WO2007136696A2 - Use of substituted azetidinone compounds with cetp inhibitors for the treatment of sitosterolemia - Google Patents

Abstract

The present invention is directed to pharmaceutical compositions comprising a sterol absorption inhibitor, a CETP inhibitor, which may further comprise an HMG-CoA reductase inhibitor as well as methods for treating sitosterolemia, hypercholesterolemia, hyperlipidemia, atherosclerosis, mixed dyslopidemia, vascular events prevention and related disorders in a mammal in need thereof by administering said pharmaceutical compositions to the mammal.

Description

USE OF SUBSTITUTED AZET.DINONE COMPOUNDS FOR THE TREATMENT OF SITOSTEROLEMIA

FIELD OF THE INVENTION

The present invention provides methods and pharmaceutical compositions for treating or preventing sitosterolemia, hypercholesterolemia (primary & mixed), hyperiipidemia, atherosclerosis and related diseases by administering to a mammal in need of such treatment an effective amount of at least one treatment composition comprising at least one sterol absorption inhibitor and optionally, an effective amount of at least one bile acid sequestrant or other lipid lowering agent.

BACKGROUND OF THE INVENTION

Sitosterolemia is a genetic lipid storage disorder, characterized by increased levels of sitosterol and other plant sterols in the plasma and other tissues, due to an increased nonselective intestinal absorption of sterols and decreased hepatic removal. Individuals having sitosterolemia can exhibit tendon and tuberous xanthomas, arthritis, hemolytic eposodes, accelerated atherosclerosis, myocardial infarctions, and die at an early age due to extensive coronary atherosclerosis. See Nguyen et al., "Regulation of cholesterol biosynthesis in sitosterolemia: effects of lovastatin. cholestyramine, and dietary sterol restriction". VoI 32, Journal of Lipid Research, pp. 1941-1948, (1991).

Sitosterolemia can be treated with bile acid sequestrants (such as cholestyramine, co/esevelam hydrochloride and colestipol), however, these compounds have a tendency to cause constipation in patients and therefore compliance with this treatment is difficult. Bile acid sequestrants (insoluble anion exchange resins) bind bile acids in the intestine, interrupting the enterohepatic circulation of bile acids and causing an increase in the fecal excretion of steroids. Use of bile acid sequestrants is desirable because of their non-systemic mode of action. Bile acid sequestrants can lower intrahepatic cholesterol and promote the synthesis of apo B/E (LDL) receptors which bind LDL from plasma to further reduce cholesterol levels in the blood.

Alternative treatments include ileal bypass surgery and selective low density lipoprotein plasmapheresis, which are physically undesirable for the patient.

An improved treatment and related disorders for sitosterolemia is needed which can reduce the concentration of sterols in plasma and tissues, and inhibit associated debilitating physical effects. Such a contribution is provided by this invention.

SUMMARY OF THE INVENTION

The present invention is directed to a method of treating or preventing sitosterolemia comprising administering to a mammal in need of such treatment an effective amount (i.e. a therapeutically effective amount) of at least one sterol absorption inhibiting compound or a prodrug or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to a method of treating or preventing sitosterolemia, comprising administering to a mammal in need of such treatment (i.e. a sitosterolemic mammal), an effective amount of at least one sterol absorption inhibitor in combination with an effective amount of at least one bile acid sequestrant or other lipid lowering agent.

In yet another embodiment, the present invention is directed to a method of treating or preventing sitosterolemia comprising administering to a mammal in need of such treatment an effective amount of at least one sterol absorption inhibiting compound, e.g., substituted azetidinone compounds further described herein below, in combination with at least one bile acid sequestrant such as, for example, cholestyramine, colesevelam hydrochloride and colestipol and/or at least one cholesteryl ester transfer protein (CETP) inhibitor or a prodrug or pharmaceutically acceptable salt thereof In still another embodiment, the present invention is directed to a method of treating or preventing sitosterolemia, hyperlipidemia, hypercholesterolemia, mixed dyslipidemia and vascular events prevention comprising administering to a mammal in need of such treatment an effective amount of at least one sterol absorption inhibiting compound, e.g., substituted azetidinone compounds further described herein below, in combination with at least one sterol biosynthesis inhibitor, e.g., a HMG COA Reductase Inhibitor such as, for example, lovastatin, pravastatin, simvastatin, atorvastatin and the like.

Other embodiments of the present invention include pharmaceutical compositions for the treatment or prevention of sitosterolemia, comprising an effective amount of the compositions or combinations used in the methods described above, in a pharmaceutically acceptable carrier.

Another embodiment of this invention is pharmaceutical compositions comprising at least one absorption inhibiting compound or a prodrug or a pharmaceutically acceptable salt thereof and at least one cholesteryl ester transfer protein (CETP) inhibitor or a prodrug or pharmaceutically acceptable salt thereof.

Another embodiment of this invention is the use of pharmaceutical compositions comprising at least one absorption inhibiting compound or a prodrug or a pharmaceutically acceptable salt thereof and at least one CETP inhibitor or a prodrug or pharmaceutically acceptable salt thereof for the treatment or prevention of sitosterolemia, hyperlipidemia, hypercholesterolemia, mixed dyslipidemia and vascular events prevention.

Another embodiment of the present invention is a method of reducing plasma and tissue concentration of at least one sterol selected from the group consisting of phytosterols, 5α-stanols, and mixtures thereof, as well as cholesterol, comprising administering to a mammal in need of such treatment an effective amount of at least one treatment composition comprising at least one sterol absorption inhibitor and optionally at least one CETP inhibitor.

Yet another embodiment of the present invention is a method of reducing plasma and tissue concentration of at least one sterol selected from the group consisting of phytosterols, 5α-stanols and mixtures thereof, as well as cholesterol, WO 2007/136696

comprising administering to a mammal in need of such treatment an effective amount of at least one treatment composition comprising at least one sterol absorption inhibitor and optionally at least one CETP inhibitor.

DETAILED DESCRIPTION

The present invention provides methods, pharmaceutical compositions and combinations for treating or preventing sitosterolemia. Useful treatment compositions comprise one or more sterol absorption inhibitors represented by Formulas (I-XI) shown below.

In one embodiment one or more sterol absorption inhibitors useful in the methods, compositions or combinations of this invention are represented by Formula (I):

Ar¹-A-Y_q-C-Z_pχ Ar^d

■ o

R⁴

-N

Cf "Ar²

(I)

or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (I) or of the isomers thereof, or prodrugs of the compounds of Formula (I) or of the isomers, salts or solvates thereof, wherein:

Ar¹ is R³-substituted aryl; Ar^ is R^-substituted aryl;

Ar³ is R⁵-substituted aryl;

Y and Z are independently selected from the group consisting of -CH2-, - CH(lower alkyl)- and -C(dilower alkyl)-; A is -O-, -S-, -S(O)- or -S(0)2-;

R¹ is selected from the group consisting of -OR⁶. -O(CO)R⁶, -0(CO)OR⁹ and - 0(CO)NR⁶R⁷; R² is selected from the group consisting of hydrogen, lower alkyl and aryl; or R¹ and R² together are =O; q is 1 , 2 or 3; p is O, 1 , 2, 3 or 4;

R5 is 1-3 substituents independently selected from the group consisting of - OR⁶, -O(CO)R⁶, -0(CO)OR⁹, -O(CH2)1-5OR⁹, -0(CO)NR⁶R⁷, -NR⁶R⁷, - NR⁶(CO)R⁷, -NR⁶(CO)OR9, -NR⁶(CO)NR⁷R⁸. -NR⁶Sθ2-lower alkyl, -NR⁶Sθ2-aryl, -CONR⁶R⁷, -COR⁶. -SO2NR⁶R⁷, S(O)0-2-alkyl, S(O)0-2-aryl, -0(CH2)1-10- COOR⁶,-O(CH2)1-1 OCONR⁶R⁷, o-halogeno, m-halogeno, o-lower alkyl, m-lower alkyl, -(lower alkylene)-COOR⁶, and -CH=CH-COOR⁶;

R3 and R4 are independently 1-3 substituents independently selected from the group consisting of R^, hydrogen, p-lower alkyl, aryl, -NO2, -CF3 and p-halogeno;

R⁶, R⁷ and Rβ are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl.

Preferred are compounds of formula I wherein Ar^ is R^-substituted phenyl, especially (4-R³)-substituted phenyl. Ar² is preferably R^-substituted phenyl, especially (4-R⁴)-substituted phenyl. Ar³ is preferably R⁵-substituted phenyl, especially (4-R⁵)-substituted phenyl. Mono-substitution of each of Ar¹, Ar² and Ar³ is preferred.

Y and Z are each preferably -CH2-. R² is preferably hydrogen. R1 is preferably -OR⁶ wherein R⁶ is hydrogen, or a group readily metabolizabfe to a hydroxyl (such as -O(CO)R⁶, -0(CO)OR⁹ and -0(CO)NR⁶R⁷, defined above). Also preferred are compounds wherein R¹ and R² together are =O. WO 2007/136696

The sum of q and p is preferably 1 or 2, more preferably 1. Preferred are compounds wherein p is zero and q is 1. More preferred are compounds wherein p is zero, q is 1, Y is -CH2- and R¹ is -OR*⁵, especially when R⁶ is hydrogen.

Another group of preferred compounds is that wherein Ar^ is R³-substituted phenyl, Ar² is R⁴-substituted phenyl and Ar³ is R⁵-substituted phenyl.

Also preferred are compounds wherein Ar-* is R³-substituted phenyl, Ar² is R⁴- substituted phenyl, Ar³ is R⁵-substituted phenyl, and the sum of p and q is 1 or 2, especially 1. More preferred are compounds wherein Ar-I is R³-substituted phenyl, Ar² is R⁴-substituted phenyl, Ar³ is R^-substituted phenyl, p is zero and q is 1.

A is preferably -O-.

R³ is preferably -COOR⁶, -CONR⁶R⁷, -COR⁶, -Sθ2NR⁶R⁷, S(O)0-2-alkyl,

S(0)o-2-ary'» NO2 or halogeno. A more preferred definition for R³ is halogeno, especially fluoro or chloro.

R⁴ is preferably hydrogen, lower alkyl, -OR⁶, -O(CO)R⁶, -O(CO)OR⁹, - 0(CO)NR⁶R⁷, -NR⁶R⁷, COR⁶ or halogeno, wherein R⁶ and R⁷ are preferably independently hydrogen or lower alkyl, and R⁹ is preferably lower alkyl. A more preferred definition for R⁴ is hydrogen or halogeno, especially fluoro or chloro.

R5 is preferably -OR⁶, -O(CO)R⁶, -0(CO)OR⁹, -0(CO)NR⁶R⁷, -NR⁶R⁷, - (lower alkyleπe)-COOR⁶ or -CH=CH-COOR⁶, wherein R⁶ and R⁷ are preferably independently hydrogen or lower alkyl, and R⁹ is preferably lower alkyl. A more preferred definition for R⁵ is -OR⁶, -(lower alkylene)-COOR⁶ or -CH=CH-COOR⁶, wherein R⁶ is preferably hydrogen or lower alkyl, is useful in the treatment of sitosterolemia.

In another embodiment, one or more sterol absorption inhibitors useful in the methods, compositions or combinations of this invention are represented by Formula (II): WO 2007/136696

(H)

or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (II) or of the isomers thereof, or prodrugs of the compounds of Formula (II) or of the isomers, safts or solvates thereof, wherein:

A is selected from the group consisting of R^-substituted heterocycloalkyl, R^- substituted heteroaryl, R2-substituted benzofused heterocycloalkyl, and R2- substituted benzofused heteroaryl;

Ar^"! is aryl or R^-substituted aryl; Ar² is aryl or R⁴-substituted aryl;

Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the V— (R⁶)_a

/_R7\l I spiro group . ^b •; and

R^"! is selected from the group consisting of

~(CH2)q-, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1 ;

-(CH2)e-G-(CH2)r, wherein G is -O-, -C(O)-, phenylene. -NR⁸- or - S(O)o-2- e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;

-(C2-C-6 alkenylene)-; and

-(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0- 5, provided that the sum of f and g is 1-6; Rδ is WO 2007/136696

8

-CH-, -C(C₁-C₆ alkyl)-, -CF-, -C(OH)-, -C(C₆H₄-R⁹), -N-. or -⁺NO^" ;

Rβ and R^ are independently selected from the group consisting of -CH2-, - CH(C 1-C6 alkyl)-, -C(di-(Ci-C6) alkyl), -CH=CH- and -C(Ci-Cβ alkyl)=CH-; or R⁵ together with an adjacent R⁶, or R⁵ together with an adjacent R?, form a -CH=CH- or a -CH=C(Ci -Ce alkyl)- group; a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided that when R⁶ is -CH=CH- or -C(Ci -Ce alkyl)=CH-, a is 1; provided that when R⁷ is - CH=CH- or -C(Ci-C6 alkyl)=CH-, b is 1 ; provided that when a is 2 or 3, the R⁶'s can be the same or different; and provided that when b is 2 or 3, the R^'s can be the same or different; and when Q is a bond, R^ also can be:

R 10 R 12 »10 _R10

-M -Y_d-C-Z_h- , -X_m-(C)_s-Y_n-(C)_t-Z_p- or -X_r(C)_v-Y_k-S(O)₀.₂-; R¹¹ R¹³ ^11 RH

M is -O-, -S-, -S(O)- or -S(O)2-;

X, Y and Z are independently selected from the group consisting of -CH2-, - CH(Ci -C6 alkyl)- and -C(di-(Ci-Cβ) alkyl);

R1° and R12 are independently selected from the group consisting of -OR¹⁴, - 0(CO)R^₁ -O(CO)OR¹6 and -O(CO)NR¹4R15_; R1 1 and R13 _are independently selected from the group consisting of hydrogen, (Ci~C6)alkyl and aryl; or R^O and

R^{1 1} together are =O, or R¹2 and R¹³ together are =O; d is 1 , 2 or 3; h is O₁ 1, 2, 3 or 4; s is 0 or 1 ; t is 0 or 1 ; m, n and p are independently 0-4; provided that at least one of s and t is 1 , and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1 , the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1 , the sum of m, t and n is 1-5; WO 2007/136696

v is 0 or 1 ; j and k are independently 1-5, provided that the sum of j, k and v is 1-5;

R2 is 1-3 substituents on the ring carbon atoms selected from the group consisting of hydrogen, (Ci-C-io)a'kyl, (C2-Cio)alkenyl, (C2-Cio)alkynyl, (C3-

C6)cycloalkyl, (C3-C6)cycloalkenyl, R^-substituted aryl, R ^-substituted benzyl, Ri7-substituted benzyloxy, Ri7-substituted aryloxy, halogeno, -NR-I⁴R¹⁵, _NR14_R15(_C1-C6 alkylene)-, NR14R15C(O)(CI-C6 alkylene)-,-NHC(O)Ri6, OH, Ci- C6 alkoxy, -OC(O)Ri⁶, -CORI⁴, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, NO2, -S(O)o-2R¹⁶. -SO2NR14R15 _aπd .(C1-C6 alkyleπe)COORi⁴; when R2 is a

0 — ^

I (CH2)i-2

U₀' substituent on a heterocycloalkyl ring, R2 is as defined, or is =O or ; and, where R² is a substituent on a substitutable ring nitrogen, it is hydrogen, (C -j- C6)alkyl, aryl, (Ci-C6)alkoxy, aryloxy, (C-)-C6)alkylcarbonyl. arylcarbonyl, hydroxy, - (CH2)1-6CONR¹⁸R¹⁸,

;j ^or

(CH2)o-4 ^

wherein J is -O-, -NH-, -NR¹⁸- or -CH2-;

R^ and R⁴ are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (Ci-C6)alkyl, -OR ^⁴, -O(CO)R1⁴, -O(CO)OR16, -O(CH2)1-5OR1⁴, -0(CO)NRi⁴RiS, -NR1⁴R15 - NR1⁴(CO)R15, -NR¹⁴(CO)OR16, -NR1⁴(CO)NR15R19, -NR1⁴SO2R1⁶, -COOR1⁴, - CONRi⁴RiS₁ -COR1⁴, -SO2NR1⁴R15, S(O)θ-2R¹⁶, -O(CH2)1-10-COOR1⁴,

-O(CH2)1-10CONR1⁴R1⁵, -(C1-C6 alkylene)-COORi⁴, -CH=CH-COORi⁴, -CF3, - CN, -NO2 and halogen; WO 2007/136696

10

R⁸ is hydrogen, (Ci-C6)alkyl, aryl (Ci-C6)alkyl, -C(O)R¹⁴ or -COOR¹⁴;

R9 and R¹⁷ are independently 1-3 groups independently selected from the group consisting of hydrogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, -COOH, NO2, -NR¹⁴R¹⁵, OH and halogeπo;

R¹⁴ and R¹5 are independently selected from the group consisting of hydrogen, (Ci-C6)alkyl, aryl and aryl-substituted (Ci-C6)alkyl;

R¹6 is (Ci-C6)alkyl, aryl or R¹⁷-substituted aryl;

R¹^ is hydrogen or (Ci-C6)alkyl; and

R¹9 is hydrogen, hydroxy or (Ci-Cβ)alkoxy.

As used in Formula (II) above, "A" is preferably an R2-substituted, 6- membered heterocycloalkyl ring containing 1 or 2 nitrogen atoms. Preferred heterocycloaJkyl rings are piperidinyl, piperazinyl and morpholinyl groups. The ring

"A" is preferably joined to the phenyl ring through a ring nitrogen. Preferred R2 substituents are hydrogen and lower alky!. R¹9 is preferably hydrogen.

Ar² is preferably phenyl or R⁴-phenyl, especially (4-R⁴)-substituted phenyl.

Preferred definitions of R⁴ are lower alkoxy, especially methoxy, and halogeno, especially fluoro.

Ar¹ is preferably phenyl or P.3-substituted phenyl, especially (4-R3)-substituted phenyl.

There are several preferred definitions for the -R¹-Q- combination of variables:

Q is a bond and R¹ is lower alkylene, preferably propylene;

Q is a spirό group as defined above, wherein preferably R^ and R⁷ are each

ethylene and R5 is -CH- or -C(OH)- ;

R 10

Q is a bond and R 1 is ^{M d} £11 ^h wherein the variables WO 2007/136696

11

are chosen such that R¹ is -O-CH2-CH(OH)-;

R¹² R¹⁰

Q is a bond and Rijs -X_m-(C)_s-Y_n-(C)rZ_p- wherein the

R¹³ _R"

variables are chosen such that R¹ is -CH(OH)-(CH2)2-; and

R

Q is a bond and R¹ is -X_j- (C)_v-Y_k- S(O)₀^- ^{wnerein tne}

R¹¹ variables are chosen such that R¹ is -CH(OH)-CH2-S(O)0-2-

In another embodiment, one or more sterol absorption inhibitors useful in the methods, compositions or combinations of this invention are represented by Formula (IH):

R

^ArS< ^⁽?^Q> -'⁰S J--N(^_N O ^NAr³

(III)

or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (III) or of the isomers thereof, or prodrugs of the compounds of Formula (III) or of the isomers, salts or solvates thereof, wherein:

Ar¹ is aryl, R¹O-substituted aryl or heteroaryl; Ar² is aryl or R⁴-substituted aryl; Ar^ is aryl or R^-substituted aryl;

X and Y are independently selected from the group consisting of -CH2-, - CH(lower alkyl)- and -C(dilower alkyl)-; WO 2007/136696

12

R is -OR⁶, -O(CO)R6, -0(CO)OR⁹ or -0(CO)NR⁶R⁷; R1 is hydrogen, lower afkyl or aryl; or R and R¹ together are =O; q is 0 or 1 ; r is 0, 1 or 2; m and n are independently 0, 1 , 2, 3, 4 or 5; provided that the sum of m, n and q is 1 , 2, 3, 4 or 5;

R4 is 1 -5 substituents independently selected from the group consisting of lower alkyl, -OR⁶, -0(CO)R⁶, -0(CO)OR⁹, -O(CH2)1-5OR⁶, -0(CO)NR⁶R⁷ -NR⁶R⁷, -NR⁶(CO)R⁷, -NR⁶(CO)OR⁹, -NR⁶(CO)NR⁷R8, -NR⁶Sθ2R⁹, -COOR⁶ -CONR⁶R⁷, -COR⁶, -SO2NR6R7 S(O)0-2R⁹. -0(CH2)1-10-COOR⁶, -O(CH2)1-10CONR6R7, - (lower alkylene)COOR⁶ and -CH=CH-COOR⁶;

R5 is 1-5 substituents independently selected from the group consisting of - OR⁶, -O(C0)R⁶, -O(CO)OR9, -O(CH2)1-5OR⁶, -0(CO)NR⁶R⁷, -NR⁶R⁷, . NR⁶(CO)R⁷ -NR⁶(CO)OR9, -NR⁶(CO)NR⁷R8, -NR⁶Sθ2R⁹, -COOR⁶, -CONR⁶R⁷, - COR⁶, -SO2NR⁶R⁷ S(O)0-2R⁹.

-0(CH2)1-10-COOR⁶, -O(CH2)1-1 OCONR⁶R⁷, -CF3, -CN, -NO2, halogen, -(lower alkyleneJCOOR⁶ and -CH=CH-COOR⁶;

R⁶, R⁷ and R⁸ are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;

R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl; and R1O is 1-5 substituents independently selected from the group consisting of lower alkyl, -OR⁶, -O(CO)R⁶, -0(QO)OR⁹, -O(CH2)1-5OR⁶, -0(CO)NR⁶R⁷, -NR⁶R⁷, -NR⁶(CO)R⁷, -NR⁶(CO)OR⁹, -NR⁶(CO)NR⁷R8, -NR⁶Sθ2R⁹, -COOR⁶, - CONR⁶R⁷ -COR⁶, -SO2NR⁶R⁷, S(0)θ-2R⁹, -0(CH2)1-10-COOR⁶ -O(CH2)1- 10CONR⁶R⁷, -CF3, -CN, -NO2 and halogen. WO 2007/136696

13

Within the scope of Formula m, there are two preferred structures. In Formula HIA, q is zero and the remaining variables are as defined above, and in Formula IHB, q is 1 and the remaining variables are as defined above:

R

^τπ J l *m I ₁ ^γn I |

O J"-K >r ₃ ^{3 R} C JT-K ^r³

TTTA UIB

R⁴, R5 and R^ ⁿ are each preferably 1-3 independently selected substituents as set forth above. Preferred are compounds of Formula (HI) wherein Ar^ is phenyl, R^O-substituted phenyl orthienyl, especially (4-R ^-substituted phenyl orthienyl. Ar² is preferably R⁴-substituted phenyl, especially (4-R⁴)-substituted phenyl. Ar³ is preferably phenyl or R5-substituted phenyl, especially (4-R⁵)-substituted phenyl. When Ar^"! is R^O-substituted phenyl, R^O is preferably halogeno, especially fluoro. When Ar² is R⁴-substituted phenyl, R⁴ is preferably -OR⁶, especially wherein R⁶ is hydrogen or lower alkyl. When Ar³ is R^-substituted phenyl, Rβ is preferably halogeno, especially fluoro. Especially preferred are compounds of formula III wherein Ar^ is phenyl, 4-fluorophenyl or thienyl, Ar² is 4-(alkoxy or hydroxy)phenyl, and Aι-3 is phenyl or 4-fluorophenyl.

X and Y are each preferably -CH2-. The sum of m, n and q is preferably 2, 3 or 4, more preferably 2. When q is 1. n is preferably 1 to 5.

Preferences for X₁ Y, Ar-I, Ar² and Ar³ are the same in each of formulae HIA and IIIB.

In compounds of formula πiA, the sum of m and π is preferably 2, 3 or 4, more preferably 2. Also preferred are compounds wherein the sum of m and n is 2, and r is 0 or 1.

In compounds of formula πiB, the sum of m and n is preferably 1, 2 or 3, more preferably 1. Especially preferred are compounds wherein m is zero and n is 1. R¹ is preferably hydrogen and R is preferably -OR^ wherein R6 is hydrogen, or a group WO 2007/136696

14

readily metabolizable to a hydroxy! (such as -O(CO)R⁶, -0(CO)OR⁹ and -

0(CO)NR⁶R⁷, defined above), or R and R¹ together form a =O group.

In another embodiment, one or more sterol absorption inhibitors useful in the methods, compositions or combinations of this invention are represented by Formula (IV):

(IV) or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (IV) or of the isomers thereof, or prodrugs of the compounds of Formula (IV) or of the isomers, salts or solvates thereof, wherein: R1 is

-CH-, -C(lower alkyl)-, -CF-, -6(OH)-, -C(C ₆H₅)-, -C(C₆H₄-R₁₅)-,

- N- or -⁺N O^" ;

R2 and R3 are independently selected from the group consisting of

-CH2-,

-CH(lower alkyl)-,

-C(di-lower alkyl)-,

-CH=CH- and

-C(lower alkyl)=CH-; or

R-j together with an adjacent R2, or Ri together with an adjacent R3, form a - CH=CH- or a -CH=C(lower alkyl)- group; u and v are independently O, 1, 2 or 3, WO 2007/136696

15 provided both are not zero; provided that when R2 is -CH=CH- or -C(lower alkyl)=CH-, v Is 1 ; provided that when R3 is -CH=CH- or-C(lower alkyl)=CH-, u is 1; provided that when v is 2 or 3, the F?2's can be the same or different; and provided that when u is 2 or 3, the R3's can be the same or different; R4 is B-(CH2)mC(0)-, wherein m is 0, 1 , 2, 3, 4 or 5;

B-(CH2)q-, wherein q is 0, 1, 2, 3, 4, 5 or 6;

B-(CH2)e-Z-(CH2)r. wherein Z is -O-, -C(O)-, phenylene,

-N(Re)- or -S(O)0-2-. e is 0, 1 , 2, 3, 4 or 5 and r is 0, 1 , 2, 3, 4 or 5, provided that the sum of e and r is 0, 1 , 2, 3, 4, 5 or 6;

B-(C2-C6 alkenylene)-;

B-(C4-Cβ alkadienylene)-;

B-(CH2)t-Z-(C2-C6 alkenylene)-, wherein Z is as defined above, and wherein t is 0, 1, 2 or 3, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;

B-(CH2)f-V-(CH2)g-. wherein V is C3-C6 cycloalkylene, f is 1, 2, 3, 4 or 5 and g is 0, 1 , 2, 3, 4 or 5, provided that the sum of f and g is 1, 2, 3, 4, 5 or 6;

B-(CH2)t-V-(C2-C6 alkenylene)- or

B-(C2-C6 alkenylene)-V-(CH2)t-, wherein V and t are as defined above, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;

B-(CH2)_a-Z-(CH2)b-V-(CH2)d-. wherein Z and V are as defined above and a, b and d are independently 0, 1 , 2, 3, 4, 5 or 6, provided that the sum of a, b and d is 0, 1 , 2, 3, 4, 5 or 6; or

T-(CH2)s-. wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1, 2, 3, 4. 5 or 6; or

R1 and R4 together form the group B-CH=C- ; WO 2007/136696

16

B is indanyl, indenyl, naphthyl, tetrahydronaphthyl, heteroaryl or W-substituted heteroaryl, wherein heteroaryl is selected from the group consisting of: pyrrolyJ, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls, the N-oxides thereof, or

/4r ^" R^Ri7*

W is 1 to 3 substituents independently selected from the group consisting of iower alkyl, hydroxy lower aJkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower alkanedioyl, allyloxy, -CF3. -OCF₃, benzyl, 17

R7-benzyl, benzyloxy,

R7-benzyloxy, phenoxy,

R7-phenoxy, dioxolanyl,

NO₂,

-N(R8)(R9).

N(R8)(Rg)-lόwer alkyleπe-,

N(Re)(R9)-lower alkylenyloxy-,

OH, halogeno,

-CN,

-N3.

-NHC(O)ORiO,

-NHC(O)RiO,

R11O2SNH-,

(RI iO₂S)₂N-,

-S(O)₂NH₂,

-S(O)0-₂R8, tert-butyldimethyl-silyloxymethyl,

-C(O)Ri₂,

-COOR19,

-CON(R₈)(Rg), -CH=CHC(O)Ri₂, -lower alkylene-C(O)Ri₂, Ri0C(O)(lower alkylenyloxy)-,

N(R8)(R9)C(O)(lower alkylenyloxy)- and ^{" CH}2~ <\ _,R_i3 for WO 2007/136696

18 substitution on ring carbon atoms, and the substituents on the substituted heteroaryl ring nitrogen atoms, when present, are selected from the group consisting of lower alkyl, lower alkoxy,

-C(O)ORiO,

-C(O)RiO,

OH,

N(R8)(R9)-lower alkylene-,

N(R8)(R9)-lower alkylenyloxy-,

-S(O)2NH2 and

2-(trimethylsilyl)-ethoxymethyl; R 7 is 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy,

-COOH,

NO2,

-N(Re)(Rg).

OH₁ and halogeno;

R8 and Rg are independently H or lower alkyl; R1O is lower alkyl, phenyl, R7-phenyl, benzyl or R7-benzyl; Ri 1 is OH, lower alkyl, phenyl, benzyl, R7-phenyl or R7-benzyl; R12 is H, OH, alkoxy, phencxy, benzyloxy, _ ' ^

-N(Re)(Rg), lower alkyl, phenyl or R7-phenyl;

R13 is -O-, -CH2-. -NH-, -N(lower alkyl)- or -NC(O)Ri 9;

R15. R16 and R17 are independently selected from the group consisting of H and the groups defined for W; or R-\ 5 is hydrogen and Rig and R17, together with adjacent carbon atoms to which they are attached, form a dioxolanyl ring; WO 2007/136696

19

R-j 9 is H, lower alkyl, phenyl or phenyl lower alkyl; and

R20 and R21 are independently selected from the group consisting of phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryl and cyclopropyl, wherein heteroaryl is as defined above.

One group of preferred compounds of formula IV is that wherein R21 is phenyl,

W-substituted phenyl, indanyl, benzofuranyl, benzodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl or cyclopropyl, wherein W is lower alkyl, lower alkoxy,

OH. halogeno,

-N(Rs)(Rg).

-NHC(O)ORiO,

-NHC(O)RiO,

NO₂,

-CN,

-N₃, 20

-SH,

-S(O)0-2-(lower alkyl), -COOR19,

-CON(R₈)(RQ), -COR12, phenoxy, benzyloxy, -OCF3,

-CH=C(O)R 12 or tert-butyldimethylsilyloxy, wherein Re, R9, R10. R12 and R19 are as defined for Formula IV. When W is 2 or 3 substituents, the substituents can be the same or different.

Another group of preferred compounds of Formula IV is that wherein R20 is phenyl or W-substituted phenyl, wherein preferred meanings of W are as defined above for preferred definitions of R21.

More preferred are compounds of Formula IV wherein R20 is phenyl or W- substituted phenyl and R21 is phenyl,

W-substituted phenyl, indanyl, beπzofuranyl, benzodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl or cyclopropyl; W is lower alkyl, lower alkoxy, WO 2007/136696

21

OH, halogeno,

-N(ReXRg).

-NHC(O)ORiO,

-NHC(O)RiO.

NO2,

-CN,

-N3,

-SH.

-S(O)o-2-(lower alkyl),

-COOR19,

-CON(R8)(R9),

-COR12, phenoxy, benzyloxy,

-CH=CHC(O)R12.

-OCF3 or tert-butyl-dimethyl-silyloxy, wherein when W is 2 or 3 substituents, the substituents can be the same or different, and wherein Re, R9. R10. R12 and R19 are as defined in Formula IV. i -<b(OH)-

Also preferred are compounds of Formula IV wherein Ri is -^CH" or

Another group of preferred compounds of Formula IV is that wherein R2 and R3 are each -CH2- and the sum of u and v is 2, 3 or 4, with u=v=2 being more preferred.

R4 is preferably B-(CH2)q- or B-(CH2)e-Z~(CH2)r. wherein B, 2, q, e and r are

?£^■

as defined above. B is preferably , wherein R-\Q and R17 are each WO 2007/136696

22 hydrogen and wherein R-|5 is preferably H, OH, lower alkoxy, especially methoxy, or halogeno, especially chloro.

A preferred definition of Z is -O-, e is preferably 0, and r is preferably 0.

A preferred definition of q is 0-2.

R20 «s preferably phenyl or W-substituted phenyl.

Preferred W substituents for R20 are lower alkoxy, especially methoxy and ethoxy, OH, and -C(O)Ri2. wherein R12 is preferably lower alkoxy.

Preferred definitions for R21 are phenyl, lower alkoxy-substituted phenyl and F- phenyl.

Especially preferred are compounds of Formula IV wherein Ri is "^CH" , or

-C(OH)- , R2 and R3 are each -CH2-, u=v=2, R4 is B-(CH2)q-, wherein B is phenyl or phenyl substituted by lower alkoxy or chloro, q is 0-2, R20 is phenyl, OH-phenyl, lower alkoxy-substituted phenyl or lower alkoxycarbonyl-substituted phenyl, and R21 is phenyl, lower alkoxy-substituted phenyl or F-phenyl.

In another embodiment, one or more sterol absorption inhibitors useful in the methods, compositions or combinations of this invention are represented by Formulas (VA) and (VB):

B" — D

(VA) and WO 2007/136696

23

(VB) or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formulas (VA) and (VB) or of the isomers thereof, or prodrugs of the compounds of Formulas (VA) and (VB) or of 4^e isomers, salts or solvates thereof, wherein:

A is -CH=CH-, -Csc- -(CH2)p- wherein p is 0, 1 or 2;

B is

=^j R3

B¹ is

R V

^ <ά <2^f v

R₃.

D is -(CH2)mC(O)- or -(CH2)q- wherein m is 1 , 2, 3 or 4 and q is 2, 3 or 4;

E is C10 to C20 alkyl or -C(O)-(Cg toC-|9)-alkyl, wherein the alkyl is straight or branched, saturated or containing one or more double bonds;

R is hydrogen, C1-C15 alkyl, straight or branched, saturated or containing one or more double bonds, or B-(CH2)r -. wherein r is 0, 1, 2, or 3;

^R1. ^R2. ^R3, R1\ R2¹. and R3' are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, carboxy, NO2, NH2. OH, halogeno, lower alkylamino, dilower alkylamino, -NHC(O)ORs, R6O2SNH- and -S(O)2NH2;

R4 is WO 2007/136696

24

F> (OR₅)_n

wherein n is 0, 1 , 2 or 3;

F?5 is lower alkyl; and

R6 is OH₁ lower alkyl, phenyl, benzyl or substituted phenyl wherein the substituents are 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, carboxy, Nθ2, NH2. OH, halogeno, lower alkylamino and dilower alkylamino.

Preferred are compounds of Formula (VA) wherein R is hydrogen, saturated or mono-unsaturated Ci -Ci 0 alkyl or phenyl. Another group of preferred compounds of Formula (VA) is that wherein D is propyl (i.e., -(CH2)q- and q is 3). A third group of preferred compounds of Formula (VA) is that wherein R4 is p-methoxyphenyl or 2,4,6- trimethoxyphenyl. Still another group of preferred compounds of Formula (VA) is that wherein A is ethylene or a bond (i.e., -(CH2)ρ- wherein p is zero). Rv, R2¹, and R3¹ are preferably each hydrogen, and preferably Ri is hydrogen, hydroxy, nitro, lower alkoxy, amino or t-butoxycarbonyl-amino and R2 and R3 are each hydrogen.

Especially preferred are compounds of Formula (VA) wherein Rv, R2'. and R3¹ are each hydrogen; Ri is hydrogen, hydroxy, nitro, lower alkoxy, amino or t- butoxycarbonyl-amino and R2 and R3 are each hydrogen; R is hydrogen, ethyl or phenyl; D is propyl; R4 is p-methoxyphenyJ or 2,4,6-trimethoxyphenyl; and A is ethylene or a bond.

Especially preferred compounds of Formula (VA), wherein B^* is phenyl, are shown in the following table:

WO 2007/136696

25

-(CH₂)3- H P-OH- p-MeO-phenyl phenyl

-(CH₂)3- H ethylene P-MeO- p-MeO-phenyl phenyl

-(CH₂)3- H 3-MeO- p-MeO-phenyl phenyl

-(CH₂)3- ethyl phenyl p-MeO-phenyl

"(CH₂)3- phenyl phenyl p-MeO-phenyl

-(CH2)3- ethyl phenyl 2,4,6-tri-MeO- phenyl

-(CH2)3- methyl phenyl p-MeO-phenyl

-(CH2)3- H P-ISIH2- p-MeO-phenyl phenyl

The first-listed compound in the above table having the (3R.4S) absolute stereochemistry is more preferred.

Preferred compounds of Formula (VB) are those wherein R is hydrogen, methyl, ethyl, phenyl or phenylpropyl. Another group of preferred compounds of Formula (VB) is that wherein R4 is p-methoxyphenyl or 2,4,6-trimethoxyphenyl. Still another group of preferred compounds of Formula (VB) is that wherein A is ethylene or a bond. Yet another group of preferred compounds of Formula (VB) is that wherein E is decyl, oleoyl or 7-Z-hexadecenyl. Preferably R-j, R2 and R3 are each hydrogen.

Especially preferred compounds of Formula (VB) are those wherein R is hydrogen, methyl, ethyl, phenyl or phenylpropyl; R4 is p-methoxyphenyl or 2,4,6- trimethoxyphenyl; A is ethylene or a bond; E is decyl, oleoyl or 7-Z-hexadecenyl; and Ri_f R2 and R3 are each hydrogen.

An especially preferred compound of Formula (VB) is that wherein E is decyl, R is hydrogen, B-A is phenyl and R4 is p-methoxyphenyl.

In another embodiment, one or more sterol absorption inhibitors useful in the methods, compositions or combinations of this invention are represented by Formula (VI): WO 2007/136696

26

R 26 r\ ^■^ - OO--G

Ar¹-R¹-Q

(VI) or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (VI) or of the isomers thereof, or prodrugs of the compounds of Formula (VI) or of the isomers, salts or solvates thereof, wherein:

R²^ iS H or OG¹ ;

G and G ¹ are independently selected from the group consisting of

9B⁵JpR⁴ QR* _OR⁴ _/ ^{OR7 ■}'"^OR3 , -/ /'"OR³ , -CH₂-( )"<IOR⁵

CO₂R² CH₂OR⁶ OR^{3 OR} .4

OR^3a R⁴³Q; . X j* and _A OR³ Λ_OΛ CH₂R^b ;

I I provided that when R26 is H or

^O '^'CH₂R³

OH, G is not H;

R, R^a and R^D are independently selected from the group consisting of H, -OH, halogeno, -NH2, azido, (C-j-C6)alkoxy(Ci-C6)-alkoxy or -W-R30_;

W is independently selected from the group consisting of -NH-C(O)-, -O-C(O)-, -O-C(O)-N(R31)-, -NH-C(O)-N(R31 )- and -O-C(S)-N(R31).;

R2 and R^ are independently selected from the group consisting of H, (C-]- C6)alkyl, aryl and aryl(Ci-C6)alkyl; WO 2007/136696

27

R³, R⁴, R⁵, R⁷, R^3a and R^4a are independently selected from the group consisting of H, (Ci-C6)alkyl, aryl(Ci-C6)alkyl, -C(O)(Ci -C6)alkyl and -C(O)aryl;

R20 is selected from the group consisting of R³²-substituted T, R³²- substituted-T-(Ci-C6)alkyl, R³²-substituted-(C2-C4)alkenyl, R³²-substituted-(Ci-

C6)alkyl, R³²-substituted-(C3-C7)cycloalkyl and R³²-substituted-(C3- C7)cycloalkyl(Ci -C6)alkyl;

R31 J₅ selected from the group consisting of H and (Ci-C4)alkyl;

T is selected from the group consisting of phenyl, furyl, thienyf, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;

R³² is independently selected from 1-3 substituents independently selected from the group consisting of halogeno, (C-i-C4)alkyl, -OH, phenoxy, -CF3, -NO2, (C-]- C4)alkoxy, methylenedioxy, oxo, (Ci-C4)alkylsulfanyl, (Ci-C4)alkylsulfinyl, (C-|- C4)alkylsulfonyl, -N(CH3)2, -C(O)-NH(Ci -C4)alkyl, -C(O)-N((Ci-C4)alkyl)2, -C(O)- (Ci-C4)alkyl, -C(O)-(Ci -C4)alkoxy and pyrrolidinylcarbonyl; or R³² is a covalent bond and R³¹ , the nitrogen to which it is attached and R³² form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morphofinyl group, or a (Ci- C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;

Ar^"! is aryl or R¹O-substituted aryl;

Ar² is aryl or R^{1 '}'-substituted aryl;

Q is a bond or, with the 3-position ring carbon of the azetidinone,

V-(R^)₃ forms the spiro group (R ¹\ — ' ; and

R1 is selected from the group consisting of

-(CH2)q-, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1 ; WO 2007/136696

28

-(CH2)e-E-(CH2)r. wherein E is -O-, -C(O)-, phenylene, -NR²²- or - S(O)0-2-. © is 0-5 and r is 0-5, provided that the sum of e and r is 1-6; -(C2-C6)alkenylene-; and -(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is O-

5, provided that the sum of f and g is 1-6; Ri2 _is

-CH-, -C(C₁-C₆ alkyl)-, -CF-, -C(OH)-, -C(C₆H₄-R²³)-, -N-, or -⁺NO" ;

R13 and R^⁴ are independently selected from the group consisting of

-CH2-,

-CH(Ci -C6 alkyl)-,

-C(di-(C1-C6) alkyl),

-CH=CH- and

-C(Ci-C6 alkyl)=CH-; or R¹² together with an adjacent R 13, or R¹² together with an adjacent R¹⁴, form a -CH=CH- or a -CH=C(Ci -CQ alkyl)- group; a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided that when R¹³ is -CH=CH- or -C(Ci-Ce alkyl)=CH-, a is 1 ; provided that when RI⁴ J_S -CH=CH- or -C(Ci-C6 alkyl)=CH-_f b is 1 ; provided that when a is 2 or 3, the R^13>s can be the same or different; and provided that when b is 2 or 3, the R¹⁴'s can be the same or different; and when Q is a bond, R¹ also can be:

~M-Y_d- RC-- Z_n- , -Xm-( rC)_s-Y_π-(C ?)¹r⁵ Z_p- or -X_f( ?C)¹ _v ⁵-Y_k- S(O)_0-2-;

R¹⁶ R« _R16 R¹⁶

M is -O-, -S-, -S(O)- or -S(O)--;

X, Y and Z are independently selected from the group consisting of -CH2-. - CH(C1-C6)alkyl- and -C(di-(Ci-C6)alkyl); 29

sub_Sft^Ri! ^{and R11 are lndependentIy SeIected f}™ the group consisting of 1-3 substⁱtuents mdependent.y selected from the group consisting of

(Ci-C6)alkyl,

-OR19

-O(CO)R19

-O(CO)OR21,

-O(CH₂)1-5OR19

-O(CO)NRi9R20_t -NR19R20,

-NRi9(co)R20_f -NR19(CO)OR21, -NR19(CO)NR20_R25 -NR19_SO₂R21_I

-COOR 19

-CONR19R20,

-COR19,

-S02NR19_R20₍

S(O)0-2R21,

-0(CH₂)1-10-COOR19

-O(CH2) 1 -1 oCONR 19_R20_f

-(C-f -C6 alkyleneJ-COORi^

-CH=CH-COORi 9

-CF₃, -CN, -NO2 and halogen;

_n,_n "^{^ and R17 arβ lnde}P^ende"«y selected from the group consisting of -OR19 . O(CO)Ri9 -O(CO)OR21 _and ._O(co)NRi9R20_; ^' 30

R ¹6 and R¹⁸ are independently selected from the group consisting of H, (C<i-C6)alkyl and aryl; or R¹⁵ and R¹⁶ together are =O, or R¹⁷ and R¹⁸ together are

=O; d is 1, 2 or 3; h is O, 1 , 2, 3 or 4; s is 0 or 1 ; t is 0 or 1 ; m, n and p are independently 0-4; provided that at least one of s and t is 1 , and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1 , the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1 , the sum of m, t and n is 1-5; v is 0 or 1 ; j and k are independently 1 -5, provided that the sum of j, k and v is 1-5;

R¹⁵

-X_j- (C)_v -Y_k-S(O)₀.₂- and when Q is a bond and R¹ is R¹⁶ , Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazoly!, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

R¹9 and R20 are independently selected from the group consisting of H₁ (Ci- C6)alkyl. aryl and aryl-substituted (Ci-C6)alkyl;

R²¹ is (Ci-C6)alkyl, aryl or R²⁴-substituted aryl;

R22 is H₁ (Ci-C6)alkyl, aryl (Ci-C6)alkyl, -C(O)R¹S or -COOR¹⁹;

R23 _ancj R24 _are independently 1-3 groups independently selected from the group consisting of H, (Ci-C6)alkyl, (Ci-C6)alkoxy, -COOH, NO2. -NR¹⁹R²O, -OH and halogeno; and

R²⁵ is H, -OH or (Ci-C6)aJkoxy.

Ar² is preferably phenyl or R^{1 1} -phenyl, especially {4-R^{1 1})-substituted phenyl.

Preferred definitions of R^{1 1} are lower alkoxy, especially methoxy, and halogeno, especially fluoro. 31

Ar¹ is preferably phenyl or Ri°-substituted phenyl, especially (4-R¹⁰)- substituted phenyl. A preferred definition of R^ is halogeno, especially fluoro.

There are several preferred definitions for the -R^ -Q- combination of variables:

Q is a bond and R^ is lower alkylene, preferably propylene;

Q is a spiro group as defined above, wherein preferably R^ 3 and R¹⁴ are

I I each ethylene and R¹² is -CH- or -C(OH)- _f and R¹ is -(CH2)q wherein q is 0-6;

R¹⁵ Q is a bond and R1 is ~ ^M "Yd~^c " ²h~ wherein the variables

_R 16 are chosen such that R¹ is -O-CH2-CH(OH)-;

R¹⁷ R¹⁵

Q is a bond and R¹ -Xm-(C)_s-Y_n-(C)_t- Z — wherein the is R¹⁸ R16 variables are chosen such that R¹ is -CH(OH)-(CH2)2-." and

R¹⁵ Q is a bond and R¹ is -X_j-(C)_v-Y_k-S(O)₀_₂- wherein the

R¹⁶ variables are chosen such that R¹ is -CH(OH)-CH2-S(O)0-2--

A preferred compound of Formula (VI) therefore, is one wherein G and G-I are as defined above and in which the remaining variables have the following definitions:

Ar-I is phenyl or RiO-substituted phenyl, wherein R1O is halogeno; Ar² is phenyl or R^{1 1}-phenyl, wherein R^{1 1} is 1 to 3 substituents independently selected from the group consisting of Ci-Ce alkoxy and halogeno;

Q is a bond and R1 is lower alkylene; Q, with the 3-position WO 2007/136696

32

R¹f-(R¹³)a ring carbon of the azetidinone, forms the group (^R )b wherein preferably

R13 and R¹^ are each ethylene and a and b are each 1, and wherein R^2 \_s

-CH- or -C(OH)- ; Q is a bond and R¹ is -O-CH2-CH<OH)-; Q is a bond and R¹ is

-CH(OH)-(CH2)2-; or ^Q is a bond and R¹ is -CH(OH)-CH2-S(O)0-2-- Preferred variables for G and C groups of the formulae

Q₁R= OR⁴ Qff jDR⁴ OR⁷

-/^~~V"OR³ — (^VΌR³ and -CH₂-^ Λ "OR⁵

(3O₂R² CH₂OR⁶ 5_R3 OR⁴ are as follows:

R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from the group consisting of H, (Ci-C6)alkyl, benzyl and acetyl.

Preferred variables for group G or G^** of the formula

)R^3a R⁴³Q ^"

OR³ Λ_o^CH₂R^b R⁴O,.^γ°

^O^CH₂R^a are as follows:

R3, R3a_t R4 _an<d R4a _are selected from the group consisting of H, (C-_]- C6)alkyl, benzyl and acetyl;

R, R^a and R^ are independently selected from the group consisting of H,

-OH, halogeno, -NH₂, azido, 33

(Ci-C6)alkoxy(Ci-C6)alkoxy and -W-R30, wherein W is -O-C(O)- or -0-C(O)-NR³¹-, R^3"! is H and

R³O is (Ci-C6)alkyl, -C(O)-(Ci -C4)alkoxy-(Ci-C6)alkyl, T , T-(Ci -C6)alkyl, or T or T-(Ci -C6)alkyl wherein T is substituted by one or two halogeno or (Ci- Cβ)alkyl groups.

Preferred R³⁰ substituents are selected from the group consisting of

2-fluorophenyl,

2,4-difluoro-phenyl,

2,6-dichlorophenyl,

2-methylphenyl,

2-thienyfmethyl,

2-methoxy-carbonylethyl, thiazol-2-yl-methyl,

2-furyl,

2-methoxycarbonylbutyl and phenyl. Preferred combinations of R, R^a and Rb are as follows:

1 ) R, Ra and R^b are independently -OH or -0-C(O)-NH-R³⁰, especially wherein R^a is -OH and R and Rb are -0-C(O)-NH-R³⁰ and R³⁰ is selected from the preferred substituents identified above, or wherein R and R^a are each

-OH and R^b is-O-C(O)-NH-R³⁰ wherein R³⁰ is 2-fluorophenyl, 2,4-difluoro- phenyl, 2,6-dichlorophenyl;

2) R^a is -OH, halogeno, azido or (Ci-C6)-alkoxy(Ci-C6)alkoxy, Rb is H, halogeno, azido or (Ci-C6)alkoxy(Ci-C6>alkoxy, and R is -0-C(O)-NH-R³⁰, especially compounds wherein R^a is -OH, R^b is H and R³⁰ is 2-fluorophenyl;

3) R, Ra and R^b are independently -OH or -0-C(O)-R³⁰ and R³⁰ is (Ci-C6)alkyl, T , or T substituted by one or two halogeno or (Ci-Cβ)alkyl WO 2007/136696

34

groups, especially compounds wherein R is -OH and R^a and R^ are -O-C(O)- R30 wherein R^O is 2-furyl; and

4) R, R^a and R^b are independently -Oft or halogeno. Three additional classes of preferred compounds are those wherein the C¹' anomeric oxy is beta, wherein the C2' anomeric oxy is beta, and wherein the R group is alpha. G and G¹ are preferably selected from:

°t* OH ^? >^OH >^OH °β^C _jpAc

-^ )-MOH , — ^ )-IlOH , -CHW ~ >^{l |}OH » ~/~>ιlθAc o-ς o-ς j— ^ W

CO₂H ^CH₂OH Q_H OH ^CO₂CH₃

PhCH₂Q, ^QCH₂Ph PhCH₂O₁- OCH₂Ph o-/*⁰"³

-Tj-IOCH₂Ph . -0"10CH₂Ph ,^"CH₂-^-IOCH₂Ph CO₂CH₂Ph ^O~\H₂OCH₂Ph OCH₂Ph°^CH2Ph

⁰^P ^^QAc op _jpπ _>^OCH ₃

-< ^Λ'^{i |}OAc , _/^~\.i|OH _t -CH₂-^J-IlOH CH₂OAc ^"So₂CH₃ OH ^OH

OH OAc

HQj. 1 _>N\0H AcQ^₁ Ϊ ΛOAC

HC^^O^^^^ , AcO^ / O^oJ'C^OAc ^O"^CH₂OH -^o -^CH₂OAc

O OH 'I

^and OH i_oΛ_CH₂OH

-^O ^CH₂OH

wherein Ac is acetyl and Ph is phenyi. WO 2007/136696

35

Preferably, R²⁶ is H or OH, more preferably H. The -O-G substituent Is preferably in the 4-position of the phenyl ring to which it is attached.

In another embodiment, one or more sterol absorption inhibitors useful in the methods, compositions or combinations of this invention are represented by Formula (VH):

R R²

Ar^X^O_q-Yn-fCVZ_p^ Ar ,3^;

R^{1 ■}K

(vπ) or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (VII) or of the isomers thereof, or prodrugs of the compounds of Formula (VIt) or of the isomers, salts or solvates thereof, wherein:

Ar^ and Ar² are independently selected from the group consisting of aryl and R⁴-substituted aryl;

Ar³ is aryl or R5-substituted aryl;

X, Y and 2 are independently selected from the group consisting of -CH2-, - CH(lower alkyl)- and -C(dilower afkyl)-;

R and R² are independently selected from the group consisting of -OR^, - O(CO)R6, -O(CO)OR9 and -O(CO)NR6R7;

R¹ and R3 are independently selected from the group consisting of hydrogen, lower alkyl and aryl; q is 0 or 1 ; r is 0 or 1 ; m, n and p are independently 0, 1 , 2, 3 or 4; provided that at least one of q and r is 1 , and the sum of m, n, p, q and r is 1 , 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1 , the sum of m. q and n is 1 , 2, 3, 4 or 5;

R⁴ is 1-5 substituents independently selected from the group consisting of 36 lower alkyl,

-Ope

-O(CO)R⁶.

-0(CO)OR⁹,

-O(CH2)1-5OR6,

-O(CO)NR6R7,

-NR⁶R⁷,

-NR6(CO)R7,

-NR6(CO)OR9,

-NR6(CO)NR⁷R8,

-NR6SO2R⁹,

-COOR6,

-CONR⁶R⁷,

-COR6,

-SO2NR⁶R⁷.

S(O)0-2R⁹. -O(CH2)1-10-COOR6,

-O(CH2)1-10CONR6R⁷, -(lower alkylene)COORδ, -CH=CH-C00R6, -CF₃, -CN,

-NO2 and halogen;

R5 is 1-5 substituents independently selected from the group consisting of -OR6, -O(CO)R6, WO 2007/136696

37

-0(CO)OR⁹,

-O(CH2)1-5OR6,

-0(CO)NR⁶R⁷,

-NR⁶R⁷,

-NR⁶(CO)R⁷,

-NR⁶(CO)OR⁹, -NR6(CO)NR7R8,

-NR⁶Sθ2R⁹,

-COOR⁶,

-CONR⁶R⁷,

-COR⁶,

-SO2NR6R7,

S(O)0-2R⁹.

-0(CH2)1-10-COOR⁶,

-0(CH2)1-10CONR⁶R7,

-(lower alkylene)COOR⁶ and -CH=CH-COOR⁶;

R⁶, R⁷ and R^ are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl.

R4 is preferably 1-3 independently selected substituents, and R⁵ is preferably 1-3 independently selected substituents.

Preferred compounds of Formula (VII) are those in which Ar¹ is phenyl or R⁴- substituted phenyl, especially (4-R⁴)-substituted phenyl. Ar2 is preferably phenyl or R⁴-substituted phenyl, especially (4-R⁴)-substituted phenyl. Ar³ is preferably R⁵- substituted phenyl, especially (4-R⁵)-substituted phenyl. When Ar¹ is (4-R⁴)- substituted phenyl, R4 is preferably a halogen. When Ar^ and Ar^ are R⁴- and R^- WO 2007/136696

38

substituted phenyl, respectively, R⁴ is preferably halogen or -OR⁶ and R⁵ is preferably -OR⁶, wherein R⁶ is lower alkyl or hydrogen. Especially preferred are compounds wherein each of Ar¹ and Ar² is 4-fluorophenyl and Ar^ is 4-hydroxyphenyl or 4-methoxyphenyl.

X, Y and Z are each preferably -CH2-- R^ and R^ are each preferably hydrogen. R and R² are preferably -OR⁶ wherein R⁶ is hydrogen, or a group readily metabolizable to a hydroxyl (such as -O(CO)R⁶, -O(CO)OR9 and -0(CO)NR⁶R⁷, defined above).

The sum of m, n, p, q and r is preferably 2, 3 or 4, more preferably 3. Preferred are compounds wherein m, n and r are each zero, q is 1 and p is 2.

Also preferred are compounds of Formula (VJI) wherein p, q and n are each zero, r is 1 and m is 2 or 3. More preferred are compounds wherein m, n and r are each zero, q is 1, p is 2, Z is -CH2- and R is -OR⁶, especially when R⁶ is hydrogen.

Also more preferred are compounds of Formula (VII) wherein p, q and n are each zero, r is 1 , m is 2, X is -CH2- and R² is -OR⁶, especially when R⁶ is hydrogen.

Another group of preferred compounds of Formula (VII) are those wherein,

Ar^"! is phenyl or R⁴-substituted phenyl,

Ar² is phenyl or R⁴-substituted phenyl and

An* is R^-substituted phenyl.

Also preferred are compounds wherein

Ar¹ is phenyl or R⁴-substituted phenyl, Ar² fs phenyl or R⁴-substituted phenyl,

Ar3 is R^-SU bstituted phenyl, and the sum of m, n, p, q and r is 2, 3 or 4, more especially 3.

More preferred are compounds wherein

Ar 1 is phenyl or R⁴-substituted phenyl, Ar² is phenyl or R⁴-substituted phenyl, WO 2007/136696

39

An³ is R⁵-substituted phenyl, and wherein m, n and r are each zero, q is 1 and p is 2, or wherein p, q and n are each zero, r is 1 and m is 2 or 3.

In a preferred embodiment the compound of Formula (VIII) (ezetimibe):

(VIH) is used for the treatment of sitosterolemia.

In another embodiment, one or more sterol absorption inhibitors useful in the methods, compositions or combinations of this invention are represented by Formula (IX):

OR¹

Ar' — CH — Q R 26

IX

or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (IX) or of the isomers thereof, or prodrugs of the compounds of Formula (IX) or of the isomers, salts or solvates thereof, wherein: R²⁶ is selected from the group consisting of: a) OH; b) OCH₃; c) fluorine and d) chlorine. WO 2007/136696

40

R¹ is selected from the group consisting of QR⁵ JDR⁴ OR⁵ JDR⁴ _ .OR⁷

-< ><IOR³ , -<f >.ilOR³ . -CH₂-< )"ⁱlOR⁵ , bθ₂R² CH₂OR⁶ OR²

OR^{3a R a}%_f^\^^R -SO₃H; natural and unnatural

OR³ Λ_o^CH₂R^b - amino acids. R⁴O/,^γ

R, R^a and R^b are independently selected from the group consisting of H, -OH, halogeno, -NH₂, azido, (C-i-C₆)alkoxy(Ci-C6)-alkoxy and -W-R³⁰;

W is independently selected from the group consisting of -NH-C(O)-, -O-C(O)-, -O-C(O)-N(R³¹)-, -NH-C(O)-N(R³I)- and -O-C(S)-N(R31)-_:

R² and R⁶ are independently selected from the group consisting of H, (Ci- C₆)alkyl, aryl and aryl(Ci-C₆)alkyl;

R3, R⁴, R⁵, R7, R³a and R^4a are independently selected from the group consisting of H, (C-i-CβJalkyl, aryl(Ci-C₆)alkyl, -C(O)(C i-CβJalkyl and -C(O)aryl;

R³⁰ is independently selected form the group consisting of R³2-substituted T, R³²-substituted-T-(Ci-C₆)alkyl, R³²-substituted-(C₂-C₄)alkenyl, R³²-substituted-(Ci-C₆)alkyl, R³²-substituted-(C₃-C7)cycloalkyl and R³²-substituted- (C₃-C7)cycloalkyl(Ci -C₆)alkyl,"

R³¹ is independently selected from the group consisting of H and (Ci-C₄)alkyl;

T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;

R³² is independently selected from 1-3 substituents independently selected from the group consisting of H, halogeno, (Ci-C4)a'kyl, -OH, phenoxy. -CF₃, -NO₂. WO 2007/136696

41

(Ci-C₄)alkoxy, methylenedioxy, oxo, (Ci-C4)alkylsulfanyl, (Ci-C₄)alkylsulflnyl, (C₁- C₄)alkylsulfonyl, -N(CH₃J₂, -C(O)-NH(C₁ -C₄)alkyl, -C(O)-N((C₁-C₄)alkyl)₂, -C(O)-(Ci- C₄)alkyl, -C(O)-(Ci -C₄JaIkOXy and pyrrolidinylcarbonyl; or R³² is a covalent bond and R³¹, the nitrogen to which it is attached and R³² form a pyrrolidinyl, piperidinyl, N- methyl-piperazinyl, indolinyl or morpholinyl group, or a (Ci-C₄)alkoxycarbonyl- substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;

Ar¹ is aryl or R¹⁰-substituted aryl;

Ar² is aryl or R¹ ^-substituted aryl;

Q is -(CH2)q-, wherein q is 2-6, or, with the 3-position ring carbon of the azetidinone,

Vf-(R¹³)_a forms the spiro group \^κ Jb ;

R1² is

-CH-, -C(C₁-C₆ alkyl)-, -CF-, -C(OH)-, -C(C₆H₄-R²³)-, -N-, Or -⁴NO^' ;

R¹³ and R¹⁴ are independently selected from the group consisting of -CH₂-, - CH(C₁-C₆ alkyl)-, -C(di-(Ci-C₆) alkyl), -CH=CH- and -C(CrC₆ alkyl)=CH-; or R1² together with an adjacent R¹³, or R¹² together with an adjacent R¹⁴, form a -CH=CH- or a -CH=C(Ci-C₆ alkyl)- group; a and b are independently O, 1, 2 or 3, provided both are not zero; provided that when R¹³ is -CH=CH- or -C(Ci-C₆ alkyl)=CH-, a is 1; provided that when R¹⁴ is - CH=CH- Or-C(Ci-C₆ alkyl)=CH-, b is 1; provided that when a is 2 or 3, the R¹³'s can be the same or different; and provided that when b is 2 or 3, the R¹⁴'s can be the same or different;

R¹⁰ and R¹¹ are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (Ci-C₆)alkyl, -OR¹⁹, -O(CO)R1⁹, -O(CO)OR²1, WO 2007/136696

42

-O(CH₂)_i-5θR¹⁹. -0(CO)NR19R20, -NR19R20, -NR¹⁹(CO)R20, -NR¹9(CO)OR21, - NR¹⁹(CO)NR20R25_i -NR¹⁹SO₂R²¹, -COOR¹⁹, -CONR¹⁹R20_i -COR¹⁹, -SO₂NRiSR²O, S(O)o-₂R²¹, -O(CH₂)I-IO-COOR19, -O(CH₂)i_ioCONRi⁹R2⁰ _i .(C₁-C₆ alkylene)- COOR¹S -CH=CH-COOR¹⁹, -CF₃, -CN, -NO₂ and halogen;

Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

R¹⁹ and R²⁰ are Independently selected from the group consisting of H, (C₁- C₆)alkyl, aryl and aryl-substituted (C-|-C₆)alkyl;

R²¹ is (Ci-C₆)alkyl, aryl or R²⁴-substituted aryl;

R²² is H₁ (Ci-C₆)alkyl, aryl (Ci-C₆)alkyl, -C(O)R¹⁹ or -COOR¹⁹;

R²³ and R²⁴ are independently 1-3 groups independently selected from the group consisting of H, (Ci-C₆)alkyl, (C₁-C₆JaIkOXy, -COOH, NO₂, -NR¹⁹R20_f _QH and halogeno; and

R²⁵ is H, -OH or (C₁-C₆JaIkOXy.

Ar² is preferably phenyl or R¹¹-phenyl, especially (4-R¹¹)-substituted phenyl. Preferred definitions of R¹¹ are lower alkoxy, especially methoxy, and halogeno, especially fluoro.

Ar¹ is preferably phenyl or R¹⁰-substituted phenyl, especially (4-R¹⁰)- substituted phenyl. A preferred definition of R¹⁰ is halogeno, especially fluoro.

Preferably Q is a lower alkyl or a spiro group as defined above, wherein

preferably R¹3 and R¹⁴ are each ethylene and R¹² is -^CH- or -C⁽OH)- .

A preferred compound of formula IX, therefore, is one wherein R¹ is as defined above and in which the remaining variables have the following definitions: Ar¹ is phenyl or R¹⁰-substituted phenyl, wherein R¹⁰ is halogeno; 43

Ar² is phenyl or Rii-phenyl, wherein R¹¹ is 1 to 3 substituents independently selected from the group consisting of C-i-Cβ alkoxy and halogeno;

Q is a lower alkyl (i.e C-1 to C-2) with Q = C-2 being preferred, or ^Q. with

the 3-position ring carbon of the azetidinone, forms the group (^R )b wherein preferably R¹³ and R¹⁴ are each ethylene and a and b are each 1 , and

wherein R¹² is -CH- or -C(OH)- _;

Preferred variables for R¹ groups of the formula

<φ⁵ OR⁴ Q-R^ JDR⁴ OR⁷

_γ^~~Y..,_OR3 _^\..,_OR³ and -CH₂-(J) -OR⁵

°^~S:O₂R² °~\H₂OR⁶ £_R3 ^OR4

are as follows:

R², R³, R⁴, R⁵, R6 and R⁷ are independently selected from the group consisting of H, (Ci-C6)alkyl, benzyl and acetyl.

Preferred variables for group R¹ of the formula

_OR3a

OR ^R34a _n ^<VA_oV^^RCH₂R^b

_R ⁴ _O.^*γ°

^O^CH₂R^a are as follows:

R³, R^3a, R⁴ and R^4a are selected from the group consisting of H, (Ci-C_βJalkyl, benzyl and acetyl;

R, R^a and R^b are independently selected from the group consisting of H₁ -OH, halogeno, -NH2, azido, (Ci-C₆)alkoxy(Ci-C₆)alkoxy and -W-R³O, wherein W is -O- C(O)- or -O-C(O)-NR3i-, R³I is H and R³O is (d-CβJalkyl, -C(OHCi-C₄)alkoxy-(Ci- C₆)alkyl, T , T-(C-|-C6)alkyl, or T or T-tCrCeJalkyl wherein T is substituted by one or two halogeno or (C-)-C6)alkyl groups. WO 2007/136696

44

Preferred R³⁰ substituents are 2-fluorophenyl, 2,4-difluoro-phenyl, 2,6- dichlorophenyl, 2-methylphenyl, 2-thienylmethyf, 2-methoxy-carbonylethyl, thiazol-2- yl-methyl, 2-furyl, 2-methoxycarbonylbutyl and phenyl. Preferred combinations of R, R^a and R^b are as follows: 1 ) R, R^a and R^b are independently -OH or -0-C(O)-NH-R³⁰, especially wherein R^a is -OH and R and R^b are -0-C(O)-NH-R³⁰ and R³⁰ is selected from the preferred substituents identified above, or wherein R and R^a are -OH and R^b is-O-C(O)-NH-R³⁰ wherein R³⁰ is 2-fluorophenyl, 2,4-difluoro-phenyl, 2,6- dichlorophenyl; 2) R^a is -OH, halogeno, azido or (Ci-C6>alkoxy(Ci-C6)alkoxy, R^b is H, halogeno, azido or (Ci-C6)alkoxy(Ci-C6)-alkoxy, and R is -0-C(O)-NH-R³⁰, especially compounds wherein R^a is -OH, R^b is H and R³⁰ is 2-fluorophenyl; 3) R, R^a and R^b are independently -OH or -0-C(O)-R³⁰ and R³⁰ is (Ci-Cβ)alkyl, T , or T substituted by one or two halogeno or (Ci-C6)aJkyl groups, especially compounds wherein R is -OH and R^a and R^b are -0-C(O)-R³⁰ wherein R³⁰ is 2-furyl; and 4) R, R^a and R^b are independently -OH or halogeno. Three additional classes of preferred are compounds are those wherein the C^1> anomeric oxy is beta, wherein the C²' anomeric oxy is beta, and wherein the R group is alpha.

R¹ is preferably selected from:

^* OH °2 _jpH OH QAc j p_Ac

-Y )-UOH , -< >M|OH , -CHW ^"VllOH , -/ >ll_θAc CO₂H ^CH₂OH ^H ^TOH ^CO₂CH₃

PhCH₂Q, OCH₂Ph PhCH₂Cv OCH₂Ph O-^° ³ — ( / — \ ) -1.1OCH₂Ph , — ( / — \ Vi IOCH₂Ph . -CHo ²-i\ / V¹OCH₂ ²Ph ,

°~i CO₂CH₂Ph O -V CH₂OCH₂Ph _Λ O$CH₂Ph OCH₂Ph

OAp OAc 5|_>OH . _O_>^OCH3

_/ >. |OAc , -/ >"IOH -CH₂-( ^)-HOH _o_y _o_^ ^■ 4 >_nμ,

CH₂OAc CO₂CH₃ OH ^OH WO 2007/136696

45

OH OAc

OH /OW H OA^Λo ^CH₂OAC

HQ//^Xs.*P^{' ■}^ XΛ)^-^CΓ.HH₂,OOHH " Ό O " ^^CH₂OAC

O

^and OH ^n^C^OH

HO,^>°

-S₃ -^CH₂OH wherein Ac is acetyl and Ph is phenyl.

Thus a preferred compound of this invention is one represented by the formula X:

OR¹

X wherein R »1 i •s- defined as above.

A more preferred compound is one represented by formula XI:

Q

HQ

OH

HO^" 9

XJ 46

Methods for making the compounds described above and other non-limiting examples of suitable compounds useful in the treatment of sitosterolemia, are well known to those skilled in the art. Their general preparation and specific examples are disclosed in U.S. Patent Nos. 5,767,115; 5,846,966; 5,756,470, 5,698,548; 5,624,920; 5,656,624; 5,688,787; 5,688,990, 5,631 ,365, 6,207,822 and U.S. Provisional Patent Application 60/279,288 filed March 28, 2001, each of which is incorporated herein by reference.

Generally, compounds of formulas I-XI can be prepared by known methods, for example WO 93/02048 describes the preparation of compounds wherein -R^ -Q- is alkylene, alkenylene or alkylene interrupted by a hetero atom, phenylene or cycloalkylene; WO 94/17038 describes the preparation of compounds wherein Q is a spirocyclic group; WO 95/08532 describes the preparation of compounds wherein - R¹-Q- is a hydroxy-substituted alkylene group; PCT/US95/03196 describes compounds wherein -R^-Q- is a hydroxy-substituted alkylene attached to the Ar^ moiety through an -O- or S(O)0-2- group; and U.S. Serial No. 08/463,619, filed June

5, 1995, describes the preparation of compounds wherein -R^"! -Q- is a hydroxy- substituted alkylene group attached the the azetidinone ring by a -S(O)0-2- group, each of which is incorporated herein by reference.

As used herein, the term "alkyl" or "lower alkyl" means straight or branched alkyl chains of 1 to 6 carbon atoms and "alkoxy" similarly refers to alkoxy groups having 1 to 6 carbon atoms.

"Alkenyl" means straight or branched carbon chains having one or more double bonds in the chain, conjugated or unconjugated. Similarly, "alkynyl" means straight or branched carbon chains having one or more triple bonds in the chain. Where an alkyl, alkenyl or alkynyl chain joins two other variables and is therefore bivalent, the terms alkylene, alkenylene and alkynylene are used.

"Cycloalkyl" means a saturated carbon ring of 3 to 6 carbon atoms, while "cycloalkylene" refers to a corresponding bivalent ring, wherein the points of attachment to other groups include all positional isomers.

"Halogeno" refers to fluorine, chlorine, bromine or iodine radicals. WO 2007/136696

47

"Aryl" means phenyl, naphthyl, indenyl, tetrahydronaphthyl or indanyl.

"Phenylene" means a bivalent phenyl group, including ortho, meta and para-substitution.

As used herein, "prodrug" means compounds that are drug precursors which, following administration to a patient, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form).

As used herein, "solvate" means a molecular or ionic complex of molecules or ions of solvent with those of solute (for example, one or more compounds of Formula I-XI, isomers of the compounds of Formula J-Xl, and prodrugs of the compounds of Formula I-XI). Non-limiting examples of useful solvents include polar, protic solvents such as water and alcohols (for example methanol).

The statements, wherein, for example, R^"*⁹, R20 and R25 are said to be independently selected from a group of substituents, means that R-*⁹, R20 _ancj R25 are independently selected, but also that where an R^⁹, R^O or R25 variable occurs more than once in a molecule, those occurrences are independently selected (e.g., if R1O j_s -OR¹⁹ wherein R¹⁹ is hydrogen, R¹¹ can be -OR¹⁹ wherein R¹⁹ is lower alkyl). Those skilled in the art will recognize that the size and nature of the substituent(s) will affect the number of substituents which can be present.

The term "therapeutically effective amount" means that amount of a therapeutic agent of the composition, such as the bile acid sequestrant(s), sterol absorption inhibitor(s) and other pharmacological or therapeutic agents described below, that will elicit a biological or medical response of a tissue, system, animal or mammal that is being sought by the administrator (such as a researcher, doctor or veterinarian) which includes alleviation of the symptoms of the sitosterolemic condition or disease being treated and the prevention, slowing or halting of progression of the sitosterolemic condition.

As used herein, "combination therapy" or "therapeutic combination" means the administration of two or more therapeutic agents, such as sterol absorption inhibitors) and bile acid sequestrant(s) or other therapeutic vascular agents, to prevent or treat WO 2007/136696

48 sitosterol mia and/or reduce the level of sterol (s) in the plasma and tissues. As used herein, "vascular" comprises cardiovascular, cerebrovascular and combinations thereof. Such administration includes coadministration of these therapeutic agents in a substantially simultaneous manner, such as in a single tablet or capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each therapeutic agent. Also, such administration includes use of each type of therapeutic agent in a sequential manner. In either case, the treatment using the combination therapy will provide beneficial effects in treating the sitosterolemic condition. A potential advantage of the combination therapy disclosed herein may be a reduction in the required amount of an individual therapeutic compound or the overall total amount of therapeutic compounds that are effective in treating the sitosterolemic condition. Therapeutic agents can be selected to provide a broader range of complementary effects or complimentary modes of action.

Compounds of the invention have at least one asymmetrical carbon atom and therefore all isomers, including enantiomers, stereoisomers, rotamers, tautomers, racemates of the compounds of Formula (I-XI) (where they exist) are contemplated as being part of this invention. The invention includes d and I isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of the Formulae I-XI. Isomers may also include geometric isomers, e.g., when a double bond is present.

Those skilled in the art will appreciate that for some of the compounds of the Formulas I-XI, one isomer will show greater pharmacological activity than other isomers.

Compounds of the invention with an amino group can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form may be regenerated by treating the salt with a suitable dilute aqueous base WO 2007/136696

49 solution such as dilute aqueous sodium bicarbonate. The free base form differs from its respective salt form somewhat in certain physical properties, such as solubility in polar solvents, but the salt is otherwise equivalent to its respective free base forms for purposes of the invention.

Certain compounds of the invention are acidic (e.g., those compounds which possess a carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.

In an alternative embodiment, the treatment composition can further comprise one or more bile acid sequestrant(s) in coadministration with or in combination with one or more sterol absorption inhibitors.

Non-limiting examples of suitable bile acid sequestrants include cholestyramine (a styrene-divinylbenzene copolymer containing quaternary ammonium cationic groups capable of binding bile acids, such as QUESTRAN® or QUESTRAN LIGHT® which are available from Bristol-Myers Squibb), colestipol (a copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane, such as COLESTID® tablets which are available from Pharmacia), coleseveJam hydrochloride (such as WelChol® Tablets (poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide) which are available from Sankyo), water soluble derivatives such as 3,3-ioene, N-(cycloalkyl) alkylamines and poliglusam, insoluble quatemized polystyrenes, saponins and mixtures thereof. Other useful bile acid sequestrants are disclosed in PCT Patent Applications Nos. WO 97/11345 and WO 98/57652, and U.S. Patents Nos. 3,692,895 and 5,703,188 which are incorporated herein by reference. Suitable inorganic cholesterol sequestrants include bismuth salicylate plus montmorillonite clay, aluminum hydroxide and calcium carbonate antacids.

The bile acid sequestra nt(s) are administered in a therapeutically effective amount to treat the specified condition, for example in a daily dose preferably ranging from about 1 to about 50 grams per day, and more preferably about 2 to about 16 WO 2007/136696

50 grams per day, given in a single dose or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on such factors as the potency of the compound administered, the age, weight, condition and response of the patient.

In yet another alternative embodiment, the treatment composition can further comprise one or more lipid lowering agents such as, for example, sterol biosynthesis inhibitors, in coadministration with or in combination with one or more sterol absorption inhibitors.

Non-limiting lipid lowering agents for use in the treatment compositions of the present invention include HMG CoA reductase inhibitors such as lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, rosuvastatin and itavastatin. Preferred HMG CoA reductase inhibitors include lovastatin, atorvastatin and simvastatin. The most preferred HMG CoA reductase inhibitors are atorvastatin and simvastatin.

In another preferred embodiment, the treatment composition comprises the compound of Formula (VIII) in combination with a bile acid sequestrant. In this embodiment, preferably the bile acid sequestrant is selected from cholestyramine, colesevelam hydrochloride and colestipol. Preferably, the treatment composition comprises one or more bile acid sequestrants such as, for example, cholestyramine, colesevelam hydrochloride and colestipol in combination with a compound of Formula (VIII)

,OH

(VIII).

In another preferred embodiment, the treatment composition comprises the compound of Formula (VIII) in combination with another lipid lowering agent. In this WO 2007/136696

51 embodiment, preferably the lipid lowering agent comprises one or more HMG CoA reductase inhibitors. Preferably, the treatment composition comprises one or more HMG CoA reductase inhibitors such as, for example, lovastatin, atorvastatin and simvastatin in combination with a compound of Formula (VHI)

Still even more preferred, the treatment composition comprises compound of formula vπi in combination with atorvastatin and/or simvastatin.

In one embodiment of the invention, the compositions or therapeutic combinations can further comprise one or more pharmacological or therapeutic agents or drugs such as cholesterol biosynthesis inhibitors and/or lipid-lowering agents discussed below.

Also useful with the invention are compositions or therapeutic combinations that can further comprise at least one (one or more) activators for peroxisome proliferator-activated receptors (PPAR). The activators act as agonists for the peroxisome proiiferator-activated receptors. Three subtypes of PPAR have been identified, and these are designated as peroxisome proliferator-activated receptor alpha (PPARα), peroxisome proliferator-activated receptor gamma (PPARK) and peroxisome proliferator-activated receptor delta (PPARJ). It should be noted that PPARδ is also referred to in the literature as PPARJ3 and as NUC1, and each of these names refers to the same receptor.

JiK*: 52

PPARαr regulates the metabolism of lipids. PPARor is activated by fibrates and a number of medium and long-chain fatty acids, and it is involved in stimulating β- oxidation of fatty acids. The PPARK receptor subtypes are involved in activating the program of adipocyte differentiation and are not involved in stimulating peroxisome proliferation in the liver. PPAR<5 has been identified as being useful in increasing high density lipoprotein (HDL) levels in humans. See, e.g., WO 97/28149.

PPARσ activator compounds are useful for, among other things, lowering triglycerides, moderately lowering LOL levels and increasing HDL levels. Useful examples of PPARσ activators include fibric acid derivatives or fibrates.

Non-limiting examples of suitable fibric acid derivatives ("fibrates") include clofibrate (such as ethyl 2-(p-chlorophenoxy)-2-methyl-propionate, for example ATROM ID-S® Capsules which are commercially available from Wyeth-Ayerst); gemfibrozil (such as 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, for example LOPID® tablets which are commercially available from Parke Davis); ciprofibrate (C.A.S. Registry No. 52214-84-3, see U.S. Patent No. 3,948,973 which is incorporated herein by reference); bezafibrate (C.A.S. Registry No. 41859-67-0, see U.S. Patent No. 3,781,328 which is incorporated herein by reference); clinofibrate (C.A.S. Registry No. 30299-08-2, see U.S. Patent No. 3,716,583 which is incorporated herein by reference); binifibrate (C.A.S. Registry No. 69047-39-8, see BE 884722 which is incorporated herein by reference); lifibrol (C.A.S. Registry No. 96609-16-4); fenofibrate (such as TRICOR® micronized fenofibrate (2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester) which is commercially available from Abbott Laboratories or LIPANTHYL® micronized fenofibrate which is commercially available from Labortoire Founier, France) and mixtures thereof. These compounds can be used in a variety of forms, including but not limited to acid form, salt form, racemates, enantiomers, zwitterions and tautomers.

Other examples of PPARσ activators useful with the practice of the present invention include suitable fluorophenyl compounds as disclosed in U.S. No. 6,028,109 which is incorporated herein by reference; certain substituted phenylpropionic compounds as disclosed in WO 00/75103 which is incorporated herein by reference; WO 2007/136696

53 and PPARσ activator compounds as disclosed in WO 98/43081 which is incorporated herein by reference.

Non-limiting examples of suitable PPARK activators include derivatives of glitazones or thiazolidinediones, such as, troglitazone (such as REZULIN® troglitazone (-5-[[4-{3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2- yl)methoxy]phenyl] methyl]-2,4-thiazolidinedione) commercially available from Parke- Davis); rosiglitazone (such as AVANDIA® rosiglitazone maleate (-5-[[4-[2-(methyl-2- pyridinylamiπo)ethoxy] phenyl] methyl]-2,4-thiazolidinedione, (2>-2-butenedioate) commercially available from SmithKJine Beecham) and pioglitazone (such as ACTOS™ pioglitazone hydrochloride (5-[[4-[2-(5-ethyl-2- pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride) commercially available from Takeda Pharmaceuticals). Other useful thiazolidinediones include ciglitazone, engiitazone, darglitazone and BRL 49653 as disclosed in WO 98/05331 which is incorporated herein by reference; PPARy activator compounds disclosed in WO 00/76488 which is incorporated herein by reference; and PPARy activator compounds disclosed in U.S. Patent No. 5,994,554 which is incorporated herein by reference.

Other useful PPARK activator compounds include certain acetylphenols as disclosed in U.S. Patent No. 5,859,051 which is incorporated herein by reference; certain quinoline phenyl compounds as disclosed in WO 99/20275 which is incorporated herein by reference; aryl compounds as disclosed by WO 99/38845 which is incorporated herein by reference; certain 1,4-disubέtituted phenyl compounds as disclosed in WO 00/63161; certain aryl compounds as disclosed in WO 01/00579 which is incorporated herein by reference; benzoic acid compounds as disclosed in WO 01/12612 and WO 01/12187 which are incorporated herein by reference; and substituted 4-hydroxy-phenylalconic acid compounds as disclosed in WO 97/31907 which is incorporated herein by reference.

PPARJ compounds are useful for, among other things, lowering triglyceride levels or raising HDL levels. Non-limiting examples of PPARJ activators include suitable thiazole and oxazole derivates, such as C.A.S. Registry No. 317318-32-4, as disclosed in WO 01/00603 which is incorporated herein by reference); certain fluoro, WO 2007/136696

54 chloro or thio phenoxy phenylacetic acids as disclosed in WO 97/28149 which is incorporated herein by reference; suitable non-β-oxidizable fatty acid analogues as disclosed in U.S. Patent No. 5,093,365 which is incorporated herein by reference; and PPARJ compounds as disclosed in WO 99/04815 which is incorporated herein by reference.

Moreover, compounds that have multiple functionality for activating various combinations of PPARa, PPARp and PPARtJ are also useful with the practice of the invention. Non-limiting examples include certain substituted aryl compounds as disclosed in U.S. Patent No. 6,248,781; WO 00/23416; WO 00/23415; WO 00/23425; WO 00/23445; WO 00/23451; and WO 00/63153, all of which are incorporated herein by reference, are described as being useful PPARσ and/or PPARp activator compounds. Other non-limiting examples of useful PPARαr and/or PPARK activator compounds include activator compounds as disclosed in WO 97/25042 which is incorporated herein by reference; activator compounds as disclosed in WO 00/63190 which is incorporated herein by reference; activator compounds as disclosed in WO 01/21181 which is incorporated herein by reference; biaryl-oxa(thia)zole compounds as disclosed in WO 01/16120 which is incorporated herein by reference; compounds as disclosed in WO 00/63196 and WO 00/63209 which are incorporated herein by reference; substituted 5-aryl-2,4-thiazolidinedioπes compounds as disclosed in U.S. Patent No.6,008,237 which is incorporated herein by reference; arylthiazolidinedione and aryloxazolidinedione compounds as disclosed in WO 00/78312 and WO 00/78313G which are incorporated herein by reference; GW2331 or (2-(4- [difluorophenyl]-1 heptylureido)ethyl]phenoxy)-2-rnethylbutyric compounds as disclosed in WO 98/05331 which is incorporated herein by reference; aryl compounds as disclosed in U.S. Patent No.6,166,049 which is incorporated herein by reference; oxazole compounds as disclosed in WO 01/17994 which is incorporated herein by reference; and dithiolane compounds as disclosed in WO 01/25225 and WO 01/25226 which are incorporated herein by reference.

Other useful PPAR activator compounds include substituted benzylthiazolidine- 2,4-dione compounds as disclosed in WO 01/14349, WO 01/14350 and WO/01/04351 which are incorporated herein by reference; mercaptocarboxylic compounds as WO 2007/136696

55 disclosed in WO 00/50392 which is incorporated herein by reference; ascofuranone compounds as disclosed in WO 00/53563 which is incorporated herein by reference; carboxylic compounds as disclosed in WO 99/46232 which is incorporated herein by reference; compounds as disclosed in WO 99/12534 which is incorporated herein by reference; benzene compounds as disclosed in WO 99/15520 which is incorporated herein by reference; o-anisamide compounds as disclosed in WO 01/21578 which is incorporated herein by reference; and PPAR activator compounds as disclosed in WO 01/40192 which is incorporated herein by reference.

The peroxisome proliferator-activated receptor(s) activator(s) are administered in a therapeutically effective amount to treat the specified condition, for example in a daily dose preferably ranging from about 50 to about 3000 mg per day, and more preferably about 50 to about 2000 mg per day, given in a single dose or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on such factors as the potency of the compound administered, the age, weight, condition and response of the patient.

In an alternative embodiment, the compositions or therapeutic combinations of the invention can further comprise one or more ileal bile acid transport ("IBAT") inhibitors (or apical sodium co-dependent bile acid transport ("ASBT") inhibitors) coadministered with or in combination with the sterol absorption inhibitor(s) discussed above. The IBAT inhibitors can inhibit bile acid transport to reduce LDL cholesterol levels. Non-limiting examples of suitable IBAT inhibitors include benzothiepines such as therapeutic compounds comprising a 2,3,4,5-tetrahydro-1-benzothiepine 1,1- dioxide structure such as are disclosed in PCT Patent Application WO 00/38727 which is incorporated herein by reference.

Generally, a total daily dosage of IBAT inhibitors) can range from about 0.01 to about 1000 mg/day, and preferably about 0.1 to about 50 mg/day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or therapeutic combinations of the invention can further comprise nicotinic acid (niacin) and/or derivatives thereof coadministered with or in combination with the sterol absorption inhibitor(s) discussed above. WO 2007/136696

56

As used herein, "nicotinic acid derivative" means a compound comprising a pyridine-3-carboxylate structure or a. pyrazine-2-carboxylate structure, including acid forms, salts, esters, zwitterions and tautomers, where available. Examples of nicotinic acid derivatives include niceritrol, nicofuranose and acipimox (5-methyl pyrazine-2- carboxylic acid 4-oxide). Nicotinic acid and its derivatives inhibit hepatic production of VLOL and its metabolite LDL and increases HDL and apo A-1 levels. An example of a suitable nicotinic acid product is NIASPAN® (niacin extended-release tablets) which are available from Kos.

Generally, a total daily dosage of nicotinic acid or a derivative thereof can range from about 500 to about 10,000 mg/day, preferably about 1000 to about 8000 mg/day, and more preferably about 3000 to about 6000 mg/day in single or divided doses.

In another alternative embodiment, the compositions or therapeutic combinations of the invention can further comprise one or more AcylCoA:Cholesterol O-acyltransferase ("ACAT") Inhibitors, which can reduce LDL and VLDL levels, coadministered with or in combination with the sterol absorption inhibitor(s) discussed above. ACAT is an enzyme responsible for esterifying excess intracellular cholesterol and may reduce the synthesis of VLDL, which is a product of cholesterol esterification, and overproduction of apo B- 100-containing lipoproteins.

Non-limiting examples of useful ACAT inhibitors include avasimibe ([[2,4,6- tris(1-methylethyl)phenyl]acetyl]sulfamic acid, 2,6-bis(1-methylethyl)phenyl ester, formerly known as CI-1011), HL-004, lecimibrde (DuP-128) and CL-277082 (Λ/-(2,4- difluorophenyl)-Λ/-[[4-(2,2-dimethylpropyl)phenyl]methyl]-Λ/-heptylurea). See P. Chang et al., "Current, New and Future Treatments in Dyslipidaemia and Atherosclerosis", Drugs 2000 Jul;60(1); 55-93, which is incorporated by reference herein.

Generally, a total daily dosage of ACAT inhibitors) can range from about 0.1 to about 1000 mg/day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or therapeutic combinations of the invention can further comprise one or more Cholesteryl Ester Transfer Protein ("CETP") Inhibitors coadministered with or in combination with the WO 2007/136696

57 sterol absorption inhibitors) discussed above. CETP is responsible for the exchange or transfer of cholesteryl ester carrying HDL and triglycerides in VLDL.

Non-limiting examples of suitable CETP inhibitors are disclosed in PCT Patent Application No. WO 00/38721, WO2005/095409, WO2000/176164, WO2000/17165, WO2000/17166 and U.S. Patent No. 6,147,090, which are incorporated herein by reference as well as the documents cited in these publications are also incorporated by reference. Pancreatic cholesteryl ester hydrolase (pCEH) inhibitors such as WAY- 121898 also can be coadministered with or in combination with the peroxisome proliferator-activated receptor(s) activator and sterol absorption inhibitor(s) discussed above.

Especially preferred CEPT inhibitors which may be used in pharmaceutical combinations with the sterol absorption inhibitor(s) discussed above are tetrahydroquinoline derivatives of the formula (I¹):

R^β N

T T

I .

(i⁽) wherein R¹ is a hydrogen atom, an optionally substituted alkoxycarbonyJ group, an optionally substituted carbamoyl group, an optionally substituted alkyl group, an optionally substituted alkanoyl group, a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen atoms (the heterocyclic group is optionally substituted), or a saturated or unsaturated monocyclic or bicylic heterocyclic carbonyl group containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen atoms (the heterocyclic group is optionally substituted); R² is a hydrogen atom or an optionally substituted alkyl group;

lliRi 58

R³ is a hydrogen atom or an optionally substituted alkyl group; R⁴ is an optionally substituted alkyleπe group;

R⁵ is a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen atoms, wherein the heterocyclic group is substituted by 1 to 5 substituents selected from the following groups, or said heterocyclic group is substituted by 1 to 5 substituents selected from the following groups and further by a halogen atom, an oxo and/or hydroxyl group; cyano group, nitro group, carboxyl group, sulfo group, C3.10 alkyl group, substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted alkenyl group, C3.10 alkoxy group, substituted alkoxy group, optionally substituted cycloalkoxy group, optionally substituted alkoxycarbonyl group, optionally substituted carbamoyl group, optionally substituted carbamimidoyl group, optionally substituted alkylthio group, optionally substituted alkylsulfinyl group, optionally substituted alkylsulfonyl group, optionally substituted allkylsuflonyl group, optionally substituted amino group, optionally substituted sulfamoyl group, optionally substituted alkanoyl group, a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen atoms (the heterocyclic group is optionally substituted), a saturated or unsaturated monocyclic or bicyclic heterocyclic oxy group containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen atoms (the heterocyclic oxy group is optionally substituted), and a saturated or unsaturated monocyclic or bicyclic heterocyclic carbonyl group containing 1 to 4 heterocyclic carbonyl group is optionally substituted);

R⁶ and R⁷, or R⁷ and R^a, or R⁸ and R⁹ may combine at the ends to form an alkylene group which alkylene group may contain 1 to 3 heteroatoms selected independently from nitrogen, sulfur and oxygen atoms, and may have a substituent(s); and 59

R¹⁰ is an aromatic ring optionally containing 1 to 3 heteroatoms selected independently from oxygen, sulfur and nitrogen atoms (the aromatic ring is optionally substituted), or a pharmaceutically acceptable salt thereof. The definitions for compounds of formula (I¹) are those described in WO 2005/095409. The compound (I") of the present invention encompasses a mixture of stereoisomers, respective stereoisomers in a purified or substantially purified form.

Another embodiment of the present invention include compounds of the formula (I) wherein R⁵ is a group of the formula:

wherein Ring A is - a ⁰ saturated- or unsaturated 5- to 8-membered heterocyclic group containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen atoms, and R¹¹ is a group selected from the following groups: cyano group; nitro group; carboxyl group; sulfo group; alkyl group substituted by a group selected from halogen atom, cyano group, hydroxyl group, carboxyl group, alkoxycarbonyl group, alkoxy group (said alkoxy group is optionally substituted by phenyl, hydroxyl or carboxyl group), alkanoyloxy group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono- or di-alkylamino group, mono- or di-alkylsulfamoylamino group, mono- or di-alkylureido group optionally substituted by morpholinyl group, oxiranyl group, dialkyldioxolanyl group, pyrrolidinyf grouop optionally substituted by alkoxycarbonyl or carboxyl group, piperidinyl group optionally substituted by alkoxycarbonyl or carboxyl group, piperazinyl group optionally substituted by alkyl group, hexahydroazepinyl grouop and morpholinyl group; 60 alkenyl group optionally substituted by carboxyl group, cyano group or benzyloxycarbonyl group; alkoxy grouop substituted by a group selected from halogen atom, cyano group, hydroxyl group, carboxyl group, alkoxycarbonyl group, alkoxy group (said alkoxy group is optionally substituted by phenyl, hydroxyl or carboxyl group), alkanoyloxy group, alkylthio group, alkylsulfonyl group, mono- or di-alkylsulfamoylamino group, mono- or di-alkylureido group optionally substituted by morpholinyl group, oxiranyl group, di- alkyldioxolanyl group, pyrrolidinyl group optionally substituted by alkoxycarbonyl or carboxyl group, piperidinyl group optionally substituted by alkoxycarbonyl or carboxyl group, piperazinyl group optionally substituted by alkyl group, hexahydroazepinyl group and morpholinyl group; alkoxycarbonyl group optionally substituted by phenyl group; mono- or di-alkylcarbamoyl group optionally substituted by carboxyl group; hydroxycarbamimidoyl group; alkylthio group; alkylsulfinyl group; alkylsulfonyl group optionally substituted by carboxyl group; mono- or di-alkylamino group optionally substituted by hydroxyl group, carboxyl group, alkoxycarbonyl group, alkoxy group, mono- or di- alkylamino group or morpholinyl group; mono- or di-alkylsulfamoyl group; morpholinyl group; optionally oxidized thiomorpholinyl group; piperazinyl group optionally substituted by a group selected from alkyl group, alkanoyl group and hydroxyalkanoyl group; pyrrolidinyl group optionally substituted by carboxyl group, carboxyalkyl group, alkyl group, alkoxycarbonyl group or alkoxycarbonylalkyl group; dioxolanyl group optionally substituted by alkyl group; WO 2007/136696

61 tetrazolyl group optionally substituted by alkyl group, hydroxyalkl group or morpholinylalkyl group; dihydrooxadiazolyl group optionally substituted by oxo group; pyrimidinyl group; or tetrahydropyranyl group; which compound is shown by the formula (I'-A):

_R4— RIO

where each symbol has the same meaning as defined above.

More preferred embodiment includes compounds of the formula (I) where R¹ is a hydrogen atom; an alkoxycarbonyl group optionally substituted by 1 to 5 substituents selected independently from cyano group, hydroxy! group, carboxyl group, alkoxycarbonyl group, alkoxy group (said alkoxy group is optionally substituted by 1 to 3 substituents selected independently from hydroxy grouop, amino group, mono- or di-alkylamiπo group, halogen atom, carboxyl grop, alkoxycarbonyl group, carboxyalkoxy group and alkoxycarbonylalkoxy group), alkylthio group, alkylsulfonyl group, alkenyl group, amino group, mono- or di-afkyfamino group, tetrazolyl group, carbamoyl group, mono- or di-alkylcarbamoyl group (said mono- or di-alkylcarbamoyl group is optionally substituted by 1 to 3 substituents selected independently from carboxyl group and alkoxycarbonyl group), alkanoylamino group (said alkanoylamino group is optionally substituted by 1 to 3 substituents selected independently from carboxyl group, alkoxycarbonyl group, hydroxyl group and halogen atom), halogen atom, cycloalkyl grop (said cycloalkyl group is optionally substituted by 1 to 3 substituents selected independently from hydroxyl group, amino group, mono- or di- WO 2007/136696

62 alkylamino group, halogen atom, oxo group, carboxyl group, alkoxycarboπyl group, carboxyalkyl group, alkoxcarbonylalkyJ group, carboxyalkoxy group and alkoxycarbonylalkoxy group), phenyl group (said phenyl group is optionally substituted by 1 to 3 substitutents selected independently from hydroxyl group, amino group, mono- or di-alkylamino group, halogen atom, carboxyl group, alkoxycarbonyl group, carboxyalkyl group, alkoxcarbonylalkyl group, carboxyalkoxy group and alkoxycarbonylalkoxy group), morpholinyl group optionally substituted by oxo group, piperidinyl group (said piperidiπyl group is optionally substituted by 1 to 3 substituents selected indepdently from hydroxyl group, amino group, mono- or di-alkylamino group, halogen atom, oxo grouop, carboxyl group, alkoxycarbonyl group, carboxyalkyl group, alkoxycarbonylalkyl group and carboxyalkoxy group, alkoxycarbonylalkoxy group), pyrrolidinyl group (said pyrrolidinyl group is optionally substituted by 1 to 3 substitutents selected independently from hydroxy group, amino group, mono- or di- alkylamino group, halogen atom, oxo group, carboxyl group, alkoxycarboπyl group and alkoxycarbonylalkoxy group), and pyrimidinyl group (said pyrimidinyl group is optionally substituted by 1 to 3 substituents selected independently from carboxyalkyl group, alkoxycarbonylalkyl group and carboxyalkoxy group, alkoxycarbonylalkoxy group); dihydrooxazolyl group optionally substituted by 1 to 2 substituents selected independently from carboxyl group, alkoxycarbonyl group, alkyl group, carboxyalkyl group, alkoxycarbonylalkyl group and hydroxyalkyl group; or a mono- or di- alkylcarbamoyl group optionally substituted by 1 to 5 substituents selected independently from halogen atom, hydroxy group, carboxyl group, alkoxycarbonyl group, alkoxy group, amino group, mono- or di-alkylamino group, morpholinyl group, pyridyl group, cycloalkyl group (said cycloalkyl group is optionally substituted by 1 to 3 substituents selected independently from carboxyl group, alkoxycarbonyl group, halogen atom, amino group and hydroxyl group) and phenyl group (said phenyl group is optionally substituted by 1 to 3 substituents selected independently from carboxyl group, alkoxycarbonyl group, halogen atom, amino group and hydroxyl group);

R² is an alkyl group;

R³ is a hydrogen atom;

R⁴ is an alkylene group; 63

Ring A and R¹¹ are the same groups as defined above;

R⁶ and R⁹ each are a hydrogen atom;

R⁷ and R^a are independently a hydrogen atom, an alkyl group optionally substituted by halogen atom, alkoxy group, or mono- or di-alkylamino group; or combine at the dns to form an alkyleπedioxy group and

R¹⁰ is a phenyl or pyridyl group, which phenyl or pyridyl group is optionally substituted by 1 to 4 substituents selected from alkyi group optionally substituted by halogen atom, alkoxy group, hydroxyl group, halogen atom, cyano group, amino group and mono- or di-alkylamino group.

Another preferred embodiment includes compouds of the formula (I¹) wherein Ring A is a saturated or unsaturated 5- to 8-membered heterocyclic group containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen atoms, and

R¹¹ is a group selected from the following groups: cyano group; nitro group; carboxyl group; sulfo group, alkyl group substituted by a group selected from halogen atom, hydroxyl group, carboxyl group, alkoxycarbonyl group, alkoxy group optionally substituted by phenyl or hydroxyl group, alkanoyloxy group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono- or di-alkylamino group, mono- or di- alkylsulfamoylamino group, mono- or dialkylureido group optionally substituted by morpholinyl group, oxiranyl group, di-alkyldioκolanyl group, pyrrolidinyl group optionally substituted by alkyl group, hexahydroazepinyl group and morpholinyl group; alkenyl group optionally substituted by carboxyl group or benzyloxycarbonyl group; alkoxy group substituted by carboxyl group, hydroxyl group, alkoxy group, alkylthio group, alkylsulfonyl group or alkoxyphenyl group; alkoxycarbonyl group optioally substituted by phenyl group, mono- or di- alkylcarbamoyl group optionally substituted by carboxyl group; hydroxycarbamimidoyl group; alkylthio group; alkylsulfinyl group; alkylsulfonyl group optionally substituted by alkoxycarbonyl group; mono- or di-afkylamino group optionally substituted by hydroxyl group, carboxyl group, alkoxycarbonyl group, alkoxy group, mono- or di-alkylamino group or morpholinyl group; mono- 64 or di-alkylsulfamoyl group; morpholinyl group; optionally oxidized thiomorpholinyl group; piperazinyl group optionally substituted by a group selected from alkyl grop, alkanoyl group and hydroxyalkanoyl group; piperidinyl group optionally substituted by carboxyl group, alkyl group or alkoxycarbonyl group; dioxolanyl group optionally substituted by alkyl group; tetrazolyl group substituted by alkyl group, hydroxyalkl group or morpholinylalkyl group; dihydrooxadiazolyl group optionally substituted by oxo group; pyrimidinyl group; or tetrahydropyranyl group.

More preferred embodiment herein included compounds of the formula (I¹) wherein R¹ is an alkoxycarbonyl group optionally substituted by a group selected from hydroxy group and alkoxy group; or a dihydrooxazolyl group optionally substituted by hydroxyalkyl group; R² is an alkyl group; R³ is a hydrogen atom; R⁴ is an alkylene group;

Ring A and R¹¹ are the same groups as defined above; R⁶ and R⁹ each are a hydrogen atom; and

R⁷ and R⁸ are independently a hydrogen atom, an alkyl group optionally substituted by 1 to 9 halogen atoms, an alkoxy group, or a mono- or di- alkyJamino group; or combine at the ends to form an alkylenedioxy group; R¹⁰ is a phenyl or pyridyl group, which phenyl or pyridyl group is optionally substituted by 1 to 4 substituents selected from afkyl group optionally substituted by 1 to 9 halogen atoms, alkoxy group, hydroxyl group, halogen atom, cyano group, amino group and mono- or di-alkylamino group.

Examples of Ring A include a pyrimidinyl group, a pyridyl group, a triazolyl group, a tetrazolyl group, an oxadiazolyl group, a dihydropyrimidinyl group, a pyrazinyl group, a thiazoyl group, an oxazolyJ group, a dihydropyrazinyl group, and the like.

More preferred compounds include those where Ring A is a pyrimidinyl group, a pyridyl grop, a tetrazolyl group, an oxadiazolyl grop, a pyrazinyl group, a thiazolyl group or an oxazolyl group; and R¹¹ is a carboxyl group; a cyano group,; a nitro group; an alkyl group substituted by a group selected from hydroxyl group, cyano group, WO 2007/136696

65 carboxyl group, alkoxycarbonyl group, alkoxy group, phenylalkoxy group, hydroxyalkoxy group, carboxyalkoxy group, alkylthiσ group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono- or di-alky!amiπo group, mono- or di- alkylsulfamoylamino group, mono- or di-alkylureido group optionally substituted by rnorpholinyl group, oxiranyl group, di-alkyldioxolanyl group, pyrrolidinyl group optionally substituted by carboxyl group, piperidinyl group optionally substituted by carboxyl group, piperazinyl group optionally substituted by alkyl group and morpholinyl group; an alkenyl group optionally substituted by carboxyl group; an alkoxy group substituted by a group selected from hydroxyl group, cyano group, carboxyl group, alkoxycarbonyl group, alkoxy group, phenylalkoxy group, hydroxyalkoxy group, carboxyalkoxy group, alkylthio group, alkylsulfonyl group, alklsulfinyl group, amino group, mono- or dialkylamino group, mono- or di-alkylsulfamoylamino group, mono- or d i-aJkylamino group, mono- or di-alkylsulfamoylamino group, mono- or di-alkylureido group optionally substituted by morpholinyl group, oxiranyl group, di-alkyldioxolanyl group, pyrrolidinyl group optionally substituted by carboxyl group, piperazinyl group optionally substituted by alkyl group and morpholinyl group; an alkoxycarbonyl group; a hydroxycarbarn/midoyl group; alkylthio group; an alkylsulfonyl group optionally substituted by carboxyl group; a mono- or di-alkyfamiπo group optionally substituted by hydroxyl group; carboxyl group, alkoxy group or mono- or di-alkylamino group; a morpholinyl group; an optionally oxidized thiomorpholinyl group; a piperazinyl group optionally oxidized thiomorpholinyl group; a piperazinyl group optionally substituted by a group selected from alkyl group, alkanyoyl group and hydroxyalkanoyl group; a pyrrolidinyl group optionally substituted by carboxyl group, alkyl group carboxyalkyl group or alkoxcarbonyl group; a piperidinyl group optionally susbstituted by carboxyl group, alkyl group, carboxyalkyl group or alkoxycarbonyl group; a tetrazolyl group optionally substituted by alkyl group, hydroxyalkyl group, or morpholinylalkyl group; an oxodihydrooxadiazolyl group; a pyrimidinyl group; or a tetrahydropyranyl group.

Still more preferred compounds include those where R¹ is an alkoxycarbonyl group optionally substituted by 1 to 5 substituents selected independently from hydroxyl group, carboxyl group, alkoxycarbonyl group, alkoxy group (said alkoxy group is optionally substituted by 1 to 3 substituents selected independently from 66 hydroxyl group, halogen atom, carboxyl group and alkoxycarbonyl group), alkenyl group, halogen atom, cycloalkyl group (said cycloalkyl group is optionally substituted by 1 to 3 substituents selected independently from hydroxy group, halogen atom, carboxyl group, alkoxycarbonyl group, carboxyalkyl group and alkoxycarbonylalkyl group), phenyl group (said phenyl group is optionally substituted by 1 to 3 substituents selected selected independently from hydroxyl group, halogen atom, carboxyl group, alkoxycarbonyl group, carboxyalkyl group and alkoxycarbonylalkyl group), piperidinyl group (said piperidinyl group is optionally substituted by 1 to 3 substituents selected independently from hydroxyl group, halogen atom, carboxyl group, alkoxycarbonyl group, carboxyalkyl group and alkoxycarbonylalkyl group), and pyrrolidinyl group (said pyrrolidinyl group is optionally substituted by 1 to 3 substituents selected independently from hydroxyl group, halogen atom, carboxyl group, alkoxycarbonyl group, carboxyalkyl group and alkoxcarbonylalky group); or a dihydrooxazolyl group optionally substituted by 1 or 2 substituents selected independently from carboxyl group, alkoxycarbonyl group, carboxyalkyl group, alkoxycarbonylalkyl group and hydroxyalkyl group;

R¹⁰ is a phenyl group substituted by 1 to 3 substituents selected from alkyl group optionally substituted by halogen atom, alkoxy group, halogen atom and cyano group;

Ring A is a pyrimidinyl group, a pyridl group, a tetrazolyl group, an oxadiazolyl group or a thiazolyl group; and

R¹¹ is a carboxyl group, a cyano group, a nitro group; and alkyl group substituted by a group selected from hydroxyl group, carboxyl group, alkoxycarbonyl group, alkoxy group, phenylalkoxy group, carboxyalkoxy group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono- or di-alkylaminio group, mono- or di-alkylsulfamoylamino group, mono- or di-alkylureido group optionally substituted by morpholinyl group, oxiranyl group, di-alkyldioxolanyl group, piperaziny/ group optionally substituted by alkyl group and morpholinyl group; an alkenyl group optiojally substituted by carboxyl group; an alkoxy group substituted by a group selected from cyano group, hydroxyl group, carboxyl group, alkoxycarbonyl group, alkoxy grouop, phenylalkoxy group, carboxyalkoxy group, alkylthio group, alkylsulfonyl WO 2007/136696

67 group, alkylsulflnyl group, amino group, mono- or di-alkylamino group, mono- or di- alkylsulfamoylamino group, mono- or di-alkyldioxolanyl group, piperazinyl group optionally substituted by alkyl group and morpholinyf group; a hydroxycarbamimidoyf group; an alkylthio group; an alkylsulfonyl group optionally substituted by alkoxycarbonyl group; a mono- or di-alkylamino group optionally substituted by hydroxyl group, carboxyl group or alkoxy group; a morpholinyf group; optionally oxidized thiomorpholinyl group, a piperazinyl group optionally substituted by a group selected from alkyl group, alkanoyl group and hydroxyalkanoyl group, a pyrrolidinyl group optionally substituted by carboxyl group, alkyl group carboxyalkyl group or alkoxycarbonyl group; a piperidinyl group optionally substituted by carboxyl group, alkyl group, carboxyalkyl group or alkoxycarbonyl group, a tetrazolyl group optionally substituted by alkyl group, hydroxyalkyl group, or mopholinylalkyl group; and oxodihydrooxadiazoyl group; a pyrimidinyl group; or a tetrahydropyranyl group.

Still furthermore preferred compounds include those where R¹ is an alkoxycarbonyl group optionally substituted by 1 or 5 substituents selected independently from carboxyl group, alkoxycarbonyl group, halogen atom, hydroxyl group and cycloalkyl group;

R¹⁰ is a phenyl group substituted by 1 to 3 substituents selected from cyano group, alkyl group optionally substituted by halogen atom and alkoxy group; Ring A is a pyrimidinyl group, a pyridyl group, a tetrazolyl grop or an oxadiazolyl group;

R¹¹ is a carboxyl group; an alkyl group substituted by hydroxyl group, carboxyl group, alkoxy group or alkylsulfonyl group; an alkenyl group optionally substituted by carboxyl group; an alkoxy group substituted by cyano group, carboxyl group, hydroxyl group, alkoxy group, alkylthio group or alkylsulfonyl group; a mono- or di-alkylamino group optionally substituted by carboxyl group or alkoxy group; a morpholinyl group; a piperidinyl group substituted by hydroxyalkyl group;

R⁷ is an alkyl group optionally substituted by halogen atom, alkoxy grouop, or mono- or di-alkylamino group; and R⁸ is a hydrogen atom. WO 2007/136696

68

Especially preferred compounds include those wherein R¹ is an ethoxycarbonyl group, a hydroxyethoxycarbonyl group, a 2-fIuoroethoxycarbonyl group, a 2,2- difluoroethoxycarboπyl group or a 2,2,2-trifIuoroethoxycarbonyl group; R² is an ethyl group; R¹⁰ is a phenyl group substituted by 1 to 2 substituents selected from cyano group, trifluoromethyl group and methoxy group; R⁷ is a trifluoromethyl group or a methoxy group. In this regard, other examples of especially preferred compounds include those wherein R¹ is a carboxy (C₂-ioalkoxy) carbonyl group or an alkoxycarbonyl (C2-ioa/koxy) carbonyl group, and R² R¹⁰and R⁷ are the same above.

Especially more preferred compounds include those wherein R¹ is an ethoxycarbonyl group or a hydroxyethoxycarbonyl group; R² is an ethyl group; R¹⁰ is a phenyl group substituted by 1 to 2 substituents selected from cyano group, trifluoromethyl group and methoxy group; R⁷ is a trifluoromethyl group or a methoxy group.

Especially preferred sterol absorption inhibitors which may be combined in pharmaceutical combinations with compounds of Formula (I") are those represented by Formula (I)

R¹

Ar -A-Y;

R*

N.

Cf ^"W²

(I)

or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (r) or of the isomers thereof, or prodrugs of the compounds of Formula (f) or of the isomers, salts or solvates thereof, wherein:

Ar^"! is R3-SU bstituted aryl; Ar^ is R4-substituted aryl; Ar^ is R⁵-substituted aryl;

Y and Z are independently selected from the group consisting of -CH2-. - CHøower alkyl)- and -C(dilower alkyl)-; WO 2007/136696

69

A is -O-, -S-, -S(O)- or -S(O)2-;

R¹ is selected from the group consisting of -OR⁶, -O(CO)R⁶, -O(CO)OR⁹ and ■ 0(CO)N R⁶R⁷;

R2 is selected from the group consisting of hydrogen, lower alkyl and aryl; or

R¹ and R² together are =O; q is 1, 2 or 3; p is O, 1, 2, 3 or 4;

R⁵ is 1-3 substituents independently selected from the group consisting of - OR⁶, -0(CO)R⁶, -O(CO)OR9 -O(CH2)1-5OR9, -0(CO)NR⁶R⁷, -NR⁶R⁷, - NR⁶(CO)R⁷, -NR⁶(C0)0R9, -NR⁶(CO)NR⁷R8, -NR⁶SO2-lower alkyl, -NR⁶SO2-aryl, -CONR⁶R⁷, -COR⁶, -SO2NR⁶R⁷ S(O)θ-2-alkyl, S(O)rj-2~aryl, -O(CH2)1-10- COOR⁶,-O(CH2)1-1 OCONR⁶R⁷, o-halogeno, m-halogeno, o-lower alkyl, m-lower alkyl, -(lower alkylene)-COOR⁶, and -CH=CH-COOR⁶;

R³ and R⁴ are independently 1-3 substituents independently selected from the group consisting of R⁵, hydrogen, p-lower alkyl, aryl, -NO2, -CF3 and p-halogeno;

R⁶, R⁷ and R^ are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl.

An especially preferred sterol absorption inhibitor which may be combined in pharmaceutical combinations with compounds of Formula (I") is wherein the sterol absorption inhibitor is represented by Formula (¹VIII)

.OH

OH

(VIIl) WO 2007/136696

70

Generally, a total daily dosage of CETP inhibitors) can range from about 0.01 to about 1000 mg/day, and preferably about 0.5 to about 20 mg/kg body weight/day in single or divided doses.

In another alternative embodiment, the compositions or therapeutic combinations of the invention can further comprise probucol or derivatives thereof (such as AGI-1067 and other derivatives disclosed in U.S. Patents Nos. 6,121,319 and 6,147,250), which can reduce LDL levels, coadministered with or in combination with the sterol absorption inhibitor(s) discussed above.

Generally, a total daily dosage of probucol or derivatives thereof can range from about 10 to about 2000 mg/day, and preferably about 500 to about 1500 mg/day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of the invention can further comprise low-density lipoprotein (LDL) receptor activators, coadministered with or in combination with the sterol absorption inhibitors) discussed above. Non-limiting examples of suitable LDL-receptor activators include HOE-402, an imidazolidinyl-pyrimidine derivative that directly stimulates LDL receptor activity. See M. Huettinger et al., "Hypolipidemic activity of HOE-402 is Mediated by Stimulation of the LDL Receptor Pathway", Arterioscler. Thromb. 1993; 13:1005-12.

Generally, a total daily dosage of LDL receptor activator(s) can range from about 1 to about 1000 mg/day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or therapeutic combinations of the invention can further comprise fish oil, which contains Omega 3 fatty acids (3-PUFA), which can reduce VLDL and triglyceride levels, coadministered with or in combination with sterol absorption inhibitor(s) discussed above. Generally, a total daily dosage of fish oil or Omega 3 fatty acids can range from about 1 to about 30 grams per day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or therapeutic combinations of the invention can further comprise natural water soluble fibers, such as psyllium, guar, oat and pectin, which can reduce cholesterol levels, coadministered with or in combination with the sterol absorption inhibitors) discussed above. WO 2007/136696

71

Generally, a total daily dosage of natural water soluble fibers can range from about 0.1 to about 10 grams per day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or therapeutic combinations of the invention can further comprise plant sterols, plant stanols and/or fatty acid esters of plant stanols, such as sitostaπol ester used in BENECOL® margarine, which can reduce cholesterol levels, coadministered with or in combination with the sterol absorption inhibitors) discussed above. Generally, a total daily dosage of plant sterols, plant stanols and/or fatty acid esters of plant stanols can range from about 0.5 to about 20 grams per day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or therapeutic combinations of the invention can further comprise antioxidants, such as probucol, tocopherol, ascorbic acid, β-carotene and selenium, or vitamins such as vitamin Be or vitamin B^, coadministered with or in combination with the sterol absorption inhibitors) discussed above. Generally, a total daily dosage of antioxidants or vitamins can range from about 0.05 to about 10 grams per day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or therapeutic combinations of the invention can further comprise monocyte and macrophage inhibitors such as polyunsaturated fatty acids (PUFA), thyroid hormones including throxine analogues such as CGS-26214 (a thyroxine compound with a fluorinated ring), gene therapy and use of recombinant proteins such as recombinant apo E, coadministered with or in combination with the sterol absorption inhibitors) discussed above. Generally, a total daily dosage of these agents can range from about 0.01 to about 1000 mg/day in single or 2-4 divided doses.

Also useful with the invention are compositions or therapeutic combinations which further comprise hormone replacement agents and compositions. Useful hormone agents and compositions for hormone replacement therapy of the present invention include androgens, estrogens, progestins, their pharmaceutically acceptable salts and derivatives thereof. Combinations of these agents and compositions are also useful. WO 2007/136696

72

The dosage of androgen and estrogen combinations vary, desirably from about 1 mg to about 4 mg androgen and from about 1 mg to about 3 mg estrogen. Examples include, but are not limited to, androgen and estrogen combinations such as the combination of esterified estrogens (sodium estrone sulfate and sodium equilin sulfate) and methyltestosterone (17-hydroxy-17-methyl-, (17B)- androst-4-en-3-one) available from Solvay Pharmaceuticals, Inc., Marietta, GA, under the tradename Estratest.

Estrogens and estrogen combinations may vary in dosage from about 0.01 mg up to 8 mg, desirably from about 0.3 mg to about 3.0 mg. Examples of useful estrogens and estrogen combinations include:

(a) the blend of nine (9) synthetic estrogenic substances including sodium estrone sulfate, sodium equilin sulfate, sodium 17 a -dihydroequilin sulfate, sodium 17 a -estradiol sulfate, sodium 17 β -dihydroequilin sulfate, sodium 17 or -dihydroequilenin sulfate, sodium 17 β -dihydroequilenin sulfate, sodium equilenin sulfate and sodium 17 β -estradiol sulfate; available from Duramed Pharmaceuticals, Inc., Cincinnati, OH, under the tradename Cenestin;

(b) ethinyl estradiol (19-nor-17 a -pregna-1 ,3,5(10)-trien-20-yne-3, 17-diol; available by Schering Plough Corporation, Kenilworth, NJ, under the tradename Estinyl;

(c) esterified estrogen combinations such as sodium estrone sulfate and sodium equilin sulfate; available from Solvay under the tradename Estratab and from Monarch Pharmaceuticals, Bristol, TN, under the tradename Menest;

(d) estropipate (piperazine estra-1 ,3,5(10)-trien-17-one, 3-(sulfooxy)- estrone sulfate); available from Pharmacia & Upjohn, Peapack, NJ, under the tradename Ogen and from Women First Health Care, Inc., San Diego, CA, under the tradename Ortho-Est; and

(e) conjugated estrogens (17 <7-dihydroequilin, 17 σ-estradiol, and 17 β- dihydroequilin); available from Wyeth-Ayerst Pharmaceuticals, Philadelphia, PA, under the tradename Premarin.

Progestins and estrogens may also be administered with a variety of dosages, generally from about 0.05 to about 2.0 mg progestin and about 0.001 mg to about 2 WO 2007/136696

73 mg estrogen, desirably from about 0.1 mg to about 1 mg progestin and about 0.01 mg to about 0.5 mg estrogen. Examples of progestin and estrogen combinations that may vary in dosage and regimen include:

(a) the combination of estradiol (estra-1.3, 5 (10)-triene-3, 17 β-diol hemihydrate) and norethindrone (17/?-acetoxy-19-nor-17 ύr-pregn-4-en-20-yn-3-one); which is available from Pharmacia & Upjohn, Peapack, NJ, under the tradename Activella;

(b) the combination of levonorgestrel (d(-)-13 £-ethyl-17 σ-ethinyl-17 β- hydroxygon- 4-en-3-one) and ethinyl estradial; available from Wyeth-Ayerst under the tradename Alesse, from Watson Laboratories, Inc., Corona, CA, under the tradenames Levora and Trivora, Monarch Pharmaceuticals, under the tradename Nordette, and from Wyeth-Ayerst under the tradename Triphasil;

(c) the combination of ethynodiol diacetate (19-nor-17 σ-pregn-4-en-20-yne- 3 β, 17-diol diacetate) and ethinyl estradiol; available from G. D. SearJe & Co., Chicago, IL, under the tradename Oemulen and from Watson under the tradename Zovia;

(d) the combination of desogestrel (13-ethyl-11- methylene- 18, 19-dinor-17 σ-pregn- 4-en- 20-yn-17-ol) and ethinyl estradiol; available from Organon under the tradenames Desogen and Mircette, and from Ortho-McNeil Pharmaceutical, Raritan, NJ, under the tradename Ortho-Cept;

(e) the combination of norethindrone and ethinyl estradiol; available from Parke-Davϊs, Morris Plains, NJ, under the tradenames Estrostep and femhrt, from Watson under the tradenames Microgestin, Necon, and Tri-Norinyl, from Ortho-McNeil under the tradenames Modicon and Ortho-Novum, and from Warner Chilcott Laboratories, Rockaway, NJ, under the tradename Ovcoπ;

(f) the combination of norgestrel ( (±)-13-ethyl-17-hydroxy-18, 19-dinor-17 σ~preg-4-en-20-yn-3-one) and ethinyl estradiol; available from Wyeth-Ayerst under the tradenames Ovral and Lo/Ovral, and from Watson under the tradenames Ogestrel and Low-Ogestrel; 74

(g) the combination of norethindrone, ethinyl estradiol, and mestranol (3- methoxy-19-nor-17 σ-pregna-1 ,3,5(10)-trien-20-yn-17-ol); available from Watson under the tradenames Brevicon and Norinyl;

(h) the combination of 17 yff-estradiol (estra-1 ,3,5(10)-triene-3,17£-diol) and micronized norgestimate (17 σ-17-(Acetyloxyl)-13-ethyl-18,19-dinorpregn-4-en-20-yn- 3-one3-oxime); available from Ortho-McNeil under the tradename Ortho-Prefest;

(i) the combination of norgestimate (18,19-dinor-17-pregn-4-en-20-yn-3- one, 17— (acetyloxyJ-IS-ethyl-.oxime, (17(or)-(⁺)-) and ethinyl estradiol; available from Ortho-McNeil under the tradenames Ortho Cyclen and Ortho Tri-Cyclen; and

(j) the combination of conjugated estrogens (sodium estrone sulfate and sodium equilin sulfate) and medroxyprogesterone acetate (20-dione, 17-(acetyloxy)-6- methyl-, (6(αr))- pregn-4-ene-3); available from Wyeth-Ayerst under the tradenames Premphase and Prempro.

In general, a dosage of progestins may vary from about .05 mg to about 10 mg or up to about 200 mg if microsized progesterone is administered. Examples of progestins include norethindrone; available from ESI Lederie, Inc., Philadelphia, PA, under the tradename Aygestin, from Ortho-McNeil under the tradename Micronor, and from Watson under the tradename Nor-QD; norgestrel; available from Wyeth-Ayerst under the tradename Ovrette; micronized progesterone (pregn-4-ene-3, 20-dione); available from Solvay under the tradename Prometrium; and medroxyprogesterone acetate; available from Pharmacia & Upjohn under the tradename Provera.

The compositions, therapeutic combinations or methods of the invention can further comprise one or more obesity control medications. Useful obesity control medications include, but are not limited to, drugs that reduce energy intake or suppress appetite, drugs that increase energy expenditure and nutrient-partitioning agents. Suitable obesity control medications include, but are not limited to, noradrenergic agents (such as diethylpropion, mazindol, phenylpropanolamine, phentermine, phendimetrazine, phendamine tartrate, methamphetamine, phendimetrazine and tartrate); serotonergic agents (such as sibutramine, fenfluramine, dexfenfluramine, fluoxetine, fluvoxamine and paroxtine); thermogenic agents (such as ephedrine, caffeine, theophylline, and selective ^3-adrenergrc WO 2007/136696

75 agonists); alpha-blocking agents; kainite or AMPA receptor antagonists; leptin-lipolysis stimulated receptors; phosphodiesterase enzyme inhibitors; compounds having nucleotide sequences of the mahogany gene; fibroblast growth factor-10 polypeptides; monoamine oxidase inhibitors (such as befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, toloxatone, pirliπdol, amiflamine, sercloremine, bazinaprine, lazabemide, milacemide and caroxazone); compounds for increasing lipid metabolism (such as evodiamine compounds); and lipase inhibitors (such as oriistat). Generally, a total dosage of the above-described obesity control medications can range from 1 to 3,000 mg/day, desirably from about 1 to 1,000 mg/day and more desirably from about 1 to 200 mg/day in single or 2-4 divided doses.

The compositions, therapeutic combinations or methods of the invention can further comprise one or more blood modifiers which are chemically different from the substituted azetidinone and substituted β-lactam compounds discussed above. Useful blood modifiers include but are not limited to anti-coagulants (argatroban, bivalirudin, dalteparin sodium, desirudin, dicumarol, lyapolate sodium, nafamostat mesylate, phenprocoumon, tinzaparin sodium, warfarin sodium); antithrombotic (anagrelide hydrochloride, bivalirudin, cilostazol, dalteparin sodium, danaparoid sodium, dazoxiben hydrochloride, efegatran sulfate, enoxaparin sodium, fluretofen, ifetroban, ifetroban sodium, lamifiban, lotrafiban hydrochloride, napsagatran, orbofiban acetate, roxifiban acetate, sibrafiban, tinzaparin sodium, trifenagrel, abciximab, zolimomab aritox); fibrinogen receptor antagonists (roxifiban acetate, fradafiban, orbofiban, lotrafiban hydrochloride, tirofiban, xemilofiban, monoclonal antibody 7E3, sibrafiban); platelet inhibitors (cilostazol, clopidogrel bisulfate, epoprostenol, epoprostenol sodium, ticlopidine hydrochloride, aspirin, ibuprofen, naproxen, sulindae, idomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, dipyridamole); platelet aggregation inhibitors (acadesine, beraprost, beraprost sodium, ciprostene calcium, itazigrel, lifarizine, lotrafiban hydrochloride, orbofiban acetate, oxagrelate, fradafiban, orbofiban, tirofiban, xemilofiban); hemorrheologic agents (pentoxifylline); lipoprotein associated coagulation inhibitors; Factor Vila inhibitors (4H-31 -benzoxazin-4-ones, 4H-3, 1-benzoxazin~4-thiones, quinazolin-4-ones, quinazoliπ-4-thiones, benzothiazin-4-ones, imidazolyl-boronic acid-derived peptide WO 2007/136696

76 analogues TFPI-derived peptides, naphthaleπe-2-sulfoπic acid {1-[3- (aminoiminomethyl)-ben2ylJ-2-oxo-pyrrolidin-3-(S)-yl} amide trifluoroacetate, dibenzofuran-2-sulfonic acid {1 -[3-(aminomethyl)-benzyl]-5-oxo-pyrrolidin-3-yl}-amide, tolulene-4-sulfonic acid {1 -[3-(aminoiminomethyl)-benzyJ]-2-oxo-pyrrolidin-3-(S)-yl)- amide trifluoroacetate, 3,4-dihydro-1H-isoquiπoline-2-sulfonic acid {1-[3- (aminoiminomethyl)-benzyl]-2-oxo-pyrrolin-3-(S)-yl}-amide trifluoroacetate); Factor Xa inhibitors (disubstituted pyrazolines, disubstituted triazolines, substituted n- [(aminoiminomethyl)phenyl] propylamides, substituted n-[(aminomethyl)phenyl] propylamides, tissue factor pathway inhibitor (TFPI), low molecular weight heparins, heparinoids, benzimidazolines, benzoxazolinones, benzopiperaziπones, indanones, dibasic (amidinoaryl) propanoic acid derivatives, amidinophenyl-pyrrolidines, amidiπophenyl-pyrrolines, amidinophenyl-isoxazolidines, amidinoindoles, amidinoazoles, bis-arlysulfonylaminobenzamide derivatives, peptidic Factor Xa inhibitors).

The compositions, therapeutic combinations or methods of the invention can further comprise one or more cardiovascular agents which are chemically different from the substituted azetidinoπe and substituted β-lactam compounds (such as compounds I-XI above) discussed above. Useful cardiovascular agents include but are not limited to calcium channel blockers (clentiazem mafeate, amlodipine besylate, isradipine, nimodipine, felodipine, nilvadipine, nifedipine, teludipine hydrochloride, diltiazem hydrochloride, belfosdil, verapamil hydrochloride, fostedil); adrenergic blockers (fenspiride hydrochloride, labetalol hydrochloride, proroxan, alfuzosin hydrochloride, acebutolol, acebutolol hydrochloride, alprenolol hydrochloride, atenolol, bunolol hydrochloride, carteolol hydrochloride, celiprolol hydrochloride, cetamolol hydrochloride, cicloprolol hydrochloride, dexpropranolol hydrochloride, diacetolol hydrochloride, dilevalol hydrochloride, esmolol hydrochloride, exaprolol hydrochloride, flestolo/ sulfate, labetalol hydrochloride, levobetaxoloJ hydrochloride, levobunolol hydrochloride, metalol hydrochloride, metoprolol, metoprolol tartrate, nadolol, pamatolol sulfate, penbutolol sulfate, practolol, propranolol hydrochloride, sotalol hydrochloride, timolol, timolol maleate, tiprenolol hydrochloride, tolamolσl, bisoprolol, bisoprolol fumarate, nebivolol); adrenergic stimulants; angiotensin converting enzyme WO 2007/136696

77

(ACE) inhibitors (benazepril hydrochloride, beπazeprilat, captopril, delapril hydrochloride, fosinopril sodium, libenzapril, moexipril hydrochloride, peπtopril, perindopril, quinapril hydrochloride, quϊnaprilat, ramipril, spirapril hydrochloride, spiraprilat, teprotide, enalapril maleate, lisinopril, zofenopril calcium, perindopril erbumine); antihypertensive agents (althiazide, benzthiazide, captopril, carved ilol, chlorothiazide sodium, clonidine hydrochloride, cyclothiazide, delapril hydrochloride, dilevalol hydrochloride, doxazosin mesylate, fosinopril sodium, guanfacine hydrochloride, methyldopa, metoprolol succinate, moexipril hydrochloride, monatepil maleate,. pelanserin hydrochloride, phenoxybenzamine hydrochloride, prazosin hydrochloride, primidolol, quinapril hydrochloride, quinaprilat, ramipril, terazosin hydrochloride, candesartan, candesartan cilexetil, telmisartan, amlodipine besylate, amlodipine maleate, bevantolol hydrochloride); angiotensin Il receptor antagonists (candesartan, irbesartan, losartan potassium, candesartan cilexetil, telmisartan); antianginal agents (amlodipine besylate, amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride, butoprozine hydrochloride, carvedilol, cinepazet maleate, metoprolol succinate, molsidomine, monatepil maleate, primidolol, ranolazine hydrochoride, tosifen, verapamil hydrochloride); coronary vasodilators (fostedil, azaclorzine hydrochloride, chromonar hydrochloride, clonitrate, diltiazem hydrochloride, dipyridamole, droprenilamine, erythrityl tetranitrate, isosorbide dinitrate, isosorbide mononitrate, lidoflazine, mioflazine hydrochloride, mixidine, molsidomine, nicorandil, nifedipine, nisoldipine, nitroglycerine, oxprenolol hydrochloride, pentrinitrol, perhexiline maleate, prenylamine, propatyl nitrate, terodiliπe hydrochloride, tolamolol, verapamil); diuretics (the combination product of hydrochlorothiazide and spironolactone and the combination product of hydrochlorothiazide and triamterene).

The compositions, therapeutic combinations or methods of the invention can further comprise one or more antidiabetic medications for reducing blood glucose levels in a human. Useful antidiabetic medications include, but are not limited to, drugs that reduce energy intake or suppress appetite, drugs that increase energy expenditure and nutrient-partitioning agents. Suitable antidiabetic medications include, but are not limited to, sulfonylurea (such as acetohexamide, chlorpropamide, gliamilide, gliclazide, glimepirrde, glipizide, glyburide, glibenclamide, tolazamide, and WO 2007/136696

78 tolbutamide), meglitinide (such as repaglinide and nateglinide), biguanide (such as metformin and buformin), alpha-glucosidase inhibitor (such as acarbose, mrglitol, camiglibose, and voglibose), certain peptides (such as amlintide, pramlintide, exendin, and GLP- 1 agonistic peptides), and orally administrable insulin or insulin composition for intestinal delivery thereof. Generally, a total dosage of the above-described antidiabetic medications can range from 0.1 to 1,000 mg/day in single or 2-4 divided doses.

Mixtures of any of the pharmacological or therapeutic agents described above can be used in the compositions and therapeutic combinations of the invention.

The treatment compositions of the invention generally additionally comprise a pharmaceutically acceptable carrier diluent, excipient or carrier (collectively referred to herein as carrier materials). Because of their sterol absorption inhibitory activity, such pharmaceutical compositions possess utility in treating sitosterolemia and related disorders.

In the treatment compositions used in the methods of the present invention, the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like. Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture. Powders and tablets may be comprised of from about 5 to about 95 percent inventive composition.

Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethyf-cellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, WO 2007/136696

79 and the like. Disintegrants include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate. Some of the terms noted above, namely disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below.

Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects, i.e. sterol absorption inhibitory activity and the like. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injections or addition of sweeteners and pacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.

For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions may take the form of creams, lotions, aerosols and/or WO 2007/136696

80 emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Preferably the compound is administered orally, intravenously or subcutaneously.

Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.

The pharmaceutical treatment compositions of the present invention can be administered to a mammal in need of such treatment in a pharmaceutically effective amount to treat sitosterolemia and/or reduce the level of sterol(s) in the plasma and tissues. The daily dose of the sterol absorption inhibitors) preferably ranges from about 0.1 to about 30 mg/kg of body weight per day, and more preferably about 0.1 to about 15 mg/kg. For an average body weight of 70 kg, the dosage level therefore ranges from about 1 mg to about 1000 mg of sterol absorption inhibitor(s) per day, given in a single dose or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.

For the pharmaceutical treatment compositions of the present invention in which the sterol absorption inhibitor(s) is administered concomitantly or in combination with a bile acid sequestrant, the typical daily dose of the sequestrant preferably ranges from about 0.1 to about 80 mg/kg of body weight per day administered in single or divided dosages, usually once or twice a day. For example, preferably about 10 to about 40 mg per dose is given 1 to 2 times a day, giving a total daily dose of about 10 to about 80 mg per day. The exact dose of sterol absorption inhibitor(s) and bile acid sequestrant(s) to be administered is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.

Where the sterol absorption inhibitor(s) and bile acid sequestrant(s) are administered in separate dosages, the number of doses of each component given per WO 2007/136696

81 day may not necessarily be the same, e.g., one component may have a greater duration of activity and will therefore need to be administered less frequently.

For the pharmaceutical treatment compositions of the present invention in which the sterol absorption inhibitor(s) is administered concomitantly or in combination with a lipid lowering agent, the typical daily dose of the lipid lowering agent preferably ranges from about 0.1 to about 80 mg/kg of body weight per day administered in single or divided dosages, usually once or twice a day. For example, for HMG CoA reductase inhibitors, preferably about 10 to about 40 mg per dose is given 1 to 2 times a day, giving a total daily dose of about 10 to about 80 mg per day. For other lipid lowering agents, preferably about 1 to about 1000 mg per dose is given 1 to 2 times a day, giving a total daily dose ranging from about 1 mg to about 2000 mg per day. The exact dose of sterol absorption inhibitor(s) and lipid lowering agent(s) to be administered is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.

Where the sterol absorption inhibitors) and lipid lowering agent(s) are administered in separate dosages, the number of doses of each component given per day may not necessarily be the same, e.g., one component may have a greater duration of activity and will therefore need to be administered less frequently.

The formulations and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable and conventional techniques. The following formulations exemplify some of the dosage forms of this invention. In each formulation, the term "active compound" designates a substituted azetidinone compound, a β-lactam compound or a compound of any of the Formulas I-XI described herein above.

EXAMPLE A Tablets

No. Ingredient mg/tablet mq/tablet

1 Active Compound 100 500

2 Lactose USP 122 113 WO 2007/136696

82

3 Corn Starch, Food Grade, as a 10% 30 40 paste in Purified Water

4 Corn Starch, Food Grade 45 40

5 Magnesium Stearate 3 7

Total 300 700

Method of Manufacture

Mix Item Nos. 1 and 2 in suitable mixer for 10-15 minutes. Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. Screen the dried granules if necessary and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to appropriate size and weight on a suitable tablet machine.

EXAMPLE B Capsules

No. Inαredient mq/tablet mq/tablet

1 Active Compound 100 500

2 Lactose USP 106 123

3 Com Starch, Food Grade 40 70

4 Magnesium Stearate NF 4 7

Total 250 700

M

ethod of Manufacture

Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine.

EXAMPLE C

Tablets No. Ingredient mg/tablet

1 Active Compound I 10

2 Lactose monohydrate NF 55 WO 2007/136696

83

3 Microcrystalline cellulose NF 20

4 Povidone (K29-32) USP 4

5 Croscarmellose sodium NF 8

6 Sodium lauryl sulfate 2

7 Magnesium stearate NF 1 Total 100

Method of Manufacture

Mix Item No.4 with purified water in suitable mixer to form binder solution. Spray the binder solution and then water over Items 1 , 2, 6 and a portion of Item 5 in a fluidized bed processor to granulate the ingredients. Continue fluidization to dry the damp granules. Screen the dried granules and blend with Item No. 3 and the remainder of Item 5. Add Item No. 7 and mix. Compress the mixture to appropriate size and weight on a suitable tablet machine.

In the present invention, the above-described tablet can be coadministered with a tablet, capsule, etc. comprising a dosage of another therapeutic agent such as are described above, for example a bile acid sequestrant as described above.

Representative formulations comprising other lipid lowering agents are well known in the art. It is contemplated that where the two active ingredients are administered as a single composition, the dosage forms disclosed above for substituted azetidinone compounds may readily be modified using the knowledge of one skilled in the art.

The treatment compositions of the present invention can inhibit the intestinal absorption of sitosterol in an animal model, as shown in the Example below. Thus, the treatment compositions of the present invention are hypositosterolemic agents by virtue of their ability to inhibit the intestinal absorption of sitosterol and can be useful in the treatment and/or prevention of atherosclerosis and sitosteroJemia in mammals, in particular in humans.

In another embodiment of the invention, the compositions and therapeutic combinations of the present invention can reduce plasma concentration of at least one sterol selected from the group consisting of phytosterols (such as sitosterol, campesterol, stigmasterol and avenosteroJ), 5α-stanols (such as cholestanol, 5α~ 84 campestanol, 5α-sitostanol), cholesterol and mixtures thereof. The plasma concentration can be reduced by administering to a mammal in need of such treatment an effective amount of at least one treatment composition or therapeutic combination comprising at least one sterol absorption inhibitor described above. The reduction in plasma concentration of sterols can range from about 1 to about 70 percent, and preferably about 10 to about 50 percent. Methods of measuring serum total blood cholesterol and total LOL cholesterol are well known to those skilled in the art and for example include those disclosed in PCT WO 99/38498 at page 11, incorporated by reference herein. Methods of determining levels of other sterols in serum are disclosed in H. Gylling et al., "Serum Sterols During Stanol Ester Feeding in a Mildly Hypercholesterolemic Population", J. Lipid Res.40: 593-600 (1999), incorporated by reference herein.

In an alternative embodiment, the plasma and tissue concentration of sterols can be reduced by administering to a mammal in need of such treatment an effective amount of at least one treatment composition comprising at least one sterol absoφtion inhibitor and an effective amount of at feast one bile acid sequestrant.

In a further embodiment, the plasma and tissue concentration of sterols can be reduced by administering to a mammal in need of such treatment an effective amount of at least one treatment composition comprising at least one sterol absorption inhibitor and an effective amount of at least one other lipid lowering agent.

Illustrating the invention are the following examples which, however, are not to be considered as limiting the invention the their details. Unless indicated otherwise, all parts and percentages in the following examples, as well as throughout the specification, are by weight.

EXAMPLE 1 In Vivo Evaluation In Mice

In vivo activity of compound VIII in mice was determined by the following procedure:

Male ApoE knockout mice, age 6wks, were received from Jackson Laboratory along with age-matched C57BL/J. The mice were housed 5 per cage, normal light cycle, normal diet. Twenty-six mice of each variety were weighed and housed, 1 per WO 2007/136696

85 cage, in suspended wire cages with normal light cycle, normal diet. After three days, the mice were reweighed. Based on body weight, the mice were divided into 5 groups for each type of treatment:

Control (corn oil) and Compositions including Compound vm at 0.3, 1, 3, and 10 mg/kg of body weight per day.

Preparation of Compositions including Compound vm based on 22g average mouse body weight:

Dosage of Compound VIII (mg/ml/day) Compound vm (ml) + corn oil (ml) 10mg/kg/day in 0.1 ml corn oil 2.2mg/ml* 10ml=22 mg in 10ml corn oil 3mg/kg : 3 ml of 10mg/kg + 7 ml corn oil;

1 mg/kg : 3 ml of 3mg/kg + 6 ml corn oil;

0.3mg/kg : 2ml of 1 mg/kg + 4.67 ml corn oil.

The mice were gavaged using a feeding needle 30 min before receiving ¹⁴C- cholesterol (NEN, NEC 018) and ³H-sitosterol (NEN, CUS 030T). The radioactive dose was prepared from:

114 μL ³H-sitosterol stock (1 μCi/μL in ethanol); 1.425 mL ¹⁴C-cholesterol stock (40 μCf/mL in ethanol); 5.7 mg cholesterol, Sigma C 8667; 5.7 mg β-sitosterol, Sigma, S 1270; The ethanol was removed under N₂;

5.7 ml of corn oil was added, and the mixture was warmed to 6O⁰C; and shaken for ihr.

Each 0.1ml dose contained 2 μCi ³H-sitosterol, 0.1 mg cold (non radioactive) sitosterol; 1 μCi ¹⁴C-cholesterol, and 0.1 mg cold (non radioactive) cholesterol. Radioactive content was verified: 5 X 10 μl counted in Beckman LSC (liquid simulation counter). Tritiated sitosterol was used as an "unabsorbable" marker to compare to the absorption of [¹⁴CJ-cholesterol in a mouse fecal isotope ratio cholesterol absorption model.

On the 4^th , 5^th , and 6^th days, feces were collected and stored at -20⁰C in vials just before dosing with Control or Compound VIII late in the day. Termination of the experiment on the 7^th day involved sacrifice by exsaπguination, removal and weighing WO 2007/136696

86 of the liver. 3 X ~250 mg samples of liver were put in vials. The liver samples were digested with 1ml of 1 N NaOH at 60° overnight, neutralized with 0.1ml 12N HCJ and counted for ¹⁴C and ³H. The blood samples were allowed to clot at room temp for 1hr, then centrifuged at 1000G for 15 min. The serum was analyzed for total cholesterol (see Wako CII; see Allain CC, Poon LS, Chan CSG, Richmond W, Fu PC. Enzymatic Determination of Total Serum Cholesterol. Clin. Chem. 1974; 20:470-475, which is incorporated by reference herein) and radioactivity (2 X 50μL). Fecal samples were analyzed for radioactivity by combustion in a Packard Oxidizer followed by Beckman LSC.

In this experiment, Wild type mice (C57BL/6J) and mice deficient in apoprotein E (Apo E KO) were found to absorb from 0.15-0.38% of the original [³HJ-sitosterol dose administered into their livers. When Compound vπi was given, it was found to dose dependently inhibit the absorption and hepatic accumulation of sitosterol as shown in Table 1 below.

WO 2007/136696

87

Table 1.

88

EXAMPLE 2 In Vivo Evaluation In Humans

In a randomized multicenter, double-blind, placebo-controlled, 8-week trial, 37 human patients previously diagnosed with homozygous sitosterolemia were randomized to receive Compound VIII (n=30) or placebo (n=7):

Treatment A - Compound VΗI given orally as 1 dose (10 mg) per day, Treatment B - Placebo (matching image of Compound VlH 10 mg) given orally as 1 dose per day, every morning for 8 consecutive weeks.

During the trial, subjects were instructed to maintain (as a minimum) a National Cholesterol Education Program (NCEP) Step 1 diet

Patients were instructed to maintain a diary of food intake and monitored prior to randomization, at baseline and during therapy. Results of the central diet analysis for each subject were reported as a RISCC score (Ratio of Ingested Saturated fat and Cholesterol to Calories) and as dietary components. RISCC scores indicate the potential for a diet to influence plasma lipid levels. A score ranging from 14 to 20 correlates with a NCEP step 1 diet.

Lipid/lipoproteins determinations

Low-Density -Lipoprotein-Cholesterol (LDL-C) results were reported as direct LDL-C (plasma concentration was determined following a standard ultra centrifugation/precipitation procedure; lipid and lipoprotein analysis, see Manual of Laboratory Operations: Lipid Research Clinics Program Report. Washington, DC: US Department of Health, Education, and Welfare publication; 1974. NIH 75-628, vol 1, which is incorporated by reference herein or beta-quantification) and calculated LDL-C (plasma concentration; based on Freidewald equation: LDL-C = Total cholesterol minus (Triglycerides divided by 5) minus High-density -lipoprotein cholesterol (HDL- C)).

Total cholesterol and Triglycerides were determined enzymatically using a Hitachi 747 analyzer; see, Steiner PM, Freidel J, Bremner WF, Stein EA: Standardization of micromethods for plasma cholesterol, triglyceride and HDL- WO 2007/136696

89 cholesterol with the Lipid Clinics' methodology [abstract]. J Clin Chem Clin Biochem 1981;19:850, which is incorporated by reference herein.

HOL-C was determined enzymatically after heparin and magnesium precipitation; see, Steele WB, Koehle DF, Azar MM, Bfaszkowski TP, Kuba K, Dempsey ME: Enzymatic determinations of cholesterol in high density lipoprotein fractions prepared by precipitation technique. Clin Chem 1976:22:98-101, which is incorporated by reference herein.

Plasma plant sterols (sitosterol and campesterol) and LDL-C were assessed at baseline (Day 1) and at endpoint (average of Weeks 6 and 8 values). See: Salen, Gerald; Shore, Virgie; Tint, GS; Forte, T: Shefer, S; Horak, I; Horak, E; Dayal, B; Nguyen, L.; Batta, AK; Lindgren, FT; Kwiterovich, Jr, PO, "Increased sitosterol absorption, decreased removal and expanded body pools compensate for reduced cholesterol synthesis in sitosterolemia with xanthomatosis", J Lipid Res, Vol. 30, pp 1319-30, (1989) and Lutjohann, D; Bjorkhem, I; Beil, UF, and von Bergmann, K, "Sterol absorption and sterol balance in phytosterolemia evaluated by deuterium- labeled sterols: effect of sitostanol treatment" J Lipid Res. Vol. 36:(8), pp 1763-73, (1995), each of which is incorporated by reference herein.

Results:

The mean (S. E.) percent (%) change from Baseline at endpoint in plant sterols and LDL-C (mean, 95% Cl) are shown in Table 1 below:

Table 1 Treatment Sitosterol Campesterol LDL-C

A -21.0% (2.8%) -24.3% (2.9%) -13.6% (-21.7%, -5.5%)

B (control) 4.0% (5.3%) 3.2% (5.5%) 16.7% (31.6%, 64.9%)

The coadministration of 10 mg of Compound VIII was well tolerated and caused a significant (p< 0.001) reduction in sitosterol and campesterol compared to placebo. WO 2007/136696

90

Preparation of Compound fVIffl

Step 1): To a solution of (S)-4-phenyl-2-oxazolidinone (41 g, 0.25 mol) in CH2CI2 (200 ml), was added 4-dimethylaminopyridine (2.5 g, 0.02 mol) and triethylamine (84.7 ml, 0.61 mol) and the reaction mixture was cooled to O⁰C. Methyl- 4-(chlorofoιmyl)butyrate (50 g, 0.3 mol) was added as a solution in CH2CI2 (375 ml) dropwise over 1 h, and the reaction was allowed to warm to 22°C. After 17 h, water and H2SO4 (2N, 100 ml), was added the layers were separated, and the organic layer was washed sequentially with NaOH (10%), NaCI (safd) and water. The organic layer was dried over MgSO4 and concentrated to obtain a semicrystalliπe product.

Step 2): To a solution of T1CI4 (18.2 ml, 0.165 mol) in CH2CI2 (600 ml) at 0⁰C, was added titanium isopropoxide (16.5 ml, 0.055 mol). After 15 min, the product of Step 1 (49.0 g, 0.17 mol) was added as a solution in CH2CI2 (100 ml). After 5 min., diisopropylethylamine (DIPEA) (65.2 ml, 0.37 mol) was added and the reaction mixture was stirred at 0⁰C for 1 h, the reaction mixture was cooled to -20⁰C, and 4- benzyloxybenzylidine(4-fluoro)aniline (114.3 g, 0.37 mol) was added as a solid. The reaction mixture was stirred vigorously for 4 h at -20⁰C, then acetic acid was added as a solution in CH2CI2 dropwise over 15 min, the reaction mixture was allowed to warm to 0⁰C, and H2SO4 (2N) was added. The reaction mixture was stirred an additional 1 h, the layers were separated, washed with water, separated and the organic layer was dried. The crude product was crystallized from ethanol/water to obtain the pure intermediate.

Step 3): To a solution of the product of Step 2 (8.9 g, 14.9 mmol) in toluene

(100 ml) at 5O⁰C, was added N,O-bis(trimethylsilyl)acetamide (BSA) (7.50 ml, 30.3 mmol). After 0.5 h, solid TBAF (0.39 g, 1.5 mmol) was added and the reaction mixture stirred at 50⁰C for an additional 3 h. The reaction mixture was cooled to 22°C, CH3OH (10 ml), was added. The reaction mixture was washed with HCI (1N), NaHCO3 (1N) and NaCI (sat'd.), and the organic layer was dried over MgSCv*. WO 2007/136696

91

Step 4): To a solution of the product of Step 3 (0.94 g, 2.2 mmol) in CH3OH (3 ml), was added water (1 ml) and UOH H2O (102 mg, 2.4 mmole). The reaction mixture was stirred at 22°C for 1 h and then additional UOH H2O (54 mg, 1.3 mmole) was added. After a total of 2 h, HCI (1 N) and EtOAc was added, the layers were separated, the organic layer was dried and concentrated in vacuo. To a solution of the resultant product (0.91 g, 2.2 mmol) in CH2CI2 at 22°C, was added CICOCOCI (0.29 ml, 3.3 mmol) and the mixture stirred for 16 h. The solvent was removed in vacuo.

Step 5): To an efficiently stirred suspension of 4-fluorophenylzinc chloride (4.4 mmol) prepared from 4-fIuorophenylmagnesium bromide (1M in THF, 4.4 ml, 4.4 mmol) and ZnCl2 (0.6 g, 4.4 mmol) at 4°C, was added tetrakis(triphenyl- phosphine)palladium (0.25 g, 0.21 mmol) followed by the product of Step 4 (0.94 g, 2.2 mmol) as a solution in THF (2 ml). The reaction was stirred for 1 h at O⁰C and then for 0.5 h at 22°C. HCI (1 N, 5 ml) was added and the mixture was extracted with

EtOAc. The organic layer was concentrated to an oil and purified by silica gel chromatography to obtain 1-(4-fluorophenyl)-4(S)-(4-hydroxyphenyl)-3(R)-(3-oxo-3- phenylpropyl)-2-azetidinone:

HRMS calc'd for C24H19F2NO3 = 408.1429. found 408.1411.

Step 6): To the product of Step 5 (0.95 g, 1.91 mmol) in THF (3 ml), was added (R)-tetrahydro-1-methyl-3,3-diphenyl-1 H,3H-pyrrolo-[1 ,2-c][1 ,3,2] oxazaborole (120 mg, 0.43 mmol) and the mixture was cooled to -20⁰C. After 5 min, borohydride- dimethylsulfide complex (2M in THF, 0.85 ml, 1.7 mmol) was added dropwise over 0.5 h. After a total of 1.5 h , CH3OH was added followed by HCI (1 N) and the reaction mixture was extracted with EtOAc to obtain 1-(4-fluorophenyl)-3(R)-[3(S)-(4- fluorophenyl)-3-hydroxypropyl)]-4(S)-[4-(phenylmethoxy)phenyl]-2-a2:etidinone (compound 6A-1) as an oil. ¹H in CDCI3 d H3 = 4.68. J = 2.3 Hz. Cl (M⁺H) 500.

Use of (S)-tetra-hydro-i -methyl-3,3-diphenyl-1 H,3H-ρyrrolo-[1 ,2-c][1 ,3,2] oxazaborole gives the corresponding 3(R)-hydroxypropyl azetidinone (compound 6B- 1). 1mn CDCl3 d H3 = 4.69. J = 2.3 Hz. Cl (M⁺H) 500. 92

To a solution of compound 6A- 1 (0.4 g, 0.8 mmol) in ethanol (2 ml), was added 10% Pd/C (0.03 g) and the reaction mixture was stirred under a pressure (60 psi) of H2 gas for 16 h. The reaction mixture was filtered and the solvent was concentrated to

obtain compound 6A. Mp 164-166°C; Cl (M⁺H) 410. ^[αJ° ⁼ ~^2SΛ° ^{(c 3l CH}3°H) Elemental analysis calc'd for C24H21F2NO3: C 70.41; H 5.17; N 3.42; found C 70.25; H 5.19; N 3.54.

Similarly treat compound 6B-1 to obtain compound 6B.

Mp 129.5-132.5^OC; Cl (M⁺H) 410. Elemental analysis calc'd for C24H21F2NO3: C 70.41; H 5.17; N 3.42; found C 70.30; H 5.14; N 3.52.

Step 6* (Alternative): To a solution of the product of Step 5 (0.14 g, 0.3 mmol) in ethanol (2 ml), was added 10% Pd/C (0.03 g) and the reaction was stirred under a pressure (60 psi) of H2 gas for 16 h. The reaction mixture was filtered and the solvent was concentrated to afford a 1:1 mixture of compounds 6A and 6B.

It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications which are within the spirit and scope of the invention, as defined by the appended claims.

Claims

93We claim:

1. A pharmaceutical composition comprising an effective amount of at least one sterol absorption inhibiting compound or a prodrug or a pharmaceutically acceptable salt thereof and an effective amount of at least one CETP inhibitor of the formula (I¹):

R²

(D wherein R¹ is a hydrogen atom, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted alkyl group, an optionally substituted alkanoyl group, a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen atoms (the heterocyclic group is optionally substituted), or a saturated or unsaturated monocyclic or bicylci heterocyclic carbonyl group containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen atoms (the heterocyclic group is optionally substituted);

R² is a hydrogen atom or an optionally substituted alkyl group; R³ is a hydrogen atom or an optionally substituted alkyl group; R⁴ is an optionally substituted alkylene group;

R⁵ is a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen atoms, wherein the heterocyclic group is substituted by 1 to 5 substituents selected from the following groups, or said heterocyclic group is substituted by 1 to 5 substituents selected from the following groups and further by a halogen atom, an oxo and/or hydroxyl group; WO 2007/136696

94 cyano group, nitro group, carboxyl group, sulfo group, C_3-10 alkyl group, substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted alkenyl group, C₃-_K) alkoxy group, substituted alkoxy group, optionally substituted cycloalkoxy group, optionally substituted alkoxycarbonyl group, optionally substituted carbamoyl group, optionally substituted carbamimidoyl group, optionally substituted alkylthio group, optionally substituted alkylsulfinyl group, optionally substituted alkylsulfonyl group, optionally substituted allkylsuflonyl group, optionally substituted amino group, optionally substituted sulfamoyl group, optionally substituted alkanoyl group, a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen atoms (the heterocyclic group is optionally substituted), a saturated or unsaturated monocyclic or bicyclic heterocyclic oxy group containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen atoms (the heterocyclic oxy group is optionally substituted), and a saturated or unsaturated monocyclic or bicyclic heterocyclic carbonyl group containing 1 to 4 heterocyclic carbonyl group is optionally substituted);

R⁶ and R⁷, or R⁷ and R⁸, or R⁸ and R⁹ may combine at the ends to form an alkylene group which alkylene group may contain 1 to 3 heteroatoms selected independently from nitrogen, sulfur and oxygen atoms, and may have a substituent(s); and

R¹⁰ is an aromatic ring optionally containing 1 to 3 heteroatoms selected independently from oxygen, sulfur and nitrogen atoms (the aromatic ring is optionally substituted), or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1 , wherein the sterol absorption inhibitor is represented by Formula (I) WO 2007/136696

95

Ar¹^A-Y₅-C-Z ^P\ Ar^J

N.

CT "Ar²

(I)

or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (I) or of the isomers thereof, or prodrugs of the compounds of Formula (I) or of the isomers, salts or solvates thereof, wherein:

Ar-I is R3-substituted aryl; Ar² is R⁴-substituted aryl; Ar3 is R5-SU bstituted aryl;

Y and Z are independently selected from the group consisting of -CH2-, - CH(lower alkyl)- and -C(dilower alkyl)-; A is -O-, -S-, -S(O)- or -S(O)2-;

R¹ is selected from the group consisting of -OR⁶, -O(CO)R⁶, -0(CO)OR⁹ and - 0(CO)NReRT";

R2 is selected from the group consisting of hydrogen, lower alkyl and aryl; or R 1 and R^ together are =O; q is 1, 2 or 3; p is O, 1 , 2, 3 or 4;

R5 is 1-3 substituents independently selected from the group consisting of - OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR⁹, -O(CO)NR6R7 -NR6R7 . NR6(CO)R7_F -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2-Iower alkyl, -NR6sθ2-aryl, -CONR6R7 -COR6, -SO2NR6R7 S(O)0-2-a/kyl, S(O)0-2-aryl, -0(CH2)1-10- COOR⁶,-O(CH2)1-10CONR6R⁷, o-halogeno, m-halogeno, o-lower alkyl, m-lower alkyl, -(lower alkylene)-COOR⁶, and -CH=CH-COOR⁶; WO 2007/136696

96

F?3 and R⁴ are independently 1-3 substituents independently selected from the group consisting of R^₁ hydrogen, p-lower alkyl, aryl, -Nθ2, -CF3 and p-halogeno;

R6, R7 and R^ are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

R9 is lower alkyl, aryl or aryl-substituted lower alkyl.

3. The pharmaceutical composition of claim 1 , wherein the sterol absorption inhibitor is a compound of the formula represented by Formula (VlTI)

OH

4. The pharmaceutical composition of claim 1 , wherein the sterol absorption inhibitor is represented by Formula (IT)

R 19

Ar¹-R¹-Q. J r^o-

(H)

or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (II) or of the isomers thereof, or prodrugs of the compounds of Formula (II) or of the isomers, salts or solvates thereof, wherein:

A is selected from the group consisting of R²-substιtuted heterocycloalkyl, R²- substituted heteroaryl, R²-substituted benzofused heterocycloalkyl, and R²- substituted benzofused heteroaryl; WO 2007/136696

97

Ar¹ is aryl or R^-substituted aryl;

Ar2 is aryl or R⁴-substituted aryl;

Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the

/_R7J ( spiro group ^{v /b} ;

R^ is selected from the group consisting of

-(CH2)q-, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1 ;

-(CH2)e-G-(CH2)r. wherein G is -O-, -C(O)-, phenylene, -MRS- or - S(O)0-2-e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6; -(C2-C6 alkenylene)-; and

-(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0- 5, provided that the sum of f and g is 1-6; Rδ js

-CH-, -C⁽C₁-C₆ alkyl)-, -CF-. -C(OH)-, -C(C₆H₄-R⁹)-_, -N-, or -+NO" ;

R6 and R⁷ are independently selected from the group consisting of -CH2-. - CH(Ci-Ce alkyl)-, -C(di-(Ci-C6) alkyl), -CH=CH- and -C(Ci-C6 alkyl)=CH-; or R⁵ together with an adjacent R⁶, or R⁵ together with an adjacent R⁷, form a -CH=CH- or a -CH=C(Ci -Cβ alkyl)- group; a and b are independently 0, 1, 2 or 3, provided both are not zero; provided that when R⁶ is -CH=CH- or -C(Ci-Ce alkyl)=CH-_p a is 1; provided that when R⁷ is - CH=CH- or-C(Ci-C6 alkyl)=CH-, b is 1; provided that when a is 2 or 3, the R⁶'s can be the same or different; and provided that when b is 2 or 3, the R⁷'s can be the same or different; and when Q is a bond, R¹ also can be: WO 2007/136696

98

R¹° Jj?¹² R¹⁰ _Rio

-M -Y_d-C-2_h- , -X_m-(C)_s-Y_n-(C)_t-2_p- or -X_r(C)_v-Y_k-S(0_)o.₂-; ^R R¹³ R" R^H

M is -O-, -S-, -S(O)- or -S(O)2-;

X, Y and Z are independently selected from the group consisting of -CH2-. - CH(C1-C6 alkyl)- and -C(di-(Ci-C6) alkyl);

R1O and R¹^ are independently selected from the group consisting of -OR¹⁴, - O(CO)R¹⁴, -O(CO)OR¹6 and -O(CO)NR¹⁴R15_;

R^{1 1} and R ¹3 are independently selected from the group consisting of hydrogen, (C-j-C6)alkyl and aryl; or R-IO and R^{1 "1} together are =O, or

R¹² and R¹³ together are =O; d is 1. 2 or 3; h is 0, 1 , 2, 3 or 4; s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4; provided that at least one of s and t is 1 , and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1 , the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1 , the sum of m, t and n is 1-5; v is 0 or 1 ; j and k are independently 1-5, provided that the sum of j, k and v is 1-5;

R2 is 1-3 substituents on the ring carbon atoms selected from the group consisting of hydrogen, (C-ι-C-jθ)alkyl, (C2-Ci o)alkenyl, <C2-Cio)alkynyl, (C3-

C6)cycloalkyl, (C3-C6)cycloalkenyl, R^{1 7>}-substituted aryl, R¹⁷-substituted benzyl, Ri7__sub_st^jtuted benzyloxy, R¹ ''-substituted aryloxy, halogeno, -NR¹⁴R¹5, NR14R15(C-| -C6 alkylene)-, NR¹⁴R¹⁵C(O)(C-I -C-6 alkylene)-,-NHC(O)R¹⁶, OH, C-j- C6 alkoxy, -OC(O)R¹⁶, -COR14, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy(Ci-Cβ)alkyl, NO2, -S(O)o-2R¹⁶, -SO2NR¹⁴R^{1 5} and -(C1-C6 alkylene)COOR¹⁴; when R2 is a

(^ /CH₂)_L2 substituent on a heterocycloalkyl ring, R2 j_s as defined, or is =O or ° ■; 99

and, where R^ is a substitueπt on a substitutable ring nitrogen, it is hydrogen, (C-) - C6)alkyl, aryl, (Ci-C6)alkoxy, aryloxy, (Ci-C6)alkylcarbonyl, arylcarbonyJ, hydroxy,

(CH2)1 -6CONR¹⁸R¹⁸,

^R >J ^\ j or ϊ )

(CH₂)₍M ^ O .

wherein J is -O-, -NH-, -NR¹⁸- or -CH2-;

R3 and R⁴ are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (Ci-C6)alkyl, -OR¹⁴, -O(CO)R¹⁴, -O(CO)OR¹⁶, -O(CH2)1-5OR¹4, -0(CO)NR¹⁴RiS₁ -NR¹⁴R¹⁵, _ NR¹⁴(CO)R¹⁵, -NR¹⁴(CO)OR¹6, -NR¹^CO)NR¹⁵R¹⁹, -NR¹⁴SO2R¹⁶, -COOR¹⁴, - CONR¹⁴R¹S₁ -COR¹⁴, -SO2NR¹⁴R¹⁵, S(O)θ-2R¹⁶, -O(CH2)1-10"COOR¹⁴, -O(CH2)1-1 OCONR¹⁴R¹⁵, -(C1-C6 alkylene)-COOR¹⁴, -CH=CH-COOR¹⁴, -CF3, - CN, -NO2 and halogen;

R⁸ is hydrogen, (Ci-C6)alkyl, aryl (Ci-C6)alkyl, -C(O)R¹⁴ or -COOR¹⁴;

R⁹ and R¹⁷ are independently 1-3 groups independently selected from the group consisting of hydrogen, (C-j-CeJalkyl, (Ci-C6)alkoxy, -COOH, NO2, -NR¹⁴R¹⁵, OH and halogeno;

R¹⁴ and R¹⁵ are independently selected from the group consisting of hydrogen, (Ci-C6)alkyl, aryl and aryl-substituted (Ci-C6)alkyl;

R¹⁶ is (Ci-C6)alkyl, aryl or R^-substituted aryl; R¹⁸ is hydrogen or (Ci-Cβ)alkyl; and R^{1 9} is hydrogen, hydroxy or (Ci-Cβ)alkoxy.

5. The pharmaceutical composition of claim 1 , wherein the sterol absorption inhibitor is represented by Formula (111) WO 2007/136696

100

R

.Ar² λ_m I ₁ Y_n J l

(in.)

or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (III) or of the isomers thereof, or prodrugs of the compounds of Formula (III) or of the isomers, salts or solvates thereof, wherein:

Ar^"! is aryl, R^ ^-substituted ^ary' °^r heteroaryl;

Ar2 is aryl or R^-substituted aryl;

Ai"3 is aryl or R^-substituted aryl;

X and Y are independently selected from the group consisting of -CH2-, - CH(lower alkyl)- and -C(dilower alkyl)-;

R is -OR6, -O(CO)R6, -O(CO)OR9 or -O(CO)NR6R7;

R1 is hydrogen, lower afkyl or aryl; or R and R^ together are =O; q is 0 or 1 ; r is 0, 1 or 2; m and n are independently 0, 1 , 2, 3, 4 or 5; provided that the sum of m, n and q is 1 , 2, 3, 4 or 5;

R⁴ is 1 -5 substituents independently selected from the group consisting of lower alkyl. -OR^, -O(CO)R6, -O(CO)OR9 -O(CH2)1-5OR⁶, -O(CO)NR6R7 -NR6R7, -NR⁶(CO)R⁷, -NR6(CO)OR9, -NR⁶(CO)NR⁷R⁸. -NR⁶Sθ2R⁹, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0-2R⁹, -0(CH2)1-10-COOR6, -O(CH2)1-10CONR6R7_> . (lower alkylene)COOR⁶ and -CH=CH-COOR⁶;

R⁵ is 1-5 substituents independently selected from the group consisting of - OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)I_5OR6, -O(CO)NR6R7, -NR6R7, . NR6(CO)R⁷, -NR6(CO)OR9 -NR6(CO)NR7R8, -NR6SO2R⁹, -COORS, -CONR6R7, . 101

COR⁶, -SO2NR⁶R⁷, S(O)0-2R⁹, -0(CH2)1-10"COOR⁶, -0(C^)I-IOCONR⁶R⁷, . CF3, -CN₁ -NO2, halogen, -(lower alkyleπe)COOR⁶ and -CH=CH-COOR⁶;

R⁶, R⁷ and R^ are independently selected from the group consisting of hydrogen, lower alky!, aryl and aryl-substituted lower alkyl;

R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl; and R1O is 1-5 substituents independently selected from the group consisting of lower alkyl, -OR⁶, -O(CO)R⁶, O(CO)OR⁹, -O(CH2)1-5OR⁶, -0(CO)NR⁶R?, -NR⁶R⁷, -NR⁶(CO)R⁷, -NR⁶(CO)OR⁹, -NR⁶(CO)NR⁷R⁸, -NR⁶SO2R⁹, -COOR⁶, -CONR⁶R⁷,

-COR⁶, -SO2NR⁶R⁷, S(O)θ-2R⁹, -O(CH2)1-1 Q-COOR⁶, -O(CH2)1-10CONR⁶R⁷, - CF3, -CN, -NO2 and halogen.

6. The pharmaceutical composition of claim 1, wherein the sterol absorption inhibitor is represented by Formula (IVA)

4

\ R

R₁-(R₂)V _A/ 20

(R₃)U-¹ /

CT R₂₁

(TVA) or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (IVA) or of the isomers thereof, or prodrugs of the compounds of Formula (IVA) or of the isomers, salts or solvates thereof, wherein: R1 is

-CH-, -C(lower alkyl)-, -CF-, -C(OH)-, -C(C ₆H₅)-. -C(C₆H₄-R₁₅)-, - N- or -⁺N O^" ;

R2 and R3 are independently selected from the group consisting of -CH2-, - CH(lower alkyl)-, -C(di-lower alkyl)-, -CH=CH- and -C(lower alkyl)=CH-; or 102

R-j and R2 together or Ri and R3 together form a -CH=CH- or a - CH=C(lower alkyl)- group; u and v are independently 0, 1 , 2 or 3, provided both are not zero; R4 is

B-(CH2)mC(O)-, wherein m is 0, 1, 2, 3, 4 or 5;

B-(CH2)q-, wherein q is 0, 1, 2, 3, 4, 5 or 6;

B-(CH2)e-Z-(CH2)r. wherein Z is -O-, -C(O)-, phenylene,

-NR8- or -S(O)0-2-, and wherein e is 0, 1, 2, 3, 4 or 5 and r is 0, 1, 2, 3,

4 or 5, provided that the sum of e and r is 0, 1 , 2, 3, 4, 5 or 6;

B-(C2-C6 alkenylene)-;

B'-(C4-C6 alkadienylene)-;

B-(CH2)t-Z-(C2-C6 alkeriylene)-, wherein Z is as defined above, and wherein t is 0, 1, 2 or 3, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;

B-(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1, 2, 3, 4 or

5 and g is 0, 1 , 2, 3, 4 or 5, provided that the sum of f and g is 1 , 2, 3, 4, 5 or 6;

B-(CH2)t-V-(C2-C6 alkenylene)- or B'-(C2-C6 alkenylene)-V-(CH2)t-. wherein V and t are as defined above, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;

B-(CH2)a-Z-(CH2)b-V-(CH2)d-. wherein Z and V are as defined above and a ,b and d are independently 0, 1 , 2, 3, 4, 5 or 6, provided that the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6;

T-(CH2)s-. wherein T is cycloalkyl of 3-6 carbon atoms and s is 1, 2, 3, 4, 5 or 6; or naphthylmethyl, heteroarylmethyl, or W-substituted heteroarylmethyl, wherein heteroaryl is selected from the group consisting of pyrrolyl, pyridϊnyl, pyrimidfnyl, pyrazinyl, tήazinyl, imidazofyl, thiazolyl, pyrazofyf, thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls, the N- oxides thereof; and wherein W is 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, WO 2007/136696

103 alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower alkanedioyl, allyloxy, -CF3, -OCF3, benzyl, R7-benzyl, benzyloxy, R7- benzyloxy, phenoxy, F?7-phenoxy, dioxolanyl, NO2, -NR8R9. NRsR9(lower alkyl)-,

NRβR9(lower alkoxy)-, OH, halogeno, -NHC(O)ORiO, -NHC(O)RiO, R11O2SNH-,

<R11O2S)2N-,

-S(O)2NH2, -S(O)o-2R8. tert-butyldimethyl-silyloxymethyl, -C(O)Ri 2,

-CH=CHC(O)Ri 2, RiθC(O)(lower alkoxy)-, NR8RgC(O)(lower aJkoxy)- and

- CH₂- N Ri3

^N — ^f for substitution on ring carbon atoms, and the substituents on the substituted heteroaryl ring nitrogen atoms, when present, are selected from the group consisting of lower alkyl, lower alkoxy, -C(O)ORi 0, -C(O)Ri O. OH₁ NReR9(lower alkyl)-, NRβR9(lower alkoxy)-, -S(O)2NH2 and 2-(trimethylsilyl)ethoxymethyl;

A is a bond; C3-C6 cycloalkylene; C1-C10 alkylene; C2-C10 alkenylene; C2-C10 alkynylene; an alkylene, alkenylene or alkynylene chain as defined above, substituted by 1 to 4 substituents independently selected from the group consisting of phenyl,

W-substituted phenyl, heteroaryl and W-substituted heteroaryl, wherein heteroaryl is as defined above; an alkylene, alkenylene or alkynylene chain as defined above interrupted by 1 to 4 groups independently selected from the group consisting of

-O-,

-S-,

-SO-,

-SO₂-,

-NR₁₄,

-C(O)-,

^C3-C6 cycloalkylene, phenylene, 104

W-substituted phenylene, heteroarylene and W-substituted heteroarylene; or an interrupted alkylene, alkenylene or alkynylene chain as defined substituted by 1 to 4 substituents independently selected from the group consisting of phenyl,

W-substituted phenyl, heteroaryl and W-substituted heteroaryl;

B is naphthyl, heteroaryl or W-substituted heteroaryl, wherein heteroaryl is as defined above, or

R7 is 1-3 groups independently selected from the group consisting of lower alkyl, lower aJkoxy, -COOH, NO2, -NReRg, OH or halogeno; RQ and Rg are independently H or lower alkyl; R1O is lower alkyl, phenyl, R7-phenyl, benzyl or R7-benzyl; R11 is OH, lower alkyl, phenyl, benzyl, R7-phenvl or R7-benzyl:

R12 is H, OH, alkoxy, phenoxy, benzyloxy, - N R₁₃

^N — ' NR8R9,

lower alkyl, phenyl or R7-phenyl;

R13 is -0-, -CH2-, -NH-, -N(lower alkyl)- or -NC(O)Ri g;

R14 is H, lower alkyl, phenyl lower alkyl or -C(O)R-Jg;

^R15. R16 and R-\j are independently selected from the group consisting of H and the groups defined for W; or R15 is hydrogen and R-) 6 and R17, together with adjacent carbon atoms to which they are attached, form a dioxolanyl ring;

R -|9 is H, lower alkyl, phenyl or phenyl lower alkyl; WO 2007/136696

105

R21 is phenyl,

W-substituted phenyl, naphthyl,

W-substituted naphthyl, benzodioxolyl, heteroaryl,

W-substituted heteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryl or cyclopropyl, wherein heteroaryl is as defined above; and R20 is H or R21.

7. The pharmaceutical composition of claim 1 , wherein the sterol absorption inhibitor is represented by Formula (IVB)

R₄

^XRi— (R₂)V _A/^R20

(R₃)U-

^<

O R₂₁

(IVB) or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (IVB) or of the isomers thereof, or prodrugs of the compounds of Formula (IVB) or of the isomers, salts or solvates thereof, wherein:

R1. R2. R3. R4. u and v are as defined for Formula (IVA),

/^1S

R5 is -CH=CH-B', wherein B¹ is \~N _ and R15, R16 and Ri 7 are as defined for Formula (IVA); 106 -C≡ C-B¹;

-(CH2)p-X-B\ wherein p is 0, 1 or 2 and X is a bond, -NH- or

-S(O)0-2-;

-C(O)-B¹; heteroaryl, benzofused heteroaryl,

W-substituted heteroaryl or

W-substituted benzofused heteroaryl, wherein heteroaryl and W are as defined for Formula (IVA); or

-(CH₂)K- N R₁₃

^Λ — ^f , wherein k is 1 or 2 and R13 is as defined for Formula (IVA); and R6 is

indanyl, benzofuranyl, benzodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl or cyclopropyl; n is 0, 1 , 2 or 3;

R18 is lower alkyl, lower alkoxy,

OH, halogeno,

-NR8R9, 107

-NHC(O)ORiO.

-NHC(O)RiO,

NO2,

-CN.

-N3,

-SH₁

-S(O)o-2-flower alkyl),

-COOR19,

-CONR8R9.

-COR12. phenoxy, benzyloxy,

-CH=CHC(O)Ri 2,

-OCF3 or tert-butyl-dimethyl-silyloxy, wherein when n is 2 or 3, the R18 groups can be the same or different, and wherein Re. R9, R10. R12 and R19 are as defined in Formula (IVA).

8. The pharmaceutical composition of claim 1 , wherein the sterol absorption inhibitor is represented by Formula (VA) or Formula (VB)

B¹ — D

(VA) (VB) 108 or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (VA) and (VB) or of the isomers thereof, or prodrugs of the compounds of Formula (VA) and (VB) or of the isomers, salts or solvates thereof, wherein:

A is -CH=CH-, .o≡C- or -(CH2)ρ- wherein p is 0, 1 or 2;

B is

/^ R₂

-=^^ R,

B' is

D is -(CH2)mC(O)- or -(CH2)q- wherein m is 1 , 2, 3 or 4 and q is 2, 3 or 4;

E is C-10 to C20 alkyl or -C(O)-(Cg toCig)-a!kyl, wherein the alkyl is straight or branched, saturated or containing one or more double bonds;

R is hydrogen, C1-C15 alkyl, straight or branched, saturated or containing one or more double bonds, or B-(CH2)r -. wherein r is 0, 1, 2, or 3;

R1. R2. R3. Rv, R2\ and R3' are independently selected from the group consisting of

hydrogen, lower alkyl, lower alkoxy, carboxy,

NO₂,

NH2,

OH, halogeno, lower alkylamino, 109 dilower alkylamino, -NHC(O)OR5, R6O2SNH- and -S(O)₂NH₂; R4 is

-^ (OR₅)n

//

wherein n is 0, 1 , 2 or 3;

R5 is lower alkyl; and R6 is OH, lower alkyl, phenyl, benzyl or substituted phenyl wherein the substituents are 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, carboxy,

NO₂,

NH₂,

OH₁ halogeno, lower alkylamino and dilower alkylamino.

9. The pharmaceutical composition of claim 1 , wherein the sterol absorption inhibitor is represented by Formula (VI) 110

R 26 f^>-O-G

Ar¹-R¹-Q

O -N_x

Ar²

(VI) or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (VI) or of the isomers thereof, or prodrugs of the compounds of Formula (VI) or of the isomers, salts or solvates thereof, wherein:

R26 js H or OG¹ ;

G and G¹ are independently selected from the group consisting of

OR 5⁵ _Λ OrR->4⁴ O OJRR⁵^ Λ ODR4⁴ __/^"

O~<

<~i_ι _7 N-iiloR⁵ _u ^ >,I_OR³ . -Z ) -IOR³ . -^CH ₂ O - -

CO₂R² CH₂OR⁶ OR^{3 υκ}

OR^3a

R⁴³C- X^ and ₄ OR³ _O ^ΛO^C r»iHι₂R pD-^> ; •

provided that when R^6 js H or

-^o^*^CH2^Ra

OH, G is not H;

R, R^a and R^ are independently selected from the group consisting of

H,

-OH, halogeno,

-NH2. azido,

(Ci-C6)alkoxy(Ci-C6)-alkoxy and

-W-R30; wherein W is independently selected from the group consisting of

-NH-C(O)-, 111

-O-C(O)-, -O-C(O)-N(R31)-,

-NH-C(O)-N(R³¹)- and -O-C(S)-N(R31 )-;

R² and R^ are independently selected from the group consisting of H,

(Ci-C6)alkyl, aryl and aryl(Ci-C6)alkyl;

R³, R⁴, R⁵, R⁷, R^3a and R^4a are independently selected from the group consisting of H,

(Ci-C₆)alkyl, aryl(Ci-C6)alkyl,

-C(O)(C 1-C6)alkyl and

-C(O)aryl; R30 is selected from the group consisting of

R³²-sυbstituted T,

R³2-substituted-T-(Ci -C6)alkyl,

R³²-substituted-(C2-C4)alkenyl,

R³²-substituted-(C 1 -C6)alkyl,

R³²-substituted-(C3-C7)cycloalkyl and

R³²-substituted-(C3-C7)cycloalkyl(Ci-C6)alkyl; R31 is selected from the group consisting of H and (C-|-C4)alkyl; T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, 112 oxazolyl, isoxazolyl, thiazoiyl, iosthiazolyl, benzothiazofyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;

R32 is independently selected from 1-3 substituents independently selected from the group consisting of halogeno, (Ci-C₄)alkyl, -OH, phenoxy, -CF₃, -NO2,

(Ci-C4)alkoxy, methylenedioxy, oxo,

(Ci -C4)alkylsulfanyl, (Ci-C4)alkylsulfinyl, (Ci -C4)alkylsulfonyl,

-N(CH3)2. -C(O)-NH(Ci -C4)alkyl,

-C(O)-N((Ci-C₄)alkyl)2, -C(O)-(Ci -C4)alkyl, -C(O)-(Ci -C4)alkoxy and pyrroiidinylcarbonyl; or

R³2 is a covalent bond and R31, the nitrogen to which it is attached and R³² form a 113 pyrrσlidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a

(Ci-C4)alkoxycarbonyl-substituted pyrrol idinyl, piperidinyl,

N-methylpiperazinyl, indofinyl or morpholinyl group;

Ar¹ is aryl or R¹⁰-substituted aryl;

Ar2 is aryl or R¹1 -substituted aryl;

Q is a bond or, with the 3-position ring carbon of the azetidinone,

R¹f-⁽R¹³)a

/014J I forms the spiro group * ^{lb !}; and

R¹ is selected from the group consisting of

-(CH2)q-, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1 ;

-(CH2)e-E-(CH2)r, wherein E is -O-, -C(O)-, phenylene, -NR²2- or - S(0)o-2-. e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;

-(C-2-C6)alkenylene-; and

-(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0- 5, provided that the sum of f and g is 1-6;

R12 is

I l I i I ,, I I

-CH-, -C(C₁-C₆ alkyl)-, -CF-, -C(OH)-, -C(C₆H₄-R²³)-, -N-. or -⁺NO^" ;

R¹³ and R¹⁴ are independently selected from the group consisting of 114

-CH₂-,

-CH(C1-C6 alkyl)-,

-C(di-(Ci-C6) alkyl),

-CH=CH- and

-C(C-I -C6 alkyl)=CH-; or

R¹² together with an adjacent R¹³, or R¹² together with an adjacent R¹^₁ form a -CH=CH- or a -CH=C(Ci -Cβ alkyl)- group; a and b are independently O₁ 1 , 2 or 3, provided both are not zero; provided that when R¹³ is -CH=CH- or -C(Ci-C6 alkyl)=CH-, a is 1; provided that when R^⁴ is -CH=CH- or -C(Ci-C6 alkyl)=CH-, b is 1; provided that when a is 2 or 3, the R^³'s can be the same or different; and provided that when b is 2 or 3, the R^⁴'s can be the same or different; and when Q is a bond, Ri also can be:

_R15 R¹⁷ R¹⁵ R15

-M -Y_d-C - Z_h- , -X_m- (C)₈-Y_n- (C), -Z_p- or -X_r(C)_v-Y_k-S(O)₀.₂-; R¹⁶ R¹⁸ _R16 R16

M is -O-, -S-, -S(O)- or -S(O )2S

X, Y and 2 are independently selected from the group consisting of -CH2-, - CH(Ci -C6)alkyl- and -C(di-(Ci-C6)alkyl);

R^{1 0} and R^{1 1} are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (Ci-C6)alkyl,

-OR19, -O(CO)R19. -0(CO)OR²¹ , -O(CH₂)1-5OR^"I 9. 115

-O(CO)NR19R20_>

-NR19R20,

-NRiS(CO)RSO₁

-NRiS(CO)OR²¹, -NR19(CO)NR²0R25,

-NR19SO2R^2"> ,

-COOR¹⁹, -CONR¹⁹R20, -COR¹9 -SO2NR¹9R20,

S(O)o-2R²¹. -O(CH2)1-10-COOR¹9,

-O(CH2)1-10CONR¹9R20_I -(C1-C6 alkylene)-COOR¹⁹,

-CH=CH-COOR¹⁹,

-CF₃,

-CN,

-NO2 and halogen;

R¹⁵ and R¹⁷ are independently selected from the group consisting of -OR¹⁹, - O(CO)R¹9, -O(CO)OR2¹ and -0(CO)NR¹⁹R20_; R16 _{and R}18 _are independently selected from the group consisting of H, (Ci-C6)alkyl and aryl; or R¹⁵ and R¹⁶ together are =O, or R¹⁷ and R¹⁸ together are =O; d is 1, 2 or 3; h is O, 1 , 2, 3 or 4; s is O or 1; t is O or 1 ; m, n and p are independently 0-4; provided that at least one of s and t is 1 , and the sum of m, n, p, s and t is 1-6; provided that when p is O 116 and t is 1, the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1, the sum of m, t and n is 1 -5; v is 0 or 1 ; j and k are independently 1-5, provided that the sum of j, k and v is 1-5;

R¹⁵ -Xj-(C)_V-Y_k-S(O)₀..,- and when Q is a bond and R Λ¹ is R¹⁶

Ar^ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, ϊmidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

R19 and R20 _are independently selected from the group consisting of H, (Ci- C6)alkyl, aryl and aryl-substituted (Ci-Cβjalkyl;

R²¹ is (Ct-C-6)alkyl, aryl or R²⁴-substituted aryl;

R²² is H, (Ci-C6)alkyl, aryl (Ci-C6)alkyl, -C(O)R19 or -COORi9;

R23 and R²⁴ are independently 1-3 groups independently selected from the group consisting of H, (Ci-C6)alkyl, (C-|-C6)alkoxy, -COOH, NO2, .-NR19R²0, -OH and halogeno; and

R²5 is H₁ -OH or (Ci-C6)alkoxy. 117

10. The pharmaceutical composition of claim 1 , wherein the sterol absorption inhibitor is represented by Formula (VII)

R 2

Ar¹-X_m-<Cλ_rY_n-(C)_rZp Ar³

R¹ R³ I I

θ' ^Ar²

(VII) or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (VE) or of the isomers thereof, or prodrugs of the compounds of Formula (VII) or of the isomers, salts or solvates thereof, wherein:

Ar^*! and Ar^ are independently selected from the group consisting of aryl and R⁴-substituted aryl;

Ar* is aryl or R^-substituted aryl;

X, Y and Z are independently selected from the group consisting of -CH2-, - CH(lower alkyl)- and -C(dilower alkyl)-;

R and R^ are independently selected from the group consisting of -OR6, - O(CO)R⁶, -O(CO)OR⁹ and -O(CO)NR6R7_;

R¹ and R^ are independently selected from the group consisting of hydrogen, lower alkyl and aryl; q is O or 1; r is O or 1 ; m, n and p are independently O, 1, 2, 3 or 4; provided that at least one of q and r is 1 , and the sum of m, n, p, q and r is 1 , 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1 , the sum of m, q and n is 1 , 2, 3, 4 or 5;

R⁴ is 1-5 substituents independently selected from the group consisting of lower alkyl, -Ope 118

-O(CO)R6,

-0(CO)OR⁹,

-O(CH₂)1-5OR6,

-O(CO)NR6R7,

-NR6R7,

-NR6(CO)R⁷,

-NR6(CO)OR9,

-NR6(CO)NR?R8,

-NR6SO2R⁹,

-COOR⁶,

-CONR6R7,

-COR6,

-SO2NR6R⁷.

-S(O)0-2R⁹.

-O(CH2)1-10-COOR6,

-O(CH2)1-10CONR6R7^',

-(lower alkylene)COOR⁶, -CH=CH-COOR6, -CF₃, -CN,

-NO2 and halogen;

R5 is 1-5 substituents independently selected from the group consisting of -OR6, -O(CO)R⁶, -O(CO)OR9, -O(CH2)1-5OR6, 119

-0(CO)NR⁶R⁷,

-NR⁶R⁷,

-NR6(CO)R⁷,

-NR⁶(CO)OR9,

-NR⁶(CO)NR⁷R8,

-NR⁶Sθ2R⁹.

-COOR6,

-CONR⁶R⁷,

-COR⁶,

-SO2NR⁶R⁷.

-S(O)0-2R⁹, -0(CHa)I-IO-COOR⁶,

-O(CH2)1-1 OCONR⁶R⁷, -(lower alkylene)COOR⁶ and -CH=CH-COOR⁶;

R⁶, R⁷ and R^ are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

Rp is lower alkyl, aryl or aryl-substituted lower alkyl.

11. The pharmaceutical composition of claim 10 wherein wherein R⁴ is 1-3 substituents independently selected from the group consisting of; lower alkyl,

-OR⁶,

-O(CO)R⁶,

-O(CO)OR⁹,

-O(CH2)1-5OR⁶

-Q(CO)NR⁶R⁷, 120

-NR⁶R⁷, -NR⁶(CO)R⁷, -NR⁶(CO)OR⁹, -NR⁶(CO)NR7R8,

-NR⁶Sθ2R⁹,

-COOR⁶,

-CONR⁶R⁷,

-COR⁶,

-SO2NR⁶R⁷,

-S(O)0-2R⁹. -0(CH2)1-10-COOR⁶,

-O(CH2)1-1 OCONR⁶R⁷,

-(lower alkylene)COOR⁶,

-CH=CH-COOR⁶,

-CF3,

-CN,

-NO2 and halogen;

12. The pharmaceutical composition of claim 10 wherein R^ is 1-3 substituents independently selected from the group consisting of

-OR⁶,

-0(CO)R⁶.

-0(CO)OR⁹,

-O(CH2)1-5OR⁶,

-0(CO)NR⁶R⁷,

-NR⁶R⁷,

-NR⁶(CO)R⁷, 121

-NR6(CO)OR9, -NR6(CO)NR7R8,

-NR6SO2R⁹,

-COOR⁶,

-CONR⁶R?,

-COR⁶,

-SO2NR⁶R⁷,

-S(O)0-₂R⁹,

-O(CH2)1-10-COOR⁶,

-O(CH2)1 -10CONR6R7,

-(lower alkylene)COOR⁶ and -CH=CH-COOR⁶;

13. The pharmaceutical composition of claim 10 wherein Ar1 is (4-R4)- substituted phenyl.

14. The pharmaceutical composition of claim 10 wherein Ar2 is (4-R4)- substituted phenyl.

15. The pharmaceutical composition of claim 10 wherein Ar3 is (4-R5)- substituted phenyl.

16. The pharmaceutical composition of claim 1 , wherein the sterol absorption inhibitor is represented by Formula (IX)

Ar¹ — CH — Q ^"^26

1 0' ^'V 122

IX

or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (IX) or of the isomers thereof, or prodrugs of the compounds of Formula (IX) or of the isomers, salts or solvates thereof, wherein: R²⁶ is selected from the group consisting of: a) OH; b) OCH₃; c) fluorine and d) chlorine.

R¹ is selected from the group consisting of

OR⁵ JDR⁴ OR⁵ JDR⁴ .OR⁷

_( ).,,,OR³ , -H( ).,,IOR³ . -CH₂-\ )-.«IOR^£

H, °^~> COoR 2² °^~V ^CH₂OR⁶ OR 3 OR »4

^{OR3a R}^%₍^J^^k -SO₃H; natural and unnatural

OR³ _^AYT^CH_OR¹⁵ . amino acids.

R⁴ ΛO/,/ T*γ O

-^O ^CHaR^a

R, R^a and R^b are independently selected from the group consisting of H, -OH, halogeno, -NH2. azido, (Ci-C6)alkoxy(Ci-C6)-alkoxy and -W-R³⁰;

W is independently selected from the group consisting of -NH-C(O)-, -O-C(O)-, -O-C(O)-N(R31)., -NH-C(O )-N(R3i)- and -O-C(S)-N(R31)-;

R² and R⁶ are independently selected from the group consisting of H₁ (C-i- CβJalkyl, aryl and aryl(Ci-C6)alkyl;

R³, R⁴, R⁵, R7, R3a and R^4a are independently selected from the group consisting of H, (C₁-C6)alkyl, aryl(Ci-C6)alkyl, -C(O)(C₁-C6)alkyl and -C(O)aryl; 123

R³⁰ is independently selected form the group consisting of R³²-substituted T, R³²-substituted-T-(Ci-C₆)alkyl, R³²-substituted-(C₂-C₄)alkenyi, R³²-substituted-(Ci-C₆)alkyl, R³²-substituted-(C₃-C7)cycloalkyl and R³²-substituted- (C₃-C7)cycloalkyl(CrC₆)alkyl;

R³¹ is independently selected from the group consisting of H and (Ci-C₄)alkyl;

T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;

R³² is independently selected from 1-3 substituents independently selected from the group consisting of H₁ halogeno, (Ci-C4)alkyl, -OH, phenoxy, -CF₃, -NO₂, (C-i-C/Oalkoxy, methylenedioxy, oxo, (Ci-C₄)alkylsulfanyl, (C-)-C4)alkylsulfinyl, (Ci- C₄)alkylsulfonyl, -N(CH₃)2. -C(O)-NH(Ci-C₄)alkyl, -C(O)-N((C₁-C₄)alkyl)₂₎ -C(O)-(Ci- C₄)alkyl, -C(O)-(Ci -C₄)alkoxy and pyrrolidinylcarbonyl; or R³² is a covalent bond and

R³¹, the nitrogen to which it is attached and R³² form a pyrrolidinyl, piperidinyl, N- methyl-piperazinyl, indolinyl or morpholinyl group, or a (Ci-C4)alkoxycarbonyl- substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;

Ar¹ is aryl or R¹⁰-substituted aryl;

Ar² is aryl or R¹¹-substituted aryl;

Q is -(CH₂)q-, wherein q is 2-6, or, with the 3-position ring carbon of the azetidinone,

Vf-(R¹³).-

/014J I forms the spiro grou'p ^v '^b ;

Rⁱ² is

-CH-, -C(C₁-C₆ alkyl)-. -CF-, -C(OH)-, -C(C₆H₄-R²³)-, -N-, or -⁺N0" ;

R¹³ and R¹⁴ are independently selected from the group consisting of -CH₂-, - CH(CrC₆ alkyl)-, -C^i-(C₁-C₆) alkyl), -CH=CH- and -C(Ci-C₆ alkyl)=CH-; or R1² 124 together with an adjacent R¹³, or R¹² together with an adjacent R¹⁴, form a -CH=CH- or a -CH=C(Ci-C₆ alkyl)- group; a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided that when R¹³ is -CH=CH- or -C(Ci-Ce alkyl )=CH-, a is 1 ; provided that when R¹⁴ is - CH=CH- or -C(Ci-C6 alkyl)=CH-, b is 1 ; provided that when a is 2 or 3, the R¹³¹S can be the same or different; and provided that when b is 2 or 3, the R¹⁴'s can be the same or different;

R¹⁰ and R^{1 1} are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C^CeJalkyl, -OR¹9, -O(CO)R¹⁹, -O(CO)OR21, -O(CH₂)1-5OR19, -O(CO)NR¹⁹R²<\ -NR¹⁹R20, -NR¹⁹(CO)R20, -NR19(CO)OR21, - NR19(CO)NR20R25, -NR19SO₂R²¹. -COOR¹⁹, -CONR¹9R20, -COR¹⁹, -SO₂NR¹⁹R²O, S(0)o-2R²¹, -O(CH₂)i-i0-COOR¹9, -O(CH₂)i-₁₀CONR¹⁹R20, -(C₁-C₆ alkylene)- COOR¹⁹, -CH=CH-COOR¹⁹, -CF₃. -CN. -NO₂ and halogen;

Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

R¹⁹ and R²⁰ are independently selected from the group consisting of H, (Ci- Ce)alkyl, aryl and aryl-substituted (Ci-Ce)alkyl;

R²¹ is (Ci-C6)alkyl, aryl or R²⁴-substituted aryl;

R²² is H. (C-i-CβJalkyl, aryl (Ci-C₆)alkyl. -C(O)R¹⁹ or -COOR¹9;

R²³ and R²⁴ are independently 1 -3 groups independently selected from the group consisting of H, (Ci-C6)alkyl, (Ci-C₆)alkoxy. -COOH. NO₂, -NR¹⁹R²⁰, -OH and halogeno; and

R²⁵ is H, -OH or (C !-C₆JaIkOXy.

17. The pharmaceutical composition of claim 16, wherein the sterol absorption inhibitor is represented by Formula (X): 125

OH

OR

X or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (X) or of the isomers thereof, or prodrugs of the compounds of Formula (X) or of the isomers, salts or solvates thereof wherein: R¹ is defined as above.

18. The pharmaceutical composition claim 16, wherein the sterol absorption inhibitor is represented by Formula (XI)

Q HQ,

HO

(XI) or isomers thereof, or pharmaceutically acceptable salts or solvates of the compounds of Formula (XI) or of the isomers thereof, or prodrugs of the compounds of Formula (XI) or of the isomers, salts or solvates thereof.

19. The pharmaceutical composition of claim 1 , further comprising administering to the mammal in need of such treatment an effective amount of at least one lipid lowering agent in combination with the at least one sterol absorption inhibitor.

20. The method of claim 19, wherein the lipid lowering agent is a HMG-CoA reductase inhibitor. 126

21. The method of claim 20, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, itavastatin and mixtures thereof.

22. The method of claim 21 , wherein the HMG-CoA reductase inhibitor is simvastatin or atorvastatin.

23. A pharmaceutical composition comprising an effective amount of ezetimibe and an effective amount of at least one CETP inhibitor.

24. The pharmaceutical composition of claim 23, which further comprises as HMG-CoA reductase inhibitor.

25. The pharmaceutical composition of claim 24, wherein the HMG-CoA reductase inhibitor is simvastatin or atorvastatin.

26. A method of treating or preventing sitosterolemia, hypercholesterolemia, hyperlipidemia, atherosclerosis, mixed dyslipidemia and vascular events prevention, which comprising administering the pharmaceutical composition of claim 1 a to a mammal in need of such treatment: