AU2011282989A1 - Imidazole derivatives - Google Patents

Abstract

Described herein are compounds of 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 2012/015693 PCT/US2011/045022 IMIDAZOLE DERIVATIVES TECHNICAL FIELD The present invention is directed to novel imidazole derivative compounds. Specifically, the compounds act as 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 Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and increased health problems. As such, obesity is recognized as an upstream risk factor for many conditions such as diabetes mellitus, lipidosis and hypertension (Journal of Japan Society for the Study of Obesity, Vol. 12, Extra Edition, 2006). Although the need to treat obesity is recognized to be important, there are extremely-limited drug therapies for obesity that are currently available, and thus, the advent of novel antiobestic drugs having a more definite action and few side-effects is desired. In general, obesity is caused by the accumulation of triacylglycerol (TG) in adipose tissue which is a result of lack of exercise, intake of excessive calories and ageing. In the body there are two TG synthesis pathways, a glycerol phosphate pathway, which is present in most organs and causes de novo TG synthesis, and a monoacylglycerol pathway, which is involved principally in absorption of aliphatic acid from the small intestine. Diacylglycerol acyltransferases (DGATs, EC 2.3.1.20), which are membrane-bound enzymes present in the endoplasmic reticulum, catalyze the final step of the TG synthesis common to the two TG synthesis pathways. The final reaction consists of transferring an acyl group of acyl-coenzyme A to the 3-position of 1,2 diacylglycerol to generate TG (Prog. Lipid Res., 43.134-176. 2004 and Ann. Med., 36, 252-261, 2004). There are two subtypes of DGATs, 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 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 the small intestine, lipid accumulation in the adipose tissue and the liver, and lipid secretion from the liver. In order to carry out in vivo examination of the physiological function(s) of DGAT1 and inhibitory activity against DGAT1, DGAT1 -knockout mice deficient in DGATI at the genetic level was produced and analized. As a result, the DGAT 1-knockout mice have been found to WO 2012/015693 PCT/US2011/045022 MRL-DOUB-00045 have smaller fat masses than those of wild-type mice and became resistant to obesity, abnormal glucose tolerance, insulin resistance and fatty liver due when fed a high-fat diet (Nature Genetics,25,87-90,2000 and JCI,109,1049-1055,2002). In addition, energy expense has been reported to be accelerated in the DGATI-knockout mice; and transplantation of the adipose tissues of DGATI-knockout mice into wild-type mice has been reported to make the wild-type mice resistant to obesity and abnormal glucose tolerance, induced by a high-fat diet (JCI,111,1715-1722,2003 and Diabetes,53,1445-1451,2004). In contrast, obesity and diabetes mellitus due to a high-fat diet have been reported to worsen in mice with overexpression of DGATI in adipose tissue (Diabetes,51,3189-3195,2002 and Diabetes,54,3379-3386). From the results, DGAT1 inhibitors are likely to be therapeutic drugs with efficacy for obesity, type 2 diabetes mellitus, lipidosis, hypertension, fatty liver, arteriosclerosis, cerebrovascular disorder, coronary artery disease and metabolic syndrome, associated with the obesity. SUMMARY OF THE INVENTION Described herein are compound of formula (1): R2 H N R3 N B X Y W I or pharmaceutically acceptable salts thereof, wherein in rings A and B are selected from the group consisting of benzene, pyridine, pyrazine and pryimidine; X, Y, Z, W, V, U, R', R 2 and Rare defined herein. The compounds of formula I act as DGAT 1 inhibitors and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity. DETAILED DESCRIPTION Compounds A compound of formula (I): 2 WO 2012/015693 PCT/US2011/045022 MfRL-L)Ub-uuu4D R2 H N R3 N R B V Y W or phannaceutically acceptable salts thereof, wherein in rings A and B are selected from the group consisting of benzene, pyridine, pyrazine and pryimidine; X and Y are independently selected from the group consisting of -N- and -CH Z is -N- or C=O; W is -N-, -N(R)-, -C(R 5 )- or -0-; V and U are independently selected from the group consisting of-C(R)- and -N-; and R', R2, R, R4, R' and R are independently selected from the group a, C-C 3 Ocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C-C 6 alkylC 3

-C

1 cycloalkyl, C 1

-C

6 alkylaryl, C 1

-C

6 alkylheteroaryl and Cj

C

6 alkylcycloheteroalkyl, wherein 0 3

-C

0 rcycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C 1 -C5alkylC 3 C 1 ocycloalkyl, C-C 6 alkylary[, C 1

-C

6 alkylheteroaryl 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 hydrogen, halogen, C-C 6 alkyl, halogen-substitutedC

C

6 alkyl, COC 1

-C

6 alkyl, oxo, -OH, C 1

-C

6 alkylOH, halogen-substitutedC-C 6 alkylOH, -OCI-C 6 alkyl, Ohalogen-substitutedC-C 6 alkyl, -COOH, -COOC-C 6 alkyl, -C 1

-C

6 alkylCOOC-Cialkyl, -C CfalkylCOOH, -OC 1 -CoalkylCOOH, -CN, C 1 C-alkylCN, -NO 2 , NIH 2 , NHC-C 6 alkyl, N(C 1

-C

6 alkyl) 2 , NHCOOH, -NHCOOQ-C 6 alkyl, -CONH 2 , -CONHCI-Csalkyl, -CON(C 1

-C

6 akyl) 2 , -NHSO 2

C

1

-C

6 alkyl, S0 2

C

1

-C

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

C

6 alkylC 3

-C

1 ocycloalkyl, C 1

-C

6 alkylaryl, C 1

-C

6 alkylheteroaryl and C 1

-C

6 alkylcycloheteroalkyl. In certain embodiments of the compounds described herein, ring A and ring B are individually selected from the group consisting of pyrazine or pyrimidine. In other embodiments, ring A and ring B are individually selected from the group consisting of benzene and pyridine. In one embodiment, ring A and ring B are both benzene. In one embodiment, ring A and ring B are both pyridine. In still other embodiments of the compounds described herein, ring A is pyrazine. In another embodiment, ring A is pyrimidine. In yet another embodiment, ring A is pyridine. In still another embodiment, ring A is benzene. In still other embodiments of the compounds described herein, ring B is pyrazine. In another embodiment, ring B is pyrimidine. In yet another embodiment, ring B is pyridine. In still another embodiment, ring B is benzene. In certain embodiments, ring B is pyridine, pyrazine or pryimidine, wherein the pyridine, pyrazine or pryimidine is bonded to the two bicyclic rings of formula I via a -C-C 3 WO 2012/015693 PCT/US2011/045022 MRL-uu0s-uu45 bond. In other embodiments, ring B is pyridine wherein the pyridine is bonded to the two bicyclic rings of formula I via a -C-C- bond. In one example of the embodiments of the compounds described herein, ring A is formula II: R2 R1 nI. In certain embodiments of the compounds described herein X is independently selected from the group consisting of -N- and -CH, n one embodiment, X is -CH-. In another embodiment, X is -N-. In certain embodiments of the compounds described herein Y is independently selected from the group consisting of -N- and -CH-. In one embodiment, Y is -CH-. In another embodiment, Y is -N-. In other embodiments of the compounds described herein Z is independently selected from the group consisting of -N- and C=0. In one embodiment, Y is -N-. In another embodiment, Y is -C=0. In certain embodiments of the compounds described herein, W is -N(R)-, -C(R)- or -0-. In some embodiments, W is-N(R)-. In other embodiments, W is -C(R 5 )-. In still other embodiments, W is -0-. In yet other embodiments, W is -N-. In other embodiments of the compounds described herein, V is independently selected from the group consisting of -C(R)- and -N-. In one embodiment, V is -N-. In another embodiment, V is C(R 6 )-. In still other embodiments, V is -CH-. In other embodiments of the compounds described herein, U is independently selected from the group consisting of -C(R 6 )- and -N-. In one embodiment, U is -N-. In another embodiment, U is C(R)-. In still other embodiments, U is -CH-. Described herein are compounds of formula I wherein, R', R2, R 3 , R4, R? and R are independently selected from the group a, C 3

-C

10 cycloalkyl, aryl, heteroaryl., cycloheteroalkyl, C 1 C 6 alkylC 3 -Ciocycloalkyl, C 1 -Cralkylaryl, C]-C 6 alkylheteroaryl and C 1 -C(alkylcycloheteroalkyl, wherein

C

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

-C

6 alkylC 3

-C

1 cycloalkyl, Q-Calkylaryl, C 1 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 hydrogen, halogen, C 1 -C5alkyl, halogen-substitutedC Csalkyl, COC-C-alkyl, oxo, -OH, C 1

-C

6 alkylOH, balogen-substitutedC,-CoalkylOH, -OC-C 6 alkyl, Ohalogen-substitutedC-C 6 alkyl, -COOH, -COOC 1

-C

6 alkyl, -C 1

-C

6 alkylCOOC-C5alkyl, -C

C

6 alkylCOOH, -0C-C 6 alkylCOOH, -CN, C 1

-C

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

-C

6 alkyl) 2 , NHCOOH, -NHCOOCrC 6 alkyl, -CONH 2 , -CONHC 1 -C5alkyl, -CON(C 1 -Coalkyl) 2 , -NHSO 2

C-C

6 alkyl, SO 2

C

1

-C

6 alkyl, C 3

-C

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

C

6 alkyIC 3

-C

1 ocycloalkyl, C 1 -Cfalkylaryl, C 1

-C

6 alkylheteroaryl and C-C 6 alkylcycloheteroalkyl. In certain embodiments described herein, R', R2, R', R, R' and RW are independently selected from the group a. 4 WO 2012/015693 PCT/US2011/045022 MRL -uutsuuuq In certain embodiments of the compounds described herein, R1 and R2 are independently selected from the group consisting of hydrogen, -CN, -OC-C5alkyl, -Ohalogen-substitutedO]-C 6 alkyl, halogen and halogen-substitutedC-CO 6 alkyl. In other embodiments, R' and R2 are independently selected from the group consisting of hydrogen, halogen, -CN-, aryl, -OC-CO 6 alkyl, -Ohalogen-substitutedC-C 6 alkyl and halogen-substitutedC-C 6 alkyl. In other embodiments of the compounds described herein, R' is independently selected from the group consisting of hydrogen, -CN, aryl, -OC 1

-C

6 alkyl, -Ohalogen-substitutedC-C 6 alkyl, halogen and halogen-substitutedCCO 6 alkyl. In other embodiments, R' is independently selected from the group consisting of -CN, -OC-Oalkyl, -Ohalogen-substitutedC-C 6 alkyl, halogen and halogen-substitutedC

CO

6 alkyl. In some embodiments, R' is selected from the group consisting of halogen and halogen substitutedC-C 6 alkyl. In one embodiment, R1 is hydrogen. In another embodiment, R' is -CN. In another embodiment, R' is -OC-C 6 alkyl. In another embodiment, R' is halogen. Suitable halogens include, but are not limited to, chlorine and fluorine. In yet another embodiment, R' is halogen substitutedCC 6 alkyl. Suitable halogen-substitutedCC 6 alkyls include, but are not limited to, trifluoromethyl. In yet another embodiment, R is -Ohalogen-substitutedC-C 6 alkyl. Suitable -Ohalogen substitutedCCO 6 alkyls include, but are not limited to, trifluoromethoxy. In some embodiments, R' is phenyl. Suitable examples of an aryl substituent, include but are not limited to, phenyl. In certain embodiments, R2 is selected from the group consisting of hydrogen and halogen. In one embodiment, R2 is hydrogen. In another embodiment, R2 is halogen. Suitable halogens include, but are not limited to, chlorine and fluorine. In specific examples, of the compounds described herein, R2 is halogen or hydrogen and R' is selected from the group consisting of halogen, -CN-, aryl, -OC-CO 6 alkyl, -Ohalogen-substitutedC-CO 6 alkyl and halogen-substituted~i-C 6 alkyl. In certain embodiments, R3 is selected from the group consisting of hydrogen, halogen, halogen substitutedCCO 6 alkyl and aryl. For example in one embodiment, R is aryl, halogen and halogen substitutedC-r~Oalkyl wherein the aryl is substituted with -COOH, -OH or halogen-substitutedC

CO

6 alkyl. In one embodiment, R3 is hydrogen. In another embodiment, R3 is halogen. Suitable halogens include, but are not limited to, chlorine, bromine and fluorine. In yet another embodiment, R3 is halogen substitutedCCO 6 alkyl. Suitable halogen-substitutedCC 6 alkyls include but are not limited to, trifluoromethyl. In still yet another embodiment, R3 is aryl. Suitable aryl groups include, but are not limited to, phenyl. In certain embodiments, when R? is phenyl, the phenyl can be unsubstituted or substituted with at least one substituents selected from a. In one embodiment of the compounds described herein, when RW is phenyl, the phenyl is substituted with -COOH. In certain embodiments of the compounds described herein, wherein W is-N(R 4 )-, R4 is selected from the group consisting of hydrogen, C 1 COalkyl, C 1

CO

6 alkylaryl, aryl, -01-C 6 alkylCOOH, - Cp

CO

6 alkylCOOCCO 6 alkyl and -COOCCO 6 alkyl wherein the CrCO 6 alkylaryl and aryl are unsubstituted or substituted with -COOH, -0 1

-C

6 alkylCOOH, -C 1

-C

6 alkylCOOO-Calkyl and -COOC-CO 6 alkyl. In one embodiment, R is hydrogen. In another embodiment, R4 is C-Csalkyl, C-Oalkylaryl, -C 5 WO 2012/015693 PCT/US2011/045022 MRL -uuV-0u4:

