WO2012024179A1 - Substituted amide derivatives as dgat-1 inhibitors - Google Patents

Abstract

Described herein are compounds of formula I. The compounds of formula I act as DGAT-1 inhibitors and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity.

Description

SUBSTITUTED AMIDE DERIVATIVES AS DGAT-1 INHIBITORS

TECHNICAL FIELD

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

BACKGROUND

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

In general, obesity is caused by the accumulation of triacylglycerol (TG) in adipose tissue which is a result of lack of exercise, intake of excessive calories and aging. In the body there are two TG synthesis pathways, a glycerol phosphate pathway, which is present in most organs and causes de novo TG synthesis, and a monoacylglycerol pathway, which is involved principally in absorption of aliphatic acid from, the small intestine. Diacylglycerol acyltransferases (DGATs, EC 2.3.1.20), which are membrane-bound enzymes present in the endoplasmic reticulum, catalyze the final step of the TG synthesis common to the two TG synthesis pathways. The final reaction consists of transferring an acyl group from acyl-coenzyme A to the 3-position of l, 2 -diacylglycerol to generate TG (Prog. Lipid Res., 43, 134-176, 2004 and Ann. Med., 36, 252-261, 2004). There are two subtypes of DGATs, DGAT-1 and DGAT-2. There is no significant homology at the generic or amino acid level between the DGAT-1 and DGAT-2, which are encoded by different genes (Proc. Natl. Acad. Sci. USA., 95, 13018-13023, 1998 and JBC, 276, 38870-38876, 2001). DGAT-1, is present in the small intestine, adipose tissue and liver and is believed to be involved in lipid absorption in the small intestine; lipid accumulation in the fat cell; and VLDL secretion and lipid accumulation in the liver (Ann. Med., 36, 252-261, 2004 and JBC, 280, 21506-21514, 2005). In consideration of these functions, a DGAT-1 inhibitor is expected to be an effective obesity treatment through inhibition of lipid absorption in the small intestine, lipid accumulation in the adipose tissue and the liver, and lipid secretion from the liver. in order to carry out in vivo examination of the physiological function(s) of DGAT-1 and inhibitory activity against DGAT-1, DGAT-1 -knockout mice deficient in DGAT-1 at the genetic level was produced and analyzed. As a result, the DGAT-1 -knockout mice have been found to have smaller fat masses than those of wild-type mice and became resistant to obesity, abnormal glucose tolerance, insulin resistance and fatty liver due when fed a high-fat diet (Nature Genetics, 25, 87-90, 2000 and JCI, 109, 1049-1055, 2002). In addition, energy expense has been reported to be accelerated in the DGAT- -knockout mice; and transplantation of the adipose tissues of DGAT-1 -knockout mice into wild-type mice has been reported to make the wild-type mice resistant to obesity and abnormal glucose tolerance, induced by a high-fat diet (JCI, 11 1, 1715-1722, 2003 and Diabetes, 53, 1445-1451, 2004). In contrast, obesity and diabetes mellitus due to a high-fat diet have been reported to worsen in mice with overexpression of DGAT-1 in adipose tissue (Diabetes, 51, 3189-3195, 2002 and Diabetes, 54, 3379-3386, 2005);

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

SUMMARY OF THE INVENTION

A compound of formula (I)

or pharmaceutically acceptable salts thereof, wherein

each occurrence of U is independently selected from the group consisting of— N- and -CH-, wherein ring A is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, Cj-C ₆alkyl and halogen-substituted Ci-C galkyl;

ring B is piperidine, piperazine, piperazinone, pyridine or pyrrolidine, wherein ring B is unsubstituted or substituted with 1 -3 substituents selected from the group consisting of halogen, Cj-C ₆alkyl and halogen-substituted Q-C ₆alkyl;

W is -(CH₂)n-C(0)NR²-(CH₂)n- or -(CH₂)n-NR²C(0)-(CH₂)n-;

X is selected from the group consisting of -(C¾)n-0-(CH₂)n-; -(CH₂)n~

C(0)NR²-(CH₂)n-; -(CH₂)n-C(0)CR1H-(C¾)n-; -(CH₂)n-C(RV(CH₂)n-; ~(C¾)n-NR²C(0> (C¾)ns -(CH₂)n-OC(0)-(CH₂)n-; -(CH₂)n-C(0)0-(C¾)n-; -(C¾)n-NR²S0₂-(CH₂)n-; - (CH₂)n-S0₂NR²-(CH₂)n-; -(CH₂)n-C(0)n-(CH₂)n-; -(CH₂)n-NR C(0)CR1H-(C¾)n-; each occurrence of R is independently selected from the group consisting of hydrogen and Cj-Cealkyl;

each occurrence of R² is independently selected from the group consisting of hydrogen and C|-C₆alkyl;

Y is C C ₆alkyl, phenyl or cycloalkyl, wherein the Ci~C ₆alkyl_f phenyl or cycloalkyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, Cj-C₆alkyl, halogen-substitutedCrCgalkyl, COCrCgalkyl, COhalogen-substitutedCj- C₆alkyl, -OH, C_rC₆alkylOH, halogen-substitutedC_rC₆alkylOH, ~OC_rC₆alkyl, -Ohalogen- substitutedCi-C₆alk l, -COOH, -COCOOH, -COOC C₆alkyl, -Ci-Cealk lCOOCi-Cealkyl, -C_r QalkylCOOH and -Od-C₆alkylCOOH;

Z is selected from the group consisting of phenyl, monocyclic cycloalkyl, monocyclic heterocycle, naphthalene, tetrahydronaphthalene,

wherein Z is unsubsiituted or substituted with lor 2 substituents selected from the group consisting of halogen, C Ce lkyl, halogen-substitutedCi-Cgalkyl, COCi~C₆alkyl, COhalogen- substitutedCrCealkyl, -OH, d-QaikylOH, halogen-substitutedC_rC₆alkylOH, -OCj -C₆alkyl, - Ohalogen-substitutedC_rC₆alkyl, -COOH, -COCOOH, -COOC C₆alkyl, -C_rC₆alkylCOOC C₆alkyl, -C C₆alkylCOOH and -Od-QalkyiCOOH; and

n is 0, 1 or 2. DETAILED DESCRIPTION OF THE INVENTION

Compounds

Described herein are compounds of formula (I):

or pharmaceutically acceptable salts thereof.

Of the compounds described herein, at each occurrence of U, U is independently selected from the group consisting of -N- and -CH-. In certain embodiments, at both

occurrences at U, U is -N-. In another embodiment, at both occurrences at U, U is -CH-, i.e. phenyl. In still other embodiments, one U is -CH- and the other is -N-. For example, ring A can be:

Ring A can be unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, Ci-C ₆alkyl and halogen-substituted C_\-C ₆alkyl. In certain embodiments, ring A is unsubstituted. In such embodiments ring A can be an unsubstituted pyridine. In other embodiments, ring A is substituted. Ring A can be substituted with one substituent. Ring A can be substituted with two substituents. Ring A can be substituted with three substituents. For example ring A can be substituted with a halogen such as fluorine. In certain embodiments ring A is phenyl substituted with fluorine. In other embodiments, ring A is substituted with Ci-C ealkyl. In still other embodiments, ring A is substituted with halogen- substituted Q-C ₆alkyl.

Of the compounds described herein, ring B is piperidine, piperazine,

piperazinone, pyridine or pyrrolidine. In certain embodiments ring B is piperidine. In other embodiments ring B is piperazine. In still other embodiments, ring B is pyridine. In yet other embodiments, ring B is pyrrolidine. In still other embodiments, ring B is piperazinone.

Ring B can be unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, Cj -C ₆alkyl and halogen-substituted Cj-C ₆alkyl. In certain embodiments, ring B is unsubstituted. For example ring B can an unsubstituted piperazine or piperazinone. In another embodiment, Ring B is an unsubstituted pyridine. In yet another embodiment, ring B is an unsubstituted pyrrolidine. In still another embodiment, ring B is an unsubstituted. piperidine.

In other embodiments, ring B is substituted with. 1-3 substituents selected from the group consisting of halogen, Ci-C ₆alkyl and halogen-substituted C_\~C ₆alkyl. Ring B can be substituted with one substituent. Ring B can be substituted with two substituents. Ring B can be substituted with three substituents. For example ring B can be substituted with a halogen such as fluorine, in certain embodiments ring B is piperidine substituted with fluorine. In other embodiments, ring B is substituted with Ci-C ^alkyl. In still other embodiments, ring B is substituted with halogen-substituted Ci-C ₆alkyl.

Also described herein are compounds of formula la:

or pharmaceutically acceptable salt thereon, wherein each occurrence of U is independently selected from the group consisting of -CH- and -N-. In certain embodiments, at both

occurrences at U, U is -N-. In another embodiment, at both occurrences at U, U is -CH-, i.e. phenyl. In still other embodiments, one U is -CH- and the other is -N-. For example, ring A

T is -C¾- or C-O. In certain embodiments T is C=0. In other embodiments, T is -C¾-

V is -CR or -N-. In certain embodiments V is -N-. In other embodiments, V is -CR⁴-, wherein R⁴ is selected from, the group consisting of hydrogen, halogen, Cr-Cealkyl and halogen-substitutedCi-Cealkyl. In certain embodiments, R⁴ is hydrogen. In other embodiments, R⁴ is halogen. In still other embodiments, R⁴ is C C₆alkyl. In yet other embodiments, R⁴ is halogen substituted C_f-Cealkyl.

Also

R is selected from the group consisting of hydrogen, halogen, Cj-C₆alkyl and halogen-substitutedCi-Cealkyl. in certain embodiments, R³ is hydrogen. In other embodiments, R³ is halogen. In still other embodiments, R³ is Cj-Qalkyi In yet other embodiments, R³ is halogen substituted Cs-C₆alkyl.

