CN106554382B

CN106554382B - Application in nucleoside phosphoramidite class compound and preparation method thereof and drug

Info

Publication number: CN106554382B
Application number: CN201510632656.XA
Authority: CN
Inventors: 刘钢; 郁楠; 吴勇勇; 唐祖建; 郑小洲; 陈强强; 邓汉文; 段小凡; 宋帅; 杨龙; 李筛; 黄海涛; 张毅涛; 赵明亮; 邓华; 钟维; 李栋宏; 曾宏; 郭先芬; 宋宏梅
Original assignee: Sichuan Kelun Botai Biological Pharmaceutical Ltd By Share Ltd
Current assignee: Sichuan Kelun Botai biological pharmaceutical Limited by Share Ltd
Priority date: 2015-09-29
Filing date: 2015-09-29
Publication date: 2019-12-03
Anticipated expiration: 2035-09-29
Also published as: CN106554382A

Abstract

The present invention provides the purposes of nucleoside phosphoramidite class compound and the compound as antiviral drugs shown in a kind of formula (I).The inhibitor that formula (I) compound of the invention is able to suppress the duplication of RNA virus, can be used as Hepatitis C Virus (HCV) NS5B polymerase.The compound of the present invention is while polymerizeing enzyme inhibition with NS5B, to the small toxicity of liver cell.

Description

Application in nucleoside phosphoramidite class compound and preparation method thereof and drug

Technical field

Purposes the present invention relates to nucleoside phosphoramidite class compound and the compound as antiviral drugs.More For body, the duplication for inhibiting RNA virus, the inhibitor that can be used as Hepatitis C Virus (HCV) NS5B polymerase are related to Nucleoside phosphoramidite class compound.

Background technique

Hepatitis C Virus (HCV) is a kind of single-stranded, positive chain RNA virus, belongs to hepatitis virus category flaviviridae.According to volume The gene of code NS5B ribonucleic acid dependent form ribonucleic acid polymerase is different, and Hepatitis C Virus is divided into 6 genotype, 50 Asias Type.Distribution of the different genotype in the whole world is all different.In North America and Europe, it was found that genotype 1,2,3, wherein genotype 1 It is in the great majority.Africa almost only exists the patient of 4 type of gene, the infection of 5 types.The common genotype of China is 1b and 2a, wherein with Based on 1b, 6 types be mainly seen in Hong Kong and Macao (Simmonds, P.Journal of General Virology, 2004,85, 3173–3188).Wherein, cirrhosis and liver cancer patient genotype 1b are apparently higher than chronic hepatitis patient.Genotype 1 b recurs the third type Hepatitis, hepatopathy are serious compared with other genotype.It is higher that genotype 1a, 2a merge hepatitis B infected incidence, most of (74%) oxyhepatitis patient is genotype 1a.Genotype 4, which infects, easily causes decompensation hepatic complications.Genotype 3a infection It is more close with the relationship of fatty liver.

Hepatitis C infection is worldwide Major health problems.According to the statistics of the World Health Organization, the whole world there are about 200000000 people infect hepatitis, annual new infections person three, 4,000,000.After infection, 20% the infected can remove virus automatically, but big Part the infected can carry virus throughout one's life.It can develop in the infected of 10%-20% as chronic liver diseases such as cirrhosis, liver cancer.Third The main reason for liver function decompensation caused by type hepatitis is all worldwide liver transplant, brings to patient and society Heavy financial burden.

In the prior art, the therapeutic scheme of standard is Peg-IFN alpha-2b joint Ribavirin.However the therapy is only right 1 patient of genotype of 40-50% and 75% genotype 2,3 patients effectively (Zeuzem, S., et al.Journal of Viral Hepatitis, 2009,16,75~90).To certain sub- crowds, Peg-IFN alpha-2b combines the curative effect of Ribavirin It is bad.Therefore, there is an urgent need to develop safely and effectively " directly effect antiviral drugs ".First generation hcv protease Inhibitor telavi and Bo Xipuwei emerge in succession.Both drugs and Peg-IFN alpha-2b/Ribavirin are combined, can be with The virus sweep rate of 1 type patient of gene is improved, the course for the treatment of is shortened.But this three new combination treatments bring new problem, example Such as more side effects, dosage regimen is complicated, Yi Fasheng drug resistance, and only effective to the patient of 1 virus of infection genotype (Kwong, A.D.et al.Current Opinion in Pharmacology, 2008,8,522~531).New " directly makees With antiviral drugs " need to meet following three points requirement: 1) it can be taken orally；2) effective to all genotype；3) it is not necessarily to With Peg-IFN alpha-2b joint Ribavirin combination.

NS5B ribonucleic acid dependent form ribonucleic acid polymerase is a kind of important antiviral molecule target spot.This virus is special Anisotropic enzyme is most important to the duplication of Hepatitis C Virus.NS5B polymerase contains about 590 amino acid, molecular weight 66KDa, tool There is all existing palm-finger-thumb structural unit in many varial polymerases.The active site of enzyme is located at palm area, It is made of three amino acid: Gly317-Asp318-Asp319 (GDD).GDD catalytic structure cell height is conservative, in all bases Because that can be found in type.The bivalent metal ion (magnesium ion or manganese ion) being coordinated by one, GDD unit and nucleoside triphosphate In conjunction with.Then, by forming diphosphonic acid ester bond, nucleoside triphosphate is connected on the RNA chain in growth.Therefore, nucleoside analog As the inhibitor of NS5B polymerase, obtained in depth as " directly effect antiviral drugs " as general genotype is expected to Research.

Nucleoside analog allows for being converted into nucleoside triphosphate, can just play the role of inhibiting varial polymerases.This Process needs the participation of three kinds of different kinases.The efficiency of phosphorylation determines nucleoside analog as viral polymerase inhibitors Activity.In addition, the activity of inhibitor also depend on nucleoside triphosphate there are the times.Nucleoside triphosphate there are the time is longer, The activity of inhibitor is also higher.During phosphorylation, nucleoside analog and its monophosphate, diphosphonic acid metabolin may be not It is the good substrates of respective kinase.Research shows that first kinases is most strong to the selectivity of substrate in Phosphorylation events.Therefore First step phosphorylation is usually most difficult step.In order to overcome this difficulty, monophosphate is transported to and is necessary into the cell Means.But monophosphate nucleosides is negatively charged, is difficult through cell membrane, and is easy to be degraded by phosphate.

Suo Feibuwei (sofosbuvir) is a kind of Hepatitis C Virus (HCV) nucleotide analog NS5B polymerase inhibition Agent, it is suitable for being infected to treat chronic hepatitis C (CHC) as the composition in combination antiviral therapy scheme.But rope Fei Buwei and its metabolite are mainly removed by kidney, for the patient of serious kidney injury, can aggravate its kidney burden.And And the prodrug based on Suo Feibuwei change structure compound metabolic mechanism it is identical as Suo Feibuwei, there is also similar to Suo Feibuwei Defect.

In addition, Suo Feibuwei is poor to the drug effect of 3 the infected of genotype, the course for the treatment of 24 weeks.And genotype 1,2 and 4 is felt The course for the treatment of of dye person needs 12 weeks.

Summary of the invention

The present invention provides a kind of nucleoside phosphoramidite class compound, the nucleoside triphosphate ratio generated after being metabolized in hepatic tissue The nucleoside triphosphate that Suo Feibuwei is generated is more.It may infer that nucleoside phosphoramidite class compound of the invention (hereinafter also referred to as " this The compound of invention ") inhibitor as Hepatitis C Virus (HCV) NS5B polymerase, drug effect peso Fei Buwei medicine is good.Cause This, the compound of the present invention will get well the drug effect peso Fei Buwei of the hepatitis of certain genotype.Also, the compound of the present invention While polymerizeing enzyme inhibition with NS5B, to the small toxicity of liver cell.

Specifically, the present invention relates to following:

[1] following formula (I) compounds represented or its pharmaceutically acceptable salt, ester, solvate, hydrate, isomers, Or their any crystal form or racemoid or their metabolite form and their mixture,

Wherein,

R₁Expression hydrogen, the C1-10 alkyl optionally replaced, the C1-10 miscellaneous alkyl optionally replaced, the C3-7 cycloalkanes optionally replaced Base, the C2-10 alkenyl optionally replaced, the C2-10 alkenyl oxygroup optionally replaced, optionally takes the C3-7 Heterocyclylalkyl optionally replaced The C2-10 alkynyl in generation, the C2-10 alkynyl oxygroup optionally replaced, the C1-10 acyl group optionally replaced, the aryl optionally replaced, optionally Substituted aryl C1-10 alkyl, the aromatic heterocyclic C1-10 alkyl that optionally replaces, optionally replaces the aromatic heterocyclic optionally replaced Alicyclic heterocyclic base or the alicyclic heterocyclic base C1-10 alkyl optionally replaced；

R₂And R₃Each independently represent hydrogen, the C1-10 alkyl that optionally replaces, the C1-10 miscellaneous alkyl optionally replaced, optionally Substituted C3-7 naphthenic base, the C3-7 Heterocyclylalkyl optionally replaced, the C2-10 alkenyl optionally replaced, the C2-10 alkene optionally replaced Base oxygroup, the C2-10 alkynyl oxygroup optionally replaced, the C1-10 acyl group optionally replaced, optionally takes the C2-10 alkynyl optionally replaced The aryl in generation, the aryl C1-10 alkyl optionally replaced, the aromatic heterocyclic optionally replaced, the aromatic heterocyclic C1-10 alkane optionally replaced Base, the alicyclic heterocyclic base optionally replaced or the alicyclic heterocyclic base C1-10 alkyl optionally replaced；Or R₂And R₃With the carbon atom being connect It is formed together carbonyl；

R₄And R₅Each independently represent hydrogen, the C1-10 alkyl that optionally replaces, the C1-10 miscellaneous alkyl optionally replaced, optionally Substituted C3-7 naphthenic base, the C3-7 Heterocyclylalkyl optionally replaced, the C2-10 alkenyl optionally replaced, the C2-10 alkene optionally replaced Base oxygroup, the C2-10 alkynyl oxygroup optionally replaced, the C1-10 acyl group optionally replaced, optionally takes the C2-10 alkynyl optionally replaced The aryl in generation, the aryl C1-10 alkyl optionally replaced, the aromatic heterocyclic optionally replaced, the aromatic heterocyclic C1-10 alkane optionally replaced Base, the alicyclic heterocyclic base optionally replaced or the alicyclic heterocyclic base C1-10 alkyl optionally replaced；Or R₄And R₅With the carbon atom being connect It is formed together the carbocyclic ring of C3-8, which is optionally further selected from the hetero atom of N, O and S containing 1-3；

R₆、R₇、R₈Each independently represent hydrogen, halogen or MR₉；

M indicates O, N, S or singly-bound；

R₉Indicate hydrogen, optionally replace C1-10 alkyl, optionally replace C2-10 alkenyl, optionally replace C1-10 acyl group, The aryl that optionally replaces, the aryl C1-10 alkyl optionally replaced, the aromatic heterocyclic optionally replaced, the aromatic heterocyclic optionally replaced C1-10 alkyl, the alicyclic heterocyclic base optionally replaced or the alicyclic heterocyclic base C1-10 alkyl optionally replaced；Condition is, when M indicates singly-bound When, R₉Do not indicate hydrogen,

Or R₆、R₇、R₈It is formed together with the phenyl ring being connect with flowering structure:

Wherein, R-portion indicates the five-ring heterocycles part or hexa-member heterocycle part being formed together with phenyl ring, and R ' is each independently Indicate hydrogen, halogen or MR₉；The R-portion optionally includes the 1-3 atoms for being selected from O, N and S,

R₁₀C1-10 alkyl, oxo base, hydroxyl, carboxyl, cyano or the nitro for each independently representing halogen, optionally replacing；

The integer of m expression 1-3；

N indicates the integer of 1-3, and condition is to work as R₁₀When indicating oxo base, n indicates 1 or 2；

Y indicates nitrogen or oxygen；

As the substituent group of " optionally replacing ", it is each independently selected from halogen, hydroxyl, carboxyl, cyano, nitro and C1-10 Alkyl；

Condition is to work as R₁For isopropyl, R₂And R₃Carbonyl is formed together with the carbon atom being connect, Y indicates N, R₄、R₅Respectively It is independent to be selected from hydrogen, methyl and R₄And R₅When different from each other, R₆、R₇、R₈It is not simultaneously hydrogen；

Also, R₆、R₇、R₈Each independently represent hydrogen, MR₉, and R₆、R₇、R₈In two be simultaneously hydrogen, and M indicates single When key, R₉Do not indicate the C3-4 naphthenic base optionally replaced；The C3-4 Heterocyclylalkyl optionally replaced；Optionally by halogen, C1-10 alkane Base, C2-10 alkenyl, nitro, the phenyl that C1-6 alkoxy, cyano replace；

Also, work as R₆、R₇、R₈When be formed together with the phenyl ring being connect with flowering structure:

R₁Ethyl, cyclohexyl are not indicated.

[2] compound according to [1] or its pharmaceutically acceptable salt, ester, solvate, hydrate, isomers, or Their any crystal form or racemoid or their metabolite form and their mixture, wherein R₁Expression optionally takes The C1-4 alkyl in generation, the phenyl optionally replaced, the benzyl optionally replaced, the C1-5 acyl group optionally replaced, the benzene first optionally replaced Acyl group, the benzo alicyclic heterocyclic base optionally replaced or the benzo alicyclic heterocyclic base C1-4 alkyl optionally replaced.

[3] compound according to [1] or [2] or its pharmaceutically acceptable salt, ester, solvate, hydrate, isomery Body or their any crystal form or racemoid or their metabolite form and their mixture, wherein R₁Indicate first Base, ethyl, n-propyl, isopropyl, isobutyl group, difluorophenyl, Fluoro-benz rLl, acetyl group, (2,3- coumaran -5- Base)-methyl, (2,3- dihydrobenzo [1,4] dioxane -6- base)-methyl, benzo [1,3] dioxolanes benzyl.

[4] according to [1]-[3] described in any item compounds or its pharmaceutically acceptable salt, ester, solvate, hydration Object, isomers or their any crystal form or racemoid or their metabolite form and their mixture, wherein R₂And R₃The C1-4 alkyl or R for each independently representing hydrogen or optionally replacing₂And R₃It is formed together with the carbon atom being connect Carbonyl.

[5] according to [1]-[4] described in any item compounds or its pharmaceutically acceptable salt, ester, solvate, hydration Object, isomers or their any crystal form or racemoid or their metabolite form and their mixture, wherein R₂And R₃Carbonyl or R are formed together with the carbon atom being connect₂And R₃It is simultaneously hydrogen.

[6] according to [1]-[5] described in any item compounds or its pharmaceutically acceptable salt, ester, solvate, hydration Object, isomers or their any crystal form or racemoid or their metabolite form and their mixture, wherein R₄And R₅The C1-4 alkyl or benzyl for each independently representing hydrogen, optionally replacing.

[7] according to [1]-[6] described in any item compounds or its pharmaceutically acceptable salt, ester, solvate, hydration Object, isomers or their any crystal form or racemoid or their metabolite form and their mixture, wherein R₄And R₅Each independently represent hydrogen or methyl.

[8] according to [1]-[7] described in any item compounds or its pharmaceutically acceptable salt, ester, solvate, hydration Object, isomers or their any crystal form or racemoid or their metabolite form and their mixture, wherein R₆、R₇、R₈It is formed together with the phenyl ring being connect with flowering structure

Representation 2,3- Dihydrobenzofuranes -6- base, benzofuran -6- base, benzo [b] [1,4] dioxane -5- Base, 4- methyl -2- oxo -3,4- dihydro-benzo [b] [1,4] morpholine -7- base, 4- methyl -3- oxo -3,4- dihydro-benzo [b] [1,4] morpholine -8- base, benzo [d] [1,3] dioxolanes -5- base, benzo [d] [1,3] dioxolanes -4- base, 3- oxo - 4- methyl -2H- benzo [b] [1,4] morpholine -7- base, 4- methyl -2H- benzo [b] [1,4] morpholine -7- base, 2- oxo -1,3- first Base -1H- benzo [b] imidazoline -4- base, 2,2- dioxo -1,3- dihydrobenzo [c] thiophene -5- base, oxo -3 4- methyl -3-, 4- dihydro -2H- benzo [b] [1,4] morpholine -6- base, 3- methyl -2H- benzo [d] -2- oxazolidone -7- base, 2- oxo -1,3- first Base -1H- benzo [b] imidazoline -5- base, 4- methyl -2H- benzo [b] [1,4] morpholine -8- base, 4- methyl -2H- benzo [b] [1, 4] morpholine -6- base, 3- methylbenzoxazole -2- oxo -5- base, the fluoro- 2,3- Dihydrobenzofuranes -4- base of 7-, benzoxazoles -5- Base, 2,3- dihydrobenzo [1,4] dioxane -5- base, 7- Fluorobenzofur -4- base, benzoxazoles -6- base, benzoxazoles -4- Base, 4- methyl -3,4- dihydrobenzo [1,4] morpholine -5- base, benzo tetrahydrofuran -6- base, 3- methylbenzoxazole -2- oxo - 6- base, benzo [1,3] dioxolanes -5- base, 4- methyl -3,4- dihydrobenzo [1,4] morpholine -8- base, 4- methyl -3,4- two Hydrogen -2H- benzo [b] [1,4] morpholine -7- base, 4- methyl -3,4- dihydro -2H- benzo [b] [1,4] morpholine -8- base, 4- methyl - 3,4- dihydrobenzo [1,4] morpholine -7- base or 2,3- dihydrobenzo [1,4] dioxane -5- base.

[9] according to [1]-[7] described in any item compounds or its pharmaceutically acceptable salt, ester, solvate, hydration Object, isomers or their any crystal form or racemoid or their metabolite form and their mixture, wherein R₇And R₈Indicate hydrogen or halogen, R₉Indicate MR₉。

[10] compound according to [9] or its pharmaceutically acceptable salt, ester, solvate, hydrate, isomers, Or their any crystal form or racemoid or their metabolite form and their mixture, wherein M indicates O or list Key, R₉Indicate phenyl, benzo [d] [1,3] dioxolanes -5- base, 2,3- coumaran -6- base, 2,2- optionally replaced Dioxo -1,3- dihydrobenzo [c] thiophene -5- base, the fluoro- 2,3- coumaran -4- base of 7-, 2,3- dihydrobenzo [1,4] Dioxane -6- base or the fluoro- 1,2- dimethyl -1H- indoles -6- base of 4-.

[11] according to [1]-[9] described in any item compounds or its pharmaceutically acceptable salt, ester, solvate, hydration Object, isomers or their any crystal form or racemoid or their metabolite form and their mixture, wherein Y Indicate nitrogen.

[12] manufacturing method of following formula (I) compounds represented, wherein passing through the method for following steps one to step 4 Prepare formula (I) compound,

Step 1: three oxyhalogen phosphorus shown in formula 2 are reacted with 1 compound represented of formula, obtain 3 compound represented of formula；

Step 2: 3 compound represented of formula is reacted with 4 compound represented of formula, obtains 5 compound represented of formula；

Step 3: 5 compound represented of formula is reacted with Pentafluorophenol shown in formula 6, obtains 7 compound represented of formula；With

Step 4: 7 compound represented of formula is reacted with 8 compound represented of formula, obtains formula (I) compound represented；

Wherein, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈Definition with Y is determined with any one of the claims [1]-[10] Justice is identical, and multiple X are identical or different, are each independently selected from halogen.

[13] pharmaceutical composition, containing compound described in any one of above-mentioned [1]~[11], its is pharmaceutically acceptable Salt, ester, solvate, hydrate, isomers, their any crystal form or racemoid, they metabolite form or they Mixture, and pharmaceutically acceptable auxiliary material.

[14] pharmaceutical composition according to [13], wherein further include can with described in above-mentioned any one of 1~10 Compound, its pharmaceutically acceptable salt, ester, solvate, hydrate, isomers, their any crystal form or racemoid, it Metabolite form or their mixture associated with other active constituents.

[15] pharmaceutical composition according to [14], wherein other active constituents associated with described include interferon, Virazole or its analog, HCV NS3 protease inhibitors, 1 inhibitor of alpha-Glucosidase, hepatoprotective, HCV NS5B polymerization Non-nucleosidic inhibitors, HCV NS5A inhibitor, TLR-7 agonist, cyclophilin inhibitor, the HCV IRES inhibitor, drug of enzyme Dynamics dose and other medicines or therapeutic agent for treating HCV, or combinations thereof.

[16] pharmaceutical composition according to [15], wherein the interferon is selected from PEGylated rIFN- α 2bPEGylated rIFN- α 2arIFN-α2b(A)、rIFN-α2a (Roferon), interferon-' alpha ' (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, Subalin), interferon alfacon-1Interferon alfa-n1 (Wellferon), Alferon NInterferon beta (Avonex DL-8234), interferon-ω (ωBiomed510)、 albinterferonα-2bIFNα-2bXL、BLX-883DA-3021, glycosyl The interferon alpha 2 b (AVI-005) of change, PEG-Infergen, PEGylated interferon lambda -1 (PEGylated IL-29) and

Described virazole and the like is selected from virazoleAnd Ta Liweilin (taribavirin)

The HCV NS3 protease inhibitors is selected from boceprevir (SCH-503034, SCH-7), tirrevir (telaprevir)(VX-950)、TMC435350、BI-1335、BI-1230、MK-7009、VBY-376、VX-500、GS- 9256、GS-9451、BMS-605339、PHX-1766、AS-101、YH-5258、YH5530、YH5531、ABT-450、ACH- 1625, ITMN-191, MK5172, MK6325 and MK2748；

1 inhibitor of alpha-Glucosidase is selected from Xi Gewei (celgosivir) (MX-3253), Miglitol and UT- 231B；

The hepatoprotective be selected from emericasan (IDN-6556), ME-3738, GS-9450 (LB-84451), Silibilin and MitoQ；

The non-nucleosidic inhibitors of the HCV NS5B polymerase are selected from PF-868554, VCH-759, VCH-916, JTK- 652、MK-3281、GS-9190、VBY-708、VCH-222、A848837、ANA-598、GL60667、GL59728、A-63890、 A-48773、A-48547、BC-2329、VCH-796(nesbuvir)、GSK625433、BILN-1941、XTL-2125、ABT- 072, ABT-333, GS-9669, PSI-7792 and GS-9190；

The HCV NS5A inhibitor is selected from ABT-267 (ombitasvir), AZD-2836 (A-831), BMS- 790052, ACH-3102, ACH-2928, MK8325, MK4882, MK8742, PSI-461, IDX719, GS-5885, GS-5816 And A-689；

The TLR-7 agonist is selected from imiquimod, 852A, GS-9620, ANA-773, ANA-975, AZD-8848 (DSP-3025) and SM-360320；

The cyclophilin inhibitor is selected from DEBIO-025, SCY-635 and NIM811；

The HCV IRES inhibitor is selected from MCI-067；

The pharmacokinetics reinforcing agent is selected from BAS-100, SPI-452, PF-4194477, TMC-41629, GS- 9350, GS-9585 and roxithromycin；With

The other drugs for treating HCV are selected from Thymosin alpha 1 (Zadaxin (Zadaxin)), Nitazoxanide (nitazoxanide)(Alinea、NTZ)、BIVN-401(virostat)、PYN-17(altirex)、KPE02003002、 actilon(CPG-10101)、GS-9525、KRN-7000、civacir、GI-5005、XTL-6865、BIT225、PTX-111、 TX2865、TT-033i、ANA971、NOV-205、tarvacin、EHC-18、VGX-410C、EMZ-702、AVI4065、BMS- 650032, BMS-791325, Bavituximab, MDX-1106 (ONO-4538), Oglufanide and VX-497 (merimepodib)。

[17] appoints according to [13]-[16] described in any item compositions wherein the composition contains in [1]~[11] Compound described in one, its pharmaceutically acceptable salt, ester, solvate, hydrate, isomers, their any crystal form or The amount of racemoid, their metabolite form or their mixture is 0.1-1000mg, preferably 1-800mg, more preferable 10- 600mg, particularly preferred 50-450mg, most preferably 100-300mg.

[18] according to [1]-[11] described in any item compounds, its pharmaceutically acceptable salt, ester, solvate, hydration Object, isomers, their any crystal form or racemoid, their metabolite form or their mixture are in preparation for controlling Treat the application in the drug of hepatitis.

[19] application in the drug for treating hepatitis is being prepared according to any one of [13]-[17] described composition.

Invention effect

Inhibitor of the compound of the present invention as Hepatitis C Virus (HCV) NS5B polymerase, can in vivo smoothly Metabolism, generates active nucleoside triphosphate metabolite, for the inhibitory effect peso Fei Buwei medicine of NS5B polymerase It is excellent.Also, the drug resistance of the invention for Hepatitis C Virus (HCV) is better than Suo Feibuwei.In addition, chemical combination of the invention Object is also small to the toxicity of liver cell while with NS5B polymerase inhibitory activity, the additional liver burden caused by patient Also small.

Specific embodiment

Illustrate the meaning of each term used in the present specification below.Each term is used with the unified meaning, is individually made Used time, or when being applied in combination with other terms, all with the use of the identical meaning.

In the present invention, " halogen " indicates fluorine atom, chlorine atom, bromine atom or iodine atom.

" C1-10 alkyl " refers to the alkyl for the straight-chain or branched that carbon atom number is 1~10, can enumerate such as first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, just oneself Base, isohesyl, n-heptyl, n-octyl, n-nonyl, positive decyl etc..It is preferred that the alkyl (i.e. C1-6 alkyl) that carbon atom number is 1~6, The alkyl (i.e. C1-4 alkyl) that more preferable carbon atom number is 1~4 can enumerate such as methyl, ethyl, n-propyl, isopropyl, just Butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohesyl.

" C2-10 alkenyl " refers to the straight-chain that the carbon atom number in abovementioned alkyl with 1 or more double bond is 2~10 Or the alkenyl of branched, such as vinyl, 1- acrylic, 2- acrylic, 1- cyclobutenyl, 2- cyclobutenyl, 3- butylene can be enumerated Base, 1,3- butadienyl, 3- methyl-2-butene base etc..

" C2-10 alkenyl oxygroup " refers to that alkenyl part is the group of above-mentioned C2-10 alkenyl.1- acrylic oxygen can be enumerated Base, 1- cyclobutenyl oxygroup, 2- pentenyl oxygroup.

" C2-10 alkynyl " refers to the straight-chain that the carbon atom number in abovementioned alkyl with 1 or more three keys is 2~10 Or the alkynyl of branched, it can enumerate such as acetenyl, propinyl, butynyl, and then also can have double bond.

" C2-10 alkynyl oxygroup " refers to that alkynyl moiety is the group of above-mentioned C2-10 alkynyl.1- propinyl oxygen can be enumerated Base, 1- butynyl oxygroup, valerylene base oxygroup.

" C1-10 miscellaneous alkyl ", which refers to, to be had in abovementioned alkyl selected from least one of N, O and S heteroatomic group, The hetero atom is inserted into alkyl, can also be connect alkyl with other groups by the hetero atom, wherein excludes two The case where above hetero atom is connected directly can enumerate C1-6 alkoxy, such as methoxyl group, ethyoxyl, propoxyl group, butoxy； C1-6 alkyl sulfenyl, such as methyl mercapto, ethylsulfanyl；Alkyl amino, such as methylamino, ethylamino；C1-6 alkoxy C 1- 4 alkyl；C1-6 alkyl sulfenyl C1-4 alkyl.

" C3-7 naphthenic base " refers to that carbon atom number is 3~7 cyclic annular saturated alkyl, can enumerate such as cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, suberyl etc..Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl is preferably listed." C3-4 naphthenic base " is Refer to that carbon atom number is 3~4 cyclic annular saturated alkyl, such as cyclopropyl, cyclobutyl can be enumerated.

" C3-7 Heterocyclylalkyl " refers to, further comprise on the ring of above-mentioned " C3-7 naphthenic base " in N, O and S extremely A few heteroatomic group, can enumerate oxetanyl, azetidinyl, Thietane base, tetrahydrofuran base, Pyrrolidinyl, imidazolidinyl, dioxanes base." C3-4 Heterocyclylalkyl " refers to, on the ring of above-mentioned " C3-4 naphthenic base " further Including epoxy ethyl, oxetanyl, azetidin can be enumerated selected from the heteroatomic group of at least one of N, O and S Alkyl, Thietane base, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl.

" C1-10 acyl group " refers to group shown in R-C (=O)-, wherein R is the group that carbon atom number is 1-10, such as It can be abovementioned alkyl, alkenyl, alkynyl, naphthenic base or aftermentioned aryl, aromatic heterocyclic, alicyclic heterocyclic base.Acetyl can be enumerated Base, propiono, benzoyl." C1-5 acyl group " refers in group shown in R-C (=O)-that R is the base that carbon atom number is 1-5 Group, is preferably formoxyl, acetyl group, propiono, bytyry.

" aryl " refers to monocyclic aromatic hydrocarbon group (example: phenyl) and polycyclic aromatic hydrocarbon radical (example: 1- naphthalene, 2- naphthalene, 1- Anthryl, 2- anthryl, 9- anthryl, 1- phenanthryl, 2- phenanthryl, 3- phenanthryl, 4- phenanthryl, 9- phenanthryl etc.).Phenyl or naphthyl is preferably listed (1- naphthalene, 2- naphthalene).

" aryl C1-10 alkyl " refers to, above-mentioned aryl and above-mentioned C1-10 it is alkyl linked made of group, for example, can arrange Lift benzyl, phenethyl, menaphthyl, naphthylethyl, preferably benzyl.

" aromatic heterocyclic " refers to monocyclic aromatic heterocycle base and fused aromatic heterocycle.

" monocyclic aromatic heterocycle base " refers to can be by having at least one heteroatomic 5~8 yuan in O, S and N in ring There is the group of key, for example, furyl, thienyl, pyrroles can be enumerated derived from aromatic rings, on substitutive any position Base, oxazolyl, thiazolyl, pyridyl group.

