CN108349907A - 1,4 (1,4)-hexichol heterocycle six luxuriant -12,43- two radical derivatives and the preparation method and application thereof - Google Patents

1,4 (1,4)-hexichol heterocycle six luxuriant -12,43- two radical derivatives and the preparation method and application thereof Download PDF

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CN108349907A
CN108349907A CN201680064922.6A CN201680064922A CN108349907A CN 108349907 A CN108349907 A CN 108349907A CN 201680064922 A CN201680064922 A CN 201680064922A CN 108349907 A CN108349907 A CN 108349907A
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heterocyclic ring
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苏熠东
冯卫东
王宝珠
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Abstract

Six luxuriant 12,43 2 radical derivative of a kind of 1,4 (1,4) hexichol heterocycle and the preparation method and application thereof is provided.The series compound can inhibit the activity of HCV, can be applied to the exploitation that treatment Hepatitis C Virus (HCV) infects relevant disease drug, have broad application prospects.See formula (I).

Description

1,4 (1,4)-hexichol heterocycle six luxuriant -12,43- two radical derivatives and the preparation method and application thereof Technical field
The invention belongs to course of drug development, and in particular to Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycle six luxuriant -12,43- two radical derivatives and the preparation method and application thereof.
Background technique
Hepatitis C virus HCV belongs to flaviviridae family, and flaviviridae family includes at least three categories: pestivirus (pestiviruses) mainly causes disease in ox and pig；The main reason for Flavivirus (flaviviruses) is the diseases such as dengue fever and yellow fever；And Hepacivirus (hepaciviruses), HCV belongs to unique member thus.Flavivirus member is more than 68, and different groups can be divided into based on serology affiliation；Diversity, including fever, encephalitis and Hemorrhagic fever etc. is presented in clinical symptoms.Whole world flavivirus related with human diseases of interest includes dengue haemorrhagic fever virus (DHF), flavivirus, shock syndrome virus and japanese encephalitis virus.Since HCV genome is similar with people's flavivirus and pestivirus in structure and phenotypic characteristic, it is classified as flaviviridae HCV.Hepatitis C Virus is positive chain RNA virus, has furcella on cyst membrane of the nucleocapsid outer wrap containing lipid, cyst membrane.HCV tri- kinds of Cell culture invitro systems of existing Huh7, Huh7.5, Huh7.5.1.Hepatitis C Virus was found for the first time in 1974, American scientist Michael marquis (Michael Houghton) in 1989 and his colleagues have found the gene order of the virus using molecular biology method, and hepatitis C virus has been cloned, it names this disease and its virus is hepatitis C (Hepatitis C) and Hepatitis C Virus (HCV).
HCV virus body is the positive chain RNA virus of coating, HCV-RNA about 9500-10000bp composition, 5 ' and 3 ' noncoding regions (NCR) have 319-341bp respectively, and 27-55bp, containing it is several forward and inverted repeats, it may be related with gene duplication, genome array sequence is 5'-C-E1-E2-p7-NS2-NS3-NS4A/4B-NS5A-NS5B-3', the polyprotein precursor that a length is about 3014 amino acid can be encoded, the latter can be after host cell and viral oneself protein enzyme effect, it is cracked into 10 kinds of virus proteins, including three kinds of structural proteins, that is the nucleocapsid protein of molecular weight 19KD (or core protein, ) and two kinds of glycoprotein (molecular weight Core For the E1 albumen of 33KD, the E2 albumen of molecular weight 72Kd), p7 encodes a kind of integral protein, and function may be a kind of ion channel.Nonstructural protein portion then includes NS2, NS3, NS4A, NS4B, NS5A and NS5B；Non-structural protein is extremely important to the life cycle of virus.NS2/3 and NS3/4A has proteinase activity, participates in the cutting of viral polyprotein precursors.In addition, NS3 albumen also has helicase activities, the HCV-RNA molecule that untwists is participated in, to assist rna replicon.The rna polymerase activity that there is NS5B RNA to rely on participates in HCV genome duplication；NS5B lacks proofreading function, so the frequency to mutate when HCV virus genome duplication is very high.The definite mechanism of action of NS5A is also not very clear, but NS5A can interact with a variety of host cell proteins, is indispensable a kind of albumen in viral genome duplication and virion packaging process, therefore NS5A is exploitation HCV specificity antivirus therapy An attractive target spot.
It has been found that HCV can be divided into six kinds of genotype 1-6, different genotype is to the responses of different treatments difference.HCV has significant heterologous and highly variable, the HCV strain of known full gene group sequence is analyzed it was found that its nucleotide and amino acid sequence there are larger differences, and the degree of variation at each position of HCV genome is not consistent, as 5 '-NCR are most conservative, homology is in 92-100%, and the 3 ' area NCR degrees of variation are higher.In the encoding gene of HCV, the area C is most conservative, the non-structural area (NS) takes second place, and coding envelope protein E2/NS1 changeability highest is known as hypervariable region.HCV virus is divided into different genotype according to the sequence similarity of HCV genome by researcher, and each genotype can also be further divided into different hypotypes, hitherto it is found that at least it has been found that 6 kinds of genotype, 24 hypotypes.HCV different genotype is different in distribution all over the world, and 1 type of gene, 2 types, 3 types exist all over the world, and 4 type of gene and 5 types are mainly distributed on the Middle East and Africa, and 6 type of gene is principally found in Southeast Asia.The U.S. is mainly 1 type of gene, account for about patient HCV 70% (wherein 1a be about 36%, 1b be about 24%), remaining 30% predominantly 3 type of 2 type of gene and gene.Chinese patient HCV about 66% is genotype 1 b, and 14% is gene 2a type.According to the epidemiology statistics for being published in CHINESE JOURNAL OF INTERNAL MEDICINE in 2014, there is obvious areal variation all over China, 2 type of gene, 3 types, 6 types account for very high ratio in western part of China and south.
Hepatitis C Virus (HCV) seriously jeopardizes human health, in a large amount of infected individual (according to estimates to lead to chronic hepatic diseases such as cirrhosis and hepatocellular carcinoma in the 2-15% of world population).HCV virus mainly passes through body fluid communication, and there are no the vaccines for preventing HCV infection so far.According to the World Health Organization, the whole world has more than 200,000,000 infected individual, and at least 3 to 4 million peoples are infected every year.After infected, about 20% people can remove the virus, but others then becomes HCV carrier.Patient HCV is a very big group, estimates the 3% about 1.7 hundred million of population in the world for patient HCV.Patient HCV in the U.S. accounts for the 1.4% of population, about 3-4 million people.China lacks the epidemic data of authoritative patient HCV, and most conservative estimation is the 0.42% of population, and some reports think that Chinese patient HCV is up to 3.8% population, estimates that Chinese patients HCV should be between 6,000,000-3 1,000 8 million according to these numbers.In patient HCV, 10% to 20% chronic infection individual is eventually developed to the destructive hardening of liver or cancer.
In very long a period of time even at present in many developing countries, either acute hepatitis C or chronic hepatitis C, standard regimens are all Peg-IFN alpha-2b (α -2a or α -2b) joint Ribavirins.Peg-IFN alpha-2b (α -2a or α -2b) combines the therapeutic scheme of Ribavirin, and there are many problems, including medication cycle are long, and toxic side effect is big, and patient's response ratio is low etc..Therefore, it is necessary to develop more effective and novel therapy, to solve the unsatisfied medical demand as caused by HCV infection.Drug (the DAA for HCV target spot developed recent years, direct acting antivirals) in this several respect huge progress is achieved, the development trend of HCV therapy is the DAA drug combination for not needing interferon and Ribavirin in the world at present.Main DAA drug is NS5B inhibitor, NS5A inhibitor, NS3/4A inhibitor.Compared with interferon combines Ribavirin, the advantage (or potential advantages) of DAA drug combination includes: high persistent virus response rate SVR (can cure substantially), shortens treatment cycle, avoids the generation of drug resistance, is pursued Broad spectrum activity (can be effective to HCV Multi-genotype).
The DAA drug being succeeded at first is NS3/4A inhibitor, including Telaprevir (Vertex/Janssen), and Boceprevir (Merck) ratifies in acquisition FDA in 2011.NS5B inhibitor includes the ABT-333 in three medicines of the Sofosvubir and Ai Baiwei of lucky moral.NS5A is the drug that these three types of DAA are finally succeeded in developing, ABT-267 in Daclatasvir including BMS, the Ledipasvir (being combined with Sofosbuvir) and three medicines of GS-5816, Ai Baiwei of lucky moral, the MK-8742 etc. of the ACH-3102 of Achillion company, Merck.Compared with NS3/4A and NS5B inhibitor, NS5A inhibitor can make the decline of virus load in patient body ground faster and more.In addition, ACH-3102 and GS-5816 is still active on many Daclatasvir and Ledipasvir medicament-resistant mutations.
