CN101573033A - Heterocyclyl-substituted anti-hypercholesterolemic compounds - Google Patents

Abstract

This invention provides cholesterol absorption inhibitors of Formula I: and the pharmaceutically acceptable salts thereof, wherein R<12> is a hydroxylated alkyl group and R<9> contains a heterocyclic ring. The compounds are useful for lowering plasma cholesterol levels, particularly LDL cholesterol, and for treating atherosclerosis and preventing atherosclerotic disease events.

Description

The compound that the heterocyclic radical of anti-hypercholesterolemiccompounds replaces

Background of invention

The 2-azetidinone (azetidinones) and pharmaceutically acceptable salt and the ester that the present invention relates to replace, and relate to the developing purposes that they are combined in treatment hypercholesterolemia and prevention separately or with other active drug, stop or slow down atherosclerotic and associated conditions and disease incident.

Recent decades, clear and definite, the blood cholesterol levels of rising is the major risk factors of coronary heart disease, and many researchs show, can reduce the risk of CHD incident by the lipopenicillinase therapy.Before 1987, the lipopenicillinase material is limited to low saturated fat and cholesterol diet substantially, cholic acid chelating agent (Cholestyramine and Colestipol), nicotinic acid (nicotinic acid), the special class of shellfish and probucol.Unfortunately, the effect of all these treatments is or/and tolerance is limited.By making lipopenicillinase diet and cholic acid chelating agent combination (adding or do not add nicotinic acid), the substance that can realize being accompanied by LDL (low-density lipoprotein) cholesterol that HDL (high-density lipoprotein (HDL)) cholesterol increases reduces.Yet this treatment is difficult for administration or tolerance, and thereby usually unsuccessful, remove non-special lipopenicillinase clinic.The special class of shellfish produces the appropriateness reduction that is accompanied by the LDL cholesterol that the HDL cholesterol increases and the substance of triglycerides reduces, because they tolerate fully by these medicines of more extensive employing.Probucol only reduces the LDL cholesterol on a small quantity and reduces the HDL cholesterol, because the inverse relation between HDL cholesterol levels and CHD risk it is generally acknowledged that this is unwelcome.Along with Lovastatin, the introducing of first kind of inhibitor of the HMG-CoA reductase that can in prescription in 1987, obtain first, the doctor can obtain to follow the very big reduction of the plasma cholesterol of few side effect.

Research clearly shows, Lovastatin, Simvastatin and Pravastatin, all members of HMG-CoA reductase inhibitor class, all development that slows down atherosclerotic lesions in crown and arteria carotis.Simvastatin and Pravastatin have also shown the risk that reduces coronary event, and under the situation of Simvastatin, the Simvastatin survival study of Scandinavian has shown the risk that the utmost point reduces coronary heart disease death and general mortality rate significantly.This research also provides some evidence that reduces cerebrovascular disease.Although the substantive risk that reduces Incidence of CHD and lethality of Simvastatin, risk still substantially is present in is treated among the patient.For example, in the Simvastatin survival study of Scandinavian, the coronary heart disease death risk reduces by 42% and still stays 5% the patient that treated and die from this 5 years flow of research because of their disease.Obviously need further to reduce risk.

The antihyperlipidemic drug of the updating type that has occurred comprises the inhibitor of cholesterol absorption.Ezetimibe is subjected to first kind of compound of regulatory approval, at present with trade name in this class

Go on the market in the U.S..Ezetimibe has following chemical constitution, and is described in U.S. Patent number Re.37721 and 5,846, in 966:

Sugar-substituted 2-azetidinone comprises glucuronidation (glucuronidated) analog of following universal architecture:

And preparation method thereof be described in U.S. Patent number 5,756, in 470, Ar wherein ¹And Ar ²Be the aryl that does not replace or replace.

Other cholesterol absorption inhibitor is described in WO2002/066464A1 (application of Kotobuki drugmaker) and US2002/0137689A1 (Glombik etc.).WO2002/066464A1 openly has the reducing blood lipid compound of following general formula

Wherein, together with other definition, A ₁, A ₃And A ₄Can be

R wherein ₂Be-CH ₂OH ,-CH ₂OC (O)-R ₁Or-CO ₂R ₁R ₃Be-OH or-OC (O) R ₁, and R ₄Be-(CH ₂) _kR ₅(CH ₂) _i-, wherein k and i be 01 or bigger integer and k+i be 10 or littler integer; R ₅Be singly-bound ,-CH=CH-,-OCH ₂-, carbonyl or-CH (OH).

US2002/0137689A1 openly has the reducing blood lipid compound of following general formula

Wherein, in its definition, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶Separate, can be (C ₀-C ₃₀)-alkylidene-(LAG), wherein one or more carbon atoms of alkylidene can by-O-,-(C=O)-,-CH=CH-,-C ≡ C-,-N ((C ₁-C ₆)-alkyl)-,-N ((C ₁-C ₆)-alkyl phenyl) or-NH-substitutes; (LAG) be saccharide residue, two saccharide residues, three saccharide residues, tetrose residue; Saccharic acid or aminosugar.

In the effort of just carrying out of finding new treatment hyperlipidemia and Atherosclerosis, the invention provides new following cholesterol absorption inhibitor.

Summary of the invention

An object of the present invention is to provide new cholesterol absorption inhibitor and the pharmaceutically acceptable salt thereof of formula I.

Second purpose of the present invention provides the method that suppresses cholesterol absorption, and it comprises the formula I compound that needs the patient treatment of such treatment effective dose.Another purpose provides the reduction plasma cholesterol, especially the LDL-cholesterol levels and the treatment hypercholesterolemia method, it comprises the formula I compound that needs the patient treatment of such treatment effective dose.

As further purpose, prevention being provided or reducing development atherosclerotic risk and prevention or slow down is the tangible method of Atheromatosis development clinically, and it comprises the formula I compound that faces development atherosclerotic risk or suffered from atheromatous patient's prevention or treatment effective dose when suitable.Another object of the present invention is that The compounds of this invention is used for the treatment of, prevents in preparation or reduces purposes in the medicine of risk of these diseases of development.Other purpose of the present invention provides the method for preparation I compound and the new Pharmaceutical composition that comprises these compounds is provided.

In addition, The compounds of this invention, especially the radioisotope of formula I compound can be used for screening test, and test wherein is designed to differentiate the new cholesterol absorption inhibitor with mechanism of action identical with ezetimibe.From following detailed description, other purpose is apparent.

Detailed Description Of The Invention

New cholesterol absorption inhibitor of the present invention is to have compound in structural formula I

And pharmaceutically acceptable salt, wherein

Ar ¹Be selected from aryl and R ⁴The aryl of-replacement;

X, Y and Z independently are selected from-CH ₂-,-CH (C _1-6Alkyl)-and-C (C _1-6Alkyl) ₂-;

R is selected from-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁸,-O (CO) NR ⁶R ⁷, saccharide residue, two saccharide residues, three saccharide residues and tetrose residue;

R ¹Be selected from-H ,-C _1-6Alkyl and aryl, or R and R ¹Be oxo together;

R ²Be selected from-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁸With-O (CO) NR ⁶R ⁷

R ³Be selected from-H ,-C _1-6Alkyl and aryl, or R ²And R ³Be oxo together;

Q and r are that each independently is selected from 0 and 1 integer, and prerequisite is that at least one is 1 among q and the r;

M, n and p are that each independently is selected from 0,1,2,3 and 4 integer, and prerequisite is that the summation of m, n, p, q and r is 1,2,3,4,5 or 6;

T is selected from 0,1 and 2 integer;

R ⁴Be when occurring, independently to be selected from a following 1-5 substituting group :-OR at every turn ⁵,-O (CO) R ⁵,-O (CO) OR ⁸,-O-C _1-5Alkyl-OR ⁵,-O (CO) NR ⁵R ⁶,-NR ⁵R ⁶,-NR ⁵(CO) R ⁶,-NR ⁵(CO) OR ⁸,-NR ⁵(CO) NR ⁶R ⁷,-NR ⁵SO ₂R ⁸,-COOR ⁵,-CONR ⁵R ⁶, COR ⁵,-SO ₂NR ⁵R ⁶,-S (O) _tR ⁸,-O-C _1-10Alkyl-COOR ⁵,-O-C _1-10Alkyl-CONR ⁵R ⁶With the fluoro base;

R ⁵, R ⁶And R ⁷When occurring, independently be selected from-H ,-C. at every turn _1-6Alkyl, aryl and aryl replace-C _1-6Alkyl;

R ⁸Be selected from-C _1-6Alkyl, aryl and aryl replace-C _1-6Alkyl;

R ⁹Be selected from-C _1-8Alkyl-Hetcy ,-(CH ₂) _0-2CH=CH-C _0-6Alkyl-Hetcy ,-C ≡ C-C _0-6Alkyl-Hetcy and-C _1-8Alkyl-NH-Hetcy,

Hetcy is selected from:

(a) contain individual heteroatomic 5 yuan of aromatics of the 1-4 that is selected from 1-4 N, 0-1 S and 0-1 O or part unsaturated heterocycle, heterocycle wherein is optional by R ¹⁴List or two replaces,

(b) contain 1-3 the heteroatomic 6 yuan of aromatic heterocycles of N, heterocycle wherein is optional by R ¹⁴Single-or two replace and

(c) contain and be selected from 1-3 N, 0-1 O and 0-1 S (O) _t1-3 heteroatomic 6 yuan of saturated heterocyclics, heterocycle wherein is optional by R ¹⁴List or two replaces;

R ^10aOne or more substituting group that is optional being selected from-OH, phenyl and 1-3 fluoro base replaces-C _1-3Alkyl;

R ¹⁰Be selected from-one or more substituting group replacement of H and optional being selected from-OH, phenyl and 1-3 fluoro base-C _1-3Alkyl;

R ¹¹Be selected from-H and optional being selected from-OH, one or more substituting group of phenyl and 1-3 fluoro base replaces-C _1-3Alkyl;

R ¹²Be selected from by-OH single or polysubstituted-C _1-15Alkyl, quilt-OH is single or polysubstituted-C _2-15Alkenyl, quilt-OH is single or polysubstituted-C _2-15Alkynyl, and-C _1-3Alkyl-C _3-6Cycloalkyl, wherein the optional quilt-OH of each carbon in the cycloalkyl ring replaces;

R ¹³Be selected from-H and-OH; With

R ¹⁴When occurring, independently be selected from: R at every turn ^10a,-C _1-3Alkyl-COOR ¹⁰,-C _1-3Alkyl-C (O) NR ¹⁰R ¹¹,-C _1-3Alkyl-SO ₂-R ^10a,-C _1-3Alkyl-O-R ^10a,-COOR ¹⁰,-OC (O)-R ^10a,-C (O) NR ¹⁰R ¹¹,-NR ¹⁰R ¹¹,-CN ,-OH and oxo base.

One embodiment of the invention (this paper is called embodiment A) are formula I compound, wherein R ⁹Be selected from-C _1-8Alkyl-Hetcy ,-(CH ₂) _0-2CH=CH-C _1-6Alkyl-Hetcy ,-C ≡ C-C _1-6Alkyl-Hetcy and-C _1-8Alkyl-NH-Hetcy, R ¹⁴When occurring, independently be selected from R at every turn ^10a,-C _1-3Alkyl-COOR ¹⁰,-C _1-3Alkyl-C (O) NR ¹⁰R ¹¹,-C _1-3Alkyl-SO ₂-R ^10a,-C _1-3Alkyl-O-R ^10a,-COOR ¹⁰,-OC (O)-R ^10a,-C (O) NR ¹⁰R ¹¹,-NR ¹⁰R ¹¹,-OH and oxo base.

Another embodiment of the invention is formula I compound and embodiment A, and wherein, when p is 0 and r when being 1, the summation of m, q and n is 1,2,3,4 or 5.

Another embodiment of the invention is formula I compound and embodiment A, wherein r be 0 and m be 0; More particularly, wherein r is 0, and m is 0, and q is 1, n be 1 and p be 1.

Another embodiment of the invention is formula I compound and the embodiment A with structural formula Ia,

And pharmaceutically acceptable salt, wherein variable (Ar ¹, R, R ¹, R ⁹, R ¹², R ¹³) suc as formula defining among I or the embodiment A.

Another embodiment of the invention is formula I compound and the embodiment A with structural formula Ib,

And pharmaceutically acceptable salt, variable (R wherein ⁹, R ¹², R ¹³) suc as formula defining among I or the embodiment A.

Another embodiment of the invention is formula I, Ia compound or embodiment A, wherein Ar ¹Be selected from aryl and R ⁴The aryl that replaces, wherein R ⁴Be when occurring, independently to be selected from a following 1-2 substituting group :-OR at every turn ⁵,-O (CO) R ⁵,-O (CO) OR ⁸,-O-C _1-5Alkyl-OR ⁵,-O (CO) NR ⁵R ⁶,-NR ⁵R ⁶,-NR ⁵(CO) R ⁶,-NR ⁵(CO) OR ⁸,-NR ⁵(CO) NR ⁶R ⁷,-NR ⁵SO ₂R ⁸,-COOR ⁵,-CONR ⁵R ⁶,-COR ⁵,-SO ₂NR ⁵R ⁶,-S (O) _tR ⁸,-O-C _1-10Alkyl-COOR ⁵,-O-C _1-10Alkyl-CONR ⁵R ⁶With the fluoro base.In a class of the present embodiment, Ar ¹Be unsubstituted, single or dibasic phenyl.In a subclass, Ar ¹By the mono-substituted phenyl of fluoro base, especially 4-fluoro-phenyl.

Another embodiment of the invention is formula I, Ia compound or embodiment A, and wherein R is-OR ⁶In this embodiment of a type, R is-OH.

Another embodiment of the invention is formula I, Ia compound or embodiment A, wherein R ¹Be-H.

Another embodiment of the invention is formula I compound or embodiment A, wherein R ²Be-OR ⁶In this embodiment of a type, R ²Be-OH.

Another embodiment of the invention is formula I compound or embodiment A, wherein R ³Be-H.

Another embodiment of the invention is formula I, Ia, Ib compound or embodiment A, wherein R ⁹Be-C _1-8Alkyl-Hetcy.In this embodiment of a type, R ⁹Be-C _2-3Alkyl-Hetcy.More particularly, make the in succession R of phenyl ring of Hetcy ⁹Moieties be positive alkyl.

Another embodiment of the invention is formula I, Ia, Ib compound or embodiment A, wherein R ⁹Be-(CH _{2) 0-2}CH=CH-C _0-6Alkyl-Hetcy.In this embodiment of a type, R ⁹Be-CH=CH-C _0-6Positive alkyl-Hetcy, more particularly, it is-CH=CH-C _0-1-alkyl-Hetcy.

Another embodiment of the invention is formula I, Ia, Ib compound or embodiment A, wherein R ⁹Be-C ≡ C-C _0-6Alkyl-Hetcy.In this embodiment of a type, R ⁹Be-C ≡ C-C _0-6Positive alkyl-Hetcy, more particularly, it is-C ≡ C-C _0-1Alkyl-Hetcy.

Another embodiment of the invention is formula I, Ia, Ib compound or embodiment A, wherein R ⁹Be-C _1-8Alkyl-NH-Hetcy.In this embodiment of a type, R ⁹Be-C _1-3Alkyl-NH-Hetcy.

Another embodiment of the invention is formula I, Ia, Ib compound or embodiment A, and wherein Hetcy contains individual heteroatomic 5 yuan of aromatics of the 1-4 that is selected from 1-4 N, 0-1 S and 0-1 O or part unsaturated heterocycle, and heterocycle wherein is optional by R ¹⁴List or two replaces.The example of this class heterocycle in the implication of Hetcy includes but not limited to following heterocycle, and they each can be chosen wantonly by R ¹⁴List or two replaces:

Another embodiment of the invention is formula I, Ia, Ib compound or embodiment A, and wherein Hetcy contains 1-3 the heteroatomic 6 yuan of aromatic heterocycles of N, and ring especially wherein contains 1-2 N, and heterocycle wherein is optional by R ¹⁴List or two replaces.The example of this class heterocycle in the implication of Hetcy includes but not limited to following heterocycle, and each in them can be chosen wantonly by R ¹⁴List or two replaces:

Another embodiment of the invention is formula I, Ia, Ib compound or embodiment A, and wherein Hetcy contains to be selected from 1-3 N, 0-1 or O and 0-1 S (O) _t1-3 heteroatomic 6 yuan of saturated heterocyclics, heterocycle wherein is optional by R ¹⁴Replace.The example of this class heterocycle in the implication of Hetcy includes but not limited to following heterocycle, and each in them can be chosen wantonly by R ¹⁴List or two replaces:

Another embodiment of the invention is formula I, Ia, Ib compound or embodiment A, wherein R ¹⁰Be selected from-H and methyl.

Another embodiment of the invention is formula I, Ia, Ib compound or embodiment A, wherein R ¹¹Be selected from-H and methyl.

Another embodiment of the invention is formula I, Ia, Ib compound or embodiment A, wherein R ¹²By-OH single or polysubstituted-C _1-15Alkyl.In this embodiment of a type, R ¹²By-OH single or polysubstituted-C _1-8Alkyl.In the subclass of this class, R ¹²By-OH single or polysubstituted-C _3-6Alkyl.In the further subclass of this class, R ¹²Be-(CH ₂) _2-3-C (OH) (CH ₂OH) ₂

Another embodiment of the invention is formula I, Ia, Ib compound or embodiment A, wherein R ¹²By-OH single or polysubstituted-C _2-15Alkenyl.In this embodiment of a type, R ¹²By-OH single or polysubstituted-C _2-8Alkenyl.In the subclass of this class, R ¹²By-OH single or polysubstituted-C _3-6Alkenyl.In the further subclass of this class, R ¹²Be-(CH ₂) _0-1-CH=CH-C (OH) (CH ₂OH) ₂

Another embodiment of the invention is formula I, Ia, Ib compound or embodiment A, wherein R ¹²By-OH single or polysubstituted-C _2-15Alkynyl.In this embodiment of a type, R ¹²By-OH single or polysubstituted-C _2-8Alkynyl.In the subclass of this class, R ¹²By-OH single or polysubstituted-C _3-6Alkynyl.In the another subclass of this class, R ¹²Be-(CH ₂) _0-1-C ≡ C-C (OH) (CH ₂OH) ₂

As any variable (for example, X, Y, Z, R ⁵, R ⁶, R ¹⁰, R ¹¹, R ¹⁴, etc.) in the time of in universal architecture, can occurring more than once, when occurring, independently select its definition at every turn, therefore, it may be identical or different in the definition of each tie point.

At each variable (that is Ar, among formula I, Ia and the Ib ¹, R, R ¹, R ⁹, R ¹²Deng) above-mentioned each embodiment, class or subclass, can with merge at above-mentioned one or more embodiments of one or more other variablees, class or subclass, the general subgroup of all these classes is closed and is comprised within the scope of the invention.

" alkyl " is intended to comprise straight chain and the side chain saturated fat alkyl with particular carbon atomicity as used herein.The example of alkyl comprises, but be not limited to, methyl (Me), ethyl (Et), n-pro-pyl (Pr), normal-butyl (Bu), n-pentyl, n-hexyl and their isomer, for example, isopropyl (i-Pr), isobutyl group (i-Bu), sec-butyl (s-Bu), the tert-butyl group (t-Bu), 1-methyl-propyl, 2-methyl butyl, 3-methyl butyl, isopentyl, isohesyl etc.

" alkenyl " means and contains at least one carbon-to-carbon double bond, and it can be the carbochain of straight or branched or their combination.Non-limiting examples of alkenyls comprises vinyl, pi-allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-acrylic, 2-cyclobutenyl, 2-methyl-2-butene base etc.

" alkynyl " means and contains at least one carbon-to-carbon triple bond, and it can be the carbochain of straight or branched or their combination.The example of alkynyl comprises acetenyl, propargyl, 3-methyl-1-pentene alkynyl, 2-heptyne base etc.

" cycloalkyl " means the monocycle saturated carbon ring.The example of cycloalkyl includes, but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc.

Some alkyl, alkenyl and alkynyl (being referred to as " alkane (alk) " chain) are defined as " quilt-OH is single or polysubstituted " herein, meaning one or more hydroxyl substituents appears on the alkane chain, the alkane chain replaces each carbon atom that obtains and can not be substituted independently or be replaced by the hydroxyl list, prerequisite is that at least one carbon atom is replaced by hydroxyl.This comprises-CH ₂OH and longer alkane chain, wherein each available carbon atom is replaced by the hydroxyl list, and wherein is not that all available carbon atoms are by the mono-substituted alkane chain of hydroxyl.In described alkenyl chain, preferred unsaturated carbon is not replaced by hydroxyl, although this class carbon can be converted into the carbon that saturated hydroxyl replaces.Single or the polysubstituted alkane chain of quilt-OH can contain at the most 15 as at R ¹²In defined carbon, comprise and contain still less carbon, for example, but be not limited to the straight chain and the side chain of 1-8 carbon (to alkyl), a 2-8 carbon, a 3-8 carbon, a 4-8 carbon, a 5-8 carbon, a 5-6 carbon etc.

During the building-up process for the end product in the preparation scope of the invention, hydroxyl protecting group can be used on the intermediate.The protecting group suitable to hydroxyl, for example, at R ¹²And R ¹³In those; include but not limited to, for example, known as hydroxyl protecting group those; for example, benzyl, acetyl group, benzoyl, t-butyldiphenylsilyl, trimethyl silyl, to methoxy-benzyl, benzal, dimethylacetal and methoxy.Selectivity adds or removes this class protecting group conditions needed and see standard textbook, for example, and Greene, T and Wuts, P.G.M., the protecting group in the organic synthesis, John Wiley﹠amp; Sons, Inc., New York, NY, 1999.

" aryl " is intended to comprise phenyl (Ph), naphthyl, indenyl, tetralyl or 2,3-indanyl as used herein.Preferred phenyl.

Term " heterocycle " and derivative thereof, for example, " heterocyclic radical " and " heterocycle " means and contains one or more carbon atoms and one or more hetero atom, for example, the aromatics of nitrogen, oxygen and sulphur, part is unsaturated or saturated rings, but under the suitable in this manual situation, for example, hetero atom type and quantity about in member's (that is, atom) quantity and/or the ring in degree of saturation, the ring may more clearly be defined.Except as otherwise noted, the tie point in the compound structure can be by causing any carbon or the nitrogen of rock-steady structure in the heterocycle.Except as otherwise noted, heterocycle can produce in ring on any available carbon of rock-steady structure or the nitrogen and be substituted.

Formula I compound can comprise one or more asymmetric (that is, chirality) center, and thereby can be used as racemic modification and racemic mixture, single enantiomter, enantiomeric mixture, non-enantiomer mixture and single diastereoisomer and occur.This class isomeric form of all of formula I compound all comprises within the scope of the invention.In addition, some crystalline form of The compounds of this invention can be used as polymorph and exists, and therefore, all amorphous and crystalline form all plan to comprise within the scope of the invention.In addition, some The compounds of this invention can form solvate with water or organic solvent.This class hydrate and solvate are also included within the scope of the invention.

Some compound as herein described can comprise the two keys of alkene, except as otherwise noted, plans to comprise single or as the E and the Z geometric isomer of mixture.

Include in some compound of this paper and can be used as dynamic isomer, for example, the ketoenol tautomerization body exists.In order to illustrate, as following giving an example, when Hetcy by the oxo base replace 5 yuan of heterocycles the time, the compound that is generated can have tautomerism:

When the interconvertible isomery of The compounds of this invention, dynamic isomer that all are independent and composition thereof all comprises within the scope of the invention.

