WO2012009217A1

WO2012009217A1 - Spirocyclic compounds

Info

Publication number: WO2012009217A1
Application number: PCT/US2011/043330
Authority: WO
Inventors: Timothy A. Cernak; James M. Balkovec; Ravi P. Nargund; Maud Reiter; Donald M. Sperbeck; Kevin D. Dykstra; Yang Yu; Spencer Dreher; Kevin M. Maloney; Zhicai Wu; Robert J. Devita; Andreas Verras
Original assignee: Merck Sharp & Dohme Corp.
Priority date: 2010-07-13
Filing date: 2011-07-08
Publication date: 2012-01-19
Also published as: CA2804970A1; JP2013531037A; AU2011279509A1

Abstract

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

Description

SPIROCYCLIC COMPOUNDS

TECHNICAL FIELD

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

BACKGROUND

Metabolic syndrome is associated with obesity and is recognized as an upstream risk factor for many conditions such as diabetes mellitus, lipidosis, hypertension (Journal of Japan Society for the Study of Obesity, Vol. 12, Extra Edition, 2006). Since metabolic syndrome is associated with an increase in the risks of arteriosclerosis, cardiovascular disorder and cerebrovascular disorder, treatment of obesity has been recognized to be important for preventing these diseases. 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 triacylglycerol (TG) in adipose tissue which is a result of lack of exercise, intake of excessive calories and ageing. 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 of acyl -coenzyme A to the 3-position of 1,2-diacylglycerol to generate TG (Prog. Lipid Res., 43.134-176. 2004 and Ann. Med., 36, 252-261, 2004). There are two subtypes of DGATs: DGATl and DGAT2. There is no significant homology at the generic or amino acid level between the DGATl and DGAT2, which are encoded by different genes (Proc.Natl.Acad.Sci.USA.,95,13018-13023,1998 and JBC,276,38870-38876,2001). DGATl 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 DGATl 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 the lipid secretion from the liver. In order to carry out in vivo examination of the physiological function(s) of DGAT1 and inhibitory activity against DGAT 1, DGAT1 -knockout mice deficient in DGAT1 at the generic level was produced, and analyses thereof were conducted. 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 101,109,1049-1055,2002). In addition, energy expense has been reported to be accelerated in the DGAT1 -knockout mice; and transplantation of the adipose tissues of DGAT1 -knockout mice into wild-type mice has been reported to make the wild-type mice resistant to obesity and abnormal glucose tolerance, induced by a high-fat diet (JCI,111,1715-1722,2003 and Diabetes,53,1445-1451,2004). In contrast, obesity and diabetes mellitus due to a high-fat diet have been reported to worsen in mice with overexpression of DGAT1 in adipose tissue (Diabetes,51,3189-3195,2002 and Diabetes,54,3379-3386,2005).

From the results, DGAT1 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 The present invention is directed to compounds of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein A is independently selected from the group consisting of benzene, pyridine, pyrazine and pyrimidine;

R, G and E are independently selected from the group consisting of -N- and -CH-, wherein if one of R, G and E is -N-, the remaining two are -CH-;

R' and R" together form ring D, wherein D is selected from the group consisting ofcycloalkyl and heterocycloalkyl wherein A, B, C and D are independently unsubstituted or substituted with one or more substituents selected from the group a, C₁-C₆alkyl, C₃-

C₁₀cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C₁-C₆alkyl C₃-C₁₀cycloalkyl, C₁-C₆alkylaryl, C₁- C₆alkylheteroaryl and C₁-C₆alkylcycloheteroalkyl, wherein C₁-C₆alkyl, C₃-C₁₀ cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C₁-C₆alkylC₃-C₁₀cycloalkyl, C₁-C₆alkylaryl, C₁-C₆alkylheteroaryl and Cj-Cealkylcycloheteroalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of a;

a is selected from the group consisting of halogen, C₁-C₆alkyl, halogen- substitutedC₁-C₆alkyl, COd-Cealkyl, oxo, -OH, halogen-substitutedC₁-C₆alkylOH, -OCi- Cealkyl, -Ohalogen-substitutedC]-Qalkyl, -COOH, -COOCj-Cealkyl, -Cj-C6aIkylCOOCi- Cealkyl, -C₁-C₆alkylCOOH, -OC₁-C₆alkylCOOH, -CN, C₁-C₆alkylCN, -NO2, NH₂, NHCj- Cealkyl, NCCi-C^alkyl^, -NHCOOH, -NHCOOQ-Cjalkyl, -CONH₂, -CONHC₁-C₆alkyl, - CON(Ci-C6alkyl)₂, -CONHC₁-C₆alkyl-NCd-Cealkyl^, -NHSC^C₁-C₆alkyl, -S02NH_2> -SO2C₁- Cealkyl, C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C₁- C₆alkylC3-C]ocycloalkyl, Cj-Cealkylaryl, C₁-C₆alkylheteroaryl and Ci-C6alkylcycloheteroalkyl.

DETAILED DESCRIPTION OF THE INVENTION

Compounds

The present invention is directed to compounds of structural formula I:

R' and R" together form ring D, wherein D is selected from the group consisting of cycloalkyl and heterocycloalkyl wherein A, B, C and D are independently unsubstituted or substituted with one or more substituents selected from the group a, Cj-Cealkyl, C3- Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, Ci-C6alkylC₃-Ciocycloalkyl, C₁-C₆alkylaryl, Cj- C6alkylheteroaryl and C₁-C6alkylcycloheteroalkyl, wherein Q-Cealkyl, C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C₁-C₆alkylCs-Ciocycloalkyl, C₁-C₆alkylaryl, Ci-C6alkylheteroaryl and C₁-C₆alkylcycloheteroalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of a;

a is selected from the group consisting of halogen, Ci-C6alkyl, halogen- substitutedC₁-C₆alkyl, COCi-C6alkyl, oxo, -OH, halogen-substitutedC₁-C₆alkylOH, -Od- Cealkyl, -Ohalogen-substitutedC₁-C₆alkyl, -COOH, -COOd-Qsalkyl, -Cj-CealkylCOOC,- Cealkyl, -d-CealkylCOOH, -OCi-OjalkylCOOH, -CN, C,-C₆alkylCN, -N0₂, NH₂, NHC,- Cealkyl, NCC-Cealkyl^, -NHCOOH, -NHCOOCi-Qsalkyl, -CONH₂, -CONHCi-Csalkyl, - CON(Ci-C6alkyl)2, -CONHC₁-C₆alkyl-NCC₁-C₆alkyl^, -NHSC^C₁-C₆alkyl, -SO2NH2, -S<¼Ci- Cealkyl, C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, Cj- C6alkylC₃-Ciocycloalkyl, C₁-C₆alkylaryl, C₁-C₆alkylheteroaryl and Cj-Cealkylcycloheteroalkyl.

In certain embodiments of the compounds described herein, A is selected from the group consisting of benzene, pyridine, pyrazine and pyrimidine. In some embodiments A is selected from the group consisting of benzene and pyridine. In other embodiments, A is benzene. In still other embodiments, A is pyridine. In yet other embodiments, A is pyrazine. In still other embodiments, A is pyrimidine. In some embodiments A is unsubstituted. In other embodiments, A is substituted.

In some embodiments, A is substituted with one or more substituents selected from a. In certain embodiments, A is further substituted with one or more substituents selected from the group consisting of halogen, Ci-C6alkyl, -OC₁-C₆alkyl, -CN, SC>₂Me and halogen- substitutedC₁-C₆alkyl. In some embodiments, A is further substituted with one substituents selected from the group consisting of halogen, C₁-C₆alkyl, -OCi-C₆alkyl, -CN, SC¾Me and halogen-substitutedC₁-C₆alkyl. In some embodiments, A is further substituted with two substituents selected from the group consisting of halogen, Cj-Cealkyl, -OC₁-C₆alkyl, -CN, SC^Me and halogen-substitutedC₁-C₆alkyl. For example, A can be substituted with one or more halogens. Examples of halogens include, but are not limited to, chlorine, bromine and fluorine. In another example, A can be substituted with one or more C₁-C₆alkyls. Examples of Ci-C^aUcyl include but are not limited to methyl and ethyl. A can also be substituted with halogen- substitutedC₁-C₆alkyl. Examples of halogen-substituted C₁-C₆alkyl, include but are not limited to, trifluoromethyl. In still other examples, A can be substituted with one or more substituents selected from the group consisting of methoxy, trifluoromethoxy, -OH, CN, CH₂CN, NHS0₂Me and SO2NH2. In yet other examples A is substituted with (C2H₄)NHCOCH3 or

CONH(C2H )N(C2H4)₂.

In some embodiments, A is substituted with one or more substituents selected from aryl, heteroaryl or cycloheteroalkyl, wherein aryl, heteroaryl or cycloheteroalkyl are unsubstituted or substituted with one or more substituents selected from a. In certain

embodiments, A is substituted with phenyl. In other embodiments, A is substituted with pyridine. The pyridine can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or halogen-substitutedC₁-C₆alkyl. Suitable examples include, but are not limited to, fluorine or trifluoromethyl. In other embodiments, A is substituted with pyrimidine. The pyrimidine can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or halogen-substitutedCi- Cealkyl. Suitable examples include, but are not limited to, fluorine and trifluoromethyl.

In still other embodiments, A is substituted with one or more substituents selected from aryl, heteroaryl or cycloheteroalkyl, wherein aryl, heteroaryl or cycloheteroalkyl are fused to A, forming a polycyclic ring structure with ring A and the pyrrole of formula I. Suitable aryls, heteroaryls or cycloheleroalkyls include phenyl, pyridine, pyrimidine and triazole. Examples include but are not limited to:

In certain embodiments, G is -N- and E is -CH-. In other embodiments, G is - CH- and E is -N-. In other embodiments, G and E are both -CH-. In other embodiments, R is - N-, G and E are both -CH-. In certain embodiments, R is -CH-, G is -N- and E is -CH-. In other embodiments, R is -CH-, G is -CH- and E is -N-. In other embodiments, R, G and E are all -CH-. In still other embodiments, R is -CH- and G or E is -CH- and the other is -N-.

In certain embodiments of the compounds described herein, B is selected from the group consisting of benzene, pyridine and pyrimidine. In some embodiments B is selected from the group consisting of benzene and pyridine. In other embodiments, B is benzene. In still other embodiments, B is pyridine. In still other embodiments, B is pyrimidine. In some embodiments B is unsubstituted. In other embodiments, B is substituted.

In certain embodiments of the compounds described herein, B is substituted with one or more substituents selected from the group consisting of a. In some embodiments, B is substituted with one or more substituents selected from the group consisting of halogen, Cj- C₆alkyl and halogen-substitutedC₁-C₆alkyl. Examples of suitable halogens include, but are not limited to chlorine and fluorine. Examples of suitable C₁-C₆alkyl include, but are not limited to methyl and ethyl and examples of suitable halogen-substitutedCi-Csalkyl include, but are not limited to trifluoromethyl.

Suitable examples of ring B and its substituents include, but are not limited to,

Ring C as shown in formula I can be substituted or unsubstituted. In certain embodiments, C is unsubstituted. In certain embodiments of the compounds described herein, C is substituted with one or more substituents selected from the group consisting of a. In some embodiments, C is substituted with one or more substituents selected from the group consisting of halogen, C₁-C₆alkyl and halogen-substitutedC₁-C₆alkyl. Examples of suitable halogens include, but are not limited to chlorine and fluorine. Examples of suitable Cj-Cealkyls include, but are not limited to methyl and ethyl and examples of suitable halogen-substitutedC₁-C₆alkyls include, but are not limited to trifluoromethyl.

As shown in formula I, R' and R" together form ring D. In certain embodiments of the compounds described herein, D is cycloalkyl or heterocycloalkyl. In one embodiment, D is cycloalkyl. Suitable examples of cycloalkyl include but are not limited to cyclohexane and bycyclic cycloalkyls, such as,

In another embodiment, D is heterocycloalkyl. For example, in one embodiment, D

wherein T is selected from the group consisting of -0-, -CH2-, -NH and -NC₁-C₆alkyl-; and V, U, Q and W are independently selected from the group consisting of -N-, -C- and -CH-. In one embodiment, T is -O- and V, U, Q and W are -CH-. In another embodiment, T is O and one of V, U, Q and W is N and the remaining variables are -CH-. In yet another embodiment, T is N(CH₃) and V, U, Q and W are -CH-. In yet another embodiment, T is -CH₂- and V, U, Q and W are -CH-.

In certain embodiments of the compounds described herein, D can be selected from the group consisting of:

wherein Ra is selected from the group consisting of H and Cr alkyl. In certain embodiments, D, when selected from the group above can be unsubstituted. In more particular embodiments, D, when selected from the group above, can be further substituted with an oxo group, such as =0. In other embodiment, when D is selected from the group above, D can be substituted with one or more substituents selected from the group consisting of oxo, -OH, -COOH, -COOCi- C6alkyl, halogen, Ci-C^alky!, C₁-C₆alkylCOOH, C₁-C₆alkylCN, cyclopropyl, halogen- substitutedC₁-C₆alkyl and C₁-C₆alkyltriazole, wherein the triazole is substituted with methyl.

In particular embodiments, D, when selected from the group above, can be further substituted with a Ci- salkylaryl group. In certain embodiments, D is substituted with a-CH₂- phenyl, wherein the -Clな-phenyl is unsubstituted. In certain embodiments, D is substituted with -CH2-phenyl, wherein the -CH2-phenyI is substituted with one or more substituents selected from the group consisting of halogen, C₁-C₆alkyl and halogen-substitutedC₁-C₆alkyl.

In other embodiments of the compounds described herein, D is selected from the group consisting of:

wherein X, Y and Z are independently selected from the group consisting of -C-, -CH-, -CH₂-, - N-, -NH- and -0-. In one embodiment, Z is N, X is Cな and Y is -CO. In another embodiment, X is O, Z is N and Y is -CO. In yet another embodiment, X and Z are both -NH. In still another embodiment, Z is -N- and X is NH.