Summary of the invention
Inventor has found a kind of 1,4 (1,4)-hexichol heterocycle six luxuriant -1 with formula (I) structure in the course of the research2,43- two radical derivatives, preparation method and application, such compound both had very high inhibitory activity to wild type HCV, also had very high inhibitory activity to Daclatasvir and Ledipasvir medicament-resistant mutation.
One aspect of the present invention provides a kind of with formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts:
Wherein:
R1: R1' it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, C1-8Alkyl, C1-8Alkoxy or C3-8Naphthenic base,
Halogen, hydroxyl, C are further optionally selected from by one or more1-8Alkyl, C1-8Alkoxy, halogen replace C1-8Alkoxy, hydroxyl replace C1-8Alkoxy, C1-8Naphthenic base or C1-8Replaced the substituent group of cycloalkyloxy；
R2、R2’、R3、R3’、R4、R4’、R5、R5' it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, C1-8Alkyl, C3-8Naphthenic base, C1-8Alkoxy or C3-8Cycloalkyloxy,
Halogen, hydroxyl, amino, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C1-8Alkoxy, C3-8Replaced cycloalkyloxy or the substituent group of 3-8 circle heterocyclic ring base oxygroup；
L, L ' is independently selected from such as flowering structure:
Halogen, hydroxyl, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
R6、R6' it is independently selected from hydrogen, deuterium, C1-8Alkyl, C1-8Alkoxy, C3-8Naphthenic base, halogenated C1-8Alkyl, C1-8Alcoxyl C1-8Alkyl, hydroxyl C1-8Alkyl ,-C (O) R14Or-C (O) OR13,
Halogen, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
R7、R7' it is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13,
Alternatively, R7Or R7' coupled nafoxidine ring is formed together the nitrogenous loop coil of 6-10 member, bridged ring or condensed ring,
Halogen, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
R8、R8' it is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13,
Halogen, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13；
R9、R9' it is independently selected from hydrogen, deuterium, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Aryl, 5-10 unit's heteroaryl ,-C0-8-C(O)R9、-C0-8-C(O)OR9Or-C0-8-C(O)NR6R7,
Halogen, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
R10、R11It is independently selected from hydrogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Ring Alkyl, 3-8 circle heterocyclic ring base, C5-10Aryl, 5-10 unit's heteroaryl or C1-8Alkyl acyl,
Halogen, hydroxyl, sulfydryl, cyano, nitro, acetylamino, azido, sulfonyl, mesyl, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C1-8Alkoxy, C1-8Alkoxy carbonyl group, C1-8Alkyl-carbonyl, C1-8Alkyl carbonyl epoxide, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl, amino, list C1-8Alkyl amino or two C1-8Replaced the substituent group of alkyl amino；
R12Selected from hydrogen, deuterium, C1-8Alkyl, C3-8Naphthenic base, halogen replace C1-8Alkyl, two C1-8Alkyl amino, phenyl or p-methylphenyl；
R13Selected from hydrogen, deuterium, C1-8Alkyl, C3-8Naphthenic base, halogen replace C1-8Alkyl or hydroxyl replace C1-8Alkyl；
R14Selected from hydrogen, deuterium, C1-8Alkyl, C1-8Alkoxy, C3-8Naphthenic base, C3-8Cycloalkyloxy, halogen replace C1-8Alkyl, halogen replace C1-8Alkoxy, hydroxyl replace C1-8Alkyl or hydroxyl replace C1-8Alkoxy；
M, m ' is independently selected from 0~3；
P, p ' is independently selected from 0~7；
R is 0,1 or 2.
As a preferred option, the compound, its stereoisomer or its pharmaceutically-acceptable salts, R6、R6' it is independently selected from hydrogen, deuterium, C1-4Alkyl, C1-4Alkoxy, C3-6Naphthenic base, halogenated C1-4Alkyl, C1-4Alcoxyl C1-4Alkyl, hydroxyl C1-4Alkyl ,-C (O) R14Or-C (O) OR13,
Halogen, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced.
As further preferred scheme, the compound, its stereoisomer or its pharmaceutically-acceptable salts, R6、R6' it is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclohexyl, methoxyl group, ethyoxyl or isopropoxy, more preferable hydrogen.
As further preferred scheme, the compound, its stereoisomer or its pharmaceutically-acceptable salts, R1、R1' it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, C1-4Alkyl, C1-4Alkoxy or C3-6Naphthenic base, more preferable hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, hydroxyl, amino, methoxyl group or cyclopropyl.
As further preferred scheme, the compound, its stereoisomer or its pharmaceutically-acceptable salts, R2、R2’、R3、R3’、R4、R4’、R5、R5' it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, C1-4Alkyl, C3-6Naphthenic base, C1-4Alkoxy or C3-8Cycloalkyloxy, more preferable hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, hydroxyl, amino, methoxyl group or cyclopropyl.
As further preferred scheme, the compound, its stereoisomer or its pharmaceutically-acceptable salts, L, L ' is independently selected from such as flowering structure:
Halogen, hydroxyl, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-4Alkenyl, C2-4Alkynyl group, C3-6Naphthenic base, 3-6 circle heterocyclic ring base, 3-6 circle heterocyclic ring base oxygroup, 3-6 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-4-S(O)rR12、-C0-4-O-R13、-C0-4-C(O)R14、-C0-4-C(O)OR13、-C0-4-O-C(O)R14、-C0-4-NR10R11、-C0-4-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
More preferably such as flowering structure:
As further preferred scheme, the compound, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that
R7、R7' it is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C1-4Alkyl, C2-6Alkenyl, C2-6Alkynyl group, C3-6Naphthenic base, 3-6 circle heterocyclic ring base, 3-6 circle heterocyclic ring base oxygroup, 3-6 circle heterocyclic ring base sulfenyl, C5-8Aryl, C5-8Aryloxy, C5-8Artyl sulfo, 5-8 unit's heteroaryl, 5-8 unit's heteroaryl oxygroup, 5-8 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13,
Alternatively, R7Or R7' coupled nafoxidine ring is formed together the nitrogenous loop coil of 6-10 member, bridged ring or condensed ring, selected from such as flowering structure:
As scheme still more preferably, the compound, its stereoisomer or its pharmaceutically-acceptable salts, selected from such as following formula (II) compound:
Wherein, R7、R7’、R8、R8’、R9、R9' as defined in claim 1.
As scheme still more preferably, the formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, R7、R7' it is independently selected from hydrogen, deuterium, fluorine, methyl, ethyl or isopropyl, alternatively, R7Or R7' coupled nafoxidine ring is formed together such as flowering structure:
As scheme still more preferably, the formula (I) compound, its stereoisomer or its pharmacy Upper acceptable salt, R8、R8' it is independently selected from hydrogen, deuterium, halogen, methyl, ethyl, isopropyl, cyclopropyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13。
As scheme still more preferably, the formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, R9、R9' be independently selected from from hydrogen, deuterium, C1-4Alkyl, allyl, acetenyl, C3-6Naphthenic base, 3-6 circle heterocyclic ring base or phenyl.
As most preferred scheme, the compound, its stereoisomer or its pharmaceutically-acceptable salts are selected from following compound:
Another aspect of the present invention provides a kind of preparation method of aforesaid compound, includes the following steps:
Wherein: Pg is amino protecting group, preferred tertbutyloxycarbonyl, allyl carbonyl, tablet held before the breast by officials methoxycarbonyl group, methoxycarbonyl group, carbethoxyl group, trimethylsilyl ethoxycarbonyl or benzyloxycarbonyl group preferably is selected from, more preferably from tertbutyloxycarbonyl；R1、R1’、R2、R2’、R3、R3’、R4、R4’、R5、R5’、R6、R6’、R7、R7’、R8、R8’、R9、R9’、R10、R11、R12、R13、R14, L, L ', p, p ', m, m ', r such as formula (I) compound defined.
As scheme still more preferably, the acid binding agent is organic base or inorganic base, the organic base is selected from or mixtures thereof trimethylamine, triethylamine, pyridine, piperidines, morpholine, diisopropylethylamine, the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, or mixtures thereof sodium acetate；The condensing agent is selected from or mixtures thereof DIC, DCC, HOBT, EDCHCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI.