Of the compounds described herein, W is -(CH₂)n-C(0)NR²-(CH₂)n~ or -(CH₂)n- NR²C(0)-(CH₂)n~. In certain embodiments, W is -(CH₂)n-C(0)NR²-(CH₂)n~. In other embodiments, W is -(CH₂)n-NR²C(0)-(CH₂)n-. Each occurence of n can be 0, 1 , or 2. in certain embodiments, W is -C(0)NR²-. In other embodiments, W is -NR²C(0)-. For example, described herein are compounds of formula Ic:

Of the compounds described herein, X is selected from the group consisting of - (CH₂)n-0-(CH₂)ns -(C¾)n-C(0)NR²-(C¾)n-; -(C¾)n-C(0)CR1H-(CH₂)ns -(CH₂)n-C(R¹)₂- (CH₂)ns -(CH₂)n-NR²C(0)-(CH₂)n-; -(CH₂)n-OC(0)-(CH₂)n-; -(CH₂)n-C(0)0-(CH₂)n-; - (CH₂)n~NR²S0₂-(CH₂)n-; -(CH₂)n-S0₂NR²-(CH₂)n-; -(CH₂)n-C(0)n-(CH₂)n-; -(CH₂)n- NR²C(0)CR1H-(CH₂)n-. Each occurrence of R¹ is independently selected from the group consisting of hydrogen and Ci-C₆alkyl. In certain embodiments, R¹ is hydrogen. In other embodiments, R¹ is Ci-QalkyL Each occurrence of R² is independently selected from the group consisting of hydrogen and Ci-C₆alkyL In certain embodiments, R² is hydrogen. In other embodiments, R^" is Ci-C₆alkyl.

In certain embodiments of the compounds described herein, X is -C¾0-, -C(O)-,

-CH₂-, -C(0)NH- or -0-. In another embodiment of the compounds described herein, X is - CH₂0-, -C(0)-, -C(0) H-₉ - NHC(O)-, -CH₂C(0)NH-, -(CH₂)₂C(0)NH- or -0-. In still another embodiment, X is -C¾0-.

Of the compounds described herein, Y is Q-C ealkyl, phenyl or cycloalkyl, wherein the Ci-C galkyl, phenyl or cycloalkyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, CrC₆aIkyl, halogen-substitutedCt-Cealkyl, COQ- C₆alkyl, COhalogen-substitutedCi-Qalkyl, -OH, CrC₆alkylOH, halogen-substitutedQ- C₆alkylOH, -OC C₆alkyl, -Ohalogen-substitutedCi-C₆alkyl, -COOH, -COCOOH, -COOC_r C₆alkyl, -Cj-CealkylCOOCi-Cealk l, -C C₆alkylCOOH and -OC C₆alkylCOOH. In certain embodiments, Y is phenyl. In other embodiments of the compounds described herein, Y is cycloalkyl. Suitable examples of cycloalkyl, include but are not limited to cyclohexane. In still other embodiments, Y is Ci-C₆alkyl. Suitable examples of Ci-C₆alkyl include, but are not limited to isobutane.

In certain embodiments of the compounds described herein, Y is substituted with

1-2 substituents selected from the group consisting of halogen, -COOH, -COOCrCgalkyl and Q- C₆alkyl. In other embodiments, Y is substituted with one substituent selected from the group consisting of halogen, -COOH, ~COOCi-C₆alkyl and Ci-Cealkyl, In still other embodiments, Y is substituted with 2 substituents selected from the group consisting of halogen, -COOH, -

COOCrQalkyl and Ci-C₆alkyl. In yet another embodiment of the compounds described herein,

Y is phenyl wherein the phenyl is substituted with -COOH.

Of the compounds described herein, Z is selected from the group consisting of phenyl, monocyclic cycloalkyl, monocyclic heterocycle, naphthalene, tetrahydronaphthalene,

wherein Z is unsubstituted or substituted with lor 2 substituents selected from the group consisting of halogen, Ci-C₆alkyl, halogen~substitutedCrC₆alkyl, COCrCealkyl, COhalogen- substitutedC_rC₆alkyl, -OH, C[-C₆alkylOH, haiogen-substitutedCi-QalkylOH, -OCi-C₆alkyl, - Ohalogen-substitutedC C₆alkyl₅ -COOH, -COCOOH, -COOd-C_fialkyl, -Ci-C₆alkylCOOCi- C₆alkyl, -C C₆alkylCOOH and -OC C₆alkylCOOH.

In certain embodiments of the compounds described herein, Z is phenyl. In yet other embodiments of the compounds described herein, Z is monocyclic cycloalkyl. Suitable examples of monocyclic cycloalkyl include cyclohexane and cyclopentane. In still other embodiments, Z is monocyclic heterocycle. Suitable examples of monocyclic heterocycle includes, pyridine, pyrimidine and pyridazine.

In certain embodiments, Z is selected from the group consisting of:

In certain embodiments of the compounds described herein, Z is naphthalene. In still other embodiments of the compounds described herein, Z is tetrahydronaphthalene. In otiier embodiments, Z is a bicyclic heterocycle, containing nitrogen, selected from the group consisting of :

or selected from the group consisting of

In other embodiments, Z is a bicyclic heterocycle, containing oxygen, selected from the group consisting of :

or from the group consisting of:

In other embodiments, Z is selected from the group consisting of:

In certain embodiments, Z is two phenyl groups separated by a bond. In other embodiments, Z is two phenyl groups separated by a linker group, wherein the linker group is - 0-, C=0, C¾ or CH₂-O-. In still other embodiments, Z is a phenyl group and a six-membered heterocyc

In still other embodiments, Z is a phenyl group and a five-membered heterocycle separated by a linker group, such as,

In still other embodiments, Z is selected from the group consisting of:

In yet other embodiments, Z is selected from the group consisting of:

In still other embodiments, Z is selected from the group consisting of:

In certain embodiments of the compounds described herein, Z is substituted with nts selected from the group consisting of halogen, -COOH, -OCi-Cealkyl, - Ohalogen-substitutedCj-Cealkyl, halogen-substitutedCj-Qalkyl, d-C₆alkyl and -NH-phenyL In some embodiments, Z is substituted with 1 substituent selected from the group consisting of halogen, -COOH, -OCj-Cgalkyl, -Ohalogen-substitutedCi-C₆alkyl₅ halogen-substitutedCj- Cgalkyl, C]-C₆alkyl and -NH-phenyL In other embodiments, Z is substituted with 2 substituents selected from the group consisting of halogen, -COOH, -OCi-C₆alkyl, -Ohalogen-substitutedCi- Cgalkyl, halogen-substitutedCi-C₆alkyl, Ci-C₆alkyl and -NH-phenyl. In certain embodiments of the compounds described herein, Z is substituted with -COOH, In other embodiments, Z is substituted with -OCj-Qalkyl, such as, but not limited to, methoxy. In still other embodiments, Z is substituted with -Ohal.ogen-substitutedCrC₆alkyi, such as, but not limited to,

trifluoromethoxy. In other embodiments, Z is substituted with -Ct-C$alkyl₅ such as, but not limited to, methyl. In still other embodiments, Z is substituted with -halogen-substitutedCj- C₆alkyl, such as, but not limited to, trifluoromethyl. In yet another embodiment, Z is substituted with -NH-phenyl.

Examples of the compounds described herein include, but are not limited to: Table

- 14-

-19-

Definitions

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

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

"Cycloalkyl" encompasses cycloalkyls having 3 to 10 carbons, forming one or more carbocyclic rings that are fused. "Cycloalkyl" also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. In one embodiment, the cycloalkyl can include 3-6 carbons, i.e. Cs-Cgcycloalkyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl,

decahydronaphthyl, indanyl and the like.

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

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

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

The term "-Ohalogen-substitutedCi-Cgalkyl" means a -OCrC₆alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different, and specifically includes, for example, a trifluoromethoxy group.

The term "-COCrCealkyl" means groups having Ci-C₆alkyl bonded to carbonyl, and encompasses alkylcarbonyl having a carbon number of 1 to 6. Specific examples thereof include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and the like.

The term "-COhalogen-substitutedC Cealkyl" means a -COCi-C₆alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different.

The term "Ci-C₆alkylOH" means a C Ce lkyl substituted with an alcohol (-OH).

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

The term "halogen-substitutedCi~C₆alkylOH" means a halogen-substitutedCi-C₆alkyl, as defined above, substituted with an alcohol (-OH). The term "halogen-substituted Ci-C₆alkyIOH" means a halogen-substituted CrC₆alkyl substituted with an alcohol (-OH).

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

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

"Heterocycle" unless otherwise specified, means an aromatic, partially aromatic or non- aromatic monocyclic or polycyclic (including bicyclic) ring having at least one ring heteroatom selected from O, S and N. Examples of heterocyclic groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, 2-oxo-(lH)-pyridinyl (2-hydroxy-pyridinyl), oxazolyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidinyl, pyrazinyl, benzisoxazolyl, benzoxazolyi, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl,

dihydrobenzothienyl, indolizinyl, cirrnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl, imidazo[l,2- jpyridinyl, [l,2,4-triazolo]|[4,3~a]pyridinyl₅ pyrazolo[l,5-a]pyridinyl, [l,2,4-triazolo][l,5- jpyridinyl, 2~oxo-l,3-benzoxazolyl, 4-oxo-3H-quinazolinyl, 3-oxo-[l ,2,4]-triazolo[4,3-a]-2H- pyridinyl, 5-oxo-[l,2,4]-4H-oxadiazolyl, 2-oxo-[l,3_>4]-3H-oxadiazolyL 2-oxo-l,3-dihydro-2H- imidazolyl, 3-oxo~2,4-dihydro-3H-l,2,4-triazolyl, and the like. Examples of "heterocycle" also include tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2_?3-dihydrofuro(2,3-i>)pyridyl, benzoxazinyl, benzoxazolinyl, 2-JJ-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6-dihydroimidazo[2₅l-6]thiazolyl₅ tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, 2- or 4-pyridones attached through the nitrogen or N-substituted-(lH, 3H)-pyrimidine-2,4-diones (N-substituted uracils). The term also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2- azabicyclo[2.2.1]heptyl, 7-azabicyclo 2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 2- azabicyclo[2.2.2]octyl, and 3-a2abicyclo[3.2.2]nonyl, and azabicyclo[2.2.1jheptanyl.

