KR20070020406A - Diphenylazetidinone derivates possessing cholesterol absorption inhibitory activity - Google Patents

Abstract

The present invention describes compounds of formula (I), pharmaceutically acceptable salts, solvates or solvates of these salts, or prodrugs thereof, and their use as cholesterol absorption inhibitors for the treatment of hyperlipidemia. The invention also describes their preparation methods and pharmaceutical compositions containing the same:

Formula I

Wherein the variable is as defined herein.

Description

DIPHENYLAZETIDINONE DERIVATES POSSESSING CHOLESTEROL ABSORPTION INHIBITORY ACTIVITY}

The present invention relates to 2-azetidinone derivatives, pharmaceutically acceptable salts, solvates or solvates of such salts, and prodrugs thereof. Because these 2-azetidinones possess cholesterol absorption inhibitory activity, they are valuable for the treatment of disease states associated with hyperlipidemia. Therefore, it is useful for the method of treating warm-blooded animals including humans. The present invention also relates to a method for preparing the 2-azetidinone derivative, a pharmaceutical composition comprising the same, and its use in the preparation of a medicament for inhibiting cholesterol absorption in warm blooded animals such as humans. A further aspect of the invention relates to the use of a compound of the invention in the treatment of a lipid metabolic condition.

Atherosclerosis Coronary artery disease is not only an important component of health care measures, but also a major cause of death and morbidity in the West. Hyperlipidemia associated with elevated levels of total cholesterol and low density lipoprotein (LDL) cholesterol is a major risk factor for cardiovascular atherosclerosis (eg, "Coronary Heart Disease: Reducing the Risk; a Worldwide View" Assman G., Carmena R. Cullen P. et al; Circulation 1999, 100, 1930-1938 and "Diabetes and Cardiovascular Disease: A Statement for Healthcare Professionals from the American Heart Association" Grundy S, Benjamin I., Burke G., et al; Circulation, 1999, 100 , 1134-46).

The concentration of plasma cholesterol depends on the combined balance of the endogenous and exogenous pathways of cholesterol metabolism. In the endogenous pathway, cholesterol is synthesized in the liver and tissues other than the liver and enters the circulation as lipoproteins or is secreted into bile. In the endoscopic route, cholesterol from dietary and bile sources is absorbed by the intestine and enters the circulation as a component of dark granules. Changes in one of these pathways will affect plasma concentrations of cholesterol.

However, the exact mechanism by which cholesterol is absorbed from the intestine is not clear. The first hypothesis was that cholesterol passed through the gut by nonspecific diffusion. However, more recent studies suggest that there are specific transporters involved in intestinal cholesterol absorption (eg New molecular targets for cholesterol-lowering therapy Izzat, NN, Deshazer, ME and Loose-Mitchell DS JPET 293: 315-320, 2000.)

A clear relationship has been established between a decrease in total cholesterol and (LDL) cholesterol and a decrease in coronary artery disease, and some types of pharmaceutical agents are used to regulate serum cholesterol. The main options for regulating plasma cholesterol include (i) cholesterol by preparations such as HMG-CoA reductase inhibitors such as simvastatin and fluvastatin, which promote the removal of cholesterol from the plasma by upregulation of LDL-receptors. To block their synthesis; (Ii) blocking bile acid reuptake by agents such as bile acid binders such as resins (e.g., cholestyramine and cholestipol) and specific agents that result in the synthesis of bile acids from cholesterol and increased bile acid excretion; And (iii) blocking intestinal absorption of cholesterol with selective cholesterol absorption inhibitors. High density lipoprotein (HDL) enhancers such as fibrate and nicotinic acid analogs have been used.

Even with the various therapeutic agents present, no significant proportion of the hypercholesterolemia population can reach the target cholesterol level, or be used for the long term necessary to reach the target level due to drug interactions or drug safety. Therefore, there is a need to develop additional agents that are more potent and tolerable.

Compounds having such cholesterol absorption inhibitory activity, such as WO 93/02048, WO 94/17038, WO # 95/08532, WO 95/26334, WO 95/35277, WO 96/16037, WO 96/19450, WO 97/16455 , WO # 02/50027, WO 02/50060, WO 02/50068, WO 02/50090, WO 02/66464, WO 04/000803, WO 04/000804, WO 04/000805, WO 04/043457, WO 04/081002 , US 5756470, US # 5767115, US 20040180860, US 20040180861 and US RE37721 have been disclosed.

The present invention is surprisingly based on the discovery that certain 2-azetidinone derivatives inhibit cholesterol absorption. Such properties are expected to be of value in treating disease states associated with hyperlipidemia. The compounds of the present invention are not mentioned in any of the applications disclosed above, and the inventors have found that these compounds possess beneficial and effective metabolic and toxicity profiles that are suitable for in vivo administration to warm blooded animals such as humans. In particular, some compounds of the present invention have lower absorption compared to conventionally known compounds but retain the ability to inhibit cholesterol absorption.

According to the invention there is provided a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, provided that 3- (R) -4- (R) -1- (phenyl ) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- [4- (N- {N-[(R) -1- (carboxy) -2- (hydroxy Oxy) ethyl] carbamoylmethyl} carbamoylmethoxy) phenyl] azetidin-2-one; Or 3- (R) -4- (R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- {4- [N- ( (R) -α- {N-[(S) -1- (carboxy) -2- (hydroxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one is Excluded from the compound]:

Where

R ¹ is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or aryl; Wherein said C _1-6 alkyl is optionally one or more hydroxy, amino, guanidino, carbamoyl, carboxy, C _1-6 alkoxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C ₁ -C ₆ alkylcarbonylamino C _1-6 alkyl S (O) _a , where a is 0 to 2, substituted with C _3-6 cycloalkyl or aryl Can be; Wherein any aryl group may be optionally substituted with one or two substituents selected from halo, hydroxy, C _1-6 alkyl and C _1-6 alkoxy;

R ² and R ⁵ are independently hydrogen, branched or derivative branched C _{1 - 6} alkyl, C _{3 - 6} cycloalkyl or aryl; Here, the C _{1 - 6} alkyl is in accordance with one or more hydroxy, amino cases, guanidino, cyano, carbamoyl, carboxy, C _1-6 alkoxy, aryl C _1-6 alkoxy, (C ₁ -C ₄ ) ₃ Si, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkylS (O) _a , C _3-6 cycloalkyl, aryl or Aryl C _1-6 alkylS (O) _a , wherein a is 0 to 2; Wherein any aryl group may be optionally substituted with one or two substituents among halo, hydroxy, C _1-6 alkyl and C _1-6 alkoxy;

R ³ is hydrogen, alkyl, halo, C _1-6 alkoxy or C _1-6 alkylS-;

R ⁴ is hydrogen, C _1-6 alkyl, halo or C _1-6 alkoxy;

R ⁶ is hydrogen, C _{1 - 6} alkyl, aryl or C _{1 - 6} alkyl;

Here, R ⁵ and R ² may form a ring having 2 to 7 carbon atoms, and R ⁶ and R ² may form a ring having 3 to 6 carbon atoms.

In one aspect of the invention, there is provided a compound of Formula I2:

Wherein the variable group is as defined above for Formula (I).

Apart from the following method schemes, further reference to formula I also applies to formula I2.

In one aspect of the invention, R ¹ is hydrogen. According to another aspect of the invention, R ² is hydrogen, branched or unbranched C _1-6 alkyl, C _3-6 cycloalkyl or aryl; Wherein said C _1-6 alkyl is optionally substituted with one or more hydroxy, amino, C _1-6 alkyl S (O) _a , where a is 0 to 2, C _3-6 cycloalkyl or aryl Can be; Here, any aryl group can be optionally substituted with hydroxy. According to another aspect of the invention, R ³ is hydrogen, methoxy, or alkyl (eg C ₁ -C ₂ alkyl), ie methyl or ethyl (eg methyl), or halogen (eg chlorine or fluorine) .

According to another aspect of the invention, R ⁴ is hydrogen or halo (eg chlorine or fluorine). According to a further aspect of the invention, R ⁶ is hydrogen, aryl or C _{1 -6} R ^6, R ² forms a ring with 3 to 6 carbon atoms.

According to one aspect of the invention, R ¹ is hydrogen, R ² is branched or unbranched C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl, R ³ and R ⁴ are halo, R ⁵ is hydrogen or C _1-6 alkyl and R ⁶ is hydrogen.

The present invention provides at least one compound selected from the following compounds:

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-N ⁶ -acetyl-D-lysine;

1- (4-fluorophenyl) -3- (R)-[2- (4-fluorophenyl) -2-hydroxyethylthio] -4- (R)-{4- [N- {N- [2- (phenyl) -1- (R)-(carboxy) ethyl] carbamoylmethyl} carbamoylmethoxy] phenyl} azetidin-2-one;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-valine;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-tyrosine;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-proline;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-lysine;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2-hydroxy-2- (4-methoxyphenyl) ethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-valine;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-2-butylnorleucine;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-S-methyl-L-cysteine;

N-{[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- (4-chlorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidine -2-yl) phenoxy] acetyl} glycyl-3-cyclohexyl-D-alanine;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-3-cyclohexyl-D-alanine;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-4-methylleucine;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -L-alanyl-D-valine;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2-hydroxy-2- (4-methylphenyl) ethyl] thio} -4-oxoazetidine -2-yl) phenoxy] acetyl} glycyl-D-valine;

N-{[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- (4-chlorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidine -2-yl) phenoxy] acetyl} glycyl-D-valine;

N-{[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- (4-chlorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidine -2-yl) phenoxy] acetyl} glycyl-3-methyl-D-valine;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-3- (2-naphthyl) -D-alanine;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-3-methyl-D-valine;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl- (3R, 4S, 5R) -3,4,5,6-tetrahydroxy-D-norleucine;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-N, 2-dimethylalanine;

N-({4-[(2R, 3R) -1- (4-fluorophenyl) -3-({2-hydroxy-2- [4- (methylthio) phenyl] ethyl} thio) -4- Oxoazetidin-2-yl] phenoxy} acetyl) glycyl-3-methyl-D-valine;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-S- (4-methylbenzyl) -D-cysteine;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-S- (t-butyl) -D-cysteine;

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-jade Pediatric zetidin-2-yl) phenoxy] acetyl} glycyl-b, b-dimethyl-D-phenylalanine.

The term "alkyl" used herein includes both straight and branched chain alkyl groups, but reference to an individual alkyl group such as "propyl" refers only to a straight chain form. For example, "C _1-6 alkyl" and "C _1-4 alkyl" include propyl, isopropyl and t-butyl. However, referring to an individual alkyl group such as 'propyl' refers only to a straight chain form, and when referring to an individual branched alkyl group such as 'isopropyl' only refers to a branched chain form. Similar regulations apply to other radicals, for example "phenylC _1-6 alkyl" includes benzyl, 1-phenylethyl and 2-phenylethyl. The term "halo" means fluoro, chloro, bromo and iodo.

Where an optional substituent is selected from "one or more" groups, it is to be understood that this definition includes a substituent selected from one of certain groups, or from two or more of certain groups.

The term "aryl" refers to a 4-10 membered aromatic monocyclic or bicyclic ring containing 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur. Examples of aryl are phenyl, pyrrolyl, furanyl, imidazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridyl, isoxazolyl, oxazolyl, 1,2,4-oxa Diazolyl, isothiazolyl, thiazolyl, 1,2,4-triazolyl, thienyl, naphthyl, benzofuranyl, benzimidazolyl, benzthienyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl , Benzisoxazolyl, 1,3-benzodioxolyl, indolyl, pyrimidimazolyl, pyrimidimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnaolinyl And naphthyridinyl. In particular, “aryl” means phenyl, thienyl, pyridyl, imidazolyl or indolyl. The term "aryl" includes both unsubstituted and substituted aromatic rings.

Examples of "C _1-6 alkoxy" include methoxy, ethoxy and propoxy. Examples of “C _1-6 alkylS (O) _a (a is 0 to 2)” include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl and ethylsulfonyl. Examples of "N- (C _1-6 alkyl) amino" include methylamino and ethylamino. Examples of “N, N- (C _1-6 alkyl) ₂ amino” include di-N-methylamino, di- (N-ethyl) amino and N-ethyl-N-methylamino. "C _3-6 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Suitable pharmaceutically acceptable salts of the compounds of the invention or other compounds disclosed herein are, for example, acid-addition salts of sufficiently basic compounds of the invention, such as inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid. And acid-addition salts with trifluoroacetic acid, citric acid, acetic acid or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts or organic bases which give a physiologically acceptable cation. Salts such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.

Compounds of formula (I), or other compounds disclosed herein, can be administered in the form of prodrugs that degrade in the human body or body to provide compounds of formula (I). Examples of prodrugs include in vivo hydrolyzable esters of compounds of formula I and in vivo hydrolyzable amides.

In vivo hydrolyzable esters of the compounds of formula (I) or other compounds disclosed herein that contain a carboxyl or hydroxy group are, for example, pharmaceutically acceptable esters that are hydrolyzed in the human or animal body to produce the parent acid or the parent alcohol. Suitable pharmaceutically acceptable esters for carboxy are C _1-6 alkoxymethyl esters such as methoxymethyl, C _1-6 alkanoyloxymethyl esters such as pivaloyloxymethyl, phthalidyl ester, C _3-8 CycloalkoxycarbonyloxyC _1-6 alkyl esters such as 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolene-2-onylmethyl esters such as 5-methyl-1,3-dioxolene-2-onylmethyl; And C _1-6 alkoxycarbonyloxyethyl esters such as 1-methoxycarbonyloxyethyl and the like, and may be formed at any carboxy group of the compounds of the present invention.

In vivo hydrolyzable esters of compounds of formula (I) or other compounds disclosed herein containing hydroxy groups are inorganic esters such as phosphate esters and α-acyloxyalkyl ethers, and decomposed as a result of in vivo hydrolysis of esters. And related compounds which yield hydroxyl groups. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. In vivo hydrolyzable ester formers for hydroxy are alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (which generates alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylamino Ethyl) -N-alkylcarbamoyl (which generates carbamate), dialkylaminoacetyl, carboxyacetyl, and the like. Examples of substituents on benzoyl include morpholino and piperazino linked to the 3- or 4-position of the benzoyl ring via a methylene group at a ring nitrogen atom.

Suitable values of the hydrolyzable amides in vivo of a compound of formula (I) containing a carboxyl group or other compounds disclosed herein are, for example, N-methyl, N-ethyl, N-propyl, N, N-dimethyl, N-ethyl- NC _1-6 alkyl or N, N-di-C _1-6 alkyl amide, such as N-methyl or N, N-diethyl amide.

Some compounds of Formula I may have chiral centers and / or geometric isomeric centers (E-isomers and Z-isomers), and the present invention relates to all such optical isomers, diastereomers and geometric isomers that possess cholesterol absorption inhibitory activity. It should be understood to include.

The present invention relates to any and all tautomeric forms of the compounds of formula (I) having cholesterol absorption inhibitory activity.

It should be understood that some compounds of Formula I may exist in solvated and unsolvated forms, such as hydrated forms. It is to be understood that the present invention includes all such solvated forms that possess cholesterol absorption inhibitory activity.

Preferred aspects of the invention relate to compounds of formula (I) or pharmaceutically acceptable salts thereof.

Another aspect of the present invention provides a method of preparing a compound of formula (I), a pharmaceutically acceptable salt thereof, solvate or solvate thereof, or a prodrug thereof, the following steps 1) to 7), and

Afterwards, as required or if desired,

Iii) converting the compound of formula I to another compound of formula I;

Ii) removing any protecting groups;

Iii) forming a pharmaceutically acceptable salt, solvate, solvate of said salt, or prodrug; or

Iii) separating two or more enantiomers

Includes:

Step 1) reacting a compound of Formula II with a compound of Formula III;

Step 2) reacting an acid of formula (IV) or an activated derivative thereof with an amine of formula (V);

Step 3) reacting an acid of formula (VI) or an activated derivative thereof with an amine of formula (VII);

Step 4) reducing the compound of formula VII;

Step 5) reacting a compound of formula (VII) with a compound of formula (VII);

Step 6) reacting a compound of formula (XI) with a compound of formula (XI); And

Step 7) Deesterification of the Compound of Formula XIII:

Where

L is a substitutable group and suitable groups as L are, for example, halogeno or sulfonyloxy groups such as chloro, bromo, methanesulfonyloxy or toluene-4-sulfonyloxy groups;

C (O) OR is an ester group and suitable groups as C (O) OR are methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl or benzyloxycarbonyl;

Unless otherwise specified, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in Formula (I).

Starting materials used in the present invention can be prepared by modifying the reaction pathways described in EP 0 792 264 B1. Alternatively, the starting material can be prepared by the following reaction.

Step 1): 0 ° C. to reflux temperature, preferably reflux temperature in a suitable solvent such as acetonitrile, dichloromethane or tetrahydrofuran in the presence of a base such as an inorganic base such as sodium carbonate or an organic base such as Hunigs base At a temperature near that, the alcohol of formula II can be reacted with the compound of formula III.

Compounds of formula II can be prepared according to the following schemes:

Wherein pMeOBz is methoxy benzyl in the para position.

Compounds of formula (IIb), (IId), (IIg) and (III) are commercially available compounds or those known in the literature, or are prepared using standard methods known to those skilled in the art.

Another aspect of the present invention provides a method of preparing a compound of Formula I2, a pharmaceutically acceptable salt thereof, solvate or solvate thereof, or a prodrug thereof, the following steps 1) to 7), and

Afterwards, as required or if desired,

Iii) converting the compound of Formula I2 into another compound of Formula I2;

Ii) removing any protecting groups;

Iii) forming a pharmaceutically acceptable salt, solvate, solvate of said salt, or prodrug; or

Iii) separating two or more enantiomers

Includes:

Step 1) reacting a compound of formula II2 with a compound of formula III;

Step 2) reacting an acid of formula IV2 or an activated derivative thereof with an amine of formula V;

Step 3) reacting an acid of formula (VI2) or an activated derivative thereof with an amine of formula (VII);

Step 4) reducing the compound of formula VII2;

Step 5) reacting a compound of formula (VII) with a compound of formula (VII);

Step 6) reacting the compound of formula VIIII with the compound of formula XIII; And

Step 7) Deesterification of the Compound of Formula XIII2:

Formula III

Formula V

Formula Ⅶ

Formula Ⅹ

Chemical Formula XII

Wherein L is a substitutable group and the C (O) OR group is an ester group.

L is a substitutable group and groups suitable as L are, for example, halogeno or sulfonyloxy groups such as chloro, bromo, methanesulfonyloxy or toluene-4-sulfonyloxy groups.

C (O) OR is an ester group and suitable groups as C (O) OR are methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and benzyloxycarbonyl.

Starting materials used in the present invention can be prepared by modifying the reaction pathways described in EP 0 792 264 B1. Alternatively, the starting material can be prepared by the following reaction.

Step 1): 0 ° C. to reflux temperature, preferably reflux temperature in a suitable solvent such as acetonitrile, dichloromethane or tetrahydrofuran in the presence of a base such as an inorganic base such as sodium carbonate or an organic base such as Hunigs base At a temperature near that, the alcohol of formula II2 can be reacted with the compound of formula III.

Compounds of formula (II2) may be prepared according to the following schemes:

Scheme 1

Wherein pMeOBz is methoxy benzyl in the para position.

Compounds of formula (IIb), (IId), (IIg2) and (III2) are commercially available compounds, or those known in the literature, or prepared using standard methods known to those skilled in the art.

Compounds of formula III may also be reacted with compounds of formula XIV.

Compounds of formula (XIV) may be prepared according to the following reaction routes:

Compounds of formula (XIVi) may be prepared according to the following reaction routes:

The compound of formula III2 may be reacted with the compound of formula XIV2.

Compounds of formula XIV2 can be prepared according to the following reaction routes:

Compounds of formula (XIVi) may be prepared according to the following reaction routes:

For both Formulas XIV and XIV2, the following applies:

Step 2) and Step 3): The acid and amine can be coupled together in the presence of a suitable coupling agent. Standard peptide coupling agents known to those skilled in the art are optionally tritriamine, pyridine or 2,6-di-alkyl-pyridine, in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine. In the presence of a base such as 2,6-lutidine or 2,6-di-t-butylpyridine), can be used as a suitable coupling agent such as carbonyldiimidazole and dicyclohexyl-carbodiimide. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide. The coupling reaction can be conveniently performed at a temperature range of -40 ° C to 40 ° C.

Suitable activated acid derivatives include halides (eg acid chlorides), and active esters (eg pentafluorophenyl esters). The reaction of this type of compound with an amine is well known to those skilled in the art, for example, the compound may be reacted in a suitable solvent as described above in the presence of a base as described above. The reaction can be conveniently carried out in the temperature range of -40 ℃ to 40 ℃.

The acids of the formulas (IV) and (VI) are suitable from the conditions of step 1) and may optionally be prepared from the compounds of the formula (II) by reacting the acid with a protected side chain. Alternatively, the acids of Formulas IV and VI can be prepared by modifying Scheme 1.

Amines of formulas (V) and (X) are commercially available compounds, or those known in the literature, or can be prepared by standard methods known to those skilled in the art.

Step 4): The compound of formula VIII can be reduced using a hydride formulation such as sodium borohydride in a solvent such as methanol at a suitable temperature of -20 ° C to 40 ° C.

Compounds of formula (VII) may be prepared from compounds of formula (III) by deprotecting the benzyl group and performing step 1). Alternatively, Formula IIk may be debenzylated, and step 1) may be followed by deprotection of the resulting compound to reveal the ketone.

Steps 5) and 6): 0 ° C. to reflux temperature, preferably in a suitable solvent such as acetonitrile, dichloromethane or tetrahydrofuran in the presence of a base such as an inorganic base such as sodium carbonate or an organic base such as Hunigs base Can react these compounds together at or near reflux.

Compounds of formulas (XI) and (XI) may be prepared by modifying Scheme 1 as appropriate.

Compounds of formula (X) and formula (XII) are either commercially available compounds, those known in the literature, or prepared by standard methods known to those skilled in the art.

Step 7): The ester of formula XIII can be deprotected under standard conditions as described above, for example methyl ester or ethyl ester can be deprotected with sodium hydroxide in methanol at room temperature.

Compounds of formula (XIII) may be prepared by modifying any of the methods described herein for the preparation of compounds of formula (I).

Certain substituents of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or formed by conventional functional group modifications either before or immediately after the above-mentioned methods, which are included in one aspect of the present invention. do. Such reactions and modifications include, for example, introduction of substituents by aromatic substitution reactions, reduction of substituents, alkylation of substituents, and oxidation of substituents. Reagents and reaction conditions for such procedures are known in the chemical art. Specific examples of aromatic substitution reactions include the introduction of nitro groups using concentrated nitric acid, for example the introduction of acyl groups using Lewis acids (such as aluminum trichloride) and acyl halides under Friedel Kratz conditions; Introduction of alkyl groups using Lewis acids (such as aluminum trichloride) and acyl halides under Friedel Kraft conditions; And halogeno groups. Specific modifications include, for example, reduction of the nitro group to an amino group by treatment with iron in the presence of hydrochloric acid simultaneously with catalytic hydrogenation or heating with a nickel catalyst; Oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl.

It will be appreciated that in some of the reactions mentioned herein it may be necessary to protect / desirable for protecting any sensitive groups in the compound. Appropriate protection methods are known in the art when protection is required or desired. Conventional protecting groups can be used in accordance with standard practice (see, eg, T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1999). Thus, when the reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

Suitable protecting groups for amino or alkylamino groups are, for example, acyl groups such as alkanoyl groups (eg acetyl), alkoxycarbonyl groups (eg methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl groups), arylmeth Oxycarbonyl group (eg benzyloxycarbonyl) or aroyl group (eg benzoyl). Deprotection conditions for the protecting group will necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or alkoxycarbonyl groups or aroyl groups can be removed by hydrolysis with suitable bases such as, for example, alkali metal hydroxides (eg lithium hydroxide or sodium hydroxide). Optionally, acyl groups such as t-butoxycarbonyl groups can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups, for example It may be removed by hydrogenation on a catalyst such as palladium on carbon or by treatment with Lewis acid such as boron tris (trifluoroacetate). Suitable optional protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with alkylamines such as dimethylaminopropylamine, or hydrazine.

Suitable protecting groups for hydroxy groups are, for example, acyl groups such as alkanoyl groups (eg acetyl), aroyl groups (eg benzoyl), or arylmethyl groups (eg benzyl). Deprotection conditions for the protecting group will necessarily vary depending upon the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or aroyl groups can be removed by hydrolysis with a suitable base such as, for example, alkali metal hydroxides (eg lithium hydroxide or sodium hydroxide). Alternatively, arylmethyl groups such as benzyl groups can be removed by hydrogenation, for example on a catalyst such as palladium on carbon.

Suitable protecting groups for carboxyl groups are, for example, esterification groups such as methyl or ethyl groups (which can be removed by hydrolysis with bases such as, for example, sodium hydroxide), or for example t-butyl groups (which are, for example, acids such as , Which may be removed by treatment with an organic acid such as trifluoroacetic acid), or, for example, a benzyl group, which may be removed by hydrogenation, for example, on a catalyst such as palladium on carbon.

The protecting group can be removed at any convenient step in the synthesis using conventional techniques well known in the chemical art.

The invention also provides a compound of formula XV or a hydrolyzable ester or amide thereof:

Where

R ⁷ is a hydroxy group or C _1-3 alkoxy group, and unless otherwise specified, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in formula (I).

The compound of formula (XV) may be an intermediate of formula (I).

As mentioned above, the compounds defined in the present invention retain cholesterol absorption inhibitory activity. These properties can be assessed using the following biological tests.

In vivo testing of cholesterol absorption inhibitors (A)

C57BL / 6 female mice were fed on a regular basis and placed in individual cages to collect stools. Mice were fasted for 3 hours and gavaged with vehicle or compound. After 30 minutes, radiolabeled cholesterol was gavaged on mice. Six hours after ¹⁴ C-cholesterol gavage feeding, blood samples were taken through the tails and plasma was prepared to determine how much cholesterol was absorbed. 24 hours after ¹⁴ C-cholesteral gavage feeding, mice were bled and killed and plasma was prepared for analysis. Stool was collected for 24 hours to evaluate the absorption efficiency.

In vivo testing of cholesterol absorption inhibitors (B)

C57BL / 6 female mice were fed on a regular basis and placed in individual cages to collect stools. Mice were fasted for 3 hours and gavaged with vehicle or compound. After 1 to 10 hours, radiolabeled cholesterol was gavaged on mice. Six hours after ¹⁴ C-cholesterol gavage feeding, blood samples were taken through the tails and plasma was prepared to determine how much cholesterol was absorbed. Twenty four hours after ¹⁴ C-cholesterol gavage feeding, mice were bled and killed and plasma was analyzed for radioactivity. In addition, the feces were collected for 24 hours to evaluate the absorption efficiency.

Reference

1. E. A. Kirk, G. L. Moe, M. T. Caldwell, J. Wong Lernmark, D. L. Wilson, R. C. LeBoeuf. Hyper- and hypo-responsiveness to dietary fat and cholesterol among inbred mice: searching for level and variability genes. J. Lipid Res. 1995, 36: 1522-1532.

2. C. P. Carter, P. N. Howles, D. Y. Hui. Genetic variation in cholesterol absorption efficiency among inbred strains of mice. J. Nutr. 1997, 127: 1344-1348.

3. C. D. Jolley, J. M. Dietschy, S. D. Turley. Genetic differences in cholesterol absorption in 129 / Sv and C57BL / 6 mice: effect on cholesterol responsiveness. Am. J. Physiol. 1999, 276: G1117-G1124.

In Example 96, 5 μmol / kg was administered to inhibit the absorption of ¹⁴ C-cholesterol by 87% (method A). In Example 94, 5 μmol / kg was administered to inhibit the absorption of ¹⁴ C-cholesterol by 89% (Method A).

In Example 91, 0.2 μmol / kg was administered to inhibit the absorption of ¹⁴ C-cholesterol by 58% (Method A). In Example 85, administration of 0.2 μmol / kg inhibited the absorption of ¹⁴ C-cholesterol by 47% (method A).

According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, as described above, together with a pharmaceutically acceptable diluent or carrier Is provided.

The composition may be in a form suitable for oral administration, such as a tablet or capsule, in a form suitable for parenteral injection (including intravenous, subcutaneous, intramuscular, endovascular or infusion), such as sterile solutions, suspensions or emulsions, for topical administration. Forms, such as ointments or creams, or forms for rectal administration, such as suppositories.

In general, the compositions can be prepared in a conventional manner using conventional excipients.

Compounds of Formula (I), pharmaceutically acceptable salts, solvates or solvates of these salts, or prodrugs thereof, are typically warmed in unit dosages ranging from about 0.02 to 100 mg / kg, preferably 0.02 to 50 mg / kg The animals are administered and this amount usually provides a therapeutically effective amount. Unit dosage forms, such as tablets or capsules, comprise for example 1 to 250 mg of active ingredient. Preferably a daily dosage of 1-50 mg / kg, in particular 0.1-10 mg / kg, is used. In another aspect, a daily dosage of 0.01-20 mg / kg is used. In one aspect of the invention, the daily dose of the compound of formula (I) is 100 mg or less. However, the daily dosage will necessarily vary depending on the subject being treated, the particular route of administration, and the severity of the disease to be treated. Thus, the optimal dosage can be determined by the practitioner treating the particular patient.

According to a further aspect of the invention there is provided a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, for use in a method of preventing or treating a warm blooded animal such as a human do.

The inventors have found that the compounds as defined herein, pharmaceutically acceptable salts, solvates or solvates of these salts, or prodrugs thereof, are effective cholesterol absorption inhibitors and are therefore valuable for the treatment of disease states associated with hyperlipidemia. .

According to this aspect of the invention there is provided a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof, as described above for use as a medicament.

According to another feature of the invention, in the preparation of a medicament for use in producing a cholesterol absorption inhibitory effect in a warm blooded animal such as a human, a compound of formula I as described above, a pharmaceutically acceptable salt, solvate thereof or The use of solvates of these salts, or prodrugs thereof, is provided.

According to another feature of the invention, in producing a cholesterol absorption inhibitory effect in a warm blooded animal such as a human, a compound of formula I as described above, a pharmaceutically acceptable salt, solvate or solvate thereof, or a salt thereof The use of prodrugs is provided.

Here, the production of a cholesterol absorption inhibitory effect or a cholesterol lowering effect is suitably related to the treatment of hyperlipidemia in warm-blooded animals such as humans. In addition, hyperlipidemia, hypertriglyceridemia, hyperbetalipoproteinemia (high LDL), hyperbetalipoproteinemia (high VLDL), hyperlipidemia, hypoproteinemia, hypercholesterolemia, hyperlipoproteinemia and hypoalpha in warm-blooded animals such as humans It is associated with the treatment of abnormal hemostatic conditions and diseases such as lipoproteinemia (low HDL). In addition, atherosclerosis, atherosclerosis, arrhythmia, hyperthrombotic state, vascular insufficiency, endothelial insufficiency, heart failure, coronary heart disease, cardiovascular disease, myocardial infarction, angina pectoris, peripheral vascular disorders, cardiovascular tissue, For example, inflammation of the heart, valves, blood vessels, arteries and veins, aneurysms, stenosis, restenosis, blood spots, vascular adipocytes, leukocytes, monocytes and / or macrophages infiltration, endometrial thickening, medial thinning, infection and trauma and It is associated with the treatment of different clinical conditions such as thrombosis, stroke and transient ischemic attacks. It is also associated with the treatment of atherosclerosis, coronary heart disease, myocardial infarction, angina pectoris, peripheral vascular disorders, stroke and transient ischemic attacks in warm-blooded animals such as humans.

The production of a cholesterol absorption inhibitory effect or a cholesterol lowering effect relates to a method for treating and / or preventing atherosclerosis lesions, a method for preventing plate rupture and a method for promoting lesion degeneration. In addition, a method for inhibiting monocyte-macrophage accumulation in atherosclerosis lesions, a method for suppressing the expression of matrix metalloproteinases in an atherosclerosis lesion, a method for inhibiting destabilization of atherosclerosis lesions, and a method for preventing atherosclerosis plate rupture And methods of treating unstable angina.

The production of a cholesterol absorption inhibitory effect or a cholesterol lowering effect is related to the method of treating cytosterolemia.

Compounds of formula (I), pharmaceutically acceptable salts, solvates or solvates of these salts, or prodrugs thereof, may be valuable for the treatment or prevention of Alzheimer's disease (see eg WO 02/096415). Thus, in a further aspect of the invention, there is provided a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof, for use in the treatment or prevention of Alzheimer's disease.

Compounds of formula (I), pharmaceutically acceptable salts, solvates or solvates of these salts, or prodrugs thereof, may be valuable for the treatment or prevention of tumors associated with cholesterol. Accordingly, in a further aspect of the present invention there is provided a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof, for use in the treatment or prevention of a tumor associated with cholesterol.

Compounds of formula (I), pharmaceutically acceptable salts, solvates or solvates of these salts, or prodrugs thereof, may be valuable for the treatment or prevention of vascular inflammation (see eg WO 03/026644). Accordingly, in a further aspect of the invention, there is provided a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof, for use in the treatment or prevention of vascular inflammation.

According to a further feature of this aspect of the present invention there is provided a method of producing said effect in a warm blooded animal such as a human being in need of producing a cholesterol absorption inhibitory effect, the method comprising: a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvent Administering to said animal an effective amount of a cargo or solvate of said salt, or prodrug thereof.

The cholesterol absorption inhibitory activity as defined above may be applied as a monotherapy or may comprise one or more substances and / or treatments in addition to the compounds of the invention. Such parallel treatment can be realized by simultaneous, sequential or separate administration of the individual therapeutic compounds. According to this aspect of the invention, a compound of formula (I) as described above, a pharmaceutically acceptable salt, solvate or solvate thereof, or a further hypolipidemic agent for the treatment of a combination of prodrug and hyperlipidemia thereof Pharmaceutical products are provided.

In a further aspect of the invention, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof, is a cholesterol biosynthesis inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of said salt or It can be administered with a prodrug. Suitable cholesterol biosynthesis inhibitors include HMG Co-A reductase inhibitors, squalene synthesis inhibitors and squalene epoxidase inhibitors. A suitable squalene synthesis inhibitor is squalenestatin 1 and a suitable squalene epoxidase inhibitor is NB-598.

In this aspect of the invention, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, may be prepared by a HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate thereof, It can be administered with a solvate or prodrug of the salt. Suitable HMG Co-A reductase inhibitors, pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts are statins known in the art. Specific statins include fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, vervastatin, dalvastatin, mevastatin and rosuvastatin, or pharmaceutically acceptable salts, solvates, solvates or proteases thereof It's a drag. Further particular statins are pitavastatin, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof. Particular statins are atorvastatin, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof. A more particular statin is the atorvastatin calcium salt. A further particular statin is rosuvastatin, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof. Particularly preferred statins are rosuvastatin calcium salts.

Therefore, in a further feature of the invention, the compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug and HMG Co-A reductase inhibitor thereof, or a pharmaceutically acceptable salt, solvate thereof, Combinations of solvates or prodrugs of such salts are provided.

Thus, according to a further aspect of the invention there is provided a method of producing a cholesterol lowering effect in a warm blooded animal such as a human being in need of a cholesterol lowering effect, the method comprising an effective amount of a compound of formula I, a pharmaceutically acceptable salt thereof, Administering a solvate or solvate of said salt, or prodrug thereof, concurrently, sequentially or separately with an effective amount of an HMG-CoA reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof do.

According to a further feature of the invention there is provided a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug and HMG Co-A reductase inhibitor thereof, or a pharmaceutically acceptable salt, solvate thereof, There is provided a pharmaceutical composition comprising a solvate or prodrug of said salt together with a pharmaceutically acceptable diluent or carrier.

According to a further aspect of the invention there is provided a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug and HMG Co-A reductase inhibitor thereof, or a pharmaceutically acceptable salt, solvate thereof, Kits are provided comprising solvates or prodrugs of such salts.

According to a further aspect of the invention,

a) a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or prodrug thereof in a first unit dosage form;

b) HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof in a second unit dosage form; And

c) container means for containing said first and second formulations

A kit comprising a is provided.

According to a further aspect of the invention,

a) a pharmaceutically acceptable diluent or carrier with a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof in a first unit dosage form;

b) HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof in a second unit dosage form; And

c) container means for containing said first and second formulations

A kit comprising a is provided.

According to another feature of the invention, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug and HMG Co-A reductase inhibitor thereof, or a pharmaceutically acceptable salt, solvate thereof Use of solvates or prodrugs of such salts in the manufacture of a medicament for use in producing a cholesterol lowering effect is provided.

According to a further aspect of the invention, an effective amount of a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier or diluent, An effective amount of an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, together with a suitable acceptable carrier or diluent, is simultaneously and sequentially administered to warm-blooded animals such as humans in need of treatment. Or combination treatment comprising administering separately.

According to a further aspect of the invention, an effective amount of a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof, optionally in combination with a pharmaceutically acceptable diluent or carrier, may be used as a substrate metalloprotein. Combination therapies comprising simultaneous, sequential or separate administration with the inhibitor are provided.

According to a further aspect of the invention, an effective amount of a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof, optionally in combination with a pharmaceutically acceptable diluent or carrier, mimics Apo A-1 Combination therapies are provided comprising concurrent, sequential or separate administration with the peptide.

According to another aspect of the invention, the compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, is an ileal bile acid (IBAT) inhibitor, or a pharmaceutically acceptable salt, solvate, It can be administered with a solvate or prodrug of the salt. Suitable compounds which possess IBAT inhibitory activity for use in combination with the compounds of the present invention are disclosed, for example WO # 93/16055, WO94 / 18183, WO94 / 18184, WO # 94/24087, WO # 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO 98/07749, WO 98/38182, WO 98/40375, WO 98/56757, WO 99/32478, WO 99/35135, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/20392, WO 00/20393, WO 00/20410, WO 00/20437, WO 00/35889, WO 01/34570, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 00/47568, WO 00/61568, WO 01/66533, WO 01/68096, WO 01/68637, WO 02/08211, DE 19825804, JP 10072371 , US 5070103, EP 251 315, EP 417 725, EP 489 423, EP 549 967, EP 573 848, EP 624 593, EP 624 594, EP 624 595, EP 864 582, EP 869 121 and EP 1 070 703 Reference is made to the compounds and these patent applications. In particular, the examples set forth above in this patent application are incorporated herein by reference. In particular, Claim 1 of this patent application is incorporated herein by reference.

Other types of IBAT inhibitors suitable for use with the compounds of the present invention are 1,2-benzothiazepine, 1,4-benzothiazepine and 1,5-benzothiazepine. A further suitable class of IBAT inhibitors is 1,2,5-benzothiadiazepines.

One particularly suitable compound having IBAT inhibitory activity is (3R, 5R) -3-butyl-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1 , 4-benzothiazepin-8-yl β-D-glucopyranosiduronic acid (EP 864 582).

A further compound possessing IBAT inhibitory activity, suitable for use in combination with a compound of the present invention is S-8921 (EP 597 107).

Further IBAT inhibitors suitable for use with the compounds of the present invention are the following compounds (WO 99/32478):

Particular IBAT inhibitors for use with the compounds of the present invention are selected from any one of Examples 1-120 of WO 02/50051, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, Example 1 To 120 are incorporated by reference. Claims 1 to 15 of WO 02/50051 are incorporated by reference. Certain IBAT inhibitors selected from WO 02/50051 for use with the compounds of the present invention are selected from any of the following compounds, pharmaceutically acceptable salts, solvates or solvates of such salts, or prodrugs thereof:

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -1'-phenyl-1 '-[N'-(carboxymethyl) carr Barmoyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(carboxymethyl) carbamoyl] -4- Hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{{(R) -1'-phenyl-1 '-[N'-(2-sulfo Ethyl) carbamoyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- (N-{(R) -1'-phenyl-1 '-[N'-(2-sulfo Ethyl) carbamoyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(2-sulfoethyl) carbamoyl]- 4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(2-sulfoethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(2-carboxyethyl) carbamoyl] Benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(2-carboxyethyl) carbamoyl]- 4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- (N-{{(R) -α- [N '-(5-carboxypentyl) carbamoyl ] Benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(2-carboxyethyl) carbamoyl] benzyl } Carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- {α- [N '-(2-sulfoethyl) carbamoyl] -2-fluoro Benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(R)-(2-hydroxy- 1-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(R)-(2-hydroxy-1 -Carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- {N-[(R) -α- (N '-{(R) -1- [N "- (R)-(2-hydroxy-1-carboxyethyl) carbamoyl] -2-hydroxyethyl} carbamoyl) benzyl] carbamoylmethoxy} -2,3,4,5-tetrahydro- 1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- (N- {α- [N '-(carboxymethyl) carbamoyl] benzyl} carbamoylme Methoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- (N- {α- [N '-((ethoxy) (methyl) phosphoryl-methyl) car Barmoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzo thiazine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- {N-[(R) -α- (N '-{2-[(hydroxy) (methyl) ) Phosphoryl] ethyl} carbamoyl) benzyl] carbamoylmethoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(2-methylthio-1-carboxyethyl) Carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- {N-[(R) -α- (N '-{2-[(methyl) (ethyl) force Foryl] ethyl} carbamoyl) -4-hydroxybenzyl] carbamoylmethoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- {N-[(R) -α- (N '-{2-[(methyl) (hydroxy)) Phosphoryl] ethyl} carbamoyl) -4-hydroxybenzyl] carbamoylmethoxy} -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α-[(R) -N '-(2-methylsulfinyl- 1-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; And

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8- [N-{(R) -α- [N '-(2-sulfoethyl) carbamoyl]- 4-hydroxybenzyl} carbamoylmethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine.

Particular IBAT inhibitors for use with the compounds of the present invention are selected from any one of Examples 1-44 of WO 03/020710, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, Example 1 To 44 are incorporated by reference. Claims 1 to 10 of WO 03/020710 are incorporated by reference. Particular IBAT inhibitors selected from WO 03/020710 for use with the compounds of the invention are selected from any of the following compounds, pharmaceutically acceptable salts, solvates or solvates of such salts, or prodrugs thereof:

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(2- (S) -3- (R ) -4- (R) -5- (R) -2,3,4,5,6-pentahydroxyhexyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5- Tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(2- (S) -3- ( R) -4- (R) -5- (R) -2,3,4,5,6-pentahydroxyhexyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5 Tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carbamoyl -2-hydroxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(hydroxycarbamoyl-methyl) carr Barmoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [N-((R) -α- {N '-[2- (N'-pyrimidine-) 2-ylureido) ethyl] carbamoyl} benzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [N-((R) -α- {N '-[2- (N'-pyridine-2) -Ilureido) ethyl] carbamoyl} benzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(1-t-butoxycarbonylpy) Ferridin-4-ylmethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(2,3-dihydroxypropyl) Carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- [N-((R) -α- {N '-[2- (3,4-dialdehyde) Oxyphenyl) -2-methoxyethyl] carbamoyl} benzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(2-aminoethyl) carbamoyl] Benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(piperidin-4-ylmethyl) Carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; or

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-(2-N, N-dimethylaminosulfa Moylethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine.

