2. BACKGROUND OF THE INVENTION The following piperazine derivatives have been reporte: U. S. patent 5, 607, 936 and International Publication WO 96/10568 discloses piperazine dèrivatives that are allegedly useful as tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma and emesis.

International Publication WO 95/04049 discloses piperazine derivatives formulas that are allegedly useful to block alA receptors, and are thus allegedly useful in the prevention of contractions of the prostate, urethra and lower urinary tract, without affecting blood pressure.

U. S. Patent 5, 418, 237 discloses aryl piperazine substituted indole derivatives that allegedly exhibit central nervous system (CNS) activity.

U. S. Patent 2, 985, 657 discloses piperazine derivatives that allegedly possess CNS depressing activity.

European Patent Application EP 0 624 584 discloses piperazine derivatives that are allegedly useful as calmodolin inhibitors.

Gizur, T., et al. , Med. Chem. Res. :3 545 (1993), discloses a phenyl piperazine derivative that is allegedly useful as an antipsychotic agent.

European Patent Application EP 0 462 638 A1 discloses piperazine derivatives that are allegedly useful to improve seratonin-lA binding (anti-depressant) activity.

U. S. Patent 4, 940, 793 discloses piperazine derivatives that allegedly inhibit carbonic anhydrase.

1- (cyanomethyl)-4-benzylpiperazine has been used as a synthetic intermediate for the preparation of l-[ß- (Aroylamino) ethyl]-4-benzylpiperazines and 1- [arylamino) carbonyll ethyl]-4-benzylpiperazines. Saxena, <BR> <BR> <BR> M.J. ; Med. Chem. :33 2970 (1990). Aryl piperazines were used to synthesize 1- [arylpiperazinelalkyllcarbonyll-ar-4-yl. <BR> <BR> <BR> <P>Gizur, T., et al. , Med. Chem. Res. :3 545 (1993). N-[(4-aryl- Anzini,M.,etal.,1-piperazinyl-alkyl]-substitutedimides.

Med. Chem. Res. :3 249 (1993). 4-benzyl-1-[2-(4- synthesizea1-[2-(4-fluorobenzamido)ethyl]piperazineto Y.E.,etal.,fluorobenzamindo)-1'-ethyl]piperazine.Ahmad, J. Ned. Chem., 40: 952 (1997). Many postsynaptic 5-HT la antagonists have a 1-(o-methoxyphenyl) piperazine fragments.

Mokrosz, M. J., et al. , Med. Chem. Res. :4 161 (1994); See also Abou-Gharbia, M., et al. , J. Med. Chem. :31 1382 (1988), Raghupathi, R. K., et al. , J. Med. Chem. :34 26343 (1991); Glennon, R. A., et al. , Drug Dev. Res. :16 335 (1989) In addition, the following thiocycles have been reporte: Perrissenin, M., et al., Bur. J. Med. 15 (6) : 563 (1980) disclose thiophene derivatives that are allegedly useful as analgesics and as CNS sedatives.

Pathak, U. S., et al., Ind. J. Med. Chem. 53 (3): 85 (1991) disclose thiophene derivatives that are allegedly useful as analgesics.

Thiophene derivatives have been used as intermediates to synthesize pharmacologically active compound for non-diabetic indications: 2-aminothieno [2,3- d]pyrimidines have been used as synthetic intermediates for the preparation of 2-aminoquinazolines, which are, in turn, potential surrogates for substituted compound useful as pharmacophoric components in medicinal chemistry. Zhang, M., et al., Bioorganic & Medicinal Chemistry Letters 7 :(13) 1629 (1997). Another 2,5-dicarboxy-3,4- dihydroxythiophene was converted into esters for use as

anticancer agents. Kumar, A., et al. , Ind. J. of Chem.

25 (b): 880 (1986). Thieno [2,3-b-]-analogues of 2-aryl-1- methoyl-4-quinolone alkaloids from thiophene isosters did not exhibit biological activity in, e. g., antibacterial and antimalarial assays. Barker, J., et al., J. Chem. Res.

(S): 155 (1986). 6,7- and 7,8-thia-4-quinazolones have been reporte to be antimalarial alkaloids. Barker, J., et al., J. Org. Chem. :18 138 (1952). See also Obrecht, D., et al Helvetica Chimica Acta 80: 531 (1997).

Piperdinomethylthiophene derivatives have been reporte to be inhibitors of H. Pylori. Kojimia, K., et al. , Bioorganic & Medicinal Chemistry Letters 6 :(15) 1795 (1996).

Thiophenesulfonamide-based compound have been reporte to be endothelin receptor-antagonists. Raju, B., et al., Bioorganic & Medicinal Chemistry Letters 7 (7): 939 (1997).

Aryl piperazines have been used as intermediates to synthesize pharmacologically active compound for non- diabetic indications, for example, as 5HT seritonin antagonists: 1- (cyanomethyl)-4-benzylpiperazine has been used as a synthetic intermediate for the preparation of 1-[ß-

(aroylamino) ethyl]-4-benzylpiperazines and 1- <BR> <BR> <BR> [ [arylamino) carbonyllethyll-4-benzylpiperazines. Saxena, M.,<BR> <BR> <BR> <BR> <BR> J. Med. Chem. 33 : 2970 (1990). Aryl piperazines were used to synthesize Gizur, T., et al. , Med. Chem. Res. 3: 545 (1993). N- [ (4-aryl-l- piperazinyalkyl]-substituted imides. Ahmad, Y. E., et al., J. <BR> <BR> <BR> <P> Med. Chem. :40 952 (1997); Mokrosz, M. J., et al. , Med. Chem.<BR> <BR> <BR> <BR> <BR> <P>Res. :4 161 (1994); See also Abou-Gharbia, M., et al., J. Med.<BR> <BR> <BR> <BR> <BR> <P>Chem. :31 1382 (1988), Raghupathi, R. K., et al. , J. Med. Chem.

34: 26343 (1991).

International Publication No. 90/09801 discloses thiazole derivatives that are allegedly useful as 5-lipoxygensase inhibitors.

International Publication No. 96/02249 discloses a genus of thiazole derivatives that are allegedly useful as selective dopamine receptor ligands.

U. S. Patent No. 3,990,879 discloses thiadiazoles that are allegedly useful as aquatic herbacides.

European Patent Publication EP 586 900 A2 describes a process for synthesizing 1,2,4-thiazole derivatives that are allegedly useful as acylating agents for preparing acylaminocephalosporin compound having antibacterial activity. See also T. Kanai et al., Bull-. Chem. Soc. Jpn.

66: 2335 (1993) (the synthesized end product, fluoromethoxyimino-substitutued thiadiazoleacetic acid, having been described as having antibacterial activity); K.

Tatsuta et al. , Bull. Chim. Soc. Jpn. :67 1701 (1994); K.

Sakagami et al. , J. Antibiotics 36 (9): 1205 (1983) (synthesis of 2-amino-1,3,4-thiadiazol-5-ylacetic acid); D. Spinelli et al., J. Heterocyclic Chem. :14 309 (1977) (studies on the decarboxylation rection of amino-1,3,4-thiadiazolecarboxylic acid to amino-1,3,4-thiadiazole); D. Spinelli et al. , J. Org.

Chem. 43 (21): 4042 (1978); and D. Spinelli et al. , J. C. S.

Perkin II 639 (1977).

D. White, et al. , J. Med. Chem. 39 : 4382 (1996) describe the synthesis of thiadiazole derivatives that allegedly show plasma lowering activity.

Various heterocyclic compound have been alleged to exhibit anti-hyperglycemic activity. These inclue sulfonyl ureas (GB 212,695,1, GB 139,856,1, GB 368,965, GB 455,896, and Australian Patent Specification No. 37,624/68m); <BR> <BR> <BR> benzenesulfonyl semicarbazides (GB 645,110, GB 038,379,1, GB 1,137,380, FR 1,519,798, Australian Patent Specification No.

32292/68 (1-substituted-4-arylsulfonylsemicarbazide)); <BR> <BR> <BR> sulfonyls (GB 1, 511353, (sulfamoylpyridines and substituted sulfonamides), GB 1, 661,292, U. S. 3,621,026 (sulfonylaminopyridine derivatives); oxazolyl alkyl- heterocycles (U. S. 5,239,080); thizolidine and pyrrolidine compound (U. S. 4,499,102 and EP 031 104 B1); a thiazole substuted steroid (Internation Patent Publication No. WO 87/02367) and 2-alkylpyrrolidines (International Publication No. WO 97/09040).

U. S. Patent No. 4,499,102, and EP Patent No. 031 104 B1 disclose thiazolidine and pyrrolidine compound that allegedly exhibit inhibitory aldose reductase activity : International Patent Publication No. WO 97/09040 discloses 2-alkylpyrrolidines allegedly useful for treating diabetes.

Australian Patent Publication AU A 69939/87 discloses thiazoles allegedly useful for treating diabetes.

European Patent Publication No. EP 337 819 discloses thiazoles that are allegedly useful for the treatment of diabetic conditions.

International Patent Publication No. WO 97/03067 discloses piperazine derivatives that are alleged to be useful for the treatment of non-insulin dependent diabetes mellitus and hyperglycemia.

Great Britain Patent Publication No. 1,053,085 discloses thiadiazole derivatives that allegedly have hypoglycemic activity.

Rondu, et al., J. Med. Chem. :40 3793 (1997) disclose imidazole-containing piperazine derivatives having hypoglycemic activity.

The present compound, compositions comprising the compound, and methods for their use, fill a persistent need for effective anti-hyperglycemic and/or anti-diabetic agents.

Citation or identification of any reference in Section 2 of this application shall not be construed as an admission that such reference is available as prior art to, or in any way pertinent to the patentability of, the present invention.

3. SUMMARY OF THE INVENTION The present invention provides novel piperazine derivatives, as well as pharmaceutically acceptable salts thereof, having anti-hyperglycemic activity, particularly in diabetic subjects; pharmaceutical compositions comprising piperazine derivatives; as well as methods for their use.

Thus the invention provides compound of formula (I):.

in which: Ar is selected from the group consisting of : a mono-, bi-or tricyclic aryl group having from 6 to 14 carbon atoms; a heteroaromatic group selected from the pyridyl, pyrimidyl, pyrrolyl, furyl, thienyl, quinolyl, indoyl, benzothienyl, benzofuryl, benzopyrranyl, benzothiopyrannyl, dibenzofuryl, carbazolyl and benzothiazinyl groups, said Ar being optionally substituted with 1 to 3 substituents selected from a Cl-C8 alkyl, (C3-C8) cycloalkyl, (C1-C6)alkyl,C1-C8alkoxy,(C3-C8)(C3-C8)cycloalkyl cycloalkyloxy (Cl-C6) alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (C1-C6) alkyl, (C3-C8)cycloalkyl(C1-C6)cycloalkyloxy, alkoxy, (Cl-C6) alkoxy (Cl-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl,heteroaryl,(C6-C14) heteroaryl (C6-C14)aryl(C1alkyl, C6) alkyl, (C1-C6)alkyl(C6-C14)aryl,(C6-C14)aryl aryloxy. (C6-C14) aryloxy (C1-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyloxy, (C6-C14) aryl (Cl-C6) alkyloxy (C1-C6) alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, amino, carboxyl, carbamoyl,(C1-C8)alkoxycarbonyl, alkylthio, (C1-C8)alkylsulphonyl,alkylsulphinyl, sulphoamino, sulphamoyland(C1-alkylsulphonylamino, C8) alkylcarbonylamino, or two of these substituents forming a methylenedioxy group; R1, R2 and R3 are selected, independently of each other, from the group consisting of: hydrogen, Cl-cob alkyl, (Cl-C6) alkoxy (Cl-C6) alkyl,

a cycloalkyl group containing from 3 to 8 carbon atoms, (C1-C6)alkyl,(C3-C8)cycloalkyloxycycloalkyl (C3-C8)cycloalkyl(C1-C6)-alkoxy(C1-C6)(C1-C6)alkyl, alkyl,alkyl,C6-C14 aryl, (C6-C14)heteroaryl(C1-C6)heteroaryl, alkyl, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)alkylaryl (Cl-C6) aryl, (C6-C14) aryl (Cl-C6) alkoxy (C1-C6) alkyl, and (C1-C6)alkyl,(C6-C14)aryloxy or alternatively R1 forms with the nitrogen atom to which R1 is attache and the Ar group a ring selected from indolinyl, quinolyl, indolyl and tetrahydroquinolyl; and R4, R5, R6 are selected, independently of each other, from the group consisting of: hydrogen, C1-C8alkyl,(C3-C8)cycloalkyl, cycloalkyl (C1-C6) alkyl, (C3-C8)cycloalkyloxyalkoxy, (C1-C6) alkyl, (C3-C8)cycloalkyl(C1-C6)cycloalkyloxy, alkoxy, (C1-C6)alkoxy(C1-C6)alkyl,(C1-C6)cycloalkyl alkoxy C6-C14aryl,(C6-C14)aryl(C1-C6)alkyl,alkyl, (C6-C14) aryl (C6-C14)aryl,(C6-C14)aryloxy,(C6-alkyl C14) aryloxy (Cl-C6) alkyl, (C6-C14) aryl (Cl-C6) alkoxy, (C6-C14) aryl (Cl-C6) alkyloxy (Cl-C6) alkyl ; halogen, trifluoromethyl, trifluoromethoxy, cyano, carboxyl, hydroxyl, nitro, amino (C1- C6) alkoxycarbonyl, carbamoyl, (C1-C8)alkylthio, alkysulphinyl, (Cl-C8) alkylsulphonyl, sulphoamino, (C1-C8) alkylsulphonylamino, sulphamoyl and (C1-Ce) alkycarbonylamino, two of these groups optionally joined to form a methylenedioxy group, each (C6-C14) aryl group being optionally substituted with 1 to 3 substituents selected from C1-C8alkoxy,halogen,trifluoromethyl,C1-C8alkyl, trifluoromethoxy, hydroxyl, nitro and amino; their solvates ) and their pharmaceutically acceptable salts, which are useful as hypoglycemic agents.

Among the compound of general formula (I) according to the invention, there may be mentioned more particularly, as preferred compound: 54-{4-[2(N-isopropyl-N-phenylamino)-2-oxoethyl]-1- piperazinyl) benzoic acid;

4- (4- [2- (N- [2, 6-dimethylphenyllamino)-2-oxoethyll- 1-piperazinyl) benzoic acid; and 4-{4-[2-(N-[2,6-diisopropylphenyl]amino)-2- oxoethyl]-1-piperazinyl}benzoicacid.

The present invention further provides compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use for use as hypoglycemic agents, as well as methods for their use.

The invention also provides a process for the preparation of the compound of general formula (I), the process comprising the steps of: (a) reacting an aromatic amine of general formula (II): in which Ar and R1 are as defined above for general formula I, with a haloacyl halide of general formula (III): in which Hal represents a chlorine or bromine atom and R2 and R3 are as defined above for the general formula I, in order to form a compound of general formula (IV):

; (b) reacting the compound of general formula (IV) with a compound of general formula (V) : in which R4, R5 and R6 are as defined as above for general formula I, and R. is a hydrogen atom or a C1-C6 alkyl group, in the presence of a basic agent such as triethylamine in order to form the compound of general formula (VI): (VI); and (c) in which aryl and R1-R7 are as defined above for general formula I, and in the case where R7 is an alkyl group, hydrolyzing this compound in order to form the compound of general formula (I).

The invention further provides compound of general formula (VII):

in which: Ar is selected from: a mono-, bi-or tricyclic aryl group having from 6 to 14 carbon atoms; a heteroaromatic group selected from the pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl, benzopyranyl, benzothiopyranyl, dibenzofuryl, carbazolyl and benzothiazinyl groups; said Ar being optionally substituted with 1 to 3 substituents selected from Cl-ce alkyl, (C3-C8) cycloalkyl, (C1-C6)alkyl,C1-C8alkoxy,(C3-C8)(C3-C8)cycloalkyl cycloalkyloxy (Cl-C6) alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (C1-C6) alkyl, (C3-C8)cycloalkyl(C1-C6)cycloalkyloxy, alkoxy, (C1-C6)alkyl,(C6-C14)aryl,(C6-C14)alkoxy heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-Cl4) aryl (Cl- C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl (C6-C14) aryl, (C6-C14) aryloxy. (C6-C14) aryloxy (C1-C6) alkyl, (C6-C14arYl alkyloxy, (C6-C14) aryl (C1-C6) alkyloxy (Cl-C6) alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, amino, carboxyl, carbamoyl,(C1-C8)alkoxycarbonyl, alkylthio, (C1-C8)alkylsulphonyl,alkylsulphinyl, sulphoamino, sulphamoyland(C1-alkylsulphonylamino, C8) alkylcarbonylamino, or two of these substituents forming a methylenedioxy group;

the 4-carboxyphenyl and substituted 4-carboxyphenyl groups being excluded from the definition of Ar; R1, R2, and R3 are selected, independently of one another from: hydrogen, C1-C8 alkyl (Cl-C6) alkoxy (Cl-C6) alkyl group; a cycloalkyl group containing from 3 to 8 carbon atoms, (C1-C6)alkyl,(C3-C8)cycloalkyloxycycloalkyl (Cl-C6) alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, C6-C14heteroaryl,(C6-C14)heteroaryl(C1-C6)alkyl,C6-C14aryl, (C6-C14) aryl (C1-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl (C6-C14) aryl, (C6-C14) aryl (Cl-C6) alkoxy (C1-C6) alkyl and (C6-Cl4) aryloxy (C1-C6) alkyl; A, B, C and D are =CH-groups, or onze or two of A, B, C and D are a nitrogen atom; and.

R4, R5 and R6 are selected, independently of one another from: hydrogen, (C3-C8)cycloalkyl,(C3-C8)alkyl, cycloalkyl (C1-C8)alkoxy,(C3-C8)cycloalkyloxyalkyl, (C3-C8)cycloalkyloxy,(C3-C8)cycloalkyl(C1-C6)(C1-C6)alkyl, alkoxy, (C3-C8) cycloalkyl (C1-C6) alkoxy (Cl-C6) alkyl, (Cl-C6) alkoxy C6-C14aryl,(C6-C14)aryl(C1-C6)alkyl,alkyl, aryl (Cl-C6) alkyl (C6-C14) aryl, (C6-Cl4)aryloxy(C C14) aryloxy (C6-C14)aryl(C1-C6)alkoxy,(C6-C14)alkyl, aryl (Cl-C.) alkyloxy (Cl-C6) alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, carboxyl, hydroxyl, nitro, amino (C1- C6) alkoxycarbonyl, carbamoyl, (C1-C8)alkylthio, alkysulphinyl, sulphoamino,(C1-C8)alkylsulphonyl, alkylsulphonylamino, sulphamoyl, and (Cl-C.) alkycarbonylamino, two of these groups optionally joined to form a methylenedioxy group or a phenyl ring condense with the ring to which they are attache, each (C6-C14) aryl or aryloxy group being optionally substituted with 1 to 3 substituents selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro and amino; their solvates and their pharmaceutically acceptable salts, which are useful as hypoglycemic agents.

The invention also relates to a process for the preparation of the compound of general formula (VII). A preparation process according to the invention comprises the rection of an aromatic amine of general formula (VIII):

in which A, B, C, D, R1, R4, R5 and R6 are as defined above for general formula VII and R, is a hydrogen atom, a C1- C6 alkyl group or a benzyl group, with a haloacyl halide of general formula (IX): in which R2 and R3 are as defined above for general formula (VII), Hal represents a chlorine or bromine atom, in order to form a compound of general formula (X); in which A, B, C, D, R1, R2, R3, R4, R5, R6, R, and Hal are as defined above for general formula (VII); and the rection of the compound of general formula (X) with a compound of general formula (XI):

in which Ar is a defined above for general formula (vil), in the presence of a basic agent, such as triethylamine, in order to form the. compound of general formula (XII): in which Ar, A, B, C, D, R1, R2, R3, R4, R5, R6 and R, are as defined above for general formula (VII).

In the case where R, is an alkyl group, the compound of general formula (XII) can be hydrolyse by conventional acidic or basic means in order to give the compound of general formula (VII).

In the case where R, is a benzyl group, the compound of general formula (XII) can be hydrogenolysed in the presence of a catalyst, such as palladium-on-charcoal, in order to give the compound of general formula (VII).

The compound of formula (VIII) and (XI) are known compound or can be prepared according to known processes.

Thus, compound of formula (VIII) are described in Organic Preparation and Procedures International, 13,189 (1981).

The compound of formula (V) are known compound.

They can be synthesized according to the procedure described by V. Prelog and Z. Blazek in Collection Czechloslov. Chem.

Communications 6,211-24 (1934) for ethyl 4- (l- piperazinyl)benzote.

The invention further provides compound, as well as compositions comprising said compound, useful as hypoglycemic agents, of general formula (XIIIa): wherein: R1 is selected from the group consisting of R16OR17,R18NHR19,R14COOR15,C1-C8alkyl,C3-C8hydrogen,halogen, cycloalkyl, (C1-C6)alkyl,(C3-C8)cycloalkylcycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)alkyl,(C6-C14)heteroaryl (C6-C14) aryl (Cl-C6) alkyl (C6-Clq) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, carbamoyl, (Cl-C.) alkylthio, (C1-C8)(C1-C8)alkylsulphinyl, alkylsulphonyl, (C1-C8) alkylsulphonylamino, sulphamoyl or (C1-Ce) alkylcarbonylamino; said Cl-Ce alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more. constituents selected from the group consisting of halogen, Cl-C6 alkyl and phenyl; said C6- C14 aryl, (C6-C14) aryl (C1-C6 alkyl),C6-C14 heteroaryl, and (C6 C14) heteroaryl (Cl-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and C1-C6 alkyl; R2 is selected from the group consisting of hydrogen, halogen, R14COOR15,C1-C8alkyl,C3-C8R18NHR19,

cycloalkyl, (C3-C8) cycloalkyl (Cl-C6) alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl (C1-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl, (C1-C6)alkyl(C6-C14)aryl,trifluoromethyl,(C6-C14)aryl nitro,(C1-C8)alkylthio,(C1-C8)trifluoromethoxy,cyano, alkylsulphinyl, (C1-C8)alkylsulphonyl, alkylsulphonylamino, sulphamoyl and (Cl-C8) alkylcarbonylamino ; said Cl-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, andphenyl;saidC6-C14aryl,(C6-C14)aryl(C1-C6C1-C6alkyl alkyl), and(C6-C14)heteroaryl(C1-C6)alkylheteroaryl, groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cl-C6 alkyl; R3 is selected from the group consisting of hydrogen, halogen, R16OR17, R18NHR19, R14COOR15, C1-C8 alkyl, (C3- C8) cycloalkyl (C1-C6) alkoxy (Cl-C6) alkyl, (C6-C, 4) aryl, (C6- C14) heteroaryl(C1-C6)alkyl,(C6-C14)aryl(C6-C14) (C6-C14)aryl(C1-C6)alkyl(C6-C14)aryl,(C1-C6)alkyl,

trifluoromethyl, trifluoromethoxy, cyano, nitro, (C1-C8) alkylthio, (C1-C8)alkylsulphonyl,(C1-alkylsulphinyl, Ce) alkylsulphonylamino, sulphamoyl and (C1-C8) alkylcarbonylamino; said Cl-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-C6 alkyl and phenyl; said C6-C14 aryl, (C6-C14) aryl (Cl-C6 alkyl), C6-Cl4 heteroaryl, and (C6-C14) heteroaryl (Cl-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cl-C6 alkyl; R4 is selected from the group consisting of hydrogen, halogen, R16OR17, R18NHR19, R14COOR15, C1-C8 alkyl, (C3- <BR> <BR> <BR> C8) cycloalkyl (Cl-C6) alkoxy (C1-C6) alkyl, (C6-C14) aryl, (C6- C14) heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl, (C6-C14) aryl (C1-C6) alkyl (C6-C14) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (C1-C8)

alkylthio, (C1-C8)alkylsulphonyl,(C1-alkylsulphinyl, CB) alkylsulphonylamino, sulphamoyl and (Cl-C.) C1-C8alkylandC3-C8cycloalkylalkylcarbonylamino;said groups being optionally substituted with one or more substituents selected from the group consisting of halogen, andphenyl;saidC6-C14aryl,(C6-C14)aryl(C1-C6C1-C6alkyl alkyl), C6-C14 heteroaryl, and (C6-C14) heteroaryl (Cl-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and C1-C6 alkyl; R8 is selected from the group consisting of NR20SO2Ar and NR20ArSO2, wherein Ar is an aryl selected from the group consisting of phenyl and phenyl (Cl-C6) alkyl; Rg selected from the group consisting of hydrogen, C1-C8 alkyl, (C1-C6) alkoxy (Cl-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6)alkyl,(C3-C8)cycloalkylcycloalkyloxy (Cl-C6) alkoxy (C1-C6) alkyl, C6-C14 aryl, C6-C14 heteroaryl, (C6- Cul4) heteroaryl (C1-C6) alkyl, (C6-C14) aryl (cl-c6) alkyl, (C6- C14) aryl (C1-C6) alkyl (Cl-C6) aryl, (C6-C14) aryl (Cl-C6) alkoxy (Cl-C6) alkyl and (C6--Clq) aryloxy (C1-C6) alkyl;