The term "pharmaceutically acceptable salt" refers to salts prepared from

pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term

"pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following; acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollyiarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitaie, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N_sN-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethyienediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethyl amine, trimethylamine, tripropylamine, tromethamine, and the like.

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

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

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

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

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

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

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

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

In the compounds of the formulas described herein, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the formulas described herein. For example, different isotopic forms of hydrogen (H) include protium (lH) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic formula can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates. Methods of Treatment

Also encompassed by the present invention are methods of treating DGAT- 1 -related diseases. The compounds described herein are effective in preventing or treating various DGAT- 1 -related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis. The compound of the invention is especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety.

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

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

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

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

More particularly, another aspect of the invention that is of interest relates to a method of treating type 2 diabetes in a mammalian patient in need of such treatment comprising

administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat type 2 diabetes.

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

The present invention is also directed to the use of a compound of structural formula I, la or lb in the manufacture of a medicament for use in treating various DGAT-1 -related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension,

nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis. The compounds described herein are especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety. For example, the present invention is directed to the use of a compound of structural formula I, la or lb in the manufacture of a medicament for use in treating obesity, diabetes, hormone secretion disorder, hyperlipemia, gout and fatty liver.

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

Pharmaceutical Compositions

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

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

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

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

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

In case where the compounds of the invention are used for prevention or treatment for the above-mentioned diseases, the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the patient and on the type and the range of the intended remedial effect. In general, when orally administered, the dose may be from 0.001 to 50 mg/kg of body weight/day, and it may be administered at one time or at several times. The dose is preferably from about 0.01 to about 25 mg/kg/day, more preferably from

about 0.05 to about 10 mg/kg/day. For oral administration, the compositions are preferably

provided in the form of tablets or capsules containing from 0.01 mg to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250,

500, 750, 850 and 1,000 milligrams of a compound described herein. This dosage regimen may be adjusted to provide the optimal therapeutic response.

Combination Therapy

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

The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of the formulas described herein or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be . administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of any of the formulas described herein. When a compound of formula I, la or lb is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of formula I, la or lb is preferred. However, the combination therapy may also include therapies in which the compound of formula I, la or lb and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of formula I, la or lb.

Examples of other active ingredients that may be administered in combination with a compound of any one the formulas described herein, and either administered separately or in the same

pharmaceutical composition, include, but are not limited to:

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

(2) insulin sensitizers, including (i) PPARy agonists, such as the glitazones (e.g. pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR ligands, including (1) PPARa/γ dual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPARa agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators (SPPARyM's), such as those disclosed in WO 2002/060388, WO 2002/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963, and (4) PPAR partial agonists; (ii) biguanides, such as metformin and its

pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortarnet®, and GlucophageXR®; (iii) protein tyrosine phosphatase- 1 B (PTP - IB) inhibitors ;

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

(4) leptin and leptin derivatives and agonists;

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

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

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

(8) glucagon receptor antagonists, such as those disclosed in WO 1998/04528, WO 1999/01423, WO 2000/39088, and WO 2000/69810;

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

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

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

(12) antiobesity compounds;

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

(14) antihypertensive agents, such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, teimisartan, and eprosartan), renin inhibitors (such as aliskiren), beta blockers.

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

(16) inhibitors of 1 Ιβ-hydroxy steroid dehydrogenase type 1, such as those disclosed in U.S. Patent No. 6,730,690; WO 2003/104207; and WO 2004/058741 ;

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

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

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

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

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

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

(23) neuromedin U receptor agonists, such as those disclosed in WO 2009/042053, including, but not limited to, neuromedin S (NMS);

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

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

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

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

2);

(28) inhibitors of fatty acid synthase;

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

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

(31) agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPC 19, GPR131, and M- BAR); and

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

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

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

(2i?,3S,5i?)-5-(l-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)-2-(2,4,5- trifiuorophenyl)tetral ydro-2H-pyran-3-amine;

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

(2R,3S, 5 ?)-2-(2 , 5 -di fiuorophenyl)tetrahydro)- 5 -(4,6-dihy dropyrrolo [3 ,4-c] pyrazol- 5 ( 1 H)-yl)

tetrahydro-2H-pyran-3 -amine;

(3J?)-4-[(3i?)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-hexahydro-3~methyl-2H-l_;4-diazepin- 2-one; 4 (3 ?)-3-amino~4-(2,5-difluorophenyl)bute^^

hydrochloride; and

(3i?)-4-[(3J?)-3-amino-4-(2₅4,5-trifluorophenyl)butanoyl]-hexahydro-3-(2,2,2-trifluoroethyl)

diazepin-2-one; and

pharmaceutically acceptable salts thereof.

Antiobesity compounds that can be combined with compounds of the formulas described herein include topiramate; zonisamide; naltrexone; phentermine; bupropion; the combination of bupropion and naltrexone; the combination of bupropion and zonisamide; the combination of topiramate and phentermine; fenfluramine; dexfenfluramine; sibutramine; lipase inhibitors, such as orlistat and cetilistat; melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists; CC -1 agonists; melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Y\ or Y5 antagonists (such as MK-0557); CBl receptor inverse agonists and antagonists (such as rimonabant and taranabant); β3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (such as bombesin receptor subtype-3 agonists); and 5-hydroxytryptamine-2c (5-HT2c) agonists, such as lorcaserin. For a review of anti-obesity compounds that can be combined with compounds of the present invention, see S. Chaki et al., "Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity," Expert Opin. Ther. Patents. 11 : 1677-1692 (2001); D. Spanswick and K. Lee, "Emerging antiobesity drugs," Expert Opin. Emerging Drugs, 8: 217-237 (2003); J.A.

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

Pharmacother., 10: 921-925 (2009).

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

N- [4-(( 15)- 1 - { 3 -(3 ,5 -dichlorophenyl)~5 - [6-(trifluoromethoxy)-2-naphthy 1] - 1 H-pyrazol- 1 - yl}ethyl)berrzoyl]^-alanine;

N- [4-(( 1 R)- 1 - { 3-(3 ,5-dichlorophenyl)-5- [6-(trifluoromethoxy)-2-naphthyl] - 1 H-pyrazol- 1 - yi } ethyl)benzoyi] -β-alanine ;

N-(4- { I - [3 -(2, 5 -dichlorophenyl)- 5 -(6-meth.QXy-2-naph.thyl)- 1 H-pyrazol- 1 -yl] ethyl } benzoyl)- β~ alanine;

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

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

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

pharmaceutically acceptable salts^' thereof. Inhibitors of stearoyl-coenzyme A delta-9 desatu ase (SCD) that can be used in combination with the compounds of the formulas described herein include, but are not limited to:

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

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

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

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

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

and

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

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

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

5-(2-hydroxy-l-methyl-ethoxy)-3-(6-methariesulfonylpyridin-3-yloxy)-N-(l-me1hyl-lH-pyrazol- 3-yl)benzamide;

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

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

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

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

3 -( {4- [2-(dimethylamino)ethoxy]phenyl } thio)-N-(3 -methyl- 1 ,2 ,4-thiadiazol-5 -yl)-6 - [(4-methyl- 4H- 1 _f2,4-triazol-3-yl)thio]pyridine-2-carboxamide;

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

4H-l,2,4-triazol-3-yl)thio3pyridine-2-carboxamide;

N-(3-methyl-l,2,4-thiadiazol-5-yl>^

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

3-[(4-{2^(2R)-2-methylpyrrolidin-l^

methyl-4H-l₅2₅4-triazol-3-yI)thio]|pyridine-2~carboxamide; and pharmaceutically acceptable salts thereof.

Agonists of the GPR-1 19 receptor that can be used in combination with the compounds of the formulas described herein include, but are not limited to: rac-cis 5-chloro-2- {4-[2-(2- { [5-(methylsulfonyl)pyridin-2-yl]oxy} ethyl)cyclopropyl] piperidin-1 - yl}pyrimidine;

5-chloro-2-{4-[(lR,2S)-2-(2-{[5-(methylsulfo^

l~yl}pyrimidine;

rac c/,s-5-chloro-2- [4-(2- {2- [4-(methylsulfonyl)phenoxy] ethyl } cyclopropyl)piperidin- 1 - yl]pyrimidine;

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

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

rac cis-5 -chloro~2- [4-(2- { 2- [3 -(methylsulfonyl)phenoxy] ethyl } cyclopropyl)piper idin- 1 - yl jpyrimidine; and

rac cis - 5 -chloro-2- [4-(2- { 2-[3 -(5 -methyl- 1 ,3₅4-oxadiazol-2-yl)phenoxy] eth l } cyclopropyl)

piperidin-1 -yl]pyrirnidine; and pharmaceutically acceptable salts thereof.

