CN107556324A

CN107556324A - Deuterated anti-hepatitis C virus reactive compound

Info

Publication number: CN107556324A
Application number: CN201610493475.8A
Authority: CN
Inventors: 王建明
Original assignee: BEIJING MEIBEITA PHARMACEUTICAL RESEARCH Co Ltd
Current assignee: BEIJING MEIBEITA PHARMACEUTICAL RESEARCH Co Ltd
Priority date: 2016-06-30
Filing date: 2016-06-30
Publication date: 2018-01-09

Abstract

The present invention relates to the anti-hepatitis C virus compound representated by Formulas I with good biological availability and its atoxic pharmaceutically acceptable salt, such compound to have potent inhibitory action to the HCV of all genotype.In structural formula I, R1, R2, R3 and R4 are each independently selected from methyl (CH₃) or deuterated methyl (CD₃)；X₁、X₂、X₃、X₄And X₅Respectively hydrogen (H) or deuterium (D)；It is deuterated methyl (CD that must have one in R1, R2, R3 and R4₃) or X₁、X₂、X₃、X₄And X₅In must to have one be deuterium (D).

Description

Deuterated anti-hepatitis C virus reactive compound

Technical field

The present invention relates to the deuterated anti-hepatitis C virus compound with good biological availability and its atoxic pharmacy Upper acceptable salt, such compound have potent inhibitory action to the HCV of all genotype.

Background technology

Viral hepatitis type C is the major disease for endangering human health, clinical existing anti-HCV medicament such as Suo Feibuwei etc. Administration must be merged with Ribavirin；But Ribavirin has serious hematotoxicity.Therefore, the more efficient safety of urgent clinical needs Anti-HCV medicament.

The present inventor has found that the deuterated compound shown in Formulas I has potent to the HCV of all genotype by numerous studies Inhibitory action, and the oral administration of such compound has good bioavilability；Unexpectedly, inventor has found deuterated mesh Compound and non-deuterated compound phase ratio are marked, the individual difference of pharmacokinetics is smaller；More unexpectedly, inventor has found deuterated Target compound and non-deuterated compound phase ratio, hepatotoxicity are smaller.

In structural formula I, R1, R2, R3 and R4 are each independently selected from methyl (- CH₃) or deuterated methyl (- CD₃)；X₁、X₂、 X₃、X₄And X₅Respectively hydrogen (H) or deuterium (D)；It is deuterated methyl (- CD that must have one in R1, R2, R3 and R4₃) or X₁、X₂、X₃、 X₄And X₅In must to have one be deuterium (D).

Therefore, the present invention provides the compound and its non-toxic pharmaceutically acceptable salt shown in Formulas I.

Therefore, compound and its non-toxic pharmaceutically acceptable salt of the present invention also shown in offer Formulas I are preparing treatment The purposes of viral hepatitis type C medicine.

Another aspect of the present invention provide containing compound shown in Formulas I and its non-toxic pharmaceutically acceptable salt as activity into Point and pharmaceutical excipient pharmaceutical composition；These pharmaceutical compositions can be various types of tablets, such as fast-release tablet, sustained release Piece, controlled release tablet, Film coated tablets, sugar coated tablet, buccal tablet, sublingual tablet, etc.；Capsule such as hard capsule, soft capsule etc..

Embodiment

Following embodiments are used to be explained in detail in the present invention, but the scope of the present invention is not limited to following embodiments.

The preparation of reference implementation example 1 (2S, 5S) -1- (t-butoxy carbonyl) -5- methylpyrrolidin- 2- carboxylic acids (II)

The first step：By 40g (155mmol) (S)-N- (tertiary butyl oxycarbonyl) -5- oxygen-pyrrolidines -2- Ethyl formates (ii- 1) add in the anhydrous THF of 300ml, lead to argon gas, be cooled to -40 DEG C.Under stirring, the diethyl ether solution of 58ml methyl-magnesium bromide is added dropwise (3.0M, 174mmol), added in 30 minutes.Reaction solution is stirred into 4hr at -40 DEG C, then stirs 1hr at 0 DEG C.It will react molten Liquid evaporated under reduced pressure, 250ml ethyl acetate and 250ml saturated ammonium chlorides are separately added into, are acidified with 1N HCl.Organic layer is separated, is used Ethyl acetate (2X100ml) aqueous phase extracted, merge organic phase, stayed overnight with anhydrous sodium sulfate drying.Solid is filtered off, by filtrate decompression It is evaporated, is separated with silica gel column chromatography, with ethyl acetate: petroleum ether (2: 8) mixed solvent elutes, component needed for collection, decompression is steamed It is dry, obtain the liquid of thick (S) -2- (t-butoxy carbonylamino) -5- oxy hexanoic acids ethyl esters (ii-2).

Second step：The ii-2 that upper step reacts to obtain is added into 200ml trifluoroacetic acid/dichloromethanes solution (1: 1 mixture), It is stirred at room temperature 4 hours.Evaporated under reduced pressure, obtain (the S) -5- methyl 3 of oily, 4- dihydro-2 h-pyrrole -2- Ethyl formates (ii-3)。

3rd step：In ii-3 made from the reaction of upper step, 600ml ethanol is added, makes dissolving, vacuumizes, led to argon gas and remove Residual air, the palladium carbon (10%w/w) that 1.5g is dried is added, lead to hydrogen (3X).Then reactant mixture is stirred under hydrogen 16 hours.Filtering, filtrate decompression is evaporated.Triturated under ether is added, filtering, obtains (2S, 5S) -5- methylpyrrolidin- 2- formic acid The white solid 17.2g of ethyl ester (ii-4).Proton nmr spectra δ (ppm, CD₃Cl, 400MHz)：4.48 (dd, 1H), 4.27 (q, 2H), 3.92-3.80 (m, 1H), 2.52-2.36 (m, 1H), 2.32-2.13 (m, 2H), 1.75-1.60 (m, 1H), 1.51 (d, 3H), 1.30 (t, 3H).

4th step：In 250ml dichloromethane, 14.0g (89mmol) ii-4, stirring and dissolving are added；Add successively under stirring Enter 22g di-tert-butyl dicarbonic acid esters ((CH₃)₃C-O-CO)₂O, 0.1mol), 35ml diisopropylethylamine (DIPEA, 0.2mol), 0.5g dimethyl aminopyridines.Reactant mixture is stirred at room temperature 16 hours.500ml 1N HCl is added, is sufficiently mixed. Organic layer is separated, is stayed overnight with anhydrous sodium sulfate drying.Solid is filtered off, filtrate decompression is evaporated, separated with silica gel column chromatography, uses second Acetoacetic ester: the elution of petroleum ether (1: 9) mixed solvent, component needed for collection, evaporated under reduced pressure, obtain (2S, the 5S) of 12.3g oilies- N- t-butyloxycarbonyl -5- methyi-pyrrofidinium -2- carboxylic acid, ethyl esters (ii-5).Proton nmr spectra δ (ppm, CD₃Cl, 400MHz)：4.50 (dd, 1H), 4.28 (q, 2H), 3.93-3.81 (m, 1H), 2.55-2.38 (m, 1H), 2.33-2.10 (m, 2H), 1.78-1.61 (m, 1H), 1.52 (d, 3H), 1.49 (s, 9H), 1.32 (t, 3H).

5th step：In 12g ii-5 made from upper step, 30ml ethanol is added, stirring and dissolving, adds 2g lithium hydroxide lists Hydrate and 12ml deionized waters.Stir the mixture for 16 hours, add 100ml saturated nacl aqueous solutions, be acidified with 1N hydrochloric acid； Then the extraction of 100ml ethyl acetate is added；Water layer is separated, is extracted again once with 50ml ethyl acetate.Combined ethyl acetate extracts Liquid, stayed overnight with anhydrous sodium sulfate drying.Solid is filtered off, filtrate decompression is evaporated, obtains II white solid 9.1g.Nuclear magnetic resonance Hydrogen spectrum δ (ppm, CD₃Cl, 400MHz)：4.47 (dd, 1H), 3.90-3.78 (m, 1H), 2.51-2.35 (m, 1H), 2.31-2.12 (m, 2H), 1.74-1.60 (m, 1H), 1.50 (d, 3H), 1.45 (s, 9H).

Reference implementation example 2 (2S, 4S)-N- (t-butoxy carbonyl) -2- (the iodo- 1H- imidazoles -2- bases of 5-) -4- methoxy methyls The preparation of base-pyrrolidines (III)

The first step：18g (71mmol) (2S, 4S)-N- (t-butoxy carbonyl) -4- cyano group pyrroles are added in 300ml methanol Cough up alkane -2- methyl formates (iii-1), stirring and dissolving.200ml 4M HCl dioxane solution is added, stirs 16h at room temperature, Evaporated under reduced pressure.200ml water is added, after being alkalized with sodium acid carbonate, is extracted (2X200ml) with dichloromethane, merges extract solution, with nothing Aqueous sodium persulfate is dried overnight, and is filtered off solid, is obtained the dichloromethane of (2S, 4S)-pyrrolidines -2,4- dicarboxylic acid methyl ester (iii-2) Solution.

