WO2012006955A1

WO2012006955A1 - Compounds for treatment of metabolic disorders

Info

Publication number: WO2012006955A1
Application number: PCT/CN2011/077130
Authority: WO
Inventors: Shaojing Hu; Geng Lai; Wei LONG; Xiaoyan Shen; Fenlai Tan; Yinxiang Wang
Original assignee: Zhejiang Beta Pharma Inc.
Priority date: 2010-07-14
Filing date: 2011-07-14
Publication date: 2012-01-19

Abstract

Compounds having activity as agonist of GPR119 and inhibitor of DPPIV are disclosed. These compounds can be used for the treatment and prevention of diseases or conditions in which GPR119 and DPP-IV are involved, selected from diabetes, obesity, impaired glucose tolerance, insulin resistance, diabetic complications, and functional dyspepsia and metabolic diseases caused by abnormal sensitivity to ingested fats in patients.

Description

THE DESCRIPTION

COMPOUNDS FOR TREATMENT OF METABOLIC DISORDERS

Technical Field

The present invention is directed to novel compounds which have dual activity as agonist of

GPR119 and inhibitor of DPP-IV. In particularly, novel compounds for the treatment of metabolic disorders including type II diabetes.

Background Art

The present invention is directed to novel compounds that have dual activity as agonist of GPR119 and inhibitor of DPP-IV. In particular, the present invention is directed to novel therapeutic compounds useful for the treatment of metabolic disorders including type II diabetes.

Drugs aimed at the pathophysiology associated with non-insulin dependent Type II diabetes have many potential side effects and do not adequately address the dyslipidaemia and hyperglycaemia in a high proportion of patients. Treatment is often focused at individual patient needs using diet, exercise, hypoglycaemic agents and insulin, but there is a continuing need for novel antidiabetic agents, particularly ones that may be better tolerated with fewer adverse effects.

Similarly, metabolic syndrome (syndrome X) places people at high risk of coronary artery disease, and is characterized by a cluster of risk factors including central obesity (excessive fat tissue in the abdominal region), glucose intolerance, high triglycerides and low HDL cholesterol, and high blood pressure. Myocardial ischemia and microvascular disease is an established morbidity associated with untreated or poorly controlled metabolic syndrome.

Obesity is characterized by an excessive adipose tissue mass relative to body size. Clinically, body fat mass is estimated by the body mass index (BMI; weight(kg)/height(m)²), or waist circumference. Individuals are considered obese when the BMI is greater than 30 and there are established medical consequences of being overweight. It has been an accepted medical view for some time that an increased body weight, especially as a result of abdominal body fat, is associated with an increased risk for diabetes, hypertension, heart disease, and numerous other health complications, such as arthritis, stroke, gallbladder disease, muscular and respiratory problems, back pain and even certain cancers.

There is a continuing need for novel antidiabetic agents, particularly ones that are well tolerated with few adverse effects and in particular for agents which are weight neutral or preferably cause weight loss. GPRl 19 (previously referred to as GPRl 16) is a GPCR identified as SNORF25 in WO00/50562 which discloses both the human and rat receptors, US 6,468,756 also discloses the mouse receptor (accession numbers: AAN95194 (human), AAN95195 (rat) and ANN95196 (mouse)).

In humans, GPRl 19 is expressed in the pancreas, small intestine, colon and adipose tissue.

The expression profile of the human GPRl 19 receptor indicates its potential utility as a target for the treatment of diabetes.

GPRl 19 agonists have been shown to stimulate the release of GLP-I from the GI tract. In doing so, GPRl 19 agonists (1) enhance glucose-dependent insulin release from the pancreas leading to improvements in oral glucose tolerance; (2) attenuate disease progression by increasing β-cell cAMP concentrations; and (3) induce weight loss possibly through GLP-I's ability to reduce food intake.

International Patent Applications WO2005/061489, WO2006/070208, WO2006/067532, WO2006/067531, WO2007/003960, WO2007/003961, WO2007/003962, WO2007/003964, WO2007/116229, WO2007/116230, WO2008/081204, WO2008/081205, WO2008/081206, WO2008/081207 and WO2008/081208 disclose GPRl 19 receptor agonists.

Dipeptidyl peptidase IV (DPP-IV) is a ubiquitous, yet highly specific, serine protease that cleaves N-terminal dipeptides from polypeptides with L-proline or L-alanine at the penultimate position. The prevention or the treatment of diabetes, studies with DPP-IV inhibitors show the principle role of DPP-IV in the inactivation GLP-I. By extending the duration of action of GLP-I, insulin secretion is stimulated, glucagon release inhibited, and gastric emptying slowed. Examples of DPP-IV inhibitors include vildagliptin, sitagliptin and saxagliptin.

The possibility of using a combination of a GPRl 19 agonist and a DPP-IV has been suggested, however this requires the administration of two separately Formulated products to the patient or the co-Formulation of two active ingredients with the inherent problems of achieving compatibility in the physicochemical and pharmacokinetic and pharmacodynamic properties of the two active ingredients.

Summary of Invention

The present invention is directed to novel compounds which have dual activity as agonist of GPRl 19 and inhibitor of DPP-IV and are useful for the treatment of metabolic disorders including type II diabetes.

The present invention is directed to compounds of Formula (I),

Formula I

and pharmaceutically acceptable salts thereof, wherein:

Ri is a member selected from the group consisting of H, Ci_ioalkyl, Ci_ioSubstituted alkyl, Cs-ycycloalkyl, C₂-i₀alkenyl, C₂-i₀alkynyl, -R4COR5, -R₄C0₂R₅, -R4CONR5R6, -S0₂R₅, a 4-7 membered heterocyclo group, aryl and a 5-10 membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo group, aryl group and heteroaryl group is optionally substituted with from 1-4 substituents independently selected from halo, Ci_ioalkyl, Ci_ioSubstituted alkyl, C₃-7cycloalkyl, C₂_i₀ alkenyl, C₂_i₀alkynyl, aryl, heteroaryl, -CN, -NR₅COR₆, -NR₅CONR₅R₆, - NO2, -OR₅, -NR5R5, -COR₅, -CO2R5, -CONR₅R₆, -S(0)_mR₅, -NR₅S(0)₂R6 and -S0₂NR₅R₆, or optionally R₅ and R₆ are combined to form a 4-6 membered ring, and R₄ is selected from the group consisting of a bond, C₂_₆alkene, C₂_₆alkyne, -C(O)-, and -C(0)-(CH₂)i_₄-, wherein the aliphatic portions of R₄ are optionally substituted with one to three members selected from halogen, Ci_₄alkyl, Ci_₄substituted alkyl and Ci_₄haloalkyl; and wherein m is selected from 1 or 2;

R₂ is hydrogen or methyl;

X is a bond, -O- or -(CH₂)_n-, wherein n is any integer selected from 1-4;

R₃ is selected from the group consisting of perhaloCi_ioalkyl, amino, Ci_ioalkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, C(0)Ci_₃alkyl, C(S)Ci_₃alkyl, S(0)_mCi_₃alkyl, iminoCi_₃alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfmyl group, each substituted or unsubstituted thereof, and a substituted or unsubstituted 3-7 membered ring;

L is a linker providing 1, 2 or 3 atom separation between Y and the ring to which L is attached, wherein the atoms of the linker providing the separation are selected from the group consisting of carbon (C), oxygen (O), nitrogen (N) and sulfur (S);

Y is selected from the group consisting of Ci_ioalkyl, C₃_i₂cycloalkyl, heteroC₃_i₂cycloalkyl, arylCi_ioalkyl, heteroarylCi_salkyl, C9-i₂bicycloaryl, heteroC₄-i₂bicycloaryl, C(0)Ci_₃alkyl, C(S)Ci_₃alkyl, S(0)_mCi_₃alkyl, iminoCi_₃alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, cyano, imino group, sulfonyl group and sulfmyl group, and each substituted or unsubstituted;

wherin

R₅ is selected from the group consisting of a bond, C₂_₆alkene, C₂_₆alkyne, -C(O)-, and - C(0)-(CH₂)i_4-, wherein the aliphatic portions of R₅ are optionally substituted with one to three members selected from halogen, Ci_₄alkyl, Ci_₄substituted alkyl and Ci_₄haloalkyl; and wherein m is 1 or 2;

Re is selected from the group consisting of a bond, C₂_₆alkene, C₂_₆alkyne, -C(O)-, and - C(0)-(CH₂)i_4-, wherein the aliphatic portions of Re are optionally substituted with one to three members selected from halogen, Ci_₄alkyl, Ci_₄substituted alkyl and Ci_₄haloalkyl; and wherein m is 1 or 2.

Substituent Ri

In regard to each of the above embodiments and variations, the present invention provides compounds wherein R₃ is selected from the group consisting of amino, Ci_ioalkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, each substituted or unsubstituted, and a substituted or unsubstituted 3-7 membered ring.

