CN101252839A

CN101252839A - Novel 2'-C-methyl and 4'-C-methyl nucleoside derivatives

Info

Publication number: CN101252839A
Application number: CNA2006800320408A
Authority: CN
Inventors: M·D·埃里安; K·R·雷迪; M·麦科斯; D·B·奥尔森
Original assignee: Merck and Co Inc; Metabasis Therapeutics Inc
Current assignee: Merck and Co Inc; Metabasis Therapeutics Inc
Priority date: 2005-08-12
Filing date: 2006-08-14
Publication date: 2008-08-27

Abstract

Novel 2'-C-methyl nucleoside 5 '-monophosphate and 4'-C-methyl nucleoside 5'- monophosphate derivatives, stereoisomers, and pharmaceutically acceptable salts or prodrugs thereof, their preparation, and their uses for the treatment of hepatitis C viral infection are described.

Description

New 2 '-C-methyl and 4 '-the C-methyl nucleoside derivatives

Related application

The priority of the U.S. Provisional Patent Application that the application requires to submit on August 12nd, 2005 U.S. provisional application is submitted to number on February 13rd, 60/707,767 and 2006 number 60/772,649 is incorporated herein by reference the two herein.

Invention field

The present invention relates to new 2 '-C-methyl nucleoside 5 '-one phosphoric acid and 4 '-C-methyl nucleoside 5 '-one phosphoric acid derivatives, their preparation method and their purposes.These new compounds are effective to treatment hepatitis C virus infections.

Background of invention

Following description about background of invention of the present invention helps to understand the present invention, but should not be considered to or describe prior art of the present invention.All publications are all incorporated the present invention into as a reference in full with it.

Hepatitis C is a viral disease, can cause the liver inflammation and further cause sclerosis, primary carcinoma of liver and other chronic complicating diseases.Nucleosides is that a well-known class can effectively be resisted the various virus infectionses compound of (comprising hepatitis B, HIV and bleb).It is reported that the minority nucleosides has the effect of inhibition hepatitis C (HCV) virus replication, comprise Ribavirin (be used as at present with the medicine of various interferon combination and sold) and comprise the nucleosides of 2 '-C-methylribose.

Nucleosides can be used as antiviral drugs usually after being converted into corresponding 5 '-nucleoside triphosphate (NTP).Conversion is undertaken by kinase whose effect in the various cells in cell.First step, promptly nucleosides is to the conversion of 5 '-Monophosphate (NMP) step slowly normally, and relates to nucleoside kinase, and this kinases can be through virus or host-encoded.NMP to the conversion of NTP usually through the catalysis of host's nucleoside kinase.NTP duplicates by suppressing the varial polymerases viral interference, and/or by being incorporated in DNA or the RNA growing chain, duplicates by the chain termination reaction viral interference subsequently.

Nucleosides is treated the purposes of viral liver infection and is understood complicated by one of two problems usually.In some cases, required nucleosides is good kinase substrate, thereby produces NTP in liver and other cells in vivo and tissue.Because the generation of NTP is usually with toxicity, its effect can be limited by the outer toxicity of liver.In other cases, required nucleosides is relatively poor kinase substrate, therefore can not be converted into NMP effectively and finally be converted into NTP.

For example, US 6,312, and 662 disclose some phosphate prodrug, and they are used for various medicines and comprise the specificity transmission of nucleosides to liver, thereby can be used for the treatment of patient's liver diseases, for example hepatitis C, hepatitis B and hepatocellular carcinoma.

Summary of the invention

The present invention relates to new 2 '-C-methyl nucleoside 5 '-one phosphoric acid and 4 '-purposes of C-methyl 5 '-one phosphoric acid derivatives, their preparation method and their treatment hepatitis C virus infectionses.

On the one hand, the present invention relates to formula I compound, its pharmaceutically acceptable salt and prodrug.

(I)

Wherein:

B is selected from following groups

With

V is selected from optional monocyclic aryl that replaces and the optional bicyclic heteroaryl that replaces;

W and W ' independently are selected from following groups :-R ², the optional monocyclic aryl that replaces and the optional bicyclic heteroaryl that replaces;

Z is selected from following groups: halogen ,-CN ,-COR ⁵,-CONR ⁴ ₂,-CO ₂R ⁵,-SO ₂R ⁵,-SO ₂NR ⁴ ₂,-OR ⁴,-SR ⁴,-R ⁴,-NR ⁴ ₂,-OCOR ⁵,-OCO ₂R ⁵,-SCOR ⁵,-SCO ₂R ⁵,-NHCOR ⁴,-NHCO ₂R ⁵,-(CH ₂) _p-OR ⁶With-(CH ₂) _p-SR ⁶Perhaps

V and Z are joined together to form optional 1 the heteroatomic cyclic group that comprises by an other 3-5 atom, and this cyclic group condenses in the β of the O that is connected with phosphorus and γ position and aromatic yl group; Perhaps

Z and W are joined together to form optional 1 the heteroatomic cyclic group that comprises by an other 3-5 atom; Perhaps

W and W ' are joined together to form optional 0-2 the heteroatomic cyclic group that comprise by an other 2-5 atom;

R ²Be selected from R ³And hydrogen;

R ³Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁴Be selected from R ³And hydrogen;

R ⁵Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁶Be selected from hydrogen and lower acyl;

R ¹²Be selected from hydrogen and lower acyl; And

P is integer 2 or 3.

On the other hand, the present invention relates to formula I compound, its pharmaceutically acceptable salt and prodrug:

(I)

Wherein:

B is

R ²Be selected from R ³And hydrogen;

R ³Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁴Be selected from R ⁵And hydrogen;

R ⁵Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁶Be selected from hydrogen and lower acyl;

R ¹²Be selected from hydrogen and lower acyl; And

P is integer 2 or 3.

On the other hand, the present invention relates to the compound of formula (IX), or its pharmaceutically acceptable salt:

(IX)

Wherein:

R ²Be selected from R ³And hydrogen;

R ³Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁴Be selected from R ³And hydrogen;

R ⁵Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁶Be selected from hydrogen and lower acyl;

R ¹²Be selected from hydrogen and lower acyl; And

P is integer 2 or 3.

On the other hand, the present invention relates to the compound of formula (X), or its pharmaceutically acceptable salt:

(X)

Wherein:

W and W ' independently be selected from-H, methyl and V, or W and W ' be methyl, and condition is when W is V, and then W ' is H;

Z is selected from following groups :-H ,-OMe ,-OEt, phenyl, C ₁-C ₃Alkyl ,-NR ⁴ ₂,-SR ⁴,-(CH ₂) _p-OR ⁶,-(CH ₂) _p-SR ⁶With-OCOR ⁵Perhaps

W and W ' are joined together to form cyclic group by an other 2-5 atom;

R ⁴Be C ₁-C ₄Alkyl;

R ⁵Be selected from C ₁-C ₄Alkyl, monocyclic aryl and monocycle aralkyl;

R ⁶Be C ₁-C ₄Acyl group;

R ⁷And R ⁸Independently be selected from hydrogen, C ₁-C ₂₂Acyl group, C ₁-C ₂₂Alkoxy carbonyl, the optional aryl carbonyl that replaces, the optional aryloxy carbonyl that replaces, the optional heteroaryl carbonyl that replaces, the optional heteroaryl oxygen base carbonyl that replaces and be connected to form the naturally occurring L-amino acid of ester by its carbonyl; Or

R at 3 '-oxygen ⁷With R at 2 '-oxygen ⁸Form cyclic carbonate together.

On the other hand, the present invention relates to the compound of formula (XIII), or its pharmaceutically acceptable salt:

(XIII)

Wherein:

R ²Be selected from R ³And hydrogen;

R ³Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁴Be selected from R ³And hydrogen;

R ⁵Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁶Be selected from hydrogen and lower acyl;

R ¹²Be selected from hydrogen and lower acyl; And

P is integer 2 or 3.

On the other hand, the present invention relates to the compound of formula (XIV), or its pharmaceutically acceptable salt:

(XIV)

Wherein:

V and Z are joined together to form optional 1 the heteroatomic cyclic group that comprises by an other 3-5 atom, and this cyclic group condenses in the β of the O that is connected with phosphorus and γ position and aromatic yl group;

Perhaps

W and W ' are joined together to form cyclic group by an other 2-5 atom;

R ⁴Be C ₁-C ₄Alkyl;

R ⁵Be selected from C ₁-C ₄Alkyl, monocyclic aryl and monocycle aralkyl;

R ⁶Be C ₁-C ₄Acyl group; With

R at 3 '-oxygen ⁷With R at 2 '-oxygen ⁸Form cyclic carbonate together.

On the other hand, the present invention relates to the compound of formula (XVII), or its pharmaceutically acceptable salt:

(XVII)

Wherein:

Perhaps R ^aBe methyl and R ^bBe hydrogen, perhaps R ^aBe hydrogen and R ^bIt is methyl;

Perhaps

W and W ' are joined together to form cyclic group by an other 2-5 atom;

R ⁴Be C ₁-C ₄Alkyl;

R ⁵Be selected from C ₁-C ₄Alkyl, monocyclic aryl and monocycle aralkyl;

R ⁶Be C ₁-C ₄Acyl group; With

R at 3 '-oxygen ⁷With R at 2 '-oxygen ⁸Form cyclic carbonate together.

Some formula I, IX, X, XIII, XIV and XVII compound have asymmetric center, its spatial chemistry does not clearly indicate, when usually addressing formula I, IX, X, XIII, XIV and XVII compound, the non-enantiomer mixture that comprises these compounds with and independent stereoisomer.

Some compound described herein can exist with dynamic isomer such as ketoenol tautomerization body and imine-enamine tautomerism bodily form formula.Formula I, IX, X, XIII, XIV and XVII compound also comprise independent dynamic isomer and their mixture.The example that is contained in the ketoenol tautomerization body in the The compounds of this invention is as follows:

Q=CH or N

The example that is contained in the imine-enamine tautomerism body in the The compounds of this invention is as follows:

Q=CH or N

The present invention also provides the pharmaceutical composition that comprises formula I, IX, X, XIII, XIV and XVII compound, its pharmaceutically acceptable salt or prodrug and pharmaceutically acceptable excipient or carrier.

The present invention also provides the method that suppresses virus replication, and this method comprises the step of formula I, IX, X, XIII, XIV and the XVII compound, its pharmaceutically acceptable salt or the prodrug that give the patient treatment effective dose.

The present invention also provides and has suppressed the method that RNA dependent form RNA viruses is duplicated, and this method comprises formula I, the IX, X, XIII, XIV and the XVII compound that give the patient treatment effective dose or the step of its pharmaceutically acceptable salt or prodrug.

The present invention also provides and has suppressed the method that HCV duplicates, and this method comprises the step of formula I, IX, X, XIII, XIV and the XVII compound, its pharmaceutically acceptable salt or the prodrug that give the patient treatment effective dose.

The present invention also provides the method for treatment virus infections, and this method comprises the step of formula I, IX, X, XIII, XIV and the XVII compound, its pharmaceutically acceptable salt or the prodrug that give the patient treatment effective dose.

The present invention also provides the method for treatment liver virus infections, and this method comprises the step of formula I, IX, X, XIII, XIV and the XVII compound, its pharmaceutically acceptable salt or the prodrug that give the patient treatment effective dose.

The present invention also provides the method for treatment RNA dependent form picornavirus infection, and this method comprises the step of formula I, IX, X, XIII, XIV and the XVII compound, its pharmaceutically acceptable salt or the prodrug that give the patient treatment effective dose.

The method that the present invention also provides treatment HCV to infect, this method comprises the step of formula I, IX, X, XIII, XIV and the XVII compound, its pharmaceutically acceptable salt or the prodrug that give the patient treatment effective dose.

The present invention also provides the method for preparation formula I, IX, X, XIII, XIV and XVII compound, its stereoisomer and pharmaceutically acceptable salt or prodrug.

Definition

Unless specialize, according to the present invention in employed following term have following definitions.

Term " alkyl " refers to have as many as and comprises the aliphatic group of saturated straight chain, side chain and the cyclic group of 10 carbon atoms.Suitable alkyl group comprises methyl, ethyl, n-pro-pyl, isopropyl and cyclopropyl.Alkyl can be by the optional replacement of 1-3 substituting group.

The aromatic group that term " aryl " refers to have 5-14 annular atoms and has 1 ring at least, described ring has the conjugated pi electron system, comprises isocyclic aryl, heterocyclic aryl and two aromatic yl group, and all these groups can be optionally substituted.Aromatic yl group can be by the optional replacement of 1-6 substituting group.

Carbon ring aromatic yl group be have 6-14 annular atoms, wherein the annular atoms on the aromatic ring is the group of carbon atom.Carbon ring aromatic yl group comprises monocycle carbon ring aromatic yl group and many rings or condensed compounds, for example optional naphthyl group that replaces.

Heterocyclic aryl or heteroaryl groups be have 5-14 atom, wherein 1-4 hetero atom is the annular atoms in the aromatic ring and remaining annular atoms is the group of carbon atom.Suitable hetero atom comprises oxygen, sulphur and nitrogen.Suitable heteroaryl groups comprises furyl, thienyl, pyridine radicals, pyrrole radicals, N-low alkyl group pyrrole radicals, pyridine radicals-N-oxide, pyrimidine radicals, pyrazinyl, imidazole radicals, indyl etc., and all these groups are all optional to be substituted.

Term " monocyclic aryl " refers to have the aromatic group of 5-6 annular atoms, comprises isocyclic aryl and heterocyclic aryl.Suitable aromatic yl group comprises phenyl, furyl, pyridine radicals and thienyl.Aromatic yl group can be substituted.

Term " bicyclic heteroaryl " refers to have 5-6 annular atoms, wherein 1-4 hetero atom is the annular atoms of aromatic ring and remaining annular atoms is the aromatic group of carbon atom.Suitable hetero atom comprises oxygen, sulphur and nitrogen.

Term " two aryl " representative has the not only aromatic yl group of an aromatic ring that comprises of 5-14 atom, comprises condensing the aromatic yl group that ring system and aromatic yl group are replaced by other aromatic yl group.This type of group can be optionally substituted.Suitable two aromatic yl groups comprise naphthyl and xenyl.

Term " optional replacement " or " replacement " comprise by 1-4 group that independently is selected from following substituting group replacement: low alkyl group; lower aryl; rudimentary aralkyl; rudimentary cyclic alkyl; rudimentary Heterocyclylalkyl; hydroxyl; lower alkoxy; rudimentary aryloxy group; the perhalogeno alkoxyl; aralkoxy; rudimentary heteroaryl; rudimentary heteroaryloxy; rudimentary heteroaryl alkyl; rudimentary assorted aralkoxy; azido; amino; halogen; lower alkylthio; oxo; the lower acyl alkyl; rudimentary carboxyl ester; carboxyl;-formamide; nitro; lower acyl oxygen base; rudimentary aminoalkyl; the low-grade alkyl amino aryl; low-grade alkylaryl; the low-grade alkyl amino alkyl; the lower alkoxy aryl; lower aryl amino; rudimentary aryl alkyl amino; the low alkyl group sulfonyl; rudimentary-the formamide alkylaryl; rudimentary-the formamide aryl; rudimentary hydroxy alkyl; low-grade halogenated alkyl; the low-grade alkyl amino alkyl carboxyl-; rudimentary carbamyl amine alkyl-; cyano group; low-grade alkoxy alkyl; rudimentary whole haloalkyl and lower aryl alkyl oxy alkyl." aryl of replacement " and " heteroaryl of replacement " refers to independently be selected from aryl and the heteroaryl groups that following substituting group replaces by 1-6: low alkyl group, lower alkoxy, rudimentary whole haloalkyl, halogen, hydroxyl, cyano group and amino.

Term " aralkyl " refers to the alkylidene group that replaced by aromatic yl group.Suitable aromatic alkyl group comprises benzyl, picolyl etc., and can be optionally substituted.Aryl moiety can have 5-14 annular atoms, and moieties can have as many as and comprise 10 carbon atoms." heteroaryl alkyl " refers to the alkylidene group that replaced by heteroaryl groups.

Term " alkylaryl-" refers to the aromatic yl group that replaced by alkyl group." low-grade alkylaryl-" refers to that wherein alkyl is the group of low alkyl group.Aryl moiety can have 5-14 annular atoms, and moieties can have as many as and comprise 10 carbon atoms.The term " rudimentary " that herein uses in organic group or the compound refers to as having as many as and comprise 10, preferred as many as and comprise 6, more preferably 1-4 carbon atom.This type of group can be straight chain, side chain or ring-type.

Term " cyclic alkyl " or " cycloalkyl " refer to the cyclic alkyl group that has 3-10 carbon atom, preferably have 3-6 carbon atom.Suitable cyclic group comprises norborny and cyclopropyl.This type of group can be substituted.

Term " heterocycle ", " heterocycle shape alkyl " or " Heterocyclylalkyl " refer to have 3-10 atom, the cyclic group of preferred 3-6 atom, and this cyclic group comprises at least 1 hetero atom, preferred 1-3 hetero atom.Suitable hetero atom comprises oxygen, sulphur and nitrogen.Heterocycle shape group can link to each other by nuclear nitrogen or by carbon atom.Heterocycloalkyl comprises unsaturated ring, fused rings and Spirocyclic group.Suitable heterocycle shape group comprises pyrrolidinyl, morpholino, morpholino ethyl and pyridine radicals.

Term " arylamino " (a) and " aryl alkyl amino " (b) refer to group-NRR ' respectively, wherein (a) R is that aryl and R ' are hydrogen, alkyl, aralkyl, Heterocyclylalkyl or aryl, and (b) R is that aralkyl and R ' are hydrogen, aralkyl, aryl, alkyl or Heterocyclylalkyl.

Term " acyl group " refers to-C (O) R that wherein R is alkyl, Heterocyclylalkyl or aryl.Term " lower acyl " refers to that R is a low alkyl group.Term C ₁-C ₄Acyl group refers to that R is C ₁-C ₄

Term " carboxyl ester " refers to-C (O) OR that wherein R is alkyl, aryl, aralkyl, cyclic alkyl or Heterocyclylalkyl, and all these groups are all optional to be replaced.

Term " carboxyl " refers to-C (O) OH.

Term " oxo " is at alkyl or heterocycloalkyl middle finger=O.

Term " amino " refers to-NRR ' that wherein R and R ' independently are selected from hydrogen, alkyl, aryl, aralkyl and Heterocyclylalkyl, and all above-mentioned groups are all optional the replacement except H; And R and R ' can form the ring-type ring system.

Term " carboxyl acyl ammonia " refers to-CONR ₂, wherein each R independently is a hydrogen or alkyl.

Term " sulfuryl amino " refers to-S (=O) ₂NR ₂, wherein each R independently is a hydrogen or alkyl.

Term " halogen " or " halo " refer to-F ,-Cl ,-Br and-I.

Term " alkyl amino alkyl carboxyl " refers to group alkyl-NR-alk-C (O)-O-, and wherein " alk " is alkylidene group, and R is H or low alkyl group.

Term " sulfonyl " refers to-SO ₂R, wherein R is H, alkyl, aryl, aralkyl or Heterocyclylalkyl.

Term " sulphonic acid ester " refers to-SO ₂OR, wherein R is-H, alkyl, aryl, aralkyl or Heterocyclylalkyl.

The unsaturated group that term " alkenyl " refers to have 2-12 atom and comprises straight chain, side chain and the ring-type of at least 1 carbon-to-carbon double bond.Kiki alkenyl group can be optionally substituted.Suitable kiki alkenyl group comprises pi-allyl." 1-alkenyl " refers to wherein the kiki alkenyl group of two keys between first and second carbon atom.If the 1-kiki alkenyl group links to each other with another group, as be the W substituting group that links to each other with annular phosphate, this group links to each other in first carbon so.

The unsaturated group that term " alkynyl " refers to have 2-12 atom and comprises straight chain, side chain and the ring-type of at least 1 carbon-to-carbon triple bond.Alkynyl group can be optionally substituted.Suitable alkynyl group comprises acetenyl." 1-alkynyl " refers to the alkynyl group between first and second carbon atom of triple bond wherein.If the 1-alkynyl group links to each other with another group, as be the W substituting group that links to each other with annular phosphate, this group links to each other in first carbon so.

Term " alkylidene " refers to the aliphatic group that divalence straight chain, side chain or ring-type are saturated.On the one hand, alkylidene group comprises as many as and comprises 10 atoms.On the other hand, alkylidene chain comprises as many as and comprises 6 atoms.On the other hand, alkylidene group comprises as many as and comprises 4 atoms.Alkylidene group can be straight chain, side chain or ring-type.Alkylidene can be by the optional replacement of 1-3 substituting group.

Term " acyloxy " refers to ester group-O-C (O) R, and wherein R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl or Heterocyclylalkyl.

Term " aminoalkyl-" refers to group NR ₂-alk-, wherein " alk " is alkylidene group, and R is selected from-H, alkyl, aryl, aralkyl and Heterocyclylalkyl.

Term " alkyl amino alkyl-" refers to group alkyl-NR-alk-, and wherein each " alk " all independently is selected from alkylidene, and R is H or low alkyl group." low-grade alkyl amino alkyl-" refers to that wherein alkyl and alkylidene group are respectively the group of low alkyl group and alkylidene.

Term " arylamino alkyl-" refers to group aryl-NR-alk-, wherein " alk " to be alkylidene group and R be-H, alkyl, aryl, aralkyl or Heterocyclylalkyl.In " lower aryl aminoalkyl-", alkylidene group is a low-grade alkylidene.

Term " alkyl amino aryl-" refer to group alkyl-NR-aryl-, wherein " aryl " is divalent group, and R is-H, alkyl, aralkyl or Heterocyclylalkyl.In " low-grade alkyl amino aryl-", alkyl group is a low alkyl group.

Term " alkoxy aryl-" refers to aromatic yl group, can be replaced by the alkyl oxy group.In " low alkyl group oxygen Ji Fangji-", alkyl group is a low alkyl group.

Term " aryloxy alkyl-" refers to the alkyl group that replaced by aryloxy group.

Term " aralkyl oxy alkyl-" refers to group aryl-alk-O-alk-, and wherein " alk " is alkylidene group." rudimentary aralkyl oxy alkyl-" refers to that wherein alkylidene group is the group of low-grade alkylidene.

Term " alkoxyl-" or " alkyl oxy-" refer to group alkyl-O-.

Term " alkoxyalkyl-" or " alkyl oxy alkyl-" refer to group alkyl-O-alk-, and wherein " alk " is alkylidene group.In " low-grade alkoxy alkyl-", each alkyl and alkylidene are respectively low alkyl group and alkylidene.

Term " alkylthio group-" refers to group alkyl-S-.

Term " alkylthio alkyl-" refers to group alkyl-S-alk-, and wherein " alk " is alkylidene group.In " lower alkylthio alkyl-", each alkyl and alkylidene are low alkyl group and alkylidene respectively.

Term " alkoxy-carbonyl oxy-" refers to alkyl-O-C (O)-O-.

Term " aryloxycarbonyl oxygen base-" refers to aryl-O-C (O)-O-.

Term " alkylthio group ketonic oxygen base-" refers to alkyl-S-C (O)-O-.

Term " acylamino-" refers to the NR that links to each other with acyl group or sulfonyl group ₂Group is as NR ₂-C (O)-, RC (O)-NR ¹-, NR ₂-S (=O) ₂-and RS (=O) ₂-NR ¹-, wherein R and R ¹Comprise-H, alkyl, aryl, aralkyl and Heterocyclylalkyl.

Term " formamide " refers to NR ₂-C (O)-and RC (O)-NR ¹-, wherein R and R ¹Comprise-H, alkyl, aryl, aralkyl and Heterocyclylalkyl.This term do not comprise urea ,-NR-C (O)-NR-.

Term " sulfenamide " refers to NR ₂-S (=O) ₂-and RS (=O) ₂-NR ¹-, wherein R and R ¹Comprise-H, alkyl, aryl, aralkyl and Heterocyclylalkyl.This term do not comprise sulfonylurea ,-NR-S (=O) ₂-NR-.

Term " formamide alkylaryl " and " formamide aryl " refer to aryl-alk-NR respectively ¹-C (O) and ar-NR ¹-C (O)-alk-, wherein " ar " is aryl, " alk " is alkylidene, R ¹Comprise H, alkyl, aryl, aralkyl and Heterocyclylalkyl with R.

Term " sulfonamido alkylaryl " and " sulfonamido aryl " refer to aryl-alk-NR ¹-S (=O) ₂-and ar-NR ¹-S (=O) ₂-, wherein " ar " is aryl, " alk " is alkylidene, R ¹Comprise with R-H, alkyl, aryl, aralkyl and Heterocyclylalkyl.

Term " hydroxy alkyl " refers to by the alkyl group of 1-OH replacement.

Term " haloalkyl " refers to by the alkyl group of 1 halogen replacement.

Term " cyano group " refers to-C ≡ N,

Term " nitro " refers to-NO ₂

Term " acyl group alkyl " refers to alkyl-C (O)-alk-, and wherein " alk " is alkylidene.

Term " carbamyl amine alkyl-" refers to group NR ₂-C (O)-N (R)-alk-, wherein R is alkyl group or H, and " alk " is alkylidene group." rudimentary carbamyl amine alkyl-" refers to that wherein " alk " is the group of low-grade alkylidene.

Term " heteroaryl alkyl " refers to the alkylidene group that replaced by heteroaryl groups.

Term " perhalogeno " refers to the group that each c h bond on wherein aliphatic and the aromatic group is replaced by C-halo key.Suitable whole haloalkyl group comprises-CF ₃With-CFCl ₂

Phrase " treatment effective dose " refer to improve, weaken or eliminate specified disease and illness one or more symptoms or prevention, improve or delay a kind of compound that one or more symptoms of specified disease or illness occur or the amount of combination of compounds.

Term " pharmaceutically acceptable salt " comprises the salt derived from formula I, the IX of The compounds of this invention and organic or inorganic acid or alkali, X, XIII, XIV and XVII compound and its prodrug.Suitable acid comprises acetate, adipic acid, benzene sulfonic acid, (+)-7,7-dimethyl-2-oxo dicyclo [2.2.1] heptane-1-methanesulfonic acid, citric acid, 1, the 2-ethionic acid, dodecyl sodium sulfonate, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloride half glycolic, HBr, HCl, HI, the 2-ethylenehydrinsulfonic acid, lactic acid, lactobionic acid, maleic acid, methanesulfonic acid, the methyl hydrogen bromic acid, methylsulfuric acid, the 2-naphthalene sulfonic acids, nitric acid, oleic acid, 4,4 '-di-2-ethylhexylphosphine oxide [3-hydroxyl-2-naphthoic acid], phosphoric acid, polygalacturonic acid, stearic acid, succinic acid, sulfuric acid, sulfosalicylic acid, tannic acid, tartaric acid, terephthalic acid (TPA) and right-toluenesulfonic acid.

Term " naturally occurring L-amino acid " refers to be generally in those natures the amino acid of protein-based molecular components, comprises alanine, valine, leucine, isoleucine, proline, phenyl alanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine and histidine.On the one hand, this term only comprises by amine and the carboxylic acid L-amino acid as charged functional group, i.e. alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine and tyrosine.On the other hand, they refer to alanine, valine, leucine, isoleucine, proline, phenylalanine and glycine.Further aspect, it refers to valine.

Term " patient " refers to the animal treated comprise mammal, for example dog, cat, ox, horse, sheep and people.On the other hand, also comprise male and female mammal.

The term of Shi Yonging " prodrug " refers to any compound herein, and when giving living things system, this compound produces bioactive compound, and this is the result of spontaneous chemical reaction, enzymatic chemical reaction and/or metabolic chemistry reaction or above composite reaction.The prodrug of standard is to utilize group to be connected in the functional group of medicine to form described functional group such as HO-, HS-, HOOC-, R ₂N-, described group cracking in vivo form.The prodrug of standard includes but not limited to carboxylate; wherein said group is the ester of alkyl, aryl, aralkyl, acyloxy alkyl, alkoxy-carbonyl oxy alkyl and hydroxyl, sulphur alkohol and amine, and wherein the group of Lian Jieing is carboxyl groups, alkoxy carbonyl, amino carbonyl, phosphate or sulfuric ester.Described group is exemplary, is not limit, and those skilled in the art can prepare other known various prodrugs.This type of prodrug of formula I, IX, X, XIII, XIV and XVII compound also is contained in the scope of the invention.Prodrug must could generate the compound of biologically active through the chemical conversion of some form or be the precursor of bioactive compound.In some cases, the prodrug biologically active, littler than medicine itself usually, and can improve its effect or safety by improving oral administration biaavailability, drug effect half life period etc.The prodrug forms of compound can be used to for example improve bioavilability, the acceptability that improves main body is (for example by covering or reducing unwanted characteristic, as bitter taste or gastrointestinal irritation), change solubility (using) as vein, release or transmission prolongation or that continue are provided, improve the easy preparation of preparation, the compound transmission of specified point position perhaps is provided.Prodrug is stated in following document: The OrganicChemistry of Drug Design and Drug Action, shown academic press, Santiago,, the 8th chapter in 1992 by Richard B.Silverman; " Prodrug and Drug deliverySystems " 352-401 page or leaf; Design of Prodrug, H.Bundgaard edits, ElsevierScience, Amsterdam, 1985; Design of Biopharmaceutical Propertiesthrough Prodrug and Analogs, E.B.Roche edits, U.S. pharmacy association, Washington, 1977; And Drug Delivery Systems, R.L.Juliano edits, Oxford University Press, Oxford, 1980.

The term of Shi Yonging " prodrug " also includes but not limited to the prodrug (Anastasi etc., Curr.Med.Chem., 2003,10,1825) of esterase cleavable of 2 ' and 3 '-oh group of formula I, IX, X, XIII, XIV and XVII compound herein.The standard group comprises acyl group and alkoxycarbonyl groups, and the ester of natural L-amino acid derivativges (Perry etc., Drugs, 1996,52,754).Also comprise the cyclic carbonate derivative that is formed by 2 ' and 3 '-oh group carbonylation, this derivative can obtain formula I, IX, X, XIII, XIV and XVII compound through the activation of body lactonase.

When being alkali, " prodrug " is preferably placed at the 6-position of purine analogue.This type of replacement can comprise H, halogen, amino, acetoxyl group or azido group.The prodrug that replaces in the 6-position of guanosine analogue hydrogen obtains required functional group (Rashidi etc., Drug Metab.Dispos.1997,25,805) by aldehyde oxidase oxidation or xanthine oxidase oxidation in body.When esterase was used for acetoxyl group group deprotection, known amine and halogenic substituent were the substrates of deaminase.The compound that also known 6-azido replaces also can obtain corresponding aminoderivative (Koudriakova etc., J.Med Chem., 1996,39,4676) by the reductase effect.

When V=W and V and W points upwards or simultaneously during directed downwards simultaneously,

Structure

Has the plane symmetry structure by the two keys of phosphorus-oxygen.

Term " 1, the annular phosphate of ammediol ", " 1, the ring-type di-phosphate ester of ammediol ", " 2-oxo 2 λ ⁵[1,3,2] two oxa-phospha cyclohexanes ", " 2-oxo-[1,3,2]-two oxa-phospha cyclohexanes " or " two oxa-phospha cyclohexanes " refer to following groups:

Phrase " V and Z are joined together to form optional 1 the heteroatomic cyclic group that comprises by an other 3-5 atom, and this cyclic group condenses in the β of the O that is connected with phosphorus and γ position and aromatic yl group " comprises following groups:

As mentioned above, V is connected by 4 other atoms with Z.

Phrase " W and W ' are joined together to form to choose wantonly by an other 2-5 atom and comprise 0-2 heteroatomic cyclic group, and V is necessary for the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement " comprises following groups:

As mentioned above, W is connected by 2 other atoms with W '.

V=aryl in the said structure, W and W ' are the cyclopropyl group of spiro-condensed.

Term " annular phosphate " refers to

The carbon that is connected with V must have c h bond.The carbon that is connected with Z also must have c h bond.

Term " cis " spatial chemistry refers to V group and the substituent spatial relationship that is connected with phosphorus atoms by the outer singly-bound of the ring on hexa-atomic 2-oxo-phospha cyclohexane ring.Following structure A and B have the cis-isomer of the 2-oxo-phospha cyclohexane of two kinds of possible 2-and 4-replacement.Structure A listed (2S, 4R)-configuration cis-isomer, and structure B listed (2R, 4S)-configuration cis-isomer.

A B

Term " trans " spatial chemistry refers to V group and the substituent spatial relationship that is connected with phosphorus atoms by the outer singly-bound of the ring on hexa-atomic 2-oxo-phospha cyclohexane ring.Following structure C and D have listed the trans-isomer of 2-oxo-phospha cyclohexane that two kinds of possible 2-and 4-replace.Structure C listed (2S, 4S)-trans-isomer of configuration, and structure D listed (2R, 4R)-trans-isomer of configuration.

C D

Term " enantiomter excess percentage (%ee) " refers to optical purity.Can obtain by following formula:

Wherein [R] is the amount of R isomer, and [S] is the amount of S isomer.When R is the advantage isomer, obtain %ee by this formula.

Term " the enantiomer enrichment " refers to the chipal compounds sample of wherein a kind of enantiomer more than another kind of enantiomer.The enantiomer enrichment degree of sample quantizes by enantiomer ratio or enantiomeric excess.

Term " liver " refers to liver organ.

Term " enhancing " refers to increase or improve certain special properties.

Term " liver specificity " refers to following ratio:

[medicine of liver organization or drug metabolite]

[medicine of blood or other tissue or drug metabolite]

By measuring with the animal of medicine or prodrug treatment.This ratio can be by organizing level to determine in specific timing, perhaps can represent the AUC that is determined by the value of 3 or more a plurality of time point determinings.

Term " increases or improves liver specificity " and refers to that with respect to the animal with the parent drug treatment animal's liver specificity of handling with prodrug improves.

Term " enhancing oral administration biaavailability " refers to the absorption increase at least 50% of parent drug amount.On the other hand, the increase of prodrug oral administration biaavailability (comparing with parent drug) is at least 100%, just absorbs to double.The measurement of oral administration biaavailability be often referred to parenteral after compare, measure the amount of prodrug, medicine or drug metabolite in blood behind the oral administration, blood plasma, tissue or the urine.

The ratio of the amount that term " therapeutic index " refers to produce the medicine of the useful reaction of treatment or prodrug and the amount that produces unwanted reaction (increasing) as death or toxicity and/or pharmacology side effect.

Term " delays to transmit " prolongation during referring to, in this period, because the prolongation of the levels of drugs of the feasible treatment of the existence of prodrug effective dose.

Term " is evaded (bypassing) drug resistance " and is referred to forfeiture of pharmacotherapy validity or part forfeiture (drug resistance), this is because due to the ability that very important biochemical route and cytoactive and medicine are evaded this resistance by other approach for the biologically active that produces and keep medicine changed, medicine can not guide these to produce the variation of resistances in other words.

Term " treatment " disease comprises and suppresses disease (slowing down or stop their development), the symptom that palliates a disease or side effect (comprising palliative treatment) and alleviate disease (causing the decline of disease).

Detailed Description Of The Invention

The present invention relates to the pharmaceutically acceptable salt of formula I compound, its stereoisomer, pharmaceutically acceptable salt or prodrug or prodrug, formula I is as follows:

(I)

Wherein:

B is selected from following groups:

With

Perhaps

R ²Be selected from R ³And hydrogen;

R ³Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁴Be selected from R ³And hydrogen;

R ⁵Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁶Be selected from hydrogen and lower acyl;

R ¹²Be selected from hydrogen and lower acyl; And

P is integer 2 or 3;

Perhaps their pharmaceutically acceptable prodrug or salt.

On the one hand, the present invention includes formula I compound:

(I)

Wherein:

B is

R ²Be selected from R ³And hydrogen;

R ³Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁴Be selected from R ⁵And hydrogen;

R ⁵Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁶Be selected from hydrogen and lower acyl;

R ¹²Be selected from hydrogen and lower acyl; And

P is integer 2 or 3;

Or its pharmaceutically acceptable prodrug or salt.

On the other hand, the present invention comprises formula I compound:

(I)

Wherein:

B is

R ²Be selected from R ³And hydrogen;

R ³Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁴Be selected from R ⁵And hydrogen;

R ⁵Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl group;

R ⁶Be selected from hydrogen and lower acyl;

R ¹²Be selected from hydrogen and lower acyl group; And

P is integer 2 or 3;

Or its pharmaceutically acceptable prodrug or salt.

On the other hand, the present invention comprises formula I compound:

(I)

Wherein:

B is

R ²Be selected from R ³And hydrogen;

R ³Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁴Be selected from R ⁵And hydrogen;

R ⁵Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁶Be selected from hydrogen and lower acyl;

R ¹²Be selected from hydrogen and lower acyl; And

P is integer 2 or 3;

Or its pharmaceutically acceptable prodrug or salt.

On the one hand, V is selected from phenyl; The phenyl that is replaced by 1-3 substituting group that independently is selected from following groups: halogen, C ₁-C ₆Alkyl ,-CF ₃,-OR ³,-OR ¹²,-COR ³,-CO ₂R ³,-NR ³ ₂,-NR ¹² ₂,-CO ₂NR ₂ ²,-SR ³,-SO ₂R ³,-SO ₂NR ₂ ²With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that is replaced by 1-2 substituting group that independently is selected from following groups: halogen, C ₁-C ₆Alkyl ,-CF ₃,-OR ³,-OR ¹²,-COR ³,-CO ₂R ³,-NR ³ ₂,-NR ¹² ₂,-CO ₂NR ₂ ²,-SR ³,-SO ₂R ³,-SO ₂NR ₂ ²With-CN, the bicyclic heteroaryl of wherein said bicyclic heteroaryl and replacement has 1-2 hetero atom that independently is selected from N, O and S, and prerequisite is

A) when there being 2 hetero atoms, and 1 when be O, then other 1 be not O or S, and

B) when there being 2 hetero atoms, and 1 when be S, then other 1 be not O or S; Perhaps

V and Z are joined together to form optional 1 the heteroatomic cyclic group that comprises by an other 3-5 atom, and this cyclic group condenses in the β of the O that is connected with phosphorus and γ position and aromatic yl group; And

R ³Be C ₁-C ₆Alkyl.

On the other hand, V is selected from following groups: phenyl; The phenyl that is replaced by 1-3 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that independently is selected from 1-2 substituting group replacement of following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN, the bicyclic heteroaryl of wherein said bicyclic heteroaryl and replacement has 1-2 hetero atom that independently is selected from N, O and S, and prerequisite is

V and Z are joined together to form 6 yuan of rings by 4 other atoms, and condense at the β of the O that is connected with phosphorus and the phenyl of γ position and phenyl or replacement.

On the other hand, V is selected from following groups: phenyl; Independently be selected from the phenyl of 1-2 substituting group replacement of following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Pyridine radicals; Independently be selected from the pyridine radicals of 1 substituting group replacement of following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Furyl; The furyl that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Thienyl; And the thienyl that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃

On the other hand, V is selected from following groups: phenyl, 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-bromo-4-fluoro phenyl, 2-pyridine radicals, 3-pyridine radicals and 4-pyridine radicals.On the other hand, V is selected from following groups: 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-pyridine radicals and 4-pyridine radicals.

On the other hand, V is selected from following groups: phenyl; The phenyl that is replaced by 1-3 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OH ,-OMe ,-NH ₂,-NMe ₂,-OEt ,-COOH ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that is replaced by 1-2 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OH ,-OMe ,-NH ₂,-NMe ₂,-OEt ,-COOH ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With--CN; The bicyclic heteroaryl of wherein said bicyclic heteroaryl and replacement has 1-2 hetero atom that independently is selected from N, O and S, and prerequisite is:

A) when there being 2 hetero atoms, and 1 when be O, then other 1 be not O or S; And

On the one hand, Z is selected from following groups :-H ,-OMe ,-OEt, phenyl, C ₁-C ₃Alkyl ,-NR ⁴ ₂,-SR ⁴,-(CH ₂) _p-OR ⁶,-(CH ₂) _p-SR ⁶With-OCOR ⁵R ⁴Be C ₁-C ₄Alkyl; R ⁵Be selected from following groups: C ₁-C ₄Alkyl, monocyclic aryl and monocycle aralkyl; And R ⁶Be C ₁-C ₄Acyl group.On the other hand, Z is selected from following groups :-H ,-OMe ,-OEt and phenyl.

On the other hand, W and W ' independently are selected from following groups :-H, C ₁-C ₆Alkyl and phenyl; Perhaps W and W ' form cyclic group together by an other 2-5 atom.On the other hand, W and W ' independently are selected from following groups :-H, methyl and V, and perhaps W and W ' are methyl, and prerequisite is when W is V, and then W ' is H.

On the one hand, V is selected from the group of optional monocyclic aryl that replaces and the optional bicyclic heteroaryl that replaces;

W and W ' independently are selected from following groups :-H, methyl and V, and perhaps W and W ' are methyl, and prerequisite is when W is V, and then W ' is H;

Perhaps

W and W ' are joined together to form cyclic group by an other 2-5 atom; And

R ⁴Be C ₁-C ₄Alkyl; R ⁵Be selected from following groups: C ₁-C ₄Alkyl, monocyclic aryl and monocycle aralkyl; And R ⁶Be C ₁-C ₄Acyl group.

On the other hand, V is selected from following groups: phenyl; The phenyl that is replaced by 1-3 substituting group that independently is selected from following groups: halogen, C ₁-C ₆Alkyl ,-CF ₃,-OR ³,-OR ¹²,-COR ³,-CO ₂R ³,-NR ³ ₂,-NR ¹² ₂,-CO ₂NR ₂ ²,-SR ³,-SO ₂R ³,-SO ₂NR ₂ ²With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that is replaced by 1-2 substituting group that independently is selected from following groups: halogen, C ₁-C ₆Alkyl ,-CF ₃,-OR ³,-OR ¹²,-COR ³,-CO ₂R ³,-NR ³ ₂,-NR ¹² ₂,-CO ₂NR ₂ ²,-SR ³,-SO ₂R ³,-SO ₂NR ₂ ²With-CN, the bicyclic heteroaryl of wherein said bicyclic heteroaryl and replacement has 1-2 hetero atom that independently is selected from N, O and S, and prerequisite is:

Perhaps

W and W ' are joined together to form cyclic group by an other 2-5 atom; And

R ³Be C ₁-C ₆Alkyl; R ⁴Be C ₁-C ₄Alkyl; R ⁵Be selected from following groups: C ₁-C ₄Alkyl, monocyclic aryl and monocycle aralkyl; And R ⁶Be C ₁-C ₄Acyl group.

On the other hand, V is selected from following groups: phenyl; The phenyl that is replaced by 1-3 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that is replaced by 1-2 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN, the bicyclic heteroaryl of described bicyclic heteroaryl and replacement has 1-2 hetero atom that independently is selected from N, O and S, and prerequisite is:

V and Z are joined together to form 6 yuan of rings by 4 other atoms, and condense at the β of the O that is connected with phosphorus and the phenyl of γ position and phenyl or replacement; Perhaps

W and W ' are joined together to form cyclic group by an other 2-5 atom; And

On the other hand, V is selected from following groups: phenyl; The phenyl that is replaced by 1-2 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Pyridine radicals; The pyridine radicals that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Furyl; The furyl that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Thienyl; And the thienyl that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃

W and W ' are joined together to form cyclic group by an other 2-5 atom; And

R ⁴Be C ₁-C ₄Alkyl; R ⁵Be selected from C ₁-C ₄Alkyl, monocyclic aryl and monocycle aralkyl; And R ⁶Be C ₁-C ₄Acyl group.

On the other hand, V is selected from following groups: phenyl, 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-bromo-4-fluoro phenyl, 2-pyridine radicals, 3-pyridine radicals and 4-pyridine radicals; And

Z is selected from following groups :-H, OMe, OEt and phenyl; And

W and W ' independently are selected from following groups :-H and phenyl, and perhaps W and W ' are methyl.

On the one hand, Z, W and W ' are-H.On the other hand, V and each bicyclic heteroaryl of all being selected from the optional monocyclic aryl that replace and choosing replacement identical with W.

On the other hand, B is

V is selected from following groups: 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base and 4-pyridine radicals; And Z, W and W ' are-H.

On the other hand, B is

On the other hand, B is

The present invention comprises formula V compound on the other hand:

(V)

Wherein:

5 ' oxygen methylene group of V and ribose part is mutually a cis;

B is selected from following groups:

With

With

V is selected from optional monocyclic aryl that replaces and the optional bicyclic heteroaryl group that replaces; Or its pharmaceutically acceptable prodrug or salt.

Further aspect the present invention includes formula V compound:

(V)

Wherein:

5 ' oxygen methylene group of V and ribose part is mutually a cis;

B is

V is selected from optional monocyclic aryl that replaces and the optional bicyclic heteroaryl that replaces; Or its pharmaceutically acceptable prodrug or salt.

B) when there being 2 hetero atoms, and 1 when be S, then other 1 be not O or S; And

R ³Be C ₁-C ₆Alkyl.

On the other hand, V is selected from following groups: phenyl; The phenyl that is replaced by 1-3 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that is replaced by 1-2 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN, the bicyclic heteroaryl of wherein said bicyclic heteroaryl and replacement has 1-2 hetero atom that independently is selected from N, O and S, and prerequisite is:

Further aspect the present invention includes formula II compound:

(II)

Wherein:

B is selected from following groups:

With

W and W ' are joined together to form cyclic group by an other 2-5 atom;

R ⁴Be C ₁-C ₄Alkyl;

R ⁵Be selected from following groups: C ₁-C ₄Alkyl, monocyclic aryl and monocycle aralkyl; And

R ⁶Be C ₁-C ₄Acyl group;

R ⁷And R ⁸Independently be selected from following groups: hydrogen, C ₁-C ₄Acyl group, C ₁-C ₄Alkoxy carbonyl, and the naturally occurring L-amino acid that is connected to form ester by its carbonyl group; Perhaps

R at 3 '-oxygen ⁷With R at 2 '-oxygen ⁸Form cyclic carbonate together;

R ⁹Be selected from following groups: amino, azido ,-N=CHN (R ⁴) ₂,-NHC (O) R ⁴With-NHC (O) OR ⁴, halogen, OR ⁴And OR ⁶And

R ¹⁰Be selected from OR ⁶, halogen and H.

On the other hand, the present invention comprises formula II compound:

(II)

Wherein:

B is selected from following groups:

With

Perhaps

W and W ' are joined together to form cyclic group by an other 2-5 atom;

R ⁴Be C ₁-C ₄Alkyl;

R ⁶Be C ₁-C ₄Acyl group;

R ⁷And R ⁸Independently be selected from following groups: hydrogen, C ₁-C ₄Acyl group, C ₁-C ₄Alkoxy carbonyl and the naturally occurring L-amino acid that is connected to form ester by its carbonyl group; Perhaps

R at 3 '-oxygen ⁷With R at 2 '-oxygen ⁸Form cyclic carbonate together; With

R ¹⁰Be selected from following groups: OR ⁴, OR ⁶, halogen and H.

The further aspect of the present invention comprises the formula III compound:

(III)

Wherein:

5 ' oxygen methylene group of V and ribose part is mutually a cis;

B is selected from following groups:

With

R ⁴Be C ₁-C ₄Alkyl;

R ⁶Be C ₁-C ₄Acyl group;

R at 3 '-oxygen ⁷With R at 2 '-oxygen ⁸Form cyclic carbonate together;

R ⁹Be selected from following groups: amino, azido ,-N=CHN (R ⁴) ₂,-NHC (O) R ⁴And-NHC (O) OR ⁴, halogen, OR ⁴And OR ⁶And

R ¹⁰Be selected from OR ⁶, halogen and H.

On the one hand, V is selected from following groups: phenyl; The phenyl that is replaced by 1-3 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that is replaced by 1-2 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN.On the other hand, V is selected from following groups: phenyl, 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-bromo-4-fluoro phenyl, 2-pyridine radicals, 3-pyridine radicals and 4-pyridine radicals.

On the other hand, the present invention includes the formula III compound:

(III)

Wherein:

5 ' oxygen methylene group of V and ribose part is mutually a cis;

B is selected from following groups:

With

R ⁴Be C ₁-C ₄Alkyl;

R ⁶Be C ₁-C ₄Acyl group;

R at 3 '-oxygen ⁷With R at 2 '-oxygen ⁸Form together cyclic carbonate and

R ¹⁰Be selected from following groups: OR ⁴, OR ⁶, NH ₂, NHR ⁴, halogen and H.

On the other hand, The compounds of this invention is formula (VI) compound:

(VI)

Wherein X is selected from following groups: NH ₂, NHCH ₃, N (CH ₃) ₂, OCH ₃And SCH ₃

Y and Y ' are independent to be O or NH;

V, W and W ' are independent to be hydrogen, alkyl, alkenyl, alkynyl, aryl and alkaryl, each all optional being substituted; And

Z is hydrogen, CHWOH, CHWOCOW ', SW or CH ₂Aryl.

On the other hand, the present invention includes formula (VII) compound:

(VII)

Wherein B is selected from following groups:

With

X is selected from following groups: NH ₂, NHCH ₃, N (CH ₃) ₂, OCH ₃, SCH ₃, OH and SH;

Y and Y ' are independent to be O or NH;

R ¹⁴Independently be selected from H and NH ₂X is selected from following groups: NH ₂, NHCH ₃, N (CH ₃) ₂, NHR ⁷, OCH ₃, OC ₂H ₅, SCH ₃, OH, SH and halogen;

Heterocyclic bases can be further replaced less than 150 substituting group by molecular weight in any position of heterocyclic bases, described substituting group is selected from following groups: halogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, acyl group and alkoxyl, and wherein said substituting group can pass through the 6 digit pairs connection of carbon, sulphur, oxygen or selenium and heterocyclic bases;

V, W and W ' are independent to be hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, each optional being substituted; And

Z is hydrogen, CHWOH, CHWOCOW ', SW or CH ₂Aryl.

On the other hand, B is selected from following groups:

With

On the other hand, B is selected from following groups:

With

On the other hand, X is NH ₂

Further aspect the present invention includes:

On the other hand, the present invention includes:

Further aspect the present invention includes:

On the other hand, the present invention includes:

Further aspect the present invention includes:

(IX)

Wherein:

Perhaps

R ²Be selected from R ³And hydrogen;

R ³Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁴Be selected from R ³And hydrogen;

R ⁵Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁶Be selected from hydrogen and lower acyl;

R ¹²Be selected from hydrogen and lower acyl; And

P is integer 2 or 3.

On the other hand, the present invention relates to the compound of formula (XI):

(XI)

Wherein 5 ' oxygen methylene group of V and ribose part is cis each other.

On the other hand, the present invention includes:

Further aspect the present invention includes:

Further aspect the present invention includes:

Further aspect the present invention includes:

On the other hand, the present invention includes the compound of formula (X), or its pharmaceutically acceptable salt:

(X)

Wherein:

Perhaps

W and W ' are joined together to form cyclic group by an other 2-5 atom;

R ⁴Be C ₁-C ₄Alkyl;

R ⁵Be selected from C ₁-C ₄Alkyl, monocyclic aryl and monocycle aralkyl;

R ⁶Be C ₁-C ₄Acyl group; With

R at 3 '-oxygen ⁷With R at 2 '-oxygen ⁸Form cyclic carbonate together.

On the other hand, the present invention relates to the compound of formula (XII):

(XII)

Wherein 5 ' oxygen methylene group of V and ribose part is cis each other.

On the other hand, the present invention includes:

On the other hand, the present invention includes:

On the other hand, the present invention includes:

On the other hand, the present invention includes:

On the other hand, the present invention includes:

(XIII)

Wherein:

Perhaps

R ²Be selected from R ³And hydrogen;

R ³Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁴Be selected from R ³And hydrogen;

R ⁵Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁶Be selected from hydrogen and lower acyl;

R ¹²Be selected from hydrogen and lower acyl; And

P is integer 2 or 3.

V and Z are joined together to form optional 1 the heteroatomic cyclic group that comprises by an other 3-5 atom, and this cyclic group condenses in the β of the O that is connected with phosphorus and γ position and aromatic yl group; And R ³Be C ₁-C ₆Alkyl.

Further aspect, V is selected from following groups: phenyl, 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-bromo-4-fluoro phenyl, 2-pyridine radicals, 3-pyridine radicals and 4-pyridine radicals.On the other hand, V is selected from following groups: 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-pyridine radicals and 4-pyridine radicals.

On the other hand, V is selected from following groups: phenyl; The phenyl that is replaced by 1-3 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OH ,-OMe ,-NH ₂,-NMe ₂,-OEt ,-COOH ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that is replaced by 1-2 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OH ,-OMe ,-NH ₂,-NMe ₂,-OEt ,-COOH ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN; The bicyclic heteroaryl of wherein said bicyclic heteroaryl and replacement has 1-2 hetero atom that independently is selected from N, O and S, and prerequisite is:

Perhaps

W and W ' are joined together to form cyclic group by an other 2-5 atom; And

Perhaps

W and W ' are joined together to form cyclic group by an other 2-5 atom; And

Z is selected from following groups :-H, OMe, OEt and phenyl; And

On the other hand, V is selected from following groups: 3-chlorophenyl, 3-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base and 4-pyridine radicals; And Z, W and W ' are-H.

On the other hand, the present invention relates to the compound of formula (XV):

(XV)

Wherein 5 ' oxygen methylene group of V and ribose part is cis each other.

On the other hand, the present invention includes:

On the other hand, the present invention includes:

On the other hand, the present invention includes:

On the other hand, the present invention includes:

(XIV)

Wherein:

W and W ' are joined together to form cyclic group by an other 2-5 atom;

R ⁴Be C ₁-C ₄Alkyl;

R ⁵Be selected from C ₁-C ₄Alkyl, monocyclic aryl and monocycle aralkyl;

R ⁶Be C ₁-C ₄Acyl group; With

R at 3 '-oxygen ⁷With R at 2 '-oxygen ⁸Form cyclic carbonate together.

On the other hand, the present invention includes the compound of formula (XVI):

(XVI)

Wherein 5 ' oxygen methylene group of V and ribose part is cis each other.

On the other hand, the present invention includes:

On the other hand, the present invention includes:

On the other hand, the present invention includes:

On the other hand, the present invention includes:

In another aspect of this invention, The compounds of this invention has the S-three-dimensional chemical configuration in the carbon place that (stereogenic) V-that produces upright structure connects, and has R-three-dimensional chemical configuration (following structure " A ") in the phosphorus center that produces upright structure.In another aspect of this invention, The compounds of this invention has the R-three-dimensional chemical configuration in the carbon place that the V-that produces upright structure connects, and has S-three-dimensional chemical configuration (following structure " B ") in the phosphorus center that produces upright structure.In another aspect of this invention, The compounds of this invention has the S-three-dimensional chemical configuration in the carbon place that the V-that produces upright structure connects, and has S-three-dimensional chemical configuration (following structure " C ") in the phosphorus center that produces upright structure.In another aspect of this invention, The compounds of this invention has the R-three-dimensional chemical configuration in the carbon place that the V-that produces upright structure connects, and has R-three-dimensional chemical configuration (following structure " D ") in the phosphorus center that produces upright structure.The invention is intended to comprise all four kinds of diastereoisomers, and the mixture of these four kinds of diastereoisomers, following situation institute example for 2 '-C-methylfuran ribosyl nucleosides like that, wherein Z, W and W ' are hydrogen:

In one embodiment of the invention, compound has the S-configuration in the carbon place that the V-that produces upright structure connects, and has R-configuration (above structure " A ") in the phosphorus center that produces upright structure.In another embodiment of the present invention, compound has the R-configuration in the carbon place that the V-that produces upright structure connects, and has S-configuration (above structure " B ") in the phosphorus center that produces upright structure.5 '-oxygen methylene group that the present invention also is intended to contain V and ribose part wherein is the mixture of these two kinds of diastereoisomers of cis each other.

On the one hand, following compounds is contained in the scope of the invention, but The compounds of this invention is not limited to the compound that listed.

Following prodrug is the preferred compound of the present invention.Because no matter these compounds are as non-enantiomer mixture or as the equal biologically active of single stereoisomers, so the spatial chemistry of the not shown compound of this paper.In the table 1 the compound of naming represent for the variable designation number in the formula with following convention: M1.V.L1.L2.M1 is the variable of the nucleosides of representative formula I, and described nucleosides is by using group P (O) (O-CH (V) CH ₂CH ₂-O) 5 '-oh group of phosphorylated connects, and obtains formula VI compound.V is for having aryl or the heteroaryl groups of 2 substituting group L1 and L2 at assigned address.V can have other substituting group.

