AU2011279509A1 - 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

WO 2012/009217 PCT/US2011/043330 SPIROCYCLIC COMPOUNDS TECHNICAL FIELD The present invention is directed to novel spirocyclic compounds. Specifically, 5 the compounds act as a diacylglycerol 0-acyltransferase type 1 inhibitors (hereinafter also referred to as "DGATI "), and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity. BACKGROUND 10 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 15 these diseases. Although the need to treat obesity is recognized to be important, there are extremely-limited drug therapies for obesity that are currently available, and thus, the advent of novel anti-obesity drugs having more definite action and few side-effects is desired. In general, obesity is caused by the accumulation triacylglycerol (TG) in adipose tissue which is a result of lack of exercise, intake of excessive calories and ageing. In the body 20 there are two TG synthesis pathways, a glycerol phosphate pathway, which is present in most organs and causes de novo TG synthesis, and a monoacylglycerol pathway, which is involved principally in absorption of aliphatic acid from the small intestine. Diacylglycerol acyltransferases (DGATs, EC 2.3.1.20), which are membrane-bound enzymes present in the endoplasmic reticulum, catalyze the final step of the TG synthesis common to the two TG 25 synthesis pathways. The final reaction consists of transferring an acyl group of acyl-coenzyme A to the 3-position of 1,2-diacylglycerol to generate TG (Prog Lipid Res., 43.134-176. 2004 and Ann. Med., 36, 252-261, 2004). There are two subtypes of DGATs: DGATI and DGAT2. There is no significant homology at the generic or amino acid level between the DGATI and DGAT2, which are encoded by different genes (Proc.Natl.Acad.Sci.USA.,95,13018-13023,1998 30 and JBC,276,38870-38876,2001). DGATI is present in the small intestine, adipose tissue and liver and is believed to be involved in lipid absorption in the small intestine; lipid accumulation in the fat cell; and VLDL secretion and lipid accumulation in the liver (Ann.Med.,36,252 261,2004 and JBC,280,21506-21514,2005). In consideration of these functions, a DGATI inhibitor is expected to be an effective obesity treatment through inhibition of lipid absorption in 35 the small intestine, lipid accumulation in the adipose tissue and the liver, and the lipid secretion from the liver. - 1- WO 2012/009217 PCT/US2011/043330 In order to carry out in vivo examination of the physiological function(s) of DGATI and inhibitory activity against DGAT 1, DGATI-knockout mice deficient in DGATI at the generic level was produced, and analyses thereof were conducted. The DGAT I-knockout mice have been found to have smaller fat masses than those of wild-type mice and became 5 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 10 (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, DGATI inhibitors are likely to be therapeutic drugs with efficacy for obesity, type 2 diabetes mellitus, lipidosis, hypertension, fatty liver, arteriosclerosis, 15 cerebrovascular disorder, coronary artery disease and metabolic syndrome, associated with the obesity. SUMMARY OF THE INVENTION 20 The present invention is directed to compounds of structural formula I: N R =G R?' A B C N ER" H I or a pharmaceutically acceptable salt thereof, wherein A is independently selected from the group 25 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 30 substituted with one or more substituents selected from the group a, C 1

-C

6 alkyl, C 3 CiOcycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C 1 -C(alkylC 3

-C

10 cycloalkyl, C-C 6 alkylaryl, C 1 C 6 alkylheteroaryl and C 1

-C

6 alkylcycloheteroalkyl, wherein C 1

-C

6 alkyl, C 3 -Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C-C 6 alkylC 3 -Cocycloalkyl, C 1

-C

6 alkylaryl, C 1

-C

6 alkylheteroaryl -2- WO 2012/009217 PCT/US2011/043330 and Cl-C 6 alkylcycloheteroalkyl 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, C 1

-C

6 alkyl, halogen substitutedC-Cralkyl, COC 1

-C

6 alkyl, oxo, -OH, halogen-substitutedC-C 6 alkylOH, -OCr 5 C 6 alkyl, -Ohalogen-substituted~l-C 6 alkyl, -COOH, -COOC-C 6 alkyl, -C1-C 6 alkylCOOC

C

6 alkyl, -C 1

-C

6 alkylCOOH, -OC 1

-C

6 alkylCOOH, -CN, C 1

-C

6 alkylCN, -NO 2 , NH 2 , NHC 1 C 6 alkyl, N(CI-C 6 alkyl) 2 , -NHCOOH, -NHCOOC-C 6 alkyl, -CONH 2 , -CONHC-C 6 alkyl, CON(CI-C 6 alkyl) 2 , -CONHC-C 6 alkyl-N(Cj-C 6 alkyl) 2 , -NHSO 2

C

1

-C

6 alkyl, -SO 2

NH

2 , -SO 2 Cj

C

6 alkyl, C 3 -Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, CI 10 C 6 alkylC 3 -Cocycloalkyl, C 1

-C

6 alkylaryl, C -C 6 alkylheteroaryl and C -C 6 alkylcycloheteroalkyl. DETAILED DESCRIPTION OF THE INVENTION Compounds The present invention is directed to compounds of structural formula I: 15 N RG R A B N C N E H or a pharmaceutically acceptable salt thereof, wherein A is independently selected from the group consisting of benzene, pyridine, pyrazine and pyrimidine; 20 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, CI -C 6 alkyl, C 3 25 CiOcycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C 1

-C

6 alkylC 3 -Ciocycloalkyl, C 1 -Cralkylaryl, C 1 C 6 alkylheteroaryl and Cl-C 6 alkylcycloheteroalkyl, wherein C 1

-C

6 alkyl, C 3 -Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C-C 6 alkylC 3 -Ciocycloalkyl, C 1

-C

6 alkylaryl, C 1 -Cfalkylheteroaryl and CiC 6 alkylcycloheteroalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of a; 30 a is selected from the group consisting of halogen, C] -C 6 alkyl, halogen substitutedC,-C 6 alkyl, COC 1

-C

6 alkyl, oxo, -01H, halogen-substitutedC-C 6 alkylOH, -OCr

C

6 alkyl, -Ohalogen-substitutedC-Calkyl, -COOH, -COOC -C 6 alkyl, -C 1

-C

6 alkylCOOC

C

6 alkyl, -C 1

-C

6 alkylCOOH, -OC 1 -CgalkylCOOH, -CN, C 1

-C

6 alkylCN, -NO 2 , NN 2 , NHCj C6alkyl, N(C 1

-C

6 alkyl)2, -NHCOOH, -NHCOOC -C 6 alkyl, -CONI 2 , -CONHC 1

-C

6 alkyl, -3- WO 2012/009217 PCT/US2011/043330

CON(C-C

6 alkyl) 2 , -CONHC 1

-C

6 alkyl-N(Cj -C 6 alkyl) 2 , -NHSO 2

C

1

C

6 alkyl, -SO 2 NIH2, -SO2C

C

6 alkyl, C 3 -Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, Cr

C

6 alkylC 3 -Cocycloalkyl, C 1

-C

6 alkylaryl, Cl-C 6 alkylheteroaryl and C 1

-C

6 alkylcycloheteroalkyl. In certain embodiments of the compounds described herein, A is selected from the 5 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. 10 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, C 1

-C

6 alkyl, -OCI-C 6 alkyl, -CN, SO 2 Me and halogen substitutedCI -C 6 alkyl. In some embodiments, A is further substituted with one substituents selected from the group consisting of halogen, C 1

-C

6 alkyl, -OC-C 6 alkyl, -CN, SO 2 Me and 15 halogen-substitutedCI-C 6 alkyl. In some embodiments, A is further substituted with two substituents selected from the group consisting of halogen, C-C 6 alkyl, -OC 1 rC 6 alkyl, -CN,

SO

2 Me and halogen-substitutedC-C 6 alkyl. 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 C-C 6 alkyls. Examples of C-C 6 alkyl 20 include but are not limited to methyl and ethyl. A can also be substituted with halogen substitutedC-C 6 alkyl. Examples of halogen-substituted C 1

-C

6 alkyl, 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, CH 2 CN, NHSO 2 Me and SO 2

NH

2 . In yet other examples A is substituted with (C2H4)NHCOCH 3 or 25 CONH(C 2 H4)N(C 2

H

4

)

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 30 pyridine. The pyridine can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen or halogen-substitutedC-C 6 alkyl. 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-substitutedC1 35 C 6 alkyl. 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 -4- WO 2012/009217 PCT/US2011/043330 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: N N N N N N N N and H H H H N N H 5 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 -CU-. 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-. 10 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. 15 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, C

C

6 alkyl and halogen-substitutedC-C 6 alkyl. Examples of suitable halogens include, but are not limited to chlorine and fluorine. Examples of suitable C-COalkyl include, but are not limited to 20 methyl and ethyl and examples of suitable halogen-substitutedC-C 6 alkyl include, but are not limited to trifluoromethyl. Suitable examples of ring B and its substituents include, but are not limited to, F F CI CI N" N and _N N Ring C as shown in formula I can be substituted or unsubstituted. In certain 25 embodiments, C is unsubstituted. In certain embodiments of the compounds described herein, C - 5 - WO 2012/009217 PCT/US2011/043330 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, C 1

-C

6 alkyl and halogen-substitutedC-C 6 alkyl. Examples of suitable halogens include, but are not limited to chlorine and fluorine. Examples of suitable CI-C 6 alkyls include, 5 but are not limited to methyl and ethyl and examples of suitable halogen-substitutedC -C 6 alkyls 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 10 bycyclic cycloalkyls, such as, In another embodiment, D is heterocycloalkyl. For example, in one embodiment, D is T Vi/ wherein T is selected from the group consisting of -O-, -CH 2 -, -NH and -NC -C 6 alkyl-; and V, 15 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(CH

3 ) and V, U, Q and W are -CH-. In yet another embodiment, T is -CH 2 - and V, U, Q and W are -CH-. 20 In certain embodiments of the compounds described herein, D can be selected from the group consisting of: 0 0 0 a0 / N N NRa -6- and -6- WO 2012/009217 PCT/US2011/043330 wherein Ra is selected from the group consisting of H and C 1

-C

6 alkyl. In certain embodiments, D, when selected from the group above can be unsubstituted. In more particular embodiments, D, when selected from the group above, can be further substituted with an oxo group, such as =O. In other embodiment, when D is selected from the group above, D can be substituted with 5 one or more substituents selected from the group consisting of oxo, -OH, -COOH, -COOC

C

6 alkyl, halogen, C-COalkyl, C 1

-C

6 alkylCOOH, Cl-C 6 alkylCN, cyclopropyl, halogen substitutedC-C 6 alkyl and C 1

-C

6 alkyltriazole, wherein the triazole is substituted with methyl. In particular embodiments, D, when selected from the group above, can be further substituted with a C 1

-C

6 alkylaryl group. In certain embodiments, D is substituted with a -CH 2 10 phenyl, wherein the -CH 2 -phenyl is unsubstituted. In certain embodiments, D is substituted with

-CH

2 -phenyl, wherein the -C-1 2 -phenyl is substituted with one or more substituents selected from the group consisting of halogen, C 1

-C

6 alkyl and halogenusubstitutedC C 6 alkyl. In other embodiments of the compounds described herein, D is selected from the group consisting of: x 151 15 Z wherein X, Y and Z are independently selected from the group consisting of -C-, -CH-, -CH 2 -, N-, -NH- and -0-. In one embodiment, Z is N, X is CH 2 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. 20 In certain embodiments of the compounds described herein, D is selected from the group consisting of: 0 N N o N N and In certain embodiments, D is substituted with one or more oxo groups. For example, D can be substituted with 25 In particular embodiments, D, when selected from the group above, can be further substituted with an aryl or heteroaryl group. In certain embodiments, D is substituted with a phenyl ring, wherein the phenyl is unsubstituted. In certain embodiments, D is substituted with a phenyl ring, wherein the phenyl is substituted with one or more substituents selected from the group consisting of -COOH, COOC 1

-C

6 alkyl, heterocycloalkyl-COOH, halogen, C 1

-C

6 alkyl, 30 halogen-substitutedC-C 6 alkyl, -OC 1

-C

6 alkylCOOH, NO 2 , -CN, C 1

-C

6 alkylCOOH, C 1 C 6 aIkylCOOC 1

-C

6 alkyl and -CF 3 0H. In certain embodiments, D is substituted with a pyridine ring, wherein the pyridine is unsubstituted. In certain embodiments, D is substituted with a -7- WO 2012/009217 PCT/US2011/043330 pyridine ring, wherein the pyridine is substituted with one or more substituents selected from the group consisting of halogen, C 1

-C

6 alkyl and halogen-substitutedC-C 6 alkyl. In still other embodiments of the compounds described herein D is selected from the group consisting of: 5 and P P is selected from the group consisting of -O- or -CH 2 -. In one embodiment, P is -0-. In another embodiment, P is -CH 2 -. 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 10 -COOH, oxo, -C,-C 6 alkylCOOH and NHSO 2 Me. 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 -C 1

-C

6 alkylCOOH. In yet another embodiment of the compounds described herein, D is selected from the group consisting of: 10 0 0 15 and0 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 -C I

C

6 alkylCOOH. Examples of D and its substituents include, but are not limited to, 00 0 1 0- -OH 0 OH 0 OH -N O -N aNd 20 In of the above described embodiments of D, D can be substituted vIith 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, C-C 6 alkyl, halogen-substitutedC-C 6 alkyl, oxo, -OH, COOH, -COOC-C 6 alkyl, -C-C 6 alkylCOOC-C 6 alkyl, -C 1

-C

6 alkylCOOH, -OC-C 6 alkylCOOH, 25 -CN, C,-C 6 alkylCN and -NHSO 2

C,-C

6 alkyl. Also described herein are compounds of formula Ia: N -G R2 N D N N H Ia -8- WO 2012/009217 PCT/US2011/043330 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-; R1 is selected from the group consisting of halogen or halogen-substitutedCi 5 C 6 alkyl; D is a C 3 -CIocycloalkyl; and

R

2 is selected from the group consisting of hydrogen, C 1

-C

6 alkyl, halogen substitutedC-C 6 alkyl, COCI-C 6 alkyl, -OHl, oxo, halogen-substitutedC-C 6 alkylOH, -0C 1 _

C

6 alkyl, -Ohalogen-substitutedCi-C 6 alkyl, -COOH, -COOC -C 6 alkyl, -C 1

-C

6 alkylCOOC1 10 C 6 alkyl, -C 1

-C

6 alkylCOOH and -0C 1

-C

6 alkylCOOH. 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: 15 In certain embodiments, D is cyclohexane. In some embodiments, R is halogen. Suitable examples of halogen include, but are not limited to, chlorine, fluorine and bromine. In some embodiments, R 1 is halogen substitutedC-C 6 alkyl. Suitable examples of halogen-substitutedC-C 6 alkyl include, but are not 20 limited to, trifluoromethyl. In certain embodiments, R2 is selected from the group consisting of -COOH, COOCi-C 6 alkyl, -C]-C 6 alkylCOOCI-C 6 alkyl and -C 1

-C

6 alkylCOOH. For example, in some embodiments R2 is selected from the group consisting of -COOH and -C 1

-C

6 alkylCOOH. Examples of -C-C 6 a1kylCOOH include, but are not limited to, -CH 2 COOH. 25 Aldo described herein are compounds of formula Ia: N G R2 N D H 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-; 30 R' is selected from the group consisting of halogen or halogen-substitutedCI-

C

6 alkyl; -9- WO 2012/009217 PCT/US2011/043330 D is a heterocycloalkyl; and R2 is selected from the group consisting of hydrogen, halogen, Cj-C 6 alkyl, halogen-substitutedC,-C 6 alkyl, COC-C 6 alkyl, oxo, -OH, halogen-substitutedCl-C 6 alkylOH, OC 1

-C

6 alkyl, -Ohalogen-substitutedC-C 6 alkyl, -COOH, -COOC 1

-C

6 alkyl, -C 1

-C

6 alkyICOOCr 5 C 6 alkyl, -C-C 6 alkylCOOH, -OC 1

-C

6 alkyICOOH, -CN, C 1

-C

6 alkylCN, -NO 2 , NH 2 , NHC 1 C 6 alkyl, N(C 1

-C

6 alkyl) 2 , -NHCOOH, -NHCOOC-C 6 alkyl, -CONH 2 , -CONHC 1

-C

6 alkyl, CON(C-C 6 alkyl) 2 , -NHSO 2

C-C

6 alkyl, -SO 2

C-C

6 alkyl, C 3 -Cocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C 1

-C

6 alky1C 3 -Ciocycloalkyl, C 1

-C

6 alkylaryl, C 1 C 6 alkylheteroaryl and C-C 6 alkylcycloheteroalkyl. 10 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 0 0 0 0 / N / N N N N I Na N Ic N [N) NN and 15 In certain embodiments, D is selected from the group consisting of: S0 10 0 N N/ N nd In certain embodiments, D is selected from the group consisting of N b and/ In certain embodiments, D is selected from the group consisting of: -10- WO 2012/009217 PCT/US2011/043330 0 N N 0 N , N ' and In some embodiments, R' is halogen. Suitable examples of halogen include, but are not limited to, chlorine, fluorine and bromine. In some embodiments, R 1 is halogen substitutedCi-C 6 alkyl. Suitable examples of halogen-substitutedCI-Cfalkyl include, but are not 5 limited to, trifluoromethyl. In certain embodiments, R2 is selected from the group consisting of halogen, C C 6 alkyl, halogen-substitutedC 1 -C 6 alkyl, oxo, -COOH, -COOC-Cralkyl, -C 1

-C

6 alkylCOOC

C

6 alkyl, -C-C 6 alkylCOOH, -OCl-C 6 alkylCOOH, -CN, C 1

-C

6 alkylCN and C 1 C 6 alkylcyclopropyl. In other embodiments R2 is selected from the group consisting of hydrogen, 10 halogen, C 1

-C

6 alkyl, halogen-substitutedC-C 6 alkyl, oxo, -OH, halogen-substitutedCl

C

6 alkylOH, -COOH, -COOC 1

-C

6 alkyl, -Cj-CalkylCOOC-C 6 alkyl, -C-C 6 alkylCOOH, -OC

C

6 alkylCOOH, -CN, C 1

-C

6 alkylCN, -NO 2 , -NHSO 2

C

1

-C

6 alkyl, -SO 2

C

1

-C

6 alkyl, C 3 C 1 cycloalkyl 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 15 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, Cl-C 6 alkyl, halogen-substitutedC-C 6 alkyl, -COOH, -COOC-C 6 alkyl, -C,-C 6 alkyICOOC 1

-C

6 alkyl, -C

C

6 alkylCOOH, -OCI-C 6 alkylCOOH and -CN. 20 Also described herein are compounds of formula Ib: R1 N G T3 N N H Q V R4

R

5 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 25 CH-; T is selected from the group consisting of -O-, -CH 2 -, -NH- and -NCr-C 6 alkyl-; V, U, Q and W are independently selected from the group consisting of -N-, -C and -CH-; - 11 - WO 2012/009217 PCT/US2011/043330 R1 is selected from the group consisting of halogen or halogen-substitutedC C 6 alkyl; and RW, R and R5 are independently selected from the group consisting of hydrogen, halogen, C 1

-C

6 alkyl, halogen-substitutedCi-C 6 alkyl, COCj-C 6 alkyl, oxo, -OH, halogen 5 substitutedC-C 6 alkylOH, -OC-C 6 alkyl, -Ohalogen-substitutedC]-Csalkyl, -COOH, -COOC

C

6 alkyl, -C 1

-C

6 alkylCOOC)-C 6 alkyl, -C-C 6 alkylCOOH, -OC -C 6 alkylCOOH, -CN, C 1 C 6 alkylCN, -NO 2 , NH 2 , NHCj-C 6 alkyl, N(C 1

-C

6 alkyl) 2 , -NHCOOH, -NHCOOC-C 6 alkyl, CONH 2 , -CONHC-C 6 alkyl, -CON(CI-C 6 alkyl) 2 , -NHSO 2 C-Csalkyl, -S0 2

CI-C

6 alkyl, C 3 Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C 1

-C

6 alkylC 3 10 CIocycloalkyl, C-C 6 alkylaryl, CI-C 6 alkylheteroaryl and CI-C 6 alkylcycloheteroalkyl, wherein the

C

3

-C

10 cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C 1

-C

6 alkylC 3 Ciocycloalkyl, C 1

-C

6 alkylaryl, Cl-C 6 alkylheteroaryl and Cl-C 6 alkylcycloheteroalkyl are unsubstituted or substituted with at least one substituent selected from the group consisting of halogen. 15 In certain embodiments, G is -N- and E is -CH-. In other embodiments, G is CH- and E is -N-. In other embodiments, G and E are both -CH-. In certain embodiment, T is -0-. In other embodiments, T is -CH2-. In still other embodiments, T is -NH-. In yet other embodiment, T is -NCH 3 . In some embodiments, R' is halogen. Suitable examples of halogen include, but 20 are not limited to, chlorine, fluorine and bromine. In some embodiments, RI is halogen substitutedC-C 6 alkyl. Suitable examples of halogen-substitutedC-C 6 alkyl 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 -Cl-I-. In other embodiments, all of V, U, Q 25 and W are -CH-. R3 is independently selected from the group consisting of hydrogen, halogen, C C 6 alkyl, halogen-substitutedC -C 6 alkyl, COCI-C 6 alkyl, oxo, -OH, halogen-substitutedC C 6 alkylOH, -OC-C 6 alkyl, -Ohalogen-substitutedC-C 6 alkyl, -COOH, -COOC-C 6 alkyl, -C 1 C 6 alkylCOOC-COalkyl, -C1-C 6 alkylCOOH, -OC 1

-C

6 alkylCOOH, -CN, C-C 6 alkylCN, -NO 2 , 30 NH 2 , NHC 1

-C

6 alkyl, N(Cj-C 6 alkyl) 2 , -NHCOOH, -NHCOOCI-C 6 alkyl, -CONH 2 , -CONHC 1 C 6 alkyl, -CON(C 1

-C

6 alkyl) 2 , -NHSO 2

C-C

6 alkyl, -SO 2

C-C

6 alkyl, C 3 -Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C-C 6 alkylC 3 -Ciocycloalkyl, C

C

6 alkylaryl, Cl-C 6 alkylheteroaryl and q-C 6 alkylcycloheteroalkyl, wherein the C 3 -Cocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C 1

-C

6 alkylC 3 -Cjocycloalkyl, C 35 C 6 alkylaryl, C 1

-C

6 alkylheteroaryl and C 1

-C

6 alkylcycloheteroalkyl are unsubstituted or substituted with at least one substituent selected from the group consisting of halogen. In certain embodiments, R 3 is selected from the group consisting of hydrogen, oxo, C-C 6 alkyl, -COOH, - 12- WO 2012/009217 PCT/US2011/043330

C

1

-C

6 alkylCOOH, C 1

-C

6 alkylCN, -SO 2

C,-C

6 alkyl, cyclopropyl, C-C 6 alkylaryl, and C

C

6 alkylcycloheteroalkyl, wherein the C 1

-C

6 alkylaryl and Cl-C 6 alkyleycloheteroalkyl are unsubstituted or substituted with at least one substituent selected from the group consisting of halogen. In other embodiments, R 3 is independently selected from the group consisting of 5 hydrogen, halogen, C 1

-C

6 alkyl, halogen-substitutedC,-C 6 alkyl, COC,-C 6 alkyl, -OH, -COOH, COOC-C 6 alkyl, -C,-C 6 alkylCOOC,-C 6 alkyl, C-C 6 alkyJCN and -C 1

-C

6 alkylCOOH. In one embodiment, R 3 is oxo. In another embodiment R 3 is hydrogen. In still another embodiment, R3 is C,-C5alkylphenyl, wherein the phenyl is unsubstituted or substituted with a halogen or COOH. 10 R4 is independently selected from the group consisting of hydrogen, halogen, C

C

6 alkyl, halogen-substitutedC,-C 6 alkyl, COC-C 6 alkyl, oxo, -OH, halogen-substitutedC,

C

6 alkylOH, -OCI-C 6 alkyl, -Ohalogen-substitutedC,-C 6 alkyl, -COOH, -COOC-C 6 alkyl, -C 1 C 6 alkylCOOC-C 6 alkyl, -C,-C 6 alkylCOOII, -OC1-C 6 alkyICOOH, -CN, C,-C 6 alkylCN, -NO 2 ,

NH

2 , NHC,-C 6 alkyl, N(C-C 6 alkyl) 2 , -NHCOOH, -NHCOOC -C 6 alkyl, -CONH 2 , -CONHCI 15 C 6 alkyl, -CON(C-C 6 alkyl) 2 , -NHSO 2

C]-C

6 alkyl, -SO 2 C1-C 6 alkyl, C 3 -Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOO-I, C1-C 6 alkylC 3 -Cjocycloalkyl, C

C

6 alkylaryl, C 1

-C

6 alkylheteroaryl and C,-C 6 alkylcycloheteroalkyl, wherein the C 3 -Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C,-C 6 alkylC 3 -Ciocycloalkyl, Cj Csalkylaryl, C-C 6 alkylheteroaryl and C -C 6 alkylcyeloheteroalkyl are unsubstituted or substituted 20 with at least one substituent selected from the group consisting of halogen. In other embodiments, R 4 is independently selected from the group consisting of halogen, C,-C 6 alkyl, halogen-substitutedC,-C 6 alkyl, COC,-C 6 alkyl, -OH, -COOH, -COOC-C 6 alkyl, -C,

C

6 alkylCOOC-C 6 alkyl and -C-C 6 alkylCOOH. In another embodiment, R4 is hydrogen. R5 is independently selected from the group consisting of hydrogen, halogen, Cj 25 C 6 alkyl, halogen-substitutedC,-Cralkyl, COC,-C 6 alkyl, oxo, -OH, halogen-substitutedCI

C

6 alkylOH, -OCI-C 6 alkyl, -Ohalogen-substitutedC,-C 6 alkyl, -COOH, -COOC,-C 6 alkyl, -C

C

6 alkylCOOC-C 6 alkyl, -C,-C 6 alkylCOOH, -OCr C 6 alkylCOOH, -CN, C-C 6 alkylCN, -NO 2 ,

NH

2 , NHC-C 6 alkyl, N(C,-C 6 alkyl) 2 , -NHCOOH, -NHCOOC-C 6 alkyl, -CONH 2 , -CONHC,

C

6 alkyl, -CON(C,-C 6 alkyl) 2 , -NHSO 2

CI-C

6 alkyl, -SO 2

C,-C

6 alkyl, C 3 -Cl ocycloalkyl, aryl, 30 heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C-C 6 alkylC 3 -Ciocycloalkyl, C1

C

6 alkylaryl, C-C 6 alkylheteroaryl and CI-C 6 alkylcycloheteroalkyl, wherein the C 3 -CIocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C,-C 6 alkylC 3 -Cocycloalkyl, C,

C

6 alkylaryl, C, -C 6 alkylheteroaryl and C, -C 6 alkylcycloheteroalkyl are unsubstituted or substituted with at least one substituent selected from the group consisting of halogen. In certain 35 embodiments, R5 is selected from the group consisting of hydrogen, oxo, C,-Coalkyl, -COOH, C,-C 6 alkylCOOH, C,-C 6 alkylCN, -S0 2 C1-C 6 alkyl, cyclopropyl, C,-C 6 alkylaryl, and C Csalkylcycloheteroalkyl, wherein the C,-C 6 alkylaryl and C,-C 6 alkylcycloheteroalkyl are - 13 - WO 2012/009217 PCT/US2011/043330 unsubstituted or substituted with at least one substituent selected from the group consisting of halogen. In other embodiments, R 5 is independently selected from the group consisting of halogen, C-C 6 alkyl, halogen-substitutedCI-C6alkyl, COC 1

-C

6 alkyl, -OH, -COOH, -COOCr. Cralkyl, -C 1

-C

6 alkylCOOC 1

-C

6 alkyl and -C 1

-C

6 alkylCOOH. In one embodiment, R 5 is 5 hydrogen. Also described herein are compounds formula Ic: R NR_ _6 N GK N M H R8 Ic 10 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, K, L and M are independently selected from the group consisting of -O-, -CH 2 -, -CH-, -C- and -N -; 15 R' is selected from the group consisting of halogen or halogen-substitutedCi

C

6 alkyl; and R 6, R 7 and RW are independently selected from the group consisting of hydrogen, halogen, C-C 6 alkyl, halogen-substitutedC-C6alkyl, COC-C 6 alkyl, oxo, -OH, halogen substitutedC 1

-C

6 alkylOH, -OC -C 6 alkyl, -Ohalogen-substitutedCI-C 6 alkyl, -COOH, -COOC 20 C 6 alkyl, -C 1

-C

6 alkylCOOC-Coalkyl, -C 1

-C

6 alkylCOOH, -OC 1 -CoalkylCOOH, -CN, C 1 C 6 alkylCN, -NO 2 , NH 2 , NHC-Coalkyl, N(C 1