Further, according to each of the above embodiments and variations, the present invention also provides compounds wherein R₃ compr the Formula (II),

Formula II

wherein R₇ and R₈ are each independently selected from the group consisting of hydrogen, perhalo(Ci_io)alkyl, amino, (Ci_io)alkyl, (C₃_i₂)cycloalkyl, hetero(C₃_i₂)cycloalkyl, aryl(Ci_ io)alkyl, heteroaryl(Ci_s)alkyl, (C9_i₂)bicycloaryl, hetero(C4_i₂)bicycloaryl, carbonyl(Ci_₃)alkyl, thiocarbonyl(Ci_₃)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfmyl group, and each substituted or unsubstituted thereof, or R₇ and R₈ are taken together to form a 4-7 membered ring, and each substituted or unsubstituted.

According to another variation of each of the above embodiments and variations, R₃ is a substituted or unsubstituted 3-7 membered ring selected from a group consisting of a substituted or unsubstituted 3-7 membered cycloalkyl, or a substituted or unsubstituted 3-7 membered heterocycloalkyl. In another variation of the above, R₃ is selected from a group consisting of a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

In one particular variation of the above embodiments and variations, R₃ is selected from the group consisting of

wherein p is any integer selected from 0-12, and each Rg is independently selected from the group consisting of halo, perhalo(Ci_io)alkyl, cyano, nitro, hydroxy, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imino group, sulfonyl group, sulfmyl group, and each substituted or unsubstituted.

According to each of the above embodiments and variations, compounds of Formula (I) in the present invention may comprise compounds wherein R₃ is a substituted or unsubstituted heteroaryl selected from the group consisting of furan, thiophene, pyrrole, pyrazole, triazole, isoxazole, oxazole, thiazole, isothiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, imidazole, benzimidazole, indole, isoindole, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyridopyridine, quinoxaline, phthalazine, benzothiazole, and each substituted or unsubstituted.

Further, according to the above embodiments and variations, R₃ may be selected from the group consisting of (C₃_i2)cycloalkyl, hetero(C₃_i2)cycloalkyl, aryl(Ci_io)alkyl, heteroaryl (Ci_ ₅)alkyl, (Cc>-i2)bicycloaryl, and hetero(C4-i2)bicycloaryl, each substituted or unsubstituted. In another variation, R₃ is a substituted or unsubstituted (C₃_₇)cycloalkyl ring, optionally comprising O, N(O), N, S, SO, S0₂ or a carbonyl group in the ring.

According to each of the above embodiments and variations, R₃ may also be substituted such that R₃ comprises a substituent selected from the group consisting of a primary, secondary or tertiary amine, a heterocycloalkyl comprising a nitrogen ring atom, and a heteroaryl comprising a nitrogen ring atom.

In particular variations of the present invention, R₃ comprises a basic nitrogen (N) atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein. In one variation, the basic nitrogen of R₃ is separated from the ring atom to which R₃ is attached by between 1-5 atoms. In another variation, the basic nitrogen atom forms part of a primary, secondary or tertiary amine. In yet another variation, the basic nitrogen atom is a nitrogen ring atom of a heterocycloalkyl or a heteroaryl.

Substituent L

In one variation of the above embodiment, the present invention comprises compounds wherein the 1, 2 or 3 atoms of L providing the separation consist of carbon atoms. In another variation, the 1 , 2 or 3 atoms of L providing the separation are selected from the group of linkers consisting of at least one oxygen or at least one nitrogen atom. In yet another variation, L separates Y from the ring atom by one atom selected from C, O, N, or S.

In one particular variation of the above embodiments, L is selected from the group consisting of -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, -C(O)-, -CH₂C(0)-, -C(0)CH₂-, -CH₂-C(0)CH₂-, -C(0)CH₂CH₂-, -CH₂CH₂C(0)-, -0-, -OCH₂-, -CH₂0-, -CH₂OCH₂-, -OCH₂CH₂-, -CH₂CH₂0-, - N(CH₃)-, -NHCH₂-, -CH₂NH-, -CH₂NHCH₂-, -NHCH₂CH₂-, -CH₂CH₂NH-, -NH-C(O)-, -NCH₃- C(O)-, -C(0)NH-, -C(0)NCH₃-, -NHC(0)CH₂-, -C(0)NHCH₂-, -C(0)CH₂NH-, -CH₂NHC(0)-, -CH₂C(0)NH-, -NHCH₂C(0)-, -S-, -SCH₂-, -CH₂S-, -SCH₂CH₂-, -CH₂SCH₂-, -CH₂CH₂S-, - C(0)S-, -C(0)SCH₂-, -CH₂C(0)S-, -C(0)CH₂S-, -CH₂SC(0)-, and each substituted or unsubstituted;

In another particular variation of the above embodiments, L is selected from the group consisting of -CH₂-, -C(O)-, -CH₂C(0)-, -C(0)CH₂-, -CH₂-C(0)CH₂-, -C(0)CH₂CH₂-, - CH₂CH₂C(0)-, and each substituted or unsubstituted.

Substituent Y

In regard to particular variations of the present invention, there is provided compounds wherein Y is selected from a substituted or unsubstituted (C₃_7)cycloalkyl, a substituted or unsubstituted (C₃_7)hetero-cycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. Further, according to each of the above variations, the invention provides compounds wherein X is a substituted or unsubstituted phenyl. In another variation according to the above variation, Y is a ring having a non-hydrogen substituent at a 2 or 3 position of the ring. According to the above variations, there is provided compounds wherein Y is a ring having a non-hydrogen substituent at a 2 or 3 position of the ring selected from the group consisting of (Ci_i₀)alkyl, (C₃_i₂)cycloalkyl, hetero(C₃_i₂)cycloalkyl, aryl(Ci_i₀)alkyl, heteroaryl(Ci_5)alkyl, (C9-i₂)bicycloaryl, hetero(C4_i₂)bicycloaryl, carbonyl(Ci_₃)alkyl, thiocarbonyl(Ci_₃)alkyl, S(0)_m(Ci_₃)alkyl, imino(Ci_₃)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, cyano, nitro, halo, imino group, sulfonyl group, sulfmyl group, and each substituted or unsubstituted and m is 1 or 2. In another variation, Y is selected from the group consisting of a substituted or unsubstituted haloaryl, haloheteroaryl, dihaloaryl or dihaloheteroaryl. In yet another variation of the above, Y is a substituted or unsubstituted halophenyl or dihalophenyl.

In one particular variation of the above embodiments, -L-Y taken together is selected from the group consisting of -(CH₂)-(2-cyano)phenyl, -(CH₂)-(3-cyano)phenyl, -(CH₂)-(2-hydroxy)- phenyl, -(CH₂)-(3 -hydroxy )phenyl, -(CH₂)-(2-alkenyl)phenyl, -(CH₂)- (3-alkenyl)-phenyl, - (CH₂)-(2-alkynyl)phenyl, -(CH₂)-(3-alkynyl)phenyl, -(CH₂)-(2- methoxy)-phenyl, -(CH₂)-(3- methoxy)phenyl, -(CH₂)-(2-nitro)phenyl, -(CH₂)-(3- nitro)phenyl, -(CH₂)-(2-carboxy)-phenyl, - (CH₂)-(3-carboxy)phenyl, -(CH₂)-(2-carboxamido)phenyl, -(CH₂)-(3-carboxamido)-phenyl, - (CH₂)-(2-sulfonamido)phenyl, -(CH₂)-(3-sulfonamido)phenyl, -(CH₂)-(2-tetrazolyl)-phenyl, - (CH₂)-(3-tetrazolyl)phenyl, -(CH₂)-(2-aminomethyl)phenyl, -(CH₂)-(3-aminomethyl)-phenyl, - (CH₂)-(2-hydroxymethyl)phenyl, -(CH₂)-(3-hydroxymethyl)phenyl, -(CH₂)-(2-phenyl)-phenyl, - (CH₂)-(3-phenyl)phenyl, -(CH₂)-(2-halo)phenyl, -(CH₂)-(3-halo)phenyl, -(CH₂)-(2- CONH₂)phenyl, -(CH₂)-(3-CONH₂)phenyl, -(CH₂)-(2-CONH(Ci_₇)alkyl)phenyl, -(CH₂)-(3- CONH(Ci_₇)alkyl)phenyl, -(CH₂)-(2-C0₂(Ci_₇)alkyl)phenyl, -(CH₂)-(3-C0₂(Ci_₇)alkyl)phenyl, - (CH₂)-(2-NH₂)phenyl, -(CH₂)-(3-NH₂)phenyl, -(CH₂)- (2-(C₃_₇)alkyl)phenyl, -(CH₂)-(3-(C₃_ ₇)alkyl)phenyl, -(CH₂)-(2-(C₃_₇)cycloalkyl)phenyl, -(CH₂)-(3-(C₃_₇)cycloalkyl)phenyl, -(CH₂)-(2- aryl)phenyl, -(CH₂)-(3-aryl)phenyl, -(CH₂)-(2-heteroaryl)phenyl, -(CH₂)-(3-heteroaryl)phenyl, - (CH₂)-2-bromo-5-fluoro phenyl, -(CH₂)-2-chloro-5-fluoro phenyl, -(CH₂)-2-cyano-5-fluoro phenyl, -(CH₂)-2,5-dichloro phenyl, -(CH₂)-2,5-difluoro phenyl, -(CH₂)-2,5-dibromo phenyl, - (CH₂)-2-bromo-3,5-difluoro phenyl, -(CH₂)-2-chloro-3,5-difiuoro phenyl, -(CH₂)-2,3,5-trifluoro phenyl, -(CH₂)-2,3,5,6-tetrafluorophenyl, -(CH₂)-2-bromo-3,5,6-trifiuoro phenyl, -(CH₂)-2- chloro-3,5,6-trifluoro phenyl, -(CH₂)-2-cyano-3,5-difluoro phenyl, -(CH₂)-2-cyano-3,5,6- trifluoro phenyl, -(CH₂)-(2-heterocycloalkyl)phenyl, -(CH₂)-(3-heterocycloalkyl)-phenyl, and each substituted or unsubstituted.