In certain embodiments of the compounds described herein, D is selected from the group consisting of:

In certain embodiments, D is substituted with one or more oxo groups. For example, D can be substituted with one =0.

In particular embodiments, D, when selected from the group above, can be further substituted with an aryl or heteroaryl group. In certain embodiments, D is substituted with a phenyl ring, wherein the phenyl is unsubstituted. In certain embodiments, D is substituted with a phenyl ring, wherein the phenyl is substituted with one or more substituents selected from the group consisting of -COOH, COOQ-Cealkyl, heterocycloalkyl-COOH, halogen, C₁-C₆alkyl, halogen-substitutedC₁-C₆alkyl, -OC₁-C₆alkylCOOH, NO2, -CN, C₁-C₆alkylCOOH, Q-

CealkylCOOC₁-C₆alkyl and -CF3OH. In certain embodiments, D is substituted with a pyridine ring, wherein the pyridine is unsubstituted. In certain embodiments, D is substituted with a pyridine ring, wherein the pyridine is substituted with one or more substituents selected from the group consisting of halogen, C₁-C₆alkyl and halogen-substitutedC₁-C₆alkyl.

In still other embodiments of the compounds described herein D is selected from the group consisting of:

P is selected from the group consisting of -O- or -CH₂-. In one embodiment, P is -0-. In another embodiment, P is -CH₂-. In particular embodiments, wherein D is selected from the group above, D is substituted with one or more substituents selected from the group consisting of -COOH, oxo, -Cj-CealkylCOOH and NHSC Me, In one embodiment, D is cyclohexane, wherein the cyclohexane is substituted with - X)OH. In another embodiment, D is cyclohexane, wherein the cyclohexane is substituted with -CpCealkylCOOH.

In yet another embodiment of the compounds described herein, D is selected from the group consisting of:

0

In particular embodiments, wherein D is selected from the group above, D is substituted with one or more substituents selected from the group consisting of -COOH and -Cj- CealkylCOOH. Examples of D and its substituents include, but are not limited to,

In of the above described embodiments of D, D can be substituted with one or more substituents selected from the group consisting of a. In certain embodiment, any of the above described embodiments of D, D can be substituted with one or more substituents selected from the group consisting of halogen, Ci-C6alkyl, halogen-substitutedC₁-C₆alkyl, oxo, -OH, - COOH, -COOC₁-C₆alkyl, -C-CealkylCOOCj-Cealkyl, -C₁-C₆alkylCOOH, -OC₁-C₆alkylCOOH, -CN, Cj-CealkylCN and -NHSなC₁-C6alkyl.

Also described herein are compounds of formula la:

or a pharmaceutically acceptable salt thereof, wherein G and E are independently selected from the group consisting of -N- and -CH-, wherein if one of G and E is -N-, the remaining one is - CHs

R¹ is selected from the group consisting of halogen or halogen-substitutedCi-

Cealkyl;

D is a C3-Ciocycloalkyl; and

R₂ is selected from the group consisting of hydrogen, Cj-Cealkyl, halogen- substitutedC₁-C₆alkyl, COC₁-C₆alkyl, -OH, oxo, halogen-substitutedC₁-C₆alkylOH, -OCi- C_$alkyl, -Ohalogen-substitutedC₁-C₆alkyl, -COOH, -COOC,-C₆alkyl, -d-CeaJkylCOOCi- Cealkyl, -C₁-C₆alkylCOOH and -OCj-CealkylCOOH.

In certain embodiments, G is -N- and E is -CH-. In other embodiments, G is - CH- and E is -N-. In other embodiments, G and E are both -CH-.

In other embodiments of the compounds described herein, D is cycloalkyl wherein the cycloalkyl is selected from the group consisting of:

In certain embodiments, D is cyclohexane.

In some embodiments, R¹ is halogen. Suitable examples of halogen include, but are not limited to, chlorine, fluorine and bromine. In some embodiments, R¹ is halogen- substitutedC₁-C₆alkyl. Suitable examples of halogen-substitutedCi -C_halky 1 include, but are not limited to, trifluoromethyl.

In certain embodiments, R² is selected from the group consisting of -COOH, -

COOC₁-C₆alkyl, -C₁-C₆alkylCOOC₁-C₆alkyl and -Cj-CealkylCOOH. For example, in some embodiments R² is selected from the group consisting of -COOH and -C₁-C₆alkylCOOH.

Examples of -Cj-QalkylCOOH include, but are not limited to, -CH₂COOH.

Aldo described herein are compounds of formula la:

or a pharmaceutically acceptable salt thereof, wherein G and E are independently selected from the group consisting of -N- and -CH-, wherein if one of G and E is -N-, the remaining one is -

CH-;

R is selected from the group consisting of halogen or halogen-substitutedCi-

C₆alkyl; D is a heterocycloalkyl; and

R2 is selected from the group consisting of hydrogen, halogen, Cj-Qalkyl, halogen-substitutedCi-C₆alkyl, COC₁-C₆alkyl, oxo, -OH, halogen-substitutedC₁-C₆alkylOH, - OC₁-C₆alkyl, -Ohalogen-substirutedC₁-C₆alkyl, -COOH, -COOC₁-C₆alkyl, -CrQalkylCOOCj- Ceallcy], -Ci-<¼alkylCOOH, -OC₁-C₆alkylCOOH, -CN, Q-CealkylCN, -N0₂, NH₂, NHCi- Qalkyl, N(C₁-C₆alkyl)₂, -NHCOOH, -NHCOOC₁-C₆alkyl, -CONH2, -CONHC₁-C₆alkyl, - CON(Ci-C6alkyl)₂, -NHSCbC₁-C₆alkyl, -S hCj-Csalkyl, C₃-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, Cj-C6alkylC3-Ciocycloalkyl, C₁-C₆alkylaryl, Ci- Cealkylheteroaryl and C₁-C₆alkylcycloheteroalkyl.

In other embodiments of the compounds described herein, D is heterocycloalkyl wherein the heterocycloalkyl is selected from the group consisting of:

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

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

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

In some embodiments, R is halogen. Suitable examples of halogen include, but are not limited to, chlorine, fluorine and bromine. In some embodiments, R¹ is halogen- substitutedC₁-C₆alkyl. Suitable examples of halogen-substitutedC₁-C₆alkyl include, but are not limited to, trifluoromethyl.

In certain embodiments, R² is selected from the group consisting of halogen, Cj- Ce lkyl, halogen-substitutedC₁-C₆alkyl, oxo, -COOH, -COOC₁-C₆alkyl, -Q-CealkylCOOCi- C₆alkyl, -C₁-C₆alkylCOOH, -Od-CealkylCOOH, -CN, Ci-CsalkylCN and Ci- C₆alkylcyclopropyl. In other embodiments R is selected from the group consisting of hydrogen, halogen, Cj-Cealkyl, halogen-substitutedC₁-C₆alkyl, oxo, -OH, halogen-substitutedCi-

CealkylOH, -COOH, -COOC-Cealkyl, -C₁-C₆alkylCOOC₁-C₆alkyl, -Ci-(¼alkylCOOH, -OQ- C₆alkylCOOH, -CN, d-CealkylCN, -NO₂, -NHSC¾C,-Qialkyl, -SOiC₁-C₆alkyl, C₃- Ciocycloalkyl and cycloheteroalkylCOOH. In another embodiment, R² is hydrogen. In still other embodiments, R² is selected from the group consisting of phenyl or pyridine, wherein the phenyl or pyridine is unsubstituted or substituted. In one embodiment, R² is phenyl. In one

embodiment, R² is pyridine. In certain embodiments, the phenyl or pyridine can be substituted with one or more substituents selected from the group consisting of halogen, Cj-Csalkyl, halogen-substitutedC₁-C₆alkyl, -COOH, -COOC₁-C₆alkyl, -Ci-C₆alkylCOOCi-C₆alkyl, -Ci- CealkylCOOH, -OC-QalkylCOOH and -CN.

Also described herein are compounds of formula lb:

or a pharmaceutically acceptable salt thereof, wherein G and E are independently selected from the group consisting of -N- and -CH-, wherein if one of G and E is -N-, the remaining one is - CH-;

T is selected from the group consisting of-O-, -CH₂-, -NH- and -NC₁-C₆alkyl-; V, U, Q and W are independently selected from the group consisting of -N-, -C- and -CH-; R is selected from the group consisting of halogen or halogen-substitutedCj-

Cealkyl; and

R³, R⁴ and R⁵ are independently selected from the group consisting of hydrogen, halogen, C₁-C₆alkyl, halogen-substitutedC₁-C₆alkyl, COC₁-C₆alkyl, oxo, -OH, halogen- substitutedC₁-C₆alkylOH, -OC₁-C₆alkyl, -Ohalogen-substitutedC₁-C₆alkyl, -COOH, -COOCi- Cealkyl, -C₁-C₆alkylCOOC-Cealkyl, -d-CealkylCOOH, -OCi-C6alkylCOOH, -CN, C,- CealkylCN, -NO₂, H₂, NHd-Cealkyl, NCC₁-C₆alkylfc, -NHCOOH, -NHCOOd-Cealkyl, - CONH2, -CONHC₁-C₆alkyl, -CONCC₁-C₆alkyl^, -NHSC^d-Cealkyl, -S0₂Ci-C6alkyl, C₃- Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C₁-C₆alkyld- Ciocycloalkyl, C₁-C₆alkylaryl, Cj-Cealkylheteroaryl and Ci-C$alkylcycloheteroalkyl, wherein the C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C₁-C₆alkylC3- Ciocycloalkyl, C₁-C₆alkylaryl, C₁-C₆alkylheteroaryl and C₁-C₆alkylcycloheteroalkyl are unsubstituted or substituted with at least one substituent selected from the group consisting of halogen.

In certain embodiments, G is -N- and E is -CH-. In other embodiments, G is -

CH- and E is -N-. In other embodiments, G and E are both -CH-.

In certain embodiment, T is -0-. In other embodiments, T is -CH₂-. In still other embodiments, T is -NH-, In yet other embodiment, T is -NCH₃.

In some embodiments, R¹ is halogen. Suitable examples of halogen include, but are not limited to, chlorine, fluorine and bromine. In some embodiments, R¹ is halogen- substitutedC₁-C₆alkyl. Suitable examples of halogen-substitutedCj-Cealkyl include, but are not limited to, trifluoromethyl.

In certain embodiments, one of V, U, Q or W is -N- and three of V, U, Q or W are selected from the group consisting of -C- and -CH-. In other embodiments, all of V, U, Q and W are -CH-.

R³ is independently selected from the group consisting of hydrogen, halogen, Ci- Cealkyl, halogen-substitutedC₁-C₆alkyl, COd-Cealkyl, oxo, -OH, halogen-substitutedCi- CisalkylOH, -OC₁-C₆alkyl, -Ohalogen-substitutedCi-C₆alkyl, -COOH, -COOCj-Cealkyl, -Ci- CealkylCOOC₁-C₆alkyl, -C-CealkylCOOH, -OC₁-C₆alkylCOOH, -CN, C₁-C₆alkylCN, -NO₂, NH₂, NHd-Cealkyl, N(Ci-C6alkyl)₂, -NHCOOH, -NHCOOC₁-C₆alkyl, -CONH₂, -CONHCi- Cealkyl, -CONfC₁-C₆alkyl^, -NHSC C₁-C₆alkyl, -S0₂Ci-C6alkyl, d-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C₁-C₆alkyld-Ciocycloalkyl, Ci- Cealkylaryl, Ci-C6alkylheteroaryl and C₁-C₆alkylcycloheteroalkyl, wherein the C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C₁-C₆alkylGj-Ciocycloalkyl, Cp Cealkylaryl, Cj-Cealkylheteroaryl and Ci-C6alk .cycloheteroalkyl are unsubstituted or substituted with at least one substituent selected from the group consisting of halogen. In certain

embodiments, R³ is selected from the group consisting of hydrogen, oxo, Cj-Cealkyl, -COOH, - Ci-C<_>alkylCOOH, C₁-C₆alkylCN, -SCbC₁-C₆alkyl, cyclopropyl, C₁-C₆alkylaryl, and Q- Cealkylcycloheteroalkyl, wherein the Ci-C6alkylaryl C₁-C₆alkylcycloheteroalkyl are unsubstituted or substituted with at least one substituent selected from the group consisting of halogen. In other embodiments, R³ is independently selected from the group consisting of hydrogen, halogen, C₁-C₆alkyl, halogen-substitutedC₁-C₆alkyl, COC₁-C₆alkyl, -OH, -COOH, - COOd-Cealkyl, -Cj-CealkylCOOC₁-C₆alkyl, C₁-C₆alkylCN and -Q-CealkylCOOH. In one embodiment, R is oxo. In another embodiment R is hydrogen. In still another embodiment, R is C₁-C₆alkylphenyl, wherein the phenyl is unsubstituted or substituted with a halogen or - COOH.

R⁴ is independently selected from the group consisting of hydrogen, halogen, Ci- Cealkyl, halogen-substitatedCj -Chalky!, COCj-Cealkyl, oxo, -OH, halogen-substitutedCi- CealkylOH, -OCi -Chalky!, -Ohalogen-substitutedC₁-C6alk l, -COOH, -COOC₁-C₆alkyl, -C CealkylCOOC₁-C₆alkyl, -Cj-CealkylCOOH, -OC-CealkylCOOH, -CN, C,-C₆alkylCN, -N0₂, N¾, NHCrCealkyl, N(Ci-C6alkyl)2, -NHCOOH, -NHCOOC₁-C₆alkyl, -CONH₂, -CONHCi- Cealkyl, -CONCC₁-C₆alkyl^, -NHSC^C₁-C₆alkyl, -S0₂C_rC6aIkyl, C₃-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, Ci-C6alkylC₃-Ciocycloalkyl, Cj- Cealkylaryl, C₁-C₆alkylheteroaryl and Cj-Cealkylcycloheteroalkyl, wherein the C3-C]ocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C₁-C6alkylC₃-Ciocycloalkyl, Ci- Qalkylaryl, C₁-C₆alkylheteroaryl and C₁-C₆alkylcycloheteroalkyl are unsubstituted or substituted with at least one substituent selected from the group consisting of halogen. In other

embodiments, R⁴ is independently selected from the group consisting of halogen, Ci-C_$alkyl, halogen-substitutedCi-Cialkyl, COC₁-C₆alkyl, -OH, -COOH, -COOC₁-C₆alkyl, -C,- C6alkylCOOCi-C6alkyl and -C₁-C₆alkylCOOH. In another embodiment, R⁴ is hydrogen.

