Under the above situation, the inventors of this invention found that the compound of this invention has the outstanding activity to inhibit DPP-IV, and the inventors completed this invention. Accordingly, this invention relates to DPP-IV inhibitor. More particularly, this invention relates to DPP-IV inhibitor useful for treating or preventing conditions mediated by DPP-IV, more particularly useful for treating or preventing altered glucose tolerance, glucosuria, hyperlipidemia , metabolic acidosis, diabetes mellitus (type 1 and type 2) , diabetic neuropathy, nephropathy, and secondary diseases in mammals caused by diabetes mellitus. That is, one object of this invention is to provide new compound and pharmaceutically acceptable salt thereof, of which activity to inhibit DPP-IV is remarkably improved against known compounds, preferably having a good oral activity and a high safety profile .

Another object of this invention is to provide a medicament and pharmaceutical composition containing the compound or pharmaceutically acceptable salt thereof as an active ingredient.^' A further object of this invention is to provide an inhibitor of DPP-IV and a method for inhibiting DPP-IV comprising administering an effective amount of the compound' or pharmaceutically acceptable salt thereof.

A further object of this invention is to provide a use of the compound and pharmaceutically acceptable salt thereof as medicaments.

A further object of this invention is to provide the compound and pharmaceutically acceptable salt thereof which are useful for the manufacture of medicaments for treating or preventing conditions mediated by DPP-IV inhibition, more particularly useful for treating or preventing altered glucose tolerance, glucosuria, hyper1 ipidemia , metabolic acidosis, diabetes mellitus (type 1 and type 2), diabetic neuropathy, diabetic nephropathy, and secondary diseases in mammals caused by diabetes mellitus, especially T2DM.

A further object of this invention is to provide the commercial package comprising the pharmaceutical composition containing the new compound.

The present invention is directed to the following compound of the formula (I) or pharmaceutically acceptable salt thereof.

[ wherein

Ar is aryl or heteroaryl, optionally substituted; R¹ is acy1 ; each R² is independently selected from the group consisting of H and lower alkyl; each R³ is independently selected from the group consisting of H and lower alkyl; each R⁴ is independently selected from the group consisting of H and lower alkyl.]

In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following.

The "aryl" means an aromatic hydrocarbon group, such as phenyl, naphthyl, indenyl, biphenyl, and the like, and it is preferably ( C6-C10 ) aryl , more preferably phenyl.

The "cycloalkyl" includes a cycloalkyl group having 3 to 10 carbon atoms, that may be crosslinked, preferably a cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl group.

The "heterocycle" includes a saturated or unsaturated 4- to 8-membered heterocyclic group which has 1 to 4 hetero atoms selected from N, S and O, and which may be a monocyclic ring, or may form a bicyclic or tricyclic fused ring by being fused with heterocycle ( s ), aryl(s) or cycloal ky1 ( s ) .

The "saturated heterocyclic group" means preferably 5- to 7-membered heterocyclic group and may fuse with cycloalkyl (s). The "saturated heterocyclic group" may include pyrrol idiny1 , imida zol idiny1 , t et rahydro furany1 , piperidinyl, tet rahydro-2H- pyranyl,' tetrahydro-2H-thiopyranyl, piperadinyl, morpholinyl, thiomorphol iny1 , azepanyl and dia zepanyl .

The "unsaturated heterocyclic group" includes heteroaryl and partially saturated heteroaryl. The "partially saturated heteroaryl" includes pyrrolinyl, imida zol iny1 , pyrazolinyl, dihydrothia zoly1 , dihydroi sothia zoly1 ,- dihydrooxa zoly1 , dihydroisoxazolyl, dihydrothiadiazolyl, dihydrooxadiazolyl , dihydrofuranyl , pyranyl, dihydropyranyl, dihydrothiopyranyl, tet rahydroa zepiny1 , dihydroa zepiny1 , azepinyl, diazepinyl, 3 , 4 -dihydro-2H- 1 , 4 -benzoxadiny1 , 3, 4-dihydro-2H-l, 4-benzothiadinyl,

1, 3-benzodioxolyl, 2 , 3-dihydro-l, 4-benzodioxinyl, chromanyl, i sochromany1 , 3 , 4 -dihydro-2H- 1 - benzothiopyranyl, 3, 4-dihydro-lH-2-benzothiopyranyl, indolinyl, i soindol iny1 , 1 , 2 , 3 , 4 -1et rahydroquinoly1 and 1 , 2, 3, 4-tetrahydroisoquinolyl.

The "heteroaryl" means preferably 5- or 6-membered or condensed aromatic heterocyclic group which contains at least one hetero atom such as nitrogen, oxygen and sulfur atom. The "heteroaryl" may include 5-membered heteroaryl group such as pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, i sothia zoly1 , thiadiazol, or the like; 6-membered heteroaryl group such as pyridinyl , pyrazinyl, pyrimidinyl, pyridazinyl, or the like; and condensed heteroaryl group such as indolyl, isoindolyl, indazolyl, purinyl, quinolyl, isoquinόlyl, benzopyrroly1 , benzoimida zoly1 , ben zot ria zoly1 , benzo furanyl , i soben zofuranyl , phthalanyl, chromenyl, chromonyl, benzothieny1 , i sobenzothieny1 , benzothia zoly1 , phthal imidy1 , or the like .

The term "acyl" can be exemplified by R-C(=O)-, R-S(=O)-, R-S (=0) 2~ r R-C (=NR)-, in which R is not specified. It is preferably, R-C(=O)-, R-S(=O)- or R-S (=0) 2~ / morepreferably, R-C(=O)- or R-S)=O)₂-, most preferably R-C(=O)-.

The term "lower" is intended to mean a group having

1 to 6 carbon atom(s), unless otherwise provided. Therefore, the "lower alkyl" means a straight or branched chain aliphatic hydrocarbon, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like. It is preferably

(C1-C4 ) alkyl, more preferably ( C1-C2 ) al kyl , most preferably methyl.

The "lower alkoxy" means a straight or branched chain aliphatic hydrocarbon oxy group, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, hexoxy, and the like. It is preferably (C1-C4 ) alkoxy, more preferably (C1-C2 ) alkoxy , most preferably methoxy.

The "halogen" may include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, more preferably a fluorine atom or a chlorine atom, most preferably a fluorine atom.