Those compounds that The compounds of this invention are called this paper " formula I " also comprise what each subclass was described, the defined compound of each scope of formula Ia and Ib for example, and the unification compound in any scope of these subclass descriptions, unless in context, for example, how to prepare mark (addressed) structure subgroup compound in the synthetic description of some compound in the structure subgroup.The compounds of this invention is called " formula I ", " formula Ia " and " formula Ib " or is used for those compounds of any other universal architecture formula of this paper, plan to include the compound in each the scope that drops on these structural formulas, the pharmaceutically acceptable salt and the ester that comprise them are if this class salt and ester may exist.Here, term " pharmaceutically acceptable salt " means the nontoxic salts that is used for compound of the present invention, it is generally by making free acid and suitable organic or inorganic alkali, especially form from cation, for example, sodium, potassium, aluminium, calcium, lithium, magnesium, those alkali reaction preparations of zinc and tetramethylammonium, and form from amine, for example, ammonia, ethylenediamine, the N-methylglucosamine, lysine, arginine, ornithine, choline, N, N '-dibenzyl-ethylenediamin, chloroprocanine, diethanol amine, procaine, the N-benzyl-1-phenylethylamine, 1-to chloro benzyl-2-pyrrolidines-1 '-Ji-tolimidazole, diethylamine, piperazine, morpholine, 2,4, those salt that 4-trimethyl-2-amylamine and three (methylol) aminomethane forms.

When The compounds of this invention was alkalescence, salt can prepare from pharmaceutically acceptable non-toxic acid, comprised inorganic or organic acid.This class acid comprises acetate, trifluoroacetic acid, benzene sulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, glactaric acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-methyl benzenesulfonic acid etc.

Equally, carboxylic acid (COOH) or alcohol groups come across under the situation of The compounds of this invention, can adopt the pharmaceutically acceptable ester of carboxylic acid derivates, for example ,-C _1-4Alkyl, by phenyl replace-C _1-4Alkyl, acetyl-amino and oxy acid methyl neopentyl, perhaps Chun acyl derivative, for example, adjacent acetyl group, adjacent valeryl, o-benzoyl base, adjacent dimethylamino and adjacent acetyl-amino.Comprise within the scope of the present invention be known in the artly to be used to modify as continuing to discharge or dissolubility or those esters of hydrolysising property and the acyl group of the compound of prodrug formulation.

Term " patient " comprises mammal, the especially people who adopts prevention of this active agents or treatment medical conditions.Administration to the patient comprises automedication and gives the patient by another people.The patient may need to treat present illness or medical conditions, perhaps may wish prophylactically to treat, with prevention or reduce because of suppressing the disease that cholesterol absorption influences and the risk of medical conditions.

Term " treatment effective dose " is intended to represent that researcher, animal doctor, doctor or other clinician look for that tissue, system, animal or human are produced the amount of the medicine of biology or medicinal response.Term " prevention effective dose " is intended to the amount of the medicine of the risk representing the prevention that researcher, animal doctor, doctor or other clinician look for or reduce tissue, system, animal or human's developmental biology or the medical events that will prevent.Especially, the dosage that can select the patient to accept is so that realize the reduction of desirable LDL cholesterol amount; The also dosage accepted of titration patient in time is to reach target LDL level.According to various factors, comprise patient's type, kind, age, body weight, sex and medical conditions; The seriousness of the illness for the treatment of; The usefulness of the selected compounds that gives; Method of administration; With patient's kidney and liver function, select to adopt the dosage of The compounds of this invention.For the needed treatment of development determining prevention, antagonism or stop illness effectively or the prevention effective dose, to the consideration of these factors fully in common clinician's scope.

The compounds of this invention is a cholesterol absorption inhibitor, when separately or with another kind of active agents, for example, antiatherosclerotic, cholesteral biosynthesis inhibitor more especially, for example, the HMG-CoA reductase inhibitor is united when using, be used to reduce blood plasma cholesterol level, especially reduce blood plasma LDL cholesterol levels.Therefore, the invention provides and suppress cholesterol absorption and treat the method that the fat obstacle comprises hypercholesterolemia, it comprises the formula I compound of the human therapy effective dose that needs this class treatment.The term hypercholesterolemia includes but not limited to homozygote familial hypercholesterolemia (HoFH) and heterozygote familial hypercholesterolemia (HeFH), and therefore, formula I compound can be used to treat HoHF and HeHF patient.These compounds also can be used for treating the hyperlipidemia of mixing, it is characterized in that, in company with the LDL cholesterol levels of undesirable low HDL cholesterol levels rising together and the triglyceride levels of rising.Formula I compound also can be used to treat or prevent sitosterolemia and/or reduce patient's blood plasma or tissue in be not the concentration of one or more sterol of cholesterol.

In case prevention further is provided or reduces the method that develops atherosclerotic risk and prevention or slow down the atheromatous development that becomes clinical events, it comprises the formula I compound that is in the atherosclerotic risk of development in due course or has suffered from atheromatous mammal prevention or treatment effective dose.

Atherosclerotic comprises vascular disease that the doctor was familiar with and understood and the illness of putting into practice in the medical science association area.Comprise that the postoperative ISR of revascularization, coronary heart disease (being also referred to as coronary artery disease or ischemic heart disease), cranial vascular disease comprise that multi-infarct dementia and peripheral vascular disease comprise that the atherosclerotic angiocardiopathy of erectile dysfunction is atherosclerotic whole clinical manifestation, and thereby included by term " atherosclerotic " and " Atheromatosis ".

But giving construction I compound is with prevention or reduce the risk that the recurrence that maybe may exist takes place for coronary event, cerebrovascular disease and/or Charcot's syndrome.Coronary event plans to comprise CHD death, myocardial infarction (that is heart attack) and the operation of coronary artery revascularization.Cerebrovascular disease plans to comprise ischemic or hemorrhagic cerebral apoplexy (being also referred to as cerebrovas-cularaccident) and transient ischemia's outbreak.Charcot's syndrome is the clinical manifestation of peripheral artery disease.Coronary event, cerebrovascular events and Charcot's syndrome are included in term " Atheromatosis incident " plan as used herein.Those people of the possibility that previous this class incident of artificial existence that has experienced the non-fatal Atheromatosis incident of one or many of expection recurs.

Therefore, the present invention also provides prevention or reduces the method for the first or secondary risk of Atheromatosis incident, and it comprises that the patient of the risk that faces this kind incident prevents the formula I compound of effective dose.During administration, the patient may suffer from or may not suffer from Atheromatosis, perhaps may be in its risk of development.

People with this therapy for treating comprises those people that are in the development Atheromatosis and suffer from the risk of Atheromatosis incident.The Atheromatosis risk factors of standard are to be practiced in known to the gengral practitioner of medical science association area.The known risk factors of this class include but not limited to the family history of hypertension, smoking, diabetes, low-level high-density lipoprotein (HDL) (HDL) cholesterol and atherosclerotic angiocardiopathy.Determine that the guide that is in the announcement that develops those people in the Atheromatosis risk can be found in: the executive overview (III of adult treatment group) of report for the third time of the high blood cholesterol levels of being grown up is just detected, estimates and treated in national cholesterol education outline (NCEP) panel of expert, JAMA, 2001; 285, the 2486-2497 page or leaf.Plan will be accredited as the people with one or more above-mentioned risk factors be included in think face the development atheromatous risk the crowd in.Plan will be accredited as the people with one or more above-mentioned risk factors and suffer from atherosclerotic people and be included in and be considered to face among the crowd who suffers from the Atheromatosis event risk.

The oral dose of formula I compound is the about 30mg/kg body weight of about 0.1-every day, the preferred about 15mg/kg body weight of about 0.1-every day.Therefore, for the average weight of 70kg, dosage level is the about 1000mg medicine of about 5mg-every day.Yet dosage will be with factor as mentioned above, comprises the usefulness of specific compound and becomes.Although the dosage that active medicine of the present invention can separate for example gives for 2-4 time every day, but still the active medicine of preferred single daily dose.As an example, daily dose can be selected from, but is not limited to, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 75mg, 80mg, 100mg and 200mg.

Can be used for the active medicine of this therapy by the oral form of this class as tablet, capsule, pill, powder, granule, elixir, tincture, supensoid agent, syrup and emulsion.Preferred oral preparation, especially solid orally ingestible, for example tablet.

For formula I compound, can give active medicine through any pharmaceutically acceptable approach with any pharmaceutically acceptable formulation.This comprises the oral conventional rapid release of employing, time sustained release and postpones to discharge (such casing) pharmaceutical dosage form.The Pharmaceutical composition that is suitable for regard to used other of the present invention is known to those those of ordinary skill in the drug world; For example, referring to the Remington pharmaceutical science, Mack Publishing Co., Easton, PA.

In the method for the invention, active medicine gives with the mixture with suitable medicinal diluent, excipient or carrier (this paper is referred to as " carrier " material) usually, and described carrier is suitably selected according to the form of medication (being oral tablet, capsule, elixir, syrup etc.) of planning and be consistent with conventional pharmacy practice.

For example, for being the oral of tablet or Capsule form, active medicine component can with nontoxic, pharmaceutically acceptable inert carrier, for example combinations such as lactose, starch, sucrose, glucose, improvement sugar, modified starch, methylcellulose and derivative thereof, Dicalcium Phosphate, calcium sulphate, mannitol, sorbierite and other reduction and non reducing sugar, dolomol, stearic acid, sodium stearyl fumarate, Tridocosanoin, calcium stearate.For being the oral of liquid form, drug component can with nontoxic, pharmaceutically acceptable inert carrier, for example combinations such as ethanol, glycerine, water.And when hope or when needing, suitable bonding, lubricant, disintegrant and colouring agent and flavouring also can mix in the mixture.Also can add stabilizing agent, antioxidant for example, Butylated Hydroxyanisole (BHA), 2 for example, 6-di-t-butyl-4-sylvan (BHT), n-propyl gallate, sodium ascorbate, citric acid, sodium metabisulfite, quinhydrones and umbelliferone, especially BHA, n-propyl gallate and combination thereof is with stabilizer type.When formula I compound and HMG-CoA reductase inhibitor, when for example Simvastatin is prepared together, preferably in composition, adopt at least a stabilizing agent.Other suitable component comprises gelatin, sweetener, natural and paragutta, for example gum Arabic, bassora gum or alginates, carboxymethyl cellulose, polyethylene glycol, wax etc.

The present invention also comprises the method for preparing Pharmaceutical composition, and it comprises makes formula I compound mix with pharmaceutically acceptable carrier.Also comprise by making the Pharmaceutical composition of formula I compound and pharmaceutically acceptable carrier combinations preparation.

One or more other active agents also can be united with formula I compound and given, and therefore, embodiment of the present invention comprise drug regimen.Drug regimen comprises the single formulation of being made up of formula I compound and one or more other active medicines, and presses dosage particles separately giving construction I compound and one or more other active medicines separately, and this allows simultaneously or give in succession various active agents.One or more other active medicines can be the fat conditioning agent, cholesteral biosynthesis inhibitor especially, for example, HMG-CoA reductase inhibitor or have the medicine of other medical active, or have the medicine of fat regulating action and other pharmacologically active simultaneously.The example that is used for the HMG-CoA reductase inhibitor of this purpose comprises that being it lactonizes or Statins and the pharmaceutically acceptable salt and the ester of dihydroxy open chain acid (open acid) form, include but not limited to Lovastatin (

Referring to U.S. Patent number 4,342,767); Simvastatin (

Referring to U.S. Patent number 4,444,784); The acid of dihydroxy open chain Simvastatin, especially their ammonium or calcium salt; Pravastatin, especially its sodium salt (PRA V

Referring to U.S. Patent number 4,346,227); Fluvastatin, especially its sodium salt (

Referring to U.S. Patent number 5,354,772); Atorvastatin, especially its calcium salt (

Referring to U.S. Patent number 5,273,995); Rosuvastatin (

Referring to U.S. Patent number 5,260,440); With the Pitavastatin that is also referred to as NK-104 (referring to PCT international publication number WO 97/23200).The example of adoptable other active medicine includes but not limited to one or more FLAP inhibitor; The 5-lipoxidase inhibitor; Other cholesterol absorption inhibitor for example, is described in U.S. Patent number Re.37721 and 5,846,966 ezetimibe

CETP (CETP) inhibitor, for example, JTT-705 and be also referred to as CP529, a holder plug cloth (torcetrapib) of 414; The HMG-CoA synthase inhibitor; The squalene epoxidase inhibitor; Inhibitor for squalene synthetic enzyme (being also referred to as squalene synthase inhibitor); Acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor comprises the selective depressant of ACAT-1 or ACAT-2 and the double inhibitor of ACAT-1 and-2; Microsomal triglyceride transfer protein (MTP) inhibitor; Nicotinic acid; Nicotinic acid receptor agonists, for example acipimox and acifran (acifran) and niacin receptor partial activator; LDL (low-density lipoprotein) receptor inducer; RA233, for example, glycoprotein iib/iiia fibrinogen deceptor antagonistic and aspirin; Human peroxisome paraphyte activated receptor γ (PPAR γ) activator, comprise the compound that is commonly referred to glitazone (glitazones), for example Pioglitazone and Rosiglitazone comprise those compounds of being contained in the structure class that is called thiazolidinedione and those PPAR gamma agonists outside the thiazolidinedione structure class; PPAR alfa agonists, for example Clofibrate, the fenofibrate that comprises the micronizing fenofibrate and Gemfibrozil; Dual α/the gamma agonist of PPAR; Cobastab ₆(being also referred to as pyridoxine) and pharmaceutically acceptable salt thereof, for example, HCl salt; Cobastab ₁₂(being also referred to as vitamin b23); Folic acid or its pharmaceutically acceptable salt or ester, for example sodium salt and methyl glucoside amine salt; Antioxidant vitamins, for example, vitamin C and E and bata-carotene; Beta blocker; Angiotensin II antagonistic, for example Losartan; Angiotensin converting enzyme inhibitor, for example enalapril and captopril; Calcium channel blocker, for example nifedipine and ground that sulphur

(diltiazam); Endothelin (endothelian) antagonistic; Promote the medicine of ABC1 gene expression; The FXR part comprises inhibitor and activator; With the LXR part, comprise the inhibitor and the activator of all hypotypes of this receptor, for example LXR α and LXR β; Bisphosphonate, for example, Alendronate sodium; And cyclooxygenase-2 inhibitor, for example, rofecoxib, celecoxib and valdecoxib.

When suitable, the formula I compound of treatment or prevention effective dose can be used to preparation and is used for above-mentioned treatment, for example, suppress cholesterol absorption and processing and/or reduction and suppressed the disease that cholesterol absorption influences and the risk of illness, for example, in case treatment fat obstacle, prevention or reduction develop atheromatous risk, stop or slow down atheromatous development and the prevention that becomes clinical manifestation or reduction Atheromatosis incident is first or the medicine of the risk of secondary.For example, medicine can be made up of the about 1000mg formula of about 5mg-I compound.Also available one or more other active medicines for example, the medicine that above-mentioned those preparations are made up of formula I compound.

Adopt following rat cholesterol absorption test, determine that The compounds of this invention suppresses cholesterol absorption.This test comprises the ability of the inhibition rat cholesterol absorption of comparative test compound and ezetimibe.Under the highest proof load, ezetimibe and tested The compounds of this invention suppress cholesterol absorption＞90%.ID 50＜the 1mg/kg of tested The compounds of this invention.

The cholesterol absorption test of rat: CD male rat (n=5/group), 5 weeks of age week, the oral 0.5ml that contains or do not contain test compound or ezetimibe (0.0003-1mg/kg) 0.25% methocel solution.0.5-16 after hour, the oral 5 μ Ci[that contain of every rat in all rats ³H]-0.5ml of cholesterol After 5 hours, painless deadly animal is collected liver and blood.Determine the cholesterol amount in liver and the blood plasma, calculate the inhibition percentage of cholesterol absorption.

Structural formula I compound of the present invention can adopt suitable raw material according to following flow process and embodiment preparation, and further the specific embodiment by subsequently illustrates.And by adopting method as herein described, those of ordinary skills can easily prepare desired other The compounds of this invention of this paper.Yet the compound of each embodiment illustrated has more than to be limited to form thinks classification of the present invention.Each embodiment further describes the preparation of The compounds of this invention.One skilled in the art will readily appreciate that the condition of following preparation procedure and the known variant of technology can be used to prepare these compounds.

Various chromatographic techniques can be used to prepare this compound.These technology include, but are not limited to: comprise common-anti-phase-with chirality high performance liquid chroma-tography (HPLC) mutually; Medium pressure liquid chromatography (MPLC), supercritical fluid chromatography; Preparation type thin-layer chromatography (prep TLC); Flash chromatography with silica gel or reverse phase silica gel; Ion-exchange chromatography; With the radial development chromatography.Except as otherwise noted, all temperature are degree centigrade.

Some abbreviation that is used for this paper comprises:

Ac=acyl group (CH ₃C (O)-); Aq=is moisture; The Bn=benzyl; The Br=bromine; C=is Celsius; The calc.=calculated value; The DCM=carrene; DIEA=N, the N-diisopropylethylamine; The DMAP=4-dimethyl aminopyridine; DMF=N, dinethylformamide; The equiv.=equivalent; ES-MS=electron spray ion massspectrum method; EtOAc=ethyl acetate; H=hour; The HPLC=high pressure liquid chromatography (HPLC); I=iodine; Min=minute; Mp or Mpt=fusing point; The MPLC=medium pressure liquid chromatography; The MS=mass spectrum; NMO=N-methyl morpholine N-oxide; The OTf=triflate; Prep.=prepares type; R.t. (or rt or RT)=room temperature; Sat.=is saturated; The TBAI=tetrabutylammonium iodide; The TBS=t-butyldimethylsilyl; The TEA=triethylamine; The TFA=trifluoroacetic acid; The THF=oxolane; The TLC=thin-layer chromatography; The TMS=trimethyl silyl.

The method of the synthetic The compounds of this invention of following generalized flowsheet explanation.Except as otherwise noted, all substituting groups and variable (for example, R ¹, R ², Ar ¹, X, Y etc.) all such as in formula I definition.In each flow process, R ^12aExpression is by hydroxyl or protected hydroxyl is single or polysubstituted alkyl.

In flow process I, can make intermediate compound I-1 be converted into I-2 by guanidine and the triethylamine that is used in the methyl alcohol, optionally to remove acetate phenolic ester (phenolic acetate); By at triethylamine or N, under the existence of N-diisopropyl-N-ethamine, in the carrene medium, handle again, intermediate phenol is converted into triflate with two (trifluoromethyl sulfonyl) aminopyridines.Then, in suitable palladium catalyst, for example four triphenyl phasphine palladiums (O) or [1,1 '-two (diphenyl phosphine) ferrocene] palladium chloride (II) etc. and cuprous iodide (I) and initator are for example under the existence of iodate four positive fourth ammoniums, with containing R ^12aThe I-3 type Terminal Acetylenes (terminal alkyne) of group is handled intermediate compound I-2.This reaction is usually at inert organic solvents, and for example among the DMF, between the time of carrying out 6-48h between room temperature to 100 ℃, product is the interior alkynes (internal alkyne) with structural formula I-4.R in the intermediate compound I-3 ^12aGroup can have and has hydroxyl protection or unprotected alkynyl-R ^12aDerivative I-3.The example of hydroxyl protecting group (PG) comprises, with before or chemical reaction subsequently consistent, for example, benzyl, acetic acid esters, acetal or any oxygen protecting group that other is suitable for or their combination.As an example, R ^12aInclude but not limited to-C _1-6Alkyl-OBn and

At suitable palladium catalyst, for example, four (triphenyl phasphine) palladium (O) and cuprous iodide (I) and initator, for example, under the existence of tetrabutylammonium iodide, with the alkynyl-(CH of I-5 type ₂) _n-heteroaryl is handled the triflate I-4 that is generated.This reaction under RT to 50 ℃, at inert organic solvents, is for example carried out the time of 1-5h usually among the DMF, product has the alkynyl-(CH of structure I-6 ₂) _n-heteroaryl.By under atmosphere of hydrogen; at solvent for example in the ethyl acetate; handled 15-24 hour with 10% palladium on carbon catalyst; this pair of hydrogenation alkynes intermediate compound I-6; be accompanied by removing of any benzyl protecting group among the I-6; can realize the hydrogenation of triple bond, but wherein benzyl protecting group survives the substituent R of these hydrogenation conditions ¹³Except.If on heteroaryl, exist well known by persons skilled in the art, in the time of need making the useful protecting group that chemistry carries out in an easy manner, can comprise that extra going protect step.These protecting groups may comprise trityl, t-butyl carbamate group or be suitable for protecting the functional group of other group or the heterocyclic radical of ining succession well known by persons skilled in the art of heterocyclic compound.At this moment, can be hydrolyzed or cracking, perhaps can before step of hydrogenation, remove non-benzyl protecting group any residual hydroxy groups protecting group.For example, can remove and be contained in R by handling with aqueous acid ^12aIn the glycol as acetal protection.Work as R ^12aWhen containing one or more acetate group, at alcoholic solvent, for example; in the ethanol, at ambient temperature, or be heated to 50 ℃ and reach 1-2 hour; go protection with potassium cyanide or trimethyl silane potassium alcoholate (trimethylsilanoate), obtain free hydroxyl group, form The compounds of this invention I-7.Work as R ¹³When being 2-benzyloxy substituting group, need under atmosphere of hydrogen, adopt 10% palladium on carbon in the ethanol to go to protect step, obtain the phenyl that replaces as the 2-hydroxyl in I-7 type structure as final de-protected second.

Flow process I

In being shown in the selective method of flow process II, at suitable palladium catalyst, for example, four (triphenyl phasphine) palladium (O) and cuprous iodide (I) and initator, for example, under the existence of tetrabutylammonium iodide, can be used for adopting in the reaction of trimethyl silyl acetylene I-8 from the intermediate compound I-4 of above flow process I.This reaction, was for example carried out among the DMF 1-5 hour at atent solvent usually at RT to 50 ℃.Subsequently, the four positive fourth ammoniums of fluoridizing among the available THF are handled the intermediate with trimethyl silyl alkynyl down at O ℃, remove the TMS group, obtain the Terminal Acetylenes of structure I-9.This intermediate can be used for, at suitable palladium catalyst, for example, four (triphenyl phasphine) palladium (O) and cuprous iodide (I) and initator, for example, under the existence of tetrabutylammonium iodide, with second cross-coupling reaction of the heteroaryl of X=Br, I or OTf-X compound wherein.This reaction, was for example carried out among the DMF 1-5 hour at atent solvent usually at RT to 50 ℃, and product has the alkynyl-heteroaryl of structure I-10.As being summarized among the flow process II, can utilize to be similar to the reactions steps described in the flow process I, obtain The compounds of this invention I-7.If when existing needs well known by persons skilled in the art to make the useful protecting group that chemistry carries out in an easy manner on the heteroaryl, may comprise that extra going protect step, for example, this pair of hydrogenation alkynes intermediate compound I-10.Can be at alcoholic solvent, for example, in the ethanol, at ambient temperature, or be heated to 50 ℃ and reach 1-2 hour, with potassium cyanide or hydrolysis of trimethyl silane potassium alcoholate or any residual hydroxy groups protecting group of cracking, obtain the free hydroxyl group of Compound I-7.Work as R ¹³When being 2-benzyloxy substituting group, need under atmosphere of hydrogen, adopt go to protect step the second time of 10% palladium on carbon in the ethanol, obtain the phenyl that replaces as the 2-hydroxyl in the I-7 type structure as finally going protection.

