WO2013074387A1 - Imidazole derivatives - Google Patents

Abstract

Disclosed herein are novel imidazole derivative compounds i.e., benzimidazole and aza-benzimidazole derivatives that act as DGAT1 inhibitors and can be useful in preventing, treating or acting as a remedial agent for hyperiipidemia, diabetes mellitus and obesity. Further disclosed are methods of treating various DGAT1 -related diseases, and the use of such imidazole compounds as described herein in the manufacture of a medicament for such treatment.

Description

IMIDAZOLE DERIVATIVES

TECHNICAL FIELD

The present invention is directed to novel imidazole derivative compounds.

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

BACKGROUND

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

In general, obesity is caused by the accumulation of triacylglycerol (TG) in adipose tissue which is a result of lack of exercise, intake of excessive calories and aging. In the body there are two TG synthesis pathways, a glycerol phosphate pathway, which is present in most organs and causes de novo TG synthesis, and a monoacylglycerol pathway, which is involved principally in absorption of aliphatic acid from the small intestine. Diacylglycerol acyltransferases (DGATs, EC 2.3.1.20), which are membrane- bound enzymes present in the endoplasmic reticulum, catalyze the final step of the TG synthesis common to the two TG synthesis pathways. The final reaction consists of transferring an acyl group from acyl-coenzyme A to the 3-position of 1 ,2-diacylglycerol to generate TG (Prog. Lipid Res., 43, 134- 176, 2004 and Ann. Med., 36, 252-261 , 2004). There are two subtypes of DGATs, DGAT-1 and DGAT-2. There is no significant homology at the generic or amino acid level between the DGAT-1 and DGAT-2, which are encoded by different genes (Proc. Natl. Acad. Sci. USA., 95, 13018-13023, 1998 and JBC, 276, 38870-38876, 2001). DGAT- 1 is present in the small intestine, adipose tissue and liver and is believed to be involved in lipid absorption in the small intestine; lipid accumulation in the fat cell; and VLDL secretion and lipid accumulation in the liver (Ann. Med., 36, 252-261 , 2004 and JBC, 280, 21506-21514, 2005). In consideration of these functions, a DGAT- 1 inhibitor is expected to be an effective obesity treatment through inhibition of lipid absorption in the small intestine, lipid accumulation in the adipose tissue and the liver, and lipid secretion from the liver.

In order to carry out in vivo examination of the physiological function(s) of DGAT-1 and inhibitory activity against DGAT-1, DGAT-1 -knockout mice deficient in DGAT-1 at the genetic level was produced and analyzed. As a result, the DGAT-1 - knockout mice have been found to have smaller fat masses than those of wild-type mice and became resistant to obesity, abnormal glucose tolerance, insulin resistance and fatty liver due when fed a high-fat diet (Nature Genetics, 25, 87-90, 2000 and JCI, 109, 1049- 1055, 2002). In addition, energy expense has been reported to be accelerated in the DGAT-1 -knockout mice; and transplantation of the adipose tissues of DGAT-1 -knockout mice into wild-type mice has been reported to make the wild-type mice resistant to obesity and abnormal glucose tolerance, induced by a high-fat diet (JCI, 1 1 1, 1715-1722, 2003 and Diabetes, 53, 1445-1451, 2004). In contrast, obesity and diabetes mellitus due to a high-fat diet have been reported to worsen in mice with overexpression of DGAT-1 in adipose tissue (Diabetes, 51, 3189-3195, 2002 and Diabetes, 54, 3379-3386, 2005).

From the results, DGAT-1 inhibitors are likely to be therapeutic drugs with efficacy for obesity, type 2 diabetes mellitus, lipidosis, hypertension, fatty liver, arteriosclerosis, cerebrovascular disorder, coronary artery disease and metabolic syndrome.

SUMMARY OF THE INVENTION

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

Described herein are compounds of formula I

I DESCRIPTION

Described herein are compounds of formula (I):

I

or pharmaceutically acceptable salts thereof wherein,

ring A is selected from the group consisting of pyridine, cycloheptane, phenyl, cyclohexane and cyclopentane;

U', U², U³, U⁴ U⁵, U⁶ and U⁷ are independently selected from the group consisting of -CH- and -N-;

X is selected from the group consisting of piperidine, spiroheptane, bicyclo2,2,2octane, cyclohexane, cyclopentane, cyclobutane wherein the

bicyclo2,2,2octane, cyclohexane, cyclopentane or cyclobutane can be unsubstituted or substituted with one or more substituents selected from the group consisting of Ci- C₆alkyl and COOH;

R¹, R², R³, R⁴and R⁵ are independently selected from the group consisting of hydrogen, halogen, Ci-C alkyl, halogen-substitutedCi-C₆alkyl, -OH, Ci-C₆aIkylOH, - OCi-C₆alkyl, -Ohalogen-substitutedCi-C₆alkyl, -OC C₆alkylOCi-C₆alkyl, -OCi- C₆alkylheterocycle, -OCi-C₆alkylheterocycleCi-C₆, -S0₂Ci-C₆alkyl, pyrazole, Q- C₆alkyl-substituted pyrazole, -N(Ci-C₆alkyl)2 and -CN or when taken together R¹ and R² form pyrazole or triazole; and

R⁶ is selected from the group consisting of COCi-C₆alkyl, COhalogen- substitutedCi-Qalkyl, -COOH, -COCOOH, -COOCi-C₆alkyl, -Ci -C₆alkylCOOC,- C₆alkyl, -d-C₆alkylCOOH, -OC,-C₆alkylCOOH, CONHOd-C₆alkyl, CONHS0₂C,- C₆alkyl, CONHS0₂C₃-C₆cycloalkyl, CONHS0₂phenyl, CONHC_rC₆alkylS0₂OH, CONHS0₂halogen-substitutedCi-C₆alkyl, CONHhalogen-substitutedC]-C₆alkyl, CONHheterocycle and COheterocycle, wherein the COheterocycle is unsubstituted or substituted with one or more substituent selected from halogen, -OH, Ci-Cealkyl, C_\- C₆alkylOH.

In certain embodiments of the compounds described herein, ring A is selected from the group consisting of pyridine, cycloheptane, phenyl, cyclohexane and cyclopentane. In certain embodiments, ring A is pyridine. In other embodiments, ring A is cycloheptane. In yet other embodiments, ring A is phenyl. In still other embodiments, ring A is cyclohexane. In certain embodiments, ring A is cyclopentane.

In certain embodiments of the compounds described herein, U¹, U², U³, U⁴ U⁵, U⁶ and U⁷ are independently selected from the group consisting of -CH- and -N-. In certain embodiments, U¹ is -CH-. In other embodiments, U¹ is -N-. In certain embodiments, U² is -CH-. In other embodiments, U² is -N-. In certain embodiments, U³ is -CH-. In other embodiments, U³ is -N-. In certain embodiments, U⁴ is -CH-. In other embodiments, U⁴ is -N-. In certain embodiments, U⁵ is -CH-. In other embodiments, U⁵ is -N-. In certain embodiments, U⁶ is -CH-. In other embodiments, U⁶ is -N-. In certain embodiments, U⁷ is -CH-. In other embodiments, U⁷ is -N-.

When U', U², U³ are U are -CH-, in certain embodiments, the hydrogen can substituted with R³ and R⁴. When U⁵, U⁶ are U⁷ are -CH-, in certain embodiments, the hydrogen can substituted with R⁵.

Of the compounds described herein, X is selected from the group consisting of piperidine, spiroheptane, bicyc!o2,2,2octane, cyclohexane, cyclopentane, cyclobutane wherein the bicyclo2,2,2octane, cyclohexane, cyclopentane, cyclobutane can be unsubstituted or substituted with one or more substituents selected from the group consisting of Q-Qalkyl and COOH. In some embodiments, X is piperidine. In other embodiments, X is spiroheptane. In certain embodiments, X is bicyclo2,2,2octane. In other embodiments, X is cyclohexane. In still other embodiments, X is cyclopentane. In yet other embodiments, X is cyclobutane.

In such embodiments, wherein X is bicyclo2,2,2octane, cyclohexane,

cyclopentane or cyclobutane such rings can be unsubstituted or substituted with one or more substituents selected from the group consisting of Ci-C₆alkyl and COOH. In certain embodiments, X is bicyclo2,2,2octane, wherein the bicyclo2,2,2octane is substituted with Ci-C₆alkyl, such as methyl or ethyl. In other embodiments, X is bicyclo2,2,2octane wherein the bicyclo2,2,2octane is substituted with COOH. In certain embodiments, X is cyclohexane, wherein the cyclohexane is substituted with Ci-C₆alkyl, such as methyl or ethyl. In other embodiments, X is cyclohexane wherein the cyclohexane is substituted with COOH. In certain embodiments, X is cyclopentane, wherein the cyclopentane is substituted with Ci-C₆alkyl, such as methyl or ethyl. In other embodiments, X is cyclopentane wherein the cyclopentane is substituted with COOH. In certain embodiments, X is cyclobutane, wherein the cyclobutane is substituted with Ci- C alkyl, such as methyl or ethyl. In other embodiments, X is cyclobutane wherein the cyclobutane is substituted with COOH.

With regards to the compounds described herein, R¹, R², R³, R⁴and R⁵ are independently selected from the group consisting of hydrogen, halogen, Ci-C₆alkyl, halogen-substitutedC,-C₆alkyl, -OH, Ci-C₆alkylOH, -OCi-C₆alkyl, -Ohalogen- substitutedC_rC₆alkyl, -OCi-C₆alkylOCi-C₆alkyl, -OCi-C₆alkylheterocycle, -OC

C₆alkylheterocycleCi-C₆, -S0₂Ci-C₆alkyl, pyrazole, Ci -C₆alkyl -substituted pyrazole, - N(Ci-C₆aIkyl)₂ and -CN or when taken together R¹ and R² form pyrazole or triazole. In certain embodiments, R¹ is selected from the group consisting of hydrogen, halogen, Q- C₆alkyl, halogen-substitutedC, -C₆alkyl, -OH, Ci-C₆alkylOH, -OQ- alkyl, -Ohalogen- substitutedC C₆alkyl, -OC_rC₆alkylOCi-C₆alkyl, -OCi-C alkylheterocycle, -OC _r C₆alkylheterocycleCi-C₆, -S0₂Ci-C₆alkyl, pyrazole, Ci-C₆alkyl-substituted pyrazole, - N(Ci-C₆alkyl)₂ and -CN. In other embodiments, R² is selected from the group consisting of hydrogen, halogen, Ci-C₆alkyl, halogen-substitutedCpCgalkyl, -OH, Ci-C₆alkylOH, - OC C₆alkyl, -Ohalogen-substitutedCi-C₆alkyl, -OCi-C₆alkylOC i-C₆alkyl, -OCj- C₆alkylheterocycle, -OCi-C₆alkylheterocycleC]-C₆, -S02Ci-C₆alkyl, pyrazole, Ci- C₆alkyl-substituted pyrazole, -N(Ci-C₆alkyl)₂ and -CN. In still other embodiments, R³ is selected from the group consisting of hydrogen, halogen, Ci-C₆alkyl, halogen- substitutedC C₆alkyl, -OH, Ci-C₆alkylOH, -OC C₆alkyl, -Ohalogen-substitutedCi- C₆alkyl, -OCrQalkylOQ-Qalkyl, -OCi-C₆alkylheterocycle, -OC _r

C₆alkylheterocycleC]-C₆, -S0₂C]-C₆alkyl, pyrazole, Ci-C₆alkyl-substituted pyrazole, - N(Ci-C₆alkyl)2 and -CN. In yet other embodiments, R⁴ is selected from the group consisting of hydrogen, halogen, Ci-C₆alkyl, halogen-substitutedCi-C alkyl, -OH, Cp C₆alkylOH, -OCi-C₆alkyl, -Ohalogen-substitutedCi-C₆alkyl, -OCi-C₆alkylOCrC₆alkyl, - OCi-C₆alkylheterocycle, -OC] -C₆alkylheterocycleCi-C , -S0₂C]-C₆alkyl, pyrazole, Ci- C₆alkyl-substituted pyrazole, -N(Ci-C₆alkyl)₂ and -CN. In other embodiments, R⁵ is selected from the group consisting of hydrogen, halogen, C]-C₆alkyl, halogen- substitutedCi-C₆alkyl, -OH, C_rC₆alkylOH, -OCi-C₆alkyl, -Ohalogen-substitutedCi- C₆alkyl, -OC_rC₆alkylOCi-C₆alkyl, -OC_rC₆alkylheterocycle, -OC,- C₆alkylheterocycleCi-C₆, -S0₂Ci-C₆alkyl, pyrazole, C_rC₆alkyl-substituted pyrazole, - N(C,-C₆alkyl)₂ and -CN.

In certain embodiments, R^! is selected from the group consisting of halogen, Q- C₆alkyl, halogen-substitutedC,-C₆alkyl, -OH, Ci-C₆alkylOH, -OCi-C₆alkyl, -Ohalogen- substitutedQ-Qalkyl, -OCi-C₆alkylOC_rC₆alkyl, -OCj-Cealkylheterocycle, -OC

C₆alkylheterocycleCi-C₆, -S0₂Ci-C₆alkyl, pyrazole, Ci-C₆alkyl-substituted pyrazole and -N(Ci-C₆alkyl)₂. In certain embodiments R' is halogen. Suitable halogens include, but are not limited to, chlorine, bromine and fluorine. In other embodiments, R'is Q- C₆alkyl. Suitable alkyls include, R'is but are not limited to, methyl, ethyl, propyl, butyl and pentyl. In still other embodiments, R'is halogen-substitutedCi-Cealkyl. Suitable halogen-substituted alkyls include, but are not limited to, mono-, di- and trifluoro methyl. In yet other embodiments, R'is -OH.

In certain embodiments, R'is Ci-C₆alkylOH. In other embodiments, R'is -OCj- C₆alkyl. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, propoxy and butoxy. In still other embodiments, R'is -Ohalogen-substitutedCpCealkyl. Suitable examples of halogen-substituted alkoxys include mono-, di, and trifluormethoxy. In yet other embodiments, R'is -OCpCealkylOCi-Cealkyl. Suitable examples include but are not limited to, -OCH₂OCH₃. In other embodiments, R'is -OCpQalkylheterocycle, -OC_r C₆alkylheterocycleC]-C₆. Suitable examples of heterocycles include, but are not limited to, oxadiazol, thiazole, oxazole. In still other embodiments, R'is -S0₂Ci-C₆alkyl.

Suitable examples include, but are not limited to, -S0₂CH₃. In yet other embodiments, R'is pyrazole. In certain embodiments, R' is Ci-Cealkyl-substituted pyrazole. In other embodiments, R'is -N(Ci-C₆alkyl)₂.

In certain embodiments, R² is selected from the group consisting of hydrogen, halogen and Ci-C₆alkyl.

In other embodiments, R³ is selected from the group consisting of hydrogen and halogen.

In still other embodiments, R⁴ is selected from the group consisting of hydrogen and halogen.

In yet other embodiments, R⁵ is selected from the group consisting of hydrogen and halogen.

With regard to the compounds described herein, R⁶ is selected from the group consisting of COC_rC₆alkyl, COhalogen-substitutedQ-Qalkyl, -COOH, -COCOOH, - COOC,-C₆alkyl, -Ci-C₆alkylCOOC_rC₆alkyl, -C_rC₆alkylCOOH, -OQ-QalkylCOOH, CONHOCi-Cealkyl, CONHS0₂Ci-C₆alkyl, CONHS0₂C₃-C₆cycloalkyl,

CONHS0₂phenyl, CONHCrC₆alkylS0₂OH, CONHS0₂halogen-substitutedCrC₆alky], CONHhalogen-substitutedCi-C₆alkyl, CONHheterocycle and COheterocycle, wherein the COheterocycle is unsubstituted or substituted with one or more substituent selected from halogen, -OH, C,-C₆alkyl, C,-C₆alkylOH.

In certain embodiments, R⁶ is selected from the group consisting of -COOH, - COOC,-C₆alkyl, -C,-C₆alkylCOOC,-C₆alkyl and -Ci-C₆alkylCOOH. In other embodiments, COheterocycle, wherein the COheterocycIe is unsubstituted or substituted with one or more substituent selected from halogen, -OH, C_rC₆alkyl, d-C₆alkylOH. Definitions

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

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

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

The term "-OC]-C ₆alkylCOOH" refers to an aikoxy group having 1 to 6 carbons substituted with a carboxylic acid (-COOH) group.

The term "halogen-substitutedCi-C₆ alkyl" encompasses Ci-C₆ alkyl with the hydrogen atoms thereof being partially or completely substituted with halogen, examples thereof including fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1 ,2- difluoroethyl, 2,2-difluoroethyl and the like.

The term "-OhaIogen-substitutedCi-C₆alkyl" means a -OCpQalkyl as defined above, which is substituted with 1 -3 halogen atoms which are identical or different, and specifically includes, for example, a trifiuoromethoxy group.

The term "-COCi-C₆alkyl" means groups having Ci-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-substitutedCi-C₆alkyl" means a -COCi-C₆alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different.

The term "Ci -C₆alkylOH" means a C]-C₆alkyl substituted with an alcohol (-OH). Examples include methanol, propanol, butanol and t-butanol.

The term "COOCi-C₆alkyl" means a -COOH group wherein the -OH is replaced with an alkoxy group as defined above. Examples include methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

The term "S0₂C|-C₆alkyl" means a group having Ci-C₆alkyl bonded to sulfonyl (-S0₂-). Specific examples thereof include methanesulfonyl, ethanesulfonyl, n- propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, sec-butanesulfonyl, tert- butanesulfonyl, and the like.

The term "C3-C6cycloalkyl" encompasses cycloalkyls having 3 to 8 carbons, forming one or more carbocyclic rings that are fused. "Cycloalkyl" also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non- aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like.

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

The term "heterocycle" means mono- or bicyclic or bridged unsaturated, partially unsaturated and saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen. Examples thereof include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, pyrido[3,2-b]pyridyl, and the like. Examples also include tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-&)pyridyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6-dihydroimidazo[2, l - »]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, tetrahydropyran, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N- substituted-(lH, 3H)-pyrimidine-2,4-diones (N-substituted uracils). The term also includes bridged rings such as 5-azabicyclo[2.2.1 ]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 2- azabicyclo[2.2.2]octyl, and 3-azabicyclo[3.2.2]nonyl, and azabicyclo[2.2.1]heptanyl.

The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide,

methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate,

phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, Ν,Ν-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

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 olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

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

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

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

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

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

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

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

experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or Intermediates.

Methods of Treatment

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

Accumulation of triglycerides leads to the obesity and associated with insulin- resistance, so inhibition of triglycerides synthesis represents a potential therapeutic strategy for human obesity and type 2 diabetes. One aspect of the invention described herein provides a method for the treatment and control of obesity or metabolic syndrome, which comprises administering to a 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 any of the formulas described herein.

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

The following diseases, disorders and conditions are related to Type 2 diabetes, and therefore may be treated, controlled or in some cases prevented, by treatment with the compounds described herein: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (1 1) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative disease, (20) retinopathy, (21) nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarian hyperandrogenism (polycystic ovarian syndrome), and other disorders where insulin resistance is a component. In Syndrome X, also known as Metabolic Syndrome, obesity is thought to promote insulin resistance, diabetes, dyslipidemia, hypertension, and increased cardiovascular risk. Therefore, DPP-4 inhibitors may also be useful to treat hypertension associated with this condition.

Another aspect of the invention that is of interest relates to a method of treating hyperglycemia, hypertriglyceridemia, diabetes or insulin resistance in a mammalian 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 any of the formulas described herein in the manufacture of a medicament for use in treating various DGAT1 -related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention

deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis. The compounds described herein are especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety.

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

Additionally, the present invention is directed to the use of a compound of any of the formulas described herein in the manufacture of a medicament for use in treating obesity.

Pharmaceutical Compositions

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

In clinical use of the compound of the invention, usually, the compound is formulated into various preparations together with pharmaceutically acceptable additives according to the dosage form, and may then be administered. By "pharmaceutically acceptable" it is meant the additive, carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. As such additives, various additives ordinarily used in the field of pharmaceutical preparations are usable. Specific examples thereof include gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose,

carboxymethylcellulose, corn starch, microcrystalline wax, white petrolatum, magnesium metasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic acid anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, and the like.

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

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

The pharmaceutical compositions may contain the compound of the invention in an amount of from 1 to 99.9 % by weight, preferably from 1 to 60 % by weight of the composition. The compositions may further contain any other therapeutical ly-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 any of the formulas described herein 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 any of the formulas described herein. When a compound of any of the formulas described herein is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of any of the formulas described herein is preferred. However, the combination therapy may also include therapies in which the compound of any of the formulas described herein 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 any of the formulas described herein.

Examples of other active ingredients that may be administered in combination with a compound of any of the formulas described herein, 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) PPARa/γ dual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPARa agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators

(SPPARyM's), such as those disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963, and (4) PPARy partial agonists; (ii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet®, and GlucophageXR®; (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;

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

(4) leptin and leptin derivatives and agonists;

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

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

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

(8) glucagon receptor antagonists, such as those disclosed in WO 98/04528, WO

99/01423, WO 00/39088, and WO 00/69810;

(9) incretin mimetics, such as GLP- 1 , GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists, such as exenatide, liraglutide, taspoglutide, AVE0010, CJC- 1 131 , and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof;

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

CoA.-cholesterol acyltransferase inhibitors, such as avasimibe;

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

(12) antiobesity compounds;

(13) agents intended for use in inflammatory conditions, such as aspirin, non-steroidal 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), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta blockers (such as and calcium channel blockers (such as;

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

0859;

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

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

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

(21) agonists of the G-protein-coupled receptors: GPR-109, GPR-1 19, and GPR-40;

(22) SSTR3 antagonists, such as those disclosed in WO 2009/01 1836;

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

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

(25) GPR-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 PF-04971729, 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 Armonoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2);

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

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

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

Other dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of any of the formulas described herein include, but are not limited to:

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

(2i?,35,5i?)-5-(l-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-y])-2-(2,4,5- trifluorophenyl)tetrahydro-2H-pyran-3-amine;

(2 ?,35',5R)-2-(2,5-difluorophenyl)tetrahydro)-5-(4,6-dihydropyrrolo[3,4-c]pyrazol- 5( lH)-yl) tetrahydro-2H-pyran-3 -amine;

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

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

(3i?)-4-[(3J?)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-hexahydro-3-(2,2,2-trifluoroethyl)-2H- l,4-diazepin-2-one; and

pharmaceutically acceptable salts thereof.

Antiobesity compounds that can be combined with compounds of any of the formulas described herein include topiramate; zonisamide; naltrexone; phentermine; bupropion; the combination of bupropion and naltrexone; the combination of bupropion and zonisamide; the combination of topiramate and phentermine; fenfluramine; dexfenfluramine; sibutramine; lipase inhibitors, such as orlistat and cetilistat; melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists; CCK-1 agonists; melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Yi or Y5 antagonists (such as MK-0557); CB 1 receptor inverse agonists and antagonists (such as rimonabant and taranabant); β3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (such as bombesin receptor subtype-3 agonists); and 5-hydroxytryptamine-2c (5-HT2c) agonists, such as lorcaserin. For a review of anti-obesity compounds that can be combined with compounds of the present invention, see S. Chaki et al., "Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity," Expert Opin. Ther. Patents, 11 : 1677-1692 (2001); D. Spanswick and . 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 any of the formulas described herein include, but are not limited to:

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

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

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

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

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

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

pharmaceutically acceptable salts thereof.

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

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

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

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

(3- {3-[4-(2-bromo-5-fluorophenoxy)piperidin- 1 -yl]- 1 ,2,4-oxadiazol-5-yl } - 1 H-pyrrol- 1 - yl)acetic acid; (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-l-yl]pyrazin-2-yl}-2H-tetrazol-2-yl)acetic acid; and

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

Glucokinase activators that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:

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

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

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

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

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

5- (2-fluoro-l -fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(l-methyl- lH-pyrazol-3-yl)benzamide;

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

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

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

3-[(4-{2-[(2R)-2-methylpyrrolidin-l -yl]ethoxy}phenyl)thio-N-(3-methyl-l ,2,4-thiadiazol-5-yl)-

6- [(4-methyl-4H-l ,2,4-triazol-3-yl)thio]pyridine-2-carboxamide; and pharmaceutically acceptable salts thereof.

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

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

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

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

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

1- yl]pyrimidine;

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

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

acceptable salts thereof.

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

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

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

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

(2i?)-2-({6-chloro-3-[6-(4-chlorophenoxy)-2-propy]pyridin-3-yl]-l ,2-benzisoxazol-5- yl}oxy)propanoic acid;

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

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

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

(2i?)-2-{3-[3-(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)- lH-indol-l- 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 any of the formulas described herein include, but are not limited to:

3- [l-(4-chlorophenyl)-tr «5-3-fluorocyclobutyl]-4,5-dicyclopropyl-r-4H- l ,2,4-triazole;3- [l -(4-chlorophenyl)-tr m-3-fluorocyclobutyl]-4-cyclopropyl-5-(l-methylcyclopropyl)-r- 4H- l ,2,4-triazole;

3-[l-(4-chlorophenyl)-tr «^-3-fluorocyclobutyl]-4-methyl-5-[2- (trifluoromethoxy)phenyl]-r-4H-l,2,4-triazole; 3-[l-(4-chlorophenyl)cyclobutyI]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4- triazole;

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

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

3-(4-{4-methyl-5-[2-(trif]uorornethyl)phenyl]-4H-l ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-l yI)-5-(3,3,3-trifIuoropropyl)-l ,2,4-oxadiazole;

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

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

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

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

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

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

Somatostatin subtype receptor 3 (SSTR3) antagonists that can be used combination with the compounds of any of the formulas described herein include, but 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 any of the formulas described herein include, but are not limited to: 3-{ l'-[(l -cyclopropyl-4-methoxy-lH-indol-6-yl)carbonyl]-4-oxospiro[chroman- 2,4'- piperidin]-6-yl}benzoic acid;

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

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

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

5- { l '-[( 1 -cyclopropyl-4-methoxy-3-methyl- 1 H-indol-6-yl)carbonyl]-4-oxo- spiro[chroman-2,4'-piperidin]-6-y]}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 any of the formulas described herein;

(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 secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;

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

(5) glucagon receptor antagonists;

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

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

(8) antiobesity compounds;

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

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

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

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

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

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

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

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

(17) agonists of the G-protein-coupled receptors: GPR-109, GPR-1 19, and GPR-

40;

(18) SSTR3 antagonists;

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

(NMS);

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

(21) GPR- 105 antagonists;

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

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

(24) inhibitors of fatty acid synthase;

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

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

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

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

(c) a pharmaceutically acceptable carrier.

In certain embodiments, the compounds described herein can be combined with a DPP- IV inhibitor, such as sitagliptin. DPP 4 is responsible on the inactivation of incretin hormones GLP-l (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide). Thus sitagliptin would inhitbit the inactivation of incretin hormones while DGAT-1 would inhibit tryglicride synthesis.

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

The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000: 1 to about 1 : 1000, preferably about 200: 1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

EXAMPLES General method: Method A (Imidazole formation, exemplified by): C0₂Me

Method B (Suzuki coupling, examplified by):

Method C (Ether formatin, examplified by):

Intermediate 1

4-(5-(3-fluoro-4-formylphenyl^')pyridin-2-yloxy bicyclo[2.2.21octane-l -carboxylic acid Step A: Methyl 4-(5-iodopyridin-2-yloxy)bicvclo[2.2.21octane-l -carboxylate

2-fluoro-5-iodopyridine (635 mg, 2.85 mmol, 1.05 equiv), methyl 4- hydroxybicyclo[2.2.2]octane-l-carboxylate (500 mg, 2.71 mmol, 1 equiv) were taken up in THF (6.8 mL) in a 20 mL thick-walled glass vial and fitted with a rubber septum under positive pressure of nitrogen. The mixture was cooled to 0 °C and solid sodium hydride (60% w/w dispersion in mineral oil, 1 14 mg, 2.85 mmol, 1.05 equiv) was carefully added then the mixture was slowly warmed to room temperature. With the nitrogen inlet still in place, the mixture was heated to 80 °C over 20 minutes during which time gas evolution occurred. At this point, the rubber septum with nitrogen inlet was removed and quickly replaced with a Teflon lined crimp cap. Heating at 80 °C was continued for 30 minutes at which point the reaction was complete as indicated by LCMS analysis. The mixture was cooled to room temperature, opened to the atmosphere, quenched with saturated aqueous ammonium chloride and poured into ethyl acetate and separated. The organic phase was washed twice with brine then dried on anhydrous sodium sulfate, filtered and

concentrated in vacuo to give a white solid which was carried forward crude: LCMS calc'd [MH]⁺ m/z 388; found m/z 388.

Step B: Methyl 4-(5-(3-fluoro-4-formylphenynpyridin-2-yloxy)bicyclo[2.2.21octane-l- carboxylate

Methyl 4-(5-iodopyridin-2-yloxy)bicyclo[2.2.2]octane-l-carboxylate (365 mg, 0.943 mmol, 1.0 equiv) from the previous step and 3-fluoro-4-formylphenylboronic acid (174 mg, 1.04 mmol, 1.1 equiv) were weighed to a vial and taken up in DME (0.5 mL) and ethanol (0.25 mL). To this mixture was added 2.0 M aqueous sodium carbonate (1.89 mL, 3.77 mmol, 4.0 equiv) and palladium tetrakis(triphenylphosphine) ( 218 mg, 0.189 mmol, 20 mol%). The mixture was sparged with nitrogen for -10 minutes then capped with a Teflon lined septum and heated at 125 °C for 25 minutes. The cooled suspension was partitioned between ethyl acetate and water. The organic layer was washed with water then brine then dried on anhydrous sodium sulfate and concentrated in vacuo to give a viscous oil. The crude mixture was purified by flash column chromatography on silica gel eluting with a gradient of 0% to 100% ethyl acetate in hexanes. This gave the title compound as a tan solid: LCMS calc'd [MH]⁺ m/z 384; found m/z 384.

Step C: 4-(5-(3-fluoro-4-formylphenyl)pyridin-2-yloxy)bicyclo[2.2.2]octane-l - carboxylic acid

Methyl 4-(5-(3-fluoro-4-formylphenyl)pyridin-2-yloxy)bicyclo[2.2.2]octane-l - carboxylate (374 mg, 0.975 mmol, 1 equiv) was suspended in THF (10 mL) and water (0.20 mL) and solid lithium hydroxide (234 mg, 9.75 mmol, 10 equiv) was added then the mixture stirred overnight at 50 °C. The reaction mixture was cooled to room temperature and acidified to pH 2 with 2M aqueous hydrochloric acid. The mixture was diluted with 40% acetonitrile in water (4 mL) and filtered through a 0.45 micron membrane then purified by preparative reverse phase HPLC on a 30 x 100 mm SunFire CI 8 column with a gradient of 20% to 70% acetonitrile in water containing 0.05% TFA. This gave the title compound as a white solid: LCMS calc'd [MH]⁺ m/z 370; found m/z 370.

Intermediate 2

Methyl 4-(5-(3-fluoro-4-formylphenyl)pyrimidin-2-yloxy)bicyclo 2.2.21octarie-l - carboxylate

Step A: Methyl 4-(5-bromopyrimidin-2-yloxy)bicyclo[2.2.2]octane-l-carboxylate

5-bromo-2-chloropyrimidine (500 mg, 2.58 mmol, 1 equiv), methyl 4- hydroxybicyclo[2.2.2]octane-l-carboxylate (524 mg, 2.84 mmol, 1.1 equiv) and solid sodium hydride (60% w/w dispersion in mineral oil, 109 mg, 2.71 mmol, 1.05 equiv) were charged to a thick walled vial fitted with a Teflon lined septum. The vessel was backfilled thrice with nitrogen and DME (7 mL) was added with the nitrogen inlet in place. The reaction was stirred at room temperature for 15 minutes at which point gas evolution had ceased. Then the nitrogen inlet was removed and the mixture heated at 1 10 °C and then 100 °C overnight. The mixture was cooled to room temperature, opened to the atmosphere, poured into ethyl acetate and washed with half-saturated ammonium chloride, dried on anhydrous sodium sulfate, filtered and concentrated in vacuo to give a light brown solid which was carried forward crude: LCMS calc'd [MH]⁺ m/z 341 ; found m/z 341.

Step B: Methyl 4-(5-(3-fluoro-4-formylphenyl)pyrimidin-2-yloxy)bicyclo[2.2.2 octane- 1-carboxylate

To a vial were added methyl 4-(5-iodopyridin-2-yloxy)bicyclo[2.2.2]octane-l - carboxylate (100 mg, 0.293 mmol, 1 equiv), 3-fluoro-4-formylphenylboronic acid (49 mg, 0.293 mmol, 1 equiv) and the XPhos based palladium precatalyst (12 mg, 15 μιτιοΐ, 5 mol%) described in: Tom Kinzel, Yong Zhang, Stephen L. Buchwald J. Am. Chem. Soc. 2010, 132 (40), 14073-14075. The vial was capped under nitrogen and deoxygenated THF (2 mL) and deoxygenated 1.6 M aqueous potassium phosphate (0.586 mL, 0.938 mmol, 3.2 equiv) were added. The mixture was heated at 80 °C under nitrogen for 18 hours at which point LCMS analysis indicated it was complete. The mixture was transferred to a scintillation vial with dichloromethane and Celite was added then volatiles removed in vacuo to provide the crude product adsorbed on Celite which was loaded onto a silica gel column and purified by medium pressure chromatography eluting with 0% to 40% acetone in dichloromethane to give the title compound as a pale yellow powder: LCMS calc'd [MH]⁺ m/z 385; found m/z 385.

