WO2012044567A2 - 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 hyperlipideraia, diabetes mellitus and obesity.

BACKGROUND

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

In general, obesity is caused by the accumulation of triacylglycerol (TG) in adipose tissue which is a result of lack of exercise, intake of excessive calories and aging. In the body there are two TG synthesis pathways, a glycerol phosphate pathway, which is present in most organs and causes de novo TG synthesis, and a monoacylglycerol pathway, which is involved principally in absorption of aliphatic acid from the small intestine. Diacylglycerol acyltransferases (DGATs, EC 2.3.1.20), which are membrane-bound enzymes present in the endoplasmic reticulum; catalyze the final step of the TG synthesis common to the two TG synthesis pathways. The final reaction consists of transferring an acyl group from acyl-coenzyme A to the 3-position of 1,2-diacylglycerol to generate TG (Prog. Lipid Res., 43, 134-176, 2004 and Ann. Med., 36, 252-261, 2004). There are two subtypes of DGATs, DGAT-1 and DGAT-2. There is no significant homology at the generic or amino acid level between the DGAT-1 and DGAT-2, which are encoded by different genes (Proc. Natl. Acad. Sci. USA., 95, 13018-13023, 1998 and JBC, 276, 38870-38876, 2001). DGAT-1, is present in the small intestine, adipose tissue and liver and is believed to be involved in lipid absorption in the small intestine; lipid accumulation in the fat cell; and VLDL secretion and lipid accumulation in the liver (Ann. Med, 36, 252-261, 2004 and JBC, 280, 21506-21514, 2005). In consideration of these functions, a DGAT-1 inhibitor is expected to be an effective obesity treatment through inhibition of lipid absorption in the small intestine, lipid accumulation in the adipose tissue and the liver, and lipid secretion from the liver. In order to carry out in vivo examination of the physiological function(s) of DGAT-1 and inhibitory activity against DGAT-1, DGAT-1 -knockout mice deficient in DGAT-1 at the genetic level was produced and analyzed. As a result, the DGAT-1 -knockout mice have been found to have smaller fat masses than those of wild-type mice and became resistant to obesity, abnormal glucose tolerance, insulin resistance and fatty liver due when fed a high-fat diet (Nature Genetics, 25, 87-90, 2000 and JCI, 109, 1049-1055, 2002). In addition, energy expense has been reported to be accelerated in the DGAT-1 -knockout mice; and transplantation of the adipose tissues of DGAT-1 -knockout mice into wild-type mice has been reported to make the wild-type mice resistant to obesity and abnormal glucose tolerance, induced by a high-fat diet (JCI, 111, 1715 722, 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 over expression 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, associated with the obesity.

SUMMARY OF THE INVENTION

A compound of formula (I):

or pharmaceutically acceptable salts thereof, wherein U, V, R¹, R², R³, R⁴ and R⁵ are defined herein.

DETAILED DESCRIPTION OF THE INVENTION

Compounds

A compound of formula (I):

or pharmaceutically acceptable salts thereof, wherein each occurrence of U and V are independently selected from -N- or -CH- and wherein all three occurrences of V are not simultaneously -N-;

R.¹ is selected from the group consisting of hydrogen, halogen, C_l-C₆alkyl and halogen-substitutedC_l-C₆alkyl or when taken together with R⁴ form a nitrogen-containing herterocycle;

R² is selected from the group consisting of halogen and hydrogen;

R³ is selected from the group consisting of hydrogen, halogen, C_l-C₆alkyl, halogen-substitutedd-Cisalkyl, -OH, CpCgaJUkylOH, halogen-substitutedC CgalkylOH, -OC_l- Cgalkyl, -Ohalogen-substi tedd-C₆alkyl, -Nな and -CN; and

R⁴ is independently selected frora the group consisting of hydrogen, halogen, C_\- Cgalkyl, halogen-substi tedd-C₆alkyl, COC Cealk l, COhdogen-substitutedC_l-Qalkyl, -OH, Q-C₆alkylOH, halogen-substitutedC_l-C₆alkylOH, -OC_l-C₆alkyl, -Ohalogen-substitutedC_l- Osalkyl, -COOH, -COOC C^alkyl, -d-C₆alkylCOOd-^alkyl, ~d-C₆alkylCOOH, -OC_l- CealkylCOOH, -CN, C_l-C₆alkylCN, -N0₂, NH& NHd-dalkyl, N(C_l-C₆alkyl)_2s -NHCOOH, - NHCOOd-C₆alkyl, -CONH2, -C_l-C₆alkyiNHCOd-C₆alkyi, -CONHC_l-C₆alkyI, -C_l- CealkylCONHhalogen-substitutedC_l-C₆alkyl, -C_l-C,jalkylCONHCrC₆alkylOH, -C_l- C₆alkylCONH-OC_l-C₆alkyl_f -C_l-C₆-UkylCONCC_l-C₆alkylX-OCrCe-Ukyl -C_l-C₆alkylCONfC_l- C₆alkyl)₂, -CON(C_l-C₆alkyl)₂, -NHS0₂CrC₆alkyl, S0₂NH_2>-S0₂C_l-C₆alkyl, phenyl, nitrogen or sulfur-containing heterocycle, C_l-C₆alkylnitrogen-containingheterocycle and C_l- CgalkylCOnitrogen-containingheterocycle;

R⁵ is independently selected from the group consisting of -OH, C_l-C₆alkylOH, halogen-substitutedC_l-C₆alkylOH, -COOH, -COOC_l-C<salkyl, -C_l-C₆alkylCOOCrCgalkyl, -C_l- C₆aikylCOOH, -Od-C₆alkylCOOH, -CN, C_l-C₆alkylCN_} -N0₂, NH₂, NHC_l-C₆alkyl, N(d- C₆alkyl)₂, -NHCOOH, -NHCOOC_l-Qsalkyl, -CONH₂, -C_l-C₆alkylNHCOC_l-C₆alkyl, -CONHC,- C₆alkyl, -C_l-C₆alkylCONHd-C₆alkyl, -C_l-C₆alkylCONHhalogen-substitutedd-C₆alkyl, -C_l- CealkylCONHC_l-C₆alkylOH, -d-C₆alkylCONH-Od-C₆alkyl, -CrC₆alkylCON(d-C6alkyl)(- OCj-C₆alkylJ.-C_l-C₆alkylCONCd-C₆alkyl^, -CON(C_l-C₆alkyl)2, -NHS0₂C_l-C₆alkyl, S0₂NH₂, - SOaC_l-C₆alkyl, -C₁-C₍5alkylC0NHC_l-C₆aikylS0₂0H_s phenyl, nitrogen or sulfur-containing heterocycle, CrCealkylnitrogen-containingheterocycle and d-C₆alkylCOnitrogen- containingheterocycle; wherein any phenyl or nitrogen or sulfur-substituted heterocycle can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, Cj-Qalkyl, oxo, halogen-substitutedC_l-C₆alkyl, -OCj-C₆alkyl, -Ohalogen- substitutedC_l-C₆allcyl, -OH and C_l-C6alkylOH, cyclopropyl, phenyl, C_l-C₆alkylphenyl and imidazole.

Of the compounds described herein, U is selected from the group consisting of - N- and -CH-. h certain embodiments of the compounds described herein, U is -N-. In other embodiments, U is -CH-.

Of the compounds described herein, R¹ is selected from the group consisting of hydrogen, halogen, C_l-C₆alkyl and halogen-substitutedC Cealkyl or when taken together with R form a nitrogen-containing herterocycle. In certain embodiments, R¹ is hydrogen. In other embodiments, R¹ is halogen. Suitable halogens include, but are not limited to, chlorine and fluorine. In still other embodiments of the compounds described herein, R¹ is C_l-C₆alkyl.

Suitable alkyls include, but are not limited to, methyl. In yet other embodiments, R¹ is halogen- substitutedC_l-C₆alkyl. Suitable halogen-substitutedC_l-C₆alkyls include, but are not limited to, trifluoromethyl. For example, in certain embodiments, R¹ is fluorine, chlorine or methyl.

Of the compounds described herein, R² is selected from the group consisting of halogen and hydrogen. In certain embodiments, R² is hydrogen. In other embodiments, R² is halogen. Suitable halogens include, but are not limited to, chlorine and fluorine.

Of the compounds described herein, R³ is selected from the group consisting of hydrogen, halogen, C_l-C₆alkyl, halogen-substitutedC_l-C₆alkyl, -OH, Ct-C₆alkylOH, halogen- substitutedCs-C₆alkylOH, -OC_l-C₆alkyl, -Ohalogen-substitutedC_l-C₆alkyl, -Nな, and -CN. In certain embodiments, R³ is hydrogen. In other embodiments, R³ is halogen. Suitable halogens include, but are not limited to, chlorine and fluorine. In still other embodiments, R³ is -Nな. In still other embodiments, R³ is -CN. In yet other embodiments, R³ is -OH. In still other embodiments of the compounds described herein, R³ is Q-C₆alkyl. Suitable alkyls include, but are not limited to, methyl. In yet other embodiments, R³ is halogen-substitutedC_I-C₆alkyl.

Suitable halogen-substitutedC_l-Qalkyis include, but are not limited to, trifluoromethyl. In yet other embodiments, R³ is -OC_l-C₆alkyl. Suitable -OC_l-C₆alkyls include methoxy and ethoxy. In certain embodiments, R³ is selected from the group consisting of hydrogen, halogen, C_l-C₆alkyl, halogen-substitutedC_l-C₆alkyl, -OCj-C₆alkyl, and CrCealkylOH. In other embodiments, R³ is hydrogen, fluorine, chlorine, trifluoromethyl, -OH, ethoxy, methoxy or -CN.

Of the compounds described herein, each occurrence of V is independently selected from -N- or --CH-, wherein all three occurrences of V are not simultaneously -N-. In certain embodiment, every occurrence of V is -CH-. In other embodiments, one V is -CH- and the remaining two occurrence of V is -N-. In still other embodiments, one V is -N- and the remaining occurrences are -CH-. In certain embodiments of the compounds described herein, the moiety:

wherein R³ and R² are described above. In all embodiments described herein, R³ and R² are bonded to a carbon.

Of the compounds described herein, R⁴ is independently selected from the group consisting of hydrogen, halogen, C_l-C₆ lkyl, halogen-substitutedCj-C₆alkyl, COC_l-C₆alkyl, COhalogen-substiwtedQ-C₆alkyl, -OH, C_l-C₆alkylOH, halogen-substitutedCrQalkylOH, -OC_l- C₆alkyl, -Oh ogen-substitutedQ-C₆alkyl, -COOH, -COOC_l-C₆alkyl, -C_l-C₆alkylCOOd- C₆alkyl, -Q-C₆alkylCOOH, -OC_l-C₆alkylCOOH, -CN, CrCealkylCN, -N0₂, NH₂, NHC_l- C₆alkyl, N(Ci-C(tfkyl)₂, -NHCOOH, -NHCOOCrCgalkyl, -CONH₂, -C C₆alkylNHCOC_l- C₆alkyl, -CONHd-C₆alkyi, -C₁-C₆alkylCONHhalogen-substitutedCrC₆alkyI, -C_l- C₆alkylCONHC_l-C₆alkylOH, -C_l-C₆alkyiCONH-OC_l-C₆alkyl₅ -e_rC₆alkylCON(C_l-C₆alkyl)(- OCrCsalky C_l-C₆alkylCONCC_l-C₆alky z, -CONCC_l-C₆alkyl)^ -NHS0₂C,.-C₆alkyl_f S0₂NH_2, - S0₂C_l-C₆alkyl, phenyl, nitrogen or sulfur-containing heterocycle, C_l-C₆alkylnitrogen- containingheterocycle and C_l-C₆alkylCOnitrogen-containingheterocycle.

In certain examples of the compounds described herein, R⁴ is halogen, C_l-C alk l, halogen-substitutedC_l-C₆alkyl, -OH, Ct-C₆alkylOH, -OCj-C₆alkyl, -Ohalogen-substitutedCr C₆alkyl, -CN, C_l-C₆alkyICN, -N0₂, NH₂, NHC_S-C₆alkyl, NCQ-Qalkyl^, -CpQsall ylNHCOCr Cealkyl, -COOCj -C₆alkyl, -CON(C_l-C₆alkyl)₂, -NHS0₂C_l-C₆alkyl, S0₂NH_2> -S0₂C_t-C₆alkyl, phenyl, nitrogen or sulfur-containing heterocycle, wherein any phenyl or nitrogen or sulfur- substituted heterocycle can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, CrC^alkyl, oxo, halogen-substitutedC_l-C₆alkyl, -OC_l- C₆alkyl, -Ohalogen-substitutedC_l-C₆alkyI, -OH, phenyl, cyclopropyl, d-C₆aikylphenyl, imidazole and C_l-QalkylOH.

Suitable halogens include but are not limited to chlorine, fluorine, iodine and bromine. Suitable C_l-C alkyls include but are not limited to methyl, ethyl and butyl. Suitable halogen-substitutedC_l-C6alkyls include trifluoromethyl. Suitable Q-C₆alkylOHs include, but are not limited to, t-butyl-OH. Suitable -OC_l-C₆alkyls include, but are not limited to, methoxy. Suitable -Ohalogen-substitutedCj -Chalky Is include, but are not limited to, trifluoromethoxy. Suitable C₁-C₆alkylCN include, but are not limited to, CなCN. Suitable NHC_l-C₆alkyls include, but are not limited to, -NHCなCH₃. N(C_l-C₆alkyl)₂, Suitable -C_l-C₆alkylNHCOC_l-C₆alkyls include (CH₂)₂NHCOCH₃. Suitable -COOC_l-C₆alkyls include -COOMe. Suitable -CON(C_l- C¾alkyl)2 include, but are not limited to, -CO(CH3)₂. Suitable -NHSOj -C₆alkyls include - HS0₂CH₂. Suitable -SOzC_l-Qalkyls include, but are not limited to SC>₂Me. Suitable nitrogen or sulfur-conteiriing heterocycles include, but are not limited to, pyridine, pyrimidine, pyrazole, imidazole, triazole, tetrazole, pyrimidine,

wherein the phenyl or nitrogen or sulfur-substituted heterocycle can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_\- Cealkyl, oxo, halogen-substitutedC_l-C₆alkyl, -OC_l-C₆alkyl, -Ohalogen-substitutedC_l-C₆alkyl, - OH, phenyl, cyclopropyl, CrC^alkylphenyl, imidazole and C_l-CsalkylOH. In certain embodiment, R⁴ is halogen is trifluoromethyl. In other embodiments, R⁴ is methoxy. In still other embodiments, R⁴ is -ON. In yet other embodiment, R⁴ is S0₂Me. In other embodiments, R⁴ is chlorine, fluorine, bromine and iodine. In still other embodiments, R⁴ is -OH. In yet other embodiment, R⁴ is -NO₂. In yet another embodiment, R⁴ is hydrogen.

In certain embodiment, R⁴ is phenyl or pyridine, wherein the phenyl or pyridine can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, Cj-C₆alkyl, oxo, halogen-substituted -C₆alkyl, -OC_l-C₆aikyI, -Ohalogen- substitutedC_l-Qjalkyl, -OH, phenyl, cyclopropyl, C_l-C₆alkylphenyl, imidazole and C_l- C₆alkylOH.

Of the compounds described herein, R^s is independently selected from the group consisting of -OH, Q-C₆alkylOH, halogen-substitutedd-C₆alkylOFI, -COOH, ~COOC_l-C₆alkyl, -d-C₆alkylCOOC_l-C₆alkyl, -d-C₆a]kylCOOH, -Od-C₆alkylCOOH, -CN, d-C₆alkylCN, -N0₂, NH₂, NHd-C₆alkyl, N(C_l-C₆alkyl)₂, -NHCOOH, -NHCOOC_l-C₆alkyl, -CONH₂, -Cr

CealkylNHCOd-C₆alkyl, -CONHC_l-C₆aIkyI, -d-C₆alkylCONHd-C₆alkyl, -C_l- CealkylCONHhalogen-substitutedCj-C₆alkyl, -C_l-C₆alkylCONHd-C₆alkylOH, -d- dalkylCONH-Od-C₆alkyl, Oj^ialkylCO CC_l-C₆alk lX-OCj-C₆alky^^Ci^alliylCONfC_l- C₆alkyl)₂, -CON(C_l-C₆alkyl)₂, -NHS0₂C_l-C₆alkyl, S0₂NH₂,-S0₂d-C₆alkyl, -C_l- C₆alkylCONHC₁-C₆alkylS0₂OH, phenyl, nitrogen or sulfur-containing heterocycle, Cj- Cgalkylnitrogen-containingheterocycle and C_l-C₆alkylCOnitrogen-containingheterocycIe, wherein any phenyl or nitrogen or sulfur-substituted heterocycle can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, Cj- Cealkyl, oxo, halogen-substitutedC_l-C^alkyl, -OCrdalkyl, -Ohalogen-substitutedC_l-C$alkyl, - OH, phenyl, cyclopropyl, C_l-C₆alkylphenyl, imidazole and d-C₆alkylOH..

In certain embodiments of the compounds described herein, R^s is selected from the group consisting of CH₂COOH and acid replacements or acid mimics. In certain

embodiments of the compounds described herein, R^s is selected from the group consisting of CH₂COOH and CH₂COOCH₂. For example, also described herein are compounds of Formula la, Formula lb and Formula Ic:

a

In still other embodiments of the compounds described herein, R^s can be -Cj- CealkylCO-nitrogen-containingheterocycle, nitrogen-containing heterocycle, -C_l-C₆alkylCONH- OCrCsalkyl, -d-C₆alkylCONHC_l-C₆alkyl-OH, -C_l-C₆alkylCON(C₁~C₆aIkyl)(-OC₁-C₆alkyl)_J - d-C₆alk lCONfC Cealky^ and -C_l-C₆alkylCONHhalogen-substitutedC_l-C₆alkyl, wherein the nitrogen-containing heterocycle is unsubst tuted or substituted with one or more substituents selected from the group consisting of halogen, Q-C₆aikyl, oxo and -OH. In certain

embodiments, R⁵ can be -Cj-C₆alkylOH, such as butanol.

In yet other embodiments of the compounds described herein, R^s can be nitrogen- containing heterocycle, CH2CO-nitrogen-containingheterocycle, CH₂CONH(CH₂)CF₃,

CH₂CON(CH₃)(OCH₃), CH₂CONH((CH₂)20CH₃), CH₂CONH(OCな)₅ CH₂CON(CH₂)₂,

CH₂CONH(CH2)₂CF₃₉ CH₂CONHCH₃ wherein the nitrogen-con^ning heterocycle is selected from the group consisting of:

0

Of the compounds described herein, R¹ can be taken together with R⁴ to form a nitrogen-containing herterocycle. Suitable nitrogen-containing heterocycles include but are not limited to pyridine, pyrmiidine, imidazole, pyrazole, triazole and tetrazole.

Examples of compounds or pharmaceutically acceptable salt thereof described herein are selected from the rou consistin of:

Definitions

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

The term "C_l-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, l-methylbutyl, 2-methylbutyI, 1,2-dimethylpropyI, l-ethylpropyl₅ n-hexyl, isohexyl, l-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, ί ,2-dimethylbutyI, 2,2- dimethylbutyl, 1-ethylbutyl, 1,1,2-trimelhylpropyl, 1,2,2-trimethylpropyl, l-ethyl-2-methylpropyl, 1 -ethyl- 1-methylpropyl, and the like.

The term "-OC_l-C ealkyl " 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 "-OC_l-C ₆alkylCOOH" refers to an alkoxy group having 1 to 6 carbons substituted with a carboxylic acid (-COOK) group.

The term "halogen-substitutedC_l-C₆ alkyl" encompasses Ct-C₆ alkyl with the hydrogen atom s thereof being partially or completely substituted with halogen, examples thereof including fluoromethyl, difluoromethyl, trifluoromethyl, 2-fiuoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl and the like. The term "-Ohalogen-substitutedCj-C₆aJkyl" means a -OCrQalkyl 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 "-COC_l-C₆alkyl" means groups having Q-C₆alkyl bonded to carbonyl, and encompasses alkylcarbonyl having a carbon number of 1 to 6. Specific examples thereof include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and the like.

The term "-COhalogen-substitutedC_l-C₆alky ' means a -COCj-C₆alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different.

The term "Cj-C₆alkylOH" means a C_l-C<;alkyl substituted with an alcohol (-OH).