Formula VI

Variable M1:

1)

Variable V: group V1

1) 2-(L1)-3 (L2)-phenyl

2) 2-(L1)-4 (L2)-phenyl

3) 2-(L1)-5 (L2)-phenyl

4) 2-(L1)-6 (L2)-phenyl

5) 3-(L1)-4 (L2)-phenyl

6) 3-(L1)-5 (L2)-phenyl

7) 3-(L1)-6 (L2)-phenyl

8) 2-(L1)-6 (L2)-3-chlorophenyl

9) 4-(L1)-5 (L2)-3-chlorophenyl

Variable V: group V2

1) 2-(L1)-3 (L2)-4-pyridine radicals

2) 2-(L1)-5 (L2)-4-pyridine radicals

3) 2-(L1)-6 (L2)-4-pyridine radicals

4) 3-(L1)-5 (L2)-4-pyridine radicals

5) 3-(L1)-6 (L2)-4-pyridine radicals

6) 2-(L1)-4 (L2)-3-pyridine radicals

7) 2-(L1)-5 (L2)-3-pyridine radicals

8) 2-(L1)-6 (L2)-3-pyridine radicals

9) 4-(L1)-5 (L2)-3-pyridine radicals

Variable V: group V3

1) 4-(L1)-6 (L2)-3-pyridine radicals

2) 5-(L1)-6 (L2)-3-pyridine radicals

3) 3-(L1)-4 (L2)-2-pyridine radicals

4) 3-(L1)-5 (L2)-2-pyridine radicals

5) 3-(L1)-6 (L2)-2-pyridine radicals

6) 4-(L1)-5 (L2)-2-pyridine radicals

7) 4-(L1)-6 (L2)-2-pyridine radicals

8) 3-(L1)-4 (L2)-2-thienyl

9) 3-(L1)-4 (L2)-2-furyl

Variables L 1

1) hydrogen

2) chloro

3) bromo

4) fluoro

5) methyl

6) trifluoromethyl

7) methoxyl group

8) dimethylamino

9) cyano group

Variables L 2

1) hydrogen

2) chloro

3) bromo

4) fluoro

5) methyl

6) trifluoromethyl

7) methoxyl group

8) dimethylamino

9) cyano group

Preferred compound is as shown in table 1, and variable M1 and V1 and L1 and L2 list in proper order with this.For example, compound 1.3.6.7 represents the structure 1 of variable M1, i.e. 7-denitrogenation-2 '-methyladenosine; The structure 3 of group V1, i.e. 2-(L1)-5-(L2) phenyl; The structure 6 of variables L 1, i.e. trifluoromethyl; And the structure 7 of variables L 2, i.e. methoxyl group.Therefore, compound 1.3.6.7. is 7-denitrogenation-2 '-methyladenosine, wherein P (O) (O-CH (V) CH ₂CH ₂O) be connected to 5 '-primary hydroxyl group, be { [1-(2-trifluoromethyl-5-methoxyphenyl)-1,3-propyl group] phosphoryl.

Preferred compound is also listed in table 1, adopts variable M1 and V2, wherein 4 digitized representation M1.V2.L1.L2.

Preferred compound also is a compound shown in the table 1, adopts variable M1 and V3, wherein 4 digitized representation M1.V3.L1.L2.

