WO2011128395A1 - N- substituted 3-amino 4 - ( pyrrolidine - 1 - carbonyl) pyrrolidine and its derivatives for use in the treatment of metabolic disorders - Google Patents

Abstract

The present invention is directed to therapeutic compounds which have activity as agonists of GPR119 and are useful for the treatment of metabolic disorders including type II diabetes. The compounds may also inhibit DPP-IV enzyme activity.

Description

, ,

IN- SUBSTITUTED 3-ΑΜΙΝΟ 4 - ( PYRROLIDINE - 1 - CARBONYL) PYRROL,IJJ±IMJ_ AIMJJ IT.

DERIVATIVES FOR USE IN THE TREATMENT OF METABOLIC DISORDERS

BACKGROUND OF THE INVENTION

The present invention is directed to therapeutic compounds useful for the treatme t of metabolic disorders including type Π diabetes. In particular, the present invention is directed to compounds which have activity as agonists of GPR119.

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

in a high proportion of patients. Treatment is often focused at individual patient needs using diet, exercise, hypoglyeaemie agents and insulin, but there is a continuing need for novel antidiabetic agents, particularly ones that may he 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 (ΒΜΪ; w ght(kg) hetght(m)'^!), 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.

GPRI 19 (previously referred to as GPR116) is a GPCR identified as SNQRF25 in

WO00750562 which discloses both the human and rat receptors, US 6,468,756 also discloses the mouse receptor (accession numbers: AAN95194 (human), AAN951 5 (rat) and A N95196 (mouse)).

In humans, GPRI 19 is expressed in the pancreas, small intestine, colon and adipose tissue. The expression profile of the human GPRI 19 receptor indicates its potential utility as a target for the treatment of diabetes. GPRl 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- 3 's ability to reduce food intake.

WO2005/061489, WO2006/070208, WO2006/067532, WO2006/067531, WO2007/003960, WO2007/00396I, WO2007/003962, WO2007/003964, WO2007/116229, WO2007/1 16230, WO2007/138362, WO2008/081204, WO2008/081205, WO2008/081206, WO2008/081207, WO2008/081208, WO2009/050522, WO2009/050971, WO20I0/004343, WO2010/004344, WO2010/004345, WO2010/004347 and WO2010/001 166 disclose GPRl 19 receptor agonists.

Dipeptidyl peptidase IV (DPP-IV) is a ubiquitous, yet highly specific, serine protease that cleaves N-terrndnai dipeptides from polypeptides with L-proline or L-aianine at the penultimate position. Studies with DPP-IV inhibitors show the principle role of DPP-IV is in the inactivation GLP-1. By extending the duration of action of GLP-1 , insulin secretion is stimulated, glucagon release inhibited, and gastric emptying slowed. DPP-IV inhibitors are of use for the treatment of type II diabetes, examples of DPP-IV inhibitors include vildagiiptin, sitagliptin, alogliptm and saxagliptin.

The possibility of using a combination of a GPRl 1 agonist and a DPP-IV inhibitor 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 compatability in the physieochemicai, pharmacokinetic and pharmacodynamic properties of the two active ingredients . International Patent Application WO2009/034388, published after die priority date of the present application, discloses compounds having dual activity as agonists of GPRl 19 and inhibitors of DPP-IV.

SUMMARY OF THE .INVENTION

The present invention is directed to compounds which have activity as agonists of GPR l 19 and may also be inhibitors of DPP-IV and are useful for the ireaiment of metabolic disorders including type II diabetes.

The present invention therefore provides compounds of formula (I) and pharmaceutically acceptable salts thereof;

(I)

wherein p and q are independently 1 or 2;

Z is N-C(0)OR⁴, N~C(0)NR⁴R-^', N-S(0)₂N(C₁„3alkyl)R⁴, N-heteroaiyl or N-CH₂- heteroaryl, and when p and q are both 2, Z may also be N-CH^"2-phenyl, in which phenyl is optionally substituted by one or two groups independently selected from Ci .4 alkyl, Ci _4 haloalkyl and halogen; Y is C¾, CF₂, CHF, O, NR^! , C(O) or

_{t w}here B is a 5-membered heteroaryl ring containing one or more heteroatoms selected from N, O and S;

when Y is CH₂, CF₂₎ CHF, O, R^l or C(O), X is an unbranched or a branched QM alkylene group; or when Y is O or NR¹, X may also be

, where A is a 5-membered heteroaryl ring containin more heteroatoms selected from N, O and S; and when Y is

, X is -O-CHR'-;

Ar is a para-substituted phenyl or a para-substituted 6-membered heteroaryl ring containing one or two nitrogen atoms, optionally substituted by one or two groups selected from C_M alkyl, Ci .4 alkoxy, C2„galkoxyalkyl, eyano, C 1 aloalkyl and halogen;

R¹ is hydrogen or C_halky!;

R² is hydrogen or C_halky!:

R³ is hydrogen or C_halky!;

R⁴ is arylj heteroaryl, C₂.6 alkyl or C3.6 cycloalkyl, which cycloalkyl is optionally substituted by Ci.₄aikyl, C4_gheierocyciyl, heterocyclic j ^alkyl, C2_6 lkoxyalk l, arylCi ^alkyl, heteroarylC \ ^alkyl or C4.gcycl0a.kylC 1 ^alk l, which cycloalkylC \ ^alkyl is optionally substituted by C _j .4 alkyl;

when Z includes heteroary!, or when is or includes aryl or lieteroaryl, said aryl or heteroaryl may be optionally substituted by one or two groups selected from halogen, C_t.₄ alkyl, Q.₄ alkoxy,

and C₃.₆ cycloalkyl optionally substituted by

R⁵ is hydrogen or C_halky!;

V is

in which T is CH₂, or when m is I , T may also be S;

when T is C¾, R° is fluoro or eyano; and when T is S, R⁶ is cyano;

n is 0 or I ;

m is 0 or i ; and

s is 0, 1 or 2.

In some embodraients the compounds of the invention have a V group with the

stereochemistry as defined below (compounds of formula (ia)). Such compounds may exhibit DPP-IV inhibitory activity;

(Ia)

DETAILED DESCRIPTION OF THE INVENTION

In some embodiments of the invention each p and q are independently 1 or 2, i.e, forming a 4-, 5- or 6-membered ring, p and q may be the same. i.e. forming a 4- or 6-membered ring. Suitably p and q may both be2. In some embodiments of the invention Z is suitably N-C(0)QR\

R⁴ may suitably be C₂-6 alkyl, such for example as propyl or butyl, e.g. isopropyl or tert- butyl..

Alternatively Z may suitably be N-heteroaryl, wherein the beteroaryl group is optionally substituted by one or two groups selected from C 3.4 alkyl, C j .4 haloaikyl, C | .5 hydroxyalkyl, C-2-4 alkoxyalkyi, C3.5 cycloalkyl optionally substituted by C \ . alkyl or halo, C } .4 alkoxy, heterocyclyl, heterocyclylaikyl, heteroarylalkyl, alkylamino, alkylaminoaikyl, eyano and halogen.

When Z is N-heteroaryl suitable heieroaryl groups include optionally substituted oxadiazoie, pyrimidine, pyridine, pyridazine, thiazoie, tetrazole, benzothiazole and thiadiazole, e.g., oxadiazoie, tetrazole, pyridine and pyrimidine.

in some embodiments Z may suitably comprise l ,2,4-oxadiazol-3-yl, 1 ,2,4-oxadiazoi-5-yl, pyridin-2-yl, pyrimidin-2-yl or tetrazoI-5-yl, which may be substituted by any of the aforementioned substituents.

