CN101589039B - Azacycloalkane derivatives as inhibitors of stearoyl-coenzyme A delta-9 desaturase - Google Patents

Abstract

Compared to other known stearoyl-CoA desaturases, the azacyclane derivatives of structural formula I are selective stearoyl-CoA Δ-9 desaturase (SCD1) inhibitors. The compounds of the present invention are useful in the prevention and treatment of conditions associated with abnormal lipid synthesis and metabolism, including cardiovascular disease such as atherosclerosis; obesity; diabetes; neuropathy; metabolic syndrome; insulin resistance and hepatic steatosis.

Description

Azacyclane Derivatives as Stearoyl-CoA Δ-9 Desaturase Inhibitors

field of invention

The present invention relates to stearoyl coenzyme AΔ-9 desaturase (SCD) inhibitor azacycloalkane (azacycloalkane) derivatives and the use of such compounds in controlling, preventing and/or treating symptoms or diseases mediated by SCD activity use. The compounds of the present invention are useful in the control, prevention and treatment of conditions and diseases associated with abnormal lipid synthesis and metabolism, including cardiovascular diseases such as atherosclerosis; obesity; diabetes; neuropathy; metabolic syndrome; insulin resistance; cancer and Hepatic steatosis.

Background of the invention

There are at least three classes of acyl-CoA (CoA) desaturases (Δ-5, Δ-6, and Δ-9 desaturases) associated with mono- and polyunsaturated acyl-CoA desaturases derived from food sources or de novo synthesis in mammals. related to the formation of double bonds. Δ-9-specific acyl-CoA desaturases (SCDs) catalyze the rate-limiting formation of the C9-C10 cis double bond of monounsaturated acyl-CoA. Preferred substrates are fatty acyl-CoA and palmitoyl-CoA, the resulting oleoyl and palmitoleyl-CoA are major components in the biosynthesis of phospholipids, triglycerides, cholesterol esters and wax esters (Dobrzyn and Natami, Obesity Reviews, 6: 169-174 (2005)).

Rat liver microsomal SCD protein was first isolated and characterized in 1974 (Strittmatter et al., PNAS, 71:4565-4569 (1974)). A number of mammalian SCD genes from multiple species have since been cloned and studied. For example, two genes were identified from rats (SCD1 and SCD2, Thiede et al., J. Biol. Chem., 261, 13230-13235 (1986)), Mihara, K., J. Biochem. (Tokyo), 108 : 1022-1029 (1990)); Four genes (SCD1, SCD2, SCD3 and SCD4) were identified from mice (Miyazaki et al., J. Biol. Chem., 278: 33904-33911 (2003)); Two genes (SCD1 and ACOD4 (SCD2)) (Zhang et al., Biochem.J., 340: 255-264 (1991); Beiraghi et al., Gene, 309: 11-21 (2003); Zhang et al., Biochem.J ., 388: 135-142 (2005)). SCD has been known to be involved in fatty acid metabolism in rats and mice since the 1970's (Oshino, N., Arch. Biochem. Biophvs. 149:378-387 (1972)). This notion is further supported by biological studies in a) Asebia mice carrying natural mutations in the SCD1 gene (Zheng et al., Nature Genetics. 23:268-270 (1999)), b) mice derived from the deletion of the target gene Suppression of SCD1 Expression in Leptin-Induced Weight Loss in SCD1 Null Mice (Ntambi et al., PNAS, 99:11482-11486 (2002), and c) (Cohen et al., Science, 297:240-243 (2002) ). The potential benefit of pharmacologically inhibiting SCD activity has been exemplified by antisense oligonucleotide inhibitors (ASO) in mice (Jiang et al., J. Clin. Invest., 115:1030-1038 (2005)). Inhibition of SCD activity by ASO decreased fatty acid synthesis and enhanced fatty acid oxidation in primary mouse hepatocytes. Treatment of mice with SCD-ASOs prevented diet-induced obesity, decreased body adiposity, hepatomegaly, steatosis, postprandial plasma insulin and glucose levels; decreased de novo fatty acid synthesis; decreased expression of lipogenic genes and increased promotion of liver and Gene expression of energy expenditure in adipose tissue. Therefore, SCD inhibition represents a novel therapeutic strategy for the treatment of obesity and related metabolic disorders.

Compelling evidence exists to support the direct involvement of several common disease processes in elevated SCD activity in humans. For example, elevated hepatic lipogenesis to triglyceride secretion in patients with nonalcoholic fatty liver disease (Diraison et al., Diabetes Metabolism. 29:478-485 (2003)); Donnelly et al., J. Clin. Invest., 115: 1343-1351 (2005)). Postprandial de novo lipogenesis is significantly elevated in obese subjects (Marques-Lopes et al., American Journal of Clinical Nutrition, 73:252-261 (2001)). There is a significant association between high SCD activity and an increased cardiovascular risk profile, including elevated plasma triglycerides, high body mass index, and decreased plasma HDL (Attie et al., J. Lipid Res., 43:1899-1907 (2002) ). SCD activity plays a key role in controlling the proliferation and survival of human mutant cells (Scaglia and Igal, J. Biol. Chem.. (2005)).

In addition to the antisense oligonucleotides mentioned above, inhibitors of SCD activity include nonselective thiofatty acid substrate analogs [B. Behrouzian and P.H. Buist, Prostaglandins. Leukotrienes. and Essential Fatty Acids. 68:107 -112 (2003)], cyclopropene-type fatty acids (Raju and Reiser, J.Biol.Chem., 242:379-384 (1967)), some conjugated long-chain fatty acid isomers (Park et al., Biochim.Biophys. Acta. 1486:285-292 (2000)), a series of pyridazine derivatives disclosed in published international patent application publications WO 2005/011653, WO 2005/011654, WO 2005/011656, WO 2005/011656 and WO2005/011657 all assigned to Xenon Pharmaceuticals, Inc., and International Patent Application Publications WO 2006/014168, WO 2006/034279, WO 2006/034312, WO 2006/034315, WO 2006/034338, WO 2006/034341, WO 2006/034440, A series of heterocyclic derivatives disclosed in WO 2006/034441 and WO 2006/034446, both assigned to Xenon Pharmaceuticals, Inc.

The present invention relates to novel azacycloalkane derivatives as inhibitors of acyl-CoA Δ-9 desaturase, which are useful in the treatment and/or prevention of various conditions and diseases mediated by SCD activity, including but not Limit to symptoms and diseases with elevated lipid levels, such as nonalcoholic fatty liver disease, cardiovascular disease, obesity, metabolic syndrome, and insulin resistance.

The role of acyl-CoA desaturases in lipid metabolism is described in M. Miyazak and J.M. Ntambi, Prostaglandins, Leukotrienes, and Essential Fatty Acids, 68: 113-121 (2003). The therapeutic potential of pharmacologically manipulating SCD activity is described in A. Dobryzn and J.M. Ntambi, "Staroyl-CoA desaturase as a new drug target for obesity treatment" Obesity Reviews, 6: 169-174 (2005).

Summary of the invention

The present invention relates to azacycloalkane derivatives of structural formula I:

These azacyclane derivatives are potent SCD inhibitors. They are therefore useful in the treatment, management or prevention of disorders responsive to SCD inhibition, such as diabetes, insulin resistance, dyslipidemia, obesity, atherosclerosis and metabolic syndrome.

The present invention also relates to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.

The present invention also relates to methods of treating, controlling or preventing disorders, diseases or conditions responsive to SCD inhibition in a subject in need thereof by administering a compound or pharmaceutical composition of the present invention.

The present invention also relates to methods of treating, controlling or preventing type II diabetes, insulin resistance, obesity, dyslipidemia, atherosclerosis and metabolic syndrome by administering the compounds or pharmaceutical compositions of the present invention.

The invention also relates to methods of treating, controlling or preventing obesity by administering a compound of the invention together with a therapeutically effective amount of another agent known to be useful in the treatment of that condition.

The present invention also relates to methods of treating, controlling or preventing type 2 diabetes by administering a compound of the present invention together with a therapeutically effective amount of another agent known to be useful in the treatment of this condition.

The invention also relates to methods of treating, controlling or preventing atherosclerosis by administering a compound of the invention together with a therapeutically effective amount of another agent known to be useful in the treatment of this condition.

The invention also relates to methods of treating, controlling or preventing dyslipidemia by administering a compound of the invention together with a therapeutically effective amount of another agent known to be useful in the treatment of that condition.

The invention also relates to methods of treating metabolic syndrome by administering a compound of the invention together with a therapeutically effective amount of another agent known to be useful in the treatment of that condition.

Detailed description of the invention

The present invention relates to azacyclane derivatives useful as SCD inhibitors. The compounds of the present invention are described in structural formula I:

or a pharmaceutically acceptable salt thereof,

where q is 0 or 1;

r is 0 or 1;

Z is O, S or ^NR4 ;

XY is NC(O), N-CR ^a R ^b , CR ¹⁴ -O, CR ¹⁴ -S(O) _0-2 or CR ¹³ -CR ^a R ^b ;

R ^{and R} are each independently hydrogen or C _1-3 alkyl, wherein the alkyl is optionally substituted by one to three substituents independently selected from fluorine and hydroxyl;

W is a heteroaryl group selected from:

^R is a heteroaryl group selected from:

Where R ^C is -(CH ₂ ) _m CO ₂ H, -(CH ₂ ) _m CO ₂ C _1-3 alkyl, -(CH ₂ ) _m -Z-(CH ₂ ) _P CO ₂ H or -(CH ₂ ) _m -Z-(CH ₂ ) _P CO ₂ C _1-3 alkyl; wherein any methylene (CH _{2 ) carbon atom in (CH 2} ) _m or ( _{CH 2} ) _P is optionally replaced by a hydroxyl group, One amino or one to two fluorine substitutions; and wherein the ^R heteroaryl ring is optionally independently selected from cyano, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkane A substituent of thio, C _1-4 alkylsulfonyl and trifluoromethyl is substituted;

Each R ^is independently selected from:

hydrogen,

halogen,

hydroxyl,

cyano,

Amino,

nitro,

C _1-4 alkyl, optionally substituted by one to five fluorines,

C _1-4 alkoxy, optionally substituted by one to five fluorines,

C _1-4 alkylthio, optionally substituted by one to five fluorines,

C _1-4 alkylsulfonyl,

carboxyl,

C _1-4 alkoxycarbonyl, and

C _1-4 alkylcarbonyl;

Ar is phenyl, naphthyl or heteroaryl, optionally substituted by one to five ^R substituents;

Each R ^is independently selected from:

C _1-6 alkyl,

C _2-6 alkenyl,

(CH ₂ ) _n -phenyl,

(CH ₂ ) _n -naphthyl,

(CH ₂ ) _n -heteroaryl,

(CH ₂ ) _n -heterocyclyl,

(CH ₂ ) _n C _3-7 cycloalkyl,

halogen,

nitro,

(CH ₂ ) _n OR ⁴ ,

(CH ₂ ) _n N(R ⁴ ) ₂ ,

(CH ₂ ) _n C≡N,

(CH ₂ ) _n CO ₂ R ⁴ ,

(CH ₂ ) _n NR ⁴ SO ₂ R ⁴ ,

(CH ₂ ) _n SO ₂ N(R ⁴ ) ₂ ,

(CH ₂ ) _n S(O) _0-2 R ⁴ ,

(CH ₂ ) _n NR ⁴ C(O)N(R ⁴ ) ₂ ,

(CH ₂ ) _n C(O)N(R ⁴ ) ₂ ,

(CH ₂ ) _n NR ⁴ C(O)R ⁴ ,

(CH ₂ ) _n NR ⁴ CO ₂ R ⁴ ,

(CH ₂ ) _n C(O)R ⁴ ,

O(CH ₂ ) _n C(O)N(R ⁴ ) ₂ ,

(CH ₂ ) _s -Z-(CH ₂ ) _t -phenyl,

(CH ₂ ) _s -Z-(CH ₂ ) _t -naphthyl,

(CH ₂ ) _s -Z-(CH ₂ ) _t -heteroaryl,

(CH ₂ ) _s -Z-(CH ₂ ) _t -heterocyclyl,

(CH ₂ ) _s -Z-(CH ₂ ) _t -C _3-7 cycloalkyl,

(CH ₂ ) _s -Z-(CH ₂ ) _t -OR ⁴ ,

(CH ₂ ) _s -Z-(CH ₂ ) _t -N(R ⁴ ) ₂ ,

(CH ₂ ) _s -Z-(CH ₂ ) _t -NR ⁴ SO ₂ R ⁴ ,

(CH ₂ ) _s -Z-(CH ₂ ) _t -C≡N,

(CH ₂ ) _s -Z-(CH ₂ ) _t -CO ₂ R ⁴ ,

(CH ₂ ) _s -Z-(CH ₂ ) _t -SO ₂ N(R ⁴ ) ₂ ,

(CH ₂ ) _s -Z-(CH ₂ ) _t -S(O) _0-2 R ⁴ ,

(CH ₂ ) _s -Z-(CH ₂ ) _t -NR ⁴ C(O)N(R ⁴ ) ₂ ,

(CH ₂ ) _s -Z-(CH ₂ ) _t -C(O)N(R ⁴ ) ₂ ,

(CH ₂ ) _s -Z-(CH ₂ ) _t -NR ⁴ C(O)R ⁴ ,

(CH ₂ ) _s -Z-(CH ₂ ) _t -NR ⁴ CO ₂ R ⁴ ,

(CH ₂ ) _s -Z-(CH ₂ ) _t -C(O)R ⁴ ,

CF ₃ ,

_{CH2CF3 ,}

OCF ₃ , and

OCH ₂ CF ₃ ;

Wherein phenyl, naphthyl, heteroaryl, cycloalkyl and heterocyclyl are optionally selected from one to three independently selected from halogen, hydroxyl, C _1-4 alkyl, trifluoromethyl and C _1-4 alkoxy is optionally substituted by one to five fluorines; and wherein any methylene (CH ₂ ) carbon atom in R ³ is optionally substituted by one to two independently selected from fluorine, hydroxyl and C _1-4 alkyl group substitution; or when two substituents are located in the same methylene (CH ₂ ) group, form a cyclopropyl group together with the carbon atom to which they are attached;

Each R ^is independently selected from:

hydrogen,

C _1-6 alkyl,

(CH ₂ ) _n -phenyl,

(CH ₂ ) _n -heteroaryl,

(CH ₂ ) _n -naphthyl, and

(CH ₂ ) _n C _3-7 cycloalkyl;

Wherein alkyl, phenyl, heteroaryl and cycloalkyl are optionally substituted by one to three groups independently selected from halogen, C _1-4 alkyl and C _1-4 alkoxy; or two ^R groups The groups together with the atoms to which they are attached form a 4 to 8 membered mono- or bicyclic ring system, optionally containing other heteroatoms selected from O, S, NH and N C _1-4 alkyl.

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from hydrogen, fluorine or C _1-3 alkyl; wherein the alkyl is optionally selected from one to three independently selected from Fluorine and hydroxyl substituent substitution;

R ¹³ is hydrogen, C _1-3 alkyl, fluorine or hydroxyl;

each R ¹⁴ is hydrogen or C _1-3 alkyl;

Each m is independently an integer from 0 to 4;

each p is independently an integer from 1 to 3;

Each n is independently an integer from 0 to 2;

each s is independently an integer from 1 to 3; and

Each t is an integer of 1 to 3 independently.

In one embodiment of the compounds of the invention, m is 1 or 2. In this type of embodiment, m is 1.

In a second embodiment of the compounds of this invention, both q and r are 1, providing a 6-membered piperidine ring.

In a third embodiment of the compounds of this invention, q is 1 and r is 0, providing a 5 membered piperidine ring.

In a fourth embodiment of the compounds of this invention, q and r are both 0, providing a 4 membered azetidine ring.

In a fifth embodiment of the compounds of this invention, XY is NC(O). In a class of such embodiments, ^R3 is phenyl substituted with one to three ^R3 substituents as defined above.

In a sixth embodiment of the compounds of this invention, XY is CH-O. In a class of such embodiments, ^R3 is phenyl substituted with one to three ^R3 substituents as defined above.

In a seventh embodiment of the compounds of this invention, XY is CH-S(O) _p . In a class of such ^embodiments Ar is phenyl substituted with one to three R substituents as defined above.

In an eighth embodiment of the compounds of this invention, XY is N-CR ^a R ^b . In a class of such ^embodiments Ar is phenyl substituted with one to three R substituents as defined above. In another class of this embodiment, Ra ^{and R} are hydrogen and Ar is phenyl substituted with one to ^three R substituents.

In a ninth embodiment of the compounds of this invention, XY is CR ^13- CR ^a R ^b . In a class of such ^embodiments Ar is phenyl substituted with one to three R substituents as defined above. In another class of this embodiment, Ra ^{, Rb} and ^R13 are hydrogen and Ar is phenyl substituted with one to three ^R3 substituents.

In yet another embodiment of the compounds of this invention, ^R5 , ^R6 , ^R7 , ^R8 , ^R9 , ^R10 , ^R11 and ^R12 are each hydrogen.

In yet another embodiment, W is heteroaryl selected from:

wherein R ^{and R} are as defined above, in a class of this embodiment ^R is hydrogen. In another class of such embodiments, W is:

wherein R ¹ and R ² are as defined above.

In another embodiment, R ^is heteroaryl selected from:

Wherein R ^c is -CH ₂ CO ₂ H or -CH ₂ CO ₂ C _1-3 alkyl. In a class of such embodiments, R ^is :

In another embodiment of the compounds of this invention, q and r are both 1; X-Y is CH-O; W is a heteroaryl selected from the group consisting of:

and ^R is a heteroaryl selected from the group consisting of:

Wherein R ^c is -CH ₂ CO ₂ H or -CH ₂ CO ₂ C _1-3 alkyl.

In a class of this embodiment, each of ^R2 , ^R5 , ^R6 , ^R7 , ^R8 , ^R9 , ^R10 , ^R11 and ^R12 is hydrogen.

In a class of such embodiments, W is:

and ^R1 is

Wherein R ^c is -CH ₂ CO ₂ H or -CH ₂ CO ₂ C _1-3 alkyl.

In a subclass of this class ^R2 , ^R5 , ^R6 , ^R7 , ^R8 , ^R9 , ^R10 , ^R11 and ^R12 are each hydrogen.

Illustrative, non-limiting examples of compounds of the invention useful as SCD inhibitors are:

and pharmaceutically acceptable salts thereof.

As used herein the following definitions apply.

"Alkyl", and other groups containing the prefix "alkyl" such as alkoxy and alkanoyl refer to linear or branched carbon chains and combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, and the like. The term alkyl also includes cycloalkyl groups and combinations of linear or branched alkyl chains combined with cycloalkyl structures when the number of carbon atoms specified allows, eg, _C3-10 . When the number of carbon atoms is not specified, it means C _1-6 .

"Cycloalkyl" is a subtype of alkyl and refers to a saturated carbocyclic ring having the indicated number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Cycloalkyl groups are generally monocyclic unless otherwise specified. Unless otherwise defined a cycloalkyl group is saturated.

The term "alkenyl" means a straight or branched chain alkene having the indicated number of carbon atoms. Examples of alkenyl groups include ethenyl, 1-propenyl, 2-butenyl, and the like.

The term "alkoxy" refers to the specified number of carbon atoms (e.g., _C1-6 alkoxy) or any number within this range [i.e. methoxy (MeO-), ethoxy, isopropoxy, etc.] Straight or branched chain alkoxylates.

The term "alkylthio" refers to the specified number of carbon atoms (e.g., _C1-6 alkylthio) or any number within this range [i.e., methylthio (MeS-), ethylthio, isopropylthio, etc. ] straight-chain or branched-chain alkyl sulfide.

The term "alkylamino" refers to the specified number of carbon atoms (e.g., _C1-6 alkylamino) or any number within this range [i.e., methylamino, ethylamino, isopropylamino, tert-butylamino, etc. ] straight-chain or branched-chain alkylamine.

The term "alkylsulfonyl" refers to the specified number of carbon atoms (e.g., C _1-6 alkylsulfonyl) or any number within this range [i.e., methylsulfonyl (MeSO ₂ -), ethylsulfonyl, iso Propylsulfonyl, etc.] linear or branched alkyl sulfones.

The term "alkylsulfinyl" refers to the specified number of carbon atoms (e.g., _C1-6 alkylsulfinyl) or any number within this range [i.e., methylsulfinyl (MeSO-), ethylsulfinyl acyl, isopropylsulfinyl, etc.] straight-chain or branched-chain alkyl sulfoxide.

The term "alkoxycarbonyl" means the number of carbon atoms specified (e.g., _C1-6 alkoxycarbonyl) or any number within this range [i.e., methoxycarbonyl (MeOCO-), ethoxycarbonyl, butoxy The linear or branched chain esters of the carboxylic acids of the present invention such as carbonyl, carbonyl, etc.].

"Aryl" refers to a mono- or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl is phenyl.

"Heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S and N, further including the oxidized forms of sulfur, namely SO and _SO2 . Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine , imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiol, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiol Hexane, thiomorpholine, 2-oxy-piperidin-1-yl, 2-oxypyrrolidin-1-yl, 2-oxazaalkan-1-yl and the like.

"Heteroaryl" refers to an aromatic or partially aromatic heterocyclic ring containing at least one heteroatom selected from O, S, and N. Heteroaryl thus includes heteroaryls fused to other types of rings such as aryl, cycloalkyl, and non-aromatic heterocycles. Examples of heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl (especially 1,3,4-oxadiazol-2- and 1,2,4-oxadiazol-3-yl), thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidinyl, benzene Isoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuryl, indolinyl, pyridazinyl, indazolyl, isoindolyl, di Hydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, Fufuryl, isophenylfuryl, benzimidazolyl, benzofuryl, benzothienyl, quinolinyl, indolyl, isoquinolyl, dibenzofuryl and the like. For heterocyclyl and heteroaryl groups, including rings or ring systems containing 3-15 atoms, 1-3 rings are formed.

"Halogen" refers to fluorine, chlorine, bromine and iodine. Chlorine and fluorine are generally preferred. Fluorine _is most preferred when halogen replaces an alkyl or alkoxy group (eg, _CF3O and _CF3CH2O ).

Compounds of formula I may contain one or more asymmetric centers and may thus be racemic and racemic compounds, individual enantiomers, diastereomeric mixtures or individual diastereomers. The present invention includes all isomeric forms of the compounds of formula I.

The compounds of formula I can be separated into their individual diastereoisomers, for example, by fractional crystallization from a suitable solvent such as methanol or ethyl acetate or mixtures thereof, or by chiral chromatography using an optically active stationary phase. Absolute stereochemistry can be determined from crystalline products or derived crystalline intermediates by X-ray crystallography, where necessary, using reagents containing asymmetric centers of known absolute configuration.

Alternatively, any stereoisomer of a compound of general formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute conformation.

If desired, racemic mixtures of the compounds may be separated such that the individual enantiomers are isolated. Separation can be achieved by methods known in the art, such as coupling a racemic mixture of a compound 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 . Coupling reactions typically employ enantiomerically pure acids or bases to form salts. The diastereomeric derivatives are then converted to the pure enantiomers by cleavage of the added chiral residue. Racemic mixtures of compounds can also be separated directly by chromatography (well known in the art) using chiral stationary phases.

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

Some of the compounds described herein may exist as tautomers, which have different hydrogen binding sites accompanied by shift of one or more double bonds. For example, a ketone and its enol form are ketoenol tautomers. Individual tautomers and mixtures thereof are included in the compounds of the present invention.

It is to be understood that as used herein, references to compounds of formula I are meant to also include pharmaceutically acceptable salts and pharmaceutically unacceptable compounds when used as precursors of the free compounds or their pharmaceutically acceptable salts or in other synthetic procedures. of salt.

The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. 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 by the term "pharmaceutically acceptable salt" refer to non-toxic salts of compounds of the present invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the invention include, but are not limited to, the following: acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartrates, borates, bromides, camphors salt, carbonate, chloride, clavulanate, citrate, edetate, edisulphonate, propionate lauryl sulfate, ethanesulfonate, fumarate, glucoheptin Sugar, gluconate, glutamate, hexylresorcinate, hydrobromide, hydrochloride, xinanate, iodide, isotreonate, lactate, lactose Aldylate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methyl Bromide, Methyl Nitrate, Methyl Sulfate, Mucate, Naphthalene Sulfonate, Nitrate, N -Methylglucamine amine salt, oleate, oxalate, pamoate (pamoate), palmitate, pantothenate, phosphate/hydrogen phosphate, polygalacturonate, Salicylates, stearates, sulfates, hypoacetates, succinates, tannates, tartrates, theochlorates, tosylate, triethiodide, and valerates . Furthermore, when the compound of the present invention possesses 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, trivalent manganese, manganese, potassium, sodium, zinc, etc. Especially preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, cyclic amines and ion exchange resins such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, Diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, iso Propylamine, lysine, meglumine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

Furthermore, when a carboxylic acid (-COOH) or alcohol group is present in the compounds of the present invention, pharmaceutically acceptable esters of carboxylic acid derivatives, such as methyl, ethyl or pivaloyloxymethyl or acyl derivatives of alcohols, may be used. compounds such as acetyl, pivaloyl, benzoyl and aminoacyl. Included are ester and acyl groups known in the art to modify solubility or hydrolytic properties for sustained release or prodrug formulations.

The present invention also includes solvates, especially hydrates, of the compounds of formula I.

The subject compounds are useful in a method of inhibiting stearoyl-CoA delta-9 desaturase in a mammalian patient in need of such inhibition comprising administering an effective amount of the compound. The compounds of the invention are therefore useful for the control, prevention and/or treatment of conditions and diseases mediated by high or abnormal SCD enzyme activity.

One aspect of the present invention therefore relates to a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need thereof, comprising administering to the patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

A second aspect of the invention relates to a method of treating non-insulin-dependent diabetes mellitus (type II diabetes) in a mammalian patient in need of such treatment, comprising administering to the patient an antidiabetic effective amount of a compound of formula I.

A third aspect of the invention relates to a method of treating obesity in a mammalian patient in need of such treatment comprising administering to said patient an amount of a compound of formula I effective to treat obesity.

A fourth aspect of the invention pertains to a method of treating metabolic syndrome and its sequelae in a mammalian patient in need of such treatment, comprising administering to said patient an amount of a compound of formula I effective to treat metabolic syndrome and its sequelae. The sequelae of metabolic syndrome include high blood pressure, elevated blood sugar levels, high triglycerides, and low levels of HDL cholesterol.

A fifth aspect of the invention relates to the treatment of dyslipidemia selected from dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia or low HDL and high HDL in a mammalian patient in need of such treatment A method comprising administering to said patient an amount of a compound of formula I effective to treat said dyslipidemia.

A sixth aspect of the invention relates to a method of treating atherosclerosis in a mammalian patient in need of such treatment comprising administering to said patient an amount of a compound of formula I effective to treat atherosclerosis.

A seventh aspect of the invention pertains to a method of treating cancer in a mammalian patient in need of such treatment comprising administering to said patient an amount of a compound of formula I effective to treat the cancer.

Another aspect of the invention relates to a method of treating a condition selected from (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, ( 5) Dyslipidemia, (6) Dyslipidemia, (7) Hyperlipidemia, (8) Hypertriglyceridemia, (9) Hypercholesterolemia, (10) Low HDL level, (11) High LDL level, (12) Atherosclerosis and its sequelae, (13) Vascular restenosis, (14) Pancreatitis, (15) Abdominal obesity, (16) Neurodegenerative diseases, (17) Retinopathy, (18) Nephropathy, (19) neuropathy, (20) fatty liver disease, (21) polycystic ovary syndrome, (22) sleep-disordered breathing, (23) metabolic syndrome, and (24) symptoms and diseases involving insulin resistance, the The method comprises administering to a patient an amount of a compound of formula I effective to treat the condition.

Yet another aspect of the invention relates to a method of delaying the onset of a condition selected from (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity in a mammalian patient in need of such treatment syndrome, (5) dyslipidemia, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL level, ( 11) High LDL level, (12) Atherosclerosis and its sequelae, (13) Vascular restenosis, (14) Pancreatitis, (15) Abdominal obesity, (16) Neurodegenerative disease, (17) Retinopathy, (18) Nephropathy, (19) Neuropathy, (20) Fatty Liver Disease, (21) Polycystic Ovary Syndrome, (22) Sleep Disordered Breathing, (23) Metabolic Syndrome, and (24) Symptoms including Insulin Resistance and disease, the method comprising administering an amount of a compound of formula I effective to delay the onset of said symptoms.

Yet another aspect of the invention relates to a method of reducing the risk of developing a disease selected from (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) in a mammalian patient in need of such treatment Obesity, (5) Dyslipidemia, (6) Dyslipidemia, (7) Hyperlipidemia, (8) Hypertriglyceridemia, (9) Hypercholesterolemia, (10) Low HDL level, (11) High LDL level, (12) Atherosclerosis and its sequelae, (13) Vascular restenosis, (14) Pancreatitis, (15) Abdominal obesity, (16) Neurodegenerative disease, (17) Retinopathy , (18) kidney disease, (19) neuropathy, (20) fatty liver disease, (21) polycystic ovary syndrome, (22) sleep-disordered breathing, (23) metabolic syndrome, and (24) symptoms including insulin resistance and diseases, the method comprising administering to the patient a compound of formula I in an amount effective to reduce the risk of developing said symptoms.

In addition to primates, such as humans, various other mammals may also be treated according to the methods of the invention. For example, mammals including, but not limited to, cows, sheep, goats, horses, cats, guinea pigs, rats, or other bovine, ovine, equine, canine, feline, rodent (e.g., mouse) species can be treated . However, the method can also be practiced in other species, such as avian (eg chicken).

The present invention further relates to a method for the production of a medicament for inhibiting stearoyl-CoAΔ-9 desaturase activity in humans and animals, which comprises combining the compound of the present invention with a pharmaceutically acceptable carrier or diluent. More specifically, the present invention relates to the use of a compound of structural formula I in the preparation of a medicament for treating a symptom selected from mammalian hyperglycemia, type II diabetes, insulin resistance, obesity and dyslipidemia, wherein the dyslipidemia is selected from From dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL.

The subject to be treated in the methods of the invention is generally a mammal, preferably a human, male or female, in whom inhibition of stearoyl-CoA delta-9 desaturase activity is desired. The term "therapeutically effective amount" refers to that amount of a subject compound that elicits the biological or medical response sought by the researcher, veterinarian, physician or other clinician in a tissue, system, animal or human.

As used herein, the term "composition" is intended to encompass products comprising the specified ingredients in the specified amounts, as well as products resulting directly or indirectly from the combination of the specified ingredients in the specified amounts. The term in relation to pharmaceutical compositions is intended to cover products comprising the active ingredient and inert ingredients making up the carrier as well as combinations, complexes or aggregates of any two or more such ingredients, or combinations of one or more such ingredients. separation, or any product resulting directly or indirectly from other type of reaction or interaction of one or more such components. Accordingly, the pharmaceutical compositions of the present invention encompass any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with other ingredients in the formulation and not harmful to its recipients.

The terms "administering" or "administering" a compound are understood to mean providing a compound of the invention or a prodrug of a compound of the invention to an individual in need of treatment.

The use of the compounds according to the invention as inhibitors of stearoyl-CoA delta-9 desaturase (SCD) activity can be exemplified by the following microsomal and intact cell-based assays.

I. SCD-Induced Rat Liver Microsome Assay:

Radiolabeled-stearoyl-CoA to oleoyl-CoA was obtained by using SCDI-induced rat liver microsomes and a previously published method (Joshi et al., L Lipid Res., 18:32-36 (1977)) with some modifications. Conversion of A measures the activity of compounds of formula I against SCD enzymes. SCD-induced livers were homogenized in 250 mM sucrose, 1 mM EDTA, 5 mM DTT, and 50 mM Tris-HCl (pH 7.5) after wista rats were fed a high carbohydrate/fat-free rodent diet (LabDiet # 5803, Purina) for three days ( 1:10 w/v). After centrifugation (18,000xg/4°C) for 20 minutes to remove tissue and cell debris, the resulting pellet was resuspended in 100 mM sodium phosphate, 20% glycerol, and 2 mM DTT and centrifuged at 100,000xg (60 minutes) to prepare microsomes. Mix the test compound in 2 μL DMSO with 180 μL microsomes (usually about 100 μg/mL, in Tris-HCl buffer (100 mM, pH 7.5), ATP (5 mM), coenzyme A (0.1 mM), TritonX-100 (0.5 mM ) and NADH (2mM)) were incubated at room temperature for 15 minutes. Add 20 μL of [ ³ H]-stearoyl-CoA (final concentration: 2 μM, radioactive concentration: 1 μCi/mL) to initiate the reaction, and add 150 μL IN sodium hydroxide to terminate the reaction. After hydrolysis of oleoyl-CoA and stearoyl-CoA at room temperature for 60 minutes, add 150 μL of 15% phosphoric acid (v/v) in ethanol (addition of 0.5 mg/mL stearic acid and 0.5 mg/mL oleic acid) to acidify the solution . [ ³ H]-oleic acid and [ ³ H]-stearic acid were quantified on an HPLC equipped with a C-18 reverse-phase column and a Packard Flow Scintillation analyzer. Alternatively, the reaction mixture (80 μL) was mixed with an aqueous calcium chloride/charcoal suspension (100 μL of 15% (w/v) activated carbon plus 20 μL of 2N CaCl ₂ ). The resulting mixture was centrifuged to precipitate the radioactive fatty acid into a stable pellet. Tritiated water from SCD-catalyzed 9,10-[3H]-stearoyl-CoA desaturation was quantified by counting 50 μL of supernatant on a scintillation counter.

II. Intact Cell Based SCD(Δ-9), Δ-5 and Δ-6 Desaturase Assays :

Human HepG2 cells were cultured on a 24-well plate containing MEM medium (Gibcocat #11095-072) supplemented with 10% heat-inactivated fetal bovine serum at 37°C in a humidified incubator with 5% CO ₂ . Subconfluent cells were incubated with test compounds dissolved in culture medium for 15 minutes at 37°C. [ ^1-14C ]stearic acid was added to each well to a final concentration of 0.05 μCi/mL to detect SCD-catalyzed formation of [ ^14C ]-oleic acid. Use 0.05 μCi/mL [1- ¹⁴ C]-eicosatrienoic acid or [1- ¹⁴ C]-linolenic acid plus 10 μM 2-amino-N-(3-chlorophenyl)benzamide (Δ-5 Desaturase inhibitors) indicate delta-5 and delta-6 desaturase activity, respectively. After 4 hours of incubation at 37°C, the medium was removed and the labeled cells were washed with PBS (3x1 mL) at room temperature. Labeled cellular lipids were hydrolyzed with 400 μL 2N sodium hydroxide plus 50 μL L-α-phospholecithin (2 mg/mL in isopropanol, Sigma #P-3556) at 65° C. for 1 hour under nitrogen. After acidification with phosphoric acid (60 μL), radioactive material was extracted with 300 μL of acetonitrile and quantified on an HPLC equipped with a C-18 reverse phase column and PackardFlow Scintillation analyzer. [ ¹⁴ C]-oleic acid to [14C]-stearic acid, [ ¹⁴ C]-arachidonic acid to [ ¹⁴ C]-eicosatrienoic acid and [ ¹⁴ C]-eicosatetraenoic acid ( 8, 11, 14, 17) vs. [ ¹⁴ C]-linolenic acid levels were used as the corresponding activity indices for SCD, Δ-5 and Δ-6 desaturases, respectively.

The SCD inhibitors of formula I, especially the inhibitors of Examples 1-20, exhibit inhibition constants IC ₅₀ below 1 μM, more specifically below 0.1 μM. In general, the delta-5 and delta-6 desaturases have _IC50 ratios for SCD of at least about 10 or greater, preferably about 100 or greater, for the compounds of formula I, particularly Examples 1-20.

In Vivo Efficacy of Compounds of the Invention

The in vivo efficacy of compounds of formula I was determined by the conversion of [ ^1-14C ]-stearic acid to [ ^1-14C ]oleic acid in animals as exemplified below. Mice were dosed with the compound of structural formula I and 1 hour later with 20 μCi/kg IV of the radioactive tracer [1- ¹⁴ C]-stearic acid. Livers were harvested 3 hours after compound administration and then hydrolyzed in 10N sodium hydroxide at 80°C for 24 hours to obtain total liver fatty acids. After acidifying the extracts with phosphoric acid, [ ^1-14C ]-stearic acid and [ ^1-14C ]oleic acid were quantified on an HPLC equipped with a C-18 reverse-phase column and a Packard FlowScintillation analyzer.

The subject compounds can be further used in combination with other agents for the prophylaxis and treatment of the diseases, disorders and conditions previously described.

The compound of the present invention can be used in combination with one or more other drugs for the treatment, prevention, suppression or alleviation of diseases or symptoms for which the compound of formula I or other drugs have utility, wherein the drug combination is safer or more effective than the single drug. These other drugs may be administered simultaneously or sequentially with the compound of formula I by commonly used routes and doses. When a compound of formula I is used concomitantly with one or more other drugs, a unit dosage pharmaceutical composition containing the other drugs and the compound of formula I is preferred. However, combination therapy also includes therapy in which the compound of formula I and one or more other drugs are administered at different overlapping times. It also includes the use of a compound of the invention or other active ingredients in lower doses than when used alone, when used in combination with one or more other active ingredients. Accordingly, the pharmaceutical compositions of the present invention include those comprising, in addition to the compound of formula I, one or more other active ingredients.

Examples of other active ingredients that may be administered in combination with a compound of formula I (either alone or in the same pharmaceutical composition) include, but are not limited to:

(a) dipeptidyl peptidase-IV (DPP-4) inhibitors

(b) Insulin sensitizers include (i) PPARγ agonists such as glitazones (e.g., troglitazone, pioglitazone, emglitazone, MCC-555, rosiglitazone, paglitazone Ketones, etc.) and other PPAR ligands, including PPARα/γ dual agonists such as KRP-297, muraglitaza, naveglitazar, Galida, TAK-559, PPARα agonists such as fenofibric acid derivatives (gemfibrozil, Clofibrate, fenofibrate and bezafibrate) and selective PPARγ modulators (SPPARγM's), for example disclosed in WO 02/060388, WO 02/08188, WO2004/019869, WO 2004/020409, WO 2004/020408 and WO 2004/066963; (ii) biguanides, such as metformin hydrochloride; (iii) protein tyrosine phosphatase-IB (PTP-IB) inhibitors;

(c) Insulin or insulin-mimetic, including short-acting insulin, regular insulin, long-acting insulin, compounded forms of insulin, etc., may be administered by any conventional route, such as subcutaneous, intradermal or intramuscular injection, oral, transdermal, intranasal, In the lungs etc.

(d) sulfonylureas and other insulin secretagogues such as tolbutamide, glibenclamide, glipizide, glimepiride and meglitinides such as nateglinide and repaglinide;

(e) Alpha-glucosidase inhibitors (such as acarbose and miglitol)

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

(g) GLP-I, GLP-I analogs or mimics, and GLP-I receptor agonists, such as exendin-4 (exenatide), liraglutide (NN-2211), CJC-1131, LY - 307161 and those disclosed in WO 00/42026 and WO 00/59887;

(h) GIP and GIP mimetics, such as those disclosed in WO 00/58360 and GIP receptor agonists;

(i) PACAP, PACAP mimetics and PACAP receptor agonists, such as those disclosed in WO01/23420;

(j) Cholesterol-lowering drugs such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, Suvastatin and other statins), (ii) sequestering agents (dialkylaminoalkyl derivatives of cholestyramine, colestipol, and cross-linked dextran), (iii) nicotinic alcohol, nicotinic acid Acids or their salts, (iv) PPARα agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPARα/γ dual agonists , such as naveglitazar and muraglitazar, (vi) cholesterol absorption inhibitors such as β-sitosterol and ezetimibe, (vii) acetyl-CoA:cholesterol acyltransferase inhibitors such as avasimibe, (viii) CETP Inhibitors such as Torchup, JTT-705 and compounds disclosed in WO2005/100298, WO2006/014357 and WO2006/014413, and (ix) phenolic antioxidants such as probucol;

(k) PPARδ agonists, such as those disclosed in WO 97/28149;

(l) Anti-obesity compounds such as fenfluramine, dexfenflurah, phentermine, sibutramine, orlistat, neuropeptide Y1 or Y5 antagonists, CB1 receptor inverse agonists and antagonists, beta3 adrenal hormone receptor agonists, melanocortin receptor agonists, especially melanocortin-4 receptor agonists, ghrelin (ghrelin) antagonists, bombesin receptor agonists (such as bombesin receptor 3-sub agonists) and melanin concentrating hormone (MCH) receptor antagonists;

(m) Ileal bile acid transporter inhibitors

(n) Medications indicated for inflammatory symptoms, such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;

(o) Antihypertensive drugs, such as diuretics, such as hydrochlorothiazide, furosemide, etc.; β-adrenergic blockers, such as propranolol, metoprolol, etc.; ACE inhibitors (such as, enalapril , lisinopril, captoprine, and tandolapril); A-II receptor blockers (such as losartan, candesartan, irbesartan, valsartan, telmisartan, and eprosartan ) and calcium channel blockers such as amlodipine, diltiazem and verapamil;

(p) glucokinase activators (GKAs), such as those disclosed in WO 03/015774, WO 04/076420 and WO 04/081001;

(q) 11/β-type I hydroxysteroid dehydrogenase inhibitors such as those disclosed in US Patent No. 6730690, WO 03/104207 and WO 04/058741.

(r) Fructose 1,6-bisphosphatase inhibitors such as those disclosed in US Pat.

(s) acetyl-CoA carboxylase-1 and/or-2 inhibitors;

(t) AMPK activators; and

(u) GPR-119 agonists.

Dipeptidyl peptidase-FV inhibitors that can be combined with compounds of formula I include US Patent No. 6699871; WO 02/076450 (October 3, 2002); WO 03/004498 (January 16, 2003); WO 03 /004496 (January 16, 2003); EP 1 258 476 (December 20, 2002); WO 02/083128 (October 24, 2002); WO02/062764 (August 15, 2002); WO 03/000250 (January 3, 2003); WO 03/002530 (January 9, 2003); WO 03/002531 (January 9, 2003); WO 03/002553 (January 9, 2003) ; WO 03/002593 (January 9, 2003); WO 03/000180 (January 9, 2003); WO 03/082817 (October 9, 2003); WO 03/000181 (January 9, 2003 WO 04/007468 (January 22, 2004); WO 04/032836 (April 24, 2004); WO 04/037169 (May 6, 2004); and WO 04/043940 (May 2004 those disclosed in 7 March). Specific DPP-IV inhibitor compounds include sitagliptin (MK-0431); vildagliptin (LAF 237); denagliptin; P93/01; saxagliptin (BMS 477118); RO0730699; MP513; alogliptin (SYR-322); ABT-279; PHX1149; GRC-8200; TS021; and pharmaceutically acceptable salts thereof.

Anti-obesity compounds that can be combined with compounds of formula I include fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y1 or Y5 antagonists, cannabinoid CBI receptor antagonists Or inverse agonists, melanocortin receptor agonists, especially melanocortin-4 receptor agonists, ghrelin agonists, bombesin receptor agonists and melanin concentrating hormone (MCH) receptor antagonists. A review of anti-obesity compounds that can be combined with compounds of formula I is found in 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); and J.A. Fernandez-Lopez et al., "Pharmacological Approaches for the Treatment of Obesity," Drugs, 62 : 915-944 (2002).

Neuropeptide Y5 antagonists that can be combined with compounds of formula I include those disclosed in U.S. Patent No. 6,335,345 (January 1, 2002) and WO 01/14376 (March 1, 2001) and GW 59884A; GW 569180A; LY366377 and specific compounds identified in CGP-71683A.

CB1 receptor antagonists or inverse agonists that can be combined with compounds of formula I include PCT application WO 03/007887; U.S. Patent No. 5624941, such as rimonabant; U.S. Patent No. 6972295, such as taranabant; PCT application WO 02/076949, For example SLV-319; US Patent No. 6028084; PCT Application WO 98/41519; PCT Application WO 00/10968; PCT Application WO 99/02499; PCT Application WO 03/087037; PCT Application WO 04/048317; PCT Application WO 03/007887; PCT Application WO 03/063781; PCT Application WO 03/075660; PCT Application WO 03/077847; PCT Application WO 03/087037; PCT Application WO 03/086288; PCT Application WO 04/012671; PCT Application WO 04/029204; PCT Application WO 04/040040; PCT Application WO 01/64632; PCT Application WO 01/64633 and those disclosed in PCT application WO 01/64634.

Melanocortin-4 receptor (MC4R) agonists that can be used in the present invention include, but are not limited to, those disclosed below, US 6294534, US 6350760, 6376509, 6410548, 6458790, US 6472398, US 5837521, US 6699873, the entire contents of which Incorporated herein by reference; U.S. Patent Application Publication Nos. US 2002/0004512, US2002/0019523, US2002/0137664, US2003/0236262, US2003/0225060, US2003/0092732, US2003/109556, US 2002/01772001, 2 187932, US 2003/0113263, the entire contents of which are incorporated herein by reference; and WO 99/64002, WO 00/74679, WO 02/15909, WO 01/70708, WO 01/70337, WO 01/91752, WO 02/ 068387, WO 02/068388, WO 02/067869, WO 03/007949, WO 2004/024720, WO 2004/089307, WO 2004/078716, WO 2004/078717, WO 2004/037797, WO 01/58891, WO 050 , WO 02/079146, WO 03/009847, WO 03/057671, WO 03/068738, WO 03/092690, WO 02/059095, WO 02/059107, WO 02/059108, WO 02/059117, WO 02/085925, WO 03/004480, WO 03/009850, WO 03/013571, WO 03/031410, WO 03/053927, WO 03/061660, WO 03/066597, WO 03/094918, WO 03/099818, WO 04/037797, WO 04/048345 , WO 02/018327, WO 02/080896, WO 02/081443, WO 03/066587, WO 03/066597, WO 03/099818, WO 02/062766, WO 03/000663, WO 03/000666, WO 03/003977, WO 03/040107, WO03/040117, WO 03/040118, WO 03/013509, WO 03/057671, WO02/079 753, WO 02/092566, WO 03/-093234, WO 03/095474 and WO 03/104761.

A particular aspect of combination therapy relates to the treatment of hypercholesterolemia, atherosclerosis, low LDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and A method for dyslipidemia comprising administering to a patient a therapeutically effective amount of a compound of formula I and an HMG-CoA reductase inhibitor.

More specifically, this aspect of combination therapy relates to the treatment of hypercholesterolemia, atherosclerosis, low LDL levels, high LDL levels, hyperlipidemia, high triglycerides in a mammalian patient in need of such treatment A method for esteremia and dyslipidemia, wherein the HMG-CoA reductase is selected from the group consisting of lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin and rosuvastatin statins.

In another aspect of the present invention is disclosed reducing the risk of a disease selected from hypercholesterolemia, atherosclerosis, low LDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia and A method for the sequelae of these conditions comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of formula I and an HMG-CoA reductase inhibitor.

In another aspect of the invention there is disclosed a method of delaying or reducing the onset or risk of atherosclerosis in a human patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound of formula I and HMG-CoA reductase Inhibitors.

More specifically, a method of delaying or reducing the onset or risk of atherosclerosis in a human patient in need of such treatment is disclosed, wherein the HMG-CoA reductase is selected from the group consisting of lovastatin, simvastatin, pravastatin The statins of cerivastatin, cerivastatin, fluvastatin, atorvastatin, and rosuvastatin.

In another aspect of the invention is disclosed a method of delaying or reducing the onset or risk of atherosclerosis in a human patient in need of such treatment, wherein the HMG-CoA reductase is a statin and further comprising administering a cholesterol absorption inhibitor.

More specifically, in another aspect of the invention is disclosed a method of delaying or reducing the onset or risk of atherosclerosis in a human patient in need of such treatment, wherein said HMG-CoA reductase is a statin and said cholesterol The absorption inhibitor is ezetimibe.

In another aspect of the present invention, a pharmaceutical composition is disclosed, comprising:

(1) a compound of structural formula I;

(2) One or more compounds selected from the following:

(a) dipeptidyl peptidase-IV (DPP-4) inhibitors

(b) Insulin sensitizers include (i) PPARγ agonists such as glitazones (e.g., troglitazone, pioglitazone, emglitazone, MCC-555, rosiglitazone, paglitazone Ketones, etc.) and other PPAR ligands, including PPARα/γ dual agonists such as KRP-297, muraglitaza, naveglitazar, Galida, TAK-559, PPARα agonists such as fenofibric acid derivatives (gemfibrozil, Clofibrate, fenofibrate and bezafibrate) and selective PPARγ modulators (SPPARγM's), for example disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408 and WO 2004/066963; (ii) biguanides, such as metformin hydrochloride; (iii) protein tyrosine phosphatase-IB (PTP-IB) inhibitors;

(c) Insulin or insulin-mimetic, including short-acting insulin, regular insulin, long-acting insulin, compounded forms of insulin, etc., may be administered by any conventional route, such as subcutaneous, intradermal or intramuscular injection, oral, transdermal, intranasal, In the lungs etc.

(d) Sulfonylureas and other insulin secretagogues such as tolbutamide, glibenclamide, glipizide, glimepiride, and meglitinides such as nateglinide and repaglinide ;

(e) Alpha-glucosidase inhibitors (such as acarbose and miglitol)

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

(g) GLP-1, GLP-1 analogs or mimics, and GLP-1 receptor agonists, such as exendin-4 (exenatide), liraglutide (NN-2211), CJC-1131, LY - 307161 and those disclosed in WO 00/42026 and WO 00/59887;

(h) GIP and GIP mimetics, such as those disclosed in WO 00/58360 and GIP receptor agonists;

(i) PACAP, PACAP mimetics and PACAP receptor agonists, such as those disclosed in WO01/23420;

(j) Cholesterol-lowering drugs such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, Suvastatin and other statins), (ii) sequestering agents (dialkylaminoalkyl derivatives of cholestyramine, colestipol, and cross-linked dextran), (iii) nicotinic alcohol, nicotinic acid Acids or salts thereof, (iv) PPARα agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate, and bezafibrate), (v) PPARα/γ dual agonists agents such as naveglitazar and muraglitazar, (vi) cholesterol absorption inhibitors such as beta-sitosterol and ezetimibe, (vii) acetyl-CoA:cholesterol acyltransferase inhibitors such as avasimibe, (viii) CETP inhibitors such as Torchup, JTT-705 and compounds disclosed in WO2005/100298, WO2006/014357 and WO2006/014413, and (ix) phenolic antioxidants such as probucol;

(k) PPARδ agonists, such as those disclosed in WO 97/28149;

(l) Anti-obesity compounds such as fenfluramine, dexfenflurah, phentermine, sibutramine, orlistat, neuropeptide Y1 or Y5 antagonists, CB1 receptor inverse agonists and antagonists, beta3 adrenal receptor agonists, melanocortin-receptor agonists, especially melanocortin-4 receptor agonists, ghrelin antagonists, bombesin receptor agonists (such as bombesin receptor 3-subtype agonists agents) and melanin concentrating hormone (MCH) receptor antagonists;

(m) ileal bile acid transporter inhibitors;

(n) Medications indicated for inflammatory symptoms, such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;

(o) Antihypertensive drugs, such as diuretics, such as hydrochlorothiazide, furosemide, etc.; β-adrenergic blockers, such as propranolol, metoprolol, etc.; ACE inhibitors (such as, enalapril , lisinopril, captoprine, and tandolapril); A-II receptor blockers (such as losartan, candesartan, irbesartan, valsartan, telmisartan, and eprosartan ) and calcium channel blockers such as amlodipine, diltiazem and verapamil;

(p) glucokinase activators (GKAs), such as those disclosed in WO 03/015774, WO 04/076420 and WO 04/081001;

(q) 11/β-type I hydroxysteroid dehydrogenase inhibitors such as those disclosed in US Patent No. 6730690, WO 03/104207 and WO 04/058741.

(r) Fructose 1,6-bisphosphatase inhibitors such as those disclosed in US Pat.

(s) acetyl-CoA carboxylase-1 and/or-2 inhibitors;

(t) AMPK activators; and

(u) GPR-119 agonists.

(3) Pharmaceutically acceptable carrier

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

The weight ratio of the compound of the present invention to the second active ingredient may vary and will depend on the effective dosage of each ingredient. In general, an effective dose of each is used. Thus, for example, when a compound of the invention is combined with another agent, the weight ratio of the compound of the invention to the other agent is generally in the range of about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200 . Combinations of the compounds of the present invention and other active ingredients are generally also within the above ranges, but in each case an effective dose of each active ingredient should be used.

In such combinations, the compounds of the present invention and other active agents may be administered alone or in combination. In addition, another drug may be administered before, simultaneously or after one element.

Can be administered orally, parenterally (eg, intramuscularly, intraperitoneally, intravenously, ICV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation spray, nasal, vaginal, workplace, sublingual, or topically Routes of administration of the compounds of the invention and may be formulated individually or together in appropriate dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and solvents suitable for each route of administration. In addition to treating warm-blooded animals such as mice, rats, horses, sheep, dogs, cats, monkeys, etc., the present dosages of the compounds of the invention are effective in humans.

Pharmaceutical compositions for the administration of the compounds of this invention may suitably be presented in unit dosage form and prepared by methods well known in the art of pharmacy. All methods involve bringing into association the active ingredient with the carrier which constitutes one or more excipients. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers or finely divided solid carriers or both, and, if necessary, shaping the product into the desired formulation. The active compound of interest is included in the pharmaceutical composition in an amount sufficient to have the desired effect on the progression or symptoms of the disease. As used herein, the term "composition" is intended to encompass products comprising the specified ingredients in the specified amounts as well as products obtained directly or indirectly from the combination of the specified ingredients in the specified amounts.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. . Compositions for oral administration may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, aromatic bases, coloring agents and preservatives. agents to provide pharmaceutically acceptable and palatable formulations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as cornstarch or alginic acid; binders such as starch, gelatin or acacia and lubricants, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained release over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. It may also be coated by the techniques described in US Pat. Nos. 4,256,108, 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for controlled release.

Formulations for oral administration may also be presented as gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or in soft capsules, in which the active ingredient is mixed with water and an oily medium, such as peanut oil, liquid paraffin, or olive oil. oil mix.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia; dispersing or wetting agents It may be a natural phospholipid, such as lecithin, or a condensation product of an olefin oxide with a fatty acid, such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a fatty acid, such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long Condensation products of chain fatty alcohols, such as heptadeceneethyleneoxycetyl alcohol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate, or ethylene oxide Condensation products with anhydrides derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate. Aqueous suspensions also contain one or more preservatives, such as ethyl or n-propyl paraben, one or more coloring agents, one or more aromatic groups and one or more sweeteners Flavoring agents such as sucrose or saccharin.

Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil, for example arachis oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents (as described above) and aromatic groups may be added to provide a palatable oral preparation. Antioxidants such as ascorbic acid can be added to preserve these compositions.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or emollients and suspending agents are exemplified by those already mentioned above. Other excipients, for example sweetening, aromatic and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as liquid paraffin, or mixtures of these. Suitable emulsifiers may be natural gums such as acacia or tragacanth, natural phospholipids such as soybean lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as polyoxyethylene sorbitan mono oil esters. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, propylene glycol or sucrose. Such formulations may also contain a wetting agent, a preservative, flavoring and coloring agents.

Pharmaceutical compositions can be in the form of sterile injectable solutions or oily suspensions. This suspension may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable suspension in a nontoxic parenterally acceptable diluent or solvent, such as 1,3-butanediol. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland oil blend may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of this invention may also be used in the form of suppositories for rectal administration of medicines. These compositions are prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compounds of this invention are applied (for purposes of this use, topical application shall include mouthwashes and gargles).

The pharmaceutical compositions and methods of the present invention further include other therapeutic compounds as mentioned herein, which are generally applied in the treatment of the pathological conditions described above.

In the treatment or prevention of conditions requiring inhibition of stearoyl-CoA delta-9 desaturase activity, suitable dosage levels are about 0.01 to 500 mg/kg of patient body weight, administered in single or multiple doses. Preferred dosage levels are from about 0.1 to about 250 mg/kg/day; more preferably from about 0.5 to about 100 mg/kg/day. Suitable dosage levels are about 0.01 to 250 mg/kg/day, about 0.05-100 mg/kg/day or about 0.1-50 mg/kg/day. Within this dosage range may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg/day. For oral administration, the composition is preferably presented in the form of tablets containing from 1.0 to 1000 mg of active ingredient, in particular 1.0, 5.0, 10.0, 15.0. 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 mg of active ingredient were used for symptomatic dose adjustments in the treated patients. The dosage regimen of the compound may be 1 to 4 times per day, preferably once or twice per day.

When treating diabetes and/or hyperglycemia or hypertriglyceridemia or other diseases for which the compound of the present invention is applicable, when administered at a daily dose of about 0.1 mg to about 100 mg/kg of animal body weight, usually the following Satisfactory results in humans are preferably administered in a single daily dose or in divided doses two to three times daily. For large mammals, the total daily dosage is from about 1.0 mg to about 1000 mg, preferably from about 1 mg to about 50 mg. In the case of a 70 kg adult, the total daily dosage will generally be from about 7 mg to about 350 mg. This dosage regimen may be adjusted to provide the optimum therapeutic response.

It is to be understood, however, that the prescribed dosage level and dosing frequency for any particular patient may vary and depend upon a variety of factors including the activity of the given compound being employed, the metabolic stability and duration of action of the compound, age, weight, health, Gender, diet, mode and timing of administration, clearance, drug combination, severity of specific symptoms, and therapy being received by the host.

List of acronyms

Alk = alkyl

APCI = atmospheric pressure chemical ionization

Ar = aryl

Boc = tert-butoxycarbonyl

Br = wide

t-BuONO = tert-butyl nitrite

d = doublet

DBU ＝1,8-diazabicyclo[5.4.0]undec-7-ene

DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DMF ＝N,N-Dimethylformamide

DIBAL-H ＝Diisobutylaluminum hydride

DMSO = dimethyl sulfoxide

ESI = electrospray ionization

ESMS = Electrospray Ion Mass Spectrometry

EtOAc = ethyl acetate

HATU ＝O-(7-azobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphorus

HPLC = high performance liquid chromatography

M = multiplet

Min = minutes

MeOH = Methanol

MS = mass spectrum

NaHMDS = sodium bis(trimethylsilyl)amide

NMP ＝1-methyl-2-pyrrolidone

NMR = nuclear magnetic resonance spectroscopy

PG = protecting group

rt or RT = room temperature

s = single peak

t = triplet

TFAA = Trifluoroacetic anhydride

Tf ₂ O = trifluoromethanesulfonic anhydride

THF = Tetrahydrofuran

TLC = thin layer chromatography

TsOH = toluene-4-sulfonic acid

Preparation of compounds of the present invention

Compounds of formula I can be prepared using appropriate materials according to the following schemes and examples and are further exemplified by the following specific examples. However, the compounds exemplified in the examples should not be construed as forming the only species belonging to the invention. The examples further illustrate methods of preparing compounds of the invention. Those skilled in the art will readily appreciate that known modifications of the conditions and procedures of the following preparative procedures can be used to prepare these compounds. All temperatures are in degrees Celsius unless otherwise indicated. Mass spectra (MS) were measured by electrospray ionization mass spectrometry (ESMS).

Method A:

Reaction of an appropriately substituted heteroaromatic amine 1 with tert-butyl nitrite and anhydrous copper(II) halide in a solvent such as acetonitrile affords halide 2 . Treatment of 2 with concentrated ammonium hydroxide in a solvent such as THF affords amide 3 . Dehydration with TFAA or _Tf2O in a solvent (eg _CH2Cl2 ) affords _the nitrile intermediate 4 .

Method B :

Reaction of an appropriately substituted haloheteroarylamine 5 with tert-butyl nitrite and anhydrous cuprous cyanide in a solvent such as acetonitrile affords the nitrile intermediate 4.

Method C :

The nitrile intermediate 4 is combined with the appropriately substituted cyclic amine 6 in the presence of a base (e.g. DBU) or alkali metal (K, Na, Cs) carbonate in a solvent (e.g. THF, 1,4-dioxane and DMF) React in the temperature range from room temperature to reflux temperature. Extraction and flash column chromatography yielded the coupled product 7.

Method D :

The ester intermediate 2 is combined with an appropriately substituted cyclic amine 6 in the presence of a base (e.g. DBU) or alkali metal (K, Na, Cs) carbonate in a solvent (e.g. THF, 1,4-dioxane and DMF) React in the temperature range from room temperature to reflux temperature. Extraction and flash column chromatography afforded the coupled product 8 . Reaction with a base such as NaOH in a solvent (such as aqueous THF) containing an alcoholic solvent (such as MeOH) at a temperature ranging from room temperature to reflux temperature gives the carboxylic acid intermediate. Then in a solvent such as THF via the corresponding acid chloride with NH ₃ or under the guidance of the amidation reaction described by McMurray [Tetrahedron Lett., 2501 (1999)] in a coupling agent such as HATU and a base such as N, N-diisopropyl The carboxylic acid is converted to the amide 9 with _NH4Cl in the presence of ethylethylamine in a solvent such as DMF. Dehydration of amide 9 with TFAA or _Tf2O in a solvent such as _CH2Cl2 affords nitrile 7.

Method E :

The nitrile intermediate 7 prepared according to method C or D is reacted with NaN in the presence of a Lewis acid _catalyst such as pyridine hydrochloride in a solvent such as NMP, or with _NaN in the presence of a Lewis acid catalyst such as _ZnBr in a solvent such as 2- Reaction of propanol and water affords tetrazole intermediate 10 . Alkylation with a haloester such as ethyl bromoacetate in the presence of a base such as _Cs2CO3 or KOt-Bu in a solvent such as DMF affords mixtures ₁₁ and 12 which can be separated by flash column chromatography . Hydrolysis of the ester groups in 11 and 12 with a base such as sodium hydroxide in a solvent such as THF containing an alcoholic solvent such as MeOH at temperatures ranging from room temperature to reflux temperature affords carboxylic acids 14 and 15 . The structures of 14 and 15 can be further confirmed by X-ray crystallography or ¹⁵ N gradient heteronuclear multiple bond correlation ( ¹⁵ N gHMBC) NMR experiments.

Method F

Reaction of the nitrile intermediate 7 prepared according to method C or D with hydrogen sulfide in the presence of a base such as triethylamine or basic sodium ethoxide in a solvent such as 1,4-dioxane or ethanol affords the thiocarbonamide 16 . The intermediate thiocarbonamide 16 is then reacted with an alpha-halo ketoester such as methyl 4-chloroacetone to obtain the ester intermediate 17 . Hydrolysis of the ester group with a base such as sodium hydroxide in a solvent (eg THF) containing an alcoholic solution (eg MeOH) at a temperature ranging from room temperature to reflux temperature affords the carboxylic acid 18 .

Method G

When W represents an isoxazole residue, reaction of a mixture of oxime 19 and acrylate 20 in the presence of a base such as potassium bicarbonate or sodium bicarbonate in a solvent such as EtOAc, THF, EtOAc- _H2O affords an ester intermediate , which is treated with ammonia in alcoholic solution or concentrated ammonium hydroxide in a solvent such as THF to give bromo isoxazoline amide 21 . Oxidation of 21 with iodine in the presence of a base such as sodium acetate, DDQ or _MnO2 in a solvent such as benzene, halobenzene and toluene at a temperature range from room temperature to reflux temperature affords the isoxazole intermediate 23 . The isoxazole amide 23 is then converted to the tetrazole 24 via the corresponding nitrile intermediate according to the appropriate steps in Methods D and E. The tetrazole 24 is then heated in the presence of a base such as _Et3N or an alkali metal (K, Na, Cs) carbonate in a solvent such as THF, 1,4-dioxane or DMF between room temperature and reflux temperature Reacts with ethyl bromoacetate over temperature range. The 2-alkylated ester tetrazole intermediate is usually obtained together with the 1-alkylated isomer which can be separated by chromatography. Hydrolysis of the ester group of the 2-alkylated ester tetrazole intermediate with a base such as sodium hydroxide in a solvent such as THF containing an alcoholic solvent such as MeOH at a temperature ranging from room temperature to reflux temperature affords threonine 25 . When the tert-butyl ester is used, cleavage of the ester group with TFAA in _a solvent such as _CH2Cl2 or with an acid such as formic acid in water at a temperature ranging from room temperature to reflux temperature affords 25 . The structure of 25 can be further verified by ¹⁵ N gHMBC NMR experiments.

Method H :

Reaction of an appropriately substituted cyclic amine 6 with cyanogen bromide in the presence of a base such as triethylamine in a solvent such as THF affords cyanamide derivatives 26 . Reaction of cyanamide 26 with hydroxylamine hydrochloride in EtOH/water in the presence of a base such as sodium carbonate at reflux temperature affords carboximide 27 . Reaction of carboximide 27 with an appropriately substituted heteroaryl acid chloride 28 in the presence of a base such as triethylamine and sodium hydride in a solvent such as THF at room temperature or reflux temperature conditions affords intermediate 29 . Alkylation of the azaaryl group with a halide ester such as ethyl bromoacetate in the presence of a base such as triethylamine or sodium hydride in a solvent such as THF affords the heteroaryl acetate intermediate. The ester group can be hydrolyzed with aqueous NaOH in solvents such as THF and MeOH at temperatures ranging from about room temperature to reflux followed by extraction and purification by flash column chromatography or recrystallization to give the final product 30 .

Method I :

The nitrile intermediate 7 prepared according to method C or D is mixed with hydroxylamine hydrochloride in the presence of a base such as an alkali metal (K, Na, Cs) carbonate in a solvent such as DMF, EtOH, THF and 1,4-dioxane Reaction at temperatures ranging from room temperature to reflux affords carboximide 31 . Reaction with an appropriately substituted carboxylate halide 32 in the presence of a base such as pyridine in _a solvent such as _CH2Cl2 affords an intermediate which can then be converted to 33 at reflux in pyridine. Cleavage of the ester group in 33 by hydrolysis with base (NaOH) in a solvent such as THF affords the final product 34 .

Method J :

Carboxylic acid 35 prepared according to method E or G (where the phenyl ring contains a halogen group as shown) was prepared under Suzuki-type _conditions with arylboronic acid and base such as _Na2CO3 in water in the presence of a catalyst such as Pd( _Ph3P ) ₄ Crosslinking in a solvent such as toluene at an appropriate temperature affords the biaryl product 36 .

Preparation of intermediates

Intermediate 1

4-[2-(Trifluoromethyl)phenoxy]piperidine

To a THF solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (25g, 124mmol), 2-hydroxy-trifluorotoluene (22g, 136mmol) and triphenylphosphine (39g, 149mmol) was added dropwise at 0°C. Diethyl azodicarboxylate (23.5 mL, 149 mmol). The mixture was then warmed to room temperature and stirred for 14 hours. The _mixture was concentrated and diluted with _Et2O , washed with 1N NaOH and water and then dried over _Na2SO4 . The mixture was concentrated and diluted with _Et2O /hexanes (35:65). The precipitated phosphorus oxide was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluting with 35% _Et2O /hexanes) to afford tert-butyl 4[2-(trifluoromethyl)phenoxy]piperidine-1-carboxylate as a solid.

To a solution of tert-butyl 4[2-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (29.5 g, 85 mmol) in _CH2Cl2 (171 _mL ) was added trifluoroacetic acid (26.3 mL, 342 mmol) . The mixture was stirred at room temperature for 16 hours. The solvent was removed by evaporation. The residue was diluted with EtOAc (200 mL), washed with 2N NaOH (3x100 mL), brine and dried over _Na2SO4 to give the title compound as an oil after evaporation to _dryness .

Intermediate 2

4-(2-Bromo-5-fluorophenoxy)piperidine

To a solution of tert-butyl 4-hydroxypiperidine 1-carboxylate (50.6 g, 251 mmol) and di-tert-butyl azodicarboxylate (71.0 g, 308 mmol) in THF (350 mL) was added 2-bromo-5-fluorophenol ( 36 mL, 324 mmol). The mixture was cooled to -78° _C and a solution of triphenylphosphine (81.5 g, 311 mmol) in _CH2Cl2 (130 mL) was added via cannula. The reaction was then warmed to room temperature and stirred overnight. The solvent was removed in vacuo and the crude oil was dissolved in EtOH (200 mL). The solution was cooled to -78°C and treated with a solution of 1,4-dioxane (450 mL) in 4M HCl. The reaction was warmed to room temperature and stirred for 24 hours. The solvent was then removed in vacuo. The salt was neutralized with 1N NaOH (750 mL) and extracted several times with a mixture of _Et2O :hexane (1:1). The organic layers were combined and concentrated to dryness. The crude was treated with heptane (1 L), and the white precipitate was filtered and discarded. The heptane layer was diluted with _Et2O and treated with 4M HCl in 1,4-dioxane (100 mL). The resulting precipitate was collected by filtration and washed three times with _Et2O :hexane (1:1). The salt was again neutralized with 1N NaOH (500 mL) and extracted several times with _Et2O :hexane (1:1). The organic layers were combined, washed with brine, dried ( _MgSO4 ), filtered and concentrated. The crude product was dissolved in heptane (2 L), washed four times with 1 N NaOH (250 mL), brine and dried (MgSO ₄ ). The organic layer was filtered and concentrated to dryness to afford the title compound as a colorless oil. ¹ H NMR (500MHz, acetone-d ₆ ): δ7.58(dd, IH), 7.00(dd, IH), 6.70(td, IH), 4.64-4.58(m, IH), 3.12-3.06(m, 2H), 2.73-2.66 (m, 2H), 2.02-1.94 (m, 2H), 1.69-1.60 (m, 2H).

Intermediate 3

5-Bromo-1,3,4-thiadiazole-2-carbonitrile

Step 1: Ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate

To a solution of ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (10 g, 58 mmol) in _CH3CN (180 mL) was added _CuBr2 (25.7 g, 115 mmol). The mixture turned dark green and was further stirred at room temperature for 15 minutes. t-BuONO, 90% (13.8 mL, 115 mmol) was added dropwise over 15-20 minutes. The mixture became slightly warm and bubbled after 5 minutes and throughout the addition. Bubbling had subsided after the addition was complete and the mixture was heated at 60°C for 30 minutes. The solvent was evaporated to dryness in vacuo. Water and EtOAc were added and the mixture was stirred in a shake flask until the dark green color disappeared. The organic phase turned light brown and the aqueous phase was green and contained insolubles. All mixture was filtered through celite and washed with EtOAc. The EtOAc layer was separated, eluted with dilute brine solution, dried (Na ₂ SO ₄ ) and concentrated to give the title compound 1H NMR (400 MHz, acetone-d ₆ ): δ 4.52 (q, 2H), 1.43 (t, 3H).

Step 2: 5-Bromo-1,3,4-thiadiazole-2-carboxamide

To a solution of ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (13.5 g, 56.9 mmol) in THF (50 mL) was added NH ₄ OH (28 wt.%, 39.6 mL, 164 mmol ). The mixture was stirred at room temperature overnight, and the aqueous layer precipitated. Volatile materials were removed in vacuo. The mixture was diluted with water and the precipitate collected, washed with water and dried in vacuo to give the title compound. ¹ H NMR (400 MHz, acetone-d ₆ ): δ 7.99 (s, IH), 7.55 (s, IH).

Step 3: 5-Bromo-1,3,4-thiadiazole-2-carbonitrile

To a solution of 5-bromo-1,3,4-thiadiazole-2-carboxamide (11 g, 53 mmol) and _Et3N (17.1 mL, 122 mmol) in THF (106 mL) was added TFAA (17 mL, 58 mmol) at 0 °C ). The mixture was warmed to room temperature and stirred for 30 minutes. The solvent was evaporated to dryness in vacuo. Dilute the residue with water. The precipitate was collected, washed with water and dried to give the title compound. ¹³ C NMR (300 MHz, CDCl ₃ ): δ77.3, 109.0, 141.7.

The following examples are provided to illustrate the invention and should not be construed as limiting the scope of the invention in any way.

Example 1

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

Step 1: 5-{4-[2-(Trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2-amine

To a solution of 4-[2-(trifluoromethyl)phenoxy]piperidine hydrochloride (5.5 g, 2.2 mmol) in DMF was added 5-bromo-1,3,4-thiadiazol-2-amine (3.3g, 2.2mmol) and _K2CO3 ( _9.1g , 6.6mmol). The reaction was heated and stirred at 80°C overnight. After cooling, the salt was removed by filtration and the filtrate was evaporated to dryness in vacuo. The residue was triturated with EtOAc to afford the title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ7.57-7.60 (m, 2H), 7.29-7.35 (m, 1H), 7.03-7.05 (m, 1H), 6.46 (s, 2H), 4.84 ( s, 1H), 3.22-3.30 (m, 4H), 1.91-2.01 (m, 2H), 1.68-1.78 (m, 2H). MS: m/z 345 (MH ⁺ ).

Step 2: 5-{4-[2-(Trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazole-2-carbonitrile

To 5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2-amine (10.0g, 29.0mmol) at room temperature CuCN (5.3 g, 59.2 mmol) and t-BuONO (90%) (8 mL, 60.0 mmol) were added to a suspension of CH ₃ CN (150 mL) in . The reaction was heated at 50-60 °C for 2 h until TLC showed disappearance of starting material. The reaction was poured into water and _{CH2Cl2 was} added. The solids were removed by filtration and _the filtrate was extracted with _CH2Cl2 , _dried ( _Na2SO4 ) and filtered. The solvent was removed in vacuo to give a crude product, which was purified by column chromatography on silica gel (eluting with 5:1 petroleum ether/EtOAc) to give the title compound. ¹ H NMR (400MHz, CDCl ₃ ): δ7.61(d, 1H), 7.50(t, 1H), 6.93-7.06(m, 2H), 4.86(br s, 1H), 3.77-3.83(m, 4H ), 2.01-2.20 (m, 4H). MS: m/z 355 (MH ⁺ ).

Step 3: 1-[5-(2H-tetrazol-5-yl)-1,3,4-thiadiazol-2-yl]-4-[2-(trifluoromethyl) Phenoxy]piperidine

5-{4-[2-(Trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazole-2-carbonitrile (4.99g, 14.1mmol), NaN ₃ (4.65g, 71.5mmol) and pyridine hydrochloride (3.43g, 29.7mmol) in NMP (50mL) was heated at 130°C for 18h. The reaction was cooled to room temperature and poured into 0.5N aqueous HCl, extracted with EtOAc, washed three times with 0.5N aqueous HCl, and three times with brine solution. The organic phase was dried (Na ₂ SO ₄ ) and filtered. The solvent was evaporated and triturated in a mixture of MeOH/ _Et2O /heptane (1:1:6) (v/v) and stirred at room temperature for 4h. Afterwards, the suspension was cooled in an ice-water bath, and the title mixture was collected by filtration as a white solid. The material was dried by heating at 50 °C for 1-2 h under high vacuum.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ7.60-7.62 (m, 2H), 7.37 (d, 1H), 7.08 (t, 1H), 4.86-4.95 (m, 1H), 3.56-3.64 ( m, 4H), 2.00-2.15 (m, 2H), 1.75-1.89 (m, 2H). MS: m/z 398 (MH ⁺ ).

Step 4: [5-(5-{4-[2-(Trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazole-2- base)-2H-tetrazol-2-yl]ethyl acetate and [5-(5-{4-[2-(trifluoromethyl)phenoxy]-piperidine-1- Base)-1,3,4-thiadiazol-2-yl)-1H-tetrazol-1-yl]ethyl acetate

1-[5-(2H-tetrazol-5-yl)-1,3,4-thiadiazol-2-yl]- 4-[2-(Trifluoromethyl)phenoxy]piperidine (262 mg, 0.66 mmol) in DMF (5 mL). The reaction was heated to 0° C. and after 10 minutes ethyl bromoacetate (150 μL, 1.35 mmol) was added dropwise. The final reaction was heated at room temperature with stirring until TLC indicated disappearance of starting material. The reaction was poured into 1N aqueous HCl, extracted with EtOAc and washed with brine. The organic phase was dried (Na ₂ SO ₄ ) and filtered. Removal of solvent in vacuo gave crude product, which was purified by column chromatography on silica gel (eluting with 10-50% EtOAc/hexanes) to give [5-(5-{4-[2-(trifluoromethyl)phenoxy]piperidine -1-yl}-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]ethyl acetate as the more polar positional isomer, R _f =0.2(50 % EtOAc/Hexane). ¹ H NMR (400MHz, acetone-d ₆ ): δ7.70-7.61(m, 2H), 7.40(d, 1H), 7.14(t, 1H), 5.81(s, 2H), 5.10-5.04(m, 1H), 4.31(q, 2H), 3.94-3.85(m, 2H), 3.86-3.77(m, 2H), 2.29-2.20(m, 2H), 2.11-2.03(dd, 2H), 1.31(t, 3H).

[5-(5-{4-[2-(Trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2-yl)-1H-tetrazole is obtained -1-yl]ethyl acetate as the less polar positional isomer, ( _Rf = 0.3 (50% EtOAc/hexanes)).

¹ H NMR (400MHz, acetone-d ₆ ): δ7.70-7.61(m, 2H), 7.40(d, 1H), 7.14(t, 1H), 5.79(s, 2H), 5.11-5.05(m, 1H), 4.27(q, 2H), 3.98-3.82(m, 4H), 2.30-2.21(m, 2H), 2.13-2.03(m, 2H), 1.28(t, 3H).

Step 5: [5-(5-{4-[2-(Trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazole-2- Base)-2H-tetrazol-2-yl]acetic acid

Treatment of [5-(5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazole-2 with 1N NaOH (1.5 mL) aqueous solution -Ethyl)-2H-tetrazol-2-yl]acetate (134 mg, 0.28 mmol) in THF/MeOH (2:1) (v/v) (4.6 mL). The reaction was stirred at room temperature until TLC indicated disappearance of starting material. The reaction was poured into 0.5N aqueous HCl, extracted with EtOAc, washed with brine. The organic phase was dried (Na ₂ SO ₄ ) and filtered. The solvent was evaporated and triturated in Et ₂ O/heptane mixture and stirred at room temperature for 1 h. Afterwards, the title compound was collected as a white solid by filtration.

¹ H NMR (500MHz, DMSO-d ₆ ): δ13.67(br s, 1H), 7.67-7.62(m, 2H), 7.41(d, 1H), 7.12(t, 1H), 5.67(s, 2H ), 5.02-4.94 (m, 1H), 3.80-3.70 (m, 4H), 2.15-2.09 (m, 2H), 1.92-1.85 (m, 2H). MS: m/z 456.1 (MH ⁺ ).

Example 2

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

The less polar positional isomer [5-(5-{4-[2-(trifluoromethyl)phenoxy) obtained from Example 1, Step 4 in a similar manner as described in Example 1, Step 5 ]piperidin-1-yl}-1,3,4-thiadiazol-2-yl)-1H-tetrazol-1-yl]ethyl acetate The title compound was prepared. ¹ HNMR (500MHz, DMSO-d ₆ ): δ13.91(br s, 1H), 7.67-7.62(m, 2H), 7.41(d, 1H), 7.12(t, 1H), 5.80(s, 2H) , 5.01-4.94 (m, 1H), 3.78-3.67 (m, 4H), 2.15-2.09 (m, 2H), 1.91-1.84 (m, 2H). MS: m/z 456.1 (MH ⁺ ).

Example 3

(5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}-2H-tetra Azol-2-yl)acetic acid

Step 1: 5-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazole-2-carbonitrile

To a solution of 4-(2-bromo-5-fluorophenoxy)piperidine (15.16 g, 52.5 mmol) in 1,4-dioxane (80 mL) was added N,N-diisopropylethylamine in turn (Hunig's base or DEPEA) (20 mL, 115 mmol) and 5-bromo-1,3,4-thiadiazole-2-carbonitrile (10.02 g, 52.7 mmol). The mixture was stirred at room temperature for 1 h. The reaction was then poured into saturated aqueous _NH4Cl , extracted with EtOAc, washed with brine, dried ( _Na2SO4 ), filtered and _concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluting with 10-40% EtOAc/hexanes) to give the desired product as a colorless oil.

¹ H NMR (500MHz, acetone-d ₆ ): δ7.63(dd, 1H), 7.14(dd, 1H), 6.78(td, 1H), 5.04-4.99(m, 1H), 4.00-3.95(m, 2H), 3.89-3.84(m, 2H), 2.27-2.21(m, 2H), 2.11-2.05(m, 2H).

Step 2: 4-(2-Bromo-5-fluorophenoxy)-1-[5-(2H-tetrazol-5-yl)-1,3,4-thiadiazole-2- base] piperidine

The title compound was prepared in a manner similar to that described in Example 1, Step 3, using 5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiabis Azole-2-carbonitrile (15.6g), _NaN3 (13.2g, 204mmol) and pyridine hydrochloride (9.47g, 82.0mmol) in NMP (70mL) were purified by trituration in a MeOH/ _Et2O /heptane mixture The desired product was obtained as a white solid.

¹ H NMR (400MHz, acetone-d ₆ ): δ7.64(dd, 1H), 7.16(dd, 1H), 6.79(td, 1H), 5.04-5.00(m, 1H), 4.02-3.94(m, 2H), 3.89-3.81(m, 2H), 2.29-2.20(m, 2H), 2.12-2.03(m, 2H). MS: m/z 428.0, 426.0(MH ⁺ ).

Step 3: (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazole-2- base}-2H-tetrazol-2-yl) ethyl acetate and (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidine-1- Base]-1,3,4-thiadiazol-2-yl}-1H-tetrazol-1-yl)ethyl acetate

4-(2-bromo-5-fluorophenoxy)-1-[5-(2H-tetrazol-5-yl)-1,3,4- Thiadiazol-2-yl]piperidine (4.54 g, 10.66 mmol), NaH (60% in oil) (512 mg, 12.80 mmol) and ethyl bromoacetate (1.6 mL, 14.37 mmol) in DMF (20 mL), Purification by column chromatography on silica gel (eluting with 10-50% EtOAc/hexanes) yielded the title compound. The more polar isomer ( _Rf = 0.3 (50% EtOAc/hexanes)) as (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl] -1,3,4-Thiadiazol-2-yl}-2H-tetrazol-2-yl)ethyl acetate.

¹ H NMR (500MHz, DMSO-d ₆ ): δ7.64(dd, 1H), 7.29(dd, 1H), 6.82(td, 1H), 5.98(s, 2H), 4.93-4.89(m, 1H) , 4.24(q, 2H), 3.84-3.77(m, 2H), 3.72-3.66(m, 2H), 2.13-2.06(m, 2H), 1.90-1.83(m, 2H), 1.24(t, 3H) .

The less polar isomer ( _Rf = 0.5 (50% EtOAc/hexanes)) as (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl] -1,3,4-Thiadiazol-2-yl}-1H-tetrazol-1-yl)ethyl acetate.

¹ H NMR (500MHz, DMSO-d ₆ ): δ7.64(dd, 1H), 7.29(dd, 1H), 6.82(td, 1H), 5.79(s, 2H), 4.94-4.89(m, 1H) , 4.19(q, 2H), 3.86-3.80(m, 2H), 3.75-3.69(m, 2H), 2.12-2.06(m, 2H), 1.90-1.84(m, 2H), 1.20(t, 3H) .

Step 4: (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazole-2- Base}-2H-tetrazol-2-yl)acetic acid

(5-{5-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiabis(5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadi Azol-2-yl}-2H-tetrazol-2-yl) ethyl acetate (2.57 g) and 1 N NaOH (10 mL) in THF/MeOH (30 mL) (v/v) (0.1 M) in Et ₂ The title compound was prepared by trituration in O/heptane to give the desired product as a white solid. ¹ HNMR (400MHz, DMSO-d ₆ ): δ13.89(br s, 1H), 7.65(dd, 1H), 7.30(dd, 1H), 6.83(td, 1H), 5.84(s, 2H), 4.95 -4.88(m, 1H), 3.86-3.78(m, 2H), 3.74-3.66(m, 2H), 2.15-2.07(m, 2H), 1.92-1.84(m, 2H). MS: m/z 485.8 , 483.8 (MH ⁺ ).

Example 4

(5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}-1H-tetra Azol-1-yl)acetic acid

The less polar positional isomer (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidine) obtained from Example 3, Step 3 in a similar manner as described in Example 1, Step 5 -1-yl]-1,3,4-Thiadiazol-2-yl}-1H-tetrazol-1-yl)ethyl acetate The title compound was prepared. ¹ H NMR (400MHz, DMSO-d ₆ ): δ13.68(br s, 1H), 7.65(dd, 1H), 7.30(dd, 1H), 6.83(td, 1H), 5.68(s, 2H), 4.98-4.87(m, 1H), 3.88-3.80(m, 2H), 3.77-3.69(m, 2H), 2.15-2.07(m, 2H), 1.93-1.83(m, 2H). MS: m/z 486.0, 484.0 (MH ⁺ ).

Example 5

(2'-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-2,5'-two-1,3-thiazol-4-yl)ethyl acid

Step 1: 2-{4-[2-(Trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-carboxylic acid methanolate ester

Methyl 2-bromo-1,3-thiazole-5-carboxylate (10 g, 45 mmol) and 4-[2-(trifluoromethyl)phenoxy]piperidine (12.1 g, 50 mmol) were dissolved in dioxane ( 160 mL) was heated at 80-85°C overnight. After cooling, the compound was diluted with water and extracted with EtOAc. The EtOAc extract was washed twice with _water , dried ( _Na2SO4 ) and concentrated. The crude material was purified by silica gel column chromatography (eluting with 50% EtOAc/hexanes) to afford the title compound as a light yellow oil. ¹ H NMR (500MHz, CDCl ₃ ): δ7.90(s, 1H), 7.62(d, 1H), 7.51(t, 1H), 7.06-7.02(m, 2H), 4.82(d, 1H), 3.85 (s, 3H), 3.80-3.70 (m, 4H), 2.12-2.02 (m, 4H).

Step 2: 2-{4-[2-(Trifluoromethyl)phenoxy]piperidin-1-yl]-1,3-thiazole-5-carboxylic acid

Methyl 2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-carboxylate (16 g, 41.4 mmol) and 1N NaOH (85 mL, 85 mmol) in THF/MeOH (1:1) (v/v) (300 mL) was heated in a water bath at 80 °C for 1 h. Volatile solvents were removed in vacuo. The residue was diluted with _H2O , acidified with 1N HCl (2.2 equiv) and extracted with EtOAc. The EtOAc extracts _were washed with _H2O , dried ( _Na2SO4 ) and concentrated to afford the title compound as a white solid.

¹ H NMR (400MHz, acetone-d ₆ ): δ7.83(s, 1H), 7.69-7.60(m, 2H), 7.39(d, 1H), 7.13(t, 1H), 5.07-5.01(m, 1H), 3.86-3.72(m, 4H), 2.22-2.13(m, 2H), 2.06-1.96(m, 2H).

Step 3: 2-{4-[2-(Trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-carboxamide

To 2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-carboxylic acid (14.5g, 39mmol), HOBt in about 15min at room temperature (5.3g, 39mmol), HATU (23.7g, 62mmol) and _NH4Cl (6.3g, 117mmol) in DMF (200mL) was added Hünig's base (34mL, 195mmol). The mixture was stirred overnight at room temperature. After dilution with water, the mixture was extracted twice with EtOAc. The EtOAc extracts were combined, washed with 0.5N NaOH (2x), dilute brine (1x), _dried ( _Na2SO4 ) and concentrated. Trituration of the residue in _Et2O /hexanes (1:1) afforded the title compound as a light yellow solid. ¹ H NMR (500MHz, acetone-d ₆ ): δ7.79(s, 1H), 7.67-7.61(m, 2H), 7.38(d, 1H), 7.12(t, 1H), 5.02(s, 1H) , 3.76(t, 2H), 3.71-3.67(m, 2H), 2.16(t, 2H), 2.00-1.94(m, 2H).

Step 4: 2-{4-[2-(Trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-carbonitrile

The CH of 2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-carboxamide (4 g, 10.8 mmol) was cooled with an ice-acetone bath ₂ Cl ₂ (100 mL) suspension. Then _Tf2O (2.0 mL, 11.9 mmol) was added dropwise over about 10 min. The mixture was stirred for 5 min and then the cooling bath was removed. After continued stirring at room temperature for 15 min, the mixture was quenched with water and extracted _twice with _CH2Cl2 . The _CH2Cl2 extracts were combined, washed twice with dilute brine, _dried ( _Na2SO4 ) and _concentrated . The crude material was purified by silica gel column chromatography (40% EtOAc/hexanes) to afford the title compound as a light yellow solid.

¹ H NMR (400MHz, acetone-d ₆ ): δ7.88(s, 1H), 7.69-7.60(m, 2H), 7.39(d, 1H), 7.14(t, 1H), 5.09-5.03(m, 1H), 3.87-3.75(m, 4H), 2.24-2.15(m, 2H), 2.06-1.98(m, 2H).

Step 5: 2-{4-[2-(Trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-thioacyl amine

To a solution of 2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-carbonitrile (354 mg, 1.0 mmol) in dioxane was added Et ₃ N (20 μL, 0.14 mmol) was then bubbled into the solution with H ₂ S (gas) for about 1 min. After stirring at room temperature for 3 h, ethanol and 21 wt.% NaOEt ethanol solution (238 μL, 0.6 mmol) were added accordingly. Bubble more _H2S (g) into the solution for 1 min. The mixture was then stirred at room temperature for 3 days. Volatile materials were removed in vacuo. The residue was taken up with EtOAc, washed twice with water, _dried ( _Na2SO4 ) and concentrated. Trituration with _Et2O afforded the title compound as a light yellow solid.

¹ H NMR (400MHz, acetone-d ₆ ): δ8.52(s, 1H), 8.32(s, 1H), 7.82(s, 1H), 7.69-7.60(m, 2H), 7.39(d, 1H) , 7.13(t, 1H), 5.04(t, 1H), 3.84-3.69(m, 4H), 2.21-2.12(m, 2H), 2.05-1.95(m, 2H).MS(+ESI)m/z 388 (MH ⁺ ).

Step 6: (2'-{4-[2-(Trifluoromethyl)phenoxy]piperidin-1-yl)-2,5'-di-1,3-thiazole -4-yl) methyl acetate

2-{4-[2-(Trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-thioamide (240mg, 0.62mmol) and 4-chloroacetone acetic acid A mixture of the methyl ester (73 μL, 0.62 mmol) in methanol (3 mL) was heated in a sealed tube at 80-85° C. overnight. After cooling, the mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed twice with _water , dried ( _Na2SO4 ) and concentrated. The crude material was purified by silica gel column chromatography (30-60% EtOAc/hexanes) to afford the title compound as a light yellow gum. ¹ H NMR (400MHz, acetone-d ₆ ): δ7.72(s, 1H), 7.69-7.60(m, 2H), 7.39(d, 1H), 7.26(s, 1H), 7.13(t, 1H) , 5.06-5.00(m, 1H), 3.86-3.67(m, 9H), 2.23-2.14(m, 2H), 2.06-1.95(m, 2H). MS(+ESI) m/z 484(MH ⁺ ) .

Step 7: (2'-(4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-2,5'-di-1,3-thiazole-4- base) acetic acid

(2'-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-2,5'-di-1,3-thiazole- 4-yl)methyl acetate (220 mg, 0.44 mmol) in THF/MeOH (4:1) (v/v) (5 mL) and heated at reflux temperature for 2 h. Volatile solvents were removed in vacuo. The residue was diluted with water, acidified with 1N HCl and extracted with EtOAc. The EtOAc extract _was washed twice with water, dried ( _Na2SO4 ) and concentrated to give the title mixture as a yellow foam. ¹ H NMR (400MHz, acetone-d ₆ ): δ10.93(s, 1H), 7.72(s, 1H), 7.69-7.61(m, 2H), 7.39(d, 1H), 7.28(s, 1H) , 7.13(t, 1H), 5.07-5.01(m, 1H), 3.85-3.68(m, 6H), 2.23-2.14(m, 2H), 2.06-1.96(m, 2H).MS(+ESI)m /z 470(MH ⁺ ).

Example 6

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

Step 1: Ethyl 3-Bromo-4,5-dihydroisoxazole-5-carboxylate

To a vigorously stirred mixture of hydroxycarbonimidic dibromide (15.5 g, 76.4 mmol) and ethacrylate (15.3 g, 153 mmol) in DMF (200 mL) was added 15 wt% aqueous _KHCO3 (102 mL, 153 mmol) . The mixture was stirred overnight at room temperature. Water was added and extracted twice with methyl tert-butyl ether. The combined extracts were washed with brine, _dried ( _Na2SO4 ) and concentrated in vacuo to afford the title compound.

Step 2: 3-Bromo-4,5-dihydroisoxazole-5-carboxamide

A mixture of ethyl 3-bromo-4,5-dihydroisoxazole-5-carboxylate (6.2 g, 28 mmol) and 2M ammonia in MeOH (56 mL) was stirred at room temperature for 1-2 h. Volatile solvents were removed in vacuo to afford the crude title compound as a white solid.

Step 3: 3-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-4,5-dihydroisoxazole-5-carboxyl amine

3-Bromo-4,5-dihydroisoxazole-5-carboxamide (1.5g, 7.77mmol), 4-(2-bromo-5-fluorophenoxy)piperidine (2.56g, 9.33mmol) and a mixture of N,N-diisopropylethylamine (3.5 mL, 20.04 mmol) in ethanol (15 mL) was heated at reflux temperature overnight. Solvent was removed in vacuo. The residue was suspended in water and stirred for 1 h. The solid was collected, washed with water and _Et2O . Drying in vacuo afforded the title compound as a light brown powder.

¹ H NMR (500MHz, acetone-d ₆ ): δ7.61(dd, 1H), 7.07(dd, 1H), 7.02(s, 1H), 6.74(td, 1H), 6.63(s, 1H), 4.85 -4.78 (m, 2H), 3.56-3.50 (m, 2H), 3.40-3.23 (m, 4H), 2.10-1.05 (m, 2H), 1.89-1.82 (m, 2H).

Step 4: 3-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]isoxazole-5-carboxamide

To stirred 3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-4,5-dihydroisoxazole-5-carboxamide (2.3g, 5.96mmol) Iodine (2 g, 7.88 mmol) was added to a suspension of sodium acetate (1.3 g, 15.85 mmol) in chlorobenzene (15 mL). The mixture was heated at reflux temperature for 3 h. After cooling, _a solution _{of Na2S2O3 ,} water and EtOAc was added. The mixture was stirred for 5 min and filtered through celite to remove insoluble material. The organic phase was then separated, washed with brine, _dried ( _Na2SO4 ) and concentrated. The residue was triturated in _Et2O to afford the title compound as a pale tan powder. ¹ H NMR (500MHz, acetone-d ₆ ) δ7.61(m, 1H), 7.51(s, 1H), 7.10(dd, 2H), 6.78(s, 1H), 6.75(td, 1H), 4.89- 4.84 (m, 1H), 3.67-3.60 (m, 2H), 3.45-3.38 (m, 2H), 2.16-2.08 (m, 2H), 1.98-1.88 (m, 2H).

Step 5: 3-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]isoxazole-5-carbonitrile

3-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]isoxazole-5-carboxamide (1.6 g, 4.2 mmol) and Et ₃ N( To a suspension of 1.5 mL, 10.8 mmol) in _CH2Cl2 (20 mL) was added TFAA (0.8 mL, 5.7 _mmol ). A homogeneous solution was obtained. After the addition, the cooling bath was removed and the mixture was stirred at room temperature for 2 h. The mixture was quenched with water (10-15 mL) followed by saturated aqueous NaHCO ₃ (15-20 mL) and extracted with CH ₂ Cl ₂ (2×30 mL). The combined _CH2Cl2 extracts were washed with dilute brine (40 mL), _dried ( _Na2SO4 ) and _concentrated . Chromatography on silica gel eluting with hexanes:EtOAc (4:1) gave the title compound as a colorless gum.

¹ H NMR (400MHz, acetone-d ₆ ): δ7.62(dd, 1H), 7.33(s, 1H), 7.10(dd, 1H), 6.76(td, 1H), 4.93-4.86(m, 1H) , 3.71-3.63 (m, 2H), 3.52-3.44 (m, 2H), 2.18-2.09 (m, 2H), 1.99-1.90 (m, 2H).

Step 6: 4-(2-Bromo-5-fluorophenoxy)-1-[5-(1H-tetrazol-5-yl)isoxazol-3-yl]piperidine

3-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]isoxazole-5-carbonitrile (1.4g, 3.82mmol), pyridine hydrochloride (0.9g, 7.79mmol) and A mixture of sodium azide (1.3 g, 20.00 mmol) in NMP (12 mL) was stirred and heated in a 130 °C bath for 2 h. After cooling, the mixture was diluted with water and acidified with 1N HCl (some precipitate appeared). The whole mixture was extracted with EtOAc. The EtOAc extracts were washed with water ₍ 3x), dried ( _Na2SO4 ) and concentrated. Trituration of the residue in diethyl ether afforded the title compound as a pale tan powder.

¹ H NMR (400MHz, acetone-d ₆ ): δ7.63(dd, 1H), 7.12(m, 2H), 6.76(td, 1H), 4.93-4.88(m, 1H), 3.77-3.69(m, 2H), 3.55-3.47 (m, 2H), 2.21-2.13 (m, 2H), 2.02-1.92 (m, 2H).

Step 7: (5-{3-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]isoxazol-5-yl}-2H- Tetrazol-2-yl) ethyl acetate

4-(2-Bromo-5-fluorophenoxy)-1-[5-(1H-tetrazol-5-yl)isoxazol-3-yl]piperidine (1.2g, 2.93mmol), bromo A mixture of ethyl acetate (0.45 mL, 4.04 mmol) and triethylamine (0.75 mL, 5.38 mmol) in THF (12 mL) was heated at reflux temperature for 2 h. After cooling, the mixture was diluted with water and extracted with EtOAc. The EtOAc extracts were washed with _water , dried ( _Na2SO4 ) and concentrated. Combi-Flash chromatography (40 g, 25-40% EtOAc in hexanes for 20 min, 35 mL/min, 18 mL/fraction) gave the title compound as a colorless gum containing about 20% of the 1-alkylated isomer.

¹ H NMR (400MHz, acetone-d ₆ ): δ7.63(dd, 1H), 7.14-7.09(m, 1H), 7.03(s, 1H), 6.76(td, 1H), 5.84(s, 2H) , 4.93-4.87(m, 1H), 4.34-4.26(m, 2H), 3.77-3.68(m, 2H), 3.55-3.46(m, 2H), 2.21-2.12(m, 2H), 2.03-1.91( m, 2H), 1.30(t, 3H).

Step 8: (5-{3-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]isoxazol-5-yl)-2H- Tetrazol-2-yl)acetic acid

To (5-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]isoxazol-5-yl}-2H-tetrazol-2-yl)ethyl acetate (1.3 g, 2.62 mmol) in THF (15 mL) and MeOH (5 mL) was added 1 M sodium hydroxide (5.25 mL, 5.25 mmol). The mixture was stirred at room temperature for 1 h. Volatile solvents were removed in vacuo. The residue was diluted with water (20 mL), acidified with 1M HCl (6 mL) and extracted with EtOAc. The EtOAc extract was washed with _water , dried ( _Na2SO4 ) and concentrated. Trituration of the residue in diethyl ether gave the crude product, containing 5% of the 1-isomer. Further purification by trituration in isopropyl acetate (2x, 80°C overnight, then room temperature overnight) afforded the title compound as a beige powder.

¹ H NMR (400MHz, DMSO-d ₆ ): δ13.90(s, 1H), 7.63(dd, 1H), 7.29-7.24(m, 2H), 6.81(td, 1H), 5.86(s, 2H) , 4.84(m, 1H), 3.63-3.55(m, 2H), 3.43-3.33(m, 2H), 2.06-2.00(m, 2H), 1.78(d, 2H).MS(+ESI) m/z 467, 469.

Example 7

(3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl}-1H-pyridine pyrol-1-yl)acetic acid

Step 1: 4-(2-Bromo-5-fluorophenoxy)piperidine-1-carbonitrile

To a solution of 4-(2-bromo-5-fluorophenoxy)piperidine (2.0g, 7.30mmol) in THF (24.3ml) at 0°C, add cyanogen bromide (0.77g, 7.30mmol) and triethyl Amine (1.01ml, 7.3mmol). The mixture was warmed to room temperature and stirred for a further 1 h. The solvent was evaporated to dryness and the residue was diluted with 1N HCl (20 mL). The aqueous phase was extracted with EtOAc (3x10 mL). The combined organic phases were washed _with water (20 mL) and dried over _Na2SO4 . The solvent was evaporated to dryness under reduced pressure to give the title compound as a solid, which was used in the next step without further purification. ¹ H NMR (500MHz, acetone-d ₆ ): δ7.62(dd, 1H), 7.08(dd, 1H), 6.76(td, 1H), 4.88-4.84(m, 1H), 3.55-3.48(m, 2H), 3.32-3.25(m, 2H), 2.16-2.09(m, 2H), 1.99-1.91(m, 2H).

Step 2: 4-(2-Bromo-5-fluorophenoxy)-N'-hydroxypiperidine-1-carboximide

A solution of 4-(2-bromo-5-fluorophenoxy)piperidine-1-carbonitrile (1.6g, 5.3mmol), hydroxylamine hydrochloride (1.1g, 16.1mmol) and Na ₂ CO ₃ (2.3g, 92mmol) A mixture of EtOH/water 4:1 (26ml) was heated at 80°C for 1h. The solvent was evaporated to dryness. The residue was acidified with 6N HCl and washed with _Et2O (2x10 mL). The aqueous phase was made basic with solid _Na2CO3 , and the solvent was evaporated to dryness _under reduced pressure to give the title compound as a foam, which was used in the next step without further purification. MS: m/z 332,334 (MH ⁺ ).

Step 3: 4-(2-Bromo-5-fluorophenoxy)-1-[5-(1H-pyrrol-3-yl)-1,2,4-oxadiazole-3- base] piperidine

To a mixture of pyrrole-3-carboxylic acid hydrate (93 mg, 0.723 mmol) in THF (2007 μL) was added oxalyl chloride (264 μL, 3.01 mmol), DMF (10 μL) at 0°C. The mixture was warmed to room temperature and stirred for 0.5h. The solvent was evaporated to dryness, the residue was diluted with THF (1 mL), evaporated to dryness again and dried under high vacuum. The residue was diluted with THF (2007 μL), and 4-(2-bromo-5-fluorophenoxy)-N′-hydroxypiperidine-1-carboximide (200 mg, 0.602 mmol) and triethylamine (252 μL , 1.806 mmol). The mixture was stirred at room temperature for 0.5 h, then heated at 80 °C for 1 h. The mixture was cooled to room temperature and sodium hydride (72.2 mg, 1.806 mmol) was added. The mixture was stirred at room temperature for 0.5 h then heated at 80 °C for 1 h. The solvent was evaporated and the residue was diluted with water (2 mL). The aqueous phase was extracted with EtOAc (3x2 mL). The combined organic phases were dried over _Na2SO4 and the solvent was _evaporated . Purification by Combiflash chromatography (SiO2 _- 12g, 30-60% EtOAc/Hexane gradient elution over 25 min) afforded the title compound. ¹ H NMR (500MHz, acetone-d ₆ ): δ7.61(s, 2H), 7.11(s, 1H), 6.99(s, 1H), 6.75(s, 1H), 6.65(s, 1H), 4.89 (s, 1H), 3.76 (s, 2H), 3.54 (s, 2H), 1.99-1.82 (m, 2H), 2.10 (s, 2H). MS: m/z 407, 409 (MH ⁺ ).

Step 4: (3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole-5- Base}-1H-pyrrol-1-yl) ethyl acetate

To 4-(2-bromo-5-fluorophenoxy)-1-[5-(1H-pyrrol-3-yl)-1,2,4-oxadiazol-3-yl]piperidine (60mg, Sodium hydride (11.8 mg, 0.3 mmol) was added to a solution of 0.15 mmol) in DMF (491 μL). After 5 min, ethyl bromoacetate (25 μL, 0.22 mmol) was added and the mixture was heated at 80° C. for 3 h. The mixture was poured into ice-cold 1N HCl (2 mL) and extracted with EtOAc (3x2 mL). The combined organic fractions were washed with water (2 mL), then _dried over _Na2SO4 . The solvent was evaporated to dryness. Purification by Combiflash chromatography (SiO2 _- 12g, 30-60% EtOAc/Hexane gradient elution over 25 min) afforded the title compound. ¹ H NMR (500MHz, acetone-d ₆ ): δ7.64-7.58(m, 2H), 7.10(dd, 1H), 6.95(s, 1H), 6.75(td, 1H), 6.62(s, 1H) , 5.03-4.92(m, 2H), 4.88(s, 1H), 4.33-4.10(m, 2H), 3.80-3.72(m, 2H), 3.56-3.49(m, 2H), 2.17-2.06(m, 2H), 1.91 (dd, 2H), 1.31-1.18 (m, 3H). MS: m/z 493, 495 (MH ⁺ ).

Step 5: (3-{3-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole-5- Base}-1H-pyrrol-1-yl)acetic acid

To (3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl}-1H-pyrrole-1 -yl) Ethyl acetate (35 mg, 0.071 mmol) in THF (236 μL) and MeOH (118 μL) was added with 1N NaOH (142 μL, 0.142 mmol). The mixture was stirred at room temperature for 10 min. THF and MeOH were evaporated under reduced pressure and the aqueous layer was washed with _Et2O (2x2 mL). The aqueous layer was acidified to pH 1 with 1N HCl and extracted with EtOAc (3x2 mL). The combined organic fractions were dried over _Na2SO4 and _the solvent was evaporated to give the title compound.

¹ H NMR (500MHz, acetone-d ₆ ): δ7.62-7.56(m, 2H), 7.08(dd, 1H), 6.94(d, 1H), 6.72(td, 1H), 6.58(s, 1H) , 4.96(s, 2H), 4.87-4.83(m, 1H), 3.76-3.69(m, 2H), 3.53-3.47(m, 2H), 2.11-2.05(m, 2H), 1.92-1.84(m, 2H). MS: m/z 465, 467 (MH ⁺ ).

Example 8

(3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl}-1H-pyridine Azol-1-yl)acetic acid

Step 1: 4-(2-Bromo-5-fluorophenoxy)-1-[5-(1H-pyrazol-3-yl)-1,2,4-oxadiazole-3- base] piperidine

A mixture of 3-pyrazolecarboxylic acid (55.7 mg, 0.497 mmol) in thionyl chloride (989 μL, 13.55 mmol) was heated at 80° C. for 2 h. Excess thionyl chloride was removed by evaporation. The residue was diluted with THF (1 mL), evaporated and dried under high vacuum. The residue was dissolved with THF (1505 μL) and (2-bromo-5-fluorophenoxy)-N′-hydroxypiperidine-1-carboximide (150 mg, 0.452 mmol) and triethylamine (189 μL, 1.355 mmol). The mixture was heated at 80 °C for 1 h. The solvent was evaporated to dryness and saturated NaHCO ₃ (2 mL) was added. The aqueous layer was extracted with EtOAc (3x2 mL). The combined organic fractions were _dried over _Na2SO4 and the solvent was evaporated. Purification by Combiflash chromatography (SiO2 _- 12g, 20-50% EtOAc/Hexane gradient elution over 25 min) afforded the title compound.

¹ H NMR (500MHz, acetone-d ₆ ): δ12.90(s, 1H), 7.98(s, 1H), 7.62(dd, 1H), 7.11(dd, 1H), 6.95(s, 1H), 6.82 -6.72(m, 1H), 4.92-4.88(m, 1H), 3.83-3.76(m, 2H), 3.64-3.55(m, 2H), 2.17-2.11(m, 2H), 1.98-1.90(m, 2H). MS: m/z 408, 410 (MH ⁺ ).

Step 2: (3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole-5- Base}-1H-pyrazol-1-yl) ethyl acetate

From 4-(2-bromo-5-fluorophenoxy)-1-[5-(1H-pyrazol-3-yl)-1,2,4 in a similar manner as described in Example 7 (step 4) -Oxadiazol-3-yl]piperidine, sodium hydride and ethyl bromoacetate prepared the title compound to give the more polar isomer. ¹ H NMR (500MHz, acetone-d ₆ ): δ7.69(s, 1H), 7.62(dd, 1H), 7.13-7.08(m, 2H), 6.76(td, 1H), 5.48(s, 2H) , 4.92(t, 1H), 4.29-4.17(m, 2H), 3.81-3.72(m, 2H), 3.62-3.55(m, 2H), 2.17-2.10(m, 2H), 1.98-1.90(m, 2H), 1.27-1.21 (m, 3H). MS: m/z 494, 496 (MH ⁺ ).

The less polar isomer isolated was (5-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole- 5-yl}-1H-pyrazol-1-yl) ethyl acetate. ¹ H NMR (500MHz, acetone-d ₆ ): δ7.69(s, 1H), 7.62(dd, 1H), 7.13-7.08(m, 2H), 6.76(td, 1H), 5.48(s, 2H) , 4.92(t, 1H), 4.29-4.17(m, 2H), 3.81-3.72(m, 2H), 3.62-3.55(m, 2H), 2.17-2.10(m, 2H), 1.98-1.90(m, 2H), 1.27-1.21 (m, 3H). MS: m/z 494, 496 (MH ⁺ ).