R⁵ is independently selected from the group consisting of hydrogen, halogen, Cp C6 lkyl, halogen-sitostitutedC₁-C₆alkyl, COC₁-C₆alkyl, oxo, -OH, halogen-substitutedCj- QjalkylOH, -OC₁-C₆alkyl, -Ohalogen-substitutedC₁-C₆alkyl, -COOH, -COOQ-Cealkyl, -d- C alkylCOOC₁-C₆alkyl, -d-CealkylCOOH, -OQ-CealkylCOOH, -CN, C,-QalkylC , -N0₂, NH₂, NHCi-C₆alkyl, NCC₁-C₆alkyl)., -NHCOOH, -NHCOOC₁-C₆alkyl, -CONH₂, -CONHCi- Cealkyl, -CONfC₁-C₆alkyl^, -NHSC Ci-C alkyl, -SC C₁-C₆alkyl, C₃-C_J0cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, Ci-C6alkylC3-Ciocycloalkyl, d- Cealkylaryl, Cj-Qalkylheteroaryl and C₁-C₆alkylcycloheteroalkyl, wherein the C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, Ci-C6alkylC3-Ciocycloalkyl, Ci- Cealkylaryl, C₁-C₆alkylheteroaryl and Q-Cealkylcycloheteroalkyl are unsubstituted or substituted with at least one substituent selected from the group consisting of halogen. In certain

embodiments, R⁵ is selected from the group consisting of hydrogen, oxo, Ci-C6alkyl, -COOH, - Cj-CealkylCOOH, C₁-C₆alkylCN, -S0₂Ci-C₆alkyl, cyclopropyl, C₁-C₆alkylaryl, and d- Cealkylcycloheteroalkyl, wherein the C₁-C₆alkylaryl and Crdalky .cycloheteroalkyl are un substituted or substituted with at least one substituent selected from the group consisting of halogen. In other embodiments, R⁵ is independently selected from the group consisting of halogen, C₁-C₆alkyl, halogen-substitutedC₁-C₆alkyl, COC₁-C₆alkyl, -OH, -COOH, -COOCi- Cealkyl, -C₁-C₆alkylCOOCj-Cealkyl and -Q-QalkylCOOH. In one embodiment, R⁵ is hydrogen.

Also described herein are compounds formula Ic:

or a pharmaceutically acceptable salt thereof, wherein G and E are independently selected from the group consisting of-N- and -CH-, wherein if one of G and E is -N-, the remaining one is - CH-;

J, , L and M are independently selected from the group consisting of -0-, -Cな-, -CH-, -C- and -N -;

R¹ is selected from the group consisting of halogen or balogen-substitutedCi -

Cealkyl; and

R⁶, R⁷ and R⁸ are independently selected from the group consisting of hydrogen, halogen, C₁-C₆alkyl, halogen-substftutedC₁-C₆alkyl, COCi-C6alkyl, oxo, -OH, halogen- substitutedC₁-C₆alkylOH, -OC₁-C₆alkyl, -Ohalogen-substitutedC₁-C₆alkyl, -COOH, -COOCi- Cealkyl, -C₁-C₆alkylCOOCpCealkyl, -Ci-C^alkylCOOH, -OC₁-C₆alkylCOOH, -CN, Ci- CealkylCN, -NO₂, NH₂, NHCi-Csalkyl, N(Ci-C6alkyl)2, -NHCOOH, -NHCOOC₁-C₆alkyl, - CONH2, -CONHC-Cealkyl, -CON(Ci-C6alkyl)₂, -NHSChCi-C^alkyl, -SC^C-Cealkyl, C₃- Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C₁-C₆alkylCa- Ciocycloalkyl, Ci-Gsalkylaryl, C₁-C₆alkylheteroaryl and C₁-C₆alkylcycloheteroalkyl, wherein the C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C₁-C₆alkylCs- Ciocycloalkyl, Ci-Ctfdkylaryl, C₁-C₆alkylheteroaryl and C₁-C₆alkylcycloheteroalkyl are unsubstituted or substituted with at least one substituent selected from the group consisting of halogen.

In some embodiments, R^l is halogen. Suitable examples of halogen include, but are not limited to, chlorine, fluorine and bromine. In some embodiments, R¹ is halogen- substitutedC₁-C₆alkyl. Suitable examples of halogen-substitutedC₁-C₆alkyl include, but are not limited to, trifluoromethyl.

In certain embodiments, J is -CH2-. In other embodiments, J is -0-. In still other embodiments, is CO. In yet another embodiment, is -N-. In one embodiment, M is -NH-. In anther embodiment, N is -CHR⁸-. In other embodiments, L is N(R⁷). In certain embodiments, J is -0-; K is -CCR⁶), wherein K⁶ is oxo; L is N(R⁷), wherein R⁷ is defined above; and M is - CH(R⁸), wherein R⁸ is hydrogen. In other embodiments, J is -0-; K is -N-; L is QTR⁶); and M is -C(R⁷)( R⁸), wherein R⁶, R⁷ and R⁸ are hydrogen.

In certain embodiments, R⁶ is oxo. In other embodiments, R⁷ is hydrogen. In still other embodiments R⁷ is selected from the group consisting of phenyl or pyridine, wherein the phenyl or pyridine is unsubstituted or substituted. In one embodiment, R⁷ is phenyl. In one embodiment, R⁷ is pyridine. In certain embodiments, the phenyl or pyridine can be substituted with one or more substituents selected from the group consisting of halogen, C]-C6alkyl,

halogen-substitutedC₁-C₆alkyl, heterocyclicalk lCOOH, -COOH, -COOC₁-C₆alkyl, -Ci- C₆alkylCOOCi-C6alkyl, -Cj-CealkylCOOH, -OC₁-C₆alkylCOOH, NC¾ and -CN. In still other embodiments, R is hydrogen.

Also described herein are compounds of formula Id:

J selected from the group consisting of -O- or -CH₂-;

R¹ is selected from the group consisting of halogen or halogen-substitutedCi-

Cealkyl; and

R⁹ is selected from the group consisting of hydrogen, C₁-C₆alkyl, halogen- substitutedCi-C₆alkyl, COC₁-C₆alkyl, -OH, halogen-substitutedC₁-C₆alkylOH, -OC₁-Csalkyl, - Ohalogen-substitutedC₁-C₆alkyl, -COOH, -COOC₁-C₆alkyl, -CrCealkylCOOC₁-C₆alkyl, -Q- CealkylCOOH, -OC-CealkylCOOH, -CN, Ct-CgalkylCN, -NC¾, -S0₂Ci-C₆alkyl, C₃- Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C]-C₆alkylC3- Ciocycloalkyl, Ci-C6alkylaryl, Ci-C₆alkylheteroary1 and Ci-Ceall ylcycloheteroalkyl, wherein the C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, Ci-C^alkylCs- Ciocycloalkyl, Ci-Cgalkylaryl, C₁-C₆alkylheteroaryl and Ci-Cialkylcycloheteroalkyl are unsubstituied or substituted with at least one substituent selected from the group consisting of - COOH.

In certain embcKiiments, G is -N- and E is -CH-. In other embodiments, G is - CH- and E is -N-. In other embodiments, G and E are both -CH-.

In certain embodiments, J is -0-. In other embodiments, J is -CH2-.

In some embodiments, R¹ is halogen. Suitable examples of halogen include, but are not limited to, chlorine, fluorine and bromine. In some embodiments, R¹ is halogen- substitutedCi-C6alkyl. Suitable examples of halogen-substitutedC₁-C₆alkyl include, but are not limited to, trifluoromethyl.

In certain embodiments, R⁹ is C₁-C₆alkyl, halogen-substitutedC₁-C₆alkyl, -OH, halogen-substitutedC₁-C₆alkylOH, -COOH, -COOC₁-C₆alkyl, -C₁-C₆alkylCOOCj-Cealkyl, -Cj- CealkylCOOH, -OC₁-C₆alkylCOOH, -CN, C₁-C₆alkylCN, -N0₂and cycloheteroalkyl, wherein the cycloheteroalkyl is substituted with -COOH. In other embodiments, R⁹ is -COOH or -Cj- CealkylCOOH.

Also described herein are compounds of formula Ie:

P selected from the group consisting of -O- or -Cな-;

R¹ is selected from the group consisting of halogen or halogen-substitutedCi-

C^alkyl;

R¹⁰ is selected from the group consisting of hydrogen, C₁-C₆alkyl, halogen- substituted d-C₆alkyl, -OH, oxo, halogen-substitutedC₁-C₆alkylOH, -COOH, -COOC₁-C₆alkyl, - C-CealkylCOOC₁-C₆alkyl, -C₁-C₆alkylCOOH and -OC₁-C₆alkylCOOH; and

Rⁿ is selected from the group consisting of halogen, Cj-Cealkyl, halogen- substituted Ci-C₆alkyl, COCi-C6alkyl, oxo, -OH, halogen-substitutedC₁-C₆alkylOH, -OCi- Cealkyl, -Ohalogen-substitutedC₁-C₆alkyl, -COOH, -COOCi -Chalky 1, -C-CealkylCOOCi- Csalkyl, -Ci-C₆alkylCOOH, -OCj-CealkylCOOH, -CN, C-CealkylCN, -N0₂, NH₂, NHC Cealkyl, N(Ci-C6alkyl)2, -NHCOOH, -NHCOOCi -Cealkyl, -CONH₂, -CONHCj-Cealkyl, - CONCCj-Qalkyl^, -NHSO2C1 -Cealkyl, -SC¾Ci -Cealkyl, C3-C₁₀cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, Cj-CealkylCa-Ciocycloalkyl, Ci-Cgalkylaryl, Cj- Cealkylheteroaryl and C₁-C₆alkylcycloheteroalkyL

In certain embodiments, G is -N- and E is -CH-. In other embodiments, G is -

CH- and E is -N-. In other embodiments, G and E are both -CH-.

In certain embodiments, P is -0-. In other embodiments, P is -CH₂-.

In some embodiments, R¹ is halogen. Suitable examples of halogen include, but are not limited to, chlorine, fluorine and bromine. In some embodiments, R¹ is halogen- substitutedC₁-C₆alkyl. Suitable examples of halogen-substitutedCj -Cealkyl include, but are not limited to, trifluoromethyl.

In certain embodiments, R¹⁰ is selected from the group consisting of oxo and - COOH. In other embodiments, R¹⁰ is hydrogen.

In certain embodiments, R¹¹ is selected from the group consisting of hydrogen. In other embodiments, R¹¹ is selected from the group consisting of -COOH, -COOCi -Cealkyl, -Ci- CsalkylCOOC₁-C₆alkyl, -C₁-C₆alkylCOOH, -OC₁-C₆alkylCOOH, -NHCOOH, -NHCOOCj- Cealkyl, -CONH₂, -CONHCj -Cealkyl, -CON(C₁-C₆alkyl)2, -NHSO2C₁ -Cealkyl and -SO2C- Cealkyl.

Also described herein are compounds of formula 1(f):

A is selected from the group consisting of benzene and pyridine, wherein A is unsubstituted or substituted with one or more substituents selected from the group a, C|-Cealkyl, C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C Ce lkylCa-Ciocycloalkyl, C₁-C₆alkylaryl, C₁-C₆alkylheteroaryl and Cj-Cealkylcycloheteroalkyl, wherein C₁-C₆alkyl, C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C₁-C₆alkylC3-Ciocycloalkyl, C₁-C₆alkylaryl, Ci- Cealkylheteroaryl and Ci-Qjalkylcycloheteroalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of a;

a is selected from the group consisting of halogen, C₁-C₆alkyl, halogen- substitutedC₁-C₆alkyl, COC_rCealkyl, oxo, -OH, halogen-substitutedC₁-C₆alkylOH, -OCi- Cealkyl, -Ohalogen-substitutedC₁-C₆alkyl, -COOH, -COOd-Cealkyl, -C₁-C₆alkylCOOCi- Cealkyl, -C₁-C₆alkylCOOH, -OCi-C₆alkylCOOH, -CN, C,-CealkylCN, -N0₂, NH₂, NHCj- Cealk l, N(C C₆alk l)₂, -NHCOOH, -NHCOOC₁-C₆alkyl, -CONH₂, -CONHCrCealkyl, - CONCC₁-Csalkylk, -CONHC₁-C₆alkyl-N C₁-C₆alkyl^, -NHSO^i-Qalkyl, -SO2NH2, -SO2C1- Cealkyl, C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, - CealkylCs-Ciocycloalky], C₁-C₆alkylaryl, C₁-C₆alkylheteroaryl and Ci-Cgalkylcycloheteroalkyl;

D selected from the group consisting of:

R¹² is selected from the group consisting of -COOH, -COOC₁-C₆alkyl, -Q- CealkylCOOC₁-C₆alkyl, -C₁-C₆alkylCOOH and -OCi-C₆aIkylCOOH.

In certain embodiments, G is -N- and E is -CH-. In other embodiments, G CH- and E is -N-. In other embodiments, G and E are both -CH-.

