CN1704423A

CN1704423A - Novel heteroaromatic inhibitors of fructose 1,6-bisphosphatase

Info

Publication number: CN1704423A
Application number: CN 200510080453
Authority: CN
Inventors: Q·党; S·R·卡斯布哈特拉; K·R·雷戴; M·D·埃里安; M·R·雷戴; A·阿加瓦尔
Original assignee: Metabasis Therapeutics Inc
Current assignee: Metabasis Therapeutics Inc
Priority date: 1998-09-09
Filing date: 1999-09-03
Publication date: 2005-12-07
Anticipated expiration: 2019-09-03
Also published as: CN101125864A; ZA200101711B; CN100349904C; RU2327700C2; CN1900087A

Abstract

Novel FBPase inhibitors of formula (I) and (X) are useful in the treatment of diabetes and other conditions associated with elevated blood glucose.

Description

New fructose 1, the heteroaromatic inhibitor of 6-diphosphatase

Invention field

Related application

The application is the part continuation application of provisional application sequence number 60/135504 (submission on September 9th, 1998) and 60/111077 (submission on December 7th, 1998), and this provisional application is attached to herein in full by reference.

The present invention relates to new heteroaromatics with phosphonate group for the fructose-1 inhibitor.The invention still further relates to that the preparation method of these compounds and these compounds suppress gluconeogenesis, glucose level control, minimizing glycogen storage or reduce insulin level at treatment diabetes and other is purposes in the useful disease.

Background of invention and introduction

Provide following description to background of the present invention helping understanding the present invention, but do not think prior art of the present invention, or to the description of prior art of the present invention.The publication of all citations all is attached to herein as a reference by reference.

Diabetes are one of most popular diseases in the world today.The diabetic subject is divided into two classes, i.e. I type or insulin-dependent diabetes and II type or non-insulin-dependent diabetes mellitus (NIDDM) (NIDDM).NIDDM accounts for the about 90% of whole diabetes, and only estimating just influences 1200-1400 ten thousand adults (population 6.6%) in the U.S..NIDDM with the empty stomach hyperglycemia and after meal plasma glucose levels excessively increase to Clinical symptoms.NIDDM and various secular complication comprise that microvascular disease (as retinopathy, ephrosis, neuropathy) is relevant with great vessels (macrovascular) disease (as coronary heart disease).Animal model studies confirm that cause-effect relationship between long-term hyperglycemia and the complication in a large number.Result from diabetes control and complication experiment (DCCT) and Stockholm perspective study has confirmed this relation first in the mankind, generation and development that the blood sugar of controlling pancreas islet rope dependent diabetes mellitus patient by strictness has significantly reduced these complication obtain proving.Strictness is kept on a diet also to expect to have and is benefited NIDDM patient.

At present treatment NIDDM patient's therapy must comprise two kinds of Hazard Factor in the control mode of life and drug intervention.A roentgenism x that is used for NIDDM is generally strictness and keeps on a diet and take exercise, because most NIDDM patients is overweight or fat (67%), loses weight and can improve secretion of insulin, increases the susceptibility of Regular Insulin and cause the blood sugar amount normal.Because severe complications and relatively poor replying in these patients, blood sugar normalizing person occurs less than 30%.It is single that oral hypoglycemic or Regular Insulin are treated subsequently with the out of contior hyperglycemic patients of sitotherapy.As of late, sulfonylurea is still a unique class oral hypoglycemic that can be used for NIDDM.Adopt sulfonylurea treatment only in 70% patient, to produce effective blood sugar and reduce, and after treatment 10 years, its effect only is 40%.Diet and the invalid patient of sulfonylurea are adopted injection of insulin treatment every day subsequently, so that obtain sufficient glycemic control.

Though concerning NIDDM patient, the treatment that sulfonylurea representative is main, 4 effects limit have been arranged its overall success.The first, as mentioned above, a big chunk of NIDDM colony does not have enough reactions (being the primitiveness failure) or produces resistance (being the Secondary cases failure) sulfonylurea treatment.This is especially like this in the NIDDM patient who suffers from NIDDM in late period, because these patients' insulin secretion is badly damaged.The second, sulfonylurea treatment is relevant with the increase of serious hypoglycemic episodes danger.The 3rd, chronic hyperinsulinemia is relevant with the cardiovascular disorder increase, though this relation is considered to controversial and does not obtain proof.At last, sulfonylurea is relevant with weight increase, and this causes the susceptibility of periphery Regular Insulin to worsen, and quickens the development of this disease thus.

The result who derives from Britain's diabetes perspective study shows that also the patient who accepts maximal dose sulfonylurea, N1,N1-Dimethylbiguanide or both combination therapys can not keep normal fasting blood glucose level during the research in 6 years.The perspective diabetes study 16.Diabetes of Britain, 44:1249-158 (1995).These results further illustrate the great demand to alternative medicine.

The gluconeogenesis that produces because of pyruvic acid and other 3-carbon precursor is the biosynthetic pathway that needs the altitude mixture control of 11 kinds of enzymes.Wherein the reaction of 7 kinds of enzyme catalysis reversible and to gluconeogenesis and glycolysis-the two is common.4 kinds of enzymes are arranged, i.e. the only reaction of catalysis gluconeogenesis of pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1 and G-6-Pase.Total flux by this approach is controlled by the specific activity of these enzymes and the validity of substrate material, and these enzymes are the catalysis corresponding step on the glycolysis-direction.Food factor (glucose, fat) and hormone (Regular Insulin, hyperglycemic-glycogenolytic factor, glucocorticosteroid, suprarenin) are on gluconeogenesis and glycolytic pathway, by genetic expression and mechanism coordination ground, translation back regulatory enzyme activity.

At 4 kinds gluconeogenesis is had in the specific enzyme, fructose-1 (after this being called " FBP enzyme ") is based on the only target of the gluconeogenesis inhibitor of validity and security consideration.Studies show that this character has been utilized and be responsible for determining that the FBP enzyme/PFK whether metabolic flux carries out circulates as major control point (metabolism switch (metabolic switch)) on glycolysis-or gluconeogenesis direction.Claus etc., The mechanism of insulin action, Belfrage, P edits, 305-321 page or leaf, Elsevier Science 1992; Regen etc., J.Theor.Biol., 111:635-658 (1984); Pilkis etc., Annu.Rev, Biochem, 57:755-783 (1988).The FBP enzyme is subjected to fructose-2 in the cell, the inhibition of 6-bisphosphate.Fructose-2,6-bisphosphate are incorporated into the substrate material site of this enzyme.AMP is incorporated into the allosteric site on this enzyme.

The existing report of the synthetic inhibitor of FBP enzyme.The McNieI report, fructose-2,6-bisphosphate analogue suppresses the FBP enzyme by being incorporated into the enzyme substrates site. J.Am, Chem.Soc., 106:7851-7853 (1984); No. the 4968790th, United States Patent (USP) (1984).Yet these compounds are quite weak, can not suppress the generation of glucose in the liver cell, and supposition is because due to the Premeabilisation of cells of difference.

The Gruber report, some ucleosides can reduce the blood sugar of whole animal by suppressing the FBP Phosphoric acid esterase.These compounds are brought into play its active function by at first making a corresponding phosphorylation thing stand phosphorylation.EP?0427799?B1。

Gruber etc. (No. the 5658889th, United States Patent (USP)) have described the purposes of the AMP site inhibitor for treating diabetes of FBP enzyme.The specific inhibitor of the FBP enzyme of treatment diabetes has been described among WO 98/39344, WO/39343 and the WO 98/39342.

Summary of the invention

The present invention relates to contain phosphate-based new heteroaromatics, they are effective FBP enzyme inhibitors.In yet another aspect, the present invention relates to the preparation method of this type compound and relate to FBP enzyme inhibition activity in the external and body of these compounds.Another aspect of the present invention relates to the clinical application of these FBP enzyme inhibitorss, and promptly it is as disease that the inhibition gluconeogenesis is responded and treatment of diseases or the prevention method that the lowering blood glucose level is responded.

Described compound also be used for the treatment of or prevent excessive glycogen storage disease, comprise the disease of atherosclerosis, myocardial ischemic injury and resemble the hypercholesterolemia that worsens because of hyperinsulinemia and hyperglycemia and the disease of hyperlipidaemia such as cardiovascular disorder such as metabolism disorder.

The present invention also comprises new compound and their method of use as shown in the formula I and X.The prodrug of formula I and X compound is also included within the scope of the invention.

Formula I formula X

Because these compounds can have asymmetric center, the present invention not only relates to the racemic mixture of these compounds, but also relates to one steric isomer.The present invention also comprises the pharmacy acceptable salt of formula I and X compound and/or useful salt, comprises acid salt.The present invention also comprises the prodrug of formula I and X compound.

Definition

According to the present invention, except as otherwise noted, following term defines with following meaning as used in this.

X and X among formula I and the X as used in this ²The group nomenclature mo is described the group be connected in phosphoric acid ester, and with the group end capping that is connected in heteroaromatic rings.For example, when X is alkylamino, then descend array structure to be intended to comprise:

(heteroaromatic rings)-NR-alk-P (O) (OR ¹) ₂

Similarly, group A, B, C, D, E, the A of heteroaromatic rings ", B ", C ", D ", E ", A ², L ², E ²And J ²Be described to term with other substituting group with the group end capping that is connected in heteroaromatic rings.In general, substituting group is named with the term of the group end capping of tie point.

Term " aryl " refers to have the aromatic group that 5-14 annular atoms and at least one ring have conjugation pi electronic system, comprises isocyclic aryl, heterocyclic aryl and dibenzyl, and all these groups all can be optionally substituted.Suitable aryl comprises phenyl and furans-2,5-two bases.

Isocyclic aryl is the group of carbon atom for the annular atoms on the aromatic ring wherein.Isocyclic aryl comprises monocycle isocyclic aryl and many rings or condensed compound, as the optional naphthyl that replaces.

Heterocyclic aryl or heteroaryl are to have 1-4 heteroatoms as the annular atoms of aromatic ring and remaining annular atoms is the group of carbon atom.Suitable heteroatoms comprises oxygen, sulphur, nitrogen and selenium (selendum).Suitable heteroaryl comprises furyl, thienyl, pyridyl, pyrryl, N-low alkyl group pyrryl, pyridyl-N-oxide compound, pyrimidyl, pyrazinyl, imidazolyl etc., and all groups are optional to be substituted.

Term " Cheng Huan " or " Cheng Huan's " refer to form on already present aryl or the heteroaryl another loop section.The new ring that forms can be carbocyclic ring or heterocycle, saturated or unsaturated, and contains 2-9 new atom, and wherein 0-3 can be the heteroatoms of taking from N, O and S.Become ring to mix atom, as the part of new formation ring from the X group.For example, phrase " L ²And E ²Be formed into the cyclic group of ring jointly ", comprise

Term " dibenzyl " expression contains the aryl of an above aromatic ring, comprises condensed ring system and the aryl that is replaced by other aryl.Such group can be optionally substituted.Suitable dibenzyl comprises naphthyl and xenyl.

Term " alicyclic radical " means the compound that is combined with aliphatic series and ring compound character.This type of ring compound includes, but is not limited to aromatics, cycloalkyl and bridge joint compound cycloalkyl.Ring compound comprises heterocycle.Cyclohexenyl ethyl and cyclohexyl ethyl are suitable alicyclic radicals.Such group can be optionally substituted.

Term " optional replacement " or " replacement " comprise the group that independently is selected from following substituting group replacement by 1-4: low alkyl group; lower aryl; rudimentary aralkyl; rudimentary alicyclic radical; hydroxyl; lower alkoxy; rudimentary aryloxy; perhaloalkyl radical; aralkoxy; heteroaryl; heteroaryloxy; heteroaralkyl; assorted aralkoxy; azido-; amino; guanidine radicals; amidino groups; halo; lower alkylthio; oxo; the acyl group alkyl; carboxyl ester; carboxyl;-formamido-; nitro; acyloxy; aminoalkyl group; the alkylamino aryl; alkylaryl; the alkylamino alkyl; alkoxy aryl; arylamino; aryl alkyl amino; phosphono; alkylsulfonyl;-formamido-alkylaryl;-formamido-aryl; hydroxyalkyl; haloalkyl; the alkylamino alkyl carboxyl-; the carbamido group alkyl-; cyano group; low-grade alkoxy alkyl; rudimentary perhaloalkyl radical and alkoxy aryl alkyl." aryl of replacement " and " heteroaryl of replacement " preferably refers to aryl and the heteroaryl by 1-3 substituting group replacement.Preferred these substituting groups are selected from low alkyl group, lower alkoxy, rudimentary perhaloalkyl radical, halo, hydroxyl and amino.When " replacement " describes R ³During group, do not comprise into ring.

Term " aralkyl " refers to the alkyl by the aryl replacement.Suitable aralkyl comprises benzyl, picolyl etc., and can be optionally substituted.Term " aralkyl-" refer to divalent group-aryl-alkylidene group-." heteroarylalkyl " refers to the alkylidene group by the heteroaryl replacement.

Term " alkylaryl-" refer to group-alk-aryl-, wherein " alk " is alkylidene group." rudimentary-alkylaryl-" refers to that wherein alkylidene group is this type of group of low-grade alkylidene.

Term " rudimentary " for example connects finger with organic group or compound respectively at this, has 10 at the most (comprising 10), preferably 6 (comprising 6) and advantageously for 1-4 carbon atom at the most.This type of group can be straight chain, side chain or cyclic.

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

Term " acyl group " refers to-C (O) R that wherein R is alkyl and aryl.

Term " carboxyl ester " refers to-C (O) OR that wherein R is alkyl, aryl, aralkyl and alicyclic radical, and all groups can be chosen replacement wantonly.

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

Term " oxo " refers in the alkyl=O.

Term " amino " refers to-NRR ' that wherein R and R ' independently are selected from hydrogen, alkyl, aryl, aralkyl and alicyclic radical, and except that H, all groups can be chosen replacement wantonly; And R and R ', can form the cyclic ring system.

Term " carbonylamino " and " carbonylamino-" refer to respectively RCONR-and-CONR-, wherein each R independently is a hydrogen or alkyl.

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

Term " oxygen base alkylamino " refers to-O-alk-NR-that wherein " alk " is that alkylidene group and R are H or alkyl.

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

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

Term " oxygen base alkyl-" refers to group-O-alk-, and wherein " alk " is alkylidene group.

Term " alkyl carboxyl alkyl-" refers to group-alk-C (O)-O-alk-, and wherein each alk independently is an alkylidene group.

Term " alkyl " refers to saturated aliphatic group, comprises straight chain, side chain or cyclic group.Alkyl group can be optional the replacement.Suitable alkyl group comprises methyl, sec.-propyl and cyclopropyl.

Term " cyclic alkyl " or " cycloalkyl " refer to be the cyclic alkyl group.Suitable cyclic group comprises norcamphyl and cyclopropyl.This type of group can be substituted.

Term " heterocyclic radical " and " Heterocyclylalkyl " refer to 3-10 atom, the more preferably cyclic group of 3-6 atom, contain at least one heteroatoms, preferred 1-3 heteroatoms.Suitable heteroatoms comprises oxygen, sulphur and nitrogen.Heterocyclic radical can connect by nitrogen on the ring or carbon atom.Suitable heterocyclic radical comprises pyrrolidyl, morpholino, morpholino ethyl and pyridyl.

Term " phosphono " refers to-PO ₃R ₂, wherein R is selected from-H, alkyl, aryl, aralkyl and alicyclic radical.

Term " alkylsulfonyl " refers to-SO ₃R-, wherein R is H, alkyl, aryl, aralkyl and alicyclic radical.

Term " alkenyl " refers to contain the unsaturated group of at least one carbon-to-carbon double bond, comprises straight chain, side chain and cyclic group.Alkenyl can be optional the replacement.Suitable alkenyl comprises allyl group." 1-alkenyl " refers to wherein the alkenyl of two keys between first and second carbon atom.If the 1-alkenyl connects another group, for example the W substituting group is connected in ring (amino) phosphoric acid ester, and then it is connected on first carbon.

Term " alkynyl group " refers to contain the unsaturated group of at least one carbon-to-carbon triple bond, comprises straight chain, side chain and cyclic group.Alkynyl group can be optional the replacement.Suitable alkynyl group comprises ethynyl." 1-alkynyl group " refers to the alkynyl group between first and second carbon atom of triple bond wherein.If the 1-alkynyl group connects another group, for example the W substituting group is connected in ring (amino) phosphoric acid ester, and then it is connected on first carbon.

Term " alkylidene group " refers to divalence straight chain, side chain or cyclic radical of saturated aliphatic group.

Term " cycloalkylidene-COOR " refers to contain 4-6 atom on divalent cycloalkyl or the ring, 0-1 heteroatomic heterocyclic radical that is selected from O, N and S.Cycloalkyl or heterocyclic radical are by-COOR ³Replace.

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

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

Term " alkyl (hydroxyl)-" refers on the alkyl chain-OH.When this term was the X group, described-OH was on the α position with respect to phosphorus atom.

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

Term " arylamino alkyl-" refers to group aryl-NR-alk-, and wherein " alk " is that alkylidene group and R are H, alkyl, aryl, aralkyl and alicyclic radical.In " lower aryl aminoalkyl group-", alkylidene group is a low-grade alkylidene.

Term " alkylamino aryl-" refer to group alkyl-NR-aryl-, wherein " aryl " is H, alkyl, aralkyl and alicyclic radical for divalent group and R.In " low-grade alkyl amino aryl-", alkylidene group is a low alkyl group.

Term " alkoxy aryl-" refers to the aryl by the alkoxyl group replacement.In " lower alkoxy aryl-", described alkyl is a low alkyl group.

Term " aryloxy alkyl-" refers to the alkyl by the aryloxy replacement.

Term " sweet-smelling alkoxy alkyl-" refers to group aryl-alk-O-alk-, and wherein " alk " is alkylidene group." rudimentary sweet-smelling alkoxy alkyl-" refers to that alkylidene group is this type of group of low-grade alkylidene.

Term " alkoxyl group-" or " alkyl oxy-" refer to group aryl-alk-O-, and wherein " alk " is alkylidene group.Term " alkoxyl group-" refers to group alkyl-O-.

Term " alkoxyalkyl-" or " alkyl oxy alkyl-" refer to group aryl-alk-O-alk-, and wherein each " alk " independently is selected from alkylidene group.In " rudimentary-alkoxyalkyl-", each alkylidene group is a low-grade alkylidene.

Term " alkylthio-" or " alkylthio-" refer to respectively group alkyl-S-and-alk-S-, wherein " alk " is alkylidene group.

Term " alkylthio alkyl-" refers to group alkyl-alk-S-alk-, and wherein each " alk " independently is selected from alkylidene group.In " rudimentary-alkylthio alkyl-", each alkylidene group is a low-grade alkylidene.

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

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

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

Term " alkoxycarbonyl amino-" refers to-alk-O-C (O)-NR ¹-, wherein " alk " is alkylidene group and R ¹Comprise-H, alkyl, aryl, alicyclic radical and aralkyl.

Term " alkyl amino-carbonyl amino-" refers to-alk-NR ¹-C (O)-NR ¹-, wherein " alk " is alkylidene group and R ¹Independently be selected from H, alkyl, aryl, aralkyl and alicyclic radical.

Term " amide group " or " formamido-" refer to NR ₂-C (O)-and RC (O)-NR ¹-, wherein R and R ¹Comprise H, alkyl, aryl, aralkyl and alicyclic radical.This term do not comprise urea ,-NR-C (O)-NR-.

Term " formamido-alkylaryl " or " formamido-aryl " refer to aryl-alk-NR respectively ¹-C (O)-and-NR ¹-C (O)-alk-, wherein " virtue " is aryl, " alk " is alkylidene group, R ¹Comprise H, alkyl, aryl, aralkyl and alicyclic radical with R.

Term " alkyl formamides base " or " alkyl-carbonyl-amino-" refer to group-alk-C (O) N (R)-, wherein " alk " is H or low alkyl group for alkylidene group and R.

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

Term " thiocarbonic ester " refers on the chain or on the cyclic group-O-C (S)-O-

Term " hydroxyalkyl " refers to the alkyl by one-OH replacement.

Term " haloalkyl " refers to the alkyl by a halogeno-group replacement that is selected from group I, Cl, Br and F.

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 group.

Term " heteroarylalkyl " refers to the alkyl by the heteroaryl replacement.

Term " 1,1-dihalo alkyl-" refer to 1 X group, so halogen is in the α position with respect to phosphorus atom.

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

Term " guanidine radicals " refers to-NR-C (NR)-NR ₂And-N=C (NR ₂) ₂, wherein each R group independently is selected from-H, alkyl, alkenyl, alkynyl group, aryl and alicyclic radical, and except that H, all groups can be chosen replacement wantonly.

Term " amidino groups " refers to-C (NR)-NR ₂, wherein each R group independently is selected from-H, alkyl, alkenyl, alkynyl group, aryl and alicyclic radical, and except that-H, all groups can be chosen replacement wantonly.

Term " pharmacy acceptable salt " comprises the salt of formula I compound and is closed and the deutero-prodrug by The compounds of this invention and organic or inorganic acid, organic or inorganic alkalization.Suitable acid comprises hydrochloric acid.

Term used herein " prodrug " refers to when giving biosystem, generates any compound of " medicine " material (bioactive compounds) because of spontaneous chemical reaction, enzymatic chemical reaction and/or metabolic chemical reaction.Use is connected in the functionality relevant with the FBP enzyme inhibitors (as HO-, HS-, HOOC-, R ₂N-) group (cracking in vivo) forms the prodrug of standard.The prodrug of standard includes, but is not limited to the ester (group that wherein is connected is acyl group, alkoxy carbonyl, aminocarboxyl, phosphoric acid ester or sulfuric ester) of carboxylicesters (wherein said group is alkyl, aryl, aralkyl, acyloxy alkyl, alkoxy-carbonyl oxy alkyl) and hydroxyl, thiol and amine.Comprise that also phosphonic standard prodrug also can be by the R among formula I and the X ¹Expression.Illustrated group only is exemplary, can not all list, and those skilled in the art can prepare the prodrug of known other kind.This type of prodrug of the compound of formula I and X all within the scope of the present invention.Prodrug must be through the chemical transformation of some form, and producing has the compound of biologic activity or be the compound of biologically active cpds precursor.In some cases, the biologic activity of prodrug is usually less than described medicine itself, and improves curative effect or security by improving oral administration biaavailability, pharmacokinetics transformation period etc.

Term used herein " prodrug ester " includes, but is not limited to the combination of following groups and these groups:

[1] acyloxy alkyl ester, its document (Farquhar etc., J.Pharm, Sci.72, fully described 324-325 (1983)) and represented by formula A

Formula A

Wherein R, R ' and R " independent be H, alkyl, aryl, alkylaryl and alicyclic radical; (see WO 90/08155; WO 90/10636).

[2] other acyloxy alkyl ester also is possible, wherein forms suc as formula the alicyclic ring basic ring shown in the B.Shown these esters by initial, continued with the supposition reaction sequence of a series of elimination reactions by taking off esterification, the phosphorous Nucleotide of generation in cell (as, Freed etc., Biochem. Pharm.38:3193-3198 (1989)).

Formula B

Wherein R is-H, alkyl, aryl, alkylaryl, alkoxyl group, aryloxy, alkylthio, arylthio, alkylamino, arylamino, cycloalkyl or alicyclic radical.

[3] (wherein R is alkoxyl group, aryloxy, alkylthio, arylthio, alkylamino and arylamino to be known as these dibasic acid esters of alkoxy-carbonyl oxy methyl esters suc as formula another kind of shown in the A; R ' and R " independent be H, alkyl, aryl, alkylaryl and alicyclic radical) in-beta-lactam antibiotics field, be carried out research (Tatsuo Nishimura etc., J.Antibiotics.1987,40 (1), 81-90; For summary, see Ferres, H., Drugs of Today, 1983,19,499.).Recently; Cathy; (Abstract from AAPS Western Regional Meeting such as M.S.; show that in April, 1997) these alkoxy-carbonyl oxy methyl esters prodrugs are to (9-[(R)-2-phosphonium mesitoyl methoxy) propyl group] VITAMIN B4 (PMPA) has the bioavailability up to 30% in dog.

[4] also use aryl ester as phosphonate prodrugs (as, Erion, DeLambert etc., J.Med.Chem.37:498,1994; Serafinowska etc., J.Med.Chem.38:1372,1995).Generated parent phosphonic acids (formula C) in the research that the preceding ester of phenyl of ester and one and many before the phenyl-replace carries out in the animal and human.Another wherein Y describe with respect to the approach of the adjacent carboxylicesters of phosphoric acid ester is existing.Khamnei and Torrence, J.Med.Chem.; 39:4109-4115 (1996).

Formula C

Wherein Y is H, alkyl, aryl, alkylaryl, alkoxyl group, acyloxy, halogen, amino, alkoxy carbonyl, hydroxyl, cyano group and alicyclic radical.

[5] report that in addition the benzyl ester can generate the parent phosphonic acids.In some cases, use substituting group can quicken hydrolytic action in contraposition.By the effect of enzyme such as oxydase, esterase etc., can make benzyl analogue [formula D, X=H, OR or O (CO) R or O (CO) OR] generate the 4-oxy-compound easilier with 4-acyloxy or 4-alkoxyl group.Mitchell etc. exist J.Chem. Soc.Perkin Trans.I 2345 (1992); Brook etc. have described the example of this type of prodrug in WO 91/19721.

Formula D

Wherein X and Y independently are H, alkyl, aryl, alkylaryl, alkoxyl group, acyloxy, hydroxyl, cyano group, nitro, perhaloalkyl radical, halo or alkoxy carbonyl; With

R ' and " independent be H, alkyl, aryl, alkylaryl, halogen and alicyclic radical.

[6] existingly describe that to contain before the Thiophosphonate that ester is passed in the liver cell at the FBP enzyme inhibitors be useful.These preceding esters contain the thio-ethyl part suc as formula the protection shown in the E.One or more oxygen in the phosphonic acid ester can be esterified.Owing to cause that the mechanism of taking off esterification need produce the free thiolate, various thiol blocking groups are possible.For example, the method reduction disulphide by reductase enzyme mediation (Puech etc., Antiviral Res., 22:155-174 (1993)).Monothioester also can generate the free thiolate after the hydrolytic action of esterase mediation.Benzaria etc., J. Med.Chem., 39:4958 (1996).Cyclic analogs also is possible and shows in isolating rat hepatocytes and discharge phosphonic acid ester.Below shown in cyclic disulfide describe before this, thereby be newly to change the house thing.

Formula E

Wherein Z is alkyl-carbonyl, alkoxy carbonyl, aryl carbonyl, aryloxycarbonyl or alkylthio.

The example of the prodrug that other is suitable comprises by Biller and Maglnin (No. the 5157027th, United States Patent (USP)); Serafinowska etc. ( J.Med.Chem.38,1372 (1995)); Starrett etc. ( J.Med.Chem.37,1857 (1994)); Martin etc. ( J.Pharm.Sci.76,180 (1987)); Alexander etc. ( Collect.Czech, Chem.Commun59,1853 (1994)) and the cited preceding ester type of EPO patent application 0632048 A1. some described structure type is optional the replacement, comprise condensed lactone (formula E-1 and E-2) that is connected on the ω position and the 2-oxo-1 that is connected in the optional replacement on the phosphorus Sauerstoffatom by methylene radical, 3-dioxole (dioxolene) (formula E-3), for example:

3-benzo [c] 2-oxo four 2-oxos-4,5-two-dehydrogenation

Furanonyl hydrogen furans-5-base-1,3-dioxolane methyl

E-1????????????????????????????????????E-2??????????????????????E-3

Wherein R is-H, alkyl, cycloalkyl or alicyclic radical; With

Wherein Y is-H, alkyl, aryl, alkylaryl, cyano group, alkoxyl group, acyloxy, halogen, amino, alicyclic radical and alkoxy carbonyl.

The prodrug of formula E-3 is the example of " the optional alicyclic radical that replaces, wherein said loop section contains carbonic ether or thiocarbonic ester ".

[7] ester also can be used to the EBP enzyme inhibitors is passed to liver cell before the phosphonic acids propyl ester.Shown in F, these preceding esters can contain hydroxyl and the hydroxy derivatives on 3 of propyl group.As shown in the formula F, R and X group can form the cyclic ring system.One or more oxygen of phosphonic acid ester can be esterified.

Formula F

Wherein R is alkyl, aryl, heteroaryl;

X is hydrogen, alkyl-carbonyl oxygen base, alkoxy-carbonyl oxy; With

Y is alkyl, aryl, heteroaryl, alkoxyl group, alkylamino, alkylthio, halogen, hydrogen, hydroxyl, acyloxy, amino.

[8] suc as formula the phosphoramidic acid ester derivative shown in the G be developed to the phosphoric acid ester prodrug (as, McGuigan etc., J.Med.Chem., 1999,42:393 and at this reference of quoting).

Formula G

Cyclic amino phosphoric acid ester as phosphonate prodrugs is also studied because infer they and acyclic phosphoramidate relatively, have height stability (as, Starrett etc., J. Med.Chem., 1994,37:1857).

Suc as formula the Nucleotide prodrug of another type shown in the H as the combination of S-acyl group-2-sulfo-ethyl ester and phosphoramidate be in the news (Egron etc., Nucleosides; Nucleotides, 1999,18,981).

Formula H

Based on bibliographical information, for example other prodrug of the ethyl of Qu Daiing also is possible, as by McGuigan etc., Bioorg Med, Chem.Lett., disclosed two (three chloroethyls) esters of 3:1207-1210 (1993) and by Meier, C. etc., Bioorg.Med.Chem.Lett., the phenyl and the benzyl bonded nucleosides acid esters of 7:99-104 (1997) report.

Work as R ⁶=R ⁶, V=W, W '=H,, V and W be all up or all down the time, following structure

Has plane by the two key symmetric motions of phosphorus-oxygen.When each-NR ⁶When quilt-O-substitutes, meet this structure equally.

Term " ring-type 1 ', 3 '-propane ester ", " ring-type 1,3-propane ester ", " ring-type 1 ', 3 '-propyl ester ", " ring-type 1,3-propyl ester " all refer to following structure:

Array structure under phrase " V and Z link together by an other 3-5 atom; form the cyclic group contain 5-7 atom (optional heteroatoms); this cyclic group is replaced by the hydroxyl that is connected in carbon atom, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described carbon atom be connected in two Y groups of phosphorus atom all at a distance of three atoms " comprises:

With

Above the structure shown in (left side) have other 3 carbon atoms that form 5 yuan of cyclic groups.Such cyclic group must have list can be oxidized the position of substitution.

Phrase " V and Z link together by an other 3-5 atom, form the optional heteroatomic cyclic group that contains, this cyclic group aryl-condensed with respect to the β position of the Y that is connected phosphorus atom and γ position " comprises time array structure:

Phrase " V and W link together by 3 other carbon atoms; form the cyclic group of the optional replacement contain 6 carbon atoms and to be replaced by a substituting group that is selected from following group: hydroxyl, acyloxy, alkoxy-carbonyl oxy, alkylthio ketonic oxygen base and aryloxycarbonyl oxygen base; this substituting group is connected with one of described other carbon atom, this carbon atom and the Y that is connected phosphorus atom be three atoms apart " comprises following structure:

Top structure has acyloxy substituting group and the optional substituting group apart from Y3 carbon atom on new 6-unit ring ,-CH ₃On following each position, has at least one hydrogen: the carbon that is connected in Z; With respect to the carbon that indicates " 3 " is two carbon of α position; " OC (O) CH above being connected in ₃" carbon.

Phrase " W and W ' link together by an other 2-5 atom, form optional 0-2 the heteroatomic cyclic group that contain, and V is necessary for the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement " comprises following structure:

For W and W ', top structure has V=aryl and spiral shell-condense propyl group.

Term " ring (amino) phosphoric acid ester " refers to

Wherein Y independently be-O-or-NR ⁶-.The carbon that is connected in V must have c h bond.The carbon that is connected in Z also must have c h bond.

Term " liver " refers to liver and contains the CYP3A4 isozyme or any other found the allied organization and the cell of the P450 isozyme of oxidable (amino) of the present invention phosphoric acid ester.According to embodiment F, we find that the prodrug of formula VI and VIII can be by optionally oxidation of Cytochrome P450 isozyme CYP3A4.According to (J.Pharm.Exp.Ther., 253,387-394 (1990)) such as DeWaziers, CYP3A4 is arranged in people's following tissue (measuring by immunoblotting and enzyme assay):

Tissue The active % of liver

Liver 100

Duodenum 50

Jejunum 30

Ileum 10

Colon＜5 (only finding the P450 isozyme)

Stomach＜5

Oesophagus＜5

Kidney does not detect

Therefore, " liver " more preferably refers to liver, duodenum, jejunum, ileum, colon, stomach and oesophagus.Most preferably, liver refers to the liver organ.

Term " enhancing " refers to increase or improve specificity.

Term " liver specificity " refers to measured ratio in the animal of medicine or prodrug treatment:

[medicine in the hepatic tissue or the meta-bolites of medicine]

[medicine in blood or other tissue or the meta-bolites of medicine].

This ratio can be by organizing level to measure or the AUC of the available value of measuring based on 3 or more times point represents in specific time measurement.

Term " increase or enhanced liver specificity " refers to prodrug treatment animal with respect to the increase with the liver specificity ratio of parent drug treatment animal.

Term " raising oral administration biaavailability " refers to the dosage increase at least 50% by the parent drug of gastrointestinal absorption or prodrug (non-the present invention).More preferably be at least 100%.The measurement of oral administration biaavailability is often referred to the comparison of measuring prodrug, medicine or the drug metabolite in blood, tissue or the urine and the back observed value that is administered systemically behind the orally give.

Term " parent drug " refers to transmit any compound of identical biologically active cpds.The parent drug form is R ⁵-X-P (O) (OH) ₂Prodrug such as ester with standard.

Term " drug metabolite " refers in vivo or the external any compound that is produced by parent drug that it can comprise biologically active drug.

After term " pharmacokinetics transformation period " was showed and given medicine or prodrug, the pharmacological reaction of observing measurement reduced half required time.When the pharmacokinetics transformation period preferably increased at least 50%, the pharmacokinetics transformation period strengthened.

After term " pharmacokinetics transformation period " was showed and given medicine or prodrug, the drug level of observed blood plasma or tissue reduced half required time.

The dosage that term " therapeutic index " refers to produce useful medicine of replying of treatment or prodrug is with respect to producing unwanted ratio of replying as dosage dead, that raise for the marker of toxicity and/or pharmacology side effect index.

Term " slowly-releasing " refers to have the blood levels of the biologic activity medicine of enough generation curative effects in the time that prolongs.

Term " bypass drug resistance " refers to because desired area in the body is produced and keep the change of important bio-chemical pathway of the biologic activity form of medicine and cytoactive and medicine by adopting forfeiture or the part forfeiture (drug resistance) to curative effect of medication due to the ability that gets around this resistance of other approach and cytoactive.

Term " biologically active drug or promoting agent " refers to produce the chemical entities of biological action.Therefore, active medicine or promoting agent are included as bioactive R ³-X-P (O) (OH) ₂Compound.

Term " treatment significant quantity " refers to have the amount of any beneficial effect in treatment disease or illness.

Preferred formula I compound

Suitable alkyl comprises the group with about 20 carbon atoms of 1-.Suitable aryl comprises the group with about 20 carbon atoms of 1-.Suitable aralkyl comprises the group with about 21 carbon atoms of 2-.Suitable acyloxy comprises the group with about 20 carbon atoms of 1-.Suitable alkylidene group comprises the group with about 20 carbon atoms of 1-.Suitable alicyclic radical comprises the group with about 20 carbon atoms of 3-.Suitable heteroaryl comprises having about 20 carbon atoms of 1-and 1-4 heteroatomic group that preferably independently is selected from nitrogen, oxygen, p and s.Suitable heterolipid cyclic group comprises having about 20 carbon atoms of 2-and 1-5 heteroatomic group that preferably independently is selected from nitrogen, oxygen, p and s.

In claimed method, following formula (I) compound and pharmaceutically acceptable prodrug thereof and salt are preferred:

With

Wherein:

Each G independently is selected from C, N, O, S and Se, and wherein having only a G can be O, S or Se;

Each G ' independently is selected from C and N, and wherein being no more than two G ' groups is N;

A is selected from-H ,-NR ⁴ ₂,-CONR ⁴ ₂,-CO ₂R ³, halo ,-S (O) R ³,-SO ₂R ³, alkyl, alkenyl, alkynyl group, perhaloalkyl radical, haloalkyl, aryl ,-CH ₂OH ,-CH ₂NR ⁴ ₂,-CH ₂CN ,-CN ,-C (S) NH ₂,-OR ³,-SR ³,-N ₃,-NHC (S) NR ⁴ ₂,-NHAc and not existing;

Each B and D independently be selected from-H, alkyl, alkenyl, alkynyl group, aryl, alicyclic radical, aralkyl, alkoxyalkyl ,-C (O) R ¹¹,-C (O) SR ³,-SO ₂R ¹¹,-S (O) R ³,-CN ,-NR ⁹ ₂,-OR ³,-SR ³, perhaloalkyl radical, halo ,-NO ₂Do not exist, except-H ,-CN, perhaloalkyl radical ,-NO ₂Outside halo, all above-mentioned groups can be chosen replacement wantonly;

E is selected from-H, alkyl, alkenyl, alkynyl group, aryl, alicyclic radical, alkoxyalkyl ,-C (O) OR ³,-CONR ⁴ ₂,-CN ,-NR ⁹ ₂,-NO ₂,-OR ³,-SR ³, perhaloalkyl radical, halo and do not exist, except-H ,-CN, perhaloalkyl radical and halo, all above-mentioned groups can be chosen replacement wantonly;

J is selected from-H and not existing;

X is the optional linking group that replaces, and this group comprises 0-1 heteroatoms that is selected from N, O and S, with R by 2-4 atom ⁵Be connected on the phosphorus atom, but except the following situation, if promptly X is for having 2 heteroatomic ureas or carbamate (through R ⁵And the shortest approach is measured between the phosphorus atom), the atom that then wherein connects phosphorus atom is a carbon atom, and does not have nitrogen-atoms in linking group, unless it is directly connected in carbonyl, or on the heterocyclic ring; And X be not 2 carbon atom-alkyl-or-alkenyl-; Prerequisite is that X can't help-COOR ²,-SO ₃R ¹Or-PO ₃R ¹ ₂Replace;

Y independently is selected from-O-and-NR ⁶-;

When Y be-during O-, then be connected in-R of O- ¹Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alicyclic radical (wherein loop section contains carbonic ether or thiocarbonic ester) that replaces, optional replace-alkylaryl ,-C (R ²) ₂OC (O) NR ² ₂,-NR ²-C (O)-R ³,-C (R ²) ₂-OC (O) R ³,-C (R ²) ₂-O-C (O) OR ³,-C (R ²) ₂OC (O) SR ³, alkyl-S-C (O) R ³, alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy,

When Y is-NR ⁶In-time, then be connected in-NR ⁶-R ¹Independently be selected from-H ,-[C (R ²) ₂] _q-COOR ³,-C (R ⁴) ₂COOR ³,-[C (R ²) ₂] _q-C (O) SR and-cycloalkylidene-COOR ³

Or independently be selected from-O-and-NR as arbitrary Y ⁶The time, R then ¹And R ¹Be together-alkyl-the S-S-alkyl-with the formation cyclic group, or R ¹And R ¹Be together

Wherein

V, W and W ' independently be selected from-heteroaryl, 1-key thiazolinyl and the 1-alkynyl group of the aryl of H, alkyl, aralkyl, alicyclic radical, aryl, replacement, heteroaryl, replacement; Or

V and Z link together by an other 3-5 atom, formation contains the cyclic group of 5-7 atom (optional heteroatoms), this cyclic group is replaced by the hydroxyl that is connected in carbon atom, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described carbon atom be connected in two Y groups of phosphorus atom all at a distance of three atoms; Or

V and Z link together by an other 3-5 atom, form the optional heteroatomic cyclic group that contains, this cyclic group aryl-condensed with respect to the β position of the Y that is connected phosphorus atom and γ position;

V and W link together by 3 other carbon atoms, formation contains 6 carbon atoms and the cyclic group of the optional replacement that replaced by a substituting group that is selected from following group: hydroxyl, acyloxy, alkoxy-carbonyl oxy, alkylthio ketonic oxygen base and aryloxycarbonyl oxygen base, this substituting group is connected with one of described carbon atom, and this carbon atom and the Y that is connected phosphorus atom are at a distance of three atoms;

Z and W link together by an other 3-5 atom, form to choose wantonly to contain a heteroatomic cyclic group, and V is necessary for the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement;

W and W ' link together by an other 2-5 atom, form optional 0-2 the heteroatomic cyclic group that contain, and V is necessary for the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement;

Z is selected from-CHR ²OH ,-CHR ²OC (O) R ³,-CHR ²OC (S) R ³,-CHR ²OC (S) OR ³,-CHR ²OC (O) SR ³,-CHR ²OCO ₂R ³,-OR ²,-SR ²,-CHR ²N ₃,-CH ₂Aryl ,-CH (aryl) OH ,-CH (CH=CR ² ₂) OH ,-CH (C ≡ CR ²) OH ,-R ²,-NR ² ₂,-OCOR ³,-OCO ₂R ³,-SCOR ³,-SCO ₂R ³,-NHCOR ²,-NHCO ₂R ³,-CH ₂The NH aryl ,-(CH ₂) _p-OR ²With-(CH ₂) _p-SR ²

P is 2 or 3 integer;

Q is 1 or 2 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H; And

B) as Z be-R ²The time, then at least one is not-H, alkyl, aralkyl or alicyclic radical among V, W and the W ';

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

Each R ⁴Independently be selected from-H and alkyl, or R ⁴And R ⁴Form cycloalkyl together;

R ⁶Be selected from-H, low alkyl group, acyloxy alkyl, alkoxy-carbonyl oxy alkyl and lower acyl;

Each R ⁹Independently be selected from-H, alkyl, aralkyl and alicyclic radical, or R ⁹And R ⁹Form cycloalkyl together;

R ¹¹Be selected from alkyl, aryl ,-NR ² ₂With-OR ²With

Prerequisite is:

1) when G ' is N, then A, B, D or E are respectively and do not exist;

2) A and B, or at least one is not selected from-H or do not exist among A, B, D and the E;

3) work as R ⁵Be 6 yuan of whens ring, then X be not any two atoms connection base, the optional replacement-alkyl-, the optional replacement-alkenyl-, the optional replacement-alkoxyl group-or optional replacement the-alkylthio-;

4) when G is N, then A or B are not halogen or the group that is directly connected in G by heteroatoms separately;

5) R ¹It or not unsubstituted C1-C10 alkyl;

6) as X be not-aryl-time, then R ⁵Can't help two or more aryl replaces.

In the method for using this compounds, preferred R ⁵Group comprises pyrryl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl group, pyrazolyl, isoxazolyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3,4-tetrazyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,3,5-triazines base, 1,2,4-triazinyl and 1,3-selenazoles base, all these groups all have at least one substituting group.

More preferably R wherein ⁵Compound for following groups:

With

Wherein

A " be selected from-H ,-NR ⁴ ₂,-CONR ⁴ ₂,-CO ₂R ³, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, C1-C6 perhalogeno alkane table C1-C6 haloalkyl, aryl ,-CH ₂OH ,-CH ₂NR ⁴ ₂,-CH ₂CN ,-CN ,-C (S) NH ₂,-OR ³,-SR ³,-N ₃,-NHC (S) NR ⁴ ₂With-NHAc;

B " and D " independently be selected from-H, alkyl, alkenyl, alkynyl group, aryl, alicyclic radical, aralkyl, alkoxyalkyl ,-C (O) R ¹¹,-C (O) SR ³,-SO ₂R ¹¹,-S (O) R ³,-CN ,-NR ⁹ ₂,-OR ³,-SR ³, perhaloalkyl radical and halo, except-H ,-CN, perhaloalkyl radical and halo, all above-mentioned groups can be chosen replacement wantonly;

E " be selected from-H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, aryl, C4-C6 alicyclic radical, alkoxyalkyl ,-C (O) OR ,-CONR ⁴ ₂,-CN ,-NR ⁹ ₂,-OR ³,-SR ³, C1-C6 perhaloalkyl radical and halo, except-H ,-CN, perhaloalkyl radical and halo, all above-mentioned groups can be chosen replacement wantonly; With

C " be selected from-H, alkyl, alkyl chain thiazolinyl, alkyl chain alkynyl, aryl, alicyclic radical, aralkyl, aryloxy alkyl and alkoxyalkyl, all above-mentioned groups can be chosen replacement wantonly;

R ⁴Be selected from-H and C1-C2 alkyl.

Especially preferred R wherein ⁵Compound for following groups:

With

Wherein

A " be selected from-H ,-NR ⁴ ₂,-CONR ⁴ ₂,-CO ₂R ³, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, C1-C6 perhaloalkyl radical, C1-C6 haloalkyl, aryl ,-CH ₂OH ,-CH ₂NR ⁴ ₂,-CH ₂CN ,-CN ,-C (S) NH ₂,-OR ³,-SR ³,-N ₃,-NHC (S) NR ⁴ ₂With-NHAc;

E " be selected from-H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, C4-C6 alicyclic radical, alkoxyalkyl ,-C (O) OR ³,-CONR ⁴ ₂,-CN ,-NR ⁹ ₂,-OR ³,-SR ³, C1-C6 perhaloalkyl radical and halo, except H ,-CN, perhaloalkyl radical and halo,

All above-mentioned groups can be chosen replacement wantonly; With

Each R ⁴Independently be selected from-H and C1-C2 alkyl.

In the method, preferred X group comprises-alkyl (hydroxyl)-,-alkyl ,-alkynyl group-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkoxyl group-,-alkylthio alkyl-,-alkylthio-,-alkyl amino-carbonyl ,-alkyl-carbonyl-amino-,-alicyclic radical-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-,-alkylamino-and-alkenyl-, all groups are optional to be replaced.

In claimed Compounds and methods for, compound and the pharmaceutically acceptable prodrug and the salt of preferred new following formula (I):

R wherein ⁵Be selected from:

With

Wherein

Each G independently is selected from C, N, O, S and Se, wherein have only a G can be O, S or Se and at the most a G be N;

A is selected from-H ,-NR ⁴ ₂,-CONR ⁴ ₂,-CO ₂R ³, halo ,-S (O) R ³,-SO ₂R ³, alkyl, alkenyl, alkynyl group, perhaloalkyl radical, haloalkyl, aryl ,-CH ₂OH ,-CH ₂R ⁴ ₂,-CH ₂CN ,-CN ,-C (S) NH ₂,-OR ³,-SR ³,-N ₃,-NHC (S) NR ⁴ ₂,-NHAc and not existing;

J is selected from-H and not existing;

X is the optional linking group that replaces, and this group comprises 0-1 heteroatoms that is selected from N, O and S, with R by 2-4 atom ⁵Be connected on the phosphorus atom, but except the following situation, if promptly X is for having 2 heteroatomic ureas or carbamate (through R ⁵And the shortest approach is measured between the phosphorus atom), the atom that then wherein connects phosphorus atom is a carbon atom, and does not wherein have nitrogen-atoms on linking group, unless it is directly connected in carbonyl, or on the heterocyclic ring; And X be not 2 carbon atom-alkyl-or-alkenyl-; Prerequisite is that X can't help-COOR ²,-SO ₃R ¹Or-PO ₃R ¹ ₂Replace;

Y independently is selected from-O-and-NR ⁶-;

When Y be-during O-, then be connected in-R of O- ¹Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alicyclic radical (wherein loop section contains carbonic ether or thiocarbonic ester) that replaces, optional replace-alkylaryl ,-C (R ²) ₂OC (O) NR ² ₂,-NR ²-C (O)-R ³,-C (R ²) ₂-OC (O) R ³,-C (R ²) ₂-O-C (O) OR ³,-C (R ²) ₂OC (O) SR ³,-alkyl-S-C (O) R ³,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy,

Or independently be selected from-O-and-NR as arbitrary Y ⁶-time, then R ¹And R ¹Be together-alkyl-the S-S-alkyl-with the formation cyclic group, or R ¹And R ¹Be together

Wherein

V, W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl group of the aryl of H, alkyl, aralkyl, alicyclic radical, aryl, replacement, heteroaryl, replacement; Or

V and W link together by 3 other atoms, formation contains 6 carbon atoms and the cyclic group of the optional replacement that replaced by a substituting group that is selected from following group: hydroxyl, acyloxy, alkoxy-carbonyl oxy, alkylthio ketonic oxygen base and aryloxycarbonyl oxygen base, this substituting group is connected with one of described carbon atom, and this carbon atom and the Y that is connected phosphorus atom are at a distance of three atoms;

Z is selected from-CHR ²OH ,-CHR ²OC (O) R ³,-CHR ²OC (S) R ³,-CHR ²OC (S) OR ³,-CHR ²OC (O) SR ³,-CHROCO ₂R ³,-OR ²,-SR ²,-CHR ²N ₃,-CH ₂Aryl ,-CH (aryl) OH ,-CH (CH=CR ² ₂) OH ,-CH (C ≡ CR ²) OH ,-R ²,-NR ² ₂,-OCOR ³,-OCO ₂R ³,-SCOR ³,-SCO ₂R ³,-NHCOR ²,-NHCO ₂R ³,-CH ₂The NH aryl ,-(CH ₂) _p-OR ²With-(CH ₂) _p-SR ²

P is 2 or 3 integer;

Q is 1 or 2 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H; And

B) as Z be-R ²The time, at least one is not-H, alkyl, aralkyl or alicyclic radical among V, W, the W ';

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

R ¹¹Be selected from alkyl, aryl ,-NR ² ₂With-OR ²With

Prerequisite is:

1) when G ' is N, then A, B, D or E are respectively and do not exist;

3) work as R ⁵Be 6 yuan of whens ring, then X be not any two atoms connection base, the optional replacement-alkyl, the optional replacement-alkenyl-, the optional replacement-alkoxyl group-or optional replacement the-alkylthio-;

5) R ¹It or not unsubstituted C1-C10 alkyl;

6) as X be not-aryl-time, then R ⁵Can't help two or more aryl replaces.

Preferred R ⁵Group comprises pyrryl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl group, pyrazolyl, isoxazolyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl and 1,3-selenazoles base, all these groups all have at least one substituting group.

In one aspect, preferred such formula I compound, wherein

A is selected from-H ,-NR ⁴ ₂,-CONR ⁴ ₂,-CO ₂R ³, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, C1-C6 perhaloalkyl radical, C1-C6 haloalkyl, aryl ,-CH ₂OH ,-CH ₂NR ⁴ ₂,-CH ₂CN ,-CN ,-C (S) NH ₂,-OR ⁴,-SR ⁴,-N ₃,-NHC (S) NR ⁴ ₂,-NHAc and not existing;

Each B and D independently be selected from-H, alkyl, alkenyl, alkynyl group, aryl, alicyclic radical, aralkyl, alkoxyalkyl ,-C (O) R ¹¹,-C (O) SR ³,-SO ₂R ¹¹,-S (O) R ³,-CN ,-NR ² ₂,-OR ³,-SR ³, perhaloalkyl radical, halo and do not exist, except-H ,-CN, perhaloalkyl radical and halo, all above-mentioned groups can be chosen replacement wantonly;

E is selected from-H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, aryl, C4-C6 alicyclic radical, alkoxyalkyl ,-C (O) OR ³,-CONR ⁴ ₂,-CN ,-NR ⁹ ₂,-OR ³,-SR ³, C1-C6 perhaloalkyl radical, halo and do not exist, except-H ,-CN, perhaloalkyl radical and halo, all above-mentioned groups can be chosen replacement wantonly; With

Each R ⁴Independently be selected from-H and C1-C2 alkyl.

Another preferred aspect, R ⁵For:

Another preferred aspect, R ⁵Be selected from:

With

Wherein

E " be selected from-H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, C4-C6 alicyclic radical, alkoxyalkyl ,-C (O) OR ³,-CONR ⁴ ₂,-CN ,-NR ⁹ ₂,-OR ³,-SR ³, C1-C6 perhaloalkyl radical and halo, except-H ,-CN, perhaloalkyl radical and halo, all above-mentioned groups can be chosen replacement wantonly; With

Each R ⁴Independently be selected from-H and C1-C2 alkyl.

More preferably such compound, wherein R ⁵Be selected from:

With

Also more preferably such compound, wherein R ⁵Be selected from:

With

Also more preferably such compound, wherein R ⁵Be selected from:

With

Preferred X group comprises-alkyl (hydroxyl)-,-alkyl-,-alkynyl group-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkoxyl group-,-alkylthio alkyl-,-alkylthio-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alicyclic radical-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino, all groups are optional to be replaced.

Preferred X group comprises-heteroaryl-,-alkyl-carbonyl-amino-,-alkyl amino-carbonyl-,-alkoxy carbonyl-and-alkoxyalkyl-.

Particularly preferred X group comprises-heteroaryl-and-alkoxy carbonyl-.Particularly preferred is furans-3,5-two bases ,-the methylamino carbonyl-and methylene radical oxygen base carbonyl-.

Wherein X also is particularly preferred suc as formula the compound shown in II, III or the IV

(II)

(III)

(IV)

Wherein X is particularly preferred suc as formula the compound shown in II and the IV.

Preferred A group comprises-H ,-NR ⁴ ₂,-CONR ⁴ ₂,-CO ₂R ³, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, C1-C6 perhaloalkyl radical, C1-C6 haloalkyl, aryl ,-CH ₂OH ,-CH ₂NR ⁴ ₂,-CH ₂CN ,-CN ,-C (S) NH ₂,-OR ³,-SR ³,-N ₃,-NHC (S) NR ⁴ ₂, do not exist and-NHAc.More preferably the A group comprises-NH ₂,-CONH ₂, halo ,-CH ₃,-CF ₃,-CH ₂-halo ,-CN ,-OCH ₃,-SCH ₃, do not exist and-H.Particularly preferred A group comprises-NH ₂,-Cl ,-Br, do not exist and-CH ₃

Preferred A " group comprises-H ,-NR ⁴ ₂,-CONR ⁴ ₂,-CO ₂R ³, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, C1-C6 perhaloalkyl radical, C1-C6 haloalkyl, aryl ,-CH ₂OH ,-CH ₂NR ⁴ ₂,-CH ₂CN ,-CN ,-C (S) NH ₂,-OR ³,-SR ³,-N ₃,-NHC (S) NR ⁴ ₂With-NHAc.More preferably A " group comprises-NH ₂,-CONH ₂, halo ,-CH ₃,-CF ₃,-CH ₂-halo ,-CN ,-OCH ₃,-SCH ₃With-H.Particularly preferred A " group comprises-NH ₂,-Cl ,-Br and-CH ₃

Preferred B group comprises-H, alkyl, alkenyl, alkynyl group, aryl, alicyclic radical, aralkyl, alkoxyalkyl ,-C (O) R ¹¹,-C (O) SR ³,-SO ₂R ¹¹,-S (O) R ³,-CN ,-NR ⁹ ₂,-OR ³,-SR ³, perhaloalkyl radical, halo and do not exist, except-H ,-CN, perhaloalkyl radical, do not exist and halo, all above-mentioned groups can be chosen replacement wantonly.More preferably the B group comprise-H ,-C (O) R ¹¹,-C (O) SR ³, alkyl, aryl, alicyclic radical, halo ,-NR ⁹ ₂,-OR ³, do not exist and-SR ³Particularly preferred B group comprises-H ,-C (O) OR ³,-C (O) SR ³, C1-C6 alkyl, alicyclic radical, halo, heteroaryl, do not exist and-SR ³

Preferred B " group comprises-H, alkyl, alkenyl, alkynyl group, aryl, alicyclic radical, aralkyl, alkoxyalkyl ,-C (O) R ¹¹,-C (O) SR ³,-SO ₂R ¹¹,-S (O) R ³,-CN ,-NR ⁹ ₂,-OR ³,-SR ³, perhaloalkyl radical and halo, except-H ,-CN, perhaloalkyl radical and halo, all above-mentioned groups can be chosen replacement wantonly.More preferably B " group comprises-H ,-C (O) R ¹¹,-C (O) SR ³, alkyl, aryl, alicyclic radical, halo ,-NR ⁹ ₂,-OR ³With-SR ³Particularly preferred B " group comprises-H ,-C (O) OR ³,-C (O) SR ³, C1-C6 alkyl, alicyclic radical, halo, heteroaryl and-SR ³

Preferred D group comprises-H, alkyl, alkenyl, alkynyl group, aryl, alicyclic radical, aralkyl, alkoxyalkyl ,-C (O) R ¹¹,-C (O) SR ³,-SO ₂R ¹¹,-S (O) R ³,-CN ,-NR ² ₂,-OR ³,-SR ³, perhaloalkyl radical, halo and do not exist, except-H ,-CN, perhaloalkyl radical, do not exist and halo, all above-mentioned groups can be chosen replacement wantonly.More preferably the D group comprise-H ,-C (O) R ¹¹, alkyl ,-C (O) SR ³, aryl, alicyclic radical, halo ,-NR ⁹ ₂, do not exist and-SR ³Particularly preferred D group comprises-H ,-C (O) OR ³, low alkyl group, alicyclic radical, do not exist and halo.

Preferred D " group comprises-H, alkyl, alkenyl, alkynyl group, aryl, alicyclic radical, aralkyl, alkoxyalkyl ,-C (O) R ¹¹,-C (O) SR ³,-SO ₂R ¹¹,-S (O) R ³,-CN ,-NR ² ₂,-OR ³,-SR ³, perhaloalkyl radical and halo, except-H ,-CN, perhaloalkyl radical and halo, all above-mentioned groups can be chosen replacement wantonly.More preferably D " group comprises-H ,-C (O) R ¹¹,-C (O) SR ³, alkyl, aryl, alicyclic radical, halo ,-NR ⁹ ₂With-SR ³Particularly preferred D " group comprises-H ,-C (O) OR ³, low alkyl group, alicyclic radical and halo.

Preferred E group comprises-H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, aryl, C4-C6 alicyclic radical, alkoxyalkyl ,-C (O) OR ³,-CONR ⁴ ₂,-CN ,-NR ⁹ ₂,-OR ³,-SR ³, C1-C6 perhaloalkyl radical, halo and do not exist, except-H ,-CN, perhaloalkyl radical, do not exist and halo, all above-mentioned groups can be chosen wantonly and be substituted.More preferably the E group comprise-H, C1-C6 alkyl, rudimentary alicyclic radical, halogen ,-CN ,-C (O) OR ³,-SR ³,-CONR ⁴ ₂Do not exist.Particularly preferred E group comprises-H ,-Br ,-Cl and not existing.

Preferred E " group comprises-H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, aryl, C4-C6 alicyclic radical, alkoxyalkyl ,-C (O) OR ³,-CONR ⁴ ₂,-CN ,-NR ⁹ ₂,-OR ³,-SR ³, C1-C6 perhaloalkyl radical and halo, except-H ,-CN, perhaloalkyl radical and halo, all above-mentioned groups can be chosen replacement wantonly.More preferably E " group comprises-H, C1-C6 alkyl, rudimentary alicyclic radical, halogen ,-CN ,-C (O) OR ³,-SR ³And CONR ⁴ ₂Particularly preferred E " group comprises-H ,-Br and-Cl.

One preferred aspect,

A " be selected from-NH ₂,-CONH ₂, halo ,-CH ₃,-CF ₃,-CH ₂-halo ,-CN ,-OCH ₃,-SCH ₃With-H;

B " be selected from-H ,-C (O) R ¹¹,-C (O) SR ³, alkyl, aryl, alicyclic radical, halo ,-CN ,-SR ³,-OR ³With-NR ⁹ ₂

D " be selected from-H ,-C (O) R ¹¹,-C (O) SR ³,-NR ⁹ ₂, alkyl, aryl, alicyclic radical, halo and-SR ³

E " be selected from-H, C1-C6 alkyl, rudimentary alicyclic radical, halo ,-CN ,-C (O) OR ³With-SR ³

X is selected from-alkyl (hydroxyl)-,-alkyl-,-alkynyl group-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkoxyl group-,-alkylthio alkyl-,-alkylthio-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alicyclic radical-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all groups are optional to be replaced.

When two Y groups be-during O-, R then ¹Independently be selected from the optional aryl that replaces, the optional benzyl that replaces ,-C (R ²) ₂OC (O) R ³,-C (R ²) ₂OC (O) OR ³With-H; Or

When a Y be-during O-, then be connected in-R of O- ¹Be the optional aryl that replaces; And another Y is-NR ⁶In-time, then be connected in-NR ⁶-R ¹Be selected from-C (R ⁴) ₂-COOR ³And C (R ²) ₂COOR ³Or

When Y be-O-or-NR ⁶-time, then R ¹And R ¹Be together

Wherein

Z is selected from-CHR ²OH ,-CHR ²OC (O) R ³,-CHR ²OC (S) R ³,-CHR ²OC (S) OR ³,-CHR ²OC (O) SR ³,-CHR ²OCO ₂R ³,-OR ²,-SR ²,-R ²,-NHCOR ²,-NHCO ₂R ³,-(CH ₂) _p-OR ²With-(CH ₂) _p-SR ²

P is 2 or 3 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H;

B) as Z be-R ²The time, then at least one is not-H, alkyl, aralkyl or alicyclic radical among V, W and the W '; With

C) two Y groups not all are-NR ⁶-;

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

R ⁶Be selected from-H and low alkyl group.

One particularly preferred aspect, R ⁵For

X is selected from methylene radical oxygen base carbonyl and furans-2,5-two bases; At least one Y group is-O-; And pharmacy acceptable salt and prodrug.More preferably such compound, wherein Y be-during O-, then be connected in-R of O- ¹Independently be selected from-H, the optional phenyl that replaces ,-CH ₂OC (O)-tBu ,-CH ₂OC (O) Et and-CH ₂OC (O)-iPr;

When Y is-NR ⁶In-time, then be connected in-NR ⁶-R ¹Independently be selected from-C (R ²) ₂COOR ³With-C (R ⁴) ₂COOR ³, or

When Y be-O-or-NR ⁶-and at least one Y be-during O-, R then ¹And R ¹Be together

Wherein

V is selected from optional aryl that replaces and the optional heteroaryl that replaces; Z, W ' and W are H; With

R ⁶Be selected from-H and low alkyl group.

Following this compounds and salt thereof are most preferred:

(1) A " be-NH ₂, X is a furans-2,5-two bases, and B " be-CH ₂-CH (CH ₃) ₂

(2) A " be-NH ₂, X is a furans-2,5-two bases, B " be-COOEt;

(3) A " be-NH ₂, X is a furans-2,5-two bases, B " be-SCH ₃

(4) A " be-NH ₂, X is a furans-2,5-two bases, B " be-SCH ₂CH ₂SCH ₃

(5) A " be-NH ₂, X is a methylene radical oxygen base carbonyl, B " be-CH (CH ₃) ₂

Another particularly preferred aspect, R ⁵For

X is a furans-2,5-two base and methylene radical oxygen base carbonyls, A " be-NH ₂At least one Y group is-O-; And pharmacy acceptable salt and prodrug.Particularly preferably be such compound, wherein

When Y be-during O-, each R then ¹Independently be selected from-H, the optional phenyl that replaces ,-CH ₂OC (O)-tBu ,-CH ₂OC (O) Et and-CH ₂OC (O)-iPr;

Or as Y be-NR ⁶-time, then each R ¹Independently be selected from-C (R ²) ₂C (O) OR ³With-C (R ⁴) ₂COOR ³

Or independently be selected from-O-and-NR as Y ⁶-time, then R ¹And R ¹Be together

Wherein

V is selected from optional aryl that replaces and the optional heteroaryl that replaces; Z, W ' and W are H.B wherein " be-SCH ₂CH ₂CH ₃This compounds also be particularly preferred.

Another particularly preferred aspect, R ⁵For

A " be-NH ₂, E " and D " be-H B " be n-propyl and cyclopropyl, X is a furans-2,5-two base and methylene radical oxygen base carbonyls; At least one Y group is-O-, and pharmacy acceptable salt and prodrug.Particularly preferably be such compound, wherein R ¹Be selected from-H, the optional phenyl that replaces ,-CH ₂OC (O)-tBu ,-CH ₂OC (O) Et and-CH ₂OC (O)-iPr,

Or independently be selected from-O-and-NR as any Y ⁶-and at least one Y be-during O-, R then ¹And R ¹Be together

Wherein

V is selected from optional aryl that replaces and the optional heteroaryl that replaces; Z, W ' and W are H.

Another particularly preferred aspect, R ⁵For

A " be-NH ₂, D " and be-H B " be n-propyl and cyclopropyl, X is a furans-2,5-two base and methylene radical oxygen base carbonyls; At least one Y group is-O-; And pharmacy acceptable salt and prodrug.Particularly preferably be such compound, wherein when Y be-during O-, R then ¹Be selected from-H, the optional phenyl that replaces ,-CH ₂OC (O)-tBu ,-CH ₂OC (O) Et and-CH ₂OC (O)-iPr;

Or when a Y be-during O-, its corresponding R ¹Be-phenyl, and when another Y be-during NH-, its corresponding R ¹Be-CH (Me) C (O) OEt, or when at least one Y group be-during O-, R then ¹And R ¹Be together

Wherein

Formula (X) compound and pharmaceutically acceptable prodrug thereof and salt are preferred:

(X)

Wherein:

G " be selected from-O-and-S-;

A ², L ², E ²And J ²Be selected from-NR ⁴ ₂,-NO ₂,-H ,-OR ²,-SR ²,-C (O) NR ⁴ ₂, halo ,-COR ¹¹,-SO ₂R ³, guanidine radicals, amidino groups, aryl, aralkyl, alkoxyalkyl ,-SCN ,-NHSO ₂R ⁹,-SO ₂NR ⁴ ₂,-CN ,-S (O) R ³, perhalogeno acyl group, perhaloalkyl radical, perhalogeno alkoxyl group, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl group and rudimentary alicyclic radical, perhaps L ²And E ²Or E ²And J ²Be formed into the cyclic group of ring together;

X ²Be the optional linking group that replaces, this group comprises 0-1 heteroatoms that is selected from N, O and S, with R by 1-3 atom ⁵Be connected on the phosphorus atom, the atom that wherein connects phosphorus atom is a carbon atom;

Prerequisite is X ²Can't help-COOR ²,-SO ₃R ¹Or-PO ₃R ¹ ₂Replace;

Y independently is selected from-O-and-NR ⁶-;

When Y be-during O-, then be connected in-R of O- ¹Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alicyclic radical (wherein loop section contains carbonic ether or thiocarbonic ester) that replaces, optional replace-alkylaryl ,-C (R ²) ₂OC (O) NR ² ₂,-NR ²-C (O)-R ³,-C (R ²) ₂-OC (O) R ³,-C (R ²) ₂-O-C (O) OR ³,-C (R ²) ₂OC (O) SR ³, alkyl-S-C (O) R ³, alkyl-S-S alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy,

Wherein

P is 2 or 3 integer;

Q is 1 or 2 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H; And

B) as Z be-R ²The time, at least one is not-H, alkyl, aralkyl or alicyclic radical among V, W and the W ';

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

R ¹¹Be selected from alkyl, aryl ,-NR ² ₂With-OR ²

Preferred G " group is-S-.

Preferred A ², L ², E ²And J ²Group comprises-H ,-NR ⁴ ₂,-S-C ≡ N, halogen ,-OR ³, hydroxyl ,-alkyl (OH), aryl, alkoxy carbonyl ,-SR ³, rudimentary perhaloalkyl radical and C1-C5 alkyl, perhaps L ²And E ²Be formed into the cyclic group of ring together.Preferred A ², E ², E ²And J ²Group comprises-H ,-NR ⁴ ₂,-S-C ≡ N, halogen, lower alkoxy, hydroxyl, low alkyl group (hydroxyl), lower aryl and C1-C5 alkyl, perhaps L ²And E ²Be formed into the cyclic group of ring together.Particularly preferred J ²Group is-H and low alkyl group.Particularly preferred A ²Group comprises-NH ₂,-H, halo and C1-C5 alkyl.

Particularly preferred compound comprises wherein L ²And E ²Independently be selected from-H ,-S-C ≡ N, lower alkoxy, C1-C5 alkyl, low alkyl group (hydroxyl), lower aryl and halogen, perhaps L ²And E ²Form the cyclic group of the Cheng Huan that contains other 4 carbon atoms together.

Preferred X ²Group comprises-alkyl-,-alkenyl-,-alkynyl group-,-alkylidene group-NR ⁴-,-alkylidene group-O-,-alkylidene group-S-,-C (O)-alkylidene group-and-alkylidene group-C (O)-.More preferably X ²Group comprises-alkylidene group-O-,-alkylidene group-S-and-alkyl-.Preferred especially X ²Group comprises-methylene radical oxygen base-.

In one aspect, preferred such formula X compound and pharmacy acceptable salt and prodrug, wherein A ²Be selected from-H ,-NH ₂,-CH ₃, Cl and Br;

L ²For-H, low alkyl group, halogen, lower alkoxy, hydroxyl ,-alkylene group-OH, or and E ²Form cyclic group together, comprise aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl;

E ²Be selected from H, low alkyl group, halogen, SCN, elementary alkoxy carbonyl, lower alkoxy, or and L ²Form cyclic group together, comprise aryl, cycloalkyl, heteroaryl or Heterocyclylalkyl;

J ²Be selected from H, halogen and low alkyl group;

G " be-S-;

X ²For-CH ₂O-; With

At least one Y group is-O-.

Also particularly preferably be such compound, wherein A ²Be NH ₂, G " and be-S-L ²Be Et, E ²Be SCN and J ²Be H.More preferably such compound, one of them Y are-O-its corresponding R ¹Be the optional phenyl that replaces, and another Y is-NH-, its corresponding R ¹For-C (R ²) ₂-COOR ³Work as R ¹For-CHR ³COOR ³The time, then accordingly-NR ⁶- ^*CHR ³COOR ³, preferably have the L stereochemistry.

Also more preferably such compound, one of them Y are-O-its corresponding R ¹For-phenyl, and another Y is-NH-, its corresponding R ¹For-CH (Me) CO ₂Et.

In formula I and X compound, preferred two Y groups are-O-; Or Y be-O-and Y be-NR ⁶-.When having only a Y to be-NR ⁶-time, preferably near the Y of W and W ' be-O-.Most preferably wherein two Y groups are-prodrug of O-.

Another particularly preferred aspect, two Y groups are-O-, and R ¹And R ¹Be together

With V be the phenyl that replaces by 1-3 halogen atom.Particularly preferably be such 3-bromo-4-fluoro phenyl, 3-chlorophenyl, 3-bromo phenyl and 3, the 5-dichlorophenyl.

Another particularly preferred aspect, Y is-O-and its corresponding R ¹Be phenyl, or be selected from-NHC (O) CH by 1-2 ₃,-F ,-Cl ,-Br ,-C (O) OCH ₂CH ₃With-CH ₃The phenyl that replaces of substituting group; And another Y is-NR ⁶-and its corresponding R ¹For-C (R ²) COOR ³Each R ²Independently be selected from-H ,-CH ₃With-CH ₂CH ₃More preferably R ⁶For-H be connected in-R of NH- ¹For-CH (Me) CO ₂Et.

In general, the preferred substituted of selecting type I and X, V, Z, W and W ' are so that they show one or more following properties:

(1) strengthens oxidizing reaction,, thereby must compete with the elimination process of medicine because this reaction is likely the step of decision speed;

(2) strengthen in the aqueous solution and the stability in the presence of other non--p450 enzyme;

(3) strengthen cell permeability, for example, substituting group is uncharged or does not have high molecular, because two specific characters can limit oral administration biaavailability and cell permeability;

(4) promote the β-eliminating after the initial oxidation reaction of generation open-loop products to react, described product has one or more following properties:

A) cyclization again;

B) the limited covalency hydration of experience;

C) promote β-elimination by helping to capture proton.

D) addition reaction that stops formation to stablize adducts, for example, mercaptan adds on the carbonyl that produces after the open loop the addition or the nucleophilic reagent of initial hydroxylation product; With

E) metabolism of limited reactions intermediate (as the ketone of open loop);

5) cause having the by product of the atoxic and non-mutagenesis of one or more following properties.Can reduce toxicity and mutagenicity by the substituting group that uses following restriction Michael addition, reaction as far as possible, for example:

That a) reduces two bond polarizations gives electronics Z group;

B) the W group of sterically hindered nucleophilic addition(Adn) to the beta carbon;

C) eliminate the Z group that tautomerization (enol → ketone) or the two keys of hydrolysis (for example enamine) elimination are passed through in the reaction back again;

D) contain and join in the alpha, beta-unsaturated ketone to form the V group of ring;

E) add the Z group that the reaction that is formed in two keys forms stabilizing ring by Michael; With

F) by the group of one or more following properties enhancings to the by product detoxification;

(i) be confined to liver; And

(ii) make detoxifcation reaction (as the ketone reduction) sensitivity; And

(6) can generate active result on the pharmacology.

In yet another aspect, preferably when Y be-during O-, then be connected in-R of O- ¹Independently be selected from-H, the optional aryl that replaces, the optional alicyclic radical (wherein loop section contains carbonic ether or thiocarbonic ester) that replaces, optional replace-alkylaryl ,-C (R ²) ₂OC (O) R ³,-C (R ²) ₂-O-C (O) OR ³,-C (R ²) ₂OC (O) SR ³,-alkyl-S-C (O) R ³With-alkyl-S-S-alkyl hydroxy;

When Y is-NR ⁶In-time, then be connected in-NR ⁶-R ¹Independently be selected from-H ,-[C (R ²) ₂] _q-COOR ³,-[C (R ²) ₂] _q-C (O) SR ³,-C (R ⁴) ₂COOR ³With-cycloalkylidene-COOR ³

Or independently be selected from-O-and-NR as arbitrary Y ⁶-time, then R ¹And R ¹Be together

Wherein

P is 2 or 3 integer;

Q is 1 or 2 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H;

C) two Y groups not all are-NR ⁶-;

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

R ⁶Be selected from-H and low alkyl group.

More preferably such compound, wherein when two Y groups be-during O-, R then ¹Independently be selected from the optional aryl that replaces, the optional benzyl that replaces ,-C (R ²) ₂OC (O) R ³,-C (R ²) ₂OC (O) OR ³With-H; And

When Y is-NR ⁶In-time, then be connected in described-NR ⁶The R of-group ¹Be selected from-C (R ⁴) ₂-COOR ³With-C (R ²) ₂COOR ³And another Y group is-during O-, then be connected in the R of described-O- ¹Be selected from the optional aryl that replaces ,-C (R ²) ₂OC (O) R ³With-C (R ²) ₂OC (O) OR ³

In yet another aspect, when a Y be-during O-, its corresponding R then ¹Be phenyl, and another Y is-NH-, its corresponding R ¹For-CH ₂CO ₂Et.

Another preferred aspect, when a Y be-during O-, its corresponding R then ¹Be phenyl, and another Y is-NH-and its corresponding R ¹For-C (Me) ₂CO ₂Et.

Another preferred aspect, when a Y be-during O-, its corresponding R then ¹Be 4-NHC (O) CH ₃-phenyl, and another Y is-NH-and its corresponding R ¹For-CH ₂COOEt.

Another preferred aspect, when a Y be-during O-, its corresponding R then ¹Be 2-CO ₂The Et-phenyl, and another Y is-NH-and its corresponding R ¹For-CH ₂CO ₂Et.

Another preferred aspect, when a Y be-during O-, its corresponding R then ¹Be 2-CH ₃-phenyl, and another Y is-NH, its corresponding R ¹For-CH ₂CO ₂Et.

In yet another aspect, wherein two Y groups are-O-, and R ¹For aryl or-C (R ²) ₂The compound of-aryl is preferred.

Wherein two Y groups are O-, at least one R ¹Be selected from-C (R ²) ₂-OC (O) R ³With-C (R ²) ₂-OC (O) OR ³Compound also be preferred.

In yet another aspect, preferred such compound, wherein two Y groups are-O-, at least one R ¹For-alkyl-S-S-alkyl hydroxy ,-alkyl-S-C (O) R ³With-alkyl-S-S-S-alkyl hydroxy, or R ¹And R ¹Be together-alkyl-the S-S-alkyl-to form cyclic group.

In one aspect, preferred especially such compound, wherein two Y groups are-O-, and R ¹Be H.

In yet another aspect, preferred especially such compound, wherein two Y groups are-O-, and R=is-CH ₂OC (O) OEt.

More preferably such compound, wherein at least one Y is-O-, and R ¹And R ¹Be together

Wherein

P is 2 or 3 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H;

B) as Z be-R ²The time, at least one is not-H, alkyl, aralkyl or alicyclic radical among V, W and the W '; With

C) two Y groups not all are-NR ⁶-;

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

R ⁶Be selected from-H and low alkyl group.

In yet another aspect, more preferably such compound, one of them Y are-O-, and R ¹Be the optional aryl that replaces; And another Y is-NR ⁶-, wherein at described-NR ⁶-on R ¹Be selected from-C (R ⁴) ₂COOR ³With-C (R ²) ₂C (O) OR ³Particularly preferably be such compound, wherein be connected in-R of O- ¹Be phenyl, and be connected in-R of NH- ¹For-CH (Me) CO ₂Et and-NH ^*CH (Me) CO ₂Et is the L configuration.

Preferred especially such compound wherein is connected in-R of O- ¹Be selected from phenyl and by 1-2 be selected from-NHAc ,-F ,-Cl ,-Br ,-COOEt and-CH ₃The phenyl that replaces of substituting group; And be connected in-NR ⁶R ¹For-C (R ²) ₂COOR ³, R wherein ²And R ³Independently be-H ,-CH ₃With-Et.In these compounds, when being connected in-R of O- ¹Serve as reasons-NHAc or-during phenyl that COOEt replaces, then preferably any-NHAc is in the 4-position, and any-COOEt in the 2-position, more preferably such compound, wherein the substituting group on the phenyl that replaces is 4-NHC (O) CH ₃,-Cl ,-Br, 2-C (O) OCH ₃CH ₃Or-CH ₃

More preferably the V group of formula VI is the heteroaryl of aryl, heteroaryl and the replacement of aryl, replacement.Preferred Y is-O-.The aryl of particularly preferred aryl and replacement comprises phenyl, asks for the phenyl in generation by 1-3 halogen.3,5-dichlorophenyl, 3-bromo-4-fluoro phenyl, 3-chlorophenyl and 3-bromo phenyl are preferred especially.

Also particularly preferably be, V is selected from bicyclic heteroaryl and contains the heteroaryl of the monocycle base replacement of at least one nitrogen-atoms.The most preferably such heteroaryl and the heteroaryl of replacement are respectively 4-pyridyl and 3-pyridine bromide base.

Also preferably link together by an other 3-5 atom as V and Z, form to choose wantonly and contain a heteroatomic cyclic group, this cyclic group aryl-condensed with respect to the β position of the Y that is connected phosphorus atom and γ position.In such compound, described aryl is preferably the optional monocyclic aryl that replaces, and the connection between the γ position of Z and aryl is selected from O, CH ₂, CH ₂CH ₂, OCH ₂Or CH ₂O.

In yet another aspect, preferably working as V and W links together by 3 other carbon atoms, formation contains 6 carbon atoms and by a cyclic group that is selected from the following mono-substituted optional replacement of substituting group: hydroxyl, acyloxy, alkoxy-carbonyl oxy, alkylthio ketonic oxygen base and aryloxycarbonyl oxygen base, this substituting group is connected with one of described other carbon atom, and this carbon atom and the Y that is connected phosphorus atom are at a distance of three atoms.In such compound, more preferably common formation of V and W is selected from-CH ₂-CH (OH)-CH ₂-, CH ₂CH (OCOR ³)-CH ₂-and-CH ₂CH (OCO ₂) R ³)-CH ₂-cyclic group.

Another preferred V group is the 1-alkene.The oxygenizement of known p450 enzyme occurs on benzyl and the allylic carbon atom.

In one aspect, be selected from-CHR as Z ²OH ,-CHR ²OCOR ³With-CHR ²OCO ₂R ³The time, preferred V group is-H.

In yet another aspect, when V was the heteroaryl of aryl, heteroaryl or replacement of aryl, replacement, preferred Z group comprised-OR ²,-SR ²,-CHR ²N ₃,-R ²,-NR ² ₂,-OCOR ²,-OCO ₂R ³,-SCOR ³,-SCO ₂R ³,-NHCOR ²,-NHCO ₂R ³,-CH ₂The NH aryl ,-(CH ₂) _pOR ²With-(CH- ₂) _p-SR ²Preferred Z group comprises-OR ²,-R ²,-OCOR ²,-OCO ₂R ³,-CH ₃,-NHCOR ²,-NHCO ₂R ³,-(CH ₂) _p-OR ²With-(CH ₂) _p-SR ²Most preferred Z group comprises-OR ²,-H ,-OCOR ²,-OCO ₂R ³With-NHCOR ²

Preferred W and W ' group comprise H, R ³, aryl, replacement the aryl of aryl, heteroaryl and replacement.Preferred W is identical group with W '.More preferably W and W ' are H.

In one aspect, the prodrug of formula VI is preferred:

Wherein V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkenyl and the 1-alkynyl group of replacement.More preferably the V group of formula VI is heteroaryl aryl, replacement, heteroaryl and replacement.Preferred Y is-O-.The aryl of special preferred aryl groups and replacement comprises the phenyl of phenyl and replacement.Particularly preferred heteroaryl comprise monocycle that replace with unsubstituted heteroaryl.Be preferably 4-pyridyl and 3-pyridine bromide base especially.

In one aspect, formula VI compound preferably has the Z group, described Z group be H, alkyl, alicyclic radical, hydroxyl, alkoxyl group,

Or NHCOR.Preferred such group, wherein the Z group reduces by product, and ethenyl aromatic yl ketone stands the trend of Michael addition reaction.Preferred Z group is the group that gives the vinyl electronics, and this is known minimizing α, and β-undersaturated carbonyl compound stands the strategy of the trend of Michael addition reaction.For example, the methyl of similar position does not cause the mutagenesis activity on the acrylamide, and unsubstituted vinyl analogue is highly mutagenic.Other group also has similar function, for example, and Z=OR, NHAc etc.Other group also can prevent the Michael addition reaction, particularly causes the group of removing two keys together, for example Z=OH ,-OC (O) R ,-OCO ₂R and NH ₂, it will experience tautomerization more apace after eliminating reaction.Some W and W ' group also help this effect, because described group competition is to the addition reaction of beta carbon or make this unstable products.Another preferred Z group can join α, the nucleophilic group on β-unsaturated double-bond, i.e. (CH for containing after eliminating reaction ₂) _pSH or (CH ₂) _nOH, wherein p is 2 or 3.Another preferred group is to be connected in after eliminating reaction can add to α, the group of the V on β-unsaturated double-bond:

In yet another aspect, the prodrug of formula VII is preferred:

VII

Wherein

Z is selected from:

-CHR ²OH ,-CHR ²OCOR ³,-CHR ²OC (S) R ³,-CHR ²OCO ₂R ³,-CHR ²OC (O) SR ³With-CHR ²OC (S) OR ³Preferred Y is-O-.Preferred group comprises-CHR ²OH ,-CHR ²OC (O) R ³With-CHR ²OCO ₂R ³

In yet another aspect, the prodrug of formula VIII is preferred:

VIII

Wherein

Z ' is selected from-OH ,-OC (O) R ³,-OCO ₂R ³With-OC (O) SR ³

D ⁴And D ³Independently be selected from-H, alkyl, OR ²,-OH and-OC (O) R ³Prerequisite is D ⁴And D ³In at least one is-H.Preferred Y is-O-.

In a preferred embodiment, W ' and Z be-H, and W and V are the heteroaryl of aryl, heteroaryl or the replacement of identical aryl, replacement, phosphonate prodrugs part like this:

The symmetrical plane that has.Preferred Y is-O-.

In another preferred embodiment, W and W ' they are H, and V is selected from aryl, the heteroaryl of aryl, replacement, the heteroaryl of replacement, and Z is selected from-and H, OR ²With-NHCOR ²More preferably such compound, wherein Z is-H.

The preferred oral bioavailability is at least 5%.More preferably oral administration biaavailability is at least 10%.

The p450 oxygenizement is to can being that phosphorus atom or the stereochemistry that has the carbon atom of aromatic group are responsive.Prodrug of the present invention has two kinds of isomeric forms around phosphorus atom.It is preferred carrying out oxidation and eliminate the stereochemistry of reacting.Preferred cis stereochemistry.

The preferred compound utilization of formula VIII can stand the Z ' group of oxidizing reaction, obtains unsettled intermediate, this intermediate can be cracked into corresponding R by eliminating reaction ⁵-X-PO ₃ ^2-, R ⁵-X-P (O) (NHR ⁶) ₂Or R ⁵-X-P (O) (O ^-) (NHR ⁶).Particularly preferred Z ' group is OH.Group D ⁴And D ³Be preferably hydrogen, alkyl ,-OR ²,-OC (O) R ³, but D ⁴Or D ³At least one is necessary for H.

In following preferred examples for compounds, following prodrug is preferred:

The acyloxy alkyl ester;

The alkoxy-carbonyl oxy alkyl ester;

Aryl ester;

The benzyl ester of benzyl and replacement;

The ester that contains disulphide;

(1, the 3-dioxole-2-ketone) methyl esters that replaces;

3-benzo [c] the furanonyl ester that replaces;

Ring-[5-hydroxyl hexamethylene-1,3-two bases] diester and hydroxyl protection form;

Ring-[2-methylol the third-1,3-two bases] diester and hydroxyl protection form;

Ring-(1-arylprop-1,3-two bases);

The phosphoramidate that one aryl ester N-replaces

The lactone that two ω replace; And all blended esters of the possible combination results of above-mentioned ester.

Yi Xia prodrug more preferably:

Two-valeryl oxygen ylmethyl ester;

Two-isobutyryl oxygen ylmethyl ester;

Ring-[1-(3-chlorophenyl) the third-1,3-two bases] diester;

Ring-[1-(3, the 5-dichlorophenyl) the third-1,3-two bases] diester;

Ring-[1-(3-bromo-4-fluoro phenyl) the third-1,3-two bases] diester;

Ring-[2-methylol the third-1,3-two bases] diester;

Ring-[2-acetoxy-methyl the third-1,3-two-yl] diester;

Ring-[2-methoxycarbonyl oxygen ylmethyl the third-1,3-two bases] diester;

Ring-[1-phenyl the third-1,3-two bases] diester;

Ring-[1-(2-pyridyl) the third-1,3-two bases] diester;

Ring-[1-(3-pyridyl) the third-1,3-two bases] diester;

Ring-[1-(4-pyridyl) the third-1,3-two bases] diester;

Two-benzoyl sulphomethyl ester;

Two-benzoyl thio-ethyl ester;

Two-benzoyl oxygen ylmethyl ester;

Two-right-fluorobenzene formyl radical oxygen ylmethyl ester;

Two-6-chloro nicotinoyl oxygen ylmethyl ester;

Two-5-bromo nicotinoyl oxygen ylmethyl ester;

Two-thiophene ketonic oxygen ylmethyl ester;

Two-this acyloxy of 2-furans first methyl ester;

Two-3-furancarbonyl oxygen ylmethyl ester;

Diphenyl;

Two-(4-p-methoxy-phenyl) ester;

Two-(2-p-methoxy-phenyl) ester;

Two-(2-ethoxyl phenenyl) ester;

List-(2-ethoxyl phenenyl) ester;

Two-(4-acetamido phenyl) ester;

Two-(4-acetoxyl group phenyl) ester;

Two-(4-hydroxyphenyl) ester;

Two-(2-acetoxyl group phenyl) ester;

Two-(3-acetoxyl group phenyl) ester;

Two-(4-morpholino phenyl) ester;

Two-[4-(1-triazolo phenyl) ester;

Two-(3-N, N-dimethylaminophenyl) ester;

Two-(1,2,3,4-naphthane-2-yl) ester;

Two-(3-chloro-4-methoxyl group) benzyl ester;

Two-(3-bromo-4-methoxyl group) benzyl ester;

Two-(3-cyano group-4-methoxyl group) benzyl ester;

Two-(3-chloro-4-acetoxyl group) benzyl ester;

Two-(3-bromo-4-acetoxyl group) benzyl ester;

Two-(3-cyano group-4-acetoxyl group) benzyl ester;

Two-(4-chloro) benzyl ester;

Two-(4-acetoxyl group) benzyl ester;

Two-(3,5-dimethoxy-4 '-acetoxyl group) benzyl ester;

Two-(3-methyl-4-acetoxyl group) benzyl ester;

Two-(benzyl) ester;

Two-(3-methoxy-4-acetoxyl group) benzyl ester;

Two-(6 '-hydroxyl-3 ', 4 '-dithia) polyhexamethylene;

Two-(6 '-acetoxy-3 ', 4 '-dithia) polyhexamethylene;

(3 ', 4 '-dithia oneself 1,6-two bases) ester;

Two-(5-methyl isophthalic acid, 3-dioxole-2-ketone-4-yl) methyl esters;

Two-(5-ethyl-1,3-dioxole-2-ketone-4-yl) methyl esters;

Two-(the 5-tertiary butyl-1,3-dioxole-2-ketone-4-yl) methyl esters;

Two-3-(5,6, the 7-trimethoxy)-phthalidyl methyl esters;

Two-(cyclohexyl oxygen base ketonic oxygen ylmethyl) ester;

Two-(sec.-propyl oxygen base ketonic oxygen ylmethyl) ester;

Two-(ethoxy carbonyl oxygen ylmethyl) ester;

Two-(methoxycarbonyl oxygen ylmethyl) ester;

Two-(isopropoxy thiocarbonyl oxygen ylmethyl) ester;

Two-(phenyloxycarbonyl oxygen ylmethyl) ester;

Two-(benzyloxycarbonyloxy ylmethyl) ester;

Two-(thiophenyl ketonic oxygen ylmethyl) ester;

Two-(right-methoxyl group phenoxy group ketonic oxygen ylmethyl) ester;

Two-(-methoxyl group phenoxy group ketonic oxygen ylmethyl) ester;

Two-(neighbour-methoxyl group phenoxy group ketonic oxygen ylmethyl) ester;

Two-(neighbour-methylphenoxy ketonic oxygen ylmethyl) ester;

Two-(right-chloro phenoxy group ketonic oxygen ylmethyl) ester;

Two-(1,4-biphenylyloxy ketonic oxygen ylmethyl) ester;

Two-[(2-phthalimido ethyl) oxygen base ketonic oxygen ylmethyl] ester;

Two-(N-phenyl-N-methylamino formyl radical oxygen ylmethyl) ester;

Two-(2,2,2-three chloroethyls) ester;

Two-(2-bromoethyl) ester;

Two-(2-iodo ethyl) ester;

Two-(2-azido-ethyl) ester;

Two-(2-acetoxyl group ethyl) ester;

Two-(2-amino-ethyl) ester;

Two-(2-N, N-dimethyl aminoethyl) ester;

Two-(2-amino-ethyl) ester;

Two-(methoxycarbonyl methyl) ester;

Two-(2-amino-ethyl) ester;

Two-[N, N-two (2-hydroxyethyl)] formamyl methyl esters;

Two-(2-amino-ethyl) ester;

Two-(2-methyl-5-thiazole ylmethyl) ester;

Two-(two-2-hydroxyethylamino formyl radical methyl) ester;

The O-phenyl-(P (O) is (N (H)-CH (Me) CO (OPh) for [N-(1-ethoxy carbonyl) ethyl] phosphoramidate ₂Et)

The O-phenyl-(P (O) is (N (H)-CH (Me) CO (OPh) for [N-(1-methoxycarbonyl) ethyl] phosphoramidate ₂Me)

O-(3-chlorophenyl)-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NH-CH (Me) CO (OPh-3-Cl) for phosphoramidate ₂Et)

O-(2-chlorophenyl)-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NH-CH (Me) CO (OPh-2-Cl) for phosphoramidate ₂Et)

O-(4-chlorophenyl)-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NH-CH (Me) CO (OPh-4-Cl) for phosphoramidate ₂Et)

O-(4-acetamido phenyl)-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NH-CH (Me) CO (OPh-4-NHAc) for phosphoramidate ₂Et)

O-(2-ethoxy carbonyl phenyl)-[N-(1-ethoxy carbonyl) ethyl] phosphoramidate (P (O) (OPh-2-CO ₂Et) (NH-CH (Me) CO ₂Et)

The O-phenyl-[N-(1-ethoxy carbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh) for phosphoramidate ₂CO ₂Et)

The O-phenyl-[N-(1-methoxycarbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh) for phosphoramidate ₂CO ₂Me)

O-(3-chlorophenyl)-[N-(1-ethoxy carbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh-3-Cl) for phosphoramidate ₂CO ₂Et)

O-(2-chlorophenyl)-[N-(1-ethoxy carbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) CO (OPh-2-Cl) for phosphoramidate ₂Et)

O-(4-chlorophenyl)-[N-(1-ethoxy carbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh-4-Cl) for phosphoramidate ₂CO ₂Et)

O-(4-acetamido phenyl)-[N-(1-ethoxy carbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh-4-NHAc) for phosphoramidate ₂CO ₂Et)

O-(2-ethoxy carbonyl phenyl)-[N-(1-ethoxy carbonyl-1-methyl) ethyl] phosphoramidate (P (O) (OPh-2-CO ₂Et) (NH-C (Me) ₂CO ₂Et)

The O-phenyl-[N-(ethoxy carbonyl) methyl] (P (O) is (NH-CH (OPh) for phosphoramidate ₂CO ₂Et)

The O-phenyl-[N-(methoxycarbonyl) methyl] (P (O) is (NH-CH (OPh) for phosphoramidate ₂CO ₂Me)

O-(3-chlorophenyl)-[N-(ethoxy carbonyl) methyl] (P (O) is (NH-CH (OPh-3-Cl) for phosphoramidate ₂CO ₂Et)

O-(2-chlorophenyl)-[N-(ethoxy carbonyl) methyl] (P (O) is (NH-CH (OPh-2-Cl) for phosphoramidate ₂CO ₂Et)

O-(4-chlorophenyl)-[N-(ethoxy carbonyl) methyl] (P (O) is (NH-CH (OPh-4-Cl) for phosphoramidate ₂CO ₂Et)

O-(4-acetamido phenyl)-[N-(ethoxy carbonyl) methyl] (P (O) is (NH-CH (OPh-4-NHAc) for phosphoramidate ₂CO ₂Et)

O-(2-ethoxy carbonyl phenyl)-[N-(ethoxy carbonyl) methyl] phosphoramidate (P (O) (OPh-2-CO ₂Et) (NH-CH ₂CO ₂Et).

Most preferred is following prodrug:

Two-valeryl oxygen ylmethyl ester;

Two-isobutyryl oxygen ylmethyl ester;

Ring-[1-(3-chlorophenyl) the third-1,3-two bases] diester;

Ring-[1-(3, the 5-dichlorophenyl) the third-1,3-two bases] diester;

Ring-[1-(3-bromo-4-fluoro phenyl) the third-1,3-two bases] diester;

Ring-(2-methylol the third-1,3-two bases) ester;

Ring-(2-acetoxy-methyl the third-1,3-two bases) ester;

Ring-(2-methoxycarbonyl oxygen ylmethyl the third-1,3-two bases) ester;

Ring-(2-cyclohexyl-carbonyl oxygen ylmethyl the third-1,3-two bases) ester;

Ring-[phenyl the third-1,3-two bases] diester;

Ring-[1-(2-pyridyl) the third-1,3-two bases] diester;

Ring-[1-(3-pyridyl) the third-1,3-two bases] diester;

Ring-[1-(4-pyridyl) the third-1,3-two bases] diester;

Two-benzoyl sulphomethyl ester;

Two-benzoyl thio-ethyl ester;

Two-benzoyl oxygen ylmethyl ester;

Two-right-fluorobenzene formyl radical oxygen ylmethyl ester;

Two-6-chloro nicotinoyl oxygen ylmethyl ester;

Two-5-bromo nicotinoyl oxygen ylmethyl ester;

Two thiophene ketonic oxygen ylmethyl esters;

Two-2-furancarbonyl oxygen ylmethyl ester;

Two-3-furancarbonyl oxygen ylmethyl ester;

Diphenyl;

Two-(2-aminomethyl phenyl) ester;

Two-(2-p-methoxy-phenyl) ester;

Two-(2-ethoxyl phenenyl) ester;

List-(4-p-methoxy-phenyl) ester;

Two-(3-bromo-4-methoxy-benzyl) ester;

Two-(4-acetoxyl group benzyl) ester;

Two-(3,5-dimethoxy-4 '-acetoxyl group benzyl) ester;

Two-(3-methyl-4-acetoxyl group benzyl) ester;

Two-(3-methoxyl group-4-acetoxyl group benzyl) ester;

Two-(3-chloro-4-acetoxyl group benzyl) ester;

Two-(cyclohexyl oxygen base ketonic oxygen ylmethyl) ester;

Two-(sec.-propyl oxygen base ketonic oxygen ylmethyl) ester;

Two-(ethoxy carbonyl oxygen ylmethyl) ester;

Two-(methoxycarbonyl oxygen ylmethyl) ester;

Two-(isopropylthio ketonic oxygen ylmethyl) ester;

Two-(phenyloxycarbonyl oxygen ylmethyl) ester;

Two-(benzyloxycarbonyloxy ylmethyl) ester;

Two-(thiophenyl ketonic oxygen ylmethyl) ester;

Two-(right-methoxyl group phenoxy group ketonic oxygen ylmethyl) ester;

Two-(-methoxyl group phenoxy group ketonic oxygen ylmethyl) ester;

Two-(neighbour-methoxyl group phenoxy group ketonic oxygen ylmethyl) ester;

Two-(neighbour-methylphenoxy ketonic oxygen ylmethyl) ester;

Two-(right-chloro phenoxy group ketonic oxygen ylmethyl) ester;

Two-(1,4-biphenylyloxy ketonic oxygen ylmethyl) ester;

Two-[(2-phthalimido ethyl) oxygen base ketonic oxygen ylmethyl] ester;

Two-(6-hydroxyl-3,4-dithia) polyhexamethylene;

The ring-(3, the 4-dithia oneself-1,6-two bases) ester;

Two-(2-bromoethyl) ester;

Two-(2-amino-ethyl) ester;

Two-(2-N, N-diamino ethyl) ester;

The O-phenyl-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NH-(OPh) for phosphoramidate ^*CH (Me) CO ₂Et)

The O-phenyl-[N-(1-methoxycarbonyl) ethyl] (P (O) is (NH-(OPh) for phosphoramidate ^*CH (Me) CO ₂Me)

O-(3-chlorophenyl)-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NH (OPh-3-Cl) for phosphoramidate ^*CH (Me) CO ₂Et)

O-(2-chlorophenyl)-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NH-(OPh-2-Cl) for phosphoramidate ^*CH (Me) CO ₂Et)

O-(4-chlorophenyl)-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NH-(OPh-4-Cl) for phosphoramidate ^*CH (Me) CO ₂Et)

O-(4-acetamido phenyl)-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NH-(OPh-4-NHAc) for phosphoramidate ^*CH (Me) CO ₂Et)

O-(2-ethoxy carbonyl phenyl)-[N-(1-ethoxy carbonyl) ethyl] phosphoramidate (P (O) (OPh-2-CO ₂Et) (NH- ^*CH (Me) CO ₂Et)

O-(2-chlorophenyl)-[N-(1-ethoxy carbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh-2-Cl) for phosphoramidate ₂CO ₂Et)

In aforementioned prodrugs, the asterisk on the carbon atom (*) refers to the L-configuration.

The following compounds of preferred formula I and pharmacy acceptable salt thereof and prodrug, wherein R ⁵Be thiazolyl Huo oxazolyl or selenazoles base or pyrazolyl or imidazolyl Huo isoxazolyl or 1,2,4-triazolyl or 1,2,4-thiadiazolyl group or 1,2,4-oxadiazole base.These preferred compounds are shown in the following structure (i)-(iv):

(i) (ii)

(iii)

(iv)

According to the following regulations: A.B.X.Y ', the numeral that preferred compound is given A, B among the top formula i-iv, X and Y ' part by appointment is listed in the table 1.For each part, structure is endowed the numeral that is shown in the following table corresponding to A, B, X and Y '.Use following term: Pr-c is cyclopropyl, and Pr-n is a n-propyl, and Pr-i sec.-propyl, Bu-n are normal-butyl, and Bu-i is an isobutyl-, and Bu-c is a cyclobutyl, and Bu-s is a sec-butyl, and Bu-t is that the tertiary butyl and hexyl-c are cyclohexyl.

Variables A is selected from 7 kinds of different substituting groups.

The A group is endowed down column of figure:

Table A.

	??1	??2	??3	??4	??5	??6	??7
	??1	??2	??3	??4	??5	??6	??7	??A＝	??H	??NH ₂	??Br	??Cl	??F	??Me	??CF ₃

Variable B is divided into 4 groups, lists 9 kinds of different substituting groups for every group.

1 group of substituting group to variable B is given down column of figure:

	??1	??2	??3	??4	??5	??6	??7	??8	??9
	??1	??2	??3	??4	??5	??6	??7	??8	??9	??B＝	??H	??Me	??Et	??Pr-n	??Pr-i	??Pr-c	??Br	??Cl	??I

2 groups of substituting groups to variable B are given down column of figure:

	??1	??2	??3	??4	??5	?6	??7	??8	??9
	??1	??2	??3	??4	??5	?6	??7	??8	??9	??B＝	??F	??CN	??CH ₂Pr-c	??CH ₂OMe	Neo-pentyl	?C(O)OMe	??OEt	??SMe	??C(O)SMe

3 groups of substituting groups to variable B are given down column of figure:

	??1	??2	??3	??4	??5	??6	??7	??8	??9
	??1	??2	??3	??4	??5	??6	??7	??8	??9	?B＝	??SEt	The 4-pyridyl	??Bu-c	??C(O)OEt	??NMe ₂	??SPr-n	??CF ₃	??Bu-n	??Bu-i

4 groups of substituting groups to variable B are given down column of figure:

	?1	??2	??3	??4	??5	??6	??7	??8	??9
	?1	??2	??3	??4	??5	??6	??7	??8	??9	??B＝	?SPr-c	??OPr-i	??OPr-c	??SPr-i	The 2-furyl	The 2-thienyl	??OMe	??CH ₂SMe	??Bn

Variable X is selected from 9 different substituting groups.

The X group is endowed down column of figure:

Table X.

	??1	??2	??3	?4	??5	??6	?7	??8	??9
	??1	??2	??3	?4	??5	??6	?7	??8	??9	?X＝	Furans-2,5-two bases	Pyridine-2,6-two bases	Oxazole-2,5-two bases	?C(O)- ?OCH ₂	??C(O)- ??NHCH ₂	??C(O)- ??SCH ₂	?C(O)-N ?(Me)CH ₂	??NHC(O) ??-CH ₂	??CH ₂O ??-CH ₂

The direction of X group is defined as suc as formula (i), (ii), (iii) and (iv) by the direction of heterocycle to phosphorus atom.

Variable Y ' be selected from 6 different substituting groups.

