WO2013130370A2 - Compounds as dgat-1 inhibitors - 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

COMPOUNDS AS DGAT-1 INHIBITORS

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 anti-obesity 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 aging. 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, DGAT-1 and DGAT-2. There is no significant homology at the generic or amino acid level between the DGAT-1 and DGAT-2, which are encoded by different genes (Proc. Natl. Acad. Sci. USA., 95, 13018-13023, 1998 and JBC, 276, 38870-38876, 2001). DGAT-1 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 DGAT- 1 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 DGAT-1 and inhibitory activity against DGAT-1, DGAT-1 -knockout mice deficient in DGAT-1 at the genetic level was produced and analyzed. As a result, the DGAT- 1 -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 DGAT-1 -knockout mice; and transplantation of the adipose tissues of DGAT-1 -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 11, 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 DGAT-1 in adipose tissue (Diabetes, 51, 3189-3195, 2002 and Diabetes, 54, 3379-3386, 2005).

From the results, DGAT- 1 inhibitors are likely to be therapeutic drugs with efficacy for obesity, type 2 diabetes mellitus, lipidosis, hypertension, fatty liver, arteriosclerosis,

cerebrovascular disorder, coronary artery disease and metabolic syndrome.

SUMMARY OF THE INVENTION

The compounds described herein are DGAT-1 inhibitors, which are useful in the treatment of obesity, type 2 diabetes mellitus, lipidosis, hypertension, fatty liver, arteriosclerosis, cerebrovascular disorder, coronary artery disease and metabolic syndrome, particularly, obesity and diabetes.

Described herein are compounds of formula (I):

I

wherein, U, V, W, X, Y, R¹, R², R³ and R⁴ are further described below.

DETAILED DESCRIPTION OF THE INVENTION

Described herein are compounds of formula (I):

or pharmaceutical salt thereof, wherein V, U, W, X and Y are independently selected from the group consisting of -N- and -CH-; R¹, R², R³ and R⁴ are each present at one of more at the ring carbons and are independently selected from the group consisting of hydrogen, halogen, -CN, halogen- substitutedCi-C₆alkyl, Ci-C₆alkyl, S0₂Ci-C₆alkyl and Ci-C₆alkoxy, or taken together R⁴ and Z form a pyrole, C3-C₆cycloalkyl, unsubstituted or substituted with -COOH, Ci-C₆alkyl;

Z is selected from the group consisting of:

hydrogen,

-OH,

-COOH,

COCi-C₆alkyl,

-Ci-C₆alkylCOOH,

-Ci-C₆alkyl,

halogen-substitutedCi-C₆alkyl,

-Ci-C₆alkoxy,

halogen-substitutedCi-C₆alkoxy,

-OCi-C₆alkylCOOH,

-OCi-C₆alkylphenyl,

-OphenylCi-C₆alkylCOOH,

-OCi-C₆alkylphenylCi-C₆alkylCOOH,

-OCi-C₆alkylphenylCOOH,

-OphenylCOOH,

-OnaphylCOOH,

phenyl,

piperidine,

piperidineCOOCi-C₆alkyl,

-OCi-C₆alkyl pyridineCOOH,

-ObenzimidizoleCOOH,

-OCi-C₆alkylthieneCOOH,

pyridine,

pyrollodiol,

S0₂NHCi-C₆alkylCOOH,

S0₂Ci-C₆alkyl,

S0₂Ci-C₆alkylphenylCOOH,

S0₂Ci-C₆alkylCOOH,

S0₂Ci-C₆alkylCOOCi-C₆alkyl,

-CN,

-OCi-C₆alkylCN,

-NH₂, -CONH₂,

-CONHCi-C₆alkyl,

-OCi-C₆alkylN(Ci-C₆alkyl)₂,

CON(Ci-C6alkyl)₂,

CONHCi-C₆alkylOH,

NHCOCi-C₆alkylCOOH,

NHCi-C₆alkylCOOH,

NHCi-C₆alkylphenylCOOH,

NHCi -C₆alkylphenylCi -C₆alkylCOOH,

NHCi-C₆alkylphenylCOOH,

NHS0₂Ci-C₆alkyl,

-SCi-C₆alkylCOOCi-C₆alkyl, and

-SCi-C₆alkylCOOH.

Described herein are compounds wherein X is selected from the group consisting of -N- and -CH-. In certain embodiments, X is -N-. In other embodiments, X is -CH-. In yet other embodimets, when X is -N-, Y and V are not both -N- and W and U are not both -N-.

Described herein are compounds wherein Y is selected from the group consisting of -N- and -CH-. In certain embodiments, Y is -N-. In other embodiments, Y is -CH-. Described herein are compounds wherein V is selected from the group consisting of -N- and -CH-. In other embodiments, V is -CH-. In certain embodiments, V is -N-. In certain embodiments, Y and V are both -CH-. In other embodiments, Y is -CH- and V is -N-. In yet other embodiments, Y is -N- and V is -CH-. In still other embodiments, Y and V are not simultaneously -N-.

Described herein are compounds wherein W is selected from the group consisting of -N- and -CH-. In certain embodiments, W is -N-. In other embodiments, W is -CH-. Described herein are compounds wherein U is selected from the group consisting of -N- and -CH-. In other embodiments, U is -CH-. In certain embodiments, U is -N-. In certain embodiments, W and U are both -CH-. In certain embodiments, W and U are both -N-. In other embodiments, W is -CH- and U is -N-. In yet other embodiments, W is -N- and U is -CH-.

Described herein are compounds wherein, R¹, R², R³ and R⁴ are present at one or more of the ring carbons and are independently selected from the group consisting of hydrogen, halogen, -CN, halogen-substitutedCi-C₆alkyl, Ci-C₆alkyl,

and Ci-C₆alkoxy, or taken together R⁴ and Z form a pyrole, C3-C₆cycloalkyl, unsubstituted or substituted with -COOH, Ci- Cgalkyl.

In certain embodiments, R¹ is present at a ring carbon and is independently selected from the group consisting of hydrogen, halogen, -CN, halogen-substitutedCi-C₆alkyl, Ci-C₆alkyl, S0₂Ci-C₆alkyl and Ci-C₆alkoxy. In certain embodiments, R¹ is hydrogen. In other

embodiments, R¹ is halogen. Suitable halogens include, but are not limited to, cholorine and fluorine. In yet other embodiments, R¹ is -CN. In still other embodiments, R¹ is halogen- substitutedCi-C6alkyl. Suitable halogen-substituted alkyls include, but are not limited to, trifluoromethyl. In certain embodiments, R¹ is Ci-C₆alkyl. Suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1 -methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1- ethylpropyl, n-hexyl, isohexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1- dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 -ethylbutyl, 1, 1,2-trimethylpropyl, 1,2,2- trimethylpropyl, 1 -ethyl-2-methylpropyl, 1 -ethyl- 1 -methylpropyl. In other embodiments, R¹ is S0₂Ci-C₆alkyl. Suitable S0₂Ci-C₆alkyls include, but are not limited to, SO₂CH₃. In still other embodiments, R¹ is Ci-C₆alkoxy. Suitable alkoxies include, but are not limited to, methoxy and ethoxy.

In certain embodiments, R² is present at a ring carbon and is independently selected from the group consisting of hydrogen, halogen, -CN, halogen-substitutedCi-C₆alkyl, Ci-C₆alkyl, S0₂Ci-C₆alkyl and Ci-C₆alkoxy. In certain, embodiments R² is hydrogen. In other embodiments, R² is halogen. Suitable halogens include, but are not limited to, cholorine and fluorine. In yet other embodiments, R² is -CN. In still other embodiments, R² is halogen- substitutedCi-C₆alkyl. Suitable halogen-substituted alkyls include, but are not limited to, trifluoromethyl. In certain embodiments, R² is Ci-C₆alkyl. Suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1 -methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1- ethylpropyl, n-hexyl, isohexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1- dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 -ethylbutyl, 1, 1,2-trimethylpropyl, 1,2,2- trimethylpropyl, 1 -ethyl-2-methylpropyl, 1 -ethyl- 1 -methylpropyl. In other embodiments, R² is S0₂Ci-C₆alkyl. Suitable

include, but are not limited to, SO₂CH₃. In still other embodiments, R² is Ci-C₆alkoxy. Suitable alkoxies include, but are not limited to, methoxy and ethoxy.

In certain embodiments, R³ is present at a ring carbon and is independently selected from the group consisting of hydrogen, halogen, -CN, halogen-substitutedCi-C₆alkyl, Ci-C₆alkyl, S0₂Ci-C₆alkyl and Ci-C₆alkoxy. In certain, embodiments R³ is hydrogen. In other embodiments, R³ is halogen. Suitable halogens include, but are not limited to, cholorine and fluorine. In yet other embodiments, R³ is -CN. In still other embodiments, R³ is halogen- substitutedCi-C₆alkyl. Suitable halogen-substituted alkyls include, but are not limited to, trifluoromethyl. In certain embodiments, R³ is Ci-C₆alkyl. Suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1 -methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1- ethylpropyl, n-hexyl, isohexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1- dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 -ethylbutyl, 1, 1,2-trimethylpropyl, 1,2,2- trimethylpropyl, 1 -ethyl-2-methylpropyl, 1 -ethyl- 1 -methylpropyl. In other embodiments, R³ is S02Ci-C6alkyl. Suitable SC Ci-Cealkyls include, but are not limited to, SO2CH3. In still other embodiments, R³ is Ci-C₆alkoxy. Suitable alkoxies include, but are not limited to, methoxy and ethoxy.

In certain embodiments, R⁴ is present at a ring carbon and is independently selected from the group consisting of hydrogen, halogen, -CN, halogen-substitutedCi-C₆alkyl, Ci-C₆alkyl,

and Ci-C₆alkoxy or taken together R⁴ and Z form a pyrole, C₃- C₆cycloalkyl, unsubstituted or substituted with -COOH, Ci-C₆alkyl. In certain, embodiments R⁴ is hydrogen. In other embodiments, R⁴ is halogen. Suitable halogens include, but are not limited to, cholorine and fluorine. In yet other embodiments, R⁴ is -CN. In still other embodiments, R⁴ is halogen-substitutedCi-C₆alkyl. Suitable halogen-substituted alkyls include, but are not limited to, trifluoromethyl. In certain embodiments, R⁴ is Ci-C₆alkyl. Suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, tert-pentyl, 1 -methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1- ethylpropyl, n-hexyl, isohexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1- dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 -ethylbutyl, 1, 1,2-trimethylpropyl, 1,2,2- trimethylpropyl, 1 -ethyl-2-methylpropyl, 1 -ethyl- 1 -methylpropyl. In other embodiments, R⁴ is SC Ci-Cealkyl. Suitable S02Ci-C6alkyls include, but are not limited to, SO2CH3. In still other embodiments, R⁴ is Ci-C₆alkoxy. Suitable alkoxies include, but are not limited to, methoxy and ethoxy. In othe embodiments, taken together R⁴ and Z form a pyrole, C₃-C₆cycloalkyl, unsubstituted or substituted with -COOH, Ci-C₆alkyl;

Described herein are compounds of formula I, wherein Z is selected from the group consisting of: hydrogen, -OH, -COOH, COCi-C₆alkyl, -Ci-C₆alkylCOOH,-Ci-C₆alkyl, halogen- substitutedCi-C₆alkyl, -Ci-C₆alkoxy, halogen-substitutedCi-C₆alkoxy, -OCi-C₆alkylCOOH, - OCi-C₆alkylphenyl,-OphenylCi-C₆alkylCOOH, -OCi-C₆alkylphenylCi-C₆alkylCOOH, -OCi- C₆alkylphenylCOOH,-OphenylCOOH, -OnaphylCOOH, phenyl, piperidine, piperidineCOOCi- C₆alkyl, -OCi-C₆alkyl pyridineCOOH,-ObenzimidizoleCOOH, -OCi-C₆alkylthieneCOOH, pyridine, pyrollodiol, S0₂NHCi-C₆alkylCOOH, S0₂Ci-C₆alkyl, S0₂Ci-C₆alkylphenylCOOH, S0₂Ci-C₆alkylCOOH, S0₂Ci-C₆alkylCOOCi-C₆alkyl, -CN, -OCi-C₆alkylCN, -NH₂, -CONH₂, - CONHCi-C₆alkyl, -OCi-C₆alkylN(Ci-C₆alkyl)₂, CON(Ci-C₆alkyl)₂, CONHCi-C₆alkylOH, NHCOCi-C₆alkylCOOH, NHCi-C₆alkylCOOH, NHCi-C₆alkylphenylCOOH, NHCi- C₆alkylphenylCi-C₆alkylCOOH, NHCi-C₆alkylphenylCOOH, NHS0₂Ci-C₆alkyl, -SCi- C₆alkylCOOCi-C₆alkyl, and -SCi-C₆alkylCOOH.

In certain emodiments, Z is hydrogen. In other embodiments, Z is -OH. In yet other embodiments, Z is -COOH. In still other embodiments, Z is COCi-C₆alkyl. In certain embodiments, Z is -Ci-C₆alkylCOOH. In some embodiments, Z is -Ci-C₆alkyl. In other embodiments, Z is halogen-substitutedCi-C₆alkyl. In yet other embodiments, Z is -Ci-C₆alkoxy. In still other embodiments, Z is halogen-substitutedCi-C₆alkoxy. In other embodiment of the compounds described herein, Z is -OCi-C6alkylCOOH. In other embodiments, Z is -(XV C₆alkylphenyl. In still other embodiments, Z is -OphenylCi-C₆alkylCOOH. In yet other embodiments, Z is -OCi-C₆alkylphenylCi-C₆alkylCOOH. In certain embodiments, Z is -(XV C₆alkylphenylCOOH. In other embodiments, Z is -OphenylCOOH. In still other embodiments, Z is -OnaphylCOOH. In certain embodiments, Z is phenyl. In other embodiments, Z is piperidine. In still other embodiments, Z is piperidineCOOCi-C₆alkyl. In yet other

embodiments, Z is -OCi-C₆alkylpyridineCOOH. In certain embodiments, Z is - ObenzimidizoleCOOH. In some embodiments, Z is -OCi-C₆alkylthieneCOOH. In other embodiments, Z is pyridine. In yet other embodiments, Z is pyrollodiol. In yet other embodiments, Z is S0₂ HCi-C₆alkylCOOH. In still other embodiments, Z is

In certain embodiments, Z is S0₂Ci-C₆alkylphenylCOOH. In some embodiments, Z is SO₂C₁- C₆alkylCOOH. In other embodiments, Z is S0₂C₁-C₆alkylCOOC₁-C₆alkyl. In yet other embodiments, Z is -CN. In still other embodiments, Z is -OCi-C₆alkylCN. In certain embodiments, Z is -NH₂. In some embodiments, Z is -CONH₂. In other embodiments, Z is - CONHCi-C₆alkyl. In still other embodiments, Z is -OCi-C₆alkylN(Ci-C₆alkyl)₂. In yet other embodiments, Z is CO (Ci-C₆alkyl)₂. In certain embodiments, Z is CONHCi-C₆alkylOH. In come embodiments, Z is NHCOCi-C6alkylCOOH. In other embodiments, Z is NHCi- C₆alkylCOOH. In still other embodiments, Z is NHCi-C₆alkylphenylCOOH. In yet other embodiments, Z is -NHCi-C₆alkylphenylCi-C₆alkylCOOH. In certain embodiments, Z is NHCV C₆alkylphenylCOOH. In other embodiments, Z is NHS0₂C₁-C₆alkyl. In still other

embodiments, Z is -SCi-C₆alkylCOOCi-C₆alkyl. In yet other embodiments, Z is -SCV

C₆alkylCOOH. DGAT1 CPM Assay

Examples were assayed as follows: 20uL substrate mixture of 300uM diolein, 40uM oleoyl- CoA, 10% ethanol and luL of the compound with different concentrations were delivered to a 384 well assay plate (Corning 3573) using a Tecan with TeMO module. Later 19uL of enzyme mixture of 1.05ug/ml human DGAT1 in buffer (200mM Tris, pH7, 200mM sucrose, 200mM MgC12 + 20ug/ml NEM-treated BSA) was added via a Multidrop Combi using a microcassette. 20uL of 90uM CPM reagent in 90% ethanol was added after 1 hour incubation at room temperature. After 30 minutes at room temperature in dark, fluorescence measurement on Envision was carried out and IC50 values were calculated.

Examples of compounds described herein include:

Examples

Example Structure IC50

Definitions

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

The term "Ci-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-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1,2-dimethylbutyl, 2,2- dimethylbutyl, 1-ethylbutyl, 1, 1,2-trimethylpropyl, 1,2,2-trimethylpropyl, l-ethyl-2- methylpropyl, 1 -ethyl- 1-methylpropyl, and the like.

The term "C3-C₆cycloalkyl" encompasses cycloalkyls having 3 to 6 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. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "-Ci-C ₆alkoxy " 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 "halogen-substitutedCi-C6 alkyl" encompasses C1-C6 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 "-halogen-substitutedCi-C₆alkoxy" means a -Ci-C₆alkoxy 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 "Ci-C₆alkylOH" means a Ci-C₆alkyl substituted with an alcohol (-OH).

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

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, methylsulfate, 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-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

A "subject" is a human or non-human mammal. In one embodiment, a subject is a human. In another embodiment, a subject is a non-human mammal, including, but not limited to, a monkey, dog, baboon, rhesus, mouse, rat, horse, cat or rabbit. In another embodiment, a subject is a companion animal, including but not limited to a dog, cat, rabbit, horse or ferret. In one embodiment, a subject is a dog. In another embodiment, a subject is a cat.

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 (IF!) and deuterium (2H). 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 DGAT 1 -related diseases. The compounds described herein are effective in preventing or treating various DGAT 1 -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.

Accumulation of triglycerides leads to the obesity and associated with insulin-resistance, so inhibition of triglycerides synthesis represents a potential therapeutic strategy for human obesity and type 2 diabetes. 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 subject 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 any of the formulas described herein.

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, 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 subjects 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.

The following diseases, disorders and conditions are related to Type 2 diabetes, and therefore may be treated, controlled or in some cases prevented, by treatment with the compounds described herein: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)

hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative disease, (20) retinopathy, (21) nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarian hyperandrogenism (polycystic ovarian syndrome), and other disorders where insulin resistance is a component. In Syndrome X, also known as Metabolic Syndrome, obesity is thought to promote insulin resistance, diabetes, dyslipidemia, hypertension, and increased cardiovascular risk. Therefore, DGAT-1 inhibitors may also be useful to treat hypertension associated with this condition.

Another aspect of the invention that is of interest relates to a method of treating hyperglycemia, hypertriglyceridemia, diabetes or insulin resistance in a mammalian subject in need of such treatment which comprises administering to said subject 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 subject in need of such treatment comprising administering to the subject 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 subject in need of such treatment comprising administering to the subject 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 any of the formulas described herein in the manufacture of a medicament for use in treating various DGAT 1 -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 any of the formulas described herein 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 any of the formulas described herein in the manufacture of a medicament for use in treating obesity.

DGAT-1 inhibitors may also serve as antiviral therapeutics that selectively suppresses HCV's (Hepatitis C virus) interation with lipid droplets without compromising the overall formation of lipid droplets in liver cells Nature Medicine, vol. 16, no. 1 1 pages 1295-1298, November 2010. Thus the compounds described herein can be useful as a treatment for HCV.

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, usually, 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 in 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 therapeutically-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 subject 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 a time or in 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 therapeutic 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 together 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 schedules. 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 separately or in the same pharmaceutical composition in combination with a compound of the formulas described herein include, but are not limited to:

(1) dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin, alogliptin, MK-3102, linagliptin, vildagliptin);

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

pioglitazone, AMG 131, MBX2044, mitoglitazone, lobeglitazone, IDR-105, rosiglitazone, and balaglitazone), and other PPAR ligands, including (1) PPARa/γ dual agonists (e.g., ZYH2, ZYH1, GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar, and naveglitazar); (2) PPARa agonists such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate), (3) selective PPARy modulators (SPPARyM's), (e.g., such as those disclosed in WO 02/060388, WO 02/08188, 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™; and (iii) protein tyrosine phosphatase- IB (PTP-IB) inhibitors (e.g., ISIS-1 13715 and TTP814); (3) insulin or insulin analogs (e.g., insulin detemir, insulin glulisine, insulin degludec, insulin glargine, insulin lispro and inhalable formulations of each);

(4) leptin and leptin derivatives and agonists;

(5) amylin and amylin analogs (e.g., pramlintide);

(6) sulfonylurea and non-sulfonylurea insulin secretagogues (e.g., tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, meglitinides, nateglinide and repaglinide);

(7) a-glucosidase inhibitors (e.g., acarbose, voglibose and miglitol);

(8) glucagon receptor antagonists (e.g., such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088, and WO 00/69810);

(9) incretin mimetics, such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists (e.g., dulaglutide, semaglutide, albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide, CJC-1 131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof);

(10) LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (e.g., simvastatin, lovastatin, pravastatin, crivastatin, fluvastatin, atorvastatin, pitavastatin and rosuvastatin), (ii) bile acid sequestering agents (e.g., colestilan, colestimide, colesevalam hydrochloride, colestipol, cholestyramine, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) inhibitors of cholesterol absorption, (e.g., ezetimibe), and (iv) acyl

CoA:cholesterol acyltransferase inhibitors, (e.g., avasimibe);

(1 1) HDL-raising drugs, (e.g., niacin and nicotinic acid receptor agonists, and extended- release versions thereof; MK-524A, which is a combination of niacin extended-release and the DP- 1 antagonist MK-524);

(12) antiobesity compounds;

(13) agents intended for use in inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, and selective cyclooxygenase-2 or COX-2 inhibitors;

(14) antihypertensive agents, such as ACE inhibitors (e.g.,lisinopril, enalapril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (e.g., losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (e.g., aliskiren), beta blockers, and calcium channel blockers;

(15) glucokinase activators (GKAs) (e.g., AZD6370);

(16) inhibitors of 1 1 β-hydroxysteroid dehydrogenase type 1, (e.g., such as those disclosed in U.S. Patent No. 6,730,690, and LY-2523199);

(17) CETP inhibitors (e.g., anacetrapib, and torcetrapib);

(18) inhibitors of fructose 1,6-bisphosphatase, (e.g., such as those disclosed in U.S. Patent Nos. 6,054,587; 6,1 10,903; 6,284,748; 6,399,782; and 6,489,476);

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

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

(21) other agonists of the G-protein-coupled receptors: (i) GPR-109, (ii) GPR-119 (e.g., MBX2982 and PSN821), and (iii) GPR-40 (e.g., TAK875, 5-[4-[[(lR)-4-[6-(3-hydroxy-3- methylbutoxy)-2-methylpyridine-3 -yl] -2,3 -dihydro- 1 H-indene- 1 -yl] oxy]phenyl] isothiazole-3 -ol 1-oxide, 5-(4-((3-(2,6-dimethyl-4-(3-

(methylsulfonyl)propoxy)phenyl)phenyl)methoxy)phenyl)iso, 5-(4-((3-(2-methyl-6-(3- hydroxypropoxy)pyridine-3-yl)-2-methylphenyl)methoxy)phenyl)isothiazole-3-ol 1-oxide, and 5-[4-[[3-[4-(3-aminopropoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]isothiazole-3-ol 1- oxide);

(22) SSTR3 antagonists (e.g., such as those disclosed in WO 2009/001836);

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

(24) SCD inhibitors;

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

(26) SGLT inhibitors (e.g., ASP1941, SGLT-3, empagliflozin, dapagliflozin, canagliflozin, BI-10773, PF-04971729, remogloflozin, TS-071, tofogliflozin, ipragliflozin, and LX-4211); (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 acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2);

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

(31) ileal bile acid transporter inhibitors;

(32) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;

(33) PPAR agonists;

(34) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;

(35) IL-lb antibodies, (e.g., XOMA052 and canakinumab); and

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

Of particular interest are dipeptidyl peptidase-rv (DPP-4) inhibitors that can be used in combination with compounds of the present invention. Such inhibitors include, without

limitation, sitagliptin (disclosed in US Patent No. 6,699,871), MK-3102, SYR-472, teneligliptin, KRP104, TS021, AMG222, SK0403, LC15-0444, vildagliptin, saxagliptin, alogliptin,

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 the formulas described herein include, but are not limited to:

(2R,3S,5R)-5-(l-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)-2-(2,4,5- trifluorophenyl)tetrahydro-2H-pyran-3-amine;

(2R,3S,5R)-5-(l-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)-2-(2,4,5- trifluorophenyl)tetrahydro-2H-pyran-3-amine;

(2R,3S,5R)-2-(2,5-difluorophenyl)tetrahydro)-5-(4,6-dihydropyrrolo[3,4-c]pyrazol- 5(lH)-yl) tetrahydro-2H-pyran-3 -amine;

(3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-hexahydro-3-methyl-2/ -l,4- diazepin-2-one;

4-[(3R)-3-amino-4-(2,5-difluorophenyl)butanoyl]hexahydro-l-methyl-2/ -l,4-diazepin- 2-one hydrochloride; and

(3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-hexahydro-3-(2,2,2-trifluoroethyl)-2/ - l,4-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, melanocortin-4 receptor agonists; CC -1 agonists;

melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Yi or Y5 antagonists (such as MK-0557); CB 1 receptor inverse agonists and antagonists (such as rimonabant and taranabant); β3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (such as bombesin receptor subtype-3 agonists); and 5-hydroxytryptamine-2c (5-HT2c) agonists, such as lorcaserin. For a review of anti-obesity compounds that can be combined with compounds of the present invention, see S. Chaki et al., "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 K. Lee, "Emerging antiobesity drugs," Expert Opin. Emerging Drugs. 8: 217-237 (2003); J.A. Fernandez-Lopez, et al., "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 I include, but are not limited to:

N-[4-((lS)-l-{3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-l f-pyrazol-l- yl}ethyl)benzoyl]- -alanine;

N-[4-(( 1R)- 1 - {3 -(3 ,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]- lH-pyrazol- 1 - yl}ethyl)benzoyl]-P-alanine;

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

N-(4- {(15)-l-[3 -(3 ,5-dichlorophenyl)-5 -(6-methoxy-2-naphthyl)- lH-pyrazol- 1 - yl]ethyl}benzoyl)-P-alanine;

N-(4-{(lS)-l-[(R)-(4-chlorophenyl)(7-fluoro-5-methyl-lH-indol-3-yl)methyl]butyl}benzoyl)-p- alanine; and

N-(4-{(lS)-l-[(4-chlorophenyl)(6-chloro-8-methylquinolin-4-yl)methyl]butyl}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 -yl)-2/ -tetrazol-2- yl] acetic acid;

(2'-{4-[2-(trifluoromethyl)phenoxy]piperidin-l-yl}-2,5'-bi-l,3-thiazol-4-yl)acetic 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 -fluorophenoxy)piperidin- 1 -yl] - 1 ,2,4-oxadiazol-5-yl } - 1 H-pyrrol- 1 -yl)acetic acid;

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

and

(5-{2-[4-(5-bromo-2-chlorophenoxy)piperidin-l-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, but are not limited to:

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

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

5 -(l-hydroxymethyl-propoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(l -methyl- lH-pyrazol- 3-yl)benzamide;

3 -(6-methanesulfonylpyridin-3 -yloxy)-5 -( 1 -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-l-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(l-methyl-lH- pyrazol-3 -yl)benzamide;

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

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

N-(3-methyl-l,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-l,2,4-triazol-3-yl)thio]-3-{[4-(2-pyrrolidin- 1 -ylethoxy)phenyl]thio}pyridine-2-carboxamide; and

3-[(4-{2-[(2R)-2-methylpyrrolidin-l-yl]ethoxy}phenyl)thio-N-(3-methyl-l,2,4-thiadiazol-5-yl)-6-[(4- methyl-4H-l,2,4-triazol-3-yl)thio]pyridine-2-carboxamide; and pharmaceutically acceptable salts thereof.

Agonists of the GPR-119 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-[(lR,2S)-2-(2-{[5-(methylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidin- l-yl}pyrimidine; rac cz^'s-5-chloro-2-[4-(2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-l- yl]pyrimidine;

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

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

rac cz5-5-chloro-2-[4-(2-{2-[3-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-l- yl]pyrimidine; and

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

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

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

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

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

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

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

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

2- {3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-lH-indol-l-yl]phenoxy}-2- methylpropanoic acid; and

(2R)-2- {3 - [3 -(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)- l//-indol- 1 - yl]phenoxy}propanoic acid; and pharmaceutically acceptable salts thereof.

Inhibitors of 11 β-hydroxysteroid dehydrogenase type 1 that can be used in combination with the compounds of formula I include, but are not limited to:

3- [l-(4-chlorophenyl)-ira«s-3-fluorocyclobutyl]-4,5-dicyclopropyl-r-4/ -l,2,4-triazole;3-[l-(4- chlorophenyl)-iraK5-3-fluorocyclobutyl]-4-cyclopropyl-5-(l-methylcyclopropyl)-r-4 ?-l,2,4- triazole;

3 - [ 1 -(4-chlorophenyl)-ira«s-3 -fluorocyclobutyl]-4-methyl-5 - [2-(trifluoromethoxy)phenyl] -r-4H- 1,2,4-triazole; 3-[l-(4-chlorophenyl)cyclobutyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-l,2,4-triazole;

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

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

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

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

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

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

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

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

5-(l,l-difluoroethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-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:

-31 -

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

5 - { 1 '- [( 1 -cyclopropyl-4-methoxy- 1 H-indol-6-yl)carbonyl]-4-oxospiro [chroman-2,4'-piperidin] - 6-yl} nicotinic acid;

-[(l-cyclopropyl-4-methoxy-lH-indol-6-yl)carbonyl]-6-(lH-tetrazol-5-yl)spiro[chroman-2,4'- piperidin]-4-one;

1 '- [( 1 -cyclopropyl-4-ethoxy-3 -methyl- 1 H-indol-6-yl)carbonyl] -6-( 1 H-tetrazol-5 - yl)spiro[chroman-2,4'-piperidin]-4-one; and

5 - { 1 '- [( 1 -cyclopropyl-4-methoxy-3 -methyl- 1 H-indol-6-yl)carbonyl]-4-oxo-spiro [chroman-2,4'- piperidin]-6-yl}nicotinic 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. AMG 131, MBX2044, mitoglitazone, lobeglitazone, IDR-105, pioglitazone, rosiglitazone, and balaglitazone) and other PPAR ligands, including (1) PPARa/γ dual agonists, such as ZYH1, YYH2, chiglitazar, GFT505, muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPARa agonists, such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate 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, such as ISI-1 13715, and TTP814;

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

(4) a-glucosidase inhibitors (e.g., acarbose, voglibose and miglitol);

(5) glucagon receptor antagonists;

(6) LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (e.g., lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (e.g., colestilan, cholestyramine, colestimide, colesevelam

hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) inhibitors of cholesterol absorption, (e.g., ezetimibe), and (iv) acyl CoA:cholesterol acyltransferase inhibitors (e.g., 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-524; and nicotinic acid receptor agonists;

(8) antiobesity compounds;

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

(10) antihypertensive agents, such as ACE inhibitors (e.g., enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (e.g., losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (e.g., aliskiren), beta blockers (e.g., calcium channel blockers);

(1 1) glucokinase activators (GKAs) (e.g., AZD6370);

(12) inhibitors of 1 1 β-hydroxysteroid dehydrogenase type 1 (e.g., such as those disclosed in U.S. Patent No. 6,730,690; WO 03/104207; and WO 04/058741);

(13) inhibitors of cholesteryl ester transfer protein (CETP), (e.g., torcetrapib and MK-

0859);

(14) inhibitors of fructose 1,6-bisphosphatase (e.g., such as those disclosed in U.S. Patent Nos. 6,054,587; 6, 1 10,903; 6,284,748; 6,399,782; and 6,489,476);

(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: (i) GPR-109, (ii) GPR-119 (e.g., MBX2982, and PSN821), and (iii) GPR-40 (e.g., TAK875, 5-[4-[[(lR)-4-[6-(3-hydroxy-3- methylbutoxy)-2-methylpyridine-3-yl]-2,3-dihydro-lH-indene-l-yl]oxy]phenyl]isothiazole-3-ol 1- oxide, 5-(4-((3-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)phenyl)methoxy)phenyl)iso, 5-(4- ((3-(2-methyl-6-(3-hydroxypropoxy)pyridine-3-yl)-2-methylphenyl)methoxy)phenyl)isothiazole-3-ol 1- oxide, and 5-[4-[[3-[4-(3-aminopropoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]isothiazole-3-ol 1 -oxide);

(18) SSTR3 antagonists (e.g., such as those disclosed in WO 2009/011836);

(19) neuromedin U receptor agonists ( e.g., such as those disclosed in WO2009/042053, including, but not limited to, neuromedin S (NMS));

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

(21) GPR-105 antagonists (e.g., such as those disclosed in WO 2009/000087);

(22) inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1; SGLT-2 (e.g., ASP1941, TS071, BI10773, tofogliflozin, LX421 1, canagliflozin, dapagliflozin 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 acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2);

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

(28) bromocriptine mesylate and rapid-release formulations thereof, and

(29) IL-lb antibodies (e.g., XOMA052, and canakinumab); 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 be 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).

Examples

General methods:

A (Examplified by):

C (Examplified by):

D (Examplified by):

2-(4-bromo-2-fluorophenyl -6-(^'trifluoromethyl -lH-benzimidazole

A 200 mL sample vial was charged with 4-bromo-2-fluorobenzaldehyde (10 g, 49.3 mmol) along with DMF (100 mL), water (10 mL) and 4-trifluoromethyl-l,2-phenyldiamine (9.54 g, 54.2 mmol). The mixture was stirred at room temperature for 5 min before OXONE (21.20 g, 34.5 mmol) was added in one portion. The resulting reaction mixture was then stirred at room temperature for 2 hours. The mixture was then partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic phases were washed with water, dried over MgS0₄, filtered and concentrated. The residue was purified by MPLC (120 g silica gel, 10 to 50% ethyl acetate in hexanes) to afford light color solid product 2-(4-bromo-2-fluorophenyl)-6-(trifluoromethyl)-lH- benzimidazole. LC-MS (ES, m/z): Ci₄H₇BrF₄N₂: 358; Found: 359 [M+H]⁺.

Intermediate 2

2-(4-bromo-phenyl -5-trifluoromethyl-lH-benzoimidazole

To solution of 4-Trifluoromethyl -benzene- 1 , 2-diamine (3 g, 17.05 mmol) and 4-bromo- benzoic acid (4.08 g, 20.3 mmol) in anhydrous pyridine (15 mL) was added triphenyl phosphite. The reaction was heated to 220°C in microwave for 30 min. The reaction was cooled to ambient temperature and LC-MS showed that the product was formed. The reaction mixture was poured to EtOAc and the organic phase was washed with water, saturated aHC03 solution and brine. The solvent evaporated in vacuum and the crude product was purified by silica gel

chromatography (10% - 25% EtOAc/Hexane) to give the product as a white solid. LC-MS found: 343 [M+H]⁺.

Intermediate 3

2-(4-bromo-phenyl)-5-chloro-lH-benzoimidazole

Performed as same as the synthesis of 2-(4-bromo-phenyl)-5-trifluoromethyl-lH- benzoimidazole, except that 4-chloro-benzene-l, 2-diamine (5 g, 35.10 mmol) and 4-bromo- benzoic acid (8.46 g, 42.1 mmol) were used as the starting materials. LC-MS found: 309

[M+H]⁺.

Intermediate 4

2-(^'4-iodophenyl -5-(^'trifluoromethyl -lH-benzimidazole

Prepared following the same procedure described for 2-(4-bromo-2-fluorophenyl)-6- (trifluoromethyl)-lH-benzimidazole, except that 4-iodobenzaldehyde was used . LC-MS found: 389 [M+H]⁺.

Intermediate 5

2-(6-bromopyridin-3-yl)-6-(trifluoromethyl)-l-H-benzimidazole

Following the same procedure as 2-(4-bromo-2-fluorophenyl)-6-(trifluoromethyl)-lH- benzimidazole, 2-(6-bromopyridin-3-yl)-6-(trifluoromethyl)-l-H-benzimidazole was prepared a solid. LC-MS (ES, m/z) CnlLBrFs s: 342; Found: 343 [M+H]⁺.

2-r2-fluoro-4-(4 A5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl1-5-(trifluoromethyl)- 1H- benzimidazole

A mixture of 2-(4-bromo-2-fluorophenyl)-5-(trifluoromethyl)-lH-benzimidazole (25.06 g, 69.6 mmol, 1.00 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (19.45 g, 77.0 mmol, 1.10 equiv), potassium acetate (20.50 g, 209.0 mmol, 3.00 equiv) and 1, 1'- bis(diphenylphoshino) ferrocene dichloropalladium (II) dichloromethane complex ( 5.09 g, 6.96 mmol, 0.1 equiv) in DMSO (200 mL) was stirred for 18 hr at 100 °C in an oil bath. The reaction mixture was cooled and washed by the addition of water, followed by extraction 3 times with EtOAc. The combined organic layer was dried over MgS0₄ filtered and concentrated in vacuo. The residue was purified by eluting through a silica gel column with a 0-60% EtOAc/Hexane solvent system to provide product 2-[2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]-5-(trifluoromethyl)-lH-benzimidazole. LC-MS (ES, m/z) C₂oH₁₉BF_{4 2}0₂

Found: 407 [M+H]⁺.

Intermediate 7

2-r4-(^'4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl phenyl1-5-(^'trifluoromethyl -lH- benzimidazole

A mixture of 2-(4-iodophenyl)-5-(trifluoromethyl)-lH-benzimidazole ( 8.08 g, 20.82 mmol, 1.00 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (5.82 g, 22.09 mmol, 1.10 equiv), potassium acetate (6.13 g, 62.5 mmol, 3.00 equiv) and 1, 1'- bis(diphenylphoshino) ferrocene dichloropalladium (II) dichloromethane complex ( 1.52 g, 2.08 mmol, 0.1 equiv) in DMSO (65 mL) was stirred for 18 hr at 100 °C in an oil bath. The reaction mixture was cooled and washed by the addition of water, followed by extraction 3 times with EtOAc. The combined organic layer was dried over MgS0₄ filtered and concentrated in vacuo. The residue was purified by eluting through a silica gel column with a 0-60% EtOAc/Hexane solvent system to provide product 2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-5- (trifluoromethyl)-lH-benzimidazole. LC-MS (ES, m/z) C₂oH₂oBF₃ 202: 388; Found: 389

[M+H]⁺.

Intermediate 8

4-[4-(4.4.5.5-Tetramethyl-[1.3.21dioxaborolan-2-yl)-phenyll-piperidine-l-carboxylic acid tert-butyl ester

Potassium acetate (1.44g, 14.69 mmol, 5 equiv.) and [Ι, Γ bis (diphenylphosphino) ferrocene]dichloro-palladium(II) CH2CI2 complex (0.308 g, 0.148 mmol, 0.05 equiv.) were added at room temperature to a solution of tert-butyl 4-(4-bromophenyl)piperidine-l-carboxylate

(l.Og, 2.94 mmol, 1 equiv.) and bis(pinacolato)diboron (0.896 g, 3.53 mmol, 1.2 equiv.) in DMF (66 mL). The reaction suspension was degassed and then stirred under 2 (g). The reaction was stirred in a 74°C oil bath. After stirring overnight, the reaction was cooled to room temperature. The reaction suspension was filtered to remove insoluble solids. The collected solution was concentrated to a brown residue. The residue was dissolved in EtOAc / ¾( .

After stirring, the EtOAc phase was separated, dried over a2S04, filtered, and concentrated to a brown residue / oil. Purification with Biotage SP-1 [ 0 > 12% 2CV, 12 > 100% 10CV, 100% 2CV ] isolated the desired product as a foam, 0.68 g. LC-MS (ES, m/z): C22H34BNO4: 387; Found 388 [M+H]⁺.

Intermediate 9

2- r4-(6-fluoropyridin-3 -vDphenyll -5-(trifluoromethyl)- 1 H-benzimidazole

To the mixture of 2-(4-bromophenyl)-5-(trifluoromethyl)-lH4oenzo[d]imidazole (1.0 g, 2.93 mmol, leq), 2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.785 g, 3.52 mmol, 1.2 eq), and Pd(dppf)Cl₂ (104 mg, 0.147 mmol, 0.05 eq) was added THF (15 mL). After the resulting suspension was purged with N₂ for 5 min, NaHC0₃ / H₂0 solution (IN, 6 mL, 2eq) was added and the solution was purged with 2 for 5 min. The reaction mixture was stirred at 70°C for 16 hr and LC-MS showed the reaction was completed. The reaction was cooled to ambient temperature and partitioned between EtOAc and water. The organic phase was washed with brine and was dried over Na₂S0₄. The solution was filtered and evaporated in vacuum. The crude product was stirred in hexane/EtOAc solution (4: 1) overnight and the solid was filtered off to give the product as a brown solid. LC-MS (ES, m/z): C1₉H11F4N₃: 357; Found 358 [M+H]⁺. Intermediate 10

6'-fluoro-2,3'-bipyridine-5-carbaldehvde In a 1L round-bottom flask equipped with magnetic stirring, 2-fluoropyridine-5-boronic acid (33.6 g, 234 mmol), 6-bromonicotinaldehyde (37 g, 195 mmol), 1 , l'-bis(di-ter- butylphospino)ferrocene palladium dichloride (6.35 g, 9.75 mmol), potassium phosphate tribasic (124 g, 585 mmol) were degassed and purged with 2 three times. To this solid mixture, THF (650 ml) was added and the solution mixture was degassed and purged with N2 three times. The reaction mixture was heated to 60°C and allowed to age overnight. The reaction mixture was cooled to RT, quenched with water and diluted with water. The layer were cut. The emulsion was filtered through pad celite and washed with EtOAc. The layers were cut, the organic layer was washed with brine, dried over Na₂S0₄ filtered and concentrated to dryness. The crude product was purified by column chromatography CombiFlash Rf (330g column; 200 min/mL flow rate; 9: 1 to 1 : 1 Hexanes:EtOAc) to afford 6'-fluoro-2,3'-bipyridine-5-carbaldehyde as a white solid. LC-MS (ES, m/z) CnH₇FN₂0: 202; Found: 203 [M+H]⁺.

Intermediate 1 1

6'-fluoro-5'-methyl-2,3'-bipyridine-5-carbaldehvde

Prepared following the procedure described above for 6'-fluoro-2,3'-bipyridine-5- carbaldehyde, starting from 2-fluro-3-methylpyridine-5-boronic acid. LC-MS (ES, m/z) C₁₂H₉FN₂O, 216; Found: 217[M+H]⁺.

Intermediate 12

5 -(6-chloro- 1 H-benzimidazol-2-yl - 6'-fluoro-2 ,3 '-bipyridine In a 2L round-bottom flask equipped with magnetic stirring and nitrogen inlet, 6'-fluoro-

2,3'-bipyridine-5-carbaldehyde (19.8 g, 98 mmol) was dissolved in DMA (350 ml) and the solution was cooled to 0°C. 4-Chloro-l,2-phenylenediamine (14.40 g, 98 mmol) was added. Water (315 ml) was added followed by slow addition of potassium peroxymonosulfate (39.1 g, 63.7 mmol). The reaction mixture became thick. 3 mL of DMAc and 2mL of water were added to facilite stirring. The dark brown slurry was allowed to age at RT. After 3h, the reaction mixture was diluted with water and the remaining slurry was allowed to age overnight at RT. The reaction mixture was filtered (slow filtration) and the wet cake was washed with additional water. The wet cake was dried over nitrogen sweep and vacuum. Later the filter cake was transfered to a round-bottom flask and treated with MeCN and heated to 70°C. After one hour the slurry was cooled to RT and allowed to age overnight. The slurry was filtered and rinsed with MeCN. The wet cake was dried over nitrogen sweep and under vacuum to afford 5-(6- chloro-lH-benzimidazol-2-yl)-6'-fluoro-2,3'-bipyridine as a solid. LC-MS (ES, m/z)

Ci₇H₁₀ClFN₄: 324; Found: 325 [M+H]⁺. Intermediates 13 to 15

Prepared following the procedure described above for 5-(6-chloro-lH-benzimidazol-2- yl)-6'-fluoro-2,3'-bipyridine, starting from 6'-fluoro-5'-methyl-2,3'-bipyridine-5-carbaldehyde and appropriate diamines.

Intermediate 16

Ethyl 3- {[(4-bromophenyl)sulfonyllamino}propanoate

To the solution of ethyl 3-aminopropanoate hydrochloride (601 mg, 3.91 mmol)in CH₂C1₂ (10 mL) at 0 °C was added triethylamine (1.64 mL, 1 1.74 mmol) and 4- bromobenzenesulfonyl chloride (1.0 g, 3.91 mmol). The mixture was warmed to RT for 2 h. Diluted with 2N a₂C0₃ (aq.) and extarcted with CH2CI2. The organic layer was dried, filtered and concentrated. The residue was purified by Biotage silica gel column (50% EtOAc in hexane) to give the product as a pale yellow solid. LC-MS (ES, m/z): CnH^Br C S: 337; Found: 338 [M+H]⁺.

2- {2-fluoro-4-r2-(methylsulfinyl)pyrimidm^

benzimidazole

Step A

2-(methylsulfanyl -5-(4^,5,5 etramethyl-l,3,2-dioxaborolan-2-yl pyrimidine

To a 100 niL one neck round bottom flask was charged with 2-methylthio-5- bromopyrimidine (1 g, 4.88 mmol) along with pinacoldiborane (1.362 g, 5.36 mmol), potassium acetate (0.957 g, 9.75 mmol), Pd(dppf)CH₂Cl₂ (0.178 g, 0.244 mmol) and DMSO (10 ml). The flask was sealed with septum and connected to manifold through a syringe needle. The system was vacuumed and refilled with nitrogen three times and the mixture was then stirred and heated in an oil bath of 100 °C for 6 hr. The reaction mixture was black. LC- MS showed complete consumption of starting material. After cooled to room temperature, the residue was diluted with ethyl acetate (100 mL) and water (50 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic phases were washed with water, dried over MgS0₄, filtered and concentrated. The residue was purified by MPLC (24 g silica gel, 10 to 60% ethyl acetate in hexanes) to afford ligh yellow solid product 2-(methylsulfanyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine. LC-MS (ES, m/z): CnH₁₇BN₂0₂S: 252; Found: 253 [M+H]⁺.

Step B

2- {2-fluoro-4-r2-(methylsulfanyl)pyrimidin-5-yl1phenyl}-6-(trifluoromethyl)-lH- benzimidazole

To a 20 mL pyrex vial was charged with 2-(4-bromo-2-fluorophenyl)-6- (trifluoromethyl)-lH-benzimidazole (1.567 g, 4.36 mmol) along with 2-(methylsulfanyl)-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (1.1 g, 4.36 mmol) and sodium carbonate (1.387 g, 13.09 mmol)and tetrakispalladium (0.252 g, 0.218 mmol) in DME (6 ml) and EtOH (6). The vial was sealed and vacuumed and refilled with nitrogen 3 times and then the mixture was exposed to MW irridiation at 120 °C for 1 hr. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated and partitioned between water (20 mL) and ethyl actate (50 mL), and worked up by extraction. The combined organic phases were dried over MgS0₄, filtered and concentrated. The residue was dissolved in small amount of ethyl acetate (10 mL) by heating and then slowly cooled to room temperature and 0 °C. The precipitated solid was filtered and washed with ethyl actate to afford crop of product. The filterate was concentrated and the residue was purified by MPLC (24 g silica gel, 10 to 40% ethyl acetate in hexanes) to afford another crop of product to total 2- {2-fluoro-4-[2- (methylsulfanyl)pyrimidin-5-yl]phenyl}-6-(trifluoromethyl)-lH-benzimidazole. LC-MS (ES, m/z): Ci₉H₁₂F_{4 4}S: 404; Found: 405 [M+H]⁺.

Step C

2- {2-fluoro-4-r2-(methylsulfinyl pyrimidin-5-yl1phenyl}-6-(trifluoromethyl -lH- benzimidazole

To a 20 mL sample vial was charged with 2-{2-fluoro-4-[2-(methylsulfanyl)pyrimidin-5- yl]phenyl}-6-(trifluoromethyl)-lH-benzimidazole (1.5 g, 3.71 mmol) along with ethyl acetate (30 ml). The solid became soluble after heating. Then the mixture was cooled to room temperature before mCPBA (0.914 g, 4.08 mmol) was added in one portion. The resulting reaction mixture was stirred at room temperature for 30 min. The product preciptated out, and was filtered and washed with ethyl acetate to afford 2-{2-fluoro-4-[2- (methylsulfinyl)pyrimidin-5-yl]phenyl}-6-(trifluoromethyl)-lH-benzimidazole. LC-MS (ES, m/z): Ci₉H₁₂F₄N₄OS: 420; Found: 421 [M+H]⁺.

Intermediate 18

2- {4-[2-(methylsulfinyl)pyrimidin-5-yllphenyl} -5-(trifluoromethyl)- lH-benzimidazole

Prepared following Steps B and C described above for 2-{2-fluoro-4-[2- (methylsulfinyl)pyrimidin-5-yl]phenyl} -5-(trifluoromethyl)- lH-benzimidazole, using [2- (methylsulfanyl)pyrimidin-5-yl]boronic acid and 2-(4-bromo-phenyl)-5-trifluoromethyl-lH- benzoimidazole as the starting materials.

Intermediate 19

Methyl 3-(5-bromopyrimidin-2-yloxy)-2.2-dimethylpropanoate

A mixture of methyl 3-hydroxy-2,2-dimethylpropanoate (3.0 g, 22.7 mmol, 1.00 equiv), 5-bromo-2-chloropyrimidine (5.27 g, 27.2 mmol, 1.2 equiv), and cesium carbonate (30.3 g, 93 mmol, 4.1 equiv) in DMF (100 mL) was stirred on MW for 1 hr at 120° C. The reaction mixture was cooled to room temperature, filtered through a Buchner funnel rinsed with EtOAc and concentrated in vacuo. The residue was purified by eluting through a silica gel column with a 0- 40% EtOAc/Hexane solvent system to provide product methyl 3-(5-bromopyrimidin-2-yloxy)- 2,2-dimethylpropanoate. LC-MS (ES, m/z) CioH₁₃Br ₂0₃: 289; Found: 291 [M+H]⁺.

Intermediate 20

Methyl 3-(5-bromopyridin-2-yloxy)-2,2-dimethylpropanoate

To a stirred solution of 5-bromopyridin-2-ol (10 g, 57.5 mmol) in anhydrous THF (200 ml) at RT was added hydroxypivalic acid methyl ester (9.16 ml, 71.8 mmol).

Triphenylphosphine (18.8 g, 71.8 mmol) was then added followed by dropwise addition of diisopropyl azodicarboxylate (14.1 ml, 71.8 mmol) at OoC. The reaction was then heated to 55 °C and allowed to stir at this temperature over night. The reaction mixture was concentrated. The residue was treated with EtOAc (70 ml) and then Hexane (70 ml), the solid was filtered off. The filtrate was concentrated, separated by MPLC (10-100% EtoAC in hexane) to give methyl 3-(5- bromopyridin-2-yloxy)-2,2-dimethylpropanoate (9.94 g). LC-MS (ES, m/z) C_uH₁₄BrN0₃: 287; Found: 288 [M+H]+.

Intermediate 21

Methyl 3-(5-bromo-3-methylpyridin-2-yloxy)-2,2-dimethylpropanoate Prepared following the procedure described above for Methyl 3-(5-bromopyridin-2- yloxy)-2,2-dimethylpropanoate, but starting with 5-bromo-3-methylpyridin-2-ol. LC-MS (ES, m/z) Ci₂H₁₆BrN0₃: 303; Found: 304[M+H]⁺ _.

Intermediate 22

Methyl 2,2-dimethyl-3-(^'5-(^'4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl pyridin-2- yloxy)propanoate

A mixture of methyl 3-(5-bromopyridin-2-yloxy)-2,2-dimethylpropanoate (4.0 g, 13.88 mmol), Bis(pinacolato)diboron (3.88 g, 15.3 mmol), potassium acetate (4.09 g, 41.6 mmol), PdCl₂(dppf) (0.508 g, 0.694 mmol) in Dioxane (75 ml) was heated at 80°C overnight under N_2. The reaction was concentrated. To the residue was added water and EtOAc, filtered through celite, separated two layers, extracted the aqueous with EtOAc, dried and concentrated. The residue was separated by MPLC ( 5-100% EtOAc in hexane) to give methyl 2,2-dimethyl-3-(5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)propanoate (2.5 g) as colorless oil. LC-MS (ES, m/z) Ci₇H₂₆BN0₅: 335; Found: 336 [M+H]⁺ _.

Intermediate 23

Methyl 3-(5-formyl-2,3'-bipyridin-6'-yloxy)-2,2-dimethylpropanoate A mixture of methyl 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yloxy)propanoate (1.5 g, 4.47 mmol), 6-Bromonicotinaldehyde (0.832 g, 4.47 mmol), [l, l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.164 g, 0.224 mmol) and sodium carbonate (0.949 g, 8.95 mmol) are suspended in DMF / H₂0, and stirrred at 80°C under 2 over night. Reaction mixture was cooled to rt and water was added, extracted with EtOAc, dried over Na2S04, filtered and purified by MPLC (5 to 50% EtOAc in Hxane 5) to give methyl 3-(5-formyl-2,3'-bipyridin-6'-yloxy)-2,2-dimethylpropanoate (1.1 g ) as white solid. LC-MS (ES, m/z) Ci₇H_{18 2}0₄: 314; Found: 315 [M+H]⁺ _.

Intermediate 24

Methyl 3-(5-(3-fluoro-4-formylphenyl)pyridin-2-yloxy)-2.2-dimethylpropanoate

A mixture of methyl 3-(5-bromopyridin-2-yloxy)-2,2-dimethylpropanoate (3 g, 10.4 mmol) and 3-fluoro-4-formylphenylboronic acid (1.75 g, 10.4 mmol) , and a₂C0₃ (2.21 g, 20.8 mmol) in DMF (10 ml) and Water (5 ml) at RT was treated with PdCl₂(dppf) (0.38 g, 0.52 mmol). The reaction mixture stir at 80°C over night, cooled to RT, added H₂0, extract with EtOAc, dried over Na₂S0₄ filtered and concentrated, purified by MPLC (5-50% EtOAc in hexane) to give methyl 3-(5-(3-fluoro-4-formylphenyl)pyridin-2-yloxy)-2,2-dimethylpropanoate (2.6 g) as yellow oil. LC-MS (ES, m/z) Ci₈H₁₈FN0₄: 331 ; Found: 332 [M+H]⁺ _.

Intermediates 25 and 26

Prepared following the procedure described for Methyl 3-(5-(3-fluoro-4- formylphenyl)pyridin-2-yloxy)-2,2-dimethylpropanoate, starting from the appropriate heteroaryl bromide (Methyl 3-(5-bromopyrimidin-2-yloxy)-2,2-dimethylpropanoate or Methyl 3-(5-bromo- 3 -methylpyridin-2-yloxy)-2,2-dimethylpropanoate) .

Example 1

5 - { 3 -fluoro-4-r5 -(trifluoromethyl)- 1 H-benzimidazol-2-yllphenyl} pyridin-2-ol

A mixture of 2-(4-bromo-2-fluorophenyl)-6-(trifluoromethyl)-lH-benzimidazole (2.2 g, 4.72 mmol), 6-hydroxypyridine-3-boronic acid pinacol ester (1.043 g), [Ι, - bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.173 g) and sodium carbonate (1.0 g) was suspended in DMF (8 mL) and water (4 mL). The mixture was purged with 2 and then stirred at 80°C overnight. The reaction mixture was cooled to RT and half of the reaction mixture was treated with water and ethyl acetate. The precipitate formed was isolated by filtration to afford 5-{3-fluoro-4-[5-(trifluoromethyl)-lH-benzimidazol-2-yl]phenyl}pyridin-2-ol as a brown solid. LC-MS (ES, m/z) CwHnRiNsO: 373; Found: 374 [M+H]⁺. Example 2

2-[4-(2-methoxypyrimidin-5-yl)phenyll-5-(trifluoromethyl)-lH-benzimidazole

To a mixture of 2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-5- (trifluoromethyl)-lH-benzimidazole (0.5 g, 1.28 mmol, 1.00 equiv), 5-bromo-2- methoxypyrimidine (0.487 g, 2.58 mmol, 2.00 equiv), palladium tetrakis (0.233 g, 0.15 mmol, 0.15 equiv) and Na₂C0₃ (0.546 g, 5.15 mmol, 4.0 equiv) was added DMF (16.0 mL)/H₂0 (4.0 mL). The reaction mixture was degassed and purged with nitrogen while stirring for 10 min, followed by MW at 155 °C for 90 min. The mixture was diluted with water and extracted 3x with EtOAc. The organic layers were combined, dried over MgS0₄ and concentrated in vacuo. The residue was purified by dissolving in MeOH/EtOAc mixture and filtered thru Buchner funnel to afford product 2-[4-(2-methoxypyrimidin-5-yl)phenyl]-5-(trifluoromethyl)-lH- benzimidazole as a white solid. LC-MS (ES, m/z) C20H22FN3O3: 370; Found: 371 [M+H]⁺.

Example 3

5- {4-[5-(trifluoromethyl)-lH-benzimidazol-2-yllphenyl}pyrimidin-2-ol To a 15 mL seal tube was charged with 2-[4-(2-methoxypyrimidin-5-yl)phenyl]-5-

(trifluoromethyl)-lH-benzimidazole (0.035 g, 0.095 mmol) along with cone HCl (1.68 g, 17.05 mmol) The mixture was MW at 100° C for 30 min. The reaction mixture was filtered and

purified by RP HPLC 20-70% ACN method with loading as a solution of DMSO:H₂0:ACN to give product 5-{4-[5-(trifluoromethyl)-lH-benzimidazol-2-yl]phenyl}pyrimidin-2-ol. LC-MS

(ES, m/z) C18H11F3 4O: 356; Found: 357 [M+H]⁺.

Example 4

3 -(5 -(4-(5 -(trifluoromethyl)- 1 H-benzo Tdl imidazol-2-yl)phenyl)pyrimidin-2-yloxy)propanoic

acid

Step A

Methyl 3-((5-(4-(5-(trifluoromethyl)-lH-benzo[dlimidazol-2-yl)phenyl)pyrimidin-2-yl)oxy)propanoate

A mixture of 5-(4-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-ol (0.05 g, 0.14 mmol, 1.00 equiv), methyl 3-bromopropanoate (0.028 g, 0.168 mmol, 1.2 equiv), and cesium carbonate (0.142 g, 0.435 mmol, 3.1 equiv) in DMF (1.6 mL) was stirred for 1.5 h at 120 °C in MW. The mixture was filtered and purified by RP HPLC 20-70% ACN method with loading as a solution of DMSO:H20:ACNto provide product Methyl 3-((5-(4-(5- (trifluoromethyl)-lH-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-yl)oxy)propanoate. LC-MS (ES, m/z) C22H17F3N4O3: 442; Found: 442 [M+H]⁺.

Step B

3 -(5 -(4-(5 -(trifluoromethyl)- 1 H-benzo fdl imidazol-2-yl)phenyl)pyrimidin-2-yloxy)propanoic acid

To a 50 ml vial was added LiOH (9.36 mg, 0.391 mmol, 7.0 equiv) dissolved in H₂0 (1.0 mL), among with methyl 3-(5-(4-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl)phenyl)pyrimidin-2-yloxy)propanoate (24.7 mg, 0.056 mmol, 1.0 equiv) in THF (2.0 mL) and MeOH (1.0 mL). The reaction mixture was stirred at 80 °C for 20 min. The mixture was acidified with cone. HC1 to pH=4 and purified by RP HPLC with loading as a solution of DMSO:H20:ACN, 20 to 80% ACN in H₂0 to give 3 -(5 -(4-(5 -(trifluoromethyl)- 1H- benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-yloxy)propanoic acid. LC-MS (ES, m/z)

C₂iH₁₅F₃ 40₃: 428; Found: 429[M+H]⁺.

Example 5

4- {4-r6-(trifluoromethyl)- lH-benzimidazol-2-yllphenyl} -1, 1 a,6,6a- tetrahydrocycloproparalindene- 1 -carboxylic acid

Step A

Ethyl 4- { r(trifluoromethyl)sulfonyl1oxy} -1, 1 a,6,6a-tetrahvdrocvclopropara1indene- 1 - carboxylate

To a 50 mL one neck round bottom flask was charged with ethyl 4-hydroxy-l, la,6,6a- tetrahydrocyclopropa[a]indene-l -carboxylate (880 mg, 4.03 mmol, prepared as described in patent application US2007/0265332) along with TEA (1224 mg, 12.10 mmol) in CH₂C1₂ (10 ml). The mixture was then cooled to -78 °C before triflic anhydride (1251 mg, 4.44 mmol) was added dropwise through a syringe in 10 min. The resulting reaction mixture was stirred at -78 °C for 30 min and then warmed to 0 °C in 30 min. The mixture was poured into ice water and extracted with methylenechloride (3x). The combined organic phases were dried over MgSC^, filtered and concentrated. The crude was purified by MPLC (40 g silica gel , 0 to 10% ethyl acetate in hexanes ) to afford clear liquid product Ethyl 4- {[(trifluoromethyl)sulfonyl]oxy}- l, la,6,6a-tetrahydrocyclopropa[a]indene-l -carboxylate. Step B:

Ethyl 4- {4-r6-(trifluoromethyl)- lH-benzimidazol-2-yllphenyl} -1, 1 a,6,6a-tetrahydro- cycloproparalindene- 1 -carboxylate

To a 5 mL pyrex vial was charged with 2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]-5-(trifluoromethyl)-lH-benzimidazole (202 mg, 0.521 mmol) along with Ethyl 4-

{ [(trifluoromethyl)sulfonyl]oxy} -1, 1 a,6,6a-tetrahydro cyclopropa[a]indene- 1 -carboxylate ( 166 mg, 0.474 mmol) and sodium carbonate (151 mg, 1.422 mmol) and Palladium (tetrakis) (54.8 mg, 0.047 mmol). The vial was sealed and vacuumed, refilled with nitrogen through a syringe needle. The solvents DME (1 ml) and EtOH (1.000 ml) was added. The mixture was then exposed to microwave irridiation at 120 °C for 60 min. LC-MS showed complete consumption of starting amterial. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated and the crude was purified by MPLC (12 g silica gel, 0 to 40% ethyl acetate in hexanes) to afford ethyl 4-{4-[6-(trifluoromethyl)-lH-benzimidazol-2-yl]phenyl}- l, la,6,6a-tetrahydrocyclopropa[a]indene-l -carboxylate. LC-MS (ES, m/z) C2₆H1₉F₃ 2O2: 434; Found: 449 [M+H]⁺.

Step C:

4- {4-r6-(trifluoromethyl)-lH-benzimidazol-2-yl1phenyl}-Lla,6,6a-tetrahydrocvclopropa ralindene-l-carboxylic acid

To a 20 ml sample vial was charged with 302272-82 (60 mg, 0.130 mmol) along with methanol,THF, water and lithium hydroxide (53 mg, 2.213 mmol). The resulting reaction mixture was then stirred at room temperature for 2 hrs. LC-MS showed complete hydrolysis of ester to acid. The mixture was then neutralized by addition of HCl (IN, 0.27 mL). The mixture was filtered and loaded to RP HPLC for purification (YMC column, 20 to 80% acetonitrile in water) to afford product 4- {4-[6-(trifluoromethyl)-lH-benzimidazol-2-yl]phenyl}-l, la,6,6a- tetrahydrocyclopropa [a]indene-l-carboxylic acid. LC-MS (ES, m/z) C25H17F₃N2O2: 434; Found: 435 [M+H]⁺.

Example 6

i Ja .6aR)-4 4 6-(trifluoromethyl)-lH-benzimidazol-2-yllphenyl}-l . la.6.6a- tetrahydrocycloproparalindene- 1 -carboxylic acid

( 15", 1 aS,6ai?)-4- {4-[6-(trifluoromethyl)- lH-benzimidazol-2-yl]phenyl} -1, 1 a,6,6a- tetrahydrocyclopropa[a]indene-l -carboxylic acid was prepared by in the same way as desribed above for 4- {4-[6-(trifluoromethyl)-lH-benzimidazol-2-yl]phenyl}-l, la,6,6a- tetrahydrocyclopropa[a]indene-l -carboxylic acid, except that in Step A, ethyl (\S,laS,6aR)-4- hydroxy-l, la,6,6a-tetrahydrocyclopropa[a]indene-l-carboxylate (Preparation described in patent application US2007/0265332) was used as starting material. LC-MS (ES, m/z)

C^HnFs zCb: 434; Found: 435 [M+H]⁺.

Example 7

4-{4-r5-(5-Trifluoromethyl-lH-benzoimidazol-2-yl -pyridin-2-yl1-phenyl}-piperidine-l- carboxylic acid tert-butyl ester

2-(6-Bromopyridin-3-yl)-6-(trifluoromethyl)-l-H-benzimidazole (0.044g, 0.129 mmol, 1 equiv.), 4-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-piperidine-l -carboxylic acid tert-butyl ester (0.5 g, 0.129 mmol, 1.0 equiv.), 1, 1'-

Bis(Diphenylphosphino)ferrocenedichloro Palladium(II) Dichloromethane complex (0.014g, 0.019 mmol, 0.15 equiv.) and sodium carbonate (0.027 g, 0.258 mmol, 2.0 equiv.) were placed in DMF (1.0 mL) / H2O (0.2 mL) and stirred under microwave conditions (120°C, 60min) and

(150°C, lhr). The reaction was cooled to room temperature. The reaction suspension was diluted with EtOAc, filtered, and concentrated to a white solid. Purification with Biotage SP- 1 [ 0 > 12% 2CV, 12 > 100% 10CV, 100% 2CV ] isolated 4- {4-[5-(5-Trifluoromethyl-lH- benzoimidazol-2-yl)-pyridin-2-yl]-phenyl}-piperidine-l -carboxylic acid tert-butyl ester (0.04 g) as a white solid. LC-MS (ES, m/z):

522; Found: 523 [M+H]⁺. Expample 8

5-(4-(5-(trifluoromethyl)-lH-benzim^ To a suspension of 2-(4-bromophenyl)-5-(trifluoromethyl)-lH-benzimidazole (0.030g,

0.088 mmol, 1 equiv.), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.024 g, 0.106 mmol, 1.2 equiv.) and l, l'-Bis(Diphenylphosphino)ferrocenedichloro Palladium(II) Dichloromethane complex (0.006g, 0.009 mmol, 0.10 equiv.) in dioxane (1.0 mL) was added IN sodium bicarbonate solution (0.264 mL , 0.264 mmol, 3.0 equiv.). The resulting reaction was purged with N2 for 5 min and then shaked at 100°C for 16 hr. The reaction was cooled to ambient temperature and was extracted between EtOAc (4mL x2) and water (lmL). The organic phase was combined and evaporated. The crude product was dissolved in DMSO(1.5 mL) and purified by using reversed-phase HPLC (generally acetonitrile with 0.1% ammonium hydroxide/formic acid/TFA : water with 0.1% ammonium hydroxide/formic acid/TFA from 10% to 90%) to give the product as a white solid. LC-MS (ES, m/z): Ci₉H₁₃F₃N4: 354; Found: 355 [M+H]⁺.

Examples 9 to 49

Prepared using 2-(4-bromo-phenyl)-5-trifluoromethyl-lH-benzoimidazole and appropriate boronic acid/ester, following the same procedure described for 5-(4-(5- (trifluoromethyl)- 1 H-benzimidazol-2-yl)phenyl)pyridin-2-amine:

Examples 50-67

Prepared using 2-(4-bromo-phenyl)-5-chloro-lH-benzoimidazole and appropriate boronic acid/ester, following the same procedure described for 5-(4-(5-(trifluoromethyl)-lH- benzimidazol-2-yl)phenyl)pyridin-2-amine:

Example 68

methyl 4-(4'-(5-(trifluoromethyl)-lH-benzo[dlimidazol-2-yl)biphenyl-4-ylthio)butanoate

To the mixture of 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-5- (trifluoromethyl)-lH-benzo[d] imidazole (150 mg, 0.386 mmol, leq), ethyl 4-(4- bromophenylthio)butanoate (141 mg, 0.464 mmol, 1.2 eq), and Pd(dppf)Cl₂ (14 mg, 0.019 mmol, 0.05 eq) was added dioxane (3 mL). After the resulting suspension was purged with N₂ for 10 min, IN NaHC0₃ /H₂0 solution (1.16 mL, 1.16 mmol, 3eq) was added and the solution was purged with N2 for 10 min. The reaction mixture was stirred at 100°C for 16 hr and LC-MS showed the reaction was completed. After cooling to ambient temperature, the reaction was extracted between EtOAc (8 mL x 2) and water (2 mL). The organic phase was washed with brine and dried over Na₂S0₄. The solution was filtered and evaporated in vacuum. The crude product was purified by using preparative reversed-phase HPLC (acetonitrile with 0.1% TFA: water with 0.1% TFA from 10% to 90%) to give the product as a yellow solid. LC-MS Found: 485 [M+H]⁺

Example 69

4-(4'-(5-(trifluoromethyl)-lH-benzord1imidazol-2-yl)biphenyl-4-ylthio)butanoic acid To a solution of methyl 4-(4'-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2-yl)biphenyl-4- ylthio)butanoate (20 mg, 0.041 mmol, 1 eq) in MeOH/THF (1 : 1, 1 mL) was added 2.5 N

L1OH/H₂O (50 μϊ_^, 0.124 mmol, 3 eq). The resulting reaction mixture was then stirred at ambient temperature for 4 hr. LC-MS showed hydrolysis was completed. The solution was concentrated in vacuum and DMSO (1.5 mL) was added. The resulting solution was neutralized with HOAc to pH = 5 and filtered. The crude product was purified by using preparative reversed-phase HPLC (acetonitrile with 0.1% formic acid: water with 0.1% formic acid from 10% to 90%) to give the product as a white solid. LC-MS found: 457 [M+H]⁺. Example 70

4-r4'-(5-Trifluoromethyl-lH-benzoimidazol-2-yl)-biphenyl-4-sulfonyl1-butyric acid ethyl ester

To a solution of methyl 4-(4'-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2-yl)biphenyl-4- ylthio)butanoate (108 mg, 0.223 mmol, leq) in DCM (2 mL) was added MCPBA (100 mg, 0.446 mmol, 2 eq). The resulting reaction mixture was stirred at ambient temperature for 30 min and quenched with water (0.5 mL). The reaction was extracted between EtOAc (10 mL x 2) and water (2 mL). The organic phase was washed with saturated aHC03 solution, brine and concentrated in vacuum. The crude product was purified by using preparative reversed-phase HPLC (acetonitrile with 0.1% formic acid: water with 0.1% formic acid from 10% to 90%) to give the product as a white solid. LC-MS Found: 517 [M+H]⁺ Example 71

4-[4'-(5-Trifluoromethyl-lH-benzoimidazol-2-yl)-biphenyl-4-sulfonyll-butyric acid

Prepared following the same procedure described 4-(4'-(5-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)biphenyl-4-ylthio)butanoic acid, but starting from 4-[4'-(5-

Trifluoromethyl-lH-benzoimidazol-2-yl)-biphenyl-4-sulfonyl]-butyric acid ethyl ester (50 mg, 0.097 mmol). LC-MS (m/z) found: 489 [M+H]⁺.

Examples 72 - 74 Prepared following the proceure described above for methyl 4-(4'-(5-(trifluoromethyl)- lH-benzo[d]imidazol-2-yl)biphenyl-4-ylthio)butanoate and 4-(4'-(5-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)biphenyl-4-ylthio)butanoic acid.

Example 75

3 -(5 -(4-(5 -(trifluoromethyl)- 1 H-benzo fdl imidazol-2-yl)phenyl)pyridin-2-ylamino)propanoic acid

To a mixture of 2-(4-(6-fluoropyridin-3-yl)phenyl)-5-(trifluoromethyl)-lH- benzo[d] imidazole (30 mg, 0.084 mmol, 1 eq), methyl 3-aminopropanoate (10.4 mg, 0.101 mmol, 1.2 eq) and aHC03 (21 mg, 0.252 mmol, 3 eq) was added anhydrous NMP (ImL). The resulting suspension was stirred at 1 10°C for 16 hr. The reaction was cooled to ambient temperature and extracted between EtOAc (4 mL x 2) and water (2 mL). The organic phase was combined and concentrated in vacuum. The residue was dissolved in MeOH/THF (1 : 1, 2mL) and treated with 2.5 N LiOH/H₂0 (0.1 mL, 0.252 mmol) at 50 °C for 2 hr. The solvent was evaporated and DMSO was added. The resulting solution was neutralized with HOAc to pH = 5 and filtered. The crude product was purified by using preparative reversed-phase HPLC

(acetonitrile with 0.1% formic acid: water with 0.1% formic acid from 10% to 90%) to give the product as a white solid. LC-MS Found: 427 [M+H]⁺ Examples 76 to 79

Prepared following the procedure described above for 3-(5-(4-(5-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)phenyl)pyridin-2-ylamino)propanoic acid, starting with 2-[4-(6- fluoropyridin-3 -yl)phenyl] -5-(trifluoromethyl)- 1 H-benzimidazole or 5 -(6-chloro- 1 H- benzimidazol-2-yl)-6'-fluoro-2,3'-bipyridine and appropriate amines.

Examples 80 to 85

Prepared following the procedure described above for 3-(5-(4-(5-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)phenyl)pyridin-2-ylamino)propanoic acid ; starting with 2-{4-[2- (methylsulfinyl)pyrimidin-5-yl]phenyl} -5-(trifluoromethyl)- 1 H-benzimidazole or 2- {2-fluoro-4- [2-(methylsulfinyl)pyrimidin-5-yl]phenyl} -5 -(trifluoromethyl)- 1 H-benzimidazole and appropriate amines.

Example 86

2-(4-(5 -(5 -chloro- 1 H-benzo fdl imidazol-2-yl)-2 ,3 '-bipyridin-6'-yloxy phenyl acetic acid

To a solution of 2-(4-hydroxyphenyl)acetic acid (18 mg, 0.1 10 mmol, 1.2 eq) in anhydrous NMP (lmL) was added K2CO₃ (50 mg, 0.462 mmol, 5 eq). The resulting suspension was stirred at ambient temperature for 20 min and then 5-chloro-2-(6'-fluoro-2,3'-bipyridin-5-yl)- 1 H-benzo [d] imidazole (30 mg, 0.092 mmol, 1 eq) was added. The resulting reaction mixture was stirred at 1 10°C for 20 hr and then cooled to ambient temperature. The solution was filtered and concentrated in vacuum. DMSO (1 mL) was added and the resulting solution was neutralized with HOAc to pH = 5 and filtered. The crude product was purified by using preparative reversed-phase HPLC (acetonitrile with 0.1% formic acid: water with 0.1% formic acid from 10% to 90%) to give the product as a white solid. LC-MS Found: 457 [M+H]⁺

Example 87

2-(4-((5-(3-fluoro-4-(5-(trifluoromethyl)-lH^

yloxy)methyl)phenyl)acetic acid To a solution of methyl 2-(4-(hydroxymethyl)phenyl)acetate (21 mg, 0.119 mmol, 2 eq) in anhydrous NMP (lmL) was added NaH (60%, 12 mg, 0.297 mmol, 5 eq) slowly. The resulting suspension was stirred at ambient temperature for 20 min and then 2-(2-fluoro-4-(2- (methylsulfinyl)pyrimidin-5-yl)phenyl)-5-(trifluoromethyl)-lH-benzo[d]imidazole (25 mg, 0.059 mmol, 1 eq) was added. The resulting reaction mixture was stirred at 110°C for 20 hr and then cooled to ambient temperature. The reaction was quenched with MeOH (0.5 mL) and stirred at ambient temperature for 2 hr. LC-MS showed that the hydrolysis was completed. The solution was concentrated in vacuum and DMSO (1 mL) was added. The resulting solution was neutralized with HOAc to pH = 5 and filtered. The crude product was purified by using preparative reversed-phase HPLC (acetonitrile with 0.1% formic acid: water with 0.1% formic acid from 10% to 90%) to give the product as a white solid. LC-MS Found: 523 [M+H]⁺

Examples 88 to 105

Prepared following the procedure described above for 2-(4-(5-(5-chloro-lH- benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)phenyl)acetic acid or 2-(4-((5-(3-fluoro-4-(5- (trifluoromethyl)- 1 H-benzo [d] imidazol-2-yl)phenyl)pyrimidin-2-yloxy)methyl)phenyl)acetic acid, starting from 5-(6-chloro-lH-benzimidazol-2-yl)-6'-fluoro-2,3'-bipyridine or 2-(2-fluoro-4- (2-(methylsulfinyl)pyrimidin-5-yl)phenyl)-5-(trifluoromethyl)-lH-benzo[d]imidazole and appropriate hydroxyl containing starting materials.

3-(5-(4-(5-cvano-lH-benzord1imidazol-2-yl -3-fluorophenyl pyridin-2-yloxy -2,2- dimethylpropanoic acid

Method 1 : To a solution of methyl 3-(5-(3-fluoro-4-formylphenyl)pyridin-2-yloxy)-2,2- dimethylpropanoate (50 mg, 0.151 mmol, leq) and 3,4-diaminobenzonitrile (40 mg, 0.302 mmol,

2 eq) in 2% HOAc/DMF (1.5 mL) was added Oxone (55 mg, 0.091mmol, 0.6 eq). The reaction was shaked at 80°C for 16 hr. LC-MS showed that the reaction was completed. The reaction was neutralized with K2CO3 (60 mg) and was filtered. 2.5 N LiOH/FLO (1 mL, 2.5 mmol) was added to the solution. The resulting reaction mixture was shaked at ambient temperature for 4 hrs. LC-MS showed that the hydrolysis was completed. HOAc (0.1 mL) was added to adjust the pH = 5. The solution was concentrated in vacuum and the residue was extracted between EtOAc (4 mL x 2) and water (2 mL). The organic phase was combined and evaporated. The residue was dissolved in DMSO (1.5 mL) and filtered. The crude product was purified by using reversed- phase HPLC (acetonitrile with 0.1% ammonium hydroxide: water with 0.1% ammonium hydroxide from 10% to 90%) to give the product as a yellow solid. LC-MS Found: 431 [M+H]⁺

Method 2: Step A:

Methyl 3-(5-(4-(5-cvano-lH-benzord1imidazol-2-yl)-3-fluorophenyl)pyridin-2-yloxy)-2,2- dimethylpropanoate

A mixture of methyl 3-(5-(3-fluoro-4-formylphenyl)pyridin-2-yloxy)-2,2- dimethylpropanoate (2.0 g, 6.04 mmol) and 3,4-diaminobenzonitrile (0.804 g, 6.04 mmol) in DMF (18.3 ml) and Water (1.83 ml) at RT was treated with potassium peroxymonosulfate (2.41 g, 3.92 mmol).The reaction mixture was stirred at RT for 1 h, and pourred into NaHCC (sat.), extracted with EtOAc, dried and concentrated, separated by MPLC (10-100% EtOAc in Hexane) to give 1.9 g solid (LC-MS showed it is not pure), which was separated again [separated condition: 4.6 x 250 mm ChiralPak IA, 2.4 mL/min, 100 bar, 40% (2: 1 MeOH: MeCN)/ C02] to give methyl 3-(5-(4-(5-cyano-lH-benzo[d]imidazol-2-yl)-3-fluorophenyl)pyridin-2-yloxy)-2,2- dimethylpropanoate (1.4 g). LC-MS (ES, m/z) C₂5H₂₁FN₄0₃: 444; Found: 445 [M+H]⁺ _.

Step B:

3-(5-(4-(5-cvano-lH-benzord1imidazol-2-yl)-3-fluorophenyl)pyridin-2-yloxy)-2,2- dimethylpropanoic acid

To a solution of methyl 3-(5-(4-(5-cyano-lH-benzo[d]imidazol-2-yl)-3- fluorophenyl)pyridin-2-yloxy)-2,2-dimethylpropanoate (700 mg, 1.58 mmol) in THF/H₂O (4: 1, 15 ml) was added Lithium hydroxide monohydrate (330 mg, 7.87 mmol). ). After stirred at 40°C for over weekend, the organic solvent was removed. The aqueous was acidified with TFA, and concentrated. The residue was dissolved in DMSO (10 ml) filtered and diluted with

DMSO/AcCN/H20 (2: 1 : 1, 14 ml), then purified by Gilson ( 20- 100% AcCN in H₂0 containing 0.05% TFA in 18 min linear, flow rate 30 ml/min, injection 1 ml). The desired fractions were collected and lyophilized to give 3-(5-(4-(5-cyano-lH-benzo[d]imidazol-2-yl)-3- fluorophenyl)pyridin-2-yloxy)-2,2-dimethylpropanoic acid (0.32 g ). LC-MS (ES, m/z)

C₂₄Hi₉FN₄0₃: 430; Found: 431 [M+H]⁺.

Examples 107-115 Prepared following the procedure described for Methold 1 of 3-(5-(4-(5-cyano-lH- benzo[d]imidazol-2-yl)-3-fluorophenyl)pyridin-2-yloxy)-2,2-dimethylpropanoic acid, starting from the appropriate aldehyde and diamines.

Examples 1 16-124

Prepared following the procedure described for Methold 1 of 3-(5-(4-(5-cyano-lH- benzo[d]imidazol-2-yl)-3-fluorophenyl)pyridin-2-yloxy)-2,2-dimethylpropanoic acid, starting from the appropriate aldehyde and diamines.

Examples 125- 135

Prepared following the procedure described for Methold 1 of 3-(5-(4-(5-cyano- lH- benzo[d]imidazol-2-yl)-3-fluorophenyl)pyridin-2-yloxy)-2,2-dimethylpropanoic acid, starting from the appropriate aldehyde and diamines.

Examples 136-139

Prepared following the procedure describe for Methold 2 of 3-(5-(4-(5-cyano-lH- benzo[d]imidazol-2-yl)-3-fluorophenyl)pyridin-2-yloxy)-2,2-dimethylpropanoic acid, starting from the appropriate aldehydes and diamines.

Example 140

3 -(5 -(5 -chloro- 1 H-benzo Tdl imidazol-2-ylV5'-methyl-2.3 '-bipyridin-6'-yloxyV2.2-dimethylpropanoic acid To a 50 ml vial was added NaH (49 mg, 1.231 mmol, 3.0 equiv 60%) dissolved in DMA

(3.0 mL), among with 3-hydroxy-2,2-dimethylpropanoic acid (53 mg, 0.451 mmol, 1.1 equiv) and 6-chloro-2-(6'-fluoro-5'-methyl-2,3'-bipyridin-5-yl)- lH-benzo[d]imidazole (139 mg, 0.41 mmol, 1.0 equiv). The reaction mixture was MW at 150° C for 1 :30 h. The mixture was

quenched with H₂0 and purified by RP HPLC with loading as a solution of DMSO:H20:ACN, 20 to 80% ACN in H₂0 to give product 3-(5-(5-chloro-lH-benzo[d]imidazol-2-yl)-5'-methyl- 2,3'-bipyridin-6'-yloxy)-2,2-dimethylpropanoic acid. LC-MS (ES, m/z) C₃₁H₂₆F_{2 4}O₂: 436;

Found: 437 [M+H]⁺.

Examples 141 and 142 Prepared following the procedure described above for 3-(5-(5-chloro-lH- benzo[d]imidazol-2-yl)-5'-methyl-2,3'-bipyridin-6'-yloxy)-2,2-dimethylpropanoic acid.

Example 143

5-r4'-(5-Trifluoromethyl-lH-benzoimidazol-2-yl)-biphenyl-4-yll-oxazolidine-2.4-dione

Step A 5-(4-Bromo-phenyl)-oxazolidine-2,4-dione

Into a 2000 ml 3-necked round bottom flask, was charged with a solution of ethyl 2-(4- bromophenyl)-2-hydroxyacetate (120 g, 463.14 mmol, 1.0 equiv) in EtOH (1200 ml) and urea (27.8 g, 463.33 mmol, 1.00 equiv). To the mixture was added EtONa (31.5 g, 463.24 mmol, 1.0 equiv). The resulting solution was stirred for 2 hours while the temperature was maintained at 90 degrees C in an oil bath. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was extracted five times with 300 ml of EtOAc and the organic layers were combined. The combined organic extract was washed three times with 100 ml of H₂O. The residue was purified by chromatography on a silica gel column eluting with a 1 :5 EtO Ac/pet-ether. This resulted in 50.78 g (41% yd) of 5-(4-bromophenyl)oxazolidine-2,4-dione as a white solid. LC-MS (ES, m/z): C₉H₅BrN0₃: 255; Found: 256 [M+H]⁺. ¹HNMR: (300MHz, CDCI₃, ppm): 512.169(lH,s), 7.626(2H,d), 7.350(2H,d), 6.030(lH,s).

Step B 5-r4'-(5-Trifluoromethyl-lH-benzoimidazol-2-yl)-biphenyl-4-yl1-oxazolidine-2,4-dione

To a microwave vial was charged with 2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]-5-(trifluoromethyl)-lH- benzimidazole (100 mg, 0.258 mmol), 5-(4-Bromo-phenyl)- oxazolidine-2,4-dione (73 mg, 0.283 mmol), Pd(dppf) C12 (9 mg, 0.013 mmol), cesium carbonate (168 mg, 0.515 mmol), DMF (2ml), flushed with nitrogen and heated to 80 °c overnight. The crude product mixture was concentrated and purifed by HPLC on a 30X100 mm, Waters Sunfire C-18 RP column, 5μ particle size, linear gradient, 5% MeCN/H20 (containing 0.1% TFA) to 90% MeCN/H20 (containing 0.1% TFA) at 50 mL/min over 15 min . The product was collected and concentrated to give 15 mg white solids. LC-MS (ES, m/z): C2₃H14F₃O₃ : 437; Found: 438 [M+H]⁺.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I):

or pharmaceutical salt thereof, wherein V, U, W, X and Y are independently selected from the group consisting of -N- and -CH-;

R¹, R², R³ and R⁴ are each present at one of more at the ring carbons and are independently selected from the group consisting of hydrogen, halogen, -CN, halogen- substitutedCi-C₆alkyl, Ci-C₆alkyl,

and Ci-C₆alkoxy, or taken together R⁴ and Z form a pyrole, C3-C₆cycloalkyl, unsubstituted or substituted with -COOH, Ci-C₆alkyl;

Z is selected from the group consisting of:

hydrogen,

-OH,

-COOH,

COCi-C₆alkyl,

-Ci-C₆alkylCOOH,

-Ci-C₆alkyl,

halogen-substitutedCi-C₆alkyl,

-Ci-C₆alkoxy,

halogen-substitutedCi-C₆alkoxy,

-OCi-C₆alkylCOOH,

-OCi-C₆alkylphenyl,

-OphenylCi-C₆alkylCOOH,

-OCi-C₆alkylphenylCi-C₆alkylCOOH,

-OCi-C₆alkylphenylCOOH,

-OphenylCOOH,

-OnaphylCOOH,

phenyl,

piperidine,

piperidineCOOCi-C₆alkyl,

-OCi-C₆alkyl pyridineCOOH,

-ObenzimidizoleCOOH,

-OCi-C₆alkylthieneCOOH, pyridine,

pyrollodiol,

S0₂NHCi-C₆alkylCOOH,

S0₂Ci-C₆alkyl,

S0₂Ci-C₆alkylphenylCOOH,

S0₂Ci-C₆alkylCOOH,

S0₂Ci-C₆alkylCOOCi-C₆alkyl,

-CN,

-OCi-C₆alkylCN,

-NH₂,

-CONH₂,

-CONHCi-C₆alkyl,

-OCi-C₆alkylN(Ci-C₆alkyl)₂,

CONCd-Cealkyl),,

CONHCi-C₆alkylOH,

NHCOCi-C₆alkylCOOH,

NHCi-C₆alkylCOOH,

NHCi-C₆alkylphenylCOOH,

NHCi -CgalkylphenylCi -C₆alkylCOOH,

NHCi-C₆alkylphenylCOOH,

NHS0₂Ci-C₆alkyl,

-SCi-C₆alkylCOOCi-C₆alkyl, and

-SCi-C₆alkylCOOH.

2. A compound of claim 1 or pharmaceutically acceptable salt thereof, wherein V

-N-.

3. A compound of claim 1 or pharmaceutically acceptable salt thereof, wherein V is

CH-.

4. A compound of claim 1 or pharmaceutically acceptable salt thereof, wherein X is

CH-.

5. A compound of claim 1 or pharmaceutically acceptable salt thereof, wherein X is

-N-.

6. A compound of claim 1 or pharmaceutically acceptable salt thereof, wherein Y is

-N-.

7. A compound of claim 1 or pharmaceutically acceptable salt thereof, wherein Y is - CH-.

8. A compound of claim 1 or pharmaceutically acceptable salt thereof, wherein U is

-N-.

9. A compound of claim 1 or pharmaceutically acceptable salt thereof, wherein U is

- CH-.

10. A compound of claim 1 or pharmaceutically acceptable salt thereof, wherein W is

-N-.

11. A compound of claim 1 or pharmaceutically acceptable salt thereof, wherein W is

- CH-.

12. A compound of any one of claims 1-1 1 or pharmaceutically acceptable salt thereof wherein R¹ is halogen-substitutedCi-C₆alkyl.

13. A compound of any one of claims 1-12 or pharmaceutically acceptable salt thereof wherein R² is hydrogen.

14. A compound of any one of claims 1-13 or pharmaceutically acceptable salt thereof wherein R³ is hydrogen.

15. A compound of any one of claims 1 - 14 or pharmaceutically acceptable salt thereof wherein R⁴ is hydrogen.

16. A compound of any one of claims 1-14 or pharmaceutically acceptable salt thereof wherein Z is -OCi-C₆alkylCOOH.

17. A compound or pharmaceutically acceptable salt thereof selected from the group

-75 -

-76-

-79-

-80-

-81 -

18. A pharmaceutical composition comprising a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. Use of a compound of any one of claims 1-17, 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.

20. 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 1-17.

21. A compound according to claim 1 for use in therapy.