" fused aromatic heterocycle " refers to has at least one heteroatomic 5~8 yuan of fragrance in O, S and N in ring Ring and 1~4 5~8 yuan of aromatic carbocyclic or other 5~8 yuan of aromatic heterocycles it is condensed, have on substitutive any position The group of key, such as benzothienyl, benzimidazolyl, quinolyl, indyl can be enumerated.

" aromatic heterocyclic C1-10 alkyl " refers to, above-mentioned aromatic heterocyclic and above-mentioned C1-10 it is alkyl linked made of group, example Such as, furans -2- methyl, thiophene -3- methyl, pyridine -4- methyl can be enumerated.

" alicyclic heterocyclic base " refers to can be in ring in 1-3 heteroatomic 5~8 member rings selected from NO and S or in this way Ring and cycloalkane (preferably 5~6 yuan of cycloalkane), phenyl ring and/or ring in have selected from N, O and S at least one is heteroatomic There is the non-aromatic heterocycle of key on the ring that ring has condensed, in substitutive any position.Alicyclic heterocyclic base can be single ring systems, It is also possible to fused ring system.

It should be noted that " non-aromatic heterocycle " as long as it is non-aromatic, then can be saturation or unsaturated.

For example, such as 1- pyrrolinyl, 2- pyrrolinyl, 3- pyrroles can be enumerated when alicyclic heterocyclic base is single ring systems Quinoline base, 1- pyrrolidinyl, 2- pyrrolidinyl, 3- pyrrolidinyl, 1- imidazolinyl, 2- imidazolinyl, 4- imidazolinyl, 1- imidazoles Alkyl, 2- imidazolidinyl, 4- imidazolidinyl, 1- pyrazolinyl, 3- pyrazolinyl, 4- pyrazolinyl, 1- pyrazolidinyl, 3- pyrazoles Alkyl, 4- pyrazolidinyl, piperidino, 2- piperidyl, 3- piperidyl, 4- piperidyl, 1- piperazinyl, 2- piperazinyl, 2- morpholine Base, morpholinyl, morpholino, THP trtrahydropyranyl, 1,2,3,4- tetrahydro isoquinolyl, 1,2,3,4- tetrahydric quinoline group, 1,3- bis- Hydrogen -2H- iso-indoles -5- base etc..

When alicyclic heterocyclic base is fused ring system, it can be 5~8 member rings and cycloalkane with 1-3 a N, O or S in ring (preferably 5~6 yuan of cycloalkane) or phenyl ring it is thick and made of the obtained group of ring, for example, it may be single ring systems alicyclic heterocyclic base with Benzo alicyclic heterocyclic base made of benzene is condensed, can specifically enumerate chromene -5- base, 2,3- coumaran -5- base, 2,3- dihydrobenzo [1,4] dioxane -6- base, benzo [1,3] dioxolanes -5- base, benzo [1,3] dioxolanes -4- base, 2,3- coumaran -6- base, 2,3- coumaran -7- base.

" alicyclic heterocyclic base C1-10 alkyl " refer to above-mentioned alicyclic heterocyclic base and C1-10 it is alkyl linked made of group, for example, can Be above-mentioned benzo alicyclic heterocyclic base and C1-10 it is alkyl linked made of group specifically can enumerate (2,3- benzo dihydros Furans -5- base)-methyl, (2,3- dihydrobenzo [1,4] dioxane -6- base)-methyl, (benzo [1,3] dioxolanes -5- Base)-methyl, (benzo [1,3] dioxolanes -4- base)-methyl, (2,3- coumaran -6- base)-methyl, (2,3- benzo Dihydrofuran -7- base)-methyl." benzo alicyclic heterocyclic base C1-4 alkyl " refers to that above-mentioned benzo alicyclic heterocyclic base and C1-4 are alkyl linked Made of group.

" C3-8 carbocyclic ring " group refers to that carbon atom number is 3~8 yuan of cyclic group.It can be saturated rings, be also possible to Unsaturated ring.The case where saturated rings, is that is, 3~8 yuan of " naphthenic base ".It may include above-mentioned in the case where unsaturated ring " cycloalkenyl ".

Wherein, in addition to 3-8 ring carbons, the carbocyclic ring is optionally further miscellaneous selected from N, O and S containing 1-3 Atom.This, which contains 1-3 heteroatomic " 3-8 member carbocyclic rings " selected from N, O and S, can be saturated rings, be also possible to unsaturated ring.

This contains 1-3 heteroatomic " 3-8 member carbocyclic rings " selected from N, O and S when being saturated rings, is equivalent to 3-8 The above-mentioned alicyclic heterocyclic base of carbon atom.

This contains 1-3 heteroatomic " 3-8 member carbocyclic rings " selected from N, O and S when being unsaturated ring, can be non-aromatic Property ring, can also be armaticity ring.Nonaro-maticity ring can be the above-mentioned unsaturated non-aromatic heterocycle with 3-8 carbon atom. Armaticity ring can be the above-mentioned aromatic heterocyclic with 4-8 carbon atom.

In the present invention, as the substituent group of " optionally replacing ", it is each independently selected from halogen, hydroxyl, carboxyl, cyano, nitre Base and C1-10 alkyl.

In addition to this, here undefined group in accordance with common definition.

Specifically, the compound of the present invention is formula (I) compound represented,

Wherein,

R₂And R₃Each independently represent hydrogen, the C1-10 alkyl that optionally replaces, the C1-10 miscellaneous alkyl optionally replaced, optionally Substituted C3-7 naphthenic base, the C3-7 Heterocyclylalkyl optionally replaced, the C2-10 alkenyl optionally replaced, the C2-10 alkene optionally replaced Base oxygroup, the C2-10 alkynyl oxygroup optionally replaced, the C1-10 acyl group optionally replaced, optionally takes the C2-10 alkynyl optionally replaced The aryl in generation, the aryl C1-10 alkyl optionally replaced, the aromatic heterocyclic optionally replaced, the aromatic heterocyclic C1-10 alkane optionally replaced Base, the alicyclic heterocyclic base optionally replaced or the alicyclic heterocyclic base C1-10 alkyl or R that optionally replace₂And R₃With the carbon atom being connect It is formed together carbonyl；

R₄And R₅Each independently represent hydrogen, the C1-10 alkyl that optionally replaces, the C1-10 miscellaneous alkyl optionally replaced, optionally Substituted C3-7 naphthenic base, the C3-7 Heterocyclylalkyl optionally replaced, the C2-10 alkenyl optionally replaced, the C2-10 alkene optionally replaced Base oxygroup, the C2-10 alkynyl oxygroup optionally replaced, the C1-10 acyl group optionally replaced, optionally takes the C2-10 alkynyl optionally replaced The aryl in generation, the aryl C1-10 alkyl optionally replaced, the aromatic heterocyclic optionally replaced, the aromatic heterocyclic C1-10 alkane optionally replaced Base, the alicyclic heterocyclic base optionally replaced or the alicyclic heterocyclic base C1-10 alkyl optionally replaced；Or R₄And R₅With the carbon atom being connect It is formed together C3-8 carbocyclic ring, which is optionally further selected from the hetero atom of N, O and S containing 1-3；

R₆、R₇、R₈Each independently represent hydrogen, halogen or MR₉；

M indicates O, N, S or singly-bound；

Wherein, R-portion indicates the part of the five-ring heterocycles part or hexa-member heterocycle that are formed together with phenyl ring, and R ' is respectively independent Ground indicates hydrogen, halogen or MR₉；The R-portion optionally includes the 1-3 atoms for being selected from O, N and S,

The integer of m expression 1-3；

Y indicates nitrogen or oxygen；

R₁Do not indicate ethyl, cyclohexyl.

In formula (I), as the substituent group of " optionally replacing ", preferably methyl, ethyl, halogen.

In formula (I), R₁The C1-4 alkyl that preferably optionally replaces, the phenyl optionally replaced, the benzyl optionally replaced, optionally Substituted C1-5 acyl group, the benzoyl optionally replaced, the benzo alicyclic heterocyclic base optionally replaced or the benzo rouge optionally replaced are miscellaneous Ring group C1-4 alkyl.

In formula (I), R₁Preferably methyl, ethyl, n-propyl, isopropyl, isobutyl group, difluorophenyl, Fluoro-benz rLl, acetyl Base, (2,3- coumaran -5- base)-methyl, (2,3- dihydrobenzo [1,4] dioxane -6- base)-methyl, benzo [1, 3] dioxolanes benzyl.

In formula (I), R₂And R₃The C1-4 alkyl for preferably each independently representing hydrogen or optionally replacing.

In formula (I), R₂And R₃It is preferred that being simultaneously hydrogen.

In formula (I), R₂And R₃It is preferred that being formed together carbonyl with the carbon atom being connect.

In formula (I), R₄And R₅It is preferred that the C1-4 alkyl or benzyl for each independently representing hydrogen, optionally replacing.

In formula (I), R₄And R₅It is preferred that each independently representing hydrogen or methyl.

In formula (I), R₆、R₇、R₈It is preferred that being formed together with the phenyl ring being connect with flowering structure

In formula (I), preferably R₇And R₈Indicate hydrogen or halogen, R₉Indicate MR₉。

In formula (I), m indicates 1,2 or 3.

In formula (I), n indicates 1,2 or 3.

In formula (I), preferably M indicates O or singly-bound, R₉Indicate phenyl, benzo [d] [1,3] dioxolanes -5- optionally replaced Base, 2,3- coumaran -6- base, 2,2- dioxo -1,3- dihydrobenzo [c] thiophene -5- base, the fluoro- 2,3- benzo two of 7- Hydrogen furans -4- base, 2,3- dihydrobenzo [1,4] dioxane -6- base or the fluoro- 1,2- dimethyl -1H- indoles -6- base of 4-.

In formula (I), Y preferably indicates nitrogen.

Formula (I) compound is preferably following compounds or its pharmaceutically acceptable salt, ester, solvate, hydrate, different Structure body or their any crystal form or racemoid or their metabolite form:

1, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (2,3- Dihydrobenzofuranes -6- oxygroup) phosphoryl) amino) third Acid esters (K1),

(S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- Dihydrobenzofuranes -6- base) phosphoryl) ammonia Base) propionic ester (K1-a),

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- Dihydrobenzofuranes -6- base) phosphoryl) ammonia Base) propionic ester (K1-b),

2, (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzofuran -6- oxygroup) phosphoryl) amino) Propionic ester (K2-b), (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidins -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzofuran -6- oxygroup) phosphoryl) amino) Propionic ester (K2-a) and its mixture,

3, (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [b] [1,4] dioxane -5- oxygroup) Phosphoryl) amino) propionic ester (K3-b), (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3, 4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [b] [1,4] dioxy Own ring -5- oxygroup) phosphoryl) amino) propionic ester (K3-a) and its mixture,

4, (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -2- oxo -3,4- dihydro-benzo [b] [Isosorbide-5-Nitrae] morpholine -7- oxygroup) phosphoryl) amino) propionic ester (K4-b), (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxy Base) (4- methyl -2- oxo -3,4- dihydro-benzo [b] [Isosorbide-5-Nitrae] morpholine -7- oxygroup) phosphoryl) amino) propionic ester (K4-a), And its mixture,

5, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- methyl -3- oxo -3,4- dihydro-benzo [b] [1,4] Quinoline -8- oxygroup) phosphoryl) amino) propionic ester (K5) and its isomers,

6, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- phenoxy-phenoxy) phosphoryl) amino) propionic ester (K6),

(S)-isopropyl ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- phenoxy-phenoxy) phosphoryl) amino) propionic ester (K6- A),

(S)-isopropyl ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- phenoxy-phenoxy) phosphoryl) amino) propionic ester (K6- B),

7, (S) -4- luorobenzyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphoryl) ammonia Base) propionic ester (K7),

(S) -4- luorobenzyl ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphinylidyne Base) amino) propionic ester (K7-a),

(S) -4- luorobenzyl ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphinylidyne Base) amino) propionic ester (K7-b),

8, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (benzo [d] [1,3] dioxolanes -4- oxygroup) phosphoryl) ammonia Base) propionic ester (K8) and its isomers,

9, (S)-isobutyl group (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphoryl) ammonia Base) propionic ester (K9) and its isomers,

10, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- (benzo [d] [1,3] dioxolanes -5- base)-phenoxy group) Phosphoryl) amino) propionic ester (K10) and its isomers,

11, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- (the fluoro- phenoxy group of the chloro- 3- of 4-)-phenoxy group) phosphoryl) ammonia Base) propionic ester (K11) and its isomers,

12, (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (3- oxo -4- methyl -2H- benzo [b] [1, 4] morpholine -7- oxygroup) phosphoryl) amino) propionic ester (K12-b), (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (3- - 4 methyl -2H- benzo [b] [Isosorbide-5-Nitrae] morpholine -7- oxygroup of oxo) phosphoryl) amino) propionic ester (K12-a) and its mixture,

13, (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -2H- benzo [b] [1,4] morpholine - 7- oxygroup) phosphoryl) amino) propionic ester (K13-b), (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- bis- - 1 (2H)-yl of carbonyl -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl - 2H- benzo [b] [Isosorbide-5-Nitrae] morpholine -7- oxygroup) phosphoryl) amino) propionic ester (K13-a) and its mixture,

14, (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2- oxo -1,3- methyl-1 H- benzo [b] miaow Oxazoline -4- oxygroup) phosphoryl) amino) propionic ester (K14-b), (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2- Oxo -1,3- methyl-1 H- benzo [b] imidazoline -4- oxygroup) phosphoryl) amino) propionic ester (K14-a) and its mixture,

15, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (2,2- dioxo -1,3- dihydrobenzo [c] thiophene -5- oxygen Base) phosphoryl) amino) propionic ester (K15) and its isomers,

16, (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -3- oxo -3,4- dihydro -2H- benzene And [b] [Isosorbide-5-Nitrae] morpholine -6- oxygroup) phosphoryl) amino) propionic ester (K16-b), (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) Methoxyl group) (4- methyl -3- oxo -3,4- dihydro -2H- benzo [b] [1,4] morpholine -6- oxygroup) phosphoryl) amino) propionic ester (K16-a) and its mixture,

17, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (3- methyl -2H- benzo [d] -2- oxazolidone -7- oxygroup) phosphorus Acyl group) amino) propionic ester (K17) and its isomers,

18, (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2- oxo -1,3- methyl-1 H- benzo [b] miaow Oxazoline -5- oxygroup) phosphoryl) amino) propionic ester (K18-b), (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2- Oxo -1,3- methyl-1 H- benzo [b] imidazoline -5- oxygroup) phosphoryl) amino) propionic ester (K18-a) and its mixture,

19, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- (2,3- coumaran -6- base) phenoxy group) phosphinylidyne Base) amino) propionic ester (K19) and its isomers,

20, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- methyl -2H- benzo [b] [1,4] morpholine -8- oxygroup) phosphorus Acyl group) amino) propionic ester (K20),

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -2H- benzo [b] [1,4] morpholine -8- oxygen Base) phosphoryl) amino) propionic ester (K20-b),

(S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -2H- benzo [b] [1,4] morpholine -8- oxygen Base) phosphoryl) amino) propionic ester (K20-a),

21, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- methyl -2H- benzo [b] [1,4] morpholine -6- oxygroup) phosphorus Acyl group) amino) propionic ester (K21) and its isomers,

22, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- (2,2- dioxo -1,3- dihydrobenzo [c] thiophene -5- Base) phenoxy group) phosphoryl) amino) propionic ester (K22) and its isomers,

23, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- (the fluoro- 2,3- coumaran -4- base of 7-) phenoxy group) Phosphoryl) amino) propionic ester (K23) and its isomers,

24, (S) -4- luorobenzyl (((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzofuran -6- oxygroup) phosphoryl) amino) propionic acid Ester (K24) and its isomers,

25, (S)-(2,3- coumaran -5- benzyl) ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane - 3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzofuran -6- oxygen Base) phosphoryl) amino) propionic ester (K25-b), (S)-(2,3- coumaran -5- benzyl) ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxy Base) (benzofuran -6- oxygroup) phosphoryl) amino) propionic ester (K25-a) and its mixture,

26, (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (3- methylbenzoxazole -2- oxo -5- oxygen Base) phosphoryl) amino) propionic ester (K26-b), (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- bis- carbonyls - 1 (2H)-yl of base -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (3- methyl benzo Oxazole -2- oxo -5- oxygroup) phosphoryl) amino) propionic ester (K26-a) and its mixture,

27, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (the fluoro- 2,3- Dihydrobenzofuranes -4- oxygroup of 7-) phosphoryl) Amino) propionic ester (K27),

(S)-isopropyl -2- ((S)-(((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (the fluoro- 2,3- Dihydrobenzofuranes -4- oxygroup of 7-) phosphinylidyne Base) amino) propionic ester (K27-b),

(S)-isopropyl -2- ((R)-(((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (the fluoro- 2,3- Dihydrobenzofuranes -4- oxygroup of 7-) phosphinylidyne Base) amino) propionic ester (K27-a),

28, (S)-isopropyl -2- ((S)-(((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzoxazoles -5- oxygroup) phosphoryl) amino) Propionic ester (K28-b), (S)-isopropyl -2- ((R)-(((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidins -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzoxazoles -5- oxygroup) phosphoryl) amino) Propionic ester (K28-a) and its mixture,

29, (S)-isopropyl ((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (2,3- dihydrobenzo [1,4] dioxane -6- base) benzene oxygen Base) phosphoryl) amino) propionic ester (K29),

(S)-isopropyl -2- ((S)-(((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (2,3- dihydrobenzo [1,4] dioxane -6- Base) phenoxy group) phosphoryl) amino) propionic ester (K29-b),

(S)-isopropyl -2- ((R)-(((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (2,3- dihydrobenzo [1,4] dioxane -6- Base) phenoxy group) phosphoryl) amino) propionic ester (K29-a),

30, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- (4- fluorophenoxy) phenoxy group) phosphoryl) amino) propionic acid Ester (K30),

(S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (4- fluorophenoxy) phenoxy group) phosphoryl) amino) Propionic ester (K30-a),

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (4- fluorophenoxy) phenoxy group) phosphoryl) amino) Propionic ester (K30-b),

31, (S) -4- fluorine benzyloxy (((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- dihydrobenzo [1,4] dioxane -5- oxygroup) Phosphoryl) amino) propionic ester (K31),

(S) -4- fluorine benzyloxy -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- dihydrobenzo [1,4] dioxane -5- Oxygroup) phosphoryl) amino) propionic ester (K31-b),

(S) -4- fluorine benzyloxy -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- dihydrobenzo [1,4] dioxane -5- Oxygroup) phosphoryl) amino) propionic ester (K31-a),

32, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- (4- chlorophenoxy) phenoxy group) phosphoryl) amino) propionic acid Ester (K32),

(S)-isopropyl ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- (4- chlorophenoxy) phenoxy group) phosphoryl) amino) propionic acid Ester (K32-b),

(S)-isopropyl ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- (4- chlorophenoxy) phenoxy group) phosphoryl) amino) propionic acid Ester (K32-a),

33, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- ((2,3- dihydrobenzo [1,4] dioxane -6- base) oxygen Base) phenoxy group) phosphoryl) amino) propionic ester (K33),

(S)-isopropyl ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- ((2,3- dihydrobenzo [1,4] dioxane -6- base) oxygen Base) phenoxy group) phosphoryl) amino) propionic ester (K33-a),

(S)-isopropyl ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- ((2,3- dihydrobenzo [1,4] dioxane -6- base) oxygen Base) phenoxy group) phosphoryl) amino) propionic ester (K33-b),

34,2- (S)-(S)-isobutyl group (((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- dihydrobenzo [1,4] dioxane -5- Oxygroup) phosphoryl) amino) propionic ester (K34) and its isomers,

35, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (7- Fluorobenzofur -4- oxygroup) phosphoryl) amino) propionic acid Ester (K35) and its isomers,

36, (S)-(2,3- dihydrobenzo [1,4] dioxane -6- base) methoxyl group -2- ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxy Base) (benzofuran -6- oxygroup) phosphoryl) amino) propionic ester (K36-b), (S)-(2,3- dihydrobenzos [Isosorbide-5-Nitrae] dioxane - 6- yl) methoxyl group -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (benzofuran -6- oxygroup) phosphoryl) amino) propionic ester (K36- A) and its mixture,

37, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (benzoxazoles -6- oxygroup) phosphoryl) amino) propionic ester (K37) and its isomers,

38, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (benzoxazoles -4- oxygroup) phosphoryl) amino) propionic ester (K38) and its isomers,

39, (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- methyl -3,4- dihydrobenzo [1,4] morpholine -5- oxygroup) Phosphoryl) amino) propionic ester (K39) and its isomers,

40, (S)-benzo [1,3] dioxolanes benzyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (dicarbapentaborane -3 2,4-, 4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo tetrahydrofuran -6- Oxygroup) phosphoryl) amino) propionic ester (K40-b), (S)-benzo [1,3] dioxolanes benzyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxy Base) (benzo tetrahydrofuran -6- oxygroup) phosphoryl) amino) propionic ester (K40-a) and its mixture,

41, (S)-benzo [1,3] dioxolanes benzyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (dicarbapentaborane -3 2,4-, 4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- dihydrobenzo furan Mutter -6- oxygroup) phosphoryl) amino) propionic ester (K41-b), (S)-benzo [1,3] dioxolanes benzyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- of -4- Base) methoxyl group) (2,3- Dihydrobenzofuranes -6- oxygroup) phosphoryl) amino) propionic ester (K41-a) and its mixture,

42, (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (3- methylbenzoxazole -2- oxo -6- oxygen Base) phosphoryl) amino) propionic ester (K42) and its isomers,

43, (S) -4- luorobenzyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzofuran -6- oxygroup) phosphoryl) amino) Propionic ester (K43-b), ((R)-((((2,4- dicarbapentaborane -3,4- dihydros are phonetic by (2R, 3R, 4R, 5R) -5- by (S) -4- luorobenzyl -2- Pyridine -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzofuran -6- oxygroup) phosphoryl) Amino) propionic ester (K43-a) and its mixture,

44, (S) -4- luorobenzyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (the fluoro- 1,2- dimethyl -1H- indoles-of 4- 6- yl)-phenoxy group) phosphoryl) amino) propionic ester (K44-b), (S) -4- luorobenzyl -2- ((R)-((((2R, 3R, 4R, 5R) - 5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (fluoro- 1, the 2- dimethyl -1H- indoles -6- base of 4-)-phenoxy group) phosphoryl) amino) propionic ester (K44-a), and its mixing Object,

45, (S) -5- (2,3- dihydro -1- benzofuran)-base -2- ((S)-((((2R, 3R, 4R, 5R) -5- (bis- carbonyl of 2,4- - 1 (2H)-yl of base -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) ((2,3- dihydrobenzene And furans -6- oxygroup) phosphoryl) amino) propionic ester (K45-b), (S) -5- (2,3- dihydro -1- benzofuran)-base -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl of -4- Tetrahydrofuran -2- base) methoxyl group) ((2,3- Dihydrobenzofuranes -6- oxygroup) phosphoryl) amino) propionic ester (K45-a), and its Mixture,

46, (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) Phosphoryl) amino) -3- Phenpropionate (K46-b), (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- bis- carbonyls - 1 (2H)-yl of base -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [d] [1, 3] dioxolanes -5- oxygroup) phosphoryl) amino) -3- Phenpropionate (K46-a) and its mixture,

47, (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (the fluoro- 1,2- dimethyl -1H- indoles-of 4- 6- yl)-phenoxy group) phosphoryl) amino) propionic ester (K47-b), S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (fluoro- 1, the 2- dimethyl -1H- indoles -6- base of 4-)-phenoxy group) phosphoryl) amino) propionic ester (K47-a) and its mixture,

48, (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [1,3] dioxolanes -5- oxygroup) phosphorus Acyl group) amino) -4- methylvaleric acid (K48-b), (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- bis- carbonyls - 1 (2H)-yl of base -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [1,3] two Butyl oxide link -5- oxygroup) phosphoryl) amino) -4- methylvaleric acid (K48-a) and its mixture,

49, (S)-benzo [1,3] dioxolanes benzyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (dicarbapentaborane -3 2,4-, 4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [1,3] dioxy penta Ring -5- oxygroup) phosphoryl) amino) propionic ester (K49-b), (S)-benzo [1,3] dioxolanes benzyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- of -4- Base) methoxyl group) (benzo [1,3] dioxolanes -5- oxygroup) phosphoryl) amino) propionic ester (K49-a) and its mixture,

50, (S)-benzo [1,3] dioxolanes benzyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (dicarbapentaborane -3 2,4-, 4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -3,4- dihydro Benzo [Isosorbide-5-Nitrae] morpholine -8- oxygroup) phosphoryl) amino) propionic ester (K50-b), (S)-benzo [1,3] dioxolanes benzyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl of -4- Tetrahydrofuran -2- base) methoxyl group) (4- methyl -3,4- dihydrobenzo [1,4] morpholine -8- oxygroup) phosphoryl) amino) propionic ester (K50-a) and its mixture,

51, (S) -4- luorobenzyl-((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -3,4- dihydro -2H- benzo [b] [Isosorbide-5-Nitrae] morpholine -7- oxygroup) phosphoryl) amino) propionic ester (K51-b), (S) -4- luorobenzyl-((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxy Base) (4- methyl -3,4- dihydro -2H- benzo [b] [Isosorbide-5-Nitrae] morpholine -7- oxygroup) phosphoryl) amino) propionic ester (K51-a), and its Mixture,

52, (S) -4- luorobenzyl ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -3,4- dihydro -2H- benzo [b] [Isosorbide-5-Nitrae] morpholine -8- oxygroup) phosphoryl) amino) propionic ester (K52-b), (S) -4- luorobenzyl ((R)-((((2R, 3R, 4R, 5R) - 5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -3,4- dihydro -2H- benzo [b] [Isosorbide-5-Nitrae] morpholine -8- oxygroup) phosphoryl) amino) propionic ester (K52-a), and its it is mixed Object is closed,

53, (S) -2,3- dihydrobenzo [b] [1,4] dioxane -6- methyl ((S)-((((2R, 3R, 4R, 5R) -5- (2, - 1 (2H)-yl of 4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphoryl) amino) propionic ester (K53-b), (S) -2,3- dihydrobenzo [b] [Isosorbide-5-Nitrae] two ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- is fluoro- for pentamethylene oxide -6- methyl 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphoryl) amino) third Acid esters (K53-a) and its mixture,

54, (S)-(2,3- dihydrobenzo [1,4] dioxane -6- base) methoxyl group -2- ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxy Base) (2,3- Dihydrobenzofuranes -6- oxygroup) phosphoryl) amino) propionic ester (K54-b), (S)-(2,3- dihydrobenzos [Isosorbide-5-Nitrae] Dioxane -6- base) methoxyl group -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- Dihydrobenzofuranes -6- oxygroup) phosphinylidyne Base) amino) propionic ester (K54-a) and its mixture,

55, (S)-(2,3- Dihydrobenzofuranes -5- base) methoxyl group -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- Dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [1, 3] dioxolanes -5- oxygroup) phosphoryl) amino) propionic ester (K55-b), (S)-(2,3- Dihydrobenzofuranes -5- base) methoxy Base -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxyl-of -4- 4- methyltetrahydrofuran -2- base) methoxyl group) (benzo [1,3] dioxolanes -5- oxygroup) phosphoryl) amino) propionic ester (K55- A) and its mixture,

56, (S)-(2,3- dihydrobenzos [Isosorbide-5-Nitrae] dioxane -6- base) methoxyl group -2- ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxy Base) (4- methyl -3,4- dihydrobenzo [Isosorbide-5-Nitrae] morpholine -8- oxygroup) phosphoryl) amino) propionic ester (K56-b), (S)-(2,3- bis- Hydrogen benzo [Isosorbide-5-Nitrae] dioxane -6- base) methoxyl group -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- bis- Hydrogen pyrimidine -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -3,4- dihydrobenzo [Isosorbide-5-Nitrae] morpholine -8- oxygroup) phosphoryl) amino) propionic ester (K56-a) and its mixture,

57, (S)-(2,3- dihydrobenzos [Isosorbide-5-Nitrae] dioxane -6- base) methoxyl group -2- ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxy Base) (4- methyl -3,4- dihydrobenzo [Isosorbide-5-Nitrae] morpholine -7- oxygroup) phosphoryl) amino) propionic ester (K57-b), (S)-(2,3- bis- Hydrogen benzo [Isosorbide-5-Nitrae] dioxane -6- base) methoxyl group -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- bis- Hydrogen pyrimidine -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -3,4- dihydrobenzo [Isosorbide-5-Nitrae] morpholine -7- oxygroup) phosphoryl) amino) propionic ester (K57-a) and its mixture,

58, (S)-(S- isobutyl group) -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin - 1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- dihydrobenzo [1,4] dioxane - 5- oxygroup) phosphoryl) amino) propionic ester (K58-b), (S)-(S- isobutyl group) -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2, - 1 (2H)-yl of 4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- Dihydrobenzo [Isosorbide-5-Nitrae] dioxane -5- oxygroup) phosphoryl) amino) propionic ester (K58-a) and its mixture,

59, (S) -4- luorobenzyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- Dihydrobenzofuranes -6- oxygroup) phosphinylidyne Base) amino) propionic ester (K59-b), (S) -4- luorobenzyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- Dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- Dihydrobenzofuranes - 6- oxygroup) phosphoryl) amino) propionic ester (K59-a) and its mixture,

60,2- (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxyl of -4- Base -4- methyltetrahydrofuran -2- base) methoxyl group) (phenoxy group) phosphoryl) amino) ethyl acetate (K60),

2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- of -4- Hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (phenoxy group) phosphoryl) amino) ethyl acetate (K60-b),

2- ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- of -4- Hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (phenoxy group) phosphoryl) amino) ethyl acetate (K60-a),

61,2- (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxyl of -4- Base -4- methyltetrahydrofuran -2- base) methoxyl group) (phenoxy group) phosphoryl) amino) -4- ethyl fluoro benzoate (K61) and its different Structure body,

62,2- ((benzo [d] [1,3] dioxolanes -5- oxygroup) ((((2R, 3R, 4R, 5R) -5- (dicarbapentaborane -3 2,4-, 4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) phosphoryl) amino)-acetic acid Ethyl ester (K62) and its isomers,

63, methyl -2- (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (phenoxy group) phosphoryl) hydroxyl) acetic acid esters (K63) and its isomery Body,

64, (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- dihydrobenzo [b] [1,4] dioxy oneself Ring -6- oxygroup) phosphoryl) amino) propionic ester (K64-b), (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2, - 1 (2H)-yl of 4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- Dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxane -6- oxygroup) phosphoryl) amino) propionic ester (K64-a) and its mixture.

" pharmaceutically acceptable salt " in this specification includes and the nothings such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid or nitric acid The salt of machine acid or with acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, malonic acid, Mandelic acid, gluconic acid, galactosaccharic acid, glucoheptonic acid, glycolic, glutamic acid, trifluoracetic acid, methanesulfonic acid, ethanesulfonic acid, benzene sulphur The salt of the organic acids such as acid, p-methyl benzenesulfonic acid, camphorsulfonic acid or naphthalene-2-sulfonic acid, with lithium ion, sodium ion, potassium ion, calcium ion, The salt of one or more metal ions such as magnesium ion, zinc ion, aluminium ion and ammonia, arginine, lysine, piperazine, choline, diethyl The salt of the amine such as base amine, 4- phenylcyclohexylamine, 2- ethylaminoethanol, tardocillin.As long as pharmaceutically acceptable salt, It is not particularly limited.Conversion by from episome to the salt can be carried out with existing method.

It should be noted that the compound of the present invention also can be used as various solvates and exist.In addition, from as the suitable of drug From the point of view of property, the case where promising hydrate.

The compound of the present invention contains one or more asymmetric centers, and thus, it is possible to racemate, racemic mixing The form of object, single enantiomter, non-enantiomer mixture and single diastereoisomer etc. exists.

The present invention provides a kind of composition, and it includes the compound of the present invention and pharmaceutically acceptable auxiliary material.It is described auxiliary Material can be carrier, excipient, diluent or combinations thereof, for forming pharmaceutical preparation.As above-mentioned carrier, excipient and dilution Agent refers to not causing apparent irritation to organism and the drug of the property of the bioactivity of not interfering given compound Non-active ingredient in composition.

As above-mentioned carrier, excipient and diluent, comprising water, lactose, glucose, fructose, sucrose, D-sorbite, sweet Reveal alcohol, polyethylene glycol, propylene glycol, starch, rubber, gel, alginates, calcium silicates, calcium phosphate, cellulose, aqueous syrup, methyl Cellulose, polyvinylpyrrolidone, para hydroxybenzene and sorb acid alkyl ester, talcum, magnesium stearate, stearic acid, glycerol, sesame Various oil of oil, olive oil, soybean oil etc. etc..

In addition, the incremental agent generally used, bonding can be mixed as needed in above-mentioned carrier, excipient or diluent The additive of agent, disintegrating agent, pH adjusting agent, lytic agent etc. can use common preparation technique as tablet, pill, capsule The oral or non-oral administration object of agent, granule, pulvis, liquor, emulsion, suspending agent, ointment, injection, skin patch etc. To prepare.The compound of the present invention for adult patient, can with it is oral or it is non-oral given, 1 day 1 time or point It is preferably 0.01-1000mg/ days, more preferable 0.1-800mg/ days, especially excellent to give total amount 0.001~1500mg/ days for several times Select 1-600mg/ days, such as 250mg/ days, 400mg/ days, 600mg/ days 500mg/ days.It should be noted that the compound of the present invention Dosage can suitably increase and decrease according to the type of the disease as treatment object, the age of patient, weight, symptom etc..

The compound of the present invention also includes more than one hydrogen atom, fluorine atom, carbon atom, nitrogen-atoms, oxygen atom, sulphur original Son is replaced into the compound of radioactive isotope or stable isotope.These labeled compounds can be used for being metabolized or medicine is for power It learns research, carry out biological analysis etc. as ligand of receptor etc..

The compound of the present invention can with one or more other active ingredient combinations for treat, prevent, inhibit or Improving disease, perhaps wherein drug is used in combination more safer than the exclusive use of any drug or more has symptom Effect.This other medicines can be this usually used approach and amount to be simultaneously or sequentially administered with the compound of the present invention. When the compound of the present invention and one or more kinds of other medicines simultaneously in use, in unit dosage forms containing the other medicines and The pharmaceutical composition of the compound of the present invention is preferably, especially to combine with pharmaceutically acceptable carrier.However, combination therapy It can also include the treatment that the compound of the present invention and one or more kinds of other medicines are given in different overlapping schedules.May be used also With expection, when with one or more kinds of other active ingredient combinations in use, the compounds of this invention and other active constituents can be with Lower dosage uses when with than being respectively used alone.Therefore, other than the compound of the present invention, pharmaceutical composition of the present invention is also Including containing those of one or more kinds of other active constituents composition.

Composition of the present invention contains compound 0.01-1000mg of the present invention, is suitably 0.5-800mg, Preferably 1-400mg, more preferably 5-200mg, particularly preferred 10-100mg, most preferably 15-50mg, e.g. 20mg, 25mg, 30mg.Pharmaceutical preparation of the present invention etc. can be unit dosage form, and unit dose contains compound 0.01- of the present invention 1000mg is suitably 0.5-800mg, preferably 1-400mg, more preferably 5-200mg, particularly preferred 10-100mg, most preferably 15-50mg, e.g. 20mg, 25mg, 30mg.

In the present invention, associated with other active constituents include interferon, virazole or its analog, HCV NS3 protease Inhibitor, 1 inhibitor of alpha-Glucosidase, hepatoprotective, the non-nucleosidic inhibitors of HCV NS5B polymerase, HCV NS5A inhibit Agent, TLR-7 agonist, cyclophilin inhibitor, HCV IRES inhibitor, pharmacokinetics dose and for treat HCV its Its drug or therapeutic agent, or combinations thereof.

The interferon is selected from PEGylated rIFN- α 2bPEGylated rIFN- α 2arIFN-α2b(A)、rIFN-α2a(Roferon), interferon-' alpha ' (MOR-22, OPC- 18, Alfaferone, Alfanative, Multiferon, subalin), interferon alfacon-1It is dry Disturb plain α-n1 (Wellferon), Alferon NInterferon beta (Avonex DL-8234), interferon-ω (ωBiomed510)、albinterferonα-2bIFNα-2bXL、BLX- 883DA-3021, glycosylated interferon alpha 2 b (AVI-005), PEG-Infergen, PEGylated interference Plain λ -1 (PEGylated IL-29) and

The HCV NS3 protease inhibitors is selected from boceprevir (SCH-503034, SCH-7), tirrevir (telaprevir)(VX-950)、TMC435350、BI-1335、BI-1230、MK-7009、VBY-376、VX-500、GS- 9256、GS-9451、BMS-605339、PHX-1766、AS-101、YH-5258、YH5530、YH5531、ABT-450、ACH- 1625, ITMN-191, MK5172, MK6325 and MK2748.

1 inhibitor of alpha-Glucosidase is selected from Xi Gewei (celgosivir) (MX-3253), Miglitol and UT- 231B。

The hepatoprotective be selected from emericasan (IDN-6556), ME-3738, GS-9450 (LB-84451), Silibilin and MitoQ.

The non-nucleosidic inhibitors of the HCV NS5B polymerase are selected from PF-868554, VCH-759, VCH-916, JTK- 652、MK-3281、GS-9190、VBY-708、VCH-222、A848837、ANA-598、GL60667、GL59728、A-63890、 A-48773、A-48547、BC-2329、VCH-796(nesbuvir)、GSK625433、BILN-1941、XTL-2125、ABT- 072, ABT-333, GS-9669, PSI-7792 and GS-9190.

The HCV NS5A inhibitor is selected from ABT-267 (ombitasvir), AZD-2836 (A-831), BMS- 790052, ACH-3102, ACH-2928, GS-5885, GS-5816, MK8325, MK4882, MK8742, PSI-461, IDX719 And A-689.

The TLR-7 agonist be selected from imiquimod, 852A, GS-9620, ANA-773, ANA-975, AZD-8848 (DSP-3025) and SM-360320.

The cyclophilin inhibitor is selected from DEBIO-025, SCY-635 and NIM811.

The HCV IRES inhibitor is selected from MCI-067.

The pharmacokinetics reinforcing agent is selected from BAS-100, SPI-452, PF-4194477, TMC-41629, GS- 9350, GS-9585 and roxithromycin.

The usual synthetic method of the compound of the present invention is as follows.These are used for the initial substance and reaction reagent of synthesis Can commercially it obtain.

Wherein, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈It is as defined above with Y.

(step 1)

Three oxyhalogen phosphorus are dissolved in organic solvent, are cooled to -60 DEG C~-20 DEG C, compound 1 and organic base is added.Reaction solution It is warming up to 15-40 DEG C, preferably 20 DEG C~35 DEG C, more preferable 25-30 DEG C, and 1-8 hours, preferably 2~6 hours are stirred, obtain chemical combination 3 crude product of object, without post-process and purifying be directly used in next step.

Wherein, the mass ratio of the material (molar ratio) of compound 1, three oxyhalogen phosphorus and organic base is 1:0.5~2:0.5~2, excellent Select 1:0.8~2:0.8~2, more preferable 1:1~1.5:1~1.5, compound 1 and organic solvent w/v (gram/milli Rise) be 1:5~30, preferred 1:10~25, more preferable 1:15~20, three oxyhalogen phosphorus and organic solvent w/v (gram/milli Rise) be 1:5~30, preferred 1:10~25, more preferable 1:10~20, organic base and organic solvent w/v (gram/milli Rise) it is 1:15~30, preferably 1:20~25.

(step 2)

It takes the crude Compound 3 of above-mentioned steps one to be dissolved in and organic solvent, is cooled to -60 DEG C~-20 DEG C, compound is added 4 and organic base.Reaction solution is warming up to 15-40 DEG C, and preferably 20 DEG C~35 DEG C, more preferable 25-30 DEG C, and stir 1-8 hours, preferably 2~6 hours.5 crude product of compound, without post-process and purifying be directly used in next step.

Wherein, the mass ratio of the material (molar ratio) of compound 3, compound 4 and organic base be 1:0.5~1.5:1.0~ 3.5, preferably 1:0.9~1.1:1.4~3.The w/v (grams per milliliter) of compound 4 and organic solvent is 1:5~30, excellent Select 1:10~25, the w/v (grams per milliliter) of organic base and organic solvent is 1:3~25, preferably 1:5~20.

(step 3)

It takes the crude Compound 5 of above-mentioned steps two to be dissolved in and organic solvent, is cooled to -60 DEG C~-20 DEG C, sequentially adding Close object 6 and organic base.Reaction solution is warming up to 15-40 DEG C, and preferably 20 DEG C~35 DEG C, more preferable 25-30 DEG C, and stir 1-8 hours, It is preferred that 2~6 hours.Fully reacting pours into reaction solution in ice water, with organic solvent extracted several times.Organic phase is collected, with saturation Salt water, preferably saturated common salt aqueous solution are washed, and concentration is then dried, filtered, and obtain 7 crude product of title intermediate compound. It is directly used in next step without being further purified.

Wherein, the mass ratio of the material (molar ratio) of compound 5, compound 6 and organic base is 1:0.5~2:0.5~2.5, It is preferred that 1:0.7~1.5:1.0~2.0.The w/v (grams per milliliter) of compound 6 and organic solvent is 1:5~30, preferably The w/v (grams per milliliter) of 1:10~25, organic base and organic solvent is 1:10~30, preferably 1:15~25.

(step 4)

Compound 8 is dissolved in organic solvent, by reaction solution under inert gas replacement protection, in 0 DEG C~25 DEG C temperature Degree is lower to be added grignard reagent, and midbody compound 7 obtained above is added after suitably stirring 1~3 hour.Reaction solution is warming up to 1 DEG C~40 DEG C, preferably 10 DEG C~30 DEG C and stir 5-20 hours, preferably 10~15 hours.After reaction, add into reaction solution Entering 2M aqueous hydrochloric acid solution to be adjusted to pH is 5~9, and preferably pH is 6~8, is extracted with organic solvent, collects organic phase and merges, carries out Washing, washing can be carried out respectively with saturated sodium bicarbonate aqueous solution, saturated salt solution, be then dried, and be filtered, dense Contracting.Residue obtains compound of formula I through column chromatographic purifying.

Wherein, the mass ratio of the material (molar ratio) of compound 7, compound 8 and Grignard Reagent is 1:0.8~2:1.5~4, It is preferred that 1:1~1.5:2~3.5.The w/v (grams per milliliter) of compound 7 and organic solvent is 1:30~70, compound 8 W/v (grams per milliliter) with organic solvent is 1:90~120.

In above-mentioned steps one, two, three, four, the organic solvent can be reaction dissolvent commonly used in the art, for example, N,N-dimethylformamide, dimethyl sulfoxide, N-Methyl pyrrolidone, saturated hydrocarbons (such as hexamethylene, hexane can be enumerated Deng), halogenated hydrocarbon (such as methylene chloride, chloroform, 1,2- dichloroethanes etc.), ethers (such as tetrahydrofuran, ether, dioxanes, 1,2- dimethoxy-ethane etc.), nitrile (such as acetonitrile etc.) and their mixed solvent etc..

The three oxyhalogen phosphorus (POX₃) in halogen X can respectively it is identical or not identical, halogen be selected from fluorine, chlorine, bromine and Iodine, such as can enumerate, trifluoro oxygen phosphorus, phosphorus oxychloride, tribromo oxygen phosphorus, triiodo oxygen phosphorus, a fluorine dibromo oxygen phosphorus, difluoro monobromo oxygen Phosphorus.It is wherein preferably phosphorus oxychloride, tribromo oxygen phosphorus.

Formula (I) non-enantiomer mixture as obtained above can be separated by preparative high-performance liquid chromatographic, be obtained To pure isomers.

By obtained non-enantiomer mixture with preparation HPLC separation can according to methods known in the art come into Row.For example, separation condition is as follows: using octadecyl silane as filler, 30 DEG C~50 DEG C of column temperature, flow velocity 5.0~ 20.0mL/min, 200~400nm of Detection wavelength, using mobile phase A (such as can be water), Mobile phase B (such as can be first Alcohol), carry out linear gradient elution.

Embodiment

It is exemplified below embodiment and test example, and then explains the present invention in detail, but they do not limit the present invention, in addition exist It can be changed without departing from the scope of the invention.

The structure for the compound recorded in embodiment below by nuclear magnetic resonance (¹HNMR) or mass spectrum (MS) determines.

Nuclear magnetic resonance (¹HNMR determining instrument) uses 400 nuclear magnetic resonance spectrometer of JEOLEclipse；Measurement solvent is deuterated methanol (CD₃OD), deuterated chloroform (CDCl₃), hexadeuterated dimethyl sulfoxide (DMSO-d6)；Internal standard substance is tetramethylsilane (TMS).

Abbreviation in nuclear magnetic resonance used in embodiment (NMR) map is shown in following.

S: unimodal (singlet), d: doublet (doublet), t: triplet (triplet), q: quartet (quartet), dd: double doublet (double doublet), qd: four doublets (quartet doublet), ddd: in pairs two Weight peak (double double doublet), ddt: triplet (double double triplet), dddd in pairs: double in pairs Doublet (double double double doublet), m: multiplet (multiplet), br: broad peak (broad), J: even Close constant, Hz: hertz, DMSO-d6: deuterodimethylsulfoxide.

Whole δ values are indicated with ppm value.

The determining instrument of mass spectrum (MS) uses Agilent (ESI) mass spectrograph, model Agilent 6120B.

In conventional synthetic method, embodiment and intermediate synthesis example, the meaning for the representative respectively abridged is as shown below.

DMF:N, dinethylformamide

DMA:N, N- dimethyl acetamide

NMP:N- methyl pyrrolidone

THF: tetrahydrofuran

Boc: tert-butoxycarbonyl

NBS；N- bromine succinimide

M-CPBA: metachloroperbenzoic acid

TFA: trifluoracetic acid

Et₂O: Anaesthetie Ether

Et₃N: triethylamine

T-BuMgCl: tert-butyl magnesium chloride

EtOH: ethyl alcohol

TLC: thin-layer chromatography

Me: methyl

DCM: methylene chloride

EA: ethyl acetate

The chloro- 5,6- dicyan -1,4- benzoquinones of DDQ:2,3- bis-

DIPEA:N, N- diisopropylethylamine

NMM:N- methyl morpholine

Room temperature: 20-38 DEG C

Embodiment 1

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (2,3- Dihydrobenzofuranes -6- oxygroup) phosphoryl) amino) third The preparation of acid esters (K1) and its isomers

Midbody compound (S)-isopropyl -2- (((phenyl-pentafluoride oxygroup) (2,3- Dihydrobenzofuranes -6- oxygroup) phosphinylidyne Base) amino) propionic ester preparation

Phosphorus oxychloride (1.53g, 10mmol) is dissolved in methylene chloride (10mL), -60 DEG C is cooled to, 6- hydroxyl is slowly added dropwise The dichloromethane solution (10mL) of base -2,3- Dihydrobenzofuranes (1.36g, 10mmol) and triethylamine (1.01g, 10mmol). It is added dropwise, removes cryostat, rise to 25 DEG C and stir 2 hours.Reaction system is further cooled to -60 DEG C, l-Alanine is added The dichloromethane solution (5mL) of triethylamine (2.53g, 25mmol) is then added dropwise in isopropyl ester hydrochloride (1.51g, 9mmol).Drop It adds complete, removes cryostat, rise to 25 DEG C and stir 2 hours.Reaction system is further cooled to -60 DEG C, Pentafluorophenol is added dropwise The dichloromethane solution (10mL) of (1.66g, 9mmol) and triethylamine (1.52g, 15mmol).It is added dropwise, removes cryostat, rise It is stirred 2 hours to 25 DEG C.Fully reacting pours into reaction system in ice water, is extracted with dichloromethane.It collects and merges organic phase use The washing of saturated common salt aqueous solution, dries, filters concentration, obtains the crude product of title compound.

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (2,3- Dihydrobenzofuranes -6- oxygroup) phosphoryl) amino) third The preparation of acid esters (K1)

By 1- (the fluoro- 4- hydroxyl -5- methylol -3- methyltetrahydrofuran -2- base of (2R, 3R, 4R, 5R) -3-) pyrimidine -2,4- (1H, 3H)-diketone (260mg, 1mmol) is dissolved in anhydrous tetrahydro furan (20mL), and argon gas is replaced three times.Tertiary fourth is added dropwise in 0 DEG C Base magnesium chloride (1.0mol/L, 2.5mL, 2.5mmol) rises to 25 DEG C and reacts 1 hour.It is cooled to 0 DEG C, above-mentioned intermediate is added dropwise Close object (S)-isopropyl -2- (((phenyl-pentafluoride oxygroup) (2,3- Dihydrobenzofuranes -6- oxygroup) phosphoryl) amino) propionic ester Anhydrous tetrahydro furan (10mL) solution of (493mg, 1mmol).It is added dropwise, is warmed to room temperature reaction 15 hours.2M hydrochloric acid is added dropwise Few drops to reaction system become clarify.Water 30mL is added to dilute, 2M hydrochloric acid is adjusted to neutrality.Reaction system is extracted with ethyl acetate, and collects Merge organic phase and use saturated sodium bicarbonate aqueous solution respectively, saturated common salt water washing dries, filters concentration, and residue is chromatographed through column Purifying, obtains title compound (K1) (250mg, yield 55%).

Its structural characterization is as follows:

ESI-MS:m/z 572.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.50 (s, 1H), 7.54 (d, J=7.6Hz, 1H), 7.16 (d, J= 10.0Hz, 1H), 6.67 (s, 1H), 6.65 (s, 1H), 6.01 (q, J=10.0Hz, 2H), 5.86 (d, J=6.0Hz, 1H), 5.53 (d, J=7.6Hz, 1H), 4.82-4.89 (m, 1H), 4.55 (t, J=8.8Hz, 2H), 4.32-4.37 (m, 1H), 4.19- 4.22 (m, 1H), 3.98-4.01 (m, 1H), 3.75-3.82 (m, 2H), 3.12 (t, J=8.8Hz, 2H), 1.24 (s, 3H), 1.22 (s, 3H), 1.16 (d, J=6.0Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ3.81

The mixture (K1) that upper step is obtained preparation HPLC separation, separation condition is as follows, with octadecyl silane For filler (20 × 250mm, 5 μm), 40 DEG C of column temperature, flow velocity 10.0mL/min, Detection wavelength 220nm, mobile phase A be water (in Property), Mobile phase B is methanol, carries out linear gradient elution.First main peak is collected, freeze-drying obtains (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl of -4- Tetrahydrofuran -2- base) methoxyl group) (2,3- Dihydrobenzofuranes -6- oxygroup) phosphoryl) amino) propionic ester (K1-a) 20mg；It receives Collect second main peak, freeze-drying obtain (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3, 4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- dihydrobenzo furan Mutter -6- oxygroup) phosphoryl) amino) propionic ester (K1-b) 120mg.

Its structural characterization is as follows:

ESI-MS:m/z 572.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.54 (s, 1H), 7.55 (d, J=5.6Hz, 1H), 7.17 (d, J= 8.0Hz, 1H), 6.67 (s, 1H), 6.65 (s, 1H), 6.02 (q, J=10.0Hz, 2H), 5.87 (d, J=6.0Hz, 1H), 5.54 (d, J=7.6Hz, 1H), 4.83-4.89 (m, 1H), 4.55 (t, J=8.8Hz, 2H), 4.32-4.37 (m, 1H), 4.19-4.22 (m, 1H), 3.98-4.01 (m, 1H), 3.75-3.82 (m, 2H), 3.12 (t, J=8.8Hz, 2H), 1.24 (s, 3H), 1.22 (s, 3H), 1.16 (d, J=6.0Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.65

Its structural characterization is as follows:

ESI-MS:m/z 572.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz)δ4.43

Embodiment 2

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzofuran -6- oxygroup) phosphoryl) amino) propionic acid Ester (K2-b) and (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzofuran -6- oxygroup) phosphoryl) amino) The preparation of propionic ester (K2-a)

In addition to using 6- hydroxyl benzofuran to replace 6- hydroxyl -2,3- Dihydrobenzofuranes, make 6- hydroxyl benzofuran Inventory be 0.134g except, it is other to operate similarly to Example 1, obtain title compound.Wherein K2-b is 25mg, and K2-a is 8mg。

Its structural characterization is as follows:

ESI-MS:m/z 570.2(M⁺+H)

¹H NMR(DMSO-d₆,400MHz)δ11.54(s,1H),7.99(s,1H),7.64-7.51(m,3H),7.15(d,J =8.0Hz, 1H), 6.96 (s, 1H), 6.14-5.90 (m, 3H), 5.54 (d, J=8.0Hz, 1H), 4.83 (m, 1H), 4.39- 3.83(m,5H),1.28-1.11(m,12H).

³¹P NMR(DMSO-d₆,162MHz)δ5.04

Its structural characterization is as follows:

ESI-MS:m/z 570.2(M⁺+H)

¹H NMR(DMSO-d₆,400MHz)δ11.54(s,1H),7.98(s,1H),7.65-7.46(m,3H),7.12(d,J =12.0Hz, 1H), 6.95 (s, 1H), 6.18-5.94 (m, 3H), 5.58 (d, J=8.0Hz, 1H), 4.83 (m, 1H), 4.43- 3.77(m,5H),1.26-1.12(m,12H)

³¹P NMR(DMSO-d₆,162MHz)δ4.85

Embodiment 3

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [b] [1,4] dioxane -5- oxygroup) phosphinylidyne Base) amino) propionic ester (K3-b) and (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- two Hydrogen pyrimidine -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [b] [1,4] dioxy oneself Ring -5- oxygroup) phosphoryl) amino) and propionic ester (K3-a) preparation.

In addition to using 2,3- dihydro -5- hydroxyl-benzo [b] [1,4] dioxane to replace 6- hydroxyl -2,3- dihydrobenzo furan It mutters, making 2,3- dihydro -5- hydroxyl-benzo [b] [Isosorbide-5-Nitrae] dioxane inventory is except 0.137g, and other and embodiment 1 is same Sample operation, obtains title compound.Wherein K3-b is 15mg, K3-a 8mg.

Its structural characterization is as follows:

ESI-MS:m/z 588.3(M⁺+H)

¹H NMR(DMSO-d₆,400MHz)δ11.52(s,1H),7.58(s,1H),6.86(m,2H),6.74-6.70(m, 1H),6.08-6.05(m,1H),5.97-5.93(m,2H),5.57(s,1H),4.85-4.81(m,1H),4.25(s,5H), 4.00(s,1H),3.82-3.80(m,1H),1.27-1.21(m,6H),1.16(s,3H),1.15(s,3H).

³¹P NMR(DMSO-d₆,162MHz)δ5.03

Its structural characterization is as follows:

ESI-MS:m/z 588.3(M⁺+H)

¹H NMR(DMSO-d₆,400MHz)δ11.52(s,1H),7.57(s,1H),6.87(m,2H),6.76-6.72(m, 1H),6.08-6.06(m,1H),5.96-5.93(m,2H),5.59(s,1H),4.84-4.81(m,1H),4.22(s,5H), 3.78(s,1H),1.27-1.22(m,6H),1.14(s,3H),1.12(s,3H).

³¹P NMR(DMSO-d₆,162MHz)δ5.09

Embodiment 4

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -2- oxo -3,4- dihydro-benzo [b] [1, 4] morpholine -7- oxygroup) phosphoryl) amino) propionic ester (K4-b) and (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- Methyl -2- oxo -3,4- dihydro-benzo [b] [1,4] morpholine -7- oxygroup) phosphoryl) amino) and propionic ester (K4-a) preparation.

In addition to using 7- hydroxy-4-methyl -2- oxo -3,4- dihydro-benzo [b] [1,4] morpholino for 6- hydroxyl -2,3- Dihydrobenzofuranes, making 7- hydroxy-4-methyl -2- oxo -3,4- dihydro-benzo [b] [Isosorbide-5-Nitrae] morpholine inventory is 0.179g Except, it is other to operate similarly to Example 1, obtain title compound.Wherein K4-b is 17mg, K4-a 2mg.

Its structural characterization is as follows:

ESI-MS:m/z 615.2(M⁺+H)

¹H NMR(DMSO-d₆,400MHz)δ11.54(s,1H),7.57(s,1H),7.15-6.91(m,3H),6.11- 5.87 (m, 2H), 5.56 (d, J=8.0Hz, 1H), 4.87 (m, 1H), 4.65 (s, 2H), 4.35-3.80 (m, 5H), 3.26 (s, 3H),1.28-1.15(m,12H).

³¹P NMR(DMSO-d₆,162MHz)δ4.91

Its structural characterization is as follows:

ESI-MS:m/z 615.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz)δ4.73

Embodiment 5

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- methyl -3- oxo -3,4- dihydro-benzo [b] [1,4] Quinoline -8- oxygroup) phosphoryl) amino) and propionic ester (K5) preparation.

In addition to using 8- hydroxy-4-methyl -3- oxo -3,4- dihydro-benzo [b] [1,4] morpholino for 6- hydroxyl -2,3- Dihydrobenzofuranes, making 8- hydroxy-4-methyl -3- oxo -3,4- dihydro-benzo [b] [Isosorbide-5-Nitrae] morpholine inventory is 0.179g Except, it is other to operate similarly to Example 1, obtain title compound 116mg, total recovery 19%.

Its structural characterization is as follows:

ESI-MS:m/z 615.2(M⁺+H)

¹H NMR(DMSO-d₆,400MHz)δ11.54(s,1H),7.58(s,1H),7.06-7.00(m,3H),6.09- 5.88 (m, 3H), 5.57 (m, 1H), 4.84 (m, 1H), 4.64 (d, J=8.0Hz, 2H), 4.37-3.78 (m, 5H), 3.27 (s, 3H),1.27-1.13(m,12H).

³¹P NMR(DMSO-d₆,162MHz)δ5.18

Embodiment 6

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- phenoxy-phenoxy) phosphoryl) amino) propionic ester (K6) Preparation

Phosphorus oxychloride (1.53g, 10mmol) is dissolved in methylene chloride (10mL), is cooled to -20 DEG C, 4- benzene oxygen is slowly added dropwise The dichloromethane solution (10mL) of base phenol (1.68g, 10mmol) and triethylamine (1.01g, 10mmol).It is added dropwise, removes Cryostat rises to 30 DEG C and stirs 2 hours.Reaction system is further cooled to -40 DEG C, l-Alanine isopropyl ester hydrochloride is added The dichloromethane solution (5mL) of triethylamine (2.53g, 25mmol) is then added dropwise in (1.51g, 9mmol).It is added dropwise, removes cold Bath rises to 20 DEG C and stirs 3 hours.Reaction system is further cooled to -60 DEG C, be added dropwise Pentafluorophenol (1.66g, 9mmol) and The dichloromethane solution (10mL) of triethylamine (1.52g, 15mmol).It is added dropwise, removes cryostat, rise to 25 DEG C and stir 4 hours. Fully reacting pours into reaction system in ice water, is extracted with dichloromethane.Merging organic phase is collected to be washed with saturated common salt aqueous solution It washs, dries, filters concentration, obtain the crude product of midbody compound, (S)-isopropyl -2- ((phenyl-pentafluoride oxygroup) (4- phenoxy group benzene Oxygroup) phosphoryl) amino) propionic ester.