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

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

(25)-2-( { 6-chloro-3 -[6-(4-fluorophenoxy)-2-propylpyridin-3-yl] -1,2 -bertzi soxazol- 5 - yl}oxy)propanoic acid;

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

acid;

(2i?)-2-({6-chloro-3-[6-(4-chlorophenoxy)-2-propylpyridin-3-yl]-l₅2-benzisoxazol-5- yl}oxy)propanoic acid;

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

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

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

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

Inhibitors of 11 β-hydroxysteroid dehydrogenase type 1 that can be used in combination with the compounds of the formulas described herein include, but are not limited to:

3- [ 1 -(4-chlorophenyl)-/raw-3-fluoiOcyclobutyl)-4,5-dicyclopropy3-r-4H- 1 ,2₅4-triazole;3~[l-(4- chiorophenyl)-iram-3-fiuorocyclobutyl]-4-cyclopropyl-5-(l-methylcyclopropyl)-r-4H-l,2,4- triazole; 3-[l -(4-cWorophenyl)-fra¾y-3 -fmorocyclobutyl] -4-methyl-5- [2-(trifluoromethoxy)phenyl]-r-4H- 1 ,2,4-triazole;

3- [ 1 -(4-chlorophenyl)cyclobutyl] -4-methyl-5 -[2-(trifluorome yl)phenyl] -4H- 1 ,2,4-triazole;

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

4- methyl-3-{4-[4-(methylsulfony

4H- 1,2,4-triazole;

3 _(4_ {4-methyl-5- [2-(trifl ororaethyl)phenyl] -AH- 1 _}2,4-triazol-3 -yl } bicyclo [2.2.2] oct- 1 -yl)-5 -

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

3-(4-{4-methyl-5-[2-(trifluorome

(3,3,3-tri:fluoroethyl)-l,2,4-oxadiazole;

5- (3,3-difiuorocyclobulyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-l,2₅4-triazol-3^ yl}bicyclo[2.2.2]oct- 1 -yl)- 1 ,2,4-oxadiazole;

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

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

2-(3,3-difluorocyclobutyl)-5-(4-^

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

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

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

and pharmaceutically acceptable salts thereof.

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

and pharmaceutically acceptable salts thereof.

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

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

l'-[0 -cyclopropyl-4-memoxy-lH-indol~6-yl)carb^

piperidin]-4-one;

1 '-[(l-cyclopropyl-4-ethoxy- 3 -methyl- 1 H-indol-6-yl)carbonyl]-6-(l H-tetrazol-5- yl)spiro[chroman-2_J4'-piperidin]-4-one; and

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

pharmaceutically acceptable salts thereof.

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

(a) a compound of structural formula I, la or lb;

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

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

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

pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR ligaiids, including (1) PPARa/γ dual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and navegtitazar, (2) PPARa agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators (SPPARyM's), and (4) PPARy partial agonists; (ii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet®, and

GlucophageXR®; (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;

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

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

(5) glucagon receptor antagonists;

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

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

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

(8) antiobesity compounds;

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

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

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

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

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

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

(15) irihibitors of acetyl Co A carboxylase- 1 or 2 (ACC1 or ACC2);

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

(17) agonists of the G-protein-coupIed receptors: GPR-109, GPR-119, and GPR-40; (18) SSTR3 antagonists;

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

(20) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD); (21) GPR-105 antagonists;

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

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

DGAT-2);

(24) inhibitors of fatty acid synthase;

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

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

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

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

(c) a pharmaceutically acceptable carrier.

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

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

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

Schemes and Examples

Scheme 2

12 Scheme 3

2. Pt0₂, H₂, EtOH-EtOAc

75-90% / 2 steps

RX

- steps

Scheme 4

"C

Scheme 5

Intermediate 1

Step A: d -(5 -mtropwidin~2-yl)piperidin-4- ypmethanol

To 5-nitro-2-chloropyridine (5.45 g, 0.0344 mol) and N-BOC-piperazine (4.75 g, 0.0412 mol) dissolved in DMF (100 mL) was added Ν,Ν-diisopropylethylamine (8.89 g, 11.4 mL, 0.0688 mol). The reaction mixture was heated at 100 °C for 4 h then cooled to RT and

concentrated. Water (200 mL) was added, and the aqueous solution was extracted with CH₂C1₂. The combined organic extract was dried (MgS0₄), filtered, and concentrated. Purification by vacuum filtration through silica gel (eluant: 7-10% MeOH/C¾Cl₂) to yield (l-(5-nitropyridin-2- yl)piperidin-4-yl)methanol as a yellow solid. LC/MS = 238 [M+l].

Step B: ( 1 -f 5-mtropyridin-2-vi)piperidin-4-yl )methyl methanesulfonate

To (l-(5-nitropyridin-2-yl)piperidin-4-yl)methanol (1.00 g, 4.21 mmol) in C¾C1₂ (30 mL) and cooled to 0 °C was added triethylamine (0.85 g, 1.2 mL, 8.43 mmol) and mesyl chloride (0.60 g, 0.41 mL, 5.27 mmol). The reaction mixture was stirred at 0 °C for 15 mins then at room temperature for 60 mins. Water (50 mL) was added, and the aqueous solution was extracted with 0¾0₂. The combined extracts were dried (MgS0₄), filtered, and concentrated to yield (l-(5- nitropyridin-2-yl)piperidin-4-yl)methyl methanesulfonate as a yellow solid. LC/MS = 316 [M+l], Step C: methyl 3-(( 1 -(5 -nitropyridin-2-yl)piperidin-4-vI methoxy)benzoate

To methyl 3-hydroxybenzoate (0.96 g, 6.28 mmol) in diy DMF (20 mL) under nitrogen was added sodium hydride (0.25 g of 60 wt% in oil, 6.28 mmol). The mixture was stirred at RT for 15 mins then added (l-(5-nitropyridin-2-yl)piperidin-4-yI)methyl methanesulfonate (1.32 g, 4.19 mmol) in dry DMF (10 mL). The resulting mixture was heated at 50 °C for 5 h then cooled and concentrated. Water (50 mL) was added, and the aqueous solution was extracted with CH2CI2- The combined extracts were dried (MgSC^), filtered, and concentrated. Purification by silica gel chromatography (eluant: 5% EtOAc/CH₂Cl₂) to yield methyl 3-((l -(5-nitropyridin-2- yl)piperidin-4-yl)methoxy)benzoate as a yellow solid. LC/MS = 372 [M+l].

Step D: methyl 3-f(l-(5-aminopyiidin-2-yl)piperidin-4-yl methoxy)benzoate

To methyl 3-((l-(5-nitropyridin-2-yl)piperidin-4-yl)methoxy)benzoate (1.21 g, 3.26 mmol) dissolved in ethyl acetate (30 mL) and isopropanol (30 mL) under a nitrogen atmosphere was added platinum dioxide catalyst (0. 8 g). The resulting reaction mixture was stirred at RT under a hydrogen atmosphere (balloon) for 16 h. The catalyst was removed by filtration through celite and washed with isopropanol. The Filtrate was concentrated to yield methyl 3-((l-(5- aminopyridin-2-yl)piperidin-4-yl)methoxy)benzoate as a light purple oil. LC/MS = 342 [M+l]. EXAMPLE 1

methyl 3- l-r5-f(2-naphthalenyicarbonyl)amino]-2-pyridinyn-4-piperidinvi methoxy|benzoate To 2-naphthoic acid (100 mg, 0.58 mmol) in dry DMF (5 mL) was added Intermediate 1 (218 mg, 0.64 mmol), HATU (442 mg, 1.16 mmol), and triethylamine (0.16 mL, 117 mg, 1.16 mmol). The reaction mixture was stirred at RT for 16 h then concentrated. Water was added, and the aqueous solution was extracted with CH₂CI2. The combined organic extract was dried (MgS04), filtered, and concentrated. Purification by silica gel chromatography (eluant: 10-20% EtOAc/CH₂Cl₂) to yield the title compound as a light pink solid. LC/MS - 497.2 [M+l].

EXAMPLE 2

3-ffl -(5-(2-naphthamido pyridin-2-yl)piperidin-4-yl methoxy)beiizoic acid

To a stirred solution of product obtained in Example 1 (190 mg, 0.383 ramol) in MeOH (3 mL), THF (3 mL), and water (2 mL) was added lithium hydroxide (80 mg, 1.92 mmol). The reaction mixture was heated at reflux for 5 h then cooled to RT. 1 N HCl (2.5 mL) was added, and the solution concentrated. Water was added, and a precipitate formed. The precipitate was filtered and washed successively with water, isopropanol (2 mL), then diethyl ether to yield the title compound as a beige solid. LC/ S = 482.2 [M+1].

The following compounds were prepared by using methods described in Examples 1-2.

Intermediate 2

Step A: t-butyl 4-(5-nitropyridin-2-yl)piperazine- -carboxylate

To 5-nitro-2-chloropyridine (10.0 g, 0.0631 mol) and N-BOC-piperazine (17.6 g, 0.0946 mol) dissolved in DMF (200 mL) was added N,N-diisopropylethylamine (24.5 g, 31.3 mL, 0.189 mol). The reaction mixture was heated at 100 °C for 16 h then cooled to RT and concentrated. Water (300 mL) was added, and the aqueous solution was extracted with 0¾¾. The combined organic extract was dried (MgS0₄), filtered, and concentrated. Purification by vacuum filtration through silica gel (eluant: 5% EtOAc/C¾Cl₂) to yield t-butyl 4-(5-nitropyridin-2-yl)piperazine- 1 -carboxylate as a yellow solid. LC/MS = 309 [M+l ].

Step B: N-(5 -nitropyridin-2-yl)piperazine

To t-butyl 4-(5-nitropyridin-2-yl)piperazine-l -carboxylate (19.45 g, 0.0631 mol) dissolved in CH2CI2 (250 mL) and cooled to 0 °C was added trifluoroacetic acid (50 mL). The resulting reaction mixture was stirred at RT for 16 h then concentrated. The crude product was dissolved in CH2CI2 (250 mL) and made basic with the addition of 1 N aqueous NaOH (200 mL) and 3 N aqueous NaOH (100 mL). The layers were separated, and the aqueous solution extracted with CH2CI2_. The combined organic extract was dried (MgS04), filtered, and concentrated to yield N-(2-fluorophenyl)-4-(5-nitropyridin-2-yl)piperazine-l-carboxamide as a yellow solid. LC/MS - 209 [M+l].

