CA2804970A1 - Spirocyclic compounds - Google Patents

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 diacylglycerol 0-acyltransferase type linhibitors (hereinafter also referred to as "DGAT1"), and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity.

BACKGROUND
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 (TO) in adipose tissue which is a result of lack of exercise, intake of excessive calories and ageing. In the body there are two TO synthesis pathways, a glycerol phosphate pathway, which is present in most organs and causes de novo TG synthesis, and a monoacylglyeerol pathway, which is involved principally in absorption of aliphatic acid from the small intestine.
Diacylglycerol acyitransferases (DGATs, EC 2.3.1.20), which are membrane-bound enzymes present in the endoplasmic reticulum, catalyze the final step of the TO synthesis common to the two TO
synthesis pathways. The final reaction consists of transferring an acyl group of aeyl-coenzyme A
to the 3-position of 1,2-diacylglyeerol to generate TO (Frog.' Lipid Res., 43.134-176. 2004 and Ann. Med., 36, 252-261, 2004). There are two subtypes of DGATs: DGAT I and DGAT2.
There is no significant homology at the generic or amino acid level between the DGAT1 and DGAT2, which are encoded by different genes (ProcNatl.Acad.Sci.USA.,95,13018-13023,1998 and JBC,276,38870-38876,2001). DGAT1 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 fated!; 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 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 JCI,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 A B C X
N) R"

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-;
Ri 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-C6alkyl, C3-Cmcycloalkyl, aryl, heteroaryl, cycloheteroalkyl, Ci-C6alky1C3-Ciocycloalkyl, C1-C6alkylaryl, C1-C6alkylheteroaryl and C1-C6alkylcycloheteroalkyl, wherein CI-C6a1kyl, C3-C1ocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, CI-C6alky1C3-Clocycloalkyl, CI-C6alkylaryl, Ci-C6alkylheteroaryl and CI-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-substitutedE1-C6alkyl, COC1-E6alkyl, oxo, -OH, halogen-substitutedCi-C6alkylOH, -0C1-C6alkyl, -Ohalogen-substitutedCi-C6alkyl, -COOH, -COOCI-C6alkyl, -C1-C6alkylCOOCi-C6alkyl, -C1-C6alky1COOH, -0C1-C6alkylCOOH, -EN, Ci-C6alkylCN, -NO2, NH2, NHC1-C6alkyl, N(C1-E6alky1)2, -NHCOOH, -NHCOOC1-C6alkyl, -CONH2, -CONHC 1-C6alkyl, -CON(Ci-C6alky1)2, -CONHCI-C6alkyl-N(Ci-C6alky1)2, -NEISO2C1-C6alkyl, -SO2NH2, -C6alkyl, C3-C10eycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C-C6alky1C3-C10cycloalkyl, C1-C6alkylaryl, CI-C6allcylheteroaryl and C1-C6alkylcycloheteroalkyl, DETAILED DESCRIPTION OF THE INVENTION
Compounds The present invention is directed to compounds of structural formula I:
A
B N/ C
R"

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 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, C1-C6alkyl, C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, CI-C6alky1C3-C1ocycloalkyl, C1-C6alkylaryl, C1-C6alkylheteroaryl and C1-C6alkylcycloheteroalkyl, wherein C1-C6alkyl, C3-C10cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C1-C6alky1C3-C1ocycloalkyl, C1-C6alkylaryl, E1-C6alkylheteroaryl and C1-C6alkylcycloheteroalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of a;
substitutedE1-C6alkyl, COC1-C6alkyl, oxo, a is selected from the group consisting of halogen, C1-C6alkyl, halogen-halogen-substitutedQ-C6alkylOH, -0C1-C6alkyl, -Ohalogen-substitutedC1-C6alkyl, -E0OH, -COOC1-C6alkyl, -C1-C6alkylCOOCI-C6alkyl, -C1-C6alkylCOOH, -0C1-C6a1ky1COOH, -CN, C1-C6alkylCN, -NO2, NH2, NHCI-C6alkyl, -C6alkyl)2, -NHCOOH, -NHCOOC 1-C6alkyl, -CONH2, -CONHC -C6alkyl, CONCI-C6alicY1)2, -CONHC1-C6aikyi-N(C1-C6alkyl)2, -NBISO2CI-C6aikyi, -SO2N1-12, -S02C1-C6alkyl, C3-C1ocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, Ci-C6alky1C3-Cioeycloalkyl, C1-C6alkylaryl, Ci-C6alkylheteroaryl and C1-C6alkylcycloheteroalkyl.
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, C1-C6alkyl, -CN, SO2Me and halogen-substitutedCI-C6alkyl. In some embodiments, A is further substituted with one substituents selected from the group consisting of halogen, CI-C6alkyl, -OCI-C6alkyl, -CN, SO2Me and halogen-substitutedC1-C6alkyl. In some embodiments, A is further substituted with two substituents selected from the group consisting of halogen, CI-C6alkyl, -OCI-C6alkyl, -CN, SO2Me 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 Ci-C6alkyls.
Examples of C1-C6alkyl include but are not limited to methyl and ethyl. A can also be substituted with halogen-substitutedCi-Colkyl. Examples of halogen-substituted Ci-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, NHSO2Me and SO2NH2. In yet other examples A is substituted with (C21-14)NHCOCH3 or CONH(C2R4)N(C21-14)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-substitutedCI-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-C6alkyl. 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 cycloheteroalkyls include phenyl, pyridine, pyrimidine and triazole. Examples include but are not limited to:

ei N N
N) N
N
L

N\ ) N N

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, CI-C6alkyl and halogen-substitutedCi-Coalicyl. 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-substitutedC1-C6alkyl include, but are not limited to trifluoromethyl.
Suitable examples of ring B and its substituents include, but are not limited to, CI CI

CI CI
111 and /

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-substitutedCi-C6alkyl. Examples of suitable halogens include, but are not limited to chlorine and fluorine. Examples of suitable Ci-C6alkyls 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, S.

In another embodiment, D is heterocycloalkyl. For example, in one embodiment, D is \1õAN 11 wherein T is selected from the group consisting of¨O-, -CH2-, -NH and ¨NCI-C6alkyl-; and V, U, Q and W are independently selected from the group consisting of ¨N-, -C-and ¨CH-. In one embodiment, T is ¨0- and V, U, Q and W are ¨CH-. In another embodiment, T is 0 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 ¨CI-12- 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:

Ra N
NM÷
/P

fb, eRas and Vir wherein Ra is selected from the group consisting of H and CI-C6alkyl. 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 =O. 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, C1-C6alkyl, C1-C6alkylCOOH, Ci-C6alkylCN, cyclopropyl, halogen-substitutedCi-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 C1-C6alkylaryl group. In certain embodiments, D is substituted with a ¨CH2-phenyl, wherein the ¨CI-12-phenyl is unsubstituted. In certain embodiments, D
is substituted with ¨CH2-phenyl, wherein the ¨CH2-phenyl is substituted with one or more substituents selected from the group consisting of halogen, Ci-C6alkyl and halogen-substitutedCi-C6alkyl.
In other embodiments of the compounds described herein, D is selected from the group consisting of:
X

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 CH2 and Y is ¨CO. In another embodiment, X is 0, 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:

> ' j and\c) 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 farther 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, COOCI-C6alkyl, heterocycloalkyl-COOH, halogen, Ci-C6alkyl, ha1ogen-substitutedC1-C6alkyl, -OCI-C6alky1C001-1, NO2, -CN, C1-C6alkylCOOH, C6alkylCOOC i-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:

1110 and 101 P is selected from the group consisting of-0- 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, -C1-C6alkylCOOH and NHSO2Me. In one embodiment, D is cyclohexane, wherein the cyclohexane is substituted with -COOH. In another embodiment, D is cyclohexane, wherein the cyclohexane is substituted with -CI-C6alkylCOOH.

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

cs-05 cs=SSO cs-5S cs-550 I
, 0 0 and -"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 -C1-C6alkylCOOH. Examples of D and its substituents include, but are not limited to, 0 R\
OR /\--'0H
artd [XI) 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, C1-C6alkyl, halogen-substitutedCI-C6alkyl, oxo, -OH, -COOH, -COOCI-C6alkyl, -C1-C6alkylCOOCI-C6alkyl, -C1-C6alkylCOOH, -0C1-C6alkylCOOH, -CN, Ci-C6alkylCN and -NHSO2CI-C6alkyl.

Also described herein are compounds of formula Ia:
Ri --NH) Ia 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-;
RI is selected from the group consisting of halogen or halogen-substitutedCi-C6alkyl;
D is a C3-Cl0cycloa1kyl; and R2 is selected from the group consisting of hydrogen, C1-C6alkyl, halogen-substitutedCi -C6alkyl, COCI-C6alkyl, -OH, oxo, halogen-substitutedCI-C6alkylOH, -Ohalogen-substitutedC1-C6alkyl, -COOH, -COOC1 -C6alkyl, -C1-C6alkylCOOCi-C6alkyl, -C1-C6alkylCOOH and -OCI-C6alkylCOOH.
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:
ONO land 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, RI is halogen-substitutedCI-C6alkyl. Suitable examples of halogen-substitutedCi-C6alkyl include, but are not limited to, trifluoromethyl.
In certain embodiments, R2 is selected from the group consisting of -COOH, -COOCI-C6alkyl, -C1-C6alkylCOOC1-C6allcyl and -C1-C6alkylCOOH. For example, in some embodiments R2 is selected from the group consisting of ¨COOH and -C1-C6alkylCOOH.
Examples of -C1-C6alkylCOOH include, but are not limited to, -CH2COOH.
Ri Aldo described herein are compounds of formula Ia:

\CM
N> Ia 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-; Rl 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, C1-C6alky1, halogen-substitutedC1-C6alkyl, COCI-C6alkyl, oxo, -OH, halogen-substitutedCi-C6alkylOH, -0C1-C6alkyl, -Ohalogen-substitutedCi-C6alkyl, -COOH, -COOC1-C6alkyl, -C1-C6alkylCOOC1-C6alkyl, -C1-C6alkylCOOH, -0C1-C6alkylCOOH, -CN, C1-C6alkylCN, -NO2, NH2, NHCI-C6alkyl, N(C1-C6alky1)2, -NHCOOH, -NHCOOCI-C6alkyl, -CONH2, -CONHCE-C6alkyl, -CON(C1-C6alky1)2, -NHSO2C1-C6alkyl, -S02C1-C6alkyl, C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C1-C6alky1C3-Ciocycloalkyl, C1-C6alkylaryl, CI-Coalkylheteromyl and CI-Colkylcycloheteroalkyl.
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 heterocycloalkyl wherein the heterocycloalkyl is selected from the group consisting of: o >
4itt, = =

' 0 and In certain embodiments, D is selected from the group consisting of:=

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

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

, >0 and In some embodiments, RI is halogen. Suitable examples of halogen include, but are not limited to, chlorine, fluorine and bromine. In some embodiments, RI is halogen-substitutedCi-C6allcyl. Suitable examples of halogen-substitutedCI-C6alkyl include, but are not limited to, trifluoromethyl.
In certain embodiments, R2 is selected from the group consisting of halogen, halogen-substitutedCi-C6alkyl, oxo, -COOH, -COOCI-C6alkyl, -C1-C6alkylCOOCi-C6alkyl, -Ci-C6alkylCOOH, -0C1-C6alkylCOOH, -CN, C1-C6alkylCN and C1-C6alkylcyclopropyl. In other embodiments R2 is selected from the group consisting of hydrogen, halogen, CI -C6alkyl, halogen-substitutedCi-C6alkyl, oxo, -OH, halogen-substitutedCi-C6alkylOH, -COOH, -COOCI-C6alkyl, -C1-C6alkylCOOCI-C6alkyl, -Ci-C6alkylCOOH, -C6alkylCOOH, -CN, C1-C6alkylCN, -NO2, -NHSO2C1-C6alkyl, -S02C1-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, Ci-C6alkyl, halogen-substitutedC1-C6alkyl, -COOH, -COOC1-C6alkyl, -CI-C6alkylCOOCI-C6alkyl, -C1-C6alkylCOOH, -0C1-C6alkylCOOH and ¨CN.
Also described herein are compounds of formula Ib:

1/,\,/ // 'R4 R5 U " 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-;

R1 is selected from the group consisting of halogen or halogen-substitutedC1-C6alkyl; and R3, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, halogen-substitutedCi-C6alkyl, COCI-C6alkyl, oxo, -OH, halogen-substitutedC1-C6alkylOH, -OCI-C6alkyl, -Ohalogen-substitutedCi-C6alkyl, -COOH, -COOCI-C6alkyl, -C1-C6alkylCOOCI-C6alkyl, -C1-C6alkylCOOH, -0C1-C6alkylCOOH, -CN, C1-C6alkylCN, -NO2, NH2, NHC1-C6alkyl, N(Ci-C6alkyl)2, -NFICOOH, -NHCO0C1-C6alkyl, -CONH2, -CONHC -C6alkyl, -CON(C -C6alky1)2, -NHSO2C -C6alkyl, -S02C1-C6alkyl, C locycloalkyl, aiyl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, Ci-C6alkyl C3-1 0 Ciocycloalkyl, C1-C6alkylatyl, Ci-C6alkylheteroaryl and C1-C6alkyleycloheteroalkyl, wherein the C3-C10cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cyclobeteroalky1C001-1, C1-C6alky1C3-C10cycloalkyl, Ci-C6alkylatyl, C1-C6alkylheteroaly1 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 -C112-. In still other embodiments, T is -NH-. In yet other embodiment, T is -NCH3.
In some embodiments, RI 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-C6alkyl 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, C6alkyl, halogen-substitutedCi-C6alkyl, COCI-C6alkyl, oxo, -OH, halogen-substitutedC1-C6alkylOH, -OCI-C6alkyl, -Ohalogen-substitutedCi-C6alkyl, -COOFI, -COOC1-C6alkyl, -C1-C6alkylCOOCI-C6alkyl, -C1-C6alkylCOOH, -0C1-C6alky1C0011, -CN, C1-C6alkyleN, -NO2, NH2, NHCI-C6alkyl, N(C1-C6alky1)2, -NHCOOH, -NHCOOC1-C6alkyl, -CONH2, -CONHCI-C6alkyl, -CON(C1-C6alky1)2, -NHSO2C1-C6alkyl, -S02CI-C6alkyl, C3-C10cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C1-C6alky1C3-C1ocycloalkyl, C1-C6alkylaryl, CI-C6alkylheteroaryl and CI-C6alkyleycloheteroalkyl, wherein the C3-C10cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, CI -C6alky1C3-Ciocycloalkyl, C1-C6alkylaryl, CI-C6alkylheteroaryl and Ci-C6alkylcycloheteroalkyl are unsubstituted or substituted with at least one sub stituent selected from the group consisting of halogen.
In certain embodiments, R3 is selected from the group consisting of hydrogen, oxo, CI-C6alkyl, -COOH, -CI-C6alkylCOOH, CI-C6alkyleN, -S02C1-C6alkyl, cyclopropyl, C1-C6alkylaryl, and C6alkylcycloheteroalkyl, wherein the C1-C6alkylaryl and Ci-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-substitutedCi-C6alkyl, COC)-C6alkyl, -OH, -COOH, -COOC1-C6alkyl, -C1-C6alkylCOOCi-C6alkyl, Ci-C6alkylCN and -C1-C6alkylCOOH. In one embodiment, R3 is oxo. In another embodiment R3 is hydrogen. In still another embodiment, R3 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, C6alkyl, halogen-substitutedCI-C6alkyl, COC1-C6alkyl, oxo, -OH, halogen-substitutedCi-C6alkylOH, -0 Ci-C6alkyl, -Ohalogen-substitutedCI-C6alkyl, -COOH, -COOCI-C6alkyl, -C 1-C6alkylCOOCI-C6alkyl, -Ci-C6alkylCOOH, -0C1-C6alkylCOOH, -CN, C1-C6alkylCN, -NO2, NH2, NHC1-C6alkyl, N(C1-C6alky1)2, -NICOOH, -NHCOOCI-C6alkyl, -CONH2, -CONHC1-C6alkyl, -CON(CI-C6alkyl)2, -NHSO2CI-C6alkyl, -S02C1-C6alkyl, C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C1-C6alky1C3-C1ocycloalkyl, C1-C6alkylatyl, CI-C6alkylheteroaryl and CI -C6allcylcyeloheteroalkyl, wherein the C3-C10cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C1-C6alky1C3-C1ocycloalkyl, C1-C6alkylaryl, Ci-C6alkylheteroaryl and C1-C6alkyleyeloheteroalkyl 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, C1-C6alkyl, halogen-substitutedC1-C6alkyl, COC1-C6alkyl, -OH, -COOH, -COOCI-C6alkyl, -C1-C6alkylCOOCI-C6alkyl and -C1-C6a1kylCOOH. In another embodiment, R4 is hydrogen.
R5 is independently selected from the group consisting of hydrogen, halogen, C6alkyl, halogen-substitutedC1-C6alkyl, COC1-C6alkyl, oxo, -OH, halogen-substitutedCI-C6alkylOH, -0C1-C6alkyl, -Ohalogen-substitutedCi-Colkyl, -COOH, -COOCI-C6alkyl, -C1-C6alkylCOOCI-C6alkyl, -C1-C6alkylCOOH, -0C1-C6alkylCOOH, -CN, Ci-C6alkylCN, -NO2, NH2, NHC1-C6alkyl, N(C1-C6alky1)2, -NHCOOH, -NHCOOCI-C6alkyl, -CONH2, -CONHC1-C6alkyl, -CON(C1-C6alky1)2, -NHSO2C1-C6alkyl, -S02C1-C6alkyl, C3-C1ocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C1-C6alky1C3-C1ocycloalkyl, C1-C6alkylaryl, CI-C6alkylheteroaryl and C1-C6alkylcycloheteroalkyl, wherein the C3-C10cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroakICOOH, CI-C6alky1C3-C1ocycloalkyl, C1-C6alkylatyl, C1-C6alkylheteroaryl and C1-C6alkyleyeloheteroalkyl 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, C1-C6alkyl, -COOH, -C1-C6alkylCOOH, CI-C6alkylEN, -S02C1-C6alkyl, cyclopropyl, CI-Colkylaryl, and C6alkyleyeloheteroalkyl, wherein the C1-C6alkylaryl and C1-C6alkylcycloheteroalkyl are unsubstituted 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-substitutedCi-C6alkyl, COCi-C6alkyl, -OH, -COOH, -COOCi-C6alkyl, -Cl-C6alkylCOOCI-C6alkyl and -C1-C6alkylCOOH. In one embodiment, R5 is hydrogen. Also described herein are compounds formula Ic:

Xm R7 " R8 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-;
K, L and M are independently selected from the group consisting of-O-, -CH2-, -CH-, -C- and -N -;RI is selected from the group consisting of halogen or halogen-substitutedCi-C6alkyl; and R6, R7 and R8 are independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, halogen-substitutedCi-C6alkyl, COCI-C6alkyl, oxo, -OH, halogen-substitutedC1-C6alkylOH, -0C1-C6alkyl, -Ohalogen-substitutedC1-C6alkyl, -COOH, -C1-C6alkylCOOCI-C6alkyl, -C1-C6alkylCOOH, -0C1-C6alkylCOOH, -CN, ColkylCN, -NO2, NH2, NHCI-C6alkyl, N(C1-C6alky1)2, -NHCOOH, -NHCOOC1-C6alkyl, -CONH2, -CONHC1-C6alkyl, -CON(C1-C6alky1)2, -NHSO2C1-C6alkyl, -S02C1-C6alkyl, C1ocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, CI-C6alkylC3-CI ocycloalkyl, C1-C6alkylaryl, C1-C6alkylheteroaryl and C1-C6alkylcycloheteroalk-yl, wherein the C3-C1ocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C1-C6alkylC3-C1 ocycloalkyl, C1-C6alkylaryl, C1-C6alkylheteroaryl and CI-Colkylcycloheteroalkyl 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 some embodiments, RI is halogen. Suitable examples of halogen include, but are not limited to, chlorine, fluorine and bromine. In some embodiments, RI is halogen-substitutedCi-C6alkyl. Suitable examples of halogen-substitutedCi-C6alkyl include, but are not limited to, trifluoromethyl.
In certain embodiments, J is ¨CH2-. In other embodiments, J is ¨0-. In still other embodiments, K is CO. In yet another embodiment, K 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 ¨C(R6), wherein R6 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 C(R6); 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, C1-C6alkyl, halogen-substitutedCi-C6alkyl, heterocyclicalkylCOOH, -COOH, -COOCI-C6alkyl, -C6alkylCOOCi-C6alkyl, -CI-C6alkylCOOH, -0C1-C6alkylCOOH, NO2 and ¨CN. In still other embodiments, R8 is hydrogen.
Also described herein are compounds of formula Id:

RI N) N

R9 Id 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 selected from the group consisting of¨O- or ¨CH2-;
RI is selected from the group consisting of halogen or halogen-substitutedCi-C6alkyl; and R9 is selected from the group consisting of hydrogen, Ci-C6alkyl, halogen-substitutedC1-C6alkyl, COCI-C6alkyl, -OH, halogen-substitutedCi-C6alkylOH, -0C1-C6alkyl, -Ohalogen-substitutedCI-C6alkyl, -CO OH, -COOC -C6alkyl, -C -C6alkylCOOC -C6alkyl, -C 1-C6alkylCOOH, -0C1-C6alkylCOOH, -CN, CI-C6alkylCN, -NO2, -S02C1-C6alkyl, C3-C ocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, Ci-C6alkyIC3-Caocycloalkyl, Ci-C6alkylaryl, Ci-Colkylheteroaryl and C1-C6alkylcycloheteroalkyl, wherein the C3-C1ocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C1-C6alky1C3-Ciocycloalkyl, C1-C6alkylaryl, C1-C6alkylheteroaryl and C1-C6alky1cycloheteroa1ky1 are unsubstituted or substituted with at least one substituent selected from the group consisting of -COOH.
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, J is -0-. In other embodiments, J is -CH-.
In some embodiments, Rl is halogen. Suitable examples of halogen include, but are not limited to, chlorine, fluorine and bromine. In some embodiments, RI is halogen-substitutedC1-C6alkyl. Suitable examples of halogen-substitutedC1-C6alkyl include, but are not limited to, trifluoromethyl.
In certain embodiments, R9 is Ci-C6alkyl, halogen-substitutedCi-C6alkyl, -OH, halogen-substitutedC1-C6alkylOH, -COOH, -COOCI-C6alkyl, -Cj-C6alkylCOOCj-C6alkyl, -C1-C6a1kylCOOH, -0C1-C6alkylCOOH, -CN, Ci-C6alkylCN, -NO2 and cycloheteroalkyl, wherein the cycloheteroalkyl is substituted with -COOH. In other embodiments, R9 is -COOH or -C1-C6alkylCOOH.
Also described herein are compounds of founula le: Rio Ri G>