Second step：17g (78mmol) di-tert-butyl dicarbonic acid ester is added portionwise in iii-2 dichloromethane solution, 30ml diisopropylethylamine, 0.4g dimethyl aminopyridines.Reactant mixture is stirred at room temperature 16 hours.Add 400ml 1N HCl, is sufficiently mixed.Organic layer is separated, is stayed overnight with anhydrous sodium sulfate drying.Solid is filtered off, filtrate decompression is evaporated, uses silicon Plastic column chromatography separates, with ethyl acetate: petroleum ether (2: 8) mixed solvent elutes, component needed for collection, evaporated under reduced pressure, obtain (2S, 4S)-N- (tert-butyl Epoxide carbonyl) -38.3 grams of pyrrolidines -2,4- dicarboxylic acid methyl ester (iii-3).

3rd step：In 150ml tetrahydrofurans, 18 grams of (65.4mmol) iii-3, ice bath stirring, in 15 minutes are added 1N NaOH solutions 64.4ml is added dropwise.5h is stirred at 0 DEG C, is then acidified with 1N HCl.It is extracted with ethyl acetate (2X100ml)； Combined ethyl acetate extract, is stayed overnight with anhydrous sodium sulfate drying.Solid is filtered off, filtrate decompression is evaporated, uses silica gel column chromatography Separation, with methanol: dichloromethane (5: 100) mixed solvent elutes, and component needed for collection, evaporated under reduced pressure, obtains (3S, 5S)-N- (t-butoxy carbonyl) -5- (methoxycarbonyl)-pyrrolidines -3- formic acid (iii-4) 13.0g.

4th step：13.0g (48mmol) iii-4 is taken, 200ml tetrahydrofurans is added, ice bath stirring, adds 10ml triethylamines With 5.5ml ethyl chloroformates.45min is stirred at 0 DEG C.Solid is filtered off, filtrate decompression is evaporated, it is molten to add 50ml tetrahydrofurans Solution, 50ml water is added, ice bath stirring, 9g NaBH are added portionwise₄, 2h is stirred at 0 DEG C.The extraction of 200ml ethyl acetate is added, will Extract is stayed overnight with anhydrous sodium sulfate drying.Solid is filtered off, filtrate decompression is evaporated, separated with silica gel column chromatography, with acetic acid second Ester: the elution of dichloromethane (5: 5) mixed solvent, component needed for collection, evaporated under reduced pressure, (2S, 4S)-N- (tert-butyl epoxides are obtained Carbonyl) -4- (methylol)-pyrrolidines -2- methyl formates (iii-5) 7.4g.

5th step：Iii-5 5.2g are taken, add 100ml dichloromethane, stirring and dissolving；Add 8.2g AgOTf and 8.8ml 2,6- di-tert-butyl-pyridiniums.Reactant mixture is cooled to 0 DEG C, is slowly added to 2ml iodomethane.1.5h is stirred at 0 DEG C, then 1.5h is stirred at room temperature.Add 100ml dichloromethane, filtering.Concentrate the filtrate to dry, with 200ml ether dissolutions, use successively 1NHCl and saturated brine washing.Organic phase is stayed overnight with anhydrous sodium sulfate drying.Solid is filtered off, filtrate decompression is evaporated, uses silicon Plastic column chromatography separates, with ethyl acetate: dichloromethane (5: 5) mixed solvent elutes, and component needed for collection, evaporated under reduced pressure, obtains (2S, 4S)-N- (tert-butyl Epoxide carbonyl) -4- (methoxy)-pyrrolidines -2- methyl formates (iii-6) 3.9g.Nuclear-magnetism Resonate hydrogen spectrum δ (ppm, CD₃Cl, 400MHz)：4.22 (t, 1H), 3.73 (s, 3H), 3.68 (m, 1H), 3.35 (m, 2H), 3.31 (s, 3H), 3.19 (t, 1H), 2.45 (m, 2H), 1.76 (m, 1H), 1.39 (s, 9H).

6th step：In 3.9g iii-6 made from the reaction of upper step, 75ml tetrahydrofurans and 30ml methanol are added, stirring is molten Solution, the 30ml 2.5M LiOH aqueous solution is added, stirs 2h at room temperature.It is acidified with 1N HCl.Use CH₂Cl₂(3x100ml) is extracted.Close And organic phase, stayed overnight with anhydrous sodium sulfate drying.Solid is filtered off, filtrate decompression is evaporated, obtains (2S, 4S)-N- (tert-butyl oxygen Base carbonyl) -4- (methoxy)-pyrrolidines -2- formic acid (iii-7) 3.7g.Proton nmr spectra δ (ppm, CD₃Cl, 400MHz)：4.32 (t, 1H), 3.63 (m, 1H), 3.34 (m, 2H), 3.30 (s, 3H), 3.15 (t, 1H), 2.44 (m, 2H), 2.11 (m, 1H), 1.43 (s, 9H).

7th step：6.7 grams of (25.8mmol) iii-7 are added on 100ml tetrahydrofurans, is stirred to dissolve, is added dropwise under ice bath 3.4ml1.0M (34mmol) borane dimethylsulfide ethereal solution.Stir at 0 DEG C 4 hours, then stir 18 hours at room temperature.Then will Mixture is cooled to 0 DEG C, and 70ml methanol is added dropwise.Stirring, is gradually warmed to room temperature.Evaporated under reduced pressure, 200ml dichloromethane is added, with full Washed with sodium acid carbonate.Organic layer is stayed overnight with anhydrous sodium sulfate drying, evaporated under reduced pressure, obtains (2S, 4S)-N- (tert-butyl epoxides Carbonyl) -2- hydroxymethyls -4- (methoxy)-pyrrolidines (iii-8) 6.1g.

8th step：5.88g made from step (23.9mmol) iii-8 is taken, 100ml dichloromethane is added, is stirred to dissolve, Sequentially add 0.075g TEMPO (0.48mmol), 0.25g sodium bromides (2.4mmol) and 0.44 sodium acid carbonate (5.3mmol).Add Enter to contain the aqueous solution (6% of 2.67g (35.9mmol) sodium hypochlorite.At room temperature, reactant mixture is stirred vigorously 2 hours.With two Chloromethanes is extracted twice (2x100ml).Organic layer is merged, and washed with saturated sodium thiosulfate solution.Organic layer is with anhydrous Sodium sulphate is dried overnight, evaporated under reduced pressure, obtains (2S, 4S)-N- (tert-butyl Epoxide carbonyl) -2- formoxyl -4- (methoxy methyls Base)-pyrrolidines (iii-9) 4.0g.

9th step：3.9g iii-9 made from step are taken, add 15ml methanol and 15ml ammonium hydroxide (99.9%), stirring Make dissolving, 12ml 40% (w/v) glyoxal water solution is added dropwise.At room temperature, vigorous stirring overnight.Decompression boils off solvent, will be surplus During excess is dissolved with 100ml ethyl acetate, washed successively with water and saturated brine.By organic layer anhydrous sodium sulfate drying mistake At night, solid is filtered off, filtrate decompression is evaporated, separated with silica gel column chromatography, is eluted with ethyl acetate, component needed for collection, decompression It is evaporated, obtains (2S, 4S)-N- (tert-butyl Epoxide carbonyl) -2- (1H- imidazoles -2- bases) -4- (methoxy)-pyrrolidines (iii-10)3.5g.Mass spectrum (LCMS-ESI⁺)：Calculated value：251.16(M⁺), measured value：252.19(M+H⁺)。

Tenth step：3.47g (13.8mmol) iii-9 is added into 70ml dioxane, is stirred to dissolve, adds 45ml water. Under stirring, 7.7g iodine (30.4mmol) and 4.54g sodium carbonate (42.8mmol) are sequentially added.Lucifuge, vigorous stirring overnight.Add 100ml ethyl acetate and the hypo solutions of 100ml 10%, mix, extraction, separate organic layer.Water layer uses 50ml acetic acid again Ethyl ester extracts 1 time.Merge organic layer, stayed overnight with anhydrous sodium sulfate drying, filter off solid, filtrate decompression is evaporated, uses silicagel column Chromatography, with ethyl acetate: petroleum ether (1: 5) mixed solvent elutes, component needed for collection, evaporated under reduced pressure, obtain (2S, 4S)-N- (tert-butyl Epoxide carbonyl) -2- (4,5- bis- iodo- 1H- imidazoles -2- bases) -4- (methoxy)-pyrrolidines (iii- 11)4.3g.Mass spectrum (LCMS-ESI⁺)：Calculated value：502.96(M⁺), measured value：503.95(M+H⁺)。

11st step：By 4.28g (8.50mmol) iii-11,75ml ethanol is added, is stirred to dissolve.75ml water is added, Stirring is lower to add 10.72g sodium thiosulfate (85.1mmol), and 100 DEG C are stirred vigorously 1 hour；Then stirred 16 hours in 90 DEG C, Stirred 5 hours then at 100 DEG C.100ml ethyl acetate and 100ml water are fallen into, extracts, separates organic layer；Aqueous layer with ethyl acetate Extraction once, merges organic layer.Stayed overnight with anhydrous sodium sulfate drying, filter off solid, filtrate decompression is evaporated, uses silica gel column chromatography Separation, with ethyl acetate: petroleum ether (1: 5) mixed solvent elutes, and component needed for collection, evaporated under reduced pressure, obtains III2.0g.Core Magnetic resonance hydrogen spectrum δ (ppm, CD₃Cl, 400MHz)：7.02 (s, 1H) 4.31 (t, 1H), 3.63 (m, 1H), 3.32 (m, 2H), 3.30 (s, 3H), 3.14 (t, 1H), 2.90 (s, 1H), 2.46 (m, 2H), 2.11 (m, 1H), 1.43 (s, 9H).