The "halogenated lower alkyl" means the above lower alkyl substituted by halogen atom(s), such as fluoromethyl , chloromethy1 , di fluoromethy1 , dichloromethyl , dibromomethy1 , t ri.fluoromethyl , t richloromethy1 , fluoroethyl, chloroethy1 , 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl , . fluoropropy1 , fluorobutyl, fL-uorohexyl, and the like. It is preferably halogenated ( C 1 -C 4 ) al kyl , more pre ferably halogenated

« (C1-C2 ) alkyl , more preferably fluorinated ( C1-C4 ) al kyl , more preferably fluorinated ( Cl -C2 ) al kyl , most preferably t ri f luoromet hy1.

The "aryl- (lower alkyl)" means the "lower alkyl" group mentioned above substituted by the aryl group, and includes benzyl, 1 -phenylethy1 , 2 -phenyIethy1 , 3 -phenylpropy1 , 4 -phenylbut y1 , 1 -naphthylmethy1 , 2-naphthylmethyl, 2-(l-naphthyl)ethyl,

2 - ( 2 -naphthy1 ) ethyl , and the like. It is preferably phenyl- ( lower alkyl), more preferably phenyl- ( Cl -C4 ) a 1 ky1 , more preferably phenyl- (C1-C3) alkyl .

The "heterocycle- ( lower alkyl) " means the "lower alkyl" group mentioned above substituted by the heterocyclic group. It is preferably het erocycle- ( C 1 -C4 ) al ky1 , more preferably heterocycle- (C1-C2 ) alkyl , more preferably heterocycle -methyl .

The "aryl- (lower alkoxy) " means the "lower alkoxy" group mentioned above substituted by the aryl group, and includes benzyloxy, 1 -phenyIethoxy , 2 -phenyIethoxy , 3 -phenylpropoxy , 4 -phenylbut oxy , 1-naphthylmethoxy, 2-naphthylmethoxy,

2-(l-naphthyl)ethoxy, 2-(2-naphthyl)ethoxy, and the like. It is preferably pheny1 -( lower alkoxy), more preferably pheny1 -( Cl -C4 ) al koxy , more preferably phenyl- ( C1-C2 ) alkoxy , most preferably benzyloxy.

The " heteroaryl- ( lower alkoxy)" means the "lower alkoxy" group mentioned above substituted by the heteroaryl group. It is preferably heteroaryl -( C 1 -C4 ) al koxy , more preferably heteroaryl- ( C1-C2 ) alkoxy , more preferably heteroaryl-methoxy.

The " (lower alkoxy) -carbonyl" means carbonyl group substituted by the above mentioned lower alkoxy group, and includes methoxycarbony1 , ethoxycarbonyl , propoxycarbony1 , i sopropoxycarbonyl , but oxycarbonyl , i sobutoxycarbonyl , t -but oxycarbony1 , pent oxycarbony1 , hexoxycarbonyl , and the like. It is preferably

( Cl-C 4 ) al koxy- carbonyl , more preferably, methoxycarbony1 or t-butoxycarbony1 , most preferably t-butoxycarbonyl .

Though the "substituent" in the definition of Compound (I) is not limited, it means general substituent. The "substituent" can be preferably selected from the group cons i st ing of lower al kyl , lower alkoxy, halogen, hydroxy, cyano, nitro, amino, carbamoyl, aminosul fony1 , carboxy, (lower alkoxy) -carbonyl, R⁶-S-, R⁶-S(O)-, R⁶-SO₂-, R⁶-SO₂NH-, R⁶-CONH-, R⁶-CONHSO₂-, R⁶-SO₂NHCO-, lower alkyl substitutedby 1 to 3 of R⁷, heteroaryl, and oxo; wherein R⁶ is lower alkyl, halogenated lower alkyl, or phenyl optionally substituted with halogen, lower alkyl or halogenated lower alkyl; R⁷ is hydroxy, lower alkoxy, carboxy, (lower al koxy ) -carbonyl , carbamoyl; and any nitrogen atoms in carbamoyl or aminosul fony1 may be substituted by lower alkyl.

The number of substituent may be two or more if possible, preferably up to 5, more preferably up to

3. In case that the number of substituent is plural, they may be identical or different to each other. For example, in case where both "Ar" and "R⁵" in the definition of the present invention have two or more subs t i tuent s , the substituents may be the same or different to each other. The Compound (I) may contain one or more asymmetric centers and thus they can exist as enantiomers or dias tereoi somers . This invention includes both mixtures and separate individual isomers.

The compounds of the formula (I) may also exist in tautomeric forms and this invention includes both mixtures and separate individual tautomers.

The Compound (I) and their salts may be in a form of a solvate such as hydrate, which is included within the scope of the present invention. Also included in the scope of this invention are radiolabel led derivatives of Compound (I) which are suitable for biological studies.

In the scope of the present invention, the prodrug of the Compound (I) is included, which prodrug i s capable of undergoing metabolic conversion to Compound (I) following administration in body. Further, in the scope of the present invention, metabolites of Compound (I) are included, which metabolites may be therapeutically active in the treatment of the targeted medical condition.

The compound of this invention can be converted to salt according to a conventional method. Suitable salts of the compounds (I) are pharmaceutically acceptable conventional non-toxic salts and include an organic acid sal t (e.g., acetate, maleate, tartrate, methanesul fonate , benzene sul fonate , formate, toluenesulfonate , t rif luoroacet ate , or the like), an inorganic acid salt (e.g., hydrochloride, hydrobromide , sulfate, phosphate, or the like), a salt with an amino acid (e.g., aspartate, glutamate, or the like), or the like.

The compound (I) may preferably include Compound (Ia) as following:

[ wherein

Ar is aryl or heteroaryl, optionally substituted; each R² is independently selected from the group consisting of H and lower alkyl; each R³ is independently selected from the group consisting of H and lower alkyl; each R⁴ is independently selected from the group consisting of H and lower alkyl;

R⁵ is lower alkyl, halogenated lower alkyl, aryl optionally substituted, heterocycle optionally substituted, cycloalkyl optionally substituted, aryl-0 optionally substituted, he t er ocycle-0 optionally substituted, aryl- (lower alkyl) optionally substituted o n t he a r y 1 , heterocycle- ( lower alkyl) optionally substituted on the heterocycle, aryl- (lower alkoxy) optionally substituted on the aryl, or heterocycle- ( lower alkoxy) optionally substituted on the heterocycle; X is -C(=O)- or -S(=O)₂-; the same applies hereinafter.]

The compound (I) may more preferably include

Compound (Ib) as following:

[ wherein Ar is aryl or heteroaryl, optionally substituted; each R² is independently selected from the group consisting of H and lower alkyl; each R³ is independently selected from the group consisting of H and lower alkyl; each R⁴ is independently selected from the group consisting of H and lower alkyl; R⁵ is lower alkyl, halogenated lower alkyl, aryl optionally substituted, heterocycle optionally substituted, cycloalkyl optionally substituted, aryl-0 optionally substituted, het erocycle-0 optionally substituted, aryl- (lower alkyl) optionally substituted on the ary1 , he terocycle- ( lower alkyl) optionally substituted on the heterocycle, aryl- (lower alkoxy) optionally substituted on the aryl, or he terocycle- ( lower alkoxy) optionally substituted on the heterocycle; the same applies hereinafter.]

In the each definition of the Compound (I) , pre f erably , (1) Ar is aryl optionally substituted;

(2) Ar is phenyl optionally substituted;

(3) the substituent (s) of Ar is selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy, cyano, nitro, amino, carbamoyl, aminosul fony1 and carboxy;

(4) the substituent ( s ) of Ar i s se lected from the group consisting of lower alkyl, halogen, cyano, nitro, carbamoyl, aminosul fony1 and carboxy;

(5) the substituent(s) of Ar is halogen; (6) thesubstituent(s) of Ar is selected from the group consisting of a fluorine atom and a chlorine atom;

(7) the subs t i tuent ( s ) of Ar is a fluorine atom;

(8) R¹ is -C(=O)-R⁵ or -S(=O)₂-R⁵, wherein R⁵ is lower alkyl, halogenated lower alkyl, aryl optionally substituted, heterocycle optionally substituted, cycloalkyl optionally substituted, aryl-0 optionally substituted, het erocycle-0 optionally substituted, aryl- (lower alkyl) optionally substituted on the aryl, he terocycle- ( lower alkyl) optionally substituted on the heterocycle, aryl- (lower alkoxy) optionally substituted on the aryl, or he terocycle- ( lower alkoxy) optionally substituted on the heterocycle;

(9) R¹ is -C(=O)-R⁵;

(10) R¹ is -C(=O)-R⁵, wherein R⁵ is lower alkyl, halogenated lower alkyl, aryl optionally substituted, heteroaryl optionally substituted, cycloalkyl optionally substituted, aryl-0 optionally substituted, heteroaryl-0 optionally substituted, aryl- (lower alkyl) optionally substituted on the aryl, he teroaryl -( lower al kyl ) opt i onal Iy subs t it ut ed on the heteroaryl, aryl-(lower alkoxy) optionally substituted on the aryl, or he teroaryl -( lower alkoxy) optionally substituted on the heteroaryl;

(11) R¹ is -C(=O)-R⁵, wherein R⁵ is lower alkyl, halogenated lower alkyl, aryl optionally substituted, heteroaryl optionally substituted, aryl- (lower alkoxy) optionally substituted on the aryl, or he teroaryl -( lower alkoxy) optionally substituted on the heteroaryl; (12) R¹ is -C(=O)-R⁵, wherein R⁵ is lower alkyl, aryl optionally substituted, heteroaryl optionally substituted, aryl-0 optionally substituted, heteroaryl-0 optionally substituted or aryl- (lower alkoxy) optionally substituted on the aryl; (13) R¹ is -C(=O)-R⁵, wherein R⁵ is lower alkyl; (14) R¹ is -C(=O)-R⁵, wherein R⁵ is aryl optionally substituted or heteroaryl optionally substituted;

(15) R¹ is -C(=O)-R⁵, wherein R⁵ is aryl optionally substituted; (16) R¹ is -C(=O)-R⁵, wherein R⁵ is heteroaryl optionally substituted;

(17) t he subs t ituent ( s ) of R⁵ i s selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy, cyano, nitro, amino, carbamoyl, aminosul fonyl , carboxy, (lower alkoxy) -carbonyl, R⁶-S-, R⁶-S(O)-, R⁶-SO₂-, R⁶-SO₂NH-, R⁶-CONH-, R⁶-CONHSO₂-, R⁶-SO₂NHCO-, lower alkyl substituted by 1 to 3 of R⁷, heteroaryl, and oxo ; wherein R⁶ is lower alkyl, halogenated lower alkyl, or phenyl optionally substituted with halogen, lower alkyl or halogenated lower alkyl; R⁷ is hydroxy, lower alkoxy, carboxy, (lower al koxy ) -carbonyl , carbamoyl; and any nitrogen atoms in carbamoyl or aminosulfony1 may be substituted by lower alkyl;

(18) the subst ituent ( s ) of R⁵ i s select ed from the group consisting of lower alkyl, lower alkoxy, halogen, carbamoyl, aminosul fony1 , carboxy and (lower alkoxy) -carbonyl;

(19) the subst ituent ( s ) of R⁵ i s select ed from the group consisting of lower alkoxy, halogen, aminosul fony1 , carboxy and (lower alkoxy) -carbonyl ;

(20) R² is H;

(21) R² is (C1-C4 ) alkyl;

(22) R² is (C1-C2 ) alkyl;

(23) R³ is H; (24) R³ is (C1-C4 ) alkyl; (25) R³ is (C1-C2 ) alkyl;

(26) R⁴ is H;

(27) R⁴ is (C1-C4) alkyl;

(28) R⁴ is (C1-C2 ) alkyl . The combination of any two or more of (1) to (28) is more preferable.