Y ' group is endowed down column of figure:

Table Y

	??1	??2	??3	??4	??5	??6
	??1	??2	??3	??4	??5	??6	?Y’＝	??S	??O	??Se	??NH	??NMe	??NEt

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??1.1.2.1??1.1.2.2??1.1.2.3??1.1.2.4

1.1.2.5??1.1.2.6??1.1.3.1??1.1.3.2??1.1.3.3??1.1.3.4??1.1.3.5??1.1.3.6??1.1.4.1??1.1.4.2

1.1.4.3??1.1.4.4??1.1.4.5??1.1.4.6??1.1.5.1??1.1.5.2??1.1.5.3??1.1.5.4??1.1.5.5??1.1.5.6

1.1.6.1??1.1.6.2??1.1.6.3??1.1.6.4??1.1.6.5??1.1.6.6??1.1.7.1??1.1.7.2??1.1.7.3??1.1.7.4

1.1.7.5??1.1.7.6??1.1.8.1??1.1.8.2??1.1.8.3??1.1.8.4??1.1.8.5??1.1.8.6??1.1.9.1??1.1.9.2

1.1.9.3??1.1.9.4??1.1.9.5??1.1.9.6??1.2.1.1??1.2.1.2??1.2.1.3??1.2.1.4??1.2.1.5??1.2.1.6

1.2.2.1??1.2.2.2??1.2.2.3??1.2.2.4??1.2.2.5??1.2.2.6??1.2.3.1??1.2.3.2??1.2.3.3??1.2.3.4

1.2.3.5??1.2.3.6??1.2.4.1??1.2.4.2??1.2.4.3??1.2.4.4??1.2.4.5??1.2.4.6??1.2.5.1??1.2.5.2

1.2.5.3??1.2.5.4??1.2.5.5??1.2.5.6??1.2.6.1??1.2.6.2??1.2.6.3??1.2.6.4??1.2.6.5??1.2.6.6

1.2.7.1??1.2.7.2??1.2.7.3??1.2.7.4??1.2.7.5??1.2.7.6??1.2.8.1??1.2.8.2??1.2.9.3??1.2.8.4

1.2.8.5??1.2.8.6??1.2.9.1??1.2.9.2??1.2.9.3??1.2.9.4??1.2.9.5??1.2.9.6??1.3.1.1??1.3.1.2

1.3.1.3??1.3.1.4??1.3.1.5??1.3.1.6??1.3.2.1??1.3.2.2??1.3.2.3??1.3.2.4??1.3.2.5??1.3.2.6

1.3.3.1??1.3.3.2??1.3.3.3??1.3.3.4??1.3.3.5??1.3.3.6??1.3.4.1??1.3.4.2??1.3.4.3??1.3.4.4

1.3.4.5??1.3.4.6??1.3.5.1??1.3.5.2??1.3.5.3??1.3.5.4??1.3.5.5??1.3.5.6??1.3.6.1??1.3.6.2

1.3.6.3??1.3.6.4??1.3.6.5??1.3.6.6??1.3.7.1??1.3.7.2??1.3.7.3??1.3.7.4??1.3.7.5??1.3.7.6

1.3.8.1??1.3.8.2??1.3.8.3??1.3.8.4??1.3.8.5??1.3.8.6??1.3.9.1??1.3.9.2??1.3.9.3??1.3.9.4

1.3.9.5??1.3.9.6??1.4.1.1??1.4.1.2??1.4.1.3??1.4.1.4??1.4.1.5??1.4.1.6??1.4.2.1??1.4.2.2

1.4.2.3??1.4.2.4??1.4.2.5??1.4.2.6??1.4.3.1??1.4.3.2??1.4.3.3??1.4.3.4??1.4.3.5??1.4.3.6

1.4.4.1??1.4.4.2??1.4.4.3??1.4.4.4??1.4.4.5??1.4.4.6??1.4.5.1??1.4.5.2??1.4.5.3??1.4.5.4

1.4.5.5??1.4.5.6??1.4.6.1??1.4.6.2??1.4.6.3??1.4.6.4??1.4.6.5??1.4.6.6??1.4.7.1??1.4.7.2

1.4.7.3??1.4.7.4??1.4.7.5??1.4.7.6??1.4.8.1??1.4.8.2??1.4.8.3??1.4.8.4??1.4.8.5??1.4.8.6

1.4.9.1??1.4.9.2??1.4.9.3??1.4.9.4??1.4.9.5??1.4.9.6??1.5.1.1??1.5.1.2??1.5.1.3??1.5.1.4

1.5.1.5??1.5.1.6??1.5.2.1??1.5.2.2??1.5.2.3??1.5.2.4??1.5.2.5??1.5.2.6??1.5.3.1??1.5.3.2

1.5.3.3??1.5.3.4??1.5.3.5??1.5.3.6??1.5.4.1??1.5.4.2??1.5.4.3??1.5.4.4??1.5.4.5??1.5.4.6

1.5.5.1??1.5.5.2??1.5.5.3??1.5.5.4??1.5.5.5??1.5.5.6??1.5.6.1??1.5.6.2??1.5.6.3??1.5.6.4

1.5.6.5??1.5.6.6??1.5.7.1??1.5.7.2??1.5.7.3??1.5.7.4??1.5.7.5??1.5.7.6??1.5.8.1??1.5.8.2

1.5.8.3??1.5.8.4??1.5.8.5??1.5.8.6??1.5.9.1??1.5.9.2??1.5.9.3??1.5.9.4??1.5.9.5??1.5.9.6

1.6.1.1??1.6.1.2??1.6.1.3??1.6.1.4??1.6.1.5??1.6.1.6??1.6.2.1??1.6.2.2??1.6.2.3??1.6.2.4

1.6.2.5??1.6.2.6??1.6.3.1??1.6.3.2??1.6.3.3??1.6.3.4??1.6.3.5??1.6.3.6??1.6.4.1??1.6.4.2

1.6.4.3??1.6.4.4??1.6.4.5??1.6.4.6??1.6.5.1??1.6.5.2??1.6.5.3??1.6.5.4??1.6.5.5??1.6.5.6

1.6.6.1??1.6.6.2??1.6.6.3??1.6.6.4??1.6.6.5??1.6.6.6??1.6.7.1??1.6.7.2??1.6.7.3??1.6.7.4

1.6.7.5??1.6.7.6??1.6.8.1??1.6.8.2??1.6.8.3??1.6.8.4??1.6.8.5??1.6.8.6??1.6.9.1??1.6.9.2

1.6.9.3??1.6.9.4??1.6.9.5??1.6.9.6??1.7.1.1??1.7.1.2??1.7.1.3??1.7.1.4??1.7.1.5??1.7.1.6

1.7.2.1??1.7.2.2??1.7.2.3??1.7.2.4??1.7.2.5??1.7.2.6??1.7.3.1??1.7.3.2??1.7.3.3??1.7.3.4

1.7.3.5??1.7.3.6??1.7.4.1??1.7.4.2??1.7.4.3??1.7.4.4??1.7.4.5??1.7.4.6??1.7.5.1??1.7.5.2

1.7.5.3??1.7.5.4??1.7.5.5??1.7.5.6??1.7.6.1??1.7.6.2??1.7.6.3??1.7.6.4??1.7.6.5??1.7.6.6

1.7.7.1??1.7.7.2??1.7.7.3??1.7.7.4??1.7.7.5??1.7.7.6??1.7.8.1??1.7.8.2??1.7.8.3??1.7.8.4

1.7.8.5??1.7.8.6??1.7.9.1??1.7.9.2??1.7.9.3??1.7.9.4??1.7.9.5??1.7.9.6??1.8.1.1??1.8.1.2

1.8.1.3??1.8.1.4??1.8.1.5??1.8.1.6??1.8.2.1??1.8.2.2??1.8.2.3??1.8.2.4??1.8.2.5??1.8.2.6

1.8.3.1??1.8.3.2??1.8.3.3??1.8.3.4??1.8.3.5??1.8.3.6??1.8.4.1??1.8.4.2??1.8.4.3??1.8.4.4

1.8.4.5??1.8.4.6??1.8.5.1??1.8.5.2??1.8.5.3??1.8.5.4??1.8.5.5??1.8.5.6??1.8.6.1??1.8.6.2

1.8.6.3??1.8.6.4??1.8.6.5??1.8.6.6??1.8.7.1??1.8.7.2??1.8.7.3??1.8.7.4??1.8.7.5??1.8.7.6

1.8.8.1??1.8.8.2??1.8.8.3??1.8.8.4??1.8.8.5??1.8.8.6??1.8.9.1??1.8.9.2??1.8.9.3??1.8.9.4

1.8.9.5??1.8.9.6??1.9.1.1??1.9.1.2??1.9.1.3??1.9.1.4??1.9.1.5??1.9.1.6??1.9.2.1??1.9.2.2

1.9.2.3??1.9.2.4??1.9.2.5??1.9.2.6??1.9.3.1??1.9.3.2??1.9.3.3??1.9.3.4??1.9.3.5??1.9.3.6

Table 1-is continuous

1.9.4.1??1.9.4.2??1.9.4.3??1.9.4.4??1.9.4.5??1.9.4.6??1.9.5.1??1.9.5.2??1.9.5.3??1.9.5.4

1.9.5.5??1.9.5.6??1.9.6.1??1.9.6.2??1.9.6.3??1.9.6.4??1.9.6.5??1.9.6.6??1.9.7.1??1.9.7.2

1.9.7.3??1.9.7.4??1.9.7.5??1.9.7.6??1.9.8.1??1.9.8.2??1.9.8.3??1.9.8.4??1.9.8.5??1.9.8.6

1.9.9.1??1.9.9.2??1.9.9.3??1.9.9.4??1.9.9.5??1.9.9.6??2.1.1.1??2.1.1.2??2.1.1.3??2.1.1.4

2.1.1.5??2.1.1.6??2.1.2.1??2.1.2.2??2.1.2.3??2.1.2.4??2.1.2.5??2.1.2.6??2.1.3.1??2.1.3.2

2.1.3.3??2.1.3.4??2.1.3.5??2.1.3.6??2.1.4.1??2.1.4.2??2.1.4.3??2.1.4.4??2.1.4.5??2.1.4.6

2.1.5.1??2.1.5.2??2.1.5.3??2.1.5.4??2.1.5.5??2.1.5.6??2.1.6.1??2.1.6.2??2.1.6.3??2.1.6.4

2.1.6.5??2.1.6.6??2.1.7.1??2.1.7.2??2.1.7.3??2.1.7.4??2.1.7.5??2.1.7.6??2.1.8.1??2.1.8.2

2.1.8.3??2.1.8.4??2.1.8.5??2.1.8.6??2.1.9.1??2.1.9.2??2.1.9.3??2.1.9.4??2.1.9.5??2.1.9.6

2.2.1.1??2.2.1.2??2.2.1.3??2.2.1.4??2.2.1.5??2.2.1.6??2.2.2.1??2.2.2.2??2.2.2.3??2.2.2.4

2.2.2.5??2.2.2.6??2.2.3.1??2.2.3.2??2.2.3.3??2.2.3.4??2.2.3.5??2.2.3.6??2.2.4.1??2.2.4.2

2.2.4.3??2.2.4.4??2.2.4.5??2.2.4.6??2.2.5.1??2.2.5.2??2.2.5.3??2.2.5.4??2.2.5.5??2.2.5.6

2.2.6.1??2.2.6.2??2.2.6.3??2.2.6.4??2.2.6.5??2.2.6.6??2.2.7.1??2.2.7.2??2.2.7.3??2.2.7.4

2.2.7.5??2.2.7.6??2.2.8.1??2.2.8.2??2.2.8.3??2.2.8.4??2.2.8.5??2.2.8.6??2.2.9.1??2.2.9.2

2.2.9.3??2.2.9.4??2.2.9.5??2.2.9.6??2.3.1.1??2.3.1.2??2.3.1.3??2.3.1.4??2.3.1.5??2.3.1.6

2.3.2.1??2.3.2.2??2.3.2.3??2.3.2.4??2.3.2.5??2.3.2.6??2.3.3.1??2.3.3.2??2.3.3.3??2.3.3.4

2.3.3.5??2.3.3.6??2.3.4.1??2.3.4.2??2.3.4.3??2.3.4.4??2.3.4.5??2.3.4.6??2.3.5.1??2.3.5.2

2.3.5.3??2.3.5.4??2.3.5.5??2.3.5.6??2.3.6.1??2.3.6.2??2.3.6.3??2.3.6.4??2.3.6.5??2.3.6.6

2.3.7.1??2.3.7.2??2.3.7.3??2.3.7.4??2.3.7.5??2.3.7.6??2.3.8.1??2.3.8.2??2.3.8.3??2.3.8.4

2.3.8.5??2.3.8.6??2.3.9.1??2.3.9.2??2.3.9.3??2.3.9.4??2.3.9.5??2.3.9.6??2.4.1.1??2.4.1.2

2.4.1.3??2.4.1.4??2.4.1.5??2.4.1.6??2.4.2.1??2.4.2.2??2.4.2.3??2.4.2.4??2.4.2.5??2.4.2.6

2.4.3.1??2.4.3.2??2.4.3.3??2.4.3.4??2.4.3.5??2.4.3.6??2.4.4.1??2.4.4.2??2.4.4.3??2.4.4.4

2.4.4.5??2.4.4.6??2.4.5.1??2.4.5.2??2.4.5.3??2.4.5.4??2.4.5.5??2.4.5.6??2.4.6.1??2.4.6.2

2.4.6.3??2.4.6.4??2.4.6.5??2.4.6.6??2.4.7.1??2.4.7.2??2.4.7.3??2.4.7.4??2.4.7.5??2.4.7.6

2.4.8.1??2.4.8.2??2.4.8.3??2.4.8.4??2.4.8.5??2.4.8.6??2.4.9.1??2.4.9.2??2.4.9.3??2.4.9.4

2.4.9.5??2.4.9.6??2.5.1.1??2.5.1.2??2.5.1.3??2.5.1.4??2.5.1.5??2.5.1.6??2.5.2.1??2.5.2.2

2.5.2.3??2.5.2.4??2.5.2.5??2.5.2.6??2.5.3.1??2.5.3.2??2.5.3.3??2.5.3.4??2.5.3.5??2.5.3.6

2.5.4.1??2.5.4.2??2.5.4.3??2.5.4.4??2.5.4.5??2.5.4.6??2.5.5.1??2.5.5.2??2.5.5.3??2.5.5.4

2.5.5.5??2.5.5.6??2.5.6.1??2.5.6.2??2.5.6.3??2.5.6.4??2.5.6.5??2.5.6.6??2.5.7.1??2.5.7.2

2.5.7.3??2.5.7.4??2.5.7.5??2.5.7.6??2.5.8.1??2.5.8.2??2.5.8.3??2.5.8.4??2.5.8.5??2.5.8.6

2.5.9.1??2.5.9.2??2.5.9.3??2.5.9.4??2.5.9.5??2.5.9.6??2.6.1.1??2.6.1.2??2.6.1.3??2.6.1.4

2.6.1.5??2.6.1.6??2.6.2.1??2.6.2.2??2.6.2.3??2.6.2.4??2.6.2.5??2.6.2.6??2.6.3.1??2.6.3.2

2.6.3.3??2.6.3.4??2.6.3.5??2.6.3.6??2.6.4.1??2.6.4.2??2.6.4.3??2.6.4.4??2.6.4.5??2.6.4.6

2.6.5.1??2.6.5.2??2.6.5.3??2.6.5.4??2.6.5.5??2.6.5.6??2.6.6.1??2.6.6.2??2.6.6.3??2.6.6.4

2.6.6.5??2.6.6.6??2.6.7.1??2.6.7.2??2.6.7.3??2.6.7.4??2.6.7.5??2.6.7.6??2.6.8.1??2.6.8.2

2.6.8.3??2.6.8.4??2.6.8.5??2.6.8.6??2.6.9.1??2.6.9.2??2.6.9.3??2.6.9.4??2.6.9.5??2.6.9.6

2.7.1.1??2.7.1.2??2.7.1.3??2.7.1.4??2.7.1.5??2.7.1.6??2.7.2.1??2.7.2.2??2.7.2.3??2.7.2.4

2.7.2.5??2.7.2.6??2.7.3.1??2.7.3.2??2.7.3.3??2.7.3.4??2.7.3.5??2.7.3.6??2.7.4.1??2.7.4.2

2.7.4.3??2.7.4.4??2.7.4.5??2.7.4.6??2.7.5.1??2.7.5.2??2.7.5.3??2.7.5.4??2.7.5.5??2.7.5.6

2.7.6.1??2.7.6.2??2.7.6.3??2.7.6.4??2.7.6.5??2.7.6.6??2.7.7.1??2.7.7.2??2.7.7.3??2.7.7.4

2.7.7.5??2.7.7.6??2.7.8.1??2.7.8.2??2.7.8.3??2.7.8.4??2.7.8.5??2.7.8.6??2.7.9.1??2.7.9.2

2.7.9.3??2.7.9.4??2.7.9.5??2.7.9.6??2.8.1.1??2.8.1.2??2.8.1.3??2.8.1.4??2.8.1.5??2.8.1.6

2.8.2.1??2.8.2.2??2.8.2.3??2.8.2.4??2.8.2.5??2.8.2.6??2.8.3.1??2.8.3.2??2.8.3.3??2.8.3.4

2.8.3.5??2.8.3.6??2.8.4.1??2.8.4.2??2.8.4.3??2.8.4.4??2.8.4.5??2.8.4.6??2.8.5.1??2.8.5.2

2.8.5.3??2.8.5.4??2.8.5.5??2.8.5.6??2.8.6.1??2.8.6.2??2.8.6.3??2.8.6.4??2.8.6.5??2.8.6.6

2.8.7.1??2.8.7.2??2.8.7.3??2.8.7.4??2.8.7.5??2.8.7.6??2.8.8.1??2.8.8.2??2.8.8.3??2.8.8.4

Table 1-is continuous

2.8.8.5??2.8.8.6??2.8.9.1??2.8.9.2??2.8.9.3??2.8.9.4??2.8.9.5??2.8.9.6??2.9.1.1??2.9.1.2

2.9.1.3??2.9.1.4??2.9.1.5??2.9.1.6??2.9.2.1??2.9.2.2??2.9.2.3??2.9.2.4??2.9.2.5??2.9.2.6

2.9.3.1??2.9.3.2??2.9.3.3??2.9.3.4??2.9.3.5??2.9.3.6??2.9.4.1??2.9.4.2??2.9.4.3??2.9.4.4

2.9.4.5??2.9.4.6??2.9.5.1??2.9.5.2??2.9.5.3??2.9.5.4??2.9.5.5??2.9.5.6??2.9.6.1??2.9.6.2

2.9.6.3??2.9.6.4??2.9.6.5??2.9.6.6??2.9.7.1??2.9.7.2??2.9.7.3??2.9.7.4??2.9.7.5??2.9.7.6

2.9.8.1??2.9.8.2??2.9.8.3??2.9.8.4??2.9.8.5??2.9.8.6??2.9.9.1??2.9.9.2??2.9.9.3??2.9.9.4

2.9.9.5??2.9.9.6??3.1.1.1??3.1.1.2??3.1.1.3??3.1.1.4??3.1.1.5??3.1.1.6??3.1.2.1??3.1.2.2

3.1.2.3??3.1.2.4??3.1.2.5??3.1.2.6??3.1.3.1??3.1.3.2??3.1.3.3??3.1.3.4??3.1.3.5??3.1.3.6

3.1.4.1??3.1.4.2??3.1.4.3??3.1.4.4??3.1.4.5??3.1.4.6??3.1.5.1??3.1.5.2??3.1.5.3??3.1.5.4

3.1.5.5??3.1.5.6??3.1.6.1??3.1.6.2??3.1.6.3??3.1.6.4??3.1.6.5??3.1.6.6??3.1.7.1??3.1.7.2

3.1.7.3??3.1.7.4??3.1.7.5??3.1.7.6??3.1.8.1??3.1.8.2??3.1.8.3??3.1.8.4??3.1.8.5??3.1.8.6

3.1.9.1??3.1.9.2??3.1.9.3??3.1.9.4??3.1.9.5??3.1.9.6??3.2.1.1??3.2.1.2??3.2.1.3??3.2.1.4

3.2.1.5??3.2.1.6??3.2.2.1??3.2.2.2??3.2.2.3??3.2.2.4??3.2.2.5??3.2.2.6??3.2.3.1??3.2.3.2

3.2.3.3??3.2.3.4??3.2.3.5??3.2.3.6??3.2.4.1??3.2.4.2??3.2.4.3??3.2.4.4??3.2.4.5??3.2.4.6

3.2.5.1??3.2.5.2??3.2.5.3??3.2.5.4??3.2.5.5??3.2.5.6??3.2.6.1??3.2.6.2??3.2.6.3??3.2.6.4

3.2.6.5??3.2.6.6??3.2.7.1??3.2.7.2??3.2.7.3??3.2.7.4??3.2.7.5??3.2.7.6??3.2.8.1??3.2.8.2

3.2.8.3??3.2.8.4??3.2.8.5??3.2.8.6??3.2.9.1??3.2.9.2??3.2.9.3??3.2.9.4??3.2.9.5??3.2.9.6

3.3.1.1??3.3.1.2??3.3.1.3??3.3.1.4??3.3.1.5??3.3.1.6??3.3.2.1??3.3.2.2??3.3.2.3??3.3.2.4

3.3.2.5??3.3.2.6??3.3.3.1??3.3.3.2??3.3.3.3??3.3.3.4??3.3.3.5??3.3.3.6??3.3.4.1??3.3.4.2

3.3.4.3??3.3.4.4??3.3.4.5??3.3.4.6??3.3.5.1??3.3.5.2??3.3.5.3??3.3.5.4??3.3.5.5??3.3.5.6

3.3.6.1??3.3.6.2??3.3.6.3??3.3.6.4??3.3.6.5??3.3.6.6??3.3.7.1??3.3.7.2??3.3.7.3??3.3.7.4

3.3.7.5??3.3.7.6??3.3.8.1??3.3.8.2??3.3.8.3??3.3.8.4??3.3.8.5??3.3.8.6??3.3.9.1??3.3.9.2

3.3.9.3??3.3.9.4??3.3.9.5??3.3.9.6??3.4.1.1??3.4.1.2??3.4.1.3??3.4.1.4??3.4.1.5??3.4.1.6

3.4.2.1??3.4.2.2??3.4.2.3??3.4.2.4??3.4.2.5??3.4.2.6??3.4.3.1??3.4.3.2??3.4.3.3??3.4.3.4

3.4.3.5??3.4.3.6??3.4.4.1??3.4.4.2??3.4.4.3??3.4.4.4??3.4.4.5??3.4.4.6??3.4.5.1??3.4.5.2

3.4.5.3??3.4.5.4??3.4.5.5??3.4.5.6??3.4.6.1??3.4.6.2??3.4.6.3??3.4.6.4??3.4.6.5??3.4.6.6

3.4.7.1??3.4.7.2??3.4.7.3??3.4.7.4??3.4.7.5??3.4.7.6??3.4.8.1??3.4.8.2??3.4.8.3??3.4.8.4

3.4.8.5??3.4.8.6??3.4.9.1??3.4.9.2??3.4.9.3??3.4.9.4??3.4.9.5??3.4.9.6??3.5.1.1??3.5.1.2

3.5.1.3??3.5.1.4??3.5.1.5??3.5.1.6??3.5.2.1??3.5.2.2??3.5.2.3??3.5.2.4??3.5.2.5??3.5.2.6

3.5.3.1??3.5.3.2??3.5.3.3??3.5.3.4??3.5.3.5??3.5.3.6??3.5.4.1??3.5.4.2??3.5.4.3??3.5.4.4

3.5.4.5??3.5.4.6??3.5.5.1??3.5.5.2??3.5.5.3??3.5.5.4??3.5.5.5??3.5.5.6??3.5.6.1??3.5.6.2

3.5.6.3??3.5.6.4??3.5.6.5??3.5.6.6??3.5.7.1??3.5.7.2??3.5.7.3??3.5.7.4??3.5.7.5??3.5.7.6

3.5.8.1??3.5.8.2??3.5.8.3??3.5.8.4??3.5.8.5??3.5.8.6??3.5.9.1??3.5.9.2??3.5.9.3??3.5.9.4

3.5.9.5??3.5.9.6??3.6.1.1??3.6.1.2??3.6.1.3??3.6.1.4??3.6.1.5??3.6.1.6??3.6.2.1??3.6.2.2

3.6.2.3??3.6.2.4??3.6.2.5??3.6.2.6??3.6.3.1??3.6.3.2??3.6.3.3??3.6.3.4??3.6.3.5??3.6.3.6

3.6.4.1??3.6.4.2??3.6.4.3??3.6.4.4??3.6.4.5??3.6.4.6??3.6.5.1??3.6.5.2??3.6.5.3??3.6.5.4

3.6.5.5??3.6.5.6??3.6.6.1??3.6.6.2??3.6.6.3??3.6.6.4??3.6.6.5??3.6.6.6??3.6.7.1??3.6.7.2

3.6.7.3??3.6.7.4??3.6.7.5??3.6.7.6??3.6.8.1??3.6.8.2??3.6.8.3??3.6.8.4??3.6.8.5??3.6.8.6

3.6.9.1??3.6.9.2??3.6.9.3??3.6.9.4??3.6.9.5??3.6.9.6??3.7.1.1??3.7.1.2??3.7.1.3??3.7.1.4

3.7.1.5??3.7.1.6??3.7.2.1??3.7.2.2??3.7.2.3??3.7.2.4??3.7.2.5??3.7.2.6??3.7.3.1??3.7.3.2

3.7.3.3??3.7.3.4??3.7.3.5??3.7.3.6??3.7.4.1??3.7.4.2??3.7.4.3??3.7.4.4??3.7.4.5??3.7.4.6

3.7.5.1??3.7.5.2??3.7.5.3??3.7.5.4??3.7.5.5??3.7.5.6??3.7.6.1??3.7.6.2??3.7.6.3??3.7.6.4

3.7.6.5??3.7.6.6??3.7.7.1??3.7.7.2??3.7.7.3??3.7.7.4??3.7.7.5??3.7.7.6??3.7.8.1??3.7.8.2

3.7.8.3??3.7.8.4??3.7.8.5??3.7.8.6??3.7.9.1??3.7.9.2??3.7.9.3??3.7.9.4??3.7.9.5??3.7.9.6

3.8.1.1??3.8.1.2??3.8.1.3??3.8.1.4??3.8.1.5??3.8.1.6??3.8.2.1??3.8.2.2??3.8.2.3??3.8.2.4

3.8.2.5??3.8.2.6??3.8.3.1??3.8.3.2??3.8.3.3??3.8.3.4??3.8.3.5??3.8.3.6??3.8.4.1??3.8.4.2

Table 1-is continuous

3.8.4.3??3.8.4.4??3.8.4.5??3.8.4.6??3.8.5.1??3.8.5.2??3.8.5.3??3.8.5.4??3.8.5.5??3.8.5.6

3.8.6.1??3.8.6.2??3.8.6.3??3.8.6.4??3.8.6.5??3.8.6.6??3.8.7.1??3.8.7.2??3.8.7.3??3.8.7.4

3.8.7.5??3.8.7.6??3.8.8.1??3.8.8.2??3.8.8.3??3.8.8.4??3.8.8.5??3.8.8.6??3.8.9.1??3.8.9.2

3.8.9.3??3.8.9.4??3.8.9.5??3.8.9.6??3.9.1.1??3.9.1.2??3.9.1.3??3.9.1.4??3.9.1.5??3.9.1.6

3.9.2.1??3.9.2.2??3.9.2.3??3.9.2.4??3.9.2.5??3.9.2.6??3.9.3.1??3.9.3.2??3.9.3.3??3.9.3.4

3.9.3.5??3.9.3.6??3.9.4.1??3.9.4.2??3.9.4.3??3.9.4.4??3.9.4.5??3.9.4.6??3.9.5.1??3.9.5.2

3.9.5.3??3.9.5.4??3.9.5.5??3.9.5.6??3.9.6.1??3.9.6.2??3.9.6.3??3.9.6.4??3.9.6.5??3.9.6.6

3.9.7.1??3.9.7.2??3.9.7.3??3.9.7.4??3.9.7.5??3.9.7.6??3.9.8.1??3.9.8.2??3.9.8.3??3.9.8.4

3.9.8.5??3.9.8.6??3.9.9.1??3.9.9.2??3.9.9.3??3.9.9.4??3.9.9.5??3.9.9.6??4.1.1.1??4.1.1.2

4.1.1.3??4.1.1.4??4.1.1.5??4.1.1.6??4.1.2.1??4.1.2.2??4.1.2.3??4.1.2.4??4.1.2.5??4.1.2.6

4.1.3.1??4.1.3.2??4.1.3.3??4.1.3.4??4.1.3.5??4.1.3.6??4.1.4.1??4.1.4.2??4.1.4.3??4.1.4.4

4.1.4.5??4.1.4.6??4.1.5.1??4.1.5.2??4.1.5.3??4.1.5.4??4.1.5.5??4.1.5.6??4.1.6.1??4.1.6.2

4.1.6.3??4.1.6.4??4.1.6.5??4.1.6.6??4.1.7.1??4.1.7.2??4.1.7.3??4.1.7.4??4.1.7.5??4.1.7.6

4.1.8.1??4.1.8.2??4.1.8.3??4.1.8.4??4.1.8.5??4.1.8.6??4.1.9.1??4.1.9.2??4.1.9.3??4.1.9.4

4.1.9.5??4.1.9.6??4.2.1.1??4.2.1.2??4.2.1.3??4.2.1.4??4.2.1.5??4.2.1.6??4.2.2.1??4.2.2.2

4.2.2.3??4.2.2.4??4.2.2.5??4.2.2.6??4.2.3.1??4.2.3.2??4.2.3.3??4.2.3.4??4.2.3.5??4.2.3.6

4.2.4.1??4.2.4.2??4.2.4.3??4.2.4.4??4.2.4.5??4.2.4.6??4.2.5.1??4.2.5.2??4.2.5.3??4.2.5.4

4.2.5.5??4.2.5.6??4.2.6.1??4.2.6.2??4.2.6.3??4.2.6.4??4.2.6.5??4.2.6.6??4.2.7.1??4.2.7.2

4.2.7.3??4.2.7.4??4.2.7.5??4.2.7.6??4.2.8.1??4.2.8.2??4.2.8.3??4.2.8.4??4.2.8.5??4.2.8.6

4.2.9.1??4.2.9.2??4.2.9.3??4.2.9.4??4.2.9.5??4.2.9.6??4.3.1.1??4.3.1.2??4.3.1.3??4.3.1.4

4.3.1.5??4.3.1.6??4.3.2.1??4.3.2.2??4.3.2.3??4.3.2.4??4.3.2.5??4.3.2.6??4.3.3.1??4.3.3.2

4.3.3.3??4.3.3.4??4.3.3.5??4.3.3.6??4.3.4.1??4.3.4.2??4.3.4.3??4.3.4.4??4.3.4.5??4.3.4.6

4.3.5.1??4.3.5.2??4.3.5.3??4.3.5.4??4.3.5.5??4.3.5.6??4.3.6.1??4.3.6.2??4.3.6.3??4.3.6.4

4.3.6.5??4.3.6.6??4.3.7.1??4.3.7.2??4.3.7.3??4.3.7.4??4.3.7.5??4.3.7.6??4.3.8.1??4.3.8.2

4.3.8.3??4.3.8.4??4.3.8.5??4.3.8.6??4.3.9.1??4.3.9.2??4.3.9.3??4.3.9.4??4.3.9.5??4.3.9.6

4.4.1.1??4.4.1.2??4.4.1.3??4.4.1.4??4.4.1.5??4.4.1.6??4.4.2.1??4.4.2.2??4.4.2.3??4.4.2.4

4.4.2.5??4.4.2.6??4.4.3.1??4.4.3.2??4.4.3.3??4.4.3.4??4.4.3.5??4.4.3.6??4.4.4.1??4.4.4.2

4.4.4.3??4.4.4.4??4.4.4.5??4.4.4.6??4.4.5.1??4.4.5.2??4.4.5.3??4.4.5.4??4.4.5.5??4.4.5.6

4.4.6.1??4.4.6.2??4.4.6.3??4.4.6.4??4.4.6.5??4.4.6.6??4.4.7.1??4.4.7.2??4.4.7.3??4.4.7.4

4.4.7.5??4.4.7.6??4.4.8.1??4.4.8.2??4.4.8.3??4.4.8.4??4.4.8.5??4.4.8.6??4.4.9.1??4.4.9.2

4.4.9.3??4.4.9.4??4.4.9.5??4.4.9.6??4.5.1.1??4.5.1.2??4.5.1.3??4.5.1.4??4.5.1.5??4.5.1.6

4.5.2.1??4.5.2.2??4.5.2.3??4.5.2.4??4.5.2.5??4.5.2.6??4.5.3.1??4.5.3.2??4.5.3.3??4.5.3.4

4.5.3.5??4.5.3.6??4.5.4.1??4.5.4.2??4.5.4.3??4.5.4.4??4.5.4.5??4.5.4.6??4.5.5.1??4.5.5.2

4.5.5.3??4.5.5.4??4.5.5.5??4.5.5.6??4.5.6.1??4.5.6.2??4.5.6.3??4.5.6.4??4.5.6.5??4.5.6.6

4.5.7.1??4.5.7.2??4.5.7.3??4.5.7.4??4.5.7.5??4.5.7.6??4.5.8.1??4.5.8.2??4.5.8.3??4.5.8.4

4.5.8.5??4.5.8.6??4.5.9.1??4.5.9.2??4.5.9.3??4.5.9.4??4.5.9.5??4.5.9.6??4.6.1.1??4.6.1.2

4.6.1.3??4.6.1.4??4.6.1.5??4.6.1.6??4.6.2.1??4.6.2.2??4.6.2.3??4.6.2.4??4.6.2.5??4.6.2.6

4.6.3.1??4.6.3.2??4.6.3.3??4.6.3.4??4.6.3.5??4.6.3.6??4.6.4.1??4.6.4.2??4.6.4.3??4.6.4.4

4.6.4.5??4.6.4.6??4.6.5.1??4.6.5.2??4.6.5.3??4.6.5.4??4.6.5.5??4.6.5.6??4.6.6.1??4.6.6.2

4.6.6.3??4.6.6.4??4.6.6.5??4.6.6.6??4.6.7.1??4.6.7.2??4.6.7.3??4.6.7.4??4.6.7.5??4.6.7.6

4.6.8.1??4.6.8.2??4.6.8.3??4.6.8.4??4.6.8.5??4.6.8.6??4.6.9.1??4.6.9.2??4.6.9.3??4.6.9.4

4.6.9.5??4.6.9.6??4.7.1.1??4.7.1.2??4.7.1.3??4.7.1.4??4.7.1.5??4.7.1.6??4.7.2.1??4.7.2.2

4.7.2.3??4.7.2.4??4.7.2.5??4.7.2.6??4.7.3.1??4.7.3.2??4.7.3.3??4.7.3.4??4.7.3.5??4.7.3.6

4.7.4.1??4.7.4.2??4.7.4.3??4.7.4.4??4.7.4.5??4.7.4.6??4.7.5.1??4.7.5.2??4.7.5.3??4.7.5.4

4.7.5.5??4.7.5.6??4.7.6.1??4.7.6.2??4.7.6.3??4.7.6.4??4.7.6.5??4.7.6.6??4.7.7.1??4.7.7.2

4.7.7.3??4.7.7.4??4.7.7.5??4.7.7.6??4.7.8.1??4.7.8.2??4.7.8.3??4.7.8.4??4.7.8.5??4.7.8.6

Table 1. is continuous

4.7.9.1??4.7.9.2??4.7.9.3??4.7.9.4??4.7.9.5??4.7.9.6??4.8.1.1??4.8.1.2??4.8.1.3??4.8.1.4

4.8.1.5??4.8.1.6??4.8.2.1??4.8.2.2??4.8.2.3??4.8.2.4??4.8.2.5??4.8.2.6??4.8.3.1??4.8.3.2

4.8.3.3??4.8.3.4??4.8.3.5??4.8.3.6??4.8.4.1??4.8.4.2??4.8.4.3??4.8.4.4??4.8.4.5??4.8.4.6

4.8.5.1??4.8.5.2??4.8.5.3??4.8.5.4??4.8.5.5??4.8.5.6??4.8.6.1??4.8.6.2??4.8.6.3??4.8.6.4

4.8.6.5??4.8.6.6??4.8.7.1??4.8.7.2??4.8.7.3??4.8.7.4??4.8.7.5??4.8.7.6??4.8.8.1??4.8.8.2

4.8.8.3??4.8.8.4??4.8.8.5??4.8.8.6??4.8.9.1??4.8.9.2??4.8.9.3??4.8.9.4??4.8.9.5??4.8.9.6

4.9.1.1??4.9.1.2??4.9.1.3??4.9.1.4??4.9.1.5??4.9.1.6??4.9.2.1??4.9.2.2??4.9.2.3??4.9.2.4

4.9.2.5??4.9.2.6??4.9.3.1??4.9.3.2??4.9.3.3??4.9.3.4??4.9.3.5??4.9.3.6??4.9.4.1??4.9.4.2

4.9.4.3??4.9.4.4??4.9.4.5??4.9.4.6??4.9.5.1??4.9.5.2??4.9.5.3??4.9.5.4??4.9.5.5??4.9.5.6

4.9.6.1??4.9.6.2??4.9.6.3??4.9.6.4??4.9.6.5??4.9.6.6??4.9.7.1??4.9.7.2??4.9.7.3??4.9.7.4

4.9.7.5??4.9.7.6??4.9.8.1??4.9.8.2??4.9.8.3??4.9.8.4??4.9.8.5??4.9.8.6??4.9.9.1??4.9.9.2

4.9.9.3??4.9.9.4??4.9.9.5??4.9.9.6??5.1.1.1??5.1.1.2??5.1.1.3??5.1.1.4??5.1.1.5??5.1.1.6

5.1.2.1??5.1.2.2??5.1.2.3??5.1.2.4??5.1.2.5??5.1.2.6??5.1.3.1??5.1.3.2??5.1.3.3??5.1.3.4

5.1.3.5??5.1.3.6??5.1.4.1??5.1.4.2??5.1.4.3??5.1.4.4??5.1.4.5??5.1.4.6??5.1.5.1??5.1.5.2

5.1.5.3??5.1.5.4??5.1.5.5??5.1.5.6??5.1.6.1??5.1.6.2??5.1.6.3??5.1.6.4??5.1.6.5??5.1.6.6

5.1.7.1??5.1.7.2??5.1.7.3??5.1.7.4??5.1.7.5??5.1.7.6??5.1.8.1??5.1.8.2??5.1.8.3??5.1.8.4

5.1.8.5??5.1.8.6??5.1.9.1??5.1.9.2??5.1.9.3??5.1.9.4??5.1.9.5??5.1.9.6??5.2.1.1??5.2.1.2

5.2.1.3??5.2.1.4??5.2.1.5??5.2.1.6??5.2.2.1??5.2.2.2??5.2.2.3??5.2.2.4??5.2.2.5??5.2.2.6

5.2.3.1??5.2.3.2??5.2.3.3??5.2.3.4??5.2.3.5??5.2.3.6??5.2.4.1??5.2.4.2??5.2.4.3??5.2.4.4

5.2.4.5??5.2.4.6??5.2.5.1??5.2.5.2??5.2.5.3??5.2.5.4??5.2.5.5??5.2.5.6??5.2.6.1??5.2.6.2

5.2.6.3??5.2.6.4??5.2.6.5??5.2.6.6??5.2.7.1??5.2.7.2??5.2.7.3??5.2.7.4??5.2.7.5??5.2.7.6

5.2.8.1??5.2.8.2??5.2.8.3??5.2.8.4??5.2.8.5??5.2.8.6??5.2.9.1??5.2.9.2??5.2.9.3??5.2.9.4

5.2.9.5??5.2.9.6??5.3.1.1??5.3.1.2??5.3.1.3??5.3.1.4??5.3.1.5??5.3.1.6??5.3.2.1??5.3.2.2

5.3.2.3??5.3.2.4??5.3.2.5??5.3.2.6??5.3.3.1??5.3.3.2??5.3.3.3??5.3.3.4??5.3.3.5??5.3.3.6

5.3.4.1??5.3.4.2??5.3.4.3??5.3.4.4??5.3.4.5??5.3.4.6??5.3.5.1??5.3.5.2??5.3.5.3??5.3.5.4

5.3.5.5??5.3.5.6??5.3.6.1??5.3.6.2??5.3.6.3??5.3.6.4??5.3.6.5??5.3.6.6??5.3.7.1??5.3.7.2

5.3.7.3??5.3.7.4??5.3.7.5??5.3.7.6??5.3.8.1??5.3.8.2??5.3.8.3??5.3.8.4??5.3.8.5??5.3.8.6

5.3.9.1??5.3.9.2??5.3.9.3??5.3.9.4??5.3.9.5??5.3.9.6??5.4.1.1??5.4.1.2??5.4.1.3??5.4.1.4

5.4.1.5??5.4.1.6??5.4.2.1??5.4.2.2??5.4.2.3??5.4.2.4??5.4.2.5??5.4.2.6??5.4.3.1??5.4.3.2

5.4.3.3??5.4.3.4??5.4.3.5??5.4.3.6??5.4.4.1??5.4.4.2??5.4.4.3??5.4.4.4??5.4.4.5??5.4.4.6

5.4.5.1??5.4.5.2??5.4.5.3??5.4.5.4??5.4.5.5??5.4.5.6??5.4.6.1??5.4.6.2??5.4.6.3??5.4.6.4

5.4.6.5??5.4.6.6??5.4.7.1??5.4.7.2??5.4.7.3??5.4.7.4??5.4.7.5??5.4.7.6??5.4.8.1??5.4.8.2

5.4.8.3??5.4.8.4??5.4.8.5??5.4.8.6??5.4.9.1??5.4.9.2??5.4.9.3??5.4.9.4??5.4.9.5??5.4.9.6

5.5.1.1??5.5.1.2??5.5.1.3??5.5.1.4??5.5.1.5??5.5.1.6??5.5.2.1??5.5.2.2??5.5.2.3??5.5.2.4

5.5.2.5??5.5.2.6??5.5.3.1??5.5.3.2??5.5.3.3??5.5.3.4??5.5.3.5??5.5.3.6??5.5.4.1??5.5.4.2

5.5.4.3??5.5.4.4??5.5.4.5??5.5.4.6??5.5.5.1??5.5.5.2??5.5.5.3??5.5.5.4??5.5.5.5??5.5.5.6

5.5.6.1??5.5.6.2??5.5.6.3??5.5.6.4??5.5.6.5??5.5.6.6??5.5.7.1??5.5.7.2??5.5.7.3??5.5.7.4

5.5.7.5??5.5.7.6??5.5.8.1??5.5.8.2??5.5.8.3??5.5.8.4??5.5.8.5??5.5.8.6??5.5.9.1??5.5.9.2

5.5.9.3??5.5.9.4??5.5.9.5??5.5.9.6??5.6.1.1??5.6.1.2??5.6.1.3??5.6.1.4??5.6.1.5??5.6.1.6

5.6.2.1??5.6.2.2??5.6.2.3??5.6.2.4??5.6.2.5??5.6.2.6??5.6.3.1??5.6.3.2??5.6.3.3??5.6.3.4

5.6.3.5??5.6.3.6??5.6.4.1??5.6.4.2??5.6.4.3??5.6.4.4??5.6.4.5??5.6.4.6??5.6.5.1??5.6.5.2

5.6.5.3??5.6.5.4??5.6.5.5??5.6.5.6??5.6.6.1??5.6.6.2??5.6.6.3??5.6.6.4??5.6.6.5??5.6.6.6

5.6.7.1??5.6.7.2??5.6.7.3??5.6.7.4??5.6.7.5??5.6.7.6??5.6.8.1??5.6.8.2??5.6.8.3??5.6.8.4

5.6.8.5??5.6.8.6??5.6.9.1??5.6.9.2??5.6.9.3??5.6.9.4??5.6.9.5??5.6.9.6??5.7.1.1??5.7.1.2

5.7.1.3??5.7.1.4??5.7.1.5??5.7.1.6??5.7.2.1??5.7.2.2??5.7.2.3??5.7.2.4??5.7.2.5??5.7.2.6

5.7.3.1??5.7.3.2??5.7.3.3??5.7.3.4??5.7.3.5??5.7.3.6??5.7.4.1??5.7.4.2??5.7.4.3??5.7.4.4

Table 1. is continuous

5.7.4.5??5.7.4.6??5.7.5.1??5.7.5.2??5.7.5.3??5.7.5.4??5.7.5.5??5.7.5.6??5.7.6.1??5.7.6.2

5.7.6.3??5.7.6.4??5.7.6.5??5.7.6.6??5.7.7.1??5.7.7.2??5.7.7.3??5.7.7.4??5.7.7.5??5.7.7.6

5.7.8.1??5.7.8.2??5.7.8.3??5.7.8.4??5.7.8.5??5.7.8.6??5.7.9.1??5.7.9.2??5.7.9.3??5.7.9.4

5.7.9.5??5.7.9.6??5.8.1.1??5.8.1.2??5.8.1.3??5.8.1.4??5.8.1.5??5.8.1.6??5.8.2.1??5.8.2.2

5.8.2.3??5.8.2.4??5.8.2.5??5.8.2.6??5.8.3.1??5.8.3.2??5.8.3.3??5.8.3.4??5.8.3.5??5.8.3.6

5.8.4.1??5.8.4.2??5.8.4.3??5.8.4.4??5.8.4.5??5.8.4.6??5.8.5.1??5.8.5.2??5.8.5.3??5.8.5.4

5.8.5.5??5.8.5.6??5.8.6.1??5.8.6.2??5.8.6.3??5.8.6.4??5.8.6.5??5.8.6.6??5.8.7.1??5.8.7.2

5.8.7.3??5.8.7.4??5.8.7.5??5.8.7.6??5.8.8.1??5.8.8.2??5.8.8.3??5.8.8.4??5.8.8.5??5.8.8.6

5.8.9.1??5.8.9.2??5.8.9.3??5.8.9.4??5.8.9.5??5.8.9.6??5.9.1.1??5.9.1.2??5.9.1.3??5.9.1.4

5.9.1.5??5.9.1.6??5.9.2.1??5.9.2.2??5.9.2.3??5.9.2.4??5.9.2.5??5.9.2.6??5.9.3.1??5.9.3.2

5.9.3.3??5.9.3.4??5.9.3.5??5.9.3.6??5.9.4.1??5.9.4.2??5.9.4.3??5.9.4.4??5.9.4.5??5.9.4.6

5.9.5.1??5.9.5.2??5.9.5.3??5.9.5.4??5.9.5.5??5.9.5.6??5.9.6.1??5.9.6.2??5.9.6.3??5.9.6.4

5.9.6.5??5.9.6.6??5.9.7.1??5.9.7.2??5.9.7.3??5.9.7.4??5.9.7.5??5.9.7.6??5.9.8.1??5.9.8.2

5.9.8.3??5.9.8.4??5.9.8.5??5.9.8.6??5.9.9.1??5.9.9.2??5.9.9.3??5.9.9.4??5.9.9.5??5.9.9.6

6.1.1.1??6.1.1.2??6.1.1.3??6.1.1.4??6.1.1.5??6.1.1.6??6.1.2.1??6.1.2.2??6.1.2.3??6.1.2.4

6.1.2.5??6.1.2.6??6.1.3.1??6.1.3.2??6.1.3.3??6.1.3.4??6.1.3.5??6.1.3.6??6.1.4.1??6.1.4.2

6.1.4.3??6.1.4.4??6.1.4.5??6.1.4.6??6.1.5.1??6.1.5.2??6.1.5.3??6.1.5.4??6.1.5.5??6.1.5.6

6.1.6.1??6.1.6.2??6.1.6.3??6.1.6.4??6.1.6.5??6.1.6.6??6.1.7.1??6.1.7.2??6.1.7.3??6.1.7.4

6.1.7.5??6.1.7.6??6.1.8.1??6.1.8.2??6.1.8.3??6.1.8.4??6.1.8.5??6.1.8.6??6.1.9.1??6.1.9.2

6.1.9.3??6.1.9.4??6.1.9.5??6.1.9.6??6.2.1.1??6.2.1.2??6.2.1.3??6.2.1.4??6.2.1.5??6.2.1.6

6.2.2.1??6.2.2.2??6.2.2.3??6.2.2.4??6.2.2.5??6.2.2.6??6.2.3.1??6.2.3.2??6.2.3.3??6.2.3.4

6.2.3.5??6.2.3.6??6.2.4.1??6.2.4.2??6.2.4.3??6.2.4.4??6.2.4.5??6.2.4.6??6.2.5.1??6.2.5.2

6.2.5.3??6.2.5.4??6.2.5.5??6.2.5.6??6.2.6.1??6.2.6.2??6.2.6.3??6.2.6.4??6.2.6.5??6.2.6.6

6.2.7.1??6.2.7.2??6.2.7.3??6.2.7.4??6.2.7.5??6.2.7.6??6.2.8.1??6.2.8.2??6.2.8.3??6.2.8.4

6.2.8.5??6.2.8.6??6.2.9.1??6.2.9.2??6.2.9.3??6.2.9.4??6.2.9.5??6.2.9.6??6.3.1.1??6.3.1.2

6.3.1.3??6.3.1.4??6.3.1.5??6.3.1.6??6.3.2.1??6.3.2.2??6.3.2.3??6.3.2.4??6.3.2.5??6.3.2.6

6.3.3.1??6.3.3.2??6.3.3.3??6.3.3.4??6.3.3.5??6.3.3.6??6.3.4.1??6.3.4.2??6.3.4.3??6.3.4.4

6.3.4.5??6.3.4.6??6.3.5.1??6.3.5.2??6.3.5.3??6.3.5.4??6.3.5.5??6.3.5.6??6.3.6.1??6.3.6.2

6.3.6.3??6.3.6.4??6.3.6.5??6.3.6.6??6.3.7.1??6.3.7.2??6.3.7.3??6.3.7.4??6.3.7.5??6.3.7.6

6.3.8.1??6.3.8.2??6.3.8.3??6.3.8.4??6.3.8.5??6.3.8.6??6.3.9.1??6.3.9.2??6.3.9.3??6.3.9.4

6.3.9.5??6.3.9.6??6.4.1.1??6.4.1.2??6.4.1.3??6.4.1.4??6.4.1.5??6.4.1.6??6.4.2.1??6.4.2.2

6.4.2.3??6.4.2.4??6.4.2.5??6.4.2.6??6.4.3.1??6.4.3.2??6.4.3.3??6.4.3.4??6.4.3.5??6.4.3.6

6.4.4.1??6.4.4.2??6.4.4.3??6.4.4.4??6.4.4.5??6.4.4.6??6.4.5.1??6.4.5.2??6.4.5.3??6.4.5.4

6.4.5.5??6.4.5.6??6.4.6.1??6.4.6.2??6.4.6.3??6.4.6.4??6.4.6.5??6.4.6.6??6.4.7.1??6.4.7.2

6.4.7.3??6.4.7.4??6.4.7.5??6.4.7.6??6.4.8.1??6.4.8.2??6.4.8.3??6.4.8.4??6.4.8.5??6.4.8.6

6.4.9.1??6.4.9.2??6.4.9.3??6.4.9.4??6.4.9.5??6.4.9.6??6.5.1.1??6.5.1.2??6.5.1.3??6.5.1.4

6.5.1.5??6.5.1.6??6.5.2.1??6.5.2.2??6.5.2.3??6.5.2.4??6.5.2.5??6.5.2.6??6.5.3.1??6.5.3.2

6.5.3.3??6.5.3.4??6.5.3.5??6.5.3.6??6.5.4.1??6.5.4.2??6.5.4.3??6.5.4.4??6.5.4.5??6.5.4.6

6.5.5.1??6.5.5.2??6.5.5.3??6.5.5.4??6.5.5.5??6.5.5.6??6.5.6.1??6.5.6.2??6.5.6.3??6.5.6.4

6.5.6.5??6.5.6.6??6.5.7.1??6.5.7.2??6.5.7.3??6.5.7.4??6.5.7.5??6.5.7.6??6.5.8.1??6.5.8.2

6.5.8.3??6.5.8.4??6.5.8.5??6.5.8.6??6.5.9.1??6.5.9.2??6.5.9.3??6.5.9.4??6.5.9.5??6.5.9.6

6.6.1.1??6.6.1.2??6.6.1.3??6.6.1.4??6.6.1.5??6.6.1.6??6.6.2.1??6.6.2.2??6.6.2.3??6.6.2.4

6.6.2.5??6.6.2.6??6.6.3.1??6.6.3.2??6.6.3.3??6.6.3.4??6.6.3.5??6.6.3.6??6.6.4.1??6.6.4.2

6.6.4.3??6.6.4.4??6.6.4.5??6.6.4.6??6.6.5.1??6.6.5.2??6.6.5.3??6.6.5.4??6.6.5.5??6.6.5.6

6.6.6.1??6.6.6.2??6.6.6.3??6.6.6.4??6.6.6.5??6.6.6.6??6.6.7.1??6.6.7.2??6.6.7.3??6.6.7.4

6.6.7.5??6.6.7.6??6.6.8.1??6.6.8.2??6.6.8.3??6.6.8.4??6.6.8.5??6.6.8.6??6.6.9.1??6.6.9.2

Table 1-is continuous

6.6.9.3??6.6.9.4??6.6.9.5??6.6.9.6??6.7.1.1??6.7.1.2??6.7.1.3??6.7.1.4??6.7.1.5??6.7.1.6

6.7.2.1??6.7.2.2??6.7.2.3??6.7.2.4??6.7.2.5??6.7.2.6??6.7.3.1??6.7.3.2??6.7.3.3??6.7.3.4

6.7.3.5??6.7.3.6??6.7.4.1??6.7.4.2??6.7.4.3??6.7.4.4??6.7.4.5??6.7.4.6??6.7.5.1??6.7.5.2

6.7.5.3??6.7.5.4??6.7.5.5??6.7.5.6??6.7.6.1??6.7.6.2??6.7.6.3??6.7.6.4??6.7.6.5??6.7.6.6

6.7.7.1??6.7.7.2??6.7.7.3??6.7.7.4??6.7.7.5??6.7.7.6??6.7.8.1??6.7.8.2??6.7.8.3??6.7.8.4

6.7.8.5??6.7.8.6??6.7.9.1??6.7.9.2??6.7.9.3??6.7.9.4??6.7.9.5??6.7.9.6??6.8.1.1??6.8.1.2

6.8.1.3??6.8.1.4??6.8.1.5??6.8.1.6??6.8.2.1??6.8.2.2??6.8.2.3??6.8.2.4??6.8.2.5??6.8.2.6

6.8.3.1??6.8.3.2??6.8.3.3??6.8.3.4??6.8.3.5??6.8.3.6??6.8.4.1??6.8.4.2??6.8.4.3??6.8.4.4

6.8.4.5??6.8.4.6??6.8.5.1??6.8.5.2??6.8.5.3??6.8.5.4??6.8.5.5??6.8.5.6??6.8.6.1??6.8.6.2

6.8.6.3??6.8.6.4??6.8.6.5??6.8.6.6??6.8.7.1??6.8.7.2??6.8.7.3??6.8.7.4??6.8.7.5??6.8.7.6

6.8.8.1??6.8.8.2??6.8.8.3??6.8.8.4??6.8.8.5??6.8.8.6??6.8.9.1??6.8.9.2??6.8.9.3??6.8.9.4

6.8.9.5??6.8.9.6??6.9.1.1??6.9.1.2??6.9.1.3??6.9.1.4??6.9.1.5??6.9.1.6??6.9.2.1??6.9.2.2

6.9.2.3??6.9.2.4??6.9.2.5??6.9.2.6??6.9.3.1??6.9.3.2??6.9.3.3??6.9.3.4??6.9.3.5??6.9.3.6

6.9.4.1??6.9.4.2??6.9.4.3??6.9.4.4??6.9.4.5??6.9.4.6??6.9.5.1??6.9.5.2??6.9.5.3??6.9.5.4

6.9.5.5??6.9.5.6??6.9.6.1??6.9.6.2??6.9.6.3??6.9.6.4??6.9.6.5??6.9.6.6??6.9.7.1??6.9.7.2

6.9.7.3??6.9.7.4??6.9.7.5??6.9.7.6??6.9.8.1??6.9.8.2??6.9.8.3??6.9.8.4??6.9.8.5??6.9.8.6

6.9.9.1??6.9.9.2??6.9.9.3??6.9.9.4??6.9.9.5??6.9.9.6??7.1.1.1??7.1.1.2??7.1.1.3??7.1.1.4

7.1.1.5??7.1.1.6??7.1.2.1??7.1.2.2??7.1.2.3??7.1.2.4??7.1.2.5??7.1.2.6??7.1.3.1??7.1.3.2

7.1.3.3??7.1.3.4??7.1.3.5??7.1.3.6??7.1.4.1??7.1.4.2??7.1.4.3??7.1.4.4??7.1.4.5??7.1.4.6

7.1.5.1??7.1.5.2??7.1.5.3??7.1.5.4??7.1.5.5??7.1.5.6??7.1.6.1??7.1.6.2??7.1.6.3??7.1.6.4

7.1.6.5??7.1.6.6??7.1.7.1??7.1.7.2??7.1.7.3??7.1.7.4??7.1.7.5??7.1.7.6??7.1.8.1??7.1.8.2

7.1.8.3??7.1.8.4??7.1.8.5??7.1.8.6??7.1.9.1??7.1.9.2??7.1.9.3??7.1.9.4??7.1.9.5??7.1.9.6

7.2.1.1??7.2.1.2??7.2.1.3??7.2.1.4??7.2.1.5??7.2.1.6??7.2.2.1??7.2.2.2??7.2.2.3??7.2.2.4

7.2.2.5??7.2.2.6??7.2.3.1??7.2.3.2??7.2.3.3??7.2.3.4??7.2.3.5??7.2.3.6??7.2.4.1??7.2.4.2

7.2.4.3??7.2.4.4??7.2.4.5??7.2.4.6??7.2.5.1??7.2.5.2??7.2.5.3??7.2.5.4??7.2.5.5??7.2.5.6

7.2.6.1??7.2.6.2??7.2.6.3??7.2.6.4??7.2.6.5??7.2.6.6??7.2.7.1??7.2.7.2??7.2.7.3??7.2.7.4

7.2.7.5??7.2.7.6??7.2.8.1??7.2.8.2??7.2.8.3??7.2.8.4??7.2.8.5??7.2.8.6??7.2.9.1??7.2.9.2

7.2.9.3??7.2.9.4??7.2.9.5??7.2.9.6??7.3.1.1??7.3.1.2??7.3.1.3??7.3.1.4??7.3.1.5??7.3.1.6

7.3.2.1??7.3.2.2??7.3.2.3??7.3.2.4??7.3.2.5??7.3.2.6??7.3.3.1??7.3.3.2??7.3.3.3??7.3.3.4

7.3.3.5??7.3.3.6??7.3.4.1??7.3.4.2??7.3.4.3??7.3.4.4??7.3.4.5??7.3.4.6??7.3.5.1??7.3.5.2

7.3.5.3??7.3.5.4??7.3.5.5??7.3.5.6??7.3.6.1??7.3.6.2??7.3.6.3??7.3.6.4??7.3.6.5??7.3.6.6

7.3.7.1??7.3.7.2??7.3.7.3??7.3.7.4??7.3.7.5??7.3.7.6??7.3.8.1??7.3.8.2??7.3.8.3??7.3.8.4

7.3.8.5??7.3.8.6??7.3.9.1??7.3.9.2??7.3.9.3??7.3.9.4??7.3.9.5??7.3.9.6??7.4.1.1??7.4.1.2

7.4.1.3??7.4.1.4??7.4.1.5??7.4.1.6??7.4.2.1??7.4.2.2??7.4.2.3??7.4.2.4??7.4.2.5??7.4.2.6

7.4.3.1??7.4.3.2??7.4.3.3??7.4.3.4??7.4.3.5??7.4.3.6??7.4.4.1??7.4.4.2??7.4.4.3??7.4.4.4

7.4.4.5??7.4.4.6??7.4.5.1??7.4.5.2??7.4.5.3??7.4.5.4??7.4.5.5??7.4.5.6??7.4.6.1??7.4.6.2

7.4.6.3??7.4.6.4??7.4.6.5??7.4.6.6??7.4.7.1??7.4.7.2??7.4.7.3??7.4.7.4??7.4.7.5??7.4.7.6

7.4.8.1??7.4.8.2??7.4.8.3??7.4.8.4??7.4.8.5??7.4.8.6??7.4.9.1??7.4.9.2??7.4.9.3??7.4.9.4

7.4.9.5??7.4.9.6??7.5.1.1??7.5.1.2??7.5.1.3??7.5.1.4??7.5.1.5??7.5.1.6??7.5.2.1??7.5.2.2

7.5.2.3??7.5.2.4??7.5.2.5??7.5.2.6??7.5.3.1??7.5.3.2??7.5.3.3??7.5.3.4??7.5.3.5??7.5.3.6

7.5.4.1??7.5.4.2??7.5.4.3??7.5.4.4??7.5.4.5??7.5.4.6??7.5.5.1??7.5.5.2??7.5.5.3??7.5.5.4

7.5.5.5??7.5.5.6??7.5.6.1??7.5.6.2??7.5.6.3??7.5.6.4??7.5.6.5??7.5.6.6??7.5.7.1??7.5.7.2

7.5.7.3??7.5.7.4??7.5.7.5??7.5.7.6??7.5.8.1??7.5.8.2??7.5.8.3??7.5.8.4??7.5.8.5??7.5.8.6

7.5.9.1??7.5.9.2??7.5.9.3??7.5.9.4??7.5.9.5??7.5.9.6??7.6.1.1??7.6.1.2??7.6.1.3??7.6.1.4

7.6.1.5??7.6.1.6??7.6.2.1??7.6.2.2??7.6.2.3??7.6.2.4??7.6.2.5??7.6.2.6??7.6.3.1??7.6.3.2

7.6.3.3??7.6.3.4??7.6.3.5??7.6.3.6??7.6.4.1??7.6.4.2??7.6.4.3??7.6.4.4??7.6.4.5??7.6.4.6

Table 1-is continuous

7.6.5.1??7.6.5.2??7.6.5.3??7.6.5.4??7.6.5.5??7.6.5.6??7.6.6.1??7.6.6.2??7.6.6.3??7.6.6.4

7.6.6.5??7.6.6.6??7.6.7.1??7.6.7.2??7.6.7.3??7.6.7.4??7.6.7.5??7.6.7.6??7.6.8.1??7.6.8.2

7.6.8.3??7.6.8.4??7.6.8.5??7.6.8.6??7.6.9.1??7.6.9.2??7.6.9.3??7.6.9.4??7.6.9.5??7.6.9.6

7.7.1.1??7.7.1.2??7.7.1.3??7.7.1.4??7.7.1.5??7.7.1.6??7.7.2.1??7.7.2.2??7.7.2.3??7.7.2.4

7.7.2.5??7.7.2.6??7.7.3.1??7.7.3.2??7.7.3.3??7.7.3.4??7.7.3.5??7.7.3.6??7.7.4.1??7.7.4.2

7.7.4.3??7.7.4.4??7.7.4.5??7.7.4.6??7.7.5.1??7.7.5.2??7.7.5.3??7.7.5.4??7.7.5.5??7.7.5.6

7.7.6.1??7.7.6.2??7.7.6.3??7.7.6.4??7.7.6.5??7.7.6.6??7.7.7.1??7.7.7.2??7.7.7.3??7.7.7.4

7.7.7.5??7.7.7.6??7.7.8.1??7.7.8.2??7.7.8.3??7.7.8.4??7.7.8.5??7.7.8.6??7.7.9.1??7.7.9.2

7.7.9.3??7.7.9.4??7.7.9.5??7.7.9.6??7.8.1.1??7.8.1.2??7.8.1.3??7.8.1.4??7.8.1.5??7.8.1.6

7.8.2.1??7.8.2.2??7.8.2.3??7.8.2.4??7.8.2.5??7.8.2.6??7.8.3.1??7.8.3.2??7.8.3.3??7.8.3.4

7.8.3.5??7.8.3.6??7.8.4.1??7.8.4.2??7.8.4.3??7.8.4.4??7.8.4.5??7.8.4.6??7.8.5.1??7.8.5.2

7.8.5.3??7.8.5.4??7.8.5.5??7.8.5.6??7.8.6.1??7.8.6.2??7.8.6.3??7.8.6.4??7.8.6.5??7.8.6.6

7.8.7.1??7.8.7.2??7.8.7.3??7.8.7.4??7.8.7.5??7.8.7.6??7.8.8.1??7.8.8.2??7.8.8.3??7.8.8.4

7.8.8.5??7.8.8.6??7.8.9.1??7.8.9.2??7.8.9.3??7.8.9.4??7.8.9.5??7.8.9.6??7.9.1.1??7.9.1.2

7.9.1.3??7.9.1.4??7.9.1.5??7.9.1.6??7.9.2.1??7.9.2.2??7.9.2.3??7.9.2.4??7.9.2.5??7.9.2.6

7.9.3.1??7.9.3.2??7.9.3.3??7.9.3.4??7.9.3.5??7.9.3.6??7.9.4.1??7.9.4.2??7.9.4.3??7.9.4.4

7.9.4.5??7.9.4.6??7.9.5.1??7.9.5.2??7.9.5.3??7.9.5.4??7.9.5.5??7.9.5.6??7.9.6.1??7.9.6.2

7.9.6.3??7.9.6.4??7.9.6.5??7.9.6.6??7.9.7.1??7.9.7.2??7.9.7.3??7.9.7.4??7.9.7.5??7.9.7.6

7.9.8.1??7.9.8.2??7.9.8.3??7.9.8.4??7.9.8.5??7.9.8.6??7.9.9.1??7.9.9.2??7.9.9.3??7.9.9.4

7.9.9.5??7.9.9.6

Therefore, in table 1 the having of name-S-as formula (i) compound of Y ' in formula I, to have as R ⁵The compound of thiazolyl.For example, use is called the compound regulation-NH of 2.6.1.1 to 1 group of variable B ₂Be A ,-Pr-c is B, furans-2,5-two base for X and-S-is Y ', this compound be 2-amino-5-cyclopropyl-4-[2-(5-phosphono) furyl as compound 3.27 for preparing among the embodiment 3] thiazole.Similarly, in table 1 the having of name-O-as formula (i) compound of Y ' for Ju You oxazolyl in formula I as R ⁵Compound.For example, use is to 1 group of variable B, and formula (i) compound that is called 2.4.1.2 in the table 1 has the structure of the 2-amino as compound 10.2-5-propyl group-4-[2-(phosphono) furyl] oxazole of preparation in embodiment 10.Similarly, in table 1 the having of name-Se-as formula (i) compound of Y ' for having the selenazoles base as R among the formula I ⁵Compound.Therefore, use 1 group to variable B, formula (i) compound that is called 2.3.1.3 in the table 1 has 2-amino-5-ethyl-4-[2-(5-phosphono) furyl as compound 3.72 of preparation in embodiment 3] structure of selenazoles.

Similarly, use is called 2-amino-5-methylthio group-4-[2-(5-phosphono) furyl as compound 3.26 of formula (i) compound of 2.8.1.1 for preparation in embodiment 3 to 2 groups of variable B in the table 1] thiazole.Use is called 2-amino-5-isobutyl--4-[2-(5-phosphono) furyl as compound 3.1 of formula (i) compound of 2.9.1.1 for preparation in embodiment 3 to 3 groups of variable B in the table 1] thiazole.

Use is called 2-amino-5-as compound 6.3 (5-thienyl)-4-[2-(5-phosphono) furyl of formula (i) compound of 2.6.1.1 for preparation in embodiment 6 to 4 groups of variable B in the table 1] thiazole.

In formula (i), (ii), (iii) and (iv) in the compound, some exemplary of the compound of the 1-4 group name that variable B is used in table 1 are listed in the table 2.

Table 2

Compound number as A.B.X.Y	Synthetic embodiment number	Structural formula	??A	Compound group wherein B is selected from:	??B	??X ^*	??Y
Compound number as A.B.X.Y	Synthetic embodiment number	Structural formula	??A	Compound group wherein B is selected from:	??B	??X ^*	??Y	??2.1.1.1	??3.13	??(i)	??NH2	??1	??H	Furans-2,5-two bases	??S
??2.2.1.1	??3.16	??(i)	??NH2	??1	??Me	Furans-2,5-two bases	??S	??2.1.1.1	??3.13	??(i)	??NH2	??1	??H	Furans-2,5-two bases	??S
??2.2.1.1	??3.16	??(i)	??NH2	??1	??Me	Furans-2,5-two bases	??S	??2.3.1.1	??3.21	??(i)	??NH2	??1	??Et	Furans-2,5-two bases	??S
??2.4.1.1	??3.24	??(i)	??NH2	??1	??Pr-n	Furans-2,5-two bases	??S	??2.3.1.1	??3.21	??(i)	??NH2	??1	??Et	Furans-2,5-two bases	??S
??2.4.1.1	??3.24	??(i)	??NH2	??1	??Pr-n	Furans-2,5-two bases	??S	??2.5.1.1	??3.2	??(i)	??NH2	??1	??Pr-i	Furans-2,5-two bases	??S
??2.6.1.1	??3.27	??(i)	??NH2	??1	??Pr-c	Furans-2,5-two bases	??S	??2.5.1.1	??3.2	??(i)	??NH2	??1	??Pr-i	Furans-2,5-two bases	??S
??2.6.1.1	??3.27	??(i)	??NH2	??1	??Pr-c	Furans-2,5-two bases	??S	??2.9.1.1	??3.1	??(i)	??NH2	??3	??Bu-i	Furans-2,5-two bases	??S
??2.5.1.1	??6.2	??(i)	??NH2	??4	The 2-furyl	Furans-2,5-two bases	??S	??2.9.1.1	??3.1	??(i)	??NH2	??3	??Bu-i	Furans-2,5-two bases	??S
??2.5.1.1	??6.2	??(i)	??NH2	??4	The 2-furyl	Furans-2,5-two bases	??S	??2.3.1.1	??3.30	??(i)	??NH2	??3	??Bu-c	Furans-2,5-two bases	??S
??2.6.1.1	??6.3	??(i)	??NH2	??4	The 2-thienyl	Furans-2,5-two bases	??S	??2.3.1.1	??3.30	??(i)	??NH2	??3	??Bu-c	Furans-2,5-two bases	??S
??2.6.1.1	??6.3	??(i)	??NH2	??4	The 2-thienyl	Furans-2,5-two bases	??S	??2.8.1.1	??4.2	??(i)	??NH2	??1	??Cl	Furans-2,5-two bases	??S
??2.7.1.1	??4.1	??(i)	??NH2	??1	??Br	Furans-2,5-two bases	??S	??2.8.1.1	??4.2	??(i)	??NH2	??1	??Cl	Furans-2,5-two bases	??S
??2.7.1.1	??4.1	??(i)	??NH2	??1	??Br	Furans-2,5-two bases	??S	??2.9.1.1	??4.3	??(i)	??NH2	??1	??I	Furans-2,5-two bases	??S
??2.8.1.1	??3.26	??(i)	??NH2	??2	??SMe	Furans-2,5-two bases	??S	??2.9.1.1	??4.3	??(i)	??NH2	??1	??I	Furans-2,5-two bases	??S
??2.8.1.1	??3.26	??(i)	??NH2	??2	??SMe	Furans-2,5-two bases	??S	??2.1.1.1	??3.59	??(i)	??NH2	??3	??SEt	Furans-2,5-two bases	??S
??2.6.1.1	??3.58	??(i)	??NH2	??3	??SPr-n	Furans-2,5-two bases	??S	??2.1.1.1	??3.59	??(i)	??NH2	??3	??SEt	Furans-2,5-two bases	??S
??2.6.1.1	??3.58	??(i)	??NH2	??3	??SPr-n	Furans-2,5-two bases	??S	??2.4.1.1	??3.55	??(i)	??NH2	??4	??SPr-i	Furans-2,5-two bases	??S
??2.9.1.1	??3.36	??(i)	??NH2	??4	??Bn	Furans-2,5-two bases	??S	??2.4.1.1	??3.55	??(i)	??NH2	??4	??SPr-i	Furans-2,5-two bases	??S
??2.9.1.1	??3.36	??(i)	??NH2	??4	??Bn	Furans-2,5-two bases	??S	??2.6.1.1	??3.33	??(i)	??NH2	??2	??C(O)OMe	Furans-2,5-two bases	??S
??2.4.1.1	??3.25	??(i)	??NH2	??3	??C(O)OEt	Furans-2,5-two bases	??S	??2.6.1.1	??3.33	??(i)	??NH2	??2	??C(O)OMe	Furans-2,5-two bases	??S
??2.4.1.1	??3.25	??(i)	??NH2	??3	??C(O)OEt	Furans-2,5-two bases	??S	??1.1.1.1	??3.3	??(i)	??H	??1	??H	Furans-2,5-two bases	??S
??1.9.1.1	??3.7	??(i)	??H	??3	??Bu-i	Furans-2,5-two bases	??S	??1.1.1.1	??3.3	??(i)	??H	??1	??H	Furans-2,5-two bases	??S
??1.9.1.1	??3.7	??(i)	??H	??3	??Bu-i	Furans-2,5-two bases	??S	??6.8.1.1	??3.50	??(i)	??Me	??2	??SMe	Furans-2,5-two bases	??S
??4.9.1.1	??5.2	??(i)	??Cl	??3	??Bu-i	Furans-2,5-two bases	??S	??6.8.1.1	??3.50	??(i)	??Me	??2	??SMe	Furans-2,5-two bases	??S
??4.9.1.1	??5.2	??(i)	??Cl	??3	??Bu-i	Furans-2,5-two bases	??S	??3.7.1.1	??4.4	??(i)	??Br	??1	??Br	Furans-2,5-two bases	??S
??3.9.1.1	??5.1	??(i)	??Br	??3	??Bu-i	Furans-2,5-two bases	??S	??3.7.1.1	??4.4	??(i)	??Br	??1	??Br	Furans-2,5-two bases	??S
??3.9.1.1	??5.1	??(i)	??Br	??3	??Bu-i	Furans-2,5-two bases	??S	??6.6.1.1	??3.42	??(i)	??Me	??1	??Pr-c	Furans-2,5-two bases	??S
??6.1.1.1	??3.4	??(i)	??Me	??1	??H	Furans-2,5-two bases	??S	??6.6.1.1	??3.42	??(i)	??Me	??1	??Pr-c	Furans-2,5-two bases	??S
??6.1.1.1	??3.4	??(i)	??Me	??1	??H	Furans-2,5-two bases	??S	??6.2.1.1	??3.17	??(i)	??Me	??1	??Me	Furans-2,5-two bases	??S
??6.7.1.1	??4.5	??(i)	??Me	??1	??Br	Furans-2,5-two bases	??S	??6.2.1.1	??3.17	??(i)	??Me	??1	??Me	Furans-2,5-two bases	??S
??6.7.1.1	??4.5	??(i)	??Me	??1	??Br	Furans-2,5-two bases	??S	??6.9.1.1	??3.2	??(i)	??Me	??3	??Bu-i	Furans-2,5-two bases	??S
??6.3.1.1	??3.41	??(i)	??Me	??1	??Et	Furans-2,5-two bases	??S	??6.9.1.1	??3.2	??(i)	??Me	??3	??Bu-i	Furans-2,5-two bases	??S
??6.3.1.1	??3.41	??(i)	??Me	??1	??Et	Furans-2,5-two bases	??S	??6.4.1.1	??3.43	??(i)	??Me	??3	??C(O)OEt	Furans-2,5-two bases	??S
??1.4.1.1	??3.65	??(i)	??H	??3	??C(O)OEt	Furans-2,5-two bases	??S	??6.4.1.1	??3.43	??(i)	??Me	??3	??C(O)OEt	Furans-2,5-two bases	??S
??1.4.1.1	??3.65	??(i)	??H	??3	??C(O)OEt	Furans-2,5-two bases	??S	??6.1.9.1.	??8.1	??(i)	??Me	??1	??H	??CH2OCH2	??S
??6.7.9.1	??8.2	??(i)	??Me	??1	??Br	??CH2OCH2	??S	??6.1.9.1.	??8.1	??(i)	??Me	??1	??H	??CH2OCH2	??S
??6.7.9.1	??8.2	??(i)	??Me	??1	??Br	??CH2OCH2	??S	??2.9.4.1	??18.16	??(i)	??NH2	??4	??Bn	??C(O)OCH2	??S
??2.1.9.1	??8.3	??(i)	??NH2	??1	??H	??CH2OCH2	??S	??2.9.4.1	??18.16	??(i)	??NH2	??4	??Bn	??C(O)OCH2	??S
??2.1.9.1	??8.3	??(i)	??NH2	??1	??H	??CH2OCH2	??S	??2.2.4.1	??18.27	??(i)	??NH2	??1	??Me	??C(O)OCH2	??S
??2.1.4.1	??18.37	??(i)	??NH2	??1	??H	??C(O)OCH2	??S	??2.2.4.1	??18.27	??(i)	??NH2	??1	??Me	??C(O)OCH2	??S
??2.1.4.1	??18.37	??(i)	??NH2	??1	??H	??C(O)OCH2	??S	??2.3.4.1	??18.3	??(i)	??NH2	??1	??Et	??C(O)OCH2	??S

??2.5.4.1	??18.20	??(i)	??NH2	??1	??Pr-i	??C(O)OCH2	??S
??2.5.4.1	??18.20	??(i)	??NH2	??1	??Pr-i	??C(O)OCH2	??S	??2.5.5.1	??18.19	??(i)	??NH2	??1	??Pr-i	??C(O)NHCH2	??S
??2.3.5.1	??18.18	??(i)	??NH2	??1	??Et	??C(O)NHCH2	??S	??2.5.5.1	??18.19	??(i)	??NH2	??1	??Pr-i	??C(O)NHCH2	??S
??2.3.5.1	??18.18	??(i)	??NH2	??1	??Et	??C(O)NHCH2	??S	??2.2.5.1	??18.24	??(i)	??NH2	??1	??Me	??C(O)NHCH2	??S
??2.1.5.1	??18.6	??(i)	??NH2	??1	??H	??C(O)NHCH2	??S	??2.2.5.1	??18.24	??(i)	??NH2	??1	??Me	??C(O)NHCH2	??S
??2.1.5.1	??18.6	??(i)	??NH2	??1	??H	??C(O)NHCH2	??S	??2.1.4.1	??18.1	??(i)	??NH2	??1	??H	??C(O)OCH2	??S
??2.7.5.1	??18.11	??(i)	??NH2	??1	??Br	??C(O)NHCH2	??S	??2.1.4.1	??18.1	??(i)	??NH2	??1	??H	??C(O)OCH2	??S
??2.7.5.1	??18.11	??(i)	??NH2	??1	??Br	??C(O)NHCH2	??S	??2.7.4.1	??18.2	??(i)	??NH2	??1	??Br	??C(O)OCH2	??S
??2.6.4.1	??18.15	??(i)	??NH2	??4	The 2-thienyl	??C(O)OCH2	??S	??2.7.4.1	??18.2	??(i)	??NH2	??1	??Br	??C(O)OCH2	??S
??2.6.4.1	??18.15	??(i)	??NH2	??4	The 2-thienyl	??C(O)OCH2	??S	??2.6.5.1	??18.12	??(i)	??NH2	??4	The 2-thienyl	??C(O)NHCH2	??S
??2.1.2.1	??3.67	??(i)	??NH2	??1	??H	Pyridine-2,6-two bases	??S	??2.6.5.1	??18.12	??(i)	??NH2	??4	The 2-thienyl	??C(O)NHCH2	??S
??2.1.2.1	??3.67	??(i)	??NH2	??1	??H	Pyridine-2,6-two bases	??S	??6.2.8.1	??18.7	??(iii)	??Me	??1	??Me	??NHC(O)CH2	??S
??2.1.1.2	??10.5	??(i)	??NH2	??1	??H	Furans-2,5-two bases	??O	??6.2.8.1	??18.7	??(iii)	??Me	??1	??Me	??NHC(O)CH2	??S
??2.1.1.2	??10.5	??(i)	??NH2	??1	??H	Furans-2,5-two bases	??O	??2.2.1.2	??10.4	??(i)	??NH2	??1	??Me	Furans-2,5-two bases	??O
??2.3.1.2	??10.3	??(i)	??NH2	??1	??Et	Furans-2,5-two bases	??O	??2.2.1.2	??10.4	??(i)	??NH2	??1	??Me	Furans-2,5-two bases	??O
??2.3.1.2	??10.3	??(i)	??NH2	??1	??Et	Furans-2,5-two bases	??O	??2.4.1.2	??10.2	??(i)	??NH2	??1	??Pr-n	Furans-2,5-two bases	??O
??2.8.1.2	??10.12	??(i)	??NH2	??3	??Bu-n	Furans-2,5-two bases	??O	??2.4.1.2	??10.2	??(i)	??NH2	??1	??Pr-n	Furans-2,5-two bases	??O
??2.8.1.2	??10.12	??(i)	??NH2	??3	??Bu-n	Furans-2,5-two bases	??O	??2.9.1.2	??10.1	??(i)	??NH2	??3	??Bu-i	Furans-2,5-two bases	??O
??2.6.1.2	??10.37	??(i)	??NH2	??2	??C(O)OMe	Furans-2,5-two bases	??O	??2.9.1.2	??10.1	??(i)	??NH2	??3	??Bu-i	Furans-2,5-two bases	??O
??2.6.1.2	??10.37	??(i)	??NH2	??2	??C(O)OMe	Furans-2,5-two bases	??O	??2.1.4.2	??18.22	??(i)	??NH2	??1	??H	??C(O)OCH2	??O
??2.5.4.2	??18.30	??(i)	??NH2	??1	??Pr-i	??C(O)OCH2	??O	??2.1.4.2	??18.22	??(i)	??NH2	??1	??H	??C(O)OCH2	??O
??2.5.4.2	??18.30	??(i)	??NH2	??1	??Pr-i	??C(O)OCH2	??O	??2.2.4.2	??18.33	??(i)	??NH2	??1	??Me	??C(O)OCH2	??O
??2.8.4.2	??18.38	??(i)	??NH2	??3	??Bu-n	??C(O)OCH2	??O	??2.2.4.2	??18.33	??(i)	??NH2	??1	??Me	??C(O)OCH2	??O
??2.8.4.2	??18.38	??(i)	??NH2	??3	??Bu-n	??C(O)OCH2	??O	??2.4.4.2	??18.40	??(i)	??NH2	??1	??Pr-n	??C(O)OCH2	??O
??2.9.1.2	??10.8	??(i)	??NH2	??4	??Bn	Furans-2,5-two bases	??O	??2.4.4.2	??18.40	??(i)	??NH2	??1	??Pr-n	??C(O)OCH2	??O
??2.9.1.2	??10.8	??(i)	??NH2	??4	??Bn	Furans-2,5-two bases	??O	??2.8.1.2	??10.34	??(i)	??NH2	??2	??SMe	Furans-2,5-two bases	??O
??2.1.1.2	??10.42	??(i)	??NH2	??3	??SEt	Furans-2,5-two bases	??O	??2.8.1.2	??10.34	??(i)	??NH2	??2	??SMe	Furans-2,5-two bases	??O
??2.1.1.2	??10.42	??(i)	??NH2	??3	??SEt	Furans-2,5-two bases	??O	??2.6.1.2	??10.43	??(i)	??NH2	??3	??SPr-n	Furans-2,5-two bases	??O
??2.4.1.2	??10.40	??(i)	??NH2	??4	??SPr-i	Furans-2,5-two bases	??O	??2.6.1.2	??10.43	??(i)	??NH2	??3	??SPr-n	Furans-2,5-two bases	??O
??2.4.1.2	??10.40	??(i)	??NH2	??4	??SPr-i	Furans-2,5-two bases	??O	??2.4.1.2	??10.27	??(i)	??NH2	??3	??C(O)OEt	Furans-2,5-two bases	??O
??1.9.1.2	??10.11	??(i)	??H	??3	??Bu-i	Furans-2,5-two bases	??O	??2.4.1.2	??10.27	??(i)	??NH2	??3	??C(O)OEt	Furans-2,5-two bases	??O
??1.9.1.2	??10.11	??(i)	??H	??3	??Bu-i	Furans-2,5-two bases	??O	??6.9.1.2	??10.19	??(i)	??Me	??2	??Bu-i	Furans-2,5-two bases	??O
??7.1.1.4	??10.22	??(i)	??CF3	??1	??H	Furans-2,5-two bases	??NH	??6.9.1.2	??10.19	??(i)	??Me	??2	??Bu-i	Furans-2,5-two bases	??O
??7.1.1.4	??10.22	??(i)	??CF3	??1	??H	Furans-2,5-two bases	??NH	??6.9.1.4	??10.21	??(i)	??Me	??3	??Bu-i	Furans-2,5-two bases	??NH
??6.9.1.5	??11.2	??(i)	??Me	??3	??Bu-i	Furans-2,5-two bases	??NMe	??6.9.1.4	??10.21	??(i)	??Me	??3	??Bu-i	Furans-2,5-two bases	??NH
??6.9.1.5	??11.2	??(i)	??Me	??3	??Bu-i	Furans-2,5-two bases	??NMe	??6.4.1.4	??10.2	??(i)	??Me	??1	??Pr-n	Furans-2,5-two bases	??NH
??6.9.1.5	??11.2	??(i)	??Me	??3	??Bu-i	Furans-2,5-two bases	??NMe	??6.4.1.4	??10.2	??(i)	??Me	??1	??Pr-n	Furans-2,5-two bases	??NH
??6.9.1.5	??11.2	??(i)	??Me	??3	??Bu-i	Furans-2,5-two bases	??NMe	??6.2.1.4	??10.34	??(iii)	??Me	??1	??Me	Furans-2,5-two bases	??NH
??2.4.1.2	??26.4	??(ii)	??NH2	??3	??C(O)OEt	Furans-2,5-two bases	??O	??6.2.1.4	??10.34	??(iii)	??Me	??1	??Me	Furans-2,5-two bases	??NH
??2.4.1.2	??26.4	??(ii)	??NH2	??3	??C(O)OEt	Furans-2,5-two bases	??O	??1.9.1.5	??25.2	??(ii)	??H	??3	??Bu-i	Furans-2,5-two bases	??NMe
??1.9.1.4	??25.1	??(ii)	??H	??3	??Bu-i	Furans-2,5-two bases	??H	??1.9.1.5	??25.2	??(ii)	??H	??3	??Bu-i	Furans-2,5-two bases	??NMe
??1.9.1.4	??25.1	??(ii)	??H	??3	??Bu-i	Furans-2,5-two bases	??H	??1.7.8.1		??(iii)	??H	??1	??Br	??NHC(O)CH2	??S
??1.1.8.1		??(iii)	??H	??1	??H	??NHC(O)CH2	??S	??1.7.8.1		??(iii)	??H	??1	??Br	??NHC(O)CH2	??S
??1.1.8.1		??(iii)	??H	??1	??H	??NHC(O)CH2	??S

^*The direction of X group is defined as the direction of R5 to phosphorus atom.

Preferred following formula I compound and pharmacy acceptable salt and prodrug, wherein R ⁵Be pyridyl or pyrimidyl or pyrazinyl or pyridazinyl.These preferred compounds be shown in following structure (v)-(ix):

According to the following regulations: A.B.X.D.E, preferred formula (v)-(ix) (compound is listed in the table 3 v)-(ix) by giving top formula by the designation number of A, B, X, D and E.For formula (vi) compound, D then indicate with numeral 0 for not existing, for formula (vii) compound, E then indicates with numeral 0 for not existing, (viii) compound, B is not for existing, then with digital 0 sign for formula.For example, (vi) compound is designated as A.B.X.O.E to all formulas of naming in table 3, (vii) compound is designated as A.B.X.D.O to all formulas of naming in table 3, (viii) compound is designated as A.O.X.D.E and formula (ix) compound that all are named is designated as 0.B.X.D.E to all formulas of naming in table 3 in table 3.For each part, structure is designated as down in the tabulation numeral that A, B, X, D and E indicated.

Variables A is selected from 8 kinds of different substituting groups.

The A group is endowed down column of figure:

Table A.

	??1	??2	??3	??4	??5	??6	??7	??8
	??1	??2	??3	??4	??5	??6	??7	??8	??A＝	??H	??NH ₂	??Br	??Cl	??F	??Me	??CF ₃	??C(O)NH ₂

Variable B is divided into 4 groups, lists 8 kinds of different substituting groups for every group.

1 group of substituting group to variable B is given down column of figure:

Table B.

	??1	??2	??3	??4	??5	??6	??7	??8
	??1	??2	??3	??4	??5	??6	??7	??8	??B＝	??H	??Me	??Et	??Pr-n	??Pr-i	??Pr-c	??Br	??Cl

2 groups of substituting groups to variable B are given down column of figure:

	??1	??2	??3	??4	??5	??6	??7	??8
	??1	??2	??3	??4	??5	??6	??7	??8	?B＝	??F	??CN	??CH ₂Pr-c	??Bu-i	??C(O)SMe	??C(O)OMe	??OEt	??SMe

3 groups of substituting groups to variable B are given down column of figure:

	??1	??2	??3	??4	??5	??6	??7	??8
	??1	??2	??3	??4	??5	??6	??7	??8	?B＝	??SEt	The 4-pyridyl	??Bu-c	??C(O)OEt	??NMe ₂	??SPr-n	??CF ₃	??OPr-n

4 groups of substituting groups to variable B are given down column of figure:

	?1	??2	??3	??4	??5	??6	??7	??8
	?1	??2	??3	??4	??5	??6	??7	??8	?B＝	?SPr-c	??OPr-i	??OPr-c	??SPr-i	The 2-furyl	The 2-thienyl	??OMe	??Bn

Variable X is divided into two groups, lists 4 different substituting groups for every group.

1 group of substituting group to variable X is given down column of figure:

Table X.

	??1	??2	?3	??4
	??1	??2	?3	??4	?X＝	Furans-2,5-two bases	Pyridine-2,6-two bases	?C(O)NHCH ₂	??C(O)OCH ₂

The direction of X group be defined as suc as formula (v), (vi), (vii), (and viii) and (ix) by the direction of heterocycle to phosphorus atom.

2 groups of substituting groups to variable X are given down column of figure:

	?1	?2	??3	?4
	?1	?2	??3	?4	??X＝	?NHC(O)CH ₂	?C(O)N(Me)CH ₂	Acetylene-1,2-two bases	?CH2OCH ₂

Variables D is divided into two groups, lists 8 different substituting groups for every group.

The D group is given down column of figure:

Table D.

	??1	??2	??3	??4	??5	??6	??7	??8
	??1	??2	??3	??4	??5	??6	??7	??8	?D＝	??H	??Me	??Et	??C(O)OEt	??SMe	??Pr-c	??Br	??Cl

2 groups of substituting groups to variables D are given down column of figure:

	??1	??2	??3	??4	??5	??6	??7	??8
	??1	??2	??3	??4	??5	??6	??7	??8	?D＝	??F	??I	??CN	??CH ₂Pr-c	??CH ₂OMe	??C(O)NH ₂	??OMe	??CF ₃

Variable E is divided into 3 groups, lists 4 kinds of different substituting groups for every group.

1 group of substituting group to variable E is given down column of figure:

Table E.