N) Ie 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-;
P selected from the group consisting of-O- or -CH2-;
RI is selected from the group consisting of halogen or halogen-substitutedCr C6alkyl;
RI is selected from the group consisting of hydrogen, Ci-C6alkyl, halogen-substitutedCi-C6alkyl, -OH, oxo, halogen-substitutedCi-C6alkylOH, -COOH, -COOC1-C6alkyl, -C1-C6alkylCOOCI-C6alkyl, -C1-C6alky1COOH and -0C1-C6alkylCOOH; and Ri1 is selected from the group consisting of halogen, Ci-C6alkyl, halogen-substitutedC1-C6alkyl, COCI-C6alkyl, oxo, -OH, halogen-substitutedCi-C6alkylOH, -0C1-C6alkyl, -Ohalogen-substitutedCi-C6alkyl, -COOH, -COOCI-C6alkyl, -C1-C6alkylCOOC1-C6alkyl, -C1-C6alkylCOOH, -0C1-C6alky1C001-1, -CN, C1-C6alkylCN, -NO2, NH2, NHCi-C6alkyl, N(CI-C6alky1)2, -NHCOOH, -NHCOOCI-C6alkyl, -CONH2, -CONHCI-C6alkyl, -CON(C1-C6alky1)2, -NHSO2CI-C6alkyl, -S02C1-C6a1ky1, C3-C10cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, -C6alkyIC3-Ciocycloalkyl, Ci-C6alkylaryl, C1-C6alkylheteroaryl and C1-C6alkyleycloheteroalkyl.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 -C1-12-.
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, RI is selected from the group consisting of oxo and -COOH. In other embodiments, RI is hydrogen.
In certain embodiments, R" is selected from the group consisting of hydrogen.
In other embodiments, R" is selected from the group consisting of -COOH, -COOCI-C6alkyl, -C1-C6alkylCOOCI-C6alkyl, -Ci-CaalkylCOOH, -0C1-C6alkylCOOH, -NHCOOH, -NHCOOCI-C6alkyl, -CONH2, -CONHCI-C6alkyl, -CON(Ci-C6alky1)2, -NHSO2C1-C6alkyl and -C6alkyl.
Also described herein are compounds of formula I(f):
N
A ) 1\14\
H
/)p12 Kt) 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-;
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, C1-C6alkyl, C3-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, CI-C6alkyIC3-Ciocycloalkyl, C1-C6alkylaryl, C1-C6alkylheteroaryl and C1-C6alkylcycloheteroalkyl, wherein Ci-C6alkyl, C3-C10cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C1-C6alkylC3-C1ocycloalkyl, Ci-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, CI-C6alkyl, halogen-substitutedC1-C6alkyl, COC1-C6alkyl, oxo, -OH, halogen-substitutedCi-ColkylOH, C6alkyl, -Ohalogen-substitutedCi-C6alkyl, -COOH, -COOC1-C6alkyl, -C1-C6alkylCOOC1-C6alkyl, -C1-C6alkylCOOH, -OCI-C6alkylCOOH, -CN, C1-C6alkylCN, -NO2, NH2, NHC1-C6alkyl, N(C1-C6alkyl)2, -NHCOOH, -NHCOOC1-C6alkyl, -CONH2, -CONHCI-C6alkyl, -CON(C1-C6alky1)2, -CONHCI-C6alkyl-N(C1-C6alkyl)2, -NHSO2C1-C6alkyl, -SO2NH2, -C6alkyl, C3-C10cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C1-C6alkyIC3-C10cycloalkyl, C1-C6alkylalyl, Ci-C6alkylheteroatyl and C1-C6alkylcycloheteroalkyl;
D selected from the group consisting of: csss. 0 0 and ;
R12 is selected from the group consisting of -COOH, -COOC1-C6alkyl, -C1-C6alkylCOOC1-C6alkyl, -C1-C6alkylCOOH and -0C1-C6alkylCOOR
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-.
Also described herein are compounds of formula Ig:

A ) N
H \ R12Ig or a pharmaceutically acceptable salt thereof, wherein 0 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-;
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, C1-C6alkyl, C3-C1ocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C1-C6alkylC3-CI0cycloalkyl, C1-C6alkylaryl, C1-C6alkylheteroaryl and C1-C6alkyleycloheteroalkyl, wherein C1-C6alkyl, C3-C1ocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C1-C6alky1C3-C10cycloalkyl, 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-substitutedCI-C6alkyl, COCI-C6alkyl, oxo, -OH, halogen-substitutedCI-C6alky101-1, -0C1-C6alkyl, -Ohalogen-substitutedCi-C6alkyl, -COOH, -COOC1-C6alkyl, -Ci-C6alkylCOOCi-C6alkyl, -C1-C6alkylCOOH, -0C1-C6alkylCOOH, -CN, C1-C6alkylCN, -NO2, NH2, NFICI-C6alkyl, N(C1-C6alky1)2, -NHCOOH, -NHCOOC1-C6alkyl, -CONH2, -CONHCI-C6alkyl, -CON(CI-C6alky1)2, -CONHC1-C6alkyl-N(Ci-C6alkyl)2, -NHSO2CI-C6alkyl, -SO2NH2, -S02Ci-C6alkyl, C3-Clocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, CI-C6alky1C3-C10cycloalkyl, C1-C6alkylaryl, C1-C6alkylheteroaxyl and C1-C6alkylcycloheteroalkyl;

- is -R12 is selected from the group consisting of -COOH, -COOCi-C6alkyl, -C1-C6alkylCOOCI-C6alkyl, -C1-C6alkylCOOH and -0C1-C6alkylCOOH.

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

F F o 0 r/
0 )--- N
la K-7)--- OC
N
" n CI N N

1100 "

' C11-0".-0(--=

CI

\ i N

, r ./¨ . 0 10 4'---C) a 0--(-)---N N

1110 .

_ H 30\ r F

Ci 0 õ_____ N õ0 , 40 K)-0Crõ
1 ...___N
.
ip N7 \--\\ N
H

_ H

F

HN
H

.
k F

. 0 N µ N
ih H

11t OH
, OH
, t___0.,_ / cõ..,.0 F F
, *MOD
= SO / \ / Fk \ N N
40 ':?---0-/, --CIX-L

\ /
* 0 OH

_ i'li 6 0 IlkN\ I

..
F F
k - r-- \-10Cr Wil 11-(( 1 , N N /

F
F
. 0 ti ri .0 F 0 =Nei>...0_,/4 0(0.1..f H

N
N

*

F

r r . =
r F 0 1 \ \ /

01 I 1 la Crib H

ill N \ /

r F

"""r"" 6 a Ol , N4-11 N N
H
v .

F

0 =F

H

N \---14 =
i I 1 F =
a F
-F F

F F
. cHz H
/ X.....,),,/za F 11101 \ \¨,,. N

F OP _ PI N

N
H *

N N \\===
1 'N...
f ...--_ F
F
= F
if = \ \f I 4 . -"...

F.t.c.

Pr-- CY-FF
F = u$.--Q--: -F
H
0 õ,.)::) F fall /X .
N ........ N

r'.... C 1-i3 F F
a 0 F
F H
F . N\ ¨

N
0..
/
N \ / N N ----H
\ 1 110 N/>----C)--N \ A---- N
B r .
=
.
-." N

-r F
F f e,...,..,0 F * \ ¨0.-=-. \ .
ii .

ON

, F
F
F
0 iiith II, r"-'--" \ 7---- \ /01 N.\ \ ..._/"=" ,,, \ ___\ /
F

F N 11111. \ VP ''',17"-\ ___.A.,51 fi N"--N7 H
. i *

r , aN '¨'11 F 0 \>¨'0-- =

N N Oil F F

¨

F r F H

; * t4,,. 0 F = 15-0-0ech /,4 '1111111P OH

F

" F ' F

' * i \"--/ -- I\ .._ NII ==='' .

OH
Br IS

F

F

F el N\>< N\:µ\ Ni/ \ ,..... 0 0 111.

11111 aq, N /1- \ k:r til N
ti ¨

F
r, F

il N \

H

' =

a II

F

Ft N

- -ON
F F

-F>r=VN l',õ.... )., ,...... F =1 N), .._., 0.,...00 =
= *
o = t4 --,4 o N ¨ ii _ ori \ /

r I

0 0i., * 0., F

* '-'0-= -F alp Ns> c )...._, N
q 0 --N
NA CH, N
0 *

H

F
r F
, * , r ti*,___ N
F
ta \

is/ ¨
o = 8.--:.

H

*

F
F
, At el F = \ \--/
VI OH
N N
IA
=
H

H ,=

CH

F
F

' . N\. \ .¨N
Ait.

ii---- I-r"\)_ 0 .
F= >--c_."--)--H
VI ON

H

CH) F F

OH
F

N
i "r=-/- CH
H, CH, N.--vN¨cm4 F
F

N

\
\ N

H
HO

Cl H

. cN3 F . 0.....
1. >. \----/ I
N N

H0 CH, t * 0 II,C OH) MO

H ,O 01 N\
---r4 HO

N HO

0 \ * 0 H

F
N
F F
/ I

N HO
..-...N
..
1 \
H .
e 141---cl-'- 0(4 a 0' \ \-../ 14 N
H

F

N HG
--N
---,--- N HO

0 I `= 0 N

H =

.., = H

ON

¨0 H30 ei \
= 4 .
\ / N

H

_ H=

i \ 43 1 N, N HO
¨N
N N
H = \

..---- \ / N

H =

H&c.,1 H

Oy...-N

-- N HO

' HsC
II f \ 0 H 111) 7.-1,1.--- N =
I. g 0,J
N---- N HO
FizN-- 0 --- / N
_N
HO

/ \ 0 I N \\
N

H =
H =

CHs H3C N

HO

¨N HO \
i 0 1 \
0 .------' H,C N'--- N \ / N

H . H

H
N r.-N 1 N HO =
/

N I 0 \ 1 \ . 0 \\ N
N N N ..õ

/ \

N

N
H N
=

N.
I I
/

N HO

N N ¨N HO
N 0 it \

H =
N

H III

N

riC
1 N, N ¨ N HO

F j \

HO .-,--- \ / N
. \..._/N .
N
o H

H = 1 II 110 N * , , F N ( = ---N HO ----'-' --N
.

F el \ 0 H

H II

, N HO
I -N
F
.,"*

HO0 = \

F \ / 111 H C
' a N

N H I) H = . HO
- N ------ N

4111 \ 0 40 \

N

H =

It HO N HO

- N

el \ 0 \

P=

= N \ \ /

H

F

N - N HO N
.-^,--, N HO

4111 I \

\ / N
H . 0 F ill N\

H

H

.

1110 \

0 N 'N=

0 \ / 1 N N

H =

H N

=

==-- N HO N H =

0 el \
et \

----N \ /
H = I N ----HO H =

.. I e F

H.

N HO

N N

H N H
=

. a _ F F

III N HO
-N

\
0 40, , \ / t4 111 HO
- N

N

H

\ / N
F

N

H
=

HO
HO

0I \ o o N \ /=

H
1 N\ \ /

: F
H =

F

= H.

0 \ * .
0 , N
o'r H
=
HP

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

F30, N õN , \ 7 F3c 0 N /
0___.--. õ

\ 7 \ K) õ \ N\___X I V

N -N

OH

, F30, N) c \ 0 F3C 00 N õ

\ 4 \)-Nr-Y:fo N ip N -N

H

F305 N\\___27 ,\,,__Na.).,.__(.. 0 FaC la .\ ____FN-N

N * 0 VP N/ \=N7 N/ \\,,,, H \--CO2H

F30 r,L1, ,,,)....i, 0 cl 40 N,--A-N 0 - N

I

Nf____\--:--N1 CO0 2Et - H
H

, FaC 0 N FaC
40 N / \\

OH \ 'L \)¨ --N = 0H O
\ / \ Nil: k-r ill N -N =
H \--i H CFa FaC 0 N/ 0 XD:r F
N t CN
N -N CI

H 40 ' II N

H

4Ik F3C is -N / ) .1-1-FaC 0 IA OH

, ip, N ii, r1.4 gp, NO2 HN

F is a N , , , ....,0*
F3C 5 N N __. =, \ OH

\ /C N N.\ _jc j 1 N -N 1 .---CF3 ---N it N N
H N H

F3 C lis N ru 0 \ / \ / \ \ i.,--f' .--N OH
N
I N it N -N \ l\----N *
H Nzzr---41.0 NH

FaC

FaC 40 N A / 0.,_.,[0 ,--N OH
\ ¨ \)----14\_X, N -N Nr1 S'--- N =

H

Facs = NH

..

I:

, 0 F3c 0 N o-f ....-N OH
\ / \ N

N = CF3 I ,--N 411 N -N

H N_.--,C-S

. NH

CI

Me _ F3C\ / \ 0 N NI/ CF3 \>--------Ni it .
N -N \ N N -N

H H

F3C, N /

0,-, , \ \ N/DUL K---N p3n0 n 0 \ 1 . _ N -N N\ / \ Ni ''---H
N ¨N

HO
_ FaC 40 N
:,.._)--treco2me OH

nN\ \---/ N it N -N

H Me0 N1 N

Me 0 CI 40 N, /0 0 \-__.N OH

\--% ---N

N N NI \---N

HH Me gill Am ....

Cl 0 N\>_< ____NI 0 me 0 NN,/ \_\_____/__\ N>,.,õ ii OH

N -N

H H

I.

Cl. N 0,-N -\ OH

">---- --N
cl 0 \>_i,,,,i_N .

N N

H

Cl 410 N 0 0 0 N_ N it OH

\>¨< '---N

01 N \ N
N -N H

H
\., /

N

o Cl I. N- .
N\v_o_N . OH

--- ----.N/

-- F Ni \--N
N aN
H
H I

\ N

-F3C si tsj,> /,,,,,,, \\ / 0,_,4-.0 OH
go N.___/-1_,N 410 \ \)-----N

FaCO IµIIIP FiN"-N
N \--N

H N \ I

_ CI I. N / 0-__,/, Cl o = OH

\ / N
N -N ---H- N F3c * FIN\/ \------\ i N F

OH

N\)-------0,, H H

l F

CI si N\>___L/ \\\?____N 0 0 F

0 N_____K-I___N * OH

N -N
H F3C Ni \--N
H
11.
OH

F

CI 0 N\>< cN 0 0 cliN - \
OH

= ''N 1 FiN\>*14/2-N =
N -N

H

.
_ F3C 0 N\> g / 0-=__-OH

\ ) N ---N e N \-N N\) C N
NN (----H
N \ /

Br F3C to õ ,õõ .\.) 0 0 , N OH

, I\>-{)--N it N \---Th H H

...

F3C . N 0 õN An N\\
47-'>_. N 41, OH

\>-- ------N a 'PP Ni \-1,4' H
H . ---.1-,N

0 .
F3C so N 0 Me 0 N\ \--/ N OH

\)-----< ---N

H H

c02H
F3C = g / 0,- F3c \ \? N\>--=C \)---N

N \ -N \
H
H
=
N \ /

Me , I

F3C,i\I N \--N"

OH

Me N m 0 Me0..,_,NN)___(_ HFaC 0 0 .
N1\4/

N' \'-'---N 0 H OH
'----õ------"----N N \ ---N ,,, I

F3C iso N\.j,/,, \_ )____N 0 CO2H

, d \-N
H F3C is N
\ / \ N 0 N ¨N
H OH

a CO2H H
F3C, N 0 N/:,_(,_,,,,N, \)-4 --.-N

N -N ill CI N ---IN
OH
H

F3C, N , \\ OH 41 /)___. N
N 0, 0 \>---C \)---N =
N ¨N
N -1\1 OH
H

0 Fsc 0 N / \ H

00 ii, OH
\ / \ Nr-rssThro N ¨N
H

N ¨N
H

\ / õ N \ 111 ell H
H

\ OH

N -NI OH

H

---< ----N

N ¨N O=

H

_ Me02C 0 Nai/0 F3C 411 N,,_____F, VN CI
N".=--N OH
H

Ni \-----NI 0 lit CO2Me H .

N.,>

H
0 ___c,,,,._N

F3C 0N õ
F
N -N
OH
\
N
-N
0 40 CO2Me H
, , F3C 0 N>< \\

p N -N

--_ )----N
'"%H

N
si \ /õ \ N
H
N
-N

H
o F3C 0 N , \\

o \>--___ \)---N
F3C 40 N>
\
OH
N -N
H
OH

\
/ )- N
N
¨N
0 .
H
o o F3c 0N õ

N
-IV
0 . NHSO2Me Et N
-N
OH
H
-H
ci F3C, N0 N
0 ,53 / \ N

/
'N
NH Et N -N
N ¨N
H
.
' Me H

5Ni\>-<_---N
FCS 4111 jia 0 N
i / \ N
N -N 0 /<0 OH
N
-N
H
OH
H, \ / \ N
NSO2Me ., N -N
le OH
H
H
F3C 0 c ENt / \

N
/
N-,o / ,---N
.r_Nl Or ,>--G-N

\
Et0 N -N
N
- N

OH
H

CN
FTC, \/ N ,N

/< \
kli \

i\>--0----IP
N -N

OH
F
H

H
F3C 0> N , N

ii0 \
.<---NF3C 0 />----N
N
N -N
N -N
OH
H

III
iv \ N
-N OH

40 c02,_ F3c N 0 0 r N -N \ NH Me0 N N -N OH

-N OH

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

The term "C1-C 6alkyl" encompasses straight alkyl having a carbon number of 1 to 6 and branched alkyl having a carbon number of 3 to 6. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethy1-2-methylpropyl, 1-ethyl-l-methylpropyl, and the like.

The term "-OCI-C 6alkyl " 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-substitutedCi-C6 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-substitutedCI-C6alkyl" means a -0C1-C6alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different, and specifically includes, for example, a trifluoromethoxy group.

The term "CI-C6alkylCOOH" means a C1-C6alkyl as defined above substituted with a carboxylic acid group (COOH).

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

The term "C3-C10cycloalkyl" 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, cyclooetyl, cyclononyl, cyclodecyl, bicyclohexyl, bycyclodecyl, bicyclononyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and adamantly.
The term "S02C1-C6alkyl" means a group having C1,6 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 "COC1.6 alkyl" means groups having C1-6 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 '1=0", such as, for example, (1) "C---(0)", that is a carbonyl group; (2) "S=(0)", that is, a sulfoxide group; and (3) 11\1----(0)", that is, an N-oxide group, such as pyridyl-N-oxide.
The term "NHCI-C6alkyl" means a group with one of the hydrogen atoms of amino (-NH2) being substituted with a C1_6 alkyl group. Specific examples thereof include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino, and the like.
The term "N(CI-C6alky1)2" means a group with the two amino hydrogen atoms each being substituted with a Ci_6 alkyl group. Specific examples thereof include dirnethylamino, diethylamino, ethylmethylamino, di(n-propyl)amino, methyl(n-propyl)amino, diisopropylamino, and the like.
The term "NHCO2C1-C6alkyl" means a group with one of the amino hydrogen atoms being substituted with Ci_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 "CONHCI-C6alkyl" means a group with one of the hydrogen atoms of carbamoyl (-CONH2) being substituted with C1_6 alkyl. Specific examples thereof include methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl, and the like.
The term "CON(C1-C6alky1)2" means a group with the two carbamoyl hydrogen atoms each being substituted with C1_6 alkyl. Specific examples thereof include dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbarnoyl, di(n-propyl)carbarnoyl, 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, benzothiazolyl, benzisothiazolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, pyrido[3,2-b]pyridyl, and the like.
"Cycloheteroalkyl" means mono- or bicyclic or bridged saturated rings containing at least one heteroatom selected from N, S and 0, 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 "cycloheteroalkyl" include tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6-dihydroimidazo[2,1-bjthiazolyl, tetrahydroquinolinyl, morpholinyl, 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-(1H, 311)-pyrimidine-2,4-diones (N-substituted uracils). The temi also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-a.zabicyclo[2.2.11heptyl, 7-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.2joctyl, and 3-azabicyclo[3.2.2]nonyl, and azabicyclo[2.2.11heptanyl. The cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogens.
"S02C1-C6alkyl" group means a group in which a Ci-C6alkyl group is attached to a sulfonyl (-SO2-) 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, isothionate, lactate, lactobionate, laurate, inalate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucarnine ammonium salt, oleate, oxalate, palmate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like.
Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylarninoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
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 foimulas 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 (1H) 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 ehromatosis. The compound of the invention is especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety.
One aspect of the invention described herein provides a method for the treatment and control of obesity or metabolic syndrome, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having the formulas described herein or a pharmaceutically acceptable salt thereof. For example, the compounds described herein are useful for treating or preventing obesity by administering to a subject in need thereof a composition comprising a compound of formula I or formula Ia.
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; andior 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 pharrnacotherapy. 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 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 abnouuality, 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 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 fothiulas 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) PPARoVy dual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPARa agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators (SPPARyM's), such as those disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO
2004/066963, and (4) PPARy partial agonists; (ii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, rnetformin hydrochloride, and extended-release formulations thereof, such as Glumetza , Fortamet , and GlucophageXR0; (iii) protein tyrosine phosphatase-1B (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) arnylin and amylin analogs, such as pramlintide;
(6) sulfonylurea and non-sulfonylurea insulin secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;

(7) a-glucosidase inhibitors (such as acarbose, voglibose and miglitol);
(8) glucagon receptor antagonists, such as those disclosed in WO 98/04528, WO
99/01423, WO
00/39088, and WO 00/69810;
(9) incretin mimetics, such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists, such as exenatide, liraglutide, taspoglutide, AVE0010, CJC-1131, and B1M-51077, including intranasal, transdermal, and once-weekly formulations thereof;
(10) LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl CoA:cholesterol acyltransferase inhibitors, such as avasimibe;
(11) HDL-raising drugs, such as niacin or a salt thereof and extended-release versions thereof;
MK-524A, which is a combination of niacin extended-release and the DP-1 antagonist MK-524; and nicotinic acid receptor agonists;
(12) antiobesity compounds;
(13) agents intended for use in inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
(14) antihypertensive agents, such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta blockers (such as and calcium channel blockers).
(15) glucokinase activators (GKAs), such as LY2599506;
(16) inhibitors of 1113-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 0-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 W02009/042053, including, but not limited to, neuromedin S (NMS);

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

(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:monoacylglycerol acyltransferase 1 and 2 (MOAT-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, carrnegliptin, dutogliptin, melogliptin, linagliptin, and pharmaceutically acceptable salts thereof, and fixed-dose combinations of these compounds with metforrnin hydrochloride, pioglitazone, rosiglitazone, simvastatin, atorvastatin, or a sulfonylurea.
Other dipeptidyl peptidase-1V (DPP-4) inhibitors that can be used in combination with compounds of any of the formulas described herein include, but are not limited to:
(2R,3S,5R)-5-(1-methy1-4,6-dihydropyrrolo[3,4-c]pyrazol-5(111)-y1)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-amine;
(2R,3S,5R)-5-(1-methy1-4,6-dihydropyrrolo[3,4-elpyrazol-5(111)-y1)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-amine;
= (2R,3S,5R)-2-(2,5-difluorophenyptetrahydro)-5-(4,6-dihydropyrrolo[3,4-c]pyrazol-5(11/)-y1) tetrahydro-2H-pyran-3-amine;
(3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoy1]-hexahydro-3-methyl-211-1,4-diazepin-2-one;
= 25 4-[(3R)-3-amino-4-(2,5-difluorophenyl)butanoyllhexahydro-I-methyl-2H-1,4-diazepin-2-one hydrochloride; and (3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyfl-hexahydro-3-(2,2,2-trifluoroethyl)-2H-1,4-diazepin-2-one; and pharmaceutically acceptable salts thereof.
Antiobesity compounds that can be combined with compounds of any of the formulas described herein include topiramate; zonisamide;,naltrexone; phentermine; bupropion; the combination of bupropion and naltrexone; the combination of bupropion and zonisamide; the combination of topiramate and phenteimine; fenfluramine; dexfenfluramine; sibutramine; lipase inhibitors, such as orlistat and cetilistat; melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists; CCK-1 agonists; melanin-concentrating hormone (MCH) receptor antagonists;
neuropeptide Yi or Y5 antagonists (such as MK-0557); CB1 receptor inverse agonists and antagonists (such as rimonabant and taranabant); f33 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (such as bombesin receptor subtype-3 agonists); and 5-hydroxytryptamine-2c (5-HT2c) agonists, such as lorcaserin. For a review of anti-obesity compounds that can be combined with compounds of the present invention, see S. Chaki et al., "Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity," Expert Opin. Ther. Patents, 11; 1677-1692 (2001); D. Spanswick and K. Lee, "Emerging antiobesity drugs," Expert Opin. Emerging Drugs, 8: 217-237 (2003); J.A.
Fernandez-Lopez, et al., "Pharmacological Approaches for the Treatment of Obesity," Drugs, 62: 915-944 (2002); and K.M. Gadde, et al., "Combination pharmaceutical therapies for obesity," Exp. Opin.
Pharmacother., 10: 921-925 (2009).
Glucagon receptor antagonists that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:
N- [4415)-1 - 3-(3 ,5-dichloropheny1)-5- [6-(trifluoromethoxy)-2-naphthyl] -1H-pyrazol-1-yllethyl)benzoy111-13-alanine;
N-[4-((1R)-1-{3-(3,5-dichloropheny1)-5-[6-(trifluoromethoxy)-2-naphthyl]-1H-pyrazol-1-y1) ethyl)benzoyli-p-alanine;
N-(4- {1- [3-(2,5-dichtoropheny1)-5-(6-methoxy-2-naphthyl)- I H-pyrazol-1-yllethyl benzoy1)-13-alanine;
N-(4- { (15)-143 -(3,5 -dichloropheny1)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl] ethyllbenzoy1)-13-alanine;
N-(4- {(1S)-1- [(R)-(4-chlorophenyl)(7-fluoro-5-methyl-1H-indo1-3-yOmethyll butyl } benzoy1)-13-alanine; and N-(4- { (15)-1 -{(4-chlorophenyl)(6-chloro-8-methylquiriolin-4-y1)methylibutyllbenzoy1)-13-alanine; and phatinaceutically acceptable salts thereof.
Inhibitors of ste,aroyl-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-{442-(trifluoromethyl)phenoxy]piperidin-1-y1}-1,3,4-thiadiazol-2 -y1)-2H-tetrazol-2-yll acetic acid;
(2'-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-y1}-2,5r-bi-1,3-thiazol-4-y1)acetic acid;
(5- {3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-Aisoxazol-5-y1}-2H-tetrazol-2-yl)acetic acid;
(3- {3- [4-(2-bromo-5-fluorophenoxy)piperidin- I -y1]-1,2,4-oxadiazol-5-y1}-1H-pyrrol- -yl)acetic acid;
(5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-y1ipyrazin-2-y1}-2H-tetrazol-2-y1)acetic acid;
and (5- {2-[4-(5-bromo-2-chlorophenoxy)piperidin-1-ylipyrimidin-5-y1}-2H-tetrazol-2-yl)acetic acid;
and pharmaceutically acceptable salts thereof.

Glucokinase activators that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:
3-(6-ethanesulfonylpyri din-3-yloxy)-5-(2-hydroxy- 1-methyl-ethoxy)-N-(1-methy1-1H-pyrazol-3-yl)benzamide;
5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yObenzamide;
5-(1-hydroxymethyl-propoxy)-3-(6-methanesulfonylpyri din-3-yloxy)-N-(1-methy1-1H-pyrazol-3 yl)benzamide;
3-(6-methanesulfonylpyri din-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1 -methy1-1H-pyrazol-3-yl)benzamide;
5-isopropoxy-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methy1-1H-pyrazol-3-y1)benzamide;
5-(2-fluoro- I -fluoromethyl-ethoxy)-3 -(6-methanesulfonylpyri din-3 -yloxy)-N-(1 -methyl-1H-pyrazol-3-yl)benzamide;
3 -( 442-(dimethylamino)ethoxy] phenyl ) thio)-N-(3 -methy1-1,2,4-thiadiazol-5 -y1)-6- [(4-methyl -4H-1,2,4-triazol-3-ypthio]pyridine-2-carboxamide;
3 -({ 4-[(1-methylazetidin-3 -yl)oxyl phenyl) thio)-N-(3 -methy1-1,2,4-thiadiazol-5-y1)-6-[(4-methyl-4H-1,2,4-triazol-3-ypthio]pyridine-2-carboxamide;
N-(3-methyl-1,2,4-thiadiazol-5-y1)-6-[(4-methyl-4H-1,2,4-triazol-3-y1)thio] -3-{ [4-(2-pyiTolidin-1-ylethoxy)phenyl]thiolpyridine-2-carboxamide; and 3-[(4- { 2- [(2R)-2-methylpyrro lidin- 1-yl] ethoxy phenyl)thio-N-(3-methy1-1,2,4-thiadiazo1-5-y1)-6- [(4-methy1-4H-1,2,4-triazol-3-y1)thiolpyridine-2-carboxamide; and pharmaceutically acceptable salts thereof.
Agonists of the GPR-119 receptor that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to:
rac-cis 5-chloro-2- {44242- { [5-(methylsulfonyl)pyridin-2-yl]oxyl ethyl)cyclopropyl] piperidin-l-yllpyrimidine;
5-chloro-2- {4- [(1R,2S)-2-(2- { [5-(methylsulfonyl)pyridin-2-yl]oxy) ethyl)cyclopropylipiperi din-1-yllpyrimidine;
rac cis-5-chloro-2- [4-(2- {2- [4-(rnethylsulfonyl)phenoxy]
ethylIcyclopropyppiperidin-1 Apyrimidine;
5-chloro-2- [44(1S,2R)-2- {2- [4-(methylsulfonyl)phenoxy]ethyl) cyclopropyl) piperidin-l-yl]pyrimidine;
5-chloro-2-[4-((lR,2S)-2-1244-(methylsu1fonyl)phenoxyl ethyl) cyclopropyl) piperidin-l-yllpyrimidine;
rac cis-5-chloro-244-(2- {243 -(methylsulfon.yl)phenoxy] ethyl ) cyclopropyl)piperi din-1-yll pyrimidine ; and rac cis -5-chloro-2- [442- {2- [3 -(5-methy1-1,3 ,4-oxadiazol-2-yl)phenoxyl ethyl ) cyclopropyl) piperidin-l-yl]pyrimidine; and pharmaceutically acceptable salts thereof.
Selective PPARy modulators (SPPARyM's) that can be used in combination with the compounds of any of the fotmulas described herein include, but are not limited to:
(25)-24 { 6-ohloro-3- [6-(4-chlorophenoxy)-2-propylpyrid in-3 -y1]-1,2-benzisoxazol-5 -yll oxy)propanoic acid;
(25)-2-({6-chloro-346-(4-fluorophenoxy)-2-propylpyridin-3-y1]-1,2-benzisoxazol-yl)oxy)propanoic acid;
(28)-2- [6-chloro-3 -(6-phenoxy-2-propylpyridin-3 -y1)-1 ,2-benzisoxazol-5-yll oxy propanoic acid;
(2R)-2-( {6-ch1oro-3-[6-(4-chlorophenoxy)-2-propylpyridin-3-y1]-1,2-benzisoxazol-5-yl)oxy)propanoic acid;
(2R)-2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylliphenoxy)butanoic acid;
(2S)-2-{3-[3-(4-methoxy)benzoy1-2-methy1-6-(trifluoromethoxy)-1H-indo1-1-yljphenoxy)butanoic acid;
2- {3- [3 -(4-methoxy)benzoy1-2-methyl-6-(trifluoromethoxy)-1H-indol-1 -yll phenoxyl -2-methylpropanoic acid; and (2R)-2- { 3 43 -(4-chloro)benzoy1-2-methyl-6-(trifluoromethoxy)-1H-indol -1-yliphenoxy)propanoic acid; and pharmaceutically acceptable salts thereof.
Inhibitors of 1113-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-chloropheny1)-trans-3-fluorocyclobutyl] -4,5 -dicyclopropyl-r-4H-1,2,4-triazole ;3 - [1 -(4-chloropheny1)-trans-3-fluorocyclobuty1]-4-cyclopropy1-5-(1-methylcyclopropy1)-r-4H-1,2,4-triazole;
341-(4-chloropheny1)-trans-3-fluoroeyclobutyl]-4-methyl-5-[2-(trifluoromethoxy)phenyl]-r-4H-1,2,4-triazole;
3- [1-(4-chlorophenyl)cyclobutyl] -4-methyl-5[2-(trifluoromethyl)phenyll -4H-1,2,4-triazo le;
3- {4- [3-(ethylsulfonyl)propyl]bicyclo [2.2.2]oct-l-y1) -4-methyl-5- [2-(trifluoromethyl)phenyl] -4H
-1,2,4-triazole;
4-methyl-3- 444-(m ethylsulfonyl)phenyl]bicycl o [2.2.2] oct-1 -y1) -5- [2-(trifluoromethyl)phenyl] -4H-1,2,4-triazole;
3-(4- {4-methy1-5-[2-(trifluoromethyl)phenyll-4H-1,2,4-triazol-3-y1)bicyclo[2,2.2]oct-1-y1)-5-(3,3,3 -trifluoropropy1)-1,2,4-oxadiazole;
3-(4-{4-methy1-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yllbicyclo[2.2.2]oct-1-y1)-5-(3,3,3-trifluoroethyl)-1,2,4-oxadiazole, 5-(3,3-difluorocyclobuty1)-3-(4-14-methy1-5-[2-(trifluoromethyl)pheny11-41-I-1,2,4-triazol-3-yl}bicycloP2.2]oct-l-y1)-1,2,4-oxadiazole;