Rlo is selected from the group consisting of hydrogen, C1-C8 alkyl, (Cl-C6) alkoxy (C1-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6)alkyl,cycloalkyloxy (C1-C6)alkoxy(C1-C6)alkyl,C6-C14aryl,C6-(C3-C8)cycloalkyl Cl, heteroaryl, (C6-C14) heteroaryl (C1-C6) alkyl, (C6-C14) aryl (C1-C6) alkyl, (C1-C6)alkyl(C1-C6)aryl,(C6-C14)aryl aryl (C1-C6) alkoxy (Cl-C.) alkyl and (C6-C14) aryloxy (Cl-C6) alkyl; Rll is selected from the group consisting of hydrogen, Cl-C. alkyl,- (Cl-C6) alkoxy (C1-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cl-C6) alkyl, (C3-C8) cycloalkyloxy (Cl-C6) alkyl, (C1-C6)alkoxy(C1-C6)alkyl,C6-C14,aryl,C6-(C3-C8)cycloalkyl C14 heteroaryl, (C1-C6)alkyl,(C6-C14)arylheteroaryl (C6-C14)aryl(C1-C6)alkyl(C1-C6)aryl,(C6-C14)(C1-C6)alkyl,

aryl(C1-C6)alkyland(C6-C14)aryloxy(C1-C6)alkoxy alkyl; R12 is selected from the group consisting of hydrogen and Cl-C6 alkyl; R13 is selected from the group consisting of R14 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cl-C6 alkyl; said Cl-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Cl-C. alkyl and phenyl; Rls is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and C1- C6 alkyl; said Ci-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl and C1-C3 alkyl; R16 is a bond or is selected f rom the group consisting of sulfonyl, C1-C8 thioalkyl, aminosulfonyl and Cl- C6 alkyl group; said Cl-C6 alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C1-C6 alkyl and phenyl; Rl, is selected from the group consisting of Ci-C6 alkyl,alkyl,C3-C8 cycloalkyl, (C6-C14)aryl(C1-C6)aryl, alkyl; said Cl-C, alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, phenyl, phenylalkyl and Cl-C3 alkyl; said C3-C6 cycloalkyl group being optionally substituted with C1-C3 alkyl; Rye is a bond or is selected from the group consisting of sulfonyl, Cl-C,, thioalkyl, aminosulfonyl,

carbonyl, aminocarbonyl and Cl-C6 alkyl, said Cl-C6 alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C1-C6 alkyl and phenyl; Rlg is selected from the group consisting of hydrogen, phenyl, phenylalkyl, and Cl-C6 alkyl; said Cl-C. alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl and C1-C3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino and Cl-C. alkyl; said phenylalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino and Cl-C6 alkyl; R20 is selected from the group consisting of hydrogen, Cl-Cl6 alkyl, hydroxy and Cl-C6 alkoxy; m is 0 or 1; o is 0 or 1; R21 is a bond or Cl-C6 alkyl; said Cl-C6 alkyl being

optionally substituted from the group consisting of benzene and an optionally substituted benzene ring; said benzene ring being optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 alkoxy and hydroxy; R22-R31 are independently selected from the group consisting of hydrogen, halogen, C1-C8 alkoxy, C1-C8 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C.) alkoxy, carboxy, <BR> <BR> C,-C,, thioalkyl hydroxy (C3-CB) cycloalkyl, (C3-C8) cycloalkyl, (Cl-C6) alkyl, Cl-cob alkoxy, (C3-C8) cycloalkyloxy (Cl-C6) alkyl, (C3-C8) cycloalkyl (Cl-C.) alkoxy (Cl-C6) alkyl, (C3-C8) cycloalkyloxy, (C1-C6)alkoxy,(C1-C6)alkoxycycloalkyl (Cl-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C6-C14) alkyl,(C6-C14)aryl(C1-C6)alkyl,(C6-C14)heteroaryl(C1-C6) aryl (C1-C6) alkyl (C6-C14)aryloxy,(C6-C14)aryl, aryloxy (Cl-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyloxy, (C6-C14) aryl (C1-C6)alkyltrifluoromethoxy,amino,alkyloxy alkylthio,(C1-C8)alkylsulphinyl(C1-C8)carbamoyl,(C1-C8)

alkylsulphonyl, sulphoamino, (C1-C8) alkylsulphonylamino, sulphamoyl or (Cl-CB) alkylcarbonylamino; said (Cl-C8) alkyl being optionally substituted with one or more constituents selected from the. group consisting of halogen and Cl-C3alkyl; said C2-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3alkyl; said C1-C8 thioalkyl being optionally substituted with one or more constituents selected from the group consisting of halogen and C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more constituents selected from the group consisting of halogen and Cl-C3 alkyl; or R22 and R23 when taken together form an aryl ring; or R23 and R24 when taken together form an aryl ring; or two of R22-R2. when taken together can form a methylene dioxy group; X3 is nitrogen or CR29; X4 is nitrogen or CR30 ; X5 iS nitrogen or CR31 ; wherein at least one of X3, X4, or X5 is a nitrogen; or R2. and CR30 when taken together form an aryl

ring; or R28 and CR29 when taken together f orm an aryl ring; with the proviso that the compound of formula (XIIIa) is not 1-[[[4-[2-(fluorophenyl]piperazin-1-yl] acetyl]amino]-6-fluorobenzothiazole ; and a pharamceutically accceptable salt or solvate thereof; and a compound having a tautomeric structure thereof.

In another embodiment of general formula (XIIIa), the invention further provides compound, as well as compositions comprising said compound, useful as hypoglycemic agents, wherein: Ri is selected from the group consisting of hydrogen, halogen, R14COOR15,C1-C8alkyl,C3-C8R18NHR19, cycloalkyl, (C6-C14) aryl, (C6-C14) aryl (Cl-C6) alkyl, trihalo (Cl-C6) alkyl, trihalo (Cl-C6) alkoxy and cyano; said C1-C8

alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl and phenyl; said C6-C14 aryl and (C6-C14) aryl (Cl-C6 alkyl) being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cl-C6 alkyl; R2 is selected from the group consisting of hydrogen, halogen, R14COOR15,C1-C8alkyl,C3-C8R18NHR19, <BR> <BR> cycloalkyl, (C6-C14) aryl, (C6-C14) aryl (Cl-C6) alkyl, trihalo (Cl-C6) alkyl, trihalo (Cl-C6) alkoxy and cyano; said C1-C9 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl and phenyl; said C6-C14 aryl and (C6-C14) aryl (Cl-C6 alkyl) being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cl-C6 alkyl; R3 is selected from the group consisting of hydrogen, halogen, R14COOR15,C1-C8alkyl,C3-C8R18NHR19, cycloalkyl, (C6-C14) aryl, (C6-C14) aryl (Cl-C6) alkyl, trihalo (Cl-C6) alkyl, trihalo (Cl-C6) alkoxy and cyano; said Cl-CB

alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl and phenyl; said C6-C14 aryl and (C6-C14) aryl (Cl-C6 alkyl) being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cl-C. alkyl; R4 is selected from the group consisting of hydrogen, halogen, R14COOR15,C1-C8alkyl,C3-C8R18NHR19, cycloalkyl, (C6-C14) aryl, (C6-C14) aryl (Cl-C6) alkyl, trihalo (Cl-C6) alkyl, trihalo (Cl-C6) alkoxy and cyano; said Cl-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-C6 alkyl and phenyl; said C6-14 aryl and (C6-C14) aryl (Cl-C6 alkyl) being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cl-C. alkyl; R8-R21, m and o are as def ined above;

R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said C1-C6 alkyl being optionally substituted with ortie or more substituents selected from the group consisting of halogen and C,-C, alkyl; said C2- C6 alkoxy being optionally substituted with halogen and Cl-C. alkyl; said C1-C8 thioalkyl being optionally substituted with one or more subsitituents consisting of halogen and Cl-C. alkyl; said carbo (C1-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; R23 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl and hydroxy; said Cl-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and. Cl-C3 alkyl; said Cl-C,, thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; R24 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carboxy, phenyl, Cl-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; said Cl-C6 alkoxy being be optionally substituted with one or more substituents selected from the group consisting of halogen or Cl-C3 alkyl; said Cl-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally

substituted with one or more substituents selected from the group consisting of halogen or Cl-C3 alkyl; R25 is selected from the group consisting of halogen, Cl-C6 alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, Cl-ces thioalkyl and hydroxy; said Cl-C. alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and or Cl-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen or Cl-C3 alkyl; said Cl-C. thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen andr Cl-cob alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen or Cl-C3 alkyl; R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C,) alkoxy, carboxy, phenyl, Cl-cob thioalkyl and hydroxy; said C1-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl; said C2- C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; wherein R22-R26 cannot all simultaneously be hydrogen; or two of R22-R26 when taken together can form methylene dioxy group; R27 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl and hydroxy; said Cl-. C6 alkyl being optionally

substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; said C1-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl; said Cl-C,, thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C8 alkyl; said carbo (Cl-C6)-alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen or Cl-C3 alkyl; R28 is selected from the group consisting of hydrogen, halogen, C1-C6alky.,trifluoromethyl,alkoxy, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl and hydroxy; said Cl-C. alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; said Cl-cob thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C8 alkyl; said carbo (C1-C6) alkoxy being

optionally substituted with one or more substituents selected from the group consisting of halogen or Cl-C3 alkyl; or R22 and R23 when taken together form an aryl ring; or R23 and R24 when taken together form an aryl ring; X3 is nitrogen or CR29; X4 is nitrogen or CR30 ; <BR> <BR> Xi ils nitrogen or CR31 ;<BR> <BR> <BR> wherein at least one of X3, X4, or Xi ils a nitrogen; R29 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl,trifluoromethyl,alkoxy, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl and hydroxy; said Cl-C, alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl; said C1-C8 thioalkyl being optionally substituted with one or

more substituents selected from the group consisting of halogen and Cl-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; R30 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl,trifluoromethyl,alkoxy, nitro, cyano, carbo (Cl-C.) alkoxy, carboxy, phenyl, C1-C8 thioalkyl and hydroxy; said C1-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3alkyl; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; said Cl-C. thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; R31 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl,trifluoromethyl,alkoxy, nitro, cyano, carbo (Cl-C.) alkoxy, carboxy, phenyl, Cl-C,,

thioalkyl and hydroxy; said C1-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen or Cl-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; said Cl-C,, thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; or R28 and CR30 when taken together form an aryl ring; or R28 and Cor2. when taken together form an aryl ring; and a pharmaceutically acceptable salt or solvate thereof; and a compound having a tautomeric structure thereof.

The present invention further provides methods for using compositions comprising a compound of formula (XIIIb) or a pharmaceutically acceptable salt or a compound having a tautomeric structure thereof, as hypoglycemic agents, the compound of formula (XIIIb) having the structure: wherein: R1 is selected from the group consisting of hydrogen, halogen, R16OR17, R18NHR19, R14COOR15, C1-C8 alkyl, C3-C8 <BR> <BR> cycloalkyl, (C3-C8) cycloalkyl (Cl-C6) alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)alkyl,(C6-C14)heteroaryl

(C6-Cl4) aryl (Cl-C6) alkyl (C6-C14) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, carbamoyl, (C1-C8) alkylthio, (C1-C8)alkylsuphonyl,(C1-C8)(C1-C8)alkylsulphinyl, alkylsulphonylamino, sulphamoyl or (C1-Ce) alkylcarbonylamino; said Cl-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, Cl-C6 alkyl and phenyl; said C6- C14 aryl, (C6-Cl4) aryl (Cl-C6 alkyl), C6-C14 heteroaryl, and (C6- C14) heteroaryl (Cl-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cl-C6 alkyl; R2 is selected from the group consisting of hydrogen, R18NHR19,R14COOR15,C1-C8alkyl,C3-C8R16OR17, cycloalkyl, (C1-C6)alkyl,(C3-C8)cycloalkylcycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl (C1-C6) alkyl, (C6-C14) aryl (C1-C6) alkyl,

(C6-C14) aryl (Cl-C6) alkyl (C6-Cl4) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (Cl-C.) alkylthio, (Cl-C8) alkylsulphinyl, (Cl-C.) alkylsulphonyl, (Cl-C,) alkylsulphonylamino, sulphamoyl and (Cl-Ce) alkylcarbonylamino; said Cl-Ce alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl and phenyl ; said (C6-C14)aryl(C1-C6aryl, alkyl), and(C6-C14)heteroaryl(C1-C6)alkylheteroaryl, groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and C1-C6 alkyl; # R3 is selected from the group consisting of hydrogen, halogen, R16OR17, R18NHR19, R14COOR15, C1-C8 alkyl, (C3- (C1-C6)alkoxy(C1-C6)alkyl,(C6-C14)aryl,(C6-C8)cycloalkyl heteroaryl, (C6-C14) heteroaryl (C1-C6) alkyl, (C6-C14) aryl (C1-C6) alkyl, (C1-C6)alkyl(C6-C14)aryl,aryl trifluoromethyl, trifluoromethoxy, cyano, nitro, (C1-C8) alkylthio, (C1-C8) alkylsulphinyl, (C1-alkylsulphonyl, Ce) alkylsulphonylamino, sulphamoyl and (Cl-Ce)

alkylcarbonylamino ; said Cl-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, andphenyl;saidC6-C14aryl,(C6-C14)aryl(C1-C6C1-C6alkyl alkyl), C6-C14 heteroaryl, and (C6-Cl4) heteroaryl (C1-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cl-C6 alkyl; R4 is selected from the group consisting of hydrogen, halogen, R16OR17, R18NHR19, R14COOR15, C1-C8 alkyl, (C3- C8) cycloalkyl (C1-C6)alkyl,(C6-C14)aryl,(C6-alkoxy C14) heteroaryl, (C6-C14) heteroaryl (C1-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl (C6-Cl4) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (C1-C8) alkylthio, (C1-C8)alkylsulphonyl,(C1-alkylsulphnyl, CB) alkylsulphonylamino, sulphamoyl and (C1-C8) alkylcarbonylamino; said Cl-cob alkyl and C3-C8 cycloalkyl

groups being optionally substituted with one or more substituents selected from the group consisting of halogen, andphenyl;saidC6-C14aryl,(C6-C14)aryl(C1-C6C1-C6alkyl alkyl), C6-C14 heteroaryl, and (C6-Clq) heteroaryl (Cl-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cl-C6 alkyl; R8 is selected from the group consisting of NR20SO2Ar and NR20ArSO2, wherein Ar is an aryl selected from the group consisting of phenyl and phenyl (Cl-C,) alkyl; R. selected from the group consisting of hydrogen, Cl-cob alkyl, (Cl-C6) alkoxy (Cl-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cl-C6) alkyl, (C1-C6)alkyl,(C3-C8)cycloalkylcycloalkyloxy (Cl-C6) alkoxy (C1-C6) alkyl, C6-C14 aryl, C6-C14 heteroaryl, (C6- C14) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (C1-C6) alkyl, (C6- (C1-C6)alkyl(C1-C6)aryl,(C6-C14)aryl(C1-C6)alkoxyC14)aryl (Cl-C6) alkyl and (C6-C14) aryloxy (Cl-C6) alkyl; RIO is selected from the group consisting of hydrogen, Cl-C. alkyl, (Cl-C6) alkoxy (C1-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C3-C8)cycloalkyloxy(C1-C6)alkyl,alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (Cl-C.) alkyl, C6-C14 aryl, C6- (C6-C14)heteroaryl(C1-C6)alkyl,(C6-C14)arylC14heteroaryl, (C1-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl (C1-C6) aryl, (C6-C14) aryl (C1-C6)alkyland(C6-C14)aryloxy(C1-C6)alkoxy alkyl; R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, (Cl-C6) alkoxy (Cl-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C3-C8)cycloalkyloxy(C1-C6)alkyl,alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (C1-C6) alkyl, CIS-C. 4 aryl, C6- C14 heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl alkyl, (C6-C14) aryl (C1-6) alkyl (C1-C6) ar'yl, (C6-C14) aryl (C1-C6) alkoxy (C1-C6) alkyl and (C6-C14) aryloxy (Cl-C6) alkyl; R12 is selected from the group consisting of hydrogen and Cl-C6 alkyl; R13 is selected from the group_consisting of

R14 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cl-C6 alkyl; said Cl-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Cl-C6 alkyl and phenyl; R15 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and C1- C6 alkyl; said Cl-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl and C1-C3 alkyl; R16 is a bond or is selected from the group consisting of sulfonyl, Cl-C. thioalkyl, aminosulfonyl and C1- C6 alkyl group; said Cl-C6 alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Cl-C. alkyl and phenyl; R17 is selected from the group consisting of Cl-C6 alkyl, C3-C8 aryl,(C6-C14)aryl(C1-C6)C6-C14 alkyl; said Cl-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, phenyl, phenylalkyl and Cl-C3 alkyl; said C3-C6 cycloalkyl group being optionally substituted with Cl-C3 alkyl; R18 is a bond or is selected from the group consisting of sulfonyl, Cl-C8 thioalkyl, aminosulfonyl, carbonyl, aminocarbonyl and Cl-C6 alkyl, said Ci-C6 alkyl group being substituted with one or more substituents selected from

the group consisting of hydrogen, halogen, Cl-C6 alkyl and phenyl; Rlg is selected from the group. consisting of hydrogen, phenyl, phenylalkyl, and Cl-C6 alkyl; said Cl-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl and Cl-C3 alkyl; said phenyl being optionally_substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino and Cl-C6 alkyl; said phenylalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino and C1-C6 alkyl; R20 is selected from the group consisting of hydrogen, Cl-Cl6 alkyl, hydroxy and Cl-C6 alkoxy ; m is 0 or 1; o is 0 or 1; R21 is a bond or Cl-C6 alkyl; said Cl-C6 alkyl being optionally substituted from the group consisting of benzene and an optionally substituted benzene ring; said benzene ring being optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogen, Cl-C6 alkoxy and hydroxy; R22-R31 are independently selected from the group consisting of hydrogen, halogen, C1-C8 alkoxy, C1-C8 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, Cl-cob thioalkyl hydroxy (C3-CB) cycloalkyl, (C3-C8) cycloalkyl, (Cl-C6) alkyl, C1-C8 alkoxy, (C3-C8) cycloalkyloxy (Cl-C6) alkyl, (C3-C8) cycloalkyl (Cl-C.) alkoxy (Cl C6) alkyl, (C3-C8) <BR> <BR> cycloalkyloxy, (C3-C8) cycloalkyl (Cl-C6) alkoxy, (Cl-C6) alkoxy (C1-C6) alkyl, (C6-C14)heteroaryl,(C6-C14)aryl, heteroaryl (C6-C14)aryl(C1-C6)alkyl,(C6-C14)alkyl, aryl (C6-C14)aryl,(C6-C14)aryloxy,(C6-C14)alkyl aryloxyaryloxy(C1-C6) alkyl, (C1-C6)alkyoxly,(C6-C14)aryl aryl (C1-C6)alkylrifluoromethoxy,amino,alkyloxy carbamoyl, (C1-C8) alkylthio, (Cl-C.) alkylsulphinyl, (Cl-C,,) alkylsulphonyl, sulphoamino, (C1-8) alkylsulphonylamino, sulphamoyl or (Cl-CB) alkylcarbonylamino; said (C1-C8) alkyl

being optionally substituted with one or more constituents selected from the group consisting of halogen and C1-C3 alkyl ; said C2-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-cob thioalkyl being optionally substituted with one or more constituents selected from the group consisting of halogen and C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more constituents selected from the group consisting of halogen and C1-C3 alkyl; or R22 and R23 when taken together form an aryl ring; or R23 and R24 when taken together form an aryl ring; or two of R22-R26 when taken together can form a methylene dioxy group; X3 is nitrogen or CR29; X4 is nitrogen or CR30 ; <BR> <BR> <BR> Xi ils nitrogen or CR31;<BR> <BR> <BR> <BR> <BR> wherein at least one of X3, X4, or Xi ils a nitrogen; or R28 and CR30 when taken together form an aryl ring;

or R2. and CR29 when taken together form an aryl ring; with the proviso that the compound of formula (XIIIb) is not 1- [ [ [4- [2- (fluorophenyllpiperazin-1-yll apharamceuticallyacetyl]amino]-6-fluorobenzothiazoleor accceptable salt or solvate thereof; or a compound having a tautomeric structure thereof.

In another embodiment of the methods using compound of general formula (XIIIb), the invention further provides compound, as well as compositions comprising said compound, useful as hypoglycemic agents, wherein: R1 is selected from the group consisting of hydrogen, halogen, R14COOR15,C1-C8alkyl,C3-C8R18NHR19, cycloalkyl, cyano,trihalo(C1-C6)alkyl,aryl, <BR> <BR> trihalo (Cl-C6) alkoxy; said C1-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen,

Cl-C6 alkyl and phenyl ; said C1-C14 aryl and (C6-C14) aryl (C1- C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cl-C6 alkyl; R2 is selected from the group consisting of hydrogen, halogen, R14COOR15,C1-C8alkyl,C3-C8R18NHR19, cycloalkyl, (C6-C14) aryl, cyano, trihalo (C,-C6) alkyl, trihalo (Cl-C6) alkoxy; said Cl-cob alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, Cl-C6 alkyl and phenyl; said C,,-C. 14 aryl and (C6-C, 4) aryl (C1- C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cl-C6 alkyl; R3 is selected from the group consisting of hydrogen, halogen, R16OR17, R18NHR19, R14COOR15, C1-C8 alkyl, C3-C8 cycloalkyl, (C6-C14) aryl, cyano, trihalo (Cl-C6) alkyl, trihalo (Cl-C6) alkoxy; said Cl-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen,

Cl-C6 alkyl and phenyl; said C6-C14 aryl and (C6-C14) aryl (Cl- C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cl-C6 alkyl; R4 is selected from the group consisting of hydrogen, halogen, R14COOR15,C1-C8alkyl,C3-C8R18NHR19, cycloalkyl, (C6-C14) aryl, cyano, trihalo (Cl-C6) alkyl, trihalo (Cl-C6) alkoxy; said Cl-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, andphenyl;saidC6-C14aryland(C6-C14)aryl(C1-C1-C6alkyl C6) alkyl being optionally-substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cl-C. alkyl; R8-R21, m and o are as defined above for general formula (XIIIa);

R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Cl-C6 alkyl, nitro, trifluoromethyl, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said C2-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl; said Cl-C8 thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R23 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C. thioalkyl being optionally substituted with halogen or Cl-C$ alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or C1-C3 alkyl; R24 is selected from the group consisting of hydrogen, bromine, chlorine, C1-C6alkyl,alkoxy,

trifluoromethyl, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, Cl-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or Ci-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl; said Cl-C,, thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or C1-C3 alkyl; R25 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C,.-C,, thioalkyl, and hydroxy; said Cl-C. alkyl being optionally substituted with halogen or Cl-C3alkyl; said Cl-C6 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said C1-C8 thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl;

R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C.) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said C1-C8 thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; wherein R22-R2,. cannot all simultaneously be hydrogen; R27 is selected from the group consisting of halogen, Cl-C6 alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C, alkyl being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with halogen or Cl-C3alkyl; said Cl-C. thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl;

R28 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl, nitro, cyans carbo (C1-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C. alkyl being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C8 thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; or R22 and R23 when taken together f orm an aryl ring; or R23 and R24 when taken together form an aryl ring; X3 is nitrogen or CR29 ; X4 is nitrogen or CR30 ; <BR> <BR> <BR> Xi ils nitrogen or CR31 ;<BR> <BR> <BR> <BR> <BR> <BR> wherein at least one of X3, X4, or Xi ils ;nitrogen R29 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, C1-C6 alkyl, nitro, cyano,

carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with one to two halogen atoms or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; R30 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, C1-C6 alkyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C. alkyl being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with C1-C3alkyl;or R31 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, C1-C6 alkyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said C1-C6 alkyl being optionally substituted with one to two halogen atoms or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; wherein up to three of R27-R31 can simultanoeously be hydrogen when only one of X3-X5 is ;nitrogen wherein up to two of R27-R31 can simultaneously be hydrogen when two of X3-X5 are nitrogen; or R28 and CR29 when taken together form an aryl ring; or R28 and CR30 when taken together form an aryl ring; or a pharmaceutically acceptable salt or solvate thereof.

