WO2014052619A1

WO2014052619A1 - Piperidine derivatives and compositions as modulators of gpr119 activity

Info

Publication number: WO2014052619A1
Application number: PCT/US2013/061959
Authority: WO
Inventors: Christopher Noel COW; Robert Epple; Victor Nikulin; Prasuna PARASELLI; Wei Pei
Original assignee: Irm Llc; Michellys, Pierre-Yves
Priority date: 2012-09-27
Filing date: 2013-09-26
Publication date: 2014-04-03

Abstract

The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of GPR119. The compounds are of Formula I: wherein the variables are as defined herein.

Description

PIPERIDINE DERIVATIVES AND COMPOSITIONS AS

MODULATORS OF GPR119 ACTIVITY

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Patent Application Number 61/706,637 filed 27 September 2012. The full disclosure of the application is incorporated herein by reference in its entirety and for all purposes.

BACKGROUND OF THE INVENTION Field of the Invention

The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of GPR1 19.

Background

GPR1 19 is a G-protein coupled receptor (GPCR) that is mainly expressed in the pancreas, small intestine, colon and adipose tissue. The expression profile of the human GPR1 19 receptor indicates its potential utility as a target for the treatment of obesity and diabetes. The novel compounds of this invention modulate the activity of GPR1 19 and are, therefore, expected to be useful in the treatment of GPR1 19-associated diseases or disorders such as, but not limited to, diabetes, obesity and associated metabolic disorders.

SUMMARY OF THE INVENTION

In one aspect, th pound of Formula I:

or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

Q is selected from phenyl and C₅.₆heteroaryl, each of which is substituted with at least two substituents independently selected from halo, d-₆alkyl, halo-substituted-d- ₆alkyl, d-ealkoxy, and halo-substituted-d-ealkoxy; R¹ is d-ealkyl substituted with 1 to 3 substituents independently selected from halo, hydroxy, amino, d-₆alkoxy, and halo-substituted-d.₆alkoxy; provided when R¹ is substituted with only one substituent, the substituent is not substituted at the terminal end of the d.₆alkyl of R¹ ; and

R⁴ is selected from R⁸ and -C(0)OR⁸, wherein R⁸ is selected from d-₆alkyl, phenyl, C₅.₆heteroaryl, C₃.₆cycloalkyl and C₃.₆heterocycloalkyl, each of which is independently optionally substituted with one to three substituents independently selected from halo, C_1-4alkyl, C₃.₆cycloalkyl, C₃.₆heterocycloalkyl, halo-substituted-d. ₄alkyl, hydroxy-substituted-d-₄alkyl, d-₆alkoxy and halo-substituted-d-₆alkoxy.

Unless specified otherwise, the term "compounds of the present invention" refers to compounds of Formula I and Formula la, n-oxides derivative, salts of the compounds, hydrates or solvates of the compounds, as well as all stereoisomers (including diastereo isomers and enantiomers), tautomers and isotopically labeled compounds (including deuterium substitutions). Compounds of the present invention further comprise polymorphs of compounds of Formula I, Formula la or salts or stereoisomers, thereof.

In a second aspect, the present invention relates to a pharmaceutical composition which contains a compound selected from Formula I, la, or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.

In a third aspect, the present invention relates to a method of treating a disease in an animal in which modulation of GPR1 19 activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or Formula 1 a, an N-oxide derivative, stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In fourth aspect, the present invention relates to a method for treating a disease or condition related to diabetes in an animal, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or Formula 1 a, an N-oxide derivative, stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In a fifth aspect, the present invention relates to the use of a compound of Formula I or la, or a salt or stereoisomer thereof, in the manufacture of a medicament for treating a disease in an animal in which GPR1 19 activity contributes to the pathology and/or symptomology of the disease.

In a sixth aspect, the present invention relates to the use of a compound of Formula I or la, or a salt or stereoisomer thereof, in the manufacture of a medicament for treating a disease or condition related to diabetes in an animal.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. "Alkoxy" as used herein refers the radical -O-alkyl, wherein the alkyl is as defined herein. C_xalkoxy and C_X-_Yalkoxy as used herein describe alkoxy groups where X and Y indicate the number of carbon atoms in the alkyl chain. Representative examples of d- ₁₀alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert- butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and decyloxy. The alkyl portion of the alkoxy may be optionally substituted, and the substituents include those described for the alkyl group below.

"Alkyl" as used herein refers to a fully saturated, branched or unbranched, hydrocarbon chain having up to 10 carbon atoms. C_x alkyl and C_X-_Y alkyl as used herein describe alkyl groups where X and Y indicate the number of carbon atoms in the alkyl chain. For example, C_H0 alkyl refers to an alkyl radical as defined above containing one to ten carbon atoms. C^o alkyl includes, but are not limited to, methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, /so-butyl, fe/t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3- methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. Alkyl represented along with another radical like arylalkyl, heteroarylalkyl, alkoxyalkyi, alkoxyalkyi, alkylamino, where the alkyl portion shall have the same meaning as described for alkyl and is bonded to the other radical. For example,

includes, benzyl, phenylethyl, 1 -phenylethyl, 3-phenylpropyl, 2-thienylmethyl, 2-pyridinylmethyl and the like.

Unless stated otherwise specifically in the specification, an alkyl group may be unsubstituted or substituted by one or more substituents to the extent that such substitution makes sense chemically. Typical substituents include, but are not limited to halo, hydroxyl, alkoxy, cyano, amino, acyl, aryl, arylalkyl, and cycloalkyl, or a

heteroforms of one of these groups, and each of which can be substituted by the substituents that are appropriate for the particular group.

"Alkenyl" as used herein refers to a straight or branched hydrocarbon chain having up to 10 carbon atoms and at least one carbon-carbon double bond. C_xalkenyl and

C_X-_Yalkenyl as used herein describe alkenyl groups where X and Y indicate the number of carbon atoms in the alkenyl chain. Examples of C₂-₇alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1 -propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. The alkenyl may be optionally substituted, and the substituents include those described for the alkyl group descried herein.

"Alkynyl" as used herein refers to a straight or branched, hydrocarbon chain having up to 10 carbon atoms and at least one carbon-carbon triple bond. C_xalkenyl and C_X-_Yalkenyl as used herein describe alkynyl groups, where X and Y indicate the number of carbon atoms in the alkynyl chain. For example, C₂-₇alkenyl include, but are not limited to, ethynyl, propargyl, 3-methyl-1 -pentynyl, 2-heptynyl and the like. An alkynyl may be optionally substituted, and the substituents include those described for the alkyl group described herein.

"Alkylene" as used herein refers to a divalent alkyl group as defined herein. Examples of d-_!oalkylene includes, but are not limited to, methylene, ethylene, n-propylene, iso- propylene, n-butylene, sec-butylene, /so-butylene, terf-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3- dimethylpentylene, n-heptylene, n-octylene, n-nonylene and n-decylene. An alkylene group may be optionally substituted, and the substituents include those described for the alkyl group described herein. "Alkenylene" as used herein refers to a divalent alkenyl group defined herein. Examples of C^alkenylene include, but are not limited to, ethene-1 ,2-diyl, propene-1 ,3-diyl, and methylene-1 ,1 -diyl. An alkenylene may be optionally substituted, and the substituents include those described for the alkyl group described herein.

"Alkynylene" as used herein refers to a divalent alkynyl group defined herein. Examples of alkynylene include ethyne-1 ,2-diylene, propyne-1 ,3-diylene, and the like. An alkynylene may be optionally substituted, and the substituents include those described for the alkyl group described herein.

"Amino" as used herein refers to the radical -NH₂. When an amino is described as "substituted" or "optionally substituted", the term includes NR'R" wherein each R' and R" is independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, aryl, cycloalkyl, arylalkyl cycloalkylalkyl group or a heteroform of one of these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl groups or heteroforms of one of these groups, is optionally substituted with the substituents described herein as suitable for the corresponding group.

Unless indicated otherwise, the compounds of the invention containing amino moieties may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, fe/t-butoxycarbonyl, benzyloxycarbonyl, and the like.

"Alkylamino" as used herein refers to the radical -NR_aR_b, where at least one of, or both, R_a and R_b are an alkyl group as described herein. A d^alkylamino group includes - NHC^alkyl and -N(C₁-₄alkyl)₂; e.g., -NHCH₃, -N(CH₃)₂, -NH(CH₂CH₃), -N(CH₂CH₃)₂, and the like.

"Aryl" as used herein refers to a 6-14 membered monocyclic or polycyclic aromatic ring assembly where all the ring atoms are carbon atoms. Typically, the aryl is a 6 membered monocyclic, a 10-12 membered bicyclic or a 14-membered fused tricyclic aromatic ring system. C_xaryl and C_X-_Yaryl as used herein describe an aryl group where X and Y indicate the number of carbon atoms in the ring system. C₆.₁₄aryls include, but are not limited to, phenyl, biphenyl, naphthyl, azulenyl, and anthracenyl. An aryl may be unsubstituted or substituted by 1 -5 (such as one, or two, or three) substituents each independently selected from the group consisting of hydroxy, thiol, cyano, nitro, d-₄alkyl, d-₄alkenyl, d-₄alkynyl, d-₄alkoxy, thiod-₄alkyl, d-₄alkenyloxy, d-₄alkynyloxy, halogen, d-₄alkylcarbonyl, carboxy, d-₄alkoxycarbonyl, amino, d- ₄alkylamino, di-d-₄alkylamino, d-₄alkylaminocarbonyl, di-d-₄alkylaminocarbonyl, d- ₄alkylcarbonylamino, d^alkylcarbony d^alky amino, sulfonyl, sulfamoyl,

alkylsulfamoyl, d-₄alkylaminosulfonyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein each of the afore-mentioned substitutents may be further substituted by one or more substituents independently selected from halogen, alkyl, hydroxyl or d-₄alkoxy groups.

When an "aryl" is represented along with another radical like "arylalkyl", "aryloxyalkyl", "aryloxycarbonyl", "aryloxy-carbonylalkyl", the aryl portion shall have the same meaning as described in the above-mentioned definition of "aryl".

"Aryloxy" as used herein, refers to the radical -O-aryl, wherein aryl is as defined herein.

"Carbamoyl" as used herein refers to the radical -OC(0)NR_aR_b where R_a and R_b are each independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyl group or a heteroform of one of these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl or heteroforms of one of these groups is optionally substituted with the substituents described herein as suitable for the corresponding group.

"Cycloalkyl", as used herein, means a radical comprising a non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic, tricyclic, fused, bridged or spiro polycyclic hydrocarbon ring system of 3-20 carbon atoms. C_xcycloalkyl and Cx-vcycloalkyl are typically used where X and Y indicate the number of carbon atoms in the ring assembly. For example, C₃-₆cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like. Exemplary bicyclic cycloalkyls include bornyl, norbornanyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1 .1 ]hexyl, bicyclo[2.2.1 ]heptyl, bicyclo[2.2.1 ]heptenyl, 6,6-dimethylbicyclo[3.1 .1 ]heptyl, 2,6,6- trimethylbicyclo[3.1 .1 ]heptyl, bicyclo[2.2.2]octyl. Exemplary tricyclic cycloalkyl groups include, for example, adamantyl. A cycloalkyl may be unsubstituted or substituted by one, or two, or three, or more substituents independently selected from the group consisting of hydroxyl, thiol, cyano, nitro, oxo, alkylimino, C -₄alkyl, d-₄alkenyl, C^alkynyl, C^alkoxy, C^thioalkyl, C ₄alkenyloxy, d^alkynyloxy, halogen, d^alkylcarbonyl, carboxy, d^alkoxycarbonyl, amino, C^alkylamino, di-d-₄alkylamino, d-₄alkylaminocarbonyl, di-d- ₄alkylaminocarbonyl, d^alkylcarbonylamino, d-₄alkylcarbonyl(d-₄alkyl)amino, sulfonyl, sulfamoyl, alkylsulfamoyl, d-₄alkylaminosulfonyl where each of the afore-mentioned hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl, alkoxy residues) may be further substituted by one or more residues independently selected at each occurrence from halogen, hydroxyl or d-₄alkoxy groups.

"Cycloalkylene", as used herein, refers to a divalent radical comprising a cycloalkyl ring assembly as defined herein.

"Cycloalkoxy", as used herein, refers to -O-cycloalkyl, wherein the cycloalkyl is defined herein. Representative examples of C₃-i₂cycloalklyoxy include, but are not limited to, monocyclic groups such as cyclopropoxy, cyclobutoxy, cyclopentyloxy,

cyclopentenyloxy, cyclohexyloxy and cyclohexenyloxy and the like. Exemplary bicyclic hydrocarbon groups include bornyloxy, indyloxy, hexahydroindyloxy,

tetrahydronaphthyloxy, decahydronaphthyloxy, bicyclo[2.1 .1 ]hexyloxy,

bicyclo[2.2.1 ]heptyloxy, bicyclo[2.2.1 ]heptenyloxy, 6,6-dimethylbicyclo[3.1 .1 ]heptyloxy, 2,6,6-trimethylbicyclo[3.1 .1 ]heptyloxy, bicyclo[2.2.2]octyloxy and the like. Exemplary tricyclic hydrocarbon groups include, for example, adamantyloxy.

"Cyano", as used herein, refers to the radical -CN.

"EC₅₀", refers to the molar concentration of an inhibitor that produces 50% efficacy. "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo.

"Haloalkyi", or halo-substituted-alkyl" as used herein, refers to an alkyl as defined herein, which is substituted by one or more halo atoms defined herein. The haloalkyi can be mono-haloalkyl, dihaloalkyi or polyhaloalkyi including perhaloalkyl. A monohaloalkyi can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihaloalky and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. C_xhaloalkyl and C_x._Yhaloalkyl are typically used where X and Y indicate the number of carbon atoms in the alkyl chain. Non-limiting examples of Cxhaloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A d^perhaloalkyl group refers to a d^alkyl group having all hydrogen atoms replaced with halo atoms. "Haloalkoxy" or "halo-substituted-alkoxy" as used herein refers to the radical - O-haloalkyl, where the haloalkyl is as defined herein.

"Heteroalkyl", as used herein, refers to an alkyl, as defined herein, where one or more of the carbon atoms within the alkyl chain are replaced by heteroatoms (typically N, O and S). Cx-yhetereoalkyl as used herein described heteroalkyl groups where X and Y represent the sum of the number of carbon atoms and heteroatoms in the group. A heteroalkyl may be optionally substituted with the substituents described herein as suitable for alkyl. "Heteroaryl", as used herein, refers to a 5-14 membered ring assembly (e.g., a 5-7 membered monocycle, an 8-10 membered bicycle, or a 13-14 membered tricyclic ring system) having 1 to 8 heteroatoms selected from N, O and S as ring atoms and the remaining ring atoms are carbon atoms. The nitrogen atoms of such heteroaryl rings can be optionally quaternerized and the sulfur atoms of such heteroaryl rings can be optionally oxidized. C_xheteroaryl and C_X-_Yheteroaryl as used herein describe heteroaryls where X and Y indicate the number of ring atoms in the heteroaryl ring. Typical C₅. yheteroaryl groups include thienyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, pyrrolinyl, thiazolyl, 1 ,3,4-thiadiazolyl, isothiazolyl, oxazolyl, oxadiazole isoxazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrazinyl, pyrimidinyl, and the like. Bicyclic or tricyclic C₈-i ₄heteroaryls include, but are not limited to, those derived from benzo[b]furan, benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline, thieno[2,3- c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine, quinazolinyle, pteridinyl, indolizine, imidazo[1 ,2a]pyridine, quinoline, quinolinyl, isoquinoline, phthalazine, quinoxaline, naphthyridine, naphthyridinyl, quinolizine, indolyl, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, imidazo[1 ,5-a]pyridine, pyrazolo[1 ,5-a]pyridine, imidazo[1 ,2-a]pyrimidine, imidazo[1 ,2-c]pyrimidine, imidazo[1 ,5- a]pyrimidine, imidazo[1 ,5-c]pyrimidine, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2- d]pyrimidine, pyrrolo[2,3-b]pyrazine, pyrazolo[1 ,5-a]pyridine, pyrrolo[1 ,2-b]pyridazine, pyrrolo[1 ,2-c]pyrimidine, pyrrolo[1 ,2-a]pyrimidine, pyrrolo[1 ,2-a]pyrazine, triazo[1 ,5- a]pyridine, pteridine, purine, purinyl, carbazole, acridine, phenazine, phenothiazene, phenoxazine, 1 ,2-dihydropyrrolo[3,2,1 - ?/]indole, indolizine, pyrido[1 ,2-a]indole and 2(1 H)-pyridinone. A heteroaryl may be unsubstituted or substituted with one or more substituents independently selected from hydroxyl, thiol, cyano, nitro, d-₄alkyl, d^alkenyl, d- ₄alkynyl, C^alkoxy, thioC^alkyl, C^alkenyloxy, C^alkynyloxy, halogen, d- ₄alkylcarbonyl, carboxy, d-₄alkoxycarbonyl, amino, d-₄alkylamino, di-d-₄alkylamino, d-₄alkylaminocarbonyl, di-d-₄alkylaminocarbonyl, d-₄alkylcarbonylamino, d- ₄alkylcarbonyl(d-₄alkyl)amino, sulfonyl, sulfamoyl, alkylsulfamoyl, d-₄alkylaminosulfonyl where each of the afore-mentioned hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl, alkoxy residues) may be further substituted by one or more residues independently selected at each occurrence from halogen, hydroxyl or d-₄alkoxy groups. When a heteroaryl is represented along with another radical like "heteroaryloxy",

"heteroaryloxyalkyl", "heteroaryloxycarbonyl", the heteroaryl portion shall have the same meaning as described in the above-mentioned definition of "heteroaryl".

"Heteroaryloxy", as used herein, refers to an -O-heteroaryl group, wherein the heteroaryl is as defined in this Application.

"Heteroatom", as used herein, refers to an atom that is not a carbon atom. Particular examples of heteroatoms include, but are not limited to nitrogen, oxygen, and sulfur. "Heterocycloalkyi", as used herein, refers to a 4-20 membered, non-aromatic, saturated or partially unsaturated, monocyclic or polycyclic ring system, comprising 1 -8

heteroatoms as ring atoms and that the remaining ring atoms are carbon atoms. The heteroatoms are selected from N, O, and S, preferably O and N. The nitrogen atoms of the heterocycloalkyi can be optionally quaternerized and the sulfur atoms of the heterocycloalkyi can be optionally oxidized. The heterocycloalkyi can include fused or bridged rings as well as spirocyclic rings. C_xheterocycloalkyl and C_X-_Yheterocycloalkyl are typically used where X and Y indicate the number of ring atoms in the ring. Typically, the .heterocycloalkyl is 4-8-membered monocyclic ring containing 1 to 3 heteroatoms, a 7 to 12-membered bicyclic ring system containing 1 -5 heteroatoms, or a 10-15- membered tricyclic ring system containing 1 to 7 heteroatoms. Examples of C_4-

₆heterocycloalkyl include azetidinyl, tetrahydrofuran (THF), dihydrofuran, 1 , 4-dioxane, morpholine, 1 ,4-dithiane, piperazine, piperidine, 1 ,3-dioxolane, imidazolidine, imidazoline, pyrazolidinyl, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1 ,3-dioxane, 1 ,3-dithiane, oxathiane, thiomorpholine, and the like A heterocycloalkyl may be unsubstituted or substituted with 1 -5 substituents (such as one, or two, or three) each independently selected from hydroxyl, thiol, cyano, nitro, oxo, alkylimino, C -₄alkyl, C₁-₄alkenyl, C₁-₄alkynyl, d-₄alkoxy, d-₄thioalkyl, C₁-₄alkenyloxy, d-₄alkynyloxy, halogen, d-₄alkylcarbonyl, carboxy, d-₄alkoxycarbonyl, amino, d- ₄alkylamino, di- d-₄alkylamino, d-₄alkylaminocarbonyl, di-d-₄alkylaminocarbonyl, d- ₄alkylcarbonylamino, d-₄alkylcarbonyl(d-₄alkyl)amino, sulfonyl, sulfamoyl,

alkylsulfamoyl, d-₄alkylaminosulfonyl where each of the afore-mentioned hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl, alkoxy residues) may be further substituted by one or more residues independently selected at each occurrence from halogen, hydroxyl or d- ₄alkoxy groups.

When a heterocycloalkyl forms part of other groups like "heterocycloalkyl-alkyl",

"heterocycloalkoxy", "heterocycloalkyl-aryl", the heteroaryl portion shall have the same meaning as described in the above-mentioned definition of "heteroaryl" "Heterocycloalkylene", as used herein, refers to a cycloalkylene, as defined in this

Application, provided that one or more of the ring member carbon atom is replaced by a heteroatom.

"Heteroform" as used herein refers to a hydrocarbon radical as defined in this

Application, provided that one or more of the carbon atom is replaced by a heteroatom.

Hydroxy, as used herein, refers to the radical -OH.

"Hydroxyalkyl" or "hydroxyl-substituted alkyl" as used herein, refers to an alkyl as defined herein, having one or more of the available hydrogen of the alkyl replaced by a hydroxyl group. For example, a hydroxyd^alkyl includes, but are not limited to, -CH₂CH₂OH, - CH(OH)CH₂CH₂OH, - CH(OH)CH2CH(OH)CH3 .

"IC₅₀" refers to the molar concentration of an inhibitor that produces 50% inhibition of the target enzyme.

"GPR1 19" means G protein-coupled receptor 1 19 (GenBank^® Accession No. AAP72125) is also referred to in the literature as RUP3 and GPR1 16. The term GPR1 19 as used herein includes the human sequences found in GeneBank accession number AY288416, naturally-occurring allelic variants, mammalian orthologs, and recombinant mutants thereof.

"Nitro", as used herein, refers to the radical -N0₂. "Oxo", as used herein, refers to the divalent radical =0

"Pharmaceutically acceptable", as used herein, means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.

"Unsubstituted or substituted" or "optionally substituted" as used herein indicate the substituent bound on the available valance of a named group or radical. "Unsubstituted" as used herein indicates that the named group or radical has no non-hydrogen substituents. "Substituted" or "optionally substituted" as used herein indicates that at least one hydrogen atom of the unsubstituted group has been (or may be) replaced by a non-hydrogen substituent.

"Sulfamoyl" or "Sulfamyl" as used herein refers to the radical -S(0)₂NR_aR_b where R_a and R_b are independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, aryl, cycloalkyi, arylalkyi cycloalkylalkyl group or a heteroform of one of these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyi groups or heteroforms of one of these groups, is optionally substituted with the substituents described herein as suitable for the corresponding group. "Sulfanyl" as used herein, means the radical -S-.

"Sulfinyl", as used herein, means the radical -S(0)-. It is noted that the term "sulfinyl" when referring to a monovalent substituent can alternatively refer to a substituted sulfinyl group, -S(=0)R, where R is hydrogen or a non-hydrogen substituent on the sulfur atom forming different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, and sulfoxides.

"Sulfonyl", as used herein, means the radical -S(0)₂- It is noted that the term "sulfonyl" when referring to a monovalent substituent can alternatively refer to a substituted sulfonyl group, -S(=0)₂R, where R is hydrogen or a non-hydrogen substituent on the sulfur atom forming different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones. "Therapeutically effective amount", as used herein, means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.

"Thiocarbonyl", as used herein, refers to the radical -C(=S)-. It is noted that the term thiocarbonyl when referring to a monovalent substituent can alternatively refer to a substituted thiocarbonyl group, -C(=S)R, where R is hydrogen or a non-hydrogen substituent on the carbon atom forming different thiocarbonyl groups including thioacids, thioamides, thioesters, and thioketones. Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group. It is noted in regard to all of the definitions provided herein that the definitions should be interpreted as being open ended in the sense that further substituents beyond those specified may be included. Hence, a d alkyl indicates that there is one carbon atom but does not indicate what are the substituents on the carbon atom. Hence, a d alkyl comprises methyl (i.e., -CH₃) as well as -CR_aR_bR_c where R_a, R_b, and R_c may each independently be hydrogen or any other substituent where the atom attached to the carbon is not a hydrogen atom. Hence, -CF₃, -CH₂OH and -CH₂CN, for example, are all dalkyls.

Description of the Preferred Embodiments

The present invention relates to compounds, compositions and methods for the treatment of diseases in which modulation of GPR1 19 activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I. In particular, the compounds can be used to treat diabetes related diseases and conditions.

In one embodiment, the compounds are of Formula I:

Q is selected from phenyl and d-₆heteroaryl, each of which is substituted with at least two substituents independently selected from halo, d-₆alkyl, halo-substituted-d- ₆alkyl, d-ealkoxy, and halo-substituted-d-ealkoxy;

R¹ is d-ealkyl substituted with 1 to 3 substituents independently selected from halo, hydroxy, amino, d-₆alkoxy, and halo-substituted-d-₆alkoxy; provided when R¹ is substituted with only one substituent, the substituent is not substituted at the terminal end of the d-₆alkyl of R¹ ; and

R⁴ is selected from R⁸ and -C(0)OR⁸, wherein R⁸ is selected from C_1-6alkyl, phenyl, d-₆heteroaryl, d-₆cycloalkyl and d-₆heterocycloalkyl, each of which is independently optionally substituted with one to three substituents independently selected from halo, d-₄alkyl, d-₆cycloalkyl, d-₆heterocycloalkyl, halo-substituted-d- ₄alkyl, hydroxy-substituted-d.₄alkyl, d-ealkoxy and halo-substituted-d-ealkoxy.

In one variation of the above embodiment, Q is phenyl or dheteroaryl, each of which is substituted with at least two substituents independently selected from halo, d-ealkyl, halo-substituted-d_₆alkyl, d_₆alkoxy, and halo-substituted-d-ealkoxy. In another variation of the above embodiment, Q is phenyl, pyrazinyl or pyridinyl, each of which is substituted with at least two substituents independently selected from halo, d- ₆alkyl, halo-substituted-d-ealkyl, d-ealkoxy, and halo-substituted-d-ealkoxy. In one variation of the above embodiment and variations, the substituents on Q are halo. In yet another variation, the substituents on Q are two fluoros.

In one variation of the above embodiment, Q is

wherein "^*" indicates the point of attachment of Q to -O- in Formula I.

In one variation of the above embodiment and variations, R¹ is propyl or butyl, each of which is substituted with one to three substituents independently selected from halo, hydroxy, amino, d-ealkoxy, and halo-substituted-d-₄alkoxy; provided when the propyl or butyl is substituted with only one substituent, the substituent is not substituted at the terminal end of the propyl or butyl.

In another variation of the above embodiment and variations, R¹ is propyl or butyl substituted with one to two hydroxyl; provided when the propyl or butyl is substituted with only one hydroxy, the hydroxy is not substituted at the terminal end of the propyl or butyl. In yet another variation, R¹ is -CH₂CH(OH)CH₂OH. In yet another variation, R¹ is -CH₂CH₂CH(OH)CH₃.

In one variation of the above embodiment and variations, R⁴ is R⁸, wherein R⁸ is a C₅. ₆heteroaryl optionally substituted with one to three substituents independently selected from halo, C_1-4alkyl, halo-substituted-d.₄alkyl, hydroxy-substituted-d.₄alkyl, d-ealkoxy and halo-substituted-d-₆alkoxy.

In another variation of the above embodiment and variations R⁴ is R⁸, wherein R⁸ is selected from a group consisting of oxadiazolyl, pyridinyl, pyrimidinyl, and pyridazinyl, each of which is optionally substituted with one to three substituents independently selected from halo, C_1-4alkyl, halo-substituted-d.₄alkyl, hydroxy-substituted-d_₄alkyl, d- ₆alkoxy and halo-substituted-d-₆alkoxy. In still another variation of the above embodiment and variations, R⁴ is -C(0)OR⁸, wherein R⁸ is selected from d-ealkyl, C₃-₆cycloalkyl and C₃-₆heterocycloalkyl, each of which is optionally substituted with one to three substituents independently selected from halo, d-₄alkyl, C₃-₆cycloalkyl, C₃-₆heterocycloalkyl, halo-substituted-d^alkyl, hydroxy- substituted-C_!^alkyl, d-ealkoxy and halo-substituted-d-ealkoxy.

In one variation of ent and variations R⁴ is N CH₃ |_n

another variation, In still another variation, R⁴ is . In still

another variation,

In a second embodiment, the compounds of the invention are of Formula la:

R⁴ is selected from R⁸ and -C(0)OR⁸, wherein R⁸ is selected from d-₆alkyl, phenyl, C₅-₆heteroaryl, C₃.₆cycloalkyl and C₃.₆heterocycloalkyl, each of which is independently optionally substituted with one to three substituents independently selected from halo, d-₄alkyl, C₃.₆cycloalkyl, C₃.₆heterocycloalkyl, halo-substituted-d- ₄alkyl, hydroxy-substituted-d-₄alkyl, d_₆alkoxy and halo-substituted-d-₆alkoxy.

In one variation of the second embodiment, R¹ is -CH₂CH(OH)CH₂OH. In another embodiment, R¹ is or -CH₂CH₂CH(OH)CH₃. In one variation of the second embodiment and variations above, R⁴ is

Particular examples of compounds according to the present invention are listed below.

The same compounds are listed in the Example section with the structure of the compounds. It is understood that when there is a discrepancy between the name and structure of a particular compound, the structure dictates. Compounds of the invention include, but are not limited to:

-methylcyclopropyl 4-(4-(1 -((2,3-dihydroxypropyl)sulfonyl)piperidin-4-yl)-2,6- difluorophenoxy)piperidine-1 -carboxylate;

(S)-1 -methylcyclopropyl 4-(4-(1 -((2,3-dihydroxypropyl)sulfonyl)piperidin-4-yl)-2,6- difluorophenoxy)piperidine-1 -carboxylate;

3-((4-(3,5-difluoro-4-((1 -(5-methylpyrimidin-2-yl)piperidin-4- yl)oxy)phenyl)piperidin-1 -yl)sulfonyl)propane-1 ,2-diol;

3-((4-(3,5-difluoro-4-((1 -(3-isopropyl-1 ,2,4-oxadiazol-5-yl)piperidin-4- yl)oxy)phenyl)piperidin-1 -yl)sulfonyl)propane-1 ,2-diol;

3-((4-(4-((1 -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5-difluorophenyl)piperidin-

1 -yl)sulfonyl)propane-1 ,2-diol;

(H)-3-((4-(4-((1 -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5- difluorophenyl)piperidin-1 -yl)sulfonyl)propane-1 ,2-diol;

(S)-3-((4-(4-((1 -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5- difluorophenyl)piperidin-1 -yl)sulfonyl)propane-1 ,2-diol;

(S)-1 ,1 ,1 -trifluoropropan-2-yl 4-(4-(1 -(((R)-2,3-dihydroxypropyl)sulfonyl)piperidin- 4-yl)-2,6-difluorophenoxy)piperidine-1 -carboxylate;

,1 ,1 -trifluoropropan-2-yl 4-(4-(1 -(((S)-2,3-dihydroxypropyl)sulfonyl)piperidin-

4-yl)-2,6-difluorophenoxy)piperidine-1 -carboxylate;

(S)-1 ,1 ,1 -trifluoropropan-2-yl 4-(4-(1 -(((S)-2,3-dihydroxypropyl)sulfonyl)piperidin-

4-yl)-2,6-difluorophenoxy)piperidine-1 -carboxylate;

,1 ,1 -trifluoropropan-2-yl 4-(4-(1 -(((R)-2,3-dihydroxypropyl)sulfonyl)piperidin-

4-yl)-2,6-difluorophenoxy)piperidine-1 -carboxylate;

(S)-4-(4-(4-((1 -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5- difluorophenyl)piperidin-1 -yl)butan-2-ol; and

( )-4-(4-(4-((1 -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5- difluorophenyl)piperidin-1 -yl)butan-2-ol. It is noted that the compounds of the present invention may be in the form of a pharmaceutically acceptable salt. It is further note that the compounds of the present inventin may be a mixture of stereoisomers, or the compound may comprise a single stereoisomer. In another aspect, the present invention is related to a pharmaceutical composition comprising as an active ingredient a compound according to any one of the above embodiments and variations in combination with a pharmaceutically acceptable excipient. In one embodiment, the composition is a solid formulation adapted for oral

administration. In another embodiment, the composition is a liquid formulation adapted for oral administration. In yet another embodiment, the composition is a tablet. In still another embodiment, the composition is a liquid formulation adapted for parenteral administration.

In another embodiment, the pharmaceutical composition comprises a compound according to any one of the above embodiments and variations, wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermal^, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, and intrathecally.

In another aspect, the invention is related to a kit which comprises a compound of any one of the above embodiments and variations, and optionally a second therapeutic agent. In one particular variation, the kit comprises the compound in a multiple dose form.

In another aspect, the invention is related to a method for treating a disease or condition wherein modulation of GPR1 19 activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the disease or condition, comprising administering to a subject a therapeutically effective amount of the compound of Formula I or la, or pharmaceutically acceptable salts or pharmaceutical compositions thereof. In one embodiment, the disease or condition being treated is selected from obesity, type 1 diabetes, type 2 diabetes mellitus, hyperlipidemia, idiopathic type 1 diabetes, latent autoimmune diabetes in adults, early-onset type 2 diabetes, youth-onset atypical diabetes, maturity onset diabetes of the young, malnutrition-related diabetes and gestational diabetes.

In another embodiment, the disease or condition being treated is selected from coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance.

In another aspect, the invention is related to a therapeutic method comprising administering a compound of the above embodiments and variations to a subject. In one embodiment, the method is for treating a disease or condition which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound of any one of the above described embodiments and variation, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and optionally in combination with a second agent, wherein the disease or condition is selected from diabetes related diseases or conditions, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance. In another embodiment, the method is for treating diabetes related diseases or conditions selected from obesity, type 1 diabetes, type 2 diabetes mellitus,

hyperlipidemia, idiopathic type 1 diabetes, latent autoimmune diabetes in adults, early- onset type 2 diabetes, youth-onset atypical diabetes, maturity onset diabetes of the young, malnutrition-related diabetes and gestational diabetes.

In a further aspect, the invention is related to use of the compound according to the above described embodiments and variations in the manufacture of a medicament for treating a disease or condition. In one embodiment, the disease or condition being treated is selected from diabetes related diseases or conditions, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance.

In another embodiment, the disease or condition being treated is diabetes related disease or condition selected from obesity, type 1 diabetes, type 2 diabetes mellitus, hyperlipidemia, idiopathic type 1 diabetes, latent autoimmune diabetes in adults, early- onset type 2 diabetes, youth-onset atypical diabetes, maturity onset diabetes of the young, malnutrition-related diabetes and gestational diabetes. In still another embodiment, the disease or condition is type 2 diabetes mellitus.

Various enumerated embodiments of the invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention.

In a first embodiment 1 , the invention provides a compound of Formula I, or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, as described in the summary of the invention.

Embodiment 2. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to Embodiment 1 , wherein Q is phenyl or C₆heteroaryl, each of which is substituted with at least two substituents independently selected from halo, d-₆alkyl, halo-substituted-d-ealkyl, d- ₆alkoxy, and halo-substituted-d-ealkoxy.

Embodiment 3. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to Embodiment 1 , wherein Q is phenyl, pyrazinyl or pyridinyl, each of which is substituted with at least two substituents independently selected from halo, d-₆alkyl, halo-substituted-d-₆alkyl, d- ₆alkoxy, and halo-substituted-d-₆alkoxy.

Embodiment 4. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 3, wherein the at least two substituents on Q are halo. Embodiment 5. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 3, wherein the at least two substituents on Q are two fluoros.

Embodiment 6. The compound according to Embodiment 1 , wherein Q is

, wherein "^*" indicates the point of attachment of Q to -O- in Formula I.

Embodiment 7. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of

Embodiments 1 to 6 above, wherein R¹ is propyl or butyl, each of which is substituted with one to three substituents independently selected from halo, hydroxy, amino, d- ₆alkoxy, and halo-substituted-d^alkoxy; provided when the propyl or butyl is substituted with only one substituent, the substituent is not substituted at the terminal end of the propyl or butyl.

Embodiment 8. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of

Embodiments 1 to 6 above, wherein R¹ is propyl or butyl substituted with one to two hydroxyl; provided when the propyl or butyl is substituted with only one hydroxy, the hydroxy is not substituted at the terminal end of the propyl or butyl.

Embodiment 9. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of

Embodiments 1 to 6 above, wherein R¹ is -CH₂CH(OH)CH₂OH.

Embodiment 10. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of

Embodiments 1 to 6 above, wherein R¹ is -CH₂CH₂CH(OH)CH₃.

Embodiment 1 1 . A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of

Embodiments 1 to 10 above, wherein R⁴ is R⁸, wherein R⁸ is a C₅-₆heteroaryl optionally substituted with one to three substituents independently selected from halo, d^alkyl, halo-substituted-C^alkyl, hydroxy-substituted-C^alkyl, d-ealkoxy and halo-substituted- d-ealkoxy. Embodiment 12. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of

Embodiments 1 to 10 above, wherein R⁴ is R⁸, wherein R⁸ is selected from a group consisting of oxadiazolyl, pyridinyl, pyrimidinyl, and pyridazinyl, each of which is optionally substituted with one to three substituents independently selected from halo, C_1-4alkyl, halo-substituted-C^alkyl, hydroxy-substituted-C^alkyl, d-ealkoxy and halo- substituted-d-ealkoxy.

Embodiment 13. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of

Embodiments 1 to 10 above, wherein R⁴ is -C(0)OR⁸, wherein R⁸ is selected from d- ₆alkyl, C₃-₆cycloalkyl and C₃-₆heterocycloalkyl, each of which is optionally substituted with one to three substituents independently selected from halo, d^alkyl, C₃-₆cycloalkyl, C₃- ₆heterocycloalkyl, halo-substituted-d-₄alkyl, hydroxy-substituted-d-₄alkyl, d-ealkoxy and halo-substituted-d-₆alkoxy.

Embodiment 14. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of

Embodiments 1 to 10 above, wherein R⁴ is

Embodiment 15. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of

Embodiments 1 to 10 above, wherein R⁴ is

Embodiment 16. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of

Embodiments 1 to 10 above, wherein R⁴ is

Embodiment 17. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of

Embodiments 1 to 10 above, wherein R⁴ is

Embodiment 18. The invention provides a compound of Formula la:

R¹ is d-ealkyl substituted with 1 to 3 substituents independently selected from halo, hydroxy, amino, d-ealkoxy, and halo-substituted-d-ealkoxy; provided when R¹ is substituted with only one substituent, the substituent is not substituted at the terminal end of the C ealkyl of R¹ ; and

R⁴ is selected from R⁸ and -C(0)OR⁸, wherein R⁸ is selected from C_1-6alkyl, phenyl, C₅-₆heteroaryl, C₃-₆cycloalkyl and C₃-₆heterocycloalkyl, each of which is independently optionally substituted with one to three substituents independently selected from halo, d^alkyl, C₃-₆cycloalkyl, C₃.₆heterocycloalkyl, halo-substituted-d- ₄alkyl, hydroxy-substituted-d.₄alkyl, d-ealkoxy and halo-substituted-d-ealkoxy.

Embodiment 19. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to Embodiment 18, wherein R¹ is -CH₂CH(OH)CH₂OH.

Embodiment 20. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to Embodiment 18, wherein R¹ is -CH₂CH₂CH(OH)CH₃. Embodiment 21 . A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of

Embodiments 18 to 20, wherein FT is

Embodiment 22. A compound of Formula 1 , or a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of

Embodiments 18 to 20, wherein R⁴ is

or

Embodiment 23. A compound of Formula I, or a salt or stereoisomer, enantiomer or tautomer thereof, according to Embodiment 1 , wherein the compound is selected from the group consisting of:

(fl)-1 -methylcyclopropyl 4-(4-(1 -((2,3-dihydroxypropyl)sulfonyl)piperidin-4-yl)-2,6- difluorophenoxy)piperidine-1 -carboxylate;

3-((4-(4-((1 -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5-difluorophenyl)piperidin- 1 -yl)sulfonyl)propane-1 ,2-diol;

( )-3-((4-(4-((1 -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5- difluorophenyl)piperidin-1 -yl)sulfonyl)propane-1 ,2-diol;

(fl)-1 ,1 ,1 -trifluoropropan-2-yl 4-(4-(1 -(((S)-2,3-dihydroxypropyl)sulfonyl)piperidin- 4-yl)-2,6-difluorophenoxy)piperidine-1 -carboxylate;

4-yl)-2,6-difluorophenoxy)piperidine-1 -carboxylate; ,1 ,1 -trifluoropropan-2-yl 4-(4-(1 -(((R)-2,3-dihydroxypropyl)sulfonyl)piperidin- 4-yl)-2,6-difluorophenoxy)piperidine-1 -carboxylate;

( )-4-(4-(4-((1 -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5- difluorophenyl)piperidin-1 -yl)butan-2-ol.

Embodiment 24. The invention provides a pharmaceutical composition comprising a compound of Formula I or Formula la, according to any one of Embodiments 1 to 23 in combination with a pharmaceutically acceptable excipient.

Embodiment 25. The invention provides a method for treating a disease or condition, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula I or Formula la, according to any one of Embodiments 1 to 22 or pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the disease or condition is selected from diabetes related diseases or conditions, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance.

Embodiment 26. The invention provides a method for treating a diabetes related disease or condition, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula I or Formula la, according to any one of Embodiments 1 to 22 or pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the diabetes related disease or condition is selected from obesity, type 1 diabetes, type 2 diabetes mellitus, hyperlipidemia, idiopathic type 1 diabetes, latent autoimmune diabetes in adults, early-onset type 2 diabetes, youth-onset atypical diabetes, maturity onset diabetes of the young, malnutrition-related diabetes and gestational diabetes.

Embodiment 27. The invention provides a use of a compound of Formula I or Formula la, according to any one of claims 1 to 22 in the manufacture of a medicament for treating a disease or condition, wherein the disease or condition is selected from diabetes related diseases or conditions, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance. Embodiment 28. The invention provides a use of a compound of Formula I or Formula la, according to any one of claims 1 to 22, in the manufacture of a medicament for treating a diabetes related disease or condition, wherein the diabetes related disease or condition is selected from obesity, type 1 diabetes, type 2 diabetes mellitus,

As used herein, the term "an optical isomer" or "a stereoisomer" refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. The term "chiral" refers to molecules which have the property of non-superimposability on their mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers" are a pair of stereoisomers that are non- superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to designate a racemic mixture where appropriate.

"Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Depending on the choice of the starting materials and procedures, the compounds can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms. The present invention is meant to include all such possible isomers, including racemic mixtures, diasteriomeric mixtures and optically pure forms. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

As used herein, the terms "salt" or "salts" refers to an acid addition or base addition salt of a compound of the invention. "Salts" include in particular "pharmaceutical acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in "Remington's

Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹ P, ³²P, ³⁵S, ³⁶CI, ¹²⁵l respectively. The invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as ³H and ¹⁴C, or those into which non-radioactive isotopes, such as ²H and ¹³C are present. Such isotopically labelled compounds are useful in metabolic studies (with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detection or imaging techniques, such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ¹⁸F or labeled compound may be particularly desirable for PET or SPECT studies. Isotopically-labeled 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 Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed. Further, substitution with heavier isotopes, particularly deuterium (i.e., ²H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I). The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium , such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D₂0, d₆- acetone, d₆-DMSO.

Compounds of the invention, i.e. compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co- crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co- crystals thereby formed. Suitable co-crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals comprising a compound of formula (I).

As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

The term "a therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1 ) at least partially alleviate, inhibit, prevent and/or ameliorate a condition, or a disorder or a disease (i) mediated by GPR1 19, or (ii) associated with GPR1 19 activity, or (iii) characterized by activity (normal or abnormal) of GPR1 19; or (2) reduce or inhibit the activity of GPR1 19; or (3) reduce or inhibit the expression of GPR1 19. In another non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of GPR1 19, or at least partially reducing or inhibiting the expression of GPR1 19.

As used herein, the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates ( e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human

As used herein, the term "inhibit", "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

As used herein, the term "treat", "treating" or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treat", "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treat", "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treat", "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.

As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.

As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration. In certain embodiments, each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 %

enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (£)- form.

Accordingly, as used herein a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof. Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.

Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term "hydrate" refers to the complex where the solvent molecule is water.

The compounds of the present invention, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.

Processes for Making Compounds of the Invention

The present invention also includes processes for the preparation of compounds of the invention. In the reactions described, it can be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.

Conventional protecting groups can be used in accordance with standard practice, for example, see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991 .

In the following schemes, methods of preparing the compounds of the present invention are illustrative. One of skill in the art will appreciate that these methods are

representative, and in no way inclusive of all methods for preparing the compounds of the present invention. The radicals in the schemes are as described in Formula I.

Alternatively, compounds can be synthesized according to the following synthetic scheme:

The invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure material.

Compounds of the invention and intermediates can also be converted into each other according to methods generally known to those skilled in the art.

Detailed descriptions of the synthesis of compounds of the Invention are given in the Examples, infra.

Pharmaceutical Compositions and Formulations

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers, etc. Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with

a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also

c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired

d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or

e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methods known in the art.

Suitable compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 -75%, or contain about 1 -50%, of the active ingredient.

Suitable compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like. Such topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and

preservatives.

As used herein a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose. Such agents, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.

Pharmacology and Utility

Compounds of the invention modulate the activity of GPR1 19 and, as such, are useful for treating diseases or disorders in which the activity of GPR1 19 contributes to the pathology and/or symptomology of the disease. This invention further provides compounds of this invention for use in the preparation of medicaments for the treatment of diseases or disorders in which GPR1 19 activity contributes to the pathology and/or symptomology of the disease.

The resultant pathologies of Type II diabetes are impaired insulin signaling at its target tissues and failure of the insulin-producing cells of the pancreas to secrete an appropriate degree of insulin in response to a hyperglycemic signal. Current therapies to treat the latter include inhibitors of the β-cell ATP-sensitive potassium channel to trigger the release of endogenous insulin stores, or administration of exogenous insulin. Neither of these achieves accurate normalization of blood glucose levels and both carry the risk of inducing hypoglycemia. For these reasons, there has been intense interest in the development of pharmaceuticals that function in a glucose-dependent action, i.e.

potentiators of glucose signaling. Physiological signaling systems which function in this manner are well-characterized and include the gut peptides GLP-I, GIP and PACAP. These hormones act via their cognate G-protein coupled receptor to stimulate the production of cAMP in pancreatic β-cells. The increased cAMP does not appear to result in stimulation of insulin release during the fasting or pre-prandial state. However, a series of biochemical targets of cAMP signaling, including the ATP-sensitive potassium channel, voltage-sensitive potassium channels and the exocytotic machinery, are modified in such a way that the insulin secretory response to a postprandial glucose stimulus is markedly enhanced. Accordingly, agonists of novel, similarly functioning, β- cell GPCRs, including GPR1 19, would also stimulate the release of endogenous insulin and consequently promote normoglycemia in Type II diabetes. It is also established that increased cAMP, for example as a result of GLP-I stimulation, promotes β-cell proliferation, inhibits β-cell death and thus improves islet mass. This positive effect on β- cell mass is expected to be beneficial in both Type II diabetes, where insufficient insulin is produced, and Type I diabetes, where β-cells are destroyed by an inappropriate autoimmune response. Some β-cell GPCRs, including GPR1 19, are also present in the hypothalamus where they modulate hunger, satiety, decrease food intake, controlling or decreasing weight and energy expenditure. Hence, given their function within the hypothalamic circuitry, agonists or inverse agonists of these receptors mitigate hunger, promote satiety and therefore modulate weight.

It is also well-established that metabolic diseases exert a negative influence on other physiological systems. Thus, there is often the codevelopment of multiple disease states (e.g. type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity or cardiovascular disease in "Syndrome X") or secondary diseases which clearly occur secondary to diabetes (e.g. kidney disease, peripheral neuropathy). Thus, it is expected that effective treatment of the diabetic condition will in turn be of benefit to such interconnected disease states. In an embodiment of the invention is a method for treatment of a metabolic disease and/or a metabolic-related disorder in an individual comprising administering to the individual in need of such treatment a therapeutically effective amount of a compound of the invention or a pharmaceutical composition thereof. The metabolic diseases and metabolic-related disorders are selected from, but not limited to, hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus, idiopathic type 1 diabetes (Type lb), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition- related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g. necrosis and apoptosis), dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance. In an embodiment of the invention are therapeutic benefits of GPR1 19 activity modulators derived from increasing levels of GIP and PPY. For example,

neuroprotection, learning and memory, seizures and peripheral neuropathy.

GLP-1 and GLP-1 receptor agonists have been shown to be effective for treatment of neurodegenerative diseases and other neurological disorders. GLP-1 and exendin-4 have been shown to stimulate neurite outgrowth and enhance cell survival after growth factor withdrawal in PC12 cells. In a rodent model of neurodegeneration, GLP-1 and exendin-4 restore cholinergic marker activity in the basal forebrain. Central infusion of GLP-1 and exendin-4 also reduce the levels of amyloid-β peptide in mice and decrease amyloid precursor protein amount in cultured PC12 cells. GLP-1 receptor agonists have been shown to enhance learning in rats and the GLP-1 receptor knockout mice show deficiencies in learning behavior. The knockout mice also exhibit increased susceptibility to kainate-induced seizures which can be prevented by administration of GLP-1 receptor agonists. GLP-1 and exendin-4 has also been shown to be effective in treating pyridoxine-induced peripheral nerve degeneration, an experimental model of peripheral sensory neuropathy.

Glucose-dependent insulinotropic polypeptide (GIP) has also been shown to have effects on proliferation of hippocampal progenitor cells and in enhancing sensorimotor coordination and memory recognition.

In an embodiment of the invention are therapeutic benefits of GPR1 19 activity modulators. For example, GLP-2 and short bowel syndrome (SBS). Several studies in animals and from clinical trials have shown that GLP-2 is a trophic hormone that plays an important role in intestinal adaptation. Its role in regulation of cell proliferation, apoptosis, and nutrient absorption has been well documented. Short bowel syndrome is

characterized by malabsorption of nutrients, water and vitamins as a result of disease or surgical removal of parts of the small intestine (eg. Crohn's disease). Therapies that improve intestinal adaptation are thought to be beneficial in treatment of this disease. In fact, phase II studies in SBS patients have shown that teduglutide, a GLP-2 analog, modestly increased fluid and nutrient absorption.

In an embodiment of the invention are therapeutic benefits of GPR1 19 activity modulators derived from increasing levels of GIP and PPY. For example, GLP-1 , GIP and osteoporosis. GLP-1 has been shown to increase calcitonin and calcitonin related gene peptide (CGRP) secretion and expression in a murine C-cell line (CA-77).

Calcitonin inhibits bone resorption by osteoclasts and promotes mineralization of skeletal bone. Osteoporosis is a disease that is caharacterized by reduced bone mineral density and thus GLP-1 induced increase in calcitonin might be therapeutically beneficial.

GIP has been reported to be involved in upregulation of markers of new bone formation in osetoblasts including collagen type I mRNA and in increasing bone mineral density. Like GLP-1 , GIP has also been shown to inhibit bone resorption. In an embodiment of the invention are therapeutic benefits of GPR1 19 activity modulators derived from increasing levels of GIP and PPY. For example, PPY and gastric emptying. GPR119 located on the pancreatic polypeptide (PP) cells of the islets has been implicated in the secretion of PPY. PPY has been reported to have profound effects on various physiological processes including modulation of gastric emptying and gastrointestinal motility. These effects slow down the digestive process and nutrient uptake and thereby prevent the postprandial elevation of blood glucose. PPY can suppress food intake by changing the expression of hypothalamic feeding-regulatory peptides. PP-overexpressing mice exhibited the thin phenotype with decreased food intake and gastric emptying rate.

In accordance with the foregoing, the present invention further provides a method for preventing or ameliorating the symptomology of any of the diseases or disorders described above in a subject in need thereof, which method comprises administering to said subject a therapeutically effective amount (See, "Administration and Pharmaceutical Compositions", infra) of a compound of Formula I or a pharmaceutically acceptable salt thereof. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.

Administration and Dosage

In general, compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5 mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g.

humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered, e.g. in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca. 1 to 50 mg active ingredient. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease. Biological Assays

The activity of a compound according to the present invention can be assessed by the following in vitro & in vivo methods.

Generation of Stable Cell Line

Flp-ln-CHO cells (Invitrogen, Cat.# R758-07) are maintained in Ham's F12 medium supplemented with 10% fetal bovine serum, 1% antibiotic mixture and 2 mM L- glutamine. The cells are transfected with a DNA mixture containing human GPR1 19 (hGPR1 19) or mouse GPR1 19 (mGPR1 19) in the pcDNA5/FRT vector (Invitrogen) and the pOG44 vector (Invitrogen) in a 1 :9 ratio using Fugene6 (Roche), according to the manufacturer's instructions. After 48 hours, the medium is changed to medium supplemented with 400 μg/mL hygromycin B to initiate the selection of stably transfected cells. The resultant cell lines are designated CHO-hGPR1 19 and CHO-mGPR1 19 respectively.

Cyclic AMP Assays

To test the activity of compounds of the invention on human GPR1 19, CHO-hGPR1 19 cells are harvested and resuspended at 300,000 cells/mL in assay media (Ham's F12 medium plus 3% lipid-depleted fetal bovine serum, 1 mM 3-isobutyl-1 -methyl-xanthine (IBMX)). Cells (5 μΙ) are placed in each well of a white 1536-well plate. A compound of the invention (50 nl_) diluted in 100% dimethyl sulfoxide (DMSO) is added to each well and the plates are incubated at 37^QC for 30 minutes. cAMP concentrations are then measured using the cAMP dynamic 2 kit (Cisbio Bioassays) according to the manufacturer's instructions. 2.5 μΙ_ of diluted CAMP-XL665 is added to each well, followed by 2.5 μΙ_ diluted anti-cAMP-Cryptate. The plate is covered and incubated for one hour at room temperature, then read on an Envision plate reader (Perkin Elmer) using the HTRF method with excitation at 337 nm, and emissions measured at 620 nm and 655 nm.

Activity of compounds of the invention on mouse GPR119 is measured by a similar method in 384-well plates. CHO-mGPR1 19 cells are harvested and resuspended in assay media at 500,000 cells/mL. 50 μΙ cells are placed in each well of a white 384-well plate. A compound of the invention (500 nl_) diluted in 100% DMSO is added to each well and the plates are incubated at 37^QC for 30 minutes. cAMP concentrations are measured as above except that 20 μΙ_ of diluted cAMP-XL665 followed by 20 μΙ_ diluted anti-cAMP-Cryptate is added to each well. Compounds of the invention, in free form or in pharmaceutically acceptable salt form, produced a concentration-dependent increase in intracellular cAMP level. Table I shows the EC₅₀ assayed by Cyclic AMP Assays described above for compounds of the invention; the EC₅₀ are between 5 nM and 35 nM, typically less than 10 nM. Accordingly, compounds of the invention exhibit inhibitory efficacy against GPR1 19.

Table 1 Inhibitory Activity of Compounds

Combination Therapy

Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations). For example, synergistic effects can occur with other anti-obesity agents, anorectic agents, appetite suppressant and related agents. Diet and/or exercise can also have synergistic effects. Anti-obesity agents include, but are not limited to, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4 agonists, cholescystokinin-A (CCK-A) agonists, serotonin and norepinephrine reuptake inhibitors (for example, sibutramine), sympathomimetic agents, β3 adrenergic receptor agonists, dopamine agonists (for example, bromocriptine), melanocyte-stimulating hormone receptor analogs, cannabinoid 1 receptor antagonists [for example, compounds described in WO2006/047516), melanin concentrating hormone antagonists, leptons (the OB protein), leptin analogues, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e., Orlistat), anorectic agents (such as a bombesin agonist), Neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone or an analogue thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon- like peptide- 1 receptor agonists, ciliary neutrotrophic factors (such as Axokine™), human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or reverse agonists, neuromedin U receptor agonists, noradrenergic anorectic agents (for example, phentermine, mazindol and the like) and appetite suppressants (for example, bupropion).

Where compounds of the invention are administered in conjunction with other therapies, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.

A combined preparation or pharmaceutical composition can comprise a compound of the invention as defined above or a pharmaceutical acceptable salt thereof and at least one active ingredient selected from:

a) anti-diabetic agents such as insulin, insulin derivatives and mimetics; insulin secretagogues such as the sulfonylureas, e.g., Glipizide, glyburide and Amaryl;

insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; insulin sensitizer such as protein tyrosine phosphatase-1 B (PTP-1 B) inhibitors such as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors such as SB- 517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands such as GW-0791 and AGN-194204; sodium-dependent glucose co-transporter inhibitors such as T-1095; glycogen phosphorylase A inhibitors such as BAY R3401 ; biguanides such as metformin; alpha-glucosidase inhibitors such as acarbose; GLP-1 (glucagon like peptide-1 ), GLP-1 analogs such as Exendin-4 and GLP-1 mimetics; DPPIV (dipeptidyl peptidase IV) inhibitors such as DPP728, LAF237 (vildagliptin - Example 1 of WO 00/34241 ), MK-0431 , saxagliptin, GSK23A ; an AGE breaker; a thiazolidone derivative (glitazone) such as pioglitazone, rosiglitazone, or ( ^ 1 -{4-[5-methyl-2-(4-trifluoromethyl- phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1 /-/-indole-2-carboxylic acid described in the patent application WO 03/043985, as compound 19 of Example 4, a non-glitazone type PPAR gamma agonist e.g. GI-262570; Diacylglycerol

acetyltransferase (DGAT) inhibitors such as those disclosed in WO 2005044250, WO 2005013907, WO 2004094618 and WO 2004047755; b) hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG- CoA) reductase inhibitors, e.g., lovastatin and related compounds such as those disclosed in U.S. Pat. No. 4,231 ,938, pitavastatin, simvastatin and related compounds such as those disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171 , pravastatin and related compounds such as those disclosed in U.S. Pat. No.4,346,227, cerivastatin, mevastatin and related compounds such as those disclosed in U.S. Pat. No. 3,983,140, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and related statin compounds disclosed in U.S. Pat. No. 5,753,675, rivastatin, pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactone derivatives as disclosed in PCT application WO 86/03488, 6-[2-

(substituted-pyrrol-1 -yl)-alkyl)pyran-2-ones and derivatives thereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a 3- substituted pentanedioic acid derivative) dichloroacetate, imidazole analogs of mevalonolactone as disclosed in PCT application WO 86/07054, 3- carboxy-2- hydroxy-propane-phosphonic acid derivatives as disclosed in French Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan and thiophene derivatives as disclosed in European Patent Application No. 0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat. No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No. 4, 499,289, keto analogs of mevinolin (lovastatin) as disclosed in European Patent Application No.0,142,146 A2, and quinoline and pyridine derivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691 ,322. In addition, phosphinic acid compounds useful in inhibiting HMG CoA reductase suitable for use herein are disclosed in GB 2205837; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acid and aspirin;

c) an anti-obesity agent or appetite regulating agent such as a CB1 activity modulator, melanocortin receptor (MC4R) agonists, melanin-concentrating hormone receptor (MCHR) antagonists, growth hormone secretagogue receptor (GHSR) antagonists, galanin receptor modulators, orexin antagonists, CCK agonists, GLP-1 agonists, and other Pre-proglucagon-derived peptides; NPY1 or NPY5 antagonsist, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, histamine receptor- 3 (H3) modulators, aP2 inhibitors, PPAR gamma modulators, PPAR delta modulators, acetyl-CoA carboxylase (ACC) inihibitors, Ι Ι -β-HSD-l inhibitors, adinopectin receptor modulators; beta 3 adrenergic agonists, such as AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other known beta 3 agonists as disclosed in U.S. Pat. Nos. 5,541 ,204, 5,770,615, 5, 491 ,134, 5,776,983 and 5,488,064, a thyroid receptor beta modulator, such as a thyroid receptor ligand as disclosed in WO 97/21993 (U. Cal SF), WO 99/00353 (KaroBio) and GB98/284425 (KaroBio), a SCD-1 inhibitor as disclosed in WO200501 1655, a lipase inhibitor, such as orlistat or ATL-962 (Alizyme), serotonin receptor agonists, (e.g., BVT- 933 (Biovitrum)), monoamine reuptake inhibitors or releasing agents, such as fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, dexamphetamine, phentermine, phenylpropanolamine or mazindol, anorectic agents such as topiramate (Johnson & Johnson), CNTF (ciliary neurotrophic factor)/Axokine^® (Regeneron), BDNF (brain-derived neurotrophic factor), leptin and leptin receptor modulators, phentermine, leptin, bromocriptine, dexamphetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, orlistat, dexfenfluramine, mazindol, phentermine, phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate, diethylpropion, benzphetamine, phenylpropanolamine or ecopipam, ephedrine, pseudoephedrine;

d) anti-hypertensive agents such as loop diuretics such as ethacrynic acid, furosemide and torsemide; diuretics such as thiazide derivatives, chlorithiazide, hydrochlorothiazide, amiloride; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na-K-ATPase membrane pump such as digoxin; neutralendopeptidase (NEP) inhibitors e.g. thiorphan, terteo-thiorphan, SQ29072; ECE inhibitors e.g. SLV306; ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril; angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan; renin inhibitors such as aliskiren, terlakiren, ditekiren, RO 66-1 132, RO-66-1 168; beta-adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol; inotropic agents such as digoxin, dobutamine and milrinone; calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists; aldosterone synthase inhibitors; and dual ET/AII antagonist such as those disclosed in WO 00/01389.

e) a HDL increasing compound;

f) Cholesterol absorption modulator such as Zetia^® and KT6-971 ;

g) Apo-A1 analogues and mimetics;

h) thrombin inhibitors such as Ximelagatran;

i) aldosterone inhibitors such as anastrazole, fadrazole, eplerenone;

j) Inhibitors of platelet aggregation such as aspirin, clopidogrel bisulfate; k) estrogen, testosterone, a selective estrogen receptor modulator, a selective androgen receptor modulator;

I) a chemotherapeutic agent such as aromatase inhibitors e.g. femara, anti- estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, antineoplastic antimetabolites, platin compounds, compounds decreasing the protein kinase activity such as a PDGF receptor tyrosine kinase inhibitor preferably Imatinib ( { N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2- methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine }) described in the European patent application EP-A-0 564 409 as example 21 or 4-Methyl-N-[3-(4-methyl-imidazol-1 -yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide described in the patent application WO 04/005281 as example 92; and

m) an agent interacting with a 5-HT₃ receptor and/or an agent interacting with 5- HT₄ receptor such as tegaserod described in the US patent No. 5510353 as example 13, tegaserod hydrogen maleate, cisapride, cilansetron;

n) an agent for treating tobacco abuse, e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the tradename Zyban^®) and nicotine replacement therapies;

o) an agent for treating erectile dysfunction, e.g., dopaminergic agents, such as apomorphine), ADD/ADHD agents (e.g., Ritalin^®, Strattera^®, Concerta^® and Adderall^®); p) an agent for treating alcoholism, such as opioid antagonists (e.g., naltrexone

(also known under the tradename ReVia^®) and nalmefene), disulfiram (also known under the tradename Antabuse^®), and acamprosate (also known under the tradename

Campral^®)). In addition, agents for reducing alcohol withdrawal symptoms may also be co-administered, such as benzodiazepines, beta- blockers, clonidine, carbamazepine, pregabalin, and gabapentin (Neurontin^®);

q) other agents that are useful including anti-inflammatory agents (e.g., COX-2 inhibitors) ; antidepressants (e.g., fluoxetine hydrochloride (Prozac^®)); cognitive improvement agents (e.g., donepezil hydrochloride (Aircept^®) and other

acetylcholinesterase inhibitors); neuroprotective agents (e.g., memantine) ; antipsychotic medications (e.g., ziprasidone (Geodon^®), risperidone (Risperdal^®), and olanzapine

(Zyprexa^®)); or, in each case a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable carrier.

Products provided as a combined preparation include a composition comprising the compound of Formula I and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of formula (I) and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.

In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent(s). Optionally, the

pharmaceutical composition may comprise a pharmaceutically acceptable carrier, as described above.

In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I). In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like. The kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration. In the combination therapies of the invention, the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent) ; (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent. The terms "co-administration" or "combined administration" or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of 3 or more active ingredients.

EXAMPLES

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Celsius. If not mentioned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art. All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21 ). Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples.

Example 1 : Synthesis of ferf-butyl 4-(4-bromo-2,6-difluorophenoxy)piperidine-1- carbo

To a solution of 12.5 g (60.0 mmol, 1 eq.) of 4-bromo-2,6-difluorophenol and 20.0 g (72.0 mmol, 1 .2 eq.) of fert-butyl 4-((methylsulfonyl)oxy)piperidine-1 -carboxylate in DMF (30 mL) was added 12.4 g (90 mmol, 1 .5 eq.) of K₂C0₃. The solution was stirred overnight at 70 °C then cooled to RT before being poured onto ice (about 1 kg) in a 2 L Erlenmeyer. The resulting precipitate was collected by filtration, washed with H₂0 twice then dried overnight to afford 21 .4 g (54.7 mmol, 91 %) of fert-butyl 4-(4-bromo-2,6- difluorophenoxy)piperidine-1 -carboxylate (a) as a light brown solid.

Example 2: Synthesis of fert-butyl 4-(2,6-difluoro-4-(pyridin-4- yl)phenoxy)piperidine-1-carboxylate (Intermediate b)

A mixture of 22 g (56.0 mmol, 1 .0 eq.) fert-butyl 4-(4-bromo-2,6- difluorophenoxy)piperidine-1 -carboxylate, 10 g (84.0 mmol, 1 .5 eq.) of 4-pyridylboronic acid, 56.0 g (168 mmol, 3.0 eq.) of Cs₂C0₃, 456 mg (0.56 mmol, 0.01 eq.) of

Pd(ddpf)₂CI₂ in 100 mL of a 1 -1 DMF-H20 mixture was heated at 80 °C overnight. After cooling, the mixture was filtered through a celite pad and the filtrate extracted with EtOAc. The organic layers were combined, washed with brine and dried over anhydrous MgS0₄. After filtration, the solvents were removed under reduced pressure and the residue purified by ISCO using EtOAc and Hexanes to afford 18.4 g (47.2 mmol, 84%) of fert-butyl 4-(2,6-difluoro-4-(pyridin-4-yl)phenoxy)piperidine-1 -carboxylate (b).

Example 3: Synthesis of fert-butyl 4-(2,6-difluoro-4-(piperidin-4- yl)phenoxy)piperidine-1 -carboxylate (Intermediate c)

To a solution of 7.8 g (20.0 mmol, 1 eq.) of fert-butyl 4-(2,6-difluoro-4-(pyridin-4- yl)phenoxy)piperidine-1 -carboxylate, 4.0 mL of TFA in 50 mL of AcOH was added. 1 g (4.4 mmol) of Pt0₂ portionwise and the reaction mixture was under H₂ atmosphere (balloon) for 3 days. After complexion of the reaction by TLC or LCMS, the mixture was filtered through a pad of Celite® and concentrated. The residue was basified with a solution of 1 N NaOH and extracted with EtOAc. The organic layers were combined, washed with brine, dried (anhydrous MgS04), filtrated and concentrated to afford 29.2 g (89%) of tert-butyl 4-(2,6-difluoro-4-(piperidin-4-yl)phenoxy)piperidine-1 -carboxylate (c) used directly in the next step.

Example 4: Synthesis of 1-(allylsulfonyl)-4-(3,5-difluoro-4-(piperidin-4- yloxy)phenyl)piperidine (Intermediate d)

c 2/ 4M HCI in dioxane d

RT

To a mixture of 235 mg (0.59 mmol, 1 .0 eq.) of tert-butyl 4-(2,6-difluoro-4- (piperidin-4-yl)phenoxy)piperidine-1 -carboxylate diluted in 3.0 ml_ of DCM was added 0.31 ml_ (1 .77 mmol, 3.0 eq.) of DIPEA followed by 165 mg (2.0 mmol, 1 .2 eq.) of prop- 2-ene-1 -sulfonyl chloride at 0°C. The mixture is slowly warmed-up to RT and once completed (LCMS monitoring) poured in water. The mixture was extracted with DCM, the organic layers were collected, washed with brine, water, dried over MgS04, filtrated and concentrated to afford the desired tert-butyl 4-(4-(1 -(allylsulfonyl)piperidin-4-yl)-2,6- difluorophenoxy)piperidine-1 -carboxylate that was purified over silica gel column chromatography (10% MeOH in DCM as eluent) . The boc protected amine was then diluted in 2.0 ml_ of dioxane and 2.0 ml_ of a 4N HCI in dioxane was added slowly at RT. After complexion (about 2 h), the solution was concentrated to afford 210 mg of 1 - (allylsulfonyl)-4-(3,5-difluoro-4-(piperidin-4-yloxy)phenyl)piperidine hydrochloride (d).

Example 5: Synthesis of 1-methylcyclopropyl 4-(4-(1-(allylsulfonyl)piperidin-4-yl)-

To a mixture of 43.6 mg (0.1 mmol) of 1 -(allylsulfonyl)-4-(3,5-difluoro-4-(piperidin- 4-yloxy)phenyl)piperidine hydrochloride (d) and 35.6 mg (0.15 mmol) of 1 - methylcyclopropyl (4-nitrophenyl) carbonate in 2.0 ml_ of DCM was added 0.06 ml_ (0.3 mmol) of DIPEA. The mixture was stirred at RT until complexion. After a similar workup as the previous step, the residue was purified over silica gel column chromatography (eluent: 80% EtOAc in hexanes) to afford 43 mg (0.056 mmol, 86%) of 1 - methylcyclopropyl 4-(4-(1 -(allylsulfonyl)piperidin-4-yl)-2,6-difluorophenoxy)piperidine-1 - carboxylate (e).

Example 6: Synthesis of fert-butyl 4-(4-(1-(3-chloropropyl)piperidin-4-yl)-2,6- d

To a solution of 5.9 g (15.0 mmol, 1 .0 eq.) of fert-butyl 4-(2,6-difluoro-4-(piperidin- 4-yl)phenoxy)piperidine-1 -carboxylate (c) in 30.0 ml_ of DCM was added 7.8 ml_ (45.0 mmol, 3.0 eq.) of DIEA followed by 3.0 g (18.0 mmol, 1 .2 eq.) of 3-chloropropane-1 - sulfonyl chloride. The mixture was stirred at RT until complexion (about 2 hours) then diluted with DCM, washed with a saturated aqueous NH4CI solution and brine. The organic layer was then dried over anhydrous Na₂S0₄, filtrated and concentrated under reduced pressure. The residue was triturated in Et₂0 and the resulting solid filtered and dried to afford 6.2 g (1 1 .5 mmol, 78%) of fert-butyl 4-(4-(1 -(3-chloropropyl)piperidin-4-yl)- 2,6-difluorophenoxy)piperidine-1 -carboxylate (f) as an off-white solid.

Example 7: Synthesis of fert-butyl 4-(4-(1-(3-acetoxypropyl)piperidin-4-yl)-2,6-

To a solution of 5.36 g (10.0 mmol, 1 .0 eq.) of fert-butyl 4-(4-(1 -(3- chloropropyl)piperidin-4-yl)-2,6-difluorophenoxy)piperidine-1 -carboxylate (f) in 20.0 ml_ of DMF was added 2.3 g (15.0 mmol, 1 .5 eq.) of Nal followed by 3 g (30.0 mmol, 3.0 eq.) of NaOAc. The resulting mixture was heated at 80 °C overnight. After cooling at Rt, the mixture was poured on crushed ice (about 1 kg) and stirred for about 2 hours. The resulting precipitate was collected by filtration and dried. MeOH was added to the resulting brown solid and the slurry sonicated for about 10 minutes. The resulting solid was filtrated and dried to afford 4.35 g (7.8 mmol, 78%) of fert-butyl 4-(4-(1 -(3- acetoxypropyl)piperidin-4-yl)-2,6-difluorophenoxy)piperidine-1 -carboxylate (g) as a light cream colored solid. Example 8: Synthesis of 3-(4-(3,5-difluoro-4-(piperidin-4-yloxy)phenyl)piperidin-1-

A mixture of 5.6 g (10.0 mmol, 1 .0 eq.) of te/t-butyl 4-(4-(1 -(3- acetoxypropyl)piperidin-4-yl)-2,6-difluorophenoxy)piperidine-1 -carboxylate (g) in 10 mL of dry dioxane was added 12.5 mL of 4N dioxane dropwise at OoC. The reaction mixture was stirred at RT until complexion (about 6 h) then concentrated. The residue (sticky white material) was triturated with Et₂0 and the precipitated solid collected by filtration and dried (lyophilizer, ON) to afford 3.9 g (78.0 mmol, 78%) of 3-(4-(3,5-difluoro-4- (piperidin-4-yloxy)phenyl)piperidin-1 -yl)propyl acetate hydrochloride (h) as an off-white solid.

Example 9: Synthesis of 3-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5-

A mixture of 2 g (4.0 mmol, 1 .0 eq.) of 3-(4-(3,5-difluoro-4-(piperidin-4- yloxy)phenyl)piperidin-1 -yl)propyl acetate hydrochloride, 2.1 mL (12.0 mmol, 3.0 eq.) of DIEA and 857 mg (6.0.0 mmol, 1 .5 eq.) of 2-chloro-5-ethylpyrimidine in 7.5 mL of DMF was heated under microwave conditions at 150 °C for 60 min. After cooling at RT, the solvents were removed under reduced pressure and the residue purified by ISCO using a gradient of EtOAc and hexanes to afford 1 .74 g (3.08 mmol, 77%) of 3-(4-(4-((1 -(5- ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5-difluorophenyl)piperidin-1 -yl)propyl acetate as a white solid (a small amount of the deacylated product was also observed).

Example 10: Synthesis of (R)- and (S)- 1-methylcyclopropyl 4-(4-(1-((2,3- dihydroxypropyl)sulfonyl)piperidin-4-yl)-2,6-difluorophenoxy)piperidine-1- carboxylate (Compounds 1 and 2)

To a mixture of 43 mg (0.086 mmol) of 1 -methylcyclopropyl 4-(4-(1 - (allylsulfonyl)piperidin-4-yl)-2,6-difluorophenoxy)piperidine-1 -carboxylate (e) and 31 mg (0.26 mmol) of NMO in 2.0 ml_ of a 1 :9 mixture of H₂0/acetone was added 0.092 ml_ (0.0086 mmol) of Os0₄ at 0°C. The mixture was stirred and slowly warmed-up to RT until complexion. After concentration and filtration, the residue was purified over silica gel column chromatography (eluent: 0-100% EtOAc in DCM; 4 gram silica column) to afford 33 mg (0.061 mmol, 71 %) of 1 -methylcyclopropyl 4-(4-(1 -((2,3- dihydroxypropyl)sulfonyl)piperidin-4-yl)-2,6-difluorophenoxy)piperidine-1 -carboxylate. Separation over chiral HPLC afforded Compounds 1 and 2.

Compound 1 : ¹ H NMR (400 MHz, CD₃OD) : 5 6.92 (m, 2H), 5 4.33 (m, 1 H), 5 4.10 (m, 1 H), 5 3.85 (m, 2H), 5 3.70 (m, 2H), 5 3.56 (m, 2H), 5 3.29 (m, 1 H), 5 3.25 (dd, J = 16.0, 4.0 Hz, 1 H), 5 3.10 (m , 1 H), 5 2.97 (m, 2H), 5 2.66 (m, 1 H), 5 1 .88 (m, 4H), 5 1 .69 (m, 4H), 5 1 .52 (s, 3H), 5 20.86 (m, 2H), 5 0.64 (m, 2H). MS (m/z): fragment (M-71 )⁺ 461 .1 .

Compound 2: ¹ H NMR (400 MHz, CDCI₃): 5 6.74 (m, 2H), 5 4.31 (m, 2H), 5 3.95 (m, 2H), 5 3.80 (dd, J = 12.0, 4.0 Hz, 1 H), 5 3.72 (m, 2H), 5 3.64 (dd, J = 12.0, 4.0 Hz, 1 H), 5 3.32 (m , 2H), 5 3.15 (m, 2H), 5 2.88 (m, 2H), 5 2.56 (m, 1 H), 5 1 .82 (m, 9H), 5 1 .55 (s, 3H), 5 0.87 (m, 2H), 5 0.63 (m, 2H). MS (m/z): fragment (M-71 )⁺ 461 .1 . Example 11 : Synthesis of 3-((4-(3,5-dif luoro-4-((1 -(5-methylpyrimidin-2-yl)piperidin- 4-yl)oxy)phenyl)piperidin-1 -yl)sulfonyl)propane-1 ,2-diol (Compound 3)

To a mixture of 22 mg (0.05 mmol) of 1 -(allylsulfonyl)-4-(3,5-difluoro-4-(piperidin- 4-yloxy)phenyl)piperidine hydrochloride (d), 13 mg (0.1 mmol) of 2-chloro-5- methylpyrimidine and 27 μΙ_ of DIPEA in 1 .0 mL of DMF was stirred at 150°C under microwave irradiation for one hour. After the usual aqueous work-up, the residue was purified over silica gel column chromatography (eluent: 0-60% EtOAc in hexanes; 12 gram silica gel column) to afford 22 mg (0.044 mmol, 89%) of 2-(4-(4-(1 - (allylsulfonyl)piperidin-4-yl)-2,6-difluorophenoxy)piperidin-1 -yl)-5-methylpyrimidine.

Compound 3 was prepared by the same procedure described in Compound 7 from 20 mg (0.04 mmol) of 2-(4-(4-(1 -(allylsulfonyl)piperidin-4-yl)-2,6- difluorophenoxy)piperidin-1 -yl)-5-methylpyrimidine, 0.043 mL (0.004 mmol) of Os04, 14 mg (0.12 mmol) of NMO in 1 mL of H₂0/acetone (1 :9 v/v). MS (m/z) (M+1 )⁺ 527.1

Example 12: Synthesis of 3-((4-(3,5-difluoro-4-((1-(3-isopropyl-1 ,2,4-oxadiazol-5- yl)piperidin-4-yl)oxy)phenyl)piperidin-1 -yl)sulfonyl)propane-1 ,2-diol (Compound 4)

To a mixture of 44 mg (0.1 mmol) of 1 -(allylsulfonyl)-4-(3,5-difluoro-4-(piperidin-4- yloxy)phenyl)piperidine hydrochloride (d), 12 mg (0.1 1 mmol) of CNBr, 29 mg (0.3 mmol) of KOAc in 1 .0 mL of MeOH was slowly warmed up from 0°C to RT and stirred until complexion of the reaction (4 hours). After concentration, the residue was purified over silica gel column chromatography (eluent: 0-80% DCM in hexanes; 12 gram silica gel column) to afford 41 mg (0.096 mmol, 96%) of 4-(4-(1 -(allylsulfonyl)piperidin-4-yl)-2,6- difluorophenoxy)piperidine-1 -carbonitrile.

To a mixture of 41 mg (0.096 mmol) of 4-(4-(1 -(allylsulfonyl)piperidin-4-yl)-2,6- difluorophenoxy)piperidine-1 -carbonitrile, 49 mg (0.48 mmol) of (Z)-N'- hydroxyisobutyrimidamide, 0.18 mL (0.14 mmol) of ZnCI₂ (1 .0 M in Et₂0 solution) in 2.0 mL of THF was stirred at RT overnight. After concentration, the residue was purified over silica gel column chromatography (eluent: 0-100% EtOAc in DCM; 12 gram silica gel column) to afford 23 mg (0.045 mmol, 47%) of 5-(4-(4-(1 -(allylsulfonyl)piperidin-4-yl)-2,6- difluorophenoxy)piperidin-1 -yl)-3-isopropyl-1 ,2,4-oxadiazole directly used in the next step.

Compound 4, (3-((4-(3,5-difluoro-4-((1 -(3-isopropyl-1 ,2,4-oxadiazol-5-yl)piperidin- 4-yl)oxy)phenyl)piperidin-1 -yl)sulfonyl)propane-1 ,2-diol), was prepared by the same procedure described in Compound 7 from 23 mg (0.045 mmol) of 5-(4-(4-(1 - (allylsulfonyl)piperidin-4-yl)-2,6-difluorophenoxy)piperidin-1 -yl)-3-isopropyl-1 ,2,4- oxadiazole, 0.048 mL (0.0045 mmol) of Os04, 16 mg (0.14 mmol) of NMO in 1 mL of H₂0/acetone (1 :9 v/v). Compound 4 was purified by mass-triggered HPLC. MS (m/z) : (M+1 )⁺ 545.2

Example 13: Synthesis of 3-((4-(4-((1 -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5- difluorophenyl)piperidin-1 -yl)sulfonyl)propane-1 ,2-diol (Compounds 5, 6 and 7)

To a mixture of 81 mg (0.1 85 mmol) of 1 -(allylsulfonyl)-4-(3,5-difluoro-4- (piperidin-4-yloxy)phenyl)piperidine hydrochloride(d), 0.1 mL (0.6 mmol) of DIEA, 40 mg (0.29 mmol) of 2-chloro-5-ethylpyrimidine in 1 .0 mL of DMF was heated under microwave irradiation for 1 h at 150 °C. After cooling and usual aqueous work-up, the residue was purified by ISCO to afford 81 mg (0.16 mmol, 87%) of 2-(4-(4-(1 - (allylsulfonyl)piperidin-4-yl)-2,6-difluorophenoxy)piperidin-1 -yl)-5-ethylpyrimidine.

To a mixture of 81 mg (0.1 85 mmol) of of 2-(4-(4-(1 -(allylsulfonyl)piperidin-4-yl)- 2,6-difluorophenoxy)piperidin-1 -yl)-5-ethylpyrimidine, and 33 mg (0.6 mmol) of NMO in 1 .0 mL of a 1 :9 mixture of H₂0/acetone was added 0.03 mL (0.0086 mmol) of Os0₄ at 0°C. The mixture was stirred and slowly warmed-up to RT until complexion. After concentration and filtration, the residue was purified over silica gel column

chromatography (eluent: 0-100% EtOAc in DCM; 4 gram silica column) to afford 32 mg (0.059 mmol, 32%) of 3-((4-(4-((1 -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5- difluorophenyl)piperidin-1 -yl)sulfonyl)propane-1 ,2-diol (Compound 5). Separation over chiral HPLC afforded Compounds 6 and 7

Compound 5: ¹ H NMR (400 MHz, CDCI₃): δ 8.19 (broad s, 2H), δ 6.76 (m, 2H), δ

4.39 (m, 1 H), δ 4.33 (m, 1 H), δ 4.26 (m, 2H), δ 3.95 (m, 2H), δ 3.78 (m, 1 H), δ 3.65 (m , 1 H), δ 3.56 (m , 3H), δ 3.20 (dd, J = 12.0, 8.0 Hz, 1 H), δ 3.14 (dd, J = 12.0, 4.0 Hz, 1 H), δ 2.90 (m, 2H), δ 2.58 (m, 1 H), δ 2.47 (m, 3H), δ 1 .99 (m, 4H), δ 1 .85 (m, 2H), δ 1 .75 (m , 2H), δ 1 .20 (t, J = 8.0 Hz, 3H). MS (m/z) (M+1 )⁺ 541 .2.

Compound 6: (f?)-3-((4-(4-((1 -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5- difluorophenyl)piperidin-1 -yl)sulfonyl)propane-1 ,2-diol. MS (m/z) : (M+1 )⁺ 541 .2.

Compound 7: (S)-3-((4-(4-((1 -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5- difluorophenyl)piperidin-1 -yl)sulfonyl)propane-1 ,2-diol. ¹ H NMR (400 MHz, CDCI₃): δ 8.22 (broad s, 2H), δ 6.76 (m, 2H), δ 4.41 (m , 1 H), δ 4.33 (m , 1 H), δ 4.25 (m, 2H), 3.96 (m, 2H), δ 3.80 (m, 1 H), δ 3.64 (m, 3H), δ 3.17 (m, 2H), δ 2.90 (m, 2H), δ 2.59 (m, 1 H), δ 2.48 (m, 2H), δ 1 .98 (m, 5H), δ 1 .88 (m, 2H), δ 1 .77 (m, 2H), δ 1 .21 (t, J = 8.0 Hz, 3H). MS (m/z): (M+1 )⁺ 541 .2

Example 14: Synthesis of 1 ,1 ,1 -trifluoropropan-2-yl 4-(4-(1 -((2,3- dihydroxypropyl)sulfonyl)piperidin-4-yl)-2,6-difluorophenoxy)piperidine-1 - carboxylate (Compounds 8, 9, 10 and 11 )

Compound 8

Compound 9

To a mixture of 218 mg (0.5 mmol) of 1 -(allylsulfonyl)-4-(3,5-difluoro-4-(piperidin- 4-yloxy)phenyl)piperidine hydrochloride and 168 mg (0.6 mmol) of 4-nitrophenyl (1 ,1 ,1 - trifluoropropan-2-yl) carbonate in 2.0 mL of DCM was added 0.21 mL of Et₃N at 0°C. The mixture was warmed-up to RT and stirred for 2 hours, quenched with saturated aqueous NH₄CI and extracted with DCM. The organic layers were then combined, washed with brine and dried over anhydrous Na₂S0₄. After filtration and concentration, the residue was purified by ISCO using EtOAc and hexanes to afford 180 mg (0.33 mmol, 68%) of 1 ,1 ,1 -trifluoropropan-2-yl 4-(4-(1 -(allylsulfonyl)piperidin-4-yl)-2,6- difluorophenoxy)piperidine-1 -carboxylate.

1 ,1 ,1 -trifluoropropan-2-yl 4-(4-(1 -(allylsulfonyl)piperidin-4-yl)-2,6- difluorophenoxy)piperidine-1 -carboxylate was subjected to the same reaction conditions described in Example 10 , followed by chiral HPLC to afford Compounds 8, 9 10 and 1 1 .

Compound 8: ¹ H NMR (400 MHz, CDCI₃): δ 6.76 (m, 2H), δ 5.25 (m, 1 H), δ 4.32

(m, 2H), δ 3.96 (m, 2H), δ 3.79 (m, 3H), δ 3.65 (dd, J = 8.0, 4.0 Hz, 1 H), δ 3.47 (m, 3H), δ 3.18 (dd, J = 12.0, 8.0 Hz, 1 H), δ 3.13 (dd, J = 12.0, 4.0 Hz, 1 H), δ 2.90 (m, 2H), δ 2.58 (m, 1 H), δ 1 .94 (m, 6H), δ 1 .76 (m, 3H), δ 1 .43 (d, J = 4.0 Hz, 3H). MS (m/z) : (M+1 )⁺ 575.2

Compound 9: MS (m/z) (M+1 )⁺ 575.2

Compound 10: ¹ H NMR (400 MHz, CDCI₃): 5 6.77 (m, 2H), 5 5.27 (m, 1 H), 5 4.35 (m, 2H), 5 3.97 (m, 2H), 5 3.80 (m, 3H), 5 3.66 (dd, J = 8.0, 4.0 Hz, 1 H), 5 3.48 (m, 3H), 5 3.20 (dd, J = 12.0, 8.0 Hz, 1 H), 5 3.13 (dd, J = 12.0, 4.0 Hz, 1 H), 5 2.91 (m, 2H), 5 2.56 (m, 1 H), 5 2.15 (broad s, 1 H), 5 1 .95 (m, 6H), 5 1 .77 (m, 2H), 5 1 .43 (d, J = 4.0 Hz, 3H). MS (m/z): (M+1 )⁺ 575.2

Compound 1 1 : MS (m/z) : (M+1 )⁺ 575.2

Example 16: Synthesis of (S)-4-(4-(4-((1 -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)- 3,5-difluorophenyl)piperidin-1 -yl)butan-2-ol (Compound 12) and (fi)-4-(4-(4-((1-(5- ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5-difluorophenyl)piperidin-1 -yl)butan-2-ol (C

To a solution of 570 mg (1 .0 mmol, 1 eq.) of 3-(4-(4-((1 -(5-ethylpyrimidin-2- yl)piperidin-4-yl)oxy)-3,5-difluorophenyl)piperidin-1 -yl)propyl acetate (Intermediate I, Ex.9) in 3.0 mL of MeOH was added 210 mg (1 .5 mmol, 1 .5 eq.) of K₂C0₃. The mixture was stirred until complexion (about 6 hours) and concentrated. Water was added to the residue and the resulting solid was filtrated, washed with water and dried. The resulting solid was dissolved in a small amount of DCM and loaded on siliga gel column (silicycle, FLH-R10030B-IS120, 12 g cartridge) and purified by Teledyne ISCO using a DCM- EtOAc gradient to afford 460 mg (0.88 mmol, 88%) of 3-(4-(4-((1 -(5-ethylpyrimidin-2- yl)piperidin-4-yl)oxy)-3,5-difluorophenyl)piperidin-1 -yl)propan-1 -ol as a white solid. MS (m/z) : (M+1 )⁺ 524.2.

To a solution of 262 mg (0.5 mmol, 1 .0 eq.) of 3-(4-(4-((1 -(5-ethylpyrimidin-2- yl)piperidin-4-yl)oxy)-3,5-difluorophenyl)piperidin-1 -yl)propan-1 -ol in 2.5 ml_ of DCM was added 323 mg (1 .5 mmol, 3.0 eq.) of PCC followed by 4A MS. The mixture was stirred at RT until complexion (about 3 h) then filtered through a pad of celite and concentrated. The resulting crude 3-(4-(4-((1 -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5- difluorophenyl)piperidin-1 -yl)propanal was directly diluted in 2.5 ml_ of anhydrous THF cooled at 0°C and a 3M solution of MeMgCI (0.5 ml_, 3.0 eq.) was added drop-wise under N₂ atmosphere. After complexion of the reaction (about 2h; monitored by LC-MS), the reaction mixture was quenched with a saturated NH₄CI solution and extracted with DCM. The combined organic layers were washed with brine, dried over MgS0₄, filtered and concentrated and purified by ISCO to afford the racemic (4-(4-(4-((1 -(5- ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-3,5-difluorophenyl)piperidin-1 -yl)butan-2-ol as an oil. The racemate was then separated over chiral HPLC (3mM 4.6x50 mm Chiral pack column, flow rate 1 mL/min solvent: hexanes -80%-/IPA -20%-) to afford both Compound 12 and Compound 13.

Compound 12: ¹ H NMR (400 MHz, CDCI₃): δ 8.19 (s, 2H), δ 6.76 (m, 2H), δ 4.38 (m, 1 H), δ 4.26 (m, 2H), δ 3.97 (m, 3H), δ 3.55 (m, 2H), δ 3.10 (m, 2H), 2.87 (m, 2H), δ 2.57 (m, 1 H), δ 2.47 (m, 2H), δ 2.02 (m, 5H), δ 1 .85 (m, 3H), δ 1 .72 (m, 2H), δ 1 .27 (d, J = 8.0 Hz, 3H), δ 1 .20 (t, J = 8.0 Hz, 3H). MS (m/z): (M+1 )⁺ 539.3.

Compound 13: MS (m/z) : (M+1 )⁺ 539.3

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims

CLAIMS WE CLAIM:

1. A compound of Formul

Q is selected from phenyl and C₅.₆heteroaryl, each of which is substituted with at least two substituents independently selected from halo, d-₆alkyl, halo-substituted-d- ₆alkyl, d-₆alkoxy, and halo-substituted-d.₆alkoxy;

R¹ is d-ealkyl substituted with 1 to 3 substituents independently selected from halo, hydroxy, amino, d-₆alkoxy, and halo-substituted-d.₆alkoxy; provided when R¹ is substituted with only one substituent, the substituent is not substituted at the terminal end of the C_halky! of R¹ ; and

R⁴ is selected from R⁸ and -C(0)OR⁸, wherein R⁸ is selected from C_halky!, phenyl, C₅-₆heteroaryl, C₃-₆cycloalkyl and C₃-₆heterocycloalkyl, each of which is independently optionally substituted with one to three substituents independently selected from halo, d-₄alkyl, C₃-₆cycloalkyl, C₃-₆heterocycloalkyl, halo-substituted-d- ₄alkyl, hydroxy-substituted-d-₄alkyl, d_₆alkoxy and halo-substituted-d-₆alkoxy.

2. The compound of Claim 1 , wherein Q is phenyl or C₆heteroaryl, each of which is substituted with at least two substituents independently selected from halo, d-₆alkyl, halo-substituted-d-₆alkyl, d-₆alkoxy, and halo-substituted-d-₆alkoxy.

3. The compound of Claim 1 , wherein Q is phenyl, pyrazinyl or pyridinyl, each of which is substituted with at least two substituents independently selected from halo, d-₆alkyl, halo-substituted-d-₆alkyl, d-₆alkoxy, and halo-substituted-d-₆alkoxy.

4. The compound according to any one of Claims 1 -3, wherein the at least two substituents on Q are halos.

5. The compound according to any one of Claims 1 -3, wherein the at least two substituents on Q are two fluoros.

6. The compound according to Claim 1 , wherein Q is

wherein "^*" indicates the point of attachment of Q to -O- in Formula I.

7. The compound according to any one of Claims 1 to 6, wherein R¹ is propyl or butyl, each of which is substituted with one to three substituents independently selected from halo, hydroxy, amino, d-₆alkoxy, and halo-substituted-d-₄alkoxy; provided when the propyl or butyl is substituted with only one substituent, the substituent is not substituted at the terminal end of the propyl or butyl.

8. The compound according to any one of Claims 1 to 6, wherein R¹ is propyl or butyl substituted with one to two hydroxyl; provided when the propyl or butyl is substituted with only one hydroxy, the hydroxy is not substituted at the terminal end of the propyl or butyl.

9. The compound according to any one of Claims 1 to 6, wherein R¹ is

-CH₂CH(OH)CH₂OH.

10. The compound according to any one of Claims 1 to 6, wherein R¹ is

-CH₂CH₂CH(OH)CH₃.

11 . The compound according to anyone of Claims 1 to 10, wherein R⁴ is R⁸, wherein R⁸ is a C₅-₆heteroaryl optionally substituted with one to three substituents independently selected from halo, d-₄alkyl, halo-substituted-d-₄alkyl, hydroxy-substituted-d-₄alkyl, d_ ₆alkoxy and halo-substituted-d-₆alkoxy.

12. The compound according to any one of Claims 1 to 10, wherein R⁴ is R⁸, wherein R⁸ is selected from a group consisting of oxadiazolyl, pyridinyl, pyrimidinyl, and pyridazinyl, each of which is optionally substituted with one to three substituents independently selected from halo, d-₄alkyl, halo-substituted-d-₄alkyl, hydroxy-substituted-d-₄alkyl, d_ ₆alkoxy and halo-substituted-d-₆alkoxy.

13. The compound according to any one of Claims 1 to 10, wherein R⁴ is -C(0)OR⁸, wherein R⁸ is selected from d-₆alkyl, C₃-₆cycloalkyl and C₃-₆heterocycloalkyl, each of which is optionally substituted with one to three substituents independently selected from halo, d-₄alkyl, C₃-₆cycloalkyl, C₃-₆heterocycloalkyl, halo-substituted-d^alkyl, hydroxy- substituted-C^alkyl, d-ealkoxy and halo-substituted-d.₆alkoxy.

14. The compound according to any one of Claims 1 to 10, wherein R⁴ is

15. The compound according to any one of Claims 1 to 10, wherein R⁴ is

16. The compound according to any one of Claims 1 to

17. The compound according to any one of Claims 1 to

10, wherein R⁴ is

18. The compound

la.

19. The compound according to Claim 18, wherein R¹ is -CH₂CH(OH)CH₂OH

20. The compound according to Claim 18, wherein R¹ is -CH₂CH₂CH(OH)CH

21 . The compound according to any one of Claims 18 to 20, wherein R⁴ is

ny one of Claims 18 to 20, wherein R⁴

23. The compound according to Claim 1 , wherein the compound is selected from the group consisting of:

(ft)-1 ,1 ,1 -trifluoropropan-2-yl 4-(4-(1 -(((S)-2,3-dihydroxypropyl)sulfonyl)piperidin- 4-yl)-2,6-difluorophenoxy)piperidine-1 -carboxylate;

(S)-1 ,1 ,1 -trifluoropropan-2-yl 4-(4-(1 -(((S)-2,3-dihydroxypropyl)sulfonyl)piperidin- 4-yl)-2,6-difluorophenoxy)piperidine-1 -carboxylate;

(ft)-1 ,1 ,1 -trifluoropropan-2-yl 4-(4-(1 -(((R)-2,3-dihydroxypropyl)sulfonyl)piperidin- 4-yl)-2,6-difluorophenoxy)piperidine-1 -carboxylate;

24. A pharmaceutical composition comprising a compound of any one of Claims 1 to 23 in combination with a pharmaceutically acceptable excipient.

25. A method for treating a disease or condition, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of any one of Claims 1 to 22 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and optionally in combination with a second agent, wherein the disease or condition is selected from diabetes related diseases or conditions, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance.

26. The method according to claim 25, wherein the diabetes related disease or condition is selected from obesity, type 1 diabetes, type 2 diabetes mellitus, hyperlipidemia, idiopathic type 1 diabetes, latent autoimmune diabetes in adults, early-onset type 2 diabetes, youth-onset atypical diabetes, maturity onset diabetes of the young, malnutrition-related diabetes and gestational diabetes.

27. Use of a compound according to any one of claims 1 to 22 in the manufacture of a medicament for treating a disease or condition, wherein the disease or condition is selected from diabetes related diseases or conditions, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance.

28. The use of Claim 27, wherein the diabetes related disease or condition is selected from obesity, type 1 diabetes, type 2 diabetes mellitus, hyperlipidemia, idiopathic type 1 diabetes, latent autoimmune diabetes in adults, early-onset type 2 diabetes, youth-onset atypical diabetes, maturity onset diabetes of the young, malnutrition-related diabetes and gestational diabetes.