The molecular weight of the compounds of the invention is preferably less than 800, more preferably less than 600, especially less than 500.

The flowing compounds of the invention are provided to give the reader an understanding of the compounds encompassed by the invention:

3 -(6-(3 - Amino-piperidin- 1 -yl)-3 - {3 - [ 1 -(3 -isopropyl- [ 1 ,2,4]oxadiazol-5 -yl)-piperidin-4-yl] - propyl} -2, 4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl)-benzonitrile;

3 -(6-(3 - Amino-piperidin- 1 -yl)-3 - {3 - [ 1 -(3 -isopropyl- [ 1 ,2,4]oxadiazol-5 -yl)-piperidin-4-yl] - butyl} -2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl)-benzonitrile;

4-{3-[4-(3-Amino-piperidin-l-yl)-3-(3-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin- l-yl]-propyl}-piperidine-l-carboxylic acid tert-butyl ester;

4-{3-[4-(3-Amino-piperidin-l-yl)-3-(3-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin- l-yl]-propyl}-piperidine-l-carboxylic acid isopropyl ester;

3-{6-(3-Amino-piperidin-l-yl)-2,4-dioxo-3-[3-(3,4,5,6-tetrahydro-2H-[l ,3']bipyridinyl-4- yl)-propyl]-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl} -benzonitrile;

3-{6-(3-Amino-piperidin-l-yl)-2,4-dioxo-3-[3-(3,4,5,6-tetrahydro-2H-[l ,4']bipyridinyl-4- yl)-propyl]-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl} -benzonitrile;

3 -(6-(3 -Amino-piperidin- 1 -yl)-3- {3-[ 1 -(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-propyl} - 2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl)-benzonitrile; 3-(6-(3-Amino-piperidin- 1 -yl)-3- {3-[l -(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-propyl} - 2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl)-benzonitrile;

3 -(6-(3 - Amino-piperidin- 1 -yl)-3 - {3 - [ 1 -(5 -isopropyl-pyrimidin-2-yl)-piperidin-4-yl] - propyl} -2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl)-benzonitrile;

3-(6-(3-Amino-piperidin-l-yl)-3-{3-[l-(5-methoxy-pyrimidin-2-yl)-piperidin-4-yl]- propyl} -2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl)-benzonitrile.

Examples of alkyl groups include ethyl, propyl, isopropyl, butyl, sec- and tert-butyl.

The term "heteroaryl" rings means 5- or 6-membered N-containing heteroaryl rings containing up to 2 additional heteroatoms selected from N, O and S. Examples of such heteroaryl rings are pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

Compounds described herein may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The present invention includes all stereoisomers of the compounds of the invention and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

When a tautomer of the compound of the invention exists, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically drawn or stated otherwise.

When the compound of the invention and pharmaceutically acceptable salts thereof exist in the form of solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. A type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include arginine, betaine, caffeine, choline, Ν',Ν'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

When the compound of the invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.

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

In the preparation of compounds of the present invention, protection of remote functionality of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. A "hydroxy- protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxyl-protecting groups (O-Pg) include for example, allyl, acetyl (Ac), silyl (like thmethylsily (TMS) or tert-butyldimethylsilyl (TBS)), benzyl (Bn), para- methoxybenzyl (PMB), trityl (Tr), para-bromobenzoyl, para-nitrobenzoyl and the like (benzylidene for protection of 1,3-diols). The need for such protection is readily determined by one skilled in the art. The compounds of the present invention can be produced by one or more of the following general reaction schemes.

Synthesis

Pyrimidinone (1) is commercial available or been prepared by conventional methods known by those skilled in the art. In step 1 of Scheme 1, the treatment of 1 with strong base such as sodium hydride in mixture solvent of DMSO and THF and followed by the addition of intermediates (2) gave Compounds of Formula (3). The R_ls R₂ and X groups has been defined above.

In step 2 of Scheme 1 , 3-aminopiperidine groups can be introduced by treating the intermediate 3 from step 1 with the appropriate reagents and procedures. For example, potassium carbonate as base and THF as solvent.

Building blocks for Compounds of Formula (2a), where R₂ is methyl (Me) and X is a bond, can be readily prepared from known compounds (Scheme 2). For example, the ethyl ester of Compounds (6) where PG is terf-butoxy carbonyl (Boc) has been previously reported (US6,518,423). Saponification and hydrogenation, under standard conditions, will yield the racemic Compounds of Formula (7). Chiral reduction of the alkenoic acid (6) under suitable conditions, such as a hydrogenation in the presence of a chiral catalyst, yields Compounds of Formula (7) in high enantiomeric excess. An example of a suitable catalyst is [Rh(norbornadiene)₂]BF₄ and (5^,)-I-[(R)-2-(di-ferf-butylphosphino)ferrocenyl]ethylbis(2- methylphenyl)phosphine. Compounds of Formula (2) can then be obtained by reduction of the carboxylic acids of Formula (7) under standard conditions, for example borane in a suitable solvent such as THF.

General Scheme 1.

General Scheme 2

Building blocks of Formula (2) where Ri is a substituted oxadiazole and R₂=H is a known compound (Siegel, M. G. et al. Tetrahedron. 1999, 55, 11619-11639). Compounds of Formula (II) where Ri is a 5-6 membered heteroaryl may also be prepared by condensation of amine (X) with a 5-6 membered heteroaryl halide of Formula (XV), as reported in literature (Buscemi, S. et al. JCS Perkin I: Org. and Bioorg. Chem., 1988, 1313; Adembri, G, et al. JCS Perkin I: Org. and Bioorg. Chem., 1981, 1703).

Other compounds of Formula (I) may be prepared by methods analogous to those described above or by methods known per se. Further details for the preparation of the compounds of Formula (I) are found in the examples.

The compounds of Formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000, compounds and more preferably 10 to 100 compounds of Formula (I). Compound libraries may be prepared by a combinatorial "split and mix" approach or by multiple parallel synthesis using either solution or solid phase chemistry, using procedures known to those skilled in the art.

During the synthesis of the Compounds of Formula (I), labile functional groups in the intermediate compounds, e.g. hydroxy, carboxy and amino groups, may be protected. The protecting groups may be removed at any stage in the synthesis of the compounds of Formula (I) or may be present on the final compound of Formula (I). A comprehensive discussion of the ways in which various labile functional groups may be protected and methods for cleaving the resulting protected derivatives is given in, for example, Protective Groups in Organic Chemistry, T.W. Greene and P.G.M. Wuts, (1991) Wiley-Inter science, New York, 2^nd edition.

The processes for the production of the Compounds of Formula (I) and intermediates thereto as described above are also included as further aspects of the present invention.

Any novel intermediates as defined in the Schemes above or in the Examples, are also included within the scope of the invention. Therefore according to a further aspect of the invention there is provided a compound of any one of Formulae (3), (5), (6), (7), (8), or (2a) as defined above. The preferred groups for variables recited above in relation to the compounds of Formula (I) also apply to the intermediates compounds.

As indicated above the compounds of the invention are useful as dual GPR119 agonists/DPP-IV inhibitors, e.g. for the treatment and/or prophylaxis of diabetes. For such use the compounds of the invention will generally be administered in the form of a pharmaceutical composition.

The invention also provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

The invention also provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient. The term "pharmaceutically acceptable excipient" refers to any of a diluent, adjuvant, excipient or carrier with which at least one compound of the present disclosure is administered..

Preferably the composition is comprised of a non-toxic therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Moreover, the invention also provides a pharmaceutical composition for the treatment of disease by modulating GPR119 and DPP-IV, resulting in the prophylactic or therapeutic treatment of diabetes, comprising a non-toxic therapeutically effective amount of compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

The pharmaceutical compositions may optionally comprise other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

In practice, the compounds of the invention, or pharmaceutically acceptable salts thereof, can be combined as the active ingredient in intimate admixture with a pharmaceutical excipient, according to conventional pharmaceutical compounding techniques. The excipients may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous).