	??1	??2	??3	??4
	??1	??2	??3	??4	??E＝	??H	??Me	??Et	??Pr-n

2 groups of substituting groups to variable E are given down column of figure:

	??1	??2	??3	??4
	??1	??2	??3	??4	?E＝	??Br	??Cl	??F	??CN

3 groups of substituting groups to variable E are given down column of figure:

	?1	??2	??3	??4
	?1	??2	??3	??4	?E＝	?C(O)OMe	??Pr-c	??SMe	??OMe

Table 3

1.1.1.1.1??1.1.1.1.2??1.1.1.1.3??1.1.1.1.4??1.1.1.2.1??1.1.1.2.2??1.1.1.2.3??1.1.1.2.4

1.1.1.3.1??1.1.1.3.2??1.1.1.3.3??1.1.1.3.4??1.1.1.4.1??1.1.1.4.2??1.1.1.4.3??1.1.1.4.4

1.1.1.5.1??1.1.1.5.2??1.1.1.5.3??1.1.1.5.4??1.1.1.6.1??1.1.1.6.2??1.1.1.6.3??1.1.1.6.4

1.1.1.7.1??1.1.1.7.2??1.1.1.7.3??1.1.1.7.4??1.1.1.8.1??1.1.1.8.2??1.1.1.8.3??1.1.1.8.4

1.1.2.1.1??1.1.2.1.2??1.1.2.1.3??1.1.2.1.4??1.1.2.2.1??1.1.2.2.2??1.1.2.2.3??1.1.2.2.4

1.1.2.3.1??1.1.2.3.2??1.1.2.3.3??1.1.2.3.4??1.1.2.4.1??1.1.2.4.2??1.1.2.4.3??1.1.2.4.4

1.1.2.5.1??1.1.2.5.2??1.1.2.5.3??1.1.2.5.4??1.1.2.6.1??1.1.2.6.2??1.1.2.6.3??1.1.2.6.4

1.1.2.7.1??1.1.2.7.2??1.1.2.7.3??1.1.2.7.4??1.1.2.8.1??1.1.2.8.2??1.1.2.8.3??1.1.2.8.4

1.1.3.1.1??1.1.3.1.2??1.1.3.1.3??1.1.3.1.4??1.1.3.2.1??1.1.3.2.2??1.1.3.2.3??1.1.3.2.4

1.1.3.3.1??1.1.3.3.2??1.1.3.3.3??1.1.3.3.4??1.1.3.4.1??1.1.3.4.2??1.1.3.4.3??1.1.3.4.4

1.1.3.5.1??1.1.3.5.2??1.1.3.5.3??1.1.3.5.4??1.1.3.6.1??1.1.3.6.2??1.1.3.6.3??1.1.3.6.4

1.1.3.7.1??1.1.3.7.2??1.1.3.7.3??1.1.3.7.4??1.1.3.8.1??1.1.3.8.2??1.1.3.8.3??1.1.3.8.4

1.1.4.1.1??1.1.4.1.2??1.1.4.1.3??1.1.4.1.4??1.1.4.2.1??1.1.4.2.2??1.1.4.2.3??1.1.4.2.4

1.1.4.3.1??1.1.4.3.2??1.1.4.3.3??1.1.4.3.4??1.1.4.4.1??1.1.4.4.2??1.1.4.4.3??1.1.4.4.4

1.1.4.5.1??1.1.4.5.2??1.1.4.5.3??1.1.4.5.4??1.1.4.6.1??1.1.4.6.2??1.1.4.6.3??1.1.4.6.4

1.1.4.7.1??1.1.4.7.2??1.1.4.7.3??1.1.4.7.4??1.1.4.8.1??1.1.4.8.2??1.1.4.8.3??1.1.4.8.4

1.2.1.1.1??1.2.1.1.2??1.2.1.1.3??1.2.1.1.4??1.2.1.2.1??1.2.1.2.2??1.2.1.2.3??1.2.1.2.4

1.2.1.3.1??1.2.1.3.2??1.2.1.3.3??1.2.1.3.4??1.2.1.4.1??1.2.1.4.2??1.2.1.4.3??1.2.1.4.4

1.2.1.5.1??1.2.1.5.2??1.2.1.5.3??1.2.1.5.4??1.2.1.6.1??1.2.1.6.2??1.2.1.6.3??1.2.1.6.4

1.2.1.7.1??1.2.1.7.2??1.2.1.7.3??1.2.1.7.4??1.2.1.8.1??1.2.1.8.2??1.2.1.8.3??1.2.1.8.4

1.2.2.1.1??1.2.2.1.2??1.2.2.1.3??1.2.2.1.4??1.2.2.2.1??1.2.2.2.2??1.2.2.2.3??1.2.2.2.4

1.2.2.3.1??1.2.2.3.2??1.2.2.3.3??1.2.2.3.4??1.2.2.4.1??1.2.2.4.2??1.2.2.4.3??1.2.2.4.4

1.2.2.5.1??1.2.2.5.2??1.2.2.5.3??1.2.2.5.4??1.2.2.6.1??1.2.2.6.2??1.2.2.6.3??1.2.2.6.4

1.2.2.7.1??1.2.2.7.2??1.2.2.7.3??1.2.2.7.4??1.2.2.8.1??1.2.2.8.2??1.2.2.8.3??1.2.2.8.4

1.2.3.1.1??1.2.3.1.2??1.2.3.1.3??1.2.3.1.4??1.2.3.2.1??1.2.3.2.2??1.2.3.2.3??1.2.3.2.4

1.2.3.3.1??1.2.3.3.2??1.2.3.3.3??1.2.3.3.4??1.2.3.4.1??1.2.3.4.2??1.2.3.4.3??1.2.3.4.4

1.2.3.5.1??1.2.3.5.2??1.2.3.5.3??1.2.3.5.4??1.2.3.6.1??1.2.3.6.2??1.2.3.6.3??1.2.3.6.4

1.2.3.7.1??1.2.3.7.2??1.2.3.7.3??1.2.3.7.4??1.2.3.8.1??1.2.3.8.2??1.2.3.8.3??1.2.3.8.4

1.2.4.1.1??1.2.4.1.2??1.2.4.1.3??1.2.4.1.4??1.2.4.2.1??1.2.4.2.2??1.2.4.2.3??1.2.4.2.4

1.2.4.3.1??1.2.4.3.2??1.2.4.3.3??1.2.4.3.4??1.2.4.4.1??1.2.4.4.2??1.2.4.4.3??1.2.4.4.4

1.2.4.5.1??1.2.4.5.2??1.2.4.5.3??1.2.4.5.4??1.2.4.6.1??1.2.4.6.2??1.2.4.6.3??1.2.4.6.4

1.2.4.7.1??1.2.4.7.2??1.2.4.7.3??1.2.4.7.4??1.2.4.8.1??1.2.4.8.2??1.2.4.8.3??1.2.4.8.4

1.3.1.1.1??1.3.1.1.2??1.3.1.1.3??1.3.1.1.4??1.3.1.2.1??1.3.1.2.2??1.3.1.2.3??1.3.1.2.4

1.3.1.3.1??1.3.1.3.2??1.3.1.3.3??1.3.1.3.4??1.3.1.4.1??1.3.1.4.2??1.3.1.4.3??1.3.1.4.4

1.3.1.5.1??1.3.1.5.2??1.3.1.5.3??1.3.1.5.4??1.3.1.6.1??1.3.1.6.2??1.3.1.6.3??1.3.1.6.4

1.3.1.7.1??1.3.1.7.2??1.3.1.7.3??1.3.1.7.4??1.3.1.8.1??1.3.1.8.2??1.3.1.8.3??1.3.1.8.4

1.3.2.1.1??1.3.2.1.2??1.3.2.1.3??1.3.2.1.4??1.3.2.2.1??1.3.2.2.2??1.3.2.2.3??1.3.2.2.4

1.3.2.3.1??1.3.2.3.2??1.3.2.3.3??1.3.2.3.4??1.3.2.4.1??1.3.2.4.2??1.3.2.4.3??1.3.2.4.4

1.3.2.5.1??1.3.2.5.2??1.3.2.5.3??1.3.2.5.4??1.3.2.6.1??1.3.2.6.2??1.3.2.6.3??1.3.2.6.4

1.3.2.7.1??1.3.2.7.2??1.3.2.7.3??1.3.2.7.4??1.3.2.8.1??1.3.2.8.2??1.3.2.8.3??1.3.2.8.4

1.3.3.1.1??1.3.3.1.2??1.3.3.1.3??1.3.3.1.4??1.3.3.2.1??1.3.3.2.2??1.3.3.2.3??1.3.3.2.4

1.3.3.3.1??1.3.3.3.2??1.3.3.3.3??1.3.3.3.4??1.3.3.4.1??1.3.3.4.2??1.3.3.4.3??1.3.3.4.4

1.3.3.5.1??1.3.3.5.2??1.3.3.5.3??1.3.3.5.4??1.3.3.6.1??1.3.3.6.2??1.3.3.6.3??1.3.3.6.4

1.3.3.7.1??1.3.3.7.2??1.3.3.7.3??1.3.3.7.4??1.3.3.8.1??1.3.3.8.2??1.3.3.8.3??1.3.3.8.4

1.3.4.1.1??1.3.4.1.2??1.3.4.1.3??1.3.4.1.4??l.3.4.2.1??1.3.4.2.2??1.3.4.2.3??1.3.4.2.4

1.3.4.3.1??1.3.4.3.2??1.3.4.3.3??1.3.4.3.4??1.3.4.4.1??1.3.4.4.2??1.3.4.4.3??1.3.4.4.4

Table 3-is continuous

1.3.4.5.1??1.3.4.5.2??1.3.4.5.3??1.3.4.5.4??1.3.4.6.1??1.3.4.6.2??1.3.4.6.3??1.3.4.6.4

1.3.4.7.1??1.3.4.7.2??1.3.4.7.3??1.3.4.7.4??1.3.4.8.1??1.3.4.8.2??1.3.4.8.3??1.3.4.8.4

1.4.1.1.1??1.4.1.1.2??1.4.1.1.3??1.4.1.1.4??1.4.1.2.1??1.4.1.2.2??1.4.1.2.3??1.4.1.2.4

1.4.1.3.1??1.4.1.3.2??1.4.1.3.3??1.4.1.3.4??1.4.1.4.1??1.4.1.4.2??1.4.1.4.3??1.4.1.4.4

1.4.1.5.1??1.4.1.5.2??1.4.1.5.3??1.4.1.5.4??1.4.1.6.1??1.4.1.6.2??1.4.1.6.3??1.4.1.6.4

1.4.1.7.1??1.4.1.7.2??1.4.1.7.3??1.4.1.7.4??1.4.1.8.1??1.4.1.8.2??1.4.1.8.3??1.4.1.8.4

1.4.2.1.1??1.4.2.1.2??1.4.2.1.3??1.4.2.1.4??1.4.2.2.1??1.4.2.2.2??1.4.2.2.3??1.4.2.2.4

1.4.2.3.1??1.4.2.3.2??1.4.2.3.3??1.4.2.3.4??1.4.2.4.1??1.4.2.4.2??1.4.2.4.3??1.4.2.4.4

1.4.2.5.1??1.4.2.5.2??1.4.2.5.3??1.4.2.5.4??1.4.2.6.1??1.4.2.6.2??1.4.2.6.3??1.4.2.6.4

1.4.2.7.1??1.4.2.7.2??1.4.2.7.3??1.4.2.7.4??1.4.2.8.1??1.4.2.8.2??1.4.2.8.3??1.4.2.8.4

1.4.3.1.1??1.4.3.1.2??1.4.3.1.3??1.4.3.1.4??1.4.3.2.1??1.4.3.2.2??1.4.3.2.3??1.4.3.2.4

1.4.3.3.1??1.4.3.3.2??1.4.3.3.3??1.4.3.3.4??1.4.3.4.1??1.4.3.4.2??1.4.3.4.3??1.4.3.4.4

1.4.3.5.1??1.4.3.5.2??1.4.3.5.3??1.4.3.5.4??1.4.3.6.1??1.4.3.6.2??1.4.3.6.3??1.4.3.6.4

1.4.3.7.1??1.4.3.7.2??1.4.3.7.3??1.4.3.7.4??1.4.3.8.1??1.4.3.8.2??1.4.3.8.3??1.4.3.8.4

1.4.4.1.1??1.4.4.1.2??1.4.4.1.3??1.4.4.1.4??1.4.4.2.1??1.4.4.2.2??1.4.4.2.3??1.4.4.2.4

1.4.4.3.1??1.4.4.3.2??1.4.4.3.3??1.4.4.3.4??1.4.4.4.1??1.4.4.4.2??1.4.4.4.3??1.4.4.4.4

1.4.4.5.1??1.4.4.5.2??1.4.4.5.3??1.4.4.5.4??1.4.4.6.1??1.4.4.6.2??1.4.4.6.3??1.4.4.6.4

1.4.4.7.1??1.4.4.7.2??1.4.4.7.3??1.4.4.7.4??1.4.4.8.1??1.4.4.8.2??1.4.4.8.3??1.4.4.8.4

1.5.1.1.1??1.5.1.1.2??1.5.1.1.3??1.5.1.1.4??1.5.1.2.1??1.5.1.2.2??1.5.1.2.3??1.5.1.2.4

1.5.1.3.1??1.5.1.3.2??1.5.1.3.3??1.5.1.3.4??1.5.1.4.1??1.5.1.4.2??1.5.1.4.3??1.5.1.4.4

1.5.1.5.1??1.5.1.5.2??1.5.1.5.3??1.5.1.5.4??1.5.1.6.1??1.5.1.6.2??1.5.1.6.3??1.5.1.6.4

1.5.1.7.1??1.5.1.7.2??1.5.1.7.3??1.5.1.7.4??1.5.1.8.1??1.5.1.8.2??1.5.1.8.3??1.5.1.8.4

1.5.2.1.1??1.5.2.1.2??1.5.2.1.3??1.5.2.1.4??1.5.2.2.1??1.5.2.2.2??1.5.2.2.3??1.5.2.2.4

1.5.2.3.1??1.5.2.3.2??1.5.2.3.3??1.5.2.3.4??1.5.2.4.1??1.5.2.4.2??1.5.2.4.3??1.5.2.4.4

1.5.2.5.1??1.5.2.5.2??1.5.2.5.3??1.5.2.5.4??1.5.2.6.1??1.5.2.6.2??1.5.2.6.3??1.5.2.6.4

1.5.2.7.1??1.5.2.7.2??1.5.2.7.3??1.5.2.7.4??1.5.2.8.1??1.5.2.8.2??1.5.2.8.3??1.5.2.8.4

1.5.3.1.1??1.5.3.1.2??1.5.3.1.3??1.5.3.1.4??1.5.3.2.1??1.5.3.2.2??1.5.3.2.3??1.5.3.2.4

1.5.3.3.1??1.5.3.3.2??1.5.3.3.3??1.5.3.3.4??1.5.3.4.1??1.5.3.4.2??1.5.3.4.3??1.5.3.4.4

1.5.3.5.1??1.5.3.5.2??1.5.3.5.3??1.5.3.5.4??1.5.3.6.1??1.5.3.6.2??1.5.3.6.3??1.5.3.6.4

1.5.3.7.1??1.5.3.7.2??1.5.3.7.3??1.5.3.7.4??1.5.3.8.1??1.5.3.8.2??1.5.3.8.3??1.5.3.8.4

1.5.4.1.1??1.5.4.1.2??1.5.4.1.3??1.5.4.1.4??1.5.4.2.1??1.5.4.2.2??1.5.4.2.3??1.5.4.2.4

1.5.4.3.1??1.5.4.3.2??1.5.4.3.3??1.5.4.3.4??1.5.4.4.1??1.5.4.4.2??1.5.4.4.3??1.5.4.4.4

1.5.4.5.1??1.5.4.5.2??1.5.4.5.3??1.5.4.5.4??1.5.4.6.1??1.5.4.6.2??1.5.4.6.3??1.5.4.6.4

1.5.4.7.1??1.5.4.7.2??1.5.4.7.3??1.5.4.7.4??1.5.4.8.1??1.5.4.8.2??1.5.4.8.3??1.5.4.8.4

1.6.1.1.1??1.6.1.1.2??1.6.1.1.3??1.6.1.1.4??1.6.1.2.1??1.6.1.2.2??1.6.1.2.3??1.6.1.2.4

1.6.1.3.1??1.6.1.3.2??1.6.1.3.3??1.6.1.3.4??1.6.1.4.1??1.6.1.4.2??1.6.1.4.3??1.6.1.4.4

1.6.1.5.1??1.6.1.5.2??1.6.1.5.3??1.6.1.5.4??1.6.1.6.1??1.6.1.6.2??1.6.1.6.3??1.6.1.6.4

1.6.1.7.1??1.6.1.7.2??1.6.1.7.3??1.6.1.7.4??1.6.1.8.1??1.6.1.8.2??1.6.1.8.3??1.6.1.8.4

1.6.2.1.1??1.6.2.1.2??1.6.2.1.3??1.6.2.1.4??1.6.2.2.1??1.6.2.2.2??1.6.2.2.3??1.6.2.2.4

1.6.2.3.1??1.6.2.3.2??1.6.2.3.3??1.6.2.3.4??1.6.2.4.1??1.6.2.4.2??1.6.2.4.3??1.6.2.4.4

1.6.2.5.1??1.6.2.5.2??1.6.2.5.3??1.6.2.5.4??1.6.2.6.1??1.6.2.6.2??1.6.2.6.3??1.6.2.6.4

1.6.2.7.1??1.6.2.7.2??1.6.2.7.3??1.6.2.7.4??1.6.2.8.1??1.6.2.8.2??1.6.2.8.3??1.6.2.8.4

1.6.3.1.1??1.6.3.1.2??1.6.3.1.3??1.6.3.1.4??1.6.3.2.1??1.6.3.2.2??1.6.3.2.3??1.6.3.2.4

1.6.3.3.1??1.6.3.3.2??1.6.3.3.3??1.6.3.3.4??1.6.3.4.1??1.6.3.4.2??1.6.3.4.3??1.6.3.4.4

1.6.3.5.1??1.6.3.5.2??1.6.3.5.3??1.6.3.5.4??1.6.3.6.1??1.6.3.6.2??1.6.3.6.3??1.6.3.6.4

1.6.3.7.1??1.6.3.7.2??1.6.3.7.3??1.6.3.7.4??1.6.3.8.1??1.6.3.8.2??1.6.3.8.3??1.6.3.8.4

Table 3-is continuous

1.6.4.1.1??1.6.4.1.2??1.6.4.1.3??1.6.4.1.4??1.6.4.2.1??1.6.4.2.2??1.6.4.2.3??1.6.4.2.4

1.6.4.3.1??1.6.4.3.2??1.6.4.3.3??1.6.4.3.4??1.6.4.4.1??1.6.4.4.2??1.6.4.4.3??1.6.4.4.4

1.6.4.5.1??1.6.4.5.2??1.6.4.5.3??1.6.4.5.4??1.6.4.6.1??1.6.4.6.2??1.6.4.6.3??1.6.4.6.4

1.6.4.7.1??1.6.4.7.2??1.6.4.7.3??1.6.4.7.4??1.6.4.8.1??1.6.4.8.2??1.6.4.8.3??1.6.4.8.4

1.7.1.1.1??1.7.1.1.2??1.7.1.1.3??1.7.1.1.4??1.7.1.2.1??1.7.1.2.2??1.7.1.2.3??1.7.1.2.4

1.7.1.3.1??1.7.1.3.2??1.7.1.3.3??1.7.1.3.4??1.7.1.4.1??1.7.1.4.2??1.7.1.4.3??1.7.1.4.4

1.7.1.5.1??1.7.1.5.2??1.7.1.5.3??1.7.1.5.4??1.7.1.6.1??1.7.1.6.2??1.7.1.6.3??1.7.1.6.4

1.7.1.7.1??1.7.1.7.2??1.7.1.7.3??1.7.1.7.4??1.7.1.8.1??1.7.1.8.2??1.7.1.8.3??1.7.1.8.4

1.7.2.1.1??1.7.2.1.2??1.7.2.1.3??1.7.2.1.4??1.7.2.2.1??1.7.2.2.2??1.7.2.2.3??1.7.2.2.4

1.7.2.3.1??1.7.2.3.2??1.7.2.3.3??1.7.2.3.4??1.7.2.4.1??1.7.2.4.2??1.7.2.4.3??1.7.2.4.4

1.7.2.5.1??1.7.2.5.2??1.7.2.5.3??1.7.2.5.4??1.7.2.6.1??1.7.2.6.2??1.7.2.6.3??1.7.2.6.4

1.7.2.7.1??1.7.2.7.2??1.7.2.7.3??1.7.2.7.4??1.7.2.8.1??1.7.2.8.2??1.7.2.8.3??1.7.2.8.4

1.7.3.1.1??1.7.3.1.2??1.7.3.1.3??1.7.3.1.4??1.7.3.2.1??1.7.3.2.2??1.7.3.2.3??1.7.3.2.4

1.7.3.3.1??1.7.3.3.2??1.7.3.3.3??1.7.3.3.4??1.7.3.4.1??1.7.3.4.2??1.7.3.4.3??1.7.3.4.4

1.7.3.5.1??1.7.3.5.2??1.7.3.5.3??1.7.3.5.4??1.7.3.6.1??1.7.3.6.2??1.7.3.6.3??1.7.3.6.4

1.7.3.7.1??1.7.3.7.2??1.7.3.7.3??1.7.3.7.4??1.7.3.8.1??1.7.3.8.2??1.7.3.8.3??1.7.3.8.4

1.7.4.1.1??1.7.4.1.2??1.7.4.1.3??1.7.4.1.4??1.7.4.2.1??1.7.4.2.2??1.7.4.2.3??1.7.4.2.4

1.7.4.3.1??1.7.4.3.2??1.7.4.3.3??1.7.4.3.4??1.7.4.4.1??1.7.4.4.2??1.7.4.4.3??1.7.4.4.4

1.7.4.5.1??1.7.4.5.2??1.7.4.5.3??1.7.4.5.4??1.7.4.6.1??1.7.4.6.2??1.7.4.6.3??1.7.4.6.4

1.7.4.7.1??1.7.4.7.2??1.7.4.7.3??1.7.4.7.4??1.7.4.8.1??1.7.4.8.2??1.7.4.8.3??1.7.4.8.4

1.8.1.1.1??1.8.1.1.2??1.8.1.1.3??1.8.1.1.4??1.8.1.2.1??1.8.1.2.2??1.8.1.2.3??1.8.1.2.4

1.8.1.3.1??1.8.1.3.2??1.8.1.3.3??1.8.1.3.4??1.8.1.4.1??1.8.1.4.2??1.8.1.4.3??1.8.1.4.4

1.8.1.5.1??1.8.1.5.2??1.8.1.5.3??1.8.1.5.4??1.8.1.6.1??1.8.1.6.2??1.8.1.6.3??1.8.1.6.4

1.8.1.7.1??1.8.1.7.2??1.8.1.7.3??1.8.1.7.4??1.8.1.8.1??1.8.1.8.2??1.8.1.8.3??1.8.1.8.4

1.8.2.1.1??1.8.2.1.2??1.8.2.1.3??1.8.2.1.4??1.8.2.2.1??1.8.2.2.2??1.8.2.2.3??1.8.2.2.4

1.8.2.3.1??1.8.2.3.2??1.8.2.3.3??1.8.2.3.4??1.8.2.4.1??1.8.2.4.2??1.8.2.4.3??1.8.2.4.4

1.8.2.5.1??1.8.2.5.2??1.8.2.5.3??1.8.2.5.4??1.8.2.6.1??1.8.2.6.2??1.8.2.6.3??1.8.2.6.4

1.8.2.7.1??1.8.2.7.2??1.8.2.7.3??1.8.2.7.4??1.8.2.8.1??1.8.2.8.2??1.8.2.8.3??1.8.2.8.4

1.8.3.1.1??1.8.3.1.2??1.8.3.1.3??1.8.3.1.4??1.8.3.2.1??1.8.3.2.2??1.8.3.2.3??1.8.3.2.4

1.8.3.3.1??1.8.3.3.2??1.8.3.3.3??1.8.3.3.4??1.8.3.4.1??1.8.3.4.2??1.8.3.4.3??1.8.3.4.4

1.8.3.5.1??1.8.3.5.2??1.8.3.5.3??1.8.3.5.4??1.8.3.6.1??1.8.3.6.2??1.8.3.6.3??1.8.3.6.4

1.8.3.7.1??1.8.3.7.2??1.8.3.7.3??1.8.3.7.4??1.8.3.8.1??1.8.3.8.2??1.8.3.8.3??1.8.3.8.4

1.8.4.1.1??1.8.4.1.2??1.8.4.1.3??1.8.4.1.4??1.8.4.2.1??1.8.4.2.2??1.8.4.2.3??1.8.4.2.4

1.8.4.3.1??1.8.4.3.2??1.8.4.3.3??1.8.4.3.4??1.8.4.4.1??1.8.4.4.2??1.8.4.4.3??1.8.4.4.4

1.8.4.5.1??1.8.4.5.2??1.8.4.5.3??1.8.4.5.4??1.8.4.6.1??1.8.4.6.2??1.8.4.6.3??1.8.4.6.4

1.8.4.7.1??1.8.4.7.2??1.8.4.7.3??1.8.4.7.4??1.8.4.8.1??1.8.4.8.2??1.8.4.8.3??1.8.4.8.4

2.1.1.1.1??2.1.1.1.2??2.1.1.1.3??2.1.1.1.4??2.1.1.2.1??2.1.1.2.2??2.1.1.2.3??2.1.1.2.4

2.1.1.3.1??2.1.1.3.2??2.1.1.3.3??2.1.1.3.4??2.1.1.4.1??2.1.1.4.2??2.1.1.4.3??2.1.1.4.4

2.1.1.5.1??2.1.1.5.2??2.1.1.5.3??2.1.1.5.4??2.1.1.6.1??2.1.1.6.2??2.1.1.6.3??2.1.1.6.4

2.1.1.7.1??2.1.1.7.2??2.1.1.7.3??2.1.1.7.4??2.1.1.8.1??2.1.1.8.2??2.1.1.8.3??2.1.1.8.4

2.1.2.1.1??2.1.2.1.2??2.1.2.1.3??2.1.2.1.4??2.1.2.2.1??2.1.2.2.2??2.1.2.2.3??2.1.2.2.4

2.1.2.3.1??2.1.2.3.2??2.1.2.3.3??2.1.2.3.4??2.1.2.4.1??2.1.2.4.2??2.1.2.4.3??2.1.2.4.4

2.1.2.5.1??2.1.2.5.2??2.1.2.5.3??2.1.2.5.4??2.1.2.6.1??2.1.2.6.2??2.1.2.6.3??2.1.2.6.4

2.1.2.7.1??2.1.2.7.2??2.1.2.7.3??2.1.2.7.4??2.1.2.8.1??2.1.2.8.2??2.1.2.8.3??2.1.2.8.4

2.1.3.1.1??2.1.3.1.2??2.1.3.1.3??2.1.3.1.4??2.1.3.2.1??2.1.3.2.2??2.1.3.2.3??2.1.3.2.4

2.1.3.3.1??2.1.3.3.2??2.1.3.3.3??2.1.3.3.4??2.1.3.4.1??2.1.3.4.2??2.1.3.4.3??2.1.3.4.4

Table 3-is continuous

2.1.3.5.1??2.1.3.5.2??2.1.3.5.3??2.1.3.5.4??2.1.3.6.1??2.1.3.6.2??2.1.3.6.3??2.1.3.6.4

2.1.3.7.1??2.1.3.7.2??2.1.3.7.3??2.1.3.7.4??2.1.3.8.1??2.1.3.8.2??2.1.3.8.3??2.1.3.8.4

2.1.4.1.1??2.1.4.1.2??2.1.4.1.3??2.1.4.1.4??2.1.4.2.1??2.1.4.2.2??2.1.4.2.3??2.1.4.2.4

2.1.4.3.1??2.1.4.3.2??2.1.4.3.3??2.1.4.3.4??2.1.4.4.1??2.1.4.4.2??2.1.4.4.3??2.1.4.4.4

2.1.4.5.1??2.1.4.5.2??2.1.4.5.3??2.1.4.5.4??2.1.4.6.1??2.1.4.6.2??2.1.4.6.3??2.1.4.6.4

2.1.4.7.1??2.1.4.7.2??2.1.4.7.3??2.1.4.7.4??2.1.4.8.1??2.1.4.8.2??2.1.4.8.3??2.1.4.8.4

2.2.1.1.1??2.2.1.1.2??2.2.1.1.3??2.2.1.1.4??2.2.1.2.1??2.2.1.2.2??2.2.1.2.3??2.2.1.2.4

2.2.1.3.1??2.2.1.3.2??2.2.1.3.3??2.2.1.3.4??2.2.1.4.1??2.2.1.4.2??2.2.1.4.3??2.2.1.4.4

2.2.1.5.1??2.2.1.5.2??2.2.1.5.3??2.2.1.5.4??2.2.1.6.1??2.2.1.6.2??2.2.1.6.3??2.2.1.6.4

2.2.1.7.1??2.2.1.7.2??2.2.1.7.3??2.2.1.7.4??2.2.1.8.1??2.2.1.8.2??2.2.1.8.3??2.2.1.8.4

2.2.2.1.1??2.2.2.1.2??2.2.2.1.3??2.2.2.1.4??2.2.2.2.1??2.2.2.2.2??2.2.2.2.3??2.2.2.2.4

2.2.2.3.1??2.2.2.3.2??2.2.2.3.3??2.2.2.3.4??2.2.2.4.1??2.2.2.4.2??2.2.2.4.3??2.2.2.4.4

2.2.2.5.1??2.2.2.5.2??2.2.2.5.3??2.2.2.5.4??2.2.2.6.1??2.2.2.6.2??2.2.2.6.3??2.2.2.6.4

2.2.2.7.1??2.2.2.7.2??2.2.2.7.3??2.2.2.7.4??2.2.2.8.1??2.2.2.8.2??2.2.2.8.3??2.2.2.8.4

2.2.3.1.1??2.2.3.1.2??2.2.3.1.3??2.2.3.1.4??2.2.3.2.1??2.2.3.2.2??2.2.3.2.3??2.2.3.2.4

2.2.3.3.1??2.2.3.3.2??2.2.3.3.3??2.2.3.3.4??2.2.3.4.1??2.2.3.4.2??2.2.3.4.3??2.2.3.4.4

2.2.3.5.1??2.2.3.5.2??2.2.3.5.3??2.2.3.5.4??2.2.3.6.1??2.2.3.6.2??2.2.3.6.3??2.2.3.6.4

2.2.3.7.1??2.2.3.7.2??2.2.3.7.3??2.2.3.7.4??2.2.3.8.1??2.2.3.8.2??2.2.3.8.3??2.2.3.8.4

2.2.4.1.1??2.2.4.1.2??2.2.4.1.3??2.2.4.1.4??2.2.4.2.1??2.2.4.2.2??2.2.4.2.3??2.2.4.2.4

2.2.4.3.1??2.2.4.3.2??2.2.4.3.3??2.2.4.3.4??2.2.4.4.1??2.2.4.4.2??2.2.4.4.3??2.2.4.4.4

2.2.4.5.1??2.2.4.5.2??2.2.4.5.3??2.2.4.5.4??2.2.4.6.1??2.2.4.6.2??2.2.4.6.3??2.2.4.6.4

2.2.4.7.1??2.2.4.7.2??2.2.4.7.3??2.2.4.7.4??2.2.4.8.1??2.2.4.8.2??2.2.4.8.3??2.2.4.8.4

2.3.1.1.1??2.3.1.1.2??2.3.1.1.3??2.3.1.1.4??2.3.1.2.1??2.3.1.2.2??2.3.1.2.3??2.3.1.2.4

2.3.1.3.1??2.3.1.3.2??2.3.1.3.3??2.3.1.3.4??2.3.1.4.1??2.3.1.4.2??2.3.1.4.3??2.3.1.4.4

2.3.1.5.1??2.3.1.5.2??2.3.1.5.3??2.3.1.5.4??2.3.1.6.1??2.3.1.6.2??2.3.1.6.3??2.3.1.6.4

2.3.1.7.1??2.3.1.7.2??2.3.1.7.3??2.3.1.7.4??2.3.1.8.1??2.3.1.8.2??2.3.1.8.3??2.3.1.8.4

2.3.2.1.1??2.3.2.1.2??2.3.2.1.3??2.3.2.1.4??2.3.2.2.1??2.3.2.2.2??2.3.2.2.3??2.3.2.2.4

2.3.2.3.1??2.3.2.3.2??2.3.2.3.3??2.3.2.3.4??2.3.2.4.1??2.3.2.4.2??2.3.2.4.3??2.3.2.4.4

2.3.2.5.1??2.3.2.5.2??2.3.2.5.3??2.3.2.5.4??2.3.2.6.1??2.3.2.6.2??2.3.2.6.3??2.3.2.6.4

2.3.2.7.1??2.3.2.7.2??2.3.2.7.3??2.3.2.7.4??2.3.2.8.1??2.3.2.8.2??2.3.2.8.3??2.3.2.8.4

2.3.3.1.1??2.3.3.1.2??2.3.3.1.3??2.3.3.1.4??2.3.3.2.1??2.3.3.2.2??2.3.3.2.3??2.3.3.2.4

2.3.3.3.1??2.3.3.3.2??2.3.3.3.3??2.3.3.3.4??2.3.3.4.1??2.3.3.4.2??2.3.3.4.3??2.3.3.4.4

2.3.3.5.1??2.3.3.5.2??2.3.3.5.3??2.3.3.5.4??2.3.3.6.1??2.3.3.6.2??2.3.3.6.3??2.3.3.6.4

2.3.3.7.1??2.3.3.7.2??2.3.3.7.3??2.3.3.7.4??2.3.3.8.1??2.3.3.8.2??2.3.3.8.3??2.3.3.8.4

2.3.4.1.1??2.3.4.1.2??2.3.4.1.3??2.3.4.1.4??2.3.4.2.1??2.3.4.2.2??2.3.4.2.3??2.3.4.2.4

2.3.4.3.1??2.3.4.3.2??2.3.4.3.3??2.3.4.3.4??2.3.4.4.1??2.3.4.4.2??2.3.4.4.3??2.3.4.4.4

2.3.4.5.1??2.3.4.5.2??2.3.4.5.3??2.3.4.5.4??2.3.4.6.1??2.3.4.6.2??2.3.4.6.3??2.3.4.6.4

2.3.4.7.1??2.3.4.7.2??2.3.4.7.3??2.3.4.7.4??2.3.4.8.1??2.3.4.8.2??2.3.4.8.3??2.3.4.8.4

2.4.1.1.1??2.4.1.1.2??2.4.1.1.3??2.4.1.1.4??2.4.1.2.1??2.4.1.2.2??2.4.1.2.3??2.4.1.2.4

2.4.1.3.1??2.4.1.3.2??2.4.1.3.3??2.4.1.3.4??2.4.1.4.1??2.4.1.4.2??2.4.1.4.3??2.4.1.4.4

2.4.1.5.1??2.4.1.5.2??2.4.1.5.3??2.4.1.5.4??2.4.1.6.1??2.4.1.6.2??2.4.1.6.3??2.4.1.6.4

2.4.1.7.1??2.4.1.7.2??2.4.1.7.3??2.4.1.7.4??2.4.1.8.1??2.4.1.8.2??2.4.1.8.3??2.4.1.8.4

2.4.2.1.1??2.4.2.1.2??2.4.2.1.3??2.4.2.1.4??2.4.2.2.1??2.4.2.2.2??2.4.2.2.3??2.4.2.2.4

2.4.2.3.1??2.4.2.3.2??2.4.2.3.3??2.4.2.3.4??2.4.2.4.1??2.4.2.4.2??2.4.2.4.3??2.4.2.4.4

2.4.2.5.1??2.4.2.5.2??2.4.2.5.3??2.4.2.5.4??2.4.2.6.1??2.4.2.6.2??2.4.2.6.3??2.4.2.6.4

2.4.2.7.1??2.4.2.7.2??2.4.2.7.3??2.4.2.7.4??2.4.2.8.1??2.4.2.8.2??2.4.2.8.3??2.4.2.8.4

Table 3-is continuous

2.4.3.1.1??2.4.3.1.2??2.4.3.1.3??2.4.3.1.4??2.4.3.2.1??2.4.3.2.2??2.4.3.2.3??2.4.3.2.4

2.4.3.3.1??2.4.3.3.2??2.4.3.3.3??2.4.3.3.4??2.4.3.4.1??2.4.3.4.2??2.4.3.4.3??2.4.3.4.4

2.4.3.5.1??2.4.3.5.2??2.4.3.5.3??2.4.3.5.4??2.4.3.6.1??2.4.3.6.2??2.4.3.6.3??2.4.3.6.4

2.4.3.7.1??2.4.3.7.2??2.4.3.7.3??2.4.3.7.4??2.4.3.8.1??2.4.3.8.2??2.4.3.8.3??2.4.3.8.4

2.4.4.1.1??2.4.4.1.2??2.4.4.1.3??2.4.4.1.4??2.4.4.2.1??2.4.4.2.2??2.4.4.2.3??2.4.4.2.4

2.4.4.3.1??2.4.4.3.2??2.4.4.3.3??2.4.4.3.4??2.4.4.4.1??2.4.4.4.2??2.4.4.4.3??2.4.4.4.4

2.4.4.5.1??2.4.4.5.2??2.4.4.5.3??2.4.4.5.4??2.4.4.6.1??2.4.4.6.2??2.4.4.6.3??2.4.4.6.4

2.4.4.7.1??2.4.4.7.2??2.4.4.7.3??2.4.4.7.4??2.4.4.8.1??2.4.4.8.2??2.4.4.8.3??2.4.4.8.4

2.5.1.1.1??2.5.1.1.2??2.5.1.1.3??2.5.1.1.4??2.5.1.2.1??2.5.1.2.2??2.5.1.2.3??2.5.1.2.4

2.5.1.3.1??2.5.1.3.2??2.5.1.3.3??2.5.1.3.4??2.5.1.4.1??2.5.1.4.2??2.5.1.4.3??2.5.1.4.4

2.5.1.5.1??2.5.1.5.2??2.5.1.5.3??2.5.1.5.4??2.5.1.6.1??2.5.1.6.2??2.5.1.6.3??2.5.1.6.4

2.5.1.7.1??2.5.1.7.2??2.5.1.7.3??2.5.1.7.4??2.5.1.8.1??2.5.1.8.2??2.5.1.8.3??2.5.1.8.4

2.5.2.1.1??2.5.2.1.2??2.5.2.1.3??2.5.2.1.4??2.5.2.2.1??2.5.2.2.2??2.5.2.2.3??2.5.2.2.4

2.5.2.3.1??2.5.2.3.2??2.5.2.3.3??2.5.2.3.4??2.5.2.4.1??2.5.2.4.2??2.5.2.4.3??2.5.2.4.4

2.5.2.5.1??2.5.2.5.2??2.5.2.5.3??2.5.2.5.4??2.5.2.6.1??2.5.2.6.2??2.5.2.6.3??2.5.2.6.4

2.5.2.7.1??2.5.2.7.2??2.5.2.7.3??2.5.2.7.4??2.5.2.8.1??2.5.2.8.2??2.5.2.8.3??2.5.2.8.4

2.5.3.1.1??2.5.3.1.2??2.5.3.1.3??2.5.3.1.4??2.5.3.2.1??2.5.3.2.2??2.5.3.2.3??2.5.3.2.4

2.5.3.3.1??2.5.3.3.2??2.5.3.3.3??2.5.3.3.4??2.5.3.4.1??2.5.3.4.2??2.5.3.4.3??2.5.3.4.4

2.5.3.5.1??2.5.3.5.2??2.5.3.5.3??2.5.3.5.4??2.5.3.6.1??2.5.3.6.2??2.5.3.6.3??2.5.3.6.4

2.5.3.7.1??2.5.3.7.2??2.5.3.7.3??2.5.3.7.4??2.5.3.8.1??2.5.3.8.2??2.5.3.8.3??2.5.3.8.4

2.5.4.1.1??2.5.4.1.2??2.5.4.1.3??2.5.4.1.4??2.5.4.2.1??2.5.4.2.2??2.5.4.2.3??2.5.4.2.4

2.5.4.3.1??2.5.4.3.2??2.5.4.3.3??2.5.4.3.4??2.5.4.4.1??2.5.4.4.2??2.5.4.4.3??2.5.4.4.4

2.5.4.5.1??2.5.4.5.2??2.5.4.5.3??2.5.4.5.4??2.5.4.6.1??2.5.4.6.2??2.5.4.6.3??2.5.4.6.4

2.5.4.7.1??2.5.4.7.2??2.5.4.7.3??2.5.4.7.4??2.5.4.8.1??2.5.4.8.2??2.5.4.8.3??2.5.4.8.4

2.6.1.1.1??2.6.1.1.2??2.6.1.1.3??2.6.1.1.4??2.6.1.2.1??2.6.1.2.2??2.6.1.2.3??2.6.1.2.4

2.6.1.3.1??2.6.1.3.2??2.6.1.3.3??2.6.1.3.4??2.6.1.4.1??2.6.1.4.2??2.6.1.4.3??2.6.1.4.4

2.6.1.5.1??2.6.1.5.2??2.6.1.5.3??2.6.1.5.4??2.6.1.6.1??2.6.1.6.2??2.6.1.6.3??2.6.1.6.4

2.6.1.7.1??2.6.1.7.2??2.6.1.7.3??2.6.1.7.4??2.6.1.8.1??2.6.1.8.2??2.6.1.8.3??2.6.1.8.4

2.6.2.1.1??2.6.2.1.2??2.6.2.1.3??2.6.2.1.4??2.6.2.2.1??2.6.2.2.2??2.6.2.2.3??2.6.2.2.4

2.6.2.3.1??2.6.2.3.2??2.6.2.3.3??2.6.2.3.4??2.6.2.4.1??2.6.2.4.2??2.6.2.4.3??2.6.2.4.4

2.6.2.5.1??2.6.2.5.2??2.6.2.5.3??2.6.2.5.4??2.6.2.6.1??2.6.2.6.2??2.6.2.6.3??2.6.2.6.4

2.6.2.7.1??2.6.2.7.2??2.6.2.7.3??2.6.2.7.4??2.6.2.8.1??2.6.2.8.2??2.6.2.8.3??2.6.2.8.4

2.6.3.1.1??2.6.3.1.2??2.6.3.1.3??2.6.3.1.4??2.6.3.2.1??2.6.3.2.2??2.6.3.2.3??2.6.3.2.4

2.6.3.3.1??2.6.3.3.2??2.6.3.3.3??2.6.3.3.4??2.6.3.4.1??2.6.3.4.2??2.6.3.4.3??2.6.3.4.4

2.6.3.5.1??2.6.3.5.2??2.6.3.5.3??2.6.3.5.4??2.6.3.6.1??2.6.3.6.2??2.6.3.6.3??2.6.3.6.4

2.6.3.7.1??2.6.3.7.2??2.6.3.7.3??2.6.3.7.4??2.6.3.8.1??2.6.3.8.2??2.6.3.8.3??2.6.3.8.4

2.6.4.1.1??2.6.4.1.2??2.6.4.1.3??2.6.4.1.4??2.6.4.2.1??2.6.4.2.2??2.6.4.2.3??2.6.4.2.4

2.6.4.3.1??2.6.4.3.2??2.6.4.3.3??2.6.4.3.4??2.6.4.4.1??2.6.4.4.2??2.6.4.4.3??2.6.4.4.4

2.6.4.5.1??2.6.4.5.2??2.6.4.5.3??2.6.4.5.4??2.6.4.6.1??2.6.4.6.2??2.6.4.6.3??2.6.4.6.4

2.6.4.7.1??2.6.4.7.2??2.6.4.7.3??2.6.4.7.4??2.6.4.8.1??2.6.4.8.2??2.6.4.8.3??2.6.4.8.4

2.7.1.1.1??2.7.1.1.2??2.7.1.1.3??2.7.1.1.4??2.7.1.2.1??2.7.1.2.2??2.7.1.2.3??2.7.1.2.4

2.7.1.3.1??2.7.1.3.2??2.7.1.3.3??2.7.1.3.4??2.7.1.4.1??2.7.1.4.2??2.7.1.4.3??2.7.1.4.4

2.7.1.5.1??2.7.1.5.2??2.7.1.5.3??2.7.1.5.4??2.7.1.6.1??2.7.1.6.2??2.7.1.6.3??2.7.1.6.4

2.7.1.7.1??2.7.1.7.2??2.7.1.7.3??2.7.1.7.4??2.7.1.8.1??2.7.1.8.2??2.7.1.8.3??2.7.1.8.4

2.7.2.1.1??2.7.2.1.2??2.7.2.1.3??2.7.2.1.4??2.7.2.2.1??2.7.2.2.2??2.7.2.2.3??2.7.2.2.4

2.7.2.3.1??2.7.2.3.2??2.7.2.3.3??2.7.2.3.4??2.7.2.4.1??2.7.2.4.2??2.7.2.4.3??2.7.2.4.4

Table 3-is continuous

2.7.2.5.1??2.7.2.5.2??2.7.2.5.3??2.7.2.5.4??2.7.2.6.1??2.7.2.6.2??2.7.2.6.3??2.7.2.6.4

2.7.2.7.1??2.7.2.7.2??2.7.2.7.3??2.7.2.7.4??2.7.2.8.1??2.7.2.8.2??2.7.2.8.3??2.7.2.8.4

2.7.3.1.1??2.7.3.1.2??2.7.3.1.3??2.7.3.1.4??2.7.3.2.1??2.7.3.2.2??2.7.3.2.3??2.7.3.2.4

2.7.3.3.1??2.7.3.3.2??2.7.3.3.3??2.7.3.3.4??2.7.3.4.1??2.7.3.4.2??2.7.3.4.3??2.7.3.4.4

2.7.3.5.1??2.7.3.5.2??2.7.3.5.3??2.7.3.5.4??2.7.3.6.1??2.7.3.6.2??2.7.3.6.3??2.7.3.6.4

2.7.3.7.1??2.7.3.7.2??2.7.3.7.3??2.7.3.7.4??2.7.3.8.1??2.7.3.8.2??2.7.3.8.3??2.7.3.8.4

2.7.4.1.1??2.7.4.1.2??2.7.4.1.3??2.7.4.1.4??2.7.4.2.1??2.7.4.2.2??2.7.4.2.3??2.7.4.2.4

2.7.4.3.1??2.7.4.3.2??2.7.4.3.3??2.7.4.3.4??2.7.4.4.1??2.7.4.4.2??2.7.4.4.3??2.7.4.4.4

2.7.4.5.1??2.7.4.5.2??2.7.4.5.3??2.7.4.5.4??2.7.4.6.1??2.7.4.6.2??2.7.4.6.3??2.7.4.6.4

2.7.4.7.1??2.7.4.7.2??2.7.4.7.3??2.7.4.7.4??2.7.4.8.1??2.7.4.8.2??2.7.4.8.3??2.7.4.8.4

2.8.1.1.1??2.8.1.1.2??2.8.1.1.3??2.8.1.1.4??2.8.1.2.1??2.8.1.2.2??2.8.1.2.3??2.8.1.2.4

2.8.1.3.1??2.8.1.3.2??2.8.1.3.3??2.8.1.3.4??2.8.1.4.1??2.8.1.4.2??2.8.1.4.3??2.8.1.4.4

2.8.1.5.1??2.8.1.5.2??2.8.1.5.3??2.8.1.5.4??2.8.1.6.1??2.8.1.6.2??2.8.1.6.3??2.8.1.6.4

2.8.1.7.1??2.8.1.7.2??2.8.1.7.3??2.8.1.7.4??2.8.1.8.1??2.8.1.8.2??2.8.1.8.3??2.8.1.8.4

2.8.2.1.1??2.8.2.1.2??2.8.2.1.3??2.8.2.1.4??2.8.2.2.1??2.8.2.2.2??2.8.2.2.3??2.8.2.2.4

2.8.2.3.1??2.8.2.3.2??2.8.2.3.3??2.8.2.3.4??2.8.2.4.1??2.8.2.4.2??2.8.2.4.3??2.8.2.4.4

2.8.2.5.1??2.8.2.5.2??2.8.2.5.3??2.8.2.5.4??2.8.2.6.1??2.8.2.6.2??2.8.2.6.3??2.8.2.6.4

2.8.2.7.1??2.8.2.7.2??2.8.2.7.3??2.8.2.7.4??2.8.2.8.1??2.8.2.8.2??2.8.2.8.3??2.8.2.8.4

2.8.3.1.1??2.8.3.1.2??2.8.3.1.3??2.8.3.1.4??2.8.3.2.1??2.8.3.2.2??2.8.3.2.3??2.8.3.2.4

2.8.3.3.1??2.8.3.3.2??2.8.3.3.3??2.8.3.3.4??2.8.3.4.1??2.8.3.4.2??2.8.3.4.3??2.8.3.4.4

2.8.3.5.1??2.8.3.5.2??2.8.3.5.3??2.8.3.5.4??2.8.3.6.1??2.8.3.6.2??2.8.3.6.3??2.8.3.6.4

2.8.3.7.1??2.8.3.7.2??2.8.3.7.3??2.8.3.7.4??2.8.3.8.1??2.8.3.8.2??2.8.3.8.3??2.8.3.8.4

2.8.4.1.1??2.8.4.1.2??2.8.4.1.3??2.8.4.1.4??2.8.4.2.1??2.8.4.2.2??2.8.4.2.3??2.8.4.2.4

2.8.4.3.1??2.8.4.3.2??2.8.4.3.3??2.8.4.3.4??2.8.4.4.1??2.8.4.4.2??2.8.4.4.3??2.8.4.4.4

2.8.4.5.1??2.8.4.5.2??2.8.4.5.3??2.8.4.5.4??2.8.4.6.1??2.8.4.6.2??2.8.4.6.3??2.8.4.6.4

2.8.4.7.1??2.8.4.7.2??2.8.4.7.3??2.8.4.7.4??2.8.4.8.1??2.8.4.8.2??2.8.4.8.3??2.8.4.8.4

3.1.1.1.1??3.1.1.1.2??3.1.1.1.3??3.1.1.1.4??3.1.1.2.1??3.1.1.2.2??3.1.1.2.3??3.1.1.2.4

3.1.1.3.1??3.1.1.3.2??3.1.1.3.3??3.1.1.3.4??3.1.1.4.1??3.1.1.4.2??3.1.1.4.3??3.1.1.4.4

3.1.1.5.1??3.1.1.5.2??3.1.1.5.3??3.1.1.5.4??3.1.1.6.1??3.1.1.6.2??3.1.1.6.3??3.1.1.6.4

3.1.1.7.1??3.1.1.7.2??3.1.1.7.3??3.1.1.7.4??3.1.1.8.1??3.1.1.8.2??3.1.1.8.3??3.1.1.8.4

3.1.2.1.1??3.1.2.1.2??3.1.2.1.3??3.1.2.1.4??3.1.2.2.1??3.1.2.2.2??3.1.2.2.3??3.1.2.2.4

3.1.2.3.1??3.1.2.3.2??3.1.2.3.3??3.1.2.3.4??3.1.2.4.1??3.1.2.4.2??3.1.2.4.3??3.1.2.4.4

3.1.2.5.1??3.1.2.5.2??3.1.2.5.3??3.1.2.5.4??3.1.2.6.1??3.1.2.6.2??3.1.2.6.3??3.1.2.6.4

3.1.2.7.1??3.1.2.7.2??3.1.2.7.3??3.1.2.7.4??3.1.2.8.1??3.1.2.8.2??3.1.2.8.3??3.1.2.8.4

3.1.3.1.1??3.1.3.1.2??3.1.3.1.3??3.1.3.1.4??3.1.3.2.1??3.1.3.2.2??3.1.3.2.3??3.1.3.2.4

3.1.3.3.1??3.1.3.3.2??3.1.3.3.3??3.1.3.3.4??3.1.3.4.1??3.1.3.4.2??3.1.3.4.3??3.1.3.4.4

3.1.3.5.1??3.1.3.5.2??3.1.3.5.3??3.1.3.5.4??3.1.3.6.1??3.1.3.6.2??3.1.3.6.3??3.1.3.6.4

3.1.3.7.1??3.1.3.7.2??3.1.3.7.3??3.1.3.7.4??3.1.3.8.1??3.1.3.8.2??3.1.3.8.3??3.1.3.8.4

3.1.4.1.1??3.1.4.1.2??3.1.4.1.3??3.1.4.1.4??3.1.4.2.1??3.1.4.2.2??3.1.4.2.3??3.1.4.2.4

3.1.4.3.1??3.1.4.3.2??3.1.4.3.3??3.1.4.3.4??3.1.4.4.1??3.1.4.4.2??3.1.4.4.3??3.1.4.4.4

3.1.4.5.1??3.1.4.5.2??3.1.4.5.3??3.1.4.5.4??3.1.4.6.1??3.1.4.6.2??3.1.4.6.3??3.1.4.6.4

3.1.4.7.1??3.1.4.7.2??3.1.4.7.3??3.1.4.7.4??3.1.4.8.1??3.1.4.8.2??3.1.4.8.3??3.1.4.8.4

3.2.1.1.1??3.2.1.1.2??3.2.1.1.3??3.2.1.1.4??3.2.1.2.1??3.2.1.2.2??3.2.1.2.3??3.2.1.2.4

3.2.1.3.1??3.2.1.3.2??3.2.1.3.3??3.2.1.3.4??3.2.1.4.1??3.2.1.4.2??3.2.1.4.3??3.2.1.4.4

3.2.1.5.1??3.2.1.5.2??3.2.1.5.3??3.2.1.5.4??3.2.1.6.1??3.2.1.6.2??3.2.1.6.3??3.2.1.6.4

3.2.1.7.1??3.2.1.7.2??3.2.1.7.3??3.2.1.7.4??3.2.1.8.1??3.2.1.8.2??3.2.1.8.3??3.2.1.8.4

Table 3-is continuous

3.2.2.1.1??3.2.2.1.2??3.2.2.1.3??3.2.2.1.4??3.2.2.2.1??3.2.2.2.2??3.2.2.2.3??3.2.2.2.4

3.2.2.3.1??3.2.2.3.2??3.2.2.3.3??3.2.2.3.4??3.2.2.4.1??3.2.2.4.2??3.2.2.4.3??3.2.2.4.4

3.2.2.5.1??3.2.2.5.2??3.2.2.5.3??3.2.2.5.4??3.2.2.6.1??3.2.2.6.2??3.2.2.6.3??3.2.2.6.4

3.2.2.7.1??3.2.2.7.2??3.2.2.7.3??3.2.2.7.4??3.2.2.8.1??3.2.2.8.2??3.2.2.8.3??3.2.2.8.4

3.2.3.1.1??3.2.3.1.2??3.2.3.1.3??3.2.3.1.4??3.2.3.2.1??3.2.3.2.2??3.2.3.2.3??3.2.3.2.4

3.2.3.3.1??3.2.3.3.2??3.2.3.3.3??3.2.3.3.4??3.2.3.4.1??3.2.3.4.2??3.2.3.4.3??3.2.3.4.4

3.2.3.5.1??3.2.3.5.2??3.2.3.5.3??3.2.3.5.4??3.2.3.6.1??3.2.3.6.2??3.2.3.6.3??3.2.3.6.4

3.2.3.7.1??3.2.3.7.2??3.2.3.7.3??3.2.3.7.4??3.2.3.8.1??3.2.3.8.2??3.2.3.8.3??3.2.3.8.4

3.2.4.1.1??3.2.4.1.2??3.2.4.1.3??3.2.4.1.4??3.2.4.2.1??3.2.4.2.2??3.2.4.2.3??3.2.4.2.4

3.2.4.3.1??3.2.4.3.2??3.2.4.3.3??3.2.4.3.4??3.2.4.4.1??3.2.4.4.2??3.2.4.4.3??3.2.4.4.4

3.2.4.5.1??3.2.4.5.2??3.2.4.5.3??3.2.4.5.4??3.2.4.6.1??3.2.4.6.2??3.2.4.6.3??3.2.4.6.4

3.2.4.7.1??3.2.4.7.2??3.2.4.7.3??3.2.4.7.4??3.2.4.8.1??3.2.4.8.2??3.2.4.8.3??3.2.4.8.4

3.3.1.1.1??3.3.1.1.2??3.3.1.1.3??3.3.1.1.4??3.3.1.2.1??3.3.1.2.2??3.3.1.2.3??3.3.1.2.4

3.3.1.3.1??3.3.1.3.2??3.3.1.3.3??3.3.1.3.4??3.3.1.4.1??3.3.1.4.2??3.3.1.4.3??3.3.1.4.4

3.3.1.5.1??3.3.1.5.2??3.3.1.5.3??3.3.1.5.4??3.3.1.6.1??3.3.1.6.2??3.3.1.6.3??3.3.1.6.4

3.3.1.7.1??3.3.1.7.2??3.3.1.7.3??3.3.1.7.4??3.3.1.8.1??3.3.1.8.2??3.3.1.8.3??3.3.1.8.4

3.3.2.1.1??3.3.2.1.2??3.3.2.1.3??3.3.2.1.4??3.3.2.2.1??3.3.2.2.2??3.3.2.2.3??3.3.2.2.4

3.3.2.3.1??3.3.2.3.2??3.3.2.3.3??3.3.2.3.4??3.3.2.4.1??3.3.2.4.2??3.3.2.4.3??3.3.2.4.4

3.3.2.5.1??3.3.2.5.2??3.3.2.5.3??3.3.2.5.4??3.3.2.6.1??3.3.2.6.2??3.3.2.6.3??3.3.2.6.4

3.3.2.7.1??3.3.2.7.2??3.3.2.7.3??3.3.2.7.4??3.3.2.8.1??3.3.2.8.2??3.3.2.8.3??3.3.2.8.4

3.3.3.1.1??3.3.3.1.2??3.3.3.1.3??3.3.3.1.4??3.3.3.2.1??3.3.3.2.2??3.3.3.2.3??3.3.3.2.4

3.3.3.3.1??3.3.3.3.2??3.3.3.3.3??3.3.3.3.4??3.3.3.4.1??3.3.3.4.2??3.3.3.4.3??3.3.3.4.4

3.3.3.5.1??3.3.3.5.2??3.3.3.5.3??3.3.3.5.4??3.3.3.6.1??3.3.3.6.2??3.3.3.6.3??3.3.3.6.4

3.3.3.7.1??3.3.3.7.2??3.3.3.7.3??3.3.3.7.4??3.3.3.8.1??3.3.3.8.2??3.3.3.8.3??3.3.3.8.4

3.3.4.1.1??3.3.4.1.2??3.3.4.1.3??3.3.4.1.4??3.3.4.2.1??3.3.4.2.2??3.3.4.2.3??3.3.4.2.4

3.3.4.3.1??3.3.4.3.2??3.3.4.3.3??3.3.4.3.4??3.3.4.4.1??3.3.4.4.2??3.3.4.4.3??3.3.4.4.4

3.3.4.5.1??3.3.4.5.2??3.3.4.5.3??3.3.4.5.4??3.3.4.6.1??3.3.4.6.2??3.3.4.6.3??3.3.4.6.4

3.3.4.7.1??3.3.4.7.2??3.3.4.7.3??3.3.4.7.4??3.3.4.8.1??3.3.4.8.2??3.3.4.8.3??3.3.4.8.4

3.4.1.1.1??3.4.1.1.2??3.4.1.1.3??3.4.1.1.4??3.4.1.2.1??3.4.1.2.2??3.4.1.2.3??3.4.1.2.4

3.4.1.3.1??3.4.1.3.2??3.4.1.3.3??3.4.1.3.4??3.4.1.4.1??3.4.1.4.2??3.4.1.4.3??3.4.1.4.4

3.4.1.5.1??3.4.1.5.2??3.4.1.5.3??3.4.1.5.4??3.4.1.6.1??3.4.1.6.2??3.4.1.6.3??3.4.1.6.4

3.4.1.7.1??3.4.1.7.2??3.4.1.7.3??3.4.1.7.4??3.4.1.8.1??3.4.1.8.2??3.4.1.8.3??3.4.1.8.4

3.4.2.1.1??3.4.2.1.2??3.4.2.1.3??3.4.2.1.4??3.4.2.2.1??3.4.2.2.2??3.4.2.2.3??3.4.2.2.4

3.4.2.3.1??3.4.2.3.2??3.4.2.3.3??3.4.2.3.4??3.4.2.4.1??3.4.2.4.2??3.4.2.4.3??3.4.2.4.4

3.4.2.5.1??3.4.2.5.2??3.4.2.5.3??3.4.2.5.4??3.4.2.6.1??3.4.2.6.2??3.4.2.6.3??3.4.2.6.4

3.4.2.7.1??3.4.2.7.2??3.4.2.7.3??3.4.2.7.4??3.4.2.8.1??3.4.2.8.2??3.4.2.8.3??3.4.2.8.4

3.4.3.1.1??3.4.3.1.2??3.4.3.1.3??3.4.3.1.4??3.4.3.2.1??3.4.3.2.2??3.4.3.2.3??3.4.3.2.4

3.4.3.3.1??3.4.3.3.2??3.4.3.3.3??3.4.3.3.4??3.4.3.4.1??3.4.3.4.2??3.4.3.4.3??3.4.3.4.4

3.4.3.5.1??3.4.3.5.2??3.4.3.5.3??3.4.3.5.4??3.4.3.6.1??3.4.3.6.2??3.4.3.6.3??3.4.3.6.4

3.4.3.7.1??3.4.3.7.2??3.4.3.7.3??3.4.3.7.4??3.4.3.8.1??3.4.3.8.2??3.4.3.8.3??3.4.3.8.4

3.4.4.1.1??3.4.4.1.2??3.4.4.1.3??3.4.4.1.4??3.4.4.2.1??3.4.4.2.2??3.4.4.2.3??3.4.4.2.4

3.4.4.3.1??3.4.4.3.2??3.4.4.3.3??3.4.4.3.4??3.4.4.4.1??3.4.4.4.2??3.4.4.4.3??3.4.4.4.4

3.4.4.5.1??3.4.4.5.2??3.4.4.5.3??3.4.4.5.4??3.4.4.6.1??3.4.4.6.2??3.4.4.6.3??3.4.4.6.4

3.4.4.7.1??3.4.4.7.2??3.4.4.7.3??3.4.4.7.4??3.4.4.8.1??3.4.4.8.2??3.4.4.8.3??3.4.4.8.4

3.5.1.1.1??3.5.1.1.2??3.5.1.1.3??3.5.1.1.4??3.5.1.2.1??3.5.1.2.2??3.5.1.2.3??3.5.1.2.4

3.5.1.3.1??3.5.1.3.2??3.5.1.3.3??3.5.1.3.4??3.5.1.4.1??3.5.1.4.2??3.5.1.4.3??3.5.1.4.4

Table 3-is continuous

3.5.1.5.1??3.5.1.5.2??3.5.1.5.3??3.5.1.5.4??3.5.1.6.1??3.5.1.6.2??3.5.1.6.3??3.5.1.6.4

3.5.1.7.1??3.5.1.7.2??3.5.1.7.3??3.5.1.7.4??3.5.1.8.1??3.5.1.8.2??3.5.1.8.3??3.5.1.8.4

3.5.2.1.1??3.5.2.1.2??3.5.2.1.3??3.5.2.1.4??3.5.2.2.1??3.5.2.2.2??3.5.2.2.3??3.5.2.2.4

3.5.2.3.1??3.5.2.3.2??3.5.2.3.3??3.5.2.3.4??3.5.2.4.1??3.5.2.4.2??3.5.2.4.3??3.5.2.4.4

3.5.2.5.1??3.5.2.5.2??3.5.2.5.3??3.5.2.5.4??3.5.2.6.1??3.5.2.6.2??3.5.2.6.3??3.5.2.6.4

3.5.2.7.1??3.5.2.7.2??3.5.2.7.3??3.5.2.7.4??3.5.2.8.1??3.5.2.8.2??3.5.2.8.3??3.5.2.8.4

3.5.3.1.1??3.5.3.1.2??3.5.3.1.3??3.5.3.1.4??3.5.3.2.1??3.5.3.2.2??3.5.3.2.3??3.5.3.2.4

3.5.3.3.1??3.5.3.3.2??3.5.3.3.3??3.5.3.3.4??3.5.3.4.1??3.5.3.4.2??3.5.3.4.3??3.5.3.4.4

3.5.3.5.1??3.5.3.5.2??3.5.3.5.3??3.5.3.5.4??3.5.3.6.1??3.5.3.6.2??3.5.3.6.3??3.5.3.6.4

3.5.3.7.1??3.5.3.7.2??3.5.3.7.3??3.5.3.7.4??3.5.3.8.1??3.5.3.8.2??3.5.3.8.3??3.5.3.8.4

3.5.4.1.1??3.5.4.1.2??3.5.4.1.3??3.5.4.1.4??3.5.4.2.1??3.5.4.2.2??3.5.4.2.3??3.5.4.2.4

3.5.4.3.1??3.5.4.3.2??3.5.4.3.3??3.5.4.3.4??3.5.4.4.1??3.5.4.4.2??3.5.4.4.3??3.5.4.4.4

3.5.4.5.1??3.5.4.5.2??3.5.4.5.3??3.5.4.5.4??3.5.4.6.1??3.5.4.6.2??3.5.4.6.3??3.5.4.6.4

3.5.4.7.1??3.5.4.7.2??3.5.4.7.3??3.5.4.7.4??3.5.4.8.1??3.5.4.8.2??3.5.4.8.3??3.5.4.8.4

3.6.1.1.1??3.6.1.1.2??3.6.1.1.3??3.6.1.1.4??3.6.1.2.1??3.6.1.2.2??3.6.1.2.3??3.6.1.2.4

3.6.1.3.1??3.6.1.3.2??3.6.1.3.3??3.6.1.3.4??3.6.1.4.1??3.6.1.4.2??3.6.1.4.3??3.6.1.4.4

3.6.1.5.1??3.6.1.5.2??3.6.1.5.3??3.6.1.5.4??3.6.1.6.1??3.6.1.6.2??3.6.1.6.3??3.6.1.6.4

3.6.1.7.1??3.6.1.7.2??3.6.1.7.3??3.6.1.7.4??3.6.1.8.1??3.6.1.8.2??3.6.1.8.3??3.6.1.8.4

3.6.2.1.1??3.6.2.1.2??3.6.2.1.3??3.6.2.1.4??3.6.2.2.1??3.6.2.2.2??3.6.2.2.3??3.6.2.2.4

3.6.2.3.1??3.6.2.3.2??3.6.2.3.3??3.6.2.3.4??3.6.2.4.1??3.6.2.4.2??3.6.2.4.3??3.6.2.4.4

3.6.2.5.1??3.6.2.5.2??3.6.2.5.3??3.6.2.5.4??3.6.2.6.1??3.6.2.6.2??3.6.2.6.3??3.6.2.6.4

3.6.2.7.1??3.6.2.7.2??3.6.2.7.3??3.6.2.7.4??3.6.2.8.1??3.6.2.8.2??3.6.2.8.3??3.6.2.8.4

3.6.3.1.1??3.6.3.1.2??3.6.3.1.3??3.6.3.1.4??3.6.3.2.1??3.6.3.2.2??3.6.3.2.3??3.6.3.2.4

3.6.3.3.1??3.6.3.3.2??3.6.3.3.3??3.6.3.3.4??3.6.3.4.1??3.6.3.4.2??3.6.3.4.3??3.6.3.4.4

3.6.3.5.1??3.6.3.5.2??3.6.3.5.3??3.6.3.5.4??3.6.3.6.1??3.6.3.6.2??3.6.3.6.3??3.6.3.6.4

3.6.3.7.1??3.6.3.7.2??3.6.3.7.3??3.6.3.7.4??3.6.3.8.1??3.6.3.8.2??3.6.3.8.3??3.6.3.8.4

3.6.4.1.1??3.6.4.1.2??3.6.4.1.3??3.6.4.1.4??3.6.4.2.1??3.6.4.2.2??3.6.4.2.3??3.6.4.2.4

3.6.4.3.1??3.6.4.3.2??3.6.4.3.3??3.6.4.3.4??3.6.4.4.1??3.6.4.4.2??3.6.4.4.3??3.6.4.4.4

3.6.4.5.1??3.6.4.5.2??3.6.4.5.3??3.6.4.5.4??3.6.4.6.1??3.6.4.6.2??3.6.4.6.3??3.6.4.6.4

3.6.4.7.1??3.6.4.7.2??3.6.4.7.3??3.6.4.7.4??3.6.4.8.1??3.6.4.8.2??3.6.4.8.3??3.6.4.8.4

3.7.1.1.1??3.7.1.1.2??3.7.1.1.3??3.7.1.1.4??3.7.1.2.1??3.7.1.2.2??3.7.1.2.3??3.7.1.2.4

3.7.1.3.1??3.7.1.3.2??3.7.1.3.3??3.7.1.3.4??3.7.1.4.1??3.7.1.4.2??3.7.1.4.3??3.7.1.4.4

3.7.1.5.1??3.7.1.5.2??3.7.1.5.3??3.7.1.5.4??3.7.1.6.1??3.7.1.6.2??3.7.1.6.3??3.7.1.6.4

3.7.1.7.1??3.7.1.7.2??3.7.1.7.3??3.7.1.7.4??3.7.1.8.1??3.7.1.8.2??3.7.1.8.3??3.7.1.8.4

3.7.2.1.1??3.7.2.1.2??3.7.2.1.3??3.7.2.1.4??3.7.2.2.1??3.7.2.2.2??3.7.2.2.3??3.7.2.2.4

3.7.2.3.1??3.7.2.3.2??3.7.2.3.3??3.7.2.3.4??3.7.2.4.1??3.7.2.4.2??3.7.2.4.3??3.7.2.4.4

3.7.2.5.1??3.7.2.5.2??3.7.2.5.3??3.7.2.5.4??3.7.2.6.1??3.7.2.6.2??3.7.2.6.3??3.7.2.6.4

3.7.2.7.1??3.7.2.7.2??3.7.2.7.3??3.7.2.7.4??3.7.2.8.1??3.7.2.8.2??3.7.2.8.3??3.7.2.8.4

3.7.3.1.1??3.7.3.1.2??3.7.3.1.3??3.7.3.1.4??3.7.3.2.1??3.7.3.2.2??3.7.3.2.3??3.7.3.2.4

3.7.3.3.1??3.7.3.3.2??3.7.3.3.3??3.7.3.3.4??3.7.3.4.1??3.7.3.4.2??3.7.3.4.3??3.7.3.4.4

3.7.3.5.1??3.7.3.5.2??3.7.3.5.3??3.7.3.5.4??3.7.3.6.1??3.7.3.6.2??3.7.3.6.3??3.7.3.6.4

3.7.3.7.1??3.7.3.7.2??3.7.3.7.3??3.7.3.7.4??3.7.3.8.1??3.7.3.8.2??3.7.3.8.3??3.7.3.8.4

3.7.4.1.1??3.7.4.1.2??3.7.4.1.3??3.7.4.1.4??3.7.4.2.1??3.7.4.2.2??3.7.4.2.3??3.7.4.2.4

3.7.4.3.1??3.7.4.3.2??3.7.4.3.3??3.7.4.3.4??3.7.4.4.1??3.7.4.4.2??3.7.4.4.3??3.7.4.4.4

3.7.4.5.1??3.7.4.5.2??3.7.4.5.3??3.7.4.5.4??3.7.4.6.1??3.7.4.6.2??3.7.4.6.3??3.7.4.6.4

3.7.4.7.1??3.7.4.7.2??3.7.4.7.3??3.7.4.7.4??3.7.4.8.1??3.7.4.8.2??3.7.4.8.3??3.7.4.8.4

Table 3-is continuous

3.8.1.1.1??3.8.1.1.2??3.8.1.1.3??3.8.1.1.4??3.8.1.2.1??3.8.1.2.2??3.8.1.2.3??3.8.1.2.4

3.8.1.3.1??3.8.1.3.2??3.8.1.3.3??3.8.1.3.4??3.8.1.4.1??3.8.1.4.2??3.8.1.4.3??3.8.1.4.4

3.8.1.5.1??3.8.1.5.2??3.8.1.5.3??3.8.1.5.4??3.8.1.6.1??3.8.1.6.2??3.8.1.6.3??3.8.1.6.4

3.8.1.7.1??3.8.1.7.2??3.8.1.7.3??3.8.1.7.4??3.8.1.8.1??3.8.1.8.2??3.8.1.8.3??3.8.1.8.4

3.8.2.1.1??3.8.2.1.2??3.8.2.1.3??3.8.2.1.4??3.8.2.2.1??3.8.2.2.2??3.8.2.2.3??3.8.2.2.4

3.8.2.3.1??3.8.2.3.2??3.8.2.3.3??3.8.2.3.4??3.8.2.4.1??3.8.2.4.2??3.8.2.4.3??3.8.2.4.4

3.8.2.5.1??3.8.2.5.2??3.8.2.5.3??3.8.2.5.4??3.8.2.6.1??3.8.2.6.2??3.8.2.6.3??3.8.2.6.4

3.8.2.7.1??3.8.2.7.2??3.8.2.7.3??3.8.2.7.4??3.8.2.8.1??3.8.2.8.2??3.8.2.8.3??3.8.2.8.4

3.8.3.1.1??3.8.3.1.2??3.8.3.1.3??3.8.3.1.4??3.8.3.2.1??3.8.3.2.2??3.8.3.2.3??3.8.3.2.4

3.8.3.3.1??3.8.3.3.2??3.8.3.3.3??3.8.3.3.4??3.8.3.4.1??3.8.3.4.2??3.8.3.4.3??3.8.3.4.4

3.8.3.5.1??3.8.3.5.2??3.8.3.5.3??3.8.3.5.4??3.8.3.6.1??3.8.3.6.2??3.8.3.6.3??3.8.3.6.4

3.8.3.7.1??3.8.3.7.2??3.8.3.7.3??3.8.3.7.4??3.8.3.8.1??3.8.3.8.2??3.8.3.8.3??3.8.3.8.4

3.8.4.1.1??3.8.4.1.2??3.8.4.1.3??3.8.4.1.4??3.8.4.2.1??3.8.4.2.2??3.8.4.2.3??3.8.4.2.4

3.8.4.3.1??3.8.4.3.2??3.8.4.3.3??3.8.4.3.4??3.8.4.4.1??3.8.4.4.2??3.8.4.4.3??3.8.4.4.4

3.8.4.5.1??3.8.4.5.2??3.8.4.5.3??3.8.4.5.4??3.8.4.6.1??3.8.4.6.2??3.8.4.6.3??3.8.4.6.4

3.8.4.7.1??3.8.4.7.2??3.8.4.7.3??3.8.4.7.4??3.8.4.8.1??3.8.4.8.2??3.8.4.8.3??3.8.4.8.4

4.1.1.1.1??4.1.1.1.2??4.1.1.1.3??4.1.1.1.4??4.1.1.2.1??4.1.1.2.2??4.1.1.2.3??4.1.1.2.4

4.1.1.3.1??4.1.1.3.2??4.1.1.3.3??4.1.1.3.4??4.1.1.4.1??4.1.1.4.2??4.1.1.4.3??4.1.1.4.4

4.1.1.5.1??4.1.1.5.2??4.1.1.5.3??4.1.1.5.4??4.1.1.6.1??4.1.1.6.2??4.1.1.6.3??4.1.1.6.4

4.1.1.7.1??4.1.1.7.2??4.1.1.7.3??4.1.1.7.4??4.1.1.8.1??4.1.1.8.2??4.1.1.8.3??4.1.1.8.4

4.1.2.1.1??4.1.2.1.2??4.1.2.1.3??4.1.2.1.4??4.1.2.2.1??4.1.2.2.2??4.1.2.2.3??4.1.2.2.4

4.1.2.3.1??4.1.2.3.2??4.1.2.3.3??4.1.2.3.4??4.1.2.4.1??4.1.2.4.2??4.1.2.4.3??4.1.2.4.4

4.1.2.5.1??4.1.2.5.2??4.1.2.5.3??4.1.2.5.4??4.1.2.6.1??4.1.2.6.2??4.1.2.6.3??4.1.2.6.4

4.1.2.7.1??4.1.2.7.2??4.1.2.7.3??4.1.2.7.4??4.1.2.8.1??4.1.2.8.2??4.1.2.8.3??4.1.2.8.4

4.1.3.1.1??4.1.3.1.2??4.1.3.1.3??4.1.3.1.4??4.1.3.2.1??4.1.3.2.2??4.1.3.2.3??4.1.3.2.4

4.1.3.3.1??4.1.3.3.2??4.1.3.3.3??4.1.3.3.4??4.1.3.4.1??4.1.3.4.2??4.1.3.4.3??4.1.3.4.4

4.1.3.5.1??4.1.3.5.2??4.1.3.5.3??4.1.3.5.4??4.1.3.6.1??4.1.3.6.2??4.1.3.6.3??4.1.3.6.4

4.1.3.7.1??4.1.3.7.2??4.1.3.7.3??4.1.3.7.4??4.1.3.8.1??4.1.3.8.2??4.1.3.8.3??4.1.3.8.4

4.1.4.1.1??4.1.4.1.2??4.1.4.1.3??4.1.4.1.4??4.1.4.2.1??4.1.4.2.2??4.1.4.2.3??4.1.4.2.4

4.1.4.3.1??4.1.4.3.2??4.1.4.3.3??4.1.4.3.4??4.1.4.4.1??4.1.4.4.2??4.1.4.4.3??4.1.4.4.4

4.1.4.5.1??4.1.4.5.2??4.1.4.5.3??4.1.4.5.4??4.1.4.6.1??4.1.4.6.2??4.1.4.6.3??4.1.4.6.4

4.1.4.7.1??4.1.4.7.2??4.1.4.7.3??4.1.4.7.4??4.1.4.8.1??4.1.4.8.2??4.1.4.8.3??4.1.4.8.4

4.2.1.1.1??4.2.1.1.2??4.2.1.1.3??4.2.1.1.4??4.2.1.2.1??4.2.1.2.2??4.2.1.2.3??4.2.1.2.4

4.2.1.3.1??4.2.1.3.2??4.2.1.3.3??4.2.1.3.4??4.2.1.4.1??4.2.1.4.2??4.2.1.4.3??4.2.1.4.4

4.2.1.5.1??4.2.1.5.2??4.2.1.5.3??4.2.1.5.4??4.2.1.6.1??4.2.1.6.2??4.2.1.6.3??4.2.1.6.4

4.2.1.7.1??4.2.1.7.2??4.2.1.7.3??4.2.1.7.4??4.2.1.8.1??4.2.1.8.2??4.2.1.8.3??4.2.1.8.4

4.2.2.1.1??4.2.2.1.2??4.2.2.1.3??4.2.2.1.4??4.2.2.2.1??4.2.2.2.2??4.2.2.2.3??4.2.2.2.4

4.2.2.3.1??4.2.2.3.2??4.2.2.3.3??4.2.2.3.4??4.2.2.4.1??4.2.2.4.2??4.2.2.4.3??4.2.2.4.4

4.2.2.5.1??4.2.2.5.2??4.2.2.5.3??4.2.2.5.4??4.2.2.6.1??4.2.2.6.2??4.2.2.6.3??4.2.2.6.4

4.2.2.7.1??4.2.2.7.2??4.2.2.7.3??4.2.2.7.4??4.2.2.8.1??4.2.2.8.2??4.2.2.8.3??4.2.2.8.4

4.2.3.1.1??4.2.3.1.2??4.2.3.1.3??4.2.3.1.4??4.2.3.2.1??4.2.3.2.2??4.2.3.2.3??4.2.3.2.4

4.2.3.3.1??4.2.3.3.2??4.2.3.3.3??4.2.3.3.4??4.2.3.4.1??4.2.3.4.2??4.2.3.4.3??4.2.3.4.4

4.2.3.5.1??4.2.3.5.2??4.2.3.5.3??4.2.3.5.4??4.2.3.6.1??4.2.3.6.2??4.2.3.6.3??4.2.3.6.4

4.2.3.7.1??4.2.3.7.2??4.2.3.7.3??4.2.3.7.4??4.2.3.8.1??4.2.3.8.2??4.2.3.8.3??4.2.3.8.4

4.2.4.1.1??4.2.4.1.2??4.2.4.1.3??4.2.4.1.4??4.2.4.2.1??4.2.4.2.2??4.2.4.2.3??4.2.4.2.4

4.2.4.3.1??4.2.4.3.2??4.2.4.3.3??4.2.4.3.4??4.2.4.4.1??4.2.4.4.2??4.2.4.4.3??4.2.4.4.4

Table 3-is continuous

4.2.4.5.1??4.2.4.5.2??4.2.4.5.3??4.2.4.5.4??4.2.4.6.1??4.2.4.6.2??4.2.4.6.3??4.2.4.6.4

4.2.4.7.1??4.2.4.7.2??4.2.4.7.3??4.2.4.7.4??4.2.4.8.1??4.2.4.8.2??4.2.4.8.3??4.2.4.8.4

4.3.1.1.1??4.3.1.1.2??4.3.1.1.3??4.3.1.1.4??4.3.1.2.1??4.3.1.2.2??4.3.1.2.3??4.3.1.2.4

4.3.1.3.1??4.3.1.3.2??4.3.1.3.3??4.3.1.3.4??4.3.1.4.1??4.3.1.4.2??4.3.1.4.3??4.3.1.4.4

4.3.1.5.1??4.3.1.5.2??4.3.1.5.3??4.3.1.5.4??4.3.1.6.1??4.3.1.6.2??4.3.1.6.3??4.3.1.6.4

4.3.1.7.1??4.3.1.7.2??4.3.1.7.3??4.3.1.7.4??4.3.1.8.1??4.3.1.8.2??4.3.1.8.3??4.3.1.8.4

4.3.2.1.1??4.3.2.1.2??4.3.2.1.3??4.3.2.1.4??4.3.2.2.1??4.3.2.2.2??4.3.2.2.3??4.3.2.2.4

4.3.2.3.1??4.3.2.3.2??4.3.2.3.3??4.3.2.3.4??4.3.2.4.1??4.3.2.4.2??4.3.2.4.3??4.3.2.4.4

4.3.2.5.1??4.3.2.5.2??4.3.2.5.3??4.3.2.5.4??4.3.2.6.1??4.3.2.6.2??4.3.2.6.3??4.3.2.6.4

4.3.2.7.1??4.3.2.7.2??4.3.2.7.3??4.3.2.7.4??4.3.2.8.1??4.3.2.8.2??4.3.2.8.3??4.3.2.8.4

4.3.3.1.1??4.3.3.1.2??4.3.3.1.3??4.3.3.1.4??4.3.3.2.1??4.3.3.2.2??4.3.3.2.3??4.3.3.2.4

4.3.3.3.1??4.3.3.3.2??4.3.3.3.3??4.3.3.3.4??4.3.3.4.1??4.3.3.4.2??4.3.3.4.3??4.3.3.4.4

4.3.3.5.1??4.3.3.5.2??4.3.3.5.3??4.3.3.5.4??4.3.3.6.1??4.3.3.6.2??4.3.3.6.3??4.3.3.6.4

4.3.3.7.1??4.3.3.7.2??4.3.3.7.3??4.3.3.7.4??4.3.3.8.1??4.3.3.8.2??4.3.3.8.3??4.3.3.8.4

4.3.4.1.1??4.3.4.1.2??4.3.4.1.3??4.3.4.1.4??4.3.4.2.1??4.3.4.2.2??4.3.4.2.3??4.3.4.2.4

4.3.4.3.1??4.3.4.3.2??4.3.4.3.3??4.3.4.3.4??4.3.4.4.1??4.3.4.4.2??4.3.4.4.3??4.3.4.4.4

4.3.4.5.1??4.3.4.5.2??4.3.4.5.3??4.3.4.5.4??4.3.4.6.1??4.3.4.6.2??4.3.4.6.3??4.3.4.6.4

4.3.4.7.1??4.3.4.7.2??4.3.4.7.3??4.3.4.7.4??4.3.4.8.1??4.3.4.8.2??4.3.4.8.3??4.3.4.8.4

4.4.1.1.1??4.4.1.1.2??4.4.1.1.3??4.4.1.1.4??4.4.1.2.1??4.4.1.2.2??4.4.1.2.3??4.4.1.2.4

4.4.1.3.1??4.4.1.3.2??4.4.1.3.3??4.4.1.3.4??4.4.1.4.1??4.4.1.4.2??4.4.1.4.3??4.4.1.4.4

4.4.1.5.1??4.4.1.5.2??4.4.1.5.3??4.4.1.5.4??4.4.1.6.1??4.4.1.6.2??4.4.1.6.3??4.4.1.6.4

4.4.1.7.1??4.4.1.7.2??4.4.1.7.3??4.4.1.7.4??4.4.1.8.1??4.4.1.8.2??4.4.1.8.3??4.4.1.8.4

4.4.2.1.1??4.4.2.1.2??4.4.2.1.3??4.4.2.1.4??4.4.2.2.1??4.4.2.2.2??4.4.2.2.3??4.4.2.2.4

4.4.2.3.1??4.4.2.3.2??4.4.2.3.3??4.4.2.3.4??4.4.2.4.1??4.4.2.4.2??4.4.2.4.3??4.4.2.4.4

4.4.2.5.1??4.4.2.5.2??4.4.2.5.3??4.4.2.5.4??4.4.2.6.1??4.4.2.6.2??4.4.2.6.3??4.4.2.6.4

4.4.2.7.1??4.4.2.7.2??4.4.2.7.3??4.4.2.7.4??4.4.2.8.1??4.4.2.8.2??4.4.2.8.3??4.4.2.8.4

4.4.3.1.1??4.4.3.1.2??4.4.3.1.3??4.4.3.1.4??4.4.3.2.1??4.4.3.2.2??4.4.3.2.3??4.4.3.2.4

4.4.3.3.1??4.4.3.3.2??4.4.3.3.3??4.4.3.3.4??4.4.3.4.1??4.4.3.4.2??4.4.3.4.3??4.4.3.4.4

4.4.3.5.1??4.4.3.5.2??4.4.3.5.3??4.4.3.5.4??4.4.3.6.1??4.4.3.6.2??4.4.3.6.3??4.4.3.6.4

4.4.3.7.1??4.4.3.7.2??4.4.3.7.3??4.4.3.7.4??4.4.3.8.1??4.4.3.8.2??4.4.3.8.3??4.4.3.8.4

4.4.4.1.1??4.4.4.1.2??4.4.4.1.3??4.4.4.1.4??4.4.4.2.1??4.4.4.2.2??4.4.4.2.3??4.4.4.2.4

4.4.4.3.1??4.4.4.3.2??4.4.4.3.3??4.4.4.3.4??4.4.4.4.1??4.4.4.4.2??4.4.4.4.3??4.4.4.4.4

4.4.4.5.1??4.4.4.5.2??4.4.4.5.3??4.4.4.5.4??4.4.4.6.1??4.4.4.6.2??4.4.4.6.3??4.4.4.6.4

4.4.4.7.1??4.4.4.7.2??4.4.4.7.3??4.4.4.7.4??4.4.4.8.1??4.4.4.8.2??4.4.4.8.3??4.4.4.8.4

4.5.1.1.1??4.5.1.1.2??4.5.1.1.3??4.4.5.1.4??4.5.1.2.1??4.5.1.2.2??4.5.1.2.3??4.5.1.2.4

4.5.1.3.1??4.5.1.3.2??4.5.1.3.3??4.5.1.3.4??4.5.1.4.1??4.5.1.4.2??4.5.1.4.3??4.5.1.4.4

4.5.1.5.1??4.5.1.5.2??4.5.1.5.3??4.5.1.5.4??4.5.1.6.1??4.5.1.6.2??4.5.1.6.3??4.5.1.6.4

4.5.1.7.1??4.5.1.7.2??4.5.1.7.3??4.5.1.7.4??4.5.1.8.1??4.5.1.8.2??4.5.1.8.3??4.5.1.8.4

4.5.2.1.1??4.5.2.1.2??4.5.2.1.3??4.5.2.1.4??4.5.2.2.1??4.5.2.2.2??4.5.2.2.3??4.5.2.2.4

4.5.2.3.1??4.5.2.3.2??4.5.2.3.3??4.5.2.3.4??4.5.2.4.1??4.5.2.4.2??4.5.2.4.3??4.5.2.4.4

4.5.2.5.1??4.5.2.5.2??4.5.2.5.3??4.5.2.5.4??4.5.2.6.1??4.5.2.6.2??4.5.2.6.3??4.5.2.6.4

4.5.2.7.1??4.5.2.7.2??4.5.2.7.3??4.5.2.7.4??4.5.2.8.1??4.5.2.8.2??4.5.2.8.3??4.5.2.8.4

4.5.3.1.1??4.5.3.1.2??4.5.3.1.3??4.5.3.1.4??4.5.3.2.1??4.5.3.2.2??4.5.3.2.3??4.5.3.2.4

4.5.3.3.1??4.5.3.3.2??4.5.3.3.3??4.5.3.3.4??4.5.3.4.1??4.5.3.4.2??4.5.3.4.3??4.5.3.4.4

4.5.3.5.1??4.5.3.5.2??4.5.3.5.3??4.5.3.5.4??4.5.3.6.1??4.5.3.6.2??4.5.3.6.3??4.5.3.6.4

4.5.3.7.1??4.5.3.7.2??4.5.3.7.3??4.5.3.7.4??4.5.3.8.1??4.5.3.8.2??4.5.3.8.3??4.5.3.8.4

Table 3-is continuous

4.5.4.1.1??4.5.4.1.2??4.5.4.1.3??4.5.4.1.4??4.5.4.2.1??4.5.4.2.2??4.5.4.2.3??4.5.4.2.4

4.5.4.3.1??4.5.4.3.2??4.5.4.3.3??4.5.4.3.4??4.5.4.4.1??4.5.4.4.2??4.5.4.4.3??4.5.4.4.4

4.5.4.5.1??4.5.4.5.2??4.5.4.5.3??4.5.4.5.4??4.5.4.6.1??4.5.4.6.2??4.5.4.6.3??4.5.4.6.4

4.5.4.7.1??4.5.4.7.2??4.5.4.7.3??4.5.4.7.4??4.5.4.8.1??4.5.4.8.2??4.5.4.8.3??4.5.4.8.4

4.6.1.1.1??4.6.1.1.2??4.6.1.1.3??4.6.1.1.4??4.6.1.2.1??4.6.1.2.2??4.6.1.2.3??4.6.1.2.4

4.6.1.3.1??4.6.1.3.2??4.6.1.3.3??4.6.1.3.4??4.6.1.4.1??4.6.1.4.2??4.6.1.4.3??4.6.1.4.4

4.6.1.5.1??4.6.1.5.2??4.6.1.5.3??4.6.1.5.4??4.6.1.6.1??4.6.1.6.2??4.6.1.6.3??4.6.1.6.4

4.6.1.7.1??4.6.1.7.2??4.6.1.7.3??4.6.1.7.4??4.6.1.8.1??4.6.1.8.2??4.6.1.8.3??4.6.1.8.4

4.6.2.1.1??4.6.2.1.2??4.6.2.1.3??4.6.2.1.4??4.6.2.2.1??4.6.2.2.2??4.6.2.2.3??4.6.2.2.4

4.6.2.3.1??4.6.2.3.2??4.6.2.3.3??4.6.2.3.4??4.6.2.4.1??4.6.2.4.2??4.6.2.4.3??4.6.2.4.4

4.6.2.5.1??4.6.2.5.2??4.6.2.5.3??4.6.2.5.4??4.6.2.6.1??4.6.2.6.2??4.6.2.6.3??4.6.2.6.4

4.6.2.7.1??4.6.2.7.2??4.6.2.7.3??4.6.2.7.4??4.6.2.8.1??4.6.2.8.2??4.6.2.8.3??4.6.2.8.4

4.6.3.1.1??4.6.3.1.2??4.6.3.1.3??4.6.3.1.4??4.6.3.2.1??4.6.3.2.2??4.6.3.2.3??4.6.3.2.4

4.6.3.3.1??4.6.3.3.2??4.6.3.3.3??4.6.3.3.4??4.6.3.4.1??4.6.3.4.2??4.6.3.4.3??4.6.3.4.4

4.6.3.5.1??4.6.3.5.2??4.6.3.5.3??4.6.3.5.4??4.6.3.6.1??4.6.3.6.2??4.6.3.6.3??4.6.3.6.4

4.6.3.7.1??4.6.3.7.2??4.6.3.7.3??4.6.3.7.4??4.6.3.8.1??4.6.3.8.2??4.6.3.8.3??4.6.3.8.4

4.6.4.1.1??4.6.4.1.2??4.6.4.1.3??4.6.4.1.4??4.6.4.2.1??4.6.4.2.2??4.6.4.2.3??4.6.4.2.4

4.6.4.3.1??4.6.4.3.2??4.6.4.3.3??4.6.4.3.4??4.6.4.4.1??4.6.4.4.2??4.6.4.4.3??4.6.4.4.4

4.6.4.5.1??4.6.4.5.2??4.6.4.5.3??4.6.4.5.4??4.6.4.6.1??4.6.4.6.2??4.6.4.6.3??4.6.4.6.4

4.6.4.7.1??4.6.4.7.2??4.6.4.7.3??4.6.4.7.4??4.6.4.8.1??4.6.4.8.2??4.6.4.8.3??4.6.4.8.4

4.7.1.1.1??4.7.1.1.2??4.7.1.1.3??4.7.1.1.4??4.7.1.2.1??4.7.1.2.2??4.7.1.2.3??4.7.1.2.4

4.7.1.3.1??4.7.1.3.2??4.7.1.3.3??4.7.1.3.4??4.7.1.4.1??4.7.1.4.2??4.7.1.4.3??4.7.1.4.4

4.7.1.5.1??4.7.1.5.2??4.7.1.5.3??4.7.1.5.4??4.7.1.6.1??4.7.1.6.2??4.7.1.6.3??4.7.1.6.4

4.7.1.7.1??4.7.1.7.2??4.7.1.7.3??4.7.1.7.4??4.7.1.8.1??4.7.1.8.2??4.7.1.8.3??4.7.1.8.4

4.7.2.1.1??4.7.2.1.2??4.7.2.1.3??4.7.2.1.4??4.7.2.2.1??4.7.2.2.2??4.7.2.2.3??4.7.2.2.4

4.7.2.3.1??4.7.2.3.2??4.7.2.3.3??4.7.2.3.4??4.7.2.4.1??4.7.2.4.2??4.7.2.4.3??4.7.2.4.4

4.7.2.5.1??4.7.2.5.2??4.7.2.5.3??4.7.2.5.4??4.7.2.6.1??4.7.2.6.2??4.7.2.6.3??4.7.2.6.4

4.7.2.7.1??4.7.2.7.2??4.7.2.7.3??4.7.2.7.4??4.7.2.8.1??4.7.2.8.2??4.7.2.8.3??4.7.2.8.4

4.7.3.1.1??4.7.3.1.2??4.7.3.1.3??4.7.3.1.4??4.7.3.2.1??4.7.3.2.2??4.7.3.2.3??4.7.3.2.4

4.7.3.3.1??4.7.3.3.2??4.7.3.3.3??4.7.3.3.4??4.7.3.4.1??4.7.3.4.2??4.7.3.4.3??4.7.3.4.4

4.7.3.5.1??4.7.3.5.2??4.7.3.5.3??4.7.3.5.4??4.7.3.6.1??4.7.3.6.2??4.7.3.6.3??4.7.3.6.4

4.7.3.7.1??4.7.3.7.2??4.7.3.7.3??4.7.3.7.4??4.7.3.8.1??4.7.3.8.2??4.7.3.8.3??4.7.3.8.4

4.7.4.1.1??4.7.4.1.2??4.7.4.1.3??4.7.4.1.4??4.7.4.2.1??4.7.4.2.2??4.7.4.2.3??4.7.4.2.4

4.7.4.3.1??4.7.4.3.2??4.7.4.3.3??4.7.4.3.4??4.7.4.4.1??4.7.4.4.2??4.7.4.4.3??4.7.4.4.4

4.7.4.5.1??4.7.4.5.2??4.7.4.5.3??4.7.4.5.4??4.7.4.6.1??4.7.4.6.2??4.7.4.6.3??4.7.4.6.4

4.7.4.7.1??4.7.4.7.2??4.7.4.7.3??4.7.4.7.4??4.7.4.8.1??4.7.4.8.2??4.7.4.8.3??4.7.4.8.4

4.8.1.1.1??4.8.1.1.2??4.8.1.1.3??4.8.1.1.4??4.8.1.2.1??4.8.1.2.2??4.8.1.2.3??4.8.1.2.4

4.8.1.3.1??4.8.1.3.2??4.8.1.3.3??4.8.1.3.4??4.8.1.4.1??4.8.1.4.2??4.8.1.4.3??4.8.1.4.4

4.8.1.5.1??4.8.1.5.2??4.8.1.5.3??4.8.1.5.4??4.8.1.6.1??4.8.1.6.2??4.8.1.6.3??4.8.1.6.4

4.8.1.7.1??4.8.1.7.2??4.8.1.7.3??4.8.1.7.4??4.8.1.8.1??4.8.1.8.2??4.8.1.8.3??4.8.1.8.4

4.8.2.1.1??4.8.2.1.2??4.8.2.1.3??4.8.2.1.4??4.8.2.2.1??4.8.2.2.2??4.8.2.2.3??4.8.2.2.4

4.8.2.3.1??4.8.2.3.2??4.8.2.3.3??4.8.2.3.4??4.8.2.4.1??4.8.2.4.2??4.8.2.4.3??4.8.2.4.4

4.8.2.5.1??4.8.2.5.2??4.8.2.5.3??4.8.2.5.4??4.8.2.6.1??4.8.2.6.2??4.8.2.6.3??4.8.2.6.4

4.8.2.7.1??4.8.2.7.2??4.8.2.7.3??4.8.2.7.4??4.8.2.8.1??4.8.2.8.2??4.8.2.8.3??4.8.2.8.4

4.8.3.1.1??4.8.3.1.2??4.8.3.1.3??4.8.3.1.4??4.8.3.2.1??4.8.3.2.2??4.8.3.2.3??4.8.3.2.4

4.8.3.3.1??4.8.3.3.2??4.8.3.3.3??4.8.3.3.4??4.8.3.4.1??4.8.3.4.2??4.8.3.4.3??4.8.3.4.4

Table 3-is continuous

4.8.3.5.1??4.8.3.5.2??4.8.3.5.3??4.8.3.5.4??4.8.3.6.1??4.8.3.6.2??4.8.3.6.3??4.8.3.6.4

4.8.3.7.1??4.8.3.7.2??4.8.3.7.3??4.8.3.7.4??4.8.3.8.1??4.8.3.8.2??4.8.3.8.3??4.8.3.8.4

4.8.4.1.1??4.8.4.1.2??4.8.4.1.3??4.8.4.1.4??4.8.4.2.1??4.8.4.2.2??4.8.4.2.3??4.8.4.2.4

4.8.4.3.1??4.8.4.3.2??4.8.4.3.3??4.8.4.3.4??4.8.4.4.1??4.8.4.4.2??4.8.4.4.3??4.8.4.4.4

4.8.4.5.1??4.8.4.5.2??4.8.4.5.3??4.8.4.5.4??4.8.4.6.1??4.8.4.6.2??4.8.4.6.3??4.8.4.6.4

4.8.4.7.1??4.8.4.7.2??4.8.4.7.3??4.8.4.7.4??4.8.4.8.1??4.8.4.8.2??4.8.4.8.3??4.8.4.8.4

5.1.1.1.1??5.1.1.1.2??5.1.1.1.3??5.1.1.1.4??5.1.1.2.1??5.1.1.2.2??5.1.1.2.3??5.1.1.2.4

5.1.1.3.1??5.1.1.3.2??5.1.1.3.3??5.1.1.3.4??5.1.1.4.1??5.1.1.4.2??5.1.1.4.3??5.1.1.4.4

5.1.1.5.1??5.1.1.5.2??5.1.1.5.3??5.1.1.5.4??5.1.1.6.1??5.1.1.6.2??5.1.1.6.3??5.1.1.6.4

5.1.1.7.1??5.1.1.7.2??5.1.1.7.3??5.1.1.7.4??5.1.1.8.1??5.1.1.8.2??5.1.1.8.3??5.1.1.8.4

5.1.2.1.1??5.1.2.1.2??5.1.2.1.3??5.1.2.1.4??5.1.2.2.1??5.1.2.2.2??5.1.2.2.3??5.1.2.2.4

5.1.2.3.1??5.1.2.3.2??5.1.2.3.3??5.1.2.3.4??5.1.2.4.1??5.1.2.4.2??5.1.2.4.3??5.1.2.4.4

5.1.2.5.1??5.1.2.5.2??5.1.2.5.3??5.1.2.5.4??5.1.2.6.1??5.1.2.6.2??5.1.2.6.3??5.1.2.6.4

5.1.2.7.1??5.1.2.7.2??5.1.2.7.3??5.1.2.7.4??5.1.2.8.1??5.1.2.8.2??5.1.2.8.3??5.1.2.8.4

5.1.3.1.1??5.1.3.1.2??5.1.3.1.3??5.1.3.1.4??5.1.3.2.1??5.1.3.2.2??5.1.3.2.3??5.1.3.2.4

5.1.3.3.1??5.1.3.3.2??5.1.3.3.3??5.1.3.3.4??5.1.3.4.1??5.1.3.4.2??5.1.3.4.3??5.1.3.4.4

5.1.3.5.1??5.1.3.5.2??5.1.3.5.3??5.1.3.5.4??5.1.3.6.1??5.1.3.6.2??5.1.3.6.3??5.1.3.6.4

5.1.3.7.1??5.1.3.7.2??5.1.3.7.3??5.1.3.7.4??5.1.3.8.1??5.1.3.8.2??5.1.3.8.3??5.1.3.8.4

5.1.4.1.1??5.1.4.1.2??5.1.4.1.3??5.1.4.1.4??5.1.4.2.1??5.1.4.2.2??5.1.4.2.3??5.1.4.2.4

5.1.4.3.1??5.1.4.3.2??5.1.4.3.3??5.1.4.3.4??5.1.4.4.1??5.1.4.4.2??5.1.4.4.3??5.1.4.4.4

5.1.4.5.1??5.1.4.5.2??5.1.4.5.3??5.1.4.5.4??5.1.4.6.1??5.1.4.6.2??5.1.4.6.3??5.1.4.6.4

5.1.4.7.1??5.1.4.7.2??5.1.4.7.3??5.1.4.7.4??5.1.4.8.1??5.1.4.8.2??5.1.4.8.3??5.1.4.8.4

5.2.1.1.1??5.2.1.1.2??5.2.1.1.3??5.2.1.1.4??5.2.1.2.1??5.2.1.2.2??5.2.1.2.3??5.2.1.2.4

5.2.1.3.1??5.2.1.3.2??5.2.1.3.3??5.2.1.3.4??5.2.1.4.1??5.2.1.4.2??5.2.1.4.3??5.2.1.4.4

5.2.1.5.1??5.2.1.5.2??5.2.1.5.3??5.2.1.5.4??5.2.1.6.1??5.2.1.6.2??5.2.1.6.3??5.2.1.6.4

5.2.1.7.1??5.2.1.7.2??5.2.1.7.3??5.2.1.7.4??5.2.1.8.1??5.2.1.8.2??5.2.1.8.3??5.2.1.8.4

5.2.2.1.1??5.2.2.1.2??5.2.2.1.3??5.2.2.1.4??5.2.2.2.1??5.2.2.2.2??5.2.2.2.3??5.2.2.2.4

5.2.2.3.1??5.2.2.3.2??5.2.2.3.3??5.2.2.3.4??5.2.2.4.1??5.2.2.4.2??5.2.2.4.3??5.2.2.4.4

5.2.2.5.1??5.2.2.5.2??5.2.2.5.3??5.2.2.5.4??5.2.2.6.1??5.2.2.6.2??5.2.2.6.3??5.2.2.6.4

5.2.2.7.1??5.2.2.7.2??5.2.2.7.3??5.2.2.7.4??5.2.2.8.1??5.2.2.8.2??5.2.2.8.3??5.2.2.8.4

5.2.3.1.1??5.2.3.1.2??5.2.3.1.3??5.2.3.1.4??5.2.3.2.1??5.2.3.2.2??5.2.3.2.3??5.2.3.2.4

5.2.3.3.1??5.2.3.3.2??5.2.3.3.3??5.2.3.3.4??5.2.3.4.1??5.2.3.4.2??5.2.3.4.3??5.2.3.4.4

5.2.3.5.1??5.2.3.5.2??5.2.3.5.3??5.2.3.5.4??5.2.3.6.1??5.2.3.6.2??5.2.3.6.3??5.2.3.6.4

5.2.3.7.1??5.2.3.7.2??5.2.3.7.3??5.2.3.7.4??5.2.3.8.1??5.2.3.8.2??5.2.3.8.3??5.2.3.8.4

5.2.4.1.1??5.2.4.1.2??5.2.4.1.3??5.2.4.1.4??5.2.4.2.1??5.2.4.2.2??5.2.4.2.3??5.2.4.2.4

5.2.4.3.1??5.2.4.3.2??5.2.4.3.3??5.2.4.3.4??5.2.4.4.1??5.2.4.4.2??5.2.4.4.3??5.2.4.4.4

5.2.4.5.1??5.2.4.5.2??5.2.4.5.3??5.2.4.5.4??5.2.4.6.1??5.2.4.6.2??5.2.4.6.3??5.2.4.6.4

5.2.4.7.1??5.2.4.7.2??5.2.4.7.3??5.2.4.7.4??5.2.4.8.1??5.2.4.8.2??5.2.4.8.3??5.2.4.8.4

5.3.1.1.1??5.3.1.1.2??5.3.1.1.3??5.3.1.1.4??5.3.1.2.1??5.3.1.2.2??5.3.1.2.3??5.3.1.2.4

5.3.1.3.1??5.3.1.3.2??5.3.1.3.3??5.3.1.3.4??5.3.1.4.1??5.3.1.4.2??5.3.1.4.3??5.3.1.4.4

5.3.1.5.1??5.3.1.5.2??5.3.1.5.3??5.3.1.5.4??5.3.1.6.1??5.3.1.6.2??5.3.1.6.3??5.3.1.6.4

5.3.1.7.1??5.3.1.7.2??5.3.1.7.3??5.3.1.7.4??5.3.1.8.1??5.3.1.8.2??5.3.1.8.3??5.3.1.8.4

5.3.2.1.1??5.3.2.1.2??5.3.2.1.3??5.3.2.1.4??5.3.2.2.1??5.3.2.2.2??5.3.2.2.3??5.3.2.2.4

5.3.2.3.1??5.3.2.3.2??5.3.2.3.3??5.3.2.3.4??5.3.2.4.1??5.3.2.4.2??5.3.2.4.3??5.3.2.4.4

5.3.2.5.1??5.3.2.5.2??5.3.2.5.3??5.3.2.5.4??5.3.2.6.1??5.3.2.6.2??5.3.2.6.3??5.3.2.6.4

5.3.2.7.1??5.3.2.7.2??5.3.2.7.3??5.3.2.7.4??5.3.2.8.1??5.3.2.8.2??5.3.2.8.3??5.3.2.8.4

Table 3-is continuous

5.3.3.1.1??5.3.3.1.2??5.3.3.1.3??5.3.3.1.4??5.3.3.2.1??5.3.3.2.2??5.3.3.2.3??5.3.3.2.4

5.3.3.3.1??5.3.3.3.2??5.3.3.3.3??5.3.3.3.4??5.3.3.4.1??5.3.3.4.2??5.3.3.4.3??5.3.3.4.4

5.3.3.5.1??5.3.3.5.2??5.3.3.5.3??5.3.3.5.4??5.3.3.6.1??5.3.3.6.2??5.3.3.6.3??5.3.3.6.4

5.3.3.7.1??5.3.3.7.2??5.3.3.7.3??5.3.3.7.4??5.3.3.8.1??5.3.3.8.2??5.3.3.8.3??5.3.3.8.4

5.3.4.1.1??5.3.4.1.2??5.3.4.1.3??5.3.4.1.4??5.3.4.2.1??5.3.4.2.2??5.3.4.2.3??5.3.4.2.4

5.3.4.3.1??5.3.4.3.2??5.3.4.3.3??5.3.4.3.4??5.3.4.4.1??5.3.4.4.2??5.3.4.4.3??5.3.4.4.4

5.3.4.5.1??5.3.4.5.2??5.3.4.5.3??5.3.4.5.4??5.3.4.6.1??5.3.4.6.2??5.3.4.6.3??5.3.4.6.4

5.3.4.7.1??5.3.4.7.2??5.3.4.7.3??5.3.4.7.4??5.3.4.8.1??5.3.4.8.2??5.3.4.8.3??5.3.4.8.4

5.4.1.1.1??5.4.1.1.2??5.4.1.1.3??5.4.1.1.4??5.4.1.2.1??5.4.1.2.2??5.4.1.2.3??5.4.1.2.4

5.4.1.3.1??5.4.1.3.2??5.4.1.3.3??5.4.1.3.4??5.4.1.4.1??5.4.1.4.2??5.4.1.4.3??5.4.1.4.4

5.4.1.5.1??5.4.1.5.2??5.4.1.5.3??5.4.1.5.4??5.4.1.6.1??5.4.1.6.2??5.4.1.6.3??5.4.1.6.4

5.4.1.7.1??5.4.1.7.2??5.4.1.7.3??5.4.1.7.4??5.4.1.8.1??5.4.1.8.2??5.4.1.8.3??5.4.1.8.4

5.4.2.1.1??5.4.2.1.2??5.4.2.1.3??5.4.2.1.4??5.4.2.2.1??5.4.2.2.2??5.4.2.2.3??5.4.2.2.4

5.4.2.3.1??5.4.2.3.2??5.4.2.3.3??5.4.2.3.4??5.4.2.4.1??5.4.2.4.2??5.4.2.4.3??5.4.2.4.4

5.4.2.5.1??5.4.2.5.2??5.4.2.5.3??5.4.2.5.4??5.4.2.6.1??5.4.2.6.2??5.4.2.6.3??5.4.2.6.4

5.4.2.7.1??5.4.2.7.2??5.4.2.7.3??5.4.2.7.4??5.4.2.8.1??5.4.2.8.2??5.4.2.8.3??5.4.2.8.4

5.4.3.1.1??5.4.3.1.2??5.4.3.1.3??5.4.3.1.4??5.4.3.2.1??5.4.3.2.2??5.4.3.2.3??5.4.3.2.4

5.4.3.3.1??5.4.3.3.2??5.4.3.3.3??5.4.3.3.4??5.4.3.4.1??5.4.3.4.2??5.4.3.4.3??5.4.3.4.4

5.4.3.5.1??5.4.3.5.2??5.4.3.5.3??5.4.3.5.4??5.4.3.6.1??5.4.3.6.2??5.4.3.6.3??5.4.3.6.4

5.4.3.7.1??5.4.3.7.2??5.4.3.7.3??5.4.3.7.4??5.4.3.3.1??5.4.3.8.2??5.4.3.8.3??5.4.3.8.4

5.4.4.1.1??5.4.4.1.2??5.4.4.1.3??5.4.4.1.4??5.4.4.2.1??5.4.4.2.2??5.4.4.2.3??5.4.4.2.4

5.4.4.3.1??5.4.4.3.2??5.4.4.3.3??5.4.4.3.4??5.4.4.4.1??5.4.4.4.2??5.4.4.4.3??5.4.4.4.4

5.4.4.5.1??5.4.4.5.2??5.4.4.5.3??5.4.4.5.4??5.4.4.6.1??5.4.4.6.2??5.4.4.6.3??5.4.4.6.4

5.4.4.7.1??5.4.4.7.2??5.4.4.7.3??5.4.4.7.4??5.4.4.8.1??5.4.4.8.2??5.4.4.8.3??5.4.4.8.4

5.5.1.1.1??5.5.1.1.2??5.5.1.1.3??5.5.1.1.4??5.5.1.2.1??5.5.1.2.2??5.5.1.2.3??5.5.1.2.4

5.5.1.3.1??5.5.1.3.2??5.5.1.3.3??5.5.1.3.4??5.5.1.4.1??5.5.1.4.2??5.5.1.4.3??5.5.1.4.4

5.5.1.5.1??5.5.1.5.2??5.5.1.5.3??5.5.1.5.4??5.5.1.6.1??5.5.1.6.2??5.5.1.6.3??5.5.1.6.4

5.5.1.7.1??5.5.1.7.2??5.5.1.7.3??5.5.1.7.4??5.5.1.8.1??5.5.1.8.2??5.5.1.8.3??5.5.1.8.4

5.5.2.1.1??5.5.2.1.2??5.5.2.1.3??5.5.2.1.4??5.5.2.2.1??5.5.2.2.2??5.5.2.2.3??5.5.2.2.4

5.5.2.3.1??5.5.2.3.2??5.5.2.3.3??5.5.2.3.4??5.5.2.4.1??5.5.2.4.2??5.5.2.4.3??5.5.2.4.4

5.5.2.5.1??5.5.2.5.2??5.5.2.5.3??5.5.2.5.4??5.5.2.6.1??5.5.2.6.2??5.5.2.6.3??5.5.2.6.4

5.5.2.7.1??5.5.2.7.2??5.5.2.7.3??5.5.2.7.4??5.5.2.8.1??5.5.2.8.2??5.5.2.8.3??5.5.2.8.4

5.5.3.1.1??5.5.3.1.2??5.5.3.1.3??5.5.3.1.4??5.5.3.2.1??5.5.3.2.2??5.5.3.2.3??5.5.3.2.4

5.5.3.3.1??5.5.3.3.2??5.5.3.3.3??5.5.3.3.4??5.5.3.4.1??5.5.3.4.2??5.5.3.4.3??5.5.3.4.4

5.5.3.5.1??5.5.3.5.2??5.5.3.5.3??5.5.3.5.4??5.5.3.6.1??5.5.3.6.2??5.5.3.6.3??5.5.3.6.4

5.5.3.7.1??5.5.3.7.2??5.5.3.7.3??5.5.3.7.4??5.5.3.8.1??5.5.3.8.2??5.5.3.8.3??5.5.3.8.4

5.5.4.1.1??5.5.4.1.2??5.5.4.1.3??5.5.4.1.4??5.5.4.2.1??5.5.4.2.2??5.5.4.2.3??5.5.4.2.4

5.5.4.3.1??5.5.4.3.2??5.5.4.3.3??5.5.4.3.4??5.5.4.4.1??5.5.4.4.2??5.5.4.4.3??5.5.4.4.4

5.5.4.5.1??5.5.4.5.2??5.5.4.5.3??5.5.4.5.4??5.5.4.6.1??5.5.4.6.2??5.5.4.6.3??5.5.4.6.4

5.5.4.7.1??5.5.4.7.2??5.5.4.7.3??5.5.4.7.4??5.5.4.8.1??5.5.4.8.2??5.5.4.8.3??5.5.4.8.4

5.6.1.1.1??5.6.1.1.2??5.6.1.1.3??5.6.1.1.4??5.6.1.2.1??5.6.1.2.2??5.6.1.2.3??5.6.1.2.4

5.6.1.3.1??5.6.1.3.2??5.6.1.3.3??5.6.1.3.4??5.6.1.4.1??5.6.1.4.2??5.6.1.4.3??5.6.1.4.4

5.6.1.5.1??5.6.1.5.2??5.6.1.5.3??5.6.1.5.4??5.6.1.6.1??5.6.1.6.2??5.6.1.6.3??5.6.1.6.4

5.6.1.7.1??5.6.1.7.2??5.6.1.7.3??5.6.1.7.4??5.6.1.8.1??5.6.1.8.2??5.6.1.8.3??5.6.1.8.4

5.6.2.1.1??5.6.2.1.2??5.6.2.1.3??5.6.2.1.4??5.6.2.2.1??5.6.2.2.2??5.6.2.2.3??5.6.2.2.4

5.6.2.3.1??5.6.2.3.2??5.6.2.3.3??5.6.2.3.4??5.6.2.4.1??5.6.2.4.2??5.6.2.4.3??5.6.2.4.4

Table 3-is continuous

5.6.2.5.1??5.6.2.5.2??5.6.2.5.3??5.6.2.5.4??5.6.2.6.1??5.6.2.6.2??5.6.2.6.3??5.6.2.6.4

5.6.2.7.1??5.6.2.7.2??5.6.2.7.3??5.6.2.7.4??5.6.2.8.1??5.6.2.8.2??5.6.2.8.3??5.6.2.8.4

