WO2015184753A1 - 抑制丙肝病毒的化合物、药物组合物及其应用 - Google Patents
抑制丙肝病毒的化合物、药物组合物及其应用 Download PDFInfo
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- WO2015184753A1 WO2015184753A1 PCT/CN2014/092902 CN2014092902W WO2015184753A1 WO 2015184753 A1 WO2015184753 A1 WO 2015184753A1 CN 2014092902 W CN2014092902 W CN 2014092902W WO 2015184753 A1 WO2015184753 A1 WO 2015184753A1
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- Prior art keywords
- group
- aryl
- heterocyclic
- compound
- alkyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 776
- 241000711549 Hepacivirus C Species 0.000 title claims abstract description 59
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 22
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- 108700008776 hepatitis C virus NS-5 Proteins 0.000 claims abstract description 15
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- 125000003118 aryl group Chemical group 0.000 claims description 237
- 125000000623 heterocyclic group Chemical group 0.000 claims description 124
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 99
- 229910052739 hydrogen Inorganic materials 0.000 claims description 85
- 239000001257 hydrogen Substances 0.000 claims description 85
- 125000000217 alkyl group Chemical group 0.000 claims description 70
- 150000002431 hydrogen Chemical class 0.000 claims description 61
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- 125000005842 heteroatom Chemical group 0.000 claims description 49
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 44
- -1 hydroxy, amino Chemical group 0.000 claims description 43
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 42
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 36
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- 125000003282 alkyl amino group Chemical group 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 29
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- 125000003277 amino group Chemical group 0.000 claims description 22
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 22
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 21
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 21
- 125000004104 aryloxy group Chemical group 0.000 claims description 21
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- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 18
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- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 17
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 17
- 125000004429 atom Chemical group 0.000 claims description 17
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
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- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 12
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 12
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 12
- 239000004593 Epoxy Substances 0.000 claims description 11
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- 125000006736 (C6-C20) aryl group Chemical group 0.000 claims description 10
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
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- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
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- 239000000126 substance Substances 0.000 claims description 6
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- 125000002877 alkyl aryl group Chemical group 0.000 claims description 5
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 4
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 claims description 4
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- 230000003362 replicative effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000004960 subcellular localization Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([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])[H] 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—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
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Definitions
- the present invention relates to compounds, pharmaceutical compositions and uses thereof for inhibiting hepatitis C virus.
- Hepatitis C virus is the major cause of most non-A, non-B hepatitis. Hepatitis C virus infection causes chronic liver diseases such as cirrhosis and liver cancer. Hepatitis C virus infection can be considered an urgent human health problem because the number of people infected with hepatitis C virus is estimated to be 3-5% of the world's population (see Lavanchy et al, J. Viral Hepatitis, 1999, 6). , 35-47; Alter et al, J. Hepatology 1999, 31, 88-91; Alberti et al, J. Hepatology 1999, 31, 17-24.).
- Hepatitis C virus is a flaviviridae positive single-stranded RNA virus that includes a nucleocapsid protein (C) and envelope proteins (E1 and E2), and some non-structural proteins (NS1, NS2, NS3). , NS4a, NS5a and NS5b).
- C nucleocapsid protein
- E1 and E2 envelope proteins
- NS4a non-structural proteins
- NS5a NS5b
- NS5A One class of compounds is effective in inhibiting HCV RNA replication by targeting NS5A.
- Biochemical studies have shown that NS5A molecular inhibitors bind directly to NS5A polypeptides. This is further evidenced by the resistant mutations in fragment I of the NS5A polypeptide chain.
- the NS5A protein is a multifunctional protein that expresses phosphorylated (p56) and hyperphosphorylated (p58) forms in exposed groups. Phosphorylation of NS5A has been implicated in various aspects of hepatitis C virus replication regulation. Although the exact mechanism of inhibition of these compounds is not clear, they have prevented the over-phosphorylation of NS5A.
- NS5A inhibitors disrupt hyperphosphorylation without affecting basal phosphorylation of the C-terminal region of NS5A. The activity of this inhibitor is independent of NS5A characteristic structural fragments II and III and is distinct from blocking NS5A hyperphosphorylated cytokinase inhibitors, and its activity is consistent with the inhibitor binding site in the N-terminal region of NS5A.
- NS5A inhibitors promoted the accumulation of intermediate polyproteins, suggesting that inhibitor-bound NS5A preferentially precedes polyprotein complexation.
- NS5A inhibitors may affect multiple aspects of the expression and regulation of hepatitis C virus.
- the technical problem to be solved by the present invention is to overcome the defects of the prior art which does not effectively inhibit the hepatitis C virus, and to provide a compound, a pharmaceutical composition and a medicament thereof which are completely different from the prior art for inhibiting hepatitis C virus.
- the compound of the present invention is effective for inhibiting hepatitis C virus NS5A, and is a medicament for preparing a disease for preventing and/or treating hepatitis C virus (HCV-NS5A) infection, and has a good market development prospect.
- the inventors of the present application have developed a large class of compounds, which are novel HCV-NS5A protein inhibitors, which can be used to effectively inhibit the hepatitis C virus protein NS5A and treat hepatitis C virus (HCV) infection.
- HCV hepatitis C virus
- the present invention enhances the inhibition of hepatitis C virus NS5A by introducing a different functional group substituent on a linear polypeptide-based structure and optimizing the structure of a novel linear polypeptide polycyclic compound.
- the biological activity provides more and better choices for further optimization and clinical application of linear polypeptide polycyclic compounds that effectively inhibit hepatitis C virus.
- the present invention provides a compound of formula Ia or Ib, a stereoisomer, tautomer, esterified or amidated prodrug, pharmaceutically acceptable salt thereof, or hydrogen contained therein, a compound in which an oxygen, nitrogen, or sulfur atom is replaced by its corresponding isotope atom,
- D and D 1 are each independently oxygen, sulfur, or Wherein, Ra is hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclic aryl, C 1 -C 20 alkoxycarbonyl , C 6 -C 20 aryloxycarbonyl, C 2 -C 20 heterocyclooxycarbonyl, C 1 -C 20 alkylaminocarbonyl, C 1 -C 20 cycloalkoxycarbonyl, C 1 -C 20 alkyl Sulfonyl, C 3 -C 20 cycloalkylsulfonyl, C 1 -C 20 alkylaminosulfonyl, C 2 -C 20 heterocyclic aminosulfonyl, or C 6 -C 20 arylaminosulfonyl; Rb and Rc Each independently is hydrogen, halogen, hydroxy, nitrile,
- D and D 1 are each independently nitrogen, CH or C(Rb); wherein Rb is defined and When it is a single bond, the definitions of Rb in D and D 1 are the same;
- Ar, Ar 1 , Ar 2 and Ar 3 are each independently a C 6 -C 20 aryl group, a C 2 -C 20 heterocyclic aryl group, a C 8 -C 20 fused ring aryl group, C 6 -C 20 a fused ring heterocyclic aryl group, or between Ar and Ar 1 or between Ar 1 and Ar 2 may be bonded as a C 10 -C 20 fused cycloalkylaryl group as indicated by a dotted line therebetween, or C fused ring 8 -C 20 aryl group; and if Ar 1 or Ar 2 does not exist, the group attached to Ar 1 or Ar 2 may be directly connected on both sides; Ar 3 is a C 6 -C 20 aryl, C 2 -C 20 heteroaryl Cycloaryl, C 8 -C 20 fused ring aryl;
- E and G are each independently nitrogen, CH or C(Rb); wherein Rb is defined and When it is a single bond, the definitions of Rb in D and D 1 are the same;
- K and K 1 are each independently a C 6 -C 20 aryl group, a C 2 -C 20 heterocyclic aryl group, a C 8 -C 20 fused ring aryl group, or a C 4 -C 20 fused ring heterocyclic aryl group; Including a heterocyclic aryl or non-aryl fused ring group containing 2-4 fused rings;
- L and L 1 are each independently oxygen, sulfur, Or L and / or L 1 each does not exist; wherein, the definition of Ra and When it is a single bond, the definitions of Ra in D and D 1 are the same;
- Q and Q 1 are each independently C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 3 -C 20 cycloalkyl, C 1 -C 20 alkylamino, C 3 -C 20 naphthenic a base amino group, a C 6 -C 20 aryl group, a C 3 -C 20 fused ring aryl group, a C 3 -C 20 heterocyclic aryl group or when L and/or L 1 are each absent, then L and L 1 are respectively linked Each of Q and Q 1 does not exist;
- W and W 1 are each independently a carbonyl group, a thiocarbonyl group C 1 -C 20 alkyl, C 6 -C 20 aryl or C 2 -C 20 heterocyclic aryl;
- W 2 and W 3 are each independently a carbonyl group, a thiocarbonyl group Sulfonyl C 1 -C 20 alkyl, C 2 -C 20 heterocyclic, C 6 -C 20 aryl, C 2 -C 20 heteroaryl;
- Y and Y 1 are each independently hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 6 -C 20 aryl, C 1 -C 20 alkylcarbonyl, C 6 -C 20 aryl Carbonyl group, C 1 -C 20 alkoxycarbonyl group, C 3 -C 20 cycloalkyloxycarbonyl group, C 1 -C 20 alkylaminocarbonyl group, C 6 -C 20 aryloxycarbonyl group, C 3 -C 20 Heterocyclic aryloxycarbonyl, C 6 -C 20 arylaminocarbonyl, C 1 -C 20 alkylsulfonyl, C 3 -C 20 cycloalkylsulfonyl, C 6 -C 20 arylsulfonyl, C 1 a -C 20 alkoxysulfonyl group, a C 3 -C 20 cycloalkoxysul
- Z and Z 1 are each independently hydrogen, hydroxy, amino, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 20 alkoxy, C 3 -C 20 cycloalkoxy, C 1 -C 20 alkylamino, C 3 -C 20 cycloalkylamino, C 2 -C 20 heterocyclyl, C 2 -C 20 heterocyclic amino, C 6 -C 20 aryl, C 6 -C 20 Aryloxy, C 6 -C 20 arylamino, C 3 -C 20 heterocyclic aryloxy, C 3 -C 20 heterocyclic arylamino, C 1 -C 20 alkylsulfonylamino, C 3 -C 20 ring Alkylsulfonylamino, C 6 -C 20 arylsulfonylamino, C 1 -C 20 alkoxysulfonylamino, C 3 -C 20 cycloal
- R 1 , R 2 , R 3 and R 4 are each independently hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 2 -C 20 heterocyclic, C 6 -C 20 aryl , C 2 -C 20 heterocyclic aryl, C 1 -C 20 alkoxycarbonyl, C 6 -C 20 aryloxycarbonyl, C 2 -C 20 heterocyclooxycarbonyl, C 1 -C 20 alkylamino a carbonyl group, a C 1 -C 20 alkylaminosulfonyl group, a C 2 -C 20 heterocyclic aminosulfonyl group, or a C 6 -C 20 arylaminosulfonyl group;
- R 5 , R 6 , R 7 and R 8 are each independently hydrogen, halogen, hydroxy, nitrile, amino, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 2 -C 20 heterocycle , C 1 -C 20 alkoxy, C 1 -C 20 alkylamino, C 2 -C 20 heterocyclic amino, C 6 -C 20 aryl, C 6 -C 20 arylamino, C 1 -C 20 alkoxycarbonylamino, C 1 -C 20 alkylaminocarbonylamino, C 1 -C 20 alkylsulfonylamino, C 2 -C 20 heterocyclosulfonylamino, C 6 -C 20 arylsulfonyl a C 1 -C 20 alkylaminosulfonylamino group; or, R 5 and R 6 may be bonded to each other to form a cyclic structure, and R 7 and R 8
- R 9 , R 10 , R 11 and R 12 are each independently hydrogen, halogen, hydroxy, nitrile, amino, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 20 alkoxy a C 1 -C 20 alkylamino group, a C 2 -C 20 heterocyclic amino group, a C 6 -C 20 aryl group, a C 6 -C 20 arylamino group, or a C 1 -C 20 alkoxycarbonylamino group; R 9 and R 10 may be connected to each other in a ring-shaped or spiro ring structure, and R 11 and R 12 may be connected to each other to form a ring or a spiro ring structure.