By 1- (the fluoro- 4- hydroxyl -5- methylol -3- methyltetrahydrofuran -2- base of (2R, 3R, 4R, 5R) -3-) pyrimidine -2,4- (1H, 3H)-diketone (260mg, 1mmol) is dissolved in anhydrous tetrahydro furan (20mL), and argon gas is replaced three times.Tertiary fourth is added dropwise in 0 DEG C Base magnesium chloride (1.0mol/L, 2.5mL, 2.5mmol) rises to 30 DEG C and reacts 1 hour.It is cooled to 0 DEG C, above-mentioned intermediate is added dropwise Close object (S)-isopropyl -2- ((phenyl-pentafluoride oxygroup) (4- phenoxy-phenoxy) phosphoryl) amino) propionic ester (545mg, 1mmol) Anhydrous tetrahydro furan (10mL) solution.It is added dropwise, rises to 25 DEG C and react 10 hours.Few drops of 2M hydrochloric acid is added dropwise to reaction system Become clarification.Water 30mL is added to dilute, 2M hydrochloric acid is adjusted to neutrality.Reaction system is extracted with ethyl acetate, and collects and merges organic phase difference With saturated sodium bicarbonate aqueous solution, saturated common salt water washing dries, filters concentration, and residue obtains title compound through column chromatographic purifying Object (K6) (186mg, yield 30%).

Its structural characterization is as follows:

ESI-MS:m/z 622.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.56 (s, 1H), 7.60 (d, J=7.6Hz, 2H), 7.41 (t, J= 9.6Hz, 2H), 7.27 (d, J=7.6Hz, 2H), 7.16 (t, J=6.5Hz, 1H), 7.05 (d, J=9.6Hz, 2H), 7.03 (d, J=8.0Hz, 2H), 6.12-6.07 (m, 2H), 5.90 (s, 1H), 5.59 (d, J=5.6Hz, 1H), 4.92-4.86 (m, 1H), 4.40(s,1H),4.27(s,1H),4.03(s,1H),3.84-3.81(m,2H),1.31-1.17(m,12H).

³¹P NMR(DMSO-d₆,162MHz)δ4.85

By gained (K6) with preparation HPLC separation, separation condition is as follows, using octadecyl silane as filler (20 × 250mm, 5 μm), 35 DEG C of column temperature, flow velocity 10.0mL/min, Detection wavelength 220nm, mobile phase A is water (neutrality), and Mobile phase B is Methanol carries out linear gradient elution.Collect first main peak, freeze-drying obtain (S)-isopropyl ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxy Base) (4- phenoxy-phenoxy) phosphoryl) amino) propionic ester (K6-a) 15mg；Second main peak is collected, freeze-drying obtains (S)-isopropyl ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- of -4- Hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- phenoxy-phenoxy) phosphoryl) amino) propionic ester (K6-b) (K6- b)80mg。

(S)-isopropyl ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- phenoxy-phenoxy) phosphoryl) amino) propionic ester (K6- b)

Its structural characterization is as follows:

ESI-MS:m/z 622.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.56 (s, 1H), 7.60 (d, J=7.6Hz, 2H), 7.41 (t, J= 9.6Hz, 2H), 7.27 (d, J=7.6Hz, 2H), 7.16 (t, J=6.5Hz, 1H), 7.05 (d, J=9.6Hz, 2H), 7.03 (d, J=8.0Hz, 2H), 6.12-6.07 (m, 2H), 5.90 (s, 1H), 5.59 (d, J=5.6Hz, 1H), 4.92-4.86 (m, 1H), 4.40(s,1H),4.27(s,1H),4.03(s,1H),3.84-3.81(m,2H),1.31-1.17(m,12H)

³¹P NMR(DMSO-d₆,162MHz)δ4.86

(S)-isopropyl ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- phenoxy-phenoxy) phosphoryl) amino) propionic ester (K6- a)

Its structural characterization is as follows:

ESI-MS:m/z 622.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz)δ4.77

Embodiment 7

(S) -4- luorobenzyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphoryl) ammonia Base) propionic ester (K7) and its isomers preparation

Phosphorus oxychloride (1.53g, 10mmol) is dissolved in methylene chloride (15mL), -40 DEG C is cooled to, sesamol is slowly added dropwise The dichloromethane solution (10mL) of (1.38g, 10mmol) and triethylamine (1.212g, 12mmol).It is added dropwise, removes cryostat, 25 DEG C are risen to stir 3 hours.Reaction system is further cooled to -20 DEG C, l-Alanine -4- fluoro-methylbenzyl ester hydrochloride is added The dichloromethane solution (5mL) of triethylamine (2.53g, 25mmol) is then added dropwise in (2.1g, 9mmol).It is added dropwise, removes cold Bath rises to 30 DEG C and stirs 2 hours.Reaction system is further cooled to -40 DEG C, be added dropwise Pentafluorophenol (1.66g, 9mmol) and The dichloromethane solution (20mL) of triethylamine (2.53g, 25mmol).It is added dropwise, removes cryostat, rise to 20 DEG C and stir 4 hours. Fully reacting pours into reaction system in ice water, is extracted with dichloromethane.Merging organic phase is collected to be washed with saturated common salt aqueous solution It washs, dries, filters concentration, obtain the crude product of midbody compound, (S) -4- luorobenzyl -2- ((phenyl-pentafluoride oxygroup) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphoryl) amino) propionic ester.

By 1- (the fluoro- 4- hydroxyl -5- methylol -3- methyltetrahydrofuran -2- base of (2R, 3R, 4R, 5R) -3-) pyrimidine -2,4- (1H, 3H)-diketone (260mg, 1mmol) is dissolved in anhydrous tetrahydro furan (20mL), and argon gas is replaced three times.Tertiary fourth is added dropwise in 0 DEG C Base magnesium chloride (1.0mol/L, 2.5mL, 2.5mmol) rises to 30 DEG C and reacts 3 hours.It is cooled to 0 DEG C, above-mentioned intermediate is added dropwise Close object (S) -4- luorobenzyl -2- ((phenyl-pentafluoride oxygroup) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphoryl) amino) propionic acid Anhydrous tetrahydro furan (15mL) solution of ester (563mg, 1mmol).It is added dropwise, rises to 20 DEG C and react 10 hours.2M salt is added dropwise Acid few drops to reaction system become clarify.Water 30mL is added to dilute, 2M hydrochloric acid is adjusted to neutrality.Reaction system is extracted with ethyl acetate, and receives Collection merges organic phase and uses saturated sodium bicarbonate aqueous solution respectively, and saturated common salt water washing dries, filters concentration, and residue is through column layer Analysis purifying, obtains title compound (K7) (200mg, yield 31%).

Its structural characterization is as follows:

ESI-MS:m/z 640.2(M⁺+H)

1H NMR(DMSO-d₆, 400MHz) and δ 11.51 (s, 1H), 7.54 (d, J=8.8Hz, 1H), 7.41-7.37 (m, 2H), 7.17 (t, J=8.7Hz, 2H), 6.88-6.58 (m, 3H), 6.12-6.06 (m, 1H), 6.00 (s, 2H), 5.90-5.86 (m, 1H), 5.57 (t, J=3.5Hz, 1H), 5.08-5.06 (m, 2H), 4.35-4.21 (m, 2H), 4.00-3.83 (m, 3H), 3.49-3.39(m,1H),1.26-1.21(m,6H).

³¹P NMR(DMSO-d₆,162MHz)δ5.04

By gained (K7) with preparation HPLC separation, separation condition is as follows, using octadecyl silane as filler (20 × 250mm, 5 μm), 35 DEG C of column temperature, flow velocity 10.0mL/min, Detection wavelength 220nm, mobile phase A is water (neutrality), and Mobile phase B is Methanol carries out linear gradient elution.Collect first main peak, freeze-drying obtain (S) -4- luorobenzyl ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) Methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphoryl) amino) propionic ester (K7-a) 5mg；Collect second master Peak, freeze-drying obtain (S) -4- luorobenzyl ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidins -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) Phosphoryl) amino) propionic ester (K7-b) 25mg.

(S) -4- luorobenzyl ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphinylidyne Base) amino) propionic ester (K7-b)

Its structural characterization is as follows:

ESI-MS:m/z 640.2(M⁺+H)

1H NMR(DMSO-d₆, 400MHz) and δ 11.54 (s, 1H), 7.55 (d, J=8.2Hz, 1H), 7.39 (dd, J= 8.2,5.8Hz, 2H), 7.18 (t, J=8.7Hz, 2H), 6.88-6.80 (m, 2H), 6.65 (d, J=8.8Hz, 1H), 6.12 (t, J=10.2Hz, 1H), 6.01-5.88 (m, 2H), 5.89 (s, 2H), 5.57 (d, J=8.1Hz, 1H), 5.13-5.01 (m, 2H), 4.34-4.32(m,1H),4.23-4.19(m,1H),4.00-3.81(m,3H),1.27-1.22(m,6H)

³¹P NMR(DMSO-d₆,162MHz)δ5.05

(S) -4- luorobenzyl ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphinylidyne Base) amino) propionic ester (K7-a)

Its structural characterization is as follows:

ESI-MS:m/z 640.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz)δ5.05

Embodiment 8

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (benzo [d] [1,3] dioxolanes -4- oxygroup) phosphoryl) ammonia Base) propionic ester (K8) preparation

In addition to using 4- hydroxy benzo [d] [1,3] dioxolanes to replace 6- hydroxyl -2,3- Dihydrobenzofuranes, making 4- hydroxyl The inventory of base benzo [d] [1,3] dioxolanes be 0.138g except, it is other to operate similarly to Example 1, obtain title compound Object 57mg, total recovery 10%.

Its structural characterization is as follows:

ESI-MS:m/z 570.2(M⁺+H)

1H NMR(DMSO-d₆, 400MHz) and δ 11.54 (s, 1H), 7.57 (s, 1H), 6.88 (d, J=7.6Hz, 1H), 6.81-6.79 (m, 2H), 6.17-6.11 (m, 1H), 6.05-6.02 (m, 3H), 5.87 (s, 1H), 5.56 (d, J=7.8Hz, 2H),4.88-4.84(m,1H),4.36(s,1H),4.26(s,1H),4.03-3.79(m,4H),1.28-1.22(m,6H), 1.16(s,3H),1.15(s,3H)

³¹P NMR(DMSO-d₆,162MHz)δ5.13

Embodiment 9

(S)-isobutyl group (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphoryl) ammonia Base) propionic ester (K9) preparation.

In addition to using l-Alanine-S- isobutyl ester hydrochloride to replace l-Alanine isopropyl ester hydrochloride, making l-Alanine-S- The inventory of isobutyl ester hydrochloride is 0.165g；6- hydroxyl -2,3- Dihydrobenzofuranes are replaced using sesamol, make sesamol Inventory be 0.138g except, it is other to operate similarly to Example 1, obtain title compound 64mg, total recovery 11%

Its structural characterization is as follows:

ESI-MS:m/z 588.2(M⁺+H)

1H NMR(DMSO-d₆, 400MHz) and δ 11.57 (s, 1H), 7.59 (d, J=6.7Hz, 1H), 6.91-6.88 (m, 2H), 6.70 (d, J=8.4Hz, 1H), 6.07-6.01 (m, 4H), 5.91 (s, 1H), 5.61 (d, J=8.0Hz, 1H), 4.74 (q, J=6.2Hz, 1H), 4.37 (s, 1H), 4.26 (s, 1H), 4.01 (s, 1H), 3.86-3.82 (m, 1H), 1.54-1.51 (m, 2H), 1.30-1.22 (m, 6H), 1.15 (d, J=5.2Hz, 3H), 0.84 (t, J=7.3Hz, 3H)

³¹P NMR(DMSO-d₆,162MHz)δ5.07

Embodiment 10

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (benzo [d] [1,3] dioxolanes -5- base)-phenoxy group) phosphorus Acyl group) amino) propionic ester (K10) preparation

Phosphorus oxychloride (1.53g, 10mmol) is dissolved in methylene chloride (10mL), -60 DEG C is cooled to, 4- (benzene is slowly added dropwise And [d] [1,3] dioxolanes -5- base) phenol (2.14g, 10mmol) and triethylamine (2.02g, 20mmol) methylene chloride it is molten Liquid (15mL).It is added dropwise, removes cryostat, rise to 20 DEG C and stir 6 hours.Reaction system is further cooled to -60 DEG C, is added The dichloromethane solution of triethylamine (3.04g, 30mmol) is then added dropwise in l-Alanine isopropyl ester hydrochloride (1.51g, 9mmol) (5mL).It is added dropwise, removes cryostat, rise to 25 DEG C and stir 6 hours.Reaction system is further cooled to -20 DEG C, is added dropwise five The dichloromethane solution (10mL) of fluorophenol (1.66g, 9mmol) and triethylamine (1.52g, 15mmol).It is added dropwise, removes cold Bath rises to 25 DEG C and stirs 6 hours.Fully reacting pours into reaction system in ice water, is extracted with dichloromethane.Collection is associated with Machine is mutually washed with saturated common salt aqueous solution, dries, filters concentration, obtains the crude product of midbody compound, (S)-isopropyl 2- ((phenyl-pentafluoride oxygroup) (4- (benzo [d] [1,3] dioxolanes -5- base)-phenoxy group) phosphoryl) amino) propionic ester.

By 1- (the fluoro- 4- hydroxyl -5- methylol -3- methyltetrahydrofuran -2- base of (2R, 3R, 4R, 5R) -3-) pyrimidine -2,4- (1H, 3H)-diketone (260mg, 1mmol) is dissolved in anhydrous tetrahydro furan (30mL), and argon gas is replaced three times.Tertiary fourth is added dropwise in 5 DEG C Base magnesium chloride (1.0mol/L, 2.5mL, 2.5mmol) rises to 20 DEG C and reacts 2 hours.It is cooled to 0 DEG C, above-mentioned intermediate is added dropwise Close object (S)-isopropyl 2- ((phenyl-pentafluoride oxygroup) (4- (benzo [d] [1,3] dioxolanes -5- base)-phenoxy group) phosphoryl) ammonia Base) propionic ester (573mg, 1mmol) anhydrous tetrahydro furan (30mL) solution.It is added dropwise, rises to 10 DEG C and react 14 hours.Drop Add few drops of 2M hydrochloric acid to become to reaction system to clarify.Water 30mL is added to dilute, 2M hydrochloric acid is adjusted to neutrality.Reaction system is extracted with ethyl acetate It takes, collects merging organic phase and use saturated sodium bicarbonate aqueous solution respectively, saturated common salt water washing dries, filters concentration, residue warp Column chromatographic purifying obtains title compound (K10) (300mg, yield 46%).

Its structural characterization is as follows:

ESI-MS:m/z 650.2(M⁺+H)

1H NMR(DMSO-d₆, 400MHz) δ 11.53 (s, 1H), 7.61-7.58 (m, 3H), 7.25 (d, J=8.6Hz, 1H), 7.22 (s, 2H), 7.11 (dd, J=8.16,1.92Hz, 1H), 6.98 (d, J=8.0Hz, 1H), 6.85 (s, 2H), 6.05-5.87 (m, 1H), 5.56 (d, J=8.2Hz, 1H), 4.85 (m, 1H), 4.39 (s, 1H), 4.25 (s, 1H), 4.02 (s, 1H), 3.84-3.80 (m, 2H), 3.50-3.48 (m, 1H), 3.42 (d, J=5.8Hz, 1H), 1.28-1.21 (m, 6H), 1.16- 1.14(m,6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.73

Embodiment 11

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (the fluoro- phenoxy group of the chloro- 3- of 4-)-phenoxy group) phosphoryl) ammonia Base) propionic ester (K11) preparation

In addition to using 4- (the fluoro- phenoxy group of the chloro- 3- of 4-)-phenol to replace 6- hydroxyl -2,3- Dihydrobenzofuranes, making 4- (4- The chloro- fluoro- phenoxy group of 3-)-phenol inventory be 0.238g except, it is other to operate similarly to Example 1, obtain title compound 101mg, total recovery 15%.

Its structural characterization is as follows:

ESI-MS:m/z 676.2(M⁺+H)

1H NMR(DMSO-d₆, 400MHz) and δ 11.53 (s, 1H), 7.56 (t, J=8.7Hz, 2H), 7.26 (t, J= 9.1Hz, 2H), 7.16-7.05 (m, 3H), 6.81 (d, J=9.1Hz, 1H), 6.16-5.88 (m, 3H), 5.59-5.54 (m, 1H),4.87-4.83(m,1H),4.39(s,1H),4.25(s,1H),4.00(s,1H),3.83-3.80(m,2H),1.28- 1.22(m,6H),1.16-1.14(m,6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.89

Embodiment 12

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (3- oxo -4- methyl -2H- benzo [b] [1,4] Quinoline -7- oxygroup) phosphoryl) amino) propionic ester (K12-b) and (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2, - 1 (2H)-yl of 4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (3- oxygen Generation -4 methyl -2H- benzo [b] [1,4] morpholine -7- oxygroups) phosphoryl) amino) propionic ester (K12-a) preparation

In addition to using -4 methyl -2H- benzo [b] [1,4] morpholino of 7- hydroxyl -3- oxo for 6- hydroxyl -2,3- dihydrobenzene And furans, make except the inventory 0.179g of 7- hydroxyl -3- oxo -4 methyl -2H- benzo [b] [Isosorbide-5-Nitrae] morpholine, it is other with it is real It applies example 1 equally to operate, obtains title compound.Wherein K12-b is 30mg, K12-a 10mg.

Its structural characterization is as follows:

ESI-MS:m/z 615.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.54 (s, 1H), 7.57 (d, J=6.8Hz, 1H), 7.15 (d, J= 8.4Hz, 1H), 6.94 (s, 1H), 6.92 (s, 1H), 6.01-6.12 (m, 2H), 5.88 (s, 1H), 5.57 (d, J=8.0Hz, 1H),4.86-4.89(m,1H),4.66(s,2H),4.36-4.38(m,1H),4.24-4.25(m,1H),4.00-4.02(m, 1H), 3.79-3.86 (m, 2H), 3.27 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H), 1.16 (d, J=6.0Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.88

Its structural characterization is as follows:

ESI-MS:m/z 615.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.54 (s, 1H), 7.59 (d, J=8.0Hz, 1H), 7.16 (d, J= 8.8Hz, 1H), 6.91 (d, J=8.8Hz, 1H), 6.89 (s, 1H), 6.03-6.18 (m, 2H), 5.94 (s, 1H), 5.61 (d, J =8.4Hz, 1H), 5.85 (t, J=4.4Hz, 1H), 4.86-4.92 (m, 1H), 4.67 (s, 2H), 4.41-4.45 (m, 1H), 4.26-4.31(m,1H),4.05-4.08(m,1H),3.75-3.84(m,2H),3.27(s,2H),1.24(s,3H),1.22(s, 3H), 1.16 (d, J=6.0Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.76

Embodiment 13

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -2H- benzo [b] [1,4] morpholine -7- oxygen Base) phosphoryl) amino) propionic ester (K13-b) and (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (bis- carbonyl of 2,4- - 1 (2H)-yl of base -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -2H- Benzo [b] [1,4] morpholine -7- oxygroup) phosphoryl) amino) and propionic ester (K13-a) preparation

In addition to using 7- hydroxy-4-methyl -2H- benzo [b] [Isosorbide-5-Nitrae] morpholino to replace 6- hydroxyl -2,3- Dihydrobenzofuranes, It is other to grasp similarly to Example 1 except the inventory 0.163g for making 7- hydroxy-4-methyl -2H- benzo [b] [Isosorbide-5-Nitrae] morpholine Make, obtains title compound.Wherein K13-b is 25mg, K13-a 7mg.

Its structural characterization is as follows:

ESI-MS:m/z 601.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.52 (s, 1H), 7.53 (d, J=7.2Hz, 1H), 6.63 (s, 2H), 6.58 (s, 1H), 5.88-6.05 (m, 3H), 5.52 (d, J=7.6Hz, 1H), 4.82-4.89 (m, 1H), 4.30-4.35 (m, 1H), 4.20-4.22(m,3H),3.97-3.99(m,1H),3.78-3.80(m,2H),3.15(s,2H),2.77(s,3H),1.24(s, 3H), 1.22 (s, 3H), 1.16 (d, J=6.0Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ5.01

Its structural characterization is as follows:

ESI-MS:m/z 601.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.53 (s, 1H), 7.53 (d, J=8.0Hz, 1H), 6.62 (s, 2H), 6.54 (s, 1H), 5.88-6.05 (m, 3H), 5.55 (d, J=8.0Hz, 1H), 4.83-4.89 (m, 1H), 4.34-4.38 (m, 1H), 4.20-4.22 (m, 3H), 4.02 (d, J=8.4Hz, 1H), 3.68-3.82 (m, 2H), 3.14-3.16 (m, 2H), 2.77 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H), 1.16 (d, J=6.0Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.88

Embodiment 14

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2- oxo -1,3- methyl-1 H- benzo [b] imidazoline - 4- oxygroup) phosphoryl) amino) propionic ester (K14-b) and (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- - 1 (2H)-yl of dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2- oxo - 1,3- methyl-1 H- benzo [b] imidazoline -4- oxygroup) phosphoryl) amino) and propionic ester (K14-a) preparation

In addition to using 4- hydroxyl -2- oxo -1,3- methyl-1 H- benzo [b] imidazoline to replace 6- hydroxyl -2,3- dihydrobenzene And furans, make 4- hydroxyl -2- oxo -1,3- methyl-1 H- benzo [b] imidazoline inventory be 0.178g except, it is other with it is real It applies example 1 equally to operate, obtains title compound, wherein K14-b 10mg, K14-a 2mg.

Its structural characterization is as follows:

ESI-MS:m/z 614.3(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.50 (s, 1H), 7.50 (d, J=7.2Hz, 1H), 7.05-7.07 (m, 1H), 7.00-7.02 (m, 2H), 6.19-6.25 (m, 1H), 5.96-6.04 (m, 2H), 5.50 (d, J=7.2Hz, 1H), 4.80- 4.86(m,1H),4.34-4.39(m,1H),4.24-4.28(m,1H),3.98-4.00(m,1H),3.77-3.88(m,2H), 3.51 (s, 3H), 3.31 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H), 1.16 (d, J=6.0Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ5.44

Its structural characterization is as follows:

ESI-MS:m/z 614.3(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.50 (s, 1H), 7.53 (d, J=7.2Hz, 1H), 7.06-7.08 (m, 1H), 6.97-7.02 (m, 2H), 6.23-6.30 (m, 1H), 5.91-6.04 (m, 2H), 5.51 (d, J=7.2Hz, 1H), 4.79- 4.85(m,1H),4.41-4.45(m,1H),4.27-4.33(m,1H),4.03-4.07(m,1H),3.75-3.87(m,2H), 3.50 (s, 3H), 3.31 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H), 1.16 (d, J=6.0Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ5.27

Embodiment 15

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (2,2- dioxo -1,3- dihydrobenzo [c] thiophene -5- oxygroup) Phosphoryl) amino) propionic ester (K15) preparation

In addition to using 4- phenoxy phenyl to replace 6- hydroxyl -2,3- Dihydrobenzofuranes, making feeding intake for 4- phenoxy phenyl Amount be 0.184g except, it is other to operate similarly to Example 1, obtain title compound 123mg, total recovery 20%.

Its structural characterization is as follows:

ESI-MS:m/z 620.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.56 (s, 1H), 7.59 (s, 1H), 7.41 (d, J=8.0Hz, 1H), 7.20-7.30 (m, 2H), 5.88-6.23 (m, 3H), 5.96-6.04 (m, 2H), 5.61-5.64 (m, 1H), 4.86-4.92 (m, 1H),4.52(s,1H),4.48(s,1H),4.37-4.42(m,1H),4.24-4.31(m,1H),4.01-4.09(m,1H), 3.78-3.87 (m, 2H), 1.24 (s, 3H), 1.22 (s, 3H), 1.18 (d, J=6.0Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.72

Embodiment 16

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -3- oxo -3,4- dihydro -2H- benzo [b] [1,4] morpholine -6- oxygroup) phosphoryl) amino) propionic ester (K16-b) and (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxy Base) (4- methyl -3- oxo -3,4- dihydro -2H- benzo [b] [1,4] morpholine -6- oxygroup) phosphoryl) amino) propionic ester (K16- A) preparation

In addition to using -4 methyl -2H- benzo [b] [1,4] morpholino of 6- hydroxyl -3- oxo for 6- hydroxyl -2,3- dihydrobenzene And furans, make except the inventory 0.179g of 6- hydroxyl -3- oxo -4 methyl -2H- benzo [b] [Isosorbide-5-Nitrae] morpholine, it is other with it is real It applies example 1 equally to operate, obtains title compound, wherein K16-b 33mg, K16-a 7mg.

Its structural characterization is as follows:

ESI-MS:m/z 615.3(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.54 (s, 1H), 7.58 (d, J=8.0Hz, 1H), 7.00-7.01 (m, 2H), 6.86 (d, J=8.0Hz, 1H), 5.96-6.17 (m, 2H), 5.65 (d, J=8.4Hz, 1H), 4.85-4.90 (m, 1H), 4.67(s,3H),4.42-4.46(m,1H),4.28-4.34(m,1H),4.08-4.10(m,1H),3.79-3.86(m,2H), 3.24 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H), 1.17 (d, J=6.0Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.77

Its structural characterization is as follows:

ESI-MS:m/z 615.3(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.54 (s, 1H), 7.58 (d, J=8.0Hz, 1H), 7.00-7.01 (m, 2H), 6.84 (d, J=8.4Hz, 1H), 5.94-6.15 (m, 2H), 5.61 (d, J=8.0Hz, 1H), 4.85-4.91 (m, 1H), 4.64(s,3H),4.41-4.45(m,1H),4.26-4.30(m,1H),4.05-4.08(m,1H),3.79-3.86(m,2H), 3.24 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H), 1.17 (d, J=6.0Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.93

Embodiment 17

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (3- methyl -2H- benzo [d] -2- oxazolidone -7- oxygroup) phosphinylidyne Base) amino) propionic ester (K17) preparation

In addition to use 7- hydroxy-3-methyl -2H- benzo [d] -2- oxazolidone replace 6- hydroxyl -2,3- Dihydrobenzofuranes, It is other to grasp similarly to Example 1 except the inventory 0.165g for making 7- hydroxy-3-methyl -2H- benzo [d] -2- oxazolidone Make, obtains title compound 108mg, total recovery 18%.

Its structural characterization is as follows:

ESI-MS:m/z 601.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.56 (s, 1H), 7.58 (d, J=8.0Hz, 1H), 7.21-7.25 (m, 1H), 7.12-7.15 (m, 2H), 6.25-6.31 (m, 1H), 6.00-6.07 (m, 1H), 5.91 (d, J=6.8Hz, 1H), 5.55 (d, J=8.0Hz, 1H), 4.85-4.91 (m, 1H), 4.41-4.45 (m, 1H), 4.29-4.32 (m, 1H), 4.01-4.04 (m, 1H), 3.83-3.90 (m, 2H), 3.37 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H), 1.17 (d, J=6.0Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ5.24

Embodiment 18

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2- oxo -1,3- methyl-1 H- benzo [b] imidazoline - 5- oxygroup) phosphoryl) amino) propionic ester (K18-b) and (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- - 1 (2H)-yl of dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2- oxo - 1,3- methyl-1 H- benzo [b] imidazoline -5- oxygroup) phosphoryl) amino) and propionic ester (K18-a) preparation

In addition to using 5- hydroxyl -2- oxo -1,3- methyl-1 H- benzo [b] imidazoline to replace 6- hydroxyl -2,3- dihydrobenzene And furans, make 5- hydroxyl -2- oxo -1,3- methyl-1 H- benzo [b] imidazoline inventory be 0.178g except, it is other with it is real It applies example 1 equally to operate, obtains title compound, wherein K18-b 15mg, K18-a 4mg.

Its structural characterization is as follows:

ESI-MS:m/z 614.3(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.55 (s, 1H), 7.58 (d, J=7.2Hz, 1H), 7.10-7.14 (m, 2H), 6.97 (d, J=8.4Hz, 1H), 6.05 (t, J=12.0Hz, 2H), 5.92 (s, 1H), 5.57 (d, J=8.0Hz, 1H), 4.85-4.97(m,1H),4.38-4.43(m,1H),4.25-4.29(m,1H),4.02-4.05(m,1H),3.81-3.90(m, 2H), 3.50 (s, 3H), 3.31 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H), 1.16 (d, J=7.2Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ5.03

Its structural characterization is as follows:

ESI-MS:m/z 614.3(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.55 (s, 1H), 7.57 (d, J=7.2Hz, 1H), 7.13 (d, J= 8.0Hz, 1H), 7.04 (s, 1H), 6.93 (d, J=8.0Hz, 1H), 6.08 (t, J=8.0Hz, 2H), 5.61 (d, J=8.0Hz, 1H), 4.86-4.93 (m, 1H), 4.61 (t, J=4.8Hz, 1H), 4.42-4.47 (m, 1H), 4.27-4.32 (m, 1H), 4.07- 4.09(m,1H),3.75-3.84(m,2H),3.52(s,3H),3.31(s,3H),1.24(s,3H),1.22(s,3H),1.16 (d, J=7.2Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.96

Embodiment 19

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (2,3- coumaran -6- base) phenoxy group) phosphoryl) Amino) propionic ester (K19) preparation

In addition to using 4- (2,3- coumaran -6- base) phenol to replace 6- hydroxyl -2,3- Dihydrobenzofuranes, making 4- The inventory of (2,3- coumaran -6- base) phenol be 0.212g except, it is other to operate similarly to Example 1, marked Inscribe compound 123mg, total recovery 19%.