C

6 alkylCOOH, -Cj-C 6 alkylCOOC-C 6 alkyl and -COOC-C 6 alkyl. Suitable C,-C 6 alkyls include, but are not limited to, methyl, ethyl, propyl, t-butyl and butyl. Suitable C-C 6 alkylaryls include, but are not limited to, CH 2 phenyl. Suitable C,-C 6 alkylCOOC,-C 6 alkyls include, but are not limited to,

CH

2

COOCH

2

CH

3 . Suitable -Cj-C 6 alkylCOOHs include, but are not limited to, CH 2 COOH. In yet another embodiment, R' is aryl, wherein the aryl is substituted with -COOH, -CI-C 6 alkylCOOH, - C

C

6 alkylCOOCI-C5alkyl and -COOC-C 6 alkyl. For example in one embodiment, RW is phenyl substituted with -COOH. Also described herein are compounds, or pharmaceutically acceptable salt thereof of formula Ia: N NR N H N N

NR

4 Ia wherein R' is halogen or halogen-substitutedC,-C 6 alkyl; and R4 is selected from the group consisting of hydrogen, C-C 6 alkyl, Cl-C 6 alkylaryl, aryl, -Cl-C 6 alkylCOOH, - C 1

-C

6 aIkyICOOC1-C 6 alkyl and -COOC-C 6 alkyl wherein the C-C 6 alkylaryl and aryl are unsubstituted or substituted with -COOH, -C,-C 6 alkylCOOH, - C,-C 6 alkylCOOCj-C 6 alkyl and -COOCI-C 6 alkyl. In some embodiments, R' is selected from the group consisting of halogen and halogen substitutedCl-C 5 alkyl In one embodiment, R' is hydrogen. In another embodiment, R' is halogen. In yet another embodiment, R' is halogen-substitutedC,-Calkyl. Suitable halogen-substitutedCrC 6 alkyls include, but are not limited to, trifluoromethyl. Suitable halogens include, but are not limited to, chlorine and fluorine. In certain embodiments, R' is selected from the group consisting of hydrogen, Cl-C 6 alkyl, C

C

6 alkylaryl, aryl, -C-C 6 alkylCOOH, - C1-C 6 alkylCOOC,-C 6 alkyl and -COOC-C 6 alkyl wherein the C

C

6 alkylaryl and aryl are unsubstituted or substituted with -COOH, -Ci-C 6 alkylCOOH, - C

C

6 alkylCOOC,-C 6 alkyl and -COOC,-C 6 alkyl. In one embodiment, R4 is hydrogen. In another embodiment, R4 is C,-C 6 alkyl, C,-C 6 alkylaryl, -C,-C 6 alkylCOOH, -C 1

-C

6 alkylCOOC-C 6 alkyl and COOCI-C 6 alkyl. Suitable C,-C 6 alkyls include, but are not limited to, methyl, ethyl, propyl, t-butyl and butyl. Suitable C 1

-C

6 alkylaryls include, but are not limited to, CH 2 phenyl. Suitable C-C 6 alkylCOOCr

C

6 alkyls include, but are not limited to, CH 2

COOCH

2

CH

3 . Suitable -C,-C 6 alkylCOOHs include, but are not limited to, CH 2 COOH. In yet another embodiment, Rt is aryl, wherein the aryl is substituted with COOH, -C1-C 6 alkylCOOH, - C1-C 6 alkylCOOC,-C 6 alkyl and -COOC,-C 6 alkyl. For example in one embodiment, Rt is phenyl substituted with -COOH. In certain embodiment, RW is C,-C 6 alkyl or aryl. In one embodiment, Rt is C,-C 6 alkyl. Suitable

C,-C

6 alkyls include, but are not limited to, methyl, ethyl, propyl, t-butyl and butyl. In another embodiment, R is aryl, wherein the aryl is phenyl. In other embodiment when R4 is aryl, the aryl group 6 WO 2012/015693 PCT/US2011/045022 M.RL -uun-vv'+ is substituted with -COOH, -C]-C 6 alkylCOOH, - C-C 6 alkyICOOC-C 6 alkyl and -COOC 1

-C

6 alkyl. In yet another embodiment, R4 is hydrogen. Examples of the compounds described herein include, but are not limited to, the following: F N F 7Q-F N H N N N N F N N F H F H N\ 0 H N N N N

N

HH 07 F H No NIN \ NF NN HO H F N&N 0F 7 WO 2012/015693 PCT/US2011/045022 F N F N F H N N N N CC H N NNN N / NO H 0 N N H 0 H N I

N

H% H F F N Nq/ 0 F N / N H 0 WO 2012/015693 PCT/US2011/045022 MRL-vbvu F N F OF ON HP O N F o N 0 0

H

3 C F N F N N N 0 N N\ 0 HO N N F 0 'U

H

3

C

WO 2012/015693 PCT/US2011/045022 MRL-ut-v4 N F N C N F H NN C N 0 0 HO N H N' N \N 0 \/-p

HO

WO 2012/015693 PCT/US2011/045022 MRLL-tnn+-l4 F F N NH

-

NN N N H FN N HN N >11 H N N / N 0 H N N a

N

0

CH

3 H N N / N

H

3 C 0 WO 2012/015693 PCT/US2011/045022 MRL-u~uu+ OH F F H N N N C H3 N H N O N N N

H

3 0

CH

3 H N F N / N 0 H F NF F N 0 F F NH NH 0 N 12 WO 2012/015693 PCT/US2011/045022 MRLwnuu' F F F N NH C N N F N F F F N H CN F O F F F FF NqN NO 7 0 N F 3 H 1F WO 2012/015693 PCT/US2011/045022 MRL-uun-vvv'Ic H N F OF N N N F 0 N--CF3 N N F H F N-N 7N CF 3 N H N \N NO N H N N N N

CF

3 N H NN

HN

Definitions Examples of "halogen" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The term "C 1 -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, 14 WO 2012/015693 PCT/US2011/045022 MIRL-jUb-_vuu41_ tert-pentyl, 1 -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 dimethylbutyl, I-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2 methylpropyl, 1-ethyl-1-methylpropyl, and the like.

"C

3

-C

6 cycloalkyl" encompasses cycloalkyls having 3 to 6 carbons, forming one or more carbocyclic rings that are fused. "Cycloalkyl" also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like. The term "-OC -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. The term "-OC 1 -C 6 alkylCOOH" refers to an alkoxy group having 1 to 6 carbons substituted with a carboxylic acid (-COOH) group. The term "halogen-substitutedCI-C 6 alkyl" encompasses C-C 6 alkyl with the hydrogen atoms thereof being partially or completely substituted with halogen, examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl and the like. The term "-Ohalogen-substitutedC-C 6 alkyl" means a -OC-C 6 alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different, and specifically includes, for example, a trifluoromethoxy group. The term "-COC 1

-C

6 alkyl" means groups having C-C 6 alkyl bonded to carbonyl, and encompasses alkylcarbonyl having a carbon number of 1 to 6. Specific examples thereof include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and the like. The term "-COhalogen-substitutedC-C 6 alkyl" means a -COCI-C 6 alkyl as defined above, which is substituted with 1-3 halogen atoms which are identical or different. The term "C 1

-C

6 alkylOH" means a C-C 6 alkyl substituted with a hydroxyl group (-OH), also known as an alcohol. Examples include methanol, propanol, butanol and t-butanol. The term "C 1

-C

6 alkylCN" means a C-C 6 alkyl substituted with an cyano group (-CN). The term "halogen-substituted CI-C 6 alkylOH" means a halogen-substituedCl-C6alkyl substituted with an alcohol (-OH). The term "COOC 1

-C

6 alkyl" means a -COOH group wherein the -OH is replaced with an alkoxy group as defined above. Examples include methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl. The term "S0 2

C

1

-C

6 alkyl" means a group having C 1

-C

6 alkyl bonded to sulfonyl (-SO2-). Specific examples thereof include methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, sec-butanesulfonyl, tert-butanesulfonyl, and the like. 15 WO 2012/015693 PCT/US2011/045022 MRL-Ijun-Vu'+., 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 "NHC- C 6 alkyl" means a group with one of the hydrogen atoms of amino (

NH

2 ) being substituted with a C)-C 6 alkyl group. Specific examples thereof include methylamino, ethylamino, n-propylarnino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino, and the like. The term "N(CI-C 6 alkyl) 2 " means a group with the two amino hydrogen atoms each being substituted with a C 1

.C

6 alkyl group. Specific examples thereof include dimethylamino, diethylamino, ethylmethylamino, di(n-propyl)amino, methyl(n-propyl.)amino, diisopropylamino, and the like. The term "NHCO 2 CI -C 6 alkyl" means a group with one of the amino hydrogen atoms being substituted with CIC 6 alkoxycarbonyl and encompasses alkoxycarbonylamino having a carbon number of 1 to 6. Specific examples thereof include methoxycarbonylamino, ethoxycarbonylamino, n-propyloxycarbonylamino, isopropyloxycarbonylamino, n butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, n pentyloxycarbonylamino, and the like. The term "NHCOCI-C 6 alkyl" means a group with one of the amino hydrogen atoms being substituted with CjC 6 alkylcarbonyl. Specific examples thereof include acetylamino, propionylamino, isobutyryl amino, valerylamino, isovalerylamino, pivaloylamino, and the like. The term "CONHC 1

-C

6 alkyl" means a group with one of the hydrogen atoms of carbamoyl (-CONH 2 ) being substituted with CIC 6 alkyl. Specific examples thereof include methylearbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl, sec-butylearbamoyl, tert-butylcarbamoyl, and the like. The term "CON(Ct-C 6 alkyl)2" means a group with the two carbamoyl hydrogen atoms each being substituted with C-C 6 alkyl. Specific examples thereof include dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, di(n-propyl)carbamoyl, methyl(n-propyl)carbamoyl, diisopropylearbamoyl, and the like. The term "NHSO 2

C

1

-C

6 alkyl" means a group with one of the amino hydrogen atoms being substituted with CIC 6 alkylsulfonyl. Specific examples thereof include methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino, isopropanesulfonylamino, n-butanesulfonylamino, sec-butanesulfonylamino, tert butanesulfonylamino, and the like. Examples of "aryl" include phenyl, naphthyl, tolyl, and the like. The term "heteroaryl" means 5-membered or 6-membered monocyclic heteroaryl containing one or more, preferably one to three, same or different heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, or otherwise means condensed-ring heteroaryl formed by condensation of such monocyclic heteroaryl and the above 16 O 2012/015693 PCT/US2011/045022 MRL-uDVn-uuu*j mentioned heteroaryl or alternatively by mutual condensation of the same or different monocyclic heteroaryl groups. Examples thereof include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, 1,2,3 thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, pyrido[3,2-b]pyridyl, and the like. "Cycloheteroalkyl" means mono- or bicyclic or bridged saturated rings containing at least one hetero atom selected from N, S and 0, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen. The term also includes monocyclic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non aromatic portion. Examples of "cycloheteroalkyl" include tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6 dihydroimidazo[2,1-bjthiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted-(lH, 3H)-pyrimidine-2,4-diones (N-substituted uracils). The term also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 7 azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.2]octyl, and 3 azabicyclo[3.2.2]nonyl, and azabicyclo[2.2.1]heptanyl. The cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogens. The term "cycloheteroalkylCOOH" refers to a cycloheteroalkyl, as defined above, substituted with a carboxylic group (-COOH).