-C

6 alkyl) 2 , -NHCOOH, -NHCOOC 1

-C

6 alkyl, CONH 2 , -CONHC-Cralkyl, -CON(Cl-C 6 alkyl) 2 , -N1SO 2

C

1

-C

6 alkyl, -SO2C1-C 6 alkyl, C 3 Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, CI-C6alkylC3 Clocycloalkyl, C 1

-C

6 alkylaryl, C 1

-C

6 alkylheteroaryl and C 1

-C

6 alkylcycloheteroalkyl, wherein the 25 C 3

-C

1 ocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C 1

-C

6 alkylC 3 C 1 ocycloalkyl, Cl-C 6 alkylaryl, C 1

-C

6 alkylheteroaryl and C-C 6 alkylcycloheteroalkyl 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 30 CH- and E is -N-. In other embodiments, G and E are both -CH-. In some embodiments, R1 is halogen. Suitable examples of halogen include, but are not limited to, chlorine, fluorine and bromine. In some embodiments, R] is halogen - 14 - WO 2012/009217 PCT/US2011/043330 substitutedC-C 6 alkyl. Suitable examples of halogen-substitutedCl-C6alkyl include, but are not limited to, trifluoromethyl. In certain embodiments, J is -C1 2 -. 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-. 5 In anther embodiment, N is -CHR 8 -. In other embodiments, L is N(R 7 ). In certain embodiments, J is -0-; K is -C(R), wherein Ri is oxo; L is N(R 7 ), wherein R7 is defined above; and M is CH(R 8 ), wherein RW is hydrogen. In other embodiments, J is -0-; K is -N-; L is C(RW); and M is

-C(R

7 )( R 2 ), wherein R, R 7 and R8 are hydrogen. In certain embodiments, R 6 is oxo. In other embodiments, R7 is hydrogen. In still 10 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, R 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, CI-C 6 alkyl, halogen-substitutedCI -C 6 alkyl, heterocyclicalkylCOOH, -COOH, -COOC 1

-C

6 ailkyl, -C 15 C 6 alkylCOOCi-C6alkyl, -C 1

-C

6 aIkylCOOH, -OC 1

-C

6 aIkylCOOH, NO 2 and -CN. In still other embodiments, RW is hydrogen. Also described herein are compounds of formula Id: N -G 0 N O N - HE

R

9 Id 20 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 -CH 2 -; 25 R' is selected from the group consisting of halogen or halogen-substitutedC 1 C 6 alkyl; and R? is selected from the group consisting of hydrogen, C 1

-C

6 alkyl, halogen substitutedC-C 6 alkyl, COC -C 6 alkyl, -OH, halogen-substitutedC-C 6 alkylOH, -OC -C 6 alkyl, Ohalogen-substitutedC-C 6 alkyl, -COOH, -COOC-C 6 alkyl, -C 1

-C

6 alkylCOOCj-C 6 alkyl, -C 30 C 6 alkylCOOH, -OCI-C 6 alkylCOOH, -CN, C 1

-C

6 alkylCN, -NO 2 , -SO 2

C

1

-C

6 alkyl, C 3 C 1 ocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C-C 6 alkylC 3 - 15 - WO 2012/009217 PCT/US2011/043330 Ciocycloalkyl, C 1

-C

6 alkylaryl, C 1

-C

6 alkylheteroaryl and C 1

-C

6 alkylcycloheteroalkyl, wherein the

C

3 -Clocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C 1

-C

6 alkylC 3 Ciocycloalkyl, C 1

-C

6 alkylaryl, C 1

-C

6 alkylheteroaryl and C 3

-C

6 alkylcycloheteroalkyl are unsubstituted or substituted with at least one substituent selected from the group consisting of 5 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 2 -. In some embodiments, R 1 is halogen. Suitable examples of halogen include, but 10 are not limited to, chlorine, fluorine and bromine. In some embodiments, R' is halogen substitutedC-C 6 alkyl. Suitable examples of halogen-substitutedC-C 6 alkyl include, but are not limited to, trifluoromethyl. In certain embodiments, R9 is C 1

-C

6 alkyl, halogen-substitutedC-C 6 alkyl, -OH, halogen-substitutedC,-C 6 alkylOH, -COOH, -COOC-C 6 alkyl, -C-C 6 alkylCOOC-C 6 alkyl, -C 15 C 6 alkylCOOH, -OC 1

-C

6 alkylCOOH, -CN, C-C 6 alkylCN, -NO 2 and cycloheteroalkyl, wherein the cycloheteroalkyl is substituted with -COOH. In other embodiments, R9 is -COOH or -C]

C

6 alkylCOOH. Also described herein are compounds of formula le: R1e R, N - G H Ie 20 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 -CH 2 -; R' is selected from the group consisting of halogen or halogen-substitutedCI 25 C 6 alkyl;

R

1 4 is selected from the group consisting of hydrogen, C-C 6 alkyl, halogen substitutedC 1

-C

6 alkyl, -OH, oxo, halogen-substitutedC-C 6 alkylOH, -COOH, -COOCI-C 6 alkyl, C, -C 6 alkylCOOC1 -C 6 alkyl, -C 1

-C

6 alkylCOOH and -OCI -C 6 alkylCOOH; and R" is selected from the group consisting of halogen, CI-C 6 alkyl, halogen 30 substitutedC-C 6 alkyl, COC-C 6 alkyl, oxo, -OH, halogen-substitutedC,-C 6 alkylOH, -OC

C

6 alkyl, -Ohalogen-substitutedC -C 6 alkyl, -COOH, -COOC-C 6 alkyl, -Cr C 6 alkylCOOC 1

C

6 alkyl, -C-C 6 alkylCOOH, -OC,-C 6 alkylCOOH, -CN, C-CsalkylCN, -NO 2 , NH 2 , NHCr -16- WO 2012/009217 PCT/US2011/043330 Csalkyl, N(Cj-C 6 alkyI) 2 , -NHCOOH, -NHCOOCI-C 6 alkyl, -CONH2, -CONHC 1

-C

6 alkyl, CON(C -C 6 alkyl) 2 , -NHSO 2

C

1

-C

6 alkyl, -SO2C-C 6 alkyl, C 3 -Ciocycloalkyl., aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C-C 6 alkylC 3 -Ciocycloalkyl, Cl-C 6 alkylaryl, C 1 C 6 alkylheteroaryl and C 1

-C

6 alkylcycloheteroalkyl. 5 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 -CU 2 -. In some embodiments, R' is halogen. Suitable examples of halogen include, but are not limited to, chlorine, fluorine and bromine. In some embodiments, R' is halogen 10 substitutedC-C 6 alkyl. Suitable examples of halogen-substitutedC,-C 6 alkyl include, but are not limited to, trifluoromethyl. In certain embodiments, R' 0 is selected from the group consisting of oxo and COOH. In other embodiments, R1 0 is hydrogen. In certain embodiments, R" is selected from the group consisting of hydrogen. In 15 other embodiments, R' is selected from the group consisting of -COOH, -COOC-C 6 alkyl, -C

C

6 alkylCOOCI -C 6 alkyl, -C-C 6 alkylCOOH, -OC 1

-C

6 alkylCOOH, -NHCOOH, -NHCOOC 1 C 6 alkyl, -CONH 2 , -CONHCI-C 6 alkyl, -CON(C-C 6 alkyl)2, -NHSO 2

C-C

6 alkyl and -S0 2

C

C

6 alkyl. Also described herein are compounds of formula I(f): N ---- GO A N D N E XR12 20 H 1(f) 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 25 unsubstituted or substituted with one or more substituents selected from the group a, CI-C 6 alkyl,

C

3 -Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C1-C 6 alkylC 3 -Ciocycloalkyl, Cl-C 6 alkylaryl, Cl-C 6 alkylheteroaryl and C-C 6 alkylcycloheteroalkyl, wherein Cl-C 6 alkyl, C 3 -Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C 1

-C

6 alkylC 3 -CiOcycloalkyl, Ci-C 6 alkylaryl, Cr

C

6 alkylheteroaryl and Cl-C 6 alkylcycloheteroalkyl are independently unsubstituted or substituted 30 with one or more substituents selected from the group consisting of a; a is selected from the group consisting of halogen, C 1

-C

6 alkyl, halogen substitutedC-COalkyl, COC 1

-C

6 alkyl, oxo, -OH, halogen-substitutedC-CalkylOH, -OCr

C

6 alkyl, -Ohalogen-substitutedC

-C

6 alkyl, -COOH, -COOC 1

-C

6 alkyl, -C 1

-C

6 alkylCOOCr

C

6 alkyl, -C 1

-C

6 alkylCOOH, -OC 1

-C

6 alkylCOOH, -CN, C 1

-C

6 alkylCN, -NO 2 , NH 2 , NHC3 -17- WO 2012/009217 PCT/US2011/043330

C

6 alkyl, N(C 1

-C

6 alkyl) 2 , -NHCOOH, -NHCOOC-C 6 alkyl, -CONH 2 , -CONHC-C 6 alkyl, CON(CI -C 6 alkyl)2, -CONHC 1

-C

6 alkyl-N(C 1

-C

6 alkyl) 2 , -NHSO 2

C-C

6 alkyl, -SO 2

NH

2 , -SO 2

C

C

6 alkyl, C 3 -Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C

C

6 alkylC 3 -Ciocycloalkyl, C 1

-C

6 alkylaryl, C-C 6 alkylheteroaryl and Cl-C 6 alkylcycloheteroalkyl; 5 D selected from the group consisting of: fs0 0 1 0 ando 0

R

12 is selected from the group consisting of -COOH, -COOC 1

-C

6 alkyl, -C 1 C 6 alkylCOOC 1 -Calkyl, -C 1

-C

6 alkylCOOH and -OC 1

-C

6 alkylCOOH. In certain embodiments, G is -N- and E is -CH-. In other embodiments, G is 10 CH- and E is -N-. In other embodiments, G and E are both -CH-. Also described herein are compounds of formula Ig: A N G N E (D R12 H Ig 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 15 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, C 1

-C

6 alkyl,

C

3

-C

1 ocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C-C 6 alkylC 3 -Cjocycloalkyl, C-COalkylaryl,

C

1

-C

6 alkylheteroaryl and C-C 6 alkylcycloheteroalkyl, wherein C-COalkyl, C 3 -Ciocycloalkyl, 20 aryl, heteroaryl, cycloheteroalkyl, C 1

-C

6 alkylC 3 -Ciocycloalkyl, C-C 6 alkylaryl, C 1 C6alkylheteroaryl and CI -C 6 alkylcycloheteroalkyl 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, C 1

-C

6 alkyl, halogen substitutede 1

-C

6 alkyl, COC 1

-C

6 alkyl, oxo, -OH, halogen-substitutedC-C 6 alkylOH, -OC 25 C 6 alkyl, -Ohalogen-substitutedC-C6alkyl, -COOH, -COOCI-C 6 alkyl, -C 1

-C

6 alkylCOOC 1 C 6 alkyl, -C 1

-C

6 alkylCOOH, -OC 1

-C

6 alkylCOOH, -CN, C 1

-C

6 alkylCN, -NO 2 , NH 2 , NHC 1 C 6 alkyl, N(C-C 6 alkyl) 2 , -NHCOOH, -NHCOOC-C 6 alkyl, -CONH 2 , -CONHC 1

-C

6 alkyl, CON(C-C 6 alkyl) 2 , -CONHC 1 -Cralkyl-N(Ci-C 6 alkyl) 2 , -NHSO 2

C-C

6 alkyl, -SO2NH2, -SO 2 Cr

C

6 alkyl, C 3 -Clocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH,

C

30 COalkylC 3 -Ciocycloalkyl, C-Csalkylaryl, C 1

-C

6 alkylheteroaryl and C 1

-C

6 alkylcycloheteroalkyl; - 18- WO 2012/009217 PCT/US201 1/043330 Rr1 2 is selected from the group consisting of -COOH, -COOC 1

-C

6 alkyl, -Cl

C

6 allcylCOOC 1

-C

6 alkyl, -C 1

-C

6 alkylCOOH and -0C 1

-C

6 alkylCOOH. Examples of compounds or pharmaceutically acceptable salt thereof include, but are not limited to: ________________________ N1 N N a N N A' N N N N H OH H0 CI N ....... A...N. -19 WO 2012/009217 PCT/US201 1/043330 F F 00 c F N N1 t N NC N N - F 0'N N F H 0 N 0N N H N N N N F 020 WO 2012/009217 PCT/US201 1/043330 F r NH N 0 NA >N C N-KN NX N N F0 NON F- F 02 -0 NN

HO

WO 2012/009217 PCT/US201 1/043330 0 ON~ OF F N N N 00 CHH N N 0 N 0- H F F N Ho -O N H-22 WO 2012/009217 PCT/US201 1/043330 F & N HO 'N -- NN HOHO H N N H H - <-s - N -N HO 01 -- H H 'N N / H 0 H 3 0/ H N X N o )= N _ HO CH 3 NHo / I N - HO N NN H o_' H Ol NN -HC- HO 'Nl N \ H oN N NN HO N Ho 00 N ~N H H H O

H

3 C,, N N HO N HO IN HO

H

3 0 N~~ N / HH H rN N N N H N N-z H / -ONH N N 0O N0 N HO H -NC 100N- N -23 - WO 2012/009217 PCT/US201 1/043330 N -N HH H K I"N N-- HO F f -41HsC N / NEK HH HHC N /0

HCH

3 C H -HO N -N HO H c H F o N HO K~N N HO o J N HN H H 0 N HO 0 NN

H

1 , H N

-

N HO N H NH HOH F N( H j\ /\ N N H N N H F K N _N HO -0 N NH H F 0 N N F F K H - 24 - WO 2012/009217 PCT/US2Ol 1/043330 Examples of compounds or pharmaceutically acceptable salt thereof described herein include, but are not limited to: _________________ FSOA N 0 F3CA N0 0 H cO - 2 H H O H FC. N 0 00 F 3 C N 0 N t 0 N COHH HH OH 0- N N Ht \-CN2 HOH NN

N--O

2 N =NI 0 FN A NH I_ ) I o O" AN 0 OH N N -NN H N N / G ,Ft H

F

3 0 C N 0O F0A N Y- OH N F''~0 O NZ N N_ N N :N N OF 3 OC H0 HH FC NH F0 'N- N N N / ON H C Ni N _C NO 00 N N N H

F

3 O N 0 HF0 FN NN - OH H NNNN\

O

2 I / HANH

F

3 0,. N to- FN N N -O NA N D-O HNH NN NI \ f N5O WO 2012/009217 PCT/US201 1/043330 F3Cm N 0 N OH ~ " I N N -N NCFt H N CF N~ S / \ ,-NH Ma