Thus, the pharmaceutical compositions can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound of the invention, or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the excipient that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid excipients or finely divided solid excipients or both. The product can then be conveniently shaped into the desired presentation.

The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

The pharmaceutical excipients employed can be, for example, a solid, liquid, or gas.

Examples of solid excipients include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid excipients are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous excipients include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while excipients such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical excipients are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.

A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free -flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.

For example, a formulation intended for the oral administration to humans may contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of excipient material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The excipient can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These Formulations may be prepared, using a compound of the invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the excipient is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable excipients include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted excipient(s) followed by chilling and shaping in molds.

In addition to the aforementioned excipient ingredients, the pharmaceutical Formulations described above may include, as appropriate, one or more additional excipient ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the Formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.

Generally, dosage levels on the order of O.Olmg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above -indicated conditions, or alternatively about 0.5mg to about 7g per patient per day. For example, obesity may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.

It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

The compounds of the invention may be used in the treatment of diseases or conditions in which GPR1 19 and DPP-IV play a role. Thus the invention also provides a method for the treatment of a disease or condition in which GPR119 and DPP-IV play a role comprising a step of administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. Such diseases or conditions diabetes, obesity, impaired glucose tolerance, insulin resistance and diabetic complications such as neuropathy, nephropathy, retinopathy, cataracts, cardiovascular complications and dyslipidaemia. And the treatment of patients who have an abnormal sensitivity to ingested fats leading to functional dyspepsia. The compounds of the invention may also be used for treating metabolic diseases such as metabolic syndrome (syndrome X), impaired glucose tolerance, hyper lipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels and hypertension.

The invention also provides a method for the treatment of type II diabetes, comprising a step of administering to a patient in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

The invention also provides a method for the treatment of obesity, metabolic syndrome (syndrome X), impaired glucose tolerance, hyper lipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels or hypertension comprising a step of administering to a patient in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition as defined above.

The invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition as defined above.

In the methods of the invention the term "treatment" includes both therapeutic and prophylactic treatment.

The compounds of the invention may exhibit advantageous properties compared to known compounds or combination therapies for the treatment of diabetes.

The compounds of the invention, or pharmaceutically acceptable salts thereof, may be administered alone or in combination with one or more other therapeutically active compounds. The other therapeutically active compounds may be for the treatment of the same disease or condition as the compounds of the invention or a different disease or condition. The therapeutically active compounds may be administered simultaneously, sequentially or separately. The compounds of the invention may be administered with other active compounds for the treatment of obesity and/or diabetes, for example insulin and insulin analogs, gastric lipase inhibitors, pancreatic lipase inhibitors, sulfonyl ureas and analogs, biguanides, a2 agonists, glitazones, PPAR-γ agonists, mixed PPAR-α/γ agonists, RXR agonists, fatty acid oxidation inhibitors, a-glucosidase inhibitors, β-agonists, phosphodiesterase inhibitors, lipid lowering agents, glycogen phosphorylase inhibitors, antiobesity agents e.g. pancreatic lipase inhibitors, MCH-I antagonists and CB-I antagonists (or inverse agonists), amylin antagonists, lipoxygenase inhibitors, somostatin analogs, glucokinase activators, glucagon antagonists, insulin signalling agonists, PTP1B inhibitors, gluconeogenesis inhibitors, antilypolitic agents, GSK inhibitors, galanin receptor agonists, anorectic agents, CCK receptor agonists, leptin, serotonergic/dopaminergic antiobesity drugs, reuptake inhibitors e.g. sibutramine, CRF antagonists, CRF binding proteins, thyromimetic compounds, aldose reductase inhibitors, glucocorticoid receptor antagonists, NHE-I inhibitors or sorbitol dehydrogenase inhibitors.

Combination therapy comprising the administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one other agent represents a further aspect of the invention.

The present invention also provides a method for the treatment of diabetes in a mammal, such as a human, which method comprises administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another agent, to a mammal in need thereof.

The invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another agent for the treatment of diabetes.

The invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in combination with another agent, for the treatment of diabetes.

The compound of the invention, or a pharmaceutically acceptable salt thereof, and the other agent(s) may be co-administered or administered sequentially or separately.

Co-administration includes administration of a Formulation which includes both the compound of the invention, or a pharmaceutically acceptable salt thereof, and the other agent(s), or the simultaneous or separate administration of different Formulations of each agent. Where the pharmacological profiles of the compound of the invention, or a pharmaceutically acceptable salt thereof, and the other agent(s) allow it, co-administration of the two agents may be preferred. The invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another agent in the manufacture of a medicament for the treatment of diabetes.

The invention also provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and another anti-obesity agent, and a pharmaceutically acceptable excipient. The invention also encompasses the use of such compositions in the methods described above.

All publications, including, but not limited to, patents and patent application cited in this specification, are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as fully set forth.

Embodiments of the present invention are illustrated by the following Examples. It is to be understood, however, that the embodiments of the invention are not limited to the specific details of these Examples, as other variations thereof will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art.

All temperatures are expressed in degrees Centigrade unless otherwise indicated.

Modes for Carrying out the Invention

EXAMPLES

Example 1

Synthesis of 3-(6-(3R-3-Amino-piperidin-l-yl)-3-{3-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-yl]-propyl}-2 -dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-benzonitrile

Step 1. Synthesis of 3-(6-Chloro-3-{3-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4- yl]-propyl}-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-benzonitrile 3a

To a cold (0^°C) solution of 3-(6-Chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l- ylmethyl)-benzonitrile 1 (lOg, 38mmol) in DMF-THF (1 : 1, 300mL) under nitrogen, was added NaH (60%, 1.6g, 39.9mmol) in portions, followed by adding LiBr (2g). The mixture was stiffed at R.T. for 20min. After adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester (8.8mL, 76mmol), the flask was sealed and stirred at this temperature for lOmin, R.T. for 2h, and 35 ^°C overnight, and then concentrated in vacuo. It will be understood that alkylation of the amine may be performed under standard conditions known in the art, including the use of a base such as NaH, LiH or the like in an organic solvent or mixture of solvents. The solvent may include DMSO, THF, DMF and the like, or mixtures thereof. In addition, additives may be used, including LiBr, Lil, Nal and the like. For example, the alkylation can be performed using methyliodide and K₂CO₃ in acetone. The reaction may be performed at about 15-45 ^°C , preferably at about 20-43 ^°C , and more preferably at about 35-41 ^°C until the reaction is complete. The residue was dissolved in CHCI₃ and washed with water and brine, dried (Na₂S0₄), and filtered then concentrated in vacuo. The crude product was crystallized from THF-Hexanes to give 7.6g (72%) of the title Compound 3a. It will also be understood by those skilled in the art that the benzonitrile may be purified in a variety of organic solvents or solvent mixtures. For example, the benzonitrile can be purified by adding a mixture of dichloromethane and heptane. Optionally, the benzonitrile may be further purified in an organic solvent or mixture of solvents such as dichloromethane, chloroform, acetonitrile, THF, ethyl acetate, isopropyl acetate and the like. Preferably, the product is purified and washed with ethyl acetate. 1H NMR (400 MHz, DMSO): δ 7.87 (d, IH, J=7.6 Hz), 7.70 (t, 1H, J=7.6 Hz), 7.51 (t, 1H, J=7.6 Hz), 7.40 (d, IH, J=8 Hz), 6.21 (s, 1H), 5.38 (s, 2H), 3.28 (s, 3H). MS (ES) (M+H)⁺ calc'd for C₂₅H₂₉CIN₆O₃, 497.9892; found 497.9801.

Step 2. 3-(6-(3R-3-Amino-piperidin-l-yl)-3-{3-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-yl]-propyl}-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-benzonitrile