Step 3: (3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole-5- Base}-1H-pyrazol-1-yl)acetic acid

From (3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxa The title compound was prepared from ethyl oxazol-5-yl}-1H-pyrazol-1-yl)acetate and aqueous NaOH. ¹ H NMR (500MHz, acetone-d ₆ ): δ7.97(s, 1H), 7.62(t, 1H), 7.12(d, 1H), 6.94(s, 1H), 6.75(s, 1H), 5.22 (s, 2H), 4.91 (s, 1H), 3.82-3.75 (m, 2H), 3.63-3.57 (m, 2H), 2.16-2.07 (m, 2H), 1.94 (s, 2H). MS: m /z 466, 468 (MH ⁺ ).

Example 9

(5-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl)-1,2,4-oxadiazol-5-yl}-1H-pyridine Azol-1-yl)acetic acid

From (5-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxa The title compound was prepared from ethyl oxazol-5-yl}-1H-pyrazol-1-yl)acetate and aqueous NaOH. ¹ H NMR (500MHz, acetone-d ₆ ): δ7.68(d, 1H), 7.62(dd, 1H), 7.14-7.08(m, 2H), 6.76(td, 1H), 5.49(s, 2H) , 4.93-4.89(m, 1H), 3.81-3.74(m, 2H), 3.66-3.55(m, 2H), 2.16-2.10(m, 2H), 1.98-1.88(m, 2H).MS: m/ z 466,468 (MH ⁺ ).

Example 10

(4-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl}-1H-pyridine Azol-1-yl)acetic acid

Step 1: 4-(2-Bromo-5-fluorophenoxy)-1-[5-(1H-pyrazol-4-yl)-1,2,4-oxadiazole-3- base] piperidine

From 4-pyrazolecarboxylic acid, thionyl chloride and (2-bromo-5-fluorophenoxy)-N'-hydroxypiperidine-1-carbimide in a similar manner as described in Example 8 (step 1) Preparation of the title compound. ¹ H NMR (500MHz, acetone-d ₆ ): δ12.82(s, 1H), 8.48(s, 1H), 8.11-7.96(m, 1H), 7.62(dd, 1H), 7.11(dd, 1H) , 6.75(td, 1H), 4.92-4.88(m, 1H), 3.80-3.73(m, 2H), 3.59-3.52(m, 2H), 2.17-2.11(m, 2H), 1.98-1.88(m, 2H). MS: m/z 408, 410 (MH ⁺ ).

Step 2: (4-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole-5- Base}-1H-pyrazol-1-yl) ethyl acetate

From 4-(2-bromo-5-fluorophenoxy)-1-[5-(1H-pyrazol-4-yl)-1,2,4- Oxadiazol-3-yl]piperidine, sodium hydride and ethyl bromoacetate to prepare the title compound.

¹ H NMR (500MHz, acetone-d ₆ ): δ8.47(s, 1H), 8.04-7.99(m, 1H), 7.62(dd, 1H), 7.11(dd, 1H), 6.75(td, 1H) , 5.19(s, 2H), 4.92-4.88(m, 1H), 4.30-4.19(m, 2H), 3.80-3.70(m, 2H), 3.59-3.52(m, 2H), 2.15-2.09(m, 2H), 1.96-1.88 (m, 2H), 1.27 (t, 3H). MS: m/z 494, 496 (MH ⁺ ).

Step 3: (4-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2.4-oxadiazole-5- Base}-1H-pyrazol-1-yl)acetic acid

From (4-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadi The title compound was prepared from ethyl azol-5-yl}-1H-pyrazol-1-yl)acetate and aqueous NaOH.

¹ H NMR (500MHz, acetone-d ₆ ): δ8.48(s, 1H), 8.03(s, 1H), 7.62(dd, 1H), 7.11(dd, 1H), 6.75(td, 1H), 5.20 (s,2H), 4.90(s,1H), 3.80-3.74(m,2H), 3.59-3.52(m,2H), 2.15-2.08(m,2H), 1.95-1.89(m,2H).MS : m/z 466,468 (MH ⁺ ).

Example 11

(5-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl)-2H-tetrazole -2-yl)sodium acetate

Step 1: 3-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole-5-carboxamide

To (2-bromo-5-fluorophenoxy)-N'-hydroxypiperidine-1-carbimide (14.5g, 43.7mmol) and pyridine (10.59mL, 131mmol) in THF (146ml) at 0°C To the solution was added methyl oxalyl chloride (8.91 mL, 96 mmol). The mixture was warmed to room temperature and stirred for 1 h. The solvent was evaporated to dryness and the residue was diluted with 1N HCl (200 mL). The aqueous layer was extracted with EtOAc (3x200 mL). The combined organic portions were washed with brine (200 mL), dried over _Na2SO4 and the solvent was evaporated _under reduced pressure. Purification by Combiflash chromatography ( _SiO2 - 300 g, 80-100% EtOAc/Hexane gradient elution over 40 min) afforded 3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1 , 2,4-Oxadiazole-5-carboxylic acid methyl ester as a less polar compound and (6E)-7-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]- 3,4,9-Trioxo-2,5-dioxa-6,8-diazadec-6-en-10-oic acid methyl ester as a more polar compound. The two compounds were combined and dissolved in MeOH (146 mL), cooled to 0 °C, sparged with ammonia gas for 5 min and stirred at 0 °C for 15 min. The mixture was then warmed to room temperature and stirring was continued for 4 h. The mixture was diluted with _Et2O (100 mL). The solid was filtered and washed with _Et2O . The filtrate was evaporated to dryness and dried in vacuo. The crude product was filtered on silica gel and eluted with 2:1 EtOAc/hexanes. The solvent was evaporated to dryness to give the title compound. MS: m/z 585,587 (MH ⁺ ).

Step 2: 3-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole-5-carbonitrile

3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole-5-carboxamide (11g, 28.6mmol) and To a solution of triethylamine (12.74ml, 91mmol) in THF (95ml) was added dropwise trifluoroacetic anhydride (6.05mL, 42.8mmol). The mixture was warmed to room temperature and stirring was continued for 30 min. The solvent was evaporated to dryness and the residue was diluted successively with _Et2O (50 mL) and dilute _NaHCO3 solution (100 mL). The aqueous layer was extracted with _Et2O (3x100 mL). The combined organic fractions were dried over _Na2SO4 and the solvent was evaporated _under reduced pressure. Purification by Combiflash chromatography ( _SiO2 - 120 g, 10-30% EtOAc/Hexane gradient elution over 25 min) afforded the title compound.

¹ H NMR (500MHz, acetone-d ₆ ): δ7.62(dd, 1H), 7.11(dd, 1H), 6.76(td, 1H), 4.95-4.90(m, 1H), 3.80-3.73(m, 2H), 3.62 (ddd, 2H), 2.17-2.10 (m, 2H), 1.98-1.91 (m, 2H).

Step 3: 4-(2-Bromo-5-fluorophenoxy)-1-[5-(1H-tetrazol-5-yl)-1,2,4-oxadiazole-3- base] piperidine

3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole-5-carbonitrile (8g, 21.79mmol), sodium azide (2.125g, 32.7mmol) and ammonium chloride (5.83g, 109mmol) in DMF (43.6ml) was heated at 100°C for 0.5h. The mixture was cooled to RT, diluted with 1N NaOH (50 mL), washed with _Et2O (2x50 mL). The aqueous layer was acidified to pH ~1 with 2N HCl and extracted with EtOAc (3x75 mL). _The combined organic fractions were washed with water (2x50 mL), then dried over _Na2SO4 . The solvent was evaporated to dryness under reduced pressure and the product was dissolved in a small amount of EtOAc and precipitated with hexane. The solid was filtered and washed with hexanes to give the title compound. MS: m/z 410,412 (MH ⁺ ).

Step 4: (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole-3- Base}-2H-tetrazol-2-yl) ethyl acetate

To 4-(2-bromo-5-fluorophenoxy)-1-[5-(1H-tetrazol-5-yl)-1,2,4-oxadiazol-3-yl]piperidine (2g , 4.88mmol) in DMF (16.25ml) was added sodium hydride (0.390g, 9.75mmol). After 5 min, ethyl bromoacetate (1.352ml, 12.19mmol) was added and the mixture was heated at 80°C for 0.5h. The reaction mixture was cooled to room temperature, then poured into ice-cold 0.5N HCl (100 mL) and extracted with EtOAc (3x25 mL). _The combined organic portions were washed with water (50 mL) and dried over _Na2SO4 . The solvent was evaporated to dryness under reduced pressure. Purification by Combiflash chromatography ( _SiO2 - 120 g, 0-10% _Et2O / _CHCl3 gradient elution over 25 min) afforded the title product as the less polar isomer.

¹ H NMR (500MHz, acetone-d ₆ ): δ7.63(dd, 1H), 7.13(dd, 1H), 6.76(td, 1H), 5.92(s, 2H), 4.97-4.92(m, 1H) , 4.31(q, 2H), 3.88-3.78(m, 2H), 3.70-3.62(m, 2H), 2.21-2.13(m, 2H), 2.01-1.93(m, 2H), 1.31(t, 3H) .

The more polar isomer isolated was (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole- 3-yl}-1H-tetrazol-2-yl) ethyl acetate. ¹ H NMR (500MHz, acetone-d ₆ ): δ7.63(dd, 1H), 7.12(dd, 1H), 6.77(td, 1H), 5.87(s, 2H), 4.97-4.93(m, 1H) , 4.29(q, 2H), 3.85-3.77(m, 2H), 3.69-3.62(m, 2H), 2.19-2.12(m, 2H), 2.01-1.93(m, 2H), 1.30-1.24(m, 3H).

Step 5: (5-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole-5- base}-2H-tetrazol-2-yl)sodium acetate

To (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-3-yl}-2H-tetrazole- 2-yl) Ethyl acetate (1.65g, 3.32mmol) in THF (11.08ml) and MeOH (5.54ml) was added IN NaOH (3.32ml, 3.32mmol) and the mixture was stirred at room temperature for 10min. THF and MeOH were evaporated to dryness. The aqueous layer was diluted with water (2 mL) and washed with _Et2O (2x10 mL). Lyophilize the aqueous layer to give the title compound.

¹ H NMR (500MHz, DMSO-d ₆ ): δ7.63(dd, 1H), 7.27(dd, 1H), 6.80(td, 1H), 5.07(s, 2H), 4.89-4.84(m, 1H) , 3.74-3.66 (m, 2H), 3.57-3.50 (m, 2H), 2.07-2.00 (m, 2H), 1.83-1.77 (m, 2H). MS: m/z 468, 470 (MH ⁺ ).

Example 12

From (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]- The title compound was prepared from ethyl 1,2,4-oxadiazol-3-yl}-1H-tetrazol-2-yl)acetate and 1N NaOH. ¹ H NMR (500MHz, DMSO-d ₆ ): δ7.66-7.58(m, 1H), 7.27(dd, 1H), 6.82-6.75(m, 1H), 5.05(s, 2H), 4.87(s, 1H), 3.71-3.63 (m, 2H), 3.55-3.48 (m, 2H), 2.04 (d, 2H), 1.80 (d, 2H). MS: m/z 468, 470 (MH ⁺ ).

Example 13

3-(3-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}-1,2, 4- Oxadiazol-5-yl)propionic acid

Step 1: 5-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-N'-hydroxy-1,3,4-thiadiazole-2- Carboimide

From 5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazole-2- Nitrile and hydroxylamine hydrochloride to prepare the title compound.

Step 2: 3-(3-(5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl)-1,3.4-thiadiazole-2- Base}-1,2,4-oxadiazol-5-yl) ethyl propionate

5-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-N'-hydroxy-1,3,4-thiadiazole-2-carboximide (500mg, 1.2 mmol) was dissolved in _CH2Cl2 (5 mL) and cooled to 0 °C in an ice-water bath _. To this solution was added pyridine (0.155 mL, 1.92 mmol) followed by ethyl 3-chloro-3-oxopropanoate (270 mg, 1.8 mmol). After stirring for 1 h, the solvent was removed in vacuo. The residue was dissolved in pyridine (8 mL) and stirred at 90°C overnight. Solvent was removed and the residue was partitioned between EtOAc and water. The combined organic layers were dried over anhydrous _Na2SO4 , filtered and evaporated to dryness _in vacuo. The crude product was purified by preparative TLC to afford the title compound.

¹ H NMR (400MHz, CDCl ₃ ): δ7.48-7.52(m, 1H), 6.61-6.70(m, 2H), 4.70-4.72(m, 1H), 4.14-4.19(m, 2H), 3.78- 3.92 (m, 4H), 3.28 (t, 2H), 2.96 (t, 2H), 2.03-2.10 (m, 4H), 1.24-1.27 (m, 3H).

Step 3: 3-(3-{5-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazole-2- Base}-1,2,4-oxadiazol-5-yl)propionic acid

From 3-(3-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4- The title compound was prepared from ethyl thiadiazol-2-yl}-1,2,4-oxadiazol-5-yl)propanoate and 1N NaOH.

¹ H NMR (400MHz, CDCl ₃ ): δ7.48-7.52(m, 1H), 6.61-6.70(m, 2H), 4.70-4.72(m, 1H), 3.85-3.92(m, 2H), 3.77- 3.83 (m, 2H), 3.29 (t, 2H), 3.05 (t, 2H), 2.03-2.10 (m, 4H). MS: m/z 498 (MH ⁺ ).

Example 14

(5-{3-[4-(5-bromo-2-chlorophenoxy)piperidin-1-yl]isoxazol-5-yl}-2H-tetrazol-2-yl) Acetic acid

Step 1: 4-(5-Bromo-2-chlorophenoxy)piperidine

The title compound was prepared in a similar manner as described for Intermediate 1 from tert-butyl 4-hydroxypiperidine-1-carboxylate and 5-bromo-2-chlorophenol.

Step 2: (5-{3-[4-(5-bromo-2-chlorophenoxy)piperidin-1-yl]isoxazol-5-yl}-2H-tetra Azol-2-yl)acetic acid

From 3-bromo-4,5-dihydroisoxazole-5-carboxamide and 4-(5-bromo-2-chlorophenoxy)piperidine in a similar manner as described in Example 6 (steps 3 to 8) Preparation of the title compound.

¹ H NMR (500MHz, acetone-d ₆ ): δ7.47(d, 1H), 7.39(d, 1H), 7.18(dd, 1H), 7.01(s, 1H), 5.81(s, 2H), 4.94 -4.89(m, 1H), 3.76-3.69(m, 2H), 3.49-3.42(m, 2H), 2.20-2.14(m, 2H), 1.99-1.91(m, 2H).MS(+ESI): m/z 483, 485 (MH ⁺ ).

Example 15

3-(3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl}-1H-pyridine Azol-1-yl)propionic acid

Step 1: 3-(3-{3-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole-5- Base)-1H-pyrazol-1-yl) ethyl propionate

From 4-(2-bromo-5-fluorophenoxy)-1-[5-(1H-pyrazol-3-yl)-1,2,4- Oxadiazol-3-yl]piperidine, sodium hydride and ethyl 3-bromopropionate prepared the title compound and obtained it as the more polar major isomer.

¹ H NMR (500MHz, acetone-d ₆ ): δ7.91-7.86(m, 1H), 7.62(dd, 1H), 7.11(dd, 1H), 6.87(d, 1H), 6.75(td, 1H) , 4.92-4.88(m, 1H), 4.58(t, 2H), 4.15-4.04(m, 2H), 3.82-3.75(m, 2H), 3.65-3.53(m, 2H), 3.00(t, 2H) , 2.17-2.11 (m, 2H), 1.99-1.89 (m, 2H), 1.21 (t, 3H). MS: m/z 508, 510 (MH ⁺ ).

Step 2: 3-(3-{3-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole-5- base}-1H-pyrazol-1-yl)propionic acid

To 3-(3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl}-1H-pyridine To a solution of ethyl azol-1-yl)propionate (75 mg, 0.148 mmol) in dioxane (492 μL) was added acetic acid (253 μL, 4.43 mmol) and concentrated HCl (363 μL, 4.43 mmol). The mixture was heated at 90 °C for 1 h. The solvent was evaporated to one third of its volume, diluted with water (2 mL) and extracted with EtOAc (2x2 mL). The combined organic portions were extracted with 1N NaOH (1 mL), the aqueous layer was acidified with 2N HCl (1 mL) and extracted with EtOAc (3x2 mL). The combined organic fractions were _dried over _Na2SO4 and the solvent was evaporated. The product was triturated in hexanes (2x2 mL) and dried under high vacuum to afford the title compound.

¹ H NMR (500MHz, acetone-d ₆ ): δ10.95(s, 1H), 7.90(s, 1H), 7.62(dd, 1H), 7.11(dd, 1H), 6.87(s, 1H), 6.75 (td, 1H), 4.90(d, 1H), 4.57(t, 2H), 3.83-3.68(m, 2H), 3.61-3.54(m, 2H), 3.03(t, 2H), 2.16-2.11(m , 2H), 1.96-1.89 (m, 2H). MS: m/z 480, 482 (MH ⁺ ).

Example 16

(2R)-3-(3-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazole-2- base}-1,2,4-oxadiazol-5-yl)2-hydroxypropionic acid

Step 1: [(4R)-2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid

To a suspension of D-(+)-malic acid (10 g, 75 mmol) in CH ₂ Cl ₂ (100 mL) was added 2,2-dimethylpropyl ether (23 g, 225 mmol) and p-toluenesulfonic acid (0.129 g, 0.75 mmol). The reaction mixture was stirred at room temperature for 4 h, filtered on silica gel (50% EtOAc/hexanes) and concentrated to give the title compound.

¹ H NMR (300MHz, CDCl ₃ ): δ9.70(s, 1H), 4.69-4.73(m, 1H), 2.97-3.04(m, 1H), 2.81-2.89(m, 1H), 1.62(s, 3H), 1.57(s, 3H).

Step 2: [(4R)-2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl]acetyl fluoride

[(4R)-2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (100 mg, 0.6 mmol) in _CH2Cl2 (2 _mL ) was mixed at 0 °C (Diethylamino)sulfur trifluoride (DAST) (111 mg, 0.7 mmol) was added to the suspension and the resulting solution was stirred at 0 °C for 1 h. More _CH2Cl2 (10 _mL ) was added. The whole mixture was washed twice with cold water, dried over anhydrous _Na2SO4 , filtered and evaporated to dryness _in vacuo to afford the title compound. ¹ H NMR (400MHz, CDCl ₃ ): δ4.68-4.71(m, 1H), 3.11-3.17(m, 1H), 2.98-3.04(m, 1H), 1.64(s, 3H), 1.58(s, 3H).

Step 3: (5R)-5-[(3-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadi Azol-2-yl}-1,2,4-oxadiazol-5-yl)methyl]-2,2-dimethyl-1,3-dioxolan-4-one

From 5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-N'-hydroxyl-1,3,4-thiadiazole in a similar manner as described in Example 13, step 2 -2-Carboximide and [(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetyl fluoride to prepare the title compound. ¹ H NMR (400MHz, CDCl ₃ ): δ7.51(dd, 1H), 6.62-6.70(m, 2H), 5.00(m, 1H), 4.71(m, 1H), 3.86-3.93(m, 2H) , 3.78-3.83(m, 2H), 3.58-3.63(m, 1H), 3.38-3.44(m, 1H), 2.04-2.10(m, 4H), 1.62(s, 3H), 1.59(s, 3H) .

Step 4: (2R)-3-(3-(5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazole -2-yl}-1,2,4-oxadiazol-5-yl)-2-hydroxypropionic acid

To (5R)-5-[(3-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazol-2-yl }-1,2,4-oxadiazol-5-yl)methyl]-2,2-dimethyl-1,3-dioxolan-4-one (200 mg, 0.36 mmol) in MeOH (5 mL ) suspension was added KOH (61 mg, 1.08 mmol). The resulting solution was stirred at room temperature overnight, adjusted to pH 1 with HCl solution (1 mol/L), and then extracted with EtOAc. The combined organic layers were dried over anhydrous _Na2SO4 , filtered and evaporated to dryness _in vacuo. The crude product was purified by preparative HPLC to afford the title compound.

¹ H NMR (300MHz, MeOH-d ₄ ): δ7.55(dd, 1H), 7.01(dd, 1H), 6.65-6.72(m, 1H), 4.80(m, 1H), 4.70(m, 1H) , 3.85-3.93(m, 2H), 3.72-3.80(m, 2H), 3.48-3.54(m, 1H), 3.35(m, 1H), 2.08-2.17(m, 2H), 1.98-2.06(m, 2H). MS: m/z 514 (MH ⁺ ).

Example 17

(2S)-3-(3-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazole-2- Base]-1,2,4-oxadiazol-5-yl)-2-hydroxypropionic acid

From 5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-N'-hydroxyl-1,3,4-thiadiazole-2 in a similar manner as described in Example 16 -Carboximide and (S)-(-)-malic acid to prepare the title compound.

¹ H NMR (400MHZ, acetone-d ₆ ): δ7.48(dd, 1H), 7.00(dd, 1H), 6.60-6.65(m, 1H), 4.83-4.87(m, 1H), 4.50-4.53( m, 1H), 3.76-3.82(m, 2H), 3.64-3.70(m, 2H), 3.37-3.42(m, 1H), 3.21-3.27(m, 1H), 2.04-2.11(m, 2H), 1.90 (m, 2H). MS: m/z 514 (MH ⁺ ).

Example 18

3-(3-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}-1,2, 4- Oxadiazol-5-yl)-L-alanine

Step 1: N-(trifluoroacetyl)-L-aspartic acid α-ethyl ester

To a suspension of L-aspartic acid (10 g, 75 mmol) in THF was added TFAA (133 g, 635 mmol) at 0° C. within 0.5 h. After the addition, the suspension was warmed to room temperature and stirring was continued for 3 h. Solvent was removed in vacuo. The white residue was heated to reflux in EtOH (200 mL) under _N2 for 30 min. The solvent was removed in vacuo to give the title compound. ¹ H NMR (400MHz, CDCl ₃ ): δ7.44(d, 1H), 4.80-4.84(m, 1H), 4.27(q, 2H), 3.15-3.20(m, 1H), 2.96-3.20(m, 1H), 1.29(t, 3H).

Step 2: Ethyl N-(trifluoroacetyl)-L-β-aspartyl chloride

To a solution of α-ethyl N-(trifluoroacetyl)-L-aspartate (3 g, 11.7 mmol) in anhydrous toluene (15 mL) was added _SOCl2 (3 mL). After stirring at reflux for 1 h, the solution was cooled to room temperature. The mixture was filtered and the solids were washed with cold toluene. Dry the solid to give the title compound. ¹ H NMR (400MHz, CDCl ₃ ): δ4.71-4.75(m, 1H), 4.28-2.36(m, 2H), 3.64-3.70(m, 1H), 3.56-3.61(m, 1H), 1.31( t, J=6Hz, 3H).

Step 3: 3-(3-{5-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazole-2- Base}-1,2,4-oxadiazol-5-yl)-N-(trifluoroacetyl)-L-alanine ethyl ester

From 5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-N'-hydroxyl-1,3,4-thiadiazole in a similar manner as described in Example 13, step 2 -2-Carboximide and ethyl N-(trifluoroacetyl)-L-β-aspartyl chloride to prepare the title compound.

¹ H NMR (400MHz, CDCl ₃ ): δ8.02(d, 1H), 7.50(dd, 1H), 6.62-6.70(m, 2H), 5.05-5.10(m, 1H), 4.71(m, 1H) , 4.26(q, 2H), 3.86-3.93(m, 2H), 3.78-3.83(m, 2H), 3.66-3.72(m, 1H), 3.57-3.66(m, 1H), 2.04-2.10(m, 4H), 1.26(t, 3H).

Step 4: 3-(3-{5-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazole-2- Base}-1,2,4-oxadiazol-5-yl)-L-alanine

To 3-(3-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}-1,2 , To a suspension of ethyl 4-oxadiazol-5-yl)-N-(trifluoroacetyl)-L-alanine (550 mg, 0.86 mmol) in EtOH (5 mL) and water (5 mL) was added NaOH (104 mg, 2.6 mmol) and the resulting solution was stirred at room temperature overnight. The solution was adjusted to pH 7 with HCl solution (1 mol/L), then extracted with EtOAc. The combined organic layers were dried over anhydrous _Na2SO4 , filtered and evaporated to _dryness in vacuo. The crude product was washed with petroleum ether/EtOAc to afford the title compound.

¹ H NMR (400MHz, MeOH-d ₄ ): δ7.56(dd, 1H), 7.04(dd, 1H), 6.68-6.73(m, 1H), 4.90(m, 1H), 4.11-4.15(m, 1H), 3.88-3.95(m, 2H), 3.76-3.88(m, 2H), 3.66-3.74(m, 1H), 3.47-3.52(m, 1H), 2.10-2.20(m, 2H), 2.00- 2.06 (m, 2H). MS: m/z 513 (MH ⁺ ).

Example 19

{5-[3-(4-{[4-chloro-4'-(trifluoromethoxy)biphenyl-3-yl]oxy}piperidin-1-yl)isoxazole -5-yl]-2H-tetrazol-2-yl}acetic acid

To (5-{3-[4-(5-bromo-2-chlorophenoxy)piperidin-1-yl]isoxazol-5-yl}-2H-tetrazol-2-yl)acetic acid (130mg , 0.269mmol), [4-(trifluoromethoxy)phenyl]boronic acid (98mg, 0.476mmol) and Pd(Ph ₃ P) ₄ (25mg, 0.022mmol) in toluene (4mL) suspension was added 2M _Na2CO3 (1.5 mL, 3.00 mmol) _in water. After purging the resulting heterogeneous mixture with nitrogen, it was stirred and heated slowly to 80 °C under nitrogen for 6 h. After cooling to room temperature, the reaction was poured into 1N aqueous HCl and extracted with EtOAc. The organic layer was washed with brine and _dried ( _Na2SO4 ). The solvent was removed under reduced pressure and the crude material was purified by column chromatography on silica gel (gradient of 0% to 3% HOAc/EtOAc). After concentration, the white solid was coevaporated to dryness twice and triturated in _Et2O /heptane to afford the title compound as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ): δ13.92(br s, 1H), 7.88-7.83(m, 2H), 7.57-7.54(m, 2H), 7.49(d, 2H), 7.30(dd , 1H), 7.27(s, 1H), 5.83(s, 2H), 5.00-4.93(m, 1H), 3.68-3.60(m, 2H), 3.41-3.35(m, 2H), 2.12-2.02(s , 2H), 1.87-1.78 (m, 2H). MS: m/z 565 (MH ⁺ ).

Example 20

(5-{2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3-oxazol-4-yl}-2H-tetrazole-2- base) acetic acid

Step 1: 2-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,3-oxazole-4-carboxylic acid ethyl ester

To a solution of 4-(2-bromo-5-fluorophenoxy)piperidine (3.281 g, 11.97 mmol) in EtOH (28.5 mL) was added ethyl 2-chlorooxazole-4-carboxylate (1 g, 5.70 mmol) and DIPEA (1.990 mL, 11.39 mmol). The reaction mixture was stirred at room temperature for 5 h. The solvent was evaporated to dryness under reduced pressure. The residue was diluted with 1N HCl and extracted with EtOAc. The combined organic layers were dried ( _MgSO4 ), filtered and evaporated to dryness under reduced pressure to give the title compound.

¹ H NMR (500MHz, acetone-d ₆ ): δ8.02(s, 1H), 7.59(dd, 1H), 7.08(dd, 1H), 6.73(td, 1H), 4.89-4.85(m, 1H) , 4.25(q, 2H), 3.79-3.72(m, 2H), 3.64-3.57(m, 2H), 2.12-2.06(m, 2H), 1.94-1.86(m, 2H), 1.28(t, 3H) .MS (+ESI) m/z 413 (MH ⁺ ).

Step 2: 2-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,3-oxazole-4-carboxamide

Dissolve ethyl 2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3-oxazole-4-carboxylate (2.26 g, 5.47 mmol) in a sealed test tube in MeOH (9 mL). The reaction mixture was cooled to 0 °C and ammonia gas was bubbled through the solution for 5 min. The reaction mixture was stirred at 60 °C for 15 h. The solvent was evaporated to dryness under reduced pressure. The purification residue was triturated overnight in diethyl ether to give the title compound.

¹ H NMR (400MHz, acetone-d ₆ ): δ7.82(s, 1H), 7.59(dd, 1H), 7.08(dd, 1H), 6.96(s, 1H), 6.73(d, 1H), 6.52 (s, 1H), 4.90-4.85(m, 1H), 3.76-3.72(m, 2H), 3.64-3.60(m, 2H), 2.10-2.05(m, 2H), 1.93-1.89(m, 2H) .MS (+ESI) m/z 386 (MH ⁺ ).

Step 3: 2-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,3-oxazole-4-carbonitrile

The title was prepared from 2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3-oxazole-4-carboxamide in a similar manner as described in Example 6, Step 5 compound.

¹ H NMR (400MHz, acetone-d ₆ ): δ8.24(s, 1H), 7.59(dd, 1H), 7.08(dd, 1H), 6.73(td, 1H), 4.91-4.87(m, 1H) , 3.77-3.73(m, 2H), 3.68-3.62(m, 2H), 2.11-2.05(m, 2H), 1.95-1.91(m, 2H). MS(+ESI) m/z 366(MH ⁺ ) .

Step 4: 4-(2-Bromo-5-fluorophenoxy)-1-[4-(2H-tetrazol-5-yl)-1,3-oxazol-2-yl] piperidine

The title compound was prepared in a similar manner as described in Example 11, Step 3 from 2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3-oxazole-4-carbonitrile.

¹ H NMR (500MHz, acetone-d ₆ ): δ8.21(s, 1H), 7.61(dd, 1H), 7.09(dd, 1H), 6.74(dt, 1H), 4.92-4.90(m, 1H) , 3.84-3.79(m, 2H), 3.71-3.67(m, 2H), 2.16-2.11(m, 2H), 1.98-1.91(m, 2H). MS(+ESI) m/z 409(MH ⁺ ) .

Step 5: (5-(2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3-oxazol-4-yl}-2H- Tetrazol-2-yl) ethyl acetate

From 4-(2-bromo-5-fluorophenoxy)-1-[4-(2H-tetrazol-5-yl)-1,3-oxazole-2 in a similar manner as described in Example 6, step 7 -yl]piperidine and ethyl bromoacetate to prepare the title compound. Purification of the positional isomer mixture by Combiflash chromatography (SiO2 _- 12g, 15-50% EtOAc/hexanes gradient elution over 25 min) gave the title product as the more polar isomer.

¹ H NMR (500MHz, acetone-d ₆ ): δ8.10(s, 1H), 7.59(dd, 1H), 7.09(dd, 1H), 6.74(dd, 1H), 5.67(s, 2H), 4.93 -4.87(m, 1H), 4.26(q, 2H), 3.86-3.79(m, 2H), 3.71-3.65(m, 2H), 2.16-2.09(m, 2H), 1.97-1.91(m, 2H) , 1.27 (t,3H). MS (+ESI) m/z 495 (MH ⁺ ).

Step 6: (5-{2-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,3-oxazol-4-yl}-2H- Tetrazol-2-yl)acetic acid

From (5-{2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3-oxazol-4-yl }-2H-tetrazol-2-yl) ethyl acetate to prepare the title compound. ¹ HNMR (400MHz, MeOH-d ₄ ): δ8.10(s, 1H), 7.59(t, 1H), 7.10(d, 1H), 6.73(t, 1H), 5.69(s, 2H), 4.85- 4.93(m, 1H), 3.78-3.85(m, 2H), 3.62-3.72(m, 2H), 2.08-2.17(m, 2H), 1.88-1.96(m, 2H).MS(+ESI)m/ z467(MH ⁺ ).

Example 21

(5-{2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3-oxazol-4-yl}-1H-tetrazole-1- base) acetic acid

Step 1: (5-(2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl)-1.3-oxazol-4-yl}-1H- Tetrazol-1-yl) ethyl acetate

Less polar fractions from Step 5 of Example 20 were pooled and concentrated to give the title compound. ¹ HNMR (500MHz, acetone-d ₆ ): δ8.26(s, 1H), 7.60(dd, 1H), 7.09(dd, 1H), 6.74(td, 1H), 5.68(s, 2H), 4.93- 4.88(m, 1H), 4.21(q, 2H), 3.84-3.77(m, 2H), 3.71-3.64(m, 2H), 2.16-2.09(m, 2H), 1.97-1.90(m, 2H), 1.22 (t,3H). MS (+ESI) m/z 495 (MH ⁺ ).

Step 2: (5-{2-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,3-oxazol-4-yl}-1H- Tetrazol-1-yl)acetic acid

From (5-{2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3-oxazol-4-yl }-1H-tetrazol-1-yl) ethyl acetate to prepare the title compound.

¹ H NMR (400MHz, MeOH-d ₄ ): δ8.25(s, 1H), 7.59(t, 1H), 7.10(d, 1H), 6.73(t, 1H), 5.69(s, 2H), 4.85 -4.93(m, 1H), 3.78-3.85(m, 2H), 3.62-3.72(m, 2H), 2.08-2.17(m, 2H), 1.88-1.96(m, 2H).MS(+ESI)m /z467(MH ⁺ ).

Examples of pharmaceutical formulations

As a specific embodiment of the oral pharmaceutical composition of the present invention, a 100 mg tablet is composed of 100 mg of any of the examples, 268 mg of microcrystalline cellulose, 20 mg of croscarmellose sodium and 4 mg of magnesium stearate. The active ingredient, microcrystalline cellulose and croscarmellose are mixed first. The mixture is then lubricated with magnesium stearate and compressed into tablets.

While the present invention has been described and illustrated with reference to specific embodiments thereof, those skilled in the art will understand that various changes, modifications and substitutions can be made without departing from the spirit and scope of the invention. For example, due to differences in human responsiveness to the particular condition being treated, effective dosages other than those listed above as preferred may be used. Similarly, the observed pharmacological responses may vary according to and depend upon the particular active compound selected or the presence or absence of a pharmaceutically acceptable carrier as well as the type of formulation and mode of administration used and may be encompassed in the results in accordance with the objectives and practice of the present invention. Expected changes or differences. It is therefore intended that the invention be limited only by the scope of the following claims and that these claims be read as broadly as reasonably possible.

Claims (15)

1. structural formula I compound:

Or its pharmacologically acceptable salts, wherein

Q is 1;

R is 1;

X-Y is CH-O;

W is selected from following heteroaryl:

R ¹For being selected from following heteroaryl:

R wherein ^CFor-(CH ₂) _mCO ₂H; (CH wherein ₂) _mIn any methylene radical (CH ₂) carbon atom is optional is replaced by a hydroxyl, an amino or one or two fluorine;

Each R ²Independently be selected from: hydrogen;

Ar is a phenyl, and is optional by one to five R ³Substituting group replaces;

Each R ³Independently be selected from:

C _1-6Alkyl,

C _2-6Alkenyl,

(CH ₂) _n-phenyl,

Halogen,

CF ₃，

CH ₂CF ₃，

OCF ₃And

OCH ₂CF ₃；

Wherein optional independently being selected from by one to three of phenyl chosen wantonly by one to five substituted C of fluorine _1-4The substituting group of alkoxyl group replaces;

R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹And R ¹²Each independently is a hydrogen;

Each m independently is 0 to 4 integer;

N is 0.

2. the compound of claim 1, wherein m is 1.

3. the compound of claim 1, wherein Ar is by one to three R ³The substituted phenyl of substituting group.

4. the compound of claim 1, wherein W is:

5. the compound of claim 1, wherein R ¹For being selected from following heteroaryl:

R wherein ^cFor-CH ₂CO ₂H.

6. the compound of claim 5, wherein R ¹For:

7. the compound of claim 1, wherein q and r are 1; X-Y is CH-O; W

For being selected from following heteroaryl:

And R ¹For being selected from following heteroaryl:

R wherein ^cFor-CH ₂CO ₂H.

8. the compound of claim 7, wherein W is:

And R ¹For:

R wherein ^cFor-CH ₂CO ₂H.

9. be selected from following compound:

Or its pharmacologically acceptable salts.

10. medicinal compsns, it comprises the compound according to claim 1 with the pharmaceutical acceptable carrier combination.

11. be used for treating the purposes in Mammals suppresses to have responsiveness to stearoyl-CoA Δ-9 desaturase the medicine of imbalance, symptom or disease in preparation according to the compound of claim 1.

12. the purposes of claim 11, wherein said imbalance, symptom or disease are selected from type ii diabetes, hyperlipemia, obesity, metabolic syndrome, fatty liver disease and cancer.

13. the purposes of claim 12, wherein said hyperlipemia are selected from dyslipidemia, hyperlipidaemia, atherosclerosis, hypercholesterolemia, low HDL and high LDL.

14. the purposes of claim 12, wherein said metabolic syndrome is an insulin resistant.

15. the purposes of claim 13, wherein said hyperlipidaemia is a HTC.