Table 1

1.1.1.1 1.1.1.2 1.1.1.3 1.1.1.4 1.1.1.5 1.1.1.6 1.1.1.7 1.1.1.8 1.1.1.9 1.1.2.1

1.1.2.2 1.1.2.3 1.1.2.4 1.1.2.5 1.1.2.6 1.1.2.7 1.1.2.8 1.1.2.9 1.1.3.1 1.1.3.2

1.1.3.3 1.1.3.4 1.1.3.5 1.1.3.6 1.1.3.7 1.1.3.8 1.1.3.9 1.1.4.1 1.1.4.2 1.1.4.3

1.1.4.4 1.1.4.5 1.1.4.6 1.1.4.7 1.1.4.8 1.1.4.9 1.1.5.1 1.1.5.2 1.1.5.3 1.1.5.4

1.1.5.5 1.1.5.6 1.1.5.7 1.1.5.8 1.1.5.9 1.1.6.1 1.1.6.2 1.1.6.3 1.1.6.4 1.1.6.5

1.1.6.6 1.1.6.7 1.1.6.8 1.1.6.9 1.1.7.1 1.1.7.2 1.1.7.3 1.1.7.4 1.1.7.5 1.1.7.6

1.1.7.7 1.1.7.8 1.1.7.9 1.1.8.1 1.1.8.2 1.1.8.3 1.1.8.4 1.1.8.5 1.1.8.6 1.1.8.7

1.1.8.8 1.1.8.9 1.1.9.1 1.1.9.2 1.1.9.3 1.1.9.4 1.1.9.5 1.1.9.6 1.1.9.7 1.1.9.8

1.1.9.9 1.2.1.1 1.2.1.2 1.2.1.3 1.2.1.4 1.2.1.5 1.2.1.6 1.2.1.7 1.2.1.8 1.2.1.9

1.2.2.1 1.2.2.2 1.2.2.3 1.2.2.4 1.2.2.5 1.2.2.6 1.2.2.7 1.2.2.8 1.2.2.9 1.2.3.1

1.2.3.2 1.2.3.3 1.2.3.4 1.2.3.5 1.2.3.6 1.2.3.7 1.2.3.8 1.2.3.9 1.2.4.1 1.2.4.2

1.2.4.3 1.2.4.4 1.2.4.5 1.2.4.6 1.2.4.7 1.2.4.8 1.2.4.9 1.2.5.1 1.2.5.2 1.2.5.3

1.2.5.4 1.2.5.5 1.2.5.6 1.2.5.7 1.2.5.8 1.2.5.9 1.2.6.1 1.2.6.2 1.2.6.3 1.2.6.4

1.2.6.5 1.2.6.6 1.2.6.7 1.2.6.8 1.2.6.9 1.2.7.1 1.2.7.2 1.2.7.3 1.2.7.4 1.2.7.5

1.2.7.6 1.2.7.7 1.2.7.8 1.2.7.9 1.2.8.1 1.2.8.2 1.2.8.3 1.2.8.4 1.2.8.5 1.2.8.6

1.2.8.7 1.2.8.8 1.2.8.9 1.2.9.1 1.2.9.2 1.2.9.3 1.2.9.4 1.2.9.5 1.2.9.6 1.2.9.7

1.2.9.8 1.2.9.9 1.3.1.1 1.3.1.2 1.3.1.3 1.3.1.4 1.3.1.5 1.3.1.6 1.3.1.7 1.3.1.8

1.3.1.9 1.3.2.1 1.3.2.2 1.3.2.3 1.3.2.4 1.3.2.5 1.3.2.6 1.3.2.7 1.3.2.8 1.3.2.9

1.3.3.1 1.3.3.2 1.3.3.3 1.3.3.4 1.3.3.5 1.3.3.6 1.3.3.7 1.3.3.8 1.3.3.9 1.3.4.1

1.3.4.2 1.3.4.3 1.3.4.4 1.3.4.5 1.3.4.6 1.3.4.7 1.3.4.8 1.3.4.9 1.3.5.1 1.3.5.2

1.3.5.3 1.3.5.4 1.3.5.5 1.3.5.6 1.3.5.7 1.3.5.8 1.3.5.9 1.3.6.1 1.3.6.2 1.3.6.3

1.3.6.4 1.3.6.5 1.3.6.6 1.3.6.7 1.3.6.8 1.3.6.9 1.3.7.1 1.3.7.2 1.3.7.3 1.3.7.4

1.3.7.5 1.3.7.6 1.3.7.7 1.3.7.8 1.3.7.9 1.3.8.1 1.3.8.2 1.3.8.3 1.3.8.4 1.3.8.5

1.3.8.6 1.3.8.7 1.3.8.8 1.3.8.9 1.3.9.1 1.3.9.2 1.3.9.3 1.3.9.4 1.3.9.5 1.3.9.6

1.3.9.7 1.3.9.8 1.3.9.9 1.4.1.1 1.4.1.2 1.4.1.3 1.4.1.4 1.4.1.5 1.4.1.6 1.4.1.7

1.4.1.8 1.4.1.9 1.4.2.1 1.4.2.2 1.4.2.3 1.4.2.4 1.4.2.5 1.4.2.6 1.4.2.7 1.4.2.8

1.4.2.9 1.4.3.1 1.4.3.2 1.4.3.3 1.4.3.4 1.4.3.5 1.4.3.6 1.4.3.7 1.4.3.8 1.4.3.9

1.4.4.1 1.4.4.2 1.4.4.3 1.4.4.4 1.4.4.5 1.4.4.6 1.4.4.7 1.4.4.8 1.4.4.9 1.4.5.1

1.4.5.2 1.4.5.3 1.4.5.4 1.4.5.5 1.4.5.6 1.4.5.7 1.4.5.8 1.4.5.9 1.4.6.1 1.4.6.2

1.4.6.3 1.4.6.4 1.4.6.5 1.4.6.6 1.4.6.7 1.4.6.8 1.4.6.9 1.4.7.1 1.4.7.2 1.4.7.3

1.4.7.4 1.4.7.5 1.4.7.6 1.4.7.7 1.4.7.8 1.4.7.9 1.4.8.1 1.4.8.2 1.4.8.3 1.4.8.4

1.4.8.5 1.4.8.6 1.4.8.7 1.4.8.8 1.4.8.9 1.4.9.1 1.4.9.2 1.4.9.3 1.4.9.4 1.4.9.5

1.4.9.6 1.4.9.7 1.4.9.8 1.4.9.9 1.5.1.1 1.5.1.2 1.5.1.3 1.5.1.4 1.5.1.5 1.5.1.6

1.5.1.7 1.5.1.8 1.5.1.9 1.5.2.1 1.5.2.2 1.5.2.3 1.5.2.4 1.5.2.5 1.5.2.6 1.5.2.7

1.5.2.8 1.5.2.9 1.5.3.1 1.5.3.2 1.5.3.3 1.5.3.4 1.5.3.5 1.5.3.6 1.5.3.7 1.5.3.8

1.5.3.9 1.5.4.1 1.5.4.2 1.5.4.3 1.5.4.4 1.5.4.5 1.5.4.6 1.5.4.7 1.5.4.8 1.5.4.9

1.5.5.1 1.5.5.2 1.5.5.3 1.5.5.4 1.5.5.5 1.5.5.6 1.5.5.7 1.5.5.8 1.5.5.9 1.5.6.1

1.5.6.2 1.5.6.3 1.5.6.4 1.5.6.5 1.5.6.6 1.5.6.7 1.5.6.8 1.5.6.9 1.5.7.1 1.5.7.2

1.5.7.3 1.5.7.4 1.5.7.5 1.5.7.6 1.5.7.7 1.5.7.8 1.5.7.9 1.5.8.1 1.5.8.2 1.5.8.3

1.5.8.4 1.5.8.5 1.5.8.6 1.5.8.7 1.5.8.8 1.5.8.9 1.5.9.1 1.5.9.2 1.5.9.3 1.5.9.4

1.5.9.5 1.5.9.6 1.5.9.7 1.5.9.8 1.5.9.9 1.6.1.1 1.6.1.2 1.6.1.3 1.6.1.4 1.6.1.5

1.6.1.6 1.6.1.7 1.6.1.8 1.6.1.9 1.6.2.1 1.6.2.2 1.6.2.3 1.6.2.4 1.6.2.5 1.6.2.6

1.6.2.7 1.6.2.8 1.6.2.9 1.6.3.1 1.6.3.2 1.6.3.3 1.6.3.4 1.6.3.5 1.6.3.6 1.6.3.7

1.6.3.8 1.6.3.9 1.6.4.1 1.6.4.2 1.6.4.3 1.6.4.4 1.6.4.5 1.6.4.6 1.6.4.7 1.6.4.8

1.6.4.9 1.6.5.1 1.6.5.2 1.6.5.3 1.6.5.4 1.6.5.5 1.6.5.6 1.6.5.7 1.6.5.8 1.6.5.9

1.6.6.1 1.6.6.2 1.6.6.3 1.6.6.4 1.6.6.5 1.6.6.6 1.6.6.7 1.6.6.8 1.6.6.9 1.6.7.1

1.6.7.2 1.6.7.3 1.6.7.4 1.6.7.5 1.6.7.6 1.6.7.7 1.6.7.8 1.6.7.9 1.6.8.1 1.6.8.2

1.6.8.3 1.6.8.4 1.6.8.5 1.6.8.6 1.6.8.7 1.6.8.8 1.6.8.9 1.6.9.1 1.6.9.2 1.6.9.3

1.6.9.4 1.6.9.5 1.6.9.6 1.6.9.7 1.6.9.8 1.6.9.9 1.7.1.1 1.7.1.2 1.7.1.3 1.7.1.4

1.7.1.5 1.7.1.6 1.7.1.7 1.7.1.8 1.7.1.9 1.7.2.1 1.7.2.2 1.7.2.3 1.7.2.4 1.7.2.5

1.7.2.6 1.7.2.7 1.7.2.8 1.7.2.9 1.7.3.1 1.7.3.2 1.7.3.3 1.7.3.4 1.7.3.5 1.7.3.6

1.7.3.7 1.7.3.8 1.7.3.9 1.7.4.1 1.7.4.2 1.7.4.3 1.7.4.4 1.7.4.5 1.7.4.6 1.7.4.7

1.7.4.8 1.7.4.9 1.7.5.1 1.7.5.2 1.7.5.3 1.7.5.4 1.7.5.5 1.7.5.6 1.7.5.7 1.7.5.8

Table 1 is continuous

1.7.5.9 1.7.6.1 1.7.6.2 1.7.6.3 1.7.6.4 1.7.6.5 1.7.6.6 1.7.6.7 1.7.6.8 1.7.6.9

1.7.7.1 1.7.7.2 1.7.7.3 1.7.7.4 1.7.7.5 1.7.7.6 1.7.7.7 1.7.7.8 1.7.7.9 1.7.8.1

1.7.8.2 1.7.8.3 1.7.8.4 1.7.8.5 1.7.8.6 1.7.8.7 1.7.8.8 1.7.8.9 1.7.9.1 1.7.9.2

1.7.9.3 1.7.9.4 1.7.9.5 1.7.9.6 1.7.9.7 1.7.9.8 1.7.9.9 1.8.1.1 1.8.1.2 1.8.1.3

1.8.1.4 1.8.1.5 1.8.1.6 1.8.1.7 1.8.1.8 1.8.1.9 1.8.2.1 1.8.2.2 1.8.2.3 1.8.2.4

1.8.2.5 1.8.2.6 1.8.2.7 1.8.2.8 1.8.2.9 1.8.3.1 1.8.3.2 1.8.3.3 1.8.3.4 1.8.3.5

1.8.3.6 1.8.3.7 1.8.3.8 1.8.3.9 1.8.4.1 1.8.4.2 1.8.4.3 1.8.4.4 1.8.4.5 1.8.4.6

1.8.4.7 1.8.4.8 1.8.4.9 1.8.5.1 1.8.5.2 1.8.5.3 1.8.5.4 1.8.5.5 1.8.5.6 1.8.5.7

1.8.5.8 1.8.5.9 1.8.6.1 1.8.6.2 1.8.6.3 1.8.6.4 1.8.6.5 1.8.6.6 1.8.6.7 1.8.6.8

1.8.6.9 1.8.7.1 1.8.7.2 1.8.7.3 1.8.7.4 1.8.7.5 1.8.7.6 1.8.7.7 1.8.7.8 1.8.7.9

1.8.8.1 1.8.8.2 1.8.8.3 1.8.8.4 1.8.8.5 1.8.8.6 1.8.8.7 1.8.8.8 1.8.8.9 1.8.9.1

1.8.9.2 1.8.9.3 1.8.9.4 1.8.9.5 1.8.9.6 1.8.9.7 1.8.9.8 1.8.9.9 1.9.1.1 1.9.1.2

1.9.1.3 1.9.1.4 1.9.1.5 1.9.1.6 1.9.1.7 1.9.1.8 1.9.1.9 1.9.2.1 1.9.2.2 1.9.2.3

1.9.2.4 1.9.2.5 1.9.2.6 1.9.2.7 1.9.2.8 1.9.2.9 1.9.3.1 1.9.3.2 1.9.3.3 1.9.3.4

1.9.3.5 1.9.3.6 1.9.3.7 1.9.3.8 1.9.3.9 1.9.4.1 1.9.4.2 1.9.4.3 1.9.4.4 1.9.4.5

1.9.4.6 1.9.4.7 1.9.4.8 1.9.4.9 1.9.5.1 1.9.5.2 1.9.5.3 1.9.5.4 1.9.5.5 1.9.5.6

1.9.5.7 1.9.5.8 1.9.5.9 1.9.6.1 1.9.6.2 1.9.6.3 1.9.6.4 1.9.6.5 1.9.6.6 1.9.6.7

1.9.6.8 1.9.6.9 1.9.7.1 1.9.7.2 1.9.7.3 1.9.7.4 1.9.7.5 1.9.7.6 1.9.7.7 1.9.7.8

1.9.7.9 1.9.8.1 1.9.8.2 1.9.8.3 1.9.8.4 1.9.8.5 1.9.8.6 1.9.8.7 1.9.8.8 1.9.8.9

1.9.9.1 1.9.9.2 1.9.9.3 1.9.9.4 1.9.9.5 1.9.9.6 1.9.9.7 1.9.9.8 1.9.9.9 2.1.1.1

2.1.1.2 2.1.1.3 2.1.1.4 2.1.1.5 2.1.1.6 2.1.1.7 2.1.1.8 2.1.1.9 2.1.2.1 2.1.2.2

2.1.2.3 2.1.2.4 2.1.2.5 2.1.2.6 2.1.2.7 2.1.2.8 2.1.2.9 2.1.3.1 2.1.3.2 2.1.3.3

2.1.3.4 2.1.3.5 2.1.3.6 2.1.3.7 2.1.3.8 2.1.3.9 2.1.4.1 2.1.4.2 2.1.4.3 2.1.4.4

2.1.4.5 2.1.4.6 2.1.4.7 2.1.4.8 2.1.4.9 2.1.5.1 2.1.5.2 2.1.5.3 2.1.5.4 2.1.5.5

2.1.5.6 2.1.5.7 2.1.5.8 2.1.5.9 2.1.6.1 2.1.6.2 2.1.6.3 2.1.6.4 2.1.6.5 2.1.6.6

2.1.6.7 2.1.6.8 2.1.6.9 2.1.7.1 2.1.7.2 2.1.7.3 2.1.7.4 2.1.7.5 2.1.7.6 2.1.7.7

2.1.7.8 2.1.7.9 2.1.8.1 2.1.8.2 2.1.8.3 2.1.8.4 2.1.8.5 2.1.8.6 2.1.8.7 2.1.8.8

2.1.8.9 2.1.9.1 2.1.9.2 2.1.9.3 2.1.9.4 2.1.9.5 2.1.9.6 2.1.9.7 2.1.9.8 2.1.9.9

2.2.1.1 2.2.1.2 2.2.1.3 2.2.1.4 2.2.1.5 2.2.1.6 2.2.1.7 2.2.1.8 2.2.1.9 2.2.2.1

2.2.2.2 2.2.2.3 2.2.2.4 2.2.2.5 2.2.2.6 2.2.2.7 2.2.2.8 2.2.2.9 2.2.3.1 2.2.3.2

2.2.3.3 2.2.3.4 2.2.3.5 2.2.3.6 2.2.3.7 2.2.3.8 2.2.3.9 2.2.4.1 2.2.4.2 2.2.4.3

2.2.4.4 2.2.4.5 2.2.4.6 2.2.4.7 2.2.4.8 2.2.4.9 2.2.5.1 2.2.5.2 2.2.5.3 2.2.5.4

2.2.5.5 2.2.5.6 2.2.5.7 2.2.5.8 2.2.5.9 2.2.6.1 2.2.6.2 2.2.6.3 2.2.6.4 2.2.6.5

2.2.6.6 2.2.6.7 2.2.6.8 2.2.6.9 2.2.7.1 2.2.7.2 2.2.7.3 2.2.7.4 2.2.7.5 2.2.7.6

2.2.7.7 2.2.7.8 2.2.7.9 2.2.8.1 2.2.8.2 2.2.8.3 2.2.8.4 2.2.8.5 2.2.8.6 2.2.8.7

2.2.8.8 2.2.8.9 2.2.9.1 2.2.9.2 2.2.9.3 2.2.9.4 2.2.9.5 2.2.9.6 2.2.9.7 2.2.9.8

2.2.9.9 2.3.1.1 2.3.1.2 2.3.1.3 2.3.1.4 2.3.1.5 2.3.1.6 2.3.1.7 2.3.1.8 2.3.1.9

2.3.2.1 2.3.2.2 2.3.2.3 2.3.2.4 2.3.2.5 2.3.2.6 2.3.2.7 2.3.2.8 2.3.2.9 2.3.3.1

2.3.3.2 2.3.3.3 2.3.3.4 2.3.3.5 2.3.3.6 2.3.3.7 2.3.3.8 2.3.3.9 2.3.4.1 2.3.4.2

2.3.4.3 2.3.4.4 2.3.4.5 2.3.4.6 2.3.4.7 2.3.4.8 2.3.4.9 2.3.5.1 2.3.5.2 2.3.5.3

2.3.5.4 2.3.5.5 2.3.5.6 2.3.5.7 2.3.5.8 2.3.5.9 2.3.6.1 2.3.6.2 2.3.6.3 2.3.6.4

2.3.6.5 2.3.6.6 2.3.6.7 2.3.6.8 2.3.6.9 2.3.7.1 2.3.7.2 2.3.7.3 2.3.7.4 2.3.7.5

2.3.7.6 2.3.7.7 2.3.7.8 2.3.7.9 2.3.8.1 2.3.8.2 2.3.8.3 2.3.8.4 2.3.8.5 2.3.8.6

2.3.8.7 2.3.8.8 2.3.8.9 2.3.9.1 2.3.9.2 2.3.9.3 2.3.9.4 2.3.9.5 2.3.9.6 2.3.9.7

2.3.9.8 2.3.9.9 2.4.1.1 2.4.1.2 2.4.1.3 2.4.1.4 2.4.1.5 2.4.1.6 2.4.1.7 2.4.1.8

2.4.1.9 2.4.2.1 2.4.2.2 2.4.2.3 2.4.2.4 2.4.2.5 2.4.2.6 2.4.2.7 2.4.2.8 2.4.2.9

2.4.3.1 2.4.3.2 2.4.3.3 2.4.3.4 2.4.3.5 2.4.3.6 2.4.3.7 2.4.3.8 2.4.3.9 2.4.4.1

2.4.4.2 2.4.4.3 2.4.4.4 2.4.4.5 2.4.4.6 2.4.4.7 2.4.4.8 2.4.4.9 2.4.5.1 2.4.5.2

2.4.5.3 2.4.5.4 2.4.5.5 2.4.5.6 2.4.5.7 2.4.5.8 2.4.5.9 2.4.6.1 2.4.6.2 2.4.6.3

2.4.6.4 2.4.6.5 2.4.6.6 2.4.6.7 2.4.6.8 2.4.6.9 2.4.7.1 2.4.7.2 2.4.7.3 2.4.7.4

2.4.7.5 2.4.7.6 2.4.7.7 2.4.7.8 2.4.7.9 2.4.8.1 2.4.8.2 2.4.8.3 2.4.8.4 2.4.8.5

2.4.8.6 2.4.8.7 2.4.8.8 2.4.8.9 2.4.9.1 2.4.9.2 2.4.9.3 2.4.9.4 2.4.9.5 2.4.9.6

2.4.9.7 2.4.9.8 2.4.9.9 2.5.1.1 2.5.1.2 2.5.1.3 2.5.1.4 2.5.1.5 2.5.1.6 2.5.1.7

2.5.1.8 2.5.1.9 2.5.2.1 2.5.2.2 2.5.2.3 2.5.2.4 2.5.2.5 2.5.2.6 2.5.2.7 2.5.2.8

Table 1 is continuous

2.5.2.9 2.5.3.1 2.5.3.2 2.5.3.3 2.5.3.4 2.5.3.5 2.5.3.6 2.5.3.7 2.5.3.8 2.5.3.9

2.5.4.1 2.5.4.2 2.5.4.3 2.5.4.4 2.5.4.5 2.5.4.6 2.5.4.7 2.5.4.8 2.5.4.9 2.5.5.1

2.5.5.2 2.5.5.3 2.5.5.4 2.5.5.5 2.5.5.6 2.5.5.7 2.5.5.8 2.5.5.9 2.5.6.1 2.5.6.2

2.5.6.3 2.5.6.4 2.5.6.5 2.5.6.6 2.5.6.7 2.5.6.8 2.5.6.9 2.5.7.1 2.5.7.2 2.5.7.3

2.5.7.4 2.5.7.5 2.5.7.6 2.5.7.7 2.5.7.8 2.5.7.9 2.5.8.1 2.5.8.2 2.5.8.3 2.5.8.4

2.5.8.5 2.5.8.6 2.5.8.7 2.5.8.8 2.5.8.9 2.5.9.1 2.5.9.2 2.5.9.3 2.5.9.4 2.5.9.5

2.5.9.6 2.5.9.7 2.5.9.8 2.5.9.9 2.6.1.1 2.6.1.2 2.6.1.3 2.6.1.4 2.6.1.5 2.6.1.6

2.6.1.7 2.6.1.8 2.6.1.9 2.6.2.1 2.6.2.2 2.6.2.3 2.6.2.4 2.6.2.5 2.6.2.6 2.6.2.7

2.6.2.8 2.6.2.9 2.6.3.1 2.6.3.2 2.6.3.3 2.6.3.4 2.6.3.5 2.6.3.6 2.6.3.7 2.6.3.8

2.6.3.9 2.6.4.1 2.6.4.2 2.6.4.3 2.6.4.4 2.6.4.5 2.6.4.6 2.6.4.7 2.6.4.8 2.6.4.9

2.6.5.1 2.6.5.2 2.6.5.3 2.6.5.4 2.6.5.5 2.6.5.6 2.6.5.7 2.6.5.8 2.6.5.9 2.6.6.1

2.6.6.2 2.6.6.3 2.6.6.4 2.6.6.5 2.6.6.6 2.6.6.7 2.6.6.8 2.6.6.9 2.6.7.1 2.6.7.2

2.6.7.3 2.6.7.4 2.6.7.5 2.6.7.6 2.6.7.7 2.6.7.8 2.6.7.9 2.6.8.1 2.6.8.2 2.6.8.3

2.6.8.4 2.6.8.5 2.6.8.6 2.6.8.7 2.6.8.8 2.6.8.9 2.6.9.1 2.6.9.2 2.6.9.3 2.6.9.4

2.6.9.5 2.6.9.6 2.6.9.7 2.6.9.8 2.6.9.9 2.7.1.1 2.7.1.2 2.7.1.3 2.7.1.4 2.7.1.5

2.7.1.6 2.7.1.7 2.7.1.8 2.7.1.9 2.7.2.1 2.7.2.2 2.7.2.3 2.7.2.4 2.7.2.5 2.7.2.6

2.7.2.7 2.7.2.8 2.7.2.9 2.7.3.1 2.7.3.2 2.7.3.3 2.7.3.4 2.7.3.5 2.7.3.6 2.7.3.7

2.7.3.8 2.7.3.9 2.7.4.1 2.7.4.2 2.7.4.3 2.7.4.4 2.7.4.5 2.7.4.6 2.7.4.7 2.7.4.8

2.7.4.9 2.7.5.1 2.7.5.2 2.7.5.3 2.7.5.4 2.7.5.5 2.7.5.6 2.7.5.7 2.7.5.8 2.7.5.9

2.7.6.1 2.7.6.2 2.7.6.3 2.7.6.4 2.7.6.5 2.7.6.6 2.7.6.7 2.7.6.8 2.7.6.9 2.7.7.1

2.7.7.2 2.7.7.3 2.7.7.4 2.7.7.5 2.7.7.6 2.7.7.7 2.7.7.8 2.7.7.9 2.7.8.1 2.7.8.2

2.7.8.3 2.7.8.4 2.7.8.5 2.7.8.6 2.7.8.7 2.7.8.8 2.7.8.9 2.7.9.1 2.7.9.2 2.7.9.3

2.7.9.4 2.7.9.5 2.7.9.6 2.7.9.7 2.7.9.8 2.7.9.9 2.8.1.1 2.8.1.2 2.8.1.3 2.8.1.4

2.8.1.5 2.8.1.6 2.8.1.7 2.8.1.8 2.8.1.9 2.8.2.1 2.8.2.2 2.8.2.3 2.8.2.4 2.8.2.5

2.8.2.6 2.8.2.7 2.8.2.8 2.8.2.9 2.8.3.1 2.8.3.2 2.8.3.3 2.8.3.4 2.8.3.5 2.8.3.6

2.8.3.7 2.8.3.8 2.8.3.9 2.8.4.1 2.8.4.2 2.8.4.3 2.8.4.4 2.8.4.5 2.8.4.6 2.8.4.7

2.8.4.8 2.8.4.9 2.8.5.1 2.8.5.2 2.8.5.3 2.8.5.4 2.8.5.5 2.8.5.6 2.8.5.7 2.8.5.8

2.8.5.9 2.8.6.1 2.8.6.2 2.8.6.3 2.8.6.4 2.8.6.5 2.8.6.6 2.8.6.7 2.8.6.8 2.8.6.9

2.8.7.1 2.8.7.2 2.8.7.3 2.8.7.4 2.8.7.5 2.8.7.6 2.8.7.7 2.8.7.8 2.8.7.9 2.8.8.1

2.8.8.2 2.8.8.3 2.8.8.4 2.8.8.5 2.8.8.6 2.8.8.7 2.8.8.8 2.8.8.9 2.8.9.1 2.8.9.2

2.8.9.3 2.8.9.4 2.8.9.5 2.8.9.6 2.8.9.7 2.8.9.8 2.8.9.9 2.9.1.1 2.9.1.2 2.9.1.3

2.9.1.4 2.9.1.5 2.9.1.6 2.9.1.7 2.9.1.8 2.9.1.9 2.9.2.1 2.9.2.2 2.9.2.3 2.9.2.4

2.9.2.5 2.9.2.6 2.9.2.7 2.9.2.8 2.9.2.9 2.9.3.1 2.9.3.2 2.9.3.3 2.9.3.4 2.9.3.5

2.9.3.6 2.9.3.7 2.9.3.8 2.9.3.9 2.9.4.1 2.9.4.2 2.9.4.3 2.9.4.4 2.9.4.5 2.9.4.6

2.9.4.7 2.9.4.8 2.9.4.9 2.9.5.1 2.9.5.2 2.9.5.3 2.9.5.4 2.9.5.5 2.9.5.6 2.9.5.7

2.9.5.8 2.9.5.9 2.9.6.1 2.9.6.2 2.9.6.3 2.9.6.4 2.9.6.5 2.9.6.6 2.9.6.7 2.9.6.8

2.9.6.9 2.9.7.1 2.9.7.2 2.9.7.3 2.9.7.4 2.9.7.5 2.9.7.6 2.9.7.7 2.9.7.8 2.9.7.9

2.9.8.1 2.9.8.2 2.9.8.3 2.9.8.4 2.9.8.5 2.9.8.6 2.9.8.7 2.9.8.8 2.9.8.9 2.9.9.1

2.9.9.2 2.9.9.3 2.9.9.4 2.9.9.5 2.9.9.6 2.9.9.7 2.9.9.8 2.9.9.9 3.1.1.1 3.1.1.2

3.1.1.3 3.1.1.4 3.1.1.5 3.1.1.6 3.1.1.7 3.1.1.8 3.1.1.9 3.1.2.1 3.1.2.2 3.1.2.3

3.1.2.4 3.1.2.5 3.1.2.6 3.1.2.7 3.1.2.8 3.1.2.9 3.1.3.1 3.1.3.2 3.1.3.3 3.1.3.4

3.1.3.5 3.1.3.6 3.1.3.7 3.1.3.8 3.1.3.9 3.1.4.1 3.1.4.2 3.1.4.3 3.1.4.4 3.1.4.5

3.1.4.6 3.1.4.7 3.1.4.8 3.1.4.9 3.1.5.1 3.1.5.2 3.1.5.3 3.1.5.4 3.1.5.5 3.1.5.6

3.1.5.7 3.1.5.8 3.1.5.9 3.1.6.1 3.1.6.2 3.1.6.3 3.1.6.4 3.1.6.5 3.1.6.6 3.1.6.7

3.1.6.8 3.1.6.9 3.1.7.1 3.1.7.2 3.1.7.3 3.1.7.4 3.1.7.5 3.1.7.6 3.1.7.7 3.1.7.8

3.1.7.9 3.1.8.1 3.1.8.2 3.1.8.3 3.1.8.4 3.1.8.5 3.1.8.6 3.1.8.7 3.1.8.8 3.1.8.9

3.1.9.1 3.1.9.2 3.1.9.3 3.1.9.4 3.1.9.5 3.1.9.6 3.1.9.7 3.1.9.8 3.1.9.9 3.2.1.1

3.2.1.2 3.2.1.3 3.2.1.4 3.2.1.5 3.2.1.6 3.2.1.7 3.2.1.8 3.2.1.9 3.2.2.1 3.2.2.2

3.2.2.3 3.2.2.4 3.2.2.5 3.2.2.6 3.2.2.7 3.2.2.8 3.2.2.9 3.2.3.1 3.2.3.2 3.2.3.3

3.2.3.4 3.2.3.5 3.2.3.6 3.2.3.7 3.2.3.8 3.2.3.9 3.2.4.1 3.2.4.2 3.2.4.3 3.2.4.4

3.2.4.5 3.2.4.6 3.2.4.7 3.2.4.8 3.2.4.9 3.2.5.1 3.2.5.2 3.2.5.3 3.2.5.4 3.2.5.5

3.2.5.6 3.2.5.7 3.2.5.8 3.2.5.9 3.2.6.1 3.2.6.2 3.2.6.3 3.2.6.4 3.2.6.5 3.2.6.6

3.2.6.7 3.2.6.8 3.2.6.9 3.2.7.1 3.2.7.2 3.2.7.3 3.2.7.4 3.2.7.5 3.2.7.6 3.2.7.7

3.2.7.8 3.2.7.9 3.2.8.1 3.2.8.2 3.2.8.3 3.2.8.4 3.2.8.5 3.2.8.6 3.2.8.7 3.2.8.8

Table 1 is continuous

3.2.8.9 3.2.9.1 3.2.9.2 3.2.9.3 3.2.9.4 3.2.9.5 3.2.9.6 3.2.9.7 3.2.9.8 3.2.9.9

3.3.1.1 3.3.1.2 3.3.1.3 3.3.1.4 3.3.1.5 3.3.1.6 3.3.1.7 3.3.1.8 3.3.1.9 3.3.2.1

3.3.2.2 3.3.2.3 3.3.2.4 3.3.2.5 3.3.2.6 3.3.2.7 3.3.2.8 3.3.2.9 3.3.3.1 3.3.3.2

3.3.3.3 3.3.3.4 3.3.3.5 3.3.3.6 3.3.3.7 3.3.3.8 3.3.3.9 3.3.4.1 3.3.4.2 3.3.4.3

3.3.4.4 3.3.4.5 3.3.4.6 3.3.4.7 3.3.4.8 3.3.4.9 3.3.5.1 3.3.5.2 3.3.5.3 3.3.5.4

3.3.5.5 3.3.5.6 3.3.5.7 3.3.5.8 3.3.5.9 3.3.6.1 3.3.6.2 3.3.6.3 3.3.6.4 3.3.6.5

3.3.6.6 3.3.6.7 3.3.6.8 3.3.6.9 3.3.7.1 3.3.7.2 3.3.7.3 3.3.7.4 3.3.7.5 3.3.7.6

3.3.7.7 3.3.7.8 3.3.7.9 3.3.8.1 3.3.8.2 3.3.8.3 3.3.8.4 3.3.8.5 3.3.8.6 3.3.8.7

3.3.8.8 3.3.8.9 3.3.9.1 3.3.9.2 3.3.9.3 3.3.9.4 3.3.9.5 3.3.9.6 3.3.9.7 3.3.9.8

3.3.9.9 3.4.1.1 3.4.1.2 3.4.1.3 3.4.1.4 3.4.1.5 3.4.1.6 3.4.1.7 3.4.1.8 3.4.1.9

3.4.2.1 3.4.2.2 3.4.2.3 3.4.2.4 3.4.2.5 3.4.2.6 3.4.2.7 3.4.2.8 3.4.2.9 3.4.3.1

3.4.3.2 3.4.3.3 3.4.3.4 3.4.3.5 3.4.3.6 3.4.3.7 3.4.3.8 3.4.3.9 3.4.4.1 3.4.4.2

3.4.4.3 3.4.4.4 3.4.4.5 3.4.4.6 3.4.4.7 3.4.4.8 3.4.4.9 3.4.5.1 3.4.5.2 3.4.5.3

3.4.5.4 3.4.5.5 3.4.5.6 3.4.5.7 3.4.5.8 3.4.5.9 3.4.6.1 3.4.6.2 3.4.6.3 3.4.6.4

3.4.6.5 3.4.6.6 3.4.6.7 3.4.6.8 3.4.6.9 3.4.7.1 3.4.7.2 3.4.7.3 3.4.7.4 3.4.7.5

3.4.7.6 3.4.7.7 3.4.7.8 3.4.7.9 3.4.8.1 3.4.8.2 3.4.8.3 3.4.8.4 3.4.8.5 3.4.8.6

3.4.8.7 3.4.8.8 3.4.8.9 3.4.9.1 3.4.9.2 3.4.9.3 3.4.9.4 3.4.9.5 3.4.9.6 3.4.9.7

3.4.9.8 3.4.9.9 3.5.1.1 3.5.1.2 3.5.1.3 3.5.1.4 3.5.1.5 3.5.1.6 3.5.1.7 3.5.1.8

3.5.1.9 3.5.2.1 3.5.2.2 3.5.2.3 3.5.2.4 3.5.2.5 3.5.2.6 3.5.2.7 3.5.2.8 3.5.2.9

3.5.3.1 3.5.3.2 3.5.3.3 3.5.3.4 3.5.3.5 3.5.3.6 3.5.3.7 3.5.3.8 3.5.3.9 3.5.4.1

3.5.4.2 3.5.4.3 3.5.4.4 3.5.4.5 3.5.4.6 3.5.4.7 3.5.4.8 3.5.4.9 3.5.5.1 3.5.5.2

3.5.5.3 3.5.5.4 3.5.5.5 3.5.5.6 3.5.5.7 3.5.5.8 3.5.5.9 3.5.6.1 3.5.6.2 3.5.6.3

3.5.6.4 3.5.6.5 3.5.6.6 3.5.6.7 3.5.6.8 3.5.6.9 3.5.7.1 3.5.7.2 3.5.7.3 3.5.7.4

3.5.7.5 3.5.7.6 3.5.7.7 3.5.7.8 3.5.7.9 3.5.8.1 3.5.8.2 3.5.8.3 3.5.8.4 3.5.8.5

3.5.8.6 3.5.8.7 3.5.8.8 3.5.8.9 3.5.9.1 3.5.9.2 3.5.9.3 3.5.9.4 3.5.9.5 3.5.9.6

3.5.9.7 3.5.9.8 3.5.9.9 3.6.1.1 3.6.1.2 3.6.1.3 3.6.1.4 3.6.1.5 3.6.1.6 3.6.1.7

3.6.1.8 3.6.1.9 3.6.2.1 3.6.2.2 3.6.2.3 3.6.2.4 3.6.2.5 3.6.2.6 3.6.2.7 3.6.2.8

3.6.2.9 3.6.3.1 3.6.3.2 3.6.3.3 3.6.3.4 3.6.3.5 3.6.3.6 3.6.3.7 3.6.3.8 3.6.3.9

3.6.4.1 3.6.4.2 3.6.4.3 3.6.4.4 3.6.4.5 3.6.4.6 3.6.4.7 3.6.4.8 3.6.4.9 3.6.5.1

3.6.5.2 3.6.5.3 3.6.5.4 3.6.5.5 3.6.5.6 3.6.5.7 3.6.5.8 3.6.5.9 3.6.6.1 3.6.6.2

3.6.6.3 3.6.6.4 3.6.6.5 3.6.6.6 3.6.6.7 3.6.6.8 3.6.6.9 3.6.7.1 3.6.7.2 3.6.7.3

3.6.7.4 3.6.7.5 3.6.7.6 3.6.7.7 3.6.7.8 3.6.7.9 3.6.8.1 3.6.8.2 3.6.8.3 3.6.8.4

3.6.8.5 3.6.8.6 3.6.8.7 3.6.8.8 3.6.8.9 3.6.9.1 3.6.9.2 3.6.9.3 3.6.9.4 3.6.9.5

3.6.9.6 3.6.9.7 3.6.9.8 3.6.9.9 3.7.1.1 3.7.1.2 3.7.1.3 3.7.1.4 3.7.1.5 3.7.1.6

3.7.1.7 3.7.1.8 3.7.1.9 3.7.2.1 3.7.2.2 3.7.2.3 3.7.2.4 3.7.2.5 3.7.2.6 3.7.2.7

3.7.2.8 3.7.2.9 3.7.3.1 3.7.3.2 3.7.3.3 3.7.3.4 3.7.3.5 3.7.3.6 3.7.3.7 3.7.3.8

3.7.3.9 3.7.4.1 3.7.4.2 3.7.4.3 3.7.4.4 3.7.4.5 3.7.4.6 3.7.4.7 3.7.4.8 3.7.4.9

3.7.5.1 3.7.5.2 3.7.5.3 3.7.5.4 3.7.5.5 3.7.5.6 3.7.5.7 3.7.5.8 3.7.5.9 3.7.6.1

3.7.6.2 3.7.6.3 3.7.6.4 3.7.6.5 3.7.6.6 3.7.6.7 3.7.6.8 3.7.6.9 3.7.7.1 3.7.7.2

3.7.7.3 3.7.7.4 3.7.7.5 3.7.7.6 3.7.7.7 3.7.7.8 3.7.7.9 3.7.8.1 3.7.8.2 3.7.8.3

3.7.8.4 3.7.8.5 3.7.8.6 3.7.8.7 3.7.8.8 3.7.8.9 3.7.9.1 3.7.9.2 3.7.9.3 3.7.9.4

3.7.9.5 3.7.9.6 3.7.9.7 3.7.9.8 3.7.9.9 3.8.1.1 3.8.1.2 3.8.1.3 3.8.1.4 3.8.1.5

3.8.1.6 3.8.1.7 3.8.1.8 3.8.1.9 3.8.2.1 3.8.2.2 3.8.2.3 3.8.2.4 3.8.2.5 3.8.2.6

3.8.2.7 3.8.2.8 3.8.2.9 3.8.3.1 3.8.3.2 3.8.3.3 3.8.3.4 3.8.3.5 3.8.3.6 3.8.3.7

3.8.3.8 3.8.3.9 3.8.4.1 3.8.4.2 3.8.4.3 3.8.4.4 3.8.4.5 3.8.4.6 3.8.4.7 3.8.4.8

3.8.4.9 3.8.5.1 3.8.5.2 3.8.5.3 3.8.5.4 3.8.5.5 3.8.5.6 3.8.5.7 3.8.5.8 3.8.5.9

3.8.6.1 3.8.6.2 3.8.6.3 3.8.6.4 3.8.6.5 3.8.6.6 3.8.6.7 3.8.6.8 3.8.6.9 3.8.7.1

3.8.7.2 3.8.7.3 3.8.7.4 3.8.7.5 3.8.7.6 3.8.7.7 3.8.7.8 3.8.7.9 3.8.8.1 3.8.8.2

3.8.8.3 3.8.8.4 3.8.8.5 3.8.8.6 3.8.8.7 3.8.8.8 3.8.8.9 3.8.9.1 3.8.9.2 3.8.9.3

3.8.9.4 3.8.9.5 3.8.9.6 3.8.9.7 3.8.9.8 3.8.9.9 3.9.1.1 3.9.1.2 3.9.1.3 3.9.1.4

3.9.1.5 3.9.1.6 3.9.1.7 3.9.1.8 3.9.1.9 3.9.2.1 3.9.2.2 3.9.2.3 3.9.2.4 3.9.2.5

3.9.2.6 3.9.2.7 3.9.2.8 3.9.2.9 3.9.3.1 3.9.3.2 3.9.3.3 3.9.3.4 3.9.3.5 3.9.3.6

3.9.3.7 3.9.3.8 3.9.3.9 3.9.4.1 3.9.4.2 3.9.4.3 3.9.4.4 3.9.4.5 3.9.4.6 3.9.4.7

3.9.4.8 3.9.4.9 3.9.5.1 3.9.5.2 3.9.5.3 3.9.5.4 3.9.5.5 3.9.5.6 3.9.5.7 3.9.5.8

Table 1 is continuous

3.9.5.9 3.9.6.1 3.9.6.2 3.9.6.3 3.9.6.4 3.9.6.5 3.9.6.6 3.9.6.7 3.9.6.8 3.9.6.9

3.9.7.1 3.9.7.2 3.9.7.3 3.9.7.4 3.9.7.5 3.9.7.6 3.9.7.7 3.9.7.8 3.9.7.9 3.9.8.1

3.9.8.2 3.9.8.3 3.9.8.4 3.9.8.5 3.9.8.6 3.9.8.7 3.9.8.8 3.9.8.9 3.9.9.1 3.9.9.2

3.9.9.3 3.9.9.4 3.9.9.5 3.9.9.6 3.9.9.7 3.9.9.8 3.9.9.9 4.1.1.1 4.1.1.2 4.1.1.3

4.1.1.4 4.1.1.5 4.1.1.6 4.1.1.7 4.1.1.8 4.1.1.9 4.1.2.1 4.1.2.2 4.1.2.3 4.1.2.4

4.1.2.5 4.1.2.6 4.1.2.7 4.1.2.8 4.1.2.9 4.1.3.1 4.1.3.2 4.1.3.3 4.1.3.4 4.1.3.5

4.1.3.6 4.1.3.7 4.1.3.8 4.1.3.9 4.1.4.1 4.1.4.2 4.1.4.3 4.1.4.4 4.1.4.5 4.1.4.6

4.1.4.7 4.1.4.8 4.1.4.9 4.1.5.1 4.1.5.2 4.1.5.3 4.1.5.4 4.1.5.5 4.1.5.6 4.1.5.7

4.1.5.8 4.1.5.9 4.1.6.1 4.1.6.2 4.1.6.3 4.1.6.4 4.1.6.5 4.1.6.6 4.1.6.7 4.1.6.8

4.1.6.9 4.1.7.1 4.1.7.2 4.1.7.3 4.1.7.4 4.1.7.5 4.1.7.6 4.1.7.7 4.1.7.8 4.1.7.9

4.1.8.1 4.1.8.2 4.1.8.3 4.1.8.4 4.1.8.5 4.1.8.6 4.1.8.7 4.1.8.8 4.1.8.9 4.1.9.1

4.1.9.2 4.1.9.3 4.1.9.4 4.1.9.5 4.1.9.6 4.1.9.7 4.1.9.8 4.1.9.9 4.2.1.1 4.2.1.2

4.2.1.3 4.2.1.4 4.2.1.5 4.2.1.6 4.2.1.7 4.2.1.8 4.2.1.9 4.2.2.1 4.2.2.2 4.2.2.3

4.2.2.4 4.2.2.5 4.2.2.6 4.2.2.7 4.2.2.8 4.2.2.9 4.2.3.1 4.2.3.2 4.2.3.3 4.2.3.4

4.2.3.5 4.2.3.6 4.2.3.7 4.2.3.8 4.2.3.9 4.2.4.1 4.2.4.2 4.2.4.3 4.2.4.4 4.2.4.5

4.2.4.6 4.2.4.7 4.2.4.8 4.2.4.9 4.2.5.1 4.2.5.2 4.2.5.3 4.2.5.4 4.2.5.5 4.2.5.6

4.2.5.7 4.2.5.8 4.2.5.9 4.2.6.1 4.2.6.2 4.2.6.3 4.2.6.4 4.2.6.5 4.2.6.6 4.2.6.7

4.2.6.8 4.2.6.9 4.2.7.1 4.2.7.2 4.2.7.3 4.2.7.4 4.2.7.5 4.2.7.6 4.2.7.7 4.2.7.8

4.2.7.9 4.2.8.1 4.2.8.2 4.2.8.3 4.2.8.4 4.2.8.5 4.2.8.6 4.2.8.7 4.2.8.8 4.2.8.9

4.2.9.1 4.2.9.2 4.2.9.3 4.2.9.4 4.2.9.5 4.2.9.6 4.2.9.7 4.2.9.8 4.2.9.9 4.3.1.1

4.3.1.2 4.3.1.3 4.3.1.4 4.3.1.5 4.3.1.6 4.3.1.7 4.3.1.8 4.3.1.9 4.3.2.1 4.3.2.2

4.3.2.3 4.3.2.4 4.3.2.5 4.3.2.6 4.3.2.7 4.3.2.8 4.3.2.9 4.3.3.1 4.3.3.2 4.3.3.3

4.3.3.4 4.3.3.5 4.3.3.6 4.3.3.7 4.3.3.8 4.3.3.9 4.3.4.1 4.3.4.2 4.3.4.3 4.3.4.4

4.3.4.5 4.3.4.6 4.3.4.7 4.3.4.8 4.3.4.9 4.3.5.1 4.3.5.2 4.3.5.3 4.3.5.4 4.3.5.5

4.3.5.6 4.3.5.7 4.3.5.8 4.3.5.9 4.3.6.1 4.3.6.2 4.3.6.3 4.3.6.4 4.3.6.5 4.3.6.6

4.3.6.7 4.3.6.8 4.3.6.9 4.3.7.1 4.3.7.2 4.3.7.3 4.3.7.4 4.3.7.5 4.3.7.6 4.3.7.7

4.3.7.8 4.3.7.9 4.3.8.1 4.3.8.2 4.3.8.3 4.3.8.4 4.3.8.5 4.3.8.6 4.3.8.7 4.3.8.8

4.3.8.9 4.3.9.1 4.3.9.2 4.3.9.3 4.3.9.4 4.3.9.5 4.3.9.6 4.3.9.7 4.3.9.8 4.3.9.9

4.4.1.1 4.4.1.2 4.4.1.3 4.4.1.4 4.4.1.5 4.4.1.6 4.4.1.7 4.4.1.8 4.4.1.9 4.4.2.1

4.4.2.2 4.4.2.3 4.4.2.4 4.4.2.5 4.4.2.6 4.4.2.7 4.4.2.8 4.4.2.9 4.4.3.1 4.4.3.2

4.4.3.3 4.4.3.4 4.4.3.5 4.4.3.6 4.4.3.7 4.4.3.8 4.4.3.9 4.4.4.1 4.4.4.2 4.4.4.3

4.4.4.4 4.4.4.5 4.4.4.6 4.4.4.7 4.4.4.8 4.4.4.9 4.4.5.1 4.4.5.2 4.4.5.3 4.4.5.4

4.4.5.5 4.4.5.6 4.4.5.7 4.4.5.8 4.4.5.9 4.4.6.1 4.4.6.2 4.4.6.3 4.4.6.4 4.4.6.5

4.4.6.6 4.4.6.7 4.4.6.8 4.4.6.9 4.4.7.1 4.4.7.2 4.4.7.3 4.4.7.4 4.4.7.5 4.4.7.6

4.4.7.7 4.4.7.8 4.4.7.9 4.4.8.1 4.4.8.2 4.4.8.3 4.4.8.4 4.4.8.5 4.4.8.6 4.4.8.7

4.4.8.8 4.4.8.9 4.4.9.1 4.4.9.2 4.4.9.3 4.4.9.4 4.4.9.5 4.4.9.6 4.4.9.7 4.4.9.8

4.4.9.9 4.5.1.1 4.5.1.2 4.5.1.3 4.5.1.4 4.5.1.5 4.5.1.6 4.5.1.7 4.5.1.8 4.5.1.9

4.5.2.1 4.5.2.2 4.5.2.3 4.5.2.4 4.5.2.5 4.5.2.6 4.5.2.7 4.5.2.8 4.5.2.9 4.5.3.1

4.5.3.2 4.5.3.3 4.5.3.4 4.5.3.5 4.5.3.6 4.5.3.7 4.5.3.8 4.5.3.9 4.5.4.1 4.5.4.2

4.5.4.3 4.5.4.4 4.5.4.5 4.5.4.6 4.5.4.7 4.5.4.8 4.5.4.9 4.5.5.1 4.5.5.2 4.5.5.3

4.5.5.4 4.5.5.5 4.5.5.6 4.5.5.7 4.5.5.8 4.5.5.9 4.5.6.1 4.5.6.2 4.5.6.3 4.5.6.4

4.5.6.5 4.5.6.6 4.5.6.7 4.5.6.8 4.5.6.9 4.5.7.1 4.5.7.2 4.5.7.3 4.5.7.4 4.5.7.5

4.5.7.6 4.5.7.7 4.5.7.8 4.5.7.9 4.5.8.1 4.5.8.2 4.5.8.3 4.5.8.4 4.5.8.5 4.5.8.6

4.5.8.7 4.5.8.8 4.5.8.9 4.5.9.1 4.5.9.2 4.5.9.3 4.5.9.4 4.5.9.5 4.5.9.6 4.5.9.7

4.5.9.8 4.5.9.9 4.6.1.1 4.6.1.2 4.6.1.3 4.6.1.4 4.6.1.5 4.6.1.6 4.6.1.7 4.6.1.8

4.6.1.9 4.6.2.1 4.6.2.2 4.6.2.3 4.6.2.4 4.6.2.5 4.6.2.6 4.6.2.7 4.6.2.8 4.6.2.9

4.6.3.1 4.6.3.2 4.6.3.3 4.6.3.4 4.6.3.5 4.6.3.6 4.6.3.7 4.6.3.8 4.6.3.9 4.6.4.1

4.6.4.2 4.6.4.3 4.6.4.4 4.6.4.5 4.6.4.6 4.6.4.7 4.6.4.8 4.6.4.9 4.6.5.1 4.6.5.2

4.6.5.3 4.6.5.4 4.6.5.5 4.6.5.6 4.6.5.7 4.6.5.8 4.6.5.9 4.6.6.1 4.6.6.2 4.6.6.3

4.6.6.4 4.6.6.5 4.6.6.6 4.6.6.7 4.6.6.8 4.6.6.9 4.6.7.1 4.6.7.2 4.6.7.3 4.6.7.4

4.6.7.5 4.6.7.6 4.6.7.7 4.6.7.8 4.6.7.9 4.6.8.1 4.6.8.2 4.6.8.3 4.6.8.4 4.6.8.5

4.6.8.6 4.6.8.7 4.6.8.8 4.6.8.9 4.6.9.1 4.6.9.2 4.6.9.3 4.6.9.4 4.6.9.5 4.6.9.6

4.6.9.7 4.6.9.8 4.6.9.9 4.7.1.1 4.7.1.2 4.7.1.3 4.7.1.4 4.7.1.5 4.7.1.6 4.7.1.7

4.7.1.8 4.7.1.9 4.7.2.1 4.7.2.2 4.7.2.3 4.7.2.4 4.7.2.5 4.7.2.6 4.7.2.7 4.7.2.8

Table 1 is continuous

4.7.2.9 4.7.3.1 4.7.3.2 4.7.3.3 4.7.3.4 4.7.3.5 4.7.3.6 4.7.3.7 4.7.3.8 4.7.3.9

4.7.4.1 4.7.4.2 4.7.4.3 4.7.4.4 4.7.4.5 4.7.4.6 4.7.4.7 4.7.4.8 4.7.4.9 4.7.5.1

4.7.5.2 4.7.5.3 4.7.5.4 4.7.5.5 4.7.5.6 4.7.5.7 4.7.5.8 4.7.5.9 4.7.6.1 4.7.6.2

4.7.6.3 4.7.6.4 4.7.6.5 4.7.6.6 4.7.6.7 4.7.6.8 4.7.6.9 4.7.7.1 4.7.7.2 4.7.7.3

4.7.7.4 4.7.7.5 4.7.7.6 4.7.7.7 4.7.7.8 4.7.7.9 4.7.8.1 4.7.8.2 4.7.8.3 4.7.8.4

4.7.8.5 4.7.8.6 4.7.8.7 4.7.8.8 4.7.8.9 4.7.9.1 4.7.9.2 4.7.9.3 4.7.9.4 4.7.9.5

4.7.9.6 4.7.9.7 4.7.9.8 4.7.9.9 4.8.1.1 4.8.1.2 4.8.1.3 4.8.1.4 4.8.1.5 4.8.1.6

4.8.1.7 4.8.1.8 4.8.1.9 4.8.2.1 4.8.2.2 4.8.2.3 4.8.2.4 4.8.2.5 4.8.2.6 4.8.2.7

4.8.2.8 4.8.2.9 4.8.3.1 4.8.3.2 4.8.3.3 4.8.3.4 4.8.3.5 4.8.3.6 4.8.3.7 4.8.3.8

4.8.3.9 4.8.4.1 4.8.4.2 4.8.4.3 4.8.4.4 4.8.4.5 4.8.4.6 4.8.4.7 4.8.4.8 4.8.4.9

4.8.5.1 4.8.5.2 4.8.5.3 4.8.5.4 4.8.5.5 4.8.5.6 4.8.5.7 4.8.5.8 4.8.5.9 4.8.6.1

4.8.6.2 4.8.6.3 4.8.6.4 4.8.6.5 4.8.6.6 4.8.6.7 4.8.6.8 4.8.6.9 4.8.7.1 4.8.7.2

4.8.7.3 4.8.7.4 4.8.7.5 4.8.7.6 4.8.7.7 4.8.7.8 4.8.7.9 4.8.8.1 4.8.8.2 4.8.8.3

4.8.8.4 4.8.8.5 4.8.8.6 4.8.8.7 4.8.8.8 4.8.8.9 4.8.9.1 4.8.9.2 4.8.9.3 4.8.9.4

4.8.9.5 4.8.9.6 4.8.9.7 4.8.9.8 4.8.9.9 4.9.1.1 4.9.1.2 4.9.1.3 4.9.1.4 4.9.1.5

4.9.1.6 4.9.1.7 4.9.1.8 4.9.1.9 4.9.2.1 4.9.2.2 4.9.2.3 4.9.2.4 4.9.2.5 4.9.2.6

4.9.2.7 4.9.2.8 4.9.2.9 4.9.3.1 4.9.3.3 4.9.3.3 4.9.3.4 4.9.3.5 4.9.3.6 4.9.3.7

4.9.3.8 4.9.3.9 4.9.4.1 4.9.4.2 4.9.4.3 4.9.4.4 4.9.4.5 4.9.4.6 4.9.4.7 4.9.4.8

4.9.4.9 4.9.5.1 4.9.5.2 4.9.5.3 4.9.5.4 4.9.5.5 4.9.5.6 4.9.5.7 4.9.5.8 4.9.5.9

4.9.6.1 4.9.6.2 4.9.6.3 4.9.6.4 4.9.6.5 4.9.6.6 4.9.6.7 4.9.6.8 4.9.6.9 4.9.7.1

4.9.7.2 4.9.7.3 4.9.7.4 4.9.7.5 4.9.7.6 4.9.7.7 4.9.7.8 4.9.7.9 4.9.8.1 4.9.8.2

4.9.8.3 4.9.8.4 4.9.8.5 4.9.8.6 4.9.8.7 4.9.8.8 4.9.8.9 4.9.9.1 4.9.9.2 4.9.9.3

4.9.9.4 4.9.9.5 4.9.9.6 4.9.9.7 4.9.9.8 4.9.9.9

5.1.1.1 5.1.1.2 5.1.1.3

5.1.1.4 5.1.1.5 5.1.1.6 5.1.1.7 5.1.1.8 5.1.1.9 5.1.2.1 5.1.2.2 5.1.2.3 5.1.2.4

5.1.2.5 5.1.2.6 5.1.2.7 5.1.2.8 5.1.2.9 5.1.3.1 5.1.3.2 5.1.3.3 5.1.3.4 5.1.3.5

5.1.3.6 5.1.3.7 5.1.3.8 5.1.3.9 5.1.4.1 5.1.4.2 5.1.4.3 5.1.4.4 5.1.4.5 5.1.4.6

5.1.4.7 5.1.4.8 5.1.4.9 5.1.5.1 5.1.5.2 5.1.5.3 5.1.5.4 5.1.5.5 5.1.5.6 5.1.5.7

5.1.5.8 5.1.5.9 5.1.6.1 5.1.6.2 5.1.6.3 5.1.6.4 5.1.6.5 5.1.6.6 5.1.6.7 5.1.6.8

5.1.6.9 5.1.7.1 5.1.7.2 5.1.7.3 5.1.7.4 5.1.7.5 5.1.7.6 5.1.7.7 5.1.7.8 5.1.7.9

5.1.8.1 5.1.8.2 5.1.8.3 5.1.8.4 5.1.8.5 5.1.8.6 5.1.8.7 5.1.8.8 5.1.8.9 5.1.9.1

5.1.9.2 5.1.9.3 5.1.9.4 5.1.9.5 5.1.9.6 5.1.9.7 5.1.9.8 5.1.9.9 5.2.1.1 5.2.1.2

5.2.1.3 5.2.1.4 5.2.1.5 5.2.1.6 5.2.1.7 5.2.1.8 5.2.1.9 5.2.2.1 5.2.2.2 5.2.2.3

5.2.2.4 5.2.2.5 5.2.2.6 5.2.2.7 5.2.2.8 5.2.2.9 5.2.3.1 5.2.3.2 5.2.3.3 5.2.3.4

5.2.3.5 5.2.3.6 5.2.3.7 5.2.3.8 5.2.3.9 5.2.4.1 5.2.4.2 5.2.4.3 5.2.4.4 5.2.4.5

5.2.4.6 5.2.4.7 5.2.4.8 5.2.4.9 5.2.5.1 5.2.5.2 5.2.5.3 5.2.5.4 5.2.5.5 5.2.5.6

5.2.5.7 5.2.5.8 5.2.5.9 5.2.6.1 5.2.6.2 5.2.6.3 5.2.6.4 5.2.6.5 5.2.6.6 5.2.6.7

5.2.6.8 5.2.6.9 5.2.7.1 5.2.7.2 5.2.7.3 5.2.7.4 5.2.7.5 5.2.7.6 5.2.7.7 5.2.7.8

5.2.7.9 5.2.8.1 5.2.8.2 5.2.8.3 5.2.8.4 5.2.8.5 5.2.8.6 5.2.8.7 5.2.8.8 5.2.8.9

5.2.9.1 5.2.9.2 5.2.9.3 5.2.9.4 5.2.9.5 5.2.9.6 5.2.9.7 5.2.9.8 5.2.9.9 5.3.1.1

5.3.1.2 5.3.1.3 5.3.1.4 5.3.1.5 5.3.1.6 5.3.1.7 5.3.1.8 5.3.1.9 5.3.2.1 5.3.2.2

5.3.2.3 5.3.2.4 5.3.2.5 5.3.2.6 5.3.2.7 5.3.2.8 5.3.2.9 5.3.3.1 5.3.3.2 5.3.3.3

5.3.3.4 5.3.3.5 5.3.3.6 5.3.3.7 5.3.3.8 5.3.3.9 5.3.4.1 5.3.4.2 5.3.4.3 5.3.4.4

5.3.4.5 5.3.4.6 5.3.4.7 5.3.4.8 5.3.4.9 5.3.5.1 5.3.5.2 5.3.5.3 5.3.5.4 5.3.5.5

5.3.5.6 5.3.5.7 5.3.5.8 5.3.5.9 5.3.6.1 5.3.6.2 5.3.6.3 5.3.6.4 5.3.6.5 5.3.6.6

5.3.6.7 5.3.6.8 5.3.6.9 5.3.7.1 5.3.7.2 5.3.7.3 5.3.7.4 5.3.7.5 5.3.7.6 5.3.7.7

5.3.7.8 5.3.7.9 5.3.8.1 5.3.8.2 5.3.8.3 5.3.8.4 5.3.8.5 5.3.8.6 5.3.8.7 5.3.8.8

5.3.8.9 5.3.9.1 5.3.9.2 5.3.9.3 5.3.9.4 5.3.9.5 5.3.9.6 5.3.9.7 5.3.9.8 5.3.9.9

5.4.1.1 5.4.1.2 5.4.1.3 5.4.1.4 5.4.1.5 5.4.1.6 5.4.1.7 5.4.1.8 5.4.1.9 5.4.2.1

Table 1 is continuous

5.4.2.2 5.4.2.3 5.4.2.4 5.4.2.5 5.4.2.6 5.4.2.7 5.4.2.8 5.4.2.9 5.4.3.1 5.4.3.2

5.4.3.3 5.4.3.4 5.4.3.5 5.4.3.6 5.4.3.7 5.4.3.8 5.4.3.9 5.4.4.1 5.4.4.2 5.4.4.3

5.4.4.4 5.4.4.5 5.4.4.6 5.4.4.7 5.4.4.8 5.4.4.9 5.4.5.1 5.4.5.2 5.4.5.3 5.4.5.4

5.4.5.5 5.4.5.6 5.4.5.7 5.4.5.8 5.4.5.9 5.4.6.1 5.4.6.2 5.4.6.3 5.4.6.4 5.4.6.5

5.4.6.6 5.4.6.7 5.4.6.8 5.4.6.9 5.4.7.1 5.4.7.2 5.4.7.3 5.4.7.4 5.4.7.5 5.4.7.6

5.4.7.7 5.4.7.8 5.4.7.9 5.4.8.1 5.4.8.2 5.4.8.3 5.4.8.4 5.4.8.5 5.4.8.6 5.4.8.7

5.4.8.8 5.4.8.9 5.4.9.1 5.4.9.2 5.4.9.3 5.4.9.4 5.4.9.5 5.4.9.6 5.4.9.7 5.4.9.8

5.4.9.9 5.5.1.1 5.5.1.2 5.5.1.3 5.5.1.4 5.5.1.5 5.5.1.6 5.5.1.7 5.5.1.8 5.5.1.9

5.5.2.1 5.5.2.2 5.5.2.3 5.5.2.4 5.5.2.5 5.5.2.6 5.5.2.7 5.5.2.8 5.5.2.9 5.5.3.1

5.5.3.2 5.5.3.3 5.5.3.4 5.5.3.5 5.5.3.6 5.5.3.7 5.5.3.8 5.5.3.9 5.5.4.1 5.5.4.2

5.5.4.3 5.5.4.4 5.5.4.5 5.5.4.6 5.5.4.7 5.5.4.8 5.5.4.9 5.5.5.1 5.5.5.2 5.5.5.3

5.5.5.4 5.5.5.5 5.5.5.6 5.5.5.7 5.5.5.8 5.5.5.9 5.5.6.1 5.5.6.2 5.5.6.3 5.5.6.4

5.5.6.5 5.5.6.6 5.5.6.7 5.5.6.8 5.5.6.9 5.5.7.1 5.5.7.2 5.5.7.3 5.5.7.4 5.5.7.5

5.5.7.6 5.5.7.7 5.5.7.8 5.5.7.9 5.5.8.1 5.5.8.2 5.5.8.3 5.5.8.4 5.5.8.5 5.5.8.6

5.5.8.7 5.5.8.8 5.5.8.9 5.5.9.1 5.5.9.2 5.5.9.3 5.5.9.4 5.5.9.5 5.5.9.6 5.5.9.7

5.5.9.8 5.5.9.9 5.6.1.1 5.6.1.2 5.6.1.3 5.6.1.4 5.6.1.5 5.6.1.6 5.6.1.7 5.6.1.8

5.6.1.9 5.6.2.1 5.6.2.2 5.6.2.3 5.6.2.4 5.6.2.5 5.6.2.6 5.6.2.7 5.6.2.8 5.6.2.9

5.6.3.1 5.6.3.2 5.6.3.3 5.6.3.4 5.6.3.5 5.6.3.6 5.6.3.7 5.6.3.8 5.6.3.9 5.6.4.1

5.6.4.2 5.6.4.3 5.6.4.4 5.6.4.5 5.6.4.6 5.6.4.7 5.6.4.8 5.6.4.9 5.6.5.1 5.6.5.2

5.6.5.3 5.6.5.4 5.6.5.5 5.6.5.6 5.6.5.7 5.6.5.8 5.6.5.9 5.6.6.1 5.6.6.2 5.6.6.3

5.6.6.4 5.6.6.5 5.6.6.6 5.6.6.7 5.6.6.8 5.6.6.9 5.6.7.1 5.6.7.2 5.6.7.3 5.6.7.4

5.6.7.5 5.6.7.6 5.6.7.7 5.6.7.8 5.6.7.9 5.6.8.1 5.6.8.2 5.6.8.3 5.6.8.4 5.6.8.5

5.6.8.6 5.6.8.7 5.6.8.8 5.6.8.9 5.6.9.1 5.6.9.2 5.6.9.3 5.6.9.4 5.6.9.5 5.6.9.6

5.6.9.7 5.6.9.8 5.6.9.9 5.7.1.1 5.7.1.2 5.7.1.3 5.7.1.4 5.7.1.5 5.7.1.6 5.7.1.7

5.7.1.8 5.7.1.9 5.7.2.1 5.7.2.2 5.7.2.3 5.7.2.4 5.7.2.5 5.7.2.6 5.7.2.7 5.7.2.8

5.7.2.9 5.7.3.1 5.7.3.2 5.7.3.3 5.7.3.4 5.7.3.5 5.7.3.6 5.7.3.7 5.7.3.8 5.7.3.9

5.7.4.1 5.7.4.2 5.7.4.3 5.7.4.4 5.7.4.5 5.7.4.6 5.7.4.7 5.7.4.8 5.7.4.9 5.7.5.1

5.7.5.2 5.7.5.3 5.7.5.4 5.7.5.5 5.7.5.6 5.7.5.7 5.7.5.8 5.7.5.9 5.7.6.1 5.7.6.2

5.7.6.3 5.7.6.4 5.7.6.5 5.7.6.6 5.7.6.7 5.7.6.8 5.7.6.9 5.7.7.1 5.7.7.2 5.7.7.3

5.7.7.4 5.7.7.5 5.7.7.6 5.7.7.7 5.7.7.8 5.7.7.9 5.7.8.1 5.7.8.2 5.7.8.3 5.7.8.4

5.7.8.5 5.7.8.6 5.7.8.7 5.7.8.8 5.7.8.9 5.7.9.1 5.7.9.2 5.7.9.3 5.7.9.4 5.7.9.5

5.7.9.6 5.7.9.7 5.7.9.8 5.7.9.9 5.8.1.1 5.8.1.2 5.8.1.3 5.8.1.4 5.8.1.5 5.8.1.6

5.8.1.7 5.8.1.8 5.8.1.9 5.8.2.1 5.8.2.2 5.8.2.3 5.8.2.4 5.8.2.5 5.8.2.6 5.8.2.7

5.8.2.8 5.8.2.9 5.8.3.1 5.8.3.2 5.8.3.3 5.8.3.4 5.8.3.5 5.8.3.6 5.8.3.7 5.8.3.8

5.8.3.9 5.8.4.1 5.8.4.2 5.8.4.3 5.8.4.4 5.8.4.5 5.8.4.6 5.8.4.7 5.8.4.8 5.8.4.9

5.8.5.1 5.8.5.2 5.8.5.3 5.8.5.4 5.8.5.5 5.8.5.6 5.8.5.7 5.8.5.8 5.8.5.9 5.8.6.1

5.8.6.2 5.8.6.3 5.8.6.4 5.8.6.5 5.8.6.6 5.8.6.7 5.8.6.8 5.8.6.9 5.8.7.1 5.8.7.2

5.8.7.3 5.8.7.4 5.8.7.5 5.8.7.6 5.8.7.7 5.8.7.8 5.8.7.9 5.8.8.1 5.8.8.2 5.8.8.3

5.8.8.4 5.8.8.5 5.8.8.6 5.8.8.7 5.8.8.8 5.8.8.9 5.8.9.1 5.8.9.2 5.8.9.3 5.8.9.4

5.8.9.5 5.8.9.6 5.8.9.7 5.8.9.8 5.8.9.9 5.9.1.1 5.9.1.2 5.9.1.3 5.9.1.4 5.9.1.5

5.9.1.6 5.9.1.7 5.9.1.8 5.9.1.9 5.9.2.1 5.9.2.2 5.9.2.3 5.9.2.4 5.9.2.5 5.9.2.6

5.9.2.7 5.9.2.8 5.9.2.9 5.9.3.1 5.9.3.2 5.9.3.3 5.9.3.4 5.9.3.5 5.9.3.6 5.9.3.7

5.9.3.8 5.9.3.9 5.9.4.1 5.9.4.2 5.9.4.3 5.9.4.4 5.9.4.5 5.9.4.6 5.9.4.7 5.9.4.8

5.9.4.9 5.9.5.1 5.9.5.2 5.9.5.3 5.9.5.4 5.9.5.5 5.9.5.6 5.9.5.7 5.9.5.8 5.9.5.9

5.9.6.1 5.9.6.2 5.9.6.3 5.9.6.4 5.9.6.5 5.9.6.6 5.9.6.7 5.9.6.8 5.9.6.9 5.9.7.1

5.9.7.2 5.9.7.3 5.9.7.4 5.9.7.5 5.9.7.6 5.9.7.7 5.9.7.8 5.9.7.9 5.9.8.1 5.9.8.2

5.9.8.3 5.9.8.4 5.9.8.5 5.9.8.6 5.9.8.7 5.9.8.8 5.9.8.9 5.9.9.1 5.9.9.2 5.9.9.3

5.9.9.4 5.9.9.5 5.9.9.6 5.9.9.7 5.9.9.8 5.9.9.9 6.1.1.1 6.1.1.2 6.1.1.3

6.1.1.4 6.1.1.5 6.1.1.6 6.1.1.7 6.1.1.8 6.1.1.9 6.1.2.1 6.1.2.2 6.1.2.3 6.1.2.4

Table 1 is continuous

6.1.2.5 6.1.2.6 6.1.2.7 6.1.2.8 6.1.2.9 6.1.3.1 6.1.3.2 6.1.3.3 6.1.3.4 6.1.3.5

6.1.3.6 6.1.3.7 6.1.3.8 6.1.3.9 6.1.4.1 6.1.4.2 6.1.4.3 6.1.4.4 6.1.4.5 6.1.4.6

6.1.4.7 6.1.4.8 6.1.4.9 6.1.5.1 6.1.5.2 6.1.5.3 6.1.5.4 6.1.5.5 6.1.5.6 6.1.5.7

6.1.5.8 6.1.5.9 6.1.6.1 6.1.6.2 6.1.6.3 6.1.6.4 6.1.6.5 6.1.6.6 6.1.6.7 6.1.6.8

6.1.6.9 6.1.7.1 6.1.7.2 6.1.7.3 6.1.7.4 6.1.7.5 6.1.7.6 6.1.7.7 6.1.7.8 6.1.7.9

6.1.8.1 6.1.8.2 6.1.8.3 6.1.8.4 6.1.8.5 6.1.8.6 6.1.8.7 6.1.8.8 6.1.8.9 6.1.9.1

6.1.9.2 6.1.9.3 6.1.9.4 6.1.9.5 6.1.9.6 6.1.9.7 6.1.9.8 6.1.9.9 6.2.1.1 6.2.1.2

6.2.1.3 6.2.1.4 6.2.1.5 6.2.1.6 6.2.1.7 6.2.1.8 6.2.1.9 6.2.2.1 6.2.2.2 6.2.2.3

6.2.2.4 6.2.2.5 6.2.2.6 6.2.2.7 6.2.2.8 6.2.2.9 6.2.3.1 6.2.3.2 6.2.3.3 6.2.3.4

6.2.3.5 6.2.3.6 6.2.3.7 6.2.3.8 6.2.3.9 6.2.4.1 6.2.4.2 6.2.4.3 6.2.4.4 6.2.4.5

6.2.4.6 6.2.4.7 6.2.4.8 6.2.4.9 6.2.5.1 6.2.5.2 6.2.5.3 6.2.5.4 6.2.5.5 6.2.5.6

6.2.5.7 6.2.5.8 6.2.5.9 6.2.6.1 6.2.6.2 6.2.6.3 6.2.6.4 6.2.6.5 6.2.6.6 6.2.6.7

6.2.6.8 6.2.6.9 6.2.7.1 6.2.7.2 6.2.7.3 6.2.7.4 6.2.7.5 6.2.7.6 6.2.7.7 6.2.7.8

6.2.7.9 6.2.8.1 6.2.8.2 6.2.8.3 6.2.8.4 6.2.8.5 6.2.8.6 6.2.8.7 6.2.8.8 6.2.8.9

6.2.9.1 6.2.9.2 6.2.9.3 6.2.9.4 6.2.9.5 6.2.9.6 6.2.9.7 6.2.9.8 6.2.9.9 6.3.1.1

6.3.1.2 6.3.1.3 6.3.1.4 6.3.1.5 6.3.1.6 6.3.1.7 6.3.1.8 6.3.1.9 6.3.2.1 6.3.2.2

6.3.2.3 6.3.2.4 6.3.2.5 6.3.2.6 6.3.2.7 6.3.2.8 6.3.2.9 6.3.3.1 6.3.3.2 6.3.3.3

6.3.3.4 6.3.3.5 6.3.3.6 6.3.3.7 6.3.3.8 6.3.3.9 6.3.4.1 6.3.4.2 6.3.4.3 6.3.4.4

6.3.4.5 6.3.4.6 6.3.4.7 6.3.4.8 6.3.4.9 6.3.5.1 6.3.5.2 6.3.5.3 6.3.5.4 6.3.5.5

6.3.5.6 6.3.5.7 6.3.5.8 6.3.5.9 6.3.6.1 6.3.6.2 6.3.6.3 6.3.6.4 6.3.6.5 6.3.6.6

6.3.6.7 6.3.6.8 6.3.6.9 6.3.7.1 6.3.7.2 6.3.7.3 6.3.7.4 6.3.7.5 6.3.7.6 6.3.7.7

6.3.7.8 6.3.7.9 6.3.8.1 6.3.8.2 6.3.8.3 6.3.8.4 6.3.8.5 6.3.8.6 6.3.8.7 6.3.8.8

6.3.8.9 6.3.9.1 6.3.9.2 6.3.9.3 6.3.9.4 6.3.9.5 6.3.9.6 6.3.9.7 6.3.9.8 6.3.9.9

6.4.1.1 6.4.1.2 6.4.1.3 6.4.1.4 6.4.1.5 6.4.1.6 6.4.1.7 6.4.1.8 6.4.1.9 6.4.2.1

6.4.2.2 6.4.2.3 6.4.2.4 6.4.2.5 6.4.2.6 6.4.2.7 6.4.2.8 6.4.2.9 6.4.3.1 6.4.3.2

6.4.3.3 6.4.3.4 6.4.3.5 6.4.3.6 6.4.3.7 6.4.3.8 6.4.3.9 6.4.4.1 6.4.4.2 6.4.4.3

6.4.4.4 6.4.4.5 6.4.4.6 6.4.4.7 6.4.4.8 6.4.4.9 6.4.5.1 6.4.5.2 6.4.5.3 6.4.5.4

6.4.5.5 6.4.5.6 6.4.5.7 6.4.5.8 6.4.5.9 6.4.6.1 6.4.6.2 6.4.6.3 6.4.6.4 6.4.6.5

6.4.6.6 6.4.6.7 6.4.6.8 6.4.6.9 6.4.7.1 6.4.7.2 6.4.7.3 6.4.7.4 6.4.7.5 6.4.7.6

6.4.7.7 6.4.7.8 6.4.7.9 6.4.8.1 6.4.8.2 6.4.8.3 6.4.8.4 6.4.8.5 6.4.8.6 6.4.8.7

6.4.8.8 6.4.8.9 6.4.9.1 6.4.9.2 6.4.9.3 6.4.9.4 6.4.9.5 6.4.9.6 6.4.9.7 6.4.9.8

6.4.9.9 6.5.1.1 6.5.1.2 6.5.1.3 6.5.1.4 6.5.1.5 6.5.1.6 6.5.1.7 6.5.1.8 6.5.1.9

6.5.2.1 6.5.2.2 6.5.2.3 6.5.2.4 6.5.2.5 6.5.2.6 6.5.2.7 6.5.2.8 6.5.2.9 6.5.3.1

6.5.3.2 6.5.3.3 6.5.3.4 6.5.3.5 6.5.3.6 6.5.3.7 6.5.3.8 6.5.3.9 6.5.4.1 6.5.4.2

6.5.4.3 6.5.4.4 6.5.4.5 6.5.4.6 6.5.4.7 6.5.4.8 6.5.4.9 6.5.5.1 6.5.5.2 6.5.5.3

6.5.5.4 6.5.5.5 6.5.5.6 6.5.5.7 6.5.5.8 6.5.5.9 6.5.6.1 6.5.6.2 6.5.6.3 6.5.6.4

6.5.6.5 6.5.6.6 6.5.6.7 6.5.6.8 6.5.6.9 6.5.7.1 6.5.7.2 6.5.7.3 6.5.7.4 6.5.7.5

6.5.7.6 6.5.7.7 6.5.7.8 6.5.7.9 6.5.8.1 6.5.8.2 6.5.8.3 6.5.8.4 6.5.8.5 6.5.8.6

6.5.8.7 6.5.8.8 6.5.8.9 6.5.9.1 6.5.9.2 6.5.9.3 6.5.9.4 6.5.9.5 6.5.9.6 6.5.9.7

6.5.9.8 6.5.9.9 6.6.1.1 6.6.1.2 6.6.1.3 6.6.1.4 6.6.1.5 6.6.1.6 6.6.1.7 6.6.1.8

6.6.1.9 6.6.2.1 6.6.2.2 6.6.2.3 6.6.2.4 6.6.2.5 6.6.2.6 6.6.2.7 6.6.2.8 6.6.2.9

6.6.3.1 6.6.3.2 6.6.3.3 6.6.3.4 6.6.3.5 6.6.3.6 6.6.3.7 6.6.3.8 6.6.3.9 6.6.4.1

6.6.4.2 6.6.4.3 6.6.4.4 6.6.4.5 6.6.4.6 6.6.4.7 6.6.4.8 6.6.4.9 6.6.5.1 6.6.5.2

6.6.5.3 6.6.5.4 6.6.5.5 6.6.5.6 6.6.5.7 6.6.5.8 6.6.5.9 6.6.6.1 6.6.6.2 6.6.6.3

6.6.6.4 6.6.6.5 6.6.6.6 6.6.6.7 6.6.6.8 6.6.6.9 6.6.7.1 6.6.7.2 6.6.7.3 6.6.7.4

6.6.7.5 6.6.7.6 6.6.7.7 6.6.7.8 6.6.7.9 6.6.8.1 6.6.8.2 6.6.8.3 6.6.8.4 6.6.8.5

6.6.8.6 6.6.8.7 6.6.8.8 6.6.8.9 6.6.9.1 6.6.9.2 6.6.9.3 6.6.9.4 6.6.9.5 6.6.9.6

6.6.9.7 6.6.9.8 6.6.9.9 6.7.1.1 6.7.1.2 6.7.1.3 6.7.1.4 6.7.1.5 6.7.1.6 6.7.1.7

6.7.1.8 6.7.1.9 6.7.2.1 6.7.2.2 6.7.2.3 6.7.2.4 6.7.2.5 6.7.2.6 6.7.2.7 6.7.2.8

Table 1 is continuous

6.7.2.9 6.7.3.1 6.7.3.2 6.7.3.3 6.7.3.4 6.7.3.5 6.7.3.6 6.7.3.7 6.7.3.8 6.7.3.9

6.7.4.1 6.7.4.2 6.7.4.3 6.7.4.4 6.7.4.5 6.7.4.6 6.7.4.7 6.7.4.8 6.7.4.9 6.7.5.1

6.7.5.2 6.7.5.3 6.7.5.4 6.7.5.5 6.7.5.6 6.7.5.7 6.7.5.8 6.7.5.9 6.7.6.1 6.7.6.2

6.7.6.3 6.7.6.4 6.7.6.5 6.7.6.6 6.7.6.7 6.7.6.8 6.7.6.9 6.7.7.1 6.7.7.2 6.7.7.3

6.7.7.4 6.7.7.5 6.7.7.6 6.7.7.7 6.7.7.8 6.7.7.9 6.7.8.1 6.7.8.2 6.7.8.3 6.7.8.4

6.7.8.5 6.7.8.6 6.7.8.7 6.7.8.8 6.7.8.9 6.7.9.1 6.7.9.2 6.7.9.3 6.7.9.4 6.7.9.5

6.7.9.6 6.7.9.7 6.7.9.8 6.7.9.9 6.8.1.1 6.8.1.2 6.8.1.3 6.8.1.4 6.8.1.5 6.8.1.6

6.8.1.7 6.8.1.8 6.8.1.9 6.8.2.1 6.8.2.2 6.8.2.3 6.8.2.4 6.8.2.5 6.8.2.6 6.8.2.7

6.8.2.8 6.8.2.9 6.8.3.1 6.8.3.2 6.8.3.3 6.8.3.4 6.8.3.5 6.8.3.6 6.8.3.7 6.8.3.8

6.8.3.9 6.8.4.1 6.8.4.2 6.8.4.3 6.8.4.4 6.8.4.5 6.8.4.6 6.8.4.7 6.8.4.8 6.8.4.9

6.8.5.1 6.8.5.2 6.8.5.3 6.8.5.4 6.8.5.5 6.8.5.6 6.8.5.7 6.8.5.8 6.8.5.9 6.8.6.1

6.8.6.2 6.8.6.3 6.8.6.4 6.8.6.5 6.8.6.6 6.8.6.7 6.8.6.8 6.8.6.9 6.8.7.1 6.8.7.2

6.8.7.3 6.8.7.4 6.8.7.5 6.8.7.6 6.8.7.7 6.8.7.8 6.8.7.9 6.8.8.1 6.8.8.2 6.8.8.3

6.8.8.4 6.8.8.5 6.8.8.6 6.8.8.7 6.8.8.8 6.8.8.9 6.8.9.1 6.8.9.2 6.8.9.3 6.8.9.4

6.8.9.5 6.8.9.6 6.8.9.7 6.8.9.8 6.8.9.9 6.9.1.1 6.9.1.2 6.9.1.3 6.9.1.4 6.9.1.5

6.9.1.6 6.9.1.7 6.9.1.8 6.9.1.9 6.9.2.1 6.9.2.2 6.9.2.3 6.9.2.4 6.9.2.5 6.9.2.6

6.9.2.7 6.9.2.8 6.9.2.9 6.9.3.1 6.9.3.2 6.9.3.3 6.9.3.4 6.9.3.5 6.9.3.6 6.9.3.7

6.9.3.8 6.9.3.9 6.9.4.1 6.9.4.2 6.9.4.3 6.9.4.4 6.9.4.5 6.9.4.6 6.9.4.7 6.9.4.8

6.9.4.9 6.9.5.1 6.9.5.2 6.9.5.3 6.9.5.4 6.9.5.5 6.9.5.6 6.9.5.7 6.9.5.8 6.9.5.9

6.9.6.1 6.9.6.2 6.9.6.3 6.9.6.4 6.9.6.5 6.9.6.6 6.9.6.7 6.9.6.8 6.9.6.9 6.9.7.1

6.9.7.2 6.9.7.3 6.9.7.4 6.9.7.5 6.9.7.6 6.9.7.7 6.9.7.8 6.9.7.9 6.9.8.1 6.9.8.2

6.9.8.3 6.9.8.4 6.9.8.5 6.9.8.6 6.9.8.7 6.9.8.8 6.9.8.9 6.9.9.1 6.9.9.2 6.9.9.3

6.9.9.4 6.9.9.5 6.9.9.6 6.9.9.7 6.9.9.8 6.9.9.9

The other group of preferred compound is as shown in table 2, and by adopting following convention to give the numeral of the variable appointment among the formula I; M1.V/Z/W.Because no matter compound is the equal biologically active of non-enantiomer mixture or single stereoisomers, so the spatial chemistry of the not shown compound of this paper.M1 is the variable of the nucleosides of representative formula I, by with group P (O) (O-CH (V) CH (Z) C (WW ')-O) 5 '-oh group of phosphorylated connects, and obtains formula I compound.

The structure of variable M1 is with mentioned above identical.

The group 1 of variable V/Z/W:V/Z/W

1) V=3-chlorophenyl; The Z=methyl; W=hydrogen

2) V=3,5-dichloro-phenyl; The Z=methyl; W=hydrogen

3) V=4-pyridine radicals; The Z=methyl; W=hydrogen

4) V=3-chlorophenyl; The Z=methoxyl group; W=hydrogen

5) V=3,5-dichloro-phenyl; The Z=methoxyl group; W=hydrogen

6) V=4-pyridine radicals; The Z=methoxyl group; W=hydrogen

7) V=3-chlorophenyl; Z=hydrogen; The W=3-chlorophenyl

8) V=3,5-dichloro-phenyl; Z=hydrogen; W=3,5-dichloro-phenyl

9) V=4-pyridine radicals; Z=hydrogen; The W=4-pyridine radicals

The group 2 of variable V/Z/W:V/Z/W

1) V=3-chlorophenyl; Z=NHAc; W=hydrogen

2) V=3,5-dichloro-phenyl; Z=NHAc; W=hydrogen

3) V=4-pyridine radicals; Z=NHAc; W=hydrogen

4) V=3-chlorophenyl; Z=hydrogen; The W=methyl

5) V=3,5-dichloro-phenyl; Z=hydrogen; The W=methyl

6) V=4-pyridine radicals; Z=hydrogen; The W=methyl

7) V=3-chlorophenyl; The Z=acetoxyl group; W=hydrogen

8) V=3,5-dichloro-phenyl; The Z=acetoxyl group; W=hydrogen

9) V=4-pyridine radicals; The Z=acetoxyl group; W=hydrogen

The group 3 of variable V/Z/W:V/Z/W

1) V=phenyl; The Z=phenyl; W=hydrogen

2) V=phenyl; Z=-CH ₂-CH ₂-, condense 6 yuan of rings of formation in V and phenyl; W=hydrogen

3) V=phenyl; Z=H; W=-CH ₂-CH ₂-, condense 6 yuan of rings of formation in V and phenyl

4) V=phenyl; Z=H; W=W '=methyl

5) V=phenyl; Z=H; W and W '=-CH ₂-CH ₂-CH ₂-CH ₂6 yuan of rings of-formation

6) V=phenyl; Z and W=-CH ₂-CH ₂-CH ₂-CH ₂6 yuan of rings of-formation

7) V=3-chlorophenyl; Z=CH ₂CH ₂CH ₂OC (O) OCH ₃W=hydrogen

8) V=3-chlorophenyl; Z=CH ₂CH ₂CH ₂SC (O) CH ₃W=hydrogen

9) V=4-pyridine radicals; Z=CH ₂CH ₂CH ₂OC (O) OCH ₃W=hydrogen

10) V=4-pyridine radicals; Z=CH ₂CH ₂CH ₂SC (O) CH ₃W=hydrogen

When not particularly pointing out, W ' is a hydrogen.

Preferred compound adopts the group 1 of group M1 and V/Z/W shown in 2.For example, compound 1.3 is represented the structure 1 of group M1, i.e. 7-denitrogenation-2 '-C-methyladenosine; And the structure 3 of the group 1 of V/Z/W, i.e. V=4-pyridine radicals, Z=methyl and W=hydrogen.Therefore, compound 1.3 is 7-denitrogenation-2 '-C-methyladenosine, wherein P (O) (O-CH (4-pyridine radicals) CH (CH ₃) CH ₂O) be connected to primary hydroxyl.

Preferred compound also lists as table 2, adopts the group 2 of group M1 and V/Z/W.

Preferred compound also lists as table 2, adopts the group 3 of group M1 and V/Z/W.

Table 2

1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9

3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9

Preferred compound also shown in the formula VI-VIII of table 1 and 2, R wherein ⁷Be the L-valyl base group that connects by carbonyl, R ⁷And R ⁸Form 5 yuan of cyclic carbonates.

In addition, The compounds of this invention can be used to suppress virus replication.On the other hand, The compounds of this invention can be used to suppress RNA dependent form RNA viruses and duplicates.Further aspect, The compounds of this invention can be used to suppress HCV and duplicate.

On the other hand, The compounds of this invention can be used for the treatment of virus infections.Further aspect, The compounds of this invention can be used for the treatment of RNA dependent form picornavirus infection.On the other hand, The compounds of this invention can be used for the treatment of the HCV infection.

On the other hand, The compounds of this invention can be used for the treatment of the liver virus infections.Further aspect, The compounds of this invention can be used for the treatment of liver rna dependent form picornavirus infection.On the other hand, The compounds of this invention can be used for the treatment of liver HCV infection.

On the one hand, the inhibition of virus replication can be measured in serum.It is relevant that the virus titer that increases reduces the minimizing of going down to posterity with the virus mutation strain, and mutant strain is relevant with drug resistance.

On the other hand, The compounds of this invention can be used to prevent the paresthesia epilepsy relevant with virus infections.

The activation of prodrug of the present invention causes producing nucleoside monophosphate (NMP).NMP is turned to the nucleoside triphosphate (NTP) of biologically active by further phosphinylidyne in the liver cell of being everlasting.Thereby removing medicine in liver cell causes the phosphorylated metabolite to be degraded to can being transported in the blood from liver cell eliminating or be transported to by kidney in the courage sweat so that the material of draining by courage sweat usually.Usually make the metabolite dephosphorization acidylate of phosphorylated become uncharged nucleosides with nucleosides base medicine.

The nucleosides that reenters systemic circulation causes systematic medicine contact.If it is active that nucleosides is a systematicness, for example, can phosphinylidyne turns to active substance by the cell that enters virus infections, the nucleosides of overflowing from liver can cause (being extrahepatic tissue, blood cell) biologically active outside the liver so.In this case, prodrug of the present invention can be used for treating the outer disease of liver, as virus infections.Because many nucleosides demonstrate relatively poor oral administration biaavailability, this is because through enzyme effect (as deaminizing through adenosine deaminase) or chemical action (as acid labile), it is decomposed, so prodrug can be used for oral administration at intestines and stomach.In addition, because in some cases, prodrug also can slowly decompose, as with respect to most of ester class prodrug, so prodrug preferably make nucleosides carry out whole body slowly, the release that delays.

Yet on the other hand, in some cases, systematicness contact nucleosides may have toxicity.This can by the nucleosides selecting preferentially to go out by the courage hidropoiesis or can be in tissue by the nucleosides of phosphorylated or can be rapidly be that the nucleosides of biological nonactive metabolite minimizes it through intrahepatic metabolism.The enzyme that exists in some liver cell nucleosides of can degrading, thereby make the medicine contact minimize (as phase I and II enzyme mutually).An example is an adenosine deaminase, and these enzymes can generate corresponding inosine analog with some adenyl residue nucleosides deamination.After the dephosphorization acidylate becomes nucleosides, can promptly nucleosides be carried out deamination in the cell, thereby limit system's contact nucleosides, reduced risk of toxicity.

The described method of embodiment A-D is used to measure the activation of The compounds of this invention.The described method of embodiment E is used to estimate the ability that The compounds of this invention produces NTP.

HCV can be according to the embodiment F evaluation duplicating of human liver tissue.Measure discovery by the described method of embodiment G, with respect to nucleosides, prodrug has liver specificity.

Tissue distribution can be determined according to the described method of embodiment H.Oral administration biaavailability can be measured by the described method of example I.Nucleoside analog can be determined by the described method of embodiment J the susceptibility of metabolism.

One aspect of the present invention, RNA dependent form picornavirus infection are sense single stranded rna dependent form virus infections.On the other hand, sense single stranded rna dependent form picornavirus infection is yellow coe virus section's (Flaviviridae) virus infections or pico+ribonucleic acid+virus section (Picornaviridae) virus infections.In such subclass, the pico+ribonucleic acid+virus coe virus infects and is rhinovirus infection, polyovirus infection or hepatitis a virus infection.In such second subclass, yellow coe virus coe virus infects and is selected from hepatitis C virus infections, yellow fever virus infection, dengue virus infection, West Nile Virus infection, japanese encephalitis virus infection, BAN infection and bovine viral dysentery virus infections.In the subclass of this subclass, yellow coe virus coe virus infects and is the hepatitis C virus infections.

Further, The compounds of this invention can increase the oral administration biaavailability of parent drug.On the other hand, The compounds of this invention can increase the oral administration biaavailability at least 5% of parent drug.On the other hand, The compounds of this invention can increase oral administration biaavailability at least 10%.On the other hand, compare, increase oral administration biaavailability 50% with the orally give parent drug.Further aspect, oral administration biaavailability can increase at least 100%.

On the other hand, The compounds of this invention can increase the therapeutic index of medicine.

On the one hand, The compounds of this invention can be used to evade drug resistance.

On the other hand, The compounds of this invention can be used for the treatment of cancer.

Preparation

The compounds of this invention can be with total daily dose 0.01-1000mg/kg administration.On the one hand, administration scope is that about 0.1mg/kg is to about 100mg/kg.On the other hand, administration scope is 0.5 to 20mg/kg.As required, dosage can be with the form administration of a plurality of divided doses.

When with other antiviral drugs administering drug combinations, The compounds of this invention can with daily dose or suitable bu dosage form administration (as, twice on the one).Prodrug can with other antiviral drugs simultaneously or administration in the close time, perhaps at different time administrations.The compounds of this invention can be used for multiple medicines object space case, is also referred to as therapeutic alliance or ' cocktail ' therapy, and the administration together of wherein multiple medicine also can be in the identical time or with different interval administration, perhaps administration in turn respectively.The compounds of this invention can administration after other pharmacotherapy a period of time, also can administration in the process of other medicines treatment, can be used as the part of therapeutic scheme, and perhaps can begin preceding administration through another kind of pharmacotherapy.

To achieve the object of the present invention, compound can pass through the variety of way administration, comprises oral, parenteral, adopts the dosage form of spraying suction, part or rectally, and described preparation comprises pharmaceutically acceptable carrier, adjuvant and medium.The term stomach and intestine of Shi Yonging comprise the intra-arterial injection administration that subcutaneous, intravenous, muscle and the various infusion techniques of employing are carried out outward herein.Intra-arterial of Shi Yonging and intravenous injection herein comprises through catheter drug delivery.Usually preferred intravenous administration.

Pharmaceutically acceptable salt comprises acetate, adipate, benzene sulfonate, bromide, d-camphorsulfonic acid salt, chloride, citrate, ethanedisulphonate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromate, hydrochloride, iodide, isethionate, lactate, Lactobionate, maleate, mesylate, MB, Methylsulfate, naphthalene sulfonate, nitrate, oleate, palmoate, phosphate, Polygalacturonate, stearate, succinate, sulphate, sulfosalicylic acid salt, tannate, tartrate, terephthalate, tosilate and three second iodide.

The pharmaceutical composition that comprises active component can be any form that is suitable for described medication.For example, when being used for oral administration, can adopt tablet, tablet, lozenge, water-based or oily suspensions, can the branch divided powder or particle, emulsion, hard or soft capsule, syrup or elixir.Liquid preparations for oral administration can be according to the method preparation of production pharmaceutical composition known in the art, and for obtaining the good preparation of mouthfeel, this based composition can comprise one or more sweeteners, flavor enhancement, colouring agent and preservative.Active component and the atoxic pharmaceutically acceptable mixed with excipients that is suitable for producing tablet can be prepared tablet.These excipient can for, for example, inert diluent is as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrant are as corn starch or alginic acid; Adhesive is as starch, gelatin or gum Arabic; And lubricant, as dolomol, stearic acid or talcum powder.Tablet can be not coated or be adopted known technology coatings, comprises adopting micro-capsule to delay disintegration and the absorption in intestines and stomach, and slow releasing function is provided thus in a long time.For example, the material of slack time for example, adopts glyceryl monostearate or glycerol distearate separately or mixes use with wax.

Be used for oral preparation and also can be the form of hard gelatin capsule, wherein active component can with inert solid diluent, for example calcium phosphate or kaolin mix, and perhaps are the Perle form, wherein active component can with water or oily medium, for example peanut oil, atoleine or mixed with olive oil.

Waterborne suspension of the present invention can be by producing active substance and being suitable for the mixed with excipients preparation of waterborne suspension.This type of excipient comprises suspending agent, as sodium carboxymethylcellulose, methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, mosanom, polyvinylpyrrolidone, bassora gum and gum Arabic, and dispersant or wetting agent, as naturally occurring phosphatide (for example lecithin), the condensation product of alkylene oxide and fatty acid (for example Myrj 45), the condensation product of oxirane and long-chain fatty alcohol (for example 17 ethyleneoxy group cetanols), oxirane and condensation product (for example polyoxyethylene sorbitan monooleate) derived from the part ester of fatty acid and hexitan.Waterborne suspension also can comprise one or more preservatives (for example right-hydroxy-benzoic acid ethyl or just-propyl diester), one or more colouring agents, one or more flavor enhancements and one or more sweeteners (for example sucrose or asccharin).

Oily suspensions can be by being suspended in active component preparation in vegetable oil (for example peanut oil, olive oil, sesame oil or cocoa butter) or the mineral oil (for example atoleine).Oral suspension can comprise thickener, for example beeswax, hard paraffin or cetyl alcohol.Can add sweetener, for example preamble described those, and also can add flavor enhancement to obtain the good oral formulations of mouthfeel.These compositions can be preserved by adding antioxidant (for example ascorbic acid).

Be suitable for preparing the branch divided powder of the present invention and the particle of waterborne suspension, can be by adding the mixture that entry obtains active component and dispersant or wetting agent, suspending agent and one or more preservatives.Those that suitable dispersant or wetting agent and suspending agent are enumerated as mentioned.Also can add other excipient, for example sweetener, flavor enhancement and colouring agent.

Pharmaceutical composition of the present invention also can be the form of oil-in-water emulsion.Oil phase can be vegetable oil (for example olive oil or peanut oil), mineral oil (for example atoleine), or these oily mixtures.Suitable emulsifier comprises naturally occurring glue (for example gum Arabic and bassora gum), naturally occurring phosphatide (for example soybean lecithin), derived from the ester or the part ester (for example Arlacel-80) of fatty acid and hexitan, and the condensation product of these part esters and oxirane (for example polyoxyethylene sorbitan monooleate).Emulsion also can comprise sweetener and flavor enhancement.

Syrup and elixir also can contain sweetener, for example glycerine, sorbierite or sucrose.This type of preparation also can comprise anodyne, preservative, flavor enhancement or colouring agent.

Pharmaceutical composition of the present invention can be aseptic injection preparation, for example the aseptic injection aqueous solution or oleagenous suspension.This suspension can adopt the preparation of suitable dispersant mentioned above or wetting agent and suspending agent according to means known in the art.Aseptic injection preparation also can be aseptic injectable solution or the suspension in nontoxic stomach and intestine acceptable diluent or solvent (for example 1,3-fourth-glycol), perhaps also can be with the form preparation of freeze-dried powder.In acceptable solvent and solvent, can adopt water, Ringer's mixture and isotonic sodium chlorrde solution.In addition, aseptic fixedly oil can be used as solvent or suspension media expediently.For this reason, the fixedly oil of any gentleness be can adopt, synthetic monoglyceride or double glyceride comprised.In addition, fatty acid (for example oleic acid) can be used to prepare injection similarly.

The amount that can mix the active component that obtains single formulation with carrier mass depend on the patient that treats and specific form of medication.For example, the sustained release agent that is used for human oral administration can comprise the carrier mass of 20-2000 μ mol (about 10-1000mg) active substance and suitable and convention amount, and this amount of substance can account for about 5-about 95% of total composition.The pharmaceutical composition of preferred for preparation can easily be measured dosage.For example, the aqueous solution that is used for intravenous infusion comprises about 0.05 to about 50 μ mol (about 0.025-25mg) active component/every ml soln, so that make the speed that suitable volume can about 30mL/h carry out infusion.

As indicated above, the preparation of the present invention that is suitable for oral administration can be the individual form: as capsule, cachet or tablet, each unit form all comprises the active component of scheduled volume; Powder or particle; Solution in water-based or non-aqueous liquid or suspension; Or oil-in-water emulsion or water-in-oil emulsion.Active component also can be with the form administration of bolus, soft extract or paste.

Tablet can prepare by compacting or molding, chooses wantonly to have one or more supplementary elements.Compressed tablets can be by suppressing preparation with the active component (for example powder or particle) of free-flowing form, optional adhesive (as polyvidone, gelatin, hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (as Explotab, PVPP, Ac-Di-Sol), surfactant or the dispersant of being mixed with in suitable machine.The molding tablet can be by will preparing with the mixture molding of the wetting powdered compounds of inert liquid diluent in suitable machine.Tablet can be chosen wantonly by dressing or cut, and can be formulated as the form that slowly-releasing or sustained release active component are provided, and the hydroxypropyl methylcellulose that for example adopts different proportion is to provide required releasing properties.Tablet can be chosen wantonly and carry out enteric coating, thereby discharges medicine in the part of the intestines beyond stomach.When formula I compound is responsive to acid hydrolysis, preferred especially this mode.

Be suitable for that the preparation of topical comprises lozenge in mouth, this lozenge comprises active component in flavoring matrix, and described matrix is generally sucrose and gum Arabic or tragacanth; The lozenge that in inert base, comprises active component, described matrix is gelatin and glycerine for example, or sucrose and gum Arabic; And the mouthwash that in suitable liquid-carrier, comprises active component.

Can prepare the suppository that is suitable for rectally with suitable matrix, this formulation comprises for example cupu oil or salicylate.

The preparation that is suitable for vagina administration can be for the form of pessary, tampon, creme, gel, paste, foam or spray, and except that active component, these preparations also can contain suitable these carriers known in the art.

The preparation that is suitable for parenteral comprises water-based and non-aqueous isotonic sterile injection solution, wherein can comprise antioxidant, buffer, bacteriostatic agent and make preparation and solute that acceptor blood pressure etc. oozes; And water-based and non-aqueous sterile suspensions, comprise suspending agent and thickener.Preparation can be present in the airtight container with single dose or multiple dose, for example, in ampoule and the bottle, and can deposit by lyophilisation condition, only needs to add rapidly before use sterile liquid carrier, for example water for injection.Injection solution and suspension can adopt aforementioned various aseptic powdery, particle and preparation tablets.

The preparation of suitable parenteral can pass through to keep somewhere pump or the administration of medical bag in the mode that continues infusion.The infusion that continues comprises by outer pump infusion.Infusion can by Hickman or PICC or other any suitable outside stomach and intestine or vein give the mode administration of preparation.

Preferred unit dose formulations comprises daily dose or unit, day sub-doses or their the suitable part of medicine.

But, it should be understood that the given dose level of any particular patient depends on various factors, comprise the activity of employed specific compound; Individual age, body weight, general health, sex and the diet situation for the treatment of; Administration time and approach; Excretion rate; The other medicines that give before this; And specific severity of disease to be treated, those skilled in the art are appreciated that this.

Another aspect of the present invention relates to the medication combined inhibition HCV NS5B polymerase, the inhibition HCV that adopt The compounds of this invention and one or more to be used for the treatment of the HCV infection and duplicates or treat the method that HCV infects.This type of medicine that can effectively resist HCV comprises the associating of associating, interferon-' alpha ' and Levovirin of associating, glycol interferon-α and the Ribavirin of (but being not limited to) Ribavirin, Levovirin, Wei Lami left alone without help (viramidine), Nitazoxanide, thymosin, interferon-beta, interferon-' alpha ', glycol interferon-α (peginterferon-α), interferon-' alpha ' and Ribavirin, and the associating of glycol interferon-α and Levovirin.Interferon-' alpha ' includes but not limited to recombinant interferon-α 2a (as deriving from Hoffmann-LaRoche, Nutley, the Roferon interferon of NJ), glycol interferon-α 2a (Pegasys ^TM), interferon-' alpha ' 2b (as deriving from Schering Corp., Kenilworth, the Intron-A interferon of NJ), glycol interferon-α 2b (PegIntron ^TM), recombinant consensus interferon (as interferon alphacon-1) and purifying alpha-interferon-α product.The brand of Amgen ' s recombinant consensus interferon is

Levovirin is the L-enantiomer of Ribavirin, has the immunoregulatory activity that is similar to Ribavirin.Wei Lami is left alone without help to be the analog that is disclosed in the Ribavirin of WO 01/60379 (transferring ICN Pharmaceuticals).The method according to this invention, in therapeutic process, each composition of composition can be in different time difference administration or simultaneously to separate or single cooperative programs administration.Therefore, be appreciated that to the present invention includes all while or cross-fire treatment schemes that term " gives " also have same implication.Be appreciated that associating that The compounds of this invention and other are used for the treatment of the other medicines that HCV infects comprises the associating of the pharmaceutical composition that infects with any treatment HCV in principle.When the active constituents of medicine drug combination of The compounds of this invention or their pharmaceutically acceptable salts and second kind of opposing HCV, the amount the when amount of every kind of compound can be with independent use compound is identical or different.

Be that treatment HCV infects, The compounds of this invention also can with the inhibitor administering drug combinations of HCV NS3 serine protease.HCV NS3 serine protease is necessary viral enzyme, and is described to suppress the fabulous target that HCV duplicates.The substrate of HCV NS3 protease inhibitors and non-substrate base inhibitor are disclosed in the following patent literature: WO 98/22496, WO 98/46630, WO 99/07733, WO 99/07734, WO 99/38888, WO 99/50230, WO 99/64442, WO 00/09543, WO 00/59929, GB-2337262, WO 02/18369, WO 02/08244, WO 02/48116, WO 02/48172, WO 05/037214 and the U.S. patent No. 6,323,180.HCV NS3 protease is the target of the HCV inhibitor development of duplicating, such material is used for the treatment of the purposes of HCV infection at B.W.Dymock, " Emerging therapies for hepatitis Cvirus infection, " Emerging Drugs, 6:13-42 addresses in (2001).Can comprise BILN2061, YX-950, SCH6, SCH7 and SCH503034 with the specific HCV NS3 protease inhibitors that The compounds of this invention merges.

Ribavirin, Levovirin and Wei Lami left alone without help can be by suppressing desmoenzyme inosine monophosphate dehydrogenase (IMPDH) thus adjusting to preserve in the guanosine cell has anti-hcv activity.IMPDH is the rate-limiting enzyme of the biosynthesis pathway in the biosynthesis of neoguanine nucleosides.Ribavirin is easy in the endocellular phosphorus acidylate, and the one phosphoric acid derivatives is the IMPDH inhibitor.Therefore, on behalf of another, the inhibition of IMPDH be used to find the useful target of HCV replication inhibitors.Therefore, The compounds of this invention also can with IMPDH inhibitor VX-497 administering drug combinations for example, VX-497 is disclosed in WO 97/41211 and WO 01/00622 (transferring Vertex); Other IMPDH inhibitor is as WO 00/25780 those disclosed (transferring Bristol-Myers Squibb); Perhaps mycophenolate [referring to A.C.Allison and E.M.Eugui, Agents Action, 44 (Suppl.): 165 (1993)].

Be that treatment HCV infects, The compounds of this invention also can with antiviral drugs amantadine (1-aminoadamantan) [the detailed description about this medicine sees also J.Kirschbaum, Anal.Profiles Drug Subs.12:1-36 (1983)] administering drug combinations.

The compounds of this invention can be united with antiviral 2 '-C-branched nucleosides and is used for the treatment of the HCV infection, and these nucleosides are disclosed in R.E.Harry-O ' kuru etc., J.Org.Chem., 62:1754-1759 (1997); M.S.Wolfe etc., Tetrahedron Lett., 36:7611-7614 (1995); U.S. the patent No. 3,480,613 (on November 25th, 1969); U.S. the patent No. 6,777,395 (on Augusts 17th, 2004); The US patent No. 6914054 (on July 5th, 2005); International publication number WO01/90121 (November 29,2001); International publication number WO 01/92282 (December 6,2001); WO 02/32920 (April 25,2002); WO 02/057287 (July 25,2002); WO02/057425 (July 25,2002); WO 04/002422 (January 8,2004); WO04/002999 (January 8,2004); WO 04/003000 (January 8,2004); WO04/002422 (January 8,2004); US 2005/0107312; US 2005/0090463; US2004/0147464; With US 2004/0063658; All above-mentioned literature contents are incorporated by reference in this text in this article to be examined.This type of 2 '-C-branched nucleosides include, but is not limited to 2 '-C-methylcytidine, 2 '-fluoro-2 '-C-methyl cytidine 2 '-the C-methyluridine, 2 '-the C-methyladenosine, 2 '-the C-methylguanosine, and 9-(2-C-methyl-β-D-ribofuranosyl)-2, the 6-diaminopurine; Furanose C-2 '; C-3 '; and the corresponding amino-acid ester of C-5 ' hydroxyl (for example 3 '-O-(L-valyl base)-2 '-C-methyl cytidine dihydrochloride; be also referred to as valopicitabine dihydrochloride or NM-283 and 3 '-O-(L-valyl base)-2 '-fluoro-2 '-C-methyl cytidine); with their 5 '-the optional ring-type 1 that replaces of the correspondence of phosphate derivative, the ammediol ester.

The compounds of this invention also can infect with other nucleosides therapeutic alliance HCV with anti-HCV character, and this type of nucleosides is as being disclosed in the following document those: US6864244 (on March 8th, 2005); WO 02/51425 (on July 4th, 2002) transfers Mitsubishi Pharma Corp.; WO 01/79246, and WO 02/32920 and WO 02/48165 (on June 20th, 2002) transfer Pharmasset, Ltd.; WO 01/68663 (September 20 calendar year 2001) transfers ICNPharmaceuticals; WO 99/43691 (on September 2nd, 1999); WO 02/18404 (7 months March in 2002) transfers Hoffmann-LaRoche; U.S.2002/0019363 (on February 14th, 2002); WO 02/100415 (December 19,2002); WO 03/026589 (April 3,2003); WO 03/026675 (April 3,2003); WO 03/093290 (November 13,2003): US 2003/0236216 (December 25,2003); US 2004/0006007 (January 8,2004); WO 04/011478 (February 5,2004); WO 04/013300 (February 12,2004); US2004/0063658 (April 1,2004); With WO 04/028481 (April 8,2004).

In one embodiment, can be selected from following compound with the nucleosides HCVNS5B AG14361 of nucleoside derivates combination of the present invention: 4 '-azido-cytidine; 4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine; 4-amino-7-(2-C-hydroxymethyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine; 4-amino-7-(2-C-methyl fluoride-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine; 4-amino-5-fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine; 2-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone; 4-amino-7-(2-C, 2-O-dimethyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine; And pharmaceutically acceptable salt and prodrug.

The compounds of this invention also can be united with the non-nucleosidic inhibitors of HCV polymerase and is used for the treatment of the HCV infection, and described inhibitor for example is disclosed in those in the following document: WO 01/77091 (October 18 calendar year 2001), transfers Tularik, Inc.; WO 01/47883 (July 5 calendar year 2001) transfers Japan Tobacco, Inc.; WO 02/04425 (on January 17th, 2002) transfers Boehringer Ingelheim; WO 02/06246 (on January 24th, 2002) transfers Istituto di Ricerche di Biologia Moleculare P.Angeletti S.P.A.; WO02/20497 (on March 3rd, 2002); WO2005/016927 (particularly JTK003) transfers Japan Tobacco, Inc; Its full content is incorporated herein by reference; And HCV-796 (Viropharma Inc.).