Particular IBAT inhibitors for use with the compounds of the present invention are selected from any one of Examples 1-7 of WO 03/022825, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, and Example 1 To 7 are incorporated by reference. Reference is also made to claims 1 to 8 of WO 03/022825. Particular IBAT inhibitors selected from WO 03/022825 for use with the compounds of the present invention are selected from any of the following compounds, pharmaceutically acceptable salts, solvates or solvates of such salts, or prodrugs thereof:

1,1-dioxo-3 (R) -3-butyl-3-ethyl-5- (R) -5-phenyl-8- [N-((R) -α-carboxybenzyl) carbamoylmethoxy ] -2,3,4,5-tetrahydro-1,4-benzothiazepine;

1,1-dioxo-3 (S) -3-butyl-3-ethyl-5- (S) -5-phenyl-8- [N-((R) -α-carboxybenzyl) carbamoylmethoxy ] -2,3,4,5-tetrahydro-1,4-benzothiazepine;

1,1-dioxo-3 (R) -3-butyl-3-ethyl-5- (R) -5-phenyl-8- (N-{(R) -α- [N- (carboxymethyl) carr Barmoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine;

1,1-dioxo-3 (S) -3-butyl-3-ethyl-5- (S) -5-phenyl-8- (N-{(R) -α- [N- (carboxymethyl) carr Barmoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine;

3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-bromo-8- (N-{(R) -α- [N- (carboxymethyl) car Barmoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine;

3,5-trans-1,1-dioxo-3- (S) -3-ethyl-3-butyl-4-hydroxy-5- (S) -5-phenyl-7-bromo-8- ( N-{(R) -α- [N- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine;

3,5-trans-1,1-dioxo-3- (R) -3-ethyl-3-butyl-4-hydroxy-5- (R) -5-phenyl-7-bromo-8- ( N-{(R) -α- [N- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine;

3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N- (carboxymethyl) car Barmoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine;

3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N- (2-sulfoethyl ) Carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine ammonia salts;

1,1-dioxo-3- (S) -3-ethyl-3-butyl-5- (S) -5-phenyl-7-methylthio-8- (N-{(R) -α- [N -(Carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine diethylamine salt; And

1,1-dioxo-3- (R) -3-ethyl-3-butyl-5- (R) -5-phenyl-7-methylthio-8- (N-{(R) -α- [N -(Carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,4-benzothiazepine diethylamine salt.

Particular IBAT inhibitors for use with the compounds of the present invention are selected from any one of Examples 1-4 of WO 03/022830, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, Example 1 Compounds 4 to 4 are incorporated by reference. Claims 1 to 8 of WO 03/022830 are incorporated by reference. Particular IBAT inhibitors selected from WO 03/022830 for use with the compounds of the present invention are selected from any of the following compounds, pharmaceutically acceptable salts, solvates or solvates of such salts, or prodrugs thereof:

1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7- (N-{(R) -α- [N- (carboxymethyl) carbamoyl] benzyl} carbox Barmoylmethylthio) -2,3,4,5-tetrahydrobenzothiene;

1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7- (N-{(R) -α- [N- (2-sulfoethyl) carbamoyl]- 4-hydroxybenzyl} carbamoylmethylthio) -2,3,4,5-tetrahydrobenzothiene ammonia salt;

1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7- {N- [α- (carboxy) -2-fluorobenzyl] carbamoylmethylthio} -2 , 3,4,5-tetrahydrobenzothiefine; And

1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7- {N- [1- (carboxy) -1- (thien-2-yl) methyl] carbamoyl Methylthio} -2,3,4,5-tetrahydrobenzothiene.

Particular IBAT inhibitors for use with the compounds of the present invention are selected from any one of Examples 1 to 39 of WO 03/022286, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, and Example 1 To 39 are incorporated by reference. Claims 1 to 10 of WO 03/022286 are incorporated by reference. Particular IBAT inhibitors selected from WO 03/022286 for use with the compounds of the present invention are selected from any of the following compounds, pharmaceutically acceptable salts, solvates or solvates of such salts, or prodrugs thereof:

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((R) -1-carboxy-2-methyl Thioethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2- ( R) -hydroxypropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2-methyl Propyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxybutyl) carba Moyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxypropyl) carba Moyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxyethyl) carba Moyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2- ( R) -hydroxypropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N- (2-sulfoethyl) carbamoyl] -4 -Hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxyethyl) carba Moyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((R) -1-carboxy-2-methyl Thioethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-{(S) -1- [N-(( S) -2-hydroxy-1-carboxyethyl) carbamoyl] propyl} carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzo Thiadiazepines;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxy-2-methyl Propyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N-((S) -1-carboxypropyl) carba Moyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines; And

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [N-((R) -α-carboxy-4-hydroxybenzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines.

Particular IBAT inhibitors for use with the compounds of the present invention are selected from any one of Examples 1-7 of WO 03/091232, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, Example 1 To 7 are incorporated by reference. Claims 1 to 10 of WO 03/091232 are incorporated by reference. Particular IBAT inhibitors selected from WO 03/091232 for use with the compounds of the invention are any compound selected from the following compounds, pharmaceutically acceptable salts, solvates or solvates of said salts, or prodrugs thereof:

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N- (2- (S) -3- (R) -4- (R) -5- (R) -2,3,4,5,6-pentahydroxyhexyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetra Hydro-1,2,5-benzothiadiazepines;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N- (2- (S) -3- (R) -4- (R) -5- (R) -2,3,4,5,6-pentahydroxyhexyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3, 4,5-tetrahydro-1,2,5-benzothiadiazepines;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [N-((R / S) -α- {N- [1- (R) -2- ( S) -1-hydroxy-1- (3,4-dihydroxyphenyl) prop-2-yl] carbamoyl} -4-hydroxybenzyl) carbamoylmethoxy] -2,3,4 , 5-tetrahydro-1,2,5-benzothiadiazepines;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- {N-[(R) -α- (N- {2- (S)-[N- (carr Barmoylmethyl) carbamoyl] pyrrolidin-1-ylcarbonylmethyl} carbamoyl) benzyl] carbamoylmethoxy} -2,3,4,5-tetrahydro-1,2,5-benzo Thiadiazepines;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [N-((R) -α- {N- [2- (3,4,5-trihydrate Oxyphenyl) ethyl] carbamoyl} benzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepines; And

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N- (2- (R) -3- (S) -4- (S) -5- (R) -3,4,5,6-tetrahydroxytetrahydropyran-2-ylmethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3, 4,5-tetrahydro-1,2,5-benzothiadiazepines.

Further suitable compounds which possess IBAT inhibitory activity for use in combination with the compounds of the invention are disclosed in WO 03/106482.

Suitable IBAT inhibitors as disclosed in WO 03/106482 for use with the compounds of the present invention are any compound selected from the following compounds, pharmaceutically acceptable salts, solvates or solvates of such salts, or prodrugs thereof:

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxyethyl) carr Barmoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxypropyl) carb Barmoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxybutyl) carr Barmoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-2- Methylpropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-2- Methylbutyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-3- Methylbutyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-2- Hydroxypropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-2- Mesylethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-3- Methylsulfonylpropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-3- Mesylpropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxyethyl) carr Barmoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxypropyl) carb Barmoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxybutyl) carr Barmoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-2- Methylpropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-2- Methylbutyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-3- Methylbutyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-) 2-hydroxyethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-2- Hydroxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-2- Methylthioethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-2- Methylsulfinylethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-2- Mesylethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-2- Methoxyethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-3- Methylthiopropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-3- Methylsulfonylpropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxy-3- Mesylpropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxypropyl) carb Barmoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; or

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R) -α- [N '-((S) -1-carboxyethyl) carr Barmoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine.

Also suitable IBAT inhibitors for use with the compounds of the invention are those disclosed in WO 04/076430.

In certain embodiments of the invention, the IBAT inhibitor or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof is an IBAT inhibitor or a pharmaceutically acceptable salt thereof.

Thus, in a further feature of the invention, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, and an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate, salt thereof Combinations of solvates or prodrugs are provided.

Thus, in a further aspect of the invention, there is provided a method of producing a cholesterol lowering effect in a warm blooded animal, such as a human, in need of a cholesterol lowering effect, the method comprising: a compound of formula (I), a pharmaceutically acceptable salt thereof, solvate Or administering an effective amount of a solvate of said salt, or prodrug thereof, and an effective amount of an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate, solvate, or prodrug thereof, to said animal simultaneously, sequentially or separately. do.

According to a further aspect of the invention, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, and an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of said salt Or a pharmaceutical composition comprising a prodrug together with a pharmaceutically acceptable diluent or carrier.

According to a further aspect of the invention, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof and an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of said salt Or a kit comprising a prodrug is provided.

According to a further aspect of the invention,

a) a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or prodrug thereof, present in a first formulation;

b) an IBAT inhibitor present in a second formulation, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof; And

c) container means for containing said first and second formulations

A kit comprising a is provided.

According to a further aspect of the invention,

a) a pharmaceutically acceptable diluent or carrier, in combination with a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof, in a first formulation;

b) an IBAT inhibitor present in a second formulation, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof; And

c) container means for containing said first and second formulations

A kit comprising a is provided.

According to a further feature of the invention, in the preparation of a medicament for use in producing a cholesterol lowering effect in a warm blooded animal such as a human, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or Prodrugs thereof and the use of IBAT inhibitors, or pharmaceutically acceptable salts, solvates, solvates or prodrugs thereof, are provided.

According to a further aspect of the invention, an effective amount of a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier or diluent, Simultaneous, sequential or separate administration to an animal such as a human in need thereof, such as an effective amount of an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, with an appropriately acceptable carrier or diluent Combination therapies are provided.

In a further aspect of the invention, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or prodrug thereof, may be selected from PPARα and / or PPARγ agonist, or a pharmaceutically acceptable salt, solvate thereof, It can be administered with a solvate or prodrug of the salt. Suitable PPARα and / or PPARγ agonists, pharmaceutically acceptable salts, solvates thereof, solvates or prodrugs of such salts are known in the art. WO 01/12187, WO 01/12612, WO 99/62870, WO 99/62872, WO 99/62871, WO 98/57941, WO 01/40170, WO 03/051821, WO 03/051822, WO 03/051826, PCT / GB03 / 02584, PCT / GB03 / 02591, PCT / GB03 / 02598, J Med Chem, 1996, 39, 665, Expert Opinion on Therapeutic Patents, 10 (5), 623-634 (especially listed on page 634 Compounds disclosed in patent applications) and compounds disclosed in J Med Chem, 2000, 43, 527, all of which are incorporated herein by reference. In particular, PPARα and / or PPARγ agonists are WY-14643, clofibrate, fenofibrate, bezafibrate, GW 9578, troglitazone, pioglitazone, rosiglitazone, eglitazone, proglitazone, NN622 / ragagaglitar, BMS 298585, BRL-49634, KRP-297, JTT-501, SB 213068, GW 1929, GW 7845, GW 0207, L-796449, L-165041 and GW 2433. Specific PPARα and / or PPARγ agonists mean (S) -2-ethoxy-3- [4- (2- {4-methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid and pharmaceutically acceptable salts thereof do.

Thus, in a further aspect of the invention, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, and a PPARα and / or PPARγ agonist, or a pharmaceutically acceptable salt, solvent thereof Combinations of solvates, solvates of these salts or prodrugs are provided.

Thus, in a further aspect of the invention, there is provided a method of producing a cholesterol lowering effect in a warm blooded animal, such as a human, in need of a cholesterol lowering effect, the method comprising: a compound of formula (I), a pharmaceutically acceptable salt thereof, solvate Or an effective amount of a solvate of said salt, or prodrug thereof, concurrently, sequentially or with the PPARα and / or PPARγ agonist, or a pharmaceutically acceptable salt, solvate, solvate of said salt, or prodrug thereof, with said effective amount Administration separately.

According to a further aspect of the invention, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, and a PPARα and / or PPARγ agonist, or a pharmaceutically acceptable salt, solvate thereof There is provided a pharmaceutical composition comprising a solvate or prodrug of said salt together with a pharmaceutically acceptable diluent or carrier.

According to a further aspect of the invention, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof and a PPARα and / or PPARγ agonist, or a pharmaceutically acceptable salt, solvate thereof , A kit comprising a solvate or prodrug of said salt is provided.

According to a further aspect of the invention,

a) a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or prodrug thereof, present in a first formulation;

b) PPARα and / or PPARγ agonists, or pharmaceutically acceptable salts, solvates, solvates or prodrugs thereof, present in a second formulation; And

c) container means for containing said first and second formulations

A kit comprising a is provided.

According to a further aspect of the invention,

a) a pharmaceutically acceptable diluent or carrier, together with a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof, present in a first formulation;

b) PPARα and / or PPARγ agonists, or pharmaceutically acceptable salts, solvates, solvates or prodrugs thereof, present in a second formulation; And

c) container means for containing said first and second formulations

A kit comprising a is provided.

According to a further aspect of the invention, in the preparation of a medicament for use in producing a cholesterol lowering effect in a warm blooded animal such as a human, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or Prodrugs thereof and the use of PPARα and / or PPARγ agonists, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts are provided.

According to a further aspect of the invention, an effective amount of a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier or diluent, Concurrently with an animal such as a human in need of treatment, such as an effective amount of a PPARα and / or PPARγ agonist, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, with an appropriately acceptable carrier or diluent, Combination therapy is provided comprising sequential or separate administration.

In another aspect of the invention, an effective amount of a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof, optionally with a pharmaceutically acceptable carrier or diluent, Combination therapy is provided, including simultaneous, sequential or separate administration with the agonist for the receptor). The HM74A agonist may be a nicotinic acid derivative. As used herein, "nicotinic acid derivative" means a compound comprising a pyridine-3-carboxylate structure or a pyrazine-2-carboxylate structure. Examples of nicotinic acid derivatives include nicotinic acid, did serie Troll, Nikko furanyl North, NIASPAN ^® and acipimox.

Thus, in a further aspect of the invention, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, a nicotinic acid derivative, or a pharmaceutically acceptable salt, solvate, solvent of said salt Combinations of cargo or prodrugs are provided.

Thus, in a further aspect of the present invention, there is provided a method of producing a cholesterol lowering effect in a warm blooded animal, such as a human, in need of a cholesterol lowering effect, the method comprising: a compound of formula (I), a pharmaceutically acceptable salt thereof, solvate or Administering an effective amount of a solvate of said salt, or prodrug thereof, together with an effective amount of nicotinic acid derivative, or a pharmaceutically acceptable salt, solvate, solvate or prodrug of said salt to said warm blooded animal, concurrently, sequentially or separately do.

According to a further aspect of the invention there is provided a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, a nicotinic acid derivative, or a pharmaceutically acceptable salt, solvate, solvate thereof Or a pharmaceutical composition comprising a prodrug together with a pharmaceutically acceptable diluent or carrier.

According to a further feature of the invention, in the preparation of a medicament for use in producing a cholesterol lowering effect in a warm blooded animal such as a human, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or Prodrugs thereof, and nicotinic acid derivatives, or pharmaceutically acceptable salts, solvates, and solvates or salts of such salts are provided.

In a further aspect of the invention, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, is prepared from a bile acid sequestrant, or a pharmaceutically acceptable salt, solvate thereof. And a solvate or prodrug of the salt. Suitable bile acid binding resins include cholestyramine, cholestipol and cosevelam hydrochloride and the like.

Thus, in a further feature of the invention, there is provided a compound of formula I, a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof with a bile acid binding resin, or a pharmaceutically acceptable salt, solvate, Combinations of solvates or prodrugs are provided.

Thus, in a further aspect of the present invention, there is provided a method of producing a cholesterol lowering effect in a warm blooded animal, such as a human, in need of a cholesterol lowering effect, the method comprising: a compound of formula (I), a pharmaceutically acceptable salt thereof, solvate or Administering an effective amount of the solvate of said salt, or prodrug thereof, simultaneously, sequentially or separately to said animal, such as an effective amount of a bile acid binding resin, or a pharmaceutically acceptable salt, solvate, solvate or prodrug of said salt. do.

According to a further aspect of the invention there is provided a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, and a bile acid binding resin, or a pharmaceutically acceptable salt, solvate, solvent of said salt There is provided a pharmaceutical composition comprising a cargo or prodrug together with a pharmaceutically acceptable diluent or carrier.

According to a further feature of the invention, in the preparation of a medicament for use in producing a cholesterol lowering effect in a warm blooded animal such as a human, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or Prodrugs thereof and bile acid binding resins, or pharmaceutically acceptable salts, solvates thereof, solvates or salts of such salts are provided.

According to a further aspect of the invention, an effective amount of a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier or diluent, Simultaneous, sequential to animals, such as humans, in need of treatment, such as an effective amount of a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, selected from Group X, together with a suitable acceptable carrier or diluent Or combination therapy comprising administering separately:

※ Antihypertensive compounds (e.g. althiazide, benzthiazide, captopril, carvedilol, chlorothiazide sodium, clonidine hydrochloride, cyclothiazide, derafril hydrochloride, direvalol hydrochloride, doxazosin mesylate, Posinopril Sodium, Guanfacin Hydrochloride, Methidopa, Metoprolol Succinate, Moexipril Hydrochloride, Monatefil Maleate, Perlanserine Hydrochloride, Phenoxybenzamine Hydrochloride, Prazosin Hydrochloride, Primidolol, Quinapril Hydrochloride, quinaprilat, ramipril, terazosin hydrochloride, candesartan, candesartan cilexetil, telmisartan, amlodipine besylate, amlodipine maleate and bevantolol hydrochloride);

※ Angiotensin converting enzyme inhibitors (e.g. alacepril, alatriopril, althiopril calcium, ancobenin, benazepril, benazepril hydrochloride, benazeprilat, benzoylcaptopril, captopril, captopri) Frill-cysteine, captopril-glutathione, seranapril, serranopril, seronapril, silazapril, silazaprilat, derafril, derafril-diacid, enalapril, enalapril, enapril, Epicaptopril, poroxitine, phosphenopril, posenopril, posenopril sodium, posinopril, posinopril sodium, posinoprilat, posinopril acid, glycofril, hemorphin-4, id Rapril, imidapril, indrolapril, indolaprilat, ribenzapril, ricinopril, lismin A, lismin B, mix anpril, moexipril, moexiprilat, moveltipril, mura Sein A, Murasein B, Murasein C, Pentopril, Perindo Reel, Perindoprilat, Fivallopril, Fibopril, Quinapril, Quinapril Hydrochloride, Quinaprillat, Ramipril, Ramiprilat, Spirapril, Spirapril, Spirapril, Spirapril, Spirapril , Temocapryl, temocapryl hydrochloride, teprotide, trandolapril, trandolapril, utivapril, zabicypril, zabicyprilat, zofenopril and zofenoprilat);

Angiotensin II receptor antagonists (eg candesartan, candesartan cilexetil, losartan, valsartan, irbesartan, tasosartan, telmisartan and eprosartan);

Adrenergic blockers (e.g., brethlium tosylate, dihydroergotamine somethylate, phentolamine mesylate, solipertin tartrate, zoletin hydrochloride, carvedilol or labetaol hydrochloride); Alpha adrenergic blockers (eg, fenpyride hydrochloride, labalol hydrochloride, prooxane and alfuzosin hydrochloride); Beta adrenergic blockers (e.g., acebutolol, acebutolol hydrochloride, alprenolol hydrochloride, atenolol, butolol hydrochloride, carteolol hydrochloride, celrolol hydrochloride, cetamolol hydrochloride, cycloprolol hydro Chloride, Dexpropranolol Hydrochloride, Diacetolol Hydrochloride, Direvalol Hydrochloride, Esmolol Hydrochloride, Exaprolol Hydrochloride, Pestolol Sulfate, Labetalol Hydrochloride, Levobetasolol Hydrochloride, Levobunol Hydrochloride Chloride, metalol hydrochloride, metoprolol, metoprolol tartrate, nadolol, parmatolol sulfate, fenbutolol sulfate, fractolol, propranolol hydrochloride, sotalol hydrochloride, timolol, timolol Maleate, thiprenolol hydrochloride, tolamolol, bisoprolol, bisoprolol fumarate and nebivolol); Or mixed alpha / beta adrenergic blockers;

※ adrenergic stimulants (e.g. combination products of chlorothiazide and metidopa, combination products of metidopa hydrochlorothiazide and metidopa, clonidine hydrochloride, clonidine, combination of chlortalidone with clonidine hydrochloride and guanfacin hydrochloride product);

※ channel blockers, such as calcium channel blockers (e.g., clentiazem maleate, amlodipine besylate, isradiffine, nimodipine, felodipine, nilvadipine, nifedipine, telludipine hydrochloride, diltiazem hydrochloride , Belfosdil, verapamil hydrochloride or postedil);

Diuretics (eg, combination products of hydrochlorothiazide and spironolactone, and combination products of hydrochlorothiazide and triamterene);

※ anti-anginal agents (e.g., amlodipine besylate, amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride, butoprozin hydrochloride, carvedilol, cinefazette maleate, metoprolol succinate, molsidomine, Monatefil maleate, primidolol, ranolazine hydrocortide, tocifen or verapamil hydrochloride);

※ vasodilators such as coronary vasodilators (e.g. postedil, azaclozin hydrochloride, chromonar hydrochloride, clonitrate, diltiazem hydrochloride, dipyridamole, droprenilamine, erythritol tetra Nitrates, isosorbide dinitrate, isosorbide mononitrate, lidofrazine, myopazine hydrochloride, mixidine, molsidomine, niconordil, nifedipine, nisoldipine, nitroglycerin, oxprenolol hydrochloride, Pentrinitrol, perhexylline maleate, prenylamine, propityl nitrate, terodidyl hydrochloride, tolamolol and verapamil);

※ anti-coagulants (argatroban, vivaludin, dalteparin sodium, decirudine, dicoumarol, iyafolate sodium, napamosat mesylate, fenprocomon, tinzaparin sodium and warfarin sodium Selected from);

※ Antithrombotic agents (e.g., Anagrelidee hydrochloride, Vivalidine, Cilostazol, Dalteparin sodium, Danapharoid sodium, Dazosiben hydrochloride, Efegatran sulfate, Enoxaparin sodium, Fluretophene , Efetroban, Efetroban Sodium, Ramipan, Lotrafiban Hydrochloride, Naphthatran, Orbopiban Acetate, Roxypiban Acetate, Cibrapiban, Tinzaparin Sodium, Trifenagrel, Absiksi Map and zolimomap aritox);

※ Fibrinogen Receptor Antagonists (e.g., roxifiban acetate, pradapiban, orbopiban, rotrapiban hydrochloride, tyropiban, xemilopanti, monoclonal antibody 7E3 and sibrapivan)

※ Platelet inhibitors (e.g. cilostazole, clopidogrel bisulfate, epoprostenol, epoprostenol sodium, ticlopidine hydrochloride, aspirin, ibuprofen, naproxen, sulinedae, indomethacin, mefenamate, doxy Camm, diclofenac, sulfinpyrazone and pyroxycam, dipyridamole);

※ Platelet aggregation inhibitors (e.g., acadecin, veraprost, veraprost sodium, cyprostenium calcium, itzigrel, liparizine, lotrapiban hydrochloride, orbopiban acetate, oxagrelate, pradapiban, orbofiban , Tyropiphan and xymilfifan)

Blood flow agents (eg pentoxifylline);

Lipoprotein-related coagulation inhibitors;

Factor VIIa inhibitors;

Factor Xa inhibitors;

Low molecular weight heparin (eg enoxaparin, nardroparin, dalteparin, sertroparin, parnaparin, leviparin and tinzaparin);

Squalene synthase inhibitors;

Squalene epoxidase inhibitors;

※ Liver X receptor (LXR) agonists, for example GW-3965 and W0 00224632, W0 00103705, W0 02090375 and W0 00054759 (claims 1 and embodiments of these four applications are described herein) Cited therein);

* Microsomal triglyceride delivery protein inhibitors, such as Implipidide and W0 03004020, W0 03002533, W0 02083658 and WO 00242291 (claims 1 and examples of these four applications are referred to herein) Cited).

Thus, according to a further feature of the invention, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof and a compound selected from group X, a pharmaceutically acceptable salt, solvate thereof or Solvates of such salts, or combinations of prodrugs thereof, are provided.

Thus, in a further aspect of the invention, there is provided a method of producing a cholesterol lowering effect in a warm blooded animal, such as a human, in need of a cholesterol lowering effect, the method comprising: a compound of formula (I), a pharmaceutically acceptable salt thereof, solvate Or an effective amount of a solvate of said salt, or prodrug thereof, simultaneously, sequentially or separately to said animal, such as a compound selected from Group X, a pharmaceutically acceptable salt, solvate or solvate of said salt, or an effective amount of a prodrug thereof Administering.

According to a further aspect of the invention, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, and a compound selected from group X, a pharmaceutically acceptable salt, solvate or salt thereof There is provided a pharmaceutical composition comprising a solvate, or prodrug thereof, together with a pharmaceutically acceptable diluent or carrier.

According to a further feature of the invention, in the preparation of a medicament for use in producing a cholesterol lowering effect in a warm blooded animal such as a human, a compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or Prodrugs thereof and compounds selected from Group X, pharmaceutically acceptable salts, solvates or solvates of such salts, or the use of prodrugs thereof, are provided.

Compounds of formula (I), pharmaceutically acceptable salts, solvates or solvates of these salts, or prodrugs thereof, are, in addition to their use as therapeutic agents, as part of new therapeutic investigations, such as cats, dogs, rabbits, monkeys, rats and mice. It is useful as a pharmacological tool in the development and standardization of in vitro and in vivo test systems for assessing the effect of inhibiting cholesterol absorption in laboratory animals.

The various intermediates disclosed herein are novel and therefore serve as further features of the present invention. For example, when compounds of formula VI are tested in the above-mentioned in vitro test assays, they exhibit cholesterol absorption inhibitory activity and thus are claimed as further features of the present invention.

Thus, according to a further feature of the invention there is provided a compound of formula (VI), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, provided that the compound is 3- (R) -4 -(R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- {4- [N- (carboxymethyl) carbamoylmethoxy ] Phenyl} azetidin-2-one.

Thus, according to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula (VI), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof together with a pharmaceutically acceptable diluent or carrier Provided that the compound is 3- (R) -4- (R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- {4 -[N- (carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one.

Thus, according to a further aspect of the present invention there is provided a compound of formula (VI), a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof, for use in a method of preventing or treating a warm blooded animal such as a human Provided that the compound is 3- (R) -4- (R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- {4 -[N- (carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one.

Accordingly, according to this aspect of the invention there is provided a compound of formula (VI), a pharmaceutically acceptable salt, solvate or solvate of said salt, or a prodrug thereof, for use as a medicament, provided that the compound is 3- ( R) -4- (R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- {4- [N- (carboxymethyl) car Not barmoylmethoxy] phenyl} azetidin-2-one.

According to another feature of the invention, in the preparation of a medicament for use in producing a cholesterol absorption inhibitory effect in a warm blooded animal such as a human, the compound of formula VI, a pharmaceutically acceptable salt, solvate or solvate of said salt Or a prodrug thereof, provided that the compound is 3- (R) -4- (R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydride Oxyethylsulfanyl] -4- {4- [N- (carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one.

According to another feature of the invention, in the preparation of a medicament for treating hyperlipidemia in a warm blooded animal such as a human, the compound of formula (VI), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof Provided, provided that the compound is 3- (R) -4- (R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl]- It is not 4- {4- [N- (carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one.

According to a further feature of this aspect of the present invention, there is provided a method of producing a cholesterol absorption inhibitory effect in a warm blooded animal such as a human being in need thereof, wherein the method is a compound of formula VI, a pharmaceutically acceptable Administering to said animal an effective amount of a salt, solvate or solvate of said salt, or prodrug thereof, provided that said compound is 3- (R) -4- (R) -1- (phenyl) -3 -[2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- {4- [N- (carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one.

According to a further feature of this aspect of the invention, there is provided a method of treating hyperlipidemia in a warm blooded animal, such as a human, in need of the treatment of hyperlipidemia, the method comprising: a compound of formula (VI), a pharmaceutically acceptable salt thereof, solvate Or administering to said animal an effective amount of a solvate of said salt, or prodrug thereof, provided that said compound is 3- (R) -4- (R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- {4- [N- (carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one.

In such other pharmaceutical compositions, processes, methods, uses and pharmaceutical preparation features, alternative and preferred embodiments of the compounds disclosed herein may be applied.

The invention will be further described through the following non-limiting examples. Unless otherwise noted, these examples used standard techniques known to those skilled in the art (chemist) and, if desired, similar techniques to those described in these examples:

(Iii) evaporation was carried out by rotary evaporation under vacuum, and the working procedure was carried out after filtration to remove residual solid such as desiccant;

(Ii) Unless otherwise noted, all reactions were carried out at room temperature in an inert atmosphere, typically in anhydrous conditions, at a temperature in the range of 18-25 ° C. using a solvent of HPLC grade;

(Iii) column chromatography (by flash procedure) was carried out on silica gel 40-63 μm (Merck);

(Iii) yields are described for purposes of illustration and do not mean the maximum yield obtainable;

(v) The structure of the final product of formula (I) was generally identified by nuclear (generally proton) magnetic resonance (NMR) and mass spectrometry techniques; Magnetic resonance chemical shift values were measured on deuterated CDCl ₃ (unless otherwise noted) at the delta scale (ppm of the shift from tetramethylsilane to downfield); Proton data were cited unless otherwise noted; Spectra were recorded on a Varian Mercury-300 MHz, Varian Unity plus-400 MHz, Varian Unity plus-600 MHz or Varian Inova-500 MHz spectrometers and data were recorded at 400 MHz unless otherwise noted; Peak multiplicity is shown as follows: s, singlet; d, doublet; dd, doublet doublet; t, triplet; tt, triple triplet; q, quartet; tq, triple quartet; m, multiplet; br, wide; ABq, AB quartet; Doublet of ABd, AB doublet, ABdd, AB doublet; dABq, doublet of AB quartet;

Mass spectra were all recorded on any of the LCT, QTOF, ZQ mass spectrometers from Waters.

LC-MS:

Gradient elution was performed using an Agilent 1100 Series Modules or Waters 1525 pump on Synergi MAX-RP (Phenomenex) C12 3 × 50 mm 4 μm. Samples were injected using the Waters 2700 Sample Manager.

Mobile phase:

As a general gradient, 5% to 95% acetonitrile was used.

Buffers containing 10 mM ammonium acetate or 5 mM ammonium formiate / 5 mM formic acid were used.

Mass spectra were recorded using a Waters ZQ2000 or Waters ZMD equipped with an electrospray interface by switching the positive and negative ionization modes. UV spectra were collected using Aglent 1100 PDA or Waters 2996 DAD, and evaporated scattered light (ELS) signals were collected using Sedere Sedex 55 or 75.

Data collection and evaporation were performed using MassLynx software.

Accurate mass data was determined using leucine enkephalin (m / z 556.2771) and LCT or QTOF MS (Waters) as lockmass. Unless stated otherwise, the quoted mass ions are (MH ⁺ ).

Analytical high performance liquid chromatography (HPLC) was performed on Prep LC 2000 (Waters), Cromasil C ₈ , 7 μm (Akzo Nobel), unless stated otherwise; MeCN and deionized water 10 mM ammonium acetate were used as mobile phase with appropriate composition;

(vii) Intermediates were generally not fully characterized and purity was assessed by thin layer chromatography (TLC), HPLC, infrared (IR), MS or NMR analysis;

(viii) when drying the solution, magnesium sulfate was a desiccant; And

(ix) The following abbreviations have been used throughout the specification:

DCM dichloromethane;

DMF N, N-dimethylformamide;

TBTU o-benzotriazol-1-yl-N, N, N ', N'-tetramethyluroniumtetrafluoroborate;

EtOAc ethyl acetate;

MeCN acetonitrile;

TFA trifluoroacetic acid;

DMAP 4- (dimethylamino) pyridine;

BSA N, O-bis (trimethylsilyl) acetamide;

TBAF tetrabutylammonium fluoride;

NMM N-methyl morpholine;

TEA triethylamine; And

DBN 1,5-diazabicyclo- [4,3,0] -non-5-ene.

Example 1

(2R)-[(N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio } -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl) amino] (phenyl) acetic acid

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycine (44 mg, 0.081 mmol), N-methylmorpholine (18 ul, 0.16 mmol), t-butyl (2R) -amino (phenyl) acetate (23 mg, 0.11 mmol) and TBTU (36 mg, 0.11 mmol) were added to methylene chloride (3 mL) and the reaction mixture was stirred at ambient temperature for 1.5 hours. The mixture was purified by column chromatography on silica gel using methylene chloride / ethyl acetate (1/1) as eluent. The resulting intermediate ester was dissolved in formic acid (2 mL) and the mixture was stirred at 45 ° C. overnight. The solvent was evaporated under reduced pressure and coevaporated with toluene. The residue was dissolved in methanol (2 mL) and NaBH ₄ (10 mg, 0.26 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes. A small amount of ammonium acetate buffer was added and methanol was removed by evaporation. The residue was purified by preparative HPLC using acetonitrile / ammonium acetate buffer (45:55) as eluent. The collected fractions were lyophilized to give 39 mg (71%, 3 steps) of the title compound. ( ¹ H-NMR, 400 MHz, CD ₃ OD): 1.8-2.0 (m, 2H), 3.75 (d, 2H), 4.3 (d, 1H), 4.55 (s, 2H), 4.65-4.80 (m, 2H), 5.05 (d, 1H), 7.0-7.4 (m, 17H), 7.95 (dd, 1H) 8.25 (t, 1H)

Example 2

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-N ⁶ -Acetyl-D-lysine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycine (20 mg, 0.037 mmol), N-methylmorpholine (18 ul, 0.16 mmol) and TBTU (13 mg, 0.041 mol) with CH ₂ Cl ₂ (2 mL) And the reaction mixture was stirred at 30 ° C. for 1.5 h. To this mixture was added N ⁶ -acetyl-D-lysine (14 mg, 0.074 mmol) and DMF (5 drops), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and methanol (2 mL) and NaBH ₄ (30 mg, 0.79 mmol) were added to the residue. The reaction mixture was stirred at room temperature for 1 hour. A small amount of ammonium acetate buffer was added and methanol was removed by evaporation. The residue was purified by preparative HPLC using acetonitrile / ammonium acetate buffer (40:60) as eluent. The collected fractions were lyophilized, dissolved in t-butanol and lyophilized again to give 4 mg (15%, 2 steps) of the title compound. ( ¹ H-NMR, 400 MHz, DMSO-d ₆ ): 1.2-1.8 (m, 11H), 2.85-2.95 (m, 2H), 3.7-3.8 (m, 2H), 4.0-4.1 (bs, 1H) , 4.25-4.3 (m, 1H), 4.5 (s, 2H), 4.7-4.8 (m, 1H), 5.05 (dd, 1H), 6.95-7.4 (m, 12H), 7.7-7.8 (m, 1H) , 7.95-8.05 (m, 1H), 8.25-8.3 (m, 1H)

Example 3

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -D-alanyl-D-phenylalanine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -D-alanine (12 mg, 0.022 mmol), t-butyl D-phenylalanine hydrochloride (7 mg, 0.028 mmol) and 4-methylmorpholine (7 Mg, 0.065 mmol) was dissolved in 0.5 mL of DCM. The mixture was stirred at rt for 5 h. TBTU (9 mg, 0.028 mmol) was added and the reaction mixture was stirred overnight, then purified on silica (2 g) using DCM first as eluent and then DCM: MeOH = 10: 1. Fractions containing product were concentrated, formic acid (1 mL) was added and the solution was stirred overnight. After evaporating formic acid, the remaining formic acid was removed by addition of toluene and evaporation. The residue was stirred for 2.5 days in methanol: triethylamine = 40: 1 (2 mL) (hydrolysis of the formed formic acid ester), the mixture was concentrated and the residue was from 20% to 0.1% in 0.1% ammonium acetate buffer as eluent. Purification was performed by preparative HPLC using 100% gradient CH ₃ CN. It was freeze-dried to give 7.3 mg (48%) of the title compound. M / z: 702.3 (M-1), NMR (DMSO, 400 MHz): 1.18 (d, 3H), 2.85-2.96 (m, 3H), 3.00-3.07 (m, 1H), 4.05-4.12 (m, 1H), 4.19-4.32 (m, 2H), 4.48 (dd, 2H), 4.68-4.76 (m, 1H), 5.0-5.07 (m, 1H), 6.89-6.95 (m, 2H), 7.05-7.17 ( m, 10H), 7.19-7.25 (m, 2H), 7.30-7.36 (m, 4H), 7.65-7.75 (m, 1H), 8.12-8.18 (m, 1H).

Example 4

N ² -[(2R) -2-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] Thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} amino) -2-phenylacetyl] -D-lysine

(2R)-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4 Oxoazetidin-2-yl) phenoxy] acetyl} amino) (phenyl) acetic acid (10 mg, 0.016 mmol), t-butyl N ^6- (t-butoxycarbonyl) -D-lysinate hydrochloride (7 mg, 0.021 mmol) and N-methylmorpholine (5 mg, 0.048 mmol) were dissolved in DCM (0.5 mL). The mixture was stirred and after 5 minutes TBTU (7 mg, 0.021) was added and the reaction mixture was stirred for 2 hours. The product was purified on a silica plug using DCM: MeOH = 100: 5 as eluent. Formic acid (0.5 mL) was added to the purified product and the mixture was stirred at 40 ° C. for 2 hours and then at room temperature overnight. Formic acid was removed under reduced pressure, toluene was added, and then the solvent was removed. The residue was dissolved in MeOH and small amount of triethylamine and stirred at room temperature overnight. The product was purified by preparative HPLC (CH ₃ CN / 0.1% ammonium acetate 20:80 to 100: 0). Fractions containing the product were lyophilized to give 4.0 mg (33%) of the title compound. M / z: 745.4 (M-1). NMR (DMSO, 400 MHz): 1.19-2.30 (m, 2H), 1.30-1.40 (m, 2H), 1.40-1.52 (m, 2H), 1.52-1.68 (m, 2H), 2.63-2.75 (m, 2H), 2.83-2.95 (m, 2H), 3.7-3.8 (m, 1H), 4.28 (dd, 1H), 4.60 (dd, 2H), 4.68-4.76 (m, 1H), 5.04 (dd, 1H) , 5.48 (d, 1H), 6.95 (d, 2H), 7.05-7.17 (m, 4H), 7.19-7.28 (m, 5H), 7.30-7.40 (m, 6H), 7.88 (d, 1H), 8.55 (d, 1H).

Example 5

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -L-tryptiphyl-D-phenylalanine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -L-tryptophan (0.015 g, 0.022 mmol) was dissolved in CH ₂ Cl ₂ (2 mL). HD-Phe-OTBU hydrochloride (0.007 g, 0.027 mmol) and N-methylmorpholine (0.007 g, 0.067 mmol) were added. After 10 minutes, TBTU (0.009 g, 0.029 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature. The mixture was then passed through a small pad of silica gel and eluted with EtOAc / CH ₂ Cl ₂ = 25/75. Pure fractions were collected and concentrated. The resulting t-butyl ester was hydrolyzed by addition of formic acid (0.5 mL) followed by stirring at room temperature overnight. The resulting product was concentrated and dissolved in 2 mL MeOH. The formylated product was hydrolyzed by addition of Et ₃ N (0.1 mL). The mixture was stirred overnight. After evaporation of the solvent, the residue was purified by preparative HPLC using 20% to 60% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as mobile phase. It was freeze-dried to give the title compound as a colorless solid (0.004 g, 22%). M / z: 817.3 (M-1). ¹ H NMR (CD ₃ CN, 400 MHz) δ 2.82-3.20 (m, 6H), 4.07-4.15 (m, 1H), 4.29-4.39 (m, 2H), 4.54-4.89 (m, 4H), 6.74- 7.53 (m, 22 H), 9.14-9.20 (m, 1 H).

Example 6

N-((2R) -2-{[(4-{(2R, 3R) -3-[(2-hydroxy-2-phenylethyl) thio] -4-oxo-1-phenylazetidine-2- Phenoxy) acetyl] amino} -2-phenylacetyl) glycine

[4-((2R, 3R) -3-{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} -4-oxo-1-phenylazetidine -2-yl) phenoxy] acetic acid (0.050 g, 0.094 mmol) was dissolved in CH ₂ Cl ₂ (5 mL). t-butyl N-[(2R) -2-amino-2-phenylacetyl] glycinate (0.030 g, 0.112 mmol) and N-methylmorpholine (0.028 g, 0.281 mmol) were added. After 5 minutes, TBTU (0.039 g, 0.122 mmol) was added. After 1 hour, HPLC showed complete conversion to the corresponding t-butylester. The reaction mixture was purified by chromatography on silica gel and eluted with EtOAc / CH ₂ Cl ₂ = 25/75. Pure fractions were collected and concentrated. The residue was dissolved in 3 mL of CH ₂ Cl ₂ and 1 mL of trifluoroacetic acid was added. The reaction mixture was stirred for 2 hours at room temperature, and the resulting acid was concentrated in vacuo. Residual TFA was removed by coevaporation with toluene (2 mL). The acid was dissolved in 3 ml of MeOH and sodium borohydride (10 mg, 0.264 mmol) was added. After 5 minutes, HPLC showed complete conversion to the corresponding alcohol. The reaction was quenched by addition of 1 ml 0.1 M NH ₄ OAc buffer and the mixture was concentrated. The residue was purified by preparative HPLC using 20% to 60% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as mobile phase and lyophilized to give the title product as a colorless solid (0.032 g, 54%). M / z: 638.5 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 2.90-2.94 (m, 2H), 3.45-3.65 (m, 2H), 4.25-4.27 (m, 1H), 4.59 (d, 1H), 4.64 (d, 1H), 4.68-4.75 (m, 1H), 5.02-5.05 (m, 1H), 5.57 (d, 1H), 6.94-7.41 (m, 19H), 8.28 (s, br, 1H), 8.55 (d, 1 H).

Example 7

N-[(4-{(2R, 3R) -3-[(2-hydroxy-2-phenylethyl) thio] -4-oxo-1-phenylazetidin-2-yl} phenoxy) acetyl] Lysyl-D-phenylalanine

N-[(4-{(2R, 3R) -4-oxo-3-[(2-oxo-2-phenylethyl) thio] -1-phenylazetidin-2-yl} phenoxy) acetyl] glycine Dissolved in CH ₂ Cl ₂ (3 mL). (R) -phenylalanine t-butyl ester hydrochloride (0.012 g, 0.045 mmol) and N-methylmorpholine (0.011 g, 0.113 mmol) were added. After 5 minutes, TBTU (0.016 g, 0.049 mmol) was added. After 1 hour complete conversion to the corresponding t-butyl ester was achieved. The reaction mixture was purified by chromatography on silica gel and eluted with EtOAc / CH ₂ Cl ₂ = 25/75. Pure fractions were collected and concentrated. The residue was dissolved in 3 mL of CH ₂ Cl ₂ and 0.5 mL of trifluoroacetic acid and the reaction stirred overnight at room temperature. The resulting acid was concentrated and dissolved in 3 ml of MeOH. Sodium borohydride (0.010 g, 0.264 mmol) was added. Complete conversion to the corresponding alcohol occurred after 5 minutes. The reaction was quenched by addition of 1 ml 0.1 M NH ₄ OAc buffer. After concentration, preparative HPLC was performed using 20% to 60% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as mobile phase to give the title product as a colorless solid after freeze-drying (0.021 g, 84%). M / z: 652.3 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 2.85-3.05 (m, 4H), 3.62-3.80 (m, 2H), 4.18-4.35 (m, 2H), 4.48 (d, 1H), 4.51 (d, 1H), 4.68-4.78 (m, 1H), 4.99-5.03 (m, 1H), 6.93-7.35 (m, 19H), 7.65-7.80 (m, 1H), 8.23-8.29 (m, 1H ).

