OA18481A

OA18481A - Diacylglycerol acyltransferase 2 inhibitors for use in the treatment of metabolic and related disorders.

Info

Publication number: OA18481A
Application number: OA1201600345
Authority: OA
Inventors: Shawn Cabral; Kentaro Futatsugi; David Hepworth; Daniel Wei-Shung Kung; Kim HUARD; Suvi Tuula Marjukka Orr; Kun SONG
Original assignee: Pfizer Inc.
Priority date: 2014-03-17
Filing date: 2015-03-03
Publication date: 2018-12-04

Abstract

Compounds of Formula I

Description

The présent invention relates to new pharmaceutical compounds, pharmaceutical compositions containing these compounds, and their use to inhibit the activity of the diacylglycérol acyltransferase 2 (DGAT2).

BACKGROUND OFTHE INVENTION

Triglycérides or triacylglycerols (TAG) represent a major form of energy storage îo In mammals. TAG’s are formed by the sequential estérification of glycerol with three fatty acids of varying chain lengths and degrees of saturation (1). TAG synthesized in the intestine or liver are packaged Into chylomicrons or very low-density lipoproteîn (VLDL), respectively, and exported to peripheral tissues where they are hydrolysed to their constituent fatty acids and glycerol by lipoproteîn lipase (LPL). The résultant non15 esterified fatty acids (NEFA) can either be metabolised further to produce energy or reesterified and stored.

Under normal physiological conditions, the energy-dense TAG remains sequestered in various adipose depots until there is a demand for its release, whereupon, it is hydrolyzed to glycerol and free fatty acids which are then released into 20 the blood stream. This process is tightly regulated by the opposing actions of insulin and hormones such as catecholamines which promote the déposition and mobilization of TAG stores under various physiological conditions. In the post-prandial setting, insulin acts to inhibit lipolysis, thereby, restraining the release of energy in the form of NEFA and ensuring the appropriate storage of dietary lipids in adipose depots.

However, In patients with type 2 diabètes, the ability of insulin to suppress lipolysis is ameliorated and NEFA flux from adipocytes Is inappropriately elevated. This, in turn, results in increased delivery of lipid to tissues such as muscle and liver. In the absence of energetic demand the TAG and other lipid métabolites, such as diacylglycérol (DAG) can accumulate and cause a loss of insulin sensitivity (2). Insulin résistance in muscle is characterized by reduced glucose uptake and glycogen storage, whilst in the liver, loss of insulin signaling gives rise to dysregulated glucose output and over-production of TAG-rich VLDL, a hallmark of type 2 diabètes (3). Elevated sécrétion of TAG-enriched VLDL, so called VLDL1 particles, is thought to stimulate the production of small, dense low-density lipoprotein (sdLDL), a proatherogenic subfraction of LDL that is associated with elevated risk of coronary heart disease (4).

Diacylglycérol acyltransferases (DGAT) catalyze the terminal step in TAG synthesis, specifically, the estérification of a fatty acid with diacylglycérol resulting ln the 5 formation of TAG. ln mammals, two DGAT enzymes (DGAT1 and DGAT2) hâve been characterized. Although these enzymes catalyze the same enzymatic reaction their respective amino acid sequences are unrelated and they occupy distinct gene familles. Mice harboring a disruption in the gene encoding DGAT1 are résistant to diet-induced obesity and hâve elevated energy expenditure and activity (5). Dgatl-/- mice exhibit 10 dysregulated postaborpative release of chylomicrons and accumulate lipld in the enterocytes (6). The metabolically favorable phenotype observed in these mice is suggested to be driven by loss of DGAT1 expression in the intestine (7). Important^, despite a defect in lactation in female Dgatl 7- mice, these animais retain the capacity to synthesize TAG suggesting the existence of additional DGAT enzymes. This 15 observation and the isolation of a second DGAT from the fungus Mortierella rammaniana led to the identification and characterization of DGAT2 (8).

DGAT2 is highly expressed in liver and adipose, and unlike DGAT1, exhibits exquisite substratespecificity for DAG (8). Délétion ofthe DGAT2 gene in rodents results in defective intraunterine growth, severe lipemia, impaired skin barrier function, 20 and early post-natal death (9). Due to the lethality caused by loss of DGAT2, much of our understanding ofthe physiological rôle of DGAT2dérivésfrom studies performed with antisense oligonucleotides (ASO) in rodent models of metabolic disease. ln this setting, inhibition of hepatic DGAT2 resulted in Improvements in plasma lipoprotein profile (decrease in total cholestérol and TAG) and a réduction of hepatic lipid burden 25 which was accompanied by improved insulin sensitivity and whole-body glucose control (10-12). Although the molecular mechanisms underlying these observations are not fully elucidated, it is clear that suppression of DGAT2 results in a down-regulation of the expression of multiple genes encoding proteins Involved in lipogensis, including sterol regulatory element-binding proteins 1c (SREBPIc) and stearoyl CoA-desaturase 1 (SCD1) (11,12). ln parallel, oxidative pathways are induced as evidenced by increased expression of genes such as camitine palmitoyl transfersase 1 (CPT1) (11). The net resuit of these changes is to decrease the levels of hepatic DAG and TAG lipld which, in tum, leads to improved insulin responsiveness in the liver. Furthermore, DGAT2 inhibition suppresses hepatic VLDL TAG sécrétion and réduction in circulating cholestérol leveis. Finally, plasma apolipoprotein B (APOB) leveis were suppressed, possibly due to decreased supply of TAG for lipidation ofthe newlysynthesized APOB protein (10,12). The bénéficiai effects of DGAT2 inhibition on both glycémie control and plasma cholestérol profile suggest that this target mlght be valuable in the treatment of 5 metabolic disease (11 ). ln addition, the observation that suppression of DGAT2 activity results in reduced hepatic lipid accumulation suggests that inhibitors of this enzyme mlght hâve utility In the treatment of non-alcoholic steatohepatitis (NASH), a highly prévalent liver disease characterized by the déposition of excess fat in the liver.

1. Coleman, R. A., and D. G. Mashek. 2011. Mammalîan triacylglycerol metabolism: 10 synthesis, lipolysis, and signaling. Chem Rev 111: 6359*6386.

2. Erion, D. M., and G. I. Shulman. 2010. Diacylglycerol-mediated insulin résistance. Nat Med 16:400-402.

3. Choi, S. H., and H. N. Ginsberg. 2011. Increased very low density lipoprotein (VLDL) sécrétion, hepatic steatosis, and insulin résistance. Trends Endocrinol Metab

22:353-363.

4. St-Pierre, A. C., B. Cantin, G. R. Dagenais, P. Mauriege, P. M. Bernard, J. P. Despres, and B. Lamarche. 2005. Low-density lipoprotein subfractions and the longterm risk of ischémie heart disease ln men: 13-year follow-up data from the Quebec Cardiovascular Study. Arterioscler Thromb Vase Biol 25: 553-559.

5. Smith, S. J., S. Cases, D. R. Jensen, H. C. Chen, E. Sande, B. Tow, D. A.

Sanan, J. Raber, R. H. Eckel, and R. V. Farese, Jr. 2000. Obesity résistance and multiple mechanisms of triglycéride synthesis in mice lacking Dgat. Nat Genet 25: 8790.

6. Buhman, K. K., S. J. Smith, S. J. Stone, J. J. Repa, J. S. Wong, F. F. Knapp, Jr., 25 B. J. Burri, R. L. Hamiiton, N. A. Abumrad, and R. V. Farese, Jr. 2002. DGAT1 is not essential for intestinal triacylglycerol absorption or chylomicron synthesis. J Biol Chem 277: 25474-25479.

7. Lee, B., A. M. Fast, J. Zhu, J. X. Cheng, and K. K. Buhman. 2010. Intestinespecific expression of acyl CoA:diacylglycerol acyltransferase 1 reverses résistance to diet-induced hepatic steatosis and obesity in Dgatl-/- mice. J Lipid Res 51:1770-1780.

8. Yen, C. L., S. J. Stone, S. Koliwad, C. Harris, and R. V. Farese, Jr. 2008. Thematic review sériés: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J Lipid Res 49:2283-2301.

9. Stone, S. J., H. M. Myers, S. M. Watkins, B. E. Brown, K. R. Feingold, P. M.

Elias, and R. V. Farese, Jr. 2004. Llpopenia and skin barrier abnormalities In DGAT2deficient mice. J Biol Chem 279:11767-11776.

10. Liu, Y., J. S. Millar, D. A. Cromley, M. Graham, R. Crooke, J. T. Billheimer, and D. J. Rader. 2008. Knockdown of acyl-CoA:diacylglycerol acyltransferase 2 with antisense oligonucleotide reduces VLDL TG and ApoB sécrétion in mice. Biochim Biophys Acta 1781:97-104.

11. Choi, C. S., D. B. Savage, A. Kulkami, X. X. Yu, Z. X. Liu, K. Morino, S. Kim, A. Distefano, V. T. Samuel, S. Neschen, D. Zhang, A. Wang, X. M. Zhang, M. Kahn, G. W. Cline, S. K. Pandey, J. G. Geisler, S. Bhanot, B. P. Monia, and G. I. Shulman. 2007. Suppression of diacylglycérol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-lnduced hepatic steatosis and Insulin résistance. J Biol Chem 282: 22678-22688.

12. Yu, X. X., S. F. Murray, S. K. Pandey, S. L. Booten, D. Bao, X. Z. Song, S. Kelly,

S. Chen, R. McKay, B. P. Monia, and S. Bhanot. 2005. Antisense oligonucleotide réduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia In obese mice. Hepatology 42: 362-371.

SUMMARY OF THE INVENTION

The présent application Is directed at compounds of Formula (I) and (la)

I (la) wherein:

D is N, CH, or CF;

R¹ is (Ci*C4)alkyl optionally substituted with one, two or three substituents each independently selected from fluoro and (C3-Ce)cycioalkyl;

R² is fluoro or (Ci-C4)alkyl;

R³ is H, (Ci-C4)alkyl, or (C3-Ce)cycloalkyi;

R⁴ is H, -(Ci-C4)alkyl, -((Ci-C4)aikyl)p-(C3-Ce)cycloalkyl, -((Ci-C4)alkyl)p-(C3Ce)heterocyclyi, -((Ci-C4)alkyl)p-aryl, or -((Ci-C4)alkyl)_P-heteroaryi wherein R⁴ Is optionally substituted with one, two, three, or four substituents selected from hato, cyano, oxo, aminyl, iminyl, -OH, -(Ci-QJalkyl, -(Ci-C4)fluoroalkyl, -(Ci-C^alkoxy, -(C3Cejcycloalkoxy, -(Ci-C^fluoroalkoxy, -((Ci-C4)alkyl)q-COOH, -((Ci-C4)alkyl)q-(C3Ce)cycloalkyl-COOH, -((Ci-C4)alkyl)q-(C3-C6)heterocyclyl-COOH, -((Ci-C^alkynq-arylCOOH, -((Ci-C4)aikyl)<_rheteroaryl-COOH, -O-((Ci-C4)alkyl)q-COOH, -O-((Ci-C4)alkyl)q15 aryl-COOH,, -O-((Ci-C4)alkyl)q-heteroaryl-COOH, -((Ci-C4)alkyl)q-(C3-Ce)cycloalkyl, ((Ci-C4)alkyi)q-(C3-Ce)heterocyclyi, -((Ci-C4)alkyl)q-aryl, -((Ci-C4)alkyl)q-heteroaryl, C(O)-(Ci-C4)alkyl, -C(O)-(Ci-C4)alkoxy, -C(0)-(C3-Ce)cycloalkyl, -C(O)-(C3Cejheterocyclyl, -C(O)-NR^eR⁷, -C(O)-((Ci-C4)alkyl)q-aryl, -C(O)-((Ci-C4)alkyl)qheteroaryl, -NR⁶R⁷, -NR^e-C(O)-R⁷,-((Ci-C4)alkyi)q-O-aryl, -((Ci-C4)alkyi)q-0-heteroaryl, 20 S(O)₂-R⁷, and -S(O)2-NR®R⁷;

or R³ and R⁴ may be joined together to form a 4- to 10- member fully saturated, or partially saturated ring system optionally substituted with one, two, three, or four substituents selected from halo, cyano, -OH, -(Ci-C4)alkyl, -(Ci-C4)fluoroalkyi, -(C1C4)alkoxy, -(C3-Ce)cycloalkoxy, -(Ci-C4)fluoroalkoxy, -((Ci-C4)alkyl)q -COOH, -((C125 C4)alkyi)q-(C3-Ce)cycloalkyl-COOH, -((Ci-C4)alkyl)q-(C3-Ce)heterocyclyl-COOH, -((C1C4)alkyl)q-aryl-COOH, -((Ci-C4)alkyl)q-heteroaryl-COOH, -O-((Ci-C4)alkyl)q-COOH, -O((Ci-C4)alkyi)q-aryl-COOH, -O-((Ci-C4)alkyl)q-heteroaryi-COOH, -((Ci-C4)alkyi)q-(C3Ce)cycioalkyl, -((Ci-C4)alkyl)q-(C3-Ce)heterocyclyl, -((Ci-C4)alkyi)q-aryl, -((Ci-C4)alkyl)qheteroaryl, -C(O)-(Ci-C4)alkyI, -C(O)-(C3-Ce)cycloalkyl, -C(O)-(C3-Ce)heterocyciyl, 30 C(O)-aryi, -C(O)- heteroaryl, -C(O)-NR^eR⁷, -C(O)-(Ci-C4)alkyl-aryl, -C(O)-(Ci-C4)alkyiheteroaryi, -NR^eR⁷, -NR^e-C(O)-R⁷,-O-aryl, -0-heteroaryl,-(Ci-C4)alkyi-0-aryl, -(C1C4)alkyl-0-heteroaryl, -O-(Ci-C4)alkyl-aryl, and -O-(Ci-C4)alkyl-heteroaryi;

φ R^s Is H, F, or cyano;

R^e is H. (Ci-CU)alkyl, or-S(0)2-R⁷;

R⁷ is H, (Ci-C4)alkyl, -(C3-Ce)cycloalkyl, -(C3-Ce)heterocyclyl, aryl, or heteroaryl;

n is 0,1,2 or 3;

p Is 0 or 1 ; and q is 0 or 1;

or a pharmaceutically acceptable sait thereof.

The présent Invention Is also directed at pharmaceutical compositions that include a compound of Formula (i) or (la) or a pharmaceutically acceptable sait of said ίο compound, présent ln a therapeutically effective amount, in admixture with at least one pharmaceutically acceptable excipient.

Furthermore, the présent Invention is directed at pharmaceutical compositions that include a compound of Formula (I) or (la) or a pharmaceutically acceptable sait of said compound, présent in a therapeutically effective amount, ln admixture with at least 15 one pharmaceutically acceptable excipient and further Including at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent, an anti-diabetic agent, and a cholesterol/lipid modulating agent.

The présent Invention is also directed at a method for the treatment of diabètes comprising the administration of an effective amount of compound of Formula (I) or (la) 20 or a pharmaceutically acceptable sait of said compound to a patient in need thereof.

The présent invention is also directed at a method for treating a metabolic or metabolic-related disease, condition or disorder comprising the step of administering to a patient a therapeutically effective amount of a compound of Formula (I) or (la) or a pharmaceutically acceptable sait of said compound.

The présent invention is also directed at a method for treating a metabolic or metabolic-related disease, condition or disorder comprising the step of administering to a patient in need of such treatment two separate pharmaceutical compositions comprising (i) a first pharmaceutical composition that includes a compound of Formula 30 (I) or (la) or a pharmaceutically acceptable sait of said compound, présent

in a therapeutically effective amount, ln admixture with at least one pharmaceutically acceptable excipient.; and a second composition comprising at least one additional pharmaceutical agent selected from the group consisting of an antl-obesity agent and an anti-diabetic agent, and at least one pharmaceutically acceptable excipient.

It Is to be understood that both the fbregolng general description and the following detailed description are exemplary and explanatory only and are not restrictive ofthe Invention, as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a characteristic x-ray powder diffraction pattem showing a crystalline form of Example 1 (Vertical Axis: Intensity (CPS); Horizontal Axis: Two thêta (degrees)).

Figure 2 represents the refined crystal structure for the Example 1 compound which was 15 plotted using the SHELXTL plotting package.

Figure 3 is acute effects of DGAT2 Inhibitors on plasma TAG levels In Sprague Dawley rats for the Examples 1, 3 and 15.

DETAILED DESCRIPTION OF THE INVENTION

The présent Invention may be understood more readily by reference to the following detailed description of exemplary embodiments of the Invention and the examples included thereîn.

It Is to be understood that this Invention Is not limited to spécifie synthetic methods of making that may of course vary. It is also to be understood that the 25 terminology used herein is for the purpose of describlng particular embodiments only and is not Intended to be limiting. In this spécification and In the claims thatfollow, reference will be made to a number of terms that shall be defined to hâve the following meanings:

As used herein in the spécification, a or an” may mean one or more. As used 30 herein in the claim(s), when used in conjunction with the word comprising, the words a or an may mean one or more than one. As used herein another may mean at least a second or more.

The term “about* refers to a relative term denoting an approximation of plus or minus 10% of the nominal value it refers, ln one embodiment, to plus or minus 5%, in 5 another embodiment, to plus or minus 2%. For the field of this dîsclosure, this level of approximation is appropriate unless the value is specifically stated to require a tighter range.

“Compounds* when used herein Includes any pharmaceutically acceptable dérivative or variation, including conformational isomers (e.g., cis and trans isomers) 10 and ail optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, as well as solvatés, hydrates, isomorphs, polymorphs, tautomers, esters, sait forms, and prodrugs. The expression prodrug refers to compounds that are drug precursors which following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being 15 brought to the physiological pH or through enzyme action is converted to the desired drug form). Exempiary prodrugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of the présent Invention include but are not limited to those having a carboxyl moiety wherein the free hydrogen is replaced by (Ci-CU)alkyl, (C2-C7)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl 20 having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N25 (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(Ci-C2)alkyl, N,N-di(Ci-C2)alkylcarbamoyl-(CiC2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl.

/ v

As used herein, an arrowhead , “ ' · or wavy line,“ F*” dénotés a point of attachment 30 of a substituent to another group.

By halo* or “halogen* is meant chloro, bromo, iodo, or fluoro.

“Fluroalkyf or fluoroalkoxy* refers to an alkyl or alkoxy group substituted with one or more fluoride atoms (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1 -difluoroethyl and the like).

By 'alkyl' is meant straight chain saturated hydrocarbon or branched chain saturated hydrocarbon. Exemplary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, Isopropyl, butyl, sec-butyl, tertiary butyl, isobutyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyi, heptyi and octyl.

By alkoxy* Is meant straight chain saturated alkyl or branched chain saturated alkyl bonded through an oxy. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy.

The term aryl means a carbocyclic aromatic system containing one, two or three 15 rings wherein such rings may be fused. If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated. The term fused” means that a second ring is présent (ie, attached or formed) by having two adjacent atoms in common (ie, shared) with the first ring. The term fused is équivalent to the term condensed. The term aryl embraces aromatic radicals 20 such as phenyl, naphthyl, tetrahydronaphthyl, Indanyl, biphenyl, benzo[b][1,4]oxazin3(4H)-onyl, 2,3-dihydro-1Hindenyl, and 1,2,3,4-tetrahydronaphthalenyl.

'Cycloalkyl' refera to a nonaromatic ring that Is fully hydrogenated having one, two or three rings wherein such rings may be fused, wherein fused is defined above. Cycloalkyl also includes bicyclic structures that may be bridged or spirocyclic in nature 25 with each individual ring within the bicycle varying from 3-8 atoms. Examples of such carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

By 'cycloalkoxy' is meant cycloalkyl bonded through an oxy. Exemplary of such cycloalkoxy groups are cyclopropoxy, cyclobutoxy, cyclopentoxy and cyclohexoxy.

The term “heteroaryl means an aromatic carbocyclic System containing one, two, 30 three or four heteroatoms selected independently from oxygen, nitrogen and sulfur and having one, two or three rings wherein such rings may be fused, wherein fused Is defined above. The term “heteroaryl Includes but is not limited to furyl, thienyl, oxazolyl, thiazolyl, imidazoiyl, pyrazolyl, triazolyl, tetrazolyi, isoxazoiyl, isothiazolyl, oxadiazolyl, φ thiadiazolyl, pyrldinyl, pyridiazinyl, pyrimidinyl, pyrazinyl, pyridin-2(1H)-onyl, pyridazin2(1H)-onyl, pyrimldin-2(1H)-onyl, pyrazin-2(1H)-onyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-aJpyridinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinoiinyl,

6.7- dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5W-cyclopenta[c]pyridinyl, 1,4,5,6- tetrahydrocyclopenta[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 5,6-dihydro4W-pyrrolo[1,2-bJpyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl, 5,6,7,8tetrahydro-[1,2,4]triazolo[ 1,5-a]py ridiny 1,4,5,6,7-tetrahydropyrazolo[1,5-a]py ridiny l,

4.5.6.7- tetrahydro-1 H-indazolyl and 4,5,6,7-tetrahydro-2W-lndazolyl.

The term ‘heterocyclyl means a nonaromatic carbocyclic system containing one, two, three or four heteroatoms selected Independently from oxygen, nitrogen and sulfur and having one, two or three rings wherein such rings may be fused, wherein fused Is defined above. Heterocyclyl also includes bicyclic structures that may be bridged or splrocyclic ln nature with each individual ring within the bicycle varying from 3-8 atoms, and containing 0,1, or 2 N, O or S atoms. The term heterocyclyl' includes but Is not limited to lactones, lactams, cyclic ethers and cyclic amines, Including the following exemplary ring Systems: pyrrolidinonyl, 2,5-dihydro-IM-pyrrolyl, piperidinonyl, morpholinonyl, piperazinonyl, oxazolidinonyl, Imldazolidinonyl, 1,3-oxazinan-2-onyl, tetrahydropyrimidin-2(1H)-onyl, epoxidyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, oxazolidinyl, thlazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, 2azabicyclo[2.1.1]hexanyl, 5-azablcyclo[2.1.1]hexanyl, 6-azabicyclo[3.1.1]heptanyl, 2azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[3.1.1]heptanyl, 3azabicyclo[3.1.0]hexanyl, 2-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.1]octanyl, 8azabicyclo[3.2.1]octanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyi, 3-oxa-925 azabicyclo[3.3.1]nonanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3azabicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl and 2-oxa-6-azaspiro[3.3]heptanyl.

It Is to be understood that if a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate through differing ring atoms without denoting a spécifie point of attachment, then ali possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term pyridyf means 2-, 3- or 4-pyridyl, the term thîenyl means 2- or 3-thienyl, and so forth.

“Patient refers to warm blooded animais such as, for example, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, cattle, goats, sheep, horses, monkeys, chimpanzees, and humans.

By pharmaceutically acceptable* Is meant that the substance or composition must be compatible chemlcally and/or toxicologically, with the other ingrédients comprising a formulation, and/or the mammal being treated therewith.

As used herein, the expressions reaction-inert solvent and inert solvent refer to a solvent or a mixture thereof which does not Interact with starting materials, reagents, Intermediates or products ln a manner which adversely affects the yield of the desired product

As used herein, the term selectivity or sélective refers to a greater effect of a compound In a first assay, compared to the effect of the same compound In a second assay. For example, ln gut sélective” compounds, the first assay is for the half life of the compound ln the Intestine and the second assay is for the half life of the compound ln the liver.

Therapeutically effective amount means an amount of a compound ofthe présent Invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) atténuâtes, améliorâtes, or éliminâtes one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

The term treating, treat or treatment as used herein embraces both preventative, I.e., prophylactic, and palliative treatment, I.e., relieve, alleviate, or slow the progression of the patients disease (or condition) or any tissue damage associated with the disease.

The compounds of the présent invention may contain asymmetric or chiral centers, and, therefore, exist In different stereoisomeric forms. Unless specified otherwise, it is intended that ail stereoisomeric forms of the compounds of the présent invention as well as mixtures thereof, including racemic mixtures, form part of the présent invention, ln addition, the présent invention embraces ail géométrie and positional Isomers. For example, if a compound ofthe présent invention Incorporâtes a double bond or a fused ring, both the cis- and trans- forms, as well as mixtures, are embraced within the scope of the Invention.

Chiral compounds of the Invention (and chiral precursors thereof) may be obtained ln enantiomerically-enriched form using chromatography, typically high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC), on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine (DEA) or isopropylamine. Concentration ofthe eluent affordsthe enriched mixture.

Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical différences by methods well known to those skilled In the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g.

chiral auxiliary such as a chiral alcohol or Mosheris acid chloride), separating the diastereoisomers and converting (e.g. hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column. Altematively, the spécifie stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer Into the other by asymmetric transformation.

Where the compounds of the présent invention possess two or more stereogenic centers and the absolute or relative stereochemistry is given In the name, the désignations R and S refer respectively to each stereogenic center In ascending numerical order (1, 2, 3, etc.) according to the conventional lUPAC number schemes for each molécule. Where the compounds of the présent invention possess one or more stereogenic centers and no stereochemistry is given in the name or structure, it is understood that the name or structure is intended to encompass ail forms of the compound, including the racemic form.

The compounds of this invention may contain olefin-îike double bonds. When such bonds are présent, the compounds of the invention exist as cis and trans configurations and as mixtures thereof. The term “cis refers to the orientation of two substîtuents with reference to each other and the plane of the ring (either both up” or both “down). Anaiogously, the term “trans refers to the orientation of two substîtuents with reference to each other and the plane of the ring (the substîtuents being on opposite sides of the ring).

It is also possible that the intermediates and compounds of the présent invention may exist in different tautomeric forms, and ail such forms are embraced within the

I scope of the Invention. The term 'tautomer* or tautomeric form’ refers to structural

Isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) Include interconversions via migration ofa proton, such as keto-enol and Imlne-enamine

Isomerizations. A spécifie example of a proton tautomer is the tetrazole moiety where the proton may migrate between the four ring nitrogen as follows.

Valence tautomers Include interconversions by reorganization of some of the bonding électrons.

Included within the scope of the claimed compounds présent invention are ail stereoisomers, géométrie isomers and tautomeric forms of the compounds of Formula (I), including compounds exhibiting more than one type of Isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion Is opticaliy active, for example, D-lactate or L-lysine, or racemic, for example, 15 DL-tartrate or DL-arginine.

The présent invention includes ail pharmaceutically acceptable isotopicallyiabelled compounds of Formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion ln the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹®F, iodine, such as ¹²³i, ^1Z4I and ^1Z5I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵0,¹⁷O and ¹⁸O, phosphorus, such as “P, and sulphur, such as ³⁵S.

Certain isotopically-labelled compounds of Formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, I.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose In view of their ease of Incorporation and ready means of détection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred ln some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ^1SO and ¹³N, can be usefui in Positron Emission Tomography (PET) studies for examining substrate receptor occupancy.

Isotopically-labelled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Préparations using an appropriate Isotopically-labelled reagentsln place ofthe non-labelled reagent previously employed.

The compounds of the présent invention may be isoiated and used perse, or when possible, in the form of its pharmaceutically acceptable sait. The term “salts* refers to inorganic and organic salts of a compound of the présent invention. These salts can be prepared in situ during the final isolation and purification of a compound, or by separateiy treating the compound with a suitable organic or inorganic acid or base and isolating the sait thus formed. The acids which are used to préparé the pharmaceuticaliy acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, (i.e., salts containing pharmacologically acceptable anlons, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, naphthylate, mesylate, glucoheptonate, iactobionate, laurylsulphonate, hexafluorophosphate, benzene sulfonate, tosylate, formate, trifluoroacetate, oxalate, besylate, palmitiate, pamoate, malonate, stéarate, laurate, malate, borate, p-toluenesulfonate and pamoate (I.e.. 1,T-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

The Invention also relates to base addition salts of the compounds of the présent invention. The chemical bases that may be used as reagents to préparé pharmaceutically acceptable base salts of those compounds ofthe présent Invention that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such | pharmacologically acceptable cations such as alkali métal cations (e.g., lithium, potassium and sodium) and alkaline earth métal cations (e.g., calcium and magnésium), ammonium or water-soluble amine addition salts such as Nmethylglucamine-(meglumine), tétraméthylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamîne, ethylamine, and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines. See e.g. Berge, et al. J. Pharm. Sci. 66,1-19 (1977).

Certain compounds of the présent Invention may exist ln more than one crystal form (generally referred to as 'polymorphe”). Polymorphe may be prepared by crystallization under various conditions, for example, using different solvents or different solvent mixtures for recrystallization; crystallization at different températures; and/or various modes of cooling, ranging from very fast to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting the compound of the présent invention followed by graduai or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

In one embodiment, D Is N or C-F; and n Is 0.

ln another embodiment, R¹ is ethyl and R² is fluoro.

ln a further embodiment, R⁵ is H; R³ is H; and R⁴ Is (Ci-C2)alkyl-aryl, (Ci20 C2)alkyl-heteroaryl, or (Cs-Ce)cycloalkyl, wherein R⁴ is optionally substituted with one, two, three, or four substituents selected from fluoro, chloro, cyano, -((Ci-C2)alkyl)qCOOH, -(Ci-C3)alkyl, -(C3-Ce)cycloalkyl, trifluoromethyl, difluoromethyl, -(Ci-C3)alkoxy, -trifluoromethoxy, and difluoromethoxy.

ln another embodiment, D îs N or CH and R⁴ is

wherein R⁴ Is optionally substituted with one, two, or three substituents selected from fluoro, chloro, methyl, cyano, cyclopropyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, and difluoromethoxy.

One embodiment of the présent invention is drawn to the compound:

2-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinamido)cyclopentane-1carboxylic acid;

(1 R,2S)-2-(6-((R)-3-(2-ethoxyphenoxy)piperidin-1 -yl)-5fluoronicotinamido)cyclopentane-1-carboxylic acid;

4-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-3methylbenzoic acid;

(R)-4-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-3methylbenzoic acid;

2-(2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)cyclopentane-1carboxylic acid; or (1R,2S)-2-(2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-510 carboxamido)cyc!opentane-1 -carboxylic acid;

or a pharmaceutically acceptable sait thereof.

Another embodiment ofthe présent invention is drawn to the compound:

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4- methylbenzoic acid; (/?)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4methylbenzoic acid;

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5methylbenzoic acid;

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5» methylbenzoic acid;

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-2methoxybenzoic acid;

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-225 methoxybenzoic acid;

3-(1-(2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)ethyl)benzoic acid;

3-((/7)-1 -(2-((/7)-3-(2-ethoxyphenoxy)piperidin-1 -yl)pyrimidine-5carboxamido)ethyl)benzoic acid;

3-((6-(3-(2-ethoxyphenoxy)piperidin-1 -yl)nicotinamido)methyl)benzoic acid; (/7)-3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)nicotinamido)methyl)benzoic acid; 3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4methoxybenzoic acid;

(/7)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-435 methoxybenzoic acid;

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid;

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5carboxamido)methyl)benzoic acid;

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimldine-5-carboxamido)methyl)-4fluorobenzoic acid;

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4fluorobenzoic acid;

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5methoxybenzoic acid; or (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrlmidine-5-carboxamIdo)methyl)-5methoxybenzoic acid;

or a pharmaceutically acceptable sait thereof.

In a further embodiment, the compound of Formula (I) or (la) or a sait of the compound is présent in a pharmaceutical composition in a therapeutically effective amount, in admixture with at least one pharmaceutically acceptable excipient.

In a further embodiment, the composition further includes at least one additional pharmaceutical agent selected from the group conslsting of an anti-obesity agent, an anti-diabetic agent, and a cholesterol/lipid modulating agent.

In a further embodiment, the anti-obesity agent Is selected from the group consisting of gut-selective MTP inhibitors (e.g., diriotapide, mitratapide and implitapide, R56918, CCKa agonists, 5HT2c agonists, MCR4 agonist, lipase inhibitor, PYY3-36, opioid antagonists, the combination of naltrexone with buproprion, oleoyl-estrone, obinepitide, pramlintide, tesofensine, leptin, liraglutide, bromocriptine, oriistat, exenatide, AOD-9604 phentermine and topîramate, and sibutramine.

In a further embodiment, the anti-diabetic agent is selected from the group consisting of an acetyl-CoA carboxylase- (ACC) inhibitor, a diacylglycérol 0acyltransferase 1 (DGAT-1) inhibitor, AZD7687, LCQ908, monoacylglycerol Oacyltransferase inhibitors, a phosphodiesterase (PDE)-10 inhibitor, an AMPK activator, a sulfonylurea, a meglitinide, an α-amylase Inhibitor, an α-glucoside hydrolase inhibitor, an α-glucosidase inhibitor, a PPARy agonist, a PPAR α/γ agonist (, a biguanide, a glucagon-like peptide 1 (GLP-1 ) modulator such as an agonist, liraglutide, albiglutide, exenatide, albiglutide, lixisenatide, dulaglutide, semaglutide, NN-9924, TTP-054, a protein tyrosine phosphatase-1 B (PTP-1B) inhibitor, SIRT-1 activator, a dipeptidyl peptidease IV (DPP-IV) Inhibitor, an insulin secreatagogue, a fatty acid oxidation Inhibitor, an A2 antagonist, a c-jun amino-terminal kinase (JNK) Inhibitor, glucokinase activators (GKa), insulin, an insulin mimetic, a glycogen phosphorylase inhibitor, a VPAC2 receptor agonist, SGLT2 Inhibitors, a glucagon receptor modulator, GPR119 5 modulators, FGF21 dérivatives or analogs, TGR5 (also termed GPBAR1) receptor modulators, GPR40 agonists, GPR120 modulators, high affinity nicotinic acid receptor (HM74A) activators, SGLT1 inhibitors, inhibitors or modulators of camitine palmitoyl transferase enzymes, inhibitors of fructose 1,6-diphosphatase, Inhibitors of aldose reductase, mlneralocorticoid receptor Inhibitors, Inhibitors of T0RC2, inhibitors of CCR2 10 and/or CCR5, Inhibitors of PKC isoforms (e.g. PKCa, PKCp, ΡΚΟγ), inhibitors of fatty acid synthetase, inhibitors of serine palmitoyl transferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostaln receptors (e.g. SSTR1, SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 family including ILIbeta, and modulators of RXRalpha.

ln a further embodiment, the cholesterol/lipid modulating agent is selected from the group consisting of HMG-CoA reductase inhibitors; squalene synthetase inhibitors; fibrates; bile acid séquestrants; ACAT inhibitors; MTP inhibitors; lipooxygenase Inhibitors; choesterol absorption Inhibitors; PCSK9 modulators and cholesteryl ester transfer protein inhibitors.

ln an embodiment, the method for the treatment of diabètes includes the administration of an effective amount of compound ofthe présent invention or a pharmaceutically acceptable sait of said compound to a patient in need thereof.

ln another embodiment, the method for treating a metabolic or metabolic-related disease, condition or disorder includes the step of administering to a patient a therapeutically effective amount of a compound of the présent invention or a pharmaceutically acceptable sait of said compound.

in another embodiment, the method for treating a condition selected from the group consisting of hyperiipidemia, Type I diabètes, Type il diabètes mellitus, idiopathic

Type 1 diabètes (Type lb), latent autoimmune diabètes in adulte (LADA), early-onset Type 2 diabètes (EOD), youth-onset atyplcal diabètes (YOAD), maturity onset diabètes of the young (MODY), malnutrition-related diabètes, gestational diabètes, coronary heart disease, ischémie stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g. necrosis and apoptosis), dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolérance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventncular hypertrophy, peripheral arterial disease, diabetic retînopathy, macular degeneration, ca tara et, diabetic nephropathy, glomerulosclerosis, chronic rénal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial Infarction, transient ischémie attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin résistance, impaired glucose metabolism, conditions of Impaired glucose tolérance, conditions of Impaired fasting plasma glucose, obesity, erectile dysfonction, skin and connective tissue disorders, foot ulcérations and ulcerative colitis, endothélial dysfonction and impaired vascular compliance, hyper apo B lipoproteinemia, Alzheimer’s, schizophrenia, impaired cognition, Inflammatory bowel disease, ulcerative colitis, Crohn’s disease, and irritable bowel syndrome, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), includes the administration of an effective amount of a compound according to the présent Invention or a pharmaceutically acceptable sait of said compound.

ln a further embodiment, the method for treating a metabolic or metabolic-related disease, condition or disorder includes the step of administering to a patient in need of such treatment two separate pharmaceutical compositions comprising (i) a first composition according to the présent invention; and (ii) a second composition comprising at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent and an anti-diabetic agent, and at least one pharmaceutically acceptable excipient.

ln yet a furtherembodiment, the method ofthe présent invention is performed when said first composition and said second composition are administered simultaneously.

ln yet another embodiment, the method of the présent Invention is performed when first composition and said second composition are administered sequentially and in any order.

In one embodiment, when two compositions are administered, the first composition and the second composition are administered simultaneously. ln another embodiment, the first composition and the second composition are administered sequentially and in any order.

Compounds ofthe présent invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly In light of the description contained herein. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wl) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described In Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis. v. 1-19, Wiley, New York (1967-1999 ed.), or Beilstelns Handbuch der orqanischen Chemie. 4, Aufl. ed. Springer-Verlag, Berlin, including suppléments (also available via the Beilstein onlinedatabase)). Many ofthe compounds used herein, are 10 related to, or are derived from compounds in which there is a large scientific Interest and commercial need, and accordingly many such compounds are commercially available or are reported in the literature or are easily prepared from other commonly available substances by methods which are reported in the literature.

For Illustrative purposes, the reaction schemes depicted below provide potential 15 routes for synthesizing the compounds of the présent invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled In the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although spécifie starting materials and reagents are discussed below, other starting materials and reagents can 20 be easily substituted to provide a variety of dérivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified In light of this disclosure using conventional chemîstry well known to those skilled in the art

In the préparation of the Formula I compounds it is noted that some of the préparation methods useful for the préparation of the compounds described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl In Formula I precursors). The need for such protection will vary depending on the nature ofthe remote functionality and the conditions ofthe préparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection/deprotection methods is also within the skill in the art For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis. John Wiley & Sons, New York, 1991.

For example, certain compounds contain primary amines or carboxylic acid functionalities which may Interfère with reactions at other sites of the molécule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group which may be removed in a subséquent step. Suitable protecting groups for amine and carboxyiic acid protection include those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethylenoxycarbonyl (Fmoc) for amines and lower alkyl or benzyl esters for carboxyiic acids) which are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering other functionality in the Formula I and la compounds.

The Reaction Schemes described below are Intended to provide a general description of the methodology employed In the préparation of the compounds of the présent invention. Some of the compounds of the présent invention contain a single chiral center with stereochemical désignation (R), in the following Schemes, the general methods for the préparation of the compounds are shown either in racemic or enantioenriched form. It will be apparent to one skilled in the art that ali of the synthetic transformations can be conducted In a precisely similar manner whether the materials are enantioenriched or racemic. Moreover the resolution to the desired optically active material may take place at any desired point in the sequence using well known methods such as described herein and In the chemistry literature.

In the Reaction Schemes that follow, the variables D, R¹, R², R³, R⁴, R⁵ and n are as described in the summary except where otherwise noted.

Reaction Scheme I outlines the general procedures that can be used to provide compounds of the présent Invention having Formula (I). Those skilled in the art will recognize that Reaction Scheme I depicts the synthesis of racemic compounds, and that these routes may be adapted to the synthesis of either enantiomer of compounds of 25 Formula (I).

Reaction Scheme I

Compounds of Formula (I) may be synthesized starting from appropriate intemnediates through methods described ln the literature such as: Eur. J. Org. Chem.

2004, 2763; Chem. Rev. 2009, 109, 2551; Rec. Res. Dev. Org. Chem. 1997, 1, 273;

Org. React. 1992, 42, 335; Angew. Chem. Int. Ed. 2011, 50,9943; J. Am. Chem. Soc. 2005, 127, 8146; J. Org. Chem. 2008, 73,284; Org. Lett. 2002, 4, 973; Métal Catalyzed Cross-Couplinq Réactions and More, Wiley-VCH, Weinhelm, Germany, 2014, 3, 995; Applications of Transition Métal Catalysîs in Drug Discovery and Development. John

Wiley & Sons, Inc., Hoboken, New Jersey, USA, 2012, 3, 97. Starting materials (1a) and (1b) are commercially available and/or may be prepared via methods known to those skilled in the art. For example, intermediates (1a) and (1b) may be synthesized through methods described in the literature such as: J. Med. Chem. 2000, 43, 3995; Org. Proc. Res. Dev. 2010,14, 936. Starting materials (2a) are commercially available or are described in the literature and may be prepared via methods known to those skilled in the art, including those described below (Reaction Scheme III).

Intermediate (3a) may be prepared from heteroaryl halide (1a) ln a nucleophilic aromatic substitution réaction by amine (2a) ln a reaction inert solvent such as dimethylsulfoxide (DMSO), /V,/V-dimethylformamide (DMF), acetonitrile, or tetrahydrofuran (THF), in the presence of a suitable base, such as triethylamine (TEA) or Λ/,/V-diisopropylethylamine (DIPEA) at a temperature between 10 °C and 120 ’C.

Preferably, Intermediates (1a) and (2a) are reacted in DMSO, THF, or acetonitrile ln the presence of triethylamine or /V,/V-diisopropylethyiamine, at a temperature between 20’C andWO’C. Alternatively, intermediate (3a) may be prepared from heteroaryl halide (1a) and amine (2a) via a metal-catalyzed coupling reaction, for example, using a palladium îo or nickel cataiyst, in a reaction inert solvent such as toluene, 1,2-dimethoxyethane, dioxane, DMSO, DMF, or THF, in the presence of a suitable ligand, and a base such as sodium, potassium, or lithium tert-butoxide, or césium carbonate, at a temperature between 20 ’C and 130 ’C.

Intermediate (4) may be prepared from ester (3a) via a hydrolysis reaction under 15 conditions well known to those skilled in the art. Preferably, intermediate (3a, R = methyl or ethyl) Is treated with an aqueous base such as sodium hydroxide, lithium hydroxide, or potassium hydroxide, In a suitable solvent or solvent mixture comprised of water, methanol, and/or THF, at a temperature between 20 ’C and 60 ’C.

Compounds of Formula (I) may be prepared from acid (4) and amine (5) under amide forming conditions well known to those skilled in the art, using coupling reagents such as propane phosphonic acid anhydride (T3P), 1,T-carbonyidiimidazole (CDI), benzotriazo-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 2(1 H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU), O-benzotriazol-l-yl-W.W.N’.N-tetramethyluronium hexafluoro phosphate (HBTU), 2-chloro-1,3-dimethylimidazolïnium chloride (DMC), W-(3dimethylaminopropyl)-N’-ethylcarbodiimide (EDCI) or 1-hydroxybenzotriazole (HOBT) in a reaction inert solvent such as dichloromethane (DCM), DMF, DMSO, or THF in the presence of a base such as triethylamine, /V-methyl-morpholine, or N.Ndiisopropylethylamine at a temperature between 10’C and 90’C, preferably between 30 20’C and 65’C.

Alternatively, compounds of Formula (I) may be prepared by a two-step sequence from Intermediate (1b) and amine (5) via an amide coupling reaction to afford intermediate (1 c), followed by a coupling reaction with amine (2a). Preferably, intermediate (1c) is prepared from acid chloride (1b, Y = Cl) and amine (5) in the

Φ presence of a base such as triethylamine or W,N-diisopropylethylamine, in a reaction inert solvent, such as dichloromethane, at a température between -20’C to 30’C, preferably between -20’C and O’C. Altemativeïy, intermediate (1c) may be prepared from acid (1b, Y = OH) and amine (5) in the presence of an amide coupling reagent, 5 such as propane phosphonic acid anhydride (T3P), 1,T-carbonyldiimidazole (CDI), benzotriazo-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 2(1H-7-azabenzotriazoi-1-yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATll), 0-benzotriazol-1-yl-A/,A/,N',A/-tetramethyluronium hexafluoro phosphate (HBTU), 2-chloro-1,3-dimethylimidazolinium chloride (DMC), N-(310 dimethylaminopropyl)-/\/^,-ethylcarbodiimide (EDCI) or 1-hydroxybenzotriazole (HOBT) in a reaction inert solvent such as dichloromethane, DMF, DMSO, or THF in the presence of a base such as triethylamine, W-methyi-morpholine, or Ν,Ν-diisopropylethylamine at a température between 10 ’C and 90 ’C.

Altemativeïy, compounds of Formula (i) may be prepared from intermediate (1c) by a two-step sequence Involving addition of amine (2b) followed by addition of phénol (6a). Intermediate (3b) may be prepared from heteroaryl halide (1c) and amine (2b) via nucleophilic aromatic substitution in a reaction inert solvent such as DMSO, DMF, acetonitrile, or THF, in the presence of a suitable base, such as triethylamine or N,Ndiisopropylethylamine at a température between 10 ’C and 120 ’C. Preferably, intermediates (1c) and (2b) are reacted in DMSO, THF, or acetonitrile in the presence of triethylamine or W,W-diisopropylethylamlne, at a température preferably between 20 ’C and 80 ’C. Altemativeïy, intermediate (3b) may be prepared from heteroaryl halide (1c) and amine (2b) via a metal-catalyzed coupling reaction, for example, using a palladium or nickel catalyst, in a reaction inert solvent such as toluene, 1,2-dimethoxyethane, 1,425 dioxane, DMSO, DMF, or THF, in the presence of a suitable ligand, and a base such as sodium, potassium, or lithium ferf-butoxide, or césium carbonate, at a température between 20 ’C and 130 ’C. Compounds of Formula (I) may then be prepared from alcohol (3b) and phenoi (6a) using methods described in the literature, such as US20050137226; W02005030765. Intermediate (3b) and intermediate (6a) may be coupled by treatment with a combination of reagents to activate the alcohol for displacement, such as triphenylphosphine or tributylphosphine and diethylazodicarboxylate (DEAD), di-ferf-butylazodicarboxylate (DBAD), diisopropylazodicarboxyiate (DIAD), or bis(2-methoxyethyl) (E)-diazene-1,2dicarboxylate, in the presence of a base such as triethylamine or Λ/, ΛΛ18481 φ diisopropylethylamine, ln a reaction inert solvent, such as dichloromethane, THF, or toluene at a température between 0 °C and 40 °C.

Reaction Scheme II outlines the synthesis of compounds of Formula (le), a subset of compounds of Formula (I) in which the R⁴ group contains a carboxylic acid 5 functional group. Compounds of Formula (le) may be prepared from compounds of Formula (lb) which contain an ester functionality ln the R⁴ group by deavage of the ester to a carboxylic acid via methods well known to those skilled in the art. Preferably, an alkyl ester (lb), such as methyl or ethyl ester, Is treated with an aqueous base such as sodium hydroxide, lithium hydroxide, or potassium hydroxide, ln a suitable solvent or 10 solvent mixture comprised of water, methanol, and/or tetrahydrofuran, at températures ranging from 0 °C to 70 °C. Altematively, a tert-butyl ester may be treated with an acid, such as hydrogen chloride, hydrogen bromide, or trifluoroacetic acid (TFA), in a solvent or solvent mixture containing water, dloxane, acetonitrile, ether, and/or dichloromethane to provtde the carboxylic acid compounds of Formula (le).

Reaction Scheme II

R⁴ contains aryl or heteroaryl, substituted with Cl, Br, I, OTf, or OTs (Id)

Altematively, compounds of Formula (le) may be prepared from compounds of Formula (Id), in which the R⁴ group contains an aryl or heteroaryl ring substituted with a φ halogen or sulfonate, by methods well known to those skilled ln the art, Including metalcatalyzed carboxylation réactions or the reaction of an appropriate organometallic species, derived from the halogen, with carbon dioxide or a carbon dioxide équivalent.

For example, metal-catalyzed carboxylation may be accomplished using methods s described in the literature, such as: Organomet. 2008, 27, 5402; J. Label. Comp.

Radiopharm. 2007, 50, 794; J. Label. Comp. Radlopharm. 2000, 43,1135; A CS Catalysis 2013, 3, 2417. A compound of Formula (Id) may be treated with a carbon monoxide source, such as carbon monoxide gas or hexacarbonylmolybdenum(O), in the presence of a métal catalyst, such as tetrakis(triphenylphosphine)pal!adium(0), palladium(ll)acetate, or palladium(ll)chloride, and optionally a suitable ligand, in the presence of water, in a solvent such as 1,4-dioxane, tetrahydrofuran, or N,Ndimethylformamide in the presence of appropriate salts or bases, such as tetraethylammonium chloride, tetra-N-propylammonium hydroxide, triethylamine, potassium acetate, or sodium carbonate, at a température between 70 ’C and 170 ’C.

Preferably, a compound of Formula (Id) containing an aryl-lodide is treated with tetrakis(triphenylphosphîne)palladium(0) and carbon monoxide, in the presence of aqueous tetra-N-propylammonium hydroxide in tetrahydrofuran to provide carboxylation product (le). Altematively, a compound of Formula (Id) may be treated with carbon dioxide, ln the presence of a catalyst, such as [1, Γ 20 bis(diphenylphosphino)ferrocene]dich!oropa!ladium(ll) or copper(l) iodide, and optionally a suitable ligand, in a solvent such as tetrahydrofuran, /V./V-dimethylacetamide, or dimethylsulfoxide, in the presence of appropriate salts or bases, such as potassium acetate, at a température between 20 ’C and 120 ’C.

Reaction Scheme III outlines the synthesis of intermediates (2a). Reaction

Scheme III depicts single enantiomers of intermediates (9), (10), and (2a). Those skilled in the art will recognize that these synthetic routes may be adapted to synthesize either enantiomer, or a racemic mixture of enantiomers, of Intermediate (2a).

φ Reaction Scheme III

The starting materials (6a), (6b), (7a), and (7b) are commercially available or are described in the literature and may prepared via methods known to those skilled In the art. Intermediate (8) may be synthesized by ether formation between a hydroxyaromatic coupling partner and an aromatic halide [(6a) and (7a), or (7b) and (6b)] using methods such as those described in: Synlett 2012, 23,101; J. Org. Chem. 2009, 74,

7187; Org. Lett. 2007, 9,643. The appropriate starting materials (6) and (7) may be treated with a métal sait, such as copper(l) chloride, copper(l)bromide, or copper(l) iodide, and a ligand such as 2,2,6_<6-tetramethylheptane-3,5-dione,1,10-phenanthroline₁or other suitable ligand, in a réaction inert solvent such as toluene, DMSO, or DMF, in the presence of a base such as potassium carbonate, césium carbonate, or potassium phosphate, at a température of 80 ’C to 120 °C. Preferably, the appropriate starting materials (6) and (7) are treated with copper(l) chloride and 2,2,6,6-tetramethyiheptane18481 φ 3,5-dione, in toluene, in the presence césium carbonate, at a température of 100 *C to

120 ’C.

Racemic amine (rac-2a) may be synthesized by réduction of pyridine (8), using methods such as those described in: EP2179988; W02008140090; Org. Proc. Res.

Dev. 2011,15, 831. For example, intermediate (8) may be treated with a catalyst such as palladium on carbon, rhodium on alumina, or platinum(IV) oxide, in the presence of a reducing agent such as hydrogen gas, ln a solvent such as acetic acid, methanol, or éthanol, optionally in the presence of an acid, such as acetic acid or hydrogen chloride. Preferably, Intermediate (8) Is reduced with hydrogen gas and rhodium on alumina, ln 10 the presence of hydrochloric acid, ln methanol or éthanol, at a température of 40 °C to 60 °C.

Intermediate (2a), stereochemlcally enriched ln one enantiomer, may be prepared from racemic intermediate (rac-2a) using methods known to those skilled ln the art, such as chiral chromatography, as described ln: Biopharm. Drug Dispos. 2001, 15 22, 291; Ann. Rev. Anal. Chem. 2010, 3, 341; Org. Proc. Res. Dev. 2011,15, 831; or dlastereomeric sait resolution, as described în: Cryst. Growth Des. 2011,11, 3761 ; Org. Proc. Res. Dev. 2011, 15, 831; Tetr.: Asymm. 2012, 23, 221; Tetr.:Asymm. 2006, 17,1337. Preferably, Intermediate (rac-2a) is treated with a chiral acid, such as Dtartaric acid, ln a reaction Inert solvent, such as acetone, at an appropriate température 20 to Induce sélective crystallization of a diastereomeric sait complex of Intermediate (2a).

Alternatively, stereochemically enriched intermediate (2a) may be prepared from stereochemlcally enriched Intermediate (9a) by a two-step sequence. Intermediate (10) may be prepared from alcohol (9a) and phénol (6a) using methods described in the literature, such as US20050137226; W02005030765. Intermediate (9a) and 25 Intermediate (6a) may be coupled by treatment with a combination of reagents to activate the alcohol for displacement, such as triphenylphosphine or tributylphosphine and diethylazodicarboxylate, di-tert-butylazodicarboxylate, diisopropylazodicarboxylate, or bis(2-methoxyethyl) (E)-diazene-1,2-dicarboxylate, optionally in the presence of a base such as triethylamlne or N, W-diisopropylethylamlne, in a reaction inert solvent, 30 such as dichloromethane, THF, or toluene at a température between 0 “C and 40 ^eC.

Preferably, the amine protecting group (PG) îs a carbamate, such as tert-butyl carbamate (Boc). Intermediate (2a) may then be prepared by removal ofthe protecting group (PG), which is well known to those skilled in the art. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups ln Organic φ Synthesis, John Wiley & Sons, New York, 1991. When PG = Boc, the deprotection conditions preferably involve treatment of intermediate (10) with acid, such as hydrogen chloride or trifluoroacetic acid, ln a réaction inert solvent, such as dichloromethane or dioxane, at a température of 20 'C to 40 ’C.

Altematively, intermediate (2a) may be prepared from Intermediate (9b) by a two· step sequence. Alcohol (9b) and halide (6b) may be coupled using methods described ln US20050137226; Angew. Chem. Int. Ed. 2011, 50, 9943; J. Am. Chem. Soc. 2005, 127,8146; J. Org. Chem. 2008, 73,284; Org. Lett. 2002, 4, 973. Alcohol (9b) and halide (6b) may be treated with a métal sait, such as copper(l) chloride, copper(l) bromide, copper(l) Iodide, palladium(ll) acetate, or allylpalladium(ll) chloride dimer, and a ligand, such as 1,10-phenanthroline, or other suitable ligand, ln a reaction inert solvent such as toluene, DMSO, or DMF, in the presence of a base such as césium carbonate, at a température of 70 ’C to 120 ’C.

Reaction Scheme IV outlines the synthesis of amines (5a), a subset of the amines (5) illustrated in Reaction Scheme I. Intermediates (11), (12), and (13) are commercially available or are reported ln the literature and may prepared via methods known to those skilled in the art For example, Intermediate (11 ) may be synthesized using methods described ln the literature such as: Chem. Eur. J. 2012,18, 2978; Synlett 2003,2237; Tetr. 2005, 61, 9908; WO2010100050. Intermediates (12) and (13) may be synthesized using methods described in the literature such as: J. Am. Chem. Soc. 1999, 121,10286; ChemBioChem 2007, 8, 68; J. Med. Chem. 2011, 54,4350; WO2010036632. Intermediate (5a) may be prepared from intermediate (11) by réduction, using methods such as those described in: Chem. Eur. J. 2005, 11, 5674; Bioorg. Med. Chem. 2013, 21, 2056; J. Med. Chem. 2004, 47, 5501; J. Med. Chem.

2005, 48, 664. For example, intermediate (11 ) may be treated with a reducing agent, such as hydrogen gas, in the presence of a métal catalyst, such as Raney nickel or palladium on carbon, In an appropriate solvent, such as methanol or éthanol, at a température of 20 °C to 60 ’C. Altematively, intermediate (11 ) may be treated with a reducing agent-metal sait combination, such as sodium borohydride and nickel(ll) chloride, in an appropriate solvent, such as methanol or tetrahydrofuran, at a température of 0 ’C to 40 ’C. Preferably, intermediate (11) is treated with palladium on carbon and hydrogen gas, ln methanol or éthanol, at a température of 20 ’C to 40 ’C.

Reaction Scheme IV

X=0,1,2,3or4

A®CH, CR or N

R=Substituents of R⁴described ln the summary

réduction

(12)

(R)x

Altematively, intermediate (5a) may be prepared from intermediate (13) using methods such as those described in: J. Org. Chem. 2006, 71. 7205; J. Org. Chem.

2009, 74. 895; W02005021532; W02005111003; US 20100009954. For example, intermediate (13) may be treated with a reducing agent, such as hydrogen gas, in the presence of a métal catalyst, such as platinum on carbon or palladium on carbon, in an appropriate solvent, such as methanol, éthanol, or ethyl acetate at a température of 20 °C to 60 °C. Altematively, Intermediate (13) may be treated with a reducing agent such îo as lithium aluminum hydride, in an appropriate solvent, such as tetrahydrofuran or diethyl ether, at a température of 0 °C to 40 ’C. Altematively, intermediate (13) may be treated with a reducing agent such as triphenylphosphine or tributylphosphine, in the presence of water, and in an appropriate solvent such as tetrahydrofuran, at a température of 20 C to 40 ^eC. Preferably, intermediate (13) is prepared by treatment of 15 intermediate (12), which contains a leaving group such as chloride, bromide, iodide, methanesulfonate, or 4-toluenesulfonate, with sodium azide in a reaction inert solvent such as methanol, ata température of 20 ’C to 70 °C, and intermediate (13) is reduced with hydrogen gas and palladium on carbon in methanol or éthanol, at a température of 20°C to 40’C.

COMBINATION AGENTS

The compounds of the présent invention can be administered alone or in combination with one or more additional therapeutic agents. By administered in combination or combination therapy it is meant that a compound of the présent 5 invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially In any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect Thus, the methods of prévention and io treatment described herein include use of combination agents.

The combination agents are administered to a mammal in a therapeutically effective amount. By therapeutically effective amount it is meant an amount of a compound ofthe présent invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat the desired disease/condition e.g., obesity, diabètes, and cardiovascular conditions such as antihypertensive agents and coronary heart disease.

Examples of suitable anti-diabetic agents include (e.g. insulins, metfomin, DPPIV inhibitors, GLP-1 agonists, analogues and mimetics, SGLT1 and SGLT2 inhibitors). Suitable anti-diabetic agents include an acetyl-CoA carboxylase- (ACC) inhibitor such as those described in W02009144554, W02003072197, WO2009144555 and

W02008065508, a diacylglycérol O-acyltransferase 1 (DGAT-1) inhibitor, such as those described in W009016462 or WO2010086820, AZD7687 or LCQ908, monoacylglycerol O-acyltransferase inhibitors, a phosphodiesterase (PDE)-10 Inhibitor, an AMPK activator, a sulfonylurea (e.g., acetohexamîde, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), a meglitinide, an α-amylase inhibitor (e.g., tendamistat, trestatin and AL-3688), an α-glucoside hydrolase inhibitor (e.g., acarbose), an α-glucosidase inhibitor (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), a PPARy agonist (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone and rosiglitazone), a PPAR α/γ agonist (e.g., CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), a biguanide (e.g., metformin), a glucagon-like peptide 1 (GLP-1) modulator such as an agonist (e.g., exendin-3 and exendin-4), liraglutide, albiglutide, exenatide (Byetta®), albiglutide, lixisenatide, dulaglutide, semaglutide, NN18481 φ 9924, ΤΤΡ-054, a protein tyrosine phosphatase-1 B (PTP-1B) inhibitor (e.g„ trodusquemine, hyrtiosal extract, and compounds disclosed by Zhang, S., et al., Drug Discovery Todav, 12(9/10), 373-381 (2007)), SIRT-1 açtivator (e.g., resveratrol, GSK2245840 or GSK184072), a dipeptidyl peptidease IV (DPP-1V) Inhibitor (e.g., those 5 In W02005116014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin), an Insulin secreatagogue, a fatty acid oxidation Inhibitor, an A2 antagonist, a c-jun amino-terminal kinase (JNK) Inhibitor, glucokinase activators (GKa) such as those described In WO2010103437, WO2010103438, WO2010013161, W02007122482, πΡ-399, πΡ-355, πΡ-547, AZD1656, ARRY403, MK-0599, TAK10 329, AZD5658 or GKM-001, Insulin, an Insulin mimetic, a glycogen phosphorylase

Inhibitor (e.g. GSK1362885), a VPAC2 receptor agonist, SGLT2 inhibitors, such as those described In E.C. Chao et al. Nature Reviews Drug Discovery 9, 551-559 (July 2010) Including dapagliflozin, canagliflozin, empagliflozin, tofoglifîozin (CSG452), Ertugliflozin, ASP-1941, THR1474, TS-071, ISIS388626 and LX4211 as well as those in 15 WO2010023594, a glucagon receptor modulator such as those described In Demong,

D.E. étal, Annual Reports in Médicinal Chemîstry 2008,43,119-137, GPR119 modulators, particularly agonists, such as those described In WO2010140092, WO2010128425, W02010128414, WO2010106457, Jones, R.M. et al. in Médicinal Chemîstry 2009, 44,149-170 (e.g. MBX-2982, GSK1292263, APD597 and PSN821),

FGF21 dérivatives or analogs such as those described in Kharitonenkov, A. et al. et al., Current Opinion In investigatîonal Drugs 2009,10(4)359-364, TGR5 (also termed GPBAR1) receptor modulators, particularly agonists, such as those described in Zhong,

M., Current Topics In Médicinal Chemîstry, 2010,10(4), 386-396 and INT777, GPR40 agonists, such as those described In Médina, J.C., Annual Reports in Médicinal

Chemistry, 2008,43,75-85, Including but not limited to TAK-875, GPR120 modulators, particularly agonists, high affinity nicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, such as GSK1614235. A further représentative listing of anti-diabetic agents that can be combined with the compounds of the présent invention can be found, for example, at page 28, line 35 through page 30, line 19 of WO2011005611. Preferred anti-diabetic agents are metformin and DPP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin). Other antidiabetic agents could include inhibitors or modulators of carnitine palmitoyl transferase enzymes, inhibitors of fructose 1,6-diphosphatase, Inhibitors of aldose reductase, mineralocorticoid receptor Inhibitors, inhibitors of TORC2, inhibitors of CCR2 and/or CCR5, Inhibitors of PKC

Isoforms (e.g. PKCa, PKCp, PKCy), inhibitors of fatty acid synthetase, inhibitors of serine palmitoyl transferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105,

Kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostain receptors (e.g.

SSTR1, SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 family Including ILIbeta, modulators of

RXRalpha. ln addition suitable anti-dlabetic agents Include mechanisms listed by Carpino, P.A., Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51.

Suitable anti-obesity agents include 11β-hydroxy steroid dehydrogenase-1 (11 βHSD type 1) inhibitors, stearoyi-CoA desaturase-1 (SCD-1) inhibitor, MCR-4 agonists, choiecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, pa adrenergic agonists, dopamine agonists (such as bromocriptine), meianocyte-stimulating hormone analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, Le. oriistat), anorectic agents (such as a bombesin agonist), neuropeptide-Y antagonists (e.g., NPY

Y5 antagonists), PYYs-m (including analogs thereof), thyromimetic agents, déhydroépiandrostérone or an analog thereof, glucocorticoid agonists or antagonists, orexin antagonists, glucagon-like peptide-1 agonists, ciliary neurotrophic factors (such as Axokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), human agouti-related protein (AGRP) inhibitors, ghrelin antagonists, histamine 3 antagonists or Inverse agonists, neuromedin U agonists, MTP/ApoB inhibitors (e.g., gut-selective MTP inhibitors, such as diriotapide), opioid antagonist, orexin antagonist, the combination of naltrexone with buproprion and the like.

Preferred anti-obesity agents for use in the combination aspects ofthe présent invention include gut-selective MTP inhibitors (e.g., diriotapide, mitratapide and Implitapide, R56918 (CAS No. 403987) and CAS No. 913541-47-6), CCKa agonists (e.g., N-benzyl-2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraazabenzo[e]azulen-6-yl]-W-isopropyl-acetamlde described in PCT Publication No. WO 2005/116034 or US Publication No. 2005-0267100 A1), 5HT2c agonists (e.g., lorcaserin), MCR4 agonist (e.g., compounds described in US 6,818,658), lipase inhibitor (e.g., Cetilistat), PYY^efas used herein “ΡΥΥ^β* Includes analogs, such as peglated PYYs-36 e.g., those described in US Publication 2006/0178501), opioid antagonists (e.g., naltrexone), the combination of naltrexone with buproprion, oleoyl-estrone (CAS No. 180003-17-2), obinepitide (TM30338), pramlintide (Symlin®), tesofensine (NS2330), φ leptin, liraglutide, bromocriptine, orlistat, exenatide (Byetta®), AOD-9604 (CAS No.

221231-10-3), phentermine and topiramate (trade name: Qsymia), and sibutramine.

Preferably, compounds of the présent invention and combination thérapies are administered in conjunction with exercise and a sensible diet.

The compounds of the présent invention may be used in combination with cholestérol modulating agents (including cholestérol lowering agents) such as a lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an HMGCoA reductase gene expression inhibitor, an HMG-CoA synthase gene expression inhibitor, an MTP/Apo B sécrétion inhibitor, a CETP inhibitor, a bile acid absorption inhibitor, a cholestérol absorption inhibitor, a cholestérol synthesis Inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, a combined squalene epoxidase/squalene cyclase inhibitor, a fibrate, niacin, an ionexchange resin, an antioxidant, an ACAT inhibitor or a bile acid séquestrant or an agent such as mipomersen.

Examples of suitable cholesterol/lipid lowering agents and lipid profile thérapies include: HMG-CoA reductase inhibitors (e.g., pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nlsbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid séquestrants (such as questran); ACAT inhibitors; MTP inhibitors; lipooxygenase inhibitors; choesterol absorption Inhibitors; and cholesteryl ester transfer protein inhibitors. Other atherosclerotic agents include PCSK9 modulators.

ln another embodiment, a compound of Formula I may be co-administered with agents for the treatment of non-alcoholic steatohepatitis (NASH) and/or non-alcoholic fatty liver disease (NAFLD), such as Orlistat, TZDs and other insulin sensitizing agents, FGF21 analogs, Metformln, Omega-3-acid ethyl esters (e.g. Lovaza), Fibrates, HMG CoA-reductase Inhibitors, Ezitimbe, Probucol, Ursodeoxycholic acid, TGR5 agonists, FXR agonists, Vitamin E, Betaine, Pentoxifylline, CB1 antagonists, Camitine, Nacetylcysteine, Reduced glutathione, lorcaserin, the combination of naltrexone with buproprion, SGLT2 Inhibitors, Phentermine, Topiramate, Incretin (GLP and GIP) analogs and Angiotensin-receptor blockers.

Additional therapeutic agents include anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, thrombolytic or

P fibrinolytic agents, anti-arrythmic agents, anti-hypertensive agents, calcium channel blockers (L-type and T-type), cardiac glycosides, diruetics, mineralocorticoid receptor antagonists, NO donating agents such as organonitrates, NO promoting agents such as phosphodiesterase inhibitors, cholesterol/lipid lowering agents and lipid profile thérapies, anti-diabetic agents, anti-depressants, anti-lnflammatory agents (steroida! and non-steroidal), anti-osteoporosis agents, hormone replacement thérapies, oral contraceptives, anti-obesity agents, anti-anxiety agents, anti-proliferative agents, antitumor agents, anti-ulcer and gastroesophageal reflux disease agents, growth hormone and/or growth hormone secretagogues, thyroid mimetics (including thyroid hormone receptor antagonist), anti-infective agents, anti-viral agents, anti-bacterial agents, and anti-fungal agents.

Agents used in an ICU setting are included, for example, dobutamine, dopamine, dpinephrine, nitroglycerin, nitroprusside etc.

Combination agents useful for treating vasculitis are included, for example, azathioprine, cyclophosphamide, mycophenolate, mofetil, rituximab etc.

In another embodiment, the présent invention provides a combination wherein the second agent is at least one agent selected from a factor Xa inhibitor, an anticoagulant agent, an anti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent, and a fibrinolytic agent Exemplary factor Xa inhibitors include apixaban and 20 rivaroxaban. Examples of suitable anti-coagulants for use in combination with the compounds of the présent Invention include heparins (e.g., unfractioned and low molecular weight heparins such as enoxaparin and dalteparin).

In another preferred embodiment the second agent is at least one agent selected from warfarin, dabigatran, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatrobanas, aspirin, ibuprofen, naproxen, sulindac, indomethacîn, mefenamate, droxlcam, diclofenac, sulfïnpyrazone, piroxicam, tîclopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, disulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase, and streptokinase.

A preferred second agent is at least one anti-platelet agent Especially preferred anti-platelet agents are aspirin and clopidogrel.

The term anti-platelet agents (or platelet Inhibitory agents), as used herein, dénotés agents that Inhibit platelet function, for example by Inhibiting the aggregation, adhesion or granular sécrétion of piatelets. Agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfînpyrazone, piroxicam, and pharmaceutically acceptable salts or prodrugs thereof. Ofthe NSAIDS, aspirin (acetylsalicyclicacid or ASA) and COX-2 inhibitors such as CELEBREX or piroxicam are preferred. Other suitable platelet Inhibitory agents include IIb/llla antagonists (e.g., tirofiban, eptifibatide, and abciximab), thromboxane-A210 receptor antagonists (e.g., ifetroban), thromboxane-A2-synthetase Inhibitors, PDE-III inhibitors (e.g., Pletal, dipyridamole), and pharmaceutically acceptable salts or prodrugs thereof.

The term anti-platelet agents (or platelet inhibitory agents), as used herein, is also intended to include ADP (adenosine diphosphate) receptor antagonists, preferably 15 antagonists of the purinergic receptors P2Y1 and P2Y12.^{with p}2^Y12 ^bein9 ^{even more} preferred. Preferred P2Y12 receptor antagonists include ticagrelor, prasugrel, ticlopldine and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrel are also preferred compounds since they are known to be gentle on the gastro-intestinal 20 tract in use.

The term thrombin inhibitors (or anti-thrombin agents), as used herein, dénotés inhibitors ofthe serine protease thrombin. By Inhibiting thrombin, various thrombin-mediated processes, such as thrombln-mediated platelet activation (that Is, for example, the aggregation of piatelets, and/or the granular sécrétion of plasminogen activator inhibitor-1 and/or serotonin) and/or fi brin formation are disrupted. A number of thrombin Inhibitors are known to one of skill In the art and these Inhibitors are contemplated to be used in combination with the present compounds. Such Inhibitors include, but are not limited to, boroarginine dérivatives, boropeptides, dabigatran, heparins, hirudin, argatroban, and melagatran, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine dérivatives and boropeptides Include N-acetyl and peptide dérivatives of boronic acid, such as C-terminal alpha-aminoboronlc acid dérivatives of lysine, omithine, arginine, homoarginine and corresponding isothiouronîum analogs thereof. The term hirudin, as used herein, Includes suitable dérivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin.

P The term thrombolytics or fibrinolytic agents (or thrombolytics or fibrinolytics), as used herein, dénoté agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator (natural or recombinant) and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase (T N K), lanoteplase (nPA), factor 5 Vlla inhibitors, PAI-1 inhibitors (Le., Inactivators of tissue plasminogen activator inhibitors), alpha2-antiplasmin Inhibitors, and anisoylated plasminogen streptokinase activator complex, including pharmaceutically acceptable salts or prodrugs thereof. The terni anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, ln EP 028,489, the disclosure of which Is 10 hereby Incorporated herein by reference herein. The term urokinase, as used herein, is intended to dénoté both dual and single chain urokinase, the latter also being referred to herein as prourokinase.

Examples of suitable anti-arrythmic agents include: Class I agents (such as propafenone); Ciass il agents (such as metoprolol, atenolol, carvadiol and propranolol);

Class III agents (such as sotalol, dofetiiide, amiodarone, azimilide and ibutîlide); Class IV agents (such as ditiazem and verapamil); K⁺ channel openers such as lAch inhibitors, and IKur inhibitors (e.g., compounds such as those disclosed in WO01/40231).

The compounds of the présent Invention may be used in combination with antihypertensive agents and such antihypertensive activity is readily determined by those skilled in the art according to standard assays (e.g., blood pressure measurements). Exampies of suitable anti-hypertensive agents include: alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine and amlodipine); vasodilators (e.g., hydralazine), diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethlazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthaiidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors; ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril); AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Patent Nos. 5,612,359 and 6,043,265); Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389); neutral endopeptidase (NEP) φ inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates). An exemplary antianginai agent Is Ivabradine.

Exampies of suitable calcium channel blockers (L-type or T-type) include diltiazem, verapamil, nifedipine and amlodipine and mybefradil.

Examples of suitable cardiac glycosides Include digitaiis and ouabain.

In one embodiment, a Formula I compound may be co-administered with one or more diuretics. Exampies of suitable diuretics include (a) loop diuretics such as furosemide (such as LASIX™), torsemide (such as DEMADEX™), bemetanide (such as BUMEX™), and ethacrynic acid (such as EDECRIN™); (b) thiazide-type diuretics such 10 as chlorothiazide (such as DIURIL™, ESIDRIX™ or HYDRODIURIL™), hydrochlorothiazide (such as MICROZIDE™ or ORETIC™), benzthiazide, hydroflumethiazide (such as SALURON™), bendroflumethiazide, methychlorthlazide, polythiazide, trichlormethiazide, and Indapamide (such as LOZOL™); (c) phthalimîdinetype diuretics such as chlorthalidone (such as HYGROTON™), and metolazone (such 15 as ZAROXOLYN™); (d) quinazoline-type diuretics such as quinethazone; and (e) potassium-sparing diuretics such as triamterene (such as DYRENIUM™), and amiloride (such as MIDAMOR™ or MODURETIC™).

In another embodiment, a compound of Formula I may be co-administered with a loop diuretic. In still another embodiment, the loop diuretic is selected from furosemide 20 and torsemide. In still another embodiment, one or more compounds of Formula I or la may be co-administered with furosemide. In still another embodiment, one or more compounds of Formula I or la may be co-administered with torsemide which may optionally be a controlied or modified release form of torsemide.

In another embodiment, a compound of Formula I may be co-administered with a thiazide-type diuretic. In still another embodiment, the thiazide-type diuretic is selected from the group consisting of chlorothiazide and hydrochlorothiazide. In still another embodiment, one or more compounds of Formula I or la may be co-administered with chlorothiazide. In still another embodiment, one or more compounds of Formula I or la may be co-administered with hydrochlorothiazide.

In another embodiment, one or more compounds of Formula I or la may be coadministered with a phthalimidine-type diuretic. In still another embodiment, the phthalimidine-type diuretic Is chlorthalidone.

Examples of suitable mineralocorticoid receptor antagonists Include sprionolactone and epierenone.

Examples of suitable phosphodiesterase inhibitors include: PDE III inhibitors (such as cllostazol); and PDE V inhibitors (such as sildenafil).

Those skilled ln the art wili recognlze that the compounds of this Invention may also be used ln conjunction with other cardiovascular or cerebrovascuiar treatments 5 Including PCI, stenting, drug eluting stents, stem cell therapy and medical devices such as implanted pacemakers, defibrillators, or cardiac resynchronization therapy.

The dosage of the additionai pharmaceutical agent îs generally dépendent upon a number of factors Inciuding the health of the subject being treated, the extent of treatment desired, the nature and klnd of concurrent therapy, if any, and the frequency 10 of treatment and the nature of the effect desired. In general, the dosage range of the additional pharmaceutical agent Is ln the range of from about 0.001 mg to about 100 mg per kilogram body weight of the Individual per day, preferably from about 0.1 mg to about 10 mg per kilogram body weight of the individual per day. However, some variability in the general dosage range may also be required depending upon the âge 15 and weight of the subject being treated, the Intended route of administration, the particular anti-obeslty agent being administered and the like. The détermination of dosage ranges and optimal dosages for a particular patient Is also weil within the ability of one of ordinary skiii ln the art having the benefît of the instant disclosure.

According to the methods of treatment of the invention, a compound of the présent Invention or a combination of a compound of the présent invention and at ieast one additional pharmaceutical agent (referred to herein as a combination) is administered to a subject in need of such treatment, preferably in the form of a pharmaceutical composition, ln the combination aspect of the invention, the compound of the présent invention and at least one other pharmaceutical agent (e.g., another anti25 obesity agent,) may be administered either separately or ln a pharmaceutical composition comprising both. It Is generally preferred that such administration be orai.

When a combination of a compound of the présent invention and at least one other pharmaceutical agent are administered together, such administration may be sequential in time or simultaneous. Simultaneous administration of drug combinations Is 30 generally preferred. For sequential administration, a compound of the présent invention and the additional pharmaceutical agent may be administered in any order. It is generally preferred that such administration be oral. It Is especially preferred that such administration be oral and simultaneous. When a compound of the présent Invention

Q and the additional pharmaceutical agent are administered sequentially, the administration of each may be by the same or by different methods.

According to the methods of the invention, a compound of the présent invention or a combination is preferably administered in the form ofa pharmaceutical composition. Accordingly, a compound of the présent invention or a combination can be administered to a patient separately or together In any conventionai oral, rectal, transdermai, parenterai (e.g., intravenous, Intramuscuiar or subcutaneous), intracistemal, intravaginal, intraperitoneal, topical (e.g., powder, ointment, cream, spray or lotion), buccal or nasal dosage form (e.g., spray, drops or Inhalant).

The compounds of the invention or combinations can be administered alone but will generally be administered In an admixture with one or more suitable pharmaceutical excipients, adjuvants, diluents or carriers known in the art and selected with regard to the intended route of administration and standard pharmaceutical practice. The compound of the Invention or combination may be formulated to provide Immédiate-, delayed-, modified-, sustained-, puised- or controlled-release dosage forms depending on the desired route of administration and the specificity of release profile, commensurate with therapeutic needs.

The pharmaceutical composition comprises a compound of the Invention or a combination in an amount generally in the range of from about 1% to about 75%, 80%, 20 85%, 90% or even 95% (by weight) of the composition, usually in the range of about

1%, 2% or 3% to about 50%, 60% or 70%, more frequently in the range of about 1%, 2% or 3% to less than 50% such as about 25%, 30% or 35%.

Methods of preparing various pharmaceutical compositions with a spécifie amount of active compound are known to those skilled ln this art For examples, see 25 Remington: The Practice of Pharmacy, Lippincott Williams and Wilkins, Baltimore Md. 20.sup.th ed. 2000.

Compositions suitable for parenterai injection generally Include pharmaceutically acceptable stérile aqueous or nonaqueous solutions, dispersions, suspensions, or émulsions, and stérile powders for reconstitution into stérile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers or diluents (including solvents and vehicles) include water, éthanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, triglycérides including vegetable oils such as olive oii, and injectable organic esters such as ethyl

P oleate. A prefrerred carrier is Miglyol.RTM. brand caprylic/capric acid ester with glycérine or propylene glycol (e.g., Miglyol.RTM. 812, Miglyol.RTM. 829, Miglyol.RTM.

840) available from Condea Vista Co., Cranford, N.J. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size In the case of dispersions, and by the use of surfactants.

These compositions for parentéral Injection may also contain excipients such as preserving, wetting, emulsifÿing, and dispersing agents. Prévention of microorganism contamination of the compositions can be accomplished with various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phénol, sorbic acid, and the 10 like. It may also be désirable to include Isotonie agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents capable of delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, chews, lozenges, pills, powders, and multi-particulate préparations (granules). In such solid dosage forms, a compound ofthe présent invention or a combination Is admixed with at least one Inert excipient, diluent or carrier. Suitable excipients, diluents or carriers include materials such as sodium citrate or dicalcium phosphate and/or (a) one or more filière or extenders (e.g., microcrystailine cellulose (available as Avicel.TM. from FMC

Corp.) starches, lactose, sucrose, mannitol, silicic acid, xylitol, sorbitol, dextrose, calcium hydrogen phosphate, dextrin, alpha-cyclodextrin, beta-cyclodextrin, polyethylene glycol, medium chain fatty acids, titanium oxide, magnésium oxide, aluminum oxide and the like); (b) one or more binders (e.g., carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia and the like); (c) one or more humectants (e.g., glycerol and the like); (d) one or more disintegrating agents (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, sodium lauryl sulphate, sodium starch glycolate (available as Explotab.TM.from Edward Mendell Co.), cross-linked polyvinyl pyrrolidone, croscarmellose sodium A-type (available as Ac-di-sol.TM.), polyacrilin potassium (an ion exchange resin) and the like); (e) one or more solution retardera (e.g., paraffin and the like); (f) one or more absorption acceleratora (e.g., quaternary ammonium compounds and the like); (g) one or more wetting agents (e.g., cetyl alcohol, glycerol monostearate

Φ and the like); (h) one or more adsorbents (e.g., kaolin, bentonite and the like); and/or (i)one or more lubricants (e.g., talc, calcium stéarate, magnésium stéarate, stearic acid, polyoxyl stéarate, cetanol, talc, hydrogenated casier oil, sucrose esters of fatty acid, dimethylpolysiloxane, microcrystalline wax, yellow beeswax, white beeswax, solid polyethylene glycols, sodium lauryl sulfate and the like). ln the case of capsules and tablets, the dosage forms may also comprise buffering agents.

Solid compositions ofa similar type may also be used as fillers ln soft or hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

îo Solid dosage forms such as tablets, dragees, capsules, and granules may be prepared with coatings and shells, such as enteric coatings and others well known In the art. They may also contain opacifying agents, and can also be of such composition that they release the compound of the présent invention and/or the additional pharmaceutical agent in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The drug may also be In microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

For tablets, the active agent wlil typically comprise less than 50% (by weight) of the formulation, for example less than about 10% such as 5% or 2.5% by weight. The prédominant portion ofthe formulation comprises fillers, diluents, disintegrants, lubricants and optionally, flavors. The composition of these excipients Is well known in the art. Frequently, the fillers/diluents will comprise mixtures of two or more of the following components: microcrystalline cellulose, mannitol, lactose (ail types), starch, and di-calcium phosphate. The filler/diluent mixtures typically comprise less than 98% of the formulation and preferably less than 95%, for example 93.5%. Preferred disintegrants include Ac-di-sol.TM., Explotab.TM., starch and sodium lauryl sulphate. When présent a disintegrant will usually comprise less than 10% ofthe formulation or less than 5%, for example about 3%. A preferred lubricant is magnésium stéarate. When présent a lubricant will usually comprise less than 5% of the formulation or less than 3%, for example about 1%.

Tablets may be manufactured by standard tabletting processes, for example, direct compression or a wet, dry or melt granulation, melt congealing process and extrusion. The tablet cores may be mono or multi-layer(s) and can be coated with appropriate overcoats known In the art.

Liquid dosage forms for oral administration include pharmaceutically acceptable émulsions, solutions, suspensions, syrups, and élixirs, ln addition to the compound of the présent invention or the combination, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl

acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil, sesame seed oil and the like), Miglyole.RTM. (available from CONDEA Vista Co., Cranfbrd, N.J.), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty 10 acid esters of sorbitan, or mixtures of these substances, and the like.

Besides such Inert diluents, the composition may also include excipients, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Oral liquid forms of the compounds of the invention or combinations include solutions, wherein the active compound is fully dissolved. Examples of solvents include ail pharmaceutically precedented solvents suitable for oral administration, particularly those in which the compounds of the invention show good solubility, e.g., polyethylene glycol, polypropylène glycol, edible oils and glyceryl- and glyceride-based système. Glyceryl- and glyceride-based Systems may include, for example, the following branded

2o products (and corresponding generic products): Captex.TM. 355 EP (glyceryl tricaprylate/caprate, from Abitec, Columbus Ohio), Crodamol.TM. GTC/C (medium chain triglycéride, from Croda, Cowick Hall, UK) or Labrafac-TM. CC (medium chain triglyides, from Gattefosse), Captex.TM. 500P (glyceryl triacetate I.e. triacetin, from Abitec), Capmul.TM. MCM (medium chain mono- and diglycerides, fromAbitec),

Migyol.TM. 812 (caprylic/capric triglycéride, from Condea, Cranford N.J.), Migyol.TM. 829 (caprylic/capric/succinic triglycéride, from Condea), Migyol.TM. 840 (propylene glycol dicaprylate/dicaprate, from Condea), Labrafil.TM. M1944CS (oleoyl macrogol-6 glycerides, from Gattefosse), Peceol.TM. (glyceryl monooleate, from Gattefosse) and Maisine.TM. 35-1 (glyceryl monooleate, from Gattefosse). Of particular interest are the medium chain (about C.sub.8 to C.sub.10) triglycéride oils. These solvents frequently make up the prédominant portion of the composition, i.e., greater than about 50%, usually greater than about 80%, for example about 95% or 99%. Adjuvants and additives may also be included with the solvents princlpally as taste-mask agents, φ palatabiiity and flavoring agents, antioxidants, stabiiizers, texture and viscosity modifiers and solubilizers.

Suspensions, in addition to the compound ofthe présent Invention or the combination, may further comprise caniers such as suspending agents, e.g., ethoxylated Isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystailine cellulose, aiuminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal or vaginal administration preferably comprise suppositories, which can be prepared by mixing a compound of the présent invention or io a combination with suitable non-lrritating excipients or caniers, such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ordinary room température, but liquid at body température, and therefore, melt in the rectum or vaginal cavity thereby releasing the active oomponent(s).

Dosage forms for topical administration of the compounds of the présent

Invention or combinations Include olntments, creams, lotions, powders and sprays. The drugs are admixed with a pharmaceutically acceptable excipient, diluent or canier, and any preservatives, buffers, or propellants that may be required.

Many of the présent compounds are poorly soluble in water, e.g., less than about 1 .mu.g/mL. Therefore, liquid compositions in solubilizing, non-aqueous solvents such 20 as the medium chain triglycéride oils discussed above are a preferred dosage form for these compounds.

Solid amorphous dispersions, including dispersions formed by a spray-drying process, are also a preferred dosage form for the poorly soluble compounds of the invention. By solid amorphous dispersion is meant a solid material in which at least a 25 portion of the poorly soluble compound is in the amorphous form and dispersed ln a water-soluble polymer. By amorphous” is meant that the poorly soluble compound Is not crystalline. By crystalline is meant that the compound exhibits long-range order in three dimensions of at least 100 repeat units in each dimension. Thus, the term amorphous Is Intended to include not only material which has essentially no order, but 30 also material which may hâve some small degree of order, but the order is in less than three dimensions and/or is only over short distances. Amorphous material may be characterized by techniques known in the art such as powder x-ray diffraction (PXRD) crystallography, solid state NMR, or thermal techniques such as differential scanning calorimetry (DSC).

Preferably, at least a major portion (i.e., at least about 60 wt %) of the poorly soluble compound in the solid amorphous dispersion is amorphous. The compound can 5 exist within the solid amorphous dispersion ln relatively pure amorphous domains or régions, as a solid solution of the compound homogeneously distributed throughout the polymer or any combination of these states or those states that lie intermediate between them. Preferably, the solid amorphous dispersion is substantially homogeneous so that the amorphous compound is dispersed as homogeneously as possible throughout the 10 polymer. As used herein, substantially homogeneous means that the fraction of the compound that is présent in relatively pure amorphous domains or régions within the solid amorphous dispersion is relatively small, on the order of less than 20 wt %, and preferably less than 10wt % ofthe total amountofdrug.

Water-soluble polymers suitable for use in the solid amorphous dispersions 15 should be inert, in the sense that they do not chemically react with the poorly soluble compound in an adverse manner, are pharmaceutically acceptable, and hâve at least some solubility in aqueous solution at physiologically relevant pHs (e.g. 1-8). The polymer can be neutral or ionizable, and should hâve an aqueous-solubility of at least 0.1 mg/mL over at least a portion of the pH range of 1-8.

Water-soluble polymers suitable for use with the présent invention may be cellulosic or non-cellulosic. The polymers may be neutral or ionizable in aqueous solution. Of these, ionizable and cellulosic polymers are preferred, with ionizable cellulosic polymers being more preferred.

Exemplary water-soluble polymers include hydroxypropyl methyl cellulose 25 acetate succinate (HPMCAS), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose phthalate (HPMCP), carboxy methyl ethyl cellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), methyl cellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO/PPO, also known as poloxamers), and 30 mixtures thereof. Especially preferred polymers include HPMCAS, HPMC, HPMCP, CMEC, CAP, CAT, PVP, poloxamers, and mixtures thereof. Most preferred is HPMCAS. See European Patent Application Publication No. 0 901 786 A2, the disclosure of which is incorporated herein by reference.

The solid amorphous dispersions may be prepared according to any process for forming solid amorphous dispersions that results in at least a major portion (at least 60%) of the poorly soluble compound being in the amorphous state. Such processes include mechanical, thermal and solvent processes. Exemplary mechanical processes include miiling and extrusion; melt processes including high température fusion, solventmodified fusion and melt-congeal processes; and solvent processes including nonsolvent précipitation, spray coating and spray drying. See, for example, the following U.S. Patents, the pertinent disclosures of which are încorporated herein by reference: Nos. 5,456,923 and 5,939,099, which describe forming dispersions by extrusion processes; Nos. 5,340,591 and 4,673,564, which describe forming dispersions by milling processes; and Nos. 5,707,646 and 4,894,235, which describe forming dispersions by melt congeal processes. In a preferred process, the solid amorphous dispersion is formed by spray drying, as disclosed in European Patent Application Publication No. 0 901 786 A2. In this process, the compound and polymer are dissolved 15 in a solvent, such as acetone or methanol, and the solvent is then rapidly removed from the solution by spray drying to form the solid amorphous dispersion. The solid amorphous dispersions may be prepared to contain up to about 99 wt % of the compound, e.g., 1 wt %, 5 wt %, 10 wt %, 25 wt %, 50 wt %, 75 wt %, 95 wt %, or 98 wt % as desired.

The solid dispersion may be used as the dosage form itself or it may serve as a manufacturing-use-product (MUP) in the préparation of other dosage forms such as capsules, tablets, solutions or suspensions. An example of an aqueous suspension is an aqueous suspension of a 1:1 (w/w) compound/HPMCAS-HF spray-dried dispersion containing 2.5 mg/mL of compound In 2% polysorbate-80. Solid dispersions for use in a tablet or capsule will generally be mixed with other excipients or adjuvants typically found in such dosage forms. For example, an exemplary filler for capsules contains a 2:1 (w/w) compound/HPMCAS-MF spray-dried dispersion (60%), lactose (fast flow) (15%), microcrystalline cellulose (e.g., Avicel.sup.(R0-102) (15.8%), sodium starch (7%), sodium lauryl sulfate (2%) and magnésium stéarate (1%).

The HPMCAS polymers are available in low, medium and high grades as

Aqoa.sup.(R)-LF, Aqoat.sup.(R)-MF and Aqoat.sup.(R)-HF respectively from Shin-Etsu Chemical Co., LTD, Tokyo, Japan. The higher MF and HF grades are generally preferred.

The following paragraphe describe exemplary formulations, dosages, etc. useful for non-human animais. The administration of the compounds of the présent invention and combinations of the compounds of the présent invention with anti-obesity agents can be effected orally or non-orally.

An amount of a compound of the présent invention or combination of a compound of the présent invention with another anti-obesity agent is administered such that an effective dose is received. Generally, a daily dose that is administered orally to an animal is between about 0.01 and about 1,000 mg/kg of body weight, e.g., between about 0.01 and about 300 mg/kg or between about 0.01 and about 100 mg/kg or between about 0.01 and about 50 mg/kg of body weight, or between about 0.01 and about 25 mg/kg, or about 0.01 and about 10 mg/kg or about 0.01 and about 5 mg/kg.

Conveniently, a compound ofthe présent invention (orcombination) can be carried in the drinking water so that a therapeutic dosage of the compound is ingested with the daily water supply. The compound can be directly metered into drinking water, is preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water-soluble sait).

Conveniently, a compound ofthe présent invention (orcombination) can also be added directly to the feed, as such, or in the form of an animal feed supplément, also referred to as a premix or concentrate. A premix or concentrate of the compound in an 20 excipient, diluent or camer is more commonly employed for the inclusion of the agent In the feed. Suitable excipients, diluents or carriers are liquid or solid, as desired, such as water, various meals such as alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal, and minerai mixes such as are commonly employed in poultry feeds. A particularly effective excipient, 25 diluent or carrier Is the respective animal feed itself; that is, a small portion of such feed. The camer facilitâtes uniform distribution of the compound in the finished feed with which the premix is blended. Preferably, the compound is thoroughly blended Into the premix and, subsequently, the feed. In this respect, the compound may be dispersed or dissolved in a suitable oîly vehicle such as soybean oil, com oil, cottonseed oil, and the 30 like, or in a volatile organic solvent and then blended with the camer. It will be appreciated that the proportions of compound in the concentrate are capable of wide variation since the amount of the compound in the finished feed may be adjusted by blending the appropriate proportion of premix with the feed to obtain a desired level of compound.

High potency concentrâtes may be blended by the feed manufacturer with proteinaceous carrier such as soybean oil meal and other meals, as described above, to produce concentrated suppléments, which are suitable for direct feeding to animais, ln such instances, the animais are permitted to consume the usual diet Altemativeïy, such 5 concentrated suppléments may be added directly to the feed to produce a nutritionally balanced, finished feed containing a therapeutically effective level of a compound ofthe présent invention. The mixtures are thoroughly blended by standard procedures, such as in a twin shell blender, to ensure homogeneity.

If the supplément is used as a top dressing for the feed, it likewise helps to îo ensure uniformity of distribution of the compound across the top of the dressed feed.

Drinking water and feed effective for increasing lean méat déposition and for Improving lean méat to fat ratio are generally prepared by mixing a compound of the présent Invention with a sufficient amount of animal feed to provide from about 1O.sub.3 to about 500 ppm of the compound ln the feed or water.

The preferred medicated swine, cattle, sheep and goat feed generally contain from about 1 to about 400 grams of a compound of the présent invention (or combination) per ton of feed, the optimum amount for these animais usually being about 50 to about 300 grams per ton of feed.

The preferred poultry and domestic pet feeds usually contain about 1 to about

400 grams and preferably about 10 to about 400 grams of a compound of the présent

Invention (or combination) per ton of feed.

For parentéral administration in animais, the compounds ofthe présent invention (or combination) may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in 25 lean méat déposition and improvement in lean méat to fat ratio is sought.

Paste Formulations may be prepared by dispersing the drug in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.

Pellets containing an effective amount of a compound of the présent Invention, pharmaceutical composition, or combination may be prepared by admixing a compound 30 of the présent Invention or combination with a diluent such as carbowax, camuba wax, and the like, and a lubricant, such as magnésium or calcium stéarate, may be added to improve the pelleting process.

It Is, of course, recognized that more than one pellet may be administered to an animal to achieve the desired dose level which will provide the Increase In lean méat déposition and improvement in lean méat to fat ratio desired. Moreover, implants may also be made periodically during the animal treatment period in order to maintain the 5 proper drug level ln the anlmal’s body.

The présent invention has several advantageous veterinary features. For the pet owner or veterinarian who wishes to increase leanness and/or trim unwanted fat from pet animais, the Instant Invention provides the means by which this may be accomplîshed. Forpoultry, beef and swine breeders, utilization ofthe method of the îo présent Invention yields leaner animais that command higher sale prices from the méat Industry.

EXAMPLES

Unless specified otherwise, starting materials are generally available from commercial sources such as Aldrich Chemicals Co. (Milwaukee, Wl), Lancaster 15 Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Company, Ltd. (Comwall, England) and Tyger Scientific (Princeton, NJ). Certain common abbreviations and acronyms hâve been employed which may Include: AcOH (acetic acid), BOP (benzotriazo-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), CDI (1,1’20 carbonyldiimidazole), DCM (dichloromethane), DEA (diethylamine), DIPEA (N,Ndiisopropylethylamine), DMAP (4-dimethylamlnopyridîne), DMF(N,Ndimethylformamide), DMSO (dimethylsulfoxide), EDCI (N-(3-dimethylaminopropyl)-A/’ethylcarbodiimide), EbO (diethyl ether), EtOAc (ethyl acetate), EtOH (éthanol), HATU (2-( 1 H-7-azabenzotriazol-1 -yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium), HBTU (0-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluora phosphate), HOBT (1-hydroxybenzotriazole), IPA (isopropyl alcohol), KHMDS (potassium hexamethyldisilazane), MeOH (methanol), MTBE (tert-butyl methyl ether), NaBH(OAc)a (sodium triacetoxyborohydride), NaHMDS (sodium hexamethyldisilazane), NMP (N-methylpyrrolidone), SEM ([2-(Trimethylsilyl)ethoxy]methyl), TEA (triethylamine), 30 TFA (trifluoroacetic acid), THF (tetrahydrofuran), and T3P (propane phosphonic acid anhydride).

Reactions were performed in air or, when oxygen- or moisture-sensitive reagents or Intermediates were employed, under an inert atmosphère (nitrogen or argon). When φ appropriate, reaction apparatuses were dried under dynamïc vacuum using a heat gun, and anhydrous solvents (Sure-Seal™ products from Aldrich Chemical Company,

Milwaukee, Wisconsin or DriSolv™ products from EMD Chemicals, Gibbstown, NJ) were employed. Commercial solvents and reagents were used without further purification. When indicated, reactions were heated by microwave irradiation using Biotage Initiator or Personal Chemistry Emrys Optimizer microwaves. Réaction progress was monitored using thin layer chromatography (TLC), liquid chromatographymass spectrometry (LCMS), high performance liquid chromatography (HPLC), and/or gas chromatography-mass spectrometry (GCMS) analyses. TLC was performed on pre-coated silica gel plates with a fluorescence indicator (254 nm exitation wavelength) and visualized under UV light and/or with I2, KMnO<, C0CI2, phosphomolybdic acid, and/or ceric ammonium molybdate stains. LCMS data were acquired on an Agitent 1100 Sériés instrument with a Leap Technologies autosampler, Gemini C18 columns, MeCN/water gradients, and either TFA, formicacid, or ammonium hydroxide modifiers.

The column eluent was analyzed using Waters ZQ mass spectrometer scanning in both positive and négative ion modes from 100 to 1200 Da. Other similar instruments were also used. HPLC data were acquired on an Agitent 1100 Sériés Instrument using Gemini orXBridge C18 columns, MeCN/water gradients, and either TFA or ammonium hydroxide modifiers. GCMS data were acquired using a Hewlett Packard 6890 oven with an HP 6890 Injector, HP-1 column (12 m*0.2 mm*0.33 pm), and hélium carrier gas. The sample was analyzed on an HP 5973 mass sélective detector scanning from 50 to 550 Da using électron ionization. Purifications were performed by medium performance liquid chromatography (MPLC) using Isco CombiFlash Companion, AnaLogix IntelliFtash 280, Biotage SP1, or Biotage Isolera One instruments and pre25 packed Isco RediSep or Biotage Snap silica cartridges. Chiral purifications were performed by chiral supercritical fluid chromatography (SFC) using Berger or Thar instruments; ChiralPAK-AD, -AS, -IC, Chiraicei-OD, or-OJ columns; and CO2 mixtures with MeOH, EtOH, IPrOH, or MeCN, alone or modified using TFA or IPrNH2. UV détection was used to trigger fraction collection.

Mass spectrometry data are reported from LCMS analyses. Mass spectrometry (MS) was performed via atmospheric pressure chemical ionization (APCI), electrospray Ionization (ESi), électron impact ionization (El) or électron scatter (ES) Ionization sources. Proton nuclear magnetic spectroscopy (¹H NMR) chemical shifts are given in parts per million downfield from tetramethylsilane and were recorded on on 300, 400,

500, or 600 MHz Varian spectrometers. Chemical shifts are expressed in parts per

Φ million (ppm, δ) referenced to the deuterated solvent residual peaks. The peak shapes are described as follows: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; m, multiplet; br s, broad singlet; app, apparent, Analytical SFC data were acquired on a Berger analytical instrument as described above. Optical rotation data were acquired 5 on a PerkinElmer model 343 polarimeter using a 1 dm cell. Silica gel chromatography was performed primarily using a medium pressure Biotage or ISCO Systems using columns pre-packaged by various commercial vendors including Biotage and ISCO. Microanalyses were performed by Quantitative Technologies Inc. and were within 0.4% of the calculated values.

Unless otherwise noted, chemical reactions were performed at room température (about 23 degrees Celsius).

The compounds and Intermediates described below were named using the naming convention provided with ChemBioDraw Ultra, Version 12.0 (CambridgeSoft Corp., Cambridge, Massachusetts). The naming convention provided with

ChemBioDraw Ultra, Version 12.0 are well known by those skilled in the art and it is believed that the naming convention provided with ChemBioDraw Ultra, Version 12.0 generally comports with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules. Unless noted otherwise, ail reactants were obtained commercially without further purifications or were prepared using methods known in the literature.

The terms “concentrated, evaporated, and concentrated ln vacuo refer to the removal of solvent at reduced pressure on a rotary evaporator with a bath température less than 60°C. The abbreviation min and h stand for “minutes and “hours respectively. The term “TLC“ refers to thin layer chromatography, “room température or 25 ambient température means a température between 18 to 25°C, “GCMS refers to gas chromatography-mass spectrometry, LCMS refers to liquid chromatography-mass spectrometry, “UPLC refera to ultra performance liquid chromatography and “HPLC refera to high pressure liquid chromatography, “SFC refera to supercritical fluid chromatography.

Hydrogénation may be performed ln a Parr Shaker under pressurized hydrogen gas, or ln Thales-nano H-Cube flow hydrogénation apparatus at full hydrogen and a flow rate between 1-2 mL/min at specified température.

HPLC, UPLC, LCMS, GCMS, and SFC rétention times were measured using the methods noted in the procedures.

Préparation of Intermediates and Examples

Intermediate 1. (R)-2-(3-(2-Ethoxyphenoxy)pîperidin-1-yl)pyrimidine-5-carboxylic acid i o

ΌΗ

Step 1. fert-Butyl (R)-3-(2-ethoxyphenoxy)piperidine-1-carboxylate

To a solution of 2-ethoxyphenol (13.72 g, 99 mmol), fert-butyl (S)-3-hydroxypîperidine-1carboxylate (20 g, 99 mmol), and triphenylphosphine (29 g, 111 mmol) in toluene (150 mL) at 20-25 ’C was added a solution of DIAD (20 mL, 104 mmol) in toluene (50 mL) over 2 hours. After 2 hours, the reaction mixture was filtered and washed with diethyl ether (300 mL). The filtrate was washed with 3N NaOH (150 mL), dried over Na2SO4, and concentrated. The crude residue was purified via column chromatography to afford fert-butyl (R)-3-(2-ethoxyphenoxy)piperidine-1-carboxylate (14.6 g, 45%). MS (ES+)

222.2 (M-100+H).

Step 2. (R)-3-(2-Ethoxyphenoxy)piperidine

To a solution of fert-butyl (R)-3-(2-ethoxyphenoxy)plperidine-1-carboxylate (73 g, 227 mmol) in CH2CI2 (300 mL) at 20-25 ’C was added trifluoroacetic acid (150 mL). The reaction mixture was allowed to stir at 20-25 ’C for 4 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved In H2O (200 mL) and basified with saturated NaHCO3 solution (200 mL). The mixture was extracted with EtOAc (3 times with 200 mL). The organic extracts were dried over Na2SO4 and concentrated to afford (R)-3-(2-ethoxyphenoxy)piperidine (45 g, 89%). MS (ES+) 222.2 (M+H).

Step 3. Ethyl (R)-2-(3-(2-ethoxyphenoxy)plperidin-1-yl)pyrimidine-5-carboxylate

To a solution of (R)-3-(2-ethoxyphenoxy)piperidine (45 g, 204 mmol) and ethyl 2chloropyrimidine-5-carboxylate (41.7 g, 224 mmol) in DMSO (300 mL) was added EbN (40 mL, 305 mmol) at 20-25 ’C. The reaction mixture was heated to 100 ’C for 2 hours, then was cooled to 20-25 ’C, diluted with H2O (300 mL) and extracted with EtOAc (3 times with 300 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain ethyl (fî)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5carboxylate (71.5 g). MS (ES+) 372.3 (M+H).

Step 4. (R)-2-(3-(2-Ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid

To a solution of ethyl (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylate (71.5 g, 193 mmol) in THF/H2O (1:1, 2 L) was added UOH.H2O (24.2 g, 578 mmol) at 20-25 °C. The reaction mixture was stirred at 20-25 ’C for 24 hours. The mixture was concentrated, and the aqueous phase was washed with diethyl ether (2 times with 500 10 mL). The aqueous phase was acidified to pH 2 with 1N HCl (~400 mL). The precipitated solid was filtered and dried to afford (R)-2-(3-(2-ethoxyphenoxy)piperidin-1yl)pyrimidine-5-carboxy!ic acid (52 g, 78%). MS (ES+) 344.18 (M+H).

Intermediate 1, Altemate Procedure. (R)-2-(3-(2-Ethoxyphenoxy)piperidin-1yl)pyrimidine-5-carboxy!ic acid ‘OH

Step 1.3-(2-Ethoxyphenoxy)pyridine

3-Bromopyridine (224 g, 1.42 mol) and 2-ethoxyphenol (275 g, 1.99 mol) were added to a jacketed reactor vessel containîng toluene (2.2 L) at 20 ’C, and the resulting mixture was stirred until ail solids were dissolved. 2,2,6,6-Tetramethylheptane-3,5-dione (118 g, 20 0.640 mol), copper(l) chloride (71.8 g, 0.71 mol), and césium carbonate (749 g, 2.27 mol) were added sequentially, and the jacket température was raised to 119 ’C. The mixture became thick, and stirring resumed as the température increased. After 20 hours, the mixture was cooled to 30 ’C. The organic layer was washed sequentially with water (0.75 L) and with aqueous 15% ammonium hydroxide solution (0.70 L), and 25 then was extracted with aqueous 3M hydrochloric acid solution (1.18 L, 3.55 mol). Ethyl acetate (1.8 L) and aqueous 15% ammonium hydroxide solution (0.500 L, 3.60 mol) were then added sequentially to the acidic aqueous phase. The blue aqueous layer was separated, and the resulting organic layer was washed sequentially with aqueous 15% ammonium hydroxide solution (0.50 L) and with 2:1 waterbrine solution (0.30 L).

φ The organic layer and Darco G60 activated charcoal (60 g) were stirred at 45 ’C for 1 hour, and then were filtered through a pad of Celite, rinsing with ethyl acetate (0.35 L).

The filtrate was concentrated under vacuum and the resulting residue was reconcentrated from methanol (0.30 L) to afford 3-(2-ethoxyphenoxy)pyridine (233 g) as a yellow oil. ’H NMR (400 MHz, DMSO-de) δ 8.25 (s, 2H), 7.34 (dd, 1 H), 7.18 (m, 4H), 6.99 (t, 1H), 4.01 (q, 2H), 1.11 (t, 3H).

Step 2. 3-(2-Ethoxyphenoxy)piperidine hydrochloride

Aqueous 12.2M hydrochloric acid solution (60.0 mL, 0.976 mol) was added slowly to a mixture of 3-(2-ethoxyphenoxy)pyridine (210 g, 0.976 moi), rhodium (5% on alumina, 21 g, 0.010 mol), and methanol (2.1 L) In a Pair reactor. The reactor was purged sequentially with nitrogen and hydrogen (4 times each), and then was heated to 50 ’C and pressurized to 50 psi with hydrogen. After 9 hours, the reactor was cooled to 25 ’C and was purged with nitrogen. The catalyst was removed by filtration, rinsing with methanol. The resulting methanol solution was distilled to a low volume under reduced pressure at 50-55 ’C; ethyl acetate (2.3 L) was added and the distillation was continued at amblent pressure and at constant volume with the addition of further ethyl acetate (1.5 L). The distillation was stopped when the solution became turbid. The mixture was cooled to 20 ’C and the resulting crystals were collected by filtration, rinsing with ethyl acetate (0.70 L), to afford after drying 3-(2-ethoxyphenoxy)piperidine hydrochloride (201

g). ’H NMR (400 MHz, DMSO-de) δ 9.20 (br s, 2H), 7.12 (d, 1 H), 7.03 (m, 2H), 6.89 (m,

1H), 4.45 (m, 1H), 4.04 (q, 2H), 3.27 (app dd, 1H), 3.05 (m, 3H), 1.94 (m, 2H), 1.72 (m, 2H), 1.35 (t, 3H). MS (ES+) 222.1 (M+H).

φ Step 3. (R)-3-(2-Ethoxyphenoxy)piperidine D-tartrate

A slurry of 3-(2-ethoxyphenoxy)piperidine hydrochloride (200 g, 0.776 mol) and Dtartaric acid (118 g, 776 mol) In acetone (3.0 L) was warmed to 56 ’C and was held at that température for 2 hours. The mixture was cooled to 20 °C and was held at that 5 température ovemight. The crystals were collected by filtration, rinsing with acetone (1 L), and then were dried to afford (R)-3-(2-ethoxyphenoxy)piperidine D-tartrate (145 g).

Chiral HPLC analysis indicated an enantiomeric ratio of 99.5:0.5 (Chiralpak AD-H, 4.6 x 250 mm, 5 pm, 210 nM, 0.2% isopropylamlne-isopropanol, 0.7 mL/min; rétention times 5.76 min (major enantiomer), 6.20 min (minor enantiomer). ¹H NMR (400 MHz, DMSO10 de) δ 12.69 (brs, 1.5H), 9.34 (brs, 1H), 8.79 (brs, 1H), 7.12 (d, 1H), 7.03 (m, 2H), 6.89 (m, 1H), 5.09 (br s, 1.5H), 4.44 (m, 1H), 4.32 (s, 2H), 4.05 (q, 2H), 3.28 (m, 1H), 3.11 (m, 1 H), 3.04 (m, 2H), 1.97 (m, 1 H), 1.92 (m, 1 H), 1.72 (m, 2H), 1.35 (s, 3H).

Step 4. (R)-2-(3-(2-Ethoxyphenoxy)piperidin-1-y!)pyrimidine-5-carboxylic acid

N./V-Diisopropylethylamine (2.91 kg, 22.5 moi) was added to a mixture of ethyl 215 chloropyrimidine-5-carboxylate (1.20 kg, 6.43 mol) and (R)-3-(2ethoxyphenoxy)piperidine D-tartrate (2.63 kg, 7.07 mol) in tetrahydrofuran (12.0 L) at 55 ’C, at a rate maintaining a température of 50-60 ’C. The mixture was held at that température for 1 hour, then was cooled to 30 ’C. The mixture was then partitioned between water (8.4 L) and 2-methyltetrahydrofuran (16.8 L). The organic layer was washed with aqueous 2M sodium chloride solution (6.8 L), and then was concentrated by distillation under reduced pressure. Tetrahydrofuran (12.0 L) and methanol (6.0 L) were added to the residue, and then an aqueous 8M potassium hydroxide solution was added at a rate to maintain the température below 55 ’C. The mixture was held at 5055 ’C for 1 hour, then was cooled to 30 ’C, and was partitioned between ethyl acetate (18.0 L) and aqueous 3M hydrochloric acîd solution (8.86 L). The organic layer was washed with aqueous 2M sodium chloride solution (6.8 L), and was then distilled to a low volume. Ethyl acetate (22 L) was added and the resulting solution was distilled at ambient pressure and at constant volume with the addition of further ethyl acetate (25 L). The mixture was cooled to and heid at 57 ’C for 2 hours as crystallization initiated.

n-Heptane (8.83 L) was added while maintaining température at 55-60 ’C. After 30 min, the slurry was cooled to 20-25 ’C and was held at that température for 11 hours. The crystals were collected by filtration, rinsing with 2:1 ethyl acetate:n-heptane (8.0 L), to afford after drying (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (1.69 kg). MS (ES+) 344.3 (M+H). The mother liquors were concentrated and the resulting residue was recrystallized from ethyl acetate (4.2 L), with the addition of n~ heptane (2.1 L) after crystallization initated, to afford after filtering and drying an additional portion of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (0.370 kg).

Intermediate 2. Methyl 3-(aminomethyl)-5-methoxybenzoate hydrochloride

o

To a solution of methyl 3-cyano-5-methoxybenzoate (280 mg, 1.46 mmol) In MeOH (15 mL) was added 10% Pd/C (150 mg). The mixture was hydrogenated under an atmosphère of H2 for 6 hours. The mixture was filtered through a pad of celite under N2 10 and the filtrate was added to an ethereal-HCI solution (6 mL). The résultant mixture was evaporated under reduced pressure and the resulting residue was triturated with ethyl acetate to obtain methyl 3-(aminomethyl)-5-methoxybenzoate hydrochloride (120 mg).

Intermediate 2A. Methyl 3-(aminomethyl)-4-methylbenzoate hydrochloride hci _o

Methyl 3-(aminomethyl)-4-methylbenzoate hydrochloride was prepared from methyl 3 cyano-4-methylbenzoate in an analogous manner to Intermediate 2.

Intermediate 2B. Methyl 3-(aminomethyl)-4-fluorobenzoate hydrochloride

HCl o

Methyl 3-(aminomethyl)-4-fluorobenzoate hydrochloride was prepared from methyl 3cyano-4-fluorobenzoate in an analogous manner to Intermediate 2.

φ Intermediate 2C. Methyl 3-(amlnomethyl)-4-methoxybenzoate hydrochloride

HCl _o

Methyl 3-(aminomethyl)-4-methoxybenzoate hydrochloride was prepared from methyl 3cyano-4-methoxybenzoate ln an analogous manner to Intermediate 2.

Intermediate 2D. Methyl 3-(aminomethyl)-5-methylbenzoate hydrochloride

HCl

Methyl 3-(aminomethyl)-5-methylbenzoate hydrochloride was prepared from methyl 3 cyano-5-methylbenzoate in an analogous manner to Intermediate 2.

Intermediate 2E. Ethyl 3-(aminomethyl)-2-methoxybenzoate hydrochloride hci _o/ _o

Ethyl 3-(aminomethyl)-2-methoxybenzoate hydrochloride was prepared from ethyl 3cyano-2-methoxybenzoate in an analogous manner to Intermediate 2.

Intermediate 2F. Ethyl 2-(3-(aminomethyl)phenyl)propanoate hydrochloride

Ethyl 2-(3-(aminomethyl)phenyl)propanoate hydrochloride was prepared from ethyl 2-(3cyanophenyl)propanoate in an analogous manner to Intermediate 2.

Intermediate 2G. Ethyl 5-(aminomethyl)-6-methylnicotinate hydrochloride hci o

φ Ethyl 5-(aminomethyl)-6-methyinicotinate was prepared from ethyl 5-cyano-6· methylnicotinate In an analogous manner to Intermediate 2.

Intermediate 3. Methyl 4-(aminomethyi)picoiinate

Stepl. Methyl 4-(azidomethyl)picoiinate

To solution of methyl 4-(bromomethyl)picolinate (350 mg, 1.52 mmol) In methanol (5 mL) was added a solution of sodium azide (198 mg, 3.04 mmol) in water (0.5 mL). The mixture was heated to reflux for 2 hours, then was concentrated. The resulting residue was dissoived In EtOAc (10 mL) and water (10 mL). The organic layer was separated, 10 dried over MgSO<, filtered and concentrated to give methyl 4-(azidomethyl)picolinate (280 mg).

Step 2. Methyl 4-(aminomethyl)picolinate

To a solution of methyl 4-(azidomethyl)picolinate (280 mg, 1.36 mmol) in methanol (20 mL) was added 10% Pd/C (50mg). The mixture was stirred under 35 psi H2 for 2 hours. The reaction mixture was filtered through Ceiite, concentrated, and purified via column chromatography to provide methyl 4-(aminomethyl)picoiinate (150 mg).

Intermediate 4: (R)-6-(3-(2-Ethoxyphenoxy)plperidin-1-yl)nicotinic acid

ΌΗ

Step 1. Ethyl (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yi)nicotinate

Triethylamine (8.1 mL, 80 mmol) was added to a stirred solution of (R)-3-(2-ethoxyphenoxy)-piperidine (10 g, 39 mmol) and ethyl 6-chloronicotinate (7.2 ml, 39 mmol) in acetonitrile (100 mL) at O’C. The reaction mixture was heated at 90 ’C for 16 h. The mixture was cooled to ambient température, water (150 mL) was added, and the mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed sequentiaily with water (100 mL) and brine (100 mL), then were dried over sodium sulfate, filtered and concentrated. The crude material was purified by column φ chromatography (13% ethyl acetate-hexanes) to afford ethyl (R)-6-(3-(2ethoxyphenoxy)piperidin-1-yl)nicotinate (8.8 g). MS (ES+) 371.0 (M+H).

Step 2. (R)-6-(3-(2-Ethoxyphenoxy)piperidin-1-yl)nicotinic acid

Aqueous 1N sodium hydroxide solution (27.1 mL, 27.0 mmol) was added to a stirred solution of ethyl (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)nicotinate (2.5 g, 6.8 mmol) in tetrahydrofuran (20 mL) at 0 °C. The reaction mixture was heated to 60 ’C for 18 h.

The mixture was then diluted with water (25 mL) and was washed with ethyl acetate (2 x 50 mL). The aqueous layer was acidified with citric acid solution (pH—2) and was extracted with ethyl acetate (3 x 50 mL). The combined organics were dried over îo sodium sulfate, filtered and concentrated. The crude solid material was purified by washing with ether and hexane to afford (R)-6-(3-(2-ethoxyphenoxy)piperidin-1yl)nicotinïc acid (2.3g) as white solid. ’H NMR (400 MHz, DMSO-de) δ 12.39 (s, 1 H),

8.57 (d, 1H), 7.87 (dd, 1 H), 7.03 (dd, 1H), 6.90 (m, 3H), 6.79 (d, 1H), 4.29 (m, 1H), 4.16 (m, 1 H), 3.91 (m, 2H), 3.76 (m, 1 H), 3.59 (m, 2H), 2.01 (m, 1H), 1.81 (m, 2H), 1.51 (m, 15 1 H), 1.23 (t, 3H). MS (ES+) 343.2 (M+H).

Intermediate 5. (R)-6-(3-(2-Ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinic acid

Step 1. Methyl (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinate

Triethylamine (0.45 mL, 3.3 mmol) was added to a stirred solution of (R)-3-(2-ethoxyphenoxy)-piperidine (0.41 g , 1.6 mmol) and methyl 6-chloro-5-fluoronicotinate (0.30 g,

1.6 mmol) in acetonitrile (15 mL) at 0’C. The reaction mixture was heated at 50 ’C for 18 h. The mixture was cooled to ambient température, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers 25 were dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (30% ethyl acetate-hexanes) to afford methyl (R)-6(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinate (0.40 g). MS (ES+) 375.2 (M+H).

Step 2. (R)-6-(3-(2-Ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinic acid φ Lithium hydroxide hydrate (62 mg, 2.6 mmol) was added to a solution of methyl (R)-6(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinate (0.65 g, 1.7 mmol) in tetrahydrofuran (8 mL) and water (8 mL), and the resulting solution was stirred at 20-25

C for 18 h. The mixture was then diluted with water (20 mL) and was washed with ethyl acetate (2 x 30 mL). The aqueous layer was acidified with citric acid solution (pH~2) and was extracted with ethyl acetate (3 x 30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to afford (R)-6-(3-(2ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinic acid as a white solid (0.50 g). ’H NMR (400 MHz, DMSO-de) δ 12.85 (brs, 1H), 8.46 (s, 1H), 7.68 (dd, 1H), 7.00 (dd, 1H), 6.87 (m, 3H), 4.39 (m, 1 H), 4.02 (dd, 1 H), 3.89 (m, 2H), 3.68 (m, 3H), 1.97 (m, 2H), 1.79 (m,

H), 1.55 (m, 1H), 1.22 (t, 3H). MS (ES+) 361.2 (M+H).

Example 1. (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1 -yl)pyrimidine-5carboxamido)methyl)benzolc acid

ΌΗ

Step 1. (R)-Methyl 3-((2-(3-(2-ethoxyphenoxy)piperldin-1-yl)pyrimidine-5carboxamido)methyl)benzoate

To a 500-mL 3-neck flask was added methyl 3-(aminomethyl)benzoate hydrochloride (12.9 g, 64.1 mmol) followed by DMSO (26 mL). The solution was cooled to 15 °C. NMethyl morpholine (27 mL, 240 mmol) was added followed by EDCI (13 g, 68 mmol) and HOBT (4.09 g, 30 mmol), maintainlng the temperature at 15 ’C. A solution of (R)-2 (3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylicacid (20.94 g, 60.98 mmol) in THF (100 mL) was added dropwise over 10 min. The reaction mixture was warmed to 20-25 °C and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water (200 mL) and pentane-ethyl acetate (1:2, 300 mL). The aqueous phase was further extracted with ethyl acetate (2 times with 100 mL). The combined organic extracts were rinsed sequentially with water (200 mL), saturated aqueous sodium bicarbonate solution (2 times with 100 mL), and brine (2 times with 25 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated to afford (R)-methyl 3-((2-(3-(218481 φ ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoate (22.3 g). MS (ES+) 491.3 (M+H).

Step 2. (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5carboxamido)methyl)benzoic add

A solution of (R)-methyl 3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5carboxamido)methyl)benzoate (21.3 g, 43.5 mmol) in THF (100 mL) was cooled to 5 °C. Aqueous 1.9M lithium hydroxide solution (50 mL, 96 mmol) was added via addition funnel, maintaining the température below 14 °C, followed by a 30-mL water rinse of the addition funnel. The reaction mixture was warmed to 20-25 °C and was stirred at that température for 72 hours. The mixture was concentrated to remove THF, and then was cooled to 6 °C. Hydrochloric acid (1N, 80 mL) was added dropwise, and a precipitate began to form. Ethyl acetate (200 mL) was added to dissolve the solids, and the layers were separated, and the aqueous phase was further extracted with ethyl acetate (2 times with 100 mL). The combined organics were washed with brine (4 times with 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude solid (20.4 g) was slurried in éthanol (250 mL) and heated to 75 °C, resulting in a yellow solution. Water (250 mL) was added slowly, forming a precipitate, and the mixture was heated to 90 °C to dissolve the solids. The solution was then cooled to 30 °C and was held at that température for 16 hours. The mixture was further cooled to 20 1.5 °C for 3 hours. The resulting crystals were collected by filtration, rinsed with water (50 mL), and then dried to afford (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1yl)pyrlmidine-5-carboxamido)methyl)benzoic acid (19.2 g). ¹H NMR (500 MHz, CD3OD) δ 8.73 (s, 2H), 8.03 (s, 1H), 7.94 (d, 1H), 7.59 (d, 1H), 7.45 (t, 1H), 7.01 (dd, 1H), 6.92 (m, 2H), 6.86 (m, 1H), 4.60 (s, 2H), 4.37 (m, 1H), 4.14 (dd, 1H), 4.06 (dd, 1 H), 3.92 (m,

4H), 2.07 (m, 1H), 1.97 (m, 2H), 1.58 (m, 1H), 1.29 (t, 3H). Chiral SFC: Chiralcel OJ-H,

4.6 mm x 25 cm, 70:30 C02:methanol, 0.2% isopropylamine, 2.5 mL/min, 210/254 nM; rétention time (R)-enantiomer (Example 1) 4.13 min, (S)-enantiomer 2.35 min. MS (ES+) 477.3 (M+H).

φ Example 1, Altemate Procedure. (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1 yl)pyrimidine-5-carboxamido)methyl)benzoic acid

N,N-Diisopropylethylamine (2.32 kg, 17.9 mol) was added via dropping funnel to a mixture of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1 -yl)pyrimidine-5-carboxylic acid (2.05 kg, 5.98 mol) and tetrahydrofuran (19.5 L) at 20-25 ’C. 1,1’-Carbonyldiimidazole (0.94 kg, 5.8 mol) was then added portion-wise, rinsing with tetrahydrofuran (1.03 L), and the mixture was heated to 43-48 ’C to dissolve the solids. Methyl 3-(aminomethyl)benzoate hydrochloride (1.39 kg, 6.88 mol) was added, and the reaction mixture was heated to lo 58-62 ’C and was held at that température for 3 hours, before being cooled to 20 ’C.

The product mixture was partitioned between aqueous 3M hydrochloric acid solution (8.6 L) and 2-methyltetrahydrofuran (30.8 L). The organic layer was washed sequentially with aqueous 1M hydrochloric acid solution (8.6 L), aqueous 15% ammonium hydroxide solution (2 times with 15 L), and aqueous 2M sodium chloride 15 solution (18 L), and then was concentrated to a low volume under reduced pressure.

Methanol (10.27 L) and tetrahydrofuran (20.54 L) were added to the residue and the resulting solution was cooled to 5-10 ’C. Aqueous 1.5M potassium hydroxide solution (15.9 L, 23.9 mol) was added at a rate maintaining the température below 10 ’C, and the température was then held at 15-20 ’C for 3 hours. The product mixture was partitioned between aqueous 3M hydrochloric acid solution (8.0 L) and ethyl acetate (30.81 L). The organic layer was washed with aqueous 2M sodium chloride solution (18 L), and then was concentrated under reduced pressure to a volume of approximately 6 L. Ethyl acetate (16.43 L) was added, and the solution was distilled at ambient pressure and at constant volume with the addition of further ethyl acetate (27 L) until the distillation pot température was stable at approximately 78 ’C. The resulting mixture was cooled to 20-25 ’C and was held at that température for 16 hours. The crystals were collected by filtration, rinsing with ethyl acetate (6.16 L), and then were dried to afford (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1 -yl)pyrimidine-5carboxamido)methyl)benzoic acid (2.27 kg). ¹H NMR (600 MHz, DMSO-de) δ 12.93 (s,

1 H), 8.93 (t, 1 H), 8.76 (br s, 2H), 7.89 (s, 1 H), 7.82 (d, 1 H), 7.54 (d. 1 H), 7.44 (t, 1 H),

7.01 (d, 1 H), 6.89 (m, 2H), 6.84 (m, 1 H), 4.50 (d, 2H), 4.29 (m, 1 H), 4.14 (dd, 1 H), 3.86 φ (m. 4Η), 3.78 (m, 1 H). 1.98 (m, 1H), 1.81 (m, 2H), 1.49 (m, 1H). 1.18 (t, 3H). Melting point 151-152 ’C. Elemental analysis for C26H28N4O5: calculated C, 65.53; H, 5.92; N,

11.76; found C, 65.41; H, 5.58; N, 11.83.

Powder X-ray Diffraction Analysis:

The powder X-ray diffraction patterns of the example 1 compound was carried out on a Bruker AXS D4 Endeavor diffractometer using copper radiation (wavelength: 1.54056A). The tube voltage and amperage were set to 40 kV and 40mA, respectively. The divergence sût was set at 0.6 mm while the secondary optics used variable slits. Diffracted radiation was detected by a PSD-Lynx Eye detector. Data was collected ln the Theta-2Theta goniometer at the Cu wavelength from 3.0 to 50.0 degrees 2-Theta using a step size of 0.009 degrees and a step time of 12.0 seconds. Samples were prepared by placing them in a customized holder and rotated during collection. Data were collected using Bruker DIFFRAC Plus software (Version 2.0) and analysis was performed by EVA diffract plus software. PXRD data file was not processed prior to peak searching. Generally, a threshold value of 1 and a Width value of 0.3 were used to make prelimlnary peak assignments. The output of automated assignments was visually checked to ensure validity and adjustments manually made if necessary.

To perform an X-ray diffraction measurement on a Bragg-Brentano instrument like the Bruker system used for measurements reported herein, the sample is typically placed into a holder which has a cavity. The sample powder is pressed by a glass slide or équivalent to ensure a random surface and proper sample height. The sample holder is then placed into the instrument The incident X-ray beam is directed at the sample, initially at a small angle relative to the plane of the holder, and then moved through an arc that continuously increases the angle between the incident beam and the plane of the holder. Measurement différences associated with such X-ray powder analyses resuit from a variety of factors including: (a) errors in sample préparation (e.g., sample height), (b) instrument errors (e.g. fiat sample errors), (c) calibration errors, (d) operator errors (including those errors présent when determining the peak locations), and (e) the nature of the material (e.g. preferred orientation and transparency errors). Calibration errors and sample height errors often resuit in a shift of ail the peaks in the same direction. Small différences in sample height when using a fiat holder will lead to large displacements in XRPD peak positions. A systematic study showed that, using a Shimadzu XRD-6000 in the typical Bragg-Brentano configuration, sample height différence of 1 mm lead to peak shifts as high as 1 ’20 (Chen et al.; J Pharmaceutical

Φ and Biomédical Analysis, 2001 ; 26,63). These shifts can be identified from the X-ray Diffractogram and can be eliminated by compensating for the shift (applying a systematic correction factor to ail peak position values) or recalibrating the instrument. As mentîoned above, it is possible to rectifÿ measurements from the various machines s by applying a systematic correction factor to bring the peak positions into agreement ln general, this correction factor will bring the measured peak positions from the Broker Into agreement with the expected peak positions and may be ln the range of 0 to 0.2 ° 2Θ.

The powder X-ray diffraction values are generally accurate to within ± 0.2 2-theta 10 degrees, due to slight variations of instrument and test conditions.

Table 1. X-ray powder diffraction pattern: Peak list for Crystalline Form of Example 1.

Angle (2-Theta ·)	Relative Intensity* G>io%)
6.9	43
9.7	10
10.3	59
11.0	50
13.0	17
14.9	15
15.1	29
15.3	17
17.1	20
17.3	14
18.2	24
18.5	10
19.1	100
20.2	10
20.7	56

21.8	13
22.0	25
22.8	19
23.2	16
23.5	13
23.8	21
24.1	31
25.4	10
25.7	34
25.9	44
26.7	17
27.2	12
27.6	11
30.5	12
31.6	18

*The relative intensifies may change depending on the crystal size and morphology.

Single Crystal X-Ray Analysis.

Single crystal for Xray crystallography analysis of (R)-3-((2-(3-(25 ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamldo)methyl)benzoic acid (Example

1) was obtained by following procedure: A solution of (R)-3-((2-(3-(2ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid in éthanol (0.14 M) at 68 °C internai température was treated with water to reach a final concentration of 0.074 M. The solution was seeded with crystalline (R)-3-((2-(3-(210 ethoxyphenoxy)piperidin-1 -yl)pyrimidine-5-carboxamido)methyl)benzoic acid and then was cooled slowly to 20-25 ’C to isolate a single crystal suitable for X-ray diffraction.

Single Crystal data collection was performed on a Broker APEX diffractometer at room température. Data collection consisted of 3 oméga scans and low angle and three at φ high angle; each with 0.5 step. ln addition, 2 phi scans were collected to improve the quality of the absorption correction.

The structure was solved by direct methods using SHELX software suite in the space group P1. The structure was subsequently refined by the full-matrix least squares method. Ail non-hydrogen atoms were found and refined using anisotropic displacement parameters. Structure exhibits pseudo inversion center. The hydrogen atoms located on nitrogen and oxygen were found from the Fourier différence map and refined with distances restrained. The remaining hydrogen atoms were placed in calculated positions and were allowed to ride on their carrier atoms. The final refinement included isotropie displacement parameters for ail hydrogen atoms. A non-stoichiometric water molécule was found in the lattice.

Analysis ofthe absolute structure using likelihood methods (R.W.W, Hooftet al. J. Appl. Cryst. (2008), 41,96-103) was performed using PLATON (A.L. Spek, J. Appl. Cryst. (2003), 36, 7-13), The results indicate that the absolute structure has been correctly assigned. The final R-index was 3.9%. A final différence Fourier revealed no missing or mlsplaced électron density. Pertinent crystal, data collection and refinement of (R)-3-((2(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid (Example 1) are summarized in Table 2, and graphically presented in Figure 2.

Table 2. Example 1. Crystal data and structure refinement for Emplrical formula C26

H28N4 05.13

Formula weiaht	478.52
Température	273(2) K
Wavelength 1.54178 A
Crystal system	Triclinic

Space group P1

Unit cell dimensions______a = 9.1042(12) A a= 99.787(8)°.

b = 10 8807(14) A B= 100.427(8)°, c = 13.4126(18) A y = 104.796(8)°,

Volume 1230.3(3) A3

Z____2

Density (calculated) 1.292 Mg/m3 φ Example 1Α: [¹¹Cl-(Æ?)-3-((2-(3-(2-ethoxyphenoxy)pîperidin-1-yl)pyrimidïne-5carboxamîdo)methyl)benzoîc add

Step 1. (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)-M-(3-lodobenzyl)pyrimldine-5carboxamîde

A mixture of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimldine-5-carboxylic add (2.00 g, 5.82 mmol), (3-lodophenyl)methanamine (1.00 mL, 7.20 mmol), N-methyl morpholine (2.00 mL, 18 mmol), EDCI (1.2 g, 5.9 mmol), and HOBT (455 mg, 2.91 mmol) in THF (30 mL) was stirred at room température ovemight The réaction was diluted with EtOAc (50 mL). The organic layer was washed with saturated aqueous solution of ΝΗ<ΟΙ (50 mL), saturated aqueous solution of NaHCOa (50 mL), and brine (50 mL), dried over NaîSO4 and concentrated to dryness. The residue was purified by flash column chromatography (0-50% EtOAc in Heptanes) to afford (R)-2-(3-(215 ethoxyphenoxy)piperidin-1 -yl)-N-(3-iodobenzyl)pyrimidine-5-carboxamide (2.39 g, 74%) as a solid. ¹H NMR (400 MHz, CDCh) δ 8.69 (s. 2H), 7.69 (m, 1H), 7.64 (m, 1H), 7.32 (m, 1 H), 7.10 (t, 1H), 6.98 (m, 2H), 6.88 (m, 2H), 6.13 (t 1H), 4.58 (d, 2H), 4.48 (dd,

1H), 4.25 (m, 1 H), 4.18 (m, 1 H), 4.01 (m, 2H), 3.77 (dd, 1H), 3.64 (m, 1H), 2.13 (m, 1H), 1.97 (m, 2H), 1.59 (m, 1 H), 1.39 (t, 3H). MS (ES+) 559.2 (M+H).

Step 2. [¹¹C]-(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5carboxamido)methyl)benzoic add

Préparation prior to the start of synthesis

A clean sequence using tetrahydrofuran (THF) was run on the GE FXc Pro automated CO module prior the start of beam. Prior to beam on, target hélium sweep was directed 25 to the CO2 trap in hot cell 1 via the microelectric valve (which allows switching between target delivery to either the CO2 trap or the CO module) for several minutes, then was switched via the microelectric valve to the CO module and the hélium gas was swept through the pre-purification unit (PPU) In the CO module for several minutes by having φ the Vx1 and Vx2 valves ln the active position. The PPU was then put through a preproduction prep which conditioned and flushed the packing material in the PPU.

ΡΌ]0θ2 production

No-carrier-added [¹¹C]C02 was prepared by proton Irradiation (30 min, 60 pamp beam) of a 9.5 mL nitrogen gas target ΡΝίρ,α)¹¹^. The target was flushed with target gas for 10 minutes, then pressurized to 300 psi and dumped three times before refilling. Two 5 min, 30 pamp pre-burns were performed before the actual beam for the synthesis. Hélium was allowed to sweep through the lines and trap ln an Ascarite trap ln a separate hot cell once beam started (this was switched to the hot cell containing the CO module after 5 min, thus keeping the delivery Unes to the CO module pressurized with hélium prior to target dump).

Sequence

The Pd(PPha)4 (stored under nitrogen in the fridge) was warmed to room température and weighed out (5.55 mg, 0.005 mmol) in an oven-dried 2 mL septum-sealed vial ln an argon glove box, then purged with nitrogen. The precursor, (R)-2-(3-(2ethoxyphenoxy)piperidin-1 -yl)-N-(3-lodobenzy!)pyrimidine-5-carboxamide, was weighed out (5.08 mg, 0.009 mmol) in an oven-dried via! ln the open air. Ten minutes before the end of beam, the production sequence for the CO module was started. Both the

Pd(PPh3)4 and the precursor were dissolved in 200 pL of anhydrous THF after the vlals were purged with nitrogen. The precursor solution was added to the Pd solution under a nitrogen stream (using the THF syringe), and the solution tumed from a yellow to a very light yellow. After several minutes the tetra-N-propylammonium hydroxide (50 pL of 1M ln water, 0.05 mmol) was added, the contents of the vial shaken, and the same polypropylène syringe was used to remove the solution. The polypropylène syringe was then fitted with a syringe filter (Nalgene 4 mm syringe filter, PTFE, 0.45 pm, cat# F26043) and the contents filtered into a separate 2 mL septum-sealed vial that was purging with nitrogen. The filtered solution was then removed with a clean 1 mL polypropylène syringe and loaded Into the CO module loop. After the delivery of [¹¹C]CO2 to the CO module, the time list for the FXc Pro was started. Following the reaction, 5 minutes at 150 °C, the crude mixture was transferred to the reaction vessel of the FXc Pro (via

0.0Γ ID PEEK line from position 3 of V3 in the CO module to the syringe port of the FXc Pro), and the THF was evaporated at 65 ’C in vacuo. The residue was diluted with 0.3 mL dimethylformamide and 1.3 mL 50% acetonitrile/0.1% formic acid, passed through the in-line polypropylene filter, and purified by semi-prep chromatography (Column: Phenomenex Luna C-18(2) 10 x 250 mm, 5 pm, cat. # 00G-4252-N0k;

Isocratic: 55% acetonitrile: water with 0.1% formic add, Flow: 6.0 mL/min; UV: 254 nm) byautomated filling ofa 2.0 mL Rheodyne loop, followed by Injection ontothe column. The peak corresponding to [¹¹C]-(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1yi)pyrimidine-5-carboxamido)methyl)benzoic acid (tR - 8.6 min) was collected and diluted with 50 mL water, followed by trapping on a Waters C8 50 mg vac cartridge (WAT054965). The cartridge was washed with 3.0 mL water, then eluted with éthanol (0.5 mL) and saline (4.5 mL). The final product was analyzed by analytical HPLC. HPLC 10 rétention time = 8.0 min (Mobîie Phase : 50% acetonitrile:0.1% formic acid; Total time of run: 15 min; Flow: 1.0 ml/min; Column: Phenomenex Luna C-18(2), 3 pm, 100 A, 150 X

4.6 mm, cat# 00F-4251-E0; Detector : UV280 nm); Synthesis time (from end of beam)=34 min; Spedfic activity = 3965 Ci/mmol; Concentration= 16 mCi/mmol; Yield (decay-corrected based on starting amount of crude [^-(^-3-((2-(3-(2- ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid ln FXc Pro reactor)=52%; Radiochemical purity = 100%; Chemical purity = 98.4%.

Example 2. (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1 -yl)pyrimidine-5carboxamido)methyl)-5-methoxybenzoic add

Step 1. Methyl (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yi)pyrimidine-5carboxamido)methyl)-5-methoxybenzoate

The préparation of methyl (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5carboxamido)methyl)-5-methoxybenzoate serves as a représentative procedure referred to as Amidation Method 1 (HATU).

To a suspension of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxyiic acid (50 mg, 0.14 mmol) and HATU (63 mg, 0.17 mmol) in dry dichloromethane (3 mL) was added N,N-diisopropylethylamine (0.075mL, 0.42 mmol) at 20-25 ’C. The mixture was stirred for 10 min, then methyl 3-(aminomethyl)-5-methoxybenzoate hydrochloride φ was added (33 mg, 0.14 mmol) at 20-25 'C. The reaction mixture was stirred at 20-25 °C for 1 hour. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate (10 mL), washed with water (2 times with 10 mL), and dried over NaSO«. The organics were concentrated under reduced pressure to obtain methyl (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimldine-5carboxamido)methyl)-5-methoxybenzoate (65 mg, 87%).

Step 2. (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1 -yl)pyrimidine-5-carboxamldo)methyl)5-methoxybenzolc acid

The préparation of (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimldine-510 carboxamldo)methyl)-5-methoxybenzoic acid serves as a représentative procedure referred to as Ester Hydrolysis Method 1 (LIOH).

To a solution of methyl (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimldine-5carboxarnido)rnethyl)-5-methoxybenzoate (60 mg, 0.11 mmol) in THRHîO (1:1, 5 mL) at 20-25 °C was added LiOH.toO (15 mg, 0.34 mmol). The mixture was stirred for 18 hours, and then was concentrated under reduced pressure. The resulting residue was diluted with water (5 mL) and washed with ethyl acetate (3 times with 5 mL). The aqueous layer was acidified to pH 2 with 1N HCl (5 mL), and then was extracted with ethyl acetate (3 times with 5 mL). The combined organic extracts were dried over Na2SO« and concentrated under reduced pressure to afford (R)-3-((2-(3-(220 ethoxyphenoxy)piperidin-1 -yl)pyrimidine-5-carboxamido)methyl)-5-methoxybenzoic acid (40 mg, 72%). ’H NMR (300 MHz, DMSO-de) δ 8.91 (m, 1H), 8.78 (s, 2H), 7.49 (s, 1H), 7.34 (s, 1H), 7.02 (m, 2H), 6.89 (m, 3H), 4.45 (d, 2H), 4.32 (m, 1H), 4.20 (d, 1H), 3.91 (m, 5H), 3.78 (s, 3H), 2.05 (m, 1H), 1.85 (m, 2H), 1.52 (m, 1 H), 1.21 (t, 3H). MS (ES+)

507.1 (M+H).

Example 3. 3-((R)-1-(2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5carboxamldo)ethyl)benzolc acid ‘OH φ Step 1. Methyl 3-((/7)-1 -(2-((/7)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5carboxamldo)ethyl)benzoate

The préparation of methyl 3-((/7)-1-(2-((/7)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine5-carboxamido)ethyl)benzoate serves as a représentative procedure referred to as

Amidation Method 2 (EDCI).

To a stirred solution of (/7)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (797 mg, 2.32 mmol) in dry DMF (2.5 mL) at 0 ’C were added triethylamine (0.36 mL, 2.5 mmol), 1-hydroxybenzotriazole (470 mg, 3.48 mmol), and 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1666 mg, 3.48 mmol). The îo mixture was stirred for 5 min and methyl (/7)-3-(1-aminoethyl)benzoate (500 mg, 2.32 mmol) was added. The reaction mixture was allowed to warm to 20-25 ’C and was stirred for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 times with 25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified via 15 column chromatography to afford methyl 3-((/7)-1 -(2-((/7)-3-(2-ethoxyphenoxy)piperidin-

1-yl)pyrimidine-5-carboxamido)ethyl)benzoate (890 mg, 76%). MS (ES+) 505.2 (M+H).

Step 2. 3-((/7)-1-(2-((/7)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5carboxamido)ethyl)benzoic acid

3-((/7)-1-(2-((/?)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-52o carboxamido)ethyl)benzoic acid was prepared from methyl 3-((/7)-1-(2-((/7)-3-(2ethoxyphenoxy)piperidin-1 -yl)pyrimidîne-5-carboxamido)ethyl)benzoate using Ester Hydrolysis Method 1 (LIOH). ¹H NMR (400 MHz, DMSO-de) 0 12.9 (br s, 1H), 8.76 (s, 2H), 8.70 (d, 1 H), 7.96 (s, 1H), 7.81 (d, 1 H),7.61 (d, 1H), 7.45 (dd, 1H), 7.03 (d, 1H),

6.89 (m, 3H), 5.18 (m, 1H), 4.30 (m, 1H), 4.19 (dd, 1H), 3.89 (m, 4H), 3.77 (m, 1H), 2.01 (m, 1 H), 1.83 (m, 2H), 1.51 (m, 1 H), 1.46 (d, 3H), 1.21 (t, 3H). MS (ES+) 491 (M+H).

Example 4. (/7)-2-(3-(2-ethoxyphenoxy)piperidin-1 -yl)-/V-ethylpyrimidine-5-carboxamide

(R)-2-(3-(2-ethoxy p hen oxy ) pi perid in-1 -yl)-N-ethylpyrimidine-5-carboxamide was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic add and ethylamine using Amidation Method 1 (HATU). ¹H NMR (300 MHz, DMSO-de) δ

8.72(s, 2H), 8.29 (appt, 1 H). 7.08 (d, 1H), 6.91 (m, 3H), 4.31 (m, 1H), 4.21 (appd, 1 H).

3,85 (m, 5H), 3.25 (m, 2H), 2.08 (m, 1H), 1.83 (m, 2H), 1.57 (m, 1H), 1.23 (t, 3H), 1.12 (t,3H). MS (ES+) 371.1 (M+H).

Example 5. (1R,2S)-2-(6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)-5fluoronicotinamido)cyclopentane-1-carboxylic acid

(1 R,2S)-2-(6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)-5fluoronicotinamido)cyclopentane-1-carboxyiic acid was prepared from (R)-6-(3-(2ethoxyphenoxy)piperldin-1-yl)-5-fluoronicotinic acid and methyl (1R,2S)-2aminocyclopentane-1-carboxylate using Amidation Method 2 (EDCI) and Ester Hydrolysis Method 1 (LIOH). ¹H NMR (400 MHz, DMSO-de) δ 11.3 (s, 1 H). 8.35 (s,

1 H), 7.59 (dd, 1 H), 7.03 (d, 1 H), 6.91 (m, 3H), 4.38 (m, 1 H), 4.05 (dd, 1 H), 3.93 (m,

3H), 3.69 (m, 1H), 3.50 (m, 2H), 2.33 (m, 1 H), 1.98 (m, 4H), 1.79 (m, 1H), 1.60 (m, 3H), 1.45 (m, 2H), 1.25 (t,3H). MS (ES+) 472.0 (M+H).

Example 6. (1 R,2S)-2-(2-((R)-3-(2-ethoxyphenoxy)piperidin-1 -yl)pyrimidine-5carboxamido)cyclopentane-1-carboxyiic acid

(1R,2S)-2-(2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5carboxamldo)cyclopentane-1-carboxyiic acid was prepared from (R)-2-(3-(2ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid and methyl (1R,2S)-2aminocyclopentane-1-carboxylate using Amidation Method 1 (HATU) and Ester

Hydrolysis Method 1 (LIOH). ¹H NMR (400 MHz, DMSO-de) δ 11.9 (s, 1 H), 8.68 (s,

2H), 8.08 (d, 1H), 7.02 (d, 1H), 6.89 (m, 3H), 4.51 (m, 1H), 4.28 (m, 2H), 3.95 (m, 3H),

3.75 (m, 2H), 2.90 (m, 1 H), 1.89 (m, 8H), 1.51 (m, 2H), 1.23 (t, 3H). MS (ES+) 455.3 (M+H).

Example 7. (R)-3-((6-(3-(2-ethoxyphenoxy)plperidin-1 -yl)nicotinamido)methyl)benzoic acid

(R)-3-((6-(3-(2-ethoxyphenoxy)piperidin-1 -yl)nicotinamido)methyl)benzoic acid was prepared from (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)nicotinic acid and methyl 3(aminomethyl)benzoate using Amidation Method 1 (HATU) and Ester Hydrolysis Method 1 (LIOH). ¹H NMR (500 MHz, CD3OD) δ 8.84 (app t, 1H), 8.58 (d, 1 H), 8.02 (s, 1H), 7.92 (dd, 2H), 7.58 (d, 1H), 7.44 (t, 1H), 7.01 (d, 1H), 6.92 (m, 2H), 6.87 (m, 1H), 6.73 (d, 1H). 4.60 (m, 2H), 4.37 (m, 1 H). 4.05 (dd, 1 H). 3.93 (m, 2H), 3.72 (m, 3H), 2.07 (m, 1H), 1.95 (m, 2H), 1.59 (m, 1H), 1.28 (t, 3H). MS (ES+) 476.3 (M+H).

Example 8. (R)-4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5fluoronicotinamido)methyl)picolinic add

(R)-4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinamido)methyl)picolinic acid was prepared from (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinicacid and methyl 4-(aminomethyl)picolinate using Amidation Method 2 (EDCI) and Ester Hydrolysis Method 1 (LIOH). ’H NMR (500 MHz, CDCh) δ 8.57 (d, 1 H), 8.42 (s, 1H), 8.16 (s, 1H), 7.67 (dd, 1H), 7.57 (d, 1H), 7.03 (dd, 1H), 6.95 (m, 1H), 6.88 (m, 2H), 6.78 (brs, 1H), 4.74 (d, 2H), 4.34 (m, 1H), 4.29 (m, 1H), 4.03 (m, 2H), 3.93 (m, 1H), 3.49 (m, 1H), 3.43 (m, 1H), 2.17 (m, 1H), 2.01 (m, 1H), 1.89 (m, 1H), 1.64 (m, 1H), 1.40 (t, 3H). MS (ES+) 495.2 (M+H).

Example 9. (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5carboxamido)methyl)-4-methylbenzoic acid

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4methylbenzoîc acid was prepared from (R)-2-(3-(2-ethoxyphenoxy)pîperidin-1yl)pyrimidine-5-carboxylic acid and methyl 3-(aminomethyl)-4-methylbenzoate hydrochloride using Amidation Method 1 (HATU) and Ester Hydrolysis Method 1 (LIOH). ’H NMR (400 MHz, DMSO-de) δ 8.82 (m, 1H), 8.78 (s, 2H), 7.85 (s, 1H), 7,72 (d, 1 H),7.15 (d, 1 H), 7.05 (d, 1H), 6.90 (m, 3H), 4.43 (d, 2H), 4.30 (m, 1H), 4.22 (d, 1H),

3.90 (m, 4H), 3.72 (m, 1H), 2.32 (s, 3H), 2.05 (m, 1H), 1.83 (m, 2H), 1.52 (m, 1H), 1.21 (t,3H). MS (ES+) 491.2 (M+H).

Example 10. (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1 -yl)pyrimidine-5carboxamido)methyl)-4-fluorobenzoic acid

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4fluorobenzoic acid was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1yl)pyrimidine-5-carboxylic acid and methyl 3-(aminomethyl)-4-fluorobenzoate hydrochloride using Amidation Method 1 (HATU) and Ester Hydrolysis Method 1 (LIOH). ’H NMR (300 MHz, DMSO-de) δ 8.92 (m, 1H), 8.78 (s, 2H), 7.91 (d, 1H), 7.85 (m, 1H), 7.19 (dd, 1H), 7.05 (d, 1H), 6.90 (m, 3H), 4.51 (d, 2H), 4.32 (m, 1H), 4.20 (d, 1H), 3.90 (m, 5H), 2.05 (m, 1H), 1.83 (m, 2H), 1.52 (m, 1H), 1.21 (t, 3H). MS (ES+) 495.0 (M+H).

Example 11. (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5carboxa mido) methyl)-4-methoxybenzoic acid

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4methoxybenzoic acid was prepared from (R)-2-(3-(2-ethoxyphenoxy)plperidin-1yl)pyrimidine-5-carboxylic acid and methyl 3-(aminomethyl)-4-methoxybenzoate hydrochloride using Amidation Method 1 (HATU) and Ester Hydrolysis Method 1 (LIOH). ’H NMR (300 MHz, DMSO-de) δ 12.6 (s, 1 H), 8.78 (app s, 3H), 7.89 (dd, 1H), 7.76 (m, 1 H), 7.10 (d, 1H), 7.05 (d, 1H), 6.89 (m, 3H). 4.45 (d, 2H), 4.38 (m, 1H), 4.18 (d, 1 H), 3.91 (m, 8H), 2.05 (m, 1H), 1.88 (m, 2H), 1.52 (m, 1H), 1.21 (t, 3H). MS (ES+)

507.1 (M+H).

Example 12. (R)-5-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5carboxa mido) methyl)-6-methyln icotinic acid

(R)-5-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamldo)methyl)-6methylnIcotinic add was prepared from (R)-2-(3-(2-ethoxyphenoxy)plperidin-1yl)pyrimidine-5-carboxylic add and ethyl 5-(aminomethyl)-6-methylnicotinate using Amidation Method 2 (EDCI) and Ester Hydrolysis Method 1 (LIOH). ’H NMR (400 MHz, DMSO-de) δ 9.17 (m, 1H), 8.95 (s, 1H), 8.80 (s, 2H), 8.45 (m, 1H), 7.03 (d, 1H),

6.90 (m, 3H), 4.58 (d, 2H), 4.35 (m, 1H), 4.12 (m, 1 H), 3.90 (m, 5H), 2.79 (s, 3H), 2.03 (m, 1H), 1.87 (m, 2H), 1.52 (m, 1H), 1.21 (t, 3H). MS (ES+) 492.2 (M+H).

Φ Example 13. (R)-4-((2-(3-(2-ethoxyphenoxy)plperidin-1-yl)pyrimidine-5carboxamido)methyl)-3-methy!benzoic acid

(R)-4-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-35 methyibenzoic add was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1yl)pyrimidine-5-carboxylic acid and methyl 4-(aminomethyl)-3-methylbenzoate using

Amidation Method 2 (EDCI) and Ester Hydrolysis Method 1 (LIOH). ¹H NMR (400

MHz, DMSO-de) δ 12.8 (s, 1H), 8.81 (m, 1 H), 8.78 (s, 2H), 7.75 (m, 2H), 7.31 (d, 1H), 7.05 (d, 1H), 6.91 (m, 3H), 4.48 (d, 2H), 4.33 (m, 1H), 4.18 (app dd, 1H), 3.90 (m, 4H),

3.80 (m, 1 H), 2.36 (s, 3H), 2.05 (m, 1 H), 1.85 (m, 2H), 1.52 (m, 1 H), 1.21 (t, 3H). MS (ES+) 491 (M+H).

Example 14. (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-y!)pyrimidine-5carboxamido)methyl)-2-methoxybenzoic add

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methy!)-2methoxybenzoic add was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1yl)pyrimidine-5-carboxylic add and ethyl 3-(aminomethy!)-2-methoxybenzoate hydrochloride using Amidation Method 1 (HATU) and Ester Hydrolysis Method 1 (LIOH). ¹H NMR (300 MHz, DMSO-de) δ 12.6 (s, 1H), 8.78 (s, 3H), 7.88 (d, 1 H), 7.78 (s,

1H), 7.10 (d, 1H), 7.05 (d, 1H), 6.90 (m, 3H), 4.45 (d, 2H), 4.36 (m, 1H), 4.18 (d, 1H),

3.90 (m, 8H), 2.05 (m, 1H), 1.87 (m, 2H), 1.52 (m, 1H), 1.21 (t, 3H). MS (ES+) 507.0 (M+H).

φ Example 15.2-(4-((2-((R)-3-(2-ethoxyphenoxy)pîpericlin-1-yl)pyrimicline-5carboxamido)methyl)phenyl)propanoic acid

2-(4-((2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5- carboxamido)methyl)phenyl)propanoic acid was prepared from (/7)-2-(3-(2ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid and ethyl 2-(3(aminomethyl)phenyl)propanoate hydrochloride using Amidation Method 2 (EDCI) and Ester Hydrolysis Method 1 (LIOH). 2-(4-((2-((R)-3-(2-Ethoxyphenoxy)piperidtn-1yl)pyrimidine-5-carboxamido)methyl)phenyl)propanoic acid was isolated by chiral SFC purification: Chiralcel-OJ-H, 5μ, 1.0x25cm, MeOH/CO2 (20/80), T = 35 ’C; rétention time, Example 15 diasteromer 7.056 min, other diastereomer 7.773 min. ¹H NMR (500 MHz, DMSO-de) δ 12.25 (br s. 1H), 8.84 (app t, 1H), 8.76 (s, 2H), 7.25 (m, 4H), 7.04 (m, 1H), 6.90 (m, 3H), 4.43 (d, 2H), 4.31 (m, 1 H), 4.19 (dd, 1H), 3.91 (m, 4H), 3.78 (m, 1H), 3.65 (q, 1H), 2.02 (m, 1H), 1.84 (m, 2H), 1.52 (m, 1H), 1.35 (d, 3H), 1.22 (t, 3H). MS (ES+) 505.2 (M+H).

Example 16. (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5carboxamido)methyl)-5-methylbenzoicacid

Step 1. Methyl (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-520 carboxamido)methyl)-5-methylbenzoate

Methyl (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)5-methylbenzoate was prepared from (R)-2-(3-(2-ethoxyphenoxy)plperidin-1yl)pyrimidine-5-carboxylic acid and methyl 3-(aminomethyl)-5-methylbenzoate hydrochloride using Amidation Method 2 (EDCI).

φ Step 2. (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1 -yl)pyrimidine-5-carboxamido)methyl)5-methylbenzoic acid

Aqueous 1N sodium hydroxide solution (1.2 mL, 1.2 mmol) was added to a solution of methyl (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)5 5-methylbenzoate (123 mg, 0.24 mmol) in THF (5 mL). The reaction mixture was heated to 60 ’C for 48 hours, and then the volatiles were evaporated under reduced pressure. The remaining aqueous phase was washed with diethyl ether (10 mL). The aqueous phase was then adjusted to pH 3 with aqueous 1N HCi (1 mL), and then was extracted with EtOAc (2 times with 10 mL). The combined organic phases were îo washed with brine (2 times with 10 mL), dried over MgSO4, filtered, and concentrated to provide (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yi)pyrimidine-5-carboxamldo)methyl)-

5-methylbenzoic acid (84.4 mg, 60%). ’H NMR (500 MHz, CDCh) δ 8.77 (br s, 2H), 7.84 (s, 1 H), 7.81 (s, 1H), 7.41 (s, 1H), 7.00 (d, 1H), 6.95 (m, 1H), 6.87 (m, 2H), 6.48 (br s, 1 H), 4.65 (d, 2H), 4.42 (m, 1 H), 4.27 (m, 1 H), 4.13 (m, 1H), 4.00 (m, 2H), 3.85 (m,

1H), 3.71 (m, 1H), 2.40 (s, 3H), 2.11 (m, 1 H). 1.97 (m, 2H), 1.60 (m, 1H), 1.38 (t, 3H).

MS (ES+) 491.1 (M+H).

Example 17. (R)-2-(3-(4-cyano-2-ethoxyphenoxy)piperidin-1-yl)-N-ethylpyrimidine-5carboxamide

N

Step 1. 2-Chioro-N-ethylpyrimidine-5-carboxamide

A solution of ethylamine (4.26 g, 0.0946 moi) and triethylamine (28.7 g, 0.284 mol) in dichloromethane (75 mL), pre-cooled to -15 to -10 ’C, was added dropwise to a solution of 2-chloropyrimidine-5-carbonyl chloride (16.64 g, 0.0946 mmol) in dry dichloromethane (250 mL) at -15 ’C, then the reaction mixture was stirred at -15 ’C for 25 1 hour. The reaction was quenched by the addition of a solution of concentrated hydrochloric acid (32.3 mL) in water (300 mL). The resulting mixture was stirred at room température for 1 hour. The layers were separated, and the aqueous phase was further extracted with dichloromethane (3 x200 mL). The combined organic extracts

P were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via column chromatography to provide 2-chloro-W-ethylpyrimidine-5-carboxamide (12.75 g,

%).

Step 2. (S)-/V-ethyl-2-(3-hydroxypiperidin-1 -yl)pyrimidine-5-carboxamide

Triethylamine (1.5 mL, 11 mmol) and 2-chloro-W-ethylpyrimidine-5-carboxamide (830 mg, 4.47 mmol) were added sequentially to a solution of (S)-piperidin-3-ol hydrochloride (677 mg, 4.92 mmol) in acetonitrile (25 mL) at 20-25 ’C. The reaction mixture was heated to 80 ’C for 16 hours. The mixture was then cooled to 20-25 ’C and was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (25 mL) and washed with saturated NH<CI (10 mL) and brine (10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to provide (S)-N-ethyl-2-(3hydroxypiperidÎn-1-yl)pyrimidine-5-carboxamide (827 mg, 73%).

Step 3. (R)-2-(3-(4-cyano-2-ethoxyphenoxy)piperidin-1 -yl)-N-ethylpyrimidine-5carboxamide

A solution of triphenylphosphine (65 mg, 0.25 mmol) in THF (1 mL) and a solution of bis(2-methoxyethyl) (E)-diazene-1,2-dicarboxylate (56 mg, 0.24 mmol) In THF (1 mL) were added sequentially to a solution of 3-ethoxy-4-hydroxybenzonitrile (26 mg, 0.16 mmol) and (S)-N-ethyl-2-(3-hydroxypiperidin-1-yl)pyrimidine-5-carboxamlde (40 mg,

0.16 mmol) in THF (2 mL) at 20-25 ’C. The reaction mixture was stirred at 20-25 ’C for

16 hours. The mixture was diluted with ether (30 mL), and was washed sequentially with aqueous 1N NaOH solution (1 mL) and brine (1 mL), The organic phase was dried over MgSO4, filtered, and concentrated to provide a crude residue, which was purified via préparative HPLC to afford (R)-2-(3-(4-cyano-2-ethoxyphenoxy)piperidin-1-yl)-Nethylpyrimldine-5-carboxamide. HPLC: Waters XBridge dC18 4.6x50mm, 5pm, 95% water/5% acetonitrile linear to 5% water/95% acetonitrile over 4.0 min, 0.03% NH«OH modifier, 2 mL/min; rétention time 2.60 min. MS (ES+) 396.1 (M+H).

Examples 18. The Examples in the following table were prepared and analyzed by the methods described below.

A solution of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-y!)pyrimidine-5-carboxy!ic acid in DMF (0.3M, 0.50 mL, 0.15 mmol), triethylamine (0.062 mL, 0.45 mmol) and a solution of HATU in DMF (0.3M, 0.50 mL, 0.15 mmol) were added sequentially to a vial containing the appropriate amino-methyl ester starting material (0.15 mmol). The vial was shaken and heated at 60 ’C for 16 hours. The solvent was then evaporated under reduced pressure. To the resulting residue were added methanol (1.0 mL) and aqueous 4.5M sodium hydroxide solution (0.20 mL, 0.90 mmol). The vial was shaken and heated at 50 ’C for 16 hours. Aqueous 1M hydrochloric acid solution was added to adjust the pH of the solution to approximately 7-8. The solvent was evaporated under reduced pressure. DMSO was added to the resulting residue and the solids were removed by filtration. The filtrate was purified by préparative HPLC to afford the specified products.

Analytical method: Xbridge C18, 2.1x50mm, 5pm, 50 ’C, Mobile Phase A 0.0375% TFA in water, Mobile Phase B 0.01875% TFA in acetonitrile, Gradient: 0.00 min 10% B, 0.50 min 10% B, 4.00 min 100% B, 0.8 mL/min, API-ES+

Example	Compound Name	-NR³R⁴	MS (ES+) (M+H)	Rétention Time (min)
18.1	(R)-4-{(2-(3-(2ethoxyphenoxy)piperidin-1 yl)pyrimidine-5carboxamido)methyl)benzoic acid	x o i	477	2.951

18.2	(R)-2-(3-((2-(3-(2ethoxyphenoxy)piperidin-1 yl)pyrimîdine-5carboxamido)methyl)phenyl)acetic acid	'Y'Q Ύ” O	491	2.974
18.3	(R)-2-(2-((2-(3-(2ethoxyphenoxy)piperidin-1yl)pyrimidlne-5ca rboxam ido)methyl)phenyl)acetic acid	^z'œ ct'oh	491	3.041

Examples 19. The Examples in the following table were prepared and analyzed by the methods described below.

Amidation Procedure: HATU Method

A solution of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid in DMF (0.2M, 0.50 mL, 0.10 mmol), triethylamine (0.060 mL, 0.40 mmol) and a solution of HATU in DMF (0.2M, 0.50 mL, 0.10 mmol) were added sequentially to a vial containing the appropriate amine (0.10 mmol). The vial was shaken and heated at 50 °C for 16 10 hours. The solvent was then evaporated under reduced pressure, and the resulting residue was purified by préparative HPLC to afford the specified product.

φ Amidation Procedure: DMC Method

A solution of (R)-2-(3-(2-ethoxyphenoxy)piperidÎn-1-yl)pyrimidine-5-carboxylic acid ln

DMF (0.2M, 0.50 mL, 0.10 mmol), triethylamine (0.060 mL, 0.40 mmol) and a solution of

2-chloro-1,3-dimethylimldazolinlum chloride (DMC) in dichloromethane (0.3M, 0.50 mL,

0.15 mmol) were added sequentially to a vial containing the appropriate amine starting material (0.10 mmol). The vial was shaken and heated at 30 ’C for 16 hours. The solvent was then evaporated under reduced pressure, and the resulting residue was purified by préparative HPLC to afford the specified product

Analytical methods:

Method A: Xbridge C1B, 2.1x50mm, 5pm, 50 ’C, Mobile Phase A 0.0375% TFA in water, Mobile Phase B 0.01875% TFA ln acetonitrile, Gradient: 0.00 min 1% B, 0.60 min 5% B, 4.00 min 100% B, 0.8 mLVmin, API-ES+.

Method B: Xbridge C18, 2.1 x50mm, 5pm, 50 ’C, Mobile Phase A 0.0375% TFA in water, Mobile Phase B 0.01875% TFA In acetonitrile, Gradient: 0.00 min 10% B, 0.50 min 10% B, 4.00 min 100% B, 0.8 mL/mln, API-ES+.

Example	Compound Name	-NR³R⁴	Amidation Procedure	MS (ES+) (M+H)	Rétention Time (min) and Analytical Method
19.1	(R)-(2-(3-(2ethoxyphenoxy)piperidin1-yl)Pyrimldin-5yl)(morpholino)methanone	^Z'“Q	HATU	413	3.112 (Method A)
19.2	(R)-2-(3-(2ethoxyphenoxy)piperidin1-yl)-N-((3hydroxyisoxazol-5yl)methyl)pyrimldine-5carboxamlde	vq OH	HATU	440	2.998 (Method A)

19.3	(R)-2-(3-(2ethoxyphenoxy)piperidin1-yl)-/V-(isoxazo!-3ylmethyl)pyrimidine-5carboxamide	Vo»	HATU	424	3.136 (Method A)
19.4	(R)-N-(cyclopropylmethyl)2-(3-(2ethoxyphenoxy)piperidin1-yl)pyrimldine-5carboxamide		HATU	397	3.147 (Method B)
19.5	(R)-N-(2-amino-2imînoethyl)-2-(3-(2ethoxyphenoxy)piperidin1-y!)pyrimidine-5carboxamide	^H NH	HATU	399	2.656 (Method A)
19.6	(R)-(2-(3-(2ethoxyphenoxy)piperidin1-yl)pyrimidin-5-yl)(1methyl-4,6dihydropyrrolo[3,4c]pyrazol-5(1 H)yljmethanone	X-N-'K \^N	HATU	449	3.094 (Method A)
19.7	(R)-N-benzy!-2-(3-(2ethoxyphenoxyjpiperidin1-yl)pyrimidine-5carboxamide		HATU	433	3.32 (Method B)
19.8	(R)-2-(3-(2ethoxyphenoxyjpiperidin1-yl)-N-(2(methylsulfonyl)ethyl)pyrim Îdine-5-carboxamide		HATU	449	2.961 (Method A)

19.9	(R)-(2-(3-(2ethoxyphenoxy)piperidin1 -y l)py rim idi n-5-y l)(3methoxyazetidin-1yl)methanone	X I	HATU	413	3.163 (Method A)
19.10	(R)-N-(2-(1 H-1,2,4-triazol1-yljethy 1)-2-(3-(2ethoxyphenoxy)piperidin1-yl)pyrimidine-5carboxamlde		HATU	438	2.847 (Method A)
19.11	(R)-azetidin-1-yl(2-(3-(2ethoxyphenoxy)piperidin1-yl)pyrimrdîn-5yljmethanone	^Λνο	HATU	383	3.158 (Method A)
19.12	(R)-(2-(3-(2ethoxyphenoxy)piperidin1-yl)pyrimldin-5yl)(isolndolin-2yljmethanone		HATU	445	3.435 (Method B)
19.13	2-((R)-3-(2ethoxyphenoxy)piperidin1 -yl)-W-«R)-5oxopyrrolidin-3yl)pyrimidine-5carboxamide	j-N H	HATU	426	2.818 (Method A)
19.14	((1R,4R)-2-oxa-5azabicyclo[2.2.1]heptan-5yl)(2-((R)-3-(2ethoxyphenoxyjpiperidin1-yl)pyrimldin-5yljmethanone	M	HATU	425	3.043 (Method A)

19.15	(R)-2-(3-(2ethoxyphenoxy)piperidin1-yl)-N-(oxazol-4ylmethyl)pyrimidine-5carboxamide	0	HATU	424	3.03 (Method A)
19.16	2-((R)-3-(2ethoxyphenoxyjpiperidin1-yl)-N-((S)-5oxopyrrolidin-3yl)pyrimidine-5carboxamide	,-NH /γίΛΟ	HATU	426	2.817 (Method A)
19.17	(R)-N-(4-amino-2-methyl4-oxobutan-2-yl)-2-(3-(2ethoxyphenoxy)piperidin1-yl)pyrimidine-5carboxamide		HATU	442	2.997 (Method A)
19.18	(^)-2-(3-(2ethoxyphenoxy)piperidin1-yl)-N-(pyrazin-2ylmethyl)pyrimidine-5carboxamide		HATU	435	2.979 (Method A)
19.19	(R)-2-(3-(2ethoxyphenoxy)piperidin1-yl)-N-(îsoxazol-3yl)pyrimidine-5carboxamide	N-O.	DMC	410	3.303 (Method A)
19.20	(R)-2-(3-(2ethoxyphenoxy)piperidin1-yl)-N-(pyrimldin-5yl)pyrimidine-5carboxamide		DMC	421	3.088 (Method A)

19.21	(R)-2-(3-(2ethoxyphenoxy)piperidin1 -y I )-/7-( 1 -hyd roxy-2methylpropan-2yl)pyrimldine-5carboxamlde	A_nX^OH H	HATU	415	3.11 (Method A)
19.22	(R)-N-cyciobutyl-2-(3-(2ethoxyphenoxy)piperidin1-yl)pyrimldine-5carboxamlde		HATU	397	3,174 (Method B)

Examples 20. The Examples ln the following table were prepared and analyzed by the methods described below.

A solution of HBTU in DMF (0.5M, 0.125 mmol), N.N-diisopropylethylamine (0.375 mmol), and the appropriate amine starting material (0.125 mmol) were added sequentially to a vial contaîning a solution of (R)-2-(3-(2-ethoxypyrldin-3-yloxy)piperidin

1-yl)pyrimidine-5-carboxylic acid (0.125 mmol) in DMF (0.5 mL), and the resulting reaction mixture was shaken for 16 hours at room température. The solvent was evaporated under reduced pressure and the resulting residue was partîtioned between ethyl acetate (1 mL) and water (1 mL). The organic layer was concentrated under reduced pressure and the resulting residue was purified by préparative HPLC to afford the title compound.

Φ Analytical method: Acquity UPLC BEH C18, 2.1x50mm, 1.7pm, 50 °C, Mobile Phase A mM NhkOAc ln 95% water and 5% acetonitrile, Mobile Phase B 10 mM NHhOAc In

5% water and 95% acetonitrile, Gradient 0.00 min 100%A, 1.20 min 100% B, 1.47 min

100% B, 1.0 mL/min, API-ES+.

Example	Compound Name	-NR³R⁴	MS (ES+) (M+H)	Rétention Time (min)
20.1	(R)-/V-(3-amino-3oxopropyl)-2-(3-(2ethoxyphenoxyjpiperidin -1 -yl)pyrimidine-5carboxamide	0	414.2	0.771
20.2	(R)-W-(3-(2H-tetrazol-5yl)propyl)-2-(3-(2ethoxyphenoxy)piperidin -1-yl)pyrimidine-5carboxamide	N-n	453.2	0.679
20.3	(R)-2-(3-(2ethoxyphenoxyjpiperidin -1-yl)-N,Ndimethylpyrimidine-5carboxamide	Fn' I	371.2	0.923
20.4	(R)-2-(3-(2ethoxyphenoxy)piperidîn -1 -yl)-A/-(3(methylamino)-3oxopropyl)pyrimidine-5carboxamide	0 H H	428.2	0.795
20.5	(R)-2-(3-(2ethoxyphenoxyjpîperidin -1 -yl)-N-((5-oxo-2,5dihydro-1 H-1,2,4-triazol-	An^W⁰H HN-NH	440.2	0.749

	3-yl)methyl)pyrimidine-5carboxamide
20.6	(R)-2-(3-(2· ethoxyphenoxy)piperidin -1-yl)-W-(2(methylamino)-2oxoethyl)pyrimidîne-5carboxamide	Aq’L	414.2	0.792
20.7	(R)-(3,3-difluoroazetidÎn1-yl){2-(3-{2ethoxyphenoxy)piperidin -1-yl)pyrimidin-5yljmethanone	F	419.1	1.013
20.6	(R)-2-(3-(2ethoxyphenoxyjpiperidin -1 -y I )-/V-(2-(5-hyd roxy1H-pyrazol-4yl)ethyl)pyrimidine-5carboxamide	^η°Ύ-νη A	453.2	0.779
20.9	(R)-(2-(3-(2ethoxyphenoxyjpiperidin -1-yl)pyrimidin-5yl)(pyrrolidin-1yl)methanone		397.2	0.976
20.10	(S)-1-(2-((R)-3-(2ethoxyphenoxy)piperidin -1-yl)pyrimidine-5carbonyl)azetidine-2carboxamide	O Z	426.2	0.608

20.11

(R)-(2-(3-(2ethoxyphenoxy)piperidin -1-yl)pyrimidin-5yl)(piperidin-1yljmethanone

^λό

411.2

1.067

Examples 21. The Examples in the following table were prepared and analyzed by the methods described below.

A solution of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxyiic acid in DMF (0.2M, 0.10 mmol), a solution of HATU in DMF (0.2M, 0.15 mmol), and triethylamine (0.30 mmol) were added sequentially to a vial containing a solution of the appropriate amine (0.10 mmol), and the resulting reaction mixture was shaken for 16 10 hours at room température. The solvent was evaporated under reduced pressure and the resulting residue was partitioned between dichloromethane and water. The organic layer was concentrated under reduced pressure and the resulting residue was purified by préparative HPLC to afford the title compound.

Analytical method: Acquity UPLC BEH C18, 2.1x50mm, 1.7pm, 50 ’C, Mobile Phase A 15 10 mM NHxOAc in 95% water and 5% acetonitrile, Mobile Phase B 10 mM NHxOAc in

5% water and 95% acetonitrile, Gradient: 0.00 min 100%A, 1.20 min 100% B, 1.47 min 100% B, 1.0 mL/min, API-ES+.

Example	Compound Name	-NR³R⁴	MS (ES+) (M+H)	Rétention Time (min)
21.1	N-((S)-2,3-dihydro-1Hinden-1-yl)-2-((R)-3-(2ethoxyphenoxy)plperidin -1-yl)pyrimidine-5carboxamide		459.3	1.111
21.2	(R)-(2-(3-(2ethoxyphenoxy)piperidin -1-yl)pyrimldin-5-yl)(3phenoxyazetidin-1yl)methanone	%.₀X)	475.3	1.112

PHARMACOLOGICAL DATA

The following protocols may of course be varied by those skiiled in the art

Génération of Human DGAT2 (hDGAT2) Construct

A construct for hDGAT2 was generated with an N-terminal FLAG tag (an octapeptide with the amino acid sequence of AspTyrLysAspAspAspAspLys). For the FLAG -tagged hDGAT2 construct, the cDNA for hDGAT2 was custom-synthesized at Genscript and cloned into the pFastBacl vector (lnvitrogen) by using BamHI/Xhol restriction enzymes 10 to generate an N-terminally FLAG-tagged pFastBacl-FLAG-hDGAT2 construct (amino acids 1-388). The construct was confirmed by sequencing in both directions.

DGAT2 Expression and Préparation of the DGAT2 Membrane Fraction

Recombinant baculovirus for the FLAG-tagged hDGAT2 was generated in SF9 insect cells using Bac-to-Bac baculovirus expression system (lnvitrogen) according to the 15 manufacturées protocol. For the expression of hDGAT2, SF9 cells (20 L) grown in

Sf900ll media were infected with hDGAT2 baculovirus at a multiplicity of infection of 1 In a Wave Bioreactor System 20/50P wave bag (GE Healthcare). After 40 hours of Infection, the cells were then harvested by centrifugation at 5,000 x g. The cell pellets φ were washed by resuspending in phosphate buffered saline (PBS) and collected by centrifugation at 5,000 x g. The cell paste was flash frozen In liquid N2 and stored at -80 °C until needed. Ail operations below were at 4 °C unless otherwise noted. The cells were resuspended in lysis buffer (50 mM Tris-HCI, pH 8.0, 250 mM sucrose) including 1 mM ethylenediaminetetraacetic acid (EDTA) and the complété protease Inhibitor cocktail (Roche Diagnostics) at a ratio of 3 ml buffer per 1 g cell paste. The cells were lysed by dounce homogenizer. The cell débris was removed by centrifugation at 1,000 x g for 20 min, and the supematant was centrifuged at 100,000 x g for 1 hour. The resulting pellet was rinsed three times by filling ultracentrifuge tubes to the top with Ice cold PBS before decanting. The washed pellet was resuspended with gentle stim'ng for 1 hour in lysis buffer containing 8 mM 3-[(3-cholamidopropyl)dimethylammonio]-1propanesulfonate (CHAPS) at a ratio of 1 mL buffer per 1 g of original cell paste and centrifuged again at 100,000 x g for 1 hour. The resulting supematant was aliquotted, flash frozen In liquid N2, and stored at -80 °C until use.

In Vitro DGAT2 Assav and Détermination of IC50 Values for DGAT2 Inhibitors

For détermination of IC50 values, the réactions were carried out in 384-well white Polyplates (Perkin Eimer) In a total volume of 20 pL. To 1 pL of compounds dissolved In 100% DMSO and spotted at the bottom of each well, 5 pL of 0.04% bovine sérum albumin (BSA) (fatty acid free, Sigma Aldrich) was added and the mixture was

Incubated at room température for 20 minutes. To this mixture, 10 pL of hDGAT2 membrane fraction (0.01 mg/mL) diluted in 100 mM Hepes-NaOH, pH 7.4,20 mM MgCh containing 200 nM methyl arachldonyl fluorophosphonate (Cayman Chemical; dried from ethyl acetate stock solution under argon gas and dissolved In DMSO as 5 mM stock) was added. After this mixture was preincubated at room température for 2 hours, DGAT2 reactions were initiated by the addition of 4 pL of substrates containing 30 pM [1-¹⁴C]decanoyl-CoA (custom-synthesized by Perkin Eimer, 50 mCI/mmol) and 125 pM 1,2-didecanoyl-sn-glycerol (Avanti Polar Lipids) dissolved in 12.5% acetone. The reaction mixtures were incubated at room température for 40 min and the reactions were stopped by addition of 5 pL of 1% H3PO4. After the addition of 45 pL MicroScint-E (Perkin-Elmer), plates were sealed with Top Seal-A covers (Perkin-Elmer) and phase partitioning of substrates and products was achieved using a HT-91100 microplate orbital shaker (Big Bear Automation, Santa Clara, CA). Plates were centrifuged at 2,000 x g for 1 min In an Allegra 6R Centrifuge (Beckman Coulter) and then were sealed again with fresh covers before reading in a 1450 Microbeta Wallac Trilux

P Scintillation Counter (Perkin Elmer). DGAT2 activity was measured by quantifying the generated product [¹⁴C]tridecanoylglycerol in the upper organic phase.

Background activity obtained using 50 μΜ of (1F?, 2R)-2-({3’-Fluoro-4'-[(6-fluoro-1, 3benzothiazol-2-yl)amino]-1,1^,-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid (US

20040224997, Example 26) or (R)-1-(2-((S)-1-(4-Chloro-1 H-pyrazol-1 -yl)ethyl)-3Hlmidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (WO 2013150416, Example 196-A) for complété inhibition of DGAT2 was subtracted from ail reactions. Inhibitors were tested at eleven different concentrations to generate ICso values for each compound. The eleven inhibitor concentrations employed typically included 50,15.8, 5,

1.58, 0.50, 0.16, 0.05, 0.016, 0.005, 0.0016, and 0.0005 μΜ. The data were plotted as percentage of inhibition versus inhibitor concentration and fit to the équation, y = 100/(1 + (x/lCso)¹], where ICso is the inhibitor concentration at 50% inhibition and z is the Hill slope (the slope of the curve at its inflection point).

Table 3 below provides the ICso values of the Examples for Inhibition of DGAT2 in accordance with the above-described assay. Results are reported as géométrie meanICso values.

Table 3. ICso values of Examples for Inhibition of DGAT2

Example number	ICso (nM)
1	91.6
2	123
3	88.4
4	35
5	66.6
6	222
7	149
8	9.7
9	38.1
10	87.3
11	122
12	62.3
13	45.2
14	76.6
15	2.4
16	47.7
17	182
18.1	165
18.2	156
18.3	182
19.1	22.6

19.2	262
19.3	10.8
19.4	18.6
19.5	124
19.6	34.9
19.7	4.3
19.8	102
19.9	14.3
19.10	32.4
19.11	26.7
19.12	1.4
19.13	46.7
19.14	21.5
19.15	11.2
19.16	122
19.17	12.2
19.18	22.5
19.19	11.1
19.20	33.3
19.21	7.9
19.22	10.7
20.1	149
20.2	431
20.3	104
20.4	53.3
20.5	68
20.6	144
20.7	7.9
20.8	29.3
20.9	24.5
20.10	170
20.11	15.7
21.1	1.5
21.2	0.6

Détermination of ICso values for DGAT2 inhibitors ln human hépatocytes

For évaluation of the effects of DGAT2 inhibitors ln a cell-based setting, cryopreserved human hépatocytes (Lot QOC and NON, Ceisis, Chicago, IL) were thawed and plated 5 onto type I collagen-coated plates according to the manufacturées instructions, After 24 hours ovemight recovery period, the cells were overlayed with media containing 250 pg/ml Matrigel (BD Biosciences, San José, CA). The following day, media was aspirated and replaced with serum-free Williams Media E (Life Technologies, Grand Island, NY)

P containing 400 μΜ sodium dodecanoate (Slgma-Aldrich, St. Louis, MO). Forty minutes later, DGAT2 inhibitors (prepared as 100X stocks in 25% DMSO, 75% Williams’ Media

E) were added to the desired final concentration. Ail wells contained a sélective DGAT1 inhibitor (Example 3, W02009016462) at a concentration (3 μΜ) that completely suppressed endogenous DGAT1 activity. After a 20 minute preincubation, 0.2 μΟΙ [1,3’⁴C]-glycerol (American Radio Chemicals, St. Louis, MO) was added to each well and mixed by gentle pipetting prior to a 3 hour incubation. At this point, media was aspirated and the cells were lysed in isopropyl alcohol: tetrahydrofuran (9:1) prior to centrifugation at 3000 rpm for 5 minutes. Radiolabeled iîpids were resolved using a 2-solvent system îo by thin layer chromatography using standard technique (solvent 1 contained ethyl acetate: isopropyl alcohol: chloroform: methanol: 0.25% potassium chloride in water (100:100:100:40.2:36.1, v/v/v/v) and solvent 2 contained hexane: diethyl ether acetic acid (70:27:3, v/v/v)). After séparation, radiolabeled lipids were visualized using a Molecular Dynamlcs* Phosphorimager system. The half maximai Inhibitory concentrations (ICso values) were determined using GraphPad Prism (GraphPad Software, Inc., La Jolla, CA).

Table 4 below provides ICso values for the Examples in accordance with the abovedescribed assay. Results were reported as average ICso values, low and high ICso range (95% confidence intervai).

Table 4. ICso values of selected DGAT2 Inhibitors in primary human hépatocytes.

Example number	ICso (nM)
1	11.2
2	11.5
3	29.2
4	6.6
5	8.4
6	57.8
7	19.2
8	51.7
9	57
10	10.4
11	6.8
12	67.5
13	20.7
15	78.8

16	45
17	19.8
18.1	116
18.2	45.7
18.3	499
19.2	341
20.5	81.6
20.8	37.8
20.10	59.8

Acute effects of DGAT2 inhibitors on plasma TAG leveis.

Blockade of hepatic DGAT2 activity has been shown to inhibit the sécrétion of VLDL TAG. To evaluate the acute effects of DGAT2 inhibitors on hepatic TAG production, male Sprague Dawley rats (-200 g, Harian Laboratories Inc.) were fed a low fat, hlgh-sucrose diet (TD03045, Harian Laboratories Inc.) for 2 days prior to dosing with DGAT2 inhibitors. At this time, animais were fasted for 4 hours and compounds administered as a solution In 1% HPMC/40mM Tris/1% HPMCAS. Two hours after treatment with DGAT2 inhibitors, blood was drawn from the latéral tail vein and plasma

TAG leveis determined using a Roche Hitachi Chemistry analyzer according to the manufacturées instructions. Data were analyzed using GraphPad Prism (GraphPad Software, Inc., La Jolla, CA) and are shown as percent change from Vehicle-treated animais. Statistical analysis was performed using one-way ANOVA followed by Dunnett’s multiple comparison test. * p<0.05, **p<0.001, ***p<0.0001.

is Figure 3 provides acute effects of DGAT2 inhibitors on plasma TAG leveis in Sprague Dawley rats for the Examples 1, 3 and 15 in accordance with the above-described method.

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application for ail purposes.

It will be apparent to those skilled ln the art that various modifications and variations can be made in the présent invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from considération of the spécification and practice of the Invention disclosed herein. It is intended that the spécification and examples be considered as

exemplary only, with a true scope and spirit of the Invention being indicated by the following claims.

Claims

What is claimed ts:

1. A compound of Formula (!)

R⁵ wherein

Dis N, CH, or CF;

R¹ is (Ci-C4)alkyl optionally substituted with one, two or three substituents each independently selected from fluoro and (Ca-Cejcyctoalkyl;

R² is fluoro or (Ci-C^Jaîkyl;

R³ is H, (Ci-C4)alkyl, or (Ca-Cejcycloalkyl;

R⁴ is H, -(Ci-C4)alkyl, -((Ci-C4)alkyl)_P-(C3-Ce)cycîoalkyl, -((Ci-C4)alkyl)p-(C3Ce)heterocyclyl, -((Ci-C4)alkyl)p-aryl, or -((Ci-C4)alkyl)_P-heteroaryl wherein R⁴ is optionally substituted with one, two, three, or four substituents selected from halo, cyano, oxo, aminyl, iminyl, -OH, -(Ci-C4)alkyl, -(Ci-C4)fluoroalkyl, -(Ci-COalkoxy, -(CaCe)cycloalkoxy, -(Ci-C4)fluoroalkoxy, -((Ci-C4)alkyl)q-COOH, -((Ci-C4)alkyl)q-(C3Ce)cycloalkyl-COOH, -((Ci-C4)alkyl)q-(C3-Ce)heterocyclyl-COOH,-((Ci-C4)atkyl)q-arylCOOH, -((Ci-C4)alkyl)q-heteroaryl-COOH, -O-((Ci-C4)alkyl)q-COOH, -O-((Ci-C4)alkyl)qaryl-COOH, -0-((Ci-C4)alkyl)q-heteroaryl-COOH, -((Ci-C4)alkyl)q-(C3-Ce)cycloalkyl, ((Ci-C4)alkyl)q-(C3-Ce)heterocyclyl, -((Ci-C4)alkyl)q-aryl, -((Ci-C4)alkyl)q-heteroaryl, C(O)-(Ci-C4)alkyl, -C(O)-(Ci-C4)alkoxy, -C(0)-(C3-Ce)cycloalkyl, -C(O)-(CsCejheterocyclyl, -C(O)-NR^eR⁷, -C(O)-((Ci-C4)alkyl)q-aryI, -C(O)-((Ci-C4)alkyl)qheteroaryl, -NR⁶R⁷, -NR^e-C(O)-R⁷,-((Ci-C4)alkyl)q-O-aryl, -((Ci-C4)alkyl)q-O-heteroaryl, S(O)2-R⁷, and -S(O)2-NR⁶R⁷;

or R³ and R⁴ may be loined together to form a 4- to 10- member fully saturated, or partially saturated ring system optionally substituted with one, two, three, or four substituents selected from halo, cyano, -OH, -<Ci-C4)alkyl, -(Ci-C4)fluoroalkyl, -(CiC^alkoxy, -(C3-Ce)cycloalkoxy, -(Ci-C4)fluoroalkoxy, -((Ci-C4)alkyl)_q -COOH, -((CiC4)alkyl)_r(C3-Ce)cycloalkyl-COOH, -((Ci-C4)alkyl)_q-(C3-Ce)heterocyclyl-COOH, -((CiC4)alkyl)<raryl-COOH, -((Ci-C^alkylJq-heteroaryl-COOH, -O-((Ci-C4)alkyl)q-COOH, -O((Ci-C^alkylJq-aryl-COOH, -O-((Ci-C4)alkyl)_q-heteroaryl-COOH, -((Ci-C4)aikyl)<r(C3Cejcycloalkyl, -((Ci-C«)alkyl)_q-(C3-Ce)heterocyclyl, -«Ci-C^JalkylJcraryl, -((Ci-C4)alkyl)_qheteroaryl, -C(O)-(Ci-C4)alkyl, -C(O)-(C3-Ce)cycloalkyl, -C(O)-(C3-Ce)heterocyclyl, C(O)-aryl, -C(O)- heteroaryl, -C(O)-NR⁸R⁷, -C(O)-(Ci-C4)alkyl-aryl, -C(O)-(Ci-C4)alkylheteroaryl, -NR^eR⁷, -NR⁰-C(O)-R⁷,-O-aryl, -0-heteroaryl,-(Ci-C4)alkyl-0-aryl, -(CiC4)alkyl-O-heteroaryl, -O-(Ci-G«)alkyl-aryl, and -O-(Ci-C4)alkyl-heteroaryl;

R⁵ is H, F, or cyano;

R^e is H, (Ci-C4)alkyl, or-S(O)2-R⁷;

R⁷ Is H, (Ci-C4)alkyl, -(C3-Ce)cycloalkyl, -(C3-Ce)heterocyclyl, aryl, or heteroaryl;

n is 0,1,2 or 3;

p Is 0 or 1; and q IsOorl;

or a pharmaceutically acceptable sait thereof.
2. The compound of claim 1 having the Formula (la) \R²)n (la) or a pharmaceutically acceptable sait thereof.
3. The compound of claim 2 or a pharmaceutically acceptable sait thereof, wherein D Is N orC-F; and n is 0.
4. The compound of claim 2 or a pharmaceutically acceptable sait thereof, wherein R¹ is ethyl and R² Is fluoro.
5. The compound of claim 3 or a pharmaceutically acceptable sait thereof, wherein R^s Is H; R³ Is H; and R⁴ is (Ci-C2)alkyl-aryl, (Ci-C2)alkyi-heteroaryl, or (Cs-Ce)cycloalkyl, wherein R⁴ Is optionally substituted with one, two, three, or four substituents selected from fluoro, chloro, cyano, -((Ci-C2)alkyl)_q-COOH, -(Ci-Csjalkyl, -(C3-Ce)cycloalkyl, trifluoromethyl, difluoromethyl, -(Ci-C3)alkoxy, trifluoromethoxy, and difluoromethoxy.
6. The compound

2-(6-(3-(2-ethoxyphenoxy)plperidin-1-yl)-5-fluoronicotinamido)cyclopentane-1carboxylic add;

(1R,2S)-2-(6-((R)-3-(2-ethoxyphenoxy)pÎperidin-1-yl)-5fluoronlcotinamldo)cyclopentane-1 -carboxylic acid;

4-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamldo)methyl)-3methylbenzolc add;

(R)-4-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-3methylbenzoic acid;

2- (2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)cyclopentane-1carboxylic acid;

(1R,2S)-2-(2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5carboxamido)cyclopentane-1-carboxylic acid;

3- ((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4methylbenzoic acid;

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4methylbenzoic acid;

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyi)-5methylbenzoic acid;

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5methylbenzolc acid;

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-2methoxybenzoic acid;

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-2methoxybenzoic acid;

100

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimldine-5-carboxamido)methyl)-4- methoxybenzoïc acid;

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4methoxybenzoic acid;

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4fluorobenzoic add;

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4fluorobenzoic acid;

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5methoxybenzoic acid; or (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5methoxybenzoic acid;

or a pharmaceutically acceptable sait thereof.
7. The compound of claim 2 or a pharmaceutically acceptable sait thereof, wherein Dis N or CH andR⁴is wherein R⁴ is optionally substituted with one, two, or three substituents selected from fluoro, chloro, methyl, cyano, cyclopropyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, and difluoromethoxy.
8. The compound:

3-(1-(2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidîne-5-carboxamido)ethyl)benzoic add;

3-((R>1 -(2-((R)-3-(2-ethoxyphenoxy)piperidin-1 -y l)py ri m idî ne-5carboxamido)ethyl)benzoic add;

3-((6-(3-(2-ethoxyphenoxy)piperidin-1-y!)nicotinamldo)methyl)benzoicacid;

(R)-3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)nicotinamido)methy!)benzoic acid;

3-((2-(3-(2-ethoxyphenoxy)plperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid; or (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5carboxamido)methyl)benzoic add;

101 or a pharmaceutically acceptable sait thereof.
9. The compound:

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoicacid; or (R)-3-((2-(3-(2-ethoxyphenoxy)plperidÎn-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid;

or a pharmaceutically acceptable sait thereof.
10. The compound having the structure:

or a pharmaceutically acceptable sait thereof.
11. A pharmaceutical composition comprising a compound according to claims 9 or 10 or a pharmaceutically acceptable sait of said compound, présent ln a therapeutically effective amount, In admixture with at least one pharmaceutically acceptable excipient
12. The composition of Claim 11 further comprising at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent, an anti-diabetic agent, and a cholesterol/îipid modulating agent
13. The composition of Claim 12 wherein said anti-obesity agent Is selected from the group consisting of gut-selective MTP inhibitors (e.g., diriotapide, mitratapide and implitapide, R56918, CCKa agonists, 5HT2c agonists, MCR4 agonist, lipase inhibitor, PYY3-38, oploid antagonists, the combination of naltrexone with buproprion, oleoylestrone, obinepitide, pramlintide, tesofensine, leptln, liraglutide, bromocriptine, oriistat, exenatide, AOD-9604 phentermlne and toplramate, and sibutramine.
14. The composition of Claim 12 wherein said anti-diabetic agent is selected from the group consisting of an acetyl-CoA carboxylase- (ACC) Inhibitor, a diacylglycérol Oacyltransferase 1 (DGAT-1) inhibitor, AZD7687, LCQ908, monoacylglycerol Oacyltransferase inhibitors, a phosphodiesterase (PDEJ-10 Inhibitor, an AMPK activator, a sulfonylurea, a meglitinide, an α-amylase inhibitor, an α-glucoslde hydrolase Inhibitor,

102

Φ an α-glucosldase inhibitor, a PPARy agonlst, a PPAR α/γ agonlst (, a biguanide, a glucagon-iike peptide 1 (GLP-1) modulator such as an agonist, liraglutide, aibiglutide, exenatide, aibiglutide, lixisenatide, dulaglutide, semaglutide, NN-9924, TTP-054, a protein tyrosine phosphatase-1B (PTP-1B) inhibitor, SIRT-1 activator, a dipeptidyl

5 peptldease IV (DPP-IV) inhibitor, an insulin secreatagogue, a fatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal kinase (JNK) inhibitor, glucokinase activât ors (GKa), Insulin, an insulin mimetic, a glycogen phosphorylase inhibitor, a VPAC2 receptor agonist, SGLT2 inhibitors, a glucagon receptor modulator, GPR119 modulators, FGF21 dérivatives or analogs, TGR5 (also termed GPBAR1 ) receptor

10 modulators, GPR40 agonists, GPR120 modulators, high affinity nicotinic acid receptor (HM74A) activa tors, SGLT1 inhibitors, inhibitors or modulators of camitine palmitoyl transferase enzymes, inhibitors of fructose 1,6-diphosphatase, inhibitors of aldose reductase, mineralocorticoid receptor Inhibitors, Inhibitors ofTORC2, inhibitors of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g. PKCa, PKCp, PKCy), Inhibitors of fatty
15 acid synthetase, inhibitors of serine palmitoyl transferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostain receptors (e.g. SSTR1, SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 family including ILIbeta, and modulators of RXRalpha.

15. The composition of Claim 12 wherein said cholesterol/lipid modulating agent is selected from the group consisting of HMG-CoA reductase inhibitors; squalene synthetase inhibitors; fibrates; bile acid séquestrants; ACAT inhibitors; MTP inhibitors; lipooxygenase inhibitors; choesterol absorption inhibitors; PCSK9 modulators and

25 cholesteryl ester transfer protein inhibitors.
16. Use of a compound according to claims 9 or 10 or a pharmaceutically acceptable sait of said compound in the manufacture of a médicament for the treatment of diabètes.
17. Use of a compound of any one of claims 9 or 10 or a pharmaceutically acceptable sait of said compound in the manufacture of a médicament for treating a metabolic or metabolic-related disease, condition or disorder.

103
18. Use of a compound according to claims 9 or 10 or a pharmaceutically acceptable sait of said compound in the manufacture of a médicament for treating a condition selected from the group consisting of hyperlipidemia, Type I diabètes, Type II diabètes mellitus, idiopathic Type I diabètes (Type lb), latent autoimmune diabètes in adults (LADA), eariy-onset Type 2 diabètes (EOD), youth-onset atypical diabètes (YOAD), maturity onset diabètes of the young (MODY), mainutrition-related diabètes, gestational diabètes, coronary heart disease, ischémie stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g. necrosis and apoptosis), dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolérance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, ieft ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic rénal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischémie attacks, stroke, vascular restenosis, hypergiycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin résistance, impaired glucose metabolism, conditions of impaired glucose tolérance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcérations and ulcerative colitis, endothélial dysfunction and impaired vascular compliance, hyper apo B lipoproteinemia, Alzheimeris, schizophrenia, impaired cognition, inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, non-alcoholic steatohepatitis (NASH), and non-alcoholic fatty liver disease (NAFLD).
19. A compound according to claims 9 or 10 or a pharmaceutically acceptable sait of said compound for use in a method for the treatment of diabètes.
20. A compound of any one of claims 9 or 10 or a pharmaceutically acceptable sait of said compound for use in a method for treating a metaboiic or metabolic-related disease, condition or disorder.
21. A compound according to claims 9 or 10 or a pharmaceutically acceptable sait of said compound for use in a method of treating a condition selected from the

104

Φ group consisting of hyperlipidemia, Type I diabètes, Type II diabètes mellltus, idiopathlc

Type I diabètes (Type lb), latent autoimmune diabètes in adults (LADA), early-onset

Type 2 diabètes (EOD), youth-onset atyplcal diabètes (YOAD), maturity onset diabètes ofthe young (MODY), malnutrition-related diabètes, gestational diabètes, coronary

5 heart disease, ischémie stroke, restenosis after angloplasty, peripheral vascular disease, Intermittent claudication, myocardial Infarction (e.g. necrosis and apoptosis), dyslipldemla, post-prandial lipemla, conditions of impalred glucose tolérance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosls, ketosls, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular

10 hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, ca tara et, diabetic nephropathy, glomerulosclerosis, chronic rénal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial Infarction, transient ischémie attacks, stroke, vascular restenosis, hyperglycemia, hyperinsullnemla,

15 hyperlipidemia, hypertrygliceridemia, Insulin résistance, Impaired glucose metabolism, conditions of Impaired glucose tolérance, conditions of Impaired fasting plasma glucose, obesity, erectile dysfonction, skin and connective tissue disorders, foot ulcérations and ulcerative colitis, endothélial dysfonction and impaired vascular compliance, hyper apo B lipoproteinemia, Alzheimeris, schizophrénie, Impaired cognition, Inflammatory bowel

20 disease, ulcerative colitis, Crohn’s disease, irritable bowel syndrome, non-alcohollc steatohepatitis (NASH), and non-alcoholic fatty liver disease (NAFLD).
22. A composition according to ciaim 12 for use in a method for treating a metabolic or metaboiic-related disease, condition or disorder, which method comprises the step 25 of administering to a patient in need of such treatment two separate pharmaceutical compositions comprising (i) a first composition according to ciaim 12; and (ii) a second composition comprising at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent and an

30 anti-diabetic agent, and at least one pharmaceutically acceptable excipient.
23. The composition for use of claim 22 wherein said first composition and said second composition are for administration simultaneously.