The system of chloro- 10,11- dihydros -5H- dibenzo [c, g] chromene -8 (9H) -one (IV) of the bromo- 3- of the 9- of reference implementation example 3 It is standby

The first step：In 850ml dimethylformamides, sequentially add the bromo- 2- of 25.6g (90.0mmol) 1- (bromomethyl)- 4- chlorobenzenes (iv-1) and 13.9g (85.7mmol) 7- hydroxyls-ALPHA-tetralone () iv-2, are stirred to dissolve；Stirring is lower to add 24g (172mmol) potassium carbonate.Logical argon gas, is stirred 18 hours.1L ethyl acetate is added, (3X300ml) 3 is washed with water in organic matter It is secondary, then washed once with salt solution 300ml.Organic layer is dried overnight with magnesium sulfate, is filtered off solid, evaporated under reduced pressure, is added methanol 500ml, stir 1 hour, filter, dry, obtain 7- (the bromo- 5- benzyl chlorides epoxides of 2-) -3,4- dihydronaphthalene -1 (2H) -one (iv-3) 28g.

Second step：27.8g (76.2mmol) iv-3 is added into 380ml dimethyl acetamides, is stirred to dissolve；Sequentially add 1.18g (3.8mmol) pivalic acid palladiums (II), 1.20g (3.8mmol) three (4- fluorophenyls) hydrogen phosphide, 2.33g (22.8mmol) are special Valeric acid and 31.8g (228mmol) potassium carbonate, are vacuumized, backfilled with argon 5 times；Under argon gas, stirred 24 hours in 60 DEG C.Will be anti- Room temperature should be cooled to, adds tertiary butyl methyl ether and water, is stirred 3 hours, and is filtered by diatomite, with tertiary butyl methyl ether Rinse.Organic layer is separated, is washed twice with water, then washed once with salt solution.Organic layer is dried overnight with magnesium sulfate, is filtered off solid Body, filtrate decompression is evaporated, separated with silica gel column chromatography, with dichloromethane: petroleum ether (5: 5) mixed solvent elutes, collect institute Component is needed, evaporated under reduced pressure, obtains chloro- 10,11- dihydros -5H- dibenzo [c, g] chromene -8 (9H) -one (iv-4) 14.9g of 3-.

3rd step：By 14.8g (52mmol) iv-4,50ml chloroforms and 50ml ethyl acetate are added, is stirred to dissolve；Add 24.3g (104mmol) copper bromide (II), is heated with stirring to 80 DEG C, continues stirring 2 hours, is subsequently cooled to room temperature.Add dichloro Methane, successively with saturated ammonium chloride, 38% ammonium hydroxide liquid and water washing.Organic layer is dried overnight with magnesium sulfate, is filtered off solid Body, filtrate decompression is evaporated, separated with silica gel column chromatography, with dichloromethane: petroleum ether (5: 5) mixed solvent elutes, collect institute Component is needed, evaporated under reduced pressure, obtains IV18.2g.¹H-NMR：400MHz, (CDCl₃)δ：8.00-7.98 (m, 1H), 7.87 (d, 1H), 7.85 (s, 1H), 7.73 (s, 1H), 7.69 (s, 1H), 4.72 (dd, 1H), 3.36-3.30 (m, 1H), 2.97-2.90 (m, 1H), 2.58-2.44 (m, 2H).

The methyl of reference implementation example 4 { (2S) -1- [(2S, 5S) -2- (heterochromatic alkene [4 ', 3 ' of chloro- 1, the 11- dihydros of 9-：6,7] naphthalene And [1,2-d] imidazoles -2- bases) -5- methylpyrrolidin- 1- yls] -3- methyl isophthalic acids-oxygen butane -2- bases carbamate (V) system It is standby

The first step：By 4.2g (11.6mmol) IV, 60ml acetonitriles are added, is stirred to dissolve, sequentially adds 2.94g (12.8mmol) II and 4.5ml (25.6mmol) DIPEA.50 DEG C of stirring 18h, add ethyl acetate, successively with 1N HCl, saturation NaHCO₃With salt water washing.By organic phase anhydrous Na₂SO₄It is dried overnight, filters, be concentrated under reduced pressure；Separated with silica gel column chromatography, With ethyl acetate: petroleum ether (2: 8) mixed solvent elutes, and component needed for collection, evaporated under reduced pressure, obtains (2S, 5S)-N- (tert-butyls Epoxide carbonyl) -2- (the chloro- 8- oxygen -8,9 of 3-, 10,11- tetrahydrochysene -5H- dibenzo [c, g] chromene -9- bases) -5- methylpyrrolidin- 2- carboxylates (v-1) 5.6g.

Second step：4.9g (9.5mmol) v-1 is added into 80ml toluene, stir it is lower add 9ml 2-methyl cellosolves and 1.8g ammonium acetates, it is heated to reflux 12 hours.Room temperature is cooled to, ethyl acetate is added, successively with water, saturation NaHCO₃Washed with salt Wash.By organic phase anhydrous Na₂SO₄It is dried overnight, filters, be concentrated under reduced pressure；Separated with silica gel column chromatography, with ethyl acetate: oil Ether (5: 5) mixed solvent elutes, and component needed for collection, evaporated under reduced pressure, obtains (2S, 5S)-N- (tert-butyl Epoxide carbonyl) -2- (9- Chloro- 4,5- dihydros -5H- naphtho-s [c, g] chromene [8,9-d] imidazoles -2- bases) -5- crassitudes (v-2) 3.7g.

3rd step：3.4gv-2 is added into 70ml CH₂Cl₂, it is stirred to dissolve；Add 20gMnO₂, it is stirred overnight, passes through silicon Diatomaceous earth filters, and uses CH₂Cl₂Filter cake is washed with methanol, merging filtrate, evaporated under reduced pressure, obtains (2S, 5S)-N- (tert-butyl epoxide carbonyls Base) -2- (chloro- 5H- naphtho-s [c, g] chromene [8, the 9-d] imidazoles -2- bases of 9-) -5- crassitudes (v-3) 3.1g.

4th step：2.8g v-3 are added to 25ml 1.25N HCl ethanol solution, are heated to 50 DEG C, stirring reaction 3h； Evaporated under reduced pressure, 30ml DMF are added, are stirred to dissolve；Add 1.5g (2.9mmol) (S) -2- (methyloxycarbonylamino) -3- first Base butyric acid, 1.5g HATU, stir lower dropwise addition 1.9ml N-methylmorpholines.Stirring reaction 1h, ethyl acetate is added, successively with full And NaHCO₃, the 5%LiCl aqueous solution and salt water washing.By organic phase anhydrous Na₂SO₄It is dried overnight, filters, be concentrated under reduced pressure；With Silica gel column chromatography separates, with ethyl acetate: petroleum ether (5: 5) mixed solvent elutes, and component needed for collection, evaporated under reduced pressure, obtains V 2.9g.Proton nmr spectra δ (ppm, CD₃OD, 400MHz)：8.25 (s, 1H), 8.20 (s, 1H), 7.90-7.00 (m, 5H), 5.30 (m, 1H), 4.33 (m, 1H), 4.24 (d, 1H), 3.53-3.25 (m, 2H), 3.25 (s, 3H), 2.67 (m, 1H), 2.56 (m, 2H), 1.20-1.93 (m, 1H), 1.58 (d, 3H), 1.06 (d, 3H), 0.99 (d, 3H).

The methyl of reference implementation example 5 { (1R) -2- [(2S, 4S) -2- (5- { 2- [(2S, 4S) -1- { (2S) -2- [(methoxyl group carbonyls Base) amino] -3- methylbutyryls base } -5- methylpyrrolidin- 2- yls] the heterochromatic alkene [4 ', 3 ' of -1,11- dihydros：6,7] naphtho- [1,2- D] imidazoles -9- bases } -1H- imidazoles -2- bases) -4- (methoxymethyl)-pyrrolidin-1-yl] -2- oxygen -1- phenethyls } amino first The preparation of acid esters (I ')

The first step：2.85g V are added into 50ml dioxane, are stirred to dissolve；Then it is double (valeryl) to sequentially add 2.0g Two boron, 1.54g KOAc, 75mg X-Phos and 240mg Pd₂dba₃.Use N₂Solution is deaerated 10min, is then heated to 90 DEG C, Continue 16h.Reaction solution is cooled to room temperature, adds ethyl acetate；Saturation NaHCO is used successively₃, salt water washing；Organic phase is used Anhydrous Na₂SO₄It is dried overnight, filters, be concentrated under reduced pressure；Separated with silica gel column chromatography, with methanol: ethyl acetate: petroleum ether (2: 50: 50) mixed solvent elutes, and component needed for collection, evaporated under reduced pressure, obtains methyl [(2S) -3- methyl isophthalic acids-{ (2S, 5S) -2- methyl -5- [9- (4,4,5,5- tetramethyls -1,3,2- dioxaborinate -2- bases) heterochromatic alkene [4 ', 3 ' of -1,11- dihydros：6,7] naphtho- [1,2- D] imidazoles -2- bases] pyrrolidin-1-yl } -1- oxygen butane -2- bases] carbamate (i-1) 2.2g.