Example 8

N-[(2R) -2-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl ] Thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} amino) -2-phenylacetyl] -L-alanine

(2R)-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4- Oxoazetidin-2-yl) phenoxy] acetyl} amino) (phenyl) acetic acid (0.040 g, 0.065 mmol) was dissolved in CH ₂ Cl ₂ (5 mL). t-butyl L-alanine hydrochloride (0.014 g, 0.078 mmol) and N-methyl-morpholine (0.020 g, 0.195 mmol) were added. After 5 minutes, TBTU (0.027 g, 0.084 mmol) was added. The reaction was stirred for 1 hour, after which the resulting t-butyl ester was purified by chromatography on silica gel and eluted with EtOAc / CH ₂ Cl ₂ = 25/75. The pure fraction was concentrated and dissolved in CH ₂ Cl ₂ (4 mL) and trifluoroacetic acid (0.5 mL). After 1.5 hours at room temperature, complete conversion to the corresponding acid was achieved. The reaction mixture was concentrated and the remaining TFA was removed by coevaporation with toluene (3 mL). Crude acid was dissolved in MeOH (3 mL) and NaBH ₄ (0.010 g, 0.260 mmol) was added. After 5 minutes complete conversion to the corresponding alcohol took place. The reaction was quenched by addition of 0.1 M NH ₄ OAc buffer (1 mL). The mixture was concentrated and the residue was purified by preparative HPLC using 20% to 50% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as mobile phase. It was freeze-dried to give the title compound as a colorless solid (0.020 g, 45%). M / z: 688.4 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 2.30-2.35 (m, 3H), 2.86-2.94 (m, 2H), 3.15-3.31 (m, 1H), 4.26-4.28 (m, 1H ), 4.59 (d, 1H), 4.64 (d, 1H), 4.70-4.76 (m, 1H), 5.04-5.07 (m, 1H), 5.46 (d, 1H), 6.94-7.36 (m, 17H), 8.43-8.55 (m, 2 H).

Example 9

N-[(2R) -2-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl ] Thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} amino) -2-phenylacetyl] -D-alanine

(2R)-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4- Oxoazetidin-2-yl) phenoxy] acetyl} amino) (phenyl) acetic acid (0.040 g, 0.065 mmol) was dissolved in CH ₂ Cl ₂ (5 mL). t-butyl D-alanineate hydrochloride (0.014 g, 0.078 mmol) and N-methyl-morpholine (0.020 g, 0.195 mmol) were added. After 5 minutes, TBTU (0.027 g, 0.084 mmol) was added. The reaction was stirred overnight and the resulting t-butyl ester was purified on silica gel, then eluted with EtOAc / CH ₂ Cl ₂ = 25/75. Pure fractions were concentrated. The residue was dissolved in CH ₂ Cl ₂ (4 mL) and trifluoroacetic acid (0.5 mL). After 1.5 hours at room temperature complete conversion to the corresponding acid was achieved. The reaction mixture was concentrated and the remaining TFA was removed by coevaporation with toluene (3 mL). Crude acid was dissolved in MeOH (3 mL) and NaBH ₄ (0.010 g, 0.260 mmol) was added. After 5 minutes complete conversion to the corresponding alcohol took place. The reaction was quenched by addition of 0.1 M NH ₄ OAc buffer (1 mL). The mixture was concentrated and the residue was purified by preparative HPLC using 20% to 50% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as mobile phase. It was freeze-dried to give the title compound as a colorless solid (0.024 g, 54%). M / z: 688.6 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 1.10-1.24 (m, 3H), 2.89-2.94 (m, 2H), 3.99-4.08 (m, 1H), 4.26-4.30 (m, 1H ), 4.60 (d, 1H), 4.64 (d, 1H), 4.70-4.78 (m, 1H), 5.02-5.08 (m, 1H), 5.53-5.56 (d, 1H), 6.94-7.40 (m, 17H ), 8.39-8.59 (m, 2 H).

Example 10

(2R)-{[(2R) -2-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2- Hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} amino) -2-phenylacetyl] amino} (phenyl) acetic acid

(2R)-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4- Oxoazetidin-2-yl) phenoxy] acetyl} amino) (phenyl) acetic acid (0.040 g, 0.065 mmol) is dissolved in CH ₂ Cl ₂ (5 mL) and t-butyl (2R) -amino (phenyl Acetate (0.016 g, 0.078 mmol) and N-methyl-morpholine (0.020 g, 0.195 mmol) were added. After 5 minutes, TBTU (0.027 g, 0.084 mmol) was added. The reaction was stirred at room temperature for 3 hours, after which the resulting t-butyl ester was purified on silica gel and eluted with EtOAc / CH ₂ Cl ₂ = 25/75. Pure fractions were concentrated. The residue was dissolved in CH ₂ Cl ₂ (3 mL) and TFA (0.5 mL). The reaction mixture was stirred at rt overnight. The resulting acid was concentrated and residual traces of TFA were removed by co-evaporation with toluene (3 mL). The acid was dissolved in MeOH (3 mL) and NaBH ₄ (0.010 g, 0.260 mmol) was added. After 5 minutes complete conversion to the corresponding alcohol took place. The reaction was quenched by addition of 1 ml 0.1 M NH ₄ OAc buffer. After concentration, the residue was purified on preparative HPLC using 20% to 50% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as mobile phase and the pure fraction was freeze-dried to give the title compound as a colorless solid (0.034 g, 70%). M / z: 750.4 (M-1) ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 2.88-2.94 (m, 2H), 4.23-4.29 (m, 1H), 4.56-4.65 (m, 2H), 4.70-4.78 (m, 1H), 4.91-5.06 (m, 2H), 5.65-5.75 (m, 1H), 6.93-7.42 (m, 22H), 8.54-8.69 (m, 2H).

Example 11

(2S)-{[(2R) -2-({[4-((2R, 3R) -1- (4- Fluorophenyl ) -3-{[2- (4- Fluorophenyl ) -2-hi Doxyrie Teal] Thio }-4- Oxoazetidine -2 days) Phenoxy ] Acetyl} amino) -2- Phenylacetyl ] Amino} (phenyl) acetic acid

(2R)-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4- Oxoazetidin-2-yl) phenoxy] acetyl} amino) (phenyl) acetic acid (0.040 g, 0.065 mmol) was dissolved in CH ₂ Cl ₂ (5 mL). t-butyl (2S) -amino (phenyl) acetate (0.016 g, 0.078 mmol) and N-methyl-morpholine (0.020 g, 0.195 mmol) were added. After 5 minutes, TBTU (0.027 g, 0.084 mmol) was added. The reaction mixture was stirred at rt for 3 h. The resulting t-butyl ester was purified on silica gel and eluted with EtOAc / CH ₂ Cl ₂ (25/75). Pure fractions were concentrated. The residue was dissolved in CH ₂ Cl ₂ (3 mL) and TFA (0.5 mL). The reaction mixture was stirred at rt overnight. The resulting acid was concentrated and residual traces of TFA were removed by co-evaporation with toluene (3 mL). The acid was dissolved in MeOH (3 mL) and NaBH ₄ (0.010 g, 0.260 mmol) was added. After 5 minutes complete conversion to the corresponding alcohol took place. The reaction was quenched by addition of 1 ml 0.1 M NH ₄ OAc buffer. After concentration, purification was carried out on preparative HPLC using 20% to 50% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as mobile phase and the pure fraction is freeze-dried to give the title compound as a colorless solid (0.037 g, 76%). M / z: 750.6 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 2.87-2.94 (m, 2H), 4.25-4.28 (m, 1H), 4.58-4.78 (m, 3H), 5.01-5.07 (m, 2H ), 5.65-5.74 (m, 1H), 6.94-7.39 (m, 22H), 8.53-8.72 (m, 2H).

Example 12

N-[(2R) -2-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl ] Thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} amino) -2-phenylacetyl] -D-serine

(2R)-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4- Oxoazetidin-2-yl) phenoxy] acetyl} amino) (phenyl) acetic acid (0.040 g, 0.065 mmol), t-butyl O- (t-butyl) -D-serinate hydrochloride (0.020 g, 0.078 mmol) and N-methyl-morpholine (0.020 g, 0.195 mmol) were dissolved in CH ₂ Cl ₂ (5 mL) at room temperature. After 5 minutes, TBTU (0.027 g, 0.084 mmol) was added. After 1 hour complete conversion to the corresponding t-butyl ester was achieved. The reaction mixture was purified on silica gel and eluted with EtOAc / CH ₂ Cl ₂ (25/75). Pure fractions were collected and concentrated. The residue was dissolved in 3 ml CH ₂ Cl ₂ and 1 ml TFA. The reaction mixture was stirred for 1.5 hours and concentrated. The remaining traces of TFA were azeotropically removed by co-evaporation with toluene (3 mL). Crude acid was dissolved in MeOH (3 mL) and NaBH ₄ (0.010 g, 0.260 mmol) was added. After 5 minutes complete conversion to the corresponding alcohol took place. The reaction was quenched by addition of 0.1 M NH ₄ OAc buffer (2 mL). After purification on preparative HPLC using 20% to 50% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as mobile phase, pure fractions were freeze-dried to afford the title compound as a colorless solid (0.032 g, 71%). . M / z: 704.7 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 2.88-2.94 (m, 2H), 3.42-3.46 (m, 1H), 3.58-3.61 (m, 1H), 3.85-3.90 (m, 1H ), 4.26-4.29 (m, 1H), 4.59 (d, 1H), 4.64 (d, 1H), 4.70-4.77 (m, 1H), 5.04-5.07 (m, 1H), 5.57-5.65 (m, 1H ), 6.95-7.41 (m, 17 H), 8.08-8.20 (m, 1 H), 8.53-8.56 (m, 1 H).

Example 13

N-[(2R) -2-({[4-((2R, 3R) -1- (4- Fluorophenyl ) -3-{[2- (4- Fluorophenyl )-2- Hydroxyethyl ] Thio }-4- Oxoazetidine -2 days) Phenoxy ] Acetyl} amino) -2- Phenylacetyl ] -L-Threonine

(2R)-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4- Oxoazetidin-2-yl) phenoxy] acetyl} amino) (phenyl) acetic acid (0.030 g, 0.049 mmol), t-butyl O- (t-butyl) -L-threoninate (0.014 g, 0.058 mmol ) And N-methyl-morpholine (0.015 g, 0.146 mmol) were dissolved in CH ₂ Cl ₂ (4 mL). After 5 minutes, TBTU (0.020 g, 0.063 mmol) was added. After 1 hour complete conversion to the corresponding t-butyl ester was achieved. The reaction mixture was purified on silica gel and eluted with EtOAc / CH ₂ Cl ₂ (25/75). Pure fractions were collected and concentrated. The residue was dissolved in 3 ml CH ₂ Cl ₂ and 1 ml TFA and the mixture was stirred for 1.5 hours. The resulting acid was concentrated. The remaining traces of TFA were azeotropically removed by co-evaporation with toluene (3 mL). Crude acid was dissolved in MeOH (3 mL) and NaBH ₄ (0.007 g, 0.195 mmol) was added. After 5 minutes complete conversion to the corresponding alcohol took place. The reaction was quenched by addition of 0.1 M NH ₄ OAc buffer (2 mL). Purification was performed by preparative HPLC using 20% to 50% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent, and the pure fractions are freeze-dried to afford the title compound as a colorless solid (0.025 g, 71 %). M / z: 721.1. ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 0.69 (d, 3H), 2.88-2.93 (m, 2H), 3.79-3.85 (m, 1H), 3.96-4.01 (m, 1H), 4.27-4.30 (m, 1H), 4.60 (d, 1H), 4.64 (d, 1H), 4.71-4.79 (m, 1H), 5.02-5.08 (m, 1H), 5.65-5.69 (m, 1H), 6.95-7.42 (m, 17H), 8.01-8.09 (m, 1H), 8.51-8.59 (m, 1H).

Example 14

N ² -[(2R) -2-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] Thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} amino) -2-phenylacetyl] -L-asparagine

(2R)-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4 Oxoazetidin-2-yl) phenoxy] acetyl} amino) (phenyl) acetic acid (0.030 g, 0.049 mmol), t-butyl L-asparazinate hydrochloride (0.013 g, 0.058 mmol) and N-methyl -Morpholine (0.015 g, 0.146 mmol) was dissolved in CH ₂ Cl ₂ (4 mL). After 5 minutes TBTU (0.020 g, 0.063 mmol) was added. After 1 hour complete conversion to the corresponding t-butyl ester was achieved. The reaction mixture was purified on silica gel and eluted with EtOAc. Pure fractions were collected and concentrated. The residue was dissolved in 3 ml CH ₂ Cl ₂ and 1 ml TFA and the mixture was stirred for 0.5 h. The resulting acid was concentrated. The remaining traces of TFA were azeotropically removed by co-evaporation with toluene (3 mL). Crude acid was dissolved in MeOH (3 mL) and NaBH ₄ (0.007 g, 0.195 mmol) was added. After 5 minutes complete conversion to the corresponding alcohol took place. The reaction was quenched by addition of 0.1 M NH ₄ OAc buffer (2 mL). Purification by preparative HPLC using 20% to 40% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent followed by freeze-drying of the pure fractions gave the title compound as a colorless solid (0.024 g, 67%). ). M / z: 731.6 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 2.16-2.23 (m, 1H), 2.32-2.42 (m, 1H), 2.87-2.95 (m, 2H), 4.20-4.30 (m, 2H ), 4.59-4.78 (m, 3H), 5.03-5.07 (m, 1H), 5.54-5.59 (m, 1H), 6.68-6.73 (m, 1H), 6.94-7.38 (m, 17H), 7.78-7.83 (m, 1 H), 8.22-8.37 (m, 1 H), 8.50-8.58 (m, 1 H).

Example 15

N-[(2R) -2-({[4-((2R, 3R) -1- (4- Fluorophenyl ) -3-{[2- (4- Fluorophenyl )-2- Hydroxyethyl ] Thio }-4- Oxoazetidine -2 days) Phenoxy ] Acetyl} amino) -2- Phenylacetyl ] -L-aspartic acid

(2R)-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4- Oxoazetidin-2-yl) phenoxy] acetyl} amino) (phenyl) acetic acid (0.020 g, 0.032 mmol), di-t-butyl L-aspartate hydrochloride (0.011 g, 0.039 mmol) and N- Methyl-morpholine (0.010 g, 0.097 mmol) was dissolved in CH ₂ Cl ₂ (3 mL). After 5 minutes, TBTU (0.014 g, 0.042 mmol) was added. After 1 hour complete conversion to the corresponding t-butyl ester was achieved. The reaction mixture was purified on silica gel and eluted with EtOAc / CH ₂ Cl ₂ (25/75). Pure fractions were collected and concentrated. The residue was dissolved in 3 ml CH ₂ Cl ₂ and 1 ml TFA. The reaction mixture was stirred for 2 hours and the resulting acid was concentrated. The remaining traces of TFA were azeotropically removed by co-evaporation with toluene (3 mL). Crude acid was dissolved in MeOH (3 mL) and NaBH ₄ (0.005 g, 0.130 mmol) was added. After 5 minutes complete conversion to the corresponding alcohol took place. The reaction was quenched by addition of 0.1 M NH ₄ OAc buffer (2 mL). After purification by preparative HPLC using 10% to 40% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent, the pure fractions were freeze-dried to afford the title compound as a colorless solid (0.018 g, 76 %). M / z: 715.7 (M-18). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 2.00-2.08 (m, 1H), 2.31-2.50 (m, 1H), 2.88-2.94 (m, 2H), 4.18-4.22 (m, 1H ), 4.27-4.30 (m, 1H), 4.60-4.78 (m, 3H), 5.03-5.08 (m, 1H), 5.55-5.65 (m, 1H), 6.94-7.40 (m, 17H), 8.22-8.39 (m, 1 H), 8.50-8.59 (m, 1 H).

Example 16

N-[(2R) -2-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl ] Thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} amino) -2-phenylacetyl] -D-valine

(2R)-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4- Oxoazetidin-2-yl) phenoxy] acetyl} amino) (phenyl) acetic acid (0.010 g, 0.016 mmol), t-butyl D-valinate hydrochloride (0.004 g, 0.020 mmol) and N-methyl-mor Pauline (0.005 g, 0.049 mmol) was dissolved in CH ₂ Cl ₂ (3 mL). After 5 minutes, TBTU (0.007 g, 0.021 mmol) was added. After 1 hour complete conversion to the corresponding t-butyl ester was achieved. The reaction mixture was purified on silica gel and eluted with EtOAc / CH ₂ Cl ₂ (25/75). Pure fractions were collected and concentrated. The residue was dissolved in 3 ml of CH ₂ Cl ₂ and 0.5 ml of TFA. The reaction mixture was stirred for 1.5 hours and concentrated. The remaining traces of TFA were azeotropically removed by co-evaporation with toluene (3 mL). Crude acid was dissolved in MeOH (2 mL) and NaBH ₄ (0.002 g, 0.065 mmol) was added. After 5 minutes complete conversion to the corresponding alcohol took place. The reaction was quenched by addition of 0.1 M NH ₄ OAc buffer (2 mL). Purification by preparative HPLC using 20% to 50% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as mobile phase, followed by freeze-drying of the pure fractions to give the title compound as a colorless solid (0.004 g, 34 %). M / z: 716.6 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 0.81-0.85 (m, 6H), 1.98-2.09 (m, 1H), 2.88-2.93 (m, 2H), 3.92-3.98 (m, 1H ), 4.22-4.30 (m, 1H), 4.60 (d, 1H), 4.64 (d, 1H), 4.70-4.78 (m, 1H), 5.02-5.07 (m, 1H), 5.62 (d, 1H), 6.94-7.40 (m, 17 H), 8.18-8.22 (m, 1 H), 8.52 (d, 1 H).

Example  17

N-[(2R) -2-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl ] Thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} amino) -2-phenylacetyl] -L-valine

(2R)-({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4- Oxoazetidin-2-yl) phenoxy] acetyl} amino) (phenyl) acetic acid (0.020 g, 0.032 mmol), t-butyl L-valinate hydrochloride (0.008 g, 0.039 mmol) and N-methyl-mor Pauline (0.010 g, 0.097 mmol) was dissolved in CH ₂ Cl ₂ (4 mL). After 5 minutes, TBTU (0.014 g, 0.042 mmol) was added. After 1 hour complete conversion to the corresponding t-butyl ester was achieved. The reaction mixture was purified on silica gel and eluted with EtOAc / CH ₂ Cl ₂ (25/75). Pure fractions were collected and concentrated. The residue was dissolved in 3 ml CH ₂ Cl ₂ and 1 ml TFA. The reaction mixture was stirred for 1.5 hours and concentrated. The remaining traces of TFA were azeotropically removed by co-evaporation with toluene (3 mL). Crude acid was dissolved in MeOH (3 mL) and NaBH ₄ (0.005 g, 0.130 mmol) was added. After 5 minutes complete conversion to the corresponding alcohol took place. The reaction was quenched by addition of 0.1 M NH ₄ OAc buffer (2 mL). After purification by preparative HPLC using 20% to 50% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent, the pure fractions were freeze-dried to afford the title compound as a colorless solid (0.011 g, 47). %). M / z: 716.5 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 0.60 (d, 3H), 0.68 (d, 3H), 1.95-2.05 (m, 1H), 2.88-2.94 (m, 2H), 4.00- 4.08 (m, 1H), 4.27-4.30 (m, 1H), 4.61 (d, 1H), 4.64 (d, 1H), 4.70-4.78 (m, 1H), 5.02-5.09 (m, 1H), 5.64- 5.75 (m, 1 H), 6.94-7.44 (m, 17 H), 8.39-8.45 (m, 1 H), 8.50-8.58 (m, 1 H).

Example 18

N-((2R) -2-{[(4-{(2R, 3R) -3-[(2-hydroxy-2-phenylethyl) thio] -4-oxo-1-phenylazetidine-2- Phenoxy) acetyl] amino} -2-phenylacetyl) -L-serine

[4-((2R, 3R) -3-{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} -4-oxo-1-phenylazetidine -2-yl) phenoxy] acetic acid (0.030 g, 0.056 mmol), t-butyl N-[(2R) -2-amino-2-phenylacetyl] -O- (t-butyl) -L-serinate (0.024 g, 0.068 mmol) and N-methyl-morpholine (0.017 g, 0.169 mmol) were dissolved in CH ₂ Cl ₂ (5 mL). After 5 minutes, TBTU (0.023 g, 0.073 mmol) was added. After 1 hour complete conversion to the corresponding t-butyl ester was achieved. The reaction mixture was purified on silica gel and eluted with EtOAc / CH ₂ Cl ₂ (25/75). Pure fractions were collected and concentrated. The residue was dissolved in 3 ml CH ₂ Cl ₂ and 1 ml TFA. The reaction mixture was stirred overnight and concentrated. The remaining traces of TFA were azeotropically removed by co-evaporation with toluene (3 mL). Crude acid was dissolved in MeOH (4 mL) and NaBH ₄ (0.009 g, 0.225 mmol) was added. After 5 minutes complete conversion to the corresponding alcohol took place. The reaction was quenched by addition of 0.1 M NH ₄ OAc buffer (2 mL). Purification by preparative HPLC using 20% to 50% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as mobile phase, followed by freeze-drying of the pure fractions to give the title compound as a colorless solid (0.022 g, 58 %). M / z: 668.5 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 2.89-2.94 (m, 2H), 3.30-3.35 (m, 1H), 3.46-3.50 (m, 1H), 3.94-4.00 (m, 1H ), 4.25-4.27 (m, 1H), 4.60 (d, 1H), 4.65 (d, 1H), 4.69-4.77 (m, 1H), 5.00-5.05 (m, 1H), 5.59-5.66 (m, 1H ), 6.94-7.39 (m, 19 H), 8.20-8.25 (m, 1 H), 8.50-8.58 (m, 1 H).

Example 19

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -D-alanyl-D-valine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} -D-alanine (0.040 g, 0.072 mmol) was dissolved in CH ₂ Cl ₂ (5 mL). t-butyl D-valinate hydrochloride (0.018 g, 0.087 mmol), N-methylmorpholine (0.022 g, 0.216 mmol) and TBTU (0.030 g, 0.094 mmol) were added. After 1.5 hours, t-butyl ester was obtained. The reaction mixture was purified on silica gel and eluted with EtOAc / CH ₂ Cl ₂ (25/75). Pure fractions were collected and concentrated. The residue was dissolved in CH ₂ Cl ₂ (4 mL) and TFA (1 mL). The reaction mixture was stirred for 3 hours and concentrated. Crude acid was dissolved in MeOH (4 mL) and NaBH ₄ (0.011 g, 0.289 mmol) was added. After 5 minutes complete conversion to the corresponding alcohol took place. The reaction was quenched by addition of 0.1 M NH ₄ OAc buffer (1 mL). The reaction mixture was concentrated and the residue was purified by preparative HPLC using 20% to 50% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent. This gave the title compound as a colorless solid (0.039 g, 82%). M / z: 654.5 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 0.79 (d, 6H), 1.21 (d, 3H), 1.96-2.05 (m, 1H), 2.85-2.95 (m, 2H), 3.91- 3.97 (m, 1H), 4.22-4.29 (m, 1H), 4.35-4.42 (m, 1H), 4.48 (d, 1H), 4.53 (d, 1H), 4.70-4.78 (m, 1H), 5.02- 5.04 (m, 1 H), 6.94-7.36 (m, 12 H), 7.70-7.77 (m, 1 H), 8.15 (d, 1 H).

Example 20

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -D-alanyl-D-alanine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} -D-alanine (0.040 g, 0.072 mmol) was dissolved in CH ₂ Cl ₂ (5 mL). t-butyl D-alanineate hydrochloride (0.016 g, 0.087 mmol), N-methylmorpholine (0.022 g, 0.216 mmol) and TBTU (0.030 g, 0.094 mmol) were added. After 1.5 hours, complete conversion to t-butyl ester was achieved. The reaction mixture was purified on silica gel and eluted with EtOAc / CH ₂ Cl ₂ (25/75). Pure fractions were collected and concentrated. The residue was dissolved in CH ₂ Cl ₂ (3 mL) and TFA (1 mL). After 2 hours complete conversion to acid at room temperature was achieved. The reaction mixture was concentrated and the remaining traces of TFA were azeotropically removed by co-evaporation with toluene (3 mL). Crude acid was dissolved in MeOH (3 mL) and NaBH ₄ (0.011 g, 0.289 mmol) was added. After 5 minutes complete conversion to the corresponding alcohol took place. The reaction was quenched by addition of 0.1 M NH ₄ OAc buffer (1 mL). The reaction mixture was concentrated and the residue was purified by preparative HPLC using 20% to 50% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as mobile phase. Pure fractions were freeze-dried to afford the title compound as a colorless solid (0.039 g, 86%). M / z: 626.4 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 1.17-1.22 (m, 6H), 2.82-2.96 (m, 2H), 3.90-3.98 (m, 1H), 4.25-4.35 (m, 2H ), 4.48-4.54 (m, 2H), 4.70-4.78 (m, 1H), 5.02-5.06 (m, 1H), 6.94-7.37 (m, 12H), 7.85-7.92 (m, 1H), 8.16 (d , 1H).

Example 21

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -D-alanyl-D-lysine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} -D-alanine (0.040 g, 0.072 mmol) was dissolved in CH ₂ Cl ₂ (5 mL). t-butyl N ^6- (t-butoxycarbonyl) -D-lysinate hydrochloride (0.029 g, 0.087 mmol), N-methylmorpholine (0.022 g, 0.216 mmol) and TBTU (0.030 g, 0.094 mmol) Was added. After 1.5 hours, complete conversion to ester took place. The reaction mixture was purified on silica gel and eluted with EtOAc / CH ₂ Cl ₂ (25/75). Pure fractions were collected and concentrated. The residue was dissolved in CH ₂ Cl ₂ (3 mL) and TFA (1 mL) and stirred overnight to form the corresponding acid. The reaction mixture was concentrated and the remaining traces of TFA were azeotropically removed by co-evaporation with toluene (3 mL). Crude acid was dissolved in MeOH (3 mL) and NaBH ₄ (0.011 g, 0.288 mmol) was added. After 5 minutes, the reduction reaction was complete. The reaction was quenched by addition of 0.1 M NH ₄ OAc buffer (1 mL). The mixture was concentrated and the residue was purified by preparative HPLC using 10% to 50% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent. Pure fractions were freeze-dried to afford the title compound as a colorless solid (0.039 g, 79%). M / z: 685.1. ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 1.21 (d, 3H), 1.22-1.69 (m, 6H), 2.62-2.70 (m, 2H), 2.82-2.93 (m, 2H), 3.78-3.84 (m, 1H), 4.22-4.33 (m, 2H), 4.48 (d, 1H), 4.52 (d, 1H), 4.70-4.78 (m, 1H), 5.01-5.06 (m, 1H), 6.95-7.37 (m, 12H), 7.56-7.63 (m, 1H), 8.27 (d, 1H).

Example 22

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -D-valyl-D-serine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} -D-valine (11 mg, 18.9 μmol) was dissolved in DCM (2 mL). t-butyl O- (t-butyl) -D-serineate hydrochloride (6.3 mg, 24.8 μmol) and N-methylmorpholine (10 μl, 91 μmol) were added. After 5 minutes, TBTU (8.2 mg, 25.5 μmol) was added and the reaction mixture of white suspension was stirred overnight. It was confirmed that an ester was formed. M / z: 780.5 (M−H). The solvent was removed under reduced pressure. The residue was dissolved in formic acid (1 mL) and stirred at 50 ° C. and overnight at room temperature for 5 hours. LC-MS analysis revealed that a formicate adduct of the product was formed. M / z: 698.24 (M + H) and 696.19 (MH). Formic acid was removed under reduced pressure and toluene (3 × 1 mL) was used to assist in the removal. The yellowish oily residue was dissolved in methanol (1 mL) and triethylamine (150 μL, 0.12 mmol) was added. The reaction mixture was stirred for 1 hour. Formiate hydrolyzed; M / z: 670.1 (M + H) and 668.0 (M-1). Sodium borohydride (8.4 mg, 0.22 mmol) was added to the methanol solution. The mixture was stirred for 5 minutes. Ammonium acetate (7 mg) was added and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC on C8 column. A gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. After freeze-drying, the title compound was obtained as a white solid (3.8 mg, 30%). H-NMR (400 MHz, DMS-d ₆ ): 0.80 (m, 6H), 1.95-2.05 (m, 1H), 2.87-2.93 (m, 2H), 3.46-3.60 (m, 2H), 3.86 (brs , 1H), 4.19-4.32 (m, 2H), 4.59 (br, 2H), 4.69-4.77 (m, 1H), 5.05 (m, 1H), 6.96 (d, 2H), 7.06-7.18 (m, 4H ), 7.20-7.26 (m, 2H), 7.30-7.39 (m, 4H), 7.70-7.77 (brs, 1H), 7.96-8.01 (d, 1H). M / z: 670.1 (M−H).

Example 23

N-{[4-((2R, 3R) -1- (4- Fluorophenyl ) -3-{[2- (4- Fluorophenyl )-2- Hydroxyethyl ] Thio }-4- Oxoazetidine -2 days) Phenoxy ] Acetyl} glycid-D-valine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyl-D-valine (0.022 g, 0.034 mmole) was dissolved in methanol (2 mL). NaBH ₄ (0.0025 g, 0.066 mmole) was added and a few drops of acetic acid were added when the reaction was completed by LC-MS. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on Kromasil C8-column using 35% MeCN in 0.1 M ammonium acetate buffer as eluent. After freeze-drying, 0.015 g (68%) of the title compound were obtained. NMR (400 MHz, CD ₃ COOD) 0.90 (d, 3H), 0.93 (d, 3H), 2.10-2.20 (m, 1H), 2.90-3.06 (m, 2H), 3.99 (s, 2H), 4.03 ( d, 0.5H), 4.05 (d, 0.5H), 4.27-4.34 (m, 1H), 4.60 (s, 2H), 4.79-4.84 (m, 1H), 4.89 (d, 0.5H), 4.91 (d , 0.5H), 6.95-7.03 (m, 4H), 7.06 (d, 2H), 7.25-7.30 (m, 2H); 7.30-7.37 (m, 4H).

Example 24

(2R) -cyclohexyl [(N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl ] Thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl) amino] acetic acid

(2R) -cyclohexyl [(N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] Thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl) amino] acetic acid (0.0085 g, 0.013 mmole) was dissolved in methanol (2 mL). NaBH ₄ (0.006 g, 0.159 mmole) was added and a few drops of acetic acid were added when the reaction was complete according to LC-MS. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC on Kromasil C8-column using MeCN in 0.1 M ammonium acetate buffer in gradual gradient order of 35%, 40% and 50%. After lyophilization, 0.007 g (82%) of the title product were obtained. NMR (500 MHz, CD ₃ COOD) 1.05-1.33 (m, 5H), 1.60-1.87 (m, 6H), 2.91-3.07 (m, 2H), 3.94-4.06 (m, 3H), 4.32 (d, 1H ), 4.60 (s, 2H), 4.79-4.86 (m, 1H), 4.90 (d, 0.5H), 4.92 (d, 0.5H), 6.96-7.03 (m, 4H), 7.03-7.08 (brd, 2H) ), 7.25-7.31 (m, 2H), 7.31-7.38 (m, 4H)

Example 25

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-3- (trimethylsilyl) alanine

Ethyl 3- (trimethylsilyl) alanine (20 mg, 0.106 mmol) was dissolved in 1.5 mL Et ₃ N, 0.2 mL MeOH and 0.2 mL H ₂ O and stirred for 5 days. The solvent was evaporated at 40 ° C. under reduced pressure. 1 ml of Et ₃ N was added and evaporated.

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycine (20 mg, 0.037 mmol) was dissolved in 1.5 ml anhydrous DMF. N-methylmorpholine (0.010 mL, 0.109 mmol) and TBTU (15 mg, 0.047 mmol) were added and the mixture was stirred for 1.5 h. Et ₃ N-salts of the hydrolyzed amino acids were added and the mixture was stirred for 3 hours. After adding a few drops of water, the mixture was stirred for 15 minutes. MeOH (2 mL) and NaBH ₄ (about 15 mg) were added. After 15 minutes, about 20 mg of NH ₄ Ac was added. The mixture was left overnight and purified using preparative HPLC on a C8 column. A gradient of 20% to 50% MeCN in 0.1 M ammonium acetate was used as the mobile phase. Pure product fractions were collected and lyophilized. Mass: 14.5 mg. The solid was placed in a vacuum oven at 40 ° C. for 5 hours. M / z: 684 (M-1). NMR (400 MHz, DMSO-d ₆ ): 8.23 (t, 1H), 7.88-7.98 (m, 1H), 7.30-7.38 (m, 4H), 7.20-7.25 (m, 2H), 7.05-7.18 (m , 4H), 6.98 (d, 2H), 5.02-5.07 (m, 1H), 4.67-4.76 (m, 1H), 4.51 (s, 2H), 4.24-4.33 (m, 1H), 4.05-4.15 (m , 1H), 3.65-3.80 (m, 2H), 2.82-2.98 (m, 2H), 0.85-1.03 (m, 2H), 0.04 (s, 9H).

Example 26

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-tyrosine

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- {4- [N- in DCM (2 mL) (Carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one (0.0227 g, 0.042 mmole), (R) -tyrosine t-butylester (0.0144 g, 0.061 mmole), N-methylmorpholine (0.012 Ml, 0.111 mmole) was stirred at room temperature. TBTU (0.018 g, 0.056 mmole) was added and the mixture was stirred overnight. Trifluoroacetic acid (0.65 mL) was added and hydrolysis was complete after 2 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on Kromasil C8-column using a 5% to 100% gradient of MeCN in 0.15% trifluoroacetic acid buffer as eluent. After removal of solvent under reduced pressure, compound (M / z 704.1) was dissolved in methanol (2 mL). NaBH ₄ (0.004 g, 0.105 mmole) was added and a few drops of acetic acid were added when the reaction was complete. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on Kromasil C8-column using 35% MeCN in 0.1 M ammonium acetate buffer as eluent. After freeze-drying, 0.021 g (71%) of the title product were obtained. NMR (400 MHz, CD ₃ COOD) 2.85-3.10 (m, 4H), 3.90 (ABq, 2H), 4.03 (d, 0.5H), 4.05 (d, 0.5H), 4.51 (dd, 1H), 4.55 ( ABq, 2H), 4.79-4.84 (m, 1H), 4.89 (d, 0.5H), 4.90 (d, 0.5H), 6.62-6.67 (m, 2H), 6.95-7.05 (m, 8H), 7.25- 7.37 (m, 6H)

Example 27

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-proline

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- {4- [N- in DCM (2 mL) (Carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one (0.0197 g, 0.036 mmole), (R) -proline t-butylester (0.0118 g, 0.069 mmole), N-methylmorpholine (0.012 Ml, 0.111 mmole) was stirred at room temperature. TBTU (0.018 g, 0.056 mmole) was added and the mixture was stirred overnight. Trifluoroacetic acid (0.65 mL) was added and after 2 hours the hydrolysis was complete. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on Kromasil C8-column using a 5% to 100% gradient of MeCN in 0.15% trifluoroacetic acid buffer as eluent. After removal of solvent under reduced pressure, compound (M / z 638.08) was dissolved in methanol (2 mL). NaBH ₄ (0.004 g, 0.106 mmole) was added and a few drops of acetic acid were added when the reaction was complete. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on Kromasil C8-column using 35% MeCN in 0.1 M ammonium acetate buffer as eluent. After freeze-drying, 0.020 g (85%) of the title product were obtained. NMR (400 MHz, CD ₃ COOD) 1.80-1.94 (m, 1H), 1.94-2.10 (m, 1.5H), 2.12-2.35 (m, 1.5H), 2.90-3.06 (m, 2H), 3.49-3.67 (m, 2H), 3.85 (d, 0.5H), 4.00-4.07 (m, 1.5H), 4.14-4.24 (m, 1H), 4.35 (dd, 0.5H), 4.41 (brd, 0.5H), 4.57 (s, 1H), 4.59 (s, 1H), 4.78-4.84 (m, 1H), 4.89 (d, 0.5H), 4.91 (d, 0.5H), 6.95-7.08 (m, 6H), 7.25-7.38 (m, 6 H).

Example 28

N-{[4-((2R, 3R) -1- (4- Fluorophenyl ) -3-{[2- (4- Fluorophenyl )-2- Hydroxyethyl ] Thio }-4- Oxoazetidine -2 days) Phenoxy ] Acetyl} Glysyl-L-threonine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyl-L-threonine (0.014 g, 0.022 mmole) was dissolved in methanol (2 mL). NaBH ₄ (0.003 g, 0.079 mmole) was added and a few drops of acetic acid were added when the reaction was complete. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on Kromasil C8-column using 35% MeCN in 0.1 M ammonium acetate buffer as eluent. After freeze-drying, 0.012 g (85%) of the title product were obtained. NMR (400 MHz, CD ₃ COOD) 1.14 (d, 3H), 2.91-3.07 (m, 2H), 4.00-4.08 (m, 3H), 4.21-4.30 (m, 1H), 4.35 (d, 1H), 4.60 (s, 2H), 4.78-4.85 (m, 1H), 4.89 (d, 0.5H), 4.91 (d, 0.5H), 6.96-7.03 (m, 4H), 7.04-7.08 (m, 2H), 7.24-7. 38 (m, 6 H).

Example 29

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-lysine

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- {4- [N- in DCM (2 mL) (Carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one (0.0209 g, 0.039 mmole), t-butyl N ^6- (t-butoxycarbonyl) -D-lysinate hydrochloride (0.0205 g , 0.060 mmole), and a mixture of N-methylmorpholine (0.012 mL, 0.111 mmole) were stirred at room temperature. TBTU (0.018 g, 0.056 mmole) was added and the mixture was stirred overnight. Trifluoroacetic acid (0.65 mL) was added and after 2 hours the hydrolysis was complete. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on Kromasil C8-column using a 5% to 100% gradient of MeCN in 0.15% trifluoroacetic acid buffer as eluent. After removal of solvent under reduced pressure, compound (M / z 669.13) was dissolved in methanol (2 mL). NaBH ₄ (0.005 g, 0.132 mmole) was added and a few drops of acetic acid were added when the reaction was complete. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on Kromasil C8-column using 35% MeCN in 0.1 M ammonium acetate buffer as eluent. After freeze-drying, 0.020 g (83%) of the title product were obtained. NMR (400 MHz, CD ₃ COOD) 1.34-1.47 (m, 2H), 1.56-1.74 (m, 3H), 1.84-1.84-1.93 (m, 1H), 2.84-3.07 (m, 4H), 3.94 (ABq , 2H), 4.02 (d, 0.5H), 4.05 (d, 0.5H), 4.27 (dd, 1H), 4.61 (s, 2H), 4.79-4.85 (m, 1H), 4.90 (d, 0.5H) , 4.91 (d, 0.5H), 6.95-7.08 (m, 6H), 7.24-7.38 (m, 6H).

Example 30

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-L-asparagine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyl-L-asparagine (0.020 g, 0.031 mmole) was dissolved in methanol (2 mL). NaBH ₄ (0.004 g, 0.106 mmole) was added and a few drops of acetic acid were added when the reaction was complete according to LC-MS. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on Kromasil C8-column using 35% MeCN in 0.1 M ammonium acetate buffer as eluent. After freeze-drying, 0.016 g (80%) of the title product were obtained. NMR (400 MHz, CD ₃ COOD) 2.62 (dd, 1H), 2.73 (dd, 1H), 2.90-3.07 (m, 2H), 3.89-4.08 (m, 3H), 4.55 (dd, 1H), 4.60 ( ABq, 2H), 4.78-4.85 (m, 1H), 4.90 (d, 0.5H), 4.92 (d, 0.5H), 6.96-7.09 (m, 6H), 7.24-7.38 (m, 6H).

Example 31

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-L-methionine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyl-L-methionine (0.015 g, 0.022 mmole) was dissolved in methanol (2 mL). NaBH ₄ (0.004 g, 0.106 mmole) was added and a few drops of acetic acid were added when the reaction was complete. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on Kromasil C8-column using 35% MeCN in 0.1 M ammonium acetate buffer as eluent. After freeze-drying, 0.015 g (99%) of the title product were obtained. NMR (400 MHz, CD ₃ COOD) 1.86-2.00 (m, 1H), 2.04 (s, 3H), 2.07-2.18 (m, 1H), 2.45-2.51 (m, 2H), 2.90-3.08 (m, 2H ), 3.97 (s, 2H), 4.04 (d, 0.5H), 4.06 (d, 0.5H), 4.36-4.43 (m, 1H), 4.60 (s, 2H), 4.77-4.85 (m, 1H), 4.90 (d, 0.5H), 4.92 (d, 0.5H), 6.95-7.08 (m, 6H), 7.25-7.38 (m, 6H).

Example 32

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2-hydroxy-2- (4-methoxyphenyl) ethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-valine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-methoxyphenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyl-D-valine (0.015 g, 0.023 mmole) was dissolved in methanol (3 mL). NaBH ₄ (0.006 g, 0.158 mmole) was added and a few drops of acetic acid were added when the reaction was complete. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on Kromasil C8-column using 25% MeCN in 0.1 M ammonium acetate buffer as eluent. After freeze-drying, 0.014 g (93%) of the title product were obtained. NMR (500 MHz, CD ₃ COOD) 0.93 (d, 3H), 0.95 (d, 3H), 2.12-2.22 (m, 1H), 2.91-3.07 (m, 2H), 3.75 (s, 1.5H), 3.76 (s, 1.5H), 3.94-4.06 (m, 3H), 4.33 (d, 1H), 4.60 (s, 2H), 4.72-4.78 (m, 1H), 4.81-4.88 (m, 1H), 6.79- 6.83 (m, 2 H), 6.97-7.08 (m, 4 H), 7.20-7.36 (m, 6 H).

Example 33

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-leucine

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- {4- [N- in DCM (2 mL) (Carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one (0.015 g, 0.028 mmole), t-butyl D-rushinate hydrochloride (0.010 g, 0.045 mmole), N-methylmorpholine (0.0092 Ml, 0.083 mmole) was stirred at room temperature. TBTU (0.012 g, 0.037 mmole) was added and the mixture was stirred overnight. After 2 hours of addition of trifluoroacetic acid (1.0 mL), the solvent was removed under reduced pressure and the residue was Kromasil C8- using a 5% to 100% gradient of MeCN in 0.15% trifluoroacetic acid buffer as eluent. Purification by preparative HPLC on the column. After removal of solvent under reduced pressure, compound (M / z 654.25) was dissolved in methanol (2 mL). NaBH ₄ (0.005 g, 0.132 mmole) was added and the mixture was stirred for 5 minutes. After adding a few drops of acetic acid and removing the solvent under reduced pressure, the residue was purified by preparative HPLC on Kromasil C8-column using 35% MeCN in 0.1 M ammonium acetate buffer as eluent. After freeze-drying, 0.014 g (76%) of the title product were obtained. NMR (400 MHz, CD ₃ COOD) 0.90-0.94 (m, 6H), 1.52-1.74 (m, 3H), 2.90-3.07 (m, 2H), 3.97 (s, 2H), 4.02 (d, 0.5H) , 4.04 (d, 0.5H), 4.40 (d, 0.5H), 4.42 (d, 0.5H), 4.59 (s, 2H), 4.78-4.84 (m, 1H), 4.89 (d, 0.5H), 4.91 (d, 0.5H), 6.95-7.08 (m, 6H), 7.24-7.37 (m, 6H).