Step C: 4-(5-Nitropyridin-2-yl)-N-(2-fiuorophenyl)piperazine- 1 -carboxamide

To N-(2-fiuorophenyl)-4-(5-nitropyridin-2-yl)piperazine-l -carboxamide (6.6 g_} 32 mmol) dissolved in dry THF (200 mL) was added triethylamine (8.8 mL, 63 mmol) and 2-fiuorophenyl isocyanate (4.3 mL, 38 mmol). The resulting reaction mixture was heated at 80 °C for 16 h then cooled to RT and concentrated. Water (150 mL) was added, and the aqueous solution was extracted with CH2CI2. The combined organic extract was dried (MgS0 ), filtered, and concentrated to give a yellow solid. The solid was triturated with water, filtered, and dried to yield 4-(5-nitropyridin-2-yl)~N-(2-fluorophenyl)piperazine-l-carboxamide as a yellow solid. LC/MS = 346 [M+l].

Step D: 4-(5-Aminopyridin-2-yl)-N~(2-fluorophenyl)piperazine- 1 -carboxamide

To 4-(5-nitropyridin-2-yl)-N-(2-fluorophenyl)piperazine-l-carboxamide (11.0 g, 31.8 mmol) suspended in ethyl acetate (100 mL) and isopropanol (100 mL) under a nitrogen atmosphere was added platinum dioxide catalyst (0.72 g, 3.18 mmol). The resulting reaction mixture was stirred at RT under a hydrogen atmosphere (balloon) for 16 h. The catalyst was removed by filtration through celite and washed with isopropanol. The filtrate was concentrated to yield 4-(5-aminopyridin-2-yl)-N-(2-fluorophenyl)piperazine-l -carboxamide as a white solid. LC/MS = 316 [M+l].

EXAMPLE 63

4-f 5 -f 2-naphthamido)pyridin-2-yl)-N-(2-fluorophenvi)piperazine- 1 -carboxamide

To 2-naphthoic acid (70 mg, 0.41 mmol) in dry DMF (6 mL) was added Intermediate 2 (167 mg, 0.53 mmol), HATU (309 mg, 0.81 mmol), and N,N-diisopropylethylamine (0.14 mL, 0.81 mmol). The reaction mixture was stirred at RT for 16 h then concentrated. Water was added, and the aqueous solution was extracted with CH2CI2. The product was crystallized from acetonitrile and water to yield the title compound as a beige solid. LC/MS - 470.3 [M+l].

The following compounds were prepared by using methods described in Example 63.

Intermediate 3

Step A: tert-butyl 4-fluoro-4-f hydroxymethyDpiperidine- 1 -carboxylate

To 1 -tert-butyl 4-ethyl 4-fluoropiperidine-l,4-dicarboxylate (5.00 g, 18.2 mmol) in dry THF (100 mL) cooled to 0 °C under nitrogen was added lithium aluminum hydride (1.0 M in THF, 18.2 mL_; 18.2 mmol). The reaction mixture was warmed slowly to RT over 90 mins then stirred at RT for 4 h. The mixture was recooled to 0 °C, and water (0.7 mL), 1 N NaOH (0.7 mL), and water (2.1 mL) were added successively. CH₂G₂ and MgS0₄ were added. The slurry was filtered to remove the aluminum salts. The aluminum salts were washed with ΰ¾¾₅ and the filtrate was concentrated. Purification by silica gel chromatography (eluant: 15-30%

EtOAc CH₂Cl₂) to yield tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l -carboxylate as a colorless oil LC/MS = 178 [M-55].

Step B: (4-fluoropiperidin-4-yl)methanol

To tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l -carboxylate (3.04 g, 13 mmol) in CH₂CI₂ (50 mL) was added 4 N HC1 in dioxane (16.3 mL, 65 mmol). The mixture was stirred at RT for 16 h then concentrated to yield (4-fluoropiperidin-4-yl)methanol. LC/MS = 134 [M+l].

Step C: i4-fluoro-l-(5-nitropyridin-2-yDpiperidin-4-yl)methanol

This compound was made by following the same method described in Intermediate 1 ,

Step A. Step D: f 4-fluoro- 1 -(5-nitropyridin-2-yl)piperidin-4-yi)methyl methanesulfonate This compound was made by following the same method described in Intermediate 1 ,

Step B.

Step E: methyl 3 -((4-fluoro- 1 -(5 ~mtropyridin-2-yl)piperidin-4- yl)methoxy benzoate

To methyl 3-hydroxybenzoate (1.15 g, 7.56 mmol) in dry DMF (25 mL) under nitrogen was added sodium hydride (0.30 g of 60 wt% in oil, 7.56 mmol). The mixture was stirred at RT for 15 mins then added (4-fluoro- 1 -(5 -nitropyridin-2-yl)piperidin-4-yl)methyl methanesulfonate (1.26 g, 3.78 mmol) and tetrabulylammonium iodide (0.70 g, 1.89 mmol). The resulting mixture was heated at 120 °C for 18 h then cooled and concentrated. Saturated NH₄C1 (50 mL) was added, and the aqueous solution was extracted with CH2CI2. The combined extracts were dried (MgS0₄), filtered, and concentrated. Purification by silica gel chromatography (eluant: 5% EtOAc/CHbCb) to yield methyl 3 -((4-fluoro- 1 -(5 -nitropyridin-2-yl)piperidin~4- yl)methoxy)benzoate_as a yellow oil. LC/MS = 390 [M+l].

Step F: methyl 3-(( 1 -(5-aminopyridin-2-yl)-4-fluoropiperidin-4- yl)methoxy)benzoate

This compound was made by following the same method described in Intermediate 1,

Step D.

The following compounds were prepared by using methods described in Example 1-2 using intermediate 3.

Intermediate 4

Step A: fert-butyl 4-(3-(methoxycarbonyl benzyl -3-oxopiperazine- 1 -carboxylate

To a solution of N-BOC-oxapiperazine (1.0 g, 5 mmol) dissolved in DMF (20 mL) was added NaH (0.3 g of 60 wt% in oil, 7.5 mmol) at RT over 10 mins. After 30 mins, methyl 3- (bromomethyl)benzoate (1.49 g, 6.5 mmol) was added over 1 min. The reaction mixture was stirred at RT for 5 h, then poured onto a saturated NH₄C1 solution. The aqueous solution was extracted with EtOAc. The combined organic extract was dried (Na₂S0 ), filtered, and concentrated. Purification by silica gel column chromatography with an ISCO system (eluant: hexane/EtOAc) to yield teri-butyl 4-(3-(methoxycarbonyi)benzyl)-3-oxopiperazine- 1 -carboxylate as a white solid. LC/MS - 349 [M+l].

Step B: methyl 3-(Y2-oxopiperazm- -yl)methyl)benzoate

To tert-butyl 4-(3-(methoxycarbonyl)benzyi)~3-oxopiperazine-l -carboxylate (1.5 g, 4.3 mmol) dissolved in CH₂C1₂ (10 mL) and cooled to 0 °C was added trifluoroacetic acid (3 mL). The resulting reaction mixture was stirred at RT for 13 h then concentrated. The crude product was dissolved in CH2CI2 (25 mL) and made basic with the addition of 1 N aqueous NaOH (20 mL). The layers were separated, and the aqueous solution extracted with CH2CI2. The combined organic extract was dried (Na₂S0₄), filtered, and concentrated to yield methyl 3-((2- oxopiperazin-l-yl)methyl)benzoate as a white solid. LC/MS = 249 [M+l].

Step C: methyl 3-((4-f 5-nitropyridin-2-yl)-2-oxopiperazin- 1 -yl)methyl)benzoate

To 5-nitro-2-chloropyridine (0.916 g, 5.7 mmol) and 3-((2-oxopiperazin-l- yl)methyl)benzoate (1.3 g, 5.24 mmol) dissolved in EtOH (16 mL) was added N,N- diisopropylethylamine (1.18 mL , 6.8 mmol). The reaction mixture was heated at 90 °C for 13 h then cooled to RT and the solid product was collected via filtration, rinsed with MeOH, and air- dried to yield methyl 3-((4-(5-nitropyridin-2-yl)-2-oxopiperazin-l-yl)methyl)benzoate as a yellow solid. LC/MS - 372 [M+l], Step D: methyl 3-f(4-(5-aminopyridin-2-ylV2-oxopiperazin-l-yl)rnethyl)berizoate

To methyl 3-((4-(5-mninopyridin~2-yl)-2-oxopiperazin-l-yl)methyl)benzoate (1.3 g, 3.5 mmol) dissolved in ethyl acetate (40 mL) and MeOH (40 mL) under a nitrogen atmosphere was added platinum dioxide catalyst (0.13 g). The resulting reaction mixture was stirred at RT under a hydrogen atmosphere (balloon) for 16 h. The catalyst was removed by filtration through celite and washed with MeOH. The filtrate was concentrated to yield methyl 3-((4-(5-aminopyridin-2- yl)-2-oxopiperazin-l-yl)methyl)benzoate as a light purple oily foam. LC/MS = 342 [M+l]. EXAMPLE 68

methyl 3 -(( 2-oxo-4-(5-(3 -phenoxyben2amido)pyridin-2-yl)piperazin- 1 ~yl)methyl benzoate

To a solution of 3-phenoxybenzoic acid (50 mg, 0.23 mmol) in CH₂C1₂ (4 mL) was added 3-((4-(5~aminopyridin-2-yl)~2-oxopiperazin-l-yl)methyl)benzoate (61 mg, 0.179 mmol), HOBT (32 mg, 0.237 mmol), EDCI (50 mg, 0.26 mmol), and ethyldiisopropylamine (0.07 mL, 0.40 mmol). The reaction mixture was stirred at RT for 14 h. CH2CI2 was added, and the organic solution was washed with 1 N NaOH. The combined organic extract was dried (MgS04), filtered, and concentrated. Purification by silica gel chromatography with an ISCO system (eluant: EtOAc/hexane) to yield the title compound as an off white solid. LC/MS = 537 [M+l]. EXAMPLE 69

3 -((2-oxo-4-(5-(3 -phenoxybenzamido)pwidin-2-vI piperazir~ 1 -yl)methyl)benzoic acid

To a stirred solution of product obtained in Example 68 (100 mg, 0.186 mmol) in MeOH (3 mL), THF (3 mL), and water (1 mL) was added lithium hydroxide (50 mg, 1.19 mmol). The reaction mixture was heated at 50 °C for 14 h then cooled to RT. 1 N HC1 (2.5 mL) was added, and the solution concentrated. The product was purified by reverse phase semi prep HPLC Gilson system (eluant: CH₃CN H₂0 HCOOH, C18 100 x 21.20 mm 5 micron column) to yield the title compound as an off white solid. LC/MS = 523 [M+l].