Second step：In 20ml DMSO and 20ml dioxane mixed liquors, 1.25g i-1 and 0.88g III are added, are stirred Mixing makes dissolving；Then 230mg Pd (PPh are sequentially added₃)₄、144mg PdCl₂(dPPf)₂With 3.2ml 2M K₂CO₃Solution.It is logical N₂Reaction solution is deaerated 10min, is heated to 95 DEG C, continues 5h.Reaction solution is cooled to room temperature, adds ethyl acetate；Use successively Saturation NaHCO₃, salt water washing；By organic phase with anhydrous MgSO₄It is dried overnight, filters, be concentrated under reduced pressure；With silica gel column chromatography point From with methanol: ethyl acetate (1: 9) mixed solvent elutes, and component needed for collection, evaporated under reduced pressure, obtains N- (tert-butyl epoxide carbonyls Base)-(2S, 4S) -2- [5- (2- { (2S, 4S) -1- [N- (methoxycarbonyl)-L- valyls base] -5- methylpyrrolidin- 2- Base } the heterochromatic alkene [4 ', 3 ' of -1,11- dihydros：6,7] naphtho- [1,2-d] imidazoles -9- bases) -1H- imidazoles -2- bases] -4- (methoxy methyls Base) pyrrolidines (i-2) 730mg.

3rd step：In the in the mixed solvent of 16ml dichloromethane and 4ml methanol, 660mg i-2 are added, are stirred to dissolve； Then 4ml 4M HCl dioxane solution is added, reactant mixture 2h is stirred into, then evaporated under reduced pressure, obtains (2S, 4S) -2- [(2- { (2S, 4S) -1- [N- (methoxycarbonyl)-L- valyls base] -5- methylpyrrolidin- 2- yls } -1,11- dihydros are heterochromatic by 5- Alkene [4 ', 3 '：6,7] naphtho- [1,2-d] imidazoles -9- bases) -1H- imidazoles -2- bases] -4- (methoxy) pyrrolidines (i-3)；Add Enter 20ml DMF, be stirred to dissolve, then add 170mg (0.21mmol) (R) -2- (methyloxycarbonylamino) -2- phenylacetic acids, 400mg(0.21mmol)COMU；Stirring is lower to be added dropwise 0.7ml (1.05mmol) DIPEA.Stirring reaction 1h, add methanol/acetic acid second Ester (1: 9) mixture, successively with saturation NaHCO₃, salt water washing；By organic phase with anhydrous MgSO₄It is dried overnight, filters, decompression Concentration；Purify to obtain I ' 270mg with HPLC.Proton nmr spectra δ (ppm, CD₃OD, 400MHz)：8.29 (s, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 7.92-7.04 (m, 10H), 5.40 (d, 2H), 5.31 (m, 1H), 5.25 (m, 2H), 4.36 (m, 1H), 4.25 (d, 1H), 3.60 (s, 3H), 3.54-3.26 (m, 5H), 3.37 (s, 3H), 3.25 (s, 3H), 2.67 (m, 1H), 2.58 (m, 2H), 1.99-1.93 (m, 4H), 1.52 (d, 3H), 1.08 (d, 3H), 0.98 (d, 3H).

The preparation of the deuterated methyi-pyrrofidinium -2- carboxylic acids (II ') of embodiment 1 (2S, 5S) -1- (t-butoxy carbonyl) -5-

The method of reference reference implementation example 1,

The first step：With deuterated methyl-magnesium bromide (CD₃- BrMg) diethyl ether solution replace methyl-magnesium bromide ether it is molten Liquid, reacted with (S)-N- (tertiary butyl oxycarbonyl) -5- oxygen-pyrrolidines -2- Ethyl formates (ii-1), it is deuterated to obtain 6- positions carbon atom (S) -2- (t-butoxy carbonylamino) -5- oxy hexanoic acids ethyl ester (ii ' -2).

Second step：Ii-2 is replaced with ii ' -2, is reacted with trifluoroacetic acid, obtains the deuterated methyl 3 of (S) -5-, 4- dihydro -2H- pyrroles Cough up -2- Ethyl formates (ii ' -3).

3rd step：Hydrogenation is carried out instead of ii-3 with ii ' -3, obtains the deuterated methylpyrrolidin- 2- first of (2S, 5S) -5- Acetoacetic ester (ii ' -4).Proton nmr spectra δ (ppm, CD₃Cl, 400MHz)：4.40 (dd, 1H), 4.23 (q, 2H), 3.89- 3.68 (t, 1H), 2.52-2.16 (m, 3H), 1.77-1.62 (m, 1H), 1.25 (t, 3H).

4th step：Ii-4 is replaced with ii ' -4, is reacted with di-tert-butyl dicarbonic acid ester, obtains (2S, 5S)-N- tert-butyl group oxygen Deuterated methyi-pyrrofidinium -2- the carboxylic acid, ethyl esters (ii ' -5) of base carbonyl -5-.Proton nmr spectra δ (ppm, CD₃Cl, 400MHz)： 4.39 (dd, 1H), 4.21 (q, 2H), 3.90-3.80 (t, 1H), 2.55-2.18 (m, 3H), 1.75-1.63 (m, 1H), 1.42 (s, 9H), 1.31 (t, 3H).

5th step：Ii-5 is replaced with ii ' -5, is reacted with lithium hydroxide, obtains II '.Proton nmr spectra δ (ppm, CD₃Cl, 400MHz)：4.40 (dd, 1H), 3.90-3.76 (t, 1H), 2.46-2.15 (m, 3H), 1.72-1.60 (m, 1H), 1.40 (s, 9H).

Embodiment 2 (2S, 4S)-N- (t-butoxy carbonyl) -2- (the iodo- 1H- imidazoles -2- bases of 5-) deuterated methoxyl groups of -4- - The preparation of methyi-pyrrofidinium (III ")

The method of reference reference implementation example 2,

5th step：Iii-5 is under AgOTf and 2, the effect of 6- di-tert -s butyl-pyridinium, with deuterated iodomethane (CD₃I) react. Obtain (2S, 4S)-N- (tert-butyl Epoxide carbonyl) -4- (deuterated methoxymethyl)-pyrrolidines -2- methyl formates (iii " - 6).Proton nmr spectra δ (ppm, CD₃Cl, 400MHz)：4.23 (t, 1H), 3.63 (m, 1H), 3.37 (m, 2H), 3.30 (s, 3H), 3.15 (t, 1H), 2.41 (m, 2H), 1.72 (m, 1H), 1.33 (s, 9H).

6th step：Iii-6 and LiOH is replaced to react (2S, 4S)-N- (tert-butyl Epoxide carbonyl) -4- (deuteriums with iii " -6 For methoxymethyl)-pyrrolidines -2- formic acid (iii " -7).Proton nmr spectra δ (ppm, CD₃Cl, 400MHz)：4.31 (t, 1H), 3.66 (m, 1H), 3.30 (m, 2H), 3.12 (t, 1H), 2.44 (m, 2H), 2.10 (m, 1H), 1.42 (s, 9H).

7th step：Replace iii-7 to be reacted with borane dimethylsulf iotade iii " -7, obtain (2S, 4S)-N- (tert-butyl epoxides Carbonyl) -2- hydroxymethyls -4- (deuterated methoxymethyl)-pyrrolidines (iii " -8).

8th step：Take iii " -8 to replace iii-8, with sodium hypochlorite reaction, obtain (2S, 4S)-N- (tert-butyl epoxide carbonyls Base) -2- formoxyls -4- (deuterated methoxymethyl)-pyrrolidines (iii " -9).

9th step：Take iii " -9 to replace iii-9, with glyoxal reaction, obtain (2S, 4S)-N- (tert-butyl epoxide carbonyls Base) -2- (1H- imidazoles -2- bases) -4- (deuterated methoxymethyl)-pyrrolidines (iii " -10).Mass spectrum (LCMS-ESI⁺) measure Value：253.18(M+H⁺)。

Tenth step：Iii " -10 is replaced into iii-9 and Iod R, obtains (2S, 4S)-N- (tert-butyl Epoxide carbonyl) -2- (4,5- bis- iodo- 1H- imidazoles -2- bases) -4- (deuterated methoxymethyl)-pyrrolidines (iii " -11).Mass spectrum (LCMS-ESI⁺) survey Definite value：506.96(M+H⁺)。

11st step：Replace iii-11 to be reacted with sodium thiosulfate iii " -11, obtain III ".Proton nmr spectra δ (ppm, CD₃Cl, 400MHz)：7.09 (s, 1H), 4.30 (t, 1H), 3.65 (m, 1H), 3.32 (m, 2H), 3.14 (t, 1H), 2.43 (m, 2H), 2.10 (m, 1H), 1.43 (s, 9H).

Embodiment 3 (2S, 4S)-N- (t-butoxy carbonyl) -2- (the iodo- 1H- imidazoles -2- bases of 5-) deuterated methoxyl groups of -4- - The preparation of deuterated methyi-pyrrofidinium (III " ')

The method of reference reference implementation example 2,

4th step：Iii-4 and ethyl chloroformate are reacted, reaction product NaBD₄Hydro-reduction, be made (2S, 4S)- N- (tert-butyl Epoxide carbonyl) -4- (hydroxyl-deuterated methyl)-pyrrolidines -2- methyl formates (iii ' -5).