- a compound of the formula Ia or Ib as described in the present invention a stereoisomer, a tautomer, an esterified or amidated prodrug, a pharmaceutically acceptable salt, or a compound thereof a compound in which a hydrogen, oxygen, nitrogen, or sulfur atom is replaced by its corresponding isotope atom, preferably, in Formula Ia or Ib,
- D and D 1 are each independently oxygen, sulfur, or Wherein, Ra is hydrogen, C 1 -C 15 alkyl, C 3 -C 15 cycloalkyl, C 6 -C 15 aryl, C 2 -C 15 heteroaryl, C 1 -C 15 alkoxycarbonyl , C 6 -C 15 aryloxycarbonyl, C 2 -C 15 heterocyclooxycarbonyl, C 1 -C 15 alkylaminocarbonyl, C 1 -C 15 cycloalkoxycarbonyl, C 1 -C 15 alkyl Sulfonyl, C 3 -C 15 cycloalkylsulfonyl, C 1 -C 15 alkylaminosulfonyl, C 2 -C 15 heterocyclic aminosulfonyl, or C 6 -C 15 arylaminosulfonyl; Rb and Rc Each independently is hydrogen, halogen, hydroxy, nitrile, C 1 halogen, hydroxy,
- D and D 1 are each independently nitrogen, CH or C(Rb); wherein Rb has the same definition as Rb in the above D and D 1 ;
- ArAr 1 , Ar 2 and Ar 3 are each independently a C 6 -C 15 aryl group, a C 2 -C 15 heterocyclic aryl group, a C 8 -C 15 fused ring aryl group, a C 6 -C 15 thick group.
- a cycloheteroaryl group, or between Ar and Ar 1 or between Ar 1 and Ar 2 may be bonded as a C 10 -C 15 fused cycloalkylaryl group as indicated by a dotted line, or C 8 - a fused ring aryl group of C 15 ; if Ar 1 or Ar 2 is absent, the groups attached to both sides of Ar 1 or Ar 2 are directly connected;
- E and G are each independently N, CH or C (Rb); wherein Rb is defined the same as defined in the Rb D 1 and the D;
- K and K 1 are each independently a C 6 -C 15 aryl group, a C 2 -C 15 heterocyclic aryl group, a C 8 -C 15 fused ring aryl group, or a C 4 -C 15 fused ring heterocyclic aryl group; Including a heterocyclic aryl or non-aryl fused ring group containing 2-4 fused rings;
- L and L 1 are each independently oxygen, sulfur, Or L and/or L 1 are each absent; wherein Ra is the same as Ra in D and D 1 above;
- Q and Q 1 are each independently C 1 -C 15 alkyl, C 1 -C 15 alkoxy, C 3 -C 15 cycloalkyl, C 1 -C 15 alkylamino, C 3 -C 15 naphthenic a base amino group, a C 6 -C 15 aryl group, a C 3 -C 15 fused ring aryl group, a C 3 -C 15 heterocyclic aryl group, or when L and/or L 1 are each absent, then L and L 1 respectively The connected Q and Q 1 also do not exist;
- W and W 1 are each independently a carbonyl group, a thiocarbonyl group, a C 1 -C 15 alkyl group, a C 6 -C 15 aryl group, or a C 2 -C 15 heterocyclic aryl group;
- W 2 and W 3 are each independently a carbonyl group, a thiocarbonyl group, a sulfonyl group C 1 -C 15 alkyl, C 2 -C 15 heterocyclic, C 6 -C 15 aryl, C 2 -C 15 heteroaryl;
- Y and Y 1 are each independently hydrogen, C 1 -C 15 alkyl, C 3 -C 15 cycloalkyl, C 6 -C 15 aryl, C 1 -C 15 alkylcarbonyl, C 6 -C 15 aryl Carbonyl group, C 1 -C 15 alkoxycarbonyl group, C 3 -C 15 cycloalkyloxycarbonyl group, C 1 -C 15 alkylaminocarbonyl group, C 6 -C 15 aryloxycarbonyl group, C 3 -C 15 Heterocyclic aryloxycarbonyl, C 6 -C 15 arylaminocarbonyl, C 1 -C 15 alkylsulfonyl, C 3 -C 15 cycloalkylsulfonyl, C 6 -C 15 arylsulfonyl, C 1 a -C 15 alkoxysulfonyl group, a C 3 -C 15 cycloalkoxysul
- Z and Z 1 are each independently hydrogen, hydroxy, amino, C 1 -C 15 alkyl, C 3 -C 15 cycloalkyl, C 1 -C 15 alkoxy, C 3 -C 15 cycloalkoxy, C 1 -C 15 alkylamino group, C 3 -C 15 cycloalkylamino group, C 2 -C 15 heterocyclic group, C 2 -C 15 heterocyclic amino group, C 6 -C 15 aryl group, C 6 -C 15 Aryloxy, C 6 -C 15 arylamino, C 3 -C 15 heterocyclic aryloxy, C 3 -C 15 heterocyclic arylamino, C 1 -C 15 alkylsulfonylamino, C 3 -C 15 ring Alkylsulfonylamino, C 6 -C 15 arylsulfonylamino, C 1 -C 15 alkoxysulfonylamino, C 3 -C 15
- R 1 , R 2 , R 3 and R 4 are each independently hydrogen, C 1 -C 15 alkyl, C 3 -C 15 cycloalkyl, C 2 -C 15 heterocyclic, C 6 -C 15 aryl , C 2 -C 15 heterocyclic aryl, C 1 -C 15 alkoxycarbonyl, C 6 -C 15 aryloxycarbonyl, C 2 -C 15 heterocyclooxycarbonyl, C 1 -C 15 alkylamino a carbonyl group, a C 1 -C 15 alkylaminosulfonyl group, a C 2 -C 15 heterocyclic aminosulfonyl group, or a C 6 -C 15 arylaminosulfonyl group;
- R 5 , R 6 , R 7 and R 8 are each independently hydrogen, halogen, hydroxy, nitrile, amino, C 1 -C 15 alkyl, C 3 -C 15 cycloalkyl, C 2 -C 15 heterocycle , C 1 -C 15 alkoxy, C 1 -C 15 alkylamino, C 2 -C 15 heterocyclic amino, C 6 -C 15 aryl, C 6 -C 15 arylamino, C 1 -C 15 alkoxycarbonylamino, C 1 -C 15 alkylaminocarbonylamino, C 1 -C 15 alkylsulfonylamino, C 2 -C 15 heterocyclosulfonylamino, C 6 -C 15 arylsulfonylamino Or a C 1 -C 15 alkylaminosulfonamide group, or R 5 and R 6 may be bonded to each other to form a cyclic structure, and R 7 and R 8 may
- R 9 , R 10 , R 11 and R 12 are each independently hydrogen, halogen, hydroxy, nitrile, amino, C 1 -C 15 alkyl, C 3 -C 15 cycloalkyl, C 1 -C 15 alkoxy a C 1 -C 15 alkylamino group, a C 2 -C 15 heterocyclic amino group, a C 6 -C 15 aryl group, a C 6 -C 15 arylamino group, or a C 1 -C 15 alkoxycarbonylamino group; R 9 and R 10 may be connected to each other to form a ring or a spiro ring structure, and R 11 and R 12 may be connected to each other to form a ring or a spiro ring structure.
- a compound of the formula Ia or Ib as described in the present invention a stereoisomer, a tautomer, an esterified or amidated prodrug, a pharmaceutically acceptable salt, or a compound thereof a compound in which a hydrogen, oxygen, nitrogen, or sulfur atom is replaced by its corresponding isotope atom, further preferably, in Formula Ia or Ib,
- D and D 1 are each independently oxygen, sulfur, or Wherein, Ra is hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 12 aryl, C 2 -C 12 heteroaryl, C 1 -C 8 alkoxycarbonyl , C 6 -C 12 aryloxycarbonyl, C 2 -C 8 heterocyclooxycarbonyl, C 1 -C 8 alkylaminocarbonyl, C 1 -C 8 cycloalkoxycarbonyl, C 1 -C 8 alkyl Sulfonyl, C 3 -C 8 cycloalkylsulfonyl, C 1 -C 8 alkylaminosulfonyl, C 2 -C 8 heterocyclic aminosulfonyl, or C 6 -C 12 arylaminosulfonyl; Rb and Rc Each independently is hydrogen, halogen, hydroxy, nitrile, C 1 halogen, hydroxy,
- D and D 1 are each independently nitrogen, CH or C(Rb); wherein Rb has the same definition as Rb in said D and D 1 ;
- Ar, Ar 1 , Ar 2 and Ar 3 are each independently a C 6 -C 12 aryl group, a C 2 -C 12 heterocyclic aryl group, a C 8 -C 15 fused ring aryl group, C 6 -C 12
- the fused ring heterocyclic aryl group, or between Ar and Ar 1 or between Ar 1 and Ar 2 may be bonded as a C 10 -C 15 fused cycloalkylaryl group, or C, as indicated by a dotted line therebetween.
- a fused ring aryl group of 8 - C 15 if Ar 1 or Ar 2 is absent, the groups attached to both sides of Ar 1 or Ar 2 are directly connected;
- E and G are each independently N, CH or C (Rb); wherein Rb is defined the same as defined in the Rb D 1 and the D;
- K and K 1 are each independently a C 6 -C 12 aryl group, a C 2 -C 12 heterocyclic aryl group, a C 8 -C 12 fused ring aryl group, or a C 4 -C 12 fused ring heterocyclic aryl group; Including a heterocyclic aryl or non-aryl fused ring group containing 2-4 fused rings;
- L and L 1 are each independently oxygen, sulfur, Or L and/or L 1 are each absent; wherein the definition of Ra is the same as the definition of Ra in D and D 1 described above;
- Q and Q 1 are each independently C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 12 cycloalkyl, C 1 -C 8 alkylamino, C 3 -C 8 naphthenic a base amino group, a C 6 -C 12 aryl group, a C 3 -C 15 fused ring aryl group, a C 3 -C 12 heterocyclic aryl group, or when L and/or L 1 are each absent, then L and L 1 respectively The connected Q and Q 1 also do not exist;
- W and W 1 are each independently a carbonyl group, a thiocarbonyl group, a C 1 -C 8 alkyl group, a C 6 -C 12 aryl group, or a C 2 -C 12 heterocyclic aryl group;
- W 2 and W 3 are each independently a carbonyl group, a thiocarbonyl group, a sulfonyl group C 1 -C 8 alkyl, C 2 -C 8 heterocyclic, C 6 -C 12 aryl, C 2 -C 12 heteroaryl;
- Y and Y 1 are each independently hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 12 aryl, C 1 -C 8 alkylcarbonyl, C 6 -C 12 aryl Carbonyl group, C 1 -C 8 alkoxycarbonyl group, C 3 -C 8 cycloalkyloxycarbonyl group, C 1 -C 8 alkylaminocarbonyl group, C 6 -C 12 aryloxycarbonyl group, C 3 -C 12 Heterocyclic aryloxycarbonyl, C 6 -C 12 arylaminocarbonyl, C 1 -C 8 alkylsulfonyl, C 3 -C 8 cycloalkylsulfonyl, C 6 -C 12 arylsulfonyl, C 1 a -C 8 alkoxysulfonyl group, a C 3 -C 8 cycloalkoxysul
- Z and Z 1 are each independently hydrogen, hydroxy, amino, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkoxy, C 1 -C 8 alkylamino, C 3 -C 8 cycloalkylamino, C 2 -C 8 heterocyclic, C 2 -C 8 heterocyclic amino, C 6 -C 12 aryl, C 6 -C 12 Aryloxy, C 6 -C 12 arylamino, C 3 -C 12 heterocycloaryloxy, C 3 -C 12 heterocyclic arylamino, C 1 -C 8 alkylsulfonylamino, C 3 -C 8 ring Alkylsulfonylamino, C 6 -C 12 arylsulfonylamino, C 1 -C 8 alkoxysulfonylamino, C 3 -C 8 cycloalkoxy
- R 1 , R 2 , R 3 and R 4 are each independently hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocyclic, C 6 -C 12 aryl , C 2 -C 12 heterocyclic aryl, C 1 -C 8 alkoxycarbonyl, C 6 -C 12 aryloxycarbonyl, C 2 -C 8 heterocyclooxycarbonyl, C 1 -C 8 alkylamino a carbonyl group, a C 1 -C 8 alkylaminosulfonyl group, a C 2 -C 8 heterocyclic aminosulfonyl group, or a C 6 -C 12 arylaminosulfonyl group;
- R 5 , R 6 , R 7 and R 8 are each independently hydrogen, halogen, hydroxy, nitrile, amino, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycle , C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, C 2 -C 8 heterocyclic amino, C 6 -C 12 aryl, C 6 -C 12 arylamino, C 1 -C 8 alkoxycarbonylamino, C 1 -C 8 alkylaminocarbonylamino, C 1 -C 8 alkylsulfonylamino, C 2 -C 8 heterocyclic sulfonylamino, C 6 -C 12 arylsulfonyl Or a C 1 -C 8 alkylaminosulfonamide group, or R 5 and R 6 may be bonded to each other to form a cyclic structure, and R 7 and R 8 may be
- R 9 , R 10 , R 11 and R 12 are each independently hydrogen, halogen, hydroxy, nitrile, amino, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy a C 1 -C 8 alkylamino group, a C 2 -C 8 heterocyclic amino group, a C 6 -C 12 aryl group, a C 6 -C 12 arylamino group, or a C 1 -C 8 alkoxycarbonylamino group; R 9 and R 10 may be connected to each other to form a ring or a spiro ring structure, and R 11 and R 12 may be connected to each other to form a ring or a spiro ring structure.