Among the compound of the general formulas (XIIIa) and (XIIIb) according to the invention, there may be mentioned more particularly, as preferred compound: 2- ( ( (4- (2-Pyridyl) piperazin-1-yl) acetyl) amino)-6- fluorobenzothiazole, 2- ( ( (4- (2-Fluorophenyl) piperazin-1-yl) acetyl) amino)-6- fluorobenzothiazole, 2- ( ( (4- (2-Pyridyl) piperazin-1-yl) acetyl) amino)-6- methoxybenzothiazole,

2- ( ( (4- (2-Pyrimidyl) piperazin-1-yl) acetyl) amino)-6- methoxybenzothiazole, 2- ( ( (4- (Benzyl) piperazin-1-yl) acetyl) amino)-6- methoxybenzothiazole, 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-6-methoxybenzothiazole, 2- ( ( (4- (2-Pyridyl) piperaz in-1-yl) ace-tyl) amino-4 methoxybenzothiazole, 2-(((4-(4-Methoxyphenyl)piperazin-1-yl)acetyl)amino-6- fluoro-benzothiazole, 2-(((4-((2-Pyridyl)piperazin-1-yl)acetyl)amino-6- ethoxybenzothiazole, 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-6-ethoxybenzothiazole, 2- ( ( (4- (3-Chlorophenyl) piperazin-1-yl) acetyl) amino)-6- methoxybenzothiazole, 2- ( ( (4- (3-Bromophenyl) piperazin-1-yl) acetyl) amino)-6- methoxybenzothiazole, 2-(((4-(3-Nitrophenyl)piperazin-1-yl)acetyl)amino-6- methoxybenzothiazole, 2-(((4-((2-Pyridyl)piperazin-1-yl)acetyl)amino-6- ethoxybenzothiazole Hydrochloride, 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-6-ethoxybenzothiazole Hydrochloride, 2- ( ( (4- (4- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-6-methoxybenzothiazole, 2- ( ( (4- (3-Methylphenyl) piperazin-1-yl) acetyl) amino)-6- methoxybenzothiazole, 2- ( ( (4- (3-Cyanophenyl) piperazin-1-yl) acetyl) amino)-6- methoxybenzothiazole, 2-(((4-(4-Bromo-3-trifluoromethylphenyl)piperazin-1- yl) acetyl) amino)-6-methoxybenzothiazole, 2-(((4-(4-Chlorobenzhydryl)piperazin-1-yl)acetyl)amino- 6-methoxybenzothiazole, 2-(((4-(3-Ethylphenyl)piperazin-1-yl)acetyl)amino)-6- methoxy benzothiazole,

2- ( ( (4- (2-Naphthyl) piperazin-1-yl) acetyl) amino)-6- methoxybenzothiazole, 2-(((4-(3-Methoxyphenyl)piperazin-1-yl)acetyl)amino-6- methoxybenzothiazole, 2-(((4-(3-Methoxy-5-trifluoromethylphenyl)piperazin-1- yl) acetyl) amino)-6-methoxybenzothiazole, 2- ( ( (4- (3,5-Dichlorophenyl) piperazin-1-yl) acetyl) amino)- 6-methoxybenzothiazole, 2- ( ( (4- (3,4-Dichlorophenyl) piperazin-1-yl) acetyl) amino)- 6-methoxybenzothiazole., The invention also relates to a process for the preparation of the compound of general formulas (XIIIa) and (XIIIb). A preparation process according to the invention comprises the rection of an aromatic amine of general formula (A1):

in which Rl, R2, R3, R4, R8, R9, and m are as defined above for formulas (XIIIa) and (XIIIb), with a haloacyl halide of general formula (IXa): in which Rlo and R,.,-are as defined above for formulas (XIIIa) and (XIIIb), Hal represents a chlorine or bromine atom, in order to form a compound of general formula (XVII);

in which R1, R2, R3, R4, R8, R9, R10, R11 and m are as defined above for formulas (XIIIa) and (XIIIb), and Hal is as defined above; and the rection of the compound of general formula (XVII) with a compound of general formula (XVIII) : in which R12, R13, and o are as defined above for formulas (XIIIa) and (XIIIb), in the presence of a basic agent, such as triethylamine or potassium carbonate in order to form the compound of general formulas (XIIIa) and (XIIIb):

(XIX) in which Ru, R2, R3, R4, R8, R9, R10, R11, R12, R13, m and o are as defined above for formulas (XIIIa) and (XIIIb) and Hal is as defined above; The invention further provides compound, as well as compositions comprising said compound, useful as hypoglycemic agents, of general formula (XIVa): wherein: R. is selected from the group consisting of hydrogen, alkyl,C3-C8cycloalkyl,(C3-C8)C1-C8 cycloalkyl C1-C8alkoxy,(C3-C8)cycloalkloxyalkyl, (Cl-C6) alkyl, (C3-C8) cycloalkyl (C1-C6) alkoxy (Cl-C6) alkyl, (C3-C8)cycloalkyl(C1-C6)alkoxy,$(C1-(C3-C8)cycloalkyloxy, (C1-C6)alkyl,(C6-C14)aryl,(C6-C14)heteroaryl,C6)alkoxy (C1-C6)alkyl,(C6-C14)aryl(C1-C6)alkyl,(C6-C14)heteroaryl (C6-C14) aryl (C6-C14)aryl,(C6-C14)aryloxy,(C6-alkyl C14) aryloxy (Cl-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyloxy, (C6- C14) aryl (C1-C6) alkyloxy (C1-C6) alkyl group, halogen, trifluoromethyl, cyano, nitro, amino, carboxyl, (Cl-C6) alkoxycarbonyl, carbamoyl, (C1-C8) alkylthio, (Cl-C8)

alkylsulphinyl, (Cl-C.) alkylsulphonyl, sulphoamino, (Cl-C.) alkylsulphonylamino, sulphamoyl and (C1-Ce) alkylcarbonylamino ; said Cl-C. alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl and phenyl; said C6- C14 aryl and (C6-C14) aryl (Cl-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy, C1-C6 alkyl and phenyl; R. is selected from the group consisting of NR20SO2Ar and NR2oArSO2, wherein Ar is an aryl selected from the group consisting of phenyl and phenyl (Cl-C6) alkyl; Rg is selected from the group consisting of hydrogen, (C1-C6)alkoxy(C1-C6)alkyl,aalkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl group,(C3-C8)cycloalkyloxy(C1-C6)alkyl alkyl, (C1-C6)alkoxy(C1-C6)alkyl,C6-C14cycloalkyl aryl, (C6-C14)heteroaryl(C1-C6)alkyl,(C6-heteroaryl, C14) aryl (C6-C14)aryl(C1-C6)alkyl(C1-C6)aryl,alkyl, (C6-C14) aryl (Cl-C.) alkoxy (Cl-C6) alkyl and (C6-C1¢) aryloxy (C1-C6) alkyl group;

R10 is selected from the group consisting of hydrogen, C1-C8 alkyl, (Cl-C6) alkoxy (C1-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl group,(C3-C8)cycloalkyloxy(C1-C6)alkyl alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, C6-C14 aryl, (C6-C14)heteroaryl(C1-C6)alkyl,(C6-heteroaryl, C14) aryl (C1-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl (Cl-C6) aryl, (C6-C14) aryl (C1-C6) alkoxy (Cl-C.) alkyl and (C6-C14) aryloxy (C1-C6) alkyl group; R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, (C1-C6) alkoxy (Cl-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C1-C6) alkyl group, (C3-C8) cycloalkyloxy (Cl-C6) alkyl, (C1-C6)alkoxy(C1-C6)alkyl,C6-C14cycloalkyl aryl, (C6-C14)heteroaryl(C1-C6)alkyl,(C6-heteroaryl, C14) aryl (C1-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl (C1-C6) aryl,

(C6-C14) aryl (Cl-C6) alkoxy (Cl-C6) alkyl and (C6-C14) aryloxy (C1-C6) alkyl group; R12 is selected from the group consisting of hydrogen and Cl-C6 alkyl; R13 is selected from the group consisting of R14 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cl-C6 alkyl; said Cl-C. alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C1-C6 alkyl and phenyl ; Rosis selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions and C1-C6

alkyl; said C1-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl, and Cl-C3 alkyl; R20 is selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy and Cl-C6 alkoxy; m is 0 or 1; n is 0 or 2; o is 0 or 1; R21 is a bond or Cl-C6 alkyl; said Cl-C6 alkyl being optionally substituted from the group consisting of benzene and an optionally substituted benzene ring; said benzene ring being optionally substituted with one or more substituents selected from the group consisting of Cl-C6 alkyl, halogen, C1-C6 alkoxy and hydroxy; R22-R31 are each independently selected from the group consisting of hydrogen, Cl-cob alkyl, C3-C8 cycloalkyl, (C1-C6)alkyl,C1-C8alkoxy,(C3-C8)(C3-C8)cycloalkyl

cycloalkyloxy (C1-C6) alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (C3-C8)cycloalkyloxy,(C3-C8)cycloalkyl(C1-C6)(C1-C6)alkyl, alkoxy, (C1-C6) alkoxy (Cl-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl (C1-C6) alkyl, (C6-C14) aryl (C1- C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl (C6-C14) aryl. (C6-C14) aryloxy(C1-C6)alkyl,(C6-C14)aryl(C1-C6)aryloxy,(C6-C14) alkyloxy, (C6-C14) aryl (Cl-C6) alkyloxy (C1-C6) alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, (Cl-C6) alkoxycarbonyl, carbamoyl, (C1-C8) alkylthio, (Cl-C.) alkylsulphinyl, sulphoamino,(C1-C8)alkylsulphonyl, alkylsulphonylamino, sulphamoyl, (C1-C8) alkylcarbonylamino, and two of these substituents forming a methylenedioxy group, or R22 and R23 when taken together form an aryl ring; or R23 and R24 when taken together fortin an aryl ring; X3 is nitrogen or CR29; X4 is nitrogen or CR30 ; X. is nitrogen or CR31; wherein at least one of X3, X4, or XS is a nitrogen; or R28 and CR30 when taken together form an aryl ring;

or R28 and CR29 when taken together form an aryl ring ; with the proviso that the compound of formula (XIVa) is not: 2- (((4-(phenyl) piperazinly-1-)(((4-(phenyl) piperazinly-1-) acetyl) amino)-4- ((carboethoxy) methyl) thiazole: 2-(((4-(2-fluorophenyl)piperazin-1-yl)- acetyl) amino)-4-((carboethoxy) methyl) thiazole; or 4-(((2-fluorophenyl)amino)acetyl)amino)-1-((N'-(2- thiazolyl))sulfonamido)benzene.

In another embodiment of general formula (XIVa), the invention further provides compound as well as comositions comprising said compound, useful as hypoglycemic agents wherein: R1 is selected from the group consisting of hydrogen, group,halogen,C6-C14aryl,(C6-C14)arylalkyl (Cl-C6) alkyl, and R14COOR15 ; said Cl-cob alkyl group being

optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C. alkyl and phenyl; said C6-C14 aryl and (C6-Cl4) aryl (Cl-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy, Cl-C6 alkyl and phenyl; m n, o, and R21 are defined as above for general formula (XIVa); R22 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl and hydroxy; said C1-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said C1-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being

optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; R23 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl,trifluoromethyl,alkoxy, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl and hydroxy; said C1-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-Ce thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; R24 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl,trifluoromethyl,alkoxy, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8

thioalkyl and hydroxy; said Cl-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3, alkyl; said C,.-C,, thioalkyl being optionally substituted with one or more substituents selected from the group. consisting of halogen and Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; R25 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, Cl-C6 alkyl, carbo (Cl-C6) alkoxy, carboxy, phenyl, Cl-C, thioalkyl and hydroxy; said C,- C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said C1-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C. alkyl;

said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; R26 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl and hydroxy; said Cl-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C. thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C. alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; or two of R22-R26 when taken together can form a methylenedioxy group;

R2, is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, Cl-cob thioalkyl and hydroxy; said Cl-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3alkyl; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Ci-C. thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; R28 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl and hydroxy; said C1-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with one or more substituents

selected from the group consisting of halogen and Cl-C3alkyl; said Cl-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-cob alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; or R22 and R23 when taken together form an aryl ring; or R23 and R24 when taken together form an aryl ring; X3 is nitrogen or CR29; X4 is nitrogen or CR30 ; <BR> <BR> <BR> Xi ils nitrogen or CR31;<BR> <BR> <BR> <BR> <BR> <BR> wherein at least one of X3, X4, or Xi ils ;nitrogen R29 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C,-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with one or more substituents selected from the

group consisting of halogen and Cl-C3 alkyl, wherein the numbered halogen atoms can be 0-2; said C1-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said C1- C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C8 alkyl; said carbo (Cl-C6) alkoxy _being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl; R30 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, trifluoromethyl, Cl-C6 alkyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl and hydroxy; said Cl-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; said Cl-C. thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C8 alkyl; said carbo (Cl-C6) alkoxy being

optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; R31 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl, wherein the numbered halogen atoms can be 0-2; said C1-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said C1- C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl;

or R28 and CR30 when taken together form an aryl ring; or R28 and Cor2, when taken together form an aryl ring; and a pharmaceutically acceptable salt or solvate thereof; and a compound having a tautomericstructure thereof; and with the proviso that the compound of formula (XIVa) is not: 2-(((4-(phenyl)piperazinly-1-)acetyl)amino)-4- ((carboethoxy) methyl) thiazole; 2-(((4-(2-fluorophenyl)piperazinyl-1)- acetyl)amino)-4-((carboethoxy)methyl)thiazole;or 4- (((2-fluorophenyl)(((2-fluorophenyl) amino) acetyl) amino)-1-((N'-(2- thiazolyl)) sulfonamidobenzene.

The present invention further provides methods for using compositions comprising a compound of formula (XIVb) or a pharmaceutically acceptable salt or a compound having a tautomeric structure thereof, as hypoglycemic agents, the compound of formula (XIVb) having the structure: wherein: R1 is selected from the group consisting of hydrogen, alkyl,C3-C8cycloalkyl,(C3-C8)C1-C8 cycloalkyl (C1-C6) alkyl, (C3-C8)cycloalkyloxyalkoxy, <BR> <BR> (Cl-C6) alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, (C3-C8)cycloalkyl(C1-C6)alkoxy,(C1-(C3-C8)cycloalkyloxy, C6) alkoxy (Cl-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)alkyl,(C6-C14)heteroaryl

(C6-C14) aryl (C6-C14)aryl,(C6-C14)aryloxy,(C6-alkyl (C1-C6)C14)aryloxy alkyl, (C1-C6)alkyloxy,(C6-aryl, C14) aryl (C1-C6) alkyloxy (C1-C6) alkyl group, halogen, trifluoromethyl, cyano, nitro, amino, carboxyl, (Cl-C6) alkoxycarbonyl, carbamoyl, (C1-C8)alkylthio, alkylsulphinyl, (CI-C,) alkylsulphonyl, sulphoamino, (C1-C8) alkylsulphonylamino sulphamoyl and (Cl-C.) alkylcarbonylamino; said Cl-C. alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl and phenyl; said C6- C14 aryl and (C6-Cl4) aryl (Cl-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy, C1-C6 alkyl and phenyl; selectedfromthegroupconsistingofNR20SO2ArR8is and NR20ArSO2, wherein Ar is an aryl selected from the group consisting of phenyl and phenyl (Cl-C6) alkyl; R9 is selected from the group consisting of hydrogen, Cl-Ca alkyl, (Cl-C6) alkoxy (Cl-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C1-C6) alkyl group, (C3-C8) cycloalkyloxy (Cl-C6) alkyl, (C1-C6)alkoxy(C1-C6)alkyl,C6-C14cycloalkyl aryl, C6-C14 heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6- (C1-C6)alkyl,(C6-C14)aryl(C1-C6)alkyl(C1-C6)aryl,C14)aryl (C1-C6)alkoxy(C1-C6)alkyland(C6-C14)aryloxy(C6-C14)aryl (Cl-C6) alkyl group; R10 is selected from the group consisting of hydrogen, Cl-cob alkyl, (C1-C6) alkoxy (Cl-C6) alkyl, a <BR> <BR> cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8)<BR> <BR> <BR> cycloalkyl (Cl-C6) alkyl group, (C3-C8) cycloalkyloxy (Cl-C6) alkyl, (C1-C6)alkoxy(C1-C6)alkyl,C6-C14cycloalkyl aryl, (C6-C14)heteroaryl(C1-C6)alkyl,(C6-heteroaryl, C14) aryl (C1-C6) alkyl, (C6-C14) aryl (C1-C6) alkyl (Cl-C6) aryl, (C1-C6)alkoxy(C1-C6)alkyland(C6-C14)aryloxy(C6-C14)aryl (Cl-C6) alkyl group; Rll is selected from the group consisting of hydrogen, Cl-cob alkyl, (Cl-C6) alkoxy (Cl-C6) alkyl, a

cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cl-C6) alkyl group, (C3-C8) cycloalkyloxy (C1-C6) alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, C6-C14 aryl, C6-C14 heteroaryl, (Cl-Cl4) heteroaryl (CI-C.) alkyl, (C6 C14) aryl (C1-C6) alkyl, (C1-C6)alkyl(C1-C6)aryl,aryl (C6-C14) aryl (Cl-C,,) alkoxy (Cl-C6) alkyl and (C6-Cl4) aryloxy (Cl-C6) alkyl group; _ R12 is selected from the group consisting of hydrogen and Cl-C6 alkyl; R13 is selected, from the group consisting of R14 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cl-C6

alkyl; said cl-c6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C1-C6 alkyl and phenyl; Rus ils selected from the group consisting-of hydrogen, monovalent metal ions, divalent metal ions and Cl-C6 alkyl; said Cl-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl, and Cl-C3 alkyl; R20 is selected from the group consisting of hydrogen, Cl-C6 alkyl, hydroxy and Cl-C6 alkoxy; m is 0 or 1; n is 0 or 2; o is 0 or 1; R21 is a bond or Cl-C6 alkyl; said Cl-C6 alkyl being optionally substituted from the group consisting of benzene and an optionally substituted benzene ring; said benzene ring being optionally substituted with one or more substituents

selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 alkoxy and hydroxy; R11-R31 are each independently selected from the group consisting of hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, (C1-C6)alkyl,C1-C8alkoxy,(C3-C8)(C3-C8)cycloalkyl cycloalkyloxy (Cl-C6) alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (C1-C6) alkyl, (C3-C8)cycloalkyl(C1-C6)cycloalkyloxy, alkoxy, (C1-C6)alkyl,(C6-C14)aryl,(C6-C14)alkoxy heteroaryl, (C6-C14) heteroaryl (C1-C6) alkyl, (C6-C14) aryl (Cl- alkyl, (C6-C4) aryl (Cl-C,) alkyl (C6-Cla)aryl( aryloxy, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)aryloxy alkyloxy, (C6-C14) aryl (C1-C6) alkyloxy (Cl-C6) alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, (Cl-C6) alkoxycarbonyl, carbamoyl, (Cl-C.) alkylthio, (C1-C8) alkylsulphinyl, (Cl-C.) alkylsulphonyl, sulphoamino, (C1-C8) alkylsulphonylamino, sulphamoyl, alkylcarbonylamino, and two of these substituents forming a methylenedioxy group, or R22 and R23 when taken together form an aryl ring; or R23 and R24 when taken together form an aryl ring; X3 is nitrogen or CR29 ;

Xi ils nitrogen or CR3. ;<BR> <BR> <BR> <BR> <BR> <BR> <BR> Xi ils nitrogen or CR31 ;<BR> <BR> <BR> <BR> <BR> <BR> <BR> wherein at least one of X3, X4, or Xi ils a nitrogen; or R28 and Cor3, when taken together form an aryl ring; or R28 and CR29 when taken together form an aryl ring; with the proviso that the compound of formula (XIVb) is not: 2-(((4-(phenyl)piperazinly-1-)acetyl)amino)-4- ((carboethoxy) methyl) thiazole: 2-(((4-(2-fluorophenyl)piperazin-1-yl)- acetyl) amino-4-((carboethoxy) methyl) thiazole; or 4- (((2-fluorophenyl)(((2-fluorophenyl) amino) acetyl) amino)-1- ( (NI- (2- thiazolyl)) sulfonamido) benzene.

In another embodiment of the methods involving compound of general formula (XIVb), the invention further

provides compositions comprising a compound of formula (XIVb) or a phamaceutically acceptable salt or a compound having a tautomeric structure thereof, as hypoglycemic agents, wherein: R, is selected from the group consisting of hydrogen, Cl-cob alkyl group, halogen, C6-C14 aryl, (C6-C14) aryl (Cl-C6) alkyl, and R14COOR1,; said C1-C8 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-C6 alkyl and phenyl; said C6-C14 aryl asid (C6-Cl4) aryl (Cl-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy, C1-C6 alkyl and phenyl; R8-R15, R20, m, n, o, and R21 are defined as above for general formula (XIVb); R22 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, Cl-C. thioalkyl and hydroxy; said Cl-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; R23 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl,trifluoromethyl,alkoxy, carbo (Cl-C6) alkoxy, carboxy, phenyl, Cl-cob thioalkyl and hydroxy; said Cl-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C8 thioalkyl being optionally substituted with one or more

substituents selected from the group consisting of halogen and C1-C8 alkyl; said carbo (Cl-C6) alkocy being optionally 3ubstituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; R24 is selected from the group consisting of zydrogen, halogen, Cl-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, Cl-C, 3 thioalkyl and hydroxy; said C1-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; said Cl-C. thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-cob alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; R25 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, Cl-C6 alkyl, carbo (Cl-C6) alkoxy, carboxy, phenyl, Cl-C. thioalkyl and hydroxy; said C1- C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-cob thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; R26 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl and hydroxy; said Cl-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C. alkoxy being optionally substituted with one or more substituents

selected from the group consisting of halogen and C1-C3 alkyl ; said C1-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; or two of R22-R26 when taken together can form a methylenedioxy group; Ru, is selected from the group consisting of hydrogen, halogen, C1-C6alkyl,trifluoromethyl,alkoxy, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl and hydroxy; said Cl-C. alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C. thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; R28 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C.) alkoxy, carboxy, phenyl, C1-C8 thioalkyl and hydroxy; said Cl-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C. thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; or R22 and R23 when taken together form an aryl ring; or R23 and R24 when taken together form an aryl ring; X3 is nitrogen or CR29; Xi ils nitrogen or CR30 ;

X. is nitrogen or CR31;<BR> <BR> <BR> wherein at least one of X3, X4, or XS is ;nitrogen R29 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl,trifluoromethyl,alkoxy, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl, wherein the numbered halogen atoms can be 0-2; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Ci- C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; R30 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, trifluoromethyl, C1-C6 alkyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl and hydroxy; said C1-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl; said Cl-C. thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl; R31 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, Cl-C. thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl, wherein the numbered halogen atoms can be 0-2; said Cl-C6 alkoxy being optionally substituted with one or more substituents selected

from the group consisting of halogen and Cl-C3 alkyl; said Cl- C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cl-C3 alkyl; or R28 and Cor30 when taken together form an aryl ring; or R28 and CR29 when taken together form an aryl ring; and a pharmaceutically acceptable salt or solvate thereof; and a compound having a tautomeric structure thereof; and with the proviso that the compound of formula (XIVb) is not: 2-(((4-(phenyl)piperazinly-1-)acethyl)amino)-4- ((carvboethoxy) methyl) thiazole; 2-(((4-(2-fluorophenyl)piperazinyl-1)- acetyl) amino-4-((carboethoxy) methyl) thiazole; or 4- (((2-fluorophenyl)(((2-fluorophenyl) amino) acetyl) amino)-1-((N'-2- thiazolyl)) sulfonamidobenzene.