The following compounds were prepared by using methods described in Examples 68-69.

EXAMPLES 73 and 74

Step A: ethyl 4-(5 -bromopyridin-2-yloxy)cycl ohexanecarboxylate

To a solution of 5-bromo-2-hydroxypyridine (1.0 g, 5.747 mmol) and ethyl 4- hydroxycyclohexanecarboxylate (0.99 g, 5.75 mmol) in THF (50 mL) was added PPh₃ (2.4 g,

9.15 mmol) and DIAD (1.8 mL, 9.14 mmol). The reaction mixture was stirred at RT for 17 h.

The solution was then concentrated and purified by silica gel column chromatography with an

ISCO system to yield ethyl 4-(5-bromopyridin-2-yloxy)cyclohexanecarboxylate as a colorless oil.

Step B: ethyl 4-( 5-(4 A5 -tetramethyl- 1.3.2-dioxaboroian-2-yl pyridin-2- vioxy)cyclohexanecarboxylate

To a solution of ethyl 4-(5-bromopyridin-2-yloxy)cyclohexanecarboxylate (1.23 g, 4.84 mmol) and bis(pinacolato)diboron (1.16 g, 3.53 mmol) in 1,4 dioxane (30 mL) was added KOAc

(1.98 g, 20.2 mmol) and Pd(dppf)Cl₂*CH2Cl₂ (164.4 mg, 0.201 mmol). The reaction mixture was heated at reflux for 15 h. The solution was cooled to RT, filtered through celite, concentrated and purified by silica gel column chromatography with an ISCO system to yield ethyl 4-(5-

(4,4,5,5-tetramethyl-l ,3 ,2-dioxaborolan~2-yl)pyridin-2~yloxy)cyclohexanecarboxylate as a colorless oil.

Step C: ethyl 4-(5 -amino-2,3 '-bipyridin-6'-yloxy cyclohexanecarboxylate

To a solution of ethyl 4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2~yl)pyridin-2- yloxy)cyclohexanecarboxylate (300 mg, 0.799 mmol) and 5-amino-2-bromopyridine (160 mg, 0.924 mmol) in 1,4 dioxane:H₂0 (3:1, 20 mL) was added

tetrakis(triphenylphosphine)palladium(0) (194 mg, 0.168 mmol) and Na₂C0₃ (267 mg, 2.52 mmol). The reaction mixture was heated at reflux for 15 h. The solution was cooled to RT, filtered through celite, concentrated and purified by silica gel column chromatography with an ISCO system to yield ethyl 4-(5-amino-2₅3'-bipyridin-6'-yloxy)cyclohexanecarboxylate as a brown oil. LC/MS = 342 [M+l].

Step D: ethyl 4-(5-(3-phenoxybenzamido)-2 3'-bipyridin-6'-yloxy cyciohexanecarboxylate To a solution of ethyl 4-(5-amino-2_;3'-bipyridin-6'-yloxy)cyclohexanecarboxylate (100 mg, 0.293 mmol) and 3-phenoxy benzoic acid (69 mg, 0.322 rnmol) in CH2CI2 (10 mL) was added HATU (167 mg, 0.440 mmol) and Hunig's base (153 pL, 0.879 mmol). The reaction mixture was stirred at RT for 17 h. The solution was then concentrated and purified by silica gel column chromatography with an ISCO system to yield ethyl 4-(5-(3-phenoxybenzamido)-2,3'- bipyridin-6'-yloxy)cyclohexanecarboxylate as a white solid. LC/MS = 538 [M+l],

Step E: 4-(5-(3-phenoxybenzamido)-2_<3'-bipyridin-6'-yloxy cyclohexanecarboxylic acid

To a solution of ethyl 4-(5-(3-phenoxyberizamido)-2_s3'-bipyridin-6'- yloxy)cyclohexanecarboxylate (85.6 mg, 0.159 mmol) in THF:H₂0 (4:1, 5 mL) was added LiOH*H₂0 (66.9 mg, 1.59 mmol). The reaction mixture was stirred at RT for 15 h. I N HC1 was added until acidic. The resulting solution was then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgS0₄), filtered and concentrated. Purification by Gilson reverse phase HPLC to yield - 5- 3- eno benzamido)-2,3'-bi yridi -6^,- yloxy)cyclohexanecarboxylic acid as a white solid. LC/MS = 510 [M+l].

Intermediate 5

Step A: methyl 2-(phenylamino)pyrimidine-4 -carbox ylate

Methyl 2-chloropyrimidine-4-carboxylate (250 mg, 1.45 mmol), aniline (0.132 mL, 1.45 mmol) and NaHC0₃ (182 mg, 2.17 mmol) were dissolved in anhydrous 1,4-dioxane (3.60 mL).

The reaction mixture was heated at reflux for 20 h then cooled to RT and concentrated to ca. 1.0 mL. EtOAc (50 mL) and 1 N HC1 (20 mL) were added, and the aqueous solution was extracted with EtOAc. The combined organic extract was successively washed with water then brine, dried

(MgS0 ), filtered, and concentrated. Purification by silica gel chromatography (eluant: 10-90%

EtOAc/hexanes) yielded the title compound as a yellow solid. LC/MS = 252.1 [M+Na].

Step B: 2-(phenylamino)pyrimidine-4-carboxylic acid

To a stirred solution of methyl 2-(phenylamino)pyrimidine-4-carboxylate (325 mg, 1.41 mmol) in MeOH (4.7 mL), THF (4.7 mL), and water (4.7 mL) was added lithium hydroxide monohydrate (296 mg, 7.05 mmol). The reaction mixture was stirred at RT for 16 h. I N HCl (9.0 mL) was then added, and the solution was concentrated. Water was added, and a precipitate formed. The precipitate was filtered and washed with water (2 mL), then dried under high vacuum to yield the title compound as a yellow solid. LC/MS = 216.2 [M+l].

Intermediates 6 and 7

6

Step A: methyl 3 -(5-bromopyridin-2-yloxyV2,2-dimethylpropanoate

Sodium hydride (60% disp. in oil, 908.0 mg, 22.7 mmol) was added portionwise at RT to a solution of 5-bromo~2-fiuoropyridine (1.16 mL, 11.4 mmol) and methyl 3-hydroxy-2,2- dimethylpropanoate (1.88 mL, 14.8 mmol) in anhydrous THF (33 mL) and dry 1 ,3 -dimethyl - 3,4,5,6-tetraliydro-2(lH)-pyrimidinone (5.0 mL) under argon. After 2 h of stirring at RT, the reaction mixture was heated at 50 °C for 10 h and then at 70 °C for 3 h. The suspension was cooled to RT and filtered over a thin celite pad. The celite pad was rinsed with Et₂0 (150 mL). The filtrate was concentrated to a volume of ca. 5 mL, then diluted with Et₂0 (150 mL), quenched with water (90 mL) and decanted. The aqueous layer was extracted with Et₂0; the combined organic extract was successively washed with water then brine, dried (MgSC^), filtered and concentrated. Purification by silica gel chromatography (eluant: 0-20%

EtOAc hexanes) yielded the title compound as a clear oil. MS = 288, 290 [M+l).

Step B: methyl 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin~2- yloxy propanoate [lJ'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (217 mg, 0.27 mmol), potassium acetate (1.57 g, 16.0 mmol), bis(pinacolato)diboron (1.62 g, 6.39 mmol) and methyl 3- (5-bromopyridm-2-yloxy)-2,2-dimethylpropanoate (1.53 g, 5.32 mmol) were mixed at RT in anhydrous 1,4-dioxane (27 mL). The reaction was degassed several times, placed under argon and stirred at 60 °C for 10 h. After cooling to RT, the mixture was filtered through a celite pad. The celite pad was washed with EtOAc, and the filtrate concentrated. Purification by silica gel chromatography (eluant: 5-95% EtOAc hexanes) yielded the title compound as a white solid. LC/MS - 336.1 [M+l].

Step C: potassium trifluoro(6-r3-methoxy-2,2-dimethvi-3-oxopropoxy pyridin-3-yl^')borate

Potassium hydrogen difluoride (525 mg, 6.72 mmol) was added at RT to a solution of methyl 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yloxy)propanoate (750 mg, 2.24 mmol) in a 2:1 mixture of water and methanol (11 mL). The reaction was stirred at RT in a polypropylene reactor for 4 h. The reaction mixture was then concentrated, and the resulting residue was triturated with ice-cold water (50 mL), quickly filtered, washed with ice-cold diethyl ether (250 mL) and dried under high vacuum to give Intermediate 6 as a white solid.