Intermediate 3

ethyl trans-4-f(5-bromopyridin-2-yl)oxy|cyclohexanecarboxylate To a mixture of 5-bromo-2-hydroxypyridine (1 1 g, 63.2 mmol), ethyl cis-4- hydroxycyclohexanecarboxylate (13.61 g, 79 mmol) and triphenylphosphine (20.73 g, 79 mmol) in THF (250 ml) at room temperature added diisopropyl azodicarboxylate (15.98 g, 79 mmol) dropwise, after that, the reaction mixture was stirred overnight a at 55°C for two days under N₂. The reaction mixture was cooled to room temperature, then concentrated under vacuum. The residue was dissolved in 100 mL of ethyl acetate, then 100 mL hexane added. Stirred over night. The mixture was filtered and concentrated, the residue was purified by a silica gel column and eluted with ethyl acetate/hexane 0-50%. This resulted in ethyl trans-4-[(5-bromopyridin-2- yl)oxy]cyclohexanecarboxylate as a white solid. LC-MS (ES, m/z) Ci₄H]₈BrN0₃: 327; Found: 328 [M+H]⁺.

Intermediate 4

ethyl cis-4-[(5-bromopyridin-2-yl)oxy1cyclohexanecarboxylate With the same procedure as preparation of Intermediate 3, ethyl cis-4-[(5- bromopyridin-2-yl)oxy]cyclohexanecarboxylate as a white solid was prepared. LC-MS (ES, m/z) Ci₄H,₈BrN0₃: 327; Found: 328 [M+H]⁺.

Intermediate 5 OOEt

ethyl trans-4-([5-(4,4,5,5-tetramethyl-K3.2-dioxaborolan-2-yl^")pyridin-2- ylloxylcyclohexanecarboxylate

A mixture of ethyl trans-4-[(5-bromopyridin-2-yl)oxy]cyclohexanecarboxylate (4g, 12.19 mmol), bis(pinacolato)diboron (3.40 g, 13.41 mmol), potassium acetate (3.59 g, 36.6 mmol) and Pd(dppf)Cl₂ (0.446 g, 0.609 mmol) in 1 ,4-dioxane (50 ml).was stirred over night at 80°C under N₂ in an oil bath. The reaction mixture was cooled to room temperature, concentrated under vacuum then applied onto a silica gel column and eluted with ethyl acetate/hexane 0-40%. This resulted in ethyl trans-4-{[5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yl]oxy}cyclohexanecarboxylate as a white solid. LC-MS (ES, m/z) C20H30BNO5: 375; Found: 376 [M+H]⁺.

Intermediate 6

ethyl cis-4-{[5-(4.4,5,5-tetramethyl-1 ,2-dioxaborolan-2-yl)pyridin-2- ylloxy}cvclohexanecarboxylate

With the same procedure as preparation of Intermediate 5, ethyl cw-4-{[5-(4,4,5,5- tetramethyl- l ,3,2-dioxaborolan-2-yl)pyridin-2- yl]oxy}cyclohexanecarboxylate as a white solid was prepared. LC-MS (ES, m/z) C20H30BNO5: 375; Found: 376 [M+H]⁺.

Intermediate 7

benzyl 3-|Y5-bromopyridin-2-yl)oxy|cyclobutanecarboxylate

To a mixture of 5-bromo-2-hydroxypyridine (lg, 5.75 mmol), benzyl 3- hydroxycyclobutanecarboxylate (1.48 g, 7.18 mmol) and triphenylphosphine (1.88 g, 28.7 mmol) in THF (25 ml) at room temperature added diisopropyl azodicarboxylate (1.45 g, 7.18 mmol) dropwise, after that, the reaction mixture was stirred overnight a at 55°C for two days under N₂. The reaction mixture was cooled to room temperature, then concentrated under vacuum. The residue was dissolved in 20 mL of ethyl acetate, then 80 mL hexane added, stirred for 4 hours. The mixture was filtered and

concentrated, the residue was purified by a silica gel column and eluted with ethyl acetate/hexane 0-50%. This resulted benzyl 3-[(5-bromopyridin-2- yl)oxy]cyclobutanecarboxylate as a white solid. LC-MS (ES, m/z) Ci₇Hi₆BrN0₃: 361 ; Found: 362 [M+H]⁺.

Intermediate 8

benzyl 3-{[5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin-2- yl^~|oxy}cvclobutanecarboxylate

A mixture of benzyl 3-[(5-bromopyridin-2-yl)oxy]cyclobutanecarboxylate (l g, 2.76 mmol), bis(pinacolato)diboron (0.771 g, 3.04 mmol), potassium acetate (0.813 g, 8.28 mmol) and Pd(dppf)Cl₂ (0.101 g, 0.138 mmol) in 1 ,4-dioxane (15 ml) was stirred over night at 80°C under N₂ in an oil bath. The reaction mixture was cooled to room temperature, concentrated under vacuum then applied onto a silica gel column and eluted with ethyl acetate/hexane 0-50%. This resulted in benzyl 3-{[5-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}cyclobutanecarboxylate as a colorless oil. LC- MS (ES, m/z) C₂₃H₂₈B 0₅: 409; Found: 410 [M+H]⁺.

Intermediate 9

benzyl 3-[(5-bromopyridin-2-yl oxy^"|cyclopentanecarboxylate

To a mixture of 5-bromo-2-hydroxypyridine (2.43 g, 13.97 mmol), benzyl 3- hydroxycyclopentanecarboxylate (3.85 g, 17.46 mmol) and triphenylphosphine (4.58 g, 17.46 mmol) in THF (50 ml) at room temperature added diisopropyl azodicarboxylate (3.53 g, 17.46 mmol) dropwise, after that, the reaction mixture was stirred overnight a at 55°C for two days under N₂. The reaction mixture was cooled to room temperature, then concentrated under vacuum. The residue was dissolved in 20 mL of ethyl acetate, then 80 mL hexane added, stirred for 4 hours. The mixture was filtered and

concentrated, the residue was purified by a silica gel column and eluted with ethyl acetate/hexane 0-50%. This resulted in benzyl 3-[(5-bromopyridin-2- yl)oxy]cyclopentanecarboxylate as a white solid. LC-MS (ES, m/z) Ci₈H_{] 8}BrN03: 375; Found: 376 [M+H]⁺.

Intermeidate 10

benzyl 3-([5-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)pyridin-2- yl]oxy I cyclopentanecarboxylate

A mixture of benzyl 3-[(5-bromopyridin-2-yl)oxy]cyclopentanecarboxylate (3.9g, 10.37 mmol), bis(pinacolato)diboron (2.9 g, 1 1.4 mmol), potassium acetate (3.05 g, 3 1.1 mmol) and Pd(dppf)Cl₂ (0.379 g, 0.518 mmol) in 1 ,4-dioxane (25 ml) was stirred over night at 80°C under N₂ in an oil bath. The reaction mixture was cooled to room temperature, concentrated under vacuum then applied onto a silica gel column and eluted with ethyl acetate/hexane 0-50%. This resulted in benzyl 3-{[5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}cyclopentanecarboxylate as a colorless oil. LC-MS (ES, m/z) C24H30BNO5: 423; Found: 424 [M+H]⁺.

Intermediate 1 1

Cis and trans ethyl 4-[(5-bromopyrimidin-2-yl^')oxy]cyclohexanecarboxylate

A mixture of ethyl 4-hydroxycyclohexanecarboxylate (1.0 g, 5.81 mmol, 1.00 equiv), 5-bromo-2-chloropyrimidine (1.34 g, 6.97 mmol, 1.2 equiv), and cesium carbonate (7.76 g, 23.81 mmol, 4.1 equiv) in DMF (20 mL) was stirred for 1 hr at 50 °C in MW. The reaction mixture was cooled to room temperature, washed with water and extracted 2x with EtOAc, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by eluting through a silica gel column with a 0-50% EtOAc/Hexane solvent system to provide product ethyl 4-[(5-bromopyrimidin-2- yl)oxy]cyclohexanecarboxylate. LC-MS (ES, m/z) ^Η_Ι7ΒΓΝ₂0₃: 328; Found: 331

[M+H]⁺. The mixture was then submitted for separation by SFC-HPLC using 50% 2: 1 MeOH:MeCN/C0₂ on OJ-H column to afford cis and trans ethyl 4-[(5-bromopyrimidin- 2-yl)oxy]cyclohexanecarboxylate.

Intermediate 12

ethyl 4-ir5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl pyrimidin-2- ylloxy } cyclohexanecarboxylate

A mixture of ethyl 4-[(5-bromopyrimidin-2-yl)oxy]cyclohexanecarboxylate (5.3 g, 16.1 mmol), bis(pinacolato)diboron (4.50 g, 17.71 mmol), potassium acetate (4.74 g, 48.3 mmol) and Pd(dppf)Cl₂ (0.589 g, 0.805 mmol) in 1 ,4-dioxane (25 ml). was stirred over night at 80°C under N₂ in an oil bath. The reaction mixture was cooled to room temperature, concentrated under vacuum then applied onto a silica gel column and eluted with ethyl acetate/hexane 0-50%. This resulted in ethyl 4-{[5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrimidin-2-yl]oxy}cyclohexanecarboxylate as white solid. LC-MS (ES, m/z) C₁₉H₂₉BN₂0₅: 376; Found: 378 [M+H]⁺.

Intermediate 13

2-(2.6-difluoro-4-(6-fluoropyridin-3-yl phenylV5-(trifluoromethvn-lH- benzolaf] imidazole

Step A. 2,6-difluoro-4-(6-fluoropyridin-3-yl)benzaldehyde.

Divided into two 20 ml microwave tubes was added 2-fluoropyridine-5-boronic acid (500 mg, 3.55 mmol), 4-bromo-2,6-difIuorobenzaldehyde and Tetrakis (410 mg, 0.355 mmol) and the tubes capped. Under a N₂ atmosphere, DME (15 ml) and EtOH (10 ml) followed by a solution of 2 M sodium carbonate (5.32 ml, 10.65 mmol) was added via syringe and the mixtures irradiated in the Biotage Initiator Microwave for 20 min. at 120 °C. The contents of the two tubes were combined and the solvent was evaporated. The resulting residue was diluted with EtOAc and washed with brine. The organic layer was dried (MgS0₄) and concentrated. Purification on the CombiFlash Companion, on a 40 g column eluting with 20 to 40 % EtOAc / Hexane afforded 760 mg of the title compound. 'H NMR (CDC13): δ 10.42 (s, 1 H), 8.51 (s, 1H), 8.05-8.01 (t, 1H), 7.23 (d, 2H), 7.14-7.12 (dd, 1H). LC-MS (M+l) = 238.

Step B: 2-(2,6-difluoro-4-(6-fluoropyridin-3-yl)phenyl)-5-(trifluoromethyl)-lH- benzo[(f| imidazole

A solution of the title compound from Step A (150 mg, 0.632 mmol) in DMF (3.5 ml) and water (0.25ml) was treated with 4-(trifluoromethyl)benzene-l,2-diamine (11 1 mg, 0.632 mmol) in small portions and the mixture stirred at 25 °C for 5 min. Potassium peroxymonosulfate (389 mg, 0.632 mmol) was then added and the mixture stirred for another 50 min. The mixture was poured in 60 ml of water containing 6 ml (2 M ₂C0₃) and the mixture stirred at 25 °C for 5 min. The mixture was diluted with EtOAc and the layers separated. The organic layer was dried (MgS0₄) and concentrated. Purification on the CombiFlash Companion on a 12 g column eluting with 20 to 40 % EtOAc / Hexane afforded 171 mg, after trituration and filtration from ether / hexane. LC-MS (M+l) = 394.

Intermediate 14

Cis-ethyl 4-(^'5-(3,5-difluoro-4-formylphenvnpyridin-2-yloxy)cvclohexanecarboxylate.

In a 20 ml microwave tube was the Cis-ethyl 4-(5-bromopyridin-2- yloxy)cyclohexanecarboxylate (500 mg, 1.523 mmol), 3,5-difluoro-4- formylphenylboronic acid (283 mg, 1.523 mmol) and Tetrakis (176 mg, 0.152 mmol). The tube was capped and under a N₂ atmosphere was added DME (9.2 ml) and EtOH (4.6 ml) followed by aqueous 2 M sodium carbonate (2.285 ml, 4.57 mmol) via syringe. The mixture was then irradiated in the Biotage Initiator Microwave for 25 mim at 120 °C. The solvent was evaporated, and the residue diluted with EtOAc and washed with brine. The organic layer was dried (MgS0₄) and concentrated. Purification on the CombiFlash Companion on a 40 g column eluting with 10 to 30 % EtOAc / Hexane afforded 394 mg. LC-MS (M+l) = 390.

5-chloro-2-(2₁6-difluoro-4-(6-fluoropyridin-3-yl)phenyl)-lH-benzo 1 imidazole.

Following the procedure described for the synthesis of Step B Intermediate 13, but using 4-chlorobenzene-l,2-diamine, Intermediate 15 was afforded. LC-MS (M+l) ^: 360.

Intermediate 16

2-(4-chloro-2,5-difluorophenyl)-5-(trifluoromethyl)-lH-benzo[(il imidazole

Step A: N-(2-amino-5-(trifluoromethyl)phenyn-4-chloro-2,5-difluorobenzamide A suspension of 4-chloro-2,5-difluorobenzoic acid (1.00 g, 5.19 mmol), 3,4- diaminobenzotrifluoride (1.006 g, 5.71 mmol) and PyBOP (2.97 g, 5.71 mmol) in DMF (15.0 ml) under a N₂ atmosphere was stirred at room temperature for 5 min. DIEA (2.72 ml, 15.58 mmol) was then added via a syringe and the mixture stirred at room

temperature for 4 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgS0₄) and concentrated. Purification on the CombiFlash Companion, on a 40 g column eluting with 10 to 30 % EtOAc / Hexane afforded 652 mg of N-(2-amino-5-(trifluoromethyl)phenyl)-4-chloro-2,5-difluorobenzamide as a cream crystalline solid. LC- S (M+l) = 351.

Step B. 2-(4-chloro-2,5-difluorophenyl)-5-(trifluoromethyl)- lH-benzo[</|imidazole

To a 20 ml microwave tube containing N-(2-amino-5-(trifluoromethyl)phenyl)-4- chloro-2,5-difIuorobenzamide from Step A, (300 mg, 0.856 mmol) was added acetic acid (4.0 ml). The tube was capped and irradiated at 180 °C in Biotage Initiator Microwave for 40 min. The resulting suspension was diluted with EtOAc and extracted with water (x3). The organic layer was dried (MgSO^ and concentrated. Purification on the CombiFlash Companion, on a 24 g column eluting with 20 to 40 % EtOAc / Hexane afforded 268 mg as a cream solid. LC-MS (M+l) = 333.

Intermediate 17

2-(4-chloro-2,5-difluorophenyl)-3H-imidazo[4,5- >]pyridine

Step A: N-(2-aminopyridin-3-yl)-4-chloro-2,5-difluorobenzamide

Following the procedure described in Step A of Intermediate 16, but with pyridine-2,3-diamine, N-(2-aminopyridin-3-yl)-4-chloro-2,5-difluorobenzamide was afforded together with it's regioisomer in the ratio 8: 1. LC-MS (M+ l) = 284.

Step B: 2-(4-chloro-2.5-difluorophenyl)-3H-imidazo[4,5-blpyridine W

Following the procedure described for Step B, Intermediate 16, but with N-(2- aminopyridin-3-yl)-4-chloro-2,5-difluorobenzamide from Step A, 2-(4-chloro-2,5- difluorophenyl)-3H-imidazo[4,5-b]pyridine was afforded as a cream solid. LC-MS (M+l) = 266.

Intermediate 18

Methyl 2-(Cis-3-(5-(3-fluoro-4-formylphenvnpyrimidin-2-yloxy^")cyclobutyl acetate Step A: Methyl 2-(3-(5-bromopyrimidin-2-yloxy cvclobutyl)acetate

In a 25 ml microwave tube was added methyl 3-hydroxycyclobutylacetate (1.0 g, 6.94. mmol, cis:trans 4: 1 ), 5-bromo-2-chloropyrimidine (1.610 g, 8.32 mmol) and cesium carbonate (9.04 g, 27.7 mmol). The tubes were capped and degassed (house vacuum) and backfilled with ₂. DMF (20 ml) was added and the mixture irradiated in the Biotage Initiator Microwave for 90 min at 120 °C. The resulting mixture was diluted with EtOAc and filtered. The filtrate was washed with water (x2) then with brine (xl ). The combined organic layer was dried (MgS0₄) and concentrated. Purification on the CombiFlash Companion, on a 40 g column eluting with 10 to 30 % EtOAc / Hexane afforded 1.2 g as a white solid (cis / trans mixture 4: 1). Ή NMR (CDC1₃) δ 8.62 (s, 2H) 5.05 (m, 1H), 3.66 (s, 3H), 2.69-2.74 (m, 1H), 2.45 (d, 2H), 2.29-2.38 (m, 1H), 1.83- 1.89 (m, 2H). LC-MS (M, M+2) = 301 , 303

Step B: Methyl 2-(Cis-3-(5-bromopyrimidin-2-yloxy)cyclobutyl)acetate

The Cis and Trans mixture from Step A were separated on the AD-H column, 30x250 mm, 35 % 2: 1 EtOH / MeCN/ C02, 70 ml /min, 100 bar, 35 °C, 220 nm, 100 mg/ml in 4 : 1 MeCN/ EtOH. 3.2 g of the Cis (white crystalline solid) and 0.8 g of Trans (cream powder) isomers were afforded. Cis isomer Ή NMR (CDC1₃) δ 8.53 (s, 2Η) 5.04 -5.10 (m, I H), 3.69 (s, 3H), 2.73-2.79 (m, I H), 2.53 (d, 2Η), 2.34-2.41 (m, 2Η), 1.90- 1.96 (dq, 2H). LC-MS (M, M+2) = 301 ,303. Trans isomer Ή NMR (CDC1₃) δ 8.53 (s, 2H) 5.25 -5.30 (m, I H), 3.71 (s, 3H), 2.80-2.85 (m, IH), 2.57 (d, 2H), 2.45-2.51 (m, 2H), 2.29- 2.34 (m, 2H). LC-MS (M, M+2) = 301 , 303.

Step C: Ethyl 2-(Cis-3-(5-(3-fluoro-4-formylphenyl)pyrimidin-2-yloxy)cvclobutyl) acetate

Methy 2-(Cis-3-(5-(3-fluoro-4-formylphenyl)pyrimidin-2-yloxy)cyclobutyl)acetate

Following the procedure described for Step B, Intermediate 1 1 but with the Cis Title compound from Step 2 and 3-fluoro-4-formylphenylboronic acid, Intermediate 18 was afforded with the Ethy Ester as a byproduct.

Intermediate 19

2-fluoro-4-(6-fluoropyridin-3-yl)benzaldehvde

To 250 mL round bottom flask with reflux condenser was added 2-fluoro-4- bormobenzaldehyde, 2-fluoro-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridine, THF (180 mL) K3PO4 and water (30 mL). To a 40 mL vial was added 20 mL THF and sparged with N₂ added Pd(OAc)₂ and Ad₂PnBu ligand aged at room temperature and the resulting yellow slurry was transferred to reaction flask under nitrogen flow. The reaction mixture was warmed to 60 °C for 1 hr. After cooled to room temperature 50 mL water was added and stirred for 20 mins. The solid product was then filtered and dried overnight under vac / nitrogen flow to afford product 2-fluoro-4-(6-fluoropyridin-3- yl)benzaldehyde. LC-MS (M+l)

Intermediate 20

2-(2-fluoro-4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-ynphenylV5-(trifluoromethyl^')- lH-benzofdlimidazole

Step A: 2-(4-bromo-2-fluorophenylV5-(trifluoromethyl^')-lH-benzo[d1imidazole

To a flask was added solution of 4-(trifluoromethyl)benzene-l ,2-diamine (4.0 g, 22.71 mmol) in DMF (80.0 mL)/H₂0 (2.0 mL) followed by 4-bromo-2- fluorobenzaldehyde (5.8 g, 24.98 mmol) slowly and then OXONE (9.77g, 15.9 mmol). The mixture was then stirred at room temperature for 1 :30 hr, quenched with a 1 M solution K2C03 and water. The resulting mixture was stirred for 5 min, diluted with water and extracted with EtOAc 3x. The combined organic layers were dried over

Mg2S04, filtered and concentrated in vacuo. The residue was purified by eluting through a silica gel column with a 0-30% EtOAc/Hexane solvent system to provide product 2-(4- bromo-2-fluorophenyl)-5-ftrifluoromethyl)-lH-benzo[d1imidazole LC-MS (ES, m/z) C₁₄H₇BrF₄N₂: 359; Found: 360 [M+H]⁺.

StepB: 2-(2-fluoro-4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)phenvn-5- (trifluoromethyl)-lH-benzofd^~)imidazole

A mixture of 2-(4-bromo-2-fluorophenyl)-5-(trifluoromethyl)-l H- benzo[d]imidazole (8.08 g, 20.82 mmol, 1.00 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi- 1 ,3,2-dioxaborolane (5.82 g, 22.09 mmol, 1.10 equiv), potassium acetate (6.13 g, 62.5 mmol, 3.00 equiv) and l , l '-bis(diphenylphoshino) ferrocene dichloropalladium (II) dichloromethane complex ( 1.52 g, 2.08 mmol, 0.1 equiv) in DMSO (65 mL) was stirred for 18 hr at 100 °C in an oil bath. The reaction mixture was cooled and washed by the addition of water, followed by extraction 3 times with EtOAc. The combined organic layer was dried over MgS0₄ filtered and concentrated in vacuo. The residue was purified by eluting through a silica gel column with a 0-60% EtOAc/Hexane solvent system to provide product 2-(2- fluoro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)-5-(trifluoromethyl)- l H- benzo[d]imidazole LC-MS (ES, m/z) C₂oH₁₉BF₄N₂0₂: 406; Found: 407 [M+H]⁺.

Intermediate 21

ethyl 3-(5-bromopyrimidin-2-yloxy)cyclobutanecarboxylate

A mixture of ethyl 3-hydroxycyclobutanecarboxylate (5.0 g, 29.2 mmol, 1.00 equiv), 5-bromo-2-chloropyrimidine (6.78 g, 35.0 mmol, 1.2 equiv), and cesium carbonate (19.98 g, 61.3 mmol, 2.1 equiv) in DMF (100 mL) was stirred for 18 hr at 50 °C in an oil bath. The reaction mixture was cooled to room temperature, filtered thru Buchner funnel rinsed with EtOAc and concentrated in vacuo. The residue was purified by eluting through a silica gel column with a 0-40% EtOAc/Hexane solvent system to provide product ethyl 3-(5-bromopyrimidin-2-yloxy)cyclobutanecarboxylate as a mixture of cis and trans. LC-MS (ES, m/z) C_uHi3BrN₂0₃: 301 ; Found: 302 [M+H]⁺.

Intermediate 22

ethyl 3-(5-(3-fluoro-4-formylphenyl)pyrimidin-2-yloxy)cyclobutanecarboxylate

To a mixture of ethyl 3-(5-bromopyrimidin-2-yloxy)cyclobutanecarboxylate (0.5 g, 1.66 mmol), 3-fluoro-4-formylphenylboronic acid (0.418 g, 2.49 mmol); tetrakis (0.288 g0.249 mmol) and Na₂C0₃ (3.4 mL, 2.0 M, 4.1 equiv) was added DME(5.0 mL)/EtOH(3.0), The reaction mixture was purged with N₂ 10 min followed by MW at 120° 20 min-LCMS 1. Solvent evaporated and mixture was diluted with water and extracted with EtOAc 2x. The organics were dried over Mg₂S0₄, filtered and

concentrated in vacuo. Residue purified by eluting through a silica gel column with a 0- 80% Hexane/EtOAc solvent system to provide product ethyl 3-(5-(3-fluoro-4- formylphenyl)pyrimidin-2-yloxy)cyclobutanecarboxylate. LC-MS (ES, m/z) Ci₈Hi₇FN₂0₄: 344; Found: 345[M+H]⁺.

Intermediate 23 and 24

Cis and trans ethyl 3-(5-bromopyrimidin-2-yloxy)cyclobutanecarboxylate

The mixture of cis and trans isomers in Intermediate 21 were separated by SFC- HPLC using 50% 2: 1 MeOH:MeCN/C0₂ on AD column to afford cis ethyl 3-(5- bromopyrimidin-2-yloxy)cyclobutanecarboxylate (RT = 3.722 min, 95%) and trans ethyl 3-(5-bromopyrimidin-2-yloxy)cyclobutanecarboxylate (RT = 2.794 min).

Intermediate 25 0₂Et

c -ethyl3-(5-(3,5-difluoro-4-formylphenynpyrimidin-2-yloxy)cvclobutanecarboxylate

In the same procedure as Intermediate 22, using cis Intermediate 23, m-ethyl 3-(5- (3,5-difluoro-4-formylphenyl)pyrimidin-2-yloxy)cyclobutanecarboxylate was prepared. LC-MS (ES, m/z) Ci₈H,₆F₂N₂0₄: 362; Found: 363 [M+H]⁺.

Intermediate 26

5',6'-difluoro-2,3'-bipyridine-5-carbaldehyde

Step A: 2 -difluoro-5-(4,4,5,5-tetramethyl- K3,2-dioxaborolan-2-yl)pyridine

To a 100 ml round bottom flask was charged with 2,3-difluoro-5-iodopyridine (1.0 g, 4.15 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi- l ,3,2-dioxaborolane (1.16 mmol), potassium acetate (1.22 g, 12.45 mmol), Pd(dppf) (0.304 g, 0.415 mmol) in DMSO. The mixture was degassed and purged with N₂ for 10 min and stirred at 100° C overnight. Mixture was washed with water and extracted with EtOAc 3x, organics dried over MgS04, filtered and concentrated in vacuo. The crude was purified by MPLC with 0-35%

Hexane/EtOAc to afford product 2,3-difluoro-5-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2- yl)pyridine.

Step B: 5',6'-difluoro-2,3'-bipyridine-5-carbaldehyde

In the same procedure as Intermediate 19, 5',6'-difluoro-2,3'-bipyridine-5- carbaldehyde was prepared. LC-MS (ES, m/z) C_nH₆F₂N₂:0 220; Found: 221 [M+H]⁺.

Intermediate 27

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

In the same procedure as Intermediate 26, Intermediate 27 6'-fluoro-5'-methyl- 2,3'-bipyridine-5-carbaldehyde was prepared. LC-MS (ES, m/z) C_{] 2}H₉FN₂:0 216; Found: 217 [M+H]⁺.

Intermediate 28

Cis and trans methyl {4-[(5-bromopyrimidin-2-v0oxy|cyclohexyl|acetate

A mixture of ethyl 4-hydroxycyclohexylacetate (29.5 g g, 171 mmol, 1.82 equiv), 5-bromo-2-hydroxypyrimidine (16.5 g, 94 mmol, 1 equiv), and

triphenylphosphine (37. lg, 141 mmol, 1.5 eq) in THF (6000 mL) was stirred while DIAD (28.6 g, 141 mmol, 1.5 eq) was added dropwise in 30 min. The reaction mixture was stirred at room temperature for 2 hrs. The mixture was then concentrated in vacuo. The residue was purified by eluting through a silica gel column with a 0-50% EtOAc/Hexane solvent system to provide product methyl {4-[(5-bromopyrimidin-2- yl)oxy]cyclohexyl} acetate. LC-MS (ES, m/z) Ci₄H,₉BrN₂0₃: 328; Found: 331 [M+H]⁺. The cis/trans mixture was then submitted for separation by SFC-HPLC using 40% EtOH/C0₂ on AD-H column to afford methyl cw-{4-[(5-bromopyrimidin-2- yl)oxy]cyclohexyl} acetate (A, RT = 1.3 min) and methyl traw-{4-[(5-bromopyrimidin- 2-yl)oxy]cyclohexyl} acetate (A, RT = 2.2 min).

methyl (c -4-{[5-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-ynpyrimidin-2- vHoxylcyclohexyDacetate

methyl (trans -4-{[5-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)pyrimidin-2- ylloxylcyclohexyOacetate

In the same procedure as the preparation of Intermediate 12, Intermediate 29 methyl (cw-4-{[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2- yl]oxy}cyclohexyl)acetate and Intermediate 30 methyl (/ra«i-4-{[5-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]oxy}cyclohexyl)acetate are prepared.

Intermediate 31

{cis-4-[5-(5-Formyl-4-methyl-pyridin-2-ylVpyrimidin-2-yloxyl-cvclohexyl>-acetic acid methyl ester

6-Br-4-Methylpyridine-3-carbaldehyde (0.35 l g, 1.754 mmol, 1.1 equiv.), {cis-4-

[5-(4,4,5,5-Tetramethyl- l ,3,2-dioxaborolan-2-yl)-pyrimidin-2-yloxy]-cyclohexyl}-acetic acid methyl ester (0.6 g, 1 .595 mmol, 1 equiv.), Tetrakis(PPh3)Pd(0) (0.276 g, 0.239 mmol, 0.15 equiv.), and 2M Na2C03 (aq) (3.19 mL, 6.38 mmol, 4equiv.) were placed in DME (3.68 mL) / EtOH (1.815 mL) and stirred at room temperature in a sealed microwave reaction vial. The reaction was placed under vacuum for 5 min (until no continuing gas evolution was detected) and then N2(g) was bubbled into the reaction suspension for 15 min. The reaction suspension was heated at 120°C under microwave conditions for 20 min. The reaction was concentrated to a residue which was then dissolved in EtOAc / brine. The EtOAc phase was dried over Na2S0zL, filtered, and concentrated to an oil. Purification with Biotage SP-1 [ FLASH 25 cartridge.

Hexanes:EtOAc 0>12% 2CV; 12>100% 10CV; 100% 4CV ] isolated 0.29 g. LC-MS (ES, m/z): C₂oH₂₃N₃0₄: 369; Found: 370 [M+H]⁺.

Intermediate 32

{trans-4-[5-f5-Formyl-4-methyl-pyridin-2-yl)-pyrimidin-2-yloxy -cyclohexyl}-acetic acid methyl ester

6-Br-4-Methylpyridine-3-carbaldehyde (0.602g, 3.01 mmol, 1.1 equiv.), {trans-4- [5-(4,4,5,5-Tetramethyl- l,3,2-dioxaborolan-2-yl)-pyrimidin-2-yloxy]-cyclohexyl}-acetic acid methyl ester (1.03 g, 2.74 mmol, 1 equiv.), Tetrakis(PPh3)Pd(0) (0.475 g, 0.41 1 mmol, 0.15 equiv.), and 2M Na2C03 (aq) (5.48 mL, 10.95 mmol, 4 equiv.) were placed in DME (9.17 mL) / EtOH (4.52 mL) and stirred at room temperature in a sealed microwave reaction vial. The reaction was placed under vacuum for 5 min (until no continuing gas evolution was detected) and then N2 (g) was bubbled into the reaction suspension for 25 min. The reaction suspension was heated at 120°C under microwave conditions for 1 hr 20 min. The reaction was concentrated to a residue which was then dissolved in EtOAc / brine. The EtOAc phase was dried over Na2S04, filtered, and concentrated to an oil. Purification with Biotage SP-1 [ FLASH 25 cartridge.

Hexanes:EtOAc 0>12% 2CV; 12>100% 10CV; 100% 5CV ] isolated 0.8 g. LC-MS (ES, m/z): C₂oH₂3N₃0₄: 369; Found: 370 [M+H]⁺.

Intermediate 33

{cis-4-[5-(5-Formyl-3-methyl-pyridin-2-yl)-pyrimidin-2-yloxy1-cvclohexyU-acetic acid methyl ester

6-Br-4-Methylpyridine-3-carbaldehyde (0.35 l g, 1.754 mmol, 1.1 equiv.), {cis-4-

[5-(4,4, 5, 5-Tetramethyl- l ,3,2-dioxaborolan-2-yl)-pyrimidin-2-yloxy]-cyclohexyl} -acetic acid methyl ester (0.6 g, 1.595 mmol, 1 equiv.), Tetrakis(PPh₃)Pd(0) (0.276 g, 0.239 mmol, 0.15 equiv.), and 2M Na2C03 (aq) (3.19 mL, 6.38 mmol, 4equiv.) were placed in DME (3.68 mL) / EtOH ( 1 .815 mL) and stirred at room temperature in a sealed microwave reaction vial. The reaction was placed under vacuum for 5 min (until no continuing gas evolution was detected) and then N2(g) was bubbled into the reaction suspension for 15 min. The reaction suspension was heated at 120°C under microwave conditions for 20 min. The reaction was concentrated to a residue which was then dissolved in EtOAc / brine. The EtOAc phase was dried over Na2S04, filtered, and concentrated to an oil. Purification with Biotage SP-1 [ FLASH 25 cartridge.