Typically, said l ,2,4-oxadiazol-3-yl, l ,2,4-oxadiazol-5-yl or tetrazol-5-yl may be substituted by C|„4 alkyl, such as propyl (e.g., 3-isopropyl-l ,2,4-oxadiazol-5-yl, 5-isopropyl- l ,2,4-oxadiazol-3- yl or 2-isopropyl-2H-tetrazoI-5-yl), C j .4 haloalkyS,such as difluorom ethyl or fluoromethylethyl,

C]„5 hydroxyalkyl (e.g. 1 -hydroxy ethyl). C2.4 alkoxyalkyi, such as methoxymethyi, or heterocyclyl.

Suitably said C 3 .5 hydroxyalkyl group may be€ .3 hydroxyalkyl, e.g. hydroxyethyl,

Pyridin-2-yl or pyrimidin-2-yl may suitably be unsubstituted or substituted with one or more halo groups, e.g. 5-chloro- or 5-fluoro- pyrimidin- or pyridine-2-yl, C | .4 alkyl, such as ethyl, propyl or butyl (e.g. 5-isopropyl- or 5-ethylpyrimidin-2-yl or 5-isopropylpyridin-2-yi), .

In a further alternative, Z may be -Cl- -phenyi, wherein the phenyl is optionally substituted by one or two groups independently selected from C] .4 alkyl, Cj _4 haloaikyl and halo. £_J

Y may suitably be C¾, O, NR¹ or V—/ _? where B is a 5-membered heteroaryl ring containing one or more heteroatoms selected from N, O and S, for example oxadiazoie, e.g.

[1 ,2,4] oxadiazoie, or thiazole. Typically Y is O.

X is suitably a branched or unbranched C2-4alkylene group. In some embodiments, for instance when Y is CH_2> O or NR* , especially when Y is O, X may suitably be C^^alkyiene, suitably propyl, which is optionally substituted by 1 or 2 methyl groups, e.g. n-propyl or 1- methylpropyl, where the methyl group is typically on the carbon atom adjacent to the ring containing Z,

When Y is a heteroaryl ring, X is suitably - O-CII ?-

When X is

, where A is a 5-membered heteroaryl ring containing one or more heieroaioms selected from N, O and S, suitable heteroaryl rings include oxadiazole, tliiazoie, triazole, tetrazoie and pyrazole.

Ar may suitably be phenyl, pyridyl or pyriminidyl. Optionally Ar may be substituted by a single methyl or fluoro group, typically in the 3-position. In some embodiments Ar may be substituted by two methyl or fluoro groups, typically in the 3- and 5- positions

R' may suitably be hydrogen or methyl.

R² may suitably be hydrogen or methyl.

may suitably be hydrogen or methyl.

T may suitably be C¾.

m may suitably be 1.

s may suitably be 0,

n may suitably be 1.

While suitable groups for each variable have generally been listed above separately for each variable, the compounds of the present invention include those in which several or each variable in formula (I) is selected from the groups mentioned particularly for each variable. Therefore, this invention is intended to include all combinations of listed groups, especially those indicated to be suitable or typical.

The molecular weight of the compounds of the invention may be less than 800, typically less than 600.

The invention also comprehends isotopically-labeled compounds, which are identical to those recited in formulae (i) and (la) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, fluorine, such as ¾, n_C, 14_C and ¾. Compounds of the present invention and salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labeied compounds of the present invention, for example those into which radioactive isotopes such as ¾, ^ ^C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ¾, and carbon- 14, i.e., ^C, isotopes are particularly preferred for their ease of preparation and detectability. and isotopes are particularly useful in PET (positron emission tomography). PET is useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., ¾, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, maybe preferred in some circumstances, isotopically labeled compounds of fonnula (I) and (ia) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopicaliy labeled reagent. In one embodiment, the compounds of formula (I) and (la) or salts thereof are not isotopically labelled.

As used herein, unless stated otherwise, "alkyl" means carbon chains which may be linear or branched. Examples of alkyl groups include ethyl, propyl, isopropyl, butyl, sec- and tert-butyl. Such alkyl groups may in some embodiments be substituted with one or more halo groups, particularly f!ouro. Generally a CF3 group may be replaced by SF5 without departing from the present invention,

The term "heteroaryi" rings means 5- or 6-membered N-containing heteroaryi rings containing up to 2 additional heteroatoms selected from N, O and S. Examples of such heteroaryi rings are yrrolyi, pyrazolyl, imidazolyi, oxazolyl, isoxazoiyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyh pyridinyl, pvridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

Reference to para substitution in relation to the ring Ar refers to the positions of the groups - Y- and -[C=0]_n-V on ring Ar.

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 raeemic 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 tauiomer 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, eihanol, 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 he 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, N,N'-dibenzylethyIenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, eihylenediamine, N-ethylmorpholine, Λ-e hylpiperidine, giucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyiglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, trieihyiamine, 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, camphorsulfomc, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, rnaleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like

Since the compounds of the invention are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% are on a weight for weight basis). The compounds of formula (I) can be prepared as described below, wherein R¹, R², R³, R^'*, R⁵, R⁶, R⁷, A, B, T, V, X, Y, Z, m, n, p, q and s are as defined for formula (Ϊ). PG is a protecting group attached to the amine functionality of V, LG is a leaving group and Hal is halogen.

Compounds of formula (I) can be prepared as outlined in Scheme 1, Deprotection of the amine functionality in compounds of formula (II), using standard conditions well known to those with skill in the art, affords compounds of formula (I) as described above.

Compounds of formula (II) where n is 1 can be prepared as outlined in Scheme 2. Acids of formula (Til) can. be treated with amines of formula (IV) under standard amide coupling conditions, for example, HOBT and EDO, in a suitable solvent, such as DCM.

Scheme 2

ίίί IV ΪΙ

Compounds of formula (Π) where n is 0 can be prepared as outlined in Scheme 3. Suitable aryl halides of formula (V) can be treated with protected amines of formula (IV) under standard SN_Ar conditions, for example. DBU and DMSO at 120°C. Alternatively, compounds of formula (II) can be prepared by reaction of suitable aryl halide of formula (V) with amines of formula (IV) under Blichwaid-Hartwig conditions, such as, Pd₂(dba)₃ and BTNA? in a suitable solvent, such as toluene at 110°C. Sel¾em« 3

IV t¾«>pmakfe of fbroiu!a fi!! tee X$» ~&*€ and. Y is 0 or MR⁵.can fee prepared as outlined In

ø£ formula: C¥l> with £trslHn.e$ erpheaefe; of formulf V¾) ajKfe* standard eoeditlasis, sueh as at PMP at ?C C¾mpou«ife of formula; (Π|) as descTl above ean ^pepard by sponifiaio of es ters of foraiid■(V^'lll) wader stand d condiifous, for example, Li I-f ϊ« 5:ί methanol/ ater. Seherae

Vi, vm

EI

C^'omp&tads of &p¾»Sa iV) X isan w mielied or a_: branche ¾^a!ky!ea«, r up or - A-CHR" sad Y is Q Or NR^f ca f>6 prepare iis Oti iiie is Ste?¾ae 5. Gomp uftcis p:f iwti a {¥!) =caa. be reated wfe ar>i hafldes of forstta!a: JK) tmder stsf¾da¾3 eoadittoask sucb as Ra<¾ in F at

Compounds of formula (V) where X is an unhranehed or a branched CY alkylene group and Y is C¾ can be prepared as outlined in Scheme 6. An aikyne of formula (XII) can be prepared from an alcohol of formula (X) by oxidation to the corresponding aldehyde (XI) using a standard oxidizing reagent, such as Dess-Martin Feriodmane, and subsequent reaction of the aldehyde of formula (XI) with trimethylsilyldiazomethane, which has previously been treated with a suitable base, such as nBuLi, Alkynes of formula (XIV) can be prepared by reaction of alkynes of formula (XII) with dihaloaryi compounds of formula (ΧΠΙ) under standard Sonogashira coupling conditions.