Example 34

N- {4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2-hydroxy-2- (4-methoxyphenyl) ethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyl-D-lysine

N- {4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-methoxyphenyl) -2-oxoethyl] thio}-in DCM (2 mL) 4-oxoazetidin-2-yl} phenoxy] acetyl} glycine (0.0177 g, 0.032 mmol), t-butyl N ^6- (t-butoxycarbonyl) -D-lysinate hydrochloride (0.0141 g, .. 0.042 mmol), N- methylmorpholine (0.0106 ㎖, 0.096 mmol) was stirred at room temperature was added TBTU (0.013 g, 0.042 mmol) , the mixture was stirred for 2 hours, addition of t- butyl-N ⁶ - (t-butoxycarbonyl) -D-lysinate hydrochloride (0.004 g, 0.012 mmol) was added after 0.5 h TBTU (0.008 g, 0.025 mmol) was added and the mixture was stirred for an additional 10 minutes. Trifluoroacetic acid (0.65 mL) was added and after 3 hours the solvent was removed under reduced pressure The residue was taken up in a preparative HPLC (0.15% 1M ammonium acetate buffer in a 5% to 100% gradient of MeCN in Kromasil C8-column). Used as eluent) It was purified. The solvent was removed under reduced pressure to give the intermediate (M / z 681.4) was dissolved in methanol (3 ㎖). Was added _{NaBH 4 (0.008 g, 0.211 mmol} ), acetic acid a few drops when the reaction is complete The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on Kromasil C8-column (using 35% gradient MeCN in 0.1 M ammonium acetate buffer as eluent), followed by 0.020 g (freeze drying). 91%) of the title compound were obtained. NMR (500 MHz, CD ₃ COOD) 1.41-1.52 (m, 2H), 1.58-1.78 (m, 3H), 1.90-2.02 (m 1H), 2.86-3.08 (m, 4H), 3.76 (s, 1.5H ), 3.77 (s, 1.5H), 3.90-4.06 (m, 3H), 4.48 (dd, 1H), 4.60-4.62 (m, 2H), 4.73-4.78 (m, 1H), 4.83-4.89 (m, 1H), 6.80-6.84 (m, 2H), 6.98-7.08 (m, 4H), 7.21-7.31 (m, 4H), 7.31-7.36 (m, 2H), 8.20 (d, NH), 8.54 (t, NH).

Example 35

N ² -{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetine -2-yl) phenoxy] acetyl} -L-glutaminyl-D-phenylalanine

N ² -{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxo Azetin-2-yl) phenoxy] acetyl} -L-glutamine (15 mg, 0.0244 mmol), t-butyl D-phenylalanine hydrochloride (8 mg, 0.0310 mmol) and N-methylmorpholine (10 Mg, 0.099 mmol) was dissolved in methylene chloride (0.5 mL). TBTU (10 mg, 0.0313 mmol) was added and the mixture was stirred at rt for 1 h. The solvent was evaporated and the residue was dissolved in formic acid (0.5 mL). The mixture was heated to 45 ° C. to 50 ° C. and stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure. Methanol (5 mL) was added and evaporated. The residue was dissolved in methanol (1 mL). Two drops of TFA were added and the mixture was stirred at rt overnight. The solvent was evaporated and the residue was purified by preparative HPLC (acetonitrile / ammonium acetate (40:60) buffer as eluent). After freeze drying, 12 mg (64%) of the title compound were obtained. ¹ H-NMR, 300 MHz, DMSO): 1.55-1.97 (m, 4H), 2.77-3.10 (m, 4H), 4.20-4.38 (m, 3H), 4.49 (s, 2H), 4.66-4.78 (m , 1H), 4.99-5.07 (m, 1H), 6.70 (s, 1H), 6.88-7.40 (m, 19H), 8.00-8.20 (m, 1H).

Example 36

N ² -{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetine -2-yl) phenoxy] acetyl} -L-glutaminyl-D-tyrosine

N ² -{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxo Azetin-2-yl) phenoxy] acetyl} -L-glutamine (22 mg, 0.0359 mmol), t-butyl D-tyrosinate hydrochloride (10 mg, 0.0421 mmol) and N-methylmorpholine (14 mg , 0.138 mmol) was dissolved in methylene chloride (0.5 mL). TBTU (14 mg, 0.0436 mmol) was added and the mixture was stirred at rt overnight. The solvent was evaporated and the residue was dissolved in formic acid (1 mL). The mixture was stirred for 4 h at 45 ° C. to 50 ° C. and then evaporated under reduced pressure. Methanol (10 mL) was added and evaporated. The residue was dissolved in methanol (2 mL). Three drops of TFA were added and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by preparative HPLC (using acetonitrile / ammonium acetate (40:60) buffer as eluent). After freeze drying, 15 mg (54%) of the title compound were obtained. ¹ H-NMR, 300 MHz, DMSO): 1.60-2.00 (m, 4H), 2.69-3.0 (m, 4H), 4.09-4.18 (m, 1H), 4.22-4.35 (m, 3H), 4.49 (s , 2H), 4.65-4.78 (m, 1H), 4.97-5.08 (m, 1H), 6.56 (d, 2H), 6.70 (s, 1H), 6.86-7.40 (m, 18H), 7.77-7.91 (m , 1H), 8.12 (d, 1H), 9.10 (bs, 1H).

Example 37

N-{[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- (4-chlorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidine -2-yl) phenoxy] acetyl} glycyl-3-cyclohexyl-D-alanine

N-{[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- (4-chlorophenyl) -2-oxoethyl] thio} -4-oxoazetidine- 2-yl) phenoxy] acetyl} glycine (20 mg, 0.0349 mmol) and N-methylmorpholine (20 mg, 0.198 mmol) were dissolved in methylene chloride (0.5 mL). TBTU (17 mg, 0.0530 mmol) was added and the mixture was stirred at rt for 15 min. 3-cyclohexyl-D-alanine (9 mg, 0.0526 mmol) was added and stirred at rt for 1 h. The solvent was evaporated and the residue was added to methanol (0.5 mL). NaBH ₄ (10 mg, 0.264 mmol) was added and the mixture was stirred at rt for 15 min. Three drops of acetic acid were added to the reaction mixture. The product was isolated by preparative HPLC (using acetonitrile / ammonium acetate (45:55) buffer as eluent). After freeze drying, 3 mg (12%) of the title compound were obtained. The product was analyzed by LC / micropath Q TO13 micro MS technology. M / z: 728.1973 (mass prediction 728.1964).

Example 38

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-3-cyclohexyl-D-alanine

N-{[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- (4-chlorophenyl) -2-oxoethyl] thio} -4-oxoazetidine- 2-yl) phenoxy] acetyl} glycine (30 mg, 0.0555 mmol) and N-methylmorpholine (30 mg, 0.296 mmol) were dissolved in DMF (0.5 mL). TBTU (23 mg, 0.0717 mmol) was added and the mixture was stirred at rt for 15 min. 3-cyclohexyl-D-alanine (15 mg, 0.0876 mmol) was added and stirred at rt for 1 h. The solvent was evaporated and the residue was added to methanol (1 mL). NaBH ₄ (10 mg, 0.264 mmol) was added and the mixture was stirred at rt for 10 min. Three drops of acetic acid were added to the reaction mixture. The product was isolated by preparative HPLC (using acetonitrile / ammonium acetate (45:60) buffer as eluent). After freeze drying, 19 mg (49%) of the title compound were obtained. ¹ H-NMR (300 MHz, DMSO): 0.68-0.93 (m, 2H), 1.0-1.75 (m, 11H), 2.78-3.00 (m, 2H), 3.73 (s, 2H), 4.00-4.14 (m , 1H), 4.23-4.35 (m, 1H), 4.51 (s, 2H), 4.65-4.78 (m, 1H), 4.99-5.09 (m, 1H), 6.90-7.44 (m, 12H), 7.72-7.86 (m, 1 H), 8.26 (t, 1 H).

Example 39

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-jade Pediatric zetidin-2-yl) phenoxy] acetyl} glycyl-L-phenylalanine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-L-phenylalanine (7 mg, 0.010 mmol) was dissolved in 1.5 mL of MeOH and NaBH ₄ (2 mg, 0.053 mmol) was added. The mixture was stirred for 30 minutes and quenched with excess NH ₄ Ac. LC / MS showed about 15% of starting material. The mixture was diluted with H ₂ O and purified using preparative chromatography on C8 column (25 × 200 mm). A gradient of 20% to 40% MeCN in 0.1 M ammonium acetate was used as the mobile phase. Product fractions were collected and partially concentrated. The mixture was lyophilized to give 2 mg (29%). M / z: 688 (M-1). NMR (400 MHz, MeOD): 6.95-7.36 (m, 17H), 4.90 (dd, 1H), 4.53-4.59 (m, 4H), 4.03 (dd, 1H), 3.90 (q, 2H), 3.17 (dd , 1H), 2.90-3.05 (m, 3H).

Example 40

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-4-methylleucine

t-butyl N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4- Oxoazetidin-2-yl) phenoxy] acetyl} glycyl-4-methyllucisinate (about 26 mg, 0.036 mmol) was dissolved in 1.5 ml formic acid and heated at 40 ° C. for 1.5 hours. Formic acid was evaporated under reduced pressure. Intermediate acid was confirmed by LC / MS analysis. M / z: 668. The crude mixture was dissolved in 2 mL of MeOH. NaBH ₄ (15 mg, 0.40 mmol) was added and the mixture was stirred for 10 minutes. NH ₄ AC (30 mg) was added. The crude mixture was dissolved in 1 ml of water and purified using preparative HPLC on C8 column (50 × 300 mm). A gradient of 20% to 40% MeCN in 0.1 M ammonium acetate buffer was used as the mobile phase. Lyophilization gave 36 mg of a white solid. NMR indicated the presence of water and HOAc. The product was dried at 40 ° C. for 1.5 hours in a vacuum oven. Mass 13 mg (52%). M / z: 668 (M-1). NMR (400 MHz, DMSO): 8.22 (t, 1H), 7.53-7.65 (m, 1H), 7.30-7.38 (m, 4H), 7.20-7.25 (m, 2H), 7.05-7.17 (m, 4H) , 6.98 (d, 2H), 5.02-5.06 (m, 1H), 4.68-4.76 (m, 1H), 4.51 (s, 2H), 4.24-4.32 (m, 1H), 4.01-4.09 (m, 1H) , 3.60-3.77 (m, 2H), 2.82-2.98 (m, 2H), 1.64 (dd, 1H), 1.33 (dd, 1H), 0.83 (s, 9H).

Example 41

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -D-seryl-D-phenylalanine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio in DCM (3 mL) } -4-oxoazetidin-2-yl) phenoxy] acetyl} -D-serine (diastereomeric mixture) (0.008 g, 0.014 mmol), D-phenylalanine t-butyl ester hydrochloride (0.005 g, 0.018 mmol) and N-methylmorpholine (0.006 mL, 0.055 mmol) solution were stirred at room temperature for 5 minutes. TBTU (0.008 g, 0.025 mmol) was added. After 3 days, the conversion to ester (M / z: 776.1) was completed and the mixture was concentrated under reduced pressure. The residue was dissolved in formic acid (3 mL) and the solution was stirred for 25 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in MeOH (4 mL) and TFA (1 mL). The solution was stirred at 40 ° C. for 6 hours. The solution was removed under reduced pressure. The residue was purified by preparative HPLC (using 20% to 50% gradient of MeCN in 0.1 M ammonium acetate as eluent). After freeze drying, 0.005 g (53% yield) of the title compound were obtained as a white solid. M / z: 720.1. ¹ H NMR (DMSO, 400 MHz): δ 2.78-2.96 (m, 3H), 3.03-3.11 (m, 1H), 3.44-3.60 (m, 2H), 4.20-4.36 (m, 3H), 4.51 (s , 2H), 4.67-4.76 (m, 1H), 5.01-5.06 (m, 1H), 5.70 (bs, HI), 6.90-6.98 (m, 2H), 7.05-7.25 (m, 11H), 7.29-7.37 (m, 4 H), 7.84-8.00 (m, 2 H).

Example 42

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -D-seryl-D-serine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio in DCM (3 mL) } -4-oxoazetidin-2-yl) phenoxy] acetyl} -D-serine (0.008 g, 0.014 mmol), Ot-butyl-D-serine t-butyl ester hydrochloride (0.005 g, 0.018 mmol) And N-methylmorpholine (0.006 mL, 0.055 mmol) solution was stirred for 5 minutes. TBTU (0.008 g, 0.025 mmol) was added. After 3 days, the conversion to ester (M / z: 772.5) was completed and the mixture was concentrated under reduced pressure. The residue was dissolved in formic acid (3 mL) and the solution stirred at rt for 26 h. The mixture was concentrated under reduced pressure and the residue was dissolved in MeOH (4 mL) and TFA (1 mL). The solution was stirred at 40 ° C. for 6 hours. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (using 20% to 50% gradient of MeCN as eluent in 0.1 M ammonium acetate buffer). After freeze drying, 0.005 g (52% yield) of the title compound were obtained as a white solid. M / z: 660.1. ¹ H NMR (DMSO, 400 MHz): δ 2.83-2.95 (m, 2H), 3.42-3.66 (m, 4), 3.91-4.01 (m, 1H), 4.25-4.31 (m, 1H), 4.32-4.39 (m, 1H), 4.54 (ABq, 2H), 4.68-4.76 (m, 1H), 5.02-5.06 (m, 1H), 5.68 (bs, 1H), 6.94-7.00 (m, 2H), 7.05-7.18 (m, 4H), 7.19-7.26 (m, 2H), 7.29-7.39 (m, 4H), 7.74-7.81 (m, 1H), 7.99 (d, 1H).

Example 43

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-2-butylnorleucine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glysil-2-butylnorleucine (0.009 g, 0.012 mmol) was dissolved in MeOH (3 mL). NaBH ₄ (0.007 g, 0.185 mmol) was added and the mixture was stirred for 10 minutes. Ammonium acetate buffer (0.1 M, 3 mL) was added and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC (using 20% to 50% gradient MeCN in 0.1 M ammonium acetate as eluent). After lyophilization, 0.008 g (94% yield) of the title compound were obtained as a white solid. M / z: 712.1. ¹ H NMR (DMSO, 400 MHz): δ 0.73-0.83 (m, 6H), 0.89-1.22 (m, 8H), 1.59-1.71 (m, 2H), 1.94-2.06 (m, 2H), 2.83-2.96 (m, 2H), 3.73 (d, 2H), 4.23-4.28 (m, 1H), 4.51 (s, 2H), 4.68-4.76 (m, 1H), 5.02-5.07 (m, 1H), 5.68 (bs , 1H), 6.94-7.00 (m, 2H), 7.05-7.18 (m, 4H), 7.19-7.26 (m, 2H), 7.29-7.39 (m, 4H), 7.53 (s, 1H), 8.30-8.36 (m, 1 H).

Example 44

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-S-methyl-L-cysteine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} in DCM (5 mL) -4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (0.015 g, 0.028 mmol), t-butyl S-methyl-L-cysteinate (0.014 g, 0.073 mmol) and N-methylmor Pauline (0.012 mL, 0.19 mmol) was stirred for 5 minutes. TBTU (0.013 g, 0.042 mmol) was added. After 20 h the conversion to ester (M / z: 714.1) was completed and the mixture was concentrated under reduced pressure. The residue was dissolved in formic acid (3 mL) and the solution was stirred at 40 ° C. for 22 hours. The mixture was diluted with toluene (2 mL) and the solvent removed again under reduced pressure. The residue was dissolved in MeOH (4 mL) and NaBH ₄ was added in portions (0.035 g total, 0.925 mmol) in portions until the reaction was complete. Ammonium acetate buffer (0.1 M, 3 mL) was added and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC (using 20% to 50% gradient MeCN in 0.1 M ammonium acetate buffer as eluent). After freeze drying, 0.013 g (72% yield) of the title compound were obtained as a white solid. M / z: 660.3. ¹ H NMR (DMSO, 400 MHz): δ 2.66-2.74 (m, 1H), 2.82-3.02 (m, 3H), 3.67-3.82 (m, 2H), 4.02-4.12 (m, 1H), 4.24-4.31 (m, 1H), 4.52 (s, 2H), 4.68-4.77 (m, 1H), 5.01-5.07 (m, 1H), 6.95-7.02 (m, 2H), 7.05-7.18 (m, 4H), 7.19 -7.26 (m, 2H), 7.29-7.40 (m, 4H), 7.73-7.82 (m, 1H), 8.30-8.37 (m, 1H).

Example 45

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-L-isoleucine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} in DCM (5 mL) -4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (0.015 g, 0.028 mmol), L-isoleucine t-butyl ester hydrochloride (0.008 g, 0.036 mmol) and N-methylmorpholine ( 0.012 mL, 0.109 mmol) was stirred for 5 minutes. TBTU (0.012 g, 0.036 mmol) was added. After 22 hours, the conversion to ester (M / z: 710.2) was completed and the mixture was concentrated under reduced pressure. The residue was dissolved in formic acid (3 mL) and the solution was stirred at 40 ° C. for 20 h. The mixture was diluted with toluene (2 mL) and the solvent was removed under reduced pressure. The residue was dissolved in MeOH (4 mL) and NaBH ₄ was added portionwise to the solution (total 0.060 g, 1.59 mmol) until the reaction was complete. Ammonium acetate buffer (0.1 M, 3 mL) was added and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC (using 20% to 50% gradient MeCN in 0.1 M ammonium acetate buffer as eluent). After freeze drying, 0.010 g (57% yield) of the title compound were obtained as a white solid. M / z: 656.2. ¹ H NMR (DMSO, 400 MHz): δ 0.76-0.84 (m, 6H), 1.05-1.17 (m, 1H), 1.32-1.44 (m, 1H), 1.67-1.78 (m, 1H), 2.82-2.95 (m, 2H), 3.78 (d, 2H), 4.03-4.11 (m, 1H), 4.23-4.29 (m, 1H), 4.51 (s, 2H), 4.68-4.77 (m, 1H), 5.01-5 . 07 (m, 1H), 6.94-7.01 (m, 2H), 7.05-7.26 (m, 6H), 7.29-7.39 (m, 4H), 7.79-7.89 (m, 1H), 8.22-8.28 (m, 1H ).

Example 46

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -L-alanyl-D-valine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} in DCM (4 mL) -4-oxoazetidin-2-yl) phenoxy] acetyl} -L-alanine (0.015 g, 0.027 mmol), D-valine t-butyl ester hydrochloride (0.008 g, 0.038 mmol) and N-methylmor Pauline (0.030 mL, 0.272 mmol) was stirred for 5 minutes. TBTU (0.013 g, 0.041 mmol) was added. After 3 h the conversion to ester (M / z: 710. 2) was complete and TFA (3 mL) was added. After 4 hours, the mixture was diluted with toluene (2 mL) and the solvent was removed under reduced pressure. The residue was dissolved in MeOH (4 mL) and NaBH ₄ was added to the solution (0.065 g total, 1.72 mmol) in portions until the reaction was complete. Ammonium acetate buffer 0.1 M, 3 mL) was added and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC (using 20% to 50% gradient MeCN in 0.1 M ammonium acetate buffer as eluent). After lyophilization, 0.014 g (77% yield) of the title compound were obtained as a white solid. M / z: 656.1. ¹ H NMR (DMSO, 400 MHz): δ 0.75-0.83 (m, 6H), 1.22 (d, 3H), 1.95-2.07 (m, 1H), 3.83-3.96 (m, 2H), 3.98-4.06 (m , 1H), 4.24-4.31 (m, 1H), 4.40-4.54 (m, 3H), 4.67-4.76 (m, 1H), 5.01-5.07 (m, 1H), 6.91-7.98 (m, 2H), 7.05 -7.17 (m, 4H), 7.19-7.25 (m, 2H), 7.29-7.39 (m, 4H), 7.84-7.95 (m, 1H), 8.07 (d, 1H).

Example 47

1-[(N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio}- 4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl) amino] cyclopentanecarboxylic acid

1-[(N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4 Oxoazetidin-2-yl) phenoxy] acetyl} glycine (0.015 g, 0.028 mmol), NMM (0.012 mL, 0.109 mmol) and TBTU (0.011 g, 0.034 mmol) at 30 ° C. in DMF (2 milligrams) After 30 minutes, 1-amino-1-cyclopentanecarboxylic acid (0.004 g, 0.030 mmol, 97%) was added and the mixture was diluted with MeOH (2 mL) NaBH ₄ (0.015 g, 0.397). mmol) and the mixture was stirred for 1 hour at 30 ° C. The reaction was quenched with water (0.2 mL) and the mixture was stirred for 10 minutes Ammonium acetate buffer (0.1 M, 3 mL) was added and most of the Methanol was removed under reduced pressure The remaining solution was purified by preparative HPLC (using 20% to 50% gradient MeCN in 0.1 M ammonium acetate buffer as eluent) After freeze drying, the title compound (0.009 g, 49% yield) as a white solid Standing to give ^{M / z:.. 654.0 1} H NMR (DMSO, 400 MHz): δ 1.56-1.66 (m, 4H), 1.78-1.87 (m, 2H), 1.97-2.07 (m, 2H), 2.84- 2.94 (m, 2H), 3.74 (d, 2H), 4.24-4.29 (m, 1H), 4.51 (s, 2H), 4.68-4.76 (m, 1H), 5.02-5.07 (m, 1H), 6.92- 7.00 (m, 2H), 7.05-7.26 (m, 6H), 7.29-7.39 (m, 4H), 8.09-8.15 (m, 2H).

Example 48

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-N-benzylglycine

TBTU (0.011 g, 0.034 mmol) was added N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4- in DMF (2 mL) at 30 ° C). Fluorophenyl) -2-oxoethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (0.015 g, 0.028 mmol) and NMM (0.020 mL, 0.182 mmol) were added to the solution. . After 30 minutes, N-benzylglycine (0.005 g, 0.030 mmol, 98%) was added and the mixture was stirred at 30 ° C. for 1 hour. The reaction was quenched with water (0.2 mL) and the mixture was diluted with MeOH (2 mL). NaBH ₄ (0.015 g, 0.397 mmol) was added and the mixture was stirred for 10 minutes. Ammonium acetate buffer (0.1 M, 3 mL) was added and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC (using 20% to 50% gradient MeCN in 0.1 M ammonium acetate as eluent). After freeze drying, the title compound (0.010 g, 53% yield) was obtained as a white solid. M / z: 690.0. ¹ H NMR (DMSO, 400 MHz): δ 2.83-2.94 (m, 2H), 3.91 (s, 1H), 3.98-4.09 (m, 3H), 4.25-4.29 (m, 1H), 4.50 (s, 2H ), 4.54 (s, 1H), 4.62 (s, 1H), 4.68-4.76 (m, 1H), 5.02-5.07 (m, 1H), 6.92-7.02 (m, 2H), 7.05-7.40 (m, 15H ), 8.14-8.21 (m, 1 H).

Example 49

[(N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4- Oxoazetidin-2-yl) phenoxy] acetyl} glycyl) amino] (diphenyl) acetic acid

TBTU (0.016 g, 0.050 mmol) was dissolved in DMF (2 mL) at 30 ° C. in [(N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- ( 4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (0.020 g, 0.037 mmol) and NMM (0.012 mL, 0.109 mmol) After 30 minutes, 2,2-diphenylglycine (0.009 g, 0.037 mmol, 98%) was added and the mixture was stirred for 2.5 h at 30 ° C. The reaction was quenched with water (0.2 mL). The mixture was diluted with MeOH (2 mL) NaBH ₄ (0.020 g, 0.529 mmol) was added and the mixture was stirred for 10 minutes Ammonium acetate buffer (0.1 M, 3 mL) was added and most of the ethanol was decompressed The remaining solution was purified by preparative HPLC (using 20% to 50% gradient of MeCN in 0.1 M ammonium acetate as eluent). After freeze drying, the title compound (0.012 g, 44% yield). Was obtained as a white solid. : 752.0. ¹ H NMR (DMSO, 400 MHz): δ 2.83-2.95 (m, 2H), 3.75 (d, 2H), 4.24-4.28 (m, 1H), 4.54 (s, 1H), 4.68-4.75 ( m, 1H), 5.02-5.06 (m, 1H), 6.95-7.03 (m, 2H), 7.04-7.38 (m, 20H), 8.43-8.51 (m, 1H), 8.90 (s, 1H).

Example 50

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glyciglycine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyglycine (0.011 g, 0.018 mmol) was dissolved in MeOH (3 mL). NaBH ₄ (0.013 g, 0.344 mmol) was added and the mixture was stirred for 10 minutes. Ammonium acetate buffer (0.1 M, 3 mL) was added and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC (using 20% to 50% gradient MeCN in 0.1 M ammonium acetate as eluent). After freeze drying, the title compound (0.011 g, 97% yield) was obtained as a white solid. M / z: 600.0. ¹ H NMR (DMSO, 400 MHz): 2.97-2.84 (m, 2H), 3.44-3.50 (m, 2H), 3.74 (d, 2H), 4.26-4.32 (m, 1H), 4.46-4.54 (m, 2H), 4.67-4.76 (m, 1H), 5.02-5.07 (m, 1H), 6.95-7.01 (m, 2H), 7.05-7.26 (m, 6H), 7.30-7.40 (m, 4H), 7.60- 7.80 (m, 1 H), 8.32-8.38 (m, 1 H).

Example 51

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-jade Pediatric zetidin-2-yl) phenoxy] acetyl} -D-valyl-L-serine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} -D-valine (6.9 mg, 11.8 μmol) was dissolved in DCM (3 mL). t-butyl O- (t-butyl) -L-serinate hydrochloride (3.7 mg, 14.2 μmol) and N-methylmorpholine (5.5 μl, 50 μmol) were added. After 5 minutes, TBTU (4.6 mg, 14.3 μmol) was added and the reaction mixture was stirred overnight. The formation of esters was confirmed. M / z: 780.57 (M-1). The mixture was extracted between DCM (5 mL) and aqueous KHSO ₄ (5 mL, pH 2). The organic phase was washed with aqueous NaHCO ₃ (5 mL, pH 9). The aqueous phase was extracted with DCM (2x5 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. Formic acid (1.5 mL) was added and the reaction mixture was stirred overnight. Formicate of the intermediate acid was obtained. The solvent was removed under reduced pressure, toluene (3 × 1 mL) was added and evaporated. The residue was dissolved in MeOH (1.5 mL) and triethylamine (90 μl, 0.65 mmol) was added and the reaction mixture was stirred for 1 hour. Sodium borohydride (4.0 mg, 0.11 mmol) was added and the reaction mixture was stirred for 1 hour. Ammonium acetate (15 mg) was added. Solvent was removed under reduced pressure and the residue was purified on HPLC using C8 column. A gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. Lyophilization gave the title compound as a white solid (5.3 mg, 67%). Estimated for C ₃₃ H ₃₅ F ₂ N ₃ O ₈ S HRMS 671.2113, found 672.2192 [M + H] ⁺ .

Example 52

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -D-valylglycine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} -D-valine (11.8 mg, 0.02 mmol), t-butyl glycinate hydrochloride (4.6 mg, 0.03 mmol) and N-methylmorpholine (10 μl, 0.09 mmol ) Was dissolved in DCM (1.5 mL). After 5 minutes, TBTU was added and the reaction mixture was stirred for 3.5 hours. The formation of esters was confirmed. M / z: 694.0 (M−H). The mixture was extracted between DCM (3 mL) and aqueous KHSO ₄ (5 mL, pH 3). The aqueous phase was extracted with DCM (2x5 mL). The combined organic phases were washed with water (2 × 5 mL), dried over Na ₂ SO ₄ , filtered and concentrated. Formic acid (3 mL) was added and the solution was heated at 40 ° C. overnight. The solvent was removed under reduced pressure, toluene was added and evaporated. The residue was dissolved in methanol (3 mL) and sodium borohydride (8.5 mg, 0.23 mmol) was added. The reaction mixture was stirred for 15 minutes. The solvent was removed under reduced pressure. The residue was purified on preparative HPLC on C8 column. A gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. Lyophilization gave the title compound as a white solid (6.2 mg, 48%). HRMS predicted for C ₃₂ H ₃₃ F ₂ N ₃ O ₇ S 641.2007, found 642.2086 [M + H] ⁺ .

Example 53

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -D-valyl-L-valine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} -D-valine (11.5, 0.02 mmol), t-butyl L-valinate hydrochloride (5.3 mg, 0.025 mmol) and N-methylmorpholine (10 μl, 0.091 mmol ) Was dissolved in DCM (1.5 mL). After 5 minutes, TBTU (7.8 mg, 0.024 mmol) was added and the reaction mixture was stirred overnight. Additional t-butyl L-valinate hydrochloride (1.5 mg, 7.2 μmol), N-methylmorpholine (6.5 μl, 58 mmol) and TBTU (2.0 mg, 6.2 μmol, 0.31 equiv) were added and the mixture was 2.5 Stir for hours. The formation of esters was confirmed. M / z: 736.1 (M−H). The reaction mixture was washed with aqueous KHSO ₄ Extracted between (5 mL, pH 3) and DCM (5 mL). The organic phase was dried over Na ₂ S0 _4, filtered and concentrated. The residue was dissolved in formic acid (2 mL) and heated at 40 ° C. overnight. The solvent was removed under reduced pressure. Toluene was added and removed under reduced pressure. The residue was dissolved in MeOH (2 mL) and sodium borohydride (8.1 mg, 0.21 mmol) was added. The mixture was stirred for 30 minutes. Ammonium acetate (16 mg) was added and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC on C8 column. A gradient of 20% to 50% MeCN in 0.1 M NH ₄ OAc buffer was used as eluent. Lyophilization gave the title compound as a white solid (7.3 mg, 54%). H-NMR (400 MHz, DMSO-d ₆ ): 0.70 (d, 3H), 0.79 (d, 3H), 0.83 (d, 6H), 2.00 (m, 2H), 2.86-2.92 (m, 2H), 4.07 (brs, 1H), 4.25-4.29 (m, 1H), 4.40 (m, 1H), 4.59 (brs, 2H), 4.72 (m, 1H), 5.03 (d, 0.5H), 5.05 (d, 0.5 H), 5.68 (brs, 1H), 6.95 (d, 2H), 7.06-7.16 (m, 4H), 7.19-7.24 (m, 2H), 7.29-7.37 (m, 4H), 7.80 (d, 1H) , 8.05-8.15 (brs, 1 H). M / z: 682.1 (M−H).

Example 54

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -D-valyl-D-valine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} -D-valyl-D-valine (11.9 mg, 0.02 mmol), t-butyl D-valinate hydrochloride (5.6 mg, 0.027 mmol) and N-methylmorpholine ( 10 μl, 0.092 mmol) was dissolved in DCM (1.5 mL). After 5 minutes, TBTU (8.2 mg, 0.0255 mmol) was added and the reaction mixture was stirred overnight. Additional t-butyl D-valinate hydrochloride (1.7 mg, 8.1 μmol), N-methylmorpholine (6.5 μl, 58 μmol), TBTU (2 mg, 6.2 μmol) were added and the mixture was stirred for 3 hours. . The formation of esters was confirmed. M / z: 736.2 (M−H). The solvent was removed under reduced pressure and the residue was purified on silica gel (1 g) using DCM: MeOH (8: 2) as eluent. Fractions were collected and concentrated. The residue was dissolved in formic acid (1 mL) and the resulting solution was stirred at 25 ° C. to 30 ° C. overnight. The solvent was evaporated and toluene was added and removed under reduced pressure. The residue was dissolved in methanol (1 mL) and sodium borohydride (8.8 mg, 0.23 mmol) was added. The mixture was stirred for 30 minutes. Ammonium acetate (18 mg) was added and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC on C8 column. A gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. Lyophilization gave the title compound as a white solid (2.5 mg, 18%). H-NMR (400 MHz, DMSO-d ₆ ): 0.75 (d, 3H), 0.79-0.87 (m, 9H), 1.92-2.06 (m, 2H), 2.86-2.92 (m, 2H), 4.01 (brs , 1H), 4.25 (d, 0.5H), 4.28 (d, 0.5H), 4.32 (t, 1H), 4.57 (d, 2H), 4.67-4.76 (m, 1H), 5.03 (d, 0.5H) , 5.05 (d, 0.5H), 5.69 (brs, 1H), 6.93 (d, 2H), 7.04-7.17 (m, 4H), 7.18-7.25 (m, 2H), 7.29-7.38 (m, 4H), 7.85 (d, 1 H), 7.96 (brs, 1 H). M / z: 682.1 (M−H).

Example 55

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -D-valyl-L-methionine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} -D-valine (13.3 mg, 0.023 mmol), t-butyl L-methioninate hydrochloride (7.4 mg, 0.031 mmol) and N-methylmorpholine (10 μl, 0.091 mmol) was dissolved in 1 mL. After 5 minutes, TBTU (8.9 mg, 0.028 mmol) was added and the resulting suspension was stirred overnight. Additional t-butyl L-methioninate hydrochloride (2.1 mg, 0087 mmol), N-methylmorpholine (5 μl, 45 μmol) and TBTU (2.1 mg, 6.54 μmol) were added and the mixture was added for 2 hours. Stirred. The formation of esters was confirmed. M / z 768.1 (MH) and 770.0 (M + H). The yellow suspension was purified on silica gel (1 g) and eluted with EtOAc: DCM (15:85). Pure fractions were concentrated and formic acid (1.5 mL) was added. The solution was stirred at 50 ° C. overnight. The solution was removed under reduced pressure. Toluene was added and removed under reduced pressure. The residue was dissolved in methanol (1 mL) and sodium borohydride (9.9 mg, 0.26 mmol) was added. The resulting reaction mixture was stirred for 10 minutes. Ammonium acetate (18.9 mg) was added and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC on C8 column. A gradient of 20% to 40% MeCN in 0.1 M ammonium acetate buffer was used as eluent. Lyophilization gave the title compound as a white solid (4.6 mg, 28%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): 0.75 (d, 3H), 0.79 (d, 3H), 1.79-1.97 (m, 3H), 1.99 (s, 3H), 2.36-2.44 (m, 2H), 2.86-2.92 (m, 2H), 2.24-4.35 (m, 3H), 4.58 (d, 2H), 4.67-4.76 (m, 1H), 5.03 (d, 0.5H), 5.05 (d, 0.5 H), 5.63 (t, 1H), 6.95 (d, 2H), 7.05-7.16 (m, 4H), 7.18-7.24 (m, 2H), 7.30-7.38 (m, 2H), 7.82 (d, 1H) , 7.37 (d, 1 H). M / z: 714.0 (M-1) and 716.1 (M + H).

Example 56

N-[(4-{(2R, 3R) -1- (4-fluorophenyl) -3-[(2-hydroxy-2-phenylethyl) thio] -4-oxoazetidin-2-yl } Phenoxyacetyl] Glysyl-D-valine

(4-{(2R, 3R) -1- (4-fluorophenyl) -4-oxo-3-[(2-oxo-2-phenylethyl) thio] azetidin-2-yl} phenoxy) acetic acid (15 mg, 0.043 mmol), t-butyl glycyl-D-valinate hydrochloride (14.3 mg, 0.054 mmol) and N-methylmorpholine (14 μl, 0.13 mmol) were dissolved in DCM (2 mL). After 5 minutes, TBTU (16.9 mg, 0.053 mmol) was added and the reaction mixture was stirred for 2.5 hours. The formation of esters was confirmed. M / z: 678.35 (M + H). The solvent was removed under reduced pressure. The residue was dissolved in EtOAc: DCM (1: 3) and purified on silica gel (1 g) using EtOAc: DCM (1: 3) as eluent. Fractions were collected and concentrated. The residue (0.029 g) was dissolved in DCM (3 mL) and TFA (0.5 mL) was added. The reaction mixture was stirred overnight. The solvent was removed under reduced pressure and toluene was added and removed under reduced pressure. The yellow residue was dissolved in MeOH (2 mL) and sodium borohydride (16.2 mg, 0.43 mmol) was added. The reaction mixture was stirred for 10 minutes. Ammonium acetate (31.4 mg) was added and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC on C8 column. A gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. Lyophilization gave the title compound as a white solid (7.6 mg, 28%). H-NMR (400 MHz, DMSO-d ₆ ): 0.79 (d, 3H), 0.81 (d, 3H) 1.95-2.05 (m, 1H), 2.84-2.96 (m, 2H), 3.79 (d, 2H) , 3.98-4.04 (m, 1H), 4.27 (d, 0.5H), 4.30 (d, 0.5H), 4.51 (s, 2H), 4.66-4.75 (m, 1H), 5.02 (d, 0.5H), 5.04 (d, 0.5H), 6.98 (d, 2H), 7.10-7.17 (m, 2H), 7.19-7.32 (m, 7H), 7.36 (d, 2H), 7.77 (t, 1H), 8.26 (t , 1H). M / z: 622.1 (MH) and 624.2 (M + H).

Example 57

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2-hydroxy-2- (4-methylphenyl) ethyl] thio} -4-oxoazetidine -2-yl) phenoxy] acetyl} glycyl-D-valine

[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-methylphenyl) -2-oxoethyl] thio} -4-oxoazetidin-2-yl Phenoxy] acetic acid (15.0 mg, 0.043 mmol), t-butyl glycyl-D-valinate hydrochloride (10.8 mg, 0.04 mmol), N-methylmorpholine (10 μl, 0.09 mmol) was added to DCM (2 mL). )). After 5 minutes, TBTU (12.1 mg, 0.4 mmol) was added and the reaction mixture was stirred overnight. The formation of esters was confirmed. M / z: 690.13 (MH) and 692.15 (M + H). The reaction mixture was purified on silica gel (1 g) and eluted with EtOAc: DCM (1: 4). The collected fractions were concentrated. The organic phase was dissolved in DCM (1.5 mL) and TFA (1 mL) was added. The reaction mixture was stirred for 2.5 hours. The solvent was evaporated. Toluene was added and evaporated to aid in the removal of TFA. The residue was dissolved in methanol (1.5 mL) and sodium borohydride (12.2 mg, 0.32 mmol) was added. Additional sodium borohydride (4.2 mg, 0.11 mmol) was added and the mixture was stirred for 15 minutes. The solvent was removed under reduced pressure and the residue was purified on preparative HPLC on C8 column. A gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. Lyophilization gave the title compound as a white solid (10.4 mg, 52%). H-NMR (400 MHz, DMSO-d ₆ ): 0.80 (d, 6H), 1.95-2.05 (m, 1H), 2.24 (brs, 3H), 2.80-2.94 (m, 2H), 3.78 (d, 2H ), 4.00 (brs, 1H), 4.23 (d, 0.5H), 4.27 (brs, 0.5H) 4.51 (s, 2H), 4.61-4.70 (m, 1H), 5.00 (m, 1H), 6.97 (d , 2H) 7.06 (d, 2H), 7.10-7.18 (m, 4H), 7.19-7.25 (m, 2H), 7.34 (d, 2H), 7.76 (brs, 1H), 8.26 (t, 1H). M / z: 636.1 (M−H) and 638. 1 (M + H).

Example 58

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -D-valyl-D-tyrosine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} -D-valine (14.7 mg, 0.025 mmol), t-butyl D-tyrosinate hydrochloride (10.5 mg, 0.038 mmol) and N-methylmorpholine (10 μl, 91 μmol) was dissolved in DCM (1.5 mL). After 5 minutes, TBTU (9.9 mg, 0.031 mmol) was added and the reaction mixture was stirred overnight. Additional t-butyl D-tyrosinate hydrochloride (3.6 mg, 0.013 mmol), N-methylmorpholine (10 μl, 91 μmol) and TBTU (3.1 mg, 9.7 μmol) were added. The mixture was stirred for 3 hours. The formation of esters was confirmed. M / z. 800.07 (MH) and 802.08 (M + H). Aqueous KHSO ₄ (3 mL) was added and the mixture (pH 2) was extracted with DCM (3 × 5 mL). The combined organic phases were washed with water (2x10 mL), dried over Na ₂ S0 ₄ , filtered and concentrated. The oily residue (22.4 mg) was dissolved in DCM (15 mL) and TFA (1.0 mL) was added. The mixture was stirred overnight. The solvent was evaporated. Toluene was added and removed under reduced pressure. The residue was dissolved in methanol (2 mL) and sodium borohydride (14 mg) was added. The solution was stirred for 10 minutes. Ammonium acetate (15 mg) was added and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC on C8 column. A gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. Lyophilization gave the title compound as a white solid (8.4 mg, 45%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): 0.70 (d, 3H), 0.76 (d, 3H), 1.90-1.99 (m, 1H), 2.73-2.80 (m, 1H), 2.86-2.95 ( m, 3H), 3.96-4.04 (m, 1H), 4.06-4.12 (m, 1H), 4.27 (d, 0.5H), 4.29 (d, 0.5H), 4.50-4.61 (m, 2H), 4.67- 4.76 (m, 1H), 5.02 (d, 0.5H), 5.04 (d, 0.5H), 6.53 (d, 2H), 6.91 (q, 4H), 7.04-7.15 (m, 4H), 7.18-7.25 ( m, 2H), 7.30-7.38 (m, 4H), 7.58-7.65 (brs, 1 H), 7. 91 (d, 1H). M / z: 746.0 (M−H).

Example 59

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -D-valyl-D-lysine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} -D-valine (14.7, 0.025 mmol), t-butyl N ^6- (t-butoxycarbonyl) -D-lysinate hydrochloride (10.3, 0.03 mmol) and N-methylmorpholine (10 μl, 91 μmol) was dissolved in DCM (1.5 mL). After 5 minutes, TBTU (9.8 mg, 0.03 mmol) was added and the reaction mixture was stirred overnight. Additional N ^6- (t-butoxycarbonyl) -D-lysinate hydrochloride (3.4 mg, 0.01 mmol), N-methylmorpholine (5 μl, 45 μmol) and TBTU (3.3 mg, 0.01 mmol) were added. Was added and the mixture was stirred for 2 hours. Aqueous KHSO ₄ (3 mL) was added and the mixture (pH 3) was extracted with DCM (3 × 5 mL). The combined organic phases were washed with water (2x5 mL) and dried over Na ₂ S0 ₄ . The solvent was removed under reduced pressure. The crude residue (17.1 mg) was dissolved in DCM (1.5 mL) and TFA (1 mL). The solution was stirred for 1.5 hours. The solvent was dried under reduced pressure. Toluene was added and evaporated to aid in the removal of TFA. The residue was dissolved in methanol (2 mL) and sodium borohydride (11.5 mg, 0.30 mmol) was added. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on C8 column. A gradient of 20% to 50% MeCN in 0.1 M ammonium acetate was used as eluent. Lyophilization gave the title compound as a white solid (7.8 mg, 43%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): 0.75 (d, 3H), 0.79 (d, 3H), 1.17-1.63 (m, 4H), 1.96-2.06 (m, lH), 2.61-2.69 ( m, 2H), 2.85-2.93 (m, 2H), 3.72-3.80 (m, 1H), 4.12 (t, 1H), 4.27 (s, 0.5H), 4.30 (s, 0.5H), 4.53-5.64 ( m, 2H), 4.67-4.76 (m, 1H), 5.01-5.05 (m, 1H), 6.94 (d, 2H), 7.03-7.16 (m, 4H), 7.29-7.39 (m, 4H), 7.50- 7.57 (brs, 1 H), 8.05 (d, 1 H). M / z: 713.1.

Example 60

N-[(4-{(2R, 3R) -3-[(2-hydroxy-2-phenylethyl) thio] -4-oxo-1-phenylazetidin-2-yl} phenoxy) acetyl] Lysyl-D-Valin

[(4-{(2R, 3R) -3-{[5,5] -dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} -4-oxo-1-phenylase Tidin-2-yl} phenoxy] acetic acid (12.6 mg, 0.024 mmol) and N-methylmorpholine (15 μl, 0.14 mmol) were dissolved in DCM (2 mL). Additional DCM (2 mL), N-methylmorpholine (20 μl, 0.18 mmol) and t-butyl glycyl-D-valinate hydrochloride (9.0 mg, 0.034 mmol) were added after 0.5 h and the mixture was 10 Stir for minutes. TBTU (10.5 mg, 0.033 mmol) was added and the mixture was stirred overnight. The formation of esters was confirmed. M / z: 746.1. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on C8 column. A gradient of 20% to 50% MeCN in 0.1 M ammonium acetate was used as eluent. After lyophilization, the resulting compound was dissolved in DCM (2 mL) and TFA (1 mL) was added. The reaction mixture was stirred for 2.5 hours. Hydrolysis of the ester was confirmed. M / z: 604.2. The solvent was removed under reduced pressure. Co-evaporation with toluene assisted in the removal of TFA. The residue was dissolved in methanol (2 mL) and sodium borohydride (9.2 mg, 0.24 mmol) was added. After 15 minutes, the solvent was evaporated off and the residue was purified by preparative HPLC on C8 column. A gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. Lyophilization gave the title compound as a white solid (4.0 mg, 28%). H-NMR (400 MHz, DMSO-d ₆ ): 0.78 (d, 6H), 1.95-2.04 (m, 1H), 2.83-2.97 (m, 2H), 3.76 (d, 2H), 3.89-3.95 (m , 1H), 4.26 (d, 0.5H), 4.30 (d, 0.5H), 4.51 (s, 2H), 4.67-4.75 (m, 1H), 5.01 (d, 0.5H), 5.03 (d, 0.5 H), 6.98 (d, 2H), 7.03 (t, 1H), 7.17-7.22 (m, 3H), 7.23-7.32 (m, 6H), 7.36 (d, 2H), 7.55-7.65 (m, 1H) , 8.29 (t, 1 H). M / z: 603.96 (MH).

Example 61

N-{[4-((2R, 3R) -1- (4-chlorophenyl) -3- [2- (4-chlorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidine- 2-yl) phenoxy] acetyl} glycyl-D-valine

[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- (4-chlorophenyl) -2-oxoethyl] thio} -4-oxoazetidin-2-yl Phenoxy] acetic acid (15.3 mg, 0.03 mmol), N-methylmorpholine (10 μl, 0.091 mmol) and t-butyl glycyl-D-valinate hydrochloride (10.4 mg, 0.039 mmol) 2 ml). After 10 minutes, TBTU (11.9 mg, 0.037 mmol) was added and the mixture was stirred overnight. The intermediate t-butyl ester was confirmed. M / z: 727.8 (M−H). The reaction mixture was extracted between water (10 mL, acidified to pH 3 with KHSO ₄ (2M)) and DCM (3 × 10 mL). The combined organic phases were washed with water (2x20 mL), dried over Na ₂ S0 _4, filtered and concentrated. The oily residue was dissolved in DCM (2 mL) and TFA (1.3 mL) was added. The mixture was stirred overnight. The solvent was evaporated and coevaporated with toluene to aid in the removal of TFA. The residue was dissolved in methanol (2 mL) and sodium borohydride (12.3 mg, 0.33 mmol) was added. After 15 minutes, ammonium acetate (17 mg) was added and the solvent was removed under reduced pressure. The residue was purified on preparative HPLC on C8 column. A gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. Lyophilization gave the title compound as a white solid (15.1 mg, 77%). H-NMR (400 MHz, DMSO-d ₆ ): 0.78 (d, 3H), 0.80 (d, 3H), 0.95-1.03 (m, 1H), 2.83-3.00 (m, 2H), 3.75-3.80 (m , 2H), 3.93-4-00 (t, 1H), 4.30 (d, 0.5H), 4.36-4.38 (brs, 0.5H), 4.52 (s, 2H), 4.69-4.77 (m, 1H), 5.02 (d, 0.5H), 5.06 (d, 0.5H), 6.96-7.00 (m; 2H), 7.18-7.22 (m, 2H), 7.31-7.38 (m, 8H), 7.60-7.74 (m, 1H ), 8.28 (t, 1 H). M / z: 671.9 (M + H).

Example 62

N-{[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- (4-chlorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidine -2-yl) phenoxy] acetyl} glycyl-D-lysine

N-{[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- (4-chlorophenyl) -2-oxoethyl] thio} -4-oxoazetidine- 2-yl) phenoxy] acetyl} glycine (14.6 mg, 0.026 mmol) and N-methylmorpholine (20 μl, 0.18 mmol) were dissolved in DCM (2 mL). t-butyl N ^6- (t-butoxycarbonyl) -D-lysinate hydrochloride (11.1 mg, 0.033 mmol) was added and after 5 minutes TBTU (9.8 mg, 0.031 mmol) was added to the suspension. The mixture was stirred overnight. Additional t-butyl N ^6- (t-butoxycarbonyl) -D-lysinate (4.8 mg, 0.014 mmol), N-methylmorpholine (10 μl, 91 mmol) and TBTU (4.6 mg, 0.014 mmol) Was added and the mixture was stirred for 2.5 h. The formation of esters was confirmed. M / z: 855.4 (M−H). DCM (3 mL) and water (5 mL) were added and the pH of the solution was acidified to 3 with KHSO ₄ (2M). The organic phase was washed with water (2x5 mL). The combined aqueous phases were extracted with DCM (2x5 mL). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The oily phase was dissolved in DCM (1.5 mL) and TFA (1 mL) was added. The mixture was stirred for 2.5 hours. The mixture was concentrated and co-evaporated with toluene to aid in the removal of TFA. The residue was dissolved in methanol (2 mL) and sodium borohydride (10.4 mg, 0.027 mmol) was added. After 15 minutes, ammonium acetate buffer (0.1 M, 1.5 mL) was added and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC on C8 column. A gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. Lyophilization gave the title compound as a white solid (10.8 mg, 59%). H-NMR (400 MHz, DMSO-d ₆ ): 1.18-1.36 (m, 2H), 1.41-1.70 (m, 4H), 2.71 (t, 2H), 2.84-2.97 (m, 2H), 3.72-3.75 (brd, 2H), 3.93 (m, 1H), 4.30 (d, 0.5H), 4.34 (d, 0.5H), 4.52 (s, 2H), 4.68-4.77 (m, 1H), 5.03 (d, 0.5 H), 5.07 (d, 0.5H), 6.98 (d, 2H), 7.20 (d, 2H), 7.31-7.38 (m, 8H), 7.63-7.72 (m, 1H), 8.34 (t, 1H). M / z: 705.1.

Example 63

(2R) -2-[(N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl ] Thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl) amino] -4-phenylbutanoic acid

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycine (14.4 mg, 0.027 mmol) and N-methylmorpholine (15 μl, 0.14 mnmol) were dissolved in DMF (3 mL). TBTU (10.3 mg, 0.032 mmol) was added and stirred at 30 ° C. for 20 minutes. (2R) -2-amino-4-phenylbutanoic acid (5.7 mg, 0.032 mmol) was added and the reaction mixture was stirred at room temperature for 1.5 hours. The formation of the intermediate acid was confirmed. M / z: 702.0. MeOH (2.5 mL) and sodium borohydride were added and the mixture was stirred for 20 minutes. Ammonium acetate (34 mg) was added. The mixture was concentrated and the residue was purified by preparative HPLC on C8 column. A gradient of 20% to 45% MeCN in 0.1 M ammonium acetate buffer was used as eluent. Lyophilization gave the title compound as a white solid (9.4 mg, 50%). H-NMR (400 MHz, DMSO-d ₆ ): 1.74-1.87 (m, 1H), 1.89-1.99 (m, 1H), 2.49-2.53 (m, 2H), 2.82-2.98 (m, 2H), 3.77 (d, 2H), 3.94-4.01 (m, lH), 4.27 (d, 0.5H), 4.31 (d, 0.5H), 4.53 (s, 2H), 4.68-4.77 (m, 1H), 5.02 (d , 0.5H), 5.05 (d, 0.5H), 6.99 (d, 2H), 7.05-7.16 (m, 7H), 7.19-7.26 (m, 4H), 7.30-7.38 (m, 4H), 7.78-7.88 (dd, 1 H), 8.35 (t, 1 H). M / z: 702.0 (M−H).

Example 64

(2R) -2-[(N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl ] Thio} 4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl) amino] -4- (4-hydroxyphenyl) butanoic acid

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} 4-oxoazeti Din-2-yl) phenoxy] acetyl} glycine (15.2 mg, 0.028 mmol) and N-methylmorpholine (15 μl, 0.14 mmol) were dissolved in DMF (2 mL). TBTU (10.5 mg, 0.033 mmol) was added and after 20 minutes (2R) -2-amino-4- (4-hydroxyphenyl) butanoic acid hydrobromide (9.2 mg, 0.033 mmol) was added. The reaction mixture was stirred for 1.5 hours. Formation of the intermediate was confirmed. M / z: 718.3. MeOH (2 mL) and sodium borohydride (10.7 mg, 0.28 mmol) were added and the reaction mixture was stirred for 20 minutes. Ammonium acetate (34 mg) was added and methanol was removed under reduced pressure. The residue was purified by preparative HPLC on C8 column. A gradient of 20% to 45% MeCN in 0.1 M ammonium acetate buffer was used as eluent. Lyophilization gave the title compound as a white solid (9.6 mg, 47%). H-NMR (400 MHz, DMSO-d ₆ ): 1.75-1.86 (m, 1H), 1.89-1.98 (m, 1H), 2.41 (t, 2H), 2.81-2.98 (m, 2H), 3.78 (d , 2H), 3.97-4.05 (m, 1H), 4.27 (d, 0.5H), 4.31 (d, 0.5H), 4.53 (s, 2H), 4.67-4.76 (m, 1H), 5.02 (d, 0.5H), 5.05 (d, 0.5H), 6.62 (d, 2H), 6.91 (d, 2H), 6.98 (d, 2H), 7.05-7.16 (m, 4H), 7.20-7.25 (m, 2H) , 7.30-7.39 (m, 4H), 7.87-7.97 (m, 1H), 8.30 (t, 1H), 8.91-9.30 (br, 1H). M / z: 718.0 (M−H).

Example 65

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2-hydroxy-2- (4-methoxyphenyl) ethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-alanine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2-methoxyphenyl) -2-oxoethyl] thio} -4-oxoazetidine-2 -Yl) phenoxy] acetyl} glycine (0.04 g, 0.072 mmol) and N-methylmorpholine (0.022 g, 0.217 mmol) were dissolved in CH ₂ Cl ₂ (4 mL). t-butyl D-alanineate hydrochloride (0.016 g, 0.087 mmol) and TBTU (0.030 g, 0.094 mmol) were added. After 2 h, the reaction mixture was purified on silica gel and eluted with EtOAc / CH ₂ Cl ₂ (25/75). Pure fractions were collected and concentrated. The residue was dissolved in CH ₂ Cl ₂ (3 mL) and TFA (2 mL). After 2 hours the hydrolysis was complete. The reaction mixture was concentrated and MeOH (3 mL) and NaBH ₄ (0.011 g, 0.290 mmol) were added. The mixture was stirred for 5 minutes. The reaction was quenched by the addition of 0.1 M NH ₄ OAc buffer (2 mL) and the solvent was evaporated. The residue was purified by preparative HPLC using 0% to 50% CH ₃ CN as eluent in 0.1 M NH4OAc buffer. The pure fraction was lyophilized to give the title compound (0.030 g, 66%) as a colorless solid. It was. M / z: 624.2, (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 1.16 (d, 3H), 2.83-2.93 (m, 2H), 3.68-3.74 (m, SH), 3.88-3.95 (m, 1H), 4.23-4.26 (m, 1H), 4.51 (s, 2H), 4.60-4.70 (m, 1H), 5.00-5.03 (m, 1H), 6.81-7.37 (m, 12H), 7.74-7.79 (m, 1H ), 8.29-8.34 (m, 1 H).

Example 66

1-[(N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxy ethyl] thio}- 4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl) amino] cyclopropanecarboxylic acid

N-methyl morpholine (0.037 g, 0.370 mmol) and TBTU (0.039 g, 0.120 mmol) were added N-{[4-((2R, 3R) -1- (4-fluorine) in DMF (2 mL) at 30 ° C. Rophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (0.025 g, 0.046 mmol) To the solution. After 1 hour 1-aminocyclopropane carboxylic acid (0.019 g, 0.185 mmol) was added. After 1 hour, the reaction was quenched by addition of water (1 mL). After 10 min, MeOH (2 mL) and NaBH ₄ (0.035 g, 0.925 mmol) were added. After 5 minutes it was converted completely to the corresponding alcohol. The reaction was quenched by the addition of 0.1 M NH ₄ OAc buffer (2 mL). The product was purified by preparative HPLC (using 0% to 50% gradient CH ₃ CN as eluent in 0.1 M NH ₄ OAc buffer). Pure fractions were lyophilized to provide the title compound (0.045 g, 78%) as a colorless solid. ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 0.78-0.88 (m, 2H), 1.08-1.22 (m, 2H), 2.84-2.94 (m, 2H), 3.63-3.72 (m, 2H ), 4.24-4.29 (m, 1H), 4.48-4.52 (m, 2H), 4.68-4.75 (m, 1H), 5.03-5.06 (m, 1H), 6.96-7.37 (m, 12H), 7.78-8.36 (m, 2 H).

Example 67

N-{[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- (4-chlorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidine -2-yl) phenoxy] acetyl} glycyl-3-methyl-D-valine

TBTU (0.020 g, 0.063 mmol) was added N-{[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- () in CH ₂ Cl ₂ (5 mL) at 30 ° C. 4-chlorophenyl) -2-oxoethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (0.030 g, 0.052 mmol) and N-methylmorpholine (0.016 g, 0.157 mmol) ) Was added to the solution. After 30 minutes, Dt-leucine (0.008 g, 0.063 mmol) was added and the mixture was stirred for 30 minutes. The reaction mixture was concentrated. Toluene (2 mL) was added and evaporated. MeOH (3 mL) and nathro borohydride (0.020 g, 0.523 mmol) were added. After 5 minutes it was converted completely to the corresponding alcohol. 0.1 M NH ₄ OAC (1 mL) buffer was added to quench the reaction and the mixture was concentrated. The residue was purified by preparative HPLC (0% to 50% CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent). Pure fractions were lyophilized to provide the title compound (0.021 g, 58%) as a colorless solid. ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 0.85 (s, 9H), 2.82-2.98 (m, 2H), 3.75-3.81 (m, 2H), 3.91-3.96 (m, 1H), 4.29-4.37 (m, 1H), 4.52 (s, 2H), 4.70-4.78 (m, 1H), 5.01-5.06 (m, 1H), 6.97-6.99 (m, 2H), 7.19-7.21 (m, 2H ), 7.32-7.36 (m, 8H), 7.52-7.63 (m, 1H), 8.27-8.32 (m, 1H).

Example 68

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-tryptophan

TBTU (0.016 g, 0.051 mmol) was added to N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4- in DMF (2 mL) at 30 ° C). Fluorophenyl) -2-oxoethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (0.025 g, 0.046 mmol) and N-methylmorpholine (0.014 g, 0.139 mmol) To the solution. After 1 hour DMSO (1 mL) and D-tryptophan (0.019 g, 0.092 mmol) were added. After 10 minutes, the reaction was quenched by addition of water (1 mL). The mixture was stirred for 10 minutes and MeOH (1 mL) and NaBH ₄ (0.035 g, 0.925 mmol) were added. After 5 minutes it was converted completely to the corresponding alcohol. The reaction was quenched by the addition of 0.1 M NH ₄ OAc buffer. The reaction mixture was concentrated and the residue was purified by preparative HPLC (0-50% CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent). This resulted in the title compound (0.028 g, 83%) as a colorless solid. M / z: 727.0 (Ml). ^l H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 2.79-3.18 (m, 4H), 3.61-3.80 (m, 2H), 4.26- 4.34 (m, 2H), 4.43-4.54 (m, 2H ), 4.68-4.78 (m, 1H), 4.97-5.04 (m, 1H), 6.84-7.55 (m, 17H), 7.65-7.82 (m, 1H), 8.22-8.25 (m, 1H), 10.73 (s , 1H).

Example 69

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-histidine

TBTU (0.016 g, 0.051 mmol) was added with N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2 at 30 ° C. -Oxoethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (0.025 g, 0.046 mmol) and N-methylmorpholine (0.014 g, 0.139 mmol) solution Was added. After 1 h, D-histidine (0.014 g, 0.092 mmol) and tetrabutylammonium bromide (0.003 g, 0.009 mmol) were added. The reaction mixture was stirred overnight (30% conversion) and water (2 mL) was added to quench the reaction. Purification by preparative HPLC (0% to 50% CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent) provided intermediate ketones, MeOH (3 mL) and NaBH ₄ (0.005 g, 0.139 mmol). ) Was added to reduce this. After 5 minutes it was converted completely to the corresponding alcohol. 0.1 M NH ₄ OAc buffer (2 mL) was added to quench the reaction and the mixture was concentrated. Purification by preparative HPLC (0-40% CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent) provided the title compound (0.001 g, 4.5%) as a colorless solid. M / z: 680.0. ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 2.82-2.93 (m, 4H), 3.71-3.80 (m, 2H), 4.11-4.30 (m, 2H), 4.52 (s, 2H), 4.68-4.73 (m, 1H), 5.04-5.07 (m, 1H), 6.68-7.50 (m, 14H), 7.90-7.96 (m, 1H), 8.27-8.33 (m, 1H).

Example 70

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-3- (2-naphthyl) -D-alanine

TBTU (0.019 g, 0.060 mmol) was added N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- in CH ₂ Cl ₂ (5 mL) at 30 ° C. (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (0.025 g, 0.046 mmol) and N-methylmorpholine (0.014 g, 0. 139 mmol) was added to the solution. After 1 h, DMF (3 mL), DMSO (1 mL) and D- (2-naphthyl) alanine (0.011 g, 0.051 mmol) were added. After 1 hour the reaction was quenched by the addition of water (1 mL). NaBH ₄ (0.035 g, 0.925 mmol) was added. After 5 minutes it was converted completely to the corresponding alcohol. The reaction was quenched by the addition of 0.1 M NH ₄ OAc buffer (1 mL) and the mixture was concentrated. Purification by preparative HPLC (0% to 55% CH ₃ CN in 0.1 M NH ₄ OAc as eluent) provided the title compound (0.017 g, 48%) as a colorless solid. M / z: 738.0 (Ml). ^l H NMR [(CD ₃ ) ₂ SO), 400 MHz] 2.75-3.27 (m, 4H), 3.55-3.83 (m, 2H), 4.25-4.55 (m, 4H), 4.68-4.79 (m, 1H) , 4.92-5.02 (m, 1 H), 6.72-7.80 (m, 20 H), 8.26-8.30 (m, 1 H).

Example 71

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-3-methyl-D-valine

TBTU (0.021 g, 0.067 mmol) was added N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[in CH ₂ Cl ₂ (5 mL) at 30 ° C. 2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (0.030 g, 0.056 mmol) and N-methyl morpholine (0.017 g, 0.166 mmol) was added to the solution. After 1.5 h, Dt-leucine (0.011 g, 0.083 mmol) was added. After 30 minutes, complete conversion to the corresponding amide. Water (1 mL) was added to quench the reaction. After 10 minutes, MeOH (3 mL) and NaBH ₄ (0.042 g, 1.11 mmol) were added. After 5 minutes, the reaction was quenched by the addition of 0.1 M NH ₄ OAc buffer (1 mL). The reaction mixture was concentrated and purified by preparative HPLC (0% to 50% CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent). The title compound (0.025 g, 69%) was obtained as a colorless solid. M / z: 654.0 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 0.86 (s, 9H), 2.82-2.98 (m, 2H), 3.76-3.81 (m, 2H), 3.92-3.96 (m, 1H), 4.26-4.33 (m, 1H), 4.52 (s, 2H), 4.68-4.76 (m, 1H), 5.02-5.07 (m, 1H), 6.97-7.37 (m, 12H), 7.58-7.63 (m, 1H ), 8.29-8.34 (m, 1 H).

Example 72

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl- (3R, 4S, 5R) -3,4,5,6-tetrahydroxy-D-norleucine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxyethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycine (0.025 g, 0.046 mmol) was dissolved in DMSO (2 mL) at 30 ° C. N-methylmorpholine (0.014 g, 0.139 mmol) and TBTU (0.018 g, 0.056 mmol) were added. After 1 hour, D-glucosamine acid (0.018 g, 0.092 mmol) and tetrabutylammonium bromide (0.001 g, 0.005 mnol) were added. The mixture was stirred for 15 minutes. Additional TBTU (18 mg, 0.056 mmol) was added. After 30 minutes, approximately 30% of the amide was formed. The reaction was quenched by the addition of 0.1 M NH ₄ OAc buffer (2 mL). Intermediate ketones were purified by preparative HPLC (0-50% CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent) and lyophilized. MeOH (3 mL) and NaBH ₄ (0.005 g, 0.139 mmol) were added. After 5 minutes, the reaction was quenched by the addition of 0.1 M NH ₃ OAc buffer (1 mL). The mixture was concentrated and purified by preparative HPLC (0% to 50% CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent) to provide the title compound (0.005 g, 16%) as a colorless solid. M / z: 718.0 (Ml). ^l H NMR [(CD ₃ ) ₂ SO), 400 MHz] 2.82-2.94 (m, 2H), 3.34-3.56 (m, 4H), 3.76-3.80 (m, 2H), 3.87-3.90 (m, 1H) , 4.07-4.11 (m, 1H), 4.27-4.32 (m, 1H), 4.52 (s, 2H), 4.68-4.76 (m, 1H), 5.02-5.05 (m, 1H), 6.97-7.39 (m, 12H), 7.63-7.70 (m, 1 H), 8.28-8.35 (m, 1 H).

Example 73

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-phenyl-D-phenylalanine

TBTU (0.018 g, 0.056 mmol) was added N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- in CH ₂ Cl ₂ (5 mL) at 30 ° C. (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (0.025 g, 0.046 mmol) and N-methylmorpholine (0.023 g, 0. 231 mmol) was added to the solution. After 1.5 h, β-phenyl-D-phenylalanine trifluoro acetic acid salt (0.033 g, 0.092 mmol) was added. The mixture was stirred for 5 minutes. Water (1 mL) was added and the mixture was concentrated. MeOH (3 mL) and NaBH ₄ (0.017 g, 0.462 mmol) were added. After 5 minutes, 0.1 M NH ₄ OAc buffer was added to quench the reaction and the mixture was concentrated. Purification by preparative HPLC (0% to 45% CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent) and lyophilization provided the title compound (0.021 g, 59%) as a colorless solid. M / z: 764.1 (Ml). ^l H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 2.82-2.95 (m, 2H), 3.42-3.49 (m, 1H), 3.66-3.74 (m, 1H), 4.25-4.33 (m, 2H ), 4.42 (d, 1H), 4.47 (d, 1H), 4.69-4.76 (m, 1H), 5.03-5.12 (m, 2H), 6.94-7.38 (m, 22H), 8.10-8.14 (m, 1H) ), 8.18-8.24 (m, 1 H).

Example 74

(2R) -4-cyclohexyl-2-[(N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl)- 2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl) amino] butanoic acid

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycine (0.025 g, 0.046 mmol) was dissolved in DMF (2 mL) at 30 ° C. N-methyl morpholine (0.034 g, 0.333 mmol) and TBTU (0.043 g, 0.133 mmol) were added. After 1 hour sodium (2R) -2-amino-4-cyclobutanoate (0.039 g, 0.189 mmol), DMSO (2 mL) and tetrabutylammonium bromide (0.004 g, 0.011 mmol) were added. The mixture was stirred for 1 hour and water (1 mL) was added. After 1 h, MeOH (2 mL) and NaBH ₄ (0.084 g, 2.220 mmol) were added. After 5 minutes it was converted completely to the corresponding alcohol. The reaction was quenched by the addition of 0.1 M NH ₄ OAc buffer (2 mL). The mixture was purified by preparative HPLC (0-50% CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent). Pure fractions were lyophilized to provide the title compound (0.034 g, 43%) as a colorless solid. M / z: 708.1 (Ml). ^l H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 0.75-1.62 (m, l5H), 2.82-2.99 (m, 2H), 3.68-3.78 (m, 2H), 3.90-3.96 (m, 1H ), 4.23-4.35 (m, 1H), 4.50 (s, 2H), 4.69-4.75 (m, 1H), 5.01-5.07 (m, 1H), 6.95-7.39 (m, 12H), 7.68-7.80 (m , 1H), 8.20-8.34 (m, 1H).

Example 75

(2R) -cyclopentyl [(N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethyl] Thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl) amino] acetic acid

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3- [2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazetidine -2-yl) phenoxy] acetyl} glycine (0.035 g, 0.065 mmol) was dissolved in DMF (2 mL) at 30 ° C. N-methyl morpholine (0.026 g, 0.259 mmol) and TBTU (0.027 g, 0.084 mmol) were added. After 1 h, (2R) -amino (cyclopentyl) acetic acid (0.014 g, 0.097 mmol) was added. The mixture was stirred for 1 hour and water (1 mL) was added. After 10 minutes MeOH (2 mL) and NaBH ₄ (0.037 g, 0.971 mmol) were added. After 5 minutes it was converted completely to the corresponding alcohol. The reaction was quenched by the addition of 0.1 M NH ₄ OAc buffer (2 mL). The mixture was purified by preparative HPLC (0-50% CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent). Pure fractions were lyophilized to provide the title compound (0.018 g, 42%) as a colorless solid. M / z: 666.0 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] 1.19-1.62 (m, 8H), 2.09-2.19 (m, 1H), 2.83-2.95 (m, 2H), 3.78 (d, 2H), 4.06 -4.10 (m, 1H), 4.25-4.30 (m, 1H), 4.51 (s, 2H), 4.68-4.75 (m, 1H), 5.03-5.06 (m, 1H), 6.97-7.37 (m, 12H) , 7.95-8.00 (m, 1 H), 8.22 (t, 1 H).

Example 76

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-3-methyl-D-isovaline

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycine (0.035 g, 0.065 mmol) was dissolved in DMF (2 mL) at 30 ° C. N-methyl morpholine (0.026 g, 0.259 mmol) and TBTU (0.027 g, 0.084 mmol) were added. After 1 hour, 3-methyl-D-isovaline (0.013 g, 0.097 mmol) was added. The mixture was stirred for 2 hours and water (1 mL) was added. After 10 minutes MeOH (2 mL) and NaBH ₄ (0.037 g, 0.971 mmol) were added. After 5 minutes the corresponding alcohol was completely converted and 0.1 M NH ₄ OAc buffer (2 mL) was added. The mixture was purified by preparative HPLC (0-50% CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent). Pure fractions were lyophilized to provide the title compound (0.020 g, 47%) as a colorless solid. M / z: 654.0 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 0.79 (d, 3H), 0.87 (d, 3H), 1.29 (s, 3H), 2.00-2.07 (m, 1H), 2.84-2.94 ( m, 2H), 3.73 (d, 2H), 4.25-4.28 (m, 1H), 4.51 (s, 2H), 4.69-4.75 (m, 1H), 5.03-5.06 (m, 1H), 6.97-7.37 ( m, 12H), 7.82 (s, 1 H), 8.24 (t, 1 H).

Example 77

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-S- (t-butyl) -D-cysteine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycine (20 mg, 0.037 mmol) and N-methylmorpholine (20 μl, 0.18 mmol) were dissolved in DMF (3 mL). TBTU (14.6 mg, 0.046 mmol) was added and the mixture was stirred at 30 ° C. for 45 minutes. S- (t-butyl) -D-cysteine hydrochloride (9.7 mg, 0.045 mmol) was added and the reaction mixture was stirred for 1.5 h. The formation of ketones of the title compound was confirmed. M / z: 700.0. Methanol (2 mL) and sodium borohydride (14.3 mg, 0.38 mmol) were added and the mixture was stirred for 30 minutes. Ammonium acetate buffer (0.1 M, 2 mL) was added and the mixture was concentrated. The residue was purified by HPLC on C8 column. A gradient of 20% to 45% MeCN in 0.1 M NH ₄ OAc buffer was used as eluent. MeCN was removed from the collected fractions under reduced pressure. The remaining aqueous solution was acidified to pH 1 with HCl (1 M) and extracted with DCM. The organic phase was concentrated under reduced pressure and the residue was dissolved in MeCN and water. After freeze drying, the title compound was obtained as a white solid (16.5 mg, 65%). H-NMR (400 MHz, DMSO-d ₆ ): 1.21 (s, 9H), 2.71-2.78 (m, 1H), 2.82-2.86 (m, 3H), 2.74-2.80 (m, 2H), 2.18-2.26 (m, 1H), 4.27 (d, 0.5H), 4.30 (d, 0.5H), 4.51 (s, 2H), 2.67-2.76 (m, 1H), 5.03 (d, 0.5H), 5.05 (d, 0.5), 6.98 (d, 2H), 7.05-7.17 (m, 4H), 7.20-7.25 (m, 2H), 7.30-7.39 (m, 4H), 7.94-8.06 (b, 1H), 8.26 (t, 1H). M / z: 700.0 (MH) and 702.1 (M + H).

Example 78

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-N, 2-dimethylalanine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} in DMF (3 mL) To a mixture of -4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (0.020 g, 0.037 mmol) and NMM (0.012 mL, 0.109 mmol) was added TBTU (0.018 g, 0.056 mmol) at 30 ° C. It was. The reaction mixture was stirred for 20 minutes, after which 2- (methylamino) isobutyric acid (0.005 g, 0.038 mmol) was added. The mixture was stirred at 30 ° C. for 20 hours and then water (1 mL) was added to quench the reaction. The mixture was diluted with MeOH (2 mL) and NaBH ₄ (0.018 g, 0.486 mmol) was added. After 10 minutes, the reaction was quenched by the addition of 0.1 M ammonium acetate buffer (2 mL) and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC (using 20% to 50% gradient MeCN in 0.1 M ammonium acetate buffer as eluent). Pure fractions were lyophilized to afford the desired product as a white solid (0.012 g, 50% yield).

Exact mass: 642.211 (M + 1) ⁺

Example 79

(2R) -3- (4-cyanophenyl) -2-{[({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluoro Lophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} amino) acetyl] amino} propanoic acid

(2R) -3- (4-cyclophenyl) -2-{[({[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluoro Phenyl) -2-oxoethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} amino) acetyl] amino} propanoic acid (0.006 g, 0.0084 mmol) in methanol (1.5 mL) Dissolved. NaBH ₄ (0.0035 g, 0.092 mmol) was added and a few drops of acetic acid were added when the reaction was complete according to LC-MS. The solvent was removed under reduced pressure and the residue was removed by preparative HPLC on a Kromasil C8 column (33.5% to 43% in 0.1 M ammonium acetate buffer and then a gradient of 5C% using MeCN as eluent). After freeze drying, 0.005 g (83%) of the desired product was obtained.

NMR (500 MHz, CD ₃ COOD) 2.91-3.12 (m, 3H), 3.26-3.32 (m, 1H), 3.91 (ABq, 2H), 4.03-4.07 (m, 1H), 4.57 (s, 2H), 4.65 (brt, 1H), 4.80-4.85 (m, lH), 4.90-4.93 (m, 1H), 6.97-7.08 (m, 6H), 7.26-7.32 (m, 2H), 7.32-7.41 (m, 6H ), 7.60 (d, 2 H)

Example 80

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2-hydroxy-2- (4-pentylphenyl) ethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyl-3-cyclohexyl-D-alanine

[4-((2R, 3R) -1- (4-fluorophenyl) -4-oxo-3-{[2-oxo-2- (4-pentylphenyl) ethyl] thio} in DMF (2 mL)) To a solution of azetidin-2-yl) phenoxy] acetic acid (0.020 g, 0.037 mmol) and NMM (0.012 mL, 0.109 mmol) was added TBTU (0.019 g, 0.059 mmol) at 30 ° C. After 15 minutes, glycyl-3-cyclohexyl-D-alanine (0.009 g, 0.039 mmol) was added and the mixture was stirred at 30 ° C. for 22 hours. The reaction was quenched by addition of water (1 mL) and the mixture was diluted with MeOH (2 mL). To the mixture was added NaBH ₄ (0.020 g, 0.529 mmol) and the mixture was stirred for 10 minutes. The reaction was quenched by addition of 0.1 M ammonium acetate buffer (3 mL) and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC (20% to 60% gradient MeCN in 0.1 M ammonium acetate buffer as buffer). Pure fractions were lyophilized to afford the desired product as a white solid (0.009 g, 32% yield).

¹ H NMR (CD ₃ OD, 400 MHz) δ: 0.82-1.03 (m, 5H), 1.10-1.45 (m, 8H), 1.48-1.74 (m, 8H), 1.75-1.85 (m, 1H) , 2.51-2.60 (m, 2H), 2.89-3.08 (m, 2H), 3.91-4.04 (m, 3H), 4.42-4.49 (m, 1H), 4.56-4.60 (m, 2H), 4.71-4.87 ( m, 2H), 6.95-7.10 (m, 6H), 7.18-7.35 (m, 6H).

Example 81

N-({4-[(2R, 3R) -1- (4-fluorophenyl) -3-({2-hydroxy-2- [4- (methylthio) phenyl] ethyl} thio) -4- Oxoazetidin-2-yl] phenoxy} acetyl) glycyl-3-cyclohexyl-D-alanine

{4-[(2R, 3R) -1- (4-fluorophenyl) -3-({2-hydroxy-2- [4 (methylthio) phenyl] ethyl} thio)-in DMF (3 mL) To a solution of 4-oxoazetidin-2-yl] phenoxy} acetic acid (0.020 g, 0.039 mmol) and NMM (0.025 mL, 0.227 mmol) was added TBTU (0.025 g, 0.078 mmol) at room temperature. The reaction mixture was stirred for 90 minutes, after which glycyl-3-cyclohexyl-D-alanine (0.010 g, 0.044 mmol) was added. The mixture was stirred for 22 hours and then water (1 mL) was added to quench the reaction. The mixture was diluted with MeOH (1 mL) and then NaBH ₄ (0.016 g, 0.423 mmol) was added. After 10 minutes, the reaction was quenched by the addition of 0.1 M ammonium acetate buffer (2 mL) and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC (using 20% to 60% gradient MeCN in 0.1 M ammonium acetate buffer as eluent). Pure fractions were lyophilized to afford the desired product as a white solid (0.009 g, 32% yield).

ES- m / z: 723.1 (M-1) ^- . ¹ H NMR (DMSO, 500 MHz) δ: 0.75-0.95 (m, 2H), 1.05-1.35 (m, 4H), 1.42-1.72 (m, 7H), 2.43-2.47 (m, 3H), 2.85-2.97 (m, 2H), 4.15-4.23 (m, 1H), 4.26-4.32 (m, 1H), 4.53 (s, 2H), 4.65-4.74 (m, 1H), 5.01- 5.07 (m, 1H), 5.66 (bs, 1H), 6.97-7.03 (m, 2H), 7.13-7.29 (m, 8H), 7.35-7.41 (m, 2H), 7.96-8.06 (m, 1H), 8.22-8.29 (m, 1H) .

Example 82

N-({4-[(2R, 3R) -1- (4-fluorophenyl) -3-({2-hydroxy-2- [4- (methylthio) phenyl] ethyl} thio) -4- Oxoazetidin-2-yl] phenoxy} acetyl) glycid-D-valine

{4-[(2R, 3R) -1- (4-fluorophenyl) -3-({2-hydroxy-2- [4- (methylthio) phenyl] ethyl} thio) in DCM (3 mL) -4-oxoazetidin-2-yl] phenoxy} acetic acid (0.015 g, 0.026 mmol), t-butyl glycyl-D-valinate hydrochloride (0.009 g, 0.034 mmol) and N-methylmorpholine ( 0.013 mL, 0.118 mmol) was stirred at room temperature for 10 minutes before TBTU (0.014 g, 0.044 mmol) was added. After 17 hours the conversion to intermediate (m / z: 724.7, M + 1) was complete. The solution was diluted with TFA (2 mL) and the mixture was stirred for 2 hours. The resulting acid (m / z: 668.6, M + 1) was concentrated and the residue was dissolved in MeOH (3 mL). NaBH ₄ (80 mg, 2.11 mmol) was added portionwise to the solution until reduction of the ketone was complete (LC / MS). After the reaction was quenched by addition of 0.1 M ammonium acetate buffer (3 mL), most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC (using 20% to 50% gradient of MeCN as eluent in 0.1 M ammonium acetate buffer). Pure fractions were lyophilized to afford the desired product (0.014 g, 70%) as a white solid.

ES-m / z: 669.0 (M-1) ^- . ¹ H NMR (CD ₃ 0D, 400 MHz) δ: 0.88-0.98 (m, 6H), 2.10-2.23 (m, 1H), 2.40-2.47 (m, 3H), 2.89-3.08 (m, 2H), 3.93 -4.06 (m, 3H), 4.31 (d, 1H), 4.59 (s, 2H), 4.73-4.84 (m, 2H), 6.95-7.07 (m, 4H), 7.13-7.18 (m, 2H), 7.21 -7.34 (m, 6 H).

Example 83

N-({4-[(2R, 3R) -1- (4-fluorophenyl) -3-({2-hydroxy-2- [4- (methylthio) phenyl] ethyl} thio) -4- Oxoazetidin-2-yl] phenoxy} acetyl) glycyl-3-methyl-D-valine

{4-[(2R, 3R) -1- (4-fluorophenyl) -3-({2-hydroxy-2- [4- (methylthio) phenyl] ethyl} thio) in DMF (3 mL) To a solution of -4-oxoazetidin-2-yl] phenoxy} acetic acid (0.020 g, 0.039 mmol) and NMM (0.020 mL, 0.182 mmol) was added TBTU (0.020 g, 0.062 mmol) at room temperature. The reaction mixture was stirred for 60 minutes and then glycyl-3-methyl-D-valine (0.008 g, 0.043 mmol) was added. The mixture was stirred for 18 hours and then water (1 mL) was added to quench the reaction. The mixture was diluted with MeOH (1 mL) and NaBH ₄ (0.040 g, 1.06 mmol) was added. After 10 minutes, the reaction was quenched by the addition of 0.1 M ammonium acetate buffer (2 mL) and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC (20% to 60% gradient MeCN in 0.1 M ammonium acetate buffer as buffer). Pure fractions were lyophilized to afford the desired product as a white solid (0.006 g, 22% yield).

ES-m / z: 683.0 (M-1) ^- . ¹ H NMR (DMSO, 500 MHz) δ: 0.88-0.94 (m, 9H), 2.44-2.46 (m, 3H), 2.85-2.98 (m, 2H), 3.80-3.87 (m, 2H), 4.01-4.07 (m, 1H), 4.27-4.35 (m, 1H), 4.55 (s, 2H), 4.66-4.75 (m, 1H), 5.01-5.07 (m, 1H), 6.97- 7.03 (m, 2H), 7.14 -7.29 (m, 8H), 7.36-7.41 (m, 2H), 7.70-7.85 (m, 1H), 8.28-8.33 (m, 1H).

Example 84

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-4-methyl-D-leucine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycine (20 mg, 0.037 mmol) was dissolved in 1.5 mL of DMF. N-methylmorpholine (13 μl, 118 mmol) and TBTU (15 mg, 0.047 mmol) were added and the mixture was stirred for 1 hour. β-t-butyl-D-alanine (11 mg, 0.076 mmol) was added and the mixture was stirred for 3 hours. Water (0.2 mL) was added and the mixture was stirred for 15 minutes. MeOH (2 mL) and NaBH ₄ (15 mg) were added. After 15 minutes NH ₄ AC (about 20 mg) was added. Purification using preparative HPLC on C8 column. A gradient of 20% to 50% MeCN in 0.1 M NH ₄ Ac was used as the mobile phase. Lyophilization gave 17.5 mg (70%) of the title compound. M / z: 668 (M-1). NMR (400 MHz, DMSO): 8.24 (t, 1H), 7.77-7.87 (m, 1H), 7.32-7.40 (m, 4H), 7.22-7.27 (m, 2H), 7.07-7.19 (m, 4H) , 6.99 (d, 2H), 5.06 (dd, 1H), 4.70-4.78 (m, 1H), 4.53 (s, 2H), 4.31 (dd, 1H), 4.09-4.17 (m, 1H), 3.65-3.81 (m, 2H), 2.84-3.00 (m, 2H), 1.65 (dd, 1H), 1.42 (dd, 1H), 0.86 (s, 9H).

Example 85

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-3-cyclopentyl-D-alanine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} in DMF (2 mL) To a solution of 4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (0.05 g, 0.092 mmol) and N-methylmorpholine (0.037 mg, 0.37 mmol), TBTU (0.039 g, 0.012) under a nitrogen atmosphere. mmol) was added. After 1.5 h, 3-cyclopentyl-D-alanine (0.022 g, 0.139 mmol) was added. The reaction was stirred for 1 hour, after which water (1 mL) was added. After 10 minutes MeOH (2 mL) and NaBH ₄ (0.035 mg, 0.926 mmol) were added. It was completely converted to the corresponding alcohol within 5 minutes. The reaction was quenched by addition of 0.1 M NH ₄ OAc buffer (2 mL) and the mixture was subjected to preparative HPLC (0-50% CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent). The product was isolated. Pure fractions were lyophilized to afford the desired compound (0.031 g, 49%) as a colorless solid. m / z: 680.7 (M < -1 >). ¹ H, NMR [(CD ₃ ) ₂ SO), 400 MHz] 0.97-1.10 (m, 2H), 1.38-1.81 (m, 9H), 2.84-2.94 (m, 2H), 3.77 (d, 2H), 4.11-4.16 (m, 1H), 4.25-4.28 (m, 1H), 4.51 (s, 2H), 4.69-4.75 (m, 1H), 5.03-5.06 (m, 1H), 6.97-7.37 (m, 12H ), 8.02-8.06 (m, 1 H), 8.22 (t, 1 H).

Example 86

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2-hydroxy-2- (4-methoxyphenyl) ethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-3-methyl-D-valine

[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-methoxyphenyl) -2-oxoethyl] thio} -4- in DMF (2 mL) To oxoazetidin-2-yl) phenoxy] acetic acid (0.04 g, 0.081 mmol) and N-methyl morpholine (0.033 g, 0.323 mmol) was added TBTU (0.034 g, 0.105 mmol) under a nitrogen atmosphere. After 15 h, glycyl-3-methyl-D-valine trifluoroacetate salt (0.037 g, 0.121 mmol) was added. The mixture was stirred for 1 hour and then water (1 mL) was added. After 10 minutes MeOH (2 mL) and NaBH ₄ (0.031 g, 0.807 mmol) were added. It was completely converted to the corresponding alcohol within 5 minutes. The reaction was quenched by addition of 0.1 M NH ₄ OAc buffer (2 mL) and the mixture was subjected to preparative HPLC (0-50% CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent). The product was isolated. Pure fractions were lyophilized to afford the desired compound (0.027 g, 50%) as a colorless solid. m / z: 666.7 (M < -1 >). H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 0.88 (s, 9H), 2.81-2.93 (m, 2H), 3.69-3.70 (m, 3H), 3.82 (d, 2H), 4.03-4.07 (m, 1H), 4.22-4.25 (m, 1H), 4.51 (s, 2H), 4.61-4.68 (m, 1H), 5.01-5.03 (m, 1H), 6.81-7.36 (m, 12H), 7.81 -7.86 (m, 1 H), 8.25 (t, 1 H).