5th step：Iii ' -5 is under AgOTf and 2, the effect of 6- di-tert -s butyl-pyridinium, with deuterated iodomethane (CD₃I it is) anti- Should.Obtain (2S, 4S)-N- (tert-butyl Epoxide carbonyl) -4- (deuterated methoxyl group-deuterated methyl)-pyrrolidines -2- methyl formates (iii”’-6).Proton nmr spectra δ (ppm, CD₃Cl, 400MHz)：4.20 (t, 1H), 3.75 (s, 3H), 3.62 (m, 1H), 3.14 (t, 1H), 2.43 (m, 2H), 1.76 (m, 1H), 1.39 (s, 9H).

6th step：With iii ", ' -6 replace iii-6 and LiOH to react (2S, 4S)-N- (tert-butyl Epoxide carbonyl) -4- (deuterated methoxyl group-deuterated methyl)-pyrrolidines -2- formic acid (iii " ' -7).Proton nmr spectra δ (ppm, CD₃Cl, 400MHz)： 4.33 (t, 1H), 3.65 (m, 1H), 3.16 (t, 1H), 2.45 (m, 2H), 2.12 (m, 1H), 1.36 (s, 9H).

7th step：Replace iii-7 to be reacted with borane dimethylsulf iotade iii " ' -7, obtain (2S, 4S)-N- (tert-butyl oxygen Base carbonyl) -2- hydroxymethyls -4- (deuterated methoxyl group-deuterated methyl)-pyrrolidines (iii " ' -8).

8th step：Take iii " ' -8 to replace iii-8, with sodium hypochlorite reaction, obtain (2S, 4S)-N- (tert-butyl epoxide carbonyls Base) -2- formoxyls -4- (deuterated methoxyl group-deuterated methyl)-pyrrolidines (iii " ' -9).

9th step：Take iii " ' -9 to replace iii-9, with glyoxal reaction, obtain (2S, 4S)-N- (tert-butyl epoxide carbonyls Base) -2- (1H- imidazoles -2- bases) 4- (deuterated methoxyl group-deuterated methyl)-pyrrolidines (iii " ' -10).Mass spectrum (LCMS-ESI⁺) Measured value：255.18(M+H⁺)。

Tenth step：Iii " ' -10 is replaced into iii-9 and Iod R, obtains (2S, 4S)-N- (tert-butyl Epoxide carbonyl) -2- (4,5- bis- iodo- 1H- imidazoles -2- bases) -4- (deuterated methoxyl group-deuterated methyl)-pyrrolidines (iii " ' -11).Mass spectrum (LCMS- ESI⁺) measured value：508.96(M+H⁺)。

11st step：Replace iii-11 to be reacted with sodium thiosulfate iii " ' -11, obtain III " '.Proton nmr spectra δ (ppm, CD₃Cl, 400MHz)：7.10 (s, 1H), 4.36 (t, 1H), 3.69 (m, 1H), 3.186 (t, 1H), 2.49 (m, 2H), 2.15 (m, 1H), 1.40 (s, 9H).

Chloro- 10,11- dihydros -5H- dibenzo [c, g] chromene -8 (9H) -one of the deuterated bromo- 3- of -9- of embodiment 42,4,5- tri- The preparation of (IV ')

The method of reference reference implementation example 3,

The first step：1- bromo- 2- (bromomethyl) -4- chlorine is replaced with 2,3, the 5- tri- deuterated bromo- 2- of -1- (bromomethyl) -4- chlorobenzenes Benzene reacts with 7- hydroxyls-ALPHA-tetralone, obtains 7- (3,4, the 6- tri- deuterated bromo- 5- benzyl chlorides epoxides of -2-) -3,4- dihydronaphthalene -1 (2H) -one (iv ' -3).

Second step：Iv ' -3 is replaced into iv-3, made in pivalic acid palladium, three (4- fluorophenyls) hydrogen phosphide, pivalic acid and potassium carbonate Under, carry out ring closure reaction, obtain 2,4,5- tri- deuterated chloro- 10,11- dihydros -5H- dibenzo [c, the g] chromenes -8 (9H) of -3- - Ketone (iv ' -4).

3rd step：Iv ' -4 is replaced into iv-4, reacts to obtain IV ' with copper bromide.¹H-NMR：400MHz, (CDCl₃)δ：7.81 (s, 1H), 7.64 (s, 1H), 4.70 (dd, 1H), 3.35-3.30 (m, 1H), 2.98-2.90 (m, 1H), 2.59-2.43 (m, 2H)。

The methyl of embodiment 5 (2S) -1- [(2S, 5S) -2- (7,8,10- tri- deuterated chloro- heterochromatic alkene of 1,11- dihydros of -9- [4 ', 3’：6,7] naphtho- [1,2-d] imidazoles -2- bases) -5- methylpyrrolidin- 1- yls] -3- methyl isophthalic acids-oxygen butane -2- bases } carbamic acid The preparation of ester (V ')

The method of reference reference implementation example 4,

The first step：IV ' is replaced into IV, is condensed under DIPEA effects with II, obtains (2S, 5S)-N- (tert-butyl epoxide carbonyls Base) -2- (2,4, the 5- tri- deuterated chloro- 8- oxygen -8,9 of -3-, 10,11- tetrahydrochysene -5H- dibenzo [c, g] chromene -9- bases) -5- methyl Pyrrolidines -2- carboxylates (v ' -1).

Second step：Replace v-1 and ammonium acetate to react v ' -1, obtain (2S, 5S)-N- (tert-butyl Epoxide carbonyl) -2- (7, 8,10- tri- deuterated chloro- 4,5- dihydros -5H- naphtho-s [c, g] chromene [8, the 9-d] imidazoles -2- bases of -9-) -5- crassitudes (v ' - 2)。

3rd step：V ' -2 is replaced into v-2 and MnO₂Reaction, obtain (2S, 5S)-N- (tert-butyl Epoxide carbonyl) -2- (7,8, Chloro- 5H- naphtho-s [c, g] chromene [8, the 9-d] imidazoles -2- bases of tri- deuterated -9- of 10-) -5- crassitudes (v ' -3).

4th step：V ' -3 is replaced into v-3, reacts de- Boc with HCl, then again with (S) -2- (methyloxycarbonylamino) -3- Methylbutanoic acid is condensed, and V ' is made.Proton nmr spectra δ (ppm, CD₃OD, 400MHz)：8.22 (s, 1H), 8.17 (s, 1H), 7.93-7.06 (m, 2H), 5.32 (m, 1H), 4.34 (m, 1H), 4.24 (d, 1H), 3.53-3.25 (m, 5H), 2.63 (m, 1H), 2.55 (m, 2H), 1.20-1.90 (m, 1H), 1.55 (d, 3H), 1.03 (d, 3H), 0.96 (d, 3H).

The methyl of embodiment 6 (2S) -1- [(2S, 5S) -2- (7,8,10- tri- deuterated chloro- heterochromatic alkene of 1,11- dihydros of -9- [4 ', 3’：6,7] naphtho- [1,2-d] imidazoles -2- bases) the deuterated methyi-pyrrofidinium -1- bases of -5-] -3- methyl isophthalic acids-oxygen butane -2- bases } ammonia The preparation of carbamate (V ")

The method of reference reference implementation example 4,

The first step：Replace IV, II ' to replace II IV ', be condensed under DIPEA effects, obtain (2S, 5S)-N- (tert-butyl oxygen Base carbonyl) -2- (2,4, the 5- tri- deuterated chloro- 8- oxygen -8,9 of -3-, 10,11- tetrahydrochysene -5H- dibenzo [c, g] chromene -9- bases) -5- Deuterated methyi-pyrrofidinium -2- carboxylates (v " -1).

Second step：Replace v-1 and ammonium acetate to react v " -1, obtain (2S, 5S)-N- (tert-butyl Epoxide carbonyl) -2- (7, 8,10- tri- deuterated chloro- 4,5- dihydros -5H- naphtho-s [c, g] chromene [8, the 9-d] imidazoles -2- bases of -9-) the deuterated methyi-pyrrofidiniums of -5- (v”-2)。

3rd step：V " -2 is replaced into v-2 and MnO₂Reaction, obtain (2S, 5S)-N- (tert-butyl Epoxide carbonyl) -2- (7,8, Chloro- 5H- naphtho-s [c, g] chromene [8, the 9-d] imidazoles -2- bases of tri- deuterated -9- of 10-) the deuterated methyi-pyrrofidiniums of -5- (v " -3).

4th step：V " -3 is replaced into v-3, reacts de- Boc with HCl, then again with (S) -2- (methyloxycarbonylamino) -3- Methylbutanoic acid is condensed, and V " is made.Proton nmr spectra δ (ppm, CD₃OD, 400MHz)：8.19 (s, 1H), 8.12 (s, 1H), 7.95-7.05 (m, 2H), 5.27 (m, 1H), 4.32 (m, 1H), 4.24 (d, 1H), 3.50-3.26 (m, 5H), 2.67 (m, 1H), 2.56 (m, 2H), 1.20-1.91 (m, 1H), 1.01 (d, 3H), 0.97 (d, 3H).