Step D: methyl 2,2-dimethyl-3 -( 5-( 4-nitrophenyl)pyridin-2-yIoxy)propanoate

Intermediate 6 potassium trifluoro(6-(3-methoxy-2,2-dimethyl-3-oxopropoxy)pyridin-3- yl)borate (175 mg, 0.55 mmol), l-bromo-4~nitrobenzene (93.3 mg, 0.46 mmol), anhydrous potassium carbonate (160 mg, 1.16 mmol) and [l,3-bis(2,6-diisopropylphenyl)imidazol-2- ylidene](3-chloropyridyl)palladium(II) dichloride (PEPPSI-z^'Pr, 31 mg, 0.046 mmol) were mixed in 1 :1 EtOH: water (4.6 mL) in a 5 mL microwave reactor vial, evacuated several times and placed under argon. The reaction mixture was sealed, heated at 60 °C for 30 mins under microwave irradiation, then cooled to RT and concentrated. Purification by silica gel

chromatography (eluant: 5-100% EtOAc/hexanes) yielded the title compound as a light beige solid. LC/MS = 331.2 [M+l].

Step E: methyl 3-(5-f4-aminophenyl pyridin-2-yloxy)-2,2-dimethylpropanoate

To methyl 2,2-dimethyl-3-(5-(4-nitrophenyl)pyridin-2-yIoxy)propanoate (122 mg, 0.37 mmol) dissolved in EtOAc (1.65 mL) and EtOH (1.65 mL) under a nitrogen atmosphere was added platinum dioxide (20 mg). The resulting reaction mixture was stirred at RT under a hydrogen atmosphere (balloon) for 16 h. The catalyst was removed by filtration through celite and washed with EtOH. The filtrate was concentrated to yield Intermediate 7 as a light beige solid. LC/MS = 301.2 [M+l]. ntermediates 8 and 9

Step A: fert-butyl 4-(( memylsulfonyloxy methyl)piperidine- 1 -carboxylate

To terf-butyl 4-(hydroxymethyl)piperidine-l-carboxylate (3.8 g, 17.4 mmol) in CH₂C1₂

(70 mL) at 0 °C was added 7Y_siV-diisopropylethylamine (6.1 mL, 34.8 mmol) and mesyl chloride (2.0 mL, 26.1 mmol). The reaction mixture was stirred at 0 °C for 20 mins then at RT for 1 h. Water (50 mL) was added, and the aqueous solution was extracted with Et₂0. The combined extract was successively washed with water then brine, dried (MgS0₄), filtered, and concentrated to yield the title compound as an orange oil.

Step B: f erf-butyl 4-(Y3 -(methoxycarbonyl phenoxy)methYl)piperidine- 1 -carboxylate

To methyl 3~hydroxybenzoate (3.97 g, 26.10 mmol) in dry DMF (50 mL) under argon was added sodium hydride (1.18 g of 60 wt% in oil, 29.6 mmol). The mixture was stirred at RT for 15 mins then added f erf-butyl 4-((methylsulfonyloxy)methyl)piperidine-l -carboxylate (5.15 g, 17.4 mmol) in dry DMF (35 mL). The resulting mixture was heated at 50 °C for 16 h then cooled and concentrated. Water (50 mL) was added, and the aqueous solution was extracted with Et₂0. The combined extracts was successively washed with water then brine, dried (MgS0₄), filtered, and concentrated. Purification by silica gel chromatography (eluant: 5-95%

EtOAc/hexanes) yielded the title compound as a solid. LC MS = 372.2 [M+Na].

Step C: methyl 3 -(piperidin-4-yImethoxy)benzoate ferf -butyl 4-((3-(memoxycarbonyl)phenoxy)methyl)piperidine-l-carboxylate was stirred at RT in 4 N HC1 in dioxane for 3 h. The reaction mixture was then concentrated, and the solid residue was triturated with Et₂0 (100 mL), filtered and rinsed with Et₂0. The residue was then dissolved in EtOAc, then successively washed with Na₂C0₃ (sat) and brine, dried (MgS0₄), filtered, and concentrated to give the Intermediate 8 as a light tan solid. LC/MS = 250.1 [M+l]. Step D: methyl 3-((l-(^'5-nitropyrimidin-2-yl)piperidin-4-yl)methoxy)benzoate

Methyl 3-(piperidin-4-ylmethoxy)benzoate (507 mg, 2.04 mmol), 2-chloro-5- nitropyrimidine (250 mg, 1.57 mmol) and N,N-diisopropylethylamine (0.55 mL, 3.13 mmol) were dissolved in α,α,α-trifluorotoluene (3.90 mL) under nitrogen in a microwave reactor vial. The reaction mixture was sealed and heated under microwave irradiation for 120 mins at 120° C. EtOAc and water were added, and the mixture was decanted. The aqueous solution was extracted with EtOAc, and the combined organic extract was successively washed with water then brine, dried (MgS0₄), filtered, and concentrated. Purification by silica gel chromatography (eluant: 10- 100% EtOAc/hexanes) yielded the title compound as a solid. LC/MS = 373.2 [M+l].

Step E: methyl 3-((l-(5-ai inop imidin-'2-yl)piperidin-4-yl)methoxy)berLzoate

To methyl 3-((l-(5-nitropyrimidin-2-yl)piperidin-4-yl)methoxy)benzoate (159 mg, 0.42 mmol) dissolved in EtOAc (1.05 mL) and EtOH (1.05 mL) under a nitrogen atmosphere was added platinum dioxide (35 mg). The resulting reaction mixture was stirred at RT under a hydrogen atmosphere (balloon) for 20 h. The catalyst was removed by filtration through celite, and the celite was washed with EtOH. The filtrate was concentrated to yield crude Intermediate 9 as a pale yellow solid. LC/MS = 343.2 [M+l].

EXAMPLE 75

methyl 3-((l-(5-(2-phenoxypyrimidine-4-carboxamido)pyridin-2-yl)piperidin-4- yl)methoxy)ben2oate

To Intermediate 5, 2-(phenylamino)pyrimidine-4-carboxylic acid (48 mg, 0.22 mmol) in dry DMF (2.2 mL) was added intermediate I (82 mg, 0.24 mmol), HATU (167 mg, 0.44 mmol), and Nj/Y-diisopropylethylamine (0.12 mL, 0.66 mmol). The reaction mixture was stirred at RT for 48 h then concentrated. Water was added, and the aqueous solution was extracted with ethyl acetate. The combined organic extract was successively washed with water then brine, dried (MgS0₄), filtered, and concentrated. Purification by Cig reverse phase chromatography (eluant: 10-100% C¾CN in water - with 0.3% HCOOH) yielded the title compound as a light yellow solid. LC/MS - 540.1 [M+l].

EXAMPLE 76

3~((i-(5-(2-phenoxypyrimidine-4-carboxamido)^ acid

To a stirred solution of Example 75 (84 mg, 0.15 mmol) in MeOH (0.5 mL), THF (0.5 mL), and water (0.5 mL) was added lithium hydroxide monohydrate (31.5 mg, 0.75 mmol). The reaction mixture was stirred at RT for 16 h. I N HCl (2.0 mL) was then added, and the solution was concentrated. The solid residue was purified by Cjg reverse phase chromatography (eluant: 10-100% CH₃CN in water - with 0.1% HCOOH) to yield the title compound as a light tan solid. LC/MS = 526.2 [M+l].

The following compounds were prepared following methods described in Examples 75- 76 and using Intermediates 5 to 9 or closely related analogues prepared similarly.

85 501.2 [Μ+1].

o 0

86 557.2 [Μ+1],

87 573.2 [Μ+1].

⁰ 0

88 555.2 [Μ+1],

89 543.2 [Μ+1].

90 559.1 [Μ+1].

° 0

EXAMPLE 94

3-(5'-[(5-Phenyl-furan-2-carbonyl)-amino]-3,4,5.6-tetrahydro-2H-[L2']bipyri

ylmethoxy} -benzoic acid

To a mixture of 2-(lH-7-Azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uranium hexafluorophosphate Methanaminium (HATU) (66.8 mg, 0.176 mmol) and 5-Phenyl-furan-2- carboxylic acid (33.1 mg, 0.176 mmol) was added 3-(5'-Amino-3,4,5,6-tetrahydro-2H~

[l,2']bipyridinyl-4-ylmethoxy)-benzoic acid methyl ester (30.0 mg, 0.088 mmol) in DMF (0.5 mL) and Et₃N (24 μΕ, 0.176 mmol). The reaction was stirred at ambient temperature for 16 h and quenched with water (1 mL). The solution was extracted with EtOAc (2 mL x 2). The combined organic layer was concentrated in vacuum. The residue was dissolved in MeOH/THF (1:1, 1 mL) and 2.5N LiOH/HaO (0.1 mL) solution was added. The mixture was stirred at 60 °C for 5 h and the volatiles were evaporated in vacuum. The residue was suspended in water (0.5 mL) and the pH was adjusted to 5 with 1 N HCI aqueous solution. The mixture was concentrated in vacuum and the residue was dissolved in DMSO (1 mL). The solution was filtered and the filtrate was purified by mass triggered reverse phase HPLC to give the desired compound, LC-MS: 498.19.

The following compounds were prepared following methods described in

Exam le 94.

The in vitro assay to identify DGAT1 inhibitors uses human DGAT1 enzyme expressed in Sf9 insect cells prepared as microsomes. The reaction is initiated by the addition of the combined substrates 1,2-dioleoyl-sn-glycerol and [¹⁴C]~palmitoyl-Co A and incubated with test compounds and microsomal membranes for 2 hours at room temperature. The assay is stopped by adding 0.5 mg wheat germ agglutinin beads in assay buffer with 1% Brij-35 and 1% 3 -cholamidopropyldimethyl-ammonio-1 -propane sulfonate. Plates are sealed with TopSeal and incubated for 18 hours to allow the radioactive triglyceride product to come into proximity with the bead. Plates are read on a TopCount instrument.