3-(6-Chloro-3-{3-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-propyl}-2,4-dioxo- 3,4-dihydro-2H-pyrimidin-l-ylmethyl)-benzonitrile 3a (330mg, 1.08mmol), (3R)-3-amino- piperidine dihydrochloride (246mg, 1.4mmol) and sodium bicarbonate (500mg, 5.4mmol) were stirred with 200 mg activated molecular sieves (4A) in dry MeOH (5mL) at 100^°C for 2h. The reaction was filtered through Celite, concentrated in vacuo, and then diluted with CHCI₃, and washed with water. The water phase was extracted with CHCI₃ and the combined organic phases were washed with water, dried (Na₂S0₄), and filtered. TFA (lmL) was added into the solution which was then concentrated in vacuo. The residue was dissolved in a small amount of MeOH, and Et₂0 was added to force precipitation. The mixture was allowed to stand at RT overnight. It will be understood by those skilled in the art that condensation with the amine or amine hydrochloride may be performed in a solvent or mixture of solvents with a base, such as potassium carbonate, sodium bicarbonate and the like, or mixtures thereof. The solvent may comprise both protic and aprotic solvents, or mixtures thereof. For example, the solvent may comprise a mixture of isopropyl alcohol and water. Further, the reaction may be heated to about 30-100^°C , preferably about 35-55 ^°C , and more preferably about 45-50 ^°C until the reaction is complete. Solvents were decanted, and the solid was washed with Et₂0 two times to give 270mg product as off-white powder. It will also be understood that the product may be further purified by washing with an organic solvent or mixture of solvents. Non- limiting examples of solvent or solvent mixtures include isopropyl acetate, ethyl acetate, dichloromethane, heptane, and the like. Further, the product may optionally be purified by column chromatography. The benzonitrile product may be isolated as the free base if desired, but preferably, the product may be further converted to the corresponding acid addition salt, such as the benzoic acid salt. Preferably, the benzonitrile product is treated with benzoic acid to form 3-(6-(3R-3-Amino-piperidin-l-yl)-3-{3- [l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-propyl}-2,4-dioxo-3,4-dihydro-2H- pyrimidin-l-ylmethyl)-benzonitrile (5a) benzoate. Preparation and isolation of the benzoate salt may be performed by conventional methods for the formation of acid addition salts. ¹H-NMR (400 MHz, CDCI₃-CD₃OD 10: 1): δ 7.82 (d, 1H, J=7.6 Hz), 7.65 (t, 1H, J=7.6 Hz), 7.46 (t, 1H, J=7.6 Hz), 7.23 (d, 1H, J=8.0 Hz), 5.42 (s, 1H), 5.50-5.00 (ABq, 2H, J=41.6, 15.2 Hz), 3.30 (m, 2H), 3.16 (s, 3H), 2.91 (m, 1H), 2.76 (m, 2H), 1.93 (m, 1H), 1.79 (m, 1H), 1.51 (m, 2H). MS (ES) (M+H)⁺ calc'd for C₃₀H₄₀N₈O₃ 561.6904; found 561.6933.

Example 2

Synthesis of 3-(6-(3R-3-Amino-piperidin-l-yl)-3-{3-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-yl]-butyl}-2, -dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-benzonitrile

The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C₃iH₄₂N₈0₃ (MH+) 575.7170, found 575.9007.

Example 3

Synthesis of 4-{3-[4-(3-Amino-piperidin-l-yl)-3-(3-cyano-benzyl)-2,6-dioxo-3,6-dihydro- 2H-pyrimidin-l-yl]-propyl}-piperidine-l-carboxylic acid tert-butyl ester

The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C30H42N6O4 (M+H)⁺ 551.6923, found 551.6907.

Example 4

Synthesis of 4-{3-[4-(3-Amino-piperidin-l-yl)-3-(3-cyano-benzyl)-2,6-dioxo-3,6-dihydro- 2H-pyrimidin-l-yl]-propy -piperidine-l-carboxylic acid isopropyl ester

The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C2 H40N6O4 (M+H)⁺ 537.6657, found 537.6667.

Example 5

Synthesis of 3-{6-(3-Amino-piperidin-l-yl)-2,4-dioxo-3-[3-(3,4,5,6-tetrahydro-2H-[l,3'] bipyridinyl-4-yl)-propyl]-3 -dihydro-2H-pyrimidin-l-ylmethyl}-benzonitrile

The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C30H37N7O2 (M+H)⁺ 528.6605, found 528.6627.

Example 6

Synthesis of 3-{6-(3-Amino-piperidin-l-yl)-2,4-dioxo-3-[3-(3,4,5,6-tetrahydro-2H-[l,4'] bipyridinyl-4-yl)-propyl]- -dihydro-2H-pyrimidin-l-ylmethyl}-benzonitrile

The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C30H37N7O2 (M+H)⁺ 528.6605, found 528.6627 .

Example 7

Synthesis of 3-(6-(3-Amino-piperidin- 1 -yl)-3- {3-[ 1 -(5-methyl-pyrimidin-2-yl)-piperidin-4- yl]-propyl} -2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl)-benzonitrile

The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C30H38N8O2 (M+H)⁺ 543.6751, found 543.6747.

Example 8

Synthesis of 3-(6-(3-Amino-piperidin- 1 -yl)-3- {3-[ 1 -(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl] -propyl} -2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl)-benzonitrile

The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C31H40N8O2 (M+H)⁺ 558.7017, found 558.7037.

Example 9

Synthesis of 3-(6-(3-Amino-piperidin-l-yl)-3-{3-[l-(5-isopropyl-pyrimidin-2-yl)-piperidin- 4-yl]-propyl}-2,4-dioxo- -dihydro-2H-pyrimidin-l-ylmethyl)-benzonitrile

The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C32H42N8O2 (M+H)⁺ 571.7283, found 571.7289.

Example 10

Synthesis of 3-(6-(3-Amino-piperidin-l-yl)-3-{3-[l-(5-methoxy-pyrimidin-2-yl)-piperidin- 4-yl]-propyl}-2,4-dioxo- -dihydro-2H-pyrimidin-l-ylmethyl)-benzonitrile

The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and adding methanesulfonic acid 3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-propyl ester used instead of adding methanesulfonic acid 3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-propyl ester calcd for C₃oH3₈N₈0₃ (MH+) 559.6745, found 559.6759.

The biological activity of the compounds of the invention may be tested in the following assay systems:

GPR119 Yeast Reporter Assay Yeast Reporter Assay

The yeast cell-based reporter assays have previously been described in the literature (e.g. see Miret J. J. et al, 2002, J. Biol. Chem., 277:6881-6887; Campbell R.M. et al, 1999, Bioorg. Med. Chem. Lett., 9:2413-2418; King K. et al, 1990, Science, 250: 121-123); W099/14344; WOOO/12704; and US6,100,042). Briefly, yeast cells have been engineered such that the endogenous yeast G-alpha (GPA1) has been deleted and replaced with G-protein chimeras constructed using multiple techniques. Additionally, the endogenous yeast GPCR, Ste3 has been deleted to allow for heterologous expression of a mammalian GPCR of choice. In the yeast, elements of the pheromone signaling transduction pathway, which are conserved in eukaryotic cells (for example, the mitogen-activated protein kinase pathway), drive the expression of Fusl. By placing β-galactosidase (LacZ) under the control of the Fusl promoter (Fuslp), a system has been developed whereby receptor activation leads to an enzymatic readout.

Yeast cells were transformed by an adaptation of the lithium acetate method described by Agatep et al, (Agatep, R. et al, 1998, Transformation of Saccharomyces cerevisiae by the lithium acetate/single-stranded carrier DNA/polyethylene glycol (LiAc/ss-DNA/PEG) protocol. Technical Tips Online, Trends Journals, Elsevier). Briefly, yeast cells were grown overnight on yeast tryptone plates (YT). Carrier single-stranded DNA (10μg), 2μg of each of two Fuslp-LacZ reporter plasmids (one with URA selection marker and one with TRP), 2μg of GPR119 (human or mouse receptor) in yeast expression vector (2μg origin of replication) and a lithium acetate/ polyethylene glycol/TE buffer was pipetted into an Eppendorf tube. The yeast expression plasmid containing the receptor/ no receptor control has a LEU marker. Yeast cells were inoculated into this mixture and the reaction proceeds at 30^°C for 60min. The yeast cells were then heat-shocked at 42 ^°C for 15min. The cells were then washed and spread on selection plates. The selection plates are synthetic defined yeast media minus LEU, URA and TRP (SD-LUT). After incubating at 30^°C for 2-3 days, colonies that grow on the selection plates were then tested in the LacZ assay.

In order to perform fluorimetric enzyme assays for β-galactosidase, yeast cells carrying the human or mouse GPR119 receptor were grown overnight in liquid SD-LUT medium to an unsaturated concentration (i.e. the cells were still dividing and had not yet reached stationary phase). They were diluted in fresh medium to an optimal assay concentration and 90μί of yeast cells added to 96-well black polystyrene plates (Costar). Compounds, dissolved in DMSO and diluted in a 10%DMSO solution to 10X concentration, were added to the plates and the plates placed at 30 ^°C for 4h. After 4h, the substrate for the β-galactosidase was added to each well. In these experiments, Fluorescein di (β-D-galactopyranoside) was used (FDG), a substrate for the enzyme that releases fluorescein, allowing a fluorimetric read-out. 20μί per well of 500μΜ FDG/2.5% Triton XIOO was added (the detergent was necessary to render the cells permeable). After incubation of the cells with the substrate for 60min, 20μΙ_^ per well of IM sodium carbonate was added to terminate the reaction and enhance the fluorescent signal. The plates were then read in a fluorimeter at 485/535 nm.

The compounds of the invention give an increase in fluorescent signal of at least 1.5-fold that of the background signal (i.e. the signal obtained in the presence of 1%DMS0 without compound). Compounds of the invention which give an increase of at least 5-fold may be preferred.

cAMP Assay

A stable cell line expressing recombinant human GPR119 was established and this cell line was used to investigate the effect of compounds of the invention on intracellular levels of cyclic AMP (cAMP). The cell monolayers were washed with phosphate buffered saline and stimulated at 37^°C for 30min with various concentrations of compound in stimulation buffer plus 1% DMSO. Cells were then lysed and cAMP content determined using the Perkin Elmer AlphaScreen™ (Amplified Luminescent Proximity Homogeneous Assay) cAMP kit. Buffers and assay conditions were as described in the manufacturer's protocol.