Hexanes:EtOAc 0>12% 2CV; 12> 100% 10CV; 100% 4CV ] isolated 0.29 g. LC-MS (ES, m/z): C₂oH₂3N₃0₄: 369; Found: 370 [M+H]⁺.

Intermediate 35

ethyl 2-(4-(5-bromopyridin-2-yloxy cvclohexyl)acetate

To a mixture of ethyl 2-(4-hydroxycyclohexyl)acetate (2.41 g, 12.9 mmol), 5- bromopyridin-2-ol (1.8 g, 10.3 mmol) and triphenylphosphine (3.39g, 12.9 mmol) in THF (40 ml) added diisopropylazodicarboxylate (2.61 g, 12.9 mmol) dropwise. The reaction mixture was heated at 55°C in an oil bath for 2 days under N₂. The reaction mixture was cooled to room temperature, concentrated under vacuum, EtOAc (10 ml)added, followed by hexane (100 ml), stirred for 1 hour, then filter. The filtration concentrated under vacuum then applied onto a silica gel column and eluted with ethyl acetate/hexane 0-50%. This resulted in 1.9 g (53.7%) of ethyl 2-(4-(5-bromopyridin-2- yloxy)cyclohexyl)acetate as a white solid. LC-MS (ES, m/z) Ci₅H₂oBrN0₃: 342; Found: 343 [M+H]⁺.

Intermediate 36

ethyl 2-(4-(5-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)pyridin-2- yloxy)cyclohexyl)acetate

A mixture of ethyl 2-(4-(5-bromopyridin-2-yloxy)cyclohexyl)acetate (1.8 g, 5.26 mmol), bis(pinacolato)diboron (1.47 g, 5.26 mmol), potassium acetate (1.55 g, 15.78 mmol) and Pd(dppf)Cl₂ (0.192 g, 0.263 mmol) in 1 ,4-dioxane (23 ml).was stirred over night at 80°C under N₂ in an oil bath. The reaction mixture was cooled to room temperature, concentrated under vacuum then applied onto a silica gel column and eluted with ethyl acetate/hexane 0-40%. This resulted in 1.4 g (68%) of ethyl 2-(4-(5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)cyclohexyl)acetate as a white solid. LC-MS (ES, m/z) C21H32BNO5: 389; Found: 390 [M+H]⁺.

Intermediate 37

ethyl 4-(5-bromopyridin-2-yloxy)-l -methylcvclohexanecarboxylate

To a solution of diisopropylamine (1.87 g, 18.43 mmol) in THF (50 ml) in acetone/dry ice bath added n-butyllithium ( 16.76 mmol) under N₂. The reaction mixture stirred for 30 minutes after the addition. Then cis-ethyl 4-(5-bromopyridin-2- yloxy)cyclohexanecarboxylate (5 g, 15.23 mmol) in THF (50 ml) added slowly to the reaction mixture. After another 30 minutes, iodomethane (2.81 g, 19.8 mmol) added to the reaction mixture, stirred for two hours. Then the reaction quenched with water (20 ml), extracted with 3x20 ml ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. Then applied onto a silica gel column and eluted with ethyl acetate/hexane 0-50%. This resulted in 2.2 g (42.2%) of ethyl 4-(5-bromopyridin-2-yloxy)-l-methylcyclohexanecarboxylate as a white solid. LC- MS (ES, m/z) C, 5H₂oBrN0₃: 342; Found: 343 [M+H]⁺.

Intermediate 38

ethyl fran5^,-4-(5-bromopyridin-2-yloxy)-l -methylcyclohexanecarboxylate

ethyl m-4-(5-bromopyridin-2-yloxy)- 1 -methylcyclohexanecarboxylate

The two isomers in Intermediate 37 were separated by SFC HPLC on chiralpak AD, 21x250mm, 5%EtOH/C0₂, 70ml/min, lOOmg/ml in MeOH to afford ethyl trans-A- (5-bromopyridin-2-yloxy)-l -methylcyclohexanecarboxylate (RT = 5.31 min) and ethyl c«-4-(5-bromopyridin-2-yloxy)-l -methylcyclohexanecarboxylate (RT = 7.64 min.

Intermediate 39

Ethyl c -4-{j5-(3-fluoro-4-formylphenynpyridin-2-ylloxy}-l - methylcyclohexanecarboxylate

Step A: Ethyl c -l -methyl-4-( [5-(4.4.5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin-2- yl1oxy)cyclohexanecarboxylate

In the same procedure as Intermediate 12, ethyl c _?-l -methyl-4-{[5-(4,4,5,5- tetramethyI-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}cyclohexanecarboxylate. LC-MS (ES, m/z): Ci_SH₂oBrN0₃: 342; Found: 344 [M+H]⁺.

Step B: Ethyl cis-4- { [5-(^"3-fluoro-4-formylphenyl)pyridin-2-yl1oxy } - 1 -methylcyclo hexanecarboxylate

A solution of ethyl cw-l-methyl-4-{[5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)pyridin-2-yl]oxy}cyclohexanecarboxylate (580 mg, 1.695 mmol) in DMF (7 ml) was added 3-fluoro-4-formylphenyl boronic acid (3 13 mg, 1.864 mmol) and PdC12(dppf)- CH2C12Adduct (69.2 mg, 0.085 mmol) in 40 mL vial. The mixture was degassed, and filled with N₂ for several times, then capped and heat at 80 °C for 16 hr under N₂. . The reaction was quenched with EtOAc, followed with added H₂0. The layers were separated. The organics was dried over MgS04 and concentrated. The residue was purified by MPLC (40% EtOAc/Hexane) to afford ethyl c s-4-{[5-(3-fluoro-4-formylphenyI)pyridin- 2-yl]oxy}-l -methylcyclo hexanecarboxylate. LC-MS (ES, m/z): C₂₂H₂₄FN0₄: 385;

Found: 386 [M+H]⁺.

Intermediate 40

Ethyl ^^^-{[S^-fluoro^-formylphenyDpyridin^-yljoxy}- !- methylcyclohexanecarboxylate

In the same procedure as Intermediate 39, ethyl trara-4-{[5-(3-fluoro-4- formylphenyl)pyridin-2-yl]oxy}- l -methylcyclohexanecarboxylate was prepared. LC-MS (Es, m/z): C₂₂H₂4FN0₄: 385; Found: 386 [M+H]⁺.

Intermediate 41

Ethyl-4-[(5-formyl-2,3'-bipyridin-6'-yl)oxyl-l-methylcyclohexanecarboxylate

Step A: Ethyl - 1 -methyl-4-{(^"5-(4,4,5,5-tetramethyl- 1.3,2-dioxaborolan-2-y0pyridin-2- ylloxylcyclohexanecarboxylate

To a 250 mL round bottom flask at - 78°C, diisopropylamine (5.21 ml, 36.6 mmol) in THF (20 mL) was added n-butyl lithium (12.19 ml, 30.5 mmol) drop wise under N₂. The mixture was stirred for 20 min, warmed to 0°C for 10 min to make sure LDA was formed. Then ethyl c«-4-[(5-bromopyridin-2-yl)oxy]-l - methylcyclohexanecarboxylate (5 g, 15.23 mmol) in THF (30 min) was slowly added to the fresh made LDA at - 78°C. After 30 mins, iodomethane (2.381 ml, 38.1 mmol) was added to the mixture. The reaction was continnue to stir at -78°C for 2 hr. LC-MS showed completion. Quenched with NH4C1 sat., and stirred for 10 min., diluted with EtOAc/H₂0, the layers were separated. The aqueous layer was washed with EtOAc (x2), and the combined organics dried (MgS0₄) and concentrated. The residue was purified by MPLC (0-20% EtOAc/Hexane). LC-MS (ES, m/z): C₂₁H₃₂BrN0₅: 389; Found: [M+H]⁺.

Step B: Ethyl-4-[(5-formyl-2,3'-bipyridin-6'-yl)oxy1-l-methylcyclohexanecarboxylate

In the same procedure as Intermediate 39 step B, ethyl-4-[(5-formyl-2,3'- bipyridin-6'-yl)oxy]- l -methylcyclohexanecarboxylate was prepared. LC-MS (Es, m/z): C₂₁H₂₄N₂0₄: 368; Found: 369 [M+ H]⁺.

Intermediate 42

Ethyl m-4-[(5-formyl-2,3'-bipyridin-6'-yl)oxy|-l -methylcyclohexanecarboxylate

Ethyl-4-[(5-formyl-2,3'-bipyridin-6'-yl)oxy]- l-methylcyclohexanecarboxylate was resolved by chiral separation with AD column, 21x250mm, 25 %EtOH+/C02, 50ml/min, 100 bar, 35C, 50mg/ml in MeOH, 220 nM to give the first eluting isomer ethyl cis-4-[(5-formyl-2,3'-bipyridin-6'-yl)oxy]-l -methylcyclohexanecarboxylate (RT = 7.07 min). LC-MS (Es, m/z): C₂₁H₂₄N₂0₄: 368; Found: 369 [M+ H]⁺.

Intermediate 43

Ethyl rranj--4-[(5-formyl-2,3'-bipyridin-6'-yl)oxyl-l -methylcyclohexanecarboxylate

In the same procedure as Intermediate 42, ethyl trans-4-[(5-formyl-2,3'-bipyridin- 6'-yl)oxy]- l -methylcyclohexanecarboxylate was prepared as slow eluting isomer (RT = 1 1.52 min). LC-MS (Es, m/z): C₂,H₂₄N₂0₄: 368; Found: 369 [M+ H]⁺.

Intermediate 44

trans-benzyl 3-(5-(3-fluoro-4-(5-fluoro-lH-benzord1imidazol-2-vnphenyl)pyridin-2- yloxy)cvclobutanecarboxylate

Step A: benzyl 3-oxocyclobutanecarboxylate

To a mixture of 3-oxocyclobutanecarboxylic acid (175 mmol) and TEA (20.4 g, 202 mmol) in DCM (300 ml) at 0°C added benzyl chloroformate (3 1.4 g, 184 mmol) slowly. After the addition, DMAP (2.14 g, 17.53 mmol) added. The reaction mixture stirred at 0°C for one hour. Then concentrated under vacuum to get 35.8 g (100%) of benzyl 3-oxocyclobutanecarboxylate as colorless oil. LC-MS (ES, m/z) C12H12O3 : 204; Found: 205 [M+H]⁺.

Step B: trans-benzyl 3-hydroxycyclobutanecarboxylate and cis-benzyl 3- hydroxycyclobutanecarboxylate and cis benzyl 3-hydroxycyclobutanecarboxylate and cis-benzyl 3-hydroxycvclobutanecarboxylate

To a solution of benzyl 3-oxocyclobutanecarboxylate (17.9 g, 88 mmol) in MeOH (150 ml) at 0°C added sodium borohydride (3.32 g, 88 mmol) slowly. After addition, the reaction mixture was allowed slowly warm up to room temperature. After stirred for one hour, the reaction quenched with ice, extracted with 3x60 ml ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. Then applied onto a silica gel column and eluted with ethyl

acetate/hexane 0-100%. This resulted in 8.5 g (47%) of benzyl 3

hydroxycyclobutanecarboxylate as colorless oil. Then separated by ChiralPak AY-20um (300x20mmI.D). Mobile phase: A for SFC C0₂ and B for isopropanol, gradient 10% B. This result in trans-benzyl 3-hydroxycyclobutanecarboxylate (4g, Rt = 3.51 min). LC-MS (ES, m/z) C, 2H ₁₄0₃: 206; Found: 207[M+H]⁺, cis-benzyl 3- hydroxycyclobutanecarboxylate (361 mg, 2.83 min). LC-MS (ES, m/z) Ci₂Hi₄0₃: 206; Found: 207[M+H]⁺

Step C: trans-benzyl 3-(5-bromopyridin-2-yloxy)cyclobutanecarboxylate To a mixture of 5-bromopyridin-2-ol (1.69 g, 9.7 mmol), trans-benzyl 3- hydroxycyclobutanecarboxylate (13.61 g, 79 mmol) and triphenylphosphine (2 g, 9.7 mmol) in THF (50 ml) at room temperature added diisopropyl azodicarboxylate (2.45 g, 12.12 mmol) dropwise, after that, the reaction mixture was stirred overnight a at 55°C for two days under N₂. The reaction mixture was cooled to room temperature, then concentrated under vacuum. The residue was dissolved in 25 ml of ethyl acetate, and then 25 ml hexane added. Stirred over night. The mixture was filtered and concentrated, and then residue was purified by a silica gel column and eluted with ethyl acetate/hexane 0- 50%. This resulted in 2 g (57%) of trans-benzyl 3-(5-bromopyridin-2- yloxy)cyclobutanecarboxylate as a white solid. LC-MS (ES, m/z) Ci₇Hi₆BrN0₃: 362; Found: 363 [M+H]⁺.

Step D: trans-benzyl 3-(5-(3-fluoro-4-formylphenyl pyridin-2-yloxy)cyclobutane carboxylate

A mixture of trans-benzyl 3-(5-bromopyridin-2- yloxy)cyclobutanecarboxylate (1 g, 2.76 mmol), 3-fluoro-4-formylphenylboronic acid (0.56 g, 3.31 mmol), sodium carbonate (0.59 g, 5.52 mmol) and Pd(PPh₃)₄ (0.19 g, 0.166 mmol) are suspended in DME (12 ml) and water (2.5 ml), The reaction mixture was put into microwave oven at 90°C for 10 minutes. The reaction mixture was cooled to room temperature, water (50 ml) added, extracted with 3x15 ml ethyl acetate. The organic layers were combined, washed with 2 10 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 0-85%. This resulted in 0.67 g (60%) of trans-benzyl 3-(5-(3-fluoro-4-formylphenyl)pyridin-2-yloxy)cyclobutanecarboxylate

as a white solid. LC-MS (ES, m/z) C₂₄H₂₀FNO₄: 405; Found: 406 [M+H]⁺.

Intermediate 45

: cis-benzyl 3-(5-(3-fluoro-4-(5-fluoro- 1 H-benzof d]imidazol-2-yl)phenyl)pyridin-2- yloxy)cyclobutanecarboxylate

In the same procedure as Intermediate 44, cis-benzyl 3-(5-(3-fluoro-4-(5-fluoro- lH-benzo[d]imidazol-2-yl)phenyl)pyridin-2-yloxy)cyclobutanecarboxylate was prepared. LC- S (ES, m/z) C24H20FNO4: 405; Found: 406 [M+H]⁺.

In the same procedure as the preparation of Intermediate 44, using methyl cis or trans 4-hydroxycyclohexylactate and corresponding aldehyde, the following

Intermediates were prepared:

Intermediate 46

methyl {tra» -4-[(5-formyl-2,3'-bipyridin-6'-yl)oxy1cyclohexy acetate

LC-MS (ES, m/z) C20H22N2O4: 354; Found: 355 [M+H]⁺

Intermediate 47

methyl {tra^-4-[(5-formyl-2,3'-bipyridin-6'-yl)oxy1cyclohexyl>acetate

LC-MS (ES, m/z) C20H22N2O4: 354; Found: 355 [M+H]⁺

Intermediate 48

methyl (trans-4-{\ 5-(3-fluoro-4-formylphenyl)pyridin-2-yl1oxy}cvclohexyl)acetate

LC-MS (ES, m/z) C₂,H₂₂FN0₄: 371 ; Found: 372 [M+H]⁺

Intermediate 49 64273

methyl (c? -4-{(^"5-(3-fluoro-4-formylphenyl)pyridin-2-yl1oxy)cvclohexyl)acetate

LC-MS (ES, m/z) C₂,H₂₂FN0₄: 371 ; Found: 372 [M+H]⁺

Intermediate 50

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

Step A: 6'-fluoro-2.3'-bipyridine-5-carbaldehyde

A mixture of (6-fluoropyridin-3-yl) boronic acid (1.515 g, 10.75 mmol), 6- bromopyridine-3-carbaldehyde (2 g, 10.75 mmol), sodium carbonate (2.279 g, 21.5 mmol) and Pd(dppf)Cl2 (0.393 g, 0.538 mmol) are suspended in N,N- Dimethylformamide (10 ml) and water (5 ml), the reaction mixture was stirred over night at 80°C under N₂ in an oil bath. The reaction mixture was cooled to room

temperature, water (20 ml) added, extracted with 3x30 mL ethyl acetate. The organic layers were combined, washed with 2x20 mL of saturated brine, dried over anhydrous sodium sulfate and concentrated under vacuum. Then applied onto a silica gel column and eluted with ethyl acetate/hexane 0-65%. This resulted in 6'-fluoro-2,3'-bipyridine- 5-carbaldehyde as a white solid. LC-MS (ES, m/z) C_nH₇FN₂0: 202; Found: 203

[M+H]⁺.

Step B: 5-(5-chloro-lH-benzimidazol-2-yl)-6'-fluoro-23'-bipyridine

A mixture of 4-chloro-l ,2-phenylenediamine (700 mg, 4.91 mmol), 6'-fluoro-2,3'- bipyridine-5-carbaldehyd (1.092 g, 5.4 mmol) and potassium peroxymonosulfate

( 1.962 g, 3.19 mmol) in DMF (6 ml) and water (0.6 ml) was stirred for 24 hours at room temperature. Then pour into 6 mL 1M K₂C0₃ solution, extracted with 3x30 mL ethyl acetate. The organic layers were combined, washed with 2x15 mL of saturated brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The

residue was purified by a silica gel column and eluted with ethyl acetate/hexane 0-80 %. This resulted in 5-(5-chloro-l H-benzimidazol-2-yl)-6'-fluoro-2,3'-bipyridine as a yelllow solid. LC-MS (ES, m/z) C,₇H_{) 0}C1FN₄: 324; Found: 325 [M+H]⁺. Intermediate 51

Ethyl 2-(3-hydroxycyclobutyl)acetate

Step A

To a suspension of aH (60% in oil, 4.09 g, 102 mmol) in THF (100 mL) was added triethyl phosphonoacetate (25.6 ml, 128 mmol) drop wise at 0°C. The mixture was stirred at 0°C for lh. 3-(benzyloxy)cyclobutanone (15 g, 85 mmol) was added dropwise at 0°C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to -78°C, quenched with sat NaHC0₃ (sat.), and then reaction mixture was warmed to room temperature, diluted with water, extracted with EtOAc, dried over MgS0₄ filtered and concentrated. Purified by MG-III (OJ-H, 50 mm x 250 mm; 10% MeOH/CC>2, 220 mL/min; 100 bar, 35°C, 220 nm; inject volume:

0.30 ml; feed concentration: 100.00 mg/mL in 1 : 1 DCM/MeOH; Dissolved in MeOH / DCM 1 : 1 , 245.00 ml ) to give Ethyl 2-(3-(benzyloxy)cyclobutylidene)acetate as brown liquid (24.5 g). LC-MS (ES, m/z) C₁₅H₁₈0₃: 246; Found: 247 [M+H]⁺

Step B

To the solution of ethyl 2-(3-(benzyloxy)cyclobutylidene)acetate (5.4 g, 21.92 mmol) in MeOH (100 ml) was added Pd(OH)₂/C (Pearlman's catalyst, 1.08 g) and then hydrogenated under 45 psLfor 18 hr. .Catalyst was filtered through celite, washed with MeOH, filtrate was concentrated, and residue was separated by column (10-100% EtOAc in hexane) to give ethyl 2-(3-hydroxycyclobutyl)acetate (3.0 g) as colorless liquid. LC- MS (ES, m/z) C₈Hi₄0₃: 158; Found: 159 [M+H]⁺

Intermediate 52

Diethyl 3-(5-bromopyridin-2-yloxy cvclobutane-l , l-dicarboxylate Performed following the procedure described in Intermediate 35 staring from 5- Bromo-2(l H)-pyridone and diethyl 3-hydroxycyclobutane-l , l-dicarboxylate (synthesized by a known procedure Avram et al. Chemische Berichte, 1957 , vol. 90, p. 1424, 1427 ) ESI-MS calc. for C 15H18BrN05 : 371.; Found: 372 (M+l).

In the same procedure as the preparation of Intermediate 44, using methyl cis or trans 4-hydroxycyclohexylactate and corresponding aldehyde, the following

Intermediates were prepared:

Intermediate 53

ethyl trans-A- i Γ5 -(3 -fluoro-4-formylphenyl)pyrazin-2-yl1oxy I cyclohexanecarboxylate

LC-MS (ES, m/z) C₂oH₂,FN20₄: 372; Found: 373 [M+H]⁺

Intermediate 54

ethyl c^-4-{ r5-(3-fluoro-4-formylphenyl)pyrazin-2-vnoxy>cvclohexanecarboxylate

LC-MS (ES, m/z) C₂₀H₂₁FN2O₄: 372; Found: 373 [M+H]⁺

Intermediate 55

methyl (^r ^-4-{ [5-(3-fluoro-4-formylphenyl)pyrazin-2-ylloxy)cyclohexynacetate

LC-MS (ES, m/z) C₂₀H₂₁FN2O₄: 372; Found: 373 [M+H]⁺ Intermediate 56

methyl (cis-A- { [5 -(3 -fluoro-4-formylphen vDpyrazin-2-νΠ oxy } cyclohexyQacetate

LC-MS (ES, m/z) C₂₀H₂₁FN2O₄: 372; Found: 373 [M+H]⁺

Intermediate 57

methyl (tro^-4-( r5-(5-formylpyrazin-2-yl)pyridin-2-ylloxy}cvclohexyl)acetate

LC-MS (ES, m/z) C,₉H₂iN₃0₄: 355; Found: 356 [M+H]⁺

Intermediate 58

methyl (c .y-4-[('5-formyl-4-methyl-2₁3'-bipyridin-6'-ynoxy1cyclohexyU acetate

LC-MS (ES, m/z) C2iH₂4N₂0₄: 368; Found: 369 [M+H]⁺

Intermediate 59

methyl {c;^' -4-[(5-formyl-3-methyl

LC-MS (ES, m/z) C₂₁H₂₄N₂0₄: 368; Found: 369 [M+H]⁺

Intermediate 60

methyl c/ -3-li5-(3-fluoro-4-formylphenynpyrimidin-2-yl1oxy)cyclobutanecarboxylate LC-MS (ES, m/z) C₁₇H₁₅N₂0₄: 330; Found: 330 [M+H]

Intermediate 61

methyl m^.y-4- (5-formyl-5'-methyl-2,3'-bipyridin-6'-ynoxy1cvclohexyl|acetate

LC-MS (ES, m/z) C₂₁H₂₄N₂0₄: 368; Found: 369 [M+H]⁺

Example 1

4-(5-(4-(4.6-difluoro-lH-benzo[d1imidazol-2-yl)-3-fluorophenynpyridin-2- yloxy^bicyclo^^^loctane-l -carboxylic acid

General method A: To a solution of 4-(5-(3-fluoro-4-formylphenyl)pyridin-2- yloxy)bicyclo[2.2.2]octane-l -carboxylic acid (Intermediate 1 , 35 mg, 0.095 mmol, 1 equiv) and 3,5-difluorobenzene-l ,2-diamine (28 mg, 0.191 mmol, 2.0 equiv) in 2%

HOAc/DMF (1.5 mL) was added Oxone (58 mg, 0.095 mmol, 1 equiv). The reaction was agitated at 80 °C for 16 hours at which point it was complete by LCMS analysis. The solution was neutralized with K2CO3 (60 mg) and was extracted between EtOAc (4 mL x 2) and water (2 mL). The organic phase was combined and evaporated under vacuum. DMSO (1.5 mL) was added to the residue. The crude product was purified with reversed- phase HPLC (Gilson, ACN with 0.05% TFA / H₂0 with 0.05% TFA: 10% ~ 80%) to give the product as a yellow solid. LCMS calc'd [MH]⁺ m/z 494; found m/z 494.

Example 2-10 were prepared according to a similar method as Example 1.

Exampe 1 1

4-(5-(3-fluoro-4-(5-methoxy-lH-imidazo[4,5-b1pyridin-2-yl^')phenyl^')pyridin-2-

Step A. Methyl 4-(5-(3-fluoro-4-formylphenyl)pyrimidin-2-yloxy)bicyclo[2.2.2]octane- 1-carboxylate (20 mg, 0.052 mmol, 1 equiv), the b ^-hydrochloride salt of 6- methoxypyrimidine-2,3 -diamine (1 1.1 mg, 0.052 mmol, 1 equiv) and Oxone (22.5 mg, 0.037 mmol, 0.7 equiv) were weighed to a vial then suspended in DMF (500 μΐ,) and stirred at room temperature for 4 hours at which point the reaction was complete as indicated by LCMS analysis. Solid potassium carbonate (7.2 mg, 0.052 mmol, 1 equiv) was added and the mixture diluted with 40% acetonitrile in water, filtered, and purified by preparative reverse phase HPLC on a 30 x 100 mm SunFire C I 8 column with a gradient of 20% to 70% acetonitrile in water containing 0.05% TFA. This gave the TFA salt of the title compound as a white solid: LCMS calc'd [MH]⁺ m/z 503; found m/z 503.

Step B. To the ester from Step 1 (1 1 mg, 0.022 mmol, 1 equiv) in THF (0.1 mL), methanol (0.1 mL) and water (0.1 mL) was added solid lithium hydroxide (5.2 mg, 0.219 mmol, 10 equiv) and the mixture heated at 50 °C for 1 hour at which point the reaction was complete as judged by LCMS analysis. The mixture was cooled to room

temperature and acidified to pH 2 with 1 M aqueous hydrochloric acid then diluted with 40% acetonitrile in water, filtered and purified by preparative reverse phase HPLC on a 30 x 100 mm SunFire C I 8 column with a gradient of 20% to 70% acetonitrile in water containing 0.05% TFA. This gave the TFA salt of the title compound as a white solid: LCMS calc'd [MH]⁺ m/z 489; found m/z 489.

Example 12

4-(5 -(3 -fluoro-4-(6-(trifluoromethyl)- 1 H-benzo \d] imidazol-2-y l)phenyl)pyridin-2-

Step A. To a vial were added methyl 4-(5-iodopyridin-2-yloxy)bicyclo[2.2.2]octane-l - carboxylate (18 mg, 0.046 mmol, 1 equiv), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)phenyl)-6-(trifluoromethyl)-lH-benzo[d]imidazole (19 mg, 0.046 mmol, 1 equiv) and the XPhos based palladium precatalyst (1.8 mg, 2.3 μιηοΐ, 5 mol%) described in: Tom Kinzel, Yong Zhang, Stephen L. Buchwald J. Am. Chem. Soc. 2010, 132 (40), 14073-14075. The vial was capped under nitrogen and THF (0.5 mL) and 1.0 M aqueous potassium phosphate (0.139 mL, 0.139 mmol, 3 equiv) were added. The mixture was heated at 80 ^°C under nitrogen for 4.5 hours at which point LCMS analysis indicated it was complete. The mixture was poured into ethyl acetate and washed with water then dried on sodium sulfate, filtered and concentrated in vacuo. The residue was taken up in DMSO, filtered, and purified by preparative reverse phase HPLC on a 30 x 100 mm SunFire CI 8 column with a gradient of 20% to 70% acetonitrile in water containing 0.05% TFA. This gave the TFA salt of the title compound as a pale yellow film: LCMS calc'd [MH]⁺ m/z 540; found m/z 540.

Step B. To the ester from Step A (20.4 mg, 0.031 mmol, 1 equiv) in THF (1 mL) was added 0.25 M lithium hydroxide (1 mL, 0.25 mmol, 8 equiv) and the mixture heated at 50 °C for 3 hours at which point the reaction was complete as judged by LCMS analysis. The excess base was quenched by addition of acetic acid (0.2 mL) and the mixture concentrated in vacuo. The residue was taken up in DMSO, filtered, and purified by preparative reverse phase HPLC on a 30 x 100 mm SunFire CI 8 column with a gradient of 20% to 70% acetonitrile in water containing 0.05% TFA. This gave the TFA salt of the title compound as a white solid: LCMS calc'd [MH]⁺ m/z 526; found m/z 526.

Example 13

4-(^,5-(3-fluoro-4-(6-fluoro-lH-benzo[d1imidazol-2-yl)phenyl)pyridin-2- yloxy)bicyclo(^"2.2.2]octane-l-carboxylic acid

Prepared according to a similar method but using 6-fluoro-2-(2-fluoro-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-lH-benzo[d]imidazole as the boronic ester in the Suzuki coupling step.

Example 14:

4-(5-f3-fluoro-4-(6-fluoro-lH-benzord]imidazol-2-yl)phenyl)pyrimidin-2- yloxy)bicyclor2.2.2]octane- 1 -carboxylic acid

Step A. Methyl 4-(5-(3 -fl uoro-4-formy lpheny l)pyrimidin-2-y loxy)bicyclo [2.2.2]octane- 1-carboxylate (Intermediate 2, 30 mg, 0.078 mmol, 1 equiv), 4-fiuorobenzene-l ,2- diamine (9.8 mg, 0.078 mmol, 1 equiv) and Oxone (31 mg, 0.051 mmol, 0.65 equiv) were weighed to a vial then suspended in DMF (126 μί) and water (4 μί) and stirred at room temperature for 90 minutes at which point the reaction was complete as indicated by LCMS analysis. Water was added and the mixture was neutralized to pH 7 with solid potassium carbonate which resulted in the formation of a brown precipitate that was collected by filtration. The brown solid was taken up in DMSO, filtered, and purified by preparative reverse phase HPLC on a 30 x 100 mm SunFire CI 8 column with a gradient of 20% to 70% acetonitrile in water containing 0.05% TFA. This gave the TFA salt of the title compound as a white solid: LCMS calc'd [MH]⁺ m/z 491 ; found m/z 491.

Step B. To the ester from Step A (30 mg, 0.050 mmol, 1 equiv) in THF (1 mL) was added 2.5 M lithium hydroxide (0.199 mL, 0.50 mmol, 10 equiv) and the mixture heated at 50 ^°C for 3 hours then at room temperature for 72 hours at which point the reaction was complete as judged by LCMS analysis. The excess base was quenched by addition of acetic acid (0.2 mL) and the mixture concentrated in vacuo. The residue was taken up in DMSO, filtered, and purified by then purified by preparative reverse phase HPLC on a 30 x 100 mm SunFire C I 8 column with a gradient of 10% to 100% acetonitrile in water containing 0.05% TFA. This gave the TFA salt of the title compound as a white solid: LCMS calc'd [MH]⁺ m/z 477; found m/z 477.

Example 15

4-(5-(3-fluoro-4-(6-(trifluoromethyl)-3H-imidazo 4,5-b1pyridin-2-yl)phenyl)pyrimidin-2- yloxy)bicyclo[2.2.21octane-l-carboxylic acid

Step A. Methyl 4-(5-(3-fluoro-4-formylphenyl)pyrimidin-2-yloxy)bicyclo[2.2.2]octane- 1-carboxylate (Intermediate 2, 30 mg, 0.078 mmol, 1 equiv), 5-(trifluorornethyl)pyridine- 2,3-diamine (15.2 mg, 0.086 mmol, 1.1 equiv) and magnesium(II) bromide diethyl etherate (20 mg, 0.078 mmol, 1 equiv) were weighed to a vial then suspended in DMSO (260 μL) stirred at 50 °C for 2.5 hours then Oxone (48 mg, 0.078 mmol, 1 equiv) was added and the mixture stirred at 50 °C overnight. The reaction mixture was diluted with DMSO, filtered, and purified by preparative reverse phase HPLC on a 30 x 100 mm SunFire C I 8 column with a gradient of 20% to 70% acetonitrile in water containing 0.05% TFA. This gave the TFA salt of the title compound as a white solid: LCMS calc'd [MH]⁺ m/z 542; found m/z 542.

Step B. To the ester from Step 1 (15 mg, 0.022 mmol, 1 equiv) in THF (1 mL) was added 0.25 M lithium hydroxide (1.0 mL, 0.25 mmol, 1 1 equiv) and the mixture heated at 50 ^°C for 4 hours at which point the reaction was complete as judged by LCMS analysis. The excess base was quenched by addition of acetic acid (0.3 mL) and the mixture concentrated in vacuo. The residue was taken up in DMSO, filtered, and purified by then purified by preparative reverse phase HPLC on a 30 x 100 mm SunFire C 18 column with a gradient of 10% to 100% acetonitrile in water containing 0.05% TFA. This gave the TFA salt of the title compound as a white solid: LCMS calc'd [MH]⁺ m/z 528; found m/z 528.

Example 16

Cis-4-(5-(3,5-difluoro-4-(5-(trifluoromethyl)-lH-benzo[(i1imidazol-2-yl)phenyl)pyridin-

2-yloxy)cvclohexanecarboxylic acid.

General Method C: To a dry 5 ml, 2-neck round bottem flask, equipped with a reflux condenser and a stirrer and a N₂ supply, was added sodium hydride (20.34 mg, 0.509 mmol) and then DMA (0.3 ml). The suspension was then cooled to 0 °C and treated with Cis-4-hydroxycyclohexane-carboxylic acid (36.7 mg, 0.254 mmol) dissolved in DMA (0.5 ml) via a syringe. After stirring at room temperature for 10 min, 2-(2,6-difluoro-4-(6- fluoropyridin-3-yl)phenyl)-5-(trifluoromethyl)-lH-benzo[(fJimidazole (100 mg, 0.254 mmol) dissolved in DMA (0.2 ml) was added via a syringe. The mixture was then stirred at 100 °C for 4 h. The reaction was monitored by LC-MS. The mixture was cool to room temperature, diluted with water and the pH adjusted to pH 4 with IN HC1. A cream ppt formed which was filtered off. The resulting solid was then purified on the Mass Directed HPLC (method: 10 to 100 % MeCN / Water w/ 0.05 % TFA on a 30 mm Column). The desired fractions were collected and freeze dry to afford Cis-4-(5-(3,5-difluoro-4-(5- (trifluoromethyl)- lH-benzo[i ]imidazoI-2-yl)phenyl)pyridin-2-yloxy)cyclohexane carboxylic acid. LC-MS (M+l) = 518.