Also described herein are compounds of formula Ig:

A is selected from the group consisting of benzene and pyridine, wherein A is unsubstituted or substituted with one or more substituents selected from the group a, Cj-Cealkyl, C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C₁-C₆alkylC₃-Ciocycloalkyl, C₁-C₆alkylaryl, C₁-C₆alkylheteroaryl and Ci-Cfialkylcycloheteroalkyl, wherein C₁-C₆alkyl, C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, Ci-C6alkylC₃-Ciocycloalkyl, C₁-C₆alkylaryl, Ci-

Cealkylheteroaryl and C₁-C6alkylcycloheteroalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of a;

a is selected from the group consisting of halogen, C₁-C₆alkyl, halogen- substitutedCi-C6alkyl, COC₁-C₆alkyl, oxo, -OH, halogen-substitutedCj-CealkylOH, -OCi- Cealkyl, -Ohalogen-substiwtedC₁-C₆alkyl, -COOH, -COOCj-Cealkyl, -C₁-C₆alkylCOOCi- Cealkyl, -Q-CealkylCOOH, -OCj-CealkylCOOH, -CN, Cj-QalkylCN, -N0₂, NH₂, NHCi- Qalkyl, Nid-Cealkyl^, -NHCOOH, -NHCOOCi-CeaJkyl, -CONH2, -CONHC₁-C₆alkyl, - CON(C,-C6alkyl)₂, -CONHd-Cealkyl-NCC₁-C₆alkyl^, -NHSOzC₁-C₆alkyl, -S0₂NH₂, -SC¾Ci- Cealkyl, C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, Ci- QalkylCs-Ciocycloalkyl, C₁-C₆alkylaryl, C₁-C₆alkylheteroaryl and C₁-C₆alkylcycloheteroalkyl; R¹² is selected from the group consisting of -COOH, -COOC₁-C₆alkyl, -Ci- CialkylCOOCi-CeaM yl, -C₁-C₆alkylCOOH and -OC₁-C₆alkylCOOH.

Examples of compounds or pharmaceutically acceptable salt thereof include, but are not limited to:

Definitions

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

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

The term "-OCj-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 "halogen-substitutedCj-Ce alkyl" encompasses C1-C6 alkyl with the hydrogen, atoms thereof being partially or completely substituted with halogen, examples thereof including fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl and the like.

The term "-Ohalogen-substitutedC₁-C₆alkyl" means a -OC₁-C₆alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different, arid specifically includes, for example, a trifluoromethoxy group.

The term "Ci-C^alkylCOOH" means a C₁-C₆alkyl as defined above substituted with a carboxylic acid group (COOH).

The term "COOC₁-C₆alkyl" means a -COOH group wherein the -OH is replaced with an alkoxy group as defined above. Examples include methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

The term "C3-Ciocycloalkyl" means a monocyclic or polycyclic, saturated or partially- unsaturated carbocyclic group having from 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutenyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclohexyl, bycyclodecyl, bicyclononyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and adamantly.

The term "SChC₁-C₆alkyl" means a group having Cj^ alkyl bonded to sulfonyl (-SO₂-). Specific examples thereof include methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, sec-butanesulfonyl, tert-butanesulfonyl, and the like.

The term "COCi-e alkyl" means groups having Ci^ alkyl 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 "oxo" means the functional group "=0", such as, for example, (1) "C=(0)", that is a carbonyl group; (2) "S=(0)ⁿ, that is, a sulfoxide group; and (3) "N={0)", that is, an N-oxide group, such as pyridyl-N-oxide.

The term "NHCi-Cgalkyl" means a group with one of the hydrogen atoms of amino (- NH₂) being substituted with a Ci-e alkyl group. Specific examples thereof include memylamino, emylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino, and the like.

The term "N(Ci-C₆alkyl)₂" means a group with the two amino hydrogen atoms each being substituted with a Ci^ alkyl group. Specific examples thereof include dimemylamino, diethylamino, ethylmethylamino, di(n-propyl)amino, methyl(n-propyl)amino, diisopropylamino, and the like.

The term "NHC0₂C₁-C₆alky means a group with one of the amino hydrogen atoms being substituted with C_1-6 alkoxycarbonyl and encompasses alkoxycarbonylamino having a carbon number of 1 to 6. Specific examples thereof include methoxycarbonylamino, ethoxycarbonylamino, n-propyloxycarbonylamino, isopropyloxycarbonylamino, n- butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, n- pentyloxycarbonylamino, and the like.

The term "CONHC₁-C₆alkyl" means a group with one of the hydrogen atoms of carbamoyl (-CONH2) being substituted with Ci^ alkyl. Specific examples thereof include methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl, and the like.

The term "CON(Ci-C₆alkyl)₂" means a group with the two carbamoyl hydrogen atoms each being substituted with C alkyl. Specific examples thereof include dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, di(n-propyl)carbamoyl, methyl(n-propyl)carbamoyl, diisopropylcarbamoyl, and the like.

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

The term "heteroaryl" means 5-membered or 6-membered monocyclic heteroaryl containing one or more, preferably one to three, same or different heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, or otherwise means condensed-ring heteroaryl formed by condensation of such monocyclic heteroaryl and the above- mentioned heteroaryl or alternatively by mutual condensation of the same or different monocyclic heteroaryl groups. Examples thereof include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,

benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzo thiazolyl, benzisothiazolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphmyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, pyrido[3,2-b]pyridyl, and the like.

"Cycloheteroalky means mono- or bicyclic or bridged saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen. The term also includes monocyclic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non- aromatic portion. Examples of "cycloheteroaUeyl' nclude teti^

pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-6)pyridyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6- dmydroimidazo[2,l-6]thiazolyl, tetrahydroquinolinyl, morpholin l, tetrahydroisoquinolinyl, dihydroindolyl, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted-ilH, 3H)-pyrimidine-2,4-diones (iV-substituted uracils). The term also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]hepryl, 2-azabicyclo[2.2.1]heptyl, 7- azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.2]octyl, and 3- azabicyclo[3.2.2]nonyl, and azabicyclo[2.2.1]heptanyl. The cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogens.

"SOjC₁-C₆alkyl" group means a group in which a C₁-C₆alkyl group is attached to a sulfonyl (-S<な-) group. Specific examples thereof include methanesulfonyl, ethanesulfonyl, n- propylsulfonyl, isopropanesulfonyl, n-butanesulfonyl, sec-butanesulfonyl and tert-butanesulfonyl groups and the like.

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

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

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

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

Methods of Treatment

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

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

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

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

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

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

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

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

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

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

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

Pharmaceutical Compositions

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

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

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

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

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

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

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

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

pharmaceutical composition, include, but are not limited to:

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

(2) insulin sensitizers, including (i) PPARy agonists, such as the glitazones (e.g. pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR ligands, including (1) PPARct γ dual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPAR agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators (SPPARyM's), such as those disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963, and (4) PPARy partial agonists; (ii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet®, and GlucophageXR®; (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;

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

(4) leptin and leptin derivatives and agonists;

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

(6) sulfonylurea and non-sulfonylurea insulin secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide; (7) α-glucosidas inhibitors (such as acarbose, voglibose and miglitol);

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

(9) incretin mimetics, such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists, such as exenatide, liraglutide, taspoglutide, AVEOO 10, C JC- 1131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof;

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

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

(12) antiobesity compounds;

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

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

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

(16) inhibitors of 1 Ιβ-hydroxysteroid dehydrogenase type 1, such as those disclosed in U.S. Patent No. 6,730,690; WO 03/104207; and WO 04/058741;

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

(18) inhibitors of fructose 1,6-bisphosphatase, such as those disclosed in U.S. Patent Nos.

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

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

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

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

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

(23) neuromedin U receptor agonists, such as those disclosed in WO2009/042053, including, 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 acyl coenzyme A :monoacy .glycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2);

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

(31) 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, rosiglitazone, simvastatin, atorvastatin, or a sulfonylurea.

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

(2Λ,3£5Λ)-5-(1 -memyl-4,6-dmydro

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

(2Λ,35,5Λ)-5-(1 -memyl-4,6^hydropyrrolo[3,4-c]pyrazol-5(lH)-yl)-2-(2,4,^

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

(22?,3S,5 )-2-(2,5-difluorophenyl)tet^

tetrahydro-2H-pyran-3-amine;

(3 )-4-[(3 )-3-amino-4-(2,4,5-triflu^

2-one;

4-[(3_R)-3-amino-4-(2,5-difluorophenyl)but^

hydrochloride; and

(3J?H-[(3^)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-hexahyd^

diazepin-2-one; and

pharmaceutically acceptable salts thereof.

Antiobesity compounds that can be combined with compounds of any of the formulas described herein include topiramate; zonisamide; naltrexone; phentermine; bupropion; the combination of bupropion and naltrexone; the combination of bupropion and zonisamide; the combination of topiramate and phentermine; fenfluramine; dexfenfluramine; sibutramine; lipase inhibitors, such as orlistat and cetilistat; melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists; CC -1 agonists; melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Yi or Y5 antagonists (such as M -0557); CB1 receptor inverse agonists and antagonists (such as rimonabant and taranabant); β3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (such as bombesin receptor subtype-3 agonists); and 5-hydroxytryptamine-2c (5-HT2c) agonists, such as lorcaserin. For a review of anti-obesity compounds that can be combined with compounds of the present invention, see S. Chaki et ah, "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 ah, "Pharmacological Approaches for the Treatment of Obesity," Drugs. 62: 915- 944 (2002); and K.M. Gadde, et al., "Combination pharmaceutical therapies for obesity," Exp. Opin. Pharmacother.. 10: 921-925 (2009).

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

N-[4-((l S)- 1 - {3-(3 ,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyI]- 1 H-pyrazoI- 1 - yl}ethyl)benzoyl]- -alanine;

N-[4-((l£)-1-{3-(3,5-dicMorophenyl)-5-[6-(tf^

yl} ethyl)benzoyl]- -alanine;

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

N-(4- { ( 1 S)- 1 -[3-(3 ,5-dichlorophenyl)-5-(6-methoxy-2-naphthyI)- 1 H-pyrazol - 1 - yl]ethyl}benzoyl)- -alanine;

N-(4-{(lS)-1-[(R)-(4-chlorophenylX7^

alanine; and

N-(4-{(lS)-1-[(4-cWorophenyl)(6-chloro-8-memylquinolm-4-yl)methyl]buty.

alanine; and

pharmaceutically acceptable salts thereof.

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

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

[5-(5-{4-[2-(rrifluorometoyl)phenoxy]pip^

yl]acetic acid;

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

(5-{3-[4-(2-bromo-5-fluorophenoxy)piperid^

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

(5-{5-[4-(2-bromo-5-fluorophenoxy)piperi ^'n ^

and

(5-{2-[4-(5-bromo-2-chlorophenoxy)piperidm-1-yl]p

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

3^6^1hanesulfonylpyridm-3-yloxy 5 2-hydroxy- 1 -methyl-ethoxy)-N-(l -methyl-1 H-pyrazol-3- yl)benzamide

5-(2-hydroxy-1-memyl-ethoxy)-3-(6-meth^

3-yl)ben2amide;

5-(l -hydroxymethyl-propoxy)-3-(6^metr^

yl)benzarnide;

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

3-yl)benzamide;

5-isopropoxy-3-(6-metoanesulfonylpyridin-3^^

5-{2-fluoro- 1 -fluoromethyl-emoxy)-3 6^methanesulfonylpyridm-3-yloxy)-N-(l -methyl- 1 H- pyrazol-3-yl)benzamide;

3-{{4-[2-(dimemylammo)eftoxy]phenyl}rofo^

4H- 1 ,2,4-triazol-3-yl)thio]pyridine-2-carboxamide;

3-({4-[(l-meftylazetid -3-yl)oxy]phe

4H-l_>2,4-triazol-3-yl)thio]pyridine-2-carboxamide;

N-(3-merayl-1^ -miadiazol-5-yl)-6 (4-^^

l-ylemoxy)phenyl]thio}pyridme-2-carboxamide; and

3-[(4-{2-[(2R)-2-meraylpvrrolidin- 1 -yl]ethoxy}phenyl)thio-N-(3-methyl-l ,2,4-thiadiazol-5-yl)-6-[(4- memyl-4H-1,2,4-triazol-3-yl)thio]py^ and pharmaceutically acceptable salts thereof.

Agonists of the GPR-119 receptor that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:

rac-cis 5-cWoro-2-{4-[2-(2-{[5-(memylsulfonyl)pyridm-2-yl]oxy}emyl)cyclopropyl] piperidin-1- yl}pyrimidine;

5-cMoro-2-{4-[(lR,2S)-2-(2-{[5-(memylsulfon^

l-yl}pyrimidine;

rac c/s-5-cWoro-2-[4-(2-{2-[4-(memylsulfo

yl]pyrimidine;

5-cWoro-2-[4-((lS^R)-2-{2-[4-(memylsulfonyl)phenoxy]emyl}cyclopropyl) piperidi

yl]pyrimidine;

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

rac cw-5-chloro-2-[4-(2-{2-[3-(memylsulfonyl)phenoxy]emyl}cyclopropyl)piperidin-1- yl]pyriroidine; and rac cis -5- hloro-2-[4-(2-{2-[3-(5-methyl-l ,3, -oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl) piperidin-1-yl]pyrimidine; and pharmaceutically acceptable salts thereof.

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

(2£)-2^{6K>Moro-3-[6^4^Morophenoxy)-2-pro

yl}oxy)propanoic acid;

(2S)-2-({6-cMoro-3-[6-(4-iluorophenoxy)^

yl}oxy)propanoic acid;

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

acid;

(2#)-2-({6-chloro-3-[6-(4-chlorophenoxy)-2-p^

yl}oxy)propanoic acid;

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

(2S)-2-{3-[3 4-memoxy)benzoyl-2-me*yW trifluoromemoxy)-lH-indol-1- yl]phenoxy}butanoic acid;

2- {3-[3-(4-methoxy)ben2X)yl-2-methyl-6^trifluoromethoxy)-lH-indol-1-^^

methylpropanoic acid; and

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

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

3- [ 1 ^4^hlorophenyl)-/rTOs-3-iluorocyclobutyl]^,5-d1cyclopropyl- H- 1 ,2,4-triazole;3-[ 1 -(4- cWorophenyl)-fraw-3-fluorocyclobutyy

triazole;

3-[H4-chlorophenyl)-/rojw-3-fluoi^^

1,2,4-triazole;

3-[ 1 -(4^hlorophenyl)(^clobutyl]-4-me

3- {4-[3-(ethylsulfonyl)propyl]bicy^^

-1,2,4-triazole;

4- memyl-3-{4-[4-(memylsulfonyl)phenyl]bicyclo[2.2.2]oct-1-yl}-5-[2 tri

4H-1,2,4-triazole;

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

3-(4-{4-memyl-5-[2-(rrifluoromemyl)pheny1H^

(3 ,3 ,3-trifluoroethyl)- 1 ,2,4-oxadiazole; 5-(3,3^ifluorocyclobutyl 3<4-{4-me

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

5-( 1 -fluoro- 1 -methylethyl)-3 4-{4-methyl-5-[2 trifluoromethyl)phenyl]^H- 1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-1-yl)-l^_s4-oxadiazole;

2<l,l Ufluoroe l)-5-(4-{4-me l-5-^

yl}bicyclo[2.2.2]oct-1-yl)-1.3,4-oxadiazole;

2-(3 -ch^uorocyclobirtyl)-5-(4-{4-me ^

y] } bicyclo[2.2.2]oct- 1 -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-1-yl)-1,2,4-oxadiazole; and pharmaceutically acceptable salts thereof.

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

and pharmaceutically acceptable salts thereof.

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

and pharmaceutically acceptable salts thereof.

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

5-{r-[(l-cyclopropyl-4-methoxy-1H-indol-6-yl)carbonyl]-4 >xospiro[chr^

yl} nicotinic acid;

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

l'-[(l-cyclopropyl-4-emoxy-3-me1hyl-1H-indol^yl)carbonyl]-6^(1H-tetr^

yl)spiro[chroman-2,4'-piperidin]-4-one; and

5-{ -[(l-cyclopropyl^memoxy-3-methyl-1H- dol-o^^

piperidb]-6-yl}nicotinic acid; and

pharmaceutically acceptable salts thereof.

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

(a) a compound of any of the structural formulas described herein;

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

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

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

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

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

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

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

(5) glucagon receptor antagonists;

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

(lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestirnide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetiraibe, 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-1 antagonist MK-524; and nicotinic acid receptor agonists;

(8) antiobesity compounds;

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

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

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

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

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

0859;

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

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

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

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

(18) SSTR3 antagonists;

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

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

(21) GPR-105 antagonists;

(22) inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1 ; SGLT-2, such as dapagliflozin and remogliflozin; and SGLT- 3; (23) inhibitors of acyl coenzyme Ardiacylglycerol 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:monoacyIglycerol 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).

Examples

Intermediates and Examples are shown below.

Scheme 1

The following is a list of abbreviations used in the description of the synthesis of the Intermediates and Examples shown below.

List of Abbreviations:

Alk alkyl

AT - aryl

Boc = tert-butoxycarbonyl

Cbz = carbobenzyloxy

CH₂C1₂ = dichloromethane

CoA - Coenzyme A

dba = dibenzylidineacetone

DIPEA - diisopropylethylamine

DMA = dimethylacetamide

DMF = dimethylformamide

DMSO = dimethyl sulfoxide

ESI = electrospray ionization

Et ethyl

EtOAc = ethyl acetate

HOAc = acetic acid

LC-MS = liquid chromatography-mass spectroscopy

LiOH = lithium hydroxide

Me = methyl

MeOH = methyl alcohol

MgS0₄ = magnesium sulfate

MS = mass spectroscopy MTBE methyl tert-butyl ether

NaOH sodium hydroxide

Na₂S0₄ sodium sulfate

NMR nuclear magnetic resonance spectroscopy

Ph phenyl

rt or RT room temperature

TEA triethylarnine

TFA triiluoroacetic acid

THF tetrahydrofuran

Intermediate 1.

2-f 6-fluoropyridm-3-yl 5^trifluoromethyl)- 1 H-benzimidazole

Step 1. Following the recommendations presented in Beaulieu, P. L. Hacbi, B. and von Moos, E. Synthesis, 2003, 1683: a solution of 2-fluoropyridine-5-carboxaldehyde (2.0 g) in DMF was added drop wise to a suspension of 4-(trifluoromethyl)phenylene-l ,2-diamine (2.8 g) and Oxone* (6.39 g) in DMF and water. The mixture was cooled in an ice bath during the addition and allowed to warm to reaction once the addition of aldehyde was complete. The reaction was stirred open to air at room temperature for 45 minutes. To the reaction was added water and the mixture was brought to pH 7 by the addition of solid potassium carbonate. The resulting light brown solid was filtered and dried in vacuo. [MH]⁺ m/z 282.8.

Intermediate 2.

5-chIoro-2- 6-chloropvridin-3-vl - 1 H-benzimidazole

Step 1. Following the recommendations presented in Beaulieu, P. L.; Hache\ B. and von Moos, E. Synthesis, 2003, 11, 1683: a solution of 2-chloropyridme-5-car1x>xaldehyde (0.60 g) in DMF was added dropwise to a suspension of 4-chlorophenylene-l ,2-diamine (0.57 g) and Oxone* (1.6 g) in DMF and water. The mixture was cooled in an ice bath during the addition and allowed to warm to reaction once the addition of aldehyde was complete. The reaction was stirred open to air at room temperature for 45 minutes. To the reaction was added water and the mixture was brought to pH 7 by the addition of solid potassium carbonate. The resulting light brown solid was filtered and dried in vacuo. [MH]⁺ m/z 264.0.

Intermediate 3.

CI

5-chloro-2-f 6-chloro-5-fluoropyridin-3-yl)-l H-benzimidazole

This compound was prepared using the same protocols as described for Intermediate 1. Intermediate 4.

2-(6^fl ioropyridm-3-viy5-memoxy-3H^

This compound was prepared using the same protocols as described for Intermediate 1.

2^6-bromo-5-fluoropyridm-3-YlV5-(trifl

Step 1. ^4-(trifluoromemyl)benzene-l^-<Maniine (44.0 mg, 1.1 equiv), 6-bromo-5- fluoronicotinaldehyde (50 mg, 1 equiv) and (ben.K)triazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (130 mg, 1 equiv) were combined in anhydrous DMF. To the solution, DIEA (0.119 mL, 3 equiv) was added and the mixture was stirred at room temperature for 2 hours. The solution was diluted with ethyl acetate and washed with saturated ammonium chloride, then water then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give N-(2-amino-4-(trifluoromethyl)phenyl)-6-bromo-5- fluoronicotinamide as a viscous brown oil: [MH]⁺ m/z 379.

Step 2. Acetic acid was added to N-(2-amincH*-(trifluoromethyl)phenyl)-6-bromo-5- fluoronicotinamide obtained in step 1, and the solution was irradiated in a microwave reactor at 180 ^*C for 40 min. The solution was diluted with 40% acetonitrile-water (4 mL) and purified by reverse phase HPLC to give 2-(6-bromo-5-fluoropyridin-3-yl)-5^trifluoromethyl)-1H- benzo[d]imidazole as a tan solid: [MH]⁺ m/z 3 1.

Intermediate 6.

3-oxo^3H-spirof 2-benzofuran- 1.4'-piperidine]-5-carboxylic acid

Step 1. 4-bromobenzene-1,3-dicarboxylic acid (600 mg, 1 equiv) was taken up in THF (12 mL) and cooled to -78 °C. A 2.5 M solution of i-butyl lithium in hexanes (3.92 mL, 4 equiv) was added dropwise over 15 minutes forming a red precipitate. After 2 hours, tert-butyl 4- oxopiperidine-1-carboxylate (488 mg, 1 equiv) was added dropwise over 10 minutes as a solution in THF. The final concentration was 0.15 M. After 2 hours, the reaction mixture was warmed to room temperature, acidified to pH ~ 0 with 1M HCl and stirred vigorously for 16 hours. Volatiles were removed in vacuo and the residue poured into water then extracted with dichloromethane. The organic layer was dried on sodium sulfate and concentrated to give Γ- (tert-butoxycarbonyl)-3-oxo-3H-spiro[2-ben2of\iran- 1 ,4'-piperidine]-5-carboxylic acid as a white oil: [MH-Boc]⁺ m/z 248.

Step 2. The residue from Step 1 (79 mg, 1 equiv) was reconstituted in dichloromethane (40 mL) and trifluoroacetic acid (3:1) and stirred for 18 hours at room temperature. Concentration and purification by reverse phase HPLC (0% acetonitrile:water with 0.05% TFA to 50%

acetonitrile:water with 0.05% TFA) to give pure S-oxo-SH-spiroP-benzofuran-l^'-piperidine]- 5-carboxylic acid as a white solid: [MH]⁺ m/z 248.

Intermediate 7.

3-biOmcH5H-spu^rfuror3.4-b1pvridine-7.4'-piperidin1-5-one

Step 1. 5-bromo-2-ic iopyridme-3-carbonitrile (6.44 g, 1 equiv) and ieri-butyl 4-oxopiperidine- 1-carboxylate (5.82 g, 1.4 equiv) taken up in toluene (65 mL) and cooled in -78 'C bath. A 1.3M solution of isopropylmagnesium chloride-lithium chloride complex in THF (22.5 mL, 1.4 equiv) was added rapidly forming a brown-black gel. After 10 minutes, the reaction was quenched by addition of methanol (5.9 mL, 7 equiv) then 50% aqueous acetic acid (16.7 mL, 7 equiv) and warmed to room temperature and stirred for 24 hours. The mixture was poured into toluene, washed with water, IN HCl then IN NaOH. The organic layer was dried on sodium sulfate and concentrated to a brown oil. Purification by silica gel chromatography (hexanes to ethyl acetate) gave feri-butyl 3-bromo-5-oxo-l Ή,δΗ-βρ^οίΓΐΐΓθΡ,^^ρ^άίηβ-Τ^'-ρίρβΓίά ηβ]-! '-carboxylate as an oil. Step 2. The oil from Step 1 (204 mg) was reconstituted in 4 mL dichl oromethane-trifl uoroacetic acid (3:1) and stirred for 5 hours at room temperature to effect Boc-removal. Concentration gave the hydrochloride salt which was used without further purification [MH]⁺ m/z 283.

Intermediate 8.

2- ^S-formylpyridm-2-ylV3-azaspi- |^'5.51undecan-9-yl)a

Sodium bicarbonate (2.70 g, 5 equiv), 2-fluoropyridine-6-carboxaldehyde (0.80 g, 1 equiv) and the hydrochloride salt of 3-azaspiro[5.5]undec-9-ylacetic acid (1.59 g, 1 equiv) were stirred at 80 °C in NMP (12 mL) for 5 hours. The mixture was cooled to room temperature, acidified with 1 M HCl (25 mL, 4 equiv), diluted with water, and extracted with dichloromethane. The combined organic layers were concentrated in vacuo and purified by silica gel chromatography (0% acetone:dichloromethane to 50% acetoneidichloromethane) to give the pure aldehyde as a white solid: [ H]⁺ m/z 317. Intermediate 9.

methyl 4-i2-methoxv-2-oxoethvlV3 ^-dihydi^spirotchromene^^'-piperid^

Step 1. Trimethyl phosophonoacetate (680 uL, 2.1 equiv) was added dropwise to a stirring suspension of sodium hydride (160 mg, 2 equiv, 60% dispersion in mineral oil) in THF (8 mL) at room termperature and the slurry stirred for 30 minutes. The reaction mixture was cooled to 0 ^*C and 1 '-ieri-butyl-6-methyl 4-oxo-3,4-dihydro-l ^spiro[chromene-2,4'^iperidine]-^carboxylate (750 mg, 1 equiv) was added dropwise as a solution in THF (4 mL). The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. Volatiles were removed in vacuo and the residue was transferred to a separatory funnel containing 1M hydrochloric acid.

Extraction with dichloromethane and concentration gave an oil that was purified by silica gel column chromatography (hexanes to ethyl acetate) to give the desired product as an oil. Step 2. Material from Step 1 (226 mg, 1 equiv) was dissolved in ethanol (2 mL) and added to 30% Pd/C (125 mg, 35 mol%) then stirred at room temperature under an atmosphere of hydrogen for 4 hours. Filtration through Celite, concentration in vacuo, and purification by silica gel column chromatography (hexanes to ethyl acetate) gave the desired product as a clear oil.

Step 3. The oil from Step 2 (154 mg) was treated with hydrochloric acid (2 equiv) in 1,4-dioxane (1.7 mL) at 40 ^*C. After 2 hours, an additional equivalent of 4M hydrochloric acid in 1,4- dioxane (89 uL) was added and the temperature raised to 60 ^*C for 1 hour. Removal of volatiles in vacuo gave the desired hydrochloride salt as a white solid: [MH]⁺ m/z 334.

Intermediate 10.

ferr-butyl 9-f2-memoxy-2K>xc^oxyV3-azaspiro[5.51imdecane-3-carboxylate

Step 1. Sodium borohydride (139 mg, 1 equiv) was added to a methanol solution of tert-butyl 9- oxo-3-azaspiro[5.5]undecane-3-carboxylate (980 mg, 1 equiv) and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the solution and the mixture was diluted with dichloromethane. The organic layer was separated and washed with water then brine then dried over sodium sulfate, filtered and concentrated in vacuo to give 950 mg of feri-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate: [MH]⁺ m/z 270.

Step 2. Potassium tert-butoxide (66.5 mg, 1.2 equiv) was added to teri-butyl 9-hydroxy-3- azaspiro[5.5]undecane-3-carboxylate (133 mg, 1,0 equiv) in anhydrous DMF and stirred at 0 ^*C for 1 hour. To the stirred pale yellow solution was added methyl 2-bromoacetate (0.070 mL, 1.5 equiv) and the solution was warmed to room temperature over 1 hour and then heated at 50 ^*C for 1 hour. The solution was cooled to room temperature, diluted with 40% acetonitrile in water then directly purified by preparative HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) to give the product as an off-white solid: [MH]⁺ m/z 342.

Example 1.

Step 1. Copper (I) iodide (19 rag, 1 equiv), cesium carbonate (98 mg, 3 equiv) and commercially available iert-butyl 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate (26 mg, 1 equiv) were weighed into a vial. To this was added ethyl /*-bromophenylacetaie (32 mg, 1.3 equiv) and 1 ,4- dioxane (0.25 mL) and the mixture stirred at 100 ^*C for 18 hours. After cooling, the reaction was quenched by addition of 1M HCl (1 mL, 10 equiv) and extracted twice with MTBE. The combined organic layers were concentrated in vacuo.

Step 2. The residue from Step 1 was dissolved in 1M solution of HCl in 1,4-dioxane (400 uL, 4 equiv) and the mixture stirred at room temperature for 4 hours to effect removal of the Boc group. Concentration in vacuo gave a crude residue which was carried forward without further purification.

Step 3. To the residue from Step 2 was added sodium bicarbonate (42 mg, 5 equiv), 2-(6- fluoropyridin-3-yl)-5^trifluoromemyl)-1H^ (28 mg, 1 equiv), andNMP (330 uL). The mixture was stirred at 120 °C for 22 hours. The reaction was neutralized by addition of acetic acid (23 uL, 4 equiv), diluted with DMSO, filtered and purified by reverse phase HPLC.

Examples 2-14 were prepared according to a similar method. For examples where the aryl group was a pyridine, the aqueous phase from the workup in Step 1 was basified with 1M NaOH and further extracted with ethyl acetate.

Example 15.

5^hlorcH2^6^UoiOpyridin-3-yl)-1H-benzimidazole (123 mg, 1 equiv), Hunig's base (408 uL, 5 equiv) and 3H-spiro[2-benzofuran-1,4'-piperidin]-3-one (95 mg, 1 equiv) were dissolved in DMA (3 mL) and heated at 140 °C in a microwave for 12 hours. The mixture was poured into water and extracted with MTBE thrice. The combined organic fractions were dried on magnesium sulfate, filtered, concentrated, then purified by column chromatography on silica gel using gradient elution (20% ethyl acetate:hexanes to 100% ethyl acetate). The title compound was obtained as a pale yellow solid: [MH]⁺ m/z 431.

Examples 16-56 (Table 2) were prepared according to the procedure described above or one of the variations described below.

Procedure A

A 5 -substituted-2-(6-chloropyridin-3 -yl)- 1 H-benzimidazole (1 equiv), Hunig's base (5 equiv) and the amine (1 equiv), as a hydrochloride or trifluoroacetate salt, were dissolved in DMA (0.3 M) and heated at 140 ^*C in a microwave until complete as judged by LCMS analysis (10-60 hours). If the conversion of starting materials to products was low within 3 hours (LCMS analysis), the reaction temperature was increased to 200 ^*C. If decomposition products were observed to form at a comparable rate to the consumption of starting material, the reaction was stopped prior to complete conversion. The mixture was cooled to room temperature, poured into water and extracted with MTBE thrice. The combined organic fractions were dried on magnesium sulfate, filtered, concentrated, then purified by column chromatography on silica gel using gradient elution (generally 20% ethyl acetaterhexanes to 100% ethyl acetate) to give the pure product.

Procedure B Performed as in Procedure A except potassium carbonate (5 equiv) was used as base and DMSO (0.3 M) was used as solvent The reaction was heated at 140 °C in a microwave until complete as judged by LCMS analysis (10-60 hours). The mixture was cooled to room temperature, diluted with a small amount of acetonitrile, filtered and purified by preparative reverse phase HPLC (generally 30% acetonitrilerwater with 0.05% TFA to 95% acetonitrile:water with 0.05% TFA) to give the pure product.

Procedure C

Performed as in Procedure A except a 5-substituted-2-(6-fluoropyridin-3-yl)-1H-benziinidazole (1 equiv) was used. The reaction was heated at 140 °C in a microwave until complete as judged by LCMS analysis (10-60 hours). The mixture was cooled to room temperature, diluted with a small amount of acetonitrile, filtered and purified by preparative reverse phase HPLC (generally 30% acetonitrilerwater with 0.05% TFA to 95% acetonitrile:water with 0.05% TFA) to give the pure product.

Procedure D

Performed as in Procedure A except sodium bicarbonate (5 equiv) was used as base and NMP (0.3 M) was used as solvent. The reaction was heated at 110 ^*C until complete as judged by LCMS analysis (10-60 hours). The mixture was cooled to room temperature, diluted with a small amount of DMSO, filtered and purified by preparative reverse phase HPLC (generally 30% acetonitrilerwater with 0.05% TFA to 95% acetonitrilerwater with 0.05% TFA) to give the pure product.

Procedure E

Performed as in Procedure A except A 5-chloro-2-(6-chloro-5-fluoropyridin-3-yl)-1H- benziraidazole (1 equiv) was used as electrophile.

Procedure F

Performed as in Procedure D except the product was saponified with aqueous sodium hydroxide or lithium hydroxide in a water miscible organic solvent such as THF, methanol, dioxane or DMA, or a mixture thereof, at room temperature or 60 'C. Carboxylic acid products were subjected to preparative reverse phase HPLC (generally 30% acetonitrilerwater with 0.05% TFA to 95% acetonitrilerwater with 0.05% TFA) to give the pure product.

Example 56.

Step 1. Cesium carbonate (337 mg, 1.4 equiv), Pd₂(dba)₃ (17 mg, 2.5 mol%) and RuPhos (69 mg, 20 mol%) were transferred to a vial which was sealed and flushed with nitrogen. Degassed THF (3 mL) was added followed by a solution of 3H-spiro[2-berAZoftiran-1,4'-pir½ridm

(165 mg, 1.1 equiv) and 4-bromo-3-fluorobenzaldehyde (150 mg, 1 equiv) in degassed THF (1 mL). The reaction mixture was heated at 70 'C for 5 hours then cooled to room temperature. The mixture was poured into water, extracted with ethyl acetate, then purified by silica gel chromatography (0% to 40% ethyl acetate:hexanes) to give 3-fluoro-4-{3-oxo-l'H,3H-spiro[2- benzoft-ran-1,4'^iperidin]-r-yl)benzaldehyde: [MH]⁺ m/z 326.

Step 2. Next, a solution of 3 -fluoro-4-(3 -oxo- 1 Ή,3 H-spiro [2-berizofuran- 1 ,4'-piperidin]- 1 '- yi)benzaldehyde (11 mg, 1 equiv), Oxone^® (13 mg, 0.65 equiv), and 4-chlorophenylene-1,2- diamine (5 mg, 1 equiv) in 1.4 mL DMF-water (30:1) was stirred open to air at room

temperature. After 2 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue purified by preparative reverse phase HPLC (30% acetonitrile:water with 0.05% TFA to 95% a(^nitrile:water with 0.05% TFA) to give the pure product as a solid: [MH]⁺ m/z 448.

Example 57.

To a vial containing ethyl 2-(3-azaspiro[5.5]undecan-9-yl)acetate (50 mg, 1 equiv) was added (BrettPhos)palladium(Il) phenethylamine chloride (CAS: 1148148-01-9, 33.4 mg, 20 mol%) and 2-(4-bromo-2-fluorophenyl)-6-(trifl (75 mg, 1 equiv). The vial was capped under nitrogen then THF (1 mL) was added through the septum and the suspension was sparged with nitrogen for 5 minutes. Then, a 1.7 M solution of potassium tert- butoxide in THF (381 uL, 3.1 equiv) was added drop wise inducing a deep, wine-red color. After stirring for 20 hours at room temperature, water (1 mL) and methanol (1 mL) were added and the mixture stirred for a further two hours. Volatiles were then removed in vacuo. The residue was dissolved in a mixture of acetic acid and DMSO and purified by preparative reverse phase HPLC (10% acetonitrile: water with 0.05% TFA to 90% acetonitrile:water with 0.05% TFA) to give the pure product as a solid: [MH]⁺ m/z 490. Example 58.

Step 1. 2-(3-(tert-birtoxycarbonyl)-3-azaspiro[5.5]u^^ acid (750 mg) was taken up in dioxane (6 mL) to which was added a 4 M solution of hydrochloric acid in dioxane (2.4 mL, 4 equiv). The mixture was heated at 60 °C for 3.5 hours then concentrated in vacuo.

Step 2. To the residue from Step 1 was added solid sodium bicarbonate (1012 mg, 5 equiv) and 5-chloropyrazine-2-carbaldehyde (400 mg, 1.2 equiv) and DMF (8 mL). The mixture was stirred at 60 °C for 18 hours then cooled and poured into water and the mixture neutralized with 1 M HCl. Extraction first with ether then with ethyl acetate gave an organic fraction that was washed four times with water, then dried on anhydrous sodium sulfate, filtered and concentrated in vacuo to give an orange solid that was carried forward crude: [MH]⁺ m z 318.

Step 3. The aldehyde from Step 2 (50 mg, 1 equiv), 4-(trifluoromemyl)benzene-l^^arnine (28 mg, 1 equiv) and Oxone* (63 mg, 0.65 equiv) were weighed to a vial. To this was added DMF (254 uL) and water (10 uL) and the mixture stirred at room temperature for 90 minutes. The mixture was poured into water and neutralized with solid potassium carbonate then the brown precipitate was collected by filtration. The brown solid was dissolved with DMSO and the residue purified by preparative reverse phase HPLC (20% acetonitrile: water with 0.05% TFA to 70% acetonitrilerwater with 0.05% TFA) to give the pure product as a brown solid: [MH]⁺ m/z 474.

Example 59.

Step 1. 2-(3-(tert-butoxy(^bonyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid (208 mg) was taken up in dioxane (2 mL) to which was added a 4 M solution of hydrochloric acid in dioxane (1 mL, 6 equiv). The mixture was heated at 60 ^*C for 1.5 hours then concentrated in vacuo.

Step 2. To the residue from Step 1 was added solid sodium bicarbonate (281 mg, 5 equiv) and 2- chlorothiazole-5-carbaldehyde (99 mg, 1.0 equiv) and DMF (2.2 mL). The mixture was stirred at 60 "C for 15 hours then cooled and filtered through a plug of cotton and diluted with DMF to a final volume of 6 mL. The resulting orange solution was carried forward to subsequent reactions assuming a concentration of 0.11 M: [MH]⁺ m/z 323.

Step 3. The aldehyde solution from Step 2 (1 mL, 1 equiv), 4-(trifluoromethyl)benzene- 1 ,2- diamine (19.4 mg, 1 equiv) and Oxone* (43 mg, 0.64 equiv) were weighed to a vial. To this was and water (32 uL) and the mixture stirred at room temperature for 16 hours. The reaction was quenched by the addition of a few drops of saturated sodium thiosulfate then the mixture was diluted with DMSO, filtered and purified by preparative reverse phase HPLC (20% acetonitrile:water with 0.05% TFA to 70% acetonitrilerwater with 0.05% TP A) to give the pure product as a pale yellow solid: [MH]⁺ m/z 479.

The compounds presented in Table 3 were prepared by a similar method.

Table 3.

Example 62.

Step 1. 4-(trifluoromethyl)benzene- 1 ,2-diamine (44.0 mg, 1.1 equiv), 6-bromo-5- fluoronicotinaldehyde (50 mg, 1 equiv) and (benzotriazol-1-yloxy)tripynx)lidinophosphonium hexafluorophosphate (130 mg, 1 equiv) were combined in anhydrous DMF. To the solution, DIEA (0.1 19 mL, 3 equiv) was added and the mixture was stirred at room temperature for 2 hours. The solution was diluted with ethyl acetate and washed with saturated ammonium chloride, then water then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give N-(2-amino-4-(trifluoromethyl)phenyl)-6-brorno-5- fluoronicotinamide as a viscous brown oil: [MH]⁺ m/z 379.

Step 2. Acetic acid was added to N-(2-amino-4-(trifluoromethyl)phenyl)-6-bromo-5- fluoronicotinamide obtained in step 1, and the solution was irradiated in a microwave reactor at 180 'C for 40 minutes. The solution was diluted with 40% acetonitrile-water (4 mL) and purified by reverse phase HPLC to give 2-{6-bromo-5-fiuoropyridin-3-yl)-5-(trifluoroniethyl)-1H- benzo[d]imidazole as a tan solid: [MH]⁺ m/z 361.

2-(6-bromo-5-fluoropyricun-3-ylV5-(ti^ (9 mg. 1 equiv). methyl 2-(3-azaspiro[5.51undecan-9-yl^')acetate (5.6 me. 1 equiv) and solid sodium bicarbonate Π4.7 mg. 7 equiv) were suspended in NMP and stirred at 110 °C for 2.5 hours. The mixture was cooled, diluted with a mixture of DMSO:acetonitrile:water and purified by preparative HPLC (20% acetonitrile:water with 0.05% TFA to 70% acetonitrile: water with 0.05% TFA). Fractions containing m z 491 or 505 by :LCMS analysis were pooled and concentrated. The residue was dissolved in a mixture of 1 : 1 : 1 THF-methanol-water to which was added solid lithium hydroxide (1.8 mg, 10 equiv). The mixture was stirred at room temperature for 30 minutes at which point LCMS indicates complete conversion to m/z 491. The mixture was diluted with a mixture of DMSO:acetonitrile:water and purified by preparative HPLC (20% acetonitrile:water with 0.05% TFA to 70% acetonitrilerwater with 0.05% TFA) to give the product as a white solid: [MH]⁺ m/z 491. Example 63.

A 5-trifluoromethyl-2-(6-fluoropyridin-3-yl)-1H-berizimidazole (30 mg, 1 equiv), Hunig's base (93 μί, 5 equiv) and the hydrochloride salt of 2-memoxy-5H-spiro[furo[3,4-b]pyridine-7,4'- piperidin]-5-one (29 mg, 1 equiv) were dissolved in DMA (0.3 M) and heated at 150 ^*C in a microwave until for 8 hours. The mixture was cooled to room temperature, put under vacuum to remove residual Hunig's base, diluted with DMSO and purified by preparative reverse phase HPLC (30% acetonitrile:water with 0.05% TFA to 95% acetonitrile:water with 0.05% TFA) to give the pure demethylated product: [MH]⁺ m/z 482. Example 64.