Compounds of the invention produced a concentration-dependent increase in intracellular cAMP level and generally had an EC50 of <10μΜ. Compounds showing and EC50 of less than 1 μΜ in the cAMP assay may be preferred.

DPP-IV Assay Method

DPP-IV activity was measured by monitoring the cleavage of the fluorogenic peptide substrate, H-Gly-Pro-7-amino-4-methylcoumarin (GP-AMC) whereby the product 7-amino-4- methylcoumarin is quantified by fluorescence at excitation 380nm and emission 460nm. Assays were carried out in 96-well plates (Black OptiPlate-96F) in a total volume of ΙΟΟμί per well consisting of 50mM Tris pH7.6, ΙΟΟμΜ GP-AMC, 10-25μΙΙ recombinant human DPP- IV and a range of inhibitor dilutions in a final concentration of l%DMSO. Plates were read in a fluorimeter after 30min incubation at 37^°C . Recombinant human DPP-IV residues Asn29-Pro766 was purchased from BioMol. Compounds of the invention generally had a Ki of <10μΜ.

Anti-diabetic effects of compounds of the invention in an in-vitro model of pancreatic beta cells (HIT-T15)

Cell Culture

HIT-T15 cells (passage 60) were obtained from ATCC, and were cultured in RPMI1640 medium supplemented with 10% fetal calf serum and 30nM sodium selenite. All experiments were done with cells at less than passage 70, in accordance with the literature, which describes altered properties of this cell line at passage numbers above 81 (Zhang HJ, Walseth TF, Robertson RP. Insulin secretion and cAMP metabolism in HIT cells. Reciprocal and serial passage-dependent relationships. Diabetes. 1989 Jan; 38(l):44-8).

cAMP assay

HIT-T 15 cells were plated in standard culture medium in 96-well plates at 100,000 cells/ O.lmL/well and cultured for 24h and the medium was then discarded. Cells were incubated for 15min at room temperature with ΙΟΟμί stimulation buffer (Hanks buffered salt solution, 5mM HEPES, 0.5mM IBMX, 0.1%BSA, pH7.4). This was discarded and replaced with compound dilutions over the range 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30μΜ in stimulation buffer in the presence of 0.5%DMSO. Cells were incubated at room temperature for 30min. Then 75uL lysis buffer (5mM HEPES, 0.3%Tween-20, 0.1%BSA, pH7.4) was added per well and the plate was shaken at 900rpm for 20min. Particulate matter was removed by centrifugation at 3000rpm for 5min, then the samples were transferred in duplicate to 384-well plates, and processed following the Perkin Elmer AlphaScreen cAMP assay kit instructions. Briefly

reactions were set up containing 8μί sample, 5μΙ, acceptor bead mix and 12μΕ detection mix, such that the concentration of the final reaction components is the same as stated in the kit instructions. Reactions were incubated at room temperature for 150min, and the plate was read using a Packard Fusion instrument. Measurements for cAMP were compared to a standard curve of known cAMP amounts (0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, 300, ΙΟΟΟηΜ) to convert the readings to absolute cAMP amounts. Data was analysed using XLfit 3 software.

Representative compounds of the invention were found to increase cAMP at an EC50 of less than 10μΜ. Compounds showing an EC50 of less than ΙμΜ in the cAMP assay may be preferred. Insulin secretion assay

HIT-T 15 cells are plated in standard culture medium in 12-well plates at 106cells/l ml/well and cultured for 3 days and the medium then discarded. Cells are washed x 2 with supplemented Krebs-Ringer buffer (KRB) containing 119mM NaCl, 4.74mM KC1, 2.54mM CaCl₂, 1.19mM MgS0₄, 1.19mM KH₂P0₄, 25mM NaHC0₃, lOmM HEPES at pH7.4 and 0.1%bovine serum albumin. Cells are incubated with 1ml KRB at 37^°C for 30min which is then discarded. This is followed by a second incubation with KRB for 30min, which is collected and used to measure basal insulin secretion levels for each well. Compound dilutions (0, 0.1, 0.3, 1, 3, 10μΜ) are then added to duplicate wells in 1ml KRB, supplemented with 5.6mM glucose. After 30min incubation at 37 ^°C samples are removed for determination of insulin levels. Measurement of insulin was done using the Mercodia Rat insulin ELISA kit, following the manufacturers' instructions, with a standard curve of known insulin concentrations. For each well, insulin levels are corrected by subtraction of the basal secretion level from the preincubation in the absence of glucose. Data is analysed using XLfit 3 software.

Compounds of the invention preferably increase insulin secretion at an EC₅₀ of less than

10μΜ.

Oral Glucose Tolerance Tests

The effects of compounds of the invention on oral glucose (Glc) tolerance were evaluated in male Sprague-Dawley rats. Food was withdrawn 16h before administration of Glc and remained withdrawn throughout the study. Rats had free access to water during the study. A cut was made to the animals' tails, then blood (1 drop) was removed for measurement of basal Glc levels 60min before administration of the Glc load. Then, the rats were weighed and dosed orally with test compound or vehicle (20%aqueous hydroxypropyl-jS-cyclodextrin) 45min before the removal of an additional blood sample and treatment with the Glc load (2g kg^"1 p.o.). Blood samples were then taken from the cut tip of the tail 5, 15, 30, 60, 120, and 180min after Glc administration. Blood glucose levels were measured just after collection using a commercially available glucose-meter (OneTouch^® UltraTM from Lifescan). Representative compounds of the invention statistically reduced the Glc excursion at doses of <100mg kg^"1.

The effects of compounds of the invention on oral glucose (Glc) tolerance may also be evaluated in male C57B1/6 or male oblob mice. Food is withdrawn 5h before administration of Glc and remained withdrawn throughout the study. Mice have free access to water during the study. A cut was made to the animals' tails, then blood (20μί) is removed for measurement of basal Glc levels 45min before administration of the Glc load. Then, the mice are weighed and dosed orally with test compound or vehicle (20% aqueous hydroxypropyl-^A-cyclodextrin or 25% aqueous Gelucire 44/14) 30min before the removal of an additional blood sample (20μί) and treatment with the Glc load (2-5g kg^"1 p.o.). Blood samples (20μί) are then taken 25, 50, 80, 120, and 180min after Glc administration. The 20μΙ_^ blood samples for measurement of Glc levels are taken from the cut tip of the tail into disposable micro-pipettes (Dade Diagnostics Inc., Puerto Rico) and the sample added to 480μί of haemolysis reagent. Duplicate 20μΙ, aliquots of the diluted haemolysed blood are then added to 180μί of Trinders glucose reagent (Sigma enzymatic (Trinder) colorimetric method) in a 96-well assay plate. After mixing, the samples are left at room temperature for 30min before being read against GIc standards (Sigma glucose/urea nitrogen combined standard set). Compounds of the invention preferably statistically reduce the GIc excursion at doses <100mg kg^"1.

Claims

THE CLAIMS What is claimed is:

1. At least one compound of Formula (I),

Formula I

pharmaceutically acceptable salts thereof, diastereomers thereof, enantiomers thereof, geometric isomers thereof, stereoisomers thereof, tautomers thereof, solvates thereof, polymorphic forms thereof, and any mixture thereof, wherein:

Ri is selected from H, Ci_ioalkyl, substituted C_1-10 alkyl, C₃_₇cycloalkyl, C₂-ioalkenyl, C₂-₁₀ alkynyl, -R4COR5, -R4C0₂R₅, -R4CONR5R5, -S0₂R₅, a 4-7 membered heterocyclo group, aryl or a 5-10 membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo group, aryl group or heteroaryl group is optionally substituted with from 1 to 4 substituents independently selected from halo, Ci_ioalkyl, Ci_ioSubstituted alkyl, C₃_₇cycloalkyl, C₂_ioalkenyl, C₂_i₀alkynyl, aryl, heteroaryl, -CN, -NR5COR5, -NR5CONR5R6, -N0₂, -OR5, -NR5R5, -COR5, - C0₂R₅, -CONR5R6, -S(0)_mR₅, -NR₅S(0)₂R₆ or -S0₂NR₅R6, or optionally R₅ and R₆ are combined to form a 4-6 membered ring, wherein

selected from a bond, C₂_₆alkene, C₂_₆alkyne, -C(O)-, or -C(0)-(CH₂)i_4-, wherein the aliphatic portions of R₄ are optionally substituted with one to three members selected from halogen, Ci_₄alkyl, Ci_₄substituted alkyl and Ci_₄haloalkyl;

R₅ is selected from a bond, C₂_₆alkene, C₂_₆alkyne, -C(O)-, and -C(0)-(CH₂)i_₄-, wherein the aliphatic portions of R₅ are optionally substituted with one to three members selected from halogen, Ci_₄alkyl, Ci_₄substituted alkyl and Ci_₄haloalkyl;