- D and D 1 are each independently oxygen (O), or
- Ra is hydrogen, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 alkylsulfonyl, C 3 -C 5 cycloalkylsulfonyl
- Rb is hydrogen
- Rc is hydrogen, hydroxy, C 1 - C 6 alkoxy, C 6 -C 12 aryloxy, C 6 -C 12 heteroaryloxy, C 6 -C 12 fused ring aryloxy, C 6 -C 12 fused epoxy, or Rb and Rc is bonded to a C 2 -C 5 cycloalkyl group or a C 2 -C 5 cyclic ether group;
- D and D 1 are each independently CH;
- Ar is a C 6 -C 8 aryl group, a C 10 -C 15 fused ring aryl group;
- Ar 1 , Ar 2 and Ar 3 are each independently a C 6 -C 8 aryl group, a C 2 -C 8 heterocyclic aryl group, a C 8 -C 10 fused ring aryl group, a C 6 -C 10 fused ring heterocyclic ring.
- An aryl group, or between Ar and Ar 1 or between Ar 1 and Ar 2 may be bonded as a C 8 -C 12 fused ring aryl group as indicated by a dotted line; if Ar 1 or Ar 2 is not present, The groups connected to both sides of Ar 1 or Ar 2 are directly connected;
- K and K 1 are each independently a C 6 -C 8 aryl group, a C 2 -C 10 heterocyclic aryl group, a C 8 -C 12 fused ring aryl group, or a C 4 -C 12 fused ring heterocyclic aryl group; Including the following heterocyclic aryl or non-aryl fused ring groups containing 2-4 fused rings;
- L and L 1 are each independently oxygen, Or L and / or L 1 each does not exist;
- Q and Q 1 are each independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylamino, C 6 -C 12 aryl a group, a C 3 -C 12 fused ring aryl group, or when each of L and/or L 1 is absent, then each of Q and Q 1 to which L and L 1 are respectively attached is also absent;
- W and W 1 are each independently a carbonyl group
- W 2 and W 3 are each independently a carbonyl group, a thiocarbonyl group Sulfonyl C 1 -C 8 alkyl, C 2 -C 8 heterocyclic, C 6 -C 12 aryl, C 2 -C 12 heteroaryl;
- Y and Y 1 are each independently hydrogen, C 1 -C 6 alkylcarbonyl, C 6 -C 10 arylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 3 -C 6 cycloalkyloxycarbonyl, a C 1 -C 6 alkylaminocarbonyl group, a C 1 -C 6 alkylsulfonyl group, a C 3 -C 6 cycloalkylsulfonyl group, or a C 6 -C 10 arylsulfonyl group;
- Z and Z 1 are each independently C 1 -C 5 alkoxy, C 3 -C 5 cycloalkoxy, or C 1 -C 5 alkylamino;
- R 1 and R 2 are each independently hydrogen;
- R 3 and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 6 -C 8 aryl;
- R 5 and R 7 are each independently hydrogen or C 1 -C 6 alkyl
- R 6 and R 8 are each independently C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 8 aryl, or R 5 and R 6 are linked to each other to form a C 1 -C 6 cyclic structure, and R 7 and R 8 are bonded to each other to form a C 3 -C 6 cyclic structure;
- R 9 , R 10 , R 11 and R 12 are each independently hydrogen, or R 9 and R 10 are bonded to each other to form a C 1 -C 5 cyclic structure, and R 11 and R 12 are bonded to each other to form C 1 - C 5 cyclic structure;
- R 13 is hydrogen, halogen (such as fluorine, chlorine, bromine or iodine), C 1 -C 6 alkyl (such as methyl, ethyl, propyl, isopropyl or t-butyl) or C 1 -C 6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy or t-butoxy).
- the n is preferably 1 or 2; the m is preferably 1;
- the D or D 1 is preferably oxygen (O),
- Said L or L 1 is preferred Or does not exist;
- the Q or Q 1 is preferably a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a C 3 -C 6 cycloalkyl group or a substituted or unsubstituted C 3 -C 12 fused ring heterocyclic group.
- the "C 1 -C 6 alkyl group” is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group or a t-butyl group;
- the "C 1 -C 6 alkoxy group” is preferably a methoxy group or an ethoxy group.
- the "C 3 -C 6 cycloalkyl group” is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group;
- an unsubstituted C 3 -C 12 fused ring heterocyclic group preferably has a hetero atom of oxygen, sulfur or nitrogen, and a substituted or unsubstituted C 3 -C 12 fused ring aryl group having from 1 to 3 , further Preferred is quinoxalinyl, isoindolyl, or Said quinoxalinyl group
- the isoindolyl group is preferred
- the substituted isoindolyl group is preferably In the "substituted or unsubstituted C 3 -C 12 fused ring aryl group", the substitution is preferably a halogen (preferably fluor fluor fluoride, a fluoride, fluoride, or fluoride,
- the E is preferably nitrogen; G is preferably CH;
- R 3 or R 4 is preferably hydrogen
- the Ar, Ar 1 , Ar 2 or Ar 3 is preferably a substituted or unsubstituted C 6 -C 12 aryl group (preferably a substituted or unsubstituted phenyl group, or a substituted or unsubstituted biphenyl group; Unsubstituted phenyl preference Said unsubstituted biphenyl preferably , substituted or unsubstituted C 6 -C 15 fused ring aryl (preferably substituted or unsubstituted naphthyl, substituted or unsubstituted fluorenyl, substituted or unsubstituted phenanthryl, substituted or unsubstituted fluorenyl) Or a substituted or unsubstituted C 6 -C 12 fused ring aryl group having a hetero atom of oxygen, sulfur or nitrogen and having 1 to 3 hetero atoms; said unsubstituted naphthyl group being preferred
- the R 5 or R 6 is preferably hydrogen, C 1 -C 5 alkyl (preferably C 1 -C 3 alkyl, further preferably isopropyl or tert-butyl), C 6 -C 10 aryl (preferably phenyl) Or R 5 and R 6 form a C 3 -C 6 cycloalkyl group (preferably cyclopropyl, cyclopentyl or cyclohexyl) or a C 3 -C 6 heterocyclic group;
- the R 7 or R 8 is preferably hydrogen, C 1 -C 5 alkyl (preferably C 1 -C 3 alkyl, further preferably isopropyl or tert-butyl), C 6 -C 10 aryl (preferably phenyl) Or R 7 and R 8 form a C 3 -C 6 cycloalkyl group (preferably cyclopropyl, cyclopentyl or cyclohexyl) or a C 3 -C 6 heterocyclic group.
- the "halogen" is fluorine, chlorine or bromine.
- Ar, Ar 1 , Ar 2 or Ar 3 is a substituted or unsubstituted C 6 -C 12 aryl group
- the substituted or unsubstituted C 6 -C 12 aryl group is substituted or not a substituted phenyl group, or a substituted or unsubstituted biphenyl group;
- the substituted or unsubstituted C 6 -C 15 fused ring aryl group a substituted or unsubstituted naphthyl group, a substituted or unsubstituted fluorenyl group, a substituted or unsubstituted phenanthryl group, a substituted or unsubstituted fluorenyl group, or a hetero atom of oxygen, sulfur or nitrogen, having a hetero atom number of 1-3 Substituted or unsubstituted C 6 -C 12 fused ring aryl;
- Ar, Ar 1 , Ar 2 or Ar 3 is a substituted or unsubstituted C 6 -C 15 fused ring heterocyclic aryl group
- the substituted or unsubstituted C 6 -C 15 fused ring Heterocyclic aryl is substituted or unsubstituted benzimidazolyl group Or Benzo-oxazolyl
- the substituted C 6 -C 15 fused ring aryl group is a substituted or unsubstituted C 6 -C 12 fused ring aryl group having a hetero atom of oxygen, sulfur or nitrogen and having 1 to 3 hetero atoms.
- the C 1 -C 6 alkyl group is a methyl group, an ethyl group, a propyl group, an isopropyl group or a t-butyl group;
- the C 1 -C 6 alkoxy group is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group or a t-butyl group.
- the C 3 -C 6 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group;
- the "substituted or unsubstituted C 3 -C 12 fused ring heterocyclic group" is a hetero atom a substituted or unsubstituted C 3 -C 12 fused ring aryl group having from 1 to 3 oxygen atoms, sulfur or nitrogen;
- the substituted fluorenyl group is a fluorenyl group substituted by one or more of F, Cl and Br;
- the substituted or unsubstituted C 6 -C 12 fused ring heterocyclic aryl group Said "the hetero atom is oxygen, sulfur or nitrogen, and the unsubstituted C 6 -C 12 fused ring aryl group having 1-3 atoms" is Furanfuranyl, thienothiophenyl or benzimidazolyl
- the hetero atom is oxygen, sulfur or nitrogen, and the number of heteroatoms is 1-3.
- the C 6 -C 12 fused ring aryl group, wherein the "hetero atom is oxygen, sulfur or nitrogen, and the number of heteroatoms is 1-3, substituted or unsubstituted C 6 -C 12 fused ring aryl" is Furanfuranyl, thienothiophenyl or benzimidazolyl.
- the "hetero atom” is Oxygen, sulfur or nitrogen, substituted or unsubstituted C 3 -C 12 fused ring aryl having 1 to 3 hetero atoms is quinoxalinyl, isoindolyl, or
- n is preferably 1 or 2; the m is preferably 1; the D or D 1 is preferably oxygen (O) or CH 2 ; the L or L 1 is preferably absent; Q or Q 1 preferably does not exist.
- Said W, W 1 , W 2 or W 3 is preferred Said E is preferably nitrogen; G is preferably CH; said R 3 or R 4 is preferably hydrogen;
- the Ar, Ar 1 , Ar 2 or Ar 3 is preferably a substituted or unsubstituted C 6 -C 12 aryl group (preferably a substituted or unsubstituted phenyl group, or a substituted or unsubstituted biphenyl group; Unsubstituted phenyl preference Said unsubstituted biphenyl preferably ),
- a substituted or unsubstituted fused ring C 6 -C 15 aryl group (the substituent of said fused ring C 6 -C 15 aryl group is preferably substituted with F, Cl or Br C 6 -C 15 condensed ring
- the plurality of substituted C 6 -C 15 fused ring aryl groups
- the R 5 or R 6 is preferably hydrogen, C 1 -C 5 alkyl (preferably C 1 -C 3 alkyl, further preferably isopropyl or tert-butyl), C 6 -C 10 aryl (preferably substituted or Unsubstituted phenyl); or R 5 and R 6 form a C 3 -C 6 cycloalkyl group (preferably cyclopropyl, cyclopentyl or cyclohexyl) or a C 3 -C 6 aryl group (preferably phenyl) And R 5 and R 6 form a C 3 -C 6 heterocyclic group (preferably an alkylene oxide group); said R 7 or R 8 is preferably hydrogen, C 1 -C 5 alkyl (preferably C 1 -C 3 alkane) Further, isopropyl or t-butyl), C 6 -C 10 aryl (preferably substituted or unsubstituted phenyl); or R 7 and R 8 form a C 3 -C
- the invention also provides a prodrug, a stereoisomer, a tautomer, an isotopic, an esterified or amidated prodrug thereof, as described by formula Ia or Ib, and a pharmaceutically acceptable a mixture of one or more of the salts.
- the compound represented by the formula Ia or Ib, a stereoisomer, a tautomer, an esterified or amidated prodrug thereof and a pharmaceutically acceptable salt described in the present invention are further preferably as shown below. Any compound:
- the present invention not only designs and synthesizes heterocyclic compounds for inhibiting hepatitis C virus, but also further studies novel heterocyclic compounds with different structures and inhibition by inhibiting the activity of heterocyclic compounds against hepatitis C virus.
- novel heterocyclic compounds with different structures and inhibition by inhibiting the activity of heterocyclic compounds against hepatitis C virus.