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

The term "d-C₆alkyiCN" means a CrCealkyl substituted with a cyano group (-CN).

The term "halogen-substituted C₁-C₆alkylOH" means a halogen-substituedCl-C6alkyl substituted with an alcohol (-OH).

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

The term "SChC Csalkyl" means a group having Q-C₆alkyl bonded to sulfonyl (-SO₂-). Specific examples thereof include methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, sec-butanesulfonyl, tert-butanesulfonyl, and the like.

The term "NHCi -C₆alkyl" means a group with one of the hydrogen atoms of amino (-

N¾) being substituted with a d.6 alkyl group. Specific examples thereof include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylammo, sec-butylamino, tert-butylamino, and the like.

The terra ⁱTSf(C₁-C6alkyi)2" means a group with the two amino hydrogen atoms each being substituted with a Ci _-6 alkyl group. Specific examples thereof include dimethylamino, diethylamino, ethylmethylamino, di(n-propyl)amino, methyl(n-propyl)amino, diisopropylamino, and the like.

The term "NHCOzC_l-C₆alkyl" means a group with one of the amino hydrogen atoms being substituted with C].₆ alkoxycarbonyl and encompasses alkoxycarbonylamino having a carbon number of 1 to 6. Specific examples thereof include methoxycarbonylamino,

ethoxycarbonylamino, n-propyloxycarbonylamino, isopropyloxycarbonylamino, n- butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, n- pentyloxycarbonylamino, and the like.

The term "CONHCrCealkyl" means a group with one of the hydrogen atoms of carbamoyl (-CONH2) being substituted with Ci.₆ alkyl. Specific examples thereof include methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl, and the like. The term "CONCCj-Qsalkyiy' means a group with the two carbamoyl hydrogen atoms each being substituted with Cj^ alkyl. Specific examples thereof include dimethylcarbamoyl, diethylcarbamoyl, eraylmethylcarbamoyl, di(n-propyl)carbai«oy methyl(n-propyl)carbamoyl, diisopropylcarbamoyl, and the like.

The term "NHS0₂C1-C6alky ' means a group with one of the amino hydrogen atoms being substituted with C_1-6 alkylsulfonyl. Specific examples thereof include

methanesulfonylamino, emanesulfonylamino, n-propanesulfonylamino,

isopropanesulfonylamino, n-butanesulfonylamino₉ sec-butanesulfonyla ino, tert- butanesulfonylamino, and the like.

The term "heterocycle" means a heterocycle containing one or more, preferably one to three, same or different heteroatoms preferably selected from the group consisting of a nitrogen atom, and a sulfur atom. Examples thereof include pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyi, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, 1,2,3-thiadiazolyi, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyI, 1,3,5-friazinyl, indolyl, benzothienyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl,

benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl 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, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,. iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimet ylammoethanol, ethanolamine, ethylenediamine, Ν-ε^^οφίιοΙίηβ, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, meroylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, ^propylamine, 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 olefi ic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

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

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

cliromatographic 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 (²H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic formula can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates. Methods of Treatment

Also encompassed by the present invention are methods of treating DGAT1 -related diseases. The compounds described herein are effective in preventing or treating various

DGAT1 -related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis. The 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 Fb 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 effective 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 various DGAT1 -related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficifhyperactivity 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, macrocrystalline wax, white petrolatum, magnesium metasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic acid anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, and the like.

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

The pharmaceutical compositions may contain the compound of the invention in an amount of from 1 to 99.9 % by weight, preferably from 1 to 60 % by weight of the

composition. The compositions may further contain any other therapeutically-effective compounds.

In case where the compounds of the invention are used for prevention or treatment for the above-mentioned diseases, the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the 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, Formula lb or Formula Ic or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula I, 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 Ϊ, 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 Fomiula 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) PPARy agonists, such as the glitazones (e.g. pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR ligands, including (1) PPARct/y 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) α-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, C JC- 1131, and BIM-51077, including intranasal, transdermal, and once- weekly formulations thereof;

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

acyltransferase inhibitors, such as avasimibe;

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

(12) antiobesity compounds;

(13) agents intended for use in inflammatory conditions, such as aspirin, nonsteroidal anti-inflammatory 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 1 β-hydroxysteroid dehydrogenase type 1 , such as those disclosed in U.S. Patent No. 6,730,690; WO 03/104207; and WO 04/058741 ;

(17) irihibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib and

M -0859;

(18) inhibitors of fructose 1,6-bisphosphatase, such as those disclosed in U.S. Patent Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476;

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

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

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

40;

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

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

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

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

(32) bromocriptine mesylate and rapid-release formulations thereof. Dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of Formula I_» 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, lmagliptin, and pharmaceutically acceptable salts thereof, and fixed-dose combinations of these compounds with metformin hydrochloride, pioglitazone, rosigiitazone, 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_JR)-5-(l-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)-2-(2,4,5- 1rifluorophenyl)tetrahydro-2H^'-pyran-3-amine;

(2£,3S,5£)-5-(l-methyl-4,6-dihydrop .

trifluorophenyl)tetrahydro-2H-pyran-3 -amine;

(2i?,3S,5i?)-2-(2,5-diflwropheny

yl) tetrahydro-2H-pyran-3 -amine;

(322>4-[(3 )-3-amino-4-(2,4,5-trifl

diazepin-2-one;

4-[(3.¾)-3-amino-4-(2,5-difluorophenyl)bm

one hydrochloride; and

(3_JR)-4-[(3i?)-3-amino-4-(2_s4_i5-trifluorophenyl)butanoyl]-hexahydro-3-(2_!2,2- trifluoroethyl)-2H-1,4-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 M -0557); CB1 receptor inverse agonists and antagonists (such as rimonabant and taranabant); β3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (such as bombesin receptor subtype-3 agonists); and 5-hydroxytryptamine-2c (5-HT2c) agonists, such as lorcaserin. For a review of anti-obesity compounds that can be combined with compounds of the present invention, see S. Chaki et al, "Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity," Expert Opin. Ther. Patents. 1 1: 1677-1692 (2001); D. Spans wick and K. Lee, "Emerging antiobesity drugs," Expert Opin. Emerging Drugs. 8: 217-237 (2003); J.A. Fernandez-Lopez, et al., "Pharmacological Approaches for the Treatment of Obesity," Drugs. 62: 915-944 (2002); and K.M. Gadde, et al., "Combination pharmaceutical therapies for obesity," Exp. Opin. Pharmacother.. 10: 921-925 (2009).

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

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

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

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

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

N-(4-{(lS)-1-[(R)-(4-chlorophenyl)(7-fluoro-5-methyl-1H-indol-3- yl)memyI]butyl}berizoyl)-p-dariine; and

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

pharmaceutically acceptable salts thereof.

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

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

(2'-{4-[2-(ttifluoromethyl)p^ acid; (5- { 3-[4-(2-bromo-5-fluorophenoxy)piperidin- 1 -yl]isoxazol-5-yl}-2H-tetrazol-2-yl)acetic acid; (3 - { 3 - 4-(2-bromo-5-fluorophenoxy)piperidin- 1 -yl] - 1 ,2,4-oxadiazol-5-y I } - 1 H-pyrrol- 1 - yl)acetic acid;

(5-{5-[4-(2-bromo-5-fluorophenoxy)piperid ^^

acid; and

(5-{2-[4-(5-bromo-2-chlorophenoxy)piperidm^^

yl)acetic acid; and pharmaceutically acceptable salts thereof.

Glucokinase 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-emanesulfonylpyridin-3-yloxy)-5-(2-hy

pyrazol-3-yl)benzamide;

5-(2-hydroxy-1-memyl-emoxy)-3-(6-meti^

pyrazol-3-yl)benzamide;

5-(l-hyikoxymemyl-propoxy)-3-(6-memanesulfonylpyrio n-3-yloxy)-N-(l-memyl-1H- pyrazoI-3 -yl)benzamide;

3-(6-memanesuIfonylpyridin-3-yloxy)-5-(l-^

pyrazol-3-yl)benzamide;

5-isopropoxy-3-(6-methanesulfonylpvridin-3-yloxy)-N-(l-methyl-1H-pyrazol-3- yl)benzamide;

5-(2-fluoro- 1 -fluoromemyl-emoxy)-3-(6-memanesulfonylpyridin-3-yloxy)-N-( 1 -methyl- 1H-pyrazol-3-yl)benzamide;

3-({4-[2-(&me%lamino)ethoxy]phenyi}to

methyl-4H- 1 ^^-tria^l-S-y miojpyridine^-carbo amide;

3-({4-[(l-memylazetidin-3-yl)oxy]phenyl}mio)-N-(3-methyl-l_>2_>4-thiadiazol-5-yl)-6-[(4- methyl-4H- 1 ,2,4-triazol-3 -yl)mio]pyridine-2-carboxamide;

N-(3-methyI- 1 ,2_i4-tliiadiazol-5-yl)-6-[(4-methyl-4H-l ,2,4-tria2ol-3-yl)thio]-3-{[4-(2- pyri li(Hn-1-ylethoxy)phenyl]thio}pyridme-2-c^boxamide; and

3-[(4-{2-[(2R)-2-me lpy^

5-yl)-6-[(4-methyl-4H~l ,2₅4-1riazol-3-yl)mio]pyridme-2-carboxarnide; 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-(memylsidfonyl)pyridinr2-yl]oxy}ethyl)cyclopropyl] piperidin-1 -yl}pyrimidine;

5-cWoro-2-{4 (lR,2S)-2-(2-{[5-(methylsulfonyl)pyridin-2- yl]oxy}ethyl)cyciopropyl3piperidin- 1 -yl }pyrimidine;

vac Cii-5-chloro-2-[4-(2-{2-[4-(memylsulfonyl)phenoxy]emyl}cyclopropyl)piperidin~l- yl]pyrimidine; 5-cliloro-2-[4-((lS,2 )-2-{2-[4-(met ylsulfonyl)phenoxy]ethyl}cyciopropyl) piperidin-1- yl]pyrimidme;

5-chloro-2-[4-((lR,2S)-2-{2-[4-(methyIsulfon.yl)phenoxy]ethyI} cyclopropyl) piperidin-1- yl]pyrimidine;

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

rac cis -5-chloro-2-[4-(2-{2-[3-(5-methyl-l_>3,4-oxadiazol-2- yl)phenoxy]ethyl}cyclopropyl) piperidin-1-yl]pyrimidine; 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:

(2_S)~2-({6^rdoro-3-[6-(4-chloropta^

yl}oxy)propanoic acid;

(2S)-2-({6-chloro-3-[6-(4-fluorophenoxy^

yl}oxy)propanoic acid;

(2iS)-2-{[6-chloro-3-(6-phenoxy-2~propylpyridin-3-yl)-1,2-benzisoxazol-5- yl]oxy}propanoic acid;

(2i2)~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)ben2»yl-2-methyl-6-(trifluoromethoxy)- lH-indol- 1 - yl]phenoxy}butanoic acid;

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

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

^• (2i)-2-{3-[3-(4-cUoro)benzoyl-2-methyl-6-(trifluoromethoxy)-lH-~indol-1- yl]phenoxy}propanoic acid; and pharmaceutically acceptable salts thereof.

Inhibitors of 1 Ιβ-hydroxysteroid dehydrogenase type 1 that can be used in combination with the compounds of Formula I, Formula Ia₉ Formula lb or Formula Ic include, but are not limited to:

3 - [ 1 -(4-chlorophenyl)-ira«5^,-3 -fluorocyclobutyl] -4,5-dicyclopropyl-r-4H- 1 ,2,4-triazole;3- [ 1 -(4-chlorophenyl)-ira«i-3 -fluorocyclobutyl]-4-cyclopropyl-5 -( 1 -methylcyclopropyl)- '-4H^'- 1,2,4-triazole;

3- [l-(4-chlorophenyl)-/ra¾s'-3-fIuorocyclobutyl]-4-methyl-5-[2- (trifluoromethoxy)phenyl] -r-4H- 1 ,2,4-triazole;

3-[l-(4-chlorophenyl)cyclobutylH

triazole; 3- {4-[3-(ethylsulfonyl)propyl]bicyclo[2.2.23oct-1-yl}-4-raethyl-5-[2- (trifluoromethyl)phenylJ-4H -1 ,2,4-triazole;

4- raet yl-3-{4-[4-(met ylsulfonyl)phenyl3bicyclo[2.2.2]oct-1-yl}-5-t2- (trifluoromethyl)phenyl]-4H- 1 ,2,4-triazole;

3-(4- (4-methyl-5-[2-(trifluoromet yl)phenyl]-4H- 1 ,2,4-triazol-3-yl} bicyclo[2.2.2]oct-1- yl)-5-(3_s3,3-1xifluoropropyl)-l_}2_s4-oxadiazole;

3-(4- {4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yI}bicyclo[2.2.2]oct- 1 - -S-CS^^-irifluoroeth lJ-l^^-oxadiazole;

5- (3,3-difluorocyclobulyl)-3-(4-{4-memyW

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

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

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

2-(3,3-difluorocyclobutyl)-5-(4-{4-me

3-yl}bicyclo[2.2.2]oct-l -yl)- 1 ,3,4-oxadiazole; and

5-(l ,1 ~difluoroethyl)-3-(4- {4-methyl-5-[2-(trifluororaethyl)phenyl]-4H- 1 ,2,4-tnazol-3- yl}bicyclo[2.2.2]oct-1-yl)-l_s2_s4-oxadiazole; and pharmaceutically acceptable salts thereof.

Somatostatin subtype receptor 3 (SSTR3) antagonists 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.

AMP-activated Protein Kinase (A PK) 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 acetyl-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-{l^,- (l-c clo ro yl-4-me1hoxy-1H-mdol-6-yl)carbo l]-4-o os iro chroman- 2,4^,- piperidin]-6-yl}benzoic acid;

5-{ -[(l-cyclo rop M-me1hoxy-1H-indol-6-yl)carbonyl]-4-o ospiro chroman-2.4^,- piperidin]-6-yl}nicotinic acid;

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

r-[(l-cyclopropyl-4-ethoxy-3-methyl-1H-indol-6-yl)carbonyl]-6-(1H-tetrazol-5- yl)spiro[chroman-2_s4'-piperidin]-4~one; and

5- { 1 '-[(1 -cyclopropyl-4-methoxy~3-methyl-l H-indol-6-yl)carbonyl]-4-oxo- spiro[chroman-2_>4'-piperidin]-6-yl}nicotinic acid; and

pharmaceutically acceptable salts thereof.

In another aspect of the invention, a pharmaceutical composition is disclosed which comprises one or more of the following agents: (a) a compound of structural Formula I, Formula Ta, 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) 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), and (4) PPARy partial agonists; (ii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet®, and GlucophageXR®; (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;

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

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

(5) glucagon receptor antagonists;

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

Co A: cholesterol acyltransferase inhibitors, such as avasimibe;

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

(8) antiobesity compounds;

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

(10) antihypertensive agents, such as ACE inhibitors (such as enalapril, lisinoprii, ramipril, captopril, quinapril, and tandolapril), Α-ΙΪ 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 1 Ιβ-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 Co A carboxylase- 1 or 2 (ACC1 or ACC2);

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

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

(18) SSTR3 antagonists;

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

(20) inhibitors of stearoyl-coenzyrne 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 Aidiacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2);

(24) inhibitors of fatty acid synthase;

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

ACC-2);

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

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

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

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

The weight ratio of the compound of the present invention to the second active ingredient may 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 <∞mbinations 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:

Method A (Exemplified by):

Method B (Exampiified by):

Intermediate 1

6-methoxypyricUne-23-diarmne

A 200 mL par-shaker vessel was charged with 6-memoxy-3-nitro-2-aminopyridine (1.5 g, 8.87 rnrnol), 10% palladium on carbon (800 mg, 0.752 mmol) and ethyl acetate. The mixture was put 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-2,3-diarnine. LC-MS (ES₅ m/z) C6な ₃0: 139; Found: 140 [M+H]⁺.

Intermidiate 2

4-(methylsulfonyl)benzene-l ,2-diamine

To a solution of 5-(methyIsulfonyl)-2-nitroaniline (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な 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 a yellowish solid 4-(methylsulfonyl)benzene-1,2-diamine. LC-MS (ES, m/z) C₇H₁₀ 2O2S: 186; Found: 187 [M+H]⁺.

Intermediate 3

6-(trifluoromethyl)pyridine-2,3 -diamine

Step A: 3-nitro-6-(trifluororoethyl)pyridin-2-amine

A 100 mL round bottom flask was charged with 6-trifluoro-2-aminopyridine (900 mg, 5.55 mmol) along with sulfuric acid (5 ml, 99 mmol). The mixture was cooled to 0 °C in an ice bath and nitric acid (5 ml, 127 mmol) was added dropwise. Then the reaction mixture was gradually warmed up to 50 °C in an oil bath for 4 hrs. LC-MS showed product formation with all starting material consumed. However major peak was amio converted to hydroxy product. The mixture was then cooled to room in ice bath and neutralized with solid sodium carbonate to pH=9. The mixture was extracted with ethyl acetate and washed with water, dried oveg MgSC>4, filtered and concentrated. The crude was purified by MPLC (24 g silica gel, 0 to 40% ethyl acetate in hexanes) to afford 3-nitro-6-(1iifluoromemyl)pyridin-2-amine. LC-MS (ES, m/z): C6H₄F3N3O2: 207; Found: 208 [M+H]⁺.

Step B: 6-ftrifluoromethvnpyridine-2.3-diamine

A 100 mL vessel was charged with 3-nitro-6-(trifluoromethyl)pyridin-2~amine (46 mg, 0.222 mmol) along with methanol and Pd/C (10%, 24 mg, 0.1 eq). The mixture was exposed to hydrogen (40psi) atomosphere on parshaker for 30 min. LC-MS showed complete reduction of nitro to amine. The catalyst was then filtered and washed with ethyl acetate (20 mL). The filtrate was concentrated to afford a white solid product 6-(trifluoromethyl)pyridine-2,3-diamine. LC-MS (ES, m/z): QH6F₃N₃: 177; Found: 178 [M+H]⁺.

Intermediate 4

H

2-(4-Bromo-phenyl -5-1iifluoromemyl-lH-benzoimidazole

To solution of 4-Trifluoromethyl-benzene-l ₃ 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 into 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+H]⁺.

Intermediate 5

2-f4-Bromo-phenvn-5-chloro-lH-benzoimidazole

Performed as same as the synthesis of Intermediate 4 except 4-chloro-benzene-l, 2- diamine (5 g, 35.10 mmol) and 4-bromo-benzoic acid (8.46 g, 42.1 mrnol) were used as the starting materials. LC-MS found: 309 [M+H]⁺.

Intermediate 6

2-f4-bromo-2-fluorophenylV6-(trifluoromethylVlH-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-1,2-phenyldiamine (9.54 g, 54.2 mmol). The mixture was stirred at room temperature for 5 min before OXONE (2 Ϊ .20 g, 34.5 mmol) was added in one portion. The resulting reaction mixture was then stirred at room temperature for 2 hours. The mixture was then partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic phases were washed with water, dried over MgSC>4, filtered and concentrated. The residue was purified by MPLC (120 g silica gel, 10 to 50% ethyl acetate in hexanes) to afford a light color solid product, 2-(4-bromo-2-fluorophenyl)-6-(trifluoromethyl)- lH-benzimidazole. LC-MS (ES, m/z): C₁₄H₇BrF₄N2: 358; Found: 359 [M+Hf.

Intermediate 7

2-(6-bromopyridin-3-vn-6-(1iifluoromemyl)-l-H-benzimidazoie

Following the same procedure as Intermediate 6, 2-(6-bromopyridin-3-yl)-6-

(trifluoromethyl)-l-H-benzimidazole was prepared. LC-MS (ES, m/z) Ci3H₇BrF₃N3: 342; Found: 343 [M+H]⁺ Intermediate 8

2-(4_¾6-cHfluoropyrid -3-ylV6-(tri Step A: 4.6-dichloropyridine-3-carbaldehvde

To a solution of methyl-4₅6-dichloropyridine-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 immediatly change to a light yellow color). After 3 h, the reaction mixture was quenched with HCl (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 refrigarator. The solid was then purification on the ISCO 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]. ^!HNM (500 MHz, CDCl₃,ppm): 5 7.53 (1H, s), 8.88 (1H, s), 10.47 (1H, s).

Step B: 2-(4.6-difluoropyridin-3-yl)-6-ftrifluoromethvn- 1 -H-benzimidazole

A solution of 4-(trifluoromethy)benzene-1,2-diamine (250 mg, 1.419 mmol) in DMF (5.0 ml) and water (0.5 ml) was treated with Intermediate from step A (250 mg, 1.419 mmol) slowly and the mixture stirred at rt 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 rt 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 compund. 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 (1H, d, 8.4 Hz), 8.08 (1H, s), 9.37 (1H, s).

Intermediate 9

3-fluoro-5-[6-(trifluorqmethy1HH-te

teifluoromethanesulfonate

Step A: N-p-amino-4-ftrifluorome^

car oxamide

To solution of 4-(trifluoromethy)benzene-1,2-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. HCl (1066 mg, 5.56 mmol), and HOBT (852 mg_s 5.56 mmol). DIEA was then added via a syring 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 were then washed with brine, dried <Τ¼80₄) and filtered. The filtrate was concentrated under vacuum to afford a viscous oil. The resulting oil was then purified on the ISCO

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) C^CL ^,: 317; Found: 318 [M+l],

Step B: 3-fluoro-5- 6-ftrifluoromemyl -lH-benzimidazoi-2-yl]pyridm-2

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) C13H7F4N30: 297; Found: 298 [M+l].

Step C: 3-fluoro-5-f6-(trifluoromefoy1HH-ber^

trifluoromethanesulfonate

To a sealed microwave tube containing the title compound from step B (100 mg, 0.336 mmol) and 2,6-di-/e/-i-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 ISCO CombiFlash Companion (with a 12g Column) eluting with 10 to 30 % ethylacetate / hexane gradient. The desired fractions were concentrated to afforded the title compound as a yellow solid. LC-MS (ES, m/z) Q₄H₆F₇N₃O₃S: 429; Found: 430 [M+l]. 'HNMR (500 MHz, CDCl₃, pw): δ 7.65 (1H, d, 8.4 Hz), 7.80 (1H, d, 7.6 Hz), 8.04 (1H, s), 8.51 (1H, d, 9.0 Hz), 8.81 (1H, s).

Intermediate 10

2-(6-cHoro-4-fluoropyridin-3-yl)-6-(trifluoromethyl)-lH-be^

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

A freshly prepared solution of LDA (100 mmol) at -78 °C was treated with 2- chloro-4-fluoropyridine (12 g, 91 mmol) and the mixture stirred at -78 °C for 30 min. Iodine dissloved 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. Crystalization from hexane followed by filtration afforded the title compound. LC-MS (ES, m/z) C₅H₂C1FIN: 257; Found: 258 [M+l]. 'HNMR (500 MHz, CDC1₃, ppm): 6 6.98 (1H, d, d, 6Hz, 6Hz), 8.31 (1H, d, d, 5.6 Hz, 5.5 Hz).

Step B : 2-chloro-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. ¹HNMR (400 MHz, CDC ,#pm): δ 7.12 (1H, d, 7.2Hz), 8.63 (1H, d_f 8.7 Hz).

Step C: 6-chloro-4-fluoropyridine-3-carbaidehvde

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 dimethylformarnide (8.2 ml) and after 30 min diluted with MTBE 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) C^C-FNO: 159; Found: 160 [M+l]. ¹HNMR (500 MHz, CDC1₃, 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-fluoropyridin-3-yl)-6-fa^

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) C₁₃H₆C1F₄N₃: 315; Found: 316 [M+l].

Intermediate 11

2-i5-chloropyrazin-2-viy6-(trifluorom

Following the procedure described for Intermediate 1 but using 5-chloropyrazine-2- carbaldehyde (445 mg, 3.12 mmole), the title compound was afforded as a powder. LC-MS (ES, m/z) C|2なC1F₃N₄: 298; Found: 299 [M+l].

Intermediate 12

2-(4-bromo-3 -fluorophenyl)-6-(trifluoromethylV 1 H-benzirhidazole

In a 20 ml microwave tube was added 4-(trifluoromeihyl)benzene-l_i2-diamine (265 mg, 1.51 mmol) and 4-bromo-3-fluoi'obenzoic 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 rt 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 CombiFlash 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].

Intermediated 13

2-(^f4-bromo-2-methoxyphenyl)-6- fluoromemylViH-ben2amidazole

Following the procedure described for Intermediate 1 but using 4-bromo-2- methoxybenzaldehyde (101 mg, 0.48 mmole), the title compound was afforded as a solid. LC-MS (ES, m/z) C15H10BF3N2O: 371; Found: 372 [M+l].

5-bromo-2-f6-(trifluoromethYl)-lH-ben2imxdazol-2-yllbenzom Following the procedure described for Intermediate 1 but using 5-bromo-2- formylbenzonitrile (350 mg, 1.67 mmole), the title compound was afforded as a solid. LC- (ES, mJz) C15H7BF3N3: 366; Found: 367 [M+l].

Intermediate 15

2-f4-f4A5.5-tetramemyl-13,2^ioxaborol^

benzimidazole

A mixture of 2-(4-iodophenyl)-5-(1rifluoromemyl)-lH^r-benzimida2ole (8.08 g,

20.82 mmol, 1.00 equiv), ^'^^.S^'^'-octamethyl^^-bi-l .S^-dioxaborolane (5.82 g, 22.09 mmol, 1.10 equiv), potassium acetate (6.13 g, 62.5 mmol, 3.00 equiv) and Ι, - bis(diphenylphoshino) ferrocene dichloropalladium (IT) dichloromethane complex ( 1.52 g, 2.08 mmol, 0.1 equiv) in DMSO (65 mL) was stirred for 18 hr at 100 °C in an oil bath. The reaction mixture was cooled and washed by the addition of water, followed by extraction 3 times with EtOAc. The combined organic layer was dried over MgS0₄ filtered and concentrated in vacuo. The residue was purified by eluting through a silica gel column with a 0-60% EtOAc Hexane solvent system to provide product 2-[4-(4,4,5,5~tetramethyl-1,3_s2-dioxaborolan-2-yl)phenyl3-5- (trifluorpmethyl)-lH-benzimidazole. LC-MS (ES, m/z) C₂oH2oBF3N₂0₂: 388; Found: 389

[M+H]⁺.

Intermediate 16

2-f2-fluoro-4-(4A5.5-tetramemyl-1 ^

lH-benzimidazole A mixture of 2-(4-bromo-2-fluorophenyl)-5-(trifluoromethyI)- 1 H-benzimidazole

(25.06 g, 69.6 mmol, 1.00 equiv), 4_>4,4^, ₅4^,,5,5_>5'_}5^,-octamethyl-2,2'-bi-1,3,2-dioxaborolane (19.45 g, 77.0 mmol, 1.10 equiv), potassium acetate (20.50 g, 209.0 mmol, 3.00 equiv) and \,V- 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 MgSO-i 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-fiuoro-4-(4_}4,5,5~tetramethyl-1,3_J2-dioxaborolan-2- yl)phenyl]-5-(trifluoromethyl)-lH-benzimidazole. LC-MS (ES, m/z) C₂oHi₉BF N₂0₂: 406;

Found: 407 [M+H]⁺.

Intermediate 17

methyl rtTO¾s^,^~r4-([rtrifluoromethvnsulfonyl1oxy>phenyl)cyclohexyl^'jacetate

Step A: methyl r4-f4-hvdroxyphenvDcyclohexylidene-lacetate

Into a 2000-mL 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sodium hydride (42.5 g, 1.06 mol, 1.01 equiv, 60%) in tetrahydrofuran (500 mL). This was followed by the addition of a solution of 4-(4- hydroxyphenyl)cyclohexanone (200 g, 1.05 mol, 1.00 equiv) in tetrahydrofuran (1000 mL) dropwise with stirring at 0°C. The resulting solution was stirred for 2 h at room temperature. The resulting solution was assigned as solution A. Into a 5000-mL 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sodium hydride (63 g, 1.7 equiv, 60%) in tetrahydrofuran (1000 mL). This was followed by the addition of a solution of methyl 2-(dimethoxyphosphoryl)acetate (229.7 g 1.2 equiv) in tetrahydrofuran (1500 mL) dropwise with stirring at 0°C. The resulting solution was stirred for 2 h at room temperature. Then, to the reaction mixture was added solution A dropwise with stirring. The resulting solution was stirred for 1 h at room temperature, then quenched by the addition of water/ice. The resulting solution was extracted with 3x500 mL of ethyl acetate. The organic layers were combined, washed with 1x1000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by re-crystallization from ether. This resulted in 200 g of methyl 2-(4-(4-hydroxyphenyl)cyclohexylidene)acetate as a white solid.

Ste B: methyl [^"fra¾y-4-i4-hydroxyphenyl)cyclohexyl^")acetate

A mixture of methyl 2-(4-(4-hydroxyphenyl)cyclohexylidene)acetate (200 g, 812.58 mmol, 1.00 equiv) and Palladium carbon (20 g) in ethyl acetate (2500 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The solid was filtered out. The filtrate was concentrated under vacuum. The crude product was re-crystallized from ethyl acetate/hexane in the ratio of 1:1. This resulted methyl ir£Jw-2-(4-(4-hydroxyphenyl)cyclohexyl)acetate as a white solid.

Step C: methyl |^"traw5'-4-(4-([(1rifluoromethyl^')sulfonyl1oxy)phenyl^')cvciohexynacetate

Into a 250-mL 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl trans-2-{4-(4- hyclroxyphenyI)cyclohexyl)acetate (7.16 g, 28.85 mmol, 1.00 equiv) in chloroform (60 mL) and triemylamine (4.37 g, 43.19 rnrnol, 1.50 equiv). This was followed by the addition of a solution of trifluoromethanesulfonic anhydride (9.76 g, 34.59 mmol, 1.20 equiv) in chloroform (10 mL) dropwise with stirring at 0°C. The resulting solution was stirred for 1 h at 0°C, then quenched by the addition of 100 mL of water/ice. The resulting mixture was washed with 1x100 mL of sodium bicarbonate solution and 1x100 mL brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue, was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1 :10), This resulted in methyl ira¾s-2-(4-(4- (trifiuoromethylsulfonyloxy)phenyl)cyclohexyl)acetate as a white solid. GCMS (ES, m/z) C₁₆Hi9F₃0₅S: 380; Found 380 [M]⁺. 1H-NMR (400MHz, COC _iPpm):h 1.11~L20(2H, m), 1.42~1.52(2H, m), 1.83-1.91(5H, m), 2.25~2.26(2H, d), 2.47~2.53(1H, t), 7.1 ~7.19(2H, d), 7.24~7.27(2H, d).

Intermediate 18

methyl fraw -r4-(4A5 -tetra emvn.3^

A 3 -neck, 500-mL, round bottom flask equipped with a thermocouple, nitrogen bubbler, magnetic stirrer, and condenser was charged with methyl trans-2-(4-(4- (trifluoromethylsulfonyloxy)phenyl) cyclohexyl)acetate (Intermediate 17, 10 g, 26.3 mmol), bis(pinacolato)diboron (10.01 g, 39.4 mmol), DPPF (0.510 g, 0.920 mmol), U'-BISCDI-TERT- BUTYLPHOSPHMO)FERROCENE PALLADIUM DICHLORIDE (0.600 g, 0.035 mmol)), and potassium acetate (7.74 g, 79 mmol). CPME was placed in a separate flask and nitrogen was bubbled into it for approx. 20 minutes. The CPME was then added to the reaction flask and the reaction was evacuated and flushed with nitrogen three times. The reaction was then heated to 80 °C overnight. The reaction was poured into 500mL water. The layers were separated. Organics were dried over anh. sodium sulfate, filtered, and concentrated. Dissolved product in 50% dichloromethane hexanes and injected onto a Btiotage Flash 300g column prepacked in 10% ethyl acetate/hexanes. Eluted 10% EA/Hex over 1 column volume, 10-25% EA Hex over 7 column volumes, and held at 25% EA/Hex over 2 column volumes. To afford white solid product, LC-MS (ES, m/z): C₂₁H₃iB0₄: 358; Found: 359 [M+H]⁺.

Intermediate 19

methyl ( ra^-4- 4-(5-formylpyridin-2-yl)phenyl|cyclohexy acetate

In a 20 ml microwave tube was added 6-bromopyridine-3-carbaldehyde (0.2 g, 1.075 mmol), Intermediate 15 methyl {tra«s^,-4-[4-(4₎4₅5_>5-tetramethyl-l_>3_s2-dioxaborolan-2-yl)phenyl] cyclohexyl} acetate (0.385 g, 1.075 mmol) and Tetrakis (0.124 g_} 0.108 mmol) and the tube sealed. Under a N2 atmosphere was added dimethoxyethane (6.0 ml) and ethanol (3.0 ml) followed by a solution of sodium carbonate (1.61 ml, 3.23 mmol, 2M) via a syringe. The mixture was irradiated in the Biotage Initiator Microwave for 25 min at 120 °C. The solvent was evaporated, diluted with EtOAc and washed with water then brine. The organic layer was dried (MgS0₄) and concentrated under vacuum. The resulting residue was purified on the ISCO CombiFlash Companion (with a 12 g Column) eluting with a 20 to 50 % ethylacetate / hexane gradient. The desired fractions were concentrated to afford the title compound as a white solid. LC-MS (ES_> m/z) C₂iH₂3N0₃: 337; Found: 338 [M+l].

Intermediate 20

Methyl rfmj¾y-4-(4'-formylbiphenyl-4>yl)cvciohexyl]acetate

To a solution of 4-bromo-benzaldehyde (0.89 g, 4.81 mmol) in DMF (8 ml) was charged with methyl {fraw-4-[4-(4,4_s5,5 eti¾memyl-1,3_J2-dioxaborolan-2-yl)phenyl]cyclohexyl}acetate (1.5 g, 4.19 mmol) followed by PdCI^dppiy^ClzAdduct (0.137 g, 0.16 mmOl), and 2M Na₂C0₃ (5 ml). The system was vacuumed and refilled with nitrogen three times. Then the mixture was heated to 80 °C for 15 h. TLC showed complete conversion of starting material to product. The mixture was quenched with ethyl acetate and water. The aqueous layer was extracted with EtOAc (x2) and the combined organics dried (MgS0₄) and concentrated under vacuum. The resulting residue was then purified on the ISCO Comb Flash Companion eluting with 0 to 40 % ethyl acetate / hexane gradient. The desired fractions afforded methyl [ir ns-4-(4'~ formylbiphenyI-4-yl)cyc hexyl3acetate . LC-MS (ES, m/z) C22H24O3: 336; Found: 337 [M+H]⁺. 'HNMR (500 MHz, CDCI3) δ: 10.0 (1H₅ s), 7.93 (2H, d, 8.0 Hz), 7.74 (2H, d, 8.5 Hz), 7.57 (2H_> d, 8.5 Hz), 7.31 (2H, d, 8.0 Hz), 3.69 (3H, s), 2.53(1H₃ m), 2.28 (2H, d, 6.5 Hz), 1.93 (5H, m), 1.55 (2H, m), 1.20 (2H, m) ppm.

Intermediate 21

F

methyl f^^^-O^'-difluoro^'-formylbiphenyM-yl)cyciohexyllacetate Following the procedure used to synthesize Intermediate 19, but using 4-bromo-2,6- difluorobenzaldehyde (370 mg, 1.67 mmol), the title compound was afforded, as a white solid. LC-MS (ES₅ m/z) sHizFa . 372; Found: 373 [M+l].

Interaiediate 22

methyl [t aw-4-n'-cvano-4'-formylbiphenyl-4-vI)cyclohexyl1acetate

Following the procedure used to synthesize Intermediate 19, but using 5-bromo-2~ formylbenzonitrile (218 mg, 1.00 mmol), the title compound was afforded as a cream solid. LC- MS (ES, m z) C23H23NO3: 361; Found: 362 [M+l].

Intermediate 23

F

methyl (fra«s-4-[4'-formyl-3'-(trifl^^

Following the procedure used to synthesize Intermediate 19, but using 4-bromo-2~ (trifluoromethyl)benzaldehyde (150 mg, 0.72 mmol), the title compound was afforded as a solid. LC-MS (ES, m/z) C23H23F3O3: 404; Found: 405 [M+l].

Intermediate 24

methyl [tmw-4-f3'-fluoro-4'-formylbiphenyl-4--yl^')cvclohexyl]acetate

Following the procedure used to synthesize Intermediate 19, but using 4-bromo-2- fluorobenzaldehyde (10.5 g, 29.3 mmol), the title compound was afforded as a solid. LC-MS (ES, m/z) C22H23FO3: 345; Found; 346 [M+l].

Intermediate 25

Methyl {im«-f-4-[4-(5-formylpyrazin-2-yI)phenyl]cyclohexyl}acetate Following the procedure used to synthesize Intermediate 19, but using 5-chIoropyrazine- 2-carbaldehyde (0.15 g, 1.05 mmol), the title compound was afforded as a solid. LC-MS (ES, m/z) C₂oH2₂N₂0₃: 338; Found: 339 [M+lj. Intermediate 26

Methyl {iran5-4-[4-(5-formylpyrazin-2-yl)phenyl]cyclohexyl}acetate

Following the procedure used to synthesize Intermediate 19, but using 2,3-difluoro-4- bromophenylcarbaldehyde (0.15 g, 1.05 mmol) to prepare the title compound was afforded as a solid. LC-MS (ES, m/z) C₂₂H₂₂F₂0₃: 338; Found: 339 [M+lj.

Intermediate 27

4'-[fr-anjf-4-(2-methoxy-2-oxoethylkyclohexyllbiphenyl-4-carboxyHc acid

Step A: fert-butyl 4'-ffrfl»5^,-4- 2-methoxy-2-oxoethvncvclohexyl]biphenyl-4- carboxylate

To a solution tert-butyl-4-bromobenzoate (1 g, 3.89 mmol) in DMF (10 ml) was added methyl {iriiw-4-[4-(4₃4_}5_i5-tetramethyl-1,3_J2-dioxaborolan-2- yl)phenyl]cyclohexyl} acetate (1.324 g, 3.69 mmol) followed by PdCl₂(dppf)-CH₂Cl₂Adduct (0.16 g, 0.19 mmol), and 2M Na₂CC>3 (3.9 ml). The system was vacuumed and refilled with nitrogen three times. Then the mixture was heated to 80 °C for 15 h. TLC showed complete conversion of starting materia! to product. The mixture was quenched with ethyl acetate arid■ water. The aqueous layer was extracted with EtOAc (x2) and the combined organics dried (MgS0₄) and concentrated under vacuum. The resulting residue was then purification on the ISCO Comb Flash Companion (with a 40 g column) eluting with 0 to 20 % ethyl acetate / hexane gradient. The desired fractions afforded a white solid feri-butyl 4'-[ira¾y-4-(2-methoxy-2- oxoethyl)cyclohexyl]biphenyl-4-carboxylate. ^!HNMR (500 MHz, CDC1₃) δ: 8.03 (2H, d, 8.5 Hz), 7.62(2H, d, 8.0 Hz), 7.55 (2H, d, 8.0 Hz), 7.23 (2H, d, 8.0 Hz), 3.69 (3H, s), 2.53(1 H, m), 2.27 (2H, d, 6.5 Hz), 1.93 (5H, m), 1.65(6H, s), 1.55 (2H, m), 1.24 (3H, s), 1.20 (2H, m) ppm.

Step B: 4'-[frg«5'-4--(^'2-methoxy-2-oxoethyl^')cyclohexyllbiphenyl-4-carboxylic acid To a solution ierr-butyl 4'-[iraw-4-(2-memoxy-2~oxoethyl) cyclohexylj biphenyl- 4-carboxylate (1.3 g, 3.18 mmol) in CH₂CI₂ (4 ml) was added TFA (2ml). The mixture was stirred at 40°C for Hi. TLC showed the complete conversion of starting material to product. Concentrated, the white solid was the desired product 4'-[ir«w5-4-(2-methoxy-2- oxoethyl)cyclohexyl]biphenyl-4-carboxylic acid. ¹HNMR (500 MHz, CDC1₃) δ: 8.16 (2H, d, 8.0 Hz), 7.68(2H, d, 8.0 Hz), 7.58 (2H, d, 7.5 Hz), 7.31 (2H_S d, 7.5 Hz), 3.69 (3I-L s), 2.53(1H, m), 2.28 (2H, d, 6.5 Hz), 1.93 (5H, m), 1.57 (2H, m)_s 1.20 (2H, m) ppm.

Intermediate 28

6-i4- trgw^(2-metfaoxy-2-oxoethyl)cvclohexyl]phenyl>pyridine-3-carboxylic acid

Intermediate 6-{4-[/raw-4-(2-me1hoxy-2-oxoe1hyl)cyclohexyl]phenyl}pyridine- 3-carboxylic acid was prepared in the same procedure as Intermediate 27 in two steps. LC-MS (ES, m/z): C21H23NO4: 409; Found: 410 [M+H]⁺. intermediate 29

4'- [4-f 2.4-dioxo- 1 ,3 -tfaiazolidin-5-vDcvclohexyi}biphenyl-4-carbaldehyde

Step A: [4-(4'-r1,31Dioxolan-2-yl-biphenyl-4-Yl)-cyclohexyl1-acetic acid methyl ester

To a microwavable vial was charged with 2-(4-Bromo-phenyl)-[l ,3]dioxolane (lg,

4.37mmol), {4-[4-(4,4,5,5-Tetramethyl-[l_}3,2]dioxab0rolan-2-yl)-phenyl]-cyclohexyl}-acetic acid (I.72g, 4.81mmol), cesium carbonate (2.85 g, 8.75 mmol), PdCl₂(dppf)CH₂Cl₂ (179 mg, 0.22 mmol) followed by l-Methyl-pyrrolidin-2-one (12 ml). It was sealed, evacuated and backfilled with N₂ three times, heated to 80 °C for 13 hr and then cooled to room temperature. It was partitioned between water and EtOAc, extracted with EtOAc. The combined extract was washed with brine, dried over Na₂S0₄, cone, to give a dark brown oil. The crude product was purified by chromatography on a 80 g ISCO cartridge eluting with 0-25% EtOAc hex over 12 cv, isocratic at 25% for 3 CV followed by rinsing with EtOAc. The desired product was obtained as a white solid LC-MS (ES, m/z) QwHig ^: 380; Found: 381 [M+H]⁺.

Step B: Bromo-[4-f4'-f 1,3]dioxolan-2-yI-biphenyl-4-yl)-cyclohexyl -acetic acid methyl ester

To a suspension of the [4-(4'-[l_}3]Dioxolan-2-yl-biphenyl-4-yl)-cyclohexyl]-acetic acid methyl ester (400 mg, 1.05 mmol) in THF (3.0 ml) under nitrogen atmosphere and cooled to -78 °C, was added of NaHMDS (1.5 ml, 1M THF). The resultant slurry was stirred at -78 °C for 30 min., TMSC1 (neat, 137mg, 1.26mmol) was added drop- wise and the slurry quickly changed into a clear solution. The reaction was stirred at -78 °C for another 30 min before NBS (206 mg 1.16 mmol) was added in one portion. The color changed to dark brown immediately and resultant solution was allowed to warm to room temperature over 2 hrs. The reaction mix was quenched with sodium bicarbonate at 0 °C and the product was extracted with EtOAc. The organic extract was washed with brine, dried over NaS0 , cone, to give an off-white solid which was purified by chromatography on silica gel (24g cartridge) eluting with 0-25% over 10 CV, 25% for 5 CV and followed by 100% EtOAc over 5 CV. The product containing fractions were collected, cone, to give the title compound as a pure white solid. LC-MS (ES, m/z): C2₄な₇Br0₄: 459; Found: 469 [M+H]⁺.

Ste C: 5-[4-f4'-[1.3]Dioxoian-2-yl-bipheny^

To a solution of the bromo-[4-(4'-[l ,3]dioxolan-2-yl-biphenyl-4-yl)-cyclohexylj- acetic acid methyl ester (300 mg, 0.65 mmol) in 4.0 ml of anhydrous EtOH was added thiourad (75 mg, 0.98 mmol) and sodium acetate (107 mg, 1.31 mmol). The resultant suspension was heated to 85 °c overnight. It was partitioned between EtOAc and water, separated, and the organic extract was washed with brine, dried over NaS0₄, cone, to give 228 mg of light brown foamy material which was used in the next step without further purification. LC-MS (ES, m/z) C₂₄H26N20₃ S: 422; Found: 423 [M+H]⁺.

Step D: 4'-[4-(2.4-Pioxo-thiazoiidin-5-yl -cvclohexyl1-biphenyl-4-carbaldehvde

To 5-[4-(4'-[l ,3]Dioxoian-2-yl-biphenyl-4-yl)-cyclohexyI]-2-miino-thiazolidin-4- one (80mg, 0.189 mmol) was added DMSO (1ml), HCl cone. (0.1 ml) and heated to 120 °C for 30 min. the suspension turned into a clear solution and it was then stirred at 100 °C for another 3 hrs. The reaction mix was concentrated under high vacuum. The product was crashed out by addition of water and collected by filtration. The residue was triturated with ACN/water and the product was collected by filtration to give a white solid which was used in the next step without further purification. LC-MS: (ES, m/z) C22H_2!N0₃S: 379; Found: 380 [M+H]⁺.

Intermediate 30

S-^-Bromo-phenvD-oxazolidine^^-dione

Step A: 5-(4-Bromo-phenylVoxazoiidine-2.4-dione

A 2000 ml 3 -necked round bottom flask, was charged with a solution of ethyl 2-(4- bromophenyl)-2-hydroxyacetate (120 g, 463.14 mmol, 1.0 equiv) in EtOH (1200 ml) and urea (27.8 g, 463.33 mmol, 1.00 equiv). To the mixture was added EtONa (31.5 g, 463.24 mmol, 1.0 equiv). The resulting solution was stirred for 2 hours while the temperature was maintained at 90 °C in an oil bath. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was extracted five times with 300 ml of EtOAc and the organic layers were combined. The combined organic extract was washed three times with 100 ml of な0. The residue was purified by chromatography on a silica gel column eluting with a 1 :5 EtO Ac/pet-ether. This resulted in 5-(4-bromophenyl)oxazolidine-2_}4-dione as a white solid. LC- MS (ES, m/z): C₉H₅BrN0₃: 255; Found: 256 [M+H]⁺. 'HNMR: (300MHz, COC , ppm) 512.l69(1H,s), 7.626(2H,d), 7.350(2H,d), 6.030(1H,s).

Intermediate 31

O

4-Hvdroxy-piperidine-4-carboxylic acid methyl ester

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

A mixture of 1 -BertzyI-4-hydroxy-piperidine-4-carboxylic acid methyl ester (Ref :

Chemical and Pharmaceutical Bulleting, 24, 1 76, 1179) (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 and it was used in the next step without further purification. LC-MS (ES, m/z): C₇H₁₃N0₃: 159; Found: 160 [ +H3⁺

Example 1

ftra» -(4-{5-[6-(trifluoromemyiy^

vUphenyl)cyclohexyll acetic acid

Step A: /rg/zy-cyclohexaneacetic acid, 4-[4-[5-f6-(trifluoromemylVlH- benzimidazol-2-vn-2-pyridinyU^ ester. ·

hi a 5 ml microwave tube was added 2-(6-bromopyridin-3-yl)-6-(trifluoromethyl)- 1-H-benzimidazole, (Intermediate 7, 0.1 g, 0.292 mmol), methyl {/Γί7«ί-4-[4-(4,4,5,5- tetramethyl-l₅3i2-dioxaborolan-2-yl)phenyl]cyclohexyl}acetate (Intermediate 34, 0.081 g, 0.092 mmol) and palladiumTetrakis (0.068 g, 0.058 mmol) and the tube sealed. Under aN₂ atmosphere was added dimethoxyethane (1.5 ml) and ethanol (1.0 ml) followed by a solution of sodium carbonate (0.292 ml, 0.585 mmol, 2M) via a syringe. The mixture was irradiated in the Biotage Initiator Microwave for 25 min at 120 °C. The solvent was evaporated, diluted with EtOAc and washed with water then brine. The organic layer was dried (MgS0₄) and concentrated under vacuum. The resulting residue was purified on the ISCO CombiFlash Companion (with a 12 g Column) eluting with a 0 to 30 % ethylacetate / hexane gradient. The desired fractions were concentrated to afford the title compound as a white solid. LC-MS (ES, m z) C28H26F3N3O2: 493; Found: 494 [M+l].

Step B: [fr<ms-4-(4- { 5-i6-(trifluoromethylV lH-benzirrudazol-2-yllpyridin-2- vnphenvncvclohexyll acetic acid

A solution of the compound (0.050 g, 0.101 mmol) from step A, Example 1, in tetrahydrofuran (1.0 ml) was treated with lithum hydroxide (0.006 g, 0.152 mmol) dissloved 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 pH was then adjusted to pH 3 with IN HQ. The resulting suspension was then extracted with ethyl acetate (x2) and the combined organic layers dried (MgSC^) and concentrated under vacuum to afford the title compound, Example 1 as the HCl salt (cream solid). LC-MS (ES, m/z) C27H24F3 3O2: 479; Found: 480 [M+l].

Following the general procedure for Example 1 and using appropriate

Intermediates described before, the Examples in Table 1 were prepared.

[irara-4-(4-{5-[6-(trifluQromeihy^

yl}phenyl)cyclohexyljacetic acid

Step A: methyl [traw^-^-IS-^-Ctrifluoro

2-vUphenyl) cvclohexyl acetate

To a solution of 4-(tTifluoromethy)benz¾ne-1,2-diamine (0.046 g, 0.260 mraol) in DMF (2.0 ml) was added water (0.07 ml) followed by methyl {ira«i-4-[4-(5-formylpyraziii-2- yl)phenyl]cyclohexyl} acetate, (0.080 g_s 0.236 mmol) slowly. After stirring at room temperature for 5 min. potassium peroxymonostilfate (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 rain, diluted with EtO Ac and the layers separated. The aqueous layer was washed with EtO Ac (x2) and the combined organics dried (MgS0₄) and concentrated under vacuum. Trituration from Hexane / Ether followed by filtration afforded the title compound as a powder. No Purification required. LC- S (ES, m/z) C27H25F3N4O2: 494; Found: 495 [M+H]⁺.

Step B:[frgra-4-(4-i5-f6-(trifluoromefayU^

yUphenyl)cyclohexyl] acetic acid

Following the procedure described for Example 1, Step B, but using the title product (0.042 g₅ 0.085 mmol) from Step A, the title compound, Example 1 , was afforded. LC- MS (ES, m/z) C26H23F3N4O2: 480; Found: 481 [M+H]⁺

Following the general method C and procedure for Example 10 and using corresponding intermediates, the examples in Table 2 were prepared

Example 34:

methyl ffrafts-4-f4-(5-f5-me1faoxy-3H-im^

yllphenyUcyclohexyl)acetate A 5 mL pyrex vial was charged with Intermediate 27 (70 mg, 0.198 mmol) along with HOBT (40.1 mg, 0.297 mmol) and EDC (57.0 mg, 0.297 mmol) in DMF (lmL) before the addition of Intermediate 1 (41.3 mg, 0.297 mmol). The mixture was stirred at room temperature for 10 min and then under microwave at 120 °C for 20 min. LC-MS showed complete coupling of the acid with amine. Then acetic acid (lmL) was added and the mixture was exposed to microwave at 200 °C for 40 min. LC-MS showed complete formation of imidiazole. The mixture was filtered and concentrated and the residue was purified by PrepTLC (2x2000 nm, ethyl acetate:hexanes=3:2) to afford product methyl (/ "aw-4-{4-[5-(5-methoxy-3H-imidazo[4_>5- 6]pyridin-2-yl)pyridin-2-yi]phenyl}cyclohexyl)acetate. LC-MS (ES, m/z) C27H28N4O3: 456; Found: 457 [M+H]⁺.

Example 35:

(tm/¾s-4-{4-|-5~f5-memoxy-3H-imida-^

vl]phenv cvclohexyl)acetic acid

To a 20 ml sample vial was charged with methyl (/ra«s^,-4-{4-[5-(5-methoxy-3H- imidazo[4,5-6]pyridin-2~yl)pyridin-2-yl]phenyl}cyclohexyl)acetate (Example 36, 19 mg, 0.042 mmol) along with methanol and sodium hydroxide (0.2 ml, 1.000 mmol). The resulting reaction mixture was then stirred in an oil bath of 45 °C for 18 hrs overnight. LC-MS showed complete hydrolysis of ester to acid. The mixture was then neutralized by addition of HCl (IN, 1 mL). The mixture was filtered and loaded to RP HPLC for purification (YMC column, 20 to 80% acetonitrile in water) to afford product TFA salt (tra¾s-4-{4-[5~(5-methoxy-3H-imidazo[4,5- &]pyridin-2-yl)pyridin-2-yl]phenyl}cyclohexyl)acetic acid. LC-MS (ES, m/z) C26H26N4O3: 442; Found: 443 [M+H]⁺.

Example 36:

ffrq^-4-f4-f5-r5-(trifluorometh^^

vUphenvDcvclohexyljacetic acid

In the same chemistry as Example 35 and using approriate Intermediate 27 and 3,

[/rara-4-(4-{5-[5-(trifluorometh^^

yl}phenyl)cyclohexyl]acetic acid was prepared. LC-MS (ES, m/z) CZ^-^^ I: 480; Found: 481 [M+H]⁺. Example 37:

[trans-4-(4- { 6- [6-(trifluoromethyl)- 1 H-benzimidazol-2-yl]pyridin-3 - yl}phenyI)cyclohexyl]acetic acid

Step A: methyl [fm¾s-4-f4-(6-[6-(trifluoromem^

3-vUphenvi cyclohexyl] acetate

In a microwave tube was added 4-(trifluoromethyl)ben2ene-l₅2-diamine (32.3 mg, 0.183 mmol) and Intermediate 17 (65 mg, 0.167 mmol) followed by pyridine (1.0 ml).

TRIPHENYL PHOSPHITE (0.052 ml, 0.200 mmol) was then added via a syringe and the mixture was stirred at rt for 5 min then at 220 °C for 15 min. The solvent was evaporated and coevaporated (x2) with toluene. The resulting residue was then purified on the CombiFIash Companion (12 g) eiuting with 5 to 20 % EtOAc / Hexane to afford the title product. LC-MS (ES, m/z) CzgH^FsNsOa: 493; Found: 494 [M+Hf.

Step B: [trans-4-(4-{6-[6-ftrifluorom

yll henyPcvclohexyl] acetic acid

Following the procedure described for Example 35, but using methyl [trans-4-(4- {6-[6-(1rifiuoromemyl)-lH-ben2imidazol-2-yl]pyridin-3-yl^ cyclohexyljacetate (0.025 g,

0.051 mmol), [fra«s-4-(4-{6-[6-(1rifluoromemyl)-lH^^

cyclohexyl] acetic acid was afforded. LC-MS (ES, m/z) C27H24F3N3O2: 479; Found: 480 [M+H]⁺.

Example 38:

trans-A- f 4-|-5-(5-chloro- 1 -ben2imida2¾?i-2-yl pyridin-2-yl]phenyl ) cyclohexyPacetic acid

To the solution of methyl {trans-4-[4-(5-formylpyridin-2- yl)phenyl] cyclohexyl} acetate (Intermediate 19,, 20 mg, 0.059 mmol) and 4-chlorobenzene-1,2- diamine (10 mg, 0.070 mmol) in DMF (1 mL) was added Oxone (25 mg, 0.041 mmol). The mixture was heated to 100 C for 16h. Diluted with IN NaHCC>₃ aqueous solution and extracted with EtOAc. The organic layer was concentrated in vacuum. The residue was dissolved in THF (lmL) and MeOH (1 mL) and LiOH aqueous solution (0.2 mL, 2.4 M) was added and the mixture was heated to 50 C for 3 h. The volatiles were removed under vacuum and the residue was purified by mass-triggered reverse phase HPLC to give the title compound. LC-MS m/z = 446.25 [M+l ]⁺ In the same procedure as Example 40, the following examples were prepared.

Example 68:

Methy fcmm^-MHo triftuorometh^^

yl ) cyclohex vDacetate

To a solution of 2-(4-bromophenyl)-6-(1rifluoromethyl)-lH-ben2jmidazole (0.24 mmol) in DMF (2 ml) was added methyl {trans -[4-(4A,5,5-t^mnethyl-l, 3,2- dioxaborolan-2-yI)phenyl]cyclohexyl}acetate (0.20 g, 0.56 mmol) followed by PdCl₂(dppf)- CH₂C1₂ (28.7 mg, 0.035 rnmOl), and 2M Na₂C0₃ (1.6 ml). The system was vacuumed and refilled with nitrogen three times. Then the mixture was heated to 80 °C for 15 h. TLC showed complete conversion of starting material to product. The mixture was quenched with ethyl acetate and water. The aqueous layer was extracted with EtOAc (x2) and the combined organics dried (MgSO- and concentrated under vacuum. The resulting residue was then purification on the ISCO Comb Flash Companion eluting with 0 to 60 % ethyl acetate / hexane gradient. The desired fractions afforded methyl (z tf^-4-{4'-[6-(trifluorome&yl)^^

yl}cyclohexyl)acetate. LC-MS (ES, m/z) C29H27F3N2O2: 492; Found: 493 [M+H]⁺.

Example 69

F

(rra¾^4-(4 6-ftrifl

vUcyciohexyPacetic acid

A 20 mL sample vial was charged with methyl (irani-4-{4'-[6-(trifluoromethyl)- lH-benzimidazol-2-yl]biphenyl-4-yl}cyclohexyl)acetate (18 mg_s 0.037 mmol) and LiOH.H₂0 (2.3 mg, 0.055 mmol) along with THF (1 ml) and water (0.25 ml). Then the mixture was heated to 40 °C for 15 h. LCMS showed complete conversion of starting material to product. The mixture was concentrated under vacuum. The resulting residue was then purification on reverse phase HPLC. The desired fractions afforded (fra^-4-{4'-[6-(trifluoromemyl)-lH-benzimidazol- 2~yl]biphenyI-4-yI}cyclohexyl)acetic acid. LC-MS (ES, m z) C28H25F3N2O2: 478; Found: 479 [M+Hf.

Example 70:

Methyl {frt¾w-4-r4'-(6-chloro- lH-benzimidazol-2-yl)biphei yl-4- yricvclohexy acetate

In the same procedure as Example 68 and using Intermediate 5, methyl {transA- [4'-(6-chloro-lH-benzimidazol-2-y ^^ was prepared. LC-MS (Es, m z): C28H27CIN2O2: 458; Found: 459 [M+H .

Example 71:

{^Κ5·-4-Γ4'-(6-ΟΜΟΓΟ-1#^

acid

In the same procedure as Example 2, {/ranj-4-[4'-(6-chloro-lH-benzimidazol-2- yl)biphenyl-4-yI]cyciohexyI}acetatic acid was prepared. LC-MS (Es, m z): C₂₇H₂sCIN₂0₂: 444; Found: 445 [M+H]⁺.

Example 72:

Metliyl (trans~A-¼-\ 5-(6-chloro- 1 H-benzmiidazol-2-yl pyridm~2- v lphenyl ) cvclohexypacetate

In the same procedure as Example 68, methyl (ίτ£)ί«5·-4-{4-1-5-(6-οΗ1θΓθ-1//- benzimidaz»l-2-yl)pyridin-2-yl]phenyl}cyclohexyl)acetate was prepared. LC-MS (Es, m/z): C27H26CIN3O2: 459; Found: 460 [M+H .

Example 73:

rrmi^-4-{4-r5-(^'6-chloro-lH-benz.midazol-2-yl)pyridin-2-

YlT)phenylcvclohexyl)acetic acid

In the same procedure as Example 69, (ira«.y-4-{4-[5-(6-chloro-lH-benzimidazol- 2-yl)pyridin-2-yl]phenyl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m/z): C₂₆H₂₄ON₃O₂: 445; Found: 446 [M+Hf.

Example 74:

Methyl {trans~4~\ 4 V6-fluoro- lH-benzimidazol-2-yl biphenvI-4- vncvciohexyl } acetate

To a 2 mL Pyrex vial was charged with 4-fluoro-1.2-phenylendiamine (43 mg, 0.34 mmol) in, Intermidiate 1 tert-butyl 4'-[fra«5^,-4-(2-methoxy-2-oxoethyl)cyclohexyl]biphenyI- 4-carboxyiate (100 mg, 0.28 mmol) followed by tripenyl phosphite (106 mg, 0.34 mmol), and pyridine (1 ml). Then the mixture was under microwave at 220 °C for 30 min. LC-MS showed complete formation of product. The mixture was quenched with ethyl acetate and water. The aqueous layer was extracted with EtOAc (x2) and the combined organics dried (MgS0 ) and concentrated under vacuum. The resulting residue was then purified on the ISCO Comb Flash eluting with 0 to 60 % ethyl acetate / hexane gradient. The desired fractions afforded methyl {tmnir-4-[4^,-(6-iluoro-lH-benzimidazol-2-yl)biphenyl-4-yl]cyclohexyl} acetate. LC-MS (Es, m/z): C₂8H27FN₂0₂: 442; Found: 443 [M+Hf.

Example 75:

{ 7>Q¾y-4- 4'-(6-fluoro- lH-benzimidazol-2-ynbiphenvi-4-yilcvciohexYl } acetatic acid

In the same procedure as Example 69, {rraw-4-[4'-(6-fiuoro-lH-benzirnidazol-2- yl)biphenyl-4-yl]cyclohexyl}acetatic acid was prepared. LC-MS (Es, m/z): C 7H25FN2O2: 428; Found: 429 [M+H]⁺.

Example 76:

Methyl ifr ras^,-4-r4'-(5,6-difluoi - lH-benzimidazol-2-vDbiDhenyl-4- vncvclohexyl > acetate In the same procedure as Example 74, methyl {tra¾s^,-4-[4'-(5_}6-difluoro-lH- benzimidazol-2-yl)biphenyl-4-yl3cyclohexyl} acetate was prepared. LC-MS (Es, m z):

C₂8H26F2N₂0₂: 460; Found: 461 [M+H]⁺.

Example 77:

{Γπ»¾?··4-Γ4'-(5. 6-cufluoro-lH-beiizi:tm^

In the same procedure as Example 69, {frara-4-[4'-(5_i 6-difluoro-lH- benzimida2oi-2-yi)biphenyl-4-yl]cycIohexyl}acetatic acid was prepared. LC-MS (Es, m/z): C28H26F2N2O2: 460; Found: 4 1 [M+H]⁺.

Example 78:

Methyl (trans-A- i 4'-r6-(trifluoromethoxy> lH-benzimidazol-2-yl1biphenyl-4-vU cyclohexyl)acetate

In the same procedure as Example 74, methyl (iraw-4-{4'-[6-(trifluoromethoxy)- lH-benzimidazol-2-yl]biphenyl-4-yl}cyclohexyl) acetate was prepared. LC-MS (Es, m/z):

C29H27F3N2O3: 508; Found: 509 [M+Hf .

Example 79:

(Trans-4- (4'-f 6-CtriiIuoromethoxy^')- lH-benzimida2ol-2-yl1biphenyi-4- yUcyclohexyl)acetic acid In the same procedure as Example 69, (/raw-4-{4'-[6-(trifluoromethoxy)-lH-- benzimidazol-2-yl]biphenyl-4-yl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m z):

C28H25F3N2O3: 494; Found: 495 [Μ+Η]⁺. Example 80:

Methyl { rQ«j^,-4-r4'-(^'5-chloro-6-fluoro-iH-beiizimida2ol-2-vDbi yllcyclohexy acetate In the same procedure as Example 74, methyl {transA-l^-iS-c loro-e-f xoTo-lH- benzimidazol-2-yi)biphenyl-4-yl3cyclohexyl}acetate was prepared. LC-MS (Es, m/z):

C₂₈H₂6FC1N₂02: 76; Found: 477 [M+Hf.

Example 81 :

( rrg¾y-4-f4'-(5-chloro-6-fluoro -lH-ben2imidazol-2-yl)biphenvI-4- yllcyclohexyl)acetic acid

In the same procedure as Example 69, (trii«-i-4-[4'-(5-chloro-6-fluoro-lH- benzimidazol-2-yl)biphenyl-4-yl]cyclohexyl}acetatic acid was prepared. LC-MS (Es, m/z):

Cwtti&j A .: 462; Found: 463 [M+H]⁺.

Example 82:

Methyl (frfl¾y-4-i4'-(^'5-cMoro-6-memyl-lH-beixzimida2X)l-2-vnbiphenyl-4 yl cyclohexyUacetate

In tine same procedure as Example 74, methyl {/ra¾y-4-[4'-(5-chIoro-6-methyl- lH-benzimidazol-2-yl)biphenyl-4-yl]cyclohexyl}acetate was prepared. LC-MS (Es, m/z):

C₂9H₂₉C1 ₂02: 473; Found: 474 [M+H]⁺.

Example 83:

H ί 7 a^-4-[4'-r5-chloro-6-methyl - lH-benzimidazol-2-yl^')biphenyl-4- vncvclohexyU acetic acid

In the same procedure as Example 69, {frans^,-4-[4'-(5-chIoro-6-methyl-lH- benzimidazol-2-yl)biphenyl-4-yl]cyclohexyl}acetatic acid was prepared. LC-MS (Es, m/z): C28H27CIN2O2: 458; Found: 459 [M+Hf .

Example 84:

Methyl f/mw-4-r4'-i5.6-dichloro -lH-benzimidazol-2-yl)biphenyl-4- yll cyclohexyl I acetate

In the same procedure as Example 74, methyl {^^^-^'-(S^-dichloro-lH- benzimidazoI-2-yl)biphenyl-4-yl]cyclohexyl}acetate was prepared. LC-MS (Es_s m/z):

C₂8H26C1₂N₂02: 493; Found: 494 [M+H]⁺.

Example 85:

0

(rm¾s-4-[4'-(5,6-dicMoro-6-mefcy^^^

yllcyclohexyU acetic acid

In the same procedure as Example 69, {tr ^~[4^5,6-di-cUoTo-6- eihyl benzimidazol-2-yl)biphenyl-4-yl]cyclohexyl}acetatic acid was prepared. LC-MS (Es, m/z): C27H24CIN2O2: 479; Found: 480 [M+H]⁺.

Example 86:

o

MemvUfraws-4-(4'-f6-(me^

biphenyl-4-yl)cvclohexyl)acetate In the same procedure as Example 74, methyl (fraw-4-{4'-[6-(methylsuIfonyl)- IH-benziinidazol-2-yl3biphenyl-4-yl}cyclohexyl)acetate was prepared. LC-MS (Es, m z):

C2₉H30N₂O₄S: 502; Found: 503 [M+Hj⁺.

Example 87:

(rmro-4-{4'-f6-(me&ylsulfon^

ylicycIohexyPacetic acid

In the same procedure as Example 69, (/m«5^,-4-{4^,-[6-(methylsulfonyl)-IH- benzimidazol-2-yl]biphenyl-4-yl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m/z):

C₂gHigN₂C>4S: 488; Found: 489 [M+H .

Example 88:

Meth^yl ffr^graj--4-f4^l-(6-cvano-lH-beiizimidazol-2-yl^')biphenvi-4- yll cyclohexylacetate

In the same procedure as Example 74, methyl {trans-4-[4'-(6-cyano-lH- benzimidazol-2-yl)biphenyI-4-yl]cyclohexyI} acetate was prepared. LC-MS (Es, m z):

C29H27N3O2: 449; Found: 450 [M+H]⁺.

Example 89:

{7 aw-4-f4'-(6-cyano-lH-benzimidazol-2-yl)biphenvI-4-yl1cyclohexynacetic acid

In the same procedure as Example 69, {irani^,-4-[4'-(6-cyano-lH-benzimidazol-2- yl) biphenyl-4-yl]cyclohexyl}acetic acid was prepared. LC-MS (Es, m/z): C28H25N3O2: 435; Found: 436 [M+H]⁺.

Example 90:

Methyl { mw^-r4'-r5J-difluoro-lH-ben2iiTddazol-2-vnbiphenyl-4- vl] cvclohexyl \ acetate

In the same pz cedure as Example 74, methyl {/rara-4-[4'-(5_s7-difluoro-lH- benzimidazol-2-yl)biphenyl-4-ylj cyclohexyl} acetate was prepared. LC-MS (Es, m/z): C₂8H₂6F2N₂0₂: 460; Found: 461 [M+H .

Example 91:

i7>'^g/2J"4-{^'4'-(^r5.7-dirIuoro-lH-ber)zimidazol-2-vnbiphe

acid

In the same procedure as Example 69, {fri2«5-4-[4'-(5,7-difluoro-lH- benzrmidazol-2-yl)biphenyl-4-yI]cyclohexyl}acetatic acid was prepared. LC-MS (Es, m/z): C₂8H26F2N₂0₂: 460; Found: 461 [M+H]⁺.

Example 92:

o

(Trans-A- (4'-f 6-( metfaylsulfonyl)- 1 H-benzimidazoI-2-yl)biphenyl-4- vUcyclohexyQacetic acid

Step A: Methyl (?m «-4-f4'-(6-siilfamoyl-lH-benzimidazol-2-vnbiphenyl-4- yllcyclohexyUacetate

In the same procedure as Example 74, methyl {/r<3!«5-4-[4'-(6-sulfamoyl-lH- benzimidazol-2-yl)biphenyI-4-yl]cyclohexyl}acetate was prepared. LC-MS (Es, m/z):

C₂gH29N₃0₄S: 503; Found: 504 [M+Hf.

Step B: (rrfl»g-4-(4'-[6-(methylsulfonyl -lH-benzimidazol-2-yllbiphenyl-4- ylcyclohexypacetic acid

In the same procedure as Example 69, {ira«5-4-[4^,-(6-sulfamoyl-lH- benzimidazol-2-yl)biphenyl-4-yl]cyclohexyl) acetic acid was prepared. LC-MS (Es, m/z): C27H27N3O4S: 489; Found: 490 [M+H]⁺. Example 93:

J

rrrafls-4-(4'-(6-ffmemyls dfonv

yl)cvclo exyll acetic acid

Step A: Methyl r?r<ms-4-f4'-f6-r(methvIsu^

yl}biphenyl-4-YDcyclohexyl1acetate

In the same procedure as Example 74, methyl [irans-4-(4'-{6- [(methylsulfonyl)armno]- 1 H-ben^

LC-MS (Es, m/z): ¾Η₃₁Ν₃0₄8: 517; Found: 518 [M+H]^÷.

Step B: frmw-4-(4'-{6-[fmemyIsuifo^

4-yl)cvclohexyii acetic acid

In the same procedure as Example 69, [i *ans'-4-(4^,-{6-[(methylsulfonyl)amino]- lH-benzimidazoI-2-yl}bipheriyl-4-yl)cyclohexyljacetic acid was prepared. LC-MS (Es, m z): C28H29N3O4S: 503; Found: 504 [M+H]⁺.

Example 94:

Methyl (tmm^ ^e-fluoro-S-foifluoro

yl)cyclohexyl)acetate

Step A: 4-fluoro-5-(trifluoromethyl^')ber-zene- 1.2-diamine

4-fluoro-5-(trifiuoromethyI) benzene- 1, 2-diamine was prepared using the same synthetic sequences as that of Intermediate 4. LC-MS (Es, m z): C7H6F4N2: 194; Found: 195

[M+H]⁺.

Step B: Methyl (trans-A- ξ 4'-r6-fluoro-5-Ctrifluoromethyl lH-benzimidazol-2- y 11 biphenyl-4- y } cyclohex vDacetate

In the same procedure as Example 76, methyl (/ra«i^,-4-{4'-[6-fluoro-5- (trifluoromethyl)-lH-benzimidazol-2-yi]biphenyl-4-yl}cyclohexyl)acetate was prepared. LC-MS (Es, m z): C29H26F4N2O2: 510; Found: 511 [M+H]⁺.

Example 95:

frraw-4-f4'-[6-fluoro-5-ftri^

yl}cyclohexyl)acetic acid

In the same procedure as Example 69, (frafii-4-{4'-[6-fluoro-5-(trifluorometiiyl)- lH-berizimidazol-2-yl]biphenyl-4-yl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m/z): C28H24F4N2O₂: 496; Found: 497 [M+H]⁺.

Example 96:

(rra¾s^-f4 6-mewoxy-lH~ben^

acid

Step A: Methyl f trans-4- 4'-( 6-methoxy- lH-ber-zimidazol-2-yl)biphenyl-4- yl]cvclohexyl)acetate

In the same procedure as Example 74, Methyl {tmj¾s~4~[4^f-(6-methoxy-lH- benzimidazol-2-yl)biphenyl-4-yl]cyclohexyl}acetate was prepared. LC-MS (Es, m/z):

C29H30N2O3: 454; Found: 455 [M+H .

Step B: frara-4-[4'-(6-metiioxY- lH-ben2imidazol-2-yl)biphenyl-4- vncvclohexyn acetic acid

In the same procedure as Example 69, {iraM5-4-[4'~(6-methoxy-lH-benzimidazol- 2-yl)biphenyl-4-yl]cycIohexyl} acetic acid was prepared. LC-MS (Es, m z): C28H28N2O3: 440; Found: 441 [M+H]⁺.

Example 97:

H3

2-Methyl-l -(trans - f 4'-r6-ftrifluoromethyl)-l H-ben2imidazol-2-yl] biphenyl-4- vUcvclohexyI) propan-2-ol

To a solution of methyl (tra?«-4-{4^,~[6~(trifluoromethyl)-lH-benzimidazol-2- yl]biphenyl-4-yl}cyclohexyl)acetate (0.065 g, 0.132 mmol) in THF anhydrous (1 ml) at -78 °C was added methyl lithium in THF (1.6M, 0.5 ml, 0.79 mmol). Then the mixture was stirred at - 78 °C for 2 h. LC-MS showed complete conversion of starting material to product. The mixture was quenched with saturated NH₄Ci solution, and then extracted with EtOAc (x2) and the combined organics dried (MgS0₄) and concentrated under vacuum. The resulting residue was then purification on the ISCO Comb Flash Companion eluting with 0 to 60 % ethyl acetate / hexane gradient. The desired fractions afforded 2-memyl-l-(/ra7¾s^-{4'-[6-(trifluoromethyl)-lH^:- benzimidazol-2-yl]biphenyl-4-yl}cyclohexyl)propan-2-ol. LC-MS (ES, m/z) C^i^^O: 492; Found: 493 [M+H]⁺.

1 - ί trans - 4'-( 6-chIoro- 1 H-tenzirmda2X)l-2-vnbiphenyl-4-vncvclohexyI -2- methylpropan-2-ol

In the same procedure as Example 97, l-{iraw-4-[4'-(6-ch]oro-lH-benzimidazol- 2-yl)biphenyl-4-yl]cyclohexyl}-2-methylpropan-2-ol was prepared. LC-MS (Es, m/z):

C29H316CIN2O: 459; Found: 460 [M+H]⁺.

Example 99:

N- emvI-2-ftmm--4-{4'-r6-( ^

cvclohexyl)acetamide

A sealed tube was charged with methyl (ira/'i-'-4-{4^,-[6-(trifluoromethyl)-lH~ benzimidazol-2-yl]biphenyl-4-yl}cyclohexyl)acetate (0.02 g, 0.0412 mmol), methylamine (0.4 ml, 0.8 mmol, 2M in MeOH. Then the mixture sealed and heated to 80 °C for 15 h. LC-MS showed complete conversion of starting material to product. Concentrated, the resulting residue was then purified by reverse HPLC to give N-memyl-2-(i!j"a«i'-4-{4^,-[6-(trifluoromemyl)-lH^'- benzimidazol-2-yl3biphenyl-4-yl}cyclohexyl)acetamjde. LC-MS (ES, m/z) C29H2SF3N3O: 491 ; Found: 492 [M+H}⁺.

Example 100:

Methyl 2- ( 4'-f tm/w-4-(2-methoxy-2H3xoethyl^')cvclohexynbiphenyI-4--yl ) - IH- benzimidazoIe-6-carboxylate

Step A: Methyl 3. 4-diaminobenzoate

To a 500 ml flask was added acetyl chloride (30 ml) dropwise to MeOH (90 ml) at 0 °C., then 1, 2diamino benzoic acid (3 g, 1 .7 mmol) was slowly added to the mixture after the mixture, was stirred for 30 min. The resulting mixture was stirred at room temperature for 15 h. LC-MS showed complete conversion of starting material to product. Concentrated, the resulting residue was neutralized with aqueous NaHC0₃, extracted with EtOAc (2x). The organics was concentrated to afford Methyl 3, 4-diaminobenzoate. LC-MS (Es, m z): C8H10N2O2: 166; Found: 167 [M+H]⁺.

Step B: Methyl 2-l4'-ffra» -4-f2-methoxy-2-oxoethyl¹)cyclohexyl1biphenyl--4-yl}- 1 H-benzimidazole-6-carboxylate

In the same procedure as Example 76, Methyl 2-{4'-ftm¾s^,-4-(2-methoxy-2- oxoemyl)cyclohexyl]biphenyl-4-yl}-lH-benzimidazole-6-carboxylate was prepared. LC-MS (Es, m/z): C30H30N2O4: 482; Found: 483 [M+H]⁺.

Example 101:

(rraro-4-(4'-[6-fchmethylcarba

y cyclohexyl)acetic acid

Step A: Methyl 2-(4-bromophenyl^')- 1 H-benzirnidazole-6-carboxylate Methyl 2-(4-bromophenyl)-lH-benzimidazole-6-carboxylate was prepared using the same synthetic sequence as that of 6~bromopyridin-3-yl)-6-(trifluoromethyl)-l-H- benzimidazole. LC-MS (Es, m/z): CisHnBri^Oz: 331; Found: 332 [M+H]⁺.

Step B: 2-(4-bromophenvn-lH-benzimidazole-6-carboxylic acid

In the same procedure as Example 2, 2-(4-bromophenyl)-lH-benzimidazole-6- carboxylic acid was prepared. LC-MS (Es, m/z): ¾Η₉ΒΓΝ₂0₂: 317; Found: 318 [M+Hf.

Step C: 2-(4-bromophenylVNJV-dimethyl-lH-ben^ A 50 ml flask was charged with 2-(4-bromophenyl)-lH-ber.zimidazole-6-carboxylic acid (60 mg, 0.189 mmol), Oxalyl Chloride (0.259 ml, 3.78 mmol), followed by catalytic amount of DMF dropwise. The mixture was stirred at 0 °C for 30 min. Then the mixture was concentrated under vacuum. The residue was added with DMC (0.6 ml), triethyl amine (0.132 ml, 0.946 mmol), then dimethyl amine at 0 °C. The resulting mixture was stirred at room temperature for 15 h. LC-MS showed the complete conversion of starting material to product. Concentrated, the resulting residue was purified by Prep. TLC (10% MeOH /CH₂CI₂) to give 2- (4-bromophenyl)-N, N-dimethyl-lH-benzirnidazole-6-carboxamide. LC-MS (Es, m z):

C,₆Hj4BrN₃0: 344; Found: 345 [M+H]⁺.

Step D: Methyl (trans-A- i4' 6-(dimethylcarbamovD- lH-benzimidazoI-2- vnbiphenyl-4-yl } cyclohexyl)acetate

In the same procedure as Example 68, methyl {trans-A~{A^l-[6- (dimethylcarbamoyI)-lH-benzimidazol-2-yl]biphenyl-4-yl}cyclohexyl)acetate was prepared. LC- MS (Es, m/z): Ca^NaC^: 495; Found: 496 [M+H]⁺.

Ste E: (trans- - f 4'-Γ6-ί dimethyl carbamoyl)- 1 H-benzimidazol-2-vIlbiphenyl-4- yllcvclohexyl^') acetic acid

In the same procedure as Example 71, (ir ns-4-{4'-[6-(dimethylcarbamoyl)-1H- benzimidazol-2-yl]biphenyl-4-yl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m/z):

C28H28N2O3: 440; Found: 441 [M+H]⁺.

Example 102:

Methyl (trfl¾ -4-{4-f6-f6-cMoro-lH-benziniidazol-2-ynpyridin-3- yl^phenyl \ cyclohexyl)acetate

In the same procedure as Example 74 using 5-{4-[fr- ¾y-4-(2-methoxy-2- oxoethyl)cyclohexyl]phenyl}pyridine-2-carboxylic acid, (trans~A- {4'-[6-(dimethylcarbamoyl)- lH-benzimidazol-2-yl]biphenyl-4-yl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m/z): C27H26CIN3O2: 459; Found: 460 [M+H]⁺.

