of a five-membered heteroaryl group, a heterocycloalkyl group, and a heterocycloalkenyl group having one N atom and one sulfur atom
- a benzene ring, a heteroaryl group, a heterocycloalkyl group or a heterocycloalkenyl group is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino Substituting one or more groups of a C 1-6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamino
- Cy 1 is selected from the group consisting of a benzene ring
- Cy 2 is selected from the group consisting of a five-membered heteroaryl group, a heterocycloalkyl group, and a heterocycloalkenyl group having one N atom and one oxygen atom
- a benzene ring, a heteroaryl group, a heterocycloalkyl group or a heterocycloalkenyl group is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino Substituting one or more groups of a C 1-6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamino
- Cy 1 is selected from the group consisting of a benzene ring
- Cy 2 is selected from the group consisting of a furan ring, a pyrrole ring, a thiophene ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, and an isoxazole.
- Cy 1 is selected from the group consisting of a benzene ring
- Cy 2 is selected from the group consisting of a furan ring, a pyrrole ring, a thiophene ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, and an isoxazole.
- the inventors of the present invention unexpectedly found that the compound of the present invention has very excellent antiviral activity when Cy 2 in the formula I is in the para or meta position of Cy 1 .
- Cy 1 is selected from the group consisting of naphthalene rings, heteroaryl groups
- Cy 2 is selected from the group consisting of hydrogen, aryl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl, wherein the naphthalene ring
- the aryl, heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 Cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, Substituting one or more groups of a C 1-6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamino acyl group, a nitro group, and a
- Cy 1 is selected from the group consisting of naphthalene rings, heteroaryl groups
- Cy 2 is selected from the group consisting of hydrogen, aryl, heteroaryl, C 3-8 heterocycloalkyl, and C 3-8 heterocycloalkenyl.
- naphthalene ring, aryl, heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2 - 4 alkynyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C Substituting one or more groups of 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, nitro, cyano.
- Cy 1 is selected from the group consisting of naphthalene rings, heteroaryl groups
- Cy 2 is selected from the group consisting of hydrogen, aryl, heteroaryl, C 3-6 heterocycloalkyl, and C 3-6 heterocycloalkenyl.
- naphthalene ring, aryl, heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-6 cycloalkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, amino, C 1-3 alkylamino, C Substituting one or more groups of 1-3 alkyl acylamino, C 1-3 alkyl acyl, amino acyl, C 1-3 alkylamino acyl, nitro, cyano.
- Cy 1 is selected from a five- or six-membered heterocyclic ring containing at least one N atom, wherein the five- or six-membered heterocyclic ring having at least one N atom is optionally Selected from halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 Alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, nitro, cyano One or more groups are substituted and Cy 2 is hydrogen.
- Cy 1 is selected from a five- or six-membered heterocyclic ring containing only one S atom of benzene, wherein the five- or six-membered heterocyclic ring in which the benzene contains only one S atom is optionally Selected from halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 Alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, nitro, cyano One or more groups are substituted and Cy 2 is hydrogen.
- Cy 1 is selected from a benzene 5- or 6-membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms, wherein the benzo five or six member contains 1, 2 or 3
- the heteroaryl ring of the nitrogen atom is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-6 alkyl, C 1-6 alkane Oxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino
- Cy 2 is hydrogen.
- Cy 1 is selected from the group consisting of a benzo-5-membered heteroaryl ring containing 1 or 2 nitrogen atoms, wherein the benzo-5-membered heteroaryl ring having 1 or 2 nitrogen atoms is optionally Selected from halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 Alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, nitro, cyano One or more groups are substituted and Cy 2 is hydrogen.
- Cy 1 is selected from the group consisting of a benzo-5-membered heteroaryl ring containing 1 nitrogen atom and 1 oxygen atom, wherein the benzoquinone contains 1 nitrogen atom and 1 oxygen atom.
- the heteroaryl ring is optionally selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, nitrate One or more groups in the cyano group are substituted, and Cy 2 is hydrogen.