Example 87

N-({4-[(2R, 3R) -3-{[2- (4-ethoxyphenyl) -2-hydroxyethyl] thio} -1- (4-fluorophenyl) -4-oxooa Zetidin-2-yl] phenoxy} acetyl) glycyl-3-methyl-D-valine

{4-[(2R, 3R) -3-{[2- (4-ethoxyphenyl) -2-oxoethyl] thio} -1- (4-fluorophenyl) -4- in DMF (2 mL) To a solution of oxoazetidin-2-yl] phenoxy] acetic acid (0.04 g, 0.078 mmol) and N-methyl morpholine (0.032 g, 0.314 mmol) was added TBTU (0.033 g, 0.102 mmol) under a nitrogen atmosphere. After 45 minutes, glycyl-3-methyl-D-valine trifluoroacetate salt (0.031 g, 0.102 mmol) was added. The mixture was stirred for 15 minutes, then water (1 mL) was added. After 10 minutes MeOH (2 mL) and NaBH ₄ (0.030 g, 0.785 mmol) were added. It was completely converted to the corresponding alcohol within 5 minutes. The reaction was quenched by addition of 0.1 M NH ₄ OAc buffer (2 mL) and the mixture was subjected to preparative HPLC (0-50% CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent). The product was isolated. Pure fractions were lyophilized to afford the desired compound (0.027 g, 50%) as a colorless solid. m / z: 680.8 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] 0.89 (s, 9H), 1.26-1.30 (m, 3H), 2.81-2.92 (m, 2H), 3.82 (d, 2H), 3.93-3.99 (m, 2H), 4.05-4.08 (m, 1H), 4.22-4.25 (m, 1H), 4.51 (s, 2H), 4.60-4.67 (m, 1H), 5.01-5.03 (m, 1H), 6.79 -7.36 (m, 12 H), 7.82-7.87 (m, 1 H), 8.25 (t, 1 H).

Example 88

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-S- (4-methoxy) -D-cysteine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} in DMF (3 mL) To a stirred solution of -4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (21.3 mg, 0.039 mmol) was added N-methylmorpholine (20 μl, 0.18 mmol). TBTU (15. 1 mg, 0.047 mmol) was added and the mixture was stirred at 30 ° C. for 35 minutes. S- (4-methoxybenzyl) -D-cysteine (12.8 mg, 0.053 mmol) was added and the mixture was stirred at 30 ° C. for 1 hour and at room temperature for 1.5 hours. The production of ketones of the title compound was confirmed. M / z: 764.11 (M + l) and 762.06 (M-1). Methanol (3 mL) and sodium borohydride (15 mg, 0.40 mmol) were added and the mixture was stirred for 20 minutes. Ammonium acetate (25 mg) was added and methanol was removed under reduced pressure. The remaining DMF-solution was purified by preparative HPLC (UV 240/260) on a C8 column. A gradient of 20% to 47% MeCN in 0.1 M NH ₄ OAc was used as eluent. MeCN was removed from the collected fractions under reduced pressure. The remaining aqueous solution was acidified to pH 1 with KHSO ₄ (2M) and extracted with DCM. The organic phase was concentrated under reduced pressure and the residue was dissolved in MeCN and water. After freeze drying, the title compound was obtained as a white solid (10.7 mg, 36%). H-NMR (400 MHz, DMSO-d ₆ ): 2.60-2.80 (m, 2H), 2.83-2.97 (m, 2H), 3.63-3.66 (bd, 2H), 3.69 (s, 3H), 3.77-3.81 (bd, 2H), 4.24-4.33 (m, 2H), 4.52 (s, 2H), 4.67-4.76 (m, 1H), 5.03 (d, 0.5H), 5.06 (d, 0.5H), 5.60-5.90 (b, 1H), 6.82 (d, 2H), 6.98 (d, 2H), 7.05-7.25 (m, 8H), 7.30-7.38 (m, 4H), 8.00-8.10 (b, 1H), 8.30 (t , 1H). M / z: 764.07 (M-1).

Example 89

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-O-benzyl-L-serine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} in DMF (2 mL) To the stirred solution of -4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (20.3 mg, 0.038 mmol) was added N-methylmorpholine (15 μl, 0.14 mmol). TBTU (14.8 mg, 0.046 mmol) was added and the mixture was stirred at 30 ° C. for 1.5 h. O-benzyl-L-serine (8.8 mg, 0.045 mmol) was added and the mixture was stirred overnight. The production of ketones of the title compound was confirmed. M / z: 718.04 (M + l) and 716.02 (M-1). Methanol (3 mL) and sodium borohydride (10.3 mg, 0.27 mmol) were added and the mixture was stirred for 1.5 h. Ammonium acetate (20 mg) was added and methanol was removed under reduced pressure. The remaining DMF solution was purified by preparative HPLC (UV 240/260 nm) on a C8 column. A gradient of 20% to 45% in 0.1 M NH ₄ OAc buffer was used as eluent. Pure fractions were collected and MeCN was removed under reduced pressure. The remaining aqueous solution with HCl (1M) was acidified to pH 1 and extracted with DCM. The combined organic phases were concentrated and the residue was dissolved in MeCN and water. After freeze drying, the title compound was obtained as a white solid (2.3 mg, 8.5%).

H-NMR (400 MHz, DMSO-d ₆ ): 2.85-2.94 (m, 2H), 3.58-3.63 (m, 1H), 3.69-3.75 (m, 1H), 3.83 (d, 2H), 4.25 (d , 0.5 H), 4.27 (d, 0.5H), 4.39-4.44 (m, 1H), 4.46 (d, 2H), 4.51 (s, 2H), 4.68-4.75 (m, 1H), 5.03 (d, 0.5 H), 5.06 (d, 0.5), 6.98 (d, 2H), 7.05-7.17 (m, 4H), 7.20-7.26 (m, 3H), 7.28-7.39 (m, 8H), 8.20 (d, 1H) , 8.25 (t, 1 H). M / z: 718.10 (M-1).

Example 90

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-S- (4-methylbenzyl) -D-cysteine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} in DMF (2.0 mL) To a stirred solution of -4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (19.9 mg, 0.037 mmol) was added N-methylmorpholine (15 μl, 0.14 mmol). TBTU (14.4 mg, 0.045 mmol) was added and the mixture was stirred at 30 ° C. for 45 minutes. S- (4-methylbenzyl) -D-cysteine (10.5 mg, 0.047 mmol) was added and the mixture was stirred at 30 ° C. for 1 hour. The production of ketones of the title compound was confirmed. M / z: 748.02 (M + l). Methanol (2 mL) and sodium borohydride (14.7 mg, 0.39 mmol) were added and the mixture was stirred for 30 minutes. Ammonium acetate (20 mg) was added and methanol was removed under reduced pressure. The remaining DMF-solution was purified by preparative HPLC (UV-detection 240/260 nm) on a C8 column. A gradient of 20% to 50% MeCN in 0.1 M NH ₄ OAc buffer was used as eluent. Pure fractions were collected and MeCN was removed under reduced pressure. The remaining aqueous solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The combined organic phases were concentrated and the residue was dissolved in MeCN and water. After freeze drying, the title compound was obtained as a white solid (8.7 mg, 31.5%). H-NMR (400 MHz, DMSO-d ₆ ): 2.24 (s, 3H), 2.60-2.68 (m, 1H), 2.72-2.79 (m, 1H), 2.86-2.94 (m, 2H), 3.68 (s , 2H), 3.82 (d, 2H), 4.25 (d, 0.5H), 4.27 (d, 0.5H), 4.39-4.46 (m, 1H), 4.52 (s, 2E [), 4.67-4.77 (m, 1H), 5.03 (d, 0.5H), 5.06 (d, 0.5H), 5.60-5.67 (bs, 1H), 6.98 (d, 2H), 7.05-7.18 (m, 8H), 7.20-7.25 (m, 2H), 4.30-4.39 (m, 4H), 8.23-8.32 (m, 2H), 12.80-12.95 (bs, 1H). M / z: 748.04 (M-1).

Example 91

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-ornithine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyl-D-ornithine (0.021 g, 0.032 mmol) was dissolved in methanol (1.5 mL). NaBH ₄ (0.0032 g, 0.085 mmol) was added and after about 15 minutes the reaction was complete by LC-MS. Several drops of acetic acid were added. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on Kromasil C8-column (37% MeCN in 0.1 M ammonium acetate as eluent). After freeze drying, 0.018 g (85%) of the desired product was obtained.

NMR (500 MHz, CD ₃ COOD) 1.62-1.80 (m, 3H), 1.91-2.00 (m, 1H), 2.92-3.10 (m, 4H), 3.98 (ABq, 2H), 4.05 (d, 0.5H) , 4.08 (d, 0.5H), 4.27-4.32 (m, 1H), 4.64 (s, 2H), 4.82-4.87 (m, 1H), 4.93 (d, 0.5H), 4.94 (d, 0.5H), 6.99-7.06 (m, 4H), 7.09 (d, 2H), 7.28-7.33 (m, 2H), 7.33-7.41 (m, 4H)

Example 92

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-N ⁶ , N ⁶ -Dimethyl-L-lysine acetate

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyl-N ⁶ , N ⁶ -dimethyl-L-lysine (0.05 g, 0.007 mmol) was dissolved in methanol (1.5 mL). NaBH ₄ (0.0065 g, 0.0172 mmol) was added and after about 15 minutes the reaction was complete by LC-MS. Several drops of acetic acid were added. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on Kromasil C8-column (33.5% of MeCN in 0.1 M ammonium acetate buffer as eluent). After lyophilization, 0.004 g (73%) of sour product was obtained as the acetate salt.

NMR (500 MHz, CD ₃ COOD) 1.33-1.43 (m, 2H), 1.62-1.78 (m, 3H), 1.85-1.98 (m, 4H), 2.83 (s, 6H), 2.91-3.08 (m, 4H ), 3.94 (s, 2H), 4.02 (d, 0.5H), 4.05 (d, 0.5H), 4.25-4.30 (m, lH), 4.61 (s, 2H), 4.79-4.85 (m, 1H), 4.90 (d, 0.5H), 4.92 (d, 0.5H), 6.96-7.08 (m, 6H), 7.25-7.30 (m, 2H), 7.30-7.38 (m, 4H)

Example 93

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxaoa Zetidin-2-yl) phenoxy] acetyl} glycyl-b, b-dimethyl-D-phenylalanine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} in DMF (2 mL) To a stirred solution of -4-oxoazetidin-2-yl) phenoxy] acetyl} glycine (25.2 mg, 0.047 mmol) was added N-methylmorpholine (30 μl, 0.027 mmol). TBTU (18.0 mg, 0.056 mmol) was added and the mixture was stirred at 30 ° C. for 1 h. β, β-dimethyl-D-phenylalanine trifluoroacetate was added and the mixture was stirred at 30 ° C. for 1.25 hours. The formation of ketones of the title compound was confirmed. M / z: 716.07 (M + l) and 714.05 (M-1). Water (0.5 mL) was added. Methanol (2 mL) and sodium borohydride (18.2 mg, 0.48 mmol) were added and the mixture was stirred for 25 minutes. Ammonium acetate (30 mg) was added and methanol was removed under reduced pressure. The remaining DMF-solution was purified by preparative HPLC. A gradient of 20% to 48% MeCN in 0.1 M NH ₄ OAc buffer was used as eluent. MeCN was removed under reduced pressure and the remaining aqueous solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The organic phase was concentrated under reduced pressure and the residue was dissolved in MeCN and water. After freeze drying, the title compound was obtained as a white solid (20.5 mg, 62%). H NMR (400 MHz, DMSO-d ₆ ): 1.27-1.32 (m, 6H), 2.75-3.05 (m, 2H), 3.55-3.67 (m, 1H), 3.79 (dd, 1H), 4.25-4.30 ( m, 0.5H), 4.40 (s, 0.5H), 4.45-4.53 (m, 3H), 4.68-4.78 (m, 1H), 4.99 (d, 0.5H), 4.05 (d, 0.5H), 6.88 -6.98 (m, 2H), 7.05-7.17 (m, 5H), 7.20-7.40 (m, 10H) 7.45-7.75 (m, 1H) 8.22 (t, 1H). M / z: 718.09 (M + l) and 716.07 (M-1).

Example 94

1- (4-fluorophenyl) -3- (R)-[2- (4-fluorophenyl) -2-hydroxyethylthio] -4- (R)-{4- [N- (α- (R)-{N- [2- (hydroxy) -1- (S)-(carboxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one

1- (4-fluorophenyl) -3- (R)-[(4-fluorobenzoyl) ethylthio] -4- (R)-{4- [N- (α- ( R)-{N- [2- (hydroxy) -1- (S)-(carboxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one (0.039 g, 0.055 mmol) was added NaBH ₄ (0.005 g, 0.135 mmol). After 10 minutes, water (2 mL) and acetic acid (2 drops) were added and then most of the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (using 20% to 60% gradient of MeCN as eluent in 0.1 M ammonium acetate buffer). The desired product was lyophilized to yield 0.038 g (96%) as a white solid. NMR (DMSO, 500 MHz): 2.90-3.00 (m, 2H), 3.50 (dd, 1H), 3.60 (dd, 1H), 4.15-4.30 (m, 2H), 4.60 (ABq, 2H), 4.70-4.80 (m, 1H), 5.00-5.05 (m, 1H), 5.65 (d, 1H), 6.95-7.45 (m, 17H), 8.30-8.45 (m, 2H); m / z: 706.4.

Example 95

1- (4-fluorophenyl) -3- (R)-[2- (4-fluorophenyl) -2-hydroxyethylthio] -4- (R)-{4- [N- (α- (R) {N- [2- (t-butoxy) -l- (s)-(carboxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azididin-2-one

1- (4-fluorophenyl) -3- (R)-[2- (4-fluorobenzoyl) methylthio] -4- (R)-{4- [N- (α) in MeOH (3 mL) -(R) {N- [2- (t-butoxy) -l- (s)-(carboxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azididin-2-one (0.002 g, 0.003 mmol) was added NaBH ₄ (0.004 g, 0. 108 mmol). After 10 minutes, water (1 mL) and acetic acid (2 drops) were added to the solution, and then the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (using 20% to 60% gradient of MeCN as eluent in 0.1 M ammonium acetate buffer). The desired product was freeze dried to yield 0.002 g (~ quantitative yield) as a white solid. NMR (DMSO, 500 MHz): 1.00 (s, 9H), 2.90-3.00 (m, 2H), 3.40-3.55 (m, 2H), 4.20-4.30 (m, 2H), 4.60 (ABq, 2H), 4.70 -4.80 (m, 1H), 5.00-5.05 (m, 1H), 5.70 (d, 1H), 6.95-7.45 (m, 17H), 8.20 (bs, 1H), 8.35 (d, 1H); m / z: 762.5.

Example 96

1- (4-fluorophenyl) -3- (R)-[2- (4-fluorophenyl) -2-hydroxyethylthio] -4- (R)-{4- [N- {N- [2 (hydroxy) -1- (R)-(carboxy) ethyl] carbamoylmethyl} carbamoylmethoxy] phenyl} azetidin-2-one

1- (4-fluorophenyl) -3- (R)-[(4-fluorobenzoyl) methylthio] -4- (R)-{4- [N- {N- [in MeOH (3 mL) NaBH ₄ (0.010) in a solution of 2- (hydroxy) -1- (R)-(carboxy) ethyl] carbamoylmethyl} carbamoylmethoxy] phenyl} azetidin-2-one (0.028 g, 0.045 mmol) g, 0.264 mmol) was added. After 10 minutes, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC (using 20% to 50% gradient MeCN in 0.1 M ammonium acetate buffer as eluent). The desired product was lyophilized to yield 0.014 g (50%) as a white solid. NMR (CD ₃ COOD, 400 MHz): 3.00-3.20 (m, 2H), 3.95 (dd, 1H), 4.00-4.15 (m, 2H), 4.25 (ABq, 2H), 4.70 (s, 2H), 4.70 -4.80 (m, 1H), 4.85-5.00 (m, 2H), 6.95-7.10 (m, 6H), 7.25-7.45 (m, 6H); m / z: 630.1.

Example 97

1- (4-fluorophenyl) -3- (R)-[2- (4-fluorophenyl) -2-hydroxyethylthio] -4- (R)-{4- [N- {N- [2- (phenyl) -l- (R)-(carboxy) ethyl] carbamoylmethyl} carbamoylmethoxy] phenyl} azetidin-2-one

1- (4-fluorophenyl) -3- (R)-[(4-fluorobenzoyl) methylthio] -4- (R)-{4- [N- {N- [2- (phenyl)- 1- (R)-(carboxy) ethyl] carbamoylmethyl} carbamoylmethoxy] phenyl} azetidin-2-one (15 mg, 0.022 mmol) was dissolved in methanol (1 mL) and sodium borohydra Id (4 mg) was added. The solvent was evaporated and the residue was purified by preparative HPLC (using 10% to 100% gradient MeCN in 0.1 M ammonium acetate buffer as mobile phase). The product fractions were lyophilized to give 8 mg (53%) of the desired product. NMR (400 MHz, CD ₃ COOD): 3.02-3.17 (m, 3H), 3.19-3.25 (m, 1H), 4.06-4.17 (m, 3H), 4.66 (s, 2H), 4.87-4.96 (m, 3H), 6.97-7.05 (m, 6H), 7.10-7.40 (m, 12H); m / z 688.3 (mH).

Examples 98-136

According to the method of Example 97, the following compounds can be prepared using different protecting groups.

Preparation of Starting Material of the Example

Way

Method 1

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} -D-alanine

[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazetidine-2 -Yl) phenoxy] acetic acid (50 mg, 0.1 mmol), t-butyl D-alanineate (23 mg, 0.12 mmol) and 4-methylmorpholine (31 mg, 0.31 mmol) in DCM (1.5 mL) Dissolved and stirred at room temperature for 5 minutes. TBTU (40 mg, 0.12 mmol) was added and the reaction mixture was stirred for 2 hours. TFA (0.7 mL) was added and the solution stirred for 90 minutes. TFA and DCM were removed under reduced pressure, and the residue was dissolved in DCM and washed with water. The organic phase was dried over sodium sulphate and the solvent was removed under reduced pressure to give 55 mg (95%) of the title compound. M / z: 553.0 (M-1).

Method 2

[4-((2R, 3R) -3-{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} -4-oxo-1- phenylazetidine -2-yl) phenoxy] acetic acid

Ethyl [4-((2R, 3R) -3-{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} -4- in MeOH (25 mL) To a solution of oxo-1-phenylazetidin-2-yl) phenoxy] acetate (0.86 g, 1.53 mmol) was added water (2.5 mL) and triethylamine (1.55 g). The reaction was stirred at 50 ° C. for 48 hours. The solvent was evaporated and the residue was purified by preparative HPLC (using 20% to 70% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer). Pure fractions were lyophilized to provide the title compound as a colorless solid. ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 0.50 (s, 3H), 1.15 (s, 3H), 2.93 (d, 1H), 2.96 (d, 1H), 3.21-3.37 (m, 4H), 4.13 (d, 1H), 4.28 (s, 2H), 4.97 (d, 1H), 6.83-7.41 (m, 14H).

Method 3

N-[(4-{(2R, 3R) -4-oxo-3-[(2-oxo-2-phenylethyl) thio] -1-phenylazetidin-2-yl} phenoxy) acetyl] glycine

Glycine t-butyl ester (0.015 g, 0.112 mmol) and N-methylmorpholine (0.028 g, 0.281 mmol) were dissolved in CH ₂ Cl ₂ (5 mL) [4-((2R, 3R) -3-{[( 5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} -4-oxo-1-phenylazetidin-2-yl) phenoxy] acetic acid (0.050 g, 0.094 mmol) ) Was added to the solution. After 10 minutes, TBTU (0.039 g, 0.122 mmol) was added. The reaction was stirred overnight. The resulting t-butyl ester was purified on silica gel and eluted with EtOAc / CH ₂ Cl ₂ (25/75). Pure fractions were collected and concentrated. CH ₂ Cl ₂ (4 mL) and TFA (1 mL) were added. After 2 hours the solvent was evaporated and the residue was purified by preparative HPLC (20% to 70% CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent). Pure fractions were lyophilized to provide the title compound as a colorless solid. M / z: 503.5 (M 1). _{^{l H NMR [(CD 3 CN}} ), 400 MHz] 3.84 (d, 2H), 4.18 (d, 1H), 4.24 (s, 2H), 4.50 (s, 2H), 5.04 (d, 1H), 6.99- 7.12 (m, 3H), 7.25-7.66 (m, 9H), 7.94-7.96 (m, 2H).

Method 4

(2R)-({[4-((2R, 3R) -1- (4-fluorophenyl) -3- [2- (4-fluorophenyl) -2-oxoethyl] thio} -4-ox Pediatric zetidin-2-yl) phenoxy] acetyl} amino) (phenyl) acetic acid

4-((2R, 3R) -1- (4-fluorophenyl) -3- [2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazetidin-2-yl ) Phenoxy] acetic acid (0.40 g, 0.827 mmol) was dissolved in CH ₂ Cl ₂ (40 mL), t-butyl (2R) -amino (phenyl) acetate (0.206 g, 0.993 mmol) and N-methylmorpholine (0.251 g, 2.48 mmol) was added. After 10 minutes, TBTU (0.345 g, 1.076 mmol) was added. The reaction was stirred overnight. The resulting t-butyl ester was concentrated and purified on silica gel (eluted with EtOAc / CH ₂ Cl ₂ 25/75). Pure fractions were collected and concentrated. CH ₂ Cl ₂ (25 mL) and TFA (3 mL) were added. The mixture was stirred for 5 days and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (20% to 70% gradient CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent). Pure fractions were lyophilized to provide the title compound as a colorless solid. M / z: 615.50 (M < -1 >). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 4.35 (d, 1H), 4.36 (d, 1H), 4.40 (d, 1H), 4.53 (d, 1H), 4.58 (d, 1H) , 4.94 (d, 1H), 5.19 (d, 1H), 6.97-7.40 (m, 15H), 8.02-8.06 (m, 2H), 8.26-8.32 (m, 1H).

Method 5

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} -D-valine

[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazetidine-2 -Yl) phenoxy] acetic acid (50.0 mg, 0.10 mmol) was dissolved in DCM (2 mL). t-butyl D-valinate hydrochloride (28.4 mg, 0.14 mmol) and N-methylmorpholine (3.0 μl, 0.31 mmol) were added. After 5 minutes, TBTU (43.7 mg, 0.14 mmol) was added and the mixture was stirred overnight. T-butylester, an intermediate of the title compound, was identified. M / z: 637.1 (M−H). The solvent was removed under reduced pressure. The yellow residue was dissolved in formic acid (1.5 mL) and heated at 50 ° C. for 5 hours. The solvent was evaporated and the residue was purified by preparative HPLC on C8 column. A gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. Lyophilization gave the title compound as a white solid (30.5 mg, 51%). ¹ H-NMR (400 MHz, DMS-d ₆ ): 0.74 (t, 6H), 1.98-2.07 (m, 1H), 3.84 (brs, 1H), 4.32 (d, 1H), 4.35 (s, 1H) , 4.36 (s, 1H), 4.50 (brs, 2H), 5.16 (d, 1H), 6.96 (d, 2H), 7.10-7.17 (m, 2H), 7.19-7.24 (m, 2H), 7.31-7.38 (m, 4H), 7.66 (brs, 1 H), 7.99-8.04 (m, 2H). M / z: 583.0 (M + H) and 581.0 (MH).

Method 6

(N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3- [2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyl-D-valine

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- {4- [N- in DCM (2 mL) (Carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one (0.0229 g, 0.042 mmol), (R) -valine t-butylester hydrochloride (0.0121 g, 0.058 mmol) and N-methylmorpholine (0.012 mL, 0.111 mmol) was stirred at rt. TBTU (0.018 g, 0.056 mmol) was added and the mixture was stirred overnight. Trifluoroacetic acid (0.65 mL) was added and after several hours the hydrolysis was completed by LC-MS. The solvent was removed under reduced pressure and purified by preparative HPLC on Kromasil C8-column (using 5% to 100% gradient MeCN in 0.15% trifluoroacetic acid buffer as eluent). The solvent was removed under reduced pressure to afford 0.022 g (81%) of the title compound. M / z 640.06.

Method 7

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyl-L-threonine

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- {4- [N- in DCM (2 mL) (Carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one (0.0188 g, 0.035 mmol), t-butyl O- (t-butyl) -L-threoninate (0.0151 g, 0.065 mmol) and N-methylmorpholine (0.012 mL, 0.lll mmol) was stirred at room temperature. TBTU (0.018 g, 0.056 mmol) was added and the mixture was stirred overnight. Trifluoroacetic acid (0.65 mL) was added and after several hours the hydrolysis was completed by LC-MS. The solvent was removed under reduced pressure and purified by preparative HPLC on Kromasil C8-column (using 5% to 100% gradient of MeCN in 0.15% trifluoroacetic acid buffer as eluent). The solvent was removed under reduced pressure and 0.014 g (63%) of the title compound were obtained. M / z 641.92.

Method 8

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyl-L-asparagine

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- {4- [N- in DCM (2 mL) (Carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one (0.0213 g, 0.039 mmol), t-butyl L-asparaginate hydrochloride (0.0141 g, 0.063 mmol) and N-methylmorpholine ( 0.012 mL, 0.111 mmol) was stirred at room temperature. TBTU (0.018 g, 0.056 mmol) was added and the mixture was stirred overnight. Trifluoroacetic acid (0.65 mL) was added and after several hours the hydrolysis was completed by LC-MS. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on Kromasil C8-column (using 5% to 100% gradient MeCN in 0.15% trifluoroacetic acid buffer as eluent). Removal of solvent under reduced pressure gave 0.020 g (77%) of the title compound. M / z 655.11.

Method 9

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-L-methionine

 3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- {4- [N- in DCM (2 mL) (Carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one (0.0197 g, 0.036 mmol), t-butyl L-methionate hydrochloride (0.0144 g, 0.060 mmol) and N-methylmorpholine ( 0.012 mL, 0.lll mmol) was stirred at room temperature. TBTU (0.018 g, 0.056 mmol) was added and the mixture was stirred overnight. Trifluoroacetic acid (0.65 mL) was added and after several hours the hydrolysis was completed by LC-MS. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on Kromasil C8-column (using 5% to 100% gradient MeCN in 0.15% trifluoroacetic acid buffer as eluent). Removal of solvent under reduced pressure gave 0.015 g (61%) of the title compound. M / z 672.10.

Method 10

t-butyl N-[(benzyloxy) carbonyl] glycid-D-valinate

N-[(benzyloxy) carbonyl] glycine (2.4 g, 11.5 mmol), t-butyl D-valinate hydrochloride (2.4 g, 11.4 mmol) and N-methylmorpholine (2.53 mL) in DCM (20 mL) , 22.9 mmol), were stirred at room temperature. TBTU (4.79 g, 14.9 mmol) was added and the mixture was stirred for 3 days. The solvent was removed under reduced pressure. Water was added and the mixture was extracted twice with toluene. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by flash chromatography (using DCM: EtOAc: acetone 4: 1: 1 as eluent) to give 3.92 g (94%) of the title compound. NMR (500 MHz, CD3COOD) 0.88-0.99 (m, 6H), 1.48 (s, 9H), 2.08-2.19 (m 1H), 3.85 (ABq, 2H), 4.24 (d, 1H), 5.12 (ABq, 2H ), 7.28-7.41 (m, 5H).

Method 11

t-butyl glycyl-D-valinate hydrochloride

t-butyl N-[(benzyloxy) carbonyl] glycyl-D-valinate (3.89 g, 10.7 mmol) and Pd on carbon (95%, 0.3 g) were mixed in EtOH (95%, 80 mL) And stirred for 2 hours under H ₂ -atmosphere. The mixture was filtered through celite 521 and the solvent was evaporated under reduced pressure. MeCN (25 mL) and pyridine hydrochloride (1.25 g, 10.8 mmol) were added. Evaporation of the solvent under reduced pressure gave 2.3 g (81%) of the title compound. NMR (500 MHz, CD ₃ COOD) 0.96-1.01 (m, 6H), 1.49 (s, 9H), 2.13-2.23 (m 1H), 3.76 (AB, 2H), 4.28-4.33 (m, 1H).

Method 12

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-methoxyphenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyl-D-valine

[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-methoxyphenyl) -2-oxoethyl] thio} -4- in DCM (2 mL) Oxoazetidin-2-yl) phenoxy] acetic acid (0.0153 g, 0.031 mmol), t-butyl glycyl-D-valinate hydrochloride (0.0099 g, 0.037 mmol) and N-methylmorpholine (0.010 mL) , 0.991 mmol) was stirred at room temperature. TBTU (0.016 g, 0.050 mmol) was added and the mixture was stirred for 3.5 h. Trifluoroacetic acid (0.5 mL) was added and after 3.5 hours the solvent was removed under reduced pressure. The residue was purified by preparative HPLC on Kromasil C8-column (using 5% to 100% gradient MeCN in 0.15% trifluoroacetic acid as eluent). Removal of solvent under reduced pressure gave 0.015 g (74%) of the title compound. M / z 652.20.

Method 13

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-methoxyphenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycine

[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-methoxyphenyl) -2-oxoethyl] thio} -4- in DCM (2 mL) Oxoazetidin-2-yl) phenoxy] acetic acid (0.l50 g, 0.30 mmol), t-butyl glycinate hydrochloride (0.0635 g, 0.38 mmol) and N-methylmorpholine (0.10 mL, 0.91 mmol ) The mixture was stirred at room temperature. TBTU (0.128 g, 0.40 mmol) was added and the mixture was stirred overnight. Trifluoroacetic acid (4.0 mL) was added and after 2 hours the solvent was removed under reduced pressure. The residue was purified by preparative HPLC on Kromasil C8 column (35% MeCN in 0.1 M ammonium acetate buffer as eluent). Removal of solvent under reduced pressure gave 0.159 g (95%) of the title compound. M / z 553.02.

Method 14

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-2-butylnorleucine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycine (0.020 g, 0.037 mmol) and NMM (0.040 mL, 0.363 mmol) were dissolved in DCM (5 mL) at 30 ° C. TBTU (total 0.016 g, 0.050 mmol) was added in portions and the mixture was stirred for 1 hour. 2-butylnorleucine (0.007 g, 0.037 mmol) was added and the mixture was stirred at 30 ° C. for 18 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (using 20% to 50% gradient of MeCN in 0.1 M ammonium acetate buffer as eluent). After freeze drying, 0.009 g (34% yield) of the title compound were obtained as a white solid. M / z: 710.1. ¹ H NMR (DMSO, 400 MHz): δ 0.73-0.82 (m, 6H), 0.88-1.22 (m, 8H), 1.56-1.69 (m, 2H), 1.96-2.07 (m, 2H), 3.71 (d , 2H), 4.32 (d, 1H), 4.36 (ABq, 2H), 4.52 (s, 2H), 5.16 (d, 1H), 6.95-7.01 (m, 2H), 7.11-7.26 (m, 4H), 7.30-7.40 (m, 4H), 7.61 (s, 1H), 7.98-8.06 (m, 2H), 8.25-8.42 (m, 1H).

Method 15

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3- [2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazetidine -2-yl) phenoxy] acetyl} -L-alanine

[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4- in DCM (4 mL) Oxoazetidin-2-yl) phenoxy] acetic acid (0.020 g, 0.041 mmol), L-alanine t-butyl ester hydrochloride (0.009 g, 0.050 mmol) and N-methylmorpholine (0.018 mL, 0. 163 mmol) was stirred for 5 minutes. TBTU (0.017 g, 0.053 mmol) was added. After 3 hours the formation of esters was confirmed. M / z: 611.1. TFA (3 mL) was added. After 2 hours, the mixture was diluted with toluene (2 mL) and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (using 20% to 50% gradient MeCN in 0.1 M ammonium acetate buffer as buffer). After freeze drying, 0.023 g (> 98%) of the title compound were obtained as a white solid. M / z: 555.1. ¹ H NMR (DMSO, 400 MHz): δ 1.17 (d, 3H), 3.73-3.82 (m, 1H), 4.33 (d, 1H), 4.35 (ABq, 2H), 4.43 (s, 2H), 5.15 ( d, 1H), 6.92-7.98 (m, 2H), 7.10-7.24 (m, 4H), 7.29-7.39 (m, 4H), 7.84 (d, 1H), 7.97-8.04 (m, 2H).

Method 16

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyl-L-phenylalanine

Methyl N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-L-phenylalanineate (20 mg, 0.029 mmol) was dissolved in 1.6 mL of MeOH and 0.2 mL of H ₂ O. Et ₃ N (0.2 mL, 1.44 mmol) was added and the mixture was stirred overnight. The mixture was heated to 80 ° C. for 7 hours. The mixture was purified by preparative HPLC using C8 column (25x300 nm). A gradient of 20% to 40% MeCN in 0.1 M ammonium acetate was used as the mobile phase. The product fractions were concentrated and lyophilized to give 7 mg (36%) M / z: 688.

Method 17

Methyl N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-L-phenylalanine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycine (66 mg, 0.12 mmol) was dissolved in 2 ml DCM. N-methylmorpholine (40 μl, 0.36 mmol), L- (S) -phenylalanine methyl ester hydrochloride (33 mg, 0.15 mmol) and finally TBTU (45 mg, 0.14 mmol) were added. The mixture was stirred overnight. The crude mixture was purified by flash chromatography on 5 g SiO ₂ . EtOAc: hexane (1: 1), DCM and finally DCM: acetone (4: 1) were used as eluent. The collected fractions were concentrated to give 67 mg (78%) of the title compound. M / z: 724.

Method 18

t-butyl N-{[4- (2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxo Pediatric zetidin-2-yl) phenoxy] acetyl} glycyl-4-methyllucisinate

N-{[4- (2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazetidine -2-yl) phenoxy] acetyl} glycine (20 mg, 0.037 mmol) was dissolved in 3 mL of DCM. N-methylmorpholine (9 μl, 0.082 mmol) and TBTU (14 mg, 0.044 mmol) were added. After 5 minutes, t-butyl-4-methyllucisinate (9 mg, 0.045 mmol) was added and the mixture was stirred for 2 hours. Additional t-butyl 4-methyllucisinate (about 3 mg, 0.015 mmol) was added. After 15 minutes, water (2 mL) was added and acidified to pH 2 with 2M KHSO ₄ . The aqueous phase was extracted with 2 ml DCM and the combined organic phases were washed with 3 ml water, dried over Na ₂ SO ₄ and filtered. Removal of solvent under reduced pressure provided the title compound. M / z: 724.

Method 19

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glyciglycine

[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4- in DCM (5 mL) Oxoazetidin-2-yl) phenoxy] acetic acid (0.200 g, 0.414 mmol), glycylglycine methyl ester hydrochloride (0.090 g, 0.493 mmol) and N-methylmorpholine (0.150 mL) were stirred for 10 minutes It was. TBTU (0.170 g) was added and the mixture was stirred for 20 hours. The formation of esters was confirmed. M / z: 612.0. The solvent was removed under reduced pressure. The residue was dissolved in a mixture of MeOH (5 mL), water (1 mL) and Et ₃ N (0.5 mL). The solution was stirred at 50 ° C. for 18 h. DBN (0.050 mL, 0.405 mmol) was added and the mixture was stirred at 50 ° C. for 2 h. Ammonium acetate buffer (0.1 M, 3 mL) was added and the mixture was concentrated. The residue was purified by preparative HPLC (using 20% to 50% gradient of MeCN as eluent in 0.1 M ammonium acetate buffer). After freeze drying, the title product (0.094 g, 38% yield) was obtained as a white solid. M / z: 598.2. ¹ H NMR (DMSO, 400 MHz): 3.50 (d, 2H), 3.75 (d, 2H), 4.32 (d, 1H), 4.35 (ABq, 2H), 4.46-4.53 (m, 2H), 5.15 (d , 1H), 6.94-7.00 (m, 2H), 7.10-7.25 (m, 4H), 7.29-7.39 (m, 4H), 7.68-7.81 (m, 1H), 7.98-8.04 (m, 2H), 8.30 -8.36 (m, 1 H).

Method 20

Ethyl {[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} acetate

Ethyl [(2-oxo-2-phenylethyl) thio] acetate (10.8 g, 45.3 mmol) was dissolved in toluene (250 mL). 2,2-dimethyl-1,3-propanediol (37.6 g, 0.36 mol) and p-toluene sulfonic acid (about 500 mg) were added. The mixture was stirred for 2 hours in a Dean Stark apparatus under reflux overnight at room temperature. The mixture was concentrated under reduced pressure. The crude oil was purified by flash chromatography (hexanes: EtOAc-7: 1) to give 11.2 g (70%) of the title compound as colorless oil. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 0.6 (s, 3H), 1.2-1.3 (t, 3H), 1.4 (s, 3H), 3.0 (s, 2H), 3.2 (s, 2H), 3.5 (s, 4H), 4.1-4.2 (q, 2H), 7.3-7.6 (m, 5H).

Method 21

{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} acetic acid

Ethyl {[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} acetate (11.2 g, 34.3 mmol) was dissolved in THF (150 mL) and cooled to 0 ° C. It was. LiOH (2.88 g, 68.7 mmol) in water (40 mL) was added and the mixture was stirred for 19 h. The solvent was evaporated. The product of the mert was extracted between water and diethyl ether. The aqueous layer was acidified with 2M HCl and extracted twice with CH ₂ Cl ₂ . The combined CH ₂ Cl ₂ layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 9.8 g (96%) of the title compound as a white solid. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 0.6 (s, 3H), 1.4 (s, 3H), 3.0 (s, 2H), 3.3 (s, 2H), 3.5 (s, 4H), 7.3- 7.6 (m, 5 H).

Method 22

(4S) -3-({[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} acetyl) -4-phenyl-1,3-oxazolidine- 2-on

{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} acetic acid (9.9 g, 33.0 mmol) was dissolved in dry CH ₂ Cl ₂ (250 mL) and 0 Cooled to C. N, N'-dicyclohexylcarbodiimide (DCC, 7.63 g, 37.0 mmol) and 4- (dimethylamino) pyridine (DMAP, 8.57 g, 70.0 mmol) were added and the mixture was stirred at 0 ° C for 20 minutes. . (S)-(+)-4-phenyl-2-oxazolidinone (5.38 g, 33.0 mmol) was added and the mixture was stirred at rt for 70 h. The mixture was filtered, concentrated under reduced pressure and purified by flash chromatography (hexanes: EtOAc-7: 3). This gave 10.2 g (70%) of the title compound as a white solid. ¹ H-NMR (CDCl ₃ , 200 MHz): 0.6 (s, 3H), 1.3 (s, 3H), 2.8 (s, 2H), 3.4 (s, 4H), 3.8 (s, 2H), 4.1-4.15 (dd, 1H), 4.6-4.8 (t, 1H), 5.35-5.45 (dd, 1H), 7.25-7.45 (m, 9H).

Method 23

Ethyl (4-{(1S, 2R) -1-anilino-2-[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} -3-oxo- 3-[(4S) -2-oxo-4-phenyl-1,3-oxazolidin-3-yl] propyl} phenoxy) acetate

Tetraisopropyl ortho titanate (0.5 mL, 1.7 mmol) was added to a solution of TiCl ₄ (1M in CH ₂ Cl ₂ , 5.1 mL, 5.1 mmol) in CH ₂ Cl ₂ (50 mL) at 0 ° C. under inert atmosphere. . (4S) -3-({[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} acetyl) -4- in dry CH ₂ Cl ₂ (60 mL) Phenyl-1,3-oxazolidin-2-one (3.0 g, 6.8 mmol) was added dropwise over 20 minutes and the mixture was stirred for 10 minutes. Ethyl {4-[(phenylimino) methyl] phenoxy} acetate (3.8 g, 13.6 mmol) in dry CH ₂ Cl ₂ (60 mL) was added dropwise over 30 minutes and the mixture was cooled to -40 ° C. and 20 minutes. Was stirred. Ethyl diisopropyl amine (2.3 mL, 13.6 mmol) was added dropwise over 10 minutes and the mixture was stirred at -40 ° C for 6 hours. The mixture was cooled to -78 ° C and isopropanol (90 mL) was added. The mixture was allowed to slowly warm up to room temperature overnight. H ₂ O (100 mL) was added and the mixture was stirred at rt for 35 min. NH ₄ Cl (10%) was added and the mixture was extracted twice with diethyl ether. The combined organic layers were washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure. Purification by flash chromatography (hexane: EtOAc 5: 1 then 7: 3 then 6: 4) gave 2.13 g (43%) of the title compound as a yellow solid. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 0.6 (s, 3H), 1.2-1.4 (m, 6H), 2.8-3.0 (m, 2H), 3.3-3.5 (m, 4H), 4.5-4.7 (m, 3H), 5.3-5.5 (m, 1H), 5.7-5.8 (d, 1H), 6.4-6.5 (d, 2H), 6.6-6.9 (m, 4H), 6.9-7.0 (d, 2H) , 7.0-7.5 (m, 7 H). M / z: 747.3 (M ⁺ + Na)

Method 24

Ethyl [4-((2R, 3R) -3-{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} -4-oxo-1-phenylase Thidin-2-yl) phenoxy] acetate

Ethyl (4-{(1S, 2R) -l-anilino-2-{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} -3-oxo 3-[(4S) -2-oxo-4-phenyl-1,3-oxazolidin-3-yl] propyl} phenoxy) acetate (2.1 g, 2.9 mmol) was dissolved in dry toluene (200 mL). And heated to 90 ° C. under inert atmosphere. N, O-bis (trimethylsilyl) acetamide (BSA, 2.1 mL, 8.7 mmol) was added and the mixture was stirred at 90 ° C. for 1 hour. Tetrabutylammonium fluoride (TBAF, about 0.1 g) was added at 45 ° C. and the mixture was stirred at 45 ° C. for 18 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes: EtOAc 5: 1). This gave 0.98 g (60%) of the title compound as a yellow oil. ¹ H-NMR (CDCl ₃ , 200 MHz): 0.6 (s, 3H), 1.2-1.4 (m, 6H), 3.0-3.2 (t, broad, 2H), 3.3-3.5 (m, 4H), 3.95 ( d, 1H), 4.2-4.4 (q, 2H), 4.6 (s, 2H), 4.8 (d, 1H), 6.9-7.1 (m, 3H), 7.2-7.6 (m, llH). MS (CI) M / z: 584.2 (M ⁺ + Na).

Method 25

t-butyl (4-{(1S, 2R) -2-{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} -1-[(4- Fluorophenyl) amino] -3-oxo-3-[(4S) -2-oxo-4-phenyl-1,3-oxazolidin-3-yl] propyl} phenoxy) acetate

Tetraisopropyl ortho titanate (0.51 mL, 1.8 mmol) was added to a solution of TiCl ₄ (1M in CH ₂ Cl ₂ , 5.1 mL, 5.1 mmol) in CH ₂ Cl ₂ (50 mL) at 0 ° C. under inert atmosphere. . The mixture was stirred for 10 minutes. (4S) -3-({[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} acetyl) -4- in dry CH ₂ Cl ₂ (50 mL) Phenyl-1,3-oxazolidin-2-one (3.0 g, 6.8 mmol) was added dropwise over 20 minutes. After 10 minutes, t-butyl (4-{[(4-fluorophenyl) imino] methyl} phenoxy) acetate (4.5 g, 13.6 mmol) in dry CH ₂ Cl ₂ (50 mL) was dried over 30 minutes. Added dropwise. The mixture was cooled to -30 ° C and stirred for 20 minutes. Ethyl diisopropyl amine (2.3 mL, 13.4 mmol) in 20 mL of dry CH ₂ Cl ₂ was added dropwise over 10 minutes and the mixture was stirred at −30 ° C. for 6 hours. The mixture was cooled to -78 ° C. Isopropanol (60 mL) was added and the temperature was raised overnight. H ₂ O (100 mL) was added and the mixture was stirred at rt for 35 min. The mixture was extracted twice with diethyl ether. The combined organic layers were washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure. Purification by flash chromatography (hexanes: EtOAc 5: 1) gave 2.95 g (56%) of the title compound as a yellow solid. M / z: 793.3 (M ⁺ + Na).