Among the compound of the general formulas (XIVa) and (XIVb) according to the invention, there may be mentioned more particularly, as preferred compound 2-(((4-(Phenyl) piperazin-1-yl) acetyl) amino)-4- (carboxymethyl) thiazole, 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-4-(carboxymethyl) thiazole, 2- ( ( (4- (2-Fluorophenyl) piperazin-1-yl) acetyl) amino)-4- (carboxymethyl) thiazole, 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole, 4-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-1- ((N'-(2-thiazolyl)) sulfonamido) benzene, 2- ( ( (4- (5- (Trifluoromethyl) pyrid-2-yl) piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole,

2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-4-(carboxymethyl) thiazole, sodium salt, 2- (((4-(3-(Trifluoromethyl)(((4-(3-(Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-4-(carboxymethyl) thiazole, potassium salt, 4-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-1-((N'-(2-thiazolyl))sulfonamido) benzene, hydrochloride salt, _ 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin=1- yl) acetyl) amino)-4-(carbomethoxymethyl) thiazole, 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-4-(carboxymethyl) thiazole, hydrochloride salut 2-(((4-(4-(Trifluoromelthyl)phenyl)piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole, 2- ( ( (4- (4- (carbomethoxy) phenyl) piperazin-1- yl) acetyl) amino)-4-(carboxyethoxymethyl) thiazole, 2- ( ( (4- (3-Chlorophenyl) piperazin-1-yl) acetyl) amino)-4- (carboethoxymethyl) thiazole, 2-(((4-(3-Bromophenyl)piperazin-1-yl)acetyl)amino)-4- (carboethoxymethyl) thiazole, 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-4-thiazole glyoxylate, 2- ( ( (4- (3- (Methyl) phenyl) piperazin-1-yl) acetyl) amino)-4- carboethoxy) methyl) thiazole, 2-(((4-(3-(trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-4-(carbopropoxymethyl) thiazole, 2-(((4-(3-(trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-4-(carbobutoxy) methyl) thiazole, 2-(((4-(3-(trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-4- (carboisopropoxymethyl) thiazole, 2-(((4-(4-Chloro-3-(trfluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole, 2- ( (4- ( (4-Chlorobenzhydryl) phenyl) piperazin-1- yl) acetyl) amino-4-(carboethoxymethyl) thiazole, 2- ( ( (4- (3-Ethylphenyl) piperazin-1-yl) acetyl) amino)-4- (carboethoxymethyl) thiazole,

2-(((4-(2-Naphthyl) piperazin-1-yl) acetyl) amino)-4- (carboethoxymethyl) thiazole, 2- ( ( (4- (3-Methoxyphenyl) piperazin-1-yl) acetyl) amino)-4- (carboethoxymethyl) thiazole, 2- ( ( (4- (3, 5-Bis- (trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-4- (carboethoxymethyl) thiazole, 2- ( ( (4- (3,5-Dichlorophenyl) piperazin-1-yl) acetyl) amino)- 4-(carboethoxy)thiazole, 2- ( ( (4- (3,4-Dichlorophenyl) piperazin-1-yl) acetyl) amino)- 4-(carboethoxymethyl)thiazole, 2-(((4-(3-Methoxy-5-(trifluoromethyl)Phenyl)piperazin-1- yl) acetyl) amino)-4-((carboethoxy) methyl) thiazole.

The invention also relates to a process for the preparation of the compound of general formulas (XIVa) and (XIVb). A preparation process according to the invention comprises the rection of an aromatic amine of general formula (A2): in which Rl, Re, Rg, m, and n are as defined above for formulas (XIVa) and (XIVb), with a haloacyl halide of general formula (XIX): in which R10, R11, are as def ined above for formulas (XIVa) and (XIVb), Hal represents a chlorine or bromine atom, in order to form a compound of general formula (XX);

in which R1, R8, R9, R10, R11, m and n are as defined above for formulas (XIVa) and (XIVb), Hal is defined as above, and the rection of the compound of general formula (XX) with a compound of general formula (XXI): in which R12, R13, and o are as defined above for formulas (XIVa) and (XIVb), in the presence of a basic agent, such as triethylamine or potassium carbonate in order to form the compound of general formulas (XIVa) and (XIVb):

in which R1, R8, R9, R10, R11, R12, R12, m, and o are as defined above for formulas (XIVa) and (XIVb), and Hal is defined as above; The invention further provides compound, as well as compositions comprising said compound, for use as hypoglycemic agents, of general formula (XVa): wherein: Ri is selected from the group consisting of R14COOR15,R14COOR15,C6-C14 aryl, (C1-C6)alkyl,C3-C6aryl cycloalkyl, thio (C6-Cl4) aryl, thio (C6-C14) heteroaryl, (C3- C8) cycloalkyl (Cl-C6) alkyl, (C3-C8) cycloalkyloxy (Cl-C6) alkyl, (C1-C6)alkoxy(C1-C6)alkyl,(C3-C8)cycloalkyl cycloalkyloxy, (C1-C6)alkoxy,(C6-C14)cycloalkyl heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl (C6-C14) aryl, (C6-C4)aryloxy(C1-C6)alkyl,and(C6-aryloxy, C14) aryl (Cl-C.) alkyloxy (C1-C6) alkyl group; said C1-C14 aryl and Cl-C6 alkyl being optionally substituted with one or more substituents selected from the

group consisting of halogen, amino, hydroxy, Cl-C6 alkoxy, Ci- C6 alkyl, trihalo (C1-C6) alkyl, and trihalo (C1-C6) alkoxy; R8, R11,R12,R13,R14,R15,R20,m,o,andR21R10, are as defined above for general formula (XVa); R22 is selected from the group consisting of hydrogen, halogen C1-C8 alkoxy, C1-C8 alkyl, trifluoromethyl, nitro, cyano, carboxy, hydroxy,C3-C8thioalkyl, <BR> <BR> <BR> cycloalkyl, (C3-C8) cycloalkyl (C3-Ce) cycloalkyloxy (Cl-C6)<BR> <BR> <BR> <BR> <BR> alkyl, C3-C6 cycloalkyl (Cl-C6) alkoxy (C1-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl, (C6-C14) aryl (C6-C14)aryl,(C6-C14)aryloxy,(C6-C14)alkyl aryloxy (C6-C14)aryl(C1-C6)alkyloxy,alkyl, trifluoromethoxy, amino, (Cl-C6) alkoxycarbonyl, carbamoyl, (C1-C6)alkylsulphinyl,(C1-C6)(C1-C6)alkylthio, alkylsulphonyl, sulphoamino, alkylsulphonylamino, sulphamoyl and (Cl-C6) alkylcarbonylamino; said C1-C8 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said C1-C8 alkoxy being optionally substituted with halogen or C1-C3

alkyl; said C1-C8 thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (CI-C.) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R23 is selected from the group consisting of hydrogen, fluorine, bromine, cl-c. alkoxy, C2-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cl-C,, alkoxy, carboxy, phenyl, hydroxy,C3-C8cycloalkyl,(C3-C8)thioalkyl, cycloalkyl (C3-Ce) cycloalkyloxy (Cl-C6) alkyl, (C3-C6) cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (Cl-C6) alkoxy, (C2-C6) alkoxy (C3-C6) alkyl, (C6-C14)heteroaryl,(C6-C14)heteroaryl(C1-C6)(C6-C14)aryl, alkyl, (C6-C14) aryl (C1-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl <BR> <BR> (C6-C14) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (C1-C6) alkyl, (C1-C6)alkyloxy,(C6-C14)aryl(C1-C6)arkyl,(C6-C14)aryl trifluoromethoxy, amino, (Cl-C6) alkoxycarbonyl, carbamoyl, (Cl-C6) alkylthio, (Cl-C6) alkylsulphinyl, (C1-C6)

alkylsulphonyl, sulphoamino, (C1-C6) alkylsulphonylamino, (C1-C6)alkylcarbonylamino;sulphamoyland said C2-C8 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said C1-C8 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said C1-C8 thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R24 is selected from the group consisting of hydrogen, halogenr Cl-C8 alkoxy, Cl-cob alkyl, trifluoromethyl, nitro, cyano, carbo Cl-C6 carboxy, phenyl, C1-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C cycloalkyloxy (C3-C6)cycloalkyl(C1-C6)alkoxyalkyl, (Cl-C6) alkyl (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (C1-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C1-C6)alkyl,(C6-C14)aryl(C1-heteroaryl C6) alkyl, (C6-C14) aryl (C1-C6) alkyl (C6-C14) aryl, (C6-C14) aryloxy, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)aryloxy alkyloxy (C1-C6)alkyl,trifluoromethoxy,amino,aryl (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C8)alkylthio,

alkylsulphinyl, sulphoamino,(C1-C8)alkylsulphonyl, alkylsulphonylamino, sulphamoyl and (C1-Ce) C1-C8alkylbeingoptionallyalkylcarbonylamino;said substituted with halogen or Cl-C3 alkyl; said C1-C8 alkoxy being optionally substituted with halogen or C1-C3 alkyl; said Cl-C8 thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R25 is selected from the group consisting of hydrogen, fluorine, bromine, Cl-C. alkoxy, trifluoromethyl, C2-C8 alkyl, nitro, cyano, carbo C1-C6 alkoxy, carboxy, phenyl, Cl-Ce thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C6) cycloalkyl (C3-C6)alkyl,(C3-C6)cycloalkyl(C1-C6)(C3-C6)cycloalkyloxy alkoxy (Cl-C,) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (C1-C6) alkoxy, (C3-C6)alkyl,(C6-C14)aryl,(C6-alkoxy Cul,) heteroaryl, (C6-Cl4) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl alkyl,alkyl,(C6-C14) aryl (C6-C14)aryl,alkyl

aryloxy, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)aryloxy alkyloxy, (C1-C6)alkyl,trifluoromethoxy,cyano,aryl amino, (Cl-C6) alkoxycarbonyl, carbamoyl, (C1-C8) alkylthio, (C1-C8) alkylsulphinyl, (Cl-C8) alkylsulphonyl, sulphoamino, (C1-C8) alkylsulphonylamino, sulphamoyl and (Cl-C8) alkylcarbonylamino; said C2-C8 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said C1-C8 alkoxy being optionally substituted with halogen or C1-C3 alkyl; said Cl-C8 thioalkyl being optionally substituted with halogen or Cl-C. alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; _ R26 is selected from the group consisting of hydrogen, halogen, Cl-C. alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo C1-C6 alkoxy, carboxy, phenyl, C1-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C6) cycloalkyl (C3-C6) cycloalkyloxy (C3-C6)cycloalkyl(C1-C6)alkoxyalkyl, (C1-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (Cl-C6) alkoxy, (C3-C6)alkyl,(C6-C14)aryl,(C6-C14)alkoxy heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (C3- (C6-C14)aryl(C1-C6)alkyl(C6-C14)aryl,(C6-C14)C6)alkyl, aryloxy, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)aryloxy alkyloxy, (C6-C14) aryl (Cl-C6) alkyl, trifluoromethoxy, cyano, amino, (Cl-C6) alkoxycarbonyl, carbamoyl, (Cl-C.) alkylthio, (C1-C8) alkylsulphinyl, (Cl-C,,) alkylsulphonyl, sulphoamino, (C1-C8) alkylsulphonylamino, sulphamoyl and (Cl-Ce) alkylcarbonylamino; said Cl-C, alkyl being optionally substituted with halogen for Cl-C3 alkyl; said C1-C6 alkoxy being optionally substituted with halogen or Cl-C3 alkyl, said Cl-C. thioalkyl being optionally substituted with halogen or Cl-Ce alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; or two of R22-R26 can form a methylenedioxy group; R27-R31 are each independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, halogen, C : L-C8 alkoxy, Cl-cob alkyl, trifluoromethyl, nitro, cyano, carbo C1-C6 alkoxy, carboxy, phenyl, hydroxy,C3-C8thioalkyl,

cycloalkyl, (C3-C6)cycloalkyloxy(C1-C6)cycloalkyl alkyl, (C1-C6)alkoxy(C1-C6)alkyl,(C3-C6)cycloalkyl <BR> <BR> <BR> cycloalkyloxy, (C3-C6) cycloalkyl (Cl-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-C14)heteroaryl,(C6-C14)aryl, heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (C3-C6) alkyl, (C6-C14) alkyl(C6-C14)aryl,(C6-C14)aryloxy,(C6-C14)aryl(C1-C6) aryloxy (Cl-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyloxy, (C6-C14) aryl (Cl-C6) alkyl, trifluoromethoxy, cyano, amino (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C8) alkylthio, (Cl-C.) alkylsulphinyl, (C1-C8) alkylsulphonyl, sulphoamino, (Cl-C.) alkylsulphonylamino, sulphamoyl and (Cl-C,,) alkylcarbonylamino ; said Cl-C8 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said C1-C8 alkoxy being optionally substituted with halogen or Cl-'C3 alkyl; said Cl-C. thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; or R22 and R23 when taken together form an aryl ring; or R23 and R24 when taken together form an aryl ring; one of X1 and X2 is nitrogen, with the other being carbon; X3 is nitrogen or CR29; <BR> <BR> <BR> Xi ils nitrogen or CR30 ;<BR> <BR> <BR> <BR> <BR> X5 iS nitrogen or CR31 ; wherein at least one of X3, X4, or X5 is ;nitrogen or R28 and CR30 when taken together form an aryl ring; or R28 and CR29 when taken together form an aryl ring; or two of R27-R31 can form a methylenedioxy group; or a pharmaceutically acceptable salt or solvate thereof; or a compound having a tautomeric structure thereof; and with the proviso that the compound of formula (XVa) is not: 2-(((4-(3-trifluoromethyl)phenyl)piperazinyl-1)- acetyl) amino-5- ( (ethoxycarbonyl)-methyl)-1,3,4-thiadiazole;

2- ( ( (4- (2-pyridyl) piperazinyl-1)-acetyl)amino)-5- ((carbomethoxy) methyl)-1,3,4-thiadiazole; or 2-(((4-(3-(trifluoromethyl)phenyl)piperazinyl-1)- acetyl) amino-S- (2- (carboxyethyl)-1,3,4-thiadiazole.

In another embodiment of general formula (XVa), the invention further provides compound, as well as compositions comprising said compound, useful as hypoglycemic agents wherein: R1 is selected from the group consisting of aryl,(C6-C14)arylC1-C6alkyl,C3-C6R14COOR15,C6-C14 (C6-C14)aryl(e.g.,thiophenyl,cycloalkyl,thio thionaphthyl), thio (C6-C14) heteroaryl (e. g., thiopyridyl, thioquinolinyl, and thiopyrazinyl); said C6-C14 aryl and (C6- C14) aryl Cl-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amine, hydroxy, Cl-C6 alkoxy, Cl-C6 alkyl, trihalo Ci- C6 alkyl, trihalo Cl-C6 alkoxy, and phenyl; said thio (C6-C14) aryl being optionally substituted with halogen, amine Cl-C. alkoxy, hydroxy, Cl-C6 alkyl, trihalo (Cl-C6) alkoxy, or trihalo (Cl-C6) alkyl; said thio (C6-C14) heteroaryl_ being optionally substituted with halogen, amine, Cl-C6 alkoxy, hydroxy, Cl-C6 alkyl trihalo (C1-C6) alkoxy, or trihalo (C1-C6) alkyl; R8 is selected from the group consisting of NR20SO2Ar and NR2oArSO2, wherein Ar is an aryl selected from the group consisting of phenyl and phenyl (Cl-C6) alkyl; R. is a group selected from the group consisting of hydrogen, (C1-C6)alkoxy(C1-C6)alkyl,cycloalkylalkyl, group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cl-C6) alkyl group, (C3-C8) cycloalkyloxy (C1-C6) alkyl, (C3- Ca) cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, C6-C14 aryl, C6-C14 heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-Cl4) aryl (C1- C6) alkyl, (C1-C6)alkyl(C1-C6)aryl,(C6-C14)arylaryl (Cl-C6) alkoxy (Cl-C6) alkyl, and (C6-C14) aryloxy (Cl-C6) alkyl group; Rlo is selected from the group consisting of hydrogen, C1-C8 alkyl, (C1-C6) alkoxy (C1-C6) alkyl, cycloalkyl

group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cl-C6) alkyl group, (C3-C8) cycloalkyloxy (Cl-C6) alkyl, (C3- C8) cycloalkyl (C1-C6)alkyl,C6-C14aryl,C6-C14alkoxy heteroaryl(C1-C6)alkyl,(C6-C14)aryl(C1-heteroaryl,(C6-C14) C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl (C1-C6) aryl, (C6-C14) aryl (Cl-C6) alkoxy (C1-C6) alkyl, and (C6-C14) aryloxy (Cl-C6) alkyl group; _ R, l is selected from the group consisting of hydrogen, C1-C8 alkyl, (Cl-C6) alkoxy (C1-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cl-C6) alkyl group, (C3-C8) cycloalkyloxy (Cl-C6) alkyl, (C3- (C1-C6)C8)cycloalkyl alkoxy C6-C14aryl,C6-C14alkyl, heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (C1- (C6-C14)aryl(C1-C6)alkyl(C1-C6)aryl,(C6-C14)arylC6)alkyl, (Cl-C6) alkoxy (C1-C6) alkyl, and (C6-Cl4) aryloxy (C1-C6) alkyl group; R12 is selected from the group consisting of hydrogen and Cl-C6 alkyl; R13 is selected from the group consisting of R14 is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and C1-C2 alkyl group; said Cl-C2 alkyl being substituted with one or more halogen, Cl-C6 alkyl or phenyl groups; R15 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and C1 C6 alkyl group; said C1-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and Cl-C3 alkyl;

R20 is selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy and Cl-C6 alkoxy; m is 0 or 1; n is 1; o is 0 or 1; R21 is a bond or C1-C6 alkyl; said C1-C6 alkyl being optionally substituted from, the group consisting of benzene and an optionally substituted benzene ring; said benzene ring optionally substitue from the group consisting of Cl-C6 alkyl, halogen, C1-C6 alkoxy and hydroxy; R22 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C,, thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or C1-C3 alkyl; R23 is selected from the group consisting of

hydrogen, fluorine, bromine, Cl-C. alkoxy, C2-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, Cl-Ce thioalkyl, and hydroxy; said C2-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C. alkoxy being optionally substituted with halogen or C1-C3 alkyl; said C1-C8 thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R24 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with halogen or Cl-C3alkyl; said Cl-C,, thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl;

R25 is selected from the group consisting of hydrogen, fluorine, bromine, C1-C6 alkoxy, C2-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, Cl-C8 thioalkyl, and hydroxy; said C2-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C. alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C. thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or cl-C, alkyl; R26 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, Cl-C,. alkyl, trifluoromethyl, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with halogen or Cl-C3alkyl; said Cl-C,, thioalkyl being optionally substituted with halogen or Cl-cob alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; or two of R22-R26 when taken together can form a methylenedioxygroup;

R27 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, Cl-C,, thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said C1-C6 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C. thioalkyl being optionally substituted with halogen or Cl-Ce alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R28 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said C1-C6 alkoxy being optionally substituted with halogen or C,,-C3alkyl; said C1-C8 thioalkyl being optionally substituted with halogen or

Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; or R22 and R23 when taken together form an aryl ring; or R23 and R24 when taken together form an aryl ring; one of X1 and X2 is nitrogen, with the other being carbon; <BR> <BR> <BR> X3 iS nitrogen or Cor2.;<BR> <BR> <BR> Xi ils nitrogen or CR30 ;<BR> <BR> <BR> Xi ils nitrogen or CR31;<BR> <BR> <BR> wherein at least one of X3, X4, or X5 iS ;nitrogen R29 is selected from the group consisting of hydrogen, alkoxy,C1-C6alkyl,trifluoromethyl,C1-C6 nitre ; cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, Cl-C. thioalkyl, and hydroxy; said C1-C6 alkyl being optionally substituted with one to two halogen atoms or C1-C3 alkyl ; said C1-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl; said Cl-C. thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C. alkyl; R30 is selected from the group consisting of

hydrogen, halogen, Cl-C6 alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, cl-c. thioalkyl, and hydroxy; said C1-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said C1-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C,, thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R31 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said C1-C6 alkyl being optionally substituted with one to two halogen atoms or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C. thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl;

or R28 and CR30 when taken together form an aryl ring; or R., and CR29 when taken together form an aryl ring; or a pharmaceutically acceptable salt or a solvate thereof; or a compound having a tautomeric structure thereof; and with the proviso that the compound of formula (XVa) is not: 2-(((4-(3-(trifluoromethyl)phenyl)piperazinyl-1)- acetyl) amino)-S- ( (ethoxycarbonyl)-methyl)-1,3,4-thiadiazole; 2-(((4-(2-pyridyl)piperazinyl-1)-acetyl)amino)-5- ((carbomethoxy) methyl)-1,3,4-thiadiazole; or 2-(((4-(3-(trifluoromethyl)phenyl)piperazinyl-1)- acetyl)amino)-5-(2-(carboxy)ethyl)-1,3,4-thiadiazole.

The present invention further provides methods for using compositions comprising a compound of formula (XVb) or a pharmaceutically acceptable salt or a compound having a tautomeric structure (XVb) thereof as hypoglycemic agents, the compound of formula (XVb) having the structure: wherein R, is selected from the group consisting of R14COOR15, C6-C14arYl. (C6-Cla)ar'yl(Cl-C6) alkyl, C3-C6 cycloalkyl, thio (C6-Clq) aryl, thio (C6-C14) heteroaryl, (C3- (C1-C6)alkyl,(C3-C8)cycloalkyloxy(C1-C6)C8)cycloalkyl alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, (C3-C8) cycloalkyloxy, (C1-C6)alkoxy,(C6-C14)cycloalkyl heteroaryl (C6-C14)aryl(C1-C6)alkyl(C6-C14)alkyl,

aryl, (C6-Cl4) aryloxy, (C6-C14) aryloxy (Cl-C6) alkyl, and (C6- C14) aryl (Cl-C6) alkyloxy (C1-C6) alkyl group; said C6-C14 aryl and Cl-C6 alkyl being optionally substituted-with one or more substituents selected from the group consisting of halogen, amino, hydroxy, C1-C6 alkoxy, C1- C6 alkyl, trihalo (Cl-C6) alkyl, and trihalo (C1-C6) alkoxy ; R8 is selected from the group consisting of NR20SO2Ar and NR2oArS02, wherein Ar is an aryl selected from the group consisting of phenyl and phenyl (Cl-C6) alkyl; R, is a groupselected from the group consisting of hydrogen, Cl-cob alkyl, (Cl-C6) alkoxy (Cl-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cl-C6) alkyl group, (C3-C8) cycloalkyloxy (C1-C6) alkyl, (C3- (C1-C6)alkoxy(C1-C6)alkyl,C6-C14aryl,C6-C14C8)cycloalkyl heteroaryl(C1-C6)alkyl,(C6-C14)aryl(C1-heteroaryl,(C6-C14) C6 alkyl, (C1-C6)alkyl(C1-C6)aryl,(C6-C14)arylaryl (Cl-C6) alkoxy (C1-C6) alkyl, and (C6-C14) aryloxy (Cl-C6) alkyl group; RIO is selected from the group consisting of hydrogen, (C1-C6)alkoxy(C1-C6)alkyl,cycloalkylalkyl,

group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C1-C6) alkyl group, (C3-C8) cycloalkyloxy (Cl-C6) alkyl, (C3- (C8) cycloalkyl (C1-C6)alkyl,C6-C14aryl,C6-C14alkoxy heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (C1- (C6-C14)aryl(C1-C6)alkyl(C1-C6)aryl,(C6-C14)arylC6)alkyl, (C1-C6)alkyl,and(C6-C14)aryloxy(C1-C6)alkyl(C1-C6)alkoxy group; R, l is selected from the group consisting of hydrogen, (C1-C6)alkoxy(C1-C6)alkyl,cycloalkylalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl group,(C3-C8)cycloalkyloxy(C1-C6)alkyl,(C3-(C1-C6)alkyl (C1-C6)alkoxy(C1-C6)alkyl,C6-C14aryl,C6-C14C8)cycloalkyl heteroaryl, (C1-C6)alkyl,(C6-C14)aryl(C1-heteroaryl <BR> <BR> <BR> C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl (Cl-C6) aryl, (C6-C14) aryl (Cl-C6) alkoxy (Cl-C6) alkyl, and (C6-C, 4) aryloxy (Cl-C6) alkyl group; R12 is selected from the group consisting of hydrogen and Cl-C6 alkyl; R13 is selected from the group consisting of

R24 is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and C1-C2 alkyl group; said C1-C2 alkyl being substituted with one or more halogen, Cl-C6 alkyl or phenyl groups; R15 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and C1 C6 alkyl group; said Cl-C. alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and Cl-C3 alkyl; R20 is selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy and Cl-C6 alkoxy; m is 0 or 1; n is 1; o is 0 or 1; R21 is a bond or Cl-C6 alkyl; said Cl-C6 alkyl being optionally substituted from the group consisting of benzene and an optionally substituted benzene ring; said benzene ring optionally substitue from the group consisting of Cl-C6 alkyl, halogen, Cl-C,, alkoxy and hydroxy; R22 is selected from the group consisting of hydrogen, halogen C1-C8alkyl,trifluoromethyl,alkoxy, nitro, cyano, carboxy, Cl-cob thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-Ce) cycloalkyloxy (Cl-C6) alkyl, C3-C6 cycloalkyl (Cl-C6) alkoxy (C1-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C3-C6) alkoxy

(C3-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl (C6-C14) heteroaryl (C1-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl, (C6-C14) aryl (C6-C14)aryl,(C6-C14)aryloxy,(C6-C14alkyl aryloxy (C1-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyloxy, trifluoromethoxy, amino, (Cl-C6) alkoxycarbonyl, carbamoyl, (C1-C6)alkylsulphinyl,(C1-C6)(C1-C6)alkylthio, alkylsulphonyl, sulphoamino, alkylsulphonylamino, sulphamoyl and (Cl-C6) alkylcarbonylamino; said C1-C8 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said C1-C8 alkoxy being optionally substituted with halogen or cl-c3 alkyl; said Cl-C. thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or C1-C3 alkyl; R23 is selected from the group consisting of hydrogen, fluorine, bromine, C2-C8alkyl,alkoxy, trifluoromethyl, nitro, cyano, carbo C1-C6 alkoxy, carboxy, phenyl, hydroxy,C3-C8cycloalkyl,(C3-C8)thioalkyl, cycloalkyl (C3-Ce) cycloalkyloxy (C1-C6) alkyl, (C3-C6) cycloalkyl (C1-C6)alkyl,(C3-C6)cycloalkyloxy,alkoxy (C3-C6) cycloalkyl (C1-C6) alkoxy, (Cl-C6) alkoxy (C3-C6) alkyl,

(C6-C14)heteroaryl,(C6-C14)heteroaryl(C1-C6)(C6-C14)aryl, alkyl, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)alkylaryl (C6-C14) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (Cl-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyloxy, (C6-Cl4) aryl (Cl-C6) alkyl, trifluoromethoxy, amino, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C6)alkylsulphinyl,(C1-C6)(C1-C6)alkylthio, alkylsulphonyl, sulphoamino, alkylsulphonylamino, sulphamoyl and (C1-C6) alkylcarbonylamino; said C2-C8 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C8 alkoxy being optionally substituted with halogen or C1-C3 alkyl; said Cl-CB thioalkyl being optionally substituted with halogen or Cl-C, alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or C1-C3 alkyl; R24 is selected from the group consisting of hydrogen, halogen, C1-C8 alkoxy, C1-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cl-C6 alkoxy, carboxy, phenyl, C1-C8

thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-C6) cycloalkyloxy (C3-C6)cycloalkyl(C1-C6)alkoxyalkyl, (Cl-C6) alkyl (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (Cl-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-Cl4) aryl, (C6-C14) heteroaryl(C1-C6)alkyl,(C6-C14)aryl(C1-heteroaryl,(C6-C14) C6) aryl(C1-C6)alkyl(C6-C14)aryl,(C6-C14)(C6-C14) aryloxy,aryloxy,(C6-C14) aryloxy (C6-C14)aryl(C1-C6)alkyl, alkyloxy (C6-C14) aryl (Cl-C6) alkyl, trifluoromethoxy, amino, (C1-C6) alkoxycarbonyl, carbamoyl, (Cl-C8) alkylthio, (Cl-C.) alkylsulphinyl, (C1-C8) alkylsulphonyl, sulphoamino, (Cl-Ce) alkylsulphonylamino, sulphamoyl and (Cl-Ce) alkylcarbonylamino ; said Cl-cob alkyl being optionally substituted with halogen or Cl-C3 alkyl; said C,-C8 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said C,-C8 thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (CI-C.) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R25 is selected from the group consisting of hydrogen, fluorine, bromine, C1-C8 alkoxy, trifluoromethyl, C2-C8 alkyl, nitro, cyano, carbo Cl-C6 alkoxy, carboxy, phenyl,

hydroxy,C3-C8cycloalkyl,(C3-C6)cycloalkylC1-C8thioalkyl, (C3-C6) cycloalkyloxy (C3-C6) alkyl, (C3-C6) cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (C1-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-C14) aryl, (C6- Cul4) heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (C3-C6) alkyl, (C6-C14) alkyl(C6-C14)aryl,(C6-C14)(C1-C6) aryloxy(C1-C6)alkyl,(C6-C14)aryl(C1-C6)aryloxy,(C6-C14) alkyloxy, (C6-C14) aryl (Cl-C6) alkyl, trifluoromethoxy, cyano, amino, carbamoyl,(C1-C8)alkylthio,alkoxycarbonyl, (C1-C8)alkylsulphonyl,sulphoamino,(C1-C8)alkylsulphinyl, (C1-C8) alkylsulphonylamino, sulphamoyl and (CI-Ce) alkylcarbonylamino; said C2-C8 alkyl being optionally substituted with halogen or C1-C3 alkyl; said Cl-cob alkoxy being optionally substituted with halogen or C1-C3 alkyl; said Cl-C,, thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said

carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R26 is selected from the group consisting of hydrogen, halogen, ci-c. alkoxy, cl-C. alkyl, trifluoromethyl, nitro, cyano, carbo Cl-C6 alkoxy, carboxy, phenyl, C1-C8 thioalkyl, hydroxy, (C3-C6)cycloalkyl(C3-C6)cycloalkyl, cycloalkyloxy (Cl-C6) alkyl, (C3-C6) cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (Ci-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C1-C6)alkyl,(C6-C14)aryl(C3-heteroaryl (C6-C14)aryl(C1-C6)alkyl(C6-C14)aryl,(C6-C14)C6)alkyl, aryloxy, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)aryloxy alkyloxy, (C1-C6)alkyl,trifluoromethoxy,cyano,aryl amino, (Cl-C6) alkoxycarbonyl, carbamoyl, (C1-C8) alkylthio, (C1-C8) alkylsulphinyl, (Cl-C8) alkylsulphonyl, sulphoamino, (C1-C8) alkylsulphonylamino, sulphamoyl and (Cl-C8) alkylcarbonylamino ; said Cl-C6 alkyl being optionally substituted with halogen for C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with halogen or Cl-C3 alkyl, said Cl-C. thioalkyl being optionally substituted with halogen or

C1-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or C1-C3 alkyl; or two of R22-R26 can form a methylenedioxy group; R27-R31 are each independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, halogen, Cl-Ce alkoxy, Cl-C. alkyl, trifluoromethyl, nitro, cyano, carbo Cl-C, alkoxy, carboxy, phenyl, C1-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C6)cycloalkyloxy(C1-C6)cycloalkyl alkyl, (C3-C6) cycloalkyl (C1-C6)alkyl,(C3-C6)alkoxy cycloalkyloxy, (C1-C6)alkoxy,(C3-C6)alkoxycycloalkyl (C3-C6)aryl,(C6-C14)heteroaryl,(C6-C14)(C6-C14) heteroaryl (Cl-C6) alkyl, (C6-Cl4) aryl (C3-C6) alkyl, (C6-C14) aryl (C6-C14)aryl,(C6-C14)aryloxy,(C6-C14)alkyl aryloxyaryloxy(C1-C6) alkyl, (C1-C6)alkyloxy,(C6-C14)aryl aryl trifluoromethoxy,cyano,amino(C1-C6)alkyl, alkoxycarbonyl, carbamoyl, (Cl-C.) alkylthio, (C1-C8) alkylsulphinyl, (Cl-C.) alkylsulphonyl, sulphoamino, (C1-C8)

alkylsulphonylamino, sulphamoyl and (C1-C8) alkylcarbonylamino ; said C3.-C8 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C8 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said CI-C8 thioalkyl being optionally substituted with halogen or CL-CL ;alkyl said carbo (Cl-C6) alkoxy being optionally substituted with halogen or C1-C3 alkyl; or R22 and R23 when taken together form an aryl ring; or R23 and R24 when taken together form an aryl ring; one of X1 and X2 is nitrogen, with the other being carbon; X3 is nitrogen or CR29; X4 iS nitrogen or CR30 ; X. is nitrogen or CR31; wherein at least one of X3, X4, or X5 is ;nitrogen or R28 and CR30 when taken together form an aryl ring; or R28 and CR29 when taken together form an aryl. ring; or two of R27-R31 can form a methylenedioxy group; or

a pharmaceutically acceptable salt or solvate thereof; or a compound having a tautomeric structure thereof; and with the proviso that the compound of formula (XVa) is not: 2-(((4-(3-trifluoromethyl)phenyl)piperazin-1 yl) acetyl) amino-5- ( (ethoxycarbonyl)-methyl)-1,3,4- thiadiazole; 2-(((4-(2-pyridyl)piperazinyl-1)-acetyl)amino)-5- ((carbomethoxy) methyl)-1,3,4-thiadiazole; or 2-(((4-(3-(trifluoromethyl)phenyl)piperazinyl-1)- acetyl)amino-5- (2- (carboxyethyl)-1,3,4-thiadiazole.

The present invention further provides. methods for using sing compositions comprising a compound of formula (XVb) or a pharmaceutically acceptable salt or tautomeric structure thereof for use for use as hypoglycemic agents, as well as methods for their use, the compound of formula (XVb) having the structure:

wherein: R1 is selected from the group consisting of hydrogen, halogen, R14COOR25, R16O17, R18NHR19, (C6-C14) aryl, (C6- C14) aryl Cl-C6 alkyl, C3-C6 cycloalkyl, thio (C6-C14 aryl, thio (C6-C14) heteroaryl (C3-C8)cycloalkyl(C1-C6)alkyl, alkyl, (C3-C8)cycloalkyloxy(C1-C6)alkyl,(C3-alkoxy, C8) cycloalkyl (C1-C6)alkyl,(C3-C8)alkoxy cycloalkyloxy, (C1-C6)alkoxy,(C1-C6)alkoxycycloalkyl (C6-C14)heteroaryl,(C6-C14)heteroaryl(C1-C6)(C1-C6)alkyl, alkyl, (C6-C14) aryl (C1-C6) alkyl (C6-Cl4) aryl, (C6-C14) aryloxy, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)alkyloxy,(C6-C14)aryloxy (C1-C6)alkyloxy(C1-C6)alkyl,trihalo(C1-C6)(C6-C14)aryl alkyl, trihalo (Cl-C6) alkoxy, cyano, nitro, carbamoyl, (Cl-C.) alkylthio, (Cl-C8) alkylsulphinyl, (Cl-C.) alkylsulphonyl, sulphoamino, (C1-C8) alkylsulphonylamino, sulphamoyl and (Cl- CB) alkylcarbonylamino; said Cl-C. alkyl group being optionally substituted with one or more halogen, C1-C6 alkyl or phenyl groups; said thiophenyl being optionally substituted with halogen, amino Cl-C. alkoxy, hydroxy, Cl-C6 alkyl, trihalo (Cl-C6) alkoxy or trihalo (C1-C6) alkyl; said thio (C6-C14) heteroaryl being optionally substituted with halogen, amino, alkoxy, hydroxy, Cl-C6 alkyl, trihalo (C1-C6) alkyl or trihalo (Cl-C6) alkoxy; said C6-C14 aryl and (C6-C14) aryl (Cl-C6) alkyl being optionally substituted with one or more substitutes selected from the group consisting of

nalogen, amino, hydroxy, Cl-C6 alkoxy, C1-C6 alkyl, trihalo Ci- C6 alkyl and trihalo C1-C6 alkoxy; R8 is selected from the group consisting of NR20SO2Ar and NR20ArSO2, wherein Ar is an aryl selected from the group consisting of phenyl and phenyl Cl-C6 alkyl ; R. is a group selected from the group consisting of hydrogen, C1-C8 alkyl, (Cl-C6) alkoxy (C1-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C1-C6) alkyl group, (C3-C8) cycloalkyloxy (C1-C6) alkyl, (C3- (C1-C6)alkoxy(C1-C6)C8)cycloalkyl alkyl, C6-C14aryl, heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (Cl- C6) alkyl, (C6-C14) aryl (C1-C6) alkyl (C1-C6) aryl, (C6-C14) aryl (C1-C6) alkoxy and(C6-C14)aryloxy(C1-C6)alkylalkyl, group; R10 is selected from the group consisting of hydrogen, C1-C8 alkyl, (Cl-C6) alkoxy (C1-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cl-C6) alkyl group, (C3-C8) cycloalkyloxy (C1-C6) alkyl, (C3- C8) cycloalkyl (C1-C6)alkoxy alkyl, C6-C14aryl, heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (C1- C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl (Cl-C6) aryl, (C6-C14) aryl (C1-C6) alkoxy (Cl-C6) alkyl, and (C6-Clq) aryloxy (C1-C6) alkyl group; R, 3. is selected from the group consisting of hydrogen, (C1-C6)alkoxy(C1-C6)alkyl,cycloalkylalkyl, group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cl-C6) alkyl group, (C3-C8) cycloalkyloxy (C1-C6) alkyl, (C3- (C1-C6)alkoxy(C1-C6)alkyl,C6-C14aryl,C6-C14C8)cycloalkyl heteroaryl, (C1-C6)alkyl,(C6-C14)aryl(C1-heteroaryl C6) alkyl, (C1-C6)alkyl(C1-C6)aryl,(C6-C14)arylaryl (Cl-C6) alkoxy (C1-C6) alkyl, and (C6-C14) aryloxy (Cl-C6) alkyl group; R12 is selected from the group consisting of hydrogen and C1-C6 alkyl; R13 is selected from the group consisting of

R14 is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cl-C2 alkyl group; said C1-C2 alkyl group being substituted with one or more hydrogen, halogen, C1-C6 alkyl or phenyl groups; R15 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and C1 C6 alkyl group; said C1-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and Cl-C3 alkyl; R16 is a bond or is selected from the group consisting of sulfonyl, Cl-C8 thioalkyl, aminosulfonyl and Cl- C6 alkyl; said Cl-C6 alkyl group being substituted with one or more hydrogen, halogen, Cl-C, alkyl or phenyl groups; R17 is selected from the group consisting of phenyl, phenyl Cl-C6 alkyl, trifluoromethyl and C1-C6 alkyl; said Cl-C6 alkyl being optionally substituted with one or more groups selected from the group consisting of halogen, phenyl, phenyl Cl-C6 alkyl, and C1-C3 alkyl; said phenyl and phenyl Cl-C6 alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, amino, and Cl-C6 alkyl; R18 is a bond or is selected from the group consisting of sulfonyl, thio Cl-C6 alkyl, aminosulfonyl, carbonyl, aminocarbonyl and C1-C6 alkyl; said Cl-C6 alkyl being substituted with one or more hydrogen, halogen, Cl-C6 alkyl or phenyl groups; R19 is selected from the group consisting of hydrogen, phenyl, phenyl Cl-C6 alkyl, and Cl-C6 alkyl; said Cl- C6 alkyl being optionally substituted with one or more

substituents selected from the group consisting of phenyl and Cl-C3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkoxy, hydroxy, amino, and Cl-C6 alkyl; said phenyl C1-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkoxy, hydroxy, amino, and Cl-C6 alkyl; R20 is a group selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy and Cl-C6 alkoxy; m is 0 or 1; n is 1; o is 0 or 1; R21 is a bond or Cl-C6 alkyl; said Cl-C6 alkyl being optionally substituted from the group consisting of benzene and an optionally substituted benzene ring; said benzene ring optionally substitue from the group consisting of Cl-C6 alkyl, halogen, Cl-C6 alkoxy and hydroxy; R22 is selected from the group consisting of hydrogen, halogen, C1-C8alkyl,trifluoromethyl,alkoxy, nitro, cyano, carboxy, Cl-C8 thioalkyl, hydroxy, C3-C8

cycloalkyl, (C3-C6)cyclalkyloxy(C1-C6)cycloalkyl alkyl, (C1-C6)alkoxy(C1-C6)alkyl,(C3-C6)cycloakyl cycloalkyloxy, (C3-C6) cycloalkyl C1-C6 alkoxy, (C3-C6) alkoxy (C6-C14)aryl,(C6-C14)heteroaryl,(C6-C14)C3-C6alkyl, heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (C1-C6) alkyl, (C6-C14) aryl (C6-C14)aryl,(C6-C14)aryloxy,(C6-C14)arylalkyl (Cl-C6) alkyl, trifluoromethoxy, amino, (C1-C6) alkoxycarbonyl, carbamoyl, (Cl-C.) alkylthio, (C1-C8) alkylsulphinyl, (Cl-C,,) alkylsulphonyl, sulphoamino, alkylsulphonylamino, sulphamoyl and (Cl-CB) alkylcarbonylamino; said Cl-C8 alkyl being optionally substituted with halogen or C1-C3 alkyl; said Cl-C. alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said C1-C8 thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R23 is selected from the group consisting of hydrogen, fluorine, bromine, C1-C8 alkoxy, C,-C8 alkyl,

trifluoromethyl, nitro, cyano, carbo C1-C6 alkoxy, carboxy, phenyl, hydroxy,C3-C8cycloalkyl,C3-C8thioalkyl, <BR> <BR> cycloalkyl (C3-CB) cycloalkyloxy (C1-C6) alkyl, (C3-C6)<BR> <BR> <BR> cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (C1-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-C14) aryl, (C6-C14)heteroaryl(C1-C6)heteroaryl, alkyl, (C1-C6)alkyl,(C6-C14)@aryl(C1-C6)alkylaryl (C6-C14) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (Cl-C6) alkyl, (C1-C6)alkyloxy,(C6-14)aryl(C1-C6)alkyl,(C6-C14)aryl trifluoromethoxy, amino, (Cl-C6) alkoxycarbonyl, carbamoyl, (C1-C8)alkylsulphinyl,(C1-C8),(C1-C8)alkylthio, alkylsulphonyl, sulphoamino, alkylsulphonylamino, sulphamoyl and (C1-Cg) alkylcarbonylamino; said, C2-C8 alkyl being optionally substituted with halogen or C1-C3 alkyl; said C1-C8 alkoxy. being optionally substituted with halogen or Cl-C3 alkyl; said C1-C8 thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R24 is selected from the group consisting of hydrogen, halogen, C1-C8alkyl,trifluoromethyl,alkoxy,

nitro, cyano, carboxy, C1-C8 thioalkyl, hydroxy, C3-C8 <BR> <BR> cycloalkyl, (C3-C8) cycloalkyl (C3-C6) cycloalkyloxy (Cl-C6)<BR> <BR> <BR> alkyl, (C3-C6) cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, (C3-C6)<BR> <BR> <BR> cycloalkyloxy, (C3-C6) cycloalkyl Cl-C6 alkoxy, (C3-C6) alkoxy C3-C6 alkyl, (C6-C14)heteroaryl,(C6-C14)aryl, heteroaryl (C6-C14)aryl(C1-C6)alkyl,(C6-C14)alkyl, aryl (C6-C14)aryl,(C6-C14)aryloxy,(C6-C14)arylalkyl (Cl-C6) alkyl, trifluoromethoxy, amino, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C8)alkylsulphinyl,(C1-C8)alkylthio, alkylsulphonyl, sulphoamino, alkylsulphonylamino, sulphamoyl and (Cl-C8) alkylcarbonylamino; said C1-C8 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C. alkoxy being optionally substituted with halogen or C1-C3 alkyl; said Cl-C8 thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl;

R25 is selected from the group consisting of hydrogen, fluorine, bromine, Cl-cob alkoxy, C,-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cl-C6 alkoxy, carboxy, phenyl, hydroxy,C3-C8cycloalkyl,C3-C8thioalkyl, <BR> <BR> cycloalkyl (C3-C8) cycloalkyloxy (Cl-C6) alkyl, (C3-C6)<BR> <BR> <BR> cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (C3-C6)alkoxy(C3-C6)alkyl,alkoxy, (C6-C14) aryl, (C6-C14)heteroaryl(C1-C6)heteroaryl, alkyl, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)alkylaryl (C6-C14)aryloxy,(C6-C14)aryloxy(C1-C6)alkyl,(C6-C14)aryl, (C1-C6)alkyloxy,(C6-C14)aryl(C1-C6)alkyl,(C6-C14)aryl trifluoromethoxy, amino, (C1-C6) alkoxycarbonyl, carbamoyl, (C1-C8)alkylsulphinyl,(C1-C8),(C1-C8)alkylthio, alkylsulphonyl, sulphoamino, alkylsulphonylamino, sulphamoyl and (Cl-C8) alkylcarbonylamino; said C2-C8 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C. alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C8 thioalkyl being optionally substituted with halogen or Cl-cob alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R26 is selected from the group consisting of hydrogen, halogen, Cl-C. alkoxy, C1-C8 alkyl, trifluoromethyl, nitro, cyano, carboxy, hydroxy,C3-C8thioalkyl, cycloalkyl, (C3-C6)cycloalkyloxy(C1-C6)cycloalkyl alkyl, (C1-C6)alkoxy(C1-C6)alkyl,(C3-C6)cycloalkyl cycloalkyloxy, (C3-C6) cycloalkyl Cl-C6 alkoxy, (C3-C6) alkoxy (C6-C14)aryl,(C6-C14)heteroaryl,(C6-C14)C3-C6alkyl, heteroaryl (C6-C14)aryl(C1-C6)alkyl,(C6-C14)alkyl, aryl (Cl-C6) alkyl (C6-C19) aryl, (C6-C14) aryloxy, (C6-Cl4) aryl <BR> <BR> (Cl-C6) alkyl, trifluoromethoxy, amino, (Cl-C6) alkoxycarbonyl, carbamoyl, (C1-C8)alkylsulphinyl,(C1-C8)alkylthio, alkylsulphonyl, sulphoamino, alkylsulphonylamino, sulphamoyl and (Cl-C8) alkylcarbonylamino; said C1-C8 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C8 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said C1-C8 thioalkyl being optionally substituted with

halogen or C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; or two of R22-R26 when taken together can form a methylenedioxy; R27-R31 are each independently selected. from the group consisting of hydrogen, C3-C8 cycloalkyl, hydrogen, halogen, C1-C8 alkoxy, Cl-ces alkyl, trifluoromethyl, nitro, cyano, carbo Cl-C6 alkoxy, carboxy, phenyl, Cl-cob thioalkyl, hydroxy, (C3-C8)cycloalkyl(C3-C6)cycloalkyl, cycloalkyloxy (Cl-C6) alkyl, (C1-C6) cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (Cl-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (Cl- C6) alkyl, (C1-C6)alkyl(C6-C14)aryl,(C6-C14)aryl aryloxy, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)aryloxy alkyloxy, (C1-C6)alkyl,trifluoromethoxy,cyano,aryl amino, (Cl-C6) alkoxycarbonyl, carbamoyl, (C1-C8) alkylthio, (C1-C8) alkylsulphinyl, (Cl-C.) alkylsulphonyl, sulphoamino, (C1-C8) alkylsulphonylamino, sulphamoyl and (Cl-C6) alkylcarbonylamino ; said Cl-C. alkyl being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C8 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said C1-C8 thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; or R22 and R23 when taken together form an aryl ring; or R23 and R24 when taken together form an aryl ring; one of X1 and X2 is nitrogen, with the other being carbon; X3 is nitrogen or CR29; <BR> <BR> Xi ils nitrogen or CR30;<BR> <BR> <BR> Xi ils nitrogen or CR31 ; wherein at least one of X3, X4, or X5 is nitrogen; or R28 and CR30 when taken together form an aryl ring; or R28 and CR29 when taken together form an aryl ring;

or two of R27-R31 when taken together can form a methylenedioxy; or a pharmaceutically acceptable salt or solvate thereof; or a compound having a tautomeric structure thereof;. and with the proviso that the compound of formula (XVb) is not: 2-(((4-(3-trifluoromethyl)phenyl)piperazinyl-1)- acetyl) amino-5- ( (ethoxycarbonyl)-methyl)-1,3,4-thiadiazole; 2-(((4-(2-pyridyl)piperazinyl-1)-acetyl)amino)-5- ((carbomethoxy) methyl)-1,3,4-thiadiazole; or 2-(((4-(3-2-(((4-(3-(trifluoromethyl) phenyl) piperazinyl-1)- acetyl) amino-5- (2- (carboxyethyl)-1, 3, 4-thiadiazole.

In another embodiment of the method for using a compound of formula (XVb), the invention further provides methods for using compositions comprising a compound of formula (XVb) or a pharmaceutically acceptable salt or a compound having a tautomeric structure thereof as hypoglycemic agents wherein: R1 is selected from the group consisting of

hydrogen, halogen, R18NHR19,C6-C14aryl,(C6-R16OR17, C14) aryl C3-C6cycloalkyl,trifluoromethyl,alkyl, thio (C6-Cl4) aryl, (e. g. , thiophenyl, thionaphthyl), thio (C6- C14) heteroaryl (e. g. , thio pyridyl, thioquinolinyl, thiopyrazinyl) and (C1-C8) alkyl; said and(C6aryl C14) aryl Cl-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, trihalo Cl- C6 alkyl and trihalo Cl-C6 alkoxy; said C1-C8 alkyl group being optionally substituted with one or more halogen, Cl-C6 alkyl or phenyl groups; said thio (C6-C14) aryl being optionally substituted with halogen, amino, Cl-C. alkoxy, hydroxy, C1-C6 alkyl, trihalo Cl-C6 alkoxy, or trihalo Cl-C6 alkyl; said thio C1-C6 heteroaryl being optionally substituted with halogen, Cl-C6 alkoxy, hydroxy, C1-C6 alkyl, trihalo Cl-C6 alkyl, or trihalo Cl-C6 alkoxy;

R8-R21, m, n and o are as defined above for formula (XVb); R22 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl,trifluoromethyl,alkoxy, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or Cl-C3alkyl; said Cl-C6 alkoxy being optionally substituted with halogen or Cl-C3alkyl; said Cl-C. thioalkyl being optionally substituted with halogen or Cl-C. alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R23 is selected from the group consisting of hydrogen fluorine, bromine, C2-C6alkyl,alkoxy, trifluoromethyl, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said C2-C6 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C. alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C. thioalkyl being optionally substituted with halogen or Cl-cob alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or C1-C3 alkyl; R24 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C.) alkoxy, carboxy, phenyl, Cl-C,, thioalkyl, and hydroxy ; said Cl-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said C1-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said C1-C8 thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R25 is selected from the group consisting of hydrogen, fluorine, bromine, trifluoromethyl,alkoxy, C2-C6 alkyl, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, Cl-cob thioalkyl, and hydroxy; said C2-C6 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C., alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said C1-C8 thioalkyl being optionally substituted with

halogen or C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; -R... is selected from the group consisting of hydrogen, halogen, cl-C. alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said C1-C6 alkyl being optionally substituted with halogen or C,-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl; said C1-C8 thioalkyl being optionally substituted with halogen or Cl-C. alkyl; said carbo (C, 1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; or two of R22-R26 when taken together can form a methylenedioxy group; R2, is selected from the group consisting of hydrogen, halogen, C1-C6alkyl,trifluoromethyl,alkoxy, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C. alkyl being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C. thioalkyl being optionally substituted with halogen or

Cl-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or C1-C3 alkyl; R28 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, Cl-cob thioalkyl, and hydroxy; said C1-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C. thioalkyl being optionally substituted with halogen or Cl-cob alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; or R22 and R23 when taken together form an aryl ring; or R23 and R24 when taken together form an aryl ring; one of X1 and X2 is nitrogen, with the other being carbon; X3 is nitrogen or CR29; X4 iS nitrogen or CR30 ;

Xi ils nitrogen or CR31 ;<BR> <BR> <BR> <BR> <BR> wherein at least one of X3, X4, or XS is a nitrogen; R29 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C1-C6) alkoxy, carboxy,phenyl,Cl- thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said C1-C8 thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or C1-C3 alkyl; R30 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C,) alkoxy, carboxy, phenyl, Cl-C. thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or C2-C3 alkyl ; said C1-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said C1-C8 thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl;

R31 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl,trifluoromethyl,alkoxy, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, Cl-cob thioalkyl, and hydroxy; said C1-C6 alkyl being optionally substituted with halogen or C,-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said C1-C8 thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; or R28. and CR30 when taken together form an aryl. ring ; or R28 and CR29 when taken together form an aryl ring; or a pharmaceutically acceptable salt or solvate thereof; or a compound having a tautomeric structure thereof; and

with the proviso that the compound of formula (XVb) is not: 2- ( ( (4- (3- (trifluoromethyl) phenyl) piperazinyl-1)- acetyl)amino)-5-((ethoxycarbonyl)-methyl)-1,3,4-thiadiazole; 2-(((4-(2-pyridyl)piperazinyl-1)-acetyl)amino)-5- ( (carbomethoxy) methyl)-1,3,4-thiadiazole; or 2-(((4-(3-(trifluoromethyl) phenyl) piperazinyl-1)- acetyl) amino)-5-(2-(carboxy) ethyl)-1,3,4-thiadiazole.

Among the compound of the general formulas (XVa) and (XVb) according to the invention, there may be mentioned more particularly, as preferred compound 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-5-((7-chloroquinolin-4-yl) thio)-1,3,4- thiadiazole, 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-5-cyclopropyl-1,3,4-thiadiazole, 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-5-((carbomethoxy) methyl)-1,3,4-thiadiazole, 2-(((4-(4-Methoxyphenyl)piperazin-1-yl)acetyl)amino)-5- carbomethoxymethyl-1,3,4-thiadiazole, 2- ( ( (-4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-5-(2-(carbomethoxy) ethyl)-1,3,4-thiadiazole, 2-(((4-(4-Methoxyphenyl) piperazin-1-yl) acetyl) amino)-5- 2-(carbomethoxy) ethyl)-1,3,4-thiadiazole, 2- ( ( (4- (2-Pyridyl) piperazin-1-yl) acetyl) amino)-S- (2- (carbomethoxy) ethyl)-1,3,4-thiadiazole The invention also relates to a process for the preparation of the compound of general formulas (XVa) and (XVb). A preparation process according to the invention comprises the rection of an aromatic amine of general formula (A3):

in which R1, R8, R9, X1, X2, and m, are as defined above for formulas (XVa) and (XVb), with a haloacyl halide of general formula (XXII): in which R10 and Roll, are as defined above for formulas (XVa) and (XVb), Hal represents a chlorine or bromine atom, in order to form a compound of general formula (XXIII); in which R1, R8, R9, R10, R11, X1, X2 and m are as defined above for formulas (XVa) and (XVb), and Hal as defined above; and the rection of the compound of general formula (XXIII) with a compound of general formula (XXIV):

in which RI. 21 R13 and o are as defined above for, formulas (XVa) and (XVb), in the presence of a basic agent, such as triethylamine or potassium carbonate in order to form the compound of general formulas (XVa) and (XVb): in which R1, R8, R9, R10, R11, R12, R13, m, Hal, and o are as defined above for formulas (XVa) or (XVb), and Hal as defined above.

The invention further provides compound, as well as compositions comprising said compound, useful as hypoglycemic agents, of general formula (XVIa):

wherein: Ri is selected from the group consisting of hydrogen and R14COOR,s% R2 is selected from the group consisting of hydrogen, halogen, C3-C8cycloalkyl,(C3-C8)R18NHR19, cycloalkyl C1-C8alkoxy,(C3-C8)cycloalkyloxyalkyl, (Cl-C6) alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (C1-C6) alkyl, (C3-C8)cycloalkyl(C1-C6)alkoxy,(C1-(C3-C8)cycloalkyloxy, (C1-C6)alkyl,(C6-C14)aryl,(C6-C14)heteroaryl,C6)alkoxy (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl, (C1-C6)alkyl(C6-C14)aryl,(C6-C14)aryloxy,(C6-(C6-C14)aryl (C1-C6)alkyl,(C6-C14)aryl(C1-C6)alkyloxy,(C6-C14)aryloxy C14) aryl (C1-C6) alkyloxy (Cl-C6) alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, (Cl-C8) thioalkyl, (Cl-C,,) alkylsulphinyl, (C1-C8) alkylsulphonyl, sulphoamino, (C2-C8) alkylsulphonylamino, and sulphamoyl; said Cl-C8 alkyl group being optionally substituted with one or more halogen, Cl-C6 alkyl or phenyl groups; said C6-C14 aryl and (C6-C14) aryl (C1-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, trihalo (Cl-C6) alkyl, and trihalo (Cl-C6) alkoxy; R3 is selected from the group consisting of hydrogen, (C3-C8)cycloalkyl(C1-C6)alkyl,cycloalkyl, (C6-C14) aryl, (C6-C14)heteroaryl(C1-C6)heteroaryl, alkyl, (C1-C6)alkyl,halogen,trifluoromethyl,aryl and cyano; said Cl-C. alkyl being optionally substituted with one or more halogen, Cl-C6 alkyl or phenyl groups; said C6-C14 aryl and (C6-C14) aryl (C1-C6) alkyl being optionally

substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cl-C6 alkoxy, C1- C6 alkyl, trihalo (Cl-C6) alkyl, and trihalo (C1-C6) alkoxy; R. is selected from the group consisting of NR20SO2Ar and NR20ArSO2, wherein Ar is an aryl selected from the group consisting of phenyl and phenylalkyl; Rg is a group selected from the-group consisting of hydrogen, C1-C8 alkyl, (Cl-C6) alkoxy (Cl-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cl-C6) alkyl group, (C3-C8) cycloalkyloxy (C1-C6) alkyl, (C3- cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, C6-C14 aryl, C6-C14 heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (C1- C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl (C1-C6) aryl, (C6-Cl4) aryl (C1-C6)alkyl,and(C6-C14)aryloxy(C1-C6)alkyl(C1-C6)alkoxy group; Rlo is selected from the group consisting of hydrogen, C1-C8 alkyl, (C1-C6) alkoxy (Cl-C,,) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C1-C6) alkyl group, (C3-C8) cycloalkyloxy (Cl-C6) alkyl, (C3- (C1-C6)alkoxy(C1-C6)alkyl,C6-C14aryl,C6-C14C8)cycloalkyl

heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (C1- C6) alkyl, (C1-C6)alkyl(C1-C6)aryl,(C6-C14)arylaryl (C1-C6) alkoxy (Cl-C6) alkyl, and (C6-C14) aryloxy (Cl-C6) alkyl group; Ril is selected from the group consisting of hydrogen, C1-C8 alkyl, (Cl-C6) alkoxy (Cl-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cl-C6) alkyl group, (C3-C8) cycloalkyloxy (Cl-C6) alkyl, (C3- (C1-C6)C8)cycloalkyl alkoxy (C1-C6) alkyl, C6-C14aryl, heteroaryl, (C6-C14) heteroaryl (C1-C6) alkyl, (C6-C14) aryl (Cl- (C6-C14)aryl(C1-C6)alkyl(C1-C6)aryl,(C6-C14)arylC6)alkyl, (C1-C6)alkyl,and(C6-C14)aryloxy(C1-C6)alkyl(C1-C6)alkoxy group; R12 is selected from the group consisting of hydrogen and C1-C6 alkyl; R13 is selected from the group consisting of

Ils a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cl-C6 alkyl group; said C1-C6 alkyl group being substituted with one or more hydrogen, halogen, Cl-C6 alkyl or phenyl groups; ( R15 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, divalent alkali metals, divalent alkali earth metals, and a C -C6 alkyl group; said C1-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and Cl-C3 alkyl; R16 is a bond or is selected from the group consisting of sulfonyl, C2-C6 thioalkyl, aminosulfonyl and C1- C6 alkyl; said Cl-C6 alkyl being substituted with one or more hydrogen, halogen, Cl-C. alkyl or phenyl groups; R17 is selected from the group consisting of phenyl, phenylalkyl, and a Cl-C6 alkyl group; said Cl-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of halogen, phenyl, phenylalkyl, and Cl-C3 alkyl; said phenyl and phenylalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C1-C6 alkoxy, amino, and Cl-C6 alkyl; R, 8 is a bond or is selected from the group consisting of sulfonyl, C2-C6 thioalkyl, aminosulfonyl, carbonyl, aminocarbonyl and Cl-C6 alkyl group, said Cl-C6 alkyl group being substituted with one or more hydrogen, halogen, Cl-C6 alkyl or phenyl groups;

R19 is selected from the group consisting of hydrogen, phenyl, phenyl (C1-C6)alkyl, and C1-C6 alkyl; said Ci- C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of phenyl and C1-C3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino, and Cl-ces alkyl; said phenyl C1-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino, or C1-C6 alkyl; R20 is selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy and Cl-C6 alkoxy; m is 0 or 1; o is 0 or 1; R21 is a bond or is selected from the group consisting Cl-C6 alkyl; said Cl-C6 alkyl being optionally substituted from the group consisting of benzene and an optionally substituted benzene ring; said benzene ring optionally substituted from the group consisting of Cl-C6 alkyl, halogen, Cl-C6 alkoxy and hydroxy;

R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C8 alkoxy, Cl-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cl-C6 alkoxy, carboxy, phenyl, C1-C8 thioalkyl, hydroxy, Cl-C6 alkyl, C3-C8 cycloalkyl, (C1-C6)alkyl,(C3-C8)cycloalkyloxy(C1-C6)(C3-C8)cycloalkyl alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cl-C6) alkoxy, (Cl-C6) alkoxy (C1-C6) alkyl, (C6-C14) aryl, (C6-C14)heteroaryl, heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl (C6-C14) aryl, (C6-C14) aryloxy, (C6-C14) aryloxyaryloxy(C1-C6) alkyl, (C1-C6)alkyloxy,(C6-C14)aryl aryl (C1-C6) alkyloxy (Cl-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (C1-C8)alkylsulpinyl,(C1-C8)alkylthio, alkylsulphonyl, sulphoamino, alkylsulphonylamino, sulphamoyl and (Cl-C8) alkylcarbonylamino; said Cl-C8 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said C2-C8 alkoxy being optionally substituted with halogen or C1-C3

alkyl; said C1-C8 thioalkyl being optionally substituted with halogen or Cl-cob alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or C1-C3 alkyl; R23 is selected from the group consisting of hydrogen, halogen, C1-C8 alkoxy, C1-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cl-C6 alkoxy, carboxy, C1-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cl-C6) alkyl, (C1-C6)alkyl,(C3-C8)cycloalkyl(C1-C6)(C3-C8)cycloalkyloxy alkoxy (C1-C6) alkyl, (C3-C8)cycloalkylcycloalkyloxy, (Cl-C6) alkoxy, (Cl-C6) alkoxy (Cl-C6) alkyl, (C6-C14) aryl, (C6- Cul,) heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (C6-C14)aryl(C1-C6)alkyl(C6-C14)aryl,(C6-C14)(C1-C6)alkyl, aryloxy, (C6-C14) aryloxy (Cl-C6) alkyl, (c6-cl4) aryl (Cl-C6) alkyloxy, (C1-C6)alkyloxy(C1-C6)alkyl,aryl trifluoromethoxy, amino, carbamoyl, (C1-C8) alkylthio, (Cl-C.) alkylsulphinyl, sulphoamino,(C1-C8)alkylsulphonyl, alkylsulphonylamino, sulphamoyl and (C2-C8) alkylcarbonylamino ; said Cl-C8 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C,,. alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said

C1-C8 thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or C1-C3 alkyl; R24 is selected from the group consisting of hydrogen, bromine, chlorine, C1-C8alkyl,alkoxy, trifluoromethyl, nitro, cyano, carbo Cl-C6 alkoxy, carboxy, hydroxy,C3-C8cycloalkyl,(C3-C8)cycloalkylC1-C8thioalkyl, (C3-C8)cycloalkyloxy(C1-C6)alkyl,(C3-C8)(C1-C6)alkyl, cycloalkyl (C1-C6)alkyl,(C3-C8)cycloalkyloxy,alkoxy (C3-C8) cycloalkyl (Cl-C6) alkoxy, (C1-C6) alkoxy (Cl-C6) alkyl, (C6-C14)heteroaryl,(C6-C14)heteroaryl(C1-C6)(C6-C14)aryl, alkyl, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)alkylaryl (C6-C14)aryloxy,(C6-C14)aryloxy(C1-C6)alkyl,(C6-C14)aryl, (C6-C14) aryl (Cl-C6) alkyloxy, (C6-C14) aryl (Cl-C6) alkyloxy (C1-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cl-C.) alkylthio, (C1-C8)alkylsulphonyl,alkylsulphinyl, sulphoamino, sulphamoyland(C1-alkylsulphonylamino,

Ce) alkylcarbonylamino; said C1-C8 alkyl being optionally substituted with halogen or C1-C3 alkyl; said C1-C8 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said C1-C8 thioalkyl being optionally substituted with halogen or Cl-Ce alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R25 is selected from the group consisting of hydrogen, halogen, C1-C8alkyl,trifluoromethyl,alkoxy, nitro, cyano, carbo C1-C6 alkoxy, carboxy, C17C. thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cl-C6) alkyl, (C1-C6)alkyl,(C3-C8)cycloalkyl(C1-C6)(C3-C8)cycloalkyloxy alkoxy (C1-C6) alkyl, (C3-C8)cycloalkylcycloalkyloxy, (C1-C6) alkoxy, (C1-C6)alkyl,(C6-C14)aryl,(C6-alkoxy C14) heteroaryl, (C1-C6)alkyl,(C6-C14)arylheteroaryl (C6-C14)aryl(C1-C6)alkyl(C6-C14)aryl,(C6-C14)(C1-C6)alkyl, aryloxy, (C6-C14) aryloxy (Cl-C.) alkyl, (C6-C14) aryl (Cl-C6) alkyloxy, (C1-C6)alkyloxy(C1-C6)alkyl,aryl trifluoromethoxy, amino, carbamoyl, (C1-C8)alkylthio, alkylsulphinyl, sulphoamino,(C1-C8)alkylsulphonyl, alkylsulphonylamino, sulphamoyl and (C2-Ce)

C1-C8alkylbeingoptionallyalkylcarbonylamino;said substituted with halogen or C,-C3 alkyl; said Cl-C8 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C, thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R26 is selected from the group consisting of hydrogen, bromine, chlorine, C.-C. alkoxy, C1-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cl-C., alkoxy, carboxy, <BR> <BR> <BR> phenyl, C1-C8 thioalkyl, hydroxy, Cl-C6 alkyl, C3-C8 cycloalkyl, (C1-C6)alkyl,(C3-C8)cycloalkyloxy(C1-C6)(C3-C8)cycloalkyl alkyl, (C3-C8) cycloalkyl (C1-C6) alkoxy (Cl-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (Cl-C6) alkoxy (C6-C14)aryl,(C6-C14)heteroaryl,(C6-C14)(C1-C6)alkyl, heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl, (C6-C14) aryl (C1-C6) alkyl (C6-C14)aryloxy,(C6-C14)aryl, aryloxy (Cl-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyloxy, (C6-C14)

aryl (Cl-C6) alkyloxy (Cl-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (C1-C8)alkylsulphinyl,(C1-C8)alkylthio, alkylsulphonyl, sulphoamino, alkylsulphonylamino, sulphamoyl and (C1-C8) alkylcarbonylamino ; said Cl-C. alkyl being optionally substituted with halogen or C1-C3 alkyl ; said C2-C,, alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C, thioalkyl being optionally substituted with halogen or Cl-C. alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; wherein R22-R26 are not all simultaneously hydrogen; or two of R22-R26 can form a methylenedioxy; R27-R31 are independently selected from the group consisting of hydrogen, halogen, C1-C8 alkoxy, C-C8 alkyl, trifluoromethyl, nitro, cyano, carbo C1-C6 alkoxy, carboxy, Cl-C. thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6)alkyl,(C3-C8)cycloalkyloxy cycloalkyl (C1-C6) alkoxy (C3-C8)cycloalkyloxy,alkyl, (C1-C6)alkoxy,(C1-C6)alkoxy(C1-C6)alkyl,(C3-C8)cycloalkyl (C6-C14)heteroaryl,(C6-C14)heteroaryl(C1-C6)(C6-C14)aryl, alkyl, (C6-C14) aryl (C1-C6) alkyl, (C6-C14) aryl (C1-C6) alkyl

(C6-C14)aryloxy,(C6-C14)aryloxy(C1-C6)alkyl,(C6-C14)aryl, (C6-C14) aryl (Cl-C6) alkyloxy, (C6-C14) aryl (C1-C6) alkyloxy (Cl-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (C1-C8) alkylthio, $(C1-C8)alkylsulphonyl,alkylsulphinyl, sulphoamino, (C1-C8) alkylsulphonylamino, sulphamoyl and (C2- saidC1-C8alkylbeingoptionallyC8)alkylcarbonylamino; substituted with halogen or C1-C3 alkyl ; said C1-C8 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C8 thioalkyl being optionally substituted with halogen or C-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; or R22 and R23 when taken together form an aryl ring; or R23 and R24 when taken together form an aryl ring; <BR> <BR> X3 iS nitrogen or CR29;<BR> <BR> <BR> Xi ils nitrogen or CR30 ; X5 is nitrogen or CR31 ; wherein at least one of X3, X4, or X5 is nitrogen;

wherein up to three of R2,-R31 can simultaneously be hydrogen when only one of X3-X, is nitrogen ; or R28 and CR30 when taken together form an aryl ring; or RZB and CR29 when taken together form an aryl ring; or a pharmaceutically acceptable salt or solvate thereof; or a compound having a tautomeric structure thereof.

In another embodiment of general formula (XVIa), the present invention further provides compound as well as compositions comprising said compound, useful as hypoglycemic agents wherein: Ri is selected from the group consisting of hydrogen and R14COOR15; R2 is selected from the group consisting of hydrogen, halogen, C6-C14aryl,(C6-C14)arylR18NHR19, C1-C6 alkyl, andC3-C6cycloalkyl;saidC6-C14aryl,alkyl, and said (Cl-Cl4) aryl Cl-C6 alkyl, being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cl-C6 alkoxy, C1-

C6 alkyl, trihalo (Cl-C6) alkyl, and trihalo (Cl-C6) alkoxy; said C1-C8 alkyl group being optionally substituted with one or more halogen, C1-C6 alkyl or phenyl groups; R3 is selected from the group consisting of hydrogen, C6-Cl4 aryl, [C6-C14] aryl (Cl-C6) alkyl, and Cl-C8 alkyl group; said C6-C14 aryl, and said (C6-Cl4) aryl (Cl-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cl-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, trihalo (Cl-C6) alkyl, and trihalo (C1-C6) alkoxy; said Cl-C8 alkyl group being optionally substituted with one or more halogen, C1-C6 alkyl or phenyl groups; R8-R21, m, and o are as defined above for formula (XVIa); R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, C1-C6 alkyl, nitro, trifluoromethyl, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl,

C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said C1-C8 thioalkyl being optionally substituted with halogen or Cl-Ce alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R23 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, Cl-C. alkyl, trifluoromethyl, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, Cl-C, thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or Ci-c. alkyl; said Cl-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl; said C1-C8 thioalkyl being optionally substituted with halogen or Cl-Ce alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R24 is selected from the group consisting of hydrogen, bromine, chlorine, Cl-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C6

optionallysubstitutedwithhalogenorC1-C3alkoxybeing alkyl; said Cl-C. thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R2S is selected from the group consisting of hydrogen, halogen, C1-C6alkyl,trifluoromethyl,alkoxy, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, C1-C6 thioalkyl, and hydroxy; said C1-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C. thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, C1-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being

optionally substituted with halogen or Cl-C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C. thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; wherein R22-R26 cannot all simultaneously be hydrogen; or two of R22-R2, when taken together can form a methylenedioxy group; R21 is selected, from the group consisting of halogen, Cl-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said C1-C8 thioalkyl being optionally substituted with halogen or Cl-C. alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R28 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl;nitro,cyano,alkoxy,

carbo (C1-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with halogen or Ci-C. alkyl; said Cl-cob thioalkyl being optionally substituted with halogen or Cl-C,, alkyl; said carbo (Ci-C.) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; or R22 and R23 when taken together form an aryl ring; or R23 and R24 when taken together form an aryl ring; X3 is nitrogen or CR29 ; Xi ils nitrogen or CR30; X. is nitrogen or CR31; wherein at least one of X3, X4, or X. is nitrogen; R29 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said C1-C6 alkyl being optionally substituted with

one to two halogen atoms or C1-C3 alkyl ; said. C, -C6 alkoxy being optionally substituted with halogen or C,-C3 alkyl; R30 is selected from the group consisting of hydrogen, halogen, Cl-C. alkoxy, C1-C6 alkyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or C,-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R31 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, Cl-C6 alkyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C. alkyl being optionally substituted with one to two halogen atoms or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl; wherein up to three of R27-R31 can simultanoeously be hydrogen when only one of X3-XS is nitrogen; wherein up to two of R27-R31 can simultaneously be hydrogen when two of X3-X5 are nitrogen; or R28 and CR29 when taken together form an aryl

ring; or R28 and CR30 when taken together form an aryl ring; or a pharmaceutically acceptable salt or solvate thereof; or a compound having a tautomeric structure thereof.

The present invention further provides methods for using compositions comprising a compound of formula (XVIb) or a pharmaceutically acceptable salt or a compound having a tautomeric structure thereof as hypoglycemic agents, the compound of formula (XVIb) having the structure:

wherein: R1 is selected from the group consisting of hydrogen and R14COORls % R2 is selected from the group consisting of hydrogen, halogen, C3-C8cycloalkyl,(C3-C8)R18NHR19, cycloalkyl (C1-C6) alkyl, (C-C8)cycloalkyloxyalkoxy, (Cl-C.) alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (C1-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cl-C6) alkoxy, (Cl- (C1-C6)alkyl,(C6-C14)aryl,(C6-C14)heteroaryl,C6)alkoxy (C1-C6)alkyl,(C6-C14)aryl(C1-C6)alkyl,(C6-C14)heteroaryl (C6-C14) aryl (Cl-C,) alkyl (C6-C14) aryl, (C6-Ci4) aryloxy ; (C6- C14) aryloxy (Cl-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyloxy, (C6- C14) aryl (C1-C6) alkyloxy (Cl-C6) alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, (Cl-C.) thioalkyl, (Cl-C8) alkylsulphinyl, (C1-C8) alkylsulphonyl, sulphoamino, (C2-C8) alkylsulphonylamino, and sulphamoyl; said C1-C8) alkyl group being optionally substituted with one or more halogen, Cl-C. alkyl or phenyl groups; said C6-C14 aryl and (C6-C14) aryl (Cl-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, trihalo (Cl-C6) alkyl, and trihalo (Cl-C6) alkoxy; R3 is selected from the group consisting of hydrogen, (C3-C8)cycloalkyl(C1-C6)alkyl,cycloalkyl, (C6-C14)heteroaryl,(C6-C14)heteroaryl(C1-C6)(C6-C14)aryl, alkyl, (C6-C14) aryl (Cl-C6) alkyl, halogen, trifluoromethyl, and cyano; said C1-C8 alkyl being optionally substituted with one or more halogen, C1-C6 alkyl or phenyl groups; said C6-C14

aryl and (C6-C14) aryl (Cl-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, C1-C6 alkoxy, C1- C6 alkyl, trihalo (C1-C6) alkyl, and trihalo (C1-C6) alkoxy; R. is selected from the group consisting of NR20SO2Ar and NR20ArSO2, wherein Ar is an aryl selected from the group consisting of phenyl and phenylalkyl; R9 is a group selected from the group consisting of hydrogen, (C1-C6)alkoxy(C1-C6)alkyl,cycloalkylalkyl, group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl group,(C3-C8)cycloalkyloxy(C1-C6)alkyl,(C3-(C1-C6)alkyl C8) cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, C6-C14 aryl, C6-C14 heteroaryl, (C1-C6)alkyl,(C6-C14)aryl(C1-heteroaryl C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl (Cl-C6) aryl, (C6-C14) aryl (Cl-C6) alkoxy (Cl-C6) alkyl, and (C6-Cl4) aryloxy (Cl-C6) alkyl group; Rlo is selected from the group consisting of hydrogen, C1-C8 alkyl, (Cl-C6) alkoxy (Cl-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl

(Cl-C6) alkyl group, (C3-C8) cycloalkyloxy (Cl-C6) alkyl, (C3-<BR> <BR> <BR> <BR> <BR> C8) cycloalkyl (Cl-C6) alkoxy (Cl-C.) alkyl, C6-C14 aryl, C6-C14 heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (C1- C6) alkyl, (C6-C14) aryl (C1-C6) alkyl (Cl-C,) aryl, (C6-C14) aryl (Cl-C.) alkoxy (Cl-C6) alkyl, and (C6-C14) aryloxy (C1-C6) alkyl group; R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, (C1-C6) alkoxy (Cl-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cl-C6) alkyl group, (C3-C8) cycloalkyloxy (C1-C6) alkyl, (C3- (C1-C6)alkoxy(C1-C6)alkyl,C6-C14aryl,C6-C14C8)cycloalkyl heteroaryl, (C6-C14) heteroaryl (Cl-C6) alkyl, (C6-Cl4)-aryl (C1- C6) alkyl, (C1-C6)alkyl(C1-C6)aryl,(C6-C14)arylaryl (Cl-C6) alkoxy (C1-C6) alkyl, and (C6-C14) aryloxy (Cl-C6) alkyl group; R12 is selected from the group consisting of hydrogen and C1-C6 alkyl; R13 is selected from the group consisting of

R14 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cl-C6 alkyl group; said Cl-C6 alkyl group being substituted with one or more hydrogen, halogen, Cl-C6 alkyl or phenyl groups; R15 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, divalent alkali metals, divalent alkali earth metals, and a C -C6 alkyl group; said Cl-C. alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and Cl-C3 alkyl; R16 is a bond or is selected from the group consisting of sulfonyl, C2-C6 thioalkyl, aminosulfonyl and Ci- C6 alkyl; said C1-C6 alkyl being substituted with one or more hydrogen, halogen, C1-C6 alkyl or phenyl groups; R17 is selected from the group consisting of phenyl, phenylalkyl, and a Cl-C6 alkyl group; said Cl-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of halogen, phenyl, phenylalkyl, and C1-C3 alkyl; said phenyl and phenylalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C1-C6 alkoxy, amino, and Cl-C. alkyl; R18 is a bond or is selected from the group consisting of sulfonyl, C2-C6 thioalkyl, aminosulfonyl, carbonyl, aminocarbonyl and Cl-C6 alkyl group, said Cl-C6 alkyl group being substituted with one or more hydrogen, halogen, Cl-C. alkyl or phenyl groups;

R19 is selected from the group consisting of hydrogen, phenyl, phenyl (Cl-C6) alkyl, and Cl-C6 alkyl; said C1- C6 alkyl being optionally substituted with one or more substituents selected from the. group consisting of phenyl and C1-C3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino, and C1-C6 alkyl; said phenyl C1-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino, or Cl-C6 alkyl; R20 is selected from the group consisting of hydrogen, Cl-C6 alkyl, hydroxy and Cl-C6 alkoxy ; m is 0 or 1; o is 0 or 1; R21 is a bond or is selected from the group consisting C1-C6 alkyl; said Cl-C, alkyl being optionally substituted from the group consisting of benzene and an optionally substituted benzene ring; said benzene ring optionally substituted from the group consisting of Cl-C6

alkyl, halogen, C1-C6 alkoxy and hydroxy; R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C8 alkoxy, C1-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cl-C., alkoxy, carboxy, phenyl, C1-C8 thioalkyl, hydroxy, C1-C6 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cl-C6) alkyl, (C3-C8) cycloalkyloxy (Cl-C6) alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (Cl-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cl-C6) alkoxy, (Cl-C6) alkoxy (C1-C6) alkyl, (C6-C14)heteroaryl,(C6-C14)aryl, heteroaryl (Cl-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl, (C6-C14) aryl (C1-C6) alkyl (C6-C14)aryloxy,(C6-C14)aryl, aryloxy (C1-C6) alkyl, (C1-C6)alkyloxy,(C6-C14)aryl aryl (Cl-C6) alkyloxy (Cl-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (C1-C8)alkylsulphinyl,(C1-C8)alkylthio, alkylsulphonyl, sulphoamino, alkylsulphonylamino, sulphamoyl and (Cl-CB) alkylcarbonylamino; said CL-CL alkyl being optionally substituted with halogen or C1-C3 alkyl ; said C2-C8 alkoxy being optionally substituted with halogen or C1-C3

alkyl; said C1-C8 thioalkyl being optionally substituted with halogen or C, -C. ;alkyl said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R23 is selected from the group consisting of. <BR> <BR> hydrogen, halogen, Cl-CE alkoxy, C1-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cl-C6 alkoxy, carboxy, C1-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cl-C6) alkyl, (C3-C8) cycloalkyloxy (Cl-C6) alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (C1-C6) alkyl, (C3-C8)cycloalkylcycloalkyloxy, (C1-C6) alkoxy, (C1-C6)alkyl,(C6-C14)aryl,(C6-alkoxy (C6-C14)heteroaryl(C1-C6)alkyl,(C6-C14)arylC14)heteroaryl, (C1-C6) alkyl, (C1-C6)alkyl(C6-C14)aryl,(C6-C14)aryl aryloxy, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)aryloxy alkyloxy, (C6-C14) aryl (Cl-C6) alkyloxy (Cl-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cl-C8) alkylthio, (C1-C8) alkylsulphinyl, (C1-C8) alkylsulphonyl, sulphoamino, (C1-Ce) alkylsulphonylamino, sulphamoyl and (C2-C8) C1-C8alkylbeingoptionallyalkylcarbonylamino;said substituted with halogen or C1-C3 alkyl ; said Cl-cob alkoxy

being optionally substituted with halogen or C1-C3 alkyl ; said C1-C8 thioalkyl being optionally substituted with halogen or C1_C8 ;alkyl said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R24 is selected from the group consisting of hydrogen, bromine, chlorine, C1-C8alkyl,alkoxy, trifluoromethyl, nitro, cyano, carbo C1-C6 alkoxy, carboxy, hydroxy,C3-C8cycloalkyl,(C3-C8)cycloalkylC1-C8thioakyl, (Cl-C6) alkyl, (C3-C8) cycloalkyloxy (C1-C6) alkyl, (C3-C8) <BR> <BR> <BR> cycloalkyl (Cl-C6) alkoxy (C1-C6) alkyl, (C3-C8) cycloalkyloxy, (C1-C6)alkoxy,(C1-C6)alkoxy(C1-C6)alkyl,(C3-C8)cycloalkyl (C6-C14)heteroaryl,(C6-C14)heteroaryl(C1-C6)(C6-C14)aryl, alkyl, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)alkylaryl (C6-C14) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (Cl-C6) alkyl, (C1-C6)alkyloxy,(C6-C14)aryl(C1-C6)alkyloxy(C6-C14)aryl (Cl-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cl-C.) alkylthio, (Cl-C,,) alkylsulphinyl, (Cl-C,) alkylsulphonyl, sulphoamino, (C1-C8) alkylsulphonylamino, sulphamoyl and (C1-

Ce) alkylcarbonylamino; said C1-C8 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said Cl-cob alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C8 thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R25 is selected from the group consisting of hydrogen, halogen, Cl-C. alkoxy, C1-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cl-C6 alkoxy, carboxy, Cl-C8 thioalkyl, hydroxy, (C3-C8)cycloalkyl(C1-C6)alkyl,cycloalkyl, (C1-C6)alkyl,(C3-C8)cycloalkyl(C1-C6)(C3-C8)cycloalkyloxy alkoxy (C1-C6) cycloalkyloxy,(C3-C8)cycloalkyl(C3-C8) (Cl-C6) alkoxy, (Cl-C6) alkoxy (C1-C6) alkyl, (C6-C14) aryl, (C6- (C6-C14)heteroaryl(C1-C6)alkyl,(C6-C14)arylC14)heteroaryl, (C6-C14)aryl(C1-C6)alkyl(C6-C14)aryl,(C6-C14)(C1-C6)alkyl, aryloxy, (C1-C6)alkyl,(C6-C14)aryl(C1-C6)aryloxy alkyloxy, (C1-C6)alkyloxy(C1-C6)alkyl,aryl trifluoromethoxy, amino, carbamoyl, (C1-C8)alkylthio, alkylsulphinyl, suplphoamino,(C1-C8)alkylsulphonyl,

alkylsulphonylamino, sulphamoyl and (C2-C8) alkylcarbonylamino; said C1-C8 alkyl being optionally. substituted with halogen or C1-C3 alkyl ; said C1-C8 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said C1-C8 thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C. alkyl; R26 is selected from the group consisting of hydrogen, bromine, chlorine, C1-C8alkyl,alkoxy, trifluoromethyl, nitro, cyano, carbo Cl-C. alkoxy, carboxy, phenyl, C1-C8 thioalkyl, hydroxy, C1-C6 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-C8)cycloalkyloxy(C1-C6)alkyl, alkyl, (C1-C6)alkoxy(C1-C6)alkyl,(C3-C8)cycloalkyl cycloalkyloxy, (C3-C8) cycloalkyl (Cl-C6) alkoxy, (Cl-C6) alkoxy (C6-C14)aryl,(C6-C14)heteroaryl,(C6-C14)(C1-C6)alkyl, heteroaryl (C,-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyl, (C6-C14) aryl (C1-C6) alkyl (C6-C14)aryloxy,(C6-C14)aryl, aryloxy (C6-C14)aryl(C1-C6)alkyloxy,(C6-C14)alkyl,

aryl (Cl-C6) alkyloxy (C1-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (C1-C8)alkylsulphinyl,(C1-C8)alkylthio, alkylsulphonyl, sulphoamino, alkylsulphonylamino, sulphamoyl and (Cl-Ce) alkylcarbonylamino; said Cl-C8 alkyl being optionally substituted with halogen or Ci-C3alkyl; said C2-C8 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C. thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (C1-C6) alkocy being optionally substituted with halogen or Cl-C3 alkyl; wherein R22-R26 are not all simultaneously hydrogen; or two of R22-R26 can form a methylenedioxy; R27-R31 are independently selected from the group consisting of hydrogen, halogen, C1-C8 alkoxy, C1-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cl-C6 alkoxy, carboxy, hydroxy,C3-C8cycloalkyl,(C3-C8)cycloalkylC1-C8thioalkyl, (Cl-C6) alkyl, (C3-C8) cycloalkyloxy (C1-C6) alkyl, (C3-C8) cycloalkyl (Cl-C6) alkoxy (C1-C6) alkyl, (C3-C8) cycloalkyloxy, <BR> <BR> (C3-C8) cycloalkyl (Cl-C6) alkoxy, (C1-C6) alkoxy (Cl-C6) alkyl, (C6-C14)heteroaryl,(C6-C14)heteroaryl(C1-C6)(C6-C14)aryl, alkyl, (C6-C14) aryl (C6-C14)aryl(C1-C6)alkylalkyl,

(C6-Cl4) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (C1-C6) alkyl, (C6-C14) aryl (Cl-C6) alkyloxy, (C6-C14) aryl (C1-C6) alkyloxy (Cl-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (C1-C8) alkylthio, (C1-C8)alkylsulphonyl,alkylsulphinyl, sulphoamino, (C1-C8) alkylsuphonylamino, sulphamoyl and (C2- Ce) alkylcarbonylamino; said Cl-C. alkyl being optionally substituted with halogen or Cl-C3 alkyl; said C1-C8 alkoxy being optionally substituted with halogen or Cl-C3alkyl; said C1-C8 thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; or R22 and R23 when taken together form an aryl ring; or R23 and R24 when taken together form an aryl ring; X3 is nitrogen or CR29; X4 is nitrogen or CR30 ; X5 is nitrogen or CR3l ; wherein at least one of X3, X4, or X5 is nitrogen ;

wherein up to three of R27-R31 can simultaneously be hydrogen when only one of X3-X5 is ;nitrogen or R28 and CR30 when taken together form an aryl ring ; or ré and CR29 when taken together form an aryl ring; or a pharmaceutically acceptable salt or solvate thereof; or a compound having a tautomeric structure thereof.

In another embodiment of general formula (XVIb), the present invention further provides methods for using comositions comprising a compound of formula (XVIb) or a pharmaceutically acceptable salt or a solvate or a compound having a tautomeric structure thereof as hypoglycemic agents, wherein: R1 is selected from the group consisting of hydrogen and R14COORl5 ; R2 is selected from the group consisting of hydrogen, halogen, R16OR17, R18NHR19, C6-C14 aryl, (C6-C14) aryl Cl-C6 alkyl, C1-C8 alkyl, and C3-C6 cycloalkyl; said C6-C14 aryl,

and said (C6-C14) aryl Cl-C6 alkyl, being optionally. substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, C1-C6 alkoxy, Cl- C6 alkyl, trihalo (Cl-C6) alkyl, and trihalo (Cl-C6) alkoxy; said C1-C8 alkyl group being optionally substituted with one or more halogen, Cl-C6 alkyl or phenyl groups; R3 is selected from the group consisting of hydrogen, C6-C14 aryl, (C6-C14) aryl (Cl-C6) alkyl, and Cl-cob alkyl group; said C6-C14 aryl, and said (C6-C14) aryl (Cl-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cl-C6 alkoxy, Cl-C6 alkyl, C3-C8 cycloalkyl, trihalo (Cl-C6) alkyl,. and trihalo (Cl-C6) alkoxy; said Cl-cob alkyl group being optionally substituted with one or more halogen, C1-C6 alkyl or phenyl groups; R8-R21, m, and o are as defined above for formula (XVIb);

R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Cl-C6 alkyl, nitro, trifluoromethyl, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said C2-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C. thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R23 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said C1-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said Cl-C6 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C8 thioalkyl being optionally substituted with halogen or Cl-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R24 is selected from the group consisting of hydrogen, bromine, chlorine, Cl-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cl-C,) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C, alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said C1-C8 thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; R25 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl,trifluoromethyl,alkoxy, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C,, alkyl being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C, thioalkyl being optionally substituted with halogen or Cl-C, alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl;

R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or. Cl-C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C. thioalkyl being optionally substituted with halogen or Cl-Ce alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or Cl-C3 alkyl; wherein R22-R26 cannot all simultaneously be hydrogen; or two of R22-R26 when taken together can form a methylenedioxy group; R21 is selected from the group consisting of halogen ; Cl-C6 alkoxy, Cl-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, Cl-cob thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with halogen or Cl-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said C1-C8 thioalkyl being optionally substituted with halogen or C1-C8 alkyl; said

carbo (C1-C6) alkoxy being optionally substituted with halogen or Cl-C3 ;alkyl R28 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, Cl-C6 alkyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, Cl-cob thioalkyl, and hydroxy; said C1-C6 alkyl being optionally substituted with halogen or C1-C3 alkyl ; said C1-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; said C1-C8 thioalkyl being optionally substituted with halogen or Cl-C. alkyl; said carbo (Cl-C6) alkoxy being optionally substituted with halogen or C1-C3 alkyl; or R22 and R23 when taken together form an aryl ring; or R23 and R24 when taken together form an aryl ring; X3 is nitrogen or CR29; <BR> <BR> X4 iS nitrogen or CR30 ;<BR> <BR> <BR> X5 iS nitrogen or CR31; wherein at least one of X3, X4, or X5 is nitrogen;

R29 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, Cl-C6 alkyl, nitro, cyano, carbo (C1-C6) alkoxy, carboxy, phenyl, Cl-cob thioalkyl, and hydroxy; said Cl-C6 alkyl being optionally substituted with one to two hålogen atoms or Cl-C3alkyl; said Cl-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; R30 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl, nitro, cyans ; carbo (C1-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said cl-C6 alkyl, being optionally substituted with halogen or C,-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with halogen or C1-C3 alkyl ; R31 is selected from the group consisting of hydrogen, halogen, Cl-C6 alkoxy, C1-C6 alkyl, nitro, cyano, carbo (Cl-C6) alkoxy, carboxy, phenyl, C1-C8 thioalkyl, and hydroxy; said C1-C6 alkyl being optionally substituted with one to two halogen atoms or Cl-C3 alkyl; said Cl-C6 alkoxy being optionally substituted with halogen or Cl-C3alkyl ; wherein up to three of R2,-R31 can simultanoeously be hydrogen when only one of X3-X5 is ;nitrogen

wherein up to two of R27-R31 can simultaneously be hydrogen when two of X3-X5 are nitrogen; or R28 and CR29 when taken together form an aryl ring; or R28 and CR30when taken together form an aryl ring; or a pharmaceutically acceptable salt or solvate thereof; or a compound having a tautomeric structure thereof.@@@ Among the compound of the general formulas (XVIa) and (XVIb) according to the invention, there may be mentioned more particularly, as preferred compound 3-(((4-(2-Fluorophenyl)piperazin-1- yl) acetyl) amino)-2- (carbomethoxy)-thiophene, 3- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino)-2- (carbomethoxy) thiophene,

3- ( ( (4- (5- (Trifluoromethyl) pyrid-2-yl) piperazin-1- yl) acetyl) amino)-2- (carbomethoxy) thiophene, 3- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino)-2- (carbomethoxy) thiophene Hydrochloride, 3- ( ( (4- ( (4-chlorobenzhydryl) phenyl) piperazin-1- yl) acetyl) amino)-2- (carbomethoxy) thiophene, 3- ( ( (4- (2- (Trifluoromethyl) quinolin-4-yl) piperazin- 1-yl) acetyl) amino)-2- (carbomethoxy) thiophene.

The invention also relates to a process for the preparation of the compound of general formulas (XVIa) and (XVIb). A preparation process according to the invention comprises the rection of an aromatic amine of general formula (A4):

in which Rl, R2, R3, R8, R9 and m are as defined above for formulas (XVIa) and (XVIb), with a haloacyl halide of general formula (XXV):

in which R10 and Rll are as defined above for formulas (XVIa) 35 and (XVIb), Hal represents a chlorine or bromine atom, in order to form a compound of general formula (XXVI);

in which R1, R2, R3, R8, R9, R10, Rll and m are as defined above for formulas (XVIa) and (XVIb) and Hal is as defined above; and the rection of the compound of general formula (XXVI) with a compound of general formula (XXVII): in which R12, R13, and o are as defined above for formulas (XVIa) and (XVIb), in the presence of a basic agent, such as triethylamine or potassium carbonate in order to form the compound of general formulas (XVIa) and (XVIb): in which Ru, R2, R3, R8, R9, R10, R11, R12, R13, m, Hal, and o are as defined above for formulas (XVIa) and (XVIb);

The present invention may be understood more fully by reference to the following detailed description and illustrative examples which are intended to exemplify non- limiting embodiments of the invention.

4. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a flow chart illustrating generally the preparation of substituted phenyl piperazines 4 and heterocyclic piperazines 5 or 9. Equation 1 shows that the preparation of piperazine 4 or 5 whereby bis- (2- chloroethyl) amine hydrochloride is treated with aniline 1, phenylalkylamine 1, or with heterocyclic amines 2. Equation 2 shows the preparation of 9 whereby haloheterocycles 6 are treated with a protected piperazine 7 to give protected heterocyclic piperazines 8, which are the deprotected to <BR> <BR> <BR> provide the desired heterocyclic piperazines 9. R2,-R2. and X3-<BR> <BR> <BR> <BR> <BR> X. are defined above in Section 3; Z is bromine or chlorine.

Figure 2 is a flow chart illustrating a-preparation of piperazine derivatives 4 whereby an optionally substituted benzothiazole A1, thiazole A2, thiadiazole A3, or thiophene A4 is first acylated with a haloacetyl halide and then condense with nucleophile 2. Rl-Rl3 are defined above in Section 3; Z is bromine or chlorine.

5. DETAILED DESCRIPTION OF THE INVENTION 5.1 COMPOUND OF FORMULA (I) The invention provides compound of formula (I): (I) in which Ar and R1-R6 are as described above for formula (I), their solvates and their pharmaceutically acceptable salts, which are useful as hypoglycemic agents.

Examples of an aryl group, inclue, but are not limited to, phenyl, a-naphthyl, R-naphthyl and fluorenyl groups.

The C. 1-C. alkyl groups may be linear or branche, and inclue, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups.

The Cl-C. alkoxy groups may likewise be linear or branche, and inclue, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy groups.

The halogens may be selected from fluorine, chlorine, bromine and iodine.

The invention also relates to the tautomeric, enantiomeric, diastereoisomeric and epimeric forms of the compound of general formula (I).

The compound of general formula (I) have a carboxylic acid functional group and may be salifie, i. e., converted into conjugate bases they then being in the form of salts with bases.

Examples of salts with bases of the compound of general formula (I) include the pharmaceutically acceptable salts such as the sodium salts, potassium salts, calcium salts and other salts of the same type.

The compound of general formula (I) can also be salifie with amines in order to form pharmaceutically acceptable salts. By way of example, it will be possible for the compound of general formula (I) to be salifie with glucamine, N-methylglucamine, N, N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.

The compound of general formula (I) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids. Examples of salts with acids of the compound of general formula (I) include the pharmaceutically acceptable salts such as, and non- exhaustively, hydrochloride, hydrobromide, sulphate, succinate, maleate, fumarate, malate, tartrate and sulphonates such as methanesulphonate, benzene-sulphonate and toluenesulphonate.

Among the compound of general formula (I) according to the invention, there may be mentioned more particularly, as preferred compound: 4-{4-[2(N-isopropyl-N-phenylamino)-2-oxoethyl]-1- piperazinyllbenzoic acid; 4-{4-[2-(N-[2,6-dimethylphenyl]amino)-2-oxoethyl]-1- 1-piperazinyl} benzoic acid; and 4- 4- [2- (N- [2, 6-diisopropylphenylJamino)-2- oxoethyll-i-pipe. razinyllbenzoic acid.

The present invention further provides compositions

comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use for use as hypoglycemic agents, as well as methods for their use.