Flow process II

The third route of synthesis of The compounds of this invention is summarized in flow process III.Can be at palladium catalyst, for example, Pd (PPh ₃) ₄Or PdCl ₂(PPh ₃) ₂Existence under, at atent solvent, for example, among the DMF, under the temperature of RT or rising, carry out the cross-coupling of iodide intermediate compound I-1 and pi-allyl or vinyl stannane intermediate (y=0,1).Adopt the suitable catalyzer that is used for olefin metathesis (metathesis) well known by persons skilled in the art, can make subsequently vinyl compound I-11 in alkene cross substitution with contain R ^12aVinyl intermediate reaction.These catalyzer can comprise " Shrock " catalyzer or " Zhan " catalyzer that generates universal architecture I-12 intermediate.Available said method is converted into triflate with acetoxyl group, and the I-13 that generation can be carried out the alkynes cross-coupling with TMS-acetylene removes silicon, described in previous for another example each flow process, carries out the cross-coupling second time with heteroaryl-X group, generates intermediate compound I-14.Can by previously described hydrogenation and finish synthetic required subsequently go to protect step, make intermediate compound I-14 be converted into The compounds of this invention I-7.

Flow process III

Flow process IV is described in R of the present invention ⁹On contain heteroatomic The compounds of this invention synthetic of the heteroaryl of ining succession.Intermediate compound I-4 can be in the cross-coupling reaction of the Pd-catalysis of adopting previously described general conditions and the alkynol reaction of universal architecture I-15.As selection, can protect the hydroxyl of I-15.The alcohol intermediate I-16 that can adopt above-mentioned general conditions hydrogenation to be generated uses condition well known by persons skilled in the art, and for example, " Dess-Martin " reagent is oxidized to aldehyde with the alcohol that is generated, and obtains intermediate compound I-17.The known condition of those skilled in the art can adopted, for example, at buffer solution, for example, in the reductive amination reaction of the sodium triacetoxy borohydride under the existence of KOAc and molecular sieve, make aldehyde group and alkyl, cycloalkyl/assorted alkyl, aryl or the reaction of heteroaryl amines of I-17.Can adopt aforementioned universal method that the product that obtains is like this gone protection, generate The compounds of this invention I-18, nitrogen-atoms wherein is in from aryl to alkyl, company's key (link) of cycloalkyl/assorted alkyl, aryl or heteroaryl.

Flow process IV

In relevant method, can be described in flow process V, preparation contains at R ⁹On the in succession generalization compound of the present invention of oxygen of heteroaryl.Can pass through the above-mentioned cross-coupling reaction of intermediate compound I-4 and alkynyl alcohol I-15 (or its protected variant), hydrogenation under usual condition subsequently, preparation intermediate compound I-19.Can form in the reaction at ether, adopt such as, triphenyl phasphine and diethylazodicarboxylate's condition, make alcohol intermediate I-19 and alkyl-, the cycloalkyl/alkyl of mixing-, aryl-or heteroaryl-OH compound or relevant tautomerism precursor reactant.Make desirable product experience the aforesaid follow-up step of going to protect again, obtain at the The compounds of this invention I-20 that contains oxygen atom from aryl to alkyl, the connection of cycloalkyl/assorted alkyl, aryl or heteroaryl.

Flow process V

Flow process VI describes wherein, and alcohol groups is comprised in from aryl to R ^12aThe preparation of the The compounds of this invention on the linking group of group.Can adopt condition well known by persons skilled in the art, for example, the tetroxide osmium of catalysis and N-methylmorpholine N-oxide are in dihydroxy reaction, make the olefine reaction of intermediate compound I-12, generate the wherein diol compound I-21 of R=H from above flow process III.Perhaps, can protect glycol subsequently as required, to adapt to subsequent chemical reaction, so reaction sequence is carried out to desirable compound.Can adopt to be similar to the intermediate compound I that those reaction treatment generated-21 that above flow process is described, generate intermediate compound I-22, I-23, suitable hydrogenation and follow-up go to protect step after, the The compounds of this invention of preparation universal architecture I-24.

Flow process VI

Flow process VII description heterocycle wherein directly is substituted in the preparation of the The compounds of this invention of phenyl moiety.Can for example under the existence of potassium acetate, in dioxane, be heated to 60 ℃ and spend the night by at weak base, the usefulness dichloro [1,1 '-two (diphenyl phosphine) ferrocene] palladium (II) and the processing of hypoboric acid two pinacol esters, make I-4 be converted into boric acid pinacol ester (I-26).At suitable palladium catalyst, for example, dichloro [1,1 '-two (diphenyl phosphine) ferrocene] palladium (II) and weak organic base, for example under the existence of triethylamine, handle the borate I-27 that is generated with halo (preferred I, the Br) aryl or the heteroaryl moieties of I-27 type.This reaction at atent solvent, for example among the DMF, was carried out 1-8 hour usually under 40 ℃-65 ℃, and product has as directly being combined in aryl or heteroaryl substituting group on the phenyl seen in the structure I-28.By under atmosphere of hydrogen,, handle for example in the ethyl acetate at solvent with 10% palladium on carbon catalyst, this alkynes of hydrogenation intermediate compound I-2815-24 hour, what can be accompanied by any benzyl protecting group among the I-28 removes the hydrogenation triple bond.If when existing needs well known by persons skilled in the art to make the useful protecting group that chemistry carries out in an easy manner on the heteroaryl, can comprise that extra going protect step.These protecting groups can comprise trityl, tert-butyl group carbamate groups or be suitable for protecting the functional group of other group or the heterocyclic group of ining succession well known by persons skilled in the art of heterocyclic compound.At this moment, the hydroxyl protecting group of hydrolyzable or any remnants of cracking, the protecting group that perhaps can before step of hydrogenation, remove non-benzyl.For example, can remove and be contained in R by handling with aqueous acid ^12aIn protection become the glycol of acetal.Work as R ^12aWhen containing one or more acetate group,, for example in the ethanol, at ambient temperature, or be heated to 50 ℃ and reach 1-2 hour, go protection, obtain free hydroxyl group, form The compounds of this invention I-29 with potassium cyanide or trimethyl silane potassium alcoholate at alcoholic solvent.Work as R ¹³When being 2-benzyloxy substituting group, need under atmosphere of hydrogen, adopt go to protect step the second time of 10% palladium on carbon in the ethanol, obtain the phenyl that replaces as the 2-hydroxyl in the I-29 type structure as finally going protection.

Flow process VII

In alternative approach, can described in flow process VIIb, prepare identical generalization compound of the present invention.In this flow process, aryl or heteroaryl moieties have boric acid, and the beta-lactam core texture contains the halogen that 4-replaces on the phenyl that N-connects.At suitable palladium catalyst for example, dichloro [1, two (diphenyl phosphine) ferrocene of 1-] palladium (II) and weak organic base are for example under the existence of triethylamine, with iodo-phenyl intermediate of I-31 type boric acid Processing Structure I-30.In the flow process formerly, acetic acid esters can be converted into aforementioned triflate.At suitable palladium catalyst, for example, four (triphenyl phasphine) palladium (O) or [1, two (diphenyl phosphine) ferrocene of 1-] palladium chloride (II) etc., and cuprous iodide (I) and initator are for example under the existence of iodate four positive fourth ammoniums, with containing R ^12aThe I-2 class Terminal Acetylenes of group is handled the triflate I-33 that is generated.Reaction is usually at inert organic solvents, for example among the DMF, carries out 6-48h between between the room temperature to 100 ℃, and product is the interior alkynes of structural formula I-34.Then according to as be described in the same procedure of flow process VII, but composite structure I-28 compound.

Flow process VIIb

In relevant method, can described in flow process VIII, prepare and between phenyl and heterocycle, contain the generalization compound I-38 of the present invention that methylene connects key (tether).In this flow process,, can prepare the aryl of I-34 type or the benzyl boric acid of heteroaryl moieties for the Suzuki cross-coupling of iodo intermediate compound I-30.Can be in suitable palladium catalyst, for example dichloro [1, two (diphenyl phosphine) ferrocene of 1-] palladium (II) and weak organic base for example under the existence of triethylamine, used the iodine substituted phenyl intermediate of I-34 type boric acid Processing Structure I-30.Before described in the above flow process, acetic acid esters can be converted into triflate for another example.Then, can be for example at suitable palladium catalyst, four (triphenyl phasphine) palladium (O) or [1,1 '-two (diphenyl phosphine) ferrocene] palladium chloride (II) etc., and cuprous iodide (I) and initator are for example under the existence of iodate four positive fourth ammoniums, with containing R ^12aThe I-2 type Terminal Acetylenes of group is handled triflate I-36.Can be at atent solvent, for example among the DMF, under room temperature to 100 ℃, react 6-48h, product should contain the interior alkynes of structural formula I-37.Then, according to as being described in the same procedure of flow process VII, can synthesize the compound of following structure I-38.

Flow process VIII

The preparation of intermediate

Acetate 5-acetenyl-2,2-dimethyl-1, the preparation of 3-dioxane-5-base ester (i-1):

Under nitrogen atmosphere, in the 250mL of drying round-bottomed flask, add THF (115mL, 57.7mmol) solution of 0.5M bromination acetenyl magnesium.In ice bath, the solution that is generated is cooled to 0 ℃.To in the solution of cooling, slowly adding 2,2-dimethyl-1,3-dioxane-5-ketone (5g, 50mL anhydrous THF solution 38.44mmol).Remove ice bath, at ambient temperature, the reactant mixture that stirring is generated 1.5 hours.Use sat.aq.NH ₄Cl (50mL) quencher reactant mixture is used ethyl acetate (100mL) extraction again.Through Na ₂SO ₄Dry organic layer filters and solvent removed in vacuo, obtains thick intermediate.

Under nitrogen atmosphere, make thick intermediate be dissolved in CH ₂Cl ₂(100mL).By syringe to the solution that is generated add simultaneously acetic anhydride (4.34mL, 46mmol) and TEA (6.4mL, 46mmol).To reactant mixture add DMAP (0.56g, 4.6mmol).When adding 1N aq.HCl (100mL) quencher, stirred reaction mixture is 3 hours under the room temperature in reaction.Reactant mixture is moved to separatory funnel, separate organic layer.Use aq.NaHCO ₃(100mL), water (50mL), salt water washing organic layer, drying is filtered and solvent removed in vacuo, obtains need not to be further purified and the title compound (i-1) that adopts. ¹HNMR(500MHz，CDCl ₃)δ：4.14(d，J＝12.6，2H)4.07(d，J＝12.6Hz，2H)，2.65(s，1H)，2.12(s，3H)，1.45(s，3H)，1.41(s，3H).

2-acetenyl propane-1,2,3-triol 1, the preparation of 3-diacetate esters (i-2):

At nitrogen atmosphere, under 0 ℃, to oxalic acid 2-oxo propane-1 through cooling, 3-two basic ester (17.5g, anhydrous THF (50mL) solution 100mmol) dropwise adds 0.5M bromination acetenyl magnesium (200mL) through syringe, and the solution that stirring is generated 3 hours is heated to room temperature.With saturated ammonium chloride solution (50mL) quencher mixture, and use the 200mL ethyl acetate extraction.Organic matter filters and vaporising under vacuum through dried over mgso.Carry out the MPLC purifying with the 10-50% ethyl acetate gradient eluent in the hexane, obtain title compound. ¹H-NMR(400MHz，CDCl ₃)δ：4.28(d，J＝11.5Hz，2H)，4.22(J＝11.5Hz，2H)，3.26(s，1H)，2.55(s，1H)，2.13(s，6H).

According to Burnett, D.S.; Caplen, M.A.; Domalski, M.S.; Browne, M.E.; DaVis, H.R.Jr.; Clader, J.W.Biorg.Med.Chem.Lett. (2002), 12,311, the preparation compound (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxy phenyl)-1-(4-iodophenyl) azetidine-2-ketone ( I-3) and ( I-4).Compound I-5It is the dihydroxy protection I-4Analog, protecting group wherein is an acetyl group.

Acetate 4-[(2S, 3R)-3-[(3S)-3-(acetoxyl group)-3-(4-fluorophenyl) propyl group]-1-(4-iodobenzene Base)-and 4-aza-oxo-cyclobutane-2-yl] preparation of phenyl ester (i-5):

Under nitrogen atmosphere, to acetate (1S)-1-(4-fluorophenyl)-3-[(2S, 3R)-2-(4-hydroxyphenyl)-1-(4-iodophenyl)-4-aza-oxo-cyclobutane-3-yl] propyl ester (i-4) (2g, and 3.58mmol) (according to Burnett, D.S.; Caplen, M.A.; Domalski, M.S.; Browne, M.E.; Davis, H.R.Jr.; Clader, J.W.Bioorg.Med.Chem.Lett. (2002), 12,311 the preparation) CH ₂Cl ₂(25mL) solution add acetic anhydride (0.4mL, 4.30mmol), triethylamine (0.7mL, 5.38mmol) and DMAP.Stirred reaction mixture is 1 hour under the RT, solvent removed in vacuo.Residue is through using the MPLC of gradient eluent (silicagel column) (the 0-100%EtOAc/ hexane is as eluent) purifying step by step; Obtain title compound (i-5).

m/z(ES)(M-OAc) ⁺. ¹HNMR(500MHz，CDCl ₃)δ：7.57(d，J＝8.6，1H)7.38-7.26(m，5H)，7.22(br?d，J＝7.1H，2H)，7.14(d，J＝8.5Hz，1H)，7.08-7.02(m，3H)，5.74(t，J＝6.7Hz，1H)，4.62(d，J＝2.3Hz，1H)，3.10(dt，J＝2.3，7.8Hz，1H)，2.34(s，3H)，2.08(s，3H)，2.09-2.03(m，2H)，1.94-1.86(m，2H).

Adopt as be described in Vaccaro, W.D. etc., Bioorg.Med.Chem., 6 volumes (1998), method among the 1429-1437, by 2, two benzyloxy acetaldehyde of 4-and 4-Iodoaniline prepare acetate (1S)-3-[(2S, 3R)-and 2-[2, two (benzyloxy) phenyl of 4-]-1-(4-iodophenyl)-4-aza-oxo-cyclobutane-3-yl]-1-(4-fluorophenyl) propyl ester (i-6).

Above intermediate i-3, i-4 and i-5 can be used for being similar to the method described in the above flow process, and wherein the introducing of the side chain on the aryl of azetidinone ring is opposite in proper order.

1-third-2-alkynes-1-base-1H-1,2, the preparation of 4-triazole (i-7):

To the 1H-1 that in ice bath, cools off, 2, (5g, ethanol 72.4mmol) (50mL) solution add NaOH, and (this causes the formation of white precipitate to the 4-triazole immediately for 2.9g, 5mL aqueous solution 74.7mmol).In the mixture that is generated, dropwise added through 1 hour propargyl bromide (8.2mL, 74.7mmol).After finishing adding, add thermal reaction mixture to RT and stirred 48 hours.Add entry (100mL), reactant mixture is gone to separatory funnel, and extract with carrene (3x75mL).The organic layer that merges is through water (2x) washing, through Na ₂SO ₄Drying is filtered solvent removed in vacuo.Residue is used CH through the column chromatography purification of silica gel ₂Cl ₂In the 2%MeOH wash-out, obtain title compound. ¹H?NMR(500MHz，CDCl ₃)δ：8.29(s，1H)，7.96(s，1H)，4.99(d，J＝2.7，2H)，2.60(t，J-2.7，1H)

According to the method described in the open WO 93/15610A1 (referring to embodiment 1,4 and 5 wherein) of PCT, preparation 3-iodo-1-trityl-1H-1,2,4-triazole (i-8) ¹HNMR(500MHz，CDCl ₃)δ：8.09(s，1H)，7.38(m，9H)，7.04(m，6H).

3-(1-trimethyl silyl acetylene-2-yl)-1-trityl-1H-1,2, the system of 4-triazole (i-9) Be equipped with:

Make nitrogen bubble feed 35 ℃ of 3-iodo-1-trityl-1H-1 of heating 30min down, 2, the 4-triazole (37.3g, 85.35mmol) and triethylamine (17.8ml, dry DMF 128mmol) (300ml) solution.Add Pd (PPh ₃) ₂Cl ₂(2.4g, 3.4mmol) and CuI (651mg, 3.4mmol), subsequently with syringe pump added through 15 hours acetenyl trimethyl silane in the dry DMF (18ml) (18ml, 128mmol).After finishing adding, 35 ℃ were descended further heating blends 5 hours.Mixture is poured in the water (700ml), and extracted with EtOAc (3x 300ml).The EtOAc layer that merges is through water (2x 500ml), sat.NaCl (250ml) washing, through Na ₂SO ₄Drying is filtered and evaporation.Residue is through silica gel MPLC purifying, with the 10%EtOAc wash-out of gradient from 100% hexane to hexane, obtains title compound. ¹HNMR(500MHz，CDCl ₃)δ：7.96(s，1H)，7.37(m，9H)，7.14(m，6H)，0.27(s，9H).

3-acetenyl-1-trityl-1H-1, the preparation of 2.4-triazole (i-10):

With fluoro tetrabutylammonium (the 1.0M THF solution of 3.8ml, 3.8mmol) add to 3-(1-trimethyl silyl acetylene-2-yl)-1-trityl-1H-1,2,4-triazole (7.75g, in anhydrous THF (50ml) solution 19mmol), stir the mixture 30min that is generated.Be evaporated to driedly, residue is allocated in CH ₂Cl ₂And between the water.Wash organic layer with sat.NaCl, through Na ₂SO ₄Drying is filtered and evaporation.Residue is through Et ₂The O/ hexane grinds, and obtains title compound. ¹HNMR(500MHz，CDCl ₃)δ：7.99(s，1H)，7.38(m，9H)，7.15(m，6H)，3.10(s，1H).

1-third-2-alkynes-1-base-1H-1,2, the preparation of 3-triazole (i-11):

According to method to intermediate (i-7), from 1H-1,2, the 3-triazole prepares title compound. ¹HNMR(500MHz，CDCl ₃)δ：7.80(s，1H)，7.74(s，1H)，5.22(d，J-2.5，2H)，2.59(t，J＝2.5，1H)

The preparation of 2-bromo thiazole-4-formamide (i-12):

Under 50 ℃, the methanol solution that contains in the heated sealant test tube (40ml, 280mmol) the 2-bromo thiazole-4-carboxylic acid, ethyl ester in (2.95g, 12.5mmol) and the mixture of 7N ammonia 15 hours.Cooling mixture, and evaporation.Residue is through Et ₂The O/ hexane grinds, and filters and drying, obtains title compound. ¹HNMR(500MHz，DMSO-d6)δ：8.27(s，1H)，7.83(br?s，1H)，7.64(br?s，1H).

The preparation of 2-bromo thiazole-5-formamide (i-13):

According to method, prepare title compound from 2-bromo thiazole-5-carboxylate methyl ester to intermediate (i-12). ¹HNMR(500MHz，DMSO-d6)δ：8.19(br?s，2H)，7.76(br?s，1H).

The preparation of 4-bromo thiazole-2-carboxylic acid (i-14):

With 2,4-two bromo thiazoles (5g, anhydrous Et 20.6mmol) ₂O (30ml) solution joins butyl lithium (the 2.5M hexane solution of 9.9ml, anhydrous Et 24.7mmol) that cools off down in 78 ℃ in the mode that dropwise adds ₂In O (70ml) solution, the speed of adding should make temperature be no more than-73 ℃.After finishing adding, stirred the mixture 1 hour under-78 ℃.Make the carbon dioxide bubbling feed mixture 5 minutes, add solid carbon dioxide pill (about 5g) again, heating blends is to room temperature.Add water (100ml), further use Et ₂O extracts the water-bearing layer.With dense HCl acidifying water-bearing layer, and use Et ₂O (3x 100ml) extraction, the Et of merging ₂The O layer is through Na ₂SO ₄Drying is filtered and evaporation.Residue is from Et ₂Crystallization in the O/ hexane obtains title compound. ¹HNMR?(500MHz，DMSO-d6)δ：8.20(s，1H).

The preparation of 4-bromo thiazole-2-carboxylate methyl ester (i-15):

Make intermediate 14 (1.98g, 9.mmol) be dissolved in methyl alcohol (50ml), add N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (2.73g, 14.3mmol), I-hydroxybenzotriazole (1.93g, 14.3mmol) and diisopropylethylamine (2.5ml, 14.3mmol).Stirred the mixture that generated under the room temperature 17 hours.Evaporating mixture makes the residue that is generated be allocated in CH ₂Cl ₂And between the water.With 1N HCl, sat.NaHCO ₃, sat.NaCl washs organic layer, through Na ₂SO ₄Drying is filtered and evaporation, obtains title compound. ¹HNMR(500MHz，CDCl ₃)δ：7.57(s，1H)，4.04(s，3H).

The preparation of 4-bromo thiazole-2-formamide (i-16):

According to method, prepare title compound from 4-bromo thiazole-2-carboxylate methyl ester to intermediate (i-12). ¹HNMR(500MHz，CDCl ₃)δ：7.54(s，1H)，7.12(br?s，1H)，5.92(brs，1H).

The preparation of 5-(trimethyl stannyl) thiazole-2-formamide (i-17):

Will two (trimethyl silyl ammonification) lithiums (the 1M THF solution of 86ml, 86mmol) add thiazole-2-formamide as for-40 ℃ of coolings (2.2g, 17.2mmol) and trimethyltin chloride (5.14g is in anhydrous THF (80ml) solution 25.8mmol).After finishing adding, heating blends is to-20 ℃ and stirred under this temperature 7 hours.Add sat.NH ₄Cl (200ml) and EtOAc (250ml) quencher.Separate organic layer, with the sat.NaCl washing, through Na ₂SO ₄Drying is filtered and evaporation.Residue with the gradient liquid wash-out of 100% hexane to the hexane of 40%EtOAc, obtains title compound through silica gel MPLC purifying. ¹HNMR(500MHz，CDCl ₃)δ：7.82(s，1H)，7.24(br?s，1H)，6.24(br?s，1H)，0.47(t，J＝28.8，9H).

The preparation of 5-iodine thiazole-2-formamide (i-18):

(1.5g, anhydrous THF (25ml) solution 5.17mmol) add N-iodine succinamide, and (1.16g 5.17mmol), stirred the mixture under this temperature 10 minutes to-55 ℃ of intermediates 17 that cool off down.Be heated to room temperature again and stirred 30 minutes.Add chloroform (50ml), with sat.NaCl (3x 70ml) purging compound, through Na ₂SO ₄Drying is filtered and evaporation.Residue grinds through hexane, filters and drying, obtains title compound. ¹HNMR(500MHz，DMSO-d6)δ：8.16(br?s，1H)，8.09(s，1H)，7.91(br?s，1H).

The preparation of 5-bromo thiazole-4-carboxylate methyl ester (i-19):

According to method, prepare title compound from 4-bromo thiazole-2-carboxylate to intermediate (i-15). ¹HNMR (500MHz, CDCl ₃) δ: 8.81 (s, 1H), 4.00 (s, 3H) preparation of .5-bromo thiazole-4-formamide (i-20):

According to method, prepare title compound 700mg from 4-bromo thiazole-2-carboxylate to intermediate (i-12). ¹HNMR(500MHz，DMSO-d6)δ：9.14(s，1H)，7.81(br?s，1H)，7.64(br?s，1H).

The preparation of 2-amino-5-methylthiazol-4-carboxylic acid, ethyl ester (i-21):

With N-bromine succinamide (36.77g, 206mmol) add to the 2-3-hydroxyethyl butyrate (13.65g, in carbon tetrachloride 103mmol) (200ml) solution, the mixture that the heating that refluxes is generated 5 hours.Cooling mixture is through diatomite

Filter evaporated filtrate.Make residue be dissolved in water (120ml), (5.49g, 72mmol), the mixture that the heating that refluxes is generated 15 minutes is cooled to room temperature, and stirs all night to add thiocarbamide.Add NH ₄The OH mixture that alkalizes filters the creaming that is generated, washing, and further use many parts of water washings.Make resolution of precipitate in CH ₂Cl ₂(500ml) and EtOH (20ml), through Na ₂SO ₄Drying is filtered and evaporation, obtains title compound. ¹HNMR(500MHz，CDCl ₃)δ：5.55(br?s，2H)，4.33(q，J＝7.1，2H)，2.59(s，3H)，1.37(t，J＝7.1，3H).