In one embodiment, can be selected from following compound with the non-nucleosides HCVNS5B AG14361 of nucleoside derivates combination of the present invention:

14-cyclohexyl-6-[2-(dimethylamino) ethyl]-7-oxo-5,6,7, the 8-tetrahydro indole is [2,1-a] [2,5] Ben Bing Er oxazole suffering-11-carboxylic acid also; 14-cyclohexyl-6-(2-morpholine-4-base ethyl)-5,6,7, the 8-tetrahydro indole is [2,1-a] [2,5] Ben Bing Er oxazole suffering-1 1-carboxylic acid also; 14-cyclohexyl-6-[2-(dimethylamino) ethyl]-3-methoxyl group-5,6,7, the 8-tetrahydro indole is [2,1-a] [2,5] Ben Bing Er oxazole suffering-11-carboxylic acid also; 14-cyclohexyl-3-methoxyl group-6-methyl-5,6,7,8-tetrahydro indole be [2,1-a] [2,5] Ben Bing Er oxazole suffering-1 1-carboxylic acid also; ({ [(14-cyclohexyl-3-methoxyl group-6-methyl-5,6,7,8-tetrahydro indole be [2,1-α] [2,5] Ben Bing Er oxazole suffering-1 1-yl also) carbonyl] amino } sulfonyl) acetate methyl ester; ({ [(14-cyclohexyl-3-methoxyl group-6-methyl-5,6,7,8-tetrahydro indole be [2,1-a] [2,5] Ben Bing Er oxazole suffering-1 1-yl also) carbonyl] amino } sulfonyl) acetate; 14-cyclohexyl-N-[(dimethylamino) sulfonyl]-3-methoxyl group-6-methyl-5,6,7, the 8-tetrahydro indole is [2,1-a] [2,5] Ben Bing Er oxazole suffering-11-carboxamide also; 3-chloro-14-cyclohexyl-6-[2-(dimethylamino) ethyl]-7-oxo-5,6,7, the 8-tetrahydro indole is the hot 11-carboxylic acid of [2,1-a] [2,5] Ben Bing Er oxazole also; N '-(11-carboxyl-14-cyclohexyl-7,8-dihydro-6H-indoles also [1,2-e] [1,5] benzoxazole suffering-7-yl)-N, N-dimethyl ethane-1,2-two ammoniums two (trifluoroacetate); 14-cyclohexyl-7,8-dihydro-6H-indoles be [1,2-e] [1,5] benzoxazole suffering-11-carboxylic acid also; 14-cyclohexyl-6-methyl-7-oxo-5,6,7,8-tetrahydro indole be [2,1-α] [2,5] Ben Bing Er oxazole suffering-11-carboxylic acid also; 14-cyclohexyl-3-methoxyl group-6-methyl-7-oxo-5,6,7,8-tetrahydro indole be [2,1-a] [2,5] Ben Bing Er oxazole suffering-11-carboxylic acid also; 14-cyclohexyl-6-[2-(dimethylamino) ethyl]-3-methoxyl group-7-oxo-5,6,7, the 8-tetrahydro indole is [2,1-a] [2,5] Ben Bing Er oxazole suffering-11-carboxylic acid also; 14-cyclohexyl-6-[3-(dimethylamino) propyl group]-7-oxo-5,6,7, the 8-tetrahydro indole is [2,1-a] [2,5] Ben Bing Er oxazole suffering-11-carboxylic acid also; 14-cyclohexyl-7-oxo-6-(2-piperidines-1-base ethyl)-5,6,7, the 8-tetrahydro indole is [2,1-α] [2,5] Ben Bing Er oxazole suffering-11-carboxylic acid also; 14-cyclohexyl-6-(2-morpholine-4-base ethyl)-7-oxo-5,6,7, the 8-tetrahydro indole is [2,1-a] [2,5] Ben Bing Er oxazole suffering-11-carboxylic acid also; 14-cyclohexyl-6-[2-(diethylamino) ethyl]-7-oxo-5,6,7, the 8-tetrahydro indole is [2,1-α] [2,5] Ben Bing Er oxazole suffering-11-carboxylic acid also; 14-cyclohexyl-6-(1-methyl piperidine-4-yl)-7-oxo-5,6,7,8-tetrahydro indole be [2,1-α] [2,5] Ben Bing Er oxazole suffering-11-carboxylic acid also; 14-cyclohexyl-N-[(dimethylamino) sulfonyl]-7-oxo-6-(2-piperidines-1-base ethyl)-5,6,7, the 8-tetrahydro indole is [2,1-a] [2,5] Ben Bing Er oxazole suffering-11-carboxamide also; 14-cyclohexyl-6-[2-(dimethylamino) ethyl]-the N-[(dimethylamino) sulfonyl]-7-oxo-5,6,7, the 8-tetrahydro indole is [2,1-α] [2,5] Ben Bing Er oxazole suffering-11-carboxamide also; 14-cyclopenta-6-[2-(dimethylamino) ethyl]-7-oxo-5,6,7, the 8-tetrahydro indole is [2,1-α] [2,5] Ben Bing Er oxazole suffering-11-carboxylic acid also; 14-cyclohexyl-5,6,7,8-tetrahydro indole be [2,1-a] [2,5] Ben Bing Er oxazole suffering-11-carboxylic acid also; 6-pi-allyl-14-cyclohexyl-3-methoxyl group-5,6,7,8-tetrahydro indole be [2,1-a] [2,5] Ben Bing Er oxazole suffering-11-carboxylic acid also; 14-cyclopenta-6-[2-(dimethylamino) ethyl]-5,6,7, the 8-tetrahydro indole is [2,1-α] [2,5] Ben Bing Er oxazole suffering-11-carboxylic acid also; 14-cyclohexyl-6-[2-(dimethylamino) ethyl]-5,6,7, the 8-tetrahydro indole is [2,1-α] [2,5] Ben Bing Er oxazole suffering-11-carboxylic acid also; 13-cyclohexyl-5-methyl-4,5,6,7-tetrahydrochysene furan assorted [3 ', 2 ': 6,7] [1,4] Er oxazole suffering [1,8-α] indoles-10-carboxylic acid; 15-cyclohexyl-6-[2-(dimethylamino) ethyl]-7-oxo-6,7,8,9-tetrahydrochysene-5H-indoles is [2,1-α] [2,6] benzodiazonine-12-carboxylic acid also; 15-cyclohexyl-8-oxo-6,7,8,9-tetrahydrochysene-5H-indoles be [2,1-α] [2,5] benzodiazonine-12-carboxylic acid also; 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indoles be [1,2-d] [1,4] benzodiazepine also

-10-carboxylic acid; And pharmaceutically acceptable salt.

2 '-C-methyl-and 4 '-C-methyl-ribonucleotide derivative is synthetic

Synthetic 5 '-nucleoside monophosphate of the present invention (NMP) prodrug can be divided into following two steps: 1. synthetic phosphorus acylation reaction precursor; 2. by nucleosides and the synthetic prodrug of prodrug moiety coupling.

Synthetic phosphorus acylation reaction precursor:

Synthetic phosphorus acylation reaction precursor also comprises 2 steps: synthesize 1,3-glycol and 2. synthetic phosphorus acylation reaction precursors 1..

Synthesize 1, the 3-glycol:

Be used to prepare 1 of following type, the various synthetic methods of 3-glycol are known: replace in their racemic or the 1-that carries out a) of enantiomer enrichment in form; B) 2-replaces; And c) 1,2-or 1,3-cyclisation.Behind synthetic glycol or synthetic prodrug, V, W, the Z group of introducing or the formula of modification I.

Synthetic 1-(aryl)-the third-1, the 3-glycol:

Suitable preparation 1, the method for 3-glycol are divided into two types: 1) synthetic racemic 1-(aryl)-the third-1,3-glycol; 2) 1-(aryl)-the third-1 of synthetic enantiomer enrichment, the 3-glycol.

Synthetic racemic 1-(aryl)-the third-1, the 3-glycol:

1, the 3-dihydroxy compounds can be synthetic by the whole bag of tricks known in several documents.By adding the enolization lithium of alkyl acetate, through ester reduction (approach A) (Turner, J.Org.Chem.55:4744 (1990)), the aromatic aldehyde that replaces is used for synthetic racemic 1-(aryl) the third-1,3-glycol then.Perhaps, aryl lithium or aryl Grignard reagent and 1-hydroxyl third-3-aldehyde carry out addition reaction, also can obtain 1-(aryl replaces) the third-1,3-glycol (approach B).This method also makes the aryl halide of various replacements can be converted into 1-(aryl replaces)-1, ammediol (Coppi etc., J.Org.Chem.53:911 (1988)).Aryl halide also can be used for by with 1, and 3-diox-4-alkene carries out the Heck coupling, and reduction and hydrolysis subsequently is used for the propane diols (Sakamoto etc., Tetrahedron Lett.33:6845 (1992)) that synthetic 1-replaces.Form by the N-oxide, in the presence of acetic anhydride, reset subsequently, pyridine radicals-, quinolyl-, isoquinolyl-third-3-01 derivatives can by hydroxyl turn to that 1-replaces-1,3-glycol (approach C) (Yamamoto etc., Tetrahedron 37:1871 (1981)).By vinyl lithium or vinyl Ge Liya addition, subsequently by hydroboration, various aromatic aldehydes can be converted into that 1-replaces-1,3-glycol (approach D).

The V=aryl, R=alkyl, R '=benzyl, M=Mg or Li, X=halide or nothing

The 1-(aryl)-the third-1 of synthetic enantiomer enrichment, the 3-glycol;

By chemistry or enzyme reagent, adopt the method for various known fractionation secondary alcohol, preparation glycol enantiomer (Harada etc., Tetrahedron Lett.28:4843 (1987)).With the 3-aryl-3-oxo-propionic acid or the ester that replace is method (the Comprehensive Asymmetric Catalysis that effectively prepares the R-or the S-isomer of beta hydroxy acid or ester with high antimer purity through the hydrogenation of transition metal catalytic, Jacobsen, E.N., Pfaltz, A., Yamamoto, H. (Eds), Springer, (1999); Asymmetric Catalysis in Organic Synthesis, Noyori, R., John Wiley, (1994)).These beta hydroxy acids or ester products can further be reduced the required 1-(aryl)-the third-1 that obtains high antimer excessive (ee), 3-glycol (approach A).The beta-keto acid or the ester substrate that carry out high-pressure hydrogenation or hydrogen transfer reaction can be prepared by the whole bag of tricks, for example, in the presence of alkali, make dimethyl carbonate and acetophenone condensation (Chu etc., J.Het Chem.22:1033 (1985)), carry out by ester condensation (Turner etc., J.Org.Chem.54:4229 (1989)) or by aryl halide (Kobayashi etc., Tetrahedron Lett.27:4745 (1986)).Perhaps, can obtain 1 of generated in high enantiomeric purity by the enantio-selectivity boron hydrogen reduction reaction of beta-hydroxy ethyl aryl ketones derivative or beta-keto acid derivative, 3-glycol (approach B) (Ramachandran etc., Tetrahedron Lett.38:761 (1997)).In other method, under catalysis asymmetric Epoxidation action condition, the cinnamyl alcohol that commerce obtains can be converted into epoxy alcohol.Reduce these epoxy alcohol by Red-Al and can obtain 1 of high ee, 3-glycol (approach C) (Gao etc., J.Org.Chem.53:4081 (1980)).With the aromatic aldehyde is raw material, is 1 of another synthetic high ee through the enantio-selectivity aldol condensation, the method (approach D) of the maturation of 3-oxidation degree of functionality (Mukaiyama, Org.React.28:203 (1982)).

The V=aryl, R=alkyl or H, R '=-CH ₂OH, CO ₂R

1 of Synthetic 2-replacement, the 3-glycol:

-1 of various 2-replacements, 3-glycol can be adopted the commercial 2-(hydroxymethyl)-1 that obtains, the preparation of 3-third-glycol.Turn usefulness into, restore subsequently by the diacid decarboxylation, (approach is (Werle a) pentaerythrite can be converted into triol, Deng, Liebigs.Ann.Chem., 1986,944), perhaps can obtain glycol-monocarboxylic acid derivative (Iwata etc. by under known conditions, carrying out decarboxylation, TetrahedronLett.1987,28,3131).Known nitro triol is eliminated reaction through reduction also can obtain triol (approach b) (Latour etc., Synthesis, 1987,8,742).Triol can carry out single acidylate or form carbonic ester carrying out derivatization (approach d) (Greeneand Wuts, Protective groups in organic synthesis, John Wiley, New York, 1990) by handling with alkane acyl chlorides or carbonochloridic acid Arrcostab.Can carry out aryl replacement (approach c) by being oxidized to aldehyde and aryl Ge Liya addition reaction.Aldehyde also can be converted into the amine (approach e) of replacement by reductive amination process.

Synthesis of cyclic-1, the 3-glycol:

Wherein formula 1 compound that condenses by 4 carbon of V-Z or V-W can the derived from cyclohexane diol, derivatives.In the third-1 of 2-replacement, under the situation of 3-glycol, the commercial cis that obtains, cis-1,3,5-cyclohexane-triol can directly use or use modified back, thereby obtains various analogs.These modifications can also can be carried out after ester forms before ester forms.Various 1,3-cyclohexane-glycol can pass through the Diels-Alder method, adopts pyrones as diene preparation (Posner etc., TetrahedronLett., 1991,32,5295).The cyclohexane diol derivative also can pass through itrile oxides-alkene addition reaction preparation (Curran etc., J.Am.Chem.Soc., 1985,107,6023).Perhaps, the cyclohexyl precursor also can be from the commercial chinic acid preparation (Rao etc., Tetrahedron Lett., 1991,32,547.) that obtains.

1 of synthetic replacement, 3-hydroxylamine and 1, the 3-diamines:

A large amount of synthetic methods can be used for preparing 1 of replacement, 3-hydroxylamine and 1, and the 3-diamines, this is owing to these functional groups in naturally occurring compound are ubiquitous.Be part method below: 1. synthesize 1 of replacement, 3-hydroxylamine through arrangement; 2. synthesize 1 of replacement, 1 of 3-diamines and the replacement of 3. synthesis of chiral, 3-hydroxylamine and 1,3-diamines.

1 of synthetic replacement, the 3-hydroxylamine:

By being leaving group with the hydroxyl-functional groups converted, handling with anhydrous ammonia or required uncle or secondary amine then, preamble described 1, the 3-glycol can be selectively converted to hydroxylamine or corresponding diamine (Corey etc., Tetrahedron Lett., 1989,30,5207:Gao etc., J.Org.Chem., 1988,53,4081).Similarly conversion reaction also can directly obtain (Hughes, D.L., Org.React., 1992,42) down in the Mitsunobu reaction condition by alcohol.

The prodrug moiety 3-aryl-3-hydroxyl-general synthesis step of third-1-amine comprises the aldol condensation of aryl ester and alkyl nitrite, then the benzoyl acetonitrile (Shih etc., Heterocycles, 1986,24,1599) of the replacement that obtains of reduction.This process also is applicable to by adopting the alkyl nitrile that replaces to form the aminopropanol that 2-replaces.In another approach, 3-aryl-3-amino-third-1-alcohols prodrug group can be from aryl aldehyde, by malonic acid, and condensation in the presence of ammonium acetate, the beta-amino acids of the replacement that reduction subsequently obtains is synthetic.These methods make can introduce various aryl substituents (Shih etc., Heterocycles., 1978,9,1277).In another method, the 1-amino of β-replacement-1-aryl ethyl dianion organo-lithium compound can be by changing carbonyls, make styrene compound and carbonyls carry out addition reaction and produce various W, W ' substituting group prepares (Barluenga etc., J.Org.Chem., 1979,44,4798).

1 of synthetic replacement, the 3-diamines:

1 of replacement, the 3-diamines can be synthetic from various substrates.Under the Hofmann rearrangement condition, by being hydrolyzed to acid amides, the aryl glutaronitrile can be converted into the diamines (Bertochio etc., Bull.Soc.Chim.Fr, 1962,1809) that 1-replaces.But, by electrophilic reagent introduce, hydride reduction is a corresponding diamine subsequently, carry out malononitrile and replace and can obtain various Z and replace.In another approach, the hydrazine reaction of cinnamic acid and hydrazine or replacement obtains corresponding pyrazoline, through catalytic hydrogenation obtain replacing 1,3-diamines (Weinhardt etc., J.Med.Chem., 1985,28,694).1, high trans-cis-selectivity that 3-replaces also can obtain (Alexakis etc., J.Org.Chem., 1992,576,4563) by pyrazoline and the addition of aryl Grignard reagent, reduction subsequently.1-aryl-1,3-diaminopropanes also can reduce 3-amino-3-aryl acrylonitrile from diborane and prepare (the aromatic compounds preparation that this compound replaces from nitrile) (Dornow etc., Chem Ber., 1949,82,254).To derive from corresponding 1,1 of 3-carbonyls, the reduction of 3-diimine is another preparation 1, the approach of 3-diamines prodrug moiety, described prodrug moiety can be handled (Barluenga etc., J.Org.Chem., 1983,48,2255) through various activated group V and/or Z.

1 of synthesis of chiral replacement, 3-hydroxylamine and 1, the 3-diamines:

The 3-aryl of enantiomeric pure-3-hydroxyl third-1-amine can be by the CBS enantio-selectivity catalytic reaction of β-chloro-benzene acetone, be replaced into the second month in a season or primary amine synthesizes (Corey etc. through the halo group as required subsequently, Tetrahedron Lett., 1989,30,5207).The chirality 3-aryl of prodrug moiety-3-amino third-1-alcohols can be undertaken 1 by the nitrone of the replacement of chiral purity alkene and aryl aldehyde, and 3-dipolar addition, reduction subsequently obtain the De isoxazole alkyl and obtain (Koizumi etc., J.Org.Chem., 1982,47,4005).Also can make the amino alcohol enantio-selectivity form by chirality phosphine palladium compound, thereby obtain 1, the chirality that forms the isoxazole alkyl that replaces in the 3-dipolar addition produces (Hori etc., J.Org.Chem., 1999,64,5017).In addition, the amino alcohol of optically pure 1-aryl replacement can obtain (Canas etc., Tetrahedron Lett., 1991,32,6931) by the selective opening reaction of carrying out corresponding chiral epoxy alcohol with required amine.

Known several method is used for 1, and the non-enantiomer selectivity of the dibasic amino alcohol of 3-is synthetic.For example, handle (E)-N-cinnamyl three chloro acetamides, obtain trans-two hydrogen oxazines with hypochlorous acid, this material can easily be hydrolyzed to erythro-β-chloro-γ-hydroxyl-γ-amphetamine (Commercon etc., Tetrahedron Lett., 1990 with high non-enantiomer selectivity, 31,3871).1, the non-enantiomer selectivity of 3-amino alcohol forms also can obtain (Haddad etc., Tetrahedron Lett., 1997,38,5981) by the reduction amination of optically pure 3-hydroxy-ketone.In another method, the 3-amino ketones can be converted into 1 with high non-enantiomer selectivity by selective hydrogenation reduction, the dibasic amino alcohol of 3-(Barluenga etc., J.Org.Chem., 1992,57,1219).

Synthesizing of phosphorus acylation reaction precursor:

Phosphorus acylation reaction precursor synthetic is divided into two step: a. and synthesizes P (III) phosphorus acylation reaction precursor, and the b. stereoselectivity is synthesized P (V) phosphorus acylation reaction precursor.

Synthetic P (III) phosphorylated precursor:

Can adopt 1 ', 3 '-propyl diester of ring-type phosphorus esterification reagent to obtain 5 '-pure phosphorylated, wherein said reagent is P (III) oxidation state.Preferred phosphorus esterification reagent is chloro phospholane (L '=chloro).Ring-type chloro phospholane can pass through with 1 of phosphorus trichloride and replacement 3-glycol prepared in reaction (Wissner etc., J.Med.Chem., 1992,35,1650) down in temperate condition.Perhaps, phosphoramidite can be used as phosphorus esterification reagent (Beaucage etc., Tetrahedron, 1993,49,6123).The phosphoramidite of suitable replacement can be by making ring-type chloro phospholane and N, N-dialkylamine prepared in reaction (Perich etc., Aust.J.Chem., 1990,43,1623.Perich etc., Synthesis, 1988,2,142), perhaps by making the third-1 of commercial dialkyl amido chlorine phosphate that obtains and replacement, 3-glycol prepared in reaction.

Synthetic P (V) phosphorus acylation reaction precursor:

Usually, the synthetic of phosphate can obtain by making the alcohol and the phosphate precursor coupling of corresponding activation, for example make chloro phosphate (L '=chloro) and nucleosides 5 '-the hydroxyl condensation is the well-known method for preparing the nucleoside phosphorylase monoesters.The precursor of activation can be by several method preparations of knowing.The chloro phosphate that is used for synthetic prodrug can be from-1 of replacement, ammediol preparation (Wissner etc., J.Med Chem., 1992,35,1650).The chloro phosphate can be by preparing (Anderson etc., J.Org.Chem., 1984,49,1304) with corresponding chloro phospholane oxidation, and described chloro phospholane derives from the reaction of the glycol and the phosphorus trichloride of replacement.Perhaps, chloro phosphate reagent can by will replace-1, the 3-glycol is with phosphorous oxychloride Processing of Preparation (Patois etc., J.Chem.Soc.Perkin Trans.I, 1990,1577).The chloro phosphate also can generate (Silverburg etc., Tetrahedron Lett., 1996,37,771) from corresponding cyclic phosphites on the spot under suitable condition, this compound can be from chloro phospholane or phosphoramidate intermediate preparation.Fluorophosphoric acid ester intermediate can be from pyrophosphate or phosphoric acid preparation, and described fluorophosphoric acid ester also can be used as the precursor (Watanabe etc., Tetrahedron Lett., 1988,29,5763) of preparation ring-type prodrug.

Phosphoramidate (L '=NRR ') also be the intermediate of well-known synthetic phosphoric acid ester.Monoalkyl or dialkyl amido phosphate (Watanabe etc., Chem Pharm Bull., 1990,38,562), triazole phosphoramidate (triazolophosphoramidate) (Yamakage etc., Tetrahedron, 1989,45,5459) and pyrrolidines phosphoramidate (pyrrolidinophosphoramidate) (Nakayama etc., J.Am.Chem.Soc., 1990,112,6936) also be the known intermediate that is used to prepare phosphate.Another effective phosphorus esterification method is the addition reaction of the metal catalytic of 2-azolactone ring-type chloro phosphate adduct.Exist down in secondary hydroxy group, this intermediate has high selectivity (Nagamatsu etc., Tetrahedron Lett., 1987,28,2375) in phosphorylated primary hydroxyl group process.These medicines can or pass through to form corresponding phosphoramidite rear oxidation preparation by chloro phosphate and amine reaction acquisition.

P (V) the phosphorylated precursor of synthetic enantiomer enrichment:

In the presence of alkali, the phosphorus esterification reagent of the activation of enantiomer enrichment can be by using formula L-P (O) Cl ₂The 1-(V)-1 of dichloro-phosphate phosphorylated enantiomer enrichment, ammediol synthesizes (Ferroni etc., J.Org.Chem.64 (13), 4943 (1999)).Dichloro-phosphate R-OP (O) Cl that the glycol of the replacement that mapping is pure obtains with for example commerce ₂Phosphorylated, wherein RO is a leaving group, preferably the aryl that is replaced by electron withdraw group (for example nitro or chloro) has produced 2 kinds of diastereoisomer intermediates.The relative configuration of phosphorus atoms can be easily by contrast ³¹P NMR spectrum is determined.The chemical shift of calm phosphinylidyne oxygen base section (trans-isomer) has higher magnetic field (Verkade etc., J.Org.Chem., 1977,42,1549) than axial isomer (cis-isomer) usually.At alkali for example in the presence of triethylamine or the DBU, these diastereoisomers can obtain trans-2 through further balance, the phosphorus esterification reagent that 4-replaces.2, the balance that 4-cis-diastereoisomer reverses fully also can obtain in the presence of the sodium phenate of suitable replacement.This equilibrium step can obtain being higher than the trans-phosphorus esterification reagent of the separation of 95%ee.

Synthetic nucleosides

All nucleoside moieties of formula I, IX, X, XIII, XIV and XVII have a detailed description in the literature.2 '-C-methyl-adenosine, 2 '-C-methyl-guanosine, 2 '-C-methyl-cytidine and 4 '-C-methyl-cytidine are by crossing the Lewis acid catalyzed reaction preparation (Walton etc. of silicyl choline (per silicyl ated base) and 1 '-acetic acid esters or benzoic ether sugar intermediate, J.Am.Chem.Soc., 1966,88,4524; Harry-O ' Kuru etc., J.Org.Chem., 1997,62,1754, WO01/90121).7-deazapurine nucleosides is as mentioned before from the sodium salt prepared in reaction (referring to U.S. Pat 6777395, it in full be incorporated herein by reference) of 1 '-bromo sugar intermediate by alkali.With glycation product through deprotection with by the ammonolysis amination.

The nucleoside moiety of formula VI-VIII of the present invention and derivative thereof can be by many known synthesizing in the universal method described in the nucleosides document.Several nucleosides described herein can be synthetic as method described in the WO04/046331 and the method for wherein quoting.These nucleosides also can be by many commercial compounds, adopt 2 '-methylribose base precursor (described in the US6777395), or by the various preparation of known glycosylation (Vorbruggen and Ruh-Pohlenz, Handbook of NucleosideSynthesis, Wiley, New York, 2001).In addition, can adopt reported method in corresponding nuclear-analog, denitrogenation and aza-nucleoside can carry out glycosylation preparation (Robins by adopting 2 '-methyl glycosylation precursor, Deng, Advances in Antiviral Drug Design, the 1st volume, 39-85 page or leaf, De Clercq, ed., JAI Press, Greenwich, CT, 1993).In addition, the alkali analog of new nucleosides can be by modifying obtainable nucleosides or synthesizing (Chemistry of Nucleosides and Nucleosides, 1-3 volume by synthetic new alkali glycosylation subsequently, Townsend, ed., Plenum, New York, 1988 and Nucleic Acid Chemistry, the 1-4 volume, Townsend and Tipson Eds., Wiley, New York, 1986).

By coupling nucleosides and the synthetic prodrug of prodrug moiety

The step of following preparation prodrug has been described the universal method of preparation NMP prodrug.Prodrug can be introduced in different synthesis phases.Under most of situation, they carried out in the later stage, because these groups have certain sensitivity to different reaction conditions.The phosphate intermediate preparation that has the activation that the optically pure prodrug of individual isomer can be by coupling mapping enrichment in the phosphorus center.

All steps described herein when Y and Y ' are oxygen, also can be used to prepare Y wherein and/or the Y ' prodrug for NH by suitable replacement or nitrogen protection.

The preparation prodrug can further be summarized as follows: 1) synthetic by P (III) intermediate, and 2) synthetic by P (V) intermediate, and 3) other method.

Synthesize prodrug by P (III) intermediate:

Wherein Q is N or CH; L is H or NH ₂, M is NH ₂Or M is OH, or N=CHN (R ⁵) ₂, NHC (O) R ⁵Or NHC (O) OR ⁵And L ' is Cl.

In the presence of organic base (as triethylamine, pyridine), with the pure phosphorylated of chloro phospholane with nucleosides.Perhaps, for example in the presence of tetrazolium or the benzimidazole fluoroform sulphonate, phosphite ester also can obtain (Hayakawa etc., J.Org.Chem., 1996,61,7996) by phosphoramidate and nucleosides coupling coupling promoter.The phosphite ester diastereoisomer can be through column chromatography or Crystallization Separation (Wang etc., Tetrahedron Lett, 1997,38,3797; Bentridge etc., J.Am.Chem.Soc., 1989,111,3981).Because alcohol is SN2 (P) reaction with the condensation of chloro phospholane or phosphoramidite, so the expection product has reverse configuration.This makes that the stereoselectivity that can be used for cyclic phosphites is synthetic.The isomer mixture of phosphorus acylation reaction also can the isomer of balance (as heat balance) for having better thermodynamic stability.

Subsequently, for example molecular oxygen or tert-butyl hydroperoxides are oxidized to corresponding phosphate prodrug (Meier etc., Bioorg, Med.Chem.Lett., 1997,7,1577) with the phosphate that obtains to adopt oxidant.Expecting the oxidation of optically pure phosphite ester can Stereoselective provides optically active prodrug (Mikolajczyk is etc., J.Org.Chem., 1978,43,2132.Cullis, P.M.J.Chem.Soc., Chem Commun., 1984,1510, Verfurth, etc., Chem.Ber., 1991,129,1627).

Synthesize prodrug by P (V) intermediate:

For the cis of synthesis type I, IX, X, XIII, XIV and XVII-or trans prodrug, can introduce prodrug moiety at different synthesis phases.Under most of the time, annular phosphate was introduced in the later stage, and this is because these groups have general susceptibility to various reaction conditions.Synthetic also can by adopt protection or unprotected nucleosides or nucleoside analog carry out, this depends on the reactivity of the functional group that exists in the compound.Cis-or the single stereoisomers of trans prodrug both can by column chromatography and/or crystallization in conjunction with separating diastereoisomer/enantiomer preparation, the phosphate intermediate of activation that also can be by adopting the enantiomer enrichment carries out enantio-selectivity and synthesizes and prepare.

The prodrug of synthetic enantiomer enrichment:

The nucleoside phosphorus acylated universal method that makes protection is nucleosides and the alkali reaction that makes due care, makes the alkoxide and the phosphorus esterification reagent reaction of generation then.The nucleosides of protection can adopt one of multiple described nucleosides guard method preparation (Greene T.W., ProtectiveGroups in Organic Chemistry, John Wiley ﹠amp by those skilled in the art; Sons, New York (1999)).Nucleosides can so that top oh group is exposed to the bound phosphate groups that is added on it, be protected other functional group on all other hydroxyls and the nucleosides simultaneously with this class methods protection, and these groups may disturb the phosphorylated step or cause producing regional isomer.On the one hand, select blocking group to make its opposing highly basic, for example ether, silyl ether and ketal.On the one hand, blocking group is optional MOM ether, MEM ether, trialkylsilyl ethers and the symmetrical ketal that replaces.On the other hand, blocking group is tert-butyl dimetylsilyl ether and isopropylidene.Further protection comprises the amino group of the alkali part of sheltering existence, to remove any sour proton.On the one hand, the N-protected group of selection is selected from dialkyl group carbonamidine, list and dialkyl group imines, list and diaryl imines.On the one hand, the N-protected group is selected from dialkyl group carbonamidine and list-alkyl imines and single aryl imine.On the one hand, list-alkyl imines is the benzyl imines, and list-aryl imine is a phenyl imine.On the other hand, the N-protected group is the symmetrical dialkyl group carbonamidine that is selected from dimethyl carbonamidine and diethyl carbonamidine.

Generation at the alkoxide of the oh group of the exposure on the nucleosides of suitable protection can be carried out in insensitive aprotic solvent to alkali with alkali, and described aprotic solvent is the mixture of THF, dialkyl group and ring-type formamide, ether, toluene and these solvents for example.On the one hand, solvent is the mixture of DMF, DMA, DEF, N-Methyl pyrrolidone, THF and these solvents.

Adopt ring-type and non-annularity phosphorus esterification reagent, many different alkali can be used for the phosphorylated of nucleosides and non-nucleoside compound.For example trialkylamine such as triethylamine (Roodsari etc., J.Org.Chem.64 (21), 7727 (1999)) or N, N-diisopropylethylamine (Meek etc., J.Am.Chem.Soc.110 (7), 2317 (1988)); Nitrogen heterocyclic ring amine, for example pyridine (Hoefler etc., Tetrahedron56 (11), 1485 (2000)), N-methylimidazole (Vankayalapati etc., J.Chem.Soc.Perk T114,2187 (2000)), 1,2,4-triazole (Takaku etc., Chem.Lett. (5), 699 (1986)) or imidazoles (Dyatkina etc., Tetrahedron Lett.35 (13), 1961 (1994)); Organic metal alkali, uncle's fourth potassium oxide (Postel etc. for example, J.Carbohyd.Chem.19 (2), 171 (2000)), butyl lithium (Torneiro etc., J.Org.Chem.62 (18), 6344 (1977)), tert-butyl magnesium chloride (Hayakawa etc., Tetrahedron Lett.28 (20), 2259 (1987)) or LDA (Aleksiuk etc., J.Chem.Soc.Chem.Comm. (1), 11 (1993)); Inorganic base, for example cesium fluoride (Takaku etc., Nippon Kagaku Kaishi (10), 1968 (1985)), sodium hydride (Hanaoka etc., Heterocycles 23 (11), 2927 (1985)), sodium iodide (Stromberg etc., J.Nucleos.Nucleot.6 (5), 815 (1987)), iodine (Stromberg etc., J.Nucleos.Nucleot.6 (5), 815 (1987)) or sodium hydroxide (Attanasi etc., Phosphorus Sulfur 35 (1-2), 63 (1988)); Metal, for example copper (Bhatia etc., Tetrahedron Lett.28 (3), 271 (1987)).Yet, when attempting to adopt preceding method coupling phosphorus esterification reagent, do not observe at the three-dimensional center of phosphorus and respond or racemization.Especially; do not observe the reaction of the ring-type phosphorus esterification reagent of aforementioned employed alkali and replacement; thereby obtain corresponding annular phosphate with high yield; sodium hydride (Thuong etc. for example; Bull.Soc.Chim.Fr.667 (1974)); pyridine (Ayral-Kaloustian etc.; Carbohy dr.Res.187 (1991)); butyl-lithium (Hulst etc.; Tetrahedron Lett.1339 (1993)); DBU (Merckling etc.; Tetrahedron Lett.2217 (1996)); triethylamine (Hadvary etc.; Helv.Chi m.Acta; 1986; 69 (8); 1862); N-methylimidazole (Li etc., Tetrahedron Lett.6615 (2001)) or first sodium oxide molybdena (Gorenstein etc., J.Am.Chem.Soc.5077 (1980)).The use of Grignard reagent has promoted phosphorus acylation reaction, produces minimum epimerization simultaneously in the phosphorus in the heart.On the one hand, Grignard reagent is alkyl and aryl Ge Liya.On the other hand, Grignard reagent is tert-butyl magnesium halide and phenyl-magnesiumhalide.On the other hand, Grignard reagent is tert-butyl magnesium chloride and phenyl-magnesium-chloride.

On the other hand, the magnane oxide is used to produce the magnesium 5 '-alkoxide of nucleosides.On the one hand, the magnane oxide is selected from Mg (O-t-Bu) ₂And Mg (O-iPr) ₂

Make the prodrug of the protection that produces as described above remove all blocking groups (Greene T.W., Protective Groups inOrganic Chemistry, John Wiley ﹠amp through deprotection steps then with method known to those skilled in the art; Sons, New York (1999)), and this also stable consistent with the phosphate prodrug.On the one hand, deprotecting regent comprises the fluoride salt of removing the silicyl blocking group; Inorganic acid or organic acid remove the unsettled blocking group of disacidify, as the N-protected group of silicyl and/or ketal and existence.On the other hand, reagent is tetrabutyl ammonium fluoride (TBAF), hydrochloric acid solution and the TFA aqueous solution.The separation and the purifying of final prodrug and all intermediates can adopt the combination of column chromatography and/or crystallization to carry out.

Described order provides the method for synthesizing single formula I, IX, X, XIII, XIV and XVII compound isomers.Owing to there is stereogenic centres on carbon, wherein V is connected on the annular phosphate reagent, and this carbon atom can have 2 different orientations, i.e. R or S.Thus from the trans-phosphate reagent of racemic diol preparation, can be with S-trans or R-anti-configuration exist, thereby obtain S-cis and R-cis prodrug mixture.C '-S-is trans-reaction of phosphate reagent produced nucleosides C '-S-cis-prodrug, and and C '-R-trans-reaction of phosphate reagent produced C '-R-cis-prodrug.

Synthetic N ⁴-, N ⁶-, 2 '-and/or the 3 '-prodrug that replaces:

The N of synthesis type II or III ⁴-, N ⁶-, 2 '-and/or the 3 '-prodrug that replaces, can be with formula I compound as raw material.For example, N ⁴-, N ⁶The prodrug of-position can be from corresponding nucleosides halo derivatives preparation.Be formula II or III compound (R wherein ⁹Or R ¹⁰For replace (as N ₃, H ,-COR) under the situation), prodrug replaces and can (before or after 5 '-prodrug forms) carries out from corresponding amino, chloro or hydroxy functional group.Method is synthesized this type of nucleosides precursor (WO 02/057287) as described above.Preparing these purine analogues by azido displacement (Aso etc., J.Chem Soc Perkin Trans II, 2000,81637) or hydrogenation (Freer etc., Tetrahedron, 2000,56,45) is known method.Subsequently, the nucleosides that these prodrug functional groups are replaced is converted into the phosphoric acid ring-type prodrug of corresponding formula II or III.Under the situation of pyrimidine analogue, N ⁴-substituting group kind for example carbamate, acid amides, amidine can be used as prodrug functional group (WO04/041203, Shimma etc., Bioorg.Med.Chem, 2000,8,1697).

Nucleoside monophosphate ring-type prodrug the selectivity 3 '-acyl groupization of formula I can be reached (Protective groups in organic synthesis, Greene and Wuts, John Wiley, New York, 1991) by method described in several documents.In addition, selectivity 3 '-acyl group turns into can being undertaken by various esterification process, and this is reflected in the tert-hydroxyl functional group without protection that exists on 2 '-position and carries out.Acyl group turns into also carrying out (WO04/002422, Hanson etc., Bioorg.Med Chem.2000,8,2681) effectively by the amino acid that uses the amine protection as previously mentioned, then, removes amine protecting group group under mild acid conditions.2 ', 3 '-diester also can adopt similar condition to make by the imidodicarbonic diamide reagent that replaces via acyl chlorides or acid.The formation of 2 ', 3 '-cyclic carbonate is the method that another ribofuranose yl nucleosides of knowing transforms.Under neutrallty condition, formula I compound forms through carbonic ester and obtains formula II or III compound (Pankiewicz, etc., J.Org.Chem., 1985,50,3319).

And the nucleosides of 5 '-protection can carry out the formation of carbonic ester under conditions of similarity, obtain 2 of nucleosides,, 3 '-cyclic carbonate, it can obtain the compound of formula X and XIV then with the prodrug moiety coupling.

Other method:

Phosphate with activation can be finished in the presence of organic base with the coupling of alcohol.For example, synthetic as mentioned before chloro phosphate reacts in the presence of alkali (for example pyridine or N-methylimidazole) with alcohol.In some cases, generating the iodo phosphate on the spot from the chloro phosphate, (Stomberg is etc., Nucleosides ﹠amp can to improve phosphorus acylation reaction; Nucleotides., 1987,5:815).In the presence of alkali (for example CsF or n-BuLi), fluoro phosphate intermediate also is used to phosphorus acylation reaction, to generate ring-type prodrug (Watanabe etc., Tetrahedron Lett., 1988,29,5763).By transition metal-catalyzed, the phosphoramidate intermediate can coupling (Nagamatsu, etc., TetrahedronLett., 1987,28,2375).

The reaction of the optically pure diastereoisomer of phosphoramidate intermediate and the hydroxyl of nucleosides can be in the presence of acid, by direct S _NThe optically pure phosphate prodrug of 2 (P) reaction generation (Nakayama, etc., J.Am.Chem.Soc., 1990,112,6936).Perhaps, optically pure phosphate precursor and fluoride source (preferred fluorinated caesium or TBAF) reaction, generation has more active fluoro phosphate, makes the hydroxyl reaction of itself and nucleosides, obtains optically pure prodrug, kept the configuration (Ogilvie on the phosphorus atoms comprehensively, Deng, J.Am.Chem.Soc., 1977,99,1277).

Formula I and XIII prodrug can be synthetic by corresponding phosphorus dichloride acid esters and alcohol reaction (Khamnei, etc., J.Med.Chem., 1996,39:4109).For example, in the presence of alkali (as pyridine and triethylamine), 1 of phosphorus dichloride acid esters and replacement, the reaction of 3-glycol obtains formula I compound.

This type of reactive phosphorus dichloride acid esters intermediate can prepare from corresponding acid and chlorinating agent, and described chlorinating agent is for example thionyl chloride (people such as Starrett, J.Med.Chem., 1994,1857), (Stowell is etc., Tetrahedron Lett. for oxalyl chloride, 1990,31:3261) and phosphorus pentachloride (Quast is etc., Synthesis, 1974,490).

The phosphorus acylation reaction of alcohol also can adopt ring-type 1 ', the 3 '-propyl diester of phosphoric acid under the Mitsunobu reaction condition, preparation (Kimura etc., Bull.Chem.Soc.Jpn., 1979,52,1191) in the presence of triphenyl phasphine and diethyl azodiformate.This method can be used for preparing from corresponding phosphoric acid the phosphate of enantiomer-pure.The phosphate prodrug also can be from free acid by Mitsunobu prepared in reaction (Mitsunobu, Synthesis, 1981,1; Campbell, J.Org.Chem., 1992,52:6331), other sour coupling reagent includes, but is not limited to carbodiimide (Alexander etc., Collect.Czech.Chem.Commun., 1994,59:1853; Casara etc., Bioorg.Med.Chem.Lett., 1992,2:145; Ohashi etc., Tetrahedron Lett., 1988,29:1189) and BTA base oxygen base three (dimethylamino) phosphonium salt (Campagne, etc., Tetrahedron Lett., 1993,34:6743).The ring-type of phosphate-1,3-propyl group prodrug are also synthetic from the third-1 of NMP and replacement, the 3-glycol, and coupling reagent for example 1 is adopted in this reaction, 3-dicyclohexylcarbodiimide (DCC), carries out in the presence of alkali (as pyridine).Other carbodiimide coupling agent for example 1,3-DIC and water-soluble reagent 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI) also can be used for the synthesis of cyclic prodrug.

The phosphate prodrug can and derive from 1 from the corresponding 4-butyl ammonium of phosphate ,-1 of the replacement of 3-glycol, the alkylated reaction preparation (Farquhar etc., Tetrahedron Lett., 1,995 36,655) between the 3-two iodo propane.In addition, can in the presence of triethyl phosphite, nucleosides be converted into the dichloride intermediate with phosphoryl chloride phosphorus oxychloride, and with replace-1, the ammediol quencher obtains phosphate prodrug (Farquhar etc., J.Org.Chem., 1983,26,1153).

Phosphorus acylation reaction also can be by the mixed anhydride of preparation phosphoric acid cyclic diester and sulfonic acid chloride (preferred 8-quinoline sulfuryl chloride), and in the presence of alkali (preferred N-methylimidazole), obtains (Takaku with the hydroxyl reaction of nucleosides; Deng, J.Org.Chem., 1982; 47,4937).In addition, also can be raw material with the cyclic diester of the enantiomer-pure of phosphoric acid obtains the phosphate (Wynberg, etc., J.Org.Chem., 1985,50,4508) of enantiomer-pure through fractionation.

Embodiment

The compounds of this invention and their preparation method can come further to be understood by embodiment, and described embodiment has described the certain methods of preparation compound.But these embodiment also are not used in the scope of the present invention that limits, now known to or the variant of the compound of Future Development, also belong to the following claimed scope of the present invention.

Formula I compound can as mentioned belowly prepare.The TLC condition that provides is used for the AnaltechUNIPLATE plate, GHLF silica gel, specification 10 * 20cm, 250 microns.

Racemic 1-(aryl) the third-1,3-glycol synthetic:

Embodiment 1: prepare 1-(2 '-furyl)-the third-1 by Ge Liya addition reaction and hydroboration, the 3-glycol:

In 0 ℃, to 2-furfural (3g, THF (34mL) solution of adding 1M vinyl bromination magnesium in THF 31.2mmol) (60mL) solution.Stir after 1 hour, add 1M BH ₃The THF solution of THF complex compound.In 0 ℃, will react with 3N NaOH (20mL) and 30% hydrogen peroxide (10mL) quencher.Separate organic moiety and concentrated.The crude product product obtains 1-(2 '-furyl) the third-1 with 5% methyl alcohol-carrene elution chromatography, 3-glycol (1g).

Embodiment 2: prepare 1-(2 '-pyridine radicals)-the third-1 by the benzyl oxidation reaction, the 3-glycol:

Steps A: (J.Org.Chem.22:589 (1957))

(10g slowly adds 30% hydrogen peroxide in acetate 72.9mmol) (75mL) solution to 3-(2 '-pyridine radicals) third-1-alcohol.Reactant mixture is heated to 80 ℃ of 16h.Vacuum concentration reactant, residue are dissolved in acetic anhydride (100mL), and in 110 ℃ of heated overnight.After reaction is finished, the evaporation of acetic acid acid anhydride.Mixture methyl alcohol-carrene (1: 9) wash-out, chromatography obtains the pure diacetin of 10.5g.

Step B:

To diacetin (5g, methanol-water 21.1mmol) (3: 1,40mL) add in the solution potash (14.6g, 105.5mmol).After stirring 3h under the room temperature, concentrated reaction mixture.Residue methyl alcohol-carrene (1: 9) wash-out, chromatography obtains 2.2g crystal glycol.

Embodiment 3: from the third-1, the 3-glycol prepares 1-(aryl)-the third-1, the 3-glycol by the Ge Liya addition:

Steps A: (J.Org.Chem.53:911 (1988))

In-78 ℃, to oxalyl chloride (5.7mL, add in carrene 97mmol) (200mL) solution dimethyl sulfoxide (DMSO) (9.2mL, 130mmol).In-78 ℃, stirred reaction mixture 20min adds 3-(benzyloxy) third-1-alcohol (11g, carrene 65mmol) (25mL) liquid then.In-78 ℃ after 1 hour, (19mL, 260mmol) quencher reaction and be warmed to room temperature are handled and are carried out column chromatography with the carrene wash-out, obtain 3-(benzyloxy) third-1-aldehyde of 8g with triethylamine.

Step B:

In 0 ℃, to 3-(benzyloxy) third-1-aldehyde (1g, THF (6.7mL, 6.7mmol) solution of adding 1M4-fluoro phenyl-magnesium-bromide in THF solution 6.1mmol).Reactant is warmed to room temperature and stirs 1h.Handle and carry out column chromatography, obtain 0.7g ethanol with the carrene wash-out.

Step C:

In ethyl acetate (10mL) solution of benzylic ether (500mg), add 10%Pd (OH) ₂C (100mg).Reaction stirred 16h under hydrogen.Through diatomite filtration reactant mixture and concentrated.Residue ethyl acetate-carrene (1: 1) wash-out, chromatography obtains the 340mg product.

Embodiment 4: prepare-the third-1 of 1-aryl replacement from aryl aldehyde, the universal method of 3-glycol:

Steps A: (J.Org.Chem.55:4744 (1990))

In the THF of-78 ℃ diisopropylamines (2mmol) (0.7mL/mmol diisopropylamine) solution, slowly add n-butyl lithium (2mmol, the hexane solution of 2.5M).In-78 ℃ of reaction stirred 15min, slowly add THF (0.14mL/mmol ethyl acetate) solution of ethyl acetate (2mmol) then.Behind-78 ℃ of stirring 30min, add the THF solution that contains aryl aldehyde (1.0mmol is in 0.28mL THF) again.In-78 ℃ of reaction stirred 30min again, be warmed to room temperature then, stir 2h again.After the aqueous solution is handled (0.5M HCl), organic layer simmer down to crude product oil (beta-hydroxy esters).

Step B:

The crude product hydroxy ester is dissolved in ether (2.8mL/mmol), is cooled to the ice bath temperature, and gradation adds lithium aluminium hydride reduction (3mmol).Reaction stirred makes the cryostat fusing, and temperature of charge is to room temperature.Stir under room temperature and spend the night, reactant is cooled to the ice bath temperature again and uses the ethyl acetate quencher.Water solution-treated (0.5M HCl) obtains the crude product glycol, through chromatography or distillation purifying.

Embodiment 4a:1-(3-methoxycarbonyl phenyl)-1, ammediol synthetic

As embodiment 4 preparation 1-(3-bromo phenyl)-1, ammediol, and further as described below deriving:

In pressure vessel, add 1-(3-bromo phenyl)-1, ammediol (2g, 8.6mmol), methyl alcohol (30mL), triethylamine (5mL) and two (triphenyl phasphine) palladium chloride (0.36g, 05mmol).The container of sealing is heated 24h with carbon monoxide in the 55psi pressurization and in 85 ℃.Open the container of cooling and, use washed with methanol through the diatomite filtration reactant mixture.Concentrate the filtrate that merges down in decompression,, obtain target compound (1.2g) through column chromatography purification residue (silica gel, hexane/ethyl acetate 1/1)

TLC: hexane/ethyl acetate 2/8; Rf=0.5

¹H NMR(CDCl ₃，Varian Gemini 200MHz)：5.05-4.95(m，1H)，3.9(s，3H)，2-1.8(m，2H).

Embodiment 4b:1-(4-methoxycarbonyl phenyl)-1, ammediol synthetic

1-(4-bromo phenyl)-1, ammediol can prepare as embodiment 4, and further reacts according to embodiment 4a.

TLC: hexane/ethyl acetate 3/7; Rf=0.35

¹H NMR(CDCl ₃，Varian Gemini 200MHz)：5.1-5(m，1H)，3.91(s，3H)，2.05-1.9(m，2H).

The 1-(aryl)-the third-1 of synthetic enantiomer enrichment, the universal method of 3-glycol:

Embodiment 5: resolution of racemic 1, and the universal method of 3-glycol:

Racemic diol synthetic among the embodiment 1-4 can be split as following method, obtains enantiomer.

Steps A:

In the THF of glycol (1.0mmol) (1.0ml) solution, add HMDS (2.1mmol), and then add the TMS triflate (2-3 drips) of catalytic amount.After stirring 1h under the room temperature, reactant is diluted with hexane (4mL), and handle with icy water subsequently.If the dimethyl silanyl ether that obtains perhaps enough pure, can directly use crude product through chromatographic purifying in next step.

Step B:

In-40 ℃, in carrene (2.0ml) solution of dimethyl silanyl ether (1.0mmol) and (-)-menthones (1.1mmol), slowly add TMS triflate (0.11mmol).Then reactant is placed-50 ℃ to-60 ℃ of 48h, add pyridine quencher reaction then.After being warmed to room temperature, crude mixture is handled through the aqueous solution with hexane (4.0ml) dilution.Two kinds of ketals of chromatography.

Step C:

By in the methanol solution (4.0mL/mmol) of the ketal that separates, adding the concentrated hydrochloric acid of catalytic amount with its hydrolysis.After stirring under the room temperature is spent the night, remove methyl alcohol under the vacuum, residue is handled through the aqueous solution.Be further purified the glycol of fractionation through chromatography or crystallization.

Embodiment 6: by the 1-(3 '-chlorophenyl)-1 of the synthetic enantiomer enrichment of Sharples asymmetric epoxidation reaction, and the 3-dihydroxypropane:

Steps A:

Under room temperature, to-(25g adds the concentrated sulfuric acid (8mL) in ethanol 137mmol) (275mL) dispersion liquid to chloro-cinnamic acid.The back flow reaction thing spends the night and concentrates.In crude product, add icy water, leach the white solid of precipitation and use cold water washing.Drying precipitated spending the night under vacuum obtains the 25g ester.(on the silica gel plate, the Rf=0.5 in the carrene)

Step B:

In-78 ℃, with 1 hour, to-the chloro-cinnamic acid ethyl ester (23g, be added dropwise in dichloromethane solution 109.5mmol) 1M DIBAL-H dichloromethane solution (229mL, 229mmol).In-78 ℃, reaction stirred 3h again.Add the excessive DIBAL-H of ethyl acetate quencher and also add saturated potassium tartrate sodium water solution, and under room temperature reaction stirred 3h.Separate organic layer, salt washs with ethyl acetate.Concentrate the organic extract that merges, and obtain the pure allyl alcohol of 14g in 120 ℃/0.1mm distillation.(on the silica gel plate, 1: 1 ethyl acetate: the Rf=0.38 in the hexane)

Step C:

To-(5g adds activation to the chloro cinnamyl alcohol in carrene 29.76mmol) (220mL) solution

Molecular sieve powder (2.5g), mixture are cooled to-20 ℃.In-20 ℃, add (+)-tartaric acid diethyl ester (0.61mL, 3.57mmol) and stir 15min, add then four different third titanium oxide (0.87g, 2.97mmol).Reaction stirred 30min again is added dropwise to heptane (10mL, the 60mmol) solution, and to keep internal temperature be-20 to-25 ℃ of the tert-butyl hydroperoxides of 5-6M.In-20 ℃ of 3h that stir the mixture again, add saturated sodium chloride (7.5mL) aqueous solution and the ether (25mL) of 10% sodium hydroxide then.Reactant is warmed to 10 ℃, stirs 15min, adds anhydrous magnesium sulfate (10g) and diatomite (1.5g) then.Again mixture is further stirred 15min, filter and concentrate in 25 ℃, obtain crude product epoxy alcohol.(on the silica gel plate, 1: 1 ethyl acetate: the Rf=0.40 in the hexane)

Step D:

Under 0 ℃, nitrogen, between the crude product that in previous reaction, obtains-be added dropwise in the solution of the dimethoxy-ethane (300mL) of chloro epoxy cinnamyl alcohol 65%Red-Al toluene solution (18.63mL, 60mmol).After stirring 3h under the room temperature, solution is with ethyl acetate (400mL) dilution and with saturated metabisulfite solution (50mL) quencher.After stirring 30min under the room temperature, the white precipitate that forms is leached and washs with ethyl acetate.Dried filtrate also concentrates.In 125-130 ℃/0.1mm, distill the crude product product, obtain (the R)-1-(3 '-chlorophenyl)-1 of 3.75g enantiomer enrichment, the 3-dihydroxypropane.(1: 1 ethyl acetate: the Rf=0.40 in the carrene)

((S, S) Whelko-0 is available from 250cm * 4.0mm ID of Regis) measures, and excessive enantiomer is defined as diacetate esters (through handling the glycol preparation with the dichloromethane solution of acetic anhydride, triethylamine, cat.DMAP) through HPLC.

(R)-and 1-(3 '-chlorophenyl)-1,3-dihydroxypropane: 91%ee

(R)-and 1-(3 '-chlorophenyl)-1, (+) diisopropyl tartrate＞96%ee in the 3-dihydroxypropane.

Also can be under same condition, via the method for reducing of asymmetric Epoxidation effect and employing (-)-tartrate, with similar yield preparation (S)-1-(3 '-chlorophenyl)-1,3-dihydroxypropane.(S)-and 3-(3 '-chlorophenyl)-1, the yield of 3-dihydroxypropane is 79%ee.

Embodiment 7: via the 1-(3 '-chlorophenyl)-1 of the synthetic enantiomer enrichment of hydrogen transfer reaction, and the 3-dihydroxypropane:

Steps A: preparation 3-(3 '-chlorophenyl)-3-oxo-methyl propionate:

22L, 3-neck round-bottomed flask are added mechanical agitator, thermocouple sheath/thermometer and nitrogen conduit (online insufflator).Charge into flask and add THF (6L), t-fourth potassium oxide (1451g) and THF (0.5L) in proper order with nitrogen.Under room temperature, stir the mixture 15min that obtains, place 20 ℃ of water-baths again.The 3L round-bottomed flask is charged into 3 '-chloroacetophenone (1000g) and diethyl carbonate (1165g), and the yellow solution that obtains is slowly added in the uncle-Ding potassium oxide solution of stirring, maintain the temperature between 16 to 31 ℃.Add after finishing that (1h 10min.), removes cryostat and with solution stirring 1 hour 30 minutes.TLC demonstration reaction is finished.5 gallons of solid phase separatory funnels are charged into frozen water (4L) and concentrated hydrochloric acid (solution of 1.3L 12M).The quencher of peony reaction solution was stirred 15 minutes to aqueous acid and with mixture.Separate each layer, water (lower floor) uses toluene (4L) to extract again.The organic extract that merges is with saturated salt solution (2 * 3L stirs 10min) washing, drying (MgSO at every turn ₄), filter and concentrate down and obtain the 1480g brown oil in decompression.Spending the night obtains 1427g should oil to place (10 holder) under high vacuum.With this material vacuum distillation (short column, fraction collector),, obtain the 1273.9g yellow oil in 108-128 ℃/1-0.5 collection collection cut.(Rf=0.36 is in 20% ethyl acetate/hexane).

Step B: preparation (S)-3-(3 '-chlorophenyl)-3-hydroxy methyl propionate:

12L, 3-neck round-bottomed flask are added mechanical agitator, thermometer, addition funnel (500mL) and nitrogen conduit (online insufflator).Flask charged into nitrogen and add formic acid (292mL, 350g).(422mL 306g) packs in the addition funnel, slowly adds in stirring down then, keeps temperature to be lower than 45 ℃ with triethylamine.(1h, 30min), agitating solution 20min on ice bath stirred 1h then again under room temperature after adding was finished.Then in flask order add 3-(3-chlorophenyl)-3-oxo-propionic acid methyl ester (1260g), DMF (2.77L comprises wash volumes) and (S, S)-Ts-DPEN-Ru-Cl-(p-cumene) (3.77g).Flask is loaded onto heating plate, and addition funnel is replaced with condenser (condensers of 5 ℃ of circulating frozen agent).The reaction solution that stirs slowly is heated to 60 ℃ (90min. reaches 60 ℃), reactant is remained in 60 ℃ of 4.25h.HPLC shows residue 3% initiation material.In 60 ℃ of agitating solution 8h again, be cooled to ambient temperature overnight then gradually.HPLC shows residue 0.5% initiation material.5 gallons of solid phase separatory funnels are charged into water (10L) and MTBE (1L).Reaction solution is inclined to mixture aqueous solution, reaction flask is cleaned in the separatory funnel with 1L MTBE.Reactant is stirred a few minutes and separates each layer.Water is used other MTBE again, and (2 * 1L) extract, and the organic extract of merging washs through salt solution (1L), and concentrate down in decompression, obtain the 1334g red oil.This oil can be directly used in next step without being further purified.

