KR20050023393A - Diphenylazetidinone derivatives for treating disorders of the lipid metabolism - Google Patents

Abstract

Compounds of formula (I), pharmaceutically acceptable salts, solvates thereof, solvates and prodrugs of such salts, and the use of these compounds as cholesterol absorption inhibitors for the treatment of hyperlipidemia are disclosed. Also disclosed are methods of preparing these compounds and pharmaceutical compositions comprising these compounds.

Formula I

In the above formula, the variable group is as defined in the specification.

Description

Diphenylazetidinone derivative for the treatment of lipid metabolism disorders {DIPHENYLAZETIDINONE DERIVATIVES FOR TREATING DISORDERS OF THE LIPID METABOLISM}

The present invention relates to 2-azetidinone derivatives or pharmaceutically acceptable salts, solvates, solvates and prodrugs of such salts. These 2-azetidinones possess cholesterol absorption inhibitory activity and are therefore valuable for the treatment of disease states associated with hyperlipidemic symptoms. Therefore, it is useful for the method of treating warm-blooded animals including humans. The present invention also relates to a method for producing the 2-azetidinone derivative, a pharmaceutical composition comprising the same, and a use in the preparation of a medicament for inhibiting cholesterol absorption in warm-blooded animals such as humans. A further aspect of the present invention relates to the use of a compound of the present 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. Hyperlipidemic conditions associated with elevated levels of total cholesterol and low density lipoprotein (LDL) cholesterol are major risk factors for cardiovascular atherosclerosis disease (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 the cholesterol mechanism. In the endogenous pathway, cholesterol is synthesized in liver and tissues other than liver and enters the circulation as lipoproteins or is secreted into bile. In the endoscopic pathway, 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 is that cholesterol passes through the intestine 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 several types of pharmaceutical agents are used to regulate serum cholesterol. The main options for controlling 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 the LDL-receptor; 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 a selective cholesterol absorption inhibitor. 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 , Compounds disclosed in WO 02/50027, WO 02/50060, WO 02/50068, WO 02/50090, WO 02/66464, US 5756470, US 5767115 and US RE37721 have been disclosed.

The present invention is based on the discovery that some benzothiazepine and benzothiadiazepine compounds surprisingly inhibit cholesterol absorption. Such properties are expected to be of value in treating disease states associated with hyperlipidemia symptoms. 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 thereof, solvate or prodrug of such salt.

Where

Ring A is selected from phenyl or thienyl;

X is -CR ² R ³ - is selected from, -O-, -NR ^x - -, and -S (O) _a; Then R ^x is hydrogen or C _1-6 alkyl and a is 0-2;

Y is -CR ⁴ R ⁵ - is selected from, -O-, -NR ^z - -, and -S (O) _a; Then R ^z is hydrogen or C _1-6 alkyl and a is 0-2; Then there is at least one -CR ² R ³ -or -CR ⁴ R ⁵ -group;

R ¹ is independently selected from halo, hydroxy, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylS (O) _a , wherein a is 0-2; Then R ¹ is independently optionally substituted on carbon by one or more halo, C _1-6 alkoxy and hydroxy;

b is 0 to 3; The value of R ¹ may be the same or different;

R ² and R ³ are independently selected from hydrogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkanoyloxy; Wherein R ² and R ³ may be optionally substituted independently on carbon by one or more halo or hydroxy; Or R ² and R ³ together form an oxo group;

R ⁴ and R ⁵ are independently selected from hydrogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkanoyloxy; Or R ⁴ and R ⁵ together form an oxo group;

R ⁶ is independently halo, nitro, cyano, hydroxy, amino, carboxy, formyl, carbamoyl, carbamoyloxy, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkenyloxy, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N -(C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino, C _1-6 alkanoyl-N- (C _1-6 alkyl) amino, C _1-6 alkylsulfonylamino, C _1-6 Alkylsulfonyl-N- (C _1-6 alkyl) amino, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, N- (C _{1- 6} alkyl) carbamoyloxy, N, N- (C _1-6 alkyl) ₂ carbamoyloxy, C _1-6 alkylS (O) _a [where a is 0 to 2], C _1-6 Alkoxycarbonyl, C _1-6 alkoxycarbonylamino, C _1-6 alkoxycarbonyl-N- (C _1-6 alkyl) amino, C _1-6 alkoxycarbonyloxy, C _1-6 alkoxycarbonylamino, Ureido, N '-(C _1-6 alkyl) ureido, N- (C _1-6 alkyl) ureido, N', N '-(C _{1- 6} alkyl) ₂ ureido, N '-(C _1-6 alkyl) -N- (C _1-6 alkyl) ureido, N', N '-(C _1-6 alkyl) ₂ -N- (C _{1 -6} alkyl) ureido, N- (C _1-6 alkyl) sulfamoyl, N, N- (C _1-6 alkyl) ₂ sulfamoyl and phenyl; Wherein R ⁷ is independently one or more halo, C _1-6 alkoxy, hydroxy, amino, carboxy, C _1-6 alkoxycarbonyl, carbamoyl, N- (C _1-6 alkyl) carbamoyl on carbon , N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkanoylamino, C _1-6 alkanoyl-N- (C _1-6 alkyl) amino, phenyl, phenoxy, benzoyl, Optionally substituted by _{phenylC 1-6} alkyl and phenylC _1-6 alkoxy;

c is 0-5; ^Wherein the value of R ⁶ may be the same or different;

R ⁷ is independently halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, Methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N, N- Dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl;

d is 0-4; ^Wherein the value of R ⁷ may be the same or different;

R ⁹ is hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Then R ⁹ may be optionally substituted on carbon by one or more substituents selected from R ²³ ; When the heterocyclyl comprises an —NH— group, the nitrogen may be optionally substituted with a group selected from R ²⁴ ;

R ¹⁰ is hydrogen or C _1-4 alkyl;

R ¹¹ and R ¹² are independently selected from hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Or R ¹¹ and R ¹² together form C _2-6 alkylene; R ¹¹ and R ¹² or R ¹¹ and R ¹² together may be optionally substituted on carbon independently with one or more substituents selected from R ²⁵ ; When the heterocyclyl comprises an —NH— moiety that nitrogen may be optionally substituted by one or more R ²⁶ ;

R ¹³ is hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Then R ¹³ may be optionally substituted on carbon by one or more substituents selected from R ²⁷ ; When the heterocyclyl comprises an —NH— moiety that nitrogen may be optionally substituted by one or more R ²⁸ ;

R ¹⁴ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 Alkynyl, C _1-10 alkoxy, C _1-10 alkoxycarbonyl, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N- (C _1-10 alkyl) amino, N, N- (C _{1 -10} alkyl) ₂ amino, N, N, N- (C _1-10 alkyl) ₃ ammonio, C _1-10 alkanoylamino, N- (C _1-10 alkyl) carbamoyl, N, N- ( C _1-10 alkyl) ₂ carbamoyl, C _1-10 alkyl S (O) _a [where a is 0-2], N- (C _1-10 alkyl) sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfamoylamino, C _1-10 alkoxycarbonylamino, carbocyclyl , CarbocyclylC _1-10 alkyl, heterocyclyl, heterocyclylC _1-10 alkyl, carbocyclyl- (C _1-10 alkylene) _e -R ^29- (C _1-10 alkylene) _f- , heterocyclyl, - (C _1-10 alkylene) _g -R ³⁰ - (C _1-10 alkylene) _h -, carboxy, Four, Pinot sulfonic, ^{phosphono, -P (O) (OR 31} ) (OR 32), -P (O) (OH) (OR 31), -P (O) (OH) (R 31) , or -P (O) (OR ³¹ ) (R ³² ), wherein R ³¹ and R ³² are independently selected from C _1-6 alkyl; Then R ¹⁴ on carbon may be optionally substituted by one or more substituents selected from R ³³ ; If said heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ³⁴ ; Or R ¹⁴ is a group of formula (IA):

In the above formula,

Z is ^{-N (R 35) -, -N} (R 35) C (O) -, -O-, and -S (O) _a - a; A is 0 to 2 and R ³⁵ is hydrogen or C _1-4 alkyl;

R ¹⁵ is hydrogen or C _1-4 alkyl;

R ¹⁶ and R ¹⁷ are independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkylS (O) _a [where a is 0 to 2], C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl, N, N- (C _1-6 alkyl) ₂ sulfamoyl, carbocyclyl, heterocyclyl , Sulfo, sulfino, amidino, phosphono, -P (O) (OR ³⁶ ) (OR ³⁷ ), -P (O) (OH) (OR ³⁶ ), -P (O) (OH) (R ³⁶ ) Or —P (O) (OR ³⁶ ) (R ³⁷ ), wherein R ³⁶ and R ³⁷ are independently selected from C _1-6 alkyl; Then R ¹⁶ and R ¹⁷ may be optionally substituted on carbon independently by one or more substituents selected from R ³⁸ ; When the heterocyclyl includes an —NH— group, that nitrogen may be optionally substituted by a group selected from R ³⁹ ;

R ¹⁸ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 Alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N- (C _1-10 alkyl) amino, N, N- (C _1-10 alkyl) ₂ amino, C _1-10 alkanoylamino, N- (C _1-10 alkyl) carbamoyl, C _1-10 alkoxycarbonyl, N, N- (C _1-10 alkyl) ₂ carbamoyl, C _1-10 alkyl S (O) _a [where a is 0-2], N- (C _1-10 alkyl) sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl Sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfamoylamino, carbocyclyl, carbocyclylC _1-10 alkyl, heterocyclyl, heterocyclylC _1-10 alkyl, carbocyclyl -(C _1-10 alkylene) _e -R ^40- (C _1-10 alkylene) _f -or heterocyclyl- (C _1-10 alkylene) _g -R ^41- (C _1-10 alkylene) _h- , carboxy, sulfo, sulfino, phosphono, -P (O) (OR ⁴² ) (OR ⁴³ ), -P (O) (OH) (OR ⁴² ), -P (O) (OH) (R ⁴² ) or -P (O) (OR ⁴² ) (R ⁴³ ), wherein R ⁴² and R ⁴³ are independently selected from C _1-6 alkyl; ; Then R ¹⁸ may be optionally substituted on carbon by one or more substituents selected from R ⁴⁴ ; When the heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ⁴⁵ ; Or R ¹⁸ is a group of formula IB:

here,

R ¹⁹ is selected from hydrogen or C _1-4 alkyl;

R ²⁰ is hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alka Noylamino, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkyl S (O) _a [where a is 0 to 2 C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl, N, N- (C _1-6 alkyl) ₂ sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino , Amidino, phosphono, -P (O) (OR ⁴⁶ ) (OR ⁴⁷ ), -P (O) (OH) (OR ⁴⁶ ), -P (O) (OH) (R ⁴⁶ ) or -P ( O) (OR ⁴⁶ ) (R ⁴⁷ ), wherein R ⁴⁶ and R ⁴⁷ are independently selected from C _1-6 alkyl; R ²⁰ may be independently substituted on carbon by one or more substituents selected from R ⁴⁸ ; When the heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ⁴⁹ ;

R ²¹ is halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl , C _1-10 alkoxy, C _1-10 alkoxycarbonyl, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N- (C _1-10 alkyl) amino, N, N- (C _1-10 Alkyl) ₂ amino, N, N, N- (C _1-10 alkyl) ₃ ammonio, C _1-10 alkanoylamino, N- (C _1-10 alkyl) carbamoyl, N, N- (C _{1 -10} alkyl) ₂ carbamoyl, C _1-10 alkyl S (O) _a [where a is 0-2], N- (C _1-10 alkyl) sulfamoyl, N, N- (C _{1- 10} alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfamoylamino, C _1-10 alkoxycarbonylamino, carbocyclyl, carbo BocyclylC _1-10 alkyl, heterocyclyl, heterocyclylC _1-10 alkyl, carbocyclyl- (C _1-10 alkylene) _e -R ^50- (C _1-10 alkylene) _f- , hetero heterocyclyl - (C _1-10 alkylene) _g -R ⁵¹ - (C _1-10 alkylene) _h -, carboxy, sulfo, Pino, ^{phosphono, -P (O) (OR 52} ) (OR 53), -P (O) (OH) (OR 52), -P (O) (OH) (R 52) , or -P (O) (OR ⁵³ ) (R ⁵³ ), wherein R ⁵² and R ⁵³ are independently selected from C _1-6 alkyl; Then R ²¹ may be independently substituted by one or more R ⁵⁴ on carbon independently; When the heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ⁵⁵ ;

p is 1-3; ^Wherein the value of R ¹⁶ may be the same or different;

q is 0 to 1;

r is 0 to 3; ^Wherein the value of R ¹⁷ may be the same or different;

m is 0-2; ^Wherein the value of R ¹³ may be the same or different;

n is 1 to 2; ^Wherein the value of R ⁹ may be the same or different;

z is 0 to 3; ^Wherein the value of R ²⁰ may be the same or different;

R ²³ , R ²⁵ , R ²⁷ , R ³³ , R ³⁸ , R ⁴⁴ , R ⁴⁸ and R ⁵⁴ are independently halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxy Aminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, C _1-10 alkoxy Carbonyl, N- (C _1-10 Alkyl) amino, N, N- (C _1-10 Alkyl) ₂ amino, N, N, N- (C _1-10 Alkyl) ₃ Ammonio, C _1-10 Alka Noylamino, N- (C _1-10 alkyl) carbamoyl, N, N- (C _1-10 alkyl) ₂ carbamoyl, C _{1-10 alkylS} (O) _a [where a is 0 to 2 L], N- (C _1-10 alkyl) sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _{1 -10} alkyl) ₂ sulfamoylamino, C _1-10 alkoxycarbonylamino, carbocyclyl, carbocyclylC _1-10 alkyl, heterocyclyl, heterocyclylC _1-10 alkyl, carbocyclyl- (C _1-10 alkylene) _e -R ^56- (C _1-10 alkylene) _f- , heterocyclyl- (C _1-10 Alkylene) _g -R ^57- (C _1-10 alkylene) _h- , carboxy, sulfo, sulfino, amidino, phosphono, -P (O) (OR ⁵⁸ ) (OR ⁵⁹ ), -P (O ) (OH) (OR ⁵⁸ ), -P (O) (OH) (R ⁵⁸ ) or -P (O) (OR ⁵⁹ ) (R ⁵⁹ ) [where R ⁵⁸ and R ⁵⁹ are independently C _1-6 Selected from alkyl]; Wherein R ²³ , R ²⁵ , R ²⁷ , R ³³ , R ³⁸ , R ⁴⁴ , R ⁴⁸ and R ⁵⁴ are independently optionally substituted on carbon with one or more R ⁶⁰ ; When the heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ⁶¹ ;

R ²⁴ , R ²⁶ , R ²⁸ , R ³⁴ , R ³⁹ , R ⁴⁵ , R ⁴⁹ , R ⁵⁵ and R ⁶¹ are independently C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkylsulfonyl, Sulfamoyl, N- (C _1-6 alkyl) sulfamoyl, N, N- (C _1-6 alkyl) ₂ sulfamoyl, C _1-6 alkoxycarbonyl, carbamoyl, N- (C _1-6 alkyl ) Carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, benzyl, phenethyl, benzoyl, phenylsulfonyl and phenyl;

R ²⁹ , R ³⁰ , R ⁴⁰ , R ⁴¹ , R ⁵⁰ , R ⁵¹ , R ⁵⁶ and R ⁵⁷ are independently -O-, -NR ^62- , -S (O) _x , -NR ⁶² C (O) NR ^63- , -NR ⁶² C (S) NR ^63- , -OC (O) N = C-, -NR ⁶² C (O)-or -C (O) NR ^62- ; Then R ⁶² and R ⁶³ are independently selected from hydrogen or C _1-6 alkyl and x is 0-2;

R ⁶⁰ is halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy , Ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N, N-dimethylcar Barmoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl;

e, f, g and h are independently selected from 0-2.

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 _1-10 alkyl", "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.

"Heterocyclyl" is a saturated, partially saturated or unsaturated, monocyclic or bicyclic ring containing at least one atom containing from 3 to 12 atoms selected from nitrogen, sulfur or oxygen, and unless otherwise stated carbon or nitrogen And -CH ₂ -groups can be optionally substituted with -C (O)-, or ring sulfur atoms can be optionally oxidized to form S-oxides. In particular, "heterocyclyl" is a saturated, partially saturated or unsaturated, monocyclic or bicyclic ring wherein at least one atom contains 5 or 6 atoms selected from nitrogen, sulfur or oxygen, unless otherwise described. May be carbon or nitrogen linked, wherein the —CH ₂ — group may be optionally substituted with —C (O) —, or the ring sulfur atoms may be optionally oxidized to form S-oxide (s). Suitable examples of the term “heterocyclyl” include thiazolidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinyl, 2,5-dioxopyrrolidinyl, 2-benzooxazolininyl, 1,1-di Oxotetrahydrothienyl, 2,4-dioxoimidazolidinyl, 2-oxo-1,3,4- (4-triazolinyl), 2-oxazolidinononyl, 5,6-dihydrourasilyl , 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo [2.2.1] heptyl, 4-thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, tetra Hydrofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl, piperidyl, 1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino, 1 , 1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl, homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl, indolyl, pyrimi And the like, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, 4-pyrido carbonyl, quinolyl and 1-isoquinolinyl nolro carbonyl.

“Carbocyclyl” is a saturated, partially saturated or unsaturated, monocyclic or bicyclic carbon ring containing 3 to 12 atoms, wherein a —CH ₂ — group may be optionally substituted with —C (O) —. In particular, "carbocyclyl" is a monocyclic ring containing 5 to 6 atoms, or a bicyclic ring containing 9 to 10 atoms. Suitable examples of “carbocyclyl” are cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoin And the like. More specifically "carbocyclyl" includes cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl or 1-oxoindanyl.

Examples of "C _1-10 alkanoyloxy" and "C _1-6 alkanoyloxy" are acetoxy. Examples of "C _1-10 alkoxycarbonyl" and "C _1-6 alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl, and the like. Examples of "C _1-10 alkoxy" and "C _1-6 alkoxy" include methoxy, ethoxy, propoxy and the like. Examples of "C _1-10 alkanoylamino" and "C _1-6 alkanoylamino" include formamido, acetamido, propionylamino and the like. Examples of "C _1-6 alkanoyl-N- (C _1-6 alkyl) amino" include acetyl-N-methylamino and propionyl-N-ethyl-amino and the like. Examples of "C _1-10 alkyl S (O) _a , wherein a is 0-2" and "C _1-6 alkyl S (O) _a [where a is 0-2]" are methylthio , Ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl and the like. Examples of "C _1-10 alkanoyl" and "C _1-6 alkanoyl" include C _1-3 alkanoyl, propionyl, acetyl, and the like. Examples of "N- (C _1-10 alkyl) amino" and "N- (C _1-6 alkyl) amino" include methylamino and ethylamino. Examples of "N, N- (C _1-10 alkyl) ₂ amino" and "N, N- (C _1-6 alkyl) ₂ amino" include di-N-methylamino, di- (N-ethyl) amino and N-ethyl-N-methylamino. Examples of "C _2-10 alkenyl" and "C _2-6 alkenyl" include vinyl, allyl, 1-propenyl and the like. Examples of "C _2-10 alkynyl" and "C _2-6 alkynyl" include ethynyl, 1-propynyl and 2-propynyl and the like. Examples of "C _2-6 alkylene" are ethylene, propylene and butylene. Examples of "C _2-6 alkenyloxy" are vinyloxy, allyloxy and 1-propenyloxy. Examples of "N- (C _1-10 alkyl) sulfamoyl" and "N- (C _1-6 alkyl) sulfamoyl" include N- (C _1-3 alkyl) sulfamoyl, N- (methyl) sulfamoyl and N- (ethyl) sulfamoyl. Examples of "N- (C _1-10 alkyl) ₂ sulfamoyl" and "N- (C _1-6 alkyl) ₂ sulfamoyl" are N, N- (dimethyl) sulfamoyl and N- (methyl) -N- (Ethyl) sulfamoyl. Examples of "N- (C _1-10 alkyl) carbamoyl" and "N- (C _1-6 alkyl) carbamoyl" are methylaminocarbonyl and ethylaminocarbonyl. Examples of "N, N- (C _1-10 alkyl) ₂ carbamoyl" and "N, N- (C _1-6 alkyl) ₂ carbamoyl" are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of "N- (C _1-10 alkyl) carbamoyl" and "N- (C _1-6 alkyl) carbamoyloxy" are methylaminocarbonyloxy and ethylaminocarbonyloxy. Examples of "N, N- (C _1-10 alkyl) ₂ carbamoyl" and "N, N- (C _1-6 alkyl) ₂ carbamoyloxy" are dimethylaminocarbonyloxy and methylethylaminocarbonyl Oxy. Examples of "C _1-6 alkylsulfonyl" are mesyl and ethylsulfonyl. Examples of "C _1-10 alkylsulfonylamino" and "C _1-6 alkylsulfonylamino" are mesylamino and ethylsulfonylamino to be. Examples of "C _1-6 alkylsulfonyl -N- (C _1-6 alkyl) amino" are mesyl -N- methyl-amino and ethyl-sulfonyl -N- propylamino. Examples of "N- (C _1-6 alkyl) ureido" are N'-methylureido and N'-i-propylureido. Examples of "N- (C _1-6 alkyl) ureido" are N-methylureido and Ni-propylureido. Examples of "N ', N'-(Ci_ ₆ alkyl) ₂ ureido" are N ', N'-dimethylureido and N'-methyl-N'-ethylureido. Examples of "N '-(C _1-6 alkyl) -N- (C _1-6 alkyl) ureido" are N', N-dimethylureido and N'-methyl-N-ethylureido. Examples of "N ', N'-(C _1-6 alkyl) ₂ -N- (C _1-6 alkyl) ureido" include N ', N'-dimethyl-N-methylureido and N'-methyl- N'-ethyl-Nt-butylureido. Examples of "N, N, N- (Ci_ ₁₀ alkyl) ₃ amonio" are trimethylamino and methyldiethylamino. Examples of "C _1-10 alkoxycarbonylamino" and "C _1-6 alkoxycarbonylamino" are methoxycarbonylamino and t-butoxycarbonylamino. Examples of "N- (C _1-10 alkyl) sulfamoylamino" are N-methylsulfamoylamino and N-ethylsulfamoylamino. Examples of "N, N- (C _1-10 alkyl) ₂ sulfamoylamino" are N, N-dimethylsulfamoylamino and N-methyl-N-ethylsulfamoylamino. Examples of “carbocyclylC _1-10 alkyl” are benzyl and phenethyl. Examples of "heterocyclylC _1-10 alkyl" are 2-morpholinopropyl and pyridylmethyl. Examples of " _{phenylC 1-6} alkoxy" are 2-phenylethoxy and 2-phenylpropoxy.

Suitable pharmaceutically acceptable salts of the compounds of the present invention or other compounds disclosed herein are, for example, acid-addition salts of sufficiently basic compounds of the present 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 which are sufficiently acidic are those which give alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts or physiologically acceptable cations. Salts with organic bases, such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.

Compounds of formula (I), or other compounds disclosed herein, may be administered in the form of prodrugs that degrade in the human or animal 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 carboxyl or hydroxy groups 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 that contain 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- and Z-isomers), and the present invention includes all such optical isomers, diastereomers, and geometric isomers that possess cholesterol absorption inhibitory activity. It should be understood to do.

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.

Specific values are as follows. These values may be used with any definitions, claims, or embodiments described above or below where appropriate.

Ring A is selected from thienyl.

Ring A is selected from phenyl.

X is -CR ² R ^3- .

X is -O-.

X is -NR ^x- ; Then R ^x is hydrogen or C _1-6 alkyl.

X is -S (O) _a - a; A is 0 to 2 at this time.

X is -CR ² R ^3- , wherein one of R ² and R ³ is hydrogen and the other is hydroxy.

X is -CH _2- .

X is -CH (OH)-.

X is -C (O)-.

X is -S-.

X is -S (O)-.

X is -S (O) _2- .

X is -CR ² R ³ -, -O- and -S (O) _a - [wherein, a is 0 to 2 Im] are selected from.

X is -CR ² R ³ -, -O- and -S (O) _a - [wherein, a is 0 to 2 Im] is selected from; Then R ² and R ³ are independently selected from hydrogen and hydroxy; Or R ² and R ³ together form an oxo group.

Y is selected from —CH ₂ —, —CH (OH) —, —C (O) —, —O—, —S—, —S (O) — and —S (O) ₂ —.

Y is -CR ⁴ R ⁵ .

Y is -O-,

Y is -NR ^z- ; Then R ^z is hydrogen or C _1-6 alkyl.

Y is -S (O) _a - [wherein, a is 0 to 2 Im] a.

Y is -CR ⁴ R ^5- , wherein R ⁴ and R ⁵ are both hydrogen.

Y is -CH _2- .

Y is -S-.

Y is -S (O)-.

Y is -CR ⁴ R ⁵ - is selected from [wherein, a is 0 or 1; - and -S (O) _a.

Y is -CR ⁴ R ⁵ - is selected from: [wherein, a is 0 or 1; - and -S (O) _a; At this time, R ⁴ and R ⁵ are both hydrogen.

Y is -CH _2- , -S- or -S (O)-,

X is -CR ² R ^3- , Y is -CR ⁴ R ⁵ -wherein one of R ² and R ³ is hydrogen and the other is hydroxyhydroxy; R ⁴ and R ⁵ are both hydrogen.

X is -CH ₂ -and Y is -S-.

X is -C (O)-and Y is -S-.

X is -CH ₂ -and Y is -S (O)-.

X is -C (O)-and Y is -S (O)-.

X is -CH ₂ -and Y is -S (O) _2- .

X is -C (O)-and Y is -S (O) _2- .

X is -O- and Y is -CH _2- .

X is -CHOH- and Y is -S (O) _a - [wherein, a is 0 to 2 Im] a.

X is -CHOH- and Y is -S-.

X is -CHOH- and Y is -S (O)-.

X is -CHOH- and Y is -S (O) _2- .

R ¹ is halo.

R ¹ is fluoro.

R ¹ is 4-fluoro when Ring A is phenyl.

b is 0 to 2; At this time, the value of R ¹ may be the same or different.

b is 0-1.

b is 1.

b is zero.

b is 1; In this case, when ring A is phenyl, the substituent is in the para position with respect to the X group.

R ² and R ³ are independently selected from hydrogen and hydroxy; Or R ² and R ³ together form an oxo group.

R ² and R ³ are independently selected from hydrogen and hydroxy.

One of R ² and R ³ is hydrogen and the other is hydroxy.

R ⁴ and R ⁵ are both hydrogen.

R ⁶ is halo or C _1-6 alkoxy.

R ⁶ is halo.

R ⁶ is fluoro or methoxy.

R ⁶ is fluoro.

R ⁶ is 4-fluoro or 4-methoxy.

R ⁶ is 4-fluoro.

c is 0 to 2; At this time, the value of R ⁶ may be the same or different.

c is 0-1.

c is 1.

c is zero.

c is 1; The substituent is then in the para position relative to the nitrogen of the azetidin-2-one ring.