5-(1-fluoro-1-methylethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-411-1,2,4-triazol-3-yllbicyclo[2.2.2]oct-1-y1)-1,2,4-oxadiazole;

241,1 -difluoroethyl)-5 -(4- {4-methyl-5- [2-(trifluoromethyl)phenyl] -4I-1-1,2,4-triazol-3 -yl 1 bicyclo [2.2.2jjoet-l-y1)-1,3,4-oxadiazole;

2-(3,3-difluorocyclobuty1)-5-(4-14-methy1-5-[2-(trifluoromethyl)pheny1]-4H-1,2,4-triazol-3-y1) bicyclo [2.2.2]oct-1 -y1)-1,3 ,4-oxadiazole; and 5-(1,1-difluoroethyl)-3-(4-14-methy1-5-[2-(trifluoromethyl)pheny1]-4H-1,2,4-triazol-3-ylIbicyclo[2.2.2]oct-1-y1)-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;

,,,OLN \ / F
=s\\\\LN \ / F
N

NH

N
N
H N \----HN
--- \
7 N¨

N¨H

/o/0 /N N -----<
5 -------/ N¨N 0 ----<0 , HN \ ---_ HN \
---s\\\LN \ / HO i N
0\\\\LN \ / F
N , NH
N
N

----- \
/ N
/

\
N/
-----/ ---N ----< N¨ 0 , /

--. N \ / F
'`µ\\\LN N

N

NH
N
N
H N
H
.......__N\

/ \NI ( N/ N
N

0 , ,and F

/ \

---N

N \

' N
I H

I
NH
N
H

N

( \ j >----0 / 0 N -----N , and pharmaceutically acceptable salts thereof.

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

HO 10) 0 .,-O 0 00 NI)_.0 I.

CI N CI N
H H

OH

0N SI N \ 0 0 N)-o 5 CI N CI N
H H
, \

N

\ 411 to N)_0 Ill 0 0 N)-0 4111 N
CI FN
H H

\

N

õ..-k., N)___ ell \ . 0 N)0 411]

CI N F N
H H

1-13C0 F a N)_.0 4111 CO2H
co2H
CI CI =N>_(:) 411k HO
40 N)__.
1\1___O 401 CO2H
, and NH =

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-cyclopropy1-4-methoxy-1H-indo1-6-yl)carbonyl]-4-oxospiro[chroman-2,4'-piperidin]-6-yl}benzoic acid;
5- fl'-{(1-cyclopropyl-4-methoxy-1H-indo1-6-yl)carbonyli -4-oxospiro [chroman-2,4'-piperidin] -6 -yl}nicotinic acid;
l'-[(1-cyclopropy1-4-methoxy-1H-indol-6-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4'-piperidin]-4-one;
1'-[(1-cyclopropy1-4-ethoxy-3-methy1-1H-indo1-6-y1)carbony11-6-(1H-tetrazol-5-yl)spiro[chroman-2,4'-piperidin]-4-one; and 5- [(1-cyclopropy1-4-methoxy-3-methy1-1H-indo1-6-ypcarbonyl]-4-oxo-spiro[chroman-2,4'-piperiditi]-6-y1}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-1V (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/y 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 (SPPARTM'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 GlucophageXR0; (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;
(3) sulfonylurea and non-sulfonylurea insulin secretagogues, such as tolbutamide, glyburide, glipizide, gliniepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;
(4) a-glucosidase inhibitors (such as acarbose, voglibose and miglitol);
(5) glucagon receptor antagonists;
(6) LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl CoA: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 anti-inflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;
(10) antihypertensive agents, such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as alisldren), beta blockers (such as and calcium channel blockers (such as;
(11) glucokinase activators (GKAs), such as LY2599506;
(12) inhibitors of 1 113-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 6-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) (}PR-105 antagonists;
(22) inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1; SGLT-2, such as dapagliflozin and remogliflozin; and SGLT-3;

(23) inhibitors of acyl coenzyme A:diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2);
(24) inhibitors of fatty acid synthase;
(25) inhibitors of acetyl-CoA carboxylase-1 and 2 (ACC-1 and ACC-2);
(26) inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2);
(27) agonists of the TGR5 receptor (also known as GPBAR1, B037, 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 Oxone H
X = F or CI

HN / )(R1 base \ R"

')<R'R---:
C% ¨NI
H KIN R"

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

List of Abbreviations:
Alk = alkyl Ar = aryl Boc = tert-butoxycarbonyl Cbz = carbobenzyloxy = dichloromethane CoA
= Coenzyme A
dba = dibenzylidineacetone DIPEA
= diisopropylethylamine DMA
= dimethylacetamide DMF
= dimethylformamide DMSO
= dimethyl sulfoxide ESI
= electrospray ionization Et = ethyl Et0Ac = ethyl acetate HOAc = acetic acid LC-MS
= liquid chromatography-mass spectroscopy LiOH
= lithium hydroxide Me = methyl Me0H
= methyl alcohol MgSO4 = magnesium sulfate MS
= mass spectroscopy MTBE = methyl tert-butyl ether NaOH = sodium hydroxide Na2SO4 sodium sulfate NMR nuclear magnetic resonance spectroscopy Ph = phenyl it or RT = room temperature TEA triethylamine TFA = trifluoroacetic acid THF tetrahydrofuran Intermediate I.

FaC N
N N
2-(6-fluoropyridin-3-y1)-5-(trifluoromethyl)- I H-benzimidazo le Step 1. Following the recommendations presented in Beaulieu, P. L.; Hache, B.
and von Moos, E. Synthesis, 2003, 11, 1683: a solution of 2-fluoropyridine-5-carboxaldehyde (2.0 g) in DMF
was added dropwise to a suspension of 4-(trifluoromethyl)phenylene-1,2-diarnine (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.
CI r\i>
N N ¨CI
5-chloro-2-(6-chloropyridin-3-y1)-1H-benzimidazole Step 1. Following the recommendations presented in Beaulieu, P. L.; Hache, B.
and von Moos, E. Synthesis, 2003, /1, 1683: a solution of 2-chloropyridine-5-carboxaldehyde (0.60 g) in DMF
was added clropwise to a suspension of 4-chlorophenylene-1,2-diamine (0.57 g) and Oxonee (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 vacua. [ME] m/z 264Ø

Intermediate 3.
=el N

5-chloro-2-(6-chloro-5-fluoropyridin-3-y1)-1H-benzimidazole This compound was prepared using the same protocols as described for Intermediate 1.

Intermediate 4.

meo^e'N N
2-(6-fluoropyridin-3-y1)-5-methoxy-3114midazo [4,5 -bl pyridine This compound was prepared using the same protocols as described for Inteimediate 1.
Intermediate 5 F3C ¨4) ¨Br ¨N
2-(6-bromo-5-fluoropyridin-3 -y1)-5-(trifluoromethy1)-1H-benzo [d] imidazole Step I . 4-(trifluoromethyl)benzene-1,2-diamine (44.0 mg, 1.1 equiv), 6-bromo-fluoronicotinaldehyde (50 mg, 1 equiv) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (130 mg, 1 equiv) were combined in anhydrous DMF. To the solution, DMA (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)pheny1)-6-bromo-fluoronicotinamide as a viscous brown oil: [Miff' m/z 379.

Step 2. Acetic acid was added to N-(2-amino-4-(trifluoromethyl)pheny1)-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-y1)-5-(trifluoromethyl)-1H-benzo[dlimidazole as a tan solid: [MFI] nilz 361.

Intermediate 6.

3-oxo-3H-spiro[2-benzofuran-1,41-piperidinej-5-carboxy1ic 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 n-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-l-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 HCI 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 1'-(tert-butoxycarbony1)-3-oxo-3H-spiro[2-benzofaran-1,41-piperidine]-5-carboxylic acid as a white oil: [MH¨Bocr m/z 248.

Step 2. The residue from Step 1 (79 mg, 1 equiv) was reconstituted in dichlorometha.ne (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 3-oxo-3H-spiro[2-benzofuran-1,4'-piperidine]-5-carboxylic acid as a white solid: [MFI] m/z 248.

Intermediate 7.

/
N_ Br 3-bromo-5H-spiro[furo[3,4-blpyridine-7,41-piperidin]-5-one Step 1. 5-bromo-2-iodopyridine-3-carbonitrile (6.44 g, 1 equiv) and tert-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, 1N HC1 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 tert-butyl 3-bromo-5-oxo-1'H,5H-spiro[furo[3,4-b]pyridine-7,4'-piperidine]-1'-carboxylate as an oil.

Step 2. The oil from Step 1 (204 mg) was reconstituted in 4 mL dichloromethane-trifluoroacetic 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 [MI-Ir m/z 283.

Intermediate 8.

OH

0 ¨N
2-(3-(5-formylpyridin-2-y1)-3-azaspirof5.5jundecan-9-y1)acetic acid 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 1M HC1 (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% acetone:dichloromethane) to give the pure aldehyde as a white solid: [MHr rn/z 317.

Intermediate 9.
Me02C

0 CO2Me methyl 4-(2-methoxy-2-oxoethyl)-3,4-dihydrospiro[chromene-2,4'-niperidinej-6-earboxy1ate Step 1. Trimethyl phosophonoacetate (680 pL, 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'-tert-buty1-6-methyl 4-oxo-3,4-dihydro-1'H-spiro[ehromene-2,41-piperidine]-dicarboxylate (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 diehloromethane 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 vacua, 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 RL) 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: [M1-1]+ in/z 334.
Intermediate 10.

) N 41) OMe tert-butyl 9- (2-methoxy-2-oxoethoxy)-3 -azaspiro 15 .51undecane-3 -carboxylate Step 1. Sodium borohydride (139 mg, 1 equiv) was added to a methanol solution of tert-butyl 9-oxo-3-azaspiro[5.51undecane-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 tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate: [Mlir m/z 270.
Step 2. Potassium tert-butoxide (66.5 mg, 1.2 equiv) was added to tert-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-bromoaeetate (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: [MH1+ tn/z 342.

Example 1.

r N ¨N

Step 1. Copper (1) iodide (19 mg, 1 equiv), cesium carbonate (98 mg, 3 equiv) and commercially available tert-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 p-bromophenylacetate (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 HCI (1 rniõ 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 HC1 in 1,4-dioxane (400 pL, 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-y1)-5-(trifluoromethyl)-1H-benzimidazole (28 mg, 1 equiv), and NMP (330 4).
The mixture was stirred at 120 C for 22 hours. The reaction was neutralized by addition of acetic acid (231,tL, 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.

Table 1. F3c N
N ¨N sR
[M111 iymr 1111Hr [M11]+
Example R in/z rn/z Example R
nez /Fez cale'd found ealc'd found 2 111 CO2H 594 594 9 = Me Me 508 3 co2n 568 568 10 4 CO2Et 580 580 11 CF3 562 it OH F3C

MeO2C

Example 15.
cl N 0 0 N N

5 5-chloro-2-(6-chloroppidin-3-y1)-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: [M1-1]+ 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-y1)-1H-benzirnidazole (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 acetate:hexanes 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% acetonitrile:water 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-y1)-1H-benzirnidazole (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% acetonitrile:water 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%
acetonitrile:water with 0.05% TFA to 95% acetonitrile:water 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-y1)-1H-benzimidazole (1 equiv) was used as electrophile.

Procedure F
Perfatmed 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% acetonitrile:water with 0.05% TFA
to 95% acetonitrile:water with 0.05% TFA) to give the pure product.

Table 2.
Example Structure 1111H1+ twir procedure m/z m/z calc'd found H \)--N
16 N -N .

H

_ _ CI 0 N,..) g ,,,,,) N/ 0,7-0 17 N \¨N

H
N \ /

CI. N\> , N/

18 N \ ¨N
, 432 432 A
H
/

N

. CI 40 I\1 i N/ 0----,----0 19 N \------N

H /

\ N
, , e d 'o 20 N \¨N \

H
N \ i CI 0 N\\_// ____N 0--_. 0 21 N"¨N --H N

\ /

= N )--< --1\1 H

.

F

CI \\ 0 0 SIN \>, ---- \)--N

N -N

OH

F

CI N i \ 0 0 0 , . ---1\1 N -N

H

_ _<
F3C so N , õ Nir 0-4% 0 25 N \ -N

H
N \ i Br , F3 0 N "

"------C ----N
N -N

H

_ F3 40N õ
\ / \ N =

N -N

.

H
, F3C 0 N õ
0 Me \28 N"/ -N \ N

C
H
=
.

F3C 401 I \1'$ N/ X
N
(-N
N \ /

\ 12 Me , F3C0N, i ..-rµ17 N \--N \

H
N\ /

C
a Me -H
Me0,....,-N

/ .N
)1_, \ / N

"-----------^N
N
NI µ /

(.,:\----/ "N a N -N

.

H

, N N (,,,, \\
)___N a -N
ilk H

F3C 40 NI, OH

\)---N 11, N -N
H

0 INI/ \'-N J ___1\1 it N
H

-F3C 40 N , \\

I "¨N it 0 N ¨N OH
H

0\

\--OH

37 F3C ,N \\

7 \)---N

N ¨N 0 40 H

Me02C , F3C0 N , \\

\>--- )---- N

N ¨N 0 104 CO2Me H

F3C 0 N , \\

\>----C \----N

N ¨N 0 40 CO2Me H

F3C 0 N , \\

\>---- )----N

N ¨N 0 404 CO2H
H
=

, 1,0 \
F3C 010 N, ,,,, õ OH

\ N

N ¨N 0 =
H

F3C 0 N õ

42 \ / \ N

N ¨N 0 4111 NHSO2Me H

F3C 40 N> , \\ 0 /7 \
--- --N NH

N --N
H

. , Me 44 F3C 40N \\ 410 `i¨N a 0 N ¨N
_ H
OH

, NSO2Me -----< ----r\1 45 N ¨N

H
1 4Ik ' _ , H r, F3C 0 N / N-.f-\>-----( ---N
N

,.

F3C 0 N , \\

----- "---N 1110 F 525 525 D

H

F3C . N , \\

\hNr-)Cr N

H

F3C si N , ,\ / .,._0 \)----- )---N k 1 =

49 N -N \ N

H

, F3C 0 N / ,0 50 ---t., \---N' X,C._ N -N \ NH
H

F3C 0 \ , K._ -o 0 51 Nk N -N
H OH

F3C . N , c \\ / \\./0--..õ-:-7 \)--N 0 ' 504 504 F
NA---NN-----\A
H OH _ \)--< --N I

Cl, r\i.___j N 0-N

I

D

, 0 F3C . N / \\

\>--(,_ ---N 111 0 OH
55 \489 489 F

N -N
H

Example 56.

4Ik 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-benzofuran-1,41-piperidini-3-one (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-benzofuran-1,4r-piperidin]-1t-yl)benzaldehyde: m/z 326.
Step 2. Next, a solution of 3-fluoro-4-(3-oxo-11-1,3H-spiro[2-benzofuran-1,4'-piperidini-l'-yObertzaldehyde (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% acetonitrile:water with 0.05%
TFA) to give the pure product as a solid: [M1-1]- m/z 448.

Example 57.

=N =0 To a vial containing ethyl 2-(3-azaspiro[5.51undecan-9-yeacetate (50 mg, 1 equiv) was added (BrettPhos)palladium(II) phenethylamine chloride (CAS: 1148148-01-9, 33.4 mg, 20 mol%) and 2-(4-bromo-2-fluoropheny1)-6-(trifluoromethyl)-1H-benzo[d]imidazole (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 (381111,, 3.1 equiv) was added dropwise 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 vacua.
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: [wir- nilz 490.

Example 58.

N v OH
N
N
Step 1. 2-(3-(tert-butoxycarbony1)-3-azaspiro[5.5]undecan-9-yl)acetic 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

HC1. 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-(trifluoromethypbenzene-1,2-diamine (28 mg, 1 equiv) and Oxone (63 mg, 0.65 equiv) were weighed to a vial. To this was added DMF
(254 !AL) and water (10 fit) 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% acetonitrile:water with 0.05% TFA) to give the pure product as a brown solid: [MI11+ rn/z 474.
Example 59.

,N
OH
NH

Step 1. 2-(3-(tert-butoxycarbony1)-3-azaspiro[5.5]andecan-9-ypacetic 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 vacua.
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]t mtz 323.

Step 3. The aldehyde solution from Step 2 (1 mL, 1 equiv), 4-(trifluoromethyl)henzene-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 4) 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%
aeetonitrile:water with 0.05% TFA to 70% aeetonitrile:water with 0.05% TFA) to give the pure product as a pale yellow solid: [mfir 479.

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

Table 3.
[Mff] imnr Example Structure neZ nilZ
0 OH caled found 60 r\lj N 111 F3CS NH ,N 111 0 OH
61 Cl = NH

Example 62. Me ,,c N 0 OH
=\>¨(3--NN
Step 1. 4-(trifluoromethyl)benzene4,2-diamine (44.0 mg, 1.1 equiv), 6-bromo-5-fluoronicotinaldehyde (50 mg, 1 equiv) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (130 mg, I_ 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)pheny1)-6-bromo-fluoronicotinamide as a viscous brown oil: [MH]+ m/z 379.
Step 2. Acetic acid was added to N-(2-amino-4-(trifluoromethyl)pheny1)-6-brorno-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-fluoropyridin-3-y1)-5-(trifluoromethyl)-1H-benzo[djimidazole as a tan solid: [MHI" m/z 361.

2-(6-brorno-5-fluoropyridin-3-y1)-5-(trifluoromethyl)-1H-benzo[d]imidazole (9 mg, 1 equiv), methyl 2-(3-azaspiro[5.5]undecan-9-yl)acetate (5.6 mg, 1 equiv) and solid sodium bicarbonate (14.7 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 miz 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% acetonitrile:water with 0.05% TFA) to give the product as a white solid: [MIA+ m/z 491.

Example 63.
F3C 40N v0 "Th N \
HO
A 54rifluoromethy1-2-(6-fluoropyridin-3-y1)-1H-benzimidazole (30 mg, 1 equiv), Hunig's base (93 tut, 5 equiv) and the hydrochloride salt of 2-methoxy-5H-spiro[furo[3,4-b]pyridine-7,4'-piperidi]-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: [MI-1] m/z 482.

Example 64.

Ns OH

N

[3-(tert-butoxycarbony1)-3-azaspiro{5.5]undec-9-y1iacetic acid (120 mg, 4.5 equiv) was dissolved in dioxane (2 mL) and a 4 M solution of hydrochloric acid (300 [AL, 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 Ili NMR indicated complete removal of the Boe group. Volatiles were removed in vacuo and to the white solid was added 2-(6-fluoropyridin-3-y1)-5-methoxy-3H-imidazo[4,5-b]pyridine (25 mg, 1 equiv), sodium bicarbonate (36 mg, 5 equiv) and NMP (330 pL). The reaction mixture was heated at 110 C
for 18 hours, neutralized with acetic acid (15 [IL, 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: [MEW m/z 436.

Examples 65-77.
Me 0 OH

Me N N

To a mixture of Oxone (9 mg, 1 equiv) and 3,5-dimethy1pheny1enediamine (10 mg, 1 equiv) was added the hydrochloride salt of [3-(5-formy1pyridin-2-y1)-3-azaspiro[5.5]undec-9-y1lacetic 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.

Table 4 OH
R \ N

=[MH1+ [Mir 1M111+ [MH]
Example R m/z m/z Example R
ni/z nilz eale'd found eale'd found , Me , F

N
433 72 01 N....-.. 441 Me N
F =N
H
H

N
.,..,..

Me H N
N
_ , H ! , CI
F3C 0 ),....,...Me ....)-----õ,-N
67 411, N ¨.... 473 -*-- 420 420 Ci N
1\(----N
H
H , Me 0 r\l..._ ...)---õ--N

75 , 1 '-- 434 H
Me'N.-----N
, H
N
õ--<----\_-N

69 N 41 .--- 423 423 76 MeN1-----N õ I ,--- 420 F H
H

N
,T\I OP NN---489 77 I .....õ N

F3C0 0 N--"
H

CI
40 N__., 0 ....... 507 507 78 H

Intermediate 11.

Boc-N

methyl {9-(tert-butoxycarbony1)-1-oxa-9-azaspiro45.5]undec-4-yljacetate Step 1. N,N-dimethy1-1-amino-3-tert-butyldimethylsilyloxy-1,3-butadiene (1.5 g, 1 equiv) was added dropwise to a stirring suspension of tert-butyl 4-oxopiperidine-1-carboxylate in 2-butanol (11 mL) at room temperature. After 2.5 hours, volatiles were removed in vacua 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 Mom 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 tert-butyl 4-oxo-l-oxa-9-azaspiro[5.5jundec-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 tert-butyl 4-oxo-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate as an oil.
Step 3. Trimethyl phosphonoacetate (149 mg, 1.1 equiv) was added dropwise 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 warmed to room temperature and stirred for 2 hours.
tert-Butyl 4-oxo-1 -oxa-9-azaspiro[5.5Iundecane-9-caxboxylate from Step 2 (200 mg) was added dropwise as a 5 solution in THF (1.4 mL). The reaction was stirred at room temperature for 2 hours at which point volatiles were removed in vacua. The mixture was poured in 1 M
hydrochloric acid and extracted with 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 tert-buty1-4-(2-methoxy-2-oxoethylidene)-1-oxa-9-azaspiro[5.51undecane-9-carboxy1ate as a clear oil.