7 deuterated methyl of embodiment { (2S) -1- [(2S, 5S) -2- (7,8,10- tri- deuterated chloro- heterochromatic alkene of 1,11- dihydros of -9- [4 ', 3 '：6,7] naphtho- [1,2-d] imidazoles -2- bases) the deuterated methyi-pyrrofidinium -1- bases of -5-] -3- methyl isophthalic acids-oxygen butane -2- Base } carbamate (V " ') preparation

The method of reference reference implementation example 4,

4th step：V " -3 is replaced into v-3, reacts de- Boc with HCl, then again with (S) -2- (deuterated methoxycarbonyl ammonia Base) condensation of -3 Methylbutanoic acid, V " ' is made.Proton nmr spectra δ (ppm, CD₃OD, 400MHz)：8.24 (s, 1H), 8.19 (s, 1H), 7.93-7.05 (m, 2H), 5.30 (m, 1H), 4.33 (m, 1H), 4.24 (d, 1H), 3.53-3.25 (m, 2H), 2.56 (m, 2H), 2.67 (m, 1H), 1.20-1.92 (m, 1H), 1.04 (d, 3H), 0.95 (d, 3H).

8 deuterated methyl of embodiment { (1R) -2- [(2S, 4S) -2- (5- { 2- [(2S, 4S) -1- { (2S) -2- [(deuterated methoxies Base carbonyl) amino] -3- methylbutyryls base } the deuterated methyi-pyrrofidinium -2- bases of -5-] -7,8,10- tri- deuterated -1,11- dihydros are different Chromene [4 ', 3 '：6,7] naphtho- [1,2-d] imidazoles -9- bases } -1H- imidazoles -2- bases) -4- (deuterated methoxyl group-deuterated methyl) pyrrole Cough up alkane -1- bases] -2- oxygen -1- phenethyls carbamate (I-1) preparation

The method of reference reference implementation example 5,

The first step：V " ' is replaced into V, in double (valeryl) two boron, KOAc, X-Phos and Pd₂dba₃.Under effect, it is made deuterated Methyl [(2S) -3- methyl isophthalic acids-the deuterated methyl -5- of (2S, 5S) -2- [9- (4,4,5,5- tetramethyls -1,3,2- dioxaborinates - 2- yls) -7,8, the 10- tri- heterochromatic alkene [4 ', 3 ' of deuterated -1,11- dihydros：6,7] naphtho- [1,2-d] imidazoles -2- bases] pyrrolidines -1- Base } -1- oxygen butane -2- bases] carbamate (i ' -1).

Second step：I ' -1 is replaced into i-1, III " ' replaces III, in Pd (PPh₃)₄、PdCl₂(dppf)₂And K₂CO₃Under effect Reaction, be made N- (tert-butyl Epoxide carbonyl)-(2S, 4S) -2- [5- (2- (2S, 4S) -1- [N- (deuterated methoxycarbonyl) - L- valyls base] the deuterated methylpyrrolidin- 2- yls of -5- } -7,8, the 10- tri- heterochromatic alkene [4 ', 3 ' of deuterated -1,11- dihydros：6,7] naphthalene And [1,2-d] imidazoles -9- bases) -1H- imidazoles -2- bases] -4- (deuterated methoxyl group-deuterated methyl) pyrrolidines (i ' -2).

3rd step：I-2 is replaced with i ' -2, is deprotected, (2S, 4S) -2- [5- (2- { (2S, 4S) -1- [N- (deuterated first is made Epoxide carbonyl)-L- valyls base] the deuterated methylpyrrolidin- 2- yls of -5- } -7,8,10- tri- deuterated-heterochromatic alkene of 1,11- dihydros [4 ', 3 '：6,7] naphtho- [1,2-d] imidazoles -9- bases) -1H- imidazoles -2- bases] -4- (deuterated methoxyl group-deuterated methyl) pyrrolidines (i’-3)；I ' -3 replaces i-3, is condensed with (R) -2- (deuterated methyloxycarbonylamino) -2- phenylacetic acids, and I-1 is made.Nuclear magnetic resonance Hydrogen spectrum δ (ppm, CD₃OD, 400MHz)：8.15 (s, 1H), 8.04 (s, 1H), 7.91-7.03 (m, 8H), 5.41 (d, 2H), 5.33 (m, 1H), 5.21 (m, 2H), 4.37 (m, 1H), 4.24 (d, 1H), 3.55-3.27 (m, 3H), 2.66 (m, 1H), 2.54 (m, 2H), 1.98-1.91 (m, 4H), 1.01 (d, 3H), 0.95 (d, 3H).

The methyl of embodiment 9 { (1R) -2- [(2S, 4S) -2- (5- { 2- [(2S, 4S) -1- { (2S) -2- [(methoxycarbonyl) Amino] -3- methylbutyryls base } the deuterated methyi-pyrrofidinium -2- bases of -5-] -7,8,10- tri- deuterated-heterochromatic alkene of 1,11- dihydros [4 ', 3’：6,7] naphtho- [1,2-d] imidazoles -9- bases } -1H- imidazoles -2- bases) -4- (deuterated methoxyl group-deuterated methyl) pyrrolidines -1- Base] -2- oxygen -1- phenethyls carbamate (I-2) preparation

The method of reference reference implementation example 5,

The first step：V " is replaced into V, in double (valeryl) two boron, KOAc, X-Phos and Pd₂dba₃.Under effect, methyl is made [(2S) -3- methyl isophthalic acids-{ the deuterated methyl -5- of (2S, 5S) -2- [9- (4,4,5,5- tetramethyls -1,3,2- dioxaborinates -2- Base) -7,8, the 10- tri- heterochromatic alkene [4 ', 3 ' of deuterated -1,11- dihydros：6,7] naphtho- [1,2-d] imidazoles -2- bases] pyrrolidines -1- Base } -1- oxygen butane -2- bases] carbamate (i " -1).

Second step：I " -1 is replaced into i-1, III " ' replaces III, in Pd (PPh₃)₄、PdCl₂(dPPf)₂And K₂CO₃Under effect Reaction, N- (tert-butyl Epoxide carbonyl)-(2S, 4S) -2- [5- (2- { (2S, 4S) -1- [N- (methoxycarbonyl)-L- figured silk fabrics is made Aminoacyl] the deuterated methylpyrrolidin- 2- yls of -5- } -7,8, the 10- tri- heterochromatic alkene [4 ', 3 ' of deuterated -1,11- dihydros：6,7] naphtho- [1,2-d] imidazoles -9- bases) -1H- imidazoles -2- bases] -4- (deuterated methoxyl group-deuterated methyl) pyrrolidines (i " -2).

3rd step：I-2 is replaced with i " -2, is deprotected, (2S, 4S) -2- [5- (2- { (2S, 4S) -1- [N- (methoxyl groups are made Carbonyl)-L- valyls base] the deuterated methylpyrrolidin- 2- yls of -5- } -7,8, the 10- tri- heterochromatic alkene [4 ', 3 ' of deuterated -1,11- dihydros： 6,7] naphtho- [1,2-d] imidazoles -9- bases) -1H- imidazoles -2- bases] -4- (deuterated methoxyl group-deuterated methyl) pyrrolidines (i " -3)； I " -3 replaces i-3, is condensed with (R) -2- (methyloxycarbonylamino) -2- phenylacetic acids, and I-2 is made.Proton nmr spectra δ (ppm, CD₃OD, 400MHz)：8.20- (s, 1H), 8.11 (s, 1H), 7.88-7.02 (m, 8H), 5.45 (d, 2H), 5.30 (m, 1H), 5.25 (m, 2H), 4.36 (m, 1H), 4.25 (d, 1H), 3.54-3.26 (m, 3H), 3.37 (s, 3H), 3.25 (s, 3H), 2.62 (m, 1H), 2.57 (m, 2H), 1.99-1.93 (m, 4H), 1.08 (d, 3H), 0.98 (d, 3H).

The methyl of embodiment 10 { (1R) -2- [(2S, 4S) -2- (5- { 2- [(2S, 4S) -1- { (2S) -2- [(methoxycarbonyl) Amino] -3- methylbutyryls base } -5- methyi-pyrrofidinium -2- bases] -7,8, the 10- tri- heterochromatic alkene [4 ', 3 ' of deuterated -1,11- dihydros： 6,7] naphtho- [1,2-d] imidazoles -9- bases } -1H- imidazoles -2- bases) -4- (deuterated methoxyl group-deuterated methyl) pyrrolidin-1-yl] - 2- oxygen -1- phenethyls } carbamate (I-3) preparation

The method of reference reference implementation example 5,

The first step：V ' is replaced into V, in double (valeryl) two boron, KOAc, X-Phos and Pd₂dba₃.Under effect, methyl is made [(2S) -3- methyl isophthalic acids-{ the deuterated methyl -5- of (2S, 5S) -2- [9- (4,4,5,5- tetramethyls -1,3,2- dioxaborinates -2- Base) -7,8, the 10- tri- heterochromatic alkene [4 ', 3 ' of deuterated -1,11- dihydros：6,7] naphtho- [1,2-d] imidazoles -2- bases] pyrrolidines -1- Base } -1- oxygen butane -2- bases] carbamate (i " ' -1).