Example 17

Trans-4-(5-(3,5-difluoro-4-(5-(trifluoromethyl^')-lH-benzo[flflimidazol-2- yl phenyl)pyridin-2-yloxy)cycIohexanecarboxylic acid.

Following the procedure described for Example 16 but with Trans-4- hydroxycyclohexane carboxylic acid, Trans-4-(5-(3,5-difluoro-4-(5-(trifluoromethyl)- lH- benzo[i ]imidazol-2-yl)phenyl)pyridin-2-yloxy)cyclohexanecarboxylic acid was afforded as a cream solid. LC-MS (M+l) = 518.

Example 18

Cis-4-(5-(4-(5-chloro- lH-benzo[cflimidazol-2-yl)-3,5-difluorophenyl)pyridin-2- yloxy)cyclohexanecarboxylic acid.

Following the procedure described for Example 16, but with Intermediate 15, 3,

5-chloro-2-(2,6-difluoro-4-(6-fluoropyridin-3-yl)phenyl)-lH-benzo[i ]imidazole was afforded Cis-4-(5-(4-(5-chloro-lH-benzo[ ]imidazol-2-yl)-3,5-difluorophenyl)pyridin-2- yloxy)cyclohexanecarboxylic acid as a cream solid. LC-MS (M+l) = 484. Example 19

Cis-4-(5-(4-(lH-benzor(ilimida2ol-2-yl)-3,5-difluorophenyl^')pyridin-2- yloxy)cvclohexanecarboxylic acid

Cis-ethyl 4-(5-(4-( lH-benzo[6nimidazol-2-yl)-3,5-difluorophenynpyridin-2- yloxy)cyclohexanecarboxylate

Following the procedure described for Example 1, Step A, but using benzene- 1,2- diamine and the aldehyde Intermediate 14, the title compound Cis-ethyl 4-(5-(4-(lH- benzo[(/]imidazol-2-yl)-3,5-difluorophenyl)pyridin-2-yloxy)cyclohexanecarboxylate was afforded. LC-MS (M+ l) = 477.

C is-4-(5 -(4-( 1 H-benzo\d] imidazol -2-yl)-3 , 5 -difluorophenyOpyridin-2- yloxy)cyclohexanecarboxylic acid

Step 2. To a mixture of Cis-ethyl 4-(5-(4-(lH-benzo[i/]imidazol-2-yl)-3,5- difluorophenyl) pyridin-2-yloxy)cyclohexanecarboxylate, (55 mg, 0.1 15 mmol) and Lithum Hydroxide (38.7 mg, 0.921 mmol, dissloved in water) was added THF (1.5 ml) and MeOH (0.75 ml) and the mixture stirred at room temerature for 3 h. The solvent was evaporated and the resulting solid treated with water 1.5 ml and acidified (pH =6) with IN HC1. The water was evaporated the residue dissloved in DMSO and purifed on the Reverse Phase Mass Directed HPLC (method : 20 to 80 % MeCN / H20 w/ 0.05 % TFA on a 30 xlOO mm, 5 micron, Waters SunFire RP C-18 column). After lyophilization of the desired fractions, 52 mg of Cis-4-(5-(4-(lH-benzo[i ]imidazol-2-yl)-3,5- difluoropheny])pyridin-2-yloxy)cyclohexanecarboxylic acid_was afforded as a white solid. LC-MS (M+ 1) 450.

Example 20

Cis-4-(5-(3,5-difluoro-4-(5-fluoro-lH-benzo[t/|imidazol-2-ynphenyl)pyridin-2- yloxy)cyclohexanecarboxylic acid.

Step 1.

Cis-ethyl 4-(5-(3,5-difluoro-4-(5-fluoro-lH-benzo|^"(/|imidazol-2-yl phenyl)pyridin-2- yloxy)cyclohexanecarboxylate.

Following the procedure described for Example 1, Step A, but using 4- fluorobenzene-l ,2-diamine and the aldehyde Intermediate 14, Cis-ethyl 4-(5-(3,5- difluoro-4-(5-fluoro-lH-benzo[< ]imidazol-2-yl)phenyl)pyridin-2- yloxy)cyclohexanecarboxylate was afforded. LC-MS (M+ l) = 496.

Cis^-CS-O.S-difluoro^-CS-fluoro-lH-benzof^imidazol^-yDphenyDpyridin^- yloxykvclohexanecarboxylic acid.

Step 2.

Following the procedure described in Step 2, Example 19, but with Cis-ethyl 4-(5-(3,5- difluoro-4-(5-fluoro- lH-benzo[<f]imidazol-2-yl)phenyl)pyridin-2-yloxy)cyclohexane carboxylate from Step 1 , Cis-4-(5-(3,5-difluoro-4-(5-fluoro-lH-benzo[<i]imidazol-2- yl)phenyl)pyridin-2-yloxy)cyclohexanecarboxylic acid was afforded as a white solid. LC-MS (M+l) 468.

Example 21

Cis-4-(5-(3,5-difluoro-4-(5-cyano-lH-benzo ( |imidazol-2-yl)phenyl)pyridiri-2- yloxy)cyclohexanecarboxylic acid.

Cis-ethyl 4-( 5-(3.5-dinuoro-4-(^'5-cyano- lH-benzo[<¾^r|imidazol-2-yl^')pheriyl)pyridin-2- yloxy yclohexanecarboxylate.

Following the procedure described for Example 1 , Step A, but using 3,4-diamino- benzonitrile and the aldehyde Intermediate 14, Cis-ethyl 4-(5-(3,5-difluoro-4-(5-cyano- lH-benzo[tf]imidazol-2-yl)phenyl)pyridin-2-yloxy)cyclohexanecarboxylate was afforded. LC-MS (M+l) = 503.

Cis-4-(5-(3,5-difluoro-4-(5-cyano-lH-benzo 6nimidazol-2-vnphenyl)pyridin-2- y loxy)cyc lohexanecarboxyl ic acid .

Step2

Following the procedure described in Step 2, Examplel9, but with Cis-4-(5-(3,5-difluoro- 4-(5-cyano-lH-benzo[< ]imidazol-2-yl)phenyI)pyridin-2-yloxy)cyclohexanecarboxylic acid from Step 1 , Cis-4-(5-(3,5-difluoro-4-(5-cyano-lH-benzo[c ]imidazol-2- yl)phenyl)pyridin-2-yloxy)cyclohexanecarboxylic acid was afforded as a yellow solid. LC-MS (M+ 1) 475.

Example 22

Cis-ethyl 4-(5-(2.5-difluoro-4-(6-(trifluoromethyl -lH-benzo < limidazol-2- ynphenvnpyridin-2-yloxy)cvclohexanecarboxylate

General method B: In a 20 ml Microwave tube was added Intermediate 6 (1 13 mg, 0.301 mmol), Intermediate 16 ( 100 mg, 0.301 mmol) and Tetrakis (34.7 mg, 0.030 mmol) . Under a N₂ was added DME (1.6 ml) and EtOH (0.8 ml) followed by aqueous sodium carbonate (2 M, 0.451 ml, 0.902 mmol). The mixture irradiated in the Biotage Initiator Microwave for 25 mim at 120 °C. The solvent was evaporated, and the residue diluted with EtOAc and washed with brine and separated. The organic layer was dried (MgS0₄) and concentrated. Purification on the CombiFlash Companion on a 12 g column eluting with 5 to 30 % EtOAc / Hexane afforded 124 mg of Cis-ethyl 4-(5-(2,5-difluoro-4-(6- (trifluoromethyl)-lH-benzo[i/]imidazol-2-yl)phenyl)pyridin-2- yloxy)cyclohexanecarboxylate. LC-MS (M+l) 546.

Example 23

Cis-4-(5-(2,5-difluoro-4-(6-(trifluoromethyn-lH-benzo </limidazol-2-vnphenyl)pyridin-

2-yloxy)cvclohexanecarboxylic acid

Following the procedure described in Step 2, Examplel9, Cis-ethyl 4-(5-(2,5-difluoro-4- (6-(trifluoromethyl)- lH-benzo[i ]imidazol-2-yl)phenyl)pyridin-2-yloxy)cyclohexane carboxylate was hydrolyzed to afford Cis-4-(5-(2,5-difluoro-4-(6-(trifluoromethyl)-lH- benzo[c ]imidazol-2-yl)phenyl)pyridin-2-yloxy)cyclohexanecarboxylic acid

as a white solid. LC-MS (M+l) 518.

Example 24 Cis-4-(3-fluoro-5-(^"6-(trifluoromethyl)-l H-benzo[<f]imidazol-2-yl)-2,3'-bipyridin-6'- yloxy)cyclohexanecarboxylic acid

Step 1.

N-(2-amino-4-(trifluoromethvnphenyl)-5.6-difluoronicotinamide

A solution of 4-(trifiuoromethyl)benzene-l ,2-diamine (980 mg, 5.56 mmol) and 5,6- difluoronicotinic acid (590 mg, 3.71 mmol) in anhydrous DMF (20 ml) was treated with EDC (1066 mg, 5.56 mmol) and ΗΟΒΤ (852 mg, 5.56 mmol) in an N₂ atmosphere. To the stirred solution was added DIEA (0.972 mL, 5.56 mmol) and the mixture stirred at room temperature overnight. The mixture was diluted with EtOAc and H₂0 and the layers separated. The organic phase was washed with H₂0 and brine, dried over Na₂S0₄, filtered and evaporated to give 860 mg of a viscous oil. Purification on the CombiFlash Companion, on a 10 g column eluting with 20-100% EtOAc/ Hexane over 15 CV. to give 660 mg of N-(2-amino-4-(trifluoromethyl)phenyl)-5,6-difluoronicotinamide as a tan solid. LC-MS (M+l) = 318.

Step 2.

3-fluoro-5-(6-(trifluoromethyl)-lH-benzo[6nimidazol-2-yl)pyridin-2-ol

A solution of N-(2-amino-4-(trifluoromethyl)phenyl)-5,6-difluoronicotinamide ( 200 mg, 0.630 mmol) in HOAC (8 mL) under a N₂ atmosphere in a 5 ml microwave tube was irradiated Biotage Microwave Initiator at 180°C for lh. The mixture was dissolved in 4 mL of 40% MeCN-H₂0 and filtered through a 0.45μ filter. Purification on the Mass Directed HPLC (HPLC conditions: column 30x 100 mm, 5μ Waters Sunfire; gradient- 20- 70% MeCN-H20 containing 0.05% TFA, flow 45 mL/min. run time 15 min. Positive ionization) to afford 165 mg of 3-fluoro-5-(6-(trifluoromethyl)-lH-benzo[i ]imidazol-2- yl)pyridin-2-ol. LC-MS (M+ l) = 298.

Step 3

3-fluoro-5-(6-(trifluoromethyn-lH-benzo[( limidazol-2-yl^')pyridin-2-yl

trifluoromethanesulfonate

3-Fluoro-5-(6-(trifluoromethyl)-lH-benzo[ii]imidazol-2-yl)pyridin-2-ol (100 mg, 0.336 mmol) and 2,6-di-tert-butyl-4-methypyridine (76 mg, 0.370 mmol) in a seal microvave tube tube under N₂ was treated with DCM (2.0 ml) followed by TriflicAnhydride (0.060 ml, 0.353 mmol) via a syringe. The mixture was then stirred at room temperature for 2 h. The reaction was quenched with water, diluted with EtOAc and filtered. The filtrate was extracted with EtOAc and the organic layer dried (MgSC^) and concentrated. Purification on the CombiFlash Companion on a 12 g column eluting with 10 to 30 % EtOAc / Hexane afforded 42 mg of 3-fluoro-5-(6-(trifluoromethyl)-l H-benzo[-/]imidazol-2- yl)pyridin-2-yl trifluoromethanesulfonate_as a yellow solid. LC-MS (M+l) 430.

Step 4

Cis-ethyl 4-(3-fluoro-5-(6-(trifluoromethyl)-lH-benzo[c |imidazol-2-vn-2.3'-bipyridin-6'- yloxy)cyclohexanecarboxylate

Following the synthesis described for Example 22 but with 3-fluoro-5-(6- (trifluoromethyl)-lH-benzo[i/]imidazol-2-yl)pyridin-2-yl trifluoromethanesulfonate from Step 3 was used, Cis-ethyl 4-(3-fluoro-5-(6-(trifluoromethyl)-lH-benzo[i ]imidazol-2-yl)- 2,3'-bipyridin-6'-yloxy)cyclohexanecarboxylate was afforded. LC-MS (M+l) = 529.

Step 5

Cis-4-i3-fluoro-5-f6-(trifluorometh^

yloxy)cyclohexanecarboxylic acid

Following the procedure described in Step 2, Examplel9, Cis-ethyl 4-(3-fluoro-5-(6- (trifluoromethyl)-lH-benzo[i/]irnidazol-2-yl)-2,3'-bipyridin-6'-yloxy)cyclohexane carboxylate was hydrolyzed to afford Cis-4-(3-fluoro-5-(6-(trifluoromethyl)-lH- benzo[<i]imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)cyclohexanecarboxylic acid as a yellow solid. LC-MS (M+l) = 501.

Example 25

Trans-4-(5-(2,5-difluoro-4-(6-(trifluoromethyl)-lH-benzo i1imidazol-2- yl)phenyl)pyridin-2-yloxy)cyclohexanecarboxylic acid

Trans-ethyl 4-(5-(2,5-difluoro-4-(6-(trifluoromethyn-lH-benzo flnimidazol-2- yl)phenyl pyridin-2-yloxy cvclohexanecarboxylate

Following the synthesis described for Example 22, using Intermediate 5 and

Intermediate 16, trans-ethyl 4-(5-(2,5-difluoro-4-(6-(trifluoromethyl)-lH- benzo[i/]imidazol-2-yl)phenyl)pyridin-2-yloxy)cyclohexanecarboxylate was prepared. LC-MS (M+l) = 546.

Step 2.

Trans-4-(5-(2,5-difluoro-4-(6-(trifluoromethyl)-lH-benzo[rf]imidazol-2- v0pheny0pyridin-2-yloxy)cyclohexanecarboxylic acid

Following the procedure described in Step 2, Example 19, trans-ethyl 4-(5-(2,5-difluoro- 4-(6-(trifluoromethyl)-lH-benzo[i/]imidazol-2-yl)phenyl)pyridin-2-yloxy)cyclohexane carboxylate was hydrolyzed to afford Trans-4-(5-(2,5-difluoro-4-(6-(trifluoromethyl)-lH- benzo[i ]imidazol-2-yl)phenyl)pyridin-2-yloxy)cyclohexanecarboxyIic acid

as a white solid. LC-MS (M+l) 518.

Example 26

Cis^-fS-^.S-difluoro^-OH-imidazo .S-^lpyridin^-ynphenynpyridin^- yloxy)cvclohexanecarboxylic acid

Cis-ethyl 4-(5-(2.5-difluoro-4-(3H-imidazor4,5-61pyridin-2-vnphenvnpyridin-2- yloxy)cyclohexanecarboxylate

Following the procedure described in Example 22, but using Intermediate 17, Cis-ethyl 4-(5-(2,5-difluoro-4-(3H-imidazo[4,5-6]pyridin-2-yl)phenyl)pyridin-2-yloxy)cyclo hexanecarboxylate_was prepared. LC-MS (M+l ) = 478.

Step 2.

Cis-4-(5-(2,5-difluoro-4-(3H-imidazo[4,5-61pyridin-2-yl)phenyl)pyridin-2- yloxy)cyclohexanecarboxylic acid

Following the procedure described in Step 2, Example 19 Cis-ethyl 4-(5-(2,5-difluoro-4- (3H-imidazo[4,5-6]pyridin-2-yl)phenyl)pyridin-2-yloxy)cyclo hexanecarboxylate was hydrolyzed to afford Cis-4-(5-(2,5-difluoro-4-(3H-imidazo[4,5-0]pyridin-2- yl)phenyl)pyridin-2-yloxy)cyclohexanecarboxylic acid. LC-MS (M+l) 45 1. Example 27

Cis-4-(5-(6-(6-(trifluoromethyl)-lH-benzo[ ]imidazol-2-yl pyridazin-3-yl)pyridin-2- yloxy)cyclohexanecarboxylic acid

Step 1.

Cis-ethyl 4-(5-(^f6-formylpyridazin-3-yl)pyridin-2-yloxy)cyclohexanecarboxylate

Following the synthesis described for intermedaite 14, but with the 6-chloropyridazine-3- carbaldehyde Cis-ethyl 4-(5-(6-formylpyridazin-3-yl)pyridin-2-yloxy)cyclohexane carboxylate was prepared. LC-MS (M+1+H₂0) = 374.

Step 2.

Cis-ethyl 4-(5-(6-(6-(trifluoromethyl)-lH-benzo[(^limidazol-2-yl)pyridazin-3-yl)pyridin-

2-yloxy^')cyclohexanecarboxylate

Following the general procedure described for the synthesis of Example 1 , but using the Cis-ethyl 4-(5-(6-formylpyridazin-3-yl)pyridin-2-yloxy)cyclohexane carboxylate from Step 1, and 4-trifluoromethyl-l,2-benzidiamine, Cis-ethyl 4-(5-(6-(6-(trifluoromethyl)- lH-benzo[i ]imidazol-2-yl)pyridazin-3-yl)pyridin-2-yloxy)cyclohexanecarboxylate was prepared. LC-MS (M+l) = 512.

Step 3.

Cis-4-(5-(6-(6-(trifluoromethyl)-lH-benzo[( ]imidazol-2-yl)pyridazin-3-yl)pyridin-2- yloxy)cyclohexanecarboxylic acid

Following the procedure described in Step 2, Example 19 m-ethyl 4-(5-(6-(6- (trifluoromethyl)-lH-benzo[cilimidazol-2-yl)pyridazin-3-yl)pyridin-2- yloxy)cyclohexanecarboxylate was hydrolyzed to afford Cis-4-(5-(6-(6-(trifluoromethyl)- lH-benzo[ ]imidazol-2-yl)pyridazin-3-yl)pyridin-2-yloxy)cyclohexanecarboxylic acid. LC-MS (M+l) 484.

3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH-benzord]imidazol-2-ynphenynpyrimidin-2- yloxy)cyclobutanecarboxylic acid

Step A: ethyl 3-(5-(3-fluoro-4-(5-(trifluoromethvn-lH-benzo[dlimidazol-2- y0phenyl)pyrimidin-2-yloxy)cyclobutanecarboxylate

To a mixture of 2-(2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-5-(trifluoromethyl)-lH-benzo[d]imidazole (0.5 g, 1.33 mmol, 1.00 equiv), ethyl 3-(5-bromopyrimidin-2-yloxy)cyclobutanecarboxylate (0.541 g, 2.66 mmol, 2.00 equiv), tetrakis (0.231 g, 0.2 mmol, 0.15 equiv) and Na₂C0₃ (2.66 mL, 2.0 M, 4.0 equiv) was added DME (13.0 mL)/EtOH (8.0 mL). The reaction mixture was degassed and purged with nitrogen with stirring for 10 min followed by MW at 120 °C for 20 min. Solvent evaporated and mixture diluted with water and extracted 3x with EtOAc. The organic layers were combined, dried over MgS0₄ and concentrated in vacuo. The residue was purified by eluting through a silica gel column with a 0-70% EtOAc/Hexane solvent system to provide product ethyl 3-(5-(3-fluoro-4-(5-(trifluoromethyl)-l H- benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-yloxy)cyclobutanecarboxylate. LC-MS (ES, m/z) C₂₅H₂oF₄N₄03: 500; Found: 501 [M+H]⁺.

Step B: 3-(5-i3-fluoro-4-(5-(trifluoromethvn-lH-benzord1imidazol-2- yl)phenyl)pyrimidin-2-yloxy)cyclobutanecarboxylic acid

To a 50 ml vial was added LiOH (0.024 g, 0.999 mmol, 5.0 equiv) dissolved in H₂0 (1.0 mL), among with ethyl 3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH- benzo[d]imidazol-2-yI)phenyl)pyrimidin-2-yloxy)cyclobutanecarboxylate (0.1 g, 0.2 mmol, 1.0 equiv) in THF (2.0 mL) and MeOH (1.0 mL). The reaction mixture was stirred at 80° C for 20 min. The mixture was acidified with cone. HC1 to pH=4 and purified by RP HPLC with loading as a solution of DMSO:H20:ACN, 20 to 80% ACN in H₂0 to give 3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl)phenyl)pyrimidin-2-yloxy)cyclobutanecarboxylic acid. LC-MS (ES, m/z)

C₂3H₁₆F₄N₄03 : 472; Found: 473[M+H]⁺.

Example 29

Cis-3-(5-(3-fluoro-4-(5-itrifluoromethyl)-lH-benzo limidazol-2-yl)phenynpyrimidin-2- yloxyVN-methoxycyclobutanecarboxamide.

A solution of 3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl)phenyl)pyrimidin-2-yloxy)cyclobutanecarboxylic acid and HATU (62.2 mg, 0.159 mmol) in DMF (0.5 ml) was treated with TEA (0.044 ml, 0.318 mmol) and the mixture stirred at 25 °C for 20 min. O-methylhydroxylamine hydrochloride (17.68 mg, 0.212 mmol) was then added and the mixture stirred at 25 °C for 2 h. The mixture was diluted with EtOAc and extracted with water (x2). The organic layer was washed with Brine, dried (MgS0₄) and concentrated. Trituration from ether / hexane followed by filtration afforded 16 mg of cis-3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH-benzo[i ]imidazol-2- yl)phenyl)pyrimidin-2-yloxy)-N-methoxycyclobutanecarboxamide as a white crystalline solid. LC-MS (M+l) = 502.

Example 30

Step A: Ethyl 3 -(5 -(4-( 1 H-benzo \d] imidazol-2-ylV 3 -fluorophenyl)pyrimidin-2- yloxy)cyclobutanecarboxylate

To a flask was added solution of the corresponding benzene- 1,2-diamine (22.71 mmol, 1.1 eq) in DMF /H₂0 ( 0.1 M), OXONE (9.77g, 1 .9 mmol), followed by ethyl 3- (5-(3-fluoro-4-formylphenyl)pyrimidin-2-yloxy)cyclobutanecarboxylate (24.98 mmol, 1.0 eq) slowly. The mixture was then stirred at room temperature for 1 :30 hr, quenched with a 1 M solution K2C03 and water. The resulting mixture was stirred for 5 min, diluted with water and extracted with EtOAc 3x. The combined organic layers were dried over Mg2S04, filtered and concentrated in vacuo. The residue was purified by eluting through a silica gel column with a 0-100% EtOAc/Hexane solvent system to provide corresponding product ethyl 3-(5-(4-(lH-benzo[d]imidazol-2-yl)-3-fluorophenyl) pyrimidin-2-yloxy)cyclobutanecarboxylate. C24H22F 4O3 : 432, Found: 433 [M+H]⁺

StepB: 3-(5-(4-(lH-benzo(^"dlimidazol-2-yl)-3-fluorophenyl)pyrimidin-2- yloxy)cyclobutanecarboxylic acid

To a 50 ml vial was added LiOH (0.999 mmol, 5.0 equiv) dissolved in H20 (1.0 mL), among with appropriate ester (0.2 mmol, 1.0 equiv) in THF (2.0 mL) and MeOH (1.0 mL). The reaction mixture was stirred at room temperature for 120 min. The mixture was acidified with cone. HC1 to pH=4 and purified by RP HPLC with loading as a solution of DMSO:H20:ACN, 20 to 80% ACN in H₂0 to give product 3-(5-(4-(lH- benzo[d]imidazol-2-yl)-3-fluorophenyl)pyrimidin-2-yloxy)cyclobutanecarboxylic acid. C₂₂H₁₇FN₄0₃: 404, Found: 405 [M+H]⁺.

Using the same procedure for the preparation of Example 30, the following 12 064273

compounds were re ared

Example 34

Cis 3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH-benzord1imidazol-2-yl)phenvnpyrimidin-2- yloxy^")cyclobutanecarboxylic acid

Step A: ethyl 3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH-benzo[dlimidazol-2-yl)phenyl) pyrimidin-2-yloxy)cyclobutanecarboxylate

To a mixture of 2-(2-fluoro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)phenyl)-5-(trifluoromethyl)-lH-benzo[d]imidazole (0.5 g, 1.33 mmol, 1.00 equiv), ethyl cis 3-(5-bromopyrimidin-2-yloxy)cyclobutanecarboxylate (Intermediate 23, 0.541 g, 2.66 mmol, 2.00 equiv), tetrakis (0.231 g, 0.2 mmol, 0.15 equiv) and Na₂C0₃ (2.66 mL, 2.0 M, 4.0 equiv) was added DME (13.0 mL)/EtOH (8.0 mL). The reaction mixture was degassed and purged with nitrogen with stirring for 10 min followed by MW at 120 °C for 20 min. Solvent evaporated and mixture diluted with water and extracted 3x with EtOAc. The organic layers were combined, dried over MgS0₄ and concentrated in vacuo. The residue was purified by eluting through a silica gel column with a 0-70% EtOAc/Hexane solvent system to provide product ethyl cis 3-(5-(3-fluoro-4-(5- (trifluoromethyl)- 1 H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2- yloxy)cyclobutanecarboxylate. LC-MS (ES, m/z) C25H20F4N4O3: 500; Found: 501 [M+H]⁺.

Step B: m-3-(5-f3-fluoro-4-(5-ftrifluoromethyn-lH-benzo[dlimidazol-2-ynphenyl) pyrimidin-2-yloxy)cyclobutanecarboxylic acid

To a 50 ml vial was added LiOH (24 mg, 0.999 mmol, 5.0 equiv) dissolved in H20 (1.0 mL), among with ethyl cis 3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-yloxy)cyclobutanecarboxylate (100.0 mg, 0.2 mmol, 1.0 equiv) in THF (2.0 mL) and MeOH (1.0 mL). The reaction mixture was stirred at 80° C for 30 min. The mixture was acidified with cone. HCl to pH=4 and purified by RP HPLC with loading as a solution of DMSO:H₂0:ACN, 20 to 80% ACN in H₂0 to give product c j^,-3-(5-(3-fiuoro-4-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl)phenyl)pyrimidin-2-yloxy)cyclobutanecarboxylic acid. LC-MS (ES, m/z)

C2 H₁₆F₄N₄0₃: 472; Found: 473 [M+H]⁺. 1H NMR (500 MHz, DMSO-d6) shift for cis proton δ 5.15(s, 1H).

Example 35

tra -3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH-benzordlimidazol-2- yl)phenyl)pyrimidin-2-yloxy)cyclobutanecarboxylic acid

In the same procedure as Example 34, using trans Intermediate 24, /rara-3-(5-(3- fluoro-4-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2- yloxy)cyclobutane carboxylic acid was prepared. LC-MS (ES, m/z) C₂₃Hi6F₄N₄0₃: 472; Found: 473 [M+H]⁺. Ή NMR (500 MHz, DMSO-d6) shift for trans proton δ 5.38(m, 1 H). Using the same procedure for the preparation of Example 30, the following compounds were prepared:

Example 39:

2-((l s sV3-(5-(3-fluoro-4-(5-ftrifluoromethvn-lH-benzordlimidazol-2- yDphenvnpyrimidin^-yloxylcvclobutanecarboxamidolethanesulfonic acid

A mixture of cw-3-(5-(3-fluoro-4-(5-(trifluoromethyl)-l H-benzo[d]imidazol-2- yl)phenyl)pyrimidin-2-yloxy)cyclobutanecarboxylic acid (35.0 mg, 0.06 mmol, 1.00 equiv), 2-aminoethanesulfonic acid (1 1.0 mg, 0.09 mmol, 1.5 equiv), EDC (17.0 mg, 0.09 mmol, 1.5 equiv), HOBT (14.0 mg, 0.09 mmol, 1.5 equiv) and TEA (30.0 mg, 0.298 mmol, 5.0 equiv) in DMF (1 mL) was stirred for 2 hr at 60 °C in an oil bath. The mixture was purified by RP HPLC with loading as a solution of DMSO:H20:ACN, 20 to 80% ACN in H₂0 to give product 2-(c«-3-(5-(3-fluoro-4-(5-(trifluoromethyl)-l H- benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-yloxy)cyclobutanecarboxamido) ethanesulfonic acid. LC-MS (ES, m/z) C25H21 F4N5O5S : 579; Found: 580 [M+H]⁺.

Example 40:

2-( ( 1 s,3sV3-( 5-(3-fluoro-4-(5-(trifluoromethylV 1 H-benzoidlimidazol-2- yl)phenyl)pyrimidin-2-yloxy)cvclobutanecarboxamido^')ethanesulfonic acid

In the same procedure as Example 39, 2-(irara--3-(5-(3-fluoro-4-(5- (trifluoromethyl)-lH-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-yloxy)cyclobutan ecarboxamido)ethanesulfonic acid was prepared. LC-MS (ES, m/z) C₂5H2iF4N₅0₅: 579; Found: 580 [M+H]⁺.

In the same procedure as Intermediate 30, Step A and Step B cw-4-(5-(5-(l H- benzo[d]imidazol-2-yl)pyridin-2-yl)pyrimidin-2-yloxy)cyclohexanecarboxylic acids were prepared. The following substituted c/s-4-(5-(5-(l H-benzo[d]imidazol-2-yl)pyridin-2- yl)pyrimidin-2-yloxy)cycl

0₂H

NC Found: 441 [M+H]⁺

Example 45

OOH c ⁱ-4-{[5-(6-chloro-lH-benzimidazol-2-yn-5'-fluoro-2,3'-bipyridin-6'- yl]oxy}cyclohexanecarboxylic acid

Step A: 5-(6-chloro-lH-benzimidazol-2-yn-5',6'-difluoro-2,3'-bipyridine

In the same procedure as Step A in Example 30 for the formation of imidazole, using Intermediate 26 and 4-chloro-2-aminoanaline, 5-(6-chloro-lH-benzimidazol-2-yl)- 5',6'-difluoro-2,3'-bipyridine was prepared. LC-MS (ES, m/z) Ci H F₂N₄: 342; Found: 343 [M+H]⁺.

Step B : c ^- S-fe-chloro-lH-benzimidazol^-vn-S'-fluoro^.S'-bipyridin-e'- ylloxylcyclohexane carboxylic acid

In the same procedure as preparation of Example 16, using the 5-(6-chloro- lH- benzimidazol-2-yl)-5',6'-difluoro-2,3'-bipyridine from step A and cis-4-hydroxy- cyclohexylcarboxylic acid as starting material, y-4-{[5-(6-chloro-lH-benzimidazol-2- yl)-5'-fluoro-2,3'-bipyridin-6'-yl]oxy} cyclohexanecarboxylic acid was prepared. LC-MS (ES, m/z) C₂₄H₂₀ClF₂N₄O₃: 466; Found: 467 [M+H]⁺.

In the same procedure as the preparation of Example 45, the following

46 cis C₂₄H₂,FN₄0₃: 432

Found: 433 [M+H]⁺

H

47 trans cry C₂₄H₂₁FN₄0₃: 432

Found: 433 [M+H]⁺

H

48 trans C₂₅H2oF4N₄0₃: 500

Found: 501 [M+H]⁺

Example 49 0₂H

c ^,-4-r{5'-methyl-5-[6-(trifluoromethyl)-lH-benzimidazol-2-yl1-2,3'-bipyridin-6'- ylloxylcyclohexanecarboxylic acid

In the same procedure as the preparation of Example 45, using Intermediate 27 as the starting material, ci 4-({5'-methyl-5-[6-(trifluoromethyl)-lH-benzimidazol-2-yl]-2,3'-bipyridin-6'-yl}oxy) cyclohexanecarboxylic acid was prepared. C₂₆H₂3F₃N₄0₃: 496 Found: 497 [M+H]⁺

Example 50 0₂H

c ^-4- 5-(lH-benzimidazol-2-yl)-5'-methyl-2.3'-bipyridin-6'- yl oxylcvclohexanecarboxylic acid

In the same procedure as the preparation of Example 45, using Intermediate 27 as the starting material, ^ ^-({S'-methyl-S-fe-^rifluoromethy^-lH-benzimidazol^-y^^^'-bipyridin-e'-ylJoxy) cyclohexanecarboxylic acid was prepared. C₂sH₂₄N₄0₃: 428 Found: 429 [M+H]⁺

c i^,-4-(^"5-(3-fluoro-4-(5-(trifluoromethyl)-l H-benzofd1imidazol-2-vnphenyl)pyrimidin-2- yloxy cvclohexanecarboxylic acid

In the same procedure as Example 34, but using cis Intermediate 1 1 as starting material, traw-4-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl)phenyl)pyrimidin-2-yloxy)cyclohexanecarboxylic acid was prepared. LC-MS (ES, m/z) C25H20F4N4O3 : 500; Found: 501 [M+H]⁺.