The preparation of 2-bromo-5-methylthiazol-4-carboxylic acid, ethyl ester (i-22):

With intermediate 21 (10g, 53.8mmol) add in batches 60 ℃ down the nitrite tert-butyls of heating (9.58ml, 80.6mmol) and copper bromide (II) (18g, 80.6mmol) in acetonitrile (200ml) mixture in.After finishing adding, in 75 ℃ of following heating blends 2 hours.Cooling mixture, and pour 1N HCl (500ml) into, and use CH ₂Cl ₂(2x 200ml) extraction.CH through merging ₂Cl ₂Extract is through Na ₂SO ₄Drying is filtered and evaporation, obtains title compound. ¹HNMR(500MHz，CDCl ₃)δ：4.39(q，J＝7.1，2H)，2.72(s，3H)，1.39(t，J＝7.1，3H).

The preparation of 2-bromo-5-methylthiazol-4-formamide (i-23):

According to method, from intermediate 22 preparation title compounds to intermediate (i-12). ¹HNMR(500MHz，DMSO-d6)δ：7.65(br?s，1H)，7.50(br?s，1H)，2.68(s，3H).

The preparation of 2-bromo thiazole-4-methyl alcohol (i-24):

(99mg, 26mmol) add to the 2-bromo thiazole-4-formaldehyde that cools off in ice bath (1g is in absolute methanol 5.2mmol) (20ml) solution in batches with sodium borohydride.After finishing adding, remove cryostat, 150min stirs the mixture.Evaporating mixture is allocated in residue between 1N HCl (50ml) and the EtOAc (50ml).With sat.NaCl (20ml) washing organic layer, through Na ₂SO ₄Drying is filtered and evaporation, obtains title compound. ¹HNMR(500MHz，CDCl ₃)δ：7.19(s，1H)，4.77(s，2H)，2.76(br?s，1H).

Methanesulfonic acid 2-bromo-1,3-thiazoles-4-yl) preparation of methyl esters (i-25):

Intermediate 24 (200mg, anhydrous CH 1mmol) to 0 ℃ of cooling ₂Cl ₂(5ml) successively add in the solution triethylamine (172 μ l, 1.2mmol) and mesyl chloride (88 μ l, 1.1mmol), heating blends is to ambient temperature overnight.Through more CH ₂Cl ₂(15ml) dilution, water, sat.NaCl washing are through Na ₂SO ₄Drying is filtered and evaporation.Residue rises to the gradient liquid wash-out of the hexane of 25%EtOAc through silica gel MPLC purifying with 100% hexane, obtain title compound. ¹HNMR(500MHz，CDCl ₃)δ：7.42(s，1H)，5.29(s，2H)，3.08(s，3H).

The preparation of 2-bromo-4-methyl sulfenyl methylthiazol (i-26):

(200mg, 0.74mmol) anhydrous EtOH (3ml) solution add sodium methyl mercaptide, and (57mg 0.8mmol), stirred the mixture that generated 30 minutes under the room temperature to intermediate 25.Evaporating mixture is allocated in CH with residue ₂Cl ₂And between the water.Through Na ₂SO ₄Dry organic layer filters and evaporation.Residue is increased to the gradient liquid wash-out of the hexane of 20%EtOAc through silica gel MPLC purifying with 100% hexane, obtain title compound. ¹HNMR(500MHz，CDCl ₃)δ：7.10(s，1H)，3.79(s，2H)，2.12(s，3H).

The preparation of 2-bromo-4-methyl sulphonyl methylthiazol (i-27):

To the intermediate 26 that in ice bath, cools off (695mg, CH 3.1mmol) ₂Cl ₂(40ml) (1.74g 7.75mmol), stirs mixture that heating down generated to room temperature all night for the 3-chlorine benzylhydroperoxide of disposable adding 77% in the solution.Mixture is through diatomite Filter, with 1NNaOH (50ml) wash filtrate, through Na ₂SO ₄Drying is filtered and evaporation, obtains title compound. ¹HNMR(500MHz，CDCl ₃)δ：7.47(s，1H)，4.42(s，2H)，2.98(s，3H).

The preparation of 2-bromo thiazole-5-methyl alcohol (i-28):

According to method, from 2-bromo thiazole-5-prepared formaldehyde title compound to intermediate (i-24). ¹HNMR(500MHz，CDCl ₃)δ：7.40(s，1H)，4.82(s，2H)，3.00(br?s，1H).

The preparation of 2-bromo-5-methyl sulphonyl methylthiazol (i-29):

According to method, prepare title compound from 2-bromo thiazole-5-methyl alcohol to intermediate (i-25, i-26, i-27). ¹HNMR (500MHz, CDCl ₃) δ: 7.60 (s, 1H), 4.45 (s, 2H), 2.92 (s, 3H).

The preparation of 5-bromo thiazole (i-30):

Through 45min, (12.58g 70mmol) adds natrium nitrosum (7.59g, 110mmol) water (26ml) solution in the mixture in phosphoric acid (106ml 86% aqueous solution) and red fuming nitric acid (RFNA) (19.2ml) to-5 ℃ of 2-amino-5-bromo thiazoles that cool off down.After finishing adding,, dropwise add hypophosphorous acid (38.8ml) through 30min again, keep temperature to be lower than 0 ℃ simultaneously in-5 ℃ of 15min that stir the mixture.The 150min that stirs the mixture under 0 ℃ is heated to ambient temperature overnight again.Mixture is poured in water (400ml) solution of NaOH (85g).Add 5N NaOH solution and reach neutral, use CH until mixture ₂Cl ₂The mixture that (3x 200ml) extraction is generated.The CH that merges ₂Cl ₂Layer is with the sat.NaCl washing, through Na ₂SO ₄Drying is filtered and evaporation.Residue is increased to the gradient liquid wash-out of the hexane of 10%EtOAc through silica gel MPLC purifying with 100% hexane, obtain title compound. ¹HNMR(500MHz，CDCl ₃)δ：8.78(s，1H)，7.83(s，1H).

The preparation of 2-bromo-4-thiazole ethyl acetate (i-31):

According to method, prepare title compound by 2-amino-4-thiazole ethyl acetate to intermediate (i-22). ¹HNMR(500MHz，CDCl ₃)δ：7.19(s，1H)，4.20(q，J＝7.1，2H)，3.82(s，2H)，1.29(t，J＝7.1，3H).

The preparation of 2-bromo thiazole-4-acetamide (i-32):

According to method, by intermediate 31 preparation title compounds to intermediate (i-12). ¹HNMR(500MHz，CDCl ₃)δ：7.15(s，1H)，6.47(br?s，1H)，5.60(br?s，1H)，3.73(s，2H).

The preparation of 2-(2-bromo-1,3-thiazoles-4-yl) ethanol (i-33):

To intermediate 31 (2.5g, anhydrous Et 10mmol) ₂O (40ml) solution adds lithium borohydride, and (381mg, 17.5mmol), (709 μ l 17.5mmol), stir the mixture 30min that is generated slowly to add methyl alcohol subsequently.Cooling mixture in ice bath adds 1N HCl (150ml) quencher.The mixture that is generated is through CH ₂Cl ₂(100ml) extraction is through Na ₂SO ₄Drying is filtered and evaporation.Residue is increased to the gradient liquid wash-out of the hexane of 50%EtOAc through silica gel MPLC purifying with 100% hexane, obtain title compound. ¹HNMR(500MHz，CDCl ₃)δ：6.98(s，1H)，3.94(t，J＝5.9，2H)，2.98(t，J＝5.9，2H)，2.59(s，1H).

2-bromo-4-[2-(methyl sulphonyl) ethyl]-preparation of 1,3-thiazoles (i-34):

According to method, from intermediate 32 preparation title compounds to intermediate (i-25, i-26, i-27). ¹HNMR(500MHz，CDCl ₃)δ：7.08(s，1H)，3.47(t，J＝8.2，2H)，3.29(t，J＝8.2)，2.88(s，3H).

2-amino-5-[(benzyloxy) methyl]-preparation of 1,3-thiazoles-4-carboxylic acid, ethyl ester (i-35):

With caustic alcohol (ethanolic solution of the 21%wt of 33.6ml, 90mmol) dropwise add 0 ℃ down the benzyloxy acetaldehyde of cooling (15g, 100mmol) and ethyl dichloroacetate (11.15ml is 90mmol) at anhydrous Et ₂In the mixture among the O (50ml).The mixture that stirring is generated under 0 ℃ 1 hour adds more Et again ₂O (50ml) and sat.NaCl (100ml).Separate organic layer, through Na ₂SO ₄Drying is filtered and evaporation.Make residue be dissolved in ethanol (100ml), and the adding thiocarbamide (6.55g, 86mmol), the mixture that the heating that refluxes is generated 4 hours.Cooling mixture, and evaporation are allocated in water and CH with residue ₂Cl ₂Between.Use CH ₂Cl ₂(x2) extraction organic layer; The CH that water, sat.NaCl washing merge ₂Cl ₂Layer is through Na ₂SO ₄Drying is filtered and evaporation.Residue is increased to the gradient liquid wash-out of the hexane of 50%EtOAc through silica gel MPLC purifying with 100% hexane, obtain title compound. ¹HNMR(500MHz，CDCl ₃)δ：7.32(m，5H)，5.78(br?s，2H)，4.99(s，2H)，4.63(s，2H)，4.33(q，J＝7.1，2H)，1.36(t，J＝7.13H).

2-amino-5-[(benzyloxy) methyl]-preparation of 1,3-thiazoles-4-formamide (i-36):

According to method, by intermediate 35 preparation title compounds to intermediate (i-22 and i-12). ¹HNMR(500MHz，CDCl ₃)δ：7.38(m，5H)，7.07(br?s，1H)，5.93(br?s，1H)，5.15(s，2H)，4.70(s，2H).

The preparation of 2-bromo-N-(3-hydroxypropyl)-1,3-thiazoles-4-formamide (i-37):

(500mg is 2.4mmol) with 3-amino third-1-alcohol (247 μ l, CH 4.8mmol) to 2-bromo thiazole-4-carboxylic acid ₂Cl ₂(15ml) solution add N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (690mg, 3.6mmol), I-hydroxybenzotriazole (486mg, 3.6mmol) and diisopropylethylamine (627 μ l, 3.6mmol).Under the room temperature, the mixture that stirring is generated 4 hours.Water, 1N HCl, sat.NaHCO ₃, the sat.NaCl purging compound, through Na ₂SO ₄Drying is filtered and evaporation, obtains title compound. ¹HNMR(500MHz，CDCl ₃)δ：8.08(s，1H)，7.55(br?s，1H)，3.70(q，J＝5.7，2H)，3.63(q，J＝6.4，2H)，3.13(t，J＝6.2，1H)，1.82(m，2H).

The preparation of 2-bromo-N-(2-ethoxy)-13-thiazole-4-carboxamide (i-38):

According to method, prepare title compound by 2-bromo thiazole-4-carboxylic acid and monoethanolamine to intermediate (i-37). ¹HNMR(500MHz，CDCl ₃)δ：8.08(s，1H)，7.65(br?s，1H)，3.85(t，J＝5.0，2H)，3.63(q，J＝5.7，2H)，2.90(br?s，1H).

The preparation of 2-An Ji oxazole-4-carboxylic acid, ethyl ester (i-39):

With ethyl bromide acetone (59.7g, 6mmol) and urea (27.6, the 460mmol) heating 24 hours that refluxes of (220ml) mixture in ethanol.Cooling mixture and evaporation.Make residue be dissolved in water, handle up to pH＞9 with 1N NaOH.Use Et ₂O (4x 100ml) extracts mixture; The Et that merges ₂The O layer is through Na ₂SO ₄Drying is filtered and evaporation.Residue is increased to the gradient liquid wash-out of the hexane of 90%EtOAc through silica gel MPLC purifying with 100% hexane.Merging and evaporation contain the flow point of product, with EtOAc/ hexane grinding residues, filter and drying, obtain title compound. ¹HNMR(500MHz，DMSO-d6)δ：8.04(s，1H)，6.90(br?s，2H)，4.18(q，J＝7.1，2H)，1.22(t，J＝7.13H).

The preparation of 2-Lv oxazole-4-carboxylic acid, ethyl ester (i-40):

With intermediate 39 (3g, 19.2mmol) add in batches 60 ℃ down the nitrite tert-butyl in the acetonitrile (100ml) of heating (93.4ml, 28.8mmol) and copper chloride (II) (3.87g is 28.8mmol) in the mixture.After finishing adding, 75 ℃ of following heating blends 2 hours.Cooling mixture, and pour among the 1N HCl (300ml), and use CH ₂Cl ₂(3x 120ml) extraction.CH through merging ₂Cl ₂Extract is through Na ₂SO ₄Drying is filtered and evaporation, obtains title compound. ¹HNMR(500MHz，CDCl ₃)δ：8.20(s，1H)，4.39(q，J＝7.3，2H)，1.39(t，J＝7.3，3H).

The preparation of 2-Lv oxazole-4-formamide (i-41):

According to method, from intermediate 40 preparation title compounds to intermediate (i-12). ¹HNMR(500MHz，DMSO-d6)δ：7.79(s，1H)，7.30(br?s，1H)，7.10(br?s，1H).

The preparation of 2-chlorine pyrimidine-4-formamide (i-42):

(122mg 2.91mmol) is dissolved in water (4ml), adds H to make lithium hydroxide ₂O ₂(30% aqueous solution of 536 μ l, 4.89mmol).This mixture is added to 2-chloro-4-cyanopyrimidine [preparing] described in WO2006072831A1 (340mg is in THF 2.45mmol) (16ml) solution.Stirred the mixture that generated under the room temperature 2 hours.Mixture is allocated between EtOAc and the water; Wash organic layer with more water, sat.NaCl, through Na ₂SO ₄Drying is filtered and evaporation.Residue is through Et ₂The O/ hexane grinds, and filters and drying, obtains title compound. ¹HNMR(500MHz，CDCl ₃)δ：8.91(d，J＝4.8，1H)，8.10(d，J＝4.8，1H)，7.68(br?s，1H)，5.99(br?s，1H).

The preparation of 5-bromo-2-cyanopyrimidine (i-43):

Make Cymag (270mg 5.43mmol) is dissolved in water (3ml), successively add DABCO (87mg, 0.8mmol) and DMSO (3ml).(1g, DMSO 5.17mmol) (3ml) solution stirred the mixture that generated 2 hours under the room temperature to add 5-bromo-2-chlorine pyrimidine to this mixture.With EtOAc (75ml) diluted mixture thing, through water, 1N HCl, sat.NaHCO ₃Washing is filtered and evaporation, obtains title compound. ¹HNMR(500MHz，CDCl ₃)δ：8.96(s，2H).

The preparation of 5-bromo pyrimi piperidine-2-formamide (i-44):

According to method, from intermediate 41 preparation title compounds to intermediate (i-42). ¹HNMR(500MHz，CDCl ₃)δ：8.97(s，2H)，7.72(br?s，1H)，6.38(br?s，1H).

The preparation of 2-hydroxyl-4-iodobenzene formaldehyde (i-45):

Make 3-iodine phenol (10g 45mmol) is dissolved in anhydrous acetonitrile (160ml), in ice bath, cool off, through 10min add in batches magnesium chloride (12.8g, 134mmol).Through 5min with triethylamine (25.3ml 363mmol) adds to this mixture, add subsequently in batches paraformaldehyde (5.47g, 636mmol).After finishing adding, backflow heating blends 18.5 hours.Cooling mixture is by adding sat.NH ₄Cl (350ml) quencher.And extract with EtOAc (3x150ml).Use sat.NaHCO ₃(2x150mml), the EtOAc layer that merges of 1N HCl (2x 150ml) and sat.NaCl (2x100ml) washing, through Na ₂SO ₄Drying is filtered and evaporation.Residue is increased to the gradient liquid wash-out of the hexane of 20%EtOAc through silica gel MPLC purifying with 100% hexane.Merging and evaporation contain the flow point of product, and crystallization again obtains title compound from hot hexane. ¹HNMR(500MHz，CDCl ₃)δ：11.02(s，1H)，9.87(s，1H)，7.46(d，1H)，7.42(dd，1H)，7.23(d，1H).

The preparation of 2-benzyloxy-4-iodobenzene formaldehyde (i-46):

To 2-hydroxyl-4-iodobenzene formaldehyde (i-45) (5g, anhydrous acetonitrile 20.2mmol) (25ml) solution successively adds 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (3.2ml, 21.2mmol), benzyl bromide a-bromotoluene (2.53ml, 21.2mmol).The 15min that stirs the mixture under the room temperature is again in 50 ℃ of heating 4 hours down.Evaporation is through the reactant mixture of cooling.Residue is allocated in 1N HCl (150ml) and Et ₂Between the O (150ml), and use Et ₂O (3x150ml) extraction.The Et that water (150ml), sat.NaCl (150ml) washing merge ₂The O layer is through MgSO ₄Drying is filtered and evaporation.Make residue crystallization again from the EtOAc/ hexane, obtain title compound. ¹HNMR(500MHz，CDCl ₃)δ：10.50(s，1H)，7.58(d，1H)，7.50-7.38(m，7H)，5.19(s，2H).

The preparation of 4-({ (1E)-[2-(benzyloxy)-4-iodophenyl] methylene } amino) phenol (i-47):

(1.1g 3.25mmol) is suspended in the propan-2-ol (10.5ml), and heating is up to dissolving fully to make 2-benzyloxy-4-iodobenzene formaldehyde (i-46).(355mg 3.25mmol) adds in this clear solution, the mixture that 50 ℃ times heating are generated 4 hours with the 4-hydroxyanilines.Evaporation is used Et through the mixture of cooling ₂The mixture grinding residues of O and hexane is filtered, and is air-dry, obtains title compound. ¹HNMR(500MHz，CD ₃OD)δ：8.84(s，1H)，7.75(d，1H)，7.52(s，1H)，7.48-7.30(m，6H)，7.10(d，2H)，6.80(d，2H)，5.20(s，2H).

Acetate 4-(2S, 3R)-3-[(3S)-3-(acetoxyl group)-3-(4-fluorophenyl) propyl group]-2-[2-(benzyloxy Base)-the 4-iodophenyl]-4-aza-oxo-cyclobutane-1-yl } preparation of phenyl ester (i-48):

According at embodiment 1, the method described in step B, C and the D is from 4-({ (1E)-[2-(benzyloxy)-4-iodophenyl] methylene } amino) phenol (i-47) preparation title compound.

¹HNMR(500MHz，CDCl ₃)δ：7.48-7.35(m，6H)，7.31-7.20(m，4H)，7.11(t，2H)，7.01-6.90(m，4H)，5.58(t，1H)，5.10(m，2H)，4.97(d，1H)，3.04(m，1H)，2.29(s，3H)，2.01(s，3H)，2.00-1.88(m，2H)，1.88-1.68(m，2H).

Acetate (1S)-3-{ (2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl fourth -1-alkynes-1-yl } phenyl)-4-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxane pentaborane -2-yl) phenyl] azetidine-3-yl }-preparation of 1-(4-fluorophenyl) propyl ester (i-49):

Nitrogen bubble is fed acetate (1S)-3-[(2S; 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl fourth-1-alkynes-1-yl } phenyl)-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-3-yl]-1-(4-fluorophenyl) propyl ester (from the intermediate of embodiment 1 step F) (1g; 1.3mmol), hypoboric acid two pinacol ester (366mg; 1.4mmol) and potassium acetate (382mg; 3.9mmol) anhydrous 1,4-dioxane (15ml) solution 15min.(95mg 0.13mmol) adds in the mixture, the mixture that 60 ℃ times heating are generated 14 hours with [1,1 '-two (diphenyl phosphine) ferrocene] palladium chloride (II).Cooling mixture is poured in the water (80ml), and extracts with EtOAc (3x 50ml).The EtOAc layer that water (100ml), sat.NaCl (50ml) washing merge is through Na ₂SO ₄Drying is filtered and evaporation.Residue is increased to the gradient liquid wash-out of the hexane of 40%EtOAc through silica gel MPLC purifying with 100% hexane.

¹HNMR(500MHz，CDCl ₃)δ：7.47(d，J＝8.2，2H)，7.32-7.27(m，6H)，7.16(d，J＝8.9，2H)，7.04(t，J＝8.7，2H)，5.72(t，J＝6.5，1H)，4.63(d，J＝2.3，1H)，4.39(d，J＝11.2，2H)，4.32(d，J＝11.2，2H)，3.14-3.12(m，2H)，2.16(s，6H)，2.11-2.03(m，5H)，1.94-1.86(m，2H)，1.26(s，12H).

2-chloro-6-[(4-methoxy-benzyl) oxygen base] preparation of pyrazine (i-50):

(186mg, dry DMF 2.68mmol) (5mL) solution add solid NaH in batches, and (2.80mmol), 0 ℃ was stirred down the solution that generated 1 hour for the dispersion in 60% oil, 112mg to placing nitrogen atmosphere and being cooled to 0 ℃ 4-methoxyl group benzylalcohol.With prefabricated 2, (200mg, DMF 2.68mmol) (1mL) solution cause in the solution of cooling the 6-dichloropyrazine, stir the mixture that is generated all night, are heated to room temperature through syringe.With saturated ammonium chloride solution (10mL) quencher reaction, with ethyl acetate (3x 7mL) extraction.Merge organic matter,, filter and concentrate through dried over sodium sulfate.Preparation type column plate purifying with 10% ethyl acetate/90% hexane wash-out, obtains title compound.M/z (ES) 251 (MH)+and 253 (M2+H)+.

2-chloro-3-[(4-methoxy-benzyl) oxygen base] preparation of pyrazine (i-51):

According to the method to intermediate (i-45), from 2, the 3-dichloropyrazine prepares title compound.M/z (ES) 251 (MH)+and 253 (M2+H)+.

3-iodo-1-trityl-1,2, the preparation of 4-triazole-5-carboxylic acid, ethyl ester (i-52):

Can be at inert atmosphere, for example, in nitrogen or the argon gas, use organic base, for example, triethylamine and trityl chloride, processing is at anhydrous solvent, for example, the 5-iodo-1H-1 among the DMF, 2,4-triazole-3-carboxylic acid, ethyl ester (Chinese Journal ofSynthetic Chemistry, 12 (2), 2004,191 pages).Under the temperature of 20 ℃ and 40 ℃, stirring the mixture 1 hour to 24 hours.By pouring processing reaction thing in the excessive water into, use organic solvent, for example, and the EtOAc extraction, the drying agent, for example, MgSO ₄Or Na ₂SO ₄Dry organic extract filters and vacuum evaporation.

3-iodo-1-trityl-1,2, the preparation of 4-triazole-5-formamide (i-53):

By under 20 ℃ of-60 ℃ of temperature, in airtight container, stir 3-iodo-1-trityl-1,2,4-triazole-5-carboxylic acid, ethyl ester for example the solution 1-36 among MeOH or the EtOH hour, prepares title compound at the alcoholic solvent of ammonia.Can separate title compound by filtering any compound that is settled out or evaporation crude product mixture.

5-cyano group-3-iodo-1-trityl-1,2, the preparation of 4-triazole (i-54):

Can be at inert atmosphere, for example under nitrogen or the argon gas, between 0 ℃-20 ℃, by slowly trifluoroacetic anhydride being added to 3-iodo-1-trityl-1,2, the anhydrous solvent of 4-triazole-5-formamide and organic base (for example pyridine or triethylamine) (CH for example ₂Cl ₂Or 1, the 4-dioxane) solution in, the preparation title compound.Under 0 ℃ of-20 ℃ of temperature, stirred the mixture 1-12 hour.By pouring processing reaction thing in the excessive water into, with organic solvent CH for example ₂Cl ₂Or the EtOAc extraction, the drying agent is MgSO for example ₄Or Na ₂SO ₄Dry organic extract filters and vacuum evaporation.