Example 103:

(Trans-4-ξΑ-16-( 6-chloro- lH-benzimidazol-2-yl)pyridin-3-vl]phenyi }

cyclohexyl)acetic acid

In the same procedure as Example 69, (tm«5-4-{4-[6-(6-chloro-lH-benzimidazol- 2-yl) pyridin-3-yl]phenyl}cyclohexyl)acetic acid. LC-MS (Es, m/z): C26H24CIN3O2: 445; Found: 446 [M+H]⁺.

Example 104:

o

(^'7>g 5'^-i4-r6-(6-fluoro-lH-berizirm^azol-2-yl^pyridin-3- yi]phenvUcvclohexyl)acetic acid

Step A: Methyl (trans - f 4-f 6-f 6-fluoro-lH-benzimidazol-2-vDpyridin-3- yll phenyl) cvclohexyl)acetate

In the same procedure as Example 74 using 5-{4-[/rara-4-(2-methoxy-2- oxoethyl)cyclohexyl]phenylpyridine-2'-carboxylic acid, Methyl (fra«5-4-{4-[6-(6-fluoro- f- benzimidazol-2-yl)pyridin-3-yl]phenyl}cyclohexyl)acetate was prepared, LC-MS (Es, m/z): C27H26FN3O2: 443; Found: 444 [M+H]⁺.

Step B: frmw-4-H-f6-(6-flu ro ^

yllphenvUcvclohexyl)acetic acid

In the same procedure as Example 71, (rraw-4-{4-[6-(6-j£luoro-lH-benzimidazol- 2-yl)pyridin-3-yl]phenyl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m/z): C26なFN30₂: 429; Found: 430 [M+H]⁺.

Example 105:

o

(Trans-A- i4- 6-(5.6-difluoro- lH-benzimidazol-2-vnpyridin-3- yHphenvUcvclohexyl)acetic acid

Step A: Methyl ( trans - ί 4-f6-( 5.6-difluoro-l H-benzimidazoI-2-yl)Dyridin-3- yllphenyl}

pyridin-3-vilphenyllcvclohexynacetate

In the same procedure as Example 74 5-{4-[ira¾y-4-(2-methoxy-2- oxoethyl)cyclohexyl]phenyl}pyridme-2-carboxylic acid, Memyl(iraw-4-{4-[6-(5,6-difluoro-lH- benzimidazol-2-yl)pyridin-3-yl]phenyI}pyridin-3-yl]phenyI} cyclohexyI)acetate was prepared. LC-MS (Es, m/z): C27H26F2N3O2: 461 ; Found: 462 [M+H]⁺.

Step B: rrrg¾ -4-i4-f6-(5,6-difluoro-lH-benzimidazol-2-yl)pyridin-3- yl^phenvUcvclohexyltacetic acid

In the same procedure as Example 69, (rra«5^,-4-{4-[6-(5₅6-difiiioro-lH- benzimidazol-2-yl)pyridin-3-yl]phenyl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m/z): C₂6H24F₂N₃02: 447; Found: 448 [M+H]⁺.

Example 106:

frrafts-4-f4-(6-[5-(trifluoro^

yl}phenyl)cvclohexyl]acetic acid

Step A; Methyl ^rmy-4-f4-f6-[5-f1rifluorom

pyridin- 3 - νΐΐ phenyl kyclohexyl] acetate

In the same procedure as Example 74 using 5-{4-[irara-4-(2-methoxy-2- oxoethyl) cyclohexyl]phenyl}pyridine~2-carboxylic acid, methyl [trans-4-(4~{6~[5- (trifmoromethoxy)-1H-benzimida^^ was prepared.

LC-MS (Es, m/z): ΟζϋΗζ^Ν^: 509; Found: 510 [M+H]⁺.

Step B: \Tram -(4-{6-[5~(tnft\iomme1 oxy)AH^

v phen l cyclohexyl] acetic acid

In the same procedure as Example 69, [imMi-4-(4-{6-[5-(trifluoromethoxy)-lH- benzimidazol-2-yl]pyridin-3-yl}phenyl)cyclohexyl]acetic acid was prepared. LC-MS (Es, m/z): C27H24F3N3O3: 495; Found: 496 [M+H]⁺.

Example 107:

o

[7>aras-4-(4-{6-r6-(methylsulfony^

phenyl)cyclohexyl-| acetic acid

Step A: Methyl \trans-4-(4- (6- 6-(methylsulfonyl)-1H-berizirrtidazol-2- vllpyridin-3-ynphenvn cvclohexyI]acetate

To a solution of 4-(methylsulfonyl) benzene- 1₅ 2-diamine (0.05 g, 0.27 mol) in DMF (3 ml) was added water (0.1 ml) followed by methyl {ira¾y-4-[4-(6-formylpyridin-3- yl)phenyI]cyclohexyl} acetate (0.1 g, 0.29 mmol) slowly. After stirring at room temperature for 5 min Oxone (0.107 g, 0.175 mmol) was added to the mixture. The mixture was then stirred at room temperature for 15 hr. LC-MS showed complete conversion of starting material to product. The mixture was poured slowly into a solution of potassium carbonate (2 ml, 1M) in 50 ml water. The resulting slurry was stirred for 10 min, diluted with EtO Ac and the layers separated. The aqueous layer was washed with EtO Ac (x2) and the combined organics dried (MgS0₄) and concentrated under vacuum. The resulting residue was purified on the ISCO Comb Flash Companion, eluting with 0 to 60 % ethyl acetate / hexane gradient The desired fractions afforded methyl [iraw-4-(4-{6-[6-(methyIsul^

yl}phenyl)cyclohexyl]acetate. LC-MS (ES, m/z) C₂gH₂₉N₃0₄S: 503; Found: 504 [M+H]⁺

Step B: rrm/w-4-(4-(6-r6-(memylsulfonylVlH-benzimidazol-2-yl1pyridin-3- vnphenvi^') cvclohexyllacetic acid

In the same procedure as Example 69, [ira«5^,-4-(4-{6-[6-(methylsulfonyl)-l H^'- benzimidazol-2-yl]pyridm-3-yl } phenyl)cyclohexyl]acetic acid was prepared. LC-MS (Es, m/z) : C27な₇N₃0₄S: 489; Found: 490 [M+HJ⁺.

Example 108:

Methyl rrrg^-4-{4-r6-(6-bromo-lH-rerizimi<ia2Ol-2-yl)pyridin-3- yll phenyl > cyclohexyl)acetate

In the same procedure as Step A in Example 107, methyl (frani-4-{4-[6-(6-bromo- lH-benzimidazol-2-yl) pyridin-3-yl]phenyl}cyclohexyl)acetate was prepared. LC-MS (Es, m/z): C2₇H26BrN₃0₂: 504; Found: 505 [M+H .

Example 109:

(rra^-4-{4-f6-f6-bromo-lH-ben^

acid

In the same procedure as Step B in Example 107, (rraii-r-4-{4-[6-(6-bromo-lH- rerizimidazol-2-yl) pyridin-3-yl]phenyi}cyclohexyl)acetic was prepared. LC-MS (Es, m/z): C₂₆H24Br ₃02: 490; Found: 491 [M+H]⁺.

Example 110:

(Trans-4-(4-i6-f6-cvano-1H-berizim^

acid

In the same synthetic sequence as Example 107, (7VaTO!-4-{4-[6-(6-cyano-lH^'- ben2ainidazol~2-yl)pyridin-3-yl]phenyl}cyclohexyl)acetic was prepared. LC-MS (Es, m/z):

C27H24N4O₂: 436; Found: 437 [M+H]⁺.

Example 111:

Methyl (frt3wy-4-{4-|-6-fl.7-dihvdroimidazo [4.5-/1 mdazol-6-yl pyridin-3-yll phenyl ΐ cvclohexyl)acetate

In the same synthetic sequence as Example 107 at step A, methyl (trans-4-{4-[6- (1 dmydroimidazo[4_i5^indaz»l-6-yl)pyridin-3-yl]phenyl}cyclohexyl)acetate was prepared. LC-MS (Es, m/z): CsgHiyNsOj: 465; Found: 466 [M+H]⁺.

Example 112:

frm?¾i--4-(4-[6-(l,7-dihvdroimidazo [4,5- ] indazol-6-yl pyridin-3- vllphenv cyclohexyl)acetic acid

In the same synthetic sequence as Example 107 at step B, (j?raw-4-{4-[6-(l ,7- dhyi.roimidazo[4-5-y]indazol-6-yl)pyridin-3-yl3phenyl}cyclohexyl)acetic acid was prepared. LC- MS (Es, m/z): C27H27N5O2: 451; Found: 452 [M+H]⁺.

Example 113:

3

Methyl ftmw-4-(4-r6- 6-methoxy-lH-benzimidazol-2-yl) pyridin-3- yll phenyl ) cvclohexyl)acetate In the same synthetic sequence as Example 107 at step A, methyl (ίί-ίϊ¾$^,-4-{4-[6- (6-methoxy-lH-benzimidazol-2-yi)pyridin-3-yl]phenyl}cyclohexyl) acetate was prepared. LC- MS (Es, m/z): C₂₈H₂9N₃0₃: 455; Found: 456 [M+Hf. Example 114:

(:. ara-4-{4-[6-f6-methoxy-lH-te

acid In the same synthetic sequence as Example 107 at step B, (fi^f-£iw-4-{4-[0~(6-methoxy- lH-beiizimidazol-2-yl)pyridiri"3-yl]phenyl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m/z): C₂₇H₂7N₃0₃: 441; Found: 442 [M+Hf.

f7r.my-4-H-[6-(7-memoxy-iH-be.^

acid

In the same synthetic sequence as Example 107, (/ra«s-4-{4-[6-(7-methoxy-lH- benzimidazol-2-yl)pyridin-3-yl]phenyl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m/z): C2₇H₂₇N₃0₃: 441; Found: 442 [M+Hf.

Example 1 16:

irra w-4-r4'-(7-methox

In the same synthetic sequence as Example 107, {ir «i-4-f4'-(7-me£hoxy-lH- benzimidazol-2-yl)biphenyl-4-yl]cyclohexyl}acetic acid was prepared. LC-MS (Es, m/z):

C2₈H₂8N₂0₃: 440; Found: 441 [M+H]⁺. Example 117:

o

(rrara-4-r4'-(6-mtro-lH-benzi^^ acid In the same synthetic sequence as Example 107, {ira«ir-4-[4'-(6-nitro-lH- benzimidazol-2-yI)biphenyl-4-yl]cyclohexyl} acetic acid was prepared. LC-MS (Es, m/z):

C27H25N3O4: 455; Found: 456 [M+H]^÷.

Example 118:

frra« ~f4'-f6-amino-lH^ acid

Step A: tert-butyl-2- {4'-[trgw-4-(^"2-methoxy-2-oxoethyl) cyclohexyllbiphenyl-4-yl) -6- nitro- 1 H-benzimi dazole- 1 -carboxylate

To a solution of methyl {frawi^-^'-ie-nitro-lH-ben m idazol^- lJbipheny - yl]cyclohexyl} acetate (0.46 g, 0.98 mmol) in CH2CI2 (5 ml) was added triethyl amine (0.68 ml, 4.9 mmol), di-tert-butyl dicarbonate (0.64 g , 2.94 mmol), and catalytic amount of 4- dimethylaminopyridine. The mixture was stirred for 15hr. LC-MS showed complete conversion of stalling material product. The mixture was concentrated; the residue was purified by Prep. TLC (20% EtOAc/Hexane) to give the solid ieri-butyl-2-{4'-[fr w-4-(2-methoxy-2-oxoethyl) cyclohexyl]biphenyl-4-yl}- 6-nitro-lH-benzimidazole-1-carboxylate. LC-MS (ES, m/z)

C3₃H₃₅N₃0₆: 569; Found: 570 [M+H]⁺.

Ste B: fe -butyl 6-amino-2-{4'-ftr w.s'-4- 2-methoxy-2- oxoethyl)cvclohexyl]biphenvI-4-yl } - 1 H-benzimidazole- 1 -carboxylate

To a solution of it? t-butyl-2-{4'-[ir«¾y-4-(2-methoxy-2- oxoemyl)cyclohexyl]biphenyl-4-yl}-6-nitro-lH-benzimidazole-1-carboxylate (0.06 g, 0.15 mmol) in EtOH (2 ml) was added Pd-C (10%wt, 0.025 g, 0.021 mmol). The system was vacuumed and refilled with hydrogen three times. Then the mixture was stirred at room temperature for 15 h underな balloon. LC-MS showed complete conversion of starting material to by-product and minor product. The mixture was filtered through celite, washed with hot

MeOH. The filtrate was concentrated to give the yellowish solid teri-butyl 6-amin0'2-{4^,-[tmras-- 4-(2-methoxy-2-oxoemyl)cyclohexyl]biphenyl-4-yl}-lH-benzimidazole-1-carboxylate. LC-MS (ES, m/z) C33H37N3O4: 539; Found: 540 [M+H]⁺ Step C: frmw^-r4'-f6-amino-lH-benzimidazoI-2-v biphenvI-4- yljcyclohexyU acetic acid

In the same procedure as Example 69, /ra«5-4-[4'-(6-amino-lH-benzimidazol-2- yl)biphenyl-4-yl]cyclohexyl} acetic acid was prepared. LC-MS (Es, m z): C2₇H2₇N3O2: 425;

Found: 426 [M+H]⁺.

Example 1 19:

(rraMs-4-(4'-[6-(ethylarmnoyi^ acid In the same synthetic sequence as Example 118, (rra«5-4-{4'-[6-(ethylamino)-lH- benzimidazoI-2-yl]biphenyl-4-yl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m z):

CJ0H31N3O2: 453; Found: 454 [M+H]⁺.

Example 120:

N0₂

( Trans - f 4'-(7-nitro- 1 H-benzimidazol-2-vnbiphenyl-4-yl]cyclohexyl ) acetic acid

In the same synthetic sequence as Example 107, {irans-4-[4'-(7-nitro-lH- benzimidazol-2-yl)biphenyl-4-yI]cyclohexyi}acetic acid was prepared. LC-MS (Es_} m/z):

C27H2SN3O4: 455; Found: 456 [M+HjV

Example 121:

H

frra^-4-[4'-(7-ammo-lH-benzim^ acid

In the same synthetic sequence as Example 1 18, /ra«i-4-[4'-(7-amino-lH- benzimidazol-2-yl)biphenyl-4-yl]cyclohexyl}acetic acid was prepared, was prepared. LC-MS (Es, m z) : C27H27N3O2: 425; Found: 426 [M+Hf. Example 122:

(rraws-4-(4'-[7-(etfaylamino^ acid In the same synthetic sequence as Example 1 18, ( ra«5^,-4-{4'-[7-(ethylamino)-lH- benzimidazol-2-yi]biphenyl-4-yl}cyclohexyl)acetic acid was prepared. LC-MS (Es_} m/z):

C₂ H₃iN₃0₂: 453; Found: 454 [M+Hf .

Example 123:

Methyl (^,fra»5^,-4-(4'-[6-chloro-5-(^'trifluoromethyn-lH-benczimida2^

yl ) cvclohexyl)acetate

Ste A: 2-(4-bromophenyiy6-chIoro-5-(trifl^

A 2 mL pyrex vial was charged with 5-chloro-2-ni1ro-4-(trifluoromemyl)aniline (45 mg, 0.18 mmol) in , 4-bromo benzaldehyde (34 mg, 0.18 mmol) followed by tripenyl phosphine (106 mg, 0.34 mmol), and pyridine (1 ml). Then the mixture was under microwave at 220 OC for 30 min. LC-MS showed complete formation of product. The mixture was quenched with ethyl acetate and water. The aqueous layer was extracted with EtOAc (x2) and the combined organics dried (MgSO- and concentrated under vacuum. The resulting residue was then purified on Prep.TLC (20 % ethyl acetate / hexane ) to afford 2-(4-bromophenyl)-6-chIoro-5- (trifluoromethyl)-lH-benzimidazole. LC-MS (Es, m/z): C14H7BJCIF3N2O2: 375; Found: 376 [M+H]⁺. ^'

Step B: Methyl (trans-A- (4'-r6-cMoro-5-ftrifluoromemvn-lH-benzimidazol- 2-yflbiphenYl-4-vi}cvclohexyl)acetate

In the same procedure as Example 68, methyl ( fl«jr-4-{4'-[6-chloro-5- (trifluoromemyl)-lH-benzirmd^^ was prepared. LC-MS

(Es_s m/z): C^HMCIFSN^ 526; Found: 527 [M+H]⁺. Example 124:

frrq -4-{4'-[6-chloro-5-ffrifl^

ylicyclohexyl)acetic acid

In the same procedure as Example 69, tran5^,-4-{4^,-[6-chloro-5~(trifluoromethyl)- lH-berizirmckzol-2-yl]biph^^ acid was prepared. LC-MS (Es, m/z): C₂8H₂4C1F3N₂0₂: 512; Found: 513 [M+Hf.

Methyl frgn -^S^-chloro-S-ftri^

vUphenvOcvclohexyllacetate

Step A: 2-(6-bromopyridin-3-v0-6-cMoro-5-(W-u^

A sealed tube was charged with 5-cUoro-2-riitro^^trifluoromethyl)ariiline (45 mg, 0.18 mmol) in , 2-bromo-5-formylpyridine (35 mg_} 0.18 mmol), Na₂S₂0₄ (1M, 0.56 ml) and EtOH (0.6 ml). Then the mixture was capped and heated at 80 c for 15 h. LC-MS showed complete formation of product. The mixture was quenched with ethyl acetate and water. The aqueous layer was extracted with EtOAc (x2) and the combined organics dried (MgS0₄) and concentrated under vacuum. Triturating from acetonitrile, CH₂CI₂ followed by filtration afforded 2-(6-bromopyridm~3-yl)-6-chloro-5-(^ LC-MS (Es, m/z):

C₁₃H₆BrClF3N₃: 376; Found: 377 [M+Hf.

Step B: Methyl j a«s-4-(4-(5-f6-crdoro-5-(1ri^

vllpyridin-2-yl ΐ phenyl¹) cyclohexyljacetate

In the same procedure as Example 68, methyl [ira«i-4-(4-{5-[6-cbioro-5- (trifluoromemyl)-lH-benzimida^ was prepared.

LC-MS (Es, m/z): C28H25CIF3N3O2: 527; Found: 528 [M+Hf.

Example 126:

frm^-4-(4-(5-f6-chloro-5-ftrifluorom

yIlphenyi)cyclohexyi]acetic acid

In the same procedure as Example 69, [ί/-α/¾5·-4-(4-{5-[6-οη1θΓθ-5- (trifluoromethyl)-lH-benzimidazol-2-yl] pyridin-2-yl}phenyl)cyclohexylj acetic acid was prepared. LC-MS (Es, m z): C27H23CIF3N3O2: 513; Found: 514 [M+Hf.

frm7w-4-{2'-fluoro-4'-i6-fmemyls fo^

yI}cyclohexyl)acetic acid

In the same synthetic sequence as Example 109, (irara5^,-4-{2'-fiuoro-4^I-[6- (methylsiiJfonyl)-lH-benz^ acid was prepared. LC

MS (Es, m/z): CasH₃₇FN₂0₄S: 506; Found: 507 [M+Hf .

Example 128:

II H

6

(rmM -IS'-fluoro^'-f^-fmem^^

yU yclohexyPacetic acid

Step A 2-f4-bromo-2-fluorophenyl)-6-(methylsulfonylVlH-benzimidazole

2-(4-bromo-2-fluorophenyl)-6-(methylsulfonyl)- 1 H-benzimidazoIe was prepared using the same synthetic sequence as that of 2-(4-bromophenyl)-6-(triffuoromethyl)-lH- benzimidazole. LC-MS (Es, m/z): Ci4HioBrFN₂Qz: 369; Found: 370 [M+H]⁺.

S^teP B Memyl ftmro-4-{3^f-fluoro-4^6-(me^

yllbiphenyl-4-yl ) cyclohexyl)acetate

In the same procedure as Example 68, methyl (irans-4-{3^,-ftaoto-4'-[&

(memylsulfonyl)-lH-benzimidazol-2-yl]biphenyl-4-yl}cyclohexyl)acetate was prepared. LC-MS (Es, m/z): C29H2 FN2O S: 520; Found: 521 [M+H]⁺.

Step C: frm^^-^'-fluoro^'-re-fmethvisulfonv -lH-benzimidazoi^- vnbiphenyl-4-yl)cvcIohexynacetic acid

In the same procedure as Example 71, (tm½s-4-{3'-fluoro-4^l-[6-(methylsuifonyl)- lH-benzimidazol-2-yl3biphenyl-4-yl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m z): C₂8H27FN₂0₄S: 506; Found: 507 [M+Hf.