- the compounds of the present invention such as those chemically synthesized or extracted from plants, can be obtained by a variety of methods well known in the art, using well-known starting materials. These methods are all included in the present invention.
- the key innovation of the present invention is to first select the compound SM1 containing a heterocyclic functional group in the following structural formula 1 and the SM2 containing a heterocyclic functional group in the structural formula 2, and synthesize the intermediate 3 (IIa) by amidation coupling or the like. Then, the protecting group (for example, PG and/or PG1) is separately obtained to obtain Intermediate 4 or 5, respectively, and a novel compound of the formula Ia is obtained by coupling or amidation reaction (see Structural Formula 3 for details).
- the protecting group for example, PG and/or PG1
- the present invention also provides a method for producing a compound represented by Formula Ia, a stereoisomer, a tautomer, an esterified or amidated prodrug thereof, and a pharmaceutically acceptable salt, which is Any of the following methods (specific synthesis methods and reaction conditions are detailed in the examples):
- the following examples are the compounds SM3 (SM-3a to SM-3cw) containing a heterocyclic functional group in the following structural formula series 1 and the heterocyclic functional group-containing compound SM4 (SM-4a to SM-4bw) in the structural formula 2,
- SM3 SM-3a to SM-3cw
- SM4 SM-4a to SM-4bw
- a series of novel compounds of formula Ia and Ib (6a-6ep and 6fa-6gq, synthesized in the catalytic coupling reaction (Scheme 3)) were synthesized by a combination of chemical preparation techniques (see the following structural formula 3 for details).
- the compound 6fa-6gq(Ib) was obtained by catalytic coupling reaction of the following compound SM3 with the compound SM4:
- the following examples are selected from the heterocyclic functional group-containing compound SM3 (SM-3a to SM-3cw) in the structural formula 1 and the heterocyclic functional group-containing compound SM4 (SM-4a to SM-4bw) in the structural formula 2, by catalysis.
- the coupling reaction (Scheme 3) synthesizes a novel compound of formula Ia-Ib 6a-6gq (see Structural Formula 3 for details).
- the structural series 1 and 2 are respectively the starting materials SM3 and SM4 required for the synthesis of the target compound Ia of the present invention, which have the following structural formula:
- the following structural formula series 2 is a specific example of the compound starting material SM4 (SM-4a to SM-4bw) which is a key structure synthesized by the present invention, and has the following structural formula:
- the invention also provides a compound of the formula Ia or Ib, a stereoisomer, tautomer, isotope, esterified or amidated prodrug thereof, pharmaceutically acceptable
- a salt in the preparation of a medicament for inhibiting HCV.
- the invention also provides a prodrug, a stereoisomer, a tautomer, an isotopic, an esterified or amidated prodrug thereof, as described by formula Ia or Ib, and a pharmaceutically acceptable
- a prodrug a stereoisomer, a tautomer, an isotopic, an esterified or amidated prodrug thereof, as described by formula Ia or Ib, and a pharmaceutically acceptable
- composition comprising: a compound of the formula Ia or Ib, a stereoisomer, tautomer, isomer, esterification or amidation thereof
- a pharmaceutically acceptable salt, a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient are also provided.
- the pharmaceutical composition of the present invention may further comprise: an immunomodulator, a hepatitis C virus HCV-NS3/4A inhibitor, a hepatitis C virus HCV-NS5B inhibitor, and a nucleoside belonging to a hepatitis C virus inhibitor. And one or more of a nucleoside derivative and a non-nucleoside, a hepatitis B virus (HBV) inhibitor, a human immunodeficiency virus (HIV) inhibitor, a cancer drug, and an anti-inflammatory drug.
- an immunomodulator a hepatitis C virus HCV-NS3/4A inhibitor, a hepatitis C virus HCV-NS5B inhibitor, and a nucleoside belonging to a hepatitis C virus inhibitor.
- a nucleoside derivative and a non-nucleoside a hepatitis B virus (HBV) inhibitor, a human immunodeficiency virus (HIV) inhibitor, a cancer drug, and an anti
- the immunomodulatory agent is preferably an interferon or an interferon derivative; wherein the interferon is preferably pegylated interferon;
- the HIV inhibitor comprises ritonavir and/or linba Ritonavir;
- said hepatitis B virus (HBV) inhibitor comprises lamivudine, telbivudine, adefovir dipivoxil (adefovir, Adefovir or Dipivoxil) , Emtricitabine, Entecavir, tenofovir (tenofovir, Tenofovir or Disoproxil) and Clevudine;
- the human immunodeficiency virus inhibitor is Lito Nawei and/or ribavirin;
- the hepatitis C virus protease inhibitors are preferably VX-950, ZN2007, ABT-450, RG-7227, TMC-435, MK-5172, MK-7009, ACH-1625 ,
- the pharmaceutically acceptable salt is present in a therapeutically effective amount, preferably from 0.01% to 99.9% by weight; the mass percentage refers to the compound of formula Ia, a compound of formula Ib, Stereoisomers, tautomers, esterified or amidated prodrugs and pharmaceutically acceptable salts are percentages of the total mass of the pharmaceutical composition.
- the invention also provides the use of the pharmaceutical composition described in the manufacture of a medicament for the inhibition of hepatitis C virus (HCV).
- HCV hepatitis C virus
- the "alkyl group” is not particularly specified, and means that it includes 1 to 20 carbon atoms. Branched and linear saturated aliphatic hydrocarbon groups, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl , isobutyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, ten a dialkyl group, and various isomers thereof, and the like; and the above alkyl group including any one of the following 1-4 substituents: an aryl group, a heterocyclic aryl group, a cycloalkyl group, a cycloalkenyl group, a cyclic ether group
- alkoxy group means a group formed by linking an alkyl group to an oxygen atom, unless otherwise specified.
- R is an alkyl group.
- the "aryl group” means any monocyclic or bicyclic ring which can be up to 7 atoms per ring, wherein at least one ring is an aromatic ring; when it is a bicyclic ring, unless otherwise specified This does not include the case where the two rings are fused, but includes the case of two ring snails.
- aryl such as phenyl or And the above aryl group comprising one or more substituents as defined in the following: aryl, heterocyclic aryl, cycloalkyl, cycloalkenyl, cycloether, heterocyclyl, alkoxycarbonyl, aryl Oxycarbonyl, heterocyclooxy, alkylamino, alkylaminocarbonyl, arylamino, heterocyclic amino, arylsulfonyl, alkylaminosulfonyl, heterocyclic aminosulfonyl, alkylsulfonylamino, heterocycle Sulfonamide, arylsulfonylamino, alkylaminosulfonylamino, alkylcarbonylamino, fused ring aryl, fused ring alkylaryl, fused cycloalkyl, fused epoxy, alkylureido, alkane Alkyl, alkylthio, alkyl
- heterocyclic aryl group means a stable monocyclic or bicyclic ring of up to 7 atoms per ring, wherein at least one ring is an aromatic ring and contains 1-4 selected, unless otherwise specified.
- heterocyclic aryl group containing one or more substituents as defined in the following: aryl, heterocyclic aryl, cycloalkyl, cycloalkenyl, ring Ether group, heterocyclic group, alkoxycarbonyl group, aryloxycarbonyl group, heterocyclic oxy group, alkylamino group, alkylaminocarbonyl group, arylamino group, heterocyclic amino group, arylsulfonyl group, alkylaminosulfonyl group, hetero Cycloaminosulfonyl, alkylsulfonylamino, heterocyclosulfonylamino, arylsulfonylamino, alkylaminosulfonylamino, alkylcarbonylamino, fused ring aryl, fused ring alkyl aryl, condensed naphthenic Base, fused epoxy, alkyl, heterocyclic aryl, cycloalkyl,
- Heterocyclic aryl groups within the scope of this definition include, but are not limited to, acridinyl, oxazolyl, porphyrin, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thiophene Benzothiazolyl, benzothienyl, benzofuranyl, quinolyl, isoquinolinyl, oxazolyl, Isoxazolyl, fluorenyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline.
- heterocyclic aryl is also understood to include any N-oxide derivative of a nitrogen-containing heterocyclic aryl group.
- heterocyclic aryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or does not contain a hetero atom, it is understood that the linkage is carried out by an aromatic ring or by a hetero atom comprising a ring, respectively.
- alkylthio group means a group formed by linking an alkyl group to a sulfur atom, unless otherwise specified.
- R is an alkyl group.
- aryloxy group means a group formed by linking an aryl group to an oxygen atom, unless otherwise specified, that is, R is an aryl group.
- arylamino group means an amino group in which one hydrogen in “NH 3 " is substituted with an aryl group, unless otherwise specified.
- the "cycloalkyl group” refers to an all-carbon monocyclic or polycyclic group, wherein each ring does not contain a double bond, unless otherwise specified.
- 3 to 20 carbon atoms are formed by 1 to 3 ring cycloalkyl groups, more preferably 3 to 10 carbons, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl a group, a cyclodecane and a cyclododecyl group;
- the cycloalkyl group may be substituted by any one of the following 1-4 substituents defined by the invention: anthracene, halogen, alkyl, alkoxy, hydroxy, aryl, aryl Oxyl, aralkyl, cycloalkyl, alkylamino, amido, oxo, acyl, arylcarbonyla
- cycloalkenyl group refers to an all-carbon monocyclic or polycyclic group, wherein each ring may contain one or more double bonds, but none of the rings have a complete conjugate, unless otherwise specified. ⁇ electronic system.
- cycloalkenyl groups formed by 3 to 20 carbons, more preferably 3 to 10 carbons, for example, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, cycloheptane Alkenyl, cyclooctenyl, cyclodecene and cyclododecenyl; cycloalkenyl may be substituted by any one or more of the substituents defined herein: hydrazine, halogen, alkyl, alkoxy , hydroxy, aryl, aryloxy, aralkyl, cycloalkyl, alkylamino, amido, oxo, carbonyl, arylcarbonylamino, amino, nitrile, fluorenyl, alkylthio and alkyl.
- a substituent of a cycloalkenyl group is substituted on a carbons, more preferably 3 to
- cycloether group means a cycloalkyl group having an ether group, unless otherwise specified.
- heterocyclic group is an aromatic or non-aromatic heterocyclic ring containing one or more selected from the group consisting of hetero atoms of O, N and S, and includes a bicyclic group, unless otherwise specified.
- heterocyclyl includes the above heterocyclic aryl as well as its dihydro or tetrahydro analog.
- heterocyclyl examples include, but are not limited to, the following: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, benzothienyl, benzoxazole Base, porphyrin group, furyl group, imidazolyl group, indanyl group, fluorenyl group, carbazolyl group, different Benzofuranyl, isoazaindole, isoquinolyl, isothiazolyl, isoxazolyl, oxazolyl, oxazoline, isoxazoline, oxocyclobutyl, pyranyl, pyrazinyl , pyrazolyl, pyridazinyl, pyridopyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinox
- the "fused ring aryl group” means a polycyclic organic compound formed by condensing two or more aryl groups and/or heterocyclic aryl groups, which are not particularly specified.
- the cycloaryl group may also be an alkyl group, an alkoxy group, an alkylthio group, an aryloxy group, an arylamino group, a heterocyclic group, a cycloalkyl group, a cycloalkenyl group, a cyclic ether group, an aryl group, a halogen, as defined in the present invention.
- a group such as a carbonyl group, a hydroxyl group or a heterocyclic aryl group is substituted in a reasonable manner.
- the "fused ring alkylaryl group” means a group formed by substituting a hydrogen on a carbon in the aryl group with a fused cycloalkyl group, unless otherwise specified.
- the "fused cycloalkyl group” means a non-aromatic polycyclic ring system formed by reduction of one or more double bonds in a fused ring aryl group, unless otherwise specified.
- the "fused epoxy group” means a group formed by linking a fused ring aryl group or a fused ring alkyl group to oxygen, unless otherwise specified, that is, R is a fused ring aryl group or a fused ring alkyl group.
- alkoxycarbonyl group means a group formed by linking an alkoxy group to a carbonyl group, unless otherwise specified.
- R is an alkyl group.
- aryloxycarbonyl group means a group formed by linking an aryloxy group to a carbonyl group, unless otherwise specified.
- R is an aryl group.
- heterocyclicoxy group means a forming group after the heterocyclic group is bonded to oxygen, unless otherwise specified.
- R is a heterocyclic group.
- alkylamino group means a group formed by linking an alkyl group and an amino group, unless otherwise specified, that is, R is an alkyl group.