[3^/e^butoxyc¾ij^nyl)-3-azaspiro[5.5]imdec-9-yl]ace!tic acid (120 mg, 4.5 equiv) was dissolved in dioxane (2 mL) and a 4 M solution of hydrochloric acid (300 uL, 14 equiv) in dioxane was added. The mixture was heated at 60 ^*C for 6 hours at which point a white precipitate had formed and analysis of an aliquot by 1H NMR indicated complete removal of the Boc group. Volatiles were removed in vacuo and to the white solid was added 2-(6- fluoropyridm-3-yl)-5-memoxy-3H mida2o[4,5-b]pyridine (25 mg, 1 equiv), sodium bicarbonate (36 mg, 5 equiv) and NMP (330 uL). The reaction mixture was heated at 110 ^*C for 18 hours, neutralized with acetic acid (15 μϋ,, 3 equiv), diluted with DMSO and purified by preparative reverse phase HPLC (10% acetonitrile:water with 0.05% TFA to 50% acetonitrile:water with 0.05% TFA) to give the pure product: [MH]⁺ m/z 436. Examples 65-77.

To a mixture of Oxone (9 mg, 1 equiv) and 3,5-dimethylphenylenediamine (10 mg, 1 equiv) was added the hydrochloride salt of [3-(5-formylpyridin-2-yl)-3-azaspiro[5.5]undec-9-yl]acetic acid (30 mg, 1 equiv), as a solution in 3% acetic acid-DMF (1 mL). The mixture was stirred at 100 'C for 16 hours, neutralized with potassium carbonate, filtered and purified by preparative reverse phase HPLC.

The compounds presented in Table 4 were prepared according to a similar method.

Intermediate 11.

methyl r9-('te^butoxvcarbonvlVl-oxa-9-azaspiro 5.51undec-4-vl-|acetate

Step 1. N,N iimethyl-1-ammo-3-ie^butyldimethyk (1.5 g, 1 equiv) was added dropwise to a stirring suspension of feri-butyl 4-oxopiperidine-1-carboxylate in 2-butanol (11 mL) at room temperature. After 2.5 hours, volatiles were removed in vacuo and the residue dissolved in diethyl ether (40 mL) then cooled to -78 °C. A solution of acetyl chloride (0.56 mL, 1.2 equiv) in diethyl ether (10 mL) was added slowly and the reaction stirred for 10 minutes then quenched by addition of saturated sodium bicarbonate (25 mL) and warmed to room temperature. The biphasic mixture was transferred to a separatory funnel with enough water to dissolve all solids and extracted with ethyl acetate thrice. The combined organic layers were dried on magnesium sulfate, filtered, concentrated and purified by flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give ferr-butyl 4-oxo-1-oxa-9-azaspiro[5.5]undec-2- ene-9-carboxylate as a colorless oil. Step 2. The residue from Step 1 (1.62 g, 1 equiv) and 30% (w/w) palladium on carbon (440 mg, 20 mol%) were stirred together at room temperature in methanol (25 mL) under an atmosphere of hydrogen for 6 hours. The mixture was filtered through a pad of Celite, concentrated and purified by flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give /erf-butyl 4-oxo- 1 -oxa-9-azaspixo[5.5]undecane-9-carboxylate as an oil.

Step 3. Trimethyl phosphonoacetate (149 mg, 1.1 equiv) was added drop wise to a stirring suspension of hodium hydride (31 mg, 60% dispersion in mineral oil, 1,05 equiv) in THF (2 mL) at 0 °C. The mixture was wanned to room temperature and stirred for 2 hours. /erf-Butyl 4-oxo- 1 -oxa-9-azaspiro [ 5.5 ]undecane-9-carbox late from Step 2 (200 mg) was added dropwise as a solution in THF (1.4 mL). The reaction was stirred at room temperature for 2 hours at which point volatiles were removed in vacuo. The mixture was poured in 1 M hydrochloric acid and extracted wit dichloromethane. The combined organic layers were washed with brine, dried on magnesium sulfate, filtered, concentrated and purified by flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give ieri-butyl-4-(2-methoxy-2-oxoethylidene)-1- oxa-9-azaspiro[5.5]undecane-9-carboxylate as a clear oil.

Step 4. re^Butyl-4-(2-memoxy-2-oxoeftylidene)-1-oxa^

from Step 3 (246 mg, 1 equiv) and palladium hydroxide (75 mg, 14 mol%) were stirred together in ethanol (5 mL) at room temperature under an atmosphere of hydrogen for 6 hours. The reaction mixture was filtered, concentrated and concentrated and purified by flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give teri-butyl 4-(2- memoxy-2<)Xoemyl)-l )xa-9-azaspiro[5.5]undecane-9-H»rboxylate as an oil.

Example 79.

Step 1. Intermediate 11 (137 mg, 1 equiv) was dissolved in 1,4-dioxane (4 mL) to which was added a 4M solution of hydrochloric acid in dioxane (418 uL, 4 equiv) and the mixture heated at heated at 60 °C for 5 hours. Volatiles were removed under a stream of nitrogen and to the remaining white solid was added 2-(6-fluoropyridin-3-yl)-5-(trifluoromemyl)-1H-ben2dmid (141 mg, 1.2 equiv), sodium bicarbonate (176 mg, 5 equiv) and NMP (1.5 mL). The suspension was stirred vigorously at 110 °C for 16 hours, cooled, diluted with DMSO (~3 mL), neutralized with acetic acid (350 uL), filtered then purified by reverse phase HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) to give methyl (9-{5-[5-(trifluoromethyl)-1H-benzirnidazol- 2-yl]pyridin-2-yl } - 1 -oxa-9-azaspiro [5.5]undec-4-yl)acetate as a yellow oil.

Step 2. methyl (9-{5-[5 triiluoromemyl)-1H-beiizinudazol-2-yl]pyridi

azaspiro[5.5]undec-4-yl)acetate from Step 1 (240 mg) was dissolved in a mixture of 1 :1:1 THF:methanol:water (1.33 mL) and lithium hydroxide hydrate (167 mg, 10 equiv) was added. After 3.5 hours of stirring at room temperature, volatiles were removed in vacuo, the residue was diluted with DMSO (~3 mL) and water (0.1 mL), neutralized with acetic acid (400 μί), filtered then purified by reverse phase HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) to give (9- { 5-[5-(trifluoromethyl)- 1 H-benzimidazol-2-yl]pyridin-2-yl } - 1 -oxa-9- azaspiro[5.5]undec-4-yl)acetic acid as a yellow oil: [MH]⁺ m/z 475. Enantiomers were separated by preparative HPLC using a Chiral Technologies 4.6 x 250 mm Chiralcel AD-H column using 25% isopropanol in supercritical carbon dioxide with an operating pressure of 100 bar, flow rate of 2.4 mL/min and temperature of 40 °C. Each enantiomer was obtained as a pale yellow solid with [MH]⁺ m/z 475. Example 80.

Step 1. BH3-THF complex (5.8 mL, 3.5 equiv, 1.0 M in THF) was added dropwise to a stirred THF solution of tert-butyl l-oxa-9-azaspiro[5.5]undec-3-ene-9-carboxylate (420 mg, 1 equiv) (Walters, M. A.; La, F.; Deshmukh, P.; Omecinsky, D. O. J. Comb. Chem. 2002, 4(2), 125-130) over 15 minutes, under an atmosphere of nitrogen. After 4 hours, the mixture was chilled to 0 °C and 30%な(¼ (3.39 mL, 20 equiv) was added dropwise, followed by a solution of 4M NaOH (8.3 mL, 20 equiv). The mixture was warmed to room temperature and stirred for 1 hour until gas evolution ceased. The mixture was partitioned between ethyl acetate and water and the organic phase was washed twice with brine and dried over sodium sulfate. The resulting crude residue was then purified by silica gel chromatography (0 to 100% ethyl acetate: hexanes) to give tert-butyl-3-hydroxy-1-oxa-9-azaspiro[5.5]undccane-9-carboxylate as an amber oil: [MNa]⁺ m/z 294.

Step 2. To a solution of /i?^butyl-3-hydroxy-l )xa-9-az2^iro[5.5]undecane-9-carboxylate (180 mg, 1 equiv) obtained from Step 1 in anhydrous THF (3 mL), under an atmosphere of nitrogen was added N-methylmorpholine N-oxide (75.4 mg, 1 equiv) followed by

tetrapropylammonium perruthenate (23.1 mg, 0.1 equiv). After stirring for 40 minutes at room temperature, the reaction was quenched with water (1.0 mL) and poured into ethyl acetate. The ethyl acetate extract was washed with water and brine and dried over sodium sulfate. The resulting crude residue was purified by silica gel chromatography (0 to 100% ethyl acetate:

hexanes) to give fe^butyl-3 )xc-1-oxa-9-azaspiro[5.5]unde<ane-9-carboxylate as a waxy solid: [MH-C₄H₉]⁺ ^z 214.

Step 3. Performed as in Intermediate 11, Step 3, to afford ieri-butyl-3-(2-methoxy-2- oxoemylidene)-l^xa-9-azaspiro[5.5]undecane-9-carboxylate: [MNa]⁺ m z 348

Step 4. Performed as in Intermediate 11 , Step 4, except 10% Pd/C was used as the catalyst and the reaction was stirred for 18 hours at room temperature, under atmospheric hydrogen and then purified by reverse phase HPLC (10% to 50% acetonitrile in water with 0.05% TFA as eluant) to give 9-(tert-butoxycarbonyl)-1-oxa-9-azaspi^ acetate: [MNa]⁺ m/z 350.

Step 5. Performed as in Example 71, Step 1, except TFA was used as the acid and DCM was used as the solvent for the Boc-deprotection. Purification by reverse phase HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) gave methyl (9-{5-[5-(trifluoromethyl)-1H- benzimidazol-2-yl]pyridin-2-yl}-1-oxa-9-azaspiro[5.5]undec-3-yl) as an amber oil: [MH]⁺ m/z 489.

Step 6. Performed as in Example 71, Step 2 to give (9-{5-[5-(trifluoromethyl)-1H-benzimidazol- 2-yl]pyridin-2-yl}-l^xa-9-azaspiro[5.5]undec-3-yl)acetic acid as a tan solid: [MH]⁺ m/z 475.

Example 81.

fert-butyl 2-(2-methoxv-2-oxc^thvlVl-oxa-8-azaspiror4.5]decane-8-carboxvlate

Step 1.

A 1.5 M solution of DIBAL-H in dichloromethane (2.85 mL, 0.97 equiv) was added slowly to a solution of tert-butyl 2-oxo-1-oxa-8-azaspiro[4.5]dec^e-8-carboxylate (1.125 g, 1.0 equiv) in anhydrous dichloromethane and the mixture chilled to -30_'C. After 2 hours, the mixture was allowed to warm to 0 _°C and aged for 2 hours. Saturated aqueous sodium bicarbonate (1 mL) was added followed by water (2 mL) forming a slurry. The slurry was filtered through a pad of Celite via buchner funnel, rinsing twice with 5 mL of dichloromethane. The rinses were combined with the filtrate and concentrated in vacuo to give /erf-butyl 2-hydroxy-l -oxa- 8- azaspiro[4.5]decane-8-carboxylate as a colorless oil: [MNa]⁺ m/z 280.

Step 2.

Methyl phosphonoacetate (217 mg, 1.1 equiv) was added to a solution of tert-butyl 2-hydroxy-l - oxa-8-azaspiro[4.5]decane-8-carboxyIate (279 mg, 1.0 equiv) from Step 1 in anhydrous THF. The mixture was chilled to 0 ^*C then potassium tert-butoxide (134 mg, 1.1 equiv) was added in one portion. The mixture was warmed to room temperature and stirred for 18 hours. The solution was treated with aqueous ammonium chloride (2 mL) and diluted with ethyl acetate. The organic phase was separated and washed twice with water then once with brine. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified using column chromatography on silica gel (0% to 100% ethyl acetate:hexanes) to give /erf-butyl 2-(2-methoxy-2-oxoethyl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate as a colorless oil: [MNa]⁺ m/z 336.

Step 3.

The carbamate from Step 2 (213 mg, 1.0 equiv) was dissolved in dichloromethane (1.0 mL) and TFA (1.0 mL) and stirred at room temperature for 1 hour. Volatiles were removed in vacuo then the residue was reconstituted in dichloromethane and concentrated in vacuo again. The tan oil thus obtained was carried forward to the next step.

Step 4.

The amine salt from Step 3 (54 mg, 1.0 equiv), 2-(6-fluoropyridm-3-yl)-5-(trifluoromethyl)-1H- berizo[d]imidazole (47 mg, 1.0 equiv) and sodium bicarbonate (139 mg, 10 equiv) was suspended in NMP (0.75 mL) and stirred at 110 °C for 4 hours. The mixture was cooled and diluted with 40% acetonitrile in water then directly purified by preparative HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) to give the product as an off-white solid: [MH]⁺ m/z 475. Step 5.

The ester from Step 4 (29 mg, 1 equiv) was dissolved irj a 1:1:1 mixture of THF-water-methanol to which was added solid lithium hydroxide (14.6 mg, 10 equiv). After stirring at room temperature for 3 hours, LCMS showed clean conversion to product. The reaction mixture was acidified to pH 2 with 2 M hydrochloric acid. The mixture was diluted with 40% acetonitrile in water then directly purified by preparative HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) to give the product as an off-white solid: [MH]⁺ m/z 461. Enantiomers were separated by preparative HPLC using a Chiral Technologies 4.6 x 250 mm ChiralPak IA column using 35% ethanol in heptane. Each enantiomer was obtained as a white solid with [MH]Vz 461.

Example 82.

Step 1. 2^8^tert-butoxycarbonyl)-lK)xa-8-azaspiro[4.5]decan-3-yl)acetic acid (203 mg, 1 equiv) was dissolved in dioxane (2 mL) then treated with a 4 M solution of hydrochloric acid in dioxane (1 mL) at 50 ^*C for 90 minutes. The mixture was then concentrated in vacuo to yield a white powder that was carried forward in subsequent steps.