Example 129:

2-frrany-4 3'-fluoro-4^l-r6-fmethylsulfonylVlH-beiizimidazo

yl>cvclohexyl -A^L(2-hvdroxyethyl)acetamide

To a 50 ml round bottle flask was charged with (ira«s-4-{3'-fluoro-4'-[6-

{methylsidfonyl)-lH-benzimidazol-2-yi3biphenyl-4-yl}cyclohexyl)acetic acid (25 mg, 0.049 mmol), Oxalyl Chloride (90 mg, 0.98 mmol), followed by catalytic amount of DMF dropwise. The mixture was stirred at 0 °C for 30 min. Then the mixture was concentrated under vacuum. The residue was added with DMC (0.6 ml), triethyl amine (0.034 ml, 0.247 mmol), then ethanolamine (0.015 ml, 0.034 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 15 h. LC-MS showed the complete conversion of starting material to product. Concentrated, the resulting residue was purified by reverse HPLC to give 2-(imns-4-{3'-fluoro- 4 6-(memylsiilfonyl)-lH-benzimM

hydroxyethyl)acetamide was prepared. LC-MS (Es, m/z): C30H32FN3O₄S: 549; Found: 550

[M+H]⁺.

Example 130:

o

l-rf3 4S)-3.4-dihvdrox^vjToi^

benzimidazol-2-yl biphenyl-4-yl } cyclohexyl)ethanone

In the same procedure as Example 129, l-[(3i?,4S)-3,4-dihydroxypyrrolidin-1-yl]- 2-(traw-4-{3'-fluoro-4'-[6-(memylsu^

yl}cyclohexyl)ethanone was prepared. LC-MS (Es, m/z): C32H3₄FN3O5S: 591 ; Found: 592

[M+H]⁺.

Example 131:

( m« ^,-4-[4'-(6-bromo-3H-imidazo[4.5-&lpyridin-2-yl)biphenyl-4-yl] cvclohexyU acetic acid Step A: Methyl ffrq»y-4-r4'-(6-bromo-3H-mida^

yllcyclohexyU acetate

A 2 mL Pyrex vial was charged with 2-amino-5-bromo-3-nitropyridine (45 mg, 0.21 mmol), methyl [trara-4-(4'-fomiylbiphen.yl-4-yl)cyclohexyl]acetate. (372 mg, 0.22 mmol) followed by tripenyl phosphine (162 mg, 0.62 mmol), and pyridine (1 ml). Then the mixture was under microwave at 220 °C for 30 min. LC-MS showed complete formation of product. The mixture was quenched with ethyl acetate and water. The aqueous layer was extracted with EtOAc (x2) and the combined organics dried (MgS0₄) and concentrated under vacuum. The resulting residue was then purified on Prep.TLC (60 % ethyl acetate / hexane) to afford methyl {tr ns-4- [4'-(5-bromo-3H-imidazo [4,5-&]pyridin-2-yl)biphenyl-4-yl]cyclohexyl}acetate. LC-MS (Es, m z): C₂7H₂₆BrN₃0₂: 504; Found: 505 [M+H]*.

Step B: ( rmTO-4-r4'-(^'6-brOmo-3H-imidazoi4.5-&1 pyridin-2-vDbiphenyl-4-yll cyclohexyUacetic acid

In the same procedure as Example 69, {rraw-4-[4^,-(6-bromo-3H-imidazo[4₎5-Z>] pyridin-2-yI)biphenyl-4-yl]cyclohexyl}acetic acid was prepared. LC-MS (Es, m/z):

C₂6H24BrN₃02: 490; Found: 491 [M+H]⁺.

Example 132:

(rro«5'-4-[4'-r6-cvano-3H-imidazor4,5-jS>]pyridin-2-yl)bipheiiyl-4- yllcyclohexyU acetic acid

Step A: tert-butyl 6-bromo-2- i4'-rtm¾y-4-t^'2-methoxy-2- oxoemyl)cvclohexyl1biphenyl^-y -3H-imidazof4,5-&1pyridine-3-carboxylate

To a solution of methyl {im¾5r-4-[4'-(6-bromo~3H-imidazo [4,5-&] pyridin-2- yl)biphenyl-4-yl] cyclohexyl}acetate (0.091 g, 0.18 mmol) in CH2CI2 (1 ml) was added triethyl amine (0.138 ml, 0.9 mmol), di-tert-butyl bicarbonate (0.12 g, 0.544 mmol), and catalytic amount of 4-dimethylaminopyridine. The mixture was stirred for 15hr. LC-MS showed complete conversion of starting material product The mixture was concentrated; the residue was purified by Prep. TLC (20% EtOAc/Hexane) to give the solid teri-butyl 6-bromo-2- {4^f- [trans-4-{2- methoxy-2-oxoethyl)cyclohexyl] biphenyl-4-yl}-3H-imidazo[4,5-6]pyridine-3-carboxylate. LC- MS (ES, m/z) C₃2H34Br ₃04: 604; Found: 605 [M+H]⁺.

Step B: Methyl {frg^-4-[4'-f6-cyano-3H-imidazor4.5-&lpyridin-2-yl^')biphenyl-4- y 11 cyclohexyl } acetate A 2 Pyrex vial was charged with tert-butyl 6-bromo-2-{4'~[tra¾y-4-(2-methoxy-2- oxoethyl)cyclohexyl]biphenyl-4-yl}-3ffi (27 nig, 0.045 mmol) and zinc cyanide (12.59 mg, 0.107 mmol), znic powder (2.103 mg, 0.032 mmol),

Pd2(dba)3 (6.54 mg, 7.15 μιηοΐ), DPPF (7.92 mg, 0.014 mmol) and, N,N-Dimethylacetamide (0.7 ml). The mixture was under microwave at 130 °C for 60 min. LC-MS showed the reaction was complete. The mixture was diluted with EtOAc (50 ml) and NaHC03, aq (20ml), and the layers were separated. The aqueous layer was washed with EtOAc (x20 ml). The combined organics dried (MgSC ) and concentrated. The residue was purified by prep. TLC (60%

EtOAc/Hex) to give methyl {/ra7W^-[4'-(6-cyano-3H-ina

yl]cyclohexyl} acetate. LC-MS (Es, m/z): C28H26N4O2: 450; Found: 451 [M+H .

Step C: (rmray-4-f4'-(^'6-cyano-3H-imidazo[4.5-61pyridin-2-ynbiphenv - yllcyciohexyl)acetic acid

In the same procedure as Example 71, {fmw-4-[4'-(6-cyano-3H-imidazo[4,5-&] pyridin-2-yl)biphenyl-4-yl]cyclohexyl} acetic acid was prepared. LC-MS (Es, m/z): C27H24N4O2: 436; Found: 437 [M+H]⁺.

Example 133:

(Trans ~ {A-\ 5-C 5-bromo-3H-imidazof 4.5-61 pyridm-2-yl)pyridin-2- vl]phenyl}cvcIohexyl)acetic acid

In the same synthetic sequence as Example 131, (ir ra-4-{4-[5-(5-bromo-3H- UBidazo[4,5-6]pyridin-2-yl)pyridin-2-yl]phenyl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m z): C eH Br^Oz: 505; Found: 506 [M+H]⁺.

Example 134:

( m?¾s- -{4-f5-(6-cvano-3H-imidazo |-4,5-61 pyridin-2-yl pyridin-2- yllphenv cvclohexyl)acetic acid

In the same synthetic sequence as Example 132, ( ra«_f-4-{4-[5-(6-cyano-3H- imidazo [4,5-&]pyridin-2-yl)pyridin-2-yl] phenyl }cyclohexyl)acetic acid was prepared. LC-MS (Es, m z): CisH^NsC^: 437; Found: 438 [M+H . Example 133:

{7>-a^-4-[4'-(6-b.romo-3H-imi^

yllcyclohexyl) acetic acid

In the same synthetic sequence as Example 132, {-rara^-^'-CG-bromo-SH- imidaz» 4,5-&]pyridin-2-yl)-3'-fluorobiphenyl-4-yl3cyclohexyl}acetic acid was prepared. LC-MS (Es, m/z): C₂6H23BrFN30₂: 508; Found: 509 [M+Hf.

Example 136:

(rraro-4-[4'-(6-cyano~3H-im^

yllcyclohexyU acetic acid

In the same synthetic sequence as Example 132, (tran5-4-[4'-(6-cyano-3H- imickzo[4_J5-&]pyridm-2-yI)-3'-fEuorobiphenyi-4-yI]cyclohexyl} cetic acid was prepared. LC-MS (Es, m/z): C27H₂₃FN₄0₂: 454; Found: 453 [M+H]⁺.

Example 137:

( rrfl« -4-[4'-(5-bromo-3H-imidazo [4.5-6] pyridm-2-yl)-3'-fluorobiphenyl-4- yllcvclohexy acetic acid

In the same synthetic sequence as Example 107, {£r<ms-4-[4'-(5-bromo-3H- imidazo [4,5-&] pyridm-2-yl)-3'-fluorobiphenyl-4-yl]cyclohexyl}acetic acid was prepared. LC- MS (Es, m/z): C^HyBrFNsC^: 508; Found: 509 [M+Hf.

Example 138:

{ mny-4-[4'-(5-cyanO'3H-imidazo 4,5-61pyridin-2-ylV3'-fluorobiphenyl-4- yllcyclohexyl > acetic acid In the same synthetic sequence as Example 134, (/r£w-4-[4'-(5~cyano-3H- imidazo [4, 5-b] pyridin-2-yl)-3'-fluorobiphenyl-4-yl] cyclohexyl} acetic acid was prepared. LC- MS (Es, m/z): C₂₇H₂₃FN₄0₂: 454; Found: 453 [M+Hf .

Example 139:

(7>gw-4-{3'-fluoro-4 6-nH-pyra^

yllcyclohexyl)acetic acid

Step A: Methyl {fraw -4-[4'-r5-bromo-lH-benzimidazoi-2--vD-3'-fIuorobiphenyl- 4-ylj|cyclohexyl>acetate

In the same synthetic sequence as Example 109 step A, methyl {trans-4-[4'-(5- bromo-lH-benzimidazol-2~yl)-3^,-fIuorobiphenyl-4-yl] cyclohexyl} acetate. LC-MS (Es, m z): C₂₈な6BrFN₂0₂: 520; Found: 521 [M+H]⁺.

Step B: fert-butyl 5-bromo-2- ί 3-fluoro-4'-{-frg¾y-4-(^'2-methoxy-2-oxoethvn cvclohexyll biphenyl-4-yl t - 1 / -benzimidazole- 1 -carboxylate

In the same synthetic sequence as Example 134 step A, tert-butyl 5-bromo-2-{3- fluoro-4'-[ira«s-4-(2-memoxy~2-oxoethyI)c^^

carboxylate was prepared. LC-MS (Es, m/z): C33H3 BrFN₂0₄: 620; Found: 621 [M+Hf.

Step C: Methyl frra¾y-4-f3'-fluoro-4'-r6-gH-Dyrazol-1-ylVlH-benzimidazol-2-yl1 biphenyl-4-yl)cvclohexyl)acetate

To a heavy wall Pyrex vial, was added tert-butyl 5-bromo-2-{3-fluoro-4'-[trans-4-

(2-methoxy-2-oxoethyl)cyclohexyl]biphenyl-4-yl }- 1 H-benzimidazole- 1 -carboxylate ( 100 mg, 0.161 mmol), copper iodide (153 mg, 0.804 mmol),potassium carbonate (1 11 mg, 0.804 mmol), pyrazole (54.8 mg, 0.804 mmol), (lR,2R')-N,r>P-dimethyl-1,2-cyclohexanediamine (114 mg, 0.804 mmol), and acetonitrile (1 ml). The vial was bubbled with N₂ for 2 min, then cap tight and the reaction was exposed to microwave at 150 °C for 2 hours. LC-MS showed the reaction was complete. Quenched with 10% MeOH/CH2C12. Filtered, then concentrated, the residue was purified by Prep. TLC. (60% EtOAc/Hexane) to afford methyl (iraw-4-{3^,-fluoro-4'-[6-(lH- pymol-1-yl)-lH-benzimidazol-2-yl]biphenyl-4-yl}cyclohexyl)acetate. LC-MS (Es, m z):

C₃₁H₂₉FN₄0₂: 508; Found: 509 [M+Hf. Step D: ( Trans A- ( 3'-fluoro-4'-r6-f 1 H-pyrazol-1 -yl lH-benziinida2x l-2- yI]biphenyl-4-v cvclohexyl)a etic acid

In the same procedure as Example 71, (irafw^-iS'-fluoro^'-fe-flH- yrazol-1-yl)- lH-berizirnidazol-2-yl]biphemyl-4-yl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m z): C30H27FN4O₂: 494; Found: 495 [M+H]⁺.

Example 140:

frrflW-4-0'-fluoro-4' 6-flH-1.2 -triazol-1-ylViH-benzimida2o

v cyclohexyl)acetic acid

In the same procedure as Example 139, (trara-4-{3'-fluoro-4'-^

1riazol-1-yl)-lH-benzimidazol-2-yl]biphenyl-4-yl}cyclohexyl)acetk acid was prepared. LC-MS (Es, m/z): C₂₉H₂₆FN₅0₂: 495; Found: 496 [M+H]⁺.

Example 141 :

( Trans-4- { 3 '-iluoro-4'-r6-f2H- 1 ,2.4-triazol-2-vIVl H-benzimidazol-2-vnbiphenyl-4- v cyclohexyl)acetic acid

In the same procedure as Example 139, (t a½s^,-4-{3'-fluoro-4^,-[6-(2H- 1,2,4- triazol-2-yl)-1H-benzimidazoi-2-yl]biphenyl-4-yl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m/z): C¼>HMF S02: 495; Found: 496 [M+Hf .

Example 142:

rrmw-4 3'-fluoro-4'-r6-r2H-tetyazol-5-yl) H-benzimidazol-2-vi1biphenyl.4- v cycIohexyl)acetic acid

H Step A: Methyl {fra« -f4'-(5-cvano-lH-bertzimida^

yl]cvclohexy acetate

In the same synthetic sequence as Example 107 step A, methyl {frani-4-[4'-(5- cyano-lH-benzimida2Ol-2-yl)-3'-fluorobipheriyl-4-yl]cyclohexyl}acetate. LC-MS (Es, m/z): C29H26FN3O2: 467; Found: 468 [M+H]⁺.

Step B: Methyl (transA- (3'-fluoro-4'- 6-f 2ff-tetrazol-5-yl)- lH-benzimidazol-2- yilbiphenyl-4-y cvclohexyilacetate

To a 50 mL round bottom flask, methyl {ir^w-4-[4'-(5-cyano-lH-berizimidazol-2- yl)-3'-fluorobiphenyl-4-yl]cyclohexyl}acetate (92 mg, 0.1 2 mmol) and azidotrimethyltin (334 mg, 1.621 mmol) in toluene (2 ml) was heated to reflux at 110 °C for 15 h under N2. LC-MS showed the reaction was complete. The mixture was concentrated. The residue was used for nest step. LC-MS (Es, m/z): K^FSNZOZ: 510; Found: 511 [M+H] ⁺.

Step C: ( TransA- {3'-fluoro-4'-r6-f2H-tetrazol-5-yiV lH-benzimidazol-2-yll biphenv.-4-vUcvclohexyl)acetic acid

In the same procedure as Example 69, transA-{3'-fiuoT A'-[6-(2H-t&trazol-5-yi H-benzimidazol-2-yl]biphenyl-4-yl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m/z): C28H25FN6O2: 496; Found: 497 [M+H]⁺.

Example 143

trans-4-(4-f 5-[5-0 -pyrazol-3-yI)- l-benzimidazol-2-vi)pyridin-2- yl>phenyl)cyclohexyi acetic acid The mixture of methyl trans-4-{4-[5-(5-bromo-1-benzimidazol-2-yl)pyridin-2- yljphenyljcyclohexyl) acetate (30 mg, 0.059 mmol), 1H-pyrazol-3-ylboronic acid (8.7 mg, 0.0776 mmol), PdCl2(dppf)-CH₂Cl₂ adduct (5 mg, 0.006 mmol), NaHC0₃ (15 mg, 0.18 mmol) in dioxane (1 mL) and water (0.3 mL) was heated to 100 C for 16 h. Diluted with water and extracted with EtOAc. The organic layer was concentrated in vacuum. The residue was dissolved in THF (0.5mL) and MeOH (0.5 mL) and LiOH aqueous solution (0.1 mL, 2.4 M) was added and the mixture was heated to 50 C for 3 h. The volatiles were removed under vacuum and the residue was purified by mass-triggered reverse phase HPLC to give the title compound. LC-MS m z = 478.31 [M+l]⁺

The following examples were prepared using the same chemistry as Example 143.

rfraw -f4-(5-r5-f2.5-difluoropheny1H

yl)phenyr)CYclohexyl]acetic acid

To a 50 ml vial was added LiOH (9.9 mg, 0.413 mmol, 7.0 equiv) dissolved in H₂0 (l .OmL), among with methyl [iraw-4-(4-{5-[5-(2,5-difluorophenyi)-lH-imidazo[4,5- £]pyridin-2-yl]pyridin-2-yl}phenyl) cyclohexyl]acetate (31.8 mg, 0.059 mmol, 1.0 equiv) in THP (2.0 mL) and MeOH (1.0 mL). The reaction mixture was stirred at 80° C for 15 min. The mixture was acidified with cone. HCl to pH=4 and purified by RP HPLC with loading as a solution of DMSO:H20:CAN, 20 to 80% ACN in H₂0 to give product [/raw-4-(4-{5-[5-(2_}5- difluorophenyl)-lH-iniidazo[4₎5-^]pyiidin-2-yl]pyridin-2-yl}phenyl)cyclohexyI] acetic acid. LC- MS (ES, m z) C₃₁H26F₂N₄0₂: 524; Found: 525 [ +H]⁺.

Example 165:

methyl [fratts-4-f4-{5-[5-(2_T4-difluorophenylVl^

vUphenvDcvclohexyllacetate

A 5 mL pyrex vial was charged with 6-{4-[fra«s-4-(2-methoxy-2- oxoethyl)cyclohexyl]phenyl}pyridine-3-carboxylic acid ( 70.0 mg, 0.198 mmol) along with EDC (49 mg, 0.257 mmol) and HOBT (39 mg, 0.257 mmol) in DMF (lmL) before the addition of 6- (2_s4-difIuorophenyl)pyridine-2₅3-diamine (44.0 mg, 0.198 mmol). The mixture was stirred at room temperature for 10 min and then under microwave at 120°C for 20 min. LC-MS showed complete coupling of the acid with amine. Then acetic acid (lmL) was added and the mixture was exposed to microwave at 200°C for 40 min. LC-MS showed complete formation of imidiazole. The mixture was filtered and purified by RP HPLC with loading as a solution of DMSO:H20:ACN to afford product methyl [^ns-4.(4-{5-[5-(2₉4-difluorophenyl)-lH- imidazo[4,5-&]pvridin-2-yI]pvridin-2-yI}phenyl)cyclohexyl]acetate. LC-MS (ES_> m/z)

C32H28F2 4O2: 538; Found: 539 [M+H]⁺. Example 166:

methyl [fra;w-4-( -(5-f5-f2 -difluorophenvD^

vUphenvDcvclohexyllacetate

A 5 mL pyrex vial was charged with 6-{4-[fr w-4-(2-methoxy-2- oxoethyl)cyclohexyl]phenyl}pyridine-3-carboxylic acid ( 70.0 mg, 0.198 mmol) along with EDC (49 mg, 0.257 mmol) and HOBT (39 mg, 0.257 mmol) in DMF (lmL) before the addition of 6- (2,5 -difluorophenyl)pyridine-2_s3 -diamine (44.0 mg, 0.198 mmol). The mixture was stirred at room temperature for 10 min and then under microwave at 120°C for 20 min. LC-MS showed complete coupling of the acid with amine. Then acetic acid (lmL) was added and the mixture was exposed to microwave at 200°C for 40 min. LC-MS showed complete formation of imidiazole. The mixture was filtered and purified by RP HPLC with loading as a solution of DMSO:H₂0:ACN to afford product methyl [ir«ny-4-(4-{5-[5-(2,5-difluoropheiiyl)-lH- imidazo[4_>5-i>]pyridin-2-yl]pyridin-2-yl}phenyl)cyclohexyl]acetate.