- Cy 1 is selected from the group consisting of a five-membered heteroaryl ring containing only one S atom, wherein the five-membered heteroaryl ring containing only one S atom of the benzene is optionally selected from Halogen, hydroxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy
- Cy 1 is selected from the group consisting of a furan ring, a pyrrole ring, a thiophene ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a triazole ring, Thiadiazole ring, oxadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, benzoazepine ring, benzoxane ring, benzothiazepine, benzodiazepine, benzene And a dioxane, a benzodithioheterocycle, a benzoxazepine, a benzothiazepine, and the Cy 2 is selected from the group consisting of hydrogen, a benzene ring, a furan
- Cy 1 is selected from the group consisting of a furan ring, a pyrrole ring, a thiophene ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a triazole ring, Thiadiazole ring, oxadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, benzofuran ring, benzopyrrole ring, benzothiophene ring, benzimidazole ring, benzopyrazole ring, a benzothiazole ring, a benzisothiazole ring, a benzoxazole ring, a benzisoxazole ring, a benzotriazole ring, a benzothiadiazole ring
- the invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof:
- R a1 is selected from the group consisting of heteroaryl, heterocycloalkyl and heterocycloalkenyl, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, alkyl, alkenyl Alkyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, alkylacyl, alkoxyacyl, aminoacyl, alkylaminoacyl, sulfonyl, sulfinyl, decyl, nitro Substituting one or more groups in the cyano group;
- R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, alkyl acyl, alkoxyacyl, aminoacyl, alkylaminoacyl, sulfonate Acyl, sulfinyl, decyl, nitro and cyano; or
- R a1 , R a2 together with the carbon atom to which they are attached constitute a heteroaryl, heterocycloalkyl or heterocycloalkenyl group;
- R a3 , R a4 , R a5 are independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, alkyl acyl, alkoxy acyl, Aminoacyl, alkylaminoacyl, sulfonyl, sulfinyl, decyl, nitro, cyano;
- R 1 , R 2 , R 3 , R 4 and R 5 have the definitions in the formula I.
- the compound of formula Ia according to the present invention or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline, in which R 1 is selected from H, C 1-6 alkyl And halogenated C 1-6 alkyl, preferably selected from H and C 1-3 alkyl; R 2 is selected from H, fluorine, chlorine and bromine, preferably selected from fluorine and chlorine; R 3 is selected from H and OH; 4 is selected from the group consisting of H and C 1-6 alkyl, wherein the alkyl group is optionally selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 1-6 Alkoxy, C 1-6 alkylamino, halogen, hydroxy, amino, nitro, cyano, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, Substituting one or more
- the invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from C 4-8 heteroaryl And a C 4-8 heterocycloalkyl group and a C 4-8 heterocycloalkenyl group, wherein said heteroaryl group, heterocycloalkyl group and heterocycloalkenyl group are optionally selected from the group consisting of halogen, hydroxy, amino, C 1- 6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Oxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, dec
- R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano; or
- R a1 , R a2 together with the carbon atom to which they are attached constitute a C 4-8 heteroaryl group, a C 4-8 heterocycloalkyl group or a C 4-8 heterocycloalkenyl group.
- the invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from at least one N atom five- or six-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl, wherein the heteroaryl, heterocycloalkyl and heterocycloalkenyl group optionally substituted selected from halogen, hydroxy, amino, C 1- 6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Oxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro,
- R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano; or
- R a1 , R a2 together with the carbon atom to which they are attached constitute a five- or six-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group containing at least one N atom.
- the invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from 1-3 N a five- or six-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl group of the atom, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogen C 1- 6 alkoxy, C 1-6 alkyla
- R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano; or
- R a1 , R a2 together with the carbon atom to which they are attached constitute a five- or six-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group having from 1 to 3 N atoms.
- the invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from the group consisting of only one S atom five- or six-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl, wherein the heteroaryl, heterocycloalkyl and heterocycloalkenyl group optionally substituted selected from halogen, hydroxy, amino, C 1- 6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Oxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl
- R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano; or
- R a1 , R a2 together with the carbon atom to which they are attached constitute a five- or six-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group containing only one S atom.
- the invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from the group consisting of one N atom a heteroaryl, heterocycloalkyl and heterocycloalkenyl group, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro, cyano Sub
- R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano.
- the present invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 , R a2 and the carbon to which they are attached
- the atoms together constitute a five- or six-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group containing one N atom, wherein the heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from Halogen, hydroxy, amino, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy , halogenated C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, Sub
- the invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from the group consisting of 2 N atoms a five-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl group, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C 1-6 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl,
- R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano; or
- R a1 and R a2 together with the carbon atom to which they are attached constitute a five-membered heteroaryl group, heterocycloalkyl group or heterocycloalkenyl group having two N atoms.
- the present invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from the group consisting of 1 N atom and a five-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl group of one sulfur atom, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogen C 1- 6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl
- R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano; or
- R a1 and R a2 together with the carbon atom to which they are attached constitute a five-membered heteroaryl group, heterocycloalkyl group or heterocycloalkenyl group containing one N atom and one sulfur atom.