Another aspect of the present invention provides a kind of pharmaceutical composition comprising compound above-mentioned, its stereoisomer or its pharmaceutically-acceptable salts for the treatment of effective dose and pharmaceutical carrier.
Another aspect of the present invention provides a kind of aforesaid compound, its stereoisomer or its pharmaceutically-acceptable salts or foregoing pharmaceutical composition and treats or prevents the application in HCV infection disease medicament in preparation.
Specific embodiment
It is described in detail: unless stated to the contrary, following that there are following meanings with term in the specification and in the claims.
“C1-8Alkyl " refers to that straight chained alkyl and containg branched alkyl radical including 1 to 8 carbon atom, alkyl refer to the aliphatic hydrocarbon group of saturation, C0-8Refer to not carbon atoms or C1-8Alkyl, such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1, 1- dimethyl propyl, 1, 2- dimethyl propyl, 2, 2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1, 1, 2- thmethylpropyl, 1, 1- dimethylbutyl, 1, 2- dimethylbutyl, 2, 2- dimethylbutyl, 1, 3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2, 3- dimethylbutyl, n-heptyl, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2, 3- dimethyl amyl group, 2, 4- dimethyl amyl group, 2, 2- dimethyl-penten Base, 3,3- dimethyl amyl group, 2- ethylpentyl, 3- ethylpentyl, n-octyl, 2,3- dimethylhexanyl, 2,4- dimethyl Hexyl, 2,5- dimethylhexanyl, 2,2- dimethylhexanyl, 3,3- dimethylhexanyl, 4,4- dimethylhexanyl, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- methyl -2- ethylpentyl, 2- methyl -3- ethylpentyl or its various branched isomer etc..
Alkyl can be substituted or unsubstituted, and when substituted, substituent group can be substituted on any workable tie point, preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
" naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, " C3-8Naphthenic base " refers to the naphthenic base including 3 to 8 carbon atoms, and " 5-10 member naphthenic base " refers to the naphthenic base including 5 to 10 carbon atoms, such as:
The non-limiting embodiment of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc..
Polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring." spiro cycloalkyl group " refers to the polycyclic moiety that a carbon atom (claiming spiro-atom) is shared between monocycle, these can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, double spiro cycloalkyl group bases or more spiro cycloalkyl groups according to the number for sharing spiro-atom between ring and ring, the non-limiting embodiment of spiro cycloalkyl group includes:
" cycloalkyl " refers to the full carbon polycyclic moiety of each ring in system and shared a pair of of the carbon atom adjoined of other rings in system, wherein one or more rings can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Bicyclic, tricyclic, Fourth Ring or polycyclic fused ring alkyl can be divided into according to a group cyclic number, the non-limiting embodiment of cycloalkyl includes:
" bridge ring alkyl " refers to that any two ring shares the full carbon polycyclic moiety of two carbon atoms being not directly connected, these can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl can be divided into according to a group cyclic number, the non-limiting embodiment of bridge ring alkyl includes:
。
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to link together with precursor structure is naphthenic base, non-limiting embodiment includes indanyl, tetralyl, benzocyclohepta alkyl etc..
Naphthenic base can be optionally substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
" heterocycle " refers to that the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)rThe hetero atom of (wherein r is integer 0,1,2), but do not include the loop section of-O-O- ,-O-S- or-S-S-, remaining annular atom is carbon." 5-10 circle heterocyclic ring base " refers to the ring group comprising 5 to 10 annular atoms, and " 3-8 circle heterocyclic ring base " refers to the ring group comprising 3 to 8 annular atoms.
The non-limiting embodiment of monocyclic heterocycles base includes pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, high piperazine base etc..
Multiring heterocyclic includes the heterocycle of loop coil, condensed ring and bridged ring." spiro heterocyclic radical " refers to that the polycyclic heterocyclic group that an atom (claiming spiro-atom) is shared between monocycle, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)rThe hetero atom of (wherein r is integer 0,1,2), remaining annular atom are carbon.These can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Spiro cycloalkyl group is divided into single spiro heterocyclic radical, double spiro heterocyclic radicals or more spiro heterocyclic radicals according to the number for sharing spiro-atom between ring and ring.The non-limiting embodiment of spiro cycloalkyl group includes:
" condensed hetero ring base " refers to the polycyclic heterocyclic group of each ring in system and shared a pair of of the atom adjoined of other rings in system, one or more rings can contain one or more double bonds, but none ring has the pi-electron system of total conjugated, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)rThe hetero atom of (wherein r is integer 0,1,2), remaining annular atom are carbon.Bicyclic, tricyclic, Fourth Ring or polycyclic fused heterocycloalkyl can be divided into according to a group cyclic number, the non-limiting embodiment of condensed hetero ring base includes:
" bridge heterocycle " refers to that any two ring shares the polycyclic heterocyclic group of two atoms being not directly connected, these can contain one or more double bonds, but none ring has the pi-electron system of total conjugated, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)rThe hetero atom of (wherein r is integer 0,1,2), remaining annular atom are carbon.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl can be divided into according to a group cyclic number, the non-limiting embodiment of bridge ring alkyl includes:
The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein the ring to link together with precursor structure is heterocycle, non-limiting embodiment includes:
Heterocycle can be optionally substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
" aryl " refers to full carbon monocycle or fused polycycle (rings of namely shared adjacent carbon atoms pair) group, has polycyclic (i.e. its ring for the having phase adjacency pair carbon atom) group of the pi-electron system of conjugation, " C5-10Aryl " refers to the full carbon aryl containing 5-10 carbon, and " 5-10 member aryl " refers to the full carbon aryl containing 5-10 carbon, such as phenyl and naphthalene.The aryl rings can be condensed on heteroaryl, heterocycle or cycloalkyl ring, wherein the ring to link together with precursor structure is aryl rings, non-limiting embodiment includes:
Aryl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
" heteroaryl " refers to comprising 1 to 4 heteroatomic heteroaromatic system, and the hetero atom includes nitrogen, oxygen and S (O)rThe hetero atom of (wherein r is integer 0,1,2), 5-7 unit's heteroaryl refers to the heteroaromatic system containing 5-7 annular atom, 5-10 unit's heteroaryl refers to heteroaromatic system containing 5-10 annular atom, such as furyl, thienyl, pyridyl group, pyrrole radicals, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical etc..The heteroaryl ring can be condensed on aryl, heterocycle or cycloalkyl ring, wherein the ring to link together with precursor structure is heteroaryl ring, non-limiting embodiment includes:
Heteroaryl can be optionally substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
" alkenyl " refers to the alkyl as defined above being made of at least two carbon atoms and at least one carbon-to-carbon double bond, C2-8Alkenyl refers to the straight chain containing 2-8 carbon or containing branched-chain alkenyl.Such as vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- cyclobutenyl etc..
Alkenyl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
" alkynyl " refers to the alkyl as defined above of at least two carbon atoms and at least one carbon-carbon triple bond composition, C2-8Alkynyl group refers to the straight chain containing 2-8 carbon or containing branch alkynyl.Such as acetenyl, 1- propinyl, 2-propynyl, 1-, 2- or 3- butynyl etc..
Alkynyl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
" alkoxy " refers to-O- (alkyl), and wherein alkyl is as defined above.C1-8Alkoxy refers to the alkyl oxy containing 1-8 carbon, and non-limiting embodiment includes methoxyl group, ethyoxyl, propoxyl group, butoxy etc..
Alkoxy can be optionally it is substituted or unsubstituted, when substituted, substituent group, preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
" cycloalkyloxy " refers to and-O- (unsubstituted naphthenic base), and wherein naphthenic base is as defined above.C3-8Cycloalkyloxy refers to the cycloalkyl oxy containing 3-8 carbon, and non-limiting embodiment includes cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..
Cycloalkyloxy can be optionally substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, independently selects halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
" halogen replaces C1-8Alkyl " refers to the optional 1-8 carbon alkyl group, such as difluoromethyl, dichloromethyl, two bromomethyls, trifluoromethyl, trichloromethyl, trisbromomethyl that are replaced by fluorine, chlorine, bromine, iodine atom etc. of the hydrogen on alkyl.
" halogen replaces C1-8The 1-8 carbon alkoxy base replaced by fluorine, chlorine, bromine, iodine atom of hydrogen optionally on alkoxy " alkyl.Such as difluoro-methoxy, dichloro methoxyl group, dibromo methoxyl group, trifluoromethoxy, trichloromethoxy, tribromo methoxyl group etc..
" halogen " refers to fluorine, chlorine, bromine or iodine.
“C(O)R10" refer to R10Substituted carbonyl.
" THF " refers to tetrahydrofuran.
Term " condensing agent " refers to the reagent that can cause condensation reaction.Condensation reaction, which refers to, synthesizes a macromolecular with covalently bonded after the interaction of two or more organic molecules, while losing water or other fairly simple inorganic or small organic molecule reactions.Small-molecule substance therein is usually water, hydrogen chloride, methanol or acetic acid etc..The corresponding Chinese of the abbreviation of various condensing agents is as shown in the table in the present invention:
Referred to as Chinese
DIC N, N- diisopropylcarbodiimide
DCC N, N- dicyclohexylcarbodiimide
HOBT I-hydroxybenzotriazole
EDC·HCl 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride
PyBOP Hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl
PyBroP Tripyrrole alkane base phosphonium bromide hexafluorophosphate
HATU 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester
HCTU 6- Chloro-Benzotriazole -1,1,3,3- tetramethylurea hexafluorophosphoric acid ester
DEPBT 3- (diethoxy phosphoryl oxy) -1,2,3- phentriazine -4- ketone
EEDQ 2- ethyoxyl -1- ethoxy carbonic acyl radical -1,2- dihydroquinoline
CDI Carbonyl dimidazoles
" optional " or " optionally " mean ground described later event or environment can with but need not occur, which includes the event or environment occurs or not spot occasion.For example, mean " optionally by alkyl-substituted heterocyclic group " alkyl can with but necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to that one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom are replaced by the substituent group of respective number independently of one another.Self-evident, substituent group is only in their possible chemistry position, and those skilled in the art can determine in the case where not paying and excessively making great efforts and (pass through experiment or theory) possible or impossible substitution.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key.
" pharmaceutical composition " indicates mixture and other components such as physiology/pharmaceutical load containing one or more compounds described herein or its physiologically/pharmaceutical salt or pro-drug and other chemical constituents Body and excipient.The purpose of pharmaceutical composition is the administration promoted to organism, plays bioactivity in turn conducive to the absorption of active constituent.
Below with reference to embodiment, the present invention is described in further detail and completely, but the limitation present invention, the present invention are also not intended to be limited to the content of embodiment by no means.
The compound of the present invention structure is by nuclear magnetic resonance (NMR) or/and LC-MS chromatography (LC-MS) come what is determined.Nmr chemical displacement (δ) is provided with the unit of hundred a ten thousandths (ppm).The measurement of NMR is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometer, and measurement solvent is dimethyl sulfoxide (DMSO) and deuterated chloroform (CDCl3) in be designated as tetramethylsilane (TMS).
The measurement of LC-MS chromatography LC-MS Agilent 1200Infinity Series mass spectrograph.The measurement of HPLC uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire 150 × 4.6mm of C18 chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini 150 × 4.6mm of C18 chromatographic column).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and the specification that TLC is used is 0.15mm~0.20mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.Column chromatography is generally carrier using 200~300 mesh silica gel of Yantai Huanghai Sea silica gel.
Starting material in the embodiment of the present invention is known and can be commercially available, or can use or synthesize according to methods known in the art.
In the case where no specified otherwise, all reactions of the invention under the stirring of continuous magnetic, carry out under drying nitrogen or argon atmospher, and solvent is dry solvent.
Argon atmospher or nitrogen atmosphere refer to that reaction flask connects the argon gas or nitrogen balloon of an about 1L volume.Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.
In the case where no specified otherwise, the solution in embodiment refers to aqueous solution.The temperature of reaction is room temperature.Room temperature is optimum reaction temperature, is 20 DEG C~30 DEG C.
The monitoring of reaction process in embodiment, which reacts used solvent system using thin-layered chromatography (TLC) or LC-MS chromatography (LC-MS), to be had: methylene chloride and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, the volume ratio of acetone, solvent can be adjusted according to the polarity difference of compound.The system of the eluant, eluent of column chromatography includes: A: methylene chloride and methanol system, B: n-hexane and ethyl acetate system, C: methylene chloride and ethyl acetate system, D: ethyl acetate and methanol, the volume ratio of solvent is different according to the polarity of compound and is adjusted, and a small amount of ammonium hydroxide and acetic acid etc. can also be added and be adjusted.
The preparation of embodiment compound
1 dimethyl of embodiment ((2S, 2'S)-((2S, 2'S)-(((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (pyrrolidines -2,1- diyl)) two (3- methyl-1s-carbonyl butane -1,2- diyl)) diurethane
Step 1: preparation of the 4,16- dibromo [2.2] to ring sweet smell
Iron powder (1.2g), bromine (20.7g) are sequentially added in methylene chloride (400mL), stir half an hour, [2.2] are added dropwise to methylene chloride (100mL) solution of ring fragrant (50g), it is heated to reflux 2 hours, then bromine (7g) and methylene chloride (100mL) mixed liquor is added dropwise in 3 hours, continue back flow reaction 3 hours, is cooled to room temperature, is stirred overnight.Reaction solution successively respectively washed once with 5% sodium sulfite, water, dry, and concentration, residue is beaten with hot toluene, cooling, and it is fragrant (33.7g) to ring that suction filtration obtains 4,16- dibromo [2.2].
1H NMR(400MHz,CDCl3) δ 7.17-7.14 (m, 2H), 6.53 (d, J=2.0Hz 2H), 6.42 (d, J=8.0Hz, 2H), 3.57-3.46 (m, 2H), 3.20-3.11 (m, 2H), 2.98-2.71 (m, 4H).
Step 2: di-tert-butyl (1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) diurethane
Under nitrogen protection; by 4; 16- dibromo [2.2] is to ring sweet smell (4.5g; 12.15mmol), (4- ((t-butoxy carbonyl) amino) phenyl) boric acid (7.2g; 30.37mmol), cesium carbonate (10g, 30.38mmol), Pd (PPh3)4(1.4g, 1.22mmol) mixing, sequentially adds n,N-Dimethylformamide (113mL), water (9mL), is warming up to 130 DEG C and reacts 4 hours.25 DEG C are cooled to, water (100mL) and methylene chloride (200mL) is added, separates organic layer, it successively respectively washed once, be concentrated with water, saturated sodium-chloride water solution, residue column chromatographs to obtain di-tert-butyl (1,4 (Isosorbide-5-Nitrae)-hexichol heterocycles six luxuriant -12,43Diyl two (4,1- phenylene)) diurethane (3.2g).
1H NMR(400MHz,DMSO-d6) δ 9.45 (s, 2H), 7.58 (d, J=8.4Hz, 4H), 7.41 (d, J=8.4Hz, 4H), 6.72 (d, J=7.6Hz, 2H), 6.60 (s, 2H), 6.42 (d, J=7.6Hz, 2H), 3.37-3.32 (m, 2H), 2.94-3.01 (m, 2H), 2.79-2.84 (m, 2H), 2.54-2.61 (m, 2H), 1.51 (s, 18H).
Step 3: 4,4'- (1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl) diphenylamines preparation
Under nitrogen protection, in di-tert-butyl (Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) the middle dioxane solution (30mL) that hydrogen chloride is added of diurethane (3.2g, 5.42mmol), methanol (10mL), it is stirred to react 6 hours.The sodium hydrate aqueous solution tune reaction solution of addition 10% is precipitated a large amount of solids, filters, filter cake is dried in vacuo to obtain 4,4'- (Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycle six luxuriant -1 to alkalinity2,43Diyl) diphenylamines (2g).
LC-MS:391.26 (M+H)+；
1H NMR(400MHz,DMSO-d6) δ 7.17 (d, J=8.4Hz, 4H), 6.68 (d, J=8.4Hz, 4H), 6.61 (d, J=7.6Hz, 2H), 6.51 (s, 2H), 6.38 (d, J=7.6Hz, 2H), 5.15 (br s, 4H), 3.37-3.40 (m, 2H), (2.94-2.88 m, 2H), 2.79-2.84 (m, 2H), (2.54-2.61 m, 2H), 1.51 (s, 18H).