Second step：I " ' -1 is replaced into i-1, III " ' replaces III, in Pd (PPh₃)₄、PdCl₂(dppf)₂And K₂CO₃Effect Lower reaction, N- (tert-butyl Epoxide carbonyl)-(2S, 4S) -2- [5- (2- { (2S, 4S) -1- [N- (methoxycarbonyl)-L- are made Valyl base] -5- methylpyrrolidin- 2- yls } -7,8, the 10- tri- heterochromatic alkene [4 ', 3 ' of deuterated -1,11- dihydros：6,7] naphtho- [1, 2-d] imidazoles -9- bases) -1H- imidazoles -2- bases] -4- (deuterated methoxyl group-deuterated methyl) pyrrolidines (i " ' -2).

3rd step：With i " " -2 i-2 is replaced, it is deprotected, (2S, 4S) -2- [5- (2- { (2S, 4S) -1- [N- (methoxies is made Base carbonyl)-L- valyls base] the deuterated methylpyrrolidin- 2- yls of -5- } -7,8,10- tri- deuterated-heterochromatic alkene of 1,11- dihydros [4 ', 3’：6,7] naphtho- [1,2-d] imidazoles -9- bases) -1H- imidazoles -2- bases] -4- (deuterated methoxyl group-deuterated methyl) pyrrolidines (i " ' - 3)；I " ' -3 replaces i-3, is condensed with (R) -2- (methyloxycarbonylamino) -2- phenylacetic acids, and I-3 is made.Proton nmr spectra δ (ppm, CD₃OD, 400MHz)：8.23 (s, 1H), 8.10 (s, 1H), 7.92-7.04 (m, 8H), 5.40 (d, 2H), 5.31 (m, 1H), 5.25 (m, 2H), 4.36 (m, 1H), 4.25 (d, 1H), 3.54-3.26 (m, 3H), 3.37 (s, 3H), 3.25 (s, 3H), 2.67 (m, 1H), 2.52 (m, 2H), 2.05-1.93 (m, 4H), 1.53 (d, 3H), 1.12 (d, 3H), 1.03 (d, 3H).

The methyl of embodiment 11 { (1R) -2- [(2S, 4S) -2- (5- { 2- [(2S, 4S) -1- { (2S) -2- [(methoxycarbonyl) Amino] -3- methylbutyryls base } -5- methyi-pyrrofidinium -2- bases] -7,8, the 10- tri- heterochromatic alkene [4 ', 3 ' of deuterated -1,11- dihydros： 6,7] naphtho- [1,2-d] imidazoles -9- bases } -1H- imidazoles -2- bases) -4- (deuterated methoxymethyl) pyrrolidin-1-yl] -2- oxygen - 1- phenethyls } carbamate (I-4) preparation

The method of reference reference implementation example 5,

Second step：I " ' -1 is replaced into i-1, III " replaces III, in Pd (PPh₃)₄、PdCl₂(dppf)₂And K₂CO₃Under effect Reaction, N- (tert-butyl Epoxide carbonyl)-(2S, 4S) -2- [5- (2- { (2S, 4S) -1- [N- (methoxycarbonyl)-L- figured silk fabrics is made Aminoacyl] -5- methylpyrrolidin- 2- yls } -7,8, the 10- tri- heterochromatic alkene [4 ', 3 ' of deuterated -1,11- dihydros：6,7] naphtho- [1,2- D] imidazoles -9- bases) -1H- imidazoles -2- bases] -4- (deuterated methoxymethyl) pyrrolidines (i " " -2).

3rd step：With i " " -2 i-2 is replaced, it is deprotected, (2S, 4S) -2- [5- (2- { (2S, 4S) -1- [N- (methoxies is made Base carbonyl)-L- valyls base] the deuterated methylpyrrolidin- 2- yls of -5- } -7,8,10- tri- deuterated-heterochromatic alkene of 1,11- dihydros [4 ', 3’：6,7] naphtho- [1,2-d] imidazoles -9- bases) -1H- imidazoles -2- bases] -4- (deuterated methoxymethyl) pyrrolidines (i " " -3)； I " " -3 replaces i-3, is condensed with (R) -2- (methyloxycarbonylamino) -2- phenylacetic acids, and I-4 is made.Proton nmr spectra δ (ppm, CD₃OD, 400MHz)：8.20 (s, 1H), 8.05 (s, 1H), 7.92-7.04 (m, 8H), 5.40 (d, 2H), 5.31 (m, 1H), 5.25 (m, 2H), 4.36 (m, 1H), 4.25 (d, 1H), 3.54-3.26 (m, 5H), 3.37 (s, 3H), 3.25 (S, 3H), 2.67 (m, 1H), 2.58 (m, 2H), 2.00-1.93 (m, 4H), 1.50 (d, 3H), 1.06 (d, 3H), 0.97 (d, 3H).

The methyl of embodiment 12 { (1R) -2- [(2S, 4S) -2- (5- { 2- [(2S, 4S) -1- { (2S) -2- [(methoxycarbonyl) Amino] -3- methylbutyryls base } -5- methyi-pyrrofidinium -2- bases] -7,8, the 10- tri- heterochromatic alkene [4 ', 3 ' of deuterated -1,11- dihydros： 6,7] naphtho- [1,2-d] imidazoles -9- bases } -1H- imidazoles -2- bases) -4- (methoxymethyl) pyrrolidin-1-yl] -2- oxygen -1- benzene Ethyl } carbamate (I-5) preparation

The method of reference reference implementation example 5,

Second step：I " ' -1 is replaced into i-1, in Pd (PPh₃)₄、PdCl₂(dppf)₂And K₂CO₃Effect is lower to react, anti-with III Should, N- (tert-butyl Epoxide carbonyl)-(2S, 4S) -2- [5- (2- { (2S, 4S) -1- [N- (methoxycarbonyl)-L- figured silk fabrics ammonia is made Acyl group] -5- methylpyrrolidin- 2- yls } -7,8, the 10- tri- heterochromatic alkene [4 ', 3 ' of deuterated -1,11- dihydros：6,7] naphtho- [1,2-d] Imidazoles -9- bases) -1H- imidazoles -2- bases] -4- (methoxymethyl) pyrrolidines (i " " ' -2).

3rd step：With i " " ' -2 replace i-2, are deprotected, (2S, 4S) -2- [5- (2- { (2S, 4S) -1- [N- (methoxies are made Base carbonyl)-L- valyls base] the deuterated methylpyrrolidin- 2- yls of -5- } -7,8,10- tri- deuterated-heterochromatic alkene of 1,11- dihydros [4 ', 3’：6,7] naphtho- [1,2-d] imidazoles -9- bases) -1H- imidazoles -2- bases] -4- (methoxymethyl) pyrrolidines (i " " ' -3)； I " " ' -3 replaces i-3, is condensed with (R) -2- (methyloxycarbonylamino) -2- phenylacetic acids, and I-5 is made.Proton nmr spectra δ (ppm, CD₃OD, 400MHz)：8.21 (s, 1H), 8.05 (s, 1H), 7.92-7.04 (m, 8H), 5.40 (d, 2H), 5.31 (m, 1H), 5.25 (m, 2H), 4.36 (m, 1H), 4.25 (d, 1H), 3.60 (s, 3H), 3.54-3.26 (m, 5H), 3.37 (s, 3H), 3.25 (s, 3H), 2.67 (m, 1H), 2.58 (m, 2H), 1.99-1.93 (m, 4H), 1.52 (d, 3H), 1.09 (d, 3H), 1.02 (d, 3H).

The methyl of embodiment 13 { (1R) -2- [(2S, 4S) -2- (5- { 2- [(2S, 4S) -1- { (2S) -2- [(methoxycarbonyl) Amino] -3- methylbutyryls base } -5- methyi-pyrrofidinium -2- bases] the heterochromatic alkene [4 ', 3 ' of -1,11- dihydros：6,7] naphtho- [1,2-d] Imidazoles -9- bases } -1H- imidazoles -2- bases) -4- (deuterated methoxyl group-deuterated methyl) pyrrolidin-1-yl] -2- oxygen -1- phenethyls } ammonia The preparation of carbamate (I-6)

The method of reference reference implementation example 5,

Second step：III " ' is replaced into III, in Pd (PPh₃)₄、PdCl₂(dppf)₂And K₂CO₃Effect is lower to react, anti-with i-1 Should, N- (tert-butyl Epoxide carbonyl)-(2S, 4S) -2- [5- (2- { (2S, 4S) -1- [N- (methoxycarbonyl)-L- figured silk fabrics ammonia is made Acyl group] -5- methylpyrrolidin- 2- yls } the heterochromatic alkene [4 ', 3 ' of -1,11- dihydros：6,7] naphtho- [1,2-d] imidazoles -9- bases) -1H- Imidazoles -2- bases] -4- (deuterated methoxyl group-deuterated methyl) pyrrolidines (i " " " -2).