3-iodo-1-trityl-1,2, the preparation of 4-triazole-5-methyl alcohol (i-55):

Can be between 0 ℃-20 ℃ temperature, at inert atmosphere for example under nitrogen or the argon gas, for example lithium aluminium hydride reduction or lithium borohydride are handled anhydrous solvent with reductant, the 3-iodo-1-trityl-1 in oxolane or the ether for example, 2,4-triazole-5-carboxylic acid, ethyl ester, preparation title compound.Can be under 0 ℃-40 ℃ temperature reaction stirred 1-12 hour.Can handle the reactant of cooling by the careful 1N of adding HCl, extract for example CH of organic solvent ₂Cl ₂Or among the EtOAc, drying agent, for example MgSO ₄, or Na ₂SO ₄Dry organic extract filters and vacuum evaporation.

The preparation of [(third-3-alkynes-1-base oxygen base) methyl] benzene or benzyl third-3-alkynes-1-base ether (i-56):

Under nitrogen atmosphere, to 3-third-1-alcohol (1.17g, dry DMF 11.88mmol) (100mL) solution add TBAI (0.87g, 2.38mmol), with after 0.5h adds oil (0.55g, 14.26mmol) the 60%NaH dispersion in batches.When stirred reaction mixture 0.5h, through syringe add benzyl bromide a-bromotoluene (2.44g, 14.26mmol).Under the room temperature, when stirred reaction mixture 16h, by adding sat.aq.NH ₄Cl (100mL) quencher reaction.Reactant mixture is moved to separatory funnel, and extract with ether (3x75mL).The organic extract that water (50mL), salt solution (75mL) washing merge, dry (Na ₂SO ₄), filter solvent removed in vacuo.Residue obtains title compound (i-56) through using MPLC (silicagel column) purifying of gradient eluent (the 0-60%EtOAc/ hexane is as eluent) step by step.

Can adopt said method, from suitable raw material, preparation relates to different the replacement and above-mentioned those the intermediate of alkyl chain length.

Embodiment 1

(3R, 4S)-4-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[(3S)-3-(4-fluorophenyl)- The 3-hydroxypropyl]-1-{4-[3-(1H-1,2,4-triazol-1-yl) propyl group] phenyl } azetidine-2-ketone

Steps A: 4-{[(1E)-(4-iodophenyl) methylene] amino } preparation of phenol

Under nitrogen atmosphere, (400g 1.724mol), makes base be dissolved in 2-propyl alcohol (950ml) again to add iodobenzene formaldehyde in round-bottomed flask.Add the 4-hydroxyanilines, the mixture to 70 that heating is generated ℃.Behind heating 3h under this temperature, in the dark-brown solvent mixture, form brown precipitation.Reaction mixture is filtered, successively with 2-propyl alcohol and ether washing.The vacuum evaporation organic matter, dried residue all night under the high vacuum obtains need not to be further purified and the title compound that adopts. ¹HNMR(500MHz，DMSO-D6)δ：9.55(s，1H)，8.59(s，1H)，7.85(d，2H)，7.63(d，2H)，7.2(d，2H)，6.80(d，2H).

Step B: (4S)-3-{ (2R)-5-(4-fluorophenyl)-2-[(S)-(4-iodophenyl) ({ 4-[(trimethyl first silicon Alkyl) oxygen base] phenyl } amino) methyl]-the 5-[(trimethyl silyl) the oxygen base] valeryl }-the 4-phenyl -1, the preparation of 3-oxaza pentane-2-ketone

Under nitrogen atmosphere ,-5 ℃, to (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxyl valeryl]-4-phenyl-1,3-oxaza pentane-2-ketone (251.6g, and 0.704mol) (according to Fu, X.; McCallister, T.L.; Thiruvengadam, T.K.; Tann, C.H.; And Su, the preparation of the method for D.Tetrahedron Lett. (2003) 44,801-804) and 4-{[(1E)-(4-iodophenyl) methylene] amino phenol (455g, 1.41mol; The steps A intermediate) at CH ₂Cl ₂Suspension (3.1L) adds N, and (640mL 3.66mol), keeps temperature to be lower than 0 ℃ to the N-diisopropylethylamine.(297mL 2.323mol), keeps temperature to be lower than 0 ℃ simultaneously to add the chloro trimethyl silane to the yellow suspension that is generated.In-5 ℃, stir the dark red solution 1h that is generated, at this moment, reaction mixture is to-30 ℃.Solution to this cooling adds TiCl ₄(90mL 0.774mol), keeps temperature to be lower than-25 ℃ simultaneously.Stirred the mulberry solution generated 2.5 hours in-30 ℃, add acetate (210mL) this moment, keeps temperature to be lower than-25 ℃ simultaneously.After finishing adding, the warp that the reactant mixture impouring is cooled off in ice/brine bath is chilled in 0 ℃ water (3.5L) solution of Rochelle ' s salt (245g, sodium potassium tartrate tetrahydrate) in advance.Under 0 ℃, the mixture that stirring is generated 1 hour at this moment, adds water (1.L) solution of sodium hydrogensulfite (250g).At ambient temperature, stir the solution that is generated all night.Add filter aid to mixture; Again by filter aid pad filter reaction mixture.Use CH ₂Cl ₂The washing solid moves to separatory funnel with filtrate.Separate each layer, use CH ₂Cl ₂(3L) extraction water-bearing layer.The organic layer that merges is through water washing, through MgSO ₄Drying is filtered and solvent removed in vacuo, up to the about 2L dark red solution of remainder.Under nitrogen atmosphere, this mixture is placed round-bottomed flask, add N, two (trimethyl silyl) acetamides of O-(216mL, 0.866mol).After finishing adding, heating blends to 45 ℃ kept this temperature 0.5 hour again.Reaction mixture, vacuum concentration is up to forming the light orange solid.Successively add a small amount of methyl tertiary butyl ether(MTBE) and heptane (2L).The suspension that stirring is generated 10 minutes filters, with the solid that heptane wash generated.Under 60 ℃, the solid that vacuum drying generated spends the night, and obtains need not to be further purified and the title compound that adopts.

Step C: (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-iodine Phenyl) preparation of azetidine-2-ketone

(4S)-3-{ (2R)-5-(4-fluorophenyl)-2-[(S)-(4-iodophenyl) in methyl tertiary butyl ether(MTBE) (180mL) (the 4-[(trimethyl silyl) and the oxygen base] phenyl } amino) methyl]-the 5-[(trimethyl silyl) the oxygen base] valeryl }-4-phenyl-1,3-oxaza pentane-2-ketone (22.13g, 26.83mmol; The intermediate of step B) suspension successively adds N, two (trimethyl silyl) acetamides of O-(12mL, 45.61mmol), fluoridize four positive fourth ammoniums (0.45g, 1.34mmol).At ambient temperature, stirred reaction mixture 2.5h at this moment, adds acetate (1.10mL), stirs the mixture 10 minutes again.Solvent removed in vacuo obtains yellow oil.Make oil be dissolved in 2-propyl alcohol (110mL), add 2N aq.H again ₂SO ₄(11mL) solution.Under the RT, stir the about 16h of mixture that is generated, pour into again in the separatory funnel that contains water and ethyl acetate.Separate each layer, extract the water-bearing layer with EtOAc.The organic layer that merges is through MgSO ₄Drying is filtered solvent removed in vacuo.(19.7g is dissolved in minimum CH to residue ₂Cl ₂In) through silica gel MPLC purifying,, obtain containing the title compound of Shao Liang oxazolidone impurity with 20%EtOAc/ heptane-60%EtOAc/ heptane gradient elution.

Step D: Acetate 4-[(2S, 3R)-3-[(3S)-3-(acetoxyl group)-3-(4-fluorophenyl) propyl group]-2-(4- Iodophenyl)-and 4-aza-oxo-cyclobutane-1-yl] preparation of phenyl ester

CH to the intermediate (16.6g, about 26.8mmol) of step C ₂Cl ₂Solution (145mL) add anhydrous pyridine (2.6mL, 32.2mmol), acetic anhydride (3.1mL, 32.2mmol) and DMAP (0.2g, about 1.3mmol).In RT stirred reaction mixture 1h, at this moment, add pyridine (1.8mL, 0.8equiv.), acetic anhydride (2.1mL, about 0.8equiv.).In the other 1h of RT stirred reaction mixture, at this moment, add pyridine (0.5mL, about 0.23equiv.), acetic anhydride (0.5mL, about 0.20equiv.).At ambient temperature, stirred reaction mixture 16h pours in the separatory funnel that contains 1N aq.HCl (200mL) solution again.Separate each layer, use sat.aq.NaHCO ₃The washing organic layer is through MgSO ₄Drying is filtered solvent removed in vacuo.Be dissolved in minimum CH ₂Cl ₂In residue through silica gel MPLC purifying, to 50%EtOAc/ heptane gradient elution, obtain title compound with the 20%EtOAc/ heptane.

¹HNMR(500MHz，CDCl ₃)δ：7.74(d，J＝8.5，2H)，7.29(m，2H)，7.26(d，J＝8.9，2H)，7.10(d，J＝8.2，2H)，7.05(t，J＝8.5，2H)，6.99(d，J＝8.7，2H)，5.72(t，J＝6.9，1H)，4.57(d，J＝2.1，1H)，3.08(m，1H)，2.29(s，3H)，2.08(s，3H)，2.08-2.01(m，2H)，1.92-1.85(m，2H).

Step e: Acetate (1S)-1-(4-fluorophenyl)-3-[(2S, 3R)-2-(4-iodophenyl)-4-oxo -1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-3-yl] preparation of propyl ester

To acetate 4-[(2S, 3R)-3-[(3S)-3-(acetoxyl group)-3-(4-fluorophenyl) propyl group]-2-(4-iodophenyl)-4-aza-oxo-cyclobutane-1-yl] phenyl ester (18g; 30mmol; Step D intermediate) MeOH (100mL) solution successively add guanidine (2.9g, 30mmol) and TEA (4.2mL, 30mmol).Stir the mixture 3h that is generated in RT, at this moment, solvent removed in vacuo.Make residue be dissolved in EtOAc (400mL) and 1N aq.HCl (200mL).Separate each layer, with salt solution (200mL) washing organic layer, through MgSO ₄Drying is filtered solvent removed in vacuo.

Make the above raw material that obtains be dissolved in CH ₂Cl ₂(100ml), again by independent syringe added simultaneously through 20 minutes pyridine (2.67mL, 33mmol) and trifluoromethanesulfanhydride anhydride (5.55mL; 33mmol).Stirred reaction mixture 1h.Successively with 1N aq. hydrochloric acid (100mL), salt solution (100ml) washing reaction mixture, through anhydrous MgSO ₄Powder for drying is filtered, and subtracts evaporating solvent under the power, obtains yellow oil.Oil is through silica gel MPLC purifying, and the gradient elution with from the 0%EtOAc/ hexane to the 70%EtOAc/ hexane obtains title compound.

¹HNMR(500MHz，CDCl ₃)δ：7.76(d，J＝8.2，2H)，7.32-7.28(m，4H)，7.18(d，J＝8.9，2H)，7.10(d，J＝8.2，2H)，7.05(t，J＝8.7，2H)，5.73(t，J＝6.7，1H)，4.59(d，J＝2.5)，3.12(m，1H)，2.08(s，3H)，2.08-2.02(m，2H)，1.93-1.86(m，2H).

Step F: Acetate (1S)-3-[(2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) first Base]-3-hydroxyl fourth-1-alkynes-1-yl } phenyl)-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base }- Phenyl) azetidine-3-yl]-preparation of 1-(4-fluorophenyl) propyl ester

Nitrogen bubble is fed acetate (1S)-1-(4-fluorophenyl)-3-[(2S, 3R)-2-(4-iodophenyl)-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-3-yl] propyl ester (10.25g, 14.83mmol; The step e intermediate), 2-acetenyl propane-1,2,3-triol 1,3-diacetate esters (3.86g, 19.28mmol; Intermediate i-2) and triethylamine (14.47mL, dry DMF 104mmol) (100mL) solution 15 minutes.Add Pd (PPh ₃) Cl ₂(1.04g, 1.48mmol) and CuI (0.057g, 2.97mmol), under nitrogen atmosphere, stirred reaction mixture 1.5h.Pour reactant mixture into water (500mL), and extract with EtOAc (3x150mL).The organic layer that merges is through water (2x500mL), salt solution (200mL) washing, through Na ₂SO ₄Drying is filtered solvent removed in vacuo.Residue with the gradient from the 0%EtOAc/ hexane to the 50%EtOAc/ hexane, is used the own wash-out of 50%EtOAc/ through silica gel MPLC purifying again, obtains title compound.

¹HNMR(500MHz，CDCl ₃)δ：7.47(d，J＝8.2，2H)，7.31-7.27(m，6H)，7.16(d，J＝9.1，2H)，7.04(t，J＝8.5，2H)，5.72(t，J＝6.6，1H)，4.63(d，J＝2.1，1H)，4.39(d，J＝11.4，2H)，4.32(d，J＝11.4，2H)，3.12(m，2H)，2.16(s，6H)，2.08(s，3H)，2.08-2.02(m，2H)，1.93-1.86(m，2H).

Step G: Acetate (1S)-3-(2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3- Hydroxyl fourth-1-alkynes-1-yl } phenyl)-4-oxo-1-{4-[3-(1H-1,2,4-triazol-1-yl) third-1-alkynes -1-yl] phenyl } azetidine-3-yl)-preparation of 1-(4-fluorophenyl) propyl ester

Nitrogen bubble is fed acetate (1S)-3-[(2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl fourth-1-alkynes-1-yl } phenyl)-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-3-yl]-1-(4-fluorophenyl) propyl ester (300mg, 0.43mmol; The step F intermediate), 1-third-2-alkynes-1-base-1H-1,2,4-triazole (i-7) (229mg, 2.1mmol), triethylamine (0.29mL, 2.1mmol) and iodate four positive fourth ammoniums (159mg, dry DMF 0.43mmol) (5mL) solution 15 minutes.Add Pd (PPh ₃) ₄(50mg, 0.043mmol) and CuI (4mg 0.022mmol), under nitrogen atmosphere, 70 ℃, added thermal reaction mixture 3 days.Reaction mixture is poured in the water (50mL) to RT, and extracts with EtOAc (3x20mL).The organic layer that merges is through water (2x50mL), salt solution (25mL) washing, through Na ₂SO ₄Drying is filtered solvent removed in vacuo.Residue with the gradient from the 0%EtOAc/ hexane to the 90%EtOAc/ hexane, with 90%EtOAc/ hexane wash-out, obtains title compound through silica gel MPLC purifying again.

¹HNMR(500MHz，CDCl ₃)δ：8.48(s，1H)，8.06(s，1H)，7.47(d，J＝8.2，2H，7.36(d，J＝8.7，2H)，7.30(m，4H)，7.20(d，J＝8.7，2H)，7.06(t，J＝8.7，2H)，5.72(t，J＝6.9，1H)，5.22(s，1H)，4.65(d，J＝2.3，1H)，4.40(d，J＝11.2，2H)，4.33(d，J＝11.2，2H)，3.10(m，1H)，2.17(s，6H)，2.09(s，3H)，2.09-2.03(m，2H)，1.94-1.87(m，2H).

Step H: Acetate (1S)-3-((2S.3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3- Hydroxybutyl } phenyl)-4-oxo-1-{4-[3-(1H-1,2,4-triazol-1-yl) propyl group] phenyl } azepine Cyclobutane-3-yl)-preparation of 1-(4-fluorophenyl) propyl ester

To acetate (1S)-3-((2S through purging with nitrogen gas, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl fourth-1-alkynes-1-yl } phenyl)-4-oxo-1-{4-[3-(1H-1,2, the 4-triazol-1-yl) third-1-alkynes-1-yl] phenyl } azetidine-3-yl)-1-(4-fluorophenyl) propyl ester (step G intermediate; 65mg, EtOAc/EtOH (4mL 0.09mmol); 10/1) solution adds 10%Pd-C (15mg).Under the atmosphere of hydrogen of room pressure, the mixture that stirring is generated 16 hours.Remove by filter catalyzer through filter aid, solvent removed in vacuo.Residue is used MeOH/CH through preparation type column plate purifying ₂Cl ₂(90/10) wash-out obtains title compound.

¹HNMR(500MHz，CDCl ₃)δ：8.08(s，1H)，7.99(s，1H)，7.31-7.27(m，4H)，7.24-7.21(m，4H)，7.06-7.03(m，4H)，5.73(t，J＝6.9，1H)，4.60(d，J＝2.2，1H)，4.18-4.11(m，6H)，3.27(m，3H)，3.18(m，1H)，2.77(m，2H)，2.57(t，J＝7.6，2H)，2.20(t，J＝7.6，2H)，2.13(s，6H)，2.08(s，3H)，2.07-2.04(m，2H)，1.91-1.86(m，4H)，1.48(m，(3H).

Step I: (3R, 4S)-4-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[(3S)-3-(4- Fluorophenyl)-the 3-hydroxypropyl]-1-{4-[3-(1H-1,2,4-triazol-1-yl) propyl group] phenyl } azacyclo- The preparation of butane-2-ketone

To acetate (1S)-3-((2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-the 3-hydroxybutyl } phenyl)-4-oxo-1-{4-[3-(1H-1,2, the 4-triazol-1-yl) propyl group] phenyl } azetidine-3-yl)-1-(4-fluorophenyl) propyl ester (35mg, 0.05mmol; EtOH step H intermediate) (3mL) solution adding trimethyl silane potassium alcoholate (2mg, 0.014mmol).The mixture that stirring is generated under the RT 16 hours.Reactant mixture is through preparation HPLC (C-18Sunfire post) purifying, with CH ₃The gradient liquid wash-out of CN/0.1%aq.TFA (5-90%).Collect each product flow point, from CH ₃Freeze-drying in the CN/ water obtains title compound.

m/z(ES)603(MH) ⁺， ¹HNMR(500MHz，DMSO-d6)δ：8.48(s，1H)，7.94(s，1H)，7.29(m，4H)，7.18(d，J＝8.0，2H)，7.11(m，6H)，5.26(d，J＝4.5，1H)，4.84(d，J＝2.2，1H)，4.49(q，J＝6.4，1H)，4.39(t，J＝5.7，2H)，4.12(t，J＝7.1，2H)，4.05(s，1H)，3.29(m，4H)，3.06(m，1H)，2.59(m，2H)，2.43(t，J＝7.4，2H)，2.01(m，2H)，1.83(m，1H)，1.72(m，3H)，1.58(m，2H)

Embodiment 2

(3R, 4S)-4-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[(3S)-3-(4-fluorobenzene Base)-the 3-hydroxypropyl]-1-{4-[2-(1H-1,2,4-triazole-5-yl) ethyl] phenyl } azetidine-2- Ketone

Steps A: Acetate (1S)-3-((2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3- Hydroxyl fourth-1-alkynes-1-yl } phenyl)-4-oxo-1-{4-[(trimethyl silyl) acetenyl] phenyl } Azetidine-3-yl)-preparation of 1-(4-fluorophenyl) propyl ester

Nitrogen bubble is fed acetate (1S)-3-[(2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl fourth-1-alkynes-1-yl } phenyl)-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-3-yl]-1-(4-fluorophenyl) propyl ester (9.77g, 12.8mmol; Embodiment 1 step F intermediate), trimethyl silyl acetylene (4.52mL, 32mmol), iodate four positive fourth ammoniums (4.72g, 12.8mmol) and triethylamine (8.92mL, dry DMF 64mmol) (100mL) solution 15 minutes.Add Pd (PPh ₃) ₄(1.48g, 1.28mmol) and CuI (0.49g 2.56mmol), under 50 ℃, nitrogen atmosphere, adds thermal reaction mixture 16h.Reaction mixture is poured in the water (500mL) to RT, and extracts with EtOAc (3x200mL).The organic layer that merges is through water (2x500mL), salt solution (200mL) washing, through Na ₂SO ₄Drying is filtered solvent removed in vacuo.Residue with the gradient from the 0%EtOAc/ hexane to the 40%EtOAc/ hexane, is used 40%EtOAc/ hexane wash-out through silica gel MPLC purifying again, obtains title compound.

¹HNMR(500MHz，CDCl ₃)δ：7.45(d，J＝8.0，2H)，7.34(d，J＝8.7，2H)，7.29(m，4H)，7.15(d，J＝8.7，2H)，7.04(t，J＝8.7，2H)，5.72(t，J＝6.6，1H)，4.63(d，J＝2.1，1H)，4.39(d，J＝11.4，2H)，4.32(d，J＝11.4)，3.09-3.05(m，2H)，2.16(s，6H)，2.08(s，3H)，2.07-2.01(m，2H)，1.93-1.86(m，2H)，0.24(s，9H).

Step B: Acetate (1S)-3-[(2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3- Hydroxyl fourth-1-alkynes-1-yl } phenyl)-1-(4-ethynyl phenyl)-4-aza-oxo-cyclobutane-3- Base]-preparation of 1-(4-fluorophenyl) propyl ester

To acetate (1S)-the 3-((2S that in ice bath, is cooled to 0 ℃, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl fourth-1-alkynes-1-yl } phenyl)-4-oxo-1-{4-[(trimethyl silyl) acetenyl] phenyl } azetidine-3-yl)-1-(4-fluorophenyl) propyl ester (5.7g, 8mmol; The steps A intermediate) anhydrous THF (60mL) solution slowly adds 1.0M and fluoridizes four positive fourth ammonium (8mL, 8mmol) solution.The limit continues cooling limit stirred reaction mixture 0.5h.Water (150mL) diluted reaction mixture, and use CH ₂Cl ₂(150mL) extraction.Through Na ₂SO ₄Dry organic layer filters solvent removed in vacuo.Residue with the 0%EtOAc/ hexane, is used the gradient from the 0%EtOAc/ hexane to the 45%EtOAc/ hexane through silica gel MPLC purifying again, with 45%EtOAc/ hexane wash-out, obtains title compound again.

¹HNMR(500MHz，CDCl ₃)δ：7.45(d，J＝8.2，2H)，7.37(d，J＝8.7，2H)，7.29(m，4H)，7.18(d，J＝8.7，2H)，7.04(t，J＝8.7，2H)，5.72(t，J＝6.6，1H)，4.63(d，J＝2.3，1H)，4.38(d，J＝11.2，2H)，4.31(d，J＝11.2，2H)，3.11(s，1H)，3.08(m，1H)，3.04(s，1H)，2.16(s，6H)，2.08(s，3H)，2.07-2.02(m，2H)，1.93-1.86(m，2H).

Step C: Acetate (1S)-3-((2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3- Hydroxyl fourth-1-alkynes-1-yl } phenyl)-4-oxo-1-{4-[(1-trityl-1H-1,2,4-triazole-3-yl) Acetenyl] phenyl } azetidine-3-yl)-preparation of 1-(4-fluorophenyl) propyl ester

Nitrogen bubble is fed acetate (1S)-3-[(2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl fourth-1-alkynes-1-yl } phenyl)-1-(4-ethynyl phenyl)-4-aza-oxo-cyclobutane-3-yl]-1-(4-fluorophenyl) propyl ester (4.0g, 6.3mmol; Step B intermediate), 3-iodo-1-trityl-1H-1,2,4-triazole (i-8) (5.47g, 12.5mmol), triethylamine (4.4mL, 31.3mmol) and iodate four positive fourth ammoniums (50 ℃ were heated 20 minutes down for 2.31g, dry DMF 6.3mmol) (5mL) solution.Add Pd (PPh ₃) ₄(0.72g, 0.63mmol) and CuI (0.2g 1.25mmol), under 50 ℃, nitrogen atmosphere, added thermal reaction mixture about 18 hours.Reaction mixture is poured in the water (700mL) to RT, and extracts with EtOAc (3x200mL).The organic layer that merges is through water (2x500mL), salt solution (200mL) washing, through Na ₂SO ₄Drying is filtered solvent removed in vacuo.Residue is through column chromatography purification, with the 0%EtOAc/ hexane, again with from the 0%EtOAc/ hexane to the 50%EtOAc/ hexane, again with gradient, with 60%EtOAc/ hexane wash-out, obtain title compound again from the 50%EtOAc/ hexane to the 60%EtOAc/ hexane.