Step 4: tert-butyl (S) -2- ((4- (43(4- ((R) -1- (t-butoxy carbonyl) pyrrolidines -2- carbon weeds acylamino-) phenyl) -1,4 (1,4)-hexichol heterocycle six is luxuriant -- and 12Base) phenyl) carbamyl) and pyrrolidines -1- carboxylate preparation
Under nitrogen protection, by 4,4'- (Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycle six luxuriant -12,43Diyl) diphenylamines (276mg, 0.71mmol), (t-butoxy carbonyl)-L-PROLINE (335mg, 1.56mmol), I-hydroxybenzotriazole (210mg, 1.56mmol), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (338mg, 1.77mmol), N-methylmorpholine (358mg, 3.54mmol) mixing, it is added to N, in the mixed liquor of dinethylformamide (7.5mL) and tetrahydrofuran (5mL), it is stirred to react at 25 DEG C 20 hours.10% aqueous citric acid solution (20mL) and the mixed liquor of ethyl acetate (20mL) is added, it stirs, separate organic layer, saturated aqueous sodium carbonate washing, concentration, residue column chromatograph to obtain tert-butyl (S) -2- ((4- (43(4- ((R) -1- (t-butoxy carbonyl) pyrrolidines -2- carbon weeds acylamino-) phenyl) -1,4 (1,4)-hexichol heterocycle six luxuriant -12Base) phenyl) carbamyl) pyrrolidines -1- carboxylate (348mg).
LC-MS:685.3 (M-Boc+H)+；
1H NMR(400MHz,DMSO-d6) δ 10.1 (s, 2H), 7.73 (d, J=7.6Hz, 4H), 7.48 (d, J=8.0Hz, 4H), 6.75 (d, J=7.2Hz, 2H), 6.64 (s, 2H), 6.44 (d, J=7.6Hz, 2H), 4.24-4.32 (m, 2H), 3.33-3.45 (m, 4H), 2.98-3.00 (m, 2H), 2.82-2.85 (m, 2H), 2.56-2.59 (m, 2H), 2.18-2.25 (m, 2H), 1.82-1.85 (m, 8H), 1.41 (s, 9H), 1.32 (s, 9H).
Step 5: (2S, 2'S)-N, N'- (1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (pyrrolidines -2- formamides) preparation
Under nitrogen protection, by tert-butyl (S) -2- ((4- (43(4- ((R) -1- (t-butoxy carbonyl) pyrrolidines -2- carbon weeds acylamino-) phenyl) -1,4 (1,4)-hexichol heterocycle six luxuriant -12Base) phenyl) carbamyl) methylene chloride (5mL), trifluoracetic acid (2mL) are added in pyrrolidines -1- carboxylate (348mg, 0.49mmol), it is stirred to react 20 hours at 25 DEG C.Methylene chloride (45mL) dilution is added, successively respectively washed once with water, saturated sodium bicarbonate, saline solution, it is dry, it is concentrated to give (2S, 2'S)-N, N'- (Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (pyrrolidines -2- formamide) (316mg).
LC-MS:585.36 (M+H)+。
Step 6: dimethyl ((2S, 2'S)-((2S, 2'S)-(((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (pyrrolidines -2,1- diyl)) two (3- methyl-1s-carbonyl butane -1,2- diyl)) diurethane preparation
Under nitrogen protection, by (2S, 2'S)-N, N'- (Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (pyrrolidines -2- formamide) (316mg, 0.54mmol), carboxyl-Valine (200mg, 1.14mmol), I-hydroxybenzotriazole (161mg, 1.19mmol), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (260mg, 1.36mmol), N-methylmorpholine (274mg, 2.71mmol) mixing, N is added, dinethylformamide (10mL) is stirred to react 16 hours at 25 DEG C.It is added ethyl acetate (30mL), it respectively washed once with water (30mL) with 10% aqueous citric acid solution (20mL), concentration, residue column chromatographic purifying obtains dimethyl ((2S, 2'S)-((2S, 2'S)-(((Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (pyrrolidines -2,1- diyl)) two (3- methyl-1s-carbonyl butane -1,2- diyl)) diurethane (150mg).
LC-MS:899.40 (M+H)+；
1H NMR(400MHz,DMSO-d6) δ 10.16 (s, 2H), 7.75-7.72 (m, 4H), 7.48 (d, J=8.4Hz, 4H), 7.35 (d, J=8.0Hz, 2H), 6.75 (d, J=8.0Hz, 2H), (6.62 s, 2H), 6.50 (d, J=7.6Hz, 2H), 4.52-4.48 (m, 2H), 4.06 (t, J=8.4Hz, 2H), 3.88-3.84 (m, 2H), (3.70-3.64 m, 2H), 3.54 (s, 6H), 3.42-3.35 (m, 2H), (3.02-2.95 m, 2H), 2.85-2.79 (m, 2H), 2.65-2.55 (m, 2 ), H 2.24-2.15 (m, 2H), 2.06-1.89 (m, 8H), 0.99-0.90 (m, 12H).
2 dimethyl of embodiment ((2S, 2'S)-((2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-(((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (octahydro -1H- indoles - 2,1- diyl)) two (3- methyl-1s-carbonyl butane -1,2- diyl)) diurethane
Step 1: the preparation of (2S, 3aS, 7aS) -1- (t-butoxy carbonyl) octahydro -1H- indole-2-carboxylic acid
At 0 DEG C, in (2S, 3aS, 7aS)-octahydro -1H- indole-2-carboxylic acid (50g, cooling 2.5M NaOH aqueous solution (200mL) is added dropwise in the mixed solution of THF (400mL) and water (200mL) 0.29mol), two dibutyl carbonates (85.4g) is added dropwise at 15 minutes, 0 DEG C in stirring, is stirred to react at room temperature 12 hours.Stop reaction, successively washed 3 times with MTBE, 1M aqueous citric acid solution is acidified water phase, ethyl acetate extracts 3 times, merge organic phase, sodium sulphate is dry, is concentrated to dryness to obtain (2S, 3aS, 7aS) -1- (t-butoxy carbonyl) octahydro -1H- indole-2-carboxylic acid preparation (74.9g).
Step 2: di-tert-butyl 2,2'- (((1, luxuriant -12,43- the diyl two (4 of 4 (1,4)-hexichol heterocycle six, 1- phenylene)) two (azane diyls)) two (carbonyls)) (2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-two (octahydro -1H- indoles -1- carboxylates) preparation
With compound 4,4'- (1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl) diphenylamines be raw material, 1 step 4 of reference implementation example, with compound (2S, 3aS, 7aS) -1- (t-butoxy carbonyl) octahydro -1H- indole-2-carboxylic acid is condensed, and obtains compound di-tert-butyl 2,2'- (((1,4 (Isosorbide-5-Nitrae)-hexichol heterocycles six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) (2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-two (octahydro -1H- indoles -1- carboxylate).
LC-MS:685.3 (M-Boc+H)+；
1H NMR(400MHz,DMSO-d6) δ 10.14 (br, 2H), 7.77 (s, 4H), 7.49 (d, J=8.0Hz, 4H), 6.76 (d, J=7.2Hz, 2H), 6.64 (s, 2H), 6.46 (d, J=7.6Hz, 2H), 4.28 (t, J=8.8Hz, 2H), 3.73-3.67 (m, 2H), 3.35-3.32 (m, 2H), 3.02-2.97 (m, 2H), 2.86-2.79 (m, 2H), 2.61-2.58 (m, 2H), 2.40-2.30 (m, 2H), 2.12-2.05 (m, 2H), 1.89-1.53 (m, 10H), 1.3.9-1.30 (m, 1 8H).
Step 3: (2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-N, N'- (1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (octahydro -1H- indole 2-carboxamides) preparation
Under nitrogen protection, by di-tert-butyl 2,2'- (((Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) (2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-two (octahydro -1H- indoles -1- carboxylate) (700mg, it 0.78mmol) is dissolved in the dioxane solution (5mL) of hydrogen chloride, it is stirred 20 hours at 25 DEG C, the sodium hydrate aqueous solution of 2M is then added dropwise to alkalinity, solid is precipitated, filtering, filter cake is dried in vacuo (2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-N, N'- (1,4 (Isosorbide-5-Nitrae)-hexichol heterocycles six luxuriant -12,43Diyl two (4,1- phenylene)) two (octahydro -1H- indole 2-carboxamides) (460mg).
LC-MS:693.45 (M+H)+。
Step 4: dimethyl ((2S, 2'S)-((2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-(((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (octahydro -1H- indoles -2,1- diyl)) two (3- methyl-1s-carbonyl butane -1,2- diyl)) diurethane preparation
1 step 6 of reference implementation example obtains compound dimethyl ((2S, 2'S)-((2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-(((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (octahydro -1H- indoles -2,1- diyl)) two (3- methyl-1s-carbonyl butane -1,2- diyl)) diurethane.