(10mg 0.046mmol) is dissolved in carrene (1mL) with the crude product hydroxy ester.Add acetic anhydride (22 μ L, 0.23mmol) and 4-(dimethylamino) pyridine (22mg, 0.18mmol), and under room temperature with solution stirring 15min.Solution is with carrene (10mL) dilution, with (3 * 3mL) washings of 1M hydrochloric acid.With organic facies drying (MgSO ₄), filter and concentrate down in decompression.Oil residues is dissolved in methyl alcohol, analyzes (Zorbax Rx-C18,250 * 4.6mm through chirality HPLC; Flowing phase: 65/35 (v/v) water/acetonitrile, isocratic elution; Flow velocity=1.5mL/min; Volume injected=15 μ L; Monitor in 220nm UV.Retention time: product=9.3min, initiation material=17.2min).Hydroxy ester is derived and is acetic acid esters, analyzes through chirality HPLC, shows to obtain 91%ee. (HPLC condition: post: Pirklecovalent (S, S) Whelk-O 10/100krom FEC, 250 * 4.6mm; Flowing phase: 70/30 (v/v) methanol, isocratic elution; Flow velocity: 1.5mL/min; Volume injected=10 μ L; Monitor in 220nm UV.Retention time: S-hydroxy ester (acetic acid esters)=9.6min, R-hydroxy ester (acetic acid esters)=7.3min.)

Step C: preparation (S)-3-(3 '-chlorophenyl)-3-hydracrylic acid:

In the 10L of crude product hydroxy ester rotary evaporator flask, add sodium hydroxide solution (2.5L, 2M solution).Under normal pressure, room temperature, the solution that obtains is stirred 2h on rotary evaporator.HPLC shows residue 5% initiation material (HPLC condition: post: Zorbax Rx-C18,250 * 4.6mm: flowing phase: 65/35 (v/v) water/acetonitrile, isocratic elution; Flow velocity=1.5mL/min; Volume injected=15 μ L; Monitor in 220nmUV.Retention time: product=3.8min, initiation material=18.9min.).PH value of solution is 11 (wide pH value test paper).Add 2M NaOH solution in addition and regulate pH to 14 (about 100mL), agitating solution 30min again.HPLC demonstration reaction is finished.Solution is transferred to 5 gallons of solid phase separatory funnels, and extracts with MTBE (2L).Separate each layer, abandon organic extract.Water is gone back to separatory funnel, and with 12M HCl solution (600mL) acidifying.(1 * 2L, 2 * 1L) extract mixture with MTBE.With the acid organic extract drying (MgSO that merges ₄), filter and concentrate down in decompression, obtain that 1262g is brown, oily is semi-solid.Residue is with ethyl acetate (1L) pulp, and be transferred to 12L, mechanical agitator be housed, in the 3-neck round-bottomed flask of heating plate, condenser and thermometer.Stirred mixture is heated to all solids dissolving (28 ℃), dark solution is cooled to 10 ℃ (forming precipitation in 11 ℃).Mixture is slowly diluted (in the 4L, 1h) with hexane, the mixture that obtains is stirred 2h in＜10 ℃.Filtering mixt also washs the solid of collecting with cold 4/1 hexane/ethyl acetate (1L), be dried to constant weight (30in.Hg, 50 ℃, 4h).Yield=837g beige solid.mp＝94.5-95.5℃

With borine-THF the sample of 50mg carboxylic acid is reduced to glycol (referring to step D).With the crude product glycol diacetylation (as described in step B) that obtains, analyze through chirality HPLC.Retention time: S-glycol (diacetate esters)=12.4min, R-glycol (diacetate esters)=8.8min.ee=98%

Separate the carboxylic acid that obtains for the second time.Concentrate the above-mentioned filtrate that obtains down in decompression, obtain the brown ooze of 260g.This material is dissolved in ethyl acetate (250mL), and the dark solution that stirs is slowly diluted with hexane (1000mL), the mixture that obtains is stirred under room temperature spend the night.Filtering mixt also washs the solid of collecting with 5/1 hexane/ethyl acetate (200mL), be dried to constant weight (30in.Hg, 50 ℃, 16h).Yield=134g beige solid.ee＝97％

Step D: preparation (S)-(-)-1-(3-chlorophenyl)-1, ammediol:

22L, 3-neck round-bottomed flask are added mechanical agitator, thermocouple sheath/thermometer and nitrogen conduit (outlet is used for bubbling).(3697g 4.2L), and is cooled to 5 ℃ with the solution that stirs to charge into 2M borine-THF in the flask.Stir THF (1245mL) solution of preparation (S)-3-(3-chlorophenyl)-3-hydracrylic acid (830g) (slowly heat absorption) down.Reaction flask is loaded onto addition funnel (1L), carboxylic acid solution is slowly added in the borine solution of stirring, keep temperature≤16 ℃.After adding is finished (3h), 1.5h stirs the mixture under the ice bath temperature.Carefully add entry (2.5L), the quencher reaction.After adding is finished (30min), add 3M NaOH solution (3.3L) (temperature rises to 35 ℃), the mixture that obtains is stirred 20min again.(temperature=30 ℃).Reactant mixture is transferred to 5 gallons of solid phase separatory funnels, separates each layer.Water extracts with MTBE (2.5L), and the organic extract of merging (THF and MTBE) is used MgSO with 20wt%NaCl solution (2L) washing ₄(830g) stir 30min.Mixture is through diatomite filtration, and concentrates down in decompression and to obtain 735g dark-brown grease.

Grease is collected cut in 135-140 ℃/0.2mm Hg and is obtained the 712.2g colorless oil through the vacuum distillation purifying.

Analyze (referring to step B) with the glycol diacetylation and through chirality HPLC (e.e.=98%).Retention time: S-glycol (diacetate esters)=12.4min, R-glycol (diacetate esters)=8.9min.[α] _D=-51.374 (5mg/mL is at CHCl ₃In)

Embodiment 8: by the 1-(4 '-pyridine radicals)-1 of the synthetic enantiomer enrichment of hydrogen transfer reaction, and the 3-dihydroxypropane:

Steps A: synthetic 3-oxo-3-(pyridin-4-yl)-methyl propionate

50L, 3-neck flask are loaded onto top agitator, heating plate and nitrogen conduit.With flask charge into THF (8L), uncle-Ding potassium oxide (5kg, 44.6mol) and THF (18L).Add the 4-acetylpyridine (2.5kg, 20.6mol), add subsequently dimethyl carbonate (3.75L, 44.5mol).Do not heat stirred reaction mixture 2.5h down, and then be heated to 57-60 ℃ of stirring 3h.Stop the heating and with the slow cool overnight of mixture (15h).Mixture filters through 45cm cloth formula funnel.Solid is retracted the 50L flask and is diluted with acetic acid aqueous solution (the 15L aqueous solution of 3L acetate).Mixture extracts (1 * 16L, 1 * 12L) with MTBE.The organic facies Na that merges ₂CO ₃The aqueous solution (the 12.5L water of 1750g), saturated NaHCO ₃The aqueous solution (8L) and salt solution (8L) washing are then through MgSO ₄Dry (500g) spend the night (15h).Filtering solution also removes through rotary evaporation and to desolvate, and obtains the 6.4kg material.The suspension that obtains is cooled off on ice bath, stir 2h.Solid collected by filtration, through MTBE (500mL) washing, in 20 ℃, dry 15h in vacuum tank obtains the 2425g ketone ester, is faint yellow solid.

Concentrate the MTBE mother liquor to about 1L.The suspension that obtains is cooled off 1h on ice bath.Solid collected by filtration, (2 * 150mL) washings in the vacuum tank drying, obtain 240g to MTBE once more.

The TLC.Merck silica gel plate, 1: 2THF/ hexane, UV lamp, the Rf=0.25 of SM, the Rf=0.3 of product.Fusing point: 74-76 ℃

Step B: synthetic S-methyl-3-hydroxyl-3-(pyridin-4-yl)-propionic ester

22L, 3-neck round-bottomed flask are loaded onto top agitator, thermocouple sheath/thermometer, addition funnel (1L) and cooler (sky).Charge into nitrogen in the flask, charge into formic acid (877g), and cool off with ice bath, (755g) adds in the addition funnel with triethylamine, and with in the formic acid that slowly was added to stirring in 50 minutes.After adding is finished, remove cryostat and use DMF (5.0L) to dilute reaction solution.Disposable adding ketone ester (2648g) adds other 0.5L DMF subsequently.Flask is loaded onto heating plate, and stirred mixture is heated to 16 ℃ gradually, with the dissolving all solids.Disposable adding catalyzer (S, S)-Ts-DPEN-Ru-Cl-(right-cumene) (18.8g), with 1h stirred mixture is heated to 55 ℃.In 55 ℃, the dark solution that obtains is stirred 16h.TLC demonstration reaction is finished.Evaporating solvent under decompression (Buchi R152 rotary evaporator under the high vacuum, bath temperature=60 ℃) obtains the 3574g brown oil.Oil is dissolved in carrene (10L) and it is transferred in 5 gallons of solid phase separatory funnels.Dark solution washs through saturated sodium bicarbonate solution (3.0L), and uses carrene (3.0L) to extract again water.The dichloromethane extract that merges is through MgSO ₄(300g) dry, filtration, and in the concentrated down 3362g brown oil that obtains of decompression.

Post: Chiralpak AD, 0.46 * 25cm; Flowing phase=10: 90, ethanol: hexane, isocratic elution; Flow velocity=1.5mL/min; Volume injected=10 μ L; Monitor in 254nmUV.

Retention time: R-hydroxy ester=19.9min.

S-hydroxy ester=21.7min.

Retention time: R-glycol=14.2min.

S-glycol=15.5min.

Hydroxy ester:

¹H NMR(CDCl ₃)：δ2.73(d，2H，J＝1.5Hz)，3.73(s，3H)，4.35(s，1H)，5.11-5.19(m，1H)，7.31(d，2H，J＝6.6Hz)，8.53(d，2H，J＝6.0Hz)

Merck silica gel 60 plates, 2.5 * 7.5cm, 250 microns; The CH of UV lamp: 5%MeOH ₂Cl ₂Liquid; The Rf=0.44 of S.M, the Rf=0.15 of product.

The S isomer of e.e.=87% hydroxy ester.

Step C: synthetic S-(-)-1-(pyridin-4-yl)-1, ammediol

22L, 4-neck round-bottomed flask are loaded onto top agitator, thermocouple sheath/thermometer, addition funnel (2L), condenser and cooler (sky).In flask, charge into nitrogen and order charge into sodium borohydride (467g, 12.3mol), (148mL 8.23mol), is dissolved in 1-butanols (1.0L) with the crude product hydroxy ester and with the solution addition funnel of packing into for 1-butanols (9.0L) and water.Add solution with 3.25h, if needed, adopt cooling to make temperature be lower than 62 ℃.After adding was finished, the 0.5h that stirs the mixture loaded onto heating plate with flask then, and with 0.75h stirred mixture is heated to 90 ℃.In the 90-93 ℃ of 2.25h that stirs the mixture, be cooled to 28 ℃ with 1.5h then.With wet chemical (10wt/vol%, 6L) quencher reactant mixture, and the 10min that stirs the mixture.Separate each layer, butanols use mutually wet chemical (10wt/vol%, 2L) and sodium chloride solution (15wt/vol%, 2L) washing.Remove desolvate (Buchi R152 rotary evaporator, high vacuum, bath temperature=60 ℃) down in decompression,, collect the 10.5L distillation until obtaining concentrated solution.With acetonitrile (3L) pack into evaporator flask and solvent evaporated under reduced pressure.The evaporator flask of again acetonitrile (9L) being packed into stirs slurries (rotating) (bathing temperature=70 ℃, atmospheric pressure) 15min in～60 ℃ on rotary evaporator.The slurry of heat filters (earlier the 250g slurry in the 1L acetonitrile being filled out 24cm cloth formula funnel in advance) through diatomite 521.Down with filtrate partial concentration (collecting the 5L distillation), the slurry that obtains is dissolved (bath temperature=65 ℃) in be heated to all solids under the atmospheric pressure on rotary evaporator in decompression.Stop heating, and the solution that obtains is stirred 10h on rotary evaporator, be cooled to room temperature gradually.The mixture that filtration obtains, with the solid collected through acetonitrile (2 * 200mL) washings, be dried to constant weight (30in.Hg, 55 ℃, 4h), obtain S-(-)-1-(4-pyridine radicals)-1, ammediol is yellow solid, weight 496g.

Fusing point=98-100 ℃

The HPLC condition:

Post: Chiralpak AD, 0.46 * 25cm; Flowing phase=10: 90, ethanol: hexane, isocratic elution; Flow velocity=1.5mL/min; Volume injected=10 μ L is monitored in the UV of 254nm place.

Retention time: R-glycol=14.2min.

S-glycol=15.5min.

Merck silica gel 60 plates, 2.5 * 7.5cm, 250 microns; The UV lamp; 15%MeOH is at CH ₂Cl ₂In; Initiation material Rf=0.38, product Rf=0.17, boron complex Rf=0.26.

Embodiment 9: by (-)-β-synthetic (S)-3-(3 '-chlorophenyl)-1 of chloro diisopinocampheylchloroborane base (diisopinocampheyl) borine (DIPCl) reduction, 3-dihydroxypropane

Steps A: preparation 3-(3-chlorophenyl)-3-oxo-propionic acid:

12L, 3-neck round-bottomed flask are added mechanical agitator and addition funnel (2L).In flask, charge into nitrogen, and add diisopropylamine (636mL) and THF (1.80L).The thermocouple detector is immersed reaction solution and the content that stirs is cooled to-20 ℃.With pack into addition funnel and slowly add of n-butyl lithium (the 2.5M hexane solution of 1.81L), keep temperature-20 to-28 ℃ in stirring down.After adding is finished (30min), addition funnel is cleaned with hexane (30mL), and the solution that stirs is cooled to-62 ℃.Stir and slowly to add acetate TMS ester (300g) down, keep temperature＜-60 ℃.After adding is finished (30min), solution is stirred 15min in-60 ℃.Slowly add 3-chlorobenzene formyl chloride (295mL) down in stirring, keep temperature＜-60 ℃.After adding is finished (65min), remove cryostat and stirring reaction solution 1.25h, be heated to 0 ℃ gradually.Reaction flask cools off with ice bath, adds entry (1.8L) then in the solution that stirs.Stirred reaction mixture 10min uses tert-butyl methyl ether (1.0L) dilution then.Separate the water of lower floor and be transferred in the 12L that is furnished with agitator, the 3-neck round-bottomed flask.Add tert-butyl methyl ether (1.8L), stirred mixture is cooled to＜10 ℃ (ice bath).Add dense HCl solution (the 12M solution of 300mL), the vigorous stirring mixture.Separate each layer and with water with further acidifying of dense HCl (30mL), and extract once again with tert-butyl methyl ether (1.0L).The MTBE extract that merges through salt solution (1L) washing, dry (MgSO4,70g), filter and concentrating under reduced pressure obtains the 827g yellow solid.The pulp and being transferred in 5L that mechanical agitator is housed, the 3-neck round-bottomed flask in hexane (2.2L) of crude product solid.In＜10 ℃, (ice bath) 1h that stirs the mixture filters then, with hexane (4 * 100mL) wash and be dried to constant weight (30in.Hg, room temperature, 14h).Yield=309g pale yellow powder.

Step B: preparation (S)-3-(3-chlorophenyl)-3-hydracrylic acid:

12L, 3-neck round-bottomed flask are loaded onto mechanical agitator and addition funnel (1L).In flask, charge into nitrogen, and add 3-(3-chlorophenyl)-3-oxo-propionic acid (275.5g) and carrene (2.2L).To be cooled to-20 ℃ in the thermocouple detector immersion reaction slurry and with the content that stirs.Adding triethylamine (211mL) to all solids with 5min in the slurry that stirs dissolves.With (-)-β ~-(1.60M, the dichloromethane solution 1.04L) addition funnel of packing into slowly adds in stirring down chloro diisopinocampheylchloroborane base borine then, keeps temperature-20 to-25 ℃.After adding is finished (35min), solution is warmed to ice bath temperature (2-3 ℃) and stirs 4h.Water (1.2L) is added in the dark orange reaction mixture, add 3M NaOH solution (1.44L) subsequently.Vigorous stirring mixture 5min is transferred to separatory funnel then.Separate each layer and alkaline aqueous solution is used ethyl acetate (1.0L) washing mutually.Water is with dense HCl (300mL) acidifying, with ethyl acetate (2 * 1.3L) extractions.The acetic acid ethyl acetate extract that merges two kinds of acidity, salt solution (600mL) washing, dry (MgSO ₄, 130g), filtering also, concentrating under reduced pressure obtains 328g yellow oil (placing the oily crystallization in back).Solid pulp and being transferred in 2L that mechanical agitator is housed, the 3-neck round-bottomed flask in ethyl acetate (180mL).The mixture of cooling and stirring is used hexane (800mL) dilution then to＜10 ℃ (ice bath).Under the ice bath temperature, stir the mixture 4h that obtains, filter then.The solid of collecting was with 4: 1 hexanes: ethyl acetate (3 * 50mL) wash and be dried to constant weight (30in.Hg, room temperature, 12h).Yield=207.5g white powder.

Step C: preparation (S)-(-)-1-(3-chlorophenyl)-1, ammediol:

Compound is as preparation as described in the step D among the embodiment 7.

Residue be dissolved in methyl alcohol (1mL) and through chirality HPLC (referring to embodiment 7; Step B) analyzes.ee＞98％。

Embodiment 10: by catalysis asymmetry hydrogenation reaction preparation 1, and the 3-glycol:

Steps A:

The 'beta '-ketoester initiation material can be synthetic as method as described in embodiment 7 steps A.

Step B:

Under room temperature, by pumping into/discharge circulation (N several times ₂) will contain the methyl alcohol of 'beta '-ketoester (1mmol) or the degassing of ethanol (5-10mL/mmol ketone ester) solution.De gassed solution moved to handbag (glove bag) and in N ₂Atmosphere has a down dip to the stainless cylinder of steel that is equipped with stirring rod and 1.0mol%Ru-BINAP catalyzer.H is removed and used to hermetically sealed can from handbag ₂Purify, then in room temperature and 150psi H ₂Under stir 18-24h.After discharging hydrogen-pressure, open gas tank, shift out reactant mixture and concentrated.The crude product beta-hydroxy esters is used for hydrolysis.

Step C:

The crude product beta-hydroxy esters is as hydrolysis as described in the embodiment 7 step C.

Step D:

The optical activity beta-hydroxy acid can be as reduction as described in the embodiment 7 step D.

Synthetic racemic phosphorylating agent:

Embodiment 11: be used for synthesis of trans-4-(aryl)-2-(4-nitrophenoxy)-2-oxo-1,3, the universal method of 2-two oxa-phospha cyclohexanes:

Formula A

Embodiment 11.1: synthesis of trans-4-(3-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Under room temperature, with 1-(3-chlorophenyl)-1, ammediol (25g, 134mmol) and triethylamine (62.5mL, THF solution 442mmol) are added to 4-nitrobenzophenone dichloro-phosphate, and (37.7g is in THF solution 147mmol), in refluxing down the solution that heating obtains.Behind the 2h, TLC shows that original glycol is exhausted, and forms the cis and the transisomer (HPLC) of 60/40 ratio.Clear yellow solution is cooled to 30 ℃, adds 4-p-nitrophenol sodium (56g, 402mmol)),, add thermal reaction mixture in refluxing down.Behind the 90min, the pale red reactant mixture is cooled to room temperature and stirs 2h under room temperature, places refrigerator overnight then.Final ratio is defined as 96/4 trans/cis by HPLC.With saturated ammonium chloride solution quencher reactant mixture, and dilute with ethyl acetate.Separate each layer, organic matter is removed nitrophenol with 0.3N sodium hydroxide washing 4 times, and then washs dried over sodium sulfate with saturated sodium chloride.Concentrated filtrate under decompression, the solid that obtains obtains a large amount of white needles things (45g, mp=115-116 ℃, purity 98A%) from ethyl acetate crystallization again.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: cis-isomer 5.6-5.8 (m, 1H), trans-isomer 5.5-5.69 (m, 1H).

The TLC condition: Merck silica gel 60F254 plate, 250 μ m are thick; Flowing phase=60/40 hexane/ethyl acetate; R _f: glycol=0.1, cis-phosphate=0.2, trans-phosphate=0.35.

HPLC condition: post=Waters μ Bondapack C18 3.9 * 300mm; Flowing phase=40/60 acetonitrile/phosphate pH of buffer 6.2; Flow velocity=1.4mL/min; Monitoring=UV@270nm; Retention time (unit minute): cis-isomer=14.46, trans-isomer=16.66,4-nitrophenol=4.14.

Embodiment 11.2: synthesis of trans-4-(3-pyridin-3-yl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

It is identical with embodiment 11.1,

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.6-5.8 (m, 1H)

Embodiment 11.3: synthesis of trans-4-(3,5-difluoro-benzene base)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1

The TLC condition: Merck silica gel 60F254 plate, 250 μ m are thick; Flowing phase=50/50 hexane/ethyl acetate; R _f: glycol=0.1, cis-phosphate=0.25, trans-phosphate=0.4.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.7-5.5 (m, 1H)

Embodiment 11.4: synthesis of trans-4-(4-aminomethyl phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(4-aminomethyl phenyl)-1, ammediol is as raw material

The TLC:50/50 hexane/ethyl acetate; Rf: cis-phosphate=0.25; Trans-phosphate=0.35.

1H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.65-5.5 (m, 1H)

Embodiment 11.5: synthesis of trans-4-(3, the 5-3,5-dimethylphenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(3, the 5-3,5-dimethylphenyl)-1, ammediol is as raw material

The TLC:50/50 hexane/ethyl acetate; Rf: cis-phosphate=0.2; Trans-phosphate=0.3.

1H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.6-5.45 (m, 1H)

Embodiment 11.6 synthesis of trans-4-(3,5-dichloro-phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(3,5-dichloro-phenyl)-1, ammediol is as raw material

The TLC:70/30 hexane/ethyl acetate; Rf: cis-phosphate=0.3; Trans-phosphate=0.5.

1H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.85-5.7 (m, 1H)

Embodiment 11.7: synthesis of trans-4-(pyridin-4-yl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(pyridin-4-yl)-1, ammediol is as raw material

TLC:95/5 carrene/ethanol; Rf: trans-phosphate=0.35.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.7-5.55 (m, 1H)

Embodiment 11.8: synthesis of trans-4-(3-methoxycarbonyl phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(3-methoxycarbonyl phenyl)-1, ammediol is as raw material

The TLC:30/70 hexane/ethyl acetate; Rf: cis-phosphate=0.5; Trans-phosphate=0.6.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.7-5.6 (m, 1H)

Embodiment 11.9: synthesis of trans-4-(4-methoxycarbonyl phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(4-methoxycarbonyl phenyl)-1, ammediol is as raw material

The TLC:30/70 hexane/ethyl acetate; Rf: cis-phosphate=0.35; Trans-phosphate=0.5.

Embodiment 11.10: synthesis of trans-4-(5-pyridine bromide-3-yl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(5-pyridine bromide-3-yl)-1, ammediol is as raw material

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.8-5.65 (m, 1H)

Embodiment 11.11: synthesis of trans-4-(2,3-dichloro-phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(2,3-dichloro-phenyl)-1, ammediol is as raw material, but as embodiment 13a, employing 4-nitrophenol and lithium hydride carry out isomerization reaction.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 6-5.9 (m, 1H)

Embodiment 11.12: synthesis of trans-4-(2,3,5-trichloro-benzene base)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(2,3,5-trichloro-benzene base)-1, ammediol is as raw material, but as embodiment 13b, employing 4-nitrophenol and triethylamine carry out isomerization reaction.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.9-5.7 (m, 1H)

Embodiment 11.13: synthesis of trans-4-(2-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(2-chlorophenyl)-1, ammediol is as raw material, but as embodiment 13a, employing 4-nitrophenol and lithium hydride carry out isomerization reaction.

Embodiment 11.14: synthesis of trans-4-(3, the 5-Dimethoxyphenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(3, the 5-Dimethoxyphenyl)-1, ammediol is as raw material, but as embodiment 13b, employing 4-nitrophenol and triethylamine carry out isomerization reaction.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.55-5.45 (m, 1H), 3.3 (s, 6H)

Embodiment 11.15: synthesis of trans-4-(2-bromo phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(2-bromo phenyl)-1, ammediol is as raw material, but as embodiment 13a, employing 4-nitrophenol and triethylamine carry out isomerization reaction.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.95-5.85 (m, 1H)

Embodiment 11.16: synthesis of trans-4-(3-bromo-5-ethoxyl phenenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(3-bromo-5-ethoxyl phenenyl)-1, ammediol is as raw material, but as embodiment 13b, employing 4-nitrophenol and triethylamine carry out isomerization reaction.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.9-5.75 (m, 1H), 4.04 (q, 2H), 1.39 (t, 3H).

Embodiment 11.17: synthesis of trans-4-(2-trifluoromethyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(2-trifluoromethyl)-1, ammediol is as raw material, but as embodiment 13b, employing 4-nitrophenol and triethylamine carry out isomerization reaction.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 6-5.75 (m, 1H).

Embodiment 11.18: synthesis of trans-4-(4-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(4-chlorophenyl)-1, ammediol is as raw material, but do not adopt isomerization reaction, from the cis/trans mixture separation trans-isomer.

TLC: hexane/ethyl acetate 1/1; Rf: cis-phosphate=0.2; Trans-phosphate=0.6.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.6-5.5 (m, 1H).

Embodiment 11.19: synthesis of trans-4-(3-aminomethyl phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(3-aminomethyl phenyl)-1, ammediol is as raw material, but do not adopt isomerization reaction, from the cis/trans mixture separation trans-isomer.

TLC: hexane/ethyl acetate 6/4; Rf: cis-phosphate=0.2; Trans-phosphate=0.5.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.65-5.5 (m, 1H).

Embodiment 11.20: synthesis of trans-4-(4-fluoro phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(4-fluoro phenyl)-1, ammediol is as raw material, but do not adopt isomerization reaction, from the cis/trans mixture separation trans-isomer.

¹H NMR (DMSO-d ₆, Varian Gemini 200MHz): C '-proton: trans-isomer 5.78-5.85 (m, 1H).

Embodiment 11.21: synthesis of trans-4-(2-fluoro phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(2-fluoro phenyl)-1, ammediol is as raw material, but do not adopt isomerization reaction, from the cis/trans mixture separation trans-isomer.

¹H NMR (DMSO-d ₆, Varian Gemini 200MHz): C '-proton: trans-isomer 5.9-6.1 (m, 1H).

Embodiment 11.22: synthesis of trans-4-(3-fluoro phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(3-fluoro phenyl)-1, ammediol is as raw material, but do not adopt isomerization reaction, from the cis/trans mixture separation trans-isomer.

¹H NMR (DMSO-d ₆, Varian Gemini 200MHz): C '-proton: trans-isomer 5.8-5.9 (m, 1H).

Embodiment 11.23: synthesis of trans-4-[4-(4-chloro phenoxy group) phenyl]-2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-[4-(4-chloro phenoxy group) phenyl]-1, ammediol is as raw material, but do not adopt isomerization reaction, from the cis/trans mixture separation trans-isomer.

¹H NMR (DMSO-d ₆, Varian Gemini 200MHz): C '-proton: trans-isomer 5.75-5.9 (m, 1H).

Embodiment 11.24: synthesis of trans-4-(3-bromo phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(3-bromo phenyl)-1, ammediol is as raw material, but do not adopt isomerization reaction, from the cis/trans mixture separation trans-isomer.

TLC: hexane/ethyl acetate 1/1; Rf: cis-phosphate=0.25; Trans-phosphate=0.5.

¹H NMR (DMSO-d ₆, Varian Gemini 200MHz): C '-proton: trans-isomer 5.8-5.95 (m, 1H).

Embodiment 11.25: synthesis of trans-4-(3,4-ethylenedioxy phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(3,4-ethylenedioxy phenyl)-1, ammediol is as raw material, but do not adopt isomerization reaction, from the cis/trans mixture separation trans-isomer.

TLC: hexane/ethyl acetate 1/1; Rf: trans-phosphate=0.6.

Embodiment 11.26: synthesis of trans-4-(2-fluoro-4-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(2-fluoro-4-chlorophenyl)-1, ammediol is as raw material, but do not adopt isomerization reaction, from the cis/trans mixture separation trans-isomer.

TLC: hexane/ethyl acetate 1/1; Rf: trans-phosphate=0.7.

¹H NMR (DMSO-d ₆, Varian Gemini 200MHz): C '-proton: trans-isomer 5.9-6 (m, 1H).

Embodiment 11.27: synthesis of trans-4-(2,6-dichloro-phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(2,6-dichloro-phenyl)-1, ammediol is as raw material, but do not adopt isomerization reaction, from the cis/trans mixture separation trans-isomer.

TLC: hexane/ethyl acetate 1/1; Rf: trans-phosphate=0.65.

¹H NMR (DMSO-d ₆, Varian Gemini 200MHz): C '-proton: trans-isomer 6.2-6.4 (m, 1H).

Embodiment 11.28: synthesis of trans-4-(2-fluoro-5-methoxyphenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(2-fluoro-5-methoxyphenyl)-1, ammediol is as raw material, but do not adopt isomerization reaction, from the cis/trans mixture separation trans-isomer.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.8-5.95 (m, 1H), 3.8 (s, 3H).

Embodiment 11.29: synthesis of trans-4-(3-fluoro-4-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(3-fluoro-4-chlorophenyl)-1, ammediol is as raw material, but as embodiment 13b, employing 4-nitrophenol and triethylamine carry out isomerization reaction.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.4-5.6 (m, 1H).

Embodiment 11.30: synthesis of trans-4-(3-chloro-4-fluoro phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(3-chloro-4-fluoro phenyl)-1, ammediol is as raw material, but as embodiment 13b, employing 4-nitrophenol and triethylamine carry out isomerization reaction.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.5-5.6 (m, 1H).

Embodiment 11.31: synthesis of trans-4-(2-fluoro-5-bromo phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(2-fluoro-5-bromo phenyl)-1, ammediol is as raw material, but as embodiment 13b, employing 4-nitrophenol and triethylamine carry out isomerization reaction.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.8-5.9 (m, 1H).

Embodiment 11.32: synthesis of trans-4-(2,3,5, the 6-tetrafluoro is for phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(2,3,5, the 6-tetrafluoro is for phenyl)-1, ammediol is as raw material, but as embodiment 13b, employing 4-nitrophenol and triethylamine carry out isomerization reaction.

¹H NMR (CDCl ₃, Varian Gemini 200MHz): C '-proton: trans-isomer 5.9-6 (m, 1H).

Embodiment 11.33: synthesis of trans-4-(2,3, the 6-trifluorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(2,3, the 6-trifluorophenyl)-1, ammediol is as raw material, but as embodiment 13b, employing 4-nitrophenol and triethylamine carry out isomerization reaction.

Embodiment 11.34: synthesis of trans-4 (R)-(phenyl)-2-(4-chloro phenoxy group)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, adopt 1 (R)-(phenyl)-1 of separating through post, ammediol does not need to carry out isomerization reaction as raw material.

Rf=0.5 (50%EtOAc is in hexane).mp 90-92℃。C ₁₅H ₁₄ClO ₄P analytical calculation value: C, 55.49; H, 4.35.Measured value: C, 55.64; H, 3.94.

Embodiment 11.35: synthesis of trans-4 (R)-(phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, adopt 1 (R)-(phenyl)-1 of separating through post, ammediol does not need isomerization reaction as raw material.

Rf=0.4 (50%EtOAc is in hexane).mp 130-131℃。C ₁₅H ₁₄NO ₆P analytical calculation value: C, 53.74; H, 4.21; N, 4.18.Measured value: C, 53.86; H, 4.07; N, 4.00.

Embodiment 11.36: synthesis of trans-4 (S)-(phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1 (S)-(phenyl)-1, ammediol is as raw material.

(5%EtOAc is at CH for Rf=0.2 ₂Cl ₂In).mp 128-129℃。C ₁₅H ₁₄NO ₆P analytical calculation value: C, 53.74; H, 4.21; N, 4.18.Measured value: C, 53.69; H, 4.53; N, 4.23.

Embodiment 11.37: synthesis of trans-4-(3-trifluoromethyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(3-trifluoromethyl)-1, ammediol is as raw material.

Rf=0.32 (35%EtOAc is in hexane).mp 78-81℃。C ₁₆H ₁₃F ₃NO ₆P analytical calculation value: C, 47.66; H, 3.25; N, 3.47.Measured value: C, 47.69; H, 3.77; N, 3.52.

Embodiment 11.38: synthesis of trans-4-(2,4-dichloro-phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 111, with 1-(2,4-dichloro-phenyl)-1, ammediol is as raw material.

Rf=0.32 (35%EtOAc is in hexane).mp 154-157℃。C ₁₅H ₁₂Cl ₂NO ₆P analytical calculation value: C, 44.58; H, 2.99; N, 3.47.Measured value: C, 44.63; H, 3.07; N, 3.47.

Embodiment 11.39: synthesis of trans-4-(3-bromo-4-fluoro phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(3-bromo-4-fluoro phenyl)-1, ammediol is as raw material.(5%EtOAc is at CH for Rf=0.2 ₂Cl ₂In).mp 108℃。C ₁₅H ₁₂NO ₆BrFP analytical calculation value: C, 41.69; H, 2.80; N, 3.24.Measured value: C, 41.90; H, 2.76; N, 3.05.

Embodiment 11.40: synthesis of trans-4-(2-pyridine radicals)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(2-pyridine radicals)-1, ammediol is as raw material.mp99-102℃。C ₁₄H ₁₃N ₂O ₆P analytical calculation value: C, 50.01; H, 3.90; N, 8.33.Measured value: C, 49.84; H, 3.41; N, 8.14.

Embodiment 11.41: synthesis of trans-4-(3,4-dichloro-phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(3,4-dichloro-phenyl)-1, ammediol is as raw material.Rf=0.15 (35%EtOAc is in hexane).mp 126-129℃。C ₁₅H ₁₂Cl ₂NO ₆P analytical calculation value: C, 44.58; H, 2.99; N, 3.47.Measured value: C, 44.71; H, 3.49; N, 3.41.

Embodiment 11.42: synthesis of trans-4-(4-tert-butyl phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(4-tert-butyl phenyl)-1, ammediol is as raw material.Rf=0.20 (35%EtOAc is in hexane).mp 108-111℃。Analytical calculation value C ₁₉H ₂₂NO ₆P:C, 58.31; H, 5.67; N, 3.58.Measured value: C, 58.04; H, 5.67; N, 3.55.

Embodiment 11.43: synthesis of trans-4-(3-thienyl (thiophenyl))-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(3-thienyl)-1, ammediol is as raw material.mp94-96℃。Analytical calculation value C ₁₃H ₁₂NO ₆PS:C, 45.75; H, 3.54; N, 4.10.Measured value: C, 45.65; H, 3.21; N, 4.24.

Embodiment 11.44: synthesis of trans-4-(3-furyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(3-furyl)-1, ammediol is as raw material.mp108-111℃。C ₁₃H ₁₂NO ₇P analytical calculation value: C, 48.01; H, 3.72; N, 4.31.Measured value: C, 48.06; H, 3.61; N, 4.26.

Embodiment 11.45: synthesis of trans-4-(2-bromo-5-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(2-bromo-5-chlorophenyl)-1, ammediol is as raw material.(5%MeOH is at CH for Rf=0.20 ₂Cl ₂In).mp 105-106℃。C ₁₅H ₁₂NO ₆BrClP analytical calculation value: C, 40.16; H, 2.70; N, 3.12.Measured value: C, 39.97; H, 2.86; N, 3.06.

Embodiment 11.46: synthesis of trans-4-(2,5-difluoro-benzene base)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(2,5-difluoro-benzene base)-1, ammediol is as raw material.Rf=0.50 (50%EtOAc is in hexane).mp 120-122℃。C ₁₅H ₁₂F ₂NO ₆P analytical calculation value: C, 48.53; H, 3.26; N, 3.77.Measured value: C, 48.46; H, 3.52; N, 3.87.

Embodiment 11.47: synthesis of trans-4-(2,4-difluoro-benzene base)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with 1-(2,4-difluoro-benzene base)-1, ammediol is as raw material.Rf=0.50 (50%EtOAc is in hexane).mp 85-87℃。C ₁₅H ₁₂F ₂NO ₆P analytical calculation value: C, 48.53; H, 3.26; N, 3.77.Measured value: C, 48.82; H, 3.55; N, 3.84.

Embodiment 11.48: synthesis of trans-4-cis-6-(diphenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with anti-form-1,3-diphenyl-1, ammediol as raw material (Yamamura, H., Araki, S., Tetrahedron, 1997, 53, 46,15685-15690), need not balance.Rf=0.29 (35%EtOAc is in hexane).mp 118-121℃。C ₂₁H ₁₈NO ₆P analytical calculation value: C, 61.32; H, 4.41; N, 3.41.Measured value: C, 60.94; H, 4.44; N, 3.53.

Embodiment 11.49: synthesis of trans-4-is trans-and 6-(diphenyl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with cis-1,3-diphenyl-1, ammediol as raw material (Yamamura, H., Araki, S., Tetrahedron, 1997, 53, 46,15685-15690), need not balance.(5%EtOAc is at CH for Rf=0.65 ₂Cl ₂In).mp 144-147℃。C ₂₁H ₁₈NO ₆P analytical calculation value: C, 61.32; H, 4.41; N, 3.41.Measured value: C, 61.21; H, 4.58; N, 3.36.

Embodiment 11.50: synthesizing cis-4-cis-6-(diphenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with cis-1,3-diphenyl-1, ammediol (Yamamura, H., Araki, S., Tetrahedron, 1997, 53, 46,15685-15690) as raw material, need not balance.(5%EtOAc is at CH for Rf=0.3 ₂Cl ₂In).mp 135-138℃。C ₂₁H ₁₈NO ₆P analytical calculation value: C, 61.32; H, 4.41; N, 3.41.Measured value: C, 61.29; H, 4.77; N, 3.46.

Embodiment 11.51: synthesizing cis-4-cis-5-(diphenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with cis-1,2-diphenyl-1, ammediol as raw material (Kristersson, P, Lindquist, K., Acta Chem.Scand.B 1980, 34, 3,213-234), need not balance.(5%EtOAc is at CH for Rf=0.35 ₂Cl ₂In).mp 136-139℃。Analytical calculation value C ₂₁H ₁₈NO ₆P:C, 61.32; H, 4.41; N, 3.41.Measured value: C, 60.95; H, 4.41; N, 3.82.

Embodiment 11.52: synthesis of trans-4-is trans-and 5-(diphenyl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexanes:

Identical with embodiment 11.1, with cis-1,2-diphenyl-1, ammediol as raw material (Kristersson, P, Lindquist, K., Acta Chem.Scand.B 1980, 34, 3,213-234), need not balance.(5%EtOAc is at CH for Rf=0.65 ₂Cl ₂In).mp 176-178℃。Analytical calculation value C ₂₁H ₁₈NO ₆P:C, 61.32; H, 4.41; N, 3.41.Measured value: C, 61.09; H, 4.46; N, 3.80.

Embodiment 11.53: synthesis of trans-4, and 4-dimethyl-6-(phenyl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexanes:

Steps A:

Under-78 ℃, nitrogen, with 30 minutes, to diisopropylamine (58.4g, add in absolute ether 577mmol) (500mL) solution n-BuLi (215mL, the hexane liquid of 2.5M, 538mmol).Reaction stirred 10min, with times of 30 minutes add ethyl acetate (55mL, 558mmol).With the benzaldehyde that will just distill in 30 minutes (47mL, ether 443mmol) (50mL) solution slowly adds, mixture is warmed to room temperature.In 0 ℃, will react with saturated ammonium chloride (150mL) quencher.The washing organic layer, dry (anhydrous Na ₂SO ₄) and concentrate, obtain the crude product addition compound product.

Step B:

In-78 ℃, (10.6g, (in THF, 180mmol), mixture is warmed to room temperature and stirs and spend the night for 60mL, 3.0M to add MeMgBr in anhydrous ether solution 54.6mmol) to thick condensation product.In 0 ℃, will react with ammonium chloride (50mL) quencher, and dilute with EtOAc (350mL).The washing organic layer, dry (anhydrous Na ₂SO ₄) and concentrate.(0-10%EtOAc is at CH through column chromatography purification for the crude product product ₂Cl ₂In), obtain 3,3-dimethyl-1-phenyl-1, ammediol (7g) is light yellow oil.

Step C:

Identical with embodiment 11.1, with 3,3-dimethyl-1-phenyl-1, ammediol need not balance as raw material.Rf=0.18 (35%EtOAc is in hexane).mp 131-133℃。C ₁₇H ₁₈NO ₆P analytical calculation value: C, 56.20; H, 4.99; N, 3.86.Measured value: C, 56.00; H, 5.03; N, 3.86.

Embodiment 11.54: synthesizing cis-4-(3-chlorophenyl)-cis-5-methoxyl group-(2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexanes and trans-4-(3-chlorophenyl)-cis-5-methoxyl group-(2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexanes (11.55):

Steps A:

In-78 ℃, by addition funnel in the THF of diisopropyl lithamide (356mmol) (500mL) solution, slowly add 2-methoxyl group-methyl acetic acid ester (38.8mL, 392mmol).In-78 ℃, reaction stirred 30min, add then 3-chlorobenzene formaldehyde (20.1mL, 178mmol).Reactant is warmed to room temperature also with saturated NH ₄The quencher of Cl (500mL) aqueous solution.(3 * 200mL) extract mixture, and the organic extract of merging is through water washing and dry (anhydrous Na with EtOAc ₂SO ₄).The crude product product obtains 3-(3-chlorophenyl)-3-hydroxyl-2-methoxyl group-methylpropionate (proprionate) (39g) through column chromatography purification (5-50%EtOAc is in hexane), is faint yellow oily thing.

Step B:

With 10 minutes, to the ester that derives from steps A (39g, divide in ethanol 159mmol) (500mL) solution 3 parts add sodium borohydrides (6.2g, 159mmol).With the reactant 3h that refluxes, reduction vaporization ethanol.Residue is dissolved in EtOAc (500mL), through water washing and dry (anhydrous Na ₂SO ₄).The crude product product is through column chromatography purification (1-5%MeOH-CH ₂Cl ₂), obtain glycol (28g), be colorless oil.

Step C:

(28g adds trimethyl orthoformate (10mL) in acetone 129mmol) (250mL) solution, and (500mg is heated to reflux 2.64mmol) and with reactant and spends the night to add right-toluenesulfonic acid subsequently to glycol.Reactant is cooled to room temperature, and vacuum is removed acetone.Residue is dissolved in ethyl acetate, and uses NaHCO ₃, water washing and dry (anhydrous Na ₂SO ₄).Ketal separates through column chromatography (5-10%EtOAc is in hexane), obtains 1,2-cis ketal (7.26g) and 1, the trans ketal of 2-(0.9g) diastereoisomer.

Step D:

With 1, (4.5g 17.5mmol) is dissolved in 70%TFA (10mL) aqueous solution, and reacts under room temperature and spend the night 2-cis ketal.Reactant dilutes with acetonitrile (30mL), and removes volatile matter under decompression.Residue is dissolved in EtOAc (300mL), and organic layer is through saturated NaHCO ₃The aqueous solution, water washing and dry (anhydrous Na ₂SO ₄).The crude product product is through column chromatography purification (1-5%MeOH-CH ₂Cl ₂), obtain 1,2-cis glycol diastereoisomer (3.5g).

After previous step was rapid, also with 1, the hydrolysis of the trans ketal diastereoisomer of 2-obtained 1, and 2-is trans-the glycol diastereoisomer.

Step e:

Adopt embodiment 11.1 described methods, make 1,2-cis-glycol diastereoisomer need not balance through phosphorus acylation reaction, obtains following two kinds of isomer.

11.54:Rf=0.57 (5%EtOAc is at CH ₂Cl ₂In).mp 110-112℃。C ₁₆H ₁₅NO ₇PCl analytical calculation value: C, 48.08; H, 3.78; N, 3.50.Measured value: C, 48.35; H, 3.56; N, 3.69.

11.55:Rf=0.34 (5%EtOAc is at CH ₂Cl ₂In).mp 131-134℃。C ₁₆H ₁₅NO ₇PCl.0.3H ₂O analytical calculation value: C, 47.44; H, 3.88; N, 3.46.Measured value: C, 47.23; H, 4.01; N, 3.46.

Embodiment 12: adopt phosphorous oxychloride synthesis of trans-4-(aryl)-2-(4-nitrophenoxy)-2-oxo-1,3, the universal method of 2-two oxa-phospha cyclohexanes.

In 0 ℃, with phosphorous oxychloride (3.4mL 36.3mmol) is added to 1-(3-chlorophenyl)-1, in the dichloromethane solution of ammediol, add again subsequently triethylamine (10.2mL, 73mmol).Behind the 2h, (10.63g 66mmol) adds in the solution of cis/trans chloro phosphate reagent, and orange reaction mixture is heated 1h down in refluxing with the 4-p-nitrophenol sodium.The solution of cooling is allocated in ethyl acetate and saturated ammonium chloride solution.Separation of organic substances is through dried over sodium sulfate, filtration and concentrated down in decompression.Residue is dissolved in THF, and (10.63g 66mmol), is heated to backflow 3h (HPLC, 95/5 trans/cis) with orange reaction mixture to add the 4-p-nitrophenol sodium.The solution of cooling is allocated between ethyl acetate and the saturated ammonium chloride solution.Separation of organic substances is with 0.3N sodium hydroxide solution and salt water washing, through dried over sodium sulfate and concentrating under reduced pressure.From ethyl acetate crystallization again, obtain the phosphate reactant as embodiment 10.

Embodiment 13:4-(aryl)-2-(4-nitrophenoxy)-2-oxo-1,3, the method for the enrichment of the trans-isomer of the cis/trans mixture of 2-two oxa-phospha cyclohexanes:

4-(3-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, the cis/trans mixture of 2-two oxa-phospha cyclohexanes such as embodiment 11 preparations, but cis and transisomer add the 4-nitrophenol then through column chromatography for separation.

By in 4-nitrophenol salting liquid, adding cis-isomer solution with following alkali preparation, make cis-4-(3-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexane isomer turn to transisomer.

Embodiment 13a:

Under room temperature, with lithium hydride (19.4mg, 2.44mmol) the THF solution of adding 4-nitrophenol.Under room temperature, stir yellow solution 30min.With cis-4-(3-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, (300mg, THF solution 0.813mmol) adds in the solution of 4-nitrophenol lithium 2-two oxa-phospha cyclohexanes.Under room temperature, stir orange reaction mixture.Behind the 5h, ratio is 92.9/5.4 trans/cis (a HPLC determined value).

Embodiment 13b:

Identical with said method, adopt triethylamine to replace lithium hydride.Behind the 20h, the trans/cis ratio is 90.8/5.3.

Embodiment 13c:

Identical with said method, adopt DBU to replace lithium hydride.Behind the 3h, the trans/cis ratio is 90.8/5.3.

The phosphorus esterification reagent of synthetic enantiomer enrichment

Embodiment 14: trans-4-(aryl)-2-(the 4-nitrophenoxy)-2-oxo-1,3 of synthetic enantiomer enrichment, and the universal method of 2-two oxa-phospha cyclohexanes:

Embodiment 14a: synthetic (+)-(4R)-trans-4-(3-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexanes

In 0 ℃, with (+)-(R)-1-(3-chlorophenyl)-1, and ammediol (3g, 16.1mmol) and triethylamine (6.03ml, 59.6mmol) THF (80mL) drips of solution add to 4-nitrophenoxy dichloro-phosphate (7.63g be in 150mL THF solution 29.8mmol).Behind about 2h, the initiation material glycol is exhausted, and forms 2 kinds of isomery 4-nitrobenzophenone phosphates, adds triethylamine (8.31mL) again, add again subsequently the 4-nitrophenol (8.29g, 59.6mmol).Stirred reaction mixture spends the night.Solvent evaporated under reduced pressure also is allocated in ethyl acetate and water with residue.Washing organic facies (0.4M NaOH, water and saturated NaCl solution) and through MgSO ₄Dry.Concentrate and, obtain the required product of 4.213g with the hexane solution chromatography residue of 30% ethyl acetate.

HNMR (200MHz, CDCl ₃): 8.26 (2H, d, J=9.7Hz), 7.2-7.5 (6H, m), 5.56 (1H, transparent d, J=11.7Hz), 4.4-4.7 (2H, m), 2.2-2.6 (1H, m), 2.0-2.2 (1H, m).

mp：114-115℃。[α] _D＝+91.71。Elementary analysis: C ₁₅H ₁₃NO ₆ClP analytical calculation value: C:48.73, H:3.54, N:3.79.Measured value: C:48.44, H:3.20, N:3.65

Embodiment 14b: synthetic (-)-(4S)-trans-4-(3-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexanes

With similar approach, from 3.116g (-)-(S)-1-(3-chlorophenyl)-1, ammediol obtains the required phosphate of 4.492g.

mp：114-115℃。[α] _D=-91.71. elementary analysis: C ₁₅H ₁₃NO ₆ClP analytical calculation value: C:48.73, H:3.54, N:3.79.Measured value: C:48.61, H:3.36, N:3.66.

Embodiment 14c: synthetic (-)-(4S)-trans-phenyl-2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexanes

Identical with embodiment 11.1, with S-(-)-1-phenyl-1, ammediol is as raw material, but as embodiment 13b, employing 4-nitrophenol and triethylamine carry out isomerization reaction.

TLC: hexane/ethyl acetate 4/1; Rf=0.4

¹H NMR (DMSO-d ₆, Varian Gemini 300MHz): C '-proton: trans-isomer 5.85-5.75 (m, 1H).

Embodiment 15: the universal method that keeps enantiomeric excess in the process of the phosphorus esterification reagent that synthesizes the enantiomer enrichment:

Embodiment 15a: synthetic (-)-(4S)-trans-(pyridin-4-yl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexanes

Add (S)-(-)-1-(pyridin-4-yl)-1 in the 12L round-bottomed flask that top agitator and nitrogen conduit are housed, (1.2kg, 7.83mol) and pyridine (6L), vigorous stirring 0.5h dissolves until all solids ammediol under room temperature.22L, 3-neck flask are loaded onto top agitator, thermocouple, cryostat and nitrogen conduit therebetween.In this container, add 4-nitrobenzophenone dichloro-phosphate (2.01kg, 7.83mol) and pyridine (6L).The mixture that obtains is cooled to 3.3 ℃.Glycol dissolves back (0.5h) fully, and (190mL 1.36mol), is transferred to slightly dark, yellow-brownish solution portioning in the 2L addition funnel of 22L flask to add triethylamine.With 3.25h solution is added in the cold dichloro-phosphate solution.After adding is finished, remove cryostat, continue to stir 3h.In this process, 50L, 3-neck flask are added mechanical agitator, thermocouple, addition funnel, cryostat (frozen water) and nitrogen conduit.Then with sodium hydride (180g, 4.5mol) and THF (1L) flask of packing into, with 4-nitrophenol (817g, THF 5.87mol) (1L) the solution addition funnel of packing into.Nitrophenol solution slowly adds in the cold sodium hydride suspension.After adding is finished, under room temperature, the bright orange suspension that obtains is stirred 1h.After glycol-the dichloride reaction was finished, black suspension was through vacuum filtration.With glassware and filter cake (triethylamine-, filtrate and the cleaning solution that merges inclined to the suspension of orange 4-p-nitrophenol sodium HCl) with THF (1L) cleaning.Then with the mixture that obtains in 40 ℃ of heating 3.5h, turn off heating plate this moment, reaction stirred 11h again under room temperature.On rotary evaporator, the crude product reactant mixture is concentrated (oil pump) in 45-50 ℃, decompression down.The dense black foam tar that obtains is dissolved in moisture HCl solution of 1.5M (12L) and ethyl acetate (8L) solution.Mixture is transferred in 12.5 gallons of separatory funnels, stirs 10min, separate each phase.Ethyl acetate layer is with other 1.3L 1.5M HCl solution washing.Add carrene (8L) in the water-soluble liquid phase that merges, the vigorous stirring mixture neutralizes with solid sodium bicarbonate carefully.Separate each layer, water layer extracts with carrene (8L).The organic layer that merges is dry and filtration through magnesium sulfate (600g).Concentrated solution is removed up to most of solvent on rotary evaporator, obtains dense suspension.Add 2-propyl alcohol (5L), evaporation is until collecting the 4L distillation.Add 2-propyl alcohol (3L), continue to be evaporated to and collect the 3L distillation.Underflow is with 2-propyl alcohol (2L) dilution, cooling (ice bath) 1h that stirs the mixture.Solid collected by filtration, through 2-propyl alcohol (2L) washing, dry in vacuum tank (30in.Hg, 55 ℃, 18h) to constant weight be 1.86kg.

mp 140-142℃

Specific rotation=-80.350 (c=1.0, MeOH); Ee=99+% is trans

The HPLC condition:

Post: Chiralpak AD, 0.46 * 25cm; Flowing phase=50: 50,2-propyl alcohol: hexane, isocratic elution; Flow velocity=1.0mL/min; Volume injected=10 μ L; Monitor in 254nm UV.

The cis/trans balance is monitored through HPLC.Stop at 92% trans, 6.6% cis.R.t.=transisomer 6.9min., cis-isomer 10.9min.

¹HNMR(DMSO-d ₆)：δ＝2.23-2.29(m，2H)，4.56-4.71(m，2H)，5.88-5.95(m，1H)，7.44(d，2H，J＝5.8Hz)，7.59(d，2H，J＝9.2Hz)，8.34(d，2H，J＝9.4Hz)，8.63(d，2H J＝5.8Hz)

Embodiment 15b: synthetic (-)-(4S)-(-)-(pyridin-4-yl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexanes

1L, 3-neck round-bottomed flask are added mechanical agitator, addition funnel, thermometer and N ₂Conduit.S-(-)-1-(pyridin-4-yl)-the third-1 that packs in the flask, (25g, 163.4mmol) and ethyl acetate (250mL), (43mL 176mmol) slowly handles the 3-glycol with 4N HCl solution De diox with the suspension that obtains with 15min.Under room temperature, stir 30min, in drag flow N ₂Down, as quickly as possible with solid form add 4-nitrobenzophenone dichloro-phosphate (41.81g, 163.4mmol).With the dry ice-propanone cryostat reactant mixture is adjusted to internal temperature and is-10 ℃.(79mL, ethyl acetate 572mmol) (100mL) solution keep temperature of charge＜-5 ℃ to add triethylamine.Add triethylamine solution finish after 30 minutes, remove cryostat, reactant mixture is stirred 1h under room temperature.Filter reaction mixture is removed triethylamine-hydrochloride, and (3 * 30mL) washings have only faint absorption until filtrate demonstration with ethyl acetate.In decompression down, evaporated filtrate is to volume 150-175mL.With the 4-nitrophenol (7.5g, 54.3mmol) and triethylamine (9mL) add to concentrated solution and the orange reaction mixture that obtains is stirred 24h under room temperature.The solid that forms in the reactant mixture is collected after filtration, with ethyl acetate (2 * 25mL) and methyl-tert-butyl ether (25mL) washing and in 55 ℃ under vacuum drying obtain the required product of 31.96g.Identical with the analysis data of embodiment 14a.

Embodiment 16: by trans-phosphate addition reaction preparation 2 '-the assorted adenosine prodrugs of C-methyl-7-denitrogenation:

16.1:4-amino-7-(cis-5 '-O-[4-(3-chlorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

Steps A:

Under room temperature, to 4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine (US6777395) (10g, 0.0356mol) anhydrous propanone (145mL) and dry DMF (35mL) solution in add right-toluenesulfonic acid monohydrate (33.8g, 0.18mol) and orthoformic acid triethyl group ester (31.2mL, 28.5mol).Reactant is warmed to～and 80 ℃, stir 3h down in nitrogen.The reduction vaporization mixture.(5%MeOH is at CH through column chromatography for the oily residue ₂Cl ₂In) purifying, obtain isopropylidene derivative (8.6g), be white solid.

Step B:

To 2 ', (0.094g adds the tert-butyl magnesium chloride to 3 '-O-isopropylidene-4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine in DMF 0.29mmol) (1.5mL) solution, and stirs 30min down in nitrogen.Then reactant mixture is cooled to-55 ℃, is added dropwise to phosphorus esterification reagent (preparation method as embodiment 11.1 as described in) (0.13g, DMF 0.35mmol) (1.5mL) liquid then.Reactant is warmed to room temperature and stirs 2h down in nitrogen.(5%MeOH is at CH in the following evaporating mixture of decompression and through chromatographic purifying ₂Cl ₂In), obtain the prodrug of 2 ', the 3 '-O-isopropylidene protection of 0.070g, be yellow solid.

Step C:

(0.15g 0.27mmol) is dissolved in the 75%TFA/H of precooling with the prodrug that derives from above-mentioned steps ₂O (20mL), and in 0 ℃ of stirring 2h.Evaporation reaction mixture under decompression.The crude product product is through flash chromatography purifying (1%NH ₄The OH aqueous solution is at CH ₂Cl ₂In 10%MeOH in), obtain the 0.142g target compound, be pale solid.

R _f=0.40 (10%MeOH is at CH ₂Cl ₂In).mp 138-141℃。C ₂₁H ₂₄ClN ₄O ₇P.0.4CH ₂Cl ₂Analytical calculation value: C, 47.18; H, 4.59; N, 10.28.Measured value: C, 46.97; H, 4.59; N, 10.11.

Following embodiment synthesizes as described in embodiment 16.1 steps A-C, adopts the phosphorus esterification reagent of embodiment 1-15.

