FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2010 COMPLETE SPECIFICATION
(See section 10; rule 13)
"NOVEL COMPOUNDS AS DPP-IV INHIBITORS AND PROCESS FOR PREPARATION
THEREOF"
CADILA PHARMACEUTICALS LIMITED
"Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat, Ahmedabad - 382210, Gujarat,
India
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:
The present invention relates to process for preparation of novel compounds which are acting as inhibitors of dipeptidyl peptidase-IV enzyme and are useful in the treatment or prevention of diseases in which the dipeptidylpeptidase-IV enzyme is involved, such as diabetes, particularly type-2 diabetes.
BACKGROUND OF INVENTION:
Various amino peptidases are present in the mammals and catalyze the sequential release of peptides from polypeptides such as pyroglutamyl aminopeptidase and prolyaminpeptidase in addition to dipeptidyl peptidase. Dipeptidyl peptidase family includes DPP-II, DPP-IV, DPP-VII, DPP-IX (Curr. Opin. Chem. Biol. 2003, 7, 496). The newly synthesized compounds provide DPP-IV inhibition activity sufficiently fast and with targeted rate. The enzyme DPP-IV also known as CD26 is a cell surface enzyme associated with immune regulation, signal transduction and apoptosis. DPP-IV enzyme works as a suppressor in the development of cancer and tumors. DPP-IV also binds to the enzyme adenosine deaminase specifically and with high affinity.
DPP-IV plays major role in glucose metabolism and is responsible for the degradation of incretins such as Glucagon-like peptide-1 (GLP-1). GLP-1 is an incretin hormone secreted by intestinal L-Cells in response to food intake. The active form of GLP-1 is a 30 amino acid peptides, which stimulate insulin release, inhibits glucagon release and slows gastric emptying; each has benefit in control of glucose homeostasis in patients with type II diabetes. GLP-1 is rapidly degraded by the plasma DPP-IV which cleaves a dipeptide from the N-terminal (Eur. J. Blochem., 1993, 214, 829 and Endocrinology 1995, 136, 3585). DPP-IV inhibitors offer several potential advantages over existing therapies including decreased risk of hypoglycemia, potential weight loss and the potential for regeneration and differentiation of pancreatic β - cells.
WO2010/029422 discloses novel hypoglycemic compounds of formula I and pharmaceutically acceptable salts thereof. The invention relates to novel amino acid derivatives of the formula I,

wherein,
A is amino acid, B is peptide bond
R-NH- wherein R is defined in the specification.
Chiral beta amino acid derivatives are reported in the "Journal of bioorganic and medicinal chemistry letters, 17 (2007), 2622-2628" wherein 2-(2, 4, 5 - trifluorophenyl)acetic acid was coupled with 2, 2-dimethyl-1,3-dioxane-4, 5-dione (meldrum's acid) using pivaloyl

chloride as an activating reagent to produce the coupled product; followed by methanolysis to yield the beta-keto ester. Reaction of beta-keto ester with ammonium acetate produced the corresponding beta-enamino ester which was converted to the chiral beta-(R)-amino esters by asymmetric catalytic hydrogenation with the chloro-(1, 5 - cyclooctadiene)rhodium (!) dimmer and (R)-(-)-1-I(S)-2(bis(4-trifluoromethylphenyl)phosphine)ferrocenyl ethyl-di-tert-phosphine under H2 (100) psi in trifiuoroethanol.
Alkyl 4-(2, 4, 5 -trifluorophenyl)-3-(R)-amino butanoate are prepared from commercially available N - Boc protected chiral 3-amino-4-(2, 4, 5 - trifluorophenyl) butanoic acid using Ci to C4 alkanol and HCI using known methods. OBJECTS OF INVENTION:
An object of the invention is to provide novel compounds having DPP-IV inhibitory activity.
Another object of the invention is to provide process for the preparation of novel compounds having DPP-IV inhibitory activity.
Another object of the invention is to provide process for preparation of N-substituted peptide derivatives of DPP-IV inhibitors.
Another object of the invention is to provide novel N-substituted peptide derivatives of 4-(2, 4, 5-trifluorophenyl)-3-amino butyric acid.
DESCRIPTION OF DRAWINGS:
Figure 1: In vivo screening results of CPL-2009-0027 Figure 2: In vivo screening results of CPL-2009-0030 Figure 3: In vivo screening results of CPL-2009-0031
DETAIL DESCRIPTION OF THE INVENTION:
The present invention provides novel compounds are inhibitors of the dipeptidyl peptidase-IV enzyme and process for preparation thereof.
The general structural formula of compounds having DPP-IV inhibitory activity according to present invention is depicted below:

Wherein,

Wherein,
Ar is phenyl or substituted phenyl having 1 to 5 halogen atoms in the phenyl ring, preferably
Ar is 2, 4, 5-trifluoro phenyl;
R is aa1 or aa1-aa2 or aa1-aa2-aa3 or aa-aa2-aa3-aa4, wherein aa1, aa2, aa3 and aa4 are
amino acids selected independently and is linked through a peptide bond;
R-i is Ci to C4 alkyl;
X is defined as an^ of the substructures X^ to X5l wherein substructures X, to X5 are
structurally depicted below:

The amino acids as described in the above table provides mono, di, tri or tetra peptide derivatives which on further reaction provides novel DPP-IV inhibitors.
The compounds of formula-VI, wherein X is -NH2 (X6), -NHPh (X7) (Ph is Phenyl), -NHBn (XB) (Bn is Bonzyl) are prepared by using standard conditions by reaction of the compounds of formula - (j||) or (IV) with suitable compounds having amino groups.
The compounds are optionally converted to its corresponding pharmaceutical^ acceptable salt form Using acids. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic or organic acids. The corresponding. salt of compound of formula XII is also prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids by the

know method in the art. Using acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, tartaric acids and the like.
The process for the preparation of compounds according to present invention using sequence of reactions as depicted in scheme 1 comprises reaction of 4-aryl-3-N-peptide substituted beta-amino acid derivatives [compounds of formula - (VI)] wherein,
1) deprotection followed by esterification of N-protected beta-amino acid (formula I) to give chiral beta amino acid ester derivatives (formula II);
2) reaction of chiral beta amino acid ester derivatives (formula II) with carboxyl terminal of N'-protected peptide compounds to give beta-amino N-acyf peptide compounds (formula 111);
3) reaction of beta-amino N-protected compound (formula III) with saponifying agent to provide beta-amino N-acylated-4-(2, 4, 5-trifluorophenyl)-3-amino butyric acid (formula IV);
4) condensation of beta-amino N-acylated-4-(2, 4, 5-trifluorophenyl)-3-amino butyric acid (formula IV) with any of substructures Xt to X5 to give corresponding amides of beta-amino N-acylated-N'-protected peptide compounds (formula V);
5) deprotection of amides of beta-amino N-acylated-N'-protected peptide compounds (formula V) to give 4-aryl-3-N-peptide substituted amino acid derivatives (formula VI).
The reaction scheme 2 for the preparation of novel compounds, wherein Ar is 2, 4, 5-trifluoro phenyl is as depicted below: Scheme - 2:


In accordance with the present invention, preparation of novel 4-(2, 4, 5-trifluorophenyl)-3-(N-peptide Substituted) amino acid derivatives of formula -XII comprises:
1) deprotection followed by esterification of N-protected beta-amino acid (formula VII) to give chiral beta ammo acid ester derivatives (formula VIII);
2) reaction of chiral beta amino acid ester derivative (formula VIII) with carboxyl terminal of N'-protected peptide compounds to give beta-amino N-acylated peptide compounds (formula IX), wherein As is 2, 4, 5-trifluoro phenyl;
3) beta-amino N-acylated peptide compounds (formula IX) are converted into beta-amino N-acylated-4-(2( 4, 5-trifluorophenyl) butanoic acids (formula X) by saponification;
4) reacting compounds of formula (X) with any of the compound (a) to (e) to give corresponding amides of formula (XI);
5) deprotection of beta-amino N-acylated-N'-protected peptide compounds of formula (XI) to give 4-aryl-3-N-peptide substituted amino acid derivatives (formula XII). Peptide bond is formed by coupling between a carboxyl group and an amino group in
presence of coupling agents. The coupling agents are selected from DCC, EDC, DIC and like. The preferable coupling agents are DCC and EDC.
The saponification reaction is carried out by using Inorganic base. The Inorganic base is selected from NaOH, KOH, LiOH and like. The preferable Inorganic bases are NaOH and LiOH. Deprotection reaction is carried out by using any prior art method.
The present invention is further illustrated with following non-limiting examples: Example-1: Preparation of 2-Amino-N-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazoIo[4,3-a]pyrazin-7-yl)-propyl]-3-phenyl-propionamide Hydrochloric Acid (Compound of Formula 6):


Reagents: (I) HCI-MeOH (II) N-Boc L-phe ,C(COOC2H5, TEA,THF (((() LiOH.H20, MeOH, THF, Water (IV) DCC, TEA, triazolopyrazine derivative (compound-7), THF (V) HCI-MeOH
Steo-l: Preparation of 3-Amino-4~(2.4.5-trifluoro-phenyl)-butyric acid methyl ester (Compound of formula 2) from 3-tert-Butoxycarbonylamino-4-(2,4,5~trifluaro-phenylk butyric acid (Compound of formula 1):