The Compound (I) is preferably selected from:

(2R) -1- (3, 4-Difluorophenyl) -4- [4- (2-methoxy- benzoyl) -1-piperazinyl] -4-oxo-2-butanamine hydrochloride;

(2R) -4- [4- (2-Methoxybenzoyl) -1-piperazinyl] -4-oxo-

1- (2, 4, 5-trifluorophenyl) -2-butanamine hydrochloride; (2R)-I- (3, 4-Difluorophenyl) -4- [4- (2, 6-dimethoxy- benzoyl) -1-piperazinyl] -4-oxo-2-butanamine hydrochloride;

(2R) -1- (3, 4-Difluorophenyl) -4- [4- (5-fluoro-2- methoxybenzoyl) -1-piperazinyl] -4-oxo-2-butanamine hydrochloride;

3- ( { 4- [ (3R) -3-Amino-4- (3, 4-difluorophenyl) - butyryl] -1-piperazinyl }-carbonyl) -4-methoxy- benzenes^'ulfonamide hydrochloride;

3- ( { 4- [ (3R) -3-Amino-4- (2, 4 , 5-trifluorophenyl) - butyryl] -1-piperazinyl }carbonyl) -4-methoxybenzene- sulfonamide hydrochloride;

3- ( { 4- [ (3R) -3-Amino-4- (3, 4-difluorophenyl) - butyryl] -1-piperazinyl }carbonyl)benzenesulfonamide hydrochloride; 3- ( { 4- [ (3R) -3 -Amino- 4- (2, 4, 5-trifluorophenyl) - butanoyl]-l-piperazinyl}carbonyl)benzoic acid hydrochloride;

4- ( {4- [ (3R) -3-Amino-4- (2 , 4, 5-trifluorophenyl) - butanoyl]-l-piperazinyl}carbonyl)benzoic acid hydrochloride;

5- ( {4- [ (3R) -3-Amino-4- ( 2 , 4, 5-trif luorophenyl) - butanoyl] -l-piperazinyl}carbonyl) isophthalic acid hydrochloride; and

5- ( { 4- [ (3R) -3-Amino-4- (2, 4 , 5-trifluorophenyl) - but anoyl ] - 1-pipera z iny1 } carbony1 ) ni cot inic acid dihydrochloride .

The Compound (I) of the present invention can be prepared according to the following Process A to C. In the following production methods, it is sometimes effective from the viewpoint of the production technique to replace a certain functional group depending on the type with an appropriate protective group, namely a group readily convertible to the functional group, at the stage of a raw material or intermediate. Afterwards, the protective group can be eliminated, if necessary, to obtain the desired compound. Examples of such a functional group include an amino group, hydroxyl group, carboxyl group and the like. Protective groups thereof are, for example, those described in Protective Groups in Organic Synthesis, the third edition (T. W. Green and P. G. M. Wuts, eds., JOHN WILLY & SONS, INC. (the contents of which are hereby incorporated by reference) ) . These may be appropriately used depending on the reaction conditions. For introducing and eliminating such protective groups, the methods described in the reference can be suitably applied. Process A

(H) (HI) ( 1 -1)

In the above formula, in case where R² is H, R^2a is a protective group, such as (lower alkoxy)- carbony1 , and when R² is lower alkyl, R^2a is lower alkyl or a protective group; the same applies hereinafter. These combinations of R² and R^2a hardly have adversely effects on the above reaction.

This process is carried out by reacting piperazinyl compound (II) with carboxylic acid Compound (III) . Compounds (II) and (III) may be purchased if it is commercial, or synthesized according to general methods obvious to the person skilled in the organic chemistry from commercial compounds.

In this process, general amide - forming reaction such as reaction using condensating agent can be employable. The condensating agent employable in this process is not particularly limited so long as it accelerates forming amide bond and may include carbodiimide compounds such as dicyclohexy1- carbodiimide (DCC), di i sopropylcarbodi imide (DIPCI), 1 -ethyl- 3- (3' -dimethylaminopropyl) carbodiimide

(wa »ter solvable carbodiimide: WSCD) .

In this case, additive is generally used. The additive employable in this process is not particularly limited so long as it can mainly make the carboxyl groups of Compound (-III) active or suppress the racemi zat ion , and may include 1 -hydroxybenzot ria zole (HOBt), 3, 4-dihydro-3-hydroxy-4-oxo-l, 2 , 3-benzotriazine

(HOOBt), l-hydroxy-7-azabenzotriazole (HOAt),

N-hydroxysuccinimide (HONSu) .

The solvent employable in this process is not particularly limited so long as it is inactive in this reaction and may include amides such as dimethy1 formamide (DMF) and dimethylacet amide (DMA); aromatic hydrocarbons such as benzene, toluene; ethers such as tetrahydrofuran (THF), 1,4-dioxane; halogenated hydrocarbons such as dichloromethane , chloroform .

This process is generally carried out by adding

Compound (II) , to the solution of Compound (III) , condensing agent and additive.

Generally, when Compound (II) is added, the mixture is cooled. The temperature after addition depends on the starting material, the solvent, or the like, and it is usually room temperature.

The reaction time after the adding depends on the starting material, the solvent, or the like, and it is usually from lhr to 24hrs.

After the reaction, the mixture is quenched with water, and extracted with organic solvent insoluble with water such as ethyl acetate, chloroform, or the like. The organic layer is washed by water such as hydrochloric acid, saturated aqueous NaHCθ3, brine, or the like. The washed organic layer is dried over anhydrous magnesium sulfate or sodium sulfate, and evaporated in vacuo. The target compound is purified by the conventional method such as silica gel chromatography to obtain Compound (I) .

The deprotection reactions, if necessary, can be carried out according to the method described in the aforementioned "Protective Groups in Organic Synthesis", the third edition.

Compound (I) can also be synthesized by following Process B. Process B

In the above formula, L is OH or a leaving group; the same applies hereinafter.

This process is carried out by reacting Compound (IV) such as carboxylic acid compound with piperazinyl compound (V) in the presence of catalyst in solvent. Compounds (IV) may be purchased if it is commercial , or synthesized according to general methods obvious to the person skilled in the organic chemistry from commercial compounds, since the structure of Compound

(IV) is relatively simple. Compounds (V) can be obtained in Process C mentioned after.

The condition described in the above mentioned Process A can be applied to this Process B, when carboxylic acid is used as compound (IV) .

In case that L is a leaving group, an acid halide

(acid chloride, or the like) or an acid anhydride can be used as compound (IV) , and then a base [an inorganic base such as potassium carbonate, sodium hydroxide, or the like, or an organic base such as t riethylamine

(TEA), di i sopropyIethylamine , pyridine, or the like] is preferably added.

The Compound (V) which is starting material of the above Process B can be prepared according to the following Process C. Process C

R^la represents aryl-(lower al koxy ) -C ( =0 ) - or heteroaryl -( lower a 1 koxy ) -C ( =0 ) - in the definition of

R¹, or lower al koxy-C ( =0 ) - , that is, each acyl group can be easily cleaved as protective group of amino group.

Process C is the process for removing of acyl group from amino group of piperazinyl moiety.

Compound (1-2) can be synthesized by Process A mentioned above.

The condition of Process C can be carried out according to the method described in the aforementioned "Protective Groups in Organic Synthesis", the third edition. Above processes, all starting materials and product compounds may be salts. The compounds of above processes can be converted to salt according to a conventional method.

The patents, patent applications and publications cited herein are incorporated by reference.

The pharmaceutical composition of the invention, which contains as effective components one type or two or more types of the compound of the invention, can be prepared according to a method usually used by using pharmaceutical carriers, excipients and the like for general use in this field. Administration thereof may be either oral via tablets, pills, capsules, granules, powders, liquids, and the like or parenteral dosing via injections such as intravenous injections, int ramus cular inj ect ions , andthelike, external agent s such as ointment s , plasters, creams, jellies, cataplasm, sprays, lotions, eyedrops, eye ointment s , andthelike, suppositories, inhalation agents, and the like.

As the solid composition for oral administration, tablets,' powders, granules and the like are used. In such a solid composition, one or more active substances are mixed with at leas t one inert excipient , forexample, lactose, mannitol, glucose, hydroxypropy1 cellulose, microcrys t a 11 ine cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate, or the like. According to general methods, the composition may contain inert additives such as lubricants, e.g., magnesium stearate, or the like; disintegrators, e.g., sodium carboxymethy1 starch, or the like; and dissolution auxiliary agents. The tablets or pills may be coated with sugar coating or stomach- soluble or enteric coating.

Examples of the liquid composition for oral administration include pharmaceutically acceptable emulsions, liquids, suspensions, syrups, elixirs, or the like, in which inert solvents for general use such as purified water, ethanol, or the like can be incorporated. In addition to the inert solvents, the composition may further contain auxiliary agents such as solubilizing agents, moistening agents and suspending agents; sweetening agents; flavoring agents; aromatic agents and preservatives.

Examples of the injections for parenteral administration include sterile aqueous or non-aqueous liquids, suspensions and emulsions. The aqueous solvents include, for example, distilled water for injections and physiological saline. The non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (under trade name) and the like. Such compositions may further contain isotonic agents, preservatives, moistening agents, emulsifying agents, dispersing agents, stabilizers and dissolution auxiliary agents. These are sterilized by filtering through bacteria -retaining filters, by incorporating sterilizing agents, or by irradiation. Alternatively, these may be produced into a sterile solid composition and then dissolved or suspended in sterile water or sterile solvents for injections prior to use.

While the dosage of therapeutically effective amount of the Compound (I) depend upon the age and condition of each individual patient, an average single dose of about 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the Compound (I) may be effective for treating the above-mentioned diseases . In general, amounts between 0.01 mg/body and about 1, 000 mg/body may be administered per day. The dose is administered once or in- separate portions.

THE BEST MODE FOR CARRYING OUT THE INVENTION

The following Examples are given only for the purpose of illustrating the present invention in more detail .

The following abbreviations are used in the Tables. Ex: Example number, REx: Reference example number, Str: Structure, Dat : phys icochemi ca 1 data (FAB: FAB-MS (M+H)⁺, FAB-N: FAB-MS(M-H)^", ESI: ES I -MS ( M+H )⁺ , ESI-N: ESI-MS(M-H)^", NMRl: δ(ppm) of characteristic peaks of¹H-NMR in DMSO-d₆, NMR2 : δ(ppm) of characteristic peaks of¹H-NMR in CDCl₃) , Sal: salt (HCl: hydrochloride, TsOH: p- toluene sul fonate , Ox: oxalate, Frm: formate, "-" or blank column: free compound, the numeral before a component means molar ratio, for example 2HCl means dihydrochlor ide ) , Syn: production method (each numeral indicates a similarly produced Example or Reference example number), Me: methyl, Et: ethyl, Pr: 1-propyl, tBu: tert-butyl, Ac: acetyl, Ph: phenyl, Bn: benzyl, Boc: t Bu-O-C ( =0 )-, and Ms: Me-S (=0)₂~. In addition, the numeral before each substituent shows the position of substitution, for example, 2 , 6- ( OMe )₂~Ph means 2 , 6-dimet hoxypheny1 and 2-F-6-OMe-Ph means 2 - fluoro- 6-methoxypheny1.

Reference example 1

To a stirred mixture of 3 - ( R ) - 1 -but oxy- carbonylamino-4- (3, 4-difluorophenyl) butyric acid (75 mg) and HOBt (35 mg) in DMF (3 mL ) , was added WSCD hydrochloride (50 mg) at ice-bath temperature. The mixture was stirred for 30 minutes at room temperature, then 1 -acetylpipera z ine (32 mg) was added to the mixture at ice-bath temperature. After addition, the resulting mixture was stirred for overnight at room temperature. The reaction mixture was poured into water (15 mL ) and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography e luting with chloroform/methanol (50: 1 to 10:1) to give t-Butyl [ (2R) -4- (4-acetyl-l-piperazinyl) -1- (3, 4-difluoro- phenyl ) -4 -oxobutyl ] carbamate (100 mg) .

Reference example 2 To a solution of t-butyl [(2R)-4-(4- benzyloxycarbonyl-1-piperazinyl) -1- (3, 4-difluoro- pheny1 )- 4 -oxobutyl ] carbamate (333 mg ) in ethanol (10 mL) , was added 10% palladium on carbon (70 mg) . The resulting mixture was stirred under atmospheric hydrogen at room temperature for 4.5 hours . The mixture was filtered through Celite and washed with ethanol. The filtrate was concentrated in vacuo to give t-Butyl [ (2R) -4- (1-piperazinyl) -1- (3, 4-difluoro-phenyl) -A- oxobuty1 ] carbamate (246 mg) as a colorless solid.

Reference example 3

To a stirred mixture of 2-methoxybenzoic acid (15.0 mg) and HOBt (14.7 mg) in DMF (300 μL), was added WSCD hydrochloride (20.8 mg) at ice-bath temperature. The mixture was stirred for 1 hour at room temperature, then a solution of t-butyl [ ( 2 R ) - 4 - ( 1 -pipera z iny1 ) - 1- (3, 4-difluorophenyl) -4-oxobutyl] carbamate (37.8 mg) in DMF (150 μL) was added dropwise to the mixture at ice-bath temperature. After addition, the resulting mixture was stirred for overnight at room temperature. The reaction mixture was poured into saturated sodium hydrogen carbonate aqueous solution and extract ed with ethyl acetate . The combined organi c layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with chloroform/methanol (50/1 to 20/1) to give t -But yl [ (2R) -4- (2-methoxybenzoyl-l-piperazinyl) -1- (3, A- di fluorophenyl )- 4 -oxobutyl ] carbamate (50.8 mg) .

Reference example 4

To a solution of diethyl 5- ( { 4 - [ ( ben zyloxy ) - carbonyl] -l-piperazinyl}carbonyl) isophthalate (1.10 g) in ethanol (5 mL ) was added a solution of potassium hydroxide (136mg) inethanol ( 4 mL ) at room temperature , and the mixture was stirred at same temperature for 5.5 hours . The react ion mixture was evaporated in vacuo and the residue was dissolved in water. The aqueous layer was washed with ethyl ether, adjusted to pH3 with 1 mol/L hydrochloric acid, and extracted with chloroform. The organic layer was dried over magnesium sulfate, and evaporated in vacuo. The residue was crystallized from a mixture of hexane and isopropyl ether (1/1) to give 3-({4- [ (benzyloxy) carbonyl] -1-piperazinyl} carbonyl) - 5 - ( ethoxycarbony1 ) benzoic acid (810 mg) as crystals.

Reference example 5

To^'a mixture of 3- ({4-[ (benzyloxy) carbonyl] - l-piperazinyl(carbonyl) -5- (ethoxycarbonyl) benzoic acid (1.00 g), THF (12.5 mL) , and t-butanol (12.5 mL) were added di-t-butyl dicarbonate (495 mg ) and 4 -dimethylaminopyridine (27 mg) at room temperature under nitrogen, and the mixture was stirred at room temperature for 18 hours. To the mixture were added di-t-butyl dicarbonate (495 mg) and 4 -dimethylaminopyridine (10 mg) , and the reaction mixture was stirred for another 8 hours. The solvent was removed in vacuo, and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. Obtained colorless solid was triturated with a mixture of petroleum ether and hexane (1/1) to give t-butyl ethyl 5- ( {4- [ (benzyloxy) carbonyl] -1-piperazinyl}- carbony1 ) i sophthalat e (1.00 g) as a colorless powder.

Reference example 6

To a suspension of chelidamic acid monohydrate (1.0 g) in ethanol (10 πiL ) was added sulfuric acid (1 mL ) on an ice-water bath, and the mixture was heated to reflux with stirring for 1 hour. After cooling, the reaction mixture was concentrated in vacuo. The residue was adjusted to pH5 with saturated sodium bicarbonate aqueous solution, and the precipitates formed were filtered off. The filtrate was washed with ether, and concentrated in vacuo. The residue was dissolved in water, and the solution was filtered through HP-20. The solution was concentrated in vacuo, and the residue was triturated with isopropyl ether to give 6- ( ethoxycarbonyl ) - 4 -hydroxy- 2 -pyrάdinecarboxylic acid (260 mg) as a powder.

Reference example 7 To a solution of 3 - ( ethoxycarbony1 ) - 5-nit robenzoic acid (2.00 g) in methanol (30 mL) was added Pd/C(200 mg) . Themixture was agitated under 2.5 atm hydrogen atmosphere for 4 hours at room temperature . The reaction mixture was filtrated and the filtrate was concentrated in vacuo. The residue (1.74 g) was dissolved in pyridine (20 mL ) . To the solution was added methyl sulfonyl chloride (644μL) and stirred for 3 hours at room temperature. The reaction mixture was concentrated in vacuo. To the residue was added ethyl acetate and 1 mol/L hydrochloric acid. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo to obtain 3- (ethoxycarbonyl) -5- [ (methylsulfonyl) amino] - benzoic acid as pale red solid (1.29 g) .

Reference example 8

To a mixture of t-Butyl [ ( 2R ) - 4 - [ 4 - ( 4 - methoxycarbonylbenzoyl) -1-piperazinyl] -1- (2, 4, 5 - tri fluorophenyl )- 4 -oxobutyl ] carbamate (190 mg ) , THF

(5.0 mL) and methanol (1.5 mL ) was added 1 mol/L NaOH aqueous^' solution (1.0 mL ) at 0⁰C. After the reaction mixture was stirred at room temperature for 1.5 hours, 1 mol/L hydrochloric acid (1.0 mL ) was added to the react ion mixture at 0⁰C. The solutionwas concentrated under reduced pressure and was added water. The precipitates were collected by filtration, then washed with water to give t-Butyl [ (2R)-4-[4-(4-carboxybenzoyl)-l-piperazinyl]-l-(2, 4 , 5 -tri fluorophenyl )- 4 -oxobutyl ] carbamate (180 mg) as white solid .

Reference example 9

A mixture of t-Butyl [ ( 2 R ) - 4 - [ 4 - ( 4 -cyano- benzoyl) -1-piperazinyl] -1- ( 2 , 4, 5-tri fluorophenyl) - 4-oxobutyl] carbamate (250 mg), NaN₃ (75 mg), NH₄Cl (65 mg) and DMF (10.0 mL ) was stirred at 100°C for 20 hours. The reaction mixture was diluted with water and extracted with chloroform. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (chloroform : methanol=l 00 : 0 to 85:15) to give t-Butyl [(2R)-4-[4-(4-tetrazol-5-ylbenzoyl)-l- piperazinyl] -1- (2, 4, 5-trif luorophenyl) -A- oxobutyl ] carbamate (240 mg ) as colorless solid.

Reference example 10

Triethylamine (0.44 mL ) was added to a suspension of hyd^'roxyl amine hydrochloride (250 mg) in dimethy1 sul foxide (DMSO, 5.0 mL ) . An insoluble material was filtered off and washed with THF. The Filtrate was concentrated in vacuo to remove THF, and t-Butyl [ (2R) -4- [4- (4-cyanobenzoyl) -1-piperazinyl] - 1- (2, 4, 5-tri fluorophenyl) -4-oxobutyl] carbamate (250 mg) was added to the DMSO solution. After stirring at 75°C for 18 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. To the aqueous solution was added 1 mol/L NaOH aqueous solution and extracted with ethyl acetate (3 x 30 mL ) . The combined organic solution was washed with brine and dried over magnesium sulfate. The s olvent was evaporated in vacuo and the residue was purified by silica gel column chromatography ( chloroform : methanol= l 00 : 0 to 75:25) . The obtained compound (180 mg) wa s di s solved in pyridine (0.050 mL) and DMF (2.0 mL ) and 2-ethylhexyl chloroformate (0.060 mL) was added dropwise to the solution under ice-cooling. After stirring at 0°C for 30 min, the reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was dissolved in xylene (3.0 mL ) . The solution was heated under reflux for 2 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography ( chloroform : methanol=l 00 : 0 to 90:10) to give t-Butyl [ ( 2 R ) - 4 - [ 4 - [ 4 - ( 5-oxo- 1 , 2 , 4 - oxadiazol-3-yl) benzoyl] -1-piperazinyl] -1- (2, 4, 5- tri fluorophenyl )- 4 -oxobutyl ] carbamate (100 mg) .

In a similar manner to the above Reference examples, the compounds of Reference examples 11 to 154 shown in the following Tables 1 to 5 were obtained, respectively. Structures and phys icochemical data of the compounds of Reference examples 1 to 154 are shown in ϊ Tables 1 to 5. Table 1-1

Table 1-2

Table 2-1

Table 2-2

Table 2-5

Table 2-6

Table 2-7

Table 2-:

Table 2-9

Table 2-10

Table 3

Table 4

Table 5

Example 1

[ (2R) -4- (4-Acetyl-l-piperazinyl) -1- (3, 4-difluoro- pheny1 ) - 4 -oxobuty1 ] amine hydrochloride To an ice cooled solution of t-butyl [(2R)- 4 - (4-acetyl-l-piperazinyl) -1- (3, 4-difluorophenyl) - 4 -oxobutyl ] carbamate (95 mg) in CH₂C^ ( 2 mL ) , was added 4 mol/L hydrogenchloride in dioxane (407 μL) . The mixture was stirred at room temperature for 1 hour. The solvent was concentrated in vacuo, and the residue was triturated with i sopropylether /ethyl acetate to give the target compound (73 mg) as a white solid.

Example 2

(2R) -4- [4- (4-fluorobenzoyl) -1-piperazinyl] - 4-oxo-l- (2, 4, 5-trifluorophenyl) -2-butanamine hydrochloride was prepared by a similar manner to the method in Reference example 3, followed by the method in Example 1.

In a similar manner to the above Examples 1 or 2, the compounds of Examples 3 to 132 shown in the following Tables 6 to 8 were obtained, respectively. Structures and phys icochemical data of the compounds of Examples

1 to 132 are shown in Tables 6 to 8.

Table 6-1

Table 6-2

Table 7-1

Tab: Le 7-3

Table 7-4

Table 7-6

Table 7-

Table 7-9

Table 7-10

T ab l e 8

In order to illustrate the usefulness of the object 5 Compound (I) , the pharmacological test is carried out as shown in the following.

Inhibition test of human plasma DPP-IV :

(i) Material and Method : 10. The effect of test compounds on DPP-IV activity in human plasma was evaluated with a modified version of the assay described by Hughes et al (Biochemistry,

38, ppll597-11603 (1999)).

Briefly, 20 μL of human plasma were mixed with 20 15 μL.of 80 mM MgCl₂ in assay buffer (25 mM HEPES, 140 mM

NaCl, 1% RIA-grade BSA, pH7.8), and were incubated in room temperature for 60 minutes. Then the reaction was initiated by the addition of both 20 μL of test compounds and 20 μL of 0.2mM substrate ( H- glycine -pro 1 ine -AMC ; AMC is 7 -amino- 4 -methy1 coumarine ) , which were dissolved in the assay buffer.

After 20 minutes incubation in room temperature (kept in the dark), fluorescence was measured (Excitation 380nm, Emission 460nm). A fluore scence -concent rat ion curve of free AMC was obtained using AMC solution in the assay buffer with appropriate concentration. Plasma DPP- IV act ivities , with or without the test compounds, were expressed as the amount of product per minute per mL . The potency of the test compounds as DPP-IV inhibitor was expressed as IC₅₀ •

( ii ) Results :

The following IC₅₀ values were obtained

Table 9

Reference compounds Ref . A and Ref . B are disclosed in WO 03/000181, Example 12 and 45, respectively.

It appeared, from the above-mentioned inhibition test, that the compound (I) or pharmaceutically acceptable salt thereof of the present invention has an inhibiting activity against DPP-IV.

Therefore, the compound (I) or pharmaceutically acceptable salt thereof is useful for treating or preventing disease mediated by DPP-IV, more particularly useful for treating or preventing altered glucose tolerance, glucosuria, hyper lipidemia , metabolic acidosis, diabetes mellitus (type 1 and type 2), diabetic neuropathy, nephropathy, and secondary diseases in mammals caused by diabetes mellitus.

Further, the compound (I) or pharmaceutically acceptable salt thereof is useful for treating or preventing autoimmune disease, arthritis, rejection of transplanted organs, systemic lupus erythematosus

(SLE), acquired immunodeficiency syndrome (AIDS), hypertension, atherosclerosis, gallbladder disease, cancer, intestinal disease and dwarfism.

' This application is based on Australian Provisional Patent Application No .2005901293 filed on March 16, 2005, the content of which is hereby incorporated by references

Claims

C L A I M S

1. A compound of formula (I) or pharmaceutically acceptable salt thereof.

(I)

[ where in

Ar is aryl or heteroaryl, optionally substituted;

R¹ is a cy1 ; each R² is independently selected from the group consisting of H and lower alkyl; eeaacchh RR³³ iiss iinnddeeppeennddeennttllyy sseelleeccted from the group consisting of H and lower alkyl; eeaacchh RR⁴⁴ iiss iinnddeeppeennddeennttllyy sseelleeccted from the group consisting of H and lower alkyl.]

2. A compound of formula (Ia) or pharmaceutically acceptable salt thereof.

[ wherein Ar is aryl or heteroaryl, optionally substituted; each R² is independently selected from the group consisting of H and lower alkyl; each R³ is independently selected from the group consisting of H and lower alkyl; each R⁴ is independently selected from the group consisting of H and lower alkyl; R⁵ is lower alkyl, halogenated lower alkyl, aryl optionally substituted, heterocycle optionally substituted, cycloalkyl optionally substituted, aryl-0 optionally substituted, het erocycle-0 optionally substituted, aryl-(lower alkyl) optionally substituted on the aryl, heterocycle- ( lower alkyl) optionally substituted on the heterocycle, aryl- (lower alkoxy) optionally substituted on the aryl , or heterocycle- ( lower alkoxy) optionally substituted on the heterocycle; X is -C(=0)- or -S(=O)₂-.]

3. A compound of formula (Ib) or pharmaceutically acceptable salt thereof.

[ wherein

Ar is aryl or heteroaryl, optionally substituted; each R² is independently selected from the group consisting of H and lower alkyl; each R³ is independently selected from the group consisting of H and lower alkyl; each R⁴ is independently selected from the group consisting of H and lower alkyl; R⁵ is lower alkyl, halogenated lower alkyl, aryl optionally substituted, heterocycle optionally substituted, cycloalkyl optionally substituted, aryl-0 optionally substituted, het erocycle-0 optionally substituted, aryl- (lower alkyl) optionally substituted on the ary1 , het erocycle- ( lower alkyl) optionally substituted on the heterocycle, aryl- (lower alkoxy) optionally substituted on the aryl, or het erocycle- ( lower alkoxy) optionally substituted on the heterocycle.]

4. The compound of Claim 1, wherein Ar is phenyl optionally substituted with subs tit uent ( s ) selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy, cyano, nitro, amino, carbamoyl, aminosul fony 1 and carboxy.

5. The compound of Claim 1, wherein Ar is phenyl optionally substituted with halogen atom(s) .

6. The compound of Claim 3, wherein R⁵ is aryl optionally substituted or heteroaryl optionally substituted; ea ch subst ituent ( s ) is(are) selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy, cyano, nitro, amino, carbamoyl, aminosulfonyl , carboxy, ( lower al koxy ) -carbonyl , R⁶-S-, R⁶-S(O)-, R⁶-SO₂-, R⁶-SO₂NH-, R⁶-CONH-, R⁶-CONHSO₂-, R⁶-SO₂NHCO-, lower alkyl substituted by 1 to 3 of R⁷, heteroaryl and oxo; wherein R⁶ is lower alkyl, halogenated lower alkyl, or phenyl optionally substituted with halogen, lower alkyl or halogenated lower alkyl; R⁷ is hydroxy, lower alkoxy, carboxy, (lower alkoxy) -carbonyl or carbamoyl; and any nitrogen atoms in carbamoyl or aminosul fony1 may be substituted by lower al kyl .

7. The compound of Claim 3, wherein R⁵ is aryl optionally substituted with subs t i tuent ( s ) selected from the group consisting of lower alkoxy, halogen, aminosul fony1 , carboxy and (lower al koxy )- carbonyl .

8. The compound any one of Claims 1 to 6, wherein R² is H.

9. The compound any one of Claims 1 to 8, wherein R³ is H.

10. The compound any one of Claims 1 to 9, wherein R⁴ is H.

11. A compound selected from:

(2R) -4- [4- (2-Methoxybenzoyl) -1-piperazinyl] -4-oxo-

1- (2, 4, 5-trifluorophenyl) -2-butanamine hydrochloride;

(2R) -1- (3, 4-Difluorophenyl) -4- [4- (2, 6-dimethoxy- benzoyl) -1-piperazinyl] -4-oxo-2-butanamine hydrochloride;

(2R) -1- (3, 4-Difluorophenyl) -4- [4- (5-fluoro-2- methoxybenzoyl) -1-piperazinyl] -4-oxo-2-butan-amine hydrochloride; 3- ( { 4- [ (3R) -3 -Amino- 4- (3, 4-dif luorophenyl) - butyryl] -1-piperazinyl }-carbonyl) -4-methoxy- benzenesulfonamide hydrochloride;

3- ( { 4- [ (3R) -3-Amino- 4- (2, 4, 5-trifluorophenyl) - butyryl] -1-piperazinyl Jcarbonyl) -4-methoxybenzene- sulfonamide hydrochloride;

3- ( {4- [ (3R) -3-Amino-4- (3, 4-difluorophenyl) - butyryl] -1-piperazinyl }carbonyl)benzenesulfonamide hydrochloride;

3- ( {4- [ (3R) -3-Amino-4- (2, 4, 5-trifluorophenyl) - but anoyl ]- 1 -pipera z inyl } carbonyl ) benzoic acid hydrochloride;

4- ( { 4- [ (3R) -3 -Amino- 4- (2, 4, 5-trifluorophenyl) - butanoyl]-l-piperazinyl}carbonyl)benzoic acid hydrochloride; 5- ( {4- [ (3R) -3-Amino-4- (2, 4, 5-trifluorophenyl) - butanoyl] -l-piperazinyl}carbonyl) isophthalic acid hydrochloride; and

5- ( { 4- [ (3R) -3-Amino-4- (2, 4 , 5-trif luorophenyl) - butanoyl] -l-piperazinyl}carbonyl)nicotinic acid dihydrochlor ide .

12. A compound of any one of Claims 1 to 11 for use as a medicament.

13. The compound of Claim 12 for use in the treatment and/or prevention of Type 2 Diabete Mellitus in human beings or animals.

14. A medicament comprising a compound of any one of Claims 1 to 11 as an active ingredient.

15. A pharmaceutical composition comprising a compound of any one of Claims 1 to 11 as an active ingredient, in association with a pharmaceutically acceptable carrier or excipient.

16. An inhibitor of DPP-IV consisting of a compound of any one of Claims 1 to 11.

17. A method for treatment and/or prevention of Type 2 Diabete Mellitus which comprises administering an effective amount of the compound of any one of Claims 1 to 11 to human beings or animals.

18. Use of the compound of any one of Claims 1 to 11 for treatment and/or prevention of Type 2 Diabete Mellitus in human beings or animals.

19. A commercial package comprising the pharmaceutical composition containing the compound identified in any one of Claims 1 to 11 and a written matter associated therewith, wherein the written matter states that the compound can or should be used for preventing or treating Type 2 Diabete Mellitus.