- the present invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from the group consisting of 1 N atom and a five-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl group of one oxygen atom, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogen C 1- 6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl
- R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano; or
- R a1 and R a2 together with the carbon atom to which they are attached constitute a five-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group having one N atom and one oxygen atom.
- the present invention provides a compound of Formula Ia, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein R a1 is selected from only one S atom Five-membered heteroaryl, heterocycloalkyl and heterocycloalkenyl, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl are optionally selected from the group consisting of halogen, hydroxy, amino, C 1-6 alkane , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy , C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro, cyano
- R a2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkoxy acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, nitro And cyano; or
- R a1 and R a2 together with the carbon atom to which they are bonded constitute a five-membered heteroaryl group, heterocycloalkyl group or heterocycloalkenyl group having only one S atom.
- the present invention provides a compound of Formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline, wherein R 1 is H, methyl, ethyl, N-propyl or isopropyl, R 2 is F, R 3 is OH, R 4 is selected from H, methyl, ethyl, n-propyl or isopropyl, and R 5 is selected from methyl, ethyl, n-propyl Base, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl or benzyl, R a1 is selected from furan ring, pyrrole ring , thiophene ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring,
- the present invention provides a compound of Formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline, wherein R 1 is H or methyl, R 2 is F, R 3 is OH, R 4 is selected from H, methyl, ethyl, n-propyl or isopropyl, and R 5 is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, positive Butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl or benzyl, R a1 is selected from furan ring, pyrrole ring, thiophene ring, imidazole ring, pyrazole ring, Thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, triazole ring,
- the present invention provides a compound of Formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline, wherein R 1 is H, methyl, ethyl, N-propyl or isopropyl, R 2 is F, R 3 is OH, R 4 is selected from H, methyl, ethyl, n-propyl or isopropyl, and R 5 is selected from methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or benzyl, R a1 , R a2 together with the carbon atom to which they are attached constitute a benzodiazepine, benzo Oxyheterocyclic ring, benzothiazepine, benzodiazepine, benzodioxane, benzodithioheterocycle,
- the present invention provides a compound of Formula Ia or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline, wherein R 1 is H, methyl, ethyl, N-propyl or isopropyl, R 2 is F, R 3 is OH, R 4 is selected from H, methyl, ethyl, n-propyl or isopropyl, and R 5 is selected from methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or benzyl, R a1 , R a2 together with the carbon atom to which they are attached constitute a benzofuran ring, benzopyrrole Ring, benzothiophene ring, benzimidazole ring, benzopyrazole ring, benzothiazole ring, benzisothiazo
- the compound of formula Ia of the invention is not the following:
- the present invention provides the following specific compounds:
- the invention provides a process for the preparation of a compound of formula I according to the invention, which process comprises the steps of:
- R 1 , R 2 , R 3 , R 4 , R 5 , Cy 1 , Cy 2 are as defined in the above formula I.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of the formula I or Ia of the present invention.
- the invention provides a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of the invention and comprises a compound, stereoisomer, pharmaceutically acceptable salt of the invention A hydrate, solvate or crystalline pharmaceutical composition for treating and/or preventing a liver disease caused by a hepatitis C virus.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the formula I or Ia, a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal, and further comprising a composition selected from the group consisting of One or more additional anti-HCV therapeutics: HCV NS3 protease inhibitor, HCV NS5B RNA-dependent RNA polymerase inhibitor, nucleoside analog, interferon alpha, pegylated interferon, ribavi Lin, L-Weiline, Veramididine, TLR7 agonist, TLR9 agonist, cyclophilin inhibitor, alpha glucosidase inhibitor, NS5A inhibitor and NS3 helicase inhibitor.
- HCV NS3 protease inhibitor HCV NS5B RNA-dependent RNA polymerase inhibitor
- nucleoside analog nucleoside analog, interferon alpha, pegylated interferon, ribavi Lin, L-Wei
- the compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of the formula I and Ia of the present invention may be prepared by mixing with a pharmaceutically acceptable carrier, diluent or excipient.
- a pharmaceutical preparation suitable for oral or parenteral administration suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes.
- the formulation may be administered by any route, such as by infusion or bolus injection, by absorption through the epithelium or skin mucosa (eg, oral mucosa or rectum, etc.) Apply. Administration can be systemic or topical.
- orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like.
- the formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally employed in the field of pharmaceutical formulations.
- the present invention provides a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of the formula I and Ia of the present invention or a pharmaceutical composition of the present invention for treating a Flaviviridae virus
- a method of infecting a subject comprising administering to the subject a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of formula I and Ia or comprising formula I and Ia
- a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystalline pharmaceutical composition is administered in an amount effective to reduce the viral load of the virus in the subject.