R ⁷ is halo, methoxy or ethoxy.

R ⁷ is fluoro or methoxy.

d is 0 to 2; In this case, the value of R ⁷ may be the same or different.

d is 0-1.

d is zero.

R ⁹ is hydrogen.

R ¹⁰ is hydrogen.

R ¹¹ and R ¹² are independently selected from hydrogen or carbocyclyl.

R ¹¹ and R ¹² are independently selected from hydrogen or phenyl.

One of R ¹¹ and R ¹² is hydrogen and the other is phenyl, or both R ¹¹ and R ¹² are hydrogen.

R ¹¹ and R ¹² are independently selected from hydrogen, C _1-4 alkyl or carbocyclyl; In this case, R ¹¹ and R ¹² may be independently substituted on carbon by one or more substituents selected from R ²⁵ .

R ¹¹ and R ¹² are independently selected from hydrogen, methyl, ethyl, butyl, isobutyl or phenyl; In this case, R ¹¹ and R ¹² may be independently substituted on carbon by one or more substituents selected from R ²⁵ .

R ¹¹ and R ¹² are independently selected from hydrogen, C _1-4 alkyl or carbocyclyl; Wherein R ¹¹ and R ¹² may be optionally substituted on carbon independently by one or more substituents selected from R ²⁵ ; Then R ²⁵ is selected from hydroxy, amino, carbamoyl, C _1-10 alkoxycarbonyl, C _1-10 alkoxycarbonylamino, carbocyclyl or carboxy; Wherein R ²⁵ may be optionally substituted on carbon by one or more R ⁶⁰ ; Wherein R ⁶⁰ is hydroxy.

R ¹¹ and R ¹² are independently selected from hydrogen, methyl, ethyl, butyl, isobutyl or phenyl; Wherein R ¹¹ and R ¹² may be optionally substituted on carbon independently by one or more substituents selected from R ²⁵ ; Then R ²⁵ is selected from hydroxy, amino, carbamoyl, ethoxycarbonyl, t-butoxycarbonylamino, phenyl or carboxy; Wherein R ²⁵ may be optionally substituted on carbon by one or more R ⁶⁰ ; Wherein R ⁶⁰ is hydroxy.

R ¹¹ and R ¹² are independently hydrogen, methyl, hydroxymethyl, 2-carbamoylethyl, 2- (ethoxycarbonyl) ethyl, 2-carboxyethyl, 4- (t-butoxycarbonylamino) butyl , 4-aminobutyl, isobutyl, phenyl, 4-hydroxyphenyl and 4-hydroxybenzyl.

One of R ¹¹ and R ¹² is hydrogen and the other is hydrogen, methyl, hydroxymethyl, 2-carbamoylethyl, 2- (ethoxycarbonyl) ethyl, 2-carboxyethyl, 4- (t-butoxy Carbonylamino) butyl, 4-aminobutyl, isobutyl, phenyl, 4-hydroxyphenyl and 4-hydroxybenzyl.

R ¹³ is hydrogen.

R ¹⁴ is C _1-10 alkyl, C _1-10 alkoxycarbonyl or carboxy; Then R ¹⁴ on carbon may be optionally substituted with one or more substituents selected from R ³³ ; Or R ¹⁴ is a group of formula (IA) disclosed above.

R ¹⁴ is C _1-6 alkyl, C _1-6 alkoxycarbonyl or carboxy; Then R ¹⁴ may be optionally substituted on carbon by one or more hydroxy; Or R ¹⁴ is a group of formula (IA) disclosed above.

R ¹⁴ is 1,2,3,4,5-pentahydroxypentyl, t-butoxycarbonyl or carboxy; Or R ¹⁴ is a group of formula (IA) disclosed above.

R ¹⁴ is hydroxy, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 alkoxycarbonyl, carboxy or sulfo; Then R ¹⁴ on carbon may be optionally substituted by one or more substituents selected from R ³³ ; Or R ¹⁴ is a group of formula (IA) (disclosed above).

R ¹⁴ is hydroxy, pentyl, methoxy, ethoxycarbonyl, t-butoxycarbonyl, carboxy or sulfo; Then R ¹⁴ on carbon may be optionally substituted by one or more substituents selected from R ³³ ; Or R ¹⁴ is a group of formula (IA) (disclosed above).

R ¹⁵ is hydrogen.

R ¹⁶ and R ¹⁷ are independently selected from hydrogen, carboxy or C _1-6 alkoxycarbonyl.

R ¹⁶ and R ¹⁷ are independently selected from hydrogen, carboxy or t-butoxycarbonyl.

One of R ¹⁶ and R ¹⁷ is hydrogen and the other is hydrogen, carboxy or t-butoxycarbonyl.

R ¹⁶ and R ¹⁷ are independently selected from hydrogen, carboxy, C _1-6 alkyl and C _1-6 alkoxycarbonyl.

R ¹⁶ and R ¹⁷ are independently selected from hydrogen, carboxy, C _1-6 alkyl and t-butoxycarbonyl.

R ¹⁸ is selected from hydroxy, C _1-10 alkoxy, C _1-10 alkoxycarbonyl or carboxy.

R ¹⁸ is selected from hydroxy, C _1-6 alkoxy, C _1-6 alkoxycarbonyl or carboxy.

R ¹⁸ is selected from hydroxy, t-butoxy, t-butoxycarbonyl or carboxy.

R ¹⁸ is selected from hydroxy, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 alkoxycarbonyl, carboxy and sulfo.

R ¹⁸ is selected from hydroxy, methyl, t-butoxy, ethoxycarbonyl, t-butoxycarbonyl, carboxy and sulfo.

p is 1.

q is zero.

r is 0 or 1;

m is zero.

m is 1.

m is 0 or 1;

n is 1.

R ¹⁴ is hydroxy, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 alkoxycarbonyl, carboxy or sulfo; Then R ¹⁴ on carbon may be optionally substituted by one or more substituents selected from R ³³ ; Or R ¹⁴ is a group of formula (IA) (disclosed above), wherein

R ¹⁵ is hydrogen;

R ¹⁶ and R ¹⁷ are independently selected from hydrogen, carboxy, C _1-6 alkyl and C _1-6 alkoxycarbonyl;

R ¹⁸ is selected from hydroxy, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 alkoxycarbonyl, carboxy and sulfo;

p is 1;

q is 0;

r is 0 or 1;

m is 0 or 1;

n is 1;

R ³³ is hydroxy.

R ¹⁴ is hydroxy, pentyl, methoxy, ethoxycarbonyl, t-butoxycarbonyl, carboxy or sulfo; Then R ¹⁴ on carbon may be optionally substituted by one or more substituents selected from R ³³ ; Or R ¹⁴ is a group of formula (IA) (disclosed above), wherein

R ¹⁵ is hydrogen;

R ¹⁶ and R ¹⁷ are independently selected from hydrogen, carboxy, C _1-6 alkyl and t-butoxycarbonyl;

R ¹⁸ is selected from hydroxy, methyl, t-butoxy, ethoxycarbonyl, t-butoxycarbonyl, carboxy and sulfo;

p is 1;

q is 0;

r is 0 or 1;

m is 0 or 1;

n is 1;

R ³³ is hydroxy.

R ²⁵ is selected from hydroxy, amino, carbamoyl, C _1-10 alkoxycarbonyl, C _1-10 alkoxycarbonylamino, carbocyclyl or carboxy; Then R ²⁵ may be optionally substituted on carbon by one or more R ⁶⁰ .

R ²⁵ is selected from hydroxy, amino, carbamoyl, ethoxycarbonyl, t-butoxycarbonylamino, phenyl or carboxy; Then R ²⁵ may be optionally substituted on carbon by one or more R ⁶⁰ .

R ²⁵ is selected from hydroxy, amino, carbamoyl, C _1-10 alkoxycarbonyl, C _1-10 alkoxycarbonylamino, carbocyclyl or carboxy; Then R ²⁵ may be optionally substituted on carbon by one or more R ⁶⁰ ; R ⁶⁰ is hydroxy.

R ²⁵ is selected from hydroxy, amino, carbamoyl, ethoxycarbonyl, t-butoxycarbonylamino, phenyl or carboxy; Then R ²⁵ may be optionally substituted on carbon by one or more R ⁶⁰ ; R ⁶⁰ is hydroxy.

R ³³ is hydroxy.

R ⁶⁰ is hydroxy.

Branched R ^14- [C (R ¹³ )] _m -C (R ¹¹ ) (R ¹² ) -N (R ¹⁰ ) -C (O)-[C (R ⁹ )] _n -O- is N- (2 Sulfoethyl) carbamoylmethoxy; N- (carboxymethyl) carbamoylmethoxy; N- (2-hydroxyethyl) carbamoylmethoxy; N- (2-methoxyethyl) carbamoylmethoxy; N- [2- (carboxy) ethyl] carbamoylmethoxy; N-[(S) -1- (carboxy) ethyl] carbamoylmethoxy; N-[(R) -1- (carboxy) ethyl] carbamoylmethoxy; N-[(S) -α- (carboxy) benzyl] carbamoylmethoxy; N-[(R) -α- (carboxy) benzyl] carbamoylmethoxy; N- (t-butoxycarbonylmethyl) carbamoylmethoxy; N- [2- (t-butoxycarbonyl) ethyl] carbamoylmethoxy; N-[(S) -1,3-bis- (carboxy) propyl] carbamoylmethoxy; N-((R) -1-carboxy-3-methylbutyl) carbamoylmethoxy; N-[(S) -1- (t-butoxycarbonyl) ethyl] carbamoylmethoxy; N-[(R) -1- (t-butoxycarbonyl) ethyl] carbamoylmethoxy; N-[(R) -α- (t-butoxycarbonyl) benzyl] carbamoylmethoxy; N-[(S) -1- (carboxy) -5- (amino) pentyl] carbamoylmethoxy; N-[(R) -1- (carboxy) -2- (hydroxy) ethyl] carbamoylmethoxy; N-[(S) -1,3-bis- (ethoxycarbonyl) propyl] carbamoylmethoxy; N-[(R) -α- (carboxy) -4- (hydroxy) benzyl] carbamoylmethoxy; N- [N- (carboxymethyl) carbamoylmethyl] carbamoylmethoxy; N-[(S) -1- (carboxy) -3- (carbamoyl) propyl] carbamoylmethoxy; N-{(R) -α- [N- (carboxymethyl) carbamoyl] benzyl} carbamoylmethoxy; N- [N- (methoxycarbonylmethyl) carbamoylmethyl] carbamoylmethoxy; N-((S) -1- {N-[(S) -1- (carboxy) ethyl] carbamoyl} ethyl) carbamoylmethoxy; N-((2- (S) -3- (R) -4- (R) -5- (R) -2,3,4,5,6-pentahydroxyhexyl) carbamoylmethoxy; N -{(R) -α- [N- (t-butoxycarbonylmethyl) carbamoyl] benzyl} carbamoylmethoxy; N-{(R) -α- [N- (2-sulfoethyl) Carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy; N- {N-[(R) -1- (carboxy) -2- (hydroxy) ethyl] carbamoylmethyl] carbamoylme Oxy; N-[(S) -1- (t-butoxycarbonyl) -5- (t-butoxycarbonylamino) pentyl] carbamoylmethoxy; N-((S) -1- {N -[(S) -1- (t-butoxycarbonyl) ethyl] carbamoyl} ethyl) carbamoylmethoxy; N-{(R) -α- [N-((S) -1- ( Carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy; N-((R) -α- {N-[(S) -1- (carboxy) -2- (hydroxy) ethyl ] Carbamoyl} benzyl) carbamoylmethoxy; N- {N-[(R) -1- (t-butoxycarbonyl) -2- (t-butoxy) ethyl] carbamoylmethyl] car Barmoylmethoxy; or N-((R) -α- {N- (S)-[1- (t-butoxycarbonyl) -2- (t-butoxy) ethyl] carbamoyl} benzyl) Yerba is gathered methoxy.

Thus, in another aspect of the invention,

Ring A is phenyl;

X is -CR ² R ^3- ;

Y is -CR ⁴ R ^5- ;

R ¹ is halo;

b is 1;

One of R ² and R ³ is hydrogen and the other is hydroxy;

R ⁴ and R ⁵ are both hydrogen;

R ⁶ is halo;

c is 1;

d is 0;

R ⁹ is hydrogen;

R ¹⁰ is hydrogen;

R ¹¹ and R ¹² are independently selected from hydrogen or carbocyclyl;

R ¹⁴ is C _1-10 alkyl, C _1-10 alkoxycarbonyl or carboxy; Then R ¹⁴ is optionally substituted on carbon by one or more substituents selected from one or more R ³³ ; R ¹⁴ is a group of formula IA;

R ¹⁵ is hydrogen;

R ¹⁶ and R ¹⁷ are independently selected from hydrogen, carboxy or C _1-6 alkoxycarbonyl;

R ¹⁸ is selected from hydroxy, C _1-10 alkoxy, C _1-10 alkoxycarbonyl or carboxy;

p is 1;

q is 0;

r is 0 or 1;

m is 0;

n is 1;

There is provided a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, wherein R ³³ is hydroxy.

Thus, in another aspect of the invention,

Ring A is selected from phenyl;

X is -CR ² R ³ -and Y is -CR ⁴ R ⁵ -wherein one of R ² and R ³ is hydrogen and the other is hydroxy; R ⁴ and R ⁵ are both hydrogen;

R ¹ is 4-fluoro;

b is 1;

R ⁶ is 4-fluoro;

c is 1;

d is 0;

R ⁹ is hydrogen;

R ¹⁰ is hydrogen;

One of R ¹¹ and R ¹² is hydrogen and the other is phenyl, or R ¹¹ and R ¹² are both hydrogen;

R ¹⁴ is 1,2,3,4,5-pentahydroxypentyl, t-butoxycarbonyl or carboxy; Or R ¹⁴ is a group of formula (IA) disclosed above;

R ¹⁵ is hydrogen;

One of R ¹⁶ and R ¹⁷ is hydrogen and the other is hydrogen, carboxy or t-butoxycarbonyl;

R ¹⁸ is selected from hydroxy, t-butoxy, t-butoxycarbonyl or carboxy;

p is 1;

q is 0;

r is 0 or 1;

m is 0;

n is 1;

There is provided a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, wherein R ³³ is hydroxy.

Thus, in another aspect of the invention

Ring A is selected from phenyl or thienyl;

X is -CR ² R ³ -, -O- and -S (O) _a - [wherein, a is 0 to 2 Im] and; R ² and R ³ are independently selected from hydrogen and hydroxy; Or R ² and R ³ together form an oxo group;

Y is -CR ⁴ R ⁵ - is selected from: [wherein, a is 0 or 1; - and -S (O) _a; Wherein R ⁴ and R ⁵ are both hydrogen;

R ¹ is halo;

b is 0 to 1;

R ⁶ is halo;

c is 0 to 1;

d is 0;

R ⁹ is hydrogen;

R ¹⁰ is hydrogen;

R ¹¹ and R ¹² are independently selected from hydrogen, C _1-4 alkyl or carbocyclyl; Wherein R ¹¹ and R ¹² may be optionally substituted on carbon independently by one or more substituents selected from R ²⁵ ; Wherein R ²⁵ is selected from hydroxy, amino, carbamoyl, C _1-10 alkoxycarbonyl, C _1-10 alkoxycarbonylamino, carbocyclyl or carboxy; Then R ²⁵ may be optionally substituted on carbon by one or more R ⁶⁰ ; Then R ⁶⁰ is hydroxy;

R ¹³ is hydrogen;

R ¹⁴ is hydroxy, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 alkoxycarbonyl, carboxy or sulfo; Then R ¹⁴ on carbon may be optionally substituted by one or more substituents selected from R ³³ ; Or R ¹⁴ is a group of formula (IA) (disclosed above), wherein

R ¹⁵ is hydrogen;

R ¹⁶ and R ¹⁷ are independently selected from hydrogen, carboxy, C _1-6 alkyl and C _1-6 alkoxycarbonyl;

R ¹⁸ is selected from hydroxy, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 alkoxycarbonyl, carboxy and sulfo;

p is 1;

q is 0;

r is 0 or 1;

m is 0 or 1;

n is 1;

There is provided a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, wherein R ³³ is hydroxy.

Thus, in another aspect of the invention,

Ring A is selected from phenyl or thienyl;

X is selected from -CH _2- , -CH (OH)-, -C (O)-, -O-, -S-, -S (O)-and -S (0) _2- ;

Y is -CH _2- , -S- or -S (O)-;

R ¹ is fluoro;

b is 0 to 1;

R ⁶ is fluoro;

c is 0 to 1;

d is 0;

R ⁹ is hydrogen;

R ¹⁰ is hydrogen;

One of R ¹¹ and R ¹² is hydrogen and the other is hydrogen, methyl, hydroxymethyl, 2-carbamoylethyl, 2- (ethoxycarbonyl) ethyl, 2-carboxyethyl, 4- (t-butoxy Carbonylamino) butyl, 4-aminobutyl, isobutyl, phenyl, 4-hydroxyphenyl and 4-hydroxybenzyl;

R ¹³ is hydrogen;

R ¹⁴ is hydroxy, pentyl, methoxy, ethoxycarbonyl, t-butoxycarbonyl, carboxy or sulfo; Then R ¹⁴ on carbon may be optionally substituted by one or more substituents selected from R ³³ ; Or R ¹⁴ is a group of formula IA (as disclosed above), wherein

R ¹⁵ is hydrogen;

R ¹⁶ and R ¹⁷ are independently selected from hydrogen, carboxy, C _1-6 alkyl and t-butoxycarbonyl;

R ¹⁸ is selected from hydroxy, methyl, t-butoxy, ethoxycarbonyl, t-butoxycarbonyl, carboxy and sulfo;

p is 1;

q is 0;

r is 0 or 1;

m is 0 or 1;

n is 1;

There is provided a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, wherein R ³³ is hydroxy.

In another aspect of the invention, a preferred compound of the invention is a compound of any one of the embodiments, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.

In another aspect of the invention, preferred compounds of the invention are as follows:

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

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N-[(R) -α- (carboxy) benzyl] Carbamoylmethoxy} phenyl) azetidin-2-one;

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N- (carboxymethyl) carbamoylmethoxy] phenyl} Azetidin-2-ones;

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N- [N- (carboxymethyl) carbamoylmethyl] Carbamoylmethoxy} phenyl) azetidin-2-one;

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N- (2-hydroxyethyl) carbamoylmethoxy ] Phenyl} azetidin-2-one;

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N- (2-methoxyethyl) carbamoylmethoxy ] Phenyl} azetidin-2-one;

3- (R) -4- (R) -1- (phenyl) -3- (4-fluorobenzoylmethylsulfanyl) -4- {4- [N- (carboxymethyl) carbamoylmethoxy] phenyl Azetidin-2-one;

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

3- (R) -4- (R) -1- (phenyl) -3- [2- (thien-3-yl) -2-hydroxyethylsulfanyl] -4- {4- [N- (carboxy Methyl) carbamoylmethoxy] phenyl} azetidin-2-one;

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

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

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; or

Pharmaceutically acceptable salts, solvates, solvates or prodrugs thereof.

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

Another aspect of the invention provides a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, wherein the method (wherein the variable group is not specifically mentioned) As defined in formula (I)),

Process 1)

Reacting a compound of formula II with a compound of formula III:

[Wherein L is a substitutable group]

Process 2)

Reacting an acid of formula IV or an activated derivative thereof with an amine of formula V:

Process 3)

R ¹⁴ is when the resulting compound of formula (I) of formula IA, step of R ¹⁴ is a carboxy to a compound, or an activated derivative thereof of formula VI, reaction of the amine with the general formula VI:

Process 4)

For compounds of formula (I) wherein R ¹⁴ is a group of formula (IA), Z is -N (R ³⁵ ) C (O)-and q is 1, an acid of formula (VII) or an activated derivative thereof is substituted with an amine of formula Reacting Process:

Process 5)

For compounds of formula I, wherein R ¹⁴ is a group of formula IA and R ¹⁸ is a group of formula IB, an acid of formula I, or an activated derivative thereof, wherein R ¹⁴ is a group of formula IA and R ¹⁸ is carboxy Reaction with amines:

Process 6)

Reacting a compound of formula X with a compound of formula XI:

[Wherein L is a substitutable group]

Process 7)

For compounds of formula (I) wherein X is selected from -0-, -NR ^x -and -S (O) _a -wherein a is 0, reacting a compound of formula (XII) with a compound of formula (XIII) fair:

[Wherein L is a substitutable group]

Process 8)

For compounds of formula (I) wherein X is selected from -O-, -NR ^x -and -S (O) _a -where a is 0, the process of reacting a compound of formula XIV with a compound of formula XV :

[Wherein L is a substitutable group]

Process 9)

For compounds of formula (I) wherein Y is selected from -O-, -NR ^z -and -S (O) _a -where a is 0, the process of reacting a compound of formula XVI with a compound of formula XVII :

[Wherein L is a substitutable group]

Process 10)

Y is -O-, -NR ^z -, and -S (O) _a - [wherein, a is zero; for a compound in the case of compounds of formula I, the formula XVIII and reacting the formula XIX compound selected from fair:

[Wherein L is a substitutable group]

Process 11)

For compounds of formula (I) wherein X or Y is -S (O) _a -and a is 1 or 2, X or Y is -S (O) _a -and a is 0 (a is 1 or 2) For compounds of formula I) or a is 1 (for compounds of formula I wherein a is 2);

After these processes, as required or if desired

i) 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 or prodrug of such salt; or

iv) separating at least two enantiomers.

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

Reaction conditions specific to the reaction are as follows.

Process 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 wherein X is selected from -CR ² R ³ -and Y is selected from -CR ⁴ R ⁵ -and R ² and R ³ together form an oxo group and both R ⁴ and R ⁵ are hydrogen, are prepared according to the following scheme can do.

The benzyl protecting group is then removed.

Compounds of formula (II) with different values of X and Y can be prepared by the above reaction scheme using modifications known to those skilled in the art. For example, compounds of formula (IIh) may be modified to have different R ² and R ³ values, or they may substitute compounds of formula (IId) for replacement compounds with the desired functional groups, which potentially replace ring A It may include.

The compound of formula III is a commercially available compound, a compound known in the literature, or a compound prepared by standard processes known in the art. Process 2), Process 3), Process 4), and Process 5): The acid and the amine can be coupled together in the presence of a suitable coupling reagent. Standard peptide coupling reagents known in the art as suitable coupling reagents, such as carbonyldiimidazole and dicyclohexyl-carbodiimide, are optionally present in the presence of catalysts such as dimethylaminopyridine or 4-pyrrolidinopyridine. And optionally in the presence of a base such as triethylamine, pyridine, or 2,6-di-alkyl-pyridine (eg 2,6-lutidine or 2,6-di-t-butylpyridine) Can be. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide. The coupling reaction can be conveniently carried out at a temperature in the range of -40 to 40 ° C.

Suitable activated acid derivatives include acid halides (eg acid chlorides) and active esters (eg pentafluorophenyl esters). Reactions of this kind of compounds with amines are known in the art and can be reacted, for example, in the presence of a base as described above in a suitable solvent including those as described above. Reaction can be performed conveniently at the temperature of -40-40 degreeC.

Acids of formula (IV) and formula (VII) can be prepared from compounds of formula (II) by reaction with a suitable, optionally protected side chain, using the conditions of process 1).

Amines of formulas V, VI, VIII and IX are commercially available compounds, or are known in the literature, or are prepared by standard methods known in the art. Process 6): 0 ° C. to reflux temperature, preferably reflux, in a suitable solvent such as acetonitrile, dichloromethane, DMF 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 The compound of formula (X) may be reacted with the compound of formula (XI) at or near the temperature. Alternatively, this reaction can be carried out using transition metal chemistry known to those skilled in the art, such as copper or palladium chemistry.

Compounds of formula (X) can be prepared according to Scheme 1 using suitable substitutes of formula (IIb), such as benzylamine, and then debenzylated at appropriate points in the synthesis reaction.

Compounds of formula (XI) are commercially available compounds, known in the literature, or prepared by methods known in the art. Processes 7), 8), 9) and 10): in the presence of a base such as an inorganic base such as sodium carbonate or an organic base such as Hunigs base, in a suitable solvent such as acetonitrile, dichloromethane or tetrahydrofuran These compounds can be reacted together at a temperature between 0 ° C. and reflux, preferably at or near reflux.

Compounds of formula (XII), (XIV), (XVI) and (XVIII) can be prepared according to Scheme 1 using appropriate substitutes for formula (IId).

Compounds of formula (XIII), (XV), (XVII) and (XIX) are commercially available, known in the literature, or prepared by standard processes known in the art. Step 11): these compounds can be oxidized under standard sulfur oxidation conditions; For example, it can be oxidized using hydrogen peroxide and trifluoroacetic acid at temperatures between 0 ° C. and reflux, preferably at or near room temperature.

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 before or immediately after the above-mentioned processes, 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 can 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 acid, for example Removable by treatment with an organic acid such as trifluoroacetic acid), or, for example, a benzyl group (which can 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.

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

In vivo testing of cholesterol absorption inhibitors

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. Two or six hours after ¹⁴ C-cholesterol gavage feeding, blood samples were taken through the tail 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 assess absorption efficiency.

Reference

1. E. A. Kirk, G. L. Moe, M. T. Caldwell, J. A. 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.

absorption

Uptake of the compounds of formula I was tested in a Caco-2 cell model (Gastroenterology 1989, 96, 736).

The following data shows that Example 24 has much less absorption than ezetimibe (US RE37721).

compound Example 24 Ezetimibe Apparent distribution number; P _app [cm / s] 0.24 x 10 ^-06 21 x 10 ^-06

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

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, forms for rectal administration, such as suppositories.

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

The compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, is typically a warm blooded animal at a unit dosage in the range of about 0.02-100 mg / kg, preferably 0.02-50 mg / kg. , The amount typically 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. Such daily dosages 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), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, for use in a method of preventing or treating a warm blooded animal such as a human. .

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

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

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

According to another feature of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, as described above for forming cholesterol absorption inhibitory effect in warm blooded animals such as humans Use is provided.

Here, the cholesterol absorption inhibitory effect or the cholesterol lowering effect production is suitably related to the treatment of hyperlipidemic conditions in warm-blooded animals such as humans. In addition, hyperlipidemia, hypertriglyceridemia, hyperbetalipoproteinemia (high LDL), hyperbetalipoproteinemia (high VLDL), hyperlipidemia, hypoproteinemia, hypercholesterolemia, hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL) It is associated with the treatment of abnormal hemostatic conditions and diseases such as. 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, eg in warm-blooded animals such as humans, eg For example, inflammation of the heart, valves, blood vessels, arteries and veins, aneurysms, stenosis, restenosis, thrombosis, vascular adipose progenitors, leukocytes, monocytes and / or macrophages infiltration, endometrial thickening, medial thinning, infection and trauma and thrombosis It is associated with the treatment of different clinical conditions, such as 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 atherosclerotic lesions, a method for inhibiting the expression of matrix metalloproteinases in atherosclerotic lesions, a method for inhibiting destabilization of atherosclerotic lesions, a method for preventing atherosclerotic plaque rupture and the treatment of unstable angina It is related to the method.

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), or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts 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), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, for use in the treatment or prevention of Alzheimer's disease.

Compounds of formula (I), or pharmaceutically acceptable salts, solvates, solvates or prodrugs thereof, may be valuable for the treatment or prevention of vascular inflammation (see, for example, WO 03/026644). Thus, in a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or 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), or a pharmaceutically acceptable salt thereof, Administering solvates, solvates or prodrugs of such salts to the animal.

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 pharmaceutical comprising a compound of formula (I) as described above, or a pharmaceutically acceptable salt, solvate thereof, solvate or prodrug of such salt and an additional hypolipidemic agent for the combined treatment of hyperlipidemia Product is provided.

In a further aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, may be used to inhibit cholesterol biosynthesis, or a pharmaceutically acceptable salt, solvate, solvate or pro of such salts. It may be administered with a drug. 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), or a pharmaceutically acceptable salt, solvate, solvate or 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 solvates thereof It's a drug. Further particular statins are pitvastatin, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts. Particular statins are atorvastatin, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts. A more particular statin is atorvastatin calcium salt. Further particular statins are rosuvastatin, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts. Particularly preferred statins are rosuvastatin calcium salts.

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

Accordingly, according to a further aspect of the invention there is provided a method for producing a cholesterol lowering effect in a warm blooded animal such as a human being in need thereof, wherein the method provides an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the animal. And administering solvates, solvates or prodrugs of such salts concurrently, sequentially or separately with an effective amount of a HMG-CoA reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof. .

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

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

According to a further aspect of the invention,

a) a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate 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 compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug of such salt and a pharmaceutically acceptable diluent or carrier 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), or a pharmaceutically acceptable salt, solvate thereof, solvate or prodrug of such salt and an HMG Co-A reductase inhibitor, 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), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, optionally with a pharmaceutically acceptable carrier or diluent, and optionally An effective amount of an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, together with an acceptable carrier or diluent, may be administered simultaneously, sequentially or to a warm-blooded animal such as a human being in need thereof. Combination therapy is provided that includes administering separately.

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

According to another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, is an ileal bile acid (IBAT) inhibitor, or a pharmaceutically acceptable salt, solvate thereof, It can be administered with a solvate or prodrug of the salt. Suitable compounds which possess such IBAT inhibitory activity are disclosed, for example WO 93/16055, WO 94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO 97 / 33882, WO 98/38182, WO 99/35135, WO 98/40375, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, DE 19825804, WO 00/38725, Hypoglycemic compounds disclosed in WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 01/66533, WO 02/50051 and EP 0 864 582 and in these patent applications, especially claims 1 Reference is made to the disclosed compounds.

In addition, suitable compounds possessing IBAT inhibitory activity are described in WO 94/24087, W098 / 07749, WO 98/56757, WO 99/32478, WO 99/35135, WO 00/20392, WO 00/20393, WO 00/20410, WO 00/20437, WO 01/34570, WO 00/35889, WO 01/68637, WO 01/68096, WO 02/08211, WO 03/020710, WO 03/022825, WO 03/022830, WO 03/022286, 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 869 121 and EP 1 070 703 The contents of these patent applications, in particular the compounds disclosed in claims 1 and the examples, are incorporated by reference.

A specific class of IBAT inhibitors suitable for use in the present invention is benzothiefine. Other suitable classes of IBAT inhibitors are 1,2-benzothiazepine, 1,4-benzothiazepine and / or 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 suitable compound that retains IBAT inhibitory activity is S-8921 (EP 597 107).

Further suitable IBAT inhibitors are compounds

(WO 99/32478).

Examples of other particularly suitable compounds that possess IBAT inhibitory activity are as follows:

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-8-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-benzothiazepine;

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;

Or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.

Further suitable IBAT inhibitors for use with the compounds of the present invention are disclosed in WO 03/020710. Further suitable compounds which possess IBAT inhibitory activity include compounds of the formula AI, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts.

Where

One of R ¹ and R ² is selected from hydrogen or C _1-6 alkyl and the other is selected from C _1-6 alkyl;

R ^z is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino , N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkylS (O) _a [where a is 0 to 2] , C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl and N, N- (C _1-6 alkyl) ₂ sulfamoyl;

v is 0-5;

One of R ⁴ and R ⁵ is a group of formula AIA:

The other of R ³ and R ⁶ and R ⁴ and R ⁵ is independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- ( C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 Alkyl S (O) _a where a is 0-2, C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl and N, N- (C _1-6 alkyl) ₂ sulfa Selected from moles; Wherein the other of R ³ and R ⁶ and R ⁴ and R ⁵ may be optionally substituted on carbon by one or more R ¹⁷ ;

X is -O-, -N (R ^a )-, -S (O) _b -or -CH (R ^a )-; Then R ^a is hydrogen or C _1-6 alkyl and b is 0-2;

Ring A is aryl or heteroaryl; Then ring A is optionally substituted on carbon with one or more substituents selected from R ¹⁸ ;

R ⁷ is hydrogen, C _1-6 alkyl, carbocyclyl or heterocyclyl; Then R ⁷ is optionally substituted on carbon with one or more substituents selected from R ¹⁹ ; If said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R ²⁰ ;

R ⁸ is hydrogen or C _1-6 alkyl;

R ⁹ is hydrogen or C _1-6 alkyl;

R ¹⁰ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 Alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N- (C _1-10 alkyl) amino, N, N- (C _1-10 alkyl) ₂ amino, N , N, N- (C _1-10 alkyl) ₃ ammonio, C _1-10 alkanoylamino, N- (C _1-10 alkyl) carbamoyl, N, N- (C _1-10 alkyl) ₂ car Barmoyl, C _1-10 alkyl S (O) _a where a is 0-2, N- (C _1-10 alkyl) sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl , N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfamoylamino, C _1-10 alkoxycarbonylamino, carbocyclyl, carbocyclylC _1-10 Alkyl, heterocyclyl, heterocyclylC _1-10 alkyl, carbocyclyl- (C _1-10 alkylene) _p -R ^21- (C _1-10 alkylene) _q -or heterocyclyl- (C _{1 -10} alkylene) _r -R ^22- (C _1-10 alkylene) _s- ; Then R ¹⁰ is optionally substituted on carbon with one or more substituents selected from R ²³ ; If said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted with a group selected from R ²⁴ ; Or R ¹⁰ is a group of formula AIB:

Where

R ¹¹ is hydrogen or C _1-6 alkyl;

R ¹² and R ¹³ are independently hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alky Nyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N- (C _1-10 alkyl) amino, N, N- (C _1-10 alkyl) ₂ amino, C _{1 -10} alkanoylamino, N- (C _1-10 alkyl) carbamoyl, N, N- (C _1-10 alkyl) ₂ carbamoyl, C _{1-10 alkylS} (O) _a [where a is 0-2], N- (C _1-10 alkyl) sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfamoylamino, carbocyclyl or heterocyclyl; Then R ¹² and R ¹³ may be optionally substituted independently on carbon with one or more substituents selected from R ²⁵ ; If said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R ²⁶ ;

R ¹⁴ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 Alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N- (C _1-10 alkyl) amino, N, N- (C _1-10 alkyl) ₂ amino, N , N, N- (C _1-10 alkyl) ₃ ammonio, C _1-10 alkanoylamino, N- (C _1-10 alkyl) carbamoyl, N, N- (C _1-10 alkyl) ₂ car Barmoyl, C _1-10 alkyl S (O) _a where a is 0-2, N- (C _1-10 alkyl) sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl , N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfamoylamino, C _1-10 alkoxycarbonylamino, carbocyclyl, carbocyclylC _1-10 Alkyl, heterocyclyl, heterocyclylC _1-10 alkyl, carbocyclyl (C _1-10 alkylene) _p -R ^27- (C _1-10 alkylene) _q -or heterocyclyl- (C _{1- 10} alkylene) _r -R ^28- (C _1-10 alkylene) _s- ; Then R ¹⁴ may be optionally substituted on carbon with one or more substituents selected from R ²⁹ ; If said heterocyclyl contains an -NH- group, that nitrogen may be optionally substituted with one or more groups selected from R ³⁰ : or R ¹⁴ is a group of formula AIC:

R ¹⁵ is hydrogen or C _1-6 alkyl;

R ¹⁶ is hydrogen or C _1-6 alkyl; Then R ¹⁶ may be optionally substituted on carbon by one or more groups selected from R ³¹ ;

n is 1 to 3; ^Wherein the value of R ⁷ may be the same or different;

R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²³ , R ²⁵ , R ²⁹ or R ³¹ are independently halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl , C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N- (C _1-10 alkyl ) Amino, N, N- (C _1-10 alkyl) ₂ amino, N, N, N- (C _1-10 alkyl) ₃ ammonio, C _1-10 alkanoylamino, N- (C _1-10 alkyl Carbamoyl, N, N- (C _1-10 alkyl) ₂ carbamoyl, C _1-10 alkyl S (O) _a where a is 0 to 2, N- (C _1-10 alkyl) Sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfamoylamino, C _{1- 10} alkoxycarbonylamino, carbocyclyl, carbocyclylC _1-10 alkyl, heterocyclyl, heterocyclylC _1-10 alkyl, carbocyclyl (C _1-10 alkylene) _p -R ^32- (C _1-10 alkylene) _q - or heterocyclyl, - (C _1-10 alkylene) _r -R ³³ - (C _1-10 It is selected from - Killen) _s; Then R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²³ , R ²⁵ , R ²⁹ or R ³¹ may be independently substituted on carbon to one or more R ³⁴ ; When the heterocyclyl contains an —NH— group, the nitrogen may be optionally substituted with a group selected from R ³⁵ ;

R ²¹ , R ²² , R ²⁷ , R ²⁸ , R ³² or R ³³ are independently -O-, -NR ^36- , -S (O) _x- , -NR ³⁶ C (O) NR ^36- , -NR ³⁶ C (S) NR ^36- , -OC (O) N = C-, -NR ³⁶ C (O)-or -C (O) NR ^36- ; Then R ³⁶ is selected from hydrogen or C _1-6 alkyl and x is 0-2;

p, q, r and s are independently selected from 0-2;

R ³⁴ is halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, e Methoxy, vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N, N-dimethylcarbamoyl, methylthio, methyl Sulfinyl, mesyl, N-methylsulfamoyl, N, N-dimethylsulfamoyl, N-methylsulfamoylamino and N, N-dimethylsulfamoylamino;

R ²⁰ , R ²⁴ , R ²⁶ , R ³⁰ or R ³⁵ are independently C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkylsulfonyl, C _1-6 alkoxycarbonyl, carbamoyl, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl.

Particular IBAT inhibitors are selected from any of Examples 1-44 of WO 03/020710, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts, the compounds of Examples 1-44 being incorporated by reference. . Claims 1 to 10 of WO 03/020710 are incorporated by reference. The particular IBAT inhibitor selected from WO 03/020710 is selected from any of the following compounds:

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) carba Moyl] 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) car Barmoyl] 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;

Or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.

Further suitable IBAT inhibitors for use with the compounds of the present invention are disclosed in WO 03/022825. Further suitable compounds which possess IBAT inhibitory activity are compounds of formula BI, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts:

Where

One of R ¹ and R ² is selected from hydrogen or C _1-6 alkyl and the other is selected from C _1-6 alkyl;

R ^y is selected from hydrogen, hydroxy, C _1-6 alkyl, C _1-4 alkoxy and C _1-6 alkanoyloxy;

R ^z is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino , N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkylS (O) _a [where a is 0 to 2] , C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl and N, N- (C _1-6 alkyl) ₂ sulfamoyl;

v is 0-5;

One of R ⁴ and R ⁵ is a group of formula BIA:

The other of R ³ and R ⁶ and R ⁴ and R ⁵ is independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- ( C _1-4 alkyl) ₂ amino, C _1-4 alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 Alkyl S (O) _a where a is 0-2, C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfa Selected from moles; Wherein the other of R ³ and R ⁶ and R ⁴ and R ⁵ may be optionally substituted on carbon by one or more R ¹⁶ ;

X is -O-, -N- (R ^a )-, -S (O) _b -or -CH (R ^a )-; Then R ^a is hydrogen or C _1-6 alkyl and b is 0-2;

Ring A is aryl or heteroaryl; Then ring A is optionally substituted by one or more substituents selected from R ¹⁷ ;

R ⁷ is hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Then R ⁷ is optionally substituted by one or more substituents selected from R ¹⁸ ;

R ⁸ is hydrogen or C _1-4 alkyl;

R ⁹ is hydrogen or C _1-4 alkyl;

R ¹⁰ is hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Then R ¹⁰ is optionally substituted by one or more substituents selected from R ¹⁹ ;

R ¹¹ is carboxy, sulfo, sulfino, phosphono, -P (O) (OR ^c ) (OR ^d ), -P (O) (OH) (OR ^c ), -P (O) (OH) (R ^d ) or —P (O) (OR ^c ) (R ^d ) wherein R ^c and R ^d are independently selected from C _1-6 alkyl; Or R ¹¹ is a group of formula BIB:

Where

Y is ^{-N- (R x) -, -N} (R x) C (O) -, -O-, and -S (O) _a - a; Where a is 0-2 and R ^x is hydrogen or C _1-4 alkyl;

R ¹² is hydrogen or C _1-4 alkyl;

R ¹³ and R ¹⁴ are independently selected from hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Then R ¹³ and R ¹⁴ may be optionally substituted independently by one or more substituents selected from R ²⁰ ;

R ¹⁵ is carboxy, sulfo, sulfino, phosphono, -P (O) (OR ^e ) (OR ^f ), -P (O) (OH) (OR ^e ), -P (O) (OH) (R ^e ) or -P (O) (OR ^e ) (R ^f ), where R ^e and R ^f are independently selected from C _1-6 alkyl;

p is 1-3; ^Wherein the value of R ¹³ may be the same or different;

q is 0 to 1;

r is 0 to 3; ^Wherein the value of R ¹⁴ may be the same or different;

m is 0-2; ^Wherein the value of R ¹⁰ may be the same or different;

n is 1 to 3; ^Wherein the value of R ⁷ may be the same or different;

R ¹⁶ , R ¹⁷ and R ¹⁸ are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino , C _1-4 alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (O) _a [where , a is 0-2], C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfamoyl; Then R ¹⁶ , R ¹⁷ and R ¹⁸ may be optionally substituted on carbon by one or more R ²¹ ;

R ¹⁹ and R ²⁰ are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alky Nyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _{1 -4} alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (O) _a [where a is 0-2], C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl, N, N- (C _1-4 alkyl) ₂ sulfamoyl, carbocyclyl, heterocyclyl, sulfo , Sulfino, amidino, phosphono, -P (O) (OR ^a ) (OR ^b ), -P (O) (OH) (OR ^a ), -P (O) (OH) (R ^a ) or -P (O) (OR ^a ) (R ^b ) wherein R ^a and R ^b are independently selected from C _1-6 alkyl; Then R ¹⁹ and R ²⁰ may be independently substituted by one or more R ²² on carbon independently;

R ²¹ and R ²² are independently halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl , Ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N , N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl.

Particular IBAT inhibitors are selected from any of Examples 1-7 of WO 03/022825, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts, the compounds of Examples 1-7 are incorporated by reference. do. The claims 1 to 8 of WO 03/022825 are also incorporated by reference. The particular IBAT inhibitor selected from WO 03/022825 is selected from any of the following compounds:

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;

Or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.

Further suitable IBAT inhibitors for use with the compounds of the present invention are those disclosed in WO 03/022830. Further suitable compounds possessing IBAT inhibitory activity are compounds of formula CI, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts:

Where

One of R ¹ and R ² is selected from hydrogen or C _1-6 alkyl and the other is selected from C _1-6 alkyl;

R ^x and R ^y are independently hydrogen, hydroxy, amino, mercapto, C _1-6 alkyl, C _1-6 alkoxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 Alkyl) ₂ amino, C _1-6 alkylS (O) _a , wherein a is 0-2;

R ^z is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino , N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkylS (O) _a [where a is 0 to 2] , C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl and N, N- (C _1-6 alkyl) ₂ sulfamoyl;

v is 0-5;

One of R ⁴ and R ⁵ is a group of formula CIA:

The other of R ³ and R ⁶ and R ⁴ and R ⁵ is independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- ( C _1-4 alkyl) ₂ amino, C _1-4 alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 Alkyl S (O) _a where a is 0-2, C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfa Selected from moles; Then another of R ³ and R ⁶ and R ⁴ and R ⁵ may be optionally substituted on carbon by one or more R ¹⁶ ;

X is -O-, -N (R ^a )-, -S (O) _b -or -CH (R ^a )-; Then R ^a is hydrogen or C _1-6 alkyl and b is 0-2;

Ring A is aryl or heteroaryl; Then ring A is optionally substituted with one or more substituents selected from R ¹⁷ ;

R ⁷ is hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Then R ⁷ is optionally substituted with one or more substituents selected from R ¹⁸ ;

R ⁸ is hydrogen or C _1-4 alkyl;

R ⁹ is hydrogen or C _1-4 alkyl;

R ¹⁰ is hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Then R ¹⁰ is optionally substituted with one or more substituents selected from R ¹⁹ ;

R ¹¹ is carboxy, sulfo, sulfino, phosphono, -P (O) (OR ^c ) (OR ^d ), -P (O) (OH) (OR ^c ), -P (O) (OH) (R ^d ) or —P (O) (OR ^c ) (R ^d ) wherein R ^c and R ^d are independently selected from C _1-6 alkyl; Or R ¹¹ is a group of formula CIB:

Where

Y is ^{-N- (R n) -, -N} (R n) C (O) -, -O-, and -S (O) _a - a; A is 0 to 2 and R ⁿ is hydrogen or C _1-4 alkyl;

R ¹² is hydrogen or C _1-4 alkyl;

R ¹³ and R ¹⁴ are independently selected from hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Then R ¹³ and R ¹⁴ may be optionally substituted independently with one or more substituents selected from R ²⁰ ;

R ¹⁵ is carboxy, sulfo, sulfino, phosphono, -P (O) (OR ^e ) (OR ^f ), -P (O) (OH) (OR ^e ), -P (O) (OH) (R ^e ) or -P (O) (OR ^e ) (R ^f ), where R ^e and R ^f are independently selected from C _1-6 alkyl;

p is 1-3; Wherein the value of R ¹³ may be the same or different;

q is 0 to 1;

r is 0 to 3; ^Wherein the value of R ¹⁴ may be the same or different;

m is 0-2; ^Wherein the value of R ¹⁰ may be the same or different;

n is 1 to 3; ^Wherein the value of R ⁷ may be the same or different;

R ¹⁶ , R ¹⁷ and R ¹⁸ are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino , C _1-4 alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (O) _a [where , a is 0-2], C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfamoyl; Then R ¹⁶ , R ¹⁷ and R ¹⁸ may be optionally substituted on carbon by one or more R ²¹ ;

R ¹⁹ and R ²⁰ are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alky Nyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _{1 -4} alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkyl S (0) _a [where a is 0-2], C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl, N, N- (C _1-4 alkyl) ₂ sulfamoyl, carbocyclyl, heterocyclyl, sulfo , Sulfino, amidino, phosphono, -P (O) (OR ^a ) (OR ^b ), -P (O) (OH) (OR ^a ), -P (O) (OH) (R ^a ) or -P (O) (OR ^a ) (R ^b ) wherein R ^a and R ^b are independently selected from C _1-6 alkyl; Then R ¹⁹ and R ²⁰ may be independently substituted by one or more R ²² on carbon independently;

R ²¹ and R ²² are independently halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl , Ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N , N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl.

Particular IBAT inhibitors are selected from any one of Examples 1-4 of WO 03/022830, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts, the compounds of Examples 1-4 are incorporated by reference. . Claims 1 to 8 of WO 03/022830 are incorporated by reference. The particular IBAT inhibitor selected from WO 03/022830 is selected from one of the following compounds:

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 ammonium 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;

Or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.

Further suitable IBAT inhibitors for use with the compounds of the present invention are those disclosed in WO 03/022286. Further suitable compounds which possess IBAT inhibitory activity are compounds of the formula DI or their pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts:

Where

R ^v is selected from hydrogen or C _1-6 alkyl;

One of R ¹ and R ² is selected from hydrogen or C _1-6 alkyl and the other is selected from C _1-6 alkyl;

R ^x and R ^y are independently hydrogen, hydroxy, amino, mercapto, C _1-6 alkyl, C _1-6 alkoxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 Alkyl) ₂ amino, C _1-6 alkylS (O) _a , wherein a is 0-2;

M is selected from -N- or -CH-;

R ^z is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkylamino, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkyl S (O) _a [where a is 0 to 2], C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl and N, N- (C _1-6 alkyl) ₂ sulfamoyl;

v is 0-5;

One of R ⁴ and R ⁵ is a group of formula DIA:

The other of R ³ and R ⁶ and R ⁴ and R ⁵ is independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- ( C _1-4 alkyl) ₂ amino, C _1-4 alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 Alkyl S (O) _a where a is 0-2, C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfa Selected from moles; Then another of R ³ and R ⁶ and R ⁴ and R ⁵ may be optionally substituted on carbon by one or more R ¹⁶ ;

X is -O-, -N- (R ^a )-, -S (O) _b -or -CH (R ^a )-; Then R ^a is hydrogen or C _1-6 alkyl and b is 0-2;

Ring A is aryl or heteroaryl; Then ring A is optionally substituted with one or more substituents selected from R ¹⁷ ;

R ⁷ is hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Then R ⁷ is optionally substituted with one or more substituents selected from R ¹⁸ ;

R ⁸ is hydrogen or C _1-4 alkyl;

R ⁹ is hydrogen or C _1-4 alkyl;

R ¹⁰ is hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Then R ¹⁰ is optionally substituted on carbon with one or more substituents selected from R ¹⁹ ;

R ¹¹ is carboxy, sulfo, sulfino, phosphono, -P (O) (OR ^c ) (OR ^d ), -P (O) (OH) (OR ^c ), -P (O) (OH) (R ^d ) or —P (O) (OR ^c ) (R ^d ) wherein R ^c and R ^d are independently selected from C _1-6 alkyl; Or R ¹¹ is a group of formula DIB or DIC:

Where

Y is -N (R ⁿ )-, -N (R ⁿ ) C (O)-, -N (R ⁿ ) C (O) (CR ^s R ^t ) _v N (R ⁿ ) C (O)-, -O-, and -S (O) _a - a; Where a is 0-2, v is 1-2, R ^t is independently selected from hydrogen or C _1-4 alkyl optionally substituted by R ²⁶ , and R ⁿ is hydrogen or C _1-4 alkyl ;

R ¹² is hydrogen or C _1-4 alkyl;

R ¹³ and R ¹⁴ are independently selected from hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; if q is 0 then R ¹⁴ may be further selected from hydroxy; R ¹³ and R ¹⁴ can be optionally substituted independently with one or more substituents selected from R ²⁰ ;

R ¹⁵ is carboxy, sulfo, sulfino, phosphono, -P (O) (OR ^e ) (OR ^f ), -P (O) (OH) (OR ^e ), -P (O) (OH) (R ^e ) or -P (O) (OR ^e ) (R ^f ), where R ^e and R ^f are independently selected from C _1-6 alkyl;

p is 1-3; Wherein the value of R ¹³ may be the same or different;

q is 0 to 1;

r is 0 to 3; ^Wherein the value of R ¹⁴ may be the same or different;

m is 0-2; ^Wherein the value of R ¹⁰ may be the same or different;

n is 1 to 3; ^Wherein the value of R ⁷ may be the same or different;

Ring B is a nitrogen bonded heterocyclyl substituted on carbon by one group selected from R ²³ and optionally further substituted on carbon by one or more R ²⁴ ; When the nitrogen-bonded heterocyclyl comprises an —NH— moiety that nitrogen may be optionally substituted by a group selected from R ²⁵ ,

R ¹⁶ , R ¹⁷ and R ¹⁸ are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino , C _1-4 alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (0) _a [where , a is 0-2], C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfamoyl; Then R ¹⁶ , R ¹⁷ and R ¹⁸ may be optionally substituted on carbon by one or more R ²¹ ;

R ¹⁹ , R ²⁰ , R ²⁴ and R ²⁶ are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl , C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl ) ₂ amino, C _1-4 alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (O) _a [where a is 0 to 2], C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl, N, N- (C _1-4 alkyl) ₂ sulfamoyl, carbocyclyl , Heterocyclyl, benzyloxycarbonylamino, sulfo, sulfino, amidino, phosphono, -P (O) (OR ^a ) (OR ^b ), -P (O) (OH) (OR ^a ),- P (O) (OH) (R ^a ) or -P (O) (OR ^a ) (R ^b ), wherein R ^a and R ^b are independently selected from C _1-6 alkyl; Wherein R ¹⁹ , R ²⁰ , R ²⁴ and R ²⁶ may be independently substituted by one or more R ²² on carbon independently;

R ²¹ and R ²² are independently halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl , Ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N , N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl.

R ²³ is carboxy, sulfo, sulfino, phosphono, -P (O) (OR ^g ) (OR ^h ), -P (O) (OH) (OR ^g ), -P (O) (OH) (R ^g ) or -P (O) (OR ^g ) (R ^h ), wherein R ^g and R ^h are independently selected from C _1-6 alkyl;

R ²⁵ is C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkylsulfonyl, C _1-6 alkoxycarbonyl, carbamoyl, N- (C _1-6 alkyl) carbamoyl, N , N- (C _1-6 alkyl) carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl.

Particular IBAT inhibitors are selected from any of Examples 1-39 of WO 03/022286, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts, the compounds of Examples 1-39 being incorporated by reference. . Claims 1 to 10 of WO 03/022286 are incorporated by reference. The particular IBAT inhibitor selected from WO 03/022286 is selected from one of the following compounds:

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; or

Pharmaceutically acceptable salts, solvates, solvates or prodrugs thereof.

Further suitable compounds which possess IBAT inhibitory activity are compounds of formula EI, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.

Where

R ^v is selected from hydrogen or C _1-6 alkyl;

One of R ¹ and R ² is selected from hydrogen or C _1-6 alkyl and the other is selected from C _1-6 alkyl;

R ^x and R ^y are independently hydrogen, hydroxy, amino, mercapto, C _1-6 alkyl, C _1-6 alkoxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 Alkyl) ₂ amino, C _1-6 alkylS (O) _a , wherein a is 0-2;

R ^z is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino , N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkylS (O) _a [where a is 0 to 2] , C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl and N, N- (C _1-6 alkyl) ₂ sulfamoyl;

v is 0-5;

One of R ⁴ and R ⁵ is a group of formula EIA:

The other of R ³ and R ⁶ and R ⁴ and R ⁵ is independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- ( C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 Alkyl S (O) _a where a is 0-2, C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl and N, N- (C _1-6 alkyl) ₂ sulfa Selected from moles; Wherein the other of R ³ and R ⁶ and R ⁴ and R ⁵ may be optionally substituted on carbon by one or more R ¹⁷ ;

X is -O-, -N (R ^a )-, -S (O) _b -or -CH (R ^a )-; Then R ^a is hydrogen or C _1-6 alkyl and b is 0-2;

Ring A is aryl or heteroaryl; Then ring A is optionally substituted on carbon by one or more substituents selected from R ¹⁸ ;

R ⁷ is hydrogen, C _1-6 alkyl, carbocyclyl or heterocyclyl; Then R ⁷ is optionally substituted on carbon by one or more substituents selected from R ¹⁹ ; When the heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ²⁰ ;

R ⁸ is hydrogen or C _1-6 alkyl;

R ⁹ is hydrogen or C _1-6 alkyl; R ¹⁰ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 Alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N- (C _1-10 alkyl) amino, N, N- (C _1-10 alkyl) ₂ amino, N , N, N- (C _1-10 alkyl) ₃ ammonio, C _1-10 alkanoylamino, N- (C _1-10 alkyl) carbamoyl, N, N- (C _1-10 alkyl) ₂ car Barmoyl, C _1-10 alkyl S (O) _a where a is 0-2, N- (C _1-10 alkyl) sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl , N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfamoylamino, C _1-10 alkoxycarbonylamino, carbocyclyl, carbocyclylC _1-10 Alkyl, heterocyclyl, heterocyclylC _1-10 alkyl, carbocyclyl- (C _1-10 alkylene) _p -R ^21- (C _1-10 alkylene) _q -or heterocyclyl- (C _{1 -10} alkylene) _r -R ^22- (C _1-10 alkylene) _s- ; Then R ¹⁰ is optionally substituted on carbon by one or more substituents selected from R ²³ ; When the heterocyclyl includes an —NH— group, that nitrogen may be optionally substituted by a group selected from R ²⁴ ; Or R ¹⁰ is a group of formula EIB:

here,

R ¹¹ is hydrogen or C _1-6 alkyl;

R ¹² and R ¹³ are independently hydrogen, halo, carbamoyl, sulfamoyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkanoyl, N- (C _1-10 alkyl) carbamoyl, N, N- (C _1-10 alkyl) ₂ carbamoyl, C _{1-10 alkylS} (O) _a [where a is 0 to 2], N- (C _1-10 alkyl) sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfamoyl Amino, carbocyclyl or heterocyclyl; Then R ¹² and R ¹³ can be optionally substituted independently on carbon by one or more substituents selected from R ²⁵ ; When the heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ²⁶ ;

R ¹⁴ is hydrogen, halo, carbamoyl, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkanoyl, N- ( C _1-10 alkyl) carbamoyl, N, N- (C _1-10 alkyl) ₂ carbamoyl, C _{1-10 alkylS} (O) _a [where a is 0 to 2], N- ( C _1-10 alkyl) sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfa Moylamino, carbocyclyl, carbocyclylC _1-10 alkyl, heterocyclyl, heterocyclylC _1-10 alkyl, carbocyclyl- (C _1-10 alkylene) _p -R ^27- (C _{1- 10} alkylene) _q -or heterocyclyl- (C _1-10 alkylene) _r -R ^28- (C _1-10 alkylene) _s- ; Then R ¹⁴ on the carbon may be optionally substituted by one or more substituents selected from R ²⁹ ; If said heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ³⁰ ; Or R ¹⁴ is a group of formula EIC:

R ¹⁵ is hydrogen or C _1-6 alkyl;

R ¹⁶ is hydrogen or C _1-6 alkyl; Then R ¹⁶ may be optionally substituted on carbon by one or more groups selected from R ³¹ ;

n is 1 to 3; ^Wherein the value of R ⁷ may be the same or different;

R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²³ , R ²⁵ , R ²⁹ or R ³¹ are independently halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl , C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N- (C _1-10 alkyl ) Amino, N, N- (C _1-10 alkyl) ₂ amino, N, N, N- (C _1-10 alkyl) ₃ ammonio, C _1-10 alkanoylamino, N- (C _1-10 alkyl ) Carbamoyl, N, N- (C _1-10 alkyl) ₂ carbamoyl, C _1-10 alkyl S (O) _a [where a is 0 to 2], N- (C _1-10 alkyl ) Sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfamoylamino, C _{1 -10} alkoxycarbonylamino, carbocyclyl, carbocyclylC _1-10 alkyl, heterocyclyl, heterocyclylC _1-10 alkyl, carbocyclyl- (C _1-10 alkylene) _p -R ^32- (C _1-10 alkylene) _q -or heterocyclyl- (C _1-10 alkylene) _r -R ^33- (C _1-10 Alkylene) _s- ; Then R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²³ , R ²⁵ , R ²⁹ or R ³¹ may be optionally substituted on carbon by one or more R ³⁴ ; When the heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ³⁵ ;

R ²¹ , R ²² , R ²⁷ , R ²⁸ , R ³² or R ³³ are independently -O-, -NR ^36- , -S (O) _x- , -NR ³⁶ C (O) NR ^36- , -NR ³⁶ C (S) NR ^36- , -OC (O) N = C-, -NR ³⁶ C (O)-or -C (O) NR ^36- ; Then R ³⁶ is selected from hydrogen or C _1-6 alkyl and x is 0-2;

p, q, r and s are independently selected from 0-2;

R ³⁴ is halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, e Methoxy, vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N, N-dimethylcarbamoyl, methylthio, methyl Sulfinyl, mesyl, N-methylsulfamoyl, N, N-dimethylsulfamoyl, N-methylsulfamoylamino and N, N-dimethylsulfamoylamino;

R ²⁰ , R ²⁴ , R ²⁶ , R ³⁰ or R ³⁵ are independently C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkylsulfonyl, C _1-6 alkoxycarbonyl, carbamoyl, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl.

Suitable IBAT having the above structure is selected from any of the following compounds:

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} benzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro -1,2,5-benzothiadiazepines (both enantiomers);

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; or

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;

Or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.

Further suitable compounds having IBAT inhibitory activity include compounds of the formula FI, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.

Where

R ¹ and R ² are independently selected from C _1-4 alkyl;

R ³ is hydrogen, hydroxy or halo;

R ⁴ is C _1-4 alkyl optionally substituted by hydroxy, methoxy and methylS (O) _a, wherein a is 0-2;

R ⁵ is hydroxy or HOC (O) CH (R ⁶ ) NH—;

R ⁶ is selected from hydrogen and C _1-3 alkyl optionally substituted by hydroxy, methoxy and methylS (O) _a, wherein a is 0-2,

Provided that both R ¹ and R ² are butyl, R ⁵ is hydroxy and R ⁴ is methylthiomethyl, methylsulfinylmethyl, methylthiomethyl, hydroxymethyl, methoxymethyl; R ³ is not hydrogen; R ¹ and R ² are both butyl, R ⁵ is HOC (O) CH (R ⁶ ) NH—, R ⁶ is hydroxymethyl and R ⁴ is hydroxymethyl; R ³ is not hydrogen.

Suitable IBAT inhibitors having the above structure are selected from any one of the following compounds.

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- (R) -α- [N '-((S) -1-carboxybutyl) 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 -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, or

Pharmaceutically acceptable salts, solvates, solvates or prodrugs thereof.

Further suitable IBAT inhibitors are compounds of the formula GI, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts.

Where

M ¹ is -CH ₂ -or -NR ^21- ;

M ² is -CR ²² R ²³ -or -NR ^24- ; Provided that when M ¹ is -NR ^21- , M ² is -CR ²² R ^23- ;

One of R ¹ and R ² is selected from hydrogen, C _1-6 alkyl or C _2-6 alkenyl, and the other is selected from C _1-6 alkyl or C _2-6 alkenyl;

R ³ is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino , N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkylS (O) _a [where a is 0 to 2] , C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl and N, N- (C _1-6 alkyl) ₂ sulfamoyl;

v is 0-5;

One of R ⁵ and R ⁶ is a group of formula GIA:

The other of R ⁴ and R ⁷ and R ⁵ and R ⁶ is independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- ( C _1-4 alkyl) ₂ amino, C _1-4 alkanoylamino, N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 Alkyl S (O) _a where a is 0-2, C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfa Selected from moles; Then the other of R ⁴ and R ⁷ and R ⁵ and R ⁶ may be optionally substituted by one or more R ²⁵ on carbon;

Z is -O-, -N- (R ^a )-, -S (O) _b -or -CH (R ^a )-; Then R ^a is hydrogen or C _1-6 alkyl and b is 0-2;

R ⁸ is hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Then R ⁸ may be optionally substituted on carbon by one or more substituents selected from R ²⁶ ; When the heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ²⁷ ;

R ⁹ is hydrogen or C _1-4 alkyl;

R ¹⁰ and R ¹¹ are independently selected from hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Or R ¹⁰ and R ¹¹ together form C _2-6 alkylene; Then R ¹⁰ and R ¹¹ or R ¹⁰ and R ¹¹ together may be optionally substituted on carbon independently by one or more substituents selected from R ²⁸ ; When the heterocyclyl comprises an —NH— moiety that nitrogen may be optionally substituted by one or more R ²⁹ ;

R ¹² is hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Then R ¹² may be optionally substituted on carbon by one or more substituents selected from R ³⁰ ; When the heterocyclyl comprises an —NH— moiety that nitrogen may be optionally substituted by one or more R ³¹ ;

R ¹³ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 Alkynyl, C _1-10 alkoxy, C _1-10 alkoxycarbonyl, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N- (C _1-10 alkyl) amino, N, N- (C _{1 -10} alkyl) ₂ amino, N, N, N- (C _1-10 alkyl) ₃ ammonio, C _1-10 alkanoylamino, N- (C _1-10 alkyl) carbamoyl, N, N- ( C _1-10 alkyl) ₂ carbamoyl, C _1-10 alkyl S (O) _a [where a is 0-2], N- (C _1-10 alkyl) sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfamoylamino, C _1-10 alkoxycarbonylamino, carbocyclyl , CarbocyclylC _1-10 alkyl, heterocyclic group, heterocyclylC _1-10 alkyl, carbocyclyl- (C _1-10 alkylene) _e -R ^32- (C _1-10 alkylene) _f Or heterocyclyl- (C _1-10 alkylene) _g -R ^33- (C _1-10 alkylene) _h- ; Then R ¹³ may be optionally substituted on carbon by one or more substituents selected from R ³⁶ ; When the heterocyclyl comprises an —NH— moiety that nitrogen may be optionally substituted by one or more groups selected from R ³⁷ ; Or R ¹³ is a group of the formula GIB:

Where

X is ^{-N (R 38) -, -N} (R 38) C (O) -, -O-, and -S (O) _a - a; A is 0 to 2 and R ³⁸ is hydrogen or C _1-4 alkyl;

R ¹⁴ is hydrogen or C _1-4 alkyl;

R ¹⁵ and R ¹⁶ are independently hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alky Nyl, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _{1 -6} alkanoylamino, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkylS (O) _a [where a is 0-2], from C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl, N, N- (C _1-6 alkyl) ₂ sulfamoyl, carbocyclyl or heterocyclic group Selected; Then R ¹⁵ and R ¹⁶ may be optionally substituted independently on carbon with one or more substituents substituted from R ⁴¹ ; When the heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ⁴² ;

R ¹⁷ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 Alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N- (C _1-10 alkyl) amino, N, N- (C _1-10 alkyl) ₂ amino, C _1-10 alkanoylamino, N- (C _1-10 alkyl) carbamoyl, C _1-10 alkoxycarbonyl, N, N- (C _1-10 alkyl) ₂ carbamoyl, C _1-10 alkyl S (O) _a [where a is 0-2], N- (C _1-10 alkyl) sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl Sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfamoylamino, carbocyclyl, carbocyclylC _1-10 alkyl, heterocyclic group, heterocyclylC _1-10 alkyl, carbosi Klylic- (C _1-10 alkylene) _e -R ^43- (C _1-10 alkylene) _f -or heterocyclyl- (C _1-10 alkylene) _g -R ^44- (C _1-10 alkylene ) _h- ; Then R ¹⁷ on carbon may be optionally substituted with one or more substituents substituted from R ⁴⁸ ; When the heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ⁴⁸ ; Or R ¹⁷ is a group of the formula GIC:

here,

R ¹⁸ is selected from hydrogen or C _1-4 alkyl;

R ¹⁹ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino , N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkylS (O) _a [where a is 0 to 2] , C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl, N, N- (C _1-6 alkyl) ₂ sulfamoyl, carbocyclyl or heterocyclic group; Then R ¹⁹ may be optionally substituted on carbon to one or more substituents substituted from R ⁵¹ ; When the heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ⁵² ;

R ²⁰ is halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl , C _1-10 alkoxy, C _1-10 alkoxycarbonyl, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N- (C _1-10 alkyl) amino, N, N- (C _1-10 Alkyl) ₂ amino, N, N, N- (C _1-10 alkyl) ₃ ammonio, C _1-10 alkanoylamino, N- (C _1-10 alkyl) carbamoyl, N, N- (C _{1 -10} alkyl) ₂ carbamoyl, C _1-10 alkyl S (O) _a [where a is 0-2], N- (C _1-10 alkyl) sulfamoyl, N, N- (C _{1- 10} alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfamoylamino, C _1-10 alkoxycarbonylamino, carbocyclyl, carbo BocyclylC _1-10 alkyl, heterocyclic group, heterocyclylC _1-10 alkyl, carbocyclyl- (C _1-10 alkylene) _e -R ^53- (C _1-10 alkylene) _f -or Heterocyclyl- (C _1-10 alkylene) _g -R ^54- (C _1-10 alkylene) _h- Become; Then R ²⁰ may be optionally substituted on carbon to one or more R ⁵⁷ ; When the heterocyclyl includes an —NH— group, that nitrogen may be optionally substituted by a group selected from R ⁵⁸ ;

p is 1-3; ^Wherein the value of R ¹⁵ may be the same or different;

q is 0 to 1;

r is 0 to 3; ^Wherein the value of R ¹⁶ may be the same or different;

m is 0-2; ^Wherein the value of R ¹² may be the same or different;

n is 1 to 2; ^Wherein the value of R ⁸ may be the same or different;

z is 0 to 3; ^Wherein the value of R ¹⁹ may be the same or different;

R ²¹ is selected from hydrogen or C _1-6 alkyl;

R ²² and R ²³ are independently hydrogen, hydroxy, amino, mercapto, C _1-6 alkyl, C _1-6 alkoxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 Alkyl) ₂ amino, C _1-6 alkylS (O) _a , wherein a is 0-2;

R ²⁴ is selected from hydrogen, hydroxy, C _1-6 alkyl, C _1-4 alkoxy and C _1-6 alkanoyloxy;

R ²⁵ is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{1- 4} alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N- (C _1-4 alkyl) amino, N, N- (C _1-4 alkyl) ₂ amino, C _1-4 alkanoylamino , N- (C _1-4 alkyl) carbamoyl, N, N- (C _1-4 alkyl) ₂ carbamoyl, C _1-4 alkylS (O) _a [where a is 0 to 2] , C _1-4 alkoxycarbonyl, N- (C _1-4 alkyl) sulfamoyl and N, N- (C _1-4 alkyl) ₂ sulfamoyl; Then R ²⁵ may be optionally substituted on carbon with one or more R ⁶⁷ ;

R ²⁶ , R ²⁸ , R 3 ^O , R ³⁶ , R ⁴¹ , R ⁴⁷ , R ⁵¹ and R ⁵⁷ are independently halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxy Aminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, C _1-10 alkoxy Carbonyl, N- (C _1-10 Alkyl) amino, N, N- (C _1-10 Alkyl) ₂ amino, N, N, N- (C _1-10 Alkyl) ₃ Ammonio, C _1-10 Alka Noylamino, N- (C _1-10 alkyl) carbamoyl, N, N- (C _1-10 alkyl) ₂ carbamoyl, C _{1-10 alkylS} (O) _a [where a is 0 to 2 N, N- (C _1-10 alkyl) sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _{1 -10} alkyl) ₂ sulfamoylamino, C _1-10 alkoxycarbonylamino, carbocyclyl, carbocyclylC _1-10 alkyl, heterocyclic group, heterocyclylC _1-10 alkyl, carbocyclyl- ( C _1-10 alkylene) _e -R ^59- (C _1-10 alkylene) _f -or heterocyclyl -(C _1-10 alkylene) _g -R ^60- (C _1-10 alkylene) _h- ; ^Wherein R ²⁶ , R ²⁸ , R 3 ^O , R ³⁶ , R ⁴¹ , R ⁴⁷ , R ⁵¹ and R ⁵⁷ may be independently substituted on carbon to one or more R ⁶³ ; When the heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ⁶⁴ ;

R ²⁷ , R ²⁹ , R ³¹ , R ³⁷ , R ⁴² , R ⁴⁸ , R ⁵² , R ⁵⁸ and R ⁶⁴ are independently C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkylsulfonyl, Sulfamoyl, N- (C _1-6 alkyl) sulfamoyl, N, N- (C _1-6 alkyl) ₂ sulfamoyl, C _1-6 alkoxycarbonyl, carbamoyl, N- (C _1-6 alkyl ) Carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, benzyl, phenethyl, benzoyl, phenylsulfonyl and phenyl;

R ³² , R ³³ , R ⁴³ , R ⁴⁴ , R ⁵³ , R ⁵⁴ , R ⁵⁹ and R ⁶⁰ are independently -O-, -NR ^65- , -S (O) _x- , -NR ⁶⁵ C (O) ^{NR 66 -, -NR 65 C (} S) NR 66 -, -OC (O) N = C-, -NR 65 C (O) - or -C (O) NR ⁶⁵ - is selected from; Then R ⁶⁵ and R ⁶⁶ are independently selected from hydrogen or C _1-6 alkyl and x is 0-2;

R ⁶³ and R ⁶⁷ are independently halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl , Methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N, N -Dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl;

e, f, g and h are independently selected from 0-2.

Further suitable IBAT inhibitors having the above structure are selected from any of the following compounds:

(+/-)-trans-1,1-dioxo-3-ethyl-3-butyl-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-1,4-benzothiazepine;

(+/-)-trans-1,1-dioxo-3-ethyl-3-butyl-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-1,4-benzothiazepine;

1,1-dioxo-3-ethyl-3-butyl-4-hydroxy-5-phenyl-7- (N- {α- [N '-(2- (S) -3- (R) -4 -(R) -5- (R) -2,3,4,5,6-pentahydroxyhexyl) carbamoyl] -2-fluorobenzyl} carbamoylmethylthio) -2,3,4, 5-tetrahydrobenzothiapine; or

1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7- (N- {1- [N '-(2- (S) -3- (R) -4 -(R) -5- (R) -2,3,4,5,6-pentahydroxyhexyl) carbamoyl] -1- (cyclohexyl) methyl} carbamoylmethylthio) -2,3, 4,5-tetrahydrobenzothiefine.

Compounds of formulas AI, BI, CI, DI, EI, FI and GI or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts can be prepared by methods known in the art.

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), or a pharmaceutically acceptable salt, solvate, solvate or prodrug of such salt and an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate thereof, Combinations of solvates or prodrugs of such salts 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 being in need thereof, wherein the method is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. , An effective amount of solvate, solvate or prodrug of such salt, and an effective amount of an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, to the animal simultaneously, sequentially or separately It involves doing.

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

According to a further aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, and an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate thereof, such Kits are provided that include solvates or prodrugs of salts.

According to a further aspect of the invention,

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

b) IBAT inhibitors, or pharmaceutically acceptable salts, solvates, solvates or prodrugs thereof, present in the 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 compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug of such salt and a pharmaceutically acceptable diluent or carrier, in a first formulation;

b) IBAT inhibitors, or pharmaceutically acceptable salts, solvates, solvates or prodrugs thereof, present in the second formulation; 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, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or solvate thereof, in the manufacture of a medicament for use in producing a cholesterol lowering effect in warm blooded animals such as humans Or the use of a prodrug and an IBAT inhibitor, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.

According to a further aspect of the invention, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier or diluent, is optionally Combinations comprising 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 acceptable carrier or diluent Treatment is provided.

In a further aspect of the invention, the compounds of formula (I), or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts, include PPAR α and / or γ agonists, or pharmaceutically acceptable salts, solvates thereof, such It can be administered with a solvate or prodrug of the salt. Suitable PPAR α and / or γ agents, 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, J Med Chem, 1996, 39, 665, Expert Opinion on Therapeutic Patents , 10 (5), 623-634 (in particular, the compounds disclosed in the patent application listed on page 634) and the compounds disclosed in J Med Chem, 2000, 43, 527, all of which are incorporated by reference. In particular, PPAR alpha and / or gamma agonists include WY-14643, clofibrate, fenofibrate, bezafibrate, GW 9578, troglitazone, pioglitazone, rosiglitazone, eglitazone, proglitazone, NN622 / ragaglitatar, BMS 298585, BRL-49634, KRP-297, JTT-501, SB 213068, GW 1929, GW 7845, GW 0207, L-796449, L-165041 and GW 2433. Specific PPAR α and / or γ 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, the compounds of formula (I), or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts and PPAR a and / or γ agents, or pharmaceutically acceptable salts thereof , Solvates, combinations of solvates or prodrugs of such salts 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 being in need thereof, wherein the method is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. , An effective amount of solvate, solvate or prodrug of such salt, together with an effective amount of a PPAR α and / or γ agonist, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, to the animal , Sequential or separate administration.

According to a further aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, and a PPAR a and / or agonist, or a pharmaceutically acceptable salt thereof Provided are pharmaceutical compositions comprising solvates, solvates or prodrugs of such salts, together with pharmaceutically acceptable diluents or carriers.

According to a further aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, and a PPAR α and / or γ agent, or a pharmaceutically acceptable salt thereof Kits are provided comprising solvates, solvates or prodrugs of such salts.

According to a further aspect of the invention,

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

b) PPAR α and / or γ agents, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts, 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 compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug of such salt and a pharmaceutically acceptable diluent or carrier, in a first formulation;

b) PPAR α and / or γ agents, or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts, 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 compound of formula (I), or a pharmaceutically acceptable salt, solvate, or solvate thereof, in the manufacture of a medicament for use in producing a cholesterol lowering effect in a warm blooded animal such as a human Or the use of a prodrug and a PPAR α and / or γ agent, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.

According to a further aspect of the invention, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier or diluent, is optionally Simultaneous, sequential or separate administration to an animal, such as a human, in need thereof, such as an effective amount of a PPAR α and / or γ agonist, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, together with an acceptable carrier or diluent Combination therapy is provided, including.

In a further aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, may be prepared using nicotinic acid derivatives, or pharmaceutically acceptable salts, solvates, solvates or pros thereof. It may be administered with a drug. 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, niceritrol, nicofuranos, NIASPAN®, and acipimox.

Thus, in a further feature of the invention, the compounds of formula (I), or pharmaceutically acceptable salts, solvates thereof, solvates or prodrugs thereof, and nicotinic acid derivatives, or pharmaceutically acceptable salts, solvates thereof, Combinations of solvates or prodrugs of such salts 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 being in need thereof, wherein the method is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. , An effective amount of solvates, solvates or prodrugs of such salts, together with the effective amount of nicotinic acid derivatives, or pharmaceutically acceptable salts, solvates, solvates or prodrugs thereof of such salts, to the warm-blooded animals Administering.

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

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

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

Thus, in a further feature of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, and a bile acid binding resin, or a pharmaceutically acceptable salt, solvate thereof Combinations of solvates or prodrugs of such salts 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 being in need thereof, wherein the method is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. , An effective amount of a solvate, solvate or prodrug of such salts, such as a bile acid binding resin, or a pharmaceutically acceptable salt, solvate, solvate or prodrug of such salt, may be simultaneously, sequentially or separately to the animal. Administering.

According to a further aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate or prodrug thereof, and a bile acid binding resin, or a pharmaceutically acceptable salt, solvate thereof, Pharmaceutical compositions are provided comprising solvates or prodrugs of such salts, together with pharmaceutically acceptable diluents or carriers.

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

According to a further aspect of the invention, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier or diluent, is optionally Concurrent, sequential or one or more of the following formulations selected from Group X with an acceptable carrier or diluent, or an animal such as a human in need thereof, such as an effective amount of a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof Combination therapy is provided that includes 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 Raffril, imidapril, indrolapril, indolaprilat, ribenzapril, ricinopril, lismin A, lismin B, mixed 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, iribesartan, tasosartan, telmisartan and eprosartan);

Adrenergic blockers (e.g., brethlium tosylate, dihydroergotamine somethylate, phentolamine mesylate, solipertin tartrate, zoletin hydrochloride, carvedilol or rabetaol hydrochloride); Alpha adrenergic blockers (eg, fenpyride hydrochloride, labetaol 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 hydrochloride 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, tellludipine 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, cinepazette 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 (from agatroban, vivaludin, dalteparin sodium, decirudine, dicumarol, iyafolate sodium, napamosat mesylate, phenprocomon, tinzaparin sodium and warfarin sodium Selected);

※ Antithrombotic agents (e.g., Anagrelidee hydrochloride, Vivalidine, Cilostazol, Dalteparin sodium, Danaparoid 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, setroparin, parnaparin, leviparin and tinzaparin);

Squalene synthase inhibitors;

Squalene epoxidase inhibitors;

* Liver X receptor (LXR) agonists such as GW-3965 and W000224632, W000103705, W002090375 and W000054759 (claims 1 and examples of these four applications are incorporated herein by reference) Those disclosed in;

* Microsomal triglyceride transfer protein inhibitors such as Implipidide and W003004020, W003002533, W002083658 and WO 00242291 (claims 1 and Examples of these four applications are incorporated herein by reference) Those disclosed in.

Thus, according to a further feature of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate or prodrug thereof, and a compound selected from group X, or a pharmaceutically acceptable salt, solvate thereof, Combinations of solvates or prodrugs of such salts 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 being in need thereof, wherein the method is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. , An effective amount of solvate, solvate or prodrug of such salt, to the animal, such as an effective amount of a compound selected from Group X, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, Or separate administration.

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

According to a further feature of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or solvate thereof, in the manufacture of a medicament for use in producing a cholesterol lowering effect in a warm blooded animal such as a human Or the use of a prodrug and a compound selected from Group X, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.

Compounds of formula (I), or pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts, in addition to their use as therapeutic agents, can be used as cat, dog, rabbit, monkey, rat, and mouse as part of a new therapeutic investigation. It is useful as a pharmacological tool in the development and standardization of in vitro and in vivo test systems for evaluating cholesterol absorption inhibitory effects in the same 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 IV 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 (IV), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof.

Thus, according to a further aspect of the present invention, there is provided a compound of formula IV as described above, or a pharmaceutically acceptable salt, solvate, solvate or prodrug of such salt, together with a pharmaceutically acceptable diluent or carrier Pharmaceutical compositions are provided.

Thus, according to a further aspect of the invention, a compound of formula (IV) as described above, or a pharmaceutically acceptable salt, solvate, solvate of such salt, or the like, for use in a method for the prophylaxis or treatment of warm blooded animals such as humans or Prodrugs are provided.

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

According to another feature of the invention, a compound of formula (IV), or a pharmaceutically acceptable salt, solvent thereof, as described above in the manufacture of a medicament for use in producing a cholesterol absorption inhibitory effect in a warm blooded animal such as a human being The use of cargoes, solvates of such salts or prodrugs is provided.

According to another feature of the invention, a compound of formula (IV) as described above, or a pharmaceutically acceptable salt, solvate, solvent of such salts in the manufacture of a medicament for treating a hyperlipidemic condition in a warm blooded animal such as a human The use of cargo or prodrugs is provided.

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 IV, or a pharmaceutical thereof. And administering to said animal an effective amount of an acceptable salt, solvate, solvate or prodrug of such salt.

According to a further feature of this aspect of the invention, there is provided a method of treating a hyperlipidemic condition in a warm blooded animal, such as a human, in need thereof, wherein the method is a compound of Formula IV, or a pharmaceutically acceptable thereof. Administering to said animal an effective amount of a possible salt, solvate, solvate or prodrug of such salt.

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:

(i) evaporation was carried out by rotary evaporation under vacuum, and the working procedure was carried out after the removal of residual solids such as desiccants by filtration;

(ii) Unless otherwise noted, all reactions were carried out at temperatures ranging from 18 to 25 ° C. using solvents of HPLC grade under inert atmosphere at ambient temperature, typically anhydrous conditions;

(iii) column chromatography (by flash procedure) was performed on silica gel 40-63 μm (Merck);

(iv) Yields are for illustrative purposes only and do not imply the maximum yield obtainable;

(v) The structure of the final product of formula (I) is 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; LCMS was recorded on Waters ZMD, LC column xTerra MS C8 (Waters) and detected with a mounted HP 1100 MS-detector diode array; Mass spectra (MS) (loop) were recorded on a VG Platform II (Fisons Instruments) equipped with an HP-1100 MS-detector diode array; Unless stated otherwise, the quoted mass ions are (MH +); Unless stated further in the specification, analytical high performance liquid chromatography (HPLC) was performed on Prep LC 2000 (Waters), Cromasil C ₈ , 7 μm (Akzo Nobel); MeCN and deionized water 10 mM ammonium acetate were used as mobile phase with appropriate composition;

(vii) the 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;

(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'-tetramethyluronium-tetrafluoroborate;

EtOAc ethyl acetate;

MeCN acetonitrile;

TFA trifluoroacetic acid;

IPA isopropanol;

DIPEA di-isopropylethylamine; And

THF tetrahydrofuran.

Example 1

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- [4- (N-{(R) -α- [N- (t -Butoxycarbonylmethyl) carbamoyl] benzyl} carbamoylmethoxy) phenyl] azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-carboxymethoxyphenyl) azetidin-2-one (method 1; 20 mg, 0.043 mmol), tert-butyl N-[(2R) -2-amino-2-phenylethanoyl] glycinate (method 4; 14 mg, 0.047 mmol) and 2,6-lutidine (25 μl , 0.21 mmol) was added to DCM (2 ml) and the mixture was stirred for 5 minutes. TBTU (18 mg, 0.056 mmol) was added and the mixture was stirred at rt for 4 h. The reaction mixture was purified by column chromatography using DCM / EtOAc (10/2) as eluent to afford 17 mg (56%) of the title compound. M / z 712.4 (mH) ^- .

Example 2

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- [4- (N-{(R) -α- [N- (carboxy Methyl) carbamoyl] benzyl] carbamoylmethoxy) phenyl] azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- [4- (N-{(R) -α- [N- (t -Butoxycarbonylmethyl) carbamoyl] benzyl} carbamoylmethoxy) phenyl] azetidin-2-one (Example 1; 17 mg, 0.024 mmol) is added to formic acid (1 ml) and the mixture is Stir at room temperature for 2.5 hours. The solvent was evaporated under reduced pressure and methanol (1 ml) and triethylamine (75 μl) were added to the residue. The mixture was stirred at rt for 4.5 h and the solvent was evaporated under reduced pressure. The residue was dissolved in MeCN / water (50/50) (3 ml) and acetic acid (1 ml). The mixture was lyophilized to give 13 mg (83%) of the title compound. NMR (300 MHz, DMSO-d ₆ ): 1.65-1.85 (m, 4H), 3.05 (bs, 1H), 3.5-3.7 (m, 3H), 4.45-4.55 (m, 1H), 4.6 (d, 2H ), 4.85 (m, 1H), 5.55 (d, 1H), 6.9 (d, 1H), 7.05-7.4 (m, 17H), 8.4-8.55 (m, 2H); m / z 656.2 (mH) ^- .

Example 3

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N-((2- (S) -3- (R ) -4- (R) -5- (R) -2,3,4,5,6-pentahydroxyhexyl) carbamoylmethoxy] phenyl] azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-carboxymethoxyphenyl) azetidin-2-one (method 1; 40 mg, 0.086 mmol), D-glucamine (16 mg, 0.09 mmol) and 2,6-lutidine (50 μl, 0.42 mmol) were added to DCM (3 ml) and 2 drops of DMF. TBTU (36 mg, 0.11 mmol) was added and the mixture was stirred at rt for 2 h. The solvent was evaporated under reduced pressure and the residue was purified twice by preparative HPLC using MeCN / ammonium acetate buffer (45:55) as eluent. The collected fractions were lyophilized to obtain 16 mg (30%) of the title compound. NMR (300 MHz, CD ₃ 0D): 1.8-2.0 (m, 4H), 3.15-3.2 (m, 1H), 3.4-4.0 (m, 8H), 4.6 (s, 2H), 4.7-4.8 (m, 1H), 4.9 (bs, 1H), 7.0-7.5 (m, 12H); m / z 629.2 (mH) ^- .

Example 4

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

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-carboxymethoxyphenyl) azetidin-2-one (method 1; 40 mg, 0.086 mmol), tert-butyl N-[(2R) -2-amino-2-phenylethanoyl] -O- (tert-butyl) -L-serinate (method 6; 33 mg, 0.095 mmol) And 2,6-lutidine (50 μl, 0.42 mmol) was added to DCM (3 ml). TBTU (36 mg, 0.11 mmol) was added and the mixture was stirred at rt for 7 h. The solvent was evaporated under reduced pressure to give a compound containing the title compound. M / z 798.4 (M−H) ⁻ .

Example 5

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

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N-((R) -α prepared in Example 4 -{N- (S)-[l- (t-butoxycarbonyl) -2- (t-butoxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one Was added to formic acid (3 ml) and the mixture was stirred at room temperature for 5 days. The solvent was evaporated under reduced pressure and methanol (4 ml) and triethylamine (0.4 ml) were added to the residue. The mixture was stirred at rt for 24 h and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC using MeCN / ammonium acetate buffer (40:60) as eluent. The collected fractions were lyophilized to give 12 mg (20%, 2 steps) of the title compound. NMR (300 MHz, CD ₃ 0D): 1.8-1.95 (m, 4H), 3.1 (bs, 1H), 3.7-3.8 (m, 2H), 4.35 (bs, 1H), 4.55-4.7 (m, 3H) 4.8 (s, 1 H), 5.65 (s, 1 H), 6.95-7.4 (m, 17 H); m / z 686.3 (mH) ^- .

Example 6

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- {N-[(R) -α- (t-butoxy Carbonyl) benzyl] carbamoylmethoxy} phenyl} azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-carboxymethoxyphenyl) azetidin-2-one (method 1; 40 mg, 0.086 mmol), tert-butyl (2R) -amino (phenyl) acetate (20 mg, 0.095 mmol) and 2,6-lutidine (50 μl, 0.42 mmol) were added to DCM (3 ml). TBTU (36 mg, 0.11 mmol) was added and the mixture was stirred at rt for 5 h. The solvent was evaporated under reduced pressure and co-evaporated with toluene. The residue was purified by column chromatography using DCM / EtOAc (10/2) as eluent to afford the title compound. M / z 655.3 (mH) ^- .

Example 7

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N-[(R) -α- (carboxy) benzyl] Carbamoylmethoxy} phenyl) azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- {N-[(R) -α prepared in Example 6 -(t-butoxycarbonyl) benzyl] carbamoylmethoxy} phenyl} azetidin-2-one was added to formic acid (3 ml) and the mixture was stirred at rt for 12 h. The solvent was evaporated under reduced pressure and co-evaporated with toluene. To the residue was added methanol (3 ml) and triethylamine (0.1 ml) and the mixture was stirred at rt for 4 h. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC using MeCN / ammonium acetate buffer (50:50) as eluent. The collected fractions were lyophilized to give 17 mg (33%, 2 steps) of the title compound. NMR (300 MHz, CD ₃ 0D): 1.8-2.0 (m, 4H), 3.05-3.15 (m, 1H), 4.5-4.7 (m, 3H), 4.8 (bs, 1H), 5.35 (d, 1H) , 6.95-7.45 (m, 17 H); m / z 599.5 (mH) ^- .

Example 8

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N- (t-butoxycarbonylmethyl) carbamoyl Methoxy] phenyl} azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-carboxymethoxyphenyl) azetidin-2-one (method 1; 40 mg, 0.086 mmol), glycine tert-butylester (18 mg, 0.091 mmol) and 2,6-lutidine (50 μl, 0.42 mmol) were added to DCM (3 ml). TBTU (36 mg, 0.11 mmol) was added and the mixture was stirred at rt for 20 h. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography using DCM / EtOAc (10/4) as eluent to afford the title compound. M / z 579.2 (mH) ^- .

Example 9

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N- (carboxymethyl) carbamoylmethoxy] phenyl} Azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N- (t-butoxycarb) prepared in Example 8 Bonylmethyl) carbamoylmethoxy] phenyl} azetidin-2-one was added to formic acid (3 ml) and the mixture was stirred at rt for 4 h. The solvent was evaporated under reduced pressure and co-evaporated with toluene. Methanol (3 ml) and triethylamine (0.1 ml) were added to the residue and the mixture was stirred at rt for 20 h. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC using MeCN / ammonium acetate buffer (45:55) as eluent. The collected fractions were lyophilized to give 14 mg (31%, 2 steps) of the title compound. NMR (300 MHz, CD ₃ 0D): 1.8-2.0 (m, 4H), 3.05-3.15 (m, 1H), 3.85 (s, 2H), 4.55 (s, 2H), 4.6-4.7 (m, 1H) 4.8 (bs, 1 H), 6.95-7.35 (m, 12 H); m / z 523.1 (mH) ^- .

Example 10

1- (4-fluorophenyl) -3- [2- (4-fluorophenoxy) ethyl] -4- {4- [N- (carboxymethyl) carbamoylmethoxy] phenyl} azetidine-2 -On

1- (4-fluorophenyl) -3- [2- (4-fluorophenoxy) ethyl] -4- [4- (carboxymethoxy) phenyl] azetidin-2-one in DCM (3 ml) (Method 8; 0.050 g, 0.110 mmol), tert-butyl glycinate hydrochloride (0.022 g, 0.131 mmol) and N-methylmorpholine (0.050 ml, 0.454 mmol) solution were stirred at room temperature for 5 minutes, then TBTU (0.046 g, 0.143 mmol) was added. After 78 hours, the conversion to ester (m / z: 567.2) was complete and the solvent was removed under reduced pressure. The residue was dissolved in formic acid (3 ml) and the solution stirred for 20 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC using 20% -50% MeCN gradient in 0.1 M ammonium acetate buffer as eluent. Fractions were lyophilized and the title compound was obtained as a white solid (0.056 g; ˜quantitative yield). NMR (CD ₃ 0D, 400 MHz) 2.25-2.40 (m, 2H), 3.25-3.35 (m, 1H), 3.90 (s, 2H), 4.05-4.20 (m, 2H), 4.50 (s, 2H), 5.00 (d, 1H), 6.80-7.05 (m, 8H), 7.25-7.40 (m, 4H); m / z: 511.1.

Example 11

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

1- (4-fluorophenyl) -3- [2- (4-fluorophenoxy) ethyl] -4- [4- (carboxymethoxy) phenyl] azetidin-2-one in DCM (5 ml) (Method 8; 0.070 g, 0.154 mmol), tert-butyl D-tyrosinate (0.044 g, 0.185 mmol) and N-methylmorpholine (0.051 ml, 0.463 mmol) solution were stirred at room temperature for 5 minutes, TBTU (0.065 g, 0.202 mmol) was added. After 20 hours, the conversion to ester (m / z: 673.4) was complete and the solvent was removed under reduced pressure. The residue was dissolved in formic acid (5 ml) and the solution stirred for 24 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC using 20% -50% MeCN gradient in 0.1 M ammonium acetate buffer as eluent. Fractions were lyophilized and the title compound was obtained as a white solid (0.052 g; 55%). NMR (CD ₃ 0D, 400 MHz) 2.25-2.40 (m, 2H), 2.85-3.15 (m, 2H), 3.25-3.40 (m, 1H), 4.05-4.20 (m, 2H), 4.35-4.50 (m , 2H), 4.55-4.65 (m, 1H), 5.00 (d, 1H), 6.55-6.65 (m, 2H), 6.80-7.05 (m, 10H), 7.25-7.35 (m, 4H); m / z: 615.2 (M ⁻ H) ⁻ .

Example 12

1- (4-fluorophenyl) -3- [2- (4-fluorophenoxy) ethyl] -4- (4- {N-[(R) -1- (carboxy) -2- (hydroxy ) Ethyl] carbamoyl] methoxy} phenyl) azetidin-2-one

1- (4-fluorophenyl) -3- [2- (4-fluorophenoxy) ethyl] -4- [4- (carboxymethoxy) phenyl] azetidin-2-one in DCM (5 ml) (Method 8; 0.070 g, 0.154 mmol), tert-butyl O- (tert-butyl) -D-serinate hydrochloride (0.047 g, 0.185 mmol) and N-methylmorpholine (0.068 ml, 0.617 mmol) Stir for 5 min, then add TBTU (0.065 g, 0.202 mmol). After 20 hours the conversion to ester (m / z: 653.4) was complete and TFA (1.5 ml) was added to the reaction mixture. After 24 hours, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC using 20% -50% MeCN as eluent in 0.1 M ammonium acetate buffer. Fractions were lyophilized to afford the title compound as a white solid (0.074 g; 89%). M / z: 541.1. NMR (CD ₃ 0D, 400 MHz) 2.25-2.40 (m, 2H), 3.25-3.35 (m, 1H), 3.80-3.95 (m, 2H), 4.05-4.20 (m, 2H), 4.40 (t, 1H ), 4.55 (s, 2H), 5.00 (d, 1H), 6.80-6.90 (m, 2H), 6.90-7.05 (m, 6H), 7.25-7.40 (m, 4H).

Example 13

1- (4-fluorophenyl) -3- [2- (4-fluorophenoxy) ethyl] -4- {4- [N-((R) -1-carboxy-3-methylbutyl) carba Moylmethoxy] phenyl} azetidin-2-one

1- (4-fluorophenyl) -3- [2- (4-fluorophenoxy) ethyl] -4- [4- (carboxymethoxy) phenyl] azetidin-2-one in DCM (5 ml) (Method 8; 0.070 g, 0.154 mmol), tert-butyl D-rucinate hydrochloride (0.042 g, 0.188 mmol) and N-methylmorpholine (0.068 ml, 0.617 mmol) solution were stirred at room temperature for 5 minutes TBTU (0.065 g, 0.202 mmol) was added. After 20 hours, the conversion to ester (m / z: 623.3) was complete and the solvent was removed under reduced pressure. The residue was dissolved in formic acid (5 ml) and the solution stirred for 20 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC using a gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer as the eluent. Fractions were lyophilized and the title compound was obtained as a white solid (0.080 g; 91%). NMR (DMSO, 400 MHz) 0.75-0.85 (m, 6H), 1.45-1.60 (m, 3H), 2.15-2.30 (m, 2H), 3.20-3.30 (m, 1H), 4.00-4.25 (m, 3H ), 4.50 (ABq, 2H), 5.05 (d, 1H), 6.85-6.95 (m, 4H), 7.00-7.25 (m, 6H), 7.30-7.40 (m, 2H), 8.05 (t, 1H); m / z: 567.3.

Example 14

1- (4-fluorophenyl) -3- [2- (4-fluorophenoxy) ethyl] -4- (4- {N-[(S) -1- (carboxy) -3- (carba Moyl) propyl] carbamoylmethoxy} phenyl) azetidin-2-one

1- (4-fluorophenyl) -3- [2- (4-fluorophenoxy) ethyl] -4- [4- (carboxymethoxy) phenyl] azetidin-2-one in DCM (5 ml) (Method 8; 0.070 g, 0.154 mmol), tert-butyl L-glutaminate hydrochloride (0.044 g, 0.184 mmol) and N-methylmorpholine (0.068 ml, 0.617 mmol) solution were stirred at room temperature for 5 minutes Then TBTU (0.065 g, 0.202 mmol) was added. After 20 hours, the conversion to ester (m / z: 638.3) was complete and the solvent was removed under reduced pressure. The residue was dissolved in formic acid (5 ml) and the solution stirred for 20 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC using a gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer as the eluent. Fractions were lyophilized and the title compound was obtained as a white solid (0.088 g; 98%). NMR (CD ₃ 0D, 400 MHz) 1.90-2.40 (m, 6H), 3.25-3.35 (m, 1H), 4.05-4.20 (m, 2H), 4.30-4.40 (m, 1H), 4.50 (s, 2H ), 5.00 (d, 1H), 6.80-7.05 (m, 8H), 7.25-7.40 (m, 4H); m / z: 582.2.

Example 15

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

1- (4-fluorophenyl) -3- [2- (4-fluorophenoxy) ethyl] -4- [4- (carboxymethoxy) phenyl] azetidin-2-one in DCM (5 ml) (Method 8; 0.051 g, 0.113 mmol), tert-butyl N-[(2R) -2-amino-2-phenylethanoyl] -O- (tert-butyl) -L-serinate (method 6; 0.047 g , 0.134 mmol) and N-methylmorpholine (0.050 ml, 0.454 mmol) solutions were stirred at room temperature for 10 minutes, after which TBTU (0.065 g, 0.202 mmol) was added. After 18 h the conversion to ester (m / z: 786.5) was complete and TFA (1.5 ml) was added to the reaction mixture. After 24 hours, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC using 30% -50% MeCN as eluent in 0.1 M ammonium acetate buffer. The fractions were lyophilized to give the title compound as a white solid (0.057 g; 75%). NMR (CD ₃ 0D, 400 MHz) 2.25-2.40 (m, 2H), 3.25-3.35 (m, 1H), 3.65-3.85 (m, 2H), 4.05-4.20 (m, 2H), 4.30-4.40 (m , 1H), 4.50-4.65 (m, 2H), 5.00 (d, 1H), 5.65 (s, 1H), 6.80-7.05 (m, 8H), 7.20-7.45 (m, 9H); m / z: 674.2.

Example 16

1- (4-fluorophenyl) -3- [2- (4-fluorophenoxy) ethyl] -4- {4- [N-{(R) -α- [N-((S) -1 -Carboxypropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy] phenyl} azetidin-2-one

1- (4-fluorophenyl) -3- [2- (4-fluorophenoxy) ethyl] -4- [4- (carboxymethoxy) phenyl] azetidin-2-one in DCM (5 ml) (Method 8; 0.050 g, 0.110 mmol), (R) -α- {N-[(S) -1- (t-butoxycarbonyl) propyl] carbamoyl} -4-hydroxybenzylamine (WO Method 11 of 03/022286; 0.046 g, 0.133 mmol) and N-methylmorpholine (0.049 ml, 0.445 mmol) solution were stirred at room temperature for 10 minutes, after which TBTU (0.046 g, 0.143 mmol) was added. After 20 hours, the conversion to ester (m / z: 744.5) was complete and the solvent was removed under reduced pressure. The residue was dissolved in formic acid (3 ml), the solution was stirred for 24 hours and then the solvent was again removed under reduced pressure. The residue was purified by preparative HPLC using 30% -50% MeCN as eluent in 0.1 M ammonium acetate buffer. The fractions were lyophilized to give the title compound as a white solid (0.052 g; 69%). NMR (CD ₃ 0D, 400 MHz) 0.70-0.80 (m, 3H), 1.55-1.70 (m, 1H), 1.75-1.90 (m, 1H), 2.25-2.40 (m, 2H), 3.25-3.35 (m , 1H), 4.05-4.20 (m, 2H), 4.20-4.30 (m, 1H), 4.55 (ABq, 2H), 5.00 (d, 1H), 5.50 (d, 1H), 6.65-6.75 (m, 2H ), 6.80-7.05 (m, 8H), 7.15-7.40 (m, 6H); m / z: 688.2.

Example 17

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

3- (R) -4- (R) -1- (phenyl) -3- (phenylethylsulfanyl) -4- [4- (carboxymethoxy) phenyl] azetidine-2- in DCM (5 ml) On (method 9; 0.050 g, 0.115 mmol), tert-butyl N-[(2R) -2-amino-2-phenylethanoyl] -0- (tert-butyl) -L-serinate (method 6; 0.049 g, 0.140 mmol) and N-methylmorpholine (0.050 ml, 0.454 mmol) solution were stirred at room temperature for 10 minutes, after which TBTU (0.075 g, 0.234 mmol) was added. After 18 h the conversion to ester (m / z: 766.5) was complete and TFA (1.5 ml) was added to the reaction mixture. After 24 hours, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC using 30% -50% MeCN as eluent in 0.1 M ammonium acetate buffer. The fractions were lyophilized to give the title compound as a white solid (0.052 g; 69%). NMR (CD ₃ 0D, 400 MHz) 2.85-3.00 (m, 4H), 3.65-3. 85 (m, 2 H), 4.00-4. 05 (m, 1 H), 4.35-4. 40 (m, 1H), 4.60 (ABq, 2H), 4.85 (d, 1H), 5.65 (s, 1H), 6.95-7. 45 (m, 19 H); m / z: 654.2.

Example 18

3- (R) -4- (R) -1- (phenyl) -3- (phenylethylsulfanyl) -4- {4- [N-{(R) -α- [N-((S)- 1-carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy] phenyl} azetidin-2-one

3- (R) -4- (R) -1- (phenyl) -3- (phenylethylsulfanyl) -4- [4- (carboxymethoxy) phenyl] azetidine-2- in DCM (5 ml) On (method 9; 0.050 g, 0.110 mmol), (R) -α- {N-[(S) -1- (t-butoxycarbonyl) propyl] carbamoyl} -4-hydroxybenzylamine ( Method 11 of WO 03/022286; 0.048 g, 0.139 mmol) and N-methylmorpholine (0.051 ml, 0.463 mmol) solution were stirred at room temperature for 10 minutes, after which TBTU (0.075 g, 0.234 mmol) was added. After 20 hours, the conversion to ester (m / z: 724.4) was complete and the solvent was removed under reduced pressure. The residue was dissolved in formic acid (3 ml) and the solution stirred for 24 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC using 30% -50% MeCN as eluent in 0.1 M ammonium acetate buffer. The fractions were lyophilized to give the title compound as a white solid (0.037 g; 48%). M / z: 668.1. NMR (CD ₃ 0D, 400 MHz) 0.65-0.80 (m, 3H), 1.50-1.70 (m, 1H), 1.75-1.90 (m, 1H), 2.85-3.00 (m, 4H), 4.00-4.05 (m , 1H), 4.20-4.30 (m, 1H), 4.55 (ABq, 2H), 4.85 (d, 1H), 4.45-4.55 (m, 1H), 6.65-6.75 (m, 2H), 6.95-7.40 (m , 16H).

Example 19

3- (R) -4- (R) -1- (phenyl) -3- (phenylethylsulfinyl) -4- {4- [N- (R) -α- [N-((S) -1 -Carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy] phenyl} azetidin-2-one

3- (R) -4- (R) -1- (phenyl) -3- (phenylethylsulfanyl) -4- {4- [N-{(R) -α- [N in DCM (3 ml) DCM in a solution of ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy] phenyl} azetidin-2-one (Example 18; 0.026 g, 0.039 mmol) MCPBA solution in portion was added until reaction was complete (LC / MS). (About 0.015 g of 70% -75% m-CPBA was added). The solvent was removed under reduced pressure and the residue was purified by preparative HPLC using 20% to 50% MeCN as eluent in 0.1 M ammonium acetate buffer. After lyophilization, the title compound was obtained as a white solid (0.018 g; 67%). NMR (CD ₃ 0D, 400 MHz) (NB: diastereomeric mixture in sulfinyl) 0.65-0.80 (m, 6H), 1.55-1.70 (m, 2H), 1.75-1.90 (m, 2H), 2.95-3.35 (m, 7H), 3.75-3.90 (m, 1H), 4.20-4.30 (m, 2H), 4.40-4.50 (m, 1H), 4.50-4.65 (m, 5H), 5.30 (d, 1H), 5.45 -5.55 (m, 2H), 5.65 (d, 1H), 6.65-6.80 (m, 4H), 6.95-7.10 (m, 6H), 7.15-7.35 (m, 22H), 7.35-7.50 (m, 4H) ; m / z: 684.4.

Example 20

3- (R) -4- (R) -1- (phenyl) -3- (4-fluorobenzoylmethylsulfanyl) -4- {4- [N- (carboxymethyl) carbamoylmethoxy] phenyl } Azetidin-2-one

3- (R) -4- (R) -1- (phenyl) -3- (4-fluorobenzoylmethylsulfanyl) -4- [4- (carboxymethoxy) phenyl] ase in DCM (5 ml) Tidin-2-one (method 10; 0.110 g, 0.236 mmol), tert-butyl glycinate hydrochloride (0.067 g, 0.400 mmol) and N-methylmorpholine (0.12 ml, 1.09 mmol) solution at room temperature for 5 minutes Was stirred and then TBTU (0.130 g, 0.4049 mmol) was added. After 66 hours, the conversion to ester (m / z: 579.2) was complete and the solvent was removed under reduced pressure. The residue was dissolved in formic acid (3 ml) and the solution was stirred at 40 ° C. for 4 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC using a gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer as eluent. After lyophilization, a white solid (0.035 g; 28%) was obtained. M / z 521.12 [M-1] ^- .

Example 21

3- (R) -4- (R) -1- (phenyl) -3- (4-fluorobenzoylmethylsulfanyl) -4- [4- (N- {N-[(R) -1- ( t-butoxycarbonyl) -2- (t-butoxy) ethyl] carbamoylmethyl} carbamoylmethoxy) phenyl] azetidin-2-one

3- (R) -4- (R) -1- (phenyl) -3- (4-fluorobenzoylmethylsulfanyl) -4- {4- [N- (carboxymethyl) carbohydrate in DCM (3 ml) Barmoylmethoxy] phenyl} azetidin-2-one (Example 20; 0.020 g, 0.038 mmol), tert-butyl O- (tert-butyl) -D-serinate hydrochloride (0.012 g, 0.047 mmol) and N-methylmorpholine (0.013 ml, 0.118 mmol) solution was stirred at room temperature for 10 minutes, then TBTU (0.016 g, 0.050 mmol) was added. After 66 hours, the solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane: EtOAc (1: 2) as eluent to afford the title compound (0.020 g; 74%). NMR (400 MHz) 1.15 (s, 9 H), 1.45 (s, 9 H), 3.50-3. 55 (m, 1 H), 3.75-3. 85 (m, 1H), 4.00-4.25 (m, 5H), 4.50 (s, 2H), 4.55-4. 65 (m, 1 H), 4.85 (d, 1 H), 6.90-7. 00 (m, 2 H), 7.00-7. 40 (m, 9H), 7. 90-8. 05 (m, 2 H); m / z: 722.1.

Example 22

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

3- (R) -4- (R) -1- (phenyl) -3- (4-fluorobenzoylmethylsulfanyl) -4- [4- (N- {N-[( R) -1- (t-butoxycarbonyl) -2- (t-butoxy) ethyl] carbamoylmethyl} carbamoylmethoxy) phenyl] azetidin-2-one (Example 21; 0.020 g , 0.146 mmol) was added TFA (1.5 ml). After 18 hours, the solvent was removed under reduced pressure and the residue was purified by preparative chromatography using a gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer as the eluent. After lyophilization, the title compound was obtained as a white solid (0.017 g; quantitative yield). NMR (CD ₃ COOH, 400 MHz) δ 3.95 (dd, 1H), 4.10 (dd, 1H), 4.15-4.35 (m, 5H), 4.65 (s, 2H), 4.70-4.80 (m, 1H), 5.05 (d, 1 H), 6.90-7.45 (m, 11 H), 7.95-8.10 (m, 2 H); m / z: 610.2.

Example 23

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

3- (R) -4- (R) -1- (phenyl) -3- (4-fluorobenzoylmethylsulfanyl) -4- [4- (carboxymethoxy) phenyl] ase in DCM (3 ml) Thidin-2-one (method 10; 0.015 g, 0.032 mmol), tert-butyl N-[(2R) -2-amino-2-phenylethanoyl] -O- (tert-butyl) -L-serinate ( Method 6: 0.017 g, 0.049 mmol) and a solution of N-methylmorpholine (0.011 ml, 0.100 mmol) were stirred for 10 minutes at room temperature, after which TBTU (0.016 g, 0.50 mmol) was added. After 19 h the conversion to ester (m / z: 798.80) was complete and TFA (1.5 ml) was added to the solution. After 7 hours, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC using a gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer as the eluent. After lyophilization, the title compound was obtained as a white solid (0.016 g; 72%). NMR (CD ₃ COOH, 400 MHz) 3.85 (dd, 1H), 4.05 (dd, 1H), 4.20-4.30 (m, 3H), 4.60-4.80 (m, 3H), 5.00 (d, 1H), 5.90- 6.00 (m, 1 H), 6.90-7.50 (m, 16 H), 8.00-8.10 (m, 2 H); m / z: 686.6.

Example 24

3- (R) -4- (R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- {4- [N- (carboxy Methyl) carbamoylmethoxy] phenyl} azetidin-2-one

3- (R) -4- (R) -1- (phenyl) -3- (4-fluorobenzoylmethylsulfanyl) -4- {4- [N- (carboxymethyl) carbohydrate in MeOH (1 ml) To a stirring solution of barmoylmethoxy] phenyl} azetidin-2-one (Example 20; 0.010 g, 0.019 mmol) sodium borohydride (0.001 g, 0.026 mmol) was added. After 10 minutes, water (1 ml) was added and the solvent removed under reduced pressure. The residue was purified by preparative HPLC using a gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer as the eluent. After lyophilization, the title compound was obtained as a white solid (0.008 g; 80%). M / z: 525.1. NMR (CD ₃ COOD, 400 MHz) 3.00-3.20 (m, 2H), 4.05-4.15 (m, 1H), 4.20 (s, 2H), 4.70 (s, 2H), 4.85-5.00 (m, 2H), 6.95-7.10 (m, 5 H), 7.20-7.45 (m, 8 H).

Example 25

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

3- (R) -4- (R) -1- (phenyl) -3- (4-fluorobenzoylmethylsulfanyl) -4- [4- (N- {N-[() in MeOH (2 ml) R) -1- (carboxy) -2- (hydroxy) ethyl] carbamoylmethyl} carbamoylmethoxy) phenyl] azetidin-2-one (Example 22; 0.015 g, 0.025 mmol) in a stirred solution Sodium borohydride (0.003 g, 0.079 mmol) was added. After 5 minutes, water (1 ml) was added and the solvent removed under reduced pressure. The residue was purified by preparative HPLC using a gradient of 20% -40% MeCN in 0.1 M ammonium acetate buffer as the eluent. After lyophilization, the title compound was obtained as a white solid (0.010 g; 66%). NMR (CD ₃ COOD, 400 MHz) 2.95-3.20 (m, 2H), 3.95 (dd, 1H), 4.05-4.15 (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, 5H), 7.20-7.45 (m, 8H).

Example 26

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

3- (R) -4- (R) -1- (phenyl) -3- (4-fluorobenzoylmethylsulfanyl) -4- (4- [N-((R)-) in MeOH (3 ml) α- {N-[(S) -1- (carboxy) -2- (hydroxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one (Example 23; 0.019 g, 0.028 mmol) was added sodium borohydride (0.005 g, 0.073 mmol) After 10 minutes, 0.1 M ammonium acetate buffer (aq, 1 ml) was added and the solvent was removed under reduced pressure. Water was purified by preparative HPLC using a gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer as eluent After lyophilization, the title compound was obtained as a white solid (0.008 g; 81%). (CD ₃ COOD, 400 MHz) 3.00-3.20 (m, 2H), 3.85 (dd, 1H), 4.00-4.15 (m, 2H), 4.65-4.80 (m, 3H), 4.85-5.00 (m, 2H) 5.95 (s 1H), 6.95-7.10 (m, SH), 7.20-7.50 (m, 13H); m / z 688.21.

Example 27

3- (R) -4- (R) -1- (phenyl) -3- (thien-3-ylcarbonylmethylsulfanyl) -4- {4- [N- (carboxymethyl) carbamoylmethoxy ] Phenyl} azetidin-2-one

3- (R) -4- (R) -1- (phenyl) -3- (thien-3-ylcarbonylmethylsulfanyl) -4- [4- (carboxymethoxy) phenyl in DCM (3 ml) ] Azetidin-2-one (Method 11; 0.039 g, <0.086 mmol), tert-butyl glycinate hydrochloride (0.020 g, 0.119 mmol) and N-methylmorpholine (0.035 ml, 0.318 mmol) solution Stir for 10 min and add TBTU (0.042 g, 0.131 mmol). After 22 hours, the solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane: EtOAc (1: 1) as eluent to afford 0.035 g of a colorless oil (m / z: 567.1). This oily substance was dissolved in formic acid (3 ml) and the solution was stirred for 18 hours at room temperature. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC using 20% to 50% MeCN as eluent in 0.1 M ammonium acetate buffer. After lyophilization, the title compound was obtained as a white solid (0.019 g; 43%). NMR (CD ₃ COOD, 400 MHz) 4.15 (ABq, 2H), 4.20 (s, 2H), 4.25 (d, 1H), 4.70 (s, 2H), 5.05 (d, 1H), 6.95-7.15 (m, 4H), 7.20-7.30 (m, 4H), 7.35-7.45 (m, 2H), 7.75-7.90 (m, 2H); m / z: 511.0.

Example 28

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

3- (R) -4- (R) -1- (phenyl) -3- (thien-3-ylcarbonylmethylsulfanyl) -4- [4- (carboxymethoxy) phenyl in DCM (4 ml) ] Azetidin-2-one (method 11; 0.039 g, <0.086 mmol), tert-butyl N-[(2R) -2-amino-2-phenylethanoyl] -O- (tert-butyl) -L- The serineate (Method 6; 0.042 g) and N-methylmorpholine (0.022 ml) solution was stirred at room temperature for 10 minutes before TBTU (0.042 g) was added. After 22 hours, the solvent was dried under reduced pressure and the residue was purified by flash chromatography using heptane: EtOAc (1: 1) as eluent to afford a colorless oily substance (0.050 g). M / z: 786.6. This oily substance was dissolved in DCM (4 ml) and TFA (1.5 ml) was added. After 19 h, the solvent was removed under reduced pressure and the residue was purified twice by preparative HPLC using a gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer. After lyophilization, the title compound was obtained as a white solid (0.019 g; 33%). NMR (CD ₃ COOD, 400 MHz) 3.85 (dd, 1H), 4.05 (dd, 1H), 4.15 (ABq, 2H), 4.20-4.30 (m, 1H), 4.60-4.75 (m, 3H), 5.05 ( d, 1H), 5.90 (s, 1H), 6.95-7.15 (m, 4H), 7.20-7.50 (m, 11H), 7.75-7.85 (m, 2H); m / z: 674.3.

Example 29

3- (R) -4- (R) -1- (phenyl) -3- [2- (thien-3-yl) -2-hydroxyethylsulfanyl] -4- {4- [N- (carboxy Methyl) carbamoylmethoxy] phenyl} azetidin-2-one

3- (R) -4- (R) -1- (phenyl) -3- (thien-3-ylcarbonylmethylsulfanyl) -4- {4- [N- (carboxymethyl) in MeOH (3 ml) To a solution of carbamoylmethoxy] phenyl} azetidin-2-one (Example 27; 0.012 g, 0.024 mmol) was added sodium borohydride (0.006 g, 0.159 mmol). After 10 minutes, 0.1 M ammonium acetate buffer (aq, 1 ml) was added and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC using a gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer as the eluent. After lyophilization, the title compound was obtained as a white solid (0.010 g; 80%). NMR (CD ₃ COOD, 400 MHz) δ 3.10-3.30 (m, 2H), 4.15 (dd, 1H), 4.20 (s, 2H), 4.70 (s, 2H), 4.95 (dd, 1H), 5.20 (dt , 1H), 6.90-7.10 (m, 5H), 7.20-7.35 (m, 5H), 7.40-7.45 (m, 2H); m / z: 511.3 (M−1) ⁻ .

Example 30

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

3- (R) -4- (R) -1- (phenyl) -3- (thien-3-ylcarbonylmethylsulfanyl) -4- {4- [N- (α-) in MeOH (3 ml) (R)-{N-[(S) -1- (carboxy) -2- (hydroxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one (Example 28 0.019 g, 0.028 mmol) was added sodium borohydride (0.005 g, 0.132 mmol). After 10 minutes, 0.1 M ammonium acetate buffer (aq, 1 ml) was added and the solvent was removed under reduced pressure. The residue was purified by flash chromatography using 20% to 50% MeCN as eluent in 0.1 M ammonium acetate buffer. After lyophilization, the title compound was obtained as a white solid (0.015 g; 79%). NMR (CD ₃ COOD, 400 MHz) 3.05-3.30 (m, 2H), 3.85 (dd, 1H), 4.05 (dd, 1H), 4.15 (dd, 1H), 4.65-4.75 (m, 3H), 4.90 ( dd, 1H), 5.15-5.25 (m, 1H), 5.95 (s, 1H), 6.90-7.10 (m, 5H), 7.20-7.50 (m, 12H); m / z 674.16 (M ⁻ H) ⁻ .

Example 31

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

1- (4-fluorophenyl) -3- [2- (4-fluorophenylthio) ethyl] -4- [4- (carboxymethoxy) phenyl] azetidin-2-one in DCM (4 ml) (Method 17; 0.100 g, 0.213 mmol), tert-butyl N-[(2R) -2-amino-2-phenylethanoyl] -0- (tert-butyl) -L-serinate (method 6; 0.150 g , 0. 428 mmol) and N-methylmorpholine (0.070 ml, 0.635 mmol) solution were stirred at room temperature for 10 minutes, then TBTU (0.140 g, 0.436 mmol) was added. After 19 hours, the solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane: EtOAc (2: 1) as eluent to afford a colorless oily substance (0.149 g; 87%). NMR (400 MHz) 0.90 (s, 9H), 1.45 (s, 9H), 2.05-2.30 (m, 2H), 2.95-3.15 (m, 2H), 3.20-3.25 (m, 1H), 3.30-3.35 ( m, 1H), 3.65 (dd, 1H), 4.40-4.60 (m, 3H), 4.60 (d, 1H), 5.50 (dd, 1H), 6.50 (dd, 1H), 6.85-7.00 (m, 6H) , 7.15-7.40 (m, 11H), 7.90 (dd, 1H); m / z: 802.8.

Example 32

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

1- (4-fluorophenyl) -3- [2- (4-fluorophenylthio) ethyl] -4- {4- [N-((R) -α- {N- in DCM (3 ml) (S)-[l- (t-butoxycarbonyl) -2- (t-butoxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one (Example 31 0.149 g, 0.186 mmol) was added TFA (1.5 ml). After 20 hours, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC using a 20% -50% MeCN gradient in 0.1 M ammonium acetate buffer as the eluent. Lyophilization gave the title compound as a white solid (0.098 g; 77%). NMR (400 MHz) 2.00-2.25 (m, 2H), 2.85-3.10 (m, 2H), 3.10-3.20 (m, 1H), 3.35-3.45 (m, 1H), 3.75-3.85 (m, 1H), 4.15-4.45 (m, 3H), 4.55 (d, 1H), 5.70 (d, 1H), 6.70-7.00 (m, 6H), 7.10-7.35 (m, 11H), 7.45-7.55 (m, 1H), 8.45-8.55 (m, 1 H); m / z: 690.5.

Example 33

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

Example 34

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

1- (4-fluorophenyl) -3- [2- (4-fluorophenylthio) ethyl] -4- {4- [N-((R) -α- {N- in DCM (5 ml) (S)-[1- (carboxy) -2- (hydroxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one (Example 32; 0.070 g, 0.102 mmol) Metachloroperoxybenzoic acid (0.035 g, 70% to 75%) was added to the stirred solution. After 20 hours, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC using 20% -40% MeCN gradient in 0.1 M ammonium acetate buffer as eluent. After lyophilization, 1- (4-fluorophenyl) -3- [2- (4-fluorophenylsulfinyl) ethyl] -4- {4- [N-((R) -α- {N- ( S)-[1- (carboxy) -2- (hydroxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one (0.022 g; 30%) NMR (CD ₃ COOD , 400 MHz) 2.15-2.45 (m, 2H), 3.10-3.35 (m, 3H), 3.85 (dd, 1H), 4.05 (dd, 1H), 4.65-4.75 (m, 3H), 4.80-4.90 (m , 1H), 5.90 (s, 1H), 6.95-7.05 (m, 4H), 7.25-7.50 (m, 11H), 7.70-7.80 (m, 2H); m / z: 706.2; And 1- (4-fluorophenyl) -3- [2- (4-fluorophenylsulfonyl) ethyl] -4- {4- [N-((R) -α- {N- ( S)-[1- (carboxy) -2- (hydroxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one (0.043 g; 59%) was added. NMR (CD ₃ COOD, 400 MHz) 2.25-2.40 (m, 2H), 3.25 (dt, 1H), 3.35-3.55 (m, 2H), 3.85 (dd, 1H), 4.05 (dd, 1H), 4.65- 4.75 (m, 3H), 4.85 (d, 1H), 5.95 (s, 1H), 6.95-7.05 (m, 4H), 7.20-7.50 (m, 11H), 7. 95-8.05 (m, 2H); m / z: 722.1.

Example 35

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N-[(S) -α- (carboxy) benzyl] Carbamoylmethoxy] phenyl) azetidin-2-one

To a solution of N-methylmorpholine (35 μl, 0.318 mmol) in DCM (2 ml) 1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl]- 4- (4-carboxymethoxyphenyl) azetidin-2-one (Method 2; 49 mg, 0.105 mmol) was dissolved. (S) -phenylglycine methyl ester hydrochloride (25 mg, 0.124 mmol) and TBTU (40 mg, 0.125 mmol) were added and the mixture was stirred at room temperature overnight. The solution was diluted with DCM (4 ml) and washed with 1% NaHCO ₃ , 0.1 M KHSO ₄ and brine. The organic phase was dried and evaporated to afford the ester. M / z: 615. THF (2 ml), water (0.5 ml) and LiOH (about lOmg, 0.418 mmol) were added and the mixture was stirred overnight. Solvent was removed and the residue was purified using preparative HPLC on C8 column. A gradient of 20% -50% MeCN in 0.1 M ammonium acetate buffer was used as the mobile phase. Lyophilization gave 40 mg (63%) of a white solid. M / z: 601.NMR (400 MHz, CD ₃ 0D): 1.75-2.06 (m, 4H), 3.06-3.13 (m, 1H), 4.47-4.67 (m, 3H), 4.79-4.82 (m, 1H) , 5.24 (d, 1 H), 6.90-7.06 (m, 6 H), 7.12-7.40 (m, 11 H).

Example 36

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- [4- (N-{(R) -α- [N-(( S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) phenyl] azetidin-2-one

To a solution of N-methylmorpholine (40 μl, 0.318 mmol) in DCM (2 ml) 1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl]- 4- (4-carboxymethoxyphenyl) azetidin-2-one (Method 2; 49 mg, 0.105 mmol) was dissolved. tert-butyl (2S) -2-{[(2R) -2-amino-2- (4-hydroxyphenyl) acetyl] amino} butanoate hydrochloride (method 14, 43 mg, 0. 125 mmol) and TBTU (40 mg, 0. 125 mmol) was added. The mixture was stirred at room temperature overnight. A further 10 mg of dipeptide (0.029 mmol) was added and after 2 hours the solution was diluted with DCM (4 ml) and washed with 1% NaHCO ₃ , 0.1 M KHS0 ₄ and brine. The organic phase was dried and evaporated to give ester. M / z: 758. Formic acid (1.5 ml) was added and the mixture was stirred overnight. Further formic acid (1 ml) dmf was added. After 3 hours, formic acid was removed, MeOH (2 ml) was added with Et ₃ N (40 μl, 0.288 mmol) and the mixture was stirred overnight. The mixture was concentrated under reduced pressure and purified using preparative chromatography. A gradient of 20% -80% MeCN in 0.1 M ammonium acetate buffer was used as the eluent. Lyophilization gave 42 mg (57%) of the title compound. NMR (400 MHz, DMSO-d ₆ ): 0.65-0.72 (m, 3H), 1.53-1.67 (m, 1H), 1.74-2.04 (m, 5H), 3.06-3.14 (m, 1H), 4. 18- 4.23 (m, 1H), 4.50-4.66 (m, 3H), 4.77-4.82 (m, 1H), 5.46 (d, 1H), 6.72 (t, 2H), 6.93-7. 06 (m, 6H), 7.18-7.36 (m, 8H); m / z: 702.

Example 37

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N- (2-hydroxyethyl) carbamoylmethoxy ] Phenyl} azetidin-2-one

To a solution of N-methylmorpholine (10 μl, 0.091 mmol) in DCM (2 ml) 1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl]- 4- (4-carboxymethoxyphenyl) azetidin-2-one (Method 2; 20 mg, 0.043 mmol) was dissolved. 2-aminoethanol (4 μl, 0.066 mmol) and TBTU (16 mg, 0.050 mmol) were added and the mixture was stirred for 3 hours. Additional 2-aminoethanol (3 μl) was added. The mixture was stirred for 2.5 days and then concentrated and purified using preparative chromatography. A gradient of 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as the eluent. Lyophilization gave 10 mg (45%) of the title compound. NMR (400MHz, CD30D): 1.75-2.06 (m, 4H), 3.05-3.12 (m, 1H), 3.38 (t, 2H), 3.61 (t, 2H), 4.51 (d, 2H), 4.57-4.66 ( m, 1H), 4.77-4.83 (m, 1H), 6.93-7.07 (m, 6H), 7.22-7.37 (m, 6H); m / z: 511.

Example 38

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyll-4- {4- [N- (2-methoxyethyl) carbamoylmethoxy ] Phenyl} azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-carboxymethoxyphenyl) azetidin-2-one (method 2, 20 mg, 0.043 mmol) was added to a solution of N-methylmorpholine (10 μl, 0.991 mmol) in DCM (2 ml). 2-methoxyethylamine (5 μl, 0.058 mmol) and TBTU (16 mg, 0.050 mmol) were added and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated and purified using preparative chromatography. A gradient of 20% -50% MeCN in 0.1 M ammonium acetate buffer was used as the eluent. Lyophilization gave 5 mg (22%) of the title compound. NMR (400 MHz, CD ₃ 0D): 1.75-2.05 (m, 4H), 3.05-3.15 (m, 1H), 3.29 (s, 3H), 3.40-3.44 (m, 4H), 4.5 (d, 2H) , 4.57-4.66 (m, 1 H), 4.78-4.82 (m, 1 H), 6.92-7.06 (m, 6H), 7.22-7.37 (m, 6H); m / z: 525.

Example 39

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N- (2-sulfoethyl) carbamoylmethoxy ] Phenyl} azetidin-2-one

TBTU (26 mg, 0.081 mmol) was added 1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- in MeCN (1 ml). Carboxymethoxyphenyl) azetidin-2-one (method 2; 29 mg, 0.062 mmol), taurine (24 mg, 0.19 mmol) and triethylamine (25 mg, 0.25 mmol) were added to the mixture. After 1 hour, DMF (1 ml) was added and MeCN was removed under vacuum at 50 ° C. After 4 days at room temperature, the mixture was purified by preparative HPLC using a gradient of MeCN / ammonium acetate buffer to afford the title compound (2 mg, 6%). NMR (CD ₃ 0D, 400 MHz) 7.40-7.20 (m, 6H), 7.05-6.95 (m, 6H), 4.8 (m, 1H), 4.7-4.55 (m, 1H), 4.5 (s, 2H), 3.75 (t, 2H), 3.1 (m, 1H), 2.95 (t, 2H), 2.0-1.8 (m, 4H).

Example 40

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N-[(S) -1- (t-butoxy Carbonyl) ethyl] carbamoylmethoxy} phenyl) azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-carboxymethoxyphenyl) azetidin-2-one (method 2; 30 mg, 0.064 mmol), tert-butyl L-alanine hydrochloride (40 mg, 0.22 mmol), triethylamine (0.036 ml, 0.26 mmol) and TBTU (35 mg, 0.11 mmol) were prepared using MeCN ( 1 ml). After 4 hours, the mixture was diluted with toluene and the solution was washed with hydrochloric acid (2 M) and sodium hydrogen carbonate solution. The solvent was removed under vacuum and the residue was purified by preparative HPLC using a gradient of MeCN / ammonium acetate buffer to afford the title compound (20 mg, 52%). NMR (CD ₃ 0D, 500 MHz) 7.40-6.90 (m), 4.8 (m), 4.7-4.3 (m), 3.95 (q), 3.2 (q), 3.1 (m), 2-1.8 (m), 1.5-1.3 (m); m / z 595.60 (M + H) ⁺ and 593.53 (MH) ^- .

Example 41

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N-[(S) -1- (carboxy) ethyl] Carbamoylmethoxy} phenyl) azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N-[(S) -1 in formic acid (1 ml) The solution of-(t-butoxycarbonyl) ethyl] carbamoylmethoxy} phenyl) azetidin-2-one (Example 40; 20 mg, 0.034 mmol) was kept at room temperature overnight. Formic acid was removed under vacuum and the residue was dissolved in methanol (4 ml). Aqueous ammonia (25%, 0.2 ml) was added and after 1 hour at room temperature, the mixture was purified by preparative HPLC using MeCN / ammonium acetate buffer to give the title compound (5 mg, 28%). NMR (CD ₃ 0D, 400 MHz) 7.4-7.2 (m, 6H), 7.1-6.9 (m, 6H), 4.8 (m, 1H), 4.7-4.6 (m, 1H), 4.5 (s, 2H), 4.3 (q, 1H), 3.1 (m, 1H), 2-1.7 (m, 4H), 1.4 (dd, 3H); m / z 539.51 (M + H) ⁺ and 537.50 (MH) ^- .

Example 42

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- [4- (N-((R) -α- [N- (2 -Sulfoethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) phenyl] azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-carboxymethoxyphenyl) azetidin-2-one (method 2; 28 mg, 0.06 mmol), 2-{[(2R) -2-amino-2- (4-hydroxyphenyl) acetyl] amino} ethanesulfonic acid (30 mg, 0.11 mmol), triethylamine (24 mg, 0.24 mmol) and TBTU (29 mg, 0.09 mmol) were mixed in DMF (1.5 ml). After stirring overnight, the reaction mixture was purified by preparative HPLC using MeCN / ammonium acetate buffer to give the title compound (18 mg, 42%). NMR (CD ₃ OD, 400 MHz) 7.4-7.1 (m), 7.1-6.9 (m), 5.4 (m), 4.8 (m), 4.7-4.5 (m), 3.65-3.55 (m), 3.15-3.05 (m), 3-2.8 (m), 2-1.7 (m); m / z 724.46 (M + H) ⁺ and 722.54 (MH) ^- .

Example 43

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N-((S) -1- {N-[( S) -1- (t-butoxycarbonyl) ethyl] carbamoyl} ethyl) carbamoylmethoxy] phenyl} azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-carboxymethoxyphenyl) azetidin-2-one (method 2; 30 mg, 0.064 mmol), tert-butyl L-alanyl-L-alanineate (25 mg, 0.12 mmol), triethylamine (0.036 ml, 0.26 mmol) and TBTU (31 mg, 0.10 mmol) in this order As-mixed in DMF (1.5 ml). After 16 h the mixture was diluted with toluene and the solution washed with water, hydrochloric acid (2 M), water and sodium bicarbonate solution and water. IPA was added and solvent removed under vacuum to afford the title compound. M / z 666.57 (M + H) ⁺ and 664.68 (MH) ^- .

Example 44

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N-((S) -1- {N-[( S) -1- (carboxy) ethyl] carbamoyl} ethyl) carbamoylmethoxy] phenyl} azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N-((S) -1- {N-[( S) -1- (t-butoxycarbonyl) ethyl] carbamoyl} ethyl) carbamoylmethoxy] phenyl} azetidin-2-one (Example 43; 54 mg, 0.081 mmol) was formic acid (2 ml). After 16 hours, formic acid was removed under vacuum and the residue was dissolved in methanol (4 ml) and aqueous ammonia (25%, 0.2 ml). After 6 hours, the mixture was purified by preparative HPLC using a gradient of MeCN / ammonium acetate buffer to give the title compound (15 mg, 30%). NMR (CD ₃ 0D, 400 MHz) 7.4-7.2 (m, 6H), 7.1-6.9 (m, 6H), 4.8 (m, 1H), 4.7-4.5 (m, 1H), 4.5 (s, 2H), 4.45 (q, 1H), 4.3-4.2 (m, 1H), 3.2 (q, 1H), 3.1-3.0 (m, 1H), 2-1.8 (m, 4H), 1.4-1.2 (dd, 6H); m / z 610.57 (M + H) ⁺ and 608.53 (MH) ^- .

Example 45

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N- [N- (methoxycarbonylmethyl) carba Moylmethyl] carbamoylmethoxy} phenyl) azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-carboxymethoxyphenyl) azetidin-2-one (method 2; 30 mg, 0.064 mmol), methyl glycylglycinate (19 mg, 0.13 mmol), triethylamine (0.036 ml, 0.26 mmol) and TBTU (31 mg, 0.10 mmol) in DMF (1.5 ml) in this order Mixed. After 16 h the mixture was diluted with toluene and the solution washed with water, hydrochloric acid (2 M), water and sodium bicarbonate solution and water. IPA was added and solvent removed under vacuum to afford the title compound. M / z 596.50 (M + H) ⁺ and 594.45 (MH) ^- .

Example 46

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyll-4- (4- {N- [N- (carboxymethyl) carbamoylmethyl] Carbamoylmethoxy} phenyl) azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N- [N- (methoxy) in THF (4 ml) Carbonylmethyl) carbamoylmethyl] carbamoylmethoxy} phenyl) azetidin-2-one (Example 45; 44 mg, 0.074 mmol) A solution of lithium hydroxide (10 mg, 0.43 mmol) in water (2 ml) ) Was added to the stirred solution. After 16 hours, the mixture was carefully neutralized with hydrochloric acid. Purification by preparative HPLC using a gradient of MeCN / ammonium acetate buffer gave the title compound (17 mg, 40%). NMR (CD30D, 400 MHz) 7.4-7. 2 (m, 6H), 7.1-6. 9 (m, 6H), 4.8 (m, 1H), 4.7-4. 6 (m, 1H), 4.6 (s, 2H), 3.95 (s, 2H), 3.8 (s, 2H), 3.1-3. 05 (m, 1 H), 2-1. 8 (m, 4 H).

Example 47

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N-[(S) -1,3-bis- ( Ethoxycarbonyl) propyl] carbamoylmethoxy} phenyl) azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-carboxymethoxyphenyl) azetidin-2-one (method 2; 30 mg, 0.064 mmol), diethyl L-glutamate (19 mg, 0.093 mmol), triethylamine (0.036 ml, 0.26 mmol) and TBTU (31 mg, 0.10 mmol) were mixed in this order in DMF (1.5 ml) It was. After 16 h the mixture was diluted with toluene and the solution washed with water, hydrochloric acid (2 M), water and sodium bicarbonate solution and water. IPA was added and solvent removed under vacuum to afford the title compound. M / z 653.56 (M + H) + and 651.60 (M-H) −.

Example 48

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N-[(S) -1,3-bis- ( Carboxy) propyl] carbamoylmethoxy} phenyl) azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N-[(S) -1-1 in ethanol (4 ml) 3.75 M sodium hydroxide solution (0.05 ml, 0.19) in a solution of, 3-bis- (ethoxycarbonyl) propyl] carbamoylmethoxy} phenyl) azetidin-2-one (Example 47; 30 mg, 0.046 mmol) mmol) was added. After 16 h, further 3.75 M sodium hydroxide solution (0.05 ml, 0.19 mmol) was added. Ethanol was removed under vacuum and THF (2.5 ml) and water (1.5 ml) were added. After 24 hours, the reaction mixture was purified by preparative HPLC using a gradient of MeCN / ammonium acetate buffer to afford the title compound (11 mg, 40%). NMR (CD ₃ 0D, 400 MHz) 7.5-6.9 (m), 5-4.8 (m), 4.75-4.6 (m), 4.5 (s), 4.45 (m), 4.4-4.3 (br s), 3.1- 3.05 (m), 2.3-2.1 (m), 2-1.8 (m); m / z 597.52 (M + H) ⁺ and 595.49 (MH) ^- .

Example 49

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N-[(s) -1- (t-butoxy Carbonyl) -5- (t-butoxycarbonylamino) pentyl] carbamoylmethoxy} phenyl) azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-carboxymethoxyphenyl) azetidin-2-one (method 2; 30 mg, 0.064 mmol), tert-butyl N ^6- (tert-butoxycarbonyl) -L-lysinate (39 mg, 0.13 mmol), triethylamine (0.036 ml, 0.26 mmol) and TBTU (31 mg, 0.096 mmol) sms DMF (1.50 ml). The mixture was stirred for 16 hours and then diluted with water and toluene. The organic phase was washed with hydrochloric acid, water, sodium bicarbonate solution and water. IPA was added to the organic phase and the solvent removed under vacuum to afford the title compound (39 mg, 81%). M / z 752.68 (M + H) ⁺ and 750.79 (MH) ⁻ .

Example 50

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N-[(S) -1- (carboxy) -5 -(Amino) pentyl] carbamoylmethoxy} phenyl) azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N-[(S) -1-(-butoxycar Bonyl) -5- (t-butoxycarbonylamino) pentyl] carbamoylmethoxy} phenyl) azetidin-2-one (Example 49; 39 mg, 0.052 mmol) was 64 hours in formic acid (2 ml) For a while. The acid was removed under vacuum and the residue was dissolved in methanol (4 ml) and aqueous ammonia (25%, 0.4 ml). After 16 hours, the solvent was removed in vacuo and the residue was purified by preparative HPLC using a gradient of MeCN / ammonium acetate buffer as eluent to afford the title compound (7 mg, 23%). NMR (CD ₃ 0D, 400 MHz) 7.4-7.2 (m, 6H), 7.05-6.95 (m, 6H), 4.8 (m, 1H), 4.65-4.6 (m, 1H), 4.5 (s, 2H), 4.35-4.3 (m, 1H), 3.1-3.05 (m, 1H), 2.9-2.8 (m, 2H), 2-1.6 (m, 6H), 1.5-1.2 (m, 4H).

Example 51

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N- [2- (t-butoxycarbonyl) ethyl ] Carbamoylmethoxy} phenyl) azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-carboxymethoxyphenyl) azetidine-2 in DMF (1 ml) Mix-on (Method 2; 47 mg, 0.101 mmol), tert-butyl β-alanineate (48 mg, 0.33 mmol), triethylamine (0.07 ml, 0.5 mmol) and TBTU (42 mg, 0.13 mmol) And left overnight. The mixture was diluted with diethyl ether and washed with potassium hydrogen sulfate solution and sodium carbonate solution. The organic phase was dried (magnesium sulfate) and the solvent removed under vacuum to afford the title compound (38 mg, 64%). M / z 595.54 (M + H) ⁺ and 593.61 (MH) ⁻ .

Example 52

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N- [2- (carboxy) ethyl] carbamoylme Methoxy} phenyl) azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N- [2- (t-butoxycarbonyl) ethyl ] Carbamoylmethoxy} phenyl) azetidin-2-one (Example 51; 38 mg, 0.064 mmol) was dissolved in formic acid (2 ml). After 16 hours, the acid was removed under vacuum with the aid of MeCN. After complete removal of the solvent, the residue was dissolved in methanol (5 ml) and aqueous ammonia (25%, 1 ml). Hydrolysis was completed within 2 hours and purification was carried out by HPLC using MeCN / ammonium acetate buffer as eluent to afford the title compound (20 mg, 59%). NMR (CD ₃ 0D, 400 MHz) 7.4-7.2 (m, 6H), 7.1-6.9 (m, 6H), 4.8 (m, 1H), 4.7-4.6 (m, 1H), 4.5 (s, 2H), 3.5 (t, 2H), 3.1-3.05 (m, 1H), 2.4 (t, 2H), 2-1.8 (m, 4H); m / z 539.42 (M + H) ⁺ and 537.50 (MH) ^- .

Example 53

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N-[(R) -1- (t-butoxy Carbonyl) ethyl] carbamoylmethoxy} phenyl) azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-carboxymethoxyphenyl) azetidin-2-one (method 2; 30 mg, 0.064 mmol), tert-butyl D-alanine hydrochloride (50 mg, 0.28 mmol), triethylamine (0.05 ml, 0.36 mmol) and TBTU (31 mg, 0.096 mmol) were DMF (1 ml) Stir for 3 hours. The mixture was diluted with toluene and washed with water, hydrochloric acid, water, sodium bicarbonate solution and water. IPA was added to the organic phase and the solvent was removed under vacuum to give 30 mg (79%) of the title compound. m / z 595.48 (M + H) ⁺ and 593.56 (MH) ^- .

Example 54

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N-[(R) -1- (carboxy) ethyl] Carbamoylmethoxy} phenyl) azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N-[(R) -1- (t-butoxy Carbonyl) ethyl] carbamoylmethoxy} phenyl) azetidin-2-one (Example 54; 30 mg, 0.05 mmol) was dissolved in formic acid (2 ml). After 16 hours, the acid was removed under vacuum and the residue was dissolved in methanol (3 ml) and aqueous ammonia (25%, 0.2 ml). The next step was HPLC, after which the mixture was purified by HPLC using a gradient of MeCN / ammonium acetate buffer to give the title compound (17 mg, 63%). NMR (CD ₃ 0D, 400 MHz) 7.4-7.2 (m, 6H), 7.1-6.9 (m, 6H), 4.8 (m, 1H), 4.7-4.6 (m, 1H), 4.5 (s, 2H), 4.3-4.2 (s, 1H), 3.1-3.05 (m, 1H), 2.2-1.8 (m, 4H), 1.5-1.4 (m, 3H).

Preparation of Starting Material

Starting materials for these examples are either commercially available or are readily prepared by standard methods from known materials. The following reactions are merely examples of the preparation of some of the starting materials used in the reaction, and are not meant to be limiting.

Method 1

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-t-butoxycarbonylmethoxyphenyl) azetidine-2- On

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-hydroxyphenyl) azetidin-2-one (J. Med Chem 1998, 41, 973-980; 50 mg, 0.122 mmol), tert-butylbromoacetate (24 μl, 0.165 mmol), sodium carbonate (80 mg, 0.76 mmol) and catalytic amount of calcium carbonate in MeCN (3 ml) And the mixture was stirred at 50 ° C. for 1.5 h. The solid was filtered off and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using DCM / EtOAc (100/7) as eluent to afford 35 mg (55%) of the title compound. NMR (300 MHz): 1.45 (s, 9H), 1.8-2.1 (m, 4H), 2.25-2.3 (m, 1H), 3.05-3.15 (m, 1H), 4.5 (s, 2H), 4.55-4.6 (m, 1 H), 4.75 (bs, 1 H), 6.9-7.3 (m, 12 H); m / z 524.3.

Method 2

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-carboxymethoxyphenyl) azetidin-2-one

1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4-t-butoxycarbonylmethoxyphenyl) azetidine-2- Warm (method 1; 50 mg, 0.096 mmol) was added to formic acid (3 ml) and the mixture was stirred at rt for 1.5 h. The solvent was evaporated under reduced pressure and methanol (3 ml) and triethylamine (150 μl) were added to the residue. The mixture was stirred at rt for 2 h and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC using MeCN / ammonium acetate buffer (35:65) as eluent. The collected fractions were lyophilized to give 32 mg (56%) of the title compound. NMR (300 MHz, CD ₃ 0D): 1.8-1.95 (m, 4H), 3.1 (bs, 1H), 4.4 (s, 2H), 4.55-4.65 (m, 1H), 4.8 (bs, 1H), 6.9 -7.35 (m, 12 H); m / z 466.1 (mH) ^- .

Method 3

tert-butyl N-((2R) -2-{[(benzyloxy) carbonyl] amino} -2-phenylethanoyl) glycinate

(2R)-{[(benzyloxy) carbonyl] amino} (phenyl) acetic acid (Z- (R) -Phg-OH with 2,6-lutidine (8.2 ml, 70.4 mmol) in DCM (200 ml) ) (10 g, 35.0 mmol) and tert-butylglycine hydrochloride (6.3 g, 37.4 mmol) were dissolved. After 5 min stirring at 0 ° C., TBTU (12.4 g, 38.6 mmol) was added and stirring continued at 0 ° C. for 1 h 30 min and at rt 3 h 45 min. The reaction mixture was washed with water (2 x 100 ml), dried (magnesium sulfate) and purified by flash chromatography (DCM: EtOAc 7: 1 → 5: 1) to afford the title compound (13 g, 94%). Got it. NMR (500 MHz): 1.45 (s, 9 H), 3.84 (d, 1 H), 4.00 (dd, 1 H), 5.10 (m, 2 H), 5.28 (br s, 1 H), 6.13 (br s, 1 H), 6.23 (br s, 1 H), 7.30-7.44 (m, 10 H).

Method 4

tert-butyl N-[(2R) -2-amino-2-phenylethanoyl] glycinate

Tert-butyl N-((2R) -2-{[(benzyloxy) carbonyl] amino} -2-phenylethanoyl) glycinate in EtOH (99%, 200 ml) and toluene (50 ml) 3; 12.8 g, 32.2 mmol) were dissolved. Pd / C (10%, 0.65 g) was added and hydrogenation was performed at atmospheric pressure and room temperature for 5 hours 30 minutes. The reaction mixture was filtered through diatomaceous earth and the solvent was evaporated to afford the title compound (8.4 g, 99%). NMR (600 MHz): 1.45 (s, 9 H), 3.93 (m, 2 H), 4.54 (s, 1 H), 7.31-7.42 (m, 5 H), 7.51 (br s, 1 H).

Method 5

tert-butyl N-((2R) -2-{[(benzyloxy) carbonyl] amino} -2-phenylethanoyl) -0- (tert-butyl) -L-serinate

(2R)-{[(benzyloxy) carbonyl] amino} (phenyl) acetic acid (Z- (R) -Phg-OH) (2.0 g, 7.0 mmol) and tert-butyl O- (in DCM (30 ml) tert-butyl) -L-serinate (2.0 g, 7.9 mmol) and 2,6-lutidine were dissolved. After 5 minutes of stirring at 0 ° C., TBTU (2.5 g, 7.8 mmol) was added and stirring continued for 30 minutes at 0 ° C. and 4 hours at room temperature. The reaction mixture was washed with water (2 × 100 ml), dried and purified by flash chromatography (DCM) to afford the title compound (3.3 g, 97%). NMR (300 MHz, CD ₃ 0D): 1.05 (s, 9H), 1.45 (s, 9H), 3.4-3.8 (m, 2H), 4.5 (bs, 1H), 4.85 (s, 2H), 5.1 (s , 2H), 5.4 (s, 1H), 7.25-7.5 (m, 10H).

Method 6

tert-butyl N-[(2R) -2-amino-2-phenylethanoyl] -O- (tert-butyl) -L-serinate

tert-butyl N-((2R) -2-{[(benzyloxy) carbonyl] amino} -2-phenylethanoyl) -0- (tert-butyl) -L-serinate (method 5; 3.3 g, 6.8 mmol) was dissolved in EtOH (95%, 30 ml), catalytic amount of Pd / C (5%) (50% in water) was added and hydrogenation was carried out at atmospheric pressure for 3 hours. The reaction mixture was filtered through diatomaceous earth and the solvent was evaporated to afford the title compound (2.35 g, 98%). NMR (500 MHz, CD ₃ 0D): 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 7

1- (4-fluorophenyl) -3- [2- (4-fluorophenoxy) ethyl] -4- [4- (t-butoxycarbonylmethoxy) phenyl] azetidin-2-one

1- (4-fluorophenyl) -3- [2- (4-fluorophenoxy) ethyl] -4- (4-hydroxyphenyl) azetidin-2-one in MeCN (10 ml) (Bioorg. Prepared according to Med. Chem. Lett 1996,6, 1271-1274; 1.00 g, 2.53 mmol), t-butyl bromoacetate (0.42 ml, 2.79 mmol) and calcium carbonate (1.00 g, 3.07 mmol) in a mixture of 40 Stir at 90 ° C. for 90 minutes. The suspension was filtered and the solid material washed with MeCN (5 ml) and EtOAc (5 ml). The filtrate was concentrated and the residue was purified by flash chromatography using hexane and EtOAc (7: 2) as eluent. The title compound was obtained as a colorless oily substance (1.045 g; 81%). NMR (600 MHz) 1.45 (s, 9H), 2.25-2.45 (m, 2H), 3.20-3.30 (m, 1H), 4.00-4.10 (m, 1H), 4.10-4.20 (m, 1H), 4.50 ( s, 2H), 4.80 (d, 1H), 6.75-7.00 (m, 8H), 7.20-7.30 (m, 4H); m / z: 501.2.

Method 8

1- (4-fluorophenyl) -3- [2- (4-fluorophenoxy) ethyl] -4- [4- (carboxymethoxy) phenyl] azetidin-2-one

1- (4-fluorophenyl) -3- [2- (4-fluorophenoxy) ethyl] -4- [4- (t-butoxycarbonylmethoxy) phenyl] ase in formic acid (4 ml) Tidin-2-one (method 7; 1.045 g, 2.051 mmol) solution was stirred at rt for 22 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM (10 ml). The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate (aq; 5 ml), water (5 ml) and brine (5 ml), dried and concentrated to give the title compound as a white solid (0.941 g; ˜quantitative yield). Got. NMR (400 MHz) 2.25-2.45 (m, 2H), 3.20-3.30 (m, 1H), 4.00-4.20 (m, 2H), 4.65 (s, 2H), 4.80 (d, 1H), 6.75-6.80 ( m, 2H), 6.85-7.00 (m, 6H), 7.20-7.30 (m, 4H); m / z: 454.0.

Method 9

3- (R) -4- (R) -1- (phenyl) -3- (phenylethylsulfanyl) -4- [4- (carboxymethoxy) phenyl] azetidin-2-one

3- (R) -4- (R) -1- (phenyl) -3- (phenylethylsulfanyl) -4- [4- (t-butoxycarbonylmethoxy) phenyl] azetidin-2-one (Method 15; 220 mg) was stirred in formic acid (2 ml) at room temperature for 20 hours. The formic acid was then evaporated. Toluene was added and evaporated to afford the title compound (180 mg). NMR (400 MHz, CD ₃ 0D): 2.86-3.00 (m, 4H), 4.03 (d, 1H), 4.66 (s, 2H), 4.87 (d, 1H), 6.93-7.35 (m, 14H).

Method 10

3- (R) -4- (R) -1- (phenyl) -3- (4-fluorobenzoylmethylsulfanyl) -4- [4- (carboxymethoxy) phenyl] azetidin-2-one

3- (R) -4- (R) -1- (phenyl) -3- (4-fluorobenzoylmethylsulfanyl) -4- (4-hydroxyphenyl) azetidine-2 in MeCN (0.5 ml) -On (prepared according to WO 96/16037; 0.100 g, 0.245 mmol), calcium carbonate (0.040 g, 0.123 mmol) and t-butyl bromoacetate (0.019 ml, 0.129 mmol) solution at room temperature for 10 minutes It was. Then calcium carbonate (0.040 g, 0.123 mmol) and t-butyl bromoacetate (0.019 ml, 0.129 mmol) were further added. After 7 hours, water (5 ml) and AcOH (0.05 ml) were added to the reaction mixture and the organic solvent was removed under reduced pressure. The aqueous layer was washed twice with DCM (2 × 5 ml) and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography using heptane: EtOAc (3: 1) as eluent to afford a colorless oily substance (0.066 g). M / z: 522.1. This oily substance was dissolved in formic acid (3 ml) and the solution was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC using 20% -50% MeCN gradient in 0.1 M ammonium acetate buffer as eluent. The title compound was obtained as a white solid (0.025 g; 22%). NMR (CD ₃ COOD, 400 MHz) 4.20 (d, 1H), 4.25 (s, 2H), 4.70 (s, 2H), 5.00 (d, 1H), 6.90-7.10 (m, 2H), 7.00-7.40 ( m, 9H), 8.00-8.10 (m, 2H); m / z: 465.9.

Method 11

3- (R) -4- (R) -1- (phenyl) -3- (thien-3-ylcarbonylmethylsulfanyl) -4- [4- (carboxymethoxy) phenyl] azetidine-2- On

3- (R) -4- (R) -1- (phenyl) -3- (thien-3-ylcarbonylmethylsulfanyl) -4- (4-hydroxyphenyl) azetidine in MeCN (6 ml) A 2-one (prepared according to WO 96/16037; 0.100 g, 0.253 mmol), calcium carbonate (0.043 g, 0.132 mmol) and t-butyl bromoacetate (0.019 ml, 0.126 mmol) solution for 10 minutes at room temperature Was stirred and then calcium carbonate (0.040 g, 0.123 mmol) and t-butyl bromoacetate (0.019 ml, 0.126 mmol) were added. After 7 hours, water (7 ml) and AcOH (0.05 ml) were added and the solvent was prepared under reduced pressure. The aqueous layer was extracted twice with DCM (2 × 3 ml) and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography using heptane: EtOAc (3: 1) as eluent to afford 0.103 g of a colorless oily substance (m / z: 510.1). This oily substance was dissolved in formic acid (3 ml) and the solution was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The solution was washed twice with water, once with brine, dried over magnesium sulfate and concentrated. This procedure gave a colorless oily substance (0.079 g) that did not require further purification. M / z: 453.9.

Method 12

1- (4-fluorophenyl) -3- (2-chloroethyl) -4- (4-hydroxyphenyl) azetidin-2-one

1- (4-fluorophenyl) -3- (2-chloroethyl) -4- [4- (benzyloxy) phenyl] azetidin-2-one in MeOH (60 ml) (Bioorg. Med. Chem. Lett Prepared according to 1996, 6, 1271-1274; a stirred mixture of 2.00 g, 4.88 mmol), Pd (OH) _{2 /} C (0.500 g, 20%) and cyclohexane (6 ml) was heated to 70 ° C. After 2 hours, the reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The solvent was removed under reduced pressure to afford the title compound (1.57 g; quantitative yield). No further purification was necessary. NMR (CD ₃ 0D, 400 MHz) 2.20-2.40 (m, 2H), 3.20-3.40 (m, 1H), 3.70 (t, 2H), 4.85 (d, 1H), 6.75-6.80 (m, 2H), 6.90-7.00 (m, 2 H), 7.15-7.30 (m, 4 H); m / z: 320.0.

Method 13

1- (4-fluorophenyl) -3- [2- (4-fluorophenylthio) ethyl] -4- (4-hydroxyphenyl) azetidin-2-one

1- (4-fluorophenyl) -3- (2-chloroethyl) -4- (4-hydroxyphenyl) azetidin-2-one in MeCN (10 ml) at room temperature (Method 12; 0.750 g, 2.35 mmol) to the stirred solution was added 4-fluorothiophenol (0.500 ml, 4.60 mmol) and triethylamine (0.500 ml, 3.59 mmol). After 20 hours, the starting material still remained (about 20%, LC / MS), further 4-fluorothiophenol (0.250 ml, 2.30 mmol) and triethylamine (0.170 ml, 1.22 mmol) were added. After 24 hours, the solvent was removed under reduced pressure and the residue was partitioned between water (20 ml) and EtOAc (20 ml). The organic layer was washed with brine (5 ml), dried over magnesium sulfate and concentrated. The residue was refluxed in heptane for 30 minutes, then the title compound was filtered off as a gray solid (0.946 g; 98%). NMR (CD ₃ 0D, 400 MHz) 2.00-2.20 (m, 2H), 3.05 (t, 2H), 3.25 (dt, 1H), 4.75 (d, 1H), 6.75-6.80 (m, 2H), 6.90- 7.05 (m, 4 H), 7.15-7.40 (m, 6 H); m / z: 412.0.

Method 14

tert-butyl (2S) -2-{[(2R) -2-amino-2- (4-hydroxyphenyl) acetyl] amino} butanoate hydrochloride

tert-butyl (2S) -2-{[(2R) -2-{[(benzyloxy) carbonyl] amino} -2- (4-hydroxyphenyl) acetyl] amino} butanoate (methods 18, 47 g, 106.2 mmol) was dissolved in 95.5% ethanol (400 ml). Pd / C (5%, 3.0 g) was added and the mixture was hydrogenated under H ₂ (g) at 1 bar pressure at room temperature. Hydrogenation was terminated after 20 hours and the catalyst was filtered over SiO ₂ and washed with ethanol. The filtrate was concentrated and the residue (about 35 g) was dissolved in MeCN (300 ml). Pyridine hydrochloride (14 g) was added and the mixture left to crystallize for 2.5 days. The salt formed was filtered off and washed with MeCN (2 × 50 ml). The solid was dried under vacuum at 40 ° C. to give 29.6 g (81%) of a white crystalline solid. NMR (300 MHz, DMSO-d ₆ ): 0.64 (t, 3H), 1.39 (s, 9H), 1.40-1.70 (m, 2H), 3.98-4.04 (m, 1H), 4.90 (brs, 1H), 6.78 (d, 2H), 7.32 (d, 2H), 8.63 (brs, 3H), 8.79 (d, 1H), 9.83 (brs, 1H).

Method 15

3- (R) -4- (R) -1- (phenyl) -3- (phenylethylsulfanyl) -4- [4- (t-butoxycarbonylmethoxy) phenyl] azetidin-2-one

3- (R) -4- (R) -1- (phenyl) -3- (phenylethylsulfanyl) -4- (4-hydroxyphenyl) azetidin-2-one (in WO 96/16037) in MeCN A mixture of 0.5 g, 1.33 mmol), t-butyl bromoacetate (0.31 g, 1.58 mmol), sodium carbonate (0.56 g, 5.28 mmol) and cesium carbonate (0.12 g, 0.36 mmol) overnight at 50 ° C. Stirred. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using (EtOAc: isohexane, 1: 6) as eluent to afford 220 mg (33%) of the title compound. M / z 490.1.

Method 16

1- (4-fluorophenyl) -3- [2- (4-fluorophenylthio) ethyl] -4- [4- (t-butoxycarbonylmethoxy) phenyl] azetidin-2-one

1- (4-fluorophenyl) -3- [2- (4-fluorophenylthio) ethyl] -4- (4-hydroxyphenyl) azetidin-2-one in MeCN (15 ml) (Method 13 0.800 g, 1.944 mmol), t-butyl bromoacetate (0.32 ml, 2.17 mmol) and calcium carbonate (0.700 g, 2.15 mmol) suspension were stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between water (20 ml) and DCM (20 ml). The aqueous layer was extracted one or more times with DCM (10 ml) and the combined organic layers were washed with brine and dried over magnesium sulfate. The residue was purified by flash chromatography using heptane: EtOAc (4: 1) as eluent. The title compound was obtained as a colorless oily substance (0.884 g; 87%). NMR (400 MHz) 1.45 (s, 9H), 2.00-2.30 (m, 2H), 2.90-3.10 (m, 2H), 3.15-3.25 (m, 1H), 4.50 (s, 2H), 4.60 (d, 1H), 6.85-7.00 (m, 6H), 7.15-7.35 (m, 6H); m / z: 526.2.