Compounds of fonnula (V) as described above can be prepared from alkynes of fonnula (XiV) under standard reductio n conditions, such as 10% palladium on carbon under an atmosphere of hydrogen in a suitable solvent such as methanol.

XI ΧΪ1 xra

V XSV

Compounds of formula (V) where X is an unbranched or a branched C₂.₄ alkylene group and Y is CHF, C(O) or CF₂ can be prepared as outlined in Scheme 7, Ketones of formula (XV) can be prepared from alkynes of formula (XIV) by treatment with mercury oxide and sulphuric acid in methanol / water at 80°C. Treatment of ketones of formula (XV) with diethylarninosulfur trifluoride in a suiable solvent, such, as DCM, gives dif!uoro compounds of formula (XVI). Alternatively, alcohols of formula (XVII) can be prepared by treatment of ketones of formula (XV) under standard conditions, for example, sodium borohydride in methanol, Treatment, of alcohols of formula (XVII) with diethylarninosulfur trifluoride in a suitable solvent, such as DCM, gives monofluoro compounds of formula (XVIII). Scheme 7

XSV XV XVI

XVII XVni

Compounds of formula (V) where Y is -B-, X is -O-CHR^''- and B is speci fically a 1 ,2,4- oxadiazol-5-yl can be prepared as outlined in Scheme (8). Axnidoximes of formula (XX) can be prepared by reaction ofnitriles of formula (XIX) and hydroxylamine hydrochloride in the prescence of a suitable base such as ₂C0₃ in a suitable solvent such as ethanol/water at 78°C. Building blocks of formula (V) as described above can be prepared by reaction of amidoxime of formula (XX) with acid of formula (XX ) under standard conditions, such as isobutyl chloroformate and triethylamine, in a suitable solvent such as DMF.

Scheme 8 NC-Ar— Ha!

XIX XX XXI V

Compounds of formula (V) where Y is -B-, X is -O-CHR³- and B is specifically a 1 ,2,4- oxadiazol-3-yl can be prepared as outlined in Scheme 9. Amidoximes of formula (ΧΧΙΠ) can be prepared by reaction ofnitriles of formula (ΧΧΪΙ) and hydroxylamine hydrochloride in the prescence of a suitable base such as K₂C0₃ in a suitable solvent such as ethanol/water at 78°C, Building blocks of formula (V) as described above can be prepared by reaction of amidoxime of formula (XXIIi) with acid of formula (XXIV) under standard conditions, such as isobutyl chlorofonnate and irieihyiamine, in a suitable solvent such as DMF. Scheme 9

Examples and syntheses of building blocks of formula (III) where X is an unbranched or a branched C2-4 alkylene group have been described elsewhere: Bradley et.aL, WO2007/003962 and Bertram et.aL , WO2008 081205.

Examples and syntheses of building blocks of formula (III) where Y is -B- and X is -O- CHR³- have been described elsewhere: Bradley et.aL, WO2007/003960.

Examples and syntheses of building blocks (IV) have been descnbed elsewhere: Zhao et.aL,

Bioorg. Med. Chem. Lett , 2005, 15 3992-3995; Fumihiko et.aL, Bioorg. Med. Chem. Lett., 2005, 15 2441-2445; Corbett et.aL, Bioorg. Med. Chem. Lett. , 2007, 17 6707-6713.

Examples and syntheses of building blocks of formula (VI) where X is -A-CHR^* have been described elsewhere: Chen et.aL, WO2008/083238 and Ma et.aL , WO2009/014910.

Examples and syntheses of building blocks of formula (VI) and (X) where X is an unbranched or a branched C3.4 alkylene group have been described elsewhere: Bradley et.aL ,

WO2007/003962 and Aiper et.aL , WO2008 097428.

Examples and syntheses of building blocks of formula (XXI). (XXII) and (XXIII) where X is -O-CHR³ have been described elsewhere: Bradley et.aL, WO2007/003960.

Other compounds of formula (I) may be prepared by methods analogous to those described above or by methods known per se.

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 syntheses 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 he 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_s (1991) Wiley-interscience, New York, 2^rA edition.

The processes for the production of the compounds of formula (I) and intermediates thereto as described above are aiso 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, 'Iherefore according to a further aspect of the invention there there are provided compounds of formulae (II), (V), (VIII), (ΧΙΪ), (XIV), (XV), (XVI), (XVII) and (XVIII) as defined above. The preferred groups for variables recited above in relation to the compounds of formula (I) aiso apply to the intermediate compounds.

As indicated above the compounds of the invention are useful as GPR119 agonists, 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 compounds of the invention may also be useful as dual GPR119 agomsts/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, in combination with a pharmaceutically acceptable carrier.

Preferably the composition is comprised of a pharmaceutically acceptable carrier and a nontoxic therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

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

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 carrier according to conventional pharmaceutical compounding techniques. The carrier 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- n-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 carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers 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 carrier employed can be, for example, a solid, liquid, or gas, Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearaie, and siearic acid. Examples of iiquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers 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 carriers 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 carriers 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 G.OSmg to about 5g of the active ingredient and each cachet or capsule preferably containing from about O.OSmg to about 5g of the active ingredient.

For example, a formulation intended for the oral administration to humans may contain, from about O.Smg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about Img to about 2g of the active ingredient, typically 25mg, 50mg, IGOmg, 2.00mg, 300mg, 400mg, 500mg, 600mg, SOOmg, or lOOOmg.

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 carrier 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 hydrophilie 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 recta! administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa batter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier 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 ihe invention, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.

Generally, dosage levels on the order of Q.Olmg/kg to about 150mg kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about O.Smg to about 7g per patient per day. For example, obesity may be effectively treated by the administration of from about 0.01 to SOmg 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 GPRl 19 and optionally DPP-IV play a role.