Percent inhibition was calculated as the percent of (test compound inhibition minus non-specific binding) relative to (total binding minus non-specific binding). IC₅o values were determined by curve fitting the data to a Sigmoidal dose-response in GrapbPad Prism utilizing the following equation;

. Y = A + (B-A)/(l+10^A((LogIC₅₀-X)))₅

where A and B are the bottom and top of the curve (highest and lowest inhibition), respectively, and X is the logarithm of concentration.

Assay 2

To a 384 well assay plate was added 1 μΐ, of a 400 μ solution of the test compound in DMSO and 20 L of a substrate mix that is 300 μΜ in diolein and 40 μΜ in oleoyl- CoA in 10% ethanol. To this was added 19 ΐ, of 1.05 μg/mL human DGAT1 -expressed yeast membrane fraction in a buffer of the following composition: 200 mM Tris, pH 7, 200 raM sucrose, 200 mM magnesium chloride, and 20 g mL N-ethylmaleimide-treated bovine serum albumin. The solution is incubated at room temperature for 1 hour after which 20 μΐ, of a 90 μΜ 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin solution in 90% ethanol was added. After incubation in the dark for 30 minutes at room temperature, fluorescence was measured on a Perkin Elmer Envision multilabel reader. The IC50 is determined from a 4 parameter fit of the plot of %Inhibition vs. Concentration of Test Compound in the reaction and is defined as the concentration at which the curve crosses the 50% inhibition line.

The inhibitory activity was calculated from the following formula: % inhibition = [1 -(fluorescence counts from test compound- average fluorescence counts from LC)/(average fluorescence counts from HC-average fluorescence counts from LC)] x 100%

LC = low control = maximal inhibition by excess amount of a Merck DGAT1 inhibitor

HC = high control = DMSO = uninhibited control

If Examples 1-94 were assayed, the compounds were assayed using Assay 1. If Examples 95-139 were assayed, the compounds were assayed using Assay 2.

Potency of DG AT- 1 Inhibitors

Example No. ICso(nM) Example No. IC₅o(nM)

2 105 85 12

4 460 89 41

6 392 90 59

13 149 91 21

14 891 94 8

15 49 95 13

16 47 96 433

17 1347 97 21

18 79 98 217

20 46 99 326

22 32 100 188

24 41 101 11

25 91 102 74

27 46 103 24

28 24 104 39

29 25 . 105 1738

30 1 ^ 106 144

31 36 107 399

32 31 108 7

33 271 109 530

34 30 110 3888

35 74 111 87 36 2419 112 207

37 55 113 1739

38 89 1 14 160

39 1264 115 30

40 752 116 156

41 126 117 981

42 499 1 18 1056

43 760 1 19 890

44 802 120 1 1

45 452 121 399

46 52 122 418

47 35 123 619

48 193 124 421

50 46 125 5783

51 37 126 537

52 989 127 215

63 68 128 10000

64 422 129 556

65 2433 130 36

66 242 131 98

67 588 132 10000

68 715 133 324

69 449 134 4570

70 760 135 953

72 531 136 192

76 213 137 29

77 12 138 90

80 1005 139 167

Claims

WHAT IS CLAIMED IS:

or pharmaceutically acceptable salts thereof, wherein

each occurrence of U is independently selected from the group consisting of ~N- and -CH-, wherein ring A is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, Q-C galkyl and halogen- substituted Cj-C ₆alkyl;

ring B is piperidine_f piperazine, piperazinone, pyridine or pyrrolidine, wherein ring B is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, Cj-C ₆alkyl and halogen-substituted Q-C ₆alkyl;

W is ~(CH₂)n-C(0)NR²-(CH₂)n- or -(CH₂)n-NR²C(0)-(CH₂)n-;

X is selected from the group consisting of -(CH₂)n-0-(CH₂)n-; -(CH₂)n- C(0)NR²-(C¾)n-; -(CH₂)n-C(0)CR1H-(CH₂)n-; -(CH₂)n-C(R¹)₂-(CH₂)n-; -(CH₂)n-NR²C(0)~ (CH₂)ns -(C¾)n-OC(0)-(CH₂)n-; ~(CH₂)n-C(0)0-(CH₂)n-; -(CH₂)n-NR²S0₂-(CH₂)ns - (CH₂)n-S0₂NR -(CH₂)n-; -(CH₂)n-C(0)n-(CH₂)n-; -(C¾)n-NR²C(0)CR1H-(CH₂)n-;

each occurrence of R^l is independently selected from the group consisting of hydrogen and Ci-C₆alkyl;

each occurrence of R² is independently selected from the group consisting of hydrogen and Ci~C₆alkyl;

Y is Ci-C ealkyl, phenyl or cycloalkyl, wherein the Q-C ₆alkyl, phenyl or cycloalkyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, Ci-Cgalk l, halogen- substitutedCi-C₆alkyl, COCi-Cgalkyl, COhalogen-substitutedC i- C₆alkyl, -OH, C_rC₆aikylOH, haIogen-substitutedCi-C₆alk lOH, -OQ-Cealkyl, -Ohalogen- substitutedCi-C₆alkyl, -COOH, -COCOOH, -COOC_rC₆alkyl_; -Ci-CeallsylCOOCi-Cealkyl, -C_r C₆alkylCOOH and -OCi-C₆alk lCOOH;

Z is selected from the group consisting of phenyl, monocyclic cycloalkyl, monocyclic heterocycle, naphthalene, tetrahydronaphthalene,

wherein Z is unsubstituted or substituted with lor 2 substituents selected from the group consisting of halogen, Ci-Cgalkyl, halogen-substitutedCrC₆alkyl, COCi-Cisalkyl, COhalogen- substitutedCi-Cealkyl, -OH, Ci-Cealk lOH, halogen-substitutedCi-C₆alkylOH, -OC_rC₆alkyl, - Ohalogen-substitutedCi-Cealkyl, -COOH, -COCOOH, -COOd-Qalkyl, -C_rC_f)alkylCOOCr C₆alkyl, -C C₆alkylCOOH and -OCi-C₆alkylCOOH; and

n is 0, 1 or 2.

2.

or pharmaceutically acceptable salt thereon, wherein

each occurrence of U is independently selected from the group consisting of-CH- and -N-;

T is -CH₂- or CO;

V is -CR⁴-, o -N-;

R³ and R⁴ are selected from the group consisting of hydrogen, halogen, Q-Cealkyl and halogen-substitutedCi-Cealkyl; and

W, X, Y, Z and n are defined as in claim 1.

3.

or pharmaceutically acceptable salt thereon, wherein

each occurrence of U is independently selected from the group consisting of -CH- and -N-;

R³ and R⁵ are selected from the group consisting of hydrogen, halogen, C_rC₆alkyl and halogen-substitutedCrCealkyl;

W is selected from the group consisting of -(CH₂)n-C(0)NR²-(C]¾)n- and - (CH₂)n-NR C(0)-(CH₂)n-; and

X, Y„ Z and n are defined as in claim 1.

4. A compound of any one of claims 1-3, or pharmaceutically acceptable salt thereof, wherein ring A is an unsubstituted pyridine.

5. A compound of any one of claims 1 -2, or pharmaceutically acceptable salt thereof, wherein ring B is piperidine.

6. A compound of any one of claims 1-2, or pharmaceutically acceptable salt thereof, wherein ring B is an unsubstituted piperazine or piperazinone.

7. A compound of any one of claims 1 or 3, or pharmaceutically acceptable salt thereof, wherein ring B is an unsubstituted pyridine.

8. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein ring B is an unsubstituted pyrrolidine.

9. A compound of any one of claims 1-8, or pharmaceutically acceptable salts thereof wherein X is -C¾0-, -C(0 , -CH₂-, -C(0)NH- or -0-.

10. A compound of any one of claims 1-9, or pharmaceutically acceptable salts thereof wherein X is -CH₂0-, -C(0>, -C(0)NH-, - NHC(O)-, -C¾C(0)NH-, - (C¾)₂C(0)NH- or -0-.

11. A compound of any one of claims 1 - 10, or pharmaceutically acceptable salts thereof wherein Y is phenyl.

12. A compound of any one of claims 1-10, or pharmaceutically acceptable salts thereof wherein Y is cycloalkyl wherein the cycloalkyl is cyclohexane.

13. A compound of any one of claims 1 - 10, or pharmaceutically acceptable salts thereof wherein Y is Ci-Cealkyl wherein the d-C^aHcyl is isobutane.

14. A compound of any one of claims 1 - 13 , or pharmaceutically acceptable salts thereof wherein Y is substituted with 1-2 substituents selected from the group consisting of halogen, -COOH, -COOCi-C₆alkyl and C C₆alkyl.

15. A compound of any one of claims 1 - 13 , or pharmaceutically acceptable salts thereof wherein Z is selected from the group consisting of:

16. A compound of any one of claims 1-13, or pharmaceutically acceptable salts thereof wherein Z is selected from the group consisting of:

17. A compound of any one of claims 1 - 13 , or pharmaceutically acceptable salts thereof wherein Z is selected from the group consisting of:

18. A compound of any one of claims 1 - 13, or pharmaceutically acceptable salts thereof wherein Z is selected from the group consisting of:

19. A compound as in any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein Z is substituted with 1 or 2 substituents selected from the consisting of halogen, -COOH, -OCrCgalfcyl, -Ohalogen-substitutedCi-Cealkyl, halogen- substitutedCi-Cealkyl, Ci-C₆alkyl and -NH-phenyl.

20. A compound or pharmaceutically acceptable salt thereof, selected from the rou consistin of:

OH

F

-97-

- 100-

21. A pharmaceutical composition comprising a compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. Use of a compound of any one of claims 1 -20, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating a condition selected from the group consisting of obesity and diabetes.

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