- the invention provides a method for the treatment and/or prevention of an RNA virus, such as a Flaviviridae viral infection, comprising administering to a subject in need of such treatment a compound of the invention, a stereoisomer thereof, pharmaceutically acceptable a salt, hydrate, solvate or crystal or a pharmaceutical composition thereof.
- the invention provides a method of inhibiting an RNA virus, such as a Flaviviridae virus infection, comprising hydrating the virus with a therapeutically effective amount of a compound of the invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, The substance, solvate or crystal or a pharmaceutical composition thereof is contacted.
- Flaviviridae virus refers to any virus of the Flaviviridae family, including those that infect humans and non-human animals, such as flaviviruses, plague viruses, and hepatitis C virus.
- the compounds and compositions of the invention are particularly useful for the therapeutic and/or prophylactic treatment of HCV.
- the invention provides a compound, stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal of the formula I and Ia of the invention for use in preventing or treating a viral infection, especially yellow Use of a virus-infected disease, and in the preparation of a medicament for preventing and/or treating a viral infection, particularly in the preparation of a medicament for preventing and/or treating an HCV viral infection, such as an HCV viral hepatitis disease.
- diseases are acute hepatitis C, chronic hepatitis C, and a mixed infection of hepatitis C and hepatitis B or hepatitis D.
- the invention provides methods for treating and/or preventing a viral infection, the method comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound of the invention or a stereoisomer thereof A pharmaceutically acceptable salt, hydrate, solvate or crystal or a pharmaceutical composition of the invention.
- the compound of the present invention, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystallization thereof or a pharmaceutical composition of the present invention can be administered to a mammal in need thereof to inhibit the virus and prevent progression of the disease.
- the method or use of treating and/or preventing a viral infection further comprises administering to the individual a compound of formula I of the invention, or a stereoisomer, pharmaceutically acceptable salt, hydrate thereof, , solvates or crystals or pharmaceutical compositions containing same, and are administered a compound of formula I of the invention
- the at least one other compound having anti-HCV activity is administered before, after or simultaneously with the stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof or the pharmaceutical composition containing the same.
- At least one of the other compounds is an interferon or ribavirin.
- the interferon is selected from the group consisting of interferon alpha 2B, PEGylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau.
- at least one of the other compounds is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, interfering RNA, antisense RNA, imiquimod, ribavirin, 5'-inosine monophosphate dehydrogenase inhibitor, amantadine and rimantadine.
- At least one of the other compounds is effective to inhibit the function of a target selected from the group consisting of HCV metalloproteinase, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV NS5B protein, HCV entry, HCV assembly, HCV release, HCV NS3/4A protein and IMPDH.
- a target selected from the group consisting of HCV metalloproteinase, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV NS5B protein, HCV entry, HCV assembly, HCV release, HCV NS3/4A protein and IMPDH.
- stereoisomer refers to an isomer produced by the different arrangement of atoms in a molecule in space. These include cis and trans isomers, enantiomers and conformational isomers. All stereoisomers are within the scope of the invention. Individual stereoisomers of the compounds of the invention may be substantially free of other isomers or may be admixed, for example, as a racemate, or with all other stereoisomers.
- pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt of a compound of the invention formed with an acid, such as, but not limited to, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, Citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid or the like.
- an acid such as, but not limited to, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, Citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid or the like.
- solvate refers to a form of a compound of the invention that forms a solid or liquid complex by coordination with a solvent molecule. Hydrates are a special form of solvates in which coordination occurs with water. Within the scope of the invention, the solvate is preferably a hydrate.
- crystalline refers to the various solid forms formed by the compounds described herein, including crystalline forms, amorphous forms.
- alkyl refers to a straight or branched saturated hydrocarbon group, preferably a hydrocarbon group of 6 or less carbon atoms.
- alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 2,2-Methylbutyl and 2,3-dimethylbutyl.
- C 1-6 alkyl refers to a straight or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms.
- C 1-4 alkyl refers to a straight or branched saturated hydrocarbon group containing from 1 to 4 carbon atoms.
- haloalkyl refers to an alkyl group substituted with at least one halogen atom.
- cycloalkyl refers to a cyclic saturated hydrocarbon group, preferably a hydrocarbon group of 8 carbon atoms or less.
- C 3-8 cycloalkyl refers to a cyclic saturated hydrocarbon group containing from 3 to 8 carbon atoms.
- C 3-6 cycloalkyl refers to a straight or branched saturated hydrocarbon group containing from 3 to 6 carbon atoms.
- alkoxy refers to -O-alkyl
- halogen means fluoro, chloro, bromo, iodo.