Method 26

t-butyl {4-[(2R, 3R) -3-{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} -1- (4-fluoro Lophenyl) -4-oxoazetidin-2-yl] phenoxy} acetate

t-butyl (4-{(1S, 2R) -2-{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} -1-[(4- Fluorophenyl) amino] -3-oxo-3-[(4S) -2-oxo-4-phenyl-1,3-oxazolidin-3- yl] propyl} phenoxy) acetate (2.6 g, 3.4 mmol) ) Was dissolved in dry toluene (250 mL) and heated to 90 ° C. under inert atmosphere. N, O-bis (trimethylsilyl) acetamide (BSA, 2.5 mL, 10.3 mmol) was added and the mixture was stirred at 90 ° C. for 1 h. The mixture was cooled to 45 ° C. and tetrabutylammonium fluoride (TBAF, about 0.5 g) was added. The mixture was stirred at 45 ° C. for 2 hours. The mixture was concentrated under reduced pressure and purified by flash chromatography (hexanes: EtOAc 7: 1). This gave 0.65 g (31%) of the title compound as a yellow solid. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 0.6 (s, 3H), 1.2 (s, 3H), 1.5 (s, 9H), 2.9-3.1 (q, broad, 2H), 3.4 (q, 4H ), 4.0 (s, 1H), 4.5 (s, 2H), 4.8 (s, 1H), 6.9-7.0 (m, 4H), 7.2-7.3 (m, 5H), 4.3-4.4 (m, 4H).

Method 27

(4-{(2R, 3R) -1- (4-fluorophenyl) -4-oxo-3-[(2-oxo-2-phenylethyl) thio] azetidin-2-yl} phenoxy) acetic acid

t-butyl {4-[(2R, 3R) -3-{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl) methyl] thio} -1- (4-fluoro Rophenyl) -4-oxoazetidin-2-yl] phenoxy} acetate (1.34 g, 2.21 mmol) was dissolved in formic acid (20 mL) and stirred for 90 minutes. The mixture was concentrated under reduced pressure (temperature <30 ° C). The crude oil was purified by flash chromatography (hexane: acetone: formic acid 60: 40: 0.1) to give 0.7 g (68%) of the title compound as a light yellow solid. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 4.15 (d, 1H), 4.22 (d, 2H), 4.71 (s, 2H), 4.91 (d, 1H), 6.92-7.00 (m, 4H), 7.24-7.30 (m, 4H), 7.46-7.63 (m, 3H), 7.94-7.99 (d, 2H). MS (CI) M / z: 464.2 (M-1).

Method 28

Ethyl ({[2- (4-methoxyphenyl) -5,5-dimethyl-1,3-dioxan-2-yl] methyl} thio) acetate

Ethyl {[2- (4-methoxyphenyl) -2-oxoethyl] thio} acetate (9.57 g, 35.7 mmol) was dissolved in benzene (250 mL). 2,2-dimethyl-1,3-propanediol (29.7 g, 0.29 mol) and p-toluene sulfonic acid (500 mg) were added. The mixture was stirred for 3 hours in a Dean Stark apparatus under reflux overnight at room temperature. The mixture was concentrated under reduced pressure. CH ₂ Cl ₂ was added and the solution was washed twice with H ₂ O and brine. The organic phase was dried (MgSO ₄ ) and purified. Concentration under reduced pressure gave a crude oil which was purified by flash-chromatography (hexanes: EtOAc 7: 1) to give 5.95 g (47%) of the title compound as a colorless oil. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 0.6 (s, 3H), 1.2-1.4 (m, 6H), 3.0 (s, 2H), 3.2 (s, 2H), 3.4 (s, 4H), 3.8 (s, 3H), 4.2 (q, 2H), 6.9 (d, 2H), 7.4 (d, 2H).

Method 29

({[2- (4-methoxyphenyl) -5,5-dimethyl-1,3-dioxan-2-yl] methyl} thio) acetic acid

Ethyl ({[2- (4-methoxyphenyl) -5,5-dimethyl-1,3-dioxan-2-yl] methyl} thio) acetate (5.95 g, 16.8 mmol) in THF (75 mL) Dissolved and cooled to 0 ° C. LiOH (2.11 g, 50.4 mmol) in water (40 mL) was added and the mixture was stirred for 90 minutes. Water was added and the mixture was extracted twice with diethyl ether. The aqueous layer was acidified with 2M HCl until pH = 4 and extracted twice with CH ₂ Cl ₂ . The combined CH ₂ Cl ₂ layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 5.4 g (> 98%) of the title compound as a white solid. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 0.6 (s, 3H), 1.4 (s, 3H), 3.0 (s, 2H), 3.4 (s, 2H), 3.5 (s, 4H), 3.9 ( s, 3H), 6.9 (d, 2H), 7.4 (d, 2H).

Method 30

(4S) -3-[({[2- (4-methoxyphenyl) -5,5-dimethyl-1,3-dioxan-2-yl] methyl} thio) acetyl] -4-phenyl-1, 3-oxazolidin-2-one

({[2- (4-methoxyphenyl) -5,5-dimethyl-1,3-dioxan-2-yl] methyl} thio) acetic acid (5.4 g, 16.5 mmol) was dried CH ₂ Cl ₂ (80 ML) and cooled to 0 ° C. N, N'-dicyclohexylcarbodiimide (DCC, 3.76 g, 18.2 mmol) and 4- (dimethylamino) pyridine (DMAP, 4.04 g, 33.1 mmol) in 20 mL CH ₂ Cl ₂ were added and the mixture was Stir at 0 ° C. for 30 minutes. (S)-(+)-4-phenyl-2-oxazolidinone (2.69 g, 16.5 mmol) was added and the mixture was stirred at rt for 17 h. The mixture was filtered, concentrated under reduced pressure and purified by flash chromatography (hexane: EtOAc 4: 1 then 2: 1). This gave 5.69 g (73%) of the title compound as a white solid. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 0.6 (s, 3H), 1.3 (s, 3H), 2.8 (s, 2H), 3.4 (s, 4H), 3.8 (s, 2H), 3.8 ( s, 3H), 4.3 (dd, 1H), 4.7 (t, 1H), 5.4 (dd, 1H), 6.9 (d, 2H), 7.3 (m, 7H).

Method 31

t-butyl (4-{(1S, 2R) -1-[(4-fluorophenyl) amino] -2-({[2- (4-methoxyphenyl) -5,5-dimethyl-1,3 -Dioxan-2-yl] methyl} thio) -3-oxo-3-[(4S) -2-oxo-4-phenyl-1,3-oxazolidin-3-yl] propyl} phenoxy) acetate

Tetraisopropyl ortho titanate (0.31 mL, 1.06 mmol) was added to a solution of TiCl ₄ (1M in CH ₂ Cl ₂ , 3.18 mL, 3.18 mmol) in CH ₂ Cl ₂ (50 mL) at 0 ° C. under inert atmosphere. . The mixture was stirred for 10 minutes. (4S) -3-[({[2- (4-methoxyphenyl) -5,5-dimethyl-1,3-dioxan-2-yl] methyl} thio in dry CH ₂ Cl ₂ (50 mL) ) Acetyl] -4-phenyl-1,3-oxazolidin-2-one (2.00 g, 4.24 mmol) was added dropwise over 20 minutes. The mixture was stirred for 10 minutes. T-butyl (4-{[(4-fluorophenyl) imino] methyl} phenoxy) acetate (2.79 g, 8.48 mmol) in dry CH ₂ Cl ₂ (50 mL) was added dropwise over 30 minutes. The mixture was cooled to -30 ° C and stirred for 20 minutes. Ethyl diisopropyl amine (1.45 mL, 8.48 mmol) in 10 mL of dry CH ₂ Cl ₂ was added dropwise over 10 minutes and stirred at −30 ° C. for 5 hours. The mixture was cooled to -78 ° C. Isopropanol (60 mL) was added and the temperature was allowed to warm overnight. H ₂ O (100 mL) was added and the mixture was stirred for 20 minutes and extracted twice with diethyl ether. The combined organic layers were washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure. Purification by flash chromatography (hexanes: EtOAc 3: 1) provided 2.00 g (59%) of the title compound as a yellow solid. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 0.6 (s, 3H), 1.3 (s, 3H), 1.5 (s, 9H), 2.6-2.9 (m, 2H), 3.3-3.5 (m, 4H ), 3.8 (s, 3H), 4.1-4.3 (m, 2H), 4.5 (s, 2H), 4.6-4.8 (m, 2H), 5.0-5.4 (s, broad, 1H), 5.4 (m, 1H ), 5.7 (d, 1H), 6.4 (m, 2H), 6.6-6.8 (m, 4H), 6.8-7.0 (m, 4H), 7.1-7.4 (m, 7H).

Method 32

t-butyl {4-[(2R, 3R) -1- (4-fluorophenyl) -3-({[2- (4-methoxyphenyl) -5,5-dimethyl-1,3-dioxane -2-yl] methyl} thio) -4-oxoazetidin-2-yl] phenoxy} acetate

t-butyl (4-{(1S, 2R) -1-[(4-fluorophenyl) amino] -2-({[2- (4-methoxyphenyl) -5,5-dimethyl-1,3 -Dioxan-2-yl] methyl} thio) -3-oxo-3-[(4S) -2-oxo-4-phenyl-1,3-oxazolidin-3-yl] propyl} phenoxy) acetate (2.0 g, 2.5 mmol) was dissolved in dry toluene (200 mL) and heated to 90 ° C. under inert atmosphere. N, O-bis (trimethylsilyl) acetamide (BSA, 1.8 mL, 7.5 mmol) was added and the mixture was stirred at 90 ° C. for 1 hour. The mixture was cooled to 45 ° C. and tetrabutylammonium fluoride (TBAF, 150 mg) was added and the mixture was stirred at 45 ° C. for 2 hours. The mixture was concentrated under reduced pressure and purified through a short column of silica (hexanes: EtOAc 4: 1). The crude oil was purified by flash chromatography (hexanes: EtOAc 5: 1) to give 0.65 g (41%) of the title compound as a yellow oil. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 0.6 (s, 3H), 1.3 (s, 3H), 1.5 (s, 9H), 3.0-3.2 (m, 2H), 3.3-3.5 (m, 4H ), 3.8 (s, 3H), 4.0 (d, 1H), 4.5 (s, 2H), 4.8 (d, 1H), 6.8-7.0 (m, 6H), 7.2-7.4 (m, 6H).

Method 33

[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-methoxyphenyl) -2-oxoethyl] thio} -4-oxoazetidine-2 -Yl) phenoxy] acetic acid

t-butyl {4-[(2R, 3R) -1- (4-fluorophenyl) -3-({[2- (4-methoxyphenyl) -5,5-dimethyl-1,3-dioxane -2-yl] methyl} thio) -4-oxoazetidin-2-yl] phenoxy} acetate (0.65 g, 1.02 mmol) was dissolved in formic acid (10 mL) and stirred for 90 minutes. The mixture was concentrated under reduced pressure (temperature <30 ° C.) and the crude oil was purified by flash chromatography (hexane: acetone: formic acid 60: 40: 0.1) to give 0.45 g (88%) of the title compound as a pale yellow solid. It was. ¹ H-NMR (CDCl ₃ , 200 MHz): 3.9 (s, 3H), 4.1 (d, 1H), 4.1 (s, 2H), 4.7 (s, 2H), 4.9 (d, 1H), 6.9-7.1 (m, 6H), 7.2-7.4 (m, 4H), 7.9-8.0 (d, 2H). MS (CI) M / z: 494.1 (M ⁺ -1), 495.1 (M ⁺ )

Method 34

Ethyl ({[5,5-dimethyl-2- (4-methylphenyl) -1,3-dioxan-2-yl] methyl} thio) acetate

Ethyl {[2- (4-methylphenyl) -2-oxoethyl] thio} acetate (12.2 g, 48. 4 mmol) was dissolved in benzene (350 mL). 2,2-dimethyl-1,3-propanediol (40.3 g, 0.387 mol) and p-toluene sulfonic acid (1 g) were added. The mixture was stirred at reflux for 2 hours in a Dean Stark apparatus, cooled and concentrated under reduced pressure. CH ₂ Cl ₂ was added and the organic phase was washed twice with brine and dried (MgSO ₄ ). Filtration and concentration under reduced pressure gave a crude oil, which was purified by flash chromatography (hexanes: EtOAc 8: 1) to give 10.0 g (61%) of the title compound as a clear oil. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 0.6 (s, 3H), 1.2-1.4 (m, 6H), 2.4 (s, 3H), 3.0 (s, 2H), 3.2 (s, 2H), 3.4-3.5 (m, 4H), 4.2 (q, 2H), 7.2-7.4 (m, 4H).

Method 35

({[5,5-dimethyl-2- (4-methylphenyl) -1,3-dioxan-2-yl] methyl} thio) acetic acid

Ethyl ({[5,5-dimethyl-2- (4-methylphenyl) -1,3-dioxan-2-yl] methyl} thio) acetate (10.1 g, 29.8 mmol) was dissolved in THF (150 mL). Cool to 0 ° C. LiOH (3.76 g, 89.5 mmol) in water (50 mL) was added and the mixture was stirred at rt for 2 h. The mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with diethyl ether. The aqueous layer was acidified to pH 3 with 2M HCl and extracted twice with CH ₂ Cl ₂ . The combined CH ₂ Cl ₂ layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 8.7 g (94%) of the title compound as a white solid. _{^{l H-NMR (CDCl 3,}} 200 MHz): δ 0.6 (s, 3H), 1.2 (s, 3H), 2.4 (s, 3H), 3.0 (s, 2H), 3.4 (s, 2H), 3.4 ( s, 4H), 7.2-7.4 (m. 4H).

Method 36

(4S) -3-[({[5,5-dimethyl-2- (4-methylphenyl) -1,3-dioxan-2-yl] methyl} thio) acetyl] -4-phenyl-1,3- Oxazolidin-2-one

({[5,5-dimethyl-2- (4-methylphenyl) -1,3-dioxan-2-yl] methyl} thio) acetic acid (8.7 g, 28.0 mmol) was dried CH ₂ Cl ₂ (120 mL) Dissolved in and cooled to 0 ° C. N, N'-dicyclohexylcarbodiimide (DCC, 6.35 g, 30.8 mmol) and 4- (dimethylamino) pyridine (DMAP, 6.85 g, 56.1 mmol) in 30 mL CH ₂ Cl ₂ were added. The mixture was stirred at 0 ° C. for 30 minutes. (S)-(+)-4-phenyl-2-oxazolidinone (4.57 g, 28.0 mmol) was added and the mixture was stirred at rt for 19 h. The mixture was filtered, concentrated under reduced pressure and purified by flash chromatography (hexanes: EtOAc 5: 1 then 4: 1). This gave 7.07 g (55%) of the title compound as a white solid. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 0.6 (s, 3H), 1.2 (s, 3H), 2.4 (s, 3H), 2.8 (s, 2H), 3.4 (s, 4H), 3.8 ( s, 2H), 4.3 (dd, 1H), 4.7 (t, 1H), 5.4 (dd, 1H), 7.2-7.5 (m, 9H).

Method 37

t-butyl (4- (1S, 2R) -2-({[5,5-dimethyl-2- (4-methylphenyl) -1,3-dioxan-2-yl] methyl} thio) -1- [ (4-fluorophenyl) amino] -3-oxo-3-[(4S) -2-oxo-4-phenyl-1,3-oxazolidin-3-yl] propyl} phenoxy) acetate

Tetraisopropyl ortho titanate (0.37 mL, 1.23 mmol) was added to a solution of TiCl ₄ (1M in CH ₂ Cl ₂ , 3.3 mL, 3.3 mmol) in CH ₂ Cl ₂ (50 mL) at 0 ° C. under inert atmosphere. . The mixture was stirred for 10 minutes. (4S) -3-[({[5,5-dimethyl-2- (4-methylphenyl) -1,3-dioxan-2-yl] methyl} thio) acetyl in dry CH ₂ Cl ₂ (50 mL) ] -4-phenyl-1,3-oxazolidin-2-one (2.0 g, 4.4 mmol) was added dropwise over 20 minutes and the mixture was stirred for 10 minutes. T-butyl (4-{[(4-fluorophenyl) imino] methyl} phenoxy) acetate (2.9 g, 8.8 mmol) in dry CH ₂ Cl ₂ (50 mL) was added dropwise over 30 minutes. The mixture was cooled to -30 ° C and stirred for 20 minutes. Ethyl diisopropyl amine (1.5 mL, 8.8 mmol) in 10 mL of dry CH ₂ Cl ₂ was added dropwise over 10 minutes. The mixture was stirred at -39 ° C for 4 h. The mixture was cooled to -78 ° C and isopropanol (60 mL) was added. The temperature was allowed to reach room temperature over 2 hours. H ₂ O (100 mL) was added and the mixture was stirred for 20 minutes and extracted twice with diethyl ether. The combined organic layers were washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure. Purification by flash chromatography (hexane: EtOAc 5: 1 then 4: 1) gave 2.55 g (74%) of the title compound as a white solid. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 0.6 (s, 3H), 1.3 (s, 3H), 1.5 (s, 9H), 2.4 (s, 3H), 2.6-2.9 (m, 2H), 3.3-3.5 (m, 4H), 4.1-4.3 (m, 1H), 4.5 (s, 2H), 4.6-4.8 (m, 2H), 5.0-5.3 (s, broad, 1H), 5.2 (m, 1H ), 5.7 (d, 1H), 6.4 (m, 2H), 6.6-6.8 (m, 4H), 6.9 (m, 2H), 7.1-7.4 (m, 9H).

Method 38

t-butyl {4-[(2R, 3R) -3-({[5,5-dimethyl-2- (4-methylphenyl) -1,3-dioxan-2-yl] methyl} thio) -1- (4-fluorophenyl) -4-oxoazetidin-2-yl] phenoxy} acetate

t-butyl (4-{(1S, 2R) -2-({[5,5-dimethyl-2- (4-methylphenyl) -1,3-dioxan-2-yl] methyl} thio) -1- [(4-fluorophenyl) amino] -3-oxo-3-[(4S) -2-oxo-4-phenyl-1,3-oxoazetidin-3-yl] propyl} phenoxy) acetate ( 2.55 g, 3.25 mmol) was dissolved in dry toluene (250 mL) and heated to 90 ° C. under inert atmosphere. N, O-bis (trimethylsilyl) acetamide (BSA, 2.38 mL, 9.75 mmol) was added and the mixture was stirred at 90 ° C. for 1 h. The mixture was cooled to 45 ° C. and tetrabutylammonium fluoride (TBAF, 0.25 g) was added and the mixture was stirred at 45 ° C. for 1 hour. The mixture was concentrated under reduced pressure and purified by flash chromatography (hexanes: EtOAc 6: 1). This gave 1.06 g (52%) of the title compound as a white solid. _{^{l H-NMR (CDCl 3,}} 200 MHz): δ 0.6 (s, 3H), 1.3 (s, 3H), 1.5 (s, 9H), 2.4 (s, 3H), 3.0-3.2 (m, 2H), 3.3-3.5 (m, 4H), 3.9 (d, 1H), 4.5 (s, 2H), 4.8 (d, 1H), 6.8-7.0 (m, 6H), 7.1-7.4 (m, 6H).

Method 39

[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-methylphenyl) -2-oxoethyl] thio} -4-oxoazetidin-2-yl ) Phenoxy] acetic acid

t-butyl {4-[(2R, 3R) -3-({[5,5-dimethyl-2- (4-methylphenyl) -1,3-dioxan-2-yl] methyl} thio) -1- (4-fluorophenyl) -4-oxoazetidin-2-yl] phenoxy} acetate (1.04 g, 1.67 mmol) was dissolved in formic acid (20 mL) and stirred for 60 minutes. The mixture was concentrated under reduced pressure (temperature <30 ° C.) and the crude oil was purified by flash chromatography (hexane: acetone: formic acid 60: 40: 0.1) to give 0.72 g (90%) of the title compound as light yellow oil. It was. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 2.4 (s, 3H), 4.1 (d, 1H), 4.2 (s, 2H), 4.7 (s, 2H), 4.9 (d, 1H), 6.9 ( m, 6H), 7.2-7.4 (m, 4H), 7.8 (d, 2H). MS (CI) M / z: 478.1 (M ⁺ -1).

Method 40

t-butyl (4-{(E)-[(4-chlorophenyl) imino] methyl} phenoxy) acetate

A suspension of NaH (60% in mineral oil, 3.69 g, 92.2 mmol) in dry DMF (70 mL) was cooled to 0 ° C. A solution of 4-hydroxybenzaldehyde (10.0 g, 82.0 mmol) in dry DMF (35 mL) was added dropwise. The mixture was stirred at 0 ° C. for 40 minutes. t-butyl bromoacetate (12.1 mL, 82.5 mmol) was added and the mixture was stirred at rt for 17 h. The mixture was concentrated under reduced pressure. Diethyl ether was added and the mixture was washed with 10% NH ₄ Cl, water and brine. The organic phase was dried (MgSO ₄ ), concentrated under reduced pressure and purified by flash chromatography (10% to 20% EtOAc in hexanes). This gave t-butyl (4-formylphenoxy) acetate (17.4 g, 73.4 mmol, 80% yield) as a colorless oil. The intermediate was dissolved in dry toluene (120 mL) and 4-chloroaniline (9.37 g, 73.4 mmol) was added. The mixture was refluxed for 20 h in a Dean Stark apparatus, cooled and concentrated under reduced pressure. Hexane was added and the precipitate formed was filtered off, washed twice with cold hexanes and dried. This gave 20.0 g (79%) of the title compound as a yellow solid. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 1.5 (s, 9H), 4.6 (s, 2H), 7.0 (d, 2H), 7.2 (d, 2H), 7.4 (d, 2H), 7.8 ( d, 2H), 8.4 (s, 1H). MS (CI) M / z: 368.0 (M ⁺ + Na, 100), 369.0 (20), 370.0 (30), 371.0 (10).

Method 41

Ethyl ({[2- (4- Chlorophenyl ) -5,5-dimethyl-1,3-dioxan-2-yl] methyl } Thio )acetate

Ethyl {[2- (4-chlorophenyl) -2-oxoethyl] thio} acetate (8.15 g, 29.9 mmol) was dissolved in toluene (165 mL). 2,2-dimethyl-1,3-propanediol (24.8 g, 238 mmol) and p-toluene sulfonic acid (300 mg) were added. The mixture was stirred at reflux for 2.5 h in a Dean Stark apparatus and concentrated under reduced pressure. The crude product was dissolved in CH ₂ Cl ₂ . The mixture was washed with H ₂ O (3 ×), brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes: EtOAc 9: 1) to give 3.36 g (31%) of the title compound as a yellow oil. MS (CI) M / z: 381.0 (M ⁺ + Na, 100), 382.0 (15), 383.0 (30), 384 (5)

Method 42

({[2- (4-chlorophenyl) -5,5-dimethyl-1,3-dioxan-2-yl] methyl} thio) acetic acid

Ethyl ({[2- (4-chlorophenyl) -5,5-dimethyl-1,3-dioxan-2-yl] methyl} thio) acetate (3.36 g, 9.36 mmol) was dissolved in THF (45 mL). And cooled to 0 ° C. LiOH (0.79 g, 18.8 mmol) in water (12 mL) was added and the mixture was stirred at rt for 18 h. The solvent was evaporated. The crude product was extracted between water and diethyl ether. The aqueous layer was acidified to pH 6 with 2M HCl and extracted twice with CH ₂ Cl ₂ . The combined CH ₂ Cl ₂ layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 2.98 g (96%) of the title compound as a yellow oil. ¹ H-NMR (CDCl ₃ , 300 MHz): δ 0.62 (s, 3H), 1.34 (s, 3H), 2.95 (s, 2H), 3.34 (s, 2H), 3.45 (s, 4H), 7.4 ( m, 4H)

Method 43

(4S) -3-[({[2- (4-chlorophenyl) -5,5-dimethyl-1,3-dioxan-2-yl] methyl} thio) acetyl] -4-phenyl-1,3 Oxazolidin-2-one

({[2- (4-chlorophenyl) -5,5-dimethyl-1,3-dioxan-2-yl] methyl} thio) acetic acid (2.00 g, 6.05 mmol) was dried CH ₂ Cl ₂ (45 mL). ) And cooled to 0 ° C. N, N'-dicyclohexylcarbodiimide (DCC, 1.43 g, 6.93 mmol) and 4- (dimethylamino) pyridine (DMAP, 1.70 g, 10.4 mmol) were added and the mixture was stirred at 0 ° C for 20 minutes. . (S)-(+)-4-phenyl-2-oxazolidinone (1.40 g, 11.5 mmol) was added and the mixture was stirred at rt for 70 h. The mixture was filtered, concentrated under reduced pressure and purified by flash chromatography (20-30% EtOAc in hexanes). This gave 1.27 g (44%) of the title compound as a white solid. ¹ H-NMR (CDCl ₃ , 300 MHz): δ 0.62 (s, 3H), 1.34 (s, 3H), 2.78 (s, 2H), 3.42 (s, 4H), 3.85 (s, 2H), 4.27- 4.33 (dd, 1H), 4.69-4.78 (t, 1H), 5.34-5.42 (dd, 1H), 7.29-7.38 (m, 9H).

Method 44

t-butyl (4-{(1S, 2R) -1-[(4- Chlorophenyl ) Amino] -2-({[2- (4- Chlorophenyl ) -5,5-dimethyl-1,3-dioxan-2-yl] methyl } Thio ) -3-oxo-3-[(4S) -2-oxo-4- Phenyl -1,3- Oxazolidine -3-yl] propyl} phenoxy) acetate

Triisopropyl ortho titanate (0.23 mL, 0.77 mmol) was added to TiCl ₄ (1M in CH ₂ Cl ₂ , 2.25 mL, 2.25 mmol) in CH ₂ Cl ₂ (22 mL) at 0 ° C. under inert atmosphere. The mixture was stirred for 10 minutes. (4S) -3-[({[2- (4-chlorophenyl) -5,5-dimethyl-1,3-dioxan-2-yl] methyl} thio) in dry CH ₂ Cl ₂ (25 mL) Acetyl] -4-phenyl-1,3-oxazolidin-2-one (1.44 g, 3.03 mmol) was added dropwise over 45 minutes and the mixture was stirred for 10 minutes. T-butyl (4-{(E)-[(4-chlorophenyl) imino] methyl} phenoxy) acetate (2.09 g, 6.04 mmol) in dry CH ₂ Cl ₂ (25 mL) was added dropwise over 80 minutes. It was. The mixture was cooled to -40 ° C and stirred for 20 minutes. Ethyl diisopropyl amine (1.03 mL, 6.02 mmol) was added dropwise over 40 minutes and the mixture was stirred at -40 ° C for 10 minutes. The mixture was cooled to -78 ° C and isopropanol (80 mL) was added. The temperature was allowed to reach room temperature over 3 hours. NH ₄ Cl (10%, 80 mL) was added and the mixture was stirred for 35 minutes. Brine (200 mL) was added and the mixture was extracted twice with 400 mL of diethyl ether. The combined organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure. Purification by flash chromatography (10-20% EtOAc in hexanes) provided 1.69 (65%) of the title compound as a white solid. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 0.65 (s, 3H), 1.3 (s, 3H), 1.5 (s, 9H), 2.6-2.9 (m, 2H), 3.4 (m, 4H), 4.2 (m, 1H), 4.5 (s, 2H), 4.6-4-8 (m, 2H), 5.3 (m, 1H), 5.7 (d, 1H), 6.4 (m, 2H), 6.7-7.4 ( m, 15H).

Method 45

t-butyl {4-[(2R, 3R) -1- (4-chlorophenyl) -3-({[2- (4-chlorophenyl) -5,5-dimethyl-1,3-dioxane-2 -Yl] methyl} thio) -4-oxoazetidin-2-yl] phenoxy} acetate

t-butyl (4-{(1S, 2R) -1-[(4-chlorophenyl) amino] -2-({[2- (4-chlorophenyl) -5,5-dimethyl-1,3-di Oxo-2-yl] methyl} thio) -3-oxo-3-[(4S) -2-oxo-4-phenyl-1,3-oxazolidin-3-yl] propyl} phenoxy) acetate (l .69 g, 2.06 mmol) was dissolved in dry toluene (140 mL) and heated to 90 ° C. under inert atmosphere. N, O-bis (trimethylsilyl) acetamide (BSA, 1.48 mL, 6.05 mmol) was added and the mixture was stirred at 90 ° C. for 1 h. The mixture was cooled to 45 ° C. and tetrabutylammonium fluoride (TBAF, 0.1 g) was added and the mixture was stirred at 45 ° C. for 1 hour and at room temperature overnight. The mixture was concentrated under reduced pressure and purified by flash chromatography (10-20% EtOAc in hexanes). This gave 0.84 g (61%) of the title compound as a white solid. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 0.6 (s, 3H), 1.2 (s, 3H), 1.5 (s, 9H), 2.9-3.1 (t, broad, 2H), 3.4 (s, 4H ), 4.0 (s, 1H), 4.5 (s, 2H), 4.8 (s, 1H), 6.9 (d, 2H), 7.2-7.4 (m, 10H).

Method 46

[4-((2R, 3R) -1- (4-fluorophenyl) -4-oxo-3-{[2-oxo-2- (4-pentylphenyl) ethyl] thio} azetidin-2-yl ) Phenoxy] acetic acid

t-butyl (4-{(2R, 3R) -1- (4-fluorophenyl) -3-[(3-nitropyridin-2-yl) dithio] -4-oxoazetidin-2-yl Phenoxy) acetate (0.20 g, 0.36 mmol) was dissolved in acetone (10 mL) at room temperature. Water (2.5 mL) and triphenyl phosphine (0.094 g, 0.36 mmol) were added. The mixture was stirred at rt for 30 min and then concentrated under reduced pressure to give crude thiol as a brown oil. The crude thiol was immediately dissolved in CH ₂ Cl ₂ (10 mL) and 2-bromo-1- (4-pentyl phenyl) ethan-1-one (0.19 g, 0.72 mmol) was added, followed by Et ₃ N (0.10 mL, 0.72 mmol) was added. The mixture was stirred at rt for 20 h, concentrated under reduced pressure and purified by flash chromatography (hexanes: EtOAc 4: 1). 0.21 g of t-butyl [4-((2R, 3R) -1- (4-fluorophenyl) -4-oxo-3-{[2-oxo-2- (4-pentylphenyl) ethyl] Thio} azetidin-2-yl) phenoxy] acetate and 2-[(3-nitropyridin-2-yl) thio] -1- (4-pentylphenyl) ethanone. The mixture was dissolved in HCOOH (10 mL) and stirred at rt for 18 h. Concentrated under reduced pressure and purified by flash chromatography (hexane: acetone: HCOOH 60: 40: 0.1) to give 0.11 g (61%) of the title compound as a light yellow solid.

¹ H-NMR (CD ₃ Cl, 300 MHz): δ 0.8-1.0 (m, 3H), 1.2-1.5 (m, 4H), 1.6-1.8 (m, 2H), 2.7 (t, 2H), 4.1 ( d, 1H), 4.2 (s, 2H), 4.7 (s, 2H), 4.9 (d, 1H) 6.9-7.1 (m, 4H), 7.2-7.4 (m, 6H), 7.9 (d, 2H).

Method 47

Sodium (2R) -2-amino-4-cyclohexylbutanoate

Ethyl (2R) -2-amino-4-cyclohexylbutanoate hydrochloride (4.00 g, 18.75 mmol) was dissolved in MeOH / water (10/5 mL). Sodium hydroxide (1.50 g, 37.50 mmol) was added. The reaction mixture was stirred for 1 h and concentrated to provide the title compound as a colorless solid (containing 100 mol% sodium chloride). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 0.83-0.97 (m, 2H), 1.10-1.33 (m, 6H), 1.48-1.78 (m, ELI), 3.15 (dd, 1H).

Method 48

N-{[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- (4-chlorophenyl) -2-oxoethyl] thio} -4-oxoazetidine- 2-yl) phenoxy] acetyl} glycine

[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- (4-chlorophenyl) -2-oxoethyl] thio} -4-oxoazetidin-2-yl ) Phenoxy] acetic acid (302.1 mg, 0.585 mmol) was dissolved in DCM (6 mL). N-methylmorpholine (190 μl, 1.728 mmol) and t-butyl glycinate hydrochloride (133.4 mg, 0.80 mmol) were added. After 10 minutes, TBTU (224.3 mg, 0.67 mmol) was added and the reaction mixture was stirred for 60 hours. T-butylester, an intermediate of the title compound, was identified. M / z: 626.88 (M−H). DCM (10 mL) and water (15 mL) were added and acidified to pH 3 with KHSO ₄ (2M). The organic phase was washed with water (2x15 mL). The combined aqueous phases were extracted with DCM (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue solution in DCM (10 mL) and TFA (4 mL) was stirred overnight. The solvent was removed under reduced pressure. Toluene was added and evaporated to aid in the removal of TFA. The residue was purified by preparative HPLC on C8 column. A gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. After freeze drying, the title compound was obtained as a white solid (166.9 mg, 50%). H-NMR (400 MHz, DMS-d ₆ ): 3.51 (d, 2H), 4.33 (d, 1H), 4.34 (s, 1H), 4.36 (s, 1H), 4.47 (s, 2H), 5.17 ( d, 1H), 6.96 (d, 2H), 7.16-7.21 (m, 2H), 7.35 (d, 4H), 7.54-7.59 (m, 2H), 7.83-7.90 (brs, 1H), 7.91-7.95 ( m, 2H). M / z: 571.04 (MH) and 572.88 (M + H).

Method 49

(2R) -cyclohexyl [(N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3- [2- (4-fluorophenyl) -2-oxoethyl] thio } -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl) amino] acetic acid

TBTU (0.0092 g, 0.029 mmol) was added 3- (R) -4- (R) -1- (4-fluorophenyl) -3- (4-fluorobenzoyl) methylthio]-in DMF (2 mL). To a mixture of 4- {4- [N- (carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one (0.016 g, 0.030 mmol) and N-methylmorpholine (0.101 mL, 0.98 mmol) was added. . The mixture was stirred overnight under N ₂ -atmosphere. Additional TBTU (0.0092 g, 0.029 mmol) was added and the mixture was stirred at 35 ° C. for 2 hours. (2R) -amino (cyclohexyl) acetic acid hydrochloride (0.0068 g, 0.035 mmol) was added. The mixture was stirred at 35 ° C. for 2 hours and at room temperature overnight. The solvent was removed under reduced pressure and purified by preparative HPLC on Kromasil C8-column (using 5% to 100% gradient MeCN in 0.15% trifluoroacetic acid buffer as eluent). The solvent was removed under reduced pressure to yield 0.009 g (47%) of the title compound.

M / z 680.01

Method 50

t-butyl N ² -[(Benzyloxy) carbonyl] -N ⁵ -(t-butoxycarbonyl) -D-ornithinate

N ² -[(benzyloxy) carbonyl] -N ^5- (t-butoxycarbonyl) -D-ornithine (l g, 2.73 mmol) was dissolved in toluene (5 mL) and left at 100 ° C. N, N-dimethylformamide di-t-butyl acetal (1.5 mL, 6.25 mmol) was added dropwise. After 40 minutes, the mixture was allowed to cool to room temperature and left to stand for 3 days. The organic layer was washed with NaHCO ₃ -solution and brine, dried (Na ₂ SO ₄ ), filtered and the solvent removed under reduced pressure. 0.67 g (58%) of the desired product was obtained.

NMR (500 MHz, CD ₃ COOD) 1.35-1.71 (m, 21H), 1.72-1.85 (m, 1H), 3.06 (t, 2H), 4.05 (dd, 1H), 5.11 (ABq, 2H), 7.29- 7.40 (m, 5H)

Method 51

t-butyl N ⁵ -(t-butoxycarbonyl) -D-ornithinate

t-butyl N ² -[(benzyloxy) carbonyl] -N ^5- (t-butoxycarbonyl) -D-ornithinate (0.67 g, 1.83 mmol) and Pd on carbon (95%, 0.115 g) Was mixed with EtOH (95%, 20 mL) and stirred for 5 h 15 min under H ₂ atmosphere. The mixture was purified through Celite 521 and the solvent was evaporated under reduced pressure to give 0.45 g (85%) of the desired product.

NMR (500 MHz, CD ₃ COOD) 1.41-1.76 (m22H), 3.07 (t, 2H), 3.32-3.36 (m 1H)

Method 52

Glysyl-3-cyclohexyl-D-alanine

 N- (t-butoxycarbonyl) glycine (2.0 g, 11.4 mmol) and DIPEA (4.0 g, 31 mmol) were dissolved in methylene chloride (25 mL). TBTU (4.1 g, 12.8 mmol) was added and the mixture was stirred at rt for 15 min. 3-cyclohexyl-D-alanine (2.1 g, 12.2 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was transferred to a separatory funnel and extracted with water / acetic acid (100 mL of 5% acetic acid). The organic layer was separated and evaporated under reduced pressure. The residue was dissolved in formic acid (20 mL) and the mixture was stirred at 40 ° C. overnight. Formic acid was removed under reduced pressure. The residue was washed with water (50 mL) and then stirred in acetone (25 mL) for 1 hour at room temperature. The solid material was filtered off and washed with acetone (20 mL). 520 mg (20%) of the title compound were obtained.

¹ H-NMR (300 MHz, CD ₃ COOD): 0.8-1.9 (m, 13H), 3.9-4.1 (m, 2H), 4.55- 4.65 (m, 1H).

Method 53

β, β-dimethyl-D-phenylalanine trifluoroacetate

N- (t-butoxycarbonyl) -b, b-dimethyl-D-phenylalanine t-butyl ammonium salt (51.2 mg, 0.14 mmol) was dissolved in DCM (15 mL). Water (10 mL) was added and the mixture was acidified to pH 1 with HCl (1M). The organic phase was washed with water (3x10 mL) and the aqueous phase was extracted with DCM (3x10 mL). The solvent was removed under reduced pressure. The residue was dissolved in DCM (4 mL) and TFA (2.5 mL) was added and the mixture was stirred for 2 hours. The solvent was removed under reduced pressure and the residue was dried under vacuum overnight. The title compound was obtained as a white solid (36.1 mg, 85%). M / z: 194.18 (M + l).

Method 54

Glysyl-3-methyl-D-valine trifluoroacetate

In a 30 ° C. solution of N- (t-butoxycarbonyl) glycine (0.450 g, 2.569 mmol) and N-methylmorpholine (1.30 g, 12.84 mmol) in CH ₂ Cl ₂ (50 mL) TBTU (0.99 g, 3.08 mmol) was added. After 1.5 h, Dt-leucine (0.303 g, 2.31 mmol) was added. After 30 minutes, the reaction was quenched by addition of water (1 mL). The mixture was concentrated and purified via preparative HPLC (0% to 40% CH ₃ CN in 0.1 M NH ₄ OAc buffer as eluent). Pure fractions were collected and concentrated. To the residue was added CH ₂ Cl ₂ (10 mL) and TFA (3 mL). After 30 minutes complete conversion to the corresponding amino acid. The reaction mixture was concentrated to give the desired compound (0.359 g, 46%) as a colorless solid. ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 0.94 (s, 9H), 3.60-3.67 (m, 2H), 4.16 (d, 1H), 7.90-8.00 (m, 3H), 8.47 ( d, 1H).

Method 55

{4-[(2R, 3R) -3-{[2- (4-t-butylphenyl) -2-oxoethyl] thio} -1- (4-fluorophenyl) -4-oxoazetidine- 2-yl] phenoxy} acetic acid

t-butyl (4-{(2R, 3R) -1- (4-fluorophenyl) -3-[(3-nitropyridin-2-yl) dithio] -4-oxoazetidin-2-yl } Phenoxy) acetate (0.20 g, 0.36 mmol) was dissolved in acetone (10 mL) at room temperature and then water (2.5 mL) and triphenyl phosphine (0.094 g, 0.36 mmol) were added. The mixture was stirred at room temperature for 15 minutes and then concentrated under reduced pressure to give crude thiol as a brown oil. The crude thiol was immediately dissolved in CH ₂ Cl ₂ (8 mL) and after addition of 2-bromo-1- (4-t-butyl-phenyl) -ethan-1-one (0.15 g, 0.72 mmol) , Et ₃ N (0.10 mL, 0.72 mmol) was added. The mixture was stirred at rt for 1.5 h, concentrated under reduced pressure and purified by flash chromatography (hexanes: EtOAc 4: 1). 0.26 g of t-butyl {4-[(2R, 3R) -3- {2- (4-t-butylphenyl) -2-oxoethyl] thio} -1- (4-fluorophenyl)- A mixture of 4-oxoazetidin-2-yl] phenoxy} acetate and 1- (4-t-butylphenyl) -2-[(3-nitropyridin-2-yl) thio] ethanone was provided. The mixture was dissolved in formic acid (10 mL) and stirred at rt for 17 h. Concentrated under reduced pressure and purified by flash chromatography (hexane: acetone: formic acid 70: 30: 0.1) to give 0.08 g (43%) of the desired compound as a white solid.

¹ H-NMR (CD ₃ Cl, 200 MHz): δ 1.30 (s, 9H), 4.10 (s, 1H), 4.15 (s, 2H), 4.60 (s, 2H), 4.85 (s, 1H), 6.80 -7.00 (m, 4H), 7.15-7.30 (m, 4H), 7.60-7.70 (m, 2H), 7.80-7.90 (m, 2H).

Method 56

N-({4-[(2R, 3R) -3-{[2- (4-t-butylphenyl) -2-hydroxyethyl] thio} -1- (4-ple Fluorophenyl) -4-oxoazetidin-2-yl] phenoxy} acetyl) glycyl-3-cyclohexyl-D-alanine

{4-[(2R, 3R) -3-{[2- (4-t-butylphenyl) -2-oxoethyl] thio} -1- (4-fluorophenyl)-in DMF (3 mL) To a solution of 4-oxoazetidin-2-yl] phenoxy} acetic acid (0.020 g, 0.038 mmol) and NMM (0.013 mL, 0.118 mmol) was added TBTU (0.019 g, 0.059 mmol) at room temperature. After 90 minutes, glycyl-3-cyclohexyl-D-alanine (0.009 g, 0.039 mmol) was added and the mixture was stirred for 18 hours and then water (1 mL) was added to quench the reaction. The mixture was diluted with MeOH (1 mL) and NaBH ₄ (0.025 g, 0.661 mmol) was added. After 10 minutes, the reaction was quenched by addition of 0.1 M ammonium acetate buffer (2 mL) and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC (using 20% to 60% gradient of MeCN as eluent in 0.1 M ammonium acetate buffer). Pure fractions were lyophilized to afford the desired product as a white solid (0.010 g, 36% yield).

ES-m / z: 733.2 (M-1) ^- . ¹ H NMR (DMSO, 500 MHz) δ: 0.70-0.93 (m, 2H), 1.00-1.35 (m, 13H), 1.35-1.71 (m, 7H), 2.84-2.96 (m, 2H), 3.72-3.80 (m, 2H), 4.12-4.22 (m, 1H), 4.22-4.28 (m, 1H), 4.50 (s, 2H), 4.60-4.72 (m, 1H), 4.98- 5.03 (m, 1H), 6.94 -7.01 (m, 2H), 7.09-7.39 (m, 10H), 7.94-8.03 (m, 1H), 8. 19-8.27 (m, 1H).