Its structural characterization is as follows:

ESI-MS:m/z 648.3(M⁺+H)

¹H NMR(DMSO-d₆,400MHz)δ11.57(s,1H),7.61-7.66(m,3H),7.27-7.33(m,3H), 7.11 (d, J=7.2Hz, 1H), 7.05 (s, 1H), 5.90-6.16 (m, 3H), 5.60 (d, J=8.0Hz, 1H), 4.86-4.92 (m, 1H), 4.60 (t, J=8.8Hz, 2H), 4.40-4.44 (m, 1H), 4.27-4.30 (m, 1H), 4.05-4.07 (m, 1H), 3.81-3.90 (m, 2H), 3.21-3.25 (t, J=8.4Hz, 2H), 1.24 (s, 3H), 1.22 (s, 3H), 1.16 (d, J= 7.2Hz,6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.68

Embodiment 20

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- methyl -2H- benzo [b] [1,4] morpholine -8- oxygroup) phosphinylidyne Base) amino) propionic ester (K20) and its isomers preparation.

Phosphorus oxychloride (1.53g, 10mmol) is dissolved in methylene chloride (10mL), -60 DEG C is cooled to, 8- hydroxyl is slowly added dropwise The dichloromethane solution of base -4- methyl -2H- benzo [b] [Isosorbide-5-Nitrae] morpholine (1.65g, 10mmol) and piperidines (0.85g, 10mmol) (10mL).It is added dropwise, removes cryostat, rise to 25 DEG C and stir 2 hours.Reaction system is further cooled to -60 DEG C, L- is added The dichloromethane solution of piperidines (2.1g, 25mmol) is then added dropwise in alanine isopropyl ester hydrochloride (1.51g, 9mmol) (10mL).It is added dropwise, removes cryostat, rise to 25 DEG C and stir 2 hours.Reaction system is further cooled to -60 DEG C, is added dropwise five The tetrahydrofuran solution (10mL) of fluorophenol (1.66g, 9mmol) and piperidines (1.28g, 15mmol).It is added dropwise, removes cold Bath rises to 30 DEG C and stirs 2 hours.Fully reacting pours into reaction system in ice water, is extracted with dichloromethane.Collection is associated with Machine is mutually washed with saturated common salt aqueous solution, dries, filters concentration, obtains the crude product of midbody compound, (S)-isopropyl -2- ((phenyl-pentafluoride oxygroup) 4- methyl -2H- benzo [b] [1,4] morpholine -8- oxygroup) phosphoryl) amino) propionic ester.

By 1- (the fluoro- 4- hydroxyl -5- methylol -3- methyltetrahydrofuran -2- base of (2R, 3R, 4R, 5R) -3-) pyrimidine -2,4- (1H, 3H)-diketone (260mg, 1mmol) is dissolved in anhydrous tetrahydro furan (20mL), and argon gas is replaced three times.Tertiary fourth is added dropwise in 0 DEG C Base magnesium chloride (1.0mol/L, 2.5mL, 2.5mmol) rises to 25 DEG C and reacts 1 hour.It is cooled to 0 DEG C, above-mentioned intermediate is added dropwise Close object (S)-isopropyl -2- ((phenyl-pentafluoride oxygroup) 4- methyl -2H- benzo [b] [1,4] morpholine -8- oxygroup) phosphoryl) amino) Anhydrous tetrahydro furan (10mL) solution of propionic ester (524mg, 1mmol).It is added dropwise, rises to 25 DEG C and react 15 hours.It is added dropwise Few drops of 2M hydrochloric acid becomes to reaction system to be clarified.Water 40mL is added to dilute, 2M hydrochloric acid is adjusted to neutrality.Reaction system is extracted with ethyl acetate It takes, collects merging organic phase and use saturated sodium bicarbonate aqueous solution respectively, saturated common salt water washing dries, filters concentration, residue warp Column chromatographic purifying obtains title compound (K20) (245mg, 41%).

Its structural characterization is as follows:

ESI-MS:m/z 601.3(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.56 (s, 1H), 7.61 (d, J=8.0Hz, 1H), 6.64-6.74 (m, 2H), 6.55 (d, J=6.8Hz, 1H), 5.85-6.09 (m, 3H), 5.58 (d, J=8.4Hz, 1H), 4.86-4.93 (m, 1H), 4.38-4.44(m,1H),4.24-4.26(m,3H),4.01-4.05(m,1H),3.82-3.88(m,2H),3.27(s,2H), 2.86 (s, 3H), 1.25 (s, 3H), 1.24 (s, 3H), 1.16 (d, J=6.0Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.81

Gained (K20) is separated with preparation HPLC, separation condition is as follows, using octadecyl silane as filler (20 × 250mm, 5 μm), 45 DEG C of column temperature, flow velocity 12.0mL/min, Detection wavelength 220nm, mobile phase A is water (neutrality), Mobile phase B For methanol, linear gradient elution is carried out.Collect first main peak, freeze-drying obtain (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- of -4- Base) methoxyl group) (4- methyl -2H- benzo [b] [1,4] morpholine -8- oxygroup) phosphoryl) amino) propionic ester (K20-a) 20mg；It receives Collect second main peak, freeze-drying obtain (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3, 4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -2H- benzo [b] [1,4] morpholine -8- oxygroup) phosphoryl) amino) propionic ester (K20-b) 80mg.

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -2H- benzo [b] [1,4] morpholine -8- oxygen Base) phosphoryl) amino) propionic ester (K20-b)

Its structural characterization is as follows:

ESI-MS:m/z 601.3(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.54 (s, 1H), 7.57 (d, J=6.8Hz, 1H), 6.62-6.71 (m, 2H), 6.51 (d, J=8.0Hz, 1H), 5.83-6.04 (m, 3H), 5.54 (d, J=8.4Hz, 1H), 4.83-4.89 (m, 1H), 4.34-4.38(m,1H),4.20-4.23(m,3H),3.99-4.01(m,1H),3.78-3.84(m,2H),3.24(s,2H), 2.83 (s, 3H), 1.22 (s, 3H), 1.20 (s, 3H), 1.16 (d, J=6.0Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.91

(S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -2H- benzo [b] [1,4] morpholine -8- oxygen Base) phosphoryl) amino) propionic ester (K20-a)

Its structural characterization is as follows:

ESI-MS:m/z 601.3(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz)δ4.71

Embodiment 21

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- methyl -2H- benzo [b] [1,4] morpholine -6- oxygroup) phosphinylidyne Base) amino) propionic ester (K21) preparation

In addition to use 6- hydroxy-4-methyl -2H- benzo [b] [1,4] morpholino for 6- hydroxyl -2,3- Dihydrobenzofuranes, It is other to grasp similarly to Example 1 except the inventory 0.165g for making 6- hydroxy-4-methyl -2H- benzo [b] [Isosorbide-5-Nitrae] morpholine Make, obtains title compound 120mg, total recovery 20%.

Its structural characterization is as follows:

ESI-MS:m/z 601.3(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.56 (s, 1H), 7.58 (d, J=8.4Hz, 1H), 6.62 (d, J= 8.4Hz, 1H), 6.54 (d, J=1.6Hz, 1H), 6.41 (d, J=8.4Hz, 1H), 5.88-6.08 (m, 3H), 5.57 (d, J= 8.4Hz,1H),4.86-4.92(m,1H),4.35-4.39(m,1H),4.19-4.23(m,3H),4.01-4.04(m,1H), 3.78-3.85 (m, 2H), 3.25 (t, J=4.0Hz, 2H), 2.83 (s, 3H), 1.28 (s, 3H), 1.26 (s, 3H), 1.18 (d, J =6.0Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.77

Embodiment 22

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (2,2- dioxo -1,3- dihydrobenzo [c] thiophene -5- base) Phenoxy group) phosphoryl) amino) and propionic ester (K22) preparation

In addition to using 4- (2,2- dioxo -1,3- dihydrobenzo [c] thiophene -5- base) phenol to replace 6- hydroxyl -2,3- two Hydrogen benzofuran, make 4- (2,2- dioxo -1,3- dihydrobenzo [c] thiophene -5- base) phenol inventory be 0.26g except, It is other to operate similarly to Example 1, obtain title compound 146mg, total recovery 21%.

Its structural characterization is as follows:

ESI-MS:m/z 696.2(M⁺+H)

¹H NMR(DMSO-d₆,400MHz)δ11.56(s,1H),7.64-7.69(m,5H),7.57-7.59(m,1H), 7.46 (d, J=7.2Hz, 1H), 7.33 (d, J=8.8Hz, 1H), 5.89-6.16 (m, 3H), 5.56-5.61 (m, 1H), 4.84- 4.87(m,1H),4.54(s,4H),4.36-4.42(m,1H),4.25-4.29(m,1H),4.01-4.04(m,1H),3.77- 3.87 (m, 2H), 1.28 (s, 3H), 1.23 (s, 3H), 1.15 (d, J=4.8Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.66

Embodiment 23

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (the fluoro- 2,3- coumaran -4- base of 7-) phenoxy group) phosphorus Acyl group) amino) propionic ester (K23) preparation

In addition to using 4- (the fluoro- 2,3- coumaran -4- base of 7-) phenol to replace 6- hydroxyl -2,3- dihydrobenzo furan Mutter, make 4- (fluoro- 2, the 3- coumaran -4- base of 7-) phenol inventory be 0.23g except, it is other similarly to Example 1 Operation, obtains title compound 122mg, total recovery 18%.

Its structural characterization is as follows:

ESI-MS:m/z 666.3(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.56 (s, 1H), 7.59-7.61 (d, J=6.0Hz, 1H), 7.52-7.54 (d, J=8.0Hz, 2H), 7.33 (d, J=8.4Hz, 2H), 7.16 (t, J=9.6Hz, 1H), 6.89-6.92 (m, 1H), 5.92- 6.22 (m, 2H), 5.55 (d, J=8.4Hz, 2H), 4.86-4.92 (m, 1H), 4.66 (t, J=9.2Hz, 2H), 4.41-4.45 (m,1H),4.27-4.31(m,1H),4.04-4.07(m,1H),3.81-3.90(m,2H),3.33-3.35(m,2H),1.26- 1.31 (m, 6H), 1.18 (d, J=6.0Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.66

Embodiment 24

(S) -4- luorobenzyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (benzofuran -6- oxygroup) phosphoryl) amino) propionic ester (K24) Preparation

Tribromo oxygen phosphorus (2.86g, 10mmol) is dissolved in chloroform (10mL), -50 DEG C is cooled to, hydroxyl -2 6- is slowly added dropwise, The dichloromethane solution (10mL) of 3- Dihydrobenzofuranes (1.36g, 10mmol) and triethylamine (1.212g, 12mmol).It is added dropwise It finishes, removes cryostat, rise to 25 DEG C and stir 2 hours.Reaction system is further cooled to -60 DEG C, l-Alanine -4- fluorine is added The dichloromethane solution (5mL) of triethylamine (2.53g, 25mmol) is then added dropwise in benzyl ester hydrochloride (2.1g, 9mmol).It drips Finish, remove cryostat, rises to 25 DEG C and stir 2 hours.Reaction system is further cooled to -60 DEG C, be added dropwise Pentafluorophenol (1.66g, 9mmol) and the dichloromethane solution (10mL) of triethylamine (1.52g, 15mmol).It is added dropwise, removes cryostat, rise to 25 DEG C and stir It mixes 6 hours.Fully reacting pours into reaction system in ice water, is extracted with dichloromethane.It collects and merges organic phase saturated common salt Aqueous solution washing, dries, filters concentration, obtains the crude product of midbody compound, (S) -4- luorobenzyl -2- ((phenyl-pentafluoride oxygroup) (benzofuran -6- oxygroup) phosphoryl) amino) propionic ester.

By 1- (the fluoro- 4- hydroxyl -5- methylol -3- methyltetrahydrofuran -2- base of (2R, 3R, 4R, 5R) -3-) pyrimidine -2,4- (1H, 3H)-diketone (260mg, 1mmol) is dissolved in anhydrous tetrahydro furan (20mL), and argon gas is replaced three times.Tertiary fourth is added dropwise in 0 DEG C Base magnesium chloride (1.0mol/L, 2.5mL, 2.5mmol) rises to 25 DEG C and reacts 2 hours.It is cooled to 0 DEG C, above-mentioned intermediate is added dropwise Close object (S) -4- luorobenzyl -2- ((phenyl-pentafluoride oxygroup) (benzofuran -6- oxygroup) phosphoryl) amino) propionic ester (560mg, Anhydrous tetrahydro furan (10mL) solution 1mmol).It is added dropwise, rises to 25 DEG C and react 10 hours.Be added dropwise few drops of 2.5M hydrochloric acid to Reaction system becomes clarification.Water 35mL is added to dilute, 2M hydrochloric acid is adjusted to neutrality.Reaction system is extracted with ethyl acetate, and collection is associated with Machine mutually uses saturated sodium bicarbonate aqueous solution respectively, and saturated common salt water washing dries, filters concentration, and residue is obtained through column chromatographic purifying Title compound (K24) (273mg, yield 43%).

Its structural characterization is as follows:

ESI-MS:m/z 636.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.56 (s, 1H), 8.02 (d, J=2.8Hz, 1H), 7.63 (d, J= 8.4Hz, 1H), 7.57 (d, J=7.6Hz, 1H), 7.52 (s, 1H), 7.38-7.41 (m, 2H), 7.15-7.20 (m, 3H), 6.98 (s, 1H), 6.24 (t, J=12.0Hz, 1H), 5.93-6.08 (m, 2H), 5.56 (d, J=8.0Hz, 1H), 5.06-5.09 (m, 2H),4.39-4.43(m,1H),4.27-4.30(m,1H),3.96-4.06(m,2H),3.79-3.89(m,1H),1.25-1.30 (m,6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.89

Embodiment 25

(S)-(2,3- coumaran -5- benzyl) ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- Dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzofuran -6- oxygroup) phosphorus Acyl group) amino) propionic ester (K25-b) and (S)-(2,3- coumaran -5- benzyl) ((R)-((((2R, 3R, 4R, 5R) - 5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzofuran -6- oxygroup) phosphoryl) amino) propionic ester (K25-a) preparation

In addition to using 2,3- coumaran -5- benzyl ester hydrochloride to replace l-Alanine isopropyl ester hydrochloride, making 2,3- The inventory of coumaran -5- benzyl ester hydrochloride is 0.23g；6- hydroxyl -2,3- two is replaced using 6- hydroxyl benzofuran Hydrogen benzofuran makes except the inventory 0.134g of 6- hydroxyl benzofuran, other to operate similarly to Example 1, is marked Inscribe compound.Wherein, K25-b 20mg, K25-a 8mg.

Its structural characterization is as follows:

ESI-MS:m/z 660.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.55 (s, 1H), 8.02 (d, J=2.4Hz, 1H), 7.64 (d, J= 8.4Hz, 1H), 7.57 (d, J=7.6Hz, 1H), 7.52 (s, 1H), 7.18 (t, J=8.8Hz, 2H), 7.00 (s, 1H), 6.80 (d, J=7.6Hz, 1H), 6.75 (s, 1H), 6.23 (t, J=12.8Hz, 1H), 6.03-6.09 (m, 1H), 5.92-5.93 (m, 1H), 5.56 (d, J=7.6Hz, 1H), 5.02 (d, J=6.0Hz, 2H), 4.54 (t, J=9.2Hz, 2H), 4.40-4.44 (m, 1H),4.27-4.31(m,1H),3.96-4.06(m,2H),3.79-3.92(m,1H),3.15-3.19(m,2H),1.25-1.30 (m,6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.96

Its structural characterization is as follows:

ESI-MS:m/z 660.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz)δ4.86

Embodiment 26

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (3- methylbenzoxazole -2- oxo -5- oxygroup) phosphinylidyne Base) amino) propionic ester (K26-b) and (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- Dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (3- methylbenzoxazole -2- Oxo -5- oxygroup) phosphoryl) amino) and propionic ester (K26-a) preparation

In addition to using 5- hydroxy-3-methyl benzoxazoles -2- ketone to replace 6- hydroxyl -2,3- Dihydrobenzofuranes, making 5- hydroxyl The inventory of base -3- methylbenzoxazole -2- ketone is 0.165g, other to operate similarly to Example 1, obtains title compound. Wherein, K26-b 18mg, K26-a 4mg.

Its structural characterization is as follows:

ESI-MS:m/z 601.1(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.54 (s, 1H), 7.57 (d, J=12Hz, 1H), 7.32 (d, J=8Hz, 1H), 7.18 (s, 1H), 7.01-6.98 (m, 1H), 6.11-5.88 (m, 3H), 5.57 (d, J=8Hz, 1H), 4.86-4.84 (s, 1H),4.37(s,1H),4.22(s,1H),4.00(s,1H),3.82(s,2H),3.31(s,3H),1.28-1.22(m,6H), 1.15-1.10(m,6H).

³¹P NMR(DMSO-d₆,162MHz):δ5.00

Its structural characterization is as follows:

ESI-MS:m/z 601.1(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz):δ4.90

Embodiment 27

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (the fluoro- 2,3- Dihydrobenzofuranes -4- oxygroup of 7-) phosphoryl) ammonia Base) propionic ester (K27) and its isomers preparation

In addition to using the fluoro- 2,3- Dihydrobenzofuranes of 4- hydroxyl -7- to replace 6- hydroxyl -2,3- Dihydrobenzofuranes, making 4- The inventory of fluoro- 2, the 3- Dihydrobenzofuranes of hydroxyl -7- is 0.152g, other to operate similarly to Example 1, obtains title compound Object K27 (3118mg), total recovery 20%；Title compound is separated using preparation HPLC, obtains title compound K27-b And K27-a, wherein K27-b is 25mg, K27-a 6mg.

Its structural characterization is as follows:

ESI-MS:m/z 590.1(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.52 (s, 1H), 7.54 (s, 1H), 7.03 (t, J=8Hz, 1H), 6.71 (d, J=8Hz, 1H), 6.10-5.85 (m, 3H), 5.57 (d, J=8Hz, 1H), 4.82 (t, J=8Hz, 1H), 4.65 (t, J= 8Hz, 2H), 4.31 (s, 1H), 4.23 (s, 1H), 3.95 (s, 1H), 3.78-3.76 (d, J=8Hz, 2H), 3.32-3.24 (m, 2H),1.24-1.20(m,6H),1.14-1.10(m,6H)

³¹P NMR(DMSO-d₆,162MHz):δ5.10

(S)-isopropyl -2- ((S)-(((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (the fluoro- 2,3- Dihydrobenzofuranes -4- oxygroup of 7-) phosphinylidyne Base) amino) propionic ester (K27-b)

Its structural characterization is as follows:

ESI-MS:m/z 590.1(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.57 (s, 1H), 7.60 (s, 1H), 7.08 (t, J=8Hz, 1H), 6.76 (d, J=8Hz, 1H), 6.15-5.90 (m, 3H), 5.62 (d, J=8Hz, 1H), 4.88 (t, J=4Hz, 1H), 4.70 (t, J= 8Hz, 2H), 4.36 (s, 1H), 4.28 (s, 1H), 4.00 (s, 1H), 3.82 (d, J=8Hz, 2H), 3.37-3.29 (m, 2H), 1.31-1.25(m,6H),1.19-1.16(m,6H)

³¹P NMR(DMSO-d₆,162MHz):δ5.19

(S)-isopropyl -2- ((R)-(((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (the fluoro- 2,3- Dihydrobenzofuranes -4- oxygroup of 7-) phosphinylidyne Base) amino) propionic ester (K27-a)

Its structural characterization is as follows:

ESI-MS:m/z 590.1(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.53 (s, 1H), 7.56 (d, J=8Hz, 1H), 7.02 (t, J=8Hz, 1H), 6.72 (d, J=8Hz, 1H), 6.14-5.90 (m, 3H), 5.59 (d, J=8Hz, 1H), 4.85 (t, J=8Hz, 1H), 4.65 (t, J=8Hz, 2H), 4.31 (s, 1H), 4.22 (s, 1H), 4.02 (s, 1H), 3.78 (d, J=8Hz, 2H), 3.32- 3.23(m,2H),1.27-1.19(m,6H),1.18-1.13(m,6H)

³¹P NMR(DMSO-d₆,162MHz):δ5.00

Embodiment 28

(S)-isopropyl -2- ((S)-(((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzoxazoles -5- oxygroup) phosphoryl) amino) propionic acid Ester (K28-b) and (S)-isopropyl -2- ((R)-(((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzoxazoles -5- oxygroup) phosphoryl) amino) The preparation of propionic ester (K28-a)

In addition to using 5- hydroxy benzo oxazole to replace 6- hydroxyl -2,3- Dihydrobenzofuranes, making 5- hydroxy benzo oxazole Inventory is 0.135g, other to operate similarly to Example 1, obtains title compound.Wherein K28-b is 35mg, and K28-a is 2mg。

Its structural characterization is as follows:

ESI-MS:m/z 571.1(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.47 (s, 1H), 8.77 (s, 1H), 7.78 (d, J=12Hz, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 7.30 (d, J=12Hz, 1H), 6.11-5.89 (m, 3H), 5.54 (d, J=8Hz, 1H), 4.82 (d, J=8Hz, 1H), 4.38 (s, 1H), 4.27 (s, 1H), 4.00 (s, 1H), 3.84 (s, 2H), 1.27-1.22 (m, 6H), 1.13-1.10(m,6H)

³¹P NMR(DMSO-d₆,162MHz):δ5.19

Its structural characterization is as follows:

ESI-MS:m/z 571.1(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz):δ5.00

Embodiment 29

(S) ((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- is fluoro- for-isopropyl 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (2,3- dihydrobenzo [1,4] dioxane -6- base) phenoxy group) Phosphoryl) amino) propionic ester (K29) and its isomers preparation.

In addition to using 4- (2,3- dihydrobenzo [1,4] dioxane -6- base) phenol to replace 6- hydroxyl -2,3- dihydrobenzo Furans, the inventory for making 4- (2,3- dihydrobenzos [Isosorbide-5-Nitrae] dioxane -6- base) phenol are 0.228g, other same with embodiment 1 Sample operation, obtains title compound K29 (100mg), total recovery 15%；Title compound is separated using preparation HPLC, Title compound K29-b and K29-a are obtained, wherein K29-b is 45mg, K29-a 10mg.

Its structural characterization is as follows:

ESI-MS:m/z 664.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.56 (s, 1H), 7.63 (d, J=8Hz, 3H), 7.30 (d, J=8Hz, 2H), 7.16 (d, J=12Hz, 2H), 6.97 (d, J=8Hz, 1H), 6.17-5.94 (m, 3H), 5.61 (d, J=8Hz, 1H), 4.90 (t, J=8Hz, 1H), 4.42 (s, 1H), 4.31 (s, 5H), 4.06 (s, 1H), 3.87 (d, J=8Hz, 2H), 1.32- 1.28(m,6H),1.22-1.18(m,6H)

³¹P NMR(DMSO-d₆,162MHz):δ4.92

(S)-isopropyl -2- ((S)-(((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (2,3- dihydrobenzo [1,4] dioxane -6- Base) phenoxy group) phosphoryl) amino) propionic ester (K29-b)

Its structural characterization is as follows:

ESI-MS:m/z 664.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.51 (s, 1H), 7.58 (d, J=8Hz, 3H), 7.25 (d, J=8Hz, 2H), 7.11 (d, J=12Hz, 2H), 6.92 (d, J=8Hz, 1H), 6.12-5.89 (m, 3H), 5.56 (d, J=8Hz, 1H), 4.85 (t, J=8Hz, 1H), 4.37 (s, 1H), 4.26 (s, 5H), 4.01 (s, 1H), 3.82 (d, J=8Hz, 2H), 1.28- 1.23(m,6H),1.17-1.13(m,6H)

³¹P NMR(DMSO-d₆,162MHz):δ4.84

(S)-isopropyl -2- ((R)-(((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (2,3- dihydrobenzo [1,4] dioxane -6- Base) phenoxy group) phosphoryl) amino) propionic ester (K29-a)

Its structural characterization is as follows:

ESI-MS:m/z 664.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz):δ4.74

Embodiment 30

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (4- fluorophenoxy) phenoxy group) phosphoryl) amino) propionic ester ) and its preparation of isomers K30

Tribromo oxygen phosphorus (2.86g, 10mmol) is dissolved in methylene chloride (10mL), -60 DEG C is cooled to, 4- (4- is slowly added dropwise Fluorophenoxy) phenol (2.04g, 10mmol) and NMM (1.01g, 10mmol) dichloromethane solution (10mL).It is added dropwise, Cryostat is removed, 25 DEG C is risen to and stirs 2 hours.Reaction system is further cooled to -60 DEG C, l-Alanine isopropyl ester hydrochloride is added The dichloromethane solution (10mL) of NMM (2.53g, 25mmol) is then added dropwise in salt (1.51g, 9mmol).It is added dropwise, removes cold Bath rises to 25 DEG C and stirs 2 hours.Reaction system is further cooled to -40 DEG C, be added dropwise Pentafluorophenol (1.84g, 10mmol) and The dichloromethane solution (10mL) of NMM (1.52g, 15mmol).It is added dropwise, removes cryostat, rise to 25 DEG C and stir 2 hours.Instead Should reaction system be poured into ice water, be extracted with dichloromethane completely.Merging organic phase is collected to be washed with saturated common salt aqueous solution It washs, dries, filters concentration, obtain intermediate (S)-isopropyl -2- ((phenyl-pentafluoride oxygroup) (4- (4- fluorophenoxy) phenoxy group) phosphorus Acyl group) amino) propionic ester crude product.

By 1- (the fluoro- 4- hydroxyl -5- methylol -3- methyltetrahydrofuran -2- base of (2R, 3R, 4R, 5R) -3-) pyrimidine -2,4- (1H, 3H)-diketone (260mg, 1mmol) is dissolved in anhydrous tetrahydro furan (20mL), and argon gas is replaced three times.Tertiary fourth is added dropwise in 5 DEG C Base magnesium chloride (1.0mol/L, 2.5mL, 2.5mmol) rises to 25 DEG C and reacts 2 hours.It is cooled to 0 DEG C, above-mentioned intermediate is added dropwise (S)-isopropyl -2- ((phenyl-pentafluoride oxygroup) (4- (4- fluorophenoxy) phenoxy group) phosphoryl) amino) propionic ester (563mg, Anhydrous tetrahydro furan (10mL) solution 1mmol).It is added dropwise, rises to 25 DEG C and react 15 hours.Few drops of 2M hydrochloric acid is added dropwise to anti- System is answered to become clarification.Water 30mL is added to dilute, 2M hydrochloric acid is adjusted to neutrality.Reaction system is extracted with ethyl acetate, and it is organic to collect merging Saturated sodium bicarbonate aqueous solution is mutually used respectively, and saturated common salt water washing dries, filters concentration, and residue must be marked through column chromatographic purifying It inscribes compound (K30) (281mg, yield 44%).

Its structural characterization is as follows:

ESI-MS:m/z 640.1(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.54 (s, 1H), 7.56 (d, J=8Hz, 1H), 7.21 (t, J=8Hz, 4H), 7.04-6.98 (m, 4H), 6.09-5.87 (m, 3H), 5.54 (d, J=8Hz, 1H), 4.85 (t, J=4Hz, 1H), 4.35 (s, 1H), 4.24 (s, 1H), 3.99 (s, 1H), 3.80 (d, J=8Hz, 2H), 1.27-1.22 (m, 6H), 1.15-1.13 (m, 6H)

³¹P NMR(DMSO-d₆,162MHz):δ4.91

Gained (K30) is separated with preparation HPLC, separation condition is as follows, using octadecyl silane as filler (20 × 250mm, 5 μm), 30 DEG C of column temperature, flow velocity 10.0mL/min, Detection wavelength 220nm, mobile phase A is water (neutrality), Mobile phase B For ethyl alcohol, linear gradient elution is carried out.Collect first main peak, freeze-drying obtain (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- of -4- Base) methoxyl group) (4- (4- fluorophenoxy) phenoxy group) phosphoryl) amino) propionic ester (K30-a) 20mg；Second main peak is collected, Freeze-drying obtains (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (4- fluorophenoxy) phenoxy group) phosphoryl) Amino) propionic ester (K30-b) 100mg.

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (4- fluorophenoxy) phenoxy group) phosphoryl) amino) Propionic ester (K30-b)

Its structural characterization is as follows:

ESI-MS:m/z 640.1(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.52 (s, 1H), 7.54 (d, J=8Hz, 1H), 7.22 (t, J=8Hz, 4H), 7.05-6.99 (m, 4H), 6.09-5.87 (m, 3H), 5.55 (d, J=8Hz, 1H), 4.85 (t, J=8Hz, 1H), 4.36 (s, 1H), 4.24 (s, 1H), 3.99 (s, 1H), 3.80 (d, J=4Hz, 2H), 1.28-1.23 (m, 6H), 1.16-1.14 (m, 6H)

³¹P NMR(DMSO-d₆,162MHz):δ4.99

(S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (4- fluorophenoxy) phenoxy group) phosphoryl) amino) Propionic ester (K30-a)

Its structural characterization is as follows:

ESI-MS:m/z 640.1(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz):δ4.79

Embodiment 31

(S) -4- fluorine benzyloxy (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (2,3- dihydrobenzo [1,4] dioxane -5- oxygroup) phosphinylidyne Base) amino) propionic ester (K31) and its isomers preparation

Tribromo oxygen phosphorus (2.87g, 10mmol) is dissolved in methylene chloride (20mL), -60 DEG C is cooled to, 5- hydroxyl is slowly added dropwise The methylene chloride of base -2,3- dihydrobenzo [Isosorbide-5-Nitrae] dioxane (1.52g, 10mmol) and triethylamine (0.81g, 0.8mmol) is molten Liquid (10mL).It is added dropwise, removes cryostat, rise to 25 DEG C and stir 2 hours.Reaction system is further cooled to -60 DEG C, is added The methylene chloride of triethylamine (1.42g, 14mmol) is then added dropwise in l-Alanine -4- fluoro-methylbenzyl ester hydrochloride (2.72g, 15mmol) Solution (15mL).It is added dropwise, removes cryostat, rise to 25 DEG C and stir 2 hours.Reaction system is further cooled to -60 DEG C, drop Add the dichloromethane solution (10mL) of Pentafluorophenol (1.66g, 9mmol) and triethylamine (1.82g, 18mmol).It is added dropwise, removes Cryostat is gone, 25 DEG C is risen to and stirs 2 hours.Fully reacting pours into reaction system in ice water, is extracted with dichloromethane.It collects and closes And organic phase is washed with saturated common salt aqueous solution, dries, filters concentration, obtains intermediate (S) -4- luorobenzyl -2- ((phenyl-pentafluoride Oxygroup) (2,3- dihydrobenzo [1,4] dioxane -5- oxygroup) phosphoryl) amino) and propionic ester crude product.

By 1- (the fluoro- 4- hydroxyl -5- methylol -3- methyltetrahydrofuran -2- base of (2R, 3R, 4R, 5R) -3-) pyrimidine -2,4- (1H, 3H)-diketone (260mg, 1mmol) is dissolved in anhydrous tetrahydro furan (30mL), and argon gas is replaced three times.Tertiary fourth is added dropwise in 0 DEG C Base magnesium chloride (1.0mol/L, 3.5mL, 3.5mmol) rises to 25 DEG C and reacts 1 hour.It is cooled to 0 DEG C, above-mentioned intermediate is added dropwise (S) -4- luorobenzyl -2- ((phenyl-pentafluoride oxygroup) (2,3- dihydrobenzo [1,4] dioxane -5- oxygroup) phosphoryl) amino) third Anhydrous tetrahydro furan (20mL) solution of acid esters (577mg, 1mmol).It is added dropwise, rises to 25 DEG C and react 15 hours.2M is added dropwise Few drops of hydrochloric acid becomes to reaction system to be clarified.Water 30mL is added to dilute, 2M hydrochloric acid is adjusted to neutrality.Reaction system is extracted with ethyl acetate, It collects merging organic phase and uses saturated sodium bicarbonate aqueous solution respectively, saturated common salt water washing dries, filters concentration, and residue is through column Chromatographic purifying obtains title compound (K31) (294mg, yield 45%).

Its structural characterization is as follows:

ESI-MS:m/z 654.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.53 (s, 1H), 7.58 (t, J=8Hz, 1H), 7.41-7.36 (m, 2H), 7.19-7.14 (m, 2H), 6.85 (t, J=8Hz, 1H), 6.74-6.66 (m, 2H), 6.09-5.87 (m, 3H), 5.60-5.54 (m, 1H), 5.06 (t, J=4Hz, 2H), 4.39 (s, 1H), 4.21 (d, J=4Hz, 5H), 4.01 (s, 1H), 3.91-3.78 (m, 2H),1.26-1.21(m,6H),

³¹P NMR(DMSO-d₆,162MHz):δ4.92.

Gained (K31) is separated with preparation HPLC, separation condition is as follows, using octadecyl silane as filler (20 × 250mm, 5 μm), 40 DEG C of column temperature, flow velocity 10.0mL/min, Detection wavelength 220nm, mobile phase A is water (neutrality), Mobile phase B For methanol, linear gradient elution is carried out.First main peak is collected, freeze-drying obtains (S) -4- fluorine benzyloxy -2- ((R) - ((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydro of -4- Furans -2- base) methoxyl group) (2,3- dihydrobenzo [1,4] dioxane -5- oxygroup) phosphoryl) amino) propionic ester (K31-a) 26mg；Collect second main peak, freeze-drying obtain (S) -4- fluorine benzyloxy -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2, - 1 (2H)-yl of 4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- Dihydrobenzo [1,4] dioxane -5- oxygroup) phosphoryl) amino) propionic ester (K31-b) 130mg.

(S) -4- fluorine benzyloxy -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- dihydrobenzo [1,4] dioxane -5- Oxygroup) phosphoryl) amino) propionic ester (K31-b)

Its structural characterization is as follows:

ESI-MS:m/z 654.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.55 (s, 1H), 7.60 (t, J=8Hz, 1H), 7.43-7.36 (m, 2H), 7.19-7.14 (m, 2H), 6.89 (t, J=8Hz, 1H), 6.77-6.71 (m, 2H), 6.14-5.94 (m, 3H), 5.60-5.54 (m, 1H), 5.06 (t, J=4Hz, 2H), 4.40 (s, 1H), 4.26 (d, J=4Hz, 5H), 4.03 (s, 1H), 3.98-3.88 (m, 2H),1.30-1.25(m,6H)

³¹P NMR(DMSO-d₆,162MHz):δ4.93

(S) -4- fluorine benzyloxy -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- dihydrobenzo [1,4] dioxane -5- Oxygroup) phosphoryl) amino) propionic ester (K31-a)

Its structural characterization is as follows:

ESI-MS:m/z 654.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.55 (s, 1H), 7.60 (t, J=8Hz, 1H), 7.43-7.36 (m, 2H), 7.19-7.14 (m, 2H), 6.89 (t, J=8Hz, 1H), 6.77-6.71 (m, 2H), 6.14-5.94 (m, 3H), 5.60-5.54 (m, 1H), 5.06 (t, J=4Hz, 2H), 4.40 (s, 1H), 4.26 (d, J=4Hz, 5H), 4.03 (s, 1H), 3.98-3.88 (m, 2H),1.30-1.25(m,6H),

³¹P NMR(DMSO-d₆,162MHz):δ4.78。

Embodiment 32

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (4- chlorophenoxy) phenoxy group) phosphoryl) amino) propionic ester (K32) and its preparation of isomers

Tribromo oxygen phosphorus (2.86g, 10mmol) is dissolved in methylene chloride (10mL), -60 DEG C is cooled to, 4- (4- is slowly added dropwise Chlorophenoxy) phenol (2.2g, 10mmol) and triethylamine (2.02g, 20mmol) dichloromethane solution (15mL).It drips Finish, remove cryostat, rises to 25 DEG C and stir 2 hours.Reaction system is further cooled to -20 DEG C, l-Alanine isopropyl ester is added The dichloromethane solution (10mL) of triethylamine (2.53g, 25mmol) is then added dropwise in hydrochloride (1.67g, 10mmol).It drips Finish, remove cryostat, rises to 25 DEG C and stir 2 hours.Reaction system is further cooled to -60 DEG C, be added dropwise Pentafluorophenol (1.66g, 9mmol) and the dichloromethane solution (10mL) of triethylamine (1.52g, 15mmol).It is added dropwise, removes cryostat, rise to 25 DEG C and stir It mixes 2 hours.Fully reacting pours into reaction system in ice water, is extracted with dichloromethane.It collects and merges organic phase saturated common salt Aqueous solution washing, dries, filters concentration, obtains intermediate (S)-isopropyl -2- ((phenyl-pentafluoride oxygroup) (4- (4- chlorophenoxy) Phenoxy group) phosphoryl) amino) and propionic ester crude product.

By 1- (the fluoro- 4- hydroxyl -5- methylol -3- methyltetrahydrofuran -2- base of (2R, 3R, 4R, 5R) -3-) pyrimidine -2,4- (1H, 3H)-diketone (260mg, 1mmol) is dissolved in anhydrous tetrahydro furan (25mL), and argon gas is replaced three times.In 0 DEG C of dropwise addition methyl Magnesium chloride (1.0mol/L, 2.5mL, 2.5mmol) rises to 25 DEG C and reacts 1 hour.It is cooled to 0 DEG C, above-mentioned intermediate (S)-is added dropwise Isopropyl -2- ((phenyl-pentafluoride oxygroup) (4- (4- chlorophenoxy) phenoxy group) phosphoryl) amino) propionic ester (580mg, 1mmol) Anhydrous tetrahydro furan (10mL) solution.It is added dropwise, rises to 30 DEG C and react 15 hours.Few drops of 2M hydrochloric acid to reaction system is added dropwise to become Clarification.Water 30mL is added to dilute, 2M hydrochloric acid is adjusted to neutrality.Reaction system is extracted with ethyl acetate, and collects merging organic phase and uses respectively Saturated sodium bicarbonate aqueous solution, saturated common salt water washing dry, filter concentration, and residue obtains title compound through column chromatographic purifying (K32) (249mg, yield 38%).

Its structural characterization is as follows:

ESI-MS:m/z 656.1(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.49 (s, 1H), 7.53 (d, J=8Hz, 1H), 7.39 (d, J=8Hz, 2H), 7.22 (d, J=8Hz, 2H), 7.03-6.93 (m, 4H), 6.02-5.81 (m, 3H), 5.52 (d, J=8Hz, 1H), 4.83 (t, J=4Hz, 1H), 4.34 (s, 1H), 4.22 (s, 1H), 3.97 (s, 1H), 3.79 (d, J=8Hz, 2H), 1.25-1.20 (m, 6H),1.13-1.09(m,6H).

³¹P NMR(DMSO-d₆,162MHz):δ4.90.

Gained (K32) is separated with preparation HPLC, separation condition is as follows, using octadecyl silane as filler (20 × 250mm, 5 μm), 40 DEG C of column temperature, flow velocity 8.0mL/min, Detection wavelength 220nm, mobile phase A is water (neutrality), and Mobile phase B is Ethyl alcohol carries out linear gradient elution.Collect first main peak, freeze-drying obtain (S)-isopropyl ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxy Base) (4- (4- chlorophenoxy) phenoxy group) phosphoryl) amino) propionic ester (K32-a) 25mg；Second main peak is collected, freezing is dry It is dry to obtain (S)-isopropyl ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (4- chlorophenoxy) phenoxy group) phosphoryl) amino) propionic ester (K32-b)95mg。

(S)-isopropyl ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- (4- chlorophenoxy) phenoxy group) phosphoryl) amino) propionic acid Ester (K32-b)

Its structural characterization is as follows:

ESI-MS:m/z 656.1(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.51 (s, 1H), 7.56 (d, J=8Hz, 1H), 7.42 (d, J=8Hz, 2H), 7.25 (d, J=8Hz, 2H), 7.06-6.97 (m, 4H), 6.10-5.87 (m, 3H), 5.55 (d, J=8Hz, 1H), 4.85 (m,1H),4.39-4.35(m,1H),4.25-4.22(m,1H),4.02-3.98(m,1H),3.87-3.78(m,2H),1.28- 1.22(m,6H),1.16-1.14(m,6H).

³¹P NMR(DMSO-d₆,162MHz):δ4.99.

(S)-isopropyl ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- (4- chlorophenoxy) phenoxy group) phosphoryl) amino) propionic acid Ester (K32-a)

Its structural characterization is as follows:

ESI-MS:m/z 656.1(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.51 (s, 1H), 7.56 (d, J=8Hz, 1H), 7.42 (d, J=8Hz, 2H), 7.25 (d, J=8Hz, 2H), 7.06-6.97 (m, 4H), 6.10-5.87 (m, 3H), 5.55 (d, J=8Hz, 1H), 4.85 (m,1H),4.39-4.35(m,1H),4.25-4.22(m,1H),4.02-3.98(m,1H),3.87-3.78(m,2H),1.28- 1.22(m,6H),1.16-1.14(m,6H)

³¹P NMR(DMSO-d₆,162MHz):δ4.89

Embodiment 33

(S)-isopropyl-(((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- ((2,3- dihydrobenzo [1,4] dioxane -6- base) oxygen Base) phenoxy group) phosphoryl) amino) propionic ester (K33) and its isomers preparation

In addition to using 4- ((2,3- dihydrobenzo [1,4] dioxane -6- base) oxygroup) phenol to replace 6- hydroxyl -2,3- two Hydrogen benzofuran, the inventory for making 4- ((2,3- dihydrobenzos [Isosorbide-5-Nitrae] dioxane -6- base) oxygroup) phenol are 0.24g, other It operates similarly to Example 1, obtains title compound K33 (88mg), total recovery 13%；Using preparation HPLC to title compound It is separated, obtains K33-b (30mg) and K33-a (7mg).

Its structural characterization is as follows:

ESI-MS:m/z 680.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.56 (s, 1H), 7.58 (d, J=8Hz, 1H), 7.22 (t, J=8Hz, 2H), 6.98 (d, J=8Hz, 2H), 6.89 (d, J=8Hz, 1H), 6.55-6.50 (m, 2H), 6.09-5.89 (m, 3H), 5.58 (d, J=8Hz, 1H), 4.88 (t, J=8Hz, 1H), 4.38 (s, 1H), 4.25 (s, 5H), 4.03 (s, 1H), 3.82 (t, J= 8Hz,2H),1.31-1.25(m,6H),1.23-1.17(m,6H)

³¹P NMR(DMSO-d₆,162MHz):δ4.91

(S)-isopropyl-((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- ((2,3- dihydrobenzo [1,4] dioxane -6- Base) oxygroup) phenoxy group) phosphoryl) amino) propionic ester (K33-b)

Its structural characterization is as follows:

ESI-MS:m/z 680.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.53 (s, 1H), 7.54 (d, J=8Hz, 1H), 7.21 (t, J=8Hz, 2H), 6.94 (d, J=8Hz, 2H), 6.85 (d, J=8Hz, 1H), 6.52-6.47 (m, 2H), 6.07-5.87 (m, 3H), 5.54 (d, J=8Hz, 1H), 4.84 (t, J=8Hz, 1H), 4.35 (s, 1H), 4.23 (s, 5H), 4.00 (s, 1H), 3.80 (t, J= 8Hz,2H),1.28-1.22(m,6H),1.16-1.13(m,6H)

³¹P NMR(DMSO-d₆,162MHz):δ4.99

(S)-isopropyl-((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- ((2,3- dihydrobenzo [1,4] dioxane -6- Base) oxygroup) phenoxy group) phosphoryl) amino) propionic ester (K33-a)

Its structural characterization is as follows:

ESI-MS:m/z 680.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz):δ4.89

Embodiment 34

2- (S)-(S)-isobutyl group (((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- dihydrobenzo [1,4] dioxane -5- oxygroup) Phosphoryl) amino) propionic ester (K34) preparation

In addition to using l-Alanine-S- isobutyl ester hydrochloride to replace l-Alanine isopropyl ester hydrochloride, making l-Alanine-S- The inventory of isobutyl ester hydrochloride is 0.165g；6- hydroxyl-is replaced using 5- hydroxyl -2,3- dihydrobenzo [1,4] dioxane 2,3- Dihydrobenzofuranes, make 5- hydroxyl -2,3- dihydrobenzo [Isosorbide-5-Nitrae] dioxane inventory be 0.152g except, it is other It operates similarly to Example 1, obtains title compound 60mg, total recovery 10%.

Its structural characterization is as follows:

ESI-MS:m/z 602.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.55 (s, 1H), 7.60 (d, J=8Hz, 1H), 6.75 (t, J=8Hz, 1H), 6.69 (d, J=8Hz, 1H), 6.42 (d, J=8Hz, 1H), 6.09-5.89 (m, 3H), 5.60 (t, J=8Hz, 1H), 4.71 (t, J=8Hz, 1H), 4.38 (s, 1H), 4.25 (d, J=8Hz, 5H), 4.00 (s, 1H), 3.83 (t, J=8Hz, 2H), (1.51 t, J=8Hz, 2H), 1.28-1.25 (m, 6H), 1.12 (t, J=4Hz, 3H), 0.82 (t, J=4Hz, 3H)

³¹P NMR(DMSO-d₆,162MHz):δ4.93.

Embodiment 35

(S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (7- Fluorobenzofur -4- oxygroup) phosphoryl) amino) propionic ester (K35) preparation

In addition to using 4- hydroxyl -7- Fluorobenzofur to replace 6- hydroxyl -2,3- Dihydrobenzofuranes, making 4- hydroxyl -7- fluorine The inventory of benzofuran is 0.152g, other to operate similarly to Example 1, obtains title compound 117mg, total recovery 20%.

Its structural characterization is as follows:

ESI-MS:m/z 588.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.53 (s, 1H), 8.12 (s, 1H), 7.55 (s, 1H), 7.24 (t, J= 8Hz, 1H), 7.13 (t, J=4Hz, 2H), 6.21-5.90 (m, 3H), 5.51 (t, J=8Hz, 1H), 4.83 (t, J=8Hz, 1H), 4.38 (s, 1H), 4.30 (s, 1H), 4.00 (s, 1H), 3.83 (t, J=8Hz, 2H), 1.28-1.18 (m, 6H), 1.14- 1.11(m,6H).

³¹P NMR(DMSO-d₆,162MHz):δ5.12

Embodiment 36

(S)-(2,3- dihydrobenzo [1,4] dioxane -6- base) methoxyl group -2- ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzene And furans -6- oxygroup) phosphoryl) amino) propionic ester (K36-b) and (S)-(2,3- dihydrobenzo [1,4] dioxane -6- base) Methoxyl group -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxyl of -4- Base -4- methyltetrahydrofuran -2- base) methoxyl group) (benzofuran -6- oxygroup) phosphoryl) amino) propionic ester (K36-a) system It is standby

In addition to using l-Alanine (2,3- dihydrobenzo [1,4] dioxane -6- base) methyl ester hydrochloride to replace the third ammonia of L- Isopropyl propionate hydrochloride, the inventory for making l-Alanine (2,3- dihydrobenzo [1,4] dioxane -6- base) methyl ester hydrochloride 0.27g；The inventory for replacing 6- hydroxyl -2,3- Dihydrobenzofuranes using 6- hydroxyl benzofuran, making 6- hydroxyl benzofuran It is other to operate similarly to Example 1 except 0.134g, obtain title compound.Wherein K36-b is 50mg, and K36-a is 10mg。

Its structural characterization is as follows:

ESI-MS:m/z 676.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.52 (s, 1H), 7.99 (s, 1H), 7.60 (d, J=8Hz, 1H), 7.54 (s, 1H), 7.48 (s, 1H), 7.12 (d, J=8Hz, 1H), 6.95 (s, 1H), 6.83 (s, 1H), 6.79 (d, J=8Hz, 2H), 6.17-5.89 (m, 3H), 5.52 (d, J=8Hz, 1H), 4.91 (d, J=4Hz, 2H), 4.36 (s, 1H), 4.25 (s, 1H), 4.20(s,5H),4.00(s,1H),4.82(s,1H),1.28-1.21(m,6H).

³¹P NMR(DMSO-d₆,162MHz):δ4.99

Its structural characterization is as follows:

ESI-MS:m/z 676.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.52 (s, 1H), 7.99 (s, 1H), 7.60 (d, J=J=8Hz, 1H), 7.54 (s, 1H), 7.48 (s, 1H), 7.12 (d, J=J=8Hz, 1H), 6.95 (s, 1H), 6.83 (s, 1H), 6.79 (d, J=J =8Hz, 2H), 6.17-5.89 (m, 3H), 5.52 (d, J=8Hz, 1H), 4.91 (d, J=4Hz, 2H), 4.36 (s, 1H), 4.25 (s,1H),4.20(s,5H),4.00(s,1H),4.82(s,1H),1.28-1.21(m,6H).

³¹P NMR(DMSO-d₆,162MHz):δ4.85

Embodiment 37

(S)-isopropyl-(((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (benzoxazoles -6- oxygroup) phosphoryl) amino) propionic ester (K37) Preparation

In addition to using 6- hydroxy benzo oxazole to replace 6- hydroxyl -2,3- Dihydrobenzofuranes, making 6- hydroxy benzo oxazole Inventory is 0.135g, other to operate similarly to Example 1, obtains title compound 85mg, total recovery 15%.

Its structural characterization is as follows:

ESI-MS:m/z 571.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.53 (s, 1H), 8.75 (s, 1H), 7.79 (d, J=8Hz, 1H), 7.68 (s, 1H), 7.57 (s, 1H), 7.28 (d, J=8Hz, 1H), 6.16 (t, J=8Hz, 1H), 6.02 (d, J=16Hz, 1H), 5.88 (s, 1H), 5.55 (d, J=8Hz, 1H), 4.85-4.75 (m, 1H), 4.39-4.28 (m, 2H), 4.01-3.84 (m, 3H), 1.28-1.12(m,12H)

³¹P NMR(DMSO-d₆,162MHz)δ4.96

Embodiment 38

(S)-isopropyl-(((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (benzoxazoles -4- oxygroup) phosphoryl) amino) propionic ester (K38) Preparation

In addition to using 4- hydroxy benzo oxazole to replace 6- hydroxyl -2,3- Dihydrobenzofuranes, making 4- hydroxy benzo oxazole Inventory is 0.135g, other to operate similarly to Example 1, obtains title compound 68mg, total recovery 12%.

Its structural characterization is as follows:

ESI-MS:m/z 571.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.53 (s, 1H), 8.79 (s, 1H), 7.62 (d, J=8Hz, 1H), 7.59- 7.57 (m, 1H), 7.43 (t, J=8Hz, 1H), 7.36 (d, J=8Hz, 1H), 6.18 (t, J=8Hz, 1H), 6.02 (d, J= 16Hz, 1H), 5.86 (s, 1H), 5.54 (d, J=8Hz, 1H), 4.86-4.83 (m, 1H), 4.45-4.31 (m, 2H), 4.02- 3.90(m,3H),1.28-1.07(m,12H)

³¹P NMR(DMSO-d₆,162MHz)δ4.72

Embodiment 39

(S)-isopropyl-(((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- methyl -3,4- dihydrobenzo [1,4] morpholine -5- oxygroup) phosphorus Acyl group) amino) propionic ester (K39) preparation

In addition to using 5- hydroxy-4-methyl -3,4- dihydrobenzo [1,4] morpholino for 6- hydroxyl -2,3- dihydrobenzo furan Mutter, make 5- hydroxy-4-methyl -3,4- dihydrobenzo [Isosorbide-5-Nitrae] morpholine inventory be 0.151g, it is other to grasp similarly to Example 1 Make, obtains title compound 72mg, total recovery 12%.

Its structural characterization is as follows:

ESI-MS:m/z 601.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.51 (s, 1H), 7.57 (d, J=8Hz, 1H), 6.92-6.87 (m, 1H), 6.82-6.78 (m, 1H), 6.64-6.61 (m, 1H), 5.99-5.96 (m, 2H), 5.54 (d, J=8Hz, 1H), 4.89-4.81 (m,1H),4.43-4.40(m,1H),4.29-4.22(m,1H),4.09-4.05(m,4H),3.85-3.83(m,2H),3.05 (s, 2H), 2.76 (s, 3H), 1.28-1.12 (m, 12H)

³¹P NMR(DMSO-d₆,162MHz)δ4.46

Embodiment 40

(S)-benzo [1,3] dioxolanes benzyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- Dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo tetrahydrofuran -6- oxygen Base) phosphoryl) amino) propionic ester (K40-b) and (S)-benzo [1,3] dioxolanes benzyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxy Base) (benzo tetrahydrofuran -6- oxygroup) phosphoryl) amino) and propionic ester (K40-a) preparation

In addition to use l-Alanine benzo [1,3] dioxolanes benzyl ester hydrochloride replace l-Alanine isopropyl ester hydrochloride, Make the inventory 0.23g of l-Alanine benzo [1,3] dioxolanes benzyl ester hydrochloride；6- is replaced using 6- hydroxyl benzofuran Hydroxyl -2,3- Dihydrobenzofuranes make except the inventory 0.134g of 6- hydroxyl benzofuran, it is other similarly to Example 1 Operation, obtains title compound.Wherein K44-b is 25mg, K44-a 5mg.

Its structural characterization is as follows:

ESI-MS:m/z 662.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.52 (s, 1H), 7.99 (s, 1H), 7.61 (d, J=8Hz, 1H), 7.53- 7.48 (m, 2H), 7.13 (d, J=8Hz, 1H), 6.95 (s, 1H), 6.89 (s, 1H), 6.86-6.80 (m, 2H), 6.19 (t, J= 8Hz, 1H), 6.00-5.90 (m, 4H), 5.52 (d, J=8Hz, 1H), 4.92-4.96 (m, 2H), 4.38-4.35 (m, 1H), 4.27-4.24(m,1H),4.00-3.93(m,3H),1.26-1.22(m,6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.99

Its structural characterization is as follows:

ESI-MS:m/z 662.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz)δ4.89

Embodiment 41

(S)-benzo [1,3] dioxolanes benzyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- Dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- Dihydrobenzofuranes - 6- oxygroup) phosphoryl) amino) propionic ester (K41-b) and (S)-benzo [1,3] dioxolanes benzyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) Methoxyl group) (2,3- Dihydrobenzofuranes -6- oxygroup) phosphoryl) amino) and propionic ester (K41-a) preparation

In addition to use l-Alanine benzo [1,3] dioxolanes benzyl ester hydrochloride replace l-Alanine isopropyl ester hydrochloride, The inventory for making l-Alanine benzo [1,3] dioxolanes benzyl ester hydrochloride is 2.3g, other to operate similarly to Example 1, is obtained To title compound.Wherein K41-b is 25mg, K41-a 6mg.

Its structural characterization is as follows:

ESI-MS:m/z 664.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.52 (s, 1H), 7.53 (s, 1H), 7.14 (d, J=8Hz, 1H), 6.90 (s, 1H), 6.88-6.82 (m, 2H), 6.65-6.63 (m, 2H), 6.13-6.00 (m, 4H), 5.86 (s, 1H), 5.52 (d, J= 8Hz, 1H), 5.01-4.94 (m, 2H), 4.54 (t, J=8Hz, 2H), 4.31-4.34 (m, 1H), 4.18-4.23 (m, 1H), 3.98-3.86 (m, 3H), 3.11 (t, J=8Hz, 2H), 1.27-1.21 (m, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.65

Its structural characterization is as follows:

ESI-MS:m/z 664.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz)δ4.53

Embodiment 42

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (3- methylbenzoxazole -2- oxo -6- oxygroup) phosphinylidyne Base) amino) propionic ester (K42) preparation

In addition to using 6- hydroxy-3-methyl -2- oxo benzoxazoles to replace 6- hydroxyl -2,3- Dihydrobenzofuranes, making 6- The inventory of hydroxy-3-methyl -2- oxo benzoxazoles is 0.165g, other to operate similarly to Example 1, obtains title compound Object 60mg, total recovery 10%.

Its structural characterization is as follows:

ESI-MS:m/z 601.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.52 (s, 1H), 7.53 (s, 1H), 7.28-7.27 (m, 1H), 7.24- 7.22 (m, 1H), 7.10-7.09 (m, 1H), 6.10-6.04 (m, 2H), 5.88-5.84 (m, 1H), 5.56-5.54 (m, 1H), 4.86-4.83 (m, 1H), 4.38-4.34 (m, 1H), 4.26-4.20 (m, 1H), 4.00-3.96 (m, 1H), 3.84-3.78 (m, 2H),3.32(s,3H),1.27-1.13(m,12H)

³¹P NMR(DMSO-d₆,162MHz)δ5.01

Embodiment 43

(S) -4- luorobenzyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzofuran -6- oxygroup) phosphoryl) amino) ((R)-((((2,4- dicarbapentaborane -3,4- dihydro is phonetic by (2R, 3R, 4R, 5R) -5- by propionic ester (K43-b) and (S) -4- luorobenzyl -2- Pyridine -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzofuran -6- oxygroup) phosphoryl) Amino) propionic ester (K43-a) preparation

In addition to using l-Alanine -4- fluoro-methylbenzyl ester hydrochloride to replace l-Alanine isopropyl ester hydrochloride, making l-Alanine -4- The inventory of fluoro-methylbenzyl ester hydrochloride is 0.23g；6- hydroxyl -2,3- Dihydrobenzofuranes are replaced using 6- hydroxyl benzofuran, are made The inventory of 6- hydroxyl benzofuran be 0.134g except, it is other to operate similarly to Example 1, obtain title compound.Wherein K43-b is 20mg, K43-a 7mg.

Its structural characterization is as follows:

ESI-MS:m/z 636.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.54 (s, 1H), 8.01 (d, J=2.0Hz, 1H), 7.63 (d, J= 8.8Hz, 1H), 7.57 (d, J=8.8Hz, 1H), 7.51 (s, 1H), 7.39 (dd, J=6.0Hz, 8.4Hz, 2H), 7.15-7.20 (m, 3H), 6.98 (s, 1H), 6.19-6.25 (m, 1H), 6.00-6.08 (m, 1H), 5.90 (d, J=5.2Hz, 1H), 5.55 (d, J=8.4Hz, 1H), 5.06 (dd, J=12.4Hz, 4.0Hz, 2H), 4.38-4.43 (m, 1H), 4.25-4.31 (m, 1H), 3.96-4.05(m,2H),3.79-3.91(m,1H),1.24-1.30(m,6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.91

Its structural characterization is as follows:

ESI-MS:m/z 636.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz)δ4.81

Embodiment 44

(S) -4- luorobenzyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (the fluoro- 1,2- dimethyl -1H- indoles-of 4- 6- yl)-phenoxy group) phosphoryl) amino) propionic ester (K44-b) and (S) -4- luorobenzyl -2- ((R)-((((2R, 3R, 4R, 5R) - 5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (the fluoro- 1,2- dimethyl -1H- indoles -6- base of 4-)-phenoxy group) phosphoryl) amino) propionic ester (K44-a) preparation

In addition to using l-Alanine -4- fluoro-methylbenzyl ester hydrochloride to replace l-Alanine isopropyl ester hydrochloride, making l-Alanine -4- The inventory of fluoro-methylbenzyl ester hydrochloride is 0.23g；6- hydroxyl is replaced using 4- (the fluoro- 1,2- dimethyl -1H- indoles -6- base of 4-) phenol Base -2,3- Dihydrobenzofuranes, make 4- (the fluoro- 1,2- dimethyl -1H- indoles -6- base of 4-) phenol inventory 0.255g it Outside, other to operate similarly to Example 1, obtain title compound.Wherein K44-b is 10mg, K44-a 2mg.