Thus the invention also provides a method for the treatment of a disease or condition in which GPR l 19 and optionally 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, hyperlipidemia, 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, hyperlipidemia, 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 in vention, 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, gas tric lipase inhi bitors, pancreatic lipase inhibitors, sulfonyl ureas and analogs, biguanides e.g. metformin, a.2 agonists, glitazones, PPAR-y agonists, mixed PPAR-α/γ agonists. RXR agonists, fatty acid oxidation inhibitors, -glucosidase inhibitors, β-agonists, phosphodiesterase inhibitors, lipid lowering agents, glycogen phosphorylase inhibitors, antiobesity agents e.g. pancreatic lipase inhibitors, MCH-1 antagonists and CB-1 antagonists (or inverse agonists), amylin antagonists, lipoxygenase inhibitors, somostatin analogs, glucokirtase activators, glucagon antagonists, insulin signalling agonists, PTFIB inhibitors, gluconeogenesis inhibitors, antilypolitic agents, GSK inhibitors, galanin receptor agonists, anorectic agents, CCK receptor agonists, leptin, serotonergic/dopaminergic antiobesity drugs, reuptake inhibitors e.g. sihutramine, CRF antagonists, CRF binding proteins, thyromiinetic compounds, aldose reductase inhibitors, glucocorticoid receptor antagonists, NHE-1 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, for example another agent for the treatment of diabetes or obesity, 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, for example another agent for the treatment of diabetes or obesity, 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 in vention, 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, coadministration 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 aiso provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and another antidiabetic agent, and a pharmaceutically acceptable carrier. 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.

The invention will now be described by reference to the following examples which are for illustrative purposes and are not to be construed as a limitation of the scope of the present invention.

EXAMPLES

Materials and methods

Column chromatography was carried out on 8iC (40-63 mesh) unless specified otherwise. LCMS data were obtained as follows:

LCMS: Atlantis 3μ C_{j 8} column (3.0 x 20.0mm, flow rate ==^: 0.85mL/min) eluiing with a H₂0- MeCN solution containing 0.1% HC0₂H over 6 min with UV detection at 220 nm. Gradient information: 0.0-0.3 min 100% H₂0; 0.3-4.25 min: Ramp up to 10% H₂C> 90% MeCN; 4.25-4.4 min: Ramp up to 100% MeCN; 4.4-4.9 min: Hold at 100% MeCN; 4.9-6.0 min: Return to 100% H₂0. The mass spectra were obtained using an electrospray ionisation source in either the positive (ES⁺) or negative (ES^~) ion modes.

Preparative HPLC purification was carried out using the following method: Gemini-NX C _% column (21.2 x 100mm, 5μΜ, flow rate 20mL/min) eluting with a I¾0-MeCN solution containing 0.1% HCOjH using a 10 minute gradient with UV detection at 220 nm.

Abbreviations and acronyms: AcOH: Acetic acid; DCM: Dichloromethane; DIPEA:

Diisopropylethylamine; EDO: (3-Dimemylaminopropyl)ethylcarbodiimide hydrochloride; Et₂Q: Diethyl ether; EtOH: Ethanol; EtOAc: Ethyl Acetate; h: hour(s); HQ: Hydrochloric acid: HCOjH: Formic acid; H₂0: Water; HOBt: 1 -Hydroxybenzotriazole monohydrate; HPLC: High performance liquid chromatography; TH: Isohexane; KH₂PO4: monopotassium phosphate; M: Molar; MeCN: Acetoniirile; MeOH: Methanol; MgS0₄: Magnesium sulphate; min: minute/^'s; NaHC(¾: Sodium hydrogen carbonate; NaOH: Sodium hydroxide; Na₂SC¼: Sodium sulphate; NH₃: Ammonia;

NH₄HCO₃: Ammonium carbamate; RT: Retention time; r.L: Room temperature; SCX: Strong Cation Exchange resin; SiC¾: Silica gel; THF: Tetrahydrofuran; TEA: Trifluoroaeetic acid.

The syntheses of the following compounds have been described elsewhere: terf-butyl 4-(3- hydroxypropyl)piperidine-l-carboxylate: Tetrahedron 1999, 55, 11619-11639; 4-[3-(4-carboxy-3- fluoro-phenoxy)-propyl]-piperidine-l -carboxylic acid isopropyl ester: Bradley et. al.

WO2007003962; 4-hydroxy-2-methylbenzoic acid methyl ester: Aquino et. al WO2008157330; (R)- 3-[l -(3-isopropyl-[l ₅2,4]oxadia2»l-5-yl)piperidin-4-yl]butan-l -ol: Fyfe et. al, WO2008081204; 6- {(R)-3-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidm-4-yl]-butoxy}-2-methyl-nicoti acid: Fyfe et «/., WO2008081207; 6-{3-[l-(3 sopr pyl 1,2,4]oxadkzol-5-yl)-piperidiii-4-yl]-propoxy}- nicotinic acid: Fyfe ei. αί,, WO2008081207; 6-{3-[l -(3-isopropyl-[l ,2,4]oxadiazol-5-yl)-piperidin-4- yl]-propoxy}-2-methyl-nicotinic acid: Fyfe et. a!., WO2008081207

All other compounds were available from commercial sources,

Preparation 1: (3J?, 4^)-3-teri-BatoxycarboaySami!io-4- ydroxymetliyl-pyrroMdiMe~I-- carboxylie acid benzyl ester

To a solution of (3i?,4R)-3-amino-4-hydroxymeihyl^yrralidiri.e-l-carboxylic acid benzyl ester hydroxy-phenyl-acetate (500 mg, 1.00 mmol) and triethylamine (0.35 mL, 2.50 mmol) in 1,4- dioxane (8mL) and H₂0 (4mL) at 0°C was added di-tert-butyldi carbonate (271 mg, 1.24 mmol) in dioxarje (2mL). The resulting reaction mixture was stirred at 0°C for 30 min and at r.t. for 96 h. The reaction mixture was diluted with EiOAc (lOOmL), washed with brine (2 x 20mL), dried (MgS0₄), filtered and concentrated in vacuo to afford the title compound: RT = 3.38 min; mi (US') = 351.37 [M÷ H]⁺.

Preparation 2: (31?, 41{)-4-terf-BQtoxycarbonyiamino-pyrroIidine-l^-dicarboxylic acid 1-henzyl ester

To a solution of KH₂PO (13,6 g, 99.9 mmol) in 100 mL of water was added NaOH solution (lM, 57 mL) to adjust the pH of the solution to pH 6.7 and afford a 1M I-LPO₄ buffer solution.

To a solution of (3/?,4i¾-3-ie^butoxycarbonylamino-4-hydroxymemyl-pyrrolidine-l- carboxylic acid benzyl ester (Preparation 1, 4.54 g. 13.0 mmol) in MeCN (100 mL) and 1M KH₂PO₄ buffer solution (77 mL) were added 2,2,6,6,-tetramethylpiperidin-l-oxyl (202 mg, .28 mmol), sodium chlorite (4.39 g, 38.9 mmol) in water (27 mL) and 0.5% aqueous sodium

hypochlorite solution (9 mL, 0.60 mmol) and the resulting reaction mixture was stirred at 35°C for 72 h. Further aqueous sodium hypochlorite solution (5 mL, 0.33 mmol) was added and heating at 35°C continued for 16 h. The reaction mixture was cooled to r.t., quenched with ice/water (250 mL), the pH adjusted to H 9 with 1M NaGH, and aqueous Na₂S0₃ solution (0.5M, 90 mL) was added. The rection mixture was extracted with EtOAc (1 x 250 mL) and the organic extract washed with aqueous NaOH solution (0.5M, 200 mL). The combined aqueous extracts were acidified with concentrated HQ, extracted with EtOAc (4 x 500 mL) and these combined organic extracts were dried (MgS0₄), filtered and concentrated in vacuo, azeotroping with toluene (3 x 100 mL), to afford the title compound: RT - 3.29 min; miz (ESI - 365.17 [Af + H]⁺.

^■1-

To a solution of (3R,4R)-4-ter^butoxycarbonylamino-pyrrolidine-l,3-dicarboxylic acid 1 - benzyl ester (Preparatisn 2, 1 ,90 g, 5.20 mmol) in DMF (50 mL) were added pyrrolidine (520 pL, 6.20 mmol), EDCi (1.20 g. 6.20 mmol) and HOBt (960 ing, 6.20 mmol) and the resulting reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with EtOAc ( 00 mL) and ¾0 (i 00 mL), the organics separated and washed with H₂0 (100 mL), brine (100 mL), dried (MgSO^), filtered and concentrated in vacuo. Purification by column chromatography (EtOAciIH; 1 : 1 to 3: 1) afforded the title compound: RT = 3.52 min; miz (ES⁺) = 4 8.28 [M + H]⁺.

Preparatiee 4: [(3S, 4i?)~4-(PyrroIidme-l~earboEyi)~pyrrolidm-3~yI]--carbamie acid feri-fosityl

A solution of (3R, 4i?)-3-iert-butoxycarbonylamino-4-(pyrrolidine- 1 -carbonyl)-pyrrolidine- 1 -carboxylic acid benzyl ester (Preparation 3, 720 mg, 1.70 mmol) in MeOH (31mL) and AcOH (6mL) was passed through an H-Cube apparatus ( 0% Pd/C Catcart 70, 1 bar, 50°C) at a flow rate of 1 mL per min. The reaction mixture was added to an SCX cartridge, eluting with MeOH followed by N¾ in MeOH solution (3.5M). The basic fractions were concentrated in vacuo to afford the title compound: RT = 1.88 min; miz (ES⁺) - 284.18 \M -v Iff.

Preparation 5: (J?)-Methanesu]fonic acid-3-[l-(3-isopropyI-[l,2,4]oxadiazol-5-yl)piperidin-4- yl] butyl ester

Methanesulfonyl chloride (0.61 mL, 7.9 mmoi) and triethylamine (2.01 mL, 15.0 mmol) were added to a solution of (R)-3-[l-(3-isopropyl-[^ ,2,4]oxadiazol-5-yl)piperidin-4-yl]butan-l -ol (2,0 g, 7.5 mmol) in DCM (30 mL) at 0°C. After stirring for 10 mm, the reaction mixture was diluted with DCM (100 mL) and poured into saturated aqueous NaHCOj solution (100 mL). The organic layer was separated, washed with 0.1M HQ (100 mL), dried (MgS0₄)₅ filtered and concentrated in vacuo, Purification by column, chromatography (EtOAc:IH, 1 :1 ) afforded the title compound: RT = 3.42 min; miz (ES⁺) - 346.1 [M+ H]⁺.

Preparation 6: (JS)-2-Chioro-5-{3-[l-(3-isopropyl-[l,2,4]oxadia7 l-5-yl)piperidiii~4- yl] biitoxylpyrimidlne

A combination of (i?)-methanesulfonie acid-3-[l-(3-isopropyl-[l ,2,4]oxadiazol-5- yl)piperidin-4-yi]butyl ester (Preparation 5, 560 mg, 1.62 mmoi), 2-chloro-5-hydroxypyrimidine (423 mg, 3.24 mmoi) and K₂C(¾ (447 mg, 3.24 mmol) in DMF (4 mL) was heated to 70°C for 24 h. The reaction mixture was diluted with water (75 mL) and extracted with EtOAc (2 x 75 mL), The combined organic extracts were washed with 1M NaOH solution, then brine, and dried (MgS(¼). Removal of the solvent in vacuo afforded the title compound: RT - 4.14 min.; miz (ES¹) = 380.1 [M + H]⁺. Preparation 7; |(3i?, 4iO-l-(5-{(^)-3-[l-(3-Isopropyl-[l^

butoxy}-pyrimidm-2-yl)-4-(pyrrolidine-l-carbonyl)-pyrro in-3-^^ add tert-hutyl ester

(R)-2-Chloro-5-{3-[l-(3-isopropyl-fl,2,4]oxadazol-5-yl)piperidin^-yl]b^

(Preparation 6, 50 mg, 100 μιηοΐ), [(31?, 4R)-4-(pyri lidine-l-carbonyl)-pyrrolidm-3-yl]-carbamic acid tart-butyl ester (Preparation 4, 40 mg, 100 μπΊθΙ) and DIPEA (37 \ih, 2 0 μmo3) in MeCN (IniL) in a sealed tube were heated at 170°C under microwave irradiation for 30 min. The solvent was removed in vacuo and the remainder purified by preparative HPLC to afford the title compound: RT - 4,12 min; miz (ES⁺) - 627,25 [M+ HI' ,

Preparation 8: 4-[3-(4-Met oxycarboByl-3-methylpheHoxy)propyilpiperidiMe-l-earboxylic scid ferf-hutyl ester

DiAD (8,00 mL, 40.9 mmol) was added to a stirred solution of 4 iydroxy~2-methyl benzoic acid methyl ester (6.00 g, 37.4 mmol), iert-butyl 4-(3-hydroxypropyl)piperidine-I-carboxylate (8.25 g. 34.0 mmol) and PPh₃ (10.71 g, 40,9 mmol) hi anhydrous THF (60 mL) at ambient temperature. After stirring for 7,5 h, the solvent was removed in vacuo, and the residue was dissolved in EtOAc and washed with 2M NaOH (x 2), then brine. The organic layer was dried (MgS0₄), concentrated in vacuo and the remainder was triturated with XH and Et₂0. The solid produced was filtered and washed with Et₂0. The combined washings and filtrate were concentrated in vacuo and purified by- column chromatography (IH:EtOAc, 9:1) to afford the title compound: RT = 4.48 min; miz (ES⁺) = 392,3 [ + H]⁺. Preparation 9: 4-{3-[l-(5-Chlorop riimdiii-2-yl)piperidla-4-yijpropoxy}-2-methyIbenzok acid

4M HCi in dioxane (7.7 mL) was added to a stirred solution of 4-[3-(4-methoxycarbonyl-3- methylphenoxy)propyl]piperidine-l-carboxylic acid tert-butyl ester (Preparation 8, 4.00 g, 10.2 mmol) in dioxane (10 rrsL) at ambient temperature. After 3 h, the mixture was diluted with E¾0 and the solid product formed was collected by filtration and washed with Et₂0 to afford the hydrochloride salt of 2-metby{-4-(3-piperidin-4-ylpropoxy)benzoic acid methyl ester: RT - 2.65 min; mlz (ES⁺) ^~ 292.4 [ + Hf .

To a stirred solution of the product (1.27 g, 3.9 mmol) in DMSO (12 mL) was added 2,5- dicbioropyrimidine (580 mg. 3.9 mmol) and DBU (1.25 mL, 8.54 mmol) and the resulting solution was stirred at: 100°C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (x 2), then the combined organic extracts were washed with brine, before being dried (MgSO,_t). Removal of the solvent in vacuo and purification by column chromatography (IBLEtOAc, 19: 1) afforded the title compound: RT - 4.80 min; mlz (ES⁺) - 404.2 [M+ Hf ,

Preparation 10: 4-{3-[l-(5-Ch!oropyrimidiii-2~yS)piperidra-4-yl]propoxy}-2-methylbeiizoic acid

A mixture of lithium hydroxide monohydrate (308 mg, 7.33 mmol) and 4-{3-[l-(5- ehlorop Tiniidin-2~yl)piperidin-4~yl]piOpoxy}-2~methylbenzoic acid methyl ester (Preparation 9, i .41 g, 3.49 mmol) in THE (48 mL) and water (4.8 mL) was heated at 65°C for 96 h. The THE was removed in vacuo, then the residue was partitioned between 2M NaOH solution and EtOAc. The aqueous phase was acidified to pH 1 with 12M HQ, before being extracted with EtOAc (x 2). The combined organic extracts were washed with brine, dried (MgSO^), filtered and concentrated in vacuo to afford the title compound: RT - 4.27 min; mlz (ES^" ) - 390.2 [ + H]^'\ Preparation 11 : [(3i?_s 4^)~l-(4-{3- l-(S~ChIoro-pyrimMiffi-2-yI)-psperidiH-4-yl]-propoxy}-2- metliyl-be¾zoyI)-4-(pyrroMd e-l-earb ¾ l)-pyrr Mdm-3-yI|-carbaBik acid ferf-butyl ester

To a solution of 4-{3-[l -(5-chloropyrimidin-2-yl)piperidin-4-yl]propoxy}-2-raethyibenzok acid (Preparation 10, 60 mg, 100 μηιοι) in DCM (3mL) at 0°C was added oxalyl chloride (14 μί, 170 μπιοί) and the resulting reaction mixture was stirred at 0°C for 1 h. The reaction mixture was concentrated in vacuo and re-dissolved in DCM (3 mL), [(3R, 4i?)-4-(pyrrolidine-l-carbonyl)- pyrrolidin-3-yl]-carbamic acid ierf-butyl ester (Preparation 4, 40 mg, ΙΟΟμτ^ηοΙ) and triethylamine (24 μΧ, 170 μπιοι) were added and the resulting reaction mixture stirred at r.t. for 2 h. The reaction mixture was diluted with DCM (5 mL), washed with R₂0 (5mL) and filtered through a phase separator. The organic layer was concentrated in vacuo and purified by preparative HPLC to afford the title compound: RT = 4.64 rain; m/z (ES^÷) = 656.29 [ + HJ⁺.

Preparation 12: 4-(3-{4~[(3if, 4^)-3~feri-B5itoxyearboBykmmo-4~(pyrrolidme-l-carb i5iyl)- pyrroOdme-l-carboiiyl]-3-fluoro- heaoxy}-propyl)-piperMiiie-l-carbi)xyIie acid isopropyl ester

To a solution of 4-[3~(4-carboxy-3~tluoro-phenoxy)-propyrj~piperidine-l -carboxylic acid isopropyl ester (60 mg, 200 μηιοΐ) in DCM (1 mL) was added l-chloro-N,N,2-trime1hyl-l- propenylamine (26 L, 190 μτηοΐ) and fee resulting reaction mixture stirred at r.t, for 2 h. [(3R, 4i?)- 4~(]5yTrolidine-l-carbonyl)-pyrrolidin-3-yl]-carbamic acid fer -butyl ester (Preparation 4, 50 mg, 200 ιηο1) in DCM (1 mL) and triethylamine (49 pL, 350 umol) were added and the resulting reaction mixture stirred at r.t. for 16 h. The reaction mixture was diluted with DCM (5 mL), washed with water (5 mL) and filtered through a phase separator. The organic layer was concentrated in vacuo and purified by preparative HPLC to afford the title compound: RT = 4.12 min; mlz (ES⁺) = 633,23 [M+ ITf, Preparation 13; [(3J?, 4i?)~l-{6~{(J?}~3-[i-C3~IsopropyHl₅2,^

b«.Gxy}~2~methy!~pyrMSne-3-earb{>ny!)-4~Cpyr^^

aeid tori-butyl ester

To a solution of 6-{(R)-3-[l-(3-isopropyl-[l ,2,4]oxadiazol-5-yl)-piperidin-4-yl]-butoxy}-2- methyl-nicotinic acid (57 mg, 140 μηιο!) in DMF (1 mL) was added [(3 J?, 4R)-4-(pyrrolidine-l- carbonyl)-pyrrolidin-3-yl]-carbamic acid tori-butyl ester (Preparation 4, 40 mg, 140 μηαοΐ), triethylamine (30 μΧ, 210 μη οΐ), HOBt (32 mg, 210 μηιοΐ) in DMF (1 mL) and EDCI (40 mg, 210 μπιοΐ) and the resulting reaction mixture was stirred at r.t. for 16 h. The reaction mixture was diluted with DCM (5 mL), washed with aqueous NaHC0₃ solution (5 mL) and H₂0 (5 mL) and filtered through a phase separator. The organic layer was concentrated in vacuo and purified by preparative HPLC to afford the title compound: RT - 4.12 min; m/z (ES⁺) = 668.23 [M+ Fff .

Preparation 14: [(3R, 4-S)-l-(6-{3-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-pipcridin-4-yl]- propoxy}~2^»metbyI~pyridiiie^»3~earbonyI)~4-(pyrrolldiHe-l-carbQsy!)-pyrro dln-3-yl|^ acid tori-butyl ester

The title compound was synthesised from 6-{3-[l -(3-isopropyl-[l ,2,4]oxadiazol-5-yl)- piperidin-4-yl]-propoxy}-2-metiiyl-nicotimc acid (55 mg, 140 μτηοΐ) and [(3ii, 4i?)-4-(pyrrolidine-l - carbonyl)-pyrrolidin-3-yl]-carbamic acid tori-butyl ester (Preparation 4, 40 mg, 140 μιηοΐ) employing a procedure similar to that outlined in Preparation 13; RT = 4.02 min; m/z (ES⁺) = 654.43 [Af+ H]⁺. Preparation 15; |{3i?₅ 4j?)-I-(0-f3«[l-(3-I§GprQpyl-[l,2,4]oxadte^

propexy}~pyr ine~3-carfoeiiyl)-4~(pyrralidM^ acid tert- batyl ester

The title compound was synthesised from 6-{3-[l-(3-isopropyl-[1.2,4]oxadiazol-5-yl)- piperidin-4-yl]-propoxy}-nicotimc acid (50 mg, 140 μκιοΐ) and [(3R, 4ii)-4-(pyrroli.dme-l-carbonyl)- pyrrolidin-3-yl]-carbamic acid ieri-butyl ester (Preparatira 4, 40 mg, 140 pmol) employing a procedure similar to that outlined in Preparation 13: RT = 3.88 min; mlz (ES^r) = 640.31 [M + H]⁺.

Example 1: [(3J?, 4i?)-4-Aii™o-l-(S-f(jS)-3-[l-(3-is propyI-[l,2,4]oxadiazol~5-yl)-piperidm-4~ yl]~b«toxy}~pyrimldiH-2~y!)~pyrroMdiii-3-yiJ-pyrTOlSdi¾- i-yl-raetfeaiione

To a solution of [(3R, 4R)-l-(5-{(R)-3-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- butoxy}-pyrimidin-2-yl)-4-(pyrroH^ acid fer -butyl ester

(Preparation 7, 46 mg, 73 μπιοί) in DCM (1 mL) was added TFA (200 μΤ, 200 μηιοΐ) and the resulting reaction mixture was stirred at r.t. for 1 hour. The reaction mixture was added to an SCX cartridge and eluted with MeOH followed by NH₃ in MeOH (3.5M) and the basic fractions conceniraied in vacuo. The remainder was dissolved in MeOH, added to an SCX phosphonic acid cartridge and eluted with MeOH followed by NH₃ in MeOH (3.5M). The basic fractions were concentrated in vacuo to afford the title compound: RT = 2.72 min; mlz (ES⁺) = 527.24 [M÷ H] ^' . Example !: [{3i?,4J -3~Ammo~4-{pyrr®Mdm

p r¾iidm-2-yI)-piperid -4-y!]-propoxy}-2-mel:hyl-phe!i I)-siieihanone

To a solution of [(3R, 4R)-l-(4-{3-[l-(5-chloro-pyriraidin-2-yl)-piperid3n-4-yl]-propoxy}-2- ffiethyl-benzojd)-4-(pyrrolidine-l-carboRyl)-p\Trolidin-3-ylj-carbamic acid ferf-butyl ester

(Preparation 11, 50 mg, 80 μπιοΐ) in DCM (2 mL) was added TFA (400 iL, 5,0 mrnol) and the reaction mixture stirred at r.t. 1 hour. The reaction mixture was added to an SCX cartridge and eiuted with MeOH followed by N¾ in MeOH (3.5M) and the basic fractions concentrated in vacuo to afford the title compound: RT = 3.05 min; mlz (ES*) = 555.23 [M+ H]⁺.

Example 3: 4-(3-{4~[(3^,4i?)-3-Ammo^-{pyrr0lidi0e-i~carboByI)~pyrrolidme~l~earbii5iySJ-3~ fluoro-phenoxy}-propyl)-piperidine-l-carboxylic acid isopropyl ester

The title compound was synthesized from 4-(3-{4-[(3i?, 4J¾)-3-teri-butoxycarbonyiamino~4- (pyrrolidine-l-carbonyl)-pyrrolM^

acid isopropyl ester (Preparation 12, 32 mg, 50 μηιοΐ) employing a procedure similar to that outlined in Example 1: RT = 2.84 min; tw'z (ES⁺) = 533.21 [M + ΗΓ.

Example 4: [(3J?,4^)-3-Ammo-4-(pyrroMdme-l-carbosiyl)-pyrroSidm-l-yl]-(6-{(i?)-3-[l-(3- isopropyi-[l,2,4]oxadia7^1-5- l)~pipe^

The title compound was synthesized from [(3i?, 4i?)-l-(6- {(i?)-3-[l-(3-isopropyl- [l ,2,4]oxadiazol-5-yl)-piperidin-4-yl] >uto^ carbonyl)-pyrrolidii5~3-yi]-earbamic acid feri-butyl ester (Preparation 13, 22 mg, 33 umol) employing a procedure similar to that outlined in Example 2: RT = 2,80 min; rn/z (ES⁺) = 568.31 [

Example S: [(3^,4i?)-3-Ammo~4-{pyrro!idine-l-ciirboayI)-pyrro dm-l-yl|-(6-{3-[l-(3- i§«prQpyHi,2,4](radiazol-5~yl)-piperidm^

The title compound was synthesized from \ 3R, 4jR)-l-(6-{3-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidk-4-yl]-pro^

carbonyl)-pyrrolidin-3-yl]-carbamic acid ferf-butyl ester (Preparation 14, 24 mg, 37 μπιοί) employing a procedure similar to that outlined in Example 2: RT = 2.73 min; mlz (ES⁺) = 554.29 [M + H]⁺.

Example 6: [(3S,4i?)-3-Aiimio-4-(pyrroik se-l-£arbi)Hyl)-pyrroHd i~l-y!]-(6-{3- I-(3~ isopriipyI~[l,2,4]oxadiazoI~S-yl)-piperMin-4-yl]~propoxy}~pyridm~3-yI)-meihan iiie

The title compound was synthesized from [(3i?. 4R)-l-(6-{3-[l-(3-isopropyl- fl,2,4Joxadiazol-5-yl)-piperidin-4-ylJ-propoxy}-pyridine-3-carbonyI)-4- pyTO

pyrrolidin-3-yl]-carbamic acid fert-butyl ester (Preparatioa IS, 24 mg, 38 μηιοΐ) employing a procedure similar to that outlined in Example 1: RT = 2,67 min; miz (ES ) = 540,29 [M + H]⁺.

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

GPR119 cAMP Assay

A stable cell line expressing recombinant human GPRl 19 was established and this ceil 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 30 min 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 may produce a concentration-dependent increase in intracellular cAMP level e.g. having an EC_5i, of <10 μΜ, Compounds showing and EC_SQ 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 fluorogenie peptide substrate, H-Giy-Pro-7-amino~4-methylcoumarin (GP-AMC) whereby the product 7-amino~4- methyicouniarin is quantified by fluorescence at excitation 380 nm and emission 460 nm. Assays were carried out in 96-well plates (Black OptiPlate-96F) in a total volume of 100 μΐ_^ per well consisting of 50 mM Tris pH 7.6, 100 μΜ GP-AMC, 10-25 μϋ recombinant human DPP-IV and a range of inhibitor dilutions in a final concentration of 1 % DMSO, Plates were read in a fluorimeter after 30 min incubation at 37°C. Recombinant human DPP-IV residues Asn29-Pro766 was purchased from BioMol.

All of Examples 1 to 6 showed activity in this assay having an IC_JO of <20 μΜ.

Compounds of the invention of formula (la) may generally have an IC₅₀ of <20 μΜ.

Activities of a representative group of compounds that were tested in the cAMP assay and the DPP-IV assay are shown in Table 1 below:

'able 1

Anti-diabetic effects of coxnpoimds of the invention is an i¾~vitro model of pancreatic beta eeMs (ΗΓΓ-TIS)

Cell Culture

IIIT-T15 cells (passage 60) were obtained from ATCC, and were cultured in RPMI1640 medium supplemented with 10% fetal calf serum and 30 nM 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-T15 cells were plated in standard culture medium in 96-well plates at 300,000 ceils/ 0.1 nil,/ well and cultured for 24 h and the medium was then discarded. Cells were incubated for 15 min at room temperature with ΙΟΟμΙ stimulation buffer (Hanks buffered salt solution, 5mM HEPES, 0,5mM 1BMX, 0.1% BSA, pH 7.4). 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, 30 uM in stimulation buffer in the presence of 0.5% DMSO. Ceils were incubated at room temperature for 30 rnin. Then 75 uL lysis buffer (5mM HEPES, 0.3% Tween-2.0, 0.3% BSA, pH 7.4) was added per well and the plate was shaken at 900 rpm for 20 min. Particulate matter was removed by eentrifugation at 3000rpm for 5 min, then the samples were transferred in duplicate to 384-weil plates, and processed following the Perkin Elmer AlphaScreen cAMP assay kit instructions. Briefly 25 μΕ reactions were set up containing 8 pL sample, 5 pL acceptor bead mix and 12 pL 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 150 min, 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, 1000 nM) to convert the readings to absolute c AMP amounts. Data was analysed using XLfit 3 software.

Representative compounds of the invention may increase cAMP at an EC₅₀ of less than 10 μΜ. Compounds showing an EC₅Q of less than 1 μΜ in the cAMP assay may be preferred.

Insulin secretion assay

HiT-Tl 5 cells are plated in standard culture medium in 12-well plates at 106 cells i ml well and cultured for 3 days and the medium then discarded. Ceils are washed x 2 with supplemented rebs-Ringer buffer (KRB) containing 119 mM NaCl, 4.74 mM KC1, 2.54 mM CaCl₂, 1.19 mM MgS0_4> 1.19 mM I¾P0_4i 25 mM NaHCOj, 10 mM HEPES at pH 7.4 and 0,1% bovine serum albumin. Cells are incubated with 1ml KRB at 37°C for 30 min which is then discarded, This is followed by a second incubation with KRB for 30 min, which is collected and used to measure basal insulin secretion levels for each well. Compound dilutions (0, 0.1 , 0.3, 1 , 3, 10 μΜ) are then added to duplicate wells in 1 ml KRB, supplemented with 5.6 mM glucose. After 30 min 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 pre-incuhation in the absence of glucose. Data is analysed using ^XI_^tit 3 software.

Compounds of the invention preferably increase insulin secretion at an EC_$o of less than 10 μΜ,

Oral GMcose Tokra&ee Tests

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

The effects of compounds of the invention on oral glucose (Glc) tolerance may also be evaluated in male C57B1/6 or male obi^'oh 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 (20 \iL) is removed for measurement of basal Gle levels 45 min before administration of the Glc load. Then, the mice are weighed and dosed orally with test compound or vehicle (20% aqueous hydroxypropyl-,5~eyclodextrin or 25% aqueous Gelucire 44/14) 30 min before the removal of an additional blood, sample (20 μΤ,) and treatment with the Gle load (2-5 g kg^"! p.o.). Blood samples (20 μΐ,) are then taken 25, 50, 80, 120, and 180 min after Glc administration, The 20 μϊ_. 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 480 μΐ. of haemolysis reagent. Duplicate 20 μΤ aliquots of the diluted haemolysed blood are then added to 180 μΐ, of Trinders glucose reageai (Sigma enzymatic (Trinder) colorinieiric method) in a 96-well assay plate. After mixing, the samples are left at room temperature for 30 rain before being read agairtsi Glc standards (Sigma glucose/urea nitrogen combined standard set). Compounds of the invention preferably statistically reduce the Glc excursion at doses <100 mg kg^"1.

Claims

CLAIMS:

1. A compound of formula (Ϊ) or a pharmaceutically acceptable salt thereof:

(I)

wherein p and q are independently 1 or 2;

Z is N-C(0)O ⁴, N-C(0)NR⁴R⁵, N-S(0)2N(C} _3alkyl)R⁴, N-heteroaryi or N-CH₂- heteroaryl, and when p and q are both 2, Z may also be N-CFPj-phenyl, in which phenyl is optionally substituted by one or two groups independently selected from C] _4 alkyl, Ci .4 haioalkyl and halogen;

Y is C¾, CF₂, CHF, O, NR^[, C(O) or

, where B is a 5-membered heteroaryl ring containing one or more heteroatoms selected from N, O and S;

when Y is CI¾, CF₂, CHF, O, NR¹ or C(0), X is an unbranched or a branched (¾_₄ alkylene group; when Y is O or NR¹ , X may also be

_t where A is a 5-membered heteroaryl ring con elected from N, O and S; or when Y

-;

Ar is a para-substituted phenyl or a para-substituted 6-membered heteroaryl ring containing one or two nitrogen atoms, opiionally substituted by one or two groups selected from C_H alkyl, C [„4 alkoxy,

haioalkyl and halogen;

R¹ is hydrogen or Cj„₄alkyi;

R² is hydrogen or

R³ is hydrogen or C^alkyl;

R⁴ is aryl, heteroaryl, C₂-f, alkyl or C₃.₆ cycloalkyl, which eycloalkyl is optionally substituted by C_halky! C4„gheterocyclyl, heterocyclylC 1.4 alkyl, C2.galkoxyalkyl,

heteroarylCj. 4a!kyl or C^gcycloalkylCj^alkyl, which cycl0aikylCi.4alk.yl is optionally substituted by C]_4 alkyi;

when Z includes heteroaryl, or when R.4 is or includes aiyl or heteroaryl, said aryl or heteroaryl may be optionally substituted by one or two groitps selected from halogen, Ci^ alkyl, Cj. alkoxy, C^haloalkyl and C₃.₆ cycloalkyl optionally substituted by C^alkyl;

R⁵ is hydrogen or

in which T is CH_¾ or wh en m is 1 , T may also be S;

when T is CH_2> R" is fluoro or cyano; and when T is S, R⁶ is cyano;

n is 0 or 1 ;

m is 0 or I ; and

s is 0, 1 or 2,

2. A compound according to claim I, or a pharmaceutically acceptable salt thereof, wherein the stereochemistry of the V groups is as shown below:

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein p and q are 2,

4, A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Z is N-C(0)OR⁴.

5. A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R^* is C2-6 alkyl,

6, A compoimd according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Z is N-heteroaryl, in which the heteroaryl moiety is optionally substituted by one or two groups selected from C^ alk l, Ci _4 haloalkyi, C j_5 hydroxyalkyl, C2-4 alkoxyalkyl, C3.5 cycloaikyl optionally substituted by Ci .4 alkyl or halo, Ci ..4 alkoxy, heterocyclyl, heteroeyelyialkyl, heteroarylalkyl, a kylamino, alkylaminoalkyl, cyano and halogen.

7. A compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein Z is optionally substituted oxadiazole, tetrazole, pyridine or pyrimidine.

8. A compound according to any one of the preceding claims, or a phannaceuiically acceptable salt thereof, wherein A is oxadiazole, thiazole, triazole, tetrazole or pyrazole.

9. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Y is CH₂, O, NR. or

, where B is a 5-membered heteroaryi ring containing one or more heteroatoms selected from N, O and S,

10. A compound according to claim 9, wherein X is a branched or unbranched C2_4alkylene group,

1 1. A compound according to claim 9, wherein Y is a heteroaryi ring and X is-Q-CI-P?-.

12. A compound according to claim 9 or claim 10, or a pharmaceutically acceptable salt thereof, wherein B is oxadiazole or thiazole.

13. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl, pyridyl or pyriminidyl.

14. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R^! is hydrogen or methyl,

15, A compound according to any one of the preceding claims, or a pharmaceutically acceptabie salt thereof, wherein R² is hydrogen or methyl.

16. A compound according to any one of the preceding claims, or a pharmaceutically acceptabie salt thereof, wherein R' is hydrogen or methyl.

17. A compound according to any one of the preceding claims, or a pharmaceutically acceptabie salt thereof, wherein T is CH₂.

18. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein m is 1 ,

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptabie salt thereof; and a pharmaceutically acceptable carrier.

20. A method for the treatment of a disease or condition in which GPR119 plays a role comprising a step of administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

21. A method for the treatment of a disease or condition in which GPR119 and DPP-XV play a role comprising a step of administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 18, or a pharmaceuticall acceptable salt thereof.

22. A method for the treatment of type II diabetes comprising a step of administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

23. A method for the treatment of obesity, metabolic syndrome (syndrome X), impaired glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels or hypertension comprising a step of administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

24. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for use in the treatment of type ΪΙ diabetes, obesity, metabolic syndrome (syndrome X), impaired glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels or hypertension.

25. A compound as ciaimed in any one of claims 1 to 18 for use in a method of treatment of type Π diabetes, obesity, metabolic syndrome (syndrome X), impaired glucose tolerance, hyperiipidaemia, hypertriglyceridaemia, hypereholesterolaeniia, low HDL levels or hypertension in humans.