¹HNMR(500MHz，CDCl ₃)δ：8.03(s，1H)，7.45(d，J＝8.0，2H)，7.44(d，J＝8.7，2H)，7.36(m，9H)，7.29(m，4H)，7.19(d，J＝8.7，2H)，7.15(m，6H)，7.04(t，J＝8.4，2H)，5.71(t，J＝6.6，1H)，4.63(d，J＝2.3，1H)，4.39(d，J＝11.5，2H)，4.32(d，J＝11.5，2H)，3.36(s，1H)，3.08(m，1H)，2.15(s，6H)，2.07(s，3H)，2.07-2.02(m，2H)，1.93-1.85(m，2H).

Step D: Acetate (1S)-3-{ (2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3- Hydroxyl fourth-1-alkynes-1-yl } phenyl)-4-oxo-1-[4-(1H-1,2,4-triazole-5-ethyl-acetylene base) phenyl] Azetidine-3-yl }-preparation of 1-(4-fluorophenyl) propyl ester

To acetate (1S)-3-((2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl fourth-1-alkynes-1-yl } phenyl)-4-oxo-1-{4-[(1-trityl-1H-1,2,4-triazole-3-yl) acetenyl] phenyl } azetidine-3-yl)-1-(4-fluorophenyl) propyl ester (600mg, 0.63mmol; Step C intermediate) acetone (10mL) solution adds 1N aq.HCl (3mL) solution.Stirred reaction mixture 16h under the RT.Pour reactant mixture into sat.aq.NaHCO ₃(60mL), and use CH ₂Cl ₂(3x30mL) extraction.The organic layer that merges is through Na ₂SO ₄Drying is filtered solvent removed in vacuo.Residue with the gradient from the 0%EtOAc/ hexane to the 100%EtOAc/ hexane, with 100%EtOAc/ hexane wash-out, obtains title compound through column chromatography purification again.

¹HNMR(500MHz，CDCl ₃)δ：8.28(s，1H)，7.43(d，J＝8.0，2H)，7.37(d，J＝8.5，2H)，7.29(m，4H)，7.18(d，J＝8.7，2H)，7.03(t，J＝8.7，2H)，5.72(t，J＝6.6，1H)，4.65(d，J＝2.1，1H)，4.39(d，J＝11.5，2H)，4.33(d，J＝11.5，2H)，3.10(m，1H)，2.15(s，6H)，2.08(s，3H)，2.07-2.00(m，2H)，1.93-1.86(m，2H).

Step e: Acetate (1S)-3-(2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3- Hydroxybutyl } phenyl)-4-oxo-1-{4-[2-(1H-1,2,4-triazole-5-yl) ethyl] phenyl } azepine Cyclobutane-3-yl)-preparation of 1-(4-fluorophenyl) propyl ester

To acetate (1S)-3-{ (2S through purging with nitrogen gas, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl fourth-1-alkynes-1-yl } phenyl)-4-oxo-1-[4-(1H-1,2,4-triazole-5-ethyl-acetylene base) phenyl] azetidine-3-yl }-1-(4-fluorophenyl) propyl ester (176mg, 0.25mmol; Step D intermediate) EtOAc/EtOH (12mL; 5/1) solution adds 10%Pd-C (50mg).Under the atmosphere of hydrogen of room pressure, the mixture that stirring is generated 16 hours.Remove by filter catalyzer through filter aid, solvent removed in vacuo.Residue is used MeOH/CH through preparation type column plate purifying ₂Cl ₂(85/15) wash-out obtains title compound.

¹HNMR(500MHz，CDCl ₃)δ：8.01(s，1H)，7.29-7.23(m，4H)，7.20(d，J＝8.0，2H)，7.15(d，J＝8.5，2H)，7.04-7.00(m，4H)，5.71(t，J＝6.6，1H)，4.58(d，J＝2.3，1H)，4.13(m，4H)，3.09-3.03(m，3H)，3.02-2.87(m，2H)，2.75(m，2H)，2.11(s，6H)，2.06(s，3H)，2.06-2.00(m，2H)，1.90-1.84(m，4H).

Step F: (3R, 4S)-4-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[(3S)-3-(4- Fluorophenyl)-the 3-hydroxypropyl]-1-{4-[2-(1H-1,2,4-triazole-5-yl) ethyl] phenyl } azacyclo- The preparation of butane-2-ketone

To acetate (1S)-3-((2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-the 3-hydroxybutyl } phenyl)-4-oxo-1-{4-[2-(1H-1,2,4-triazole-5-yl) ethyl] phenyl } azetidine-3-yl)-1-(4-fluorophenyl) propyl ester (10.33g, 14.47mmol; Anhydrous EtOH (175mL) the solution adding trimethyl silane potassium alcoholate step e intermediate) (2.43g, 18.8mmol).Under the RT, the mixture that stirring is generated 2 hours.By adding dense HCl (about 1.25mL), reactant mixture is adjusted to pH=5-6, vacuum evaporation is to about 70ml volume.Filter reaction mixture is removed precipitation, make again filtrate through preparation HPLC (post: purifying C-18Sunfire OBD 5 μ m30x100mm), with CH ₃CN/0.1%aq.TFA (20-40%) gradient 750 μ L inject wash-out.The product flow point of collection through merging adds sat.aq.NaHCO ₃The solution that neutralization is generated, vacuum is removed most of organic solvent, is settled out the white crystals raw material.Cross filter solid, vacuum drying obtains title compound.

Mpt?104℃m/z(ES)589(MH) ⁺； ¹H?NMR(500MHz，DMSO-d6+D ₂O)δ：8.01(s，1H)，7.29-7.26(m，4H)，7.18(d，J＝8.0，2H)，7.11-7.06(m，6H)，4.82(d，J＝1.9，1H)，4.47(t，J＝6.2，1H)，3.28(m，4H)，3.04(m，1H)，2.87(s，4H)，2.58(m，2H)，1.86-1.78(m，1H)，1.75-1.66(m，3H)，1.56(m，2H).

Embodiment 3

(3R, 4S)-4-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[(3S)-3-(4-fluorobenzene Base)-the 3-hydroxypropyl]-1-{4-[3-(1,3-thiazoles-2-base is amino) propyl group] phenyl } azetidine-2- Ketone.

Steps A: Acetate (1S)-3-[(2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3- Hydroxyl fourth-1-alkynes-1-yl } phenyl)-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base }-phenyl) Azetidine-3-yl]-preparation of 1-(4-fluorophenyl) propyl ester

Nitrogen bubble is fed acetate (1S)-1-(4-fluorophenyl)-3-[(2S, 3R)-2-(4-iodophenyl)-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-3-yl] propyl ester (5g, 8.31mmol; Embodiment 1 step e intermediate), acetate 5-acetenyl-2,2-dimethyl-1,3-dioxane-5-ester (2.48g, 12.52mmol; Intermediate i-1) and triethylamine (8.10mL, dry DMF 58.17mmol) (75mL) solution 15 minutes.Add Pd (PPh ₃) Cl ₂(633mg, 0.90mmol) and CuI (0.316g, 1.66mmol), under nitrogen atmosphere, stirred reaction mixture 1.5h.Pour reactant mixture in the water (250mL), and extract with EtOAc (3x100mL).The organic layer that merges is through water (2x500mL), salt solution (200mL) washing, through Na ₂SO ₄Drying is filtered solvent removed in vacuo.Residue is through silica gel MPLC purifying, and with the gradient from the 0%EtOAc/ hexane to the 50%EtOAc/ hexane, 50%EtOAc/ hexane wash-out obtains title compound again.m/z(ES)702(MH-OAc) ⁺，784(M+Na) ⁺.

Step B: Acetate (1S)-3-[(2S, 3R)-2-(4-{5-(acetoxyl group)-22-dimethyl-13-dioxy six Ring-5-yl } acetenyl } phenyl)-1-{4-[3-(benzyloxy) third-1-alkynes-1-yl] phenyl }-4-oxo nitrogen Heterocycle butane-3-yl)-preparation of 1-(4-fluorophenyl) propyl ester

According to embodiment 1, the method for step G is from the intermediate preparation title compound of steps A.m/z(ES)698(MH-OAc) ⁺.

Step C: Acetate (1S)-3-[(2S, 3R)-(3-two for 4-{2-[5-(acetoxyl group)-2,2-dimethyl-1 for 2- Oxygen six ring-5-yls } ethyl } phenyl)-1-[4-(3-hydroxypropyl) phenyl]-4-aza-oxo-cyclobutane-3- Base }-preparation of 1-(4-fluorophenyl) propyl ester

According to embodiment 1, the method for step H is from the intermediate preparation title compound of step B.m/z(ES)616(MH-OAc) ⁺.698(M+Na) ⁺.

Step D: Acetate (1S)-3-[(2S, 3R)-(3-two for 4-{2-[5-(acetoxyl group)-2,2-dimethyl-1 for 2- Oxygen six ring-5-yls } ethyl } phenyl)-4-oxo-1-[4-(3-oxopropyl) phenyl]-azetidine -3-yl }-preparation of 1-(4-fluorophenyl) propyl ester

Through syringe, to deriving from embodiment 3, the intermediate (75mg of step C, 0.11mmol) carrene (1.5mL) solution dropwise add carrene (the 630 μ L of 15% weight Dess Martin, 0.12mmol) solution, under room temperature, nitrogen atmosphere, the mixture that stirring is generated 2 hours.Use saturated sodium bicarbonate solution (2mL) quencher mixture again, and extract with carrene (2x2mL).Merge organic matter,, filter, then vaporising under vacuum through dried over sodium sulfate.Preparation type column plate purifying with 60% ethyl acetate/40% hexane purifying, obtains title compound, m/z (ES) 674 (MH) ⁺.

Step e: Acetate (1S)-3-(2S, 3R)-2-(4-{2-[5-(acetoxyl group)-2,2-dimethyl-1,3-dioxy Six ring-5-yls } ethyl } phenyl)-4-oxo-1-{4-[3-(1,3-thiazoles-2-base is amino) propyl group] phenyl }- Azetidine-3-yl)-preparation of 1-(4-fluorophenyl) propyl ester

To deriving from from embodiment 3, the intermediate of step D (15mg, carrene 0.02mmol) (0.5mL) and acetate (10 μ L) solution successively add thiazolamine (2mg, 0.02mmol) and the molecular sieve of 4A crushing, under room temperature, nitrogen atmosphere, the mixture that stirring is generated 8 hours.(12mg 0.06mmol) adds in the solution, and room temperature stirs the suspension that is generated all night with sodium triacetoxy borohydride again.Use saturated sodium bicarbonate solution (2mL) quencher mixture again, and extract with carrene (2x 5mL).Merge organic matter,, filter, under vacuum, evaporate again through dried over sodium sulfate.Preparation type column plate purifying with 80% ethyl acetate/20% hexane wash-out, obtains title compound, m/z (ES) 758 (MH) ⁺.

Step F: Acetate 3-[4-((2S, 3R)-3-[(3S)-3-(acetoxyl group)-3-(4-fluorophenyl) propyl group]-4- Oxo-1-{4-[3-(1,3-thiazoles-2-base is amino) propyl group] phenyl } azetidine-2-yl) benzene Base]-1, the preparation of two (methylol) propyl ester of 1-

Through syringe, to deriving from embodiment 3, (4.0mg, carrene 0.005mmol) (0.5mL) solution adds trifluoroacetic acid (0.2mL) to the intermediate of step e, the solution that stirring is generated 2 hours.Vacuum concentrated mixture, it need not purifying and is used for next reaction, m/z (ES) 718 (MH)+.

Step G: (3R, 4S)-4-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[(3S)-3-(4- Fluorophenyl)-the 3-hydroxypropyl]-1-{4-[3-(1,3-thiazoles-2-base is amino) propyl group] phenyl } azetidine The preparation of-2-ketone

According to embodiment 1, the method for step I, from embodiment 3, the intermediate preparation title compound of step F.m/z(ES)634(M+H) ⁺.

Employing is similar to above-mentioned those method, the following examples from suitable feedstock production table 1:

Table 1

Can adopt said method, have heterocycle R from suitable feedstock production ⁹Be connected to different alkyl chain length and above-mentioned those relevant compounds of the other parts of structure.

Embodiment 44

(3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[2,3,4,5-tetrahydroxy-4-(methylol) Amyl group] phenyl }-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } azetidine-2-ketone

Steps A: Acetate (1S)-3-[(2S, 3R)-2-(4-allyl phenyl)-4-oxo-1-(4-{[(fluoroform Base) sulfonyl] the oxygen base } phenyl) azetidine-3-yl]-preparation of 1-(4-fluorophenyl) propyl ester

To acetate (1S)-1-(4-fluorophenyl)-3-[(2S; 3R)-and 2-(4-iodophenyl)-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-3-yl] propyl ester (1.5g; 2.17mmol; referring to embodiment 1; step e) anhydrous dioxane (25mL) solution adds lithium chloride (275mg; 6.50mmol) and four palladiums (palladium tetrakis) (255mg; 0.22mmol); the solution that is generated is placed under the nitrogen atmosphere; again through syringe with allyl tributyltin (780 μ L; 2.60mmol) add in the solution, through 16 hours mixtures to 80 of being generated of heating ℃.After being cooled to room temperature, vacuum evaporated solution makes residue be dissolved in ethyl acetate (100mL).Water (50mL), salt solution (50mL) washing organic matter through dried over mgso, filter vacuum evaporation.The MPLC purifying adopts the Horizon instrument, and the 0-60% ethyl acetate gradient elution with in the hexane obtains title compound, m/z (ES) 546 (M-OAc) ⁺With 606 (M+H) ⁺.

Step B: Acetate 2-[(acetoxyl group) methyl]-preparation of 2-hydroxyl fourth-3-alkene-1-base ester

To pack into the oxalic acid 2-oxo propane-1 of the anhydrous THF of 20mL of the 100mL round-bottomed flask that places the drying under the nitrogen atmosphere, (10g 57.4mmol), and adopts ice/water-bath to be cooled to 0 ℃ to 3-two basic esters.(0 ℃ was stirred the solution that generated down 1 hour for 57.4mL, 57.4mmol) solution to add THF of 1.0M vinyl bromination magnesium to this solution through cooling.Remove ice bath, at ambient temperature, other 1.5 hours of the reactant mixture that stirring is generated.Use sat.aq.NH ₄Cl (50mL) quencher reactant mixture is used ethyl acetate (100mL) extraction again.Through Na ₂SO ₄Dry organic layer filters and solvent removed in vacuo, obtains thick intermediate.The Horizon MPLC purifying of the gradient eluent of the 10-60% ethyl acetate in the band hexane obtains title compound.

¹HNMR(500MHz，CDCl ₃)：5.86(dd，J＝11.0，17.1Hz，1H)，5.47(dd，J＝0.8，17.2Hz，1H)，5.30(dd，J＝0.8，11.0Hz，1H)，4.1(ABx?q，J＝11.4Hz，4H)，2.08(s，6H).

Step C: Acetate (1S)-3-[(2S, 3R)-2-(4-{ (2E)-5-(acetoxyl group)-4-[(acetoxyl group) first Base]-4-hydroxyl penta-2-alkene-1-yl } phenyl)-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } Phenyl) azetidine-3-yl]-preparation of 1-(4-fluorophenyl) propyl ester

Under nitrogen atmosphere; to acetate (1S)-3-[(2S; 3R)-and 2-(4-allyl phenyl)-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-3-yl]-1-(4-fluorophenyl) propyl ester (510mg; 0.84mmol; the steps A intermediate) and acetate 2-[(acetoxyl group) methyl]-2-hydroxyl fourth-3-alkene-1-base ester (250mg; 1.02mmol; step B intermediate) anhydrous methylene chloride (5mL) solution adds Zhan catalyst I (670mg; 1.02mmol), stirred the mixture that generated under the room temperature 2 hours.Vacuum evaporation reactant mixture again.Preparation type column plate purifying with 40% ethyl acetate/60% hexane wash-out, obtains title compound, m/z (ES) 780 (MH) ⁺720 (M-OAc) ⁺.

Step D: Acetate (1S)-3-[(2S, 3R)-2-(4-{5-(acetoxyl group)-4-[(acetoxyl group) first Base]-2,3,4-three hydroxyl amyl groups } phenyl)-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) Azetidine-3-yl]-preparation of 1-(4-fluorophenyl) propyl ester

To acetone: acetate (the 1S)-3-[(2S in 8: 1 (4.5mL) solution of water; 3R)-2-(4-{ (2E)-5-(acetoxyl group)-4-[(acetoxyl group) methyl]-4-hydroxyl penta-2-alkene-1-yl } phenyl)-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-3-yl]-1-(4-fluorophenyl) propyl ester (200mg; 0.26mmol; step C intermediate) solution; successively add N-methylmorpholine-N-oxide (52mg; 0.52mmol) and isopropyl alcohol (the 228 μ L of 2.5% weight osmium tetroxide; 0.002mmol) solution, stirred the mixture that generated under the room temperature 3 hours.With carrene (20mL) diluted mixture thing, successively use 1N HCl (15mL), salt solution (15mL) washing.Organic matter filters and concentrates through dried over mgso.Preparation type column plate purifying with 60% ethyl acetate/40% hexane wash-out, obtains title compound, m/z (ES) 814 (MH) ⁺754 (M-OAc) ⁺.

Step e: Acetate (1S)-3-[(2S, 3R)-2-(4-{5-(acetoxyl group)-4-[(acetoxyl group) first Base]-2,3,4-trihydroxy amyl group } phenyl)-4-oxo-1-(4-{[(1-trityl-1H-1,2,4-triazole -3-yl) acetenyl] phenyl) azetidine-3-yl]-preparation of 1-(4-fluorophenyl) propyl ester

Method according to embodiment 1 step G; from acetate (1S)-3-[(2S; 3R)-and 2-(4-{5-(acetoxyl group)-4-[(acetoxyl group) methyl]-2; 3,4-three hydroxyl amyl groups } phenyl)-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base phenyl) azetidine-3-yl]-1-(4-fluorophenyl) propyl ester (step D intermediate) and I-10The preparation title compound.M/z (ES) 999 (MH) ⁺, 757 (MH-trityls) ⁺.

Step F: Acetate (1S)-3-{2S, 3R)-2-(4-{5-(acetoxyl group)-4-[(acetoxyl group) first Base]-2,3,4-three hydroxyl amyl groups } phenyl)-4-oxo-1-[4-(1H-1,2,4-triazole-3-yl) acetenyl) benzene Base] azetidine-3-yl]-preparation of 1-(4-fluorophenyl) propyl ester

Method according to embodiment 2 step D, from acetate (1S)-3-[(2S, 3R)-and 2-(4-{5-(acetoxyl group)-4-[(acetoxyl group) methyl]-2,3,4-three hydroxyl amyl groups } phenyl)-4-oxo-1-(4-{[(1-trityl-1H-1,2,4-triazole-3-yl) acetenyl] phenyl) azetidine-3-yl]-1-(4-fluorophenyl) propyl ester (step e intermediate) preparation title compound.m/z(ES)757(MH) ⁺.

Step G: Acetate (1S)-3-((2S, 3R)-2-(4-{5-(acetoxyl group)-4-[(acetoxyl group) first Base]-2,3,4-three hydroxyl amyl groups } phenyl)-4-oxo-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] benzene Base } azetidine-3-yl]-preparation of 1-(4-fluorophenyl) propyl ester

Method according to embodiment 2 step e, from acetate (1S)-3-{ (2S, 3R)-and 2-(4-{5-(acetoxyl group)-4-[(acetoxyl group) methyl]-2,3,4-three hydroxyl amyl groups } phenyl)-4-oxo-1-[4-(1H-1,2,4-triazole-3-yl) acetenyl) phenyl] azetidine-3-yl]-1-(4-fluorophenyl) propyl ester (step F intermediate), the preparation title compound.m/z(ES)761(MH) ⁺.

Step H: (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[2,3,4, the 5-tetrahydroxy -4-(methylol) amyl group] phenyl }-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } azacyclo- The preparation of butane-2-ketone

Method according to embodiment 2 step F, from acetate (1S)-3-((2S, 3R)-and 2-(4-{5-(acetoxyl group)-4-[(acetoxyl group) methyl]-2,3,4-three hydroxyl amyl groups } phenyl)-4-oxo-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } azetidine-3-yl]-1-(4-fluorophenyl) propyl ester (step G intermediate), the preparation title compound.m/z(ES)635(MH) ⁺.

Embodiment 45 (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[1,2,3,4-four Hydroxyl-3-(methylol) butyl] phenyl }-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } nitrogen Heterocycle butane-2-ketone

Employing is similar to above-mentioned those methods among the embodiment 44 formerly, except replacing the wherein used allyl tributyltin with the vinyl tributyl tin, and from suitable raw material, preparation title compound, m/z (ES) 621 (MH) ⁺.

Embodiment 46

Steps A: Acetate (1S)-3-[(2S, 3R)-2-(4-{ (2E)-5-(acetoxyl group)-4-[(acetoxyl group) first Base]-4-hydroxyl penta-2-alkene-1-yl } phenyl)-4-oxo-1-(4-[(1-trityl-1H-1,2,4-triazole -3-yl) acetenyl] phenyl) azetidine-3-yl]-preparation of 1-(4-fluorophenyl) propyl ester

Method according to embodiment 1 step G; from acetate (1S)-3-[(2S; 3R)-2-(4-{ (2E)-5-(acetoxyl group)-4-[(acetoxyl group) methyl]-4-hydroxyl penta-2-alkene-1-yl phenyl)-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base phenyl) azetidine-3-yl]-1-(4-fluorophenyl) propyl ester (embodiment 44, step C) and I-10, the preparation title compound.M/z (ES) 965 (MH) ⁺, 723 (MH-trityls) ⁺.

Step B: Acetate (1S)-3-((2S, 3R)-2-(4-(5-(acetoxyl group)-4-[(acetoxyl group) methyl]-4- The hydroxyl amyl group) phenyl)-and 4-oxo-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } azacyclo- Butane-3-yl)-preparation of 1-(4-fluorophenyl) propyl ester

To ethyl acetate/ethanol (3/1; 10% palladium on carbon (40mg) suspension 2mL) adds acetate (1S)-3-((2S, 3R)-2-(4-{ (2E)-5-(acetoxyl group)-4-[(acetoxyl group) methyl]-4-hydroxyl penta-2-alkene-1-yl } phenyl)-4-oxo-1-(4-[(1-trityl-1H-1,2,4-triazole-3-yl) acetenyl] phenyl) azetidine-3-yl]-1-(4-fluorophenyl) propyl ester (22mg, 0.03mmol, the steps A intermediate) ethanol (0.2mL) solution, the mixture that is generated is placed under the atmosphere of hydrogen, and thoroughly stir.Adopt Gilmen PTFE 0.45 μ M syringe filter sheet elimination catalyzer, with ethanol (10mL) washing.Concentrate organic matter to dry, obtain crude product.Compound is used for next reaction through being further purified.m/z(ES)729(MH) ⁺.

Step C: (3R, 4S)-4-{4-[4,5-dihydroxy-4-(methylol) amyl group] phenyl }-3-[(3S)-3-(4- Fluorophenyl)-the 3-hydroxypropyl]-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } azetidin The preparation of alkane-2-ketone

Method according to embodiment 2 step F, from acetate (1S)-3-((2S, 3R)-2-(4-{5-(acetoxyl group)-4-[(acetoxyl group) methyl]-4-hydroxyl amyl group) phenyl)-4-oxo-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } azetidine-3-yl)-1-(4-fluorophenyl) propyl ester (step C intermediate), the preparation title compound.m/z(ES)603(MH) ⁺.