LC-MS:1007.25 (M+H)+；
1H NMR(400MHz,DMSO-d6) δ 10.18 (s, 2H), 7.75 (d, J=7.6Hz, 4H), 7.53 (d, J=8.0Hz, 2H), 7.48 (d, J=8.4Hz, 4H), 6.75 (d, J=8.0Hz 2H), 6.63 (s, 2H), 6.46 (d, J=8.0Hz 2H), 4.48 (t, J=9.2Hz 2H), 4.37-4.32 (m, 2H), 3.85 (t, J=8.8Hz, 2H), 3.55 (s, 6H), 3.40-3.33 (m, 2H), 3.05-2.96 (m, 2H), 2.85-2.80 (m, 2H), 2.64-2.58 (m, 2H), 2.35-2. 25 (m, 2H), 2.14-2.01 (m, 2H), 2.03-1.90 (m, 6H), 1.77-1.52 (m, 8H), 1.49-1.43 (m, 2H), 1.32-1.17 (m, 4H), 0.93-0.84 (m, 12H).
3 methyl of embodiment ((2S, 2'S, 3R, 3'R)-((2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-(((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (octahydro -1H- indoles -2,1- diyl)) two (3- methoxyl group -1- carbonyl butane -1,2- diyls)) diurethane
Step 1: the preparation of N- methoxycarbonyl group-O- methyl-L-threonine
By O- methyl-L-threonine (5.0g, 37.6mmol) it is dissolved in 1, in the mixed liquor of 4- dioxane (20mL) and THF (20mL), it is cooled to 0 DEG C, NaOH (4.5g NaOH is dissolved in 56mL water) aqueous solution is added dropwise, methylchloroformate (4.3g) is added, is warmed to room temperature and stirs 7h.It is successively acidified with 3N hydrochloric acid, ethyl acetate (60mL) extracts three times, merges organic phase, is dried over sodium sulfate, and filters, and concentration obtains N- methoxycarbonyl group-O- methyl-L-threonine (5.3g).
LC-MS:192.1 (M+H)+。
Step 2: methyl ((2S, 2'S, 3R, 3'R)-((2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-(((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (octahydro -1H- indoles -2,1- diyl)) two (3- methoxyl group -1- carbonyl butane -1,2- diyls)) diurethane preparation
With di-tert-butyl 2,2'- (((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) (2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-two (octahydro -1H- indoles -1- carboxylates) are raw material, and 1 step 6 of reference implementation example obtains methyl ((2S, 2'S, 3R, 3'R)-((2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-(((1,4 (Isosorbide-5-Nitrae)-hexichol heterocycles six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (octahydro -1H- indoles -2,1- diyl)) two (3- methoxyl group -1- carbonyl butane -1,2- diyls)) diurethane.
LC-MS:1039.40 (M+H)+；
1H NMR(400MHz,DMSO-d6) δ 10.18 (s, 2H), 7.75 (d, J=8.0Hz, 4H), 7.62 (d, J=7.6Hz, 2H), (7.48 d, J=8.4Hz, 4H), 6.75 (d, J=8.0Hz, 2H), 6.63 (s, 2H), 6.46 (d, J=7.6Hz, 2H), 4.47 (t, J=8.8Hz, 2H), 4.38-4.35 (m, 2H), 4.11 (t, J=8.4Hz, 2H), 3.55 (s, 6H), 3.51-3.47 (m, 2H), 3.41-3.27 (m, 2H), 3.25 (d, J=5.2Hz, 6H), (3.02-2.97 m, 2H), 2.85 - 2.80 (m, 2H), 2.61-2.55 (m, 2H), 2.37-2.31 (m, 2H), 2.16-2.10 (m, 2H), 2.02-1.91 (m, 4H), 1.79-1.61 (m, 8H), 1.45-1.41 (m, 2H), 1.32-1.20 (m, 4H), 1.12-1.09 (m, 6H).
4 dimethyl of embodiment ((2S, 2'S)-((6S, 6'S)-(((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (5- azaspiro [2.4] heptane -6,5- diyl)) two (3- methyl-1s-carbonyl butane -1,2- diyl)) diurethane
Step 1: di-tert-butyl 6,6'- (((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) and (6S, 6'S)-two (5- azaspiro [2.4] heptane -5- carboxylate) preparation
1 step 4 of reference implementation example, 4,4'- (Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycles six luxuriant -12,43Diyl) diphenylamines and (S) -5- (t-butoxy carbonyl) -5- azaspiro [2.4] heptane -6- carboxylic acid be condensed to yield di-tert-butyl 6,6'- (((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) (6S, 6'S)-two (5- azaspiro [2.4] heptane -5- carboxylate).
LC-MS:637.30 (M-2Boc+H)+。
Step 2: (6S, 6'S)-N, N'- (1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (5- azaspiro [2.4] heptane -6- formamides) preparation
1 step 5 of reference implementation example, di-tert-butyl 6,6'- (((Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycle six luxuriant -12,43Diyl two (4; 1- phenylene)) two (azane diyls)) two (carbonyls)) (6S; 6'S)-two (5- azaspiro [2.4] heptane -5- carboxylates) deprotection obtains (6S; 6'S)-N; N'- (1; 4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (5- azaspiro [2.4] heptane -6- formamides).
LC-MS:637.30 (M+H)+。
Step 3: dimethyl ((2S, 2'S)-((6S, 6'S)-(((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (5- azaspiro [2.4] heptane -6,5- diyl)) two (3- methyl-1s-carbonyl butane -1,2- diyl)) diurethane preparation
1 step 6 of reference implementation example, (6S, 6'S)-N, N'- (Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (5- azaspiro [2.4] heptane -6- formamides) are condensed to yield dimethyl ((2S, 2'S)-((6S, 6'S)-(((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (5- azaspiro [2.4] heptane -6,5- diyl)) two (3- methyl-1s-carbonyl butane -1,2- diyl)) diurethane.
LC-MS:951.40 (M+H)+；
1H NMR (400MHz, DMSO) δ 10.12 (s, 2H), 7.72 (d, J=6.8Hz, 4H), 7.48 (d, J=8.4Hz, 4H), 6.75 (d, J=7.6Hz, 2H), 6.62 (s, 2H), 6.46 (d, J=7.6Hz, 2H), 4.64 (t, J=7.6Hz, 2H), 3.96 (t, J=9.6Hz, 2H), 3.74 (d, J=9.6Hz, 2H), 3.67 (d, J=9.6Hz, 2H), 3.54 (s, 6H), 3.02-2.96 (m, 2H), 2.85-2.79 (m, 2H), (2.62-2.59 m, 2H), 2.1 5-2.09 (m, 2H), 2.02-1.96 (m, 4H), 1.28-1.23 (m, 4H), 0.99-0.97 (m, 6H), 0.90-0.88 (m, 6H), 0.70-0.68 (m, 2H), 0.64-0.56 (m, 6H).
5 dimethyl of embodiment ((2S, 2'S, 3R, 3'R)-((6S, 6'S)-(((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (5- azaspiro [2.4] heptane -6,5- diyl)) two (3- methoxyl group -1- carbonyl butane -1,2- diyls)) diurethane
1 step 6 of reference implementation example, (6S, 6'S)-N, N'- (Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (5- azaspiro [2.4] heptane -6- formamides) and N- methoxycarbonyl group-O- methyl-L-threonine be condensed to yield dimethyl ((2S, 2'S, 3R, 3'R)-((6S, 6'S)-(((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (5- azaspiro [2.4] heptane -6,5- diyl)) two (3- methoxyl group -1- carbonyl butane -1,2- diyls)) diurethane.
LC-MS:983.50 (M+H)+；
1H NMR (400MHz, DMSO) δ 10.04 (s, 2H), 7.72 (d, J=7.6Hz, 4H), 7.48 (d, J=8.4Hz, 4H), 7.34 (d, J=7.2Hz, 2H), 6.75 (d, J=8.0Hz, 2H), 6.64 (s, 2H), 6.46 (d, J=7.6Hz, 2H), 4.63 (t, J=7.2Hz, 2H), 4.21 (t, J=7.6Hz, 2H), 3.77-3.70 (m, 4H), 3.55 (s, 6H), 3.52-3.47 (m, 2H), 3.38-3.35 (m, 6H), 3.28 (s, 3H), 3.27 (s, 3H) 3.02-2.97 (m, 2H), 2.85-2.80 (m, 2H), 2.64-2.61 (m, 2H), 2.16-2.11 (m, 2H), 2.02-1.97 (m, 2H), 1.20-1.18 (m, 6H), 0.72-0.69 (m, 2H), 0.63-0.56 (m, 4H).
