WO2012096813A1 - Imidazole derivatives - Google Patents

Abstract

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

Description

IMIDAZOLE DERIVATIVES

TECHNICAL FIELD

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

BACKGROUND

Obesity is a medical condition i 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, 111, 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

A compound of formula (I):

or pharmaceutically acceptable salts thereof, wherein U, X, R , R , R , R , R , R , R , m and n are described herein. 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.

DETAILED DESCRIPTION OF THE INVENTION

Compounds

Described herein are compounds of formula (I):

or pharmaceutically acceptable salts thereof, wherein U is selected from the group consisting of- N- and -CH-, wherein the hydrogen can be replaced with any one of R¹, R², R³ or R⁴;

X is selected from the group consisting of -CH₂-, -O- and -NH-, wherein any one of the hydrogens can be replaced with any one of R⁵, R⁶ or R⁷;

R¹ is selected from the group consisting of halogen, Cs-Cgalkyl, halogen-substitutedCr C₆alkyl, -OCs-C₆alkyl, -Ohalogen-substitutedCi-C₆alkyl, -CN, C_rC₆alkylCN and -S0₂C_r Cealkyl;

R², R³, R⁴ and R⁵ are independently selected from the group consisting of hydrogen, halogen, -COOH and C_rC₅alkyl;

R⁶ and R⁷ are independently selected from the group consisting of hydrogen, halogen, Ci~ C₆alkyl, halogen-substitutedCi-C₆alkyl, ~COCi-C₆alkyl, -COC_rC₆alkylCOOH, COhalogen- substitutedCj-Cgalkyl, -OH, CrC₆alkylOH, halogen-substitutedC_rC₆alkylOH, -OQ -Cealkyl, - Ohalogen-substitutedCi-Cealkyl, -COOH, -COOC_rC₆alkyl, -C_rC₆alkylCOOC C₆alkyl, -Q- CgalkylCOOH, -OC_-C₆alk lCOOH, -CN, Ci-C₆alkylCN, -CONH₂, -CONHC C₆alkyl, -

CON(C_-C₆alkyl)_2i C_rC₆alkylCONR⁸R⁹, Ci-C₆alkylpyridine, C_rC₆alkylthiazole, oxazolidone, phenyl and Ci-Gsalkylphenyl, wherein the phenyl is unsubstituted or substituted with -CN, halogen or -COOH; or when taken together R⁶ and R⁷ form cyclohexane, phenyl or a 4-6 membered, nitrogen-containing ring, wherein the cyclohexane, phenyl or a 4-6 membered, nitrogen-containing ring are unsubstituted or substituted with -COOH, C Cealkyl or -C|- C₆alkylCOOH;

R⁸ and R⁹ are independently selected from the group consisting of hydrogen, halogen, C_t- C₆alkyl, halogen-substitutedCi-C₆alkyl, Cj-CealkylOd-Cealkyl, C_rC₆alkylCOOH,

cyclopropylCOOH and C3-C₆cycloalkyl, or when taken together R⁸ and R⁹ and the nitrogen on which they are attached form azetidine, pyrrolidine, morphiline or piperdine, wherein the azetidine, pyrrolidine or piperdine is unsubstituted or substituted with one or two substituents selected from the group consisting of -OH, -OCj -Cealkyl and halogen; and

m and n are independently 1 or 2.

In certain embodiments described herein, m is 1. In other embodiments, m is 2. In other embodiments described herein, n is 1. In still other embodiments, n is 2. For example, in one embodiment m and n are both 1. In another embodiment, m is 2 and n is 1. In yet another embodiment, m and n are both 2. In still another embodiment, m is 1 and n is 2.

Also described herein are compounds or pharmaceutically acceptable salts thereof having formula la, formula lb or formula Ic:

In certain embodiments described herein, X is -0-. In other embodiments, X is -CH₂-.

In still other embodiments, X is -C¾-, wherein one or both of the hydrogens can be replaced with any one of R⁵, R⁶ or R⁷. In one embodiment, X is -CHR⁵-. In yet another embodiment, X is -CHR⁶-. In still another embodiment, X is -CR⁶R⁵-. In other embodiments, X is -CR⁶R⁷-.

In certain embodiments described herein, X is-NH-. In other embodiments, X is -NH-, wherein the hydrogen can be replaced with any one of R⁵, R⁶ or R⁷ In certain embodiments, X is-NR⁵-. In other embodiments, X is-NR⁶-. In yet other embodiments, X is-NR⁷-, Of the compounds described herein, each occurrence of U is independently selected from the group consisting of ~N- and -CH-. In certain embodiments, each occurrence of U is independently selected from the group consisting of -N- and-CH-, wherein when U is -CH- the

R¹

In other embodiments of the compounds described herein, the moeity

is selected from the group consisting of:

In such embodiments, R can replace any available hydrogen on the left-hand ring and R⁴ can replace any of the available hydrogen on the right-hand ring.

In certain embodiments of the compounds described herein, the moiety:

Of the compounds described herein, R is selected from the group consisting of halogen, Ci-Cealkyl, halogen-substitutedCi-Cgalkyl, -OC C_Galk l, -Ohalogen-substitutedCs-Csalkyl, - CN, Ci-CsalkylCN and -SOiCrCgalkyi. In certain embodiments, R¹ is selected from the group consisting of trifluoromethyl, trifluoromethoxy, methoxy, fluorine, iodine, chlorine, -CN and - SOjMe. In one embodiment, R¹ is halogen. In another embodiment, R^] is Ci-C₆alkyl or halogen-substltatedCi-C_fialkyl. In yet another embodiment, R¹ is -OCj-Cfialkyl or -Ohalogen- substitutedCi-C₆alkyl. In still another embodiment, R¹ is -CN, Ci-CgalkylCN or -S0₂Ci-C₆alkyl.

Of the compounds described herein, R² is selected from the group consisting of hydrogen, halogen, -COOH and Ci-C₆alkyl. In certain embodiment, R² is hydrogen or halogen. In some embodiments, R² is hydrogen. In other embodiments, R² is halogen. Suitable halogens, but are not limited to, chlorine, fluorine, iodine and bromine.

Of the compounds described herein, R³ is selected from the group consisting of hydrogen, halogen, -COOH and Ci-Qalkyl. In certain embodiment, R³ is hydrogen or halogen. In some embodiments, R³ is hydrogen. In other embodiments, R³ is halogen. Suitable halogens, but are not limited to, chlorine and fluorine.

Of the compounds described herein, R⁴ is selected from the group consisting of hydrogen, halogen, -COOH and CrCgalkyl. In certain embodiment, R⁴ is hydrogen, Cj-Cgalkyl or halogen. In other embodiment, R⁴ is hydrogen, methyl or halogen. In some embodiments, R⁴ is hydrogen. In other embodiments, R⁴ is halogen. Suitable halogens, but are not limited to, chlorine, fluorine, iodine and bromine. In still other embodiments, R⁴ is Ci-Cealkyl. Suitable halogens, but are not limited to, methyl.

Of the compounds described herein, R⁵ is selected from the group consisting of hydrogen, halogen, -COOH and Ci-C₆alkyl. h certain embodiment, R⁵ is hydrogen, Ci-C₆alkyl or COOH. In other embodiment, R⁵ is hydrogen, methyl or COOH. In some embodiments, R^s is hydrogen, in other embodiments, R⁵ is COOH. In still other embodiments, R⁵ is Ci-C₆alkyl. Suitable halogens, but are not limited to, methyl.

Of the compounds described herein, R⁶ and R⁷ are independently selected from the group consisting of hydrogen, halogen, Ci-C₆alkyl, halogen-substitutedCi-C^alkyl, -COCi-Cgalkyl, - COCi-C₆alkylCOOH, COhalogen-substitutedC C₆alkyl, -OH, Ci-C₆alkylOH, halogen- substitutedCi~C₆alkylOH, -OC_t-C₆alkyl, -Ohalogen-substitutedCL-Cealkyl, -COOH, -COOQ- Cealkyl, -Q-OsalkylCOOd-Cealkyl, -C C₆alkylCOOH, -OC,-C₆alkylCOOH, -CN, C

QalkyiCN, -CONH_¾ -CONHCi-Qalkyl, -CON(Cs-C₆alkyl)₂₅ C_rC₆alkylCONR⁸R⁹, C

Cgalkylpyridine, Ci-C₆alkylthiazole, oxazolidone, phenyl and C Cealk lphen l, wherein the phenyl is unsubstituted or substituted with -CN, halogen or -COOH; or when taken together R⁶ and R⁷ form cyclohexane, phenyl or a 4-6 membered, nitrogen-containing ring, wherein the cyclohexane, phenyl or a 4-6 membered, nitrogen-containing ring are unsubstituted or substituted with -COOH, Cj-Csalkyl or -Ci-C₆alkylCOOH.

Of the compounds described herein, R⁶ is selected from the group consisting of hydrogen, halogen, Ci-C₆alkyi, halogen-substitutedC_rC₆alkyl, -COC_rC₆alkyL -COC^CgalkylCOOH, COhalogen-substitutedCs-Cealkyl, -OH, C C₆alkylOH, halogen-substitutedCrCealkylOH, - OCi-Cealkyl, -Ohalogen-substitutedCi-C₆alkyl, -COOH, -COOCi-C₆alkyl, -C_rC₆alkylCOOCi- Qalkyl, -C₁-C₆alkylCOOH, -OCi-C₆alkylCOOH, -CN, Ci-C₆alkylCN, -CONH_2} -CONHCi- Csalkyl, -CON(C_rC₆alkyl)₂, C_rC₆alkylCONR¾⁹, d-C₆alkylpyridine, C C₆alkylthiazole, oxazolidone, phenyl and d-Qalkylphenyl, wherein the phenyl is unsubstituted or substituted with -CN, halogen or -COOH. In certain embodiments, R⁶ is selected from the group consisting of hydrogen, halogen, C_rC₆alkyl, -COCi-C₆alkylCOOH, -OH, -COOH, -COOd-C₆alkyl, -Ci- CealkylCOOCi-Cealkyl, -C_rC₆alkylCOOH, -OCi-C₆alkylCOOH, -CN, -CONHCi-Cealkyl, C,- Cgalkylpyridine, CrQalkylthiazole, oxazolidone, phenyl and Ci-Qalkylphenyl, wherein the phenyl is unsubstituted or substituted with -CN, halogen or -COOH. In certain embodiments, R⁶ is hydrogen. In other embodiments, R⁶ is phenyl. In still other embodiments, R⁶ is C_r Cealkylphenyl. In certain embodiments, the phenyl is unsubstituted. In other embodiments, the phenyl is substituted with with -CN, halogen or -COOH. In still other embodiments, R⁶ is selected from the group consisting of -COOH, -COOCi-C₆alkyl, -Ci-CealkylCOOCi-Cealkyl, - Ci-C₆alkylCOOH and -OC C₆alkylCOOH.

In certain embodiments of the compounds described herein, R⁶ is C[-C6alkylCONR⁸R⁹, wherein R⁸ and R⁹ are independently selected from the group consisting of hydrogen, halogen, Ci-Qalkyl, halogen-substitutedCj-C₆alkyl, C-C^aikylOC-Cealkyl, Ci-C₆aikylCOOH, cyclopropylCOOH and Cs-Cecycloaikyl, or when taken together R and R and the nitrogen on which they are attached form azetidine, pyrrolidine, morphiline or piperdine, wherein the azetidine, pyrrolidine or piperdine is unsubstituted or substituted with one or two substituents selected from the group consisting of -OH, -OCrC₆alkyl and halogen. In one embodiment, R⁶ is CH₂CONR⁸R⁹. In another embodiment, R⁶ is (CH₂)₂CONR⁸R⁹. In yet another embodiment, R⁶ is (CH₂)₃CONR⁸R⁹. In still another embodiment, R⁶ is (CH₂)₄CONR⁸R⁹.

Of the compounds described herein, R⁸ is hydrogen, halogen, C Cgalkyl, halogen- substitutedCi-C₅alkyl, Ci-C₆alkylOCi-C₆alkyl, Ci-C₆alkylCOOH, cyclopropylCOOH or C₃- Cgcycloalkyl. In one embodiment, R is hydrogen. In another embodiment, R is halogen. Suitable halogens include, but are not limited to, fluorine. In another embodiment, R⁸ is Cj- Cealkyl. Suitable Q-Qalkyls include, but are not limited to, methyl, ethyl and propyl. In another embodiment, R⁸ is halogen-substitutedCi-Cealkyl. Suitable halogen-substitutedCi-

Csalkyls include, but are not limited to, trifiuoromethoxy. In yet another embodiment, R⁸ is C_r CsalkylOCi-C_fsalkyl. In still another embodiment, R^s is Q-CealkylCOOH. In still another embodiment, R⁸ is cyclopropylCOOH. In another embodiment, R⁸ is C3-C₆cycloalkyl. Suitable C₃-C₆cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Of the compounds described herein, R⁹ is hydrogen, halogen, d-Qalkyl, halogen- substitutedCi-Cealkyl, Ci-C₆alkylOCi-C₆alkyl_> C_rC₆alkylCOOH, cyclopropylCOOH or C₃- Qcycloalkyl. In one embodiment, R⁹ is hydrogen. In another embodiment, R⁹ is halogen.

Suitable halogens include, but are not limited to, fluorine. In another embodiment, R⁹ is Cp Qalkyl. Suitable Cj-Cealkyls include, but are not limited to, methyl, ethyl and propyl. In another embodiment, R⁹ is halogen-substitutedCi-Cealkyl. Suitable halogen-substitutedCp Qalkyls include, but are not limited to, trifluoromethoxy. In yet another embodiment, R⁹ is d- QalkylOCrCealkyl. In still another embodiment, R⁹ is Ci~C₆alkyICOOH. In still another embodiment, R⁹ is cyclopropylCOOH. In another embodiment, R⁹ is C₃-C₆cycloaikyL Suitable C₃-C<;cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments of the compounds described herein, when taken together R⁸ and R⁹ and the nitrogen on which they are attached form azetidine, pyrrolidine, morphiline or piperdine, wherein the azetidine, pyrrolidine or piperdine is unsubstituted or substituted with one or two substituents selected from the group consisting of -OH, -OCi-C₆alkyl and halogen. In one embodiment, when taken together R⁸ and R⁹ and the nitrogen on which they are attached form azetidine. In certain embodiment, the azetidine is unsubstituted. In other embodiments the azetidine is substituted with -OH. In one embodiment, when taken together R⁸ and R⁹ and the nitrogen on which they are attached form pyrrolidine. In certain embodiment, the pyrrolidine is unsubstituted. In other embodiments the pyrrolidine is substituted with one or two substituents selected from the group consisting of -OH, methoxy and fluorine. In one embodiment, when taken together R⁸ and R⁹ and the nitrogen on which they are attached form piperdine. In certain embodiment, the piperdine is unsubstituted. In other embodiments the piperdine is substituted with one or two substituents selected from the group consisting of -OH, methoxy, flourine. In one embodiment, when taken together R⁸ and R⁹ and the nitrogen on which they are attached form morphiline. In certain embodiment, the morphiline is unsubstituted.

Of the compounds described herein, R⁷ is selected from the group consisting of hydrogen, halogen, Ci-C₆alkyl, halogen-substitutedCt-Qalkyl, -COC_rC₆alkyl, -COQ-CealkylCOOH, COhalogen-substitutedCi-Cgalkyl, -OH, Cj-C₆alkylOH, halogen- substitutedd-dalkyiOH, - OCi-C₆alkyl, -Ohalogen-substitutedC_rC₆alkyl, -COOH, -COOC_rC₆alkyl, -C, -C₆alkylCOOd- Qalkyl, -Ci-C₆alkylCOOH, -Od-CealkylCOOH, -CN, Ci-C₆alkyICN, -CONH₂, -CONHCp C₆alkyl, -CON(C_rC₆aIkyl)₂, Ci-C₆alkyiCONR⁸R⁹, d-Qalkylpyridine, Ci-C₆alkyIthiazole, oxazolidone, phenyl and CrCealkylphenyl, wherein the phenyl is unsubstituted or substituted with -CN, halogen or -COOH. In certain embodiments, R⁷ is selected from the group consisting of hydrogen, halogen, Q-Cgalkyl, -OH, -COOH. In some embodiment, of the compounds described herein, R⁷ is hydrogen. In other embodiments, R⁷ is halogen. Suitable halogens include, but are not limited to, chlorine and fluorine. In other embodiments, R⁷ is C Ceaikyl. Suitable Q-Qalkyls include, but are not limited to, methyl.

In certain embodiments of the compounds described herein, R⁷ is Ci-C₆alkylCONR⁸R⁹, wherein R⁸ and R⁹ are independently selected from the group consisting of hydrogen, halogen, CrC₆alkyl, halogen-substitutedQ-Qalkyl, Cj -C₆alkylOC_rC₆alkyl, C_rC₆alkylCOOH, cyclopropylCOOH and C3-C₆cycloalkyl, or when taken together R⁸ and R⁹ and the nitrogen on which they are attached form azetidine, pyrrolidine, morphiline or piperdine, wherein the azetidine, pyrrolidine or piperdine is unsubstituted or substituted with one or two substituents selected from the group consisting of -OH, -OC[-C₆alkyl and halogen. In one embodiment, R⁷ is CH₂CONR⁸R⁹. In another embodiment, R⁷ is (CH₂)₂CONR⁸R⁹. In yet another embodiment, R⁷ is (CH₂)₃CONR⁸R⁹. In still another embodiment, R⁷ is (CH₂)₄CONR⁸R⁹. Further embodiments of R and R are discussed above.

Additionally, when taken together, R⁶ and R⁷ may form cyclohexane, phenyl or a 4-6 membered, nitrogen-containing ring. In certain embodiment, the cyclohexane, phenyl or a 4-6 membered, mtrogen-containing ring are unsubstituted. In other embodiments, the cyclohexane, phenyl or a 4-6 membered, nitrogen-containing ring are substituted with -CO OH, C_rC_<$alkyl or - Ci-CgalkylCOOH. In certain embodiments, when taken together R and R from cyclohexane, phenyl, imidazole, azetidinone, piperidinone or oxazolidinedione. In certain embodiment, the cyclohexane, phenyl, imidazole, azetidinone, piperidinone or oxazolidinedione are unsubstituted. In other embodiments, the cyclohexane, phenyl, imidazole, azetidinone, piperidinone or oxazolidinedione are substituted with -COOH, CrCgalkyl or -Ci-QalkylCOOH.

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Definitions

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

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

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

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

The term "-Ohalogen-substitutedCi-Cealkyl" means a -OC_rC₆alkyl 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 "-COCrQalkyl" means groups having Cj-Qalkyl bonded to carbonyl, and encompasses alk lcarbonyl having a carbon number of 1 to 6. Specific examples thereof include acetyl, propionyi, butyryl, isobutyryl, valeryi, isovaleryl, pivaloyl, and the like.

The term "-COhalogen-substitutedCi-Qalky means a -COC]-C₆alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different.

The term "C C₆alkylOH" means a Ci-Cgalkyl substituted with an alcohol (-OH). Examples include methanol, propanol, butanol and t-butanol.

The term "Ci-CgalkylCN" means a Ci-Qalkyl substituted with an cyano group (-CN).

The term "halogen-substituted Ci-C₃alkylOH" means a halogen-substituedCl-C6alkyI substituted with an alcohol (-OH).

The term "COOCi-Cealkyl" means a -COOH group wherein the -OH is replaced with an alkoxy group as defined above. Examples include methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

The term

means a group having CrCealkyl bonded to sulfonyl (-S0₂-). Specific examples thereof include methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, sec-butanesuifonyl, tert-butanesulfonyl, and the like.

The term "NHCOCi-C₆alky]" means a group with one of the amino hydrogen atoms being substituted with Q.g alkylcarbonyl. Specific examples thereof include acetylamino, propionylamino, isobutyryl amino, valerylamino, isovalerylamino, pivaloylammo, and the like.

The term "CON(Ci-C₆aIk l)₂" means a group with the two carbamoyl hydrogen atoms each being substituted with Ci_6 alkyl. Specific examples thereof include dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, di(n-propyI)carbamoyi, methyl(n-propyl)carbamoyl, diisopropylcarbamoyl, and the like.

The term "4-6-membered nitrogen containing heterocycle" means a 4, 5 or 6-membered ring containing at least one nitrogen atom. Examples thereof include pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, 1 ,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyi, quinazolinyl, cinnolinyl, piperidinyl, pyrido[3,2- bjpyridyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3- dihydrofuro(2,3-&)pyridyl, azetidinonyl, piperidinonyl or oxazolidinedionyl and the like.

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, glutaraate, glycollylarsanilate, hexyiresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, ethylbromide, 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, diethylarnine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolaraine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, giucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

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

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

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

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

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

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

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

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

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

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

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

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

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 patients in need thereof. The treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.

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

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

More particularly, another aspect of the invention that is of interest relates to a method of treating type 2 diabetes in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat type 2 diabetes.

Yet another aspect of the invention that is of interest relates to a method of treating non- insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effecti ve to treat non- insulin dependent diabetes mellitus. The present invention is also directed to the use of a compound of structural formula I, formula la, formula lb or formula Ic in the manufacture of a medicament for use in treating vaiious DGATl-related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis. The compounds described herein are especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety.

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

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

Pharmaceutical Compositions

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

In clinical use of the compound of the invention, 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 arable, 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 patient and on the type and the range of the intended remedial effect. In general, when orally administered, the dose may be from 0.001 to 50 mg/kg of body weight/day, and it may be administered at 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, formula la, fonnuia lb or formula Ic or the other drugs may have utiliiy, 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 fonnuia I, formula la, formula lb or formula Ic. When a compound of formula I, formula la, formula lb or formula Ic 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, formula la, formula lb or formula Ic is preferred. However, the combination therapy may also include therapies in which the compound of formula I, formula la, formula lb or formula Ic 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, formula la, formula lb or formula Ic.

Examples of other active ingredients that may be administered in combination with a compound of formula I, formula la, formula lb or formula Ic, and either administered separately or in the same pharmaceutical composition, include, but are not limited to:

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

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

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

(4) leptin and leptin derivatives and agonists;

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

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

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

(8) glucagon receptor antagonists, such as those disclosed in WO 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, such as exenatide, liraglutide, taspoglutide, AVE0010, 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 (lovastatin, simvastatin, pravastatin, cenvastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl Co A: cholesterol acyltransf erase inhibitors, such as avasimibe;

(11) 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-3 antagonist MK-524; and nicotinic acid receptor agonists;

(12) antiobesity compounds;

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

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

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

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

(17) inhibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib and MK-0859; (18) inhibitors of fructose 1 ,6-bisphosphatase, such as those disclosed in U.S. Patent Nos.

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

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

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

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

(22) SSTR3 antagonists, such as those disclosed i WO 2009/0 Ϊ 1836;

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

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

(25) GPR-1 5 antagonists, such as those disclosed in WO 2009/000087;

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

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

2);

(28) inhibitors of fatty acid synthase;

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

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

(31 ) agonists of the TG 5 receptor (also known as GPBAR1 , BG37, GPCR19, GPR131 , and M- BAR); and

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

Dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of formula I, formula la, formula lb or formula Ic include, but are not limited to, sitagliptin (disclosed in US Patent No. 6,699,871), vildagliptin, saxagliptin, alogliptin, denagliptin, carmegliptin, dutogliptin, melogliptin, linagliptin, and pharmaceutically acceptable salts thereof, and fixed-dose combinations of these compounds with metformin hydrochloride, pioglitazone, rosiglitazone, simvastatin, atorvastatin, or a sulfonylurea.

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

(2 ?,35',5^)-5-(l -methyl-4,6-dihydropynOlo[3,4-c]pyrazol-5(lH)-yl)-2-(2,4,5- trifluorophenyl)tetrahydro-2H-pyran- 3 -amine;

(2i?,35,5i?)-5-(l -methyl-4_!6-dihydropyrrolo[3_i4-c]pyrazol-5(lH)-yl)-2-(2_J4,5- triiluorophenyl)tetrahydro-2H-pyran-3-amine;

(2R S,5R)-2-(2,5 -difluorophenyl)tetraliydro)-5-(4,6-dihydropyiTolo [3 ,4-c]pyrazol-5 ( 1 H)-yl)

tetrahydro-2H-pyran-3 -amine ;

(3J?)-4-[(3/?)-3-amino-4-(2,4,5-trifluorophenyl)butanoyI]-hexahydro-3-methyl-2H- 1 ,4-diazepin- 2-one;

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

(3i¾)-4-[(3i -3-amino-4-(2,4,5 riiluoro^^

diazepin-2-one; and

pharmaceutically acceptable salts thereof.

Antiobesity compounds that can be combined with compounds of formula I, formula la, formula lb or formula Ic 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;

CCK-1 agonists; melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Yi or Y5 antagonists (such as MK-0557); CBl receptor inverse agonists and antagonists (such as rimonabant and taranabant); 3 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/¹ Exp. Opin. Pharmacother., 10: 921-925 (2009).

Glucagon receptor antagonists that can be used in combination with the compounds of formula I, formula ia, formula lb or formula lc include, but are not limited to:

N-[4 (l$) -{3-(3,5-dichlorophenyl)-5-[6-(trifiuoromethoxy)-2-naphthyI]-lH-pyrazol-l - yl}ethyl)benzoyl]-P-alanine;

N-[4-(( 1 R)- 1 - { 3 -(3 ,5-dic orophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl] - 1 H-pyrazol- 1 - yl } ethyl)benzoyl]-p-alanine;

N-(4- { 1 - [3 -(2 , 5 -dichlorophenyl)-5 -(6-methoxy-2 -naphthyl) - 1 H-pyrazol- 1 -yljethyl } benzoyrj-β- alanine;

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

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

N-(4-{(l S)-l-[(4-chJorophenyl)(6-chloro-8-methylquinoHn-4-yl)methyl]butyl}benzoyl)-p- 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, formula Ia, formula lb or formula Ic include, but are not limited to:

[5-(5- (4- [2-(trifluoiOmethyl)phenoxy]piperidin- 3 -yl } - 1 ,3 ,4-thiadiazol-2 -yl)-2H-tetrazol-2- yl] acetic acid;

(2'-{4-[2-(trifiuoromethyl)phenoxy]piperidin- 1 -yl} -2,5'-bi~l ,3-thiazol-4-yl)acetic acid;

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

(3- {3-[4-(2-bromo-5-fluorophenoxy)piperidin- 1 -yl]- 1 ,2₃4-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.

Gmcokinase activators that can be used in combination with the compounds of formula I, formula la, formula lb or formula Ic include, but are not limited to: 3-(6-ethanesiilfonylpyridin-3-yloxy)-5-(2-hydroxy-l-methyl-ethoxy)-N-(l-methyl-lH-pyrazol-3- yl)benzamide;

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

5 -(1 -hydroxymethyl-propoxy)-3-(6-methanesulfonylpyridin-3 -yloxy)-N-( 1 -methyl- 1 H-pyrazol-3 - yl)benzamide;

3 -(6-methanesu lfonylpyridin-3 -yloxy)-5 -( 1 -methoxymethyl-prop xy)-N-( 1 -methyl- 1 H-pyrazol- 3-yl)benzarnide;

5 -isopropoxy- 3 -(6-me thanesulfonylpyridin-3 -yloxy)-N-( 1 -methyl- 1 H-pyrazol-3 -yl)benzami de; 5 -(2-fluoro- 1 -fluoromethyl-ethoxy)- 3 -(6-m ethanesulfony lpyridin-3-yloxy)-N-( 1 -methyl - 1 H- pyrazol- 3 -yl)benzamide;

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

3-({4-[(l-methylazetidin-3-yl)oxy]phenyl}t o)-N-(3-methyl-l,2,4-thiadia2ol-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-methylpyrrolidm-l-yl]eta

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, formula la, formula lb or formula Ic 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-cUoro-2-{4-[(lR,2S)-2-(2-{[5-(methylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidin- l-yl}pyrimidine;

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

5-chloro-2-[4-(( 1 S ₅2R)-2- (2- [4-(methylsulfonyl)phenoxy] ethyl } cyclopropyl) piperidin- 1 - yljpyrimidine;

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

rac c r 5-chloro-2- [4-(2- {2- [3 -(methylsulfonyl)phenoxyj ethyl } cyclopropyl)piperidin- 1 - yljpyrimidine; and

rac cis -5-chloro-2-[4-(2-{2-[3-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxyJethyl} cyclopropyl) piperidin- 1 -yljpyrimidine; and pharmaceutically acceptable salts thereof. Selective PPARy modulators (SPPARyM's) that can be used in combination with the compounds of formula I, formula la, formula lb or formula Ic 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;

(25)-2-({6-chloro-3-[6-C4-fluorophenoxy)-2-propyipyridin-3-yl]-l,2-benzisoxa2;ol-5- yl}ox propanoic acid;

(2S)-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] -1 ,2-benzisoxazol-5 - yl}oxy)propanoic acid;

(2R)-2- { 3 -[3-(4-methoxy)benzoyl-2-methyl-6-(trifiuoromethoxy)- 1 H-indol- 1 ~

yl]phenoxy}butanoic acid;

(2S)-2-{3-[3-(4-methoxy)berKoyl-2-methyl-6-(trifluoromethoxy)--lH-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

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

Inhibitors of 1 1 β-hydroxysteroid dehydrogenase type 1 that can be used in combination with the compounds of formula I, formula la, formula lb or formula Ic include, but are not

limited to:

3- [l-(4-chlorophenyl)-imw-3-fluorocyclobutyl]-4,5-dicycIopropyl-r--4H-l,2,4-triazole;3-[l-(4- chlorophenyl)-frao5'-3-fluorocyclobutyl]~4-cyclopropyl-5-(l-methylcyclopropyl)-r-4H-l,2,4- triazole;

3-[l-(4-chlorophenyl)-frans'-3-fluorocyclobutyl]-4-methyl-5-[2-(trifluoromethoxy)phenyl]-r~4H- 1,2,4-triazole;

3-[l-(4-chlorophenyl)cyclobutyl]-4-methyl-5-[2-(trifluoromemyl)phenyl]-4H-l,2,4-triazole;

3- {4-[3-(emylsulfonyl)propyl]bicyclo[2,2.2]oct-l-yl}-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H -1,2,4-triazole;

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

(3,3,3-trifluoropropyl)- 1 ,2,4-oxadiazole;

3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H.1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct- 1 -yl)-5- (S^jS-trifluoroethy^-l^^-oxadiazole; 5-(3,3-difiuorocyclobutyl)-3-(4-{4-me^

yl}bicyclo[2.2.2]ocM-yl)-l ,2,4-oxadiazole;

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

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

2-(3_f3-difiuorocyclobulyl)-5-(4-{4-methyI-5-[2-(trifluoromethyl)pheny]]-4H-l,2₅4 ri yl } bicyclo [2.2.2 ] oct- 1 -yl)- 1 ,3 ,4-oxadiazole ; and

5-(l , 1 -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 Ϊ, formula la, formula lb or formula Ic include, but are not limited to:

and pharmaceutically acceptable salts thereof.

AMP-activated Protein Kinase (AMPK) activators that can be used in combination with the compounds of formula I, formula la, formula lb or formula Ic include, but are not limited to:

and pharmaceutically acceptable salts thereof.

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

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

5-{l'-[(l-cyclopropyl-4-methoxy-lH-in^

yl} nicotinic acid;

l'-[(l-cyclopropyl-4-methoxy-lH-indol-6^

piperidin]-4-one;

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

5 - { - [( 1 -cyclopropyl-4-methoxy-3 -meth l- 1 H-indol-6-yl)carbonyl] -4-oxo- spiro [chroman^^¹- piperidm]-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, formula la, formula lb or formula Ic;

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

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

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

pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR ligands, including (1) PPAR /γ dual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPARa agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators (SPPARyM's), 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- 1 B (PTP- 1 B) inhibitors;

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

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

(5) glucagon receptor antagonists;

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

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

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

(8) antiobesity compounds;

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

(10) antihypertensive agents, such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapri.1), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta blockers (such as and calcium channel blockers (such as;

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

(12) inhibitors of 11 β-hydroxysteroid dehydrogenase type 1 ;

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

0859;

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

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

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

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

(18) SSTR3 antagonists;

(1 ) neuromedin U receptor agonists, including, but not limited to, neuromedin S ( MS);

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

(21) GPR-105 antagonists; (22) inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1; SGLT-2, such as 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 acetyl-CoA carboxylase-1 and 2 (ACC-1 and

ACC-2);

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

(27) agonists of the TGR5 receptor (also known as GPBA 1, BG37, GPCR19, GPRI 31 , and M-BAR); and

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

(c) a pharmaceutically acceptable carrier.

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

The weight ratio of the compound of the present invention to the second active ingredient may 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 method:

A (Exemplified by):

C (Exemplified by):

Intermediate 1

6-methoxyp yridine-2,3 -diamine

A 200 mL par-shaker vessel was charged with 6-methoxy~3-nitro-2-aminopyridine (1.5 g, 8.87 mmol), 10% palladium on carbon (800 mg, 0.752 mmol) and ethyl acetate. The mixture was put on par-shaker under 40 psi hydrogen for 2 hrs. The catalyst was then filtered and washed with ethyl acetate. The filtrate was concentrated to afford a dark color solid product 6- methoxypyridine-2_s3-diamine. LC-MS (ES, m/z); QH9N₃O: 139; Found: 140 [M+H .

Intermediate 2

4-(methylsulfonyl)benzene- 1 ,2-diamine To a solution 5-(methylsulfonyl)-2-nitroaniIme (1 g, 4.63 mmol) in EtOH (10 ml) was added Pd-C (10%wt, 0.54 g, 0.46 mmol). The system was vacuumed and refilled with hydrogen three times. Then the mixture was stirred at room temperature for 15 h under ¾ balloon. LC- MS showed complete conversion of starting material to product. The mixture was filtered through celite, washed with hot MeOH. The filtrate was concentrated to give the yellowish solid 4-(methylsulfonyl)benzene-l,2-diamine. LC-MS (ES, m/z) C₇H]oN₂0₂S: 186; Found: 187

[M+Hf,

hitermediate 3

2-(4-bromo-phenyi)-5-trifluoromethyl-lH-benzoimidazole

To solution of 4-Trifluoromethyl-benzene-l, 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 NaHC0₃ 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+Hf.

Intermediate 4

Performed as same as the synthesis of Intermediate 3 except 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]⁺. termediate 5

2-(4-bromo-2-fluorophenyl)-6-(trifiuoromethyl)- 1 H-benzimidazole

A 200 mL sample vial was charged with 4-bromo-2-fiuorobenzaldehyde (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 (3 ). 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-fluoropheny3)-6-(trifluoromethyl)-lH- benzimidazole. LC-MS (ES, m/z): Ci4H₇BrF₄N₂: 358; Found: 359 [M+Hf.

Intermediate 6

2-(6-bromopyridin-3-yl)-6-(trifluoromethyl)- 1 -H-benzimidazole Following the same procedure as Intermediate 3, 2-(6-bromopyridin-3-yl)-6- (trifluoromethyl)-l-H-benzimidazole was prepared as a solid. LC-MS (ES, m/z) Ci3H₇BrF₃N₃: 342; Found: 343 [M+H]⁺

Intermediate 7

2-(^'4.6-difluoropyridin-3-yD-6-rtrifluoromethyl)-l-H-beiizimidazole

Step A: 4,6-di chloropyridme-3 -cafbaldehyde

To a solution of methyl-4,6-dichIoropyridine-3-carboxylate (500 mg, 2.427 mmol) in DCM (2.5 ml) at -78 °C was added, dropwise, DIBAL-H (2.67 ml, 2.67 mmol, 1M) and the mixture stirred at -78 °C (the mixture immediately change to a light yellow color). After 3 h, the reaction mixture was quenched with HC1 (IN, 9.34 ml) at -78 °C and then stirred at room temperature for 30 min. The layers were separated and the organic layer dried (MgS0₄) and concentrated under vacuum to afford an oil which solidified over night in the refrigerator. The solid was then purification on the I SCO CombiFlash Companion (with a 20 g column) eluting with 2 to 5 % ethylacetate / hexane gradient. The desired fractions were concentrated under vacuum to afford the title compound as a white solid. LC-MS (ES, m/z) C6H3CI₂NO: 176;

Found: 176, 178, 180 [M, M+2.M+4]. ^!HNMR (500 MHz, COC , ppm) δ 7.53 (1H, s), 8.88 (1H, s), 10.47 (1H, s).

Step B: 2-(4,6-difluoropyridin-3 -yl)-6-(trifluoromethyl)- 1 -H-benzimidazole

A solution of 4-(trifluoromethy)benzene-l ,2-diamine (250 mg, 1.419 mmol) in DMF (5.0 ml) and water (0.5 ml) was treated with the Intermediate from Step A (250 mg, 1.419 mmol) slowly and the mixture stirred at room temperature for 5 min. Potassium peroxymonosulfate (873 mg, 1.419 mmol) was then added and the mixture stirred for another 50 min. The mixture was poured slowly in 75 ml of water containing 6 ml (2 M K₂CO₃) and the mixture stirred at room temperature for 5 min. The mixture was diluted with EtOAc and the layers separated. The organic layer was dried (MgS0₄) and concentrated under vacuum. The resulting residue was then purification on the ISCO CombiFlash Companion (with a 24 g column) eluting with 20 to 40 % ethylacetate / hexane gradient The desired fractions were concentrated to afford the title compound. LC-MS (ES_> m/z) C13H6CI₂F₃N₃: 332; Found: 332, 334, 336 [M, M+2.M+4].

'HNMR (500 MHz, COCh, ppm) δ 7.58 (1H, s), 7.66 (1H, d, 8.5 Hz), 7.84 (1 H, d, 8.4 Hz), 8.08 (1H, s), 9.37 (1H, s).

Intermediate 8

3-fluoro-5-[6-(trifluoromethyl)-lH-benzimidazoI-2-yl1pyridin-2-Yl trifluoromethanesulfonate

Step A: N-r2-amino-4-ftrifluoromethyl phenyl]-5,6-difluoropyridine-3-carboxai¾ide A solution of 4-(trifluoromethy)benzene-l ,2-diamine (980 mg, 5.56 mmol) in anhydrous

DMF (20 ml) under nitrogen atmosphere was added 5,6-difluoropyridine-3-carboxylic acid (590 mg, 3.71 mmol), EDC. HC1 (1066 mg, 5.56 mmol), and HOBT (852 mg, 5.56 mmol). DIEA was then added via a syringe and the mixture was stirred at room temperature over night. The reaction was quenched with water and washed with ethyl acetate (x2). The combined organic layers was then washed with brine, dried (NajSO.;) and filtered. The filtrate was concentrated under vacuum to afford a viscous oil. The resulting oil was then purified on the 1SCO CombiFlash Companion (with a 10 g Biotog Snap Column) eluting with 20 to 100 % ethylacetate / hexane gradient. The desired fractions were concentrated to afford the title compound as a tan solid. LC-MS (ES, m/z) C₁₃H6CI₂F3 ₃: 317; Found: 318 [M+l].

Step B: 3-fluoro-5-[6-(trifluoromethyl)-lH-benzimidazol-2-yl]pyridin-2-ol

In a 5 ml microwave tube was added the Intermediate from Step A (200 mg, 0.630 mmol) and acetic acid (8 ml) and the resulting solution irradiated in the Biotage microwave reactor at 180 °C for 1 h. The resulting mixture was diluted with a 40 % acetonitrile / water mixture and purified on the Mass Directed Reverse Phase HPLC equipped with a 30 x 100 mm, Waters Xtera column, eluting with a 20 to 70 % acetonitrile / water (containing 0.05 % TFA) gradient at a flow rate of 45 ml / min and a run time of 15 min. The desired fractions were evaporated in a Genevac evaporator to afford the title compound as a tan solid. LC-MS (ES, m/z) C₁3H₇F₄N3O: 297; Found: 298 [M+l ].

Step C: 3-fluoro-5-j^'6-(trifluoromethyI -lH-benzimidazol--2-yl1pyridin-2-yl

trifluoromethanesulfonate To a sealed microwave tube containing the title compound from Step B (100 mg , 0.336 mmol) and 2_J6-di-teri-butyl-4-methylpyridine (79 mg, 0.353 mmol) under a nitrogen atmosphere was added dichloromethane (2.0 ml) at room temperature. The resulting solution was then treated with acetic anhydride (0.06 ml, 0.35 mmol) via a syringe and the mixture stirred at room temperature for 2 h. After quenching the reaction with water the mixture was extracted with ethyl acetate and the combined organic layers was dried (MgS0₄) and concentrated under vacuum. The resulting residue was purified on the 1SCO CombiFlash Companion (with a 12g Column) eluting with 10 to 30 % ethylacetate / hexane gradient. The desired fractions were concentrated to afford the title compound as a yellow solid. LC-MS (ES, m/z) C^H^^C^S: 429; Found: 430 [M+l]. ^lHNMR (500 MHz, COCh, ppm): δ 7.65 (1H, d, 8.4 Hz), 7.80 (1H, d, 7.6 Hz), 8.04 (1H, s), 8.51 (l H, d, 9.0 Hz), 8.81 (lH, s).

Intermediate 9

2-(6-chloro-4-fluoropwidin-3-yl)-6-(trifluorometiwl)-lH-benziroidazole

Step A: 2-chloro-4-fluoro-3-iodopyridine

A freshly prepared solution of LDA (100 mmol) at -78 °C was treated with 2-chIoro-4- fiuoropyridine (12 g, 91 mmol) and the mixture stirred at -78 °C for 30 min. Iodine dissolved in THF was then added to the mixture and after 20 min the reaction was diluted with MTBE and treated with 10 % sodium sulfite. The suspension was filtered and the filtrated concentrated under vacuum. Crystallization from hexane followed by filtration afforded 15.5 g of the title compound. LC-MS (ES, m/z) C₅H₂C1FIN: 257; Found: 258 [M+l]. ^]HNMR (500 MHz, CDC1₃, ppm): δ 6.98 (1H, d, d, 6Hz, 6Hz), 8.31 (1H, d, d, 5.6 Hz, 5.5 Hz).

Step B: 2-c oro-4-fluoro-5-iodopyridine

A solution of the title compound from Step A (8.00g, 31.1 mmol) in tetrahydrofuran ( ml) at -20 °C was treated with LDA (15.54 ml, 31.1 mmol) dropwise over a 2 h period. After 45 min the mixture was diluted with MTBE and water and the layers separated. The water layer was washed with MTBE and the combined organics dried (MgS0₄) and concentrated under vacuum. Chromatography on a silica gel column eluting with EtOAc / Hexane (10 %) afforded the title compound. ^!HNMR (400 MHz, CDC1₃, ppm): δ 7.12 (IB, d, 7.2Hz), 8.63 (1H, d, 8.7 Hz). Step C: 6-chloro-4-fluoropyridine-3-carbaldehyde

To solution of the title product from Step B (6.27 g, 24.36 mmol) in tetrahydrofuran (50 ml) at -20 °C was added isopropylmagnesium chloride (18.7 ml, 24.36 mmol) and the mixture stirred at -20 °C for 30 min. The mixture was then treated with dimethyiformamide (8.2 ml) and after 30 min diluted with TBE and saturated ammonium chloride. The layers were separated and the aqueous layer washed with MTBE. The combined organic layers were dried (MgS0₄) and concentrated in vacuum. Chromatography on a silica gel column eluting with EtOAc / Hexane 0 to 10 % afforded the title compound. LC-MS (ES, m/z) C₆H₃C1FN0: 159; Found: 160 [M+l], ¹H R (500 MHz, CDCI3, ppm): δ 7.27 (1H, d, 9.3 Hz), 8.88 (1H, d, 9.5 Hz) 10.35 (1H, s).

Step D: 2-(6-chloro-4-fiuoropyridin-3-yl -6-(trifluoromethyl)-lH-ben2imidazole

Following the procedure described for Intermediate 1 but using the title compound (aldehyde, 181 mg, 1.13 mmole) from Step C, the title compound was afforded as a tan solid. LC-MS (ES, m/z) C₀H6CIF_{4 3}: 315; Found: 316 [M+l].

Intermediate 10

2-(5-chloropyrazin-2-yl)-6-(^'trifluoromethyl)-lH-benzimidazole

Following the procedure described for Intermediate 3 but using 5-chloropyrazine-2~ carbaldehyde (445 mg, 3.12 mmole), the title compound was afforded as a powder. LC-MS (ES, m/z) C₁₂H₆C1F₃N₄: 298; Found: 299 [M+l].

Intermediate 11

2-(4-bromo-3-fluorophenyl)-6-ftrifluoromethyl)-lH-benzimidazole

In a 20 ml microwave tube was added 4-(trifiuoromethyl)benzene-l,2-diamine (265 mg. 1.51 mmol) and 4-bromo-3-fiuorobenzoic acid (300 mg, 1.37 mmol). The tube was then sealed and pyridine (4.0 ml) was added followed by triphenyl phosphite (0.431 ml, 1.644 mmol) via a syringe. The mixture was then stirred at room temperature for 5 min then irradiated in the Biotage Initiator Microwave at 220 °C for 15 min. The solvent was evaporated and azothrope (x2) with toluene. The resulting residue was purified on the ISCO CombiFIash Companion (with a 40 g Column) eluting with a 5 to 40 % ethylacetate / hexane gradient. The desired fractions were concentrated to afford the title compound as a solid. LC-MS (ES, m/z) Ci₄H₇BrF4N₂: 359; Found: 360 [M+l].

Intermediate 12

2- 4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl] -5-(trifluoromethyD- 1 H- benzimidazole

A mixture of 2-(4-iodophenyl)-5-(trifluoromethyl)-lH-benzimidazole (Intermediate 4, 8.08 g, 20.82 mmol, 1.00 equiv), 4_}4_>4^,,4^, _f5,5,5^,,5^,-octamethyl-2,2^,-bi-l,3,2-dioxaborolane (5.82 g_j 22;09 mmol, 1.10 equiv), potassium acetate (6.13 g, 62.5 mmol, 3.00 equiv) and \,V~ 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 time 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_J5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-5- (tnfluoromethyl)-lH-benzimidazole. LC-MS (ES, m/z) C₂₀H₂oBF₃N202: 388; Found: 389

[M+Hf.

Intermediate 13

2-r2-fluoro-4-(4.4.5.5-tetrametl l-L3,2-dioxaborolmi-2-yi)phenyl]-5-(trifluoromethyr)-lH- benzimidazole A mixture of 2-(4-bromo-2-fluorophenyl)-5-(trifluoromethyl)- 1 H-benzimidazole (Intennediate 6, 25.06 g, 69.6 mmol, 1.00 equiv), 4,4,4'_s4'_>5,5₅5^,,5^,~octamethyl-2_J2'-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 l,r-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 MgSC 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-l₅3,2- dioxaborolan-2-yl)phenyl]-5-(trifiuoromethyl)-lH~benzimidazole. LC-MS (ES_t mfz)

C20H19BF4N2O2: 406; Found: 407 [M+Hf .

Intermediate 14

Ethyl { 1 -f 5-(4,4.5,5-tetramethyl-l ,3.2-dioxaborolan-2-yl pyridin-2-yllpiperidin-4-yl} acetate Step A: Ethyl ί 1 -(5-iodopyridm-2-yl)piperidin-4-yl]acetate

2-fluoro~5-iodopyridine (2.2 g, 9.86 mmol, 1.1 equiv.) and ethyl piperidin-4-ylacetate (1.535 g, 8.96 mmol, 1.0 equiv.) were dissolved in DMF (12 mL) and stirred. Cesium carbonate (4.38 g, 13.45 mmol, 1.5 equiv.) was added to the solution, and the resulting reaction suspension was reacted under microwave conditions (160°C, Ihr). After cooling to room temperature, the reaction suspension was filtered to remove solids. The collected solution was concentrated to a residue. Purification with SP-1 Biotage [ Hexanes:EtOAc 0 > 5% 2CV 5 > 40% 10CV 40% 2CV ] isolated the desired product Ethyl [l-(5-iodopyridin-2-yl)piperidm-4-yl]acetate. LC-MS (ES, m/z): C1 H19IN2O2: 374; Found: 375 [M+H]+.

Ste B: |^"5'-(4,4.5,5-Tetramethvl-ri,3,21dioxaborolan-2-yl)-3,4,5,6-tetrahydro-2H- [L2'lbipyridinyl-4-yl1-acetic acid ethyl ester

Ethyl [l-(5-iodopyridin-2-yl)piperidin-4-yl]acetate (0.047 g, 0.126 mmol, 1.0 equiv.),

Bis(pinacolato)diboron (0.041 g, 0.161 mmol, 1.29 equiv.), 1,1 '-

Bis(diphenylphosphino)ferrocene-Paliadium(II) dichloride dichloromethane complex (0.022 g, 0.027 mmol, 0.21 equiv.) and Potassium acetate (0.062 g, 0.628 mmol, 5 equiv.) were suspended in DMF (4.5 mL). The reaction suspension was stirred under vacuum until gas had completely escaped. N2 (g) was bubbled directly into the reaction suspension, then placed under vacuum again. After bubbling the reaction again with N2 (g), the reaction was heated in a 45°C oil bath for 10 hrs. The reaction suspension was filtered to remove solids; the collected solution was concentrated, diluted with EtOAc / 1¾0, and the EtOAc phase was separated. The EtOAc phase was dried over Na2S04_> filtered, and concentrated to a brown oil. Purification with Biotage SP-1

[ 0 > 12% 2CV, 12 > 100% 10CV, 100% 2CV ] isolated the desired product [5'-(4,4,5,5- Tetramethyl-[l ,3,2]dioxaborolan-2-yl)-3,4,5.6-tetrahydro-2H-[l ,2 bipyridinyl-4-yl]-acetic acid ethyl ester. LC-MS (ES, m/z): C₂oH3 sBN₂0₄: 374; Found: 375 [M+H]⁺.

Intermediate 15

ethyl [1 -(5-bromopyrimidin-2-yl)piperidin-4-yl]acetate

,

A mixture of ethyl piperidm-4-ylacetate (5.0 g, 29.2 mmoi, 1.00 equiv), 5-bromo-2- chloropyrimidine (6.78 g, 35.0 mmol, 1.2 equiv), and cesium carbonate (19.98 g, 61.3 mrnol, 2.1 equiv) in DMF (100 mL) was stirred for 18 hr at 50 °C in an oil bath. 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 ethyl [l-(5-bromopyrimidm-2- yl)piperidin-4-yl]acetate. LC-MS (ES, m/z) Ci₃H,₈BrN₃0₂: 327; Found: 330 [M+Hf . intermediate 16

ethyl \l~(5 -bromo-6-methylpyridin-2-yl)piperidin-4-yl acetate In the same procedure as Intermediate 15, using 3-bromo-6-fluoro-2-methylpyridine as starting material, ethyl [l-(5-bromo-6-methylpyridin-2-yl)piperidin-4-yl]acetate was prepared. LC-MS (ES, m/z) C)₅H₂iBrN₂0₂: 340; Found: 341 [M+H]⁺.

Intennediate 17

ethyl f l-[5-(4A5,5-tetramethyi 3,,2-dioxaboro^

A mixture of ethyl [l -(5-bromopyrimidm-2-yl)piperidin-4~yl]acetate (8.6 g, 26.2 mmol, 1.00 equiv), 4,4_s4',4',5_f5,5',5'-octamethyl-2₅2'-bi-l_!3_>2-dioxaborolane (7.32 g, 28.8 mmol, 1.10 equiv), potassium acetate (7.71 g, 79.0 mmol, 3.00 equiv) and l, -bis(diphenyIphoshino) ferrocene dichloropalladium (II) dichloromethane complex ( 1 ,91 g, 2.62 mmol, 0.1 equiv) in DMSO (200 mL) was purged with N₂ for 1 min and 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 ethyl { l-[5-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)pyrimidin-2-yl]piperidin-4^»yl} acetate. LC-MS (ES, m/z) C₁₉H₃0BN₃O₄: 375; Found: 376 [M+H]⁺.

Intermediate 18

ethyl { 1 - [5~f 3 -fluoro-4-formylphenyl pyrimidin-2-yl1piperidin-4-yl } acetate

To a mixture of ethyl { l-[5-(4,4_f5,5-tetramethyl-13_>2-dioxaborolan-2-yl)pyrimidin--2- yl]piperidin-4-yl} acetate (Intermediate 17), 0.5 g, 1.33 mmol, 1.00 equiv), 4-bromo-2- fluorobenzaldehyde (0.541 g, 2.66 mmol, 2.00 equiv), tetrakis (0.231 g, 0.2 mmol, 0.15 equiv) and Na₂C0₃ (2.66 mL, 2.0 M, 4.0 equiv) was added DME (13.0 mL)/EtOH (8.0 mL). The reaction mixture was degassed and purged with nitrogen with stirring for 10 min followed by MW at 120 °C for 20 min. Solvent evaporated and mixture 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 eluting through a silica gel column with a 0-70% EtOAc/Hexane solvent system to provide product ethyl { l-[5-(3-fluoro-4-formylphenyl)pyrimidin-2- yl]piperidin-4-yl}acetate. LC-MS (ES, m/z) C₂₀H₂₂FN₃O₃: 371; Found: 372 [M+H .

Intermediate 19

ethyl { l-i^"5-(^"5-formylpyrazin-2-vl)pyrimidin-2-yl]piperidin-4-vnacetate

To a mixture of ethyl {l-[5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yi)pyrimidin-2- yl]piperidin-4-yl} acetate (Intermediate 18), 0.5 g, 1.33 mmol, 1.00 equiv), 5-chJoropyrazine-2- carbaldehyde (0.377 g, 2.66 mmol, 2.00 equiv), tetrakis (0.231 g, 0.2 mmol, 0.15 equiv) and Na₂P¾ (2.66 mL, 2.0 M, 4.0 equiv) was added DME (13.0 mL)/EtOH (8.0 mL). The reaction mixture was degassed and purged with nitrogen with stirring for 10 min followed by MW at 120 °C for 20 min. Solvent evaporated and mixture 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 eluting through a silica gel column with a 0-70% EtOAc/Hexane solvent system to provide product ethyl { l-[5-(5-formylpyrazin-2-yi)pyrimidin-2-yl]piperidin-4-yl}acetate. LC- MS (ES, m/z) CisH₂₁N₅0₃: 355; Found: 356 [M+H)⁺.

Intermediate 20

ethyl { l- 5-(3-fluoro-4-formylphenyl)pyridin-2-Yllpiperidin-4-yl}acetate To a 5 mL pyrex vial was charged with 3-fluoro-4-fonnyiphenylboronic acid (76 mg, 0.450 mmol) along with Intermediate 14 (140 mg, 0.375 mmol) and sodium carbonate (SO mg, 0.750 mmol) and Pd(tetrakis) (21.67 mg, 0.019 mmol) in DMF (lmL) and water. The vial was sealed and vacuumed and refilled with nitrogen 3 times and then the mixture was exposed to MW at 150 °C for 1 hr. LC-MS showed complete consumption of starting and formation of product with lots of unknown peaks. The reaction was worked up and. the product was purified by MPLC (12 g silica gel₅ 0 to 20% ethyl acetate in hexanes) to afford light yellow solid product ethyl { l-[5-(3~fluoro-4-formylphenyl)pyridin-2-yl]piperidin-4-yl}acetate. . LC-MS (ES, m/z) C₂₁H₃₃FN₂0₃: 370; Found: 371 [M+H]⁺.

Intermediate 21

ethyl ( l-r3-fluoro-5-i3-fluoro-4-formylphenyl pyridin-2-yllpiperidin-4-yl}acetate

With the same procedure as Intermediate 20, ethyl { l-[3-fiuoro-5-(3-fluoro-4- formylphenyl)pyridin-2-yl]piperidin-4-yl}acetate was prepared. LC-MS (ES, m/z)

388; Found: 389 [M+Hf.

Intermediate 22

ethyl n-[5-(4-fonnylphenyl)pyridin-2-Yllpiperidin-4-yl}acetate With the same procedure as Intermediate 20, ethyl { l -[5-(4-formylphenyl)pyridin-2- yl]piperidin-4-yl} acetate was prepared. LC-MS (ES, m/z)

352; Found: 352

[M+Hf.

Intermediate 23

ethyl { 1 -i^"5-(3-chloro-4-formylphenyI)pyridin-2-yllpiperidin-4-yU acetate

With the same procedure as Intermediate 20, ethyl { l -[5-(3-chloro-4- formylphenyl)pyridin-2-yl]piperidin-4-yl} acetate was prepared. LC-MS (ES, m/z)

C₂]H₂₃C1N₂0₃: 387; Found: 388 [M+Hf.

Intermediate 24

Step A: 4-[4'-f 5-Chloro- lH-benzoimidazol-2-yl)-biphenyl-4-yll-piperazine- 1 -carboxylic acid tert-butyl ester

To the mixture of 2-(4-bromo-phenyl)-5-trifluoromethyl-lH-benzoimidazole (leq

Intermediate 4, 1 g, 3.26 mmol), 4-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]- piperazine-l -carboxylic acid feri-butyl ester (1.89 g, 4.89 mmol) (2 eq), and Pd(dppf)Cl₂ (0.05 eq) was added dioxane. After the resulting suspension was purged with N₂ for 10 min, IN NaHC0₃ /H₂0 solution (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 partitioned between water and EtOAc. The organic phase was washed with water, brine and was dried over Na₂S0₄. The solution was filtered and evaporated in vacuum. The crude product was added DCM (100 mL) and stirred for 16 hi. The solid was filtered and dried in vacuum to give the product as a yellow solid. LC-MS found: 489 [M+H]⁺.

Step B: 5-Chloro-2-(4'-piperazin- 1 -yl-biphenyl-4-yl)- 1 H-benzoimidazole

To a suspension of 4-[4'-(5-Chloro-lH-benzoimidazol-2-yl)-biphenyL4-yl]-piperazine-l- carboxylic acid ½r/-butyl ester (1 ,3 g, 2.66 mmol) in dioxane (5 mL) was added 4N HCl/dioxane (5mL). The resulting reaction was stirred at ambient temperature for 16 hr. LC-MS showed that the reaction was completed. The solvent was evaporated in vacuum to give the product as a yellow solid. LC-MS found: 389 [M+H]⁺.

Intemiediate 25

2-[4-(6-Piperazm-l-yl-pyridin-3-yl)-phenyll-5-trifluoromethyl-lH-benzoimidazole

Performed as same as the synthesis of Intermediate 22 except 2-(4-bromo-phenyl)-5- trifluoromethyl-1 H-benzoimidazole and 4-[5-(4,4_i5,5-Tetramethyl-[l,3_f2]dioxaborolan-2-yl)- p)Tidin-2-yl]-piperazine-l-carboxylic acid tert-butyl ester were used as the starting materials in Step A. The crude product of was added EtOAc/Hexane (1 :2) and stirred for 16hr. The solid was filtered and dried under vacuum to give 4-{5-[4-(5-Trifluoromethyl-lH-benzoimidazol-2-yl)- phenyl]-pyridin-2-yl}-piperazine-l -carboxylic acid tert-butyl ester as a brown solid. The LC-MS of final product 2-[4~(6-Piperazin-l-yl-pyridin-3-yl)~phenyl]-5-trifiuoromethyl-lH- benzoimidazole was found: 424 [M+H]⁺,

InteiTnediate 26

4-Hvdroxy-piperidme-4-carboxylic acid methyl ester

Step A: 4-Hydroxy-piperidine-4-carboxylic acid methyl ester

A mixture of 1 -Benzyl-4-hydroxy piperidine-4~carboxylic acid methyl ester (1.30 g, 4.55 mmol) and Palladium hydroxide (20%, 250mg) in ethanol/water (10/0.5 ml) was hydrogenated at 45 psi at room temperature overnight. The Palladium catalyst was removed by filtration. The filtrate was concentrated under vacuum to afford the title compound. LC-MS (ES, m/z):

C₇H]₃N0₃: 159; Found: 160 [M+H]⁺

Intermediate 27

2-{2-fluoro-4-[2-(methylsulfinyl)pyrimidin-5-vl]phenyl|-5-(trifluoromethyl)-lH- benzimidazole

Step A: 2-(methylsulfanyl)-5-(4.4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2- yppyrimidine

A 100 mL 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 at 100 OC for 6 hr. LC-MS showed complete consumption of starting material. After being cooled to room temperature, the residue was diluted with ethyl acetate (1 0 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 gS0₄, filtered and concentrated. The residue was purified by MPLC (24 g silica gel, 10 to 60% ethyl acetate in hexanes) to afford a light yellow solid product 2- (meihylsuIfanyl)-5-(4,4,5,5-tetam LC-MS (ES, m/∑):

C11H17BN2O2S: 252; Found: 253 [M+Hf.

Step B: 2-{2-fluoro-4-[2'(metjhylsulfanvl)pyrimidin-5-Yllphenyl}-6- (trifluoromethvD-lH-benzimidazole To a 20 mL pyrex vial was charged with 2-(4-bromo-2-fluoropheiryl)-6~

(trifluoromethyl)-lH-benzimidazole (Intermediate 5, 1.567 g, 4.36 mmol) along with 2- (methylsuIfanyl)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaboroian-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 20 °C for 1 hi-. 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 MgSC^, 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 a 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- fiuoro-4- [2-(methylsulfanyl)pyrimidin-5 -yl]phenyl } -6-(trifluoromethyl)- 1 H-benzimidazole. LC-MS (ES, m/z) Ci₉Hi2F₄N₄S: 404; Found: 405 [M+Hf. Step C: 2- (2-fluoro-4-[2-(methylsulilnyl)pyrimidin-5-Yllphenv -6-(trifluoromethylV 1 H- benzimidazole

To a 20 mL sample vial was charged with 2-{2-fhioro-4-[2- (methylsulfanyl)pyrimidin-5-yl]phenyl}-6-^ (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-(methylsulfmyl)pyrimidm-5-yl]phenyl}~6-(trifluoromethyl)-lH-benzimidazole. LC-MS (ES, m/z): Ci H₁₂F₄N₄OS: 420; Found: 421 [M+Hf. Intermediate 28

The same procedure for the preparation of Intermediate 27 was applied and 2-{4-[2-

(methylsulfmyl)pyrimidin-5~yl]phenyl}-5-(trifluoromethyl)-lH-benzimidazole as white solid was prepared. LC-MS (BS, mix): C19H13F3N4OS: 402; Found: 403 [M+Hf

Intermediate 29

5-(5-chloro-lH-benzimidazol-2-yl)-6'-fluoro-2,3'-bipyridine

Step A: 6'-fluoro-2,3'-bipyridine-5-carbaldehyde

A mixture of (6-fluoropyridin-3-yl) boronic acid (1. 15 g, 10.75 mmol), 6- bromopyridine-3-carbaldehyde (2 g, 10.75 mmol), sodium carbonate (2.279 g, 21.5 mmol) and Pd(dppf)Cl₂ (0.393 g, 0.538 mmol) are suspended in N,N-Dimethylformamide (10 ml) and water (5 ml), the reaction mixture was stirred over night at 80°C under N₂ in an oil bath. The reaction mixture was cooled to room temperature, water (20 ml) added, extracted with 3x30 mL ethyl acetate. The organic layers were combined, washed with 2x20 mL of saturated brine, dried over anhydrous sodium sulfate and concentrated under vacuum. Then applied onto a silica gel column and eluted with ethyl acetate/hexane 0-65%. This resulted in 6'-fluoro-2,3^!- bipyridine-5-carbaldehyde as a white solid. LC-MS (ES, m/z) CuH₇FN₂0: 202; Found: 203 ^' [M+Hf.

Step B: 5-(5-chloro-lH-benzimidazol-2-yl)-6'-¾oro-2.3'-bipyridine

A mixture of 4-chloro-l,2-phenylenediamine (700 mg, 4.91 mmol), 6'-ί1υοΓθ-2,3'- bipyridine-5-carbaldehyd (1.092 g, 5.4 mmol) and potassium peroxymono sulfate (1.962 g, 3.19 mmol) in DMF (6 ml) and water (0.6 ml) was stirred for 24 hours at room temperature. Then pour into 6 mL 1M K₂CO₃ solution, extracted with 3x30 rnL ethyl acetate. The organic layers were combined, washed, with 2x15 mL of saturated brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column and eluted with ethyl acetate/hexane 0-80 %. This resulted in 5-(5-chloro-lH-benzimidazol-2-yI)- 6'-fluoro-2,3'-bipyridine as a yelllow solid. LC-MS (ES, m/z) CnH₁₀CIFN₄: 324; Found: 325 [M+Hf. Intermediate 30

2- \4-( 6-fluoropyridin-3 -vDphenyl] -5 -(trifluoromethyl - 1 H-benzimidazole In the same procedure as the preparation of Intermediate 29, 2-[4-(6- fluoropyridin-3-yl)phenyl]-5-(trifluoromethyl)-lH-benzimidazole was prepared as a yelllow solid. LC-MS (ES, m/z) C₁₉HnF4N₃: 357; Found: 358 [M+H]⁺.

Intermediate 31

ethyl {l-f5-(5-formylpyridin-2-yl pyrimidin-2-yl]piperidin-4-vn acetate

To a mixture of ethyl { l -[5-(4,4,5,5-tetramethyl-l,3₅2-dioxaborolan-2-yI)pyrimidin-2- yl]piperidin-4-yl} acetate (Intermediate 18), 0.5 g, 1.33 mmol, 1.00 equiv), 2-bromopyridine-5- carbaldehyde (0.377 g, 2.66 mmol, 2.00 equiv), tetrakis (0.231 g, 0.2 mmol, 0.15 equiv) and Na₂C0₃ (2.66 mL, 2.0 M, 4.0 equiv) was added DME (13.0 mL)/EtOH (8.0 mL). The reaction mixture was degassed and purged with nitrogen with stirring for 10 mi followed by microwave at 120 °C for 20 min. Solvent evaporated and mixture 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 eluting through a silica gel column with a 0-70% EtOAc/Hexane solvent system to provide product ethyl { l-[5-(5-formylpyridin-2-yl)pyiimidin-2-yl]piperidin-4- yljacetate. LC-MS (ES, m/z) Ci₉H₂₂N₄0₃: 354; Found: 355 [M+H]⁺.

Intermediate 32

l -(5"formyl-2,3'-bipyridin-6'-yl)-4-methylpiperidine-4-carboxylic acid A mixture of 6^!-fluoro-2,3'-bipyridine-5-carbaldehyde (Step A, Intermediate 28, 0.8 g, 3.96 mmol), 0.5 g, sodium bicarbonate (1.994 g, 23.74 mmol), 4-methylpiperidine-4-carboxylic acid hydrochloride (1.422 g, 7.91 mmol) in DMSO (10 mL) was heated 120 °C overnight under nitrogen. The mixture was then dried and. the residue was purified by MPLC (gredient to acetone) to afford product l-(5-fonnyl-2,3'-bipyridin-6'-yl)-4-methylpiperidine-4-carboxylic acid. LC-MS (ES, m/z) C₁₈Hi₉N₃0₃: 325; Found: 326 [M+H]⁺.

Example 1

( 1 - { 5- [3-chloro-4-(5-methoxy-3H-imidazo [4,5 -&]pyridin-2-yl)phenyl]pyridin-2-yl } piperidin-4- yl)acetic acid

Step A (see General Method A):

ethyl (l-{5-[3-chloro-4-(5-methoxy-3H-imidazo[4,5-6]pyridin-2-yl)phenyl]pyridin-2- yl } piperidin-4-yl)acetate

To a solution of 6-methoxypyridine-2, 3 -diamine (0.065 mg, 0465 mmol) in DMF (2.0 ml) was added water (0.07 ml) followed by ethyl { 1 -[5-(3-chloro-4-formylphenyl)pyridin-2- yl]piperidin-4-y]} acetate (0.150 g, 0.388 mmol) slowly. After stirring at room temperature for 5 min potassium peroxymonosulfate (0.145 g, 0.236 mmol) was added to the mixture. The mixture was then stirred at room temperature for 60 min and poured slowly into a solution of potassium carbonate (3 ml, 1M) in 60 ml water. The resulting slurry was stirred for 10 min, diluted with EtOAc and the layers separated. The aqueous layer was washed with EtOAc (x2) and the combined organics dried (MgSdt) and concentrated under vacuum. Trituration from Hexane / Ether followed by filtration afforded the title compound as a powder. The ethyl (l -{5-[3-chloro- 4-(5-methoxy-3H-imidazo[4,5-5]pyridin-2-yl)phenyl]pyridin-2-yl}piperidin-4-yl)acetate was afforded. LC-MS (ES, m/z) C27H28CIN5O3: 505; Found: 506 [M+H]⁺.

Step B: A solution of ethyl (l -{5-[3-chloro-4-(5-methoxy-3H-imidazo[4,5-ii]pyridin-2- yl)phenyl]pyridin-2-yl}piperidin-4-yl)acetate (0.043 g, 0.085 mmol) from Step A, in

tetrahydrofuran (1.0 ml) was treated with lithium hydroxide (0.006 g, 0.152 mmol) dissolved in water followed by methanol (0.5 ml). The mixture was then stirred at 55 °C for 18 h. The solvent was evaporated and the resulting suspension diluted with water. The H was then adjusted to pH 3 with IN HC1. The resulting suspension was then extracted with ethyl acetate (x2) and the combined organic layers dried (MgS0₄) and concentrated under vacuum to afford (l-{5-[3- chloro-4-(5-methoxy-3H-imidazo

acid. LC-MS (ES, m/z) C₂₇H₂₈C1N₅0₃: 477; Found: 478 [M+H]⁺

Example 2

[ 1 -(5- {3 -chloro-4- [6-(trifiuoromethyl)- 1 H-benzimidazol-2-yl]phenyl } pyridin-2-yl)piperidin-4- yl] acetic acid

The procedure describe for the preparation of Example 1 (Step A and B) was used to prepare Example 2 but using 4-(trifluoromethy)benzene-l ,2-diamine (0.050 g, 0.284 mmol). The title compound, Example 2, was afforded as the TFA salt after RP HPLC purification. LC-MS (ES, m/z) C₂6H2₂C1F₃ 40₂:514; Found: 515 [M+I-I]

Example 3

f 1 -f 5 - { 3 -chloro-4- f 6-f trifluoromethoxy - 1 H-benzimidazol_:2-yl] phenyl } pYridin-2~yl)piperidin-4- yl]acetic acid

The procedure describe for the preparation of Example 1 (Step A and B) was used to prepare Example 3 but using 4-(trifluoromethoxy)benzene-l_J2-diamine (0.055 g, 0.284 mmol). The title compound, Example 3, was afforded as the TFA salt after RP HPLC purification. LC- MS (ES, m/z) C₂6H₂₂.ClF₃N₄O₃:530; Found: 531 [M+H]⁺

Examples 4-7

Using the appropriate aldehyde intermediates and diamines, following the

procedure as Example 1, Examples 4-7 were prepared:

Example 8

( 1 - ( 5-[^~3-fluoro-4-(6-fluoro- lH-benzimidazol-2-yl phenyl]pvridin-2-ynpiperidm-4-yl)acetic acid Step A: Ethyl (1 - (5-i3-fluoro-4-f6-fluoro-lH-ben2imidazol-2-yl)phenyl]pvridin-2- yl } piperidin-4-yl)acetate

A 20 rnL sample vial was charged with Intermediate 20 (25 mg, 0.067 ramol) along with

DMF, water and 4-fluorophenyldiamine (12.77 mg, 0.101 mmol). The mixture was stirred at room temperature for 5 min before OXONE (29.0 mg, 0.047 mmol) was added in one portion. The resulting reaction mixture was then stirred at room temperature for 2 hours. LC-MS showed complete product formation. 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 (12 g silica gel, 10 to 50% ethyl acetate in hexanes) to afford light color solid product ethyl (l-{5-[3-fluoro-4-(6-fluoro-lH-benzimidazol-2-yl)phenyl]pyridin-

2-yl}piperidh 4-yl)acetate. LC-MS (ES, m/z) C₂8H₂3F₂N₃0₂: 475; Found: 476 [M+Hf.

Step B: Same procedure as Step B in Example 1 for the hydrolysis of ester afforded { 1- { 5-[3-fluoro-4-(6-fluoro- 1 H-benzimidazol-2-yl)phenyl]pyridin-2-yl } piperidin-4-yl)acetic acid. LC-MS (ES, m/z) C2₇H₂₁F₂N₃0₂: 461 ; Found: 462 [M+H]⁺.

Example 9

1 -( 5 - (4- [6 -(trifluoromethyl)- 1 H-benzimidazol-2-νΠ phenyl } pyridin-2-yl)piperidin-4-yl] acet ic acid

In the same chemistry as Example 8, using Intermediate 22, [l-(5-{4-[6-(trifluoromethyl)- lH-benzimidazol-2-yl]phenyl}pyridin-2-yl)piperidin-4-yl]acetic acid was prepared. LC-MS (ES, m/z) C27H23F3N4O2: 480; Found: 481 [M+H]⁺.

Example 10

Fl-(6-methyl-5-{4-f6-(trifIuoromethyin

yljacetic acid

Step A: Ethyl [ I -(6-methyl-5 - { 4- [6-(trifluoromethyl)- 1 H-benzimidazol-2- yl 1 phenyl } pyridin-2-yl)pi peri din-4-yll acetate

A 5 rnL pyrex vial was charged with Intermediate 12 (92 mg, 0.237 mmol) along with Intermediate 16 (81 mg, 0.237 mmol) and sodium carbonate (75 mg, 0.712 mmol) and Palladium (tetrakis) (27.4 mg, 0.024 mmol). The vial was sealed and vacuum and refilled with nitrogen through a syringe needle. The DME (1 ml) and EtOH (1.000 ml) were added. The mixture was then exposed to microwave irradiation at 120 °C for 1 hr. LC-MS showed complete consumption of starting material, however some side product formed. The reaction was worked up by diluted with ethyl acetate and washed with water. The crude was purified by MPLC (12 g silica gel, 0 to 40% ethyl acetate in hexanes) to afford product ethyl [l-(6-methyl-5-{4-[6-(trifluoromethyl)-lH- benzimidazol-2-yl]phenyI}pyridin-2-yl)piperidin-4-yl]acetate. LC-MS (ES, m/z) C₂9H₂ F₃N40₂: 522; Found: 522 [M+H]⁺ (see General Method B). Step B: Same procedure as Step B in Example 1 to afford [l-(6-methyl-5-{4-[6-

(trifluoromethyl)-lH-benzimidazol-2-yl]pheiiyl}pyridin-2-yl)piperidin-4-yl]acetic acid. LC-MS (ES, m/z) C28H27F3N4O2: 508; Found: 509 [M+H]⁺.

Examples 1 1 -14

Using the same procedure as Example 10 and corresponding boronic ester, Examples 11- 14 were prepared.

Example 15

Using the same procedure as Example 10, using Intermediate 5 and corresponding boro ic ester, Example 15 was prepared.

Example 16

f4-[4'-(5-chloro-lH-benzimidazol-2-yl bipbenyl-4-yl]piperazin-l -yl}acetic acid

To a suspension of 5-chloro-2~(4'-piperazin-l-yl-biphenyl-4-yl)-lH-benzoimidazole (Intermediate 23, leq) and 2-bromo ethyl acetate (leq) in anhydrous DMSO was added K2CO3 (2eq). The mixture was stirred at 1 10°C in microwave for 1 hr. 2N L1OH H2O (3 eq) was added and the reaction was stirred at ambient temperature for 1 hr. The solution was concentrated in vacuum and neutralized to pH = 5 with HO Ac. The resulting solution was filtered and purified by preparative reverse phase HPLC to afford product {4-[4'-(5-cMoro-lH-benzimidazol-2- yl)biphenyl-4-yl]piperazin-l -yl} acetic acid. LC-MS (ES, m/z) C25H23CIN4O2: 446; Found: 447 [M+H]⁺.

Examples 17-25

In the same procedure as Example 16, using Intermediate 23 and corresponding bromoalkyl ester, the following Examples 17-25 were prepared.

Examples 26-31

In the same procedure as Example 1 , using intermediate 24 and corresponding bromoalkyl ester, the following Examples 26-31 were prepared.

Examples 32-42

Examples 32-42 were prepared using the following general procedure:

To a solution of 2-{4-[2-(methylsulfmyl)pyrimidin-5-yl]phenyl}-5- (trifluoromethyl)-lH-benzimidazoIe (intermediate 28, leq) and primary/secondary amine substrate (2 eq) in NMP was added NaHCO^ (5 eq). The resulting mixture was stirred at 110°C for 20 hr. The reaction was partitioned between EtOAc and water and the organic phase was concentrated in vacuum. The residue was dissolved in MeOH/THF (1 :1) and treated with 2.5 N LiOH/H₂0 at 50°C for 2 hr. The solvent was evaporated and the residue was neutralized with HOAc. The crude product was purified by preparative reverse phase HPLC (generally 10% acetonitrile: water with 0.1% ammonium hydroxide/formic acid/TFA to 95% acetonitrile: water with 0.1% ammonium hydroxide/formic acid/TFA) to give the product as a solid.

Intermediate 26 Example 32-42

Table 5

Examples 43-61

Performed as in the same procedure as Examples 32-42, except 2-{2-fluoro-4-[2- (methylsulfmyl)pyrimidin-5-yl]phenyI -5-(trifluoromethyl)-lH-beri2imidazole (Intermediate 27) was used as starting material, Examples 43-61 were prepared.

Example 62

7-[5-f5-CMoro-lH-benzoimidazol-2^

spiro [4 , 5 ]decane-2.4-dione

Performed as in same procedure as Examples 32-42, except 5-(5-Chloro-lH- benzoimidazol-2-yl)-6'-fluoro~[2,3']bipyridinyl (Intermediate 29) was used as the starting material and the spiro piperidne, 7-[5-(5-Chloro-lH-benzoimidazol-2-yl)-[2,3^,]bipyridinyl-6'-yl]- 3-ethyU-oxa-3,7-diaza-spiro[4.5]decane-2,4-dione. LC-MS (ES, m/z): C₂₆H₂₃CIN6O3: 502; Found: 503 [M+Hf.

Example 63

5'^5-Chloro-lH-benzoimidazol^^

carboxylic acid ethylamide

Performed as in same procedure as Examples 32-42, except 5-(5-Chloro-lH- benzoimidazol-2-yl)-6'-fluoro-[2,3'3bipyridinyl (Intermediate 29, leq) was used as starting material and the piperidne, 5''-(5-Chloro-lH-benzoiraidazol-2-yl)-3-hydroxy-3,4,5,6-tetrahydro- 2H-[l,2';5',2"]terpyridine-3-carboxylic acid ethylamide (Prepared from Intermediate 26 by aminolysis of ester by ethylamine in methanol. LC-MS (ES, m/z): C25H25CIN6O3: 476; Found: 477 [M+Hf .

Example 64

5''-f5-Chloro-lH-benzoimidazol-2-yl^

carboxylic acid methyl ester

Performed as in same procedure as Example 32, except 5-(5-Chloro-lH-benzoimidazol~ 2~yl)-6'-fluoro-[2_!3']bipyridinyl (Intermediate 29, leq) was used as starting material and the piperidne, 5"-(5-Chloro-lH~benzoimidazol-2-yl)-4-methoxy-3,4_J5,6-tetrahydro-2H- [l₅2';5',2"]terpyridine-4-carboxylic acid methyl ester (Intermediate 26). LC-MS (ES, m/z):

C₂₄H₂₂C1N₅0₃: 463; Found: 464 [M+H]⁺.

Example 65

S'^iS-Chloro-lH-berizoimidazol^-yl

carboxylic acid

To a solution of 5"-(5-Chloro-lH-benzoimidazol-2-yl)-4-methoxy-3,4_f5,6-tetrahydro-2H- [l,2';5',2"]terpyridine-4-carboxylic acid methyl ester (771 mg, 1.66 mmol) in 4 ml of MeOH was added NaOH (5M, 1 .66 ml, 8.31 mrnol). The resultant solution was stirred at room temperature overnight. HC1 (cone. Excess) was added and the excess HC1 and solvent was removed under reduced pressure. The crude product was dissolved in DMSO, filtered and then purified by HPLC on a C-18 RP column, 5μ particle size, linear gradient from 20% eCN/¾0 (containing 0.1 % TFA) to 70% MeCN/¾0 (containing 0.1% TFA) to afford the title compound. LC-MS (ES, m/z): C23H20CINSO3: 449; Found: 450 [M+H .

Example 66

Ethyl fl -(5-{4-[6-fluoro-5~(trifluoromethv

yl)piperidin-4-yl1 acetate

Step A: 2~( 4-bromophenyj)-6-fluoro-5-f trifluoromethyl)- 1 H-benzimidazole

2-(4-bromophenyl)-6-fluoro~5-(trifluoromethyl)- 1 H-benzimidazole was prepared using the same synthetic sequence as that of 2~(4-bromopheny3)-6-(trifluoromethyl)-l H-benzimidazole (Intermediate 5). LC-MS (ES, m/z): CwHyBrF.^: 359; Found: 360 [M+H]⁺.

Step B: Ethyl [ 1 -(5- { 4- [^-fiuoro-S -(trifluoromethyl)- 1 H-benzimidazol-2- yl1phenyl}pyrimidin-2-yl)piperidin-4-vnacetate

In the same procedure as Example 10, using 2-(4-bromophenyl)-6-fluoro-5- (trifluoromethyl)- lH-benzimidazole and methyl { 1 -[5-(4,4_i5,5-tetramethyl- 1 ,3,2-dioxaboroIan- 2-yl)pyrimidin-2-yl]piperidin-4-yl} acetate (Intermediate 17) for Suzuki coupling, ethyl [l -(5-{4- [6-fluoro- 5 -(trifluoromethyl)- 1 H-benzim^

yl]acetate was prepared. LC-MS (ES, m/z): C27H25F4N5O2: 527; Found: 528 [M+H]⁺.

Example 67

[I -f 5- {4-[6-fluoro-5-(trif uoromethyl)- 1 H-benzimidazoi-2-yll phenyl }pyrimidin-2-yl)piperidin-4- yll acetic acid In the same procedure as Step B in Example 1, [l-(5-{4-[6-fluoro-5-(trifluoromethyl)-lH- benzimidazol-2~yl]phenyl}pyrimidin-2-yl)piperidin"4-yl]acetic acid was prepared. LC-MS (Es, m/z): C2SH23N3O S: 499; Found: 500 [ +H]⁺. Example 68

(1 - { 5-[3-fluoro-4-(5-iodo-3H-imidazo[4,5-&]pyri^^

ypacetic acid

In the same synthetic sequence as Example 67, (l-{5-[3-fluoro-4-(5-iodo-3H- imidazo[4,5- )]pyridin-2-yl)phenyl]pyrimidin-2--yl}piperidin-4--yl)acetic acid was prepared. LC- MS (Es, m/z): C₂₃H₂oFIN₆0₂: 558; Found: 559 [M+H]⁺.

Example 69

ethyl l-(5-(4-[5-(tiifluoromediYl)-lH-benzimidazol-2-vllphenyl}pyrimidin-2-y

yl] acetate

To a mixture of 2-[4-(4,4,5,5-tetramethyl-13₅2-dioxaborolan-2-yl)phenyl]-5- (trifluoromethyl)-lH-benzimidazole (Intermediate 12, 0.08 g, 0.206 mmol, 1.00 equiv), ethyl [1- (5-bromopyrimidin-2-yl)piperidin-4-yl]acetate (Intermediate 17, 0.135 g, 0.412 mmol, 2.00 equiv), Paladium tetrakis (0.036 g, 0.031 mmol, 0.15 equiv) and Na₂C0₃ (0.087 g, 0.824 mmol, 4.0 equiv) was added DMF (2.0 mL)/H₂0 (0.5 mL). The reaction mixture was degassed and purged with nitrogen with stirring for 10 min followed by microwave at 155 °C for 90 min. The solvent was evaporated and mixture was diluted with water and extracted 3x with EtOAc. The organic layers were combined, dried over MgS0 and concentrated in vacuo. The residue was purified by eluting through a silica gel column with a 0-70% EtOAc/Hexane solvent system to provide product ethyl [l-(5-{4-[5-(trifluoromethyl)-lH-beixzimidazol-2-yl]phenyl}pyrimidin-2- yl)piperidin-4-yl)acetate. LC-MS (ES, m/z) C₂7H₂₆F3N₅0₂: 509; Found: 510 [M+H]\ Example 70

[ 1 -(5- {4-[5-(tiifluoromethyl)- lH-berjzimidazol-2-yl phenyl}py iim

acid

In the same procedure as Step B in Example 1 of hydrolysis of ester in Example 69, [ 1 -(5- {4- [5 -(trifluoromethyl)- 1 H-benzimidazol-2-yl] phenyl } pyrirmdin-2-yl)piperidin-4- yljacetic acid was prepared. LC-MS (ES, m/z) C25H22F3N5O2: 481 ; Found: 482 [ +H]⁺.

Example 71

ethyl [ 1 -(5- { 5- [5 -(trifluoromethyl V 1 H-benzimida2ol-2-yllpyridin-2-yi }pyrimidin-2-yI piperidin-

4-yl]acetate

To a mixture of 2-[4-(4,4.5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl]-5-

(trifluoromethyl)- lH-benzimidazole (Intemiediate 17, 0.08 g, 0.206 mmol, 1.00 equiv), 2-(6- bromopyridin-3-yl)-5-(trifluoromethyl)-lH-benzimidazole (Intermediate 6, 0.135 g, 0.412 mmol, 2.00 equiv), tetrakis (0.036 g, 0.031 mmol, 0.15 equiv) and Na₂C0₃ (0.087 g, 0.824 mmol, 4.0 equiv) was added DMF (2.0 mL)/H₂0 (0.5 mL). The reaction mixture was degassed and purged with nitrogen with stirring for 10 min followed by microwave at 155 °C for 90 min. The solvent was evaporated and the mixture was diluted with water and extracted 3x with EtOAc. The organic layers were combined, dried over MgS0 and concentrated in vacuo. The residue was purified by eluting through a silica gel column with a 0-70% EtOAc/Hexane solvent system to provide product ethyl [l -(5-{5-[5-(trifluoromethyl)-lH-benzimidazoi-2-yl]pyridin-2- yl}pyrimidin-2-yl)piperidin-4-yl]acetate was prepared. LC- S (ES, m/z) C26H25F3N6O2: 510; Found: 511 [M+H .

Example 72

[l-f5-(5-f5-(trifluoromethylVIH-b^

y¾] acetic acid In the same procedure as Step B in Example 1 hydrolysis of the ester in Example

71 , [ 1 -(5- {5- [5-(trifluoromethyl)- 1 H-benzimidazol-2-yl )pyridin-2-yl } pyriraidin-2-yl)piperidin-4- yl]acetic acid was prepared. LC- S (ES, mJi) C₂₄H₂iF₃N₆0₂: 482; Found: 483 [M+Hf .

Example 73

ethyl ( 1 - { 5- [ 5 -( 5 -chloro- 1 H~berizimidazol-2-yl)pyridin-2-yl1 pyrimidin-2-yl } piperidin-4- yDacetate

To a mixture of 2-[4-(4,4.5,5-tetramethyi-l,3,2-dioxaborolan-2-yl)phenyl]-5- (trifluoromethyl)-lH-benzimidazole (Intermediate 17, 0.05 g, 0.133 mmo!, 1.00 equiv), 2-(6- bromopyridin-3-yl)-5-chloro-lH-benzimidazole (intermediate 4, 0.082 g, 0.266 mmol, 2.00 equiv), tetrakis (0.023, 0.02mmol, 0.15 equiv) and Na₂C0₃ (0.056, 0.533oL 4.0 equiv) was added DMF (1.5)/¾0 (0.5 mL). The reaction mixture was degassed and purged with nitrogen with stirring for 10 min followed by microwave at 155 °C for 90 min. The solvent was evaporated and the mixture was diluted with water and extracted 3 with EtOAc. The organic layers were combined, dried over gS0 and concentrated in vacuo. The residue was purified by eluting through a silica gel column with a 0-70% EtOAc/Hexane solvent system to provide product ethyl (l-{5-[5-(5-chloro-lH-benzimidazol-2-yl)p^ was prepared. LC-MS (ES, m/z) C₂5H₂₅C1N₆0₂: 476; Found: 477 [M+Hf. Example 74

(l-(5-r5-(5-chloro-lH-benzimidaz^ In the same procedure as Step B in Example 1 of hydrolysis of ester in Example 73, (l-{5-[5-(5~chloro-lH-benzimidazol-2 y

acid was prepared. LC-MS (ES, m/z) C23H₂₁CIN6O₂: 448; Found: 449 [M+H]⁺. Example 75

ethyl ( 1 - { 5- [5-(6-fluoro- 1 H-benzimidazol"2-yl. pyridin-2-yl^"1pyrimidin-2-v piperidm-4- yPacetate To a flask was added solution of 4-fluorobenzene-l,2-diamine (0.035 g, 0.277 mmol) in

DMF (2.0 mL)/H₂0 (0.15 mL) followed by ethyl { l -[5-(5-formylp ridin-2-yl)p rimidin-2- yl]piperidin-4-yl}acetate (Intermediate 31, 0.108 g, 0.305 mmol) slowly and then OXONE (0.1 19 g, 0.194 mmol). The mixture was then stirred at room temperature for 1 :30 hr, quenched with a 1 M solution K₂CO3 and water. The resulting mixture was stirred for 5 min, diluted with water and extracted with EtOAc 3x. The combined organic layers were dried over Mg₂S0₄, filtered and. concentrated in vacuo. The residue^' was purified by eluting through a silica gel column with a 0- 70% EtOAc/Hexane solvent system to provide product ethyl (l-{5-[5-(6-fluoro-lH- benzimidazol-2-yl)pyridin-2-yl]pyrimidin-2-yl}piperidin-4-yl)acetate. LC-MS (ES, m/z) C₂₅H₂₅FN₆O₂: 460; Found: 461 [M+Hf.

Example 76

( 1 - { 5-[5 -f 6-fluoro- 1 H-benzimidazol-2-yl^')pyridin-2-yl]pyrimidin-2-yl } piperidin-4-yl)acetic acid In the same procedure as Step B in Example 1 hydrolysis of ester from Example

75 , ( 1 - { 5 - [5 -(6-fluoro- 1 H-benzimidazol-2-yl)pyridi n-2-yl]pyrimidin-2-yl } piperidin-4-yl)acetic acid was prepared. LC-MS (ES, m/z) C₂₃H₂iFN₆0₂: 432; Found: 433 [M+H]⁺.

ethyl n-{5-r5-(5-methoxy-3H-imidazor4,^

4-yl)acetate

In the sam.e procedure as Example 75, but using 6-methoxypyridine-2,3 -diamine hydrochloride (Intermediate 1 , 0.05g, 0.285 mmol), ethyl (l-{5~[5-(5-methoxy-3H-imidazo[4,5- i>]pyridin-2-yl)pyridin-2-yl]pyrimidin-2-yl}piperidin-4-yl)acetate was prepared. LC-MS (ES, m/z) C₂5H₂7N₇0₃: 473; Found: 474 [M+H]⁺.

Example 78

fl-(5-[5-(S-methoxy-3H-imidazo[4,5-&]pyridin^

yDacetic acid

In the same procedure as Step B in Example 1 hydrolysis of ester from Example 77, ( 1 ~ { 5 - [5-(5 -methoxy-3H-imidazo [4 , 5 -&]pyridin-2-yl)pyridin-2-yl]pyrimidin-2 -yl } piperidin-4- yl)acetic acid was prepared. LC-MS (ES, m/z) C23H23N7O3: 445; Found: 446 [M+H .

Example 79

ethyl (1 - { 5 - [^"5-(4,6-difluoro- 1 H-benzimidazol-2-yl)pyridin-2-yl1 pyrimidin-2-yl }piperidin-4- vDacetate

In the same procedure as Example 75, but using 2-(6-brornopyridin-3-yi)-4,6- difluoro-lH-benzimidazole, ethyl (l -{5-[5-(4,6-difluoro-lH-benzimidazoi-2-yI)pyridin-2- yl]pyrimidin-2-yl}piperidin-4-yl)acetate was prepared. LC-MS (ES, m/z) C25H2 F2 6O2: 478; Found: 479 [M+Hf.

(1 -f 5-f5-f4,6-difluoro-lH-benzto

acid

In the same procedure as Step B in Example 1 hydrolysis of ester from Example 79, (1 - { 5 -[5-(4,6-difluoro- lH-benzimidazol-2-yl)pyridin-2-yl]pyrimidm-2-yl } iperidin-4- yl)aceiic acid was prepared. LC-MS (ES, m/z) C₂3H₂oF₂N₆0₂: 450; Found: 451 [M+H]⁺.

Example 81

ethyl [ 1 -(5- (3 -fiuoro-4- 6-(trifluoromethyl)- 1 H-benzimidazol-2-yl] phenyl ) pyrimidin-2- yl)piperidm-4-yl]acetate

In the same procedure as Example 75, but using 4-(trifluoromethyl)benzene-l ,2- diamine and ethyl { l -[5-(3-fluoro-4-formylphenyl)pyrimidin-2-yl]piperidin-4-yl}acetate (Intermediate 18), ethyl [l-(5-{3-fluoro-4-[6-(trifluoromethyl)-lH-benzimidazol-2- yl]phenyl}pyrimidin-2-yl)piperidin-4-yl]acetate was prepared. LC-MS (ES, m/z) C27H25F4N5O2: 527; Found: 528 [M+H]⁺.

[l-f5-{3-fluoro-4-[6-(trifluoromethyl)-lH- yllacetic acid

In the same procedure as Step B in Example 1 hydrolysis of ester from Example 81 , [l -(5-{3-i3uoro-4-[6-(trifluoromethyl)-lH-benzimidazol-2-yl]phenyl}pyrimidin-2- yl)piperidin-4-yl] acetic acid was prepared. LC-MS (ES, m/z) C25H21F4N5O2: 432; Found: 433 [M+H .

ethyl [ 1 -(5- { 5-f 6-(trifluoromethoxy)- lH~benzimidazoi-2-yI]pyridin-2-yl} pyrimidin-2- yl)piperidin-4-yljacetate

In the same procedure as Example 75, but using 4-(trifiuoromethoxy)benzene-l ,2- diamine and ethyl {l-[5-(5-formylpyridin-2-yl)pyrimidin~2-yl]piperidin-4-yl}acetate

(Intermediate 18), ethyl [i~(5-{5-[6-(trifluoromethoxy)-lH-benzimidazol-2-yl]pyridin-2- yl}pyrimidin-2-yl)piperidin-4-yl] acetate was prepared. LC-MS (ES, m/z) C26H25F3N6O3: 526; Found: 527 [M+H]⁺.

Example 84

Γ 1 -(5- ( 5- 6-f trifluoromethoxy)- 1 H-benzimidazol-2-yl] pyridin-2-yl } pyrimidin-2-yl pipertdin-4- yl]acetic acid

In the same procedure as Step B in Example 1 hydrolysis of ester from Example 83, [l-(5-{5-[6-(trifluoromethoxy)-lH-berizimidazol-2-yl]pyridin-2-yl}pyrimidm^

4-yl]acetic acid was prepared. LC-MS (ES, m/z) C24H21F3N6O3 : 498; Found: 499 [M+H]⁺.

Example 85

(l-{5-[4-(5,6~difluoro H-benzimidazol-2^

yl)acetetic acid hi the same procedure as Examples 75-76, but using 4,5-difluorobenzene-l ,2- diamine and ethyl { l -[5-(5-formylpyridin-2-yl)pyrimidin-2-yl]piperidin-4-yl}acetate

(Intermediate 18), (l-{5-[4-(5,6-difluoro-lH-benzimidazol-2-yl)-3-fluorophenyl]pyrimidm-2- yl}piperidin-4-yI)acetic acetic. LC-MS (ES, m/z) C24H20F3N5O2: 467; Found: 468 [M+H]⁺.

Example 86

(l-{5-[5-f5,6-difluoro-lH-benzim^

acid In the same procedure as preparation of Examples 75-76, (I-{5~[5-(5,6-difluoro- lH-benzimidazol-2-yl)pyridin~2-yl]pyri^ acid was prepared. LC-

MS (ES, m/z) C₂₃¾oF₂N₆0₂: 450; Found: 451 [M+H]⁺.

[l-(5-(3-fluoro-4-[6-(trifluoromethoxy H^

4-yll acetic acid In the same procedure as preparation of Examples 75-76, [l-(5-{3-fluoro-4-[6-

(trifiuoromethoxy)-lH-berizimidazol-2-yl]phenyl}pyrimidin-2-yl)piperidin-4^»yl]acetic acid was prepared. LC-MS (ES, m/z) C25H21F4N5O3 : 515; Found: 516 [ +H]⁺.

Example 88

(I-{5-[4-(5,6-dichloro-lH-benzimidazol-2-yl)-3-fluorophenyl]pyrimidin-2-v piperi

vDacetic acid

In the same procedure as preparation of Examples 75-76, (l -{5-[4-(5,6-dichloro- lH-be]izimidazol-2-yl)-3-fluorophenyl]pyrimidin-2-yl}piperidin'-4-yi)acetic acid was prepared. LC-MS (ES, m/z) C₂4H2oCl₂FN₅02: 499; Found: 500 [M+H]⁺.

Example 89

Q-{5~[ -f6-ch oro H-benzimidazol-2^

acid

In the same procedure as preparation of Examples 75-76, (l-{5-[4-(6-chioro-lH- benzimidazol-2-yl)-3-fluorophenyl]pyrimidin-2.-yl}piperidin-4-yl)acetic acid was prepared. LC- MS (ES, m/z) C₂₄H₂₁C1FN₅0₂: 465; Found: 466 [M+H]⁺. Example 90

(l-{5-f3-fluoro-4-(5-methoxy-3H-imida^

ypacetic acid In the same procedure as preparation of Examples 75-76, (l-{5-[3-fluoro-4-(5- methoxy-3H-imidazo[4,5-0]pyridin-2-yl)phenyl]pyrimidin-2-yl}piperidin-4-yl)acetic acid was prepared. LC-MS (ES, m/z) C₂₄H₂₃FN₆0₃: 462; Found: 463 [M+Hf.

Example 91

ethyl 1 -(5 - { 3 -fluoro-4-[6-(trifluoromethyl)- 1 H-benzimidazol-2-yl]phenyl )pyrimidin-2- yl)piperidine-3 -carbox ylate

In the same procedure as Example 75, but using 4-(trifluoromethyl)benzene-l,2- diamine and ethyl l -[5-(3-fluoro-4-formylphenyl)pyrimidin-2-yl]piperidine-3-carboxylate₅ ethyl 1 -(5 - { 3 -fiuoro-4- [6-(trifluoromethyl)- 1 H -benzimidazol-2-yl]phenyl } pyrimidin~2-yl)piperidine-3 - carboxylate was prepared. LC-MS (ES, m/z) C₂₆i½F Ns0₂: 526; Found: 527 [M+H]⁺.

Example 92

l-(5-{3-fluoro₇4-[6-ftrifluorom

carboxylic acid

In the same procedure as Step B in Example 1 hydrolysis of ester from Example 91 , 1 -(5 - { 3 -fluoro-4- [6-(trifluoromethyl)- 1 H-benzimidazol-2-yl]phenyl } pyrimidin-2- yl)piperidine-3-carboxylic acid was prepared. LC-MS (ES, m/z) C24H19F4N5O2: 485; Found: 486 [M+Hf.

Example 93

1 -( 5- {3 -fluoro-4- [6- trifluorom

3 -carboxylic acid

In the same procedure as the preparation of Examples 75-76, 1 -(5- {3 -fluoro-4- [6- (trifluoromethoxy)-lH-benzimidazol-2-yl]phenyl}pyrirnidin-2-yl)piperidine-3-carbo acid was prepared. LC-MS (ES, m/z) C24H19F4N5O3: 501 ; Found: 502 [M+Hf.

Example 94

1 - { - [4-f 6-chloro- 1 H-benzimidazol -2-y0-3 -fluorophenyl] pyrimidin-2-yl } piperidine-3 -carboxylic

acid In the same procedure as preparation of Examples 75-76, l-{5-[4-(6-chloro- lH- benzimidazol-2-yI)-3-fluorophenyl]pyrimM^ acid was prepared.

LC-MS (ES, m/z) C₂3H₁9CIFN₅O2: 451 ; Found: 452 [M+Hf. Example 95

1 - ( 5 - [4-(6-cyano- 1 H-benzimidazol -2-ylV 3 -fluorophenyll pyrimidin-2-yl } piperidine-3 -carboxylic

acid

In the same procedure as the preparation of Examples 75-76, l-{5-[4-(6-cyano- lH-benzimidazol-2-yl)-3-fluorophenyl]pyrimidin-2-yl}piperidine-3-carboxylic acid was prepared. LC-MS (ES, m/z) C₂₄H₁₉FN₆0₂: 442; Found: 443 [M+Hf.

[l-(5-{3-fluoro-4-[6-(trifluorometh^

yl]acetic acid

In the same procedure as the preparation of Examples 75-76, [l-(5-{3-fiuoro-4-[6- (trifluoromethyl)-lH-beirzimidazol-2-yl]phenyl}p)Timidin-2-yl)piperidin-3-yl]acetic acid was prepared. LC-MS (ES, m/z) C₂₅H₂iF₄N₅0₂: 499; Found: 500 [M+Hf.

Example 97

1 - ( 5- [3 -fluoro-4-f 5 -methoxy-3 H-imidazo f 4,5 -61pyridin-2-yl)phenyll pyrimidin-2-yl } piperidine-

3-carboxyiic acid In the same procedure as the preparation of Examples 75-76, l-{5-[3-fluoro-4-(5- methoxy-3H-imidazo[4,5-¾]pyridin-2-yl)phenyl]pyrimidin-2-yl}piperidine-3-carboxylic acid was prepared. LC-MS (ES, m/z) C2₃H21FN₆O₃: 448; Found: 449 [M+H .

Example 98

ethyl l-{5-f3-fluoro-4-(5-methoxy-3H-imidazof4,5- ?lpyridin-2-yl phenyl1pyrimidin-2- yl } piperidine-3 -carboxylate

In the same procedure as Example 75, but using 6-methoxypyridine-2,3-diamine and ethyl l-[5-(3-fluoro-4-forrnyIphenyl)pyrimidin-2-yl]piperidine-3-carboxylate, ethyl l-{5~[3- fluoro-4-(5-methoxy-3H-imidazo[4,5-i?]pyridin-2-yl)phenyl]pyrimidin-2-yl}piperidine-3- carboxylate was prepared. LC-MS (ES, m z) C₂₅H₂₅FN₆0₃: 476; Found: 477 [M+H]⁺.

Example 99

ethyl (3i$^-l-(5-{3-fluoro-4- 6-(trifluoromethyl -lH-benzimidazol-2-yllphenyHpyrimidin-2- yl)piperidine-3 -carboxylate

In the same procedure as Example 75, but using 4-(trifluoromethyl)benzene-l ,2- diamine and ethyl (35)-l ~[5-(3-fluoro-4-formylphenyl)pyrimidin-2-yl]piperidine-3-carboxylate, ethyl (3 S)- 1 -(5 - { 3 -fluoro-4-[6-(trifluoromethyl)- 1 H-benzimidazol-2-yl] henyl } pyrimidm-2- yl)piperidine-3 -carboxylate was prepared. LC-MS (ES, m/z) C2₆H23F₄N₅0₂: 513; Found: 514 [M+H]⁺.

Example 100

(3S)- 1 -(5- { 3 -fluoro-4- Γ 6-( trifluoromethyl)- 1 H-beiizimidazol-2-yI]pheny] ) pyrimidin-2- yl)piperidine-3-carboxylic acid

In the same procedure as Step B Example 1 hydrolysis of ester from Example 99, 1 (35)- 1 -(5 - { 3 -fluoro-4-[6-(trifluoromethyl)- 1 H-benzimidazol-2-yl] phenyl } pyrimidin-2- yl)piperidine-3-carboxylic acid was prepared. LC-MS (ES, m/z) C24H1 F4NSO2: 485; Found: 486 [M+H]⁺.

Example 101

ί -(5 - f 4-P5 - f 2,4-difluorophenyl>3H-imidazo [^"4.5- &1pyridm-2-yI1 -3 -fluorophenyl } pyrimidin-2- yl)piperidine-3-carboxylic acid

In the same procedure as the preparation of Examples 75-76, l-(5~{4-[5-(2,4- difluorophenyl)-3H-imidazo[4,5-£]pyridin-2-y^^

carboxylic acid_.was prepared. LC-MS (ES, m/z)

530; Found: 531 [M+H .

Example 102

4-ylloxy) acetic acid

In the same procedure as the preparation Example 32 using Intermediate 27, {[1- (5 - { 3 -fluoro -4- [6- (trifluoromethyl)- 1 H-benzimidazol-2-yl]phenyl } pyrimidin-2-yl)piperidin-4- yl]oxy} acetic acid was prepared. LC-MS (ES, m/z) C2SH21F4N5O3: 515; Found: 516 [M+H]⁺. Example 103

(3i^~l-f5 3-fluoro-4- 6-ftrifluorom

yl)piperidine-3-carboxylic acid

In the same procedure as preparation of Example 32 using Intermediate 27, (3R)~ 1 -(5- {3-fluoro-4-[6-(trifluoromethyi)-l H-ben2drrudazoi-2-yl]phenyl}pyrimidin-2-yl)piperidine-3- carboxylic acid was prepared. LC-MS (ES, m/z) C₂₄H_i9F₄N₅0₂: 485; Found: 486 [M+H]⁺. Example 104

OS)- 1 -f 5-{3-fluoro-4- 6-ftrifluoromethyl -l H-berrzimidazol-2-ynphenYUpyridin-2-yl)piperidine-

3-carboxylic acid In the same procedure as the preparation of Example 76, (3S)-l-(5-{3-fluoro-4~[6-

(trifluoromethyl)- lH-benzimidazol-2-yI]phenyl}pyridin-2-yl)piperidine-3-carboxylic acid was prepared. LC-MS (ES, m/z) C₂₅H₂oF₄N₄0₂: 484; Found: 485 [M+H]⁺.

Example 105

OR)- 1 -( 5- ( 3 -fluoro-4- 6-(trifluoromethyl)- 1 H-benzimidaz:ol-2-vI1 phenyl } pyridin-2- yl)piperidine-3-carboxyiic acid

In the same procedure as the preparation of Example 76, (3i?)-l -(5-{3-fluoro-4-[6- (trifluoromethyl)-lH-benzimidazol-2-yl]phenyl}pyridin-2-yl)piperidine-3-carboxylic acid was prepared. LC-MS (ES, m/z) C₂₅H₂oF₄N₄0₂: 484; Found: 485 [M+H]⁺.

Example 106

(3 R)- 1 - { 5 - [5 -f trifluoromethyl)- 1 H-benzimidazol-2-ylV2,3 '-bipyridin-6'-yl } piperidine-3 - carboxylic acid In the same procedure as the preparation of Example 76, (3i?)-l-{5-[5-

(trifluoromethyl)-lH-benzim^ acid was prepared. LC-MS (ES, m/z) C24H20F3N5O2: 467; Found: 468 [M+H]⁺.

Example 107

OS)- 1 - { 5- [5 -f trifluoromethyl)- 1 H-benzimidazol-2-yI] -2,3 '-bipyridin-6'-v piperidine-3- carboxylic acid

In the same procedure as the preparation of Example 76, (35)-l-{5-[5- (trifluoromethyl)-lH-benzimidazol-2-yl]-2_!3'-bipyridin-6'-yl}piperidirie-3-carboxylic acid prepared. LC-MS (ES, m/z) Cz4¾oF₃NsQ₂: 467; Found: 468 [M+H]⁺.

Example 108

[5''-f5-Trifluorome&yl-lH-ben2oimi^^

yll-acetic acid

Step A: r5"-(5-Trifluoromethyl-lH-benzoimidazol-2-yl)-3,4,5,6-tetrahydro-2H-f 1,2';5',2"1 terpyridin-4-yl] acetic acid ethyl ester

2-(6-bromo-pyridin-3-yl)-5-trifjuoromethyl-lH-benzoimidazole (0.063 g, 0.184 mmol,

1.0 equiv.), [5'-(4,4,5,5-Tetramethyl-[l ,3,2]dioxaborolan-2-yl)-3,4,5,6-tetrahydro-2H- [1 , 2'] bipyridinyl-4-yl] -acetic acid ethyl ester (Intermediate 15, 0.069 g, 0.184 mmol, 1.0 equiv.), tetrakis(tripheny]phosphine)palladium(0) (0.0106 g, 9.21 μπιοΐ, 0.05 equiv.) and sodium carbonate (0.039 g, 0.368 mmol, 2.0 equiv.) were placed in a reaction tube with DMF (0.56 mL) / H2O (0.056 mL) as solvent. The reaction vial was then sealed. The resulting reaction suspension was stirred under vacuum until gas evolution was no longer detected. The reaction vessel was filled with N2 (g) while stirring continued. The reaction was evacuated / filled with

N2 (g) twice more. The reaction suspension was stirred under microwave conditions: 150°C, lhr. The reaction cooled to room temperature. The reaction suspension was concentrated to an oil, which was then diluted with ¾0 / EtOAc. After shaking, the EtOAc phase was dried over Na2S04, filtered, and concentrated to an oil. Purification with Biotage SP-1 [ 0 > 12% 2CV; 12

> 100% 10CV; 100% 2CV ] isolated product as a yellow solid. LC-MS (ES, m/z):

C27H26F3N5O2: 509; Found: 510 [M+H .

Step B: |^'5"-(5-Trifluoromethyl-lH-benzoimidazol-2-yl -3.4.5.6-tetrahvdro-2H-ri .2';5^,.2^,1 terpyridin-4-yl|-acetic acid

[5"-(5 -Trifluoromethyl- 1 H-benzoimidazoi-2-yl)-3 ,4,5 ,6-tetrahydro-2H-

[l_f2' 5',2"]terpyridin-4-yl]-acetic acid ethyl ester (0.08 g, 0.157 mmol, 1.0 equiv.) was dissolved in THF (IraL): MeOH (1 mL): H2O (1 mL) and stirred at room temperature. Lithium hydroxide hydrate (0.067 g, 1.595 mmol, 10.16 equiv.) was added to the solution, which then stirred for 2 hrs as a suspension. 1 N HC1 (aq) (1.59 mL) was added to the reaction and a suspension remained. IN NaOH (aq) (0.05 mL) was added to neutralize to a solution with minimal solid in suspension. The suspension was filtered and the collected solution was purified on reverse phase HPLC (YMC column) to provide the desired product as a TFA salt. LC-MS (ES, m z):

C25H22F3N5C C2HF3O2: 481 ; Found 482 [M+H .

Example 109

f "-(5-Chloro-lH-berrzoimidazol-2-yl)^

acid

In the same Procedure as Example 108, [5"-(5-Chloro-lH-benzoimidazol-2-yl)-3,4,5,6- tetrahydro-2H-[l₅2';5',2"]terpyridin-4-yl]-acetic acid was prepared as a TFA salt. LC-MS (ES, m/z): C24H22CIN5O2: 447; Found 448 [M+H]⁺.

Example 1 10

{5'-H-f5-Chloro-lH-benzoimidazol-2-yl)-3-fluojro-phep

[ 1 ,2']bipyridinyl-4-yl } -acetic acid

bipyridinyl-4-yI} -acetic acid ethyl ester

[5'-(3-Fluoro-4-formyl-phenyl)-3 ,4,5,6-tetrahydro-2H-[l ,2']bipyridinyl-4-yl]-acetic acid ethyl ester (Intermediate 20, 0.05 lg, 0.138 mmol, 1.0 equiv.) and 4-Chloro-benzene-l,2-diamine (0.029 g, 0.207 rnmol, 1.5 equiv.) were dissolved in DMF (3.6 mL) / ¾0 (0.9 mL) and stirred at room temperature. Oxone (0.059 g, 0.096 mmol, 0.7 equiv.) was added and stirring continued in a sealed flask overnight. The reaction was poured into 1M K2CO3 (aq) ImL / ϊ¾0 3-4 mL and stirred. The work-up suspension was extracted several times with EtOAc. The combined EtOAc phases were dried over Na2SO_i, filtered, and concentrated. Purification with Biotage SP-1 [ hexanes:EtOAc solvent system ] isolated the desired product. LC-MS (ES, m/z);

C₂₇H₂₆C1FN40₂: 492; Found: 493 [M+H]⁺.

Ste B: f 5'-f4-f 5-Chloro- 1 H-ben2oimidazol-2-yl)-3-fluoro-phenyl1-3.4,5,6-tetrahvdro-2H- i^"! ,2'lbi yridinyl-4-yI.}_i -acetic acid

{5'-f4-(5-Chloro-lH-benzoimidazol-2-yl)-3-fluoro-phenyl]-3,4,5,6-tetrahydro-2H-

[l,2']bipyridmyI-4-yl} -acetic acid ethyl ester (0.062 g, 0.126 mmol, 1 equiv.) was dissolved in H2O (1 mL) / MeOH (1 mL) / THF (1 mL) and stirred at room temperature. Lithium hydroxide hydrate (0.03 g, 1.258 mmol, 10 equiv.) was added; stirring continued. After stirring overnight, the reaction was acidified with 2M HC1 (aq) (0.629 mL). After a suspension formed, IN NaOH (aq) was added dropwise until the stirring suspension formed a solution once again. The solution was filtered and the collected solution was purified by reverse phase HPLC (YMC column) to isolate the desired product as a TFA salt, 0.051 lg. LC-MS (ES,m/z): C₂5H₂₂C1FN₄0₂-C₂HF₃0₂: 464; Found: 465 [M+H]⁺. Examples 11 1-114

Using the sample procedure for Example 110 above with [5'-(3-Fluoro-4-formyl-phenyl)- 3_>4_s5,6-tetrahydro-2H-[l,2']bipyridinyl-4-yl]-acetic acid ethyl ester, Examples 1 1 1-114 were prepared:

Example 1 15

I_, - { 5- [3 -Fiuoro-4-f 5 -trifluoromethYl- 1 H-benzo imidazol-2-yl)-phenyll -pyrazin-2-yI } -piperidin-4- vD-acetic acid

Step A: ethyl \ 1 -(5 -chloropyrazm-2-y )piperidm-4-yl] acetate

2,5-Dichloropyrazine (1.42 g, 9.53 mmol, 1.0 equiv.) and ethyl piperidin-4-ylacetate

(1.66 g, 9.69 mmol, 1.02 equiv.) were dissolved in DMF (23 mL) and stirred at room

temperature. Cesium carbonate (5.0 g, 15.35 mmol, 1.61 equiv.) was added and the resulting reaction suspension was stirred in a 55°C oil bath for 3 hrs while under N2(g)- The reaction suspension was filtered to remove solids and to collect the DMF solution, which was mostly concentrated to a suspension. The suspension was dissolved in EtOAc / 1¾0. After shaking, the

EtOAc phase was dried over Na2S04, filtered, and concentrated to a residue. Purification with Biotage SP-1 [ SNAP lOOg cartridge Hexanes:EtOAc 0 > 10% 2CV; 10 > 80% 10CV; 80% 2CV ] isolated the desired product. LC-MS (ES, m z): Ci₃H_l8ClN₃02: 283; Found: 284

[M+Hf. Step B: ( 1 - { 5- [3-Fluoro-4-(5 -trifluoromethyl- 1 H-benzoimidazol-2-yl)-phenyl1 -pyrazin- 2-yi}-piperidin-4-yl)-acetic acid ethyl ester

2-[2-Fluoro-4-(4,4,5₅5 etramethyl-[1 ,2]dioxaborolan-2~yl)-phenyl]-5-lxifluoromethyl- lH-benzoimidazole (Intermediate 13, 0.045 g, 0.111 m.mol, 1.0 equiv.), ethyl [l-(5- chloropyrazin-2-yl)piperidin-4-yl]acetate (0.047 g, 0.166 mmol, 1.5 equiv.)

tetrakistriphenylphosphine palladium (0) (0.026 g, 0.022 mmol, 0.2 equiv.), and sodium carbonate (2M_f 0.22 mL, 0.443 mmol, 4 equiv.) were suspended in DME (1.26 mL) / Ethanol

(1.26 mL). The reaction suspension was stirred in a sealed vial. The reaction was degassed under vacuum and then 2 (g) was bubbled into the suspension for 15 min. The reaction suspension was microwaved at 150°C for 1 hr. The reaction suspension was concentrated to a residue, which was then dissolved / suspended in EtOAc / ¾0. After shaking, the EtOAc phase was dried over Na2S0 , filtered, and concentrated to a yellow solid. Purification with Biotage

SP-1 [Flash 25+S. Hexanes:EtOAc 0 > 12% 2CV; 12 > 100% 10CV; 100% 2CV ] isolated the desired product. LC-MS (ES, m/z): C27H25F4NSOZ: 527; Found: 528 [M+H]⁺.

Step C: ( 1 - { 5 - [3 -Fluon 4-(5 -trifluoromethyl- 1 H-benzoimidazoi-2-yl Vphenyll -pyrazin- 2-yl|-piperidin-4-yl -acetic acid

( 1 - { 5 ~[3~Fluoro-4-(5 -trifluoromethyl- 1 H-benzoimidazol-2-yl)-phenyl]-pyrazin-2-yl } - piperidin-4-yl)-acetic acid ethyl ester (0.032 g, 0.061 mmol, 1.0 equiv.) was suspended in THF (0.8 mL) / MeOH (0.8 mL) / Water (1.6 mL) and stirred in a sealed flask at room temperature. Lithium hydroxide hydrate (0.031 g, 0.739 mmol, 12.18 equiv.) was added in one portion and stirring continued over the weekend. The reaction was neutralized with 1M HCl (aq) (0.061 mL, 1.0 equiv.). Purification with Reverse Phase HPLC (YMC column) isolated possible product. LC-MS (ES, m/z): C₂₅H_2]F₄N_s0₂: 499; Found: 500 [M+H]+.

Examples 116-131

To a solution of 5-(5-Chloro-lH-benzoimidazol-2-yl)-6'-fluoro-[2,3']bipyridinyl (Intermediate 29, leq) and primary/secondary amine substrate (2 eq) in NMP was added

NaBCOs (5 eq). The resulting mixture was stirred at 110°C for 20 hr. The reaction was partitioned between EtOAc and water and the organic phase was concentrated in vacuum. The residue was dissolved in MeOH/THF (1 : 1) and treated with 2.5 N LiOH/H₂0 at 50°C for 2 hr. The solvent was evaporated and the residue was neutralized with HOAc. The crude product was purified by preparative reverse phase HPLC (generally 10% acetonitrile: water with 0.1% ammonium hydroxide/formic acid/TFA to 95% acetonitrile: water with 0.1 % ammonium hydroxide/formic acid/TFA) to give the product as a solid (see General Method C).

intermediate 29 Examples 1 16-131

Examples 132-142

Intermediate 30 Examples 132-142 To a solution of 2-[4-(6-Fluoro-pyridin-3-yl)-phenyl]-5-trifluoromethyi-lH- benzoimidazole (intermediate 30, 1 eq) and primary/secondary amine substrate (2 eq) in NMP was added NaHCC>3 (5 eq). The resulting mixture was stirred at 1 10°C for 20 hr. The reaction was partitioned between EtOAc and water and the organic phase was concentrated in vacuum. The residue was dissolved in MeOH/THF (1 :1) and treated with 2.5 N LiOH/¾0 at 50°C for 2 hr. The solvent was evaporated and the residue was neutralized with HO Ac. The crude product was purified by preparative reverse phase HPLC (generally 10% acetonitrile: water with 0.1% ammonium hydroxide/formic acid TFA to 95% acetonitrile: water with 0.1% ammonium hydroxide/formic acid/TFA) to give the product as a solid.

Examples 143-161

^E*^am?^{le 1 08} Examples 143-

161

To a solution of [5''-(5-Trifluoromethyl-lH-berizoimidazol-2-yl)-3,4,5,6-tetrahydro-2H- [l ,2';5',2"]terpyridin-4-yl]-acetic acid (Example 108, leq), and primary/secondary amine substrate (2 eq) in DMF was added HATU (2eq) and DIEA (2eq). The resulting mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered and purified by preparative reverse phase HPLC (generally 10% acetonitrile: water with 0.1% ammonium hydroxide/formic acid TFA to 95% acetonitrile: water with 0.1% ammonium hydroxide/formic acid/TFA) to give the product as a solid.

Examples 162-173

intermediate 32 Exampies 162-173

To a mixture of diamine (2eq) and OXONE (2eq) was added l-(5-formyl-2,3'-bipyridin- 6'-yl)-4-methylpiperidine-4-carboxylic acid (Intermediate 32, 1 eq) in 3% HOAc/DMF. The reaction was stirred at 100°c for 16hr. LC-MS showed that the reaction was completed. The solution was neutralized with 2CO3. The reaction mixture was filtered and purified by preparative reverse phase HPLC (generally 10% acetonitriie: water with 0.1% ammonium hydroxide/formic acid/TFA to 95% acetonitriie: water with 0.1% ammonium hydroxide/formic acid/TFA) to give the product as a solid.

Examples 162-173

DGATl CPM Assay

20uL substrate mixture of 300uM dioiein, 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 DGATl 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 IC50s were calculated.

59.4 90 197 162 1.6

60.0 91 599 163 31.5

8.00 92 4.34 164 2000

47.4 93 3.05 165 5.58

192 94 13.1 166 1.7

69.6 95 76.3 167 1.9

65.1 96 7.18 168 36.9

95.7 97 44.6 169 23.6

242 98 865 170 30

142 99 377 171 10

56.7 100 2.51 172 4.8

22.9 101 28.6 173 2.1

45.2 102 12.4

280 103 4.25

101 104 1.57

387 105 2.15

89.5 106 7.68

522 107 3.01

30.2 108 8.97

72.9 109 10.2

34.1 1 10 7.81

217 1 11 676

48.6 1 12 15.6

66.1 113 2.77

48.4 1 4 57.6

63.8 115 30.2

197 1 16 100

16.1 117 4.46

9.38 118 14.2

2.42 119 51.9

15.3 120 4.50

12.2 121 2.51

35.3 122 106

26.6 122 88.8

10.8 123 57.7

47.4 124 48.7 15.1 125 11.5

20.5 126 109

6.96 127 28.7

16.7 128 18.3

413 129 49.0

5.93 130 21.3

434 131 18.6

27.9 132 5.02

97.2 133 4.98

1 1.4 134 3.60

214 135 7.5

764 136 4.40

39.8 137 108

24.3 138 3.7

822 139 8.1

6.54 140 11.1

11.2 141 34.7

489 142 11.81

6.34 143 53.5

11.9 144 17.3

296 145 24.7

23.0 146 6.13

965 147 5.47

193 148 23

748 149 23.8

482 150 27.5

70.4 151 13.32

11.1 152 87.9

133 153 56.1

6.79 154 1 1.2

979 155 82.1

621 156 190

77.6 157 116

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (Ϊ):

X is selected from the group consisting of-C¾-, -0- and -NH-, wherein any one of the hydrogens can be replaced with any one of R 5 , R 6 or R 7 ;

R¹ is selected from the group consisting of halogen, Ci-Cealkyl, halogen-substitutedC

Cealkyl, -OC C₆alkyl, -Ohalogen-substitutedC_rC₆aIkyl₅ -CN, C C₆alkylCN and -S0₂C C₆alkyl;

R , R^J, R and R^J are independently selected from the group consisting of hydrogen, halogen, -COOH and C C₆alkyl;

R⁶ and R⁷ are independently selected from the group consisting of hydrogen, halogen, Cj-

C₆alkyl, halogen-substitutedCi-C₆alkyl, -COCi-C₆alkyl, -COC_rC₆alkylCOOH, COhalogen- substitutedC_rC₆alkyl, -OH, Ci-C₆alkylOH, halogen- substitutedCi-QalkylOH, -OC_rC,salkyl, - Ohalogen-substitutedCj-C₆alkyl, -COOH, -COOC,-C₆alkyl, -C₁-C₆alkylCOOC₁-C₆alkyl, -d- C₆alkylCOOH, -OC_rC₆alkylCOOH, -CN, CrQalkylCN, -CONH₂, -CONHC_rC₆alkyI, - CON(C C₆alkyl)₂, C_rC₆alkylCONR^sR⁹, Ci-C«alkylpyridine, d-Cgalkylthiazole, oxazolidone, phenyl and Ci-CealkylphenyL wherein the phenyl is unsubstituted or substituted with -CN, halogen or -COOH; or when taken together R and R form cyclohexane, phenyl or a 4-6 membered, nitrogen-containing ring, wherein the cyclohexane, phenyl or a 4-6 membered, nitrogen-containing ring are unsubstituted or substituted with -COOH, Cj-Qalkyl or -Ci- C₆alkylCOOH;

R^s and R⁹ are independently selected from the group consisting of hydrogen, halogen, Ci- C₆alkyl, halogen-substitutedC C₆alkyl, Ci-C₆alkylOCi-C₆alkyl, C_rC₆alkylCOOH,

cyclopropylCOOH and C3-C<;cycloalkyl, or when taken together R and R and the nitrogen on which they are attached form azetidine, pyrrolidine, morphiline or piperdine, wherein the azetidine, pyrrolidine or piperdine is unsubstituted or substituted with one or two substituents selected from the group consisting of -OH, -OCi-Csalkyl and halogen; and m and n are independently 1 or 2.

2. A compound of claim 1 or pharmaceutically acceptable salt thereof having formula la, formula lb or formula Ic:

4. A compound of any one of claims 1 -3 or pharmaceutically acceptable salt thereof wherein X is -0-.

5. A corapound of any one of claims 1-3 or pharmaceutically acceptable salt thereof wherein X is -CH₂-. wherein any one of the hydrogens can be replaced with any one of R⁵ ₅ R¹⁵ or R⁷.

6. A compound of any one of claims 1-3 or pharmaceutically acceptable salt thereof wherein X is-ΝΗ-, wherein the hydrogen can be replaced with any one of R⁵, R⁶ or R⁷.

7. A corapound of any one of claims 1 -6 or pharmaceutically acceptable salt thereof wherein the moeity

is selected from the group consisting of:

8. A compound of any one of claims 1-7, or pharmaceutically acceptable salt thereof, wherein R¹ is selected from the group consisting of trifluoromethyl, trifluoromethoxy, methoxy, fluorine, iodine, chlorine, -CN and -S0₂Me.

9. A compound of any one of claims 1 -8 or pharmaceutically acceptable salt thereof wherein R² is hydrogen or halogen.

10. A compound of any one of claims 1-9 or pharmaceutically acceptable salt thereof wherein R³ is hydrogen or halogen.

11. A compound of any one of claims 1-10 or pharmaceutically acceptable salt thereof wherein R⁴ is hydrogen, methyl or halogen.

12. A compound of any one of claims 1-11 or pharmaceutically acceptable salt thereof wherein R^s is hydrogen, methyl or -COOH.

13. A compound of any one of claims 1-12 or pharmaceutically acceptable salt thereof wherein R⁶ is selected from the group consisting of hydrogen, halogen, Cj-Cgalkyl, -COCi- QalkylCOOH, -OH, -COOH, -COOCi-C₆alkyl, -Ci-C₆alkylCOOC_rC₆alkyl, -Ci-C₆alkylCOOH, -OC_rC₆alkylCOOH, -CN, -CONHQ-Qalkyl, C i-Qalkylpyridine, d-Qalkylthiazole, oxazolidone, phenyl and C_rC₆alkylphenyl, wherein the phenyl is unsubstituted or substituted with -CN, halogen or -COOH.

14. A compound of any one of claims 1-13 or pharmaceutically acceptable salt thereof wherein R⁷ is selected, from the group consisting of hydrogen, halogen, Ci-Cealkyl, -OH, -

COOH.

15. A compound of any one of claims 1-12 or pharmaceutically acceptable salt thereof wherein taken together R⁶ and R⁷ from cyclohexane, phenyl, imidazole, azetidinone,

piperidinone or oxazolidinedione, wherein the cyclohexane, phenyl, imidazole, azetidinone, piperidinone or oxazolidinedione are unsubstituted or substituted with -COOH, Ci-Cgalkyl or - C C₆alkylCOOH.

16. A compound of any one of claims 1 - 12 or pharmaceutically acceptable salt thereof wherein R⁷ is Ci-QalkylCONR⁸R⁹, wherein R⁸ and R⁹ are independently selected from the group consisting of hydrogen, halogen, Ci-C$alkyl, halogen-substitutedCi-Cealkyl, Ci- C6alk lOC₁-C alkyl, Cj-CealkylCOOH, cyclopropylCOOH and C3-C6cycloalkyl_f or when taken together R⁸ and R⁹ and the nitrogen on which they are attached form azetidine, pyrrolidine, morphiline or piperdine, wherein the azetidine, pyrrolidine or piperdine is unsubstituted or 5 substituted with one or two substituents selected from the group consisting of -OH, -OCr C_fjalkyl and halogen

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

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

19. Use of a compound of any o e of claims 1-17_{) 0}r 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 phaimaceutical composition comprising the compound of any one of claims 1-17.