Example 52

tr n -4-(5-(3-fluoro-4-(5-(trifluoromethyl)-l H-benzo dlimidazol-2-yl)phenyl)pyrimidin-2- yloxy)cyclohexanecarboxylic acid

In the same procedure as Example 34, but using trans Intermediate 1 1 as starting material, tr «^-4-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2-yl)phenyl) pyrimidin-2-yloxy)cyclohexanecarboxylic acid was prepared. LC-MS (ES, m/z)

C₂₅H₂oF₄N40₃ : 500; Found: 501 [M+H]⁺.

Example 53

[cw-4-(|5-[4-(lH-benzimidazol-2-yl) -fluorophenyllpyrirnidin-2- yl}oxy)cyclohexyl1acetic acid

Step A: 2-fluoro-4-(2-{ lc^-4-(2-oxopropyncvclohexyl1oxy)pyrimidin-5- yObenzaldehyde

To a 20 mL pyrex vial was charged with 3-fluoro-4-formylphenylboronic acid (0.842 g, 5.01 mmol) along with Intermediate 28 methyl cw-{4-[(5-bromopyrimidin-2- yl)oxy]cyclohexyl} acetate (1 .50 g, 4.56 mmol), sodium carbonate (0.966 g, 9.11 mmol) and Pd(tetrakis) (0.263 g, 0.228 mmol) in D E (8 ml) and Ethanol (8 mL). The vial was sealed and vacuumed and refilled with nitrogen 3 times and then the mixture was exposed to MW at 150 °C for 1 hr. LC-MS showed complete consumption of starting and formation of product. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated and the residue was purified by MPLC (40 g silica gel, 0 to 30% ethyl acetate in hexanes) to afford white solid product 2-fluoro-4-(2-{ [cw-4-(2- oxopropyl)cyclohexyl]oxy}pyrimidin-5-yl)benzaldehyde. LC-MS (ES, m/z) C₂oH₂]FN₂0₃: 356; Found: 357 [M+H]⁺.

Step B: methyl [c j'-4-({5-r4-(lH-benzimidazol-2-yl)-3-fluorophenyllpyrimidin-2- yl ) oxy)cyclohexy 1] acetate

To a 250 mL round bottom flask was charged with 2-fluoro-4-(2-{[m-4-(2- oxopropyl)cyclohexyl]oxy}pyrimidin-5-yl)benzaldehyde (2.61 g, 7.01 mmol) along with DMF (20 mL), water ( 1 mL) and phenylenediamine (1.137 g, 10.51 mmol). The mixture was stirred at room temperature for 5 min before Oxone (3.02 g, 4.91 mmol) was added in one portion. The resulting reaction mixture was then stirred at room temperature for 2 hour. LC-MS showed complete formation of imidazole with 10% diimine. The reaction was worked by partitioned between ethyl acetate and water. The crude product was purified by MPLC (80 g silica gel, 5-40% ethyl acetate in methylene chloride, product has very small solubility in hexanes) to afford product which contained small amount of diimine. The product was purified again by recrystalization in ethyl acetate to afford light color solid product methyl [cw-4-({5-[4-(lH-benzimidazol-2-yl)-3-fluorophenyl] pyrimidin-2-yl}oxy)cyclohexyl]acetate. LC-MS (ES, m/z) C₂6H₂₅FN₄0₃: 460; Found: 461 [M+H]⁺.

Step C: [c -4-({5-[4-(l//-benzimidazol-2-yl)-3-fiuorophenyl1pyrimidin-2-y oxy)cyclo hexyljacetic acid

To 100 mL one neck round bottom flask was charged with [cw-4-({5-[4-(lH- benzimidazol-2-yl)-3-fluorophenyl] pyrimidin-2-yl}oxy)cyclohexyl]acetate (1.75 g, 3.80 mmol) along with THF (10 ml), MeOH (20 ml). The mixture was stirred and sodium hydroxide (9.50 ml, 19.00 mmol) was added. The resulting reaction mixture was stirred ar 50 °C for 1 hr. LC-MS showed complete hydrolysis of ester to acid. The mixtuer was then cooled to room temperature, filtered and then the organic solvent was removed by rotary evaporation to small volumn when solid crush out. Water (10 mL) was added and the solution was heated until all solid dissolved. The mixture was slowly cooled and sodium salt precipitated. The solid was filtered after cooled in refrigerator for half hour. The solid was washed by small amount of cold water(5 mL), IPA (5 mL) and dried under high vacuum to afford product [cw-4-({5-[4-(lH-benzimidazol-2-yl)-3-fluorophenyl]pyrimidin- 2-yl}oxy)cyclo hexyljacetic acid. LC-MS (ES, m/z) C₂₅H₂₃FN₄0₃: 446; Found: 447

[M+H]⁺.

In the same procedure of the preparation of Example 53, the follow compounds (Example 54-78) were prepared by using 2-fluoro-4-(2-{[cw-4-(2- oxopropyl)cyclohexyl]oxy}pyrimidin-5-yl)benzaldehyde from Step A of Example 53 and different aromatic 1 ,2-diamines for the benzimidazole formation.

Exam le 54-78

P T/US2012/064273

In the same procedure of the preparation of Example 53, the follow compounds (Example 79-99) were prepared by starting from Intermediate 28 methyl cis-{4-[(5- bromopyrimidin-2-yl)oxy]cyclohexyl}acetate and different aromatic 1 ,2-diamines for the benzimidazole formation.

Example 98 521 522 Example 99 545 546

F

Example 100

c; -4-(^'{5- 3-fluoro-4-(4,5,6J-tetrahvdro-lH-benzimidazol-2-ynphenyllpyrimidin-2- ylloxy)cyclohexyl^"|acetic acid

Step A: Methyl \cis-4-( { 5 - Γ3 -fluoro-4-(4, 5 ,6 J-tetrahydro- 1 H-benzimidazol-2- yl)phenyl1pyrimidin-2-yl}oxy)cyclohexyl]acetate

To mixture of methyl 2-(m-4-(5-(3-fluoro-4-formylphenyl)pyrimidin-2- yloxy)cyclohexyl)acetate (0.1 g, 0.269 mmol), 2-hydroxycyclohexanone (0.031 g, 0.269 mmol) and ammonium acetate (0.062 g, 0.806 mmol) in EtOH was stirred for 10 min at room temperature followed by the addition of iodine (0.02 g, 0.081 mmol). The resulting mixture was stirred at 80° C for 5 hr . To the crude was added 15% aqueous Na2S203 and extracted with EtOAc (2x). The organic layer was dried over MgS0₄, filtered and concentrated in vacuo. Residue purified by eluting through a silica gel column with a 50- 100% Hexane/EtOAc solvent system to provide product methyl 2-((ls,4s)-4-(5-(3-fluoro- 4-(4,5,6,7-tetrahydro-lH-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-yloxy)cyclohexyl) acetate. LC-MS (ES, m/z) C26H29FN4O3 : 464; Found: 645[M+H]⁺.

Step B: rc/5--4-((5-r3-fluoro-4-(4.5.6.7-tetrahvdro-lH-benzimidazol-2- yl)phenyl]pyrimidin-2-yl I oxylcyclohexyll acetic acid

In the same procedure as in Example 34, Step B, 2-((ls,4s)-4-(5-(3-fluoro-4-(4,5,6,7- tetrahydro-lH-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-yloxy)cyclohexyl)acetic acid was prepared. LC-MS (ES, m/z) C₂₅H₂₇FN₄0₃: 450; Found: 451 [M+H]⁺. Ή NMR (500 MHz, DMSO-d6) shift for trans proton δ 4.98(s, 1H). ]⁺. 1H NMR (500 MHz, DMSO-d6) shift for cis proton δ 5.25(s, 1H).

Example 101

ftran5-4-( 5-[3-fluoro-4-f4,5.6J-tetrah

yUoxy)cyclohexyl] acetic acid

In the same procedure as Example 100, [tra«₁s^,-4-({5-[3-fluoro-4-(4,5,6,7-tetrahydro- lH- benzimidazol-2-yl)phenyl]pyrimidin-2-yl}oxy)cyclohexyl]acetic acid was parepared. Η

[c^-4-({5-[5-(6-fluoro-lH-benzimidazol-2-yl^')pyridin-2-yllpyrimidin-2- yl)oxy)cyclohexyl1 acetic acid

Step A: Methyl (cis- - { [5 -(5 -formylpyridin-2-yl)pyrimidin-2-yll oxy } cyclohexyDacetate

To a 20 mL pyrex vial was charged with Intermediate 29 (0.6 g, 1.59 mmol) along with 2-bromo-5-formylpyridine (0.326 g, 1.754 mmol), sodium carbonate (0.966 g, 6.38 mmol) and Pd(tetrakis) (0.184 g, 0.159 mmol) in DME (4 ml) andEthanol (2 mL). The vial was sealed and vacuumed and refilled with nitrogen 3 times and then the mixture was exposed to MW at 120 °C for 20 min. LC-MS showed complete consumption of starting and formation of product. The reaction mixture was concentrated and worked up with water and ethyl acetate. The crude was purified by MPLC (40 g silica gel, 0 to 30% ethyl acetate in hexanes) to afford white solid product methyl (cw-4-{[5-(5-formylpyridin-2- yl)pyrimidin-2-yl]oxy}cyclohexyl)acetate. LC-MS (ES, m/z) C19H21N3O4: 355; Found: 356 [M+H]⁺.

Step B: methyl [c/₁y-4-({5-r4-(lH-benzimidazol-2-yl)-3-fluorophenyllpyrimidin-2- y 11 oxy)cyclohexy 11 acetate To a 250 mL round bottom flask was charged with methyl (cis-4-{[5-(5- formylpyridin-2-yl)pyrimidin-2-yl]oxy}cyclohexyl)acetate (0.07 g, 0.197 mmol) along with DMF (2 mL), water (0.2 mL) and 4-fluoro-phenylenediamine (0.0.025 g, 0.197 mmol). The mixture was stirred at room temperature for 5 min before Oxone (0.121 g, 0.197 mmol) was added in one portion. The resulting reaction mixture was then stirred at room temperature for 2 hour. The reaction was quenched by K₂C0₃ (1M, 0.2 mL) and worked by partitioned between ethyl acetate and water. The organic layer was dried by MgS0₄, filtered and concentrated to afford product methyl [cw-4-({5-[5-(6-fluoro- lH- benzimidazol-2-yl)pyridin-2-yl]pyrimidin-2-yl}oxy)cyclohexyl]acetate. LC-MS (ES, m/z) C₂5H₂₄FN₅0₃: 461 ; Found: 462 [M+H]⁺.

Step C: [c .y-4-((5- 5-(6-fluoro-lH-benzimidazol-2-ynpyridin-2-yllpyrimidin-2- yUoxy)cyclohexyl^~|acetic acid

To 25 mL one neck round bottom flask was charged with methyl [cw-4-({5-[5-(6- fluoro-lH-benzimidazol-2-yl)pyridin-2-yl]pyrimidin-2-yl}oxy)cyclohexyl]acetate (0.088 g, 0.191 mmol) along with THF (1 ml), MeOH (0.5 ml) and water (0.5 mL). The mixture was stirred and lithium hydroxide (0.046 ml, 1.907 mmol) was added. The resulting reaction mixture was stirred ar 50 °C for 1 hr. LC-MS showed complete hydrolysis of ester to acid. The mixtuer was then cooled to room temperature and neutralized to pH = 7 by HC1 (IN). The crude was purified by RP HPLC (20 -80% acetonitril in water with 0.5% TFA) to afford product [cis-4-( { 5 -[5 -(6-fluoro- 1 H-benzimidazol-2-y l)pyridin-2-yl]pyrimidin-2- yl}oxy)cyclohexyl]acetic acid. LC-MS (ES, m/z) C₂4H22F ₅0₃: 447; Found: 448 [M+H]⁺.

In the same procedure of the preparation of Example 102, the follow compounds (Example 103-1 19) were prepared by starting from methyl (cw-4-{[5-(5-formylpyridin-2- yl)pyrimidin-2-yl]oxy}cyclohexyl)acetate and different aromatic 1 ,2 -diamines for the benzimidazole formation.

Example 103-1 19

Example 1 15 461 462

H

Example 1 16 481 482

Example 1 17 444 445

Example 1 8 498 499

H

Example 119

Cis-4-(5-(3-fluoro-4-(4,5,6,7-tetrahvdro-lH-benzo[6f1imidazol-2-yl)phenyl)pyridin-2- yloxy)cyclohexanecarboxylic acid

Step 1.

2-(2-fluoro-4-(6-fluoropyridin-3-yl^")phenylV4,5,6,7-tetrahydro-lH-benzo <i1imidazole

A mixture of 2-hydroxycyclohexanone (104 mg, 0.912 mmol), Intermediate 19 (200 mg, 0.912 mmol) and ammonium actate (176 mg, 2.281 mmol) in Ethanol (4.0 ml) was treated with I₂ (23.16 mg, 0.091 mmol) and the mixture stirred at 75 °C for 4 h. The mixtue was diluted with 15 % aqueous Na₂S₂0₃. The solvent was evaporated and the resulting slurry diluted with EtOAc. The layers were separated and the aqueous layer washed with EtOAc (x2). Then combined organic layers was dried (MgS0₄) and concentrated. Purification on the CombiFlash Companion eluting with 20 to 60 % EtOAc / Hexane afforded 94 mg of the desired product 2-(2-fluoro-4-(6-fluoropyridin-3- yl)phenyl)-4,5,6,7-tetrahydro-lH-benzo[i¾imidazole. LC-MS (M+l) 312.

Step 2.

Cis-4-(5-(3-fluoro-4-(4,5,6,7-tetrahydro- lH-benzo[( |imidazol-2-yl)phenyl)pyridin-2- yloxy)cyclohexanecarboxylic acid

Following the procedure described for the synthesis of Example 16, but with 2-(2-fluoro- 4-(6-fluoropyridin-3-yl)phenyl)-4,5,6,7-tetrahydro-l H-benzo[(i]imidazole, Cis-4-(5-(3- fluoro-4-(4,5,6,7-tetrahydro-lH-benzo[i/]imidazol-2-yl)phenyl)pyridin-2- yloxy)cyclohexanecarboxylic acid was prepared. LC-MS (M+l) = 436.

In the same procedure of the preparation of Example 102, the follow compounds (Example 120-138) were prepared by starting from Intermediate 30 methyl (irani--4-{[5-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]oxy}cyclohexyl)acetate in Step A and different aromatic 1 ,2-diamines for the benzimidazole formation.

Example 120-138

Example 135 488 489

Example 136 528 529

Example 137 504 505

2-(Trans-4-(5-(4-( lH-benzo ( limidazol-2-yl^')-3-chlorophenvnpyrimidin-2- yloxy^cyclohexyDacetic acid

Step A: Methyl 2-fTrans-4-(5-(^'3-chloro-4-formylphenynpyrimidin-2-yloxy^')cvclohexyl) acetate

Following the procedure described for the synthesis of Example 102, Step A, but with Intermediate 30 and 4-bromo-2-chlorobenzaldehyde, methyl 2-(Trans-4-(5-(3-chloro-4- formylphenyl)pyrimidin-2-yloxy)cyclohexyl) acetate was afforded as a cream solid. LC- MS (M+l) = 389.

Step B: Methyl 2-(Trans-4-(^"5-f4-(lH-benzo[(f|imidazol-2-vn-3-chlorophenynpyrimidin- 2-yloxy)cyclohexy0acetate

Following the general procedure described for the synthesis of Example 102, Step B, but using methyl 2-(Trans-4-(5-(3-chloro-4-formylphenyl)pyrimidin-2-yloxy)cyclohexyl) acetate and benzene- 1 ,2-diamine, methyl 2-(Trans-4-(5-(4-(lH-benzo[i ]imidazol-2-yl)-3- chlorophenyl)pyrimidin-2-yloxy)cyclohexyl)acetate was afforded as a cream solid. LC- MS (M+l) = 477. Step C: 2-(Trans-4-(S-(4-(lH-benzo[(f|imidazol-2-yl)-3-chlorophenyl)pyrimidin-2- yloxy)cyclohexyl acetic acid

Following the procedure described in Example 102, Step C, but , methyl 2-(Trans-4-(5- (4-(lH-benzo[i ]imidazol-2-yl)-3-chlorophenyl)pyrimidin-2-yloxy)cyclohexyl)acetate, 2- (Trans-4-(5-(4-( lH-benzo[c/]imidazol-2-yl)-3-chloropheny])pyrimidin-2- yloxy)cyclohexyl)acetic acid was afforded as a white solid. LC-MS (M+ l) 463. C0₂H

Example 139-141

In the same procedure as the synthesis of Example 138, the cis analogs Exampl 141 were prepared.

Example 142

2-(Cis-3-(5-(4-( lH-benzo[ /]imidazol-2-yl)-3-fluorophenyl)pyrimidin-2- yloxy^'lcvclobutyDacetic acid Step A: Ethyl 2-(Cis-3-(5-(4-(lH-benzorcnimidazol-2-vn-3-fluorophenvnpyrimidin-2- yloxy cyclobutyl acetate

Following the general procedure A described for the synthesis of Example 102, Step 2, but using Intermediate 45, and benzene- 1 ,2-diamine, Ethyl 2-(Cis-3-(5-(4-(lH- benzo[t/]imidazol-2-yl)-3-fluorophenyl)pyrimidin-2-yloxy)cyclobutyl)acetate was afforded as a tan solid. LC-MS (M+l) = 447.

Step B: 2-(Cis-3-(5-(4-(l H-benzo(^"< ]imidazol-2-yl)-3-fluorophenynpyrimidin-2- yloxy cyclobutyl^')acetic acid

Following the procedure described in Step C, Example 102, but with Ethyl 2-(Cis- 3-(5-(4-(lH-benzo[(i]imidazol-2-yl)-3-fluorophenyl)pyrimidin-2- yloxy)cyclobutyl)acetate, 2-(Cis-3-(5-(4-(lH-benzo[< ]imidazol-2-yl)-3- fluoropheny])pyrimidin-2-yloxy)cyclobutyl) acetic acid was afforded as a white solid. LC-MS (M+ l ) 419.

In the same procedure as the synthesis of Exmple 143, the following compounds were prepared.

Example 143

2-(Cis-3-(5-(3-fluoro-4-(5-(trifluoromethyl - lH-benzor<ai1imidazol-2- ynphenynpyrimidin-2-yloxy cyclobutynacetic acid

. LC-MS (M+ l) = 487

Example 144

2-(Cis-3-(5-(3-fluoro-4-(5-fluoro- lH-benzo|^"(^limidazol-2-yl)phenyl)pyrimidin-2-

LC-MS (M+l) 437.

Example 145

2-(Cis-3-(5-(4-(5₁6-difluoro- lH-benzof^imidazol-2-yl)-3-fluorophenvnpyrimid

yloxy)cyclobutyOacetic acid

LC-MS (M+l) 455.

Example 146

2-rCis-3-(5-(3-fluoro-4-r6-rtrifluoromethylV3H-imidazor4.5-&lpyridin-2- yl)phenyl)pyrimidin-2-yloxy)cyclobutyl^')acetic acid

Step A: Methyl 2-(Cis-3-(5-(3-fluoro-4-(6-rtrifluoromethylV3H-imidazor4.5-&1pyridin-2- yOphenyOpyrimidin^-yloxylcvclobutvOacetate

A solution of Intermediate 18 (150 mg, 0.436 mmol) in DMSO (8.0 ml) was treated with 5-(trifluoromethyI)pyridine-2,3-diamine (85 mg, 0.479 mmol) and the mixture stirred at 70°C for 2 h. After cooling to room temperature the reaction was quenched with water to afford a precepitate. The precepitate was filtered off and washed with water. The filtered solid was dissolved in EtOAc and washed with NaHC0₃, brine, and dried (MgS0₄) and concentrated. Trituration of the solid from ether / hexane followed by filtration afforded 143 mg of Methyl 2-(Cis-3-(5-(3-fluoro-4-(6-(trifluoromethyl)-3H-imidazo[4,5-)]pyridin-2-yl)phenyl)pyrimidin-2-yloxy)cyclobutyl)acetate as a tan solid. LC-MS (M+l)

502.

Step B: 2-(Cis-3-i5-G-fluoro-4-(^'6-(^,trifluoromethvn-3H-imidazor4.5-61pyridin-2- yDphenyl pyrimidin-2-yloxy cvclobutyl)acetic acid Following the procedure described in Step B, Example 143, but with Methyl 2-(Cis-3-(5- (3-fluoro-4-(6-(trifluoromethyl)-3H-imidazo[4,5-0]pyridin-2-yl)phenyl)pyrimidin-2- yloxy)cyclobutyl)acetate was hydrolyzed to afford (Cis-3-(5-(3-fluoro-4-(6- (trifluoromethyl)-3H-imidazo[4,5-0]pyridin-2-yl)phenyl)pyrimidin-2-yloxy)cyclobutyl) acetic acid as a white solid. LC-MS (M+l) 488.

Example 147

2-(d^4-(5-(3-fluoro-4-(4,5,6,7-tetrahydro-lH-benzo[d1imidazol-2-yl^')phenyl pyrimidin-2- yloxy)cyclohexyl)acetic acid

Step A: methyl 2-(g^-4-(5-(3-fluoro-4-(4,5,6.7-tetrahydro-lH-benzo[dl imidazol-2- v0phenv0pyrirnidin-2-yloxy)cyclohexyl)acetate

To mixture of methyl 2-(cz5-4-(5-(3-fluoro-4-formylphenyl)pyrimidin-2- yloxy)cyclohexyl)acetate (0.1 g, 0.269 mmol), 2-hydroxycyclohexanone (0.031 g, 0.269 mmol) and ammonium acetate (0.062 g, 0.806 mmol) in EtOH was stirred for 10 min at room temperature followed by the addition of iodine (0.02 g, 0.081 mmol). The resulting mixture was stirred at 80° C for 5 hr - LCMS 1. To the crude was added 15% aqueous Na2S203 and extracted with EtOAc (2x). The organic layer was dried over MgS04, filtered and concentrated in vacuo. Residue purified by eluting through a silica gel column with a 50-100% Hexane/EtOAc solvent system to provide product methyl 2-(cw-4-(5-(3- fluoro-4-(4,5,6,7-tetrahydro-l H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2- yloxy)cyclohexyl)acetate. LC-MS (ES, m/z) C26H29F 4O3 : 464; Found: 465[M+H]⁺.

Step B : In the same procedure as in Example 102, Step C 2-(cw-4-(5-(3-fluoro-4- (4,5,6,7-tetrahydro- lH-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2- yloxy)cyclohexyl)acetic acid was prepared. LC-MS (ES, m/z) C25H₂₇FN₄0₃: 450; Found: 451 [M+H]⁺. Ή NMR (500 MHz, DMSO-d6) shift for trans proton δ 4.98(s, 1H). ]⁺. Ή NMR (500 MHz, DMSO-d6) shift for cis proton δ 5.25(s, 1H). Example 148

2-( s-4-(5-(5-(4,5,6J-tetrahydro-l H-be

yloxylcyclohexyDacetic acid

Step A :methyl 2-(m-4-(5-(^'5-(^'4.5.6,7-tetrahvdro-lH-benzofd1imidazol-2-vn pyridin-2-y0pyrimidin-2-yloxy)cvclohexyl)acetate

In the same procedure as in Example 148, Step A, methyl methyl 2-(cw-4-(5-(5- (4,5,6,7-tetrahydro-lH-benzo[d]imidazol-2-yl)pyridin-2-yl)pyrimidin-2- yloxy)cyclohexyl)acetate was prepared. LC-MS (ES, m/z) C₂5H₂₉N₅0₃: 447; Found: 448 [M+H]⁺.

Step B: In the same procedure as in Example 148, Step B, 2-(c/s-4-(5-(5-(4, 5,6,7- tetrahydro-l H-benzo[d]imidazol-2-yl)pyridin-2-yl)pyrimidin-2-yloxy)cyclohexyl)acetic acid was prepared. LC-MS (ES, m/z) C₂₄H_{27 5}0₃: 433; Found: 438 [M+H]⁺. 1H NMR (500 MHz, DMSO-d6) shift for cis proton δ 5.25(s, 1H).

Example 149

ftran^-l S^-fluoro-lH-benzimidazol^-vn^.S'-bipyrimidin^'- ylloxylcvclohexyDacetic acid

Step A :Methyl (//- n -4-{ [5-(hvdroxymethylV2,5'-bipyrimidin-2'-yl1oxylcvclo hexyDacetate

(2-Chloropyrimidin-5-yl)methanol (0.49g, 3.39 mmol, 1.0 equiv.), {trans-4-[5- (4,4,5,5-Tetramethyl-l ,3,2-dioxaborolan-2-yl)-pyrimidin-2-yloxy]-cyclohexyl}-acetic acid methyl ester (1.275 g, 3.39 mmol, 1 equiv.), Pd(dppf) (0.124 g, 0.169 mmol, 0.05equiv.), and 2 Na2C03 (aq) (5.48 mL, 10.95 mmol, 4 equiv.) were placed in DMF (15 mL) and stirred at room temperature in a sealed microwave reaction vial. The reaction was placed under vacuum for 5 min (until no continuing gas evolution was detected) and then 2 (g) was bubbled into the reaction suspension for 25 min. The reaction suspension was heated at 120°C under microwave conditions for 1 hr 20 min. The reaction was concentrated to a residue which was then dissolved in EtOAc / brine. The EtOAc phase was dried over Na2SC>4, filtered, and concentrated to an oil. Purification with Biotage SP-1 [ FLASH 25 cartridge. Hexanes:EtOAc 0>12% 2CV; 12> 100% 10CV; 100% 5CV ] to afford methyl (tran5-4-{[5-(hydroxymethyl)-2,5'-bipyrimidin-2'-yl]oxy}cyclohexyl)acetate. LC-MS (ES, m/z): C 17H20N4O4: 344; Found: 344 [M+H]⁺.

Step B: methyl {^^^-[(S-formyl^^'-bipyrimidin^'-yDoxylcyclohexyljacetate To 100 ml round bottom flask was charged with methyl (trans-4-{[5- (hydroxymethyl)-2,5'-bipyrimidin-2'-yl]oxy}cyclohexyl)acetate (0.05 g, 0.14 mmol), NMO(0.025 g, 0.209 mmol) along with activated 4A molecular sieve (50 mg). The mixture was stirred while TPAP(2.4 mg, 6.98 μιηοΐ) was added in one shot. Reaction was stirred at room temperature for 30 min The crude was purified directly by MPLC (12 g silica gel, 0 to 40% ethyl acetate in hexanes) to afford methyl {fr<my-4-[(5-formyl-2,5'- bipyrimidin-2'-yl)oxy]cyclohexyI }acetate. LC-MS (ES, m/z): C17H 18N4O4: 342; Found: 343 [M+H]⁺.

Step C and D: (/w^-4-|[^"5-(6-fluoro-lH-benzimidazol-2-yl)-2,5'-bipyrimidin-2'- yl]oxy)cyclohexyl acetic acid

Following the general method A for the formation of benzimidazole and hydrolysis of ester to acid, (iran5^,-4-{[5-(6-fluoro- lH-benzimidazol-2-yl)-2,5'-bipyrimidin- 2'-yl]oxy}cyclohexyl)acetic acid was prepared. LC-MS (ES, m/z): C23H21FN6O3: 448; Found: 449 [M+H]⁺.

Example 150

2-(fraw-4-(5-(5-(4,5,6J-tetrahydro-lH^

yloxy)cvclohexyl)acetic acid

In the same procedure as in Example 147, 2-irara--4-(5-(5-(4,5,6,7-tetrahydro-lH- benzo[d]imidazol-2-yl)pyridin-2-yl)pyrimidin-2-yloxy)cyclohexyl)acetic acid was prepared. LC-MS (ES, m/z) C₂4H₂7N₅0₃: 433; Found: 438 [M+H]⁺. 1H NMR (500 MHz, DMSO-d6) shift for trans proton δ 4.98(s, 1H).

Example 151

2-(rm .s^,-4-(5-C3-fluoro-4-(4,5₁6,7-tetrahydro-lH-benzo[dlimidazol-2-yl)phenyl)pyrimidin-

2-yloxy)cyclohexy0acetic acid

In the same procedure as in Example 147, 2-((lr,4r)-4-(5-(3-fluoro-4-(4,5,6,7- tetrahydro-l H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-yloxy)cyclohexyl)acetic acid was prepared. LC-MS (ES, m/z) C₂5H₂₇FN₄0₃: 450; Found: 451 [M+H]⁺. Ή NMR (500 MHz, DMSO-d6) shift for trans proton δ 4.98(s, 1H).

Example 152

(trans-4-{5- 5-( lH-Benzimidazol-2-ylV6-methyl-pyridin-2-yl1-pyrimidin-2-yloxy|- cyclohexyP-acetic acid

Step A: (trans-4-[5-(5-Fortnyl-6-methyl-pyridin-2-yn-pyrimidin-2-yloxy]-cvclohexylj- acetic acid methyl ester

6-Cl-2-Methylpyridine-3-carbaldehyde (0.227g, 1.462 mmol, 1.1 equiv.), {4-[5- (4,4,5,5-Tetramethyl-l ,3,2-dioxaborolan-2-yl)-pyrimidin-2-yloxy]-cyclohexyl}-acetic acid methyl ester (0.5 g, 1.329 mmol, 1 equiv.), Tetrakis(PPh₃)Pd(0) (0.23 g, 0.199 mmol, 0.15 equiv.), and 2M Na2C03 (aq) (2.66 mL, 5.32 mmol, 4equiv.) were placed in DME (3.56 mL) / EtOH (1.75 mL) and stirred at room temperature in a sealed microwave reaction vial. The reaction was placed under vacuum for 5 min (until no continuing gas evolution was detected) and then N2(g) was bubbled into the reaction suspension for 25 min. The reaction suspension was heated at 120°C under microwave conditions for 1 hr

30 min. The reaction was concentrated to a residue which was then dissolved in EtOAc / brine. The EtOAc phase was dried over Na2S04, filtered, and concentrated to an oil.

Purification with Biotage SP-1 [ FLASH 25 cartridge. Hexanes:EtOAc 0> 12% 2CV; 12> 100% 10CV; 100% 5CV ] isolated 0.4 g. LC-MS (ES, m/z): CzoEbNsC : 369; Found: 370 [M+H]⁺.

Step B: (trans-4-{5-[5-(l H-Benzimidazol-2-yl)-6-methyl-pyridin-2-yl]-pyrimidin-2- yloxyl-cyclohexyD-acetic acid methyl ester

{trans-4-[5-(5-Formyl-6-methyl-pyridin-2-yl)-pyrimidin-2-yloxy]-cyclohexyl}- acetic acid methyl ester (0.14 g, 0.379 mmol, 1 equiv.) and benzene- 1,2-diamine (0.057 g, 0.531 mmol, 1.4 equiv.) were dissolved in DMF (2.14 mL) / water (0.1 1 mL). After stirring for 5 min at room temperature, oxone (0.163 g, 0.265 mmol, 0.7 equiv.) was added in small portions over several minutes. Stirring continued overnight. 1M K2CO3

(aq) was added to reaction, diluting the reaction solution to a volume of 20 mL. The diluted reaction solution was poured into water and then extracted with EtOAc twice. The combined EtOAc solution was dried over Na2SC>4, filtered, and concentrated to an oil. Purification with Biotage SP-1 [ SNAP 50g cartridge. Hexanes:EtOAc 0 > 12% 2CV; 12 > 100% 10CV; 100% 5CV ] isolated the desired product as a solid, 0.125 g. LC-MS (ES, m/z): C₂₆H₂₇N₅0₃: 457; Found 458 [M+H]⁺.

Step C: (trans-4-{5-[5-(l H-Benzimidazol-2-yl)-6-methyl-pyridin-2-yll-pyrimidin-2- yloxy)-cvclohexyl)-acetic acid

(trans-4-{5-[5-(l H-Benzimidazol-2-yl)-6-methyl-pyridin-2-yl]-pyrimidin-2- yloxy}-cyclohexyl)-acetic acid methyl ester (0.125 g, 0.273 mmol, 1 equiv.) was dissolved in THF (0.75 mL) / MeOH (0.75 mL)/ ¾0 (0.75 mL) and stirred at room temperature. Lithium hydroxide monohydrate (0.12 g, 2.86 mmol, 10.47 equiv.) was added and stirring continued for 1 hr. 1 M HCl (aq) (2.86 mL) was added to the reaction and the neutralized reaction solution was then filtered. The product in solution was purified by Reverse Phase HPLC (acetonitrile/H₂0/TFA; YMC-Pack ODS-A column) to isolate the product. The product was lyophilized to a solid (TFA salt), 0.746g.

LC-MS (ES, m/z): C₂5H₂₅N₅0₃ C₂HF₃0₂: TFA salt 557, parent 443; Found 444

[M+H]⁺.