C

1

-C

6 alkylC 3 -CiOcycloalkyl, C 1

-C

6 alkylaryl, C-C 6 alkylheteroaryl and C

C

6 alkylcycloheteroalkyl refer to a C 1

-C

6 alkylgroup substituted with a C 3 -Ciocycloalkyl, aryl, heteroaryl and cycloheteroalkyl, as defined above. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, furmarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, 17 WO 2012/015693 PCT/US2011/045022 MRL-u1vn-_vutm*J lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2 dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. The compounds of the present invention contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of these compounds. Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. 18 WO 2012/015693 PCT/US2011/045022 MRL-uunujVVuQ, Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. It will be understood that, as used herein, references to the compounds of the formulas described herein are meant to also include the pharmaceutically acceptable salts, and also salts that are not phannaceutically acceptable when they are used as precursors to the free compounds or their phannaceutically acceptable salts or in other synthetic manipulations. Solvates, and in particular, the hydrates of the compounds of the formulas described herein are included in the present invention as well. Some of the compounds described herein may exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of the present invention. In the compounds of the formulas described herein, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the formulas described herein. For example, different isotopic forms of hydrogen (H) include protium (I H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic formula can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates. Methods of Treatment Also encompassed by the present invention are methods of treating DGAT 1-related diseases. The compounds described herein are effective in preventing or treating various DGAT1 -related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature 19 WO 2012/015693 PCT/US2011/045022 MNRL-"Uut-vvu'*i delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis. The compound of the invention is especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety. One aspect of the invention described herein provides a method for the treatment and control of obesity or metabolic syndrome, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having the formulas described herein or a pharmaceutically acceptable salt thereof. For example, the compounds described herein are useful for treating or preventing obesity by administering to a subject in need thereof a composition comprising a compound of formula I or formula Ia. Methods of treating or preventing obesity and conditions associated with obesity refer to the administration of the pharmaceutical formulations described herein to reduce or maintain the body weight of an obese subject or to reduce or maintain the body weight of an individual at risk of becoming obese. One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds or combinations of the present invention. Another outcome of treatment may be preventing body weight, regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy and preventing weight gain from cessation of smoking. Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases. Yet another outcome of treatment may be decreasing the risk of developing diabetes in an overweight or obese subject. The treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof. The treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss. Prevention of obesity and obesity-related disorders refers to the administration of the pharmaceutical formulations described herein to reduce or maintain the body weight of a subject at risk of obesity. One outcome of prevention may be reducing the body weight of a subject at risk of obesity relative to that subject's body weight immediately before the administration of the compounds or combinations of the present invention. Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Another outcome of prevention may be decreasing the occurrence and/or severity of obesity-related disorders if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Moreover, if treatment is commenced in already obese subjects, such treatment may prevent the occurrence, progression or severity of obesity-related disorders, such as, but not 20 WO 2012/015693 PCT/US2011/045022 MRL0-00014uuq limited to, arteriosclerosis, type 2 diabetes, polycystic ovary disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis. Another aspect of the invention that is of interest relates to a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat hyperglycemia, diabetes or insulin resistance. More particularly, another aspect of the invention that is of interest relates to a method of treating type 2 diabetes in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with the fonnulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat type 2 diabetes. Yet another aspect of the invention that is of interest relates to a method of treating non insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat non-insulin dependent diabetes mellitus. The present invention is also directed to the use of a compound of formula I or formula Ia in the manufacture of a medicament for use in 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, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis. The compounds described herein are especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety. For example, the present invention is directed to the use of a compound of formula I or formula Ia in the manufacture of a medicament for use in treating obesity, diabetes, hormone secretion disorder, hyperlipemia, gout and fatty liver. Additionally, the present invention is directed to the use of a compound of formula I or formula la in the manufacture of a medicament for use in treating obesity. Pharmaceutical Compositions 21 WO 2012/015693 PCT/US2011/045022 MRLL')Uj-VU4D Compounds of the invention may be administered orally or parenterally. As formulated into a dosage form suitable for the administration route, the compound of the invention can be used as a pharmaceutical composition for the prevention, treatment, or remedy of the above diseases. In clinical use of the compound of the invention, usually, the compound is formulated into various preparations together with pharmaceutically acceptable additives according to the dosage form, and may then be administered. By "pharmaceutically acceptable" it is meant the additive, carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. As such additives, various additives ordinarily used in the field of pharmaceutical preparations are usable. Specific examples thereof include gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, corn starch, microcrystalline wax, white petrolatum, magnesium metasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic acid anhydride, 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 such as tablets, capsules, granules, powders, suppositories; and liquid preparations such as syrups, elixirs, injections. These may be formulated according to conventional methods known in the field of pharmaceutical preparations. The liquid preparations may also be in such a form that may be dissolved or suspended in water or in any other suitable medium in their use. Especially for injections, if desired, the preparations may be dissolved or suspended in physiological saline or glucose liquid, and a buffer or a preservative may be optionally added thereto. The pharmaceutical compositions may contain the compound of the invention in an amount of from 1 to 99.9 % by weight, preferably from 1 to 60 % by weight of the composition. The compositions may further contain any other therapeutically-effective compounds. In case where the compounds of the invention are used for prevention or treatment for the above mentioned diseases, the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the patient and on the type and the range of the intended remedial effect. In general, when orally administered, the dose may be from 0.001 to 50 mg/kg of body weight/day, and it may be administered at a time or in several times. The dose is preferably from about 0.01 to about 25 mg/kg/day, more preferably from about 0.05 to about 10 mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets or capsules containing from 0.01 mg to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 750, 850 and 1,000 milligrams of a compound described herein. This dosage regimen may be adjusted to provide the optimal therapeutic response. Combination Therapy 22 WO 2012/015693 PCT/US2011/045022 MRL-uut,-uvv',+j The compounds of the present invention are further useful in methods for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other therapeutic agents. The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of fonnula I or formula Ia 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 therefor, contemporaneously or sequentially with a compound of formula I or formula Ia. When a compound of formula I or formula Ia is used contemporaneously with one or more other drugs, a phannaceutical composition in unit dosage form containing such other drugs and the compound of formula I or formula Ia is preferred. However, the combination therapy may also include therapies in which the compound of formula I or formula Ia and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of formula I or formula Ia. Examples of other active ingredients that may be administered in combination with a compound of formula I or fonnula Ia, and either administered separately or in the same pharmaceutical composition, include, but are not limited to: (1) dipeptidyl peptidase-IV (DPP-4) inhibitors; (2) insulin sensitizers, including (i) PPARy agonists, such as the glitazones (e.g. pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR ligands, including (1) PPARa/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 phannaceutically acceptable salts, in particular, metformin hydrochloride, and extended release formulations thereof, such as Glumetza®, Fortamet@, and GlucophageXR@; (iii) protein tyrosine phosphatase-IB (PTP- I B) inhibitors; (3) insulin or insulin analogs, such as insulin lispro, insulin detemir, insulin glargine, insulin glulisine, and inhalable fonnulations of each thereof; (4) leptin and leptin derivatives and agonists; (5) amylin and amylin analogs, such as pramlintide; (6) sulfonylurea and non-sulfonylurea insulin secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide; (7) a-glucosidase inhibitors (such as acarbose, voglibose and miglitol); (8) glucagon receptor antagonists, such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088, and WO 00/69810; 23 WO 2012/015693 PCT/US2011/045022 MIRL0-00045uu' (9) incretin mimetics, such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists, such as exenatide, liraglutide, taspoglutide, AVEO10, CJC-1131, and BIM-5 1077, including intranasal, transdermal, and once-weekly formulations thereof; (10) LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl CoA:cholesterol acyltransferase inhibitors, such as avasinibe; (11) HDL-raising drugs, such as niacin or a salt thereof and extended-release versions thereof; MK 524A, which is a combination of niacin extended-release and the DP-1 antagonist MK-524; and nicotinic acid receptor agonists; (12) antiobesity compounds; (13) agents intended for use in inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors; (14) antihypertensive agents, such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-I 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; (15) glucokinase activators (GKAs), such as LY2599506; (16) inhibitors of 11 I-hydroxysteroid dehydrogenase type 1, such as those disclosed in U.S. Patent No. 6,730,690; WO 03/104207; and WO 04/058741; (17) inhibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib and MK-0859; (18) inhibitors of fructose 1,6-bisphosphatase, such as those disclosed in U.S. Patent Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476; (19) inhibitors of acetyl CoA carboxylase-1 or 2 (ACCI or ACC2); (20) AMP-activated Protein Kinase (AMPK) activators; (21) agonists of the G-protein-coupled receptors: GPR-109, GPR-119, and GPR-40; (22) SSTR3 antagonists, such as those disclosed in WO 2009/011836; (23) neuromedin U receptor agonists, such as those disclosed in W02009/042053, including, but not limited to, neuromedin S (NMS); (24) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD); (25) GPR-105 antagonists, such as those disclosed in WO 2009/000087; (26) inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1; SGLT-2, such as dapagliflozin and remogliflozin; and SGLT-3; (27) inhibitors of acyl coenzyme A:diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2); (28) inhibitors of fatty acid synthase; (29) inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2); 24 WO 2012/015693 PCT/US2011/045022 MRL-uuts-uuu'n (30) agonists of the TGR5 receptor (also known as GPBARI, BG37, GPCR19, GPRI 31, 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 fonnula I or formula Ia include, but are not limited to, sitagliptin (disclosed in US Patent No. 6,699,871), vildagliptin, saxagliptin, alogliptin, denagliptin, cannegliptin, dutogliptin, melogliptin, linagliptin, and pharmaceutically acceptable salts thereof, and fixed-dose combinations of these compounds with metformin hydrochloride, pioglitazone, rosiglitazone, simvastatin, atorvastatin, or a sulfonylurea. Other dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of formula I or formula Ia include, but are not limited to: (2R,3S,5R)-5-(I -methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-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(1H)-yl)-2-(2,4,5 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; 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)butanoyll-hexahydro-3-(2,2,2-trifluoroethyl)-2H-1,4-diazepin-2 one; and pharmaceutically acceptable salts thereof Antiobesity compounds that can be combined with compounds of formula I or formula Ia 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; dexfenflurainine; sibutramine; lipase inhibitors, such as orlistat and cetilistat; melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists; CCK-1 agonists; melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Y l or Y5 antagonists (such as MK-0557); CB I receptor inverse agonists and antagonists (such as rimonabant and taranabant); P3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (such as bombesin receptor subtype-3 agonists); and 5-hydroxytryptamine-2c (5-HT2c) agonists, such as lorcaserin. For a review of anti-obesity compounds that can be combined with compounds of the present invention, see S. Chaki et al., "Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity," Expert Opin. Ther. Patents, 11: 1677-1692 (2001); D. Spanswick and K. Lee, "Emerging antiobesity drugs," Expert Opin. Emerging Drugs, 8: 217-237 (2003); JA. Fernandez-Lopez, et al., "Pharmacological Approaches for the Treatment of Obesity," Drgs, 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 formula I or formula la include, but are not limited to: 25 WO 2012/015693 PCT/US2011/045022 IvtRL-L'ub-uuu42' N-[4-((1S)-I- {3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-1H-pyrazol- 1 yl} ethyl)benzoylj-3-alanine; N-[4-((IR)- 1-{3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]- 1H-pyrazol- I yl}ethyl)benzoylj-$-alanine; N-(4- { 1-[3-(2,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-iH-pyrazol- 1 -yl]ethyl}benzoyl)-P alanine; N-(4- {(IS)-1 -[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)- IH-pyrazol-1-yljethyl}benzoyl)-p alanine; N-(4- f(I S)-1 -[(R)-(4-chloropbenyl)(7-fluoro-5-methyl- 1 H-indol-3-yl)methyl]butyl}benzoyl)-p-alanine; and N-(4-{(1S)-I-[(4-chlorophenyl)(6-chloro-8-inethylquinolin-4-yl)methyllbutyl}benzoyl)-p-alanine; and phannaceutically acceptable salts thereof Inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) that can be used in combination with the compounds of formula I or formula Ia include, but are not limited to: [5-(5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2 -yl)-2H-tetrazol-2 yllacetic acid; (2'-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-2,5'-bi-1,3-thiazol-4-yl)acetic acid; (5-{3-[4-(2-bromo-5-fluorophenoxy)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 (5-{2-[4-(5-bromo-2-chlorophenoxy)piperidin- 1-yl]pyrimidin-5-yl}-2H-tetrazol-2-yl)acetic acid; and pharmaceutically acceptable salts thereof Glucokinase activators that can be used in combination with the compounds of formula I or formula Ia include, but are not limited to: 3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(I-methyl-1H-pyrazol-3 yl)benzamide; 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-methalnesulfoylpyridin-3-yloxy)-N-(1-methyl-IfH-pyrazol-3 yl)benzamide; 3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1-methyl-iH-pyrazol-3 yl)benzamide; 5-isopropoxy-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-l H-pyrazol-3-yl)benzamide; 5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(I-methyl-IH-pyrazol-3 yl)benzamide; 3-({4-[2-(dimethylamino)ethoxy]phenyl}thio)-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4 triazol-3-yl)thio]pyridine-2-carboxamide; 26 WO 2012/015693 PCT/US2011/045022 MRL-v)UJ5-vtsIK 3-({4-[(1-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)thiojpyridine-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 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-1 19 receptor that can be used in combination with the compounds of fonnula I or formula la include, but are not limited to: rac-cis 5-chloro-2-{4-[2-(2-{[5-(methylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl] piperidin-1-yl}pyrimidine; 5-chloro-2-{4-[(I R,2S)-2-(2-{[5-(methylsulfonyl)pyridin-2-ylloxy}ethyl)cyclopropyljpiperidin-1 yl} pyrimidine; rac cis-5-chloro-2-[4-(2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1 yl]pyrimidine; 5-chloro-2-[4-((1S,2R)-2-(2-[4-(methylsulfonyl)phenoxyethyl}cyclopropyl) piperidin-1 yl]pyrimidine; 5-chloro-2- [4-((l R,2S)-2- {2- [4-(methylsulfonyl)phenoxy] ethyl } cyclopropyl) piperidin-1 yl]pyrimidine; rac cis-5-chloro-2-[4-(2- {2-[3-(methylsulfonyl)phenoxy]ethyl} cyclopropyl)piperidin- 1 -yl]pyrimidine; and 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 formula I or formula la include, but are not limited to: (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 acid; (2R)-2-({6-cbloro-3-[6-(4-chlorophenoxy)-2-propylpyridin-3-yl]-1,2-benzisoxazol-5-yl}oxy)propanoic acid; (2R)-2-{3-[3-(4-methoxy)benzoyl-2-inethyl-6-(trifluoromethoxy)-1H-indol-1 yl]phenoxy}butanoic acid; (2S)-2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1 yl]phenoxy}butanoic acid; 2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-IH-indol-1-yljphenoxy}-2 methylpropanoic acid; and 27 LO 2012/015693 PCT/US2011/045022 (2R)-2-{3-[3-(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)- 1H-indol- 1 yl]phenoxy}propanoic acid; and pharmaceutically acceptable salts thereof. Inhibitors of I p-hydroxysteroid dehydrogenase type 1 that can be used in combination with the compounds of formula I or formula Ia 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 chlorophenyl)-trans-3-fluorocyclobutyl]-4-cyclopropyl-5-(1-methylcyclopropyl)-r-4H-1,2,4 triazole; 3-{l-(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)propyl]bicyclo[2.2.2]oct-1-yl}-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H -1,2,4-triazole; 4-methyl-3-{4-[4-(methylsulfonyl)phenyllbicyclo[2.2.2]oct-1-yl}-5-[2-(trifluoromethyl)phenyl] 4H- 1,2,4-triazole; 3 -(4- {4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-I ,2,4-triazol-3-yi} bicyclo[2.2.2joct- 1 -yl)-5 -(3,3,3 trifluoropropyl)- 1,2,4-oxadiazole; 3-(4-{4-methyl-5-[2-(trifluoronethyl)phenyl]-4H- 1,2,4-triazol-3 -yl } bicyclo[2.2.2]oct- 1 -yl)-5-(3 ,3 , trifluoroethyl)-1,2,4-oxadiazole; 5-(3,3-difluorocyclobutyl)-3-(4- {4-metbyl-5-[2-(trifluoromethyl)phenyl]-4H- 1,2,4-triazol-3 yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole; 5-(I-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; 2-(1,1-difluoroethyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-41-1-,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-i-yl)-1,3,4-oxadiazole; and 5-( 1,1-difluoroethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3 yl}bicyclo[2.2.2]oct- I-yl)-1,2,4-oxadiazole; and pharmaceutically acceptable salts thereof Somatostatin subtype receptor 3 (SSTR3) antagonists that can be used in combination with the compounds of formula I or formula Ia include, but are not limited to: HN -- ~HN NNF N N F NH NH N N H N H N N-- N-H N--N N-N 28 WO 2012/015693 PCT/US2011/045022 MRL-uuuu HN HN F \F NH N NH N N H N N N HN O0 F F N NN HN HHN N NH N N O N-N 0 0 and F N NH H N N -0 e 0 -o 0I and pharmaceutically acceptable salts thereof AMP-activated Protein Kinase (AMPK) activators that can be used in combination with the compounds of formula I or formula la include, but are not limited to: N HO ~- N 1 N _ :5 OO2H o CO 2 H CH C1H OH F N N N N O' CO0 2 H "'O CO 2 H C1 C1 29 WO 2012/015693 PCT/US2011/045022 MRL-VUjs-uuu4D OH N N o 00co2H 1 o cO 2 H C1 N F N H H F N N o c2H 1\ O CO 2 H N N C1 N F H H c