6 dimethyl ((2S of embodiment, 2'S)-((1R, 1'R, 3S, 3'S, 4S, 4'S)-(((1,4 (1,4)-luxuriant -12,43- diyl two (4,1- phenylene) of hexichol heterocycle six) two (azane diyls)) two (carbonyls)) two (2- azabicyclic [2.2.1] heptane -3,2- diyl)) two (3- methyl-1s-carbonyl butane -1,2- diyl)) diurethane
Step 1: di-tert-butyl 3,3'- (((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) (1R, 1'R, 3S, 3'S, 4S, 4'S)-two (2- azabicyclic [2.2.1] heptane -2- carboxylates) preparation
1 step 4 of reference implementation example, 4,4'- (Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycles six luxuriant -12,43Diyl) diphenylamines and (1R, 3S, 4S) -2- (t-butoxy carbonyl) -2- azabicyclic [2.2.1] heptane -3- carboxylic acid be condensed, obtain di-tert-butyl 3,3'- (((Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) (1R, 1'R, 3S, 3'S, 4S, 4'S)-two (2- azabicyclic [2.2.1] heptane -2- carboxylates) preparation.
LC-MS:637.30 (M-2Boc+H)+。
Step 2: (1R, 1'R, 3S, 3'S, 4S, 4'S)-N, N'- (1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (2- azabicyclic [2.2.1] heptane -3- formamides) preparation
1 step 5 of reference implementation example, di-tert-butyl 3,3'- (((Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) (1R, 1'R; 3S, 3'S, 4S; 4'S)-two (2- azabicyclic [2.2.1] heptane -2- carboxylates) deprotection obtains (1R, 1'R, 3S; 3'S; 4S, 4'S)-N, N'- (1; 4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (2- azabicyclic [2.2.1] heptane -3- formamides).
LC-MS:637.30 (M+H)+。
Step 3: dimethyl ((2S, 2'S)-((1R, 1'R, 3S, 3'S, 4S, 4'S)-(((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (2- azabicyclic [2.2.1] heptane -3,2- diyl)) two (3- methyl-1s-carbonyl butane -1,2- diyl)) diurethane preparation
1 step 6 of reference implementation example, (1R, 1'R, 3S, 3'S, 4S, 4'S)-N, N'- (Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (2- azabicyclic [2.2.1] heptane -3- formamides) are condensed to yield dimethyl ((2S, 2'S)-((1R, 1'R, 3S, 3'S, 4S, 4'S)-(((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (2- azabicyclic [2.2.1] heptane -3,2- diyl)) two (3- methyl-1s-carbonyl butane -1,2- diyl)) diurethane.
LC-MS:951.35 (M+H)+；
1H NMR (400MHz, DMSO) δ 10.3 (s, 2H), 7.73 (d, J=8.0Hz, 4H), 7.46 (d, J=8.0Hz, 4H), 6.74 (d, J=7.6Hz, 2H), 6.68 (d, J=7.6Hz, 2H), 6.62 (s, 2H), 6.45 (d, J=7.6Hz, 2H), 4.51 (s, 2H), 4.13-4.06 (m, 2H), 4.05 (s, 2H), 3.55 (s, 6H), 3.35-3.30 (m, 2H), 3.02-2.96 (m, 2H), 2.85-2.79 (m, 2H), (2.62-2.59 m, 2H), 2.15-2. 09 (m, 2H), 2.12-2.06 (m, 4H), 2.03-1.97 (m, 6H), 1.51-1.41 (m, 4H), 1.02-1.00 (m, 6H), 0.94-0.92 (m, 6H).
7 dimethyl of embodiment ((2S, 2'S, 3R, 3'R)-((1R, 1'R, 3S, 3'S, 4S, 4'S)-(((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (2- azabicyclic [2.2.1] heptane -3,2- diyl)) two (3- methoxyl group -1- carbonyl butane -1,2- diyls)) diurethane
1 step 6 of reference implementation example, (1R, 1'R, 3S, 3'S, 4S, 4'S)-N, N'- (Isosorbide-5-Nitrae (Isosorbide-5-Nitrae)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (2- azabicyclic [2.2.1] heptane -3- formamides) and N- methoxycarbonyl group-O- methyl-L-threonine be condensed to yield dimethyl ((2S, 2'S, 3R, 3'R)-((1R, 1'R, 3S, 3'S, 4S, 4'S)-(((1,4 (1,4)-hexichol heterocycle six luxuriant -12,43Diyl two (4,1- phenylene)) two (azane diyls)) two (carbonyls)) two (2- azabicyclic [2.2.1] heptane -3,2- diyl)) two (3- methoxyl group -1- carbonyl butane -1,2- diyls)) diurethane.
LC-MS:983.35 (M+H)+；
1H NMR (400MHz, DMSO) δ 10.08 (s, 2H), 7.72 (d, J=8.6Hz, 4H), 7.48 (d, J=8.4Hz, 4H), 7.28 (d, J=8.0Hz, 2H), 6.75 (d, J=7.6Hz, 2H), 6.62 (s, 2H), 6.46 (d, J=7.6Hz, 2H), 4.57 (s, 2H), 4.32 (t, J=7.6Hz, 2H), 4.25-4.23 (m, 1H), 4.02 (s, 2H), 3.55 (s, 6H), 3.52-3.47 (m, 1H), 3.34-3.30 (m, 4H), 3.28 (s, 3H), 3.27 (s, 3 ), H 2.99-2.96 (m, 2H), 2.79-2.85 (m, 2H), 2.73-2.70 (m, 2H), 2.61-2.59 (m, 2H), 2.10-2.12 (m, 2H), 1.68-1.80 (m, 4H), 1.48-1.42 (m, 4H), 1.24-1.19 (m, 6H).
Biological assessment
(measurement of wild type hepatitis C virus HCV gene 1b inhibitory activity)
The compounds of this invention to the HCV inhibitory activity replicated is measured by HCV replicon luciferase reporter gene analysis method (HCV Replicon Reporter Luciferase Assay).
1, the cell model of experiment: the Huh-7 cell line that HCV replicon luciferase reporter gene surely turns.
2, experimental solutions preparation method:
Untested compound stock solution is formulated as 10mM with dimethyl sulfoxide, is diluted to test maximum concentration with DMSO when experiment, then carries out 3 times with culture medium and be serially diluted, be generally diluted to 8 to 10 concentration points, each concentration point sets duplicate hole.Dimethyl sulfoxide final concentration of 0.5%.Experiment includes internal reference compound every time, and 1 is reference compound (ACH-3102), and another 1 is Cyclosporine.
3, measuring step:
1) cell is grown on 96 well culture plates, the untested compound of various concentration and internal reference compound is added to the cell of culture after 24 hours.
2) after 48 hours, uciferase activity is detected with microplate reader.
3) initial data is analyzed, calculates test-compound various concentration point to the inhibition of uciferase activity i.e. to the suppression percentage of HCV replicon.
4) non linear fit analysis is carried out to suppression percentage data using GraphPad Prism software and obtains the half-inhibitory concentration IC of compound50Value.