Example 153

(cis-4-{ 5-[5-(5-Fluoro-lH-benzimidazol-2-yl)-6-methyl-pyridin-2-yl]-pyrimidin-2- yloxyl-cyclohexyD-acetic acid

Step A: {cis-4-[5-(5-Formyl-6-methyl-pyridin-2-yl -pyrimidin-2-yloxy1-cyclohexylj- acetic acid methyl ester

6-Cl-2-Methylpyridine-3-carbaldehyde (0.227g, 1.462 mmol, 1.1 equiv.), {4-[5-

(4,4,5,5-Tetramethyl-l ,3,2-dioxaborolan-2-yl)-pyrimidin-2-yloxy]-cyclohexyl}-acetic acid methyl ester (0.5 g, 1.329 mmol, 1 equiv.), Tetrakis(PPh3)Pd(0) (0.23 g, 0.199 mmol, 0.15 equiv.), and 2M Na2C03 (aq) (2.66 mL, 5.32 mmol, 4equiv.) were placed in DME (3.56 mL) / EtOH (1.75 mL) and stirred at room temperature in a sealed microwave reaction vial. The reaction was placed under vacuum for 5 min (until no continuing gas evolution was detected) and then N2(g) was bubbled into the reaction suspension for 25 min. The reaction suspension was heated at 120°C under microwave conditions for 1 hr

30 min. The reaction was concentrated to a residue which was then dissolved in EtOAc / brine. The EtOAc phase was dried over Na2S04, filtered, and concentrated to an oil,

0.189 g. Purification with Biotage SP-1 [ hexanes:EtOAc 0>12% 2CV; 12>100% 10CV; 100% 5CV ] isolated 0.4 g. LC-MS (ES, m/z): C20H23N3O4: 369; Found: 370 [M+H]⁺.

Step B: (cis-4-{5- 5-(5-Fluoro-l H-benzimidazol-2-yl)-6-methyl-pyridin-2-yll- pyrimidin-2-yloxy}-cyclohexyl)-acetic acid methyl ester

4-fluorobenzene- l ,2-diamine (0.044g, 0.352 mmol, 1.3 equiv.) and {cis-4-[5-(5- Formyl-6-methyl-pyridin-2-yl)-pyrimidin-2-yloxy]-cyclohexyl}-acetic acid methyl ester (O. l g, 0.271 mmol, 1.0 equiv.) were dissolved in DMF (1.259 mL) / ¾0 (0.095 mL) and stirred at room temperature. After 5 min, oxone (0.1 16 g, 0.189 mmol, 0.7 equiv.) was added to the solution, which continued to stir at room temperature. The reaction continued stirring overnight. The reaction was diluted with 1M K2CO3 (aq) to a 20 mL volume. The resulting suspension was poured into EtOAc / H2O. After shaking, the phases were separated. The aqueous phase was extracted again with EtOAc, and the combined EtOAc phases were dried over a2S04, filtered, and concentrated to an oil,

0.6g. Purification with Biotage SP-1 [ SNAP 50g cartridge. Hexanes:EtOAc 0>12% 2CV; 12>100% 10CV; 100% 5CV ] isolated the product as an oil, 0.1 l g. LC-MS (ES, m/z): C₂6H₂₆FN₅0₃: 475; Found 476 [M+H]⁺.

Step C: (cis-4-(5- 5-(^'5-Fluoro- l H-benzimidazol-2-yn-6-methyl-pyridin-2-yl]- pyrimidin-2-yloxy)-cyclohexyl)-acetic acid

Using the same procedure as in Example 152, (cis-4-{5-[5-(5-Fluoro-lH-benzimidazol-2- yl)-6-methyl-pyridin-2-yl]-pyrimidin-2-yloxy}-cyclohexyl)-acetic acid was prepared as a TFA salt. LC-MS (ES, m/z): C₂₅H₂₄FN₅0₃: 461 ; Found 462 [M+H]⁺.

Using General Method A with Intermediate 31 {cis-4-[5-(5-Formyl-4-methyl-pyridin-2- yl)-pyrimidin-2-yloxy]-cyclohexyl}-acetic acid methyl ester, Examples 154-157 were prepared:

Using General Method A with Intermediate 31 {trans-4-[5-(5-Formyl-4-methyl-pyridin- 2-yl)-pyrimidin-2-yloxy]-cyclohexyl}-acetic acid methyl ester, Examples 158-160 were prepared:

Using General Method A with Intermediate 33 {cis-4-[5-(5-Formyl-3-methyl-pyridin-2- yl)-pyrimidin-2-yloxy]-cyclohexyl}-acetic acid methyl ester, Examples 161 -162 were

Example 163

trans ^-{ S-fS-chloro-lH-benzimidazol^-yn^J'-bipyridin^'-vnoxylcy clohexanecarboxylic acid

Step A: ethyl trans-4-{[5-(5-chloro-lH-benzimidazol-2-yl -2,3^,-bipyridin-6'-ylloxy}cv Clohexanecarboxylate

A mixture of 4-chloro-l ,2-phenylenediamine (200 mg, 1.403 mmol), ethyl trans- 4-[(5-formyl-2,3'-bipyridin-6'-yl)oxy]cyclohexanecarboxylate (Intermediate 34, 487 mg, 1.403 mmol) and potassium peroxymonosulfate(0.560 g, 0.912 mmol) in DMF (6 ml) and water (0.6 ml) was stirred for 24 hours at room temperature. Then pour into 10 mL 1M K₂C0₃ solution, extract with 3x20 mL ethyl acetate. The organic layers were combined, washed with 2x10 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 0.47 g (70%) of ethyl trans-4-{[5-(5-chloro-lH- benzimidazol-2-yl)-2,3'-bipyridin-6'-yl]oxy}cy clohexanecarboxylate as a white solid. LC-MS (ES, m/z) C₂₆H₂₅C1N₄0₃: 476; Found: 477 [M+H]⁺.

Step B: trans -4-{ [5-(5-chloro-lH-benzimidazol-2-yl)-2,3'-bipyridin-6'-yl]oxy}cy clohexanecarboxylic acid

A mixture of ethyl trans-4-{[5-(5-chloro-lH-benzimidazol-2-yl)-2,3'-bipyridin- 6'-yl]oxy}cy clohexanecarboxylate (70 mg, 0.147 mmol) and lithium hydroxide (17 mg, 0.734 mmol) in MeOH ( 1 ml), THF (1 ml), water (0.5 ml). The reaction mixture heat at 40°C in an oil bath over night, and then concentrated under vacuum, adjust PH=7 with IN HCl, then purified by Gilson acetonitril (0.05%TFA)/water (0.05%TFA) 30-100%. This resulted in 42 mg (5 1%) of trans -4-{[5-(5-chloro-lH-benzimidazol-2-yl)-2,3'- bipyridin-6'-yl]oxy}cy clohexanecarboxylic acid as a white solid. LC-MS (ES, m/z) C₂₄H₂iClN₄0₃: 448; Found: 449 [M+H]⁺. OOH

trans-4-(l5- 5-(trifluoromethyl)-lH-benzimidazol-2-yl]-2,3'-bipyridin-6'- yUoxy)cyclohexanecarboxylic acid

00 Et

ethyl trans-4-({5-r5-(trifluoromethyl)-lH-benzimidazol-2-vn-2,3'-bipyridin-6'- yl }oxy)cyclohexanecarboxylate Step A: Ethyl trans-4-((5-[5-(trifluoromethyl -lH-benzimidazol-2-yl -2,3'-bipyridin-6'- yl }oxy)cyclohexanecarboxylate

A mixture of 2-(6-bromopyridin-3-yl)-5-(trifluoromethyl)-lH-benzimidazole (638 mg, 1.865 mmol), trans-4-{[5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin- 2- yl]oxy}cyclohexanecarboxylate (700 mg, 1.865 mmol), sodium carbonate (395 mg, 3.73 mmol) and Pd(dppf)Cl₂ (68.2 mg, 0.093 mmol) are suspended in DMF (6 ml) and water (3 ml), The reaction mixture was stirred over night at 80°C under N₂ in an oil bath. The reaction mixture was cooled to room temperature, water (20 ml) added, extracted with 3x20 mL ethyl acetate. The organic layers were combined, washed with 2x10 mL of saturated brine, dried over anhydrous sodium sulfate and concentrated under vacuum. Then purified by Gilson acetonitril (0.05%TFA)/water (0.05%TFA) 30-100%. This resulted in 0.69 g (72%) of ethyl trans-4-({5-[5-(trifluoromethyl)- l H-benzimidazol-2-yl]- 2,3'-bipyridin-6'- yl}oxy)cyclohexanecarboxylate as a white solid. LC-MS (ES, m/z) C27H25F3N4O3 : 510; Found: 51 1 [M+H]⁺.

Step B: trans-4-({ 5-[5-(trifluoromethyl)-l H-benzimidazol-2-yl -2,3'-bipyridin-6'- yl|oxy)cyclohexanecarboxylic acid

A mixture of ethyl trans-4-({5-[5-(trifluoromethyl)-l H-benzimidazol-2-yl]-2,3'- bipyridin-6'- yl}oxy)cyclohexanecarboxylate (100 mg, 0.196 mmol) and lithium hydroxide (23 mg, 0.979 mmol) in MeOH (1 ml), THF (1 ml), water (0.5 ml). The reaction mixture heat at 40°C in an oil bath over night, and then concentrated under vacuum, adjust PH=7 with IN HC1, then purified by Gilson acetonitril

(0.05%TFA)/water (0.05%TFA) 30-100%. This resulted in 68 mg (58%) of trans-4-({5- [5-(trifluoromethyl)-lH-benzimidazol-2-yl]-2,3'-bipyridin-6'- yl}oxy)cyclohexanecarboxylic acid as a white solid. LC-MS (ES, m/z) C₂5H₂iF₃N₄0₃: 482; Found: 483 [M+H]⁺.

In the same procedure of the preparation of Example 163, the follow compounds (Example 165- 172) were prepared by starting from Intermediate 34 ethyl trans-4-[(5-formyl-2,3'- bipyridin-6'-yl)oxy]cyclohexanecarboxylate in Step A and different aromatic 1 ,2-diamines for the benzimidazole formation. OOH

Example 165-172

Example 173 HOO

trans-4-[(5-n-fluoro-4 5-(trifluoromethyl)- l H-benzimidazol-2-yllphenv Upyridin-2- yl)oxy^"|cyclohexanecarboxylic acid

Step A: ethyl trans -4-{[5-f3-fluoro-4-formylphenyl)pyridin-2-yl]oxy)cvclohexane carboxylate

A mixture of ethyl trans-4-[(5-bromopyridin-2-yl)oxy]cyclohexanecarboxylate (2g, 6.09 mmol), 3-fluoro-4-formylphenylboronic acid (1.126 g, 6.70 mmol), sodium carbonate (1.292 g, 12.19 mmol) and Pd(dppf)Cl₂ (0.223 g, 0.305 mmol) are suspended in N,N-Dimethylformamide (6 ml) and water (3 ml), the reaction mixture was stirred over night at 80°C under N₂ in an oil bath. The reaction mixture was cooled to room temperature, water (20 ml) added, extracted with 3x20 mL ethyl acetate. The organic layers were combined, washed with 2x 10 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 5-50%. This resulted in 1.58 g (70%) of ethyl trans - 4-{ [5-(3-fluoro-4-formylphenyl)pyridin-2-yl]oxy}cyclohexanecarboxylate as a white solid. LC-MS (ES, m/z) C21H22FNO4: 371 ; Found: 372 [M+H]⁺.

Step B : trans-4- { [5-(3-fluoro-4-formylphenyl)pyridin-2-yl^"|oxy) cyclohexanecarboxylic acid

A mixture of ethyl trans -4-{ [5-(3-fluoro-4-formylphenyl)pyridin-2- yl]oxy}cyclohexanecarboxylate (200mg 0538 mmol) and lithium hydroxide (77mg 3.23 mmol) in MeOH (2 ml), THF (2ml), water (1 ml) stirred at room temperature for 50 mins. Concentrated under vacuum then adjust PH=7 with IN HC1. Extracted with 4x 15ml DCM. The organic layers were combined and concentrated under vacuum, which resulted in 58 mg (31%) of product trans-4-{[5-(3-fluoro-4-formylphenyl) pyridine- 2yl]oxy}cyclohexanecarboxylic acid as oil. LC-MS (ES, m/z) C19H18FNO4 : 343; Found: 344 [M+H]⁺.

Step C: trans-4-[(5-{3-fluoro-4- 5-(trifluoromethyl)-l H-benzimidazol-2-yl]pheny Upyridin-2-yl)oxy^~|cyclohexanecarboxylic acid

A mixture of 3,4-diaminobenzotrifluoride (25.7 mg, 0.146 mmol), trans-4-{[5- (3-fluoro-4-formylphenyl)pyridin-2-yl]oxy}cyclohexanecarboxylic acid (50 mg, 0.146 mmol) and potassium peroxymonosulfate (90 mg, 0.146 mmol) in DMF (1.5 ml) and water (0.15 ml) was stirred for 24 hours at room temperature. Then pour into 2 mL 1M 2C0₃ solution, then purified by Gilson acetonitril (0.05%TFA)/water (0.05%TFA) 30- 100%. This resulted in 20 mg (22%) of trans-4-[(5-{3-fluoro-4-[5-(trifluoromethyl)-l H- benzimidazol-2-yl]pheny l}pyridin-2-yl)oxy]cyclohexanecarboxyIic acid as a white solid. LC-MS (ES, m/z) C26H21F4N3O3 : 499; Found: 500 [M+H]⁺.

In the same procedure of the preparation of Example 173, the follow compounds (Example 174-185) were prepared by starting from Intermediate 34 trans -4-{[5-(3-fluoro- 4-formylphenyl)pyridin-2-yl]oxy}cyclohexanecarboxylate in Step A and different aromatic 1 ,2-diamines for the benzimidazole formation.

OOH

Example 174 -185

cis-S-fS-fS-ftrifluoromethyl lH-benzofdlimidazol^-yl^ '-bipyridin^' yloxy) cyclobutanecarboxylic acid

Step A: benzyl 3-({5- 5-(trifluoromethyl)-l H-benzimidazol-2-yl1-2,3'-bipyridin-6'- y oxy cyclobutanecarboxylate

A mixture of 2-(6-bromopyridin-3-yl)-5-(trifluoromethyl)-l H-benzimidazole (150 mg, 0.438 mmol), benzyl 3-{[5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-y])pyridin-2- yl]oxy} eye lobutanecarboxy late (179mg, 0.438 mmol), sodium carbonate (93 mg, 0.877 mmol) and Pd(dppf)Cl₂ (16 mg, 0.022 mmol) are suspended in DMF (3 ml) and water (1.5 ml), The reaction mixture was stirred over night at 80°C under N₂ in an oil bath. The reaction mixture was cooled to room temperature, water (20 ml) added, extracted with 3x20 mL ethyl acetate. The organic layers were combined, washed with 2x 10 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 100 mg (42 %) of benzyl 3-({5-[5-(trifluoromethyl)-l H-benzimidazol-2-yl]- 2,3'-bipyridin-6'-yl}oxy)cyclobutanecarboxyIate as a white solid. LC-MS (ES, m/z) C₃oH23F_{3 4}0₃: 544; Found: 545 [M+H]⁺.

Step B : benzyl cis-3-((5-r5-(trifluoromethyn- l H-benzimidazol-2-yl1-2₁3'-bipyridin-6'- yl}oxy)cyclobutanecarboxylate and benzyl trans-3 -( { 5-f 5 -(trifluoromethy 1) - 1 H- benzimidazol-2-yl]-2.3'-bipyridin-6'-yUoxy)cyclobutanecarboxylate

Benzyl 3-({5-[5-(trifluoromethyl)-l H-benzimidazol-2-yl]-2,3'-bipyridin-6'- yl}oxy)cyclobutanecarboxylate (100 mg) was separated by chiralPak AD-3 column (250x30mmI.D) to get benzyl cis-3-({5-[5-(trifluoromethyl)-lH-benzimidazol-2-yl]- 2,3'-bipyridin-6'-yl}oxy)cyclobutanecarboxylate (93 mg). LC-MS (ES, m/z)

C30H23F3N4O3 : 544; Found: 545 [M+H]+. And benzyl trans-3-({5-[5- (trifluoromethyl)-lH-benzimidazol-2-yl]-2,3'-bipyridin-6'-yl}oxy)cyclobutane carboxylate (5.4 mg). LC-MS (ES, m/z) C30H23F3N4O3: 544; Found: 545 [M+H]+.

Step C: cis-3-(5-(5-(trifluoromethyl)-lH-benzofd1imidazol-2-yl)-2.3'-bipyridin-6' yloxy) cyclobutanecarboxylic acid

A mixture of benzyl cis-3-({5-[5-(trifluoromethyl)-lH-benzimidazol-2-yl]-2,3'-bipyridin- 6'-yl}oxy)cyclobutanecarboxylate (6 mg, 9.18 μηιοΐ) and lithium hydroxide (1 mg, 0.046 mmol) in MeOH (1 ml), THF (1ml), water (0.5 ml). The reaction mixture heat at 40°C in an oil bath over night, and then concentrated under vacuum, adjust PH=7 with IN HC1, then purified by Gilson acetonitril (0.05%TFA)/water (0.05%TFA) 30-100%. This resulted in 3.6 mg (69%) of cis-3-(5-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2-yl)- 2,3'-bipyridin-6' yloxy)cyclobutanecarboxylic acid as a white solid. LC-MS (ES, m/z) C₂₃H,₇F₃N₄0₃: 454; Found: 455 [M+H]⁺. Example 187

trans-3-(5-(5-(trifluoromethyn-lH-benzo d ^idazol-2-vn-2,3'-bipyridin-6' yloxy) cyclobutanecarboxylic acid

A mixture of benzyl trans-3-({5-[5-(trifluoromethyl)-lH-benzimidazol-2-yl]-2,3'- bipyridin-6'-yl}oxy)cyclobutanecarboxylate (32 mg, 0.059 mmol) and lithium hydroxide (7 mg, 0.294 mmol) in MeOH (1 ml), THF (1ml), water (0.5 ml). The reaction mixture heat at 40°C in an oil bath over night, and then concentrated under vacuum, adjust PH=7 with IN HC1, then purified by Gilson acetonitril (0.05%TFA)/water (0.05%TFA) 30- 100%. This resulted in 16 mg (48%) of trans-3-(5-(5-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)-2,3'-bipyridin-6' yloxy)cyclobutanecarboxylic acid as a white solid. LC-MS (ES, m/z) ¾Η₁₇Ρ₃Ν₄θ3 : 454; Found: 455 [M+H]⁺.

(l S.3R 3-(5-r5-rt ifluoromethyl)-l H-benzoίdlimidazol-2-ylV2.3'-bipyridin-6^,- yloxy)cvclopentanecarboxyl ic acid

A mixture of benzyl (I S, 3R)-3-({5-[5-(trifluoromethyl)-l H-benzimidazol-2- yl]-2,3'-bipyridin-6'-yl}oxy)cyclopentanecarboxylate (50 mg, 0.09 mmol) and lithium hydroxide (10.7 mg, 0.448 mmol) in MeOH (2 ml), THF (2 ml), water (1 ml). The reaction mixture stirred at room temperature over night, and then concentrated under vacuum, then purified by Gilson acetonitril (0.05%TFA)/water (0.05%TFA) 20-100%. This resulted in 38 mg (73%) of (I S, 3R)-3-(5-(5-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)cyclopentanecarboxylic acid as a white solid. LC-MS (ES, m/z) C24H₁₉F₃N₄0₃: 468; Found: 469 [M+H]⁺.

nR RV3-(5-(5-(trifluoromethylVlH-benzord1imidazol-2-ylV2 '-bipyridin-6'- yloxy)cyclopentanecarboxylic acid

Performed as same as Example 188 except that benzyl (1R, 3R)-3-({5-[5- (trifluorom ethyl)- 1 H-benzimidazol-2-yl]-2,3 '-bipyridin -6'- yl}oxy)cyclopentanecarboxylate was used as the starting materials. This resulted in 62 mg (60%) of (1R, 3R)-3-(5-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2-yl)-2,3'- bipyridin-6'-yloxy)cyclopentanecarboxylic acid as a white solid. LC-MS (ES, m/z) C2₄H₁₉F₃N₄0₃: 468; Found: 469 [M+H]⁺.

Example 190

lRJS -S-fS-rS-Ctrifluoromethvn-lH-benzordlimidazol^-yD^J'-bipyridin-e'- yloxy cyclopentanecarboxylic acid

Performed as same as Example 188 except that benzyl (1R, 3S)-3-({5-[5- (trifluoromethyl)-lH-benzimidazol-2-yl]-2,3'-bipyridin -6'- yl}oxy)cyclopentanecarboxylate was used as the starting materials. This resulted in 22 mg (42%) of (1R, 3S)-3-(5-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2-yl)-2,3'- bipyridin-6'-yloxy)cyclopentanecarboxylic acid as a white solid. LC-MS (ES, m/z) C24H19F3N4O3 : 468; Found: 469 [M+H]⁺.

Example 191

(l S3S)-3-(5-r5-(trifluoromethylV lH-benzordlirnidazol-2-yl)-2,3'-bipyridin-6'- yloxy)cyclopentanecarboxylic acid

Performed as same as Example 188 except that benzyl (I S, 3S)-3-({5-[5- (trifluoromethyl)- lH-benzimidazol-2-yl]-2,3'-bipyridin -6'- yl}oxy)cyclopentanecarboxylate was used as the starting materials. This resulted in 66 mg (63%) of (I S, 3S)-3-(5-(5-(trifluoromethyl)-l H-benzo[d]imidazol-2-yl)-2,3'- bipyridin-6'-yloxy)cyclopentanecarboxylic acid as a white solid. LC-MS (ES, m/z) C₂₄Hi9F₃N₄03: 468; Found: 469 [M+H]⁺.

Example 192

trans-4-(5-(5-(5-(trifluoromethyl)-lH-benzo[d1imidazol-2-yl)pyridin-2-ynpyrimidin-2- yloxy)cyclohexanecarboxylic acid

Step A: ethyl 4-(5-(4,4,S,5-tetramethyl-1.3,2-dioxaborolan-2-vnpyrimidin-2- yloxy cyclohexanecarboxylate

A mixture of ethyl 4-(5-bromopyrimidin-2-yloxy)cyclohexanecarboxylate (5.3 g, 16. 1 mmol), bis(pinacolato)diboron (4.5 g, 17.71 mmol), potassium acetate (4.74 g, 48.3 mmol) and Pd(dppf)Cl₂ (0.589 g, 0.805 mmol) in 1 ,4-dioxane (60 ml) was stirred over night at 80°C under N₂ in an oil bath. The reaction mixture was cooled to room temperature, concentrated under vacuum then applied onto a silica gel column and eluted with ethyl acetate/hexane 0-50%. This resulted in 5.7 g (94%) of ethyl 4-(5-(4,4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyrimidin-2-yloxy)cyclohexanecarboxylate as a white solid. LC-MS (ES, m/z) C19H29BN2O5: 376; Found: 377 [M+H]⁺. Step B : ethyl 4-(5-f5-(5-(trifluoromethyl)-l H-benzo[d1imidazol-2-vnpyridin-2- yl)pyrimidin-2-yloxy)cyclohexanecarboxylate

A mixture of ethyl 4-(5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)pyrimidin-2-yloxy)cyclohexanecarboxylate (0.77 g, 2.05 mmol), 2-(6-bromopyridin-3- yl)-5-(trifluoromethyl)-lH-benzo[d]imidazole (0.7 g, 2.05 mmol), sodium carbonate (0.434 g, 4.09 mmol) and Pd(dppf)Cl₂ (0.075 g, 0.102 mmol) are suspended in DMF (10 ml) and water (2.5 ml), The reaction mixture was stirred over night at 80°C under N₂ in an oil bath. The reaction mixture was cooled to room temperature, water (50 ml) added, extracted with 3x30 mL ethyl acetate. The organic layers were combined, washed with 2x 15 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 15- 100%. This resulted in 0.7 g (67%) of ethyl 4-(5-(5-(5-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)pyridin-2-yl)pyrimidin-2-yloxy)cyclohexanecarboxylate as a white solid. LC-MS (ES, m/z) C₂₆H₂₄F₃N₅0₃: 51 1 ; Found: 512 [M+H]⁺.

trans-ethyl 4-(5-(5-(5-(trifluoromethyl)-lH-benzo d1imidazol-2-yl)pyridin-2- yDpyrimidin-2-yloxy)cyclohexanecarboxylate

cis-ethyl 4-(5-(5-(5-(trifluoromethyl)-lH-benzo dlimidazol-2-yl)pyridin-2-yl)pyrimidin-

2-yloxy)cyclohexanecarboxylate

Step C: trans-ethyl 4-(5-(5-(5-(trifluoromethyl)- lH-benzo[dlimidazol-2-yl)pyridin-2- yl)pyrimidin-2-yloxy)cvclohexanecarboxylate and cis-ethyl 4-(5-(5-(5-(trifluoromethyl)- lH-benzo d1imidazol-2-yl pyridin-2-yl)pyrimidin-2-yloxy cyclohexanecarboxylate

Ethyl 4-(5-(5-(5-(trifluoromethyl)- 1 H-benzo[d]imidazol-2-yl)pyridin-2- yl)pyrimidin-2-yloxy)cyclohexanecarboxylate (0.7 g, 1.37 mmol) was separated by chiralCel OD-H (250x30mmI.D) column. Mobile phase: A for SF C0₂ and B for methanol (0.2% DEA) Gradient: B 35 %. This result in trans-ethyl 4-(5-(5-(5- (trifluoromethyl)-lH-benzo[d]imidazol-2-yl)pyridin-2-yl)pyrimidin-2- yloxy)cyclohexanecarboxylate (129 mg, 0.252 mmol). LC-MS (ES, m/z) C₂₆H24F₃N₅0₃: 51 1 ; Found: 512[M+H]⁺ and cis-ethyl 4-(5-(5-(5-(trifluoromethyl)-l H-benzo[d]imidazol- 2-yl)pyridin-2-yl)pyrimidin-2-yloxy)cyclohexanecarboxylate (327 mg, 0.639 mmol). LC- MS (ES, m/z) C₂₆H₂4F₃N₅0₃: 51 1 ; Found: 512[M+H]⁺.

Step D: trans-4-(5-(5-(5-(trifluoromethyl)-lH-benzo d1imidazol-2-yl)pyridin-2- yl)pyrimidin-2-yloxy)cyclohexanecarboxylic acid

A mixture of trans-ethyl 4-(5-(5-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl)pyridin-2-yl)pyrimidin-2-yloxy)cyclohexanecarboxylate (60 mg, 0.1 17 mmol) and lithium hydroxide (14 mg, 0.587 mmol) in MeOH (2 ml), THF (2 ml), water (1 ml). The reaction mixture stirred at room temperature over night, and then concentrated under vacuum, then purified by Gilson acetonitril (0.05%TFA)/water (0.05%TFA) 20- 100%. This resulted in 32 mg (46%) of trans-4-(5-(5-(5-(trifluoromethyl)-l H-benzo[d]imidazol- 2-yl)pyridin-2-yl)pyrimidin-2-yloxy)cyclohexanecarboxylic acid as a white solid. LC-MS (ES, m/z) C₂₄H₂₀F₃NsO₃ : 483; Found: 484 [M+H]⁺.

Example 193

cis-4-(5-(5-(5-(trifluoromethyl)-lH-benzo[d1imidazol-2-yl)pyridin-2-yl)pyrimidin-2- yloxy)cyclohexanecarboxylic acid

A mixture of cis-ethyl 4-(5-(5-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl)pyridin-2-yl)pyrimidin-2-yloxy)cyclohexanecarboxylate (100 mg, 0.196 mmol) and lithium hydroxide (23.4 mg, 0.978 mmol) in MeOH (2 ml), THF (2 ml), water (1 ml). The reaction mixture stirred at room temperature over night, and then concentrated under vacuum, then purified by Gilson acetonitril (0.05%TFA)/water (0.05%TFA) 20-100%. This resulted in 68 mg (58%) of cis-4-(5-(5-(5-(trifluoromethyl)- lH-benzo[d]imidazol-2- yl)pyridin-2-yl)pyrimidin-2-yloxy)cyclohexanecarboxylic acid as a white solid. LC-MS (ES, m/z) C₂₄H2oF3N₅0₃ : 483; Found: 484 [M+H]⁺.

In the same procedure of the preparation of Example 163, the follow compounds (Example 194-21 1) were prepared by starting from ethyl cis-4-[(5-formyI-2,3'-bipyridin- 6'-yl)oxy]cyclohexanecarboxylate in Step A and different aromatic 1,2-diamines for the benzimidazole formation.

Example 194 -21 1

In the same procedure of the preparation of Example 173, the follow compounds (Example 212-232) were prepared by starting from cz^'5^,-4-{[5-(3-fluoro-4-formylphenyl)pyridin-2- yl]oxy}cyclohexanecarboxylate in Step A and different aromatic 1 ,2-diamines for the benzimidazole formation.

Example 212-232

Example 233 ethyl 2-(trans-4-(5-(5-(trifluoromethyl)- l H-benzo[d]imidazol-2-yl)-2J'-bipyridin-6'- yloxy)cvclohexyl)acetate

A mixture of ethyl 2-(4-(5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin- 2 yloxy)cyclohexyl)acetate (0.8 g, 2.05 mmol), 2-(6-bromopyridin-3-yl)-5- (trifluoromethyl)-lH-benzo[d]imidazole (0.7 g, 2.05 mmol), sodium carbonate (0.434 g, 4.09 mmol) and Pd(dppf)Cl₂ (0.075 g, 0.102 mmol) are suspended in DMF (15 ml) and water (3.75 ml), The reaction mixture was stirred over night at 80°C under N₂ in an oil bath. The reaction mixture was cooled to room temperature, water (50 ml) added, extracted with 3x30 mL ethyl acetate. The organic layers were combined, washed with 2x15 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 15- 100%. This resulted in 1 g (93%) of ethyl 2-(4-(5-(5-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)cyclohexyl)acetate as a white solid. LC- MS (ES, m/z) C₂₈H2₇F₃N₄0₃: 524; Found: 525 [M+H]⁺.

Example 234

ethyl 2-(cis-4-(5-(5-(trifluoromethyl)-lH-benzordlimidazol-2-yl)-2.3'-bipyridin-6'- yloxy)cyclohexyl)acetate

Ethyl 2-(4-(5-(5-(trifluoromethyl)-l H-benzo[d]imidazol-2-yl)-2,3'-bipyridin-6' yloxy)cyclohexyl)acetate (1 g, 1.91 mmol) was separated by chiralPak AD-H (250x30mmI.D) column. Mobile phase: A for SF C0₂ and B for ethanol (0.2% DEA) Gradient: B 40 %. This result in ethyl 2-(trans-4-(5-(5-(trifIuoromethyl)-lH- benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)cyclohexyl)acetate (203mg, 0.387 mmol). LC-MS (ES, m/z) C₂₈H₂7F₃N₄0₃: 524; Found: 525[M+H]⁺ and ethyl 2-(cis-4-(5-(5- (trifluoromethyl)-lH-benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)cyclohexyl)acetate (335 mg, 0.639 mmol). LC-MS (ES, m/z) C₂₈H₂₇F₃N₄0₃: 524; Found: 525[M+H]⁺.

Example 235

2-(trans-4-(5-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2-yl)-2.3'-bipyridin-6'- yloxy)cyclohexyl acetic acid

A mixture of ethyl 2-(trans-4-(5-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl)-2,3'-bipyridin-6'-yloxy)cyclohexyl)acetate (100 mg, 0.191 mmol) and lithium hydroxide (22.8 mg, 0.953 mmol) in MeOH (2 ml), THF (2 ml), water (1 ml). The reaction mixture stirred at room temperature over night, and then concentrated under vacuum, then purified by reverse phase HPLC. This resulted in 22 mg (22.5%) of 2- (trans-4-(5-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'- yloxy)cyclohexyl)acetic acid as a white solid. LC-MS (ES, m/z) C₂6H₂₃F₃N₄0₃: 496; Found: 497 [M+H]⁺.

Example 236

2-fc? 4-(5-(5-(trifluoromethyn-lH-benzo dlimidazol-2-yl)-2,3'-bipyridin-6'- yloxy)cvclohexyl)acetic acid

A mixture of ethyl 2-(cis-4-(5-(5-(trifluoromethyl)- l H-benzo[d]imidazol-2-yl)- 2,3'-bipyridin-6'-yloxy)cyclohexyl)acetate (100 mg, 0.191 mmol) and lithium hydroxide (22.8 mg, 0.953 mmol) in MeOH (2 ml), THF (2 ml), water (1 ml). The reaction mixture stirred at room temperature over night, and then concentrated under vacuum, then purified by reverse phase HPLC. This resulted in 65 mg (65.4%) of 2-(cis-4-(5-(5- (trifluoromethyl)-lH-benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)cyclohexyl)acetic acid as a white solid. LC-MS (ES, m/z) C26H23F3N4O3 : 496; Found: 497 [M+H]⁺

Example 237

cis-4-(5-(5-fluoro- 1 H-benzo[d1imidazol-2-yl)-23'-bipyridin-6'-yloxy)- 1 - methylcyclohexanecarboxylic acid

Step A: ethyl 4-(5-(5-fluoro-lH-benzo dlimidazol-2-yn-2,3'-bipyridin-6'-yloxyVl - methylcyclohexanecarboxylate

Performed as same as general method B, except that ethyl l-methyl-4-(5- (4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)cyclohexanecarboxylate and 2-(6-bromopyridin-3-yl)-5-fluoro-lH-benzo[d]imidazole were used as the starting materials. This resulted in 350 mg (57.4%) of ethyl 4-(5-(5-fluoro-lH-benzo[d]imidazol- 2-yl)-2,3'-bipyridin-6'-yloxy)-l-methylcyclohexanecarboxylate as a white solid. LC-MS (ES, m/z) C27H27FN4O3: 474; Found: 475 [M+H]⁺.