- alkylamino refers to -NH-alkyl or -N-(alkyl)(alkyl).
- alkyl acyl refers to -C(O)-alkyl.
- aminoacyl refers to -C (O) -NH 2
- alkylamino group refers to -C (O) -NH- or a group -C (O) -N- (alkyl) (alkyl ).
- sulfonyl refers to -S(O) 2 -alkyl
- sulfinyl refers to -S(O)-alkyl
- aryl refers to an aromatic hydrocarbon group containing one or more benzene rings. Suitable aryl groups include phenyl, naphthyl.
- heteroaryl refers to an aromatic group in which at least one carbon atom of the aryl group is replaced by a hetero atom.
- the hetero atom is O, S, N.
- the heteroaryl groups described herein include, but are not limited to, pyridinyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, imidazolyl, triazolyl , tetrazolyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.
- heterocycloalkyl refers to a saturated cyclic group containing at least one heteroatom, wherein the heteroatom is N, O or S.
- heterocyclenyl refers to an unsaturated cyclic group containing at least one heteroatom, wherein the heteroatom is N, O or S.
- Step 2 (2S)-2-(((4-(3-fluoropyridin-2-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo) -3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl preparation
- the product obtained in step 1 is 4-(3-fluoropyridin-2-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxygenation.
- the target compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -2'-fluoro-2'-methyluridine as a starting material.
- Step 2 (2S)-2-((4-(2-Fluoropyridin-4-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo) -3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl preparation
- Step 2 (2S)-2-(((4-(Pyridin-4-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo-3, Preparation of 4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester
- step 1 The product obtained in step 1 is 4-(pyridin-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxy-2'.
- the desired compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -fluoro-2'-methyluridine as a starting material.
- the title compound was obtained by the same procedure as in the step 1 of Example 1 from the crude product of 4-bromo-1-methyl-1H-pyrazole-3-carboxylate and 4-hydroxyphenylboronic acid.
- the product obtained in the step 3 is 4-(1-methyl-3-cyano-1H-pyrazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- Step 2 (2S)-2-(((4-(Pyridin-3-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo-3, 4-Dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester
- step 1 The product obtained in step 1 is 4-(pyridin-3-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxy-2'.
- the desired compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -fluoro-2'-methyluridine as a starting material.
- the product obtained in step 1 is 4-(5-fluoropyridin-2-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxygenation.
- the target compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -2'-fluoro-2'-methyluridine as a starting material.
- Step 2 (2S)-2-(((4-(2-chloropyridin-4-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo) -3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester
- step 2 The product obtained in step 2 is 4-(5-methylthiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- step 2 The product obtained in step 2 is 5-hydroxy-1-methyl-1H-indole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxygenation.
- the target compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -2'-fluoro-2'-methyluridine as a starting material.
- the product obtained in the step 2 is 2-fluoro-4-(1-methyl-1H-pyrazol-3-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and 2'R)-2'-deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- step 1 4-bromo-5-methylthiazole and 5g of NBS in a 250mL single-mouth bottle, add 80mL of carbon tetrachloride to dissolve, reflux reaction for 2h, after the reaction is finished, cool to room temperature, concentrate, column layer
- the title compound was purified by chromatography.
- step 3 4-bromo-5-hydroxymethylthiazole in a 100 mL single-mouth bottle, add 30 mL of dichloromethane to dissolve, add 1.5 g of chlorochromic acid pyridine (PCC) in portions, add, and react at room temperature for 3 h. After the reaction is completed, it is concentrated and purified by column chromatography to give the title compound.
- PCC chlorochromic acid pyridine
- step 6 4-(thiazol-5-carbazin-4-yl)phenol in a 100 ml single-mouth bottle, add 10 mL of THF, add 8 mL of pyridine and 8 mL of trifluoroacetic anhydride, and react at room temperature for 12 h. After completion, it was cooled to room temperature, concentrated and purified by column chromatography.
- step 7 The product obtained in step 7 is 4-(5-cyanothiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- the product obtained in the step 2 is 6-hydroxy-3-methylbenzo[d]isoxazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2.
- the target compound was obtained by the same procedure as in the steps 2 and 3 of Example 1 using '-deoxy-2'-fluoro-2'-methyluridine as a starting material.
- step 1 4-(thiazol-4-yl)phenol in a 100 mL single-mouth bottle, add 50 mL of dichloromethane to dissolve, add 0.75 g of NCS, add the mixture, and react at room temperature for 12 h. After the reaction is finished, concentrate. Purification by column chromatography gave the title compound.
- the product obtained in step 2 is 4-(5-chlorothiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxygenation.
- the target compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -2'-fluoro-2'-methyluridine as a starting material.