- alkylaminocarbonyl group means a group formed by linking an alkylamino group to a carbonyl group, unless otherwise specified.
- R is an alkyl group.
- arylamino group means a group formed by linking an aryl group and an amino group, unless otherwise specified, that is, R is an aryl group.
- heterocyclic amino group means a generating group after linking a heterocyclic group to an amino group, unless otherwise specified.
- R is a heterocyclic group.
- arylaminosulfonyl group means a group formed by linking an arylamino group and a sulfonyl group, unless otherwise specified, that is, R is an aryl group.
- alkylaminosulfonyl group means a group formed by linking an alkylamino group and a sulfonyl group, unless otherwise specified.
- R is an alkyl group.
- heterocyclic aminosulfonyl group means a group formed by linking a heterocyclic amino group to a sulfonyl group, unless otherwise specified.
- R is a heterocyclic group.
- alkylsulfonylamino group means a group formed by linking an alkyl group and a sulfonamide group, unless otherwise specified.
- R is an alkyl group.
- heterocyclic sulfonylamino group means a forming group after the heterocyclic group is bonded to the sulfonamide group, unless otherwise specified.
- R is a heterocyclic group.
- arylsulfonylamino group means a group formed by linking an aryl group and a sulfonamide group, unless otherwise specified, that is, R is an aryl group.
- alkylaminosulfonylamino group means a group formed by linking an alkylamino group and a sulfonamide group, unless otherwise specified.
- R is an alkyl group.
- alkylcarbonylamino group means a group formed by linking an alkyl group to a carbonyl group and then to an amino group, unless otherwise specified.
- R is an alkyl group.
- alkylureido group means a group formed by linking an alkyl group to a ureido group and then to an amino group, unless otherwise specified.
- R is an alkyl group.
- alkylthioureido group means a group formed by linking an alkyl group to a thiourea group and then to an amino group, unless otherwise specified.
- R is an alkyl group.
- halogen means fluorine, chlorine, bromine, iodine or hydrazine.
- amino is used to mean
- the "ureido group" means
- the substituent of the "C x1 - y1 " having a carbon number range (x1 and y1 is an integer), an alkyl group such as “C x1 - y1 ", and an alkoxy group of "C x1 - y1 " are determined.
- the reagents and starting materials used in the present invention are commercially available.
- the positive effect of the present invention is characterized in progress: 1) First, the present invention introduces the following two designs containing substituent group "L, Q and / or L 1, Q 1" or novel heterocyclic double bond functional group: And the heterocyclic functional group of the formula Ib which does not contain "L, Q and L 1 , Q 1 ": Furthermore, a novel linear heterocyclic functional group-containing polypeptide compound capable of effectively inhibiting hepatitis C virus, particularly a novel heterocyclic functional group-containing compound which selectively inhibits hepatitis C virus NS5A, is synthesized.
- the compound of the present invention has an advantage of significantly inhibiting the activity of hepatitis C virus (NS5A), and the present invention further develops a structure for optimizing various novel heterocyclic linear compounds which effectively inhibit hepatitis C virus infection.
- the main use of the compound prepared by the present invention is to inhibit hepatitis C virus NS5A, and can also inhibit viruses such as HCV in combination with any other drug or drugs, and can provide more and better new products to the society in the field of new drug research and development. .
- the invention is further illustrated by the following examples, which are not intended to limit the invention.
- the experimental methods in the following examples which do not specify the specific conditions are selected according to conventional methods and conditions, or according to the product specifications, or by CRO companies such as Zannan Technology, according to WO2008/021927 A2, WO2010/132601 A1, and WO2011/075615 A1, etc.
- the reference materials were prepared to obtain the key intermediates SM1, SM2, SM3, and SM4 compounds of this project.
- the compounds of the invention may contain a tricyclic functional group and one or more heterocyclic asymmetric centers.
- the compounds can be in racemic and racemic mixtures, single enantiomers, tautomeric forms.
- the compound 6a-6ax(Ia) prepared by the invention is a chiral heterocyclic compound, and the optical purity of the natural amino acid and the unnatural amino acid in the product are determined by optical rotation or/and chiral column, respectively, and each final product (including Structural characterization of 6a-6gq and the following reference compounds Ref-1 (BMS790052), Ref-2 (GS5885), Ref-3, Ref-4 (DIX-719), etc. by LC-MS and hydrogen spectroscopy respectively ( 1 H-NMR analysis confirmed.
- Infrared spectral data is employed ⁇ Corporation (Thermo Nicolet) companies Fourier Transform AVATAR TM 360 ESP TM obtained infrared analysis instrument to be expressed in units of cm -1.
- Mass spectrometry data was analyzed by a liquid chromatography instrumentation of Finnigan LCQ Advantage, among other needs, and all reactions were operated under dry argon-protected anhydrous anaerobic conditions.
- the solid metal organic compound is stored in an argon-protected dry box.
- Tetrahydrofuran and diethyl ether are obtained by distillation, and sodium metal and benzophenone are added thereto during distillation.
- Dichloromethane (DCM), pentane and hexane were treated with calcium hydride.
- the special raw materials and intermediates in the present invention are provided by Zannan Technology Co., Ltd., and other chemical reagents from Shanghai Reagent Company, Aldrich, Acros and other reagents. Supplier purchase. If the intermediate or product required for the reaction in the synthesis is insufficient for the next step, the synthesis is repeated a plurality of times.
- HCV-NS5A prepared inhibitory activity of compounds of the invention (EC 50) and toxicity test (MTD) Experiments performed by CRO WuXi AppTec other service units.
- CDI N, N'-carbonyl diimidazole
- HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
- NBS N-bromosuccinimide
- HMTA hexamethylenetetramine
- PE petroleum ether
- the starting material SM-3a (0.11 g, 0.24 mmol) and SM-4i (0.168 g, 0.24 mmol, 1.0 eq.) were dissolved in 5 mL of DMF and potassium carbonate (0.1 g, 0.72 mmol, 3.0 eq.) was added with stirring. And water (3 mL), heated to 100 ° under nitrogen, then add tetrakis(triphenylphosphine palladium) (0.01 g) in one portion and stir at 100 ° until the reaction is complete. After the completion of the reaction, the reaction mixture was filtered. EtOAc was evaporated. %.
- the synthesis method of the compound 6g was carried out in the same manner as in Example 1, and a 6 g product was obtained by a one-step catalytic coupling reaction in which the compounds SM-3m (0.08 mmol) and SM-4m (0.08 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave 6 g (0.013 g) of product as a yellow solid, yield: 14%.
- the synthesis of the compound 6j was carried out in the same manner as in Example 1, and the product 6j was obtained by a one-step catalytic coupling reaction in which the compounds SM-3c (0.19 mmol) and SM-4p (0.19 mmol) were used instead of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6j (0.04 g), yield: 20%.
- the synthesis method of the compound 6s was carried out in the same manner as in Example 1, and the product 6s was obtained by a one-step catalytic coupling reaction in which the compounds SM-3a (0.17 mmol) and SM-4s (0.17 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6s (0.05 g), yield: 31%.
- the synthesis method of the compound 6aa was carried out in the same manner as in Example 1, and the product 6aa was obtained by a one-step catalytic coupling reaction in which the compounds SM-3z (0.54 mmol) and SM-4a (0.54 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6aa (0.142 g), yield: 34%.
- the synthesis method for preparing compound 6ac is the same as in Example 1, and the product 6ac is obtained by a one-step catalytic coupling reaction. Among them, the compounds SM-3aa (0.19 mmol) and SM-4n (0.19 mmol) were used in the reaction instead of the compounds SM-3a and SM-4i to give a yellow solid product 6ac (0.08 g), yield: 42%.
- the synthesis method of the compound 6ag was carried out in the same manner as in Example 1, and the product 6ag was obtained by a one-step catalytic coupling reaction in which the compounds SM-3ab (0.24 mmol) and SM-4a (0.24 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6ag (0.15 g), yield: 65%.
- the synthesis method of the compound 6ah was carried out in the same manner as in Example 1, and the product 6ah was obtained by a one-step catalytic coupling reaction in which the compounds SM-3ab (0.24 mmol) and SM-4n (0.24 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6ah (0.033 g), yield: 14.2%.
- the synthesis method of the compound 6ai was carried out in the same manner as in Example 1, and the product 6ai was obtained by a one-step catalytic coupling reaction in which the compounds SM-3ab (0.03 mmol) and SM-4i (0.03 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6ai (0.075 g), yield: 25%.
- the synthesis method of the compound 6an was carried out in the same manner as in Example 1, and the product 6an was obtained by a one-step catalytic coupling reaction in which the compound SM-3ae (0.2 mmol) and SM-4i (0.2 mmol) were used in place of the compound SM-3a. And SM-4i gave a yellow solid product 6an (yield: 52%).
- the synthesis method of the compound 6ap was carried out in the same manner as in Example 1, and the product 6ap was obtained by a one-step catalytic coupling reaction in which the compounds SM-3ae (0.2 mmol) and SM-4ac (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6 ap (yield: 53%).
- the synthesis method of the compound 6aq was carried out in the same manner as in Example 1, and the product 6aq was obtained by a one-step catalytic coupling reaction in which the compounds SM-3af (0.2 mmol) and SM-4a (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6aq (yield: 53%).
- the synthesis method of the compound 6as was carried out in the same manner as in Example 1, and the product 6as was obtained by a one-step catalytic coupling reaction in which the compounds SM-3ah (0.2 mmol) and SM-4a (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave the yellow solid product 6as (yield: 54%).
- the synthesis method of the compound 6ax was carried out in the same manner as in Example 1, and the product 6ax was obtained by a one-step catalytic coupling reaction in which the compounds SM-3an (0.2 mmol) and SM-4a (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6ax (yield: 54%).
- the synthesis method of the compound 6ay was carried out in the same manner as in Example 1, and the product 6ay was obtained by a one-step catalytic coupling reaction in which the compounds SM-3ac (0.2 mmol) and SM-4ag (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6ay (yield: 53%).
- the synthesis of the compound 6bg was carried out in the same manner as in Example 1, and the product 6bg was obtained by a one-step catalytic coupling reaction in which the compounds SM-3g (0.11 mmol) and SM-4h (0.11 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave 6bg (0.014 g) as a yellow solid product, yield: 15%.
- the synthesis method of the compound 6bn was carried out in the same manner as in Example 1, and the product 6bn was obtained by a one-step catalytic coupling reaction in which the compounds SM-3n (0.2 mmol) and SM-4af (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6bn (yield: 61%).
- the synthesis method of the compound 6 bp was carried out in the same manner as in Example 1, and a product of 6 bp was obtained by a one-step catalytic coupling reaction in which the compounds SM-3ap (0.2 mmol) and SM-4n (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6 bp (yield: 56%).
- the synthesis of the compound 6bu was carried out in the same manner as in Example 1, and the product 6bu was obtained by a one-step catalytic coupling reaction in which the compounds SM-3at (0.2 mmol) and SM-4ad (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6bu (yield: 56%).
- the synthesis method of the compound 6by was carried out in the same manner as in Example 1, and the product 6by was obtained by a one-step catalytic coupling reaction in which the compound SM-3b (0.2 mmol) and SM-4ag (0.2 mmol) were used in place of the compound SM-3a. And SM-4i gave a yellow solid product 6by (yield: 56%).
- the synthesis method of the compound 6cc was carried out in the same manner as in Example 1, and a 6 cc product was obtained by a one-step catalytic coupling reaction in which the compounds SM-3av (0.2 mmol) and SM-4ah (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6 cc (yield: 58%).
- the synthesis method of the compound 6cg was carried out in the same manner as in Example 1, and the product 6cg was obtained by a one-step catalytic coupling reaction in which the compounds SM-3bg (0.2 mmol) and SM-4ak (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave 6 cg of a yellow solid product (yield: 52%).
- the synthesis method of the compound 6ch was carried out in the same manner as in Example 1, and the product 6ch was obtained by a one-step catalytic coupling reaction in which the compound SM-3bi (0.2 mmol) and SM-4am (0.2 mmol) were used instead of the compound in the reaction.
- SM-3a and SM-4i gave a yellow solid product (yield: 53%).