16.2:4-amino-7-(cis-5 '-O-[4-(2,5-difluoro-benzene base)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.35 (10%MeOH is at CH ₂Cl ₂In).mp 145-148℃。C ₂₁H ₂₃N ₄O ₇F2P.1.35H ₂O.1.0CF ₃CO ₂H analytical calculation value: C, 42.45; H, 4.14; N, 8.62.Measured value: C, 42.18; H, 3.77; N, 8.42.

16.3:4-amino-7-(cis-5 '-O-[4-(3-chloro-4-fluoro phenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.30 (10%MeOH is at CH ₂Cl ₂In).mp 128-130℃。C ₂₁H ₂₃N ₄O ₇FClP.2H ₂O.1.9CF ₃CO ₂H analytical calculation value: C, 38.11; H, 3.73; N, 7.17.Measured value: C, 38.04; H, 3.28; N, 7.02.

16.4:4-amino-7-(cis-5 '-O-[6,6-dimethyl-4-phenyl-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.40 (10%MeOH is at CH ₂Cl ₂In).mp 140-142℃。C ₂₃H ₂₉N ₄O ₇P.1H ₂O.0.4CF ₃CO ₂H analytical calculation value: C, 50.32; N, 5.57; N, 9.86.Measured value: C, 50.38; H, 5.12; N, 9.96.

16.5:4-amino-7-(cis-5 '-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.45 (10%MeOH is at CH ₂Cl ₂In).mp 135-138℃。C ₂₁H ₂₄ClN ₄O ₇P.0.2H ₂O.0.4CH ₂Cl ₂Analytical calculation value: C, 46.87; H, 4.63; N, 10.22.Measured value: C, 47.02; H, 4.25; N, 9.99.

16.6:4-amino-7-(cis-5 '-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine mesylate.

R _f=0.45 (10%MeOH is at CH ₂Cl ₂In).mp 125-128℃。C ₂₁H ₂₄N ₄O ₇ClP.1.6CH ₃SO ₃H.1.0H ₂O analytical calculation value: C, 39.76; H, 4.78; N, 8.21; S, 7.52.Measured value: C, 39.39; H, 4.30; N, 8.30; S, 7.96.

16.7:4-amino-7-(cis-5 '-O-[4-(S)-(pyridin-4-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.40 (CH of 15%MeOH ₂Cl ₂-1%NH ₄OH liquid).mp 183-185℃。C ₂₀H ₂₄N ₅O ₇P.1.6H ₂O analytical calculation value: C, 47.45; H, 5.42; N, 13.83.Measured value: C, 47.78; H, 5.47; N, 13.77.

16.8:4-amino-7-(cis-5 '-O-[4-(3-fluoro phenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.15 (10%MeOH is at CH ₂Cl ₂In).C ₂₁H ₂₄FN ₄O ₇P.0.3H ₂O analytical calculation value: C, 50.46; H, 4.96; N, 11.21.Measured value: C, 50.63; H, 5.35; N, 10.94.

16.9:4-amino-7-(cis-5 '-O-[4-(3-bromo phenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

(15%MeOH is at CH for Rf=0.48 ₂Cl ₂-1%NH ₄Among the OH).C ₂₁H ₂₄BrN ₄O ₇P.0.5H ₂O analytical calculation value: C, 44.70; H, 4.47; N, 9.93.Measured value: C, 44.58; H, 4.52; N, 9.56.

16.10:4-amino-7-(cis-5 '-O-[4-(2-bromo phenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.15 (10%MeOH is at CH ₂Cl ₂In).mp 132-135℃。Analytical calculation value C ₂₁H ₂₄BrN ₄O ₇P.0.5H ₂O:C, 44.7; H, 4.47, N; 9.93.Measured value: C, 44.73; H, 4.69; N, 9.82.

16.11:4-amino-7-(cis-5 '-O-[4-(5-pyridine bromide-3-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _fMp 132-135 ℃ of=0.35 (10%MeOH be in EtOAc).C ₂₀H ₂₃N ₅O ₇BrP.0.5H ₂O.0.5EtOAc analytical calculation value: C, 43.36; H, 4.63; N, 11.49.Measured value: C, 43.37; H, 4.80; N, 11.16.

16.12:4-amino-7-(cis-5 '-O-[4-(S)-phenyl-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.42 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).mp 115-118℃。Analytical calculation value C ₂₁H ₂₅N ₄O ₇P.0.4EtOAc.1.0H ₂O:C, 51.25; H, 5.75; N, 10.58.Measured value: C, 51.07; H, 5.88; N, 10.35.

16.13:4-amino-7-(cis-5 '-O-[4,5-cis-diphenyl-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine trifluoroacetate.

R _f=0.45 (10%MeOH is at CH ₂Cl ₂In).mp 174-177℃。C ₂₉H ₃₀F ₃N ₄O ₉P.1.75H ₂O analytical calculation value: C, 49.90; H, 4.48; N, 8.03.Measured value: C, 49.68; H, 4.82; N, 8.1.

16.14:4-amino-7-(cis-5 '-O-[4-(2-chlorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine

R _f=0.48 (10%MeOH is at CH ₂Cl ₂In).mp 187-190℃。C ₂₁H ₂₄ClN ₄O ₇P.H2O.0.2DMF analytical calculation value: C, 47.72; H, 5.05; N, 10.77.Measured value: C, 47.66; H, 5.02; N, 10.96.

16.15:4-amino-7-(cis-5 '-O-[4-(2-fluoro-5-bromo phenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine

R _f=0.48 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).C ₂₁H ₂₃BrFN ₄O ₇P.1.3H ₂O analytical calculation value: C, 42.27; H, 4.32; N, 9.39.Measured value: C, 42.26; H, 4.03; N, 9.36.

16.16:4-amino-7-(cis-5 '-O-[4,6-cis-diphenyl-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine trifluoroacetate.

R _f=0.20 (10%MeOH is at CH ₂Cl ₂In).mp 140-143℃。C ₂₇H ₂₉N ₄O ₇P.1.25H ₂O.CF ₃CO ₂H analytical calculation value: C, 50.55; H, 4.75; N, 8.13.Measured value: C, 50.25; H, 4.88; N, 7.99.

16.17:4-amino-7-(cis-5 '-O-[4 (3,5-is two-trifluoromethyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.15 (10%MeOH is at CH ₂Cl ₂In).mp 130-134℃。C ₂₃H ₂₃N ₄O ₇P.0.6H ₂O analytical calculation value: C, 44.33; H, 3.91; N, 8.99.Measured value: C, 44.29; H, 4.13; N, 8.98.

16.18:4-amino-7-(trans-5 '-O-[4,6-cis-diphenyl-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine trifluoroacetate.

(15%MeOH is at CH for Rf=0.48 ₂Cl ₂-1%NH ₄Among the OH).mp＞220℃。C ₂₇H ₂₉N ₄O ₇P.0.9H ₂O analytical calculation value: C, 57.02; H, 5.46; N, 9.85.Measured value: C, 57.55; H, 5.97; N, 9.88.

16.19:4-amino-7-(trans-5 '-O-[4-(3-bromo-pyridin-4-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.3 (10%MeOH is in EtOAc).mp 116-120℃。C ₂₀H ₂₃N ₅O ₇BrP.1H ₂O.0.6EtOAc analytical calculation value: C, 42.90; H, 4.79; N, 11.17.Measured value: C, 42.90; H, 4.42; N, 10.82.

16.20:4-amino-7-(trans-5 '-O-[4-(2,4 dichloro benzene base)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.15 (10%MeOH is at CH ₂Cl ₂In).mp 184-188℃。C ₂₂H ₂₄F ₃N ₄O ₇P.0.6H ₂O analytical calculation value: C, 47.59; H, 4.57; N, 10.09.Measured value: C, 47.46; H, 4.96; N, 10.10.

16.21:4-amino-7-(trans-5 '-O-[4-(3-trifluoromethyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.15 (10%MeOH is at CH ₂Cl ₂In).mp 120-124℃。C ₂₁H ₂₃Cl ₂N ₄O ₇P.0.5H ₂O analytical calculation value: C, 45.50; H, 4.36; N, 10.11.Measured value: C, 45.32; H, 4.58; N, 10.26.

16.22:4-amino-7-(trans-5 '-O-[4,5-cis-diphenyl-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.75 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).mp 160-163℃。Analytical calculation value C ₂₇H ₂₉N ₄O ₇P.1.2H ₂O:C, 56.48; H, 5.51; N, 9.76.Measured value: C, 56.34, H, 5.75; N, 9.71.

16.23:4-amino-7-(cis-5 '-O-[cis-(5-methoxyl group-4-phenyl) 2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine trifluoroacetate.

R _f=0.25 (10%MeOH is at CH ₂Cl ₂In).mp 116-120℃。Analytical calculation value C ₂₂H ₂₆N ₄O ₈PCl.1.75H ₂O.1.5CF ₃CO ₂H:C, 40.39; H, 4.20; N, 7.54.Measured value: C, 39.95; H, 3.85; N, 7.38.

16.24:4-amino-7-(cis-5 '-O-[is trans-(5-methoxyl group-4-phenyl) 2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine trifluoroacetate.

R _f=0.30 (10%MeOH is at CH ₂Cl ₂In).mp 140-143℃。Analytical calculation value C ₂₂H ₂₆N ₄O ₈PCl.2.5H ₂O.2.2CF ₃CO ₂H:C, 37.89; H, 4.00; N, 6.70.Measured value: C, 37.73; H, 3.61; N, 6.85.

16.25:4-amino-7-(cis-5 '-O-[4-(2-bromo-5-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).mp 193-196℃。C ₂₁H ₂₃N ₄O ₇PClBr.1.75H ₂O.1CF ₃CO ₂H analytical calculation value: C, 37.57; H, 3.77; N, 7.62.Measured value: C, 37.20; H, 3.49; N, 7.36.

16.26:4-amino-7-(cis-5 '-O-[4-(3, the 5-dichlorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).mp 182-185℃。C ₂₁H ₂₃N ₄O ₇Cl ₂P.0.3MeOH.0.5H ₂O analytical calculation value: C, 45.37; H, 4.50; N, 9.93.Measured value: C, 45.36; H, 4.18; N, 9.58.

16.27:4-amino-7-(cis-5 '-O-[4-(3, the 5-difluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.35 (10%MeOH is at CH ₂Cl ₂In).mp 135-140℃。C ₂₁H ₂₃N ₄O ₇F ₂P.1.0H ₂O analytical calculation value: C, 47.55; H, 4.75; N, 10.56.Measured value: C, 47.29; H, 4.51; N, 10.28.

16.28:4-amino-7-(cis-5 '-O-[4-(R)-(3-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

(10%MeOH is at CH for Rf=0.45 ₂Cl ₂In).mp 126-128℃。C ₂₁H ₂₄ClN ₄O ₇P.1.0H ₂O analytical calculation value: C, 47.69; H, 4.96; N, 1059.Measured value: C, 47.31; H, 4.77; N, 10.3.

16.29:4-amino-7-(cis-5 '-O-[4-(2-trifluoromethyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

(10%MeOH is at CH for Rf=0.5 ₂Cl ₂In).mp 115-120℃。C ₂₂H ₂₄F ₃N ₄O ₇P.1.0H ₂O.1.0CF ₃CO ₂H analytical calculation value: C, 42.61; H, 4.02; N, 8.28.Measured value: C, 42.78; H, 4.07; N, 8.27.

16.30:4-amino-7-(cis-5 '-O-[4-(R)-(pyridin-4-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.3 (20%MeOH is in EtOAc).mp 132-136℃。C ₂₀H ₂₄N ₅O ₇P.0.03H ₂O.0.7CH ₂Cl ₂Analytical calculation value: C, 46.52; H, 4.79; N, 13.14.Measured value: C, 46.13; H, 4.39; N, 13.50.

16.31:4-amino-7-(cis-5 '-O-[4-(3-bromo-4-fluoro-phenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.35 (10%MeOH is in EtOAc).mp 122-125℃。C ₂₁H ₂₃N ₄O ₇FBrP.0.2CF ₃CO ₂H analytical calculation value: C, 43.12; H, 3.92; N, 9.40.Measured value: C, 42.82; H, 3.76; N, 9.57.

16.32:4-amino-7-(cis-5 '-O-[4-(pyridin-3-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.30 (10%MeOH is in EtOAc).mp 134-138℃。C ₂₀H ₂₄N ₅O ₇P.1.5H ₂O analytical calculation value: C, 47.62; H, 5.40; N, 13.88.Measured value: C, 47.89; H, 5.08; N, 13.97.

16.33:4-amino-7-(cis-5 '-O-[4-(pyridine-2-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine trifluoroacetate.

R _f=0.50 (10%MeOH is at CH ₂Cl ₂In).mp 88-90℃。C ₂₀H ₂₄N ₅O ₇P.2.3H ₂O.1.3CF ₃CO ₂H analytical calculation value: C, 40.69; H, 4.52; N, 10.50.Measured value: C, 40.38; H, 4.86; N, 10.90.

16.34:4-amino-7-(cis-5 '-O-[4-(R)-(phenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.30 (10%MeOH is at CH ₂Cl ₂In).mp 177-180℃。C ₂₁H ₂₅N ₄O ₇P.0.1EtOAc.0.2CF ₃CO ₂H analytical calculation value: C, 51.54; H, 5.16; N, 11.03.Measured value: C, 51.92; H, 4.78; N, 10.75.

16.35:4-amino-7-(cis-5 '-O-[4-(4-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine trifluoroacetate.

R _f=0.45 (10%MeOH is at CH ₂Cl ₂In).mp 182-184℃。C ₂₁H ₂₄N ₄O ₇ClP.2.0H ₂O.2.9CF ₃CO ₂H analytical calculation value: C, 36.68; H, 3.55; N, 6.38.Measured value: C, 36.33; H, 3.35; N, 6.44.

16.36:4-amino-7-(cis-5 '-O-[4-(2, the 3-difluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine trifluoroacetate.

R _f=0.5 (10%MeOH is at CH ₂Cl ₂In).mp 177-180℃。C ₂₁H ₂₃F ₂N ₄O ₇P.1.9H ₂O.1.1CF ₃CO ₂H analytical calculation value: C, 41.46; H, 4.18; N, 8.34.Measured value: C, 42.07; H, 4.02; N, 8.68.

16.37:4-amino-7-(cis-5 '-O-[4-(2-fluoro-5-methoxyphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine trifluoroacetate.

R _f=0.4 (10%MeOH is at CH ₂Cl ₂In).mp 80-85℃。C ₂₂H ₂₆N ₄O ₈FP.0.4H ₂O.2.0CF ₃CO ₂H analytical calculation value: C, 41.11; H, 3.82; N, 7.37.Measured value: C, 41.13; H, 3.50; N, 7.54.

16.38:4-amino-7-(cis-5 '-O-[4-(2-chloro-4-fluoro phenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine trifluoroacetate.

(15%MeOH is at CH for Rf=0.46 ₂Cl ₂In).mp 138-141℃。C ₂₁H ₂₃ClFN ₄O ₇P.0.3H ₂O.0.9CF ₃CO ₂H analytical calculation value: C, 43.00; H, 3.88; N, 8.80.Measured value: C, 42.73; H, 4.21; N, 8.55.

16.39:4-amino-7-(cis-5 '-O-[4-(2-fluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

(15%MeOH is at CH for Rf=0.48 ₂Cl ₂-1%NH ₄Among the OH).mp 101-103℃。C ₂₁H ₂₄FN ₄O ₇P.1.5H ₂O analytical calculation value: C, 48.37; H, 5.22; N, 10.74.Measured value: C, 48.70; H, 5.47; N, 10.43.

16.40:4-amino-7-(cis-5 '-O-[4-(2-cyano-phenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

(15%MeOH is at CH for Rf=0.42 ₂Cl ₂-1%NH ₄Among the OH).C ₂₂H ₂₄N ₅O ₇P.2H ₂O.0.1CF ₃CO ₂H analytical calculation value: C, 48.58; H, 5.16; N, 12.76.Measured value: C, 48.86; H, 5.51; N, 12.70.

16.41:4-amino-7-(cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine trifluoroacetate.

R _f=0.45 (10%MeOH is at CH ₂Cl ₂In).mp 145-148℃。C ₂₁H ₂₄N ₄O ₇PCl.0.7CH ₂Cl ₂.1.2CF ₃CO ₂H analytical calculation value: C, 40.93; H, 3.79; N, 7.92; F, 9.67.Measured value: C, 40.43; H, 3.77; N, 8.22; F, 9.47.

16.42:4-amino-7-(cis-5 '-O-[4-phenyl-5,6-tetramethylene-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.24 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).mp 110-113℃。C ₂₅H ₃₁N ₄O ₇P.2.0H ₂O analytical calculation value: C, 53.00; H, 6.23; N, 9.89.Measured value: C, 53.03; H, 5.93; N, 9.91.

16.43:4-amino-7-(cis-5 '-O-[4-(3-cyano-phenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.51 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).mp 157-160℃。C ₂₂H ₂₄N ₅O ₇P.2.5H ₂O analytical calculation value: C, 48.35; H, 5.35; N, 12.82.Measured value: C, 48.50; H, 5.72; N, 12.77.

16.44:4-amino-7-(cis-5 '-O-[4-(3, the 4-dichlorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.25 (10%MeOH is at CH ₂Cl ₂In).C ₂₁H ₂₃N ₄O ₇PCl ₂.0.2H ₂O.0.3EtOAc analytical calculation value: C, 46.34; N, 4.52; N, 9.74. measured value: C, 46.00; H, 4.26; N, 9.43.

16.45:4-amino-7-(cis-5 '-O-[4-(S)-(3-pyridine radicals)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.3 (10%MeOH is in EtOAc).

16.46:4-amino-7-(cis-5 '-O-[4-(R)-(3-pyridine radicals)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.3 (10%MeOH is in EtOAc).

16.47:4-amino-7-(cis-5 '-O-[4-phenyl-2-oxo-6-spirocyclohexyl-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.35 (10%MeOH is at CH ₂Cl ₂In).C ₂₆H ₃₃N ₄O ₇P.0.2H ₂O.0.2CF ₃CO ₂H.0.2EtOAc analytical calculation value: C, 55.51; H, 6.03; N, 9.52. measured value: C, 55.72; H, 5.87; N, 9.18.

16.48:4-amino-7-(cis-5 '-O-[4-phenyl-2-oxo-6-spirocyclopentyl-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.6 (10%MeOH is at CH ₂Cl ₂In).C ₂₅H ₃₁N ₄O ₇P.1.0CF ₃CO ₂H analytical calculation value: C, 50.31; H, 5.00; N, 8.69. measured value: C, 49.99; H, 4.99; N, 8.68.

16.49:4-amino-7-(cis-5 '-O-[4,4-dimethyl-6-(4-pyridine radicals)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine

R _f=0.35 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).MH ⁺The analytical calculation value, C ₂₂H ₂₈N ₅O ₇P:506. measured value: 506.

16.50:4-amino-7-(cis-5 '-O-[4-(4-cyano-phenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.40 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).C ₂₂H ₂₄N ₅O ₇P.2.2H ₂O analytical calculation value: C, 48.67; H, 5.31; N, 12.90. measured value: C, 48.74; H, 5.61; N, 12.54.

16.51:4-amino-7-(cis-5 '-O-[6-(3-chlorphenyl)-4,4-dimethyl-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine

R _f=0.58 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).Analytical calculation value C ₂₃H ₂₈ClN ₄O ₇P.2.0H ₂O:C, 48.05; H, 5.61; N, 9.74. measured value: C, 48.36; H, 5.74; N, 9.62.

16.52:4-amino-7-(cis-5 '-O-[4-(3-chlorphenyl)-2-oxo-6-Spirocyclopropyl-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine

R _f=0.35 (12%MeOH is at CH ₂Cl ₂In).C ₂₅H ₂₇ClF ₃N ₄O ₉P.1.6H ₂O.0.5CH ₂Cl ₂Analytical calculation value: C, 42.26; H, 4.34; N, 7.72. measured value: C, 41.95; H, 3.95; N, 7.43.

Embodiment 17: by trans-phosphate addition reaction preparation 2 '-C-Beta-methyl-7-denitrogenation guanosine prodrug:

Parent nucleosides 2-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone can synthesize as described in US6777395.

Nucleosides can be converted into corresponding prodrug as described in embodiment 16 steps A, B and C.

The following example can synthesize as described in steps A-C.

17.1:2-amino-7-(cis-5 '-O-[4-(3-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.30 (10%MeOH is at CH ₂Cl ₂In).C ₂₁H ₂₄CIN ₄O ₈P.1.2CF ₃CO ₂NH ₄.1.0CF ₃CO ₂H analytical calculation value: C, 38.22; H, 3.76; N, 9.13.Measured value: C, 37.93; N, 3.80; N, 9.40.

17.2:2-amino-7-(cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.15 (10%MeOH is at CH ₂Cl ₂In).mp 175℃。C ₂₁H ₂₄ClN ₄O ₈P.0.5H ₂O analytical calculation value: C, 47.07; H, 4.70; N, 10.46.Measured value: C, 46.73; H, 4.90, N, 10.16.

17.3:2-amino-7-(cis-5 '-O-[4-(5-bromo-2-fluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.41 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).C ₂₁H ₂₃BrFN ₄O ₈P.0.5H ₂O.0.2CF ₃CO ₂H analytical calculation value: C, 41.38; H, 3.93; N, 9.02.Measured value: C, 41.60; H, 4.32; N, 8.77.

17.4:2-amino-7-(cis-5 '-O-[4-(3-bromophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone trifluoroacetate.

R _f=0.38 (CH of 15%MeOH ₂Cl ₂-1%NH ₄OH).mp 142-145℃。C ₂₁H ₂₄N ₄O ₈P.0.7H ₂O.0.9CF ₃CO ₂H analytical calculation value: C, 39.89; H, 3.86; N, 8.16.Measured value: C, 39.53; H, 3.65; N, 8.43.

17.5:2-amino-7-(cis-5 '-O-[4-(3-chloro-4-fluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.45 (CH of 20%MeOH ₂Cl ₂C ₂₁H ₂₃N ₄O ₈FClP.1.4H ₂O analytical calculation value: C, 44.24, H, 4.78; N, 9.83.Measured value: C, 43.77; H, 4.78; N, 10.31.

17.6:2-amino-7-(cis-5 '-O-[4-(2, the 5-difluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.35 (20%MeOH is at CH ₂Cl ₂In).mp 170-173℃。C ₂₁H ₂₃F ₂N ₄O ₈P.2.0H ₂O.0.4CF ₃CO ₂NH ₄Analytical calculation value: C, 42.45; H, 4.67; N, 9.99.Measured value: C, 42.28; H, 4.76N, 9.96.

17.7:2-amino-7-(cis-5 '-O-[4-(2-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.25 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).C ₂₁H ₂₄ClN ₄O ₈P.1.25H ₂O.0.2CF ₃CO ₂H analytical calculation value: C, 44.92; H, 4.70; N, 9.79.Measured value: C, 44.93; H, 5.09; N, 10.08.

17.8:2-amino-7-(cis-5 '-O-[4-(pyridine-2-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone trifluoroacetate.

R _f=0.4 (15%MeOH is at CH ₂Cl ₂In).mp 180-190℃。C ₂₀H ₂₄N ₅O ₈P.1.3CF ₃CO ₂H.0.3CH ₂Cl ₂Analytical calculation value: C, 41.23; H, 3.91; N, 10.50.Measured value: C, 40.96; H, 3.46; N, 11.05.

17.9:2-amino-7-(cis-5 '-O-[4-(2-trifluoromethyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone trifluoroacetate.

R _f=0.4 (10%MeOH is at CH ₂Cl ₂In).mp 185-188℃。C ₂₂H ₂₄N ₄O ₈F ₃P.0.8CF ₃CO ₂H analytical calculation value: C, 43.50; H, 3.84; N, 8.60.Measured value: C, 43.55; H, 3.97; N, 8.98.

17.10:2-amino-7-(cis-5 '-O-[4-(R)-(3-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone trifluoroacetate.

(15%MeOH is at CH for Rf=0.50 ₂Cl ₂In).mp 170-180℃。

17.11:2-amino-7-(cis-5 '-O-[4-(3, the 5-difluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone trifluoroacetate.

R _f=0.30 (10%MeOH is at CH ₂Cl ₂In) mp 182-185 ℃.C ₂₁H ₂₃N ₄O ₈F ₂P.0.3EtOAc.0.2CF ₃CO ₂H analytical calculation value: C, 46.99; H, 4.47; N, 9.70.Measured value: C, 47.26; H, 4.32; N, 9.46.

17.12:2-amino-7-(cis-5 '-O-[4-(3, the 5-dichlorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.35 (10%MeOH is at CH ₂Cl ₂In).mp 177-180℃。C ₂₁H ₂₃N ₄O ₈C ₁₂P.0.1EtOAc.0.2CF ₃CO ₂H analytical calculation value: C, 44.16; H, 4.08; N, 9.45.Measured value: C, 44.33; H, 4.44; N, 9.18.

17.13:2-amino-7-(cis-5 '-O-[4-(S)-(pyridin-4-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.21 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).mp 138-141℃。C ₂₀H ₂₄N ₅O ₈P.2.2H ₂O analytical calculation value: C, 45.07; H, 5.33; N, 13.14.Measured value: C, 45.12; H, 5.40; N, 12.89.

17.14:2-amino-7-(cis-5 '-O-[4-(3-fluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.25 (10%MeOH is at CH ₂Cl ₂In).mp 170℃。C ₂₁H ₂₄FN ₄O ₈P.1.5H ₂O analytical calculation value: C, 46.93; H, 5.06; N, 10.42.Measured value: C, 46.92; H, 5.12; N, 10.44.

17.15:2-amino-7-(cis-5 '-O-[4-(3-bromo-4-fluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.25 (10%MeOH is at CH ₂Cl ₂In).mp 175-179℃。C ₂₁H ₂₃BrFN ₄O ₈P.0.5H ₂O.0.5EtOAc analytical calculation value: C, 43.01; H, 4.39; N, 8.72.Measured value: C, 43.03; H, 4.49; N, 8.49.

17.16:2-amino-7-(cis-5 '-O-[4-(R)-phenyl-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

(10%MeOH is at CH for Rf=0.30 ₂Cl ₂In).mp 128-133℃。C ₂₁H ₂₅N ₄O ₈P.1.1H ₂O.0.3CF ₃CO ₂H analytical calculation value: C, 47.48; H, 5.07; N, 10.25.Measured value: C, 47.61; H, 5.36; N, 9.91.

17.17:2-amino-7-(cis-5 '-O-[4,5-cis-diphenyl-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone trifluoroacetate.

R _f=0.45 (20%MeOH is at CH ₂Cl ₂In).mp 187-190℃。C ₂₇H ₂₉N ₄O ₈P.2 H ₂O.1.3CF ₃CO ₂H analytical calculation value: C, 47.23; H, 4.59; N, 7.44.Measured value: C, 46.83; H, 4.33; N, 7.31.

17.18:2-amino-7-(cis-5 '-O-[6,6-dimethyl-4-phenyl-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone trifluoroacetate.

R _f=0.40 (20%MeOH is at CH ₂Cl ₂In).mp 192-194℃。C ₂₃H ₂₉N ₄O ₈P.2.0H ₂O.1.0CF ₃CO ₂H analytical calculation value: C, 44.78; H, 5.11; N, 8.36.Measured value: C, 44.40; H, 4.67; N, 8.22.

17.19:2-amino-7-(cis-5 '-the O-[cis-(5-methoxyl group-4-(3-chlorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.30 (20%MeOH is at CH ₂Cl ₂In).mp 148-151℃。C ₂₂H ₂₆N ₄O ₉ClP.1.0H ₂O analytical calculation value: C, 45.96; H, 4.91; N, 9.75.Measured value: C, 46.03; H, 4.80; N, 9.64.

17.20:2-amino-7-(cis-5 '-O-[4-(2, the 3-difluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone trifluoroacetate.

R _f=0.5 (10%MeOH is at CH ₂Cl ₂In).mp 215-220℃。C ₂₁H ₂₃N ₄O ₈F ₂P.1.0H ₂O.1.0CF ₃CO ₂H analytical calculation value: C, 41.83; H, 3.97; N, 8.48.Measured value: C, 41.70; H, 3.77; N, 8.50.

17.21:2-amino-7-(cis-5 '-O-[4-(2-bromophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.15 (10%MeOH is at CH ₂Cl ₂In).mp 180℃。C ₂₁H ₂₄BrN ₄O ₈P.1.1H ₂O analytical calculation value: C, 42.67; H, 4.47; N, 9.48.Measured value: C, 42.51, H, 4.60; N, 9.58.

17.22:2-amino-7-(cis-5 '-O-[4-(3, the 4-dichlorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.30 (10%MeOH is at CH ₂Cl ₂In).mp 192-195℃。Analytical calculation value C ₂₁H ₂₃N ₄O ₈Cl ₂P.0.2CF ₃CO ₂H.0.2EtOAc:C, 44.31; H, 4.15; N, 9.31.Measured value: C, 44.40; H, 3.94; N, 9.21.

17.23:2-amino-7-(cis-5 '-O-[4-(3,5-two-(trifluoromethyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.15 (10%MeOH is at CH ₂Cl ₂In).mp 155-175℃。C ₂₃H ₂₃F ₆N ₄O ₈P.0.6H ₂O analytical calculation value: C, 43.22; H, 3.82; N, 8.76.Measured value: C, 43.08; H, 4.03; N, 8.94.

17.24:2-amino-7-(cis-5 '-O-[4-(3-trifluoromethyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.15 (10%MeOH is at CH ₂Cl ₂In).mp 145-165℃。C ₂₂H ₂₄F ₃N ₄O ₈P.1H ₂O analytical calculation value: C, 45.68; H, 4.53; N, 9.69.Measured value: C, 45.31; H, 4.88; N, 9.71.

17.25:2-amino-7-(cis-5 '-O-[4-(2,4 dichloro benzene base)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.15 (10%MeOH is at CH ₂Cl ₂In).mp 175℃。C ₂₁H ₂₃C ₁₂N ₄O ₈P.1H ₂O analytical calculation value: C, 43.54; H, 4.35; N, 9.67.Measured value: C, 43.32; H, 4.35; N, 9.55.

17.26:2-amino-7-(cis-5 '-O-[4-(5-bromo-pyridin-3-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).mp 185-189℃。C ₂₀H ₂₃N ₅O ₈BrP.1.5CF ₃CO ₂H analytical calculation value: C, 37.16; H, 3.32; N, 9.42.Measured value: C, 37.23; H, 3.44; N, 9.33.

17.27:2-amino-7-(cis-5 '-O-[4-(pyridin-3-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidines-4 (3H)-ketone.

R _f=0.15 (10%MeOH is at CH ₂Cl ₂In); C ₂₀H ₂₄N ₅O ₈P.1H ₂O.0.4EtOAc analytical calculation value: C, 47.46; H, 5.38; N, 12.81.Measured value: C, 47.40; H, 5.17; N, 12.78.

Embodiment 18:5 '-O-[4-(3-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine:

2 '-C-methyladenosine can be as J.Med.Chem.1998,41,1798 described preparations.

Steps A:

Universal method from the glycol synthesis of cyclic phosphoramidite that replaces:

In-78 ℃, with 30 minutes, in THF (5mL) solution of the commercial diisopropyl phosphoramidous dichloride (1mmol) that obtains, adding 1, THF (5mL) liquid of 3-glycol (1mmol) and triethylamine (4mmol).Reactant slowly is heated to room temperature and stirs spend the night.Filter reaction mixture removes and desalts, and concentrated filtrate obtains the crude product product.Obtain 1 through silica gel column chromatography, the pure ring-type diisopropylphosphoramidite of 3-glycol.

Step B:

The universal method of nucleosides-ring-type phosphoramidite coupling and oxidation:

(J.Org.Chem.，1996，61，7996)

In the DMF (10mL) of nucleosides (1mmol) and ring-type phosphoramidite (1mmol) solution, add benzimidazoles fluoroform sulphonate (1mmol).Reaction stirred 30min under room temperature.Cooling mixture is to-40 ℃, adds tert-butyl hydroperoxides (2mmol) then and in kept at room temperature overnight.Concentrating under reduced pressure and chromatography crude product product obtain pure ring-type propyl group prodrug.

R _f=0.46 (12%MeOH is at CH ₂Cl ₂In).mp 153℃。Analytical calculation value C ₂₀H ₂₃ClN ₅O ₇P:C, 46.93; H, 4.53; N, 13.63.Measured value: C, 47.06; H, 4.36; N, 13.68.

Embodiment 19: cis-5 '-O-[4-(3-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-guanosine:

2 '-C-methylguanosine is as preparation as described in the WO01/90121.

R _f=0.35 (25%MeOH is at CH ₂Cl ₂In).mp＞230℃。C ₂₀H ₂₃ClN ₅O ₈P analytical calculation value: C, 45.51; H, 4.39; N, 13.27.Measured value: C, 45.89; H, 4.44; N, 13.23.

Embodiment 20: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-guanosine.

According to being similar to embodiment 19 described flow processs, adopt synthetic this compound of phosphorus esterification reagent (its preparation method as embodiment 14 as described in preparation).

R _f=0.35 (20%MeOH is at CH ₂Cl ₂In).mp＞180℃。C ₂₀H ₂₃N ₅O ₈ClP.1.0H ₂O.0.8CF ₃CO ₂H analytical calculation value: C, 40.72; H, 4.08; N, 10.99.Measured value: C, 40.43; N, 4.41; N, 11.34.

Embodiment 21: by trans-phosphate addition reaction preparation 2 '-C-methyl-adenosine prodrugs:

2 '-C-methyladenosine can be as J.Med.Chem.1998,41,1708 described preparations.

Nucleosides can be converted into corresponding prodrug as method as described in embodiment 16 steps A, B and the C.

Among the step B employed trans-phosphorus esterification reagent can be synthetic as method as described in the embodiment 1-15.

21.1: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-adenosine trifluoroacetate.

R _f=0.3 (5%MeOH is in EtOAc).mp 125-128℃。C ₂₀H ₂₃ClN ₅O ₇P.1.7CF ₃CO ₂H analytical calculation value: C, 39.83; H, 3.53; N, 9.92.Measured value: C; 39.52, H; 3.46, N; 10.21.

21.2: cis-5 '-O-[4-(3-cyano-phenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-adenosine.

R _f=0.43 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).mp 153-156℃。C ₂₁H ₂₃N ₆O ₇P.1.1H ₂O analytical calculation value: C, 48.30; H, 4.86; N, 16.09.Measured value: C, 48.53; H, 5.11; N, 15.75.

21.3: cis-5 '-O-[4-(2, the 5-difluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-adenosine.

R _f=0.60 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).mp 75-78℃。C ₂₀H ₂₂F ₂N ₅O ₇P.0.3CH ₂Cl ₂Analytical calculation value: C, 45.25; H, 4.23; N, 13.00.Measured value: C, 45.07; H, 3.94; N, 12.69.

21.4: cis-5 '-O-[4-(3, the 5-difluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-adenosine.

R _f=0.65 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).mp 120-123℃。C ₂₀H ₂₂F ₂N ₅O ₇P.1.5H ₂O.0.1C ₆H ₁₄Analytical calculation value: C, 45.07; H, 4.85; N, 12.76.Measured value: C, 45.04; H, 5.25; N, 12.59.

21.5: cis-5 '-O-[4-(S)-(pyridin-4-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-adenosine.

R _f=0.55 (CH of 15%MeOH ₂Cl ₂-1%NH ₄OH).C ₁₉H ₂₃N ₆O ₇P.2.5H ₂O analytical calculation value: C, 43.60; H, 5.39; N, 16.06.Measured value: C, 43.35; H, 5.54; N, 16.05.

21.6: cis-5 '-O-[4-(3-bromophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine.

R _f=0.5 (10%MeOH is at CH ₂Cl ₂In).mp 108-110℃。C ₂₀H ₂₃N ₅O ₇BrP.1.5H ₂O.0.4CF ₃CO ₂H analytical calculation value: C, 39.72; H, 4.23; N, 11.14.Measured value: C, 39.44; H, 4.55; N, 11.18.

21.7: cis-5 '-O-[4-(pyridine-2-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-adenosine trifluoroacetate.

R _f=0.4 (10%MeOH is at CH ₂Cl ₂In).mp 118-120℃。C ₁₉H ₂₃N ₆O ₇P.2.0H ₂O.1.0CF ₃CO ₂H analytical calculation value: C, 40.14; H, 4.49; N, 13.37.Measured value: C, 40.36; H, 4.92; N, 13.63.

21.8: cis-5 '-O-[4-(4-mesyl phenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-adenosine trifluoroacetate.

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).mp 185-187℃。C ₂₁H ₂₆N ₅O ₉PS.0.6H ₂O.0.6CF ₃CO ₂H analytical calculation value: C, 42.01; H, 4.41; N, 11.03.Measured value: C, 41.93; H, 4.73; N, 10.97.

21.9: cis-5 '-O-[4-(pyridin-3-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-adenosine.

R _f=0.2 (10%MeOH is in EtOAc).mp 137-140℃。C ₁₉H ₂₃N ₆O ₇P.1.5H ₂O.0.4EtOAc analytical calculation value: C, 45.76; H, 15.54; N, 5.44.Measured value: C; 45.88; H, 15.19; N, 5.09.

21.10: cis-5 '-O-[4-(5-bromo-3-pyridine radicals)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine.

R _f=0.15 (10%MeOH is in EtOAc).C ₁₉H ₂₂N ₆O ₇BrP.1.0H ₂O.0.4EtOAc analytical calculation value: C, 40.52; H, 4.49; N, 13.76. measured value: C, 40.39; H, 4.22; N, 13.42.

21.11: cis-5 '-O-[4-(2-bromophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine.

R _f=0.35 (5%MeOH is at CH ₂Cl ₂In).C ₂₀H ₂₃BrN ₅O ₇P.1.5H ₂O.0.1CH ₂Cl ₂Analytical calculation value: C, 40.79; H, 4.46; N, 11.83. measured value: C, 40.49; H, 4.46; N, 11.49.

21.12: cis-5 '-O-[4-(3-methyl sulphonyl phenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl] 2 '-C-methyladenosine

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).Analytical calculation value C ₂₁H ₂₆N ₅O ₉PS.1.4H ₂O.1.0CH ₂Cl ₂: C, 39.70; H, 4.66; N, 10.52. measured value: C, 39.61; H, 4.11; N, 10.22.

21.13: cis-5 '-O-[4-(3, the 5-dichlorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyladenosine trifluoroacetate

R _f=0.15 (10%MeOH is in EtOAc).C ₂₀H ₂₂N ₅O ₇Cl ₂P.1.0H ₂O.1.0CF ₃CO ₂H analytical calculation value: C, 38.95; H, 3.71; N, 10.32. measured value: C, 38.56; H, 3.52; N, 10.57.

21.14: cis-5 '-O-[4-(3-fluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine.

R _f=0.5 (10%MeOH is at CH ₂Cl ₂In).C ₂₀H ₂₃N ₅O ₇FP.0.4CF ₃CO ₂H analytical calculation value: C, 46.18; H, 4.36; N, 12.94. measured value: C, 46.09; H, 4.39; N, 13.01.

21.15: cis-5 '-O-[6-(3-chlorphenyl)-4,4-dimethyl-2-oxo-1,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine.

R _f=0.50 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).C ₂₂H ₂₇ClN ₅O ₇P.1.0H ₂O.0.5CH ₃OH analytical calculation value: C, 47.09; H, 5.44; N, 12.20. measured value: C, 47.00; H, 5.81; N, 12.21.

21.16: cis-5 '-O-[4-(3, the 4-dichlorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyladenosine trifluoroacetate

R _f=0.40 (10%MeOH is at CH ₂Cl ₂In).C ₂₀H ₂₂N ₅O ₇Cl ₂P.1.7CF ₃CO ₂H.2.7H ₂O analytical calculation value: C, 35.63; H, 3.72; N, 8.88. measured value: C, 35.17; H, 3.55; N, 8.80.

21.17: cis-5 '-O-[4-(3-fluoro-4-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine

R _f=0.45 (10%MeOH is at CH ₂Cl ₂In).C ₂₀H ₂₂N ₅O ₇PClF.0.8CF ₃CO ₂H.0.9H ₂O analytical calculation value: C, 40.71; H, 3.89; N, 10.99. measured value: C, 40.46; H, 3.93; N, 10.98.

21.18: cis-5 '-O-[4-(3-acetylphenyl)-2-oxo-1,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine.

R _f=0.40 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).Analytical calculation value C ₂₂H ₂₆N ₅O ₈P.0.4CH ₂Cl ₂.1.0H ₂O:C, 47.08; H, 5.08; N, 12.26. measured value: C, 47.03; H, 4.94; N, 12.15.

21.19: cis-5 '-O-{4-[3-(morpholine-4-sulfonyl) phenyl]-2-oxo-1,3-two oxa-phosphorus heterocycles oneself-the 2-yl-2 '-the C-methyladenosine

R _f=0.60 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).C ₂₄H ₃₁N ₆O ₁₀PS.0.6H ₂O.0.5CH ₂Cl ₂Analytical calculation value: C, 43.28; H, 4.92; N, 12.36. measured value: C, 43.65; H, 4.88; N, 11.98.

21.20: cis-5 '-O-{4,4-dimethyl-6-(4-pyridine radicals)-2-oxo-1,3-two oxa-phosphorus heterocycles oneself-the 2-yl-2 '-the C-methyladenosine.

R _f=0.40 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).C ₂₁H ₂₇N ₆O ₇P.0.9H ₂O.0.4CH ₂Cl ₂Analytical calculation value: C, 46.18; H, 5.36; N, 15.10. measured value: C, 46.00; H, 4.98; N, 15.09.

21.21: cis-5 '-O-[4-(R)-(3-chlorphenyl)-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-adenosine.

R _f=0.3 (5%MeOH is in EtOAc).C ₂₀H ₂₃N ₅O ₇ClP.1.0H ₂O.0.2EtOAc analytical calculation value: C, 45.63; H, 4.90; N, 12.79. measured value: C, 45.53; H, 4.75; N, 12.50.

21.22: cis-5 '-O-[4-(2, the 3-difluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-adenosine.

R _f=0.35 (15%MeOH is at CH ₂Cl ₂In).C ₂₀H ₂₂N ₅O ₇F ₂P.0.75H ₂O analytical calculation value: C, 45.59; H, 4.50; N, 13.29. measured value: C, 45.49; H, 4.08; N, 13.30.

21.23: cis-5 '-O-[4-(R)-(4-pyridine radicals)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-adenosine.

R _f=0.3 (20%MeOH is in EtOAc).Analytical calculation value C ₁₉H ₂₃N ₆O ₇.1.7H ₂O:C, 44.83; H, 5.23; N, 16.51. measured value: C, 44.73; H, 5.06; N, 16.30.

21.24: cis-5 '-O-[4,4-dimethyl-6-phenyl-2-oxo-1.3.2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyladenosine trifluoroacetate.

R _f=0.3 (10%MeOH is in EtOAc).Analytical calculation value C ₂₂H ₂₈N ₅O ₇P.1.0H ₂O.1.5CF ₃CO ₂H.0.1EtOAc:C, 43.38; H, 4.63; N, 9.96. measured value: C, 43.38; H, 4.71; N, 9.71.

21.25: cis-5 '-O-[4-(4-cyano-phenyl)-2-oxo-1,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine.

R _f=0.60 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).C ₂₁H ₂₃N ₆O ₇P.1.0H ₂O.0.1EtOAc analytical calculation value: C, 48.47; H, 4.84; N, 16.15. measured value: C, 48.89; H, 4.42; N, 15.68.

21.26: cis-5 '-O-[4-phenyl-2-oxo-6-spirocyclohexyl-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyladenosine trifluoroacetate.

R _f=0.3 (10%MeOH is in EtOAc).C ₂₁H ₂₃N ₆O ₇P.1.0H ₂O.0.1EtOAc analytical calculation value: C, 44.69; H, 5.02; N, 9.31. measured value: C, 44.40; H, 5.00; N, 9.39.

21.27: cis-5 '-O-{4-(4-fluoro-3-trifluoromethyl)-2-oxo-1,3-two oxa-phosphorus heterocycles oneself-the 2-yl-2 '-the C-methyladenosine.

R _f=0.55 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).C ₂₁H ₂₂F ₄N ₅O ₇P.H ₂O analytical calculation value: C, 43.38; H, 4.16; N, 12.05. measured value: C, 43.41; H, 3.85; N, 12.04.

21.28: cis-5 '-O-{4-[3-(2-furyl) pyridine-5-yl]-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl-2 '-the C-methyladenosine.

R _f=0.5 (10%MeOH is at CH ₂Cl ₂In).C ₂₃H ₂₅N ₆O ₈P.3.0H ₂O.0.1CF ₃CO ₂H analytical calculation value: C, 45.69; H, 5.14; N, 13.78. measured value: C, 45.64; H, 5.03; N, 14.05.

21.29: cis-5 '-O-{4-[3-(2-thienyl) pyridine-5-yl]-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl-2 '-the C-methyladenosine.

R _f=0.55 (10%MeOH is at CH ₂Cl ₂In).Analytical calculation value C ₂₃H ₂₅N ₆O ₇SP.2.3H ₂O.2.0CF ₃CO ₂H:C, 39.07; H, 3.84; N, 10.13. measured value: C, 38.70; H, 3.64; N, 10.28.

21.30: cis-5 '-O-[4-(2-methoxyl group-pyridine-5-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine.

R _f=0.3 (15%MeOH is at CH ₂Cl ₂In).C ₂₀H ₂₅N ₆O ₈P.1.0CF ₃CO ₂H.1.2H ₂O analytical calculation value: C, 41.03; H, 4.44; N, 13.05. measured value: C, 40.96; H, 4.97; N, 13.70.

21.31: cis-5 '-O-[4,4-dimethyl-6-(3, the 4-dichlorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine.

R _f=0.25 (10%MeOH is at CH ₂Cl ₂In).C ₂₂H ₂₆C ₁₂N ₅O ₇P.1.3H ₂O.0.6CH ₂Cl ₂Analytical calculation value: C, 41.70; H, 4.62; N, 10.74. measured value: C, 41.57; H, 4.78; N, 10.83.

21.32: cis-5 '-O-[6-(3, the 5-difluorophenyl)-4,4-dimethyl-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine.

R _f=0.28 (10%MeOH is at CH ₂Cl ₂In).C ₂₂H ₂₆F ₂N ₅O ₇P.2.0H ₂O.0.3CF ₃CO ₂H analytical calculation value: C, 44.38; H, 4.99; N, 11.45. measured value: C, 44.56; H, 5.18; N, 11.21.

21.33: cis-5 '-O-[4-(2-bromo-5-fluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyladenosine trifluoroacetate

R _f=0.3 (10%MeOH is in EtOAc).Analytical calculation value C ₂₀H ₂₂N ₅O ₇BrFP.3.4H ₂O.2.2CF ₃CO ₂H.0.1EtOAc:C, 33.27; H, 3.58; N, 7.82. measured value: C, 32.94; H, 3.24; N, 7.52.

21.34: cis-5 '-O-[4,4-dimethyl-6-(3-fluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine

R _f=0.5 (10%MeOH is at CH ₂Cl ₂In).C ₂₂H ₂₇N ₅O ₇FP.1.8H ₂O.1.5CF ₃CO ₂H analytical calculation value: C, 41.31; H, 4.45; N, 9.63. measured value: C, 40.94; H, 4.50; N, 9.38.

21.35: cis-5 '-O-[4,4-dimethyl-6-(2, the 3-difluorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine.

R _f=0.4 (10%MeOH is at CH ₂Cl ₂In).C ₂₂H ₂₆F ₂N ₅O ₇P.0.5H ₂O analytical calculation value: C, 48.00; H, 4.94; N, 12.72. measured value: C, 47.62; H, 4.90; N, 12.67.

21.36: cis-5 '-O-[6,6-dimethyl-4-(3, the 5-dichlorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyladenosine trifluoroacetate

R _f=0.2 (10%MeOH is in EtOAc).MH ⁺Analytical calculation value C ₂₂H ₂₆Cl ₂N ₅O ₇P:575. measured value: 575.

21.37: cis-5 '-O-{4-[2-(2-furyl) pyridin-4-yl]-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl-2 '-the C-methyladenosine.

R _f=0.5 (10%MeOH is at CH ₂Cl ₂In).C ₂₃H ₂₅N ₆O ₈P.1.5H ₂O.1.5CF ₃CO ₂H analytical calculation value: C, 42.06; H, 4.00; N, 11.32. measured value: C, 41.67; H, 4.30; N, 11.13.

21.38: cis-5 '-O-{[4-(2-methyl sulfo--pyridin-4-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine.

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).C ₂₂H ₂₆F ₃N ₆O ₉PS.2.4H ₂O analytical calculation value: C, 38.76; H, 4.55; N, 12.33. measured value: C, 38.39; H, 4.12; N, 12.09.

21.39: cis-5 '-O-{[4-(2-cyanopyridine-5-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine.

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).C ₂₀H ₂₂N ₇O ₇P.0.5H ₂O.2.2CF ₃CO ₂H analytical calculation value: C, 38.40; H, 3.33; N, 12.85. measured value: C, 38.09; H, 3.25; N, 12.57.

21.40: cis-5 '-O-[4,4-diethyl-6-phenyl-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine.

R _f=0.55 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).C ₂₄H ₃₂N ₅O ₇P.0.3H ₂O analytical calculation value: C, 53.49; H, 6.10; N, 13.00. measured value: C, 53.97; H, 6.40; N, 12.61.

21.41: cis-5 '-O-[4-(5-methyl-pyridin-3-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-the C-methyladenosine.

R _f=0.2 (10%MeOH is at CH ₂Cl ₂In).C ₂₀H ₂₅N ₆O ₇P.1.2H ₂O analytical calculation value: C, 46.73; H, 5.37; N, 16.35. measured value: C, 46.64; H, 5.21; N, 16.15.

21.42: cis-5 '-O-[6-(5-bromo-2,3-difluorophenyl)-4,4-dimethyl-1,3-two oxa-s-2-oxo phospha cyclohexane-2-yl]-2 '-the C-methyladenosine.

R _f=0.45 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).C ₂₂H ₂₅BrF ₂N ₅O ₇P.1.0CH ₃OH analytical calculation value: C, 42.34; H, 4.48; N, 10.73. measured value: C, 42.82; H, 4.84; N, 10.66.

Embodiment 22: preparation 2 '-universal method of 3 '-acetyl derivative of C-methyl-7-denitrogenation adenosine ring-type prodrug:

In 0 ℃, to 5 '-add acetic anhydride (0.6mL) in pyridine (3mL) solution of the ring-type propyl group prodrug (0.3mmol) that replaces.Reactant is placed 0 ℃ of 18h.With ethanol (3mL) quencher excessive acetic anhydride via.Enriched mixture is with other ethanol (2 * 5mL) azeotropic.Chromatography crude product residue obtains pure monoacylated compound, is solid.

22.1:4-amino-7-(3 '-O-acetyl group-cis-5 '-O-[4-(S)-(pyridin-4-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.35 (15%MeOH is at CH ₂Cl ₂In).mp 182-185℃。C ₂₂H ₂₆N ₅O ₈P.1.5H ₂O.0.2CH ₂Cl ₂Analytical calculation value: C, 47.32; H, 5.56; N, 12.43.Measured value: C, 47.19; H, 4.78; N, 12.09.

22.2:4-amino-7-(3 '-O-acetyl group-cis-5 '-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.35 (10%MeOH is at CH ₂Cl ₂In).mp 90-93℃。C ₂₃H ₂₆N ₄O ₈ClP.1.0H ₂O analytical calculation value: C, 48.39; H, 4.94; N, 9.81.Measured value: C, 48.79; H, 4.85; N, 9.91.

Embodiment 23: preparation 2 '-universal method of 2 ', 3 '-cyclic carbonate derivative of C-methyl-7-denitrogenation adenosine ring-type prodrug:

In 0 ℃, to 5 '-add carbonyl dimidazoles (CDI) (0.5mmol) in DMF (2.5mL) solution of the ring-type propyl group prodrug (0.25mmol) that replaces.Reactant is heated to room temperature and stirs 4h.Removal of solvent under reduced pressure, the crude product product obtains 2 ', 3 '-carbonic ester through chromatography, is solid.

23.1:4-amino-7-(2 ', 3 '-O-carbonyl-cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.45 (10%MeOH is at CH ₂Cl ₂In).mp 127-130℃。C ₂₂H ₂₂N ₄O ₈PCl.1.0H ₂O analytical calculation value: C, 47.62; H, 4.36; N, 10.10.Measured value: C, 47.94; H, 4.10; N, 10.13.

23.2:4-amino-7-(2 ', 3 '-O-carbonyl-cis-5 '-O-[4-(S)-(pyridin-4-yl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.4 (20%MeOH is at CH ₂Cl ₂In).mp 192-195℃。C ₂₁H ₂₂N ₅O ₈P.1.0H ₂O analytical calculation value: C, 48.37; H, 4.64; N, 13.43.Measured value: C, 48.41; H, 4.39; N, 13.60.

Embodiment 24: preparation 2 '-3 '-L-valyl base ester derivant of C-methyl-7-denitrogenation adenosine ring-type prodrug:

24.1:4-amino-7-(cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-3 '-O-L-valyl base-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

The ring-type prodrug (16.5) of 5 '-replacement can be as preparation as described in the embodiment 16.

Steps A:

To the BOC-L-valine (217mg, add in THF 1.0mmol) (5mL) solution carbonyl dimidazoles (CDI) (162mg, 1mmol).Warm reactant to 50 ℃ stirs 1h.In the mixture that obtains, add 5 '-ring-type prodrug (16.5) DMF (3mL) solution (0.50mmol) that replaces, and then add triethylamine (1.5mL) and 4-dimethylaminopyridine (6mg, 0.05mmol).In 80 ℃ of heating reactant 3h.Concentrating under reduced pressure reactant mixture and with crude product 10%MeOH-CH ₂Cl ₂Extract.Organic extract is through water washing, dry and concentrated.The crude product residue is through 5%-10%MeOH-CH ₂Cl ₂Elution chromatography obtains 3 '-BOC-L-Val derivative (200mg) of 5 '-ring-type propyl group prodrug.

Step B:

In 0 ℃, the prodrug (200mg) of BOC protection is dissolved in 70% trifluoroacetic acid (10mL) aqueous solution of precooling.In 0 ℃, reaction stirred 3h.The concentrating under reduced pressure mixture and with ethanol (2 * 5mL) azeotropic.The crude product residue CH of 5%-20%MeOH ₂Cl ₂Elution chromatography obtains the prodrug (140mg) of BOC deprotection.

R _f=0.35 (15%MeOH is at CH ₂Cl ₂In).mp 132-135℃。

C ₂₆H ₃₃N ₅O ₈ClP.2.3CF ₃CO ₂H.2.1H ₂O analytical calculation value: C, 40.38; H, 4.37; N, 7.70.Measured value: C, 39.94; H, 3.93; N, 7.48.

Embodiment 25: preparation 2 '-the 6-azido derivative of C-methyl-7-denitrogenation adenosine 5 '-one phosphoric acid ring-type prodrug:

4-chloro-7-(2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine can be as preparation as described in the US6777395.

Steps A:

Under room temperature, to 4-chloro-7-(2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine (162mg, add in DMF 0.54mmol) (5mL) solution sodium azide (70mg, 1.08mmol).Reactant is heated to 60 ℃, stirs 18h.Enriched mixture, and use CH ₂Cl ₂To 5%MeOH-CH ₂Cl ₂Wash-out carries out chromatography, obtains azido substitution product (102mg).

25.1:4-azido-7-(2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine.

R _f=0.4 (5%MeOH is at CH ₂Cl ₂In).mp 179-180℃。C ₁₂H ₁₄N ₆O ₄Analytical calculation value: C, 47.06; H, 4.61; N, 27.44.Measured value: C, 46.97; H, 4.71; N, 27.28.

Step B:

One phosphoric acid ring-type prodrug of 5 ' of 4-azido-7-(2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine-replacement can be as preparation as described in the embodiment 16.

Embodiment 26:

As US6, the parent of preparation described in 777,395 nucleosides.

As synthetic prodrug as described in steps A, B and the C of embodiment 16.As preparation phosphorus esterification reagent as described in the embodiment 11-16.

26.1: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-2-amino-7-denitrogenation-adenosine trifluoroacetate

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).C ₂₁H ₂₅N ₅O ₇ClP.2.0CF ₃CO ₂H analytical calculation value: C, 39.83; H, 3.61; N, 9.29. measured value: C, 39.70; H, 3.57; N, 9.55.

26.2: cis-5 '-O-[4-(3, the 5-dichlorophenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-2-amino-7-denitrogenation-adenosine

R _f=0.2 (10%MeOH is in EtOAc).C ₂₁H ₂₄Cl ₂N ₅O ₇P.1.0H ₂O.0.25CH ₃OH analytical calculation value: C, 43.53; H, 4.64; N, 11.94. measured value: C, 43.50; H, 4.25; N, 11.55.

26.3: cis-5 '-O-[4-(3-pyridine radicals)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-2-amino-7-denitrogenation-adenosine.

R _f=0.2 (15%MeOH is at CH ₂Cl ₂In).Analytical calculation value C ₂₀H ₂₅N ₆O ₇P.1.2H ₂O:C, 46.73; H, 5.37; N, 16.35. measured value: C, 46.41; H, 5.02; N, 16.14.

26.4: cis-5 '-O-[6-(2, the 3-difluorophenyl)-4,4-dimethyl-1,2,3-two oxa-s-2-oxo-phospha cyclohexane-2-yl]-2 '-C-methyl-2-amino-7-denitrogenation-adenosine.