Its structural characterization is as follows:

ESI-MS:m/z 757.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.55 (s, 1H), 7.61 (d, J=8.0Hz, 1H), 7.54 (d, J= 8.0Hz, 2H), 7.43 (dd, J=8.0Hz, 5.6Hz, 2H), 7.30-7.35 (m, 3H), 7.13-7.21 (m, 3H), 6.35 (s, 1H), 6.24 (t, J=12.0Hz, 1H), 6.04-6.08 (m, 1H), 5.92 (d, J=6.0Hz, 1H), 5.60 (d, J=8.4Hz, 1H), 5.11 (t, J=15.6Hz, 2H), 4.40-4.45 (m, 1H), 4.28-4.32 (m, 1H), 3.96-4.07 (m, 2H), 3.83-3.90(m,1H),3.73(s,3H),2.45(s,3H),1.26-1.33(m,6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.79

Its structural characterization is as follows:

ESI-MS:m/z 757.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz)δ4.69

Embodiment 45

(S) -5- (2,3- dihydro -1- benzofuran)-base -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane - 3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) ((2,3- dihydrobenzo Furans -6- oxygroup) phosphoryl) amino) propionic ester (K45-b) and (S) -5- (2,3- dihydro -1- benzofuran)-base -2- ((R) - ((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydro of -4- Furans -2- base) methoxyl group) ((2,3- Dihydrobenzofuranes -6- oxygroup) phosphoryl) amino) and propionic ester (K45-a) preparation

In addition to using l-Alanine -5- (2,3- dihydro -1- benzofuran) ester hydrochloride to replace l-Alanine isopropyl ester salt Hydrochlorate, the inventory for making l-Alanine -5- (2,3- dihydro -1- benzofuran) ester hydrochloride are 0.26g, other and embodiment 1 Same operation, obtains title compound.Wherein K45-b is 25mg, K45-a 6mg.

Its structural characterization is as follows:

ESI-MS:m/z 662.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.51 (s, 1H), 7.52 (d, J=7.2Hz, 1H), 7.13-7.18 (m, 2H), 6.79 (d, J=8.0Hz, 1H), 6.73 (m, 1H), 6.63-6.65 (m, 2H), 6.07-6.13 (m, 1H), 6.00-6.04 (m, 1H), 5.85-5.87 (m, 1H), 5.51 (d, J=7.6Hz, 1H), 5.00 (dd, J=13.2Hz, 12.4Hz, 2H), 4.49- 4.56(m,4H),4.32-4.36(m,1H),4.18-4.23(m,1H),3.75-4.00(m,3H),3.09-3.16(m,4H), 1.22-1.27(m,6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.58

Its structural characterization is as follows:

ESI-MS:m/z 662.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz)δ4.45

Embodiment 46

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphinylidyne Base) amino) -3- Phenpropionate (K46-b) and (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane - 3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [d] [1,3] two Butyl oxide link -5- oxygroup) phosphoryl) amino) and -3- Phenpropionate (K46-a) preparation

In addition to using L-phenylalanine isopropyl ester hydrochloride to replace l-Alanine isopropyl ester hydrochloride, keeping L-phenylalanine different The inventory of propyl ester hydrochloride is 0.23g；The throwing for replacing 6- hydroxyl -2,3- Dihydrobenzofuranes using sesamol, making sesamol Doses be 0.134g except, it is other to operate similarly to Example 1, obtain title compound.Wherein K46-b is 55mg, and K46-a is 15mg。

Its structural characterization is as follows:

ESI-MS:m/z 650.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.51 (s, 1H), 7.47 (d, J=4.4Hz, 1H), 7.15-7.23 (m, 5H), 6.78 (d, J=8.8Hz, 1H), 6.66 (s, 1H), 6.48 (d, J=8.8Hz, 1H), 6.13 (t, J=12.0Hz, 1H), 5.98 (s, 3H), 5.81 (s, 1H), 5.52 (d, J=7.6Hz, 1H), 4.71-4.77 (m, 1H), 4.14-4.16 (m, 1H), 4.01-4.03 (m, 1H), 3.85-3.91 (m, 2H), 3.70-3.78 (m, 1H), 2.77-2.92 (m, 2H), 1.22 (d, J= 19.2Hz, 3H), 1.07 (d, J=6.0Hz, 3H), 0.95 (d, J=6.0Hz, 3H)

³¹P NMR(DMSO-d₆,162MHz)δ4.87

Its structural characterization is as follows:

ESI-MS:m/z 650.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz)δ4.67

Embodiment 47

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (the fluoro- 1,2- dimethyl -1H- indoles -6- base of 4-) - Phenoxy group) phosphoryl) amino) propionic ester (K47-b) and S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- bis- - 1 (2H)-yl of carbonyl -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) ((4- is fluoro- by 4- 1,2- dimethyl -1H- indoles -6- base)-phenoxy group) phosphoryl) amino) propionic ester (K47-a) preparation

In addition to using 4- (the fluoro- 1,2- dimethyl -1H- indoles -6- base of 4-) phenol to replace 6- hydroxyl -2,3- dihydrobenzene And furans, make 4- (fluoro- 1, the 2- dimethyl -1H- indoles -6- base of 4-) phenol inventory be 2.55g except, other and embodiment 1 same operation, obtains title compound.Wherein K47-b is 45mg, K47-a 10mg.

Its structural characterization is as follows:

ESI-MS:m/z 691.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.53 (s, 1H), 7.59 (d, J=8Hz, 1H) 7.54 (d, J=8Hz, 2H), 7.31 (d, J=8Hz, 3H), 7.14 (t, J=8Hz, 1H), 6.32 (s, 1H), 6.01-6.14 (m, 2H), 5.89 (s, 1H), 5.58 (d, J=8Hz, 1H), 4.83-4.90 (m, 1H), 4.27-4.40 (m, 2H), 4.02-4.03 (m, 1H), 3.81-3.88 (m,2H),3.69(s,3H),2.42(s,3H),1.15-1.29(m,12H).

³¹P NMR(DMSO-d₆,162MHz)δ4.85

Its structural characterization is as follows:

ESI-MS:m/z 691.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz)δ4.66

Embodiment 48

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [1,3] dioxolanes -5- oxygroup) phosphoryl) Amino) -4- methylvaleric acid (K48-b) and (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (dicarbapentaborane -3 2,4-, 4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [1,3] dioxy penta Ring -5- oxygroup) phosphoryl) amino) and -4- methylvaleric acid (K48-a) preparation

In addition to using L-Leu isopropyl ester hydrochloride to replace l-Alanine isopropyl ester hydrochloride, making L-Leu isopropyl ester The inventory of hydrochloride is 0.2g；The inventory for replacing 6- hydroxyl -2,3- Dihydrobenzofuranes using sesamol, making sesamol It is other to operate similarly to Example 1 except 0.134g, obtain title compound.Wherein K48-b is 40mg, K48-a 12mg.

Its structural characterization is as follows:

ESI-MS:m/z 616.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) δ 11.54 (s, 1H), 7.56 (d, J=8Hz, 1H), 6.87 (d, J=8Hz, 1H), 6.81 (d, J=4Hz, 1H), 6.63-6.66 (m, 1H), 5.97-6.03 (m, 4H), 5.85-5.87 (m, 1H), 5.56 (d, J=8Hz, 1H), 4.81-4.87 (m, 1H), 4.32-4.36 (m, 1H), 4.19-4.22 (m, 1H), 3.98-4.01 (m, 1H), 3.64-3.80(m,2H),1.61-1.68(m,1H),1.40-1.49(m,2H),1.22-1.27(m,3H),1.13-1.17(m, 6H),0.81-0.84(m,6H).

³¹P NMR(DMSO-d₆,162MHz)δ5.40

Its structural characterization is as follows:

ESI-MS:m/z 616.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz)δ5.30

Embodiment 49

(S)-benzo [1,3] dioxolanes benzyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- Dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [1,3] dioxolanes - 5- oxygroup) phosphoryl) amino) propionic ester (K49-b) and (S)-benzo [1,3] dioxolanes benzyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) Methoxyl group) (benzo [1,3] dioxolanes -5- oxygroup) phosphoryl) amino) and propionic ester (K49-a) preparation

In addition to use l-Alanine benzo [1,3] dioxolanes benzyl ester hydrochloride replace l-Alanine isopropyl ester hydrochloride, Make the inventory 0.25g of l-Alanine benzo [1,3] dioxolanes benzyl ester hydrochloride；Hydroxyl -2 6- are replaced using sesamol, 3- Dihydrobenzofuranes make except the inventory 0.134g of sesamol, other to operate similarly to Example 1, obtain titled Close object.Wherein K49-b is 55mg, K49-a 14mg.

Its structural characterization is as follows:

ESI-MS:m/z 666.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.54 (s, 1H), 7.57 (d, J=8Hz, 1H), 6.84-6.93 (m, 5H), 6.67-6.69 (m, 1H), 6.00-6.14 (m, 6H), 5.88-5.94 (m, 1H), 5.59 (d, J=8Hz, 1H), 4.97-5.04 (m,2H),4.34-4.38(m,1H),4.20-4.26(m,1H),3.88-4.03(m,3H),1.24-1.30(m,6H).

³¹P NMR(DMSO-d₆,162MHz)δ5.04

Embodiment 50

(S)-benzo [1,3] dioxolanes benzyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- Dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -3,4- dihydrobenzene And [1,4] morpholine -8- oxygroup) phosphoryl) amino) propionic ester (K50-b) and (S)-benzo [1,3] dioxolanes benzyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl of -4- Tetrahydrofuran -2- base) methoxyl group) (4- methyl -3,4- dihydrobenzo [1,4] morpholine -8- oxygroup) phosphoryl) amino) propionic ester (K50-a) preparation

In addition to use l-Alanine benzo [1,3] dioxolanes benzyl ester hydrochloride replace l-Alanine isopropyl ester hydrochloride, Make the inventory 0.25g of l-Alanine benzo [1,3] dioxolanes benzyl ester hydrochloride；Use 8- hydroxyl 4- methyl -3,4- two Hydrogen benzo [1,4] morpholino replaces 6- hydroxyl -2,3- Dihydrobenzofuranes, makes 8- hydroxyl 4- methyl -3,4- dihydrobenzo [1,4] The inventory of quinoline be 0.16g except, it is other to operate similarly to Example 1, obtain title compound.Wherein K50-b is 60mg, K50-a is 11mg.

Its structural characterization is as follows:

ESI-MS:m/z 693.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.50 (s, 1H), 7.56 (d, J=8Hz, 1H), 6.82-6.90 (m, 3H), 6.60-6.69 (m, 2H), 6.51 (d, J=8Hz, 1H), 5.86-6.00 (m, 5H), 5.53 (d, J=8Hz, 1H), 4.95-5.01 (m,2H),4.32-4.36(m,1H),4.20-4.22(m,3H),3.88-3.99(m,3H),3.21-3.23(m,2H),2.82 (s,3H),1.21-1.27(m,6H).

³¹P NMR(DMSO-d₆,162MHz)δ4.89

Its structural characterization is as follows:

ESI-MS:m/z 693.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz)δ4.85

Embodiment 51

(S) -4- luorobenzyl-((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -3,4- dihydro -2H- benzo [b] [1,4] Quinoline -7- oxygroup) phosphoryl) amino) propionic ester (K51-b) and (S) -4- luorobenzyl-((R)-((((2R, 3R, 4R, 5R) -5- (2, - 1 (2H)-yl of 4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- first Base -3,4- dihydro -2H- benzo [b] [1,4] morpholine -7- oxygroup) phosphoryl) amino) and propionic ester (K51-a) preparation

In addition to using l-Alanine -4- fluoro-methylbenzyl ester hydrochloride to replace l-Alanine isopropyl ester hydrochloride, making l-Alanine -4- The inventory of fluoro-methylbenzyl ester hydrochloride is 0.23g；Use 7- hydroxy-4-methyl -3,4- dihydro -2H- benzo [b] [1,4] morpholino For 6- hydroxyl -2,3- Dihydrobenzofuranes, make feeding intake for 7- hydroxy-4-methyl -3,4- dihydro -2H- benzo [b] [1,4] morpholine Amount be 0.16g except, it is other to operate similarly to Example 1, obtain title compound.Wherein K51-b is 23mg, and K51-a is 7mg。

Its structural characterization is as follows:

ESI-MS:m/z 667.2(M+H)⁺

¹H NMR(DMSO-d₆, 400MHz) and δ 11.52 (s, 1H), 7.56 (d, J=8.1Hz, 1H), 7.45-7.38 (m, 2H), 7.26 (d, J=8.7Hz, 2H), 7.04-6.95 (m, 2H), 6.20-5.95 (m, 1H), 6.10-5.87 (m, 3H), 5.56 (d, J=8.0Hz, 1H), 5.18-5.04 (m, 2H), 4.40-4.22 (m, 4H), 4.03-3.99 (m, 2H), 3.25-3.23 (m, 2H),2.86(s,3H),1.33-1.27(m,6H).

³¹P NMR(DMSO-d₆,162MHz)δ4.99

Its structural characterization is as follows:

ESI-MS:m/z 667.2(M+H)⁺

¹H NMR(DMSO-d₆, 400MHz) and δ 11.52 (s, 1H), 7.57 (d, J=8.0Hz, 1H), 7.46-7.40 (m, 2H), 7.26 (d, J=8.7Hz, 2H), 7.11-7.04 (m, 2H), 7.04-6.95 (m, 2H), 6.20-5.95 (m, 2H), 5.87 (d, J=6.5Hz, 1H), 5.56 (d, J=8.0Hz, 1H), 4.89-4.83 (m, 1H), 4.40-4.22 (m, 2H), 4.03-3.99 (m,1H),3.87-3.79(m,2H),1.33-1.12(m,13H)

³¹P NMR(DMSO-d₆,162MHz)δ4.79

Embodiment 52

(S) -4- luorobenzyl ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -3,4- dihydro -2H- benzo [b] [1,4] Quinoline -8- oxygroup) phosphoryl) amino) propionic ester (K52-b) and (S) -4- luorobenzyl ((R)-((((2R, 3R, 4R, 5R) -5- (2, - 1 (2H)-yl of 4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- first Base -3,4- dihydro -2H- benzo [b] [1,4] morpholine -8- oxygroup) phosphoryl) amino) and propionic ester (K52-a) preparation

In addition to using l-Alanine -4- fluoro-methylbenzyl ester hydrochloride to replace l-Alanine isopropyl ester hydrochloride, making l-Alanine -4- The inventory of fluoro-methylbenzyl ester hydrochloride is 0.23g；Use 8- hydroxy-4-methyl -3,4- dihydro -2H- benzo [b] [1,4] morpholino For 6- hydroxyl -2,3- Dihydrobenzofuranes, make feeding intake for 8- hydroxy-4-methyl -3,4- dihydro -2H- benzo [b] [1,4] morpholine Amount be 0.16g except, it is other to operate similarly to Example 1, obtain title compound.Wherein K52-b is 22mg, and K52-a is 5mg。

Its structural characterization is as follows:

ESI-MS:m/z 667.2(M+H)⁺

¹H NMR(DMSO-d₆, 400MHz) and δ 11.51 (s, 1H), 7.56 (d, J=8.2Hz, 1H), 7.45-7.34 (m, 2H), 7.24-7.10 (m, 2H), 6.64 (m, 2H), 6.51 (dd, J=7.9Hz, 1.8Hz, 1H), 6.11-5.79 (m, 3H), 5.53 (d, J=8.0Hz, 1H), 5.14-5.01 (m, 2H), 4.36 (dd, J=11.4Hz, 5.6Hz, 1H), 4.20 (q, J= 5.2Hz, 3H), 4.03-3.89 (m, 2H), 3.22 (t, J=4.3Hz, 2H), 2.82 (s, 3H), 1.24 (m, 7H)

³¹P NMR(DMSO-d₆,162MHz)δ4.87

Its structural characterization is as follows:

ESI-MS:m/z 667.2(M+H)⁺

³¹P NMR(DMSO-d₆,162MHz)δ4.77

Embodiment 53

(S) -2,3- dihydrobenzo [b] [1,4] dioxane -6- methyl ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- - 1 (2H)-yl of dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphoryl) amino) propionic ester (K53-b) and (S) -2,3- dihydrobenzo [b] [1,4] dioxy Own ring -6- methyl ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- of -4- Hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphoryl) amino) propionic acid The preparation of ester (K53-a)

In addition to using l-Alanine (2,3- dihydrobenzo [1,4] dioxane -6- base) methyl ester hydrochloride to replace the third ammonia of L- Isopropyl propionate hydrochloride, the inventory for making l-Alanine (2,3- dihydrobenzo [1,4] dioxane -6- base) methyl ester hydrochloride 0.27g；6- hydroxyl -2,3- Dihydrobenzofuranes are replaced using sesamol, are made except the inventory 0.134g of sesamol, it is other It operates similarly to Example 1, obtains title compound.Wherein K53-b is 28mg, K53-a 6mg.

Its structural characterization is as follows:

ESI-MS:m/z 679.5(M+H)⁺

¹H NMR(DMSO-d₆, 400MHz) and δ 11.54 (s, 1H), 7.56 (d, J=8.2Hz, 1H), 6.93-6.77 (m, 5H), 6.70-6.65 (m, 1H), 6.21-5.94 (m, 4H), 5.89 (s, 1H), 5.58 (d, J=8.1Hz, 1H), 5.02-4.93 (m, 2H), 4.34 (d, J=7.6Hz, 1H), 4.24 (s, 5H), 4.07-3.75 (m, 3H), 1.27 (dd, J=7.6Hz, 6H)

³¹P NMR(DMSO-d₆,162MHz)δ5.05

Its structural characterization is as follows:

ESI-MS:m/z 679.5(M+H)⁺

³¹P NMR(DMSO-d₆,162MHz)δ4.95

Embodiment 54

(S)-(2,3- dihydrobenzo [1,4] dioxane -6- base) methoxyl group -2- ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2, 3- Dihydrobenzofuranes -6- oxygroup) phosphoryl) amino) propionic ester (K54-b) and (S)-(2,3- dihydrobenzo [1,4] dioxy oneself Ring -6- base) methoxyl group -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (2,3- Dihydrobenzofuranes -6- oxygroup) phosphoryl) amino) The preparation of propionic ester (K54-a)

In addition to using l-Alanine (2,3- dihydrobenzo [1,4] dioxane -6- base) methyl ester hydrochloride to replace the third ammonia of L- Isopropyl propionate hydrochloride, the inventory for making l-Alanine (2,3- dihydrobenzo [1,4] dioxane -6- base) methyl ester hydrochloride It is other to operate similarly to Example 1 except 0.27g, obtain title compound.Wherein K54-b is 45mg, K54-a 10mg.

Its structural characterization is as follows:

ESI-MS:m/z 678.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.53 (s, 1H), 7.54 (d, J=8Hz, 1H), 7.17 (d, J=8Hz, 1H), 6.85 (d, J=8Hz, 3H), 6.66 (d, J=8Hz, 2H), 6.11-5.89 (m, 3H), 5.54 (d, J=8Hz, 1H), 4.98 (d, J=8Hz, 2H), 4.57 (t, J=8Hz, 2H), 4.32-4.27 (m, 1H), 4.23 (s, 5H), 4.01-3.96 (m, 1H),3.87-3.78(m,2H),3.26-3.12(m,2H),1.30-1.24(m,6H)

³¹P NMR(DMSO-d₆,162MHz):δ4.63

Its structural characterization is as follows:

ESI-MS:m/z 678.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz):δ4.53

Embodiment 55

(S)-(2,3- Dihydrobenzofuranes -5- base) methoxyl group -2- ((S)-((((2R, 3R, 4R, 5R) -5- (bis- carbonyl of 2,4- Base -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [1,3] two Butyl oxide link -5- oxygroup) phosphoryl) amino) propionic ester (K55-b) and (S)-(2,3- Dihydrobenzofuranes -5- base) methoxyl group -2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl of -4- Tetrahydrofuran -2- base) methoxyl group) (benzo [1,3] dioxolanes -5- oxygroup) phosphoryl) amino) propionic ester (K55-a) system It is standby

In addition to use l-Alanine benzo [1,3] dioxolanes benzyl ester hydrochloride replace l-Alanine isopropyl ester hydrochloride, Make the inventory 0.23g of l-Alanine benzo [1,3] dioxolanes benzyl ester hydrochloride；Hydroxyl -2 6- are replaced using sesamol, 3- Dihydrobenzofuranes make except the inventory 0.134g of sesamol, other to operate similarly to Example 1, obtain titled Close object.Wherein K55-b is 60mg, K55-a 11mg.

Its structural characterization is as follows:

ESI-MS:m/z 664.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.49 (s, 1H), 7.53 (d, J=8Hz, 1H), 7.17 (d, J=8Hz, 1H), 6.85-6.78 (m, 3H), 6.73 (s, J=8Hz, 1H), 6.65 (d, J=8Hz, 1H), 6.11-6.01 (m, 4H), 5.89 (s, 1H), 5.55 (d, J=8Hz, 1H), 5.0 (t, J=8Hz, 2H), 4.51 (t, J=8Hz, 2H), 4.32-4.27 (m, 1H), 4.23(s,1H),4.01-3.90(m,3H),3.16-3.12(m,2H),1.27-1.22(m,6H)

³¹P NMR(DMSO-d₆,162MHz):δ5.05

Its structural characterization is as follows:

ESI-MS:m/z 664.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz):δ4.87

Embodiment 56

(S)-(2,3- dihydrobenzos [Isosorbide-5-Nitrae] dioxane -6- base) methoxyl group -2- ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- Methyl -3,4- dihydrobenzo [1,4] morpholine -8- oxygroup) phosphoryl) amino) propionic ester (K56-b) and (S)-(2,3- dihydrobenzene And [Isosorbide-5-Nitrae] dioxane -6- base) ((R)-((((2,4- dicarbapentaborane -3,4- dihydros are phonetic by (2R, 3R, 4R, 5R) -5- by methoxyl group -2- Pyridine -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -3,4- dihydrobenzo [1,4] Morpholine -8- oxygroup) phosphoryl) amino) and propionic ester (K56-a) preparation

In addition to using l-Alanine (2,3- dihydrobenzo [1,4] dioxane -6- base) methyl ester hydrochloride to replace the third ammonia of L- Isopropyl propionate hydrochloride, the inventory for making l-Alanine (2,3- dihydrobenzo [1,4] dioxane -6- base) methyl ester hydrochloride 0.27g；6- hydroxyl -2,3- dihydrobenzo furan is replaced using 8- hydroxy-4-methyl -3,4- dihydro -2H- benzo [b] [1,4] morpholino Mutter, make 8- hydroxy-4-methyl -3,4- dihydro -2H- benzo [b] [Isosorbide-5-Nitrae] morpholine inventory be 0.16g except, it is other with implement Example 1 equally operates, and obtains title compound.Wherein K56-b is 75mg, K56-a 21mg.

Its structural characterization is as follows:

ESI-MS:m/z 707.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.51 (s, 1H), 7.56 (d, J=8Hz, 1H), 6.85 (s, 1H), 6.80 (s, 2H), 6.67-6.62 (t, J=8Hz, 2H), 6.52 (d, J=8Hz, 1H), 6.01-5.86 (m, 3H), 5.53 (d, J= 8Hz, 1H), 4.96 (t, J=8Hz, 2H), 4.34 (s, 1H), 4.22 (s, 7H), 3.99-3.91 (m, 3H), 3.22 (s, 2H), 2.82(s,3H),1.27-1.22(m,6H)

³¹P NMR(DMSO-d₆,162MHz):δ4.88

Its structural characterization is as follows:

ESI-MS:m/z 707.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz):δ4.78

Embodiment 57

(S)-(2,3- dihydrobenzos [Isosorbide-5-Nitrae] dioxane -6- base) methoxyl group -2- ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- Methyl -3,4- dihydrobenzo [1,4] morpholine -7- oxygroup) phosphoryl) amino) propionic ester (K57-b) and (S)-(2,3- dihydrobenzene And [Isosorbide-5-Nitrae] dioxane -6- base) ((R)-((((2,4- dicarbapentaborane -3,4- dihydros are phonetic by (2R, 3R, 4R, 5R) -5- by methoxyl group -2- Pyridine -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -3,4- dihydrobenzo [1,4] Morpholine -7- oxygroup) phosphoryl) amino) and propionic ester (K57-a) preparation

In addition to using l-Alanine (2,3- dihydrobenzo [1,4] dioxane -6- base) methyl ester hydrochloride to replace the third ammonia of L- Isopropyl propionate hydrochloride, the inventory for making l-Alanine (2,3- dihydrobenzo [1,4] dioxane -6- base) methyl ester hydrochloride 0.27g；6- hydroxyl -2,3- Dihydrobenzofuranes are replaced using 7- hydroxy-4-methyl -3,4- dihydrobenzo [1,4] morpholino, make 7- The inventory of hydroxy-4-methyl -3,4- dihydrobenzo [Isosorbide-5-Nitrae] morpholine be 0.16g except, it is other to operate similarly to Example 1, obtain To title compound.Wherein K57-b is 29mg, K57-a 8mg.

Its structural characterization is as follows:

ESI-MS:m/z 707.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.50 (s, 1H), 7.52 (d, J=8Hz, 1H), 6.83 (d, J=8Hz, 3H), 6.59 (d, J=8Hz, 3H), 6.01-5.86 (m, 3H), 5.51 (d, J=8Hz, 1H), 4.96 (t, J=8Hz, 2H), 4.30(s,1H),4.22(s,7H),3.99-3.87(m,3H),3.17(s,2H),2.77(s,3H),1.27-1.21(m,6H)

³¹P NMR(DMSO-d₆,162MHz):δ4.99

Its structural characterization is as follows:

ESI-MS:m/z 707.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz):δ4.79

Embodiment 58

(S)-(S- isobutyl group) -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- dihydrobenzo [1,4] dioxane -5- Oxygroup) phosphoryl) amino) propionic ester (K58-b) and (S)-(S- isobutyl group) -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2, - 1 (2H)-yl of 4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- Dihydrobenzo [1,4] dioxane -5- oxygroup) phosphoryl) amino) and propionic ester (K58-a) preparation

In addition to using l-Alanine-S- isobutyl ester hydrochloride to replace l-Alanine isopropyl ester hydrochloride, making l-Alanine-S- The inventory of isobutyl ester hydrochloride is 0.18g；Hydroxyl -2 6- are replaced using 5- hydroxyl -2,3- dihydrobenzo [1,4] dioxane, 3- Dihydrobenzofuranes, make 5- hydroxyl -2,3- dihydrobenzo [Isosorbide-5-Nitrae] dioxane inventory be 0.15g except, it is other with it is real It applies example 1 equally to operate, obtains title compound.Wherein K58-b is 18mg, K58-a 4mg.

Its structural characterization is as follows:

ESI-MS:m/z 602.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.52 (s, 1H), 7.57 (d, J=8Hz, 1H), 6.87 (d, J=8Hz, 1H), 6.75 (t, J=8Hz, 1H), 6.68 (d, J=8Hz, 1H), 6.02-5.87 (m, 3H), 5.56 (t, J=8Hz, 1H), 4.72 (t, J=8Hz, 1H), 4.39 (s, 1H), 4.25 (d, J=8Hz, 5H), 3.99 (s, 1H), 3.82 (t, J=8Hz, 2H), 1.50 (t, J=8Hz, 2H), 1.27-1.22 (m, 6H), 1.12 (d, J=4Hz, 3H), 0.81 (t, J=4Hz, 3H)

³¹P NMR(DMSO-d₆,162MHz):δ4.95

Its structural characterization is as follows:

ESI-MS:m/z 602.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz):δ4.85

Embodiment 59

(S) -4- luorobenzyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- Dihydrobenzofuranes -6- oxygroup) phosphinylidyne Base) amino) propionic ester (K59-b) and (S) -4- luorobenzyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (dicarbapentaborane -3 2,4-, 4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- dihydrobenzo furan Mutter -6- oxygroup) phosphoryl) amino) and propionic ester (K59-a) preparation

In addition to using l-Alanine -4- fluoro-methylbenzyl ester hydrochloride to replace l-Alanine isopropyl ester hydrochloride, making l-Alanine -4- The inventory of fluoro-methylbenzyl ester hydrochloride be 0.23g except, it is other to operate similarly to Example 1, obtain title compound.Wherein K59- B is 26mg, K59-a 4mg.

Its structural characterization is as follows:

ESI-MS:m/z 638.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz): δ 11.52 (s, 1H), 7.53 (s, 1H), 7.39 (s, 2H), 7.16 (d, J= 8Hz, 3H), 6.63 (s, 2H), 6.11-5.87 (m, 3H), 5.53 (d, J=4Hz, 1H), 5.07 (s, 2H), 4.55 (d, J= 8Hz,2H),4.33(s,1H),4.22(s,1H),3.98-3.93(m,3H),3.11(s,2H),1.26-1.22(m,6H)

³¹P NMR(DMSO-d₆,162MHz):δ4.62

Its structural characterization is as follows:

ESI-MS:m/z 638.2(M⁺+H)

³¹P NMR(DMSO-d₆,162MHz):δ4.50

Embodiment 60

2- (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxyl-of -4- 4- methyltetrahydrofuran -2- base) methoxyl group) (phenoxy group) phosphoryl) amino) ethyl acetate (K60) and its isomers preparation

The preparation of midbody compound 2- (((phenyl-pentafluoride oxygroup) (phenoxy group) phosphoryl) amino) ethyl acetate

Phosphorus oxychloride (1.53g, 10mmol) is dissolved in methylene chloride (10mL), -60 DEG C is cooled to, phenol is slowly added dropwise The dichloromethane solution (10mL) of (0.94g, 10mmol) and triethylamine (1.01g, 10mmol).It is added dropwise, removes cryostat, rise It is stirred 2 hours to 25 DEG C.Reaction system is further cooled to -78 DEG C, be added 2- ethyl aminoacetate hydrochloride (1.25g, 9mmol), the dichloromethane solution (5mL) of triethylamine (2.53g, 25mmol) is then added dropwise.It is added dropwise, removes cryostat, rise to 25 DEG C are stirred 2 hours.Reaction system is further cooled to -78 DEG C, Pentafluorophenol (1.66g, 9mmol) and triethylamine is added dropwise The dichloromethane solution (10mL) of (1.52g, 15mmol).It is added dropwise, removes cryostat, rise to 25 DEG C and stir 2 hours.It has reacted Entirely, reaction system is poured into ice water, is extracted with dichloromethane.It collects merging organic phase to be washed with saturated common salt aqueous solution, do Dry, filtering and concentrating obtains the crude product of title compound.