HO

2 Cx N N )-o N CoH ON CO2H F1 N N11 NH Hand 1H and pharmaceutically acceptable salts thereof. Inhibitors of acetyl-CoA carboxylase-l1 and 2 (ACC-1I and ACC-2) that can be used in combination with the compounds of formula I or formula Ia include, but are not limited to: 3-{(1'-[(1-cyclopropyl-4-methoxy-l1H-indol.-6-yl)carbonyl]-4-o.xospiro[chroman- 2,4'-piperidin]-6 yl}benzoic acid; 5-{(1'-[(1 -cyclopropyl-4-methoxy- IH-indol-6-yl)carbonyl]-4-oxospiro[chroman-2,4'-piperidin]-6 yl}nicotinic acid; 1l-[(1 -cyclopropyl-4-methoxy- 1H-indol-6-yl)carbonylj-6-(1IH-tetrazol-5-yl)spiro~chroman-2,4'-piperidin] 4-one; l '-[(1 -cyclopropyl-4-ethoxy-3 -methyl-ilH-indol-6-yI)carbonyl]-6-( 1Hotetrazol-5-yl)spiro[chroman-2,4 piperidin]-4-one; and 5-{(1'-[(1 -cyclopropyl-4-methoxy-3-methyl- 1H-indol-6-yl)carbonyl]-4-oxo-spiro [chromnan-2,4'-piperidin] 6-yl}nicotinic acid; and pharmaceutically acceptable salts thereof. In another aspect of the invention, a pharmaceutical composition is disclosed which comprises one or more of the following agents: (a) a compound of formula I or formula Ia; 30 WO 2012/015693 PCT/US2011/045022 MRL-v0u6-00043 (b) one or more compounds selected from the group consisting of: (1) dipeptidyl peptidase-IV (DPP-4) inhibitors; (2) insulin sensitizers, including (i) PPARy agonists, such as the glitazones (e.g. pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR ligands, including (1) PPARa/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 hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet@, and GlucophageXR@; (iii) protein tyrosine phosphatase-iB (PTP-IB) inhibitors; (3) sulfonylurea and non-sulfonylurea insulin secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide; (4) a-glucosidase inhibitors (such as acarbose, voglibose and miglitol); (5) glucagon receptor antagonists; (6) LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl CoA:cholesterol acyltransferase inhibitors, such as avasimibe; (7) HDL-raising drugs, such as niacin or a salt thereof and extended-release versions thereof; MK-524A, which is a combination of niacin extended-release and the DP-1 antagonist MK-524; and nicotinic acid receptor agonists; (8) antiobesity compounds; (9) agents intended for use in inflammatory conditions, such as aspirin, non-steroidal anti inflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors; (10) antihypertensive agents, such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta blockers (such as and calcium channel blockers; (11) glucokinase activators (GKAs), such as LY2599506; (12) inhibitors of 11 I-hydroxysteroid dehydrogenase type 1; (13) inhibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib and MK-0859; (14) inhibitors of fructose 1,6-bisphosphatase; (15) inhibitors of acetyl CoA carboxylase- 1 or 2 (ACC 1 or ACC2); (16) AMP-activated Protein Kinase (AMPK) activators; (17) agonists of the G-protein-coupled receptors: GPR-109, GPR- 119, and GPR-40; (18) SSTR3 antagonists; (19) neuromedin U receptor agonists, including, but not limited to, neuromedin S (NMS); 31 WO 2012/015693 PCT/US2011/045022 MRL-"Uisn-uuu+j (20) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD); (21) GPR-105 antagonists; (22) inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1; SGLT-2, such as dapagliflozin and remogliflozin; and SGLT-3; (23) inhibitors of acyl coenzyme A:diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT 2); (24) inhibitors of fatty acid synthase; (25) inhibitors of acetyl-CoA carboxylase-1 and 2 (ACC-1 and ACC-2); (26) inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase I and 2 (MGAT-1 and MGAT-2); (27) agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M BAR); and (28) bromocriptine mesylate and rapid-release formulations thereof; and (c) a pharmaceutically acceptable carrier. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention. The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s). Examples General synthetic methods: 32 WO 2012/015693 PCT/US2011/045022 MRL-tnjnUvvu'*., Method A: R2 1) EDC, HOBT 0 R

R

2 N''2 DMF, 100 C R 2 N N + HOOC-- N\\ -NN R1 NH 2 X 2) AcOH, 200 C R 1 H X Method B: 0 1) EDC, HOBT 2 NH 2 DMF, 100 0 C R 2 HNNZ'N cC Ri

R

1

NH

2 2) AcOH, 200 C H X Cul, K2C03, MS 4A, 0 Dioxane, 110*C R 2 N NN H I X MeHN NHMe Intermediate I O NH N HOOC Ethyl 4-(2-oxo-1,2-dihydroimidazo[4,5-blpyridin-3-vl)benzoate Reference: J. Med. Chem. 1978, 21(9), 965-978. Step A: ethyl 4-(3-nitropyridin-2-ylamino)benzoate A mixture of 2-chloro-3-nitropyridine (50 g, 318.47 mmol, 1.00 equiv) and ethyl 4 aminobenzoate (157.6 g, 955.15 mmol, 3.00 equiv) was stirred for 90 min at 1704C in an oil bath. The reaction mixture was cooled to room temperature, then it was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10). This resulted in ethyl 4-(3 nitropyridin-2- ylamino)benzoate as a white solid. LC-MS (ES, m/z) C 14

H

1 3

N

3 0 4 : 287; Found: 288 [M+1]*. Step B: ethyl 4-(3-aminopyridin-2-ylamino)benzoate 33 ivm 2012/015693 PCT/US2011/045022 A mixture of ethyl 4-(3-nitropyridin-2-ylamino)benzoate (5 g, 17.42 mmol, 1.00 equiv) and Palladium carbon (10%, 1 g) in methanol (500 mL) and THF (100 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The solid was filtered out. The filtrate was concentrated under vacuum, which resulted in product ethyl 4-(3-aminopyridin-2 ylamino)benzoate as a gray solid. LC-MS (ES, m/z): C 4 1

H

15

N

3 0 2 : 257; Found: 258 [M+H]*. Step D: ethyl 4-(2-oxo-1,2-dihydroimidazo[4,5-b]pyridin-3-yl)benzoate Into a 1 00-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of ethyl 4-(3-aminopyridin-2-ylamino)benzoate (2 g, 7.78 mmol, 1.00 equiv) in toluene (20 mL). This was followed by the addition of a solution of triphosgene (3.7 g, 12.58 mmol, 1.61 equiv) in toluene (30 mL) dropwise with stirring at 25 0 C over 10 min. The resulting solution was stirred overnight at room temperature, and then quenched by the addition of 200 mL of water/ice, followed by extraction with 3x50 mL of ethyl acetate. The organic layers were combined, washed with 2x50 mL of saturated brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was washed with 3x20 mL of ether and dried to afford product ethyl 4-(2-oxo-1,2-dihydroimidazo[4,5-b]pyridin-3 yl)benzoate as a red solid. LC-MS (ES, m/z): C 15

H

13

N

3 0 3 : 283; Found: 284 [M+H]*. 'HNMR (400 MHz, CDCl 3 , ppm): 6 1.41 (3H, t), 4.42(2H, m), 7.11(lH, m), 7.41(1H, d, J=81-z), 7.92(2H, d, J=8.Hz), 8.11 (1H4, t), 8.24(2H, d, J=8.8Hz), 10.05(1H, s). Step E: 4-(2-oxo-1,2-dihydroimidazo[4,5-blpyridin-3-yl)benzoic acid Into a 100-mL 3-necked round-bottom flask was placed a solution of ethyl 4-(2-oxo-1,2 dihydroimidazo[4,5-b]pyridin-3-yl)benzoate (2 g, 7.07 mmol, 1.00 equiv) in tetrahydrofuran (30 mL). This was followed by the addition of a solution of sodium hydroxide (3N, 840 mg, 21.00 mmol, 3.00 equiv) in water (7 mL) in portions at <25 0 C over 5 min. The resulting solution was stirred overnight at room temperature, and then concentrated under vacuum. The residue was dissolved in 150 mL of water, then adjusted to pH 2~3 with HCl (6 mol/L). The isolated solid was collected by filtration, then dried in an oven under reduced pressure to afford product 4-(2 oxo-1,2-dihydroimidazo[4,5-bjpyridin-3-yl)benzoic acid as a white solid. LC-MS: (ES, m/z)

C

13

H

9

N

3 0 3 : 255; Found: 256 [M+H]*. 'HNMR (400MHz, DMSO-D6, ppm): 6 7.13-7.16(1H, in), 7.43-7.45(1H, m), 7.92-7.94(2H, t), 7.98-7.99(1H, in), 8.09-8.11(2H, in), 11.51(11H, s), 12.89(1H, s). Intermediate 2 34 tvuQWO 201 2 /015 6 93 PCT/US2011/045022 HO N NH N 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b-lpyridin-1-Vlbenzoic acid Step A: 2-nitropyridin-3-yl trifluoromethanesulfonate Into a 3000 ml 3-neck round-bottom flask was placed a suspension of Nal (95 g, 2.77 mol, 1.96 equiv, 70%) in THF (150 ml), then added 2-nitropyridin-3-ol (A-1) (390 g, 2.78 mol, 1.00 equiv) while maintaining the contents at room temperature. To the above mixture was added trifluoromethanesulfonic anhydride (786 g, 2.79 mol, 1.09 equiv) dropwise with stirring. The resulting solution was stirred for 72 hours while the temperature was maintained at reflux in an oil bath. The reaction mixture was cooled and quenched by the addition of water, followed by extraction 2 times with 1000 mL of CH 3 Cl. The combined organic layer was dried and concentrated under vacuum. The residue was purified by eluting through a silica gel column with a 1:10 EtOAc/PE solvent system to provide product 2-nitropyridin-3-yl trifluoromethanesulfonate as a colorless solid. LC-MS: m/e = 273 [M+H]* Step B: ethyl 4-[(2-nitropyridin-3-vl)amino]benzoate Into a 2000 ml 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of 2-nitropyridin-3-yl trifluoromethanesulfonate (350 g, 1.29 mol, 1.00 equiv) in toluene (1500 ml), ethyl 4-aminobenzoate (255.5 g, 1.55 mol, 1.10 equiv), K 3

PO

4 (409.5 g, 1.93 mol, 1.50 equiv), Pd(dppf)Cl 2 (47 g, 64.38 mmol, 0.05 equiv) and dppf (70 g, 130.11 mmol, 0.01 equiv). The resulting mixture was stirred for 24 hours at 90 'C. The reaction mixture was cooled, dried over Na 2

SO

4 and concentrated under vacuum. The residue was purified by eluting through a column with a 1:2 EtOAc/hexane solvent system to provide ethyl 4-(2-nitropyridin-3-ylamino)benzoate as a yellow solid. LC-MS: m/e = 288 [M+H] Step C: ethy1 4-[(2-aminopyridin-3-l)aminolbenzoate A 1000 ml round-bottom flask was purged, flushed and maintained with a hydrogen atmosphere, then were added a solution of ethyl 4-(2-nitropyridin-3-ylamino)benzoate (100 g, 348.43 mmol, 1.00 equiv) in MeOH (500 ml) and Pd/C (10 g, 0.10 equiv). The resulting solution was stirred overnight at room temperature under a hydrogen atmosphere. A filtration was 35 WO 2012/015693 PCT/US2011/045022 performed. The filtrate was concentrated under vacuum which resulted product ethyl 4-(2 aminopyridin-3-ylamino)benzoate as a white solid. LC-MS: m/e = 258 [M+H]+ Step D: ethyl 4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)benzoate Into a 500 ml round-bottom flask were placed a solution of ethyl 4-(2 aminopyridin-3-ylamino)benzoate (10 g, 38.91 mmol, 1.00 equiv) in THF (500 ml), di(lH imidazol-1-yl)methanone (25 g, 154.32 mmol, 4.00 equiv) and Et 3 N (16 g, 158.42 mmol, 4.00 equiv). The resulting solution was stirred for 72 hours at room temperature. A filtration was performed. The filter cake was washed 3 times with 100 ml of ether and dried to afford product ethyl 4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)benzoate as a white solid. LC-MS: m/e= 284 [M+Hj Step E: 4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)benzoic acid Into a 1000 ml round-bottom flask was placed a solution of ethyl 4-(2-oxo-2,3 dihydroimidazo[4,5-b]pyridin- 1-yl)benzoate (85 g, 300.35 mmol, 1.00 equiv) in THF/water(1:1) (700 ml). This was followed by the addition of a solution of LiOH (62.5 g) in water (100 ml) dropwise with stirring. The resulting solution was stirred for 3 hours at room temperature, then concentrated under vacuum. The residual solution was washed three times with 300 ml of EtOAc. The aqueous layer was adjusted to pH 5 by the addition of HCI (1 mol/l). The isolated solid was collected and dried to afford product 4-(2-oxo-2,3- dihydroimidazo[4,5-b]pyridin-1 yl)benzoic acid as a pink solid. LC-MS: m/e = 256 [M+H]*. 1 H-NMR (400MHz, DMSO-d6, ppm): 8.10 (2H, d), 7.99 (1H, s), 7.71 (2H, d) 7.45 (1H, d), 7.03 (IH, s). Intermediate 3 CooH N >=N N N H 5-(2-oxo-2,3-dihydro-1--imidazo[4,5-blpyridin-1-yl)pyridine-2-carboxylic acid Intermediate 3 was prepared using the same synthetic sequence as that of Intermediate 2 using methyl 5-aminopyridine-2-carboxylate in StepB. 5-(2-oxo-2,3-dihydro-1H-imidazo[4,5 36 WO 2012/015693 PCT/US2011/045022 b]pyridin-1-yl)pyridine-2-carboxylic acid: LC-MS (ES, m/z): C,1HsN 4 0 3 : 256; Found: 257 [M+H]. Intermediate 4 N N o N tert-butyl 4-(2-oxo-2,3-dihydro-IH-imidazo[4,5-bpyridin-1-yl)benzoate Intermediate 4 was prepared using the same synthetic sequence as that of Intermediate 2 using tert-butyl 4-aminobenzoate. tert-butyl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 yl)benzoate: LC-MS (ES, m/z): C 17 H1 7

N

3 0 3 : 311; Found: 312 [M+H]*. 1HNMR (500 MHz, CDCl 3 ) 5: 10.9 (1 H, br), 8.17 (3H, in), 7.64 (211, d, 8.5 Hz), 7.37 (11H, d, 7.5 Hz), 7.07 (11H, dd, 5.5, 2.0 Hz), 1.62 (911, s) ppm. Intermediate 5 >N F 3 C X N H 2-(4-iodophenyl)-6-trifluoromethl)-1H-benzimidazole A solution of 4-(trifluoromethyl)benzene-1,2-diamine (4.0 g, 22.71 mmol) in DMF (80 mL) was added water (2.0 mL) followed by 4-iodobenzaldehyde (5.8 g, 24.98 mmol) slowly and then OXONE (9.77 g, 15.9 mmol). The mixture was then stirred at room temperature for 1.5 hr and poured slowly into a 1 M solution 50 mL K 2 C0 3 in 250 mL water. The resulting mixture was stirred for 10 min, diluted with EtOAc and layers separated. The aqueous layer was extracted with EtOAc twice and the combined organic phases were dried over MgSO 4 and concentrated in vacuo. Residue was purified by MPLC (120 gr Redi Sep Rf filter column on CombiFlash with 0 20% Hexane/EtOAc) to afford product 2-(4-iodophenyl)-6-(trifluoromethyl)-1H-benzimidazole. LC-MS (ES, m/z): C 14

H

8

F

3 1N 2 : 388; Found: 389 [M+H]*. Example 1: 37 WO 2012/015693 PCT/US2011/045022 MRL-nnvu, N CF 3 N H H RN

A

0 \ 1{- 4-6-(trifluoromethyll-1H-benzimidazol-2-yllphenyl} -1 .3-dihydro-2H-imidazo[4,5 bjpyridin-2-one To a 5 mL Pyrex vial was charged with Intermediate 2 (100 mg, 0.392 mmol) along with EDC (98 mg, 0.509 mmol) and HOBT (68.8 mg, 0.509 mmol) in DMF (lmL) before the addition of 4-trifluoromethyl-1,2-phenyldiamine (69.0 mg, 0.392 mmol). The mixture was stirred at room temperature for 10 min and then under microwave at 120 0 C for 20 min. Then acetic acid (lmL) was added and the mixture was exposed to microwave at 200 0 C for 40 min. The mixture was filtered and concentrated and the residue was purified by RP HPLC (loading as solution of

DMSO:CH

3

CN:H

2 0, 20 to 80% acetonitrile in water on YMC column) to afford product 1-4 [6-(trifluoromethyl)-1H-benzimidazol-2-yl]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2 one. LC-MS (ES, m/z): C 2 0H 1 2

F

3

N

5 0: 395; Found: 396 [M+H]. 'HNMR (500 MHz, CD 3 0D) 8: 8.32 (2H, dd, 6.5, 1.5 Hz), 8.06 (1H, d, 5.0 Hz), 8.04 (1H, s), 7.90 (3H, m), 7.73 (1H, d, 8.5 I-z), 7.55 (1H, dd, 8.5, 1.5 Hz), 7.13 (11H, dd, 8.0, 2.5 Hz). Using the above sample procedures and Intermediates 1 - 3, Examples 2-9 were prepared: R1 N \ R 2 N N HN O Example Ri R2 X,Y,Z Parent Ion mn/z (M+H) 2 H CF 3 CHN,CH 396 3 H F N,CH,CH 346 4 F F N,CH,CH 364 5 H Cl N,CH,CH 362 6 H Ph N,CH,CH 404 38 WO 2012/015693 PCT/US2011/045022 M4RL-U±-UUU'D 7 H CN N,CH,CH 353 8 H OCF 3 N,CH,CH 412 9 H CF 3 CHCHN 396 Example 10: H N N N HNE 1-[4-(1H-indol-2-ylphenvl]-L.3-dihydro-2H-imidazof4,5-blpyridin-2-one Step A: N-[4-(IH-indol-2-yl)phenyll-2-nitropyridin-3-amine To a Pyrex vial (20 mL) was charged with 3-bromo-2-nitropyridine (318 mg, 1.567 mmol) along with 4-(1H-indol-2-yl)aniline (326 mg, 1.567 mmol), cesium carbonate (1531 mg, 4.70 mmol), BINAP (98 mg, 0.157 mmol), and palladium acetate (35.2 mg, 0.157 mmol). The vial was sealed with septum cap and was connected to manifold through a thin needle. The system was vacuumed and refilled with nitrogen three times before toluene was added through syringe. Then the mixture was exposed to Microwave irridation for 60 min at 120 OC. LC-MS showed complete conversion of starting material to product. The mixture was filtered and washed with ethyl acetate. Then the filtrate was concentrated and the residue was purified by MPLC (40 g silicagel, 0 to 30%ethyl acetate in hexanes) to afford orange product N-[4-(1H indol-2-yl)phenyl]-2-nitropyridin-3-amine. LC-MS (ES, m/z): C 19

H

14

N

4 0 2 : 330; Found: 331 [M+H]. Step B: N[4-(1H-indol-2-yl)phenyllpyridine-2,3-diamine To a parshaker vessel (100 mL) was charged with N-[4-(lH-indol-2-yl)phenyl]-2 nitropyridin-3-amine (180 mg, 0.545 mmol) along with palladium on carbon (58.0 mg, 0.054 mmol) and methanol/water (25 / 2 mL). The system was treated on parshaker under 40 psi hydrogen for 15 hours overnight. LC-MS showed complete reduction of nitro to amine. The catalyst was filtered and washed with methanol. The filtrate was concentrated and product was 39 rWO 2012/015693 PCT/US2011/045022 purified by MPLC (12 silica gel, 40 to 100% ethyl acetate in hexanes) to N-[4-(1H-indol-2 yl)phenyl]pyridine-2,3-diamine. LC-MS (ES, m/z): C 19

H

1 6

N

4 : 300; Found 301 [M+H]. Step: C: 1-[4-(IH-indol-2-yl)phenyll-1,3-dihydro-21-I-imidazof4,5-blpyridin-2-one To a 20 mL sample vial was charged with N-[4-(1H-indol-2-yl)phenyl]pyridine-2,3 diamine (83 mg, 0.276 mmol) along with CDI (67.2 mg, 0.415 mmol) and THF. The vial was capped and the mixture was stirred and heated in an oil bath of 80 OC for 6 hrs. LC-MS showed almost complete conversion. The mixture was concentrated and the crude was purified by MPLC (12 g silica gel, 40 to 100% ethyl acetate in hexanes) to afford white solid product 1-[4-(IH indol-2-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. LC-MS (ES, m/z): C 20

H

14

N

4 0: 326; Found: 327 [M+H]*. 1HNMR (500 MHz, CDCl 3 ) 8: 8.05 (1H, d, 4.5 Hz), 7.95 (2H, d, 8.5 Hz), 7.62 (1K, d, 8.0 Hz), 7.57 (2H, d, 8.0 Hz), 7.48 (1H1, d, 8.5 Hz), 7.46 (1H, d, 8.0 Hz), 7.40 (IH,d, 7.5 Hz), 7.18 (lH, t, 7.5Hz), 7.09 (2H, t, 6.5 Hz), 6.89 (1H, s) ppm. Example 11: N

CF

3 N N N N N / 0 HO [4-(2-oxo-1-{44-[6-(trifluoromethyl)-1H-benzimidazol-2-yllphenyl} -1 ,2-dihydro-3H imidazo[4,5-blpyridin-3-yl)phenyllacetic acid Step A: tert-butyl 4-11-44-(2-ethoxy-2-oxoethyl)phenyll-2-oxo-1,2-dihydro-3H imidazo[4,5-blpyridin-3-vllbenzoate To a 5 mL microwave reaction vial was charged with Intermediate 4 (321 mg, 1.031 mmol) along with ethyl 4-iodo-phenylacetate (359 mg, 1.237 mmol), copper iodide (19.64 mg, 0.103 mmol), CyDMEDA (29.3 mg, 0.206 mmol), potassium carbonate (285 mg, 2.062 mmol) (oven dried), molecular sieves 4A (300 mg) and dioxane (6 mL). The vial was sealed and connected to manifold through a syringe needle. The system was then vacuumed and refilled with nitrogen three times. The mixture was then stirred and heated in an oil bath of 110 OC for 40 WO 2012/015693 PCT/US2011/045022 MRL 6-n-uuu 72 hrs. The mixture was then filtered and concentrated. The residue was purified by MPLC (24 g silica gel, 0 to 60% ethyl acetate in hexanes) to afford light color sticky oil product tert-butyl 4 { 1-[4-(2-ethoxy-2-oxoethyl)phenyl}-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl}benzoate. LC-MS (ES, m/z): C 27

H

27

N

3 0 5 : 473; Found : 474 [M+H]*. 1 HNMR (500 MHz, CDCl 3 ) 6: 8.16 (2H, d, 8.5 Hz), 8.11 (1H, d, 1.0 Hz), 7.71 (2H, d, 8.5 Hz), 7.67 (2H, d, 8.5 Hz), Step B: 4-f3-[4-(2-ethoxy-2-oxoethyl)phenvll-2-oxo-2,3-dihydro-IH-imidazo[4,5 bjpyridin- I -vl I benzoic acid To a 20 mL sample vial was charged with tert-butyl 4-{1-[4-(2-ethoxy-2 oxoethyl)phenyl]-2-oxo-1,2-dihydro-3H-inidazo[4,5-b]pyridin-3-yl}benzoate (300 mg, 0.634 mmol) along with methylene chloride. The mixture was stirred and TFA (1445 mg, 12.67 mmol) was added by syringe dropwise in 1 min. The resulting reaction mixture was then stirred at room temperature for 1 hour. LC-MS showed complete hydrolysis of t-butyl ester with no effect on the ethyl ester. The mixture was then concentrated by evaporation and the TFA was traced out by co-evaporation with HCl/dioxane to afford product HC salt 4-{3-[4-(2-ethoxy-2 oxoethyl)phenyl]-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl}benzoic acid. LC-MS (ES, m/z): C 23