To a 3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid (Compound of formula 1) (12gm, 0.036 mole), HCI-MeOH was added at room temperature and stirred for 3-4 hours. After being stirred methanol was evaporated and residue was taken into water. pH of the solution was adjusted to basic using by solid bicarbonate and DCM is added to reaction mixture. Aq. layer was extracted with DCM. The combined organic layers were dried over anhydrous Na2S04, concentrated under vacuum to give 3-Amino-4-(2,4,5-trifluoro-phenyl)-butyric acid methyl ester (Compound of formula 2) as oil. (Yield = 8.5gm, 96%)
Step-ll: Preparation of 3~(2-tert-Butoxycarbonylamino-3-ohenvl-oropionylamino)-4-(2,4,5-trifluoro~phenvfl-butyric acid methyl ester (Compound of formula 3) from 3~ AminQ'4-(2A,5-trifluoro-phenvI)-butyric acid methyl ester (Compound of formula 2):
To a stirred solution of N-Boc-L-phe (6.97gm, 0.0263mole) in THF, triethylamine and ethylchloroformate were added at 0°C and reaction mixture was stirred for 1 hour at room temperature. To this stirred reaction mixture, 3-Amino-4-(2,4,5-trifluoro-phenyl)-butyric acid methyl ester (Compound of formula 2) (5gm, 0.0202 mole) was added at 0°C and was stirred for overnight. After being stirred, THF was evaporated; residue was taken into water and aq. layer was extracted with dichloromethane. The combined organic layers were washed with bicarbonate solution and 1N HCl solution; dried over anhydrous Na2SO^ and concentrated to give crude. The crude was purified by silica gel column chromatography using MeOH/CH2CI2 (0.2:9.8) to give 3-(2-tert-Butoxycarbonylamino-3-phenyl-propionylamino)-4-(2,415-trifluoro-phenyl)-butyric acid methyl ester (Compound of formula 3). (Yield = 5.4 gm, 52%).
Step-Ill: Preparation of 3~(2~tert-Butoxvcarbonylamino-3-ohenyl-propionvlamino)-4-(2,4,5-trifluoro-ohenyfl-butvric acid (Compound of formula 4} from 3-(2-tert-Butoxycarbonvlamino-3-phenvl-propionvlamino)~4~(2.4.5-trifluoro-ohenvl)-butvric acid methyl ester (Compound of formula 3):
To a stirred solution of 3-(2-tert-Butoxycarbonylamino-3-phenyl-propionylamino)-4-
(2,4,5-trifiuoro-phenyl)-butyric acid methyl ester (Compound of formula 3) (5.4gm,
0.011 mole) in THF; MeOH, water and LiOHH20 (0.55gm, 0.0133mole) were added at room
temperature and stirred for 3 hours. After being stirred, solvent was evaporated and residue
was taken into water. pH of the solution was adjusted to acidic using sodium hydrogen
sulphate and aq. layer was extracted with dichloromethane. The combined organic layers
were washed with water, dried over anhydrous Na2S04 and concentrated under vacuum to
give 3-(2-tert-Butoxycarbonylamino-3-phenyl-propionylamino)-4-(2,4,5-trifluoro-phenyl)-
butyric acid (Compound of formula 4) as white solid. (Yield = 5 gm, 96%).

Step-IV: Preparation of {1-f3-OxO'1-(2.4.5-trifluoro-benzyf)-3-(3-trifluoromethvi-5t6-dihvdro-8H-F1.2,4ltriazolof4.3-a]pvrazin-7-vl)-propylcarbamovn-2'Phenvl-ethyl)' carbamic acid tert-butyl ester (Compound of formula 5) from 3-(2-tert-Butoxvcarbonylamina-3-phenvl'ProoionylaminQ)-4-(2.4,5-trifluoro-phenyl)-butyric acid
(Compound of formula 4):
To a stirred solution of 3-(2-tert-Butoxycarbonylamino-3-phenyl-propionylamino)-4-(2,4,5-trif!uoro-phenyl)-butyric acid (Compound of formula 4) (5gm, 0.0104mole) and piperazine derivative (compound of formu\a 7) (2.7gm, 0.0135mole), HOBT was added followed by the addition of triethylamine and N.N'-dicyclohexylcarbodiimde (DCC) at 0°C and stirred for overnight. After being stirred, dicyclohexylurea (DCU) and hydrochloride salt was removed by filtration and filtrate was concentrated under vacuum to give crude. The crude was purified by silica gel column chromatography using MeOH/CH2CI2 to give {1-[3-Oxo-1-(2,4,5-trifluoro-benzyl)-3-(34rifiuoromethyi-5,6-dihydro-8H-f1,2l4]triazoJof4(3-a]pyrazin-7-y))-propyIcarbamoyl]-2-phenyl-ethy[}-carbamic acid tert-butyl ester (Compound of formula 5). (Yield = 6.0 gm, 86%).
Step-V: Preparation of 2-Amino-N-[3-oxo-1-(2,4,5-trifluoro-benzvl)-3-{3-trifluoromethvl-5,6-dihydro-8H41,2,4ltriazolof4,3-a}pvrazin'7-yl)-propvl]-3-phenyi-propJonamide Hydrochloric Acid (Compound of formula 6) from {1-[3-Oxo- 1-(2,4,5-trifluoro-benzyl)-3-{3-triftuoromethvl-5,6-dihvdro-8H-f1,2Altriazolof4.3-alPvrazin-7-yf)-propylcarbamovtl-2-phenvt-ethyi)-carbamic acid tert-butyl ester (Compound of formula 5):
To a {1-[3-Oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5f6-dihydro-8H-[1,2,4]triazolo[413-a]pyrazin-7-yl)-propylcarbarnoyl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (Compound of formula 5), HCi-MeOH was added at room temperature and stirred for 2-3 hours. After being stirred, methanol was evaporated under vacuum to give 2-Amino-N-[3-oxo-1-(2t4,5-trifluoro-benzyl)-3-(3-trifluoromethyl~516-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-3-phenyl-propionamide Hydrochloric Acid (Compound of formula 6).
Example-2: Preparation of 2-Amino-3-methyl-pentanoic acid r3-oxo-1-f2.4,5-trifluoro-benzvn-3-f3>trifluoromethvl-5,6-dihvdro-8H-ri,2.4nriazolor4,3-alpyrazin-7-vh-propvn-amide Hydrochloric Acid (Compound of Formula 11V



Reagents: (I) N-Boc L-ILe ,C1C00C2H5, TEA.THF (II) UOH H20, MeOH, THF, Water (111) DCC, TEA, triazolopyrazine derivative(compound-7), THF (IV) HCI-MeOH
Step-/: Preparation of 3-(2-tert-Butoxycarbonyfamfno-3-methyI-pentanoylamino)-4-(2.4.5-trifluoro-phenvlhbutvric acid methyl ester (Compound of formula 8) from 3-AminO'4-(2,4,5-trifluoro-phenvI)-butyric acid methyl ester (Compound of formula 2J:
To a stirred solution of N-Boc-L-lle (12.34 gm, 0.0534 mole) in THF, triethylamine
and ethylchloroformate were added at 0°C and reaction mixture was stirred for 1 hour at
room temperature. To this stirred reaction mixture 3-Amino-4-(2,4,5-trifluoro-phenyr)-butyric
acid methyl ester (Compound of formula 2) (8 gm, 0.0202 mole) was added at 0°C and was
stirred for overnight- After being stirred THF was evaporated and residue was taken into
water. Aq. layer was extracted with dichtoromethane. The combined organic layers were
washed with bicarbonate solution and- 1N HCI solution, dried over anhydrous sodium
sulphate and concentrated under vacuum to give crude. The crude was purified by silica gel
column chromatography using MeOH/CH2CI2 (0.2:9.8) to give 3-(2-tert-
Butoxycarbonylamino-3-methyl-pentanoylamino)-4-(2,4,5-trifluoro-phenyl)-butyric acid
methyl ester (Compound of formula 8). (Yield = 9.7 gm, 67%).
Step-ll: Preparation of 3-(2-tert-Butoxvcarbonvlamino-3-methvl-pentanovIamino)-4~ (2,4.5-trifluoro-ohenvfl-butyric acid (Compound of formula 9) from 3-(2-tert-Butoxvcarbonvlamino-3-methyl-pentanovlamino)-4-(2,4,5-trifluoro-phenyl)-butyric acid methyl ester (Compound of formula 8):
To a stirred solution of 3-(2-tert-Butoxycarbonylamino-3-methyl-pentanoylamino)-4-(2,4,5-trifluoro-phenyl)-butyric acid methyl ester (Compound of formula 8) (9.7gm,0.021mole) in THF, MeOH, water and LiOHH20 (1.1gm,0.0262mo!e) were added at room temperature and stirred for 3-hours. After being stirred, the solvent was evaporated, residue was taken into water, pH of the solution was adjusted to acidic with sodium hydrogen sulphate and aq.