2- (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxyl-of -4- 4- methyltetrahydrofuran -2- base) methoxyl group) (phenoxy group) phosphoryl) amino) ethyl acetate (K60) preparation

By 1- (the fluoro- 4- hydroxyl -5- methylol -3- methyltetrahydrofuran -2- base of (2R, 3R, 4R, 5R) -3-) pyrimidine -2,4- (1H, 3H)-diketone (260mg, 1mmol) is dissolved in anhydrous tetrahydro furan (20mL), and argon gas is replaced three times.Tertiary fourth is added dropwise in 0 DEG C Base magnesium chloride (1.0mol/L, 2.5mL, 2.5mmol) rises to 25 DEG C and reacts 1 hour.It is cooled to 0 DEG C, above-mentioned intermediate is added dropwise Close the anhydrous tetrahydro furan of object 2- (((phenyl-pentafluoride oxygroup) (phenoxy group) phosphoryl) amino) ethyl acetate (425mg, 1.0mmol) (10mL) solution.It is added dropwise, rises to 25 DEG C and react 15 hours.Few drops of 2M hydrochloric acid is added dropwise becomes to reaction system and clarifies.Add water 30mL dilution, 2M hydrochloric acid are adjusted to neutrality.Reaction system is extracted with ethyl acetate, and collects merging organic phase and uses unsaturated carbonate hydrogen respectively Sodium water solution, saturated common salt water washing dry, filter concentration, and residue obtains non-enantiomer mixture through column chromatographic purifying (150mg, 30%).

Its structural characterization is as follows:

ESI-MS:m/z 502.1(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.52 (s, 1H), 7.57 (m, 1H), 7.39 (t, J=8.0Hz, 2H), 7.24-7.17 (m, 3H), 6.06-5.91 (m, 2H), 5.72 (m, 1H), 5.57 (q, J=8.0Hz, 1H), 4.42-4.35 (m, 1H), 4.30-4.24 (m, 1H), 4.04 (m, 1H), 3.96 (t, J=6.0Hz, 2H), 3.86 (s, 1H), 3.13-3.05 (m, 2H),1.96(s,3H),1.34-1.22(m,3H)

³¹P NMR(DMSO-d₆,162MHz)δ6.34

The preparation of diastereoisomer

By above-mentioned resulting product K60 preparation HPLC separation, separation condition is as follows.It is to fill out with octadecyl silane It fills agent (20 × 250mm, 5 μm), 40 DEG C of column temperature, flow velocity 10.0mL/min, Detection wavelength 220nm, mobile phase A is water (neutrality), Mobile phase B is methanol, carries out linear gradient elution.Collect first main peak, freeze-drying obtain 2- ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) Methoxyl group) (phenoxy group) phosphoryl) amino) ethyl acetate (K60-a) 20mg；Second main peak is collected, freeze-drying obtains 2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl of -4- Tetrahydrofuran -2- base) methoxyl group) (phenoxy group) phosphoryl) amino) ethyl acetate (K60-b) 75mg.

Its structural characterization is as follows:

ESI-MS:m/z 502.1(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.51 (s, 1H), 7.54 (d, J=8.1Hz, 1H), 7.38 (t, J= 7.7Hz, 2H), 7.23-7.17 (m, 3H), 6.04 (d, J=19.5Hz, 2H), 5.95 (s, 1H), 5.78-5.71 (m, 1H), 5.58 (d, J=8.0Hz, 1H), 4.40-4.36 (m, 2H), 4.06-4.02 (m, 1H), 3.95 (t, J=5.6Hz, 2H), 3.79 (d, J=23.7Hz, 1H), 3.11-3.03 (m, 2H), 1.96 (s, 3H), 1.27-1.21 (m, 3H)

³¹P NMR(DMSO-d₆,162MHz)δ6.23

Its structural characterization is as follows:

ESI-MS:m/z 502.1(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.54 (s, 1H), 7.56 (m, 1H), 7.41 (t, J=8.0Hz, 2H), 7.22-7.16(m,3H),6.06-5.91(m,2H),5.72(m,1H),5.59-5.55(m,1H),4.42-4.35(m,1H), 4.26-4.23 (m, 1H), 4.04 (m, 1H), 3.96 (t, J=6.0Hz, 2H), 3.75 (s, 1H), 3.13-3.05 (m, 2H), 1.96(s,3H),1.34-1.22(m,3H).

³¹P NMR(DMSO-d₆,162MHz)δ6.45

Embodiment 61

2- (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxyl-of -4- 4- methyltetrahydrofuran -2- base) methoxyl group) (phenoxy group) phosphoryl) amino) -4- ethyl fluoro benzoate (K61) preparation.

In addition to using 2- amino-ethyl -4- fluorobenzoate to replace l-Alanine isopropyl ester hydrochloride, making 2- amino-ethyl - The inventory of 4- fluorobenzoate is except 0.165g, and other and embodiment 60 equally operates, and obtains title compound 58mg, always Yield 10%.

Its structural characterization is as follows:

ESI-MS:m/z 582.1(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.57 (s, 1H), 7.58 (t, J=8.0Hz, 1H), 7.43-7.39 (m, 3H), 7.31-7.12 (m, 8H), 6.08-5.95 (m, 2H), 5.82-5.75 (m, 1H), 5.62 (q, J=8.0Hz, 1H), 4.43- 4.37(m,1H),4.32-4.25(m,1H),4.09-4.05(m,1H),3.14-3.09(m,3H),1.30-1.23(m,3H).

³¹P NMR(DMSO-d₆,162MHz)δ6.35

Embodiment 62

2- ((benzo [d] [1,3] dioxolanes -5- oxygroup) ((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- two Hydrogen pyrimidine -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) phosphoryl) amino)-ethyl acetate (K62) preparation.

In addition to using sesamol to replace phenol, make except the inventory 0.138g of sesamol, other and embodiment 60 is same Sample operation, obtains title product 60mg, total recovery 11%.

Its structural characterization is as follows:

ESI-MS:m/z 546.1(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.57 (s, 1H), 7.58 (s, 1H), 6.91 (d, J=12.0Hz, 1H), 6.87-6.85 (m, 1H), 6.69 (d, J=8.0Hz, 1H), 6.07-5.95 (m, 2H), 6.04 (s, 2H), 5.73-5.66 (m, 1H), 5.62 (q, J=8.0Hz, 1H), 4.40-4.35 (m, 1H), 4.29-4.23 (m, 1H), 4.04 (s, 1H), 3.96 (t, J= 8.0Hz,1H),3.64-3.60(m,1H),3.11-3.06(m,2H),1.99(s,3H),1.80-1.76(m,1H),1.31- 1.24(m,3H)

³¹P NMR(DMSO-d₆,162MHz)δ6.79

Embodiment 63

Methyl -2- (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- of -4- Hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (phenoxy group) phosphoryl) hydroxyl) acetic acid esters (K63) preparation

In addition to the inventory for using hydroxy methyl acetate to replace 2- ethyl aminoacetate hydrochloride, make hydroxy methyl acetate It is other equally to be operated with embodiment 60 except 93mg, obtain title compound 58mg, total recovery 12%.

Its structural characterization is as follows:

ESI-MS:m/z 489.1(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.58 (s, 1H), 7.50 (s, 1H), 7.42 (t, J=8.0Hz, 2H), 7.27-7.23 (m, 3H), 5.97 (s, 2H), 5.57 (q, J=8.0Hz, 1H), 4.83 (s, 1H), 4.80 (s, 1H), 4.51- 4.45(m,2H),4.02(s,1H),3.88-3.82(m,1H),3.70(s,3H),1.25-1.14(m,3H)

³¹P NMR(DMSO-d₆,162MHz)δ-9.89

Embodiment 64

(S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- dihydrobenzo [b] [1,4] dioxane -6- oxygen Base) phosphoryl) amino) propionic ester (K64-b) and (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (bis- carbonyl of 2,4- - 1 (2H)-yl of base -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- dihydrobenzene And [b] [1,4] dioxane -6- oxygroup) phosphoryl) amino) propionic ester (K64-a) preparation

In addition to using 2,3- dihydro -6- hydroxyl-benzo [b] [1,4] dioxane to replace 6- hydroxyl -2,3- dihydrobenzo furan It mutters, making 2,3- dihydro -6- hydroxyl-benzo [b] [Isosorbide-5-Nitrae] dioxane inventory is except 0.137g, and other and embodiment 1 is same Sample operation, obtains title compound.Wherein K64-b is 20mg, K64-a 2mg.

Its structural characterization is as follows:

ESI-MS:m/z 588.2(M⁺+H)

¹H NMR(DMSO-d₆, 400MHz) and δ 11.52 (s, 1H), 7.55 (d, J=8Hz, 1H), 6.83-6.81 (m, 1H), 6.75 (s, 1H), 6.68-6.66 (m, 1H), 5.98-5.95 (m, 2H), 5.85 (bs, 1H), 5.54 (d, J=8Hz, 1H), 4.87-4.84(m,1H),4.34-4.32(m,1H),4.21(bs,5H),3.98(bs,1H),3.79-3.77(m,2H),1.27- 1.22(m,6H),1.16-1.14(m,6H)

³¹P NMR(DMSO-d₆,162MHz)δ4.96

Test example

Test example 1

The test of 1.1 HCV GT1b and GT1a replicons

This test uses HCV GT1bHuh7 and GT1a H77 replicon cell system, in luciferase report gene method Series compound is had detected to the inhibitory activity of HCV GT1b and GT1a Replicate Sub-system.

Inoculation 1b and 1a cell is to 384 orifice plates and 96 orifice plates respectively, be added the compound of the present invention be respectively 0.25 μ L and Echo 550:1 μ L, 3 times of gradient dilutions, 11 concentration are repeated twice experiment, are the positive with sofosbuvir (i.e. Suo Feibuwei) Control.5%CO₂Culture cell 72 hours of 37 DEG C of incubator；Add 100 μ L luciferase luminous substrates, with chemiluminescence detection system The Envision that unites is detected, and GraphPad Prism software carries out data analysis.

Inhibiting rate calculation formula is as follows: % inhibition=100- (Test-AVE HPE)/(AVE ZPE-AVE HPE) * 100. Percentage importing GraphPad Prism will be inhibited to be further processed and obtain homologous thread and medium effective concentration EC₅₀Value.Wherein Test is the fluorescence signal value of compound well, and AVE HPE (Average hundred percent effect) is 100% effective Effect control fluorescence signal average value, AVE ZPE (Average zero percent effect) are that invalid effect compares fluorescence Signal averaging.

Test result shows that within the scope of test concentrations, the compounds of this invention shows to inhibit HCVGT1b and GT1a sub- The activity of type replicon.EC of the sofosbuvir to GT1b and GT1a₅₀Respectively 0.130 μM and 0.091 μM；Chemical combination of the invention EC of the object to GT1b and GT1a₅₀Respectively less than 0.130 μM and 0.091 μM.As a result as shown in table 1-1 and table 1-2.

Table 1-1: inhibiting effect of the compounds of this invention to HCV GT1b

Table 1-2: inhibiting effect of the compounds of this invention to HCV GT1a

As seen from the above table, for GT1b and GT1a hypotype replicon, the compound of the present invention is shown and positive control Sofosbuvir compares more excellent antiviral activity.

The test of 1.2 HCV GT2a replicons

This test further uses HCV GT2a Huh7 replicon cell system, with the inspection of luciferase report gene method The compound of the present invention has been surveyed to the inhibitory activity of HCV GT2a Replicate Sub-system.

Huh7 cell is inoculated with to 96 orifice plates, the compound of the present invention series of digestion is in DMSO, 3 times of gradient dilutions, and 11 Concentration is repeated twice experiment.5%CO₂Culture cell 72 hours of 37 DEG C of incubator.Add 100 μ L luciferase luminous substrates, with change Luminescent detection system Envision detection is learned, GraphPad Prism software carries out data analysis.Inhibiting rate calculation formula is such as Under: % inhibiting rate=100- (Test-AVE HPE)/(AVE ZPE-AVE HPE) * 100.Percentage will be inhibited to import GraphPad Prism, which is further processed, obtains homologous thread and EC₅₀Value.

Wherein Test is the fluorescence signal value of compound well, AVE HPE (Average hundred percent Effect fluorescence signal average value, AVE ZPE (Average zero percent effect)) are compareed for 100% useful effect To act on control fluorescence signal average value in vain.

Test result shows that within the scope of test concentrations, the compound of the present invention shows to inhibit HCVGT2a hypotype multiple The activity of system.The results are shown in Table 2.

Table 2: inhibiting effect of the compounds of this invention to HCV GT2a

As seen from the above table, for GT2a hypotype replicon, the compound of the present invention activities present goes out more excellent disease-resistant Cytotoxic activity, EC₅₀Substantially between 0.015-0.200 μM.

2. cytotoxicity test of experimental example

Cytotoxicity of this test evaluation series compound to human liver cancer cell Huh7.

Compound is added in orifice plate, Huh7 cell is added in the orifice plate containing compound, orifice plate is placed in 37 DEG C, 5%CO₂Incubator is incubated for 20min；Incubation finishes, and CellTiter-Blue (50 hole μ l/) is added into orifice plate, 37 DEG C of incubations Fluorescence signal (relative light unit) is read with microplate reader after 10min.CC is calculated using following formula₅₀Value: %effect=100- (Test value)/AVE CELL only wells)*100.Percentage will be inhibited to import GraphPad Prism further to locate Reason obtains homologous thread and half cytotoxic concentration CC₅₀Value.

Wherein Test value is compound test value, and " AVE CELL only wells " is every hole average cell number.

Test result shows within the scope of test concentrations, CC of the compound of the present invention to Huh-7₅₀150 μ Μ are all larger than, Illustrate the compound of the present invention to the toxicity very little of liver cell.The results are shown in Table 3.

Table 3: cytotoxicity of the series compound to Huh7

As seen from the above table, compound of the embodiment of the present invention is small to the cytotoxicity of liver cell, shows chemical combination of the invention Object has excellent safety, provides extensive selectivity for patent medicine.

3. drug resistance Journal of Sex Research of experimental example

NS5B Primary mutations site is S282T, and the method that this test uses point mutation to transiently transfect tests chemical combination of the present invention Object is mutated the antiviral effect of wild type and mutant strain to verify the compound of the present invention induction HCV 1b replicon high-frequency Whether site is true drug resistance, including wild type WT, NS5B mutant strain S282T.

In the HCV replicon rna of wild type or NS5B mutant, it is thin that Huh7 is transfected into containing synthesis and electroporation in vitro The Renilla luciferase Reporter System of born of the same parents.After electroporation transfection 1 day, test compound is added to culture plate, 5%CO₂Training Culture cell 72 hours of 37 DEG C of case is supported, by detecting the activity of Renilla luciferase, to assess compound to HCV replication activity It influences.Inhibiting rate calculation formula is as follows: %inhibition=100- (Test-AVE HPE)/(AVE ZPE-AVE HPE) * 100。

Percentage importing GraphPad Prism will be inhibited to be further processed and obtain homologous thread and EC₅₀Value.

Compound is directed to S282T antibody-resistant bacterium EC₅₀It is compared with the EC50 for wild-type strain, obtains EC₅₀Increase The multiple added, as drug resistance multiple is the index for measuring phenotypic resistance.To HCV NS5B wild type or S282T mutant strain Suppression result and EC to mutant strain₅₀Migration multiple is shown in table 4-1 and table 4-2.Wherein data 4-1 shows in test concentrations In range, S282T (1b) EC of K31-b and K20-b, K13-b compound₅₀Drug resistance multiple is better than sofosbuvir.Table 4-2 is aobvious Show, EC of K7-b, K31-b, K2-b compound to NS5B wild type₅₀Also superior to sofosbuvir.

The EC of table 4-1:HCV 1b wild type and NS5B S282T₅₀Drug resistance multiple

In addition, the compound of the present invention is to also showing excellent EC50 value with Drug-resistant mutant S282T, it was demonstrated that this The drug resistance that invention compound has had.It is shown in Table 4-2

Table 4-2: EC of the compounds of this invention to S282T mutant strain₅₀

As seen from the above table, wild type (1b) or NS5B S282T type saltatory replication, the compound of the present invention are shown The characteristic of its generation that can prevent virus drug resistance well out, i.e., drug resistance property of the invention are better than sofosbuvir.

Test example 4, pharmacokinetics in rats research

Male SD rat Suo Feibuwei and compound K 2-b, K1-b, K27-b and K20-b are given by single oral gavage respectively, Investigate the metabolic rule of the triphosphoric acid metabolite (K-65) in liver.Dosage is 50mg/kg, and vehicle system is 10%DMSO:10%solutol:80% water.After P of Rats O administration respectively at 2,4,8, put to death for 24 hours, collect blood and hepatic tissue. Hepatic tissue is homogenized with the homogenate of the pre-cooling of 5 times of volumes immediately after taking out, and homogenate is methanol: 20mM EDTA aqueous solution (7:3, V/V)。

30 μ L of hepatic tissue sample is taken, after 100 μ L dilution in acetonitrile, carries out LC-MS/MS analysis, is measured dense in hepatic tissue Degree.20 μ L inner mark solutions are added in liver tissue homogenate's liquid after being centrifuged, and analyze after being uniformly mixed through LC-MS.

The LC-MS/MS method of triphosphoric acid metabolin: mass spectrum API4500 is analyzed, liquid phase is Shimadzu LC-20AD system System.Chromatographic column is Waters X-BridgeAmide (2.1*150mm, 3.5 μm)；Mobile phase A be mutually 20mM ammonium acetate solution+ 0.1% ammonium hydroxide, B phase is acetonitrile :+0.1% ammonium hydroxide of H2O (100:5, V/V)+10mM ammonium acetate.Flow velocity is 0.45mL/min, column temperature It is 40 DEG C, 20 μ L of sampling volume.Use ion source for the source ESI negative ion mode, scanning mode is that multiple reaction monitors (MRM).

The P of Rats K result of study of K2-b, K1-b, K27-b, K20-b are shown in table 5.

Table 5: the concentration mensuration result of rat liver triphosphoric acid metabolin and parent nucleus

As shown in Table 5, the compound of the present invention can be smoothly metabolized in rat body, and generate three active phosphorus Sour nucleoside metabolism substance K-65, is efficiently used by body and generates corresponding active function.

Note: nucleoside triphosphate metabolite K-65 is

Experimental example 5.hERG detection

Using fluorescence polarization method, assesses compound and QT interval prolongation is potentially caused to act on.It is sequentially added in porous plate Compound/positive reference substance/negative controls, the membrane-bound fragment containing the channel hERG have high affinity with the channel hERG Tracer, 25 DEG C, 250rpm is incubated for 4 hours.The fluorescence polarization value in each hole is measured with multi-function microplate reader, calculates compound pair The relative inhibition in the channel hERG and 50% inhibition concentration (IC₅₀).In the case where E-4031 is as positive control, if 30.0 μM Test sample to the relative inhibition of hERG less than 50%, then IC of the test sample to the channel hERG₅₀Greater than 30.0 μM.Test result It is shown in Table 6.

The external hERG suppression result of table 6

Test result shows that inhibiting rate of the compound of the present invention under 30 μM of concentration is respectively less than 50%, illustrates IC₅₀It is big In 30 μM, thus prove that the compound of the present invention does not generate hERG toxicity, has excellent safety.

Preparation example

Preparation example 1

The tablet of the compounds of this invention, the ingredient including following weight proportion:

Preparation step:

1) dry granulation part:

Dry granulation partial material mixes after the rotation pelletizing machine sieving of Φ 2.0mm sieve.

Charging rate is 70rmp, roller pressure 40bar, roller speed 5rpm, roller gap 2.0mm.By dry granulation plus Enter, roll-in slabbing, strip or block.After cutter are smashed, thick 2.0 sieve of mistake, after 0.63 sieve, formation Grain.

2) Extra Section:

Microcrystalline cellulose, croscarmellose sodium, the superfine silica gel powder of particle and Extra Section that step 1) is obtained Addition is mixed into total mix bucket.Later, magnesium stearate is added, remixes, obtains mixed particle.

3) high speed tabletting

Mixed particle carries out high speed tabletting, range of the control weight in 1050.0mg ± 3.0% on tablet press machine.

4) it is coated

Coating powder containing ethyl cellulose and hydroxypropyl methylcellulose (1:4) is made into consolidating for 8% (w/w) with 95% ethyl alcohol Content.Piece obtained in step 3) is coated in coating pan, 28-38 DEG C of coating tablet bed tempertaure.Coating weight gain range exists 1%-3%.

Preparation example 2

Embodiment k1-b 40g

Lauryl sodium sulfate 5.6g

Amylum pregelatinisatum 135g

Preparation method:

1) it is stirred evenly after mixing embodiment x compound with lauryl sodium sulfate, obtains pulverulent solids；

2) the resulting powder of step 1) is uniformly mixed with amylum pregelatinisatum, direct tablet compressing obtains tablet

Preparation example 3

Preparation method:

2) the resulting powder of step 1) after mixing by mannitol and povidone ratio by weight, is added thereto, mixes It closes uniformly, obtains pulverulent solids, direct tablet compressing obtains tablet.

Industrial applicability

The present invention provides a kind of novel nucleoside phosphoramidite class compound, can smoothly be metabolized in vivo, generation has Active nucleoside triphosphate metabolite wants excellent for the drug effect peso Fei Buwei of hepatitis.Also, the compounds of this invention is resistance to Pharmacological property is better than Suo Feibuwei.Therefore, novel nucleoside phosphoramidite class compound of the invention can be used for treating hepatitis.

Claims

1. compound or its pharmaceutically acceptable salt, the compound are selected from:

(2) (S)-isopropyl -2- (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (benzofuran -6- oxygroup) phosphoryl) amino) propionic ester；

(6) (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- is fluoro- for (S)-isopropyl 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- phenoxy-phenoxy) phosphoryl) amino) propionic ester；

(7) (S) -4- luorobenzyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphoryl) ammonia Base) propionic ester；

(10) (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (benzo [d] [1,3] dioxolanes -5- base)-phenoxy group) phosphorus Acyl group) amino) propionic ester；

(11) (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (the fluoro- phenoxy group of the chloro- 3- of 4-)-phenoxy group) phosphoryl) ammonia Base) propionic ester；

(13) (S)-isopropyl -2- (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- methyl -2H- benzo [b] [1,4] morpholine -7- oxygroup) phosphorus Acyl group) amino) propionic ester；

(19) (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (2,3- coumaran -6- base) phenoxy group) phosphoryl) Amino) propionic ester；

(20) (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- methyl -2H- benzo [b] [1,4] morpholine -8- oxygroup) phosphinylidyne Base) amino) propionic ester；

(23) (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (the fluoro- 2,3- coumaran -4- base of 7-) phenoxy group) phosphorus Acyl group) amino) propionic ester；

(24) (S) -4- luorobenzyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (benzofuran -6- oxygroup) phosphoryl) amino) propionic ester；

(25) (S)-(2,3- coumaran -5- benzyl) (((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro Pyrimidine -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzofuran -6- oxygroup) phosphinylidyne Base) amino) propionic ester；

(27) (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (the fluoro- 2,3- Dihydrobenzofuranes -4- oxygroup of 7-) phosphoryl) ammonia Base) propionic ester；

(29) ((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- is fluoro- for (S)-isopropyl 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (2,3- dihydrobenzo [1,4] dioxane -6- base) phenoxy group) Phosphoryl) amino) propionic ester；

(30) (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (4- fluorophenoxy) phenoxy group) phosphoryl) amino) propionic acid Ester；

(32) (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (4- chlorophenoxy) phenoxy group) phosphoryl) amino) propionic acid Ester；

(35) (S)-isopropyl (((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (7- Fluorobenzofur -4- oxygroup) phosphoryl) amino) propionic ester；

(40) (S)-benzo [1,3] dioxolanes benzyl -2- (((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro Pyrimidine -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo tetrahydrofuran -6- oxygroup) phosphorus Acyl group) amino) propionic ester；With

(41) (S)-benzo [1,3] dioxolanes benzyl -2- (((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro Pyrimidine -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- Dihydrobenzofuranes -6- oxygen Base) phosphoryl) amino) propionic ester.

2. compound or its pharmaceutically acceptable salt, the compound are selected from:

(1) (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- Dihydrobenzofuranes -6- oxygroup) phosphoryl) ammonia Base) propionic ester；

(2) (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzofuran -6- oxygroup) phosphoryl) amino) propionic acid Ester；

(6) (S)-isopropyl ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- phenoxy-phenoxy) phosphoryl) amino) propionic ester, (S)-isopropyl ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- of -4- Hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- phenoxy-phenoxy) phosphoryl) amino) propionic ester；

(7) (S) -4- luorobenzyl ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) phosphinylidyne Base) amino) propionic ester, (S) -4- luorobenzyl ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidins -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo [d] [1,3] dioxolanes -5- oxygroup) Phosphoryl) amino) propionic ester；

(13) (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -2H- benzo [b] [1,4] morpholine -7- oxygen Base) phosphoryl) amino) propionic ester, (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- bis- Hydrogen pyrimidine -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -2H- benzo [b] [1, 4] morpholine -7- oxygroup) phosphoryl) amino) propionic ester；

(20) (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -2H- benzo [b] [1,4] morpholine -8- oxygen Base) phosphoryl) amino) propionic ester, (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- bis- Hydrogen pyrimidine -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- methyl -2H- benzo [b] [1, 4] morpholine -8- oxygroup) phosphoryl) amino) propionic ester；

(25) (S)-(2,3- coumaran -5- benzyl) ((S)-((((2R, 3R, 4R, 5R) -5- (dicarbapentaborane -3 2,4-, 4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzofuran -6- oxygroup) Phosphoryl) amino) propionic ester；

(27) (S)-isopropyl -2- ((S)-(((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (the fluoro- 2,3- Dihydrobenzofuranes -4- oxygroup of 7-) phosphinylidyne Base) amino) propionic ester, (S)-isopropyl -2- ((R)-(((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidins -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (the fluoro- 2,3- Dihydrobenzofuranes -4- oxygen of 7- Base) phosphoryl) amino) propionic ester；

(29) (S)-isopropyl -2- ((S)-(((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (2,3- dihydrobenzo [1,4] dioxane -6- Base) phenoxy group) phosphoryl) amino) propionic ester, (S)-isopropyl -2- ((R)-(((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane - 3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (2,3- dihydrobenzene And [1,4] dioxane -6- base) phenoxy group) phosphoryl) amino) propionic ester；

(30) (S)-isopropyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidin -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (4- fluorophenoxy) phenoxy group) phosphoryl) amino) Propionic ester, (S)-isopropyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- dihydro-pyrimidins -1 (2H) - Base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (4- (4- fluorophenoxy) phenoxy group) phosphoryl) amino) Propionic ester；

(32) (S)-isopropyl ((S)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) - The fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of 4-) methoxyl group) (4- (4- chlorophenoxy) phenoxy group) phosphoryl) amino) propionic acid Ester, ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) -4- is fluoro- for (S)-isopropyl 3- hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (4- (4- chlorophenoxy) phenoxy group) phosphoryl) amino) propionic ester；

(40) (S)-benzo [1,3] dioxolanes benzyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- Dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo tetrahydrofuran -6- oxygen Base) phosphoryl) amino) propionic ester, (S)-benzo [1,3] dioxolanes benzyl -2- ((R)-((((2R, 3R, 4R, 5R) -5- (2, - 1 (2H)-yl of 4- dicarbapentaborane -3,4- dihydro-pyrimidin) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (benzo Tetrahydrofuran -6- oxygroup) phosphoryl) amino) propionic ester；

(41) (S)-benzo [1,3] dioxolanes benzyl -2- ((S)-((((2R, 3R, 4R, 5R) -5- (2,4- dicarbapentaborane -3,4- Dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- Dihydrobenzofuranes - 6- oxygroup) phosphoryl) amino) propionic ester, (S)-benzo [1,3] dioxolanes benzyl -2- ((R)-((((2R, 3R, 4R, 5R) - 5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methoxyl group) (2,3- Dihydrobenzofuranes -6- oxygroup) phosphoryl) amino) propionic ester；With

(60) 2- ((R)-((((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidin) fluoro- 3- of -4- Hydroxy-4-methyl tetrahydrofuran -2- base) methoxyl group) (phenoxy group) phosphoryl) amino) ethyl acetate.

3. pharmaceutical composition, containing compound according to any one of claims 1 to 2 or its pharmaceutically acceptable salt, with And pharmaceutically acceptable auxiliary material.

4. pharmaceutical composition according to claim 3, wherein further include with described in any one of claim 1~2 Compound or its pharmaceutically acceptable salt associated with other active constituents.

5. pharmaceutical composition according to claim 4, wherein other active constituents associated with described be selected from interferon, Virazole, HCV NS3 protease inhibitors, 1 inhibitor of alpha-Glucosidase, hepatoprotective, HCV NS5B polymerase non-nucleosides Inhibitor, HCV NS5A inhibitor, TLR-7 agonist, cyclophilin inhibitor, HCV IRES inhibitor, pharmacokinetics enhancing Agent and other medicines or therapeutic agent for treating HCV, or combinations thereof.

6. the described in any item compositions of claim 3-5, wherein the composition contains any one of claim 1-2 describedization The amount for closing object or its pharmaceutically acceptable salt is 0.1-1000mg.

7. -2 described in any item compounds or its pharmaceutically acceptable salt are being prepared for treating hepatitis according to claim 1 Application in drug.

8. preparing the application in the drug for treating hepatitis according to any one of the claim 3-6 composition.