5.6.3.1.1??5.6.3.1.2??5.6.3.1.3??5.6.3.1.4??5.6.3.2.1??5.6.3.2.2??5.6.3.2.3??5.6.3.2.4

5.6.3.3.1??5.6.3.3.2??5.6.3.3.3??5.6.3.3.4??5.6.3.4.1??5.6.3.4.2??5.6.3.4.3??5.6.3.4.4

5.6.3.5.1??5.6.3.5.2??5.6.3.5.3??5.6.3.5.4??5.6.3.6.1??5.6.3.6.2??5.6.3.6.3??5.6.3.6.4

5.6.3.7.1??5.6.3.7.2??5.6.3.7.3??5.6.3.7.4??5.6.3.8.1??5.6.3.8.2??5.6.3.8.3??5.6.3.8.4

5.6.4.1.1??5.6.4.1.2??5.6.4.1.3??5.6.4.1.4??5.6.4.2.1??5.6.4.2.2??5.6.4.2.3??5.6.4.2.4

5.6.4.3.1??5.6.4.3.2??5.6.4.3.3??5.6.4.3.4??5.6.4.4.1??5.6.4.4.2??5.6.4.4.3??5.6.4.4.4

5.6.4.5.1??5.6.4.5.2??5.6.4.5.3??5.6.4.5.4??5.6.4.6.1??5.6.4.6.2??5.6.4.6.3??5.6.4.6.4

5.6.4.7.1??5.6.4.7.2??5.6.4.7.3??5.6.4.7.4??5.6.4.8.1??5.6.4.8.2??5.6.4.8.3??5.6.4.8.4

5.7.1.1.1??5.7.1.1.2??5.7.1.1.3??5.7.1.1.4??5.7.1.2.1??5.7.1.2.2??5.7.1.2.3??5.7.1.2.4

5.7.1.3.1??5.7.1.3.2??5.7.1.3.3??5.7.1.3.4??5.7.1.4.1??5.7.1.4.2??5.7.1.4.3??5.7.1.4.4

5.7.1.5.1??5.7.1.5.2??5.7.1.5.3??5.7.1.5.4??5.7.1.6.1??5.7.1.6.2??5.7.1.6.3??5.7.1.6.4

5.7.1.7.1??5.7.1.7.2??5.7.1.7.3??5.7.1.7.4??5.7.1.8.1??5.7.1.8.2??5.7.1.8.3??5.7.1.8.4

5.7.2.1.1??5.7.2.1.2??5.7.2.1.3??5.7.2.1.4??5.7.2.2.1??5.7.2.2.2??5.7.2.2.3??5.7.2.2.4

5.7.2.3.1??5.7.2.3.2??5.7.2.3.3??5.7.2.3.4??5.7.2.4.1??5.7.2.4.2??5.7.2.4.3??5.7.2.4.4

5.7.2.5.1??5.7.2.5.2??5.7.2.5.3??5.7.2.5.4??5.7.2.6.1??5.7.2.6.2??5.7.2.6.3??5.7.2.6.4

5.7.2.7.1??5.7.2.7.2??5.7.2.7.3??5.7.2.7.4??5.7.2.8.1??5.7.2.8.2??5.7.2.8.3??5.7.2.8.4

5.7.3.1.1??5.7.3.1.2??5.7.3.1.3??5.7.3.1.4??5.7.3.2.1??5.7.3.2.2??5.7.3.2.3??5.7.3.2.4

5.7.3.3.1??5.7.3.3.2??5.7.3.3.3??5.7.3.3.4??5.7.3.4.1??5.7.3.4.2??5.7.3.4.3??5.7.3.4.4

5.7.3.5.1??5.7.3.5.2??5.7.3.5.3??5.7.3.5.4??5.7.3.6.1??5.7.3.6.2??5.7.3.6.3??5.7.3.6.4

5.7.3.7.1??5.7.3.7.2??5.7.3.7.3??5.7.3.7.4??5.7.3.8.1??5.7.3.8.2??5.7.3.8.3??5.7.3.8.4

5.7.4.1.1??5.7.4.1.2??5.7.4.1.3??5.7.4.1.4??5.7.4.2.1??5.7.4.2.2??5.7.4.2.3??5.7.4.2.4

5.7.4.3.1??5.7.4.3.2??5.7.4.3.3??5.7.4.3.4??5.7.4.4.1??5.7.4.4.2??5.7.4.4.3??5.7.4.4.4

5.7.4.5.1??5.7.4.5.2??5.7.4.5.3??5.7.4.5.4??5.7.4.6.1??5.7.4.6.2??5.7.4.6.3??5.7.4.6.4

5.7.4.7.1??5.7.4.7.2??5.7.4.7.3??5.7.4.7.4??5.7.4.8.1??5.7.4.8.2??5.7.4.8.3??5.7.4.8.4

5.8.1.1.1??5.8.1.1.2??5.8.1.1.3??5.8.1.1.4??5.8.1.2.1??5.8.1.2.2??5.8.1.2.3??5.8.1.2.4

5.8.1.3.1??5.8.1.3.2??5.8.1.3.3??5.8.1.3.4??5.8.1.4.1??5.8.1.4.2??5.8.1.4.3??5.8.1.4.4

5.8.1.5.1??5.8.1.5.2??5.8.1.5.3??5.8.1.5.4??5.8.1.6.1??5.8.1.6.2??5.8.1.6.3??5.8.1.6.4

5.8.1.7.1??5.8.1.7.2??5.8.1.7.3??5.8.1.7.4??5.8.1.8.1??5.8.1.8.2??5.8.1.8.3??5.8.1.8.4

5.8.2.1.1??5.8.2.1.2??5.8.2.1.3??5.8.2.1.4??5.8.2.2.1??5.8.2.2.2??5.8.2.2.3??5.8.2.2.4

5.8.2.3.1??5.8.2.3.2??5.8.2.3.3??5.8.2.3.4??5.8.2.4.1??5.8.2.4.2??5.8.2.4.3??5.8.2.4.4

5.8.2.5.1??5.8.2.5.2??5.8.2.5.3??5.8.2.5.4??5.8.2.6.1??5.8.2.6.2??5.8.2.6.3??5.8.2.6.4

5.8.2.7.1??5.8.2.7.2??5.8.2.7.3??5.8.2.7.4??5.8.2.8.1??5.8.2.8.2??5.8.2.8.3??5.8.2.8.4

5.8.3.1.1??5.8.3.1.2??5.8.3.1.3??5.8.3.1.4??5.8.3.2.1??5.8.3.2.2??5.8.3.2.3??5.8.3.2.4

5.8.3.3.1??5.8.3.3.2??5.8.3.3.3??5.8.3.3.4??5.8.3.4.1??5.8.3.4.2??5.8.3.4.3??5.8.3.4.4

5.8.3.5.1??5.8.3.5.2??5.8.3.5.3??5.8.3.5.4??5.8.3.6.1??5.8.3.6.2??5.8.3.6.3??5.8.3.6.4

5.8.3.7.1??5.8.3.7.2??5.8.3.7.3??5.8.3.7.4??5.8.3.8.1??5.8.3.8.2??5.8.3.8.3??5.8.3.8.4

5.8.4.1.1??5.8.4.1.2??5.8.4.1.3??5.8.4.1.4??5.8.4.2.1??5.8.4.2.2??5.8.4.2.3??5.8.4.2.4

5.8.4.3.1??5.8.4.3.2??5.8.4.3.3??5.8.4.3.4??5.8.4.4.1??5.8.4.4.2??5.8.4.4.3??5.8.4.4.4

5.8.4.5.1??5.8.4.5.2??5.8.4.5.3??5.8.4.5.4??5.8.4.6.1??5.8.4.6.2??5.8.4.6.3??5.8.4.6.4

5.8.4.7.1??5.8.4.7.2??5.8.4.7.3??5.8.4.7.4??5.8.4.8.1??5.8.4.8.2??5.8.4.8.3??5.8.4.8.4

6.1.1.1.1??6.1.1.1.2??6.1.1.1.3??6.1.1.1.4??6.1.1.2.1??6.1.1.2.2??6.1.1.2.3??6.1.1.2.4

6.1.1.3.1??6.1.1.3.2??6.1.1.3.3??6.1.1.3.4??6.1.1.4.1??6.1.1.4.2??6.1.1.4.3??6.1.1.4.4

6.1.1.5.1??6.1.1.5.2??6.1.1.5.3??6.1.1.5.4??6.1.1.6.1??6.1.1.6.2??6.1.1.6.3??6.1.1.6.4

6.1.1.7.1??6.1.1.7.2??6.1.1.7.3??6.1.1.7.4??6.1.1.8.1??6.1.1.8.2??6.1.1.8.3??6.1.1.8.4

Table 3-is continuous

6.1.2.1.1??6.1.2.1.2??6.1.2.1.3??6.1.2.1.4??6.1.2.2.1??6.1.2.2.2??6.1.2.2.3??6.1.2.2.4

6.1.2.3.1??6.1.2.3.2??6.1.2.3.3??6.1.2.3.4??6.1.2.4.1??6.1.2.4.2??6.1.2.4.3??6.1.2.4.4

6.1.2.5.1??6.1.2.5.2??6.1.2.5.3??6.1.2.5.4??6.1.2.6.1??6.1.2.6.2??6.1.2.6.3??6.1.2.6.4

6.1.2.7.1??6.1.2.7.2??6.1.2.7.3??6.1.2.7.4??6.1.2.8.1??6.1.2.8.2??6.1.2.8.3??6.1.2.8.4

6.1.3.1.1??6.1.3.1.2??6.1.3.1.3??6.1.3.1.4??6.1.3.2.1??6.1.3.2.2??6.1.3.2.3??6.1.3.2.4

6.1.3.3.1??6.1.3.3.2??6.1.3.3.3??6.1.3.3.4??6.1.3.4.1??6.1.3.4.2??6.1.3.4.3??6.1.3.4.4

6.1.3.5.1??6.1.3.5.2??6.1.3.5.3??6.1.3.5.4??6.1.3.6.1??6.1.3.6.2??6.1.3.6.3??6.1.3.6.4

6.1.3.7.1??6.1.3.7.2??6.1.3.7.3??6.1.3.7.4??6.1.3.8.1??6.1.3.8.2??6.1.3.8.3??6.1.3.8.4

6.1.4.1.1??6.1.4.1.2??6.1.4.1.3??6.1.4.1.4??6.1.4.2.1??6.1.4.2.2??6.1.4.2.3??6.1.4.2.4

6.1.4.3.1??6.1.4.3.2??6.1.4.3.3??6.1.4.3.4??6.1.4.4.1??6.1.4.4.2??6.1.4.4.3??6.1.4.4.4

6.1.4.5.1??6.1.4.5.2??6.1.4.5.3??6.1.4.5.4??6.1.4.6.1??6.1.4.6.2??6.1.4.6.3??6.1.4.6.4

6.1.4.7.1??6.1.4.7.2??6.1.4.7.3??6.1.4.7.4??6.1.4.8.1??6.1.4.8.2??6.1.4.8.3??6.1.4.8.4

6.2.1.1.1??6.2.1.1.2??6.2.1.1.3??6.2.1.1.4??6.2.1.2.1??6.2.1.2.2??6.2.1.2.3??6.2.1.2.4

6.2.1.3.1??6.2.1.3.2??6.2.1.3.3??6.2.1.3.4??6.2.1.4.1??6.2.1.4.2??6.2.1.4.3??6.2.1.4.4

6.2.1.5.1??6.2.1.5.2??6.2.1.5.3??6.2.1.5.4??6.2.1.6.1??6.2.1.6.2??6.2.1.6.3??6.2.1.6.4

6.2.1.7.1??6.2.1.7.2??6.2.1.7.3??6.2.1.7.4??6.2.1.8.1??6.2.1.8.2??6.2.1.8.3??6.2.1.8.4

6.2.2.1.1??6.2.2.1.2??6.2.2.1.3??6.2.2.1.4??6.2.2.2.1??6.2.2.2.2??6.2.2.2.3??6.2.2.2.4

6.2.2.3.1??6.2.2.3.2??6.2.2.3.3??6.2.2.3.4??6.2.2.4.1??6.2.2.4.2??6.2.2.4.3??6.2.2.4.4

6.2.2.5.1??6.2.2.5.2??6.2.2.5.3??6.2.2.5.4??6.2.2.6.1??6.2.2.6.2??6.2.2.6.3??6.2.2.6.4

6.2.2.7.1??6.2.2.7.2??6.2.2.7.3??6.2.2.7.4??6.2.2.8.1??6.2.2.8.2??6.2.2.8.3??6.2.2.8.4

6.2.3.1.1??6.2.3.1.2??6.2.3.1.3??6.2.3.1.4??6.2.3.2.1??6.2.3.2.2??6.2.3.2.3??6.2.3.2.4

6.2.3.3.1??6.2.3.3.2??6.2.3.3.3??6.2.3.3.4??6.2.3.4.1??6.2.3.4.2??6.2.3.4.3??6.2.3.4.4

6.2.3.5.1??6.2.3.5.2??6.2.3.5.3??6.2.3.5.4??6.2.3.6.1??6.2.3.6.2??6.2.3.6.3??6.2.3.6.4

6.2.3.7.1??6.2.3.7.2??6.2.3.7.3??6.2.3.7.4??6.2.3.8.1??6.2.3.8.2??6.2.3.8.3??6.2.3.8.4

6.2.4.1.1??6.2.4.1.2??6.2.4.1.3??6.2.4.1.4??6.2.4.2.1??6.2.4.2.2??6.2.4.2.3??6.2.4.2.4

6.2.4.3.1??6.2.4.3.2??6.2.4.3.3??6.2.4.3.4??6.2.4.4.1??6.2.4.4.2??6.2.4.4.3??6.2.4.4.4

6.2.4.5.1??6.2.4.5.2??6.2.4.5.3??6.2.4.5.4??6.2.4.6.1??6.2.4.6.2??6.2.4.6.3??6.2.4.6.4

6.2.4.7.1??6.2.4.7.2??6.2.4.7.3??6.2.4.7.4??6.2.4.8.1??6.2.4.8.2??6.2.4.8.3??6.2.4.8.4

6.3.1.1.1??6.3.1.1.2??6.3.1.1.3??6.3.1.1.4??6.3.1.2.1??6.3.1.2.2??6.3.1.2.3??6.3.1.2.4

6.3.1.3.1??6.3.1.3.2??6.3.1.3.3??6.3.1.3.4??6.3.1.4.1??6.3.1.4.2??6.3.1.4.3??6.3.1.4.4

6.3.1.5.1??6.3.1.5.2??6.3.1.5.3??6.3.1.5.4??6.3.1.6.1??6.3.1.6.2??6.3.1.6.3??6.3.1.6.4

6.3.1.7.1??6.3.1.7.2??6.3.1.7.3??6.3.1.7.4??6.3.1.8.1??6.3.1.8.2??6.3.1.8.3??6.3.1.8.4

6.3.2.1.1??6.3.2.1.2??6.3.2.1.3??6.3.2.1.4??6.3.2.2.1??6.3.2.2.2??6.3.2.2.3??6.3.2.2.4

6.3.2.3.1??6.3.2.3.2??6.3.2.3.3??6.3.2.3.4??6.3.2.4.1??6.3.2.4.2??6.3.2.4.3??6.3.2.4.4

6.3.2.5.1??6.3.2.5.2??6.3.2.5.3??6.3.2.5.4??6.3.2.6.1??6.3.2.6.2??6.3.2.6.3??6.3.2.6.4

6.3.2.7.1??6.3.2.7.2??6.3.2.7.3??6.3.2.7.4??6.3.2.8.1??6.3.2.8.2??6.3.2.8.3??6.3.2.8.4

6.3.3.1.1??6.3.3.1.2??6.3.3.1.3??6.3.3.1.4??6.3.3.2.1??6.3.3.2.2??6.3.3.2.3??6.3.3.2.4

6.3.3.3.1??6.3.3.3.2??6.3.3.3.3??6.3.3.3.4??6.3.3.4.1??6.3.3.4.2??6.3.3.4.3??6.3.3.4.4

6.3.3.5.1??6.3.3.5.2??6.3.3.5.3??6.3.3.5.4??6.3.3.6.1??6.3.3.6.2??6.3.3.6.3??6.3.3.6.4

6.3.3.7.1??6.3.3.7.2??6.3.3.7.3??6.3.3.7.4??6.3.3.8.1??6.3.3.8.2??6.3.3.8.3??6.3.3.8.4

6.3.4.1.1??6.3.4.1.2??6.3.4.1.3??6.3.4.1.4??6.3.4.2.1??6.3.4.2.2??6.3.4.2.3??6.3.4.2.4

6.3.4.3.1??6.3.4.3.2??6.3.4.3.3??6.3.4.3.4??6.3.4.4.1??6.3.4.4.2??6.3.4.4.3??6.3.4.4.4

6.3.4.5.1??6.3.4.5.2??6.3.4.5.3??6.3.4.5.4??6.3.4.6.1??6.3.4.6.2??6.3.4.6.3??6.3.4.6.4

6.3.4.7.1??6.3.4.7.2??6.3.4.7.3??6.3.4.7.4??6.3.4.8.1??6.3.4.8.2??6.3.4.8.3??6.3.4.8.4

6.4.1.1.1??6.4.1.1.2??6.4.1.1.3??6.4.1.1.4??6.4.1.2.1??6.4.1.2.2??6.4.1.2.3??6.4.1.2.4

6.4.1.3.1??6.4.1.3.2??6.4.1.3.3??6.4.1.3.4??6.4.1.4.1??6.4.1.4.2??6.4.1.4.3??6.4.1.4.4

Table 3-is continuous

6.4.1.5.1??6.4.1.5.2??6.4.1.5.3??6.4.1.5.4??6.4.1.6.1??6.4.1.6.2??6.4.1.6.3??6.4.1.6.4

6.4.1.7.1??6.4.1.7.2??6.4.1.7.3??6.4.1.7.4??6.4.1.8.1??6.4.1.8.2??6.4.1.8.3??6.4.1.8.4

6.4.2.1.1??6.4.2.1.2??6.4.2.1.3??6.4.2.1.4??6.4.2.2.1??6.4.2.2.2??6.4.2.2.3??6.4.2.2.4

6.4.2.3.1??6.4.2.3.2??6.4.2.3.3??6.4.2.3.4??6.4.2.4.1??6.4.2.4.2??6.4.2.4.3??6.4.2.4.4

6.4.2.5.1??6.4.2.5.2??6.4.2.5.3??6.4.2.5.4??6.4.2.6.1??6.4.2.6.2??6.4.2.6.3??6.4.2.6.4

6.4.2.7.1??6.4.2.7.2??6.4.2.7.3??6.4.2.7.4??6.4.2.8.1??6.4.2.8.2??6.4.2.8.3??6.4.2.8.4

6.4.3.1.1??6.4.3.1.2??6.4.3.1.3??6.4.3.1.4??6.4.3.2.1??6.4.3.2.2??6.4.3.2.3??6.4.3.2.4

6.4.3.3.1??6.4.3.3.2??6.4.3.3.3??6.4.3.3.4??6.4.3.4.1??6.4.3.4.2??6.4.3.4.3??6.4.3.4.4

6.4.3.5.1??6.4.3.5.2??6.4.3.5.3??6.4.3.5.4??6.4.3.6.1??6.4.3.6.2??6.4.3.6.3??6.4.3.6.4

6.4.3.7.1??6.4.3.7.2??6.4.3.7.3??6.4.3.7.4??6.4.3.8.1??6.4.3.8.2??6.4.3.8.3??6.4.3.8.4

6.4.4.1.1??6.4.4.1.2??6.4.4.1.3??6.4.4.1.4??6.4.4.2.1??6.4.4.2.2??6.4.4.2.3??6.4.4.2.4

6.4.4.3.1??6.4.4.3.2??6.4.4.3.3??6.4.4.3.4??6.4.4.4.1??6.4.4.4.2??6.4.4.4.3??6.4.4.4.4

6.4.4.5.1??6.4.4.5.2??6.4.4.5.3??6.4.4.5.4??6.4.4.6.1??6.4.4.6.2??6.4.4.6.3??6.4.4.6.4

6.4.4.7.1??6.4.4.7.2??6.4.4.7.3??6.4.4.7.4??6.4.4.8.1??6.4.4.8.2??6.4.4.8.3??6.4.4.8.4

6.5.1.1.1??6.5.1.1.2??6.5.1.1.3??6.5.1.1.4??6.5.1.2.1??6.5.1.2.2??6.5.1.2.3??6.5.1.2.4

6.5.1.3.1??6.5.1.3.2??6.5.1.3.3??6.5.1.3.4??6.5.1.4.1??6.5.1.4.2??6.5.1.4.3??6.5.1.4.4

6.5.1.5.1??6.5.1.5.2??6.5.1.5.3??6.5.1.5.4??6.5.1.6.1??6.5.1.6.2??6.5.1.6.3??6.5.1.6.4

6.5.1.7.1??6.5.1.7.2??6.5.1.7.3??6.5.1.7.4??6.5.1.8.1??6.5.1.8.2??6.5.1.8.3??6.5.1.8.4

6.5.2.1.1??6.5.2.1.2??6.5.2.1.3??6.5.2.1.4??6.5.2.2.1??6.5.2.2.2??6.5.2.2.3??6.5.2.2.4

6.5.2.3.1??6.5.2.3.2??6.5.2.3.3??6.5.2.3.4??6.5.2.4.1??6.5.2.4.2??6.5.2.4.3??6.5.2.4.4

6.5.2.5.1??6.5.2.5.2??6.5.2.5.3??6.5.2.5.4??6.5.2.6.1??6.5.2.6.2??6.5.2.6.3??6.5.2.6.4

6.5.2.7.1??6.5.2.7.2??6.5.2.7.3??6.5.2.7.4??6.5.2.8.1??6.5.2.8.2??6.5.2.8.3??6.5.2.8.4

6.5.3.1.1??6.5.3.1.2??6.5.3.1.3??6.5.3.1.4??6.5.3.2.1??6.5.3.2.2??6.5.3.2.3??6.5.3.2.4

6.5.3.3.1??6.5.3.3.2??6.5.3.3.3??6.5.3.3.4??6.5.3.4.1??6.5.3.4.2??6.5.3.4.3??6.5.3.4.4

6.5.3.5.1??6.5.3.5.2??6.5.3.5.3??6.5.3.5.4??6.5.3.6.1??6.5.3.6.2??6.5.3.6.3??6.5.3.6.4

6.5.3.7.1??6.5.3.7.2??6.5.3.7.3??6.5.3.7.4??6.5.3.8.1??6.5.3.8.2??6.5.3.8.3??6.5.3.8.4

6.5.4.1.1??6.5.4.1.2??6.5.4.1.3??6.5.4.1.4??6.5.4.2.1??6.5.4.2.2??6.5.4.2.3??6.5.4.2.4

6.5.4.3.1??6.5.4.3.2??6.5.4.3.3??6.5.4.3.4??6.5.4.4.1??6.5.4.4.2??6.5.4.4.3??6.5.4.4.4

6.5.4.5.1??6.5.4.5.2??6.5.4.5.3??6.5.4.5.4??6.5.4.6.1??6.5.4.6.2??6.5.4.6.3??6.5.4.6.4

6.5.4.7.1??6.5.4.7.2??6.5.4.7.3??6.5.4.7.4??6.5.4.8.1??6.5.4.8.2??6.5.4.8.3??6.5.4.8.4

6.6.1.1.1??6.6.1.1.2??6.6.1.1.3??6.6.1.1.4??6.6.1.2.1??6.6.1.2.2??6.6.1.2.3??6.6.1.2.4

6.6.1.3.1??6.6.1.3.2??6.6.1.3.3??6.6.1.3.4??6.6.1.4.1??6.6.1.4.2??6.6.1.4.3??6.6.1.4.4

6.6.1.5.1??6.6.1.5.2??6.6.1.5.3??6.6.1.5.4??6.6.1.6.1??6.6.1.6.2??6.6.1.6.3??6.6.1.6.4

6.6.1.7.1??6.6.1.7.2??6.6.1.7.3??6.6.1.7.4??6.6.1.8.1??6.6.1.8.2??6.6.1.8.3??6.6.1.8.4

6.6.2.1.1??6.6.2.1.2??6.6.2.1.3??6.6.2.1.4??6.6.2.2.1??6.6.2.2.2??6.6.2.2.3??6.6.2.2.4

6.6.2.3.1??6.6.2.3.2??6.6.2.3.3??6.6.2.3.4??6.6.2.4.1??6.6.2.4.2??6.6.2.4.3??6.6.2.4.4

6.6.2.5.1??6.6.2.5.2??6.6.2.5.3??6.6.2.5.4??6.6.2.6.1??6.6.2.6.2??6.6.2.6.3??6.6.2.6.4

6.6.2.7.1??6.6.2.7.2??6.6.2.7.3??6.6.2.7.4??6.6.2.8.1??6.6.2.8.2??6.6.2.8.3??6.6.2.8.4

6.6.3.1.1??6.6.3.1.2??6.6.3.1.3??6.6.3.1.4??6.6.3.2.1??6.6.3.2.2??6.6.3.2.3??6.6.3.2.4

6.6.3.3.1??6.6.3.3.2??6.6.3.3.3??6.6.3.3.4??6.6.3.4.1??6.6.3.4.2??6.6.3.4.3??6.6.3.4.4

6.6.3.5.1??6.6.3.5.2??6.6.3.5.3??6.6.3.5.4??6.6.3.6.1??6.6.3.6.2??6.6.3.6.3??6.6.3.6.4

6.6.3.7.1??6.6.3.7.2??6.6.3.7.3??6.6.3.7.4??6.6.3.8.1??6.6.3.8.2??6.6.3.8.3??6.6.3.8.4

6.6.4.1.1??6.6.4.1.2??6.6.4.1.3??6.6.4.1.4??6.6.4.2.1??6.6.4.2.2??6.6.4.2.3??6.6.4.2.4

6.6.4.3.1??6.6.4.3.2??6.6.4.3.3??6.6.4.3.4??6.6.4.4.1??6.6.4.4.2??6.6.4.4.3??6.6.4.4.4

6.6.4.5.1??6.6.4.5.2??6.6.4.5.3??6.6.4.5.4??6.6.4.6.1??6.6.4.6.2??6.6.4.6.3??6.6.4.6.4

6.6.4.7.1??6.6.4.7.2??6.6.4.7.3??6.6.4.7.4??6.6.4.8.1??6.6.4.8.2??6.6.4.8.3??6.6.4.8.4

Table 3-is continuous

6.7.1.1.1??6.7.1.1.2??6.7.1.1.3??6.7.1.1.4??6.7.1.2.1??6.7.1.2.2??6.7.1.2.3??6.7.1.2.4

6.7.1.3.1??6.7.1.3.2??6.7.1.3.3??6.7.1.3.4??6.7.1.4.1??6.7.1.4.2??6.7.1.4.3??6.7.1.4.4

6.7.1.5.1??6.7.1.5.2??6.7.1.5.3??6.7.1.5.4??6.7.1.6.1??6.7.1.6.2??6.7.1.6.3??6.7.1.6.4

6.7.1.7.1??6.7.1.7.2??6.7.1.7.3??6.7.1.7.4??6.7.1.8.1??6.7.1.8.2??6.7.1.8.3??6.7.1.8.4

6.7.2.1.1??6.7.2.1.2??6.7.2.1.3??6.7.2.1.4??6.7.2.2.1??6.7.2.2.2??6.7.2.2.3??6.7.2.2.4

6.7.2.3.1??6.7.2.3.2??6.7.2.3.3??6.7.2.3.4??6.7.2.4.1??6.7.2.4.2??6.7.2.4.3??6.7.2.4.4

6.7.2.5.1??6.7.2.5.2??6.7.2.5.3??6.7.2.5.4??6.7.2.6.1??6.7.2.6.2??6.7.2.6.3??6.7.2.6.4

6.7.2.7.1??6.7.2.7.2??6.7.2.7.3??6.7.2.7.4??6.7.2.8.1??6.7.2.8.2??6.7.2.8.3??6.7.2.8.4

6.7.3.1.1??6.7.3.1.2??6.7.3.1.3??6.7.3.1.4??6.7.3.2.1??6.7.3.2.2??6.7.3.2.3??6.7.3.2.4

6.7.3.3.1??6.7.3.3.2??6.7.3.3.3??6.7.3.3.4??6.7.3.4.1??6.7.3.4.2??6.7.3.4.3??6.7.3.4.4

6.7.3.5.1??6.7.3.5.2??6.7.3.5.3??6.7.3.5.4??6.7.3.6.1??6.7.3.6.2??6.7.3.6.3??6.7.3.6.4

6.7.3.7.1??6.7.3.7.2??6.7.3.7.3??6.7.3.7.4??6.7.3.8.1??6.7.3.8.2??6.7.3.8.3??6.7.3.8.4

6.7.4.1.1??6.7.4.1.2??6.7.4.1.3??6.7.4.1.4??6.7.4.2.1??6.7.4.2.2??6.7.4.2.3??6.7.4.2.4

6.7.4.3.1??6.7.4.3.2??6.7.4.3.3??6.7.4.3.4??6.7.4.4.1??6.7.4.4.2??6.7.4.4.3??6.7.4.4.4

6.7.4.5.1??6.7.4.5.2??6.7.4.5.3??6.7.4.5.4??6.7.4.6.1??6.7.4.6.2??6.7.4.6.3??6.7.4.6.4

6.7.4.7.1??6.7.4.7.2??6.7.4.7.3??6.7.4.7.4??6.7.4.8.1??6.7.4.8.2??6.7.4.8.3??6.7.4.8.4

6.8.1.1.1??6.8.1.1.2??6.8.1.1.3??6.8.1.1.4??6.8.1.2.1??6.8.1.2.2??6.8.1.2.3??6.8.1.2.4

6.8.1.3.1??6.8.1.3.2??6.8.1.3.3??6.8.1.3.4??6.8.1.4.1??6.8.1.4.2??6.8.1.4.3??6.8.1.4.4

6.8.1.5.1??6.8.1.5.2??6.8.1.5.3??6.8.1.5.4??6.8.1.6.1??6.8.1.6.2??6.8.1.6.3??6.8.1.6.4

6.8.1.7.1??6.8.1.7.2??6.8.1.7.3??6.8.1.7.4??6.8.1.8.1??6.8.1.8.2??6.8.1.8.3??6.8.1.8.4

6.8.2.1.1??6.8.2.1.2??6.8.2.1.3??6.8.2.1.4??6.8.2.2.1??6.8.2.2.2??6.8.2.2.3??6.8.2.2.4

6.8.2.3.1??6.8.2.3.2??6.8.2.3.3??6.8.2.3.4??6.8.2.4.1??6.8.2.4.2??6.8.2.4.3??6.8.2.4.4

6.8.2.5.1??6.8.2.5.2??6.8.2.5.3??6.8.2.5.4??6.8.2.6.1??6.8.2.6.2??6.8.2.6.3??6.8.2.6.4

6.8.2.7.1??6.8.2.7.2??6.8.2.7.3??6.8.2.7.4??6.8.2.8.1??6.8.2.8.2??6.8.2.8.3??6.8.2.8.4

6.8.3.1.1??6.8.3.1.2??6.8.3.1.3??6.8.3.1.4??6.8.3.2.1??6.8.3.2.2??6.8.3.2.3??6.8.3.2.4

6.8.3.3.1??6.8.3.3.2??6.8.3.3.3??6.8.3.3.4??6.8.3.4.1??6.8.3.4.2??6.8.3.4.3??6.8.3.4.4

6.8.3.5.1??6.8.3.5.2??6.8.3.5.3??6.8.3.5.4??6.8.3.6.1??6.8.3.6.2??6.8.3.6.3??6.8.3.6.4

6.8.3.7.1??6.8.3.7.2??6.8.3.7.3??6.8.3.7.4??6.8.3.8.1??6.8.3.8.2??6.8.3.8.3??6.8.3.8.4

6.8.4.1.1??6.8.4.1.2??6.8.4.1.3??6.8.4.1.4??6.8.4.2.1??6.8.4.2.2??6.8.4.2.3??6.8.4.2.4

6.8.4.3.1??6.8.4.3.2??6.8.4.3.3??6.8.4.3.4??6.8.4.4.1??6.8.4.4.2??6.8.4.4.3??6.8.4.4.4

6.8.4.5.1??6.8.4.5.2??6.8.4.5.3??6.8.4.5.4??6.8.4.6.1??6.8.4.6.2??6.8.4.6.3??6.8.4.6.4

6.8.4.7.1??6.8.4.7.2??6.8.4.7.3??6.8.4.7.4??6.8.4.8.1??6.8.4.8.2??6.8.4.8.3??6.8.4.8.4

7.1.1.1.1??7.1.1.1.2??7.1.1.1.3??7.1.1.1.4??7.1.1.2.1??7.1.1.2.2??7.1.1.2.3??7.1.1.2.4

7.1.1.3.1??7.1.1.3.2??7.1.1.3.3??7.1.1.3.4??7.1.1.4.1??7.1.1.4.2??7.1.1.4.3??7.1.1.4.4

7.1.1.5.1??7.1.1.5.2??7.1.1.5.3??7.1.1.5.4??7.1.1.6.1??7.1.1.6.2??7.1.1.6.3??7.1.1.6.4

7.1.1.7.1??7.1.1.7.2??7.1.1.7.3??7.1.1.7.4??7.1.1.8.1??7.1.1.8.2??7.1.1.8.3??7.1.1.8.4

7.1.2.1.1??7.1.2.1.2??7.1.2.1.3??7.1.2.1.4??7.1.2.2.1??7.1.2.2.2??7.1.2.2.3??7.1.2.2.4

7.1.2.3.1??7.1.2.3.2??7.1.2.3.3??7.1.2.3.4??7.1.2.4.1??7.1.2.4.2??7.1.2.4.3??7.1.2.4.4

7.1.2.5.1??7.1.2.5.2??7.1.2.5.3??7.1.2.5.4??7.1.2.6.1??7.1.2.6.2??7.1.2.6.3??7.1.2.6.4

7.1.2.7.1??7.1.2.7.2??7.1.2.7.3??7.1.2.7.4??7.1.2.8.1??7.1.2.8.2??7.1.2.8.3??7.1.2.8.4

7.1.3.1.1??7.1.3.1.2??7.1.3.1.3??7.1.3.1.4??7.1.3.2.1??7.1.3.2.2??7.1.3.2.3??7.1.3.2.4

7.1.3.3.1??7.1.3.3.2??7.1.3.3.3??7.1.3.3.4??7.1.3.4.1??7.1.3.4.2??7.1.3.4.3??7.1.3.4.4

7.1.3.5.1??7.1.3.5.2??7.1.3.5.3??7.1.3.5.4??7.1.3.6.1??7.1.3.6.2??7.1.3.6.3??7.1.3.6.4

7.1.3.7.1??7.1.3.7.2??7.1.3.7.3??7.1.3.7.4??7.1.3.8.1??7.1.3.8.2??7.1.3.8.3??7.1.3.8.4

7.1.4.1.1??7.1.4.1.2??7.1.4.1.3??7.1.4.1.4??7.1.4.2.1??7.1.4.2.2??7.1.4.2.3??7.1.4.2.4

7.1.4.3.1??7.1.4.3.2??7.1.4.3.3??7.1.4.3.4??7.1.4.4.1??7.1.4.4.2??7.1.4.4.3??7.1.4.4.4

Table 3-is continuous

7.1.4.5.1??7.1.4.5.2??7.1.4.5.3??7.1.4.5.4??7.1.4.6.1??7.1.4.6.2??7.1.4.6.3??7.1.4.6.4

7.1.4.7.1??7.1.4.7.2??7.1.4.7.3??7.1.4.7.4??7.1.4.8.1??7.1.4.8.2??7.1.4.8.3??7.1.4.8.4

7.2.1.1.1??7.2.1.1.2??7.2.1.1.3??7.2.1.1.4??7.2.1.2.1??7.2.1.2.2??7.2.1.2.3??7.2.1.2.4

7.2.1.3.1??7.2.1.3.2??7.2.1.3.3??7.2.1.3.4??7.2.1.4.1??7.2.1.4.2??7.2.1.4.3??7.2.1.4.4

7.2.1.5.1??7.2.1.5.2??7.2.1.5.3??7.2.1.5.4??7.2.1.6.1??7.2.1.6.2??7.2.1.6.3??7.2.1.6.4

7.2.1.7.1??7.2.1.7.2??7.2.1.7.3??7.2.1.7.4??7.2.1.8.1??7.2.1.8.2??7.2.1.8.3??7.2.1.8.4

7.2.2.1.1??7.2.2.1.2??7.2.2.1.3??7.2.2.1.4??7.2.2.2.1??7.2.2.2.2??7.2.2.2.3??7.2.2.2.4

7.2.2.3.1??7.2.2.3.2??7.2.2.3.3??7.2.2.3.4??7.2.2.4.1??7.2.2.4.2??7.2.2.4.3??7.2.2.4.4

7.2.2.5.1??7.2.2.5.2??7.2.2.5.3??7.2.2.5.4??7.2.2.6.1??7.2.2.6.2??7.2.2.6.3??7.2.2.6.4

7.2.2.7.1??7.2.2.7.2??7.2.2.7.3??7.2.2.7.4??7.2.2.8.1??7.2.2.8.2??7.2.2.8.3??7.2.2.8.4

7.2.3.1.1??7.2.3.1.2??7.2.3.1.3??7.2.3.1.4??7.2.3.2.1??7.2.3.2.2??7.2.3.2.3??7.2.3.2.4

7.2.3.3.1??7.2.3.3.2??7.2.3.3.3??7.2.3.3.4??7.2.3.4.1??7.2.3.4.2??7.2.3.4.3??7.2.3.4.4

7.2.3.5.1??7.2.3.5.2??7.2.3.5.3??7.2.3.5.4??7.2.3.6.1??7.2.3.6.2??7.2.3.6.3??7.2.3.6.4

7.2.3.7.1??7.2.3.7.2??7.2.3.7.3??7.2.3.7.4??7.2.3.8.1??7.2.3.8.2??7.2.3.8.3??7.2.3.8.4

7.2.4.1.1??7.2.4.1.2??7.2.4.1.3??7.2.4.1.4??7.2.4.2.1??7.2.4.2.2??7.2.4.2.3??7.2.4.2.4

7.2.4.3.1??7.2.4.3.2??7.2.4.3.3??7.2.4.3.4??7.2.4.4.1??7.2.4.4.2??7.2.4.4.3??7.2.4.4.4

7.2.4.5.1??7.2.4.5.2??7.2.4.5.3??7.2.4.5.4??7.2.4.6.1??7.2.4.6.2??7.2.4.6.3??7.2.4.6.4

7.2.4.7.1??7.2.4.7.2??7.2.4.7.3??7.2.4.7.4??7.2.4.8.1??7.2.4.8.2??7.2.4.8.3??7.2.4.8.4

7.3.1.1.1??7.3.1.1.2??7.3.1.1.3??7.3.1.1.4??7.3.1.2.1??7.3.1.2.2??7.3.1.2.3??7.3.1.2.4

7.3.1.3.1??7.3.1.3.2??7.3.1.3.3??7.3.1.3.4??7.3.1.4.1??7.3.1.4.2??7.3.1.4.3??7.3.1.4.4

7.3.1.5.1??7.3.1.5.2??7.3.1.5.3??7.3.1.5.4??7.3.1.6.1??7.3.1.6.2??7.3.1.6.3??7.3.1.6.4

7.3.1.7.1??7.3.1.7.2??7.3.1.7.3??7.3.1.7.4??7.3.1.8.1??7.3.1.8.2??7.3.1.8.3??7.3.1.8.4

7.3.2.1.1??7.3.2.1.2??7.3.2.1.3??7.3.2.1.4??7.3.2.2.1??7.3.2.2.2??7.3.2.2.3??7.3.2.2.4

7.3.2.3.1??7.3.2.3.2??7.3.2.3.3??7.3.2.3.4??7.3.2.4.1??7.3.2.4.2??7.3.2.4.3??7.3.2.4.4

7.3.2.5.1??7.3.2.5.2??7.3.2.5.3??7.3.2.5.4??7.3.2.6.1??7.3.2.6.2??7.3.2.6.3??7.3.2.6.4

7.3.2.7.1??7.3.2.7.2??7.3.2.7.3??7.3.2.7.4??7.3.2.8.1??7.3.2.8.2??7.3.2.8.3??7.3.2.8.4

7.3.3.1.1??7.3.3.1.2??7.3.3.1.3??7.3.3.1.4??7.3.3.2.1??7.3.3.2.2??7.3.3.2.3??7.3.3.2.4

7.3.3.3.1??7.3.3.3.2??7.3.3.3.3??7.3.3.3.4??7.3.3.4.1??7.3.3.4.2??7.3.3.4.3??7.3.3.4.4

7.3.3.5.1??7.3.3.5.2??7.3.3.5.3??7.3.3.5.4??7.3.3.6.1??7.3.3.6.2??7.3.3.6.3??7.3.3.6.4

7.3.3.7.1??7.3.3.7.2??7.3.3.7.3??7.3.3.7.4??7.3.3.8.1??7.3.3.8.2??7.3.3.8.3??7.3.3.8.4

7.3.4.1.1??7.3.4.1.2??7.3.4.1.3??7.3.4.1.4??7.3.4.2.1??7.3.4.2.2??7.3.4.2.3??7.3.4.2.4

7.3.4.3.1??7.3.4.3.2??7.3.4.3.3??7.3.4.3.4??7.3.4.4.1??7.3.4.4.2??7.3.4.4.3??7.3.4.4.4

7.3.4.5.1??7.3.4.5.2??7.3.4.5.3??7.3.4.5.4??7.3.4.6.1??7.3.4.6.2??7.3.4.6.3??7.3.4.6.4

7.3.4.7.1??7.3.4.7.2??7.3.4.7.3??7.3.4.7.4??7.3.4.8.1??7.3.4.8.2??7.3.4.8.3??7.3.4.8.4

7.4.1.1.1??7.4.1.1.2??7.4.1.1.3??7.4.1.1.4??7.4.1.2.1??7.4.1.2.2??7.4.1.2.3??7.4.1.2.4

7.4.1.3.1??7.4.1.3.2??7.4.1.3.3??7.4.1.3.4??7.4.1.4.1??7.4.1.4.2??7.4.1.4.3??7.4.1.4.4

7.4.1.5.1??7.4.1.5.2??7.4.1.5.3??7.4.1.5.4??7.4.1.6.1??7.4.1.6.2??7.4.1.6.3??7.4.1.6.4

7.4.1.7.1??7.4.1.7.2??7.4.1.7.3??7.4.1.7.4??7.4.1.8.1??7.4.1.8.2??7.4.1.8.3??7.4.1.8.4

7.4.2.1.1??7.4.2.1.2??7.4.2.1.3??7.4.2.1.4??7.4.2.2.1??7.4.2.2.2??7.4.2.2.3??7.4.2.2.4

7.4.2.3.1??7.4.2.3.2??7.4.2.3.3??7.4.2.3.4??7.4.2.4.1??7.4.2.4.2??7.4.2.4.3??7.4.2.4.4

7.4.2.5.1??7.4.2.5.2??7.4.2.5.3??7.4.2.5.4??7.4.2.6.1??7.4.2.6.2??7.4.2.6.3??7.4.2.6.4

7.4.2.7.1??7.4.2.7.2??7.4.2.7.3??7.4.2.7.4??7.4.2.8.1??7.4.2.8.2??7.4.2.8.3??7.4.2.8.4

7.4.3.1.1??7.4.3.1.2??7.4.3.1.3??7.4.3.1.4??7.4.3.2.1??7.4.3.2.2??7.4.3.2.3??7.4.3.2.4

7.4.3.3.1??7.4.3.3.2??7.4.3.3.3??7.4.3.3.4??7.4.3.4.1??7.4.3.4.2??7.4.3.4.3??7.4.3.4.4

7.4.3.5.1??7.4.3.5.2??7.4.3.5.3??7.4.3.5.4??7.4.3.6.1??7.4.3.6.2??7.4.3.6.3??7.4.3.6.4

7.4.3.7.1??7.4.3.7.2??7.4.3.7.3??7.4.3.7.4??7.4.3.8.1??7.4.3.8.2??7.4.3.8.3??7.4.3.8.4

Table 3-is continuous

7.4.4.1.1??7.4.4.1.2??7.4.4.1.3??7.4.4.1.4??7.4.4.2.1??7.4.4.2.2??7.4.4.2.3??7.4.4.2.4

7.4.4.3.1??7.4.4.3.2??7.4.4.3.3??7.4.4.3.4??7.4.4.4.1??7.4.4.4.2??7.4.4.4.3??7.4.4.4.4

7.4.4.5.1??7.4.4.5.2??7.4.4.5.3??7.4.4.5.4??7.4.4.6.1??7.4.4.6.2??7.4.4.6.3??7.4.4.6.4

7.4.4.7.1??7.4.4.7.2??7.4.4.7.3??7.4.4.7.4??7.4.4.8.1??7.4.4.8.2??7.4.4.8.3??7.4.4.8.4

7.5.1.1.1??7.5.1.1.2??7.5.1.1.3??7.5.1.1.4??7.5.1.2.1??7.5.1.2.2??7.5.1.2.3??7.5.1.2.4

7.5.1.3.1??7.5.1.3.2??7.5.1.3.3??7.5.1.3.4??7.5.1.4.1??7.5.1.4.2??7.5.1.4.3??7.5.1.4.4

7.5.1.5.1??7.5.1.5.2??7.5.1.5.3??7.5.1.5.4??7.5.1.6.1??7.5.1.6.2??7.5.1.6.3??7.5.1.6.4

7.5.1.7.1??7.5.1.7.2??7.5.1.7.3??7.5.1.7.4??7.5.1.8.1??7.5.1.8.2??7.5.1.8.3??7.5.1.8.4

7.5.2.1.1??7.5.2.1.2??7.5.2.1.3??7.5.2.1.4??7.5.2.2.1??7.5.2.2.2??7.5.2.2.3??7.5.2.2.4

7.5.2.3.1??7.5.2.3.2??7.5.2.3.3??7.5.2.3.4??7.5.2.4.1??7.5.2.4.2??7.5.2.4.3??7.5.2.4.4

7.5.2.5.1??7.5.2.5.2??7.5.2.5.3??7.5.2.5.4??7.5.2.6.1??7.5.2.6.2??7.5.2.6.3??7.5.2.6.4

7.5.2.7.1??7.5.2.7.2??7.5.2.7.3??7.5.2.7.4??7.5.2.8.1??7.5.2.8.2??7.5.2.8.3??7.5.2.8.4

7.5.3.1.1??7.5.3.1.2??7.5.3.1.3??7.5.3.1.4??7.5.3.2.1??7.5.3.2.2??7.5.3.2.3??7.5.3.2.4

7.5.3.3.1??7.5.3.3.2??7.5.3.3.3??7.5.3.3.4??7.5.3.4.1??7.5.3.4.2??7.5.3.4.3??7.5.3.4.4

7.5.3.5.1??7.5.3.5.2??7.5.3.5.3??7.5.3.5.4??7.5.3.6.1??7.5.3.6.2??7.5.3.6.3??7.5.3.6.4

7.5.3.7.1??7.5.3.7.2??7.5.3.7.3??7.5.3.7.4??7.5.3.8.1??7.5.3.8.2??7.5.3.8.3??7.5.3.8.4

7.5.4.1.1??7.5.4.1.2??7.5.4.1.3??7.5.4.1.4??7.5.4.2.1??7.5.4.2.2??7.5.4.2.3??7.5.4.2.4

7.5.4.3.1??7.5.4.3.2??7.5.4.3.3??7.5.4.3.4??7.5.4.4.1??7.5.4.4.2??7.5.4.4.3??7.5.4.4.4

7.5.4.5.1??7.5.4.5.2??7.5.4.5.3??7.5.4.5.4??7.5.4.6.1??7.5.4.6.2??7.5.4.6.3??7.5.4.6.4

7.5.4.7.1??7.5.4.7.2??7.5.4.7.3??7.5.4.7.4??7.5.4.8.1??7.5.4.8.2??7.5.4.8.3??7.5.4.8.4

7.6.1.1.1??7.6.1.1.2??7.6.1.1.3??7.6.1.1.4??7.6.1.2.1??7.6.1.2.2??7.6.1.2.3??7.6.1.2.4

7.6.1.3.1??7.6.1.3.2??7.6.1.3.3??7.6.1.3.4??7.6.1.4.1??7.6.1.4.2??7.6.1.4.3??7.6.1.4.4

7.6.1.5.1??7.6.1.5.2??7.6.1.5.3??7.6.1.5.4??7.6.1.6.1??7.6.1.6.2??7.6.1.6.3??7.6.1.6.4

7.6.1.7.1??7.6.1.7.2??7.6.1.7.3??7.6.1.7.4??7.6.1.8.1??7.6.1.8.2??7.6.1.8.3??7.6.1.8.4

7.6.2.1.1??7.6.2.1.2??7.6.2.1.3??7.6.2.1.4??7.6.2.2.1??7.6.2.2.2??7.6.2.2.3??7.6.2.2.4

7.6.2.3.1??7.6.2.3.2??7.6.2.3.3??7.6.2.3.4??7.6.2.4.1??7.6.2.4.2??7.6.2.4.3??7.6.2.4.4

7.6.2.5.1??7.6.2.5.2??7.6.2.5.3??7.6.2.5.4??7.6.2.6.1??7.6.2.6.2??7.6.2.6.3??7.6.2.6.4

7.6.2.7.1??7.6.2.7.2??7.6.2.7.3??7.6.2.7.4??7.6.2.8.1??7.6.2.8.2??7.6.2.8.3??7.6.2.8.4

7.6.3.1.1??7.6.3.1.2??7.6.3.1.3??7.6.3.1.4??7.6.3.2.1??7.6.3.2.2??7.6.3.2.3??7.6.3.2.4

7.6.3.3.1??7.6.3.3.2??7.6.3.3.3??7.6.3.3.4??7.6.3.4.1??7.6.3.4.2??7.6.3.4.3??7.6.3.4.4

7.6.3.5.1??7.6.3.5.2??7.6.3.5.3??7.6.3.5.4??7.6.3.6.1??7.6.3.6.2??7.6.3.6.3??7.6.3.6.4

7.6.3.7.1??7.6.3.7.2??7.6.3.7.3??7.6.3.7.4??7.6.3.8.1??7.6.3.8.2??7.6.3.8.3??7.6.3.8.4

7.6.4.1.1??7.6.4.1.2??7.6.4.1.3??7.6.4.1.4??7.6.4.2.1??7.6.4.2.2??7.6.4.2.3??7.6.4.2.4

7.6.4.3.1??7.6.4.3.2??7.6.4.3.3??7.6.4.3.4??7.6.4.4.1??7.6.4.4.2??7.6.4.4.3??7.6.4.4.4

7.6.4.5.1??7.6.4.5.2??7.6.4.5.3??7.6.4.5.4??7.6.4.6.1??7.6.4.6.2??7.6.4.6.3??7.6.4.6.4

7.6.4.7.1??7.6.4.7.2??7.6.4.7.3??7.6.4.7.4??7.6.4.8.1??7.6.4.8.2??7.6.4.8.3??7.6.4.8.4

7.7.1.1.1??7.7.1.1.2??7.7.1.1.3??7.7.1.1.4??7.7.1.2.1??7.7.1.2.2??7.7.1.2.3??7.7.1.2.4

7.7.1.3.1??7.7.1.3.2??7.7.1.3.3??7.7.1.3.4??7.7.1.4.1??7.7.1.4.2??7.7.1.4.3??7.7.1.4.4

7.7.1.5.1??7.7.1.5.2??7.7.1.5.3??7.7.1.5.4??7.7.1.6.1??7.7.1.6.2??7.7.1.6.3??7.7.1.6.4

7.7.1.7.1??7.7.1.7.2??7.7.1.7.3??7.7.1.7.4??7.7.1.8.1??7.7.1.8.2??7.7.1.8.3??7.7.1.8.4

7.7.2.1.1??7.7.2.1.2??7.7.2.1.3??7.7.2.1.4??7.7.2.2.1??7.7.2.2.2??7.7.2.2.3??7.7.2.2.4

7.7.2.3.1??7.7.2.3.2??7.7.2.3.3??7.7.2.3.4??7.7.2.4.1??7.7.2.4.2??7.7.2.4.3??7.7.2.4.4

7.7.2.5.1??7.7.2.5.2??7.7.2.5.3??7.7.2.5.4??7.7.2.6.1??7.7.2.6.2??7.7.2.6.3??7.7.2.6.4

7.7.2.7.1??7.7.2.7.2??7.7.2.7.3??7.7.2.7.4??7.7.2.8.1??7.7.2.8.2??7.7.2.8.3??7.7.2.8.4

7.7.3.1.1??7.7.3.1.2??7.7.3.1.3??7.7.3.1.4??7.7.3.2.1??7.7.3.2.2??7.7.3.2.3??7.7.3.2.4

7.7.3.3.1??7.7.3.3.2??7.7.3.3.3??7.7.3.3.4??7.7.3.4.1??7.7.3.4.2??7.7.3.4.3??7.7.3.4.4

Table 3-is continuous

7.7.3.5.1??7.7.3.5.2??7.7.3.5.3??7.7.3.5.4??7.7.3.6.1??7.7.3.6.2??7.7.3.6.3??7.7.3.6.4

7.7.3.7.1??7.7.3.7.2??7.7.3.7.3??7.7.3.7.4??7.7.3.8.1??7.7.3.8.2??7.7.3.8.3??7.7.3.8.4

7.7.4.1.1??7.7.4.1.2??7.7.4.1.3??7.7.4.1.4??7.7.4.2.1??7.7.4.2.2??7.7.4.2.3??7.7.4.2.4

7.7.4.3.1??7.7.4.3.2??7.7.4.3.3??7.7.4.3.4??7.7.4.4.1??7.7.4.4.2??7.7.4.4.3??7.7.4.4.4

7.7.4.5.1??7.7.4.5.2??7.7.4.5.3??7.7.4.5.4??7.7.4.6.1??7.7.4.6.2??7.7.4.6.3??7.7.4.6.4

7.7.4.7.1??7.7.4.7.2??7.7.4.7.3??7.7.4.7.4??7.7.4.8.1??7.7.4.8.2??7.7.4.8.3??7.7.4.8.4

7.8.1.1.1??7.8.1.1.2??7.8.1.1.3??7.8.1.1.4??7.8.1.2.1??7.8.1.2.2??7.8.1.2.3??7.8.1.2.4

7.8.1.3.1??7.8.1.3.2??7.8.1.3.3??7.8.1.3.4??7.8.1.4.1??7.8.1.4.2??7.8.1.4.3??7.8.1.4.4

7.8.1.5.1??7.8.1.5.2??7.8.1.5.3??7.8.1.5.4??7.8.1.6.1??7.8.1.6.2??7.8.1.6.3??7.8.1.6.4

7.8.1.7.1??7.8.1.7.2??7.8.1.7.3??7.8.1.7.4??7.8.1.8.1??7.8.1.8.2??7.8.1.8.3??7.8.1.8.4

7.8.2.1.1??7.8.2.1.2??7.8.2.1.3??7.8.2.1.4??7.8.2.2.1??7.8.2.2.2??7.8.2.2.3??7.8.2.2.4

7.8.2.3.1??7.8.2.3.2??7.8.2.3.3??7.8.2.3.4??7.8.2.4.1??7.8.2.4.2??7.8.2.4.3??7.8.2.4.4

7.8.2.5.1??7.8.2.5.2??7.8.2.5.3??7.8.2.5.4??7.8.2.6.1??7.8.2.6.2??7.8.2.6.3??7.8.2.6.4

7.8.2.7.1??7.8.2.7.2??7.8.2.7.3??7.8.2.7.4??7.8.2.8.1??7.8.2.8.2??7.8.2.8.3??7.8.2.8.4

7.8.3.1.1??7.8.3.1.2??7.8.3.1.3??7.8.3.1.4??7.8.3.2.1??7.8.3.2.2??7.8.3.2.3??7.8.3.2.4

7.8.3.3.1??7.8.3.3.2??7.8.3.3.3??7.8.3.3.4??7.8.3.4.1??7.8.3.4.2??7.8.3.4.3??7.8.3.4.4

7.8.3.5.1??7.8.3.5.2??7.8.3.5.3??7.8.3.5.4??7.8.3.6.1??7.8.3.6.2??7.8.3.6.3??7.8.3.6.4

7.8.3.7.1??7.8.3.7.2??7.8.3.7.3??7.8.3.7.4??7.8.3.8.1??7.8.3.8.2??7.8.3.8.3??7.8.3.8.4

7.8.4.1.1??7.8.4.1.2??7.8.4.1.3??7.8.4.1.4??7.8.4.2.1??7.8.4.2.2??7.8.4.2.3??7.8.4.2.4

7.8.4.3.1??7.8.4.3.2??7.8.4.3.3??7.8.4.3.4??7.8.4.4.1??7.8.4.4.2??7.8.4.4.3??7.8.4.4.4

7.8.4.5.1??7.8.4.5.2??7.8.4.5.3??7.8.4.5.4??7.8.4.6.1??7.8.4.6.2??7.8.4.6.3??7.8.4.6.4

7.8.4.7.1??7.8.4.7.2??7.8.4.7.3??7.8.4.7.4??7.8.4.8.1??7.8.4.8.2??7.8.4.8.3??7.8.4.8.4

8.1.1.1.1??8.1.1.1.2??8.1.1.1.3??8.1.1.1.4??8.1.1.2.1??8.1.1.2.2??8.1.1.2.3??8.1.1.2.4

8.1.1.3.1??8.1.1.3.2??8.1.1.3.3??8.1.1.3.4??8.1.1.4.1??8.1.1.4.2??8.1.1.4.3??8.1.1.4.4

8.1.1.5.1??8.1.1.5.2??8.1.1.5.3??8.1.1.5.4??8.1.1.6.1??8.1.1.6.2??8.1.1.6.3??8.1.1.6.4

8.1.1.7.1??8.1.1.7.2??8.1.1.7.3??8.1.1.7.4??8.1.1.8.1??8.1.1.8.2??8.1.1.8.3??8.1.1.8.4

8.1.2.1.1??8.1.2.1.2??8.1.2.1.3??8.1.2.1.4??8.1.2.2.1??8.1.2.2.2??8.1.2.2.3??8.1.2.2.4

8.1.2.3.1??8.1.2.3.2??8.1.2.3.3??8.1.2.3.4??8.1.2.4.1??8.1.2.4.2??8.1.2.4.3??8.1.2.4.4

8.1.2.5.1??8.1.2.5.2??8.1.2.5.3??8.1.2.5.4??8.1.2.6.1??8.1.2.6.2??8.1.2.6.3??8.1.2.6.4

8.1.2.7.1??8.1.2.7.2??8.1.2.7.3??8.1.2.7.4??8.1.2.8.1??8.1.2.8.2??8.1.2.8.3??8.1.2.8.4

8.1.3.1.1??8.1.3.1.2??8.1.3.1.3??8.1.3.1.4??8.1.3.2.1??8.1.3.2.2??8.1.3.2.3??8.1.3.2.4

8.1.3.3.1??8.1.3.3.2??8.1.3.3.3??8.1.3.3.4??8.1.3.4.1??8.1.3.4.2??8.1.3.4.3??8.1.3.4.4

8.1.3.5.1??8.1.3.5.2??8.1.3.5.3??8.1.3.5.4??8.1.3.6.1??8.1.3.6.2??8.1.3.6.3??8.1.3.6.4

8.1.3.7.1??8.1.3.7.2??8.1.3.7.3??8.1.3.7.4??8.1.3.8.1??8.1.3.8.2??8.1.3.8.3??8.1.3.8.4

8.1.4.1.1??8.1.4.1.2??8.1.4.1.3??8.1.4.1.4??8.1.4.2.1??8.1.4.2.2??8.1.4.2.3??8.1.4.2.4

8.1.4.3.1??8.1.4.3.2??8.1.4.3.3??8.1.4.3.4??8.1.4.4.1??8.1.4.4.2??8.1.4.4.3??8.1.4.4.4

8.1.4.5.1??8.1.4.5.2??8.1.4.5.3??8.1.4.5.4??8.1.4.6.1??8.1.4.6.2??8.1.4.6.3??8.1.4.6.4

8.1.4.7.1??8.1.4.7.2??8.1.4.7.3??8.1.4.7.4??8.1.4.8.1??8.1.4.8.2??8.1.4.8.3??8.1.4.8.4

8.2.1.1.1??8.2.1.1.2??8.2.1.1.3??8.2.1.1.4??8.2.1.2.1??8.2.1.2.2??8.2.1.2.3??8.2.1.2.4

8.2.1.3.1??8.2.1.3.2??8.2.1.3.3??8.2.1.3.4??8.2.1.4.1??8.2.1.4.2??8.2.1.4.3??8.2.1.4.4

8.2.1.5.1??8.2.1.5.2??8.2.1.5.3??8.2.1.5.4??8.2.1.6.1??8.2.1.6.2??8.2.1.6.3??8.2.1.6.4

8.2.1.7.1??8.2.1.7.2??8.2.1.7.3??8.2.1.7.4??8.2.1.8.1??8.2.1.8.2??8.2.1.8.3??8.2.1.8.4

8.2.2.1.1??8.2.2.1.2??8.2.2.1.3??8.2.2.1.4??8.2.2.2.1??8.2.2.2.2??8.2.2.2.3??8.2.2.2.4

8.2.2.3.1??8.2.2.3.2??8.2.2.3.3??8.2.2.3.4??8.2.2.4.1??8.2.2.4.2??8.2.2.4.3??8.2.2.4.4

8.2.2.5.1??8.2.2.5.2??8.2.2.5.3??8.2.2.5.4??8.2.2.6.1??8.2.2.6.2??8.2.2.6.3??8.2.2.6.4

8.2.2.7.1??8.2.2.7.2??8.2.2.7.3??8.2.2.7.4??8.2.2.8.1??8.2.2.8.2??8.2.2.8.3??8.2.2.8.4

Table 3-is continuous

8.2.3.1.1??8.2.3.1.2??8.2.3.1.3??8.2.3.1.4??8.2.3.2.1??8.2.3.2.2??8.2.3.2.3??8.2.3.2.4

8.2.3.3.1??8.2.3.3.2??8.2.3.3.3??8.2.3.3.4??8.2.3.4.1??8.2.3.4.2??8.2.3.4.3??8.2.3.4.4

8.2.3.5.1??8.2.3.5.2??8.2.3.5.3??8.2.3.5.4??8.2.3.6.1??8.2.3.6.2??8.2.3.6.3??8.2.3.6.4

8.2.3.7.1??8.2.3.7.2??8.2.3.7.3??8.2.3.7.4??8.2.3.8.1??8.2.3.8.2??8.2.3.8.3??8.2.3.8.4

8.2.4.1.1??8.2.4.1.2??8.2.4.1.3??8.2.4.1.4??8.2.4.2.1??8.2.4.2.2??8.2.4.2.3??8.2.4.2.4

8.2.4.3.1??8.2.4.3.2??8.2.4.3.3??8.2.4.3.4??8.2.4.4.1??8.2.4.4.2??8.2.4.4.3??8.2.4.4.4

8.2.4.5.1??8.2.4.5.2??8.2.4.5.3??8.2.4.5.4??8.2.4.6.1??8.2.4.6.2??8.2.4.6.3??8.2.4.6.4

8.2.4.7.1??8.2.4.7.2??8.2.4.7.3??8.2.4.7.4??8.2.4.8.1??8.2.4.8.2??8.2.4.8.3??8.2.4.8.4

8.3.1.1.1??8.3.1.1.2??8.3.1.1.3??8.3.1.1.4??8.3.1.2.1??8.3.1.2.2??8.3.1.2.3??8.3.1.2.4

8.3.1.3.1??8.3.1.3.2??8.3.1.3.3??8.3.1.3.4??8.3.1.4.1??8.3.1.4.2??8.3.1.4.3??8.3.1.4.4

8.3.1.5.1??8.3.1.5.2??8.3.1.5.3??8.3.1.5.4??8.3.1.6.1??8.3.1.6.2??8.3.1.6.3??8.3.1.6.4

8.3.1.7.1??8.3.1.7.2??8.3.1.7.3??8.3.1.7.4??8.3.1.8.1??8.3.1.8.2??8.3.1.8.3??8.3.1.8.4

8.3.2.1.1??8.3.2.1.2??8.3.2.1.3??8.3.2.1.4??8.3.2.2.1??8.3.2.2.2??8.3.2.2.3??8.3.2.2.4

8.3.2.3.1??8.3.2.3.2??8.3.2.3.3??8.3.2.3.4??8.3.2.4.1??8.3.2.4.2??8.3.2.4.3??8.3.2.4.4

8.3.2.5.1??8.3.2.5.2??8.3.2.5.3??8.3.2.5.4??8.3.2.6.1??8.3.2.6.2??8.3.2.6.3??8.3.2.6.4

8.3.2.7.1??8.3.2.7.2??8.3.2.7.3??8.3.2.7.4??8.3.2.8.1??8.3.2.8.2??8.3.2.8.3??8.3.2.8.4

8.3.3.1.1??8.3.3.1.2??8.3.3.1.3??8.3.3.1.4??8.3.3.2.1??8.3.3.2.2??8.3.3.2.3??8.3.3.2.4

8.3.3.3.1??8.3.3.3.2??8.3.3.3.3??8.3.3.3.4??8.3.3.4.1??8.3.3.4.2??8.3.3.4.3??8.3.3.4.4

8.3.3.5.1??8.3.3.5.2??8.3.3.5.3??8.3.3.5.4??8.3.3.6.1??8.3.3.6.2??8.3.3.6.3??8.3.3.6.4

8.3.3.7.1??8.3.3.7.2??8.3.3.7.3??8.3.3.7.4??8.3.3.8.1??8.3.3.8.2??8.3.3.8.3??8.3.3.8.4

8.3.4.1.1??8.3.4.1.2??8.3.4.1.3??8.3.4.1.4??8.3.4.2.1??8.3.4.2.2??8.3.4.2.3??8.3.4.2.4

8.3.4.3.1??8.3.4.3.2??8.3.4.3.3??8.3.4.3.4??8.3.4.4.1??8.3.4.4.2??8.3.4.4.3??8.3.4.4.4

8.3.4.5.1??8.3.4.5.2??8.3.4.5.3??8.3.4.5.4??8.3.4.6.1??8.3.4.6.2??8.3.4.6.3??8.3.4.6.4

8.3.4.7.1??8.3.4.7.2??8.3.4.7.3??8.3.4.7.4??8.3.4.8.1??8.3.4.8.2??8.3.4.8.3??8.3.4.8.4

8.4.1.1.1??8.4.1.1.2??8.4.1.1.3??8.4.1.1.4??8.4.1.2.1??8.4.1.2.2??8.4.1.2.3??8.4.1.2.4

8.4.1.3.1??8.4.1.3.2??8.4.1.3.3??8.4.1.3.4??8.4.1.4.1??8.4.1.4.2??8.4.1.4.3??8.4.1.4.4

8.4.1.5.1??8.4.1.5.2??8.4.1.5.3??8.4.1.5.4??8.4.1.6.1??8.4.1.6.2??8.4.1.6.3??8.4.1.6.4

8.4.1.7.1??8.4.1.7.2??8.4.1.7.3??8.4.1.7.4??8.4.1.8.1??8.4.1.8.2??8.4.1.8.3??8.4.1.8.4

8.4.2.1.1??8.4.2.1.2??8.4.2.1.3??8.4.2.1.4??8.4.2.2.1??8.4.2.2.2??8.4.2.2.3??8.4.2.2.4

8.4.2.3.1??8.4.2.3.2??8.4.2.3.3??8.4.2.3.4??8.4.2.4.1??8.4.2.4.2??8.4.2.4.3??8.4.2.4.4

8.4.2.5.1??8.4.2.5.2??8.4.2.5.3??8.4.2.5.4??8.4.2.6.1??8.4.2.6.2??8.4.2.6.3??8.4.2.6.4

8.4.2.7.1??8.4.2.7.2??8.4.2.7.3??8.4.2.7.4??8.4.2.8.1??8.4.2.8.2??8.4.2.8.3??8.4.2.8.4

8.4.3.1.1??8.4.3.1.2??8.4.3.1.3??8.4.3.1.4??8.4.3.2.1??8.4.3.2.2??8.4.3.2.3??8.4.3.2.4

8.4.3.3.1??8.4.3.3.2??8.4.3.3.3??8.4.3.3.4??8.4.3.4.1??8.4.3.4.2??8.4.3.4.3??8.4.3.4.4

8.4.3.5.1??8.4.3.5.2??8.4.3.5.3??8.4.3.5.4??8.4.3.6.1??8.4.3.6.2??8.4.3.6.3??8.4.3.6.4

8.4.3.7.1??8.4.3.7.2??8.4.3.7.3??8.4.3.7.4??8.4.3.8.1??8.4.3.8.2??8.4.3.8.3??8.4.3.8.4

8.4.4.1.1??8.4.4.1.2??8.4.4.1.3??8.4.4.1.4??8.4.4.2.1??8.4.4.2.2??8.4.4.2.3??8.4.4.2.4

8.4.4.3.1??8.4.4.3.2??8.4.4.3.3??8.4.4.3.4??8.4.4.4.1??8.4.4.4.2??8.4.4.4.3??8.4.4.4.4

8.4.4.5.1??8.4.4.5.2??8.4.4.5.3??8.4.4.5.4??8.4.4.6.1??8.4.4.6.2??8.4.4.6.3??8.4.4.6.4

8.4.4.7.1??8.4.4.7.2??8.4.4.7.3??8.4.4.7.4??8.4.4.8.1??8.4.4.8.2??8.4.4.8.3??8.4.4.8.4

8.5.1.1.1??8.5.1.1.2??8.5.1.1.3??8.5.1.1.4??8.5.1.2.1??8.5.1.2.2??8.5.1.2.3??8.5.1.2.4

8.5.1.3.1??8.5.1.3.2??8.5.1.3.3??8.5.1.3.4??8.5.1.4.1??8.5.1.4.2??8.5.1.4.3??8.5.1.4.4

8.5.1.5.1??8.5.1.5.2??8.5.1.5.3??8.5.1.5.4??8.5.1.6.1??8.5.1.6.2??8.5.1.6.3??8.5.1.6.4

8.5.1.7.1??8.5.1.7.2??8.5.1.7.3??8.5.1.7.4??8.5.1.8.1??8.5.1.8.2??8.5.1.8.3??8.5.1.8.4

8.5.2.1.1??8.5.2.1.2??8.5.2.1.3??8.5.2.1.4??8.5.2.2.1??8.5.2.2.2??8.5.2.2.3??8.5.2.2.4

8.5.2.3.1??8.5.2.3.2??8.5.2.3.3??8.5.2.3.4??8.5.2.4.1??8.5.2.4.2??8.5.2.4.3??8.5.2.4.4

Table 3-is continuous

8.5.2.5.1??8.5.2.5.2??8.5.2.5.3??8.5.2.5.4??8.5.2.6.1??8.5.2.6.2??8.5.2.6.3??8.5.2.6.4

8.5.2.7.1??8.5.2.7.2??8.5.2.7.3??8.5.2.7.4??8.5.2.8.1??8.5.2.8.2??8.5.2.8.3??8.5.2.8.4

8.5.3.1.1??8.5.3.1.2??8.5.3.1.3??8.5.3.1.4??8.5.3.2.1??8.5.3.2.2??8.5.3.2.3??8.5.3.2.4

8.5.3.3.1??8.5.3.3.2??8.5.3.3.3??8.5.3.3.4??8.5.3.4.1??8.5.3.4.2??8.5.3.4.3??8.5.3.4.4

8.5.3.5.1??8.5.3.5.2??8.5.3.5.3??8.5.3.5.4??8.5.3.6.1??8.5.3.6.2??8.5.3.6.3??8.5.3.6.4

8.5.3.7.1??8.5.3.7.2??8.5.3.7.3??8.5.3.7.4??8.5.3.8.1??8.5.3.8.2??8.5.3.8.3??8.5.3.8.4

8.5.4.1.1??8.5.4.1.2??8.5.4.1.3??8.5.4.1.4??8.5.4.2.1??8.5.4.2.2??8.5.4.2.3??8.5.4.2.4

8.5.4.3.1??8.5.4.3.2??8.5.4.3.3??8.5.4.3.4??8.5.4.4.1??8.5.4.4.2??8.5.4.4.3??8.5.4.4.4

8.5.4.5.1??8.5.4.5.2??8.5.4.5.3??8.5.4.5.4??8.5.4.6.1??8.5.4.6.2??8.5.4.6.3??8.5.4.6.4

8.5.4.7.1??8.5.4.7.2??8.5.4.7.3??8.5.4.7.4??8.5.4.8.1??8.5.4.8.2??8.5.4.8.3??8.5.4.8.4

8.6.1.1.1??8.6.1.1.2??8.6.1.1.3??8.6.1.1.4??8.6.1.2.1??8.6.1.2.2??8.6.1.2.3??8.6.1.2.4

8.6.1.3.1??8.6.1.3.2??8.6.1.3.3??8.6.1.3.4??8.6.1.4.1??8.6.1.4.2??8.6.1.4.3??8.6.1.4.4

8.6.1.5.1??8.6.1.5.2??8.6.1.5.3??8.6.1.5.4??8.6.1.6.1??8.6.1.6.2??8.6.1.6.3??8.6.1.6.4

8.6.1.7.1??8.6.1.7.2??8.6.1.7.3??8.6.1.7.4??8.6.1.8.1??8.6.1.8.2??8.6.1.8.3??8.6.1.8.4

8.6.2.1.1??8.6.2.1.2??8.6.2.1.3??8.6.2.1.4??8.6.2.2.1??8.6.2.2.2??8.6.2.2.3??8.6.2.2.4

8.6.2.3.1??8.6.2.3.2??8.6.2.3.3??8.6.2.3.4??8.6.2.4.1??8.6.2.4.2??8.6.2.4.3??8.6.2.4.4

8.6.2.5.1??8.6.2.5.2??8.6.2.5.3??8.6.2.5.4??8.6.2.6.1??8.6.2.6.2??8.6.2.6.3??8.6.2.6.4

8.6.2.7.1??8.6.2.7.2??8.6.2.7.3??8.6.2.7.4??8.6.2.8.1??8.6.2.8.2??8.6.2.8.3??8.6.2.8.4

8.6.3.1.1??8.6.3.1.2??8.6.3.1.3??8.6.3.1.4??8.6.3.2.1??8.6.3.2.2??8.6.3.2.3??8.6.3.2.4

8.6.3.3.1??8.6.3.3.2??8.6.3.3.3??8.6.3.3.4??8.6.3.4.1??8.6.3.4.2??8.6.3.4.3??8.6.3.4.4

8.6.3.5.1??8.6.3.5.2??8.6.3.5.3??8.6.3.5.4??8.6.3.6.1??8.6.3.6.2??8.6.3.6.3??8.6.3.6.4

8.6.3.7.1??8.6.3.7.2??8.6.3.7.3??8.6.3.7.4??8.6.3.8.1??8.6.3.8.2??8.6.3.8.3??8.6.3.8.4

8.6.4.1.1??8.6.4.1.2??8.6.4.1.3??8.6.4.1.4??8.6.4.2.1??8.6.4.2.2??8.6.4.2.3??8.6.4.2.4

8.6.4.3.1??8.6.4.3.2??8.6.4.3.3??8.6.4.3.4??8.6.4.4.1??8.6.4.4.2??8.6.4.4.3??8.6.4.4.4

8.6.4.5.1??8.6.4.5.2??8.6.4.5.3??8.6.4.5.4??8.6.4.6.1??8.6.4.6.2??8.6.4.6.3??8.6.4.6.4

8.6.4.7.1??8.6.4.7.2??8.6.4.7.3??8.6.4.7.4??8.6.4.8.1??8.6.4.8.2??8.6.4.8.3??8.6.4.8.4

8.7.1.1.1??8.7.1.1.2??8.7.1.1.3??8.7.1.1.4??8.7.1.2.1??8.7.1.2.2??8.7.1.2.3??8.7.1.2.4

8.7.1.3.1??8.7.1.3.2??8.7.1.3.3??8.7.1.3.4??8.7.1.4.1??8.7.1.4.2??8.7.1.4.3??8.7.1.4.4

8.7.1.5.1??8.7.1.5.2??8.7.1.5.3??8.7.1.5.4??8.7.1.6.1??8.7.1.6.2??8.7.1.6.3??8.7.1.6.4

8.7.1.7.1??8.7.1.7.2??8.7.1.7.3??8.7.1.7.4??8.7.1.8.1??8.7.1.8.2??8.7.1.8.3??8.7.1.8.4

8.7.2.1.1??8.7.2.1.2??8.7.2.1.3??8.7.2.1.4??8.7.2.2.1??8.7.2.2.2??8.7.2.2.3??8.7.2.2.4

8.7.2.3.1??8.7.2.3.2??8.7.2.3.3??8.7.2.3.4??8.7.2.4.1??8.7.2.4.2??8.7.2.4.3??8.7.2.4.4

8.7.2.5.1??8.7.2.5.2??8.7.2.5.3??8.7.2.5.4??8.7.2.6.1??8.7.2.6.2??8.7.2.6.3??8.7.2.6.4

8.7.2.7.1??8.7.2.7.2??8.7.2.7.3??8.7.2.7.4??8.7.2.8.1??8.7.2.8.2??8.7.2.8.3??8.7.2.8.4

8.7.3.1.1??8.7.3.1.2??8.7.3.1.3??8.7.3.1.4??8.7.3.2.1??8.7.3.2.2??8.7.3.2.3??8.7.3.2.4

8.7.3.3.1??8.7.3.3.2??8.7.3.3.3??8.7.3.3.4??8.7.3.4.1??8.7.3.4.2??8.7.3.4.3??8.7.3.4.4

8.7.3.5.1??8.7.3.5.2??8.7.3.5.3??8.7.3.5.4??8.7.3.6.1??8.7.3.6.2??8.7.3.6.3??8.7.3.6.4

8.7.3.7.1??8.7.3.7.2??8.7.3.7.3??8.7.3.7.4??8.7.3.8.1??8.7.3.8.2??8.7.3.8.3??8.7.3.8.4

8.7.4.1.1??8.7.4.1.2??8.7.4.1.3??8.7.4.1.4??8.7.4.2.1??8.7.4.2.2??8.7.4.2.3??8.7.4.2.4

8.7.4.3.1??8.7.4.3.2??8.7.4.3.3??8.7.4.3.4??8.7.4.4.1??8.7.4.4.2??8.7.4.4.3??8.7.4.4.4

8.7.4.5.1??8.7.4.5.2??8.7.4.5.3??8.7.4.5.4??8.7.4.6.1??8.7.4.6.2??8.7.4.6.3??8.7.4.6.4

8.7.4.7.1??8.7.4.7.2??8.7.4.7.3??8.7.4.7.4??8.7.4.8.1??8.7.4.8.2??8.7.4.8.3??8.7.4.8.4

8.8.1.1.1??8.8.1.1.2??8.8.1.1.3??8.8.1.1.4??8.8.1.2.1??8.8.1.2.2??8.8.1.2.3??8.8.1.2.4

8.9.1.3.1??8.8.1.3.2??8.8.1.3.3??8.8.1.3.4??8.8.1.4.1??8.8.1.4.2??8.8.1.4.3??8.8.1.4.4

8.8.1.5.1??8.8.1.5.2??8.8.1.5.3??8.8.1.5.4??8.8.1.6.1??8.8.1.6.2??8.8.1.6.3??8.8.1.6.4

8.8.1.7.1??8.8.1.7.2??8.8.1.7.3??8.8.1.7.4??8.8.1.8.1??8.8.1.8.2??8.8.1.8.3??8.8.1.8.4

8.8.2.1.1??8.8.2.1.2??8.8.2.1.3??8.8.2.1.4??8.8.2.2.1??8.8.2.2.2??8.8.2.2.3??8.8.2.2.4

8.8.2.3.1??8.8.2.3.2??8.8.2.3.3??8.8.2.3.4??8.8.2.4.1??8.8.2.4.2??8.8.2.4.3??8.8.2.4.4

8.8.2.5.1??8.8.2.5.2??8.8.2.5.3??8.8.2.5.4??8.8.2.6.1??8.8.2.6.2??8.8.2.6.3??8.8.2.6.4

Table 3-is continuous

8.8.2.7.1??8.8.2.7.2??8.8.2.7.3??8.8.2.7.4??8.8.2.8.1??8.8.2.8.2??8.8.2.8.3??8.8.2.8.4

8.8.3.1.1??8.8.3.1.2??8.8.3.1.3??8.8.3.1.4??8.8.3.2.1??8.8.3.2.2??8.8.3.2.3??8.8.3.2.4

8.8.3.3.1??8.8.3.3.2??8.8.3.3.3??8.8.3.3.4??8.8.3.4.1??8.8.3.4.2??8.8.3.4.3??8.8.3.4.4

8.8.3.5.1??8.8.3.5.2??8.8.3.5.3??8.8.3.5.4??8.8.3.6.1??8.8.3.6.2??8.8.3.6.3??8.8.3.6.4

8.8.3.7.1??8.8.3.7.2??8.8.3.7.3??8.8.3.7.4??8.8.3.8.1??8.8.3.8.2??8.8.3.8.3??8.8.3.8.4

8.8.4.1.1??8.8.4.1.2??8.8.4.1.3??8.8.4.1.4??8.8.4.2.1??8.8.4.2.2??8.8.4.2.3??8.8.4.2.4

8.8.4.3.1??8.8.4.3.2??8.8.4.3.3??8.8.4.3.4??8.8.4.4.1??8.8.4.4.2??8.8.4.4.3??8.8.4.4.4

8.8.4.5.1??8.8.4.5.2??8.8.4.5.3??8.8.4.5.4??8.8.4.6.1??8.8.4.6.2??8.8.4.6.3??8.8.4.6.4

8.8.4.7.1??8.8.4.7.2??8.8.4.7.3??8.8.4.7.4??8.8.4.8.1??8.8.4.8.2??8.8.4.8.3??8.8.4.8.4

Therefore, has the formula in table 3, named from 1 group each variable B, the X, D and the E substituting group that are called 2.4.1.1.1 (v) compound appointment-NH ₂Be A ,-Pr-n is B, furans-2,5-two bases are X ,-H be D and-H is E, thereby this compound be 2-amino-5-propyl group-6-[2-(5-phosphono) furyl as compound 15.14 for preparing in embodiment 15] pyridine.Formula (in the table 3 v) the name compound for have pyridyl as formula I in R ⁵Compound.Similarly, use the formula that is called 2.1.1.1.3 in 1 group the substituent table 3 of each variable B, X, D and E (v) compound has 2-amino-3-ethyl-6-[2-(5-phosphono) furyl as compound 15.12 of preparation in embodiment 15] structure of pyridine.

Formula (in the table 3 vi) the name compound for have pyrazinyl as formula I in R ⁵Compound.(a preferred pyrazine compound of name is 2.1.1.0.4 vi) in the formula of table 3.Use each variable of 1 group, 2.1.1.0.4 has 2-amino-3-propyl group-6-[2-(phosphono) furyl] structure of pyrazine and in embodiment 17 as compound 17.3 preparations.Similarly, formula (in the table 3 vii) the name compound for have pyrimidyl as formula I in R ⁵Compound.In table 3, be called 2.4.1.1.0 formula (vii) compound (using all variablees of 1 group) has 2-amino-5-propyl group-6-[2-(phosphono) furyl] structure of pyrimidine and in embodiment 16 as compound 16.1 preparations.Similarly, formula (in the table 3 viii) the name compound for have pyrimidyl as formula I in R ⁵Compound.Therefore, use 1 group variable, the compound that is called 1.0.1.1.1 in table 3 has 2-[2-(5-phosphono) furyl] structure of pyrimidine and in embodiment 16 as compound 16.5 preparations.

Formula (v), (vi), (vii), (viii) and (ix) in the compound, in table 3, use 1-4 group to variable B, to the 1-2 group of variable X, list in the table 4 to the 1-3 group of variables D with to some exemplary of the compound of the 1-3 group name of variable E.

Table 4

Compound number for A.B.X.D. E	Synthetic embodiment number	Structural formula	??A	Group ^*	??B	Group ^*	??X ^**	Group ^*	??D	Group ^*	??E
Compound number for A.B.X.D. E	Synthetic embodiment number	Structural formula	??A	Group ^*	??B	Group ^*	??X ^**	Group ^*	??D	Group ^*	??E	??1.1.1.1.1	??15.6	??(v)	??H	??1	??H	??1	Furans-2,5-two bases	??1	??H	??1	??H
??1.1.2.1.1	??12.1	??(v)	??H	??1	??H	??1	Pyridine-2,6-two bases	??1	??H	??1	??H	??1.1.1.1.1	??15.6	??(v)	??H	??1	??H	??1	Furans-2,5-two bases	??1	??H	??1	??H
??1.1.2.1.1	??12.1	??(v)	??H	??1	??H	??1	Pyridine-2,6-two bases	??1	??H	??1	??H	??6.1.4.2.1	??13.1	??(v)	??Me	??1	??H	??5	??CH2OCH2	??2	??Me	??1	??H
??6.1.1.2.1	??15.15	??(v)	??Me	??1	??H	??1	Furans-2,5-two bases	??1	??Me	??2	??Br	??6.1.4.2.1	??13.1	??(v)	??Me	??1	??H	??5	??CH2OCH2	??2	??Me	??1	??H
??6.1.1.2.1	??15.15	??(v)	??Me	??1	??H	??1	Furans-2,5-two bases	??1	??Me	??2	??Br	??4.1.1.1.1	??15.9	??(v)	??Cl	??1	??H	??1	Furans-2,5-two bases	??1	??H	??1	??H
??1.8.1.1.2	??15.10	??(v)	??H	??1	??Cl	??1	Furans-2,5-two bases	??1	??H	??2	??Cl	??4.1.1.1.1	??15.9	??(v)	??Cl	??1	??H	??1	Furans-2,5-two bases	??1	??H	??1	??H
??1.8.1.1.2	??15.10	??(v)	??H	??1	??Cl	??1	Furans-2,5-two bases	??1	??H	??2	??Cl	??6.7.1.1.1	??15.5	??(v)	??Me	??1	??Br	??1	Furans-2,5-two bases	??1	??H	??1	??H
??2.1.1.1.1	??15.1	??(v)	??NH2	??1	??H	??1	Furans-2,5-two bases	??1	??H	??1	??H	??6.7.1.1.1	??15.5	??(v)	??Me	??1	??Br	??1	Furans-2,5-two bases	??1	??H	??1	??H
??2.1.1.1.1	??15.1	??(v)	??NH2	??1	??H	??1	Furans-2,5-two bases	??1	??H	??1	??H	??2.7.1.1.1	??15.2	??(v)	??NH2	??1	??Br	??1	Furans-2,5-two bases	??1	??H	??1	??H
??2.7.1.1.1	??15.3	??(v)	??NH2	??1	??Br	??1	Furans-2,5-two bases	??1	??H	??2	??Br	??2.7.1.1.1	??15.2	??(v)	??NH2	??1	??Br	??1	Furans-2,5-two bases	??1	??H	??1	??H
??2.7.1.1.1	??15.3	??(v)	??NH2	??1	??Br	??1	Furans-2,5-two bases	??1	??H	??2	??Br	??2.3.1.1.3	??15.4	??(v)	??NH2	??1	??Et	??1	Furans-2,5-two bases	??1	??H	??1	??Et
??2.1.1.1.3	??15.12	??(v)	??NH2	??1	??H	??1	Furans-2,5-two bases	??1	??H	??1	??Et	??2.3.1.1.3	??15.4	??(v)	??NH2	??1	??Et	??1	Furans-2,5-two bases	??1	??H	??1	??Et
??2.1.1.1.3	??15.12	??(v)	??NH2	??1	??H	??1	Furans-2,5-two bases	??1	??H	??1	??Et	??2.3.1.1.1	??15.13	??(v)	??NH2	??1	??Et	??1	Furans-2,5-two bases	??1	??H	??1	??H
??2.4.1.1.1	??15.14	??(v)	??NH2	??1	??Pr-n	??1	Furans-2,5-two bases	??1	??H	??1	??H	??2.3.1.1.1	??15.13	??(v)	??NH2	??1	??Et	??1	Furans-2,5-two bases	??1	??H	??1	??H
??2.4.1.1.1	??15.14	??(v)	??NH2	??1	??Pr-n	??1	Furans-2,5-two bases	??1	??H	??1	??H	??2.4.1.1.0	??16.1	??(vii)	??NH2	??1	??Pr-n	??1	Furans-2,5-two bases	??1	??H		Do not have
??2.4.1.1.0	??16.2	??(vii)	??NH2	??2	??Bu-i	??1	Furans-2,5-two bases	??1	??H		Do not have	??2.4.1.1.0	??16.1	??(vii)	??NH2	??1	??Pr-n	??1	Furans-2,5-two bases	??1	??H		Do not have
??2.4.1.1.0	??16.2	??(vii)	??NH2	??2	??Bu-i	??1	Furans-2,5-two bases	??1	??H		Do not have	??2.4.4.2.0	??13.2	??(vii)	??NH2	??1	??Pr-n	??2	??CH2OCH2	??1	??Me		Do not have
??2.1.1.2.0	??16.6	??(vii)	??NH2	??1	??H	??1	Furans-2,5-two bases	??1	??Me		Do not have	??2.4.4.2.0	??13.2	??(vii)	??NH2	??1	??Pr-n	??2	??CH2OCH2	??1	??Me		Do not have
??2.1.1.2.0	??16.6	??(vii)	??NH2	??1	??H	??1	Furans-2,5-two bases	??1	??Me		Do not have	??6.1.1.1.0	??16.8	??(vii)	??Me	??1	??H	??1	Furans-2,5-two bases	??1	??H		Do not have
??2.1.1.1.0	??16.3	??(vii)	??NH2	??1	??H	??1	Furans-2,5-two bases	??1	??H		Do not have	??6.1.1.1.0	??16.8	??(vii)	??Me	??1	??H	??1	Furans-2,5-two bases	??1	??H		Do not have
??2.1.1.1.0	??16.3	??(vii)	??NH2	??1	??H	??1	Furans-2,5-two bases	??1	??H		Do not have	??2.3.1.1.0	??16.4	??(vii)	??NH2	??1	??Et	??1	Furans-2,5-two bases	??1	??H		Do not have
??1.0.1.7.2	??16.5	??(viii)	??H		Do not have	??1	Furans-2,5-two bases	??1	??H	??1	??H	??2.3.1.1.0	??16.4	??(vii)	??NH2	??1	??Et	??1	Furans-2,5-two bases	??1	??H		Do not have
??1.0.1.7.2	??16.5	??(viii)	??H		Do not have	??1	Furans-2,5-two bases	??1	??H	??1	??H	??6.0.1.7.2	??16.9	??(viii)	??Me		Do not have	??1	Furans-2,5-two bases	??1	??Br	??1	??Me
??6.2.1.0.1	??17.1	??(vi)	??Me	??1	??Me	??1	Furans-2,5-two bases		Do not have	??1	??H	??6.0.1.7.2	??16.9	??(viii)	??Me		Do not have	??1	Furans-2,5-two bases	??1	??Br	??1	??Me
??6.2.1.0.1	??17.1	??(vi)	??Me	??1	??Me	??1	Furans-2,5-two bases		Do not have	??1	??H	??4.1.1.0.1	??17.2	??(vi)	??Cl	??1	??H	??1	Furans-2,5-two bases		Do not have	??1	??H
??2.1.1.0.4	??17.3	??(vi)	??NH2	??1	??H	??1	Furans-2,5-two bases		Do not have	??1	??Pr-n	??4.1.1.0.1	??17.2	??(vi)	??Cl	??1	??H	??1	Furans-2,5-two bases		Do not have	??1	??H
??2.1.1.0.4	??17.3	??(vi)	??NH2	??1	??H	??1	Furans-2,5-two bases		Do not have	??1	??Pr-n	??2.8.1.0.1	??15.19	??(vii)	??NH2	??1	??Cl	??1	Furans-2,5-two bases	??1	??H		Do not have
??2.1.1.5.0	??16.11	??(vii)	??NH2	??1	??H	??1	Furans-2,5-two bases	??1	??SMe		Do not have	??2.8.1.0.1	??15.19	??(vii)	??NH2	??1	??Cl	??1	Furans-2,5-two bases	??1	??H		Do not have
??2.1.1.5.0	??16.11	??(vii)	??NH2	??1	??H	??1	Furans-2,5-two bases	??1	??SMe		Do not have	??1.8.1.0.1	??17.6	??(vi)	??H	??2	??SMe	??I	Furans-2,5-two bases		Do not have	??1	??H
??2.7.1.5.0	??16.12	??(vii)	??NH2	??1	??Br	??1	Furans-2,5-two bases	??1	??SMe		Do not have	??1.8.1.0.1	??17.6	??(vi)	??H	??2	??SMe	??I	Furans-2,5-two bases		Do not have	??1	??H

??2.8.1.0.1	??17.7	??(vi)	??NH2	??2	??SMe	??1	Furans-2,5-two bases		Do not have	??1	??H
??2.8.1.0.1	??17.7	??(vi)	??NH2	??2	??SMe	??1	Furans-2,5-two bases		Do not have	??1	??H	??2.1.1.0.3	??17.8	??(vi)	??NH2	??1	??H	??1	Furans-2,5-two bases		Do not have	??3	??SMe
??2.8.1.0.1	??17.9	??(vi)	??NH2	??1	??Cl	??1	Furans-2,5-two bases		Do not have	??3	??CO2Me	??2.1.1.0.3	??17.8	??(vi)	??NH2	??1	??H	??1	Furans-2,5-two bases		Do not have	??3	??SMe
??2.8.1.0.1	??17.9	??(vi)	??NH2	??1	??Cl	??1	Furans-2,5-two bases		Do not have	??3	??CO2Me	??1.1.3.1.1	??18.8	??(v)	??H	??1	??H	??1	??C(O)NHCH2	??1	??H	??1	??H
??1.1.1.1.1	??18.9	??(v)	??H	??1	??H	??2	??NHC(O)CH2	??1	??H	??1	??H	??1.1.3.1.1	??18.8	??(v)	??H	??1	??H	??1	??C(O)NHCH2	??1	??H	??1	??H
??1.1.1.1.1	??18.9	??(v)	??H	??1	??H	??2	??NHC(O)CH2	??1	??H	??1	??H	??2.1.1.1.2	??15.19	??(v)	??NH2	??1	??H	??1	Furans-2,5-two bases	??1	??H	??3	??Pr-c
??2.6.1.1.1	??15.20	??(v)	??NH2	??1	??Pr-c	??1	Furans-2,5-two bases	??1	??H	??1	??H	??2.1.1.1.2	??15.19	??(v)	??NH2	??1	??H	??1	Furans-2,5-two bases	??1	??H	??3	??Pr-c
??2.6.1.1.1	??15.20	??(v)	??NH2	??1	??Pr-c	??1	Furans-2,5-two bases	??1	??H	??1	??H	??2.8.1.0.1	??17.10	??(vi)	??NH2	??2	??SMe	??1	Furans-2,5-two bases		Do not have	??1	??H
??6.2.1.1.1	??15.22	??(v)	??Me	??2	??CN	??1	Furans-2,5-two bases	??1	??H	??1	??H	??2.8.1.0.1	??17.10	??(vi)	??NH2	??2	??SMe	??1	Furans-2,5-two bases		Do not have	??1	??H
??6.2.1.1.1	??15.22	??(v)	??Me	??2	??CN	??1	Furans-2,5-two bases	??1	??H	??1	??H	??2.2.1.2.4	??15.23	??(v)	??NH2	??2	??CN	??1	Furans-2,5-two bases	??1	??Me	??2	??CN
??1.1.3.1.1	??30.1	??(v)	??H	??1	??H	??2	Acetylene-1,2-two bases	??1	??H	??1	??H	??2.2.1.2.4	??15.23	??(v)	??NH2	??2	??CN	??1	Furans-2,5-two bases	??1	??Me	??2	??CN
??1.1.3.1.1	??30.1	??(v)	??H	??1	??H	??2	Acetylene-1,2-two bases	??1	??H	??1	??H	??2.1.1.1.1	??18.23	??(v)	??NH2	??1	??H	??2	??NHC(O)CH2	??1	??H	??1	??H
??4.1.1.3.1	??15.24	??(v)	??Cl	??1	??H	??1	Furans-2,5-two bases	??2	??CN	??1	??H	??2.1.1.1.1	??18.23	??(v)	??NH2	??1	??H	??2	??NHC(O)CH2	??1	??H	??1	??H
??4.1.1.3.1	??15.24	??(v)	??Cl	??1	??H	??1	Furans-2,5-two bases	??2	??CN	??1	??H	??2.0.1.8.1	??16.14	??(viii)	??NH2		Do not have	??1	Furans-2,5-two bases	??1	??Cl	??1	??H
??2.1.1.1.1	??18.25	??(v)	??NH2	??1	??H	??2	??NHC(O)CH2	??1	??H	??2	??Br	??2.0.1.8.1	??16.14	??(viii)	??NH2		Do not have	??1	Furans-2,5-two bases	??1	??Cl	??1	??H
??2.1.1.1.1	??18.25	??(v)	??NH2	??1	??H	??2	??NHC(O)CH2	??1	??H	??2	??Br	??2.7.1.1.1	??18.26	??(v)	??NH2	??1	??Br	??2	??NHC(O)CH2	??1	??H	??2	??Br
??2.3.1.1.3	??18.28	??(v)	??NH2	??1	??Et	??2	??NHC(O)CH2	??1	??H	??1	??Et	??2.7.1.1.1	??18.26	??(v)	??NH2	??1	??Br	??2	??NHC(O)CH2	??1	??H	??2	??Br
??2.3.1.1.3	??18.28	??(v)	??NH2	??1	??Et	??2	??NHC(O)CH2	??1	??H	??1	??Et	??2.8.1.2.0	??33.1	??(vii)	??NH2	??1	??Cl	??1	Furans-2,5-two bases	??1	??Me		Do not have
??2.0.1.7.1	??33.13	??(viii)	??NH2		Do not have	??1	Furans-2,5-two bases	??2	??OMe	??1	??H	??2.8.1.2.0	??33.1	??(vii)	??NH2	??1	??Cl	??1	Furans-2,5-two bases	??1	??Me		Do not have
??2.0.1.7.1	??33.13	??(viii)	??NH2		Do not have	??1	Furans-2,5-two bases	??2	??OMe	??1	??H	??1.7.1.0.1	??33.14	??(vi)	??H	??4	??OMe	??1	Furans-2,5-two bases		Do not have	??1	??H
??1.7.1.0.1	??33.27	??(vi)	??H	??2	??OEt	??1	Furans-2,5-two bases		Do not have	??1	??H	??1.7.1.0.1	??33.14	??(vi)	??H	??4	??OMe	??1	Furans-2,5-two bases		Do not have	??1	??H
??1.7.1.0.1	??33.27	??(vi)	??H	??2	??OEt	??1	Furans-2,5-two bases		Do not have	??1	??H	??4.1.1.3.1	??33.36	??(v)	??Cl	??1	??H	??1	Furans-2,5-two bases	??2	??CN	??1	??H
??4.1.1.6.1	??33.38	??(v)	??Cl	??1	??H	??1	Furans-2,5-two bases	??2	??C(O)NH2	??1	??H	??4.1.1.3.1	??33.36	??(v)	??Cl	??1	??H	??1	Furans-2,5-two bases	??2	??CN	??1	??H
??4.1.1.6.1	??33.38	??(v)	??Cl	??1	??H	??1	Furans-2,5-two bases	??2	??C(O)NH2	??1	??H	??4.1.1.4.1	??33.39	??(v)	??Cl	??1	??H	??1	Furans-2,5-two bases	??1	??CO2Et	??1	??H
??4.1.1.2.4	??33.41	??(v)	??Cl	??1	??H	??1	Furans-2,5-two bases	??1	??Me	??2	??CN	??4.1.1.4.1	??33.39	??(v)	??Cl	??1	??H	??1	Furans-2,5-two bases	??1	??CO2Et	??1	??H
??4.1.1.2.4	??33.41	??(v)	??Cl	??1	??H	??1	Furans-2,5-two bases	??1	??Me	??2	??CN	??4.1.1.8.4	??33.43	??(v)	??Cl	??1	??H	??1	Furans-2,5-two bases	??2	??CF3	??2	??CN
??0.2.1.2.1	??33.44	??(ix)	Do not have	??1	??Me	??1	Furans-2,5-two bases	??1	??Me	??2	??Br	??4.1.1.8.4	??33.43	??(v)	??Cl	??1	??H	??1	Furans-2,5-two bases	??2	??CF3	??2	??CN
??0.2.1.2.1	??33.44	??(ix)	Do not have	??1	??Me	??1	Furans-2,5-two bases	??1	??Me	??2	??Br	??0.2.1.2.2	??33.45	??(ix)	Do not have	??1	??Me	??1	Furans-2,5-two bases	??1	??Me	??2	??Cl
??3.2.1.1.0	??33.46	??(vii)	??Br	??1	??Me	??1	Furans-2,5-two bases	??1	??H		Do not have	??0.2.1.2.2	??33.45	??(ix)	Do not have	??1	??Me	??1	Furans-2,5-two bases	??1	??Me	??2	??Cl
??3.2.1.1.0	??33.46	??(vii)	??Br	??1	??Me	??1	Furans-2,5-two bases	??1	??H		Do not have	??3.7.1.1.0	??33.47	??(vii)	??Br	??1	??Br	??1	Furans-2,5-two bases	??1	??H		Do not have
??3.1.1.2.0	??33.48	??(vii)	??Br	??1	??H	??1	Furans-2,5-two bases	??1	??Me		Do not have	??3.7.1.1.0	??33.47	??(vii)	??Br	??1	??Br	??1	Furans-2,5-two bases	??1	??H		Do not have
??3.1.1.2.0	??33.48	??(vii)	??Br	??1	??H	??1	Furans-2,5-two bases	??1	??Me		Do not have	??3.8.1.7.0	??33.50	??(vii)	??Br	??1	??Cl	??1	Furans-2,5-two bases	??1	??Br		Do not have
??2.1.1.7.0	??33.52	??(vii)	??NH2	??1	??H	??1	Furans-2,5-two bases	??1	??Br		Do not have	??3.8.1.7.0	??33.50	??(vii)	??Br	??1	??Cl	??1	Furans-2,5-two bases	??1	??Br		Do not have
??2.1.1.7.0	??33.52	??(vii)	??NH2	??1	??H	??1	Furans-2,5-two bases	??1	??Br		Do not have	??3.1.1.7.0	??33.54	??(vii)	??Br	??1	??H	??1	Furans-2,5-two bases	??1	??Br		Do not have
??3.1.1.8.0	??33.55	??(vii)	??Br	??1	??H	??1	Furans-2,5-two bases	??1	??Cl		Do not have	??3.1.1.7.0	??33.54	??(vii)	??Br	??1	??H	??1	Furans-2,5-two bases	??1	??Br		Do not have
??3.1.1.8.0	??33.55	??(vii)	??Br	??1	??H	??1	Furans-2,5-two bases	??1	??Cl		Do not have	??1.7.1.0.1	??33.56	??(vi)	??H	??1	??Br	??1	Furans-2,5-two bases		Do not have	??1	??H

??2.8.1.0.1	??33.57	??(vi)	?NH2	??1	??Cl	??1	Furans-2,5-two bases		Do not have	??3	??CO2Me
??2.8.1.0.1	??33.57	??(vi)	?NH2	??1	??Cl	??1	Furans-2,5-two bases		Do not have	??3	??CO2Me	??1.8.1.0.1	??33.59	??(vi)	?H	??3	?OPr-n	??1	Furans-2,5-two bases		Do not have	??1	??H
??6.1.1.1.1	??33.97	??(v)	?Me	??1	??H	??2	??NHC(O)CH2	??1	??H	??1	??H	??1.8.1.0.1	??33.59	??(vi)	?H	??3	?OPr-n	??1	Furans-2,5-two bases		Do not have	??1	??H
??6.1.1.1.1	??33.97	??(v)	?Me	??1	??H	??2	??NHC(O)CH2	??1	??H	??1	??H	??1.2.1.1.1	??33.98	??(v)	?H	??1	??Me	??2	??NHC(O)CH2	??1	??H	??1	??H
??2.1.1.1.2	??33.99	??(v)	?NH2	??1	??H	??2	??NHC(O)CH2	??1	??H	??2	??Cl	??1.2.1.1.1	??33.98	??(v)	?H	??1	??Me	??2	??NHC(O)CH2	??1	??H	??1	??H
??2.1.1.1.2	??33.99	??(v)	?NH2	??1	??H	??2	??NHC(O)CH2	??1	??H	??2	??Cl	??2.8.1.1.1	??33.100	??(v)	?NH2	??1	??Cl	??2	??NHC(O)CH2	??1	??H	??1	??H
??6.1.1.2.1	??33.102	??(v)	?Me	??1	??H	??2	??NHC(O)CH2	??1	??Me	??1	??H	??2.8.1.1.1	??33.100	??(v)	?NH2	??1	??Cl	??2	??NHC(O)CH2	??1	??H	??1	??H
??6.1.1.2.1	??33.102	??(v)	?Me	??1	??H	??2	??NHC(O)CH2	??1	??Me	??1	??H	??1.1.1.1.2	??33.103	??(v)	?H	??1	??H	??2	??NHC(O)CH2	??1	??H	??2	??Cl
??1.1.1.1.1	??33.104	??(v)	?H	??1	??H	??2	??NHC(O)CH2	??1	??H	??2	??Br	??1.1.1.1.2	??33.103	??(v)	?H	??1	??H	??2	??NHC(O)CH2	??1	??H	??2	??Cl
??1.1.1.1.1	??33.104	??(v)	?H	??1	??H	??2	??NHC(O)CH2	??1	??H	??2	??Br	??5.1.1.1.1	??33.105	??(v)	?Me	??1	??H	??2	??NHC(O)CH2	??1	??H	??2	??Br
??1.1.1.1.1	??33.106	??(v)	?H	??1	??H	??2	??NHC(O)CH2	??1	??H	??1	??H	??5.1.1.1.1	??33.105	??(v)	?Me	??1	??H	??2	??NHC(O)CH2	??1	??H	??2	??Br
??1.1.1.1.1	??33.106	??(v)	?H	??1	??H	??2	??NHC(O)CH2	??1	??H	??1	??H	??1.1.1.1.2	??33.107	??(v)	?H	??1	??H	??2	??NHC(O)CH2	??1	??H	??1	??Me
??1.1.1.2.1	??33.108	??(v)	?H	??1	??H	??2	??NHC(O)CH2	??1	??Me	??1	??H	??1.1.1.1.2	??33.107	??(v)	?H	??1	??H	??2	??NHC(O)CH2	??1	??H	??1	??Me
??1.1.1.2.1	??33.108	??(v)	?H	??1	??H	??2	??NHC(O)CH2	??1	??Me	??1	??H	??6.8.1.2.0	??33.109	??(vii)	?Me	??1	??Cl	??2	??NHC(O)CH2	??1	??Me		Do not have
??4.1.1.0.1	??33.110	??(vi)	?Cl	??1	??H	??2	??NHC(O)CH2	??1	Do not have	??1	??H	??6.8.1.2.0	??33.109	??(vii)	?Me	??1	??Cl	??2	??NHC(O)CH2	??1	??Me		Do not have
??4.1.1.0.1	??33.110	??(vi)	?Cl	??1	??H	??2	??NHC(O)CH2	??1	Do not have	??1	??H	??1.7.1.1.2	??33.111	??(v)	?H	??1	??Br	??2	??NHC(O)CH2	??1	??H	??1	??Me
??1.1.1.3.1	??33.114	??(v)	?H	??1	??H	??2	??NHC(O)CH2	??1	??Et	??1	??H	??1.7.1.1.2	??33.111	??(v)	?H	??1	??Br	??2	??NHC(O)CH2	??1	??H	??1	??Me
??1.1.1.3.1	??33.114	??(v)	?H	??1	??H	??2	??NHC(O)CH2	??1	??Et	??1	??H	??6.3.1.1.1	??33.115	??(v)	?Me	??1	??Et	??2	??NHC(O)CH2	??1	??H	??1	??H
??6.1.1.1.1	??33.116	??(v)	?Me	??1	??H	??2	??NHC(O)CH2	??1	??H	??2	??Br	??6.3.1.1.1	??33.115	??(v)	?Me	??1	??Et	??2	??NHC(O)CH2	??1	??H	??1	??H
??6.1.1.1.1	??33.116	??(v)	?Me	??1	??H	??2	??NHC(O)CH2	??1	??H	??2	??Br	??1.7.1.1.2	??33.117	??(v)	?H	??1	??Br	??2	??NHC(O)CH2	??1	??H	??1	??Me
??1.2.1.1.1	??33.118	??(v)	?H	??1	??Me	??2	??NHC(O)CH2	??1	??H	??2	??Br	??1.7.1.1.2	??33.117	??(v)	?H	??1	??Br	??2	??NHC(O)CH2	??1	??H	??1	??Me
??1.2.1.1.1	??33.118	??(v)	?H	??1	??Me	??2	??NHC(O)CH2	??1	??H	??2	??Br	??6.7.1.1.1	??33.119	??(v)	?Me	??1	??Br	??2	??NHC(O)CH2	??1	??H	??2	??Br
??1.1.3.1.1	??33.120	??(v)	?H	??1	??H	??1	??C(O)NHCH2	??I	??H	??1	??H	??6.7.1.1.1	??33.119	??(v)	?Me	??1	??Br	??2	??NHC(O)CH2	??1	??H	??2	??Br
??1.1.3.1.1	??33.120	??(v)	?H	??1	??H	??1	??C(O)NHCH2	??I	??H	??1	??H	??6.1.3.1.1	??33.121	??(v)	?Me	??1	??H	??1	??C(O)NHCH2	??1	??H	??1	??H
??3.1.3.1.1	??33.123	??(v)	?Br	??1	??H	??1	??C(O)NHCH2	??1	??H	??1	??H	??6.1.3.1.1	??33.121	??(v)	?Me	??1	??H	??1	??C(O)NHCH2	??1	??H	??1	??H
??3.1.3.1.1	??33.123	??(v)	?Br	??1	??H	??1	??C(O)NHCH2	??1	??H	??1	??H	??4.1.3.1.1	??33.124	??(v)	?Cl	??1	??H	??1	??C(O)NHCH2	??1	??H	??1	??H
??1.1.3.8.1	??33.125	??(v)	?H	??1	??H	??1	??C(O)NHCH2	??1	??Cl	??1	??H	??4.1.3.1.1	??33.124	??(v)	?Cl	??1	??H	??1	??C(O)NHCH2	??1	??H	??1	??H
??1.1.3.8.1	??33.125	??(v)	?H	??1	??H	??1	??C(O)NHCH2	??1	??Cl	??1	??H	??1.1.3.0.1	??33.127	??(vi)	?H	??1	??H	??1	??C(O)NHCH2		Do not have	??1	??H
??1.8.3.1.1	??33.130	??(v)	?H	??3	?OPr-n	??1	??C(O)NHCH2	??1	??H	??1	??H	??1.1.3.0.1	??33.127	??(vi)	?H	??1	??H	??1	??C(O)NHCH2		Do not have	??1	??H
??1.8.3.1.1	??33.130	??(v)	?H	??3	?OPr-n	??1	??C(O)NHCH2	??1	??H	??1	??H	??4.8.3.1.1	??33.131	??(v)	?Cl	??1	??Cl	??1	??C(O)NHCH2	??1	??H	??1	??H
??4.7.3.1.1	??33.132	??(v)	?Cl	??3	??CF3	??1	??C(O)NHCH2	??1	??H	??1	??H	??4.8.3.1.1	??33.131	??(v)	?Cl	??1	??Cl	??1	??C(O)NHCH2	??1	??H	??1	??H
??4.7.3.1.1	??33.132	??(v)	?Cl	??3	??CF3	??1	??C(O)NHCH2	??1	??H	??1	??H	??1.8.3.8.2	??33.134	??(v)	?H	??1	??Cl	??1	??C(O)NHCH2	??1	??Cl	??2	??Cl
??1.1.3.0.2	??33.140	??(vi)	?H	??1	??H	??1	??C(O)NHCH2		Do not have	??1	??Me	??1.8.3.8.2	??33.134	??(v)	?H	??1	??Cl	??1	??C(O)NHCH2	??1	??Cl	??2	??Cl
??1.1.3.0.2	??33.140	??(vi)	?H	??1	??H	??1	??C(O)NHCH2		Do not have	??1	??Me	??1.2.3.1.1	??33.141	??(v)	?H	??1	??Me	??1	??C(O)NHCH2	??1	??H	??1	??H
??4.8.3.8.2	??33.142	??(v)	?Cl	??1	??Cl	??1	??C(O)NHCH2	??1	??Cl	??2	??Cl	??1.2.3.1.1	??33.141	??(v)	?H	??1	??Me	??1	??C(O)NHCH2	??1	??H	??1	??H
??4.8.3.8.2	??33.142	??(v)	?Cl	??1	??Cl	??1	??C(O)NHCH2	??1	??Cl	??2	??Cl

* the group number before B, X, D or the E indicates compound group, and wherein corresponding B, X, D or E are selected.