- the synthesis method of the compound 6 cm was carried out in the same manner as in Example 1, and a product of 6 cm was obtained by a one-step catalytic coupling reaction in which the compounds SM-3a (0.2 mmol) and SM-4an (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product (yield: 6 ⁇ RTIgt;
- the synthesis method of the compound 6cv was similar to that of Example 1, and the product was obtained by a one-step catalytic coupling reaction, followed by Boc removal, and after neutralization, 6cv was obtained, wherein the compound SM-3b (0.2 mmol) and SM-4av (0.2 mmol) were used in the reaction. Replacing the compounds SM-3a and SM-4i gave the product as a yellow solid Boc (110 mg), which was taken in 10 mL of 3N HCl/Et 2 O, and the mixture was neutralized to basic at room temperature, and purified by preparative TLC to give a yellow solid 6c. ), the above two-step reaction yield: 32%.
- the synthesis method of the compound 6da is the same as in the first embodiment, and the product 6da is obtained by a one-step catalytic coupling reaction.
- the compounds SM-3bk (0.2 mmol) and SM-4b (0.2 mmol) were used in the reaction instead of the compounds SM-3a and SM-4i to obtain a yellow solid product 6da, yield: 32%.
- the synthesis method of the compound 6db was carried out in the same manner as in Example 1, and the product 6db was obtained by a one-step catalytic coupling reaction in which the compounds SM-3bm (0.2 mmol) and SM-4b (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6db, yield: 22%.
- the synthesis method of the compound 6dd was carried out in the same manner as in Example 1, and the product 6dd was obtained by a one-step catalytic coupling reaction in which the compounds SM-3bp (0.2 mmol) and SM-4b (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6dd (20 mg), yield: 28%.
- the synthesis of the compound 6de was carried out in the same manner as in Example 1, and the product 6de was obtained by a one-step catalytic coupling reaction in which the compounds SM-3bf (0.2 mmol) and SM-4a (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6de, yield: 35%.
- the synthesis method of the compound 6dg was carried out in the same manner as in Example 1, and a 6dg product was obtained by a one-step catalytic coupling reaction in which a compound SM-3b (0.2 mmol) and SM-4ax (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6dg, yield: 36%.
- the synthesis method of the compound 6dj was carried out in the same manner as in Example 1, and the product 6dj was obtained by a one-step catalytic coupling reaction in which the compounds SM-3bs (0.2 mmol) and SM-4a (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6dj, yield: 46%.
- the synthesis of the compound 6dk was carried out in the same manner as in Example 1, and the product 6dk was obtained by a one-step catalytic coupling reaction in which the compounds SM-3br (0.2 mmol) and SM-4ay (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6dk, yield: 36%.
- the synthesis method of the compound 6dn was carried out in the same manner as in Example 1, and the product 6dn was obtained by a one-step catalytic coupling reaction in which the compounds SM-3bq (0.2 mmol) and SM-4ay (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6dn, yield: 30%.
- the synthesis method of the compound 6dr was carried out in the same manner as in Example 1, and the product 6dr was obtained by a one-step catalytic coupling reaction in which the compounds SM-3bu (0.2 mmol) and SM-4b (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6d, yield: 33%.
- the synthesis method of the compound 6ee was carried out in the same manner as in Example 1, and the product 6ee was obtained by a one-step catalytic coupling reaction in which the compounds SM-3at (0.2 mmol) and SM-4ad (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6ee (yield: 52%).
- the synthesis method of the compound 6fa was carried out in the same manner as in Example 1, and the product 6fa was obtained by a one-step catalytic coupling reaction in which the compounds SM-3cb (0.2 mmol) and SM-4b (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6fa (69 mg), yield: 43%.
- the synthesis method of the compound 6fe was carried out in the same manner as in Example 1, and the product 6fe was obtained by a one-step catalytic coupling reaction in which the compounds SM-3cn (0.2 mmol) and SM-4bf (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6fe (53 mg), yield: 35%.
- the synthesis method of the compound 6fg was carried out in the same manner as in Example 1, and the product 6fg was obtained by a one-step catalytic coupling reaction in which the compounds SM-3cp (0.2 mmol) and SM-4a (0.2 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave 6fg (81 mg) as a yellow solid product, yield: 48%.
- the synthesis method of the compound 6ft was carried out in the same manner as in Example 1, and the product was subjected to a catalytic coupling reaction to obtain 6 ft of a product in which the compounds SM-3ch (0.2 mmol) and SM-4ag (0.2 mmol) were used in place of the compounds SM-3a and SM-. 4i gave a yellow solid product 6 ft (82 mg), yield: 48%.
- the synthesis of the compound 6gb was carried out in the same manner as in Example 1, and the product 6gb was obtained by a one-step catalytic coupling reaction in which the compounds SM-3ct (0.44 mmol) and SM-4ag (0.44 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave 6 gb (180 mg) as a yellow solid.
- the synthesis method of the compound 6gd was carried out in the same manner as in Example 1, and the product 6gd was obtained by a one-step catalytic coupling reaction in which the compounds SM-3cu (0.44 mmol) and SM-4b (0.44 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave 6 gd (100 mg) as a yellow solid product, yield: 26%.
- the synthesis method of the compound 6gf was carried out in the same manner as in Example 1, and the product 6gf was obtained by a one-step catalytic coupling reaction in which the compounds SM-3cv (0.39 mmol) and SM-4bf (0.39 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave 6 gf (50 mg) as a yellow solid. Yield: 14%.
- the synthesis of the compound 6gg was carried out in the same manner as in Example 1, and the product 6gg was obtained by a one-step catalytic coupling reaction in which the compounds SM-3cm (0.39 mmol) and SM-4bg (0.39 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6 gg (31 mg), yield: 16%.
- the synthesis method of the compound 6gh was carried out in the same manner as in Example 1, and the product 6gh was obtained by a one-step catalytic coupling reaction in which the compounds SM-3cn (0.86 mmol) and SM-4bg (0.86 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6 gh (190 mg), yield: 29%