Step B: cis-ethyl 4-(5-(5-fluoro-l H-benzo[dlimidazol-2-yl)-2.3'-bipyridin-6'-yloxy)-l - methylcyclohexanecarboxylate and trans-ethyl 4-(5-(5-fluoro-lH-benzo[d^~|imidazol-2- y0-2,3'-bipyridin-6'-yloxy)- l -methylcyclohexanecarboxylate

Ethyl 4-(5-(5-fluoro-lH-benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)-l - methylcyclohexanecarboxylate was separated by SFC-HPLC (60% 2: 1 MeOH/MeCN on IA) to get cis-ethyl 4-(5-(5-fluoro- lH-benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)-l - methylcyclohexanecarboxylate (58 mg). LC-MS (ES, m/z) C₂₇H₂₇FN₄0₃: 474; Found: 475 [M+H]⁺. trans-ethyl 4-(5-(5-fluoro-lH-benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'- yloxy)-l -methylcyclohexanecarboxylate ( 16 mg). LC-MS (ES, m/z) C₂₇H₂₇FN₄0₃: 474; Found: 475 [M+H]⁺.

Step C: cis-4-(5-(5-fluoro- 1 H-benzofd] imidazol-2-yl)-2,3 '-bipyridin-6'-yloxy)- 1 - methylcyclohexanecarboxylic acid

A mixture of cis-ethyl 4-(5-(5-fluoro-lH-benzo[d]imidazol-2-yl)-2,3'-bipyridin- 6'-yloxy)-l -methylcyclohexanecarboxylate (38 mg, 0.08 mmol) and hydrochloride acid (1 ml, 18.5%>) heated at 90°C for 30 minutes, then purified by Gilson acetonitril

(0.05%TFA)/water (0.05%TFA) 20-100%. This resulted in 18 mg (40.1%) of cis-4-(5-(5- fluoro-lH-benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)-l- methylcyclohexanecarboxylic acid as a white solid. LC-MS (ES, m/z) C₂5H₂₃FN₄0₃: 446; Found: 447 [M+H]⁺.

Example 238

trans-4-(5-(5-fluoro-lH-benzo[d1imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)-l- methylcyclohexanecarboxylic acid Performed as same as the step C in Example 237 except that trans-ethyl 4-(5-(5- fluoro-lH-benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)-l -methyl

cyclohexanecarboxylate was used as the starting materials. This resulted in 6 mg (39.1%) of trans-4-(5-(5-fluoro-l H-benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)-l- methylcyclohexanecarboxylic acid as a white solid. LC-MS (ES, m/z) C₂5H₂₃FN₄0₃: 446; Found: 447 [M+H]⁺.

Example 239

cz 4-({5-F4-(4-chloro-3H-imidazo[4,5-clpyridi

1 -methylcyclohexanecarboxylic acid

Step A : Ethyl m-4-(|5-r4-(^"4-chloro-3H-imidazor4,5-c1pyridin-2-vn-3- fluorophenyllpyridin-2-y 11 oxy)- 1 -methylcyclohexanecarboxy late

In the same procedure as general method A, ethyl c«-4-({5-[4-(4-chloro-3H- imidazo[4,5-c]pyridin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)-l-methylcyclo

hexanecarboxylate was prepared. LC-MS (ES, m/z): C₂₇H₂₆C1FN₄0₃: 508; Found: 509 [M+H]⁺.

Step B : c^-4-({5-[4-(4-chloro-3H-imidazo[4,5-c1pyridin-2-yn-3-fluorophenyl]pyridin-2- yl }oxy)- 1 -methylcyclohexanecarboxylic acid

Ethyl cw-4-({5-[4-(4-chloro-3H-imidazo[4,5-c]pyridin-2-yl)-3-fluorophenyl] pyridin-2-yl}oxy)-l-methylcyclohexanecarboxylate (74 mg, 0.15 mmol) was added con. HC1/H₂0 (0.8ml/0.2 ml). The mixture was heated to 80 °C for 30 min. Concentrated, the residue was purified by reverse phase HPLC to afford cw-4-({5-[4-(4-chloro-3H- imidazo[4,5-c]pyridin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)-l-methylcyclohexane carboxylic acid. LC-MS (ES, m/z): C₂₅H₂₂C1FN₄0₃: 480; Found: 481 [M+H]⁺. In the same procedure as the preparation of Example 239, the following compounds were prepared as Example 240-252.

OH

Example 240 -252

Example 252 _CI^^N

In the same procedure as the preparation of Example 239, the following compounds were prepared as Example 253-256.

Example 253 -256

Example 256

In the same procedure as the preparation of Example 239, the following compounds were prepared as Example 257-267.

Example 257 -267

Example 267 509 510

In the same procedure as the preparation of Example 239, the following compounds were prepared as Example 268-277.

Example 267-277

Example 277 562 563

Example 278

trans-3-(5-(3-fluoro-4-(5-fluoro- lH-benzo[d1imidazol-2-yl phenyl)pyridin-2- yloxy)cvclobutanecarboxylic acid

Step A: trans-benzyl 3-Γ5- 3 -fluoro-4-formylpheny l~)pyridin-2-yloxy)cyclobutane carboxylate

A mixture of trans-benzyl 3-(5-bromopyridin-2-yloxy)cyclobutane carboxylate (Intermediate 44, 1 g, 2.76 mmol), 3-fluoro-4-formylphenylboronic acid (0.56 g, 3.31 mmol), sodium carbonate (0.59 g, 5.52 mmol) and Pd(PPh₃)₄ (0.19 g, 0.166 mmol) are suspended in DME (12 ml) and water (2.5 ml), The reaction mixture was put into microwave oven at 90°C for 10 minutes. The reaction mixture was cooled to room temperature, water (50 ml) added, extracted with 3x15 ml ethyl acetate. The organic layers were combined, washed with 2x10 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 0-85%. This resulted in 0.67 g (60%) of trans-benzyl 3-(5-(3-fluoro-4-formylphenyl)pyridin-2-yloxy)cyclobutanecarboxylate

as a white solid. LC-MS (ES, m/z) C₂₄H₂₀FNO₄: 405; Found: 406 [M+H]⁺.

Step B: trans-3-(5-(3-fluoro-4-(5-fluoro-lH-benzo[d1imidazol-2-yl)phenyl)pyridin-2- yloxy)cyclobutanecarboxylic acid

A mixture of trans-benzyl 3-(5-(3-fluoro-4-(5-fluoro-lH-benzo[d]imidazol-2- yl)phenyl)pyridin-2-yloxy)cyclobutanecarboxylate (70 mg, 0.137 mmol) and lithium hydroxide (17 mg, 0.684 mmol) in THF (2 ml), water (1 ml). The reaction mixture stirred at room temperature over night, and then concentrated under vacuum, then purified by reverse phase HPLC. This resulted in 18 mg (24.6%) of trans-3-(5-(3-fluoro-4-(5-fluoro- lH-benzo[d]imidazol-2-yl)phenyl)pyridin-2-yloxy)cyclobutanecarboxylic acid as a white solid. LC-MS (ES, m/z) C₂3Hi₇F₂N₃0₃: 421 ; Found: 422 [M+H]⁺.

Example 279

Trans 3-(5-(3-fluoro-4-(5-fluoro-lH-benzo[dlimidazol-2-yl)phenyl)pyridin-2- yloxy)cyclobutanecarboxylic acid

In the same procedure for the preparation of Example 278, using cw-benzyl 3-(5- bromopyridin-2-yloxy)cyclobutane carboxylate (Intermediate 45), Trans 3-(5-(3-fluoro-

4-(5-fluoro-l H-benzo[d]imidazol-2-yl)phenyl)pyridin-2-yloxy)cyclobutanecarboxylic acid was prepared.

In the same procedure as the preparation of Example 278, the following compounds were prepared as Example 280-289.

Example 280-289

In the same procedure as the preparation of Example 278, the following compounds were prepared as Example 290-289.

Example 298

cis-3 -(5 -(4-(5 -chloro- 1 H-benzo[d] imidazol-2-y l)-3 -fluorophenyl)pyridin-2-yloxy)- 1 - methylcyclobutanecarboxylic acid

Step A: methyl 3-(5-bromopyridin-2-yloxy)-l -methylcyclobutanecarboxylate

Performed in the same procedure as the preparation of Intermediate 37, except that trans-methyl 3-(5-bromopyridin-2 yloxy)cyclobutanecarboxylate was used as the starting materials. This resulted in 0.9 g (21.5%) of methyl 3-(5-bromopyridin-2-yloxy)- 1 -methylcyclobutanecarboxylate as a white solid. LC-MS (ES, m/z) Ci₂Hi₄BrN0₃: 300; Found: 301 [M+H]⁺.

Step B: methyl 3-(5-(4-(5-chloro-lH-benzo dlimidazol-2-vn-3-fluorophenyl)pyridin-2- yloxyVl -methylcyclobutanecarboxylate

Performed used the general method B, except that methyl 3-(5-bromopyridin-2- yloxy)-l -methylcyclobutanecarboxylate and 5-chloro-2-(2-fluoro-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)-lH-benzo[d]imidazole were used as the starting materials. This resulted in 300 mg (48%) of methyl 3-(5-(4-(5-chloro-lH- benzo[d]imidazol-2-yl)-3-fluorophenyl)pyridin-2-yloxy)-l- methylcyclobutane carboxylate as a white solid. LC-MS (ES, m/z) C₂₅H₂iClFN₃0₃: 465; Found: 466 [M+H]⁺.

Step C: trans-methyl 3-(5-(4-(5-chloro-lH-benzo[dlimidazol-2-yl)-3-fluorophenyl) pyridin-2-yloxy)-l -methylcyclobutanecarboxylate and cis-methyl 3-(5-(4-(5-chloro-lH- benzo[dlimidazol-2-yl)-3-fluorophenyl)pyridin-2-yloxy)-l -methylcyclobutane

carboxylate

Methyl 3-(5-(4-(5-chloro-lH-benzo[d]imidazol-2-yl)-3-fluorophenyl) pyridin-2-yloxy)-l -methylcyclobutanecarboxylate was separated by SFC-HPLC (45% 2: 1 MeOH/MeCN on AS) to get trans-methyl 3-(5-(4-(5-chloro-lH-benzo[d]imidazol-2- yl)-3-fluorophenyl)pyridin-2-yloxy)-l-methylcyclobutanecarboxylate (55 mg, RT = 4.788 min). LC-MS (ES, m/z) C₂₅H₂iClFN₃0₃: 465; Found: 466 [M+H]⁺. cw-methyl 3- (5-(4-(5-chloro-lH-benzo[d]imidazol-2-yl)-3-fluorophenyl)pyridin-2-yloxy)-l- methylcyclo butanecarboxylate (180 mg, RT = 2.503 min). LC-MS (ES, m/z)

C₂₅H₂,C1FN₃0₃: 465; Found: 466 [M+H]⁺.

Step D: cis-3-(5-f4-f5-chloro-lH-benzo[dlimidazol-2-yl)-3-fluorophenyl)pyridin-2- yloxy)- 1 -methyleyclobutanecarboxylic acid

Performed in same way by hydrolysis of cis-methyl 3-(5-(4-(5-chloro-lH- benzo[d]imidazol-2-yl)-3-fluorophenyl)pyridin-2-yloxy)-l-methylcyclobutane carboxylate was used as the starting materials. This resulted in 28 mg (38.4%) of cis-3- (5-(4-(5-chloro-lH-benzo[d]imidazol-2-yl)-3-fluorophenyl)pyridin-2-yloxy)-l- methylcyclobutanecarboxylic acid as a white solid. LC-MS (ES, m/z) C₂₄Hi9ClFN₃0₃: 451 ; Found: 452 [M+H]⁺.

Example 299

trans-3-(5-(4-(5-chloro-lH-benzo[dlimidazol-2-yl)-3-fluorophenyl)pyridin-2-yloxy)-l- methyleyclobutanecarboxylic acid

Hyrdolysis in general method of trans-methyl 3-(5-(4-(5-chloro-lH- benzo[d]imidazol-2-yl)-3-fluorophenyI)pyridin-2-yloxy)-l- methylcyclobutanecarboxylate was used as the starting materials. This resulted in 31 mg (63.8%») of trans-3-(5-(4-(5-chloro-lH-benzo[d]imidazol-2-yl)-3-fluorophenyl)pyridin-2- yloxy)-l -methyleyclobutanecarboxylic acid as a white solid. LC-MS (ES, m/z)

C₂₄H₁₉C1FN₃0₃: 451; Found: 452 [M+H]⁺.

Example 300

OOH

cis-3-(5-(3-fluoro-4-^('5-(trifluoromethyl)-lH-benzo[d]imidazol-2-ynphenvnpyra2in-2- yloxy)cyclobutanecarboxylic acid

Step A: ethyl 3- (5-bromopyrazin-2-ynoxy]cyclobutanecarboxylate

In the same procedure as the preparation of Intermediate 35 using

Mitsunobu reaction condition, 2-bromo-5-hydroxypyrazine, ethyl 3- hydroxycyclobutylcarboxylate as starting material, ethyl 3-[(5-bromopyrazin-2- yl)oxy]cyclobutanecarboxylate was prepared. LC-MS (ES, m/z) CiiHi₃BrN₂0₃: 300; Found: 301 [M+H]⁺.

Step B: ethyl 3-(^'5-(3-fluoro-4-(5-(trifluoromethyl^')-lH-benzo[d1imidazol-2- y0phenyl)pyrazin-2-yloxy cyclobutanecarboxylate

Performed as same as general method B except that ethyl 3-(5-bromopyrazin-2- yloxy)cyclobutanecarboxylate and 2-(2-fluoro-4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan- 2-yl)phenyl)-5-(trifluoromethyl)-lH-benzo[d]imidazole were used as the starting materials. This resulted in 2.5 g of ethyl 3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)phenyl)pyrazin-2-yloxy)cyclobutanecarboxylate as a white solid. LC-MS (ES, m/z) C25H20F4N4O3: 500; Found: 501 [M+H]⁺.

Step C: cis-ethyl 3-(5-(3-fluoro-4- 5-rtrifluoromethvn-lH-benzo[dlimidazol-2- yDphenyDpyrazin-2-yloxy)cyclobutanecarboxylate and trans-ethyl 3-(5-(3-fluoro-4-(5- (^"trifluoromethyl)-lH-benzo[d1imidazol-2-ynphenynpyrazin-2- yloxy)cyclobutanecarboxylate

Ethyl 3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl)phenyl)pyrazin-2-yloxy)cyclobutanecarboxylate separated by ChiralPak AD-H (250x30mmI.D). Mobile phase: A for SFC C0₂ and B for Ethanol, gradient 40% B. This result in cis-ethyl 3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl)phenyl)pyrazin-2-yloxy)cyclobutanecarboxylate (523 mg). LC-MS (ES, m/z)

C₂₅H2oF4N40₃: 500; Found: 501 [M+H]⁺ and trans-ethyl 3-(5-(3-fluoro-4-(5- (trifluoromethyl)-lH-benzo[d]imidazol-2-yl)phenyl)pyrazin-2- yloxy)cyclobutanecarboxylate (273 mg). LC-MS (ES, m/z) C₂₅H2oF4N₄0₃ : 500;

501 [M+H]⁺.

Step D: cis-3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl)pheny0pyrazin-2-yloxy)cyclobutanecarboxylic acid

Hydrolysis of cw-ethyl 3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)phenyl)pyrazin-2-yloxy)cyclobutanecarboxylate resulted in 140 mg (59.7%) of cis-3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl)phenyl)pyrazin-2-yloxy)cyclobutanecarboxylic acid as a white solid. LC-MS (ES, m/z) C₂₃Hi₆F₄N₄03 : 472; Found: 473 [M+H]⁺.

Example 301

trans-3-r5-(3-fluoro-4-(5-(trifluoromethyl)-lH-benzofd1imidazol-2-yl)phenyl)pyrazin-2- yloxy)cyclobutanecarboxylic acid

Hydrolysis of trans-ethyl 3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)phenyl)pyrazin-2-yloxy)cyclobutanecarboxylate resulted in 72 mg (51.2%) of trans-3-(5-(3-fluoro-4-(5-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl)phenyl)pyrazin-2-yloxy)cyclobutanecarboxylic acid as a white solid. LC-MS (ES, m/z) C₂3H₁₆F₄N₄0₃: 472; Found: 473 [M+H]⁺. OOH

cis-3-(5-(3-fluoro-4-(5-fluoro-lH-benzo|^"dlimidazol-2-yl)phenyl)pyrazin-2- yloxy^cyclobutanecarboxylic acid

Step A: ethyl 3-(5-(3-fluoro-4-(5-fluoro-lH-benzo[d1imidazol-2-yl)phenyl)pyrazin-2- yloxy cyclobutanecarboxylate

Performed as same as the Example 299 except that ethyl 3-(5- bromopyrazin-2-yloxy)cyclobutanecarboxylate and 5-fluoro-2-(2-fluoro-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-lH-benzo[d]imidazole were used as the starting materials. This resulted in 2.9 g of ethyl 3-(5-(3-fluoro-4-(5-fluoro-lH- benzo[d]imidazol-2-yl)phenyl)pyrazin-2-yloxy)cyclobutanecarboxylate as a white solid. LC-MS (ES, m/z) C₂₄H₂oF₂N₄0₃: 450; Found: 451 [M+H]⁺.

Step B: cis-ethyl 3-(5-(3-fluoro-4-(5-fluoro-lH-benzo[d]imidazol-2-ynphenyl)pyrazin-2- yloxy)cyclobutanecarboxylate and trans-ethyl 3-(5-(3-f1uoro-4-(^"5-fluoro-lH- benzo[d]imidazol-2-ynphenyl)pyrazin-2-yloxy)cyclobutanecarboxylate

Ethyl 3 -(5 -(3 -fluoro-4-(5 -fluoro- 1 H-benzo[d]imidazol-2-yl)pheny l)pyrazin-2- yloxy)cyclobutanecarboxylate separated by ChiralCel AOJ-H (250x50mmI.D). Mobile phase: A for SFC C0₂ and B for Ethanol, gradient 40% B. This result in cis-ethyl 3-(5-(3- fluoro-4-(5-fluoro-lH-benzo[d]imidazol-2-yl)phenyl)pyrazin-2- yloxy)cyclobutanecarboxylate (473 mg). LC-MS (ES, m/z) C₂4H2oF₂N₄0₃: 450; Found: 451 [M+H]⁺ and trans-ethyl 3-(5-(3-fluoro-4-(5-fluoro-lH-benzo[d]imidazol-2- yl)phenyl)pyrazin-2-yloxy)cyclobutanecarboxylate (262 mg). LC-MS (ES, m/z)

C24H20F2 4O3: 450; Found: 451 [M+H]⁺.

Step C: cis-3-(^"5-(3-fluoro-4-(5-fluoro-lH-benzo[^"d]imidazol-2-yl)phenyl)pyrazin-2- yloxy)cyclobutanecarboxylic acid

Hyrdolysis of cis-ethyl 3-(5-(3-fluoro-4-(5-fluoro-lH-benzo[d]imidazol-

2- yl)phenyl)pyrazin-2-yloxy)cyclobutanecarboxylate resulted in 151 mg (66.7%) of cis-

3- (5-(3-fluoro-4-(5-fluoro-lH-benzo[d]imidazol-2-yl)phenyl)pyrazin-2

yloxy)cyclobutanecarboxylic acid_as a white solid. LC-MS (ES, m/z) C22H16F2 4O3 : 422; Found: 423 [M+H]⁺.

Example 303

trans-3 -(5 -(3-fluoro-4-(5 -fluoro- 1 H-benzo[d] imidazol-2-yl)phenyl pyrazin-2- yloxy)cyclobutanecarboxylic acid

Hyrdolysis of trans-ethyl 3-(5-(3-fluoro-4-(5-fluoro-lH- benzo[d]imidazol-2-yl) phenyl)pyrazin-2-yloxy)cyclobutanecarboxylate resulted in 92 mg (64.4%) of trans-3-(5-(3-fluoro-4-(5-fluoro-lH-benzo[d]imidazol-2- yl)phenyl)pyrazin-2 yloxy)cyclobutanecarboxylic acid_as a white solid. LC-MS (ES, m/z) C₂₂H₁₆F₂N₄0₃: 422; Found: 423 [M+H]⁺.

2-(trans-4-(5-(^"lH-benzo[d]imidazol-2-yl)-2,3^,-bipyridin-6'-yloxy)cyclohexynacetic acid

Step A: methyl 2-(trans-4-(5-(lH-benzordlimidazol-2-yl)-2,3'-bipyridin-6'- yloxy)cyclohexyl)acetate

Performed using general method B, using 2-(6-bromopyridin-3-yl)-lH- benzo[d] imidazole and methyl 2-(trara-4-(5-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2- yl)pyridin-2-yloxy)cyclohexyl)acetate were used as the starting materials. This resulted in 0.38 g of methyl 2-(trans-4-(5-(lH-benzo[d]imidazol-2-yl)-2_J3'-bipyridin-6'- yloxy)cyclohexyl)acetate as a white solid. LC-MS (ES, m/z) C₂6H₂₆N₄0₃: 442; Found: 443 [M+H]⁺.

Step B: 2-(trans-4-(5-(lH-benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)cvclohexyn acetic acid

Hydrolysis of methyl 2-(trans-4-(5-(lH-benzo[d]imidazol-2-yl)-2,3'- bipyridin-6'-yloxy)cyclohexyl)acetate resulted in 78 mg (53%) of 2-(trans-4-(5-(lH- benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)cyclohexyl)acetic acid as a white solid. LC-MS (ES, m/z) C25H24N4O3: 428; Found: 429 [M+H]⁺.

Example 305

H

2-(trans-4-(5-(4-(lH-benzo d1imidazo]-2-yl)-3-fluorophenyl)pyridin-2- yloxy)cyclohexyl)acetic acid

Step A: methyl 2-( (I r,4r)-4-(5 -( 4-( 1 H-benzo [dl imidazol-2-yl)-3 -fluorophenyl)pyridin-2- yloxy)cyclohexyl)acetate

Performed with general method A,using methyl 2-(trans-4-(5-bromopyridin-2- yloxy)cyclohexyl)acetate and benzene- 1 ,2-diamine were used as the starting material. This resulted in 0.09 mg (42.4%) of methyl 2-(trans-4-(5-(4-(lH-benzo[d]imidazol-2-yl)- 3-fluorophenyl)pyridin-2-yloxy)cyclohexyl)acetate as a white solid. LC-MS (ES, m/z) C₂₇H₂₆FN₃0₃ : 459; Found: 460 [M+H]⁺.

Step B: 2-(trans-4-(5-(4-( l H-benzo [d]imidazol-2-yl)-3-fluorophenyDpyridin-2- yloxy)cyclohexyl)acetic acid

Hydrolysis of methyl 2-(trans-4-(5-(4-(lH-benzo[d]imidazol-2-yI)-3- fluorophenyl)pyridin-2-yloxy)cyclohexyl)acetate resulted in 68 mg (62.1 %) of 2-(trans-4- (5-(4-(lH-benzo[d]imidazol-2-yl)-3-fluorophenyl)pyridin-2-yloxy)cyclohexyl)acetic acid as a white solid. LC-MS (ES, m/z) C₂₆H₂₄FN₃0₃: 445; Found: 446 [M+H]⁺.

In the same procedure as the preparation of Example 305, the following compounds were prepared by using different aromatic diamine and Intermediate 48 methyl (tr ra-4-{[5-(3-fluoro-4-formylphenyl)pyridin-2-yl]oxy}cyclohexyl)acetate. Example 306-325. COOH

Example 306-325

Example 315 513 514

Example 316 446 447

Example 317 476 477

Example 318 473 474

Example 319 459 460

Example 320 473 474

Example 321 460 461

Example 322 ■ X 473 474

H

Example 323 501 502

H

Example 324 XX>'- 473 474

H

Example 325 459 460

H

In the same procedure as the preparation of Example 305, the following compounds were prepared by using different aromatic diamine and Intermediate 49 methyl (cw-4-{[5-(3-fluoro-4-formylphenyl)pyridin-2-yl]oxy}cyclohexyl)acetate.

In the same procedure as the preparation of Example 304, the following compounds were prepared by using different aromatic diamine and Intermediate 46 methyl {iraw-4-[(5-formyl-2,3'-bipyridin-6'-yl)oxy]cyclohexyl}acetate. COOH

Example 343-354

P T/US2012/064273

In the same procedure as the preparation of Example 305, the following

compounds were prepared by using different aromatic diamine and Intermediate 47 methyl {cw-4-[(5-formyl-2,3'-bipyridin-6'-yl)oxy]cyclohexyl}acetate.

Example 355-366

Example 365 497 498

Example 366 473 474

Example 367

H

2-(trans-4-(5-(5-(lH-benzofd1imidazol-2-vnpyrimidin-2-yl)pyridin-2- yloxy)cyclohexyl)acetic acid

Step A: 2-(2-chloropyrimidin-5-yO-lH-benzordlimidazole

Performed for the benzimidazole formation using 2-chloropyrimidine-5- carbaldehyde and benzene- 1,2-diamine were used as the starting material. This resulted in 5.8 g (71.7%) of 2-(2-chloropyrimidin-5-yl)-lH-benzo[d]imidazole as a yellow solid. LC-MS (ES, m/z) C_n H7ClN₄: 230; Found: 231 [M+H]⁺.

Step B: methyl 2-(trans-4-(5-(5-( lH-benzord1imidazol-2-yl)pyrimidin-2-yl)pyridin-2- yloxy)cyclohexyl)acetate

Performed as general method B using 2-(2-chloropyrimidin-5-yl)-lH- benzo[d]imidazole and methyl 2-(trans-4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yloxy)cyclohexyl)acetate were used as the starting materials. This resulted in 46 mg of methyl 2-(trans-4-(5-(5-(lH-benzo[d]imidazol-2-yl)pyrimidin-2-yl)pyridin-2- yloxy)cyclohexyl)acetate as a white solid. LC-MS (ES, m/z) C^LL^NsC^ : 443; Found: 444 [M+H]⁺.

Step C: 2-(trans-4-(5-(5-(lH-benzo[d1imidazol-2-yl)pyrimidin-2-yl pyridin-2- yloxy cyclohexyl)acetic acid

Hydrolysis of methyl 2-(trans-4-(5-(5-(l H-benzo[d]imidazol-2-yl)pyrimidin-2- yl)pyridin-2-yloxy)cyclohexyl)acetate resulted in 168 mg (68.5%) of 2-(trans-4-(5-(5- (lH-benzo[d]imidazol-2-yl)pyrimidin-2-yl)pyridin-2-yloxy)cyclohexyl)acetic acid as a white solid. LC-MS (ES, m/z) C24H23N5O3: 429; Found: 430 [M+H]⁺.

Example 368

c ^-ilS-rS-fluoro^-iESa^.S^J^.Sa-octah drocvcloheptafdlimidazol^- yl)phenyl}pyridin-2-yl}oxy)cyclohexanecarboxylic acid.

Step A: 2-hydroxycycloheptanone

Cycloheptane-l ,2-diol (0.60 g, 4.61 mmol) in Acetonitrile (4 ml) and Water (4.40 ml) was added NaBr0₃ (0.835 g, 5.53 mmol) and NaHS0₃ (0.576 g, 5.53 mmol). The mixture was stirred at room temperature for 2 hr, TLC showed product (by stain).

Continue to stir for 2 hr, no improvement, by product formed. The reaction was quenched with ether, and organic layer was separated, concentrated, the residue was use for next step without purification.

Step B: Ethyl m-4-({5-r3-fluoro-4-( L3a.4,5.6.7.8.8a-octahvdrocvcloheptardlimidazol-2- yl)phenyllpyridin-2-yl}oxy)cyclohexanecarboxylate

2-hydroxycycloheptanone (34.5 mg, 0.269 mmol) in EtOH (2 ml) was added ethyl cis-4- { [5 -(3 -fluoro-4-formy Ipheny l)pyridin-2-y 1] oxy } cyclohexanecarboxy late (100 mg, 0.269 mmol), ammonium acetate (62.3 mg, 0.808 mmol), and catalytic amount of Iodine (6.83 mg, 0.027 mmol). The mixture was hated to 80 °C for 16 hr. Quenched with Na₂S₂0₃ solution, extracted with EtOAc. Separated the organic layer, dried over MgS04, filtered and concentrated, the residue was purified with Prep. TLC (40%

EtOAc/Hexane). LC-MS (ES, m/z): CasI^F^Cb: 477; Found: 478 [M+H]⁺.

ynphenyl1pyridin-2-vUoxy)cyclohexanecarboxylic acid

Hydrolysis of ethyl cw-4-({5-[3-fluoro-4-(l ,3a,4,5,6,7,8,8a-octahydrocyclo hepta[d]imidazol-2-yl)phenyl]pyridin-2-yl}oxy)cyclohexanecarboxylate resulted in cw-4- ({5-[3-fluoro-4-(l ,3a,4,5, 6,7,8, 8a-octahydrocyclohepta[d]imidazol-2-yl)phenyl]pyridin- 2-yl}oxy)cyclohexanecarboxylic acid was prepared. LC-MS (ES, m/z): C₂₆H₂₈FN₃0₃: 449; Found: 450 [M+H]⁺.

Example 369

c .y-4-(^f(5-[3-fluoro-4-(^'6-methyl-3a.4,5,6,7Ja-hexahydro-lH-benzimidazol-2- ynphenyl pyridin-2-yl}oxy)cvclohexanecarboxylic acid

In the same procedure as Example 368, cw-4-({5-[3-fluoro-4-(6-methyl- 3a,4,5,6,7,7a-hexahydro- lH-benzimidazol-2-yl)phenyl]pyridin-2-yl}oxy)cyclohexane carboxylic acid.was prepared. LC-MS (ES, m/z): C₂6H₂₈FN₃0₃: 449; Found: 450 [M+H]⁺.

Example 370

ci -4-({5-[3-fluoro-4-(L4,5,6-tetrahydrocvclopenta[d]imidazol-2-yl)phenyl1pyridin-2- yl}oxy)cyclohexanecarboxylic acid

In the same procedure as Example 368, c/,y-4-({5-[3-fluoro-4-(l ,4,5,6- tetrahydrocyclopenta[d]imidazol-2-yl)phenyl]pyridin-2-yl}oxy)cyclohexanecarboxylic acid was prepared. LC-MS (ES, m/z): C₂₄H₂₄FN₃0₃: 421 ; Found: 422 [M+H]⁺.

Example 371

c/ -4-r(5-{4-f4-(2,2-dimethylpropyl)-lH-imidazol-2-yl1-3-fluorophenyUpyridin-2- vDoxylcyclohexanecarboxylic acid

In the same procedure as Example 368, m-4-[(5-{4-[4-(2,2-dimethylpropyI)- l H- imidazol-2-yl]-3-fluorophenyl}pyridin-2-yl)oxy]cyclohexanecarboxylic acid was prepared. LC-MS (ES, m/z): C26H30FN3O3 : 451 ; Found: 452 [M+H]⁺.

Example 372

(3 ,3-difluoropyrrolidin- 1 -y\) { cis-4-\(5- (3-fluoro-4-[5-itrifluoromethyl)- 1 H- benzimidazol-2-yllphenyl|pyridin-2-yl oxy]-l-methylcvclohexy methanone

To a 20 niL vial, a mixture of cw-4-[(5-{3-fluoro-4-[5-(trifluoromethyl)-lH- benzimidazol-2-yl]phenyl}pyridin-2-yl)oxy]-l-methylcyclohexanecarboxylic acid (, Example 250, 50 mg, 0.097 mmol) in Pyridine (1 ml) was added EDC (44.8 mg, 0.23 mmol), and 3,3-difluoropyrrolidine (1 1.47 mg, 0.107 mmol). The mixture was heated to 55 °C for 16 hr. Quenched with H₂0 and EtOAc, the organic was dried over MgS0₄, Concentrated, the residue was purified by Prep. TLC (40% EtOAc/Hexane) to give the title compound £3,3-difluoropyrrolidin-l -yl){cw-4-[(5-{3-fluoro-4-[5-(trifluoromethyl)- lH-benzimidazol-2-yl]phenyl}pyridin-2-yl)oxy]-l -methylcyclohexyl}methanone. LC- MS (ES, m/z): C₃iH₂₈F₆N₄0₂: 602; Found: 603 [M+H]⁺.

Example 373

{ cisA-\(5 - {3 -fluoro-4-[5 -f trifluoromethyl^")- 1 H-benzimidazol-2- ynphenyl)pyridin-2-yl)oxyl-l-methylcyclohexylKmorpholin-4-yl)methanone

In the same procedure as Example 372, {cw-4-[(5-{3-fluoro-4-[5- (trifluoromethyl)-lH-benzimidazol-2-yl]phenyl}pyridin-2-yl)oxy]-l- methylcyclohexyl}(morpholin-4-yl)methanone was prepared. LC-MS (ES, m/z):

C₃iH₃₀F₄N₃O₃: 581 ; Found: 582 [M+H]⁺.