Embodiment 47

Steps A: 5-acetenyl-2,2,2 ', 2 '-tetramethyl-45 '-two-13-dioxane-5,5 '-system of glycol Be equipped with

Add 2 of the anhydrous THF of 20ml to the 100mL round-bottomed flask that places the drying under the nitrogen atmosphere, 2-dimethyl-1, (5g 38.4mmol), adopts ice/water-bath to be cooled to 0 ℃ to 3-dioxane-5-ketone.(0 ℃ was stirred the solution that generated down 30 minutes for 76.8mL, 38.4mmol) solution to add THF of 0.5M bromination acetenyl magnesium to this solution through cooling.Remove ice bath, at ambient temperature, other 1.5 hours of the reactant mixture that stirring is generated.Use sat.aq.NH ₄Cl (50mL) quencher reactant mixture is used ethyl acetate (100mL) extraction again.Through Na ₂SO ₄Dry organic layer filters and solvent removed in vacuo, obtains thick intermediate.Horizon MPLC purifying with the 10-60% ethyl acetate gradient eluent in the band hexane obtains title compound. ¹HNMR(500MHz，CDCl ₃)δ：4.63(s，1H)，4.32(d，J＝12.2Hz，1H)，4.08(dd，J＝1.2，12.2Hz，1H)，4.04(s，1H)，3.98(app?t，J＝12.2Hz，2H)，3.82(d，J＝12.1H，1H)3.78(dd，J＝1.2，12.2Hz，1H)，3.66(s，1H)，2.69(s，1H)，1.51(s，3H)，1.50(s，3H)，1.48(s，3H)，1.47(s，3H).

Step B: Acetate (1S)-3-[(2S, 3R)-2-{4-[(5,5 '-dihydroxy-2,2,2 ', 2 '-tetramethyl-4,5 '-two -1,3-dioxane-5-yl) acetenyl] phenyl }-4-oxo-1-(4-{[(trifluoromethyl) sulphonyl Base] the oxygen base } phenyl) azetidine-3-yl]-preparation of 1-(4-fluorophenyl) propyl ester

Method according to the step F of embodiment 1; by 5-acetenyl-2; 2; 2 ', 2 '-tetramethyl-4,5 '-two-1; 3-dioxane-5; 5 '-glycol (steps A intermediate) and acetate (1S)-1-(4-fluorophenyl)-3-[(2S, 3R)-2-(4-iodophenyl)-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-3-yl] propyl ester (intermediate of the step e of embodiment 1), synthesising title compound.m/z(ES)850(MH) ⁺.

Step C: Acetate (1S)-3-[(2S, 3R)-2-{4-[(5,5 '-dihydroxy-2,2,2 ', 2 '-tetramethyl-4,5 '-two -1,3-dioxane-5-yl) acetenyl] phenyl }-4-oxo-1-{4-[(1-trityl -1H-1,2,4-triazole-3-yl) acetenyl] phenyl } azetidine-3-yl]-1-(4-fluorophenyl) phenyl ester Preparation

Method according to embodiment 1 step G; from acetate (1S)-3-[(2S; 3R)-2-{4-[(5; 5 '-dihydroxy-2; 2,2 ', 2 '-tetramethyl-4; 5 '-two-1,3-dioxane-5-yl) acetenyl] phenyl-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base-phenyl) azetidine-3-yl]-1-(4-fluorophenyl) propyl ester (step B intermediate) and I-10The preparation title compound.M/z (ES) (MH) ⁺, 793 (MH-trityls) ⁺

Step D: Acetate (1S)-3-[(2S, 3R)-2-{4-[(5,5 '-dihydroxy-2,2,2,2 '-tetramethyl-4,5 '-two -1,3-dioxane-5-yl) ethyl] phenyl }-4-oxo-1-{4-[2-(1H-1,2,4-triazole-3- Base) ethyl] phenyl } azetidine-3-yl]-preparation of 1-(4-fluorophenyl) propyl ester

Method according to embodiment 46 step B, from acetate (1S)-3-[(2S, 3R)-2-{4-[(5,5 '-dihydroxy-2,2,2 ', 2 '-tetramethyl-4,5 '-two-1,3-dioxane-5-yl) acetenyl] phenyl }-4-oxo-1-{4-[(1-trityl-1H-1,2,4-triazole-3-yl) acetenyl] phenyl } azetidine-3-yl]-1-(4-fluorophenyl) propyl ester (step C intermediate) preparation title compound.

M/z (ES) 801 (MH) ⁺. ¹HNMR (500MHz, CDCl ₃) δ: 7.98 (s, 1H), 7.32-7.28 (m, 2H), 7.24-7.18 (m, 2H), 7.17 (d, J=8.5Hz, 2H), 7.06-7.00 (m, 3H), 5.72 (t, J=6.7Hz, 1H), 4.58 (d, J=1.8Hz, 1H), 4.15 (dd, J=7.8,12.6Hz, 2H), 3.97 (d, J=12.6Hz, 1H), 3.85 (d, J=11.7Hz, 1H), 3.8 (d, 4.0Hz, 1H), 3.60 (dd, J=2.4Hz, 11.7Hz, 1H), 3.52 (s, 1H), 3.50 (d, J=12.8,1H), 3.42 (br s, 1H), and 3.10-2.98 (m, 4H), 2.80-2.70 (m, 1H), 2.72-2.64 (m, 1H), 2.12-2.00 (m, 3H), 2.08 (s, 3H), 1.92-1.84 (m, 2H), 1.48 (s, 3H), 1.45 (s, 3H), 1.43 (overlapping unimodal, 6H).

Step e: Acetate (1S)-1-(4-fluorophenyl)-3-((3R, 4S)-2-oxo-4-{4-[3,4,5, the 6-tetrahydroxy -3, two (methylol) hexyls of 5-] phenyl }-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } nitrogen Heterocycle butane-3-yl) preparation of propyl ester

To acetate (1S)-3-[(2S, 3R)-2-{4-[(5,5 '-dihydroxy-2,2,2 ', 2 '-tetramethyl-4,5 '-two-1,3-dioxane-5-yl) ethyl] phenyl }-4-oxo-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } azetidine-3-yl]-the THF/ water (10/1 of 1-(4-fluorophenyl) propyl ester (step D intermediate); 1.65mL) solution adds trifluoroacetic acid (03mL), stirs the solution that generated under the room temperature 3 hours.Vacuum evaporation with toluene (3x5mL) azeotropic, is removed trace water and excessive TFA.Residue need not be further purified and be used for next step reaction.m/z?(ES)721(MH) ⁺.

Step F: (3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[3,4,5, the 6-tetrahydrochysene -3, two (methylol) hexyls of 5-] phenyl }-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } nitrogen The preparation of heterocycle butane-2-ketone

Method according to embodiment 2 step F, by acetate (1S)-1-(4-fluorophenyl)-3-((3R, 4S)-2-oxo-4-{4-[3,4,5,6-tetrahydroxy-3, two (methylol) hexyls of 5-] phenyl }-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } azetidine-3-yl) propyl ester (step e intermediate), the preparation title compound.m/z(ES)679(MH) ⁺.

Embodiment 48

Steps A; (2R, 3S, 5R, 6S)-2,3,4,5, the preparation of 6-five (benzyloxy)-1-ethynylcyclohexanol

Under the nitrogen atmosphere, and the THF solution of adding 0.5M bromination acetenyl magnesium in the 100mL of drying round-bottomed flask (1.0mL, 0.50mmol).In ice bath, cool off the solution to 0 that generated ℃.To through the cooling solution slowly add (2R, 3S, 5R, 6S)-2,3,4,5,6-five (benzyloxy) cyclohexanone (300mg, 0.5mL anhydrous THF solution 0.48mmol).Remove ice bath, under the environmental temperature, the reactant mixture that stirring is generated 1.5 hours.Use sat.aq.NH ₄Cl (50mL) quencher reactant mixture is used ethyl acetate (100mL) extraction again.Through Na ₂SO ₄Dry organic layer filters and solvent removed in vacuo.Preparation type column plate purifying with 20% ethyl acetate/80% hexane wash-out, obtains title compound.

Can be according to Posternak, T is at E.G.Ball (editor), Biochemical Preparations, the II volume, John Wiley and Sons, Inc, New York, 57 pages (1952) and Billington D.C, Baker R, Kulagowski JJ, Mawer I.M be at J.Chem Soc Chem Comm (4), the described method of 314-316 page or leaf (1987), by myo-inositol single ketones (myo-inosose)-2 preparation (2R, 3S, 5R, 6S)-2,3,4,5,6-five (benzyloxy) cyclohexanone.

Step B: Acetate (1S)-1-(4-fluorophenyl-3-[(3R, 4S)-2-oxo-4-(4-{[2R, 3S, 5R, 6S)- 2,3,4,5,6-five (benzyloxy)-1-hydroxy-cyclohexyl] acetenyl } phenyl)-1-(4-{[(trifluoromethyl) sulphur Acyl group] the oxygen base } phenyl) azetidine-3-yl] preparation of propyl ester

Method according to the step F of embodiment 1; by (2R; 3S, 5R, 6S)-2; 3; 4,5,6-five (benzyloxy)-1-ethynylcyclohexanol (steps A intermediate) and acetate (1S)-1-(4-fluorophenyl)-3-[(2S; 3R)-and 2-(4-iodophenyl)-4-oxo 1-(4{[((trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-3-yl] propyl ester (intermediate of embodiment 1 step e), synthesising title compound.m/z(ES)1218(MH) ⁺.

Step C: second Acid (1S)-1-(4-fluorophenyl)-3-((3R, 4S)-2-oxo-4-(4-{[2R, 3S, 5R, 6S)- 2,3,4,5,6-five (benzyloxy)-1-hydroxy-cyclohexyl] acetenyl } phenyl)-the 1-{4-[(1-trityl -1H-1,2,4-triazole-3-yl) acetenyl] phenyl } azetidine-3-yl] preparation of propyl ester

According to the method for embodiment 1 step G, from the intermediate of step B and I-10The preparation title compound.M/z (ES) 1403 (MH) ⁺, 1160 (MH-trityls) ⁺.

Step D: Acetate (1S)-1-(4-fluorophenyl)-3-((3R, 4S)-the 2-oxo -4-(4-{2-[(2R, 3S, 5R, 6S)-2,3,4,5, and 6-five (benzyloxy)-1-hydroxy-cyclohexyl] ethyl } benzene Base)-and 1-{4-[2-(1H-1,24-triazole-3-yl) ethyl] phenyl } azetidine-3-yl] propyl ester Preparation

According to the method for embodiment 46 step B, from acetate (1S)-1-(4-fluorophenyl)-3-((3R, 4S)-2-oxo-4-(4-{[2R, 3S, 5R, 6S)-2,3,4,5,6-five (benzyloxy)-1-hydroxy-cyclohexyl] acetenyl } phenyl)-1-{4-[(1-trityl-1H-1,2,4-triazole-3-yl) acetenyl] phenyl } azetidine-3-yl] propyl ester (step C intermediate), preparation title (mainly) compound.M/z (ES) 1169 (MH) ⁺. can find less percentile 4 kinds of other mixture of products.Differentiate that through LC-MS they are the hydroxy compounds of single-[m/z (ES) 809,5%], two-[m/z (ES) 899,15%] and three-benzyl [m/z (ES) 989,25%] protection; And trace remove benzyl product [m/z (ES) 719, about 1%] fully.Mixture is used for next reaction.

Step e: Acetate (1S)-1-(4-fluorophenyl)-3-((2R, 3S)-2-(4-{2-[2R, 3S, 4S, 5R, 6S)- 1,2,3,4,5,6-hexahydroxy cyclohexyl] ethyl } phenyl)-4-oxo-1-{4-[2-(1H-1,2,4-triazole-3- Base) ethyl] phenyl } azetidine-3-yl] preparation of propyl ester

Hydrogen cube (H-cube) hydrogenation: hydrogen cube (H-cube) is set reaches 10 crust hydrogen, subsequently with 1.0mL/ minute ethanol elution.Ethanol (15mL) solution for preparing intermediate (mixture 42mg) again, and 10% palladium on carbon tube by hydrogen cube (H-cube) from step D.After 20mL ethanol has passed through, close hydrogen, heat this post to 50 ℃.Make other 20mL ethanol by this post, all compounds of washing catalyst tube again.From the H-cube during second batch of 20mL washing with alcohol more after flow point in observe product.Merge these flow points, and be concentrated into dried.The Gilson HPLC purifying of the eluent of the gradient of band 10-70% acetonitrile/water (0.1%TFA buffer solution) obtains title compound.m/z(ES)719(MH) ⁺.

Step F: (3R, 4S)-3-{ (3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{2-[(2R, 3S, 4S, 5R, 6S)-1,2,3,4,5,6-hexahydroxy cyclohexyl] ethyl } phenyl)-1-{4-[2-(1H-1,2,4-triazole-3-yl) Ethyl] phenyl } preparation of azetidine-2-ketone

According to the method for embodiment 2 step F, from acetate (1S)-1-(4-fluorophenyl)-3-((2R, 3S)-2-(4-{2-[2R, 3S, 4S, 5R, 6S)-1,2,3,4,5,6-hexahydroxy cyclohexyl] ethyl } phenyl)-4-oxo-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } azetidine-3-yl] propyl ester (step e intermediate), the preparation title compound.m/z(ES)677(MH) ⁺.

Embodiment 49

Steps A: The preparation of 2-hydroxyl-5-iodobenzene formaldehyde

To the salicylide (10.65ml, anhydrous CH 100mmol) that cool off down in 0 ℃ ₂Cl ₂(40ml) solution adds iodime iodine monochloride (the 1.0M CH of 100ml ₂Cl ₂Solution, 100mmol).After finishing adding, heating blends is to room temperature and stirred 16 hours.Add 10% moisture Na ₂SO ₃(150ml) quencher reaction.Separate organic layer, water (200ml) washing is through MgSO ₄Drying is filtered and evaporation.Residue obtains title compound from cyclohexane crystallization again. ¹HNMR (500MHz, CDCl ₃) δ: 9.85 (s, 1H), 7.86 (d, J=2.3,1H), 7.78 (dd, J=8.7 and 2.3,1H), 6.82 (d, J=8.7,1H).

Step B: The preparation of 2-benzyloxy-5-iodobenzene formaldehyde

To 2-hydroxyl-5-iodobenzene formaldehyde (10.4g, 41.9mmol; The intermediate of steps A) solution of anhydrous THF (100ml) add in batches sodium hydride (60% the suspension in oil of 1.85g, 46.1mmol).After finishing adding, stirred the mixture 15 minutes, (5.48ml 46.1mmol), stirred the mixture that generated 3 days under the room temperature to add benzyl bromide a-bromotoluene again.Mixture is poured in the water (250ml), and extracted with EtOAc (3x 100ml).The EtOAc layer that water (200ml), sat.NaCl (100ml) washing merge is through Na ₂SO ₄Drying is filtered and evaporation.Residue is through Et ₂The mixture of O and hexane grinds, and filters and drying, obtains title compound. ¹HNMR (500MHz, CDCl ₃) δ: 10.44 (s, 1H), 8.12 (d, J=2.3,1H), 7.79 (dd, J=8.6 and 2.3), 7.44 (m, 5H), 6.86 (d, J=8.6,1H), 5.19 (s, 2H).

Step C: 4-{[(1E)-(3-benzyloxy-5-iodophenyl) methylene] amino } phenol

According to the method for embodiment 1 steps A, prepare title compound from 2-benzyloxy-5-benzaldehyde iodine (from the intermediate of step B) and 4-hydroxyanilines. ¹HNMR (500MHz, CDCl ₃) δ: 8.87 (s, 1H), 8.47 (d, J=2.3,1H), 7.67 (dd, J=8.7 and 2.3,1H), 7.44-7.35 (m, 5H), 7.19 (d, J=8.7,2H), 6.87 (d, J=8.7,2H), 6.79 (d, J=8.7,1H).

Step D: Acetate 4-[(2S, 3R)-3-[(3S)-3-(acetoxyl group)-3-(4-fluorophenyl) propyl group]-2-(2- Benzyloxy-5-iodophenyl)-and 4-aza-oxo-cyclobutane-1-yl] phenyl ester

Method according to embodiment 1 step B, C and D, from 4-{[(1E)-(3-benzyloxy-5-iodophenyl) methylene] amino } phenol (from the intermediate of step C) and (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxyl valeryl]-4-phenyl-1,3-oxaza pentane-2-ketone (according to Fu, X.; McCallister, T.L.; Thiruvengadam, T.K.; Tann, C.H.; And Su, the method preparation of D.Tetrahedron Lett. (2003) 44,801-804), the preparation title compound.

¹HNMR(500MHz，CDCl ₃)δ：7.58(dd，J＝8.5and?2.1，1H)，7.47(d，J＝2.1，1H)，7.42(m，3H)，7.36(m，2H)，7.25(d，J＝8.9，2H)，7.15(dd，J＝8.5and?5.2，2H)，7.00(d，J＝8.7，2H)，6.97(t，J＝8.7，2H)，6.78(d，J＝8.7，1H)，5.58(t，J＝6.6，1H)，5.11(q，J＝13.8and?11.6，2H)，4.96(d，J＝2.6)，3.10(m，1H)，2.28(s，3H)，2.01(s，3H)，2.00-1.92(m，2H)，1.86-1.72(m，2H).

Step e: Acetate (1S)-1-(4-fluorophenyl)-3-[(2S, 3R)-2-(2-benzyloxy-5-iodophenyl)-4-oxygen Generation-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-3-yl] preparation of propyl ester

Method according to embodiment 1 step e, from acetate 4-[(2S, 3R)-3-[(3S)-3-(acetoxyl group)-3-(4-fluorophenyl) propyl group]-2-(2-benzyloxy-5-iodophenyl)-4-aza-oxo-cyclobutane-1-yl] phenyl ester (from the intermediate of step D), the preparation title compound.

¹HNMR(500MHz，CDCl ₃)δ：7.61(dd，J＝8.5and?2.1，1H)，7.46(d，J＝2.1，1H)，7.43(m，3H)，7.36(m，2H)，7.30(d，J＝8.9，2H)，7.17(m，4H)，6.99(t，J＝8.7，2H)，6.81(d，J＝8.7，1H)，5.61(t，J＝6.6，1H)，5.15(d，J＝11.7，1H)，5.09(d，J＝11.7，1H)，4.97(d，J＝2.5，1H)，3.17(m，1H)，2.07(s，3H)，2.07-1.96(m，2H)，1.86-1.74(m，2H).

Step F: Acetate (1S)-3-[(2S, 3R)-2-[5-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3- Hydroxyl fourth-1-alkynes-1-yl }-2-(benzyloxy) phenyl]-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] The oxygen base } phenyl) azetidine-3-yl]-preparation of 1-(4-fluorophenyl) propyl ester

Method according to embodiment 1 step F; from acetate (1S)-1-(4-fluorophenyl)-3-[(2S; 3R)-and 2-(2-benzyloxy-5-iodophenyl)-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-3-yl] propyl ester (from the intermediate of step e) and 2-acetenyl propane-1; 2; 3-triol 1; 3-diacetate esters (intermediate i-2), the preparation title compound.

¹HNMR(500MHz，CDCl ₃)δ：7.44-7.39(m，4H)，7.37(m，2H)，7.31(d.J＝9.2，2H)，7.26(d，J＝1.8，1H)，7.19-7.14(m，4H)，7.01-6.96(m，3H)，5.59(t，J＝6.6，1H)，5.18(d，J＝11.5，1H)，5.12(d，J＝11.7，1H)，5.01(d，J＝2.3，1H)，4.33(dd，J＝11.4and?4.1，2H)，4.27(dd，J＝11.4and?3.2，2H)，3.14(m，1H)，2.09(s，6H)，2.02(s，3H)，2.00-1.94(m，2H)，1.86-1.74(m，2H).

Step G: Acetate (1S)-3-((2S, 3R)-2-[5-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3- Hydroxyl fourth-1-alkynes-1-yl }-2-(benzyloxy) phenyl]-4-oxo-1-{4-[(trimethyl silyl) second Alkynyl] phenyl) azetidine-3-yl)-preparation of 1-(4-fluorophenyl) propyl ester

Method according to embodiment 2 steps A; from acetate (1S)-3-[(2S, 3R)-2-[5-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl fourth-1-alkynes-1-yl }-2-(benzyloxy) phenyl]-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-3-yl]-1-(4-fluorophenyl) propyl ester (from the intermediate of step F) and trimethyl silyl acetylene prepares title compound.

¹HNMR(500MHz，CDCl ₃)δ：7.47-7.42(m，3H)，7.39-7.35(m，5H)，7.20(d.J＝1.8，1H)，7.18-7.14(m，4H)，6.99-6.96(m，3H)，5.58(t，J＝6.7，1H)，5.17(d，J＝11.4，1H)，5.12(d，J＝11.4，1H)，5.01(d，J＝2.1，1H)，4.33(d，J＝11.4，2H)，4.27(d，J＝11.4，2H)，3.07(m，1H)，2.09(s，6H)，2.01(s，3H)，2.00-1.94(m，2H)，1.88-1.72(m，2H)，0.24(s，9H).

Step H: Acetate (1S)-3-[(2S, 3R)-2-[5-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3- Hydroxyl fourth-1-alkynes-1-yl }-2-(benzyloxy) phenyl]-1-(4-ethynyl phenyl)-4-oxo-azetidin Alkane-3-yl)-preparation of 1-(4-fluorophenyl) propyl ester

Method according to embodiment 2 step B, from acetate (1S)-3-((2S, 3R)-and 2-[5-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl fourth-1-alkynes-1-yl }-2-(benzyloxy) phenyl]-4-oxo-1-{4-[(trimethyl silyl) acetenyl] phenyl) azetidine-3-yl)-1-(4-fluorophenyl) propyl ester (from the intermediate of step G), the preparation title compound.

¹HNMR(500MHz，CDCl ₃)δ：7.45-7.43(m，3H)，7.40-7.37(m，5H)，7.23(d.J＝2.1，1H)，7.19(d，J＝8.5，2H)，7.15(dd，J＝8.7and?5.5，2H)，7.00-6.96(m，3H)，5.58(t，J＝6.6，1H)，5.17(d，J＝11.5，1H)，5.12(d，J＝11.5，1H)，5.01(d，J＝2.3，1H)，4.33(d，J＝11.3，2H)，4.26(d，J＝11.3，2H)，3.08(m，1H)，3.05(s，1H)，2.09(s，6H)，2.01(s，3H)，2.00-1.94(m，2H)，1.88-1.72(m，2H).

Step I: Acetate (1S)-3-[(2S, 3R)-2-[5-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3- Hydroxyl fourth-1-alkynes-1-yl }-2-(benzyloxy) phenyl]-1-(4-{[4-(amino carbonyl)-1-3-thiazol-2-yl] Acetenyl } phenyl)-4-aza-oxo-cyclobutane-3-yl]-preparation of 1-(4-fluorophenyl) propyl ester

Method according to embodiment 2 step C, from acetate (1S)-3-[(2S, 3R)-2-[5-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl fourth-1-alkynes-1-yl }-2-(benzyloxy) phenyl]-1-(4-ethynyl phenyl)-4-aza-oxo-cyclobutane-3-yl)-1-(4-fluorophenyl) propyl ester (from the intermediate of step H) and 2-bromo thiazole-4-formamide ( I-12), the preparation title compound. ¹HNMR(500MHz，CDCl ₃)δ：8.18(s，1H)，7.51(d，J＝8.7，2H)，7.44-7.41(m，3H)，7.44-7.41(m，3H)，7.39-7.36(m，3H)，7.28-7.13(m，4H)，7.17-7.14(m，3H)，7.00-6.96(m，3H)，5.76(br?s，1H)，5.58(t，J＝6.7，1H)，5.18(d，J＝11.7，1H)，5.12(d，J＝11.7，1H)，5.02(s，1H)，4.32(d，J＝11.4，2H)，4.26(d，J＝11.4，2H)，3.11(m，1H)，2.09(s，6H)，2.01(s，3H)，2.00-1.94(m，2H)，1.88-1.72(m，2H).