- the synthesis method of the compound 6gm was carried out in the same manner as in Example 1, and a product of 6 gm was obtained by a one-step catalytic coupling reaction in which the compounds SM-3ca (0.33 mmol) and SM-4bt (0.33 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6gm (50mg), yield: 20%
- the synthesis method of the compound 6gp was carried out in the same manner as in Example 1, and the product 6gp was obtained by a one-step catalytic coupling reaction in which the compounds SM-3cw (0.25 mmol) and SM-4bt (0.25 mmol) were used in place of the compounds SM-3a and SM- in the reaction. 4i gave a yellow solid product 6gp (32mg), yield: 13%
- the synthesis method of the compound Ref-3 was carried out in the same manner as in Example 1, and the product Ref-3 was obtained by a one-step catalytic coupling reaction in which the compound SM-3cm (0.2 mmol) and SM-4ag (0.2 mmol) were used in place of the compound SM- in the reaction. 3a and SM-4i gave the yellow solid product Ref-3 (69 mg), yield: 40%.
- HCV has a very low level of autonomous replication in normal hepatocytes in vitro, and its only infective animal is a chimpanzee, there is currently no suitable animal model for preclinical efficacy studies of anti-hepatitis C virus drugs.
- HCV human liver tissue was transplanted into immunodeficient mice to establish a mouse model in vivo, but the breeding of this mouse is technically difficult, the model is unstable, and lacks a normal immune response, and hepatitis C The pathogenesis of the disease is too different, so it has not been used to evaluate animal models of hepatitis B efficacy studies.
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Abstract
Description
Claims (16)
- 一种如式Ia或Ib所示的化合物,其立体异构体、互变异构体、酯化或酰胺化的前体药物、药学上可接受的盐,或其中所含的氢、氧、氮、或硫原子被其相应同位素原子取代的化合物,其中,n=1,2或3;m=1,2或3;为单键时,D和D1各自独立地为氧、硫、 其中,Ra为氢、C1-C20烷基、C3-C20环烷基、C6-C20芳基、C2-C20杂环芳基、C1-C20烷氧基羰基、C6-C20芳氧基羰基、C2-C20杂环氧基羰基、C1-C20烷基氨基羰基、C1-C20环烷氧基羰基、C1-C20烷基磺酰基、C3-C20环烷基磺酰基、C1-C20烷基氨基磺酰基、C2-C20杂环氨基磺酰基、或C6-C20芳氨基磺酰基;Rb和Rc各自独立地为氢、卤素、羟基、腈基、C1-C20烷基、C3-C20环烷基、C2-C20杂环基、C6-C20芳基、C1-C20烷氧基、C1-C20烷硫基、C1-C20烷氧基羰基、C6-C20芳氧基、C6-C20杂环芳氧基、C6-C20稠环芳氧基、C6-C20稠环氧基、C6-C20芳氧基羰基、C2-C20杂环氧基羰基、C2-C20杂环芳基、C1-C20烷基氨基、C2-C20杂环氨基、C6-C20芳基氨基、C1-C20烷基氨基羰基、C1-C20烷基羰基氨基、C1-C20烷基磺酰胺基、C2-C20杂环磺酰胺基、C6-C20芳基磺酰胺基、C1-C20烷基氨基磺酰胺基;或Rb和Rc之间连接成为 C2-C20环烷基、C2-C20环烯基或C2-C20环醚基;Ar、Ar1、Ar2和Ar3各自独立地为C6-C20芳基、C2-C20杂环芳基、C8-C20稠环芳基、C6-C20的稠环杂环芳基;或者,Ar和Ar1之间或者Ar1和Ar2之间如二者之间虚线所示连接成为C10-C20稠环烷基芳基、或者C8-C20稠环芳基;如果Ar1或Ar2不存在,Ar1或Ar2两边相连的基团可以直接相连;Ar3为C6-C20芳基、C2-C20杂环芳基、C8-C20稠环芳基;K和K1各自独立地为C6-C20芳基、C2-C20杂环芳基、C8-C20稠环芳基、或C4-C20稠环杂环芳基;其中包括含有2-4个稠环的杂环芳基或非芳基稠环基团;Q和Q1各自独立地为C1-C20烷基、C1-C20烷氧基、C3-C20环烷基、C1-C20烷基氨基、C3-C20环烷基氨基、C6-C20芳基、C3-C20稠环芳基、C3-C20杂环芳基或当L和/或L1各自不存在时,则L和L1分别相连的Q和Q1各自亦不存在;W和W1各自独立地为羰基、硫代羰基、C1-C20烷基、C6-C20芳基或C2-C20杂环芳基;W2和W3各自独立地为羰基、硫代羰基、磺酰基、C1-C20烷基、C2-C20杂环基、C6-C20芳基、C2-C20杂环芳基;Y和Y1各自独立地为氢、C1-C20烷基、C3-C20环烷基、C6-C20芳基、C1-C20烷基羰基、C6-C20芳基羰基、C1-C20烷氧基羰基、C3-C20环烷基氧基羰基、C1-C20烷基氨基羰基、C6-C20芳氧基羰基、C3-C20杂环芳氧基羰基、C6-C20芳基氨基羰基、C1-C20烷基磺酰基、C3-C20环烷基磺酰基、C6-C20芳基磺酰基、C1-C20烷氧基磺酰基、C3-C20环烷氧基磺酰基、或C6-C20芳氧基磺酰基;Z和Z1各自独立地为氢、羟基、氨基、C1-C20烷基、C3-C20环烷基、C1-C20烷氧基、C3-C20环烷氧基、C1-C20烷基氨基、C3-C20环烷基氨基、C2-C20杂环基、C2-C20 杂环氨基、C6-C20芳基、C6-C20芳氧基、C6-C20芳氨基、C3-C20杂环芳氧基、C3-C20杂环芳氨基、C1-C20烷基磺酰胺基、C3-C20环烷基磺酰胺基、C6-C20芳基磺酰胺基、C1-C20烷氧基磺酰胺基、C3-C20环烷氧基磺酰胺基、C6-C20芳氧基磺酰胺基、C1-C20烷氨基磺酰胺基、C3-C20环烷氨基磺酰胺基、C6-C20芳氨基磺酰胺基;R1、R2、R3和R4各自独立地为氢、C1-C20烷基、C3-C20环烷基、C2-C20杂环基、C6-C20芳基、C2-C20杂环芳基、C1-C20烷氧基羰基、C6-C20芳氧基羰基、C2-C20杂环氧基羰基、C1-C20烷基氨基羰基、C1-C20烷基氨基磺酰基、C2-C20杂环氨基磺酰基、或者C6-C20芳氨基磺酰基;R5、R6、R7和R8各自独立地为氢、卤素、羟基、腈基、氨基、C1-C20烷基、C3-C20环烷基、C2-C20杂环基、C1-C20烷氧基、C1-C20烷基氨基、C2-C20杂环氨基、C6-C20芳基、C6-C20芳基氨基、C1-C20烷氧基羰基氨基、C1-C20烷基氨基羰基氨基、C1-C20烷基磺酰胺基、C2-C20杂环磺酰胺基、C6-C20芳基磺酰胺基、C1-C20烷基氨基磺酰胺基、或者,R5与R6之间相互连接成环状结构,R7与R8之间相互连接成环状结构;R9、R10、R11和R12各自独立地为氢、卤素、羟基、腈基、氨基、C1-C20烷基、C3-C20环烷基、C1-C20烷氧基、C1-C20烷基氨基、C2-C20杂环氨基、C6-C20芳基、C6-C20芳基氨基、或C1-C20烷氧基羰基氨基;其中,R9与R10之间可以相互连接成环状或螺环结构,R11与R12之间可以相互连接成环状或螺环结构。
- 如权利要求1所述的如式Ia或Ib所示的化合物,其立体异构体、互变异构体、酯化或酰胺化的前体药物、药学上可接受的盐,或其中所含的氢、氧、氮、或硫原子被其相应同位素原子取代的化合物,其特征在于:为单键时,D和D1各自独立地为氧、硫、 其中,Ra为氢、C1-C15烷基、C3-C15环烷基、C6-C15芳基、C2-C15杂环芳基、C1-C15烷氧基羰基、C6-C15芳氧基羰基、C2-C15杂环氧基羰基、C1-C15烷基氨基羰基、C1-C15环烷氧基羰基、C1-C15烷基磺酰基、C3-C15环烷基磺酰基、C1-C15烷基氨基磺酰基、C2-C15杂环氨基磺酰基、或C6-C15芳氨基磺酰基;Rb和Rc各自独立地为氢、卤素、羟基、腈基、C1-C15烷基、C3-C15环烷基、C2-C15杂环基、C6-C15芳基、C1-C15烷氧基、C1-C15烷硫基、C1-C15烷氧基羰基、C6-C15芳氧基、C6-C15杂环芳氧基、C6-C15稠环芳氧基、C6-C15稠环氧基、C6-C15芳氧基羰基、C2-C15杂环氧基羰基、C2-C15杂环芳基、C1-C15烷基氨基、C2-C15杂环氨基、C6-C15芳基氨基、 C1-C15烷基氨基羰基、C1-C15烷基羰基氨基、C1-C15烷基磺酰胺基、C2-C15杂环磺酰胺基、C6-C15芳基磺酰胺基、C1-C15烷基氨基磺酰胺基;或者,Rb和Rc之间连接成为C2-C15环烷基、C2-C15环烯基或C2-C15环醚基;Ar、Ar1、Ar2和Ar3各自独立地为C6-C15的芳基、C2-C15的杂环芳基、C8-C15的稠环芳基、C6-C15的稠环杂环芳基、或者,Ar和Ar1之间或者Ar1和Ar2之间如二者之间虚线所示连接成为C10-C15的稠环烷基芳基、或者C8-C15的稠环芳基;如果Ar1或Ar2不存在,Ar1或Ar2两边相连的基团直接相连;E和G各自独立地为氮、CH或C(Rb);其中,Rb的定义与所述的D和D1中的Rb的定义相同;K和K1各自独立地为C6-C15芳基、C2-C15杂环芳基、C8-C15稠环芳基、或C4-C15稠环杂环芳基;其中包括含有2-4个稠环的杂环芳基或非芳基稠环基团;Q和Q1各自独立地为C1-C15烷基、C1-C15烷氧基、C3-C15环烷基、C1-C15烷基氨基、C3-C15环烷基氨基、C6-C15芳基、C3-C15稠环芳基、C3-C15杂环芳基、或者当L和/或L1各自不存在时,则L和L1分别相连的Q和Q1各自亦不存在;W和W1各自独立地为羰基、硫代羰基、C1-C15烷基、C6-C15芳基、或C2-C15杂环芳基;W2和W3各自独立地为羰基、硫代羰基、磺酰基、C1-C15烷基、C2-C15杂环基、C6-C15芳基、C2-C15杂环芳基;Y和Y1各自独立地为氢、C1-C15烷基、C3-C15环烷基、C6-C15芳基、C1-C15烷基羰基、C6-C15芳基羰基、C1-C15烷氧基羰基、C3-C15环烷基氧基羰基、C1-C15烷基氨基羰基、C6-C15芳氧基羰基、C3-C15杂环芳氧基羰基、C6-C15芳基氨基羰基、C1-C15烷基磺酰基、C3-C15环烷基磺酰基、C6-C15芳基磺酰基、C1-C15烷氧基磺酰基、C3-C15环烷氧基磺酰基、或C6-C15芳氧基磺酰基;Z和Z1各自独立地为氢、羟基、氨基、C1-C15烷基、C3-C15环烷基、C1-C15烷氧基、C3-C15环烷氧基、C1-C15烷基氨基、C3-C15环烷基氨基、C2-C15杂环基、C2-C15 杂环氨基、C6-C15芳基、C6-C15芳氧基、C6-C15芳氨基、C3-C15杂环芳氧基、C3-C15杂环芳氨基、C1-C15烷基磺酰胺基、C3-C15环烷基磺酰胺基、C6-C15芳基磺酰胺基、C1-C15烷氧基磺酰胺基、C3-C15环烷氧基磺酰胺基、C6-C15芳氧基磺酰胺基、C1-C15烷氨基磺酰胺基、C3-C15环烷氨基磺酰胺基、C6-C15芳氨基磺酰胺基;R1、R2、R3和R4各自独立地为氢、C1-C15烷基、C3-C15环烷基、C2-C15杂环基、C6-C15芳基、C2-C15杂环芳基、C1-C15烷氧基羰基、C6-C15芳氧基羰基、C2-C15杂环氧基羰基、C1-C15烷基氨基羰基、C1-C15烷基氨基磺酰基、C2-C15杂环氨基磺酰基、或C6-C15芳氨基磺酰基;R5、R6、R7和R8各自独立地为氢、卤素、羟基、腈基、氨基、C1-C15烷基、C3-C15环烷基、C2-C15杂环基、C1-C15烷氧基、C1-C15烷基氨基、C2-C15杂环氨基、C6-C15芳基、C6-C15芳基氨基、C1-C15烷氧基羰基氨基、C1-C15烷基氨基羰基氨基、C1-C15烷基磺酰胺基、C2-C15杂环磺酰胺基、C6-C15芳基磺酰胺基、或C1-C15烷基氨基磺酰胺基、或者,所述的R5与R6之间相互连接成环状结构,所述的R7与R8之间相互连接成环状结构;R9、R10、R11和R12各自独立地为氢、卤素、羟基、腈基、氨基、C1-C15烷基、C3-C15环烷基、C1-C15烷氧基、C1-C15烷基氨基、C2-C15杂环氨基、C6-C15芳基、C6-C15芳基氨基、或C1-C15烷氧基羰基氨基;其中,R9与R10之间可以相互连接成环状或螺环结构,R11与R12之间可以相互连接成环状或螺环结构。