Example 374

(c ^,-4-[(^"5-(3-fluoro-4-[5-(trifluoromethyl)-lH-benzimidazol-2- yl Jphenyl } p yridin-2-y Doxy] - 1 -methylc yclohexyl I f 4-methylpiperazin- 1 -vDmethanone

In the same procedure as Example 372, {cw-4-[(5-{3-fluoro-4-[5- (trifluoromethyl)-lH-benzimidazol-2-yl]phenyl}pyridin-2-yl)oxy]-l- methylcyclohexyl} (4-methylpiperazin- l-yl)methanone was prepared. LC-MS (ES, m/z): C₃2H₃2F4N₅0₂: 595; Found: 596 [M+H]⁺.

Example 375

(3S,3aR.6R.6aR)-6-r5-r5-chloro-lH-benzordlimidazol-2-vn-2.3'-bipyridin-6'- yloxy hexahydrofuro[3,2-b]furan-3-ol

Following general method C for the ether formation and using Intermediate 50 and (3R,3aR,6S,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-ol (Marko Vogler, etal. Synthesis, 2004, No. 8, 121 1-1228), the title compound can be obtained in 13% yield. LC-MS (ES, m/z) C₂₃Hi₉ClN₄0₄: 450; Found: 451 [M+H]⁺

Example 376

(3R aR.6S.6aRV6-(5-(5-chloro-lH-ben2o dlimidazol-2-yl -2.3'-bipyridin-6'- yloxy)hexahydrofuro[^'3.2-b]furan-3-ol

Following general method C for the ether formation and using Intermediate 50 and (3S,3aR,6R,6aS)-6-methoxyhexahydrofuro[3,2-b]furan-3-ol (Marko Vogler, etal. Synthesis, 2004, No. 8, 121 1-1228), the title compound can be obtained in 13% yield. LC-MS (ES, m/z) C₂₃Hi₉ClN₄0₄: 450; Found: 451 [M+H]⁺

Example 377

(3R.3aR.6R.6aR)- 6-(5-(5-chloro-lH-benzordlimidazol-2-vn-2J'-bipyridin-6'- yloxy hexahvdrofurof3,2-blfuran-3-ol

Following general method C for the ether formation and using Intermediate 50 and (3R,3aR,6R,6aR)-hexahydrofuro[3,2-b]furan-3,6-diol, the title compound can be obtained. LC-MS (ES, m/z) C₂₃Hi₉ClN₄0₄: 450; Found: 451 [M+H]⁺

Example 378

(2S,3R,5S)-5-(5-(5-chloro-lH-benzofdlimidazol-2-yl)-2,3'-bipyridin-6'-yloxy)-2- (hydroxymethyl)tetrahydro-2H-pyran-3-ol

Following general method C for the ether formation and using Intermediate 50 and (2S,3R,5S)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol the title compound can be obtained. LC-MS (ES, m/z) C₂₃H₂iClN₄0₄: 452; Found: 453 [M+H]⁺ _.

Example 379

tmw-4-( r5-(lH-benzimidazol-2-yn-2.3'-bipyridin-6'-ylloxy}cyclohexanecarboxylic acid

In the same procedure as the preparation of Example 163, using 1 ,2-benzidiamine and ethyl trans-4-[(5-formyl-2,3'-bipyridin-6'-yl)oxy]cyclohexanecarboxylate (Intermediate 34, 487 mg, 1.403 mmol) as starting meterial, irans-4-{[5-(lH-benzimidazol-2-yI)-2,3'- bipyridin-6'-yl]oxy}cyclohexanecarboxylic acid was prepared. LC-MS (ES, m/z) C₂₄H₂₂N₄0₃: 414; Found: 415 [M+H]⁺ _.

Example 380

ns,4s)-4-(5-(lH-benzordlimidazol-2-yl)-2.3'-bipyridin-6'-yloxy)-N-(2.2 - trifluoroethyPcyclohexanecarboxamide

To a 7 ml vial was charged with ira« -4-{[5-(lH-benzimidazol-2-yl)-2,3'- bipyridin-6'-yl]oxy}cyclohexanecarboxylic acid (Example 379, 75 mg, 0.17 mmol) in a solution of DMF (2ml), 2,2,2-trifluoroethanamine ( 36 mg, 0.36 mmol), HATU (83 mg, 0,22 mmol) and finally triethylamine (74 mg, 0.57 mmol) at r.t. and the resultant mixture was stirred at 40 c overnight. The product was purified by HPLC on a 19X100 mm, Waters X-Bridge C-l 8, 5μ particle size, linear gradient, standard 5% MeCN/H20 (containing 0.2% NH40H) to 90% MeCN/H20 (containing 0.2% or NH40H) @ 50 mL/min over 10 min (mass directed Fractionlynx). The desired product was collected and concentrated under reduced pressure to remove solvent to give the title compound as white solids (25 mg, 28% yd). LC-MS (ES, m/z) C₂₆H₂4 F₃N₅0₂: 495; Found: 496

[M+H]⁺

The following Examples were synthesized using the approperiate acid

intermediates either 1 cis-4-{[5-(5-fluoro-lH-benzimidazol-2-yl)-2,3'-bipyridin-6'- yl]oxy}cyclohexanecarboxylic acid or trans-4-{[5-(lH-benzimidazol-2-yl)-2,3'-bipyridin- 6'-yl]oxy}cyclohexanecarboxylic acid and appropriate amines, following method described for Example 3.

The following compounds were prepared using the procedure: To a mixture of cw-4-{[5-(6-fluoro-lH-benzimidazol-2-yl)-2,3'-bipyridin-6'- yl]oxy}cyclohexanecarboxylic acid (Example 202, 30 mg, 0.069 mmol), corresponding sulfonylamide (2 eq) and HATU (78 mg, 0.205 mmol) was added DCM (anhydrous, 2 mL) and DIEA (63 μί, 0.342 mmol). The reaction was stirred at ambient temperature for 16 hours. The solvent was evaporated and HOAc (60 μί) was added. The resulting mixture was extracted between EtOAc (4 mL x 2) and water (ImL). The organic phase was combined and concentrated. The crude product was purified by using reversed-phase HPLC to give the product as a TFA salt.

Example 391

3-(5-(3-fluoro-4-(5-fluoro-lH-benzo[d[imidazol-2-yllphenvnpyridine-2- yloxy)cyclobutane- 1 , 1 -dicarboxylic acid

Step A: diethyl 3-(5-(3-fluoro-4-(5-fluoro-lH-benzo[d1imidazol-2-vDphenynpyridin-2- yloxylcyclobutane- 1 , 1 -dicarboxylate

3-fluoro-4-(5-fluoro-lH-benzo[d]imidazol-2-yl)phenylboronic acid (1.47 g, 5.36 mmol), diethyl 3-(5-bromopyridin-2-yloxy)cyclobutane-l,l-dicarboxylate (2.0 g, 5.36 mmol), sodium carbonate (1.14 g, 10.73 mmol) and [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.196 g, 0.268 mmol) are suspended in DMF / H₂0 in a round bottle and heated at 80°C under N₂ over night. After cooled to rt., the reaction mixture was poured into water, extract with EtOAc. dried over Na₂S0₄, concentrated and separated by HPLC (Column: Synergi CI 8 lOu, 250x50mm I.D.;Mobile phase: A for H₂0 (0.1%TFA) and B for Acetonitrile (0.1%TFA); Gradient: B 20%-50% in 30min linearly;Flow rate: 80ml/min; Sample preparation: dissolved in Acetonitrile, 155mg/ml; Injection: 5ml per injection). After separation, the desired fractions were concentrated to remove the organic phases via rotary evaporator at bath temperature 40D. The aqueous layer was lyophilized to give diethyl 3-(5-(3-fluoro-4-(5- fluoro-lH-benzo[d]imidazol-2-yl)phenyl)pyridin-2-yloxy)cyclobutane- 1,1 -dicarboxylate (938.8mg ). ESI-MS calc. for C28H25F2N305: 521.; Found: 522 (M+l).

Step B: 3-(5-(3-fluoro-4-(5-fluoro-lH-benzo[d[imidazol-2-yljphenyllpyridine-2- yloxy)cyclobutane- 1 , 1 -dicarboxylic acid To the solution of diethyl 3-(5-(3-fluoro-4-(5-fluoro-lH-benzo[d]imidazol-2- yl)phenyl)pyridin-2-yloxy)cyclobutane-l,l-dicarboxylate (100 mg, 0.192 mmol) in ethanol (2.0 ml) was added NaOH (5.0 M, 0.19 ml, 0.96 mmol) and stirred under nitrogen at rt overnight. The reaction mixture was acidified by HC1 (37%, 0.157 ml, 1.918 mmol) and then reaction mixture was concentrated, separated by prep HPLC (Column: Synergi CI 8 lOu, 250x50mm I.D;Mobile phase: A for H20 and B for Acetonitrile; Gradient: B 20% -50% in 30min linearly; Flow rate: 80ml/min;Sample preparation: dissolved in Acetonitrile, 20mg/ml; Injection: 7ml per injection) .After separation, the fraction was concentrated to remove the organic phases via rotary evaporator at bath temperature 35. The aqueous layer was lyophilized to give 3-(5-(3- fluoro-4-(5-iluoro-lH-benzo[d]imidazol-2-yl)phenyl)pyridin-2-yloxy)cyclobutane-l,l- dicarboxylic acid ( 3.1mg ) ESI-MS calc. for C24H17F2N305: 465.; Found: 466 (M+1).

Example 392

2-(4-(5-(lH-benzo dlimidazol-2-yl)-2,3'-bipyridin-6'-yloxy)cyclohexyl propan-2-ol

To the solution of ethyl 4-(5-(lH-benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'- yloxy)cyclohexanecarboxylate (Precursor ester for Example 379, 400 mg, 0.904 mmol) in THF (10 ml) was added methyllithium (1.21 ml, 3.62 mmol) and stirred at - 78°C for 5 hrs. LC-MS showed S.M haven't disappeared, added more methyllithium (1.21 ml, 3.62 mmol) and continued to stir at - 78°C for another 2 hrs. The reaction mixture was quench with NH₄C1 (10 ml) , extracted with EtOAc, dried over MgS0₄ and concentrated, and separated by MG II preparative SFC (Column: ChiralCel OJ-H, 250x30 mmI.D.;Mobile phase: A for SF C0₂ and B for Methanol ; Gradient: B 35 % ;Flow rate: 60 mL /min; Sample preparation: dissolved in ethanol, ~10mg/ml;Injection: 3 ml per injection.) to give 2-(4-(5-(lH-benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)cyclohexyl)propan-2-ol (Dl faster elution , 68 mg) ESI-MS calc. for C26H28N402: 428.; Found: 429 (M+1) and 2-(4-(5-(lH-benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'-yloxy)cyclohexyl)propan-2-ol (D2 slower elution, 55 mg) ESI-MS calc. for C26H28N402: 428.; Found: 429 (M+1).

Example 393

To a suspension of (l s,4s)-4-(5-(5-fluoro-lH-benzo[d]imidazol-2-yl)-2,3'-bipyridin-6'- yloxy)cyclohexanecarboxylic acid (Example 202, 50 mg, 0. 16 mmol) in DCM (6 ml) was added 2,3,5-trimethylpyridine (0.031 ml, 0.243 mmol), and then added ethyl chloro formate (0.019 ml, 0.197 mmol) in DCM (1 ml). Reaction mixture was continued to stir at rt for 1 h and then concentrated. The residue was suspended in THF (3 ml), and added coenzyme A Trilithium salt dehydrate (133 mg, 0.162 mmol, dissolved in 4 ml of water and adjusted PH 8 with 1.0 M LiOH) slowly and kept PH to 8 with Li OH (1 M). After completed addition, adjusted PH to 5 with perchloric acid ( 10%), then the reaction mixture was concentrated and lyophilized. Crude product was separated by Reverse HPLC ( on a 19X100 mm, Waters XBridge C 18 column, 5μ particle size, linear gradient, standard 5% ACN/H₂0 to 19% ACN/H₂0 buffering with 0.16% Ammonium Hydroxide @ flow rate 50 mL/min over 5.0 min.) to give title compound (6.5 mg) as white solid. ESI-MS calc. for C24H21FN403: 1 182; Found: 1 183 (M+H).

In the same procedure as the preparation of Example 304, the following compounds were prepared.

Example 396

(4-{[5-(6-chloro-lH-benzimidazol-2-yl)-23'-bi^

acid

Following general method C, using Intermediate 50 5-(5-chloro-lH- benzimidazol-2-yl)-6'-fluoro-2,3'-bipyridine and (4-hydroxypiperidin-l-yl)acetic acid as the starting material to afford product (4-{[5-(6-chloro-lH-benzimidazol-2-yl)-2,3'- bipyridin-6'-yl]oxy}piperidin-l-yl)acetic acid. LC-MS (ES, m/z) C₂₄H₂₂C1N₅0₃: 463; Found: 464 [M+H]⁺

Example 397

6-([5-(6-chloro-lH-benzimidazol-2-yl)-2,3'-bipyridin-6'-ynoxy)spiro 3.31heptane-2- carboxylic acid

Following general method C, using Intermediate 50 5-(5-chloro-lH- benzimidazol-2-yI)-6'-fiuoro-2,3'-bipyridine and 6-hydroxyspiro[3.3]heptane-2- carboxylic acid as the starting material to afford product 6-{[5-(6-chloro-lH- benzimidazol-2-yl)-2,3'-bipyridin-6'-yl]oxy}spiro[3.3]heptane-2-carboxylic acid. LC-MS (ES, m/z) C₂₅H2,C1N₄0₃: 460; Found: 461 [M+H]⁺

Following the procedure in general method A, using Intermediates 53 to 61 and corresponding aromatic diamine, the following compounds were prepard.

ı75

Example 478

(- ^-4-(P5-(3-fl_Uoro-4-(5-rr3-methyl-l,2,4-oxadiazol-5-yl methoxy1-3H-imidazo[4,5- 61pyridin-2-yUphenynpyrimidin-2-yl1oxy)cyclohexyl acetic acid

Step A: 6- f3-methyl-l ,2,4-oxadiazol-5-ynmethoxy1-3-nitropyridin-2-amine To a 50 mL one neck round bottom flask was charged with 6-chloro-3-nitro-2- aminopyridine (300 mg, 1.729 mmol) along with (3-methyl-l,2,4-oxadiazol-5- yl)methanol (197 mg, 1.729 mmol), DMF (5 ml) and finally cesium carbonate (1126 mg, 3.46 mmol). The resulting reactio nmixture was then stirred at room temperature for 16 hor overnight. LC-MS showed formation of product with small amount of starting material left and dimer formed. The mixture was diluted with ethyl acetate (20 mL) and washed with water (10 mL). The organic layer was separated and the aqueous layer was extracted by ethyl acetate (3x). The combined organic phases were dride over MgS04, filtered and concentrated. The crude was purified by MPLC (12 g silica gel, 10 to 50% ethyl acetate in hexanes) to afford product 6-[(3-methyl-l,2,4-oxadiazol-5-yl)methoxy]- 3-nitropyridin-2-amine. LC-MS (ES, m/z) C9H9N5O3 : 251 ; Found: 252 [M+H]⁺.

Step B: Methyl(m-4-{|^"5-(3-fluoro-4-(5- (3-methyl-1.2.4-oxadiazol-5-yl)methoxyl-3H- imidazo[4,5-6]pyridin-2-yl}phenyl)pyrimidin-2-yl oxy|cyclohexyl)acetate

To a 20 mL sample vial was charged with methyl (cw-4-{[5-(5-formylpyridin-2- yl)pyrimidin-2-yl]oxy}cyclohexyl)acetate (100 mg, 0.269 mmol) along with 6-[(3- methyl-l,2,4-oxadiazol-5-yl)methoxy]-3-nitropyridin-2-amine (81 mg, 0.322 mmol), and acetic acid (2 ml). The vial was then heated in an oil bath of 40 °C and zinc(5 eq) was added and the mixture was stirred for 4 hrs. The solvent was concentrated and the residue was partitioned between ethyl acetate (10 mL) and water (5 ml). TLC showed still small amount of starting material left. The remaining zinc was filtered and washed with ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic phases were washed with NaHC0₃ (sat, 5 mL), dried over MgS0₄, filtered and concentrated. The crude was then purified by MPLC (12 g silica gel, 15 to 70% acetone in methylenechloride) to afford light yellow solid product methyl(c/ -4-{[5-(3-fluoro-4-{5-[(3-methyl-l,2,4-oxadiazol-5-yl)methoxy]-3//- imidazo[4,5-Z)]pyridin-2-yl}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetate. LC-MS (ES, m/z) C29H28FN7O5 : 573; Found: 574 [M+H]⁺.

Step C: (c .y-4-{ r5-(3-fluoro-4-i5-r(3-methyl-1.2.4-oxadiazol-5-vnmethoxyl-3H- imidazo[4,5-Z)1pyridin-2-yl}phenyl)pyrimidin-2-ylloxy|cyclohexyl)acetic acid

To a 20 mL sample vial was charged with methy](cw-4-{[5-(3-fluoro-4-{5-[(3- methyl- 1 ,2,4-oxadiazol-5-yl)methoxy]-3H-imidazo[4,5-£]pyridin-2-yl }phenyl)pyrimidin- 2-yl]oxy}cyclohexyl)acetate (65 mg, 0.1 13 mmol) along with lithium hydroxide hydrate (23.78 mg, 0.567 mmol), THF (2 ml) and Water (1 ml). The resulting reaction mixture was stirred at room temperature for 3 hrs. LC-MS showed complete hydrolysis of ester to acid. The mixture was then neutralized by addition of HC1 (IN, 567 uL), diluted with acetonitril (2 mL) and loaded RP HPLC for purification (20 to 80% acetonitrile in water with 0.5% TFA) to afford product (cw-4-{[5-(3-fluoro-4-{5-[(3-methyl-l,2,4-oxadiazol- 5-yl)methoxy]-3H-imidazo[4,5-0]pyridin-2-yl}phenyl)pyrimidin-2- yl]oxy}cyclohexyl)acetic acid. . LC-MS (ES, m/z) C₂₈H₂₆F ₇O₅: 564; Found: 565

[M+H]⁺. :

Example 484 0 N 544 545

DGATl CPM Assay

Examples were assayeded as follows: 20uL substrate mixture of 300uM diolein, 40uM oleoyl-CoA, 10% ethanol and luL of the compound with different concentrations were delivered to a 384 well assay plate (Corning 3573) using a Tecan with TeMO module. Later 19uL of enzyme mixture of 1.05ug/ml human 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. hDGATI IC50 hDGATI IC50 hDGATI IC50

Example (nM) Example (nM) Example (nM)

Example 1 4.571 Example 162 3.997 Example 323 3.642

Example 2 1.939 Example 163 2.005 Example 324 3.293

Example 3 20.1 Example 164 3.036 Example 325 3.392

Example 4 8.961 Example 165 119.6 Example 326 1.298

Example 5 2.998 Example 166 6.015 Example 327 1.572

Example 6 5.366 Example 167 136.5 Example 328 11.1

Example 7 2.533 Example 168 123.7 Example 329 1.343

Example 8 12.57 Example 169 53.93 Example 330 4.103

Example 9 440.9 Example 170 13.66 Example 331 1.366

Example 10 5.42 Example 171 1.284 Example 332 3.452

Example 11 8.073 Example 172 2.505 Example 333 1.002

Example 12 1.997 Example 173 11.3 Example 334 3.636

Example 13 7.006 Example 74 261.7 Example 335 6.235

Example 14 3.926 Example 175 4.097 Example 336 5.333

Example 15 7.289 Example 176 88.82 Example 337 20.1

Example 16 0.8209 Example 177 188.2 Example 338 4.799

Example 17 1.327 Example 178 32.04 Example 339 2.104 Example 18 0.6192 Example 179 7.362 Example 340 4.707

Example 19 5.193 Example 180 1.311 Example 341 1.603

Example 20 1.951 Example 181 1026 Example 342 1.506

Example 21 3.29 Example 182 31.91 Example 343 10.28

Example 22 77.53 Example 183 210.4 Example 344 2.257

Example 23 0.8275 Example 184 58.06 Example 345 2.897

Example 24 1.183 Example 185 1.961 Example 346 2.081

Example 25 2.185 Example 186 2.118 Example 347 1.505

Example 26 250.7 Example 187 2.923 Example 348 10.88

Example 27 2.236 Example 188 1.209 Example 349 13.86

Example 28 4.345 Example 189 1.475 Example 350 59.27

Example 29 14.42 Example 190 1.06 Example 351 9.689

Example 30 179.9 Example 191 1.234 Example 352 2.653

Example 31 6.653 Example 192 2.264 Example 353 7.526

Example 32 35.86 Example 193 2.765 Example 354 7.255

Example 33 179.6 Example 194 77.68 Example 355 6.316

Example 34 3.149 Example 195 3.244 Example 356 1.721

Example 35 2.594 Example 196 2.129 Example 357 2.071

Example 36 12.1 1 Example 97 101.3 Example 358 3.578

Example 37 23.06 Example 198 43.74 Example 359 1.283

Example 38 966.3 Example 199 31.93 Example 360 3.151

Example 39 2.857 Example 200 10.69 Example 361 30.77

Example 40 13.89 Example 201 1.362 Example 362 11.5

Example 41 6.98 Example 202 4.825 Example 363 2.447

Example 42 2.619 Example 203 1.253 Example 364 1.581

Example 43 3.199 Example 204 3.939 Example 365 7.047

Example 44 1.207 Example 205 4.018 Example 366 6.736

Example 45 1.751 Example 206 2.67 Example 367 77.52

Example 46 7.783 Example 207 2.371 Example 368 16.03

Example 47 27.51 Example 208 1.478 Example 369 52.34

Example 48 3.271 Example 209 4.586 Example 370 209.5

Example 49 1.294 Example 210 2.06 Example 371 35.76

Example 50 8.98 Example 211 4.139 Example 372 50.22

Example 51 0.8937 Example 212 64.7 Example 373 12.49 Example 52 1.031 Example 213 1.808 Example 374 7.723

Example 53 6.414 Example 214 0.8974 Example 375 7.198

Example 54 1.404 Example 215 32.98 Example 376 5.416

Example 55 1.078 Example 216 59.12 Example 377 20.05

Example 56 86.97 Example 217 5.462 Example 378 21.76

Example 57 7.519 Example 218 4.878 Example 379 2.447

Example 58 1.876 Example 219 0.8179 Example 380 54.08

Example 59 18.23 Example 220 1.44 Example 381 30.93

Example 60 5.134 Example 221 1.072 Example 382 7.374

Example 61 2.505 Example 222 1.238 Example 383 49.06

Example 62 1.994 Example 223 4.271 Example 384 28.29

Example 63 3.971 Example 224 1.69 Example 385 5.066

Example 64 7.764 Example 225 0.8392 Example 386 5.153

Example 65 4.635 Example 226 1.862 Example 387 2.336

Example 66 1.581 Example 227 14.51 Example 388 0.7172

Example 67 7.437 Example 228 1.387 Example 389 1.876

Example 68 2.207 Example 229 6.966 Example 390 1.98

Example 69 27.9 Example 230 3.219 Example 391 181.8

Example 70 12.13 Example 231 4.115 Example 392 53.82

Example 71 3.137 Example 232 1.354 Example 393 5.365

Example 72 8.635 Example 233 23.65 Example 394

Example 73 5.399 Example 234 1.955 Example 395 6.52

Example 74 1688 Example 235 39.06 Example 396 45.11

Example 75 5.558 Example 236 5.63 Example 397 2.846

Example 76 26.3 Example 237 2.441 Example 398 26.16

Example 77 4.656 Example 238 4.139 Example 399 8.878

Example 78 41.41 Example 239 24.41 Example 400 3.166

Example 79 26.47 Example 240 41 Example 401 8.179

Example 80 9.656 Example 2 14.46 Example 402 1.663

Example 81 10.79 Example 242 5.14 Example 403 1.286

Example 82 5.151 Example 243 3.997 Example 404 76.74

Example 83 5.67 Example 244 1.636 Example 405 46.31

Example 84 57.76 Example 245 9.519 Example 406 23.44

Example 85 32.24 Example 246 2.706 Example 407 19.59 Example 86 3.154 Example 247 73.59 Example 408 3.74

Example 87 87.64 Example 248 1 .071 Example 409 6.131

Example 88 2.567 Example 249 0.09 Example 410 29.15

Example 89 176 Example 250 1.064 Example 411 233.3

Example 90 16.2 Example 251 24.41 Example 412 57.19

Example 91 9.915 Example 252 10.88 Example 413 10.92

Example 92 9.702 Example 253 131.8 Example 414 4.588

Example 93 5.227 Example 254 5.195 Example 415 79.96

Example 94 7636 Example 255 5.512 Example 416 10.77

Example 95 176 Example 256 5.252 Example 417 64.35

Example 96 3.464 Example 257 4.139 Example 418 17.24

Example 97 14.09 Example 258 6.789 Example 419 6.128

Example 98 1 12.3 Example 259 2.739 Example 420 38.35

Example 99 3.524 Example 260 3.979 Example 421 44.48

Example 100 35.6 Example 261 7.832 Example 422 153.4

Example 101 118.4 Example 262 9.817 Example 423 3.192

Example 102 5.857 Example 263 13.12 Example 424 21.51

Example 103 1 1.84 Example 264 2.526 Example 425 23.36

Example 04 26.22 Example 265 1 1.82 Example 426 20.64

Example 105 2.971 Example 266 1.817 Example 427 2.202

Example 106 7.527 Example 267 12.46 Example 428 5.428

Example 107 5.53 Example 268 2.441 Example 429 4.281

Example 108 10.39 Example 269 16.66 Example 430 53.64

Example 109 9.686 Example 270 0.7819 Example 431 31.84

Example 1 10 2.833 Example 271 21 .64 Example 432 29.9

Example 1 1 14.52 Example 272 1.241 Example 433 19.47

Example 1 12 3.365 Example 273 4.186 Example 434 6.923

Example 1 13 24.18 Example 274 2.91 1 Example 435 134.7

Example 1 4 6.975 Example 275 4.283 Example 436 64.47

Example 5 3.707 Example 276 3.869 Example 437 6.58

Example 1 16 1 .719 Example 277 1.55 Example 438 38.74

Example 1 17 103.4 Example 278 22.91 Example 439 5.884

Example 1 18 7.502 Example 279 66.73 Example 440 432

Example 1 9 1 1 .02 Example 280 22.91 Example 441 4.629 Example 120 14.24 Example 281 0.5736 Example 442 6.436

Example 121 5.694 Example 282 17.77 Example 443 8.015

Example 122 2.455 Example 283 2.258 Example 444 12.29

Example 123 6.905 Example 284 0.988 Example 445 116.9

Example 124 2.425 Example 285 3.547 Example 446 14.43

Example 125 14.95 Example 286 22.29 Example 447 41.34

Example 126 13.58 Example 287 66.82 Example 448 12.69

Example 127 29.64 Example 288 9.024 Example 449 15

Example 128 3.043 Example 289 5.214 Example 450 154.5

Example 129 100.8 Example 290 3.767 Example 451 8.369

Example 130 4.698 Example 291 122.6 Example 452 3.656

Example 131 3.421 Example 292 51.92 Example 453 13

Example 132 2.653 Example 293 71.57 Example 454 94.87

Example 133 23.42 Example 294 66.73 Example 455 146

Example 134 5.586 Example 295 6.682 Example 456 42.09

Example 135 28.92 Example 296 2.454 Example 457 186.5

Example 136 8.687 Example 297 81.97 Example 458 11.15

Example 137 82.36 Example 298 1.21 Example 459 390.1

Example 138 49.6 Example 299 7.038 Example 460 23.06

Example 139 6.004 Example 300 3.999 Example 461 966.3

Example 140 3.166 Example 301 16.55 Example 462 246.8

Example 141 1.82 Example 302 63.27 Example 463 4.802

Example 142 80.16 Example 303 370.7 Example 464 78.57

Example 143 2.555 Example 304 6.316 Example 465 83.7

Example 144 31.97 Example 305 12.76 Example 466 50.47

Example 145 21.15 Example 306 4.091 Example 467 24.71

Example 146 64.04 Example 307 1.812 Example 468 31.03

Example 147 35.6 Example 308 2.523 Example 469 16.22

Example 148 33.01 Example 309 4.796 Example 470 132.1

Example 149 315.1 Example 310 4.248 Example 471 25.37

Example 150 39.09 Example 31 1 12.11 Example 472 130.7

Example 151 1 18.4 Example 312 12.12 Example 473 390.9

Example 152 6828 Example 313 1.568 Example 474 10.29

Example 153 1535 Example 314 15.51 Example 475 50.63 Example 154 7.36 Example 315 1.932 Example 476 16.69

Example 155 3.257 Example 316 412.1 Example 477 16.73

Example 156 4.772 Example 317 7.966 Example 478 20.99

Example 157 12.62 Example 318 6.978 Example 479 11.75

Example 158 20.06 Example 319 16.38 Example 480 25.62

Example 159 33.16 Example 320 9.844 Example 481 41.93

Example 160 19.39 Example 321 57.46 Example 482 20.99

Example 161 24.64 Example 322 4.206 Example 483 14.67

Example 484 27.52

Claims

WHAT IS CLAIMED IS:

I

or pharmaceutically acceptable salts thereof wherein,

ring A is selected from the group consisting of pyridine, cycloheptane, phenyl, cyclohexane and cyclopentane;

U', U², U , U⁴ U⁵, U⁶ and U⁷ are independently selected from the group consisting of -CH- and -N-;

X is selected from the group consisting of piperidine, spiroheptane, bicyclo2,2,2octane, cyclohexane, cyclopentane, cyclobutane wherein the

bicyclo2,2,2octane, cyclohexane, cyclopentane, cyclobutane can be unsubstituted or substituted with one or more substituents selected from the group consisting of Ci- C₆alkyl and COOH;

R¹, R², R³, R⁴and R⁵ are independently selected from the group consisting of hydrogen, halogen, Ci-C₆alkyl, halogen-substitutedCi-C₆alkyl, -OH, Ci-C₆alkylOH, - OC,-C₆alkyl, -Ohalogen-substitutedCi-C₆alkyl, -OCi-C₆alkylOCi-C₆alkyl, -OC

C₆alkylheterocycle, -OCi-C₆alkylheterocycleC[-C₆, -S0₂Ci-C₆alkyl, pyrazole, Ci- Cealkyl-substituted pyrazole, -N(Ci-C₆aIkyl)₂ and -CN or when taken together R and R form pyrazole or triazole; and

R⁶ is selected from the group consisting of COCi-C₆alkyl, COhalogen- substitutedCi-C₆alkyl, -COOH, -COCOOH, -COOCi-C₆alkyl, -C,-C₆alkylCOOCi- C₆alkyl, -Ci-C₆alkylCOOH, -OCi-C₆alkylCOOH, CONHOCi-C₆alkyl, CONHS0₂C_r C₆alkyl, CONHS0₂C₃-C₆cycloalkyl, CONHS0₂phenyl, C0NHCi-C₆alkylS0₂0H, CONHS0₂halogen-substitutedCi-C₆alkyl, CONHhalogen-substitutedC,-C₆alkyl, CONHheterocycle and COheterocycle, wherein the COheterocycle is unsubstituted or substituted with one or more substituent selected from halogen, -OH, Ci-C₆alkyl, Ci- C₆alkylOH.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A is pyridine.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein U¹, U², U³ and U⁴ are all -CH-.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein U⁵, U⁶ and U⁷ are all -CH-.

6. The compounds of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is bicyclo2,2,2octane.

7. The compounds of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is cyclohexane.

8. The compounds of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R^s selected from the group consisting of hydrogen, halogen, C]-C₆alkyl, halogen-substitutedCi-C₆alkyl, -OH, Ci-C₆alkylOH, -OC C₆alkyl, -Ohalogen- substitutedCi-C₆alkyI, -OCi-C₆alkylOC_rC₆alkyl, OCi-Qalkylheterocycle, -S0₂C_r C₆alkyl, pyrazole, Ci-C₅alkyl-substituted pyrazole and -N(C]-C₆alkyl)₂.

9. The compounds of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R'is selected from the group consisting of halogen, Ci-C₆alkyl, halogen- substitutedC C₆alkyl, -OH, C_rC₆alkylOH, -OC_rC₆alkyl, -Ohalogen-substitutedC _r Cealkyl, -OCi-C₆alkylOCi-C₆alkyl, OCi-Cealkylheterocycle, -S0₂C C₆alkyl, pyrazole, Ci-C₆alkyl-substituted pyrazole and -N(Ci-C₆alkyl)₂.

10. The compounds of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R² is selected from the group consisting of hydrogen, halogen and Ci-C₆alkyl.

1 1 . The compounds of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R³ is selected from the group consisting of hydrogen and halogen.

12. The compounds of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R⁴ is selected from the group consisting of hydrogen and halogen.

13. The compounds of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R⁵ is selected from the group consisting of hydrogen and halogen.

14. The compounds of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R⁶ is selected from the group consisting of -COOH, -COOCi-C₆alkyl, -Cj- C₆alkylCOOCi-C₆alkyl and -Q-QalkylCOOH.

15. The compounds of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R⁶ is COheterocycle, wherein the COheterocycle is unsubstituted or substituted with one or more substituent selected from halogen, -OH, Q-Cealkyl, C C₆alkylOH.

16. The compounds of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R¹ and R² taken together form pyrazole or triazole.

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

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

19. Use of a compound of any one of claims 1- 17, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating a condition selected from the group consisting of obesity and diabetes.

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