LC-MS (ES, m/z) C₃2H28F₂N₄02: 538; Found: 539 [M+H]⁺.

Example 167:

tra^-4- 4-i5-i5-f2^-difluorophenyl -lH-imidazor4.5-blpyridin-2-vi]pyridin-2- yUphenyl)cvclohexyllacetic acid in the same procedure as Example 165, [tr fis-4-(4-{5~[5-(2,4-c[ijEIuorophenyI)- lH-imidaz»[4,5-i]pyridin-2-yl]pyridin-2-yi}phenyl)cyclohexyl]acetic acid was prepared. LC-MS (ES, mJz) C31H26F2 4O2: 524; Found: 525 [M+H]⁺. Example 168:

H

N-me&oxy-2-fns.4s -4-(4'-(5-fmemy^

yl)cyclohexyl)acetamide Met oxy methyl amine-HCl salt (25 mg, 0.205 mmol was mixed together with 1 ml dichloromethane and 0. 3 ml Hunigs base. The mixture was stirred together for 15 min to neutralize the salt completely. To the solution of compound Example 98 (50 mg. 0.102 mmol) in dichloromethane, HATU (39 mg , 0.102 mmol) was added followed by addition of O- methylhydroxylamine ( free base form step 1) and additional Hunigs base (0.1 ml, 0.2 mmol). The resulting reaction mixture was allowed to stir at room temperature over night. Up on completion the reaction was worked up by quenching with water (20 ml), crude product was extracted in ethyl acetate (3X 20 ml EtOAc). The product was purified by flash chromatography (ISCO 24 g flash silica column, eluted with EtOAc / Hexane gradient 20% to 80 % EtOAc ) to afford N-methoxy-2-((l s,4s)-4-(4'-(5-(methylsulfonyl)- 1 H-benzo[d]imidazol-2-yl)biphenyl-4- yl)cyciohexyI)acetamide. LC-MS (ES, m/z): C29H31N304S: 517.64; Found: 518.20 [M+H]⁺ at Rf. 2.15 min.

With the same chemistry as Example 168, using corresponding acids and amines for the couping, the following examples were prepared:

Example 180:

2-fQ r -f4'-(5-aH-pyrazol-4-yl)^

yPcyclohexyl)acetic acid

Step A: methyl 2-((lr₅4r)-4-(4^,-(5-bromo-1H-benzo[d]imidazol-2-yl)-3'- fluorobiphenyl-4-yl)cyclohexyl)acetate ( Intermediate 2) was reacted with boron c ester- (4- (4_s4,5_}5-tetramethyl-1,3 ,2-dioxaboroiaii-2-yl)-1H-pyrazoIe in presence of sodium bicarbonate, Pd-dppf catalyst , dioxane (4 ml) and water ( ml) (previously mixed together and degassed). The resulting reaction mixture was heated in Rxn block at 110°C overnight under oxygen free environment. The reaction was worked up by quenching with water (20 ml). Product was extracted in EtOAc (2 X 30 ml). Purified by isco flash column 24 g flash silica column / eluted by EtOAc Hexane gradient (30% EtOAc to 90 % EtOAc), giving product.

Step B: The exemplified analog was obtained after a sapponification of the methyl ester as fallows. The methyl ester, (150 mg, 0.295 mmol) obtained from step Iwas reacted with Lithium hydroxide (70 mg, 2.95 mmol) in presence of 4ml THF and 1 ml water. The resulting reaction mixture was stirred at room temperature overnight. The reaction was monitored by LC- MS and up on completion was worked up by evaporating THF in vacuo. The residue was diluted with water (3 mi) and acidified to pH 4 with IN HCL. The desired product precipitated under acidic conditions and was isolated by filtration. The product was further purified by washing with water (10 ml) and triturating with 10 ml ether. After drying under vacuum product was obtained. LC-MS (ES, m/z): C30H27FN4O2: 494.56; Found: 495.12 [M+H] ⁺ at Rf. 2.19 mm.

Example 181:

i^'trans-4-(4'-[5-riJ-dioxido-3.6-dihvdro-2H-thiopyran-4-ylV1H-benzi

fluorobiphenyl-4-yl} cyclohexyllacetic acid

Step A: methyl 2-((lr,4r)-4-(4'-(5-bromo-1H-benzo[d]imidazol-2-yl)-3'- fluorobiphenyl-4-yl)cyclohexyl)acetate (70 mg, 0.134 mmol) was reacted with 2-(l,l-dioxido- 3,6-dihydro-2H~thiopyran-4^ (43 mg, 0.134 mmol) in presence of cesium carbonate (87 mg, 0.268 mmol), Pd-tetrakis catalyst (15mg, 0.013 mmol), dioxane(4 ml) and water (1 ml), (previously mixed together and degassed). The resulting reaction mixture was heated in Rxn block at 110°C overnight under oxygen free environment. The reaction was worked up by quenching with water (20 ml). Product was extracted in EtOAc (2 X 30 ml). Crude product was purified by reverse phase HPLC using acetonitrile and water/ 0.01 % TFA. Under the reaction condition some hydrolysis of methyl ester to corresponding acid was obtained. Purified acid was isolated and registered, the ester was further hydrolyzed as described below.

Step B: The exemplified analog was obtained after a sapponification of the methyl ester as fallows. The methyl ester (27 mg, 0.05 mmol) was reacted with Lithium hydroxide (10 mg, 0.4 mmol) in presence of 4ml THF and 1 ml Water. The resulting reaction mixture was stirred at room temperature overnight. Up on completion of the reaction THF was evaporated in vacuo. The residue was diluted with 3 ml water and acidified to pH 4 with IN HCL. The desired product precipitated under acidic conditions and was isolated by filtration. The product was further purified by washing with water (10 ml) and triturating with 10 ml ether. LC-MS (ES, m/z): C32H31F 204S: 558.66; Found: 559.32 [M+H]⁺ at Rf. 1.73 min.

Example 182:

2-(( 1 r.4rV4-f 4'-f 5-f 1H-pyrazol-5-vP- 1 H-ber^o d]imidazol-2-yl)-3'-fluorobiohenyl-4- vDcyclohexyTiacetic acid

Step A: methyl 2-((lr,4r)-4-(4^,-(5-bromo-1H-benzo[d]imidazol-2-yl)-3'- fluorobiphenyl-4-yl)cyclohexyl)acetate (70mg, 0.134 mmol) was reacted with 1H-pyrazol-5- ylboronic acid in presence of cesium carbonate ( 87mg, 0.268 mmol), Pd-tetrakis catalyst (15mg, 0.013-mmol ), dioxane (4 ml) and water (I ml) (previously mixed together and degassed) . The resulting reaction mixture was heated in Rxn block at 1 1 °C overnight under oxygen free environment. The reaction was worked up by quenching with water (20 ml). Product was extracted in EtOAc (2 X 30 ml). Crude product was purified by reverse phase HPLC using acetonitrile and water/ 0.01% TFA to separate acid and ester. Under the reaction condition some hydrolysis of methyl ester to corresponding acid was obtained. The ester was further hydrolyzed as described below.

Step B: The exemplified analog was obtained after a sapponification of the methyl ester as fallows. The methyl ester from step 1 ( 25 mg, 0.04 mmol) was reacted with Lithium hydroxide (10 mg, 0,4 mmol) in presence of 4ml THF and 1 ml Water. The resulting reaction mixture was stirred at room temperature overnight. The reaction was monitored by LC-MS and up on completion THF was evaporated in vacuo. The residue was diluted with 3 ml water and acidified to pH 4 with IN HCL. The desired product precipitated under acidic conditions and was isolated by filtration. The product was further purified by washing with water (10 ml) and triturating with 10 ml ether. LC-MS (ES, m/z): C30H27FN4O2; Found: 494.56 ; Found : 495.27 [M+H] ⁺ at Rf. 1.75 min.

Example 183:

trans-4-{4-r5-(l H -benzimidazol-2-yl pyridin-2- yllphenyllcvclohexyl)ace tic acid

Step A: Methyl trans -4-(4-Γ5-(1 H -benzimidazol-2-vnpyridin-2- yl]phenyl}cyclohexyi¾ acetate

A mixture of o-phenylenediamine (38 mg, 0.351 mmol), methyl {4-[4-(5- formylpyridin-2-yl)phenyl]cyclohexyl} acetate (130 mg, 0.387 mmol) and potassium

peroxymonosulfate (140 mg, 140 mmol) in DMF (2 ml) and water (0.2 ml) was stirred for 24 hours at room temperature. Then poured into 5 mL 1M K₂CO3 solution, extract with 3x10 mL ethyl acetate. The organic layers were combined, washed with 2x5 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 0-80%. This resulted in methyl trans -4-{4-[5-(l H - benzimidazol-2-yI)pyridin-2-yl]phenyl}cyclohexyl) acetate as a white solid. LC-MS (ES, m/z) C27H27N302: 425; Found: 426 [M+H]⁺.

Step B: trans-4-f 4-Γ5-Π H -ben2imidazol-2-yl)pyridin-2-yl] henyl )cyclohexyl)ace tic id

A mixture of Methyl trans -4-{4-[5-(l H -benzhmdazol-2-yi)pyridin-2- yl]phenyl}cyclohexyl) acetate (100 mg, 0.235 mmol) and lithium hydroxide (17 mg, 0.705 mmol) in THF (2.5 ml), water (0.6 ml). The reaction mixture heat at 40°C in an oil bath over night, and then concentrated under vacuum, adjust PH=7 with IN HQ, then purified by Gilson acetonitril (0.05%TFA)/water (0.05%TFA) 30-100%. This resulted in trans-4-{4-[5-(l H -benzimidazol-2- yl)pyridin-2-yl]phenyl}cyclohexyl)ace tic acid as a white solid. LC-MS (ES, m/z) C26H25N302: 411; Found: 412 [M+H]⁺. Method A (Exemplified by):

Method B (Exemplified by):

Method C (Exemplified by):

Intermediate 32

Methyl {trans-^ -^-fluoro-S-form^

In a microwave reaction tube (20 ml) was added 6-chloro-4-fluoropyridine-3- carbaldehyde (0.534 g, 3.35 mmol), methyl {fri2«ir-4-[4-(4,4_}5,5-tetramethyl-l_>3_>2-dioxaborolan- 2-yl)phenyl3cyclohexyl}acetate (1.0 g, 2.79 mmol) and Palladium Tetrakis (0.323 g, 0.279 mmol) and the tube sealed. The tube was evacuated and backfilled with DME (12.0 ml) and EtOH

(8.0 ml) followed by N ₂C0₃ (4.19 ml, 2N, 8.37 mmol) was added via syringe and the mixture irradiated in the microwave for 25 min at 120 °C. LCMS showed all starting material gone and desired product present. The solvent was evaporated, diluted with EtOAc and washed with water. The organic layer was dried (MgSC>4) and cone, in vacuo. CombiFIash companion purification eluting with 0 to 15 % EtOAc / Hexane on a 40 g column afforded 173 mg of the desired product as a white solid. LC-MS (ES, m/z) C₂].H₂₂FN0₃: 355; Found: 356 [M+H]⁺.

Intermediate 33

2^hloro-NJV-dimethyl-5-r6-(trir uorome1hyl)-iH^

In the same chemistry as the preparation of intermediate 6, using 6-chloro-4- (dimethylamino)pyridine-3-carbaldehyde as starting material for the imidazole formation, 2- chloro-N,N-<iimethyl-5-[6-(tri

prepared. LC-MS (ES, m/z) C15H12CIF3N4: 340; Found: 341 [M+H]⁺.

Example 184

(trans-4- ( 3'-fluoro-4'-r6-QH .2.4-triazol-l -ylV lH-berizimidazol-2-yllbiDhenyl-4- yUcyclohexyl)acetic acid

In the same procedure as Example 139, (friw¾s-4-{3^,-fluoro-4^l-[6-(li-^r-1,2,3- triazol-1-yl)-lH-benzimidazol-2-yl]biphenyl-4-yl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m/z): C29H26FN5O2: 495; Found: 496 [M+H]⁺.

Example 185

rt -aKy-4-(3'-fluoro-4'-[6-flH-tetTazol-1-vD-lH-beri2a

v cyclohexyl)acetic acid

In the same procedure as Example 139, (irans^,-4-{3^f-fluoro-4'-[6-(lH-tetrazol-1- yl)-lH-benzimidazol-2-yl]biphenyl-4-yl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m/z): C₂₈H25FN₆02 496; Found: 497 [M+H]⁺.

Example 186

acid

In the same procedure as Example 139, (/r«¾y-4-{4'-[7"(lH-tetrazol-1-yl)-iH-- benzimidazol-2-yl]bip enyl-4-yl}cyclohexyl)acetic acid was prepared. LC-MS (Es, m/z): C₂gH26N60₂: 478; Found: 479 [M+H]⁺.

Example 187

f trans~4~(4- ( 4-f^diniethylamirio^')-5-r 6-(trifIuoromethyl^')- lH-benzimidazol-2-yllpyridin-2- yl>phenyl)cvclohexyl1acetic acid

In the same procedure as Example 68 and 69, general method C, (trans-4-{4-{4- (dime&ylamino)-5-[6-(1rifluorom

yl}phenyl)cyclohexyl]acetic acid was prepared. LC-MS (Es, m/z): C2 H2 F3N₄O2: 522; Found: 523 [M+H]⁺.

The following compounds can also be made using the methods described herein:

The followin com ounds can also be made usin the methods described herein:

DGATl CPM Assay

20uL substrate mixture of 300uM diolein, 40uM oleoyl-CoA_> 10% et anol 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.

Claims

WHAT IS CLAIMED IS:

A compound of formula (I):

2

or pharmaceutically acceptable salts thereof, wherein each occurrence of U and V are independently selected from ~N- or -CH- and wherein all three occurrences of V are not simultaneously -N-;

R¹ is selected from the group consisting of hydrogen, halogen, d-C₆alkyl and halogen-substitutedC_l-Qalkyl or when taken together with R⁴ form a nitrogen-containing herterocycle;

R² is selected from the group consisting of halogen and hydrogen;

R³ is selected from the group consisting of hydrogen halogen, -C₆alkyl, halogen-substitutedC_l-C₆alkyl, -OH, C_l-C₆alkylOH, halogen-substitutedC_l-C₆alkylOH, -OC_l- Cealkyl, -Ohalogen-substitutedC_l-C₆alkyl, -NH₂ and -CM; and

R⁴ is independently selected from the group consisting of hydrogen, halogen, d-

Cealkyl, halogen-substitutedC_l-C₆alkyl, COd-C₆alkyl, COhalogen-substitutedC_l-C₆alkyl, -OH, C_l-C₆alkylOH, halogen-substitutedC_l-C₆alkylOH, -OC_l-C₆alkyl, -Ohalogen-substitutedCj- C₆alkyl, -COOH, -COOC_l-C₆alkyl, -d-QalkylCOOd-C₆alkyl, -d-C₆alkylCOOH, -OC_l- C₆alkylCOOH, -CN, d-C₆alkyICN, -N0₂, NH₂, NHC_l-Qalkyl, N(d-C₆alkyl)2, -NHCOOH, - NHCOOCrQalkyl, -CONH₂, -Cj-C₆alkyl HCOd-C₆alkyl, -CONHC_l-C₆alkyl, -d- CealkylCONHhalogen-substitutedd-C₆alkyl, -CrC₆alkylCONHC_l-C₆alkylOH, -Ci- C₆alkylCONH-OC,-C₆alkyl, -C_l-C₆alk lCO Cd-C₆alkylX-OCrCealky C_l-C₆al ylCONid- C₆alkyl)₂, -CON(C_l-C₆alkyl)₂, -NHS0₂C₁-C₆alkyl, S0₂NH₂. -S0₂d-C₆alkyl, phenyl, nitrogen or sulfur-containing heterocycle, C_l-C₆alkylnitrogen-containingheterocycle and d- CgalkylCOnitrogen-containingheterocycle;

R⁵ is independently selected from the group consisting of -OH, d-C6alkylOH, halogen-substitutedCrC₆alkylOH, -COOH, -COOC_l-C₆alkyl_s -C_l-C₆alkylC00d-C6alkyl, -d- C₆alkylCOOH, -OC_l-C₆alkylCOOH, -CN, d-C₆alkylCN, -NOz, N¾ NHC_l-C₆alkyl_s N(d- C₆alkyl)₂, -NHCOOH, -NHCOOC_l-C₆alkyl, -CONH₂, -d-C₆alkylNHCOd-C₆aJkyl, -CONH - C₆alkyl, -d-C₆alkylCONHd-C₆alkyl, -C CealkylCONHhalogen-substitutedd-Csalkyl, -Cj- C₆alkylCONHd-C6alkylOH, -d^

OCrC₆alkyl),-C_l-C6alkylCON(C₁-C₆alkyl)₂, -CON(Cj-C₆alkyl)₂, -NHSOzd-dalkyl, S0₂NH_2> - SC^Q-Csalkyl, -C₁-C₆alkylCONHC₁-C₍}alkylS0₂0H₅ phenyl, nitrogen or sulfur-containing heterocycle, C_l-C₆alkylnitrogen-containingheterocycle and CrC₆a3kylCOnitrogen- containingheterocycle;

wherein any phenyl or nitrogen or sul ur-substituted heterocycle can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_l-C₆alkyl, oxo, halogen-substimtedC_l-C₆alkyl, -OC_l-C₆alk l, -Ohalogen- substitutedC_l-C₆alkyl, -OH and Ct-C₆alkylOH, cyclopropyl, phenyl, Cj-C₆alkylphenyl and imidazole. 2. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein U is -N-.

3. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein U is -CH-.

4. A compound of any one of claims 1-3 or pharmaceutically acceptable salt thereof wherein R¹ is hydrogen.

5. A compound of any one of claims 1-3 or pharmaceutically acceptable salt thereof wherein R* is fluorine, chlorine or methyl.

6. A compound of any one of claims 1-6 or pharmaceutically acceptable salt thereof wherein R² is hydrogen.

7. A compound of any one of claims 1-7 or pharmaceutically acceptable salt thereof wherein the moiety:

is selected from the group consisting of:

8. A compound of any one of claims 1 -8, or pharmaceutically acceptable salt thereof, wherein R³ is selected from the group consisting of hydrogen, halogen, C_l-C₆alkyl, halogen-substitutedC_l-C₆alkyl, >Od-C₆alkyl, and C_l-QalkylOH.

9. A compound of any one of claims 1-8 or pharmaceutically acceptable salt thereof wherein R³ is halogen.

10. A compound of any one of claims 1-8 or pharmaceutically acceptable salt thereof wherein R³ is hydrogen.

11. A compound of any one of claims 1 - 11 or pharmaceutically acceptable salt thereof wherein R⁴ is halogen, d-C₆alkyl, halogen-substitutedC_l-C₆alkyi, -OH, C_l-C₆alkylOH, - OC_l-Qalkyl, -Ohalogen-substitutedC_l-C^kyl, -CN, C_f-C₆alkylCN, -N0₂, NH_2s NHC_l-C₆alkyl_} NCd-C₆alk i, -d-C₆alkylNHCOd-C₆alkyl, -COOd-C₆alkyl, -CON(CrC₆aIkyl)₂₅ - NHSChC_l-C₆alkyl, SO₂NH₂, -SOid-C₆alk i, phenyl, nitrogen or sulfur-containing heterocycle;

wherein any phenyl or nitrogen or sulfur-substituted heterocycle can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, d-dalkyl, oxo, halogen-substitutedC_l-Qalkyl, -OC_l-C₆alkyl, -Ohalogen- substitutedd-C₆alkyl, -OH, phenyl, cyclopropyl, CrGgalkylphenyl, imidazole and d- dalkylOH.

12. A compound of any one of claims 1 - 12 or pharmaceutically acceptable salt thereof wherein R⁵ is selected from the group consisting of CなCOOH and CH₂COOCH₂-

13. A compound of any one of claims 1 - 12 or pharmaceutically acceptable salt thereof wherein R⁵ -CHzCO-nitrogen-contamingheterocycle, nitrogen-containing heterocycle and -CrCgalkylCONHh ogen-substitutedCj-C₆alkyl, wherein the nitrogen-containing heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_l-Qalkyl, oxo and -OH.

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

ı22

15. A pharmaceutical composition comprising a compound of any ^one of claims 1-15_? o a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. Use of a compound of any one of claims 1 - 15_{s 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.

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