- 如权利要求1所述的如式Ia或Ib所示的化合物,其立体异构体、互变异构体、酯化或酰胺化的前体药物、药学上可接受的盐,或其中所含的氢、氧、氮、或硫原子被其相应同位素原子取代的化合物,其特征在于:为单键时,D和D1各自独立地为氧、硫、 其中,Ra为氢、C1-C8烷基、C3-C8环烷基、C6-C12芳基、C2-C12杂环芳基、C1-C8烷氧基羰基、C6-C12芳氧基羰基、C2-C8杂环氧基羰基、C1-C8烷基氨基羰基、C1-C8环烷氧基羰基、C1-C8烷基磺酰基、C3-C8环烷基磺酰基、C1-C8烷基氨基磺酰基、C2-C8杂环氨基磺酰基、或C6-C12芳氨基磺酰基;Rb和Rc各自独立地为氢、卤素、羟基、腈基、C1-C8烷基、C3-C8环烷基、C2-C8杂环基、C6-C12芳基、C1-C8烷氧基、C1-C8烷硫基、C1-C8烷氧基羰基、C6-C12芳氧基、C6-C12杂环芳氧基、C6-C12稠环芳氧基、C6-C12稠环氧基、C6-C12芳氧基羰基、C2-C8杂环氧基羰基、C2-C12 杂环芳基、C1-C8烷基氨基、C2-C8杂环氨基、C6-C12芳基氨基、C1-C8烷基氨基羰基、C1-C8烷基羰基氨基、C1-C8烷基磺酰胺基、C2-C8杂环磺酰胺基、C6-C12芳基磺酰胺基、C1-C8烷基氨基磺酰胺基;或Rb和Rc之间连接成为C2-C8环烷基、C2-C8环烯基或C2-C8环醚基;Ar、Ar1、Ar2和Ar3各自独立地为C6-C12的芳基、C2-C12的杂环芳基、C8-C15的稠环芳基、C6-C12的稠环杂环芳基、或者,Ar和Ar1之间或者Ar1和Ar2之间如二者之间虚线所示连接成为C10-C15的稠环烷基芳基、或C8-C15的稠环芳基;如果Ar1或Ar2不存在,Ar1或Ar2两边相连的基团直接相连;E和G各自独立地为氮、CH或C(Rb);其中,Rb的定义与所述的D和D1中的Rb的定义相同;K和K1各自独立地为C6-C12芳基、C2-C12杂环芳基、C8-C12稠环芳基、或C4-C12稠环杂环芳基;其中包括含有2-4个稠环的杂环芳基或非芳基稠环基团;Q和Q1各自独立地为C1-C8烷基、C1-C8烷氧基、C3-C12环烷基、C1-C8烷基氨基、C3-C8环烷基氨基、C6-C12芳基、C3-C15稠环芳基、C3-C12杂环芳基、或当L和/或L1各自不存在时,则L和L1分别相连的Q和Q1各自亦不存在;W和W1各自独立地为羰基、硫代羰基、C1-C8烷基、C6-C12芳基、或C2-C12杂环芳基;W2和W3各自独立地为羰基、硫代羰基、磺酰基、C1-C8烷基、C2-C8杂环基、C6-C12芳基、C2-C12杂环芳基;Y和Y1各自独立地为氢、C1-C8烷基、C3-C8环烷基、C6-C12芳基、C1-C8烷基羰基、C6-C12芳基羰基、C1-C8烷氧基羰基、C3-C8环烷基氧基羰基、C1-C8烷基氨基羰基、C6-C12芳氧基羰基、C3-C12杂环芳氧基羰基、C6-C12芳基氨基羰基、C1-C8烷基磺酰基、C3-C8环烷基磺酰基、C6-C12芳基磺酰基、C1-C8烷氧基磺酰基、C3-C8环烷氧基磺酰基、或C6-C12芳氧基磺酰基;Z和Z1各自独立地为氢、羟基、氨基、C1-C8烷基、C3-C8环烷基、C1-C8烷氧基、 C3-C8环烷氧基、C1-C8烷基氨基、C3-C8环烷基氨基、C2-C8杂环基、C2-C8杂环氨基、C6-C12芳基、C6-C12芳氧基、C6-C12芳氨基、C3-C12杂环芳氧基、C3-C12杂环芳氨基、C1-C8烷基磺酰胺基、C3-C8环烷基磺酰胺基、C6-C12芳基磺酰胺基、C1-C8烷氧基磺酰胺基、C3-C8环烷氧基磺酰胺基、C6-C12芳氧基磺酰胺基、C1-C8烷氨基磺酰胺基、C3-C8环烷氨基磺酰胺基、C6-C12芳氨基磺酰胺基;R1、R2、R3和R4各自独立地为氢、C1-C8烷基、C3-C8环烷基、C2-C8杂环基、C6-C12芳基、C2-C12杂环芳基、C1-C8烷氧基羰基、C6-C12芳氧基羰基、C2-C8杂环氧基羰基、C1-C8烷基氨基羰基、C1-C8烷基氨基磺酰基、C2-C8杂环氨基磺酰基、或C6-C12芳氨基磺酰基;R5、R6、R7和R8各自独立地为氢、卤素、羟基、腈基、氨基、C1-C8烷基、C3-C8环烷基、C2-C8杂环基、C1-C8烷氧基、C1-C8烷基氨基、C2-C8杂环氨基、C6-C12芳基、C6-C12芳基氨基、C1-C8烷氧基羰基氨基、C1-C8烷基氨基羰基氨基、C1-C8烷基磺酰胺基、C2-C8杂环磺酰胺基、C6-C12芳基磺酰胺基、或C1-C8烷基氨基磺酰胺基、或者,R5与R6之间相互连接成环状结构,R7与R8之间相互连接成环状结构;R9、R10、R11和R12各自独立地为氢、卤素、羟基、腈基、氨基、C1-C8烷基、C3-C8环烷基、C1-C8烷氧基、C1-C8烷基氨基、C2-C8杂环氨基、C6-C12芳基、C6-C12芳基氨基、或C1-C8烷氧基羰基氨基;其中,R9与R10之间可以相互连接成环状或螺环结构,R11与R12之间可以相互连接成环状或螺环结构。
- 如权利要求1所述的如式Ia或Ib所示的化合物,其立体异构体、互变异构体、酯化或酰胺化的前体药物、药学上可接受的盐,或其中所含的氢、氧、氮、或硫原子被其相应同位素原子取代的化合物,其特征在于:为单键时,D和D1各自独立地为氧、其中,Ra为氢、C1-C5烷氧基羰基、C1-C5烷基磺酰基、C3-C5环烷基磺酰基;Rb为氢,Rc为氢、羟基、C1-C6烷氧基、C6-C12芳氧基、C6-C12杂环芳氧基、C6-C12稠环芳氧基、C6-C12稠环氧基,或Rb和Rc之间连接成为C2-C5环烷基、或C2-C5环醚基;Ar为C6-C8芳基、C10-C15稠环芳基;Ar1、Ar2和Ar3各自独立地为C6-C8芳基、C2-C8杂环芳基、C8-C10稠环芳基、C6-C10的稠环杂环芳基、或者,Ar和Ar1之间或者Ar1和Ar2之间如二者之间虚线所示连接成为C8-C12的稠环芳基;如果Ar1或Ar2不存在,Ar1或Ar2两边相连的基团直接相连;E为氮;G为CH;K和K1各自独立地为C6-C8芳基、C2-C10杂环芳基、C8-C12稠环芳基、或C4-C12稠环杂环芳基;其中包括下列含有2-4个稠环的杂环芳基或非芳基稠环基团;Q和Q1各自独立地为C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6环烷基氨基、C6-C12芳基、C3-C12稠环芳基、或当L和/或L1各自不存在时,则L和L1分别相连的Q和Q1各自亦不存在;W和W1各自独立地为羰基;W2和W3各自独立地为羰基、硫代羰基、磺酰基、C1-C8烷基、C2-C8杂环基、C6-C12芳基、C2-C12杂环芳基;Y和Y1各自独立地为氢、C1-C6烷基羰基、C6-C10芳基羰基、C1-C6烷氧基羰基、C3-C6环烷基氧基羰基、C1-C6烷基氨基羰基、C1-C6烷基磺酰基、C3-C6环烷基磺酰基、或C6-C10芳基磺酰基;Z和Z1各自独立地为C1-C5烷氧基、C3-C5环烷氧基、或C1-C5烷基氨基;R1和R2各自独立地为氢;R3和R4各自独立地为氢、C1-C6烷基、C3-C6环烷基、或C6-C8芳基;R5和R7各自独立地为氢、或C1-C6烷基;R6和R8各自独立地为C1-C6烷基、C3-C6环烷基、C6-C8芳基;或者,R5与R6之间相互连接成C3-C6环状结构,R7与R8之间相互连接成C1-C6环状结构;R9、R10、R11和R12各自独立地为氢,或者R9和R10之间相互连接成C1-C5环状结构,R11与R12之间相互连接成C1-C5环状结构;R13为氢、卤素、C1-C6烷基或C1-C6烷氧基。
- 如权利要求1所述的如式Ia或Ib所示的化合物,其立体异构体、互变异构体、同位素异构体、酯化或酰胺化的前体药物、药学上可接受的盐,其特征在于:n为1或2;所述的m为1;所述的Q或Q1为C1-C6烷基、C1-C6烷氧基、C3-C6环烷基或者取代或未取代的C3-C12稠环杂环基;所述的“取代或未取代的C3-C12稠环芳基”中,所述的取代为被卤素、C1-C3烷氧基和C4杂环芳基中的一个或多个所取代;所述的E为氮;G为CH;所述的R3或R4为氢;所述的Ar、Ar1或Ar2为取代或未取代的C6-C12的芳基、取代或未取代的C6-C15的稠环芳基、或者,Ar和Ar1之间或者Ar1和Ar2之间如二者之间虚线所示连接成为取代或未取代的C6-C15稠环芳基;如果Ar1或Ar2不存在,Ar1或Ar2两边相连的基团直接以化学键相连;所述的取代或未取代的C6-C12的芳基、或者取代或未取代的C6-C15的稠环芳基中所述的取代为被F、Cl和Br中的一个或多个所取代;Ar3为为取代或未取代的C6-C12的芳基、取代或未取代的C6-C15的稠环芳基、取代或未取代的C6-C15的稠环杂环芳基;所述的K优选所述的K1优选所述的R5或R6为氢、C1-C5烷基、C6-C10芳基或者R5与R6形成C3-C6的环烷基或C3-C6的杂环基;所述的R7或R8为氢、C1-C5烷基、C6-C10芳基或者R7与R8形成C3-C6的环烷基或C3-C6的杂环基。
- 如权利要求5所述的如式Ia或Ib所示的化合物,其立体异构体、互变异构体、 同位素异构体、酯化或酰胺化的前体药物、药学上可接受的盐,其特征在于:当所述的Q或Q1中所述的取代为被卤素取代时,所述的“卤素”为氟、氯或溴;当所述的Q或Q1中所述的取代为被C1-C3烷氧基取代时,所述的“C1-C3烷氧基”为甲氧基;当所述的Q或Q1中所述的取代为被C4杂环芳基取代时,所述的“C4杂环芳基”为噻吩基;当所述的Ar、Ar1、Ar2或Ar3为取代或未取代的C6-C12的芳基时,所述的取代或未取代的C6-C12的芳基为取代或未取代的苯基,或者取代或未取代的联苯基;当所述的Ar、Ar1、Ar2或Ar3为取代或未取代的C6-C15的稠环芳基时,所述的取代或未取代的C6-C15的稠环芳基为取代或未取代的萘基、取代或未取代的蒽基、取代或未取代的菲基、取代或未取代的芴基、或者杂原子为氧、硫或氮,杂原子数为1-3个的取代或未取代的C6-C12稠环芳基;当所述的Ar、Ar1、Ar2或Ar3为取代或未取代的C6-C15的稠环杂环芳基时,所述的取代或未取代的C6-C15的稠环杂环芳基为取代或未取代的苯并咪唑基优选或苯并噁唑基(Benzo-oxazolyl)优选当所述的Ar和Ar1之间或者Ar1和Ar2之间如二者之间虚线所示连接成为取代或未取代的C6-C15稠环芳基时,所述的取代或未取代的C6-C15稠环芳基为杂原子为氧、硫或氮,杂原子数为1-3个的取代或未取代的C6-C12稠环芳基。
- 如权利要求6所述的如式Ia或Ib所示的化合物,其立体异构体、互变异构体、同位素异构体、酯化或酰胺化的前体药物、药学上可接受的盐,其特征在于:当所述的Q或Q1为C1-C6烷基时,所述的C1-C6烷基为甲基、乙基、丙基、异丙基或叔丁基;当所述的Q或Q1为C1-C6烷氧基时,所述的C1-C6烷氧基为甲氧基、乙氧基、丙氧基、异丙氧基或叔丁氧基;当所述的Q或Q1为C3-C6环烷基时,所述的C3-C6环烷基为环丙基、环丁基、环戊基或环己基;当所述的Q或Q1为取代或未取代的C3-C12稠环杂环基时,所述的“取代或未取代的C3-C12稠环杂环基”为杂原子为氧、硫或氮,杂原子数为1-3个的取代或未取代的C3-C12稠环芳基;当所述的Ar、Ar1、Ar2或Ar3为取代的芴基时,所述的取代的芴基为被F、Cl和Br中的一个或多个所取代的芴基;当所述的Ar、Ar1、Ar2或Ar3中杂原子为氧、硫或氮,杂原子数为1-3个的取代或未取代的C6-C12稠环杂环芳基时,所述的“所述的杂原子为氧、硫或氮,杂原子数为1-3个的未取代的C6-C12稠环芳基”为呋喃并呋喃基、噻吩并噻吩基或苯并咪唑基
- 如权利要求7所述的如式Ia或Ib所示的化合物,其立体异构体、互变异构体、同位素异构体、酯化或酰胺化的前体药物、药学上可接受的盐,其特征在于:当所述的Q或Q1为杂原子为氧、硫或氮,杂原子数为1-3个的取代或未取代的C3-C12稠环芳基时,所述的“杂原子为氧、硫或氮,杂原子数为1-3个的取代或未取代的C3-C12稠环芳基”为喹喔啉基、异吲哚啉基、
- 如权利要求5所述的如式Ia或Ib所示的化合物,其立体异构体、互变异构 体、同位素异构体、酯化或酰胺化的前体药物、药学上可接受的盐,其特征在于:当所述的R5或R6为C1-C5烷基时,所述的C1-C5烷基为C1-C3烷基;当所述的R5或R6为C6-C10芳基时,所述的C6-C10芳基为取代或未取代的苯基;当所述的R5与R6形成C3-C6的环烷基时,所述的C3-C6的环烷基为环丙基、环戊基或环己基;当所述的R5与R6形成C3-C6的杂环基时,所述的C3-C6的杂环基为环氧烷基;当所述的R7或R8为C1-C5烷基时,所述的C1-C5烷基为C1-C3烷基;当所述的R7或R8为C6-C10芳基时,所述的C6-C10芳基为取代或未取代的苯基;当所述的R7与R8形成C3-C6的环烷基时,所述的C3-C6的环烷基为环丙基、环戊基或环己基;当所述的R7与R8形成C3-C6的杂环基时,所述的C3-C6的杂环基为环氧烷基。11、如权利要求1所述的如式Ia或Ib所示的化合物,其立体异构体、互变异构体、同位素异构体、酯化或酰胺化的前体药物、药学上可接受的盐,其特征在于:所述的如式Ia或Ib所示的化合物、其立体异构体、互变异构体、同位素异构体、酯化或酰胺化的前体药物和药学上可接受的盐为如下表所示的任一化合物,式Ia所示的化合物结构如下:式Ib所示的化合物结构如下:。
- 如权利要求1~11任一项所述的如式Ia或Ib所示的化合物,其立体异构体、互变异构体、同位素异构体、酯化或酰胺化的前体药物、药学上可接受的盐在制备用于抑制HCV的药物中的应用。
- 一种药物组合物,其特征在于包含:如权利要求1~11任一项所述的如式Ia或Ib所示的化合物,其立体异构体、互变异构体、酯化或酰胺化的前体药物、药学上可接受的盐,以及药学上可接受的赋形剂。
- 如权利要求13所述的药物组合物,其特征在于还包括:免疫调节剂、丙型肝炎病毒HCV-NS3/4A抑制剂、丙型肝炎病毒HCV-NS5B抑制剂、属于丙型肝炎病毒抑制剂的核苷和核苷衍生物以及非核苷类、乙型肝炎病毒抑制剂、人类免疫缺陷病毒(HIV)抑制剂、癌症药物和抗发炎药物中的一种或多种。
- 如权利要求14所述的药物组合物,其特征在于:其中,所述的免疫调节剂为干扰素或干扰素衍生物;所述的乙型肝炎病毒抑制剂包含拉米夫定、替比夫定、阿德福韦酯、恩曲他滨、恩替卡韦、替诺福韦酯和克来夫定;所述的人类免疫缺陷病毒抑制剂为利托那韦和/或利巴韦林;所述的丙型肝炎病毒蛋白酶抑制剂为VX-950、ZN2007、ABT-450、RG-7227、TMC-435、MK-5172、MK-7009、ACH-1625、GS-9256、TG2349、BMS-650032、IDX320、磷酸依米他韦、或赛拉瑞韦钾;所述的丙型肝炎病毒聚合酶抑制剂为GS-5885、TMC647055、ABT-267、BMS-791325、PPI-383、或ALS-002158。
- 如权利要求15所述的药物组合物,其特征在于:其中所述的干扰素为聚乙二醇干扰素。
- 如权利要求13~16任一项所述的药物组合物在制备用于抑制丙型肝炎病毒的药物中的应用。
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PT3153515T (pt) | 2020-11-11 |
AU2014396578B2 (en) | 2018-11-22 |
PE20170266A1 (es) | 2017-04-14 |
JP6523440B2 (ja) | 2019-05-29 |
CA2951317C (en) | 2019-10-01 |
RU2016151193A3 (zh) | 2018-07-17 |
MX2016016119A (es) | 2017-03-28 |
EP3153515B1 (en) | 2020-08-12 |
IL249403B (en) | 2021-01-31 |
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