Step 2. The amine salt from Step 1 (80 mg, 1 equiv), 2-(6-fluoropyridin-3-yl)-5- (trifluoromemyl)-1H-ben2»[d]imidazole (95 mg, 1 equiv) and sodium bicarbonate (199 mg, 7 equiv) were dissolved in NMP (1 mL) and stirred at 110 'C for 16 hours. The mixture was diluted with DMSO, filtered and purified by preparative HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) to give the product as a yellow solid: [MH]⁺ m/z 475.

The compounds presented in Table 7 were prepared according to a similar method.

Example 85-86.

Step 1. 2^8^tert-butoxycarix)nyl)-l^xa-8-azaspiro[4.5]decan-3-yl)acetic acid (800 mg, 1 equiv) was stirred in a 1.25 M solution of hydrochloric acid in methanol (5 mL) at 50 ^*C for 2 hours. Then additional hydrochloric acid was added as a 4M solution in dioxane (1 mL) followed by an additional 90 minutes of stirring at 50 ^*C. The mixture was then concentrated in vacuo to yield a white powder that was carried forward in subsequent steps. Step 2. The amine salt from Step 1 (617 mg, 1 equiv), 2-(6-fluoropyridin-3-yl)-5- (tri fluoromethyl)- 1 H-benzo [d] imidazole (736 mg, 1 equiv) and sodium bicarbonate (1100 mg, 5 equiv) were dissolved in NMP (8.7 mL) and stirred at 110 "C for 18 hours. The mixture was poured into ice water and ethyl acetate and saturated aqueous ammonium chloride were added until complete dissolution of solids occurred. The layers were shaken and separated. The organic layer was then washed five times with water, once with brine then dried on anhydrous sodium sulfate, filtered and concentrated in vacuo to yield a brown solid: [MH]⁺ m/z 475. Purification was performed by preparative HPLC on a Chiral Technologies 4.6 x 250 mm Chiralcel OD column using 40% methanol in supercritical carbon dioxide. This yielded two separated enantiomers: A and B. Each enantiomer was obtained as an off-white solid with [MH]- z 475.

Step 4. Enantiomer A of the ester from Step 3 was dissolved in methanol (300 uL) and THF (300 uL) to which was added 2.5 M lithium hydroxide. The reaction was stirred at 50 ^*C for 2 hours then quenched by the addition of glacial acetic acid (150 uL) and concentrated in vacuo. The mixture was diluted with DMSO, filtered and purified by preparative HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) to give the carboxylic acid (Enantiomer A) as a white solid: [MH]⁺ m/z 461.

Step 5. Enantiomer B of the ester from Step 3 was dissolved in methanol (300 uL) and THF (300 uL) to which was added 2.5 M lithium hydroxide. The reaction was stirred at 50 ^*C for 2 hours then quenched by the addition of glacial acetic acid (150 μΐ,) and concentrated in vacuo. The mixture was diluted with DMSO, filtered and purified by preparative HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) to give the carboxylic acid (Enantiomer B) as a white solid: [MH]⁺ m/z 461.

Intermediate 12.

methyl l-oxa-9-azaspiro[5.5]undecane-3-carboxylate (TFA salt)

Step 1. A 60% oil dispersion of sodium hydride (0.438 g, 1.2 equiv) was added to a solution of tert-butyl 4-allyM-hydroxypiperidme-1- arboxylate (2.2 g, 1 equiv) (Walters, M. A.; La, F.; Deshmukh, P.; Omecinsky, D. O. J. Comb. Chem. 2002, 4(2), 125-130) in anhydrous DMF (170 mL) and the mixture cooled to 0 ^*C. The mixture was warmed to room temperature over 1 hour and methyl 2-(bromomethyl)acrylate (1.63 g, 1 equiv) was added dropwise to the solution over 5 minutes. The mixture was aged for 72 hours. A saturated solution of ammonium chloride was added to the reaction mixture and the mixture was diluted with ethyl acetate. The organic phase was separated and washed twice with water then brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified using column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give 920 mg of iert-butyl 4-{[2- (memoxycarbonyl)pror 2-en-1-yl]oxy}-4-^ as a colorless oil: [ Naf m/z 362.

Step 2. tert-butyl 4- { [2-(methoxycarbonyl)prop-2-en- 1 -yljox } -4-(prop-2-en- 1 -yl)piperidine- 1 - carboxylate from Step 1 (340 mg, 1 equiv) in anhydrous 1,2-dichloroethane (75 mL) was combined with benzylidene[ 1 ,3-bis(2,4,6-trime&ylphenyl)-2-irm

(tricyclohexylphosphine)ruthenium (85 mg, 10 mol%) and the mixture was heated at 85 "C for 18 hours. The mixture was cooled to room temperature, -then diluted with ethyl acetate and washed with water twice with brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give tert-butyl 3 -oxo- 1 -oxa-9-azaspiro [5.5 ]undecane-9- carboxylate as an oil [MNa]⁺ m/z 334. Step 3. An ethanol solution of the product from Step 2 was subjected to hydrogenation by a single pass through a Thales H-Cube Flow Hydrogenation Reactor (Jones, R. V.; Godorhazy, L.; Varga, N. Szalay, D.; Urge, L.; Darvas, F. J. Comb. Chem 2006, 8, 110-116) using a palladium hydroxide cartridge at 50 °C and 60 bar. Volatiles were then removed in vacuo and the residue purified by preparative HPLC (10% to 98% acetonitrile in water with 0.05% TFA as eluant) to give the product as an oil: [MNa]⁺ m/z 336. Step 4. The residue from Step 3 was dissolved in dichlorome hane (4 raL) and TFA (4 mL) and stirred at room temperature for 90 minutes at which point volatiles were removed in vacuo. The residue was reconstituted in dichloromethane and concentrated again to afford an amber oil which was purified by preparative HPLC (10% to 98% acetonitrile in water with 0.05% TFA as eluant) to give the TFA salt of methyl l-oxa-9-azaspiro[5.5]undecane-3-carboxylate as an oil: [MH]⁺ w z 214.

Example 87.

Step 1. To the amine salt from Step 4 above (60 mg, 1 equiv), 2-(6-fluoropvridin-3-vl -5- (trifluoromethviyi H-heriTimidazole (79 me. 1 equiv) and sodium bicarbonate (236 me. 10 equiv') was added NMP (2 mL) and the mixture stirred at 110 ^*C for 2.5 hours. The mixture was cooled to room temperature, diluted with 40% acetonitrile in water, filtered and purified by preparative HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) to give methyl 9-(5-(5-(trifluoromemyl 1H-benzo[d]^

azaspiro[5.5]undecane-3-carboxylate as a tan solid: [MH]⁺ m/z 475.

Step 2. The ester from Step 1 (130 mg, 1 equiv) was dissolved in a 1 : 1 : 1 mixture of THF-water- methanol and treated with lithium hydroxide (65.6 mg, 10 equiv) at room temperature for 2 hours. The reaction mixture was cooled in an ice bath and acidified to pH 2 with 2M

hydrochloric acid. The mixture was diluted with 40% acetonitrile in water, filtered and purified by preparative HPLC (20% to 70% acetonitrile in water with 0,05% TFA as eluant) to give the product as an off-white solid: [MH]⁺ m/z 461. The compounds presented in Table 5 were prepared according to a similar method.

Examples 90-91.

Enantiomers of Example 86 were separated by preparative HPLC using a Chiral Technologies 4.6 x 250 mm ChiralPak IA column using 50% ethanol in heptane. Enantiomer A was obtained as a white solid with [MH]⁺ m/z 475 and Enantiomer B was obtained as a white solid with [MH]⁺ m z 475. Absolute stereochemistry was arbitrarily assigned

Intermediate 13. O — ' ^N— ' OMe

The TFA salt of methyl 1 -oxa-9-azaspiro [5.5 ]undecane-3 -carboxylate (876 mg, 1 equiv) and 2- fluoropyridine-5-carboxaldehyde (352 mg, 1.05 equiv) were added to sodium bicarbonate (1124 mg, 5 equiv) in DMF (10.5 mL) and the mixture stirred overnight at 80_^eC. The mixture was then cooled and filtered through a 0.45 micron membrane and this solution used crude in subsequent steps: [MH]⁺ m/z 319.

Examples 92-101 in Table 6 were prepared from Intermediate 13 in two steps. First,

Intermediate 13 and the appropriate diamine were allowed to react at room temperature under influence of Oxone^® in DMF and water as previously described . For examples 100-101, the diamine and aldehyde were heated at 65 ^*C for 2 hours prior to addition of Oxone^®. The resulting benzimidazoles were purified by preparative HPLC then subjected to saponification with lithium hydroxide then purified as previously described.

Potency of selected DGAT1 inhibitors.

To a 384 well assay plate was added 1 uL of a 400 μΜ solution of the test compound in DMSO and 20 uL of a substrate mix that is 300 uM in diolein and 40 μΜ in oleoyl- CoA in 10% ethanol. To this was added 19 uL of 1.05 ug mL human DGAT1 -expressed yeast membrane fraction in a buffer of the following composition: 200 mM Tris, pH 7, 200 mM sucrose, 200 mM magnesium chloride, and 20 ug mL N-ethylmaleimide-treated bovine serum albumin. The solution is incubated at room temperature for 1 hour after which 20 uL of a 90 uM 7-diemylamino-3-(4'-maleimidylphenyl)-4-memylcoumarin 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

Table 7.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula I:

R, G and E are independently selected f om the group consisting of -N- and -CH-, wherein if one of R, G and E is -N-, the remaining two are -CH-;

R' and R' together form ring D, wherein D is selected from the group consisting of cycloalkyl and heterocycloalkyl wherein A, B, C and D are independently unsubstituted or substituted with one or more substituents selected from the group a, Ci-C$alkyl, C₃- Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, Cj-CealkylCa-Ciocycloalkyl, C₁-C₆alkylaryl, Ci- Cealkylheteroaryl and Ci-C6alkylcycloheteroalkyl, wherein C₁-C₆alkyl, C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, Cj-CealkylCs-Ciocycloalkyl, C₁-C₆alkylaryl, C₁-C₆alkylheteroaryl and C₁-C₆alkylcycloheteroalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of a;

a is selected from the group consisting of halogen, C₁-C6alkyl, halogen- substitutedC₁-C₆alkyl, COC-Cealkyl, oxo, -OH, halogen-substitutedC₁-C₆alkylOH, -OQ- C$alkyl, -Ohalogen-substitutedC_!-Cealkyl, -COOH, -COOC₁-C₆alkyl, -C₁-C₆alkylCOOCj- Cealkyl, -C-CealkylCOOH, -OC₁-C₆alkylCOOH, -CN, C₁-C₆alkylCN, -NO2, NH₂, HCj- Cealkyl, N(Ci-C6alkyl)₂, -NHCOOH, -NHCOOd-Cealkyl, -CONH₂, -CONHC₁-C₆alkyl, - CON(Ci-Q5alkyl)2, -CONHCi-Q^lkyl-N(Ci-C6alkyl)2, -NHSOjC-Cealkyl, -SO2NH2, -S<¼C_r C¾all yl, C3-Cjocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, Cj-

CealkylCs-Ciocycloalkyl, C₁-C₆alkylaryl, C₁-C₆alkylheteroaryl and C₁-C₆alkylcycloheteroalkyl.

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

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

4. A compound of any one of claims 1 -3 , or a pharmaceutically acceptabl salt thereof, wherein A is substituted with one or more substituents selected from the group consisting of halogen, Ci-C^alkyl, -OCi-C$alkyl, -C , SC^ e and halogen-substitutedCi- Cealkyl.

5. A compound of any one of claims 1 -4, or a pharmaceutically acceptabl salt thereof, wherein one of R is -CH- and G or E is -CH- and the other is -N-.

6. A compound of any one of claims 1 -4, or a pharmaceutically acceptable salt thereof, wherein R, G and E are-CH-.

7. A compound of any one of claims 1 -6, or a pharmaceutically acceptable salt thereof, wherein C is unsubstituted. 8. A compound of any one of claims 1 -7, or a pharmaceutically acceptable salt thereof, wherein D is a cycloalkyl.

9. A compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein D is cyclohexane.

10. A compound of any one of claims 1 -7, or a pharmaceutically acceptable salt thereof, wherein D is a heterocycloalkyl.

11. A compound of any of claims 1 -7, or a pharmaceutically acceptable salt thereof, wherein D is

wherein T is selected from the group consisting of -0-, -CH₂-, -NRa and -NC₁-C₆alkyl-, wherein

Ra is selected from the group consisting of H and -Cealkyl; and

V, U, Q and W are independently selected from the group consisting of -N-, -C- and -CH-.

12. A compound of any of claims 1 -7, or a pharmaceutically acceptable salt thereof, wherein D is selected from the group consisting of:

wherein Ra is selected from the group consisting of H and Q-Cealkyl.

13. A compound of any one of claims 1 -7, or a pharmaceutically acceptable salt thereof, wherein D is selected from the group consisting of:

wherein X, Y and Z are independently selected from the group consisting of -C-, -CH-, -CH₂-, N-, -NH- and -0-. 14. A compound of any one of claims 1 -7, or a pharmaceutically acceptable salt thereof, wherein D is selected from the group consisting of:

IS. A compound of any of claims 1 -7, or a pharmaceutically acceptable salt thereof, wherein D is substituted with one or more substituents selected from the group consisting of halogen, C₁-C₆alkyl, halogen-substitutedC₁-C₆alkyl, oxo, -OH, -COOH, -COOCj- Cealkyl, -Ci-CealkylCOOCi-Qsalkyl, -Ci-CoalkylCOOH, -OC,-C6alkylCOOH, -CN, Ci- CealkylCN and -NHSC^C₁-C₆alkyl.

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

17. A pharmaceutical composition comprising a compound of ^my ^one of claims 1-16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. Use of a compound of any one of claims 1 -16, 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. 19. 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 1-16.