F

3 C x N 0y 0OF 3 F, N F 0 O N N '~ N -Nh H H E 3 N N N-_NN F 3 ,C N~ N 0 H- <:N N C' H N~ I HO

F

3 C N 0 CO 3 Me N O N' / \ N N N\/N H MeO N N N H Cl wN -0 o Me 0 AN N ~ e~ N N H H cIl N N -0O H HH CI NI 0 I I N ~ J N -O ciN N N H me/ H 0 AN 00 OH SN N \ - O > NN - N N H NH N N N 1 N IH /NO HH H N\ N N 26 H WO 2012/009217 PCT/US201 1/043330 CIx N0 0 0 "'~ N x N OH -~N N F,0 N N H H ClN 0 F0 ' ~ N x N OH NN ~N I( \N / H CIA IN 0 0 F 0 > N xN -O N H OHH F 0 0 1 y N 0 x N - -OH NX N CN N NDC HH HH H3 N \ N N N.-O Br N3 N 0 N - OH N CN/ '\N N H, a_, N X C02H FC> N 0 N "' N x N -OH N N N N H N

CF

3

F

3 C> N 0 Me N0 O :5N- N OH N N N NI N N H H FCx N IN0 0 C02H N HN N N 0 N\ H Me _ _ _ _ _ _ _ _ _ _ _ _ _ - 27 - WO 2012/009217 PCT/US201 1/043330 ' N N H N I F F 0 xlF) N OH me N N N 0 H H 0'aCN MeO N N -Q0 N 3 ~ N \ N N N OH N N N~

F

3 C > N CO 2 H 'N N N H 1FC> N 0 N0:N -NO H O

F

3 C ,~ N CO 2 H H0 N' C,, No ' N N IN N OH H% O H

F

3

C

7 N OH z N ~ ~ "aN N ' OH H O FSCA :N OH N OH J\~0 \ '\ N H 'N N H

F

3 C N 0 FaCC N> xOH N 'N C N -N OHNH O F 3 C~ N 0 0 VOH N \\OH

F

3 C N H ' N N0 MeO) 2 C x N 0 0 F C N 'Nc N N OH I N H d N -t N0 CO 2 Me - 28 - WO 2012/009217 PCT/US201 1/043330 H0 2 C ~ N 0 0

F

3 C . N F ~' N ~N NOH I"~N H o' N _ N CO 2 Me H0 2 C F 3 0,C

F

3 C 'CNCN NO " " N H H N N C0 2 H 0 FC N 0 0 F3O N OH N N00OH H N -N 0 0 H

F

3 C N x N 0 0 H NHSo 2 Me Eta N N N O O3 N~ N 0 0 '3-> N~N NH Et"' / -N N OH NN N H Me H0 0 NN/ -N/ FaC H OHO N3 N 3 S, H <):N -N OH OICN NO HH

F

3 C w N N 0 0 > )N N 'a rooNN N O:4H H 0 H3 H

F

3 N 0x N0 0 < C -N F/ Int N N, OH H * H

FC

7 N 0 H~-~ ~ ~N 0~~ 0 '' N N 0F N N N O OH H02 - 29 - WO 2012/009217 PCT/US2011/043330 FC N 00 H F CN HO Me N H N/ S/ NNN N H N N NO 002

F

3 C ~~ N 0 00 a ~rqO NH M.0 N:3 N -NO H H

F

3 0 N 0 0 N N N OH Definitions Examples of "halogen" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. 5 The term "C-C 6 alkyl" 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, I -methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, I -ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2 10 dimethylbutyl, 1 -ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, I -ethyl-2 methylpropyl, 1-ethyl- 1 -methylpropyl, and the like. The term "-OC 1 -C 6 alkyl " 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. 15 The term "halogen-substitutedC 1

-C

6 alkyl" encompasses C 1

-C

6 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-substitutedC-C6alkyl" means a -OC-C 6 alkyl as defined above, 20 which is substituted with 1-3 halogen atoms which are identical or different, and specifically includes, for example, a trifluoromethoxy group. The term "C 1

-C

6 alkylCOOH" means a C 1

-C

6 alkyl as defined above substituted with a carboxylic acid group (COOH). The term "COOC-COalkyl" means a -COOH group wherein the -OH is replaced with an 25 alkoxy group as defined above. Examples include methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl. The term "C 3 -CI ocycloalkyl" means a monocyclic or polycyclic, saturated or partially unsaturated carbocyclic group having from 3 to 10 carbon atoms, for example, cyclopropyl, - 30 - WO 2012/009217 PCT/US2011/043330 cyclobutenyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclohexyl, bycyclodecyl, bicyclononyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and adamantly. The term "SO 2

C-C

6 alkyl" means a group having Cl-r 6 alkyl bonded to sulfonyl (-SO 2 -). 5 Specific examples thereof include methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, sec-butanesulfonyl, tert-butanesulfonyl, and the like. The term "COC.

6 alkyl" means groups having C 1

.

6 alkyl bonded to carbonyl, and encompasses alkylcarbonyl having a carbon number of I to 6. Specific examples thereof include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and the like. 10 The term "oxo" means the functional group "=O", such as, for example, (1) "C=(O)", that is a carbonyl group; (2) "S=(O)", that is, a sulfoxide group; and (3) "N=(O)", that is, an N-oxide group, such as pyridyl-N-oxide. The term "NHCI-C 6 alkyl" means a group with one of the hydrogen atoms of amino ( Nil 2 ) being substituted with a C 1 6 alkyl group. Specific examples thereof include methylamino, 15 ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino, and the like. The term "N(C 1

-C

6 alkyl) 2 " means a group with the two amino hydrogen atoms each being substituted with a C 1

.

6 alkyl group. Specific examples thereof include dimethylamino, diethylamino, ethylmethylamino, di(n-propyl)amino, methyl(n-propyl)amino, diisopropylamino, 20 and the like. The term "NHCO 2

C-C

6 alkyl" means a group with one of the amino hydrogen atoms being substituted with C 1

-

6 alkoxycarbonyl and encompasses alkoxycarbonylamino having a carbon number of 1 to 6. Specific examples thereof include methoxycarbonylamino, ethoxycarbonylamino, n-propyloxycarbonylamino, isopropyloxycarbonylamino, n 25 butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, n pentyloxycarbonylamino, and the like. The term "CONHC-C 6 alkyl" means a group with one of the hydrogen atoms of carbamoyl (-CONH 2 ) being substituted with C 1

.-

6 alkyl. Specific examples thereof include methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl, 30 sec-butylcarbamoyl, tert-butylcarbamoyl, and the like. The term "CON(CI-C 6 alkyl) 2 " means a group with the two carbamoyl hydrogen atoms each being substituted with C 1

.

6 alkyl. Specific examples thereof include dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, di(n-propyl)carbamoyl, methyl(n-propyl)carbamoyl, diisopropylcarbamoyl, and the like. 35 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 - 31 - WO 2012/009217 PCT/US2011/043330 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, firyl, thienyl, imidazolyl, 5 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, 10 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 froin 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 15 aromatic portion. Examples of "cycloheteroalkyl" include tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6 dihydroimidazo[2,1-b]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like. The term also includes partially unsaturated monocyclic rings that 20 are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted-(lH, 3H)-pyrimidine-2,4-diones (N-substituted uracils). The term also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 7 azabicyclo[2.2. I ]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.2joctyl, and 3 azabicyclo[3.2.2]nonyl, and azabicyclo[2.2.1]heptanyl. The cycloheteroalkyl ring may be 25 substituted on the ring carbons and/or the ring nitrogens. "S0 2

CI-C

6 alkyl" group means a group in which a CI-C 6 alkyl group is attached to a sulfonyl (-SO 2 -) group. Specific examples thereof include methanesulfonyl, ethanesulfonyl, n propylsulfonyl, isopropanesulfonyl, n-butanesulfonyl, sec-butanesulfonyl and tert-butanesulfonyl groups and the like. 30 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. 35 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, - 32 - WO 2012/009217 PCT/US2011/043330 estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, 5 pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, 10 magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from phannaceutically 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-diethylaminoethanol, 2 15 dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucaniine, 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 20 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 25 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 30 synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. It will be understood that, as used herein, references to the compounds of the structural formulas described herein are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free 35 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. - 33 - WO 2012/009217 PCT/US2011/043330 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. 5 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 10 example, different isotopic forms of hydrogen (H) include protium (1 H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic formula can be prepared without 15 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 20 Also encompassed by the present invention are methods of treating DGAT 1-related diseases. The compounds described herein are effective in preventing or treating various DGATI-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, 25 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 30 delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis. The compound of the invention is especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety. One aspect of the invention described herein provides a method for the treatment and 35 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 -34- WO 2012/009217 PCT/US2011/043330 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 5 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 innediately 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 10 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 15 specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof. The treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from 20 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 25 compounds or combinations of the present invention. Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Another outcome of prevention may be decreasing the occurrence and/or severity of obesity-related 30 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, 35 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 - 35 - WO 2012/009217 PCT/US2011/043330 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 5 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 10 administering to the patient a compound in accordance with the formulas described herein or a phannaceutically 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 DGAT 1-related 15 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, 20 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 25 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. 30 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 35 into a dosage form suitable for the administration route, the compound of the invention can be used as a phannaceutical composition for the prevention, treatment, or remedy of the above diseases. -36- WO 2012/009217 PCT/US2011/043330 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 5 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, 10 hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic acid anhydride, tale, 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 15 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 20 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 i to 99.9 % by weight, preferably from I to 60 % by weight of the composition. The compositions may further contain any other therapeutically-effective compounds. 25 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 30 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 35 be adjusted to provide the optimal therapeutic response. Combination Thera -37- WO 2012/009217 PCT/US2011/043330 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 5 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 10 described herein is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of any of the formulas described herein is preferred. However, the combination therapy may also include therapies in which the compound of any of the formulas described herein and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more 15 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 20 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) 25 PPARt/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 (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 30 particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza@, Fortamet@, and GlucophageXR@; (iii) protein tyrosine phosphatase- I B (PTP- I B) 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; 35 (5) amylin and amylin analogs, such as pramlintide; (6) sulfonylurea and non-sulfonylurea insulin secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide; - 38 - WO 2012/009217 PCT/US2011/043330 (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 5 receptor agonists, such as exenatide, liraglutide, taspoglutide, AVE0010, CJC-l 131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof; (10) LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, 10 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; 15 (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, 20 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 I 1-hydroxysteroid dehydrogenase type 1, such as those disclosed in U.S. Patent No. 6,730,690; WO 03/104207; and WO 04/058741; 25 (17) inhibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib and MK-08 59; (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 (ACCI or ACC2); (20) AMP-activated Protein Kinase (AMPK) activators; 30 (21) agonists of the G-protein-coupled receptors: GPR-109, GPR- 119, and GPR-40; (22) SSTR3 antagonists, such as those disclosed in WO 2009/011836; (23) neuromedin U receptor agonists, such as those disclosed in W02009/042053, including, but not limited to, neuromedin S (NMS); (24) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD); 35 (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 isoforns, such as SGLT-1; SGLT-2, such as dapagliflozin and remogliflozin; and SGLT-3; -39- WO 2012/009217 PCT/US2011/043330 (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 (MGAT-1 and 5 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 10 the formulas described herein include, but are not limited to, sitagliptin (disclosed in US Patent No. 6,699,871), vildagliptin, saxagliptin, alogliptin, denagliptin, carmegliptin, dutogliptin, melogliptin, linagliptin, and pharmaceutically acceptable salts thereof, and fixed-dose combinations of these compounds with metformin hydrochloride, pioglitazone, rosiglitazone, simvastatin, atorvastatin, or a sulfonylurea. 15 Other dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of any of the formulas described herein include, but are not limited to: (2R,3S,5R)-5-(1 -methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1 H)-yl)-2-(2,4,5 trifluorophenyl)tetrahydro-2H-pyran-3-amine; (2R,3S,5R)-5-(1 -methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)-2-(2,4,5 20 trifluorophenyl)tetrahydro-2H-pyran-3-amine; (2R,3S,5R)-2-(2,5-difluorophenyl)tetrahydro)-5-(4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl) tetrahydro-2H-pyran-3-amine; (3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-hexahydro-3-methyl-2H-1,4-diazepin 2-one; 25 4-[(3R)-3-amino-4-(2,5-difluorophenyl)butanoyl]hexahydro-1-methyl-2H-1,4-diazepin-2-one hydrochloride; and (3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-hexahydro-3-(2,2,2-trifluoroethyl)-2H-1,4 diazepin-2-one; and pharmaceutically acceptable salts thereof 30 Antiobesity compounds that can be combined with compounds of any of the formulas described herein include topiramate; zonisamide; naltrexone; phentermine; bupropion; the combination of bupropion and naltrexone; the combination of bupropion and zonisamide; the combination of topiramate and phentermine; fenfluramine; dexfenfluramine; sibutramine; lipase inhibitors, such as orlistat and cetilistat; melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists; CCK-1 35 agonists; melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Y I or Y5 antagonists (such as MK-0557); CB 1 receptor inverse agonists and antagonists (such as rimonabant and taranabant); P3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (such as -40- WO 2012/009217 PCT/US2011/043330 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 5 and K. Lee, "Emerging antiobesity drugs," Expert Opin. Emerging Drugs, 8: 217-237 (2003); JA. 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 10 formulas described herein include, but are not limited to: N-[4-((1S)-1-{3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]- 1H-pyrazol- 1 yl}ethyl)benzoyl]-p-alanine; N-{4-(( R)-1- {3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-IH-pyrazol-1 yl} ethyl)benzoyl]-p-alanine; 15 N-(4-{ 1-[3 -(2,5 -dichlorophenyl)-5-(6-methoxy-2-naphthyl)- I H-pyrazol- 1 -yl]ethyl} benzoyl)-p alanine; N-(4-{(IS)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1 yl]ethyl} benzoyl)-p-alanine; N-(4-{(1S)-1-[(R)-(4-chlorophenyl)(7-fluoro-5-methyl-1H-indol-3-yl)methyl]butyl}benzoyl)-0 20 alanine; and N-(4-{(IS)-1-[(4-chlorophenyl)(6-chloro-8-methylquinolin-4-yl)methyl]butyl}benzoyl)-p alanine; and pharmaceutically acceptable salts thereof Inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) that can be used in 25 combination with the compounds of any of the formulas described herein include, but are not limited to: [5-(5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2 -yl)-2H-tetrazol-2 yl]acetic acid; (2'- {4- [2-(trifluoromethyl)phenoxy]piperidin- 1 -yl} -2,5'-bi- 1,3 -thiazol-4-yl)acetic acid; 30 (5-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]isoxazol-5-yl}-2H-tetrazol-2-yl)acetic acid; (3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl}-1H-pyrrol-1-yl)acetic acid; (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrazin-2-yl}-2H-tetrazol-2-yl)acetic acid; and 35 (5-{2-[4-(5-bromo-2-chlorophenoxy)piperidin-1-yl]pyrimidin-5-yl}-2H-tetrazol-2-yl)acetic acid; and pharmaceutically acceptable salts thereof - 41- WO 2012/009217 PCT/US2011/043330 Glucokinase activators that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to: 3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-I -methyl-ethoxy)-N-(1-methyl-iH-pyrazol-3 yl)benzamide; 5 5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-iH-pyrazol 3-yl)benzamide; 5-(1 -hydroxymethyl-propoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-iH-pyrazol-3 yl)benzamide; 3-(6-methanesulfonylpyridin-3-yloxy)- 5 -(1-methoxymethyl-propoxy)-N-(1-methyl-l-pyrazol 10 3-yl)benzamide; 5-isopropoxy-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl1iH-pyrazol-3-yl)benzamide; 5-(2-fluoro- I -fluoromethyl-ethoxy)-3 -(6-methanesulfonylpyridin-3 -yloxy)-N-(1 -methyl-lH pyrazol-3-yl)benzamide; 3-({4-[2-(dimethylamino)ethoxy]phenyl }thio)-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl 15 41H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide; 3-({4-[(I -methylazetidin-3-yl)oxy]phenyl}thio)-N-(3-methyl- 1,2,4-thiadiazol-5-yl)-6-[(4-methyl 4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide; N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H- 1,2,4-triazol-3-yl)thio]-3- {[4-(2-pyrrolidin 1-ylethoxy)phenyl]thio}pyridine-2-carboxamide; and 20 3-[(4-{2-[(2R)-2-methylpyrrolidin-1-yl]ethoxy}phenyl)thio-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4 methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide; 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: 25 rac-cis 5-chloro-2-{4-[2-(2-{[5-(methylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl] piperidin-1 yl}pyrimidine; 5-chloro-2- {4- [(1 R,2S)-2-(2- { [5-(methylsulfonyl)pyridin-2-yl] oxy) ethyl)cyclopropyl]piperidin 1-yl}pyrimidine; rac cis-5-chloro-2-[4-(2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1 30 yl]pyrimidine; 5 -chloro-2- [4-((1 S,2R)-2- {2- [4-(methylsulfonyl)phenoxyjethyl} cyclopropyl) piperidin- 1 yl]pyrimidine; 5 -chloro-2- [4-((1 R,2S)-2- {2- [4-(methylsulfonyl)phenoxyl ethyl } cyclopropyl) piperidin-1 yl]pyrimidine; 35 rac cis-5-chloro-2- [4-(2- {2-[3 -(methylsulfonyl)phenoxy]ethyl } cyclopropyl)piperidin- 1 yl]pyrimidine; and - 42 - WO 2012/009217 PCT/US2011/043330 rac cis -5-chloro-2-[4-(2-{2-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl) piperidin-1-yl]pyrimidine; and pharmaceutically acceptable salts thereof Selective PPARy modulators (SPPARyM's) that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to: 5 (2S)-2-({6-chloro-3-[6-(4-chlorophenoxy)-2-propylpyridin-3-yl]-1,2-benzisoxazol-5 yl } oxy)propanoic acid; (2S)-2-({6-chloro-3-[6-(4-fluorophenoxy)-2-propylpyridin-3-yl]-1,2-benzisoxazol-5 yl}oxy)propanoic acid; (2S)-2-{[6-chloro-3-(6-phenoxy-2-propylpyridin-3-yl)-1,2-benzisoxazol-5-yljoxy}propanoic 10 acid; (2R)-2-({ 6-chloro-3-[6-(4-chlorophenoxy)-2-propylpyridin-3-yl]-1,2-benzisoxazol-5 yl}oxy)propanoic acid; (2R)-2-(3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)- 1H-indol-1 yl]phenoxy}butanoic acid; 15 (2S)-2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-IH-indol-1 yl]phenoxy}butanoic acid; 2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}-2 methylpropanoic acid; and (2R)-2-(3-[3-(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)-lH I-indol-1 20 yl]phenoxy}propanoic acid; and pharmaceutically acceptable salts thereof Inhibitors of 11p -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-chlorophenyl)-trans-3-fluorocyclobutyl]-4,5-dicyclopropyl-r-4H-1,2,4-triazole;3-[1-(4 chl.orophenyl)-trans-3 -fluorocyclobutyl]-4-cyclopropyl-5-(1 -methylcyclopropyl)-r-4H- 1,2,4 25 triazole; 3-[1-(4-chlorophenyl)-trans-3-fluorocyclobutyl]-4-methyl-5-[2-(trifluoromethoxy)phenyl]-r-4H 1,2,4-triazole; 3-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 3-{4-[3-(ethylsulfonyl)propyljbicyclo[2.2.2]oct-1-yl}-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H 30 -1,2,4-triazole; 4-methyl-3- {4-[4-(methylsulfonyl)phenyl]bicyclo[2.2.2] oct-i -yl} -5- [2-(trifluoromethyl)phenyl] 4H-1,2,4-triazole; 3 -(4- {4-methyl-5 - [2-(trifluoromethyl)phenyl]-4H- 1,2,4-triazol-3 -yl } bicyclo [2.2.2] oct-i -yi)-5 (3,3,3 -trifluoropropyl)- 1,2,4-oxadiazole; 35 3-(4-f{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-5 (3,3,3-trifluoroethyl)-1,2,4-oxadiazole; -43- WO 2012/009217 PCT/US2011/043330 5-(3,3-difluorocyclobutyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-411-1,2,4-triazol-3 yl}bicyclo[2.2.2]oct-1 -yl)-1,2,4-oxadiazole; 5-(1 -fluoro- 1 -methylethyl)-3-(4- {4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1,2,4-triazol-3 yl}bicyclo[2.2.2]oct-i -yl)-1,2,4-oxadiazole; 5 2-(1,1 -difluoroethyl)-5-(4- {4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3 yl } bicyclo [2.2.2]oct- 1-yl)-1,3,4-oxadiazole; 2-(3,3-difluorocyclobutyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3 yl}bicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole; and 5-(1,1-difluoroethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3 10 yl}bicyclo[2.2.2]oct-1-yJ)-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: H F HN N ONN NH NH N N H N H N / o

/

N7N - N N 0/ 0 15 NF N F N N F H N H N 7N- 7 , N--\ -44-< /0 /0 HN -~HN

-

N FF NH NH N N H NH N 7N NXN N /0 0 0 ,and - 44 - WO 2012/009217 PCT/US2011/043330 F N NH N_ HH N NH I NN\ -o 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: 5 HO N O- N N2H OHO C0 2 H C1 N CN H H OH F N ANN

CO

2 H I> Ol CO 2 H C1 N C1 N H H OH NN I O1CO 2 H F O C0 2 H c1 N F N H H F F N tA OCO2H I O CO 2 H 'N N N CH H -45- WO 2012/009217 PCT/US2011/043330

H

3 00 F N N Co 2 H OCO2H Ci N CII N H H

HO

2 C N, A HO N 0 CO 2 H I O' CO2H F NNH H and 5 and pharmaceutically acceptable salts thereof. Inhibitors of acetyl-CoA carboxylase- I and 2 (ACC-I and ACC-2) that can be used in combination with the compounds of any of the formulas described herein include, but are not limited to: 3-{1'-[(1-cyclopropyl-4-methoxy-1H-indol-6-yl)carbonyl]-4-oxospiro[chroman- 2,4'-piperidin] 6-yl}benzoic acid; 10 5-f{ 1[(1-cyclopropyl-4-methoxy-11-indol-6-yl)carbonyl]-4-oxospiro[chroman-2,4'-piperidin]-6 yl}nicotinic acid; l'-[(I-cyclopropyl-4-methoxy-1H-indol-6-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4' piperidin]-4-one; 1'-[(1-cyclopropyl-4-ethoxy-3-methyl-1H-indol-6-yl)carbonyl]-6-(1H-tetrazol-5 15 yl)spiro[chroman-2,4 1 -piperidin]-4-one; and 5-{l'-[(1-cyclopropyl-4-methoxy-3-methyl-iH-indol-6-yl)carbonyl]-4-oxo-spiro[chroman-2,4' piperidin]-6-yl.} nicotinic acid; and pharmaceutically acceptable salts thereof. In another aspect of the invention, a pharmaceutical composition is disclosed which comprises 20 one or more of the following agents: (a) a compound of any of the structural formulas described herein; (b) one or more compounds selected from the group consisting of: (1) dipeptidyl peptidase-IV (DPP-4) inhibitors; (2) insulin sensitizers, including (i) PPARy agonists, such as the glitazones (e.g. 25 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 (SPPARyM's), and (4) PPARy partial agonists; (ii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin - 46 - WO 2012/009217 PCT/US2011/043330 hydrochloride, and extended-release formulations thereof, such as Glumetza@, Fortamet@, and GlucophageXR@; (iii) protein tyrosine phosphatase- I B (PTP- 1 B) inhibitors; (3) sulfonylurea and non-sulfonylurea insulin secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide; 5 (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, 10 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; 15 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, 20 ramipril, captopril, quinapril, and tandolapril), A-IL receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta blockers (such as and calcium channel blockers (such as; (11) glucokinase activators (GKAs), such as LY2599506; (12) inhibitors of I I -hydroxysteroid dehydrogenase type 1; 25 (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; 30 (17) agonists of the G-protein-coupled receptors: GPR-109, GPR- 119, and GPR-40; (18) SSTR3 antagonists; (19) neuromedin U receptor agonists, including, but not limited to, neuromedin S (NMS); (20) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD); (21) GPR-105 antagonists; 35 (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; -47- WO 2012/009217 PCT/US2011/043330 (23) inhibitors of acyl coenzyme A:diacylglycerol acyltransferase I and 2 (DGAT-1 and DGAT-2); (24) inhibitors of fatty acid synthase; (25) inhibitors of acetyl-CoA carboxylase- 1 and 2 (ACC-l and 5 ACC-2); (26) inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2); (27) agonists of the TGRS receptor (also known as GPBAR1, BG37, GPCRl9, GPR13 1, and M-BAR); and 10 (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 15 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 20 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 25 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. 30 Scheme 1 - 48- WO 2012/009217 PCT/US2011/043330 R NH Oxone* o NF 1 NH 2 0 NH X=F or C1 HN :" base / N KR R-- N H The following is a list of abbreviations used in the description of the synthesis of the 5 Intermediates and Examples shown below. List of Abbreviations: Alk = alkyl Ar = aryl 10 Boc = tert-butoxycarbonyl Cbz = carbobenzyloxy

CH

2 Cl 2 = dichloromethane CoA = Coenzyme A dba = dibenzylidineacetone 15 DIPEA = diisopropylethylamine DMA = dimethylacetamide DMF = dimethylformamide DMSO = dimethyl sulfoxide ESI = electrospray ionization 20 Et = ethyl EtOAc = ethyl acetate HOAc = acetic acid LC-MS = liquid chromatography-mass spectroscopy LiOH = lithium hydroxide 25 Me = methyl MeOH = methyl alcohol MgSO4 = magnesium sulfate MS = mass spectroscopy - 49 - WO 2012/009217 PCT/US2011/043330 MTBE = methyl tert-butyl ether NaOH = sodium hydroxide Na 2

SO

4 = sodium sulfate NMR = nuclear magnetic resonance spectroscopy 5 Ph = phenyl r or RT = room temperature TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran 10 Intermediate 1.

F

3 C N ~rN N H 2-(6-fluoropyridin-3-yl)-5-(trifluoromethl)-IH-benzimidazole 15 Step 1. Following the recommendations presented in Beaulieu, P. L.; Hach6, 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-diamine (2.8 g) and Oxone* (6.39 g) in DMF and water. The mixture was cooled in an ice bath during the addition and allowed to warm to reaction once the addition of aldehyde was complete. The reaction was 20 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. 25 / Cl N N H 5-chloro-2-(6-chloropyridin-3-y)-IH-benzimidazole Step 1. Following the recommendations presented in Beaulieu, P. L.; Hachd, B. and von Moos, E. Synthesis, 2003, 11, 1683: a solution of 2-chloropyridine-5-carboxaldehyde (0.60 g) in DMF 30 was added dropwise to a suspension of 4-chlorophenylene-1,2-diamine (0.57 g) and Oxone* (1.6 g) in DMF and water. The mixture was cooled in an ice bath during the addition and allowed to warm to reaction once the addition of aldehyde was complete. The reaction was stirred open to air at room temperature for 45 minutes. To the reaction was added water and the mixture was - 50 - WO 2012/009217 PCT/US2011/043330 brought to pH 7 by the addition of solid potassium carbonate. The resulting light brown solid was filtered and dried in vacuo. [MH]* m/z 264.0. 5 Intermediate 3. F N N4 H 5-chloro-2-(6-chloro-5-fluoropyridin-3-yl)-1 H-benzimidazole This compound was prepared using the same protocols as described for Intermediate 1. 10 Intermediate 4. SN F MeO N N N H 2-(6-fluoropyridin-3-yl)-5-methoxy-3H-imidazo[4,5-blpyridine This compound was prepared using the same protocols as described for Intermediate 1. 15 Intermediate 5 F F3C Br N NN H 2-(6-bromo-5-fluoropyridin-3 -yl)-5-(trifluoromethyl)- I H-benzo[djimidazole Step 1._4-(trifluoromethyl)benzene-1,2-diamine (44.0 mg, 1.1 equiv), 6-bromo-5 fluoronicotinaldehyde (50 mg, 1 equiv) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium 20 hexafluorophosphate (130 mg, 1 equiv) were combined in anhydrous DMF. To the solution, DIEA (0.119 mL, 3 equiv) was added and the mixture was stirred at room temperature for 2 hours. The solution was diluted with ethyl acetate and washed with saturated ammonium chloride, then water then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give N-(2-amino-4-(trifluoromethyl)phenyl)-6-bromo-5 25 fluoronicotinamide as a viscous brown oil: [MH] 4 rn/z 379. Step 2. Acetic acid was added to N-(2-amino-4-(trifluoromethyl)phenyl)-6-bromo-5 fluoronicotinamide obtained in step 1, and the solution was irradiated in a microwave reactor at 180 "C for 40 min. The solution was diluted with 40% acetonitrile-water (4 mL) and purified by - 51 - WO 2012/009217 PCT/US2011/043330 reverse phase HPLC to give 2-(6-bromo-5-fluoropyridin-3-yl)-5-(trifluoromethyl)-1H benzo[d]imidazole as a tan solid: [MH] m/z 361. Intermediate 6. 0 0 5 HN

-

CO

2 H 3-oxo-3H-spirof2-benzofuran-1,4'-piperidinel-5-carboxylic acid Step 1. 4-bromobenzene-1,3-dicarboxylic acid (600 mg, 1 equiv) was taken up in THF (12 mL) and cooled to -78 'C. A 2.5 M solution of 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 10 oxopiperidine-1-carboxylate (488 mg, 1 equiv) was added dropwise over 10 minutes as a solution in THF. The final concentration was 0.15 M. After 2 hours, the reaction mixture was warmed to room temperature, acidified to pH - 0 with I M 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' 15 (tert-butoxycarbonyl)-3-oxo-3H-spiro[2-benzofuran-1,4 t -piperidine]-5-carboxylic acid as a white oil: [MH-Boc]* m/z 248. Step 2. The residue from Step 1 (79 mg, 1 equiv) was reconstituted in dichloromethane (40 mL) and trifluoroacetic acid (3:1) and stirred for 18 hours at room temperature. Concentration and 20 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: [MH]* m/z 248. Intermediate 7. 0 0 25 HN N- Br 3-bromo-5H-spiro[furof3,4-b]pyridine-7,4 1 -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) 30 was added rapidly forming a brown-black gel. After 10 minutes, the reaction was quenched by addition of methanol (5.9 mL, 7 equiv) then 50% aqueous acetic acid (16.7 mL, 7 equiv) and warmed to room temperature and stirred for 24 hours. The mixture was poured into toluene, washed with water, IN HC then IN NaOH. The organic layer was dried on sodium sulfate and - 52 - WO 2012/009217 PCT/US2011/043330 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. 5 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 [MH]* m/z 283. Intermediate 8. 0 OH N 10 0 N 2-(3-(5-formylpyridin-2-yl)-3-azaspirof5.5]undecan-9-yl)acetia 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, I equiv) were stirred at 80 *C in NMP (12 mL) for 5 hours. The mixture was cooled to room temperature, acidified with 15 1 M HCl (25 mL, 4 equiv), diluted with water, and extracted with dichloromethane. The combined organic layers were concentrated in vacuo and purified by silica gel chromatography (0% acetone:dichloromethane to 50% acetone:dichloromethane) to give the pure aldehyde as a white solid: [MH]* m/z 317. 20 Intermediate 9. MeO 2 C

CIH

2 N O CO2Me methyl 442-methoxy-2-oxoethll-3,4-dihydrospiro[chromene-2,4'-piperidinej-6-carboxylate 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 25 room termperature and the slurry stirred for 30 minutes. The reaction mixture was cooled to 0 *C and 1tert-butyl-6-methyl 4-oxo-3,4-dihydro-1'H-spiro~chromene-2,4'-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. 30 Extraction with dichloromethane and concentration gave an oil that was purified by silica gel column chromatography (hexanes to ethyl acetate) to give the desired product as an oil. - 53 - WO 2012/009217 PCT/US2011/043330 Step 2. Material from Step 1 (226 mg, 1 equiv) was dissolved in ethanol (2 mL) and added to 30% Pd/C (125 mg, 35 mol%) then stirred at room temperature under an atmosphere of hydrogen for 4 hours. Filtration through Celite, concentration in vacuo, and purification by silica gel column chromatography (hexanes to ethyl acetate) gave the desired product as a clear oil. 5 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 kL) was added and the temperature raised to 60 'C for 1 hour. Removal of volatiles in vacuo gave the desired hydrochloride salt as a white solid: [MH]* m/z 334. 10 Intermediate 10. 0 0 0 OMe tert-butyl 9-(2-rnethoxy-2-oxoethoxy)-3-azaspiro(5.5]undecane-3-carboxylate Step 1. Sodium borohydride (139 mg, 1 equiv) was added to a methanol solution of tert-butyl 9 15 oxo-3-azaspiro[5.5]undecane-3-carboxylate (980 mg, 1 equiv) and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the solution and the mixture was diluted with dichloromethane. The organic layer was separated and washed with water then brine then dried over sodium sulfate, filtered and concentrated in vacuo to give 950 mg of tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate: [MH]* m/z 270. 20 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-bromoacetate (0.070 mL, 1.5 equiv) and the solution was warmed to room temperature over 1 hour and then heated at 50 *C 25 for 1 hour. The solution was cooled to room temperature, diluted with 40% acetonitrile in water then directly purified by preparative HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) to give the product as an off-white solid: [MH]* m/z 342. Example 1. F3C N 0 N N ~' N NN H 30

C

2 H - 54 - WO 2012/009217 PCT/US2011/043330 Step 1. Copper (I) 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 5 quenched by addition of 1 M HCI (1 mL, 10 equiv) and extracted twice with MTBE. The combined organic layers were concentrated in vacuo. Step 2. The residue from Step 1 was dissolved in 1 M solution of HCl in 1,4-dioxane (400 gL, 4 equiv) and the mixture stirred at room temperature for 4 hours to effect removal of the Boc 10 group. Concentration in vacuo gave a crude residue which was carried forward without further purification. Step 3. To the residue from Step 2 was added sodium bicarbonate (42 mg, 5 equiv), 2-(6 fluoropyridin-3-yl)-5-(trifluoromethyl)-1H-benzimidazole (28 mg, I equiv), and NMP (330 piL). 15 The mixture was stirred at 120 'C for 22 hours. The reaction was neutralized by addition of acetic acid (23 gL, 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 IM NaOH and 20 further extracted with ethyl acetate. Table 1.

F

3 C N N NF N [MH]* [MH] t [MH]* [MH]* Example R m/z m/z Example R m/z m/z cale'd found calc'd found 1 552 552 8 CF 3 563 563 ____o -- \00 2 H __ _ _N___ 0 2 O2H 594 594 9 - / Me 508 508 ____ 0~0 2 H _ _ _ _ _ _ Me 3

C

2 H 568 568 10 508 508 4 580 580 11 CF 3 562 562 5C 2 Et - 55 - WO 2012/009217 PCT/US2011/043330 - OH

F

3 C 5 592 592 12 562 562 -N 6 CN 519 519 13 495 495 MeO 2 C 7 _ / NO 2 539 539 14 552 552 Example 15. CI N O 0 N H 5 5-chloro-2-(6-chloropyridin-3-yl)-IH-benzimidazole (123 mg, 1 equiv), Hunig's base (408 [L, 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 10 using gradient elution (20% ethyl acetate:hexanes to 100% ethyl acetate). The title compound was obtained as a pale yellow solid: [MH]* m/z 431. Examples 16-56 (Table 2) were prepared according to the procedure described above or one of the variations described below. 15 Procedure A A 5-substituted-2-(6-chloropyridin-3-yl)-1HU-benzimidazole (1 equiv), Hunig's base (5 equiv) and the amine (1 equiv), as a hydrochloride or trifluoroacetate salt, were dissolved in DMA (0.3 M) and heated at 140 *C in a microwave until complete as judged by LCMS analysis (10-60 hours). 20 If the conversion of starting materials to products was low within 3 hours (LCMS analysis), the reaction temperature was increased to 200 0 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, 25 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 - 56 - WO 2012/009217 PCT/US2011/043330 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 5 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 -yl)- I H-benzimidazole 10 (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. 15 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 20 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 25 Performed as in Procedure A except A 5-chloro-2-(6-chloro-5-fluoropyridin-3-yl)-H benzimidazole (1 equiv) was used as electrophile. Procedure F Performed as in Procedure D except the product was saponified with aqueous sodium hydroxide 30 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. 35 Table 2. Example Structure Jm/z [M/z procedure -57- WO 2012/009217 PCT/US201 1/043330 calc'd found C -, N 0 1 ' \ N 16 N N N 417 417 A H CI> N00 x \\ N 17 ' -CN N 432 432 B HN CI> N00 N \' N 1N N 432 432 A 18 H N 19 >1N N432 432 A H/

F

3 C> N 0 0 I\ N 20 < ' N 466 466 D H N\ C I N 0 0 I N 21 N NN 432 432 A C N 0 N 22 ~ -N N ~ 435 435 B H C I N 0 N N N 23 H 475 475 B OH 24N449 449 E N - N 25N N -544 544 C 25 H N\ - 58 - WO 2012/009217 PCT/US2011/043330

F

3 G N 0 26 F NN 509 509 C H ________ C0 2 H _ _ _ _ F3C N 0 F3CN O O 27 N H N 463 463 H

F

3 C N oMe 30I N 54 54N MeO~ ~ \ N42 49D 28 FC NC 465 465 C H F3C3 N 0 HN N-9 29 H N\ 480 480 C F 3 C~ N0 'N N N~ 30 H N\ 514 514 C CI _______ ~Me _ _ _ _ _ MeO N NH 0 / / N 31N429 429 D' N~

F

3 C ~- N C0 2 H N 32 N \N> 493 493 D' H

F

3 C N C0 2 H \\ N 33 Nc N- N 499 499 D H 0

F

3 0 x N OH 34 N473 473 D ~- N -OH 35 N405 405 D' -59- WO 2012/009217 PCT/US2011/043330 36 .. . N O H 459 459 D

F

3 C N 509 509 D 37 N, N N H AO__ __________ MeO2C F3C N 595 595 D 3581 581 F N 40 F 3 C NN 567 567 F 1F 3 C N H 523 523D NN NH2Me 5 60 42 I N OH 523 523 D N NN H 44 F 3 0 N o 51 51 N N 0 NS 2 Me 45 N N NH58 52 H 44~~ ~ ~ 60C N- 2 2 WO 2012/009217 PCT/US2011/043330 F3CX NH NCN 46 F3 N NF 525 525 D

F

3 CN N K N N N 48 H NK 536 536 C CO2

F

3 CN NNO 4N N K 538 538 C 48H / CO2H

F

3 CC N0 50 FN NH 418 418 D 51 F3C NN OH 476 476 F 52 FC N -N OH 504 504 F

F

3 C N N 53 504 524 D H ~~OH ____ CN N 54 H 488 488 D HOH 5 F3C NN O OH 489 489 F HO Example 56. - 61 - WO 2012/009217 PCT/US2011/043330 F C NNO0 O N 'N N H Step 1. Cesium carbonate (337 mg, 1.4 equiv), Pd 2 (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-1,4'-piperidin]-3-one 5 (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-1'H,3H-spiro[2 benzofuran-1,4'-piperidin]-1'-yl)benzaldehyde: [MH]* mn/z 326. 10 Step 2. Next, a solution of 3-fluoro-4-(3-oxo-l'H,3H-spiro[2-benzofuran-1,4-piperidin]-1' yl)benzaldehyde (11 mg, 1 equiv), Oxone* (13 mg, 0.65 equiv), and 4-chlorophenylene-1,2 diamine (5 mg, 1 equiv) in 1.4 mL DMF-water (30:1) was stirred open to air at room temperature. After 2 hours, water was added and the mixture was extracted with ethyl acetate. 15 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: [MH] 4 m/z 448. Example 57. HF 0 20 F3N To a vial containing ethyl 2-(3-azaspiro[5.5]undecan-9-yl)acetate (50 mg, I equiv) was added (BrettPhos)palladium(II) phenethylamine chloride (CAS: 1148148-01-9, 33.4 mg, 20 mol%) and 2-(4-bromo-2-fluorophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (75 mg, 1 equiv). The 25 vial was capped under nitrogen then THF (1 mL) was added through the septum and the suspension was sparged with nitrogen for 5 minutes. Then, a 1.7 M solution of potassium tert butoxide in THF (381 pL, 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 vacuo. The residue was 30 dissolved in a mixture of acetic acid and DMSO and purified by preparative reverse phase HPLC (10% acetonitrile:water with 0.05% TFA to 90% acetonitrile:water with 0.05% TFA) to give the pure product as a solid: [MH]* mI/z 490. - 62 - WO 2012/009217 PCT/US2011/043330 Example 58. 0

F

3 C N N- OH C N N\/ NC H Step 1. 2-(3-(tert-butoxycarbonyl)-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 5 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 I M 10 HCl. Extraction first with ether then with ethyl acetate gave an organic fraction that was washed four times with water, then dried on anhydrous sodium sulfate, filtered and concentrated in vacuo to give an orange solid that was carried forward crude: [MH]* m/z 318. Step 3. The aldehyde from Step 2 (50 mg, 1 equiv), 4-(trifluorometbyl)benzene-1,2-diamine (28 15 mg, 1 equiv) and Oxone* (63 mg, 0.65 equiv) were weighed to a vial. To this was added DMF (254 [tL) and water (10 ptL) 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 20 70% acetonitrile:water with 0.05% TFA) to give the pure product as a brown solid: [MH]* m/z 474. Example 59. 0 N N OH Nl Nz S o F NH 25 Step 1. 2-(3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid (208 mg) was taken up in dioxane (2 mL) to which was added a 4 M solution of hydrochloric acid in dioxane (1 mL, 6 equiv). The mixture was heated at 60 0C for 1.5 hours then concentrated in vacuo. Step 2. To the residue from Step I was added solid sodium bicarbonate (281 mg, 5 equiv) and 2 30 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 - 63 - WO 2012/009217 PCT/US2011/043330 final volume of 6 mL. The resulting orange solution was carried forward to subsequent reactions assuming a concentration of 0.11 M: [MH] t m/z 323. Step 3. The aldehyde solution from Step 2 (1 mL, 1 equiv), 4-(trifluoromethyl)benzene-1,2 5 diamine (19.4 mg, 1 equiv) and Oxone* (43 mg, 0.64 equiv) were weighed to a vial. To this was and water (32 pL) and the mixture stirred at room temperature for 16 hours. The reaction was quenched by the addition of a few drops of saturated sodium thiosulfate then the mixture was diluted with DMSO, filtered and purified by preparative reverse phase HPLC (20% acetonitrile:water with 0.05% TFA to 70% acetonitrile:water with 0.05% TFA) to give the pure 10 product as a pale yellow solid: [MHJ] m/z 479. The compounds presented in Table 3 were prepared by a similar method. Table 3. [MH]*+ [MR]* Example Structure n/z m/z calc'd found 0 N OH 60 N S 511 511

F

3 CS / NH 0 N OH I N 61 N_ 459 459 NH CI_ Me 15 Example 62. F 0

F

3 C N OH ~~-N H Step 1._4-(trifluoromethyl)benzene-1,2-diamine (44.0 mg, 1.1 equiv), 6-bromo-5 fluoronicotinaldehyde (50 mg, I equiv) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium 20 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 - 64 - WO 2012/009217 PCT/US2011/043330 hours. The solution was diluted with ethyl acetate and washed with saturated ammonium chloride, then water then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give N-(2-amino-4-(trifluoromethyl)phenyl)-6-bromo-5 fluoronicotinamide as a viscous brown oil: [MH]* n/z 379. 5 Step 2. Acetic acid was added to N-(2-amino-4-(trifluoromethyl)phenyl)-6-bromo-5 fluoronicotinamide obtained in step 1, and the solution was irradiated in a microwave reactor at 180 'C for 40 minutes. The solution was diluted with 40% acetonitrile-water (4 mL) and purified by reverse phase HPLC to give 2-(6-bromo-5-fluoropyridin-3-yl)-5-(trifluoromethyl)-1H 10 benzo[d]imidazole as a tan solid: [MH]* m/z 361. 2-(6-bromo-5-fluoropyridin-3-vl)-5-(trifluoromethyl)-1H-benzo[dlimidazole (9 mg, 1 equiv), methyl 2-(3-azaspiro[5.5]undecan-9-vl)acetate (5.6 mag 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 15 cooled, diluted with a mixture of DMSO:acetonitrile:water and purified by preparative HPLC (20% acetonitrile:water with 0.05% TFA to 70% acetonitrile:water with 0.05% TFA). Fractions containing m/z 491 or 505 by :LCMS analysis were pooled and concentrated. The residue was dissolved in a mixture of 1:1:1 THF-methanol-water to which was added solid lithium hydroxide (1.8 mg, 10 equiv). The mixture was stirred at room temperature for 30 minutes at which point 20 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: [MH] t m/z 491. 25 Example 63.

F

3 C NN 00 I " N ~' N N H N\ I HO A 5-trifluoromethyl-2-(6-fluoropyridin-3-yl)-1H-benzimidazole (30 mg, 1 equiv), Hunig's base (93 pL, 5 equiv) and the hydrochloride salt of 2-methoxy-5H-spiro[furo[3,4-b]pyridine-7,4' piperidin]-5-one (29 mg, 1 equiv) were dissolved in DMA (0.3 M) and heated at 150 *C in a 30 microwave until for 8 hours. The mixture was cooled to room temperature, put under vacuum to remove residual Hunig's base, diluted with DMSO and purified by preparative reverse phase HPLC (30% acetonitrile:water with 0.05% TFA to 95% acetonitrile:water with 0.05% TFA) to give the pure demethylated product: [MH]+ m/z 482. -65- WO 2012/009217 PCT/US2011/043330 Example 64. 0 > N - "-OH MeO N N N H [3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undec-9-yl]acetic acid (120 mg, 4.5 equiv) was 5 dissolved in dioxane (2 mL) and a 4 M solution of hydrochloric acid (300 [L, 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 'H NMR indicated complete removal of the Boe group. Volatiles were removed in vacuo and to the white solid was added 2-(6 fluoropyridin-3-yl)-5-methoxy-3H-imidazo{4,5-b]pyridine (25 mg, 1 equiv), sodium bicarbonate 10 (36 mg, 5 equiv) and NMP (330 kL). The reaction mixture was heated at 110 *C for 18 hours, neutralized with acetic acid (15 pL, 3 equiv), diluted with DMSO and purified by preparative reverse phase HPLC (10% acetonitrile:water with 0.05% TFA to 50% acetonitrile:water with 0.05% TFA) to give the pure product: [MH] m/z 436. 15 Examples 65-77. Me0 N - OH ~ N Me N N H To a mixture of Oxone* (9 mg, 1 equiv) and 3,5-dimethylphenylenediamine (10 mg, I equiv) was added the hydrochloride salt of [3-(5-formylpyridin-2-yl)-3-azaspiro[5.5]undec-9-yl]acetic acid (30 mg, 1 equiv), as a solution in 3% acetic acid-DMF (I mL). The mixture was stirred at 20 100 *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. 25 Table 4 RO H [MH]* [MH]* [ MH]* [MH]* Example R m/z m/z Example R m/z m/z calc'd found -66- WO 2012/009217 PCT/US2011/043330 Me F 65 \- 433 433 72 N>- 441 441 M>N F& N H H x N F . N \> 41-9 66 Me> N 419 419 73 F 3 F N r')N H __ _H _ _ _ _ C1 Me 67 473 473 74 \ 420 420 ciN N H H Me 68 C1439 439 75 434 434 C N 71 -- 57 50 785 N N F456- 434 CO2H HNe N 69 F C423 423 76 NF >!, 420 420 _ _ _H _ _ _ _ _H_ _ _ _ Boc-N 70 F3C- IC C H 551 551 Nix F71 507 507 78 N N 456 456

F

3 C ,. N H Intermediate 11.

-C

2 H Boc-Na 0 methyl [9-(tert-butoxyarbonyl I -oxa-9-azaspiro[5.51undec-4-yllacetate 5 Step 1. NN-dimethyl-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 vacuo and the residue dissolved in diethyl ether (40 mL) then cooled to -78 0 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 10 quenched by addition of saturated sodium bicarbonate (25 mL) and warmed to room temperature. The biphasic mixture was transferred to a separatory fuinel with enough water to dissolve all solids and extracted with ethyl acetate thrice. The combined organic layers were dried on - 67 - WO 2012/009217 PCT/US2011/043330 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-1-oxa-9-azaspiro[5.5]undec-2 ene-9-carboxylate as a colorless oil. 5 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-l-oxa-9-azaspiro[5.5]undecane-9-carboxylate as an oil. 10 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[5.5]undecane-9-carboxylate from Step 2 (200 mg) was added dropwise as a 15 solution in THF (1.4 mL). The reaction was stirred at room temperature for 2 hours at which point volatiles were removed in vacuo. The mixture was poured in I 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-butyl-4-(2-methoxy-2-oxoethylidene)- 1 20 oxa-9-azaspiro(5.5]undecane-9-carboxylate as a clear oil. Step 4. tert-Butyl-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 25 reaction mixture was filtered, concentrated and concentrated and purified by flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give tert-butyl 4-(2 methoxy-2-oxoethyl)-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate as an oil. Example 79.

F

3 C N S N ~N 0 30 H 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 kL, 4 equiv) and the mixture heated at heated at 60 'C for 5 hours. Volatiles were removed under a stream of nitrogen and to the remaining white solid was added 2-(6-fluoropyridin-3-yl)-5-(trifluoromethyl)-1H-benzimidazole 35 (141 mg, 1.2 equiv), sodium bicarbonate (176 mg, 5 equiv) and NMP (1.5 mL). The suspension - 68 - WO 2012/009217 PCT/US2011/043330 was stirred vigorously at 110 'C for 16 hours, cooled, diluted with DMSO (-3 mL), neutralized with acetic acid (350 gL), filtered then purified by reverse phase HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) to give methyl (9-{5-[5-(trifluoromethyl)-1H-benzimidazol 2-yl]pyridin-2-yl}-1-oxa-9-azaspiro[5.5]undec-4-yl)acetate as a yellow oil. 5 Step 2. methyl (9-{5-{5-(trifluoromethyl)-1H-benzimidazol-2-yl]pyridin-2-yl}-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 10 diluted with DMSO (-3 mL) and water (0.1 mL), neutralized with acetic acid (400 pL), 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-yl}-1-oxa-9 azaspiro[5.5]undec-4-yl)acetic acid as a yellow oil: [MH]* m/z 475. 15 Enantiomers were separated by preparative HPLC using a Chiral Technologies 4.6 x 250 mm Chiralcel AD-H column using 25% isopropanol in supercritical carbon dioxide with an operating pressure of 100 bar, flow rate of 2.4 mL/min and temperature of 40 *C. Each enantiomer was obtained as a pale yellow solid with [MH]* m/z 475. 20 Example 80. FN OH > N N0 H Step 1. BH 3 -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[5.5]undec-3-ene-9-carboxylate (420 mg, 1 equiv) (Walters, M. A.; La, F.; Deshmukh, P.; Omecinsky, D. 0. J. Comb. Chem. 2002, 4(2), 125-130) 25 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 30 residue was then purified by silica gel chromatography (0 to 100% ethyl acetate: hexanes) to give tert-butyl-3-hydroxy- I -oxa-9-azaspiro[5.5]undecane-9-carboxylate as an amber oil: [MNa]* m/z 294. Step 2. To a solution of tert-butyl-3-hydroxy-l-oxa-9-azaspiro[5.5]undecane-9-carboxylate 35 (180 mg, I equiv) obtained from Step 1 in anhydrous THF (3 mL), under an atmosphere of - 69 - WO 2012/009217 PCT/US2011/043330 nitrogen was added N-methylmorpholine N-oxide (75.4 mg, I 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 5 resulting crude residue was purified by silica gel chromatography (0 to 100% ethyl acetate: hexanes) to give tert-butyl-3-oxo-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate as a waxy solid:

[MH-C

4

H

9

]

t m/z 214. Step 3. Performed as in Intermediate 11, Step 3, to afford tert-butyl-3-(2-methoxy-2 10 oxoethylidene)-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate: [MNa}* m/z 348 Step 4. Performed as in Intermediate 11, Step 4, except 10% Pd/C was used as the catalyst and the reaction was stirred for 18 hours at room temperature, under atmospheric hydrogen and then purified by reverse phase HPLC (10% to 50% acetonitrile in water with 0.05% TFA as eluant) to 15 give 9-(tert-butoxycarbonyl)-1-oxa-9-azaspiro[5.5]undee-3-yl]methyl acetate: [MNa]* m/z 350. Step 5. Performed as in Example 71, Step 1, except TFA was used as the acid and DCM was used as the solvent for the Boc-deprotection. Purification by reverse phase HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) gave methyl (9-{5-[5-(trifluoromethyl)-1H 20 benzimidazol-2-yl]pyridin-2-yl}-1-oxa-9-azaspiro[5.5]undec-3-yl) as an amber oil: [MH] 4 m/z 489. Step 6. Performed as in Example 71, Step 2 to give (9-{5-[5-(trifluoromethyl)-1H-benzimidazol 2-yl]pyridin-2-yl}-l-oxa-9-azaspiro[5.5]undec-3-yl)acetic acid as a tan solid: [MH)* m/z 475. 25 Example 81.

F

3 C N SN N OCDOH H OH tert-butyl 2-(2-methoxy-2-oxoethyl-l-oxa-8-azaspiro[4.51decane-8-carboxylate Step 1. 30 A 1.5 M solution of DIBAL-H in dicbloromethane (2.85 mL, 0.97 equiv) was added slowly to a solution of tert-butyl 2-oxo-l-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.125 g, 1.0 equiv) in anhydrous dichloromethane and the mixture chilled to -30_*C. After 2 hours, the mixture was allowed to warm to 0 _*C and aged for 2 hours. Saturated aqueous sodium bicarbonate (1 mL) was added followed by water (2 mL) forming a slurry. The slurry was filtered through a pad of 35 Celite via buchner funnel, rinsing twice with 5 mL of dichloromethane. The rinses were -70 - WO 2012/009217 PCT/US2011/043330 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: [MNa]* m/z 280. Step 2. 5 Methyl phosphonoacetate (217 mg, 1.1 equiv) was added to a solution of tert-butyl 2-hydroxy-1 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 animonium chloride (2 mL) and diluted with ethyl acetate. 10 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-azaspiro{4.5]decane-8-carboxylate as a colorless oil: [MNa]* m/z 336. 15 Step 3. The carbamate from Step 2 (213 mg, 1.0 equiv) was dissolved in dichloromethane (1.0 mL) and TFA (1.0 mL) and stirred at room temperature for 1 hour. Volatiles were removed in vacuo then the residue was reconstituted in dichloromethane and concentrated in vacuo again. The tan oil 20 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-yl)-5-(trifluoromethyl)- 1 H benzo[d]imidazole (47 mg, 1.0 equiv) and sodium bicarbonate (139 mg, 10 equiv) was 25 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]* ni/z 475. 30 Step 5. The ester from Step 4 (29 mg, I 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 - 71 - WO 2012/009217 PCT/US2011/043330 acidified to pH 2 with 2 M hydrochloric acid. The mixture was diluted with 40% acetonitrile in water then directly purified by preparative HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) to give the product as an off-white solid: [MH]* m/z 461. 5 Enantiomers were separated by preparative HPLC using a Chiral Technologies 4.6 x 250 mm ChiralPak IA column using 35% ethanol in heptane. Each enantiomer was obtained as a white solid with [MH]* m/z 461. Example 82.

F

3 C N N S N ~N OH 10 H Step 1. 2-(8-(tert-butoxycarbonyl)-l-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 15 powder that was carried forward in subsequent steps. Step 2. The amine salt from Step 1 (80 mg, I equiv), 2-(6-fluoropyridin-3-yl)-5 (trifluoromethyl)-1H-benzo[d]imidazole (95 mg, I 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 20 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. 25 _Table 7. R N H [MHl+ [MH]+ Example R m/z m/z calc'd found H 83 >- 427 427 C1 N H SN 84 - 393 393 -72- WO 2012/009217 PCT/US2011/043330 Example 85-86.