The direction of * X group is defined as from R ⁵Direction to phosphorus atom.

Specified numeral also relates to preferred benzothiazole and the benzoazole compounds of formula X in the table 3.These preferred compounds be shown in following structural formula (x) and (xi) in:

(x) (xi)

According to the following regulations: B.X.A.D.E, preferred formula (x) and (xi) compound by give top formula (x) and (xi) in the designation number of B, X, A, D and E list in the table 3.For each part, structure is endowed the numeral in the following table of being shown in to B, X, A, D and E.

Variable B is divided into 2 groups, lists 8 kinds of different substituting groups for every group.The substituting group of his-and-hers watches 3 Chinese styles (x) and variable B (xi) is given down column of figure:

1 group of substituting group of his-and-hers watches 3 Chinese styles (x) and variable B (xi) is given down column of figure:

	??1	??2	??3	??4	??5	??6	??7	??8
	??1	??2	??3	??4	??5	??6	??7	??8	??B＝	??H	??Me	??Et	??Pr-n	??Pr-c	??Pr-i	??Br	??Cl

2 groups of substituting groups to variable B are given down column of figure:

	??1	??2	??3	??4	??5	??6	?7	??8
	??1	??2	??3	??4	??5	??6	?7	??8	?B＝	??CN	??F	??OMe	??OEt	??SMe	??SEt	?CH ₂OH	??C(O)OEt

Variable X is selected from 8 different substituting groups, uses following numeral:

Table X.

	??1	??2	??3	?4	??5	??6	??7	?8
	??1	??2	??3	?4	??5	??6	??7	?8	??X＝	??OCH ₂	??SCH ₂	??CH ₂CH ₂	?CH ₂CH ₂CH ₂	??CH ₂CF ₂	??NHCH ₂	??OC(O)	?SC(O)

The direction of X group be defined as suc as formula (x) and (xi) by the direction of heterocycle to phosphorus atom.

Variables A is selected from 4 kinds of following numeral different substituting groups:

Table A.

	??1	??2	??3	??4
	??1	??2	??3	??4	??A＝	??H	??NH ₂	??Br	??Cl

Variables D is selected from 8 kinds of following numeral different substituting groups:

Table D.

	??1	??2	??3	??4	??5	??6	??7	??8
	??1	??2	??3	??4	??5	??6	??7	??8	?D＝	??H	??Me	??Et	??C(O)OMe	??CH ₂OMe	??SMe	??SEt	??OMe

Variable E is selected from 4 kinds of following numeral different substituting groups:

Table E.

	??1	??2	??3	??4
	??1	??2	??3	??4	??E＝	??H	??Me	??Et	??F

Therefore, use is to 1 group of variable B, and formula (x) compound regulation-H that is called 1.1.2.1.1 in table 3 is B ,-OCH ₂-be X ,-NH ₂Be A ,-H be D and-H is E, and this compound be the 2-amino as the compound 34.2-4-phosphonium mesitoyl methoxy benzothiazole for preparing among the embodiment 34.Similarly, use is to 1 group of variable B, and formula (x) compound regulation-H that is called 1.2.2.1.1 in the table 3 is B ,-SCH ₂-be X ,-NH ₂Be A ,-H be D and-H is E, and this compound is as the 2-amino-4-phosphono methylthio group benzo thiazole of compound 46.1 among the embodiment 46.

Similarly, use is called 2-amino as the compound 37.4-7-ethoxy carbonyl-4-phosphonium mesitoyl methoxy benzothiazole of formula (x) compound of 8.1.2.1.1 for preparation in embodiment 37 to 2 groups of variable B in the table 3.

The example of the preferred compound of formula X also includes, but is not limited to the pharmacy acceptable salt and the prodrug of the compound of name in table 5:

Table 5

	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Ph	??OCH2
	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Ph	??OCH2	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Pr-i	??OCH2
	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Pr-c	??OCH2	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Pr-i	??OCH2
	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Pr-c	??OCH2	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Br	??OCH2
	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Cl	??OCH2	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Br	??OCH2
	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Cl	??OCH2	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??F	??OCH2
	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??I	??OCH2	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??F	??OCH2
	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??I	??OCH2	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??NMe2	??OCH2
	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??C(O)OEt	??OCH2	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??NMe2	??OCH2
	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??C(O)OEt	??OCH2	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??C(O)NH2	??OCH2
	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??OMe	??OCH2	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??C(O)NH2	??OCH2
	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??OMe	??OCH2	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??OH	??OCH2
	??H	??S	??C7(CH2)3C6	??C7(CH2)3C6	??H	??OCH2	??NH2	??S	??C7(CH2)3C6	??C7(CH2)3C6	??OH	??OCH2
	??H	??S	??C7(CH2)3C6	??C7(CH2)3C6	??H	??OCH2	??H	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Me	??OCH2
	??H	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Et	??OCH2	??H	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Me	??OCH2
	??H	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Et	??OCH2	??H	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Ph	??OCH2
	??H	??S	??C7(CH2)3C6	??C7(CH2)3C6	??OMe	??OCH2	??H	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Ph	??OCH2
	??H	??S	??C7(CH2)3C6	??C7(CH2)3C6	??OMe	??OCH2	??H	??S	??C7(CH2)3C6	??C7(CH2)3C6	??C(O)OMe	??OCH2
	??H	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Br	??OCH2	??H	??S	??C7(CH2)3C6	??C7(CH2)3C6	??C(O)OMe	??OCH2
	??H	??S	??C7(CH2)3C6	??C7(CH2)3C6	??Br	??OCH2	??H	??S	??C7(CH2)3C6	??C7(CH2)3C6	??OH	??OCH2
??36.2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??H	??OcH2	??H	??S	??C7(CH2)3C6	??C7(CH2)3C6	??OH	??OCH2
??36.2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??H	??OcH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Me	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Et	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Me	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Et	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Pr-i	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Pr-c	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Pr-i	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Pr-c	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??OMe	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Br	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??OMe	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Br	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??I	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Cl	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??I	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Cl	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??F	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??NMe2	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??F	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??NMe2	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??C(O)OMe	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??C(O)OEt	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??C(O)OMe	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??C(O)OEt	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Ph	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??CF3	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Ph	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??CF3	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??CN	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??C(O)NH2	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??CN	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??C(O)NH2	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??SMe	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??SEt	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??SMe	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??SEt	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??CO2H	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??OH	??OCH2	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??CO2H	??OCH2
	??NH2	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??OH	??OCH2	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??H	??OCH2
	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Me	??OCH2	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??H	??OCH2
	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Me	??OCH2	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??H	??OCH2
	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Me	??OCH2	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??H	??OCH2
	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Me	??OCH2	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Et	??OCH2
	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??OMe	??OCH2	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Et	??OCH2
	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??OMe	??OCH2	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Ph	??OCH2
	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Br	??OCH2	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Ph	??OCH2
	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Br	??OCH2	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Cl	??OCH2
	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??OH	??OCH2	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??Cl	??OCH2
	??H	??S	??C7(CH＝CH＝CH＝CH)C6	??C7(CH＝CH＝CH＝CH)C6	??OH	??OCH2	??NH2	??S	??C7OCH＝CHC6	??C7OCH＝CHC6	??H	??OCH2
	??NH2	??S	??C7O-CH＝CHC6	??C7O-CH＝CHC6	??Me	??OCH2	??NH2	??S	??C7OCH＝CHC6	??C7OCH＝CHC6	??H	??OCH2

??NH2	??S	??C7O-CH＝CHC6	??C7O-CH＝CHC6	??Ph	??OCH2
??NH2	??S	??C7O-CH＝CHC6	??C7O-CH＝CHC6	??Ph	??OCH2	??NH2	??S	??C7O-CH＝CHC6	??C7O-CH＝CHC6	??Br	??OCH2
??NH2	??S	??C7O-CH＝CHC6	??C7O-CH＝CHC6	??OH	??OCH2	??NH2	??S	??C7O-CH＝CHC6	??C7O-CH＝CHC6	??Br	??OCH2
??NH2	??S	??C7O-CH＝CHC6	??C7O-CH＝CHC6	??OH	??OCH2	??NH2	??S	??C7O-CH＝CHC6	??C7O-CH＝CHC6	??OMe	??OCH2
??NH2	??S	??C7CH＝CH-OC6	??C7CH＝CH-OC6	??H	??OCH2	??NH2	??S	??C7O-CH＝CHC6	??C7O-CH＝CHC6	??OMe	??OCH2
??NH2	??S	??C7CH＝CH-OC6	??C7CH＝CH-OC6	??H	??OCH2	??NH2	??S	??C7CH＝CH-OC6	??C7CH＝CH-OC6	??Me	??OCH2
??NH2	??S	??C7CH＝CH-OC6	??C7CH＝CH-OC6	??Br	??OCH2	??NH2	??S	??C7CH＝CH-OC6	??C7CH＝CH-OC6	??Me	??OCH2
??NH2	??S	??C7CH＝CH-OC6	??C7CH＝CH-OC6	??Br	??OCH2	??NH2	??S	??C7CH＝CH-OC6	??C7CH＝CH-OC6	??Ph	??OCH2
??NH2	??S	??C7CH＝CH-OC6	??C7CH＝CH-OC6	??OH	??OCH2	??NH2	??S	??C7CH＝CH-OC6	??C7CH＝CH-OC6	??Ph	??OCH2
??NH2	??S	??C7CH＝CH-OC6	??C7CH＝CH-OC6	??OH	??OCH2	??NH2	??S	??C7CH＝CH-OC6	??C7CH＝CH-OC6	??OMe	??OCH2
??NH2	??S	??C7S-CH＝CHC6	??C7S-CH＝CHC6	??H	??OCH2	??NH2	??S	??C7CH＝CH-OC6	??C7CH＝CH-OC6	??OMe	??OCH2
??NH2	??S	??C7S-CH＝CHC6	??C7S-CH＝CHC6	??H	??OCH2	??NH2	??S	??C7S-CH＝CHC6	??C7S-CH＝CHC6	??Me	??OCH2
??NH2	??S	??C7S-CH＝CHC6	??C7S-CH＝CHC6	??Ph	??OCH2	??NH2	??S	??C7S-CH＝CHC6	??C7S-CH＝CHC6	??Me	??OCH2
??NH2	??S	??C7S-CH＝CHC6	??C7S-CH＝CHC6	??Ph	??OCH2	??NH2	??S	??C7S-CH＝CHC6	??C7S-CH＝CHC6	??OH	??OCH2
??NH2	??S	??C7S-CH＝CHC6	??C7S-CH＝CHC6	??OMe	??OCH2	??NH2	??S	??C7S-CH＝CHC6	??C7S-CH＝CHC6	??OH	??OCH2
??NH2	??S	??C7S-CH＝CHC6	??C7S-CH＝CHC6	??OMe	??OCH2	??NH2	??S	??C7S-CH＝CHC6	??C7S-CH＝CHC6	Isobutyl-	??OCH2
??NH2	??S	??Me	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2	??NH2	??S	??C7S-CH＝CHC6	??C7S-CH＝CHC6	Isobutyl-	??OCH2
??NH2	??S	??Me	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2	??NH2	??S	??Et	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2
??NH2	??S	??Pr-n	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2	??NH2	??S	??Et	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2
??NH2	??S	??Pr-n	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2	??NH2	??S	??OMe	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2
??NH2	??S	??OH	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2	??NH2	??S	??OMe	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2
??NH2	??S	??OH	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2	??NH2	??S	??OCH3	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2
??NH2	??S	??Cl	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5??	??OCH2	??NH2	??S	??OCH3	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2
??NH2	??S	??Cl	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5??	??OCH2	??NH2	??S	??Br	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2
??NH2	??S	??F	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2	??NH2	??S	??Br	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2
??NH2	??S	??F	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2	??NH2	??S	??CH2OH	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2
??NH2	??S	??H	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2	??NH2	??S	??CH2OH	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2
??NH2	??S	??H	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2	??NH2	??S	??C(O)OMe	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2
??NH2	??S	??H	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2	??NH2	??S	??C(O)OMe	??C6(CH＝CH＝CH＝CH)C5	??C6(CH＝CH＝CH＝CH)C5	??OCH2
??NH2	??S	??H	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2	??NH2	??S	??Me	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
??NH2	??S	??Et	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2	??NH2	??S	??Me	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
??NH2	??S	??Et	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2	??NH2	??S	??OH	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
??NH2	??S	??OMe	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2	??NH2	??S	??OH	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
??NH2	??S	??OMe	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2	??NH2	??S	??CH2OH	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
??NH2	??S	??Br	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2	??NH2	??S	??CH2OH	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
??NH2	??S	??Br	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2	??NH2	??S	??Cl	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
??NH2	??S	??C(O)OMe	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2	??NH2	??S	??Cl	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
??NH2	??S	??C(O)OMe	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2	??NH2	??S	??H	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2
??NH2	??S	??Me	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2	??NH2	??S	??H	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2
??NH2	??S	??Me	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2	??NH2	??S	??Et	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2
??NH2	??S	??CH2OH	??C6O-CH＝CHC5	??C6O-CH＝CHC5????????	??OCH2	??NH2	??S	??Et	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2
??NH2	??S	??CH2OH	??C6O-CH＝CHC5	??C6O-CH＝CHC5????????	??OCH2	??NH2	??S	??Br	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2
??NH2	??S	??Cl	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2	??NH2	??S	??Br	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2
??NH2	??S	??Cl	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2	??NH2	??S	??Ph	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2
??NH2	??S	??OMe	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2	??NH2	??S	??Ph	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2
??NH2	??S	??OMe	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2	??NH2	??S	??Pr-n	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2
??NH2	??S	??C(O)OMe	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2	??NH2	??S	??Pr-n	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2
??NH2	??S	??C(O)OMe	??C6O-CH＝CHC5	??C6O-CH＝CHC5	??OCH2	??NH2	??S	??H	??C6S-CH＝CHC5	??C6S-CH＝CHC5	??OCH2
??NH2	??S	??Me	??C6S-CH＝CHC5	??C6S-CH＝CHC5	??OCH2	??NH2	??S	??H	??C6S-CH＝CHC5	??C6S-CH＝CHC5	??OCH2
??NH2	??S	??Me	??C6S-CH＝CHC5	??C6S-CH＝CHC5	??OCH2	??NH2	??S	??Et	??C6S-CH＝CHC5	??C6S-CH＝CHC5	??OCH2
??NH2	??S	??OH	??CS6-CH＝CHC5	??C6S-CH＝CHC5	??OCH2	??NH2	??S	??Et	??C6S-CH＝CHC5	??C6S-CH＝CHC5	??OCH2
??NH2	??S	??OH	??CS6-CH＝CHC5	??C6S-CH＝CHC5	??OCH2	??NH2	??S	??OMe	??C6S-CH＝CHC5	??C6S-CH＝CHC5	??OCH2

In the table 1 specified numeral also be expressed as follows formula (xii) and (xiii) shown in the preferred prodrug of formula I compound:

(xii)

(xiii)

At following formula (xii) with (xiii), Ar represents aryl, comprises heteroaryl, and by R ²⁵Replace.According to the following regulations: X.R ⁵.R ²⁵.Ar, preferred formula (xii) and (xiii) compound list in by give following formula (xii) and (xiii) in X, R ⁵, R ²⁵In the table 1 of the numeral of Ar.

Variable X is selected from 7 different substituting groups, uses following numeral:

Table X.

	??1	?2	??3	?4	??5	?6	??7
	??1	?2	??3	?4	??5	?6	??7	?X＝	Furans-2,5-two bases	?C(O)O ?CH ₂	??C(O)NH ??CH ₂	?NHC(O)CH ₂	Pyridine-2,6-two bases	?CH ₂OCH ₂	??C(O)SCH ₂

Table 5

Synthetic embodiment number	??A	??Y	??B	??D	??E	??X
Synthetic embodiment number	??A	??Y	??B	??D	??E	??X		??Me	??S	??C7(CH2)4C6	??C7(CH2)4C6	??Pr-n	??OCH2
	??Me	??S	??C7(CH2)4C6	??C7(CH2)4C6	??Ph	??OCH2		??Me	??S	??C7(CH2)4C6	??C7(CH2)4C6	??Pr-n	??OCH2
	??Me	??S	??C7(CH2)4C6	??C7(CH2)4C6	??Ph	??OCH2		??Me	??S	??C7(CH2)4C6	??C7(CH2)4C6	??OH	??OCH2
	??Me	??S	??C7(CH2)4C6	??C7(CH2)4C6	??Br	??OCH2		??Me	??S	??C7(CH2)4C6	??C7(CH2)4C6	??OH	??OCH2
	??Me	??S	??C7(CH2)4C6	??C7(CH2)4C6	??Br	??OCH2		??Me	??S	??C7(CH2)4C6	??C7(CH2)4C6	??Cl	??OCH2
	??Me	??S	??C7(CH2)4C6	??C7(CH2)4C6	??C(O)OMe	??OCH2		??Me	??S	??C7(CH2)4C6	??C7(CH2)4C6	??Cl	??OCH2
	??Me	??S	??C7(CH2)4C6	??C7(CH2)4C6	??C(O)OMe	??OCH2		??Me	??S	??C7(CH2)4C6	??C7(CH2)4C6	??NMe2	??OCH2
	??NH2	??S	??H	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2		??Me	??S	??C7(CH2)4C6	??C7(CH2)4C6	??NMe2	??OCH2
	??NH2	??S	??H	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2		??NH2	??S	??Me	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
	??NH2	??S	??Et	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2		??NH2	??S	??Me	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
	??NH2	??S	??Et	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2		??NH2	??S	??Pr-n	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
	??NH2	??S	??Br	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2		??NH2	??S	??Pr-n	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
	??NH2	??S	??Br	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2		??NH2	??S	??Cl	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
	??NH2	??S	??OH	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2		??NH2	??S	??Cl	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
	??NH2	??S	??OH	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2		??NH2	??S	??CF3	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
	??NH2	??S	??C(O)OMe	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2		??NH2	??S	??CF3	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
	??NH2	??S	??C(O)OMe	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2		??NH2	??S	??Ph	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
	??NH2	??S	??NMe2	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2		??NH2	??S	??Ph	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2
	??NH2	??S	??NMe2	??C6(CH2)4C5	??C6(CH2)4C5	??OCH2	??44.1	??Br	??S	??C7(CH2)4C6	??C7(CH2)4C6	??H	??OCH2

In table 1 specified numeral also be expressed as follows formula (xii) and (xiii) shown in the prodrug of preferred formula I compound:

(xii)

(xiii)

At following formula (xii) with (xiii), Ar represents aryl, comprises heteroaryl, and by R ²⁵Replace.According to the following regulations: X.R ⁵.R ²⁵.Ar, preferred formula (xii) and (xiii) compound list in by give following formula (xii) and (xiii) in X, R ⁵, R ²⁵In the table 1 of the designation number of Ar.

Table X.

Variable R ⁵Be selected from 9 kinds of different substituting groups giving down column of figure:

Table R ⁵

Variable R ²⁵Be selected from 9 kinds of different substituting groups giving down column of figure:

Table R ²⁵

	??1	??2	??3	??4	??5	??6	??7	??8	??9
	??1	??2	??3	??4	??5	??6	??7	??8	??9	?R ²⁵＝	??F	??Cl	??Br	??CN	??CF ₃	??Me	??Et	??OMe	??NHAc

Variables A r is selected from 6 kinds of different substituting groups giving down column of figure:

Table A r

The formula (xii) or formula (xiii) compound of name are expressed by each numeral in the table 1 in formula of listing in (xii) or the formula (xiii) in table 1, but undeclared stereochemistry is because this compound all has biologic activity as non-enantiomer mixture or as single steric isomer.

Use is to X, R ⁵, R ²⁵With the variable of Ar, the formula of called after 1.2.2.2 (xii) compound regulation furans-2 in table 1,5-two bases are R for X, 4-(2-amino-5-isobutyl-) thiazole ⁵, chloro is R ⁵With the 3-chlorophenyl be Ar; this compound is 2-amino-5-isobutyl--4-{2-[5-(1-(3-chlorophenyl)-1, the 3-propyl group) phosphono as compound 19.46 (main isomer) and 19.45 (less important isomer) of preparation among the embodiment 19] furyl } thiazole.

In table 3 specified numeral also be expressed as follows formula (xiv) and (xv) shown in the prodrug of preferred formula I compound:

(xiv)

(xv)

In formula (xiv) with (xv) in the compound, Ar represents aryl and heteroaryl, and by R ²⁵Replace.According to the following regulations: R ⁵.R ²³.Ar.R ²⁵.X, preferred formula (xiv) and (xv) compound list in by give following formula (xiv) and (xv) in R ⁵, R ²³, Ar, R ²⁵In the table 3 of the designation number of X.For each part, structure is endowed and is shown in the following table corresponding to R ⁵, R ²³, Ar, R ²⁵Numeral with X.

Variable R ⁵Be selected from 8 kinds of different substituting groups giving down column of figure:

Table R ⁵

Variable R ²³Be selected from 8 kinds of different substituting groups giving down column of figure:

Table R ²³

Variables A r is selected from 4 kinds of different substituting groups giving down column of figure:

Table A r

Variable R ²⁵Be selected from 8 kinds of different substituting groups giving down column of figure:

Table R ²⁵

	??1	??2	??3	??4	??5	??6	??7	??8
	??1	??2	??3	??4	??5	??6	??7	??8	?R ²⁵＝	??F	??Cl	??Br	??NHAc	??CF ₃	??Me	??CO ₂Et	??OMe

Variable X is selected from 4 kinds of different substituting groups giving down column of figure:

Table X

	??1	??2	??3	??4
	??1	??2	??3	??4	??X＝	Furans-2,5-two bases	??C(O)OCH ₂	??C(O)NHCH ₂	??NHC(O)CH ₂

Therefore, use R ⁵, R ²³, Ar, R ²⁵With the variable of X, the formula of called after 2.7.2.2.1 (viv) compound regulation 4-(2-amino-5-isobutyl-) thiazolyl is R in table 3 ⁵,-CH (Me) CO ₂Me is R ²³, the 3-chlorophenyl is Ar, chloro is R ²⁵And furans-2,5-two bases are X, this compound be among the embodiment 31 preparation the 2-amino-5-isobutyl--4-{2-[5-as compound 31.6 (O-phenyl-N-(1-(1-methoxycarbonyl) ethyl) phosphono] furyl thiazole.

In table 3 specified numeral also be expressed as follows formula (xvi) and (xvii) shown in the prodrug of preferred formula I compound:

(xvi) (xvii)

At following formula (xvi) with (xvii), Ar represents aryl, comprises heteroaryl, and by R ²⁴And R ²⁵Replace.According to the following regulations: R ²⁴.R ²⁵.Ar.R ⁵.R ²³, preferred formula (xvi) and (xvii) compound list in by giving the R of following formula ²⁴, R ²⁵, Ar, R ⁵And R ²³The table 3 of designation number in.For each part, structure is endowed and is shown in the following table corresponding to R ²⁴, R ²⁵, Ar, R ⁵And R ²³Numeral.

Variable R ²⁴Be selected from 8 kinds of different substituting groups giving down column of figure:

Table R ²⁴

	??1	??2	??3	??4	??5	??6	??7	??8
	??1	??2	??3	??4	??5	??6	??7	??8	?R ²⁴＝	??F	??Cl	??Br	??NHAc	??CF ₃	??Me	??CO ₂Et	??OMe

Table R ²⁵

Variables A r is divided into two groups, lists 4 kinds of different substituting groups for every group.1 group of substituting group for variables A r is endowed down column of figure:

2 groups of substituting groups for variables A r are endowed down column of figure:

Table R ⁵

Variable R ²³Be divided into two groups, list 4 kinds of different substituting groups for every group.For variable R ²³1 group of substituting group be endowed down column of figure:

For variable R ²³2 groups of substituting groups be endowed down column of figure:

Table R ⁵

Table X

	??1	??2	??3	??4
	??1	??2	??3	??4	?X＝	Furans-2,5-two bases	??C(O)OCH ₂	??C(O)NHCH ₂	??NHC(O)CH ₂

The example of the prodrug of preferred formula I compound is named in table 6, as shown in following formula (xi) prodrug:

R ⁵-X-P’??(xix)

According to the following regulations: P ' .R ⁵.X, preferred formula (xix) compound is listed in P ', the R by giving following formula (xix) ⁵In the table 6 of the designation number of X.For each part, structure is endowed and is shown in the following table corresponding to P ', R ⁵Numeral with X.

Variable P ' is divided into two groups, lists 7 kinds of different substituting groups for every group.1 group of substituting group for variable P ' is endowed down column of figure:

Table P '.

2 groups of substituting groups for variable P ' are endowed down column of figure:

Table R ⁵

Variable X is selected from 6 different substituting groups, uses following numeral:

Table X.

Table 6

1.1.1??1.1.2??1.1.3??1.1.4??1.1.5??1.1.6??1.2.1??1.2.2??1.2.3??1.2.4??1.2.5??1.2.6

1.3.1??1.3.2??1.3.3??1.3.4??1.3.5??1.3.6??1.4.1??1.4.2??1.4.3??1.4.4??1.4.5??1.4.6

1.5.1??1.5.2??1.5.3??1.5.4??1.5.5??1.5.6??1.6.1??1.6.2??1.6.3??1.6.4??1.6.5??1.6.6

1.7.1??1.7.2??1.7.3??1.7.4??1.7.5??1.7.6??1.8.1??1.8.2??1.8.3??1.8.4??1.8.5??1.8.6

1.9.1??1.9.2??1.9.3??1.9.4??1.9.5??1.9.6??2.1.1??2.1.2??2.1.3??2.1.4??2.1.5??2.1.6

2.2.1??2.2.2??2.2.3??2.2.4??2.2.5??2.2.6??2.3.1??2.3.2??2.3.3??2.3.4??2.3.5??2.3.6

2.4.1??2.4.2??2.4.3??2.4.4??2.4.5??2.4.6??2.5.1??2.5.2??2.5.3??2.5.4??2.5.5??2.5.6

2.6.1??2.6.2??2.6.3??2.6.4??2.6.5??2.6.6??2.7.1??2.7.2??2.7.3??2.7.4??2.7.5??2.7.6

2.8.1??2.8.2??2.8.3??2.8.4??2.8.5??2.8.6??2.9.1??2.9.2??2.9.3??2.9.4??2.9.5??2.9.6

3.1.1??3.1.2??3.1.3??3.1.4??3.1.5??3.1.6??3.2.1??3.2.2??3.2.3??3.2.4??3.2.5??3.2.6

3.3.1??3.3.2??3.3.3??3.3.4??3.3.5??3.3.6??3.4.1??3.4.2??3.4.3??3.4.4??3.4.5??3.4.6

3.5.1??3.5.2??3.5.3??3.5.4??3.5.5??3.5.6??3.6.1??3.6.2??3.6.3??3.6.4??3.6.5??3.6.6

3.7.1??3.7.2??3.7.3??3.7.4??3.7.5??3.7.6??3.8.1??3.8.2??3.8.3??3.8.4??3.8.5??3.8.6

3.9.1??3.9.2??3.9.3??3.9.4??3.9.5??3.9.6??4.1.1??4.1.2??4.1.3??4.1.4??4.1.5??4.1.6

4.2.1??4.2.2??4.2.3??4.2.4??4.2.5??4.2.6??4.3.1??4.3.2??4.3.3??4.3.4??4.3.5??4.3.6

4.4.1??4.4.2??4.4.3??4.4.4??4.4.5??4.4.6??4.5.1??4.5.2??4.5.3??4.5.4??4.5.5??4.5.6

4.6.1??4.6.2??4.6.3??4.6.4??4.6.5??4.6.6??4.7.1??4.7.2??4.7.3??4.7.4??4.7.5??4.7.6

4.8.1??4.8.2??4.8.3??4.8.4??4.8.5??4.8.6??4.9.1??4.9.2??4.9.3??4.9.4??4.9.5??4.9.6

5.1.1??5.1.2??5.1.3??5.1.4??5.1.5??5.1.6??5.2.1??5.2.2??5.2.3??5.2.4??5.2.5??5.2.6

5.3.1??5.3.2??5.3.3??5.3.4??5.3.5??5.3.6??5.4.1??5.4.2??5.4.3??5.4.4??5.4.5??5.4.6

5.5.1??5.5.2??5.5.3??5.5.4??5.5.5??5.5.6??5.6.1??5.6.2??5.6.3??5.6.4??5.6.5??5.6.6

5.7.1??5.7.2??5.7.3??5.7.4??5.7.5??5.7.6??5.8.1??5.8.2??5.8.3??5.8.4??5.8.5??5.8.6

5.9.1??5.9.2??5.9.3??5.9.4??5.9.5??5.9.6??6.1.1??6.1.2??6.1.3??6.1.4??6.1.5??6.1.6

6.2.1??6.2.2??6.2.3??6.2.4??6.2.5??6.2.6??6.3.1??6.3.2??6.3.3??6.3.4??6.3.5??6.3.6

6.4.1??6.4.2??6.4.3??6.4.4??6.4.5??6.4.6??6.5.1??6.5.2??6.5.3??6.5.4??6.5.5??6.5.6

6.6.1??6.6.2??6.6.3??6.6.4??6.6.5??6.6.6??6.7.1??6.7.2??6.7.3??6.7.4??6.7.5??6.7.6

6.8.1??6.8.2??6.8.3??6.8.4??6.8.5??6.8.6??6.9.1??6.9.2??6.9.3??6.9.4??6.9.5??6.9.6

7.1.1??7.1.2??7.1.3??7.1.4??7.1.5??7.1.6??7.2.1??7.2.2??7.2.3??7.2.4??7.2.5??7.2.6

7.3.1??7.3.2??7.3.3??7.3.4??7.3.5??7.3.6??7.4.1??7.4.2??7.4.3??7.4.4??7.4.5??7.4.6

7.5.1??7.5.2??7.5.3??7.5.4??7.5.5??7.5.6??7.6.1??7.6.2??7.6.3??7.6.4??7.6.5??7.6.6

7.7.1??7.7.2??7.7.3??7.7.4??7.7.5??7.7.6??7.8.1??7.8.2??7.8.3??7.8.4??7.8.5??7.8.6

7.9.1??7.9.2??7.9.3??7.9.4??7.9.5??7.9.6

Specified numeral also is expressed as follows the prodrug of the preferred formula X compound shown in the formula (xx) in table 1:

(xx)。

In following formula (xx), Ar represents aryl, comprises heteroaryl, and by R ²⁵Replace.According to the following regulations: Ar ' .R ²⁵.R ²³.Ar, preferred formula (xx) compound is listed in by giving Ar ', R ²⁵, R ²³In the table 1 of the designation number of Ar.For each part, structure is endowed and is shown in the following table corresponding to Ar ', R ²⁵, R ²³With the numeral of Ar, wherein R ²⁵For being connected in the substituting group of Ar.

Variables A r ' is selected from 7 kinds of different substituting groups giving down column of figure:

Table A r '

Table R ²⁵

	??1	??2	??3	??4	??5	??6	??7	??8	??9
	??1	??2	??3	??4	??5	??6	??7	??8	??9	?R ²⁵＝	??F	??Cl	??Br	??NHAc	??CF ₃	??Me	??Et	??OMe	??CO ₂Et

Variable R ²³Be selected from 9 kinds of different substituting groups giving down column of figure:

Table R ²³

Table A r

Specified numeral also is expressed as follows the prodrug of the preferred formula X compound shown in the formula (xxi) in table 6:

(xxi)

In following formula (xxi), Ar represents aryl, comprises heteroaryl, and by R ²⁵Replace. according to the following regulations: Ar ' .R ²⁵.Ar, preferred formula (xxi) compound is listed in by giving Ar ', R ²⁵In the table 6 of the designation number of Ar.For each part, structure is endowed and is shown in the following table corresponding to Ar ', R ²⁵Numeral with Ar.

Table A r '

Table R ²⁵

	??1	??2	??3	??4	??5	??6	??7	??8	??9
	??1	??2	??3	??4	??5	??6	??7	??8	??9	?R ²⁵＝	??F	??Cl	??Br	??NHAc	??CF ₃	??Me	??Et	??OMe	??CN

Table A r

Specified numeral also is expressed as follows the prodrug of the preferred formula X compound shown in the formula (xxii) in table 6:

(xxii)

According to the following regulations: P ' .R ' .R ", preferred formula (xxii) compound is listed in by giving P ', R ' and R " the table 6 of designation number in.For each part, structure is endowed and is shown in the following table corresponding to P ', R ' and R " numeral.

Table P '.

Variable R ' be selected from 9 kinds of different substituting groups giving down column of figure:

Table R '

	??1	??2	??3	??4	??5	??6	??7	??8	??9
	??1	??2	??3	??4	??5	??6	??7	??8	??9	?R’＝	??H	??Me	??Et	??OMe	??Br	??Cl	??CO ₂Et	??Pr-i	??Pr-c

Variable R " be selected from 6 kinds of different substituting groups giving down column of figure:

Table R ".

	??1	??2	??3	??4	??5	??6
	??1	??2	??3	??4	??5	??6	?R”＝	??H	??Br	??Cl	??SCN	??Me	??OMe

Part 1.

Synthesizing of formula I compound

The compound that the present invention includes synthetic generally include following general step partly or entirely: the preparation of (1) phosphonate prodrugs; (2) phosphonic acid ester go the protection; (3) heterocyclic is modified; (4) coupling of heterocycle and phosphonic acid ester composition; (5) heterocyclic makes up; (6) closed loop has the heterocycle of phosphonic acid ester part and the preparation of (7) useful as intermediates with structure.These steps are at the following formula I compound (R wherein that is used for ⁵Be 5-unit hetero-aromatic ring) flow process in be illustrated.Formula I compound (R wherein ⁵Be 6-unit's hetero-aromatic ring or other hetero-aromatic ring) preparation in a similar manner.This method generally also is used for formula I compound, and wherein two Y groups not all are-O.

(1) preparation of phosphonate prodrugs

Prodrug can be introduced in the synthetic different step.These prodrugs are owing to its easy generative nature, and the most common phosphonic acids by formula 2 prepares.These prodrugs are introduced comparatively favourable in the stage early, and prerequisite is the reaction conditions that it is able to take later step.

Under the nucleophilic substitution reaction condition, can make formula 2 alkylations with electrophilic reagent (as alkylogen, alkyl sulfonate esters etc.), obtain phosphonic acid ester.For example, formula I compound, wherein R ¹Be the acyloxy alkyl, can be at suitable alkali (as N, N '-dicyclohexyl-4-morpholine carbonamidine, triethylamine, Hunig ' s alkali etc.) exist down, at suitable solvent as 1,1-dimethyl formamide (" DMF ") (Starrett etc., J.Med.Chem., 1994,1857), by with suitable acyloxy alkylogen (as Cl, Br, I; Elhaddadi etc., Phosphorus Sulfur, 1990,54 (1-4): 143; Hoffmann, Synthesis, 1988,62) the direct alkylation of formula 2 compounds is synthesized.The carboxylicesters composition of these acyloxy alkylogens includes, but is not limited to acetic ester, propionic ester, isobutyrate, pivalate, benzoic ether and other carboxylicesters.When suitable, after these acyloxy phosphonate esters form, can design further modification, as the reduction nitro.For example, at suitable reductive condition (Dickson etc., J.Med.Chem., 1996,39:661; Iyer etc., TetrahedronLett., 1989,30:7141; Srivastva etc., Bioorg.Chem., 1984,12:118) under, wherein A is NO ₂Formula 3 compounds of group can be converted into wherein, and A is H ₂Formula 3 compounds of N-group.These methods can expand to prodrug synthetic of other type, for example formula I compound, wherein R ¹Be 3-benzo [c] furanonyl, 2-oxo-4,5-two dehydrogenations-1,3-dioxolane methyl or 2-oxo-tetrahydrofuran-5-base (Biller etc., US 5157027; Serafinowska etc., J.Med.Chem., 1995,38:1372; Srarrett etc., J.Med.Chem., 1994,37:1857; Martin etc., J.Pharm.Sci.1987,76:180; Alexander etc., Collect.Czech.Chem.Commun, 1994,59:1853; Synthesizing EPO 0632048A1).Also can use N, dinethylformamide acetal dialkyl group alcohol makes phosphonic acids alkylation (Alexander, P. etc., Collect.Czech.Chem.Commun., 1994,59,1853).R wherein ¹For the formula I compound of cyclic carbonate ester, lactone or phthalidyl also can suitable alkali (as NaH or diisopropylethylamine, Biller etc., US 5157027; Serafinowska etc., J.Med.Chem., 1995,38:1372; Starrett etc., J.Med.Chem., 1994,37:1857; Martin etc., J.Pharm.Sci.1987,76,180; Alexander etc., Collect.Czech.Chem.Commun, 1994,59:1853; EPO 0632048A1) exists down, adopt synthetic by free phosphonic acids and suitable halid direct alkylating.

Perhaps, these phosphonate prodrugs also can be synthetic by corresponding dichloro phosphonic acid ester and alcohol reaction (Alexander etc., Collect.Czech.Chem.Commun, 1994,59:1853).For example, in the presence of alkali (as pyridine, triethylamine etc.), make dichloro phosphonic acid ester and suitable phenol and aralkyl alcohol reaction, obtain formula I compound, wherein R ¹Be aryl (Khamnei etc., J.Med.Chem., 1996,39:4109; Serafinowska etc., J.Med.Chem., 1995,38:1372; DeLombaert etc., J.Med.Chem., 1994,37:498) or aralkyl (Mitchell etc., J.Chem.Soc.Perkin Trans.1,1992,38:2345).Contain disulphide prodrug (Puech etc., Antiviral Res., 1993,22:155) also can under standard conditions, make by dichloro phosphonic acid ester and 2-hydroxyethyl disulphide.The dichloro phosphonic acid ester also is useful to the various phosphamides that prepare as prodrug.For example, obtain a phosphamide and two phosphamides with ammonia treatment dichloro phosphonic acid ester; Handle the dichloro phosphonic acid ester with 1-amino-3-propyl alcohol and obtain ring-type 1,3-propyl group phosphamide; In the presence of suitable alkali, handle clodronic acid-phenylester with amino acid ester, obtain replacing-phenyl one phosphoramidate.

Reactive dichloro phosphonic acid ester like this can be from corresponding phosphonic acids and chlorizating agent (as thionyl chloride: Starrett etc., J.Med.Chem., 1994,1857; Oxalyl chloride: Stowell etc., Tetrahedron Lett., 1990,31:3261; And phosphorus pentachloride: Quast etc., Synthesis, 1974,490) the reaction generation.Perhaps, the dichloro phosphonic acid ester also can by its corresponding dimethyl silanyl phosphonic acid ester (Bhongle etc., Synth.Commun., 1987,17:1071) or dialkyl phosphonate (Still etc., Tetrahedron Lett., 1983,24:4405; Patois etc., Bull.Soc.Chim.Fr., 1993,130:485) generate.

Adopt the above-mentioned method that is used for synthetic dichloro phosphonic acid ester, can prepare clodronic acid one phenylester by a Phenylphosphine acid esters, and a Phenylphosphine acid esters can be made through alkali (as sodium hydroxide) hydrolysis by its corresponding diphenylphosphine acid esters easily.Perhaps, handle the dichloro phosphonic acid ester with 1 equivalent phenol, then suitable alkali (as pyridine or triethylamine) under add amine (as alanine ethyl ester), also can obtain-phenyl one phosphoramidate.When replacing phenol with the phenols that replaces or other aryl-OH, these methods can be used for synthetic various-aryl one phosphoramidate as formula I compound prodrug so.

In addition, these prodrugs can adopt Mitsumobu reaction (Mitsunobu, Synthesis, 1981,1; Campbell, J.Org.Chem., 1992,52:6331) and other coupled reaction (as using carbodiimide: Alexander etc., Collect.Czech.Chem.Commun, 1994,59:1853; Casara etc., Bioorg.Med.Chem.Lett., 1992,2:145; Ohashi etc., TetrahedronLett., 1988,29:1189, and benzotriazole base oxygen base three-(dimethylamino) phosphonium salt: Campagne etc., Tetrahedron Lett., 1993,34:6743) preparation.

R ¹Also can introduce, as long as it and subsequent reactions step adapt at this synthetic commitment.For example, R wherein ¹For the formula I compound of aryl can then be caught the negatively charged ion preparation with diaryl chloro phosphoric acid ester by the metalation (as using LDA) of 2-furyl heterocycle.

Can imagine, formula I compound can mix with phosphonic acid ester (as phenyl and benzyl ester or phenyl and acyloxy alkyl ester), comprises chemically combined mixed ester, for example by (Bioorg.Med.Chem.Lett. such as Meier, 1997,7:99) Bao Dao phenyl and benzyl bonded prodrug.

Ring-type propyl phosphonous acid ester can be by making 1 of corresponding dichloro phosphonic acid ester and replacement, and the ammediol reaction perhaps uses the coupled reaction of suitable coupling reagent (as DCC, EDCI, pyBOP:Hoffman, Synthesis, 1988,62) to synthesize.These are used to prepare 1, and the certain methods in the method for ammediol is discussed below.

1, ammediol synthetic

Can adopt prepared in various methods 1, ammediol replaces as (i) 1-, and (ii) 2-replaces, and (iii) 1,2-or 1.3-become 1 of ring, ammediol.Substituting group on the prodrug moiety of formula I compound (promptly 1, the substituting group on the ammediol part) can be introduced or modify between the synthesis phase of these glycol or in the synthetic back of formula 2 compounds.

(i) 1 of the 1-replacement, ammediol

Be used for 1 of synthetic The compounds of this invention, ammediol can adopt various synthetic method preparations.Aryl Grignard is added to obtains 1 of 1-aryl-replacement in 1-hydroxyl-third-3-aldehyde, (approach a) for ammediol.This method is applicable to various aryl halides is converted into 1 of 1-aryl replacement, ammediol (Coppi etc., J.Org.Chem., 1988,53,911).Adopt Heck reaction (for example with 1, the 3-diox-4-ene coupling), then by reduction and hydrolysis reaction subsequently (Sakamoto etc., Tetrahedron Lett., 1992,33:6845) can realize that aryl halide is converted into that 1-replaces 1, ammediol.Adopt alkenyl Grignard addition reaction, then also various aromatic aldehydes can be converted into 1 of 1-replacement, ammediol through hydroboration-oxidizing reaction (approach b).

Aldol reaction between enolate of carboxylic acid derivative (as tert.-butyl acetate) (as the enolate of lithium, boron, tin) and the aldehyde, and these reactions (as Evana ' s aldol reaction) are used in particular for chirality 1, the asymmetric synthesis of ammediol.For example, the metal enolate of tert.-butyl acetate and aromatic aldehyde reaction, then the reduction reaction (approach e) by ester obtains 1, ammediol (Turner., J.Org.Chem., 1990,55,4744).Perhaps, adopt known method (as Sharpless epoxidation and other asymmetric epoxidation reaction) to make the styryl carbinol epoxidation, then obtain through reduction reaction (as using Red-Al) various 1, ammediol (approach c).Asymmetric reduction reaction (as the chirality borane reduction) by 3-hydroxyl-ketone can obtain mapping pure 1, ammediol (Ramachandran etc., Tetrahedron Lett., 1997,38 761).Perhaps, adopt the whole bag of tricks (as enzyme method or chemical process) to analyse to separate racemic 1, ammediol also can obtain mapping pure 1, ammediol.Adopt the N-oxide compound to form reaction, then through under the diacetyl oxide condition through rearrangement reaction, can make third-3-alcohol obtain 1 of 1-replacement through oxidation with 1-heteroaryl substituting group (as pyridyl, quinolyl or isoquinolyl), ammediol (approach d) (Yamamoto etc., Tetrahedron, 1981,37,1871).

(ii) 2-replace 1, ammediol:

Adopt the conventional chemical method, can by various other 1, ammediol is (as 2-(methylol)-1, ammediol) preparation be used for that the various 2-of synthetic compound of formula i replace 1, ammediol (Larock, Comprehensive Organic Transformations, VCH, New York, 1989).

For example, under known condition, (approach a) tri-alkoxy carbonyl methane obtains triol or obtains two (methylol) acetate by one of described ester group of selective hydrolysis, and remaining two other ester groups that then reduce obtain triol by reduction fully.The also known nitro triol that makes can obtain triol (approach b) (Latour etc., Synthesis, 1987,8,742) through the reduction elimination reaction.In addition, adopt known chemical process (Greene etc., the blocking group in the organic synthesis; Wiley, NewYork, 1990), use acyl chlorides or carbonochloridic acid alkyl ester (as Acetyl Chloride 98Min. or methyl chlorocarbonate) can make 2-(methylol)-1, ammediol is converted into the derivative (as ethanoyl, methoxycarbonyl) (approach d) of an acylations.Also can adopt other functional group treatment process preparation 1, ammediol, for example, with 2-(methylol)-1, a methylol in the ammediol is oxidized to aldehyde, then carries out addition reaction (approach c) with aryl Grignard.Also aldehyde can be converted into alkylamine (approach e) by the reductive amination reaction.

(iii) 1 of Cheng Huan, ammediol:

Formula I compound, wherein V and Z or V and W are connected to form ring by 4 carbon atoms, can be by 1, the preparation of 3-cyclohexanediol.For example, cis, cis-1,3, the 5-phloroglucite can be modified (as part (ii) described in) obtain various other 1,3, the 5-phloroglucite, it can be used for preparation I compound, wherein R ¹And R ¹Be together

Wherein V and W are joined together to form by 3 atoms and contain cyclic group 6 carbon atoms, that replaced by hydroxyl.Can infer that these modifications can be at cyclic phosphonic acid 1, the ammediol ester carries out before or after forming.It is various 1 to adopt Diels-Alder reaction (as using pyrone as diene: Posner etc., Tetrahedron Lett., 1991,32,5295) also can prepare, the 3-cyclohexanediol.2-methylol hexalin and 2-methylol cyclopentanol can be used for preparation I compound, wherein R ¹And R ¹Be together

Wherein V and Z are joined together to form the cyclic group that contains 5 or 6 carbon atoms by 2 or 3 atoms.Cycloaddition reaction method by other also can prepare 1, the 3-Cyclohexanediole derivatives.For example, the cycloaddition thing that derives from the cycloaddition reaction of nitrile oxide and alkene can be converted into 2-ketone alcohol derivative, adopt known chemical process (Curran etc., J.Am.Chem.Soc., 1985,107,6023) latter further can be converted into 1, ammediol (comprising 1,3-cyclohexanediol, 2-methylol hexalin and 2-methylol cyclopentanol).Perhaps, can prepare 1 by quinic acid, and the precursor of 3-cyclohexanediol (Rao etc., Tetrahedron Lett., 1991,32:547).

2) phosphonic acid ester go the protection

Adopt known phosphoric acid ester and phosphonic acid ester cracking condition, can be by phosphonic acid ester preparation I compound, wherein R ¹Be H.Usually use the various phosphonic acid esters of silyl halide cracking, subsequently the silyl phosphonic acid ester that generates is carried out gentle hydrolysis and obtain required phosphonic acids.When needing, acid scavenger (as 1,1,1,3,3,3-hexamethyldisilazane, 2,6-lutidine etc.) can be used for synthesizing sour unstable compound.Such silyl halide comprises chloro trimethyl silane (Rabinowitz, J.Org.Chem., 1963,28:2975), bromo trimethyl silane (McKenna etc., TetrahedronLett., 1977,155) and iodo trimethyl silane (Blackburn etc., J.Chem.Soc., Chem.Commun., 1978,870).Perhaps, phosphonic acid ester can (as HBr or HCl:Moffatt etc., United States Patent (USP) 3524846,1970) cracking under strong acidic condition.These esters also can pass through the dichloro phosphonic acid ester and (use halogenating agent (as phosphorus pentachloride, thionyl chloride, BBr ₃: Pelchowicz etc., J.Chem.Soc., 1961,238) preparation of processing ester) cracking, then obtain phosphonic acids through hydrolysis.Aryl and benzylphosphonic acid ester can be under the hydrogenolysis condition (Lejczak etc., Synthesis, 1982,412; Elliott etc., J.Med.Chem., 1985,28:1208; Baddiley etc., Nature, 1953,171:76) or under the metallic reducing condition (Shafer etc., J.Am.Chem.Soc., 1977,99:5118) cleaved.Also can adopt electrochemistry (Shono etc., J.Org.Chem., 1979,44:4508) and pyrolysis (Gupta etc., Synth.Commun., 1980,10:299) the various phosphonic acid esters of condition cracking.

(3) existing heterocyclic is modified

Heterocyclic in the compound of coming into the open is synthetic to have carried out sufficient research and description (seeing part 4) has been arranged in many summaries to being included in.Although before formula 4 compounds are synthetic, it is favourable having the required substituting group that is present in these heterocycles, but in some cases, required substituting group can not be compatible with subsequent reaction, thereby existing heterocycle need adopt the conventional chemical method to modify (Larock, Comprehensive Organic Transformations, VCH in the later stage of synthesis flow, New York, 1989; Trost, Comprehensive Organic Synthesis; Pergamon press, New York, 1991).For example, formula I compound (wherein A, A " or B be halo or cyano group) can prepare by with various copper (I) salt (as Cul, CuBr, CuCl, CuCN) corresponding amido being converted into diazo.Also can introduce halogen by the direct halogenation of various heterocyclic.For example, adopt all ingredients (as NIS, NBS, NCS) to be converted into 2-amino-5-halo thiazole by 5-is unsubstituted-thiazolamine.Heteroaryl halogen also is coupled reaction such as Suzuki, Heck or Stille reaction (Farina etc., organic reaction, the 50th volume that useful as intermediates and being easy to is impelled by transition metal; Wiley New York, 1997; Mitchell, synthetic, 1992,808; Suzuki, Pure App.Chem., 1991,63,419; Heck, the palladium reagent in the organic synthesis; Academic Press:San Diego, 1985) be converted into other substituting group (as A, A ", B, B ", C ", D, D ", E and E ").Formula I compound (wherein A is a formamyl) can be by separating its corresponding alkyl carboxylic acid ester's preparation with various amine ammonia, (wherein A is-CH to formula I compound in the modification of described alkyl carboxylic acid ester's conventional func group ₂The OH group or-CH ₂-halo group) synthetic is useful.Introducing such as A, A are also represented in the substitution reaction of halogenated heterocyclic (as 2-bromethiazole, 5-bromethiazole) and various nucleophilic reagents (as HSMe, HOMe etc.) ", B, B " substituent another kind of method.For example, the substitution reaction of 2-chloro thiazole and thiomethyl alcohol obtains corresponding 2-methylthio group thiazole.

Can infer, in case of necessity, for example adopt alkylated reaction of standard (with alkylogen, aralkyl halogen, alkyl sulfonic ester or sweet-smelling alkyl sulfonic acid ester) or Mitsunobu reaction (with pure) easily to carry out described heterocycle (as imidazoles, 1,2,4-triazole and 1, the alkylation of the nitrogen-atoms 2,3,4-tetrazolium).

(4) coupling of heterocycle and phosphonic acid ester composition

The compound of practicality disclosed by the invention can advantageously prepare by the convergent synthesis approach that makes heterocycle and the coupling of phosphonic acid diester composition.

Transition metal-catalyzed coupled reaction, for example Stille or Suzuki reaction is particularly suitable for the synthetic of formula I compound.(Farina etc., organic reaction, the 50th volume under the catalytic reaction conditions of palladium; Wiley New York, 1997; Mitchell, synthetic, 1992,808; Suzuki, Pure App.Chem., 1991,63,419), heteroaryl halogen or triflate (as the 2-pyridine bromide) and M-PO ₃R ¹Coupled reaction between (wherein M is 2-(5-tributyl stannyl) furyl or 2-(5-boronyl) furyl) obtains formula I compound, and wherein X is a furans-2,5-two bases.Can infer, also can be opposite (for example, trialkyl stannyl or boronyl heterocycle and halo-X-P (O) (O-alkyl) to the character of the coupling part of these reactions ₂Coupling).Other coupled reaction between organic stannane and alkenyl halogen or the alkenyl triflate also has report, and these reactions can be used for preparation I compound, and wherein X is an alkenyl.Can adopt Heck prepared in reaction formula I compound wherein X be alkynyl group (Heck, the palladium reagent in the organic synthesis; Academic Press:San Diego, 1985).These reactions are particularly suitable for synthetic various heteroaromaticss, as R ⁵To many available halogenated heterocyclic given in the formula I compound, these reactions are particularly suitable for parallel synthetic (as the combination of solid phase synthetic (Bunin, B.A., The Combinatorial Index; Academic press; San Diego, 1998) or the combination of liquid phase synthetic (Flynn, D.L. etc., Curr.Op.Drug.Disc.Dev., 1998, I, 1367)), to produce big combinatorial libraries (combinatorial libries).For example, under suitable coupled reaction condition, 5-iodo-2-furyl phosphinic acid ethyl ester can be coupled on Wang ' the s resin.Then can be with 5-iodo-2-[5-(O-ethyl-O-Wang ' s resin) phosphono of resin-coupling] furans and organo-borane and organotin stand transition metal-catalyzed Suzuki and Stille reaction (as mentioned above) in a parallel manner; obtain the storehouse of formula 3 compounds; wherein X is a furans-2,5-two bases.

Substitution reaction is useful to the coupling of heterocycle and phosphonic acid diester composition.For example, cyanuryl chloride can be replaced by mercaptoalkyl dialkyl alkylphosphonate or aminoalkyl group dialkyl alkylphosphonate, obtains formula I compound, wherein R ⁵Be 1,3,5-triazines, X is alkylthio or alkylamino.Alkylated reaction also can be used for the coupling of heterocycle and phosphonic acid diester composition.For example, available dialkyl methyl phosphonate derivative is (as ICH ₂P (O) (OEt) ₂, TsOCH ₂P (O) (OEt) ₂, TfOCH ₂P (O) (OEt) ₂) make heteroaromatic mercaptan (as 1,3,4-thiadiazoles-2-mercaptan) alkylation, obtain formula I compound, wherein X is an alkylthio.In yet another aspect, heteroaromatic carboxylic acids (as the thiazole-4-carboxylic acid) and dialkyl methyl phosphonate derivative are (as ICH ₂P (O) (OEt) ₂, TsOCH ₂P (O) (OEt) ₂, TfOCH ₂P (O) (OEt) ₂) alkylated reaction obtain formula I compound, wherein X is an alkoxy carbonyl, and heteroaromatic thiocarboxylic acid (as thiazole-4-thiocarboxylic acid) and dialkyl methyl phosphonate derivative are (as ICH ₂P (O) (OEt) ₂, TsOCH ₂P (O) (OEt) ₂, TfOCH ₂P (O) (OEt) ₂) alkylated reaction obtain formula I compound, wherein X is the alkylthio carbonyl.Haloalkyl heterocycle (as 4-haloalkyl thiazole) is useful with the substitution reaction of the nucleophilic reagent that contains phosphonate group (hydroxymethyl phosphonic acid diethyl ester) to the preparation of formula I compound (wherein X is alkoxyalkyl or alkylthio alkyl).For example, can be with hydroxymethyl phosphonic acid dialkyl and suitable alkali (as sodium hydride) by 2-chloro picoline or 4-chloro methylthiazol preparation I compound, wherein X is-CH ₂OCH ₂-group.It also is possible making the nucleophilic reagent of substitution reaction and the incompatibility of electrophilic reagent, promptly haloalkyl-and/or the heterocycle (as 2-hydroxyalkyl pyridine, 2-mercaptoalkylpyridin or 4-Qiang base Wan Ji oxazole) that the alkylsulfonyl phosphonate ester can be contained nucleophilic reagent replace.

Also can adopt known amido linkage to form reaction (as method, the carbodiimide method of carboxylic acid halides method, blended acid anhydrides) and make heteroaromatic carboxylic acids and the coupling of phosphonic acid diester composition, obtain formula I compound, wherein X is alkyl amino-carbonyl or alkoxy carbonyl.For example, the coupling of thiazole-4-carboxylic acid and aminoalkyl group dialkyl alkylphosphonate or hydroxyalkyl dialkyl alkylphosphonate obtains formula I compound, wherein R ⁵Be thiazole, X is alkyl amino-carbonyl or alkoxy carbonyl.Perhaps, can reverse the character of coupling part, to obtain formula I compound, wherein X is an alkyl-carbonyl-amino.For example, under these reaction conditionss, thiazolamine can with (RO) ₂P (O)-alkyl-CO ₂H (as diethyl phosphonyl acetate) coupling obtains formula I compound, wherein R ⁵Be thiazole, X is an alkyl-carbonyl-amino.These reaction pair compound libraries also are useful by the parallel synthetic of combinational chemistry of solid phase or liquid phase.For example, adopt above-mentioned reaction, can make HOCH ₂P (O) is (O-resin), H (OEt) ₂NCH ₂P (O) is (O-resin) and HOOCCH (OEt) ₂P (O) (OEt) (O-resin) (adopting the currently known methods preparation) is coupled on the various heterocycles, obtains the storehouse of formula 3 compounds, and wherein X is-C (O) OCH ₂-or-C (O) NHCH ₂-or-NHC (O) CH ₂-.

The compound that also can adopt the rearrangement reaction preparation the present invention includes.For example, in the presence of hydroxyalkyl dialkyl alkylphosphonate or aminoalkyl group dialkyl alkylphosphonate, thiazole-4-carboxylic acid's Curtius ' s resets and obtains formula I compound, and wherein X is alkyl amino-carbonyl amino or alkoxycarbonyl amino.The combination that also can adopt these reactions to be used for the various storehouses of formula 3 compounds is synthesized.For example, heterocyclic carboxylic acid and HOCH ₂P (O) is (O-resin) or H (OEt) ₂NCH ₂P (O) (OEt) Curtius ' the s rearrangement reaction between (O-resin) can obtain formula I compound library, and wherein X is-NHC (O) OCH ₂-or-NHC (O) NHCH ₂-.

For X wherein is the formula I compound of alkyl, adopt other common phosphonic acid ester formation method as Michaelis-Arbuzov reaction (Bhattacharya etc., Chem.Rev., 1981,81:415), Michaelis-Becker reaction (Blackburn etc., J.Organomet.Chem., 1988,348:55) and phosphorus atom add to the reaction of electrophilic reagent (as aldehyde, ketone, carboxylic acid halides, imines and other carbonyl derivative), can introduce phosphate-based.

Also can introduce the phosphonic acid ester composition by lithiation.For example, use suitable alkali lithiumation 2-ethynyl pyridine, then catch the negatively charged ion of generation like this, obtain formula I compound, wherein R with the chloro dialkyl alkylphosphonate ⁵Be pyridyl, X is 1-(2-phosphono) ethynyl.

(5) heterocyclic makes up

Although existing heterocycle is useful to the synthetic of formula I compound, when needing, also can make up the heterocycle that can obtain The compounds of this invention, and in some cases, may be preferred to the preparation of some compounds.Sufficient description (Joule etc., Heterocyclic Chemistry have been carried out to adopting various reaction conditionss to make up heterocycle in the document; Chapman hall, London, 1995; Boger, Weinreb, Hetero Diels-Alder Methodology In OrganicSynthesis; Academic press, San Diego, 1987; Padwa, 1,3-dipole cycloaddition chemistry; Wiley, New York, 1984; Katritzsky etc., Comprehensive HeterocyclicChemistry; Pergamon press, Oxiford; Newkome etc., contemporary heterocyclic chemistry: synthesize, react and use; Wiley, New York, 1982; Synthesizing of heterogeneous ring compound; Consultants Bureau, New York).The certain methods that is used to prepare The compounds of this invention provides as embodiment in the following discussion.

(i) structure of thiazole ring system

Adopt the various annulations of fully describing easily to prepare thiazole of the present invention (Metzger, thiazole and derivative thereof, part 1 and part 2; Wiley ﹠amp; Sons, New York, 1979).The cyclization of thioamides (as thioacetamide, thiocarbamide) and α-Lu Daitangjihuahewu (as α-Lu Daitong, alpha-halogen aldehyde) is useful especially to the structure of thiazole ring system.For example, thiocarbamide and 5-diethyl phosphonyl-2-[(2-bromo-1-oxo) alkyl] cyclization between the furans can be used for formula I compound (R wherein ⁵Be thiazole, A is a furans-2 for amino and X, 5-two bases) synthesize; Cyclization between thiocarbamide and the bromo acetone acid alkyl ester obtains 2-amino-4-alkoxy carbonyl thiazole, and the latter is to formula 1 compound (R wherein ⁵For thiazole and X are alkyl amino-carbonyl, alkoxy carbonyl, alkyl amino-carbonyl amino or alkoxycarbonyl amino) synthetic be useful.Thioamides can adopt prepared in reaction (Trost, the Comprehensive OrganicSynthesis that reports in the document; The 6th volume; Pergamon press, New York, 1991,419-434 page or leaf), α-Lu Daitangjihuahewu is easy to obtain (Larock, ComprehensiveOrganic Transformations, VCH, New York, 1989) by popular response.For example, use Lawesson ' s reagent or P ₂S ₅, acid amides can be converted into thioamides, can be with various halide reagents (as NBS, cuprous bromide) with the ketone halogenation.

(the structure of) oxazole ring system ii

The whole bag of tricks in the employing document can prepare and be used for De oxazole of the present invention (Turchi ， oxazole; Wiley ﹠amp; Sons, New York, 1986).Can adopt the reaction between isocyanide (as tolylsulfonyl ylmethyl isocyanide) and the carbonyl compound (as aldehyde and acyl chlorides) to come structure to build oxazole ring system (vanLeusen etc., Tetrahedron Lett., 1972,2369).Perhaps, the cyclization of acid amides (as urea, methane amide) and α-Lu Daitangjihuahewu is commonly used to Gou Jian oxazole ring system.For example, urea and 5-diethyl phosphonyl-2-[(2-bromo-1-oxo) alkyl] reaction of furans can be used for formula I compound (R wherein ⁵Wei oxazole, A is a furans-2 for amino and X, 5-two bases) synthesize.Reaction between amine and the imidoether also can be used to Gou Jian oxazole ring system (Meyers etc., J.Org.Chem., 1986,51 (26), 5111).

The (iii) structure of pyridine ring system

The pyridine that is used for synthetic compound of formula i can adopt various known synthetic method preparation (Klingsberg, pyridine and derivatives thereof; Interscience Publishers, New York, 1960-1984).Can make 1,5-dicarbonyl compound or derivatives thereof and ammonia maybe can generate the compound reaction of ammonia, producing 1, and the 4-dihydropyridine, it is easy to through dehydrogenation is pyridine.When with unsaturated 1,5-dicarbonyl compound or its Equivalent (as the pyrans ion) can directly generate pyridine during with ammonia react.Adopt the conventional chemical method can prepare 1,5-dicarbonyl compound or its Equivalent.For example, by many approach, add to ketenes (enone) (or precursor Mannich alkali (Gill etc., J.Am.Chem.Soc. as enolate Michael, 1952,74,4923) reaction), the reaction (Duhamel etc. of the ozonolysis of cyclopentenes precursor or silyl enol ether and 3-methoxyl group allyl alcohol, Tetrahedron, 1986,42:4777) can obtain 1, the 5-diketone.When a carbonyl carbon is in the acid oxidase state, then this type reaction produces the 2-pyridone, and it can easily be converted into 2-haloperidid (Isler etc., Helv.Chim.Acta, 1955,38,1033) or 2-aminopyridine (Vorbruggen etc., Chem.Ber., 1984,117,1523).Perhaps, can be by classical H antzsch synthetic (Bossart etc., Angew.Chem.Int.Ed.Engl., 1981,20,762) by aldehyde, 1,3-dicarbonyl compound and ammonia prepare pyridine.1,3-dicarbonyl compound (or its Equivalent) also can be used to produce pyridine (, Mariella, Org.Synth Coll.IV volume, 1963,210 synthetic as Guareschi) with the reaction of 3-amino-ketenes or 3-amino-nitrile.By to corresponding 1, the oxidizing reaction of 3-glycol or aldol reaction product can prepare 1,3-dicarbonyl compound (Mukaiyama, Org.Reactions, 1982,28,203).Cycloaddition reaction also can be used to pyridine synthesis, for example (Naito etc., Chem.Pharm.Bull., 1965 of the cycloaddition reaction between ， oxazole and the alkene, 13,869) and 1,2, the reaction of the Diels-Alder between 4-triazine and the enamine (Boger etc., J.Org.Chem., 1981,46,2179).

The (iv) structure of pyrimidine ring system

Being used for the synthetic pyrimidine ring system of formula I compound is (Brown, the pyrimidine that is easy to obtain; Wiley, New York, 1994).Be used for method of pyrimidine synthetic and comprise 1,3-dicarbapentaborane composition (or its Equivalent) and the segmental coupling of N-C-N.N-C-N composition-urea (Sherman etc., Org.Synth., Coll.Vol.IV, 1963,247), amidine (Kenner etc., J.Chem.Soc., 1943,125) or guanidine (Burgess, J.Org.Chem., 1956,21,97; VanAllan, Org.Synth., CollVol.IV, 1963,245)-selection control pyrimidine product C-2 on replacement.This method is synthetic for the formula I compound that has various A groups to be useful especially.In another method, by the nitrogen hetero-Diels-Alder reaction between cycloaddition reaction such as 1,3,5-triazines and enamine or the ynamine (Boger etc., J.Org.Chem., 1992,57,4331 and at this document of quoting) can prepare pyrimidine.

(the v) structure of imidazo ring systems

Adopt various synthetic method easily to prepare and be used for the synthetic imidazoles of formula I compound.General various cyclizations such as amidine and the α-Lu Daitong (Mallick etc. of adopting, J.Am.Chem.Soc., 1984,106 (23), 7252) or alpha-alcohol ketone (Shi etc., Synthetic, Comm., 1993,23 (18), 2623) reaction between the reaction between, urea and the α-Lu Daitong, and aldehyde and 1, imidazoles is synthesized in the reaction between the 2-dicarbonyl compound (in the presence of amine).

(vi) structure of isoxazole ring system

Adopt the whole bag of tricks (as the cycloaddition reaction, 1 between nitrile oxide and alkene or the activity methene compound, 3-dicarbonyl compound or α, β-acetylene series carbonyl compound or α, the oximation reaction of β-dihalo carbonyl compound etc.) can easily synthesize and be used for the synthetic isoxazole of formula I compound, these methods can be used to synthesizing isoxazole ring system (， isoxazole such as Grunanger; Wiley ﹠amp; Sons, New York, 1991).For example, in the presence of alkali (as triethylamine, Hunig ' s alkali, pyridine), the reaction between alkynes and 5-diethyl phosphonyl-2-chloro oximido furans can be used for formula I compound (R wherein ⁵Wei isoxazole and X be furans-2,5-two bases) synthetic.

(the vii) structure of pyrazoles ring system

Adopt the whole bag of tricks (Wiley, pyrazoles, pyrazoline, pyrazolidine, indazole and condensed ring; Interscience Publishers, New York, 1967), for example, hydrazine and 1,3-dicarbonyl compound or 1, the reaction between the 3-dicarbapentaborane Equivalent (masked as carbonyl is enamine or ketal or acetal), and hydrazine is to the addition reaction of vinyl cyanide, cyclization subsequently (Dom etc., Org.Synth., 1973, Coll. the 5th volume, 39) can easily prepare and be used for the synthetic pyrazoles of formula I compound.The reaction of 2-(2-alkyl-3-N, N-dimethylamino) acryl-5-diethyl phosphonyl furans and hydrazine can be used for formula I compound (R wherein ⁵Be pyrazoles, X is a furans-2,5-two bases and B " be alkyl) synthetic.

(viii) 1,2, the structure of 4-triazole ring system

Be used for 1,2 of synthetic compound of formula i, the 4-triazole can easily obtain (Montgomery, 1,2,4-triazole by several different methods; Wiley, New York, 1981).For example, the reaction between hydrazides and imidoether or the thioimido ester (Sui etc., Bioorg.Med.Chem.Lett., 1998,8,1929; Catarzi etc., J.Med.Chem., 1995,38 (2), 2196), 1,3, reaction between 5-triazine and the hydrazine (Grundmann etc., J.Org.Chem., 1956,21,1037) and the reaction between aminoguanidine and the carboxylicesters (Ried etc., Chem.Ber., 1968,101,2117) all can be used to synthetic 1,2, the 4-triazole.

(6) closed loop has the heterocycle of phosphonic acid ester with structure

But adopt also preparation formula 4 compounds of ring-closure reaction, to make up heterocycle from the precursor that contains the phosphonic acid ester composition.For example, thiocarbamide and 5-diethyl phosphonyl-2-[(2-bromo-1-oxo) alkyl] cyclization between the furans can be used for synthetic compound of formula i (R wherein ⁵Be thiazole, A is a furans-2 for amino and X, 5-two bases).De oxazole of the present invention also can adopt the ring-closure reaction preparation.In this case, urea and 5-diethyl phosphonyl-2-[(2-bromo-1-oxo) alkyl] reaction of furans can be used for synthetic compound of formula i (R wherein ⁵Wei oxazole, A is a furans-2 for amino and X, 5-two bases).5-diethyl phosphonyl-2-furfural, alkylamine, 1, the reaction between 2-diketone and the ammonium acetate can be used for synthetic compound of formula i (R wherein ⁵For imidazoles and X are furans-2,5-two bases).The ring-closure reaction of these types also can be used to synthetic be used for pyridine of the present invention or pyrimidine.For example; in the presence of alkali; 5-diethyl phosphonyl-2-[3-dimethylamino-2-alkyl) acryl] reaction of furans and malonamide nitrile obtains 5-alkyl-3-cyano group-6-[2-(5-diethyl phosphonyl) furyl]-2-pyridone (Jain etc.; Tetrahedron Lett.; 1995; 36,3307).These 2-pyridones will obtain formula I compound, wherein R to the conversion (seeing the document of quoting in the part 3 (heterocyclic modification)) of corresponding 2-haloperidid subsequently ⁵Be pyridine, A is the halo group, and X is a furans-2, and 5-two bases and B are alkyl.5-diethyl phosphonyl-2-[3-dimethylamino-2-alkyl) acryl] furans and amidine react in the presence of alkali and obtain 5-alkyl-6-[2-(5-diethyl phosphonyl)-furyl] pyrimidine, it will obtain formula I compound, wherein R ⁵Be pyrimidine, X is a furans-2, and 5-two bases and B are alkyl.

(7) be used for the preparation of the various precursors of cyclization

Adopt in the document existent method or existing methods is revised, can prepare usually and be used for the synthetic required intermediate of The compounds of this invention.This paper describes the synthetic of some intermediates be used for synthetic The compounds of this invention.

Various arylphosphonic acid dialkyls are useful especially to the synthetic of formula I compound.For example, wherein X is a furans-2, and the formula I compound of 5-two bases can be by various furyl precursor preparation.Can envision, the synthetic of other precursor can carry out according to some or all steps in these reactions steps, and some modifications in these reactions may need different precursors.5-dialkyl phosphine acyl group-2-furans carbonyl compound (as 5-diethyl phosphonyl-2-furfural, 5-diethyl phosphonyl-2-acetyl furan) is well suited for the synthetic of formula I compound (wherein X is a furans-2,5-two bases).These intermediates can adopt conventional chemical method such as lithiation, the protection of carbonyl and the protection of going of carbonyl to be prepared by furans or furan derivatives.For example, (26:1) lithiumation furans then adds phosphorylating agent (as ClPO for Gschwend, Org.React.1979 with known method ₃R ₂) obtain 2-dialkyl phosphine acyl group-furans (as 2-diethyl phosphonyl furans).This method also can be applicable to the furans (as the 2-furancarboxylic acid) that 2-replaces, and obtains the furans (as 5-diethyl phosphonyl-2-furancarboxylic acid) that 5-dialkyl phosphine acyl group-2-replaces.Can infer that other aryl phosphine acid esters also can adopt the amending method preparation of this method or this method.Perhaps, adopt transition metal-catalyzed reaction (Balthazar etc., J.Org.Chem., 1980, the 45:5425 of other method such as aryl halide or triflate; Petrakis etc., J.Am.Chem.Soc., 1987,109:2831; Lu etc., Synthesis, 1987,726) with preparation aryl phosphine acid esters.The aryl phosphine acid esters also can be by aryl phosphate ester preparation (Melvin, Tetrahedron Lett., 1981,22,3375 under the anionoid rearrangement condition; Casteel etc., Synthesis, 1991,691).N-alkoxy aryl salt with alkali metal derivant of dialkyl alkylphosphonate provide the universal synthesis method that another kind is used for heteroaryl-2-phosphonic acid ester (Redmore, J.Org.Chem., 1970,35:4114).

Second lithiumation step can be used to add second group such as aldehyde radical, trialkyl stannyl or halo group on the arylphosphonic acid dialkyl, though also can dream up other known method (as the Vilsmeier-Hack reaction or the Reimar-Teimann that are used for synthetic aldehyde react) that can generate these functionality (as aldehyde).In second lithiumation step, (, use DMF, HCO as for aldehyde with the reagent that directly generates required functional group ₂R etc.) aromatic ring of processing lithiumation is perhaps with the aromatic ring that can cause being subsequently converted to through known chemistry the agent treated lithiumation of required functional group (can be converted into aldehyde as alcohol, ester, nitrile, alkene).For example; 2-dialkyl phosphine acyl group furans (as 2-diethyl phosphonyl furans) is under normal operation after (as LDA in THF) lithiumation; then catch the negatively charged ion of generation like this, produce the functionalized 2-dialkyl phosphine acyl group furans (as 5-tributyl stannyl-2-diethyl phosphonyl furans or 5-iodo-2-diethyl phosphonyl furans) of 5-with electrophilic reagent (as tributyltin chloride or iodine).Can also guess, the order of these reactions can be put upside down, and promptly can at first add the aldehyde part, then carries out phosphorylation reaction.The order of this reaction will depend on reaction conditions and blocking group.Before phosphorylation, can also guess, with some methods of knowing (as with aldehyde as the protection of acetal, aminal; Ketone is protected as ketal) in these functional groups some are protected may be favourable.Bao Hu functional group needn't be sheltered after phosphorylation then.(the blocking group of organic synthesis; Greene, T.W., 1991, Wiley, New York).For example; with the 2-furfural as contracting 1; the ammediol protection; then also catch negatively charged ion with chloro phosphate dialkyl ester (as chloro di(2-ethylhexyl)phosphate ethyl ester) through lithiumation step (use) as LDA; under standard is removed protective condition, make the acetal functionality go protection subsequently, produce 5-dialkyl phosphine acyl group-2-furfural (as 5-diethyl phosphonyl-2-furfural).Another example is the preparation of 5-ketone group-2-dialkyl phosphine acyl group furans; it comprises the following steps: to make under the Friedel-Crafts reaction conditions furans acidylate to obtain 2-ketone group furans; subsequently ketone is protected (as 1 as ketal; ammediol ring ketal); then as mentioned above through the lithiumation step; obtain 5-dialkyl phosphine acyl group-2-furanone (with ketone as 1; the protection of ammediol ring ketal); for example under acidic conditions, make ketal go protection at last, obtain 2-ketone group-5-dialkyl phosphine acyl group furans (as 2-ethanoyl-5-diethyl phosphonyl furans).Perhaps, can Synthetic 2-ketone group furans by the reaction between the catalytic 2-trialkyl stannyl of palladium furans (as 2-tributyl stannyl furans) and the acyl chlorides (as Acetyl Chloride 98Min., isobutyryl chloride).It is favourable having the phosphonate moiety that is present in the 2-trialkyl stannyl furans (as 2-tributyl stannyl-5-diethyl phosphonyl furans).2-ketone group-5-dialkyl phosphine acyl group furans also can then add Grignard reagent and be prepared by 5-dialkyl phosphine acyl group-2-furancarboxylic acid (as 5-diethyl phosphonyl-2-furancarboxylic acid) by described acid is converted into corresponding acyl chlorides.

Some above-mentioned intermediates also can be used for the synthetic of other useful as intermediates.For example, 2-ketone group-5-dialkyl phosphine acyl group furans can further be converted into and be used to prepare 1 of pyrazoles, pyridine or pyrimidine, 3-Dicarbonyl derivatives.Two alkanols (as the dimethyl formamide dimethyl acetal) reaction of contracting of 2-ketone group-5-dialkyl phosphine acyl group furans (as 2-ethanoyl-5-diethyl phosphonyl furans) and dialkylformamide obtains being 1 of 2-(3-dialkyl amido-2-alkyl-acryl)-5-dialkyl phosphine acyl group furans (as 2-(3-dimethylamino acryl)-5-diethyl phosphonyl furans), 3-dicarbapentaborane Equivalent.

Expect that the aforesaid method that is used for synthetic furan derivatives can directly or be applied to the synthetic of various other useful as intermediates such as aryl phosphine acid esters (as thienyl phosphonic acid ester, Phenylphosphine acid esters or pyridyl phosphonic acid ester) after some are revised.

Be appreciated that, in the time can using, can adopt above-mentioned synthetic method for solid phase or parallel synthetic in solution, with the detection of quick SAR (structure-activity relationship) that the FBP enzyme inhibitors that comprises in the present invention is provided, as long as method can successfully be used for these reactions.

Part 2

Synthesizing of formula X compound

The compound that the present invention includes synthetic generally include following general step partly or entirely: the preparation of (1) phosphonate prodrugs; (2) phosphonic acid ester go the protection; (3) heterocyclic makes up; (4) introducing of phosphonic acid ester composition; (5) anils is synthetic.Step (1) and step (2) are discussed in part 1, and the discussion of step (3), step (4) and step (5) provides hereinafter.These methods generally also are used for formula X compound, and wherein two Y groups not all are-O.

(3) heterocyclic makes up

I benzothiazole ring system:

Formula 3 compounds (wherein G "=S), promptly benzothiazole can prepare with the various synthetic methods of reporting in the document.The example that has two kinds of conducts hereinafter will discuss in these methods provides.A kind of method is that the benzothiazole derivant of commercially available acquisition is modified, to obtain the suitable functionality on the benzothiazole ring.Another kind method is the annulation of various aniline (suc as formula 4 compounds), to make up the thiazole part on the benzothiazole ring.For example, formula 3 compounds (wherein G "=S, A=NH ₂, L ², E ², J ²=H, X ²=CH ₂O and R '=Et) can prepare in proper order by two steps by the 4-methoxyl group-thiazolamine of commercially available acquisition: with reagent such as BBr ₃(Node; M. etc.; J.Org.Chem.45; 2243-2246; 1980) or aluminum chloride in the presence of mercaptan (as EtSH), 4-methoxyl group-2-aminobenzothiazole is converted into 4-hydroxyl-2-aminobenzothiazole (McOmie, J.F.W. etc.; Org.Synth.Collect. the 5th roll up; 412,1973), then in the presence of suitable alkali (as sodium hydride); in polar aprotic solvent (as DMF); with diethyl phosphonyl methyl trifluoro methyl sulphonate (Phillion, D.P. etc., Tetrahedron Lett.27; 1477-1484,1986) make the phenolic groups alkylation obtain required compound.

There is several method can be used for various aniline are converted into benzothiazole (Sprague, J.M.; Land, A.H.Heterocycle.Compd.5,506-13,1957).For example, (formula 3 is A=NH wherein for the 2-aminobenzothiazole ₂) can adopt various common methods, through type 4 compounds (W wherein ²=H) annulation preparation.A kind of method comprises the aniline with KSCN and the mixture process suitable replacement of copper sulfate in methyl alcohol, the 2-aminobenzothiazole (Ismail, the I.A. that obtain replacing; Sharp, D.E; Chedekel, M.R.J.Org.Chem.45,2243-2246,1980).Perhaps, in the presence of KSCN, by the Br in acetate ₂Processing also can prepare 2-aminobenzothiazole (Patil, D.G.; Chedekel, M.R.J.Org.Chem.49,997-1000,1984).This reaction also can be undertaken by the order in two steps.For example, use Br ₂At CHCl ₃2-aminobenzothiazole (Patil, D.G. that the middle phenylthiourea of handling replacement obtains replacing; Chedekel, M.R.J.Org.Chem.49,997-1000,1984).The 2-aminobenzothiazole also can pass through adjacent iodo aniline and thiocarbamide at Ni catalyzer (NiCl ₂(PPh ₃) ₂) condensation prepared (Takagi, K.Chem.Lett.265-266,1986) under existing.

Benzothiazole can stand close electric aromatics and replace benzothiazole (Sprague, the J.M. that obtains the 6-replacement; Land, A.H.Heterocycle.Compd.5,606-13,1957).For example, in polar solvent (as AcOH), with bromine bromination formula 3 compounds, wherein G "=S, A=NH ₂, L ², E ², J ²=H, X ²=CH ₂O and R '=Et obtains formula 3 compounds, wherein E ²=Br.

In addition, but by corresponding aminocompound preparation formula 3 compounds, wherein A is halo, H, alkoxyl group, alkylthio or alkyl (Larock, Comprehensive OrganicTransformations, VCH, New York, 1989; Trost, Comprehensive OrganicSynthesis; Pergamon press, New York, 1991).

Ii. benzoxazole:

Formula 3 compounds (wherein G "=O), promptly benzoxazole can be by Ortho-Aminophenol and suitable reagent (as halogen cyan (A=NH ₂Alt, K.O etc., J.Heterocyclic Chem.12,775,1975) or acetate (A=CH ₃Saa, J.M.; J.Org.Chem.57,589-594,1992) or alkyl orthoformate (A=H; Org.Prep.Proced.Int., 22,613,1990)) become the ring preparation.

(4) introducing of phosphonic acid ester composition

Formula 4 compounds (X wherein ²=CH ₂O and R '=alkyl) can (for example adopt alkylation and nucleophilic substitution reaction) in a different manner makes.Generally with suitable alkali (as sodium hydride) processing formula 5 compounds in polar aprotic solvent (as DMF, DMSO), M '=OH wherein, the phenol salt anion that obtains can be with suitable electrophilic reagent (being preferably with the phosphonic acid ester composition) (as iodo-methyl diethyl phosphonate, trifluoromethyl sulfo group methyl-phosphorous acid diethyl ester, right-methyl toluene sulfo group methyl-phosphorous acid diethyl ester) alkylation.Alkylation also can be applicable to the formula 5 compounds precursor compound of (wherein having the phenol part), its available composition alkylation that contains phosphonic acid ester.Perhaps, formula 4 compounds also can prepare from the nucleophilic substitution reaction of the precursor compound of formula 5 compounds (halo group wherein, preferred fluoro or chloro are present in the ortho position of nitro).For example, formula 4 compounds (X wherein ²=CH ₂O and R '=Et) can be by using NaOCH ₂P (O) (OEt) ₂In DMF, handle 2-chloro-1-nitrobenzene derivative and prepare.Similarly, but also preparation formula 4 compounds, wherein X ²=-alkyl-S-or-alkyl-N-.

(5) anils is synthetic

Reported the method for many synthetic anilss, these methods can be applicable to the synthetic of useful as intermediates, can obtain formula X compound by these intermediates.For example, various alkenyls or aryl can be incorporated into (WO 98/39343, is incorporated herein by reference for Kasibhatla, S.R etc.) on the phenyl ring by transition metal-catalyzed reaction; Aniline also can be by reduction reaction (as the hydrogenation in the presence of 10%Pd/C or use SnCl in HCl ₂Reduction reaction (Patil, D.G.; Chedekel, M.R.J.Org.Chem.49,997-1000,1984)) from corresponding nitro-derivative preparation.

Part 3

Replace 1,3-azanol and 1,3-diamines synthetic

Because the ubiquitous character of these functionality has many synthetic methods to can be used for preparing 1 of replacement, 3-azanol and 1,3-diamines in the naturally occurring compound.In these class methods some separately are described below: 1. replace 1,3-azanol synthetic; 2. replace 1,3-diamines synthetic and 3. chiralitys replace 1,3-azanol and 1,3-diamines synthetic.

I. replace 1,3-azanol synthetic:

By hydroxy functionality is converted into leavings group and handles, can make with anhydrous ammonia or required primary amine or secondary amine describe in the previous section 1, the 3-glycol optionally is converted into azanol or corresponding diamine (Corey etc., Tetrahedron Lett., 1989,30,5207; Gao etc., J.Org.Chem., 1988,53,4081).Adopt Mitsunobu type reaction conditions, also can directly realize similarly transforming (Hughes, D.L., Org.React., 1992,42) by alcohol.The universal synthesis method that is used for 3-aryl-3-hydroxyl-third-1-amine prodrug moiety comprises the aldol condensation of aryl ester and alkyl nitrile, then the substituted benzoyl acetonitrile (Shih etc., Heterocycles, 1986,24,1599) of reduction generation.This method is also applicable to the aminopropanol by replacing with the alkyl nitrile formation 2-that replaces.In another approach, in the presence of ammonium acetate, by the condensation of propanedioic acid and aryl aldehyde, then the amino acid of the replacement of reduction generation can synthesize 3-aryl-3-amino-third-1-alcohols prodrug group by aryl aldehyde.These two kinds of methods all can cause the multiple replacement (Shih etc., Heterocycles, 1978,9,1277) of aryl.In an alternate method, the organolithium compound of the replacement of the 1-amino-1-aryl ethyl dianion that is generated by styrene compound and carbonyl compound obtain W, the W ' (Barluenga etc. by the replacement of carbonyl compound variant after addition reaction, J.Org.Chem., 1979,44,4798).

Ii. replace 1,3-diamines synthetic:

1 of replacement, the 3-diamines is begun to synthesize by various Substrates.The aryl trimethylene cyanide can be converted into the diamines (Bertochio etc., Bull, Soc.Chim.Fr, 1962,1809) that 1-replaces by being hydrolyzed to acid amides and Hoffman rearrangement condition.Yet propane dinitrile replaces by electrophilic reagent to be introduced, and then hydride reduction is that corresponding diamine can be carried out various Z replacements.In another approach, the hydrazine reaction of phenylacrolein and hydrazine or replacement obtains corresponding pyrazoline, and it produces 1 of replacement, 3-diamines (Weinhardt etc., J.Med.Chem., 1985,28,694) through catalytic hydrogenation.By the aryl Grignard addition reaction to pyrazoline, then reduction also can reach 1 of high trans-cis-selectivity, and 3-replaces (Alexakis etc., J.Org.Chem., 1992,576,4563).1-aryl-1,3-diaminopropanes also can prepare by the diborane reduction of 3-amino-3-aryl vinyl cyanide, and 3-amino-3-aryl vinyl cyanide makes (Dornow etc., Chem Ber., 1949,82,254) by the aromatic substance that nitrile replaces successively.Reduction derives from corresponding 1,1 of 3-dicarbonyl compound, and the 3-diamines is 1, another source of 3-diamines prodrug moiety, this part allows various activatory group V and/or Z (Barluenga etc., J.Org.Chem., 1983,48,2255).

Iii. chirality replace 1,3-azanol and 1,3-diamines synthetic

Pass through chlorophenyl.The catalytic reaction of CBS enantioselectivity of ethyl ketone is then replaced the halo group and is synthesized the pure 3-aryl of mapping-3-hydroxyl third-1-amine (Corey etc., Tetrahedron Lett., 1989,30,5207) to make required secondary amine or primary amine.1 of the nitrone of the alkene by chiral purity and the replacement of aryl aldehyde, the 3-dipolar addition.Then reduction generates 3-aryl-3 amino third-1-alcohols prodrug moiety (Koizumi etc., J.Org.Chem., 1982,47,4005) that the De isoxazole alkyl can obtain chirality.1, the importing chirality of 3-dipolar addition also can cause that the formation of the enantioselectivity of amino alcohol obtains (Hori etc., J.Org.Chem., 1999,64,5017) by chirality phosphine palladium mixture to form replacement De isoxazole alkyl.Perhaps, by make corresponding chiral epoxy alcohol selective opening obtain the amino alcohol (Canas etc., Tetrahedron Lett., 1991,32,6931) that optically pure 1-aryl replaces with required amine.

Knownly severally be used for 1, the cis-selectivity synthetic method of the dibasic amino alcohol of 3-.For example, handle (E)-N-cinnamyl trichloroacetamide with hypochlorous acid and obtain trans-Er Qing oxazines, the latter is easy to be hydrolyzed to red-chloro-hydroxyl-phenylpropylamine (Commercon etc., Tetrahedron Lett., 1990,31,3871) through high cis-selectivity.Also can reach the formation 1 of cis-selectivity, 3-amino alcohol (Haddad etc., Tetrahedron Lett., 1997,38,5981) by the reductive amination of optically pure 3-hydroxyketone.In an alternate method, the 3-keto-amine can be converted into 1 with highly-solid selectively, the dibasic amino alcohol of 3-(Barluenga etc., J.Org.Chem., 1992,57,1219) by hydride reduction optionally.

All aforesaid methods also can be used for preparing corresponding V-Z or V-W becomes the ring chiral amino alcohol.And this type of optically-active pure amino alcohol also is the source that obtains the pure diamines of optically-active by the method described in the part in front.

Preparation

The compounds of this invention is with the total dose orally give of about 0.01mg/kg/ dosage-Yue 100mg/kg/ dosage (preferably about 0.1mg/kg/ dosage-Yue 10mg/kg/ dosage) every day.Can preferably adopt the rate of release of timing-delivery formulations with the control activeconstituents.For simplicity, described dosage can give with many divided doses.When adopting other method (giving), give compound to affected tissue with the speed of 0.05-10mg/kg/ hour (preferred 0.1-1mg/kg/ hour) as vein.As hereinafter discussing, when vein gave these compounds, such speed was easy to keep.

For the purposes of the present invention, can comprise oral, parenteral, suction spraying, part or rectum, give this compound with the dosage form that contains pharmaceutically acceptable carrier, auxiliary and solvent by variety of way.Comprise the intra-arterial injection of subcutaneous, intravenously, intramuscular and the various infusion techniques of employing at this used term parenteral.Comprise in this used intra-arterial and intravenous injection and to pass through catheter drug delivery.Oral administration generally is preferred.

The medicinal compositions that contains activeconstituents can be any form that is fit to predetermined medication.For example, when being used for oral administration, can prepare tablet, dragee, lozenge, water-based or oily suspensions, dispersible powder or granule, emulsion, hard or soft capsule, syrup or elixir.Being intended to be used for oral composition can be according to this area for producing any currently known methods preparation of medicinal compositions, and such composition can contain one or more reagent, comprises sweeting agent, seasonings, tinting material and sanitas, so that agreeable to the taste preparation is provided.The tablet that contains with atoxic pharmaceutically acceptable vehicle (described vehicle is suitable for preparing tablet) blended activeconstituents is acceptable.These vehicle can be, for example, and inert diluent such as lime carbonate or yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent such as W-Gum or alginic acid; Tackiness agent such as starch, gelatin or gum arabic; And lubricant such as Magnesium Stearate, stearic acid or talcum powder.Tablet not dressing or available known technology comprises the microencapsulation dressing, so that postpone disintegration and absorption in gi tract, and is provided at the retarding action in the long term thus.For example, can be separately or mix material such as Zerol or the Stearic diglyceride that uses time-delay with wax.

The preparation that orally uses also can be used as hard gelatin capsule (wherein activeconstituents and inert solid diluent such as calcium phosphate or kaolin mix) or soft gelatin capsule (wherein activeconstituents and water or oil medium such as peanut oil, whiteruss or mixed with olive oil) provides.

Waterborne suspension of the present invention contains the active substance with the mixed with excipients that is suitable for preparing waterborne suspension.Such vehicle comprises suspension agent such as Xylo-Mucine, methylcellulose gum, Vltra tears, sodiun alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic, and dispersion agent or wetting agent such as naturally occurring phosphatide (as Yelkin TTS), the condensation product of the condensation product of alkylene oxide and lipid acid (as polyoxyethylene stearic acid ester), oxyethane and long chain aliphatic alcohol (as 17 carbon inferior ethoxyl cetyl alcohols), oxyethane and derived from the condensation product (as the polyethenoxy sorbitan monooleate) of the partial ester of lipid acid and hexitan.Waterborne suspension also can contain one or more sanitass for example ethyl p-hydroxybenzoate or n-propyl ester, one or more tinting materials, one or more seasoningss and one or more sweeting agents such as sucrose or asccharin.

Oily suspensions can be by being suspended in activeconstituents vegetables oil such as peanut oil, sweet oil, sesame oil or Oleum Cocois, or prepare in mineral oil such as the whiteruss.Oral suspension can contain thickening material such as beeswax, paraffinum durum or hexadecyl alcohol.Can add sweeting agent, for example mentioned above those, and seasonings is to provide agreeable to the taste oral preparations.These compositions can be preserved by adding antioxidant such as xitix.

Being suitable for adding dispersive powder of the present invention and the particle that water prepares aq suspension provides and dispersion agent or wetting agent, suspension agent and one or more sanitas blended activeconstituentss.Suitable dispersion agent or wetting chaste tree and suspension agent illustrate with those disclosed above.Other vehicle, for example sweeting agent, seasonings and tinting material also can exist.

Medicinal compositions of the present invention also can be oil-in-water emulsion.Oil phase can be vegetables oil such as sweet oil or peanut oil, the mixture of mineral oil such as whiteruss or these materials.Suitable emulsifying agent comprises naturally occurring natural gum, as gum arabic and tragacanth gum, naturally occurring phosphatide such as soybean lecithin, derived from ester or the partial ester such as the anhydro sorbitol monooleate of lipid acid and hexitan, and the condensation product of these partial esters and oxyethane, as the polyethenoxy sorbitan monooleate.Emulsion also can contain sweeting agent and seasonings.

Syrup and elixir can be prepared with sweeting agent such as glycerine, sorbyl alcohol or sucrose.This type of preparation also can contain negative catalyst, sanitas, seasonings or tinting material.

Medicinal compositions of the present invention can be the form of aseptic injection, as aseptic injection water-based or oily suspension.This suspension can be according to known technology, with those suitable dispersion agents or wetting agent and suspension agent (above mentioning) preparation.Aseptic injection also can be aseptic injectable solution or the suspension that makes in atoxic parenteral acceptable diluent or solvent, as the solution in 1,3 butylene glycol or be prepared as lyophilized powder.In operable acceptable solvent and solvent, water, Ringer ' s solution and isotonic sodium chlorrde solution are arranged.In addition, aseptic fixed oil can be used as solvent or suspension medium routinely.For this purpose, can use the fixed oil of any gentleness, comprise synthetic one-or two glyceryl ester.In addition, lipid acid such as oleic acid can be used for injection equally.

The amount that can mix with carrier substance with the activeconstituents that generates single formulation will change according to the concrete mode of host to be treated and administration.For example, the time release formulation that is intended for use the orally give people can contain and carrier substance suitable and convenient amount (it can account between about 5-95% of total composition and change) the about 1-1000mg active substance of blended.This medicinal compositions preferably is prepared as can provide the dosage that is easy to measure.For example, the aqueous solution that is intended to venoclysis should contain the 3-330 μ g activeconstituents/every ml solution of having an appointment, so that with the speed infusion appropriate volume of about 30ml/hr.

As mentioned above, the preparation of the present invention that is suitable for oral administration can be used as independently unit existence, as every capsule, cachet or tablet that contains the activeconstituents of predetermined amount; As powder or granule; As solution in water-based or non-aqueous liquid or suspension; As oil-in-water liquid emulsion or water-in-oil liquid emulsion.Activeconstituents also can be used as bolus, electuary or paste and gives.

Tablet can make by compacting or mold pressing, optional one or more ancillary components that contains.Compressed tablets can prepare by stranglehold liquid form such as powder in suitable machine or particulate activeconstituents, described activeconstituents optional and tackiness agent (as polyvidone, gelatin, Vltra tears), lubricant, inert diluent, sanitas, disintegrating agent (as sodium starch glycollate, polyvinylpolypyrrolidone, croscarmellose sodium), tensio-active agent or dispersion agent.The mixture of the powdered compounds that molded tablet can be got wet with inert liquid diluent by the suitable machine mold pressing makes.Tablet can be chosen dressing or indentation wantonly, and can be with the feasible slow release or the sustained release that activeconstituents can be provided of Vltra tears preparation of for example different ratios, so that required release profile to be provided.The form that tablet can be chosen wantonly with the band enteric coating provides, to be provided at the release of enteron aisle rather than stomach.When this compounds was easy to by acid hydrolysis, this point was particularly advantageous to formula I and X compound.

The preparation that is suitable for oral cavity local medication comprises the lozenge that contains the activeconstituents in flavoured base (being generally sucrose and gum arabic or tragacanth gum), contains the pastille of the activeconstituents in inert base (as gelatin and glycerine or sucrose and gum arabic) and the collutory that contains the activeconstituents in suitable liquid vehicle.

The preparation that is used for rectal administration can be used as the suppository with the suitable matrix that comprises theobroma oil for example or salicylate and exists.

The preparation that is suitable for vagina administration can be used as vaginal suppository, vagina plug, creme, gel, paste, foaming agent or sprays and exists, and except that containing activeconstituents, also comprises suitable carriers known in the art in these preparations.

The preparation that is suitable for parenteral admin comprises water-based and non-aqueous isotonic sterile injection liquid, and it can contain antioxidant, buffer reagent, bacteriostatic agent and solute, and the latter can make blood of preparation and intended recipient etc. ooze; Water-based and non-aqueous sterile suspensions can comprise suspending agent and thickening material.Said preparation can exist with unitary dose or multiple doses sealed vessel such as ampoule and glass tube vial, and can store under lyophilize (freeze-drying) condition, needs to add sterile liquid carrier facing with preceding, and for example water for injection gets final product.Injection liquid and suspension can be by aforesaid sterilized powder, particle and tablet preparation.

Preferred unit dose formulations is the fructose-1 inhibitor compound that contains per daily dose or unit, day sub-doses or its suitable part.

Should be appreciated that, will depend on multiple factor, comprise the activity of used specific compound for any concrete patient's given dose; Receive treatment individual age, body weight, general health situation, sex and food habits; Time of administration and approach; Excretion rate; The severity of the medication history of other medicines and disease to be treated, this is that those skilled in the art fully understand.

Purposes

The FBP enzyme inhibitors can be used for treating diabetes, lowering blood glucose level and suppresses gluconeogenesis.

The FBP enzyme inhibitors also can be used for treating the disease of excessive glycogen storage.Excessive liver starch is stored up among the patient who is found in the disease of suffering from some glycogen storage.Because approach obviously helps glycogen to synthesize (Shulman, G.I. indirectly Phys.Rey.72:1019-1035 (1992)), suppress the excessive generation that indirect approach (gluconeogenesis flux (flux)) reduces glycogen.

The FBP enzyme inhibitors also can be used for the insulin level diseases associated for the treatment of or preventing and raising.The insulin level that raises relevant with cardiovascular complication with atherosclerotic dangerous rising (Folsom etc., Stroke, 25:66-73 (1994); Howard, G. etc., Circulation93:1809-1817 (1996)).Expectation FBP enzyme inhibitors reduces the post-prandial glucose level by promoting hepatic glucose to absorb.Infer that this effect betides in the non-diabetic individuality (or prediabetes, promptly do not have the hepatic glucose output " after this being called HGO " or the fasting blood glucose level that raise).Increase hepatic glucose and absorb and to reduce insulin secretion, reduce the disease that the insulin level because of rising causes or the danger of complication thus.

One aspect of the present invention relates to the new ring-type 1 of use, and the method for 3-propyl diester, this method cause effective conversion of ring-type (amino) phosphoric acid ester.The compound that contains phosphonic acid ester (through the p450 enzyme) has a large amount of discoveries in liver and other contain the tissue of these specific enzymess.

In another aspect of the present invention, because ring-type of the present invention (amino) phosphoric acid ester can prevent the effect of enzyme liberating parent drug, the method for this prodrug also can be used for the prolong drug kinetics transformation period.

In another aspect of the present invention and since various new prodrugs in liver with different speed by slow oxidation, the method for this prodrug can be used for obtaining the slow release of parent drug.

New ring-type 1 of the present invention, the method for 3-propyl diester also can be used for increasing the distribution of concrete medicine in liver, contain a large amount of p450 isozymes in liver, and it is responsible for ring-type 1 of the present invention, and the oxidation of 3-propyl diester is so that produce free (amino) phosphoric acid ester.

In another aspect of the present invention, ring-type (amino) phosphoric acid ester prodrug can increase the oral administration biaavailability of medicine.

Below these aspects will be described more at large.

The evidence of liver specificity also can show behind the prodrug that oral and vein give to describe in embodiment E in vivo.

After giving formula VI-VIII medicine as follows, in liver, also can detect medicine:

VI

VII

VIII

The prodrug of formula VI, VII and VIII is particularly preferred.

Can carry out cracking mechanism by following mechanism.Can demonstrate the further evidence of these mechanism by the by product of analytical pyrolysis.Wherein Y be-the formula VI prodrug of O-generates phenyl vinyl ketone, and the prodrug of formula VIII has shown and can generate phenol (embodiment H).

Although ester of the present invention is not subjected to the restriction of above-mentioned mechanism, in general, various esters contain the group that is subject to the microsome oxidation or atom (as the methine protons of alcohol, benzyl), and it is created in the aqueous solution intermediate of cracking or parent compound by the β-elimination reaction of (amino) phosphoric acid ester diacid successively.

Embodiment

1. formula I compound is synthetic

Embodiment 1

The preparation of 5-diethyl phosphonyl-2-furfural (1)

Steps A. in-78 ℃, handle THF (tetrahydrofuran (THF)) solution of 2-furfural diethyl acetal (1mmol) with n-Butyl Lithium (1mmol).After 1 hour, add chloro diethyl phosphoric acid (1.2mmol), stirred this reactant 40 minutes.Extraction and evaporation obtain brown oil.

Step B. is in-90 ℃, the brown oil that generates with 80% acetic acid treatment 4 hours.Extraction and chromatography obtain compound 1, are clarifying yellow oil.Perhaps, this aldehyde can as described belowly be prepared by furans.

Step C. is in-78 ℃, with TMEDA (N, N, N ', N '-Tetramethyl Ethylene Diamine) (1mmol) and the diethyl ether solution of n-Butyl Lithium (2mmol) processing furans (1mmol) 0.5 hour.Add chloro diethyl phosphoric acid (1.2mmol) in this reaction mixture and restir 1 hour.Extraction and distillation obtain 2-furans diethyl phosphonate, are clarified oil.

Step D. is in-78 ℃, handles the THF solution 20 minutes of 2-furans diethyl phosphonate (1mmol) with LDA (1.12mmol, N, N-di-isopropyl lithamide).Add methyl-formiate (1.5mmol) and stirred this reactant 1 hour.Extraction and chromatography obtain compound 1, are clarified yellow oil.This aldehyde is preferably as follows and is describedly prepared by the 2-furfural.

Step e. with 2-furfural (1mmol) and N, the toluene solution of N '-dimethyl-ethylenediamine (1mmol) refluxes, and collects the water that generates by the Dean-Stark trap simultaneously.After 2 hours, solvent removed in vacuo, residue obtains furans-2-(N, N '-methylimidazole alkane) through distillation, is clear colorless oil.bp?59-61℃(3mmHg)。

Step F. in-40 to-48 ℃, handle furans-2-(N, N '-methylimidazole alkane) (1mmol) and the THF solution of TMEDA (1mmol) with n-Butyl Lithium (1.3mmol).Stir this reactant 1.5 hours in 0 ℃, be cooled to-55 ℃ and with the THF solution-treated of chloro diethyl phosphoric acid (1.1mmol) then.After 12 hours, this reaction mixture obtains 5-diethyl phosphonyl-furans-2-(N, N '-methylimidazole alkane) through evaporation and extraction, is brown oil in 25 ℃ of stirrings.

The step G. vitriol oil is handled 5-diethyl phosphonyl-furans-2-(N, N '-dimethyl-imidazolidine) aqueous solution (1mmol) until pH=1.Extraction and chromatography obtain compound 1, are clarified yellow oil.

Embodiment 2

5-diethyl phosphonyl-2-[(1-oxo) alkyl] furans and 6-diethyl phosphonyl-2-[(1-oxo) alkyl] preparation of pyridine

Steps A. in 56 ℃, the toluene solution of usefulness 4-methylvaleric acid (1mmol), trifluoroacetic anhydride (1.2mmol) and boron trifluoride etherate (0.1mmol) processing furans (1.3mmol) 3.5 hours.With sodium bicarbonate aqueous solution (1.9mmol) quencher refrigerative reaction mixture, filter by Celite pad.Extract, evaporation and distillation obtain 2-[(4-methyl isophthalic acid-oxo) amyl group] furans, for brown oil (bp 65-77 ℃, 0.1mmHg).

Step B. is in refluxing down, and spent glycol (2.1mmol) and right-toluenesulphonic acids (0.05mmol) are handled 2-[(4-methyl isophthalic acid-oxo) amyl group] benzole soln 60 hours of furans (1mmol), remove by the Dean-Stark trap simultaneously and anhydrate.Add triethyl orthoformate (0.6mmol), with other 1 hour of the mixture reflux that generates.Extract and evaporate and obtain 2-(2-furyl)-2-[(3-methyl) butyl]-1, the 3-dioxolane is orange liquid.

Step C. is in-45 ℃, with TMEDA (1mmol) and n-Butyl Lithium (1.1mmol) processing 2-(2-furyl)-2-[(3-methyl) butyl]-1, the THF solution of 3-dioxolane (1mmol), in-5 to 0 ℃ of reaction mixtures that stirring obtains 1 hour.The reaction mixture that obtains is cooled to-45 ℃,, it is added in the THF solution of chloro diethyl phosphoric acid with conduit in-45 ℃.Made this reaction mixture slowly be warmed to room temperature with 1.25 hours.Extraction and evaporation obtain 2-[2-(5-diethyl phosphonyl) furyl]-the 2-[(3-methyl) butyl]-1, the 3-dioxolane is dark oil.

Step D. handles 2-[2-(5-diethyl phosphonyl) furyl in 60 ℃ with lN hydrochloric acid (0.2mmol)]-the 2-[(3-methyl) butyl]-1, the methanol solution of 3-dioxolane (1mmol) 18 hours.Extract and distillation obtains 5-diethyl phosphonyl-2-[(4-methyl isophthalic acid-oxo) amyl group] furans (2.1), for light orange oil (bp 152-156 ℃, 0.1mmHg).

Prepare following compounds according to this method:

(2.2) 5-diethyl phosphonyl-2-acetyl furan: bp 125-136 ℃, 0.1mmHg.

(2.3) 5-diethyl phosphonyl-2-[(1-oxo) butyl] furans: bp 130-145 ℃, 0.08mmHg.

Perhaps, these compounds can prepare with following method:

Step e. in refluxing down, use N, N-dimethylhydrazine (2.1mmol) and trifluoroacetic acid (0.05mmol) processing 2-[(4-methyl isophthalic acid-oxo) amyl group] benzole soln 6 hours of furans (1mmol prepares as steps A).Extraction and evaporation obtain 2-[(4-methyl isophthalic acid-oxo) amyl group] furans N, N-dimethyl hydrazone is brown liquid.

Step F. make 2-[(4-methyl isophthalic acid-oxo) amyl group] furans N; N-dimethyl hydrazone is through the method for step C; obtain 2-[(4-methyl isophthalic acid-oxo for brown liquid) amyl group]-5-diethyl phosphonyl furans N; N-dimethyl hydrazone; in 25 ℃, it was handled 6 hours in alcohol-water with cupric chloride (II) (1.1 equivalent).Extraction and distillation obtain compound 2.1, are light orange oil.

Adopt following method to prepare some 5-diethyl phosphonyl-2-[(1-oxo) alkyl] furans:

Step G. handles compound 1 (1mmol) and 1, the chloroformic solution of 3-dimercaptopropane (1.1mmol) 24 hours in 25 ℃ with boron trifluoride etherate (0.1mmol).Evaporation and chromatography 2-(2-(5-diethyl phosphonyl) furyl)-], the 3-dithiane is light yellow oil.

With 2-(2-(5-diethyl phosphonyl) furyl)-1; the THF solution of 3-dithiane (1mmol) is cooled to-78 ℃, handles with n-Butyl Lithium (1.2mmol), after 1 hour; handle this reaction mixture in-78 ℃ with the cyclopropane monobromomethane, stirred this reactant other 1 hour in-78 ℃.Extraction and chromatography obtain 2-(2-(5-diethyl phosphonyl) furyl)-2-cyclopropane methyl isophthalic acid, and the 3-dithiane is oily matter.

In 25 ℃, handle 2-(2-(5-diethyl phosphonyl) furyl)-2-cyclopropane methyl isophthalic acid, the acetonitrile-aqueous solution of 3-dithiane (1mmol) 24 hours with [two (trifluoroacetyl oxygen base) iodo] benzene (2mmol).Extraction and chromatography obtain 5-diethyl phosphonyl-2-(2-cyclopropane ethanoyl) furans, are light orange oil.

Prepare following compounds according to this method:

(2.4) 5-diethyl phosphonyl-2-(2-ethoxy carbonyl ethanoyl) furans

(2.5) 5-diethyl phosphonyl-2-(2-methylmercaptan ethyl acyl group) furans

(2.6) 6-diethyl phosphonyl-2-acetylpyridine

Embodiment 3.

4-[2-(5-phosphono) furyl] thiazole, 4-[2-(6-phosphono) pyridyl] thiazole and 4-[2-(5-phosphono) furyl] preparation of selenazoles

Steps A. in refluxing down, (2.2mmol) handle the ethanolic soln 3 hours of compound 2.1 (1mmol) with cupric bromide (II).Filter refrigerative reaction mixture and evaporated filtrate to doing.Dark oil by chromatography purification generates obtains 5-diethyl phosphonyl-2-[(2-bromo-4-methyl isophthalic acid-oxo) amyl group] furans, be orange oil.

Step B. is with 5-diethyl phosphonyl-2-[(2-bromo-4-methyl isophthalic acid-oxo) amyl group] the ethanolic soln reflux 2 hours of furans (1mmol) and thiocarbamide (2mmol).The refrigerative reaction mixture is evaporated to dried, makes the yellow foam thing of generation be suspended in (pH=8) in saturated sodium bicarbonate and the water.Collect the yellow solid that generates by filtering, obtain 2-amino-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] thiazole.

Step C. is in 25 ℃, handles 2-amino-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl with bromo trimethyl silane (10mmol)] dichloromethane solution of thiazole (1mmol) 8 hours.Evaporate this reaction mixture to doing, residue is suspended in water.Filter and collect the solid that generates, obtain 2-amino-5-isobutyl--4-[2-(5-phosphono) furyl] thiazole (3.1), be pale solid.mp＞250℃。C ₁₁H ₁₅N ₂O ₄The analytical calculation value of PS+1.25HBr: C:32.75; H:4.06; N:6.94.Measured value: C:32.39; H:4.33; N:7.18.

According to aforesaid method or under the situation that these methods are made an amendment slightly, adopt the conventional chemical method to prepare following compounds:

(3.2) 2-methyl-5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.C ₁₂H ₁₆NO ₄PS+HBr+0.1CH ₂Cl ₂The analytical calculation value: C:37.20; H:4.44; N:3.58.Measured value: C:37.24; H:4.56; N:3.30.

(3.3) 4-[2-(the 5-phosphono] furyl] thiazole.C ₇H ₆NO ₄The analytical calculation value of PS+0.65HBr: C:29.63; H:2.36; N:4.94.Measured value: C:29.92; H:2.66; N:4.57.

(3.4) 2-methyl-4-[2-(5-phosphono) furyl] thiazole.mp?235-236℃。C ₈H ₈NO ₄PS+0.25H ₂The analytical calculation value of O: C:38.48; H:3.43; N:5.61.Measured value: C:38.68; H:3.33; N:5.36.

(3.5) 2-phenyl-5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.C ₁₇H ₁₈NO ₄The analytical calculation value of PS+HBr: C:45.96; H:4.31; N:3.15.Measured value: C:45.56; H:4.26; N:2.76.

(3.6) 2-sec.-propyl-4-[2-(5-phosphono) furyl] thiazole.mp?194-197℃。C ₁₀H ₁₂NO ₄The analytical calculation value of PS: C:43.96; H:4.43; N:5.13.Measured value: C:43.70; H:4.35; N:4.75.

(3.7) 5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.mp?164-166℃。C ₁₁H ₁₄NO ₄The analytical calculation value of PS: C:45.99; H:4.91; N:4.88.Measured value: C:45.63; H:5.01; N:4.73.

(3.8) amino thiocarbonyl-4-[2-(5-phosphono) furyl of 2-] thiazole.mp?189-191℃。C ₈H ₇N ₂O ₄PS ₂The analytical calculation value: C:33.10; H:2.43; N:9.65.Measured value: C:33.14; H:2.50; N:9.32.

(3.9) 2-(piperidino)-5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.C ₁₆H ₂₃N ₂O ₄The analytical calculation value of PS+1.3HBr: C:40.41; H:5.15; N:5.89.Measured value: C:40.46; H:5.36; N:5.53.

(3.10) 2-(2-thienyl)-5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.C ₁₅H ₁₆NO ₄PS ₂+ 0.75H ₂The analytical calculation value of O: C:47.05; H:4.61; N:3.66.Measured value: C:47.39; H:4.36; N:3.28.

(3.11) 2-(3-pyridyl)-5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.C ₁₆H ₁₇N ₂O ₄The analytical calculation value of PS+3.75HBr: C:28.78; H:3.13; N:4.20.Measured value: C:28.73; H:2.73; N:4.53.

(3.12) 2-acetamido-5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.mp?179-181℃。C ₁₃H ₁₇N ₂O ₅PS+0.25H ₂The analytical calculation value of O: C:44.76; H:5.06; N:8.03.Measured value: C:44.73; H:5.07; N:7.89.

(3.13) 2-amino-4-[2-(5-phosphono) furyl] thiazole.C ₇H ₇N ₂O ₄The analytical calculation value of PS: C:34.15; H:2.87; N:11.38.Measured value: C:33.88; H:2.83; N:11.17.

(3.14) 2-methylamino-5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.mp?202-205℃。C ₁₂H ₁₇N ₂O ₄PS+0.5H ₂The analytical calculation value of O: C:44.30; H:5.58; N:8.60.Measured value: C:44.67; H:5.27; N:8.43.

(3.15) 2-(N-amino-N-methyl) amino-5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.mp?179-181℃。C ₁₂H ₁₈N ₃O ₄The analytical calculation value of PS+1.25HBr: C:33.33; H:4.49; N:9.72.Measured value: C:33.46; H:4.81; N:9.72.

(3.16) 2-amino-5-methyl-4-[2-(5-phosphono) furyl] thiazole.mp?200-220℃。C ₈H ₉N ₂O ₄The analytical calculation value of PS+0.65HBr: C:30.72; H:3.11; N:8.96.Measured value: C:30.86; H:3.33; N:8.85.

(3.17) 2,5-dimethyl-4-[2-(5-phosphono) furyl] thiazole.195 ℃ of mp (decomposition).C ₉H ₁₀NO ₄The analytical calculation value of PS+0.7HBr: C:34.22; H:3.41; N:4.43.Measured value: C:34.06; H:3.54; N:4.12.

(3.18) the amino thiocarbonyl of 2--5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.C ₁₂H ₁₅N ₂The analytical calculation value of OxPSx+0.1HBr+0.3EtOAc: C:41.62; H:4.63; N:7.35.Measured value: C:41.72; H:4.30; N:7.17.

(3.19) 2-ethoxy carbonyl-4-[2-(5-phosphono) furyl] thiazole.mp?163-165℃。C ₁₀H ₁₀NO ₆PS+0.5H ₂The analytical calculation value of O: C:38.47; H:3.55; N:4.49.Measured value: C:38.35; H:3.30; N:4.42.

(3.20) 2-amino-5-sec.-propyl-4-[2-(5-phosphono) furyl] thiazole.C ₁₀H ₁₃N ₂O ₄The analytical calculation value of PS+1HBr: C:32.53; H:3.82; N:7.59.Measured value: C:32.90; H:3.78; N:7.65.

(3.21) 2-amino-5-ethyl-4-[2-(5-phosphono) furyl] thiazole.mp＞250℃。C ₉H ₁₁N ₂O ₄The analytical calculation value of PS: C:39.42; H:4.04; N:10.22.Measured value: C:39.02; H:4.15; N:9.92.

(3.22) 2-cyano methyl-4-[2-(5-phosphono) furyl] thiazole.mp?204-206℃。C ₉H ₇N ₂O ₄The analytical calculation value of PS: C:40.01; H:2.61; N:10.37.Measured value: C:39.69; H:2.64; N:10.03.

(3.23) the amino thio-carbonyl-amino of 2--5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.mp177-182℃。C ₁₂H ₁₆N ₃O ₄PS ₂The analytical calculation value of+0.2 hexane+0.3HBr: C:39.35; H:4.78; N:10.43.Measured value: C:39.61; H:4.48; N:10.24.

(3.24) 2-amino-5-propyl group-4-[2-(5-phosphono) furyl] thiazole.mp?235-237℃。C ₁₀H ₁₃N ₂O ₄PS+0.3H ₂The analytical calculation value of O: C:40.90; H:4.67; N:9.54.Measured value: C:40.91; H:4.44; N:9.37.

(3.25) 2-amino-5-ethoxy carbonyl-4-[2-(5-phosphono) furyl] thiazole.mp?248-250℃。C ₁₀H ₁₁N ₂O ₆The analytical calculation value of PS+0.1HBr: C:36.81; H:3.43; N:8.58.Measured value: C:36.99; H:3.35; N:8.84.

(3.26) 2-amino-5-methylthio group-4-[2-(5-phosphono) furyl] thiazole.mp?181-84℃。C ₈H ₉N ₂O ₄PS ₂+ 0.4H ₂The analytical calculation value of O: C:32.08; H:3.30; N:9.35.Measured value: C:32.09; H:3.31; N:9.15.

(3.27) 2-amino-5-cyclopropyl-4-[2-(5-phosphono) furyl] thiazole.C ₁₀H ₁₁N ₂O ₄PS+1H ₂The analytical calculation value of O+0.75HBr: C:32.91; H:3.80; N:7.68.Measured value: C:33.10; H:3.80; N:7.34.

(3.28) 2-amino-5-methylsulfinyl-4-[2-(5-phosphono) furyl] thiazole.mp＞250℃。C ₈H ₉N ₂O ₅PS ₂The analytical calculation value of+0.35NaCl: C:29.23; H:2.76; N:8.52.Measured value: C:29.37; H:2.52; N:8.44.

(3.29) 2-amino-5-benzyloxycarbonyl-4-[2-(5-phosphono) furyl] thiazole.C ₁₅H ₁₃N ₂O ₆PS+0.2H ₂The analytical calculation value of O: C:46.93; H:3.52; N:7.30.Measured value: C:46.64; H:3.18; N:7.20.

(3.30) 2-amino-5-cyclobutyl-4-[2-(5-phosphono) furyl] thiazole.C ₁₁H ₁₃N ₂O ₄PS+0.15HBr+0.15H ₂The analytical calculation value of O: C:41.93; H:4.30; N:8.89.Measured value: C:42.18; H:4.49; N:8.53.

(3.31) 2-amino-5-cyclopropyl-4-[2-(5-phosphono) furyl] thiazole hydrobromide salt.C ₁₀H ₁₁N ₂O ⁴PSBr+0.73HBr+0.15MeOH+0.5H ₂The analytical calculation value of O: C:33.95; H:3.74; N:7.80; S:8.93; Br:16.24.Measured value: C:33.72; H:3.79; N:7.65; S:9.26; Br:16.03.

(3.32) 2-amino-5-[(N, the N-dimethyl) amino methyl]-4-[2-(5-phosphono) furyl] the thiazolyl-dihydro bromate.C ₁₀H ₁₆N ₃O ₄Br ₂PS+0.8CH ₂Cl ₂The analytical calculation value: C:24.34; H:3.33; N:7.88.Measured value: C:24.23; H:3.35; N:7.64.

(3.33) 2-amino-5-methoxycarbonyl-4-[2-(5-phosphono) furyl] thiazole.227 ℃ of Mp (decomposition).C ₉H ₉N ₂O ₆PS+0.1H ₂The analytical calculation value of O+0.2HBr: C:33.55; H:2.94; N:8.69.Measured value: C:33.46; H:3.02; N:8.49.

(3.34) 2-amino-5-ethylmercapto group carbonyl-4-[2-(5-phosphono) furyl] thiazole.245 ℃ of Mp (decomposition).C ₁₀H ₁₁N ₂O ₅PS ₂The analytical calculation value: C:35.93; H:3.32; N:8.38.Measured value: C:35.98; H:3.13; N:8.17.

(3.35) 2-amino-5-propoxycarbonyl-4-[2-(5-phosphono) furyl] thiazole.245 ℃ of Mp (decomposition).C ₁₁H ₁₃N ₂O ₆The analytical calculation value of PS: C:39.76; H:3.94; N:8.43.Measured value: C:39.77; H:3.72; N:8.19.

(3.36) 2-amino-5-benzyl-4-[2-(5-phosphono) furyl] thiazole.C ₁₄H ₁₃N ₂O ₄PS+H ₂The analytical calculation value of O: C:47.46; H:4.27; N:7.91.Measured value: C:47.24; H:4.08; N:7.85.

(3.37) 2-amino-5-[(N, the N-diethyl) amino methyl]-4-[2-(5-phosphono) furyl] the thiazolyl-dihydro bromate.C ₁₂H ₂₀N ₃O ₄Br ₂The analytical calculation value of PS+0.1HBr+1.4MeOH: C:29.47; H:4.74; N:7.69.Measured value: C:29.41; H:4.60; N:7.32.

(3.38) 2-amino-5-[(N, the N-dimethyl) formamyl]-4-[2-(5-phosphono) furyl] thiazole.C ₁₀H ₁₂N ₃O ₅PS+1.3HBr+1.0H ₂The analytical calculation value of O+0.3 acetone: C:28.59; H:3.76; N:9.18.Measured value: C:28.40; H:3.88; N:9.01.

(3.39) 2-amino-5-carboxyl-4-[2-(5-phosphono) furyl] thiazole.C ₈H ₇N ₂O ₆PS+0.2HBr+0.1H ₂The analytical calculation value of O: C:31.18; H:2.42; N:9.09.Measured value: C:31.11; H:2.42; N:8.83.

(3.40) 2-amino-5-isopropoxy carbonyl-4-[2-(5-phosphono) furyl] thiazole.240 ℃ of Mp (decomposition).C ₁₁H ₁₃N ₂O ₆The analytical calculation value of PS: C:39.76; H:3.94; N:8.43.Measured value: C:39.42; H:3.67; N:8.09.

(3.41) 2-methyl-5-ethyl-4-[2-(5-phosphono) furyl] thiazole.C ₁₀H ₁₂O ₄PNS+0.75HBr+0.35H ₂The analytical calculation value of O: C:36.02; H:4.13; N:4.06.Measured value: C:36.34; H:3.86; N:3.69.

(3.42) 2-methyl-5-cyclopropyl-4-[2-(5-phosphono) furyl] thiazole.C ₁₁H ₁₂NO ₄PS+0.3HBr+0.5CHCl ₃The analytical calculation value: C:37.41; H:3.49; N:3.79.Measured value: C:37.61; H:3.29; N:3.41.

(3.43) 2-methyl-5-ethoxy carbonyl-4-[2-(5-phosphono) furyl] thiazole.C ₁₁H ₁₂NO ₆The analytical calculation value of PS: C:41.64; H:3.81; N:4.40.Measured value: C:41.61; H:3.78; N:4.39.

(3.44) amino 2-[(N-ethanoyl)]-5-methoxymethyl-4-[2-(5-phosphono) furyl] thiazole.C ₁₁H ₁₃N ₂O ₆The analytical calculation value of PS+0.15HBr: C:38.36; H:3.85; N:8.13.Measured value: C:38.74; H:3.44; N:8.13.

(3.45) 2-amino-5-(4-morpholinyl) methyl-4-[2-(5-phosphono) furyl] the thiazolyl-dihydro bromate.C ₁₂H ₁₈Br ₂N ₃O ₅The analytical calculation value of PS+0.25HBr: C:27.33; H:3.49; N:7.97.Measured value: C:27.55; H:3.75; N:7.62.

(3.46) 2-amino-5-cyclo propyl methoxy carbonyl-4-[2-(5-phosphono) furyl] thiazole.Mp238 ℃ (decomposition).C ₁₂H ₁₃N ₂O ₆The analytical calculation value of PS: C:41.86; H:3.81; N:8.14. measured value: C:41.69; H:3.70; N:8.01.

(3.47) 2-amino-5-methylthio group-4-[2-(5-phosphono) furyl] thiazole N, N-dicyclohexyl ammonium salt.Mp＞250℃。C ₈H ₉N ₂O ₄PS ₂+ 1.15C ₁₂H ₂₃The analytical calculation value of N: C:52.28; H:7.13; N:8.81.Measured value: C:52.12; H:7.17; N:8.81.

(3.48) amino 2-[(N-dansyl base)]-5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.C ₂₃H ₂₆N ₃O ₆PS ₂The analytical calculation value of+0.5HBr: C:47.96; H:4.64; N:7.29.Measured value: C:48.23; H:4.67; N:7.22.

(3.49) 2-amino-5-(2,2, the 2-trifluoroethyl)-4-[2-(5-phosphono) furyl] thiazole.C ₉H ₈N ₂F ₃O ₄The analytical calculation value of PS: C:32.94; H:2.46; N:8.54.Measured value: C:32.57; H:2.64; N:8.14.

(3.50) 2-methyl-5-methylthio group-4-[2-(5-phosphono) furyl] thiazole.C ₉H ₁₀NO ₄PS ₂The analytical calculation value: C:37.11; H:3.46; N:4.81.Measured value: C:36.72; H:3.23; N:4.60.

(3.51) 2-amino-5-methylthio group-4-[2-(5-phosphono) furyl] the thiazole ammonium salt.C ₈H ₁₂N ₃O ₄PS ₂The analytical calculation value: C:31.07; H:3.91; N:13.59.Measured value: C:31.28; H:3.75; N:13.60.

(3.52) 2-cyano group-5-ethyl-4-[2-(5-phosphono) furyl] thiazole.C ₁₀H ₉N ₂O ₄The analytical calculation value of PS: C:42.26; H:3.19; N:9.86.Measured value: C:41.96; H:2.95; N:9.76.

(3.53) 2-amino-5-methylol-4-[2-(5-phosphono) furyl] thiazole.C ₈H ₉N ₂O ₅The analytical calculation value of PS: C:34.79; H:3.28; N:10.14.Measured value: C:34.57; H:3.00; N:10.04.

(3.54) 2-cyano group-5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.C ₁₂H ₁₃N ₂O ₄The analytical calculation value of SP+0.09HBr: C:46.15; H:4.20; N:8.97.Measured value: C:44.81; H:3.91; N:8.51.

(3.55) 2-amino-5-iprotiazem base-4-[2-(5-phosphono) furyl] thiazole hydrobromide salt.C ₁₀H ₁₄BrN ₂O ₄PS ₂The analytical calculation value: C:29.94; H:3.52; N:6.98.Measured value: C:30.10; H:3.20; N:6.70.

(3.56) 2-amino-5-thiophenyl-4-[2-(5-phosphono) furyl] thiazole.C ₁₃H ₁₁N ₂O ₄PS ₂The analytical calculation value: C:44.07; H:3.13; N:.91.Measured value: C:43.83; H:3.07; N:7.74.

(3.57) 2-amino-uncle 5-butylthio-4-[2-(5-phosphono) furyl] thiazole.C ₁₁H ₁₅N ₂O ₄PS ₂+ 0.6CH ₂Cl ₂The analytical calculation value: C:36.16; H:4.24; N:7.27.Measured value: C:36.39; H:3.86; N:7.21.

(3.58) 2-amino-5-rosickyite base-4-[2-(5-phosphono) furyl] thiazole hydrobromide salt.C ₁₀H ₁₄BrN ₂O ₄PS ₂The analytical calculation value: C:29.94; H:3.52; N:6.98.Measured value: C:29.58; H:3.50; N:6.84.

(3.59) 2-amino-5-ethylmercapto group-4-[2-(5-phosphono) furyl] thiazole.C ₉H ₁₁N ₂O ₄PS ₂The analytical calculation value of+0.25HBr: C:33.11; H:3.47; N:8.58.Measured value: C:33.30; H:3.42; N:8.60.

(3.60) amino 2-[(N-tert-butoxycarbonyl)]-5-methoxymethyl-4-[2-(5-phosphono) furyl] thiazole.C ₁₄H ₁₉N ₂O ₇The analytical calculation value of PS: C:43.08; H:4.91; N:7.18. measured value: C:42.69; H:4.58; N:7.39.

(3.61) 2-hydroxyl-4-[2-(5-phosphono) furyl] thiazole.C ₇H ₆NO ₅The analytical calculation value of PS: C:34.02; H:2.45; N:5.67.Measured value: C:33.69; H:2.42; N:5.39.

(3.62) 2-hydroxyl-5-ethyl-4-[2-(5-phosphono) furyl] thiazole.C ₉H ₁₀NO ₅The analytical calculation value of PS: C:39.28; H:3.66; N:5.09.Measured value: C:39.04; H:3.44; N:4.93.

(3.63) 2-hydroxyl-5-sec.-propyl-4-[2-(5-phosphono) furyl] thiazole.C ₁₀H ₁₂NO ₅The analytical calculation value of PS+O.1HBr: C:40.39; H:4.10; N:4.71.Measured value: C:40.44; H:4.11; N:4.68.

(3.64) 2-hydroxyl-5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.C ₁₁H ₁₄NO ₅The analytical calculation value of PS: C:43.57; H:4.65; N:4.62.Measured value: C:43.45; H:4.66; N:4.46.

(3.65) 5-ethoxy carbonyl-4-[2-(5-phosphono) furyl] thiazole.C ₁₀H ₁₀NO ₆The analytical calculation value of PS: C:39.61; H:3.32; N:4.62.Measured value: C:39.60; H:3.24; N:4.47.

(3.66) 2-amino-5-vinyl-4-[2-(5-phosphono) furyl] thiazole.C ₉H ₉N ₂O ₄The analytical calculation value of PS+0.28HCl: C:37.66; H:3.26; N:9.46.Measured value: C:37.96; H:3.37; N:9.10.

(3.67) 2-amino-4-[2-(6-phosphono) pyridyl] thiazole hydrobromide salt.

(3.68) 2-methylthio group-5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.C ₁₂H ₁₆NO ₄PS ₂The analytical calculation value: C:43.24; H:4.84; N:4.20.Measured value: C:43.55; H:4.63; N:4.46.

(3.69) 2-amino-5-isobutyl--4-[2-(3-phosphono) furyl] thiazole.C ₁₁H ₁₅N ₂O ₄PS+0.1H ₂The analytical calculation value of O: C:43.45; H:5.04; N:9.21.Measured value: C:43.68; H:5.38; N:8.98.

(3.70) 2-amino-5-isobutyl--4-[2-(5-phosphono) furyl] selenazoles.C ₁₁H ₁₅N ₂O ₄The analytical calculation value of PSe+0.14HBr+0.6EtOAc: C:38.93; H:4.86; N:6.78. measured value: C:39.18; H:4.53; N:6.61.

(3.71) 2-amino-5-methylthio group-4-[2-(5-phosphono) furyl] selenazoles.C ₈H ₉N ₂O ₄The analytical calculation value of PSSe+0.7HBr+0.2EtOAc: C:25.57; H:2.75; N:6.78.Measured value: C:25.46; H:2.49; N:6.74.

(3.72) 2-amino-5-ethyl-4-[2-(5-phosphono) furyl] selenazoles.C ₉H ₁₁N ₂O ₄The analytical calculation value of PSe+HBr: C:26.89; H:3.01; N:6.97.Measured value: C:26.60; H:3.16; N:6.81.

Embodiment 4

5-halo-4-[2-(5-phosphono) furyl] preparation of thiazole

Steps A. in 25 ℃, (1.5mmol) handles 2-amino-4-[2-(5-diethyl phosphonyl) furyl with N-bromosuccinimide (NBS)] thiazole (preparing) chloroformic solution (1mmol) 1 hour as embodiment 3 step B.Extracting also, chromatography obtains 2-amino-5-bromo-4-[2-(5-diethyl phosphonyl) furyl] thiazole, be brown oil.

Step B. makes 2-amino-5-bromo-4-[2-(5-diethyl phosphonyl) furyl] thiazole obtains 2-amino-5-bromo-4-[2-(5-phosphono) furyl through embodiment 3 step C] thiazole (4.1), be yellow solid.mp＞230℃。C ₇H ₆N ₂O ₄The analytical calculation value of PSBr: C:25.86; H:1.86; N:8.62.Measured value: C:25.93; H:1.64; N:8.53.

Prepare following compound according to this method:

(4.2) 2-amino-5-chloro-4-[2-(5-phosphono) furyl] thiazole.C ₇H ₆N ₂O ₄The analytical calculation value of PSCl: C:29.96; H:2.16; N:9.98.Measured value: C:29.99; H:1.97; N:9.75.

(4.3) 2-amino-5-iodo-4-[2-(5-phosphono) furyl] thiazole.C ₇H ₆N ₂O ₄The analytical calculation value of PSI: C:22.42; H:2.28; N:6.70.Measured value: C:22.32; H:2.10; N:6.31.

(4.4) 2,5-two bromos-4-[2-(5-phosphono) furyl] thiazole.C ₇H ₄NO ₄PSBr ₂The analytical calculation value: C:21.62; H:1.04; N:3.60.Measured value: C:21.88; H:0.83; N:3.66.

Embodiment 5

2-halo-4-[2-(5-phosphono) furyl] preparation of thiazole

Steps A. in 0 ℃, with cupric bromide (II) (1.2mmol) and Isopentyl nitrite (1.2mmol) handle 2-amino-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] thiazole (preparing) acetonitrile solution (1mmol) 1 hour as embodiment 3 step B.Extracting also, chromatography obtains 2-bromo-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] thiazole, be brown solid.

Step B. makes 2-bromo-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] thiazole obtains 2-bromo-5-isobutyl--4-[2-(5-phosphono) furyl through embodiment 3 step C] thiazole (5.1), be yellow hygroscopic solid.C ₁₁H ₁₃NO ₄The analytical calculation value of PSBr: C:36.08; H:3.58; N:3.83.Measured value: C:36.47; H:3.66; N:3.69.

Prepare following compound according to this method:

(5.2) 2-chloro-5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.C ₁₁H ₁₃NO ₄The analytical calculation value of PSCl: C:41.07; H:4.07; N:4.35.Measured value: C:40.77; H:4.31; N:4.05.

(5.3) 2-bromo-5-methylthio group-4-[2-(5-phosphono) furyl] thiazole.C ₈H ₇NO ₄PS ₂The analytical calculation value of Br: C:26.98; H:1.98; N:3.93.Measured value: C:27.21; H:1.82; N:3.84.

Embodiment 6

4-[2-(5-phosphono) furyl that various 2-and 5-replace] preparation of thiazole

Steps A. under 100 ℃ and nitrogen; handle 2-bromo-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl with tributyl (vinyl) tin (5mmol) and two (triphenyl phosphine) palladium chloride (0.05mmol)] the DMF solution of thiazole (1mmol is as the preparation of embodiment 5 steps A).After 5 hours, transpiration-cooled reaction mixture, residue obtains 2-vinyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl through chromatography] thiazole, be yellow solid.

Step B. makes 2-vinyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] thiazole obtains 2-vinyl-5-isobutyl--4-[2-(5-phosphono) furyl through embodiment 3 step C] thiazole (6.1), be yellow solid.C ₁₃H ₁₆NO ₄PS+1HBr+0.1H ₂The analytical calculation value of O: C:39.43; H:4.38; N:3.45.Measured value: C:39.18; H:4.38; N:3.56.

This method also can be used for preparing 4-[2-(5-phosphono) furyl that various 5-replace by their corresponding halogenide] thiazole.

Step C. makes 2-amino-5-bromo-4-[2-(5-diethyl phosphonyl) furyl] thiazole experience steps A; as the coupling part, obtain 2-amino-5-(2-furyl)-4-[2-(5-diethyl phosphonyl) furyl with 2-tributyl stannyl furans] thiazole.

Step D. makes 2-amino-5-(2-furyl)-4-[2-(5-diethyl phosphonyl) furyl] thiazole obtains 2-amino-5-(2-furyl)-4-[2-(5-phosphono) furyl through embodiment 3 step C] thiazole (6.2), mp 190-210 ℃.C ₁₁H ₉N ₂O ₅The analytical calculation value of PS+0.25HBr: C:39.74; H:2.80; N:8.43.Measured value: C:39.83; H:2.92; N:8.46.

Prepare following compounds according to this method:

(6.3) 2-amino-5-(2-thienyl)-4-[2-(5-diethyl phosphonyl) furyl] thiazole.C ₁₁H ₉N ₂O ₄PS ₂The analytical calculation value of+0.3EtOAc+0.11HBr: C:40.77; H:3.40; N:7.79.Measured value: C:40.87; H:3.04; N:7.45.

Embodiment 7

2-ethyl-4-[2-(5-phosphono) furyl] preparation of thiazole

Steps A. under 1 normal atmosphere hydrogen, handle 2-vinyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl with palladium on carbon (0.05mmol)] ethanolic soln of thiazole (1mmol is as the steps A preparation of embodiment 6) 12 hours.Filter this reaction mixture, evaporated filtrate, residue obtains 2-ethyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl through chromatography purification] thiazole, be yellow foam thing.

Step B. makes 2-ethyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] thiazole obtains 2-ethyl-5-isobutyl--4-[2-(5-phosphono) furyl through embodiment 3 step C] thiazole (7.1), be yellow solid.C ₁₃H ₁₈NO ₄The analytical calculation value of PS+1HBr: C:39.41; H:4.83; N:3.53.Measured value: C:39.65; H:4.79; N:3.61.

Embodiment 8

The preparation of 4-phosphonium mesitoyl methoxy methylthiazol

Steps A. in 0 ℃, successively use sodium hydride (1.2mmol) and 2-methyl-4-chloro methylthiazol (1mmol) to handle the DMF solution of hydroxymethyl phosphonic acid diethyl ester (1mmol) and stirred 12 hours in 25 ℃.Extracting also, chromatography obtains 2-methyl-4-(diethyl phosphonyl methoxyl ylmethyl) thiazole.

Step B. makes 2-methyl-4-diethyl phosphonyl methoxyl ylmethyl thiazole obtain 2-methyl-4-phosphonium mesitoyl methoxy methylthiazol (8.1) through embodiment 3 step C.C ₆H ₁₀NO ₄PS+0.5HBr+0.5H ₂The analytical calculation value of O: C:26.43; H:4.25; N:5.14.Measured value: C:26.52; H:4.22; N:4.84.

Step C. makes 2-methyl-4-diethyl phosphonyl methoxyl ylmethyl thiazole earlier after embodiment 4 steps A and embodiment 3 step C obtain 5-bromo-2-methyl-4-phosphonium mesitoyl methoxy methylthiazol (8.2).C ₆H ₉NO ₄The analytical calculation value of PSBr+0.5HBr: C:21.04; H:2.80; N:4.09. measured value: C:21.13; H:2.69; N:4.01.

Step D. is with 2-[(N-Boo) amino]-methylene dichloride (10ml) solution of 4 thiazole carboxylic acid ethyl ester (1mmol) is cooled to-78 ℃, and (1M 5ml) handles with DIBAL-H.Stirred these reactants 3 hours, the suspension quencher of usefulness Sodium Fluoride/water (1g/1ml) in-60 ℃.The mixture that filtration obtains, concentrated filtrate obtain being solid 2-[(N-Boc) amino]-the 4-hydroxymethylthiazole.

Step e. with 2-[(N-Boc) amino]-DMF (10ml) solution of 4-hydroxymethylthiazole (1mmol) is cooled to 0 ℃, handles with sodium hydride (1.1mmol).Under room temperature, stir this mixture 30 minutes, add (phosphonomethyl) triflate (1.1mmol) then.After stirring 4 hours under the room temperature, be evaporated to this reactant dried.The chromatography residue obtains being solid 2-[(N-Boc) amino]-4-diethyl phosphonyl methoxyl ylmethyl thiazole.

Step F. make 2-[(N-Boc) amino]-4-diethyl phosphonyl methoxyl ylmethyl thiazole obtains being solid 2-amino-4-phosphonium mesitoyl methoxy methylthiazol (8.3) through embodiment 3 step C.C ₅H ₉N ₂O ₄The analytical calculation value of PS+0.16HBr+0.1MeOH: C:25.49; H:4.01; N:11.66.Measured value: C:25.68; H:3.84; N:11.33.

Embodiment 9

2-formamyl-4-[2-(5-phosphono) furyl] preparation of thiazole

Steps A. in 25 ℃ of 2-ethoxy carbonyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] solution of thiazole (1mmol) in saturated methyl alcohol system ammonia solution 12 hours.Evaporation and chromatography obtain 2-formamyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] thiazole, be white solid.

Step B. makes 2-formamyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] thiazole obtains 2-formamyl-5-isobutyl--4-[2-(5-phosphono) furyl through embodiment 3 step C] thiazole (9.1), be solid.mp?185-186℃。C ₁₂H ₁₅N ₂O ₅The analytical calculation value of PS: C:43.64; H:4.58; N:8.48.Measured value: C:43.88; H:4.70; N:8.17.

Prepare following compounds according to this method:

(9.2) 2-formamyl-4-[2-(5-phosphono) furyl] thiazole.mp?195-200℃。C ₈H ₇N ₂O ₅PS+0.25H ₂The analytical calculation value of O: C:34.48; H:2.71; N:10.05.Measured value: C:34.67; H:2.44; N:9.84.

2-ethoxy carbonyl-4-[2-(5-diethyl phosphonyl) furyl] thiazole can be converted into also that other 2-replaces-4-[2-(5-phosphono) furyl] thiazole.

Step C. is in 25 ℃, handles 2-ethoxy carbonyl-4-[2-(5-diethyl phosphonyl) furyl with sodium borohydride (1.2mmol)] methanol solution of thiazole (1mmol) 12 hours.Extracting also, chromatography obtains 2-methylol-4-[2-(5-diethyl phosphonyl) furyl] thiazole.

Step D. makes 2-methylol-4-[2-(5-diethyl phosphonyl) furyl]-thiazole obtains 2-methylol-4-[2-(5-phosphono) furyl through embodiment 3 step C] thiazole (9.3).mp?205-207℃。C ₈H ₈NO ₅PS+0.25H ₂The analytical calculation value of O: C:36.16; H:3.22; N:5.27.Measured value: C:35.98; H:2.84; N:5.15.

Prepare following compounds according to this method:

(9.4) 2-methylol-5-isobutyl--4-[2-(5-phosphono) furyl] thiazole.mp?160-170℃。C ₁₂H ₁₆NO ₅The analytical calculation value of PS+0.75HBr: C:38.13; H:4.47; N:3.71.Measured value: C:37.90; H:4.08; N:3.60.

Step e. in 25 ℃, handle 2-methylol-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl with phosphorus tribromide (1.2mmol)] dichloromethane solution of thiazole (1mmol) 2 hours.Extracting also, chromatography obtains 2-bromomethyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] thiazole.

Step F. make 2-bromomethyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl]-thiazole obtains 2-bromomethyl-5-isobutyl--4-[2-(5-phosphono) furyl through embodiment 3 step C] thiazole (9.5).mp?161-163℃。C ₁₂H ₁₅BrNO ₄The analytical calculation value of PS+0.25HBr: C:35.99; H:3.84; N:3.50.Measured value: C:36.01; H:3.52; N:3.37.

Prepare following compounds according to this method:

(9.6) 2-bromomethyl-4-[2-(5-phosphono) furyl] thiazole.mp＞250℃。C ₈H ₇BrNO ₄The analytical calculation value of PS: C:29.65; H:2.18; N:4.32.Measured value: C:29.47; H:1.99; N:4.16.

Step G. is in 25 ℃, handles 2-methylol-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl with thionyl chloride (1.2mmol)] dichloromethane solution of thiazole (1mmol) 2 hours.Extracting also, chromatography obtains 2-chloro methyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] thiazole.

Step H. makes 2-chloro methyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl]-thiazole obtains 2-chloro methyl-5-isobutyl--4-[2-(5-phosphono) furyl through embodiment 3 step C] thiazole (9.7).mp?160-162℃。C ₁₂H ₁₅ClNO ₄The analytical calculation value of PS+0.45HBr: C:38.73; H:4.18; N:3.76.Measured value: C:38.78; H:4.14; N:3.73.

Step I. is in 25 ℃, handles 2-bromomethyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl with potassium phthalimide (1.2mmol)] the DMF solution of thiazole (1mmol) 12 hours.Extracting also, chromatography obtains 2-phthalimide-based methyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] thiazole.

Step J. is in 25 ℃, handles 2-phthalimide-based methyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl in ethanol with hydrazine (1.5mmol)] thiazole (1mmol) 12 hours.Filtering, evaporate also, chromatography obtains 2-amino methyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] thiazole.

Step K. make 2-amino methyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl]-thiazole obtains 2-amino methyl-5-isobutyl--4-[2-(5-phosphono) furyl through embodiment 3 step C] thiazole (9.8).mp?235-237℃。C ₁₂H ₁₇N ₂O ₄The analytical calculation value of PS+0.205HBr: C:43.30; H:5.21; N:8.41.Measured value: C:43.66; H:4.83; N:8.02.

According to top method or under the situation that these methods are made an amendment slightly, the preparation following compounds:

(9.9) 2-formamyl-5-cyclopropyl-4-[2-(5-phosphono) furyl] thiazole.C ₁₁H ₁₁N ₂O ₅The analytical calculation value of PS+0.15HBr: C:40.48; H:3.44; N:8.58.Measured value: C:40.28; H:3.83; N:8.34.

(9.10) 2-formamyl-5-ethyl-4-[2-(5-phosphono) furyl] thiazole.C ₁₀H ₁₁N ₂O ₅PS+0.75H ₂The analytical calculation value of O: C:38.04; H:3.99; N:8.87. measured value: C:37.65; H:3.93; N:8.76.

Embodiment 10.

4-[2-(5-phosphono) furyl] oxazole and 4-[2-(5-phosphono) furyl] preparation of imidazoles

Steps A. reflux down, handle 5-diethyl phosphonyl-2-[(2-bromo-4-methyl isophthalic acid-oxo with urea (10mmol)) amyl group] t-butanol solution 72 hours of furans (1mmol).Filtering, evaporate also, chromatography obtains 2-amino-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] imidazoles and 2-hydroxyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] imidazoles.

Step B. makes 2-amino-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] oxazole obtain 2-amino-5-isobutyl--4-[2-(5-phosphono) furyl] oxazole (10.1) through embodiment 3 step C.250 ℃ of mp (decomposition).C ₁₁H ₁₅N ₂O ₅The analytical calculation value of P: C:46.16; H:5.28; N:9.79.Measured value: C:45.80; H:5.15; N:9.55.

Step C. makes 2-hydroxyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] imidazoles obtains 2-hydroxyl-5-isobutyl--4-[2-(5-phosphono) furyl through embodiment 3 step C] imidazoles (10.14).205 ℃ of mp (decomposition).C ₁₁H ₁₅N ₂O ₅The analytical calculation value of P: C:46.16; H:5.28; N:9.79.Measured value: C:45.80; H:4.90; N:9.73.

Perhaps, 4-[2-(5-phosphono) furyl] oxazole and 4-[2-(5-phosphono) furyl] imidazoles can be prepared as follows:

Step D. is in 100 ℃, with sodium acetate (2mmol) and ammonium acetate (2mmol) processing 5-diethyl phosphonyl-2-[(2-bromo-4-methyl isophthalic acid-oxo) amyl group] acetic acid solution 4 hours of furans (1mmol).Evaporation and chromatography obtain 2-methyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl]-oxazoles, 2-methyl-4-isobutyl--5-[2-(5-diethyl phosphonyl) furyl] oxazole and 2-methyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] imidazoles.

Step e. make 2-methyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] oxazole, 2-methyl-4-isobutyl--5-[2-(5-diethyl phosphonyl) furyl] oxazole and 2-methyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl] imidazoles obtains following compounds through embodiment 3 step C:

(10.18) 2-methyl-4-isobutyl--5-[2-(5-phosphono) furyl] oxazole hydrobromate.mp＞230℃。C ₁₂H ₁₇BrNO ₅P+0.4H ₂The analytical calculation value of O: C:38.60; H:4.81; N:3.75.Measured value: C:38.29; H:4.61; N:3.67.

(10.19) 2-methyl-5-isobutyl--4-[2-(5-phosphono) furyl] oxazole hydrobromate.C ₁₂H ₁₇BrNO ₅The analytical calculation value of P: C:39.36; H:4.68; N:3.83.Measured value: C:39.33; H:4.56; N:3.85.

(10.21) 2-methyl-5-isobutyl--4-[2-(5-phosphono) furyl] the imidazoles hydrobromate.C ₁₂H ₁₈BrN ₂O ₄P+0.2NH ₄The analytical calculation value of Br: C:37.46; H:4.93; N:8.01.Measured value: C:37.12; H:5.11; N:8.28.

Perhaps, 4-[2-(5-phosphono) furyl] imidazoles can be prepared as follows:

Step F. in 80 ℃, the ethanolic soln of usefulness trifluoro ethanamidine (2mmol) processing 5-diethyl phosphonyl-2-(bromo ethanoyl) furans (1mmol) 4 hours.Evaporation and chromatography obtain 2-trifluoromethyl-4-[2-(5-diethyl phosphonyl) furyl into oily matter] imidazoles.

Step G. makes 2-trifluoromethyl-4-[2-(5-diethyl phosphonyl) furyl] imidazoles is through embodiment 3

Step C obtains 2-trifluoromethyl-4-[2-(5-phosphono)-furyl] imidazoles (10.22).188 ℃ of mp (decomposition).C ₈H ₆F ₃N ₂O ₄The analytical calculation value of P+0.5HBr: C:29.79; H:2.03; N:8.68.Measured value: C:29.93; H:2.27; N:8.30.

Perhaps, 4,5-dimethyl-1-isobutyl--2-[2-(5-phosphono) furyl] imidazoles can be prepared as follows:

Step H. is in 100 ℃, and with 5-diethyl phosphonyl-2-furfural (1mmol), ammonium acetate (1.4mmol), 3, the glacial acetic acid solution of 4-dimethyl diketone (3mmol) and isobutylamine (3mmol) heated 24 hours.Evaporation and chromatography obtain 4,5-dimethyl-1-isobutyl--2-[2-(5-diethyl phosphonyl) furyl] imidazoles, be yellow solid.

Step I. makes 4,5-dimethyl-1-isobutyl--2-[2-(5-diethyl phosphonyl) furyl]-imidazoles obtains 4 through embodiment 3 step C, 5-dimethyl-1-isobutyl--2-[2-(5-phosphono) furyl] imidazoles (10.23) .C ₁₃H ₁₉N ₂O ₄The analytical calculation value of P+1.35HBr: C:38.32; H:5.03; N:6.87.Measured value: C:38.09; H:5.04; N:7.20.

(10.2) .2-amino-5-propyl group-4-[2-(5-phosphono) furyl] oxazole.250 ℃ of mp (decomposition).C ₁₀H ₁₃N ₂O ₅The analytical calculation value of P: C:44.13; H:4.81; N:10.29.Measured value: C:43.74; H:4.69; N:9.92.

(10.3) .2-amino-5-ethyl-4-[2-(5-phosphono) furyl] oxazole .C ₉H ₁₁N ₂O ₅P+0.4H ₂The analytical calculation value of O: C:40.73; H:4.48; N:10.56.Measured value: C:40.85; H:4.10; N:10.21.

(10.4) .2-amino-5-methyl-4-[2-(5-phosphono) furyl] oxazole.C ₈H ₉N ₂O ₅P+0.1H ₂The analytical calculation value of O: C:39.07; H:3.77; N:11.39.Measured value: C:38.96; H:3.59; N:11.18.

(10.5) .2-amino-4-[2-(5-phosphono) furyl] oxazole.C ₇H ₇N ₂O ₅P+0.6H ₂The analytical calculation value of O: C:34.90; H:3.43; N:11.63.Measured value: C:34.72; H:3.08; N:11.35.

(10.6) .2-amino-5-isobutyl--4-[2-(5-phosphono) furyl] oxazole hydrobromate.C ₁₁H ₁₆N ₂O ₅BrP+0.4H ₂The analytical calculation value of O: C:35.29; H:4.52; N:7.48.Measured value: C:35.09; H:4.21; N:7.34.

(10.7) .2-amino-5-phenyl-4-[2-(5-phosphono) furyl] oxazole.C ₁₃H ₁₁N ₂O ₅The analytical calculation value of P: C:50.99; H:3.62; N:9.15.Measured value: C:50.70; H:3.43; N:8.96.

(10.8) .2-amino-5-benzyl-4-[2-(5-phosphono) furyl] oxazole.C ₁₄H ₁₃N ₂O ₅P+1.1H ₂The analytical calculation value of O: C:49.45; H:4.51; N:8.24.Measured value: C:49.35; H:4.32; N:8.04.

(10.9) .2-amino-5-cyclohexyl methyl-4-[2-(5-phosphono) furyl] oxazole.C ₁₄H ₁₉N ₂O ₅P+0.3H ₂The analytical calculation value of O: C:50.70; H:5.96; N:8.45.Measured value: C:50.60; H:5.93; N:8.38.

(10.10) .2-amino-5-allyl group-4-[2-(5-phosphono) furyl] oxazole.C ₁₀H ₁₁N ₂O ₅P+0.4HBr+0.3H ₂The analytical calculation value of O: C:39.00; H:3.93; N:9.10.Measured value: C:39.31; H:3.83; N:8.76.

(10.11) .5-isobutyl--4-[2-(5-phosphono) furyl] oxazole.C ₁₁H ₁₄NO ₅The analytical calculation value of P: C:48.72; H:5.20; N:5.16.Measured value: C:48.67; H:5.02; N:5.10.

(10.12) .2-amino-5-butyl-4-[2-(5-phosphono) furyl] oxazole.C ₁₁H ₁₅N ₂O ₅P+0.2H ₂The analytical calculation value of O: C:45.59; H:5.36; N:9.67.Measured value: C:45.32; H:5.29; N:9.50.

(10.13) .5-isobutyl--4-[2-(5-phosphono) furyl] oxazole-2-ketone.C ₁₁H ₁₄NO ₆The analytical calculation value of P+0.39HBr: C:41.45; H:4.55; N:4.39.Measured value: C:41.79; H:4.22; N:4.04.

(10.15) .5-cyclohexyl methyl-2-hydroxyl-4-[2-(5-phosphono) furyl] imidazoles.C ₁₄H ₁₉N ₂O ₅The analytical calculation value of P+0.05HBr: C:50.90; H:5.81; N:8.48.Measured value: C:51.06; H:5.83; N:8.25.

(10.16) .5-butyl-2-hydroxy-4-[2-(5-phosphono) furyl].C ₁₁H ₁₅N ₂O ₅P+O.2H ₂The analytical calculation value of O: C:45.59; H:5.36; N:9.67.Measured value: C:45.77; H:5.34; N:9.39.

(10.17) .5-benzyl-2-hydroxyl-4-[2-(5-phosphono) furyl] imidazoles.C ₁₄H ₁₃N ₂O ₅The analytical calculation value of P: C:52.51; H:4.09; N:8.75.Measured value: C:52.29; H:4.15; N:8.36.

(10.20) .2-methyl-5-propyl group-4-[2-(5-phosphono) furyl] the imidazoles hydrobromate.C ₁₁H ₁₆BrN ₂O ₄P+0.5H ₂The analytical calculation value of O: C:36.69; H:4.76; N:7.78.Measured value: C:36.81; H:4.99; N:7.42.

(10.24) .2-amino-5-(2-thienyl methyl) 4-[2-(5-phosphono) furyl] oxazole.C ₁₂H ₁₁N ₂O ₅The analytical calculation value of PS+0.9HBr: C:36.12; H:3.01; N:7.02.Measured value: C:36.37; H:2.72; N:7.01.

(10.25) .2-dimethylamino-5-isobutyl--4-[2-(5-phosphono) furyl] oxazole hydrobromate.C ₁₃H ₂₀BrN ₂O ₅The analytical calculation value of P+0.05HBr: C:39.11; H:5.06; N:7.02.Measured value: C:39.17; H:4.83; N:6.66.

(10.26) .2-sec.-propyl-5-isobutyl--4-[2-(5-phosphono) furyl] oxazole.C ₁₄H ₂₀NO ₅The analytical calculation value of P+0.8HBr: C:44.48; H:5.55; N:3.71.Measured value: C:44.45; H:5.57; N:3.73.

(10.27) .2-amino-5-ethoxy carbonyl-4-[2-(5-phosphono) furyl] oxazole.245 ℃ of mp (decomposition).C ₁₀H ₁₁N ₂O ₇The analytical calculation value of P: C:39.75; H:3.67; N:9.27.Measured value: C:39.45; H:3.71; N:8.87.

(10.28) .2-methylamino-5-isobutyl--4-[2-(5-phosphono) furyl] oxazole hydrobromate.C ₁₂H ₁₈BrN ₂O ₅P+0.7H ₂The analytical calculation value of O: C:36.60; H:4.97; N:7.11.Measured value: C:36.50; H:5.09; N:7.04.

(10.29) .2-ethyl-5-isobutyl--4-[2-(5-phosphono) furyl] oxazole hydrobromate.C ₁₃H ₁₉BrNO ₅The analytical calculation value of P: C:41.07; H:5.04; N:3.68.Measured value: C:41.12; H:4.84; N:3.62.

(10.30) .2-ethylamino-5-isobutyl--4-[2-(5-phosphono) furyl] oxazole hydrobromate.C ₁₃H ₂₀BrN ₂O ₅The analytical calculation value of P: C:39.51; H:5.10; N:7.09.Measured value: C:39.03; H:5.48; N:8.90.

(10.31) .2-vinyl-5-isobutyl--4-[2-(5-phosphono) furyl] oxazole.C ₁₃H ₁₆NO ₅The analytical calculation value of P+0.25HBr: C:49.18; H:5.16; N:4.41.Measured value: C:48.94; H:5.15; N:4.40.

(10.32) .2-amino-5-amyl group-4-[2-(5-phosphono) furyl] oxazole.C ₁₂H ₁₇N ₂O ₅P+0.5H ₂The analytical calculation value of O: C:46.61; H:5.87; N:9.06.Measured value: C:46.38; H; 5.79; N:9.07.

(10.33) .5-amyl group-2-hydroxyl-4-[2-(5-phosphono) furyl] imidazoles.C ₁₂H ₁₇N ₂O ₅The analytical calculation value of P: C:48.00; H:5.71; N:9.33.Measured value: C:48.04; H:5.58; N:9.26.

(10.45) .2-amino-5-methylthio group-4-[2-(5-phosphono) furyl] oxazole.196 ℃ of mp (decomposition).C ₈H ₉N ₂O ₅The analytical calculation value of PS: C:34.79; H:3.28; N:10.14.Measured value: C:34.60; H:2.97; N:10.00.

(10.35) .2-amino-5-benzyloxycarbonyl-4-[2-(5-phosphono) furyl] oxazole.230 ℃ of mp (decomposition).C ₁₅H ₁₃N ₂O ₇P+0.7H ₂The analytical calculation value of O: C:47.81; H:3.85; N:7.43.Measured value: C:47.85; H:3.88; N:7.21.

(10.36) .2-amino-5-isopropoxy carbonyl-4-[2-(5-phosphono) furyl] oxazole.221 ℃ of mp (decomposition).C ₁₁H ₁₃N ₂O ₇P+0.9H ₂The analytical calculation value of O: C:39.75; H:4.49; N:8.43.Measured value: C:39.72; H:4.25; N:8.20.

(10.37) .2-amino-5-methoxycarbonyl-4-[2-(5-phosphono) furyl] oxazole.240 ℃ of mp (decomposition).C ₉H ₉N ₂O ₇P+0.3H ₂The analytical calculation value of O+0.1 acetone: C:37.31; H:3.43; N:9.36.Measured value: C:37.37; H:3.19; N:9.01.

(10.38) formamyl .2-amino-5-[(N-methyl)]-4-[2-(5-phosphono) furyl] oxazole.235 ℃ of mp (decomposition).C ₉H ₁₀N ₃O ₆The analytical calculation value of P: C:37.64; H:3.51; N:14.63.Measured value: C:37.37; H:3.22; N:14.44.

(10.39) .2-amino-5-ethylmercapto group carbonyl-4-[2-(5-phosphono) furyl] oxazole.225 ℃ of mp (decomposition).C ₁₀H ₁₁N ₂O ₆The analytical calculation value of PS: C:37.74; H:3.48; N:8.80.Measured value: C:37.67; H:3.27; N:8.46.

(10.40) .2-amino-5-iprotiazem base-4-[2-(5-phosphono) furyl] oxazole.C ₁₀H ₁₃N ₂O ₅The analytical calculation value of PS+0.2HBr: C:37.48; H:4.15; N:8.74.Measured value: C:37.39; H:4.11; N:8.56.

(10.41) .2-amino-5-thiophenyl-4-[2-(5-phosphono) furyl] oxazole.C ₁₃H ₁₁N ₂O ₅The analytical calculation value of PS+0.25HBr: C:43.55; H:3.16; N:7.81.Measured value: C:43.82; H:3.28; N:7.59.

(10.42) .2-amino-5-ethylmercapto group-4-[2-(5-phosphono) furyl] oxazole.C ₉H ₁₁N ₂O ₅The analytical calculation value of PS+0.85HBr: C:30.11; H:3.33; N:7.80.Measured value: C:30.18; H:3.44; N:7.60.

(10.43) .2-amino-5-rosickyite base-4-[2-(5-phosphono) furyl] oxazole.C ₁₀H ₁₃N ₂O ₅+ H ₂The analytical calculation value of O: C:37.27; H:4.69; N:8.69; H ₂O:5.59.Measured value: C:37.27; H:4.67; N:8.60; H ₂O:5.66.

(10.44) .2-amino-uncle 5-butylthio-4-[2-(5-phosphono) furyl] oxazole.C ₁₁H ₁₅N ₂O ₅The analytical calculation value of PS+0.25HBr: C:39.03; H:4.54; N:8.28.Measured value: C:39.04; H:4.62; N:8.06.

(10.34) .4,5-dimethyl-2-[2-(5-phosphono) furyl] imidazoles.C ₉H ₁₁N ₂O ₄P+1.25H ₂The analytical calculation value of O: C:40.84; H:5.14; N:10.58. measured value: C:41.02; H:5.09:N:10.27.

Embodiment 11

The alkylating 4-[2-of N-(the 5-phosphono] furyl] imidazoles and 4-[2-(the 5-phosphono] preparation of furyl] oxazole

Steps A. in 25 ℃, handle cesium carbonate (1.5mmol) and 2-methyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl with methyl iodide (1.5mmol)] suspension of imidazoles (1mmol) in DMF 16 hours.Extracting also, chromatography obtains 1,2-dimethyl-4-isobutyl--5-[2-(5-diethyl phosphonyl)-furyl] imidazoles and 1,2-dimethyl-5-isobutyl--4-[2-(5-diethyl phosphonyl)-furyl] imidazoles.

Step B. makes 1,2-dimethyl-4-isobutyl--5-[2-(5-diethyl phosphonyl) furyl]-imidazoles and 1,2-dimethyl-5-isobutyl--4-[2-(5-diethyl phosphonyl) furyl]-imidazoles obtains following compounds through embodiment 3 step C:

(11.1) 1,2-dimethyl-5-isobutyl--4-[2-(5[phosphono) furyl] the imidazoles hydrobromate.C ₁₃H ₂₀N ₂O ₄PBr+0.8H ₂The analytical calculation value of O: C:39.67; H:5.53; N:7.12.Measured value: C:39.63; H:5.48; N:7.16.

Embodiment 12

2-[2-(6-phosphono) pyridyl] preparation of pyridine

Steps A. in 0 ℃, between using-and chloro propoxy benzoic acid (2mmol) processing 2, the solution of 2 '-bipyridyl (1mmol) in methylene dichloride stirred these reaction mixtures 2 hours in 25 ℃.Extract the well chromatography and obtain 2,2 '-bipyridyl-N-oxide compound.

Step B. (Redmore, D., J.Org.Chem., 1970,35,4114) in-30 ℃, with 2, the solution of 2 '-bipyridyl-N-oxide compound methyl ether (1mmol, by methyl-sulfate and 2,2 '-bipyridyl-N-oxide compound prepares in diethyl phosphite) slowly adds in-30 ℃ the diethyl phosphite solution of n-Butyl Lithium (1mmol).The reaction mixture that obtains in 25 ℃ of stirrings 12 hours.Extracting also, chromatography obtains 2-[2-(6-diethyl phosphonyl) pyridyl] pyridine.

Step C. makes 2-[2-(6-diethyl phosphonyl) pyridyl] pyridine obtains 2-[2-(6-phosphono) pyridyl through embodiment 3 step C] .mp 158-162 ℃ of pyridine (12.1).C ₁₀H ₉N ₂O ₃P+0.5H ₂The analytical calculation value of O+0.1HBr: C:47.42; H:4.02; N:11.06. measured value: C:47.03; H:3.67; N:10.95.

Embodiment 13

4, the preparation of 6-dimethyl-2-(phosphonyl methoxyl ylmethyl) pyridine

Steps A. in 80 ℃, the carbon tetrachloride solution of usefulness NBS (5mmol) and dibenzoyl peroxide base (0.25mmol) processing 2 (1mmol) 12 hours.This reaction mixture is cooled to 0 ℃, filtering precipitate.Vacuum concentrated filtrate.Chromatography obtains 2-bromomethyl-4, the 6-lutidine.

Step B. with the toluene solution of sodium hydride (1.1mmol) processing hydroxymethyl phosphonic acid diethyl ester (1mmol), after 15 minutes, adds 2-bromomethyl-4,6-lutidine (1mmol) in 0 ℃.After 3 hours, make this reaction mixture obtain 2-diethyl phosphonyl methyl-4,6-lutidine through extraction and chromatography.

Step C. makes 2-diethyl phosphonyl methyl-4, and the 6-lutidine obtains 4 through embodiment 3 step C, 6-dimethyl-2-(phosphonyl methoxyl ylmethyl) pyridine (13.1). and mp 109-112 ℃.C ₉H ₁₄NO ₄P+1.0H ₂The analytical calculation value of O+0.5HBr: C:37.32; H:5.74; N:4.84. measured value: C:37.1 8; H:538; N:4.67.

Prepare following compounds similarly:

(13.2) 2-amino-4-methyl-5-propyl group-6-phosphonium mesitoyl methoxy methylpyrimidine.mp??153-156℃。C ₁₀H ₁₈N ₃O ₄P+1.25H ₂The analytical calculation value of O+1.6HBr: C:28.11; H:5.21; N:9.84.Measured value: C:28.25; H:4.75; N:9.74.

Embodiment 14.

The preparation of 5-tributyl stannyl-2-furans diethyl phosphonate (14)

The THF solution of 2-furans diethyl phosphonate (1mmol, as embodiment 1 step C preparation) is cooled to-78 ℃, and in-78 ℃ with the THF solution that joined N-sec.-propyl-N-cyclohexyl lithamide in 15 minutes by conduit in.The mixture that obtains in-78 ℃ of stirrings 2 hours, and in-78 ℃ with the THF solution that joined tributyltin chloride (1mmol) in 20 minutes by conduit in.Stirred these mixtures 1 hour in-78 ℃, stirred 12 hours in 25 ℃.Extraction and chromatography obtain the compound (14) into faint yellow oily thing.

Embodiment 15

6-[2-(5-phosphono) furyl] preparation of pyridine

Steps A. in 160-165 ℃, in sealed tube, handle 2, the ethanolic soln of 6-dichloropyridine (120mmol) 60 hours with ammonia soln (28%, excessive).Extraction and chromatography obtain 2-amino-6-chloro-pyridine, are white solid.

Step B. refluxes down, with the right-xylene solution 12 hours of four (triphenyl phosphine) palladium (0.05mmol) processing 2-amino-6-chloro-pyridine (1mmol) and compound 14 (1mmol).Extraction and chromatography obtain 2-amino-6-[2-(5-diethyl phosphonyl) furyl] pyridine, be faint yellow solid.

Step C. makes 2-amino-6-[2-(5-diethyl phosphonyl) furyl] pyridine obtains 2-amino-6-[2-(5-phosphono) furyl through embodiment 3 step C] pyridine (15.1).mp?186-187℃。C ₉H ₉N ₂O ₄The analytical calculation value of P+0.4HBr: C:39.67; H:3.48; N:10.28.Measured value: C:39.95; H:3.36; N:10.04.

Step D. is in 25 ℃, with the acetic acid solution of bromine (1N 1mmol) handles 2-amino-6-[2-(5-diethyl phosphonyl) furyl] acetic acid solution of pyridine (1mmol) 0.5 hour.Evaporation and chromatography obtain 2-amino-5-bromo-6-[2-(5-diethyl phosphonyl) furyl] pyridine and 2-amino-3,5-two bromos-6-[2-(5-diethyl phosphonyl) furyl] pyridine.

Step e. make 2-amino-5-bromo-6-[2-(5-diethyl phosphonyl) furyl] pyridine and 2-amino-3,5-two bromos-6-[2-(5-diethyl phosphonyl) furyl] pyridine obtains following compounds through embodiment 3 step C:

(15.2) .6-amino-3-bromo-2-[2-(5-phosphono) furyl] pyridine.C ₉H ₈BrN ₂O ₄P+0.7H ₂O+0.9HBr+0.12PhCH ₃The analytical calculation value: C:28.44; H:2.73; N:6.74.Measured value: C:28.64; H:2.79; N:6.31.

(15.3) .6-amino-3,5-two bromos-2-[2-(5-phosphono) furyl] pyridine.mp?233-235℃。C ₉H ₇Br ₂N ₂O ₄The analytical calculation value of P+1.2HBr: C:21.84; H:1.67; N:5.66.Measured value: C:21.90; H:1.52; N:5.30.

Step F. in 85 ℃, with tributyl (vinyl) tin (1.2mmol) and four (triphenyl phosphine) palladium (0.2mmol) processing 2-amino-3,5-two bromos-6-[2-(5-diethyl phosphonyl) furyl] the DMF solution of pyridine (1mmol) 4 hours.Evaporation and chromatography obtain 2-amino-3, two (vinyl)-6-[2-(5-diethyl phosphonyl) furyls of 5-] pyridine.

Step G. handles 2-amino-3 with palladium on carbon (10%) under 25 ℃, 1 normal atmosphere hydrogen, two (vinyl)-6-[2-(5-diethyl phosphonyl) furyls of 5-] ethyl acetate solution of pyridine (1mmol) 12 hours.Filtering, evaporate also, chromatography obtains 2-amino-3,5-diethyl-6-[2-(5-diethyl phosphonyl) furyl] pyridine.

Step H. makes 2-amino-3,5-diethyl-6-[2-(5-diethyl phosphonyl) furyl] pyridine obtains 2-amino-3 through embodiment 3 step C, 5-diethyl-6-[2-(5-phosphono) furyl] pyridine

(15.4).mp?217-218℃。C ₁₃H ₁₇N ₂O ₄P+0.7H ₂The analytical calculation value of O+1.0HBr: C:40.06; H:5.02; N:7.19.Measured value: C:40.14; H:4.70; N:6.87.

Step 1. is in 0 ℃, handles the 2-amino-solution of 6-picoline (1mmol) in 48% Hydrogen bromide (4.4mmole) 1 hour with bromine (3mmol).Add sodium nitrite in aqueous solution (2.5mmol) then, stirred this reaction mixture 0.5 hour in 0 ℃.Add aqueous sodium hydroxide solution (9.4mmol) then, stirred this reaction mixture l hour in 25 ℃.Extracting also, chromatography obtains 2,3-two bromos-6-picoline and 2,3,5-three bromo-6-picolines.

Step J. makes 2, and 3-two bromos-6-picoline obtains 5-bromo-2-methyl-6-[2-(5-phosphono) furyl through embodiment 15 step B and embodiment 3 step C] pyridine (15.5).mp?207-208℃。C ₁₀H ₉BrNO ₄The analytical calculation value of P+0.6HBr: C:32.76; H:2.64; N:3.88.Measured value: C:32.62; H:2.95; N:3.55.

According to top method or under the situation that these methods are made an amendment slightly, adopt ordinary method to prepare following compounds:

(15.6) .2-[2-(5-phosphono) furyl] pyridine.mp?220-221℃。C ₉H ₈NO ₄P+0.1H ₂The analytical calculation value of O+0.45HBr: C:41.05; H:3.31; N:5.32.Measured value: C:41.06; H:3.10; N:5.10.

(15.7) .2-amino-3-nitro-6-[2-(5-phosphono) furyl] pyridine.mp?221-222℃。C ₉H ₈N ₃O ₆P+0.55HBr+0.02PhCH ₃The analytical calculation value: C:33.12; H:2.65; N:12.68.Measured value: C:33.22; H:2.43; N:12.26.

(15.8) .2,3-diamino-6-[2-(5-phosphono) furyl] pyridine.mp?150-153℃。C ₉H ₁₀N ₃O ₄P+1.5HBr+0.05PhCH ₃The analytical calculation value: C:29.46; H:3.15; N:11.02.Measured value: C:29.50; H:3.29; N:10.60.

(15.9) .2-chloro-6-[2-(5-phosphono) furyl] pyridine.mp?94-96℃。C ₉H ₇ClNO ₄The analytical calculation value of P+0.25HBr: C:38.63; H:2.61; N:5.01.Measured value: C:38.91; H:3.00; N:5.07.

(15.10) .3,5-dichloro--2-[2-(5-phosphono) furyl] pyridine.mp?180-181℃。C ₉H ₆Cl ₂NO ₄The analytical calculation value of P+0.7HBr: C:31.61; H:2.01; N:3.94.Measured value: C:31.69; H:2.09; N:3.89.

(15.11) .3-chloro-5-trifluoromethyl-2-[2-(5-phosphono) furyl] pyridine.mp?253-254℃。C ₁₀H ₆ClF ₃NO ₄The analytical calculation value of P: C:36.67; H:1.85; N:4.28.Measured value: C:36.69; H:1.89; N:4.30.

(15.12) .2-amino-3-ethyl-6-[2-(5-phosphono) furyl] pyridine.mp?220-221℃。C ₁₁H ₁₃N ₂O ₄P+0.6HBr+0.2H ₂The analytical calculation value of O: C:41.24; H:4.40; N:8.74.Measured value: C:41.02; H:4.57; N:8.68.

(15.13) .6-amino-3-ethyl-2-[2-(5-phosphono) furyl] pyridine.C ₁₁H ₁₃N ₂O ₄P+1.0HBr+0.3H ₂The analytical calculation value of O: C:37.27; H:4.15; N:7.90.Measured value: C:37.27; H:4.19; N:7.51.

(15.14) .6-amino-3-propyl group-2-[2-(5-phosphono) furyl] pyridine.mp?252-253℃。C ₁₂H ₁₅N ₂O ₄P+1.0HBr+1.0H ₂O+0.32PhCH ₃The analytical calculation value: C:41.65; H:5.05; N:6.82.Measured value: C:41.97; H:5.19; N:6.83.

(15.15) .2,4-dimethyl-3-bromo-6-[2-(5-phosphono) furyl] pyridine.mp?232-233℃。C ₁₁H ₁₁BrNO ₄The analytical calculation value of P+0.45HBr: C:35.85; H:3.13; N:3.80.Measured value: C:35.98; H:3.10; N:3.71.

(15.16) .2-chloro-4-amino-6-[2-(5-phosphono) furyl] pyridine.C ₉H ₈N ₂O ₄PCl+HBr+0.5H ₂The analytical calculation value of O+MeOH: C:30.99; H:3.38; N:7.23.Measured value: C:31.09; H:3.21; N:6.96.

(15.17) .3-hydroxyl-2-[2-(5-phosphono) furyl] pyridine.C ₉H ₈NO ₅P+1.1HBr+0.3CH ₃The analytical calculation value of Ph: C:37.26; H:3.24; N:3.91.Measured value: C:37.66; H:3.55; N:3.84.

(15.19) .2-amino-3-cyclopropyl-6-[2-(5-phosphono) furyl] pyridine.C ₁₂H ₁₃N ₂O ₄PCl+HBr+0.4H ₂The analytical calculation value of O: C:39.13; H:4.05; N:7.61.Measured value: C:39.06; H:3.85; N:7.37.

(15.20) .2-amino-5-cyclopropyl-6-[2-(5-phosphono) furyl] pyridine.C ₁₂H ₁₃N ₂O ₄P+HBr+0.7CH ₃The analytical calculation value of Ph: C:47.69; H:4.64; N:6.58.Measured value: C:47.99; H:4.62; N:6.91.

(15.21) .5-amino-2-methoxyl group-6-[2-(5-phosphono) furyl] pyridine.C ₁₀H ₁₁N ₂O ₅P+0.2H ₂The analytical calculation value of O: C:43.87; H:4.20; N:10.23.Measured value: C:43.71; H:3.77; N:9.77.

(15.22) .2-methyl-5-cyano group-6-[2-(5-phosphono) furyl] pyridine.C ₁₁H ₉N ₂O ₄P+0.75HBr+0.5H ₂The analytical calculation value of O+0.5MePh: C:45.84; H:3.91; N:7.37.Measured value: C:45.93; H:3.56; N:7.36.

(15.23) .2-amino-3, two (cyano group)-4-methyl-6-[2-(5-phosphono) furyls of 5-] pyridine.C ₁₂H ₉N ₄O ₄P+0.7H ₂The analytical calculation value of O: C:45.49; H:3.31; N:17.68.Measured value: C:45.48; H:3.06; N:17.51.

(15.24) .2-chloro-4-cyano group-6-[2-(5-phosphono) furyl] pyridine.C ₁₀H ₆N ₂O ₄The analytical calculation value of PCl: C:42.20; H:2.13; N:9.84.Measured value: C:41.95; H:2.10; N:9.47.

Embodiment 16.

2-[2-(5-phosphono) furyl] pyrimidine and 4-[2-(5-phosphono) furyl] preparation of pyrimidine

Steps A. with 5-diethyl phosphonyl base-2-[(1-oxo) amyl group] N of furans, dinethylformamide dimethyl acetal solution reflux 12 hours.Evaporation and chromatography obtain 5-(2-propyl group-3-N, N-dimethylamino) acryl-2-furans diethyl phosphonate.

Step B. was in 80 ℃, with the ethanolic soln of guanidinesalt hydrochlorate (1.2mmol) and sodium ethylate (1mmol) processing 5-(2-propyl group-3-N, N-dimethylamino) acryl-2-furans diethyl phosphonate (1mmol) 12 hours.Evaporate this reaction mixture, make residue soluble in water.With hydrochloric acid (2N) neutralize this aqueous solution and concentrating under reduced pressure.Make residue and toluene coevaporation obtain 2-amino-5-propyl group-4-[2-(5-ethyl phosphono)-furyl] pyrimidine, be yellow solid.

Step C. is with 2-amino-5-propyl group 4-[2-(5-ethyl phosphono)-furyl] pyrimidine (1mmol) and thionyl chloride be in the heating down 2 hours that refluxes.Evaporate this reaction mixture to doing, residue be dissolved in the methylene dichloride, in 25 ℃ with excess pyridine and Ethanol Treatment 12 hours.Evaporation and chromatography obtain 2-amino-5-propyl group-4-[2-(5-diethyl phosphonyl) furyl] pyrimidine.

Step D. makes 2-amino-5-propyl group-4-[2-(5-diethyl phosphonyl) furyl] pyrimidine obtains 2-amino-5-propyl group-4-[2-(5-phosphono) furyl through embodiment 3 step C] pyrimidine (16.1).mp258-259℃。C ₁₁H ₁₄N ₃O ₄P+1.33H ₂The analytical calculation value of O: C:43.01; H:5.47; N:13.68.Measured value: C:43.18; H:5.31; N:13.30.

Prepare following compounds according to this method:

(16.2) 2-amino-5-isobutyl--4-[2-(5-phosphono) furyl] pyrimidine.mp?218-220℃。C ₁₂H ₁₆N ₃O ₄P+0.75HBr+0.3PhCH ₃The analytical calculation value: C:43.92; H:5.01; N:10.90.Measured value: C:44.02; H:4.62; N:10.69.

Perhaps can prepare other 4-[2-(5-phosphono) furyl according to following method] pyrimidine:

Step e. make compound 2.2 obtain 5-(3-N, N-dimethylamino) acryl-2-furans diethyl phosphonate, be orange solids through embodiment 16 steps A.

Step F. in 55 ℃, with the solution of 5-(3-N, N-dimethylamino) acryl-2-furans diethyl phosphonate (1mmol), alcohol sodium alcohol solution (2mmol) and guanidinesalt hydrochlorate (1.1mmol) heating 2 hours.This reaction mixture of cooling is also with the neutralization of 1N hydrochloric acid in ice bath.Evaporation and chromatography obtain 2-amino-4-[2-(5-diethyl phosphonyl)-furyl] pyrimidine, be yellow solid.

Step G. makes 2-amino-4-[2-(5-diethyl phosphonyl) furyl] pyrimidine obtains 2-amino-4-[2-(5-phosphono) furyl through embodiment 3 step C]-pyrimidine (16.3).mp＞230℃。C ₈H ₈N ₃O ₄P+0.75H ₂The analytical calculation value of O+0.2HBr: C:35.48; H:3.61; N:15.51.Measured value: C:35.42; H:3.80; N:15.30.

Step H. is in 25 ℃, handles 2-amino-4-[2-(5-diethyl phosphonyl) furyl with NBS (1.5mmol)] methyl alcohol of pyrimidine (1mmol) and chloroformic solution 1 hour.Extracting also, chromatography obtains 2-amino-5-bromo-4-[2-(5-diethyl phosphonyl) furyl] pyrimidine, be yellow solid.

Step I. makes 2-amino-5-bromo-4-[2-(5-diethyl phosphonyl) furyl] pyrimidine is through embodiment 15 step F and G, then obtains 2-amino-5-ethyl-4-[2-(5-phosphono) furyl through embodiment 3 step C] pyrimidine (16.4).mp＞225℃。C ₁₀H ₁₂N ₃O ₄P+1.4H ₂O+0.2HBr+0.25PhCH ₃The analytical calculation value: C:42.30; H:5.14; N:12.59.Measured value: C:42.74; H:4.94; N:12.13.

According to aforesaid method or these methods are being done slightly under the situation of some modification, adopt ordinary method to prepare following compounds:

(16.5) .2-[2-(5-phosphono) furyl] pyrimidine.mp?194-196℃。C ₈H ₇N ₂O ₄P+0.1H ₂The analytical calculation value of O+0.55HBr: C:35.27; H:2.87; N:10.28.Measured value: C:35.26; H:2.83; N:9.89.

(16.6) .2-amino-6-methyl-4-[2-(5-phosphono) furyl] pyrimidine.mp?238-239℃。C ₉H ₁₀N ₃O ₄The analytical calculation value of P+0.9HBr: C:32.96; H:3.35; N:12.81.Measured value: C:33.25; H:3.34; N:12.46.

(16.7) .2-methylthio group-4-[2-(5-phosphono) furyl] pyrimidine.mp?228-229℃。C ₉H ₉N ₂O ₄PS+0.5H ₂The analytical calculation value of O: C:38.44; H:3.58; N:9.96.Measured value: C:38.19; H:3.25; N:9.66.

(16.8) .2-methyl-4-[2-(5-phosphono) furyl] pyrimidine.mp?206-212℃。C ⁹H ₉N ₂O ₄P+0.9H ₂The analytical calculation value of O+0.25HBr: C:34.05; H:3.30; N:8.82.Measured value: C:34.02; H:3.06; N:8.75.

(16.9) .4,6-dimethyl-5-bromo-2-[2-(5-phosphono) furyl] pyrimidine.mp?251-252℃。C ₁₀H ₁₀BrN ₂O ₄The analytical calculation value of P: C:36.06; H:3.03; N:8.41.Measured value: C:35.89; H:2.82; N:8.11.

(16.10) .2-amino-5-chloro-4-[2-(5-phosphono) furyl] pyrimidine.C ₈H ₇ClN ₃O ₄P+0.5H ₂The analytical calculation value of O: C:33.76; H:2.83; N:14.76.Measured value: C:33.91; H:2.86; N:14.20.

(16.11) .2-amino-6-methylthio group-4-[2-(5-phosphono) furyl] pyrimidine.C ₉H ₁₀N ₃O ₄The analytical calculation value of PS+HBr: C:29.36; H:3.01; N:11.41.Measured value: C:29.63; H:3.02; N:11.27.

(16.12) .2-amino-5-bromo-6-methylthio group-4-[2-(5-phosphono) furyl] pyrimidine.C ₉H ₉N ₃O ₄The analytical calculation value of PSBr+0.8HBr+0.2MePh: C:27.80; H:2.56; N:9.35.Measured value: C:27.74; H:2.40; N:8.94.

(16.13) .2-amino-(4-morpholino)-4-[2-(5-phosphono) furyl] pyrimidine.mp＞230℃。C ₁₂H ₁₅N ₄O ₅The analytical calculation value of P+HBr+0.05MePh: C:36.02; H:4.01; N:13.61.Measured value: C:35.98; H:4.04; N:13.33.

(16.14) .6-amino-4-chloro-2-[2-(5-phosphono) furyl] pyrimidine.mp＞230℃。C ₈H ₇N ₃O ₄PCl+0.5H ₂The analytical calculation value of O: C:33.76; H:2.83; N:14.76.Measured value: C:33.83; H:2.54; N:14.48.

Embodiment 17.

2-[2-(5-phosphono) furyl] pyrazine and 2-[2-(5-phosphono) furyl] preparation of triazine

Steps A. the method for describing in embodiment 16 also can be applicable to 2-[2-(5-phosphono) furyl] pyrazine and 2-[2-(5-phosphono) furyl] triazine analogue synthetic; just in some cases these methods are made an amendment slightly, adopt ordinary method to carry out.Correspondingly prepare following compounds:

(17.1) 2,5-dimethyl-3-[2-(5-phosphono) furyl] pyrazine.mp?212-213℃。C ₁₀H ₁₁N ₂O ₄The analytical calculation value of P+0.75HBr: C:38.15; H:3.76; N:8.90.Measured value: C:38.41; H:3.93; N:8.76.

(17.2) 2-chloro-6-[2-(5-phosphono) furyl] pyrazine.mp?204-205℃。C ₈H ₆ClN ₂O ₄P+0.3HBr+0.02PhCH ₃The analytical calculation value: C:34.10; H:2.27; N:9.77.Measured value: C:34.36; H:2.07; N:9.39.

(17.3) 2-amino-3-propyl group-6-[2-(5-phosphono) furyl] pyrazine.mp?227-228℃。C ₁₁H ₁₄N ₃O ₄The analytical calculation value of P+0.7HBr: C:38.87; H:4.36; N:12.36.Measured value: C:39.19; H:4.36; N:11.92.

(17.4) 2-amino-6-[2-(5-phosphono) furyl] pyrazine.mp?235-236℃。C ₈H ₈N ₃O ₄P+1.15H ₂O+0.03PhCH ₃The analytical calculation value: C:37.26; H:4.01; N:15.88.Measured value: C:37.09; H:3.67; N:15.51.

(17.5) 2-amino-3-bromo-6-[2-(5-phosphono) furyl] pyrazine.C ₈H ₇N ₃O ₄The analytical calculation value of PBr+1HBr: C:23.97; H:2.01; N:10.48.Measured value: C:24.00; H:2.00; N:10.13.

(17.6) 3-methylthio group-2-[2-(5-phosphono) furyl] pyrazine.C ₉H ₉N ₂O ₄PS+0.3H ₂The analytical calculation value of O: C:38.94; H:3.49; N:10.09.Measured value: C:38.99; H:3.11; N:9.67.

(17.7) 6-amino-3-methylthio group-2-[2-(5-phosphono) furyl] pyrazine.C ₉H ₁₀N ₃O ₄PS+1.5H ₂The analytical calculation value of O+1.7HBr+0.25MePh: C:27.19; H:3.54; N:8.85.Measured value: C:27.10; H:3.85; N:8.49.

(17.8) 6-amino-5-methylthio group-2-[2-(5-phosphono) furyl] pyrazine.C ₉H ₁₀N ₃O ₄The analytical calculation value of PS+1.1HBr+0.05MePh: C:29.49; H:3.04; N:11.03.Measured value: C:29.23; H:2.79; N:10.87.

(17.9) 6-amino-5-methoxycarbonyl-3-chloro-2-[2-(5-phosphono) furyl] pyrazine.C ₁₀H ₉N ₃O ₆The analytical calculation value of PCl+0.3HBr+0.04MePh: C:34.15; H:2.68; N:11.62.Measured value: C:34.20; H:2.90; N:11.21.

(17.10) 6-amino-3-methylthio group-2-[2-(5-phosphono) furyl] the pyrazine ammonium salt.C ₉H ₁₃N ₄O ₄The analytical calculation value of PS+0.8HBr: C:29.30; H:3.77; N:15.18.Measured value: C:29.03; H:3.88; N:15.08.

(17.11) 2-amino-4-phenyl-6-[2-(5-phosphono) furyl] triazine.C ₁₃H ₁₁N ₄O ₄The analytical calculation value of P+HBr+0.1EtOAc: C:39.45; H:3.16; N:13.73. measured value: C:39.77; H:3.26; N:13.48.

Embodiment 18.

Having X is the preparation of the analogue of methoxycarbonyl, methylthio group carbonyl, methylamino carbonyl and methyl carbonylamino

The preparation of 4-phosphonium mesitoyl methoxy carbonyl thiazole and 4-phosphonium mesitoyl methoxy Tang Ji oxazole

Steps A. under room temperature, handle 1 of 2-amino-4-ethoxy carbonyl thiazole (1mmol), 4-dioxane (5ml) solution with two dimethyl dicarbonate butyl esters (1.2mmol), TMEDA (0.1mmol) and DMAP (0.1mmol).Stir this reactant after 20 hours, the evaporation as for.Residue obtains 2-[N-Boc (amino) through extraction]-4-ethoxy carbonyl thiazole, be yellow solid.

Step B. is in 60 ℃, with sodium hydroxide (3N 3mmol) handles 2-[N-Boc (amino)]-4-ethoxy carbonyl thiazole (1mmol) is at ethanol: the solution in 2: 1 the mixture (10m1) of water, stirred these reactants 4 hours in 60 ℃.Make this reactant be cooled to 0 ℃ and also be neutralized to pH 5, collect the solid that generates, obtain 2-[N-Boc (amino) by filtering with 3N HCl]-4-carboxyl thiazole, be white solid.

Step C. handles 2-[N-Boc (amino) with thionyl chloride (4mmol) under room temperature]-methylene dichloride (5ml) aaerosol solution of 4-carboxyl thiazole (1mmol).Stir after 4 hours, evaporate this reactant to doing.Residue is dissolved in the methylene dichloride (5ml) and in 0 ℃ of methylene dichloride (5ml) solution that joins (methylol) diethyl phosphonate (1.5mmol) and pyridine (2mmol).Make this reactant be warmed to room temperature and stirred 4 hours.This reactant of water quencher makes this mixture obtain 2-[N-Boc (amino) through extraction]-4-diethyl phosphonyl methoxyl base carbonyl thiazole, be thick yellow oil.

Perhaps adopt the mixed anhydride method of enumerating as following step can form ester bond:

Under room temperature, with Tosyl chloride (2mmol) and (methylol) diethyl phosphonate (2mmol) first aftertreatment 2-[N-Boc (amino)]-pyridine (5ml) solution of 4-carboxyl thiazole (1mmol) 4 hours.Evaporation, extraction and chromatography obtain 2-[N-Boc (amino)]-4-diethyl phosphonyl methoxyl base carbonyl thiazole, be thick yellow oil.

Step D. is in 0 ℃, with 2-[N-Boc (amino)]-methylene dichloride (5ml) of 4-diethyl phosphonyl methoxyl base carbonyl thiazole (1mmol) and methyl-phenoxide (0.1mmol) and trifluoroacetic acid (5ml) solution stirring 1 hour, under room temperature, stirred 1 hour again.Evaporation, extraction and chromatography obtain solid 2-amino-4-diethyl phosphonyl methoxyl base carbonyl thiazole.

Step e. make 2-amino-4-diethyl phosphonyl methoxyl base carbonyl thiazole obtain solid 2-amino-4-phosphonium mesitoyl methoxy carbonyl thiazole (18.1) through the step C of embodiment 3.Mp＞240 ℃ (decomposition).C ₅H ₇N ₂O ₅The analytical calculation value of PS: C:25.22; H:2.96; N:11.76.Measured value: C:25.30; H:2.86; N:11.77.

Step F. under room temperature, handle 2-[N-Boc (amino) with bromine (2mmol)]-methylene dichloride (5ml) solution of 4-diethyl phosphonyl methoxyl base carbonyl thiazole (1mmol) 4 hours.Evaporation and extraction obtain 2-[N-Boc (amino)]-5-bromo-4-diethyl phosphonyl methoxyl base carbonyl thiazole, be orange oil.With its step D, then obtain solid 2-amino-5-bromo-4-phosphonium mesitoyl methoxy carbonyl thiazole (18.2) through the step C of embodiment 3 through embodiment 18.Mp＞230 ℃ (decomposition).C ₅H ₆N ₂O ₅The analytical calculation value of PSBr: C:18.94; H:1.91; N:8.84.Measured value: C:19.08; H:1.76; N:8.67.

Step G. is in 60 ℃, handles 2-[N-Boc (amino) with tributyl (vinyl) tin (2.5mmol)]-5-bromo-4-diethyl phosphonyl methoxyl base carbonyl thiazole (1mmol) and dichloro pair (triphenyl phosphine) palladium (II) DMF (5ml) solution (0.1mmol) 2 hours.Remove and desolvate, residue is dissolved in the ethyl acetate and with 2mmol NaF in 5ml water, stirred 1 hour.Extracting also, chromatography obtains 2-[N-Boc (amino)]-5-vinyl-4-diethyl phosphonyl methoxyl base carbonyl thiazole, be yellow solid.

Step H. is under room temperature and hydrogen (air bag) atmosphere, with 2-[N-Boc (amino)]-5-vinyl-4-diethyl phosphonyl methoxyl base carbonyl thiazole (1mmol) and 10%Pd/C (0.5mmol) suspension in methyl alcohol (5ml) stirred 15 hours.Filter and evaporate and obtain 2-[N-Boc (amino)]-5-ethyl-4-diethyl phosphonyl methoxyl base carbonyl thiazole; be yellow solid; with its step D, then obtain solid 2-amino-5-ethyl-4-phosphonium mesitoyl methoxy carbonyl thiazole (18.3) through the step C of embodiment 3 through embodiment 18.Mp＞230 ℃ (decomposition).C ₇H ₁₁N ₂O ₅The analytical calculation value of PS: C:31.58; H:4.16; N:10.52.Measured value: C:31.80; H:4.04; N:10.18.

Step I. is in-78 ℃, with two (methylthio group) methylene radical of N-[] anhydrous THF (2ml) solution of glycine methyl ester (1mmol) joins in anhydrous THF (10ml) solution of t-BuOK (1.4mmo1), stirs this mixture 30 minutes.Anhydrous THF (2ml) solution that adds ethyl mustard oil (1mmol) then stirred these reactants 30 minutes in-78 ℃, stirred 2 hours under room temperature again.This reactant of water quencher; extracting also, chromatography obtains 2-methylthio group-5-(N-ethylamino)-4-methoxycarbonyl thiazole; be yellow solid; with its step B and C, then obtain solid 2-methylthio group-5-(N-ethylamino)-4-phosphonium mesitoyl methoxy carbonyl thiazole (18.4) through the step C of embodiment 3 through embodiment 18.Mp＞200 ℃ (decomposition).C ₈H ₁₃N ₂O ₅PS ₂The analytical calculation value of+0.1HBr: C:29.99; H:4.12; N:8.74.Measured value: C:29.71; H:4.10; N:8.60.

The preparation of II.4-phosphono methylthio group carbonyl thiazole

Step J. is with 2-[N-Boc (amino)]-methylene dichloride (5ml) solution of 4-thiazole formyl chloride (1mmol) and pyridine (2mmol) is cooled to-78 ℃, with H ₂S (g) bubbling fed this solution 10 minutes.Stir these reactants 30 minutes in-78 ℃, be warmed to room temperature then.Wash this mixture with 3N HCl.Separate organic phase, the dry and concentrated 2-[N-Boc (amino) that obtains]-4-thiazole thiocarboxylic acid, be yellow solid.

Step K. with 2-[N-Boc (amino)]-THF (5ml) solution of 4-thiazole thiocarboxylic acid (1mmol) is cooled to-78 ℃, and handles on a small quantity with sodium hydride (2mmol) gradation.After 10 minutes, with this reactant of THF (5ml) solution-treated of diethyl phosphonyl methyl trifluoro methanesulfonates.Stirred this reactant 1 hour, water quencher then in-78 ℃.Extracting also, chromatography obtains 2-[N-Boc (amino)]-4-diethyl phosphonyl methyl thiocarbonyl thiazole; be thick oily matter; with its step D, then obtain solid 2-amino-4-(phosphonomethyl) thiocarbonyl thiazole (18.5) through the step C of embodiment 3 through embodiment 18.Mp＞230 ℃ (decomposition).C ₅H ₇N ₂O ₄PS ₂The analytical calculation value: C:23.62; H:2.78; N:11.02.Measured value: C:23.77; H:2.61; N:10.73.The 4-[(N-(phosphonomethyl)) formamyl] thiazole, 3-[(N-(phosphonomethyl)) formamyl] isothiazole and 2-[(N-(phosphonomethyl)) formamyl] preparation of pyridine

Step L. is under room temperature, with 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI, 1.5mmol) and I-hydroxybenzotriazole hydrate (HOBt, 1.5mmol) handle 2-[N-Boc (amino)]-DMF (5ml) solution of 4 thiazole carboxylic acid (1mmol), then under room temperature with 24 hours adding aminomethylphosphonic acid diethyl esters (1.5mmol).This reactant is obtained the 2-[N-Boc (amino) of white solid through evaporation, extraction and chromatography]-4-[(N-diethyl phosphonyl methyl) formamyl] thiazole; with its step D, then obtain light brown solid 2-amino-4-[(N-(phosphonomethyl) through the step C of embodiment 3 through embodiment 18) formamyl] thiazole (18.6).Mp＞245 ℃ (decomposition).C ₅H ₈N ₃O ₄The analytical calculation value of PS+1.05HBr: C:18.64; H:2.83; N:13.04.Measured value: C:18.78; H:2.43; N:12.97.