HI

9

N

3 0 5 : 417; Found: 418 [M+H]*. Step C: ethyl [4-(2-oxo-1-{4-[5-(trifluoromethyl)-2,3-dihydro-1H-benzimidazol-2 yllphenyll-1,2-dihydro-3H-imidazo[4,5-blpyridin-3-vl)phenyllacetate To a 5 mL Pyrex vial was charged with 4-{3-[4-(2-ethoxy-2-oxoethyl)phenyll-2-oxo-2,3 dihydro-lH-imidazo[4,5-b]pyridin-1-yllbenzoic acid (70 mg, 0.154 mmol) along with HOBT (31.3 mg, 0.231 mmol) and EDC (44.3 mg, 0.231 mmol) in DMF (1 mL) before the addition of 4-trifluoromethyl-1,2-phenyldiamine (32.6 mg, 0.185 mmol). The mixture was stirred at room temperature for 10 min and then under microwave at 120 *C for 20 min. Then acetic acid (lmL) was added and the mixture was exposed to microwave at 200 OC for 40 min. LC-MS showed complete formation of imidiazole. The mixture was filtered and concentrated and the residue was purified by PrepTLC (2x2000 nm, ethyl acetate:hexanes=3:2) to afford product ethyl [4-(2-oxo 1-{4-[5-(trifluoromethyl)-2,3-dihydro-1H-benzimidazol-2-yl]phenyl}-1,2-dihydro-3H imidazo[4,5-b]pyridin-3-yl)phenyl]acetate. LC-MS (ES, m/z): C 30 H22N 5

F

3 0 3 : 557; Found: 558 [M+H]. 'HNMR (500 MHz, CDC 3 ) 5: 8.25 (2H, d, 8.0 Hz), 8.20 (1lH, d, 4.0Hz), 7.80 (2H, d, 8.5Hz), 7.71 (lH, m), 7.70 (2H, d, 8.0Hz), 7.54 (2H, d, 8.5 Hz), 7.51 (11H, m) 7.44 (2H, m), 7.15 (IH, t, 5.0 Hz), 4.15 (21H, q, 8.0 Hz), 3.69 (2H, s), 1.25 (3h, t, 8.0 Hz) ppm. 41 WO 2012/015693 PCT/US2011/045022 NMRL-0060v45 Step D: [4-(2-oxo- 1-{4- [6-(trifluoromethyl)- I H-benzimidazol-2-yll phenyl -1,2-dihydro 3H-imidazo[4,5-blpyridin-3-yl)phenyllacetic aci To a 20 mL sample vial was charged with ethyl [4-(2-oxo-1-{4-[5-(trifluoromethyl)-2,3 dihydro- 1 H-benzimidazol-2-yl]phenyl} -1,2-dihydro-3H-imidazo[4,5 -b]pyridin-3 yl)phenyl]acetate (25 mg, 0.045 mmol) along with ethanol and sodium hydroxide (0.1 ml, 0.500 mmol). The resulting reaction mixture was then stirred at room temperature for 30 min. LC-MS showed complete hydrolysis of ester to acid. The mixture was then neutralized with HCI (IN, 500 I) and concentrated. The residue was purified by RP HPLC to afford product TFA salt [4 (2-oxo-1-{4-[6-(trifluoromethyl)-1H-benzimidazol-2-yl]phenyl}-1,2-dihydro-3H-imidazo[4,5 b]pyridin-3-yl)phenyl]acetic acid. LC-MS (Es, m/z): C 2 8H 13

N

5

F

3 0 3 : 529; Found: 530 [M+H]. 1 HNMR (500 MHz, CDC 3 ) 8: 8.37 (2H, d, 8.0 Hz), 8.12 (1H, s), 8.09 (lH, d, 5.0Hz), 8.05 (211, d, 8.5 Hz), 7.98 (111, d, 8.5 Hz), 9.84 (IH, d, 8.5 Hz), 7.67 (2H, d, 8.5 Hz), 7.52 92H, d, 8.5 Hz), 7.23 (1 H, dd, 8.0, 5.0 Hz), 3.72 (2H, s) ppm. Example 12: N CI NN H N- N 00 HO (4-{1-F4-(6-chloro-1H-benzimidazol-2-yl)phenyll-2-oxo-1,2-dihydro-3H-imidazo[4,5 blpyridin-3-vl phenylIacetic acid In the same procedure as Example 11, (4-{I-[4-(6-chloro-IH-benzimidazol-2-yl)phenyl] 2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)acetic acid was prepared. LC-MS (Es, mlz): C 27

H

3

F

3

N

5 Cl0 3 : 495; Found: 496 [M+H]*. Example 13 42 WO 2012/015693 PCT/US2011/045022 MRL-unuu. N CF 3 N H NN N N 00 HOOC 4-(2-oxo-1-14-[6-(trifluoromethyl)-1H-benzimidazol-2-yl]phenyl}-1,2-dihydro-3H imidazo[4,5-blpyridin-3-yl)benzoic acid In the same procedure as Example 11, (4-{ 1-[4-(6-chloro-1H-benzimidazol-2-yl)phenyl] 2-oxo- 1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)acetic acid was prepared. LC-MS (Es, m/z): C 27

H

6

F

3

N

5 0 3 : 515; Found: 516 [M+H}*. Example 14: N r') CF 3 Br N/ N-N 8-bromo-3-14-[6-(trifluoromethyl)-1H-benzimidazol-2-yllphenvl[.,2,41triazolof4.3 a-pyridine Step A: 3-bromo-2-hydrazinylpyridine To a stirring solution of 3-bromo-2-chloropyridine (3.74 g, 19.43 mmol) in pyridine (40 mL) was added hydrazine (2 g, 62.4 mol). The resulting mixture was stirred at 60*C for 24 h. After cooled to room temperature and refrigerated, product precipitated out as a white needle solid. The product was filtered and washed with water, dried under high vacuum overnight to afford product 3-bromo-2-hydrazinylpyridine. Step B: tert-butyl 4-{[2-(3-bromopyridin-2-vl)hydrazinIyllcarbonylbenzoate To a 250 one neck round bottom flask was charged with 4-tert-butoxycarbonylbenzoic acid (1000 mg, 4.50 mmol) along with H1OBT (912 mg, 6.75 mnol) and EDC (1294 mg, 6.75 43 WO 2012/015693 PCT/US2011/045022 MRL-vvu4D mmol) in CH 2 C1 2 (40 ml) before the addition of 3-bromo-2-hydrazinylpyridine (846 mg, 4.50 mmol). The mixture was stirred at room temperature for 18 hrs overnight. LC-MS showed complete coupling and the mixture was concentrated by rotary evaporation. The residue was then suspended in ethyl acetate (15 mL) and water (50 mL) and stirred for 1 hour. The solid was filtered and washed with water 3 times and dried under vacuum for 4 hours for afford white solid product tert-butyl 4- { [2-(3-bromopyridin-2-yl)hydrazinyl] carbonyl} benzoate. LC-MS (Es, m/z):

C

7 HisBrN 3 0 3 : 391; Found: 392 [M+H]. Step C: 4-(8-bromoF1,2,4]triazolof4,3-alpyridin-3-yl)benzoic acid To a 25 ml microwave reaction vessel was charged with tert-butyl 4-{[2-(3 bromopyridin-2-yl)hydrazinyl]carbonyl}benzoate (500 mg, 1.275 mmol) along with acetic Acid (10 ml). The mixture was stirred at room temperature for 10 min and then under microwave at 200 OC for 2 hrs. LC-MS showed complete formation of product as solid precipitated out. The product was then filtered and washed with water, dried under high vacuum overnight to afford light color powder product 4-(8-bromo[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzoic acid. LC-MS (ES, m/z): C 1 3 HsBrN 3 0 2 : 317; Found: 318 [M+H]. Step D: 8-bromo-3-{4-[6-(trifluoromethyl)- 1H-benzimidazol-2 yllphenyl} [1 ,2,4ltriazolo[4,3-alpvridine To a 5 mL Pyrex vial was charged with 4-(8-bromo[1,2,4]triazolo[4,3-alpyridin-3 yl)benzoic acid (300 mg, 0.943 mmol) along with HOBT (191 mg, 1.415 mmol) and EDC (271 mg, 1.415 mmol) in DMF (lmL) before the addition of 4-trifluoromethyl-1,2-diaminobenzene (249 mg, 1.415 mmol). The mixture was stirred at room temperature for 10 min and then under microwave at 120 OC for 20 min. LC-MS showed complete coupling of the acid with amine. Then acetic acid (lmL) was added and the mixture was exposed to microwave at 200 OC for 40 min. LC-MS showed complete fonnation of imidiazole. The reaction mixture was then concentrated and worked up regularly. The product had very small solubility and filtered to afford crude product, small amount was purified by RPHPLC to afford 8-bromo-3-{4-[6 (trifluoromethyl)-IH-benzimidazol-2-yl]phenyl}[1,2,4]triazolo[4,3-a]pyridine. LC-MS (ES, m/z): C 2 0 HIIBrF 3

N

5 : 457; Found: 458 [M+H]. 'HNMR (500 MHz, CDC 3 ) 8: 8.66 (11H, 2, 7.0 Hz), 8.37 (2H, d, 8.5 Hz), 8.19 (2H, 2, 8.5 Hz), 8.08 (1H, s), 7.93 (1H, d, 8.0 hz), 7.85 (lH, d, 6.0 Hz), 7.77 (IH, d, 8.0 Hz), 7.07 (lH, t, 7.5 Hz) ppm. 44 WO 2012/015693 PCT/US2011/045022 MRJA)Ut$-00U4), Example 15: HOOC - / HN \ / CF 3 X- I N NXO H 3-(2-oxo-1-{4-[5-(trifluoromethyll-IH-benzimidazol-2-yl]phenvl }-2,3-dihydro-1H imidazo[4,5 -bpyridin-6-yl)benzoic acid Step A: 4-(6-iodo-2-oxo-2,3-dihydro-1H-imidazo[4,5 -bipyridin-1-vl)benzoic acid A mixture of Intermediate 2 (1000 mg, 3.92 mmol) in acetic acid (2 mL), water (0.4 mL), sulfuric acid (0.125 mL) and Periodic acid (179 mg, 0.784 mmol) was allowed to stirred at 90 OC for 15 min. Iodine crystals (796 mg, 3.13 nunol) were added in portions. After it was stirred for 1 hr, the reaction mixture was poured into water and the solid was filtered and washed with water, ethyl acetate to afford white solid product. 4-(6-iodo-2-oxo-2,3-dihydro-1H imidazo[4,5-b]pyridin-1-yl)benzoic acid. LC-MS (ES, m/z): C 13 1 8

N

3 0 3 : 381; Found: 382 [M+H]*. StepB: 6-iodo-1-14-[5-(trifluorometl-yl)-H-benzimidazol-2-y lphenyl}-1,3-dihydro-2H imidazo[4,5-blpyridin-2-one To a 5 mL Pyrex vial was charged with 4-(6-iodo-2-oxo-2,3-dihydro-1H-imidazo[4,5 b]pyridin-1-yl)benzoic acid (52 mg, 0.136 mmol) along with EDC (34.0 mg, 0.177 mmol) and HOBT (23.97 mg, 0.177 mmol) in DMF (lmL) before the addition of 4-trifluoromethyl-1,2 phenyldiamine (31.2 mg, 0.177 mmol). The mixture was stirred at room temperature for 10 min and then under microwave at 120 "C for 20 min. LC-MS showed complete coupling of the acid with amine. Then acetic acid (1mL) was added and the mixture was exposed to microwave at 200 OC for 40 min, LC-MS showed complete formation of imidiazole. The mixture was filtered and concentrated and the residue was purified by RP HPLC (20 to 80% acetonitrile in water on YMC colunm) to afford product 6-iodo-1-{4-[5-(trifluoromethyl)-1H-benzimidazol-2 yl]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. LC-MS (ES, m/z): C 20

H

11

F

3 1N 5 0: 521; Found: 522 [M+H]*. 'IHNMR (500 MHz, CD 3 0D) 6: 8.35 (2H, d, 9.0 Hz), 8.29 (1 H, s), 8.11 (1H, s), 7.98 (liH, d, 5.5 Hz), 7.96 (2H, d, 8.5 Hz), 7.83 (1H, d, 9.0 Hz), 7.78 (1H, s) ppm. 45 WO 2012/015693 PCT/US2011/045022 MRL L-uus-uuu% Step C: ethyl 3-(2-oxo-1-14-[5-(trifluoromethvl)-1H-benzimidazol-2-yllphenyl1-2,3 dihydro-1H-imidazo[4,5-blpyridin-6-yl)benzoate To a 2 ml biotage micoreaction tube was charged with 6-iodo-1-{4- [5-(trifluoromethyl) IH-benzimidazol-2-yl]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (29 mg, 0.046 mmol) along with 3-ethoxycarbonylphenyl boronic acid (11.51 mg, 0.059 mmol), Pd(dppf) (3.34 mg, 4.57 pmol), sodium carbonate (14.52 mg, 0.137 mmol), DMF (1.5 mL) and water (0.3 mL). The flask was put under nitrogen and the reaction mixture was stirred and heated in an oil bath of 60 C for 15 hours overnight. LC-MS showed almost complete conversion of starting material to product. After cooled to room temperature, the mixture was diluted with ethyl acetate (50 mL) and water (30 mL) and the insoluble solid was filtered and washed with ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2x). The combined organic phases were washed with water, brine, dried over MgS04, filtered and concentrated. The residue was purified by PrepTLC (1000 nm, ethyl acetate) to afford solid product ethyl 3 -(2-oxo- 1- {4- [5-(trifluoromethyl)- 1 H-benzimidazol-2-yl]phenyl }-2,3 -dihydro- 1 H imidazo[4,5-bjpyridin-6-yl)benzoate. LC-MS (ES, m/z): C 29

H

2 0

F

3

IN

5 03: 543; Found: 544 [M+H]*. Step D: 3-(2-oxo-1-14-[5-(trifluoromethvl)-1H-benzimidazol-2-yllphenyl}-2,3-dihydro 1H-imidazo[4,5-b]pyridin-6-yl)benzoic acid To a 20 mL sample vial was charged with ethyl 3-(2-oxo-l-{4-[5-(trifluoromethyl)-1H benzimidazol-2-yljphenyl}-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)benzoate (17 mg, 0.031 mmol) along with methanol and NaOH (5N). The mixture was stirred at 45 'C for 30 min. LC MS showed complete hydrolysis of ester. The mixture was neutralized by HC (IN) and then concentrated. The residue was purified by RP HPLC (YMC column, 20 to 80% acetonitrile in water) to afford product 3-(2-oxo-I-{4-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]phenyl}-2,3 dihydro-IH-imidazo[4,5-b]pyridin-6-yl)benzoic acid. LC-MS (ES, m/z): C 27

H

1 6

F

3 1N 5 03: 515; Found: 516 [M+H]f. Example 16: 46 WO 2012/015693 PCT/US2011/045022 N

CF

3 NN H N N

N

0 4-benzyl- 1 -4-[6-(trifluoromethyl)-IH-benzimidazol-2-yllphenylI -1,4-dihydro-2H imidazo[4,5-blpyridin-2-one Step A: To a 35 mL sealed vial was charged with intermediate 2 (1000 fig, 3.92 mmol) along with potassium carbonate (650 mg, 4.70 mmol) and benzyl bromide (737 mg, 4.31 mmol) in DMF (lOmL). The mixture was stirred at room temperature for 18 hrs. LC-MS showed formation of three products. The mixture was then partitioned between ethyl acetate (40 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic phases were washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified by MPLC (solid load on silica gel, 40 to 100% ethyl acetate in hexanes) to afford three products: benzyl 4-(3-benzyl-2-oxo-2,3-dihydro lH-imidazo[4,5-b]pyridin-1-yl)benzoate. LC-MS (ES, m/z): C27H21N305: 435; Found: 436 [M+H]*. 'HNMR (500 MHz, CDCl 3 ) 6: 8.22 (2H, d, 8.5 Hz), 8.12 (IH, d, 4.0Hz), 7.64 (2H, d, 8.5 bz), 7.56 (2H, d, 7.4 Hz), 7.44 (2H, d, 7.4 Hz), 7.38 (2H, t, 6.1 Hz), 7.32 (4H, m), 7.25 (1H, t, 7.3Hz), 6.99 (1H, t, 5.2 Hz), 5.38 (2H, s), 5.21 (2H, s) ppm; benzyl 4-(2-oxo-2,3-dihydro-1H imidazo[4,5-b]pyridin-1-yl)benzoate, LC-MS (ES, m/z): C 20

H

15

N

3 0 5 : 345; Found: 346 [M+H]*. 1 HNMR (500 MHz, CDCl 3 ) 6: 10. 9 (1H, br), 8.26 (2H, d, 8.5 Hz), 8.18 (1H, 4.1 Hz), 7.68 (2H, d, 7.1 Hz), 7.47 (2H, d, 7.2 Hz), 7.36 (4H, m), 7.06 (1H,t, 6.2 Hz) ppm; and benzyl 4-(4-benzyl 2-oxo-2,4-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzoate): LC-MS (ES, m/z): C 27 H2 1

N

3 05: 435; Found: 436 [M+H]*. 'HNMR (500 MHz, CDCl 3 ) 6: 8.19 (2H, d, 8.6 Hz), 7.64 (2H, d, 8.6 Hz), 7.46 (3H, m), 7.34 (6H, m), 7.07 (1H, d, 7.2 Hz), 6.65 (1H, t, 7.2 Hz), 5.54 (2H, s), 5.39 (2H, s). StepB: lithium 4-(3-benzyl-2-oxo-2,3-dihydro-IH-imidazo f4,5-b]pyridin-1-yl)benzoate To a 20 mL sample vial was charged with benzyl 4-(3-benzyl-2-oxo-2,3-dihydro-1H imidazo[4,5-b]pyridin-1-yl)benzoate (100 mg, 0.230 mmol) in THF/ water along with lithium 47 WO 2012/015693 PCT/US2011/045022 MRL-J-Urt. hydroxide (11.56 mg, 0.276 mmol). The resulting reaction mixture was then stirred at room temperature for 2 hrs. LC-MS showed complete hydrolysis of the ester. The mixture was then concentrated and the residue was dried by coevaporated with toluene to afford lithium 4-(3 benzyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzoate. LC-MS (ES, m/z):

C

20

H

14 LiN 3 0 3 : 345; Found: 346 [M+H]*. Step C: 4-benzyl- 1- {4- [6-(trifluoromethyl)- 1 H-benzimidazol-2-yll phenyl} 1-4-dihydro 2H-imidazor 45-bpyridin-2-one To a 5 mL Pyrex vial was charged with lithium 4-(3-benzyl-2-oxo-2,3-dihydro-1IH imidazo[4,5-b]pyridin-1-yl)benzoate (81 mg, 0.231 mmol) along with EDC (57.5 mg, 0.300 mmol) and HOBT (40.5 mg, 0.300 mmol) in DMF (1mL) before the addition of 4 trifluoromethyl-1,2-phenyldiamine (40.6 mg, 0.231 mmol). The mixture was stirred at room temperature for 10 min and then under microwave at 120 oC for 20 min. LC-MS showed complete coupling of the acid with amine. Then acetic acid (1mL) was added and the mixture was exposed to microwave at 200 OC for 40 min. LC-MS showed complete formation of imidiazole. The mixture was filtered and concentrated and the residue was purified by RP HPLC to afford product TFA salt 4-benzyl- 1-{4-[6-(trifluoromethyl)-1H-benzimidazol-2-yl]phenyl} 1,4-dihydro-2H-imidazo[4,5-b]pyridin-2-one. LC-MS (ES, m/z): C 27

H

18

F

3

N

5 0: 485; Found: 486 [M+H]*. Example 17: N / CF 3 N H N- N 4-benzyl- 1-{4-[6-(trifluoromethyl)- 1H-benzimidazol-2-yl]phenyll-1,4-dihydro-2H imidazo[4,5-bjpyridin-2-one Following the same synthesis for Example 15, using the intermediate benzyl 4-(4-benzyl 2-oxo-2,4-dihydro-IH-imidazo[4,5-b]pyridin-1-yl)benzoate) from Step A, 4-benzyl-1-{4-[6 48 WO 2012/015693 PCT/US2011/045022 MRL-DUB3-00U4 (trifluoromethyl)- 1 H-benzimidazol-2-yl]phenyl} -1,4-dihydro-2H-imidazo[4,5-b]pyridin-2-one was prepared. LC-MS (ES, m/z): C 27

H

18

F

3

N

5 0: 485; Found: 486 [M+H]t. Example 18: N

CF

3 N o N O HO (2-oxo-1-{4-[6-(trifluoromethyl)-1H-benzimidazol-2-yl]phenyl}-1,2-dihydro-3H imidazo[4,5-blpyidin-3-yl)acetic acid Step A: benzyl 4-[3 -(2-ethoxy-2-oxoethyl)-2-oxo-2 3-dihydro-1.H-imidazo[4,5-blpvridin-1I yljbenzoate and benzyl 4-44-(2-ethoxy-2-oxoethyl)-2-oxo-2,4-dihydro-lH-imidazo[4,5 b]pyridin-1-yllbenzoate To a 35 mL sealed vial was charged with benzyl 4-(2-oxo-2,3-dihydro-lH-imidazo[4,5 b]pyridin-1-yl)benzoate (280 mg, 0.811 mmol) from Step A Example 15, along with potassium carbonate (146 mg, 1.054 mmol) and ethyl 2-bromoacetate (176 mg, 1.054 mmol) in DMF (1 OmL). The mixture was stirred at room temperature for 18 hrs. LC-MS showed formation of product plus two bisaclkylated product. The mixture was then partitioned between ethyl acetate (40 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic phases were washed with water, brine, dried over MgS04, filtered and concentrated. The residue was purified by MPLC (solid load on silica gel, 40 to 100% ethyl acetate in hexanes) to afford two products: benzyl 4-[3-(2-ethoxy-2-oxoethyl) 2-oxo-2,3-dihydro-IH-imidazo[4,5-b]pyridin-1-yl]benzoate: LC-MS (ES, m/z): C 2 4H2 1

N

3 0 5 : 431; Found: 432 [M+H]*. 'HNMR (500 MHz, CDCl 3 ) a: 8.22 (2H, d, 6.5 Hz), 8.07 (1H, d, 1.0 Hz), 7.66 (2H, d, 8.5 Hz), 7.44 (2H, d, 7.3 Hz), 7.37 (4H, n), 7.02 (1H, t, 5.1 Hz), 5.38 (2H, s), 4.79 (2H, s), 4.25 (2H, q, 7.1 Hz), 1.28 (3H, t, 7.1 Hz) ppm; benzyl 4-[4-(2-ethoxy-2-oxoethyl) 2-oxo-2,4-dihydro-1H-imidazo[4,5-b]pyridin-1-yl]benzoate: LC-MS (ES, m/z): C 24

H

2 1

N

3 0 5 : 431; Found: 432 [M+H]f. 1 HNMR (500 MHz, CDCl 3 ) a: 8.19 (2H, d, 8.5 Hz), 7.64 (2H, d, 8.5 Hz), 7.45 (2H, d, 7.4 Hz), 7.39 (2H, t, 7.0 Hz), 7.35 (11H, d, 7.0 Hz), 7.25 (11H, 2, 6.8 Hz), 7.11 49 M L O 2012/015693 PCT/US2011/045022 (IH, d, 7.3 Hz), 6.69 (1H, t, 7.1 Hz), 5.38 (2H, s), 5.13 (2H, s), 4.26 (2H, q, 7.1 Hz), 1.30 (3H, t, 7.1 Hz) ppm. Step B: 4-[3-(2-ethoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-blpyridin-1 llbenzoic acid To a parshaker vessel (50 mL) was charged with benzyl 4-[3-(2-ethoxy-2-oxoethyl)-2 oxo-2,3-dihydro-IH-imidazo[4,5-b]pyridin- 1 -yl]benzoate (220 mg, 0.510 mmol)along with Pd/C (100 mg, 0.094 mmol)and ethyl acetate (20 mL). The system was treated on parshaker under 40 psi hydrogen for 15 hours overnight. LC-MS showed complete reduction of nitro to amine. The catalyst was filtered and washed with methanol. The filtrate was concentrated to afford white solid product 4-[3-(2-ethoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5 b]pyridin-l -ylJbenzoic acid. LC-MS (ES, m/z): C 17 Hi 5

N

3 0 5 : 341; Found: 342 [M+H] t . Step C: ethyl (2-oxo-1-{4-[6-(trifluoromethyl)-1H-benzimidazol-2-yllphenyll-1,2 dihydro-3H-imidazoF4,5-bjpyridin-3-yl)acetate and (2-oxo-1-{4-[6-(trifluoromethyl)-1H benzimidazol-2-vllphenv1}I-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)acetic acid To a 5 mL Pyrex vial was charged with 4-[3-(2-ethoxy-2-oxoethyl)-2-oxo-2,3-dihydro 1H-imidazo[4,5-b]pyridin-1-ylIbenzoic acid (89 mg, 0.261 mmol) along with EDC (65.0 mg, 0.339 mmol) and HOBT (45.8 mg, 0.339 mmol) in DMF (imL) before the addition of 4 trifluoromethyl-1,2-phenyldiamine (50.5 mg, 0.287 mmol). The mixture was stirred at room temperature for 10 min and then under microwave at 120 'C for 20 min. LC-MS showed complete coupling of the acid with amine. Then acetic acid (lmL) was added and the mixture was exposed to microwave at 200 OC for 40 min. LC-MS showed complete formation of imidiazole. The mixture was filtered and concentrated and the residue was purified by RP HPLC to afford products ethyl (2-oxo-1-{4-[6-(trifluoromethyl)-1H-benzimidazol-2-yl]phenyl}-1,2 dihydro-3H-imidazo[4,5-b]pyridin-3-yl)acetate: LC-MS (ES, m/z): C 24 Hi 8

F

3

N

5 0 3 : 481; Found: 482 [M+H]*; and (2-oxo-1-{4-[6-(trifluoromethyl)-1H-benzimidazol-2-yl]phenyl}-1,2-dihydro 3H-imidazo[4,5-b]pyridin-3-yl)acetic acid: LC-MS (ES, m/z): C 22

H

1 4F3N 5 0 3 : 453; Found: 453 [M+H)f. 50 WO 2012/015693 PCT/US2011/045022 MRL-uub5-uuu'o Example 19: HN

CF

3 F N N N 0 6-fluoro-1-{4-[6-(trifluoromethyll-IH-benzimidazol-2-yllphenyl}-1,3-dihydro-2H pyrrolo[3,2-blpyridin-2-one A 5 ml seal tube was treated with 6-fluoro-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (100 mg, 0.657 mmol), intermediate 5 (253 mg, 0.651 mmol), copper(I) iodide (25.04 mg, 0.131 mmol) and potassium carbonate (182 mg, 1.315 nmnol), capped and evacuated and backfilled with N2. Dioxane (6.0 ml) followed by trans-(1R,2R)-N,N'-bismethyl-1,2-cyclohexanediamine (0.021 ml, 0.131 mmol) was then added under N2 and the mixture stirred at 85 'C for 20 hr. The mixture was diluted with EtOAc, filtered and washed with warm EtOAc. The filtrate was conc. in vaccu and CombiFlash companion purification eluting with 5:3 5:40, MeOH:EtOAc:Hexane afforded 6-fluoro- 1- {4- [6-(trifluoromethyl)- 1 H-benzimidazol-2-yl]phenyl} -1,3 -dihydro-2H pyrrolo[3,2-b]pyridin-2-one: LC-MS (ES, m/z): C 21

H

13

F

4

N

4 0: 381; Found: 382 [M+H]. Following the same procedure for Example 18, the following compounds were prepared: H

-

CF 3 HNJ> N R1 51 WO 2012/015693 PCT/US2011/045022 Example R1 Name Parent Ion m/z [M+H]* 20 6-chloro- 1-{4-[5-(trifluoromethyl)-1IH- 427 N \ benzimidazol-2-yl]phenyl}-1,3-dihydro-2H

....................

_pyrrolo[3,2-b]pyridin-2-one 21 \ Ny 1-{4-[5-(trifluoromethyl)-lH-benzimidazol- 394 o 2-yl]phenyl-1,3-dihydro-2H-indol-2-one 22 6-(trifluoromethyl)-l-{4-[5- 463 N N (trifluoromethyl)- 1 H-benzimidazol-2 yl]phenyl} -1,3-dihydro-2H-pyrrolo[3,2 b]pyridin-2-one 23 FC methyl 2-oxo-6-(trifluoromethyl)-1-{4-[5- 521 N / N (trifluoromethyl)-IH-benzimidazol-2 MeO2C yl]phenyl}-2,3-dihydro-lH-pyrrolo[3,2 b]pyridine-3-carboxylate 24 N 7-bromo-3-{4-[5-(trifluoromethyl)-1H- 474 Br O benzimidazol-2-yljphenyl}-1,3-benZoxazol 2(3H)-one 25 3-{4-[5-(trifluoromethyl)-1H-benzimidazol- 396 4o 2-yl]phenyl}-1,3-benzoxazol-2(3H)-one Example 26: N Ci / N 1-[4-(6-chloro-1H-benzimidazol-2-yl)phenyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5 5 b]pyridin-2-one To a 20 ml sample vial was charged with 1-[4-(6-chloro-JH-benzimidazol-2-yl)phenyl] 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (example 4) ( 100 mg, 0.276 mmol) along with potassium carbonate (38 mg, 0.276 mmol) in DMF. Then methyl iodide (118 mg, 0.829 mmol) before the reaction mixture was stirred at room temperature for 18 hr overnight. The mixture - 52 - WO 2012/015693 PCT/US2011/045022 was filtered and crude was purified directly by R-P HPLC (20 to 80% acetonitrile) to afford product 1-[4-(6-chloro-IH-benzimidazol-2-yl)phenyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5 b]pyridin-2-one. LC-MS (ES, m/z): C 20

H

14 C1N 5 0: 375; Found: 376 [M+H]*. N / CI N R 1NH NAi R/ \\ Example Ri Name Parent Ion n/z [M+H]+ 27 Ethyl 1-[4-(6-chloro-1H-benzimidazol-2- 380 yl)phenyl] -3-ethyl- 1,3 -dihydro-2H imidazo[4,5-b]pyridin-2-one 28 Butyl 1-[4-(6-chloro-lH-benzimidazol-2- 408 yl)phenyl]-3-butyl-1,3-dihydro-2H imidazo[4,5-b]pyridin-2-one 29 'Propyl 1-[4-(6-chloro-IH-benzimidazol-2- 394 yl)phenyl]-3-isopropyl-1,3-dihydro-2H imidazo[4,5-b]pyridin-2-one 5 DGAT1 CPM Assay 20uL substrate mixture of 300uM diolein, 40uM oleoyl-CoA, 10% ethanol and luL of the compound with different concentrations were delivered to a 384 well assay plate (Coming 3573) using a Tecan with TeMO module. Later 19uL of enzyme mixture of 1.05ug/ml human DGATi 10 in buffer (200mM Tris, pH7, 200mM sucrose, 200mM MgCI2 + 20ug/ml NEM-treated BSA) was added via a Multidrop Combi using a microcassette. 20uL of 90uM CPM reagent in 90% ethanol was added after 1 hour incubation at room temperature. After 30 minutes at room temperature in dark, fluorescence measurement on Envision was carried out and IC50s were calculated. Example IC50 (nM) Example IC50 (nM) - 53 - WO 2012/015693 PCT/US2011/045022 1 7.339 18 12.74 2 1134 19 116.8 3 39.98 20 868.2 4 21.62 21 88.08 5 13.16 22 7708 6 15.17 23 8363 7 86.76 24 38.05 8 9.123 25 62.11 10 2297 26 1089 11 532 27 651.8 12 34.81 28 654.9 13 782.1 29 654.9 14 20.97 15 966.8 - 54 -

Claims (27)

1. A compound of formula (I): R2 HN R 3 UBN B V W 5 or pharmaceutically acceptable salts thereof, wherein in rings A and B are selected from the group consisting of benzene, pyridine, pyrazine and pryim-idine; X and Y are independently selected from the group consisting of -N- and -CH-; Z is -N- or C=0; W is -N-, -N(R4)-, -C(R5)- or -O-; 10 V and U are independently selected from the group consisting of -C(R6)- and -N-; and R', R2, R3, R4, RW and RW are independently selected from the group a, Cr-Ciocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, Cr-CoalkylCr-Cjeycloalkyl, Cl-Cealkylaryl, Cl-Calkylheteroaryl and Cj Coalkyleycloheteroalkyl, wherein Cr-Clocycloalkyl, aryl, heteroaryl, cycloheteroalkyl, Cl-CoalkylCr Clocycloalkyl, Cr-Cralkylaryl, Cr-Cealkylheteroaryl and Cr-Coalkylcycloheteroalkyl are independently 15 unsubstituted or substituted with one or more substituents selected from the group consisting of a; a is selected from the group consisting of hydrogen, halogen, Cr-Cealkyl, halogen-substitutedCr Coalkyl, COCIrCoalkyl, oxo, -OH1, Cr-CoalkylOH-, halogen-substitutedCl-CoalkylOH, -OCr-Coalkyl, Ohalogen-substitutedciC~alkyl, -COOH, -COOCr-Coalkyl, -C1-CoalkylCOOCj-Calkyl, -Ce CoalkylCOOH, -OCr-CoalkylCOOH, -CN, C1-CoalkylCN, -NO2, NH2, NHCr-Coalkyl, N(C)-Coalky1)2, 20 NHCOOH, -NHCOOCr-Coalkyl, -CONH2, -COl@HIC~alkyl, -CON(Cr-Cealkyl)2, -NHSO2Cr-Calkyl, SO2Cj-Qalkyl, Cr-Clcycloalkyl, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylCOOH, Cj CealkylCr-Cacycloalkyl, Cr-Coalkylaryl, Cl-Coalkylheteroaryl and Cl-Cealkylcycloheteroalkyl. 25

2. A compound of claim I or pharmaceutically acceptable salt thereof wherein ring A and ring B are individually selected from the group consisting of benzene and pyridine.

3. A compound of any one of claims 1-2 or pharmaceutically acceptable salt thereof wherein ring A is formula II: - 55 - WO 2012/015693 PCT/US2011/045022 R 2 I~a R' IL.

4. A compound of any one of claims 1-3 or pharmaceutically acceptable salt thereof wherein ring B is pyridine. 5

5. A compound of any one of claims 1-3 or pharmaceutically acceptable salt thereof wherein ring B is benzene.

6. A compound of any one of claims 1-5 or pharmaceutically acceptable salt thereof 10 wherein X is -CH-.

7 A compound of any one of claims 1-6 or pharmaceutically acceptable salt thereof wherein Y is -N-. 15

8. A compound of any one of claims 1-7 or pharmaceutically acceptable salt thereof wherein Z is -C=0.

9. A compound of any one of claims 1-8 or pharmaceutically acceptable salt thereof wherein R2 is hydrogen. 20

10. A compound of any one of claims 1-9 or phannaceutically acceptable salt thereof wherein R' and R2 are independently selected from the group consisting of hydrogen, halogen, -CN-, aryl, -OC 1 -C 6 alkyl, -Ohalogen-substitutedCrC 6 alkyl and halogen-substitutedCrCalkyl. 25

11. A compound of any one of claims 1-8 or pharmaceutically acceptable salt thereof wherein R2 is halogen or hydrogen and R' is selected from the group consisting of halogen, -CN-, aryl, OC-C 6 alkyl, -Ohalogen-substitutedC-Coalkyl and halogen-substitutedC-C 6 alkyl. 30

12. A compound of any one of claims 1-8 or pharmaceutically acceptable salt thereof wherein R' is selected from the group consisting of halogen and halogen-substitutedC-C 6 alkyl. -56- WO 2012/015693 PCT/US2011/045022

13. A compound of any one of claims I- 12 or pharmaceutically acceptable salt thereof wherein W is -N(R4), wherein 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C] C 6 alkylaryl, aryl, -C 1 -C 6 alkylCOOH, - C-C 6 alkylCOOC-C 6 alkyl and -COOC-C 6 alkyl wherein the C 1 C 6 alkylaryl and aryl are unsubstituted or substituted with -COOH, -C 1 -C 6 alkylCOOH, - C 1 5 C 6 alkylCOOC 1 -C 6 alkyl and -COOC-C 6 alkyl.

14. A compound of any one of claims 1-12 or pharmaceutically acceptable salt thereof wherein W is -N(R), wherein R4 is hydrogen. 10

15. A compound of any one of claims 1-12 or pharmaceutically acceptable salt thereof wherein W is -N(RW), wherein R4 is CI-C 6 alkyl, C 1 -C 6 alkylaryl, -Q-C 6 alkylCOOH, -C 1 -C 6 aIkylCOOC, C 6 alkyl and -COOC 1 -C 6 alkyl.

16. A compound of any one of claims 1-12 or pharmaceutically acceptable salt thereof 15 wherein W is -N(RW), wherein R4 is aryl, wherein the aryl is substituted with -COOH, -C 1 C 6 alkyICOOH, - C 1 -C 6 alkylCOOC 1 -C 6 alkyl and -COOC 1 -Cfalkyl.

17. A compound of any one of claims 1-16 or pharmaceutically acceptable salt thereof wherein V is -N- and U is -CH. 20

18. A compound of any one of claims 1-17 or pharmaceutically acceptable salt thereof wherein RW is hydrogen.

19. A compound of any one of claims 1-18 or pharmaceutically acceptable salt thereof 25 wherein R3 is aryl, halogen and halogen-substitutedC-C 6 alkyl wherein the aryl is substituted with COOH, -OH or halogen-substitutedC-C 6 alkyl.

20. A compound, or pharmaceutically acceptable salt thereof of formula Ia: N RI NN N H N NR o la 30 wherein R 1 is halogen or halogen-substitutedC-C 6 alkyl; and -57- WO 2012/015693 PCT/US2011/045022 R 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -Csalkylaryl, aryl, -C-C 6 alkylCOOH, - C 1 C 6 alkylCOOC-C 6 alkyl and -COOC 1 -C 6 alkyl wherein the C 1 -C 6 alkylaryl and aryl are unsubstituted or substituted with -COOH, -C 1 -C 6 alkylCOOH, - C-C 6 alkylCOOC 1 -C 6 alkyl and -COOC 1 -Csalkyl. 5

21. A compound of claim 17 or pharmaceutically acceptable salt thereof, wherein R, is fluorine or trifluoromethyl.

22. A compound of claim 17 or pharmaceutically acceptable salt thereof, wherein R 4 is C 1 C 6 alkyl or aryl. 10

23. A compound of claim 17 or pharmaceutically acceptable salt thereof, wherein R{ is phenyl.

24. A compound or pharmaceutically acceptable salt thereof selected from the group 15 consisting of: F N -F F N N H o N F N NF H F N H 0 H N N H - 58 - WO 2012/015693 PCT/US2011/045022 F H N NN F N O H NC H N - 5F 0N *F NN HH N F NN H N N / N N N N H 0 - 59 - WO 2012/015693 PCT/US2011/045022 H N N / N N NN H H F F N I 0 xF N N N HO 0 0F FF F N H N N N 0 N 0 HOC F60 WO 2012/015693 PCT/US2O1 1/045022 "N,, N F 7\ F N- N 00 H 3 0 N N H 100 /.0 F N H Ne N 00 HO WO 2012/015693 PCT/US2011/045022 N C N H 0 HO F HF N N N NH N O H 7 2H 3 H H F N N -- N H N N / N 0 OH 3 - 62 - WO 2012/015693 PCT/US2011/045022 H N N / N N 0X OHC H NN N( C NN NN H3C H N F o OH F F H N N N H _N IN cl N /N H 3 C- CH 8 H N F F 0 - 63 - WO 2012/015693 PCT/US2011/045022 N F Br 0 N N H N NFH /F C N F F N N H C N I N F64 WO 2012/015693 PCT/US2011/045022 F F F N N 1-10 F 0 F F F F N N / NN O N H N No N N -O CF 3 NN - 65 - WO 2012/015693 PCT/US2011/045022 H N F F N N F F AND F N

25. A pharmaceutical composition comprising a compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 5

26. Use of a compound of any one of claims 1-26, 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

27. 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 1-26. -66-