Step J: Acetate (1S)-3-[(2S, 3R)-2-[5-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3- The hydroxyl butyl }-2-(benzyloxy) phenyl]-1-(4-{2-[4-(amino carbonyl)-1-3-thiazol-2-yl] ethyl } Phenyl)-4-aza-oxo-cyclobutane-3-yl]-preparation of 1-(4-fluorophenyl) propyl ester

Method according to embodiment 2 step e, from acetate (1S)-3-[(2S, 3R)-and 2-[5-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl fourth-1-alkynes-1-yl }-2-(benzyloxy) phenyl]-1-(4-{[4-(amino carbonyl)-1-3-thiazol-2-yl] acetylene } phenyl)-4-aza-oxo-cyclobutane-3-yl]-1-(4-fluorophenyl) propyl ester (from the intermediate of step I), the preparation title compound.

¹HNMR(500MHz，CDCl ₃)δ：8.01(s，1H)，7.44-7.39(m，5H)，7.20(d，J＝8.2，2H)，7.16-7.07(m，6H)，6.98-6.95(m，4H)，5.72(br?s，1H)，5.58(t，J＝6.4，1H)，5.14(d，J＝11.6，1H)，5.09(d，J＝11.6，1H)，5.05(d，J＝1.6，1H)，4.06(m，4H)，3.27(t，J＝7.3，2H)，3.08-3.04(m，3H)，2.62-2.56(m，2H)，2.09(s，6H)2.04-1.96(m，5H)，1.88-1.67(m，5H).

Step K: 2-[2-(4-{ (2S, 3R)-2-{2-(benzyloxy)-5-[3,4-dihydroxy-3-(methylol) butyl] Phenyl }-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-1-yl } phenyl) Ethyl]-preparation of 1,3-thiazoles-4-formamide

Method according to embodiment 2 step F, from acetate (1S)-3-[(2S, 3R)-and 2-[5-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl butyl }-2-(benzyloxy) phenyl]-1-(4-{2-[4-(amino carbonyl)-1-3-thiazol-2-yl] ethyl } phenyl)-4-aza-oxo-cyclobutane-3-yl]-1-(4-fluorophenyl) propyl ester (from the intermediate of step J), the preparation title compound.

¹HNMR(500MHz，DMSO-d6)δ：8.05(s，1H)，7.63(br?s，1H)，7.51(br?s，1H)7.40(d，J＝7.1，2H)，7.36-7.32(m，3H)，7.20(dd，J＝8.5and?6.0，2H)，7.16(d，J＝8.2，2H)，7.08-7.04(m，6H)，7.00(s，1H)，5.21(d，J＝4.6，1H)，5.15(d，J＝12.1，1H)，5.10(d，J＝12.1，1H)，5.03(d，J＝1.6，1H)，4.42(m，1H)，4.35(t，J＝5.7，2H)，4.01(s，1H)，3.24(m，6H)，3.14(m，1H)，2.97(t，J＝7.8，2H)，2.46(m，1H)，1.80(m，1H)，1.76-1.64(m，3H)，1.50-1.46(m，2H).

Step L: 2-[2-(4-{ (2S, 3R)-2-{5-[3,4-dihydroxy-3-(methylol) butyl]-the 2-oxybenzene Base }-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-1-yl } phenyl) second Base]-preparation of 1,3-thiazoles-4-formamide

10% palladium on carbon (20mg) is added to the 2-[2-(4-{ (2S that nitrogen wash is crossed, 3R)-2-{2-(benzyloxy)-5-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-1-yl } phenyl) ethyl]-1,3-thiazole-4-carboxamide (from the intermediate of step K) (80mg, 0.106mmol) ethanol (5ml) solution, stirred the mixture that generated under the atmosphere of hydrogen 72 hours.Remove by filter catalyzer by filter aid, solvent removed in vacuo.Residue is through preparation HPLC (C 18Sunfire post) purifying, with gradient CH ₃CN/0.1%aq.TFA (10 to 60%) wash-out, the suitable flow point of freeze-drying obtains title compound.m/z(ES)466(100％)(M-OH) ⁺；754(M-OAc) ⁺.

¹HNMR (500MHz, DMSO-d6) δ: 9.56 (s, 1H), 8.05 (s, 1H), 7.63 (br s, 1H), 7.50 (br s, 1H) 7.28 (dd, J=8.2 and 5.7,2H), 7.17 (m, 2H), 7.12-7.08 (m, 4H), 6.95 (s, 1H), 6.91 (d, J=8.2,1H), 6.74 (d, J=8.3,1H), 4.95 (s, 1H), 4.47 (t, J=6.0,1H), 3.24 (m, 5H), 3.15 (m, 1H), 2.97 (t, J=7.8,2H), 2.43 (m, 2H), 1.83 (m, 1H), 1.79-1.70 (m, 3H), 1.46 (m, 2H).

Embodiment 50

(3R, 4S)-4-{4-[3,4-dihydroxy-3-(methylol) butyl]-the 2-hydroxyphenyl }-3-[(3S)-3-(4-fluorine Phenyl)-the 3-hydroxypropyl]-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } azetidine The preparation of-2-ketone

Can adopt and be summarized in flow process I, especially be expressed in the method for embodiment 1 step D-H and embodiment 49 step K and L, from acetate 4-(2S, 3R)-3-[(3S)-3-(acetoxyl group)-3-(4-fluorophenyl) propyl group]-2-[2-(benzyloxy)-4-iodophenyl]-4-aza-oxo-cyclobutane-1-yl phenyl ester ( I-48) and intermediate 3-acetenyl-1-trityl-1H-1,2, the 4-triazole ( I-10), the preparation title compound.

Embodiment 51

Steps A: Trifluoromethanesulfonic acid 4-[(2S, 3R)-3-[3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4- Iodophenyl)-and 4-aza-oxo-cyclobutane-1-yl] preparation of phenyl ester

To in (the 3R of 0 ℃ of cooling, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-hydroxy phenyl)-4-(4-iodophenyl) azetidine-2-ketone (from the intermediate of embodiment 1 step C) (26.6g, 47.6mmol) and pyridine (4.6ml, anhydrous CH 57.1mmol) ₂Cl ₂(300ml) solution slowly add trifluoromethanesulfanhydride anhydride (8.8ml, 52.3mmol).The mixture that stirring is generated under 0 ℃ 2 hours, water (500ml), sat.NaCl (100ml) washing again is through MgSO ₄Drying is filtered and evaporation.Residue to be increased to the gradient elution of 60%EtOAc the hexane from 100% hexane, obtains title compound through silica gel MPLC purifying.

¹HNMR(500MHz，CDCl ₃)δ：7.74(d，J＝8.2，2H)，7.32-7.29(m，4H)，7.17(d，J＝9.2，2H)，7.10(d，J＝8.5，2H)，7.03(t，J＝8.7，2H)，4.72(m，1H)，4.62(d，J＝2.5，1H)，3.13(m，1H)，2.33(d，J＝2.6，1H)，2.05-1.88(m，4H).

Step B: Acetate 2-[(acetoxyl group) methyl]-4-{4-[(2S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3- Hydroxypropyl]-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-2-yl] Phenyl }-preparation of 2-hydroxyl fourth-3-alkynes-1-base ester

Method according to embodiment 1 step F, from trifluoromethanesulfonic acid 4-[(2S, 3R)-3-[3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-iodophenyl)-4-aza-oxo-cyclobutane-1-yl] phenyl ester (from the intermediate of steps A) and 2-acetenyl propane-1,2,3-triol 1, the 3-diacetate esters, the preparation title compound.

¹HNMR(500MHz，CDCl ₃)δ：7.46(d，J＝8.3，2H)，7.31-7.28(m，6H)，7.16(d，J＝9.1，2H)，7.03(t，J＝8.7，2H)，4.72(m，1H)，4.66(d，J＝2.3，1H)，4.38(d，J＝11.5，2H)，4.31(d，J＝11.5，2H)，3.23(s，1H)，3.13(m，1H)，2.42(d，J＝3.0，1H)，2.15(s，6H)，2.05-1.86(m，4H).

Step C: Acetate 2-[(acetoxyl group) methyl]-4-{4-[(2S, 3R)-3-[3-(4-fluorophenyl)-3-oxo Propyl group]-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-2-yl] benzene Base }-preparation of 2-hydroxyl fourth-3-alkynes-1-base ester

To acetate 2-[(acetoxyl group) methyl]-4-{4-[(2S; 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-2-yl] phenyl }-2-hydroxyl fourth-3-alkynes-1-base ester (from the intermediate of step B) (960mg, anhydrous CH 1.33mmol) ₂Cl ₂(20ml) solution adds Dess-Martin and crosses iodine alkane (periodinane) (734mg 1.73mmol), stirred the mixture that generated 2 hours under the room temperature.Use sat.NaHCO ₃, the sat.NaCl purging compound, through Na ₂SO ₄Drying is filtered and evaporation.Residue to be increased to the gradient elution of the 45%EtOAc the hexane from 100% hexane, obtains title compound through silica gel MPLC purifying.

¹HNMR(500MHz，CDCl ₃)δ：8.01(m，2H)，7.46(d，J＝8.3，2H)，7.33(m，4H)，7.19-7.14(m，4H)，4.80(d，J＝2.6，1H)，4.38(d，J＝11.2，2H)，4.31(d，J＝11.2，2H)，3.34-3.28(m，1H)，3.25-3.16(m，2H)，3，04(s，1H)，2.48-2.43(m，1H)，2.35-2.28(m，1H)，2.16(s，6H).

Step D: (3R, 4S)-4-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[3-(4-fluorobenzene Base)-the 3-oxopropyl]-1-{4-[2-(1H-1.2.4-triazole-3-yl) ethyl] phenyl } azetidine The preparation of-2-ketone

According to the universal method of summarizing among embodiment 2 steps A-F; from acetate 2-[(acetoxyl group) methyl]-4-{4-[(2S; 3R)-3-[3-(4-fluorophenyl)-3-oxopropyl]-4-oxo-1-(4-{[(trifluoromethyl) sulfonyl] the oxygen base } phenyl) azetidine-2-yl] phenyl }-2-hydroxyl fourth-3-alkynes-1-base ester (from the intermediate of step C), the preparation title compound.m/z(ES)587(100％)(M+H) ⁺.

¹HNMR(500MHz，DMSO-d6)δ：7.99(m，3H)，7.33-7.27(m，4H)，7.15(d，J＝8.0，2H)，7.09(m，4H)，4.93(d，J＝1.6，1H)，3.27(m，4H)，3.21-3.18(m，2H)，3.12-3.09(m，1H)，2.86(m，4H)，2.58-2.55(m，2H)，2.10(q，J＝7.3，2H)，1.58-1.54(m，2H).

Embodiment 52

3-[2-(4-{ (2S, 3R)-2-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[(3S)-3-(4- Fluorophenyl)-the 3-hydroxypropyl]-4-aza-oxo-cyclobutane-1-yl } phenyl) ethyl]-1H-1,2, the 4-triazole The preparation of-5-formamide

Can adopt the method that is summarized in flow process II and is described in embodiment 2, from acetate (1S)-3-[(2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl fourth-1-alkynes-1-yl } phenyl)-1-(4-ethynyl phenyl)-4-aza-oxo-cyclobutane-3-yl]-1-(4-fluorophenyl) propyl ester (from the intermediate of embodiment 2 step B) and intermediate 3-iodo-1-trityl-1,2,4-triazole-5-formamide (i-53), the preparation title compound.

Embodiment 53

3-[2-(4-{ (2S, 3R)-2-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[(3S)-3-(4- Fluorophenyl)-the 3-hydroxypropyl]-4-aza-oxo-cyclobutane-1-yl } phenyl) ethyl]-1H-1,2, the 4-triazole The preparation of-5-nitrile

Can adopt the method that is summarized in flow process II and is described in embodiment 2, from acetate (1S)-3-[(2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl fourth-1-alkynes-1-yl } phenyl)-1-(4-ethynyl phenyl)-4-aza-oxo-cyclobutane-3-yl]-1-(4-fluorophenyl) propyl ester (from the intermediate of embodiment 2 step B) and intermediate 5-cyano group-3-iodo-1-trityl-1,2,4-triazole (i-54), the preparation title compound.

Embodiment 54

(3R, 4S)-4-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[(3S)-3-(4-fluorobenzene Base)-the 3-hydroxypropyl]-1-(4-{2-[5-(methylol)-1H-1,2,4-triazole-3-yl] ethyl } phenyl) azepine The preparation of cyclobutane-2-ketone

Can adopt the method that is summarized in flow process II and is described in embodiment 2, from acetate (1S)-3-[(2S, 3R)-2-(4-{4-(acetoxyl group)-3-[(acetoxyl group) methyl]-3-hydroxyl fourth-1-alkynes-1-yl } phenyl)-1-(4-ethynyl phenyl)-4-aza-oxo-cyclobutane-3-yl]-1-(4-fluorophenyl) propyl ester (from the intermediate of embodiment 2 step B) and intermediate 3-iodo-1-trityl-1,2,4-triazole-5-methyl alcohol (i-55), the preparation title compound.

Although, describe and illustrated the present invention, skilled person in the art will appreciate that wherein and can carry out various changes, modification and replacement, and do not break away from the spirit and scope of the present invention with reference to some particular of the present invention.Therefore, be intended to use scope definition the present invention of claim subsequently, and broadly explain this class claim according to reasonability.

Claims (20)

1. compound in structural formula I and pharmaceutically acceptable salt thereof,

Wherein

Ar ¹Be selected from aryl and R ⁴The aryl of-replacement;

X, Y and Z independently are selected from-CH ₂-,-CH (C _1-6Alkyl)-and-C (C _1-6Alkyl) ₂

R is selected from-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁸,-O (CO) NR ⁶R ⁷, saccharide residue, two saccharide residues, three saccharide residues and tetrose residue;

R ¹Be selected from-H ,-C _1-6Alkyl and aryl, or R and R ¹Be the oxo base together;

R ²Be selected from-OR ⁶,-O (CO) R ⁶,-O (CO) OR ⁸With-O (CO) NR ⁶R ⁷

R ³Be selected from-H ,-C _1-6Alkyl and aryl, perhaps, R ²And R ³Be oxo together;

Q and r are that each independently is selected from 0 and 1 integer, and prerequisite is that at least one is 1 among q and the r;

M, n and p are that each independently is selected from 0,1,2,3 and 4 integer, and prerequisite is that the summation of m, n, p, q and r is 1,2,3,4,5 or 6;

T is selected from 0,1 and 2 integer;

R ⁴Be when occurring, independently to be selected from a following 1-5 substituting group :-OR at every turn ⁵,-O (CO) R ⁵,-O (CO) OR ⁸,-O-C _1-5Alkyl-OR ⁵,-O (CO) NR ⁵R ⁶,-NR ⁵R ⁶,-NR ⁵(CO) R ⁶,-NR ⁵(CO) OR ⁸,-NR ⁵(CO) NR ⁶R ⁷,-NR ⁵SO ₂R ⁸,-COOR ⁵,-CONR ⁵R ⁶,-COR ⁵,-SO ₂NR ⁵R ⁶,-S (O) _tR ⁸,-O-C _1-10Alkyl-COOR ⁵,-O-C _1-10Alkyl-CONR ⁵R ⁶With the fluoro base;

R ⁵, R ⁶And R ⁷When occurring, independently be selected from-H ,-C. at every turn _1-6Alkyl, aryl and aryl replace-C _1-6Alkyl;

R ⁸Be selected from-C _1-6Alkyl, aryl and aryl replace-C _1-6Alkyl;

R ⁹Be selected from-C _1-8Alkyl-Hetcy ,-(CH ₂) _0-2CH=CH-C _0-6Alkyl-Hetcy ,-C ≡ C-C _0-6Alkyl-Hetcy and-C _1-8Alkyl-NH-Hetcy;

Hetcy is selected from:

(a) contain individual heteroatomic 5 yuan of aromatics of the 1-4 that is selected from 1-4 N, 0-1 S and 0-1 O or part unsaturated heterocycle, heterocycle wherein is optional by R ¹⁴Single-or two replacements,

(b) contain 1-3 the heteroatomic 6 yuan of aromatic heterocycles of N, heterocycle wherein is optional by R ¹⁴Single or two replace and

(c) contain and be selected from 1-3 N, 0-1 or O and 0-1 S (O) _t1-3 heteroatomic 6 yuan of saturated heterocyclics, and heterocycle wherein is optional by R ¹⁴List or two replaces;

R ^10aThe one or more substituting groups that are optional being selected from-OH, phenyl and 1-3 fluoro base replace-C _1-3Alkyl;

R ¹⁰Be selected from-one or more substituting groups replacements of H and optional being selected from-OH, phenyl and 1-3 fluoro base-C _1-3Alkyl;

R ¹¹Be selected from-one or more substituting groups replacements of H and optional being selected from-OH, phenyl and 1-3 fluoro base-C _1-3Alkyl;

R ¹²Be selected from by-OH single or polysubstituted-C _1-15Alkyl, quilt-OH is single or polysubstituted-C _2-15Alkenyl, quilt-OH is single or polysubstituted-C _2-15Alkynyl and-C _1-3Alkyl-C _3-6Cycloalkyl, wherein the optional quilt-OH of the carbon of each in cycloalkyl ring replaces;

R ¹³Be selected from-H and-OH; With

R ¹⁴When occurring, independently be selected from: R at every turn ^10a,-C _1-3Alkyl-COOR ¹⁰,-C _1-3Alkyl-C (O) NR ¹⁰R ¹¹,-C _1-3Alkyl-SO ₂-R ^10a,-C _1-3Alkyl-O-R ^10a,-COOR ¹⁰,-OC (O)-R ^10a,-C (O) NR ¹⁰R ¹¹,-NR ¹⁰R ¹¹,-CN ,-OH and oxo base.

2. the compound of claim 1, wherein R ⁹Be selected from-C _1-8Alkyl-Hetcy ,-(CH ₂) _0-2CH=CH-C _1-6Alkyl-Hetcy ,-C ≡ C-C _1-6Alkyl-Hetcy and-C _1-8Alkyl-NH-Hetcy and R ¹⁴When occurring, independently be selected from R at every turn ^10a,-C _1-3Alkyl-COOR ¹⁰,-C _1-3Alkyl-C (O) NR ¹⁰R ¹¹,-C _1-3Alkyl-SO ₂-R ^10a,-C _1-3Alkyl-O-R ^10a,-COOR ¹⁰,-OC (O)-R ^10a,-C (O) NR ¹⁰R ¹¹,-NR ¹⁰R ¹¹,-OH and oxo base.

3. the compound of claim 1, wherein R ⁹Be-C _1-8Alkyl-Hetcy and R ¹²By-OH single or polysubstituted-C _1-8Alkyl.

4. the compound of claim 3, wherein R ⁹Be-C _2-3Positive alkyl-Hetcy and R ¹²By-OH single or polysubstituted-C _3-8Alkyl.

5. the compound of claim 3, wherein R ¹²Be-(CH ₂) _2-3-C (OH) (CH ₂OH) ₂

6. the compound of claim 1, wherein r is 0, m is 0, q is 1, n be 1 and p be 1.

7. the compound that has the claim 6 of structural formula Ia

And pharmaceutically acceptable salt.

8. the compound of claim 7, wherein R ⁹Be-C _1-8Alkyl-Hetcy and R ¹²By-OH single or polysubstituted-C _1-8Alkyl.

9. the compound of claim 8, wherein R ⁹Be-C _2-3Positive alkyl-Hetcy and R ¹²By-OH single or polysubstituted-C _3-8Alkyl.

10. the compound of claim 8, wherein R ¹²Be-(CH ₂) _2-3-C (OH) (CH ₂OH) ₂

11. have the compound of the claim 7 of structural formula Ib

And pharmaceutically acceptable salt.

12. the compound of claim 11, wherein R ⁹Be-C _1-8Alkyl-Hetcy and R ¹²By-OH single or polysubstituted-C _1-8Alkyl.

13. the compound of claim 12, wherein R ⁹Be-C _2-3Positive alkyl-Hetcy and R ¹²By-OH single or polysubstituted-C _3-8Alkyl.

14. the compound of claim 12, wherein R ¹²Be-(CH ₂) _2-3-C (OH) (CH ₂OH) ₂

15. the compound of claim 1 and pharmaceutically acceptable salt thereof, it is selected from:

(3R, 4S)-4-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-{4-[3-(1H-1,2,4-triazol-1-yl) propyl group] phenyl } azetidine-2-ketone;

(3R, 4S)-4-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-{4-[2-(1H-1,2,4-triazole-5-yl) ethyl] phenyl } azetidine-2-ketone;

(3R, 4S)-4-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-{4-[3-(1,3-thiazoles-2-base is amino) propyl group] phenyl } azetidine-2-ketone;

(3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[2,3,4,5-tetrahydroxy-4-(methylol) amyl group] phenyl }-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } azetidine-2-ketone;

(3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[1,2,3,4-tetrahydroxy-3-(methylol) butyl] phenyl }-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } azetidine-2-ketone;

(3R, 4S)-4-{4-[4,5-dihydroxy-4-(methylol) amyl group] phenyl }-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl) azetidine-2-ketone;

(3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[3,4,5,6-tetrahydroxy-3, two (methylol) hexyls of 5-] phenyl }-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } azetidine-2-ketone;

(3R, 4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-{4-[3,4,5,6-tetrahydroxy-3, two (methylol) hexyls of 5-] phenyl }-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } azetidine-2-ketone;

2-[2-(4-{ (2S, 3R)-2-{5-[3,4-dihydroxy-3-(methylol) butyl]-the 2-hydroxy phenyl }-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-1-yl } phenyl) ethyl]-1,3-thiazoles-4-formamide;

(3R, 4S)-4-{4-[3,4-dihydroxy-3-(methylol) butyl]-the 2-hydroxy phenyl }-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } azetidine-2-ketone;

(3R, 4S)-4-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[3-(4-fluorophenyl)-3-oxopropyl]-1-{4-[2-(1H-1,2,4-triazole-3-yl) ethyl] phenyl } azetidine-2-ketone;

3-[2-(4-{ (2S, 3R)-2-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-1-yl } phenyl) ethyl]-1H-1,2,4-triazole-5-formamide;

3-[2-(4-{ (2S, 3R)-2-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-aza-oxo-cyclobutane-1-yl } phenyl) ethyl]-1H-1,2,4-triazole-5-nitrile;

(3R, 4S)-4-{4-[3,4-dihydroxy-3-(methylol) butyl] phenyl }-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-{2-[5-(methylol)-1H-1,2,4-triazole-3-yl] ethyl } phenyl) azetidine-2-ketone.

16. have the compound and the pharmaceutically acceptable salt thereof of the claim 1 of following structural formula:

This structural formula has and is selected from following R ⁹Group:

17. a method that reduces blood plasma LDL-cholesterol levels, it comprises the compound of the claim 1 that needs the patient treatment of such treatment effective dose.

18. the method for claim 17, it comprises the compound of the claim 1 of the treatment effective dose that is selected from least a other active drug combination in lipid regulating agent, antidiabetic and the anti-obesity medicine that needs such patient who treats and treatment effective dose.

19. a reduction has the method for the risk of Atheromatosis incident, it comprises that the patient of the risk that faces this class incident prevents the compound of the claim 1 of effective dose.

20. a Pharmaceutical composition, it comprises the compound and the pharmaceutically acceptable carrier of claim 1, and optional at least a other active drug that is selected from lipid regulating agent, antidiabetic and the anti-obesity medicine that comprises.