The activity of compound of the embodiment of the present invention and reference compound (ACH-3102) is measured by above test, wild type hepatitis C virus HCV gene 1b inhibitory activity IC50Value the results are shown in Table 1:
Embodiment number IC50(nM)
Embodiment 1 0.011
Embodiment 2 0.0064
Embodiment 3 0.0023
Embodiment 4 0.0037
Embodiment 5 0.002
Embodiment 7 0.050
Reference compound ACH-3102 0.0190

Claims (16)

  1. One kind having formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts:
    Wherein:
    R1、R1' it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, C1-8Alkyl, C1-8Alkoxy or C3-8Naphthenic base,
    Halogen, hydroxyl, C are further optionally selected from by one or more1-8Alkyl, C1-8Alkoxy, halogen replace C1-8Alkoxy, hydroxyl replace C1-8Alkoxy, C1-8Naphthenic base or C1-8Replaced the substituent group of cycloalkyloxy；
    R2、R2’、R3、R3’、R4、R4’、R5、R5' it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, C1-8Alkyl, C3-8Naphthenic base, C1-8Alkoxy or C3-8Cycloalkyloxy,
    Halogen, hydroxyl, amino, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C1-8Alkoxy, C3-8Replaced cycloalkyloxy or the substituent group of 3-8 circle heterocyclic ring base oxygroup；
    L, L ' is independently selected from such as flowering structure:
    Halogen, hydroxyl, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
    R6、R6' it is independently selected from hydrogen, deuterium, C1-8Alkyl, C1-8Alkoxy, C3-8Naphthenic base, halogenated C1-8Alkyl, C1-8Alcoxyl C1-8Alkyl, hydroxyl C1-8Alkyl ,-C (O) R14Or-C (O) OR13,
    Halogen, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
    R7、R7' it is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13,
    Alternatively, R7Or R7' coupled nafoxidine ring is formed together the nitrogenous loop coil of 6-10 member, bridged ring or condensed ring,
    Halogen, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、 -C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
    R8、R8' it is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13,
    Halogen, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13；
    R9、R9' it is independently selected from hydrogen, deuterium, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Aryl, 5-10 unit's heteroaryl ,-C0-8-C(O)R9、-C0-8-C(O)OR9Or-C0-8-C(O)NR6R7,
    Halogen, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
    R10、R11It is independently selected from hydrogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Aryl, 5-10 unit's heteroaryl or C1-8Alkyl acyl,
    Halogen, hydroxyl, sulfydryl, cyano, nitro, acetylamino, azido, sulfonyl, mesyl, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C1-8Alkoxy, C1-8Alkoxy carbonyl group, C1-8Alkyl-carbonyl, C1-8Alkyl carbonyl epoxide, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl, amino, list C1-8Alkyl amino or two C1-8Replaced the substituent group of alkyl amino；
    R12Selected from hydrogen, deuterium, C1-8Alkyl, C3-8Naphthenic base, halogen replace C1-8Alkyl, two C1-8Alkyl amino, phenyl or p-methylphenyl；
    R13Selected from hydrogen, deuterium, C1-8Alkyl, C3-8Naphthenic base, halogen replace C1-8Alkyl or hydroxyl replace C1-8Alkyl；
    R14Selected from hydrogen, deuterium, C1-8Alkyl, C1-8Alkoxy, C3-8Naphthenic base, C3-8Cycloalkyloxy, halogen replace C1-8Alkyl, halogen replace C1-8Alkoxy, hydroxyl replace C1-8Alkyl or hydroxyl replace C1-8Alkoxy；
    M, m ' is independently selected from 0~3；
    P, p ' is independently selected from 0~7；
    R is 0,1 or 2.
  2. It is according to claim 1 that there are formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that R6、R6' it is independently selected from hydrogen, deuterium, C1-4Alkyl, C1-4Alkoxy, C3-6Naphthenic base, halogenated C1-4Alkyl, C1-4Alcoxyl C1-4Alkyl, hydroxyl C1-4Alkyl ,-C (O) R14Or-C (O) OR13,
    Halogen, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced.
  3. It is according to claim 2 that there are formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that R6、R6' it is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclohexyl, methoxyl group, ethyoxyl or isopropoxy, preferably hydrogen.
  4. It is according to claim 1 that there are formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that R1、R1' it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, C1-4Alkyl, C1-4Alkoxy or C3-6Naphthenic base, preferably hydrogen, deuterium, fluorine, hydroxyl, amino, methyl, ethyl or cyclopropyl.
  5. It is according to claim 1 that there are formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that R2、R2’、R3、R3’、R4、R4’、R5、R5' it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, C1-4Alkyl, C3-6Naphthenic base, C1-4Alkoxy or C3-8Cycloalkyloxy, preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, hydroxyl, amino, methoxyl group or cyclopropyl.
  6. It is according to claim 1 that there are formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that L, L ' it is independently selected from such as flowering structure:
    Halogen, hydroxyl, cyano, nitro, azido, C are further optionally selected from by one or more1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl group, C3-6Naphthenic base, 3-6 circle heterocyclic ring base, 3-6 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-4-S(O)rR12、-C0-4-O-R13、-C0-4-C(O)R14、-C0-4-C(O)OR13、-C0-4-O-C(O)R14、-C0-4-NR10R11、-C0-4-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13Substituent group replaced；
    It is preferred that such as flowering structure:
  7. It is according to claim 1 that there are formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that
    R7、R7' it is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C1-4Alkyl, C2-6Alkenyl, C2-6Alkynyl group, C3-6Naphthenic base, 3-6 circle heterocyclic ring base, 3-6 circle heterocyclic ring base oxygroup, 3-6 circle heterocyclic ring base sulfenyl, C5-8Aryl, C5-8Aryloxy, C5-8Artyl sulfo, 5-8 unit's heteroaryl, 5-8 unit's heteroaryl oxygroup, 5-8 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13,
    Alternatively, R7Or R7' coupled nafoxidine ring is formed together the nitrogenous loop coil of 6-10 member, bridged ring or condensed ring, selected from such as flowering structure:
  8. It is according to claim 1 that there are formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that selected from such as following formula (II) compound:
    R7、R7’、R8、R8’、R9、R9' as defined in claim 1.
  9. It is according to claim 1 that there are formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that R7、R7' it is independently selected from hydrogen, deuterium, fluorine, methyl, ethyl or isopropyl, alternatively, R7Or R7' coupled nafoxidine ring is formed together such as flowering structure:
  10. It is according to claim 1 that there are formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that R8、R8' it is independently selected from hydrogen, deuterium, halogen, methyl, ethyl, isopropyl, cyclopropyl ,-C0-8-S(O)rR12、-C0-8-O-R13、-C0-8-C(O)R14、-C0-8-C(O)OR13、-C0-8-O-C(O)R14、-C0-8-NR10R11、-C0-8-C(O)NR10R11、-N(R10)-C(O)R14Or-N (R10)-C(O)OR13。
  11. It is according to claim 1 that there are formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that R9、R9' be independently selected from from hydrogen, deuterium, C1-4Alkyl, allyl, acetenyl, C3-6Naphthenic base, 3-6 circle heterocyclic ring base or phenyl.
  12. According to claim 1, -11 is described in any item with formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that are selected from following compound:
  13. According to claim 1, -12 any described have formula (I) compound, its stereoisomer or its pharmacy The preparation method of upper acceptable salt, includes the following steps:
    Wherein: Pg is amino protecting group, preferred tertbutyloxycarbonyl, allyl carbonyl, tablet held before the breast by officials methoxycarbonyl group, methoxycarbonyl group, carbethoxyl group, trimethylsilyl ethoxycarbonyl or benzyloxycarbonyl group preferably is selected from, more preferably from tertbutyloxycarbonyl；R1、R1’、R2、R2’、R3、R3’、R4、R4’、R5、R5’、R6、R6’、R7、R7’、R8、R8’、R9、R9’、R10、R11、R12、R13、R14, L, L ', p, p ', m, m ', r it is as defined in claim 1.
  14. Preparation method according to claim 13, it is characterized in that, the acid binding agent is organic base or inorganic base, the organic base is selected from or mixtures thereof trimethylamine, triethylamine, pyridine, piperidines, morpholine, diisopropylethylamine, the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, or mixtures thereof sodium acetate；The condensing agent is selected from or mixtures thereof DIC, DCC, HOBT, EDCHCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI.
  15. A kind of pharmaceutical composition comprising treatment effective dose -12 any described has formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts and pharmaceutical carrier according to claim 1.
  16. - 12 any application with formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts or pharmaceutical composition according to claim 15 in preparation treatment or prevention HCV infection disease medicament according to claim 1.
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WO2012166716A2 (en) * 2011-05-27 2012-12-06 Achillion Pharmaceuticals, Inc. Subsituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero-heteraphanes and metallocenes useful for treating hcv infections
WO2013106520A1 (en) * 2012-01-13 2013-07-18 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
WO2015026454A1 (en) * 2013-07-17 2015-02-26 Bristol-Myers Squibb Company Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis c virus

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WO2012166716A2 (en) * 2011-05-27 2012-12-06 Achillion Pharmaceuticals, Inc. Subsituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero-heteraphanes and metallocenes useful for treating hcv infections
WO2013106520A1 (en) * 2012-01-13 2013-07-18 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
WO2015026454A1 (en) * 2013-07-17 2015-02-26 Bristol-Myers Squibb Company Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis c virus

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