- Step 2 (2S)-2-(((4-(3,5-Dimethylisoxazol-4-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2) ,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino) Isopropyl propionate
- step 1 The product obtained in step 1 is 4-(3,5-dimethylisoxazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R).
- the target compound was obtained by the same procedure as in Example 2, Steps 2 and 3, using -2'-deoxy-2'-fluoro-2'-methyluridine as a starting material.
- the product obtained in the first step is 4-(4-chloro-1-methyl-1H-pyrazol-3-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and 2'R)-2'-deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- the product obtained in the step 3 is 4-(5-methyloxazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'.
- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- step 2 The product obtained in step 2 is N-methyl-4-hydroxyindole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxy-2'.
- the desired compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -fluoro-2'-methyluridine as a starting material.
- step 3 The product obtained in step 3 is 4-(oxazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxy-2
- the target compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using '-fluoro-2'-methyluridine as a starting material.
- Step 2 (2S)-2-((4-(5-Fluorothiazol-4-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo) -3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl preparation
- step 1 The product obtained in step 1 is 4-(5-fluoro-thiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- step 1 2-fluoro-4-(thiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- step 1 The product obtained in step 1 is 4-(thien-2-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxy-2'.
- the desired compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -fluoro-2'-methyluridine as a starting material.
- the product obtained in the first step is 3-fluoro-4-(thiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- Step 2 (2S)-2-(((3-Methyl-4-(thiazol-4-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2,4-di) Oxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propanoic acid isopropyl ester
- step 1 3-methyl-4-(thiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2' Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- Step 2 (2S)-2-(((3-Methyl-4-(1-methyl-1H-imidazol-4-yl)phenyloxy)(((2R,3R,4R,5R)-5) -(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl Amino) isopropyl propionate
- the product obtained in the first step is 3-methyl-4-(1-methyl-1H-imidazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and 2'R)-2'-deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- Step 2 (2S)-2-(((4-(3-chloropyridin-2-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo) -3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl preparation
- the product obtained in the first step is 3-chloro-2-(4-hydroxyphenyl)pyridine, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- Step 2 (2S)-2-(((4-(5-chloropyridin-2-yl)phenyloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo) -3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl preparation
- the product obtained in step 1 is 4-(5-chloropyridin-2-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxygenation.
- the target compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -2'-fluoro-2'-methyluridine as a starting material.
- Step 2 (2S)-2-((4-(5-Chloropyridin-2-yl)-3-methylphenyloxy)(((2R,3R,4R,5R)-5-(2, 4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propyl Isopropyl acrylate
- Step 2 (2S)-2-((4-(3-Fluoropyridin-2-yl)-3-methylphenyloxy)(((2R,3R,4R,5R)-5-(2, 4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propyl Isopropyl acrylate
- step 4 The product obtained in step 4 is 4-(5-chlorooxazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- the product obtained in the first step is 3-fluoro-4-(1-methyl-1H-imidazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2)
- the target compound was obtained by the same procedure as in the steps 2 and 3 of Example 1, using 'R)-2'-deoxy-2'-fluoro-2'-methyluridine as a starting material.
- step 1 The product obtained in step 1 is 4-(2-methylthiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-2'- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- step 1 The product obtained in step 1 is 4-(5-chloro-2-methylthiazol-4-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R).
- the target compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -2'-deoxy-2'-fluoro-2'-methyluridine as a starting material.
- the product obtained in the first step of Example 40 was 4-(5-chloro-2-methylthiazol-4-yl)phenol, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2' R)-2'-deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- the product obtained in the second step of Example 18 was 4-(5-chlorothiazol-4-yl)phenol, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2'R)-2'.
- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- the product obtained in the first step of Example 2 was 4-(3-fluoropyridin-2-yl)phenol, phosphorus oxychloride, L-alanine ethyl ester hydrochloride, pentafluorophenol and (2'R)-2'.
- Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- the product obtained in step 1 is 4-(3-methylthiophen-2-yl)phenol, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxygenation.
- the target compound was obtained by the same procedure as in Steps 2 and 3 of Example 1, using -2'-fluoro-2'-methyluridine as a starting material.
- Step 1 of Example 49 The product obtained in Step 1 of Example 49 was 4-(3-methylthiophen-2-yl)phenol, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)- Using 2'-deoxy-2'-fluoro-2'-methyluridine as a starting material, the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- step 1 The product obtained in step 1 is 4-(5-methylthien-2-yl)phenol, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxygenation.
- the target compound was obtained by the same procedure as in Example 1 using -2'-fluoro-2'-methyluridine as a starting material.