2-[(N-phosphono ethanoyl) amino] thiazole and 2-[(N-phosphono ethanoyl) amino] preparation of pyridine.

Step M. handles 2-amino-4, DMF (5ml) solution of 5-dimethylthiazole hydrochloride (2mmol) and diethyl phosphonyl acetate (1mmol) 24 hours with EDCI (1.5mmol), HOBt (1.5mmol) and triethylamine (2mmol) under room temperature.This reactant is obtained the 2-[(N-diethyl phosphonyl ethanoyl of yellow solid through evaporation, extraction and chromatography) amino]-4; the 5-dimethylthiazole; with its step D through embodiment 18; then obtain light brown solid 4,5-dimethyl-2-[(N-phosphono ethanoyl through the step C of embodiment 3) amino] thiazole (18.7).mp＞250℃。C ₇H ₁₁N ₂O ₄The analytical calculation value of PS: C:33.60; H:4.43; N:11.20.Measured value: C:33.62; H:4.29; N:10.99.

Adopt some aforesaid method or under the situation that some aforesaid method is made an amendment slightly, adopt ordinary method to prepare following compounds:

(18.8) formamyl .2-[(N-(phosphonomethyl))] pyridine.C ₇H ₉N ₂O ₄P+HBr+0.67H ₂The analytical calculation value of O: C:27.20; H:3.70; N:9.06.Measured value: C:27.02; H:3.71; N:8.92.

(18.9) amino .2-[(N-phosphono ethanoyl)] pyridine.C ₇H ₉N ₂O ₄P+HBr+0.67H ₂The analytical calculation value of O: C:27.20; H:3.70; N:9.06.Measured value: C:27.05; H:3.59; N:8.86.

(18.10) amino .4-ethoxy carbonyl-2-[(N-phosphono ethanoyl)] thiazole.C ₈H ₁₁N ₂O ₆The analytical calculation value of PS: C:32.66; H:3.77; N:9.52.Measured value: C:32.83; H:3.58; N:9.20.

(18.11) formamyl .2-amino-5-bromo-4-[(N-(phosphonomethyl))] thiazole.232 ℃ of Mp (decomposition).C ₅H ₇N ₃O ₄The analytical calculation value of PSBr+0.15HBr+0.1 hexane: C:19.97; H:2.56; N:12.48.Measured value: C:19.90; H:2.29; N:12.33.

(18.12) formamyl .2-amino-5-(2-thienyl)-4-[(N-(phosphonomethyl))] thiazole.Mp245 ℃ (decomposition).C ₉H ₁₀N ₃O ₄PS ₂The analytical calculation value of+HBr+0.1EtOAc: C:27.60; H:2.91; N:10.27.Measured value: C:27.20; H:2.67; N:9.98.

(18.13) .4,5-two chloro-3-[(N-(phosphonomethyl)s) formamyl] isothiazole.Mp?189-191℃。C ₅H ₅N ₂O ₄PSCl ₂The analytical calculation value: C:20.63; H:1.73; N:9.62.Measured value: C:20.43; H:1.54; N:9.51.

(18.14) .2-amino-5-bromo-4-{[N-(1-phosphono-1-phenyl) methyl] formamyl } thiazole.Mp＞250℃。C ₁₁H ₁₁N ₃O ₄The analytical calculation value of PSBr: C:33.69; H:2.83; N:10.71.Measured value: C:33.85; H:2.63; N:10.85.

(18.15) .2-amino-5-(2-thienyl)-4-phosphonium mesitoyl methoxy carbonyl thiazole.Mp＞230 ℃ (decomposition).C ₉H ₉N ₂O ₅PS ₂The analytical calculation value: C:33.75; H:2.83; N:8.75.Measured value: C:33.40; H:2.74; N:8.51.

(18.16) .2-amino-5-benzyl-4-phosphonium mesitoyl methoxy carbonyl thiazole.Mp＞230 ℃ (decomposition).C ₁₂H ₁₃N ₂O ₅The analytical calculation value of PS: C:43.91; H:3.99; N:8.53.Measured value: C:43.77; H:4.03; N:8.25.

(18.17) .2-methylthio group-5-methylamino-4-phosphonium mesitoyl methoxy carbonyl thiazole.C ₇H ₁₁N ₂O ₅PS ₂+ 0.2NHBr analytical calculation value: C:26.74; H:3.59; N:8.91.Measured value: C:26.79; H:3.89; N:8.89.

(18.18) formamyl .2-amino-5-ethyl-4-[(N-(phosphonomethyl))] thiazole.180 ℃ of Mp (decomposition).C ₇H ₁₂N ₃O ₄PS+HBr+0.4CH ₂Cl ₂The analytical calculation value: C:23.49; H:3.67; N:11.18.Measured value: C:23.73; H:3.29; N:11.42.

(18.19) formamyl .2-amino-5-sec.-propyl-4-[(N-(phosphonomethyl))] thiazole.Mp247-250℃。C ₈H ₁₄N ₃O ₄The analytical calculation value of PS: C:34.41; H:5.05; N:15.05.Measured value: C:34.46; H:4.80; N:14.68.

(18.20) .2-amino-5-sec.-propyl-4-phosphonium mesitoyl methoxy carbonyl thiazole.Mp＞230℃。C ₈H ₁₃N ₂O ₅The analytical calculation value of PS: C:34.29; H:4.68; N:10.00.Measured value: C:33.97; H:4.49; N:9.70.

(18.21) .2-amino-5-phenyl-4-phosphonium mesitoyl methoxy carbonyl thiazole.Mp＞230℃。C ₁₁H ₁₁N ₂O ₅The analytical calculation value of PS: C:42.04; H:3.53; N:8.91.Measured value: C:42.04; H:3.40; N:8.72.

(18.22) .2-amino-4-phosphonium mesitoyl methoxy Tang Ji oxazole.C ₅H ₇N ₂O ₆The analytical calculation value of P+0.09HBr: C:26.18; H:3.12; N:12.21.Measured value: C:26.29; H:3.04; N:11.90.

(18.23) amino .2-amino-6-[(N-phosphono ethanoyl)] pyridine.C ₇H ₁₀N ₃O ₄The analytical calculation value of P+1.1HBr+0.25MeOH: C:26.54; H:3.72; N:12.80. measured value: C:26.79; H:3.63; N:12.44.

(18.24) formamyl .2-amino-5-methyl-4-[(N-(phosphonomethyl))] thiazole.Mp＞250℃。C ₆H ₁₀N ₃O ₄The analytical calculation value of PS+0.06EtOAc: C:29.22; H:4.12; N:16.38.Measured value: C:29.03; H:3.84; N:16.01.

(18.25) amino .2-amino-3-bromo-6-[(N-phosphono ethanoyl)] pyridine.C ₇H ₉N ₃O ₄The analytical calculation value of PBr+1.25HBr+0.8EtOAc: C:25.43; H:3.48; N:8.72.Measured value: C:25.58; H:3.71; N:8.56.

(18.26) .2-amino-3,5-two bromos-6-[(N-phosphono ethanoyl) amino] pyridine.C ₇H ₈N ₃O ₄PBr ₂The analytical calculation value of+HBr+0.5EtOAc: C:21.03; H:2.55; N:8.18.Measured value: C:21.28; H:2.55; N:7.91.

(18.27) .2-amino-5-methyl-4-phosphonium mesitoyl methoxy carbonyl thiazole.230 ℃ of Mp (decomposition).C ₆H ₉N ₂O ₅The analytical calculation value of PS: C:28.58; H:3.60; N:11.11.Measured value: C:28.38; H:3.49; N:11.10.

(18.28) .2-amino-3,5-diethyl-6-[(N-phosphono ethanoyl) amino] pyridine.C ₁₁H ₁₈N ₃O ₄The MS calculated value of P+H: 288, measured value: 288.

(18.29) .2-amino-3,5-two bromos-6-{[N-(2,2-two bromos-2-phosphono) ethanoyl] amino } pyridine.C ₇H ₆N ₃O ₄PBr ₄The analytical calculation value of+0.5HBr+EtOAc: C:19.56; H:2.16; N:6.22.Measured value: C:19.26; H:2.29; N:5.91.

(18.30) .2-amino-5-sec.-propyl-4-phosphonium mesitoyl methoxy Tang Ji oxazole.C ₈H ₁₃N ₂O ₆The analytical calculation value of P: C:34.27; H:4.75; N:9.99.Measured value: C:34.47; H:4.84; N:9.83.

(18.31) .2-amino-5-[1-(2-cyclohexyl methyl) ethynyl]-4-phosphonium mesitoyl methoxy carbonyl thiazole.230 ℃ of mp (decomposition).C ₁₄H ₁₉N ₂O ₅The analytical calculation value of PS+0.1HBr: C:45.89; H:5.25; N:7.64.Measured value: C:45.85; H:4.96; N:7.44.

(18.32) .2-amino-5-[1-(4-cyano group) butynyl]-4-phosphonium mesitoyl methoxy carbonyl thiazole.Mp230 ℃ (decomposition).C ₁₀H ₁₀N ₃O ₅The analytical calculation value of PS+0.25HBr: C:35.80; H:0.08; N:12.53.Measured value: C:35.92; H:2.99; N:12.20.

(18.33) .2-amino-5-methyl 4-phosphonium mesitoyl methoxy Tang Ji oxazole.C ₆H ₉N ₂O ₆The analytical calculation value of P+0.15HBr: C:29.03; H:3.71; N:11.28.Measured value: C:28.98; H:3.66; N:11.21.

(18.34) .2-amino-5-[1-(4-cyano group) butyl]-4-phosphonium mesitoyl methoxy carbonyl thiazole.230 ℃ of mp (decomposition).C ₁₀H ₁₄N ₃O ₅The analytical calculation value of PS: C:37.62; H:4.42; N:13.16.Measured value: C:37.23; H:4.18; N:12.79.

(18.35) .2-amino-5-amyl group-4-phosphonium mesitoyl methoxy Tang Ji oxazole.C ₁₀H ₁₇N ₂O ₆The analytical calculation value of P: C:41.10; H:5.86; N:9.59.Measured value: C:41.16; H:5.75; N:9.50.

(18.36) .2-[N-Boc (amino)]-the 4-[(N-phosphono) ethoxy carbonyl] thiazole.C ₁₁H ₁₇N ₂O ₇PS：C：37.50；H：4.86；N：7.95。Measured value: C:37.10; H:4.59; N:7.84.

(18.37) ethoxy carbonyl .2-amino-4-[(2-phosphono)] thiazole hydrobromide salt.C ₆H ₉N ₂O ₅The analytical calculation value of PS+HBr: C:21.63; H:3.03; N:8.41.Measured value: C:22.01; H:2.99; N:8.15.

(18.38) .2-amino-5-butyl-4-phosphonium mesitoyl methoxy Tang Ji oxazole.C ₉H ₁₅N ₂O ₆The analytical calculation value of P: C:38.86; H:5.43; N; 10.07.Measured value: C:38.59; H:5.43; N:9.96.

(18.39) .2-amino-5-[1-(1-oxo-2,2-dimethyl) propyl group]-4-phosphonium mesitoyl methoxy carbonyl thiazole.C ₁₀H ₁₅N ₂O ₆The analytical calculation value of PS: C:37.27; H:4.69; N:8.69.Measured value: C:37.03; H:4.69; N:8.3.

(18.40) 2-amino-5-propyl group-4-phosphonium mesitoyl methoxy Tang Ji oxazole.C ₈H ₁₃N ₂O ₆The analytical calculation value of P+0.35EtOAc+0.05HBr: C:37.75; H:5.34; N:9.37.Measured value: C:37.69; H:5.21; N:9.03.

(18.41) 2-amino-5-propyl group-4-phosphonium mesitoyl methoxy carbonyl thiazole.134 ℃ of Mp (decomposition).C ₈H ₁₃N ₂O ₅The analytical calculation value of PS: C:34.29; H:4.68; N:10.00.Measured value: C:33.90; H:4.30; N:9.61.

(18.42) 2-amino-5-amyl group-4-phosphonium mesitoyl methoxy carbonyl thiazole.130 ℃ of Mp (decomposition).C ₁₀H ₁₇N ₂O ₅The analytical calculation value of PS: C:38.96; H:5.05; N:9.09.Measured value: C:38.69; H:5.25; N:8.85.

(18.43) 2-amino-5-bromo-4-(phosphonomethyl) thiocarbonyl thiazole.230 ℃ of Mp (decomposition).C ₅H ₆N ₂O ₅PS ₂The analytical calculation value of Br: C:18.03; H:1.82; N:8.41.Measured value: C:18.40; H:1.93; N:8.18.

(18.44) 2-amino-5-(2-furyl)-4-phosphonium mesitoyl methoxy carbonyl thiazole.230 ℃ of Mp (decomposition).C ₉H ₉N ₂O ₆The analytical calculation value of PS: C:35.53; H:2.98; N:9.21.Measured value: C:35.78; H:0.05; N:8.11.

(18.45) 2-amino-5-ethyl-4-phosphonium mesitoyl methoxy Tang Ji oxazole.141 ℃ of Mp (decomposition).C ₇H ₁₁N ₂O ₆The analytical calculation value of P: C:33.61; H:4.43; N:11.20.Measured value: C:33.79; H:4.4; N:11.09.

(18.46) formamyl .5-methyl-4-[(N-(phosphonomethyl))] imidazoles.C ₆H ₁₀N ₃O ₄The analytical calculation value of P: C:32.89; H:4.60; N:19.18.Measured value: C:33.04; H:4.65; N:18.84.

Embodiment 19.

Preparation as the various phosphonic acid diesters of prodrug

With 2-methyl-5-isobutyl--4-[2-(5-phosphono) furyl] suspension returning heating in the thionyl chloride (5ml) of thiazole (1mmol) 4 hours.The refrigerative reaction mixture is evaporated to dried, the yellow residue of generation is dissolved in the methylene dichloride and with the dichloromethane solution processing of corresponding benzylalcohol (4mmol) and pyridine (2.5mmol).After 24 hours, chromatography obtains title compound to reaction mixture through extracting also in 25 ℃ of stirrings.Prepare following compounds according to this method:

(19.1) two (4-new pentane acyloxy benzyl) phosphonos of 2-methyl-5-isobutyl--4-{2-[5-] furyl } thiazole.C ₃₆H ₄₄NO ₈PS+0.4H ₂The analytical calculation value of O: C:62.76; H:6.55; N:2.03.Measured value: C:62.45; H:6.44; N:2.04.

(19.2) two (3,4-diacetoxy benzyl) phosphonos of 2-methyl-5-isobutyl--4-{2-[5-] furyl } thiazole.C ₃₄H ₃₆NO ₁₂PS+0.8H ₂The analytical calculation value of O: C:56.09; H:5.21; N:1.92.Measured value: C:55.90; H:4.98; N:1.94.

(19.3) two (4-acetoxy-3-methoxy-benzyl) phosphonos of 2-methyl-5-isobutyl--4-{2-[5-] furyl } thiazole.C ₃₂H ₃₆NO ₁₀The analytical calculation value of PS: C:58.44; H:5.52; N:2.13.Measured value: C:58.16; H:5.34; N:2.13.

(19.4) two (4-acetoxy-3-methyl-benzyl) phosphonos of 2-methyl-5-isobutyl--4-{2-[5-] furyl } thiazole.C ₃₂H ₃₆NO ₈The analytical calculation value of PS: C:61.43; H:5.80; N:2.24.Measured value: C:61.34; H:5.89; N:2.25.

(19.5) two (3,4-diacetoxy benzyl) phosphonos of 2-amino-5-isobutyl--4-{2-[5-] furyl } thiazole.C ₃₃H ₃₅N ₂O ₁₂The analytical calculation value of PS: C:55.46; H:4.94; N:3.92.Measured value: C:55.06; H:4.96; N:3.79.

(19.6) two (4-acetoxyl group benzyl) phosphonos of 2-amino-5-isobutyl--4-{2-[5-] furyl } thiazole.C ₂₉H ₃₁N ₂O ₈The analytical calculation value of PS: C:58.19; H:5.22; N:4.68.Measured value: C:57.82; H:4.83; N:4.50.

This method also is used to be prepared as the Phenylphosphine acid esters of prodrug, and is used to prepare following compounds:

(19.7) 2-methyl-5-isobutyl--4-[2-(5-diphenylphosphine acyl group) furyl] thiazole.C ₂₄H ₂₄NO ₄PS+0.1H ₂The analytical calculation value of O: C:63.31; H:5.36; N:3.08.Measured value: C:63.22; H:5.34; N:3.14.

(19.63) 2-amino-5-isobutyl--4-[2-(5-diphenylphosphine acyl group) furyl] thiazole.Mp?128-129℃。C ₂₃H ₂₃N ₂O ₄The analytical calculation value of PS: C:60.78; H:5.10; N:6.16.Measured value: C:60.68; H:4.83; N:6.17.

(19.64) 2-amino-5-isobutyl--4-[2-(5-Phenylphosphine acyl group) furyl] thiazole.Mp＞250℃。C ₁₇H ₁₉N ₂O ₄The analytical calculation value of PS: C:53.96; H:5.06; N:7.40.Measured value: C:53.81; H:4.87; N:7.41.

(19.65) 2-amino-5-isobutyl--4-[2-(two (3-chlorophenyl) phosphonos of 5-) furyl] thiazole.C ₂₃H ₂₁N ₂O ₄PSCl ₂+ 0.5H ₂The analytical calculation value of O: C:51.89; H:4.17; N:5.26.Measured value: C:51.55; H:3.99; N:5.22.

(19.67) 2-amino-5-isobutyl--4-[2-(two (4-p-methoxy-phenyl) phosphonos of 5-) furyl] thiazole.C ₂₅H ₂₇N ₂O ₆PS+0.5H ₂The analytical calculation value of O: C:57.35; H:5.39; N:5.35.Measured value: C:57.11; H:5.36; N:5.75.

This method also be used to be prepared as prodrug some contain the phosphonic acid ester of sulfo-, and preparation following compounds:

(19.8) two (2-methyl carbonyl thio-ethyl) phosphonos of 2-methyl-5-isobutyl--4-{2-[5-] furyl } thiazole.C ₂₀H ₂₈NO ₆PS ₃The analytical calculation value: C:47.51; H:5.58; N:2.77.Measured value: C:47.32; H:5.56; N:2.77.

(19.9) two (thiobenzoyl ylmethyl) phosphonos of 2-methyl-5-isobutyl--4-{2-[5-] furyl } thiazole.C ₂₈H ₂₈NO ₆PS ₃The analytical calculation value: C:55.89; H:4.69; N:2.33.Measured value: C:55.73; H:4.72; N:2.28.

This method also be used for by make phosphonic acids and various glycol (as 1, ammediol, see synthetic some 1, the embodiment 21 of ammediol) coupling is prepared as the annular phosphonate (as ring-type 1, the ammediol phosphonic acid ester) of prodrug, and the preparation following compounds:

(19.10) 5-isobutyl--2-methyl-4-{2-[5-(1-hydroxyl-3,5-cyclohexyl) phosphono] furyl } thiazole (less important isomer).C ₁₈H ₂₄NO ₅PS+0.33H ₂The analytical calculation value of O: C:53.60; H:6.16; N:3.47.Measured value: C:53.75; H:6.53; N:3.45.

(19.11) 5-isobutyl--2-methyl-4-{2-[5-(1-hydroxyl-3,5-cyclohexyl) phosphono] furyl } thiazole (main isomer).C ₁₈H ₂₄NO ₅The analytical calculation value of PS: C:54.40; H:6.09; N:3.52.Measured value: C:54.44; H:6.11; N:3.63.

(19.12) 5-isobutyl--2-methyl-4-{2-[5-(2-methylol-1,3-propyl group) phosphono] furyl } thiazole.C ₁₆H ₂₂NO ₅PS+0.3CH ₂Cl ₂+ 0.5H ₂The analytical calculation value of O: C:48.24; H:5.86; N:3.45.Measured value: C:47.94; H:5.59; N:3.57.

(19.13) 5-isobutyl--2-methyl-4-{2-[5-(1-phenyl-1,3-propyl group) phosphono] furyl } thiazole (less important isomer).C ₂₁H ₂₄NO ₄PS+0.25H ₂The analytical calculation value of O: C:59.77; H:5.85; N:3.32.Measured value: C:59.76; H:5.69; N:3.38.

(19.14) 5-isobutyl--2-methyl-4-{2-[5-(1-phenyl-1,3-propyl group) phosphono] furyl } thiazole (main isomer).C ₂₁H ₂₄NO ₄PS+0.25H ₂The analytical calculation value of O: C:59.14; H:5.91; N:3.28.Measured value: C:59.27; H:5.85; N:3.38.

(19.15) 2-amino-5-isobutyl--4-[2-(5-[2-(methoxycarbonyl oxygen ylmethyl)-the third-1,3-yl] phosphono) furyl] thiazole (less important isomer).mp?170-173℃。C ₁₇H ₂₃N ₂O ₇The analytical calculation value of PS: C:47.44; H:5.39; N:6.51.Measured value: C:47.28; H:5.27; N:6.47.

(19.16) 2-amino-5-isobutyl--4-[2-(5-[2-(methoxycarbonyl oxygen ylmethyl)-the third-1,3-yl] phosphono) furyl] thiazole (main isomer).C ₁₇H ₂₃N ₂O ₇PS+0.5H ₂The analytical calculation value of O: C:46.47; H:5.51; N:6.38.Measured value: C:46.38; H:5.29; N:6.20.

(19.17) 5-isobutyl--2-methyl-4-{2-[5-(1-(4-pyridyl)-1,3-propyl group) phosphono] furyl } thiazole.C ₂₀H ₂₃N ₂O ₄PS+2H ₂O+0.4CH ₂Cl ₂The analytical calculation value: C:50.16; H:5.74; N:5.74.Measured value: C:50.36; H:5.36; N:5.80.

(19.18) 2-amino-5-isobutyl--4-(2-{5-[1-(4-pyridyl)-the third-1,3-yl] phosphono } furyl) thiazole.mp?101-106℃。C ₁₉H ₂₂N ₃O ₄PS+0.75H ₂The analytical calculation value of O: C:52.71; H:5.47; N:9.71.Measured value: C:52.59; H:5.49; N:9.65.

(19.20) 2-amino-5-isobutyl--4-{2-[5-(1-phenyl-1,3-propyl group) phosphono] furyl } thiazole (less important isomer).C ₂₀H ₂₃N ₂O ₄The analytical calculation value of PS+0.33HCl: C:55.80; H:5.46; N:6.51.Measured value: C:55..95; H:5.36; N:6.46.

(19.21) 2-amino-5-isobutyl--4-{2-[5-(1-phenyl-1,3-propyl group) phosphono] furyl } thiazole (main isomer).C ₂₀H ₂₃N ₂O ₄The analytical calculation value of PS+0.33HCl: C:55.80; H:5.46; N:6.51.Measured value: C:55..77; H:5.19; N:6.44.

(19.22) 2-amino-5-ethyl-4-{2-[5-(1-phenyl-1,3-propyl group) phosphono] furyl } thiazole (less polar isomer).C ₁₈H ₁₉N ₂O ₄PS+0.2HCl+0.25H ₂The analytical calculation value of O: C:53.75; H:4.94; N:6.97.Measured value: C:53.86; H:4.70; N:6.87.

(19.23) 2-amino-5-ethyl-4-{2-[5-(1-phenyl-1,3-propyl group) phosphono] furyl }-thiazole (than the isomer of high polarity).C ₁₈H ₁₉N ₂O ₄PS+0.2HCl+0.25H ₂The analytical calculation value of O: C:53.75; H:4.94; N:6.97.Measured value: 53.92; H:4.82; N:6.92.

(19.24) 2-amino-5-ethyl-4-{2-[5-(1-{4-pyridyl }-1,3-propyl group) phosphono] furyl } thiazole.C ₁₇H ₁₈N ₃O ₄PS+0.1HCl+0.5H ₂The analytical calculation value of O: C:50.54; H:4.76; N:10.40.Measured value: C:50.38; H:4.53; N:10.25.

(19.25) 2-methyl-4-{2-[5-(2-acetoxy-methyl the third-1,3-two bases) phosphono] furyl } thiazole.C ₁₄H ₁₆NO ₆PS+0.5H ₂The analytical calculation value of O: C:45.90; H:4.68; N:3.82.Measured value: C:45.50; H:4.55; N:3.45.

(19.26) 2-methyl-4-(2-{5-[1-(4-pyridyl) the third-1,3-two bases] phosphono } furyl) thiazole.C ₁₆H ₁₅N ₂O ₄PS+0.75H ₂The analytical calculation value of O: C:51.13; H:4.42; N:7.45.Measured value: 50.86; H:4.72; N:7.11.

(19.27) 2-amino-5-methylthio group-4-(2-{5-[1-(4-pyridyl) the third-1,3-two bases] phosphono } furyl) thiazole.C ₁₆H ₁₆N ₃O ₄PS ₂The analytical calculation value of+0.4HCl: C:45.32; H:3.90; N:9.91.Measured value: 45.29; H:3.80; N:9.83.

(19.28) 2-amino-5-isobutyl--4-{2-[5-(1-(3-bromo phenyl) the third-1,3-two bases) phosphono] furyl } thiazole (main isomer).C ₂₀H ₂₂N ₂O ₄The analytical calculation value of PBrS: C:48.30; H:4.46; N:5.63.Measured value: C:48.51; H:4.21; N:5.33.

(19.29) 2-amino-5-methylthio group-4-{2-[5-(1-(R)-phenyl-1,3-propyl group) phosphono] furyl } thiazole.C ₁₇H ₁₇N ₂O ₄The analytical calculation value of PS+HCl: C:49.46; H:4.39; N:6.79.Measured value: C:49.77; H:4.13; N:6.54.

(19.30) 2-amino-5-isobutyl--4-{2-[5-(1-(3-bromo phenyl)-1,3-propyl group) phosphono] furyl } thiazole (less important isomer).C ₂₀H ₂₂N ₂O ₄The analytical calculation value of PSBr+0.25HCl: C:47.43; H:4.43; N:5.53.Measured value: C:47.58; H:4.16; N:5.31.

(19.31) 2-amino-5-isobutyl--4-{2-[5-(2-benzyl-1,3-propyl group) phosphono] furyl } thiazole.C ₂₁H ₂₅N ₂O ₄The analytical calculation value of PS: C:58.32; H:5.83; N:6.48.Measured value: C:57.98; H:5.65; N:6.47.

(19.32) 2-amino-5-cyclopropyl-4-{2-[5-(1-(4-pyridyl)-1,3-propyl group) phosphono] furyl } thiazole.C ₁₈H ₁₈N ₃O ₄PS+0.5H ₂The analytical calculation value of O: C:52.42; H:4.64; N:10.19.Measured value: 52.62; H:4.51; N:9.89.

(19.33) 2-methyl-5-isobutyl--4-{2-[5-(1-(S)-phenyl-1,3-propyl group) phosphono] furyl } thiazole, less important isomer.C ₂₁H ₂₄NO ₄The analytical calculation value of PS: C:60.42; H:5.79; N:3.36.Measured value: C:60.10; H:5.58; N:3.32.

(19.34) 2-methyl-5-isobutyl--4-{2-[5-(1-(S)-phenyl-1,3-propyl group) phosphono] furyl } thiazole, main isomer.C ₂₁H ₂₄NO ₄PS+0.33H ₂The analytical calculation value of O: C:59.57; H:5.87; N:3.31.Measured value: C:59.45; H:5.83; N:3.30.

(19.35) 2-azido--5-ethyl-4-{2-[5-(1-phenyl-1,3-propyl group) phosphono] furyl } thiazole, main isomer.C ₁₈H ₁₇N ₄O ₄PS+0.25H ₂O+0.1 isoamyl alcohol (C ₅H ₁₂O) analytical calculation value: C:51.71; H:4.39; N:13.04.Measured value: C:51.80; H:4.20; N:12.78.

(19.36) 2-azido--5-ethyl-4-{2-[5-(1-phenyl-1,3-propyl group) phosphono] furyl } thiazole, less important isomer.C ₁₈H ₁₇N ₄O ₄PS+0.15 isoamyl alcohol (C ₅H ₁₂O) analytical calculation value: C:52.42; H:4.41; N:13.04.Measured value: C:52.27; H:4.47; N:12.76.(19.37) 2-amino-5-isobutyl--4-{2-[5-(1-(1-naphthyl)-1,3-propyl group) phosphono] furyl } thiazole.C ₂₄H ₂₅N ₂O ₄The analytical calculation value of PS: C:61.53; H:5.38; N:5.98.Measured value: C:61.40; H:5.12; N:6.11.

(19.38) 2-amino-5-isobutyl--4-{2-[5-(1-(2-bromo phenyl)-1,3-propyl group) phosphono] furyl) thiazole.C ₂₀H ₂₂N ₂O ₄PSBr+0.1C ₅H ₅The analytical calculation value of N: C:48.73; H:4.49; N:5.82.Measured value: C:48.63; H:4.26; N:5.70.

(19.39) 2-amino-5-isobutyl--4-{2-[5-(1-(4-bromo phenyl)-1,3-propyl group) phosphono] furyl } thiazole, less important isomer.C ₂₀H ₂₂N ₂O ₄The analytical calculation value of PSBr: C:48.30; H:4.46; N:5.63.Measured value: C:48.23; H:4.30; N:5.77.

(19.40) 2-amino-5-isobutyl--4-{2-[5-(1-(4-bromo phenyl)-1,3-propyl group) phosphono] furyl } thiazole, main isomer.C ₂₀H ₂₂N ₂O ₄The analytical calculation value of PSBr: C:48.30; H:4.46; N:5.63.Measured value: C:48.20; H:4.63; N:5.41.

(19.41) 2-amino-5-isobutyl--4-{2-[5-(1-(4-fluoro-3-bromo phenyl)-1,3-propyl group) phosphono] furyl } thiazole, less important isomer.C ₂₀H ₂₁N ₂O ₄PSBrF+0.1C ₅H ₅The analytical calculation value of N: C:47.06; H:4.14; N:5.62.Measured value: C:47.00; H:3.84; N:5.48.

(19.42) 2-amino-5-isobutyl--4-{2-[5-(1-(4-fluoro-3-bromo phenyl)-1,3-propyl group) phosphono] furyl } thiazole, main isomer.C ₂₀H ₂₁N ₂O ₄PSBrF+0.1C ₅H ₅The analytical calculation value of N: C:46.61; H:4.11; N:5.44; P:6.01.Measured value: C:46.81; H:4.23; N:5.65; P:5.65.

(19.43) 2-amino-5-isobutyl--4-{2-[5-(1-(4-trifluoromethyl)-1,3-propyl group) phosphono] furyl } thiazole, less important isomer.C ₂₁H ₂₂N ₂O ₄PSF ₃+ 0.1H ₂The analytical calculation value of O: C:51.66; H:4.58; N:5.74.Measured value: C:51.54; H:4.28; N:5.46.

(19.44) 2-amino-5-isobutyl--4-{2-[5-(1-(4-trifluoromethyl)-1,3-propyl group) phosphono] furyl } thiazole, main isomer.C ₂₁H ₂₂N ₂O ₄PSF ₃+ 0.1H ₂The analytical calculation value of O: C:51.66; H:4.58; N:5.74.Measured value: C:51.48; H:4.62; N:5.81.

(19.45) 2-amino-5-isobutyl--4-{2-[5-(1-(3-chlorophenyl)-1,3-propyl group) phosphono] furyl } thiazole, less important isomer.C ₂₀H ₂₂N ₂O ₄PSCl+0.5H ₂The analytical calculation value of O: C:52.01; H:5.02; N:6.06.Measured value: C:52.10; H:4.92; N:5.82.

(19.46) 2-amino-5-isobutyl--4-{2-[5-(1-(3-chlorophenyl)-1,3-propyl group) phosphono] furyl } thiazole, main isomer.C ₂₀H ₂₂N ₂O ₄PSCl+0.5H ₂The analytical calculation value of O: C:52.52; H:4.96; N:6.12.Measured value: C:52.70; H:4.79; N:5.91.

(19.47) 2-amino-5-isobutyl--4-{2-[5-(1-(3,5-dichloro-phenyl)-1,3-propyl group) phosphono] furyl } thiazole, less important isomer.C ₂₀H ₂₁N ₂O ₄PSCl ₂The analytical calculation value: C:49.29; H:4.34; N:5.75.Measured value: C:49.47; H:4.60; N:5.89.

(19.48) 2-amino-5-isobutyl--4-{2-[5-(1-(3,5-dichloro-phenyl)-1,3-propyl group) phosphono] furyl } thiazole, main isomer.C ₂₀H ₂₁N ₂O ₄PSCl ₂The analytical calculation value: C:49.29; H:4.34; N:5.75; Cl:14.55.Measured value: C:49.26; H:4.36; N:5.71; Cl:14.66.

(19.49) 2-amino-5-isobutyl--4-{2-[5-(2-(4-methoxy-benzyl)-1,3-propyl group) phosphono] furyl } thiazole.Mp?185-188℃。C ₂₂H ₂₇N ₂O ₅The analytical calculation value of PS: C:57.13; H:5.88; N:6.06.Measured value: C:56.86; H:5.71; N:5.73.

(19.50) 2-amino-5-isobutyl--4-{2-[5-(2-mesyloxy methyl isophthalic acid, 3-propyl group) phosphono] furyl } thiazole.C ₁₆H ₂₃N ₂O ₇PS ₂+ 0.2H ₂The analytical calculation value of O: C:42.32; H:5.19; N:6.17.Measured value: C:42.15; H:4.94; N:5.95.

(19.51) 2-amino-5-isobutyl--4-{2-[5-(2-azido methyl-1,3-propyl group) phosphono] furyl } thiazole.Mp?187-189℃。C ₁₅H ₂₀N ₅O ₄The analytical calculation value of PS: C:45.34; H:5.07; N:17.62.Measured value: C:45.09; H:4.82; N:17.72.

(19.52) 2-amino-5-isobutyl--4-{2-[5-(2-aminomethyl-1,2,3-propyl group) phosphono] furyl } thiazole.C ₁₅H ₂₂N ₃O ₄PS+0.3H ₂The analytical calculation value of O+0.1HCl: C:47.36; H:6.01; N:11.04.Measured value: C:47.55; H:5.62; N:10.64.

(19.53) 2-amino-5-isobutyl--4-{2-[5-(1-(4-tert-butyl-phenyl)-1,3-propyl group) phosphono] furyl } thiazole, less important isomer.Mp?141-143℃。C ₂₄H ₃₁N ₂O ₄The analytical calculation value of PS+1.5HCl: C:54.47; H:6.19; N:5.29.Measured value: C:54.44; H:5.85; N:4.92.

(19.54) 2-amino-5-isobutyl--4-{2-[5-(1-(4-tert-butyl-phenyl)-1,3-propyl group) phosphono] furyl } thiazole, main isomer.178 ℃ of Mp (decomposition).C ₂₄H ₃₁N ₂O ₄PS+H ₂The analytical calculation value of O: C:58.52; H:6.75; N:5.69.Measured value: C:58.20; H:6.31; N:5.29.

(19.55) 2-amino-5-isobutyl--4-{2-[5-(1-(4-chlorophenyl)-1,3-propyl group) phosphono] furyl } thiazole, main isomer.Mp?102-104℃。C ₂₀H ₂₂N ₂O ₄PSCl+H ₂The analytical calculation value of O+0.2EtOAc: C:51.14; H:5.28; N:5.73.Measured value: C:50.86; H:5.09; N:5.34.

(19.56) 2-amino-5-isobutyl--4-{2-[5-(1-(2,4-dichloro-phenyl)-1,3-propyl group) phosphono] furyl } thiazole, main isomer.Mp?173-174℃。C ₂₀H ₂₁N ₂O ₄PSCl ₂The analytical calculation value: C:49.29; H:4.34; N:5.75.Measured value: C:49.55; H:4.32; N:5.46.

(19.57) 2-amino-5-isobutyl--4-{2-[5-(1,3-(S, s)-phenylbenzene)-1,3-propyl group) phosphono] furyl } thiazole.Mp?105-107℃。C ₂₆H ₂₇N ₂O ₄PS+0.5H ₂The analytical calculation value of O+0.5HCl: C:59.85; H:5.51; N:5.37.Measured value: C:59.83; H:5.18; N:5.27.

(19.58) 2-amino-5-isobutyl--4-{2-[5-(1-(4-chlorophenyl)-1,3-propyl group) phosphono] furyl } thiazole, less important isomer.Mp?102-104℃。C ₂₀H ₂₂N ₂O ₄The analytical calculation value of PSCl: C:53.04; H:4.90; N:6.19.Measured value: C:52.80; H:4.70; N:6.07.

(19.59) 2-amino-5-isobutyl--4-{2-[5-(1-(3,5-phenyl-difluoride base)-1,3-propyl group) phosphono] furyl } thiazole, less important isomer.Mp?152-154℃。C ₂₀H ₂₁N ₂O ₄PSF ₂+ 0.5H ₂The analytical calculation value of O+0.3EtOAc: C:51.98; H:5.02; N:5.72.Measured value: C:51.67; H:4.77; N:5.42.

(19.60) 2-amino-5-isobutyl--4-{2-[5-(1-(3,5-phenyl-difluoride base)-1,3-propyl group) phosphono] furyl } thiazole, main isomer.Mp?94-95℃。C ₂₀H ₂₁N ₂O ₄PSF ₂The analytical calculation value: C:52.86; H:4.66; N:6.16.Measured value: C:52.68; H:4.73; N:5.90.

(19.61) 2-amino-5-isobutyl--4-{2-[5-(1-(3,5-dibromo-benzene base)-1,3-propyl group) phosphono] furyl } thiazole, main isomer.Mp?113-115℃。C ₂₀H ₂₁N ₂O ₄PSBr ₂The analytical calculation value of+0.3EtOAc: C:42.25; H:3.91; N:4.65.Measured value: C:42.52; H:3.91; N:4.96.

(19.62) 2-amino-5-isobutyl--4-{2-[5-(1-(3,5-dibromo-benzene base)-1,3-propyl group) phosphono] furyl } thiazole, less important isomer.Mp?209-210℃。C ₂₀H ₂₁N ₂O ₄PSBr ₂The analytical calculation value: C:41.69; H:3.67; N:4.86.Measured value: C:41.93; H:3.71; N:4.74.

(19.66) 2-amino-5-isobutyl--4-{2-[5-(1-(3-pyridyl)-1,3-propyl group) phosphono] furyl } the thiazole dihydrochloride.C ₁₉H ₂₂N ₃O ₄PS+2HCl+2H ₂The analytical calculation value of O: C:43.19; H:5.34; N:7.95.Measured value: C:43.10; H:5.25; N:7.85.

(19.68) 2-amino-5-isobutyl--4-{2-[5-(1-oxo-1-phospha-2,5,8-trioxa-3,4-benzo) ring suffering-1-yl] furyl } thiazole.C ₁₉H ₂₁N ₂O ₅PS+0.75H ₂The analytical calculation value of O: C:52.59; H:5.23; N:6.46.Measured value: C:52.38; H:4.85; N:6.08.

Preferred adopt followingly 1,3-dicyclohexylcarbodiimide (DCC) coupled reaction condition prepares ring-type 1, the ammediol phosphonic acid ester.

With DCC (2mmol) and 3-(3, the 5-dichloro-) phenyl-1, the first aftertreatment 2-amino of ammediol (1.1mmol)-5-isobutyl--4-[2-(5-phosphono) furyl] thiazole (1mmol) is at DMF: pyridine (5: 1, the 10ml) suspension in.The mixture that generates in 80 ℃ of heating 8 hours.Evaporation then column chromatography obtains 2-amino-5-isobutyl--4-{2-[5-(1-(3,5-dichloro-phenyl)-1,3-propyl group) phosphono] furyl } thiazole, main isomer (19.48) is solid.

This method is by making phosphonic acids and 5-methyl-4-methylol-2-oxo-1,3-dioxole and 5-methyl-4-methylol-2-thiono-1, the 3-dioxole is (as described in example 23 above by 4,5-dimethyl-2-oxo-1, the preparation of 3-dioxole) coupling, also can be used for the preparation of (the 2-oxo-1 that 5-replaces, 3-Dioxol-4-yl) methyl and (the 2-thiocarbonyl-1 that 5-replaces, 3-Dioxol-4-yl) methyl-phosphorous acid ester prodrugs.Adopt this method to prepare following compounds.

(19.19) 2-methyl-5-isobutyl--4-{2-[5-(two (5-methyl-2-sulfo--3,5-Dioxol-4-yl) methyl)-phosphono] furyl } thiazole.C ₂₂H ₂₄NO ₈PS ₃The analytical calculation value: C:47.39; H:4.34; N:2.51.Measured value: C:47.42; H:4.30; N:2.52.

Perhaps, according to reported method (Chem.Pharm.Bull.1984,32 (6), 2241), by in 25 ℃ in the presence of sodium hydride, make phosphonic acids and 5-methyl-4-bromomethyl-2-oxo-1, the 3-dioxole reacts in DMF, can prepare these compounds.

According to aforesaid method; use 2-(3-benzo [c] furanonyl) ethanol (by 2-benzo [c] furanone-3-acetate preparation of embodiment 22), also can prepare two (3-benzo [c] furanonyl-2-ethyl) phosphonos of 2-amino-5-isobutyl--4-{2-[5-] furyl }-thiazole.

Embodiment 20.

Preparation as the acyloxy alkyl and the alkoxy-carbonyl oxy alkyl phosphonic acid diester of prodrug

In 0 ℃, handle 2-methyl-4-[2-(5-phosphono) furyl with oxy acid methyl neopentyl iodine (4mmol)] acetonitrile and the N of thiazole (1mmol), N, N-diisopropylethylamine (5mmol) solution 24 hours.Extracting also, chromatography obtains 2-methyl-4-[2-(5-two oxy acid methyl neopentyl phosphonos) furyl]-thiazole (20.1).C ₂₀H ₂₈NO ₈The analytical calculation value of PS: C:50.59; H:6.03; N:2.65.Measured value: C:50.73; H:5.96; N:2.96.

Prepare following compounds according to this method:

(20.2) 2-methyl-5-isobutyl--4-{2-[5-(O-isobutyl acyl-oxygen ylmethyl-O-oxy acid methyl neopentyl)-phosphono] furyl } thiazole.C ₂₃H ₃₄NO ₈The analytical calculation value of PS: C:53.58; H:6.65; N:2.72.Measured value: C:53.81; H:6.83; N:2.60.

(20.3) 2-methyl-5-isobutyl--4-{2-[5-(two oxy acid methyl neopentyls) phosphono] furyl } thiazole.C ₂₄H ₃₆NO ₈The analytical calculation value of PS: C:54.43; H:6.85; N:2.64.Measured value: C:54.46; H:7.04; N:2.55.

(20.4) 2-amino-5-isobutyl--4-{2-[5-(two oxy acid methyl neopentyls) phosphono] furyl } thiazole.C ₂₃H ₃₅N ₂O ₈The analytical calculation value of PS: C:52.07; H:6.65; N:5.28.Measured value: C:52.45; H:6.78; N:5.01.

(20.5) 2-bromo-5-isobutyl--4-{2-[5-(two oxy acid methyl neopentyls) phosphono] furyl } thiazole.C ₂₃H ₃₃NO ₈The analytical calculation value of PSBr: C:47.00; H:5.75; N:2.32.Measured value: C:47.18; H:5.46; N:2.30.

According to Farquhar ' s method (Farquhar, D. etc., Tetrahedron Lett.1995,36,655), also can prepare ring-type acyloxy phosphonate ester in a similar fashion.

(20.13) 2-amino-5-isobutyl--4-{2-[5-(1-benzoyloxy propane-1,3-two bases) phosphono] furyl } thiazole, than the isomer of high polarity.C ₂₁H ₂₃N ₂O ₆The MS calculated value of PS+H: 463, measured value 463.

(20.14) 2-amino-5-isobutyl-4-{2-[5-(1-benzoyloxy propane-1,3-two bases) phosphono] furyl } thiazole, less polar isomer.C ₂₁H ₂₃N ₂O ₆The MS calculated value of PS+H: 463, measured value 463.

According to aforesaid method, be modified as follows slightly, also can prepare the alkoxy-carbonyl oxy phosphonate ester:

Use N; N '-dicyclohexyl-4-morpholine carbonamidine (5mmol) and ethyl propoxycarbonyl oxygen ylmethyl iodine (5mmol) are (according to reported method (Nishimura etc.; J.Antibiotics; 1987; 40 (1), 81-90) by chloro methyl chloride subtituted acid ester preparation) handle 2-methyl-5-isobutyl-4-[2-(5-phosphono) furyl] the DMF solution of thiazole (1mmol).Stirred these reaction mixtures 24 hours in 25 ℃, evaporation, then chromatography obtains two (the ethoxy carbonyl oxygen ylmethyl) phosphonos of 2-methyl-5-isobutyl--4-{2-[5-] furyl } thiazole (20.6).C ₂₀H ₂₈NO ₁₀The analytical calculation value of PS: C:47.52; H:5.58; N:2.77.Measured value: C:47.52; H:5.67; N:2.80.

Prepare following compounds according to this method:

(20.7) two (isopropoxy carbonyl oxygen ylmethyl) phosphonos of 2-methyl-5-isobutyl--4-{2-[5-]-furyl } thiazole.C ₂₂H ₃₂NO ₁₀The analytical calculation value of PS: C:49.53; H:6.05; N:2.63.Measured value: C:49.58; H:6.14; N:2.75.

(20.8) two (phenyloxycarbonyl oxygen ylmethyl) phosphonos of 2-amino-5-isobutyl--4-{2-[5-]-furyl } thiazole.C ₂₇H ₂₇N ₂O ₁₀The analytical calculation value of PS: C:53.82; H:4.52; N:4.65.Measured value: C:54.03; H:4.16; N:4.30.

(20.9) two (ethoxy carbonyl oxygen ylmethyl) phosphonos of 2-amino-5-isobutyl--4-{2-[5-]-furyl } thiazole.C ₁₉H ₂₇N ₂O ₁₀The analytical calculation value of PS: C:45.06; H:5.37; N:5.53.Measured value: C:45.11; H:5.30; N:5.43.

(20.10) two (isopropylthio ketonic oxygen the ylmethyl)-phosphonos of 2-methyl-5-isobutyl--4-{2-[5-] furyl } thiazole.C ₂₂H ₃₂NO ₈The analytical calculation value of PS+0.2EtOAc: C:46.95; H:5.81; N:2.40.Measured value: C:47.06; H:5.86; N:2.73.

(20.11) two (isopropoxy carbonyl oxygen ylmethyl) phosphonos of 2-amino-5-isobutyl--4-{2-[5-] furyl } thiazole.C ₂₁H ₃₁N ₂O ₁₀The analytical calculation value of PS: C:47.19; H:5.85; N:5.24.Measured value: C:47.33; H:5.66; N:5.57.

(20.12) two (benzoyloxy methyl) phosphonos of 2-methyl-5-isobutyl--4-{2-[5-] furyl } thiazole.C ₂₈H ₂₈NO ₈PS+0.2CH ₂Cl ₂The analytical calculation value: C:59.31; H:5.40; N:2.64.Measured value: C:59.25; H:5.27; N:2.44.

(20.15) two (1-(1-ethoxy carbonyl oxygen base) ethyl) phosphonos of 2-amino-5-isobutyl--4-{2-[5-]-furyl } thiazole.Mp?76-78℃。C ₂₁H ₃₁N ₂O ₁₀The analytical calculation value of PS: C:47.19; H:5.85; N:5.42.Measured value: C:48.06; H:5.80; N:5.16.

According to this method, use 3-bromo-5,6,7-trimethoxy-2-benzo [c] furanone is as alkylating agent, but also two (3-(5,6, the 7-trimethoxy)-phthalidyl)-phosphonos of Synthetic 2-amino-5-isobutyl--4-{2-[5-] furyl } thiazole.

Embodiment 21.

3-(2-pyridyl) the third-1, the preparation of 3-glycol:

Steps A. (J.Org.Chem., 1957,22,589) in 80 ℃, with the acetic acid solution of 30% hydrogen peroxide treatment 3-(2-pyridyl) propyl alcohol 16 hours.This reactant of vacuum concentration is dissolved in the diacetyl oxide and in 110 ℃ residue and heated 12 hours.Evaporation and chromatography obtain 3-(2-pyridyl)-1, ammediol diacetate esters.

Step B. handles 3-(2-pyridyl)-1, methanol-water (3: the 1) solution of ammediol diacetate esters (1mmol) 3 hours in 25 ℃ with salt of wormwood (5mmol).Evaporation and chromatography obtain solid 3-(2-pyridyl)-1, ammediol.

Embodiment 22.

The preparation of 3-(2-hydroxyethyl)-2-benzo [c] furanone:

In 0 ℃, handle the THF solution 1 hour of 2-benzo [c] furanone-3-acetate (1mmol) with borine methyl-sulfide (1.5mmol), in 25 ℃ 24 hours.Extraction and chromatography obtain 2-(3-benzo [c] furanonyl) ethanol, are faint yellow oily thing: Rf=0.25,50%EtOAc-hexane.

Embodiment 23.

5-methyl-4-methylol-2-oxo-1, the preparation of 3-dioxole

With 4,5-dimethyl-2-oxo-1, the dioxane solution reflux of 3-dioxole (1mmol) and tin anhydride (2.5mmol) 1 hour.Evaporation, extraction and chromatography obtain 5-methyl-4-methylol-2-oxo-1, and the 3-dioxole is yellow oil: TLC:Rf=0.5,5% methyl alcohol-methylene dichloride.

In 25 ℃, handle 5-methyl-4-methylol-2-oxo-1, the DMF solution of 3-dioxole (1mmol) 24 hours with tertiary butyl dimethylsilane (1.2mmol) and imidazoles (2.2mmol).Extracting also, chromatography obtains 5-methyl-4-t-butyldimethylsilyloxy ylmethyl-2-oxo-1,3-dioxole.

With 5-methyl-4-t-butyldimethylsilyloxy ylmethyl-2-oxo-1, the toluene solution of 3-dioxole (1mmol) and Lawesson ' s reagent (1.2mmol) be heated to 120 ℃ 12 hours.Extracting also, chromatography obtains 5-methyl-4-t-butyldimethylsilyloxy ylmethyl-2-sulfo--1,3-dioxole.

In 0 ℃, with 5-methyl 4-t-butyldimethylsilyloxy ylmethyl-2-sulfo--1, the methyl alcohol system hydrogen chloride solution of 3-dioxole stirred 1 hour, stirred 12 hours in 25 ℃, extracting also, chromatography obtains 5-methyl-4-methylol-2-sulfo--1,3-dioxole.

Embodiment 24.

The preparation of hydroxyethyl disulfide group (disulfidyl) ethylphosphonic acid diester

With 2-methyl-5-isobutyl--4-[2-(5-phosphono) furyl] the suspension returning heating of thiazole (1mmol) in thionyl chloride (5ml) 4 hours.The refrigerative reaction mixture is evaporated to dried, handles the yellow residue that generates with the dichloromethane solution of 2-hydroxyethyl disulphide (4mmol), pyridine (2.5ml).In 25 ℃ stir 4 hours after; chromatography obtains two kinds of compounds to reactant through extracting also: two (the 6 '-hydroxyls-3 ' of 2-methyl-5-isobutyl--4-{2-[5-; 4 '-disulphide) hexyl phosphono] furyl } thiazole and 2-methyl-5-isobutyl--4-{2-[5-(3 ', 4 '-disulphide) encircle phosphono the ninth of the ten Heavenly Stems]-furyl } thiazole.

Embodiment 25.

3-[2-(5-phosphono) furyl] preparation of thiazole

Steps A. in 80 ℃, handle the ethanolic soln of 5-(2-isobutyl--3-N, N-dimethylamino) acryl-2-furans diethyl phosphonate (1mmol is according to the preparation of embodiment 17 steps A) with hydrazine (1.2mmol) and handled 12 hours.Evaporation and chromatography obtain 4-isobutyl--3-[2-(5-diethyl phosphonyl) furyl] pyrazoles.

Step B. makes 4-isobutyl--3-[2-(5-diethyl phosphonyl) furyl] pyrazoles obtains 4-isobutyl--3-[2-(5-phosphono) furyl through embodiment 3 step C] pyrazoles (25.1).mp?210-215℃。C ₁₁H ₁₅N ₂O ₄The analytical calculation value of P: C:48.89; H:5.60; N:10.37.Measured value: C:48.67; H:5.55; N:10.20.

Step C. makes 4-isobutyl--3-[2-(5-diethyl phosphonyl) furyl] pyrazoles obtains 1-methyl-4-isobutyl--3-[2-(5-diethyl phosphonyl) furyl through embodiment 11 steps A] pyrazoles.

Step D. makes 1-methyl-4-isobutyl--3-[2-(5-diethyl phosphonyl) furyl] pyrazoles obtains 1-methyl-4-isobutyl--3-[2-(5-phosphono) furyl through embodiment 3 step C] pyrazoles (25.2).C ₁₂H ₁₇N ₂O ₄P+0.85HBr+0.75H ₂The analytical calculation value of O: C:39.32; H:5.32; N:7.64.Measured value: C:39.59; H:5.30; N:7.47.

Embodiment 26.

The preparation of 3-[2-(5-phosphono) furyl] isoxazole

Steps A. in 25 ℃, the ethanolic soln of usefulness azanol (1.1mmol) and sodium acetate (2.2mmol) processing 5-diethyl phosphonyl-2-furfural (1mmol) 12 hours.Extracting also, chromatography obtains 5-diethyl phosphonyl-furfural oxime.

Step B. is in 25 ℃, handles the DMF solution 12 hours of 5-diethyl phosphonyl-furfural oxime (1mmol) with N-chlorosuccinimide (1.1mmol).Extraction obtains 5-diethyl phosphonyl-2-chloro oximido furans.

Step C. is in 25 ℃, handles the diethyl ether solution 12 hours of 5-diethyl phosphonyl-2-chloro oximido furans (1mmol) and ethyl propionate (5mmol) with triethylamine (2mmol).Extracting also, chromatography obtains 5-ethoxy carbonyl-3-[2-(5-diethyl phosphonyl) furyl] isoxazole.

Step D. makes 5-ethoxy carbonyl-3-[2-(5-diethyl phosphonyl) furyl] isoxazole through embodiment 9 steps A, then obtains 5-formamyl-3-[2-(5-phosphono) furyl] isoxazole (26.1) through embodiment 3 step C.mp?221-225℃。C ₈H ₇N ₂O ₆The analytical calculation value of P+0.25EtOH: C:37.86; H:3.18; N:10.39.Measured value: C:37.90; H:3.02; N:10.05.

Prepare following compounds according to this method:

(26.2) 5-ethoxy carbonyl-4-methyl-3-[2-(5-phosphono) furyl] isoxazole.mp?150-152℃。C ₁₁H ₁₂NO ₇P+0.25H ₂The analytical calculation value of O+0.15HBr: C:41.57; H:4.01; N:4.41.Measured value: C:41.57; H:4.20; N:4.54.

Two (ethoxy carbonyl)-3-[2-(5-phosphono) the furyl] isoxazoles of (26.3) 4,5-.C ¹³H ₁₄NO ⁹The analytical calculation value of P: C:43.47; H:3.93; N:3.90.Measured value: C:43.26; H:3.92; N:3.97.

(26.4) 5-amino-4-ethoxy carbonyl-3-[2-(5-phosphono) furyl] isoxazole.190 ℃ of mp (decomposition).C ₁₀H ₁₁N ₂O ₇The analytical calculation value of P+0.25HBr: C:37.25; H:3.52; N:8.69.Measured value: C:37.56; H:3.50; N:8.85.

Two (formamyl)-3-[2-(5-phosphono) the furyl] isoxazoles of (26.5) 4,5-.mp＞250℃。C ₉H ₈N ₃O ₇The analytical calculation value of P: C:35.90; H:2.68; N:13.95.Measured value: C:35.67; H:2.55; N:13.62.

(26.6) 4-ethoxy carbonyl-5-trifluoromethyl-3-[2-(5-phosphono) furyl] isoxazole.C ₁₁H ₉F ₃NO ₇The analytical calculation value of P+0.25HBr: C:35.20; H:2.48; N:3.73.Measured value: C:35.25; H:2.34; N:3.98.

(26.7) 5-amino-4-(2-furyl)-3-[2-(5-phosphono) furyl] isoxazole.mp＞220℃。C ₁₂H ₉N ₂O ₇The analytical calculation value of P+0.1AcOEt: C:44.73; H:2.97; N:8.41.Measured value: C:45.10; H:2.58; N:8.73.

(26.8) 4-amino-5-cyano-3-[2-(5-phosphono) furyl] isoxazole.C ₈H ₈N ₃O ₅P+0.1H ₂The analytical calculation value of O+0.2HBr: C:35.18; H:2.36; N:15.39.Measured value: C:35.34; H:2.50; N:15.08.

(26.9) 4-cyano group-5-phenyl-3-[2-(5-phosphono) furyl] isoxazole.C ₁₄H ₉N ₂O ₅The analytical calculation value of P+0.15HBr: C:51.21; H:2.81; N:8.53.Measured value: C:51.24; H:3.09; N:8.33.

Embodiment 27.

2-[2-(5-phosphono) furyl] preparation of thiazole

Steps A. make 5-tributyl stannyl-2-furans phosphonic acid diester and 2-bromo-4-ethoxy carbonyl thiazole obtain 4-ethoxy carbonyl-2-[2-(5-diethyl phosphonyl) furyl through embodiment 6 steps A] thiazole.

Step B. makes 4-ethoxy carbonyl-2-[2-(5-diethyl phosphonyl) furyl] thiazole is through embodiment 9 steps A, then obtains 4-formamyl-2-[2-(5-phosphono) furyl through embodiment 3 step C] thiazole (27.1).mp?239-240℃。C ₈H ₇N ₂O ₅PS+0.2H ₂The analytical calculation value of O: C:34.59; H:2.68; N:10.08.Measured value: C:34.65; H:2.69; N:9.84.

Embodiment 28.

The preparation of 4-(3,3-two fluoro-3-phosphino--1-propyl group) thiazole

Steps A. in 0 ℃, with the powder molecular sieve (4A, 0.5 equivalent, wt/wt) and methylene dichloride (7ml) solution of pyridinium chlorochromate (1.5mmol) processing 3-(tertiary butyl-phenylbenzene siloxy-)-1-propyl alcohol (1mmol).The mixture that stirring obtains under room temperature 2 hours, with ether (7ml) dilution, restir is 30 minutes under room temperature.Filtration, evaporation and chromatography obtain 3-(tert-butyl diphenyl siloxy-)-1-propyl alcohol, are clarification oily matter.

Step B. was in-78 ℃, with the THF solution of the solution-treated LDA (1.06mmol) of difluoro methylphosphonic acid diethyl ester (1mmol) 45 minutes.Use this reactant of THF solution-treated of 3-(tert-butyl diphenyl siloxy-)-1-propyl alcohol (1.07mmol) then, in other 4 hours of-78 ℃ of solution that stir to generate.With this reactant of chloro bamic acid phenyl ester (2.14mmol) quencher, extraction and this reaction mixture of chromatography obtain 4-(tert-butyl diphenyl siloxy-)-3-phenoxy group thiocarbonyl oxygen base-2, and 2-difluoro butyl phosphine diethyl phthalate is a clarification oily matter.

Step C. handles 4-(tert-butyl diphenyl siloxy-)-3-phenoxy group thiocarbonyl oxygen base-2 with hydrogenation three-normal-butyl tin (1.5mmol) and AIBN (0.1mmol), toluene (1ml) solution of 2-difluoro butyl phosphine diethyl phthalate (1mmol) is heated to backflow 2 hours with the compound of reaction that obtains.Evaporation and chromatography obtain 4-(tert-butyl diphenyl siloxy-)-2, and 2-difluoro butyl phosphine diethyl phthalate is clarification oily matter.

Step D. is in 0 ℃, and (4N 4mmol) handles 4-(tert-butyl diphenyl siloxy-)-2, methyl alcohol (1mmol) solution of 2-difluoro butyl phosphine diethyl phthalate (1mmol), the reactant that stirring obtains under room temperature 2 hours with hydrochloric acid.Evaporation and chromatography obtain 4-hydroxyl-2, and 2-difluoro butyl phosphine diethyl phthalate is clarification oily matter.

Step e. in 0 ℃, use Jones ' s reagent (10mmol) to handle 4-hydroxyl-2, acetone (10ml) solution of 2-difluoro butyl phosphine diethyl phthalate (1mmol) 30 minutes.With this reactant of 2-propyl alcohol (10ml) quencher, filter the mixture that obtains by Celite pad.Evaporated filtrate then extracts and obtains 3-carboxyl-2, and 3-difluoro propyl phosphonous acid diethyl ester is oily matter.

Step F. with 3-carboxyl-2, thionyl chloride (3ml) solution of 3-difluoro propyl phosphonous acid diethyl ester (1mmol) is heated to and refluxed 2 hours.This reactant is evaporated to dried, residue is dissolved in the ether (1ml), in 0 ℃, with the ether system solution-treated of diazomethane (10mmol) 30 minutes.With the acetic acid solution of HBr (30%, 1ml) join in this reactant, under room temperature, stirred the solution that obtains 1 hour.This reactant is evaporated to dried, make residue be dissolved in THF-EtOH (1: 1,5ml), handle with thiocarbamide (1mmol).With the reaction mixture that obtains be heated to 75 ℃ 1 hour.Evaporation is then extracted and chromatography obtains solid 2-amino-4-[1-(3-diethyl phosphonyl-3,3-difluoro) propyl group] thiazole, it is obtained solid 2-amino-4-[1-(3-phosphono-3,3-difluoro) propyl group through embodiment 3 step C] thiazole.C ₆H ₉N ₂O ₃PSF ₂The analytical calculation value of+HBr: C:21.25; H:2.97; N:8.26.Measured value: C:21.24; H:3.25; N:8.21.

Prepare following compounds in a similar fashion:

2-amino-5-methylthio group-4-[1-(3-phosphono-3,3-difluoro) propyl group] thiazole (28.2).MS?m/e305(M+H)。

Embodiment 29.

2-methylthio group-5-phosphono methylthio group-1,3, the preparation of 4-thiadiazoles and 2-phosphono methylthio group pyridine

Steps A. in 0 ℃, the usefulness sodium hydride (60%, 1.1mmol) handle 2-methylthio group-1,3, THF (5ml) solution of 4-thiadiazoles-5-mercaptan (1mmol), the mixture that stirring obtains under room temperature 30 minutes.Then reactant being cooled to 0 ℃ also handles with diethyl phosphonyl methyl trifluoro methanesulfonates (1.1mmol).After stirring 12 hours under the room temperature, with this reactant of saturated ammonium chloride quencher.Extracting also, chromatography obtains buttery 2-methylthio group-5-diethyl phosphonyl methylthio group-1,3,4-thiadiazoles.

Step B. makes 2-methylthio group-5-diethyl phosphonyl methylthio group-1,3, and the 4-thiadiazoles obtains 2-methylthio group-5-phosphono methylthio group-1,3 through embodiment 3 step C, and 4-thiadiazoles (29.1) is yellow solid.C ₄H ₇N ₂O ₃PS ₃The analytical calculation value of+0.2HBr: C:17.50; H:2.64; N:10.21.Measured value: C:17.64; H:2.56; N:10.00.

Perhaps, adopt in the following method the heteroaromatics that (as the example that synthesizes with 2-phosphono methylthio group pyridine) preparation phosphono methylthio group replaces:

Steps A. in 0 ℃, handle 2, the THF solution of 2 '-pyridyl disulfide (1mmol) with three-normal-butyl phosphine (1mmol) and hydroxymethyl phosphonic acid diethyl ester.The reactant solution that stirring obtains under room temperature 18 hours.Extraction and chromatography obtain the 2-diethyl phosphonyl methylthio group pyridine of yellow oily.

Step D. makes 2-diethyl phosphonyl methylthio group pyridine obtain 2-phosphono methylthio group pyridine (29.2) through embodiment 3 step C, is yellow solid.C ₆H ₈NO ₃The analytical calculation value of PS+0.62HBr: C:28.22; H:3.40; N:5.49.Measured value: C:28.48; H:3.75; N:5.14.

Embodiment 30.

The 2-[(2-phosphono) ethynyl] preparation of pyridine

Steps A. in 0 ℃, THF (5ml) solution of usefulness LDA (1.2mmol) processing 2-ethynyl pyridine (1mmol) 40 minutes.Chloro diethyl phosphoric acid (1.2mmol) is added in this reactant the reactant solution that stirring obtains under room temperature 16 hours.Should react with the saturated ammonium chloride quencher, then extraction and chromatography obtain the 2-[(2-diethyl phosphonyl of yellow oily) ethynyl] pyridine.

Step B. makes the 2-[(2-diethyl phosphonyl) ethynyl] pyridine obtains 2-[1-(2-phosphono) ethynyl through embodiment 3 step C] pyridine (30.1), be brown solid.160 ℃ of Mp (decomposition).MS?m/e?184(M+H)。

Embodiment 31.

A. as the preparation of the various phosphamides of prodrug

Steps A. with 2-methyl-5-sec.-propyl-4-[2-(5-phosphono) furyl] thiazole dichloride (as generation as described in the embodiment 19) methylene dichloride (5ml) solution (1mmol) is cooled to 0 ℃ and with the methylene dichloride (0.5ml) of benzylalcohol (0.9mmol) and the solution-treated of pyridine (0.3ml).In 0 ℃ of reaction soln that stir to generate 1 hour, add the THF solution of ammonia (excessive) then.After stirring 16 hours under the room temperature; this reactant is evaporated to dried, residue obtains 2-methyl-5-sec.-propyl-4-[2-(5-phosphono monoamide base) furyl into hard yellow jelly through chromatography purification] thiazole (31.1) and be 2-methyl-5-sec.-propyl-4-[2-(5-phosphono diamide base) furyl of hard yellow jelly] thiazole (31.2).

(31.1) 2-methyl-5-sec.-propyl-4-[2-(5-phosphono monoamide base) furyl] thiazole: MS m/e299 (M-H).

(31.2) 2-methyl-5-sec.-propyl-4-[2-(5-phosphono diamide base) furyl] thiazole: MS m/e298 (M-H).

Perhaps, adopt a kind of diverse ways to be prepared as follows other phosphamide that step is enumerated:

Step B. is with 2-amino-5-methylthio group-4-[2-(5-phosphono) furyl] aaerosol solution of thiazole dichloride (as generation as described in the embodiment 19) methylene dichloride (5ml) (1mmol) is cooled to 0 ℃ and fed this reaction solution 10 minutes with ammonia (excessive) bubbling.After stirring 16 hours under the room temperature, this reactant is evaporated to dried, residue obtains foamed 2-amino-5-methylthio group-4-[2-(5-phosphono diamide base) furyl through chromatography purification] thiazole (31.3).C ₈H ₁₁N ₄O ₂PS ₂The analytical calculation value of+1.5HCl+0.2EtOH: C:28.48; H:3.90; N:15.82.Measured value: C:28.32; H:3.76; N:14.21.

Prepare following compounds according to aforesaid method or under some situation that these methods are made an amendment slightly:

(31.4) 2-amino-5-isobutyl--4-[2-(5-phosphono monoamide base) furyl] thiazole.Mp?77-81℃。C ₁₁H ₁₆N ₃O ₃PS+H ₂O+0.8Et ₃The analytical calculation value of N: C:47.41; H:7.55; N:13.30.Measured value: C:47.04; H:7.55; N:13.67.

(31.5) 2-amino-5-isobutyl--4-[2-(5-idol phosphorus diamide base (phosphoroadiamido)) furyl] thiazole.C ₁₁H ₁₇N ₄O ₂PS+0.5H ₂The analytical calculation value of O+0.75HCl: C:39.24; H:5.61; N:16.64.Measured value: C:39.05; H:5.43; N:15.82.

(31.28) the even phosphorus diamide base of 2-amino-5-isobutyl--4-{2-[5-(N, N '-diisobutyl)] furyl }-thiazole.Mp?182-183℃。C ₁₉H ₃₃N ₄O ₂The analytical calculation value of PS: C:55.32; H:8.06; N:13.58.Measured value: C:54.93; H:7.75; N:13.20.

(31.29) 2-amino-5-isobutyl--4-{2-[5-(N, N '-(1, two (the ethoxy carbonyl)-1-propyl group of 3-) even phosphorus) diamide base] furyl } thiazole.C ₂₉H ₄₅N ₄O ₁₀The analytical calculation value of PS: C:51.78; H:6.74; N:8.33.Measured value: C:51.70; H:6.64; N:8.15.

(31.30) the even phosphorus diamide base of 2-amino-5-isobutyl--4-{2-[5-(N, N '-(1-benzyloxycarbonyl)-1-ethyl)] furyl } thiazole.C ₃₁H ₃₇N ₄O ₆The analytical calculation value of PS: C:59.60; H:5.97; N:8.97.Measured value: C:59.27; H:5.63; N:8.74.

(31.31) two (2-methoxycarbonyl-1-azacyclopropane base) even phosphorus diamide bases of 2-amino-5-isobutyl--4-{2-[5-] furyl } thiazole.C ₁₉H ₂₅N ₄O ₆PS+0.3CH ₂Cl ₂The analytical calculation value: C:46.93; H:5.22; N:11.34.Measured value: C:58.20; H:5.26; N:9.25.

(31.39) the even phosphorus diamide base of 2-amino-5-isobutyl--4-{2-[5-(N, N '-2-(1-ethoxy carbonyl) propyl group)] furyl } thiazole.C ₂₃H ₃₇N ₄O ₆PS+0.6EtOAc+0.1CH ₂Cl ₂The analytical calculation value: C:51.91; H:7.18; N:9.50.Measured value: C:51.78; H:7.17; N:9.26.

But a phenyl-phosphonic amide derivative according to aforesaid method also preparation formula I:

Step C. under room temperature, with lithium hydroxide (1N 1.5mmol) handles 2-amino-5-isobutyl--4-[2-(5-diphenylphosphine acyl group) furyl] thiazole (according to the method preparation of embodiment 19) acetonitrile (9ml) and water (4ml) solution 4 hours (1mmol).This reaction soln is evaporated to dried, makes in the residue water-soluble (10ml), be cooled to 0 ℃, the pH of this solution is transferred to 4 by adding 6N HCl.Filter the white solid of collecting generation and obtain 2-amino-5-isobutyl--4-[2-(5-Phenylphosphine acyl group) furyl] thiazole (19.64).

Step D. is with 2-amino-5-isobutyl--4-[2-(5-Phenylphosphine acyl group) furyl] suspension of thiazole (1mmol) in thionyl chloride (3ml) is heated to and refluxed 2 hours.This reaction soln is evaporated to dried, residue is dissolved in the anhydrous methylene chloride (2ml), the solution that generates is joined in the pyridine (0.8ml) and methylene dichloride (3ml) solution of L-alanine methyl ester hydrochloride (1.2mmol) in 0 ℃.The reaction soln that stirring obtains under room temperature 14 hours.Evaporation and chromatography obtain 2-amino-5-isobutyl--4-{2-[5-(O-phenyl-N-(1-methoxycarbonyl) ethyl) phosphono amido] furyl } thiazole (31.6), be oily matter.C ₂₁H ₂₆N ₃O ₅The analytical calculation value of PS: C:54.42; H:5.65; N:9.07.Measured value: C:54.40; H:6.02; N:8.87.

According to the method for preparing following compounds:

(31.7) 2-amino-5-isobutyl--4-{2-[5-(O-phenyl phosphonic amido (phosphonamido))] furyl } thiazole.205 ℃ of mp (decomposition).C ₁₇H ₂₀N ₃O ₃PS+0.3H ₂The analytical calculation value of O+0.3HCl: C:51.86; H:5.35; N:10.67.Measured value: C:51.58; H:4.93; N:11.08.

(31.8) 2-amino-5-isobutyl--4-{2-[5-(O-phenyl-N-ethoxy carbonyl methyl) phosphono amido] furyl } thiazole.C ₂₁H ₂₆N ₃O ₅The analytical calculation value of PS: C:54.42; H:5.65; N:9.07.Measured value: C:54.78; H:5.83; N:8.67.

(31.9) 2-amino-5-isobutyl--4-{2-[5-(O-phenyl-N-isobutyl-) phosphono amido] furyl } thiazole.mp?151-152℃。C ₂₁H ₂₈N ₃O ₃The analytical calculation value of PS: C:58.18; H:6.51; N:9.69.Measured value: C:58.12; H:6.54; N:9.59.

(31.18) 2-amino-5-isobutyl--4-{2-[5-(O-phenyl-N-(1-(1-ethoxy carbonyl-2-phenyl) ethyl) phosphono amido)] furyl } thiazole.C ₂₈H ₃2N ₃O ₅The analytical calculation value of PS: C:60.75; H:5.83; N:7.59.Measured value: C:60.35; H:5.77; N:7.37.

(31.19) 2-amino-5-isobutyl--4-{2-[5-(O-phenyl-N-(1-(1-ethoxy carbonyl-2-methyl) propyl group) phosphono amido)] furyl } thiazole.C ₂₃H ₃₀N ₃O ₅The analytical calculation value of PS: C:56.20; H:6.15; N:8.55.Measured value: C:55.95; H:5.80; N:8.35.

(31.20) 2-amino-5-isobutyl--4-{2-[5-(O-phenyl-N-(1-(1,3-two (ethoxy carbonyl) propyl group) phosphono amido)] furyl thiazole.C ₂₆H ₃₄N ₃O ₇PS+0.2CH ₂Cl ₂The analytical calculation value: C:54.20; H:5.97; N:7.24.Measured value: C:54.06; H:5.68; N:7.05.

(31.21) furyl 2-amino-5-isobutyl--4-{2-[5-(O-(3-chlorophenyl)-N-(1-(1-methoxycarbonyl) ethyl) propyl group) phosphono amido)] } thiazole.C ₂₁H ₂₅N ₃O ₅The analytical calculation value of PSCl: C:50.65; H:5.06; N:8.44.Measured value: C:50.56; H:4.78; N:8.56.

(31.22) 2-amino-5-isobutyl--4-{2-[5-(O-(4-chlorophenyl)-N-(1-(1-methoxycarbonyl) ethyl) phosphono amido)] furyl } thiazole.C ₂₁H ₂₅N ₃O ₅PSCl+1HCl+0.2H ₂The analytical calculation value of O: C:46.88; H:4.95; N:7.81.Measured value: C:47.33; H:4.71; N:7.36.

(31.23) 2-amino-5-isobutyl-4-{2-[5-(O-phenyl-N-(1-(1-two (ethoxy carbonyl) methyl) phosphono amido)] furyl } thiazole.C ₂₄H ₃₀N ₃O ₇The analytical calculation value of PS: C:53.83; H:5.65; N:7.85.Measured value: C:53.54; H:5.63; N:7.77.

(31.24) 2-amino-5-isobutyl--4-{2-[5-(O-phenyl-N-(1-morpholinyl) phosphono amido)] furyl } thiazole.C ₂₁H ₂₆N ₃O ₄The analytical calculation value of PS: C:56.37; H:5.86; N:9.39.Measured value: C:56.36; H:5.80; N:9.20.

(31.25) 2-amino-5-isobutyl--4-{2-[5-(O-phenyl-N-(1-(1-benzyloxycarbonyl) ethyl) phosphono amido)] furyl } thiazole.C ₂₇H ₃₀N ₃O ₅The analytical calculation value of PS: C:60.10; H:5.60; N:7.79.Measured value: C:59.80; H:5.23; N:7.53.

(31.32) 2-amino-5-isobutyl--4-{2-[5-(O-phenyl-N-benzyloxycarbonyl methyl) phosphono amido] furyl } thiazole.C ₂₆H ₂₈N ₃O ₅The analytical calculation value of PS: C:59.42; H:5.37; N:8.00.Measured value: C:59.60; H:5.05; N:7.91.

(31.36) 2-amino-5-isobutyl--4-{2-[5-(O-(4-p-methoxy-phenyl)-N-(1-(1-methoxycarbonyl) ethyl) phosphono amido)] furyl } thiazole.C ₂₂H ₂₈N ₃O ₆PS+0.1CHCl ₃The analytical calculation value of+0.1MeCN: C:52.56; H:5.62; N:8.52.Measured value: C:52.77; H:5.23; N:8.87.

(31.37) phosphono amido 2-amino-5-isobutyl--4-{2-[5-(O-phenyl-N-2-methoxycarbonyl) propyl group)] furyl } thiazole.C ₂₂H ₂₈N ₃O ₅PS+0.6H ₂The analytical calculation value of O: C:54.11; H:6.03; N:8.60.Measured value: C:53.86; H:5.97; N:8.61.

(31.38) 2-amino-5-isobutyl--4-{2-[5-(O-phenyl-N-(2-(1-ethoxy carbonyl) propyl group) phosphono amido)] furyl } thiazole.C ₂₃H ₃₀N ₃O ₅The analytical calculation value of PS: C:56.20; H:6.15; N:8.55.Measured value: C:55.90; H:6.29; N:8.46.

The reaction in the presence of suitable alkali (as pyridine, triethylamine) of dichloro phosphonic acid ester and 1-amino-3-propyl alcohol also can be used for preparing the cyclic amino phosphoric acid ester as the prodrug phosphonic acid ester.Prepare following compounds by this way:

(31.10) 2-methyl-5-isobutyl--4-{2-[5-(1-phenyl-1,3-propyl group) phosphono amido] furyl } thiazole (less important isomer).C ₂₁H ₂₅N ₂O ₃PS+0.25H ₂The analytical calculation value of O+0.1HCl: C:59.40; H:6.08; N:6.60.Measured value: C:59.42; H:5.72; N:6.44.

(31.11) 2-methyl-5-isobutyl--4-{2-[5-(1-phenyl-1,3-propyl group) phosphono amido] furyl } thiazole (main isomer).C ₂₁H ₂₅N ₂O ₃PS+0.25H ₂The analytical calculation value of O: C:59.91; H:6.11; N:6.65.Measured value: C:60.17; H:5.81; N:6.52.

(31.12) 2-amino-5-isobutyl--4-{2-[5-(1-phenyl-1,3-propyl group) phosphono amido] furyl } thiazole (main isomer).C ₂₀H ₂₄N ₃O ₃PS+0.25H ₂O+0.1CH ₂Cl ₂The analytical calculation value: C:55.27; H:5.27; N:9.57.Measured value: C:55.03; H:5.42; N:9.37.

(31.13) 2-amino-5-isobutyl--4-{2-[5-(1-phenyl-1,3-propyl group) phosphono amido] furyl } thiazole (less important isomer).C ₂₀H ₂₄N ₃O ₃PS+0.15CH ₂Cl ₂The analytical calculation value: C:56.26; H:5.69; N:9.77.Measured value: C:56.36; H:5.46; N:9.59.

(31.14) 2-amino-5-methylthio group-4-{2-[5-(1-phenyl-1,3-propyl group) phosphono amido] furyl } thiazole (less polar isomer).C ₁₇H ₁₈N ₃O ₃PS ₂The analytical calculation value of+0.4HCl: C:48.38; H:4.39; N:9.96.Measured value: C:48.47; H:4.21; N:9.96.

(31.15) 2-amino-5-methylthio group-4-{2-[5-(1-phenyl-1,3-propyl group) phosphono amido] furyl } thiazole (than the isomer of high polarity).C ₁₇H ₁₈N ₃O ₃PS ₂The analytical calculation value: C:50.11; H:4.45; N:10.31.Measured value: C:49.84; H:4.19; N:10.13.

(31.16) 2-amino-5-methylthio group-4-{2-[5-(N-methyl isophthalic acid-phenyl-1,3-propyl group) phosphono amido] furyl } thiazole.C ₁₈H ₂₀N ₃O ₃PS ₂The analytical calculation value of+0.25HCl: C:50.21; H:4.74; N:9.76.Measured value: C:50.31; H:4.46; N:9.79.

(31.17) 2-amino-5-methylthio group-4-{2-[5-(1-phenyl-1,3-propyl group)-N-ethanoyl phosphono amido] furyl] thiazole.C ₂₂H ₂₆N ₃O ₄PS+1.25H ₂The analytical calculation value of O: C:54.82; H:5.96; N:8.72.Measured value: C:55.09; H:5.99; N:8.39.

(31.26) 2-amino-5-isobutyl--4-{2-[5-(1-oxo-1-phospha-2-oxa--7-azepine-3,4-benzo (beno) ring heptan-1-yl)] furyl } thiazole (main isomer).Mp?233-234℃。C ₂₁H ₂₄N ₃O ₅PS+0.2CHCl ₃The analytical calculation value: C:52.46; H:5.03; N:8.66.Measured value: C:52.08; H:4.65; N:8.58.

(31.27) 2-amino-5-isobutyl--4-{2-[5-(1-oxo-1-phospha-2-oxa--7-azepine-3,4-benzo (beno) ring heptan-1-yl)] furyl } thiazole (less important isomer).C ₂₁H ₂₄N ₃O ₅The MS calculated value of PS+H: 462, measured value: 462.

(31.34) 2-amino-5-isobutyl--4-{2-[5-(3-(3, the 5-dichlorophenyl)-1,3-propyl group) phosphono amido] furyl } thiazole.C ₂₀H ₂₂N ₃O ₃PSCl ₂The analytical calculation value: C:49.39; H:4.56; N:8.64.Measured value: C:49.04; H:4.51; N:8.37.

(31.35) 2-amino-5-isobutyl--4-{2-[5-(4,5-phendioxin-oxo-1-phospha-2-oxa--6-azepine) hexamethylene-1-yl] furyl } thiazole.C ₁₈H ₂₀N ₃O ₃PS+0.7H ₂The analytical calculation value of O: C:53.78; H:5.37; N:10.45.Measured value: C:53.63; H:5.13; N:10.36.

Embodiment 32

5-[2-(5-phosphono) furyl] preparation of tetrazolium

Steps A. in the mixture of 1ml DMF, add benzyl chloride for methyl ether (1.2mmol) to the tetrazolium (1mmol) and the pulverous salt of wormwood (1.5mmol) that are cooled to 0 ℃,, under room temperature, stirred 16 hours then in 0 ℃ of mixture that stir to generate 30 minutes.Water and ether dilute this mixture.Extraction and chromatography obtain 2-benzyloxymethyl tetrazolium, are colorless oil.

Step B. is in-78 ℃, adds the hexane solution (1mmol) of n-Butyl Lithium in the 3ml diethyl ether solution to 2-benzyloxymethyl tetrazolium (1mmol) and TMEDA (2mmol).It was stirred 5 minutes in-78 ℃, then it is joined (n-Bu) in the 2ml ether ₃In pre-cooled (78 ℃) solution of SnCl (1mmol).After 30 minutes, water and ether dilute it in-78 ℃ of stirrings.Extraction and chromatography obtain 2-benzyloxymethyl-5-(tributyl stannyl) tetrazolium, are colorless oil.

Step C. with 5-iodo-2-diethyl phosphonyl furans (1mmol), 2-benzyloxymethyl-5-(tributyl stannyl) tetrazolium (1.05mmol), four (triphenyl phosphine) palladium (O) (0.03mmol) and cuprous iodide (I) (0.07mmol) mixture in 3ml toluene refluxed 20 hours in 110 ℃.Evaporation and chromatography obtain buttery 2-benzyloxymethyl-5-[2-(5-diethyl phosphonyl) furyl] tetrazolium.

Step D. in 70 ℃-with 2-benzyloxymethyl-5-[2-(5-diethyl phosphonyl) furyl] tetrazolium (1mmol) and 6M HCl (1ml) the mixing solutions heating in 10ml ethanol 20 hours; evaporation concentration solvent then; make with 1N sodium hydroxide to be alkalescence, and use ethyl acetate extraction.Make water layer be acid and use ethyl acetate extraction.Evaporation of acetic acid ethyl ester extract obtains solid 5-[2-(5-diethyl phosphonyl) furyl] tetrazolium, its step C through embodiment 3 is obtained 5-[2-(5-phosphono) furyl] tetrazolium (32.1).mp?186-188℃。C ₅H ₅N ₄O ₄P+1.5H ₂The analytical calculation value of O: C:24.70; H:3.32; N:23.05.Measured value: C:24.57; H:2.57; N:23.05.

Step e.

Step 1. is in 80 ℃; with 5-[2-(5-diethyl phosphonyl) furyl] tetrazolium (1mmol), 1-iodo-2-methylpropane (2mmol) and the mixture of pulverous salt of wormwood (2mmol) in 5mlDMF stirred 48 hours; with methylene dichloride and water dilution, separate each layer then.The evaporation dichloromethane layer also merges with the subsequent reaction product that is used for chromatography.

Step 2. makes the water layer steaming of step 1 be acid and use ethyl acetate extraction.Evaporate this extract, in 80 ℃ through this residue at 2ml SOCl ₂Middle heating 3 hours, evaporating solvent then.Residue is dissolved in the 5ml methylene dichloride, adds 0.3ml triethylamine and 0.5ml ethanol.In stirring this mixture under the room temperature after 1 hour, with methylene dichloride and water dilution.The organic extraction of this organic extraction and step 1 is merged, and chromatography obtains 1-isobutyl--5-[2-(5-diethyl phosphonyl) furyl] tetrazolium and 2-isobutyl--5-[2-(5-diethyl phosphonyl) furyl] tetrazolium, be oily matter.

Step 3. makes 1-isobutyl--5-[2-(5-diethyl phosphonyl) furyl] tetrazolium obtains solid 1-isobutyl--5-[2-(5-phosphono) furyl through the step C of embodiment 3] tetrazolium (32.2).mp200-202℃。C ₉H ₁₃N ₄O ₄The analytical calculation value of P: C:39.71; H:4.81; N:20.58.Measured value: C:39.64; H:4.63; N:20.21.

Step F. under room temperature, with 2-isobutyl--5-[2-(5-diethyl phosphonyl) furyl] tetrazolium (1mmol) and TMSBr (10mmol) mixture in the 10ml methylene dichloride stirred 16 hours.Evaporating solvent makes residue be dissolved in 10: 1 acetonitriles: in the water, and evaporating solvent; by adding dicyclohexylamine (2mmol) residue is precipitated from acetone; obtain 2-isobutyl--5-[2-(5-phosphono) furyl] tetrazolium N, N-dicyclohexyl ammonium salt (32.3) is solid.mp?226-228℃。C ₉H ₁₃N ₄O ₄P+C ₁₂H ₂₃The analytical calculation value of N: C:55.62; H:8.00; N:15.44.Measured value: C:55.55; H:8.03; N:15.07.

Embodiment 33.

The high yield of the heteroaromatics that various 2-(5-phosphono) furyl replaces is synthetic

Steps A. preparing the heteroaromatics that various 2-(5-diethyl phosphonyl) furyl replaces with method like the embodiment 15 step category-Bs, it is synthetic that some in these compounds are used for the high yield of the listed compound of table 33.1 and table 33.2.

Step B. under the room temperature with 2-chloro-6-[2-(5-diethyl phosphonyl) furyl] pyridine (0.01mmol) and TMSBr (0.1ml) mixture in methylene dichloride (0.5ml) stirred 16 hours, evaporate then and with 9: 1 acetonitriles of 0.5ml: water dilutes.Evaporation obtains 2-chloro-6-[2-(5-phosphono) furyl] pyridine.

Step C. is in 85 ℃, with 2-chloro-6-[2-(5-diethyl phosphonyl) furyl] (0.25M, mixture 0.4ml) left standstill 14 hours for pyridine (0.01mmol) and the solution of freshly prepared sodium propylate in propyl alcohol.Evaporate this reaction mixture, residue obtains 2-propoxy--6-[2-(5-phosphono) furyl through the step B of embodiment 33] pyridine.

Step D. is in 145 ℃, with 2-chloro-6-[2-(5-diethyl phosphonyl) furyl] pyridine (0.01mmol) and the mixture heating up of 1-methylpiperazine (0.2ml) in ethylene glycol (0.2ml) 24 hours.Further dilute this mixture with 0.5ml acetonitrile and 0.1ml water, add 150mgDowex 12-100 manthanoate resin then.Stir this mixture after 30 minutes, filter, with DMF (210min), acetonitrile (210min) and 9: 1 acetonitriles: water (110min) washs this resin successively.Use 9 at last: 1TFA: water stirred this resin 30 minutes, filtered and evaporated filtrate.The residue that obtains obtains 2-[1-(4-methyl) piperazinyl through the step B of embodiment]-6-[2-(5-phosphono) furyl] pyridine.

Step e. with 3-chloro-5-[2-(5-diethyl phosphonyl) furyl] pyrazine (0.01mmol), 5-tributyl stannyl thiophene (0.04mmol), Pd (PPh ₃) ₄(0.001mmol) and the mixture of cuprous iodide (0.002mmol) in dioxane (0.5ml) in 85 ℃ of heating 16 hours, evaporating solvent then.Residue that stir to produce under room temperature and the 0.5ml dichloromethane solution of TMSBr (0.1ml) 16 hours, evaporate then and with 9: 1 acetonitriles of 0.5ml: water dilutes.In this solution, add 150mg Dowex 12-100 manthanoate resin, stirs after 30 minutes, filtration, with DMF (210min), acetonitrile (210min) and 9: 1 acetonitriles: water (110min) washs this resin successively.Use 9 at last: 1TFA: water stirred this resin 30 minutes, filtered and evaporated filtrate.Obtain the 3-[2-thienyl)-5-[2-(5-phosphono) furyl] pyrazine.

Step F. with 3-chloro-5-[2-(5-diethyl phosphonyl) furyl] pyrazine (0.01mmol), 1-hexin (0.04mmol), diisopropylethylamine (0.1mm0l), Pd (PPh ₃) ₄(0.001mmol) and the mixture of cuprous iodide (0.002mmol) in dioxane (0.5ml) in 85 ℃ of heating 16 hours, evaporating solvent then.The residue that obtains obtains 3-(1-hexin-1-yl)-5-[2-(5-phosphono) furyl through step B] pyrazine.

The preparation of carboxymethyl phosphonate resins

Step G. refluxes toluene (25ml) solution of phosphine acyl acetic acid trimethyl (30.9mmol), 2-(trimethyl silyl) ethanol (10.4mmol) and DMAP (3.1mmol) 48 hours under nitrogen.After the cooling, dilute this solution and use 1N HCl and water elder generation after scouring with ethyl acetate.Through dried over mgso organic solution, vacuum concentration obtains oily matter.2-butanone solution (30ml) with LiI (10.4mmol) is handled this residue, spends the night in refluxed under nitrogen.Dilute this solution with ethyl acetate, with 1N HCl washing, through dried over sodium sulfate, concentrating under reduced pressure obtains the carboxyl monomethyl phosphonic acid ester of SEM protection, is colorless oil.

Step H. slowly vibrated 20 minutes by mixing with anhydrous THF (40ml), removed excessive solvent through conduit then and prepared the methylol polystyrene (2.35mmol) that is used for coupling.Repeat this method 3 times.The swollen resin is suspended among THF (40ml) and the DIPEA (21.2mmol) again.The carboxyl monomethyl phosphonic acid ester (in step G, preparing) that in this mixture, adds SEM protection by conduit (7.1mmol), THF (15ml) solution of DIAD (7.1mmol) and three (4-chlorophenyl) phosphine (7.1mmol), before the adding with its stirring 15 minutes.Under nitrogen covers, after this mixture shaken overnight, filter resin, with THF (3 * 40ml), DMF (3 * 40ml) and THF (3 * 40ml) wash successively, and vacuum-drying obtains the phosphonate resins of 3.8g coupling then.

Step I. adds the THF solution (12ml) of 1MTBAF in the phosphonate resins (2.41mmol) of the coupling in THF (100ml).With this mixture shaken overnight, filter then, (3 * 40ml) washing resins obtain required carboxymethyl phosphonate resins, are 4-butyl ammonium with THF.

The coupling of carboxymethyl phosphonate resins and heteroaromatic amine

Step J. mixes heteroaromatic amine (0.14mmol), resin (0.014mmol), PyBOP (0.14mmol) and TEA (0.36mmol) in the 2ml pond in DMF (1.45ml), jolting is 48 hours under room temperature.The resin crossed of filtration treatment washs with DMF (3 *) and methylene dichloride (3 *) then.Isolating resin is suspended in the methylene dichloride (900L), merged and mix 6 hours with TMSBr (100L).Filter this mixture, (500L) washs this resin with anhydrous methylene chloride, concentrated filtrate under the vacuum.In isolating residue, add acetonitrile/water (9: 1,300L) solution.After the jolting 30 minutes, removing desolvates obtains the heteroaromatic analogue that required [{ N-(phosphono) ethanoyl } amino] replaces.According to these method synthetic compound 33.97-33.119 and 33.146-33.164, these compounds are listed in table 33.1 and the table 33.2.

The preparation of aminomethylphosphonic acid ester resin

Step K. in 2-butanone (150ml) solution of Phthalimide ylmethyl dimethyl phosphonate (37mmol), add LiI (38.9mmol).After refluxed under nitrogen is spent the night, dilute this solution with ethyl acetate, with 1N HCl washing, obtain Phthalimide ylmethyl phosphonic acids one methyl esters through dried over mgso and concentrating under reduced pressure, be white solid.

Step L. makes Phthalimide ylmethyl phosphonic acids one methyl esters and the coupling of methylol polystyrene obtain Phthalimide ylmethyl phosphonic acids one methyl esters of resin-coupling as above described in the step H.

Step M. adds anhydrous hydrazine (3ml) in Phthalimide ylmethyl phosphonic acids one methyl esters (6.8mmol) of the resin coupling in DMF (7ml).In jolting under the room temperature after 24 hours, filter resin, with DMF (3 * 10ml), (3 * 10ml) washings, vacuum-drying obtains aminomethylphosphonic acid one methyl esters of the required resin-coupling of 832mg to methylene dichloride then.

The coupling of aminomethylphosphonic acid one methyl esters of various heteroaromatic carboxylic acids and resin-coupling

Step N. mixes heteroaromatic carboxylic acids (0.2mmol), resin (0.02mmol), EDC (0.2mmol) and HOBT (0.2mmol) in the 2ml pond in DMF (0.5ml), jolting is 24 hours under room temperature.The resin crossed of filtration treatment washs with DMF (3 *) and methylene dichloride (3 *) then.Make isolating resin resuspending in methylene dichloride (500L), merged and mix 6 hours with TMSBr (50L).Filter this mixture, (500L) washs this resin with anhydrous methylene chloride, concentrated filtrate under the vacuum.In isolating residue, add acetonitrile/water (9: 1,300L) solution.After the jolting 30 minutes, evaporating solvent obtains the heteroaromatic analogue that required (N-(phosphonomethyl)) formamyl replaces.According to these method synthetic compounds 33.120-33.145, these compounds are listed in the table 33.2.

According to part or all of method for preparing following compounds.These compounds identify that by HPLC (as described below) and mass spectrum (APC1 negative ion) characteristic is listed in table 33.1 and the table 33.2.

HPLC uses YMC ODS-Aq, Aq-303-5, and 2504.6mm ID, S-5 μ m, the 120A post is with the UV detector that is arranged at 280nm.

HPLC elution program: 1.5ml/min flow velocity

Time (min) % acetonitrile (A) % damping fluid ^* (B)

0????????????10??????????90

7.5??????????90??????????10

12.4?????????90??????????10

12.5?????????10??????????90

15???????????10??????????90

^*Damping fluid=95: 5: 0.1 water: methyl alcohol: acetate

Table 33.1

^*When A or B when not existing, so corresponding G is N.