3rd step：With i " " " -2 i-2 is replaced, it is deprotected, (2S, 4S) -2- [5- (2- { (2S, 4S) -1- [N- (methoxies is made Base carbonyl)-L- valyls base] the deuterated methylpyrrolidin- 2- yls of -5- } the heterochromatic alkene [4 ', 3 ' of -1,11- dihydros：6,7] naphtho- [1, 2-d] imidazoles -9- bases) -1H- imidazoles -2- bases] -4- (methoxymethyl) pyrrolidines (i " " " -3)；I " " " -3 replaces i-3, with (R) -2- (methyloxycarbonylamino) -2- phenylacetic acids are condensed, and I-6 is made.Proton nmr spectra δ (ppm, CD₃OD, 400MHz)： 8.29 (s, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 7.92-7.04 (m, 10H), 5.40 (d, 2H), 5.31 (m, 1H), 5.25 (m, 2H), 4.36 (m, 1H), 4.25 (d, 1H), 3.54-3.26 (m, 3H), 3.37 (s, 3H), 3.25 (s, 3H), 2.67 (m, 1H), 2.58 (m, 2H), 1.99-1.93 (m, 4H), 1.52 (d, 3H), 1.08 (d, 3H), 0.97 (d, 3H).

The methyl of embodiment 14 { (1R) -2- [(2S, 4S) -2- (5- { 2- [(2S, 4S) -1- { (2S) -2- [(methoxycarbonyl) Amino] -3- methylbutyryls base } -5- methyi-pyrrofidinium -2- bases] the heterochromatic alkene [4 ', 3 ' of -1,11- dihydros：6,7] naphtho- [1,2-d] Imidazoles -9- bases } -1H- imidazoles -2- bases) -4- (deuterated methoxymethyl) pyrrolidin-1-yl] -2- oxygen -1- phenethyls } amino first The preparation of acid esters (I-7)

The method of reference reference implementation example 5,

Second step：III " is replaced into III, in Pd (PPh₃)₄、PdCl₂(dppf)₂And K₂CO₃Effect is lower to react, anti-with i-1 Should, N- (tert-butyl Epoxide carbonyl)-(2S, 4S) -2- [5- (2- { (2S, 4S) -1- [N- (methoxycarbonyl)-L- figured silk fabrics ammonia is made Acyl group] -5- methylpyrrolidin- 2- yls } the heterochromatic alkene [4 ', 3 ' of -1,11- dihydros：6,7] naphtho- [1,2-d] imidazoles -9- bases) -1H- Imidazoles -2- bases] -4- (deuterated methoxymethyl) pyrrolidines (i " " " ' -2).

3rd step：With i " " " ' -2 replace i-2, are deprotected, (2S, 4S) -2- [5- (2- { (2S, 4S) -1- [N- (first is made Epoxide carbonyl)-L- valyls base] the deuterated methylpyrrolidin- 2- yls of -5- } the heterochromatic alkene [4 ', 3 ' of -1,11- dihydros：6,7] naphtho- [1,2-d] imidazoles -9- bases) -1H- imidazoles -2- bases] -4- (methoxymethyl) pyrrolidines (i " " " ' -3)；I " " " ' -3 replaces i- 3, it is condensed with (R) -2- (methyloxycarbonylamino) -2- phenylacetic acids, I-7 is made.Proton nmr spectra δ (ppm, CD₃OD, 400MHz)：8.24 (s, 1H), 8.23 (s, 1H), 8.03 (s, 1H), 7.92-7.04 (m, 10H), 5.40 (d, 2H), 5.31 (m, 1H), 5.25 (m, 2H), 4.36 (m, 1H), 4.25 (d, 1H), 3.54-3.26 (m, 5H), 3.37 (s, 3H), 3.25 (s, 3H), 2.67 (m, 1H), 2.58 (m, 2H), 1.99-1.93 (m, 4H), 1.52 (d, 3H), 1.08 (d, 3H), 0.99 (d, 3H).

The evaluation of the anti-HCV activity of embodiment 15 and cytotoxicity

Using HCV Replicate Sub-systems (1.Science.1999；285：110-3.2.J Virol 2003；77(5)：3007- 109.) anti-HCV activity of target compound is evaluated.

The Huh-7 cells for transfecting HCV Replicate Sub-systems are inoculated in 96 orifice plates, cell number 8x 10³It is individual；Add containing not With the nutrient solution of acute drug, 3 parallel holes are set；The 3rd day upon administration, add 40 μ l/ holes luciferase luminous substrates Bright-Glo (Promega Products), after 5 minutes, utilize luminescent activity detector Topcount microwell plate liquid shwoot light Calculating instrument detects.EC is calculated with GraphPad Prim softwares₅₀.It the results are shown in Table 1.

Hep G 2.2.15 cells are inoculated in 96 orifice plates, cell number 5.5x 10⁴It is individual, continue culture 3 days, add containing not With the new nutrient solution of acute drug, 3 parallel holes are set；The 3rd day upon administration, MTT to 7.5mg/ml is added, continues culture 2 Hour, supernatant discarding, addition contains 10% tween X-100 isopropanols, 120 μ l/ holes, adds 0.4 μ l/ holes, is determined with enzyme-linked instrument Absorption at 540nm, calculate 50%CC₅₀Value.It the results are shown in Table 1.

The in-vitro evaluation result of table 1

The evaluation of the Oral Administration in Rats bioavilability of embodiment 16

After target compound gavage or intravenously administrable being determined using high performance liquid chromatography-tandem mass method (HPLC-MS/MS) The Blood drug concentration of different time points.Instrument：U.S. Finnigan company's T SQ Quantum type liquid chromatograph-mass spectrometers (LC/MS/MS), by Finnigan Surveyor LC pumps, Surveyor AS automatic samplers, electro-spray ionization ionization source (ESI) and thtee-stage shiplock mass spectrum forms.Control software is Xcalibur 1.4, and MASS SPECTRAL DATA ANALYSIS uses the data of Lcquan 2.0 Processing system.Chromatographic column is Discovery ODS posts (250mm × 4.6mm, 5 μm), C18 guard columns (4mm × 3.0mm), is flowed It is mutually methanol-water (10-30：90-70V/V), flow velocity 0.7ml/min；The μ L of sample size 20；Column temperature is room temperature.

Male SD rat, fasting 16h, random packet, 3/group.Gavage is given the 10mg/kg that Tween 80 is suspended and treated respectively Survey compound；Before administration and 0.25,0.5,0.75,1.0,1.5,2.0,3.0,6.0,12.0,24.0 hour after administration, Yu great Rathole bottom veniplex blood sampling 0.5mL, 3500r.p.m. centrifugation 10min, isolates blood plasma, to be measured in -20 DEG C of freezen protectives.

Male SD rat separately is taken, random packet, 3/group.By testing compound respectively with pH2.0 5% ethanol, 35% The mixed solvent wiring solution-forming of polyethylene glycol 400 and 60% water, 5mg/kg intravenous injections.Respectively before administration with after administration 5min, 15min, 30min, 45min, 1.0h, 2.0h, 3.0h, 6.0h, 8.0h, 12.0h in eyeground vein clump take a blood sample 0.5mL, from Heart 10min (3500r.p.m.), isolates blood plasma, to be measured in -20 DEG C of freezen protectives, and the drug plasma for determining different time is dense Degree.

By blood concentration-time data input computer, pharmacokinetic parameter is calculated using non-room modelling.T_maxWith C_maxUsing measured value, AUC is calculated with trapezoidal method_0-tValue and AUC_0-∞Value, with semilog graphing method, by the concentration of elimination phase end Point, which calculates, eliminates constant (Ke) and t_1/2, and obtain main pharmacokinetic parameter.By tested rat respectively orally with intravenous injection Area (AUC under mean blood plasma concentration-time graph afterwards_0-∞), Oral Administration in Rats absolute bioavailability is calculated, the results are shown in Table 2。

The measure of the Oral Administration in Rats bioavilability of table 2

Compound	Bioavilability (%)
		i-4	28.5±44.34
I-1	44.8±18.37
		I-2	43.5±19.4
I-3	42.9±21.9
		I-4	41.7±25.6
I-5	32.8±30.34
		I-6	40.28±26.28
I-7	39.0±29.30

The evaluation of the hepatotoxicity of embodiment 17

Kunming mouse (20g), it is random to be grouped (every group 8).Tween 80 suspension is given by orally giving gavage respectively Testing compound, 1 times/day, successive administration 7 days.24 hours after last time administration, blood sampling takes serum specimen, determines ALT, AST.It the results are shown in Table 3.

The evaluation result of the hepatotoxicity of table 3

Claims

1. compound and its non-toxic pharmaceutically acceptable salt representated by Formulas I：

In structural formula I, R1, R2, R3 and R4 are each independently selected from methyl (- CH₃) or deuterated methyl (- CD₃)；X₁、X₂、X₃、X₄ And X₅Respectively hydrogen (H) or deuterium (D)；It is deuterated methyl (- CD that must have one in R1, R2, R3 and R4₃) or X₁、X₂、X₃、X₄With X₅In must to have one be deuterium (D).

2. compound according to claim 1, is selected from：

3. contain compound described in claim 1~2 and its atoxic pharmaceutically acceptable salt as active component with And the pharmaceutical composition that suitable excipients are formed.These pharmaceutical compositions can be solution, tablet, capsule or injection； These pharmaceutical compositions can be administered orally or injection administration.

4. compound and its atoxic pharmaceutically acceptable salt described in claim 1~2, and contain claim 1 Compound and its atoxic pharmaceutically acceptable salt described in~2 are preparing anti-third as the pharmaceutical composition of active component Purposes in hepatopathy cytotoxic drug.