R _f=0.40 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).Analytical calculation value C ₂₃H ₂₈F ₂N ₅O ₇P.0.8H ₂O:C, 48.47; H, 5.24; N, 12.29. measured value: C, 48.67; H, 5.39; N, 11.94.

26.5: cis-5 '-O-[4-(2, the 3-difluorophenyl)-1,2,3-two oxa-s-2-oxo-phospha cyclohexane-2-yl]-2 '-C-methyl-2-amino-7-denitrogenation-adenosine.

R _f=0.60 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).C ₂₁H ₂₄F ₂N ₅O ₇P.1.0H ₂O analytical calculation value: C, 46.24; H, 4.80; N, 12.84. measured value: C, 46.12; H, 4.87; N, 12.63.

26.6: cis-5 '-O-(4,4-dimethyl-6-phenyl-1,2,3-two oxa-s-2-oxo-phospha cyclohexane-2-yl)-2 '-C-methyl-2-amino-7-denitrogenation-adenosine.

R _f=0.64 (15%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).C ₂₃H ₃₀N ₅O ₇P.0.8H ₂O analytical calculation value: C, 51.74; H, 5.97; N, 13.12. measured value: C, 51.91; H, 5.90; N, 12.75.

26.7: cis-5 '-[4-(4-(S)-pyridine radicals)-1,2,3-two oxa-s-2-oxo-phospha cyclohexane-2-yl]-2 '-C-methyl-2-amino-7-denitrogenation-adenosine.

R _f=0.3 (20%MeOH is at CH ₂Cl ₂-1%NH ₄Among the OH).C ₂₀H ₂₅N ₆O ₇P.1.3H ₂O.1.1CF ₃CO ₂H analytical calculation value: C, 41.58; H, 4.51; N, 13.11. measured value: C, 41.14; H, 4.10; N, 13.59.

Embodiment 27:

27.1:2,4-diaminourea-5-fluoro-7-[5 '-(4-(S)-cis-and trans-(3-chlorphenyl)-1,3-two oxa-s-2-oxo phospha cyclohexane-2-yl)-2 '-C-methyl-β-D-ribofuranosyl] pyrrolo-[2,3-d] pyrimidine.

The preparation of prodrug is as described in embodiment 18 steps A and the B.

MH ⁺Analytical calculation value C ₂₁H ₂₄ClFN ₅O ₇P:544. measured value: 544.

Embodiment 28:

Synthesizing as described in example 21 above of prodrug

Form the general procedure of N6-carbamate: (Bioorg.Med.Chem.8:1697 (2000).

In 0 ℃ in 15 minutes to the drips of solution of prodrug (1mmol) in anhydrous THF (6mL) and pyridine (4mL) add chloro-carbonic acid n-pentyl ester (0.37mL, 2mmol).Mixture is warming to room temperature and stirs 30min again, use methyl alcohol (3mL) quencher reaction afterwards.The concentrating under reduced pressure reactant mixture is used the purification by silica gel column chromatography product then.

28.1: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,3,2-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N-6-just-amyl group carbamoyl-adenosine trifluoroacetic acid.

R _f=0.6 (5%MeOH is at CH ₂Cl ₂In).C ₂₆H ₃₃N ₅O ₉ClP.0.8CF ₃CO ₂H analytical calculation value: C, 46.22; H, 4.75; N, 9.76. measured value: C, 46.00; H, 4.84; N, 9.97.

Embodiment 29:

Synthesizing as described in example 21 above of two kinds of prodrugs.Form L-valine ester by operation described in subsequent embodiment 24 steps A and the B.

29.1: cis-(S)-5 '-[4-(4-pyridine radicals)-1,3-two oxa-s-2-oxo phospha cyclohexane-2-yl]-3 '-O-L-valyl base-2 '-C-methyladenosine trifluoroacetate

R _f=0.15 (25%MeOH is at CH ₂Cl ₂In).C ₂₄H ₃₂N ₇O ₈P.1.7H2O.3.0CF ₃CO ₂H.0.1C ₂H ₅O ₂Analytical calculation value: C, 37.92; H, 4.07; N, 10.32. measured value: C, 37.65; H, 3.72; N, 9.87.

29.2: cis-(S)-5 '-[4-(3-chlorphenyl)-1,3-two oxa-s-2-oxo phospha cyclohexane-2-yl]-3 '-O-L-valyl base-2 '-C-methyladenosine trifluoroacetate

R _f=0.4 (15%MeOH is at CH ₂Cl ₂In).C ₂₅H ₃₂N ₆O ₈C1P.1.2H ₂O.2.0CF ₃CO ₂H analytical calculation value: C, 40.47; H, 4.26; N, 9.76. measured value: C, 40.03; H, 4.33; N, 10.19.

Embodiment 30:

The preparation of 5 '-Monophosphate prodrug is as described in the embodiment 21.Embodiment 23 described operations are followed in the preparation of 2 ', 3 '-carbonic ester.

30.1: cis-5 '-O-[4-(S)-(4-pyridine radicals)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine.

R _f=0.4 (15%MeOH is at CH ₂Cl ₂In).C ₂₁H ₂₁N ₅O ₈ClP.1.0H ₂O analytical calculation value: C, 45.38; H, 4.17; N, 12.60. measured value: C, 45.21; H, 3.97; N, 12.41.

30.2: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine.

R _f=0.45 (10%MeOH is at CH ₂Cl ₂In).C ₂₁H ₂₁N ₅O ₈ClP.1.0H ₂O analytical calculation value: C, 45.38; H, 4.17; N, 12.60. measured value: C, 45.21; H, 3.97; N, 12.41.

30.3: cis-5 '-O-[4-(3-fluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine.

R _f=0.6 (10%MeOH is at CH ₂Cl ₂In).C ₂₁H ₂₁N ₅O ₈FP.0.7CH ₂Cl ₂Analytical calculation value: C, 44.87; H, 3.89; N, 12.06. measured value: C, 44.67; H, 3.86; N, 12.01.

30.4: cis-5 '-O-[4-(2, the 3-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine

R _f=0.35 (10%MeOH is at CH ₂Cl ₂In).C ₂₁H ₂0N ₅O ₈F ₂P.1.0H ₂O analytical calculation value: C, 45.25; H, 3.98; N, 12.56. measured value: C, 44.88; H, 3.74; N, 12.47.

30.5: cis-5 '-O-[6-(3-chlorphenyl)-4,4-dimethyl-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine.

R _f=0.42 (10%MeOH is at CH ₂Cl ₂In).C ₂₃H ₂₅ClN ₅O ₈P.1.0H ₂O analytical calculation value: C, 47.31; H, 4.66; N, 11.99. measured value: C, 47.15; H, 4.83; N, 11.95.

30.6: cis-5 '-O-[4,4-dimethyl-6-phenyl-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine.

R _f=0.50 (10%MeOH is at CH ₂Cl ₂In).C ₂₃H ₂₆N ₅O ₈P.0.5H ₂O analytical calculation value: C, 51.11; H, 5.04; N, 12.96. measured value: C, 51.16; H, 5.28; N, 13.09.

30.7: cis-5 '-O-[4-(3, the 4-dichlorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-2-base-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine.

R _f=0.35 (10%MeOH is at CH ₂Cl ₂In).C ₂₁H ₂₀Cl ₂N ₅O ₈P analytical calculation value: C, 44.07; H, 3.52; N, 12.39. measured value: C, 43.68; H, 3.90; N, 12.43.

30.8: cis-5 '-O-[4-(3, the 5-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine

R _f=0.40 (10%MeOH is at CH ₂Cl ₂In).C ₂₁H ₂₀F ₂N ₅O ₈P.1.5H ₂O analytical calculation value: C, 44.53; H, 4.09; N, 12.36. measured value: C, 44.31; H, 3.75; N, 12.18.

30.9: cis-5 '-O-[6-(3, the 5-difluorophenyl)-4,4-dimethyl-2-oxo-1,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine.

R _f=0.39 (10%MeOH is at CH ₂Cl ₂In).C ₂₃H ₂₄F ₂N ₅O ₈P.0.3CH ₂Cl ₂Analytical calculation value: C, 47.20; H, 4.18; N, 11.81. measured value: C, 47.56; H, 3.84; N, 11.51.

30.10: cis-5 '-O-[6-(2, the 3-difluorophenyl)-4,4-dimethyl-2-oxo-1,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine.

R _f=0.35 (5%MeOH is at CH ₂Cl ₂In).Analytical calculation value C ₂₃H ₂₄F ₂N ₅O ₈P.0.6H ₂O:C, 47.77; H, 4.39; N, 12.11. measured value: C, 47.30; H, 3.92; N, 11.90.

30.11: cis-5 '-O-[6-(3, the 4-dichlorophenyl)]-4,4-dimethyl-2-oxo 1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine.

R _f=0.45 (10%MeOH is at CH ₂Cl ₂In).MH ⁺Analytical calculation value C ₂₃H ₂₄Cl ₂N ₅O ₈P:601. measured value: 601.

30.12: cis-5 '-O-[6-(3-fluorophenyl)-4,4-dimethyl-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine.

R _f=0.4 (5%MeOH is at CH ₂Cl ₂In).C ₂₃H ₂₅N ₅O ₈FP.0.4H ₂O analytical calculation value: C, 49.63; H, 4.67; N, 12.58. measured value: C, 49.43; H, 4.60; N, 12.71.

30.13: cis-5 '-O-[6-(pyridin-4-yl)-4,4-dimethyl-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine.

R _f=0.32 (10%MeOH is at CH ₂Cl ₂In).C ₂₂H ₂₅N ₆O ₈P.2.0H ₂O analytical calculation value: C, 46.48; H, 5.14; N, 14.78. measured value: C, 46.30; H, 4.80; N, 14.56.

30.14: cis-5 '-O-[4-(3, the 5-dichlorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine

R _f=0.3 (10%MeOH is in EtOAc).Analytical calculation value C ₂₁H ₂₀ClN ₅O ₈P.1.0H ₂O.0.5 imidazoles: C, 43.28; H, 3.87; N, 13.46. measured value: C, 43.28; H, 3.92; N, 13.79.

30.15: cis-5 '-O-[6-(3, the 5-dichlorophenyl)-4,4-dimethyl-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine.

R _f=0.3 (5%MeOH is in EtOAc).C ₂₃H ₂₄Cl ₂N ₅O ₈P analytical calculation value: C, 46.02; H, 4.03; N, 11.67. measured value: C, 45.39; H, 3.10; N, 10.79.

30.16: cis-5 '-O-[6-(5-bromo-2,3-difluorophenyl)-4,4-dimethyl-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine.

R _f=0.5 (10%MeOH is at CH ₂Cl ₂In).C ₂₃H ₂₃BrF ₂N ₅O ₈P.1.2CH ₂Cl ₂Analytical calculation value: C, 38.85; H, 3.42; N, 9.36. measured value: C, 38.51; H, 3.38; N, 9.66.

30.17: cis-5 '-O-[4-(5-bromo-pyridin-4-yl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-C-methyladenosine trifluoroacetate.

R _f=0.30 (10%MeOH is at CH ₂Cl ₂In).C ₂₀H ₂₀N ₆O ₈BrP.0.9H ₂O.1.0CF ₃CO ₂H analytical calculation value: C, 37.03; H, 3.22; N, 11.78. measured value: C, 36.68; H, 3.11; N, 12.15.

Embodiment 31: the universal method for preparing 2 ', 3 '-carbonic acid ester derivative of nucleosides by the nucleosides of 5 '-protection.

Steps A:

In the solution of nucleosides (0.5mmol) in DMF (5mL), add imidazoles (1.5mmol) at 0 ℃, add tert-butyldimethylsilyl chloride (0.6mmol) subsequently.Reaction is warming to room temperature and stirs 3h.The reduction vaporization mixture.Residue CH ₂Cl ₂Extract, washing is also dry.The evaporation organic extract, product passes through column chromatography purification.

Step B:

In the solution of nucleosides (0.25mmol) in DMF (2.5mL) of 5 '-t-butyldimethylsilyl oxygen base protection, add carbonyl dimidazoles (CDI) (0.5mmol) at 0 ℃.Reaction is warming to room temperature and stirs 3h.Removal of solvent under reduced pressure and chromatography crude product obtain solid 2 ', 3 '-carbonic ester.

Step C:

With the nucleosides-2 ' of 5 '-t-butyldimethylsilyl oxygen base protection, 3 '-carbonic ester (0.15mmol) is dissolved in the pre-cooled 75%TFA aqueous solution (3mL) and at 0 ℃ and stirs 2h.The reduction vaporization reactant mixture.By flash chromatography purifying crude product.

31.1:8-bromo-2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine.

R _f=0.65 (10%MeOH is at CH ₂Cl ₂In).C ₁₂H ₁₂N ₅O ₅Br.0.2CH ₃OH analytical calculation value: C, 37.33; H, 3.29; N, 17.84. measured value: C, 37.48; H, 3.37; N, 17.45.

31.2:4-amino-7-(2 ', 3 '-O-carbonyl-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo-[2,3-d] pyrimidine trifluoroacetate.

R _f=0.5 (10%MeOH is at CH ₂Cl ₂In).C ₁₃H ₁₄N ₄O ₅.1.0H ₂O.2.0CF ₃CO ₂H analytical calculation value: C, 36.97; H, 3.28; N, 10.14. measured value: C, 37.18; H, 3.10; N, 9.80.

31.3:2 ', 3 '-O-carbonyl-2 '-C-methyl cytidine trifluoroacetate.

R _f=0.2 (10%MeOH is at CH ₂Cl ₂In).C ₁₁H ₁₃N ₃O ₆.0.8H ₂O.0.9CF ₃CO ₂H analytical calculation value: C, 38.41; H, 3.90; N, 10.50. measured value: C, 38.14; H, 3.72; N, 10.77.

31.4:2 ', 3 '-O-carbonyl-2 '-the C-methylinosine.

R _f=0.25 .C in the 20%MeOH-carrene ₁₂H ₁₂N ₄O ₆.0.3CF ₃CO ₂H.0.1C ₂H ₅O analytical calculation value: C, 45.02; H, 3.88; N, 16.28. measured value: C, 44.63; H, 3.65; N, 16.15

31.5:2 ', 3 '-O-carbonyl-2 '-the C-methyladenosine.

R _f=0.5 (10%MeOH is at CH ₂Cl ₂In).C ₁₂H ₁₃N ₅O ₅.0.7CF ₃CO ₂H analytical calculation value: C, 41.58; H, 3.57; N, 18.09. measured value: C, 41.26; H, 3.42; N, 18.02.

31.6:2 ', 3 '-O-carbonyl-2 '-the C-methylguanosine.

R _f=0.1 (10%MeOH is at CH ₂Cl ₂In).R _f=0.25 (10%MeOH is at CH ₂Cl ₂In).C ₁₂H ₁₃N ₅O ₆.0.2CF ₃CO ₂H analytical calculation value: C, 43.04; H, 3.84; N, 20.24. measured value: C, 43.15; H, 3.86; N, 20.52.

31.7:2 ', 3 '-O-carbonyl-4 '-C-methyl cytidine.

R _f=0.45 (15%MeOH is at CH ₂Cl ₂In).C ₁₁H ₁₃N ₃O ₆.0.8CF ₃CO ₂H analytical calculation value: C, 40.42; H, 3.71; N, 11.22. measured value: C, 40.26; H, 3.77; N, 11.60.

Embodiment 32: the universal method for preparing nucleosides 2 ', 3 '-carbonic acid ester derivative by single pot process (single-pot) 5 '-protection and 2 ', 3 '-carbonylation.

Steps A:

In the solution of nucleosides (0.5mmol) in DMF (5mL), add imidazoles (1.5mmol) at 0 ℃, follow by tert-butyldimethylsilyl chloride (0.6mmol).Reaction is warming to room temperature and stirs 3h.In case all consumption of raw materialss finish, just carbonyl dimidazoles (CDI) (0.6mmol) is added in the reaction at 0 ℃.Then reactant is warming to room temperature and stirs 3h again.The reduction vaporization reactant.Mixture CH ₂Cl ₂Extract, washing is also dry.Evaporation organic extract and product pass through chromatographic purifying.

Step B:

With embodiment 31 step C.

32.1:2,4-diaminourea-7-(2 ', 3 '-O-carbonyl-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo--[2,3-d] pyrimidine.

R _f=0.4 (10%MeOH is at CH ₂Cl ₂In).C ₁₃H ₁₅N ₅O ₅.0.6CF ₃CO ₂H analytical calculation value: C, 43.77; H, 4.03; N, 17.99. measured value: C, 43.51; H, 3.97; N, 17.60.

Embodiment 33: a step synthesis procedure of 2 ', 3 '-carbonic ester of nucleosides

Embodiment 31.5 is also by following operation preparation.

To 2 '-the C-methyladenosine (28mg, 0.1mmol) add in the solution in DMF (2mL) dipheryl carbonate base ester (32mg, 0.15mmol).Under microwave condition, in sealed tube, reaction is heated to 250 ℃ of lasting 5min.The concentrating under reduced pressure mixture also is used in CH ₂Cl ₂Middle 5-10%MeOH elution chromatography obtains the required product of 13mg.

Embodiment 34: the general procedure for preparing the NMP prodrug from 2 ', 3 '-carbonic ester of nucleosides.

Adding tert-butyl group chlorination magnesium and reactant mixture stir 30min under nitrogen in the solution of 2 ', 3 '-carbonic ester (0.25mmol) in DMF (1.5mL) of nucleosides.Then reactant mixture is cooled to-55 ℃, and the phosphorylation agent (preparing) among the dropping DMF (1.5mL) (0.35mmol) described in embodiment 14b and 15a.Reaction is warming to stirring 2h under room temperature and the nitrogen.Reduction vaporization reactant mixture and use saturated NH ₄The quencher of the Cl aqueous solution.Be used in CH ₂Cl ₂Middle 10%MeOH extracts mixture, and washing is also dry.Evaporation organic extract and product pass through chromatographic purifying.

34.1:2,4-diaminourea-7-[(cis-5 '-O-4-(S)-(3-chlorphenyl)-2-oxo-1,3-two oxa-phosphorus heterocycles oneself-the 2-yl)-2 ', 3 '-O-carbonyl-2 '-C-methyl-β-D-ribofuranosyl]-7H-pyrrolo--[2,3-d] pyrimidine trifluoroacetate.

R _f=0.6 (10%MeOH is at CH ₂Cl ₂In).C ₂₂H ₂₃N ₅O ₈ClP.1.1CF ₃CO ₂H analytical calculation value: C, 42.92; H, 3.59; N, 10.34. measured value: C, 42.49; H, 3.37; N, 10.23.

34.2:2,4-diaminourea-7-(cis-5 '-O-[4-(S)-(pyridin-4-yl)-2-oxo-1,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-carbonyl-2 '-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo--[2,3-d] pyrimidine trifluoroacetate.

R _f=0.4 (15%MeOH is at CH ₂Cl ₂In).C ₂₁H ₂₃N ₆O ₈P.2.3CF ₃CO ₂H analytical calculation value: C, 39.39; H, 3.27; N, 10.77. measured value: C, 39.97; H, 2.96; N, 10.70.

Embodiment 35

As Carbohyd.Res., the described preparation 2 ' of 166:219-232 (1987)-C-methyl cytidine.

N4-dimethylamino methylene-2 ', the general procedure that the prodrug of 2 '-C-methyl-cytidine of 3 '-isopropylidene protection forms:

Steps A:

Operation as the steps A of embodiment 16 is converted into corresponding 2 ', 3 '-acetonide with 2 '-C-methyl cytidine

Step B:

2 ', 3 '-acetonide of 2 '-C-methyl cytidine in pyridine (30mL) (1.4g 4.71mmol) adds N in the solution, and the dinethylformamide dimethyl ketal (0.8mL, 5.87mmol).Spend the night at the stirring at room reactant.Concentrating under reduced pressure mixture then.The chromatography crude product obtains dimethylamino methylene addition product on the silicagel column of 5%MeOH wash-out in carrene.

Step C:

Adopt as the operation among the embodiment 16 step B and carry out prodrug formation.By the trans phosphorylation agent that adopts among the operation synthesis step C described in embodiment 11,14 and 15.

Step D:

The prodrug (0.15g) of the amine protection that will obtain from above-mentioned steps is dissolved in the 75%TFA/H of precooling ₂Among the O (10mL) and allow to stir 8h at 0 ℃.The reduction vaporization reactant mixture.By flash chromatography (1%NH ₄The OH aqueous solution is at CH ₂Cl ₂In 10%MeOH in) the purifying crude product obtains the deprotection prodrug of pale solid.

35.1: cis-5 '-O-[4-(S)-(pyridin-4-yl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl cytidine trifluoroacetate.

R _f=0.2 (10%MeOH is at CH ₂Cl ₂In).MH ⁺Analytical calculation value C ₁₈H ₂₃N ₄O ₈P:455. measured value: 455.

35.2: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl cytidine trifluoroacetate.

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).C ₁₉H ₂₃N ₃O ₈ClP.0.5H ₂O.0.3CF ₃CO ₂H analytical calculation value: C, 44.33; H, 4.61; N, 7.91. measured value: C, 44.39; H, 4.42; N, 7.84.

35.3: cis-5 '-O-[4-(3-bromophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl cytidine trifluoroacetate.

R _f=0.38 (15%MeOH is at CH ₂Cl ₂In).C ₁₉H ₂₃N ₃O ₈BrP.1.4CF ₃CO ₂H analytical calculation value: C, 37.84; H, 3.55; N, 6.07. measured value: C, 37.73; H, 3.60; N, 6.21.

35.4: cis-5 '-O-[4-(3, the 5-dichlorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl cytidine trifluoroacetate.

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).C ₁₉H ₂₂N ₃O ₈Cl ₂P.0.4CF ₃CO ₂H analytical calculation value: C, 41.88; H, 3.98; N, 7.40. measured value: C, 42.14; H, 3.61; N, 7.59.

35.5: cis-5 '-O-[4-(3, the 5-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl cytidine trifluoroacetate.

R _f=0.26 (10%MeOH is at CH ₂Cl ₂In).C ₁₉H ₂₂N ₃O ₈F ₂P.0.7CF ₃CO ₂H analytical calculation value: C, 43.05; H, 4.02; N, 7.38. measured value: C, 42.79; H, 4.17; N, 7.48.

35.6: cis-5 '-O-[4-(S)-(3, the 5-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl cytidine

Present embodiment is by 2 '-C-methyl cytidine and (-)-(4S)-trans-4-(3, the 5-difluorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes prepare.

35.7: cis-5 '-O-[4-(R)-(3, the 5-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl cytidine

This embodiment is by 2 '-C-methyl cytidine and (+)-(4R)-trans-4-(3, the 5-difluorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3, and 2-two oxa-phospha cyclohexanes prepare.

35.8: cis-5 '-O-[4-(pyridin-3-yl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl cytidine.

R _f=0.25 (10%MeOH is at CH ₂Cl ₂In).C ₁₈H ₂₃N ₄O ₈P.0.1CF ₃CO ₂H.1.3H ₂O analytical calculation value: C, 44.69; H, 5.30; N, 11.45. measured value: C, 44.89; H, 5.22; N, 11.11.

35.9: cis-5 '-O[-4-(3-fluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-cytidine trifluoroacetate

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).C ₁₉H ₂₃N ₃O ₈FP.1.0CF ₃CO ₂H analytical calculation value: C, 43.09; H, 4.13; N, 7.18. measured value: C, 42.99; H, 4.42; N, 7.35.

35.10: cis-5 '-O-[4,4-dimethyl-6-(2, the 3-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl cytidine trifluoroacetate.

R _f=0.32 (10%MeOH is at CH ₂Cl ₂In).C ₂₁H ₂₆N ₃O ₈F ₂P.1.0CF ₃CO ₂H.1.6H ₂O analytical calculation value: C, 39.60; H, 4.21; N, 5.68. measured value: C, 39.28; H, 4.25; N, 5.62.

35.11: cis-5 '-O-[4-(2-pyridine radicals)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl cytidine trifluoroacetate.

R _f=0.15 (20%MeOH is at CH ₂Cl ₂In).MH ⁺Analytical calculation value C ₁₉H ₂₃ClN ₃O ₈P:455. measured value: 455.

35.12: cis-5 '-O-[4-(2-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-cytidine

R _f=0.15 (20%MeOH is at CH ₂Cl ₂In).MH ⁺Analytical calculation value C ₁₉H ₂₃ClN ₃O ₈P:488. measured value: 488.

35.13: cis-5 '-O-[4-(2, the 5-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl cytidine trifluoroacetate.

R _f=0.18 (20%MeOH is at CH ₂Cl ₂In).C ₁₉H ₂₂N ₃O ₈F ₂P.1.0CF ₃CO ₂H analytical calculation value: C, 41.80; H, 3.84; N, 6.96. measured value: C, 41.48; H, 3.82; N, 7.26.

35.14: cis-5 '-O-[4-(2-bromophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-cytidine trifluoroacetate.

R _f=0.25 (20%MeOH is at CH ₂Cl ₂In).C ₁₉H ₂₃N ₃O ₈BrP.1.4CF ₃CO ₂H.0.2C ₂H ₅O analytical calculation value: C, 38.41; H, 3.77; N, 5.95. measured value: C, 38.24; H, 3.65; N, 6.23.

35.15: cis-5 '-O-[4-(2, the 3-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-cytidine trifluoroacetate.

R _f=0.2 (20%MeOH is at CH ₂Cl ₂In).C ₁₉H ₂₂N ₃O ₈F ₂P.1.2CF ₃CO ₂H analytical calculation value: C, 41.05; H, 3.73; N, 6.71. measured value: C, 40.79; H, 3.88; N, 7.03.

35.16: cis-5 '-O-[4-(2-trifluoromethyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl cytidine trifluoroacetate.

R _f=0.3 (20%MeOH is at CH ₂Cl ₂In).Analytical calculation value C ₂₀H ₂₃N ₃O ₈F ₃P.1.2CF ₃CO ₂H:C, 40.88; H, 3.71; N, 6.38. measured value: C, 40.77; H, 3.54; N, 6.59.

35.17: cis-5 '-O-[4-(3-bromopyridine-5-yl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-cytidine trifluoroacetate.

R _f=0.15 (20%MeOH is at CH ₂Cl ₂In).C ₁₈H ₂₂N ₄O ₈BrP.1.2CF ₃CO ₂H analytical calculation value: C, 36.57; H, 3.49; N, 8.36. measured value: C, 36.07; H, 3.48; N, 8.89.

35.18: cis-5 '-O-[4-(5-bromo-2-fluoro-phenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl cytidine trifluoroacetate.

R _f=0.25 (10%MeOH is at CH ₂Cl ₂In).C ₁₉H ₂₂N ₃O ₈BrFP.1.7CF ₃CO ₂H analytical calculation value: C, 36.16; H, 3.21; N, 5.65. measured value: C, 35.88; H, 2.87; N, 5.76.

Embodiment 36:

Follow embodiment 23 described operations and carry out 2 ', 3 '-carbonylation of 35.1.

36.1: cis-5 '-O-[4-(S)-(pyridin-4-yl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-C-methyl cytidine trifluoroacetate.

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).C ₁₉H ₂₁N ₄O ₉P.1.7H ₂O.2.0CF ₃CO ₂H analytical calculation value: C, 37.38; H, 3.60; N, 7.58. measured value: C, 37.17; H, 3.23; N, 7.97.

36.2: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-C-methyl cytidine.

R _f=0.35 (10%MeOH is at CH ₂Cl ₂In).Analytical calculation value C ₂₀H ₂₁N ₃O ₉ClP.0.2CF ₃CO ₂H.1.4H ₂O.1.6 imidazoles: C, 45.23; H, 4.34; N, 12.98. measured value: C, 45.11; H, 4.12; N, 13.31.

36.3: cis-5 '-O-[4-(3, the 5-dichlorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-C-methyl cytidine.

R _f=0.35 (10%MeOH is at CH ₂Cl ₂In).C ₂₀H ₂₀N ₃O ₉Cl ₂P.1.0H ₂O analytical calculation value: C, 42.42; H, 3.92; N, 7.42. measured value: C, 42.59; H, 3.71; N, 7.47.

36.4: cis-5 '-O-[4-(3, the 5-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-C-methyl cytidine.

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).Analytical calculation value C ₂₀H ₂₀N ₃O ₉F ₂P.0.4H ₂O.1.2 imidazoles: C, 46.91; H, 4.27; N, 12.52. measured value: C, 46.66; H, 3.93; N, 12.74.

36.5: cis-5 '-O-[4,4-dimethyl-6-(2, the 3-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl] 2 ', 3 '-O-carbonyl-2 '-C-methyl cytidine.

R _f=0.45 (10%MeOH is at CH ₂Cl ₂In).Analytical calculation value C ₂₂H ₂₄N ₃O ₉P.0.1CH ₂Cl ₂.0.5H ₂O:C, 47.78; H, 4.46; N, 7.56. measured value: C, 47.87; H, 4.82; N, 7.52.

Embodiment 37:

As Biosci.Biotech.Biochem., the described preparation 4 ' of 57:1433-1438 (1993)-C-methyl cytidine.

2 ', 3 '-carbonic ester of 4 '-C-methyl cytidine synthesizes and as embodiment 34 preparations 5 '-Monophosphate prodrug by embodiment 31 is described.

37.1: cis-5 '-O-[4-(S)-(4-pyridine radicals)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-4 '-C-methyl cytidine.

R _f=0.45, in 40%MeOH-acetone.MH ⁺Analytical calculation value C ₁₉H ₂₁N ₄O ₉P:481. measured value: 481.

37.2 cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-4 '-C-methyl cytidine.

R _f=0.3, in the 20%MeOH-carrene.MH ⁺Analytical calculation value C ₂₀H ₂₁N ₃O ₉ClP:514. measured value: 514.

Embodiment 38

Steps A:

As described in steps A, B and the C of embodiment 35, prepare N ⁴The prodrug of-dimethylamino methylene and the protection of 2 ', 3 '-isopropylidene.

General post processing comes selectivity to remove N4-dimethylamino methylene blocking group in prodrug formation (step C) by following.

With excessive saturated aqueous ammonium chloride quencher reactant mixture and stir 3h.The concentrating under reduced pressure mixture also extracts with 20% methyl alcohol-carrene then.Wash organic extract and dry with water.Evaporation and column chromatography to residue obtain the prodrug that 2 ' 3 ' pure-isopropylidene is protected.

Step B:

The N that is used for the prodrug of 2 ' 3 '-isopropylidene protection ⁴The general procedure that-carbamate forms:

In carrene (5mL) solution of the prodrug (0.5mmol) that 2 ', the 3 '-isopropylidene that is cooled to 0 ℃ in ice bath is protected, add triethylamine (0.75mmol) and commercially available carbonochloridic acid ester reactant (0.6mmol).Reactant mixture is warming to room temperature and stirs 16h, concentrate then and remove carrene.By the column chromatography purification residue on silica gel.

From corresponding alcohol by following the known procedure (Helv.Chim.Acta.78 (2): 447 (1995)) prepare the commercial carbonochloridic acid ester reactant that can not obtain that describes the document.

Step C:

The N of the prodrug of 2 ' 3 '-isopropylidene protection that will as above obtain by the described operation of the step D that follows embodiment 35 ⁴-carbamate deprotection.

38.1: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(just-and amyl group oxygen base carbonyl) cytidine.

R _f=0.65 (10%MeOH is at CH ₂Cl ₂In).C ₂₅H ₃₃N ₃O ₁₀ClP.0.2CH ₂Cl ₂.0.5H ₂O analytical calculation value: C, 49.14; H, 5.46; N, 6.84. measured value: C, 48.97; H, 5.26; N, 6.80.

38.2: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(propyl group-2-oxygen base carbonyl) cytidine.

R _f=0.35 (10%MeOH is at CH ₂Cl ₂In).C ₂₃H ₂₉N ₃O ₁₀ClP.0.2CF ₃CO ₂H analytical calculation value: C, 47.10; H, 4.93; N, 7.04. measured value: C, 46.89; H, 4.89; N, 7.01.

38.3: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(benzyl oxygen base carbonyl) cytidine.

R _f=0.35 (10%MeOH is at CH ₂Cl ₂In).C ₂₇H ₂₉N ₃O ₁₀ClP.0.8H ₂O analytical calculation value: C, 50.96; H, 4.85; N, 6.60. measured value: C, 51.02; H, 5.04; N, 6.48.

38.4: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-[(-) menthyl oxygen base carbonyl] cytidine.

R _f=0.35 (10%MeOH is at CH ₂Cl ₂In).C ₃₀H ₄₁N ₃O ₁₀ClP.0.6H ₂O analytical calculation value: C, 52.92; H, 6.25; N, 6.17. measured value: C, 52.71; H, 5.98; N, 5.99.

38.5: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(ethyl oxygen base carbonyl) cytidine.

R _f=0.35 (10%MeOH is at CH ₂Cl ₂In).Analytical calculation value C ₂₂H ₂₇N ₃O ₁₀ClP.0.6H ₂O:C, 46.30; H, 4.98; N, 7.36. measured value: C, 46.25; H, 4.84; N, 7.20.

38.6: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-[2,2-(dimethyl) propyl group oxygen base carbonyl] cytidine.

R _f=0.35 (10%MeOH is at CH ₂Cl ₂In).C ₂₅H ₃₃N ₃O ₁₀ClP.0.2CF ₃CO ₂H analytical calculation value: C, 48.83; H, 5.36; N, 6.73. measured value: C, 48.68; H, 4.98; N, 6.61.

38.7: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(cyclopentyloxy carbonyl) cytidine.

R _f=0.35 (10%MeOH is at CH ₂Cl ₂In).C ₂₅H ₃₃N ₃O ₁₀ClP.0.2CF ₃CO ₂H analytical calculation value: C, 48.99; H, 5.05; N, 6.75. measured value: C, 49.01; H, 4.97; N, 6.88.

38.8: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-[2-(benzyl oxygen base) ethyl oxygen base carbonyl] cytidine.

R _f=0.30 (10%MeOH is at CH ₂Cl ₂In).C ₂₉H ₃₃N ₃O ₁₁ClP.0.3CF ₃CO ₂H analytical calculation value: C, 50.77; H, 4.79; N, 6.00. measured value: C, 50.66; H, 4.80; N, 6.17.

38.9: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(2-oxo-1,3-dioxane amyl group-4-base-methylene oxygen base carbonyl) cytidine.

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).C ₂₄H ₂₇N ₃O ₁₃ClP.0.7H ₂O analytical calculation value: C, 44.72; H, 4.44; N, 6.52. measured value: C, 44.52; H, 4.33; N, 6.41.

38.10: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(3-acetyl group oxygen base-2,2-dimethyl-propyl group oxygen base carbonyl) cytidine.

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).C ₂₇H ₃₅N ₃O ₁₂ClP analytical calculation value: C, 49.13; H, 5.35; N, 6.37. measured value: C, 48.89; H, 5.11; N, 6.08.

38.11: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-[2-(2-ethyl oxygen base-ethyoxyl)-ethyl oxygen base carbonyl) the cytidine trifluoroacetate.

R _f=0.25 (10%MeOH is at CH ₂Cl ₂In).C ₂₆H ₃₅N ₃O ₁₂ClP.1.0CF ₃CO ₂H.1.0H ₂O analytical calculation value: C, 43.11; H, 4.91; N, 5.39. measured value: C, 42.90; H, 4.69; N, 5.31.

38.12: cis-5 '-O-[4-(3, the 5-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(n-pentyl oxygen base carbonyl) cytidine.

R _f=0.25 (5%MeOH is at CH ₂Cl ₂In).C ₂₅H ₃₂N ₃O ₁₀F ₂P.1.0H ₂O analytical calculation value: C, 48.31; H, 5.51; N, 6.76. measured value: C, 48.28; H, 5.21; N, 6.68.

Embodiment 39

Cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-2 ', described in the preparation of 3 '-isopropylidene-cytidine such as embodiment 38 steps A.

Steps A:

From nitrobenzene chloro-formate reactant, the N of the prodrug of 2 ' 3 '-isopropylidene protection ⁴The general procedure that-methylene oxygen aminocarbamic acid ester forms:

Cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-2 ', 3 '-isopropylidene-cytidine (0.5mmol), (it prepares as J.Org.Chem. suitable chloro-carbonic acid nitrobenzophenone ester (0.5mmol), 62:1356 (1997) and J.Med.Chem.31:318 (1988) are described), and the mixture of diisopropyl ethyl amine (0.7mmol) in the THF of 20mL stir 16h, then with the EtOAc dilution and use saturated NaHCO ₃, the salt water washing, dry and evaporation is carried out silica gel column chromatography with residue and is obtained pure methylene oxygen aminocarbamic acid ester.

Step B:

The N of the prodrug of 2 ' the 3 '-isopropylidene protection that as above obtains ⁴-methylene oxygen aminocarbamic acid ester carries out deprotection by operation described in the embodiment 35 step D.

39.1: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(isobutyryl oxygen methylene oxygen base-carbonyl) cytidine.

R _f=0.15 (10%MeOH is at CH ₂Cl ₂In).C ₂₅H ₃₁N ₃O ₁₂ClP.0.1CF ₃CO ₂H.0.6H ₂O analytical calculation value: C, 46.27; H, 4.98; N, 6.42. measured value: C, 45.97; H, 5.24; N, 6.46.

39.2: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(benzyl acyloxy methylene oxygen base-carbonyl) cytidine.

R _f=0.15 (10%MeOH is at CH ₂Cl ₂In).C ₂₈H ₂₉N ₃O ₁₂ClP.0.3CF ₃CO ₂H analytical calculation value: C, 49.06; H, 4.22; N, 6.00. measured value: C, 48.83; H, 4.56; N, 6.30.

39.3: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(acetyl group oxygen methylene oxygen base-carbonyl) cytidine.

R _f=0.2 (10%MeOH is at CH ₂Cl ₂In).C ₂₃H ₂₇N ₃O ₁₂ClP.0.6CF ₃CO ₂H analytical calculation value: C, 43.23; H, 4.14; N, 6.25. measured value: C, 43.13; H, 4.16; N, 6.22.

Embodiment 40

Cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-2 ', the preparation of 3 '-isopropylidene-cytidine such as embodiment 38 steps A.

Steps A:

The N of the prodrug of 2 ' 3 '-isopropylidene protection of carrying out from acyl chlorides ⁴The general procedure that-acid amides forms:

To 2 ', the prodrug (0.5mmol) of 3 '-isopropylidene protection is to be cooled in the ice bath to add triethylamine (0.75mmol) and commercially available acyl chlorides (0.6mmol) in the solution in 0 ℃ the carrene (5mL).Reactant mixture is warming to room temperature and stirs 16h, concentrate then and remove carrene.By the purification by silica gel column chromatography residue.

The N of the prodrug of 2 ' 3 '-isopropylidene protection of carrying out from acid ⁴The general procedure that-acid amides forms:

To 2 '; add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.6mmol) in the solution of prodrug (0.3mmol) in dimethyl formamide (3mL) of 3 '-isopropylidene protection; I-hydroxybenzotriazole (0.65mmol), and acid (0.4mmol).Reactant mixture is warming to 40 ℃, stirs 16h, then cool to room temperature and the concentrated dimethyl formamide of removing.Then by the purification by silica gel column chromatography residue.

Step e:

Follow the N of operation described in the step D of embodiment 35 to the prodrug of 2 ' 3 '-isopropylidene protection ⁴-acid amides carries out deprotection.

40.1: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(4-fluorine benzyl acyl group) cytidine.

R _f=0.65 (10%MeOH is at CH ₂Cl ₂In).C ₂₆H ₂₆N ₃O ₉FClP.1.5H ₂O analytical calculation value: C, 49.03; H, 4.59; N, 6.60. measured value: C, 48.93; H, 4.47; N, 6.52.

40.2: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(octadecanoyl) cytidine.

R _f=0.7 (10%MeOH is at CH ₂Cl ₂In).C ₃₇H ₅₇N ₃O ₉ClP.0.6CF ₃CO ₂H analytical calculation value: C, 58.92; H, 7.62; N, 5.57. measured value: C, 58.61; H, 7.77; N, 5.36.

40.3: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(3,4,5-trimethoxy benzyl acyl group) cytidine.

R _f=0.52 (10%MeOH is at CH ₂Cl ₂In).C ₂₉H ₃₃N ₃O ₁₂ClP.0.3CF ₃CO ₂H analytical calculation value: C, 49.64; H, 4.69; N, 5.87. measured value: C, 49.63; H, 4.63; N, 5.79.

40.4: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(3-ethoxy carbonyl-propiono) cytidine.

R _f=0.49 (10%MeOH is at CH ₂Cl ₂In).C ₂₅H ₃₁N ₃O ₁₁ClP.0.2CF ₃CO ₂H analytical calculation value: C, 47.76; H, 4.92; N, 6.58. measured value: C, 47.64; H, 5.11; N, 6.52.

40.5: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(heptanoyl group) cytidine.

R _f=0.6 (10%MeOH is at CH ₂Cl ₂In).C ₂₆H ₃₅N ₃O ₉ClP.0.5CF ₃CO ₂H analytical calculation value: C, 49.36; H, 5.45; N, 6.40. measured value: C, 49.64; H, 5.33; N, 6.36.

40.6: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(pentamethylene carbonyl) cytidine trifluoroacetate.

R _f=0.45 (10%MeOH is at CH ₂Cl ₂In).C ₂₅H ₃₁N ₃O ₉ClP.0.6CF ₃CO ₂H analytical calculation value: C, 48.24; H, 4.88; N, 6.44. measured value: C, 48.07; H, 4.81; N, 6.39.

40.7: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(3,5-dimethoxy benzyl acyl group) cytidine.

R _f=0.45 (10%MeOH is at CH ₂Cl ₂In).Analytical calculation value C ₂₈H ₃₁N ₃O ₁₁ClP.0.3CF ₃CO ₂H:C, 50.06; H, 4.60; N, 6.12. measured value: C, 49.92; H, 4.23; N, 6.00.

40.8: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(benzyl acyl group) cytidine

R _f=0.56 (10%MeOH is at CH ₂Cl ₂In).C ₂₆H ₂₇N ₃O ₉ClP. analytical calculation value: C, 52.76; H, 4.60; N, 7.10. measured value: C, 52.55; H, 4.58; N, 6.82.

40.9: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(3,5-benzyl dichloride acyl group) cytidine.

R _f=0.5 (10%MeOH is at CH ₂Cl ₂In).Analytical calculation value C ₂₆H ₂₅N ₃O ₉Cl ₃P.0.15CF ₃CO ₂H:C, 46.60; H, 3.74; N, 6.20. measured value: C, 46.77; H, 3.45; N, 5.95.

40.10: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(tert-butyl group-2-oxo-1,3-two oxa-s penta cyclenes-4 bases-carbonyl) cytidine.

R _f=0.4 (10%MeOH is at CH ₂Cl ₂In).C ₂₇H ₃₁N ₃O ₁₂ClP.0.5CH ₂Cl ₂Analytical calculation value: C, 47.29; H, 4.62; N, 6.02. measured value: C, 47.44; H, 4.48; N, 5.75.

40.11: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴-(nicotinoyl base) cytidine trifluoroacetate.

R _f=0.6 (10%MeOH is at CH ₂Cl ₂In).C ₂₅H ₂₆N ₄O ₉ClP.3.8CF ₃CO ₂H analytical calculation value: C, 38.16; H, 2.93; N, 5.46. measured value: C, 38.04; H, 2.78; N, 5.72.

Embodiment 41

Steps A:

Follow the prodrug that operation will obtain described in the step B of embodiment 35 and carry out the protection of selective N 4-dimethylamino methylene in embodiment 35.

Step B:

Form the general procedure of 3 '-ester:

With N ⁴The prodrug (0.25mmol) of-dimethylamino methylene protection; acid (0.3mmol) (adopting the acid of BOC-protection in the situation that the L-valine replaces), N-(dimethylaminopropyl)-N '-ethyl carbodiimide (0.45mmol) and 4-dimethylamino-pyridine (0.04mmol) are at 2mLCH ₂Cl ₂In mixture stir 2h in rt.Just under reduced pressure concentrate in case finish reaction, residue is chromatography on silicagel column.

Step C:

Follow the operation among the step D of embodiment 35, to the N of above acquisition ⁴The prodrug of-amidine protection carries out deprotection.

41.1: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-3 '-(octadecanoyl) cytidine.

R ^f=0.2 (10%MeOH is at CH ₂Cl ₂In).C ₃₇H ₅₇N ₃O ₉ClP analytical calculation value: C, 58.92; H, 7.62; N, 5.57. measured value: C, 58.59; H, 7.44; N, 5.33.

41.2: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-3 '-(L-valyl base) cytidine trifluoroacetate.

R _f=0.15 (10%MeOH is at CH ₂Cl ₂In).C ₂₄H ₃₂N ₄O ₉ClP.2.2CF ₃CO ₂H.2.5H ₂O analytical calculation value: C, 38.64; H, 4.48; N, 6.35. measured value: C, 38.34; H, 4.14; N, 6.64.

41.3: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-3 '-(2-methyl-propiono) cytidine.

R _f=0.18 (20%MeOH is in EtOAc).C ₂₃H ₂₉N ₃O ₉ClP.0.25CH ₃CO ₂C ₂H ₅.1.5H ₂O analytical calculation value: C, 47.85; H, 5.60; N, 6.97. measured value: C, 47.74; H, 5.37; N, 7.07.

41.4: cis-5 '-O-[4-(S)-(3, the 5-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-3 '-(2-ethyl-bytyry) cytidine.

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).C ₂₅H ₃₂N ₃O ₉F ₂P.0.5H ₂O analytical calculation value: C, 50.34; H, 5.58; N, 7.04. measured value: C, 50.42; H, 5.34; N, 6.82.

Embodiment 42

Steps A:

With compound 5 (1.50g, 5.83mmol) and dimethylformamide dimethyl acetal (DMFDMA, 2.3mL, 17.5mmol) and the mixture of 50mL pyridine stir 4h at rt.Suspension residue 16h in EtOAc, the solid that the filtration collection obtains is white solid so that 1.68g (92%) N4-dimethyl formamide intermediate to be provided.With this solid (1.68g, 5.38mmol) with tert-butyldimethylsilyl chloride (TBS-Cl, 1.05g, 6.98mmol) and imidazoles (550mg 8.08mmol) merges in the DMF of 30mL, at the rt 16h that stirs the mixture.Evaporating solvent, and residue is dissolved in CH ₂Cl ₂In/the methyl alcohol and be adsorbed onto the SiO of 10g ₂And carry out chromatography (at the SiO of 120g ₂On, be used in 10% methanol-eluted fractions among the EtOAc) obtain the 1.00g mixture, it is compound 6 and the mixture that does not contain the substituent analog of N4-dimethyl formamide.(0.5mL 3.76mmol) merges, and stirs 4h, evaporating solvent at rt with the DMFDMA in residue and the 10mL pyridine.Residue is dissolved in CH ₂Cl ₂In/the methyl alcohol and be adsorbed onto 5g SiO ₂And carry out chromatography (at 40g SiO ₂On, be used in 10% methanol-eluted fractions among the EtOAc) 877mg (38%) compound 6 is provided, be amorphous solid.

Step B:

Rt with compound 6 (250mg, 0.59mmol), isobutyric acid (0.56mL, 6.44mmol), EDCI (1.24g, 6.5mmol) and DMAP (79mg is 0.65mmol) at 28mL CH ₂Cl ₂In mixture stirred 7 days, be adsorbed onto 8g SiO then ₂And carry out chromatography (at 40g SiO ₂On, be used in CH ₂Cl ₂In 2% methanol-eluted fractions) 200mg (60%) compound 7 is provided.

Step C:

Rt with compound 7 (200mg, 0.35mmol), Et ₄NF (210mg, 1.26mmol) and acetate (the 1M solution of 1.26mL is at CH ₂Cl ₂In, 1.26mmol) mixture in the DMF of 3mL stirs 18h, evaporating solvent.At CH ₂Cl ₂Dissolving residue and be adsorbed onto the SiO of 2g in/the methyl alcohol ₂And carry out chromatography (at 12g SiO ₂On, be used in CH ₂Cl ₂Middle 1-4% methyl alcohol gradient elution) provides 90mg (60%) compound 8, be amorphous solid.

Step D:

(90mg, (15min stirs the mixture for 0.15mL, 0.30mmol) the 2M solution at THF to add t-BuMgCl in 2mL DMF solution 0.20mmol) to compound 8 at 0 ℃.Add then phosphate 9 as solid (111mg, 0.30mmol).At the rt 4h that stirs the mixture, add 4M NH then ₄Cl (0.5mL, 2mmol) aqueous solution.Stir after the 16h evaporating solvent, residue and CH ₂Cl ₂Mix and filtration.To leach thing and be adsorbed onto 1g SiO ₂And carry out chromatography (at 12g SiO ₂On, be used in CH ₂Cl ₂Middle 2-5% methyl alcohol gradient elution) obtains 60mg (48%) compound 10, be amorphous solid.

42.1: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-2,3 '-two-(2-methyl-propiono) cytidines.

R _f=0.44 (10%MeOH is at CH ₂Cl ₂In).C ₂₇H ₃₅N ₃O ₁₀ClP analytical calculation value: C, 51.64; H, 5.62; N, 6.69. measured value: C, 51.30; H, 5.55; N, 6.61.

Embodiment 43

N ⁴The operation described in embodiment 38 and 40 is followed in the preparation of the prodrug analog that-carbamate or acid amides replace.

N ⁴The preparation of 2 ', 3 '-cyclic carbonate of the prodrug analog that-carbamate or acid amides replace is as described in the embodiment 23.

43.1: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-C-methyl-N ⁴-(n-pentyl oxygen base carbonyl)-cytidine.

R _f=0.75 (10%MeOH is at CH ₂Cl ₂In).C ₂₆H ₃₁N ₃O ₁₁ClP.1.0H ₂O analytical calculation value: C, 48.61; H, 5.12; N, 6.54. measured value: C, 48.86; H, 5.52; N, 6.93.

43.2: cis-5 '-O-[4-(3, the 5-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-carbonyl-2 '-C-methyl-N ⁴-(n-pentyl oxygen base carbonyl)-cytidine.

R _f=0.3 (5%MeOH is at CH ₂Cl ₂In).C ₂₆H ₃₀N ₃O ₁₁F ₂P analytical calculation value: C, 49.61; H, 4.80; N, 6.68. measured value: C, 49.45; H, 4.73; N, 6.61.

43.3: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-O-carbonyl-2 '-C-methyl-N ⁴-(4-fluorine benzyl acyl group)-cytidine.

R _f=0.75 (10%MeOH is at CH ₂Cl ₂In).C ₂₇H ₂₄N ₃O ₁₀ClFP.1.0H ₂O analytical calculation value: C, 49.59; H, 4.01; N, 6.43. measured value: C, 49.52; H, 3.85; N, 6.40.

Embodiment 44

N ⁴The operation described in embodiment 38 and 40 is followed in the preparation of the prodrug analog that-carbamate or acid amides replace

Steps A:

N ⁴The preparation of 3 '-ester of the prodrug analog that-carbamate or acid amides replace is according to the operation described in the step B of embodiment 41.

44.1: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-3 '-(2-methyl-propiono)-2 '-C-methyl-N ⁴-(n-pentyl oxygen base carbonyl)-cytidine.

R _f=0.3 (10%MeOH is at CH ₂Cl ₂In).C ₂₉H ₃₉N ₃O ₁₁ClP.1.1H ₂O analytical calculation value: C, 50.34; H, 6.00; N, 6.07. measured value: C, 50.03; H, 6.19; N, 6.08.

44.2: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-3 '-bytyry-2 '-C-methyl-N ⁴-(n-pentyl oxygen base carbonyl)-cytidine.

R _f=0.35 (10%MeOH is at CH ₂Cl ₂In).C ₂₉H ₃₉N ₃O ₁₁ClP.1.1H ₂O analytical calculation value: C, 51.83; H, 5.85; N, 6.25. measured value: C, 51.66; H, 5.53; N, 6.26.

44.3: cis-5 '-O-[4-(3, the 5-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-3 '--(2-ethyl-bytyry)-2 '-C-methyl-N ⁴-(n-pentyl oxygen base carbonyl)-cytidine.

R _f=0.25 (5%MeOH is at CH ₂Cl ₂In).C ₃₁H ₄₂N ₃O ₁₁F ₂P.0.8C ₃H ₇CO ₂H analytical calculation value: C, 54.12; H, 6.55; N, 5.29. measured value: C, 53.80; H, 6.56; N, 4.94.

Embodiment 45

N ⁴Operation described in embodiment 38 and 40 is followed in the preparation of the prodrug analog that-carbamate replaces.

Steps A:

Acetylizad general procedure:

N ⁴The prodrug (0.4mmol) that-carbamate replaces, acetate (4mmol), N-(dimethylaminopropyl)-N '-ethyl carbodiimide (4mmol) and 4-dimethylamino-pyridine (0.1mmol) are at 6mL CH ₂Cl ₂In mixture stir 40h at rt.The concentrating under reduced pressure reactant.Crude product chromatography wash-out is obtained pure diacetate esters, follow by the monoacetate product.

45.1: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-3 '-acetyl group-2 '-C-methyl-N ⁴-(n-pentyl oxygen base carbonyl)-cytidine.

R _f=0.54 (10%MeOH is at CH ₂Cl ₂In).C ₂₇H ₃₅N ₃O ₁₁ClP.0.2H ₂O analytical calculation value: C, 50.08; H, 5.51; N, 6.49. measured value: C, 49.71; H, 5.83; N, 6.59.

45.2: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-diacetyl-2 '-C-methyl-N ⁴-(n-pentyl oxygen base carbonyl)-cytidine.

R _f=0.5 (10%MeOH is at CH ₂Cl ₂In).C ₂₉H ₃₇N ₃O ₁₂ClP.0.1H ₂O analytical calculation value: C, 50.64; H, 5.45; N, 6.11. measured value: C, 50.25; H, 5.80; N, 6.21.

45.3: cis-5 '-O-[4-(3, the 5-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-3 '--acetyl group-2 '-C-methyl-N ⁴-(n-pentyl oxygen base carbonyl)-cytidine.

R _f=0.2 (5%MeOH is at CH ₂Cl ₂In).C ₂₇H ₃₄N ₃O ₁₁F ₂P.0.3H ₂O analytical calculation value: C, 49.82; H, 5.36; N, 6.46. measured value: C, 49.59; H, 5.19; N, 6.51.

45.4: cis-5 '-O-[4-(3, the 5-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 ', 3 '-diacetyl-2 '-C-methyl-N ⁴-(n-pentyl oxygen base carbonyl)-cytidine.

R _f=0.3 (5%MeOH is at CH ₂Cl ₂In).C ₂₉H ₃₆N ₃O ₁₂F ₂P.1.0H ₂O analytical calculation value: C, 49.36; H, 5.43; N, 5.96. measured value: C, 49.58; H, 5.20; N, 5.58.

Embodiment 46

The step B that follows embodiment 35 carries out N4-dimethylamino methylene with embodiment 35.2 and replaces.

46.1: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴(dimethylamino-methylene) cytidine.

R _f=0.45 (10%MeOH is at CH ₂Cl ₂In).C ₂₂H ₂₈N ₄O ₈ClP.0.7CH ₂Cl ₂.0.5H ₂O analytical calculation value: C, 44.60; H, 5.01; N, 9.16. measured value: C, 44.57; H, 5.28; N, 9.09.

Embodiment 47

Steps A:

To cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-2 ', (0.2g 0.37mmole) adds Cs to 3 '-(isopropylidene) cytidine (steps A as embodiment 38 obtains) in the agitating solution of anhydrous methylene chloride (5.0mL) ₂CO ₃(0.37g, 1.11mmole) and Et ₃N (0.1mL) is followed by the tert-butyl group-2-oxo, and 1,3-Dioxol-4-yl-methylene (methelenyl) bromine (Tetrahedron Lett., 43:1161,2002) (105mg, 0.56mmol).At stirring at room reactant mixture 48h, use CH ₂Cl ₂(50mL) and water (5mL) dilution.The washing organic layer is also dry.The concentrating under reduced pressure extract is by using CH ₂Cl ₂-10%CH ₂Cl ₂The column chromatography purification crude product compound of/MeOH wash-out obtains brown solid product (120mg).

Step B:

Carry out 2 ', 3 '-isopropylidene deprotection by the operation among the step D of embodiment 35.

47.1: cis-5 '-O-[4-(S)-(3-chlorphenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-N ⁴(tert-butyl group-2-oxo, 1,3-Dioxol-4-yl-methylene) cytidine.

R _f=0.4 (10%MeOH is at CH ₂Cl ₂In).C ₂₇H ₃₃N ₃O ₁₁ClP.0.5CH ₂Cl ₂.0.6CF ₃CO ₂H analytical calculation value: C, 45.79; H, 4.63; N, 5.58. measured value: C, 45.44; H, 4.38; N, 5.64.

Embodiment 48:

Steps A:

As preparation 'beta '-ketoester (methyl-3-oxo-3-(3, the 5-difluorophenyl)-propionic ester) as described in the steps A of embodiment 8.

Step B:

Enantioselectivity reduction by hydrogen transfer reaction is to abide by the operation of embodiment 8 step B to carry out, adopt (R, R)-Ts-DPEN-Ru-Cl-(to methyl. cumene) catalyzer.

Step C:

Obtain the reduction of (R)-methyl-3-hydroxyl-3-(3, the 5-difluorophenyl)-propionic ester by the described operation of embodiment 8 step C.