Method 17

1- (4-fluorophenyl) -3- [2- (4-fluorophenylthio) ethyl] -4- [4- (carboxymethoxy) phenyl] azetidin-2-one

1- (4-fluorophenyl) -3- [2- (4-fluorophenylthio) ethyl] -4- [4- (t-butoxycarbonylmethoxy) phenyl] ase in formic acid (5 ml) Tidin-2-one (method 16; 0.880 g, 1.67 mmol) solution was stirred at rt for 19 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM (25 ml). The organic phase was washed twice with water (1 × 10 ml and 1 × 5 ml), once with brine (5 ml), dried over magnesium sulfate and concentrated. The colorless oily substance (0.800 g; quantitative yield) was obtained through the above process. NMR (CD ₃ COOD, 400 MHz) 2.10-2.30 (m, 2H), 3.10 (dt, 2H), 3.30-3.40 (m, 1H), 4.75 (s, 2H), 4.80 (d, 1H), 6.95- 7.05 (m, 6 H), 7.25-7.40 (m, 6 H); m / z: 470.2.

Method 18

tert-butyl (2S) -2-{[(2R) -2- (benzyloxy) carbonyl] amino} -2- (4-hydroxyphenyl) acetyl] amino} butanoate

(R) -N-benzyloxycarbonyl-4-hydroxyphenylglycine (J. Chem. Soc. Perkin Trans. 1, EN, 7,1991, 1629-1635; 24.9 g, 82.6 mmol), (S)- 2-Aminobutyric acid t-butyl ester hydrochloride (18.6 g, 95.0 mmol) and N-methylmorpholine (23.0 g, 227.4 mmol) were dissolved in 220 ml of DMF. TBTU (33.7 g, 105.0 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 1 hour. About 100 ml of solvent were evaporated from the solution. Water (250 ml) was added to the residual solution to precipitate the product. After the mixture was left overnight, the solid was filtered off and washed with 30% methanol (200 ml) and hexane (100 ml). The solid was dissolved in 100 ml of t-butyl methyl ether and stirred for 1 hour. The solid was filtered off, washed with t-butyl methyl ether (100 ml) and dried under vacuum at 40 ° C. to give 34.7 g (95%) of the title compound. NMR (300 MHz, DMSO-d ₆ ): 0.71 (t, 3H), 1.37 (s, 9H), 1.40-1.70 (m, 2H), 3.91-4.01 (m, 1H), 5.02 (d, 2H), 5.23 (d, 1H), 6.67 (d, 2H), 7.22 (d, 2H), 7.27-7.36 (m, 5H), 7.67-7.74 (m, 1H), 8.32 (d, 1H), 9.37 (brs, 1H).

Claims (36)

A compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof: Where Ring A is selected from phenyl or thienyl; X is -CR ² R ³ - is selected from, -O-, -NR ^x - -, and -S (O) _a; Then R ^x is hydrogen or C _1-6 alkyl and a is 0-2; Y is -CR ⁴ R ⁵ - is selected from, -O-, -NR ^z - -, and -S (O) _a; Then R ^z is hydrogen or C _1-6 alkyl and a is 0-2; Then there is at least one -CR ² R ³ -or -CR ⁴ R ⁵ -group; R ¹ is independently selected from halo, hydroxy, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylS (O) _a , wherein a is 0-2; Then R ¹ is independently optionally substituted on carbon by one or more halo, C _1-6 alkoxy and hydroxy; b is 0 to 3; The value of R ¹ may be the same or different; R ² and R ³ are independently selected from hydrogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkanoyloxy; Wherein R ² and R ³ may be optionally substituted independently on carbon by one or more halo or hydroxy; Or R ² and R ³ together form an oxo group; R ⁴ and R ⁵ are independently selected from hydrogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkanoyloxy; Or R ⁴ and R ⁵ together form an oxo group; R ⁶ is independently halo, nitro, cyano, hydroxy, amino, carboxy, formyl, carbamoyl, carbamoyloxy, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkenyloxy, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N -(C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino, C _1-6 alkanoyl-N- (C _1-6 alkyl) amino, C _1-6 alkylsulfonylamino, C _1-6 Alkylsulfonyl-N- (C _1-6 alkyl) amino, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, N- (C _{1- 6} alkyl) carbamoyloxy, N, N- (C _1-6 alkyl) ₂ carbamoyloxy, C _1-6 alkylS (O) _a [where a is 0 to 2], C _1-6 Alkoxycarbonyl, C _1-6 alkoxycarbonylamino, C _1-6 alkoxycarbonyl-N- (C _1-6 alkyl) amino, C _1-6 alkoxycarbonyloxy, C _1-6 alkoxycarbonylamino, Ureido, N '-(C _1-6 alkyl) ureido, N- (C _1-6 alkyl) ureido, N', N '-(C _{1- 6} alkyl) ₂ ureido, N '-(C _1-6 alkyl) -N- (C _1-6 alkyl) ureido, N', N '-(C _1-6 alkyl) ₂ -N- (C _{1 -6} alkyl) ureido, N- (C _1-6 alkyl) sulfamoyl, N, N- (C _1-6 alkyl) ₂ sulfamoyl and phenyl; Wherein R ⁷ is independently one or more halo, C _1-6 alkoxy, hydroxy, amino, carboxy, C _1-6 alkoxycarbonyl, carbamoyl, N- (C _1-6 alkyl) carbamoyl on carbon , N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkanoylamino, C _1-6 alkanoyl-N- (C _1-6 alkyl) amino, phenyl, phenoxy, benzoyl, Optionally substituted by _{phenylC 1-6} alkyl and phenylC _1-6 alkoxy; c is 0-5; ^Wherein the value of R ⁶ may be the same or different; R ⁷ is independently halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, Methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N, N- Dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl; d is 0-4; ^Wherein the value of R ⁷ may be the same or different; R ⁹ is hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Then R ⁹ may be optionally substituted on carbon by one or more substituents selected from R ²³ ; When the heterocyclyl comprises an —NH— group, the nitrogen may be optionally substituted with a group selected from R ²⁴ ; R ¹⁰ is hydrogen or C _1-4 alkyl; R ¹¹ and R ¹² are independently selected from hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Or R ¹¹ and R ¹² together form C _2-6 alkylene; R ¹¹ and R ¹² or R ¹¹ and R ¹² together may be optionally substituted on carbon independently with one or more substituents selected from R ²⁵ ; When the heterocyclyl comprises an —NH— moiety that nitrogen may be optionally substituted by one or more R ²⁶ ; R ¹³ is hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; Then R ¹³ may be optionally substituted on carbon by one or more substituents selected from R ²⁷ ; When the heterocyclyl comprises an —NH— moiety that nitrogen may be optionally substituted by one or more R ²⁸ ; R ¹⁴ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 Alkynyl, C _1-10 alkoxy, C _1-10 alkoxycarbonyl, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N- (C _1-10 alkyl) amino, N, N- (C _{1 -10} alkyl) ₂ amino, N, N, N- (C _1-10 alkyl) ₃ ammonio, C _1-10 alkanoylamino, N- (C _1-10 alkyl) carbamoyl, N, N- ( C _1-10 alkyl) ₂ carbamoyl, C _1-10 alkyl S (O) _a [where a is 0-2], N- (C _1-10 alkyl) sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfamoylamino, C _1-10 alkoxycarbonylamino, carbocyclyl , CarbocyclylC _1-10 alkyl, heterocyclyl, heterocyclylC _1-10 alkyl, carbocyclyl- (C _1-10 alkylene) _e -R ^29- (C _1-10 alkylene) _f- , heterocyclyl, - (C _1-10 alkylene) _g -R ³⁰ - (C _1-10 alkylene) _h -, carboxy, Four, Pinot sulfonic, ^{phosphono, -P (O) (OR 31} ) (OR 32), -P (O) (OH) (OR 31), -P (O) (OH) (R 31) , or -P (O) (OR ³¹ ) (R ³² ), wherein R ³¹ and R ³² are independently selected from C _1-6 alkyl; Then R ¹⁴ on carbon may be optionally substituted by one or more substituents selected from R ³³ ; If said heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ³⁴ ; Or R ¹⁴ is a group of formula (IA): Formula IA In the above formula, Z is ^{-N (R 35) -, -N} (R 35) C (O) -, -O-, and -S (O) _a - a; A is 0 to 2 and R ³⁵ is hydrogen or C _1-4 alkyl; R ¹⁵ is hydrogen or C _1-4 alkyl; R ¹⁶ and R ¹⁷ are independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkylS (O) _a [where a is 0 to 2], C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl, N, N- (C _1-6 alkyl) ₂ sulfamoyl, carbocyclyl, heterocyclyl , Sulfo, sulfino, amidino, phosphono, -P (O) (OR ³⁶ ) (OR ³⁷ ), -P (O) (OH) (OR ³⁶ ), -P (O) (OH) (R ³⁶ ) Or —P (O) (OR ³⁶ ) (R ³⁷ ), wherein R ³⁶ and R ³⁷ are independently selected from C _1-6 alkyl; Then R ¹⁶ and R ¹⁷ may be optionally substituted on carbon independently by one or more substituents selected from R ³⁸ ; When the heterocyclyl includes an —NH— group, that nitrogen may be optionally substituted by a group selected from R ³⁹ ; R ¹⁸ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 Alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N- (C _1-10 alkyl) amino, N, N- (C _1-10 alkyl) ₂ amino, C _1-10 alkanoylamino, N- (C _1-10 alkyl) carbamoyl, C _1-10 alkoxycarbonyl, N, N- (C _1-10 alkyl) ₂ carbamoyl, C _1-10 alkyl S (O) _a [where a is 0-2], N- (C _1-10 alkyl) sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl Sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfamoylamino, carbocyclyl, carbocyclylC _1-10 alkyl, heterocyclyl, heterocyclylC _1-10 alkyl, carbocyclyl -(C _1-10 alkylene) _e -R ^40- (C _1-10 alkylene) _f -or heterocyclyl- (C _1-10 alkylene) _g -R ^41- (C _1-10 alkylene) _h- , carboxy, sulfo, sulfino, phosphono, -P (O) (OR ⁴² ) (OR ⁴³ ), -P (O) (OH) (OR ⁴² ), -P (O) (OH) (R ⁴² ) or -P (O) (OR ⁴² ) (R ⁴³ ), wherein R ⁴² and R ⁴³ are independently selected from C _1-6 alkyl; ; Then R ¹⁸ may be optionally substituted on carbon by one or more substituents selected from R ⁴⁴ ; When the heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ⁴⁵ ; Or R ¹⁸ is a group of formula IB: Formula IB here, R ¹⁹ is selected from hydrogen or C _1-4 alkyl; R ²⁰ is hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alka Noylamino, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkyl S (O) _a [where a is 0 to 2 C _1-6 alkoxycarbonyl, N- (C _1-6 alkyl) sulfamoyl, N, N- (C _1-6 alkyl) ₂ sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino , Amidino, phosphono, -P (O) (OR ⁴⁶ ) (OR ⁴⁷ ), -P (O) (OH) (OR ⁴⁶ ), -P (O) (OH) (R ⁴⁶ ) or -P ( O) (OR ⁴⁶ ) (R ⁴⁷ ), wherein R ⁴⁶ and R ⁴⁷ are independently selected from C _1-6 alkyl; R ²⁰ may be independently substituted on carbon by one or more substituents selected from R ⁴⁸ ; When the heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ⁴⁹ ; R ²¹ is halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl , C _1-10 alkoxy, C _1-10 alkoxycarbonyl, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N- (C _1-10 alkyl) amino, N, N- (C _1-10 Alkyl) ₂ amino, N, N, N- (C _1-10 alkyl) ₃ ammonio, C _1-10 alkanoylamino, N- (C _1-10 alkyl) carbamoyl, N, N- (C _{1 -10} alkyl) ₂ carbamoyl, C _1-10 alkyl S (O) _a [where a is 0-2], N- (C _1-10 alkyl) sulfamoyl, N, N- (C _{1- 10} alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _1-10 alkyl) ₂ sulfamoylamino, C _1-10 alkoxycarbonylamino, carbocyclyl, carbo BocyclylC _1-10 alkyl, heterocyclyl, heterocyclylC _1-10 alkyl, carbocyclyl- (C _1-10 alkylene) _e -R ^50- (C _1-10 alkylene) _f- , hetero heterocyclyl - (C _1-10 alkylene) _g -R ⁵¹ - (C _1-10 alkylene) _h -, carboxy, sulfo, Pino, ^{phosphono, -P (O) (OR 52} ) (OR 53), -P (O) (OH) (OR 52), -P (O) (OH) (R 52) , or -P (O) (OR ⁵³ ) (R ⁵³ ), wherein R ⁵² and R ⁵³ are independently selected from C _1-6 alkyl; Then R ²¹ may be independently substituted by one or more R ⁵⁴ on carbon independently; When the heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ⁵⁵ ; p is 1-3; ^Wherein the value of R ¹⁶ may be the same or different; q is 0 to 1; r is 0 to 3; ^Wherein the value of R ¹⁷ may be the same or different; m is 0-2; ^Wherein the value of R ¹³ may be the same or different; n is 1 to 2; ^Wherein the value of R ⁹ may be the same or different; z is 0 to 3; ^Wherein the value of R ²⁰ may be the same or different; R ²³ , R ²⁵ , R ²⁷ , R ³³ , R ³⁸ , R ⁴⁴ , R ⁴⁸ and R ⁵⁴ are independently halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxy Aminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, C _1-10 alkoxy Carbonyl, N- (C _1-10 Alkyl) amino, N, N- (C _1-10 Alkyl) ₂ amino, N, N, N- (C _1-10 Alkyl) ₃ Ammonio, C _1-10 Alka Noylamino, N- (C _1-10 alkyl) carbamoyl, N, N- (C _1-10 alkyl) ₂ carbamoyl, C _{1-10 alkylS} (O) _a [where a is 0 to 2 L], N- (C _1-10 alkyl) sulfamoyl, N, N- (C _1-10 alkyl) ₂ sulfamoyl, N- (C _1-10 alkyl) sulfamoylamino, N, N- (C _{1 -10} alkyl) ₂ sulfamoylamino, C _1-10 alkoxycarbonylamino, carbocyclyl, carbocyclylC _1-10 alkyl, heterocyclyl, heterocyclylC _1-10 alkyl, carbocyclyl- (C _1-10 alkylene) _e -R ^56- (C _1-10 alkylene) _f- , heterocyclyl- (C _1-10 Alkylene) _g -R ^57- (C _1-10 alkylene) _h- , carboxy, sulfo, sulfino, amidino, phosphono, -P (O) (OR ⁵⁸ ) (OR ⁵⁹ ), -P (O ) (OH) (OR ⁵⁸ ), -P (O) (OH) (R ⁵⁸ ) or -P (O) (OR ⁵⁹ ) (R ⁵⁹ ) [where R ⁵⁸ and R ⁵⁹ are independently C _1-6 Selected from alkyl]; Wherein R ²³ , R ²⁵ , R ²⁷ , R ³³ , R ³⁸ , R ⁴⁴ , R ⁴⁸ and R ⁵⁴ may be optionally substituted independently on carbon with one or more R ⁶⁰ ; When the heterocyclyl comprises an —NH— group, that nitrogen may be optionally substituted by a group selected from R ⁶¹ ; R ²⁴ , R ²⁶ , R ²⁸ , R ³⁴ , R ³⁹ , R ⁴⁵ , R ⁴⁹ , R ⁵⁵ and R ⁶¹ are independently C _1-6 alkyl, C _1-6 alkanoyl, C _1-6 alkylsulfonyl, Sulfamoyl, N- (C _1-6 alkyl) sulfamoyl, N, N- (C _1-6 alkyl) ₂ sulfamoyl, C _1-6 alkoxycarbonyl, carbamoyl, N- (C _1-6 alkyl ) Carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, benzyl, phenethyl, benzoyl, phenylsulfonyl and phenyl; R ²⁹ , R ³⁰ , R ⁴⁰ , R ⁴¹ , R ⁵⁰ , R ⁵¹ , R ⁵⁶ and R ⁵⁷ are independently -O-, -NR ^62- , -S (O) _x , -NR ⁶² C (O) NR ^63- , -NR ⁶² C (S) NR ^63- , -OC (O) N = C-, -NR ⁶² C (O)-or -C (O) NR ^62- ; Then R ⁶² and R ⁶³ are independently selected from hydrogen or C _1-6 alkyl and x is 0-2; R ⁶⁰ is halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy , Ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N, N-dimethylcar Barmoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl; e, f, g and h are independently selected from 0-2. The compound of claim 1, wherein X is from -CH _2- , -CH (OH)-, -C (O)-, -O-, -S-, -S (O)-, and -S (0) _2- . A compound of formula (I) selected, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof. The compound of formula (I) according to claim 1 or 2, wherein Y is -CH _2- , -S- or -S (O)-, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof . The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, wherein R ¹ is halo. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, wherein b is 0-1. The compound of formula (I) according to any one of claims 1 to 5, wherein R ⁶ is halo, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof. 7. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, wherein c is 0-1. 8. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, according to any one of claims 1 to 7, wherein d is zero. The compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, according to any one of claims 1 to 8, wherein R ⁹ is hydrogen. ^10. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, according to any one of claims 1 to 9, wherein R ¹⁰ is hydrogen. The compound of claim 1, wherein R ¹¹ and R ¹² are independently selected from hydrogen, C _1-4 alkyl or carbocyclyl; Wherein R ¹¹ and R ¹² may be optionally substituted on carbon independently by one or more substituents selected from R ²⁵ ; Then R ²⁵ is selected from hydroxy, amino, carbamoyl, C _1-10 alkoxycarbonyl, C _1-10 alkoxycarbonylamino, carbocyclyl or carboxy; Wherein R ²⁵ may be optionally substituted on carbon by one or more R ⁶⁰ ; Wherein R ⁶⁰ is hydroxy, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof. 12. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, according to any one of claims 1 to 11, wherein R ¹³ is hydrogen. The method according to any one of claims 1 to 12, R ¹⁴ is hydroxy, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 alkoxycarbonyl, carboxy or sulfo; Then R ¹⁴ on carbon may be optionally substituted by one or more substituents selected from R ³³ ; Or R ¹⁴ is a group of formula (IA) (disclosed above): R ¹⁵ is hydrogen; R ¹⁶ and R ¹⁷ are independently selected from hydrogen, carboxy, C _1-6 alkyl or C _1-6 alkoxycarbonyl; R ¹⁸ is selected from hydroxy, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 alkoxycarbonyl, carboxy and sulfo; p is 1; q is 0; r is 0 or 1; m is 0 or 1; n is 1; R ³³ is hydroxy, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof. 14. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, according to any one of claims 1 to 13, wherein m is 0 or 1. The compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, according to any one of claims 1 to 14. Ring A is selected from phenyl or thienyl; X is selected from -CH _2- , -CH (OH)-, -C (O)-, -O-, -S-, -S (O)-and -S (0) _2- ; Y is -CH _2- , -S- or -S (O)-; R ¹ is fluoro; b is 0 to 1; R ⁶ is fluoro; c is 0 to 1; d is 0; R ⁹ is hydrogen; R ¹⁰ is hydrogen; One of R ¹¹ and R ¹² is hydrogen and the other is hydrogen, methyl, hydroxymethyl, 2-carbamoylethyl, 2- (ethoxycarbonyl) ethyl, 2-carboxyethyl, 4- (t-butoxy Carbonylamino) butyl, 4-aminobutyl, isobutyl, phenyl, 4-hydroxyphenyl and 4-hydroxybenzyl; R ¹³ is hydrogen; R ¹⁴ is hydroxy, pentyl, methoxy, ethoxycarbonyl, t-butoxycarbonyl, carboxy or sulfo; Then R ¹⁴ on carbon may be optionally substituted by one or more substituents selected from R ³³ ; Or R ¹⁴ is a group of formula (IA) (as disclosed above): wherein R ¹⁵ is hydrogen; R ¹⁶ and R ¹⁷ are independently selected from hydrogen, carboxy, C _1-6 alkyl and t-butoxycarbonyl; R ¹⁸ is selected from hydroxy, methyl, t-butoxy, ethoxycarbonyl, t-butoxycarbonyl, carboxy and sulfo; p is 1; q is 0; r is 0 or 1; m is 0 or 1; n is 1; R ³³ is hydroxy; (I) A compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof. 1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N-((R) -α- {N- (S )-[1- (carboxy) -2- (hydroxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one; 1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N-[(R) -α- (carboxy) benzyl] Carbamoylmethoxy} phenyl) azetidin-2-one; 1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N- (carboxymethyl) carbamoylmethoxy] phenyl} Azetidin-2-ones; 1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- (4- {N- [N- (carboxymethyl) carbamoylmethyl] Carbamoylmethoxy} phenyl) azetidin-2-one; 1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N- (2-hydroxyethyl) carbamoylmethoxy ] Phenyl} azetidin-2-one; 1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4- {4- [N- (2-methoxyethyl) carbamoylmethoxy ] Phenyl} azetidin-2-one; 3- (R) -4- (R) -1- (phenyl) -3- (4-fluorobenzoylmethylsulfanyl) -4- {4- [N- (carboxymethyl) carbamoylmethoxy] phenyl Azetidin-2-one; 3- (R) -4- (R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- {4- [N- (carboxy Methyl) carbamoylmethoxy] phenyl} azetidin-2-one; 3- (R) -4- (R) -1- (phenyl) -3- [2- (thien-3-yl) -2-hydroxyethylsulfanyl] -4- {4- [N- (carboxy Methyl) carbamoylmethoxy] phenyl} azetidin-2-one; 3- (R) -4- (R) -1- (phenyl) -3- [2- (thien-3-yl) -2-hydroxyethylsulfanyl] -4- {4- [N-(( R) -α- {N-[(S) -1- (carboxy) -2- (hydroxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one; 3- (R) -4- (R) -1- (phenyl) -3- (4-fluorobenzoylmethylsulfanyl) -4- (4- [N-((R) -α- {N- [ (S) -1- (carboxy) -2- (hydroxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one; and 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 A compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, selected from (I). A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, wherein Process 1) Reacting a compound of formula II with a compound of formula III: Process 2) Reacting an acid of formula IV or an activated derivative thereof with an amine of formula V: Process 3) R ¹⁴ is when the resulting compound of formula (I) of formula IA, step of R ¹⁴ is carboxy is to make the compound, or an activated derivative thereof of formula VI reacted with the amine of formula VI: Process 4) For compounds of formula (I) wherein R ¹⁴ is a group of formula (IA), Z is -N (R ³⁵ ) C (O)-and q is 1, an acid of formula (VII) or an activated derivative thereof is substituted with an amine of formula Reacting Process: Process 5) For compounds of formula I, wherein R ¹⁴ is a group of formula IA and R ¹⁸ is a group of formula IB, an acid of formula I, or an activated derivative thereof, wherein R ¹⁴ is a group of formula IA and R ¹⁸ is carboxy Reaction with amines: Process 6) Reacting a compound of formula X with a compound of formula XI: Process 7) For compounds of formula (I) wherein X is selected from -0-, -NR ^x -and -S (O) _a -wherein a is 0, reacting a compound of formula (XII) with a compound of formula (XIII) fair: Process 8) For compounds of formula (I) wherein X is selected from -O-, -NR ^x -and -S (O) _a -where a is 0, the process of reacting a compound of formula XIV with a compound of formula XV : Process 9) For compounds of formula (I) wherein Y is selected from -O-, -NR ^z -and -S (O) _a -where a is 0, the process of reacting a compound of formula XVI with a compound of formula XVII : Process 10) For compounds of formula I wherein Y is selected from -O-, -NR ^z -and -S (O) _a -wherein a is 0, the process of reacting a compound of formula XVIII with a compound of : Process 11) For compounds of formula (I) wherein X or Y is -S (O) _a -and a is 1 or 2, X or Y is -S (O) _a -and a is 0 (a is 1 or 2) For compounds of formula I) or a is 1 (for compounds of formula I wherein a is 2); After these processes, if necessary or if desired, i) 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 or prodrug of such salt; or iv) separating at least two enantiomers. Formula II Formula III Formula IV Formula V Formula VI Formula VII Formula VIII Formula IX Formula X Formula XI Formula XII Formula XIII Formula XIV Formula XV Formula XVI Formula XVII Formula XVIII Formula XIX [Wherein L is a substitutable group, The other variable is as defined in claim 1] A pharmaceutical composition comprising a compound of formula (I) of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, together with a pharmaceutically acceptable diluent or carrier. 17. A compound of formula I according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, for use in a method for the prophylaxis or treatment of warm blooded animals, including humans. 17. A compound of formula (I) of any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, for use as a medicament. 17. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or pros thereof, of any one of claims 1 to 16, in producing a cholesterol absorption inhibitory effect in warm blooded animals, including humans. Use of Drugs. 17. A method of treating a hyperlipidemic condition in a warm blooded animal, including a human, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof of any one of claims 1 to 16 Usage. 17. A compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, as claimed in any one of claims 1 to 16 in the manufacture of a medicament for use in producing a cholesterol absorption inhibitory effect in a warm blooded animal, including humans, Use of solvates or prodrugs of such salts. 17. A compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, as claimed in any one of claims 1 to 16, in the manufacture of a medicament for use in treating hyperlipidemic conditions in warm-blooded animals, including humans. Use of solvates or prodrugs of salts. A method for producing a cholesterol absorption inhibitory effect in a warm blooded animal, including a human, which requires the production of a cholesterol absorption inhibitory effect, comprising: the compound of formula (I) of any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvent thereof; A method comprising administering to the animal an effective amount of a cargo, solvate of such salt, or prodrug. A method of treating a hyperlipidemic condition in a warm blooded animal, including a human, in need of treatment of the hyperlipidemic condition, the method comprising: a compound of formula I of any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate thereof, A method comprising administering to said animal an effective amount of solvate or prodrug. The compound of formula (I) of any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof, and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt thereof. , Solvates, combinations of solvates or prodrugs of such salts. The method of claim 28, wherein the HMG Co-A reductase inhibitor is fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, vervastatin, dalvastatin, pivastatin, mevastatin and rosuvastatin, or a thereof Combinations selected from pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts. A pharmaceutical composition comprising the combination of claims 28 or 29 together with a pharmaceutically acceptable diluent or carrier. Use of the combination of claims 28 or 29 in producing cholesterol lowering effects in warm blooded animals, including humans. Use of the combination of claims 28 or 29 in the treatment of hyperlipidemic conditions in warm-blooded animals, including humans. 30. Use of the combination of claims 28 or 29 in the manufacture of a medicament for use in producing a cholesterol lowering effect. Use of the combination of claims 28 or 29 in the manufacture of a medicament for use in the treatment of a hyperlipidemic condition. A method for producing a cholesterol absorption inhibitory effect in a warm blooded animal, including a human being, which requires the production of a cholesterol absorption inhibitory effect, the method comprising administering to the animal an effective amount of the combination of claim 28 or 29. A method of treating a hyperlipidemic condition in a warm blooded animal, including a human, in need thereof, comprising administering to said animal an effective amount of the combination of claims 28 or 29.