Re is selected from a bond, C₂_₆alkene, C₂_₆alkyne, -C(O)-, and -C(0)-(CH₂)i_₄-, wherein the aliphatic portions of R₆ are optionally substituted with one to three members selected from halogen, Ci_₄alkyl, Ci_₄substituted alkyl and Ci_₄haloalkyl;

m is selected from 1 or 2;

R₂ is hydrogen or methyl;

R₃ is selected from perhaloCi_i₀alkyl, amino, Ci_i₀alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, C(0)Ci_₃alkyl, C(S)Ci_₃alkyl, S(0)_mCi_₃alkyl, iminoCi_₃alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group or sulfmyl group, each substituted or unsubstituted thereof; or a substituted or unsubstituted 3-7 membered ring;

X is a bond, -O- or -(CH₂)_n-, wherein n is 1 , 2, 3 or 4;

Y is selected from Ci_ioalkyl, C₃_i₂cycloalkyl, heteroC₃_i₂cycloalkyl, arylCi_ioalkyl, heteroaryl Ci_₅alkyl, C9-i₂bicycloaryl, heteroC₄-i₂bicycloaryl, C(0)Ci_₃alkyl, C(S)Ci_₃alkyl, S(0)_mCi_₃alkyl, imino Ci_₃alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, cyano, imino group, sulfonyl group or sulfmyl group, each substituted or unsubstituted thereof;

L is a linker providing 1 , 2 or 3 atom separation between Y and the ring to which L is attached, wherein the atoms of the linker providing the separation are selected from the group consisting of carbon, oxygen, nitrogen, or sulfur.

2. The at least one compound according to claim 1 , wherein Ri is selected from Ci_₆alkyl, Ci_₆substituted alkyl, C₄-₆cycloalkyl, C₂_₆alkenyl, C₂-₆alkynyl, a 4-6 membered heterocyclo group, or a 5-6 membered heteroaryl group, and each substituted or unsubstituted thereof.

3. The at least one compound according to claim 1 , wherein Ri is selected from C₂_₄alkyl, substituted C₂_₄alkyl, Cs-₆cycloalkyl, C₂_₄alkenyl, C₃-₄alkynyl, a 5-6 membered heterocyclo group, or a 6 membered heteroaryl group, and each substituted or unsubstituted thereof.

4. The at least one compound according to claim 1 , wherein Ri is selected from -R₄COR₅,

5. The at least one compound according to claim 1 , wherein the stereochemistry at the carbon to which it is attached is in the (R)-configuration when R₂ is methyl.

6. The at least one compound according to claim 1 , wherein R₂ is H.

7. The at least one compound according to claim 1 , wherein R₃ is selected from Ci_₆alkyl, perhaloCi_6 alkyl, arylCi_₆alkyl, Cs-i₂heteroaryl, or Ci_ioalkoxy, and each substituted or unsubstituted thereof.

8. The at least one compound according to claim 7, wherein R₃ is selected from Ci_₄ alkyl, perhaloCi_₄ alkyl, arylCi_₄ alkyl, or Ci_₆alkoxy, and each substituted or unsubstituted thereof.

9. The at least one compound according to any one of claims 1-6, wherein R3 comprises the Formula (II), ^ ^Kg

Formula II

wherein R₇ and R₈ are each independently selected from hydrogen, perhalo(Ci_i₀)alkyl, amino, (Ci_i₀)alkyl, (C₃_i₂)cycloalkyl, hetero(C₃_i₂)cycloalkyl, aryl(Ci_i₀)alkyl, heteroaryl (Ci_ ₅)alkyl, (C9-i2)bicycloaryl, hetero(C4-i2)bicycloaryl, carbonyl (Ci_3)alkyl, thiocarbonyl (Ci_3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group or sulfmyl group, and each substituted or unsubstituted thereof, or R₇ and Rg are taken together to form a 4-7 membered ring, and each substituted or unsubstituted thereof.

10. The at least one compound according to any one of claims 1-6, wherin R₃ is selected from a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

11. The at least one compound according to claim 10, wherein R₃ is selected from

wherein p is any integer selected from 0-12;

each R₉ is independently selected from halo, perhalo(Ci_io)alkyl, CF₃, cyano, nitro, hydroxy, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imino group, sulfonyl group or sulfmyl group, and each substituted or unsubstituted thereof.

12. The at least one compound according to claim 1, wherein R₃ is a substituted or unsubstituted heteroaryl selected from furan, thiophene, pyrrole, pyrazole, triazole, isoxazole, oxazole, thiazole, isothiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, imidazole, benzimidazole, indole, isoindole, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyridopyridine, quinoxaline, phthalazine or benzothiazole, and each substituted or unsubstituted thereof.

13. The at least one compound according to claim 1, wherein R₃ is selected from (C_3-12) cycloalkyl, hetero(C₃_i2)cycloalkyl, aryl(Ci_io)alkyl, heteroaryl(Ci_s)alkyl, (C9_i2)bicycloaryl, or hetero(C6-i2)bicycloaryl, and each substituted or unsubstituted thereof.

14. The at least one compound according to claim 13, wherein R₃ is selected from a substituted or unsubstituted (C₃_₇)cycloalkyl.

15. The at least one compound according to claim 13, wherein R₃ is selected from a substituted or unsubstituted (C₃_₇)cycloalkyl comprising O, N(O), N, S, SO, SO2 or a carbonyl group.

16. The at least one compound according to claim 1, wherein R₃ is a heterocycloalkyl comprising a nitrogen ring atom, or a heteroaryl comprising a nitrogen ring atom.

17. The at least one compound according to claim 1, wherein R₃ comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein.

18. The at least one compound according to claim 17, wherein said basic nitrogen of R₃ is separated from the ring atom to which R₃ is attached by between 1-5 atoms.

19. The at least one compound according to claim 1, wherein said 1, 2 or 3 atoms of L providing the separation are selected from linkers consisting of at least one carbon atom, at least one oxygen atom, at least one nitrogen atom, or at least one sulfur atom.

20. The at least one compound according to claim 1, wherein said 1, 2 or 3 atoms of L providing the separation are one atom selected from C, O, N, or S.

21. The at least one compound according to claim 1, wherein L is selected from -CH₂-, - CH₂CH₂-, -CH₂CH₂CH₂-, -C(O)-, -CH₂C(0)-, -C(0)CH₂-, -CH₂-C(0)CH₂-, -C(0)CH₂CH₂-, - CH₂CH₂C(0)-, -0-, -OCH₂-, -CH₂0-, -CH₂OCH₂-, -OCH₂CH₂-, -CH₂CH₂0-, -N(CH₃)-, - NHCH₂-, -CH₂NH-, -CH₂NHCH₂-, -NHCH₂CH₂-, -CH₂CH₂NH-, -NH-C(O)-, -NCH₃-C(0)-, - C(0)NH-, -C(0)NCH₃-, -NHC(0)CH₂-, -C(0)NHCH₂-, -C(0)CH₂NH-, -CH₂NHC(0)-, - CH₂C(0)NH-, -NHCH₂C(0)-, -S-, -SCH₂-, -CH₂S-, -SCH₂CH₂-, -CH₂SCH₂-, -CH₂CH₂S-, - C(0)S-, -C(0)SCH₂-, -CH₂C(0)S-, -C(0)CH₂S-, -CH₂SC(0)-, and each substituted or unsubstituted thereof.

22. The at least one compound according to claim 21, wherein L is selected from -CH₂-, - C(O)-, -CH₂C(0)-, -C(0)CH₂-, -CH₂-C(0)CH₂-, -C(0)CH₂CH₂-, -CH₂CH₂C(0)-, and each substituted or unsubstituted thereof.

23. The at least one compound according to claim 1, wherein Y is selected from Ci_₄alkyl, C₃_₇cycloalkyl, 3-7 membered heterocycloalkyl, arylCi_₄alkyl, heteroaryl, Ci_₄alkyl, C₆_ioaryl, 5- 10 membered heteroaryl, Ci_ioalkoxy, C₂_ioalkenyl, or C₂_ioalkynyl, and each substituted or unsubstituted thereof.

24. The at least one compound according to claim of 23, wherein Y is selected from a substituted or unsubstituted (C₄_₆)cycloalkyl, a substituted or unsubstituted 4-6 membered heterocycloalkyl, a substituted or unsubstituted C₆-9aryl, or a substituted or unsubstituted 5-6 membered heteroaryl.

25. The at least one compound according to claim 24, wherein Y is a substituted or unsubstituted phenyl.

26. The at least one compound according to claim 1, wherein Y is selected from a substituted or unsubstituted haloaryl, haloheteroaryl, dihaloaryl or dihaloheteroaryl.

27. The at least one compound according to claim 26, wherein the Y is a substituted or unsubstituted halophenyl or dihalophenyl.

28. The at least one compound according to claim 1, wherein Y is a ring having a non- hydrogen substituent at a 2 or 3 position of the ring.

29. The at least one compound according to claim 28, wherein said ring of Y has a non- hydrogen substituent at a 2 or 3 position of the ring selected from Ci_i₀alkyl, C₃_i₂cycloalkyl, heteroC₃_i₂cycloalkyl, arylCi_i₀alkyl, heteroarylCi_₅alkyl, C₉_i₂bicycloaryl, heteroC₄_i₂bicycloaryl, carbonylCi_₃alkyl, thiocarbonylCi_₃alkyl, S(0)_n(Ci_₃)alkyl, iminoCi_₃alkyl, Ci_ioalkoxy, and each substituted or unsubstituted; and n is 1 or 2.

30. The at least one compound according to claim 1, wherein -L-Y taken together is selected from -(CH₂)-(2-cyano)phenyl, -(CH₂)-(3-cyano)phenyl, -(CH₂)-(2-hydroxy)-phenyl, - (CH₂)-(3-hydroxy)phenyl, -(CH₂)-(2-alkenyl)phenyl, -(CH₂)-(3-alkenyl)-phenyl, -(CH₂)-(2- alkynyl)phenyl, -(CH₂)-(3-alkynyl)phenyl, -(CH₂)-(2-methoxy)-phenyl, -(CH₂)-(3-methoxy) phenyl, -(CH₂)-(2-nitro)phenyl, -(CH₂)-(3-nitro)phenyl, -(CH₂)-(2-carboxy)-phenyl, -(CH₂)-(3- carboxy)phenyl, -(CH₂)-(2-carboxamido)phenyl, -(CH₂)-(3-carboxamido)-phenyl, -(CH₂)-(2- sulfonamido)phenyl, -(CH₂)-(3-sulfonamido)phenyl, -(CH₂)-(2-tetrazolyl)-phenyl, -(CH₂)-(3- tetrazolyl)phenyl, -(CH₂)-(2-aminomethyl)phenyl, -(CH₂)-(3-aminomethyl)-phenyl, -(CH₂)-(2- hydroxymethyl)phenyl, -(CH₂)-(3-hydroxymethyl)phenyl, -(CH₂)-(2-phenyl)-phenyl, -(CH₂)-(3- phenyl)phenyl, -(CH₂)-(2-halo)phenyl, -(CH₂)-(3-halo)phenyl, -(CH₂)-(2-CONH₂)phenyl, - (CH₂)-(3-CONH₂)phenyl, -(CH₂)-(2-CONH(Ci_₇)alkyl)phenyl, -(CH₂)-(3-CONH(Ci_₇)alkyl) phenyl, -(CH₂)-(2-C0₂(Ci_₇)alkyl)phenyl, -(CH₂)-(3-C0₂(Ci_₇)alkyl)phenyl, -(CH₂)-(2-NH₂) phenyl, -(CH₂)-(3-NH₂)phenyl, -(CH₂)-(2-(C₃_₇)alkyl)phenyl, -(CH₂)-(3-(C₃_₇)alkyl)phenyl, - (CH₂)-(2-(C₃_₇)cycloalkyl)phenyl, -(CH₂)-(3-(C₃_₇)cycloalkyl)phenyl, -(CH₂)-(2-aryl)phenyl, - (CH₂)-(3-aryl)phenyl, -(CH₂)-(2-heteroaryl)phenyl, -(CH₂)-(3-heteroaryl)phenyl, -(CH₂)-2- bromo-5-fluoro phenyl, -(CH₂)-2-chloro-5-fluoro phenyl, -(CH₂)-2-cyano-5-fluoro phenyl, - (CH₂)-2,5-dichloro phenyl, -(CH₂)-2,5-difluoro phenyl, -(CH₂)-2,5-dibromo phenyl, -(CH₂)-2- bromo-3,5-difluoro phenyl, -(CH₂)-2-chloro-3,5-difluoro phenyl, -(CH₂)-2,3,5-trifluoro phenyl, - (CH₂)-2,3,5,6-tetrafluorophenyl, -(CH₂)-2-bromo-3,5,6-trifluoro phenyl, -(CH₂)-2-chloro-3,5,6- trifluoro phenyl, -(CH₂)-2-cyano-3,5-difluoro phenyl, -(CH₂)-2-cyano-3,5,6-trifluoro phenyl, - (CH₂)-(2-heterocycloalkyl)phenyl, or -(CH₂)-(3-heterocycloalkyl)-phenyl, and each substituted or unsubstituted thereof.

31. The at least one compound according to claim 1 , wherein the compound is selected from 3-(6-( 3R-3 - Amino-piperidin- 1 -yl)-3 - {3 - [ 1 -(3 -isopropyl- [ 1 ,2,4]oxadiazol-5 -yl)-piperidin-4- yl] -propyl} -2, 4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-benzonitrile; 3- (6-( 3R-3 - Amino-piperidin- 1 -yl)-3 - {3 - [ 1 -(3 -isopropyl- [ 1 ,2,4]oxadiazol-5 -yl)-piperidin-4- yl]-butyl} -2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl)-benzonitrile;

4- {3-[4-(JR-3-Amino-piperidin-l-yl)-3-(3-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H- pyrimidin-l-yl]-propyl}-piperidine-l-carboxylic acid tert-butyl ester

4-{3-[4-(JR-3-Amino-piperidin-l-yl)-3-(3-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H- pyrimidin-l-yl]-propyl}-piperidine-l-carboxylic acid isopropyl ester

3-{6-(JR-3-Amino-piperidin-l-yl)-2,4-dioxo-3-[3-(3,4,5,6-tetrahydro-2H-[l,3']bipyridinyl- 4-yl)-propyl] -3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl} -benzonitrile;

3-{6-(JR-3-Amino-piperidin-l-yl)-2,4-dioxo-3-[3-(3,4,5,6-tetrahydro-2H-[l,4']bipyridinyl- 4-yl)-propyl] -3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl} -benzonitrile;

3-(6-(JR-3-Amino-piperidin- 1 -yl)-3- {3-[ 1 -(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]- propyl} -2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl)-benzonitrile;

3-(6-(JR-3-Amino-piperidin- 1 -yl)-3- {3-[ 1 -(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-propyl} - 2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl)-benzonitrile;

3-(6-(JR-3-Amino-piperidin-l-yl)-3-{3-[l-(5-isopropyl-pyrimidin-2-yl)-piperidin-4-yl]- propyl} -2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl)-benzonitrile;

3-(6-(JR-3-Amino-piperidin- 1 -yl)-3-{3-[ 1 -(5-methoxy-pyrimidin-2-yl)-piperidin-4-yl]- propyl} -2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyl)-benzonitrile.

32. The at least one compound according to any one of claims of 1-31, the molecular weight of the compounds is preferably less than 800.

33. The at least one compound according to any one of claims of 1-31, the molecular weight of the compounds is less than 600.

34. The at least one compound according to any one of claims of 1-31, the molecular weight of the compounds is less than 500.

35. A pharmaceutical composition comprising at least one compound according to any one of claims 1-34, and at least one pharmaceutically acceptable excipient.

36. A method for the treatment of a disease or condition in which GPR119 and DPP-IV play a role comprising a step of administering to a subject in need thereof an effective amount of at least one compound according to any one of claims 1-34, or the pharmaceutical composition of claim 35.

37. The method according to claim 36, for the treatment of a disease or condition in which GPR119 and DPP-IV play a role, wherein said disease or condition is selected from type II diabetes, type I diabetes, obesity, impaired glucose tolerance, insulin resistance, diabetic complications, patients having an abnormal sensitivity to ingested fats leading to functional dyspepsia and/or metabolic diseases.

38. The method according to claim 37, for the treatment of type II diabetes, comprising a step of administering to a subject in need thereof an effective amount of at least one compound of any one claims of 1-34, or the pharmaceutical composition according to claim 35.

39. The method according to claim 37, for the treatment of diabetic complications, wherein said diabetic complication is selected from neuropathy, nephropathy, retinopathy, cataracts, cardiovascular complications and/or dyslipidaemia result from diabetic.

40. The method according to claim 37, for the treatment of metabolic diseases, wherein said metabolic diseases is selected from metabolic syndrome (syndrome X), impaired glucose tolerance, hyper lipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels and/or hypertension.

41. The method according to claim 40, for the treatment of metabolic syndrome, impaired glucose tolerance, hyper lipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels and/or hypertension comprising a step of administering to a patient in need thereof an effective amount of at least one compound according to any one of claims of 1-34, or the pharmaceutical composition according to claim 35.

42. The method according to claim 36, for the treatment of the diseases or conditions resulted from GPR119 and DPP-IV, comprising a step of administering to a subject in need thereof an amount of at least one compound according to claim 1-34, at dosage levels on the order of O.Olmg/kg to about 150mg/kg of body weight per day.

43. The method according to claim 42, for the treatment of the diseases or conditions resulted from GPR119 and DPP-IV, comprising a step of administering to a human in need thereof an amount of at least one compound according to claim 1-34, at dosage levels on the order of 0. lmg/kg to about 1 OOmg/kg of body weight per day.