Method 57

{4-[(2R, 3R) -3-{[2- (4-ethoxyphenyl) -2-oxoethyl] thio} -1- (4-fluorophenyl) -4-oxoazetidine-2 -Yl] phenoxy} acetic acid

t-butyl (4-{(2R, 3R) -1- (4-fluorophenyl) -3-[(3-nitropyridin-2-yl) dithio] -4-oxoazetidin-2-yl Phenoxy) acetate (0.25 g, 0.45 mmol) was dissolved in acetone (10 mL) at room temperature. Water (2.5 mL) and triphenyl phosphine (0.12 g, 0.45 mmol) were added. The mixture was stirred at room temperature for 15 minutes and then concentrated under reduced pressure to give crude thiol as a brown oil. The crude thiol was immediately dissolved in CH ₂ Cl ₂ (10 mL) and 2-bromo-3-ethoxy acetophenone (0.22 g, 0.90 mmol) was added, followed by Et ₃ N (0.13 mL, 0.90 mmol). Was added. The mixture was stirred at rt for 19 h, concentrated under reduced pressure and purified by flash chromatography (hexanes: EtOAc 3: 1). This gave a colorless oil which was dissolved in formic acid (10 mL) and stirred at room temperature for 18 hours. Concentrated under reduced pressure and purified by flash chromatography (hexane: acetone: formic acid 60: 40: 0.1) to give 0.13 g (57%) of the desired product as a pale yellow solid.

¹ H-NMR (CD ₃ Cl, 200 MHz): 1.4 (t, 3H), 4.0-4.1 (m, 5H), 4.5 (s, 2H), 4.8 (d, 2H), 6.8-7.0 (m, 6H ), 7.1-7.3 (m, 4H), 7.9 (d, 2H).

Method 58

t-butyl (4-{[(4-fluorophenyl) imino] methyl} phenoxy) acetate

t-butyl (4-formylphenoxy) acetate (21.6 g, 0.09 mol) was dissolved in dry toluene (150 mL) and 4-fluoroaniline (8.8 mL, 0.091 mol) was added. The mixture was refluxed for 23 h in a Dean Stark apparatus, cooled and concentrated under reduced pressure. Hexane was added and concentrated under reduced pressure to afford 30.0 g (quantitative yield) of the title compound as an off-white solid. NMR (200 MHz): 1.5 (s, 9H), 4.6 (s, 2H), 7.0-7.2 (m, 6H), 7.8 (d, 2H), 8.4 (s, 1H).

Method 59

(4S) -3-{[(4-methoxybenzyl) thio] acetyl} -4-phenyl-1,3-oxazolidin-2-one

(4-methoxy-benzylsulfanyl) -acetic acid (1.3 g, 6.1 mmol) was dissolved in dry DCM (40 mL) and cooled to 0 ° C. N, N'-dicyclohexylcarbodiimide (6.1 g, 6.1 mmol) and DMAP (1.6 g, 12.9 mmol) were added and the mixture was stirred for 30 minutes. (S)-(+)-4-phenyl-2-oxazolidinone (1.0 g, 6.1 mol) was added and the mixture was stirred at rt for 24 h. The mixture was filtered, concentrated under reduced pressure and purified by flash chromatography (hexanes: EtOAc 8: 2 then 1: 1). This gave 1.7 g (77%) of the title compound as a white solid. NMR (200 MHz): 3.46-3.59 (m, 3H), 3.74-3.76 (m, 4H), 4.23-4.28 (m, 1H), 4.68 (t, 1H), 5.38-5-42 (m, 1H) , 6.78 (d, 2H), 7.14 (d, 2H), 7.32-7.40 (m, 5H).

Method 60

t-butyl (4-{(lR) -1- (4-fluoroanilino) -2-[(4-methoxybenzyl) thio] -3-oxo-3-[(4S) -2-oxo- 4-phenyl-1,3-oxazolidin-3-yl] propyl} phenoxy) acetate

TiCl ₄ (1M in DCM, 7.2 mL, 7.2 mmol) was added to a solution of tetraisopropyl ortho titanate (0.71 mL, 2.4 mmol) in DCM (4 mL) that was left at 0 ° C. under inert atmosphere. The mixture was stirred for 1.5 minutes, then (4S) -3-{[(4-methoxy benzyl) thio] acetyl} -4-phenyl-1,3-oxazolidine-2- in dry DCM (20 mL). Warm (3.4 g, 9.6 mmol) was added and the mixture was stirred for 5 minutes. Then t-butyl (4-{[(4-fluorophenyl) imino] methyl} phenoxy) acetate (6.3 g, 19.0 mmol) in dry DCM (30 mL) was added and the mixture was brought to -40 ° C. Made and stirred for 20 minutes. Ethyl diisopropyl amine (3.3 mL, 19.0 mmol) was added and the mixture was stirred at −40 ° C. for 19 h. Then the mixture was brought to -78 ° C, isopropanol (50 mL) was added and allowed to come to room temperature overnight. Water (100 mL) was added and the mixture was stirred at rt for 35 min and then extracted twice with diethyl ether. The combined organic layers were washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure. The crude product was dissolved in methanol and formed an off-white precipitate. Filtration and drying gave 1.7 g (26%) of the title compound as off white solid. NMR (200 MHz): 1.5 (s, 9H), 3.65 (s, 1H), 3.8 (s, 3H), 4.1 (m, 1H), 4.4-4.6 (m, 4H), 5.0-5.2 (m, 2H ), 5.4 (m, 1H), 6.4-6.6 (m, 2H), 6.7-7-4 (m, 15H).

Method 61

3- (R) -4- (R) -1- (4-fluorophenyl) -3- (4-methoxybenzylsulfanyl) -4- [4- (t-butoxycarbonyl methoxy) phenyl ] Azetidin-2-one

t-butyl (4-{(1R) -1- (4-fluoroanilino) -2-[(4-methoxybenzyl) thio] -3-oxo-3-[(4S) -2-oxo- 4-phenyl-1,3-oxazolidin-3-yl] propyl} phenoxy) acetate (1.3 g, 1.9 mmol) was dissolved in dry toluene (140 mL) and heated to 90 ° C. under inert atmosphere. BSA (1.4 mL, 5.7 mmol) was added and the mixture was stirred at 90 ° C. for 1 h. Then the mixture was cooled to 45 ° C. and TBAF (dried, 0.1 g) was added. After 18 hours, additional BSA (0.5 mL, 2.0 mmol) was added and left at 45 ° C. for an additional 6 hours. After cooling, the mixture was concentrated under reduced pressure and purified by flash chromatography (hexanes: EtOAc 5: 1). This gave 0.55 g (55%) of the title compound as a white solid. NMR (200 MHz): 1.5 (s, 9H), 3.7 (s, 3H), 3.9 (m, 3H), 4.5 (m, 3H), 6.7 (d, 2H), 6.8-7.0 (m, 4H), 7.0-7.2 (m, 6 H).

Method 62

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(3-nitropyridin-2-yl) dithio] -4- [4- (t-butoxycar Carbonyl methoxy) phenyl] azetidin-2-one

3- (R) -4- (R) -1- (4-fluorophenyl) -3- (4-methoxybenzylsulfanyl) -4- [4- (t-butoxycarbonyl methoxy) phenyl ] Azetidin-2-one (0.65 g, 1.24 mmol) was dissolved in DCM (50 mL) at room temperature and brought to 0 ° C. under inert atmosphere. 3-nitro-2-pyridinesulphenyl chloride (0.28 g, 1.49 mmol) was added and the mixture was stirred at 0 ° C. for 75 minutes. Then additional 3-nitro-2-pyridinesulphenyl chloride (0.05 g, 0.27 mmol) was added and the mixture was stirred at 0 ° C. for an additional 45 minutes. Concentrated under reduced pressure and purified by flash chromatography (hexanes: EtOAc 4: 1 then 2: 1) to give 0.67 g (97%) of the desired product as a yellow oil. NMR (200 MHz): 1.6 (s. 9H), 4.3 (d, 1H), 4.5 (s, 2H), 5.2 (d, 1H), 6.8-7.0 (m, 4H), 7.1-7.3 (m, 4H ), 7.4 (m, 1 H) 8.5 (d, 1 H), 8.9 (d, 1 H).

Method 63

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- [4- (t-butoxycarbonyl methoxy ) Phenyl] azetidin-2-one

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(3-nitropyridin-2-yl) dithio] -4- [4- (t-butoxycar Bonyl methoxy) phenyl] azetidin-2-one (0.67 g, 1.2 mmol) was dissolved in acetone (50 mL) at room temperature, then water (10 mL) and tributyl phosphine (0.30 mL, 1.2 mmol) were added. It was. The mixture was stirred at rt for 30 min and then concentrated under reduced pressure to give crude thiol as a brown oil. The crude thiol was immediately dissolved in DCM (40 mL) and 2-bromo-4-fluoroacetophenone (0.29 g, 1.3 mmol) was added followed by Et ₃ N (0.20 mL, 1.4 mmol). . The mixture was stirred at rt for 90 min, concentrated under reduced pressure and purified by flash chromatography (hexanes: EtOAc 4: 1). This gave 0.42 g (65% in total over two steps) of the title compound as a white solid.

NMR (200 MHz) 1.44 (s, 9H), 4.06 (d, J = 2.4 Hz, 1H), 4.13 (d, J = 3.8 Hz, 2H), 4.48 (s, 2H), 4.81 (d, J = 2.2 Hz, 1H), 6.83-6.93 (m, 4H), 7.05-7. 21 (m, 6 H), 7.90-7.97 (m, 2 H).

Method 64

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- [4- (carboxymethoxy) phenyl] azetidine 2-on

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- [4- (t butoxycarbonylmethoxy) Phenyl] azetidin-2-one (0.42 g, 0.78 mmol) was dissolved in DCM (30 mL) at 0 ° C. and TFA (7.5 mL) was added dropwise. The mixture was brought to room temperature over several hours and then stirred overnight at room temperature. Concentrated under reduced pressure and purified by flash chromatography (EtOAc, then 5% MeOH in EtOAc) to give 0.32 g (85%) of the title compound as a white solid. NMR (CD ₃ OD, 300 MHz): 4.1 (d, 1H), 4.2 (s, 2H), 4.5 (s, 2H), 5.0 (d, 1H), 6.9-7.0 (m, 4H), 7.1-7.3 (m, 6H), 8.0 (m, 2H).

Method 65

t-butyl N-[(2R) -2-amino-2-phenylacetyl] -O- (t-butyl) -L-serinate

t-butyl N-((2R) -2-{[(benzyloxy) carbonyl] amino} -2-phenylethanoyl) -O- (t-butyl) -L-serinate (method 15; 3.3 g , 6.8 mmol) was dissolved in EtOH (95%, 30 mL) and catalytic amount of Pd / C (5%) (50% in water) was added and hydrogenation was carried out for 3 hours at room temperature and atmospheric pressure. The reaction mixture was filtered through diatomaceous earth and the solvent was evaporated to give the title compound (2.35 g, 98%). NMR (500 MHz, CD ₃ OD): 1.1 (s, 9H), 1.45 (s, 9H), 3.45-3.8 (m, 2H), 4.5 (t, 1H), 4.55 (s, 1H), 4.85 (s , 2H), 7.3-7.5 (m, 5H).

Method 66

1- (4-fluorophenyl) -3- (R)-[(4-fluorobenzoyl) methylthio] -4- (R)-{4- [N- (α- (R)-{N- [2- (t-butoxy) -l- (S)-(t-butoxycarbonyl) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- [4- (carboxyme in DMF (6 mL) Methoxy) phenyl] azetidin-2-one (0.090 g, 0.186 mmol), t-butyl N-[(2R) -2-amino-2-phenylacetyl] -O- (t-butyl) -L-serinate (Method 8; 0.098 g, 0.280 mmol) and N-methylmorpholine (0.062 mL, 0.563 mmol) were stirred at room temperature for 10 minutes before TBTU (0.096 g, 0.299 mmol) was added. After 22 hours, water (15 mL) was added to the reaction mixture and extracted three times with ether (3 × 10 mL). The combined organic layer was washed with brine (10 mL), dried over MgSO ₄ and concentrated. The residue was purified by flash chromatography on silica gel (using heptane: EtOAC (6: 4) as eluent). 0.053 g (35%) of the desired product was obtained as a white solid. NMR (400 MHz): 0.90 (s, 9H), 1.45 (s, 9H), 3.35 (dd, 1H), 3.65 (dd, 1H), 4.10 (d, 1H), 4.15 (ABq, 2H), 4.50 ( ABq, 2H), 4.50-4.60 (m, 1H), 4.85 (d, 1H), 5.55 (d, 1H), 6.40 (d, 1H), 6.90-7.00 (m, 4H), 7.10-7.40 (m, llH), 7.90-8.00 (m, 3H); m / z: 816.7.

Method 67

1- (4-fluorophenyl) -3- (R)-[(4-fluorobenzoyl) methylthio] -4- (R)-{4- [N- (α- (R)-{N- [2- (hydroxy) -1- (S)-(carboxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one

And

Method 68

1- (4-fluorophenyl) -3- (R)-[(4-fluorobenzoyl) methylthio] -4- (R)-{4- [N- (α- (R)-{N- [2- (t-butoxy) -l- (S)-(carboxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one

TFA (2 mL) was added 1- (4-fluorophenyl) -3- (R)-[(4-fluorobenzoyl) methylthio] -4- (R)-{4 in DCM (5 mL) at room temperature. -[N- (α- (R)-{N- [2- (t-butoxy) -1- (S)-(t-butoxycarbonyl) ethyl] carbamoyl} benzyl) carbamoylme To oxy] phenyl} azetidin-2-one (0.050 g, 0.061 mmol) solution. After 2.5 hours, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC (using 20% to 60% gradient MeCN in 0.1 M ammonium acetate buffer as eluent). After freeze drying, 0.039 g (90%) of 1- (4-fluorophenyl) -3- (R)-[(4-fluorobenzoyl) methylthio] -4- (R)-{4- [N -(α- (R)-{N- [2- (hydroxy) -1- (S)-(carboxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one Obtained.

NMR (DMSO, 400 MHz): 3.35 (dd, 1H), 3.50 (dd, 1H), 3,95-4.05 (m, 1H), 4.30 (d, 1H), 4.35 (ABq, 2H), 4.60 (ABq , 2H), 5.15 (d, 1H), 5.65 (d, 1H), 6. 90-7.00 (m, 2H), 7.10-7.40 (m, 13H), 7.95-8.05 (m, 2H), 8.25 (d , 1H), 8.55 (d, 1H); m / z: 704.5.

0.002 g (4%) of 1- (4-fluorophenyl) -3- (R)-[(4-fluorobenzoyl) methylthio] -4- (R)-{4- [N- (α- Obtain (R)-{N- [2- (t-butoxy) -1- (S)-(carboxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one It was. NMR (CD ₃ COOD, 400 MHz): 1.00 (s, 9H), 3.50 (dd, 1H), 3.80 (dd, 1H), 4.20-4.30 (m, 3H), 4.70 (s, 2H), 4.80-4.85 (m, 1H), 5.00-5.05 (m, 1H), 5.90-6.00 (m, 1H), 6.95-7.05 (m, 4H), 7.15-7.50 (m, llH), 8.00-8.10 (m, 2H) ; m / z: 760.5.

All of these were white solids.

Method 69

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- {4- [N (carboxymethyl) carbamoyl Methoxy] phenyl} azetidin-2-one

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- [4- (carboxyme in DCM (5 mL) Methoxy) phenyl] azetidin-2-one (0.200 g, 0.414 mmol), glycine t-butyl ester hydrochloride (0.113 g, 0.674 mmol) and N-methylmorpholine (0.180 mL, 1.63 mmol) at room temperature for 10 minutes After stirring, TBTU (0.193 g, 0.601 mnol) was added. After 25 h, conversion to ester (m / z: 597.43 (M + 1) ⁺ ) was confirmed and TFA (2 mL) was added to the solution. After 1 hour, the solvent was removed under reduced pressure and purified by preparative HPLC (using 20% to 50% gradient of MeCN in 0.1 M ammonium acetate buffer as eluent). After freeze drying, 0.093 g (41%) of the desired product was obtained as a white solid. NMR (DMSO, 500 MHz): 3.65 (d, 2H), 4.35 (d, 1H), 4.40 (ABq, 2H), 4.50 (s, 2H), 5.20 (d, 1H), 6.95-7.05 (m, 2H ), 7.15-7.40 (m, 8H), 8.00-8.15 (m, 3H); m / z: 541.3.

Method 70

1- (4-fluorophenyl) -3- (R)-[(4-fluorobenzoyl) methylthio] -4- (R)-{4- [N- {N- [2- (hydroxy) -1- (R)-(carboxy) ethyl] carbamoylmethyl} carbamoylmethoxy] phenyl} azetidin-2-one

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- {4- [N- in DCM (4 mL) (Carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one (0.030 g, 0.056 mmol), D-serine t-butyl ester hydrochloride (0.017 g, 0.067 mmol) and N-methylmorpholine (0.019 ML, 0.1172 mmol) was stirred at rt for 10 min, after which TBTU (0.023 g, 0.072 mmol) was added. After 22 hours the conversion to ester was complete (m / z: 740.58 (M + 1) ⁺ ). TFA (1.5 mL) was added to the solution, after 2 h the solvent was removed under reduced pressure and the residue was purified by preparative HPLC (using 20% to 50% gradient of MeCN in 0.1 M ammonium acetate buffer as buffer). . After freeze drying, 0.035 g (~ quantitative amount) of the desired product were obtained as a white solid. NMR (CD ₃ COOD, 400 MHz): 3.95 (dd, 1H), 4.10 (dd, 1H), 4.20-4.30 (m, 5H), 4.65 (s, 2H), 4.70-4.80 (m, 1H), 5.00 (d, 1H), 6.95-7.10 (m, 4H), 7.15-7.45 (m, 6H), 8.00-8.10 (m, 2H); m / z: 628.4

Method 71

1- (4-fluorophenyl) -3- (R)-[(4-fluorobenzoyl) methylthio] -4- (R)-{4- [N- {N- [2- (phenyl)- 1- (R)-(carboxy) ethyl] carbamoylmethyl} carbamoylmethoxy] phenyl} azetidin-2-one

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- {4- [N- (carboxymethyl) carba Molemethoxy] phenyl} azetidin-2-one (21 mg, 0.039 mmol), t-butyl D-phenylalanineate HCl (12 mg, 0.047 mmol) and 4-methylmorpholine (12 mg, 0.12 mmol) Was mixed in DCM (1 mL). After 5 minutes TBTU (15 mg, 0.046 mmol) was added and the mixture was stirred for 20 hours. The solvent was removed under reduced pressure and purified by chromatography on silica (using 1: 1 hexanes: EtOAc as eluent). The product was dissolved in formic acid and stirred for 20 hours. Formic acid was removed under reduced pressure then toluene was added and evaporated to give 21 mg (64%). M / z 686.3 (M−H) ⁻ .

Method 72

{4-[(2R, 3R) -l- (4-fluorophenyl) -3-({2-hydroxy-2- [4- (methylthio) phenyl] ethyl} thio) -4-oxoazeti Din-2-yl] phenoxy} acetic acid

t-butyl (4-{(2R, 3R) -1- (4-fluorophenyl) -3-[(3-nitropyridin-2-yl) dithio] -4-oxoazetidin-2-yl } Phenoxy) acetate (0.25 g, 0.45 mmol) was dissolved in acetone (10 mL) at room temperature and then water (2.5 mL) and triphenyl phosphine (0.12 g, 0.45 mmol) were added. The mixture was stirred at room temperature for 15 minutes and then concentrated under reduced pressure to give crude thiol as a brown oil. The crude thiol was immediately dissolved in CH ₂ Cl ₂ (10 mL) and 2-bromo-3-thiomethyl acetophenone (0.22 g, 0.90 mmol) was added, followed by Et ₃ N (0.13 mL, 0.90). mmol) was added. The mixture was stirred for 19 h at rt, concentrated under reduced pressure and purified by flash chromatography (hexanes: EtOAc 4: 1 then 3: 1). 0.4 g of t-butyl {4-[(2R, 3R) -1- (4-fluorophenyl) -3-({2- [4- (methylthio) phenyl] -2-oxoethyl} thio ) -4-oxoazetidin-2-yl] phenoxy} acetate and 1- [4- (methylthio) phenyl] -2-[(3-nitropyridin-2-yl) thio] ethanone It was. The mixture was dissolved in HCOOH (15 mL) and stirred at rt for 19 h. Concentrated under reduced pressure and purified by flash chromatography (hexane: acetone: HCOOH 60: 40: 0.1) to give 0.16 g (70%) of the desired compound as a pale yellow solid.

¹ H-NMR (CD ₃ Cl, 200 MHz): 2.5 (s, 3H), 4.0 (d, 1H), 4.1 (s, 2H), 4.6 (s, 2H), 4.8 (d, 1H), 6.8- 7.0 (m, 4H), 7.1-7.3 (m, 6H), 7.8 (d, 2H).

Method 73

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyl-D-ornithine

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- {4- [N- in DCM (3 mL) (Carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one (0.020 g, 0.037 mmol), t-butyl N ^5- (t-butoxycarbonyl) -D-ornithinate (0.012 g, 0.042 mmol), and N-methylmorpholine (0.012 mL, 0.1111 mmol) were stirred at room temperature. TBTU (0.018 g, 0.056 mmol) was added and the mixture was stirred overnight. Trifluoroacetic acid (1.0 mL) was added and after 6 hours the solvent was removed under reduced pressure. Purification by preparative HPLC on Kromasil C8-column (using 5% to 100% gradient of MeCN in 0.1 M ammonium acetate buffer as eluent). The solvent was removed under reduced pressure to afford 0.021 g (87%) of the desired product. M / z 655.21

Method 74

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycyl-N ⁶ , N ⁶ -Dimethyl-L-lysine

3- (R) -4- (R) -1- (4-fluorophenyl) -3-[(4-fluorobenzoyl) methylthio] -4- {4- [N- (carboxymethyl) carba Molemethoxy] phenyl} azetidin-2-one (0.10 g, 0.018 mmol) and N-methylmorpholine (0.006 mL, 0.055 mmol) were dissolved in DMF (0.5 mL). TBTU (0.0099 g, 0.031 mmol) was added. The mixture was stirred at 30 ° C. to 40 ° C. for 30 minutes under N ₂ -atmosphere. N ⁶ , N ⁶ -dimethyl-L-lysine hydrochloride (0.0045 g, 0.021 mmol) was added and the mixture was stirred at 30 ° C. to 40 ° C. for several hours and then at room temperature overnight. A few drops of water were added and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC on C8-column using 5% to 100% gradient of MeCN as eluent in 0.1 M ammonium acetate buffer. Removal of solvent under reduced pressure gave 0.OO5 g (39%) of desired product.

M / z 697.31

Method 75

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} glycine

 [4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-methoxyphenyl) -2-oxoethyl] thio} -4 in DCM (2 mL) Oxoazetidin-2-yl) phenoxy] acetic acid (0.0153 g, 0.031 mmol), t-butyl glycyl-D-valinate hydrochloride (0.0099 g, 0.037 mmol) and N-methylmorpholine (0.010 mL) , 0.991 mmol) was stirred at room temperature. TBTU (0.016 g, 0.050 mmol) was added and the mixture was stirred for 3.5 h. Trifluoroacetic acid (0.5 mL) was added and the solvent was removed after 3.5 hours under reduced pressure. Purification by preparative HPLC on Kromasil C8-column (using 5% to 100% gradient of MeCN in 0.15% trifluoroacetic acid as eluent). The solvent was removed under reduced pressure and 0.015 g (74%) of the title compound were obtained. M / z 652.20.

Method 76

[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- (4-chlorophenyl) -2-oxoethyl] thio} -4-oxoazetidin-2-yl ) Phenoxy] acetic acid

t-butyl {4-[(2R, 3R) -1- (4-chlorophenyl) -3-({[2- (4-chlorophenyl) -5,5-dimethyl-1,3-dioxane-2 -Yl] methyl} thio) -4-oxoazetidin-2-yl] phenoxy} acetate (1.69 g, 2.57 mmol) was dissolved in formic acid (25 mL) and stirred for 2 hours. The mixture was concentrated under reduced pressure (temperature <30 ° C.) and the crude oil was purified by flash chromatography (hexane: acetone: formic acid 60: 40: 0.1) to give 1.08 g (81%) of the title compound as a pale yellow solid. It was. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 4.0-4.2 (m, 3H), 4.7 (s, 2H), 4.9 (d, 1H), 6.9 (d, 2H), 7.2-7.4 (m, 6H ), 7.5 (d, 2H), 7.9 (d, 2H). MS (CI) M / z: 514.2 (M -), 515.2 (30), 516.1 (70), 517.2 (20).

Examples of Intermediates of Formulas VI and XV

Method 77

N-{[4-((2R, 3R) -1- (4- Fluorophenyl ) -3-{[2- (4- Fluorophenyl )-2- Hydroxyethyl ] Thio }-4- Oxoazetidine -2 days) Phenoxy ] Acetyl} -D-alanine

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} -D-alanine was dissolved in methanol (1.5 mL). Sodium borohydride was added and the mixture was stirred for 30 minutes. Ammonium acetate / H ₂ O solution (2 mL) was added and methanol was evaporated. The product was purified by preparative HPLC (CH ₃ CN / 0.1% ammonium acetate buffer 20: 80-100: 0). Fractions containing the product were lyophilized and 27 mg (48%) of the title product were obtained. M / z: 555.0 (M-1).

Method 78

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -L-tryptophan

[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazetidine-2 -Yl) phenoxy] acetic acid (0.050 g, 0.103 mmol) was dissolved in CH ₂ Cl ₂ (5 mL). Tryptophan t-butyl ester hydrochloride (0.037 g, 0.12 mmol) and N-methylmorpholine (31 mg, 0.31 mmol) were added. After 10 minutes, TBTU (43 mg, 0.13 mmol) was added and the mixture was stirred for 4 hours. The crude ester was purified on silica gel and eluted with EtOAc / CH ₂ Cl ₂ (25/75). Fractions containing pure esters were concentrated. CH ₂ Cl ₂ (5 mL) and TFA (1 mL) were added and the reaction stirred for 4 hours. The mixture was concentrated and the remaining traces of TFA were azeotropically removed by coevaporation with toluene (2x5 mL). The residue was dissolved in 5 mL of MeOH and sodium borohydride (0.016 g, 0.414 mmol) was added. After 5 minutes the reaction was quenched by the addition of 0.1 M NH ₄ OAc buffer (1 mL). The mixture was concentrated and purified by preparative HPLC (using 20% to 50% gradient CH ₃ CN in 0.1 M ammonium acetate buffer as eluent). Pure fractions were lyophilized to provide the title compound as a colorless solid (0.040 g, 58%). M / z: 670.3 (M-1). ¹ H NMR [(CD ₃ ) ₂ SO), 400 MHz] δ 2.85-2.95 (m, 2H), 3.07-3.12 (m, 1H), 3.22-3. 27 (m, 1H), 4.24-4.27 (m, 1H), 4.34-4.38 (m, 1H), 4.41 (s, 2H), 4.70-4.76 (m, 1H), 5.01-5.04 (m, 1H), 6.80-7.35 (m, 16H), 7.50-7.53 (m, 1H), 7.85-7.92 (m, 1H), 10.76 (s, 1H).

Method 79

N ² -{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazeti Din-2-yl) phenoxy] acetyl} -L-glutamine

[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4-oxoazetidine-2 -Yl) phenoxy] acetic acid (50 mg, 0.103 mmol), t-butyl L-glutaminate hydrochloride (30 mg, 0.124 mmol) and N-methylmorpholine (40 mg, 0.396 mmol) were added to methylene chloride (1). Ml). TBTU (40 mg, 0.125 mmol) was added and the mixture was stirred for 90 minutes. The solvent was evaporated and the residue was dissolved in formic acid (1 mL). The mixture was heated at 45 ° C. to 50 ° C. for 4 hours. The reaction mixture was evaporated under reduced pressure. Toluene (5 mL) was added and evaporated. The residue was dissolved in methanol (1 mL). NaBH ₄ (30 mg, 0.793 mmol) was added and the mixture was stirred for 15 minutes. Acetic acid (50 mg, 0.83 nmol) was added and the reaction mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (using acetonitrile / ammonium acetate buffer (35:65) as eluent). 47 mg (74%) of the title compound were obtained after freeze drying. ¹ H-NMR (300 MHz, DMSO): 1.72-2.16 (m, 4H), 2.81-2.95 (m, 2H), 4.08-4.20 (m, 1H), 4.26-4.31 (m, 1H), 4.50 (s , 2H), 4.65-4.78 (m, 1H), 5.03-5.08 (m, 1H), 6.68 (s, 1H), 6.89-7.44 (m, 14H), 8.29 (d, 1H).

Method 80

N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -D-serine

[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-oxoethyl] thio} -4- in DCM (4 mL) Oxoazetidin-2-yl) phenoxy] acetic acid (0.050 g, 0.103 mmol), O- (t-butyl) -D-serine t-butyl ester hydrochloride (0.032 g, 0.147 mmol) and N-methylmor Pauline (0.035 mL, 0.318 mmol) was stirred for 5 minutes. TBTU (0.044 g, 0.137 mmol) was added. After 3 hours the formation of esters was confirmed. M / z: 683.1. TFA (2 mL) was added and the mixture was stirred for 22 hours. The solvent was removed under reduced pressure. The residue was dissolved in MeOH (4 mL) and NaBH ₄ (0.130 g total, 3.44 mmol) was added in portions. The reaction was quenched by the addition of 0.1 M ammonium acetate buffer (3 mL). Methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC (using 20% to 60% gradient MeCN in 0.1 M ammonium acetate buffer as eluent). After freeze drying, 0.021 g (36% yield) of the title compound were obtained as a white solid. M / z: 573.1. ¹ H NMR (DMSO, 400 MHz): δ 2.84-2.96 (m, 2H), 3.47 (dd, 1H), 3.69 (dd, 1H), 3.97-4.06 (m, 1H), 4.27-4.32 (m, 1H ), 4.52 (ABq, 2H), 4.68-4.77 (m, 1H), 5.04-5.09 (m, 1H), 5.65 (bs, 1H), 6.99 (d, 2H), 7.07-7.41 (m, 10H), 7.89 (d, 1 H).

Those skilled in the art will appreciate that the above embodiments may be modified within the scope of the invention as the invention is not limited to the specific embodiments.

Water absorption

The uptake of the compounds of formula (I) in the Caco-2 cell model was tested.

(Gastrointestinal 1989, 96, 736):

Compound (I) Caco value (10 ^-6 cm / sec) N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-valine 0.06 N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-tyrosine 0.07 N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-lysine 0.2 1- (4-fluorophenyl) -3- (R)-[2- (4-fluorophenyl) -2-hydroxyethylthio] -4- (R)-{4- [N- {N- [2- (phenyl) -l- (R)-(carboxy) ethyl] carbamoylmethyl} carbamoylmethoxy] phenyl} azetin-2-one 0.09

Claims (20)

A compound of formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or prodrug thereof, provided that (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- [4- (N- {N-[(R) -1- (carboxy) -2- (hydroxy) ethyl] carbamoyl Methyl} carbamoylmethoxy) phenyl] azetidin-2-one; Or 3- (R) -4- (R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- {4- [N- ( (R) -α- {N-[(S) -1- (carboxy) -2- (hydroxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one is Excluded from the compound]: Formula I

Where R ¹ is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or aryl; Wherein said C _1-6 alkyl is optionally one or more hydroxy, amino, guanidino, carbamoyl, carboxy, C _1-6 alkoxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C ₁ -C ₆ alkylcarbonylamino C _1-6 alkylS (O) _a , where a is 0 to 2, C _3-6 cycloalkyl or aryl May be substituted; Wherein any aryl group may be optionally substituted with one or two substituents selected from halo, hydroxy, C _1-6 alkyl and C _1-6 alkoxy; R ² and R ⁵ are independently hydrogen, branched or unbranched C _1-6 alkyl, C _3-6 cycloalkyl or aryl; Wherein said C _1-6 alkyl is optionally one or more hydroxy, amino, guanidino, cyano, carbamoyl, carboxy, C _1-6 alkoxy, aryl C _1-6 alkoxy, (C ₁ -C ₄ ) ₃ Si, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkylS (O) _a , C _3-6 cycloalkyl, aryl or Aryl C _1-6 alkylS (O) _a , wherein a is 0 to 2; Wherein any aryl group may be optionally substituted with one or two substituents selected from halo, hydroxy, C _1-6 alkyl and C _1-6 alkoxy; R ³ is hydrogen, alkyl, halo, C _1-6 alkoxy or C _1-6 alkylS-; R ⁴ is hydrogen, C _{1 - 6} alkyl, halo, or C _{1 - 6} alkoxy; R ⁶ is hydrogen, C _{1 - 6} alkyl or aryl C _{1 - 6} alkyl; Here, R ⁵ and R ² may form a ring having 2 to 7 carbon atoms, and R ⁶ and R ² may form a ring having 3 to 6 carbon atoms. A compound of formula (I2), a pharmaceutically acceptable salt, solvate thereof, or solvate thereof, or a prodrug thereof, provided that 3- (R) -4- (R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- [4- (N- {N-[(R) -1- (carboxy) -2- (hydroxy) ethyl] carbamoyl Methyl} carbamoylmethoxy) phenyl] azetidin-2-one; Or 3- (R) -4- (R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- {4- [N- ( (R) -α- {N-[(S) -1- (carboxy) -2- (hydroxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one is Excluded from the compound]: Formula I2

Where R ¹ is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or aryl; Wherein said C _1-6 alkyl is optionally one or more hydroxy, amino, guanidino, carbamoyl, carboxy, C _1-6 alkoxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C ₁ -C ₆ alkylcarbonylamino C _1-6 alkylS (O) _a , where a is 0 to 2, C _3-6 cycloalkyl or aryl Can be substituted; Wherein any aryl group may be optionally substituted with one or two substituents selected from halo, hydroxy, C _1-6 alkyl and C _1-6 alkoxy; R ² and R ⁵ are independently hydrogen, branched or unbranched C _1-6 alkyl, C _3-6 cycloalkyl or aryl; Wherein said C _1-6 alkyl is optionally one or more hydroxy, amino, guanidino, cyano, carbamoyl, carboxy, C _1-6 alkoxy, aryl C _1-6 alkoxy, (C ₁ -C ₄ ) ₃ Si, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkylS (O) _a , C _3-6 cycloalkyl, aryl or Aryl C _1-6 alkylS (O) _a , wherein a is 0 to 2; Wherein any aryl group may be optionally substituted with one or two substituents selected from halo, hydroxy, C _1-6 alkyl and C _1-6 alkoxy; R ³ is hydrogen, alkyl, halo, C _1-6 alkoxy or C _1-6 alkylS-; R ⁴ is hydrogen, C _1-6 alkyl, halo or C _1-6 alkoxy; R ⁶ is hydrogen, C _1-6 alkyl or arylC _1-6 alkyl; Here, R ⁵ and R ² may form a ring having 2 to 7 carbon atoms, and R ⁶ and R ² may form a ring having 3 to 6 carbon atoms. The compound of claim 1 or 2, wherein R ¹ is hydrogen or phenyl. To claim 1, wherein A method according to any one of claim 3, wherein, R ² is hydrogen, branched or derivative branched C _{1 - 6} alkyl, C _{3 - 6} cycloalkyl or aryl; Here, the C _{1 - 6} alkyl is in one or more of hydroxy, amino, acylamino, as appropriate, C _{1 - 6} alkyl S (O) _a (wherein a is 0 to 2;), C _{3 - 6} cycloalkyl, or May be substituted with aryl; Wherein any aryl group may be optionally substituted with hydroxy, alkyl, alkoxy or cyano. 5. The compound of claim 1, wherein R ³ is hydrogen, C ₁ -C ₂ alkyl, halo or methoxy. 6. The compound of claim 1, wherein R ³ is hydrogen, methyl, chlorine, fluorine, C _1-6 alkylS- or methoxy. 7. The compound of any one of claims 1-6, wherein R ⁴ is hydrogen or halo. 8. The compound of claim 1, wherein R ⁴ is chlorine or fluorine. 9. The ring of claim 1, wherein R ⁶ is hydrogen, C _1-6 alkyl or arylC _1-6 alkyl, or R ⁶ and R ² are rings having 3 to 6 carbon atoms. To form compounds. The method of claim 1, R ¹ is hydrogen; R ² is optionally substituted branched or unbranched C _1-4 alkyl, alkylS-, optionally substituted with C _3-6 cycloalkyl, aryl, amino, N- (C _{1- 6} alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino or aryl C _1-6 alkylS (O) _a , wherein a is 0 to 2; R ³ and R ⁴ are halo; R ⁵ is hydrogen or C _1-6 alkyl; R ⁶ is hydrogen. N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-N ⁶ -acetyl-D-lysine; 1- (4-fluorophenyl) -3- (R)-[2- (4-fluorophenyl) -2-hydroxyethylthio] -4- (R)-{4- [N- {N- [2- (phenyl) -1- (R)-(carboxy) ethyl] carbamoylmethyl} carbamoylmethoxy] phenyl} azetidin-2-one; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-valine; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-tyrosine; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-proline; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-lysine; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2-hydroxy-2- (4-methoxyphenyl) ethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-D-valine; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-2-butylnorleucine; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-S-methyl-L-cysteine; N-{[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- (4-chlorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidine -2-yl) phenoxy] acetyl} glycyl-3-cyclohexyl-D-alanine; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-3-cyclohexyl-D-alanine; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-4-methylleucine; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} -L-alanyl-D-valine; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2-hydroxy-2- (4-methylphenyl) ethyl] thio} -4-oxoazetidine -2-yl) phenoxy] acetyl} glycyl-D-valine; N-{[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- (4-chlorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidine -2-yl) phenoxy] acetyl} glycyl-D-valine; N-{[4-((2R, 3R) -1- (4-chlorophenyl) -3-{[2- (4-chlorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidine -2-yl) phenoxy] acetyl} glycyl-3-methyl-D-valine; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-jade Pediatric zetidin-2-yl) phenoxy] acetyl} glycyl-3- (2-naphthyl) -D-alanine; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-3-methyl-D-valine; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl- (3R, 4S, 5R) -3,4,5,6-tetrahydroxy-D-norleucine; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-N, 2-dimethylalanine; N-({4-[(2R, 3R) -1- (4-fluorophenyl) -3-({2-hydroxy-2- [4- (methylthio) phenyl] ethyl} thio) -4- Oxoazetidin-2-yl] phenoxy} acetyl) glycyl-3-methyl-D-valine; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-S- (4-methylbenzyl) -D-cysteine; N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-S- (t-butyl) -D-cysteine; And N-{[4-((2R, 3R) -1- (4-fluorophenyl) -3-{[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoa Zetidin-2-yl) phenoxy] acetyl} glycyl-b, b-dimethyl-D-phenylalanine At least one compound selected from. A compound of formula (XV), a hydrolyzable ester or amide thereof, a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, provided that 3- (R) -4- (R) -1- ( Phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- [4- (N- {N-[(R) -1- (carboxy) -2- ( Hydroxy) ethyl] carbamoylmethyl} carbamoylmethoxy) phenyl] azetidin-2-one; Or 3- (R) -4- (R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- {4- [N- ( (R) -α- {N-[(S) -1- (carboxy) -2- (hydroxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one is Excluded from the compound]: Formula XV

Where R ¹ is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or aryl; Wherein said C _1-6 alkyl is optionally one or more hydroxy, amino, guanidino, carbamoyl, carboxy, C _1-6 alkoxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C ₁ -C ₆ alkylcarbonylamino C _1-6 alkyl S (O) _a , where a is 0 to 2, substituted with C _3-6 cycloalkyl or aryl Can be; Wherein any aryl group may be optionally substituted with one or two substituents selected from halo, hydroxy, C _1-6 alkyl and C _1-6 alkoxy; R ² and R ⁵ are independently hydrogen, branched or unbranched C _1-6 alkyl, C _3-6 cycloalkyl or aryl; Wherein said C _1-6 alkyl is optionally one or more hydroxy, amino, guanidino, carbamoyl, carboxy, C _1-6 alkoxy, aryl C _1-6 alkoxy, (C ₁ -C ₄ ) ₃ Si, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkyl S (O) _a, aryl C _1-6 alkyl S (O) _a ( Wherein a is 0 to 2), C _3-6 cycloalkyl or aryl; Wherein any aryl group may be optionally substituted with one or two substituents selected from halo, hydroxy, C _1-6 alkyl and C _1-6 alkoxy; R ³ is hydrogen, alkyl, halo, C _{1 - 6} alkoxy or C _{1 - 6} alkyl and S-; R ⁴ is hydrogen, C _1-6 alkyl, halo or C _1-6 alkoxy; R ⁶ is hydrogen, C _1-6 alkyl or arylC _1-6 alkyl; R ⁷ is a hydroxy group or a C _1-3 alkoxy group; Here, R ⁵ and R ² may form a ring having 2 to 7 carbon atoms, and R ⁶ and R ² may form a ring having 3 to 6 carbon atoms. A method of treating or preventing hyperlipidemia, comprising administering to a mammal in need thereof an effective amount of a compound according to any one of claims 1 to 12. A method of treating or preventing atherosclerosis comprising administering an effective amount of a compound according to any one of claims 1 to 12 to a mammal in need of treatment or prevention of atherosclerosis. A method for treating or preventing Alzheimer's disease, comprising administering to a mammal in need thereof an effective amount of a compound according to any one of claims 1 to 12. A method for treating or preventing a tumor associated with cholesterol, comprising administering to a mammal in need thereof an effective amount of a compound according to any one of claims 1 to 12. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 12 together with a pharmaceutically acceptable adjuvant, diluent and / or carrier. A combination of a compound according to formula (I) or formula (I2) with a PPARα and / or PPARγ agonist. Combination of a compound according to Formula I or Formula I and HMG Co-A reductase inhibitor. A process for preparing a compound of Formula (I), a pharmaceutically acceptable salt, solvate or solvate thereof, or a prodrug thereof, comprising the following steps 1) to 7), and Afterwards, as required or if desired, Iii) converting the compound of formula I to another compound of formula I; Ii) removing any protecting groups; Iii) forming a pharmaceutically acceptable salt, solvate, solvate of said salt, or prodrug; or Iii) separating two or more enantiomers How to include: Step 1) reacting a compound of Formula II with a compound of Formula III; Step 2) reacting an acid of formula (IV) or an activated derivative thereof with an amine of formula (V); Step 3) reacting an acid of formula (VI) or an activated derivative thereof with an amine of formula (VII); Step 4) reducing the compound of formula VII; Step 5) reacting a compound of formula (VII) with a compound of formula (VII); Step 6) reacting a compound of formula (XI) with a compound of formula (XI); And Step 7) Deesterification of the Compound of Formula XIII: Formula II

Formula III

Formula IV

Formula V

Formula VI

Formula Ⅶ

Formula Ⅷ

Formula Ⅸ

Formula Ⅹ

Formula (XI)

Chemical Formula XII

Chemical Formula XIII

Where L is a substitutable group and suitable groups as L are, for example, halogeno or sulfonyloxy groups such as chloro, bromo, methanesulfonyloxy or toluene-4-sulfonyloxy groups; C (O) OR is an ester group and suitable groups as C (O) OR are methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl or benzyloxycarbonyl; Unless otherwise specified, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in Formula (I).