Step 4. tert-Buty1-4-(2-methoxy-2-oxoethylidene)-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate 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 colunm chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give tert-butyl 4-(2-methoxy-2-oxoethy1)-1-oxa-9-azaspiro[5.51undecane-9-carboxylate as an oil.

Example 79.

õc N

¨N 0 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 pt, 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-y1)-5-(trifluoromethyl)-1H-benzimidazole (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 ItL), filtered then purified by reverse phase HPLC (20%
to 70% acetonitrile in water with 0.05% TFA as eluant) to give methyl (9-{545-(trifluoromethyl)-1H-benzimidazol-2-yllpyridin-2-y1}-1-oxa-9-azaspiro [5 .51undec-4-yl)acetate as a yellow oil.
Step 2. methyl (9- { 5 -[5 -(trifluoromethyl)-1H-benzimidazol-2-yljpyridin-2-y1 -1-oxa-9-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 inL), neutralized with acetic acid (400 ILL), 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)-1H-benzimidazol-2-yl]pyridin-2-y1}-1-oxa-9-azaspiro [5 .5]undec-4-yl)acetic acid as a yellow oil: [MEW 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 [MF1J+ m/z 475.

Example 80. 0 F N\>._, 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 1-oxa-9-azaspiro[5.5jundec-3-ene-9-carboxylate (420 mg, 1 equiv) (Walters, M. A.; La, F.; Deshmukh, P.; Omeeinsky, D. 0. 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% H202 (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-buty1-3-hydroxy-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate as an amber oil: [MNar m/z 294.

Step 2. To a solution of tert-butyl-3-hydroxy-l-oxa-9-azaspiro[5.5]undecane-9-carboxylate (180 mg, I 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 tert-bu1y1-3-oxo4-oxa-9-azaspiro[5.5]undecane-9-carboxylate as a waxy solid:
[MH¨C4H9] m/z 214.

Step 3. Performed as in Intermediate 11, Step 3, to afford tert-buty1-3-(2-methoxy-2-oxoethylidene)-1-oxa-9-azaspiro [5 .5] undecane-9-carboxylate : [MNar 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-butoxycarbony1)-1-oxa-9-azaspiro [5 .51undec-3-yl] methyl acetate: [MNaj+ 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-{545-(tiifluoromethyl)-1H-benzimidazol-2-yl]pyridin-2-y1}-1-oxa-9-azaspiro[5.5]undec-3-y1) as an amber oil: [MH] 4 in/Z
489.

Step 6. Performed as in Example 71, Step 2 to give (9-1545-(trifluorornethyl)-1H-benzimidazol-2-Apyridin-2-y1}-1-oxa-9-azaspiro(5.51undec-3-y1)acetic acid as a tan solid:
[MIT]+ nilz 475.
Example 81.

N ¨N \-OH

tert-butyl 2-(2-methoxy-2-oxoethyl)-1-oxa-8-azaspiro f4.51decane-8-carboxylate 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]decane-8-carboxylate (1.125 g, 1.0 equiv) in anhydrous dichloromethane and the mixture chilled to -30f 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 tert-butyl 2-hydroxy-l-oxa-8-azaspiro[4.5]decane-8-carboxylate as a colorless oil: [MNal+ tn/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-carboxylate (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 tert-butyl 2-(2-methoxy-2-oxoethyl)-1-oxa-8-azaspiro14.51decane-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 vacua 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-fluoropyridin-3-y1)-5-(trifluoromethyl)-1H-benzo[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]
nitz 475.

Step 5.
The ester from Step 4 (29 mg, 1 equiv) was dissolved in 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: [MHT 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 [Mlir m/z 461.

F3 Example 82. N \)--=N 0 N -N OH

Step 1. 2-(8-(tert-butoxycarbony1)-1-oxa-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, I equiv), 2-(6-fluoropyridin-3-y1)-(trifluoromethyl)-1H-benzo[djimidazole (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.

Table 7.

-N OH
[m11.]+ 1111111+
Example R in& nez calct d found Ci Example 85-86.
F3 N(OH F3C N
OH
N \ 0 0 N -N \ 0 Step I. 2-(8-(tert-butoxycarbony1)-1-oxa-8-azaspiro[4.51decan-3-ypacetic acid (800 mg, I 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-y1)-(trifluoromethyl)-1H-benzo[d]imidazole (736 mg, I 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 vacua to yield a brown solid:
[M11]4. 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]F m/z 475.

Step 4. Enantiomer A of the ester from Step 3 was dissolved in methanol (300 p.L) and THF (300 L) 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 pL) and concentrated in vacua. 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: [M1114- m/z 461.

Step 5. Enantiomer B of the ester from Step 3 was dissolved in methanol (300 pt) and THF (300 1,LL) 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 ',it) and concentrated in vaeuo. 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: [MHir m/z 461.
Intermediate 12.

HN 0 OMe methyl 1-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-ally1-4-hydroxypiperidine-l-carboxylate (2.2 g, 1 equiv) (Walters, M. A.; La, F.;
Deshmukh, P.; Omecinsky, D. 0. 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 tert-butyl (methoxycarbonyl)prop-2-en-1-yl] oxy} -4-(prop-2-en-1 -yppiperidine-l-carboxylate as a colorless oil: [MNa] m/z 362.
Step 2. tert-butyl 4- { [2-(methoxycarbonyl)prop-2-en-l-yl]oxy}-4-(prop-2-en-1-y1)piperidine-1-caiboxylate from Step 1 (340 mg, 1 equiv) in anhydrous 1,2-dichloroethane (75 mL) was combined with benzylidene [1,3 -bi s(2,4,6-trimethylpheny1)-2-imidazolidinylidene] dichloro-(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 [MNar 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% aeetonitrile 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 dichloromethane (4 mL) 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 1-oxa-9-azaspiro[5.5]undecane-3-carboxylate as an oil:
[MH]+ Wz 214.

Example 87.
F3 N> 0 0 N ¨N OH

Step I. To the amine salt from Step 4 above (60 mg, 1 equiv), 2-(6-fluoropyridin-3-y1)-5-(trifluoromethyl)-1H-benzimidazole (79 mg, 1 equiv) and sodium bicarbonate (236 mg, 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 945 -(5-(trifluoromethyl)-1H-benzo [d] imidazol-2-yl)pyridin-2-y1)-1-oxa-9-azaspiro [5. 5jundecane-3-carboxylate as a tan solid: [M11] 4- in/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: [MEW rn/z 461.

The compounds presented in Table 5 were prepared according to a similar method.

Table 5 R 0 OH

[MHI+ [Mif]' Example R m/z ealeid found 88 Ci 427 427 89 1.1 411 411 Examples 90-91.
,3c. N 0 0 õc N

=N -N OH N
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. Enantiorner A
was obtained as a white solid with [MEW 222/z 475 and Enantiomer B was obtained as a white solid with [ya]
n2/z 475. Absolute stereochemisty was arbitrarily assigned.

Intermediate 13.

0 -N OMe The TFA salt of methyl 1-oxa-9-azaspiro[5.5jundecane-3-carboxylate (876 mg, I
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 C. The mixture was then cooled and filtered through a 0.45 micron membrane and this solution used crude in subsequent steps: [MH] nilz 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.

Table 6.

_ [Mir [Ma]
[Mli] [mH]

Example R
nilz in/z Example R rn/z In&

eale'd found eale'd found H
H
N

001 N......

421 421 97 Me I. t\l/
Et N
Me ,..
Me .
N.....

93 ==¨= 455 455 98 ... Et N
A

H

Nõ..-------N

-*-- 493 493 99 ''"¨ 408 408 M eft----N

H
H
N
F C3 =_-,.,¨N

95 110 ...¨ 477 477 100 i ---' 462 462 ---.. --;,-----N N
. .

H
H

H
N

1 96 1/>¨ 422 422 101 CC, '"'"' 424 424 Et0 N
Me07.14- N
-Potency of selected DGAT1 inhibitors.

To a 384 well assay plate was added 1 pt of a 400 [tM solution of the test compound in DMSO and 20 uL of a substrate mix that is 300 JAM in diolein and 40 uM in oleoyl-CoA in 10% ethanol. To this was added 19 ill, of 1.05 pg/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 ItglmL N-ethylmaleimide-treated bovine serum albumin. The solution is incubated at room temperature for 1 hour after which 20 ILL of a 90 ttM

7-diethy1amino-3-(4'-ma1eimidy1pheny1)-4-methy1cournarin 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 1050 is detetwined 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.
Example IC50 (nM) Example I IC50 (nM) 1 3 37 <25 2 11 41 <25 3 6 44 <100 13 49 49 <25 17 11 54 <25 18 70 56 <25 20 3 63 <100 23 4 66 <100 25 27 72 <100 26 3 80 <100 29 12 82 <25 30 42 85 <25 31 <100 86 <25 34 <25 87 <25 36 <25 95 <100

Claims (19)

1. A compound of 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 R1 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, C1-C6alkyl, C3-C10cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C1-C6alkylC3-C10cycloalkyl, C1-C6alkylaryl, C1-C6alkylheteroaryl and C1-C6alkylcycloheteroalkyl, wherein C1-C6alkyl, C3-C10cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C1-C6alkylC3-C10cycloalkyl, 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, COC1-C6alkyl, oxo, -OH, halogen-substitutedC1-C6alkylOH, -OC1-C6alkyl, -Ohalogen-substitutedC1-C6alkyl, -COOH, -COOC1-C6alkyl, -C1-C6alkylCOOC1-C6alkyl, -C1-C6alkylCOOH, -OC1-C6alkylCOOH, -CN, C1-C6alkylCN, -NO2, NH2, NHC1-C6alkyl, N(C1-C6alky¦)2, -NHCOOH, -NHCOOC1-C6alkyl, -CONH2, -CONHC1-C6alkyl, -CON(C1-C6alkyl)2, -CONHC1-C6alkyl-N(C1-C6alkyl)2, -NHSO2C1-C6alkyl, -SO2NH2, -C6alkyl, C3-C10cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C1-C6alkylC3-C10cycloalkyl, 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 acceptable salt thereof, wherein A is substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, -OC1-C6alkyl, -CN, SO2Me and halogen-substitutedC1-C6alkyl.

5. A compound of any one of claims 1-4, or a pharmaceutically acceptable 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 -O-, -CH2-, -NRa and -NC1-C6alkyl-, wherein Ra is selected from the group consisting of H and C1-C6alkyl; 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 C1-C6alkyl.

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 -O-.

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:

15. 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, -COOC1-C6alkyl-C1-C6alkylCOOC1-C6alkyl, -C1-C6alkylCOOH, -OC1-C6alkylCOOH, -CN, C1-C6alkylCN and -NHSO2C1-C6alkyl.

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

-84- -

17. A pharmaceutical composition comprising a compound of any 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.