layer was extracted with dichloromethane. The combined organic layers were dried over Na2SC>4 and concentrated under vacuum to give 3-(2-tert-ButoxycarbonyIamino-3-methy!-pentanoyIamino)-4-(2,4,5-trifluoro-phenyl)-butyric acid (Compound of formula 9) as white solid (Yield = 9gm, 95%).
Step-til: Preparation of (2-Methyl-1-f3-oxo-1~(2.4.5-trifluoro-benzyl)-3-(3-
trifluoromethvl-5,6-dihvdro-8H-f1t2AJtriazoloF4r3-a]pvrazin-7-vl)-propylcarbamovlh butvlhcarbamic acid tert-butvl ester (Compound of formula 10) from 3-(2-tert-Botoxvcarbonviam/no-3-mefhvi-pentanoviammo)-4-f2.4.5-tr/ffuoro-phenv0-faufvr)*c acid (Compound of formula 9):
To a stirred solution of 3-(2-tert-Butoxycarbonylamino-3-methy)-pentanoylamino)-4-(2,4,5-trifluoro-pheny|)-butyric acid (Compound of formula 9) (6gm, 0.0104mole) and triazolopyrazine derivative (Compound-7) (3.2gm, 0.0135mole), HOBT was added followed by the addition of triethylamine and N,N'-dicylohexyldicarbodiimide (DCC) at 0°C and stirred for overnight. After being stirred dicyclohexylurea (DCU), hydrochloride salt was removed by filtration and filtrate was concentrated under vacuum to give crude. The crude was purified by silica gel column chromatography using MeOH/CH2CI2 to give {2-Methyl-1-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4)3-a]pyrazin-7-yl)-propylcarbamoyl]-butyl}-carbamic acid tert-butyl ester (Compound of formula 10). (Yield = 5gm, 60%).
Step-IV: Preparation of 2-Amino-3-methvl-oentanoic acid [3-oxo-1'(2,4,5-trifluoro-
benzvlh3-(3-trifluoromethvl-5,B-dihvdro-8H-n3Altriazolo[4,3'alov
amide Hydrochloric Acid (Compound of formula 11) from {2-Methyt-1-[3-oxo-1-(2,4.5-
trifluoro-benzvl)-3-(3-trifluoromethyl-5.G-dihvdro-8H-F1,2,4ltriazolo[4,3-a^^
propylcarbamoyfl-butvll-carbamic acid tert-butvl ester (Compound of formula 10):
To a {2-Methyl-1-[3-oxo-1-(2l4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5l6-dthydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propylcarbamoy!]-butyl}-carbamic acid tert-butyl ester (Compound of formula 10), HCI-MeOH was added at room temperature and stirred for 2-3 hours. After being stirred, methanol was evaporated under vacuum to give 2-Amino-3-methyl-pentanoic acid [3-oxo-1 -(2,4,5-trifluoro-benzyl)-3-(3-tnfluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-amide Hydrochloric Acid (Compound of formula 11).
Example-3: Preparation of 1-f2-Amino-3-methvl-butvrvn-byrrolidine-2-carboxvlic acid f3-oxo-1-f2,4,5-trifluoro-benzv))-3-f3-trifluoromethvl-5,6-dihvdro-8H-[1,2.41triazolor4,3-alpyrazin-7-vO-propvn-amide Hydrochloric Acid (Compound of Formula 15):


Step-I: Preparation of 3-{(1-(2-t6rt-Butoxvcarbonylamino-3-methvl-butvrvll-pvrrolidine-2-carbonvtl~amino)-4-(2.4.5-trifluoro-ohenvl)-butvric acid methyl ester (Compound of formula 12} from 3-Amino-4-(2,4,5-trjfluoro-phenvt}-butyric acid methyl ester (Compound of formula 2):

To a stirred solution of N-Boc-L-Val-Pro (1.2gm, 0.0038mole) in THF, triethylamine and ethylchloroformate were added at 0°C and reaction mixture was stirred for 1 hour at room temperature. To this stirred reaction mixture, 3-Amino-4-(2,4,5--trifluoro-phenyl)-butyric acid methyl ester (Compound of formula 2) (1.3gm, 0.0052mole) was added at 0°C and stirred for overnight. After being stirred, THF was evaporated, residue was taken info wafer and aq. layer was extracted with dichloromethane. The combined organic layers were washed with bicarbonate solution and 1N HCI solution, dried over anhydrous sodium sulphate and concentrated under vacuum to give crude. The crude was purified by silica gel column chromatography using MeOH/CH2CI2 (0.2:9.8) to give 3-{[1 -(2-tert-Butoxycarbonylamtno-3-methyl-butyryl)-pyrrolidine-2-carbony|]-amino}-4-(2,4,5-trifluoro--phenyl)-butyric acid methyl ester (Compound of formula 12) (Yield = 0.8gm, 27%).
Step-ll: Preparation of 3-{f1~(2-tert-ButoxvcarbonYlamino-3-methYl-butvryl}-pvrroiiQ,ine'2'CarbonvlJ'amino}'4-(2,4t5-triftuoro-DhenvI)'butvr/c acid (Compound of formula 13) from 3-ff1-(2-tert-Butoxvcarbonvfamino-3-methvf-butvrvf}-pyrrolidine-2-carbonvll-amino)-4-(2.4,5-triffuoro-phenyI)-butvric acid methyl ester (Compound of formula 12):
To a stirred solution of 3-{[1-(2-tert-Butoxycarbony)amino-3-methyl-butyryl)-pyrrolidine-2-carbonyl]-amino}-4-(2,4,5-trifluoro-phenyl)-butyric acid methyl ester (Compound of formula 12) (0.780gm, 0.0014mo!e) in THF, MeOH, water and LiOH.H20 (0.066gm,0.0016mole) were added at room temperature and stirred for 3-hours. After being stirred, the solvent was evaporated, residue was taken into water, pH of the solution was adjusted to acidic with sodium hydrogen sulphate and aq. layer was extracted with dichloromethane. The combined organic layers were dried over Na2S04 and concentrated under vacuum to give 3-{[1-(2-tert-Butoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2-carbonyl]-amino}-4-(2,4,5-trifluoro-phenyi)-butyric acid (Compound of formula 13) as white solid (Yield = 0.674gm, 93.6%).
Step-Ill: Preparation of (2-Methvl-1-{2-f3-oxO'1-/2.4.5-trifluoro-benzy/)-3-(3-trifluorQmethvl-5,6-dihvdro-8H'f1,2.41triazolof4.3-alpvrazin-7-vn-propylcarbamovl]-pyrrolidine~1-carbonyl}-propyl)-carbamic acid tert-butyl ester (Compound of formula 14) from 3~ff1-(2-tert-Butoxycarbonvlamino-3-methyl-butvrvl)-ovrrolidine-2-carbonylh amino}-4-(2.4.5-trifluoro-phenvl)-butyric acid (Compound of formula 13):
To a stirred solution of 3-{[1-(2-tert-Butoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2-carbonyl]-amino}-4-(2,4,5-trifiuoro-phenyl)-butyric acid (Compound of formula 13) (0.650, 0.0013mole) and piperazine derivative (compound-7) (0.320gm, 0.0014mole),

HOBT was added followed by the addition of triethylamine and N, N'-dicyclohexylcarbodiimide (DCC) at 0°C and stirred for overnight. After being stirred, dicyclohexylurea (DCU) and hydrochloride salt were removed by filtration and the filtrate was concentrated under vacuum to give crude. The crude was purified by silica gef column chromatography using MeOH/CH2CI2 to give (2-Methyl-1-{2-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propylcarbamoyl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid tert-butyl ester (Compound of formula 14) (Yield = 0.504gm, 58.60%).
Step-IV: Preparation of 1-(2-Amino-3-methyl-butyryl)~oyrrolidine-2-carboxylic acid F3-oxo-1-f2A.5-tr}fluoro-benzvl)'3-(3-trifluoromethvJ-5r6-dihvdro-8H-f1r2A]trte^ alpyrazin-7-vl)-proDvn-amide Hydrochloric Acid (Compound of formula 15) from (2-Methvl-l^'fS-oxo-I^A.S'trifiuoro'benzvO'S'fS-trifluoromethvi-S.e-dihvdro-SH-f1,2Altriazolo[4,3-a1pvrazin-7-vl)-propvlcarbamoyn-pvrrolidine-1-carbonvl}-propyf)~ carbamic acid tert-butyl ester (Compound of formula 14):
To the (2-Methyi-1-{2-[3-oxo-1-(2,4,5-trifluoro-ben2yl)-3-(3-trffluoromethyl-5,6-dihydro-SH-tl^^ltriazoloK.S-alpyrazin-y-yO-propylcarbamoylJ-pyrrolidine-l-carbonyl}-propyl)-carbamic acid tert-butyl ester (Compound of formula 14), HCI-MeOH was added at room temperature and stirred for 2-3 hours. After being stirred, methanol was evaporated under vacuum to give of 1-(2-Amino-3-methyl-butyryl)-pyrrolidine-2-carboxylic acid [3-oxo-1-(2l4,5-trifluoro-benzyf)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1l2l4Itriazoio[4,3-a]pyrazin-7-yl)-propyl]-amide Hydrochloric Acid (Compound of formula 15).
Example-4: Preparation of 2-Amino-N-r3-f2-cvano-pyrrolidin-1-vh-3-oxo-1-f2.4.5-trifluoro-benzvl)-propvn-3-phenyl-propionamide trifluoro-acetic acid (Compound of Formula 181:



Step t: Preparation of {1-[3-{2-Carbamovl-pvrrotidin-1-vl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-oropytcarbamoylh2-ohenyl-ethyl}-carbamic acid tert-butyl ester (Compound of formula 16) from 3-(2-tert-Butoxvcarbonylamino-3'phenvl-propionylamino)-4-(2,4,5-trifluoro-phenyQ-butvric acid (Compound of formula 4):
To a stirred solution of 3-(2-tert-Butoxycarbonylamino-3-phenyl-propiony[amino)-4-(2,4,5-trifluoro-phenyl)-butyric acid (Compound of formula 4) (2.52gm, 0.0052mole), N, N-Diisopropylethylamine (DIPEA) (1,26 ml, 0.00781 mol) in THF and 1 -hydroxybenztriazole (0.95 gm, 0.00624 mol) was added at 0°C and stirred at room temperature for 1 hour. To the stirred solution, EDCiHCI (1.29 gm, 0.00676 mol) and tri-fluoro acetic acid salt of prolinamide (1.2 gm, 0.00520 mol) were added at 0°C and stirred at room temperature overnight. After being stirred, the reaction mass was concentrated over the rotary evaporator, saturated aq. NaHC03 was added and filtered to give crude. The crude was washed with 1N HCI followed by washed by hexane and dried to give pure (1-[3-(2-Carbamoyl-pyrrolidin-1-yl)-3-oxo-1-(2,4,54rifluoro-benzyl)-propylcarbamoyl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (Compound of formula 16). (Yield = 1.80 gm, 60%)
Step f-A: Preparation of 1-[3-(2-Amino-3-phenvf~propionvlamino)-4-(2,4.5-triffuoro-phenvl)-butvrvn-pyrrofidine-2-carboxyUc acid amide trifluoro acetic acid (Compound

of formula 1S-A) from {1-[3-(2-Carbamovl-pyrrolidin-1-yl)-3-oxo-1-(2.4.5-trifluoro-benzvO-propvlcarbamovn-2-phenyl-ethyl}-carbamic acid tert-butyl ester (Compound
of formula 16):
To the solution of {1-[3-(2-CarbamoyI-pyrroIidin-1-yl)-3-oxo-1-(2,4,5-trifiuoro-benzyl)-propylcarbamoyl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (Compound of formula 16) (500 mg) in dichloromethane (10 ml), Tri-fluoro acetic acid (1 ml)) was added at 0°C and stirred for 1 hours at room temperature. After being stirred, the reaction mixture was concentrated over rota vapour to give crude. The crude was dried under the vacuum and purified to give V[3-(2-Amino-3-phenyl-propionylamino)-4-(2,4,5-trifluoro-pheny,|)-butyryl]-pyrrolidine-2-carboxylic acid amide trifluoro acetic acid (Compound of formula 16-A). (Yield = 350mg,68%).
Step II: Preparation of f1-F3-(2-Cvano-Pvrrolidin-1-vl)-3-oxo-1-(2,4.5-trifluoro-benzyl)-propvfcarbamovlJ-2-phenvf-ethvft-carbamic acid tert-butvl ester (Compound of formula 17) from {1-f3-(2-Carbamovl-Pvrrolidin-1-vl)-3-oxo-1-(2.4,5-trifluoro~benzvl)~ DropvIcarbamoyl]-2'Phenvl-ethvl)-carbamic acid tert-butyl ester (Compound of formula 16):
To the solution of dichloromethap (30 ml) and pyridine (1 ml), {1-[3-(2-Carbamoyl-pyrrolidin~1-y|)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propylcarbamoyl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (Compound of formula 16) (1 gm, 0.00173 mol) was added at 0° C followed by the addition of tri-fluoro acetic anhydride (0.6 mi, 0.00432 mol) drop-wise at 0° C and stirred for 3-5 hours. The mixture of toluene (5 ml) and ethyl acetate (10 ml) was added and stirred followed by concentrated to give crude. The crude was purified by column chromatography to give {1-[3-(2-Cyano-pyrrolidin-1-yl)-3-oxo-1-(2,4,5-trifluoro-benzyJ)-propylcarbamoyl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (Compound of formula 17). (Yield = 157 mg, 16%)
Step U-A: Preparation of 2-Am'mo-N-[3~(2-cyano~oyrroiidin-1-yl)-3-oxo-1'-(2,4.5-trifluoro-benzyl)-propyll-3-phenvl-propionamide trifluoro-acetic acid (Compound of formula 18) from (1-f3-(2-Cyano-pyrrolidin-1-v\)-3-oxo-1-(2,4.5-trifluoro-benzyl)-propylcarbamoyI]-2-phenyl-ethvl}-carbamic acid tert-butvl ester (Compound of formula 17):
To the solution of {1-[3-(2-Cyano-pyrrolidin-1-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propylcarbamoyl]-2-phenyl-ethy!}-carbarnic acid tert-butyl ester (Compound of formula 17) (700 mg) in dichloromethane (15 ml), Tri-fluoro acetic acid (2 ml)) was added at 0° C and stirred for 1 hours at room temperature. After being stirred, the reaction mixture was

concentrated over rota vapour to give crude. The crude was dried under the vacuum and purified to give 2-Amino-N-[3-(2-cyano-pyrro!idin-1-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-3-phenyl-propionamide trifluoro-acetic acid (Compound of formula 18). (Yield = 205 mg, 29%).
Examples - 5: Preparation of Pyrrolidine-2-carboxylic acid [3-oxo-1-(2J4]5-trifluoro-benzylJ-aKS-trifluoromethyf-S.e-dihydro-SH-n^^jtriazoio^.S-alpyrazin-Z-yO-propyfj-amide Hydrochloric Acid {Compound of Formula 21):

Reagents: (I) N-BOC Proline, HOBT, EDC HCI, DIPEA, THF (lla) LiOH.H20,THF, MeOH, Water (Mb) Compound C-1, HOBT, EDC HCI, DIPEA, Piperazine derivative (III) HCI-EtOAc
Step -- /: Preparation of 2'F1-MethoxycarbonyImethyl-2-(2,4,5-trif}uoro-phenyi)-ethytcarpamoylhovrrolidine-l-carboxylic acid tett-butvl ester (Compound of formula 19) from 3-Amino-4-(2,4,5-trifluoro-phenvl)-butyric acid methyl ester (Compound of formula 2):
To a stirred solution of N-Boc-Proline (2.6gm, 0.0121mole), 1-hydroxybenztriazole (2.2gm, 0.0145mole) and N, N'-diisopropylethylethylamine (2.6gm, 0.0204mole) in THF (30ml), the mixture of EDC.HCI (3.0gm, 0.0157mole).and 3-Amino-4-(2,4,5-trifluoro-phenyl)-butyric acid methyl ester (Compound of formula 2) (3gmf 0.0121 mole) were added at 0

°C.The reaction mixture was then stirred at room temperature for overnight. After being stirred, THF was evaporated and residue was taken into water. Aq. layer was extracted with ethyl acetate (120 ml). The combined organic layers were washed with 1N HC\ and aq. bicarbonate followed by drying over sodium sulphate and concentrated under vacuum to give 2-ft-(V!e£hoxyca^bonyfmefhy^2-(2,4l5-tr(flruoro-phenyfj-ethyfcarbamoy/^py^rofldlne-T-carboxylic acid tert-butyl ester (Compound of formula 19) as white solid (Yield = 4.3 gms, 81%).
Sfep //■■ Preparation of 2-F3-OxO'1-(2,4,5-trifluoro-benzvl)-3-(3-trifluoromethvl-5,6-dihvdro-8H-f1,2.41triazolof4,3-alpyrazin-7-vl)-propylcarbamovl]-pvrrolidine-1-carboxylic acid tert-butyl ester (Compound of formula 20) 2-F1-Methoxvcarbonylmethvl-2-(2t4.5-trifluorO'Dhenvl)-ethvlcarbamovll-pyrrolidine-1-carboxylic acid tert-butyl ester (Compound of formula ?9j:
To a stirred solution of 2-[1-Methoxycarbonylmethyl-2-(2,4,5-trifluoro-phenyl)-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (Compound of formula 19) (4.3 gms, 0.0096 mole) in THF (20ml); methanol (6ml), water (6ml) and LiOH.H20 (0.487gm, 0.0116mo!e) were added at room temperature and reaction mixture was stirred for 3 hours. After being stirred, solvent was evaporated and resulting residue was taken into water. The aq. layer was acidified with 1N HCI and extracted with ethyl acetate (140ml). The combined organic layers were dried over sodium sulphate and concentrated in vacuum to give compound of formula 19a as white solid (Yield = 4.0gm, 97%).
To this stirred solution of compound of formula 19a (4.0gm, 0.009 mole), 1-hydroxybenztriazole (1.7g, 0.0111 mole), piperazine derivative (2.3gm, 0.0102 mole) and N,N-diisopropylethylamine (2.6gm, 0.0204 mole) in THF, EDC.HCI (2.3gm, 0.0120mole) and N,N-diisopropylethylamine (2.0gm, 0.0156mole) were added at 0°C and reaction mixture was stirred for overnight at room temperature. After being stirred, THF was evaporated and residue was taken into water. The aq. layer was extracted with ethyl acetate (150mi). The combined organic layers were washed with 1N HCI and aq. bicarbonate followed by dried over sodium sulphate and concentrated in vacuum to give crude. The crude was purified by column chromatography to give 2-[3-Oxo~1-(2,4,5-trifluoro^benzyl)-3-(3-trifluoromethyl-5,6-dihydro-SH-tl^^ltriazolo^.S-alpyrazin^-yO-propylcarbamoylJ-pyrrolidine-l-carboxylic acid tert-butyl ester (Compound of formula 20) as off-white solid. (Yield = 4.9gm, 87%).
Step III: Preparation of Pvrrolidine-2-carboxvlic acid f3-oxo-1-(2,4.5-trifluoro-benzvl)-3-(3-trifluoromethvl-5,6-dihYdro-8H-F1.2.41triazoloF4.3-alpyrazin-7-yl)-propvl1-amide Hydrochloric Acid (Compound of Formula 21) from 2-f3-Qxo-1-(2.4,5-trifluoro-benzvI)'

3-(3-trifIuoromethyh5,6-dibydrO'8H-f1,2Altriazolof4.3-alPYrazin-7'Vl}--QropvlcarbamovlhDvrroltdine-1~carboxvlic acid tert-butyl ester (Compound of formula
m
To the 2-[3-Oxo-1-(2,4,5-trifluoro-ben2y])-3-{34rifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propylcarbamoyl]-pyrroIidine-1-carboxylic acid tert-butyl ester (Compound of formula 20) (4.0gm, 0.0066mole), hydrochloride solution in ethyl acetate was added at room temperature and stirred for 2 hours. After being stirred, ethyl acetate was evaporated in vacuum and resulting oily material was triturated with diisopropylether to give Pyrrolidine-2-carboxylic acid [3-oxo-1-{2,4,5~trifluoro-benzy!)-3-(3-trifluoromethyl-5,6~dihydro-8H41,2,4]triazolo[4,3-aJpyrazin-7--yl)-propyl]-arnide Hydrochloric Acid (Compound of Formula 21) as white solid (Yield = 3.3gm, 94%).
Example 6: Preparation of 2-Amino-N-[3-oxo-1-{2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-S.S-dihydro-BH-tl^^Itriaiolo^^-alpyrazin-r-ylJ-propyll-propionarnide Hydrochloric Acid (Compound of Formula 24):

Reagents: (I) N-BOC Alanine, HOBT, EDC HC1, DIPEA, THF (Ma) LiOH H20,THF, MeOH, Water (lib) Compound c-1 HOBT, EDC HCI, DtPEA, Piperazine derivative (III) HCI-EtOAc

Step ~ I: Preparation of 3'(2-tert-Butoxycarbonylam'mo-orooionvlam'mo)-4'(2,4,5-trifluoro-ohenvl)-butyric acid methyl ester (Compound of formula 22) from 3-Amino-4-(2.4.5-trifluoro-phenvl)~butvric acid methyl ester (Compound of formula 2):
To a stirred solution of N-BOC-Alanine (2.2gm, 0.0121mole), 1-hydroxybenztriazole (2.2gm, 0.0145mo!e) and N,N-diisopropylethylethylamine (2.6gm, 0.0204mole) in THF (30ml), EDC.HC1 (3.0gm, 0.0157mole) and 3-Amino-4-(2,4,5-trifluoro-pheny!)-butyric acid methyl ester (Compound of formula 2) (3gm, 0.0121mole) were added at 0 °C. The reaction mixture was then stirred at room temperature for overnight. After being stirred, THF was evaporated and residue was taken into water. It was then extracted with ethyl acetate (120ml). The combined organic layers were washed with 1N HCI and aq. bicarbonate followed by dried over sodium sulphate and concentrated in vacuum to give 3-(2-tert-Butoxycarbonylamino-propionylamino)-4-(2,4,5-trifluoro~phenyl)-butyric acid methyl ester (Compound of formula 22) as white solid (Yield = 4.7gm, 94%).
Step - //: Preparation of {1-f3-Oxo-1-(2,4,5-trifluoro~benzyl)-3-(3-trifluoromethyl-5.6-dihydro^8H-f112A1triazofof4J-alpyrazin-7-vfl-propv(carbamoyir-ethv(}-carbamic acid tert-butyt ester (Compound of formula 23) from 3-(2-tert-Butoxvcarbonyiamino-propion_ylamino)-4-(2,4,5-trifluoro~phenyl)-butyric acid methyl ester (Compound of formula 22):
To a stirred solution of 3-(2-tert-Butoxycarbonylamino-propionylamino)-4-(2,4,5-trifluoro-phenylj-butyric acid methyl ester (Compound of formula 22) (4.7gm, 0.0112mole) in THF (20ml), methanol (6ml), water (6ml) and LiOH.H20 (0.566gm, 0.0l34mole) were added at room temperature and reaction mixture was stirred for 3 hours. After being stirred, solvent was evaporated and resulting residue was taken into water. Aq. layer was acidified with 1N HCI and extracted with ethyl acetate (140ml). The combined organic layers were dried over sodium sulphate and concentrated in vacuum to give compound of formula 22a as white solid. (Yield = 4.5gm, 97%).
To this stirred solution of compound of formula 22a (4.5gm, 0.011mole), 1-hydroxybenztriazole (2.0g, 0.0133moie), piperazine derivative (2.7gm, 0.0122mole) and KN-diiSopropytethyiam'me (3.1 gm, D.D244mo)e) in THF, BDC.HC) (2.7.gm, 0.0144mo)e) and N,N-diisapropylethylamine (2.4gm, O'.0187mole) were added at 0°C and reaction mixture was stirred for overnight at room temperature. After being stirred, THF was evaporated and residue was taken into water. The aq. layer was extracted with ethyi acetate (150ml). The combined organic layers were washed with 1N HCI and aq, bicarbonate, dried over sodium sulphate and concentrated in vacuum to give crude. The crude was purified by column chromatography to give {1-[3-Oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-

8H-[1,2,4]tria2oio[4,3-a]pyrazjn-7-yl)-propyicarbamoyi]-ethyl}-carbamic acid tert-butyl ester (Compound of formula 23) as off-white solid. (Yield = 5.3gm, 82%).
Step - C: Preparation of 2-Amino-N'f3-oxO'1-(2,4.5-trifluoro-benzyl)'3-(3' trifluoromethvl-5.6-dihvdro-8H'[1,Z4ltriazoh[4,3'alpyrazin~7-vl)-oropvfl^ Hydrochloric Acid (Compound of formula 24) from {1-f3-Oxo-1~(2,4,5-trifluorO'benzyl)-3-(3'trifluoromethyl-5,6-dihvdro-8H-f1X4Uriazolo[4.3-alPvraz'm-7-vlhropylcarbamovlh ethylhcarbamic acid tert-butyl ester (Compound of formula 23:
To this {l-CS-Oxo-l^a^.S-trffluora-benzytJ-a^a^rffluoromethyf-S.e-dihydro-SH-[1,2,4]tria2olo[4,3~a]pyrazin-7-yl)-propylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester (Compound of formula 23) (4.0gm, O.G069mole), hydrochloride solution in ethyl acetate was added at room temperature and stirred for 2 hours. After being stirred, ethyl acetate was evaporated in vacuum and resulting oily material was triturated with diisopropylether to give 2-Amino-N-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[l^^ltriazolo^^ajpyrazin^-ylj-propylj-propionamide Hydrochloric Acid (Compound of formula 24) as white solid. (Yield = 3.2gm, 91%).
Example 7: Preparation of 1-(2-Amino-3-phenyl-propionyl)-pyn-olidine-2-carboxyIicacid [3-oxo-1-(2,4,54rifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1,2J4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-amide hydrochloric acid (Compound of formula 32):



Reagents: (!) N-BOC-Phe-Pro, HOBT, EDC.HCI, DIPEA, THF (lla) LiOH.H20, THF, MeOH, Water (lib) Compound 31a, HOBT, EDC HCI, DIPEA, Piperazine derivative (III) HCI-EtOAc
STEP - /: Preparation of 3-{f1-(2-tert-Butoxvcarbonvlamino-3-ohenyl-propionvl)-pyrrolidine-2-carbonvll-amino}-4-(2.4.5-trifluoro-ohenyl)--butyric acid methyl ester (Compound of formula 31) from 3'AminO'4-(2,4,5-trifluoro-phenvl)-butyric acid methvl ester /Compound of formula 2):
To a stirred solution of N-Boc-Phe-Pro (LOgrn, 0.0027mole), 1-hydroxybenztriazole (0.496gm, 0.0032mole) and N,N-diisopropylethylethylamine (0.58gm, 0.0045mo!e) in THF (30m)), EDC.HCJ (0.672gm, 0.0035moJe) and 3-Amino-4-(2,4,5-trifJuoro-pbenyl)-butyric acid methyl ester (Compound of formula 2) (0.68, 0.0027mole) were added at 0°C. The reaction mixture was then stirred at room temperature for overnight. After being stirred, THF was evaporated and residue was taken into water. It was then extracted with ethyl acetate (70ml). The combined organic layers were washed with 1N HCI and aq. bicarbonate, dried over sodium sulphate and concentrated in vacuum to give 3-{[1-(2-tert-Butoxycarbonylamino-3-phenyl-propionyl)-pyrrolidine-2-carbonyl]-amino}-4-(2,4,5-trifluoro-phenyl)-butyric acid methyl ester (Compound of formula 31) as white solid {Yield = 1.5gm, 93%).
STEP - //: Preparation of (1'Benzvl-2-oxo-2-(2~F3-oxQ-1-(2,4.5-trifluoro-benzyl)-3-(3~ trifluoromethvl-5r6'dihydro*8HJ1,2Altria2olof4,3-alpvra2in-7-vl)-propylcarbamovih pyrrolidin~1-vl}-ethvl)-carbamic acid tert-butvl ester {Compound of formula 32) from 3~ ff1-(2-tert-Butoxycarbonylamino-3-phenvl-propionvl)-pyrrolfdine-2-carbonyl1-amino)-4-(2.4.5-trifluoro-phenvi)-butvric acid methyl ester (Compound of formula 31):

To a stirred solution of 3-{[1-(24ert-Butoxycarbonylamino-3-phenyl-propionyl)~ pyrrolidine-2-carbonyl]-annino}-4-(2,4(5-trifiuoro-pheny1)-butyric acid methyl ester (Compound of formula 31) (1.5gm, 0.0025mole) in THF (10ml), methanol (3ml), water (3ml) and LiOH.H20 (0.127gm, 0.0030mole) were added at room temperature and reaction mixture was stirred for 3 hours. After being stirred, solvent was evaporated and resulting residue was taken into water. The aq. layer was acidified with 1N HCI and extracted with ethyl acetate (60ml). The combined organic layers were dried over sodium sulphate and concentrated in vacuum to give compound of formula 31-a as white solid. (Yield = 1.0gm,68%).
To this stirred solution of compound of formula 31-a (1.0gm, 0.0017mole), 1-hydroxybenztriazole (0.26gm, 0.0017mole), piperazine derivative (0.407gm, 0.0017mole) and N.N-diisopropylethylamine (0.37gm, 0.00287mole) in THF (25ml), EDC.HCI (0.42gm, 0.0022mole) and N.N-diisopropylethylamine (0.460gm, 0.00356mole) were added at 0°C and reaction mixture was stirred for overnight at room temperature. After being stirred, THF was evaporated and residue was taken "into water. The aq. layer was extracted with ethyl acetate (60ml). The combined organic layers were washed with 1N HCI and aq. bicarbonate, dried over sodium sulphate and concentrated in vacuum to gfre crude. The crude was purified by column chromatography to give (1-Benzyl-2-oxo-2-{2-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3'(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propylcarbamoyl]-pyrrolidin-1-yl}-ethyl)-carbamic acid tert-butyl ester (Compound of formula 32) as off-white solid. (Yield = 0.7gm, 50%).
STEP ~-]ti; Preparation of 1-(2-Amino-3-phenyl-propionvl)-pyrrolidine-2-carboxyUcacid [3-oxo-iJ2A£-triftuoro-benzvl)-3-(3-trifluoromethyl-5£-dihvdro-8^ a]pyrazin-7-vl)-propyl]-amide hydrochloric acid (Compound of formula 33) from (1-Benzvl-&oxo-2-{2'f3-oxo-1-{2AM-trifluoro-benzvl)-3-(3-trifiuoromethvl-5,6-dfo^ f1JAltri^zofof4^a1ovrazin'7-vn-DropyfcarbamoviJ-pyrrofidm'1-vf}-ethvh-carbamic acid tert-butvf ester (Compound of formula 32):
To this Cf-Benzyf-2-oxo-2-{2-[3-oxo-1-(2,4,5-triffuoro^benzyl)-3-(3-tnTfuoromethyf-5,6-dihydro-8H-[1-2,4]triazolo[4,3-a]pyrazin-7-yl)-propylcarbamoy|]-pyrrolidin-1-yl}-ethyl)-carbamic acid tert-butyl ester (Compound of formula 32) (0.5gm, 0.00066mole), hydrochloride solution in ethyl acetate was added at room temperature and stirred for 2 hours. After being stirred ethyl acetate was evaporated in vacuum and resulting oily material was triturated with diisopropylether to give 1-(2-Amino-3-phenyl-propionyl)-pyrrolidine-2-carboxylic acid 1-(2-Amino-3-phenyl-propionyl)-pyrrolidine-2-carboxylicacid [3-oxo-1-(2,4,5-trif!uoro-benzyl)-3-(3~trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazoio[4,3-a]pyrazin-7-yl)-propyl]-amide hydrochloric acid (Compound of formula 33) as white solid (Yield = 0.4gm, 87%).

Example-8: Preparation of 2-Ammo-N41-f3-oxo-1-(2.4.5-trifluoro-benzvl)-3-(3-trifiuoromethv(-5,6^\hvdro-8H-f1.2.4Uriazolor4,3-a1Pvrazin-7-vi^proPvtcarbamovn-ethvfl-3-phenvl-propionamide (Compound of Formula 39):

Reagents: (I) N-Boc Alanine, HOBT, EDC-HQ, OIPBAJHF (11) UOHH20, MeOH, THF, Water (ill) HOBT, DiPEA, EDC-HC1, triazolopyrazine derivative(compound-7), THF (IV) EtOAc-HCl, Na2C03, MDC (V) N-Boc-Pbe-AJa, EDC-HQ, HOBT, D)PBA (VJ)EtOAc-HCf

Steo-I: Preparation of 3-(2-ten-Butoxycarbonylamino-propionylam'mQ)-4'(2t4,5-trifluoro-phenvD'butvric acid methyl ester (Compound of formula 34) from 3-Amino-4~ (2.4.5-trifluoro-phenyl)-butyric acid methyl ester (Compound of formula 2):
To a stirred solution of N-Boc-Alanine (2.2 gm, 0.0121 mol) in THF, hydroxyl benztriazole and N, N - diisopropyl ethyl amine were added at 0°C and reaction mixture was stirred at room temperature. To this stirred reaction mixture, 3-Amino-4-(2,4,5-trifluoro-phenyl)-butyric acid methyl ester (Compound of formula 2) (3 gm, 0.0121 mol) and EDC-HCl were added at 0°C and was stirred for overnight at room temperature. After being stirred, THF was evaporated and residue was taken into saturated #q. NaHC03 solution (50 ml). Aq. layer was extracted with dichloromethane. The combined organic layers were washed with 1N HCI, dried over anhydrous sodium sulphate and concentrated under vacuum to give crude. The crude was purified by crystallization to give 3-(2-tert-Butoxycarbonylamino-propionylamino)-4-(2,4,5-trifluoro-phenyl):butyric acid methyl ester (Compound of formula 34). (Yield = 4.7 gm, 94%).
Step-//: Preparation of 3-(2-tert-Butoxycarbonylamino-propionylamino)-4-(2,4.5-trifluoro -phenvD-butvric acid (Compound of formula 35) from 3-(2-tert-Butoxvcarbonylamino-propionvlamino)-4-(214J5-trifluoro'Phenyl)-butvric acid methyl ester (Compound of formula 34):
To a stirred solution of 3-(2-tert-Butoxycarbony|amino-propionylarnino)-4-(2,4,5-trifluoro-phenyl)-butyric acid methyl ester (Compound of formula 34) (4.7gm, 0.0112 mol) in THF, MeOH, water and LiOHH20 (0.566 gm, 0.0134 mol) were added at room temperature and stirred for 3-hours. After being stirred, THF was evaporated, residue was taken into water, pH of the solution was adjusted to acidic with 1N HCI and aq. layer was extracted with dichloromethane. The combined organic layers were dried over Na2S04 and concentrated under vacuum to give 3-(2-tert-Butoxycarbonylamino-propionylamino)-4-(2,4,5-trrfluoro -phenyl)-butyric acid (Compound of formula 35). (Yield = 4.5 gm, 96%). Step-lit: Preparation of {1-r3-Oxo-1-(2.4.5-trifluoro-benzvt}-3-(3-trifiuoromethyl-5,6-d'mvdro-8H~f1,2Altriazolo[4,3-alPvrazin-7-Yl)'propvlcarbamovll-ethvl}-carbamic acid tert-butvi ester (Compound of formula 36) from 3'(2-tert-Butoxycarbonylamina-oropionvlamino)-4-(2,4,5-trif)uoro -phenyp-butyric acid /Compound of formula 35):
To a stirred solution of 3-(2-tert-Butoxycarbonyiamino-propionylamino)-4-(214,5-trifluoro -phenyl)-butyric acid (Compound of formula 35) (4.5 gm, 0.0111 mol) in THF, triazolopyrazine derivative (Compound-7) (2.7 gm, 0.0133 mol), HOBT, triethylamine and N,N'-dicylohexyldicarbodiimide (DCC) were added at 0°C and stirred for overnight at room temperature. After being stirred, THF was evaporated and residue was taken into water. The aqueous layer was extracted with EtOAc (150 ml). The combined EtOAc layers were washed with 1N HCI and aqueous NaHC03. The layers were dried over Na2S04 and concentrated under vacuum to give crude. The crude was purified by coloumn chromatography to give {1-[3-Oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6~dihydro-

8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propylcarbamoyl]-ethyl}'Carbamic acid tert-butyl ester
(Compound of formula 36). (Yield = 5.3 gm, 82 %).
Step-IV: Preparation of 2-Amino-N-F3-oxo-1-(2,4.5-trifluoro~benzvl)-3'(3-
trifluoromethyl-5.6-dihvdro'8H-riX41triazoloF4J-alDvrazin-7-vt)'DroDVlh^
(Compound of formula 37) from (1-r3-Oxo-1-(2.4.5-trifluoro-benzvl)-3-(3-
triftuoromethvl-5.6-dihvdro-8H-[1.2Altriazolo[4,3-alDvrazin-7^
ethyfl-carbaroic acid tert-butyl ester (Compound of formula 36):
{I^S-Oxo-I^^.S-trifluoro-benzyO-S-ta-trifluoromethyl-S.B-dihydro-SH-[l^^ltriazoloK^-alpyrazin-T-yO-propylcarbamoyll-ethylVcarbamic acid tert-butyl ester (Compound of formula 36) (5.3 gm), EtOAc-HCI (40 ml) was added at room temperature and stirred for 2-3 hours. After being stirred, The reaction mixture was concentrated and separated 2 gm 2-Amino-N-[3-oxo-1-(2,4l5-trifluoro~benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]tria2olo[4,3-a]pyrazin-7-yl)-propyl]-propionamide hydrochloric acid.
To the 2-Amino-N-[3-oxo-1-(2l4,5-trifluoro-benzyl)'3-(3-trifluoromethyI-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-propionamide hydrochloric acid, Na2C03 was added and stirred for few minutes. pH of the solution was added above 7 and extracted by UDC followed by dried over Na2S04. The Solution mixture was concentrated and solidified by ether treatment to give crude. The crude was dried under high vacuum to give 2-Amino-N-[3-oxo-1-(2,4,5-tnfluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-y])-propyl]-propionamide (Compound of formula 37). (Yield = 4.8 gm, 97.95%) Steo-V: Preparation {1-Benzv!-2-{1J3-oxo-1-{2,4.5-trifluoro-benzvl)-3-(3-trif!uoromethvl -5r6-dihydrO'8H^1JA1triazoiof4l3-a]pvrazin-7-vl)'propYlcarbamovn-ethviamino)'alM)-carbamic acid tert-butyl ester (Compound of formula 38) from 2-Amino-NJ3-oxo-1-r2A5-triffuoro-benzv»-3-f3-trifluoromet^5,^^^ 7-yl)-propyl]-propionamide (Compound of formula 37):
To a stirred solution of THF and DIPEA, HOBT (0.94 gm), N-Boc-Phe-Alanine (1.4 gm, 0.0052 mol) and DIPEA were added at 0° C and reaction mixture was stirred after 10 minutes at 0° C. To this stirred reaction mixture, EDC-HCI (1.3 gm) was added at 0° C and reaction mixture was stirred after 10 minutes at room temperature. 2-Amino~N-[3-oxo-1-{2,4,5-trifluoro-benzyl)-3-(3-trifluoromethy1-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-propionamide (Compound of formula 37) (2.5 gm) was added into the reaction mixture and stirred at room temperature for over night. After being stirred, the reaction mixture was concentrated and 1N HCI was added to the concentrated reaction mixture. Then reaction mixture was filtered and washed with aqueous NaHC03 and dried. The mixture was washed with hexane (50 ml) and ether (10 ml) and dried under high vacuum to give (1-Benzyl-2-{1-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4] triazoto [4,3-a]pyrazin-7-yl)-propylcarbamoyi]-ethylamino}-allyl)-carbamic acid tert-butyl ester (Compound of formula 38) as white crude. (Yield - 3.13 gm, 32.36%).

STEP - VI: Preparation of 2-Amino-N-{1'f3-oxo-1'(2,4,5'trifluoro-benzvl)-3-(3' trifluoromethvl'5M-dihvdro-8H-[1,2Altriazojo[4^3-alPvrazin'7-vl)-propv{carbam ethvl)-3-phenvl-propionamide (Compound^ of formula 39) from (1-{1-F3-Oxo-1-(2.4,5' tr}fIuoro-benzvJ)-343'trifluoromethvl-5r6-dihvdro-8H-F1JAltriazoloM^^ propytcarbamovl1-ethvlcarbamovlh2-phenyl~ethvn-carbamic acid tert-butvl ester (Compound of formula 38):
To (1-{1-[3-Oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifJuoi-omethyl~5,6-dihydro-8H-[1,2,4] triazolo[4,3-a]pyrazin-7-yl)-propylcarbamoylI-ethyfcarbamoyl}-2-phenyl-ethy()-carbamic acid tert-butyl ester (Compound of formula 38) (3 gm), EtOAc (50 ml) was added at room temperature and stirred for 2 hours. After being stirred, ether (20 ml) was added and stirred for 10-15 minutes to give white residue. The residue was filtered and washed with ether (10 ml) and dried under high vacuum to give-2-Amino-N-{1-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazo!o[4,3-a]pyrazin-7'yl)-propylcarbamoyl]-ethyl}-3-phenyl-propionamide (Compound of formula 39) (Yield = 2.67 gm, 97.80 %).
In accordance with the present invention the following novel compounds were synthesized according the process described above and these compound were tested for the in vivo screening to evaluate their anti diabetic activity.


1 -I2-Amino~3-(4-benzyloxy-phenyl)-propionyl]-pyrrolidine-2-carboxylic acid [3-(2-cyano-pyrrolidin-l-yl)-3-oxo-l-(2,4,5-trifluoro-benzyl)-propyl]-amide hydrochloric acid
\ -(2-Amino-4-methyi-pentanoyl)-pyrrolidine-2-carboxylic acid [3-(2-cyano-pyrrolidin-l -yl)-3-oxo-1 -(2,4,5-trifUioro-benzyl)-pn3pyl]-amide hydrochloric Acid
2-Amino-4-methyl-pentanoic acid
{\ 4M2-cyano-pyrro\id'm-l -yV)-3-oxo-1 -(2,4,5-trifluoro-benzyI)-propylcarbamoyl]-ethyl}-amide hydrochloric acid


2-Amino-N-{l-[3-(2-cyano-pyrrolidin-1 -yl)-3-oxo-l -(2,4,5-trifluoro-benzyl)-
propylcarbamoyl]-ethyl}-3-phenyl-propionamide hydrochloric Acid
2-Amino-N-[3-oxo-l -(2,4,5-
trifluoro-benzyl)-3-(3-
trifluoromethyl-5,6-dihydro-8H-
[l,2,4]triazo!o[4,3-a]pyrazin-7-yl)-
propyl]-3-phenyl-propionamide
hydrochloric acid
2-Amino-N-[3-(3-cyano-2-aza-bicyclo[3.1.0]hex-2-yl)-3-oxo-l-(2,4,5-trifIuoro-benzyi)-propyi]-3-phenyl-propionam ide hydrochloric Acid
2-Amino-N-{ 1 -[3-(3-cyano-2-aza-bicyclo[3.1.0]hex-2-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propylcarbamoyl]-ethyl}-3-phenyl-propionarnide hydrochloric Acid
2-Amino-N-{ 1 -[3-(2-cyano-pyrrolidin-1 -yl)-3-oxo-1 -(2,4,5-trifluoro-benzyl)-propylcarbamoyl]-ethyl}-3-(l H-imidazol-4-yl)-propionamide hydrochloric Acid

GENERAL PROCEDIJRE F0R /w VfV0 SCREENING:
The novel hypoglycemic compounds according to present invention on reaction with DPP IV enzyme release an entity tnat jnhjbits tne DPP !V enzyme. The inhibition of DPP IV enzyme by compouny of formu|a X|| is attributed to the particular amino acid analogues

synthesized as per present invention. These are evaluated by the in vivo screening of the compounds of present invention.
In vivo study of synthesized compounds:
The efficacy of compounds as per table 1 was evaluated through Oral Glucose Tolerance Test in animals. Each group consist of 10-12 weeks old Wistar female rats. The animals were divided into 4 different groups of 6 animals per group. The group [ received vehical (WFI Placebo), Group II, Group III and Group IV compound as per Table 1. All animals had over night fasting. All compounds as per table 1 were administered in equimolar Dose (In mg/kg) of active at 0 hour to all the study group animals with 10 mL/kg of dose volume.
Table: 01 Dose groups, no. of animals and dose of drugs for in vivo study:

Group No. of animals Drugs Dose (In mg/kg) Dose volume (mUkcj)
1 6 Normal control 0.0 10
II 6 CPL-2009-0027 11.7 10
III 6 CPL-2009-0030 11.28 10
IV 6 CPL-2009-0031 12.0 10
The compounds were administered orally. The glucose (2 gm / Kg body weight) was administered 3 hrs after the administration of compounds. Blood glucose was measured at the time of administration of compound, glucose and 30 min, 1 hr, 2 hr, 3 hr and 4 hr after the glucose administration. The change in glucose levels over time is shown in figure 1. Al! animals showed rise in blood glucose level following administration of glucose. The rise was maximum at 30 min after glucose administration. The rise in glucose is significantly lower when compound of present invention were administered compared to no treatment group. The difference between no treatment group and other three groups is maximum at 30 min and it decreases over time (Figure 01-03). The findings also show that the compound of present invention does not alter the fasting glucose levels from 0 to 3 Hrs. Thus, the compound of present invention reduces hyperglycaemic effect of glucose without inducing hypoglycaemia. In other words, compounds of present invention provide hypoglycaemic effect only to reduce post-prandial hyperglycaemia without inducing fasting hypoglycaemia.
To confirm the finding the experiment was repeated three times and the percentage change in glucose level over time of three experiments is presented in table 02. The repeat experiments also confirm the findings. The results of these experiments are depicted in figure 1-3.

This is further evaluated by following analytical method.
Analytical Method to analyze the DPP IV compounds of present invention:
Reagents and Solvents: The reagents, solvents, standards and equipments to analyze the
DPP IV compounds of present invention are as under:
• Trifluoro Acetic acid (AR grade)
• Acetonitrile (HPLC grade)
• Willi Q water
• Sitagliptin Base as working standard DPP IV inhibitor
• Shimadzu LC-2010 equipped with UV detector and Auto Sampler
• Diluent: Acetonitrile
Preparation of Buffer
Transfer accurately measured 1000 mL Midi Q water in a beaker. Adjust pH 2.00+0.05 with Trifluoro acetic acid. Shake it gently and filter through 0.45u membrane filter. Preparation of Mobile phase
Transfer 300 mL acetonitrile in 1000 mL volumetric flask and make the volume up to the mark with buffer phi 2.00+0.05
Standard Preparation
Exactly weigh about 20 mg control drug as working standard in 10 mL volumetric flask. Add 5.0 mL diluent and sonicate it (if required) to dissolve the solids and make the volume up to the mark with diluent giving a standard solution having concentration 2000 ppm (Stock solution).
Above stock solution was further diluted to get different concentration solution varying from 0.025uM to 100 uM. Linearity curve of peak area against concentration in uM was plotted for different concentration. Sample Preparation
Extracted samples (after removing proteneous matter) were provided from different organs (Liver, Kidney and Pancreas) and serum samples which were directly injected on to HPLC system.
Chromatographic conditions:
The liquid chromatography is equipped with variable wavelength UV detector, Auto sampler and Data processor
• Column ypersil BDS C8, 4.6mm x 250 mm, 5M
• Detector wavelength : 54 nm

• Flow Rate 1.0mL/min
• Injection volume 20uL
• Column Temperature : 60° C
Procedure
Inject blank (diluent) and blank extraction samples, inject standard preparation of varying concentration from 0.025uM to 100 uM and plot a graph of Area under curve against concentration in uM. Inject sample preparation and record the chromatogram. Disregard any peak due to blank and calculate concentration of an entity which is released from the extracted samples collected at different time intervals.
Similarly in identical experiments were performed to evaluate the in vivo screening of compounds as per present invention. The result of in vivo screening for evaluation of antidiabetic effect of CPL-2009-0005, CPL-2009-0033, CPL-2009-0029, CPL-2009-0079, CPL-2011-0089, CPL-2011-0103 and like are also showing inhibition of DPP IV enzyme.
The above results indicate that the novel compounds according to present invention are showing antidiabetic activity when compared with standard drugs.

We claim:
1. Novel DPP-IV inhibitors of formula VI,

Wherein, Ar is phenyl or substituted phenyl having 1 to 5 halogen atoms in the phenyl ring, preferably 2, 4, 5-trifluorophenyl;-
R is aa1 or aai-aa2 or aai-aa2-aa3 or aa-aa2-aa3-aa4, wherein aai, aa2, aa3 and aa4 are amino acids selected independently and is linked through a peptide bond; wherein The Amino acid (aa1/aa2/aa3/aa4) is selected from any of the following:

2. Novel DPP-IV inhibitors of formula XII,

3. A process for the preparation of DPP-IV inhibitors of formula VI,

using sequence of reactions as depicted in scheme 1 comprises:
a. Deprotection followed by esterification of N-protected beta-amino acid (formula I) to
give chiral beta amino acid derivatives (formula II);
b. reaction of chiral beta amino acid derivatives (formula II) with carboxyl terminal N'-
protected peptide compounds to give beta-amino N-acetyl peptide compounds
(formula III);

c. reaction of beta-amino N-protected compound (formula III) with saponifying agent to
provide beta-amino N-acylated-4-(2, 4, 5-trifluorophenyl)-3-amino butyric acid
(formula IV);
d. condensation of beta-amino N-acylated-4-(2, 4, 5-trifluorophenyl)-3-amino butyric
acid (formula IV) with any of the compound (a) to (e) to give corresponding amides
of beta-amino N-acylated-N'-protected peptide compounds (formula V);
e. deprotection of amides of beta-amino N-acylated-N'-protected peptide compounds
(formula V) to give 4-aryl-3-N-peptide substituted amino acid derivatives (formula
VI). 4. A process for the preparation of novel DPP-IV inhibitor of formula XII, using sequence of reactions as depicted in scheme 2 comprises:

(Compounf of Formula XII)
a. deprotection followed by esterification of N-protected beta-amino acid (formula VII)
to give chiral beta amino acid derivatives (formula VIII);
b. reaction of chiral beta amino acid derivative (formula VIII) with carboxyl terminal N'-
protected peptide compounds to give beta-amino N-acylated peptide compounds
(formula IX), wherein As is 2, 4, 5-trifluoro phenyl;
c. beta-amino N-acylated peptide compounds (formula IX) are converted into beta-
amino N-acylated-4-(2, 4, 5-trifluorophenyl) butanoic acids (formula X) by
saponification;
d. reacting compounds of formula (X) with any of the compound (a) to (e) to give
corresponding amides of formula (XI);
e. deprotection of beta-amino N-acylated-N'-protected peptide compounds of formula
(XI) to give 4-aryl-3-N-peptide substituted amino acid derivatives (formula XII).
5. The process as claimed in claim 3 and/or 4, wherein Peptide bond is formed by coupling
between a carboxyl group and an amino group in presence of coupling agents.
6. The coupling agents as claimed in claim 5 are selected from DCC, EDC, D1C and like.
The preferable coupling agents are DCC and EDC.
7. The process as claimed in claim 3 and/or 4, the saponification reaction is carried out by
using Inorganic base.
8. The Inorganic base as claimed in claim 7 is selected from NaOH, KOH, LiOH and like,
preferably NaOH and LiOH,

9. The compound of formula

10. The compound of formula

14. The compound as claimed in claim 3, 4 and 9 is 2-Amino-N~[3-oxo-1-(2)4J5-trifluoro-ben2yl)-3-(3-trifluoromethyl-5,6-dihydro-8H-t1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-3-phenyl-propionamide hydrochloric acid structurally depicted as;

15. The compound as claimed in claim 3, 4 and 9 is 2-Amino-3-methyl-pentanoic acid [3-oxo-l-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1l2,4]triazolo[4I3-a]pyrazin-7-yl)-propyl]-amide hydrochloric acid structurally depicted as:


16. The compound as claimed in claim 3, 4 and 9 is 1-(2-Amino-3-methyl-butyryl)-pyrrolidine-2-carboxylic acid [3-oxo-1 -(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-amide hydrochloric acid structurally depicted as;

17. The compound as claimed in claim 3, 4 and 10 is 2-Amino~N-[3-(2-cyano-pyrrolidin-1-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-3-phenyl-prQpionamidetrifluoro-aceticacid structurally depicted as;

18. The compound as claimed in claim 3, 4 and 9 is 1-(2-Amino-3-phenyl-propionyl)-pyrrolidine-2-carboxylic acid [3-oxo~1-(2,4,5-trifluoro-bftnzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-amide hydrochloric acid structurally depicted as;


19. The compound as claimed in claim 3, 4 and 9 is 2-Amino-N-{1-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propylcarbarnoyl]-ethyl}-3-phenyl-propionamide hydrochloric acid structurally depicted as;

20. The compound as claimed in claim 3, 4 and 11 is 1-[3-(2-Amino-3-phenyl-
propionylamino)-4-{2,4,5-trifluoro-phenyl)-butyryl]-pyrrc)lidine-2-carboxylic acid amide trifluoro-acetic acid structurally depicted as;