Table 33.2

??33.45	Do not have	??CH3	Furans-2,5-two bases	??Me	??Cl	??9.25	??287
??33.45	Do not have	??CH3	Furans-2,5-two bases	??Me	??Cl	??9.25	??287	??33.46	??Br	??CH3	Furans-2,5-two bases	??H	Do not have	??5.62	??317/319
??33.47	??Br	??Br	Furans-2,5-two bases	??H	Do not have	??3.54	??38l/383/385	??33.46	??Br	??CH3	Furans-2,5-two bases	??H	Do not have	??5.62	??317/319
??33.47	??Br	??Br	Furans-2,5-two bases	??H	Do not have	??3.54	??38l/383/385	??33.48	??Br	??H	Furans-2,5-two bases	??Me	Do not have	??5.55	??317/319
??33.49	??H	??NH2	Furans-2,5-two bases	??Br	Do not have	??4.78	??318/320	??33.48	??Br	??H	Furans-2,5-two bases	??Me	Do not have	??5.55	??317/319
??33.49	??H	??NH2	Furans-2,5-two bases	??Br	Do not have	??4.78	??318/320	??33.50	??Br	??Cl	Furans-2,5-two bases	??Br	Do not have	??8.38	??417/419
??33.51	??SMe	??Ph	Furans-2,5-two bases	??Br	Do not have	??9.26	??425/427	??33.50	??Br	??Cl	Furans-2,5-two bases	??Br	Do not have	??8.38	??417/419
??33.51	??SMe	??Ph	Furans-2,5-two bases	??Br	Do not have	??9.26	??425/427	??33.52	??NH2	??H	Furans-2,5-two bases	??Br	Do not have	??4.87	??318/320
??33.53	??NH2	??H	Furans-2,5-two bases	??OH	Do not have	??3.70	??256	??33.52	??NH2	??H	Furans-2,5-two bases	??Br	Do not have	??4.87	??318/320
??33.53	??NH2	??H	Furans-2,5-two bases	??OH	Do not have	??3.70	??256	??33.54	??Br	??H	Furans-2,5-two bases	??Br	Do not have	??9.64	??381/383/385
??33.55	??Br	??H	Furans-2,5-two bases	??C1	Do not have	??9.64	??337/339	??33.54	??Br	??H	Furans-2,5-two bases	??Br	Do not have	??9.64	??381/383/385
??33.55	??Br	??H	Furans-2,5-two bases	??C1	Do not have	??9.64	??337/339	??33.56	??H	??Br	Furans-2,5-two bases	Do not have	??H	??5.08	??303/305
??33.57	??NH2	??Cl	Furans-2,5-two bases	Do not have	??C(O)OMe	??3.34	??332	??33.56	??H	??Br	Furans-2,5-two bases	Do not have	??H	??5.08	??303/305
??33.57	??NH2	??Cl	Furans-2,5-two bases	Do not have	??C(O)OMe	??3.34	??332	??33.58	??OPr-n	??H	Furans-2,5-two bases	??Me	Do not have	??8.14	??297
??33.59	??H	??OPr-n	Furans-2,5-two bases	Do not have	??H	??8.45	??283	??33.58	??OPr-n	??H	Furans-2,5-two bases	??Me	Do not have	??8.14	??297
??33.59	??H	??OPr-n	Furans-2,5-two bases	Do not have	??H	??8.45	??283	??33.60	??H	??O(CH2)2OEt	Furans-2,5-two bases	Do not have	??H	??7.82	??313
??33.61	??NH2	Do not have	Furans-2,5-two bases	??OH	??H	??3.97	??256	??33.60	??H	??O(CH2)2OEt	Furans-2,5-two bases	Do not have	??H	??7.82	??313
??33.61	??NH2	Do not have	Furans-2,5-two bases	??OH	??H	??3.97	??256	??33.62	??NH2	Do not have	Furans-2,5-two bases	??OPr-n	??H	??7.84	??298
??33.63	??OPr-n	??H	Furans-2,5-two bases	??CH2OH	??H	??4.36	??312	??33.62	??NH2	Do not have	Furans-2,5-two bases	??OPr-n	??H	??7.84	??298
??33.63	??OPr-n	??H	Furans-2,5-two bases	??CH2OH	??H	??4.36	??312	??33.64	??OBu-n	??H	Furans-2,5-two bases	??CH2OH	??H	??8.58	??326
??33.65	??O(CH2)2OEt	??H	Furans-2,5-two bases	??CH2OH	??H	??4.13	??342	??33.64	??OBu-n	??H	Furans-2,5-two bases	??CH2OH	??H	??8.58	??326
??33.65	??O(CH2)2OEt	??H	Furans-2,5-two bases	??CH2OH	??H	??4.13	??342	??33.66	??NH2	??H	Furans-2,5-two bases	??OPr-n	Do not have	??7.96	??298
??33.67	??H2	??H	Furans-2,5-two bases	??OBu-n	Do not have	??3.86	??312	??33.66	??NH2	??H	Furans-2,5-two bases	??OPr-n	Do not have	??7.96	??298
??33.67	??H2	??H	Furans-2,5-two bases	??OBu-n	Do not have	??3.86	??312	??33.68	??H	??OBu-i	Furans-2,5-two bases	Do not have	??H	??8.80	??297
??33.69	??H	??O(CH2)2OEt	Furans-2,5-two bases	Do not have	??H	??7.14	??299	??33.68	??H	??OBu-i	Furans-2,5-two bases	Do not have	??H	??8.80	??297
??33.69	??H	??O(CH2)2OEt	Furans-2,5-two bases	Do not have	??H	??7.14	??299	??33.70	??H	??O(CH2)2NMe2	Furans-2,5-two bases	Do not have	??H	??4.57	??312
??33.71	??NH2	Do not have	Furans-2,5-two bases	??OBu-i	??H	??8.06	??312	??33.70	??H	??O(CH2)2NMe2	Furans-2,5-two bases	Do not have	??H	??4.57	??312
??33.71	??NH2	Do not have	Furans-2,5-two bases	??OBu-i	??H	??8.06	??312	??33.72	??NH2	Do not have	Furans-2,5-two bases	??O(CH2)2OMe	??H	??4.84	??314
??33.73	??NH2	??H	Furans-2,5-two bases	??OBu-i	Do not have	??8.70	??312	??33.72	??NH2	Do not have	Furans-2,5-two bases	??O(CH2)2OMe	??H	??4.84	??314
??33.73	??NH2	??H	Furans-2,5-two bases	??OBu-i	Do not have	??8.70	??312	??33.74	??Br	??H	Furans-2,5-two bases	??c(O)NH2	??H	??7.68	??346/348
??33.75	??NH2	Do not have	Furans-2,5-two bases	??Cl	??H	??4.77	??274	??33.74	??Br	??H	Furans-2,5-two bases	??c(O)NH2	??H	??7.68	??346/348
??33.75	??NH2	Do not have	Furans-2,5-two bases	??Cl	??H	??4.77	??274	??33.76	??NH(CH2)2OH	??H	Furans-2,5-two bases	??Me	Do not have	??4.56	??298
??33.77	??H	??NH(CH2)2OH	Furans-2,5-two bases	Do not have	??H	??4.55	??284	??33.76	??NH(CH2)2OH	??H	Furans-2,5-two bases	??Me	Do not have	??4.56	??298
??33.77	??H	??NH(CH2)2OH	Furans-2,5-two bases	Do not have	??H	??4.55	??284	??33.78	??NH2	Do not have	Furans-2,5-two bases	??NH(CH2)2OH	??H	??4.58	??299
??33.79	??NH(CH2)2OH	??H	Furans-2,5-two bases	??NH2	Do not have	??4.58	??299	??33.78	??NH2	Do not have	Furans-2,5-two bases	??NH(CH2)2OH	??H	??4.58	??299
??33.79	??NH(CH2)2OH	??H	Furans-2,5-two bases	??NH2	Do not have	??4.58	??299	??33.80	??NH(CH2)2OH	??H	Furans-2,5-two bases	??CH2OH	??H	??4.44	??313
??33.81	??NH2	??H	Furans-2,5-two bases	??NH(CH2)2OH	Do not have	??4.33	??299	??33.80	??NH(CH2)2OH	??H	Furans-2,5-two bases	??CH2OH	??H	??4.44	??313
??33.81	??NH2	??H	Furans-2,5-two bases	??NH(CH2)2OH	Do not have	??4.33	??299	??33.82	??NHCH2- ??CH(OH)Me	??H	Furans-2,5-two bases	??CH3	Do not have	??4.65	??312
??33.83	??NH2	Do not have	Furans-2,5-two bases	??NHCH2- ??CH(OH)Me	??H	??4.63	??313	??33.82	??NHCH2- ??CH(OH)Me	??H	Furans-2,5-two bases	??CH3	Do not have	??4.65	??312
??33.83	??NH2	Do not have	Furans-2,5-two bases	??NHCH2- ??CH(OH)Me	??H	??4.63	??313	??33.84	??NHCH2- ??CH(OH)Me	??H	Furans-2,5-two bases	??NH2	Do not have	??4.63	??313
??33.85	??NHCH2- ??CH(OH)Me	??H	Furans-2,5-two bases	??CH2OH	??H	??4.52	??327	??33.84	??NHCH2- ??CH(OH)Me	??H	Furans-2,5-two bases	??NH2	Do not have	??4.63	??313
??33.85	??NHCH2- ??CH(OH)Me	??H	Furans-2,5-two bases	??CH2OH	??H	??4.52	??327	??33.86	??NH2	??H	Furans-2,5-two bases	??NHCH2- ??CH(OH)Me	Do not have	??4.65	??313
??33.87	??NH(CH2)3OH	??H	Furans-2,5-two bases	??Me	Do not have	??4.62	??312	??33.86	??NH2	??H	Furans-2,5-two bases	??NHCH2- ??CH(OH)Me	Do not have	??4.65	??313
??33.87	??NH(CH2)3OH	??H	Furans-2,5-two bases	??Me	Do not have	??4.62	??312	??33.88	??NH2	Do not have	Furans-2,5-two bases	??NH(CH2)3OH	??H	??4.48	??313
??33.89	??NH(CH2)3OH	??H	Furans-2,5-two bases	??NH2	Do not have	??4.48	??313	??33.88	??NH2	Do not have	Furans-2,5-two bases	??NH(CH2)3OH	??H	??4.48	??313
??33.89	??NH(CH2)3OH	??H	Furans-2,5-two bases	??NH2	Do not have	??4.48	??313	??33.90	??NH2	??NH(CH2)3OH	Furans-2,5-two bases	Do not have	??C(O)NH- ??(CH2)3OH	??4.76	??414
??33.91	??H	The 4-morpholinyl	Furans-2,5-two bases	Do not have	??H	??6.46	??310	??33.90	??NH2	??NH(CH2)3OH	Furans-2,5-two bases	Do not have	??C(O)NH- ??(CH2)3OH	??4.76	??414
??33.91	??H	The 4-morpholinyl	Furans-2,5-two bases	Do not have	??H	??6.46	??310	??33.92	The 4-morpholinyl	??H	Furans-2,5-two bases	??Me	Do not have	??6.53	??324

??33.93	??NH2	Do not have	Furans-2,5-two bases	The 4-morpholinyl	??H	??6.15	??325
??33.93	??NH2	Do not have	Furans-2,5-two bases	The 4-morpholinyl	??H	??6.15	??325	??33.94	The 4-morpholinyl	??H	Furans-2,5-two bases	??NH2	Do not have	??4.84	??325
??33.95	??NH2	The 4-morpholinyl	Furans-2,5-two bases	Do not have	C (O) (4-morpholinyl)	??7.47	??438	??33.94	The 4-morpholinyl	??H	Furans-2,5-two bases	??NH2	Do not have	??4.84	??325
??33.95	??NH2	The 4-morpholinyl	Furans-2,5-two bases	Do not have	C (O) (4-morpholinyl)	??7.47	??438	??33.96	??NH2	??H	Furans-2,5-two bases	The 4-morpholinyl	Do not have	??5.30	??325
??33.97	??Me	??H	??NHC(O)CH2	??H	??H	??6.58	??229	??33.96	??NH2	??H	Furans-2,5-two bases	The 4-morpholinyl	Do not have	??5.30	??325
??33.97	??Me	??H	??NHC(O)CH2	??H	??H	??6.58	??229	??33.98	??H	??Me	??NHC(O)CH2	??H	??H	??6.60	??229
??33.99	??NH2	??H	??NHC(O)CH2	??H	??Cl	??6.63	??264	??33.98	??H	??Me	??NHC(O)CH2	??H	??H	??6.60	??229
??33.99	??NH2	??H	??NHC(O)CH2	??H	??Cl	??6.63	??264	??33.100	??NH2	??Cl	??NHC(O)CH2	??H	??H	??6.63	??264
??33.101	??H	??OH	??NHC(O)CH2	??H	??H	??6.54	??231	??33.100	??NH2	??Cl	??NHC(O)CH2	??H	??H	??6.63	??264
??33.101	??H	??OH	??NHC(O)CH2	??H	??H	??6.54	??231	??33.102	??Me	??H	??NHC(O)CH2	??Me	??H	??6.59	??243
??33.103	??H	??H	??NHC(O)CH2	??H	??Cl	??7.02	??249	??33.102	??Me	??H	??NHC(O)CH2	??Me	??H	??6.59	??243
??33.103	??H	??H	??NHC(O)CH2	??H	??Cl	??7.02	??249	??33.104	??H	??H	??NHC(O)CH2	??H	??Br	??8.01	??293/295
??33.105	??Me	??H	??NHC(O)CH2	??H	??Br	??6.64	??307/309	??33.104	??H	??H	??NHC(O)CH2	??H	??Br	??8.01	??293/295
??33.105	??Me	??H	??NHC(O)CH2	??H	??Br	??6.64	??307/309	??33.106	??H	??H	??NHC(O)CH2	??H	??H	??6.72	??215
??33.107	??H	??H	??NHC(O)CH2	??H	??Me	??6.54	??229	??33.106	??H	??H	??NHC(O)CH2	??H	??H	??6.72	??215
??33.107	??H	??H	??NHC(O)CH2	??H	??Me	??6.54	??229	??33.108	??H	??H	??NHC(O)CH2	??Me	??H	??6.53	??229
??33.109	??Me	??Cl	??NHC(O)CH2	??Me	Do not have	??3.93	??279	??33.108	??H	??H	??NHC(O)CH2	??Me	??H	??6.53	??229
??33.109	??Me	??Cl	??NHC(O)CH2	??Me	Do not have	??3.93	??279	??33.110	??Cl	??H	??NHC(O)CH2	Do not have	??H	??4.20	??251
??33.111	??H	??Br	??NHC(O)CH2	??H	??Me	??6.44	??307/309	??33.110	??Cl	??H	??NHC(O)CH2	Do not have	??H	??4.20	??251
??33.111	??H	??Br	??NHC(O)CH2	??H	??Me	??6.44	??307/309	??33.112	??NH2	??H	??NHC(O)CH2	??NH(Ph-4-Br)	Do not have	??4.42	??401/403
??33.113	??NH2	??Bn	??NHC(O)CH2	??H	??Bn	??6.49	??410	??33.112	??NH2	??H	??NHC(O)CH2	??NH(Ph-4-Br)	Do not have	??4.42	??401/403
??33.113	??NH2	??Bn	??NHC(O)CH2	??H	??Bn	??6.49	??410	??33.114	??H	??H	??NHC(O)CH2	??Et	??H	??6.57	??243
??33.115	??Me	??Et	??NHC(O)CH2	??H	??H	??6.54	??257	??33.114	??H	??H	??NHC(O)CH2	??Et	??H	??6.57	??243
??33.115	??Me	??Et	??NHC(O)CH2	??H	??H	??6.54	??257	??33.116	??Mc	??H	??NHC(O)CH2	??H	??Br	??6.55	??307/309
??33.117	??H	??Br	??NHC(O)CH2	??H	??Me	??6.51	??307/309	??33.116	??Mc	??H	??NHC(O)CH2	??H	??Br	??6.55	??307/309
??33.117	??H	??Br	??NHC(O)CH2	??H	??Me	??6.51	??307/309	??33.118	??H	??Me	??NHC(O)CH2	??H	??Br	??6.52	??307/309
??33.119	??Me	??Br	??NHC(O)CH2	??H	??Br	??6.19	??385/387/389	??33.118	??H	??Me	??NHC(O)CH2	??H	??Br	??6.52	??307/309
??33.119	??Me	??Br	??NHC(O)CH2	??H	??Br	??6.19	??385/387/389	??33.120	??H	??H	??C(O)NHCH2	??H	??H	??3.74	??215
??33.121	??Me	??H	??C(O)NHCH2	??H	??H		??229	??33.120	??H	??H	??C(O)NHCH2	??H	??H	??3.74	??215
??33.121	??Me	??H	??C(O)NHCH2	??H	??H		??229	??33.122	??OH	??H	??C(O)NHCH2	??H	??H	??3.72	??231
??33.123	??Br	??H	??C(O)NHCH2	??H	??H	??5.02	??293/295	??33.122	??OH	??H	??C(O)NHCH2	??H	??H	??3.72	??231
??33.123	??Br	??H	??C(O)NHCH2	??H	??H	??5.02	??293/295	??33.124	??Cl	??H	??C(O)NHCH2	??H	??H	??4.60	??249/251
??33.125	??H	??H	??C(O)NHCH2	??Cl	??H	??5.18	??249/251	??33.124	??Cl	??H	??C(O)NHCH2	??H	??H	??4.60	??249/251
??33.125	??H	??H	??C(O)NHCH2	??Cl	??H	??5.18	??249/251	??33.126	??H	??Br	??C(O)NHCH2	??OH	??H	??3.60	??310/312
??33.127	??H	??H	??C(O)NHCH2	Do not have	??H	??3.70	??216	??33.126	??H	??Br	??C(O)NHCH2	??OH	??H	??3.60	??310/312
??33.127	??H	??H	??C(O)NHCH2	Do not have	??H	??3.70	??216	??33.128	??H	??H	??C(O)NHCH2	??NO2	??H	??5.00	??260
??33.129	??H	??H	??C(O)NHCH2	??H	??Bu-n	??8.35	??271	??33.128	??H	??H	??C(O)NHCH2	??NO2	??H	??5.00	??260
??33.129	??H	??H	??C(O)NHCH2	??H	??Bu-n	??8.35	??271	??33.130	??H	??OPr-n	??C(O)NHCH2	??H	??H	??7.46	??273
??33.13	??C1	??Cl	??C(O)NHCH2	??H	??H	??4.23	??283/285/287	??33.130	??H	??OPr-n	??C(O)NHCH2	??H	??H	??7.46	??273
??33.13	??C1	??Cl	??C(O)NHCH2	??H	??H	??4.23	??283/285/287	??33.132	??Cl	??CF3	??C(O)NHCH2	??H	??H	??8.05	??317/319
??33.133	??H	??Cl	??C(O)NHCH2	??H	??CF3	??6.49	??317/319	??33.132	??Cl	??CF3	??C(O)NHCH2	??H	??H	??8.05	??317/319
??33.133	??H	??Cl	??C(O)NHCH2	??H	??CF3	??6.49	??317/319	??33.134	??H	??Cl	??C(O)NHCH2	??Cl	??C1	??7.20	??318/320/322
??33.135	??H	??C(O)Ph	??C(O)NHCH2	??H	??H	??7.00	??319	??33.134	??H	??Cl	??C(O)NHCH2	??Cl	??C1	??7.20	??318/320/322
??33.135	??H	??C(O)Ph	??C(O)NHCH2	??H	??H	??7.00	??319	??33.136	??H	??OEt	??C(O)NHCH2	??H	??CF3	??6.65	??327
??33.137	??SMe	??Cl	??C(O)NHCH2	??H	Do not have	??5.82	??296/298	??33.136	??H	??OEt	??C(O)NHCH2	??H	??CF3	??6.65	??327
??33.137	??SMe	??Cl	??C(O)NHCH2	??H	Do not have	??5.82	??296/298	??33.138	??SMe	??Br	??C(O)NHCH2	??H	Do not have	??5.40	??340/342
??33.139	??H	??O(Ph-3-CF3)	??C(O)NHCH2	Do not have	??H		??376	??33.138	??SMe	??Br	??C(O)NHCH2	??H	Do not have	??5.40	??340/342
??33.139	??H	??O(Ph-3-CF3)	??C(O)NHCH2	Do not have	??H		??376	??33.140	??H	??H	??C(O)NHCH2	Do not have	??Me	??3.75	??230
??33.141	??H	??Me	??C(O)NHCH2	??H	??H	??4.96	??229	??33.140	??H	??H	??C(O)NHCH2	Do not have	??Me	??3.75	??230
??33.141	??H	??Me	??C(O)NHCH2	??H	??H	??4.96	??229	??33.142	??Cl	??Cl	??C(O)NHCH2	??Cl	??Cl	??9.18	??351/353/355 ??/357
??33.143	??H	??F	??C(O)NHCH2	??OH	Do not have		??250	??33.142	??Cl	??Cl	??C(O)NHCH2	??Cl	??Cl	??9.18	??351/353/355 ??/357
??33.143	??H	??F	??C(O)NHCH2	??OH	Do not have		??250	??33.144	??Me	??F	??C(O)NHCH2	??OH	Do not have		??264
??33.145	??OH	??F	??C(O)NHCH2	??OH	Do not have	??3.93	??266	??33.144	??Me	??F	??C(O)NHCH2	??OH	Do not have		??264

^*When A, B, D or E when not existing, so corresponding G ' is N.

Synthesizing of part 2. formula X compounds

Embodiment 34.

The preparation of 2-amino-4-phosphonium mesitoyl methoxy-6-bromo benzothiazole

Steps A. EtSH (10ml) solution of aluminum chloride (5mmol) is cooled to 0 ℃ also with 2-amino-4-methoxyl group benzo thiazole (1mmol) processing.Stirred this mixture 2 hours in 0-5 ℃.Evaporation and extraction obtain 2-amino-4-hydroxy benzothiazole, are white solid.

Step B. stirred 2-amino-4-hydroxy benzothiazole (1mmol) and the mixture of sodium hydride (1.3mmol) in DMF (5ml) 10 minutes in 0 ℃, used diethyl phosphonyl methyl trifluoro methyl sulphonate (1.2mmol) processing then.After stirring 8 hours under the room temperature, chromatography obtains 2-amino-4-diethyl phosphonyl methoxyl base benzothiazole through extracting also to make this reactant, is oily matter.

Step C. is cooled to 10 ℃ and the bromine (1.5mmol) that is used among the AcOH (2ml) with AcOH (6ml) solution of 2-amino-4-(diethyl phosphonyl methoxyl base) benzothiazole (1mmol) and handles.After 5 minutes, under room temperature, stirred this mixture 2.5 hours.Collect the xanchromatic precipitation and use washed with dichloromethane by filtering, obtain 2-amino-4-diethyl phosphonyl methoxyl base-6-bromo benzothiazole.

Step D. is in 0 ℃; handle methylene dichloride (4ml) solution of 2-amino-4-diethyl phosphonyl methoxyl base-6-bromo benzothiazole (1mmol) with TMSBr (10mmol); after stirring 8 hours under the room temperature, it is dried that this reactant is evaporated to, and makes in the residue water-soluble (5ml).Collect the precipitation that produces by filtering, wash with water and obtain 2-amino-4-phosphonium mesitoyl methoxy-6-bromo benzothiazole (34.1), be white solid.Mp＞220 ℃ (decomposition).C ₈H ₈N ₂O ₄The analytical calculation value of PSBr: C:28.34; H:2.38; N:8.26.Measured value: C:28.32; H:2.24; N:8.06.

Similarly, according to the method for preparing following compounds:

(34.2) 2-amino-4-phosphonium mesitoyl methoxy benzothiazole.mp＞250℃。C ₈H ₉N ₂O ₄PS+0.4H ₂The analytical calculation value of O: C:35.93; H:3.69; N:10.48.Measured value: C:35.90; H:3.37; N:10.37.

Embodiment 35.

The preparation of 2-amino-4-phosphonium mesitoyl methoxy-6-bromo-7-chloro benzo thiazole

Steps A. chloroform (10ml) solution of 1-(2-methoxyl group-5-chlorophenyl)-2-thiocarbamide (1mmol) is cooled to 10 ℃ and the bromine (2.2mmol) that is used in the chloroform (10ml) handles.Stirred these reactants 20 minutes in 10 ℃, under room temperature, stirred 0.5 hour.The suspension returning that obtains was heated 0.5 hour.Obtain 2-amino-4-methoxyl group-7-chloro benzo thiazole by filtering collecting precipitation (using washed with dichloromethane), it is obtained 2-amino-4-phosphonium mesitoyl methoxy-6-bromo-7-chloro benzo thiazole (35.1) through embodiment 34 steps A, B, C and D.Mp＞220 ℃ (decomposition).C ₈H ₇N ₂O ₄The analytical calculation value of PSClBr: C:25.72; H:1.89; N:7.50.Measured value: C:25.66; H:1.67; N:7.23.

Similarly, according to the method for preparing following compounds:

(35.2) 2-amino-4-phosphonium mesitoyl methoxy-6-bromo-7-methylbenzothiazole.Mp＞220 ℃ (decomposition).C ₉H ₁₀N ₂O ₄The analytical calculation value of PSBr: C:30.61; H:2.85; N:7.93.Measured value: C:30.25; H:2.50; N:7.77.

(35.3) 2-amino-4-phosphonium mesitoyl methoxy-7-methylbenzothiazole.Mp＞220 ℃ (decomposition).C ₉H ₁₁N ₂O ₄PS+1.0H ₂The analytical calculation value of O: C:36.99; H:4.48; N:9.59.Measured value: C:36.73; H:4.23; N:9.38.

(35.4) 2-amino-4-phosphonium mesitoyl methoxy-7-chloro benzo thiazole.Mp＞220 ℃ (decomposition).C ₈H ₈N ₂O ₄PSCl+0.1H ₂The analytical calculation value of O: C:32.41; H:2.79; N:9.45.Measured value: C:32.21; H:2.74; N:9.22.

Embodiment 36.

2-amino-4-phosphonium mesitoyl methoxy-5,6,7, the preparation of 8-tetrahydrochysene naphtho-[1,2-d] thiazole

Steps A. with 3-amino-2-hydroxyl-5,6,7, the 8-naphthane obtains 3-amino-2-diethyl phosphonyl methoxyl base-5,6,7,8-naphthane through embodiment 34 step B.

Step B. is under room temperature, with 3-amino-2-diethyl phosphonyl methoxyl base-5,6,7, methyl alcohol (10ml) solution of methyl alcohol (5ml) the solution-treated KSCN (16mmol) of 8-naphthane (1mmol) and copper sulfate (7.7mmol).With this mixture reflux 2 hours.Filtration, extraction and chromatography obtain 2-amino-4-diethyl phosphonyl methoxyl base-5,6,7, and 8-tetrahydrochysene naphtho-[1,2-d] thiazole is the light brown solid.

Step C. is with 2-amino-4-diethyl phosphonyl methoxyl base-5,6,7, and 8-tetrahydrochysene naphtho-[1,2-d] thiazole obtains the amino 4-phosphonium mesitoyl methoxy-5,6,7 of 2-, 8-tetrahydrochysene naphtho-[1,2-d] thiazole (36.1) through embodiment 34 step D.Mp＞220 ℃ (decomposition).C ₁₂H ₁₅N ₂O ₄PS+0.5H ₂The analytical calculation value of O: C:45.86; H:4.81; N:8.91.Measured value: C:44.68; H:4.77; N:8.73.

Also can prepare following compounds according to aforesaid method:

(36.2) 2-amino-4-phosphonium mesitoyl methoxy-[1,2-d] aphthothiazoles.Mp＞240 ℃ (decomposition).C ₁₂H ₁₁N ₂O ₄The analytical calculation value of PS+0.2HBr: C:44.15; H:3.46; N:8.58.Measured value: C:44.13; H:3.46; N:8.59.

(36.3) 2-amino-5,7-dimethyl-6-thiocyano-4-phosphonium mesitoyl methoxy aphthothiazoles.Mp＞240 ℃ (decomposition).C ₁₁H ₁₂N ₃O ₄PS ₂+ 0.2CH ₂Cl ₂The analytical calculation value: C:37.13; H:3.45; N:11.60.Measured value: C:37.03 H:3.25; N:11.65.

Embodiment 37.

The preparation of 2-amino-7-methoxyl group-6-thiocyano-4-phosphonium mesitoyl methoxy benzothiazole

Steps A. 2-hydroxy-5-methyl oxygen base oil of mirbane is obtained 2-diethyl phosphonyl methoxyl base-5-methoxy nitrobenzene through embodiment 34 step B.

Step B. will join at the tin chloride solution (4mmol) among the methyl alcohol system HCl of prepared fresh (10ml) in methyl alcohol (5ml) solution of 2-diethyl phosphonyl methoxyl base-5-methoxy nitrobenzene (1mmol) of refrigerative (0 ℃).This mixture is warmed to room temperature and stirred 3 hours, evaporation, extract and chromatography obtains 2-diethyl phosphonyl methoxyl base-5-anisidine.

Step C. makes 2-diethyl phosphonyl methoxyl base-5-anisidine obtain 2-amino-4-diethyl phosphonyl methoxyl base-6-sulfo-cyano group-7-methoxyl group benzo thiazole through embodiment 36 step B, and it is obtained 2-amino-7-methoxyl group-6-thiocyano-4-phosphonium mesitoyl methoxy benzothiazole (37.1) through embodiment 34 step D.Mp＞170 ℃ (decomposition).C ₁₀H ₁₀N ₃O ₅PS ₂The analytical calculation value: C:34.58; H:2.90; N:12.10.Measured value: C:34.23; H:2.68; N:11.77.

Similarly, according to the method for preparing following compounds:

(37.2) .2-amino-5,6-two fluoro-4-phosphonium mesitoyl methoxy benzothiazoles.Mp＞240 ℃ (decomposition).C ₈H ₇N ₂O ₄PSF ₂The analytical calculation value: C:32.44; H:2.38; N:9.46.Measured value: C:32.30; H:2.26; N:9.17.

(37.3) .2-amino-5-fluoro-7-bromo-4-phosphonium mesitoyl methoxy benzothiazole.Mp＞190 ℃ (decomposition).C ₈H ₇N ₂O ₄The analytical calculation value of PSBrF: C:26.91; H:1.98; N:7.84.Measured value: C:27.25; H:1.92; N:7.54.

(37.4) .2-amino-7-ethoxy carbonyl-4-phosphonium mesitoyl methoxy benzothiazole.Mp＞240 ℃ (decomposition).C ₁₁H ₁₃N ₂O ₆The analytical calculation value of PS+0.2HBr+0.1DMF: C:38.15; H:3.94; N:8.27.Measured value: C:38.51; H:3.57; N:8.66.

Embodiment 38.

The preparation of 2-amino-7-bromo-6-thiocyano-4-phosphonium mesitoyl methoxy benzothiazole

Steps A. DMF (5ml) solution of 2-fluoro-5-bromo nitryl benzene (1mmol) is cooled to 0 ℃, uses DMF (5ml) solution-treated of the hydroxymethyl phosphonic acid diethyl ester sodium salt (1.2mmol) of prepared fresh.Under room temperature, stirred this mixture 16 hours.Evaporation, extraction and chromatography obtain 2-diethyl phosphonyl methoxyl base-5-bromo nitryl benzene.

Step B. makes 2-diethyl phosphonyl methoxyl base-5-bromo nitryl benzene obtain 2-amino-7-bromo-6-thiocyano-4-phosphonium mesitoyl methoxy benzothiazole (38.1) through embodiment 37 step B, embodiment 36 step B and embodiment 34 step D.Mp＞250 ℃ (decomposition).C ₉H ₇N ₃O ₄PS ₂The analytical calculation value of Br: C:27.29; H:1.78; N:10.61.Measured value: C:26.90; H:1.58; N:10.54.

Similarly, according to the method for preparing following compounds:

(38.2) 2-amino-7-fluoro-6-thiocyano-4-phosphonium mesitoyl methoxy benzothiazole.Mp＞136 ℃ (decomposition).C ₉H ₇N ₃O ₄PFS ₂The analytical calculation value of+0.3HBr: C:30.07; H:2.05; N:11.69.Measured value: C:30.27; H:2.01; N:11.38.

Embodiment 39.

The preparation of 2-amino-7-methylol-6-thiocyano-4-phosphonium mesitoyl methoxy benzothiazole

Steps A. 2-chloro-5-formyl radical oil of mirbane is obtained 2-diethyl phosphonyl methoxyl base-5-formyl radical oil of mirbane through embodiment 38 steps A.

Step B. handles methyl alcohol (5ml) solution 12 hours of 2-diethyl phosphonyl methoxyl base-5-formyl radical oil of mirbane (1mmol) with 10% palladium on carbon (0.05mmol) under room temperature and 1 normal atmosphere hydrogen.Filtration then evaporation obtains 2-diethyl phosphonyl methoxyl base-5-hydroxymethyl aniline, and it is obtained 2-amino-7-methylol-6-thiocyano-4-phosphonium mesitoyl methoxy benzothiazole (39.1) through embodiment 36 step B and embodiment 34 step D successively.mp＞181-184℃。C ₁₀H ₁₀N ₃O ₅PS ₂+ 0.35H ₂The analytical calculation value of O: C:33.97; H:3.05; N:11.88.Measured value: C:33.76; H:2.66; N:11.61.

Embodiment 40.

The preparation of 2-amino-6-bromo-7-fluoro-4-phosphonium mesitoyl methoxy benzothiazole

Steps A. 2-diethyl phosphonyl methoxyl base-4-bromo-5-fluoro aniline (1mmol is as embodiment 4 step B preparation) and AcOH (8ml) solution of KSCN (2mmol) are cooled to 10 ℃, with AcOH (5ml) solution-treated of bromine (2mmol).After stirring 0.5 hour under the room temperature; be evaporated to this reaction mixture dried; make residue obtain 2-amino-7-fluoro-6-bromo-4-diethyl phosphonyl methoxyl base benzothiazole, it is obtained 2-amino-6-bromo-7-fluoro-4-phosphonium mesitoyl methoxy benzothiazole (40.1) through embodiment 34 step D through chromatography purification.C ₈H ₇N ₂O ₄The analytical calculation value of PSBrF+0.1HBr: C:26.31; H:1.96; N:7.67.Measured value: C:25.96; H:1.94; N:7.37.

Embodiment 41.

The preparation of 2-amino-7-ethyl-6-thiocyano-4-phosphonium mesitoyl methoxy benzothiazole

Steps A. handle 2-diethyl phosphonyl methoxyl base-5-bromo nitryl benzene (1mmol with tributyl (vinyl) tin (1.2mmol) and two (triphenyl phosphine) palladium chloride (0.1mmol); as embodiment 37 steps A preparations) DMF (5ml) solution; under nitrogen, this mixture was heated 6 hours in 60 ℃.Evaporation and chromatography obtain 2-diethyl phosphonyl methoxyl base-5-vinyl oil of mirbane; be oily matter, it is obtained 2-amino-7-ethyl-6-thiocyano-4-phosphonium mesitoyl methoxy benzothiazole (41.1) through embodiment 38 step B, embodiment 36 step B and embodiment 34 step D.Mp＞167 ℃ (decomposition).C ₁₁H ₁₂N ₃O ₄PS ₂The analytical calculation value: C:38.26; H:3.50; N:12.17.Measured value: C:37.87; H:3.47; N:11.93.

Embodiment 42.

The preparation of 2-amino-7-cyclopropyl-6-thiocyano-4-phosphonium mesitoyl methoxy benzothiazole

Steps A. in 0 ℃, handle 2-diethyl phosphonyl methoxyl base-5-vinyl oil of mirbane (1mmol is as the preparation of embodiment 40 steps A) and Pd (OAc) with the ethereal solution of diazomethane (generating) by 3.0g 1-methyl-3-nitro-1-nitrosoguanidine ₂(0.1mmol) suspension in ether (8ml).After stirring 20 hours under the room temperature; be evaporated to this reactant dried; residue obtains 2-diethyl phosphonyl methoxyl base-5-cyclopropyl oil of mirbane through chromatography, and it is obtained 2-amino-7-cyclopropyl-6-thiocyano-4-phosphonium mesitoyl methoxy benzothiazole hydrobromate (42.1) through embodiment 37 step B, embodiment 36 step B and embodiment 34 step D.C ₁₂H ₁₃N ₃O ₄PS ₂The analytical calculation value of Br+0.1HBr: C:27.76; H:2.72; N:8.09.Measured value: C:27.54; H:3.05; N:7.83.

Embodiment 43.

The preparation of 2-amino-4-phosphonium mesitoyl methoxy-6-chloro-7-methylbenzothiazole

Steps A. make 2-methoxyl group-4-chloro-5-monomethylaniline obtain 2-amino-4-phosphonium mesitoyl methoxy-6-chloro-7-methylbenzothiazole (43.1) through embodiment 34 steps A and B, embodiment 36 step B and embodiment 34 step D.Mp＞250 ℃ (decomposition).C ₉H ₁₀N ₂O ₄PS ₂Cl+0.3H ₂The analytical calculation value of O+0.4HBr: C:31.20; H:3.20; N:8.09.Measured value: C:31.37; H:2.87; N:7.89.

Similarly, according to the method for preparing following compounds:

(43.2) 2-amino-7-phenyl-6-thiocyano-4-phosphonium mesitoyl methoxy benzothiazole.Mp＞250 ℃ (decomposition).C ₁₅H ₁₂N ₃O ₄PS ₂+ 0.2H ₂The analytical calculation value of O: C:45.38; H:3.15; N:10.58.Measured value: C:45.25; H:3.21; N:10.53.

Embodiment 44.

2-bromo-4-diethyl phosphonyl methoxyl base-5; 6; 7; the preparation process A. of 8-tetrahydrochysene naphtho-[1,2-d] thiazole is with 2-amino-4-diethyl phosphonyl methoxyl base-5,6; 7; acetonitrile (4ml) solution of 8-tetrahydrochysene naphtho-[1,2-d] thiazole (1mmol) is cooled to 0 ℃, handles by dripping cuprous bromide (1.2mmol) and Isopentyl nitrite (1.5mmol).The dark mixture that obtains was stirred 3.5 hours.Evaporation and chromatography obtain 2-bromo-4-diethyl phosphonyl methoxyl base-5,6,7, and 8-tetrahydrochysene naphtho-[1,2-d] thiazole is oily matter.

Step B. makes 2-bromo-4-diethyl phosphonyl methoxyl base-5,6,7, and 8-tetrahydrochysene naphtho-[1,2-d] thiazole obtains being solid 2-bromo-4-phosphonium mesitoyl methoxy-5,6,7,8-tetrahydrochysene naphtho-[1,2-d] thiazole (44.1) through embodiment 34 step D.Mp?220-230℃。C ₁₂H ₁₃NO ₄The analytical calculation value of PSBr: C:38.11; H:3.46; N:3.70.Measured value: C:37.75; H:3.26; N:3.69.

Embodiment 45.

4-diethyl phosphonyl methoxyl base-5; 6; 7; the preparation process A. of 8-tetrahydrochysene naphtho-[1,2-d] thiazole is in 65 ℃, with 2-amino-4-diethyl phosphonyl methoxyl base-5; 6; 7, DMF (1ml) solution of DMF (3ml) the solution-treated Isopentyl nitrite (1.5mmol) of 8-tetrahydrochysene naphtho-[1,2-d] thiazole (10mmol).After 30 minutes; the refrigerative reactant solution is obtained 4-diethyl phosphonyl methoxyl base-5,6,7 through evaporation and chromatography; 8-tetrahydrochysene naphtho-[1; 2-d] thiazole, be oily matter, it is obtained the phosphonium mesitoyl methoxy-5 into solid 4-through embodiment 34 step D; 6; 7,8-tetrahydrochysene naphtho-[1,2-d] thiazole (45.1).Mp?215-220℃。C ₁₂H ₁₄NO ₄The analytical calculation value of PS+1.3HBr: C:35.63; H:3.81; N:3.46.Measured value: C:35.53; H:3.46; N:3.40.

Embodiment 46.

The preparation of 2-amino-4-phosphono methylthio group benzo thiazole

Steps A. make 2-diethyl phosphonyl methylthio group aniline (according to embodiment 34 step B preparation) obtain 2-amino-4-diethyl phosphonyl methylthio group benzo thiazole through embodiment 36 step B.

Step B. make 2-ammonia send out-diethyl phosphonyl methylthio group benzo thiazole obtains foamed 2-amino-4-phosphono methylthio group benzo thiazole (46.1) through embodiment 34 step D.C ₈H ₁₀N ₂O ₃PS ₂+ 0.4H ₂The analytical calculation value of O: C:35.63, H:3.81; N:3.46.Measured value: C:35.53; H:3.46; N:3.40.

Embodiment 47.

The preparation of the various prodrugs of benzothiazole.

Steps A. with DCC (3mmol) and 3-(3, the 5-dichloro) phenyl-1, the first aftertreatment 2-amino of ammediol (1.1mmol)-4-phosphonium mesitoyl methoxy-5,6,7, the suspension of 8-tetrahydrochysene naphtho-[1,2-d] thiazole (1mmol) in DMF (10ml).The mixture that obtains in 80 ℃ of heating 8 hours.Evaporation then column chromatography obtains solid 2-amino-4-{[3-(3, the 5-dichlorophenyl) the third-1,3-two bases] phosphonium mesitoyl methoxy }-5,6,7,8-tetrahydrochysene naphtho-[1,2-d] thiazole (47.1).mp＞230℃。C ₂₁H ₂₁N ₂O ₄PSCl ₂The analytical calculation value: C:50.51; H:4.24; N:5.61.Measured value: C:50.83; H:4.34; N:5.25.

Step B. makes 4-phosphonium mesitoyl methoxy-5; 6,7,8-tetrahydrochysene naphtho-[1; 2-d] thiazole dichloride (generating as embodiment 19) methylene dichloride (5ml) solution (1mmol) is cooled to 0 ℃, with the methylene dichloride (0.5ml) and pyridine (0.3ml) solution-treated of benzylalcohol (0.9mmol).The reactant solution that obtains in 0 ℃ of stirring 1 hour adds the THF solution of ammonia (excessive) then.After stirring 16 hours under the room temperature, this reactant is evaporated to dried, residue obtains 4-phosphono monoamide ylmethoxy-5,6,7 through chromatography purification, 8-tetrahydrochysene naphtho-[1,2-d] thiazole.

Perhaps, example as shown in following step adopts diverse ways to prepare other phosphamide.

Step C. makes 4-phosphonium mesitoyl methoxy-5,6,7, and 8-tetrahydrochysene naphtho-[1,2-d] thiazole dichloride (generating as embodiment 19) methylene dichloride (5ml) aaerosol solution (1mmol) is cooled to 0 ℃, and ammonia (excessive) bubbling was fed this reactant 10 minutes.After stirring 16 hours under the room temperature, this reactant is evaporated to dried, residue obtains 4-(even phosphorus diamide base) methoxyl group-5,6,7,8-tetrahydrochysene naphtho-[1,2-d] thiazole through chromatography purification.

According to aforesaid method, but an also phenyl-phosphonic amide derivative of preparation formula X compound:

Step D. is under room temperature, and (1N 1.5mmol) handles 4-phenylbenzene phosphonium mesitoyl methoxy-5,6,7,8-tetrahydrochysene naphtho-[1,2-d] thiazole (as the method preparation of the embodiment 19) acetonitrile (9ml) (1mmol) and the solution of water (4ml) 24 hours with lithium hydroxide.This reactant solution is evaporated to dried, makes in the residue water-soluble (10ml), be cooled to 0 ℃, the pH of this solution is transferred to 4 by adding 6N HCl.Filter and collect the white solid that generates, obtain 4-phenyl phosphonic ylmethoxy-5,6,7,8-tetrahydrochysene naphtho-[1,2-d] thiazole.

Step e. with 4-phenyl phosphonic ylmethoxy-5,6,7, the suspension of 8-tetrahydrochysene naphtho-[1,2-d] thiazole (1mmol) in thionyl chloride (3ml) is heated to and refluxed 2 hours.This reaction soln is evaporated to dried, residue is dissolved in the anhydrous methylene chloride (2ml),, the solution that generates is joined in the solution of the pyridine (0.8ml) of L-alanine ethyl ester hydrochloride (1.2mmol) and methylene dichloride (3ml) in 0 ℃.The reaction soln that stirring generates under room temperature 14 hours.Evaporation and chromatography obtain 4-[O-phenyl-N-(1-ethoxy carbonyl) ethyl phosphono amido] methoxyl group-5,6,7,8-tetrahydrochysene naphtho-[1,2-d] thiazole.

Step F. use N; N '-dicyclohexyl-4-morpholine carbonamidine (5mmol) and ethyl propoxycarbonyl oxygen ylmethyl iodine (5mmol) are [according to reported method (Nishimura etc.; L.Antibiotics; 1987,40,81) by the preparation of chloro methyl chloride subtituted acid ester] processing 4-phosphonium mesitoyl methoxy-5; 6; 7, the DMF solution of 8-tetrahydrochysene naphtho-[1,2-d] thiazole (1mmol).Stirred this reaction mixture 24 hours in 25 ℃.Evaporation and chromatography obtain two (the ethoxy carbonyl oxygen ylmethyl) phosphonium mesitoyl methoxies-5,6,7 of 4-, 8-tetrahydrochysene naphtho-[1,2-d] thiazole.

Also can prepare 4-(two oxy acid methyl neopentyls) phosphonium mesitoyl methoxy-5,6,7 in a similar fashion, two (the isobutyl acyl-oxygen ylmethyl) phosphonium mesitoyl methoxies-5,6,7 of 8-tetrahydrochysene naphtho-[1,2-d] thiazole and 4-, 8-tetrahydrochysene naphtho-[1,2-d] thiazole.

The embodiment of the purposes of the inventive method comprises more following.Should be appreciated that these embodiment are exemplary, and method of the present invention is not limited in these embodiment.

For the purpose of brief and concise, in following biology embodiment, compound is with reference to synthetic embodiment numbering.

Except the following example, the assay method that can be used for identifying the compound that suppresses gluconeogenesis comprises the animal model of following diabetes:

I. has animal (as mouse, rat, dog and the monkey of streptozotocin-processing) by specific chemical cytotoxin such as tetraoxypyrimidine (Alloxan) or streptozotocin destructive pancreas b-cell.Kodama, H., Fujita, M., Yamaguchi, I., Japanese Journal of Pharmacology 66, 331-336 (1994) (mouse); Youn, J.H., Kim, J.K., Buchanan, T.A., Diabetes 43, 564-571 (1994) (rat); Le Marchand, Y., Loten, E.G., Assimacopoulos-Jannet, F. etc., Diabetes 27, 1182-88 (1978) (dog); And Pitkin, R.M., Reynolds, W.A., Diabetes 19, 70-85 (1970) (monkey).

Ii. the mutant strain mouse is as from Jackson Laboratory, the C57BL/Ks db/db of Bar Harbor, C57BL/Ks ob/ob and C57BL/6J ob/ob strain, and other is as Yellow Obese, T-KK, and New Zealand Obese.Coleman, D.L., Hummel, K.P. Diabetologia3,238-248 (1967) (C57BL/Ks db/db); Coleman, D.L., Diabetologia 14, 141-148 (1978) (C57BL/6J ob/ob); Wolff, G.L., Pitot, H.C., Genetics 73, 109-123 (1973) (Yellow Obese); Dulin, W.E., Wyse, B.M., Diabetologia 6, 317-323 (1970) (T-KK); And Bielschowsky, M., Bielschowsky, F.Proceedings of the University of Otago Medical School 31, 29-31 (1953) (New Zealand Obese).

Iii. the mutant strain rat is as making the Zucker fa/fa rat that suffers from diabetes with streptozotocin or ground rice pine, the Zucker diabetes endomorphy type (Diabetic Fatty) rat and theWistar Kyoto endomorphy type rat.Stolz, K.J., Martin, R.J. Journal of Nutrition 112, 997-1002 (1982) (streptozotocin); Ogawa, A., Johnson, J.H., Ohnbeda, M., McAllister, C.T., Inman, L., Alam, T., Unger, R.H., The Journal Clinical Investigation 90, 497-504 (1992) (dexamethasone); Clark, J.B., Palmer, C.J., Shaw, W.N., Proceedings of the Society for Experimental Biology and Medicine 173, 68-75 (1983) (Zucker diabetes endomorphy type rat); And Idida, H., Shino, A., Matsuo, T. etc., Diabetes 30, 1045-1050 (1981) (Wistar Kyoto endomorphy type rat).

Iv. the animal that suffers from spontaneous diabetes is as Chinese hamster, cavy, New Zealand white rabbit and non-human primates such as macaque and Squirrel monkey.Gerritsen, G.C., Connel, M.A., Blanks, M.C., Proceedings of the Nutrition Society 40, 237 245 (1981) (Chinese hamsters); Lang, C.M., Munger, B.L., Diabetes 25, 434-443 (1976) (cavy); Conaway, H.H., Brown, C.J., Sanders, L.L. etc., Journal of Heredity 71, 179-186 (1980) (New Zealand white rabbit); Hansen, B.C., Bodkin, M.L., Diabetologia 29, 713-719 (1986) (macaque); And Davidson, I.W., Lang, C.M., Blackwell, W.L., Diabetes 16, 395-401 (1967) (Squirrel monkey).

V. the animal that suffers from nutrition inductive diabetes is as Sand rat, Spiny mouse, mongolian gerbils and Cohen Sucrose-inductive diabetes rat.Schmidt-Nielsen, K., Hainess, H.B., Hackel, D.B., Science 143, 689-690 (1964) (Sand rat); Gonet, A.E., Stauffacher, W., Pictet, R. etc., Diabetologia 1, 162-171 (1965) (Spiny mouse); Boquist, L., Diabetologia 8, 274-282 (1972) (mongolian gerbils); And Cohen, A.M., Teitebaum, A., Saliternik, R., Metabolism 21, 235-240 (1972) (Cohen sucrose-inductive diabetes rat).

Vi. have by hereditary inducement, genetic engineering, selectivity hemorrhage, or one or more any other animal of combination of the following feature that causes of chemistry or nutrition inducement: the gluconeogenesis of impaired glucose tolerance, insulin resistant, hyperglycemia, obesity, acceleration, the output of the hepatic glucose of increase.

Biology embodiment

Embodiment A: the inhibition of people liver FBP enzyme

Obtain the e. coli bl21 strain of personnel selection liver FBP enzyme-coding plasmid conversion from the Dr.M.R.El-Maghrabi of the State University of New York of Stony Brook.Described enzyme generally as M.Gidh-Jain etc. (1994, The Journal of Biological Chemistry 269, the 27732-27738 page or leaf) and described, purifying from 10 liters of recombination bacillus coli nutrient solutions.Adopt phosphoglucose isomerase and glucose-6-phosphate dehydrogenase as the coupling enzyme, passing through NADP ⁺And use the spectrophotometry enzymic activity in the reaction of phenazine methosulfate (PMS) product (fructose-1, 6-diphosphate) that makes formation and reductive dimethylthiazole phenylbenzene tetrazolium bromide (MTT) coupling.(200 μ l) is formulated on the titer plate of 96-hole with reaction mixture, it contains 50mM Tris-HCl (pH7.4), 100mM Repone K, 5mM EGTA, 2mM magnesium chloride, 0.2mM NADP, 1mg/mlBSA, 1mM MTT, 0.6mM PMS, 1 unit/ml glucose phosphate isomerase, 2 units/ml glucose-6-phosphate dehydrogenase and 0.150mM substrate (1, the 6-hexose diphosphate).Inhibitor concentration changes between 0.01 μ M-10 μ M.Begin reaction by the pure hlFBP enzyme that adds 0.002 unit, and go up in 590nm place monitoring 7 minutes in Molecular Devices plate reader (37 ℃).

Following table provides the IC of several compounds that prepared ₅₀Value.IC to AMP ₅₀Be 1 μ M.

Compound number IC ₅₀(hlFBP enzyme), μ M

3.1??????????0.025

3.2??????????0.1

3.25?????????0.014

3.26?????????0.015

3.58?????????82

3.67?????????2

3.69?????????1

3.70?????????0.04

6.3??????????0.044

10.1?????????0.12

10.27????????0.038

10.43????????0.07

15.20????????0.04

15.14????????0.032

16.1?????????0.06

17.6?????????0.62

17.11????????0.78

18.3?????????0.05

18.11????????0.33

18.20????????0.039

18.25????????2

25.2?????????0.4

28.2?????????2.8

41.1?????????0.022

The inhibition of rats'liver FBP enzyme

Obtain e. coli bl21 strain from the Dr.M.R.El-Maghrabi of the State University of New York of Stony Brook with rats'liver FBP enzyme-coding plasmid conversion.Reorganization FBP enzyme is as (El-Maghrabi, M.R. and Pilkis, S.J. (1991) Biochem.Biophys.Res.Commun.176,137-144) described purifying.Enzyme assay is identical with above-mentioned assay method to people liver FBP enzyme.

Following table provides the IC of several compounds that prepared ₅₀Value.IC to AMP ₅₀Be 20 μ M.

Compound number IC ₅₀(rlFBP enzyme), μ M

3.1????????????0.18

3.2????????????2.5

3.25???????????0.5

3.26???????????0.25

3.70???????????0.15

6.3????????????0.5

10.1???????????2

10.2???????????2.5

10.27??????????2.9

10.43??????????0.8

15.2???????????1.3

15.4???????????4.1

15.6???????????7

15.20??????????0.6

15.14??????????0.68

16.1???????????1.8

18.20??????????0.28

18.3???????????0.49

41.1???????????0.16

Embodiment B: AMP site combination

For whether assessing compound combines with the allosteric AMP binding site of hlFBP enzyme, the incubation in the presence of the test compound of certain limit concentration with this enzyme and radiolabeled AMP.Described reaction mixture comprises 0.25mM ³H-AMP (54mCi/mmol) and 0-1000mM test compound (at 25mM Tris-HCl, pH7.4,100mM Repone K and 1mM magnesium chloride).Add at last the 1.45mg homogeneous the FBP enzyme (± 1nmol).Behind the incubation 1 minute, (" Ultrafree-MC ", Millipore) (operation instructions according to manufacturers is used) will open in conjunction with the AMP and the unconjugated AMP branch of FBP enzyme by the centrifugal ultrafiltration device.The radioactivity that uses Beckman liquid scintillation calculating instrument that this device is gone up the equal portions liquid (100 μ l) of chamber (retentate, it contains enzyme and marker) and following chamber (filtrate, it contains unconjugated marker) carries out quantitatively.By the counting of filtrate (unconjugated marker) and the grand total of retentate are compared the amount that AMP is incorporated into this enzyme of calculating.

Embodiment C: the selectivity of AMP site/enzyme

For determining the selectivity of compound, adopt following assay method to measure the effect of FBP enzyme inhibitors to 5 important AMP desmoenzymes to the FBP enzyme:

E.C. 2.7.1.20: as (Spychala, J., Datta such as Spychala, N.S., Takabayashi, K., Datta, M., Fox, I.H., Gribbin, T. and Mitchell, B.S. (1996) Proc.Natl.Acad.Sci.USA 93,1232-1237) described, from escherichia expression system purifying people E.C. 2.7.1.20.Roughly as Yamada etc. (Yamada, Y., Goto, H., Ogasawara, N. (1988) Biochim.Biophys, Acta 660,36-43) described (only having done the little modification in several places) measured active.Measure mixture and contain 50mM TRIS-maleate damping fluid (pH7.0), 0.1%BSA, 1mMATP, 1mM magnesium chloride, 1.0 μ M[U- ¹⁴C] adenosine (400-600mCi/mmol) and the double concentration inhibitor that changes.By inciting somebody to action ¹⁴C-AMP absorbs on the Zhiyin ion exchange paper (Whatman) and makes it with unreacted ¹⁴The C-adenosine separates and is quantitative through scintillation counting.

Adenylic acid deaminase: basic as (Smiley, K.L., Jr, Berry, A.J. and Suelter, C.H. (1967) J.Biol.Chem. such as Smiley 242, 2502-2506) described, by phosphorylated cotton step purifying Pigs Hearts AMPDA.In 37 ℃, (it contains inhibitor, about 0.005U AMPDA, 0.1 bovine serum albumin, 10mM ATP, 250mMKCl and 50mM MOPS, pH6.5) middle mensuration the active inhibition of AMPDA to measure mixture at 0.1ml.The concentration of substrate A MP changes between 0.125-10.0mM.Start katalysis in the reaction mixture completely by enzyme being joined other, after 5 minutes by being injected into termination reaction in the HPLC system.Determine active by the amount of the IMP that during 5 minutes, forms.(4.6mm * 25cm) carries out HPLC to use the BeckmanUltrasil-SAX anion-exchange column, with buffer system such as degree such as grade (12.5mM potassiumphosphate, 30mM Repone K, pH3.5), IMP is separated with AMP, and carry out the spectrophotometry detection by absorbing at the 254nm place.

Phosphofructokinase: buy enzyme (rabbit liver) from Sigma.Measure in reaction in 30 ℃ active, wherein form 1, the 6-hexose diphosphate is coupled on the NADH of oxidation by the effect of zymohexase, triose-phosphate isomerase and a-phosphoglycerol dehydrogenase.(200 μ l) is formulated on the titer plate of 96-hole with reaction mixture, and reads number in the 340nm place on Molecular Devices plate reader.This mixture contains 200mM Tris-HCl (pH7.0), 2mMDTT, 2mM magnesium chloride, 0.2mM NADH, 0.2mM ATP, 0.5mM fructose-1, 6-diphosphate, the 1 zymohexase/ml of unit, 3 units/ml triose-phosphate isomerase and 4 units/ml a-phosphoglycerol dehydrogenase.Test compound concentration is in 1-500 μ M scope.Begin to react and monitored 15 minutes by the phosphofructokinase that adds 0.0025 unit.

Glycogen phosphorylase: buy enzyme (rabbit muscle) from Sigma.In 37 ℃ of mensuration activity in reaction, wherein the Cori's eater Cori of Xing Chenging is coupled on the reductive NADP by phosphoglucomutase and glucose-6-phosphate dehydrogenase.Be determined on the titer plate of 96-hole and carry out, and on Molecular Devices plate reader, read number in the 340nm place.Reaction mixture contains 20mM imidazoles (pH7.4), 20mM magnesium chloride, 150mM potassium acetate, 5mM potassiumphosphate, 1mM DTT, 1mg/ml BSA, 0.1mM NADP, 1 unit/ml phosphoglucomutase, 1 unit/ml glucose-6-phosphate dehydrogenase, 0.5% glycogen.Test compound concentration is in 1-500 μ M scope.Begin to react and monitored 20 minutes by adding 17 μ g enzymes.

Myokinase: buy enzyme (rabbit muscle) from Sigma.In 37 ℃ of reaction mixtures (100 μ l) that containing 100mM Hepes (pH7.4), 45mM magnesium chloride, 1mM EGTA, 100mM Repone K, 2mg/mlBSA, 1mM AMP and 2mM ATP, measure active.Begin reaction and after 5 minutes, pass through to add 17 μ l perchloric acid termination reactions by adding the 4.4ng enzyme.Centrifugally remove sedimentary protein, by adding in 33 μ l 3M potassium hydroxide/3M saleratus and supernatant liquor.Make the clarification of neutral solution by centrifugal and filtration, (25 * 4.6cm) carry out HPLC to ADP content (enzymic activity) analyzes to adopt YMC ODSAQ post.Gradient development from 0.1M potassium primary phosphate (pH6,8mM hydrogen sulfate TBuA) to 75% acetonitrile.In 254nm place monitoring absorbancy.

Following table provides the selective data to compound 10.1 and 3.1.

10.1(μM)??? 3.1(μM)

FBP enzyme (inh.) 0.1 0.025

E.C. 2.7.1.20 (inh)＞＞10＞＞10

AMP desaminase (inh)＞＞10＞＞10

Myokinase (inh.)＞500＞500

Glycogen phosphorylase (act.)＞100＞100

Phosphofructokinase (act.)＞500＞500

Embodiment D: to the inhibition of gluconeogenesis in the rat hepatocytes

According to Berry and Friend (Berry, M.N., Friend, D.S., 1969, J.Cell.Biol.43, method 506-520) is (through Groen (Groen, A.K., Sips, H.J., Vervoorn, R.C., Tager, J.M., 1982, Eur.J.Biochem.122 87-93) revises), from Sprague-Dawley rat (250-300g) the preparation liver cell of overnight fasting.With the liver cell (incubation in 1ml Krebs-bicarbonate buffer (containing 10mM lactic acid salt, 1mM pyruvate salt, 1mg/ml BSA and concentration test compound) of 75mg weight in wet base/ml) in 1-500 μ M scope.Incubation carries out under 95% oxygen, 5% carbon dioxide atmosphere in airtight, 50-ml Falcon test tube, and this test tube is immersed in the water-bath (37 ℃) of quick oscillation.After 1 hour, take out equal portions (0.25ml), move in the Eppendorf pipe also centrifugal.Then, according to the glucose content in the working instructions usefulness Sigma glucose oxidase kit measurement 50 μ l supernatant liquors of manufacturers.

Be used to select the IC of compound in this mensuration ₅₀Be shown in the following table.

Compound number IC ₅₀Glucose produces, μ M

3.1????????????????2.5

3.2????????????????26

3.26???????????????10

3.58???????????????1.2

10.1???????????????15

10.2???????????????16

16.1???????????????10

19.18??????????????10

19.48??????????????6.5

20.9???????????????2.2

31.6???????????????2.3

31.8???????????????3

Embodiment E: the inhibition and 1 that glucose produces in the rat hepatocytes, the accumulating of 6-hexose diphosphate

Described in embodiment D, prepare isolating rat hepatocytes and incubation under identical condition.By shifting out the cell suspending liquid termination reaction of equal portions (250 μ l), its rotation is entered in the 10% perchloric acid layer (100 μ l) by an oil reservoir (0.8ml silicone/mineral oil, 4/1).After removing oil reservoir, by the 3M potassium hydroxide/3M saleratus neutralizing acid sexual cell extract layer that adds 1/3 volume.Through mix and centrifugal after, the glucose content in the clear liquid analytically described in embodiment D, and 1, the content of 6-hexose diphosphate.By with 1, the 6-hexose diphosphate is a glycerol 3-phosphate through enzymatic conversion, with the NADH coupling of oxidation, carries out 1 again, the spectrophotometry of 6-hexose diphosphate, and its process is monitored at the 340nm place.Reaction mixture (1ml) contains 200mM Tris-HCl (pH7.4), 0.3mM NADH, 2 units/ml glycerol 3-phosphate desaturase, 2 units/ml triose-phosphate isomerase and 50-100 μ l cell extract.After 30 minutes, add 1 unit/ml zymohexase in 37 ℃ of preincubation, change the absorbancy of measuring, until obtaining stationary value.In this reaction, be present in every mole 1 in the cell extract, the 6-hexose diphosphate has 2 moles of NADH oxidized.

Dosage-dependence that glucose produces suppresses with 1, and it is hit enzyme, the i.e. repressed indication of FBP enzyme of gluconeogenesis approach that the dosage-dependence of 6-hexose diphosphate (substrate of FBP enzyme) is accumulated.

Embodiment F: vein gives the reduction of blood sugar behind the fasting rat

Make Sprague Dawley rat (250-300g) fasting 18 hours, vein gives the FBP enzyme inhibitors of salt solution or 10mg/kg then.Inhibitor is dissolved in the water and this solution transferred to and be neutral with sodium hydroxide.Before facing injection and inject after 1 hour, obtain blood sample from the tail vein of conscious animal.Use the glucose analyser of HemoCue Inc. to measure blood sugar according to the operation instructions of manufacturers.

The glucose that compound caused when the following table demonstration was compared with the control animal of brine treatment reduces (%).

Compound number i.v. glucose reduces, %

3.1????????????65

3.2????????????55(30mg/kg)

3.25???????????76

3.26???????????73

3.58???????????82

3.71???????????72

6.3????????????24

10.1???????????51

10.43??????????61

15.20??????????24

18.2???????????80

18.3???????????75

35.3???????????65

41.1???????????80

There are several compounds also under＜10mg/kg dosage level, to test.For example, compound 3.26 has been carried out test under 3mg/kg dosage and found that blood sugar reduces by 52%.

Embodiment G: the analysis that rat Chinese traditional medicine level and liver are accumulated

Make Sprague-Dawley rat (250-300g) fasting 18 hours, vein gives 10.1 or 3.1 (the n=3/ groups) of salt solution (n=3) or 10mgs/kg then.Compound is soluble in water and regulate this solution to neutral with NaOH.Inject after 1 hour, use the halothane anesthesia rat, get liver living tissue (about 1g) and from postcaval vein blood sample collection (2ml).Use syringe and the syringe needle that soaked with heparin during blood sampling.Immediately with the homogenize, centrifugal in ice-cooled 10% perchloric acid (3ml) of liver sample, with in the 3M potassium hydroxide/3M saleratus of 1/3 volume and supernatant liquor.Through centrifugal and filter after, through HPLC analyze 50 μ l in and 10.1 content in the extract.Use YMCODS AQ post (250 * 4.6cm) and use gradient liquid wash-out from 10mM sodium phosphate (pH5.5) to 75% acetonitrile.In 310-325nm place monitoring absorbancy.By the centrifugal blood plasma that from blood sample, prepares, add methyl alcohol to 60% (v/v) and extract.By centrifugal and filtration the extract of methyl alcohol system is clarified, analyzed through HPLC as mentioned above then.The results are shown in the following table.

Compound number plasma concentration (μ M) liver concentration (nmoles/g)

10.1????????18±2.8??????????35.6±4.2

10.2????????22±1.5

5.1?????????100+5.7??????????6.7±0.7

3.21????????25±1

15.20???????66.3±3.9????????13.1±2.3

3.26????????56±2

Embodiment H: the reduction of glucose behind the orally give fasting rat

Give 18 hours Sprague-Dawley rat of fasting (250-300g, n=3/4/ group) with compound per os tube feed.In de-ionized water, prepare phosphonic acids, with sodium hydroxide this solution is transferred to and be neutral.Prodrug is dissolved in the polyoxyethylene glycol (mw 400).(HemoCue Inc., Mission Viejo CA) measured blood sugar with the HemoCue glucose analyser every 1 hour before facing administration and after the administration.Following table shows with respect to the reduction to greatest extent that gives the brinish glucose that control animal is obtained.

Compound number % glucose reduces dosage, mg/kg time point, h

3.26????????70??????????????30?????????????2

3.27????????61??????????????60?????????????3

10.1????????55??????????????90?????????????3

10.2????????36??????????????90?????????????3

19.42???????26??????????????30?????????????3

19.48???????63??????????????30?????????????2

19.46???????53??????????????30?????????????2

20.9????????67??????????????90?????????????3

31.6????????60??????????????10?????????????3

Example I: the estimation of the oral administration biaavailability of phosphonic acids and prodrug thereof

Make phosphonic acids soluble in water, with sodium hydroxide this solution is transferred to and be neutral.Prodrug is dissolved in 10% ethanol/90% polyoxyethylene glycol (mw 400).Give fasting 18 hours Sprague-Dawley rat (220-250g) with the dosage per os tube feed of 10-50mg/kg scope compound.Subsequently these rats are placed metabolic cage, collect 24 hours urine.Described in embodiment G, be excreted to phosphonic acids amount in the urine through the HPLC assay determination.In one is independently studied, after giving compound (under the situation at prodrug, vein gives suitable parent phosphonic acids), vein (tail vein) measures the rate of recovery in the urine.By the rate of recovery of compound in the twenty-four-hour urine behind the orally give and vein being given the percentage that the rate of recovery in the twenty-four-hour urine of back is relatively estimated oral administration biaavailability.

The phosphonic acids of selecting and the oral administration biaavailability of phosphonic prodrug are shown in the following table.

Compound number % oral administration biaavailability

3.1????????????4

3.26???????????18

3.27???????????32

10.1???????????21

10.2???????????22

19.42??????????10

19.9???????????18.5

19.17??????????16.2

19.48??????????12

20.1???????????46

20.3???????????17.5

20.4???????????11

20.9???????????17.4

31.6???????????19

31.8???????????14

The reduction of the blood sugar in the embodiment J:Zucker diabetes endomorphy type rats (oral)

(Indiannapolis Indiana) buys and feeds with Purina 5008 foods of recommending Zucker diabetes endomorphy type rat (8 age in week) from Genetics Models Inc..12 weeks are during ages, and the glucose level of selecting 16 nursings is the animal between the 500-700mg/dl and be divided into two groups (n=8) with the average blood sugar level that equates on the statistical significance.Give a treated animal (in 1pm) with compound 3.26 with the dosage per os tube feed of 100mg/kg.Preparation is used for the drug solution (25mg/ml) of this kind processing in deionized water, makes by Dropwise 5 N sodium hydroxide to transfer to neutrality.Second group of rat (n=8) is with the mode orally give salt solution of parallel control.Before facing administration or giving salt solution, after 6 hours every rat is measured blood sugar with administration.According to the working instructions of manufacturers, these measure employing HemoCue blood sugar analyzer, and (HemoCue Inc., Mission Viejo CA) carries out.As shown in the table, with respect to the control group with brine treatment, compound 3.26 is handled and is caused that 15.4% blood sugar reduces (P=0.01).

Blood sugar, mg/dl

Treatment group 1pm 7pm

Salt solution 575 ± 28 587 ± 26

3.26????????573±26????497±14

Data show that compound 3.26 is effective oral antidiabetic drug in Zucker diabetes endomorphy type rat type ii diabetes model.

The reduction of the blood sugar in the embodiment K:Zucker diabetes endomorphy type rats (intravenously)

With Purina 5008 foods keep 12 the week age Zuoker diabetes endomorphy type rat (GeneticModels Inc., Indiannapolis, Indiana), the test that morning 8 time to rat caudal artery and tail venous cannula instrumentation.In research all the other times on the same day, remove food.Began at 12 o'clock at noon,, animal infusion of saline or compound 3.26 are reached 6 hours by the tail venous cannula with 1,3 or the speed of 30mg/kg/h.When infusion begins, and after this obtained blood sample from the caudal artery intubate every l hour.According to the working instructions of manufacturers, adopt HemoCue analyser (HemoCue Inc., Mission Viejo, CA) glucose in the working sample.

At 6 hours time points, with respect to the control group of saline infusion, cause respectively that with the speed infusion compound 3.26 of 3mg/kg/h and 30mg/kg/h 29% and 39% blood sugar obviously reduces.Studies show that when vein gave Zucker diabetes endomorphy type rat (a kind of important type ii diabetes rodent model), compound 3.26 was effective antidiabetic drugs.

Embodiment L:FBP enzyme inhibitors is to the inhibition of Zucker diabetes endomorphy type rat gluconeogenesis

Described in embodiment K, give Zucker diabetes endomorphy type rat after 6 hours at speed infusion compound 3.26 or salt solution with 3mg/kg/h, give through the tail venous cannula is disposable ¹⁴C-supercarbonate (40 μ Ci/100g body weight).After 20 minutes, take blood sample (0.6ml) through caudal artery.Blood (0.5ml) is diluted in the 6ml deionized water, by adding 1ml zinc sulfate (0.3N) and 1ml hydrated barta (0.3N) precipitating proteins.Centrifugal (20 minutes, 1000Xg) this mixture, supernatant liquor that 5ml is generated and 1g mixed-bed ion exchange resin (1 part of AG 50W-X8,100-200 order, Hydrogen, and 2 parts of AG 1-X8,100-200 order, acetate type) mix then, to separate ¹⁴C-supercarbonate type ¹⁴C-glucose.This silt oar of vibration is 4 hours under room temperature, makes precipitation then.In the 5ml liquid scintillation cocktail, an equal portions supernatant liquor (0.5ml) is counted again.Pick up from the sample of drug treating animal by using ¹⁴The average cpm of C-glucose calculates the percent inhibition of the gluconeogenesis of drug treating rat divided by picking up from salt solution-average cpm of injection animal.

Discovery in the rat of 3.26-infusion, ¹⁴The generation of C-glucose is suppressed 75%.This result provides such evidence, and promptly the hypoglycemic activity (embodiment K) of compound 3.26 in Zucker diabetes endomorphy type rat is that inhibition to gluconeogenesis causes.

Embodiment M: the blood sugar of the rat of streptozotocin-processing reduces

(Sigma Chemical Co.) brings out diabetes in male Sprague-Dawley rat (250-300g) by abdominal injection 55mg/kg streptozotocin.After 6 days, as mensuration blood sugar as described in the embodiment F.The blood glucose value (8am) that selection has a nursing between 350-600mg/dl animal and be divided into two groups.One group of oral administration give compound (10-100mg/kg) and second group give isopyknic salt solution.Remove food to animal.Give medicine/salt solution 2 and after 4 hours, measuring blood sugar once more.

Embodiment N: the oral absorption of prodrug is measured in the rat

With 30mg/kg dosage through abdominal injection and through buccal tubes raise give normal, feed and raise rat prodrug 19.42,19.48,31.6 and 31.8 (n=3 rat/compound/route of administration).Subsequently rat is placed metabolic cage, collect 24 hours urine.Described in embodiment G, quantitative to the parent compound (3.1) in the urine through reversed-phase HPLC.The amount that is excreted to the parent compound in the urine after orally give and abdominal cavity given compares, and calculates the oral absorption rate (%) of every kind of prodrug.The result is as follows:

Compound % excretion rate p.o. % excretion rate i.p. % specific absorption

19.42?????8.1?????????????15.4????????????52

19.48?????11.6????????????11.3????????????100

31.6??????16.5????????????38.9????????????43

31.8??????12.3????????????18.4????????????43

After giving, all the 4 kinds prodrug oral administration of being tried all are easy to be absorbed (43-100%).

Embodiment O: handle the normalizing that causes db/db Mouse Liver glycogen levels with the FBP enzyme inhibitors

(Maine), registration is studied when 11 ages in week for JacksonLabs., Bar Harbor for acquisition db/db mouse in 8 age in week and their non-diabetic db/+littermates.When that morning 8 of research and at 2 o'clock in afternoon orally give salt solution or compound 3.26 (100mg/kg) handle the db/db mouse.Use brine treatment db/+ mouse according to identical program.6 o'clock in the afternoon, use the halothane anesthesia mouse, downcut a small pieces liver (0.5g) through freezing clamp technology.Abundant freezing liver sample in being immersed in liquid nitrogen, homogenize in the cold 0.6N perchloric acid of 5 volumes then.By Keppler and Decker (Keppler D and Decker K in Methods of Enzymatic Analysis, Bergmeyer, HU, editor, Verlag Chemie International, Deerfield Beach, F1,1974) method measure the homogenate glycogen content with enzyme method.The results are shown in the following table to each group mouse assay with respect to the value of pre-treatment (8am):

Liver starch, μ mol glucose/g

Treatment group morning, 8am afternoon, 6pm

Db/db, contrast 102.9 ± 1.9 (n=3) 83.2 ± 22.5 (n=7)

db/db，3.26????-???????????????????34.4±7.1(n＝3)

Db/+, contrast 120.2 ± 6.7 (n=3) 15.7 ± 7.2 (n=3)

These data show, in contrast (salt solution-processings) diabetes db/db mouse, liver starch was not stored and significantly reduced in test same day, and contrast, tangible glycogen mobilization is arranged in the non-diabetic db/+ mouse.Db/db mouse with 3.26 acute treatment causes that the glycogen storage is reduced to the level that non-diabetic db/+ mouse reaches.

Claims

1. the pharmaceutically acceptable prodrug of formula (I) compound:

R wherein ⁵Be selected from: pyrryl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl group, pyrazolyl, isoxazolyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl and 1,3-selenazoles base, all these groups all have at least one substituting group;

Wherein, R ⁵Described in substituting group be selected from :-H ,-NR ⁴ ₂,-CONR ⁴ ₂,-CO ₂R ³, halo ,-S (O) R ³,-SO ₂R ³, alkyl, alkenyl, alkynyl group, perhaloalkyl radical, haloalkyl, aryl ,-CH ₂OH ,-CH ₂NR ⁴ ₂,-CH ₂CN ,-CN ,-C (S) NH ₂,-OR ³,-SR ³,-N ₃,-NHC (S) NR ⁴ ₂,-NHAc, alicyclic radical, aralkyl, alkoxyalkyl ,-C (O) R ¹¹,-C (O) SR ³,-SO ₂R ¹¹,-NR ⁹ ₂,-NO ₂Do not exist, except-H ,-CN, perhaloalkyl radical ,-NO ₂Outside halo, all above-mentioned groups can be chosen replacement wantonly;

X is the optional linking group that replaces, be selected from :-alkyl (hydroxyl)-,-alkyl-,-alkynyl group-,-aryl-,-heteroaryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkoxyl group-,-alkylthio alkyl-,-alkylthio-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alicyclic radical-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino, all groups are optional to be replaced;

Y independently is selected from-O-and-NR ⁶-;

When Y be-during O-, then be connected in-R of O- ¹The alicyclic radical that independently be selected from-H, alkyl, the optional aryl that replaces, the optional wherein loop section that replaces contains carbonic ether or thiocarbonic ester,, optional replace-alkylaryl ,-C (R ²) ₂OC (O) NR ² ₂,-NR ²-C (O)-R ³,-C (R ²) ₂-OC (O) R ³,-C (R ²) ₂-O-C (O) OR ³,-C (R ²) ₂OC (O) SR ³,-alkyl-S-C (O) R ³,-alkyl-S-S-alkyl hydroxy and alkyl-S-S-S-alkyl hydroxy,

When Y is-NR ⁶In-time, then be connected in-NR ⁶-R ¹Independently be selected from-H ,-[C (R ²) ₂] _q-COOR ³,-C (R ⁴) ₂COOR ³,-[C (R ²) ₂] _q-C (O) SR ³With-cycloalkylidene-COOR ³

Or independently be selected from-O-and-NR as arbitrary Y ⁶-time, then R ¹And R ¹Be together-alkyl-the S-S alkyl-with the formation cyclic group, or R ¹And R ¹Be together

Wherein

V and Z link together by an other 3-5 atom, formation contains the cyclic group of 5-7 atom, wherein optional heteroatoms, this cyclic group is replaced by the hydroxyl that is connected in carbon atom, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described carbon atom be connected in two Y groups of phosphorus atom all at a distance of three atoms; Or

V and Z link together by an other 3-5 atom, form the optional heteroatomic cyclic group that contains, this cyclic group aryl-condensed with respect to the β position of the Y that is connected described phosphorus atom and γ position;

P is 2 or 3 integer;

Q is 1 or 2 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H; And

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

R ¹¹Be selected from alkyl, aryl ,-NR ² ₂With-OR ²With

Prerequisite is:

1) works as R ⁵Be 6 yuan of whens ring, then X be not any two atoms connection base, the optional replacement-alkyl-, the optional replacement-alkenyl-, the optional replacement-alkoxyl group-or optional replacement-alkylthio;

2) R ¹It or not unsubstituted C1-C10 alkyl;

3) as X be not-aryl-time, then R ⁵Can't help two or more aryl replaces;

Wherein, described replacement or the optional group that replaces comprise the group that independently is selected from following substituting group replacement by 1-4: low alkyl group, lower aryl, rudimentary aralkyl, the lower member ester cyclic group, hydroxyl, lower alkoxy, rudimentary aryloxy, perhaloalkyl radical, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkyl, assorted aralkoxy, azido-, amino, guanidine radicals, amidino groups, halo, lower alkylthio, oxo, the acyl group alkyl, carboxyl ester, carboxyl,-formamido-, nitro, acyloxy, aminoalkyl group, the alkylamino aryl, alkylaryl, the alkylamino alkyl, alkoxy aryl, arylamino, aryl alkyl amino, phosphono, alkylsulfonyl,-formamido-alkylaryl,-formamido-aryl, hydroxyalkyl, haloalkyl, the alkylamino alkyl carboxyl-, the carbamido group alkyl-, cyano group, low-grade alkoxy alkyl, rudimentary perhaloalkyl radical and alkoxy aryl alkyl;

Wherein, described rudimentary being meant has the corresponding substituted radical of 10 carbon atoms at the most, and this type of group can be straight chain, side chain or cyclic.

2. the prodrug of claim 1, wherein R ⁵Be selected from:

With

Wherein

Each R ⁴Independently be selected from-H and C1-C2 alkyl;

Wherein, the group of described optional replacement comprises the group that independently is selected from following substituting group replacement by 1-4: low alkyl group, lower aryl, rudimentary aralkyl, the lower member ester cyclic group, hydroxyl, lower alkoxy, rudimentary aryloxy, perhaloalkyl radical, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkyl, assorted aralkoxy, azido-, amino, guanidine radicals, amidino groups, halo, lower alkylthio, oxo, the acyl group alkyl, carboxyl ester, carboxyl,-formamido-, nitro, acyloxy, aminoalkyl group, the alkylamino aryl, alkylaryl, the alkylamino alkyl, alkoxy aryl, arylamino, aryl alkyl amino, phosphono, alkylsulfonyl,-formamido-alkylaryl,-formamido-aryl, hydroxyalkyl, haloalkyl, the alkylamino alkyl carboxyl-, the carbamido group alkyl-, cyano group, low-grade alkoxy alkyl, rudimentary perhaloalkyl radical and alkoxy aryl alkyl;

3. the prodrug of claim 2, wherein R ⁵Be selected from:

With

4. the prodrug of claim 2, wherein R ⁵Be selected from:

With

5. the prodrug of claim 2, wherein R5 is selected from:

With

6. the prodrug of claim 2, wherein X is the optional linking group that replaces, be selected from: (hydroxyl)-,-alkynyl group-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkoxyl group-,-alkylthio alkyl-,-alkylthio-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alicyclic radical-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all groups are optional to be replaced;

7. the prodrug of claim 3, wherein X is the optional linking group that replaces, be selected from :-alkyl (hydroxyl)-,-alkynyl group-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkoxyl group-,-alkylthio alkyl-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alicyclic radical-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino, all groups are optional to be replaced;

8. the prodrug of claim 4, wherein X is the optional linking group that replaces, be selected from :-alkyl (hydroxyl)-,-alkyl-,-alkynyl group-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkylthio alkyl-,-alkylthio-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alicyclic radical-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino, all groups are optional to be replaced;

9. the prodrug of claim 5, wherein X is the optional linking group that replaces, be selected from :-alkyl (hydroxyl)-,-alkyl-,-alkynyl group-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkylthio alkyl-,-alkylthio-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alicyclic radical-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino, all groups are optional to be replaced;

10. the prodrug of claim 1, wherein X be selected from-heteroaryl-,-alkyl-carbonyl-amino-,-alkyl amino-carbonyl-,-alkoxy carbonyl-and-alkoxyalkyl-.

11. the prodrug of claim 10, wherein X be selected from-heteroaryl-and-alkoxy carbonyl-.

12. the prodrug of claim 1, wherein said compound are the compound of formula II, III or IV

And

13. the prodrug of claim 2, wherein X be selected from-heteroaryl-,-alkyl-carbonyl-amino-,-alkyl amino-carbonyl-,-alkoxy carbonyl-and-alkoxyalkyl-.

14. the prodrug of claim 13, wherein said compound are the compound of formula II or IV:

15. the prodrug of claim 13, wherein A " be selected from-NH ₂,-CONH ₂, halo ,-CH ₃,-CF ₃,-CH ₂-halo ,-CN ,-OCH ₃,-SCH ₃With-H.

16. the prodrug of claim 13, wherein each B " be selected from-H ,-C (O) R ¹¹,-C (O) SR ³, alkyl, aryl, alicyclic radical, halo ,-CN ,-SR ³,-NR ⁹ ₂With-OR ³

17. the prodrug of claim 13, wherein D " be selected from-H ,-C (O) R ¹¹,-C (O) SR ³, alkyl, aryl, alicyclic radical, halo ,-NR ⁹ ₂With-SR ³

18. the prodrug of claim 13, wherein E " be selected from-H, C1-C6 alkyl, rudimentary alicyclic radical, halogen ,-CN ,-C (O) OR ³,-SR ³With-CONR ⁴ ₂

19. the prodrug of claim 1, wherein two Y groups are-O-; Perhaps one of them Y is-NR ⁶-, a Y is-O-.

20. the prodrug of claim 2, wherein two Y groups are-O-; Perhaps one of them Y is-NR ⁶-, a Y is-O-.

21. the prodrug of claim 1, wherein when Y be-during O-, then be connected in-R of O- ¹The alicyclic radical that independently be selected from-H, the optional aryl that replaces, the optional wherein loop section that replaces contains carbonic ether or thiocarbonic ester, optional replace-alkylaryl ,-C (R ²) ₂OC (O) R ³,-C (R ²) ₂-O-C (O) OR ³,-C (R ²) ₂OC (O) SR ³,-alkyl-S-C (O) R ³With-alkyl-S-S alkyl hydroxy;

Or when arbitrary Y independently be selected from-O-and-during NR6-, R then ¹And R ¹Be together:

Wherein

P is 2 or 3 integer;

Q is 1 or 2 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H;

C) two Y groups not all are-NR ⁶-;

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

R ⁶Be selected from-H and low alkyl group;

22. the prodrug of claim 21, wherein when two Y groups be-during O-, R then ¹Independently be selected from the optional aryl that replaces, the optional benzyl that replaces ,-C (R ²) ₂OC (O) R ³,-C (R ²) ₂OC (O) OR ³With-H; With

When Y is-NR ⁶In-time, then be connected in described-NR ⁶The R of-group ¹Be selected from-C (R ⁴) ₂-COOR ³With-C (R ²) ₂COOR ³-; Another Y group is-during O-, then be connected in the R of described-O- ¹Be selected from the optional aryl that replaces ,-C (R ²) ₂OC (O) R ³With-C (R ²) ₂OC (O) OR ³

23. the prodrug of claim 13, wherein two Y groups are-O-R ¹For aryl or-C (R ²) ₂-aryl; Perhaps wherein two Y groups are-O-, at least one R ¹Be selected from-C (R ²) ₂-OC (O) R ³With-C (R ²) ₂-OC (O) OR ³Perhaps wherein two Y groups are-O-, at least one R ¹For-alkyl-S-S-alkyl hydroxy ,-alkyl-S-C (O) R ³With-alkyl-S-S-S-alkyl hydroxy, or R ¹And R ¹Be together-alkyl-the S-S-alkyl-to form cyclic group.

24. the prodrug of claim 13, wherein at least one Y is-O-, and R ¹And R ¹Be together

Wherein

P is 2 or 3 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H;

C) two Y groups not all are-NR ⁶-;

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

R ⁶Be selected from-H and low alkyl group;

25. the prodrug of claim 22, one of them Y is-O-R ¹Be the optional aryl that replaces; And another Y is-NR ⁶-, wherein be connected in described-NR ⁶-R ¹Be selected from-C (R ⁴) ₂COOR ³With-C (R ²) ₂C (O) OR ³

26. the prodrug of claim 25 wherein is connected in-R of O- ¹Be selected from phenyl and be selected from-NHC (O) CH by 1-2 ₃,-F ,-Cl ,-Br ,-C (O) OCH ₂CH ₃With-CH ₃The phenyl that replaces of substituting group; And wherein be connected in-NR ⁶-R ¹For-C (R ²) ₂COOR ³Each R ²Independently be selected from-CH ₃,-CH ₂CH ₃With-H.

27. the prodrug of claim 26, the substituting group of the phenyl of wherein said replacement are selected from 4-NHC (O) CH ₃,-Cl ,-Br, 2-C (O) OCH ₂CH ₃With-CH ₃

28. the prodrug of claim 2, wherein

B " be selected from-H ,-C (O) R ¹¹,-C (O) SR ³, alkyl, aryl, alicyclic radical, halo ,-CN ,-SR ³, OR ³With-NR ⁹ ₂

X is the optional linking group that replaces, be selected from :-alkyl (hydroxyl)-,-alkyl-,-alkynyl group-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkoxyl group-,-alkylthio alkyl-,-alkylthio-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alicyclic radical-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino, all groups are optional to be replaced;

When a Y be-during O-, then be connected in-R of O- ¹Be the optional aryl that replaces; And another Y is-NR ⁶-, then be connected in-NR ⁶-R ¹Be selected from-C (R ⁴) ₂COOR ³With-C (R ²) ₂C (O) OR ³Or

When Y be-O-or-NR ⁶-time, then R ¹And R ¹Be together

Wherein

P is 2 or 3 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H;

C) two Y groups not all are-NR ⁶-;

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

R ⁶Be selected from-H and low alkyl group;

29. the prodrug of claim 2, wherein R ⁵For

X is selected from methylene radical oxygen base carbonyl and furans-2,5-two bases; At least one Y gene is-O-.

30. the prodrug of claim 29, wherein when Y be-during O-, then be connected in-R of O- ¹Independently be selected from-H, the optional phenyl that replaces ,-CH ₂OC (O)-tBu ,-CH ₂OC (O) Et and-CH ₂OC (O)-iPr;

Wherein

R ⁶Be selected from-H and low alkyl group;

31. the prodrug of claim 30, wherein A " be-NH ₂, X is a furans-2,5-two bases, B " be-CH ₂-CH (CH ₃) ₂,-COOEt or-SMe.

32. the prodrug of claim 2, wherein R ⁵For

X is a furans-2,5-two base and methylene radical oxygen base carbonyls, A " be-NH ₂At least one Y is-O-.

33. the prodrug of claim 32, wherein

Wherein

V is selected from optional aryl that replaces and the optional heteroaryl that replaces: Z, W ' and W are H;

34. the prodrug of claim 33, wherein B " be-SCH ₂CH ₂CH ₃X is a furans-2,5-two bases.

35. the prodrug of claim 34, wherein two Y groups are-O-and R ¹For-H.

36. the prodrug of claim 2, wherein R ⁵For

A " be-NH ₂, E " and D " be-H B " be n-propyl and cyclopropyl, X is a furans-2,5-two base and methylene radical oxygen base carbonyls; At least one Y group is-O-.

37. the prodrug of claim 36, wherein

Or independently be selected from-O-and-NR as Y ⁶-, R then ¹And R ¹Be together

Wherein

V is selected from optional aryl that replaces and the optional heteroaryl that replaces; Z, W ' and W are H;

38. the prodrug of claim 2, wherein R ⁵For

A " be-NH ₂, D " and be-H B " be n-propyl and cyclopropyl, X is a furans-2,5-two base and methylene radical oxygen base carbonyls; At least one Y group is-O-.

39. the prodrug of claim 38, wherein

Or when Y independently be selected from-O-or-NR ⁶-time, then R ¹And R ¹Be together

Wherein

40. the pharmaceutically acceptable prodrug of formula (I) compound is used for the treatment of application in the medicine of animal fructose-1 dependence disease or illness in preparation, its Chinese style (I) compound is:

R wherein ⁵Be selected from: pyrryl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl group, pyrazolyl, isoxazolyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3,4-tetrazyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,3,5-triazines base, 1,2,4-triazinyl and 1,3-selenazoles base, all these groups all have at least one substituting group;

Wherein, R ⁵Described in substituting group be selected from :-H ,-NR ⁴ ₂,-CONR ⁴ ₂,-CO ₂R ³, halo ,-S (O) R ³,-SO ₂R ³, alkyl, alkenyl, alkynyl group, perhaloalkyl radical, haloalkyl, aryl ,-CH ₂OH ,-CH ₂NR ⁴ ₂,-CH ₂CN ,-CN ,-C (S) NH ₂,-OR ³,-SR ³,-N ₃,-NHC (S) NR ⁴ ₂,-NHAc, alicyclic radical, aralkyl, alkoxyalkyl ,-C (O) R ¹¹,-C (O) SR ³,-SO ₂R ¹¹,-NO ₂Do not exist, except-H ,-CN, perhaloalkyl radical ,-NO ₂Outside halo, all above-mentioned groups can be chosen replacement wantonly;

X is the optional linking group that replaces, be selected from :-alkyl (hydroxyl)-,-alkyl-,-alkynyl group-,-aryl-,-heteroaryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkoxyl group-,-alkylthio alkyl-,-alkylthio-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alicyclic radical-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino, all bases are stranded optional the replacement;

Y independently is selected from-O-and-NR ⁶-;

When Y be-during O-, then be connected in-R of O- ¹The alicyclic radical that independently be selected from-H, alkyl, the optional aryl that replaces, the optional wherein loop section that replaces contains carbonic ether or thiocarbonic ester, optional replace-alkylaryl ,-C (R ²) ₂OC (O) NR ² ₂,-NR ²-C (O)-R ³,-C (R ²) ₂-OC (O) R ³,-C (R ²) ₂-O-C (O) OR ³,-C (R ²) ₂OC (O) SR ³,-alkyl-S-C (O) R ³, alkyl-S-S alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy,

Wherein

V and Z link together by an other 3-5 atom, form to contain 5-7 atom, optional heteroatomic cyclic group, and this cyclic group is by the hydroxyl that is connected in carbon atom, acyloxy, alcoxyl

Base ketonic oxygen base or aryloxycarbonyl oxygen base replace, described carbon atom be connected in two Y groups of phosphorus atom all at a distance of three atoms; Or

P is 2 or 3 integer;

Q is 1 or 2 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H; And

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

R ¹¹Be selected from alkyl, aryl ,-NR ² ₂With-OR ²With

Prerequisite is:

2) R ¹It or not unsubstituted C1-C10 alkyl;

3) as X be not-alkyl-time, then R ⁵Can't help two or more alkyl replaces;

41. the described application of claim 40, wherein R ⁵Be selected from:

And

Wherein

R ⁴Be selected from-H and C1-C2 alkyl; With

R ¹¹Be selected from alkyl, aryl ,-NR ² ₂With-OR ²

42. the described application of claim 40, wherein R ⁵Be selected from:

With

Wherein

E " be selected from-H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, C4-C6 alicyclic radical, alkoxyalkyl ,-C (O) OR ³,-CONR ⁴ ₂,-CN ,-NR ⁹ ₂,-OR ³,-SR ³, C1-C6 perhaloalkyl radical and halo, except H ,-CN, perhaloalkyl radical and halo, all above-mentioned groups can be chosen replacement wantonly; With

Each R ⁴Independently be selected from-H and C1-C2 alkyl;

43. the pharmaceutically acceptable prodrug of the FBP enzyme inhibitors of formula (I) is used for the treatment of application in the medicine of diabetes or glycogenosis in preparation, the FBP enzyme inhibitors of its Chinese style (I) is:

X is the optional linking group that replaces, be selected from :-alkyl (hydroxyl)-,-alkyl-,-alkynyl group-,-aryl-,-heteroaryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkoxyl group-,-alkylthio alkyl-,-alkylthio-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alicyclic radical-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all bases are stranded optional the replacement;

Y independently is selected from-O-and-NR ⁶-;

When Y be-during O-, then be connected in-R of O- ¹The alicyclic radical that independently be selected from-H, alkyl, the optional aryl that replaces, the optional wherein loop section that replaces contains carbonic ether or thiocarbonic ester, optional replace-alkylaryl-C (R ²) ₂OC (O) NR ² ₂,-NR ²-C (O)-R ³,-C (R ²) ₂-OC (O) R ³,-C (R ²) ₂-O-C (O) OR ³,-C (R ²) ₂OC (O) SR ³, alkyl-S-C (O) R ³, alkyl-S-S alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy,

Wherein

V and Z link together by an other 3-5 atom, formation contains 5-7 atom, optional heteroatomic cyclic group, this cyclic group is replaced by the hydroxyl that is connected in carbon atom, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described carbon atom be connected in two Y groups of phosphorus atom all at a distance of three atoms; Or

V and W link together by 3 other carbon atoms, formation contains 6 carbon atoms and the cyclic group of the optional replacement that replaced by a substituting group that is selected from following group: hydroxyl, acyloxy, alkoxy-carbonyl oxy, alkylthio ketonic oxygen base and aryloxycarbonyl oxygen base, this substituting group is connected with one of described carbon atom, and the Y that this carbon atom is connected with phosphorus atom is at a distance of three atoms;

Z is selected from-CHR ²OH ,-CHR ²OC (O) R ³,-CHR ²OC (S) R ³,-CHR ²OC (S) OR ³,-CHR ²OC (O) SR ³,-CHR ²OCO ₂R ³,-OR ²,-SR ²,-CHR ²N ₃,-CH ₂Aryl ,-CH (aryl) OH ,-CH (CH=CR ² ₂) OH, CH (C ≡ CR ²) OH ,-R ²,-NR ² ₂,-OCOR ³,-OCO ₂R ³,-SCOR ³,-SCO ₂R ³,-NHCOR ²,-NHCO ₂R ³,-CH ₂The NH aryl ,-(CH ₂) _p-OR ²With-(CH ₂) _p-SR ²

P is 2 or 3 integer;

Q is 1 or 2 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H; And

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

R ¹¹Be selected from alkyl, aryl ,-NR ² ₂With-OR ²With

Prerequisite is:

1) works as R ⁵Be 6 yuan of whens ring, then X be not any two atoms connection base, the optional replacement-alkyl-, the optional replacement-alkenyl-, the optional replacement-alkoxyl group-or optional replacement the-alkylthio-;

2) R ¹It or not unsubstituted C1-C10 alkyl;

3) as X be not-aryl-time, then R ⁵Can't help two or more aryl replaces;

44. the described application of claim 43, wherein R ⁵Be selected from:

With

Wherein

R ⁴Be selected from-H and C1-C2 alkyl; With

R ¹¹Be selected from alkyl, aryl ,-NR ² ₂With-OR ²

45. the described application of claim 43, wherein R ⁵Be selected from:

With

Wherein

E " be selected from-H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, C4-C6 alicyclic radical, alkoxyalkyl ,-C (O) OR ³,-CONR ⁴ ₂,-CN ,-NR ⁹ ₂,-OR ³,-SR ³, C1-C6 can alkylhalide group and halo, except-H ,-CN, perhaloalkyl radical and halo, all above-mentioned groups can be chosen replacement wantonly; With

Each R ⁴Independently be selected from-H and C1-C2 alkyl;

46. the described application of claim 45, wherein X is the optional linking group that replaces, be selected from :-alkyl (hydroxyl)-,-alkyl-,-alkynyl group,-aryl-,-heteroaryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkoxyl group-,-alkylthio alkyl-,-alkylthio-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alicyclic radical-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-,-alkyl amino-carbonyl amino,-alkylamino-and-alkenyl-, all groups are optional to be replaced;

47. the described application of claim 46, wherein X be selected from-heteroaryl-,-alkyl-carbonyl-amino-,-alkyl amino-carbonyl-,-alkoxy carbonyl-and-alkoxyalkyl-.

48. the described application of claim 40, wherein said disease or illness are selected from atherosclerosis, hyperinsulinemia, hypercholesterolemia and hyperlipidaemia.

49. the described application of claim 40, FBP enzyme inhibitors of its Chinese style (I) and pharmacy acceptable salt thereof are used to prepare the medicine that prevents treating myocardial ischemia damage.

50. the pharmaceutically acceptable prodrug of formula (X) compound:

Wherein:

G " be selected from-O-and-S-;

A ², L ², E ²And J ²Be selected from-NR ⁴ ₂,-NO ₂,-H ,-OR ₂,-SR ²,-C (O) NR ⁴ ₂, halo ,-COR ¹¹,-SO ₂R ³, guanidine radicals, amidino groups, aryl, aralkyl, alkoxyalkyl ,-SCN ,-NHSO ₂R ⁹,-SO ₂NR ⁴ ₂,-CN ,-S (O) R ³, perhalogeno acyl group, perhaloalkyl radical, perhalogeno alkoxyl group, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl group and rudimentary alicyclic radical, perhaps L ²And E ²Or E ²And J ²Form cyclic group together;

Prerequisite is X ²Can't help-COOR ²,-SO ₃R ¹Or-PO ₃R ¹ ₂Replace;

Y independently is selected from-O-and-NR ⁶-;

When Y be-during O-, then be connected in-R of O- ¹The alicyclic radical that independently be selected from-H, alkyl, the optional aryl that replaces, the optional wherein loop section that replaces contains carbonic ether or thiocarbonic ester, optional replace-alkylaryl ,-C (R ²) ₂OC (O) NR ² ₂,-NR ²-C (O)-R ³,-C (R ²) ₂-OC (O) R ₃,-C (R ²) ₂-O-C (O) OR ³,-C (R ²) ₂OC (O) SR ³, alkyl-S-C (O) R ³,-alkyl-S-S-alkyl hydroxy and alkyl-S-S-S-alkyl hydroxy,

Wherein

V and Z link together by an other 3-5 atom, formation contains the optional heteroatomic cyclic group of 5-7 atom, this cyclic group replaces by being connected in hydroxyl on the carbon atom, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described carbon atom be connected in two Y groups of phosphorus atom all at a distance of three atoms; Or

P is 2 or 3 integer;

Q is 1 or 2 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H; And

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

R ¹¹Be selected from alkyl, aryl ,-NR ² ₂With-OR ²

51. the described prodrug of claim 50, the pharmacy acceptable salt of wherein said formula (X) compound is become with organic or inorganic acid, organic or inorganic alkalization symphysis by described formula (I) compound.

52. the described prodrug of claim 51, wherein said mineral acid are hydrochloric acid.

53. the prodrug of claim 50, wherein G " be-S-.

54. the prodrug of claim 50, wherein A ², L ², E ²And J ²Independently be selected from-H ,-NR ⁴ ₂,-S-C ≡ N, halogen ,-OR ³, hydroxyl ,-alkyl (OH), aryl, alkoxy carbonyl ,-SR ³, rudimentary perhaloalkyl radical and C1-C5 alkyl, perhaps L ²And E ²Be formed into the cyclic group of ring together;

55. the prodrug of claim 50, wherein when Y be-during O-, then be connected in-R of O- ¹The alicyclic radical that independently be selected from-H, the optional aryl that replaces, the optional wherein loop section that replaces contains carbonic ether or thiocarbonic ester, optional replace-alkylaryl ,-C (R ²) ₂OC (O) R ³,-C (R ²) ₂-O-C (O) OR ³,-C (R ²) ₂OC (O) SR ³, alkyl-S-C (O) R ³With-alkyl-S-S-alkyl hydroxy;

Wherein

P is 2 or 3 integer;

Q is 1 or 2 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H;

C) two Y groups not all are-NR ⁶-;

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

R ⁶Be selected from-H and low alkyl group;

56. the prodrug of claim 55, wherein when two Y groups be-during O-, R then ¹Independently be selected from the optional aryl that replaces, the optional benzyl that replaces ,-C (R ²) ₂OC (O) R ³,-C (R ²) ₂OC (O) OR ³With-H; With

When Y is-NR ⁶In-time, then be connected in described-NR ⁶-R ¹Be selected from-C (R ⁴) ₂-COOR ³,-C (R ²) ₂COOR ³With-H; And another Y group is-O-, is connected in the R of described-O-group ¹Group be selected from the optional aryl that replaces ,-C (R ²) ₂OC (O) R ³With-C (R ²) ₂OC (O) OR ³

57. the pharmacy acceptable salt of formula (X) compound is used for the treatment of application in the medicine of animal fructose-1 dependence disease or illness in preparation, its Chinese style (X) compound and pharmacy acceptable salt thereof are:

Wherein:

G " be selected from-O-and-S-;

Prerequisite is X ²Can't help-COOR ²,-SO ₃R ¹Or-PO ₃R ¹ ₂Replace;

Y independently is selected from-O-and-NR ⁶-;

When Y be-during O-, then be connected in-R of O- ¹The alicyclic radical that independently be selected from-H, alkyl, the optional aryl that replaces, the optional wherein loop section that replaces contains carbonic ether or thiocarbonic ester, optional replace-alkylaryl ,-C (R ²) ₂OC (O) NR ² ₂,-NR ²-C (O)-R ³,-C (R ²) ₂-OC (O) R ³,-C (R ²) ₂-O-C (O) OR ³,-C (R ²) ₂OC (O) SR ³, alkyl-S-C (O) R ³,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy,

Wherein

V and Z link together by an other 3-5 atom, formation contains 5-7 atom, optional heteroatomic cyclic group, this cyclic group is replaced by the hydroxyl that is connected in carbon atom, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, and two Y groups that described carbon atom is connected in phosphorus atom apart all have three atoms; Or

V and Z link together by an other 3-5 atom, form the optional heteroatomic cyclic group that contains, this cyclic group aryl-condensed with respect to the β position of the Y that is connected to phosphorus atom and γ position;

Z is selected from-CHR ²OH ,-CHR ²OC (O) R ³,-CHR ²OC (S) R ³,-CHR ²OC (S) OR ³,-CHR ²OC (O) SR ³,-CHR ²OCO ₂R ³,-OR ²,-SR ²,-CHR ²N ₃,-CH ₂Aryl ,-cH (aryl) OH ,-CH (CH=CR ² ₂) OH ,-CH (C ≡ CR ²) OH ,-R ²,-NR ² ₂,-OCOR ³,-OCO ₂R ³,-SCOR ³,-SGO ₂R ³,-NHCOR ²,-NHCO ₂R ³,-CH ₂The NH aryl ,-(CH ₂) _p-OR ²With-(CH ₂) _p-SR ²

P is 2 or 3 integer;

Q is 1 or 2 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H, and

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

R ¹¹Be selected from alkyl, aryl ,-NR ₂ ²With-OR ²

58. the pharmaceutically acceptable prodrug of the FBP enzyme inhibitors of formula (X) is used for the treatment of application in the medicine of diabetes, the FBP enzyme inhibitors and the pharmacy acceptable salt thereof of its Chinese style (X) in preparation:

Wherein:

G " be selected from-O-and-S-;

A ², L ², E ²And J ²Be selected from-NR ⁴ ₂,-NO ₂,-H ,-OR ²,-SR ²,-C (O) NR ⁴ ₂, halo ,-COR ¹¹,-SO ₂R ³, guanidine radicals, amidino groups, aryl, aralkyl, alkoxyalkyl ,-SCN ,-NHSO ₂R ⁹,-SO ₂NR ⁴ ₂,-CN ,-S (O) R ³, perhalogeno acyl group, perhaloalkyl radical, perhalogeno alkoxyl group, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl group and rudimentary alicyclic radical, perhaps L ²And E ²Or E ²And J ²Form cyclic group together;

Prerequisite is X ²Can't help-COOR ²,-SO ₃R ¹Or-PO ₃R ¹ ₂Replace;

Y independently is selected from-O-and-NR ⁶-;

When Y be-during O-, then be connected in-R of O- ¹The alicyclic radical that independently be selected from-H, alkyl, the optional aryl that replaces, the optional wherein loop section that replaces contains carbonic ether or thiocarbonic ester, optional replace-alkylaryl ,-C (R ²) ₂OC (O) NR ² ₂,-NR ²-C (O)-R ³,-C (R ²) ²-OC (O) R ³,-C (R ²) ₂-O-C (O) OR ³,-C (R ²) ₂OC (O) SR ³,-alkyl-S-C (O) R ³,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy,

Wherein

V and W link together by 3 other carbon atoms, formation contains 6 carbon atoms and the cyclic group of the optional replacement that replaced by a substituting group that is selected from following group: hydroxyl, acyloxy, alkoxy-carbonyl oxy, alkylthio ketonic oxygen base and aryloxycarbonyl oxygen base, this substituting group is connected with one of described carbon atom, this carbon atom be connected the former Y that gives of phosphorus at a distance of three atoms;

P is 2 or 3 integer;

Q is 1 or 2 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H; And

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

R ¹¹Be selected from alkyl, aryl ,-NR ² ₂With-OR ²

59. the pharmaceutically acceptable prodrug of the FBP enzyme inhibitors of formula (X) is used for the treatment of application in the medicine of glycogenosis, the FBP enzyme inhibitors and the pharmacy acceptable salt thereof of its Chinese style (X) in preparation:

Wherein:

G " be selected from-O-and-S-;

A ², L ², E ²And J ²Be selected from NR ⁴ ₂,-NO ₂,-H ,-OR ²,-SR ²,-C (O) NR ⁴ ₂, halo ,-COR ¹¹,-SO ₂R ³, guanidine radicals, amidino groups, aryl, aralkyl, alkoxyalkyl ,-SCN ,-NHSO ₂R ⁹,-SO ₂NR ⁴ ₂,-CN ,-S (O) R ³, perhalogeno acyl group, perhaloalkyl radical, perhalogeno alkoxyl group, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl group and rudimentary alicyclic radical, perhaps L ²And E ²Or E ²And J ²Form cyclic group together;

Prerequisite is X ²Can't help-COOR ²,-SO ₃R ¹Or-PO ₃R ¹ ₂Replace;

Y independently is selected from-O-and-NR ⁶-;

When Y be-during O-, then be connected in-R1 of O-independently is selected from-H, alkyl, the optional aryl that replaces, the optional wherein loop section that replaces contain carbonic ether or thiocarbonic ester alicyclic radical, the optional replacement-alkylaryl ,-C (R ²) ₂OC (O) NR ² ₂,-NR ²-C (O)-R ³,-C (R ²) ₂-, OC (O) R ³,-C (R ²) ₂-O-C (O) OR ³, C (R ²) ₂OC (O) SR ³,-alkyl-S-C (O) R ³,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy,

Wherein

P is 2 or 3 integer;

Q is 1 or 2 integer;

Prerequisite is:

A) V, Z, W, W ' not all are-H; And

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical and aralkyl;

R ¹¹Be selected from alkyl, aryl ,-NR ² ₂With-OR ²

60. prodrug according to claim 1, the acyloxy alkyl ester that wherein said prodrug is represented for formula A,

Formula A

Wherein R, R ' and R " independent be H, alkyl, aryl, alkylaryl and alicyclic radical.

61. prodrug according to claim 1, the acyloxy alkyl ester that wherein said prodrug is represented for formula B,

Formula B

62. the dibasic acid esters of the alkoxy-carbonyl oxy methyl esters that prodrug according to claim 1, wherein said prodrug are represented for formula A,

Formula A

Wherein R is alkoxyl group, aryloxy, alkylthio, arylthio, alkylamino and arylamino; R ' and R " be H, alkyl, aryl, alkylaryl and alicyclic radical independently.

63. prodrug according to claim 1, the aryl ester that wherein said prodrug is represented for formula C

Formula C

64. prodrug according to claim 1, the benzyl ester that wherein said prodrug is represented for formula D

Formula D

Wherein X and Y independently are H, alkyl, aryl, alkylaryl, alkoxyl group, acyloxy, hydroxyl, cyano group, nitro, perhaloalkyl radical, halo or alkoxyl group dress base; With

R ', and R " be H, alkyl, aryl, alkylaryl, halogen and alicyclic radical independently.

65. prodrug according to claim 1, the preceding ester of Thiophosphonate that wherein said prodrug is represented for formula E,

Formula E

Ester before the phosphonic acid ester that 66. prodrug according to claim 1, wherein said prodrug are formula E-1, E-2 and E-3 to be represented,

E-1???????????????????????????????E-2???????????????????????????E-3

Wherein R is-H, alkyl, cycloalkyl or alicyclic radical; With

67. prodrug according to claim 1, the phosphonic acids propyl ester that wherein said prodrug is represented for formula F,

Formula F

Wherein R is alkyl, aryl, heteroaryl;

X is hydrogen, alkyl-carbonyl oxygen base, alkoxy-carbonyl oxy; With

68. prodrug according to claim 1, the phosphoramidate that wherein said prodrug is represented for formula G,

Formula G.

69. prodrug according to claim 1, wherein said prodrug are the cyclic amino phosphoric acid ester.

70. the S-acyl group-2-sulfo-ethyl ester that prodrug according to claim 1, wherein said prodrug are represented for formula H and the combination of phosphoramidate,

Formula H.