- the product obtained in the step 1 of Example 51 was 4-(5-methylthien-2-yl)phenol, phosphorus oxychloride, isopropyl ester of L-alanine, pentafluorophenol and (2'R)- Using 2'-deoxy-2'-fluoro-2'-methyluridine as a starting material, the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- Step 51 of Example 51 The product obtained in Step 51 of Example 51 was 4-(5-methylthien-2-yl)phenol, phosphorus oxychloride, L-alanine ethyl ester hydrochloride, pentafluorophenol and (2'R)-2.
- the target compound was obtained by the same procedure as in the steps 2 and 3 of Example 1 using '-deoxy-2'-fluoro-2'-methyluridine as a starting material.
- the product obtained in the first step of Example 26 is 4-(thien-2-yl)phenol, phosphorus oxychloride, L-alanine methyl ester hydrochloride, pentafluorophenol and (2'R)-2'-deoxy- Using 2'-fluoro-2'-methyluridine as a starting material, the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- the product obtained in the first step of Example 26 is 4-(thien-2-yl)phenol, phosphorus oxychloride, and L-alanine neopentyl ester.
- the hydrochloride salt, pentafluorophenol and (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine were used as starting materials, and the same procedure as in the steps 2 and 3 of Example 1 was carried out to obtain the target compound.
- the Huh7 1b cell line was provided by Shanghai WuXi PharmaTech Development Co., Ltd. as a Huh7 cell line containing the HCV 1b replicon with a stable luciferase (Luc) reporter. It cloned the HCV non-structural protein gene, neo (G418 resistance) and luciferase reporter gene into pBR vector by gene recombination technology. The vector carrying the HCV replicon was then transfected into huh7 cells, and by G418 resistance screening, the HCV replicon was stably replicated and the related protein and luciferase were stably expressed in huh7 cells. This cell model is used for in vitro screening of anti-HCV compounds.
- the anti-HCV activity of the compounds was determined by examining the level of chemiluminescence of the luciferase luminescent substrate. See Lohmann V, et al. 1999. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science. 285 (5424): 110-113.
- each compound was formulated into a mother liquor in DMSO, and then diluted to a total concentration of 10 ⁇ M in DMEM containing 0.5% DMSO as a compound, and diluted 3 times, total 10 For each concentration, the compounds were separately added to the 96-well plate using a POD 810 fully automated microplate pretreatment system (LabCyte, USA); an ineffective control group (complete culture medium containing 0.5% DMSO instead of the compound) and 100 were set up. % effective control group (only complete culture medium containing 0.5% DMSO);
- Bright-Glo assay 100 ⁇ l of luciferase luminescent substrate Bright-Glo was added to each well, and the fluorescence signal value was measured within 5 minutes using a chemiluminescence detection system EnVision (PerkinElmer, USA), and the obtained data was used for compound viability calculation.
- CPD Fluorescence signal value of compound pore
- CPD chemiluminescence signal value of compound pore
- the experimental results show that the compound of the present invention has an EC 50 of between about 0.05 ⁇ M and 1 ⁇ M and has a very good ability to inhibit HCV virus. Some data are shown in Table 2.
- Example 20 0.0783 Example 21 0.173 Example 22 0.104 Example 23 0.265 Example 24 0.055 Example 25 0.204 Example 26 0.019 Example 27 0.169 Example 28 0.142 Example 31 0.103 Example 32 0.174 Example 33 0.130 Example 34 0.196 Example 35 0.051 Example 36 0.146 Example 42 0.065 Example 46 0.055 Example 49 0.049 Example 50 0.063 Example 51 0.018 Example 52 0.021 Example 53 0.097 Example 54 0.020 Example 55 0.032 Example 56 0.028 Example 57 0.030
- the current best anti-HCV drug sofosbuvir has an EC 50 value of 0.102 ⁇ M for gene type 1b in the HCV replicon assay, see http://www.gilead. Com/ ⁇ /media/Files/pdfs/medicines/liver-disease /sova ldi/sovaldi_pi.pdf .
- the compounds of the invention have anti-HCV viral activity comparable to or superior to sofosbuvir.
- the compound of the present invention prepared in the above examples was used, and a 10 mM mother liquid was prepared in DMSO, and then diluted to 1000 nM in a DMEM complete medium containing 0.5% DMSO, and then diluted 3 times in total for a total of 8 concentrations.
- Huh 7.5.1 cells provided by Shanghai WuXi PharmaTech Development Co., Ltd.
- the J399EM (HCV genotype 2a) virus a full-length HCV mutant transfected with EGFP (enhanced green fluorescent protein), has the same infectious ability as the JFH-1 wild type, and passes through the NS5A region. Inserting the EGFP coding sequence into the domain, the fluorescence of the NS5A-EGFP fusion protein can be directly observed in infected cells, and provided by Shanghai WuXi PharmaTech Development Co., Ltd.
- Huh 7.5.1 Cell preparation Huh 7.5.1 cells in log phase were collected, resuspended in DMEM complete medium, seeded in 96-well plates (7 ⁇ 10 3 cells / well), placed at 37 ° C Incubate overnight in a 5% CO 2 incubator;
- Drug treatment The compounds of the present invention were separately added to a 96-well plate, and the compounds were always at a concentration of 1000 nM, and each compound was double-replicated, 3 times diluted, a total of 8 concentrations, and a final concentration of DMSO of 0.5%; Ineffective control group (complete culture medium containing 0.5% DMSO instead of compound) and 100% effective control group (added to virus-free cells);
- Viral infection J399EM virus supernatant was added to a 96-well plate at a concentration of 0.2 MOI per well. It was then placed in a 37 ° C, 5% CO 2 incubator for 3 days.
- Inhibition% (RLU s -RLU c )/(RLU V -RLU c ) ⁇ 100
- RLU V indicates the chemiluminescence intensity of the virus control group (complete culture medium containing 0.5% DMSO instead of compound)
- RLU S indicates the chemiluminescence intensity of the corresponding compound treatment group
- RLU C indicates the cell control group (cells without virus infection) Chemiluminescence intensity
- Cytotoxicity assay The cell and compound treatment methods were the same as above, but the medium was replaced with the virus and added to the experimental plate. After culturing for 3 days at 37 ° C in a 5% CO 2 incubator, the cell viability assay reagent Alamar Blue was added, and the Fluorescence signal value was detected by a spectrophotometer. The data obtained were used for the calculation of compound cytotoxicity with the formula:
- Viability% RFU S /RFU M ⁇ 100
- RFU M represents the fluorescence intensity of the vehicle control group (complete culture medium containing 0.5% DMSO instead of the compound), and RFU S represents the fluorescence intensity of the corresponding compound treatment group;
- EC 50 values for the compounds of the present invention is substantially between 40nM-150nM, CC 50 were greater than 1000nM, e.g. EC compound of Example 20 50 53.4nM, CC 50> 1000nM.
- EC 50 values of the compounds of this invention is smaller, e.g. EC 50 Example 26 is 9.3nM, CC 50> 1000nM. From this, it can be seen that the compound of the present invention has excellent antiviral activity, has small cytotoxicity, and is safe.
- the inventors of the present invention have found that the compound of the present invention has a good plasma protein binding rate and is suitable for medicine, and has a very good clinical application prospect. While the invention has been described hereinabove, it will be understood by those skilled in the art that various modifications and changes of the invention may be made without departing from the spirit and scope of the invention. The scope of the invention is not limited to the details described above, but rather to the claims.
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Abstract
La présente invention concerne le domaine de la chimie médicale, et plus particulièrement un composé présentant un bon effet d'inhibition du virus de l'hépatite C, un procédé de préparation associé, une composition contenant le composé, et une utilisation du composé ou de la composition comme médicament pour le traitement d'infections causées par le virus de l'hépatite C. Le composé de la présente invention fait preuve d'une excellente activité antivirale et en même temps d'une faible cytotoxicité et d'une innocuité et d'un taux de liaison aux protéines plasmatiques élevés, convient à la fabrication de médicaments et offre de grandes perspectives d'application clinique.
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US20210155890A1 (en) * | 2018-04-13 | 2021-05-27 | National University Corporation Kumamoto University | Incubator device, cell culture environment control system, and cell culture environment control method |
CN113861223A (zh) * | 2021-09-07 | 2021-12-31 | 暨南大学 | 一种噻唑并[3,2-a]苯并咪唑类化合物的合成方法及其应用 |
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CN106554382B (zh) * | 2015-09-29 | 2019-12-03 | 四川科伦博泰生物医药股份有限公司 | 核苷磷酰胺类化合物及其制备方法和药物中的应用 |
EP3515923A1 (fr) * | 2016-09-23 | 2019-07-31 | Katholieke Universiteit Leuven | Promédicaments de phosphonates de nucléosides acycliques fluorés |
CN108602842B (zh) * | 2016-11-02 | 2020-10-09 | 四川科伦博泰生物医药股份有限公司 | 杂环化合物及其制备方法和用途 |
CN111051326A (zh) * | 2017-10-23 | 2020-04-21 | 四川科伦博泰生物医药股份有限公司 | 核苷磷酸类化合物及其制备方法和用途 |
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