WO2012047772A2 - Imidazole derivatives - Google Patents

Abstract

Described herein are compounds of formula (I). The compounds of formula (I) act as DGAT1 inhibitors and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity.

Description

IMIDAZOLE DERIVATIVES

TECHNICAL FIELD

The present invention is directed to novel imidazole derivative compounds.

Specifically, the compounds act as diacylglycerol O-acyltransferase type 1 inhibitors (hereinafter also referred to as "DGAT1 "), and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity.

BACKGROUND

Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and increased health problems. As such, obesity is recognized as an upstream risk factor for many conditions such- as diabetes mellitus, lipidosis and hypertension (Journal of Japan Society for the Study of Obesity, Vol. 12, Extra Edition, 2006). Although the need to treat obesity is recognized to be important, there are extremely limited drug therapies for obesity that are currently available, and thus, the advent of novel antiobesity drugs having more definite action and few side-effects is desired.

In general, obesity is caused by the accumulation of triacylglycerol (TG) in adipose tissue which is a result of lack of exercise, intake of excessive calories and ageing. In the body there are two TG synthesis pathways, a glycerol phosphate pathway, which is present in most organs and causes de novo TG synthesis, and a monoacylglycerol pathway, which is involved principally in absorption of aliphatic acid from the small intestine. Diacylglycerol acyltransferases (DGATs, EC 2.3.1.20), which are membrane-bound enzymes present in the endoplasmic reticulum, catalyze the final step of the TG synthesis common to the two TG synthesis pathways. The final reaction consists of transferring an acyl group from acyl-coenzyme A to the 3-position of 1 ,2-diacylglycerol to generate TG (Prog. Lipid Res., 43,134-176, 2004 and Ann. Med., 36, 252-261, 2004). There are two subtypes of DGATs: DGAT1 and DGAT2.

There is no significant homology at the generic or amino acid level between DGAT1 and

DGAT2, which are encoded by different genes (Proc. Natl. Acad. Sci.USA., 95, 13018-13023, 1998 and JBC, 276, 38870-38876, 2001). DGAT1, is present in the small intestine, adipose tissue and liver and is believed to be involved in lipid absorption in the small intestine; lipid accumulation in the fat cell; and VLDL secretion and lipid accumulation in the liver (Ann. Med., 36, 252-261, 2004 and JBC, 280, 21506-21514, 2005). In consideration of these functions, a DGAT1 inhibitor is expected to be an effective obesity treatment through inhibition of lipid absorption in the small intestine, lipid accumulation in the adipose tissue and the liver, and lipid secretion from the liver. In order to carry out in vivo examination of the physiological function(s) of DGATl and inhibitory activity against DGATl, DGATl -knockout mice deficient in DGATl at the genetic level was produced and analyzed. As a result, the DGATl -knockout mice have been found to have smaller fat masses than those of wild-type mice and became resistant to obesity, abnormal glucose tolerance, insulin resistance and fatty liver due when fed a high-fat diet (Nature Genetics, 25, 87-90, 2000 and JCI, 109, 1049-1055, 2002). In addition, energy expense has been reported to be accelerated in the DGATl -knockout mice; and transplantation of the adipose tissues of DGATl -knockout mice into wild-type mice has been reported to make the wild-type mice resistant to obesity and abnormal glucose tolerance, induced by a high-fat diet (JCI, 1 1 1 , 1715-1722, 2003 and Diabetes, 53, 1445-1451, 2004). In contrast, obesity and diabetes mellitus due to a high-fat diet have been reported to worsen in mice with overexpression of DGATl in adipose tissue (Diabetes, 51, 3189-3195, 2002 and Diabetes, 54, 3379-3386, 2005).

From these results, DGATl inhibitors are likely to be therapeutic drugs with efficacy for obesity, type 2 diabetes mellitus, lipidosis, hypertension, fatty liver, arteriosclerosis, cerebrovascular disorder, coronaiy artery disease and metabolic syndrome, associated with obesity.

SUMMARY OF THE INVENTION

A compound of formula (I)

I

or pharmaceutically acceptable salts thereof, wherein Y is selected from the group consisting of: -(CH₂)n-0-(CH₂)n-; -(CH₂)n-C(0)NH-(CH₂)n-; -(CH₂)n-C(0)CR²H-(CH₂)n~; ~(CH₂)n-CR²H- (C¾)ns -(CH₂)n-C(0)C(R²)HC¾)n-; -(CH₂)n-C(R )₂-(CH₂)n -(CH₂)n-NHC(0)-(CH₂)n-; - (CH₂)n-OC(0)-(CH₂)n-; -(CH₂)n-C(0)0-(C¾)n-; -(CH₂)n-NHS0₂-(CH₂)n-; ~(CH₂)n-S0₂NH- (CH₂)n-; -(CH₂)n-C(0)n-(CH₂)n-; -(CH₂)n-NHC(0)CR²H-(CH₂)n-;

Z is selected from the group consisting of d-Cgalkyl, aryl, cycloalkyl and heterocycle, wherein the Ci~C₆alkyl, aryl, cycloalkyl and heterocycle can be unsubstituted or substituted with 1-3 substituents selected from a;

R¹ is selected from a;

R² is selected from the group consisting of halogen, halogen- substituted C_\~ Qjalkyl, -OH and C C₆alkyl; a is selected from the group consisting of halogen, C Cealk l, halogen- substitutedCrCealkyl, COCi-C₆alkyl, COhalogen-substitutedCrCgalkyi, oxo, -OH, C_\- QalkylOH, d-QalkylOHCOOH, halogen-substitutedCrQalkylOH, -OC_rC₆alkyl, -Ohalogen- substitutedCi-C₆aIkyI, -COOH, -COCOOH, -COOC C₆alkyl, -Ci-C₆aIkylCOOCi-C₆alkyl, -C CealkylCOOH, -OCi-C₆alkylCOOH, -CN, C_rC₆alkylCN, -N0_2> NH_2j NHCi-C₆alk l, N(C_r C₆alkyl)₂, -NHCOOH, -NHCOOC C₆alkyl, -CONH₂, -CONHC Qalkyl, -NHCOC_rC₆alkyl, - CON(Ci-C₆alkyl)₂, -NHS0₂Ci-C₆alkyl, S0₂NH_2f -S0₂Ci-C6alk l; and

each occurrence of n is independently selected from the list consisting of 0, 1 or 2. DETAILED DESCRIPTION OF THE INVENTION

Compounds

A compound of formula (I):

I

or pharmaceutically acceptable salts thereof

Of the compounds of formula I, Y is selected from the group consisting of: -

(CH₂)n-0-(CH₂)n-; -(CH₂)n-C(0)NH-(CH₂)n-; -(CH₂)n-C(0)CR²H-(CH₂)n-; -(CH₂)n-CR²H- (CH₂)n-; -(CH₂)n-C(0)C(R²)₂-(CH₂)n-; -(CH₂)n-C(R²)₂-(CH₂)n-; -(CH₂)n-NHC(0)-(CH₂)n-; - (CH₂)n-OC(0)~(CH₂)n-; -(CH₂)n-C(0)0-(CH₂)n-; -(CH₂)n-NHS0₂-(CH₂)n-; -(CH₂)n-S0₂NH- (CH₂)n-; -(CH₂)n-C(0)n-(CH₂)n-; -(CH₂)n-NHC(0)CR²H-(CH₂)n-. In certain embodiments, Y is selected from the group consisting of -(CH₂)n-C(0)NH-(CH₂)n-; ~(CH₂)n-C(0)CR H-(CH₂)n-; -(CH₂)n-C(0)n-(CH₂)n- and -(CH₂)n-C(0)C(R²)₂-(CH₂)n-;

In other embodiments, Y is -(CH₂)n-0-(CH₂)n-. In still other embodiments, Y is - (CH₂)n-C(0)NH-(CH₂)n- or -(CH₂)n-NHC(0)-(CH₂)n-. In yet other embodiments, Y is - (CH₂)n-C(0)CR²H-(CH₂)n- or -(CH₂)n-C(0)C(R²)₂-(CH₂)n-. In other embodiments, Y is - (CH₂)n-CR²H-(CH₂)n- or -(CH₂)n-C(R²)₂-(CH₂)n-. In still other embodiments, Y is -(CH₂)n- OC(0)-(CH₂)n-. In other embodiments, Y is -(CH₂)n-C(0)0-(C¾)n-. In yet other

embodiments, Y is -(CH₂)n-NHS0₂-(C¾)n- or -(CH₂)n-S0₂NH-(CH₂)n-. In other

embodiments, Y is -(CH₂)n-C(0)n-(CH₂)n-. In yet another embodiments, Y is -(CH₂)n- NHC(0)CR H-(CH₂)n-.

In certain examples of the embodiments described herein, Y is selected from the group consisting of -CH₂0-, -CONH-, -COCHOH-, -COCH3OH-, -CHOHCH₂-, - CH₂CHOH-, - NHCO-, -OCO-, ~S0₂NH-, -NHS0₂-, -0-, -COCO-, -CO-, -COCOHC¾-, -CH₂OH- and - NHCOCHOH-. In other examples of the embodiments described herein, Y is selected from the group consisting of -CONH-, -COCHOH-, -COC(CH₃)(OH)-₅ -COCH₂-, -COCO-, -CO-, in one example, Y is -COCO- or -CO-. In another example, Y is -COCHOH-. In yet another example,

Y is -CH₂O-. In still another example, Y is -CONH- or -NHCO-. In another example, Y is - COCHOH-, -COC(CH₃)(OH)-, -CHOHCH₂-, -CH₂OH- or - CI¾CHOH-. In still another example, Y is -S0₂NH- or -NHSO₂-. In still other examples, Y is -0-. In yet another example,

Y is -NHCOCHOH-.

In any of the embodiments described above, each occurrence of n is independently selected from the list consisting of 0, 1 or 2. In certain embodiments, n is 0. In other

embodiments, n is 1. In still other embodiments, n is 2.

Of the compounds of formula I, Z is selected from the group consisting of Cj-

C₆alkyl, aryl, cycloalkyl and heterocycle, wherein the Ci-Cealkyl, aryl, cycloalkyl and heterocycle can be unsubstituted or substituted with 1-3 substituents selected from a. In certain

embodiments, Z is unsubstituted. In other embodiments Z is substituted with 1 substituent selected from a. In another embodiment, Z is substituted with 2 substituents selected from the group consisting of a. In yet another embodiment, Z is substituted with 3 substituents selected from the groups consisting of a. In still yet another embodiment, Z is substituted with 1 or 2' substituents selected from the group consisting of a. In some embodiments, Z is substituted with Ϊ-3 substituents independently selected from the group consisting of halogen, Cj-Qalkyl, halogen-substitutedCrCealkyl, -OH, -COOH, -COOCrQalkyl, -C C₆alkylCOOC]-C₆alkyl, - d-QaikylCOOH, Ci-C₆alk lOHCOOH, -CN and -CONH₂. In another embodiment, Z is substituted with 1-3 substituents independently selected from the group consisting of fluorine and trifluoromethyl.

In certain embodiments of the compounds described herein Z is CrCealkyl. In some embodiments, the d-Cealkyl is unsubstituted. In other embodiments, the Cj-Cealkyl is substituted. Suitable examples of Cj-C₆alkyl are methyl, ethyl, butyl, isobutyl, t-butyl and propyl. In embodiments, Z is Ci-C₆alkyl, wherein the Q-Cealkyl is substituted with -COOH. From example, in certain embodiments of the compounds described herein, Z is propyl, t-butyl or isobutyl, wherein the propyl, t-butyl or isobutyl can be substituted with -COOH.

In certain embodiments of the compounds described herein Z is aryl. In some embodiments, the aryl is unsubstituted. In other embodiments, the aryl is substituted. A suitable example of aryl is phenyl. In embodiments, Z is aryl, wherein the aryl is substituted with halogen, C_rC₆aIkyl, halogen-substitutedCi-C₆alkyl, -OH, C_rC₆alkylOH, -COOH, -COCOOH, - COOCi-C₆alkyl, -C_rC₆alkylCOOC_rC₆alkyI, -Ci-C₆alk lCOOH, -OCj-C₆alkylCOOH, -CN, C C₆alkylCN or -CON¾. From example, in certain embodiments of the compounds described herein, Z is phenyl, wherein the phenyl can be substituted with -COOH, -COOMe, - COOC¾CH₃, fluorine, methyl, -OH, triflouromethyl or -CN. In certain embodiments of the compounds described herein Z is cycloalkyl. In some embodiments, the cycloalkyl is unsubstituted. In other embodiments, the cycloalkyl is substituted. Suitable examples of cycloalkyl include, but are not limited to, cyclohexane, cyclobutyl and cylcopentane. In embodiments, Z is cycloalkyl, wherein the cycloalkyl is substituted with halogen, CrCealkyl, halogen-substitutedC Cealkyl, -OH, Ci-C₆alkylOH, - COOH, -COCOOH, -COOC_rC₆alkyl, -Cj-CealkylCOOCj-Cealkyl, -Q-QalkylCOOH, -OC CealkylCOOH, -CN_} C)-C₆alkylCN or -CONH₂. From example, in certain embodiments of the compounds described herein, Z is cyclohexane, cyclobutyl or cylcopentane, wherein the cyclohexane, cyclobutyl or cylcopentane can be substituted with -COOH. In certain

embodiments of the compounds described herein, Z is cyclohexane, cyclobutyl or cylcopentane, wherein the cyclohexane, cyclobutyl or cylcopentane can be unsubstituted.

In certain embodiments of the compounds described herein Z is heterocycle. In some embodiments, the heterocycle is unsubstituted. In other embodiments, the heterocycle is substituted. Suitable examples of heterocycle include, but are not limited to, benzodioxolane or pyridine. In embodiments, Z is heterocycle, wherein the heterocycle is substituted with halogen, Ci-Cealkyl, halogen-substitutedC_rC₆alkyl, -OH, Ci-C₆alkylOH, -COOH, -COCOOH, -COOC,- C₆alkyl, -C_rC₆aIkylCOOC,-C₆alkyl, -C C₆alkylCOOH, -OC_rC₆alkylCOOH, -CN, d- C₆aIkyICN or -CON¾. From example, in certain embodiments of the compounds described herein, Z is benzodioxolane or pyridine, wherein the benzodioxolane or pyridine can be substituted with -COOH, halogen-substitutedCi-Csalkyl or -Ci-C₆alkylCOOH. In certain embodiments of the compounds described herein, Z is benzodioxolane or pyridine, wherein the benzodioxolane or pyridine can be unsubstituted

Of the compounds of formula I, R¹ is selected from a. In certain embodiments, R is selected from the group consisting of halogen, Ci-C₆alkyl, halogen-substitutedCrQalkyl. Suitable examples of R¹ include, but are not limited to, chlorine, fluorine and trifluromethyl.

In certain embodiments of the compounds described herein, R¹ can be positioned as follows:

Of the compounds of formula I, R² is selected from the group consisting of halogen, halogen-substitutedQ-Cgalkyl, -OH and Cj-Cealkyl In certain embodiments, R is - OH. In other embodiment, R² is halogen. Suitable halogens include, but are not limited to, chlorine, bromine and fluorine. In still other embodiments, R² is halogen-substitutedC Cealkyl. Suitable examples include, but are not limited to, txifluoromethyl. In yet other embodiments, R² is Ci-Cealkyl. Suitable examples include, but are not limited to, methyl and ethyl. Of the compounds of formula I, a is selected from the group consisting of halogen, Ci-C₆alkyl, halogen-substitutedCj-Cealkyl, COCi-Cealkyl, COhalogen-substitutedC] - C₆alkyl, oxo, -OH, Ci-C₆alkylOH, C C₆alkylOHCOOH, halogen-substitutedC C₆alkylOH, - OCi-Cealkyl, -Ohalogen-substitutedCi-C₆alkyl_} -COOH, -COCOOH, -COOC C₆alkyl, -C C₆alkylCOOC_rC₆alkyl, -C_rC₆alkylCOOH, -OC C₆alkylCOOH, -CN, C_rC₆alkylCN, -N0₂, N¾, NHC_rC₆alkyl₅ N(Ci-C6alkyl)₂, -NHCOOH, -NHCOOCi-C₆alkyl, -CON¾, -CONHC_r Qalkyl, -NHCOCrQalkyl, -CON(d-C₆alkyl)₂, -NHS0₂C C₆alkyl, S0₂NH_2> -S0₂C₁-C₆alkyl In certain embodiments described herein, a is selected from the group consisting of fluorine, methyl, -OH, -COOH, COOMe, trifluormethyl, -CN and -CONH₂.

Examples of the compounds described herein include:

2-(2-fluorophenyl)-2-hydroxy- 1 -(4-(5 - (5-(trifluoromethyl)-lH- benzo[d]imidazoI-2-yl)pyridin-2- yl)piperazin- 1 -yl)ethanone

2-(2,5-difluorophenyl)-2-hydroxy - 1 -(4- (5-(5-(trifluoromethyl)-lH- benzo [d] imidazol- 2-y l)pyridin-2- yl)piperazin- 1 -yl)ethanone

2-(2,5-dimethyIphenyI)-2-hydroxy- 1 -(4- (5 -(5-(trifluoromethyl)- 1 H- benzo[d]imidazol-2-yl)pyridin-2- yl)piperazin- 1 -yl)ethanone

F

(R)-2-hydroxy-2-phenyl- 1 -(4-(5-(5- (trifluoromethyl)- 1 H-benzo [d] imidazol- 2-yl)pyridin-2-yl)piperazin- 1 - yl)ethanone* 0

(R)-l-(4-(5-(5-chloro-lH- benzo [d] imidazol-2-yl)pyridin-2 - yl)piperazin- 1 -yl)-2-cyclohexyl-2- hydroxyethanone o

(R)-2-cyclohexyl-2-hydroxy~ 1 -(4-(5-(5- (trifluoromethyl) - 1 H-benzo [d] imidazol- 2-yl)pyridin-2-yl)piperazin- 1 - yl)ethanone . 0 F

2-hydroxy-2-(3 -hydroxyphenyl)- 1 -(4- (5 -(5 -(trifluoromethyl)- 1 H- benzo[d]imidazol-2-yl)pyridin-2- yl)piperazin-l -yl)eth.anone o

1 -(4-(5 ~(5 -chloro- 1 H- benzo[d]imidazol-2-yl)pyridin-2- yl)piperazin- 1 -yl)-2-(4-fluorophenyl)-2- hydroxyethanone l-(4-(5-(5-chloro-lH- benzo [d] imidazol-2 -yl)pyridin-2- yl)piperazin- 1 -yl)-2-(3 , 5 - difluorophenyl)-2-hydroxyethanone l-(4-(5-(5-chloro-lH- benzo[d]imidazol-2-yI)pyridin~2- yl)piperazin- 1 -yl)-2-(3 ,4- difluorophenyl)-2-hydroxyethanone

methyl 4-(2-(4-(5 -(5 -chloro- 1H- benzo [d] imidazol-2-yl)pyridin-2- yl)piperazin- 1 -yl)- -hydroxy-2- oxoethyl)benzoate o

4-(2-(4-(5-(5-chloro-lH- benzo [d] imidazol-2-yl)pyridin-2- yl)piperazin- 1 -yl)-2-oxoacetyl)benzoic

acid 0 methyl 4-(2-(4-(5-(5-chloro-lH- benzo [d] imidazol-2-yl)pyridin-2- ₃ yl)piperazin- 1 -yl)-2-oxoacetyl)benzoate

2-(3-(4-(5-(5-chloro-lH- benzo [d] imidazol-2-yl)pyridin-2 - yl)piperazine- 1 -carbonyl)phenyl)-2- oxoacetic acid l-(4-(5-(5-chloro-lH- benzo [d] imidazol-2-yl)pyridin-2- yl)piperazin- 1 -yl)-2-hydroxy-2-(4-

(trifluoromethyl)phenyl)ethanone

2-(benzo[d][l ,3]dioxol-5-yl)- i -(4-(5- (5~cbIoro- 1 H-benzo [d] imidazol-2- yl)pyridin-2-yl)piperazin- 1 -yl)-2- hydroxyethanone o l-(4-(5-(5-chloro-lH- ft — N

benzo [d] imidazol-2-yl)pyridin-2- ,V HO CHj y piperazin- 1 -yl)-2-hydroxy~2- phenylpropan- 1 -one 0

CI

2-(3-(4-(5-(5-chloro-lH- benzo [d] imidazo l-2-yl)pyridin-2- yl)piperazine- 1 -carbonyl)phenyl)-2- hydroxyacetic acid O OH

methyl 3-(2-(4-(5-(5-chloro-lH- benzo [d] imidazo l-2-yl)pyridm-2- yl)piperazin- 1 -yl)- -hydroxy-2- ' 1! 1! ⁰ o

oxoethyl)benzoate

3-(2-(4-(5-(5-chloro-lH- benzo [d] imidazo l-2-yl)pyridin-2- yl)piperazin- 1 -yl)- 1 -hydroxy-2 - II if °^H o

oxoethyl)benzoic acid

3~(l-hydroxy-2-oxo-2-(4-(5-(5- (trifluoromethyl)- 1 H-benzo [d] imidazol- 2~yl)pyridin-2-yl)piperazm- 1 -

yl)ethyl)benzoic acid

3-(2-(4-(5-(5-chloro-lH- benzo[d]imidazol-2-yl)pyridin-2- yl)piperazin- 1 -y l)-2- o

oxoethyl)benzonitrile

l-(4-(5-(5-chloro-lH- ^H .

benzo [d] imidazol-2-yl)pyridin-2- J yl)piperazin- 1 -yl)-2-(2- fluorophenyl)ethanone CI

l-(4-(5-(5-chloro-lH- benzo [d] imidazol-2-yl)pyridin-2- yl )piperazin- 1 -yl)-2-(pyridin~3 - yl)ethane- 1 ,2-dione N

( lR,2R)-2-(4-(5-(5-chloro- 1 H- benzo[d]iniidazol-2-yl)pyridin-2- yl)piperazine-l- carbonyl)cyclopentanecarboxylic acid

3-(2-(4-(5-(5-chloro-lH- benzo [d] imidazol-2-y l)pyrid in-2- yl)piperazin- 1 -yl)-2-

oxoethyl)benzamide

3-(2-(4-(5-(5-chloro-lH- benzo [d] imidazol-2~yI)pyridiii-2- yl)piperazin- 1 -yl)~2-oxoethyl)benzoic I I I I ^0H o

acid

l-(4-(5-(5-chloro-lH- ^H 1

benzo [d] imidazol-2-yl)pyridin-2- yl)piperazin- 1 -yl)-2-hydroxy-2- (pyridin- 3 -yl)ethanone N 4-(5-(5-chloro-lH-benzo[d]irnidazol~2- yl)pyridin-2-yl)-N-o olylpiperazine- 1 -

carboxamide

and pharmaceutically acceptable salts thereof.

Definitions

Examples of "halogen" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The term "Q-C ₆alkyl" encompasses straight alkyl having a. carbon number of 1 to 6 and branched alkyl having a carbon number of 3 to 6. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylhutyl, 1 ,2-dimethylpropyl, 1 -ethylpropyl, n-hexyl, isohexyl, 1-methylpenlyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1 ,2-dimethylbutyl, 2,2- dimethylbufyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, l -ethyl-2- methylpropyl, 1 -ethyl- 1 -methylpropyl, and the like.

"Cycloalkyl" encompasses cycloalkyls having 3 to 10 carbons, forming one or more carbocyclic rings that are fused. "Cycloalkyl" also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. In one embodiment, the cycloalkyl can include 3-6 carbons, i.e. C3-C₆cycloalkyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl,

decahydronaphthyl, indanyl and the like.

The term "-OCi-C galkyl" refers to an alkyl group having 1 to 6 carbons linked to oxygen, also known as an alkoxy group. Examples include methoxy, ethoxy, butoxy and propoxy.

The term "-OCj-C salkylCOOH" refers to an alkoxy group having 1 to 6 carbons substituted with a carboxylic acid (-COOH) group.

The term "halogen-substitutedCi-Ce alkyl" encompasses Q-Q alkyl with the hydrogen atoms thereof being partially or completely substituted with halogen, examples thereof including fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1 ,2-difluoroethyl, 2,2-difluoroethyl and the like.

The term "-Ohalogen-substitutedC5-C₆alkyl" means a -OCrCealkyl as defined above, which is substituted with 1 -3 halogen atoms which are identical or different, and specifically includes, for example, a trifluoromethoxy group. The term "-COCi-C₆alkyl" means groups having Ci-Ce lk l bonded to carbonyl, and encompasses alkylcarbonyl having a carbon number of 1 to 6. Specific examples thereof include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and the like.

The term "-COhalogen-substitutedCi-Cealkyl" means a -COC_rC₆alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different.

The term "Ci-C₆alkylOH" means a Cj-Cealkyl substituted with an alcohol (-OH).

Examples include methanol, propanol, butanol and t-butanol.

The term "halogen-substitutedCi-CealkylOH" means a halogen-substitutedCj-C₆alkyl, as defined above, substituted with an alcohol (-OH).

The term "Ci-CealkylOHCOOH" means a C, -Qalkyl substituted with an alcohol (-OH) and a carboxylic acid group (-COOH).

The term "Ct-CealkylCN" means a C]-C₆alkyl substituted with an cyano group (-CN).

The term "COOd-Cgalkyl" means a -COOH group wherein the -OH is replaced with an alkoxy group as defined above. Examples include methoxycarbonyl, ethoxycarbonyl and butoxy carbonyl.

The term "S0₂C C₆alkyr means a group having Ci-Cgalkyl bonded to sulfonyl (-SO₂-). Specific examples thereof include methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, sec-butanesulfonyl, tert-butanesulfonyl, and the like.

The term "oxo" means the functional group "=0", such as, for example, (1) "C=(0)'\ that is a carbonyl group; (2) "S=(0)", that is, a sulfoxide group; and (3) " =(0) , that is, an N-oxide group, such as pyridyl-N-oxide.

The term "NHCj-C₆alkyl" means a group with one of the hydrogen atoms of amino (- NH₂) being substituted with a C_1-6 alkyl group. Specific examples thereof include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butyiamino, and the like.

The term "N(Ci-C₆alkyI)₂" means a group with the two amino hydrogen atoms each being substituted with a Ci.₆ alkyl group. Specific examples thereof include dimethylammo, diethylamino, ethylmethylamino, di(n-propyl)amino, methyl(n-propyl)amino, diisopropylamino, and the like.

The term "NHC0₂C C₆alkyl" means a group with one of the amino hydrogen atoms being substituted with

alkoxycarbonyl and encompasses alkoxycarbonylamino having a carbon number of 1 to 6. Specific examples thereof include methoxycarbonylamino, ethoxycarbonylamino, n-propyloxycarbonylamino, isopropyloxycarbonylamino, n- butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, n- pentyloxycarbonylamino, and the like. The term "NHCOCj-Cealkyl" means a group with one of the amino hydrogen atoms being substituted with Ci_-6 alkylcarbonyl. Specific examples thereof include acetylamino, propionylamino, isobutyryl amino, valerylamino, iso valerylamino, pivaloylamino, and the like.

The term "CONHC C₆aIkyP' means a group with one of the hydrogen atoms of carbamoyl (-CONH₂) being substituted with C_1-6 alkyl. Specific examples thereof include methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl, and the like.

The term "CON(CrC₆alkyl)2" means a group with the two carbamoyl hydrogen atoms each being substituted with Ci_-6 alkyl. Specific examples thereof include dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, di(n-propyl)carbamoyl, methyl(n-propyl)carbamoyl, diisopropylcarbamoyl, and the like.

The term "NHSC^Ci-Cealkyl" means a group.with one of the amino hydrogen atoms being substituted with C[.s alkylsulfonyl. Specific examples thereof include

methanesulfonylamino, ethanesulfonylamino, n-propanesuifonylamino,

isopropanesulfonylamino, n-butanesulfonylamino, sec-butanesulfonylamino, tert- butanesulfonyiamino, and the like.

Examples of "aryl" include phenyl, naphthyl, tolyl, and the like.

"Heterocycle" unless otherwise specified., means an aromatic, partially aromatic or non- aromatic monocyclic or polycyclic (includmg bicyclic) ring having at least one ring heteroatom selected from O, S and N. Examples of heterocyclic groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, 2-oxo-(lH)-pyridinyl (2-hydroxy-pyridinyl), oxazolyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl, imidazo[l,2- a]pyridinyl, [l,2,4-triazolo][4,3-a]pyridinyl, pyrazolo[l,5-a]pyridinyl, [l,2,4-triazolo][l,5- ajpyridinyl, 2-oxo-l,3-benzoxazoiyl, 4-oxo-3H~quinazolinyl, 3-oxo-[l,2,4]-triazolo[4_f3-a]-2H- pyridinyl, 5-oxo-[l ,2,4]-4H-oxadiazoiyl, 2-oxo-[l,3,4]-3H-oxadiazolyl, 2~oxo-l ,3-dihydro-2H- imidazolyl, 3-oxo-2,4-dihydro-3H-l,2,4-triazolyl, and the like. Examples of "heterocycle" also include tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-d ydrofuro(2,3-6)pyridyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6-dihydroimidazo[2,l-6]thiazolyl, tetrahydroquinolinyl, mo holίnyl, tetrahydroisoquinolinyl, dihydromdolyl, 2- or 4-pyridones attached through the nitrogen or N-substituted-(lH, 3H)-pyrimidine-2,4-diones (TV-substituted uracils). The term also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2- azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2Joctyl₅ 2- azabicyclo[2.2,2]octyl, and 3-azabicyclo[3.2.2]nonyl, and azabicyclo[2.2.1]heptanyl.

The term "pharmaceutically acceptable salt" refers to salts prepared from

pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term

"pharmaceutically acceptable salt" refer to non- toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine., hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, Ν,Ν-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorphoHne, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

The compounds of the present invention contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of these compounds.

Some of the compounds described herein contain olefmic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by

chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

It will be understood that, as used herein, references to the compounds of the structural formulas described herein are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.

Solvates, and in particular, the hydrates of the compounds of the structural formulas described herein are included in the present invention as well.

Some of the compounds described herein may exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of the present invention.

In the compounds of the formulas described herein, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the formulas described herein. For example, different isotopic forms of hydrogen (H) include protium (lH) and. deuterium (¾). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic formula can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.

Methods of Treatment

Also encompassed by the present invention are methods of treating DGATl -related diseases. The compounds described herein are effective in preventing or treating various DGATl -related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and. other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis. The compound of the invention is especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety.

One aspect of the invention described, herein provides a method for the treatment and control of obesity or metabolic syndrome, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having the formulas described herein or a pharmaceutically acceptable salt thereof. For example, the compounds described herein are useful for treating or preventing obesity by administering to a subject in need thereof a composition comprising a compound of formula I.

Methods of treating or preventing obesity and conditions associated with obesity refer to the administration of the pharmaceutical formulations described herein to reduce or maintain the body weight of an obese subject or to reduce or maintain the body weight of an individual at risk of becoming obese. One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds or combinations of the present invention. Another outcome of treatment may be preventing body weight gain, regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy and preventing weight gain from cessation of smoking. Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases. Yet another outcome of treatment may be decreasing the risk of developing diabetes in an overweight or obese subject. The treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof The treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.

Prevention of obesity and obesity-related disorders refers to the administration of the pharmaceutical formulations described herein to reduce or maintain the body weight of a subject at risk of obesity. One outcome of prevention may be reducing the body weight of a subject at risk of obesity relative to that subject's body weight immediately before the administration of the compounds or combinations of the present invention. Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Another outcome of prevention may be decreasing the occurrence and/or severity of obesity-related disorders if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Moreover, if treatment is commenced in already obese subjects, such treatment may prevent the occurrence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, type 2 diabetes, polycystic ovary disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.

Another aspect of the invention that is of interest relates to a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat hyperglycemia, diabetes or insulin resistance.

More particularly, another aspect of the invention that is of interest relates to a method of treating type 2 diabetes in a mammalian patient in need of such treatment comprising

administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat type 2 diabetes.

Yet another aspect of the invention that is of interest relates to a method of treating non- insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat non- insulin dependent diabetes mellitus.

The present invention is also directed to the use of a compound of structural formula I in the manufacture of a medicament for use in treating various DGAT1 -related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis. The compounds described herein are especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety.

For example, the present invention is directed to the use of a compound of structural formula I in the manufacture of a medicament for use in treating obesity, diabetes, hormone secretion disorder, hyperlipemia, gout and fatty liver.

Additionally, the present invention is directed to the use of a compound of structural formula I in the manufacture of a medicament for use in treating obesity.

Pharmaceutical Compositions

Compounds of the invention may be administered orally or parenterally. As formulated into a dosage form suitable for the administration route, the compound of the invention can be used as a pharmaceutical composition for the prevention, treatment, or remedy of the above diseases.

In clinical use of the compound of the invention, usual ly, the compound is formulated into various preparations together with pharmaceutically acceptable additives according to the dosage form, and may then be administered. By "pharmaceutically acceptable" it is meant the additive, carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. As such additives, various additives ordinarily used in the field of pharmaceutical preparations are usable. Specific examples thereof include gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, corn starch, microcrystalline wax, white petrolatum, magnesium metasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic acid anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, and the like.

Preparations to be formed with those additives include, for example, solid preparations such as tablets, capsules, granules, powders, suppositories; and liquid preparations such as syrups, elixirs, injections. These may be formulated according to conventional methods known in the field of pharmaceutical preparations. The liquid preparations may also be in such a form that may be dissolved or suspended in water or in any other suitable medium for their use.

Especially for injections, if desired, the preparations may be dissolved or suspended in

physiological saline or glucose liquid, and a buffer or a preservative may be optionally added thereto.

The pharmaceutical compositions may contain the compound of the invention in an

amount of from 1 to 99.9 % by weight, preferably from 1 to 60 % by weight of the composition.

The compositions may further contain any other therapeuti cally-effective compounds.

In case where the compounds of the invention are used for prevention or treatment for the above-mentioned diseases, the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the patient and on the type and the range of the intended remedial effect. In general, when orally administered, the dose may be from 0.001 to 50 mg/kg of body weight/day, and it may be administered at one time or at several times. The dose is preferably from about 0.01 to about 25 mg/kg/day, more preferably from

about 0.05 to about 10 mg/kg/day. For oral administration, the compositions are preferably

provided in the form of tablets or capsules containing from 0.01 mg to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250,

500, 750, 850 and 1 ,000 milligrams of a compound described herein. This dosage regimen may be adjusted to provide the optimal therapeutic response.

Combination Therapy

The compounds of the present invention are further useful in methods for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other therapeuti agents.

The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions . for which compounds of formula I or the other drugs may have utility, where the combination of the drugs toge he are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of formula I When a compound of formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of formula I is preferred. However, the combination therapy may also include therapies in which the compound of formula I and one or more other drugs are administered on different overlapping schedule It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of formula I. Examples of other active ingredients that may be administered in combination with a compound of formula I, and either administered separately or in the same pharmaceutical composition, include, but are not limited to:

(I) dipeptidyl peptidase-IV (DPP-4) inhibitors;

(2) insulin sensitizers, including (i) PPARy agonists, such as the glitazones (e.g. pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR ligands, including (1) PPARa/γ dual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPARa agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators (SPPARyM's), such as those disclosed in WO

2002/060388, WO 2002/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963, and (4) PPARy partial agonists; (ii) biguanides, such as metformin and its

pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet®, and GlucophageXR®; (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;

(3) insulin or insulin analogs, such as insulin Hspro, insulin detemir, insulin glargine, insulin glulisine, and inhalable formulations of each thereof;

(4) leptin and leptin derivatives and agonists;

(5) amylin and amylin analogs, such as pramlintide;

(6) sulfonylurea and non-sulfonylurea insulin secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;

(7) a-glucosidase inhibitors (such as acarbose, voglibose and miglitol);

(8) glucagon receptor antagonists, such as those disclosed in WO 1998/04528, WO 1999/01423, WO 2000/39088, and WO 2000/69810;

(9) incretin mimetics, such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists, such as exenatide, liraglutide, taspoglutide, AVEOOIO, CJC-1131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof;

(10) LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl CoA holesterol acyltransferase inhibitors, such as avasimibe;

(I I) HDL-raising drugs, such as niacin or a salt thereof and extended-release versions thereof; MK-524A, which is a combination of niacin extended-release and the DP-1 antagonist M -524; and nicotinic acid receptor agonists;

(12) antiobesity compounds;

(13) agents intended for use in inflammatory conditions, such as aspirin, non-steroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors; (14) antihypertensive agents, such as ACE inhibitors (such as enalapril, iisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aiiskiren), beta;

(15) glucokinase activators (GKAs), such as LY2599506;

(16) inhibitors of 11 β-hydroxysteroid dehydrogenase type 1 , such as those disclosed in U. S.

Patent No. 6,730,690; WO 2003/104207; and WO 2004/058741;

(17) inhibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib and MK-0859;

(18) inhibitors of fructose 1,6-bisphosphatase, such as those disclosed in U.S. Patent Nos.

6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476;

( 19) inhibitors of acetyl CoA carboxylase- 1 or 2 (ACC 1 or ACC2);

(20) AMP-activated Protein Kinase (AMPK) activators;

(21) agonists of the G-protein-coupled receptors: GPR-109, GPR-1.19, and GPR-40;

(22) SSTR3 antagonists, such as those disclosed in WO 2009/011836; ^'

(23) neuromedin U receptor agonists, such as those disclosed in WO 2009/042053, including, bt not limited to, neuromedin S (NMS);

(24) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD);

(25) GPR-105 antagonists, such as those disclosed in WO 2009/000087;

(26) inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1 ; SGLT-2, such as dapagliflozin and remoglifiozin; and SGLT-3;

(27) inhibitors of acyl coenzyme A:diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-

2),

(28) inhibitors of fatty acid synthase;

(29) inhibitors of acetyl-CoA carboxylase-1 and 2 (ACC-1 and ACC-2);

(30) inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2);

(31) agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M- BAR); and

(32) bromocriptine mesylate and rapid-release formulations thereof.

Dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of formula I include, but are not limited to, sitagliptin (disclosed in US Patent No. 6,699,871), vildagliptin, saxagliptin, alogliptin, denagliptin, carmegliptin, dutogliptin, melogliptin, linagliptin, and

pharmaceutically acceptable salts thereof, and fixed-dose combinations of these compounds with metformin hydrochloride, pioglitazone, rosiglitazone, simvastatin, atorvastatin, or a sulfonylurea.

Other dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of formula I include, but are not limited to:

(2i?,35,5i?)-5-(l-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)-2-(2,4,5- trifluorophenyl)tetrahydro-2H-pyran-3-amine; (2i?_!3S_J5i?)-5»(l-methyl-4,6-dihydropyrrolo[3_J4-c]pyrazol-5(lH)-yl)-2-(2,4,5- trifluorophenyl)tetrahydro-2H-pyran-3 -amine ;

(2i S,5j?)-2-(2,5-difluorophenyl)tefr^

tetrahydro-2H^:pyran-3-amine;

(3i?)-4-[(3i?)-3-araino-4-(2,4,5~trifluorophen^

2~one;

4-[(3i?)-3-amino-4-(2_}5-difluorophenyl)butanoyl]hexahydro-l-methyl-2H-l,4-diazepin-2-one hydrochloride; and

(3#)-4-[(3#)-3-amino-4-(2,4,5-trifluoropheny^

diazepin-2-one; and

pharmaceutically acceptable salts thereof.

Antiobesity compounds that can be combined with compounds of formula I include topiramate; zonisamide; naltrexone; phentermine; bupropion; the combination of bupropion and naltrexone; the combination of bupropion and zonisamide; the combination of topiramate and phentermine;

fenfluramine; dexfenfluramine; sibutramine; lipase inhibitors, such as orlistat and cetilistat;

melanocortin receptor agonists, in particular, melanocortm-4 receptor agonists; CCK-1 agonists;

melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Yi or Y5 antagonists (such as MK-0557); CB1 receptor inverse agonists and antagonists (such as rimonabant and taranabant); β3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (such as bombesin receptc subtype-3 agonists); and 5-hydroxytryptamine-2c (5-HT2c) agonists, such as lorcaserin. For a review o anti-obesity compounds that can be combined with compounds of the present invention, see S. Chaki et al._f "Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity," Expert Opin. Ther. Patents, 11 : 1677-1692 (2001); D. Spanswick and . Lee, "Emerging antiobesity drugs," Expert Opin. Emerging Drugs, 8: 217-237 (2003); J.A. Fernandez-Lopez, et ah, "Pharmacological Approaches for the Treatment of Obesity " Drugs, 62: 915-944 (2002); and K.M. Gadde, et al., "Combination pharmaceutical therapies for obesity," Exp. Opin. Pharmacother., 10: 921- 925 (2009).

Glucagon receptor antagonists that can be used in combination with the compounds of formula ] include, but are not limited to:

N-[4-((l^-l-{3~(3_J5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naph l]-lH-pyrazol-l- yl}ethyl)benzoyl]-p-alanine;

N-[4 -(( 1 i?)- 1 - { 3 ~(3 , 5 -dichlorophenyl)- 5 - [6-(trifluoromethoxy)-2-naphthyl] - 1 H-pyrazo 1- 1 - yl} ethyl)benzoyl] -β-alanine;

N-(4-{ l-[3-(2,5-dichlorophenyi)-5-(6-methoxy-2-naphthyl)-lH-pyrazol-l-yl]ethyl}benzoyl)-p- alanine;

7Y-(4- {(15)- 1 -[3-(3,5-dichloi phenyl)-5-(6-methoxy-2-naphthyl)- lH-pyrazol- 1 - yl]ethyl }benzoyl)-p~alanine; N-(4- {(1 S)-l -[(R)-(4-chlorophenyl)(7-fiuoro-5-methyl~ 1 H-indol-3-yl)methyl]butyl}benzoyl)-p- alanine; and

N-(4~ { ( 1 S)- 1 - [(4-chlorophenyl)(6-chloro-8-meiliylquinolin-4-yl)methyl]butyi } benzoyl)- β- alanine; and

pharmaceutically acceptable salts thereof.

Inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) that can be used in combination with the compounds of formula I include, but are not limited to:

[5-(5-{4-[2-(trifluoromethyl)phenoxy]piperidin-l-yl}-l,3,4-thiadiazol-2 -yi)-2H-tetrazoI-2- yl] acetic acid;

(2'-{4-[2-(trifluoi methyl)phenoxy]piperidm-l-yl}-2,5'-bi-l_f3-tliiazol-4-yl)acelic acid;

(5 - { 3- [4-(2-bromo-5-fluorophenoxy)piperidin- 1 -yl] isoxazol-5 -yl } -2H-tetrazol-2-yl)acetic acid;

(3 - { 3 - [4-(2-bromo - 5~fiuorophenoxy)piperidin- 1 -yl] - 1 ,2 ,4-oxadi azol-5-yl } - 1 H-pyrrol- 1 ~yl)acetic acid;

(5- { 5-[4-(2-bromo-5-fluorophenoxy)piperidin- 1 -yl]pyrazin-2-yl } -2H-tetrazol-2-yl)acetic acid; and

(5- {2-[4-(5-bromo-2-chlorophenoxy)piperidin- 1 -yl]pyrimidin-5-yl}-2H-tetrazol-2-yl)acetic acid; and pharmaceutically acceptable salts thereof.

Glucokinase activators that can be used in combination with the compounds of formula I include, but are not limited to:

3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy- 1 -methyl-ethoxy)~N-(l -methyl- 1 H-pyrazol-3- yl)benzamide;

5-(2-hydroxy-l-memyl-ethoxy)-3-(6-methaiiesulfonylpyridin-3-yloxy)-N-(l-methyl-lH-pyrazol- 3-yl)benzamide;

5-( 1 -hydroxymethyl-propoxy)- 3 -(6-methanesulfony lpyridin-3 -yloxy)-N-( 1 -methyl- 1 H-py razo 1-3 - yl)benzamide;

3-(6-methanesulfonylpyridin-3-yIoxy)-5-(l -methoxymethyl-propoxy)-N-( 1 -methyl- 1 H-pyrazol- 3-yl)benzamide;

5-isopropoxy-3-(6-methanesulfonylpyridin-3-yloxy)-N-(l-methyl-lH-pyrazol-3-yl)benzamide; 5 -(2-fluoro- 1 -fiuoromethyl-ethoxy)-3 -(6-methanesulfonylpyridin-3 -yloxy)-N-( 1 -methyl- 1 H- pyrazol-3-yl)benzamide;

3 -( { 4-[2-(dimethylamino)ethoxy]phenyl } thio)-N-(3 -methyl- 1 ,2₅4~thiadiazol-5-yl)-6- [(4-methyl- 4H-l₅2,4-triazol-3-yl)thio]pyridine-2-carboxamide;

3-({4-[(l-m.ethylazetidin-3-yl)oxy]phenyl}thio)-N-(3-methyl-l,2,4~thiadiazol-5-yl)-6-[(4-methyl- 4H-l,2,4-triazol-3-yI)thio]pyridine-2-carboxamide;

N-(3-med yl-l,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-l,2,4-triazol-3-yl)tMo]-3-{[4-(2-pyrroli 1 -ylethoxy)phenyl]thio } pyridine-2-carboxamide ; and 3-[(4-{2-[(2R>2-methylpyrrolidin-l-yl]eta

methyl-4H-l ,2,4-txiazol-3-yl)thio]pyridine-2-carboxamide; and pharmaceutically acceptable salts thereof.

Agonists of the GPR-1 19 receptor that can be used in combination with the compounds of formula I include, but are not limited to:

rac-cis 5-chloro-2- {4-[2-(2-{ [5-(methylsulfonyl)pyridin-2-yl]oxy} ethyl)cyclopropyl] piperidin- 1 - yl}pyrimidine;

5-chloro~2- {4- [( 1 R,2S)-2-(2- { [5 -(methylsulfonyl)pyridin-2-yl] oxy } ethyl)cyclopropyl] piperidin- l~yl}pyrimidine;

rac cis-5 -chloro-2- [4-(2- {2- [4-(methylsulfonyl)phenoxy] ethyl } cyclopropyl)piperidin- 1 - yljpyrimidine;

5 -chloro-2~[4-(( 1 S,2R)-2- { 2- [4-(methylsulfonyl)phenoxy]ethyl } cyclopropyl) piperidin- 1 - yljpyrimidine;

5~chloro-2- [4-(( 1 R,2S)-2- {2- [4-(methylsulfonyi)phenoxy] ethyl } cyclopropyl) piperidin- 1 - yljpyrimidine;

rac m-5-chloro-2-[4-(2- {2-[3~(methylsulfonyI)phenoxyjethyl} cyclopropyl)piperidin-l - yljpyrimidine; and

rac cis -5-chloro-2-[4-(2-{2-[3-(5-methyl-l ,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl) piperidin- -yljpyrimidine; and pharmaceutically acceptable salts thereof.

Selective PPARy modulators (SPPARyM's) that can be used in combination with the compounc of formula I include, but are not limited to:

(25)-2 -( { 6-chloro-3 - [6-(4-chlorophenoxy)-2-propylpyridin- 3-yl ] - 1 ,2-benzisoxazol-5- yl}oxy)propanoic acid;

(2S)-2-( { 6-chloro-3- [6-(4-fluorophenoxy)-2-propylpyridin-3 -yl ] - 1 , 2-benzisoxazol-5 - yl}oxy)propanoic acid;

(2S)-2-{[6-chloro-3-(6-phenoxy-2-propylpyridin-3-yl)-l ,2-benzisoxazol-5-yl]oxy}propanoic acid;

(2i?)-2-( { -chloro-3 - [6-(4-chlorophenoxy)-2-propylpyridin-3 -yl j ~ 1 ,2~benzisoxazol-5- yl}oxy)propanoic acid;

(2R)-2- { 3 - [3 -(4-methoxy)benzoyl-2 -methyl-6-(trifluoromethoxy)- 1 H-indol- 1 - yl]phenoxy}butanoic acid;

(2S)'2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-lH-indol-l- yljphenoxy}butanoic acid;

2- { 3 - [3 -(4-methoxy)benzoyl~2~methyl -6-(trifluoromethoxy)- 1 H-indol- 1 -yl jphenoxy } -2- methylpropanoic acid; and

(2i?)-2-{3-[3-(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)-lH~indoI-l- yl]phenoxy}propanoic acid; and pharmaceutically acceptable salts thereof. Inhibitors of 1 1 β-hydroxysteroid dehydrogenase type 1 that can be used in combination with the compounds of formula I include, but are not limited to:

3 - [ 1 -(4-chlorophenyl)-traw-3 -fluorocyclobutyl]~4,5-dicyclopropyl-r-4H- 1 ,2,4-triazole;3 - [ 1 -(4- chlorophenyl)-/rara-3-fluorocyclobutyl3-4-cyclopropyl-5-(l-methylcyclopropyl)-r-4H-l,2₅4- triazole;

3_ [ 1.(4~chlorophenyl)-tr£if2i'-3 -fluorocyclobutyl] -4-methyl-5- [2-(trifluoromethoxy)phenyl] -r-AH- 1 ,2,4-triazole;

3~[l~(4-chlorophenyl)cyclobutyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-l_J2₅4-triazole;

3 - { 4- [3 -(ethylsulfonyl)propyl]bicyclo [2.2.2] oct- 1 -yl } -4-methyl-5- [2-(trifiuoromethyl)phenyl] -4H

-1,2,4-triazole;

4- methyl-3 - { 4-[4-(methylsulfonyI)phenyl]bicyclo [2.2.2] oct- 1 -yl } -5- [2-(trifluoromethyl)phenyl] - AH- 1,2,4-triazole;

3 4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-l_J2,4-triazol-3-yl}bicyclo[2.2.2]oct-l-yl)-5- (3,3,3-trifluoropropyl)-l,2,4-oxadiazole;

3-(4- {4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yl} bicyclo[2.2.2]oct- 1 -yl)-5- (3 ,3 ,3-trifluoroethyl)- 1 ,2,4-oxadiazole;

5- (3,3-difluorocyclobutyl)-3-(4- {4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-l-yl)-l,2,4-oxadiazole;

5-(l-fluoro-l-meraylethyl)-3-(4-{4-mem^^

yl } bicyclo [2.2.2] oct- 1 -yl)- 1 ,2 ,4-oxadiazole;

2-(l , 1 -difluoroethyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-l ₅2,4-triazol-3- yl } bicyclo [2.2.2] oct- 1 -yl)- 1 ,3 ,4-oxadiazole;

2-(3 ,3 -difluorocyclobutyl)-5 -(4- {4-methyl-5-[2-(trifluoromethyl)phenyl] -4H- 1 ,2,4-triazol-3 - yl}bicyclo[2.2.2]oct-l-yl)-l,3,4-oxadiazole; and

5-(l, 1 -difluoroethyl)-3-(4- {4-methyl-5-[2-(trifluoromethyl)phenyl3-4H-l ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-l-yl)-l_}2,4-oxadiazole; and pharmaceutically acceptable salts thereof.

Somatostatin subtype receptor 3 (SSTR3) antagonists that can be used in combination with the compounds of formula I include, but are not limited to:

-28-

and pharmaceutically acceptable salts thereof.

Inhibitors of acetyl-CoA carboxylase- 1 and 2 (ACC-1 and ACC-2) that can be used in combination with the compounds of formula I include, but are not limited to:

3- { 1 '-[(1 -cyclopropyl-4-methoxy- 1 H-indol-6-yl)carbonyl]-4-oxospiro[chroman- 2,4'-piperidin]- 6-yl} benzoic acid;

5-{ -[(l-cyclopropyl-4-methoxy-lH-indol-6-yl)carbonyl]-4-oxospiro[chroman-2₎4'-piperidin]-6- yl} nicotinic acid;

r-[(l-cyclopropyl-4~methoxy-IH-indol-6-yl)carbonyl]-6-(lH-tetrazol-5-yl)spiro[chroman-2₅4'- piperidin]-4-one;

- [( 1 -cyclopropyl-4-ethoxy-3 -methyl- 1 H-indol-6-y l)carbonyl] -6~( 1 H-tetrazol- 5 - yl)spiro[chroman-2,4'-piperidin]-4-one; and 5-{ 1 '-[(1 -cyclopropyl-4-methoxy-3-methyl-lH-indol-6-yl)carbonyl]-4-oxo-spiro[cliromaii-2,4'- piperidm]-6-yl}mcotinic acid; and

pharmaceutically acceptable salts thereof.

In another aspect of the invention, a pharmaceutical composition is disclosed which comprises one or more of the following agents:

(a) a compound of structural formula I;

(b) one or more compounds selected from the group consisting of:

(1) dipeptidyl peptidase-IV (DPP-4) inhibitors;

(2) insulin sensitizers, including (i) PPARy agonists, such as the glitazones (e.g.

pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR Hgands, including (1) PPARa/γ dual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPARa agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrati and bezafibrate), (3) selective PPARy modulators (SPPARyM's), and (4) PPARy partial agonists; (ii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet®, and

GlucophageXR®; (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;

(3) sulfonylurea and non-sulfonylurea insulin secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;

(4) a-glucosidase inhibitors (such as acarbose, voglibose and miglitol);

(5) glucagon receptor antagonists;

(6) LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors

(lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl Co A: cholesterol acyltransferase inhibitors, such as avasimibe;

(7) HDL-raising drugs, such as niacin or a salt thereof and extended-release versions thereof; MK-524A, which is a combination of niacin extended-release and the DP-1 antagonist MK-52^ and nicotinic acid receptor agonists;

(8) antiobesity compounds;

(9) agents intended for use in inflammatory conditions, such as aspirin, non-steroidal ant inflammatory drugs ( SAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;

(10) antihypertensive agents, such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), Α-Π receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta;

(1 1) glucokinase activators (G As), such as LY2599506; (12) inhibitors of 11 β-hydroxysteroid dehydrogenase type 1;

(13) inhibitors of cholesteryl ester transfer protein (CBTP), such as torcetrapib and MK-

0859;

(14) inhibitors of fructose 1,6-bisphosphatase;

(15) inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2);

(16) AMP -activated Protein Kinase (AMPK) activators;

(17) agonists of the G-protein-coupled receptors: GPR-109, GPR-119, and GPR-40;

(18) SSTR3 antagonists;

(19) neuromedin U receptor agonists, including, but not limited to, neuromedin S (NMS^

(20) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD);

(21) GPR-105 antagonists;

(22) inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1; SGLT-2, such as dapagiiflozin and remogliflozin; and SGLT 3;

(23) inhibitors of acyl coenzyme A:diacylglycerol acyltransferase 1 and 2 (DGAT-1 and

DGAT-2);

(24) inhibitors of fatty acid synthase;

(25) inhibitors of acetyl-CoA carboxylase-1 and 2 (ACC-1 and ACC-2);

(26) inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2);

(27) agonists of the TGR5 receptor (also known as GPBAR1 , BG37, GPCR19, GPR131 and M-BAR); and

(28) bromocriptine mesylate and rapid-release formulations thereof; and (c) a pharmaceutically acceptable carrier.

When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the present invention to the second active ingredient may 1 varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1 : 1000, preferably about 200: 1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s). Genera! Schemes and Examples

The following is a list of abbreviations used in the description of the Schemes and synthesis of the Intermediates and Examples shown below.

List of Abbreviations:

DMF = dimethylformamide

EtOAc = ethyl acetate

HATU 2-( 1 H- 7- Azabenzotriazol- 1 -yl)— 1,1,3,3 -tetramethyl

uronium hexafluorophosphate Methanaminium

LiOH = lithium hydroxide

Na₂S0₄ = sodium sulfate

rt or RT room temperature

THF tetrahydrofuran

Scheme 1

INTERMEDIATE 1

5-chlorQ-2-[^"6-fpiperazm-l-vl pyridine-3-vI1-lH-benzonrc/]irnidazole

A mixture of 5-chloro-2-(6-fluoropyridin-3-yl)piperidin-4-ylmetlTanol (2.96 g, 11.94 mmol), piperazine (5.13 g, 59.70 mmol) and triethylamine (2.41 g, 3.26 mL, 23.88 mmol) in DM.F (5.0 mL) was heated at 125 °C overnight then cooled to RT. Water (100 mL) was added to precipitate the product. The precipitate was filtered, washed with water (20 mL) then isopropanol (10 mL), and dried under vacuum to yield Intermediate 1 as a pale yellow solid. LC/MS = 314.2 [M+1].

1 -i4-i5-(5-chloro- lH-benzor</limidazoi-2-yl)pyridin-2-yllpiperazin- 1 -yl]-2-(2-fluorophenyl)-2- hydroxyethanone

To a stirred solution of the Intermediate 1 (94 mg, 0.30 mmol), 2-(2-fluorophenyl)-2- hydroxyacetic acid (61 mg, 0.36 mmol), HATU (148 mg, 0.39 mmol) in DMF (2.0 mL) was added N,N- diisopropylethylamine (1 15 mg, 0.16 mL, 0.90 mmol). The reaction mixture was stirred at RT for 4 h then purified by a Gilson HPLC to yield the title compound as a pale yellow solid. LC/MS = 466.3 [M+1].

The following compounds were prepared by using methods described in Examplel ,

methyl 4-2-4-f5-(5-chloro-lH-benzorrflimidazol-2-yl)pyridin-^ oxpehyljbenzoate To a stirred solution of the product obtained in Example 16 (40 mg, 0.08 mmol) in EtOH (2 mL) was added sodium borohydride (5 mg, 0.12 mmol) at RT. The reaction mixture was stirred at RT for 2 h then purified by Gilson HPLC to yield the title compound as a pale yellow solid. LC/MS = 506.3 [M+l].

The following compounds were prepared by using methods described in Example 32.

526.3 [M+l],

449.2 [M+l].

4- Γ5 -(5-chloro- 1 H-benzoFt/] iro ι dazol-2-y Dpyri din-2-y 1] -N-o-tolylpiperazme- 1 -carboxamide

To a stirred solution of the Intermediate 1 (94 mg, 0.30 mmol) and l-isocyanato-2- methylbenzene (48 mg, 0.36 mmol) in THF (5 mL) was added triethylamine (91 mg, 0.12 mL, 0.90 mmol). The reaction mixture was stirred at RT for 2 h then concentrated and purified by Giison HPLC to yield the title compound as a white solid. LG/MS = 447.2 [M+l].

Assay

The in vitro assay to identify DGAT1 inhibitors uses human DGAT1 enzyme expressed in Sf insect cells prepared as microsomes. The reaction is initiated by the addition of the combined substrates 1₅2-dioleoyl-sn-glycerol and [¹⁴C]-palmitoyl-Co A and incubated with test compounds and microsomal membranes for 2 hours at room temperature. The assay is stopped by adding 0.5 mg wheat germ agglutinin beads in assay buffer with 1% Brij-35 and 1% 3- cholamidopropyldimethyl-ammonio-l -propane sulfonate. Plates are sealed with TopSeal and incubated for 18 hours to allow the radioactive triglyceride product to come into proximity with the bead. Plates are read on a TopCount instrument. Percent inhibition was calculated as the percent of (test compound inhibition minus nonspecific binding) relative to (total binding minus non-specific binding). IC50 values were determined by curve fitting the data to a Sigmoidal dose-response in GraphPad Prism utilizing the following equation:

Y - A + (B-A)/(l+10^(LogIC₅o-X))),

where A and B are the bottom and top of the curve (highest and lowest inhibition), respectively, and X is the logarithm of concentration.

Potency of DGAT-1 Inhibitors

Claims

WHAT IS CLAIMED IS:

A compound of formula (I):

or pharmaceutically acceptable salts thereof, Y is selected from the group consisting of: -(CH₂)n- 0-(CH₂)n-; -(CH₂)n-C(0)NH-(CH₂)n-; -(CH₂)n-C(0)CR²H-(CH₂)n-; -(CH₂)n-CR²H-(CH₂)n-; - (CH₂)n-C(0)C(R²)₂-(CH₂)n-; -(CH₂)n-C(R²)₂-(CH₂)n-; -(CH₂)n-NHC(0)-(CH₂)n-; -(CH₂)n- OC(0)-(CH₂)n-; -(CH₂)n-C(0)0-(CH₂)n-; -(CH₂)n-NHS0₂-(CH₂)n-; -(CH₂)n-S0₂NH-(CH₂)n-; - (CH₂)n-C(0)n-(CH₂)n-; -(CH₂)n-NHC(0)CR²H-(CH₂)n-;

Z is selected from the group consisting of Ci-C₆alkyl₉ aryl, cycloalkyl and heterocycle, wherein the Ci-C₆alkyl, aryl, cycloalkyl and heterocycle can be unsubstituted or substituted with 1-3 substituents selected from a;

R¹ is selected from a;

R² is selected from the group consisting of halogen, halogen-substituted d- C₆alkyl₅ -OH and d-Qalkyl;

a is selected from the group consisting of halogen, Ci-C₆alkyl, halogen- substitutedCi-C₆alkyl, COd-Cgalkyl, COhalogen-substitutedd-Cealkyl, oxo, -OH, d- C₆alkyiOH, Ci-C₆alk lOHCOOH, halogen-substitutedC C₆alkylOH₅ -OC_rC₆alkyl, -Ohalogen- substitutedC,-C₆alkyl, -COOH, -COCOOH, -COOC C₆alkyl, -C C₆alkylCOOC₁-C₆alkyl, -C C₆alkylCOOH, -OC C₆alkylCOOH, -CN, C_rC₆alkylCN, -N0₂, NH₂, NHCi-C₆alkyl, N(d- C₆alkyl)₂, -NHCOOH, -NHCOOCi-C₆alkyl_f -CONH₂, -CONHC_rC₆alkyl, -NHCOd-dalkyl, - CON(Ci-C₆alkyl)₂, -NHS0₂C_rC₆alkyl₅ S0₂NH₂, -S0₂C₁-C₆alkyl; and

each occuiTence of n is independently selected from the list consisting of 0, 1 or 2. 2. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein Y is selected from the group consisting of -CH₂0-, -CONH-, -COCHOH-, -COCH₃OH- , -CHOHCHr, - CH₂CHOH-, -NHCO-, -OCO-, -S0₂NH-, -NHS0₂-_? -0-, -COCO-, -CO-, - COCOHCH₂-, -CH₂OH- and - HCOCHOH-. 3. A compound of any one of claims 1-2 or pharmaceutically acceptable salt thereof wherein R¹ is selected from the group consisting of halogen, Ci-C₆alkyl, halogen- substitutedC ₁ -C₆alkyl .

4. A compound of any one of claims 1 -2 or pharmaceutically acceptable salt thereof wherein R¹ is selected from the group consisting of chlorine, fluorine and trifluromethyl.

5. A compound of any one of claims 1-4 or pharmaceutically acceptable salt thereof wherein Z is phenyl.

6. A compound of any one of claims 1-4 or pharmaceutically acceptable salt thereof wherein Z is a cycloalkyl, wherein the cycloalkyl is cyclohexane, cyclopentane or cyclobutane.

7. A compound of any one of claims 1-4 or pharmaceutically acceptable salt thereof wherein Z is Ci-Cgalkyl.

8. A compound of any one of claims 1 -4 or pharmaceutically acceptable salt thereof wherein Z is a heterocycle, wherein the heterocycle is benzodioxolane or pyridine.

9. A compound of any one of claims 1-8 or pharmaceutically acceptable salt thereof wherein Z is unsubstituted. 0. A compound of any one of claims 1-8 or pharmaceutically acceptable salt thereof wherein Z is substituted with 1-3 substituents independently selected from the group consisting of halogen, CrCgalkyl, halogen- substitutedCi-Cealkyl, -OH, -COOH, -COOCi- C₆alkyl, -CrC₆alkylCOOCi-C₆alkyl, -Q-CealkylCOOR C C₆a3kylOHCOOH, -CN and - CONH₂.

1 1. A compound of any one of claims 1-8 or pharmaceutically acceptable salt thereof wherein Z is substituted with 1-3 substituents independently selected from the group consisting of fluorine and trifluoromethyl.

12. A compound or pharmaceutically acceptable salt thereof selected from the group consisting of:

-45 -

-46-

-47-

-48-

.49.

-50-

13. A pharmaceutical composition comprising a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. Use of a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating a condition selected from the group consisting of obesity and diabetes.

15. A method for the treatment of a condition selected from the group consisting of obesity and diabetes comprising administering to an individual a pharmaceutical composition comprising the compound of any one of claims 1-12.