Step D:

With (R)-1-(3, the 5-difluorophenyl)-1, ammediol is converted into (4R)-trans-4-(3, the 5-difluorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexanes by the dichloro phosphate coupling described in the embodiment 14a.Realize the isomerization of gained mixture by the sodium salt of 4-nitrophenol.The chromatography product, and further obtain the compound of enantiomer-pure from the crystallization of 30%EtOAc-hexane.

Step e:

Follow condition described in embodiment 38 steps A, by coupling (4R)-trans-4-(3, the 5-difluorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexanes and 4-dimethylamino methylene-2 ', 3 '-isopropylidene-2 '-methyl cytidine forms prodrug.

Step F:

Follow operation described in the embodiment 35 step D, the prodrug of 2 ' 3 '-isopropylidene protection of as above gained is carried out deprotection.

48.1: cis-5 '-O-[4-(R)-(3, the 5-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-cytidine trifluoroacetate.

R _f=0.25 (10%MeOH is at CH ₂Cl ₂In).C ₁₉H ₂₂N ₃O ₈F ₂P.1.2CF ₃CO ₂H analytical calculation value: C, 41.05; H, 3.73; N, 6.71. measured value: C, 40.93; H, 3.49; N, 6.85.

Embodiment 49:

Steps A:

Step B:

Enantioselectivity reduction by hydrogen transfer reaction is to abide by the operation of embodiment 8 step B to carry out, adopt (S, S)-Ts-DPEN-Ru-Cl-(to methyl. cumene) catalyzer.

Step C:

Obtain the reduction of (S)-methyl-3-hydroxyl-3-(3, the 5-difluorophenyl)-propionic ester by the described operation of embodiment 8 step C.

Step D:

With (S)-1-(3, the 5-difluorophenyl)-1, ammediol is converted into (4S)-trans-4-(3, the 5-difluorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexanes by the chlorine phosphate coupling described in the embodiment 14a.Realize the isomerization of gained mixture by the sodium salt of 4-nitrophenol.

The chromatography product, and further obtain the compound of enantiomer-pure from the crystallization of 30%EtOAc-hexane.

Step e:

Follow condition described in embodiment 38 steps A, by coupling (4S)-trans-4-(3, the 5-difluorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-two oxa-phospha cyclohexanes and 4-dimethylamino methylene-2 ', 3 '-isopropylidene-2 '-methyl cytidine forms prodrug.

Step F:

49.1: cis-5 '-O-[4-(S)-(3, the 5-difluorophenyl)-2-oxo-1,2,3-two oxa-phosphorus heterocycles oneself-the 2-yl]-2 '-C-methyl-cytidine trifluoroacetate.

R _f=0.25 (10%MeOH is at CH ₂Cl ₂In).C ₁₉H ₂₂N ₃O ₈F ₂P.1.5CF ₃CO ₂H analytical calculation value: C, 40.01; H, 3.59; N, 6.36. measured value: C, 39.82; H, 3.27; N, 6.62.

Biological Examples

The embodiment of the purposes of using method of the present invention is as described below.Be appreciated that these embodiment are exemplary, method of the present invention is not limited only to these embodiment.

For clear and for purpose of brevity, in following biological Examples, compound refers to the numbering among the synthetic embodiment.

Embodiment A: rat liver microsome is to the external activation of prodrug analog.Undertaken quantitatively by catching accessory substance.

Can pass through prodrug accessory substance catch assay, the activation of prodrug analog in the test rat liver microsome.

Method:

Can adopt separation to carry out the prodrug activation determination, use induced by dexamethasone to strengthen CYP3A4 activity (Human Biologics Inc., Phoenix AZ) from the liver microsomes of rat.2mg/mL rat liver microsome, 100mM KH are adopted in research ₂PO ₄, 10mM glutathione, 25 μ M or 250 μ M compounds and 2mM NADPH carry out 0-7.5min 6 times in 37 ℃, speed in the hot blender 5436 of Eppendorf.Reaction can be by adding NADPH, beginning through precincubation in 2 minutes subsequently.Reaction through 60% methyl alcohol in quencher in 0,2.5,5 and 7.5 minute.(S-(3-oxo-3-(3-chlorophenyl) propyl group) cysteinyl glycine (the glutathione adduct of the accessory substance of prodrug activation (3-chlorophenyl vinyl ketone)) carries out quantitatively using 1.5 volumes methanol abstraction reaction things before to L-glutamyl-L-.The sample that extracts is in 14, and 000rpm is centrifugal in the Eppendorf microcentrifugal tube, by HPLC L-glutamyl-L-(S-(3-oxo-3-(3-chlorophenyl) propyl group) the cysteinyl glycine content in the clear liquid analytically.L-glutamyl-the L-of preparation mark in the 2mg/mL microsome, under reaction condition (S-(3-oxo-3-(3-chlorophenyl) propyl group) cysteinyl glycine standard items (1-30 μ M), quencher and handle unknown sample then with the same manner.Analyze for carrying out HPLC, last sample flowing phase buffer solution (buffer A) consist of 9: 1 ratio (v/v) 20mM potassium phosphate (pH 6.2) and acetonitrile.The extract (100 μ L) that will come together be injected into BeckmanUltrasphere ODS post (4.6 * 250mM, part#235329).This post is carried out gradient elution to 60% acetonitrile.L-glutamyl-L-(monitor in 245nm by the wash-out (retention time 10.4 minutes) of S-(3-oxo-3-(3-chlorophenyl) propyl group) cysteinyl glycine.

The result:

The activation of compound in the rat liver microsome:

Compound	Activation (250 μ M) (nmol/mg/min)
Compound	Activation (250 μ M) (nmol/mg/min)	18	4.7
16.5	0.24	18	4.7
16.5	0.24	17.2	0.397

Conclusion:

(formation of S-(3-oxo-3-(3-chlorophenyl) propyl group) cysteinyl glycine shows that the activation rate of compound 18 prodrugs is 4.7nmol/mg/min to product L-glutamyl-L-.

Embodiment B: rat liver microsome is to the external activation of prodrug analog.Carry out quantitatively through LC-MS/MS.

Be determined in the reaction of rat liver microsome catalysis the activation of prodrug analog and be NMP.

Method:

Can adopt separation to carry out the prodrug activation determination, use induced by dexamethasone to strengthen CYP3A4 activity (Human Biologics Inc., Phoenix AZ) from the liver microsomes of rat.Reaction can be in 0.1M KH ₂PO ₄In the presence of 2mM NADPH and liver microsomes (1mg/mL), carry out in (pH 7.4).Reactant mixture can be in the hot blender 5436 of Eppendorf (37 ℃, speed 6) incubation 5 minutes, reaction stops by adding 1.5 volumes methanol.The extract that obtains can be in 14,000rpm centrifugal in the Eppendorf micro-centrifuge tube (20min.) clarification.Supernatant (200 μ L) vacuum evaporation also is heated to dried.Dry residue is with 200 μ L water reconstruct, and mixture is in 14, the centrifugal 10min of 000rpm.With 35 μ L supernatant aliquots and 35 μ L mobile phase A (20mM N, 20% methanol solution of N-dimethylhexylamine and 10mM propionic acid) mixture is analyzed (Applied Biosystems through LC-MS/MS, API 4000), this system is furnished with Agilent 1100 two-phase pumps and LEAP syringe.NMP is through MS/MS mode (M ^-/ 78.8) detect, and compare with phosphoric acid Lamivudine standard items and to carry out quantitatively.

The result:

Compound activating in the rat liver microsome:

Compound	Activation (250 μ M) (nmol/mg/min)
Compound	Activation (250 μ M) (nmol/mg/min)	16.2	0.158
16.3	0.159	16.2	0.158
16.3	0.159	16.4	0.020
16.5	0.195	16.4	0.020
16.5	0.195	16.7	0.365
17.2	1.764	16.7	0.365
17.2	1.764	16.8	0.160
16.9	0.126	16.8	0.160
16.9	0.126	16.10	0.077
16.11	0.142	16.10	0.077
16.11	0.142	16.12	0.070
16.13	0.001	16.12	0.070
16.13	0.001	16.14	0.082
16.15	0.215	16.14	0.082
16.15	0.215	16.16	0.070
16.17	0.006	16.16	0.070
16.17	0.006	16.18	0.058
16.19	0.213	16.18	0.058
16.19	0.213	16.20	0.063
16.21	0.040	16.20	0.063
16.21	0.040	16.22	0.081
16.23	0.001	16.22	0.081
16.23	0.001	16.24	0.004
16.25	0.068	16.24	0.004
16.25	0.068	16.26	0.256
16.27	0.286	16.26	0.256
16.27	0.286	16.28	0.121
17.3	1.119	16.28	0.121

16.29	0.172
16.29	0.172	17.4	0.862
17.5	1.173	17.4	0.862
17.5	1.173	17.6	1.758
16.30	0.108	17.6	1.758
16.30	0.108	16.31	0.217
16.32	0.186	16.31	0.217
16.32	0.186	17.7	0.761
17.8	0.264	17.7	0.761
17.8	0.264	17.9	0.488
17.10	1.033	17.9	0.488
17.10	1.033	17.11	1.996
17.12	0.918	17.11	1.996
17.12	0.918	17.13	1.039
17.14	1.636	17.13	1.039
17.14	1.636	17.15	0.969
17.16	0.863	17.15	0.969
17.16	0.863	17.18	0.095
17.20	1.091	17.18	0.095
17.20	1.091	17.21	0.623
17.22	0.599	17.21	0.623
17.22	0.599	17.23	0.094
17.24	0.240	17.23	0.094

Embodiment C: in the MC external activation of human liver.Catch the activation of carrying out quantitatively in the human liver microsome, measuring the prodrug analog through accessory substance.

Method:

The human liver microsome can be available from In Vitro Technologies (IVT1032).2mg/mL human liver microsome, 100mM KH are adopted in research ₂PO ₄, 10mM glutathione, 25 μ M or 250 μ M compounds and 2mM NADPH be in the hot blender 5436 of Eppendorf, carry out 0-7.5min 6 times in 37 ℃, speed.This reaction is by adding NADPH earlier, beginning through precincubation in 2 minutes.Reaction is through 60% methyl alcohol, in quencher in 0,2.5,5 and 7.5 minute.((the glutathione adduct of the accessory substance of prodrug activation (3-chlorophenyl vinyl ketone) carries out quantitatively reactant being extracted with 1.5 volumes methanol S-(3-oxo-3-(3-chlorophenyl) propyl group) cysteinyl glycine before to L-glutamyl-L-.The sample that extracts is in 14, and 000rpm is centrifugal in the Eppendorf centrifuge tube, through HPLC L-glutamyl-L-(S-(3-oxo-3-(3-chlorophenyl) propyl group) cysteinyl glycine content in the clear liquid analytically.(S-(3-oxo-3-(3-chlorophenyl) propyl group) cysteinyl glycine standard items (1-30 μ M) can be handled unknown sample with the same manner with the 2mg/mL microsome in reaction condition preparation down to the L-glutamyl-L-of mark then.Analyze for carrying out HPLC, last sample flowing phase buffer solution (buffer A) consist of 9: 1 ratio (v/v) 20mM potassium phosphate (pH 6.2) and acetonitrile.With extract (100 μ L) be injected into Beckman Ultrasphere ODS post (4.6 * 250mM, part#235329).Post carries out the acetonitrile of gradient elution to 60%.L-glutamyl-L-(monitor in 245nm by the wash-out (retention time 10.4min.) of S-(3-oxo-3-(3-chlorophenyl) propyl group) cysteinyl glycine.

Conclusion:

(formation of S-(3-oxo-3-(3-chlorophenyl) propyl group) cysteinyl glycine shows that prodrug can be in the external activation of human liver microsome to product L-glutamyl-L-.

Embodiment D: the prodrug analog is in the MC external activation of human liver.Quantitative through LC-MS/MS.

Be determined in the reaction of human liver microsome catalysis the activation of prodrug analog and be NMP.

Method:

Employing is measured the prodrug activation available from the human liver microsome of In Vitro Technologies (IVT 1032), reacts on 0.1M KH ₂PO ₄Carry out in the presence of 2mM NADPH and liver microsomes (1mg/mL) (pH 7.4).Reactant mixture was gone up incubation 5 minutes at the hot blender 5436 of Eppendorf (37 ℃, speed 6).Reaction stops by adding 1.5 volumes methanol.With the extract that obtains in the Eppendorf microcentrifugal tube in 14,000rpm centrifugal (20min.) clarification.With supernatant (200 μ L) vacuum evaporation and be heated to dried.Dry residue is with 200 μ L water reconstruct, with mixture in 14, centrifugal 10 minutes of 000rpm.35 μ L supernatant aliquots and 35 μ L mobile phase A (20mM N, 20% methyl alcohol of N-dimethylhexylamine and 10mM propionic acid) LC-MS/MS (Applied Biosystems, API 4000) of mixture through being furnished with Agilent 1100 two-phase pumps and LEAP syringe analyzes.NMP detects through MS/MS mode (M-/78.8), and compares with phosphoric acid Lamivudine standard items and to carry out quantitatively.

The result:

Compound activating in the human liver microsome:

Compound	Activation (250 μ M) (nmol/mg/min)
Compound	Activation (250 μ M) (nmol/mg/min)	16.2	0.301
16.3	0.162	16.2	0.301
16.3	0.162	16.4	0.049
16.5	0.463	16.4	0.049
16.5	0.463	16.7	0.213
17.2	2.040	16.7	0.213
17.2	2.040	16.8	0.436
16.9	0.316	16.8	0.436
16.9	0.316	16.10	0.241
16.11	0.100	16.10	0.241
16.11	0.100	16.12	0.394
16.13	0.002	16.12	0.394
16.13	0.002	16.14	0.282
16.15	0.335	16.14	0.282
16.15	0.335	16.16	0.075
16.17	0.021	16.16	0.075
16.17	0.021	16.18	0.044
16.19	0.171	16.18	0.044
16.19	0.171	16.20	0.137
16.21	0.043	16.20	0.137
16.21	0.043	16.22	0.077
16.23	0.013	16.22	0.077
16.23	0.013	16.24	0.031
16.25	0.242	16.24	0.031
16.25	0.242	16.26	0.223

16.27	0.455
16.27	0.455	16.28	0.293
17.3	1.677	16.28	0.293
17.3	1.677	17.4	1.324
17.5	0.952	17.4	1.324
17.5	0.952	17.6	2.086
16.30	0.037	17.6	2.086
16.30	0.037	16.31	0.138
16.32	0.074	16.31	0.138
16.32	0.074	17.7	1.024
17.8	0.322	17.7	1.024
17.8	0.322	17.9	0.314
17.10	0.626	17.9	0.314
17.10	0.626	17.11	1.439
17.12	0.750	17.11	1.439
17.12	0.750	17.13	0.499
17.14	1.164	17.13	0.499
17.14	1.164	17.15	0.733
17.16	0.497	17.15	0.733
17.16	0.497	17.18	0.085
17.20	1.381	17.18	0.085
17.20	1.381	17.21	0.626
17.22	0.484	17.21	0.626
17.22	0.484	17.23	0.089
17.24	0.455	17.23	0.089

Embodiment E: NTP gathering in liver cell behind nucleoside analog and prodrug incubation thereof

Estimate the ability of nucleoside analog and prodrug generation NTP thereof with the rat hepatocytes of aquatic foods separation.It has been generally acknowledged that the NTP form of nucleosides is effective antiviral drugs.

Method:

According to improved Berry of Groen and Friend (Berry, M.N.Friend, D.S., J.CellBiol.43:506-520 (1969)) method (Groen, A.K. etc., Eur.J.Biochem 122:87-93 (1982)), the preparation of the Sprague-Dawley rat (250-300g) behind feeding liver cell.With liver cell (20mg/mL weight in wet base,＞85% trypan blue dyeing survival rate) in 37 ℃, comprising incubation 2h in the 2mL Krebs-bicarbonate buffer of 20mM glucose and 1mg/mL BSA, in the presence of 1-250 μ M nucleosides or prodrug (deriving from the stock solution of 25mM in DMSO).After incubation was finished, the cell suspending liquid of centrifugal 1600 μ L aliquots added to 300 μ L acetonitriles in the precipitation, and rotation is also ultrasonic until resolution of precipitate.Add 200 μ L water then, obtain 60% acetonitrile solution.In 14,000rpm is transferred to the supernatant that obtains in the new bottle after centrifugal 10 minutes, and is almost dry in being evaporated in Savant SpeedVac Plus under the room temperature.Dry residue is with 200 μ L water reconstruct, and in 14,000rpm is with the centrifugal 10min of mixture.With 35 μ L supernatant aliquots and 35 μ L mobile phase A (20mM N, 20% methanol solution of N-dimethylhexylamine and 10mM propionic acid) mixture is analyzed with the LC-MS/MS (Applied Biosystems, API 4000) that is furnished with Agilent 1100 two-phase pumps and LEAP syringe.Through MS/MS pattern (M ^-/ 78.8) detect NTP, and compare with triphosphoric acid Lamivudine standard items and to carry out quantitatively.

The result:

Behind elementary rat hepatocytes incubation, observed NTP forms and represents with nmol/g in 2 hours with 25 μ M or 250 μ M nucleosides and prodrug.

Compound	Formation is from the NTP (nmol/g) of 25 μ M compounds	Formation is from the NTP (nmol/g) of 250 μ M compounds
Compound	Formation is from the NTP (nmol/g) of 25 μ M compounds	Formation is from the NTP (nmol/g) of 250 μ M compounds	2 '-C-methyladenosine	193	798
2 '-C-methylguanosine	1.3	4.7	2 '-C-methyladenosine	193	798
2 '-C-methylguanosine	1.3	4.7	19	13.8	56.7
18		51.8	19	13.8	56.7
18		51.8	16.1	85	160
19		130.9	16.1	85	160
19		130.9	16.2		130.3
16.3		102.6	16.2		130.3
16.3		102.6	16.4		55.0
16.7.		347.7	16.4		55.0
16.7.		347.7	17.2		4.2
16.8		160.6	17.2		4.2
16.8		160.6	16.9		115.1
16.10		17.6	16.9		115.1
16.10		17.6	16.11		63.2
16.12		18.3	16.11		63.2
16.12		18.3	16.13		3.4
16.14		18.6	16.13		3.4
16.14		18.6	16.15		34.5
16.16		6.3	16.15		34.5
16.16		6.3	16.17		7.2
16.18		13.8	16.17		7.2
16.18		13.8	16.19		70.1
16.20		19.4	16.19		70.1
16.20		19.4	16.21		10.2
16.22		10.9	16.21		10.2
16.22		10.9	16.23		2.7
16.24		4.4	16.23		2.7

16.25	22.5
16.25	22.5	16.26	58.5
16.27	63.9	16.26	58.5
16.27	63.9	16.28	19.8
17.3	2.2	16.28	19.8
17.3	2.2	16.29	14.1
17.4	3.1	16.29	14.1
17.4	3.1	17.5	2.0
17.6	3.5	17.5	2.0
17.6	3.5	16.30	36.7
16.31	16.5	16.30	36.7
16.31	16.5	16.32	49.5
17.7	1.3	16.32	49.5
17.7	1.3	17.8	1.6
17.9	2.0	17.8	1.6
17.9	2.0	17.10	2.1
17.11	3.4	17.10	2.1
17.11	3.4	17.12	1.9
17.13	3.8	17.12	1.9
17.13	3.8	17.14	4.0
17.15	1.8	17.14	4.0
17.15	1.8	17.16	1.5
17.17	0.2	17.16	1.5
17.17	0.2	17.18	4.1
17.19	0.1	17.18	4.1
17.19	0.1	17.20	2.1
17.21	1.2	17.20	2.1
17.21	1.2	17.22	1.8
17.23	0.3	17.22	1.8
17.23	0.3	17.24	3.9

2 '-C-methyl cytidine 35.1	0 26.1
2 '-C-methyl cytidine 35.1	0 26.1	35.2	309.7
35.3	134.3	35.2	309.7
35.3	134.3	35.4	168.3
35.5	148	35.4	168.3

Conclusion:

The compounds of this invention demonstrates the ability that generates NTP in the rat hepatocytes of fresh separated.

The human liver section that embodiment F: HCV infects is measured

Adopt following assay method evaluation in the human liver tissue, to suppress the ability that HCV duplicates.

Method:

Implementation:

The ice-cold Viaspan (Dupont Pharmaceutical) of perfusion preserves solution and obtains on ice in Viaspan in the liver of the human patients of the HCV of brain death antibody positive.

Preparation accurately cutting～liver section of 200-250 μ m thickness and 8cm diameter and in Waymouth Schwann Cells medium (Gibco, Inc.) in 37 ℃ of cultivations, described culture media supplemented has 10% hyclone and 10mL/L Fungi-Bact, charges into carbon gaseous mixture (95%O with 0.75L/min ₂, 5%CO ₂).Histologic section keeps 72h in culture fluid.Change the cell culture medium that comprises test compounds solution every day.

Behind liver section incubation reasonable time, collect liver section and medium and be used for HCVRNA (tissue and medium) and nucleosides (NTP) analysis.The medium of all collections and histologic section remain in the liquid nitrogen to be measured.

According to disclosed method (Bonacini etc., 1999), analyze the HCV RNA in medium and the tissue sample, this method can adopt the technology of automation, many circulations, polymerase chain reaction (PCR) base.This mensuration is 100 virus copy/ml to the detection lower bound of HCV RNA.

Organize NTP to analyze:

Freezing liver section can adopt following method to break: adopt ultrasonic probe BransonSonifief 450 (Branson Ultrasonics, Danbury, CT) ultrasonic and with Dounce taper pestle homogenizing on 200 μ l10% (v/v) perchloric acid (PCA).After 2,500 * g 5min is centrifugal, with supernatant 3M KOH/3M KHCO ₃Neutralization also fully mixes.The sample of neutralization is in 2, the centrifugal 5min of 500g, and the NTP level adopts Whatman Partisil 5SAX through ion exchange phase HPLC (Hewlett Packard 1050), and (5 μ m, 4.6 * 250mm) posts are measured.With the injection of solution of sample (50 μ L) in 70%10mM ammonium phosphate buffer solution and 30%1M ammonium phosphate buffer solution (be pH 3.5 and comprise 6% ethanol) in post.Nucleoside triphosphate with 1M ammonium phosphate (pH 3.5)/6% ethanol buffer solution of linear gradient to 80%, in flow velocity 1.25mL/min wash-out on post, and detect is absorbed (254nm) with UV.

The result:

With 2 '-C-methylguanosine and compound 19 incubations after, the HCVRNA level in the liver section medium is compared untreated contrast section and is reduced.

Compound concentration (μ M)	After the processing of 2 '-C-methylguanosine, the Log that the 48-72h viral RNA reduces with respect to contrast ₁₀	After compound 19 processing, the Log that 48-72 h viral RNA reduces with respect to contrast ₁₀
Compound concentration (μ M)			0.25	0.51	1.27
1	--	1.61	0.25	0.51	1.27
1	--	1.61	2.5	1.74	1.70
25	1.48	1.72	2.5	1.74	1.70

Conclusion:

Handle the human liver section 72h that HCV infects with 2 '-C-methylguanosine or compound 19, the amount that 48-72h is released into the HCV RNA of medium reduces.For the viral RNA in reducing medium produces, be that compound 19 is handled than handling more effective with nucleosides 2 '-C-methylguanosine with prodrug.

Embodiment G: the liver target of nucleoside analog and prodrug thereof

The generation of nucleosides in generation by measuring NTP in the liver and the blood plasma, relatively before the liver specificity of drug compound 19 and its parent nucleosides 2 '-C-methylguanosine and preceding drug compound 21.1 and its parent nucleosides 2 '-C-methyladenosine.

Method:

Give C57BL/6 mouse compound 19 or 2 '-C-methylguanosine through intraperitoneal, dosage is 30mg/kg nucleosides equivalent (30mg/kg 2 '-C-methylguanosine and a 53.27mg/kg compound 19).Give C57BL/6 mouse compound 21.1 or 2 '-C-methyladenosine through vein, dosage is about 5.5mg/kg nucleosides equivalent (5.5mg/kg 2 '-C-methyladenosine and 10mg/kg compound 21.1).The plasma concentration of 2 '-C-methylguanosine, compound 19,2 '-C-methyladenosine and compound 21.1 is determined through HPLC-UV, the liver concentration of 5 '-triguaiacyl phosphate of 2 '-C-methylguanosine and 2 '-C-methyladenosine adopts standard ionomer pairing chromatographic process to measure triguaiacyl phosphate through LC-MS and measures, as described in embodiment E.Conventional SAX HPLC-UV can't distinguish endogenous GTP and 2 '-C-methylguanyl triphosphate.Owing to can't obtain the standard of believable 2 '-C-methylguanyl triphosphate, so the liver concentration of nucleosides identical with embodiment E mensuration approximately.

The result:

Can prove the compound 19 of 2 '-C-methylguanyl triphosphate and be the liver target of the compound 21.1 of 2 '-C-methyladenosine triphosphoric acid with prodrug is clear.The multiple of relevant liver NTP AUC value, blood plasma nucleosides AUC value, liver target ratio (liver/blood plasma) and prodrug improvement effect is as shown in the table.Compound 19 shows that than free nucleosides 30 times of prodrugs of liver target improve.Compound 21.1 shows that than free nucleosides the prodrug greater than 32 times of liver target improves, and after giving compound 21.1, the amount of blood plasma middle reaches freestone glycosides is lower than the lower limit of quantification.

Nucleosides [prodrug]	Liver NTP AUC (nmol*h/g)	Blood plasma nucleosides AUC (μ M*h)	Liver target index (liver/blood plasma)	Prodrug improves (multiple)
Nucleosides [prodrug]	Liver NTP AUC (nmol*h/g)	Blood plasma nucleosides AUC (μ M*h)	Liver target index (liver/blood plasma)	Prodrug improves (multiple)	2 '-C-methylguanosine	64	73.7	0.87	--
19	485	18.5	26.2	30	2 '-C-methylguanosine	64	73.7	0.87	--
19	485	18.5	26.2	30	2 '-C-methyladenosine	119	26.8	4.4	--
21.1	502	＜3.6	＞141.4	＞32	2 '-C-methyladenosine	119	26.8	4.4	--

Embodiment H: the tissue distribution behind nucleoside analog and the prodrug oral administration thereof

Relatively prodrug and parent nucleoside analog inhibitor thereof are at the liver specificity of liver and other possible toxicity target organ.

Method:

Nucleoside analog and prodrug thereof are given the rat of fasting with the dosage oral administration gavage of 30mg/kg (according to the nucleosides equivalent).As described in embodiment J, measure the plasma concentration of nucleosides and prodrug through HPLC-UV, as described in embodiment E, adopt standard ionomer that chromatography is measured liver, skeletal muscle, heart, kidney, small intestine and other organ concentration of nucleoside 5 '-triphosphoric acid through LC-MS by measuring triguaiacyl phosphate.

The result:

The result has proved the liver target of nucleoside analog prodrug and provides prodrug than the independent evidence with safety of improvement of nucleosides.This situation just can take place at prodrug or in the liver target of the other nucleoside metabolism that the nucleoside monophosphate dephosphorylation is derived.Under latter event, nucleosides can change peripheral organization over to from liver, thereby causes other tissue contact nucleosides and cause the outer toxicity of potential liver.The metabolism that nucleosides also can pass through nucleosides in nucleoside monophosphate or the liver cell from the release of liver reduces; be decomposed into inosine as the adenyl residue nucleoside monophosphate by deaminase and nucleotidase, perhaps the adenyl residue nucleosides is decomposed into inosine and hypoxanthine by adenosine deaminase and purine nucleosides phosphorylated enzyme.

Example I: the oral administration biaavailability evaluation of nucleoside analog in the normal male rat and prodrug thereof.

The oral administration biaavailability of nucleoside analog and prodrug thereof (OBAV) can adopt the normal male rat to estimate.

Method:

Compound is dissolved in the solvent that is suitable for intravenous and oral administration.Oral and vein or abdominal cavity give every group of 4 rat 30mg/kg (nucleosides equivalent) compound, calculate the ratio of AUC of the NTP concentration time curve of liver organ, estimate OBAV thus.The liver organ sample can be after administration 20min, 1,3,5,8,12 and 24h obtain.The NTP concentration of liver organ can be analyzed definite through LC-MS/MS (embodiment E) or HPLC (embodiment F).

The result:

The oral administration biaavailability of normal male rat:

Compound	％F
Compound	％F	16.32	31.7

Embodiment J: nucleoside analog in rat liver S9 part or the liver cell that separates to the susceptibility of metabolism

In the liver cell of rat liver S9 part or separation, estimate the susceptibility of purine nucleoside analogs to metabolism.

Method:, purine nucleoside analogs (100 μ M) (for example 2 '-C-methyladenosine) is cultivated together at the rat hepatocytes of rat liver S9 part or separation in 37 ℃.Time point respectively at as many as 2h makes the stopping of reaction, extracts deproteinising with 60% acetonitrile then.After centrifugal, supernatant is evaporated to dried, the residue use flowing phase reconstruct that obtains.The potential metabolite of single these samples of HPLC network analysis of diode array detector is equipped with in employing.Separate nucleosides (as 2 '-C-methylinosine) and alkali (as hypoxanthine) and in Beckman Ultrasphere C-18 reversed-phase column (on 4.5 * 250mm), adopting buffer A (100mM potassium phosphate, pH 6) and buffer B (methanol solution of 25%v/v) to carry out gradient elution in flow velocity 1.5mL/min carries out quantitatively.Post adopts nonlinear gradient 0% buffer B to 100% buffer B (% pump buffer B=100 * (time [min]/40) ³) wash-out 40min, detect the UV absorptance in 260nm.Metabolite is identified with true standard items co-elute and/or UV Spectral matching.

The result: purine nucleoside analogs depends on type and the position that homologous structure is modified to the susceptibility of metabolism.Introducing some pharmacophore (as 2 '-C-methyl group of 2 '-C-methyladenosine) can cause the resistance of purine remedial pathway enzymes metabolism is increased (as adenosine deaminase and purine nucleosides phosphorylated enzyme).(referring to Eldrup AB, Allerson CR, Bennett CF, Deng (2004) J.Med.Chem.47 (9): 2283-2295, " Structure-activity relationship of purineribonucleotides for inhibition of hepatitis C virus RNA-dependent RNApolymerase. ")

Embodiment K: the liver target of nucleoside analog and prodrug thereof is fixed

By measuring N TP in liver than the generation of nucleosides in blood plasma, relatively before drug compound 35.3,35.4 and 35.5 liver specificities with respect to parent nucleosides 2 '-C-methyl cytidine.

Method: preceding drug compound 35.3,35.4,35.5,38.3,38.6,40.1,40.6,40.7,40.8,41.2 or 2 '-C-methyl cytidine through intraperitoneal administration to male Sprague-Dawley rat, dosage is 5mg/kg, based on the nucleosides equivalent (5mg/kg 2 '-C-methyl cytidine and～7-10mg/kg before drug compound).The measurement of the liver concentration of 5 '-triguaiacyl phosphate of the plasma concentration and 2 ' of 2 '-C-methyl cytidine-C-methyl cytidine is by LC-MS, adopts standard ionomer to chromatography determination nucleosides and triguaiacyl phosphate, as described in embodiment E respectively.Conventional SAX HPLC-UV can not distinguish endogenous CTP and 2 '-C-methyl cytidine triguaiacyl phosphate.

The result:

Liver target as the compound of the triguaiacyl phosphate of 2 '-C-methyl cytidine is clearly proved by prodrug.At C _MaxLiver NTP concentration, at C _MaxBlood plasma nucleosides concentration, liver target be summarized in following table than the improvement multiple of (liver/blood plasma) and prodrug.These prodrugs have been proved aspect liver target the specific ionization nucleosides and have been improved above thousands of times.

Nucleosides [prodrug]	At C _maxLiver NTP (nmol/g)	At C _maxBlood plasma nucleosides (μ M)	Liver target index (liver/blood plasma)	Prodrug improves (multiple)
Nucleosides [prodrug]	At C _maxLiver NTP (nmol/g)	At C _maxBlood plasma nucleosides (μ M)	Liver target index (liver/blood plasma)	Prodrug improves (multiple)	2 '-C-methyl cytidine	1.88	25.51	0.074	--
35.3	149.20	0.24	611	8257	2 '-C-methyl cytidine	1.88	25.51	0.074	--
35.3	149.20	0.24	611	8257	35.4	71.60	0.036	1988	26877
35.5	192.73	0.18	1053	14230	35.4	71.60	0.036	1988	26877
35.5	192.73	0.18	1053	14230	38.3	161.65	0.24	685	9257
38.6	19.8	0.03	660	8919	38.3	161.65	0.24	685	9257
38.6	19.8	0.03	660	8919	40.1	37.76	0.078	484	6541
40.6	40.09	0.19	216	2919	40.1	37.76	0.078	484	6541
40.6	40.09	0.19	216	2919	40.7	15.28	0.031	493	6662
40.8	62.61	0.12	501	6770	40.7	15.28	0.031	493	6662
40.8	62.61	0.12	501	6770	41.2	101.47	0.34	302	4081

Embodiment L: estimate nucleoside analog and the oral administration biaavailability of its prodrug in the normal male rat

The oral administration biaavailability (OBAV) of nucleoside analog and its prodrug is estimated in the normal male rat.

Method:

Compound dissolution is in suitable vein and oral administration carrier.By calculating respectively to every group of four rat after oral and i.v. administration 10 and 5mg/kg (according to the nucleosides equivalent) compound, the normalized AUC value of the dosage of the liver organ concentration time curve of NTP (from 0 to 24h and from 0 to infinitary value) ratio estimates OBAV.In administration 20min and 1,3,5,8,12, and after the 24h, obtain the liver organ sample.Analyze the liver organ concentration of determining NTP by LC-MS/MS (embodiment E).

The result:

Oral administration biaavailability in the normal male rat

Compound

％F(AUC 0-24hr)

%F (AUC infinitary value)

35.5

3

10

Claims

1. the compound of formula (IX), or its pharmaceutically acceptable salt:

Wherein:

R ²Be selected from R ³And hydrogen;

R ³Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁴Be selected from R ³And hydrogen;

R ⁵Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁶Be selected from hydrogen and lower acyl;

R ¹²Be selected from hydrogen and lower acyl; And

P is integer 2 or 3.

2. the compound of formula (X), or its pharmaceutically acceptable salt:

Wherein:

W and W ' are joined together to form cyclic group by an other 2-5 atom;

R ⁴Be C ₁-C ₄Alkyl;

R ⁵Be selected from C ₁-C ₄Alkyl, monocyclic aryl and monocycle aralkyl;

R ⁶Be C ₁-C ₄Acyl group;

R ⁷And R ⁸Form cyclic carbonate together, R ⁷At 3 '-carbon place.

3. the compound of claim 1, wherein:

V is selected from phenyl; The phenyl that is replaced by 1-3 substituting group that independently is selected from following groups: halogen, C ₁-C ₆Alkyl ,-CF ₃,-OR ³,-OR ¹²,-COR ³,-CO ₂R ³,-NR ³ ₂,-NR ¹² ₂,-CO ₂NR ₂ ²,-SR ³,-SO ₂R ³,-SO ₂NR ₂ ²With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that is replaced by 1-2 substituting group that independently is selected from following groups: halogen, C ₁-C ₆Alkyl ,-CF ₃,-OR ³,-OR ¹²,-COR ³,-CO ₂R ³,-NR ³ ₂,-NR ¹² ₂,-CO ₂NR ₂ ²,-SR ³,-SO ₂R ³,-SO ₂NR ₂ ²With-CN, the bicyclic heteroaryl of wherein said bicyclic heteroaryl and replacement has 1-2 hetero atom that independently is selected from N, O and S, and prerequisite is

R ³Be C ₁-C ₆Alkyl.

4. the compound of claim 3, wherein:

V is selected from following groups: phenyl; The phenyl that is replaced by 1-3 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that independently is selected from 1-2 substituting group replacement of following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN, the bicyclic heteroaryl of wherein said bicyclic heteroaryl and replacement has 1-2 hetero atom that independently is selected from N, O and S, and prerequisite is

5. the compound of claim 4, wherein:

V is selected from following groups: phenyl; Independently be selected from the phenyl of 1-2 substituting group replacement of following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Pyridine radicals; Independently be selected from the pyridine radicals of 1 substituting group replacement of following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Furyl; The furyl that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Thienyl; And the thienyl that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃

6. the compound of claim 5, wherein V is selected from phenyl, 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-bromo-4-fluoro phenyl, 2-pyridine radicals, 3-pyridine radicals and 4-pyridine radicals.

7. the compound of claim 6, wherein V is selected from 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-pyridine radicals and 4-pyridine radicals.

8. the compound of claim 1, wherein Z be selected from-H ,-OMe ,-OEt, phenyl, C ₁-C ₃Alkyl ,-NR ⁴ ₂,-SR ⁴,-(CH ₂) _p-OR ⁶,-(CH ₂) _p-SR ⁶With-OCOR ⁵

R ⁴Be C ₁-C ₄Alkyl;

R ⁵Be selected from C ₁-C ₄Alkyl, monocyclic aryl and monocycle aralkyl; With

R ⁶Be C ₁-C ₄Acyl group.

9. the compound of claim 8, wherein Z be selected from-H ,-OMe ,-OEt and phenyl.

10. the compound of claim 1, wherein:

W and W ' independently are selected from following groups :-H, C ₁-C ₆Alkyl and phenyl; Perhaps

W and W ' are joined together to form cyclic group by an other 2-5 atom.

11. the compound of claim 1, wherein W and W ' independently are selected from following groups :-H, methyl and V, and perhaps W and W ' are methyl, and prerequisite is when W is V, and then W ' is H.

12. the compound of claim 1, wherein:

W and W ' are joined together to form cyclic group by an other 2-5 atom; And

R ⁴Be C ₁-C ₄Alkyl;

R ⁵Be selected from C ₁-C ₄Alkyl, monocyclic aryl and monocycle aralkyl; And

R ⁶Be C ₁-C ₄Acyl group.

13. the compound of claim 12, wherein:

V is selected from following groups: phenyl; Independently be selected from the phenyl that following groups replaces by 1-3: halogen, C ₁-C ₆Alkyl ,-CF ₃,-OR ³,-OR ¹²,-COR ³,-CO ₂R ³,-NR ³ ₂,-NR ¹² ₂,-CO ₂NR ₂ ²,-SR ³,-SO ₂R ³,-SO ₂NR ₂ ²With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that is replaced by 1-2 substituting group that independently is selected from following groups: halogen, C ₁-C ₆Alkyl ,-CF ₃,-OR ³,-OR ¹²,-COR ³,-CO ₂R ³,-NR ³ ₂,-NR ¹² ₂,-CO ₂NR ₂ ²,-SR ³,-SO ₂R ³,-SO ₂NR ₂ ²With-CN, the bicyclic heteroaryl of wherein said bicyclic heteroaryl and replacement has 1-2 hetero atom that independently is selected from N, O and S, and prerequisite is

R ³Be C ₁-C ₆Alkyl.

14. the compound of claim 13, wherein:

V is selected from following groups: phenyl; Independently be selected from the phenyl of 1-3 substituting group replacement of following groups: Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that independently is selected from 1-2 substituting group replacement of following groups: Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN, and the bicyclic heteroaryl of wherein said bicyclic heteroaryl and replacement has 1-2 hetero atom that independently is selected from N, O and S, and prerequisite is

15. the compound of claim 14, wherein V is selected from following groups: phenyl; The phenyl that is replaced by 1-2 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Pyridine radicals; The pyridine radicals that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Furyl; The furyl that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Thienyl; And the thienyl that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃

16. the compound of claim 1, wherein:

V is selected from following groups: phenyl, 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-bromo-4-fluoro phenyl, 2-pyridine radicals, 3-pyridine radicals and 4-pyridine radicals; With

Z is selected from following groups :-H, OMe, OEt and phenyl; And

W and W ' independently are selected from following group :-H and phenyl, and perhaps W and W ' are methyl.

17. the compound of claim 1, wherein Z, W and W ' are-H.

18. the compound of claim 1, wherein V is identical with W, and all is selected from optional monocyclic aryl that replaces and the optional bicyclic heteroaryl that replaces.

19. the compound of claim 1, wherein:

V is selected from following groups: 3-chlorophenyl, 3,5-difluoro-benzene base and 4-pyridine radicals; With

Z, W and W ' are-H.

20. the compound of claim 19, wherein said compound is:

21. the compound of claim 19, wherein said compound is:

22. the compound of claim 1, wherein said compound are the compounds of formula (XI):

Wherein 5 ' oxygen methylene group of V and ribose part is cis each other.

23. the compound of claim 2, wherein said compound are the compounds of formula (XII):

Wherein 5 ' oxygen methylene group of V and ribose part is cis each other.

24. the compound of claim 23, wherein:

V is selected from following groups: phenyl; The phenyl that is replaced by 1-3 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that independently is selected from 1-2 substituting group replacement of following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN.

25. the compound of claim 24, wherein:

V is selected from following groups: phenyl, 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-bromo-4-fluoro phenyl, 2-pyridine radicals, 3-pyridine radicals and 4-pyridine radicals.

26. the compound of claim 25, wherein said compound has the R-spatial chemistry at the carbon place that V-connects, and has the S-spatial chemistry in the phosphorus center.

27. the compound of claim 25, wherein said compound has the S-spatial chemistry at the carbon place that V-connects, and has the R-spatial chemistry in the phosphorus center.

28. the compound of claim 23, wherein: V is selected from following groups: 3-chlorophenyl, 3,5-difluoro-benzene base and 4-pyridine radicals; With

R ⁷And R ⁸Form cyclic carbonate together, R ⁷At 3 '-carbon place.

29. the compound of claim 28, wherein said compound is:

30. the compound of claim 28, wherein said compound is:

31. the compound of claim 23, wherein: V is selected from following groups: phenyl; Independently be selected from the phenyl that following groups replaces by 1-3: halogen, C ₁-C ₆Alkyl ,-CF ₃,-OR ³,-OR ¹²,-COR ³,-CO ₂R ³,-NR ³ ₂,-NR ¹² ₂,-CO ₂NR ₂ ²,-SR ³,-SO ₂R ³,-SO ₂NR ₂ ²With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that is replaced by 1-2 substituting group that independently is selected from following groups: halogen, C ₁-C ₆Alkyl ,-CF ₃,-OR ³,-OR ¹²,-COR ³,-CO ₂R ³,-NR ³ ₂,-NR ¹² ₂,-CO ₂NR ₂ ²,-SR ³,-SO ₂R ³,-SO ₂NR ₂ ²With-CN, the bicyclic heteroaryl of wherein said bicyclic heteroaryl and replacement has 1-2 hetero atom that independently is selected from N, O and S, and prerequisite is

R ³Be C ₁-C ₆Alkyl.

32. the compound of claim 31, wherein: V is selected from following groups: phenyl; Independently be selected from the phenyl of 1-3 substituting group replacement of following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that independently is selected from 1-2 substituting group replacement of following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN, and the bicyclic heteroaryl of wherein said bicyclic heteroaryl and replacement has 1-2 hetero atom that independently is selected from N, O and S, and prerequisite is

33. the compound of claim 32, wherein V is selected from following groups: phenyl; The phenyl that is replaced by 1-2 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Pyridine radicals; The pyridine radicals that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Furyl; The furyl that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Thienyl; And the thienyl that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃

34. the compound of claim 33, wherein: V is selected from following groups: phenyl, 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-bromo-4-fluoro phenyl, 2-pyridine radicals, 3-pyridine radicals and 4-pyridine radicals.

35. the compound of claim 34, wherein: V is selected from following groups: 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-pyridine radicals and 4-pyridine radicals.

36. the compound of claim 23, wherein said compound has the R-spatial chemistry at the carbon place that V-connects, and has the S-spatial chemistry in the phosphorus center.

37. the compound of claim 23, wherein said compound has the S-spatial chemistry at the carbon place that V-connects, and has the R-spatial chemistry in the phosphorus center.

38. pharmaceutical composition, this pharmaceutical composition comprise the pharmaceutically compound and the pharmaceutically acceptable carrier of the claim 1 of effective dose.

39. pharmaceutical composition, this pharmaceutical composition comprise the pharmaceutically compound and the pharmaceutically acceptable carrier of the claim 2 of effective dose.

40. suppress the method for human patients virus replication, described method comprises the compound of the claim 1 that gives described human patients treatment effective dose.

41. suppress the method for human patients virus replication, described method comprises the compound of the claim 2 that gives described human patients treatment effective dose.

42. being RNA dependent form RNA viruses, the method for claim 40, wherein said virus replication duplicate.

43. being HCV, the method for claim 40, wherein said virus replication duplicate.

44. the method for treatment human patients virus infections, described method comprise the compound of the claim 1 that gives described human patients treatment effective dose.

45. the method for treatment human patients virus infections, described method comprise the compound of the claim 2 that gives described human patients treatment effective dose.

46. the method for claim 44, wherein said virus infections are RNA dependent form picornavirus infection.

47. being HCV, the method for claim 44, wherein said virus infections infect.

48. the method for claim 47, wherein said formula I compound is united use with second kind of medicament active component of the antagonism HCV of treatment effective dose.

49. the method for claim 48, second kind of medicament active component of wherein said antagonism HCV is Ribavirin; Levovirin; Wei Lami is left alone without help; Thymosin; Interferon-beta; The NS3 serpin; Inosine monophosphate dehydrogenase inhibitor; Interferon-' alpha ' or glycol interferon-α unite use separately or with Ribavirin or Levovirin.

50. the method for claim 49, second kind of medicament active component of wherein said antagonism HCV is interferon-' alpha ' or glycol interferon-α, unites use separately or with Ribavirin or Levovirin.

51. the compound of formula (XIII), or its pharmaceutically acceptable salt:

Wherein:

R ²Be selected from R ³And hydrogen;

R ³Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁴Be selected from R ³And hydrogen;

R ⁵Be selected from alkyl, aryl, Heterocyclylalkyl and aralkyl;

R ⁶Be selected from hydrogen and lower acyl;

R ¹²Be selected from hydrogen and lower acyl; And

P is integer 2 or 3.

52. the compound of formula (XIV), or its pharmaceutically acceptable salt:

Wherein:

W and W ' are joined together to form cyclic group by an other 2-5 atom;

R ⁴Be C ₁-C ₄Alkyl;

R ⁵Be selected from C ₁-C ₄Alkyl, monocyclic aryl and monocycle aralkyl;

R ⁶Be C ₁-C ₄Acyl group; With

R at 3 '-oxygen ⁷With R at 2 '-oxygen ⁸Form cyclic carbonate together.

53. the compound of claim 51, wherein:

R ³Be C ₁-C ₆Alkyl.

54. the compound of claim 53, wherein:

55. the compound of claim 54, wherein: V is selected from following groups: phenyl; Independently be selected from the phenyl of 1-2 substituting group replacement of following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Pyridine radicals; Independently be selected from the pyridine radicals of 1 substituting group replacement of following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Furyl; The furyl that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Thienyl; And the thienyl that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃

56. the compound of claim 55, wherein V is selected from phenyl, 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-bromo-4-fluoro phenyl, 2-pyridine radicals, 3-pyridine radicals and 4-pyridine radicals.

57. the compound of claim 56, wherein V is selected from 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-pyridine radicals and 4-pyridine radicals.

58. the compound of claim 51, wherein Z be selected from-H ,-OMe ,-OEt, phenyl, C ₁-C ₃Alkyl ,-NR ⁴ ₂,-SR ⁴,-(CH ₂) _p-OR ⁶,-(CH ₂) _p-SR ⁶With-OCOR ⁵

R ⁴Be C ₁-C ₄Alkyl;

R ⁶Be C ₁-C ₄Acyl group.

59. the compound of claim 58, wherein Z be selected from-H ,-OMe ,-OEt and phenyl.

60. the compound of claim 51, wherein:

W and W ' are joined together to form cyclic group by an other 2-5 atom.

61. the compound of claim 51, wherein W and W ' independently are selected from following groups :-H, methyl and V, and perhaps W and W ' are methyl, and prerequisite is when W is V, and then W ' is H.

62. the compound of claim 51, wherein:

W and W ' are joined together to form cyclic group by an other 2-5 atom; And

R ⁴Be C ₁-C ₄Alkyl;

R ⁶Be C ₁-C ₄Acyl group.

63. the compound of claim 62, wherein:

R ³Be C ₁-C ₆Alkyl.

64. the compound of claim 63, wherein:

65. the compound of claim 64, wherein V is selected from following groups: phenyl; The phenyl that is replaced by 1-2 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Pyridine radicals; The pyridine radicals that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Furyl; The furyl that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Thienyl; And the thienyl that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃

66. the compound of claim 51, wherein:

Z is selected from following groups :-H, OMe, OEt and phenyl; And

67. the compound of claim 51, wherein Z, W and W ' are-H.

68. the compound of claim 51, wherein V is identical with W, and all is selected from optional monocyclic aryl that replaces and the optional bicyclic heteroaryl that replaces.

69. the compound of claim 51, wherein:

V is selected from following groups: 3-chlorophenyl and 4-pyridine radicals; With

Z, W and W ' are-H.

70. the compound of claim 69, wherein said compound is:

71. the compound of claim 69, wherein said compound is:

72. the compound of claim 51, wherein said compound are the compounds of formula (XV):

Wherein 5 ' oxygen methylene group of V and ribose part is cis each other.

73. the compound of claim 52, wherein said compound are the compounds of formula (XVI):

Wherein 5 ' oxygen methylene group of V and ribose part is cis each other.

74. the compound of claim 73, wherein: V is selected from following groups: phenyl; The phenyl that is replaced by 1-3 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that independently is selected from 1-2 substituting group replacement of following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN.

75. the compound of claim 74, wherein: V is selected from following groups: phenyl, 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-bromo-4-fluoro phenyl, 2-pyridine radicals, 3-pyridine radicals and 4-pyridine radicals.

76. the compound of claim 75, wherein said compound has the R-spatial chemistry at the carbon place that V-connects, and has the S-spatial chemistry in the phosphorus center.

77. the compound of claim 75, wherein said compound has the S-spatial chemistry at the carbon place that V-connects, and has the R-spatial chemistry in the phosphorus center.

78. the compound of claim 73, wherein: V is selected from following groups: 3-chlorophenyl, 3,5-difluoro-benzene base and 4-pyridine radicals; With

R ⁷And R ⁸Form cyclic carbonate together, R ⁷At 3 '-carbon place.

79. the compound of claim 78, wherein said compound is:

80. the compound of claim 78, wherein said compound is:

81. the compound of claim 73, wherein: V is selected from following groups: phenyl; Independently be selected from the phenyl that following groups replaces by 1-3: halogen, C ₁-C ₆Alkyl ,-CF ₃,-OR ³,-OR ¹²,-COR ³,-CO ₂R ³,-NR ³ ₂,-NR ¹² ₂,-CO ₂NR ₂ ²,-SR ³,-SO ₂R ³,-SO ₂NR ₂ ²With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that is replaced by 1-2 substituting group that independently is selected from following groups: halogen, C ₁-C ₆Alkyl ,-CF ₃,-OR ³,-OR ¹²,-COR ³,-CO ₂R ³,-NR ³ ₂,-NR ¹² ₂,-CO ₂NR ₂ ²,-SR ³,-SO ₂R ³,-SO ₂NR ₂ ²With-CN, the bicyclic heteroaryl of wherein said bicyclic heteroaryl and replacement has 1-2 hetero atom that independently is selected from N, O and S, and prerequisite is

R ³Be C ₁-C ₆Alkyl.

82. the compound of claim 81, wherein: V is selected from following groups: phenyl; Independently be selected from the phenyl of 1-3 substituting group replacement of following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that independently is selected from 1-2 substituting group replacement of following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN, and the bicyclic heteroaryl of wherein said bicyclic heteroaryl and replacement has 1-2 hetero atom that independently is selected from N, O and S, and prerequisite is

83. the compound of claim 82, wherein V is selected from following groups: phenyl; The phenyl that is replaced by 1-2 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Pyridine radicals; The pyridine radicals that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Furyl; The furyl that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃Thienyl; And the thienyl that is replaced by 1 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl and-CF ₃

84. the compound of claim 83, wherein: V is selected from following groups: phenyl, 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-bromo-4-fluoro phenyl, 2-pyridine radicals, 3-pyridine radicals and 4-pyridine radicals.

85. the compound of claim 84, wherein: V is selected from following groups: 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-pyridine radicals and 4-pyridine radicals.

86. the compound of claim 73, wherein said compound has the R-spatial chemistry at the carbon atom place that V-connects, and has the S-spatial chemistry in the phosphorus center.

87. the compound of claim 73, wherein said compound has the S-spatial chemistry at the carbon atom place that V-connects, and has the R-spatial chemistry in the phosphorus center.

88. pharmaceutical composition, this pharmaceutical composition comprise the pharmaceutically compound and the pharmaceutically acceptable carrier of the claim 51 of effective dose.

89. pharmaceutical composition, this pharmaceutical composition comprise the pharmaceutically compound and the pharmaceutically acceptable carrier of the claim 52 of effective dose.

90. suppress the method for human patients virus replication, described method comprises the compound of the claim 51 that gives described human patients treatment effective dose.

91. suppress the method for human patients virus replication, described method comprises the compound of the claim 52 that gives described human patients treatment effective dose.

92. being RNA dependent form RNA viruses, the method for claim 91, wherein said virus replication duplicate.

93. being HCV, the method for claim 91, wherein said virus replication duplicate.

94. the method for treatment human patients virus infections, described method comprise the compound of the claim 51 that gives described human patients treatment effective dose.

95. the method for treatment human patients virus infections, described method comprise the compound of the claim 52 that gives described human patients treatment effective dose.

96. the method for claim 95, wherein said virus infections are RNA dependent form picornavirus infection.

97. being HCV, the method for claim 95, wherein said virus infections infect.

98. the method for claim 97, wherein said formula (VIII) compound is united use with second kind of medicament active component of the antagonism HCV of treatment effective dose.

99. the method for claim 98, second kind of medicament active component of wherein said antagonism HCV is Ribavirin; Levovirin; Wei Lami is left alone without help; Thymosin; Interferon-beta; The NS3 serpin; Inosine monophosphate dehydrogenase inhibitor; Interferon-' alpha ' or glycol interferon-α unite use separately or with Ribavirin or Levovirin.

100. the method for claim 99, second kind of medicament active component of wherein said antagonism HCV is interferon-' alpha ' or glycol interferon-α, unites use separately or with Ribavirin or Levovirin.

101. the compound of formula (XVII), or its pharmaceutically acceptable salt:

Wherein:

W and W ' are joined together to form cyclic group by an other 2-5 atom;

R ⁴Be C ₁-C ₄Alkyl;

R ⁵Be selected from C ₁-C ₄Alkyl, monocyclic aryl and monocycle aralkyl;

R ⁶Be C ₁-C ₄Acyl group; With

R at 3 '-oxygen ⁷With R at 2 '-oxygen ⁸Form cyclic carbonate together.

102. the compound of claim 101, wherein R ^aBe methyl and R ^bBe hydrogen.

103. the compound of claim 101, wherein R ^aBe hydrogen and R ^bIt is methyl.

104. the compound of claim 102, wherein R ⁷And R ⁸Be hydrogen.

105. the compound of claim 104, wherein Z, W and W ' are hydrogen.

106. the compound of claim 22, wherein: V is selected from following groups: phenyl; The phenyl that is replaced by 1-3 substituting group that independently is selected from following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN; Bicyclic heteroaryl; And the bicyclic heteroaryl that independently is selected from 1-2 substituting group replacement of following groups :-Cl ,-Br ,-F, C ₁-C ₃Alkyl ,-CF ₃,-COCH ₃,-OMe ,-NMe ₂,-OEt ,-CO ₂Tert-butyl ,-CO ₂NH ₂,-SMe ,-SO ₂Me ,-SO ₂NH ₂With-CN.

107. the compound of claim 106, wherein: V is selected from following groups: phenyl, 3-chlorophenyl, 3-bromo phenyl, 2-bromo phenyl, 3,5-dichloro-phenyl, 3,5-difluoro-benzene base, 3-bromo-4-fluoro phenyl, 2-pyridine radicals, 3-pyridine radicals and 4-pyridine radicals.

108. the compound of claim 107, wherein V is 3,5-difluoro-benzene base.

109. the compound of claim 107, wherein said compound has the R-three-dimensional chemical configuration at the carbon place that V-connects, and has the S-three-dimensional chemical configuration in the phosphorus center.

110. the compound of claim 107, wherein said compound has the S-three-dimensional chemical configuration at the carbon atom place that V-connects, and has the R-three-dimensional chemical configuration in the phosphorus center.

111. the compound of claim 19, wherein said compound is:

Or its pharmaceutically acceptable salt.

112. the compound of claim 111, in mark the carbon atom place of the upright structure of generation of * have (R)-three-dimensional chemical configuration, have (S)-three-dimensional chemical configuration in the phosphorus center that produces upright structure:

113. the compound of claim 14, structural formula are XVIII, in mark the carbon atom place of the upright structure of generation of * have (S)-three-dimensional chemical configuration, have (R)-three-dimensional chemical configuration in the phosphorus center that produces upright structure:

114. a pharmaceutical compositions contains the compound and the pharmaceutically acceptable carrier of claim 101.

115. the method that hepatitis C virus (HCV) infects in the treatment human patients comprises the compound of the claim 101 of the described patient treatment effective dose of administration.

116. the method for claim 115, wherein the described compound of claim 101 is united use with second kind of medicament active component of the antagonism HCV infection of treatment effective dose.

117. be used for the treatment of purposes aspect the HCV medicine for treating viral infections in the human patients that these needs are being arranged in preparation according to the compound of claim 101.

118. the compound of claim 28, wherein said compound is:

119. the compound of claim 78, wherein said compound is: