WO2013096093A1 - Compounds as dgat-1 inhibitors - Google Patents

Abstract

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

Description

COMPOUNDS AS DGAT-1 INHIBITORS

TECHNICAL FIELD

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

BACKGROUND

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

In general, obesity is caused by the accumulation of triacylglycerol (TG) in adipose tissue which is a result of lack of exercise, intake of excessive calories and aging. In the body there are two TG synthesis pathways, a glycerol phosphate pathway, which is present in most organs and causes de novo TG synthesis, and a monoacylglycerol pathway, which is involved principally in absorption of aliphatic acid from the small intestine. Diacylglycerol acyltransferases (DGATs, EC 2.3.1.20), which are membrane-bound enzymes present in the endoplasmic reticulum, catalyze the final step of the TG synthesis common to the two TG synthesis pathways. The final reaction consists of transferring an acyl group from acyl-coenzyme A to the 3-position of 1,2- diacylglycerol to generate TG (Prog. Lipid Res., 43, 134-176, 2004 and Ann. Med., 36, 252-261, 2004). There are two subtypes of DGATs, DGAT-1 and DGAT-2. There is no significant homology at the generic or amino acid level between the DGAT-1 and DGAT-2, which are encoded by different genes (Proc. Natl. Acad. Sci. USA., 95, 13018-13023, 1998 and JBC, 276, 38870-38876, 2001). DGAT-1 is present in the small intestine, adipose tissue and liver and is believed to be involved in lipid absorption in the small intestine; lipid accumulation in the fat cell; and VLDL secretion and lipid accumulation in the liver (Ann. Med., 36, 252-261, 2004 and JBC, 280, 21506-21514, 2005). In consideration of these functions, a DGAT-1 inhibitor is expected to be an effective obesity treatment through inhibition of lipid absorption in the small intestine, lipid accumulation in the adipose tissue and the liver, and lipid secretion from the liver. In order to carry out in vivo examination of the physiological function(s) of DGAT-1 and inhibitory activity against DGAT-1, DGAT-1 -knockout mice deficient in DGAT-1 at the genetic level was produced and analyzed. As a result, the DGAT-1 -knockout mice have been found to have smaller fat masses than those of wild-type mice and became resistant to obesity, abnormal glucose tolerance, insulin resistance and fatty liver due when fed a high-fat diet (Nature Genetics, 25, 87-90, 2000 and JCI, 109, 1049-1055, 2002). In addition, energy expense has been reported to be accelerated in the DGAT-1 -knockout mice; and transplantation of the adipose tissues of DGAT-1 -knockout mice into wild-type mice has been reported to make the wild-type mice resistant to obesity and abnormal glucose tolerance, induced by a high-fat diet (JCI, 111, 1715- 1722, 2003 and Diabetes, 53, 1445-1451, 2004). In contrast, obesity and diabetes mellitus due to a high-fat diet have been reported to worsen in mice with overexpression of DGAT-1 in adipose tissue (Diabetes, 51, 3189-3195, 2002 and Diabetes, 54, 3379-3386, 2005).

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

cerebrovascular disorder, coronary artery disease and metabolic syndrome.

SUMMARY OF THE INVENTION

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 a (I):

I

wherein, T, U, V, X, Y, R¹ and R³ are further described below.

DETAILED DESCRIPTION OF THE INVENTION

Compounds

Described herein are compounds of formula (I):

or pharmaceutical salt thereof, wherein V is selected from the group consisting of -N- and -CH-;

X is selected from the group consisting of -N- and -CH-;

Y is selected from the group consisting of -N- and -CH- and -CR -;

Z is seleced from the group consisting of -N- and -CH- and -CR²-, wherein at least one of X, Y and Z must be -N-;

U is selected from the group consisting of phenyl, pyridine, pyrimidine, piperidine, azaspiroundecanyl and cyclohexane, wherein U is unsubstituted or substituted with - OH;

T is -O- or a bond;

R¹ is selected from the group consisting hexahydrofurofuran, C_!-C₆alkylCOOH, C C₆alkylCOOC₁-C₆alkyl, CrQalkoxy, pyridine, Q-Qalkylpyridine, cyclohexane, C_\- C₆alkylcyclohexane, phenyl and C_t-Cealkylphenyl, wherein the hexahydrofurofuran, pyridine, phenyl or cyclohexane can be unsubstituted or substituted with one or more substituents selected from the group consisting of COOH, C C₆alkylCOOH, C₁-C₆alkylCOOC₁-C₆alkyl, -OH, d- C₆alkyl and halogen;

R² is selected from the group consisting heterocycle, d-Cealkyl, phenyl, Q- C₆alkylphenyl, halogen-substitutedCi-C₆alkyl and C₃-C₆cycloalkyl, wherein the heterocycle, phenyl, or cycloalkyl can be unsubstituted or substituted with one or more substituents selected from the group consisting of C Cealkyl, halogen-substitutedC_t-Qalkyl and halogen.

R³ is optionally present at one of more at the ring carbons and is selected from the group consisting of halogen, -CN, Ci-Qalkyl and Q-Cealkoxy.

With regard to V, in certain embodiments V is selected from the group conisisting of -island -CH-. In some embodiments, V is -N-. In other embodiments, V is -CH-.

With regard to X, Y and Z, in certain embodiments X is selected from the group conisisting of -N- and -CH-. In some embodiments, X is -N-. In other embodiments, X is -CH- . In certain embodiments, Y is selected from the group consisting of -N- and -CH- and -CR²-. In some embodiments, Y is -N-. In other embodiment, Y is -CH-. In still other embodiments, Y is -CR²-. In certain embodiments, Z is selected from the group consisting of-N- and -CH- and - CR²-. In some embodiments, Z is -N-. In other embodiment, Z is -CH-. In still other embodiments, Y is -CR -.

In certain embodiments, at least one of X, Y or Z is -N-. In other words in no

embodiment are X, Y and Z simultaneously -CH- or In certain embodiments, Y is selected from the group consisting of -N- and -CH- and -CR²-. In some embodiments, Y is -N-. In other embodiment, Y is -CH- or -CR²-.

With respect to U, U is selected from the group consisting of phenyl, pyridine, pyrimidine, piperidine, azaspiroundecanyl and cyclohexane. In some embodiments of the compounds described herein, U is phenyl. In other embodiments U is pyridine. In still other embodiments, U is pyrimidine. In yet other embodiments, U is piperidine. In other

embodiments, U is azaspiroundecanyl. In still other embodiments, U is cyclohexane. In certain embodiments U is selected from the group consisting of phenyl and pyridine.

U can be unsubstituted of substituted. In certain embodiments, U is substituted with -

OH. In some embodiments, U is piperidine subsitututed with -OH.

With respect to T, T is selected from the group consisting or -O- or a bond. In some embodiments of the compounds described herein, T is -0-. In other embodiments, T is a bond.

With respect to R¹, R¹ is selected from the group consisting hexahydrofurofuran, d- C₆alkylCOOH, C₁-C₆alkylCOOC₁-C₆alkyl, d-C₆alkoxy, pyridine, C₁-C₆alkylpyridine, cyclohexane, d-C₆alkylcyclohexane, phenyl and d-C₆alkylphenyl. In some embodiments, of the compounds described herein, R¹ is d-C₆alkylCOOH. In other embodiments, R¹ is d- C₆alkylCOOd-C₆alkyl. In still other embodiments, R¹ is Ci-C₆alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, butoxy and propoxy. In yet other embodiments, R¹ is pyridine. In other embodiments, R¹ is d-Cgalkylpyridine. In yet other embodiments, R¹ is cyclohexane. In still other embodiments, R¹ is phenyl. In other embodiments of the compounds described herein, R¹ is d-C₆alkylphenyl. In yet other embodiments, R¹ is hexahydrofurofuran.

R¹ can be unsubstituted. In some embodiments, wherein R¹ is hexahydrofurofuran, pyridine, phenyl or cyclohenxane, R¹ can substituted with one or more substituents selected from the group consisting of COOH, d-C₆alkylCOOH, d-C₆alkylCOOd-C₆alkyl, -OH, Ci-C₆alkyl and halogen.

In some embodiments, R¹ is substituted with one substituent selected from the group consisting of COOH, d-C₆alkylCOOH, d-C₆alkylCOOd-C₆alkyl, -OH, d-C₆alkyl and halogen. In other embodiments, R¹ is substituted with two substituents selected from the group consisting of COOH, C C₆alkylCOOH, d-CgalkylCOOd-dalkyl, -OH, C C₆alkyl and halogen. In other embodiments, R¹ is substituted with three substituents selected from the group consisting of COOH, d-C₆alkylCOOH, d-C₆alkylCOOd-C₆alkyl, -OH, Ci-C₆alkyl and halogen. In other embodiments, R¹ is substituted with four substituents selected from the group consisting of COOH, d-C₆alkylCOOH, d-dalkylCOOd-dalkyl, -OH, d-C₆alkyl and halogen.

In some embodiments, R¹ is substituted with COOH. In still other embodiments, R¹ is substituted with d-C₆alkylCOOH. In other embodiments, R¹ is substituted with d- C₆alkylCOOd-C₆alkyl. In yet other embodiments, R¹ is substituted with -OH. In some embodiments, R¹ is substituted with d-C₆alkyl. In yet other embodiments, R¹ is substituted with halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine, and iodine. In certain embodiments, R¹ is substituted with one or more substituents selected from the group consisting of COOH, d-C₆alkylCOOH and d-C₆alkylCOOd-C₆alkyl. In certain embodiments, R is cyclohexene substituted with d-CealkylCOOH.

When R¹ includes an alkyl or any substituent of R¹ includes an alkyl, suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

With regard to R², R² is selected from the group consisting of heterocycle, Ci-Cealkyl, phenyl, CrCealkylphenyl, halogen-substitutedC_!-C₆alkyl and C₃-C₆cycloalkyl. In some embodiments, R² is heterocycle. Suitable heterocycles include, but are not limited to, pyridine, pyrimidine, sulfolane, pyrrole, furan, thiene, imidazole, pyrazole, thiazole, oxazole, thiadiazole, pyrazine, and benzofuran. In other embodiments, R² is CrCealkyl. Suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. In still other embodiments, R² is phenyl. In yet other embodiments, R² is CrCealkylphenyl. In other embodiments, R² is halogen-substitutedd-Cealkyl. Suitable halogen-substituted alkyls include, but are not limited to, mono-, di-, and trifluoromethyl. In yet other embodiments, R is C₃-C₆cycloalkyl. Suitable cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

R² can be unsubstituted. In certain embodiments, wherein R² is heterocycle, phenyl, or cycloalkyl, R² can be substituted with one or more substituents selected from the group consisting of Q-Qalkyl, halogen-substitutedCrQalkyl and halogen. In some embodiments, R is substituted with one substituent selected from the group consisting of Ci-Cealkyl, halogen- substitutedQ-Cealkyl and halogen. In some embodiments, R² is substituted with two substituents selected from the group consisting of Q-Cealkyl, halogen-substitutedCrCealkyl and halogen. In some embodiments, R² is substituted with three substituents selected from the group consisting of Q-Qalkyl, halogen-substitutedCrCealkyl and halogen. In some embodiments, R² is substituted with four substituents selected from the group consisting of Q-Cealkyl, halogen- substitutedQ-Qalkyl and halogen.

In certain embodiments, R² is substituted with Ci-C₆alkyl. Suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. In other embodiments, R² is substituted with halogen-substitutedd-Cealkyl. Suitable halogen- substituted alkyls include, but are not limited to, mono-, di-, and trifluoromethyl. In still other embodiments, R² is substituted with halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine, and iodine.

With respect to R³, R³ is optionally present at one of more at the ring carbons and is selected from the group consisting of halogen, -CN, C_!-C₆alkyl and Ci-C₆alkoxy. In certain embodiments, R is -CN. In other embodiments, R is halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine, and iodine. In still other embodiments, R is Ci- C₆alkyl. In yet other embodiments, R is Q-Cealkoxy.

Examples of compounds described herein include:

Definitions

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

The term "Ci-C ₆alkyl" encompasses straight alkyl having a carbon number of 1 to 6 and branched alkyl having a carbon number of 3 to 6. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2- dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, l-ethyl-2- methylpropyl, 1 -ethyl- 1-methylpropyl, and the like. The term "C₃-C₆cycloalkyl" encompasses cycloalkyls having 3 to 6 carbons, forming one or more carbocyclic rings that are fused. "Cycloalkyl" also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

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

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

The term "-halogen-substitutedQ-Cealkoxy" means a -Q-Qalkoxy as defined above, which is substituted with 1-3 halogen atoms which are identical or different, and specifically includes, for example, a trifluoromethoxy group.

The term "Q-CealkylOH" means a d-Cealkyl substituted with an alcohol (-OH).

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

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(2,3-0)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 (TV-substituted uracils). The term also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 7- azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]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.

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

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

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

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

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

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

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

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

In the compounds of the formulas described herein, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the formulas described herein. For example, different isotopic forms of hydrogen (H) include protium (lH) and deuterium (^H). 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 subject in need of such treatment a therapeutically effective amount of a compound having the formulas described herein or a pharmaceutically acceptable salt thereof. For example, the compounds described herein are useful for treating or preventing obesity by administering to a subject in need thereof a composition comprising a compound of any of the formulas described herein.

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

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

The following diseases, disorders and conditions are related to Type 2 diabetes, and therefore may be treated, controlled or in some cases prevented, by treatment with the

compounds described herein: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative disease, (20) retinopathy, (21) nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarian hyperandrogenism (polycystic ovarian syndrome), and other disorders where insulin resistance is a component. In Syndrome X, also known as Metabolic Syndrome, obesity is thought to promote insulin resistance, diabetes, dyslipidemia, hypertension, and increased cardiovascular risk. Therefore, DGAT-1 inhibitors may also be useful to treat hypertension associated with this condition.

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

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

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

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

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

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

DGAT-1 inhibitors may also serve as antiviral therapeutics that selectively suppresses HCV's (Hepatitis C virus) interation with lipid droplets without compromising the overall formation of lipid droplets in liver cells Nature Medicine, vol. 16, no. 11 pages 1295-1298, November 2010. Thus the compounds described herein can be useful as a treatment for HCV.

Pharmaceutical Compositions

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

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

Especially for injections, if desired, the preparations may be dissolved or suspended in physiological saline or glucose liquid, and a buffer or a preservative may be optionally added thereto.

The pharmaceutical compositions may contain the compound of the invention in an amount of from 1 to 99.9 % by weight, preferably from 1 to 60 % by weight of the composition. The compositions may further contain any other therapeutically-effective compounds.

In case where the compounds of the invention are used for prevention or treatment for the above-mentioned diseases, the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the subject and on the type and the range of the intended remedial effect. In general, when orally administered, the dose may be from 0.001 to 50 mg/kg of body weight/day, and it may be administered at a time or in several times. The dose is preferably from about 0.01 to about 25 mg/kg/day, more preferably from about 0.05 to about 10 mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets or capsules containing from 0.01 mg to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 750, 850 and 1,000 milligrams of a compound described herein. This dosage regimen may be adjusted to provide the optimal therapeutic response.

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

The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of 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) α-glucosidase inhibitors (such as acarbose, voglibose and miglitol);

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

(9) incretin mimetics, such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists, such as exenatide, liraglutide, lixisnatide, taspoglutide, AVE0010, CJC-1131, and

BIM-51077, including intranasal, transdermal, and once- weekly formulations thereof;

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

(11) HDL-raising drugs, such as niacin or a salt thereof and extended-release versions thereof; MK-524A, which is a combination of niacin extended-release and the DP-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 antiinflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;

(14) antihypertensive agents, such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), 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 11 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; 6,110,903; 6,284,748; 6,399,782; and 6,489,476;

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

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

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

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

(23) neuromedin U receptor agonists, such as those disclosed in WO2009/042053, including, bu1 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 A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2);

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

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

Dipeptidyl peptidase-IV (DPP -4) inhibitors that can be used in combination with compounds of 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?,3S,5 ?)-5-(l-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)-2-(2,4,5- trifluorophenyl)tetrahydro-2H-pyran-3-amine;

(2i?,3S,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?)-2-(2,5-difluorophenyl)tetrahydro)-5-(4,6-dihydropyrrolo[3,4-c]pyrazol-5(l/i -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-[(3i?)-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 topiramati and phentermine; fenfluramine; dexfenfluramine; sibutramine; lipase inhibitors, such as orlistat and cetilistat; melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists; CCK-1 agonists; melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Yi or Y5 antagonists (such as MK-0557); CBl receptor inverse agonists and antagonists (such as rimonabant and taranabant); β3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (such as bombesin receptor subtype-3 agonists); and 5-hydroxytryptamine-2c (5-HT2c) agonists, such as lorcaserin. For a review of anti-obesity compounds that can be combined with compounds of the present invention, see S. Chaki et al., "Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity," Expert Opin. Ther. Patents. 11 : 1677-1692 (2001); D. Spanswick and K. Lee, "Emerging antiobesity drugs," Expert Opin. Emerging Drugs. 8: 217-237 (2003); J.A.

Fernandez-Lopez, et al., "Pharmacological Approaches for the Treatment of Obesity," Drugs, 62: 915- 944 (2002); and K.M. Gadde, et al., "Combination pharmaceutical therapies for obesity," Exp. Opin. Pharmacother.. 10: 921-925 (2009).

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

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

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

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

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

pharmaceutically acceptable salts thereof.

Inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) that can be used in

combination with the compounds of any of the formulas described herein include, but are not limited to:

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

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

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

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

and

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

and pharmaceutically acceptable salts thereof.

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

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

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

5 -( 1 -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- 1 H-pyrazol-3 -yl)benzamide;

5-(2-fluoro- 1 -fluoromethyl-ethoxy)-3 -(6-methanesUlfonylpyridin-3 -yloxy)-N-( 1 -methyl- 1 H- pyrazol-3 -yl)benzamide;

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

3 -( {4- [( 1 -methylazetidin-3 -yl)oxy]phenyl} thio)-N-(3 -methyl- 1 ,2,4-thiadiazol-5-yl)-6- [(4-methyl- 4H- 1 ,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-pyrrolM

1 -ylethoxy)phenyl]thio } pyridine-2-carboxamide; and

3-[(4-{2-[(2R)-2-methylpyrrolidin- 1 -yl]ethoxy}phenyl)thio-N-(3-methyl- 1 ,2,4-thiadiazol-5-yl)-6-[(4- methyl-4H-l,2,4-triazol-3-yl)thio]pyridine-2-carboxamide; and pharmaceutically acceptable salts thereof.

Agonists of the GPR-119 receptor that can be used in combination with the compounds of 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-1- yl}pyrimidine;

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

vac c j^,-5-chloro-2-[4-(2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-l- yl]pyrimidine;

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

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:

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

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

(25)-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-propylpyridin-3-yl]-l,2-benzisoxazol-5- yl}oxy)propanoic acid;

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

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

Inhibitors of 1 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)-^ «5^,-3-fluorocyclobutyl]-4,5-dicyclopropyl-r-4H-l,2,4-triazole;3-[l-(4- chlorophenyl)-irara-3-fluorocyclobutyl]-4-cyclopropyl-5-(l-methylcyclopropyl)-r-4H-l,2,4- triazole;

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

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

3- {4-[3-(ethylsulfonyl)propyl]bicyclo[2.2.2]oct-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- 1,2,4-triazole; 3-(4-{4-methyl-5-[2-(trifluoromethy^

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

3-(4-{4-methyl-5-[2-(trifluoromethyl^

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

5-(3,3-difluorocyclobutyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-l,2,^ 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-l-yl)-l,2,4-oxadiazole;

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

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

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

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

and pharmaceutically acceptable salts thereof.

AMP -activated Protein Kinase (AMPK) activators that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:

and pharmaceutically acceptable salts thereof.

Inhibitors of acetyl-CoA carboxylase- 1 and 2 (ACC-1 and ACC-2) that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to: 3 - { Γ-[( 1 -cyclopropyl-4-methoxy- 1 H-indol-6-yl)carbonyl] -4-oxospiro [chroman- 2,4'-piperidin] - 6-yl} benzoic acid;

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

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

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

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

pharmaceutically acceptable salts thereof.

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

(a) a compound of 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, aleghtazar, 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 CoA holesterol acyltransferase inhibitors, such as avasimibe;

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

(8) antiobesity compounds;

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

(10) antihypertensive agents, such as ACE inhibitors (such as enalapril, Hsinopril, 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;

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

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

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

0859;

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

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

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

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

(18) SSTR3 antagonists;

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

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

(21) GPR-105 antagonists;

(22) inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1; SGLT-2, such as 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 for the Preparation of Benzimidazoles

To a solution of 4-((l-(5-formylpyridin-2-yl)piperidin-4-yloxy)methyl)bicyclo[2.2.2] octane- 1-carboxylic acid (35 mg, 0.094 mmol, 1 equiv) and diamine (20 - 35 mg, 0.188 mmol, 2 equiv) in 2% HOAc/DMF (1.5 mL) was added Oxone (20 mg, 0.056 mmol, 0.6 equiv) and the mixture agitated at 80 °C for 16 hours at which point LCMS analysis of an aliquot indicated complete conversion to product. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was suspended in water (2 mL) and extracted into ethyl acetate (2 x 4 mL) then the combined organic layers were concentrated in vacuo and

reconstituted in DMSO, filtered and purified by preparative HPLC on a CI 8 reverse-phase column eluting with 10% to 90% acetonitrile in water containing 0.1% TFA to give the desired product, typically as a yellow solid.

Examples

General methods:

A Exemplified by):

B (Exemplified by): OOH

C (Exemplified by):

3 -(4-iodophenyl -5 -phenyl-4H- 1 ,2,4-triazole

Benzimidic acid methyl ester hydrochloride (2 g, 11.65 mmol) was treated with EtOH ( 10 mL) and cooled in ice- water bath. Sodium ethoxide (0.793 g, 11.7 mmol) was added at 0°C, and then stirred for 20 min at RT. 4-iodobenzhydrazide (3.05 g, 11.65 mmol) was added and the mixture was heated at reflux for lh. The mixture was then concentrated to dryness. After the residue was azetroped with toluene once, it was treated with xylene (50 ml) and heated at 160°C for lh, and then cooled to RT. The solvent was removed in vacuo, and the residue was purified by ISCO (120 g column, 10% -100% acetone in DCM) to obtained 3-(4-iodophenyl)-5-phenyl- 4H-l,2,4-triazole as solid. LC-MS (ES, m/z) C₁₄H₁₀IN₃: 347; Found: 348 [M+H]⁺

Intermediate 2

5-(^,4-bromophenylV3 -phenyl- 1 H-pyrazole

A solution of l-(4-bromophenyl)-3-phenylpropane-l,3-dione (1.5 g, 4.95 mmol) in EtOH (25 mL) was treated with hydrazine hydrate (0.480 ml, 9.90 mmol). After heated under N₂ at 90°C overnight, the reaction was cooled to RT, treated with water (-30 mL), stirred at RT. The solid was filtered off, solid was washed with EtOH (~ 5mL) and then water (3x~20 mL), then dried in the filtration funnel with air passing through. The filtration was concentrated and extracted with EtOAc (3x), dried over Na₂S0₄. The solid and the extracts were combined and purified by SFC (Instrument: Thar 80 preparative SFC; Column: ChiralCel OD-H, 250x50mmI.D., 5μιη; Mobile phase: A for C0₂ and B for Methanol; Gradient: B 45 %; Flow rate: 80mL /min; Back pressure: lOObar; Column temperature: 38°C; Wavelength: 220nm; Cycletime: 3min; Sample preparation: Compound was dissolved in methanol to ~50mg/ml; Injection: 4 ml per injection). After separation, the fractions were dried off via rotary evaporator at bath temperature 40°C to get 5-(4-bromophenyl)-3-phenyl-lH-pyrazole (1.36 g ) as yellow solid. LC-MS (ES, m/z) ¾ΗΠΒΓΝ₂: 300; Found: 301 [M+H]⁺.

Intermediate 3

Methyl (trans&cis-4-hvdroxycvclohexyi)acetate Methyl (trans&cis-4-hydroxycyclohexyl)acetate was prepared from methyl 2-(4- hydroxyphenyl) acetate according to a known procedure (Birch, Alan Martin et. al. PCT Int. Appl, 2009024821, 26 Feb 2009). LC-MS (ES, m/z): C₉H₁₆0₃: 172; Found: 173 [M+H]⁺.

Intermediates 4 and 5

OH

C0₂Me methyl (trans-4-hvdroxycvclohexyDacetate

methyl (cis-4-hydroxycyclohexyl)acetate

Methyl (trans&cis-4-hydroxycyclohexyl)acetate was separated by SFC (ChiralPak Κ 5μ, 250x50mmI.D, Mobile phase: A for C0₂ and B for ethanol. Gradient: B 15%) to afford methyl (trans-4-hydroxycyclohexyl) acetate, LC-MS (ES, m/z): C₉H₁₆0₃: 172; Found: 156 [M-16]⁺ and methyl (cis-4-hydroxycyclohexyl)acetate), LC-MS (ES, m/z): C₉H₁₆0₃: 172; Found: 173

[M+H]⁺.

Intermediates 6 and 7

cis-Methyl 2-(4-((5-bromopyridin-2-yl oxy)cvclohexyl acetate

trans-Methyl 2-(4-((5 -bromopyridin-2-yr)oxy)cvclohexyl)acetate

To a stirred solution of 5-bromo-2(lH)-pyridone (43.4 g, 250 mmol) in anhydrous THF (200 ml) at RT was added Methyl (trans&cis-4-hydroxycyclohexyl)acetate (43 g, 250 mmol). Triphenylphosphine (82 g, 312 mmol) was then added followed by dropwise addition of diisopropyl azodicarboxylate (61.4 ml, 312 mmol) at 0°C. The reaction was heated to 55 °C and allowed to stir at this temperature over night. The rxn was concentrated, the residue was treated with 200 ML EtOAc and then 200 mL Hex. solid was filtered out and discarded. The filtrate was concentrated. The separation was first carried out on ChiralCel OD-ΙΟμηι, 300 <50mmI.D (Mobile phase: A for SF C0₂ and B for Ethanol, B 20 %) to remove the impurity. The isomers were then separated by SFC(Instrument: Thar 200 preparative SFC, olurnn: ChiralPak AD-ΙΟμιη, 300x50mmI.D., Mobile phase: A for SF C0₂ and B for Methanol, B 35 % , Flow rate: 200mL /min) to afford separated isomers. The first peak was determined to be cis-Methyl 2-(4-((5- bromopyridin-2-yl)oxy)cyclohexyl)acetate. LC-MS (ES, m/z): C₁₄H₁₈BrN0₃: 327; Found: 328 [M+H]⁺. The second peak was determined to be trans-Methyl 2-(4-((5-bromopyridin-2- yl)oxy)cyclohexyl)acetate. LC-MS (ES, m/z): C₁₄H₁₈BrN0₃: 327; Found: 328 [M+H]⁺.

Intermediate 8

Methyl 2-( ( 1 s.4s>4-( ( 5 -( 4.4.5.5 -tetramethyl- 1.3.2-dioxaborolan-2-vnpyridin-2- yl)oxy)cvclohexyl)acetate

A mixture of cis-Methyl 2-(4-((5-bromopyridin-2-yl)oxy)cyclohexyl)acetate (3.50 g, 10.7 mmole), bis(pinacolato)diboron (2.98 g, 11.73 mmol), potassium acetate (3.14 g, 32.0 mmol), PdCl₂(dppf) (0.390 g, 0.533 mmol) in dioxane (30 ml) was heated at 80°C overnight under N₂. The reaction was concentrated. The residue was separated by MPLC (5-50% EtOAc in hexane) to give Methyl 2-((ls,4s)-4-((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yl)oxy)cyclohexyl)acetate. LC-MS (ES, m/z) C₂oH₃₀BN0₅: 375; Found: 376 [M+H]⁺.

Intermediate 9

Methyl 2-(ΠΓ AV4-(Y5-(4 A5.5-tetramethyl-l 3.2-dioxaborolan-2-vnpyridin-2- yl)oxy)cyclohexyl)acetate

Prepared according to the procedure described for Methyl 2-((ls,4s)-4-((5-(4,4,5,5 tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)cyclohexyl)acetate, starting with trans Methyl 2-(4-((5-bromopyridin-2-yl)oxy)cyclohexyl)acetate.

Intermediate 10

methyl 2-(^'(ls_<4s)-4-(5-cvano-2,3'-bipyridin-6'-yloxy cvclohexyl)acetate

A mixture of 6-bromonicotinonitrile (0.697 g, 3.81 mmol), methyl 2-((ls,4s)-4-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)cyclohexyl)acetate (1.3 g, 3.46 mmol), sodium carbonate (0.734 g, 6.93 mmol) and [Ι,Γ- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.127 g, 0.173 mmol) are suspended in DMF / H2O in a round bottle and heated at 80°C under N2 over night. Reaction mixture was cooled to rt and water was added, extracted with EtOAc, dried over Na₂S0₄, filtered and purified by MPLC (5 to 100% EtOAc in hexane ) to give methyl 2-((ls,4s)-4-(5-cyano-2,3'- bipyridin-6'-yloxy)cyclohexyl)acetate. LC-MS (ES, m/z) C₂oH₂₁N₃0₃: 351 ; Found: 352 [M+H]⁺.

Intermediate 11

methyl 2-(( 1 r,4r -4-((^"5-cyano- [2,3 '-bipyridin[-6'-yl oxy)cyclohexyl)acetate

Prepared according the procedure described for methyl 2-((ls,4s)-4-(5-cyano-2,3'- bipyridin-6'-yloxy)cyclohexyl)acetate, starting from Methyl 2-((lr,4r)-4-((5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)cyclohexyl)acetate LC-MS (ES, m/z) C₂₀H₂₁N₃O₃: 351 ; Found: 352 [M+H]⁺.

Methyl 2-(3 -(5 -cvanopyridin-2- yl -3 -azaspiro Γ5.5 ] undecan-9-yl)acetate

Commercially available 2-(3 -(tert-butoxycarbonyl)-3 -azaspiro [5.5]undecan-9-yl)acetic acid (3.0 g, 9.63 mmol, 1 equiv) was dissolved in 1.25 M methanolic hydrochloric acid (30 mL) and heated at 65 °C for 3.5 hours. Concentration in vacuo gave a the hydrochloride salt of methyl 2-(3-azaspiro[5.5]undecan-9-yl)acetate as a white solid which was carried forward without further purification. To the hydrochloride salt of methyl 2-(3-azaspiro[5.5]undecan-9- yl)acetate (1.42 g, 5.42 mmol, 1 equiv) were added 2-chloro-5-cyanopyridine (752 mg, 5.42 mmol, 1 equiv), sodium bicarbonate (2.278 g, 27.1 mmol, 5 equiv) and NMP (18 mL) and the mixture stirred at 110 °C for 18 hours. The mixture was poured into water (300 mL) and extracted with ether (3 x 100 mL) and ethyl acetate (2 x 100 mL) and the combined organic layers were washed with water (2 x 100 mL) then brine (100 mL) then dried on anhydrous magnesium sulfate, filtered and concentrated to yield a gummy yellow residue. Purification of the residue by flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) gave the title compound as a white crystalline solid: [MH]⁺ calc'd m/z 328; found m/z 328.

Intermediate 13

tert-Butyl 4-(3 -(ethoxycarbonyl phenyl -4-hvdroxypiperidine- 1 -carboxylate Ethyl 3-iodobenzoate (35.7 g, 129 mmol, 1 equiv) was dissolved in THF (500 mL) and chilled to -50 °C then a 1.3 M THF solution of isopropylmagnesium chloride lithium chloride complex was added via syringe pump over 1 hour. Solid 4-Boc-piperidone (25.8 g, 129 mmol, 1 equiv) was added in one portion and the reaction was allowed to slowly warm to room temperature and stirred overnight. Excess Grignard reagent was quenched by the slow addition of saturated aqueous ammonium chloride (5 mL) then the reaction was partitioned between water and ethyl acetate. The organic layer was washed with brine then dried on anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give the title compound as an oil: [MH - Boc]⁺ calculated m/z 250; found m/z 250.

Intermediate 14

Ethyl 3-d-(5-cvanopyridin-2-ylV4-hvdroxypiperidin-4-yl)cvclohexanecarboxylate

Step 1

A I L autoclave was charged with tert-butyl 4-(3-(ethoxycarbonyl)phenyl)-4- hydroxypiperidine-l-carboxylate (30 g, 89.4 mmol, 1 equiv) and 5% (w/w) rhodium on carbon (6 g, ) and methanol (300 mL) then heated at 80 °C under 400 psi of hydrogen for 20 hours. The mixture was cooled and filtered through a pad of Celite and concentrated then carried forward crude.

Step 2

tert-butyl 4-(3-(ethoxycarbonyl)cyclohexyl)-4-hydroxypiperidine-l-carboxylate (2.6 g, 7.31 mmol, 1 equiv) was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (5 mL) and aged at room temperature for 2.5 hours at which time NMR indicated complete removal of the Boc group. Volatiles were removed in vacuo and to the residue was added 2-chloro-5- cyanopyridine (1.01 g, 7.31 g, 1 equiv), sodium bicarbonate (3.07 g, 36.6 mmol, 5.0 equiv), and NMP (8 mL) then the mixture stirred at 60 °C overnight. The reaction mixture was poured into water and ethyl acetate then washed with water four times then brine. The organic layer was dried on anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by flash column chromatography on silica gel (20% to 100% ethyl acetate in hexanes) to give ethyl 3-(l-(5-cyanopyridin-2-yl)-4-hydroxypiperidin-4-yl)cyclohexanecarboxylate as a yellow oil: [MH - H₂0]⁺ calculated m/z 340; found m/z 340. Intermediate 15

cis-ethyl 4-hydroxycvclohexanecarboxylate

Dissolved 1.67 g of KRED, 1.67 g of NAPD, and 1.67 g of GDH (CDX-901), and 106 g (588 mmol) of D-glucose in 1.5 L of 0.1M pH 7 phosphate buffer. To this was added 50 g (268 mmol) of ethyl 4-oxocyclohexanecarboxylate dissolved in 137 mL of DMSO. The pH of the reaction mixture was monitored and adjusted as needed with 5 N NaOH to maintain a constant pH of 7. The reaction was stirred for 20 h ar room temperature. To the reaction mixture was added 1.5 L of a 1 :1 mixture of EtOH/MTBE and the layers were separated. The aqueous layer was back extracted with MTBE (3 X 5Q0 mL). The combined organic extractes were washed with brine (2 X 250 mL), dried over sodium sulfate, filtered and concentrated to give cis-ethyl 4- hydroxycyclohexanecarboxylate as a colorless oil with > 99:1 cis/trans selectivity.

Intermediate 16

trans-ethyl 4-hydroxycyclohexanecarboxylate To a solution of 1.427 L of water was added 9.7 g of mono potassium phosphate and 12.4 grams of dipotassium phosphate. To this was added 5.71 g of MIF-20 and 1.43 g of NAPD to give a pH of 7. To the mixture was added 256.78 g (1.509 mol) of ethyl 4- oxocyclohexanecarboxylate in 1.427 L of 2-propanol. The pH of the mixture was controled at 7 by the addition of 1 M HCl. Stirred the mixture at 30 °C for 20 h. The reaction mixture was then extracted with 1.5 L of MTBE. The aqueous layer was back extracted with a 3:1 mixture of MTBE/2-propanol (2 X 600 mL). The organic layer was then concentrated under reduced pressure and re-dissolved in 1.5 L of MTBE. The organic layer was washed with brine (2 X 300 mL), dried over sodium sulfate, concentrated and flushed with 1 L of MTBE to give ethyl trans- 4-hydroxycyclohexanecarboxylate as colorless oil with > 99:1 trans/cis selectivity.

Intermediate 17

ethyl trans-4-[(^"5-bromopyridin-2-yl oxylcvclohexanecarboxylate

To a mixture of 5-bromo-2-hydroxypyridine (11 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) C₁₄H₁₈BrN0₃: 327; Found: 328 [M+H]⁺.

Intermediate 18

ethyl cis-4-r(5-bromopyridin-2-yl oxy]cvclohexanecarboxylate

With the same procedure as preparation of ethyl trans-4-[(5-bromopyridin-2- yl)oxy]cyclohexanecarboxylate, ethyl cis-4- [(5 -bromopyridin-2-yl)oxy] cyclohexane- carboxylate as a white solid was prepared. LC-MS (ES, m/z) C₁₄H₁₈BrN0₃: 327; Found: 328 [M+H]⁺.

Intermediate 19

OOEt

ethyl trans-4-{r5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yl] oxy I cyclohexanecarboxylate 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) C₂oH₃oBN0₅: 375; Found: 376 [M+H]⁺.

ethyl cis-4-{|^"5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl pyridin-2- yl]oxy) cyclohexanecarboxylate

With the same procedure as preparation of ethyl trans-4-{[5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl]oxy}cyclohexanecarboxylate, ethyl cis-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 21

oOEt

Ethyl c '-4-{[5-(^'3-fluoro-4-formylphenyl pyridin-2-yl1oxy}cvclohexanecarboxyla^!te

4-Bromo-3-fluoro-benzaldehyde (1.2 g, 5.09 mmol) in DMF (10 ml) was added ethyl cis- 4-{[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy} cyclohexanecarboxylate (2.107g, 5.62 mmol), and 2 M sodium bicarbonate (7.4 ml, 14.8 mmol), PdCl₂(dppi> CH₂Cl₂Aduct (0.24 g, 0.3 mmol). The mixture was heated at 80°C under N₂ for 16 hours. Quenched with water, and extracted with ethyl acetate (2X100 ml). Dried over MgS0₄, filtered and concentrated. The residue was purified by MPLC (40% EtOAc/Hexane) to give the title compound as a white solid. LC-MS (ES, m/z): C₂iH₂₂FN0 : 371; Found: 372 [M+H]⁺. Intermediate 22

methyl 2-(trans-4-(5 -(3 -fluoro-4-formylphenyl)pyridin-2-yloxy cvclohexyl^')acetate

Performed following the procedure described for Ethyl cis-4-{[5-(3-fluoro-4- formylphenyl)pyridin-2-yl]oxy}cyclohexanecarb0kylate except that methyl 2-(trans-4-(5- bromopyridin-2-yloxy)cyclohexyl)acetate and 3-fluoro-4-formylphenylboronic acid were used as the starting material. This resulted methyl 2-(trans-4-(5-(3-fluoro-4-formylphenyl)pyridin-2- yloxy)cyclohexyl)acetate as a white solid. LC-MS (ES, m/z) C₂₁H₂₂FN0₄: 371; Found: 372 [M+H]⁺.

Intermediate 23

OH

OH

4,4-dimethylpentane- 1 ,2-diol

A solution of 4,4-dimethyl-l-pentane (700 mg, 7.12 mmol) in Acetone/H₂0 (4 ml/1 ml) was added NMO (835 mg, 7.13 mmol) and Os0₄ in isobutanol(2.5%wt, 20 ul). The mixture was stirred at room temperature for 16 hours. The mixture was quenched with solid N₂S₂0₄, and stirred for 10 minutes, then filtered through celite. The filtrate was concentrated by rotary evaporation to give 4,4-dimethylpentane- 1 ,2-diol. Intermediate 24

OH

O

l-hvdroxy-4_<4-dimethylpentan-2-one A solution of 4,4-dimethylpentane- 1,2-diol (800 mg, 6.05 mmol) in acetonitrle (8 ml) was added a solution of NaBr0₃ (1.82 g, 12.1 mmol) in water (10 ml). Then NaHS0₃ (1.26 g, 12.1 mmol) in water (5 ml) was added drop wise to the mixture at an ice bath. The mixture was stirred at room temperature for 2 hours. Then mixture was quenched with ether, and the organic layer was separated and concentratedthe residue was purified by MPLC (20% EtOAc/Hexane) to afford 1 -hydroxy-4,4-dimethylpentan-2-one.

Intermediate 25 Intermediate 26

cis methyl {4-[(5-bromopyrimidin-2-vDoxy]cvclohexyl>acetate

trans methyl { 4- f(5-bromopyrimidin-2-vDoxy1cvclohexyl} 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 drop wise 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) C₁₄H₁₉BrN₂0₃: 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 trans- {4-[(5-bromopyrimidin-2- yl)oxy]cyclohexyl}acetate (A, RT = 2.2 min).

methyl (^"c^-l S-^^ ^-tetramethyl-U^-dioxaborolan^-vDpyrimidin^- yl]oxy}cyclohexyl acetate

methyl (trans -4-{ [5-(4 A5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl pyrimidin-2- yljoxy} cyclohexyllacetate

To a 250 mL one neck round bottom flask was charged with cw-{4-[(5-bromopyrimidin- 2-yl)oxy]cyclohexyl} acetate (2.77 g, 8.41 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi- 1,3,2- dioxaborolane (2.35 g, 9.26 mmol), Pd (dppf) (0.616 g, 0.841 mmolO, potassium acetate (2.477 g, 25.2 mmol) dissolved in DMSO (35 mL). The mixture was degassed and purged with N₂ for 10 min and stirred at 100° C overnight. The mixture was washed with water and extracted with EtOAc (3x). The combined organic phases was dried over MgS0₄, filtered and concentrated in vacuo. The residue was then purified on 120 gr Redi Sep Rf filter column on CombiFlash with 0-40% Hexane/EtOAc to afford methyl (cw-4-{[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrimidin-2-yl]oxy}cyclohexyl)acetate. LC-MS (ES, m/z) C₁₉H₂₉BN₂0₅: 376; Found: 377 [M+H]⁺.

Following the same procedure described aboved, methyl (tr «5'-4-{[5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]oxy}cyclohexyl)acetate was prepared. LC- MS (ES, m/z) C₁₉H₂₉BN₂0₅: 376; Found: 377 [M+FI]⁺.

Intermediate 29

methyl (cis- -{ \ 5-(4-cvano-3-fluorophenyl)pyrimidin-2-yl oxy}cvclohexyl acetate

To a 20 mL pyrex vial was charged with 4-cyano-3-fluorophenylboronic acid (0.827 g, 5.01 mmol) along with cis methyl {4-[(5-bromopyrimidin-2-yl)oxy]cyclohexyl}acetate (1.50 g, 4.56 mmol) and sodium carbonate (0.966 g, 9.11 mmol) andPd(dppf) (0.263 g, 0.228 mmol) in DME (8 ml) andEthanol (8 mL). The vial was sealed and vacuumed and refilled with nitrogen 3 times and then the mixture was exposed to MW at 150 oc 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 methyl (cz^'s-4-{[5-(4- cyano-3-fluorophenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetate. LC-MS (ES, m/z) C₂₀H₂oFN₃0₃: 369; Found: 370 [M+H]⁺.

Intermediate 30

methyl 2-((lr,4r)-4-(^'(5-(^'4-cvano-3-fluorophenyl)pyrimidin-2-yl)oxy)cvclohexyl)acetate Prepared according the procedure described for methyl (cis-4-{[5-(4-cyano-3- fluorophenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetate, starting with trans methyl {4-[(5- bromopyrimidin-2-yl)oxy]cyclohexyl}acetate LC-MS (ES, m/z) C₂oH₂oFN₃0₃: 369; Found: 370 [M+H]⁺.

To a mixture of methyl (cis-4-{[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrimidin-2-yl]oxy}cyclohexyl)acetate (2.68 g, 7.12 mmol), 6-bromonicotinonitrile (1.43 g, 7.84 mmol); tetrakis (0.823 g 0.712 mmol) and Na₂C0₃ (14.25 mL, 2.0 M, 4.0 equiv) was added DME(15.0 mL)/EtOH(7.5), The reaction mixture was purged with N₂ 10 min followed by MW at 120° for 20 min. The reaction mixture was filtered and concentrated in vacuo. Residue purified by eluting through a silica gel column with a 0-60% Hexane/EtOAc solvent system to provide product methyl 2-((ls,4s)-4-(5-(5-cyanopyridin-2-yl)pyrimidin-2-yloxy)cyclohexyl) acetate. LC- MS (ES, m/z) C₁₉H₂₀N₄O₃: 352; Found: 353[M+H]⁺. 1H NMR (500 MHz, CDC1₃) shift for a characteristic proton δ 5.4 (s, 1H).

Intermediate 32

methyl 2-((lr,4r -4-(5-(5-cvanopyridin-2-yl)pyrimidin-2-yloxy cyclohexyl acetate

In the same procedure as methyl 2-((ls,4s)-4-(5-(5-cyanopyridin-2-yl)pyrimidin-2- yloxy)cyclohexyl)acetate, methyl 2-((lr,4r)-4-(5-(5-cyanopyridin-2-yl)pyrimidin-2- yloxy)cyclohexyl)acetate was prepared. LC-MS (ES, m/z) C₁₉H₂₀N₄O₃: 352; Found: 353[M+H]⁺. 1H NMR (500 MHz, CDC1₃) shift for a characteristic proton δ 5.03 (m, 1H).

Intermediate 33

2-bromo-5-(^'5-(3,4-difluorophenvn-4H-1.2,4-triazol-3-yl)pyridine To a mixture of 6-bromonicotinonitrile (0.2 g, 1.093 mmol), 3,4-difluorobenzohydrazide

(0.376 g, 2.186 mmol), K₂C0₃ (0.151 g, 1.093 mmol) was added n-BuOH (7.0 n L). The reaction mixture was heated at 150°C for 18 h. The reaction mixture was concentrated in vacuo. Residue purified by eluting through a silica gel column with a 0-100% Hexane/EtOAc solvent system to provide product 2-bromo-5-(5-(3,4-difluorophenyl)-4H-l,2,4-triazol-3-yl)pyridine. LC-MS (ES, m/z) C₁₃H₇BrF₂N₄: 337; Found: 338[M+H]⁺.

Intermediate 34

ethyl 8-methyl-l ,4-dioxaspiro 4.5]decane-8-carboxylate

A solution of lithium diisopropylamide (31.1 ml, 46.7 mmol) in THF (100 ml) was cooled to -78°C. A solution of ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate (5 g, 23.34 mmol) in THF (100 ml) was added slowly and the mixture was stirred for 30 min. iodomethane (3.65 ml, 58.3 mmol) was added, and the mixture was continued to stirred for 2 hr at -78 °C. The reaction mixture was quenched with water (100 ml), separated two layers, the aqueous layer was extracted with Et₂0 (2x150 ml), dried over Na₂S0₄, concentrated and separated by MPLC (0- 50% EtOAc in Hexane) to give ethyl 8-methyl-l,4-dioxaspiro[4.5]decane-8-carboxylate (4.4 g) as yellow oil. LC-MS (ES, m/z) C₁₂H₂₀O₄: 228; Found: 229 [M+H]⁺ Intermediate 35

Ethyl 1 -methyl-4-oxocvclohexanecarboxylate

To a solution of ethyl 8-methyl-l,4-dioxaspiro[4.5]decane-8-carboxylate (2.0 g, 8.76 mmol) in aceton (60 ml) was added HC1 (2.5 M, 60 ml, 150 mmol) at rt . After stirred at rt over weekend, the reaction mixture was poured into DCM , the organic layer was then separated and the aqueous was extracted with DCM, washed with brine, dried over Na₂S0₄ , filtered and concentrated, and purified by MPLC (5-60% EtOAc in hexane ) to provide ethyl l-methyl-4- oxocyclohexanecarboxylate as colorlee liquid (1.12 g). LC-MS (ES, m/z) C₁₀H₁₆O₃: 184; Found: 185 [M+H]⁺

Intermediate 36

Ethyl 4-hydroxy- 1 -methylcvclohexanecarboxylate

To a solution of ethyl l-methyl-4-oxocyclohexanecarboxylate (7.02 g, 38.1 mmol) in methanol (15 ml) at 0°C added sodium borohydride (0.721 g, 190.5 mmol) in small portions over 30 min. The reaction mixture aged for 1 hour. Then concentrated under vacuum and applied onto a silica gel column and eluted with ethyl acetate/hexane 10-100%. This resulted in ethyl 4- hydroxy-l-methylcyclohexane-carboxylate (cis&trans mixture) as colorless oil. LC-MS (ES, m/z): C₁₀H₁₈O₃: 186; Found: 187 [M+H]⁺

Intermediate 37

ethyl 4-((5-bromopyridin-2-vnoxyVl-methylcvclohexanecarboxylate

To a stirred solution of 5-bromo-2(lH)-pyridone (2.7 g, 15.52 mmol) in anhydrous THF (40 ml) at RT was added Ethyl 4-hydroxy-l-methylcyclohexanecarboxylate. PPh₃ (4.88 g, 18.62 mmol) was then added followed by dropwise addition of diisopropyl azodicarboxylate (3.67 ml, 18.62 mmol) at 0°C. The reaction was heated to 55 °C and allowed to stir at this temperature 48 h.. The reaction was concentrated, added EtO Ac/Hex (1 :1, 80 nil), stirred for 2 hrs, filtered . The filtrate was concentrated and purified by silica gel column eluted with 0-40% EtO Ac in hexace to afford ethyl 4-((5-bromopyridin-2-yl)oxy)-l-methylcyclohexanecarboxylate as a mixture of cis and trans isomers. The mixture was separated by SFC (ChifalPak AD-H, 250 <30mmI.D. Mobile phase: A for SF C02 and B for Ethanol, Gradient: A: B 85:15, Flow rate: 60mL /min) to give two separated isomers. The two isomers were albeit mixed together for the next step.

Intermediate 38

ethyl 4-((^'5- 4-cvano-3-fluorophenyl pyridin-2-yl oxyVl-methylcvclohexanecarboxylate

Prepared following the procedure described for Ethyl cis-4-{[5-(3-fluoro-4- formylphenyl)pyridin-2-yl]oxy}cyclohexanecarboxylate, starting with ethyl 4-((5-bromopyridin- 2-yl)oxy)-l-methylcyclohexanecarboxylate (mixture of cis and trans isomer) and 4-cyano-3- fluorophenylboronic acid. LC-MS (ES, m/z) C₂₂H₂₃FN₂0₃: 382; Found: 383 [M+H]+.

Intermediates 39 and 40

trans-ethyl 4-(^'5-(^'3-fluoro-4-(^'5-phenyl-4H-l,2,4-triazol-3-vnphenyl pyridin-2-yloxy -l- methylcyclohexanecarboxylate

cis-ethyl 4-(^'5-(3-fluoro-4-(5-phenyl-4H-l,2,4-triazol-3-ynphenvnpyridin-2-yloxyVl- methylcyclohexanecarboxylate

To a mixture of ethyl 4-(5-(4-cyano-3-fluorophenyl)pyridin-2-yloxy)-l- methylcyclohexanecarboxylate (a mixture of cis and trans) (400 mg, 1.046 mmol) and benzohydrazide (285 mg, 2.092 mmol) in n-BuOH (5 ml) added potassium carbonate (145 mg, 1.046 mmol). The reaction mixture heat at 150°C in an oil bath for two days, then concentrated under vacuum. The mixture was separated by ChiralCel OJ- H (250x30 mml.D). Mobile phase: A for SF C0₂ and B for Ethanol (0.2%DEA), gradient: B 40 %. This resulted in trans-ethyl 4-(5- (3 -fluoro-4-(5-phenyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)pyridin-2-yloxy)- 1 - methylcyclohexanecarboxylate. LC-MS (ES, m/z) C₂₉H₂₉FN₄0₃: 500; Found: 501[M+H]+. cis- ethyl 4-(5-(3-fluoro-4-(5-phenyl-4H-l,2,4-triazol-3-yl)phenyl)pyridin-2-yloxy)-l- methylcyclohexanecarboxylate. LC-MS (ES, m/z) C₂₉H₂₉FN₄0₃: 500; Found: 501 [M+H]⁺.

Intermediate 41

Methyl 2,2-dimethyl-3-(pyridin-4-yloxy)propanoate

To a stirred solution of 4-hydroxypyridine (10 g, 105 mmol) in anhydrous THF (200 ml) at RT was added hydroxypivalic acid methyl ester (16.77 ml, 131 mmol). Triphenylphosphine (34.5 g, 131 mmol) was then added followed by dropwise addition of diisopropyl azodicarboxylate (25.9 ml, 131 mmol) at 0 °C. The reaction was then heated to 55 °C and allowed to stir at this temperature over night. The reaction mixture was concentrated. The residue was treated with EtOAc (100 ml) and then Hex.ane (100 ml), the solid was filtered off. The filtrate was concentrated, separated by Thar 200 preparative SFC (column: ChiralPak AD-H, 250x50 mml.D. ; Mobile phase: A for SF C02 and B for Ethanol; Gradient: B 30%; Flow rate: 150 ml/min; Sample preparation: dissolved in ethanol, 200 mg/ml; Injection: 4.5 ml per injection). After separation, the desired fractions were dried off via rotary evaporator at bath temperature 40 °C to give Methyl 2,2-dimethyl-3-(pyridin-4-yloxy)propanoate (26.2 g, containing some solvent). LC-MS (ES, m/z) CnHi₅N0₃: 209; Found: 210 [M+H]⁺

Intermediate 42

Methyl 2,2-dimethyl-3 -(piperidin-4-yloxy)propanoate

Method A:

To a solution of methyl 2,2-dimethyl-3-(pyridin-4-yloxy)propanoate (11.25 g, 53.8 mmol) in acetic acid (100 ml) was added Rh/C (5%, 2.25 g ), then the reaction mixture was hydrogenated under 40 psi at 80°C for 18 hrs. The catalyst was filtered through celite, washed with MeOH and filtrate was concentrated to give Methyl 2,2-dimethyl-3-(piperidin-4- yloxy)propanoate. LC-MS (ES, m/z) C_nH₂₁N0₃: 215; Found: 216 [M+H]⁺

Method B:

Methyl 2,2-dimethyl-3-(pyridin-4-yloxy)propanoate (1 g, 4.78 mmol) was dissolved in acetic acid (70 ml). The solution passed through Rh/C cartridge on H-Cube at 80°C under 80 bars. The reaction mixture concentrated under vacuum to afford methyl 2,2-dimethyl-3- (piperidin-4-yloxy)propanoate as a colorless oil. LC-MS (ES, m/z) CnLLjNOa: 215; Found: 216 [M+H]⁺.

Intermediate 43

methyl 3-((l-(5-cvanopyridin-2-yl^')piperidin-4-yl oxy -2,2-dimethylpropanoate

A mixture of 6-fluoropyridine-3-carbonitrile (1.2 g, 9.83 mmol), methyl 2,2-dimethyl-3- (piperidin-4-yloxy)propanoate (3.81 g, 8.85 mmol) and NaHC0₃ (16.51 g, 197 mmol) inDMSO (19.66 ml) was heated at 110°C overnight. The reaction was cooled to RT, quenched with water, and extracted with EtOAc. The organic layers were washed with brine, dried (Na₂S0₄), and concentrated. The residue was purified by MPLC eluted with 10% EtOAc in hex to EtOAc to afford methyl 3-((l-(5-cyanopyridin-2-yl)piperidin-4-yl)oxy)-2,2-dimethylpropanoate. LC-MS (ES, m/z) C₁₇H₂₃N₃0₃: 317; Found: 318 [M+H]⁺.

Intermediate 44

butyl 2,2-dimethyl-3-(l-(5-r5-phenyl-4H-1.2^-triazol-3-yl idin-2-vnpiperidin-4- yloxy)propanoate

Performed following the procedure described for trans-ethyl 4-(5-(3-fIuoro-4-(5-phenyl- 4H- 1 ,2,4-triazol-3 -yl)phenyl)pyridin-2-yloxy)- 1 -methylcyclohexanecarboxylate, except that methyl 3-(l-(5-cyanopyridin-2-yl)piperidin-4-yloxy)-2,2-dimethylpropanoate was used as the starting material. This resulted in butyl 2,2-dimethyl-3-(l-(5-(5-phenyl-4H-l,2,4-triazol-3- yl)pyridin-2ryl)piperidin-4-yloxy)propanoate as a white solid. LC-MS (ES, m/z) C₂7H₃₅N₅0₃: 477; Found: 478 [M+H]⁺.

Intermediate 45

methyl 2-(trans-4-(^"4-(^,5-formylpyridin-2-yDphenyl)cyclohexyl)acetate

A mixture of methyl 2-(trans-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclohexyl)acetate (1.926 g, 5.38 mmol, a known compound described in WO 2010107768), 6-bromonicotinaIdehyde (1 g, 5.38 mmol), sodium carbonate (1.14 g, 10.75 mmol) and Pd(dppf)Cl₂ (0.197 g, 0.269 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 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 0-70%. This resulted in methyl 2-(trans-4-(4-(5- formylpyridin-2-yl)phenyl)cyclohexyl)acetate as a white solid. LC-MS (ES, m/z) C₂₁H₂₃N0₅: 337; Found: 338 [M+H]⁺.

Intermediate 46

methyl 2-(trans-4-(^'5-(^'3-fluoro-4-(^'5-phenyl-lH-iniidazol-2-yl phenyDpyridin-2- yloxy)cyclohexyl acetate

To a mixture of methyl 2-(trans-4-(5-(3-fluoro-4-formylphenyl)pyridin-2 yloxy)cyclohexyl)acetate (83 mg, 0.224 mmol) and ammonium acetate (86 mg, 0.224 mmol) in methanol (2 ml) was added, over a period of 10 min, a solution of 2-oxo-2-phenylacetaldehyde (30 mg, 0.224 mmol) in methanol (2 ml). The reaction mixture stirred at room temperature over night then concentrated under vacuum. The mixture was applied onto a silica gel column and eluted with ethyl acetate/hexane 0-100%. This resulted in methyl 2-(trans-4-(5-(3-fluoro-4-(5- phenyl-lH-imidazol-2-yl)phenyl)pyridin-2-yloxy)cyclohexyl)acetate as a white solid. LC-MS (ES, m/z) C₂₉H₂₈FN₃0₃: 485; Found: 486 [M+H]⁺.

Intermediate 47

Methyl 2-((lr,4r)-4-(4-(5-cyanopyridin-2-vf)phenyl cvclohexyl)acetate

A mixture of 2-Bromo-5-cyanopyridine (10 g, 54.6 mmol), methyl 2-((lr,4r)-4-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate (19.6 g, 54.6 mmol, a known compound described in WO 2010107768 Al 20100923), sodium carbonate (11.6 g, 109 mmol) and [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.00 g, 2.73 mmol) are suspended in DMF(100 mL) / H₂0 (50 mL) and stirred in a sealed reaction vessel. The reaction mixture was blown with N₂, sealed and heated at 80°C over night. The reaction mixture was poured into water, extract with EtOAc. dried over Na₂S0₄, filtered and concentrated, purified by MPLC (0-70% EtOAc in hexane ) to give methyl 2-((lr,4r)-4-(4-(5-cyanopyridin-2- yl)phenyl)cyclohexyl)acetate. LC-MS (ES, m/z) C₂₁H₂₂N₂0₂: 334; Found: 335 [M+H]⁺

Intermediate 48

benzyl 4-(trans-4-(2-methoxy-2-oxoethyl)cvclohexyloxy)piperidine- 1 -carboxylate

Methyl 2-(trans-4-hydroxycyclohexyl)acetate (8 g, 46.5 mmol) was dissolved in anhydrous THF (100 ml) at 0°C, TEA (7.12 ml, 51.1 mmol) added, followed by drop wise addition of TMS-C1 (6.23 ml, 48.8 mmol). The reaction mixture aged for 30 min then diluted with hexane (100 ml) and filtered through a small pad of celite eluting with hexane and concentrated. The crude product and benzyl 4-oxopiperidine-l -carboxylate (10.40 g, 44.6 mmol) dissolved in dichloride methane (150 ml) at -60-65°C, triethylsilane (7.42 ml, 46.5 mmol) added, followed by drop wise addition of TMS-OTf (4.20 ml, 23.23 mmol) and allow to warm to 0°C and aged for 30 min. The reaction mixture diluted with EtOAc (50 ml), 1 M H₃P0₄ (30 ml) added, the organic layer washed with brine (2x 20 ml) and dried over anhydrous sodium sulfate and concentrated under vacuum. Then applied onto a silica gel column and eluted with ethyl acetate/hexane 0-70%. This resulted in benzyl 4-(trans-4-(2-methoxy-2-oxoethyl)cyclohexyloxy) piperidine-1 -carboxylate as colorless oil. LC-MS (ES, m/z) C₂₂H₃iN0₅: 389; Found: 390 [M+H]⁺.

Intermediate 49

methyl 2-(trans-4-(piperidin-4-yloxy^cyclohexyl acetate

Benzyl 4-(trans-4-(2-methoxy-2-oxoethyl)cyclohexyloxy)piperidine- 1 -carboxylate (3.12 g, 8.01 mmol) was dissolved in methanol (10 ml), palladium on carbon (0.043 g, 0.4 mmol) added. The reaction mixture stir at 1 atm H₂ over night. The reaction mixture concentrated under vacuum to result in methyl 2-(trans-4-(piperidin-4-yloxy)cyclohexyl)acetate as a colorless oil. LC-MS (ES, m/z) C₁₄H₂₅N0₃: 255; Found: 256 [M+H]⁺.

Intermediates 50 and 51

benzyl 4-(cis-4-(2-methoxy-2-oxoethyl cyclohexyloxy piperidine- 1 -carboxylate benzyl 4-(^"trans-4-(2-methoxy-2-oxoethvDcyclohexyloxy)piperidine- 1 -carboxylate Methyl 2-(trans&cis-4-hydroxycyclohexyl)acetate (15 g, 87 mmol) was dissolved in anhydrous THF (150 ml) at 0°C, TEA (13.35 ml, 96 mmol) added, followed by drop wise addition of TMS-Cl (11.69 ml, 91 mmol). The reaction mixture aged for 30 min then diluted with hexane (100 ml) and filtered through a small pad of celite eluting with hexane and concentrated. The crude product and benzyl 4-oxopiperidine-l -carboxylate (10.40 g, 44.6 mmol) dissolved in dichloride methane (150 ml) at -60-65°C, triethylsilane (13.91 ml, £>7 mmol) added, followed by drop wise addition of TMS-OTf (7.87 ml, 43.5 mmol) and allow to warm to 0°C and aged for 30 min. The reaction mixture diluted with EtOAc (100 ml), 1 M H₃P0₄ (30 ml) added, the organic layer washed with brine (2x 20 ml) and dried over anhydrous sodium sulfate and concentrated under vacuum. This trans/cis mixture separated by SFC, chiralPak AD- ΙΟμιη, 300x50 mml.D. Mobile phase: A for SF C0₂ and B for ethanol. Gradient: B 40 %. Benzyl 4-(cis- 4-(2-methoxy-2-oxoethyl)cyclohexyloxy)piperidine-l-carboxylate 15 g (64%). LC-MS (ES, m/z): C22H31N05: 389; Found: 390 [M+H]⁺. Benzyl 4-(trans-4-(2-methoxy-2- oxoethyl)cyclohexyloxy)piperidine-l -carboxylate 8 g (32%) LC-MS (ES, m/z): C₂₂H₃₁N0₅: 389; Found: 390 [M+H]⁺.

Intermediate 52

methyl 2-(cis-4-(piperidin-4-yloxy)cyclohexyl^')acetate

Benzyl 4-(cis-4-(2-methoxy-2-oxoethyl)cyclohexyloxy)piperidine-l -carboxylate (9 g, 23.11 mmol) was dissolved in methanol (40 ml), palladium on carbon (0.123 g, 1.155 mmol) added. The reaction mixture stir at 1 atm H₂ for 2 days. The reaction mixture concentrated under vacuum to result in methyl 2-(cis-4-(piperidin-4-yloxy)cyclohexyl)acetate as a colorless oil. LC- MS (ES, m/z) C₁₄H₂₅N0₃: 255; Found: 256 [M+H]⁺.

Intermediate 53

2-(trans-4-(piperidin-4-yloxy cyclohexyl) acetic acid

A mixture of methyl 2-(trans-4-(piperidin-4-yloxy)cyclohexyl)acetate (1.7 g, 6.66 mmol) and lithium hydroxide (487 mg, 19.97 mmol) in THF (2 ml), MeOH (2 ml) and water (1 ml). The reaction mixture stirred at room temperature over night then concentrated under vacuum to result in 1.6 g (100%) of 2-(trans-4-(piperidin-4-yloxy)cyclohexyl)acetic acid as a colorless oil. LC-MS (ES, m/z) Q3H23NO3: 241; Found: 242 [M+H]⁺.

Intermediate 54

2-(cis-4-(piperidin-4-yloxy cvclohexyl acetic acid

A mixture of methyl 2-(cis-4-(piperidin-4-yloxy)cyclohexyl)acetate (2.23 g, 8.73 mmol) and lithium hydroxide (627 mg, 26.2 mmol) in THF (4 ml), MeOH (6 ml) and water (3 ml). The reaction mixture stirred at room temperature over night then concentrated under vacuum to result in 2 g (95%) of 2-(cis-4-(piperidin-4-yloxy)cyclohexyl)acetic acid as a colorless oil. LC-MS (ES, m/z) C₁₃H₂₃N0₃: 241; Found: 242 [M+H]⁺.

Intermediate 55

2-(trans-4-(l-(^"5-cvanopyridin-2-yl piperidin-4-yloxy)cyclohexynacetic acid

A mixture of 2-(trans-4-(piperidin-4-yloxy)cyclohexyl)acetic acid (800 mg, 3.32 mmol), 6-fluoronicotinonitrile (405 mg, 3.32 mmol), and sodium bicarbonate (1.67 g, 19.9 mmol) are suspended in DMSO (6 ml), the reaction mixture was stirred over night at 110°C under N₂ in an oil bath. The reaction mixture was cooled to room temperature, and concentrated under vacuum. Then applied onto a silica gel column and eluted with Acetone/DCM 0-80%. This resulted in 0.58 g (51%) of 2-(trans-4-(l-(5-cyanopyridin-2-yl)piperidin-4-yloxy)cyclohexyl)acetic acid as a white solid. LC-MS (ES, m/z) C₁₉H₂5N₃03: 343; Found: 344 [M+H]⁺.

Intermediate 56

2-(cis-4-d-(^'5-cvanopyridin-2-yl^')pipefidin-4-yloxy)cvclohexynacetic acid

Performed following the procedure described for 2-(trans-4-(l-(5-cyanopyridin-2- yl)piperidin-4-yloxy)cyclohexyl)acetic acid, except that 2-(cis-4-(piperidin-4- yloxy)cyclohexyl)acetic acid was used as the starting material. This resulted in 2-(cis-4-(l-(5- cyanopyridin-2-yl)piperidin-4-yloxy)cyclohexyl)acetic acid as a white solid. LC-MS (ES, m/z) C₁₉H₂₅N₃0₃: 343; Found: 344 [M+H]⁺.

Intermediate 57

Methyl 2-(4-(pyridin-4-vDcyclohex-3 -envDacetate

To 20 mL Pyrex vials (3 vials evenly) was charged with pyridin-4-ylboronic acid (2.98 g, 21.83 mmol) along with methyl 2-(4-(trifluoromethylsulfonyloxy)cyclohex-3-enyl)acetate (6.0 g, 19.85 mmol, a known compound described in WO 2009016462) sodium carbonate (6.3 g, 59.5 mmol) and palladium tetrakis (1.14 g, 0.992 mmol) in DMF (lmL). DME (10 ml) and Ethanol (10 mL) were then added to the vial and the vial was sealed and vacuumed and refilled with nitrogen 3 times. The mixture was then exposed to MW at 150 °C for 1 h. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated and the residue was purified by the Isco MPLC on an 80 g silica gel column, eluting with 0 to 40% ethyl acetate in hexanes, to afford Methyl 2-(4-(pyridin-4-yl)cyclohex-3-enyl)acetate. LC-MS (ES, m/z) C₁₄H₁₇N0₂: 231; Found: 232 [M+H]⁺.

Intermediate 58

cis&trans Methyl 2-(4-(pyridin-4-yl cvclohexyl acetate A solution of Methyl 2-(4-(pyridin-4-yl)cyclohex-3-enyl)acetate (2.33 g, 10.07 mmol) in

EtOAc (50 ml) was treated with 10 % Palladium on Carbon (2.144 g, 2.015 mmol) and the mixture shake on the Parr shaker under H₂ atmosphere at 45 psi for 1.5 h. The mixture was filtered through celite and washed with EtOAc. The filtrate was concentrated to afford cis&trans Methyl 2-(4-(pyridin-4-yl)cyclohexyl)acetate as a cis and trans mixture. LC-MS (ES, m/z) C₁₄H₁₉N0₂: 233; Found: 234 [M+H]⁺.

Intermediate 59 Intermediate 60

trans Methyl 2-(4-(pyridin-4-yl cyclohexyl¼cetate cis Methyl 2-(4-(^"pyridin-4-yl cyclohexyl acetate cis&trans Methyl 2-(4-(pyridin-4-yl)cyclohexyl)acetate (2.08 g ) was resolved on the OJ-

H column using SFC(OJ-H Column 20 xl50 mm, 10 % MeOH / ACN (2:1) / CO, 50 ml / min, 100 barr, 100 mg/ ml in MeOH, 35°C). The first eluting isomer was determined to be trans methyl 2-(4-(pyridin-4-yl)cyclohexyl)acetate. LC-MS (ES, m/z) C₁₄H₁₉N0₂: 233; Found: 234 [M+H]⁺. The second eluting isomer was determined to be cis methyl 2-(4-(pyridin-4- yl)cyclohexyl)acetate. LC-MS (ES, m z) C₁₄H₁₉N0₂: 233; Found: 234 [M+H]⁺.

Intermediate 61

cis Methyl 2-(4-fpiperidin-4-yl)cyclohexyl acetate A solution of cis Methyl 2-(4-(pyridin-4-yl)cyclohexyl)acetate (700 mg, 3.00 mmol) in AcOH (30 ml) in a 250 ml Parr Shaker Bottle was treated with 20 % palladium hydroxide on carbon (316 mg, 0.450 mmol) and the mixture shake on the Parr Shaker under H₂ (50 psi) atmosphere at 25 °C for 40 h. The mixture was filtered through a Glass Acrodisc using a syringe and the filtrate concentrated to afford cis Methyl 2-(4-(piperidin-4-yl)cyclohexyl)acetate as the acetic acid salt. LC-MS (ES, m/z) C₁₄H₂₅N0₂: 239; Found: 240 [M+H]⁺.

Intermediate 62

methyl 2-((ls.4s -4-d-(5-cyanopyridin-2-yl piperidin-4-yl cvclohexyl acetate

A 5 ml Pyrex vial charged with 2-bromo-5-cyanopyridine (225 mg, 1.229 mmol), cis Methyl 2-(4-(piperidin-4-yl)cyclohexyl)acetate (405 mg, 1.352 mmol) and cesium carbonate (2003 mg, 6.15 mmol) was capped under N₂ atmosphere and NMP (4.0 ml) added via a syringe. The mixture was then stirred at 110 °C in an oil bath for 8 h. The mixture was diluted with water and extracted (x2) with EtOAc. The organic layer was dried (MgS0₄) and concentrate.

Purification on the CombiFlash companion on a 24 g column eluting with 15 to 30 % EtOAc / Hexane afforded methyl 2-((ls,4s)-4-(l-(5-cyanopyridin-2-yl)piperidin-4-yl)cyclohexyl)acetate. LC-MS (ES, m/z) C₂₀H₂₇N₃O₂: 341; Found: 342 [M+H]⁺.

Intermediate 63

2-(4-( 1 -(5-cvanopyridin-2-yl)piperidin-4-yl phenyl acetic acid

To commercially available 2-(4-(piperidin-4-yl)phenyl)acetic acid (0.7 g, 2.74 mmol) and 6-fluoronicotinonitrile (0.334 g, 2.74 mmol) in DMSO (6.84 ml) was added sodium bicarbonate (1.380 g, 16.42 mmol) and the reaction was stirred at 110 °C overnight. The reaction was cooled to rt and acidified with IN HCl (aq.) to pH 2 and lyophilized. The residue was purified by MPLC (0-100% acetone in DCM) to give 0.71 g solid (not pure), which was purified by prep HPLC (Instrument: Shimadzu LC-20AP Prep HPLC; Column: Synergi C18 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, lOOmg/ml ; Injection: 3ml per injection.) After HPLC, The fraction was concentrated to remove the organic phases via rotary evaporator at bath temperature 35°C. The material was lyophilized to give 2-(4- (l-(5-cyanopyridin-2-yl)piperidin-4-yl)phenyl)acetic acid. LC-MS (ES, m/z) C₁9H₁₉N₃0 : 321; Found: 322 [M+H]⁺.

Intermediate 64

6'-(((3S. aR,6R,6aR)-6-hvdroxyhexahvdrofa

carbonitrile

Step 1

To a 250 mL round bottom flask was placed 9.3 g (50.8 mmol) of 2-bromo5- cyanopyridine, 7.88 g (55.9 mmol) of 2-fluoro5-pyridineboronic acid, 27 g (127.0 mmol) of potassium phosphate tribasic, and 100 mL of THF and 18 mL of water and the mixture was degassed for 15 min. In a separate 40 mL reaction Vial was plabed 570 mg (2.54 mmol) of Pd(OAc)₂, 196 mg (0.546 mmol) of catacxium A and 5 mL of THF and this was degassed for 15 min. The active catalyst was then added to the first solution and was warmed to 60 °C for 30 min. The reaction mixture was cooled to rt and diluted with EtOAc and filtered to remove insoluble materials. The layers were separated the organic layer was washed with brine, dried over MgS0₄, filtered and concentrated under reduced pressure. The resulting solid was slurred in 2:1 hexane MTBE and filtered to provide 9.1 g (90%) of 6'-fluoro-2,3'-bipyridine-5- carbonitrile that was sufficiently pure for subsequent transformations.

Step 2

To a 100 ml flask was charged with 5.0 g (19.2 mmol) of (3S,3aR,6R,6aS)-6-(tert- butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-ol (Vogler, et. al. Synthesis, 2004, 1211- 1228), DMSO (20ml) and NaH (0.92 g, 23 mmol) in one portion. The resultant mixture was stirred at rt for 30 min, before 6'-fluoro-2,3'-bipyridine-5-carbonitrile (3.82 g, 19.2 mmol) was added as a DMSO (20 ml) solution. The resultant reaction mix was stirred at 30 °c, for 4 hrs. The reaction mixture was diluted with water, extracted with ethyl acetate. The combined extract was washed with brine, dried over Na₂S0₄, filtered and concentrated under vacuum. The crude product mixture was purified by a silica gel column eluting with ethyl acetate/hexane 0-50%. This provided 6'-((3S,3aR,6R,6aR)-6-(2-(trimethylsilyl)propan-2-yloxy)hexahydrofuro[3,2- b]furan-3-yloxy)-2,3'-bipyridine-5-carbonitrile as yellow solid. LC-MS (ES, m/z) C₂₃H₂₉N₃0₄Si: 439; Found: 440 [M+H]⁺.

Step 3 To a solution of 6'-((3S,3aR,6R,6aR)-6-(2-(trimethylsilyl)propan-2- yloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-2,3'-bipyridine-5-carbonitrile (1.22 g, 2.78mmol) in THF (3 ml) was added acetonitrile (3 ml) and water (6 ml) and TFA (1.59 g, 14 mmol). The mixture was stirred at rt for 12 hours. The reaction mixture was concentrated under vacuum to afford the title compound as colorless oil. LC-MS (ES, m/z) C17H15N3O4: 325; Found: 326

[M+H]⁺.

Intermediate 65

Ethyl l-(5-(4-cvano-3-fluorophenyl)pyridin-2-yl -4-fluoropiperidine-4-carboxylate

Step 1

To a 250 mL round bottom flask was placed 12.00 g (77 mmol) of 4-chloro-2- fluorobenzonitrile, 10.87 g (77 mmol) of 2-fluoro5-pyridineboronic acid, 49.1 g (231.0 mmol) of potassium phosphate tribasic, and 120 mL of THF and 25 mL of water and the mixture was degassed for 15 min. In a separate 40 mL reaction vial was placed 866 mg (3.86 mmol) of Pd(OAc)₂, 3.68 g (7.71 mmol) of X-Phos and 20 mL of THF and this was degassed for 15 min. The active catalyst was then added to the first solution and was warmed at reflux for 1 h. The reaction mixture was cooled to rt and diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried over MgS0₄ and concentrated under reduced pressure. The crude solid was slurred in MTBE and then filtered to give 15.0 g (90%) of 2- fluoro-4-(6-fluoropyridin-3-yl)benzonitrile that was sufficiently pure for subsequent transformations.

Step 2

To a solution of 2-fluoro-4-(6-fluoropyridin-3-yl)benzonitrile (1.85 g, 8.57 mmol) in

DMSO (9.85 ml) was added 1.90 g (9.02 mmol) of 4-(ethoxycarbonyl)-4-fluoropiperidinium chloride (WO2008 108957A2) and sodium bicarbonate (3.79 g, 45.1 mmol). The mixture was stirred at 80°C under N₂ for 2 hours. The reaction mixture was cooled to room temperature then diluted with water (300 ml) and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under vacuum and purified by a silica gel column eluting with ethyl acetate/hexane 0-50% to afford ethyl l-(5-(4-cyano-3- fluorophenyl)pyridin-2-yl)-4-fluoropiperidine-4-carboxylate as white solid. LC-MS (ES, m/z) C₂oH₁₉F₂N₃0₂: 371; Found: 372 [M+H]⁺. Example 1

2-( ( 1 r.4r)-4-(4'-( 5 -phenyl-4H- 1.2.4-triazol-3 -ylVf 1.1 '-biphenyll-4-yl cvclohexyl¼cetic acid

Step 1

A mixture of 3-(4-iodophenyl)-5-phenyl-4H-l,2,4-triazole (1.0 g, 2.88 mmol), methyl 2- ((lr,4r)-4-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl) acetate (1.032 g, 2.88 mmol, a known compound described in WO 2010107768), sodium carbonate (0.611 g, 5.76 mmol) and [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.105 g, 0.144 mmol) are suspended in DMF (6 mL) / H₂0 (3 mL) and stirred in a sealed reaction vessel. After blown with N₂ , the reaction was sealed and heated at 80°C over night. The reaction mixture was poured into water, extract with EtOAc, dried over Na₂S0₄, filtered and concentrated. The residue was purified by ISCO (0-100% EtOAc in hexane) to give methyl 2-((lr,4r)-4-(4'-(5-phenyl-4H-l,2,4- triazol-3-yl)-[l,r-biphenyl]-4-yl)cyclohexyl) acetate. LC-MS (ES, m/z) C₂₉H₂₉N₃0₂: 451 ;

Found: 452 [M+H]⁺

Step 2 To a mixture of methyl 2-((lr,4r)-4-(4*-(5-phenyl-4H-l,2,4-triazol-3-yl)-[l,r-biphenyl]-4- yl)cyclohexyl) acetate (165 mg, 0.365 mmol) in THF (1.5 ml) /water (1 ml)/MeOH (1.5 ml) was added LiOH monohydrate (92 mg, 2.192 mmol). The reaction mixture was stirred at 40°C over night. The mixture was cooled to RT and neutralized by HC1 (2N, aq). The mixture was then concentrated and purified by reverse HPLC eluted with a gradient of MeCN and water to afford 2-((lr,4r)-4-(4*-(5-phenyl-4H-l,2,4-triazol-3-yl)-[l,r-biphenyl]-4-yl)cyclohexyl)acetic acid. LC- MS (ES, m/z) C₂₈H₂₇N₃0₂: 437; Found: 438 [M+H]⁺

Example 2

2-(( 1 r,4r)-4-((5-(4-(3 -phenyl- 1 H-pyrazol-5 -yl)phenyl pyridin-2-yl)oxy cyclohexyl)acetic acid Step 1

A mixture of 5 -(4-bromophenyl)-3 -phenyl- lH-pyrazole (0.191 g, 0.640 mmol), methyl 2-

((lr,4r)-4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)cyclohexyl)acetate (0.2 g, 0.533 mmol), sodium carbonate (0.113 g, 1.07 mmol) and [Ι,Γ- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.039 g, 0.053 mmol) are suspended in DMF / 1¾0 (2:1, 4,5 ml) and heated at 80°C under N₂ over night. The reaction mixture was poured into water, extract with EtOAc, dried over Na₂S0₄, filtered and concentrated. The residue was purified by reverse HPLC (Instrument: Gilson 281; Column: YMC-pack ODS-AQ, 5u 150x20mm I.D.; Mobile phase: A for H₂0 and B for Acetonitrile; Gradient: B 40%-70% in

30min linearly; Flow rate: 25 ml/min; Column temperature: 40°C; Wavelength: 220nm; Sample preparation: Compound dissolved in Acetonitrile, ~10mg/ml; Injection: 1.2ml per injection). After separation, the fraction was concentrated to remove the organic phases via rotary evaporator at bath temperature 35°C. The aqueous layer was lyophilized to get methyl 2-((lr,4r)- 4-(5-(4-(3-phenyl-lH-pyrazol-5-yl)phenyl)pyridin-2-yloxy)cyclohexyl)acetate. LC-MS (ES, m/z) C₂₉H₂₉N₃0₃: 467; Found: 468 [M+H]⁺.

Step 2

Methyl 2-((lr,4r)-4-(5-(4-(3-phenyl-lH-pyrazol-5-yl)phenyl)pyridin-2-yloxy)

cyclohexyl)acetate (100 mg, 0.214 mmol) was treated with THF (3 ml) followed by water (1 ml). The supsension was treated with LiOH (30.7 mg, 1.283 mmol) and then heated at 50°C overnight under N₂. The reaction was concentrated and the residue was purified by reverse HPLC eluted with a gradient of MeCN/water to afford 2-((lr,4r)-4-((5-(4-(3-phenyl-lH-pyrazol-5- yl)phenyl)pyridin-2-yl)oxy)cyclohexyl)acetic acid. LC-MS (ES, m/z) C₂₈H₂₇N₃0₃: 453; Found: 454[M+H]⁺

Example 3

Methyl 2-(4'-C5-phenyl-4H- 1 ,2,4-triazol-3-yl)-2,3 A5-tetrahvdro-IT , 1 '-biphenyll-4-vnacetate 3-(4-iodophenyl)-5-phenyl-4H-l,2,4-triazole (500 mg, 1.440 mmol), Na₂C0₃ (305 mg, 2.88 mmol), methyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l- yl)acetate (444 mg, 1.584 mmol, a known compound described in WO2009016462) was treated with N,N-Dimethylformamide (3 ml) and water (1.5 ml). The mixture was purged with N₂ for 5 min. [Ι, -bis (diphenylphosphino)ferrocene]dichloropalladium (II) (52.7 mg, 0.072 mmol) was added. The mixture was purged with N₂ for 5 min. The mixture was then heated under N2 at 80°C overnight. The mixture was diluted with water, extracted with EtOAc (2x). The organic layers were washed with brine, dried (Na₂S0₄) and concentrated. The residue was purified by MPLC eluted with DCM gradient to acetone to afford methyl 2-(4'-(5-phenyl-4H-l,2,4-triazol-3- yl)-2,3,4,5-tetrahydro-[l,l'-biphenyl]-4-yl)acetate. LC-MS (ES, m/z) C₂₃H₂₃N₃0₂: 373; Found: 374 [M+H]⁺.

Example 4

2-(4'-r5-phenyl-4H-l,2_>4-triazol-3-vn-2_>3,4,5-tetrahvdro-ri.r-biphenyl1-4-yl acetic acid

Prepared according the procedure described for 2-((lr,4r)-4-(4'-(5-phenyl-4H-l,2,4- triazol-3-yl)-[l, -biphenyl]-4-yl)cyclohexyl)acetic acid (Step 2), starting from Methyl 2-(4'-(5- phenyl-4H-l,2,4-triazol-3-yl)-2,3,4,5-tetrahydro-[l,r-biphenyl]-4-yl)acetate. LC-MS (ES, m/z) C₂₂H₂₁N₃0₂: 359; Found: 360 [M+H]⁺.

Example 5

2-r3-r5-r5- rifluoromethylV4H-1 ,4-triazol-3-vnpyridin-2-ylV3-azaspiror5.51undecan-9- vDacetic acid

Methyl 2-(3-(5-cyanopyridin-2-yl)-3-azaspiro[5.5]undecan-9-yl)acetate (29 mg, 0.089 mmol, 1.0 equiv) was charged in a vial fitted with a Teflon-lined crimp cap then 2,2,2- trifluoroacetohydrazide (110 mg, 0.859 mmol, 9.7 equiv), acetic acid (39 μΕ) and dioxane (350 \\L) were added. The vial was sealed with inclusion of air and heated at 200 °C for 4 hours. The cooled mixture was directly purified by preparative reverse phase HPLC (20% to 80% acetonitrile in water with 0.05% TFA) to obtain the TFA salt of methyl 2-(3-(5-(5- (trifluoromethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-3-azaspiro[5.5]undecan-9-yl)acetate as a white solid (1.9 mg): [MH]⁺ calculated m/z 438; found m/z 438. The ester was dissolved in 1 mL each of THF, water and methanol. Solid lithium hydroxide hydrate (5 mg, 0.119 mmol, 35 equiv) was added and the mixture stirred at 50 °C for 3 hours at which point LCMS analysis showed clean conversion to the acid. The reaction was neutralized by addition of glacial acetic acid (8 μ^) and concentrated in vacuo. The residue was dissolved in DMSO and purified by preparative reverse phase HPLC (30% to 100% acetonitrile in water with 0.05% TFA) to obtain the TFA salt of 2-(3-(5-(5-(trifluoromethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-3- azaspiro[5.5]undecan-9-yl)acetic acid as a white solid: [MH]⁺ calculatedd m/z 424; found m/z 424.

Example 6

3 -( 1 -(5 -(5 -(3 -chlorophenyl)-4H- 1 ,2.4-triazol-3 - yl)pyridin-2-yl)-4-hvdroxypiperidin-4- vDcvclohexanecarboxylic acid

3-chlorobenzohydrazide (91 mg, 0.532 mmol, 1 equiv), ethyl 3-(l-(5-cyanopyridin-2-yl)- 4-hydroxypiperidin-4-yl)cyclohexanecarboxylate (190 mg, 0.532 mmol, 1 equiv) and solid potassium carbonate (74 mg, 0.532 mmol, 1 equiv) were charged to a vial then taken up in n- butanol (6.6 mL). The vial was fitted with a Teflon-lined cap and heated at 150 ^°C for 70 hours. Volatiles were removed in vacuo and the residue was reconstituted in THF (2 mL) and methanol (2 mL) then treated with 2.5 M aqueous lithium hydroxide (2.1 mL) for 2 hours at room temperature at which point LCMS analysis indicated complete saponification to the acid. The mixture was acidified with glacial acetic acid (450 μί) then concentrated in vacuo. The residue was dissolved in DMSO and wet acetonitrile then purified by preparative reverse phase HPLC (20% to 80% acetonitrile in water with 0.05% TFA) to obtain the TFA salt of 3-(l-(5-(5-(3- chlorophenyl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)-4-hydroxypiperidin-4-yl)cyclohexane carboxylic acid: [MH]⁺ calculated m/z 482; found m/z 482.

Example 7 OOH

(ls,4s -4-(^'(^'5-(3-fluoro-4-(4-neopentyl-lH-imidazol-2-yl phenyl pyridin-2- yl oxy)cvclohexanecarboxylic acid

Step 1

l-hydroxy-4,4-dimethylpentan-2-one (34.5 mg, 0.269 mmol) in EtOH (2 ml) was added ethyl cw-4-{[5-(3-fluoro-4-formylphenyl)pyridin-2-yl]oxy}cyclohexane carboxylate (100 mg, 0.269 mmol), amonium 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 overnight. LC-MS showed completion of the reaction. Quenched with Na₂S₂0₃ solution, and extracted with EtOAc (2X50 ml). Seperated the organic, dried over MgS04, filtered and concentrated, the residue was purified with Prep. TLC(40% EtOAc/Hexane) to provide (ls,4s)-ethyl 4-((5-(3-fluoro-4-(4-neopentyl-lH-imidazol- 2-yl)phenyl)pyridin-2-yl)oxy)cyclohexanecarboxylate. LC-MS (ES, m/z): C₂₈H₃FN₃0₃: 479; Found: 480 [M+H]⁺. Step 2

A mixture of (ls,4s)-ethyl 4-((5-(3-fluoro-4-(4-neopentyi-lH-imidazol-2- yl)phenyl)pyridin-2-yl)oxy)cyclohexanecarboxylate (20 mg, 0.042 mmol) in THF/tLO was added lithium hydroxide (1.750 mg, 0.042 mmol). The resulting mixture was stirred at 40°C for 16 hours. Concentrated, the residue was purified by reverse HPLC to afford (ls,4s)-4-((5-(3- fluoro-4-(4-neopentyl-lH-imidazol-2-yl)phenyl)pyridin-2-yl)oxy)cyclohexane carboxylic acid. LC-MS (ES, m/z): C₂₆H₃oFN₃0₃: 451 ; Found: 452 [M+H]⁺.

2-⁽ar,4ry4-(5-(5-(5-(3,4-difluorophenyl H-L

yloxytevclohexyDacetic acid Step 1

To a mixture of methyl 2-((lr,4r)-4-((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrimidin-2-yl)oxy)cyclohexyl)acetate (0.112 g, 0.298 mmol), 2-bromo-5-(5-(3,4- difluorophenyl)-4H-l,2,4-triazol-3-yl)pyridine (0.11 g, 0327 mmol); tetrakis (0.034 g 0.03 mmol) and Na₂C0₃ (0.596 mL, 2.0 M, 4.0 equiv) was added DME(2.5 mL)/EtOH(0.75 mL). The reaction mixture was purged with N₂ for 10 min followed by microwave at 120°C for 20 min. The reaction mixture was filtered and concentrated in vacuo. Residue purified by eluting through a silica gel column with a 0-60% Hexane/EtOAc solvent system to provide product methyl 2- ((1 r,4r)-4-((5-(5-(5-(3 ,4-difluorophenyl)-4H- 1 ,2,4-triazol-3-yl)pyridin-2-yl)pyrimidin-2- yl)oxy)cyclohexyl)acetate. LC-MS (ES, m/z) C₂₆H₂₄F₂N₆0₃: 507; Found: 506[M+H]⁺.

Step 2

To a 50 ml vial was added 5.0 M NaOH (0.073 mL, 0.365 mmol, 5.0 equiv) dissolved in H20 (1.0 mL), among with methyl 2-((lr,4r)-4-(5-(5-(5-(3,4-difluorophenyl)-4H-l,2,4-triazol-3- yl)pyridin-2-yl)pyrimidin-2-yloxy)cyclohexyl)acetate (0.037 g, 0.073 mmol, 1.0 equiv) in THF (2.0 mL) and MeOH (1.0 mL). The reaction mixture was stirred at 60° C for 45 min. The mixture was acidified with cone. HCl to pH=7 and purified by RP HPLC with loading as a solution of DMSO:H₂0:ACN, 20 to 80% ACN in H₂0 to give 2-((lr,4r)-4-(5-(5-(5-(3,4- difluorophenyl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)pyrimidin-2-yloxy)cyclohexyl)acetic acid. LC- MS (ES, m/z) C₂₅H₂₂F₂N₆0₃: 492; Found: 493[M+H]⁺.

Example 9

2-butoxy-5-(^'5- 5-(3,4-difluorophenylV4H-L2,4-triazol-3-yl^')pyridin-2-vnpyrimidine

To a 50 ml vial was added methyl 2-((lr,4r)-4-(5-(5-cyanopyridin-2-yl)pyrimidin-2- yloxy)cyclohexyl)acetate (0.1 g, 0.284 mmol, 1.0 equiv), 3,4-difluorobenzohydrazide (0.098 g, 0.568 mmol, 2.0 equiv) and potassium carbonate (0.118 g, 0.851 mmol, 3.0 equiv) in n-BuOH (3.0 mL). The reaction mixture was stirred at 150° C for 48 hr. The mixture was washed with water and extracted with EtOAc 2x, organics dried over MgS04, filtered and concentrated in vacuum. The residue was purified by eluting through a silica gel column with a 0-70% DCM/EtOAc solvent system to provide product 2-butoxy-5-(5-(5-(3,4-difluorophenyl)-4H-l,2,4- triazol-3-yl)pyridin-2-yl)pyrimidine. LC-MS (ES, m/z) C₂₁H₁₈F₂N₆0: 408; Found: 409[M+H]⁺. Examples 10 and 11

Prepared according the procedure described for 2-butoxy-5-(5-(5-(3,4-difluorophenyl)- 4H-l,2,4-triazol-3-yl)pyridin-2-yl)pyrimidine, starting with methyl 2-((lr,4r)-4-(5-(5- cyanopyridin-2-yl)pyrimidin-2-yloxy)cyclohexyl)acetate and appropriate hydrazides.

Example 12

cis-4-(5-(3 -fluoro-4-(5 -phenyl-4H- 1 ,2,4-triazol-3 -vnphenyl)pyridin-2-yloxyV 1^■

methylcyclohexanecarboxylic acid Cis-ethyl 4-(5-(3-fluoro-4-(5-phenyl-4H-l,2,4-triazol-3-yl)phenyl)pyridin-2-yloxy)-l- methylcyclohexanecarboxylate (98 mg, 0.196 mmol) dissolved in water (1 ml) and

hydrochloride acid (1 ml, 18.5%). The reaction mixture was refluxed for 1 hr. then concentrated under vacuum. The product was purified with acetonitril (0.1%TFA)/water (0.1%TFA) 54-84%. This resulted in 42 mg (9.6%) of cis-4-(5-(3-fluoro-4-(5-phenyl-4H-l,2,4-triazol-3- yl)phenyl)pyridin-2-yloxy)- 1 -methylcyclohexanecarboxylic acid

as a white solid. LC-MS (ES, m/z) C₂₇H₂₅C1N₄0₃: 472; Found: 473 [M+H]⁺.

Example 13

trans-4-(5-(3 -fluoro-4-(5 -phenyl-4H- 1 ,2,4-triazol-3 -yl)phenyl pyridin-2-yloxy)- 1 - methylcyclohexanecarboxylic acid

Performed as same as the step 2 except that trans-ethyl 4-(5-(3-fluoro-4-(5-phenyl-4H- l,2,4-triazol-3-yl)phenyl)pyridin-2-yloxy)-l-methylcyclohexanecarboxylate was used as the starting material. This resulted in 12 mg (27%) of trans-4-(5-(3-fluoro-4-(5-phenyl-4H-l,2,4- triazol-3-yl)phenyl)pyridin-2-yloxy)l -methylcyclohexanecarboxylic acid as a white solid. LC- MS (ES, m/z) C₂₇H₂₅C1N₄0₃: 472; Found: 473 [M+H]⁺.

Example 14

2,2-dimethyl-3-(l-(5-(5-phenyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)piperidin-4-yloxy)propanoic acid

A mixture of butyl 2,2-dimethyl-3-(l-(5-(5-phenyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)piperidin 4-yloxy)propanoate (100 mg, 0.209 mmol) and lithium hydroxide (35.1 mg, 1.466 mmol) in MeOH (1 ml), THF (1ml), water (0.5 ml). The reaction mixture was stirred at room temperature over night, and then concentrated under vacuum. Purified by Gilson, acetonitril (0.1%TFA)/water (0.1%TFA) 20-45%. This resulted 2,2-dimethyl-3-(l-(5-(5-phenyl-4H-l,2,4- triazol-3-yl)pyridin-2-yl)piperidin-4-yloxy) propanoic acid as a white solid. LC-MS (ES, m/z) C₂₃H₂₇N₅0₃ : 421 ; Found: 422 [M+H]⁺.

Example 15

methyl 2-(trans-4-(4-(5-(4-phenyl- 1 H-imidazol-2-yl pyridin-2-yl phenyl cyclohexyl acetate

A mixture of methyl 2-(trans-4-(4-(5-formylpyridin-2-yl)phenyl)cyclohexyl)acetate (100 mg, 0.296 mmol), 2-hydroxy-l-phenylethanone (52.5 mg, 0.385 mmol), ammonium acetate (1.14 g, 14.82 mol) and copper(II) acetate (140 mg, 0.771 mmol) in acetic acid (2 ml) was heated to 120°C under N₂ for 25 minutes. Then reaction mixture cooled to room temperature, water (2 ml), ethyl acetate (2 ml), ammonium hydroxide (1 ml) added, stirred over night. Then concentrated under vacuum, the reaction mixture was filtered and purified by RHPLC. This resulted in 17.4 mg (10.4%) of methyl 2-(trans-4-(4-(5-(4-phenyl-lH-imidazol-2-yl)pyridin-2- yl)phenyl)cyclohexyl)acetate as a white solid. LC-MS (ES, m/z) C₂₉H₂₉N₃0₂: 451; Found: 452 [M+H]⁺.

Example 16

2-(trans-4-(4-(5-(4-phenyl- 1 H-imidazol-2-yl)pyridin-2-yl phenyl cyclohexyl acetic acid Performed following the procedure described above for 2,2-dimethyl-3-(l-(5-(5-phenyl-

4H-l,2,4-triazol-3-yl)pyridin-2-yl)piperidin-4-yloxy)propanoic acid, except that methyl 2-(trans- 4-(4-(5-(4-phenyl-lH-imidazol-2-yl)pyridin-2-yl)phenyl)cyclohexyl) acetate was used as the starting material. This resulted in 2-(trans-4-(4-(5-(4-phenyl-lH-imidazol-2-yl)pyridin-2- yl)phenyl)cyclohexyl)acetic acid as a white solid. LC-MS (ES, m/z) C28H2₇N₃02: 437; Found: 438 [M+H]⁺. Example 17

2-(trans-4-(^'5-(3-fluoro-4-(^'5-phenyl-lH-imidazol-2-yl phenyl pyridin-2-yloxy cvclohexy acetic , acid

Performed following the procedure described above for 2,2-dimethyl-3-(l-(5-(5-phenyl- 4H-l,2,4-triazol-3-yl)pyridin-2-yl)piperidin-4-yloxy)propanoic acid, except that methyl 2-(trans- 4-(5-(3-fluoro-4-(5-phenyl-lH-imidazol-2-yl)phenyl)pyridin-2-yloxy)cyclohexyl)acetate was used as the starting material. This resulted in 2-(trans-4-(5-(3-fluoro-4-(5-phenyl-lH-imidazol-2- yl)phenyl)pyridin-2-yloxy)cyclohexyl)acetic acid as a white solid. LC-MS (ES, m/z) C₂₈H2₆FN₃0₃: 471; Found: 472 [M+H]⁺.

Example 18

2-(^"(lr,4r)-4-(4-(^"5-(5-phenyl-4H-l,2,4-triazol-3-yl pyridin-2-yl phenvncvclohexyl acetic acid To a mixture of methyl 2-((lr,4r)-4-(4-(5-cyanopyridin-2-yl)phenyl)cyclohexyl)acetate (30 mg, 0.090 mmol, leq) and benzohydrazide (24.5 mg, 0.180 mmol, 2eq) in anhydrous n- BuOH(2 mL) was added K₂C0₃ (54.3 mg, 0.45 mmol, 5 eq). The reaction was shaked at 150°C for 40 hr. LC-MS showed that the product was formed. The supernatant was transferred into a new vial and the solid was rinsed with DMF. The DMF solution was filtered and combined with previous supernatant. The resulting solution was concentrated and the residue was dissolved in MeOH/THF (1 :1, 2 mL). 2.5 N LiOH/H₂0 (0.5 mL) was added and the reaction was shaked at ambient temperature for 16 hr. LC-MS showed that the hydrolysis was completed. The solvent was concentrated in vacuum and DMSO (1.5mL) was added. The resulting solution was added HOAc to adjust the pH = 5 and filtered. The crude product was purified by using preparative reversed-phase HPLC (acetonitrile with 0.1% formic acid : water with 0.1% formic acid from 10% to 90%) to give the product as a white solid. LC-MS Found: 439 [M+H]⁺.

Examples 19 to 33

Prepared following the procedure described above for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, starting with appropriate hydrazides.

Examples 34 to 52

Prepared following the procedure described above for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, but starting with methyl 2-(3-(5- cyanopyridin-2-yl)-3-azaspiro[5.5]undecan-9-yl)acetate and appropriate hydrazides.

Examples 53 to 80

Prepared following the procedure described above for 2-((lr,4r)-4-(4-(5-(5- phenyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, but starting with i 3-((l -(5-cyanopyridin-2-yl)piperidin-4-yl)oxy)-2,2-dimethylpropanoate and appropriate hydrazides.

Examples 81 to 90 Prepared according the procedure described for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H-l,2,4- triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, starting from 2-(cis-4-(l-(5- cyanopyridin-2-yl)piperidin-4-yloxy)cyclohexyl)acetic acid and appropriate hydrazides, but omitting the hydrolysis step.

Examples 91 to 105 Prepared according the procedure described for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H-l,2,4- triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, starting from 2-(trans-4-(l-(5- cyanopyridin-2-yl)piperidin-4-yloxy)cyclohexyl)acetic acid and appropriate hydrazides, but omitting the hydrolysis step.

Examples 106 to 112 Prepared following the procedure described above for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, but starting with methyl 2-((ls,4s)- 4-(l-(5-cyanopyridin-2-yl)piperidin-4-yl)cyclohexyl)acetate and appropriate hydrazides.

Examples 113 to 121 Prepared following the procedure described above for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, but starting with 2-(4-(l-(5- cyanopyridin-2-yl)piperidin-4-yl)phenyl)acetic acid and appropriate hydrazides. The saponification step was omitted since the starting material was an acid.

Examples 122 to 131

Prepared following the procedure described above for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, starting with methyl 2-((lr,4r)-4- ((5-cyano-[2,3'-bipyridin]-6'-yl)oxy)cyclohexyl)acetate and the appropriate hydrazides.

Examples 132 to 141

Prepared following the procedure described above for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, starting with methyl 2-((ls,4s)-4- (5-(5-cyanopyridin-2-yl)pyrimidin-2-yloxy)cyclohexyl)acetate and the appropriate hydrazides.

Examples 142 to 147

Prepared following the procedure described above for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, starting with methyl 2-((ls,4s)-4- (5-(5-cyanopyridin-2-yl)pyrimidin-2-yloxy)cyclohexyl)acetate and the appropriate hydrazides.

Examples 148 to 155

Prepared following the procedure described above for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, starting with methyl 2-((lr,4r)-4-(5- (5-cyanopyridin-2-yl)pyrimidin-2-yloxy)cyclohexyl)acetate and the appropriate hydrazides.

Examples 156 to 160

Prepared following the procedure described above for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, starting with methyl (cis-4-{[5-(4- cyano-3-fluorophenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetate or methyl 2-((lr,4r)-4-((5-(4- cyano-3-fluorophenyl)pyrimidin-2-yl)oxy)cyclohexyl)acetate and the appropriate hydrazides.

Example Structure [ΜΗΓ m/z found

Examples 161 to 174

Prepared following the procedure described above for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, starting with 6'-(((3S,3aR,6R,6aR)- 6-hydroxyhexahydrofuro [3 ,2-b]furan-3 -yl)oxy)- [2,3'-bipyridine] -5 -carbonitrile and the appropriate hydrazides, omitting the hydrolysis step.

Examples 175 to 182

Prepared following the procedure described above for 2-((lr,4r)-4-(4-(5-(5-phenyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)phenyl)cyclohexyl)acetic acid, starting with Ethyl l-(5-(4-cyano-3- fluorophenyl)pyridin-2-yl)-4-fluoropiperidine-4-carboxylate and the appropriate hydrazides.

DGAT1 CPM Assay

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

ASSAY RESULTS

Example hDGATl Example hDGATl Example hDGATl

1 5.833 62 55.4 123 15.57

2 436.4 63 70.5 124 14.45

3 2122 64 615.8 125 31.36

4 6326 65 5708 126 238.2

5 4375 66 1824 127 455.8

6 860.9 67 352.6 128 20.97

7 35.76 68 1339 129 10.59

8 13.66 69 6250 130 51.66

9 276.4 70 574.9 131 8.383

10 1888 71 405.6 132 6.305

11 299.6 72 4856 133 105.2

12 21.4 73 3646 134 12.36

13 5.862 74 27.67 135 138.9

14 157.2 75 8970 136 11.11

15 254.6 76 3720 137 11.34

16 4.838 77 2714 138 5.659

17 9.147 78 280.7 139 2.068

18 2.088 79 16.77 140 4.691

19 36.04 80 14.26 141 3.742

20 13.3 81 14.19 142 17.32

21 1.902 82 1225 143 18.55

22 525.5 83 14.12 144 25.4

23 5.134 84 23.12 145 105 Example hDGATl Example hDGATl Example hDGATl

24 290.1 85 905.1 146 13.14

25 19.72 86 33.04 147 53.67

26 4.414 87 1402 148 92.51

27 13.83 88 58.1 149 17.67

28 1.644 89 54.36 150 5.531

29 3.598 90 1302 151 9.788

30 95.63 91 3556 152 100.4

31 14.29 92 2079 153 139

32 896.2 93 80.41 154 7.081

33 28.03 94 288.1 155 12.91

34 6089 95 59.75 156 18.23

35 6731 96 3262 157 261.8

36 7596 97 23.75 158 99.2

37 678.9 98 373.7 159 99.53

38 262.9 99 153.8 160 96.83

39 127.8 100 28.69 161 518

40 167.4 101 4691 162 2261

41 832.2 102 2426 163 300

42 1090 103 55.42 164 480.8

43 4057 104 20.77 165 1387

44 1378 105 212.6 166 352.9

45 4133 106 12.02 167 1143

46 4393 107 102 168 303.1

47 177.1 108 16.57 169 224.8

48 406.7 109 27.87 170 426.9

49 120.5 110 12.5 171 855.8

50 91.76 111 12.92 172 6104

51 6501 112 21.24 173 955.5

52 3916 113 21.1 174 395.2

53 4694 114 12.12 175 508.3

54 6729 115 42.47 176 4312

55 4371 116 353.7 177 1458

56 636 117 4.881 178 498.8

57 2508 118 8.354 179 334.2

58 116.4 119 14.29 180 956 Example hDGATl Example hDGATl Example hDGATl

59 113.7 120 30.86 181 567.9

60 776 121 172.4 182 9789

61 807.9 122 19.45

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I):

or pharmaceutical salt thereof, wherein V is selected from the group consisting of

-N- and -CH-;

X is selected from the group consisting of -N- and -CH-;

Y is selected from the group consisting of -N- and -CH- and -CR²s

Z is seleced from the group consisting of -N- and -CH- and -CR²-, wherein at least one of X, Y and Z must be -N-;

U is selected from the group consisting of phenyl, pyridine, pyrimidine, piperidine, azaspiroundecanyl and cyclohexane, wherein U is unsubstituted or substituted with - OH;

T is -O- or a bond;

R¹ is selected from the group consisting hexahydrofurofuranj Ci-C₆alkylCOOH, CpCealkylCOOCi-Cealkyl, d-Cealkoxy, pyridine, C Qalkylpyridine, cyclohexane, Ci- C₆alkylcyclohexane, phenyl and Ci-C₆alkylphenyl, wherein the hexahydrofurofuran, pyridine, phenyl or cyclohexane can be unsubstituted or substituted with one or more substituents selected from the group consisting of COOH, CrQalkylCOOH, d-QalkylCOOCi-Cealkyl, -OH, Q- C₆alkyl and halogen;

R² is selected from the group consisting heterocycle, C_!-C₆alkyl, phenyl, Ci- C₆alkylphenyl, halogen-substitutedC_!-C₆alkyl and C₃-C₆cycloalkyl, wherein the heterocycle, phenyl, or cycloalkyl can be unsubstituted or substituted with one or more substituents selected from the group consisting of Ci-Cealkyl, halogen-substitutedC Cealkyl and halogen.

R³ is optionally present at one of more at the ring carbons and is selected from the group consisting of halogen, -CN, CrQalkyl and C₁-C₆alkoxy.

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

-N-.

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

-CH-.

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

-CH-.

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

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

-N-.

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

- CR²-.

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

-N-.

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

- CR²-.

10. A compound of any one of claims 1-9 or pharmaceutically acceptable salt thereof wherein U is phenyl or pyridine.

11. A compound of any one of claims 1 - 10 or pharmaceutically acceptable salt thereof wherein T is -0-.

12. A compound of any one of claims 1-11 or pharmaceutically acceptable salt thereof wherein R¹ is cyclohexane substituted with C QalkylCOOH.

13. A compound of any one of claims 1-12 or pharmaceutically acceptable salt thereof wwhheerreeiiin R is phenyl.

14. A compound of any one of claims 1-12 or pharmaceutically acceptable salt thereof wherein R is CrQalkyl.

15. A compound of any one of claims 1-12 or pharmaceutically acceptable salt thereof wherein R² is heterocycle, wherein the heterocyle is selected from the group consisting of pyridine, pyrimidine, sulfolane, pyrrole, furan, thiene, imidazole, pyrazole, thiazole, oxazole, thiadiazole, pyrazine, and benzofuran.

16. A compound of any one of claims 1 - 15 or pharmaceutically acceptable salt thereof wherein R³ is hydrogen.

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

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

19. Use of a compound of any one of claims 1 - 17, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating a condition selected from the group consisting of obesity and diabetes.

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

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