F

3 C NNOH F3C N OH N~- N h rN N H H Step 1. 2-(8-(tert-butoxycarbonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)acetic acid (800 mg, 1 equiv) 5 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. 10 Step 2. The amine salt from Step 1 (617 mg, I equiv), 2-(6-fluoropyridin-3-yl)-5 (trifluoromethyl)-lLH-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 15 organic layer was then washed five times with water, once with brine then dried on anhydrous sodium sulfate, filtered and concentrated in vacuo to yield a brown solid: [MHI] 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 20 [MH]* n/z 475. Step 4. Enantiomer A of the ester from Step 3 was dissolved in methanol (300 L) and THF (300 jL) 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 p.L) and concentrated in vacuo. The 25 mixture was diluted with DMSO, filtered and purified by preparative HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) to give the carboxylic acid (Enantiomer A) as a white solid: [MH] m/z 461. Step 5. Enantiomer B of the ester from Step 3 was dissolved in methanol (300 p2L) and THF (300 30 pL) to which was added 2.5 M lithium hydroxide. The reaction was stirred at 50 0C for 2 hours then quenched by the addition of glacial acetic acid (150 psL) and concentrated in vacuo. The mixture was diluted with DMSO, filtered and purified by preparative HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) to give the carboxylic acid (Enantiomer B) as a white solid: [MH]* m/z 461. 35 Intermediate 12. - 73 - WO 2012/009217 PCT/US2011/043330 0 H 0NOMe 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-allyl-4-hydroxypiperidine-l-carboxylate (2.2 g, I equiv) (Walters, M. A.; La, F.; 5 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, I 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 10 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 4-{[2 (methoxycarbonyl)prop-2-en-1-yl]oxy}-4-(prop-2-en-1-yl)piperidine-1-carboxylate as a colorless oil: [MNa]* m/z 362. 15 Step 2. tert-butyl 4-{[2-(methoxycarbonyl)prop-2-en-1-yl]oxy}-4-(prop-2-en-1-yl)piperidine-1 caiboxylate from Step 1 (340 mg, 1 equiv) in anhydrous 1,2-dichloroethane (75 mL) was combined with benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylideneldichloro (tricyclohexylphosphine)ruthenium (85 mg, 10 mol%) and the mixture was heated at 85 *C for 18 20 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-l-oxa-9-azaspiro[5.5]undecane-9 carboxylate as an oil [MINa]* m/z 334. 25 Step 3. An ethanol solution of the product from Step 2 was subjected to hydrogenation by a single pass through a Thales H-Cube Flow Hydrogenation Reactor (Jones, R. V.; Godorhazy, L.; Varga, N.; Szalay, D.; Urge, L.; Darvas, F. J Comb. Chem. 2006, 8, 110-116) using a palladium hydroxide cartridge at 50 "C and 60 bar. Volatiles were then removed in vacuo and the residue purified by preparative HPLC (10% to 98% acetonitrile in water with 0.05% TFA as eluant) to 30 give the product as an oil: [MNa]P m/z 336. - 74 - WO 2012/009217 PCT/US2011/043330 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 5 eluant) to give the TFA salt of methyl 1-oxa-9-azaspiro[5.5]undecane-3-carboxylate as an oil: [MH]* m/z 214. Example 87. F3C N 0 0 -N N O H 10 Step 1. To the amine salt from Step 4 above (60 mg, I equiv), 2-(6-fluoropyridin-3-vl)-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 15 9-(5-(5-(trifluoromethyl)-IH-benzo[d]imidazol-2-yl)pyridin-2-yl)- 1 -oxa-9 azaspiro[5.5]undecane-3-carboxylate as a tan solid: [MH]* m/z 475. Step 2. The ester from Step 1 (130 mg, 1 equiv) was dissolved in a 1:1:1 mixture of THF-water methanol and treated with lithium hydroxide (65.6 mg, 10 equiv) at room temperature for 2 20 hours. The reaction mixture was cooled in an ice bath and acidified to pH 2 with 2M hydrochloric acid. The mixture was diluted with 40% acetonitrile in water, filtered and purified by preparative HPLC (20% to 70% acetonitrile in water with 0.05% TFA as eluant) to give the product as an off-white solid: [MH]* m/z 461. 25 The compounds presented in Table 5 were prepared according to a similar method. Table 5 R N OH [MH]* [MH]* Example R m/z m/z calc'd found -75- WO 2012/009217 PCT/US2011/043330 H 88 1 427 427 H 89 411 411 _ _ _ _F N_ _ Examples 90-91. F3C N 0 F3C N 0 NNI ': N SN NOH N N OH H H Enantiomers of Example 86 were separated by preparative HPLC using a Chiral Technologies 5 4.6 x 250 mm ChiralPak IA column using 50% ethanol in heptane. Enantiomer A was obtained as a white solid with [MH]* m/z 475 and Enantiomer B was obtained as a white solid with [MHI] m/z 475. Absolute stereochemistry was arbitrarily assigned. Intermediate 13. 0 0 10 0 OMe The TFA salt of methyl 1-oxa-9-azaspiro[5.5]undecane-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 15 subsequent steps: [MH]* m/z 319. Examples 92-101 in Table 6 were prepared from Intermediate 13 in two steps. First, Intermediate 13 and the appropriate diamine were allowed to react at room temperature under influence of Oxone* in DMF and water as previously described . For examples 100-101, the 20 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. R N OH - 76 - WO 2012/009217 PCT/US2011/043330

[MH]

t [MH]+ [MHJ [MHJ Example R m/z m/z Example R nvz m/z calc'd found calc'd found H 92 E>- 421 421 97 Me449 449 Me H H C1 N N 93 />- 455 455 98 F 3 C 501 501 Et:] : >3 N H H -~N N 94N)- 493 493 99 408 408

F

3 CS N Me N N H H

NF

3 0 N 95 477 477 100 462 462

F

3 CONN N H H N N 96 >- 422 422 101 ,- 424 424 EtO C N MeO N N Potency of selected DGAT 1 inhibitors. To a 384 well assay plate was added 1 gL of a 400 pM solution of the test 5 compound in DMSO and 20 pL of a substrate mix that is 300 pM in diolein and 40 pM in oleoyl CoA in 10% ethanol. To this was added 19 gL of 1.05 gg/mL human DGATI-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 gg/mL N-ethylmaleimide-treated bovine serum albumin. The solution is incubated at room temperature for 1 hour after which 20 piL of a 90 pM 10 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcounarin solution in 90% ethanol was added. After incubation in the dark for 30 minutes at room temperature, fluorescence was measured on a Perkin Elmer Envision multilabel reader. The IC50 is determined from a 4 parameter fit of the plot of %Inhibition vs. 15 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 = [l-(fluorescence counts from test compound- average fluorescence counts from LC)/(average fluorescence counts from HC-average fluorescence counts from LC)] x 100% 20 - 77 - WO 2012/009217 PCT/US2011/043330 LC = low control = maximal inhibition by excess amount of a Merck DGATI inhibitor HC = high control = DMSO = uninhibited control Table 7. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ TExample IC 5 (nM) Example C 5 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 5 -78-

Claims (19)

1. A compound of formula J: N R G R' B C A B~ /NCK N E R" 5 HI 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-, 10 wherein if one of R, G and E is -N-, the remaining two are -CH-; R' and R' together form ring D, wherein D is selected from the group consisting of cycloalkyl and heterocycloalkyl wherein A, B, C and D are independently unsubstituted or substituted with one or more substituents selected from the group a, CI-C 6 alkyl, C 3 Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C-C 6 alkylC 3 -Ciocycloalkyl, C 1 -C 6 alkylaryl, C 15 C 6 alkylheteroaryl and C-C 6 alkylcycloheteroalkyl, wherein CI-C 6 alkyl, C 3 -C 1 ocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C)-C 6 alkylC 3 -Ciocycloalkyl, C-C 6 alkylaryl, C-C 6 alkylheteroaryl and C-C 6 alkylcycloheteroalkyl 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-C 6 alkyl, halogen 20 substitutedC-C 6 alkyl, COC-C 6 alkyl, oxo, -OH, halogen-substitutedC-C 6 alkylOH, -OCr C 6 alkyl, -Ohalogen-substitutedC 1 -C 6 alkyl, -COOH, -COOC 1 -C 6 alkyl, -Ce-C 6 alkylCOOC C 6 alkyl, -C 1 -C 6 alkylCOOH, -OC-C 6 alkylCOOH, -CN, C 1 -C 6 alkylCN, -NO 2 , NH 2 , NHC C 6 alkyl, N(C-C 6 alkyl) 2 , -NHCOOH, -NHCOOC-C 6 alkyl, -CONH 2 , -CONHCI-C 6 alkyl, CON(C-C 6 alkyl) 2 ; -CONHCrCjalkyl-N(CrCalkyl) 2 , -NHSO 2 C-C 6 alkyl, -SO 2 NH 2 , -SO 2 C 25 C 6 alkyl, C 3 -Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, C 1 C 6 alkylC 3 -C 1 ocycloalkyl, C-COalkylaryl, C 1 -C 6 alkylheteroaryl and C 1 -C 6 alkylcycloheteroalkyl.

2. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is benzene. 30

3. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is pyridine. - 79 - WO 2012/009217 PCT/US2011/043330

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, CI-C 6 alkyl, -OC-C 6 alkyl, -CN, SO 2 Me and halogen-substitutedC 1 C 6 alkyl. 5

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 10 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. 15

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. 20

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

I1. A compound of any of claims 1-7, or a pharmaceutically acceptable salt 25 thereof, wherein D is T Q wherein T is selected from the group consisting of -O-, -CH 2 -, -NRa and -NCI -C 6 alkyl-, wherein Ra is selected from the group consisting of H and C 1 -C 6 alkyl; and V, U, Q and W are independently selected from the group consisting of -N-, -C- and -CH-. 30

12. A compound of any of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein D is selected from the group consisting of: -80- WO 2012/009217 PCT/US2011/043330 o 0 0 0 0 /,N / , N NN N N NRa / 1 land wherein Ra is selected from the group consisting of H and C 1 -C 6 alkyl.

13. A compound of any one of claims 1-7, or a pharmaceutically acceptable 5 salt thereof, wherein D is selected from the group consisting of: x wherein X, Y and Z are independently selected from the group consisting of -C-, -CH-, -CH 2 , N-, -NH- and -0-. 10

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: o ~ N N o N N , and N CN

15. A compound of any of claims 1-7, or a pharmaceutically acceptable salt 15 thereof, wherein D is substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 6 alkyl, halogen-substitutedC-C6alkyl, oxo, -OH, -COOH, -COOCr. C 6 alkyl, -C 1 -C 6 alkylCOOC 1 -C 6 alkyl, -C 1 -C 6 alkylCOOH, -OC-C 6 alkylCOOH, -CN, C 1 C 6 alkylCN and -NHSO 2 C 1 -C 6 alkyl. 20

16. A compound or pharmaceutically acceptable salt thereof selected from the group consisting of: F3 N 00 Fc H ' O2H H OH -81 WO 2012/009217 PCT/US201 1/043330 F 3 0 7 tt ~ 0 a F3 N 0~f Di N- a_ N\0 N N, H CO 2 H HOH FsC~ N o 0 FtC, N N N>C THN N N NN-N H \ / E H -OH 0 F 3 C N ~ N 3 'K NH NO N N' H H / COEt H COH N 0 F 3 Cx N 00 FA l ~ ~ ~ C C, Hl ~0 O N N N H CF 3 Hf I N F H F 3 CA N a-rl 0F H F 0 I" "I F 3 C N> -OH N N N N 2 I/\ H 3 N F 3 C- N \ 0F 3 N N- -OH NCN " N Noo No -N N I- H NN N F3CA N 0-f N OH 7 NN N H NH F 3 C / N F 3 C A-I N <OH H N F 3 CS / : N FSCN N\0OH -- N IN\/CFS I H N~ S /\NH O3 0 0CF3 F 0 F 3 ~ _ F3G-O 1 N > -OH 'N N NN /N N N H H - 82 - WO 2012/009217 PCT/US201 1/043330 F 3 C N N ID rb N3 t0 'N N N N FC. N 00 H '' NN H N\ F 3 0C N 0 -- O C 2 Me N0O N NN MeO( N N N CI ' N -0 Me 0 IN \N OH XN mJN Ie N H /H CI N 0 .- N OH 'N N MN N N HH CIl N 0 0 cI 0 \ ~- N -OH N N N - N N H -y N\/ H C I N 00 N - OH 4 N Ilo\/ H H CIl N 0 0 0. -O 'N NN N N O H >- yIH XN F3 X N 0 - N -OH \ N I~\/ 'N:) N N - F, 0 N NI C cl N 0 0 0I N - N - O H ' N N 3 N N N H N s, (H %l 0 F 'N N N -x N -OH I" \/N H N N N Hc 6 F H____________________ -83 - WO 2012/009217 PCT/US201 1/043330 GIla,,N 0 O F IN N - OH H N 3 H H C k ~OH , C N F 0 c 1 l N 00 xOH ~ ~ N N ' N N N N -N -~H H F 3 C~ N 0 NN OH NN ' N -N N N( H N/ N H Br F 3 CN 00 NN N -OH - N\ N00I H Nt4 N N GO 2 H F 3 C~ N 0 xN -O N N N N H O( HH CF 3 F3CX N 0Me 0 ' ~N - OH N N N" N N H H F30x N 00 -CO 2 H FsC~ N ' \ N I N -N - N N 0 H N/ H Me _ _ _ _ _ _ _ _ _ _ _ _ FsC~ N 0 0 \ N ' N N H N F F 0 C! F X\ ND' H m e '-N H_ MeC N N -0 0aC N/\ NC / N -N 0 - N N H OH NK \ - 84 - WO 2012/009217 PCT/US201 1/043330 F 3 C N CO 2 H I N <N N -N H FC~ N 0 N N N OH H O F 3 0 N CO 2 H H "'IN N 0 'N N cN N N OH H O H E 3 C N -OH > N 0-1 ' N N N N - OH H O0 aC OH xN OH j\_O~ 0 x N N -N0 ' N N H F 3 C. N 0 F 3 C ,aN OH I N N I " "'I N D 'N-ccHN N N 0 H H O F 3 C~ N 0 0 VOH X> N OH F 3 C N H-NN0 H 'N N 0 MeO 2 C C - N 0 0 FsC~ N ci' N -N OH I"~ N H NCN -N 0CO 2 Me H0 2 0 0 0 F 3 C N N N N O I N H N N 'N0 CO 2 Me H H0 2 C N C N 0 0 F 3 ~ NN N -N OH --Nll H N d N 4 0 C0 2 H - 85 - WO 2012/009217 PCT/US2O11/043330 O F 3 C. N 0 0 F 3 0 N OH NO NPO N H N N 0 0 H F 3 0,C N ,.- N 0 0 Hx~b I HOM Et NN N N 0 0 H0M H Me H0 0 F 3 C ~. N OH N N N H O Me H F 3 C .N 7 :N F3S r O N N\N N h O H OH 0 H 0 H F 3 0 C N N - N 0 0 N N /EtON N OH) H o N N ON F3CX N H 0 0 N N-- 0 F 1 N N OH H Fsx N 0x N 0 0 N3 - N F 3 0 N NCf N N 0 0 HNO NI N 0 0 N N N H N0H FCN 0 N 0 0 HO NIC N /0~ 0 N N N O0H -86- WO 2012/009217 PCT/US2011/043330

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. 5

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. 10

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. - 87 -