The invention also provides a process for the preparation of the compound of general formula (I). A process of preparation according to the invention comprises reacting an aromatic amine of general formula (II): in which Ar and R1 are as de-fine above for formula (I), with a halocyl halide of general formula (III):

in which Hal represents a chlorine or bromine atom, and R2 and R3 are as defined above for formula (I), in order to form a compound of general formula (IV): in which Ar, Rl, R2, R3 and Hal are as defined above for formula (I), and reacting the compound of general formula (IV) with a compound of general formula (V): in which R4, Rs and R6, are as defined above for- formula (I) and R, is a hydrogen atom or a Cl-C6 alkyl group, in the presence of a basic agent such as triethylamine in order to form the compound of general formula (VI):

in which Ar, R1, R2, R3, R4, R5, R6 and R, are as defined above for formula (I).

In the case where R, is an alkyl group, the compound of general formula (VI) can be hydrolyzed by conventional acidic or basic means in order to give the compound of general formula (I): in which Ar, R1, R2, R3, R4, R5 and R6 are as defined above for formula (I).

The compound of formula (V) are known compound.

They can be synthesized according to the procedure described by V. Prelog and Z. Blazek in Collection Czechloslov. Chem.

Communications 6,211-24 (1934) for ethyl 4- (l- piperazinyl)benzote.

By way of example, the compound (VI), in which R, is an alkyl group, can be hydrolyzed in the presence of a basic agent such as dilute sodium hydroxide.

The enantiomers of the compound of formula (I) can be separated by successive recrystallization of the salt of the acid (I) with an optically active based from solvents such as acetone, ethyl acetate or isopropanol, followed by displacement from the salt into an optically active acid by an inorganic or organic acid, according to a conventional method.

5.2 COMPOUND OF FORMULA (VII) The invention further provides compound of general formula (VII):

in which Ar, R1-R6 and A, B, C and D are described above for formula (VII), their solvates and their pharmaceutically acceptable salts, which are useful as hypoglycemic agents.

Examples of aryl groups inclue, but are not limited to, phenyl, a-naphthyl, ß-naphthyl and fluorenyl groups.

The C1-C8 alkyl groups can be linear or branche, and inclue, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups.

The Cl-C8 alkoxy groups can like likewise be linear or branche, and inclue, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy groups.

The halogens can be selected from fluorine, chlorine, bromine and iodine.

The heteroaryl groups. in the definition of R1, R2 and R3 may be defined in particular as defined for the heteroaromatic groups in the definition of Ar.

The invention also relates to the tautomeric forms and to the enantiomers, diastereoisomers and epimers of the compound of general formula (VII).

The compound of general formula (VII) possess a carboxylic acid functional group and can be salifie, i. e., converted into conjugate bases they then-being in the form of salts with bases.

Examples of salts with bases of the compound of. general formula (VII) include the pharmacologically acceptable salts, such as the sodium salts, potassium salts, calcium salts and other salts of the same type.

The compound of general formula (VII) can also be salifie with amines in order to form pharmaceutically acceptable salts. By way of example, the compound of general formula (VII) could be salifie with glucamine, N- methylglucamine, N, N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.

The compound of general formula (VII) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids. Examples of salts with acids of the compound of general formula (VII) include the pharmaceutically acceptable salts, such as, and non- exhaustively, the hydrochloride, the hydrobromide, the sulphate, the succinate, maleate, fumarate, malate or tartrate and the sulphonates, such as the methanesulphonate, the benzenesulphonate or the toluenesulphonate.

The invention also relates to a process for the preparation of the compound of general formula (VII). A preparation process according to the invention comprises the rection of an aromatic amine of general formula (VIII):

(VIII) in which A, B, C, D, Rl, R4, Rs and R6 are as defined above for formula (VII) and R7 is a hydrogen atom, a Cl-C6 alkyl group or a benzyl group, with a haloacyl halide of general formula (IX): in which R2 and R3 are as defined above for formula (VII), Hal represents a chlorine or bromine atom, in order to form a compound of general formula (X); in which A, B, C, D, Rl, R2, R3, R4, Rs, R6, R7 and Hal are as defined above for formula (VII); and the rection of the compound of general formula (X) with a compound of general formula (XI): in which Ar is as defined above for formula (VII), in the presence of a basic agent, such as triethylamine, in order to form the compound of general formula (XII) :

in which Ar, A, B, C, D, Rl, R2, R3, R4, R5, R6 and R7 are as defined above forformula (VII).

In the case where R, is an alkyl group, the compound of general formula (XII) can be hydrolyse by conventional acidic or basic means in order to give the compound of general formula (VII).

In the case where R7 is a benzyl group, the compound of general formula (XII) can be hydrogenolysed in the presence of a catalyst, such as palladium-on-charcoal, in order to give the compound of general formula (VII).

The compound of Formulae (VIII) and (XI) are known compound or can be prepared according to known processes.

Thus, compound of formula (VIII) are described in Organic Preparation and Procedures International, 13,189, 1981.

The compound of formula (XI) can be prepared as described by R. Ratouis et al. (J. Med. Chem., 8,104,1965) or by Prelog et al. (Collection Czechoslov. Chem.

Communications, 6,211,1934).

By way of example, the compound (XII), in which R, is an alkyl group, can by hydrolyse in the presence of a basic agent, such as dilute sodium hydroxide.

The enantiomers of the compound of formula (VII) can be separated by successive recrystallization of the salt ouf té acid (VII) with an optically active base in solvents such as acetone, ethyl acetate or isopropanol and then displacement from the salt into an optically active acid by an inorganic or organic acid, according to a conventional method.

5.3 COMPOUND OF FORMULAS (XIIIa) AND (XIIIb) The invention further provides compound, useful as hypoglycemic agents, of general formula (XIIIa):

wherein R1-R4, R8-R13, m and o are defined above for formula (XIIIa), or pharmaceutically acceptable salts or compound having a tautomeric structure thereof.

In addition, the present invention provides compositions comprising a compound of formula (XIIIb) or a pharmaceutically acceptable salt or a compound having a tautomeric structure thereof for use as hypoglycemic agents, as well as methods for their use, the compound of formula (XIIIb) having the structure: wherein R,-R4, R.-Rl3, m and o are defined above for formula (XIII).

The invention also relates to the tautomeric forms and to the enantiomers, diastereoisomers and epimers of the compound of general formula (XIIIa) and (XIIIb).

The compound of general formula (XIIIa) and (XIIIb) which may possess a carboxylic acid functional group

can be salifie, i. e. , converted into conjugate bases they then being in the form of salts with bases.

Examples of salts with bases of the compound of general formula (XIIIa) and (XIIIb) include the pharmacologically acceptable salts, such as the sodium salts, potassium salts, calcium salts and other salts of the same type.

The compound of general formula (XIIIa) and (XIIIb) which possess a carboxyllic acid functional group can also be salifie with amines in order to form pharmaceutically acceptable salts. By way of example, the compound of general formula (XIIIa) and (XIIIb) could be salifie with glucamine, N-methylglucamine, N, N- dimethylglucamine, ethanolamine, morpholine, Ni methylmorpholine or lysine.

The compound of general formulas (XIIIa) and (XIIIb) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids. Examples of salts with acids of the compound of general formulas (XIIIa) and (XIIIb) include the pharmaceutically acceptable salts, such as, and non-exhaustively, the hydrochloride, the hydrobromide, the sulphate, the succinate, maleate, fumarate, malate or tartrate and the sulphonates, such as the methanesulphonate, the benzenesulphonate or the toluenesulphonate.

Among the compound of the general formula (XIIIa) according to the invention, there may be mentioned more particularly, as preferred compound: 2- ( ( (4- (2-Pyridyl) piperazin-1-yl) acetyl) amino)-6- fluorobenzothiazole, 2-(((4-(2-Fluorophenyl)piperazin-1- yl) acetyl) amino)-6-fluorobenzothiazole, 2- ( ( (4- (2-Pyridyl) piperazin-1-yl) acetyl) amino)-6- methoxybenzothiazole, 2-(((4-(2-Pyrimidyl)piperazin-1-yl)acetyl)amino)-6- methoxybenzothiazole,

2- ( ( (4- (Benzyl) piperazin-1-yl) acetyl) amino)-6- methoxybenzothiazole, 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-6-methoxybenzothiazole, 2-(((4-(2-Pyridyl)piperazin-1-yl)acetyl)amino-4- methoxybenzothiazole, 2-(((4-(4-Methoxyphenyl)piperazin-1- yl) acetyl) amino)-6-fluoro-benzothiazole, 2- ( ( (4- ( (2-Pyridyl) piperazin-1-yl) acetyl) amino)-6- ethoxybenzothiazole, 2- (((4-(3-(Trifluoromethyl)(((4-(3-(Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-6-ethoxybenzothiazole, 2-(((4-(3-Chlorophenyl)piperazin-1- yl) acetyl) amino)-6-methoxybenzothiazole, 2- ( ( (4- (3-Bromophenyl) piperazin-1-yl) acetyl) amino)- 6-methoxybenzothiazole, 2- ( ( (4- (3-Nitrophenyl) piperazin-1-yl) acetyl) amino)- 6-methoxybenzothiazole, 2-(((4-((2-Pyridyl)piperazin-1-yl)acetyl)amino)-6- ethoxybenzothiazole Hydrochloride, 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-6-ethoxybenzothiazole Hydrochloride, 2- ( ( (4- (4- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-6-methoxybenzothiazole, 2-(((4-(3-Methylphenyl)piperazin-1- yl) acetyl) amino)-6-methoxybenzothiazole, 2-(((4-(3-Cyanophenyl)piperazin-1-yl)acetyl)amino)- 6-methoxybenzothiazole, 2- ( ( (4- (4-Bromo-3-trifluoromethylphenyl) piperazin- 1-yl)acetyl)amino)-6-methoxybenzothiazole, 2-(((4-(4-Chlorobenzhydryl)piperazin-1- yl) acetyl) amino)-6-methoxybenzothiazole, 2-(((4-(3-Ethylphenyl)piperazin-1-yl)acetyl)amino)- 6-methoxy benzothiazole, 2- ( ( (4- (2-Naphthyl) piperazin-1-yl) acetyl) amino)-6- methoxybenzothiazole,

2- ( ( (4- (3-Methoxyphenyl) piperazin-1- yl)acetyl)amino)-6-methoxybenzothiazole, 2- ( ( (4- (3-Methoxy-5- trifluoromethylphenyl) piperazin-1-yl) acetyl) amino)-6- methoxybenzothiazole, 2- ( ( (4- (3,5-Dichlorophenyl)piperazin-1- yl) acetyl) amino)-6-methoxybenzothiazole, _ 2- ( ( (4- (3,4-Dichlorophenyl)piperazin-1- yl) acetyl) amino)-6-methoxybenzothiazole The invention also relates to a process for the preparation of the compound of general formulas (XIIIa) and (XIIIb). A preparation process according to. the invention comprises the rection of an aromatic amine of general formula (A1):

in which Ru, R2, R3, R4, R8, Rg, and m are as defined above for formulas (XIIIa) and (XIIIb), with a haloacyl halide of general formula (IXa):

in which Rio and R3., are as defined above for formulas (XIIIa) and (XIIIb), Hal represents a chlorine or bromine atom, in order to form a compound of general formula (XVII);

in which R1, R2, R3, R4, R8, R9, R10, R11 and m are as defined above for formulas (XIIIa) and (XIIIb), and Hal is as defined above; and the rection of the compound of general formula (XVII) with a compound of general formula (XVIII): in which Rlz, R13, and o are as defined above for formulas (XIIIa) and (XIIIb), in the presence of a basic agent, such as triethylamine or potassium carbonate in order to form the compound of general formulas (XIIIa) and (XIIIb):

in which R1, R2, R3, R4, R8, R9, R10, R11, R12, R13, m and o are as defined above for formulas (XIIIa) and (XIIIb), and Hal is as defined above; Benzothiazoles can be prepared according to methods described by P. T. S. Lau [P. T. S. Lau and T. E. Gompf, J. Org.

Chem., Vol. 35, No. 12, 1970] ; T. Mase [T. Mase, H. Arima, K.

Tomioka, T. Yamada and K. Murase, J. Med. Chem., 1986,29, 386-394] ; Wel'tman [Wel'tman Ukr. Khim. Zh., 22,1956,363- 365, Chem. Abstr. 1957, 4358] ; P. K. Srivastava [P. K.

Srivastava and P. N. Srivastava, J. Med. Chem., 1970, Vol. 13, No. 5; P. K. Srivastava and S. K. Rai, The Quarterly Journal of Surgical Sciences, Vol. 15, No. 2, pp. 73-76 (1979)] ; Murayama M. [Murayama, M., Inoue, S., Ohata, K., Tsutsui, S.

JP 48076866; Murayama, M., Inoue, S., Ohata, K., Sugawara, Y, Tsutsui, S., JP 7368566, 1973] ; J. S. Upadhyaya (J. S.

Upadhyaya, Indian J. Pharm. Sci., 1980,43, pp. 133-135] ; E.

Cullen [E. Cullen, R. Becker, K. Freter, T. LeClerge, G.

Possanza, H-Ch. Wong, J. Med. Chem., 1992,35, 350-361] ; H. P.

Kaufmann [H. P. Kaufmann, Archiv der Pharmazie und Bericht der Deutschen Pharm. Gesselschaft, 203-215, 1928] ; and E. Cullen et al. [E. Cullen et al., DE 2833671 A1,1978; E. Cullen et al. DE 2736652 A1, 1977).

The compound of formula (XVIII) can be prepared as described by R. Ratouis et al. (J. Med. Chem., 8,104,1965) or by Prelog et al. (Collection Czechoslov. Chem.

Communications, 6, 211, 1934).

Compound of formula (XVIII) can also be made according to the following methods: M. Dukat [M. Dukat, A. A. Abdel-Rahman, A. M.

Ismaiel, S. Ingher, M. Futler, L. Gyermak, R. A. Glennon,. J.

Med. Chem 1996,39, 4017-4026] ; P. C. Unangst [P. C. Unangst, T. Capiris, D. T. Connor, Th. G. Heffner, R. G. MacKenzie, St.

R. Miller, Th. A. Pugsley, L. D. Wise, J. Med. Chem, 1997,40, 2688-2693] ; W. C. Lumma [W. C. Lumma, W. S. Saari, U. S. Patent 4,078,063, 1978] ; Prelog, V. [Prelog, V., Driza, G. J., Collet. Czech. Chem. Commun., 1933,5,497-502]; H. Prunier [H. Prunier, S. Ravet, J.-Ch. Lancelot, M. Robba et al., J.

Med. Chem, 1997,40, 1808-1819] ; P. A. J. Janssen [P. A. J.

Janssen, U. S. Patent 2,985,657, 1961] ; Yevich, J. P. [Yevich, J. P., New, J. S., Smith, D., Lobech, W. G. et al., J. Med.

Chem. 1986,29, 359-369] ; R. Henning [R. Hennin, R.

Lattrell, H. J. Gerhards, M. Leven, J. Med. Chem., 1987,30, 814-819] ; T. R. Elworthy. [T. R. Elworthy, A. P. D. W. Ford, G. W.

Bantle, D. J. Morgans, Jr., R. S. Ozer et al., J. Med. Chem., 1997,40,2674-2687]; G. S. Poindexter [G. S. Poindexter, M. A.

Bruce, K. L. LeBoulluee, I. Menkovic Tetrahedron Letters, Vol.

35, No. 40, pp. 7331-7334,1994]; and Wolfe and Buchwald [Wolfe, J. P., Buchwald, S. L., J.. Org. Chem. 1997,62,1264- 1267.

5.4 COMPOUND OF FORMULAS (XIVa) AND (XIVb) The invention further. provides compound, useful as hypoglycemic agents, of general formulas (XIVa) and (XIVb):

wherein Rl, Re-R13, m, n and o are defined above, and pharmaceutically acceptable salts and tautomeric structures

thereof, with the proviso that the compound of formula (XIVa) is not: #2-(((4-(phenyl)piperazinly-1-)acetyl)amino)-4- ((carboethoxy) methyl) thiazole; or 2- ( ( (4- (2-fluorophenyl) piperazinyl-1)- acetyl) amino)-4- ( (carboethoxy) methyl) thiazole.

In addition, the present invention provides compositions comprising a compound of formula (XIVb) or a pharmaceutically acceptable salt or tautomeric structure thereof for use for use as hypoglycemic agents, as well as methods for their use, the compound of formula (XIVb) having the structure: wherein R1, R8-R13, n, m and o are as defined above for formula (XIVb), with the proviso that the compound of formula (XIVb) is not: 2-(((4-(phenyl)piperazinly-1-)acetyl)amino)-4- ((carboethoxy) methyl) thiadiazole; 2-(((4-(2-fluorophenyl)piperazinyl-1)- acetyl) amino)-4- ( (carboethoxy) methyl) thiazole; or The compound of general formulas (XIVa) and (XIVb), may possess a carboxylic acid functional group and can be salifie, i. e., converted into conjugate bases they then being in the form of salts with bases.

Examples of salts with bases of the compound of general formulas (XIVa) and (XIVb) include the pharmacologically acceptable salts, such as the sodium salts, potassium salts, calcium salts and other salts of the same type.

The compound of general formulas (XIVa) and (XIVb) which possess a carboxyllic acid functional group may also be salifie with amines in order to form pharmaceutically acceptable salts. By way of example, the compound of general formulas (XIVa) and (XIVb), could be salifie with glucamine, N-methylglucamine, N, N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.

The compound of general formulas (XIVa) and (XIVb), possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids. Examples of salts with acids of the compound of general formulas (XIVa) and (XIVb), include the pharmaceutically acceptable salts, such as, and non-exhaustively, the hydrochloride, the hydrobromide, the sulphate, the succinate, maleate, fumarate, malate or tartrate and the sulphonates, such as the methanesulphonate, the benzenesulphonate or the toluenesulphonate.

Among the compound of the general formulas (XIVa) and (XIVb) according to the invention, there may be mentioned more particularly, as preferred compound:

2- ( ( (4- (Phenyl) piperazin-1-yl) acetyl) amino)-4- (carboxymethyl) thiazole, 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-4- (carboxymethyl) thiazole, 2-(((4-(2-Fluorophenyl)piperazin-1- yl) acetyl) amino)-4- (carboxymethyl) thiazole, 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-4- (carboethoxymethyl) thiazole, 4- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-1- ( (N'- (2-thiazolyl)) sulfonamido) benzene, 2-(((4-(5-(Trifluoromethyl)pyrid-2-yl)piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole, 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-4-(carboxymethyl) thiazole, sodium salt, 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-4-(carboxymethyl) thiazole, potassium salt,

4- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-l- ( (N'- (2-thiazolyl)) sulfonamido) benzene, hydrochloride salt, 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-4-(carbomethoxymethyl) thiazole, 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-4- (carboxymethyl) thiazole, hydrochloride salt, 2- ( ( (4- (4- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole, 2- ( ( (4- (4- (carbomethoxy) phenyl) piperazin-1- yl) acetyl) amino)-4-(carboxyethoxymethyl)thiazoi e, 2-(((4-(3-Chlorophenyl)piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole, 2-(((4-(3-Bromophenyl) piperazin-1-yl) acetyl) amino)- 4-(carboethoxymethyl)thiazole, 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-4-thiazole glyoxylate, 2- ( ( (4- (3- (Methyl) phenyl) piperazin-1- yl) acetyl) amino)-4-carboethoxy) methyl) thiazole, 2- ( ( (4- (3- (trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-4-(carbopropoxymethyl) thiazole, 2- ( ( (4- (3- (trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-4-(carbobutoxy) methyl) thiazole, 2- ( ( (4- (3- (trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-4-(carboisopropoxymethyl) thiazole, 2- ( ( (4- (4-Chloro-3- (trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-4- (carboethoxymethyl) thiazole, 2- ( (4- ( (4-Chlorobenzhydryl) phenyl) piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole, 2- ( ( (4- (3-Ethylphenyl) piperazin-1-yl) acetyl) amino)- 4-(carboethoxymethyl)thiazole, 2- ( ( (4- (2-Naphthyl) piperazin-1-yl) acetyl) amino)-4- (carboethoxymethyl) thiazole, 2-(((4-(3-Methoxyphenyl)piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole,

2- ( ( (4- (3, 5-Bis- (trifluoromethyl) phenyl) piperazin- 1-yl) acetyl) amino)-4-(carboethoxymethyl) thiazole, 2- ( ( (4- (3,5-Dichlorophenyl)piperazin-1- yl) acetyl) amino)-4-(carboethoxy) thiazole, 2- ( ( (4- (3,4-Dichlorophenyl)piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole, 2- ( ( (4- (3-Methoxy-5- (trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-4- ( (carboethoxy) methyl) thiazole.

The invention also relates to a process for the preparation of the compound of general formulas (XIVa) and (XIVb). A preparation process according to the invention comprises the rection of an aromatic amine of general formula (A2): in which Rl, Re, Rg, m, and n are as defined above for formulas (XIVa) and (XIVb), with a haloacyl halide of general formula (XIX): in which R10 and Rll are as defined above for formulas (XIVa) and (XIVb), Hal represents a chlorine or bromine atom, in order to form a compound of general formula (XX):

in which Rl, R8, R9, R10, R11, m, and n are as defined above for formulas (XIVa) and (XIVb), and Hal is as defined above, and the rection of the compound of general formula (XX) with a compound of general formula (XXI): in which R12, R13 and o are as defined above for formulas (XIVa) and (XIVb), in the presence of a basic agent, such as triethylamine or potassium carbonate in order to form the compound of general formulas (XIVa) and (XIVb):

in which R1, R8, R9, R10, R11, R12, R13, m, n and o are as defined above for formulas (XIVa) and (XIVb), and Hal is as defined above: Thiazoles can be obtained according to procedures described by P. Lesimple [P. Lesimple, Dennis C. W., Bigg, Synthesis, 763-764,1991]; S. C. Mehra [S. C. Mehra and S.

Zaman, Journal of Chemical and Engineering Data, Vol. 23, No.

1, pp. 89-90, 1978] ; H. Kanno [H. Kanno, K. Osanai, T. Nishi et al. Bioorganic and Medicinal Chemistry Letters, Vol. 6, No. 13, pp. 1487-1490,1996]; M. Bachir [M. Bachir, J.-P.

Riffaud, J.-Y Lacotte, J. Lemoine, A. de Almeida, P.

Mouziaux, B. Dannee, Eur. J. Med. Chem., 25,71-74, 1990] ; M.

Chiai [M. Ochiai, A. Marimoto, Y. Matsushita and T. Okada, The Journal of Antibiotics, 160-170, Feb. 1981] ; K. D. Hardy [K. D. Hardy, F. P. Harrington and A. V. Stachulski, J. Chem.

Soc. Perkin Trans., 1,1227-1235, 1984] ; and R. A. Parent [R. A. Parent, J. Org. Chem., 1962,27, 2282-2283].

The compound of formula (XXI) can be prepared as described by R. Ratouis et al. (J. Med. Chem., 8,104,1965) or by Prelog et al. (Collection Czechoslov. Chem.

Communications, 6,211,1934).

Compound of formula (XXI) can also be made according to the following methods: M. Dukat [M. Dukat, A. A. Abdel-Rahman, A. M.

Ismaiel, S. Ingher, M. Futler, L. Gyermak, R. A. Glennon, J.

Med. Chem., 1996,39,4017-4026]; P. C. Unangst [P. C. Unangst, T. Capris, D. T. Connor, Th. G. Heffner, R. G. MacKenzie, St. R.

Miller, Th. A. Pugsley, L. D. Wise, J. Med. Chem., 1997,40, 2688-2693]; W. C. Lumma [W. C. Lumma, W. S. Saari, U. S. Patent 4,078,063, 1978] ; Prelog, V. [Prelog, V., Driza, G. J., Collet. Czech. Chem. Commun., 1933,5, 497-502] ; H. Prunier [H. Prunier, S. Ravet, J-Cl. Lancelot, M. Robba et al., J.

Med. Chem., 1997,40, 1808-1819] ; P. A. J. Janssen [P. A. J.

Janssen, U. S. Patent 2,985,657, 1961] ; Yevich, J. P. [Yevich, J. P, New, J. S., Smith, D., Lobeck, W. G. et al., J. Med.

Chem., 1986,29,359-369]; R. Henning [R. Hennin, R.

Lattrell, H. J. Gerhards, M. Leven, J. Med. Chem., 1987,30,

814-819]; T. R. Elworthy [T. R. Elworthy, A. P. D. W. Ford, G. W.

Bantle, D. J. Morgans, Jr., R. S. Ozer et al., J. Med. Chem., 1997,40, 2674-2687] ; G. S. Poindexter [G. S. Poindexter, M. A.

Bruce, K. L. LeBoulluee, I. Menkovic Tetrahedron Letters, Vol. 35, No. 40, pp. 7331-7334,1994]; and Wolfe and Buchwald [Wolfe, J. P., Buchwald, S. L., J. Orn. Chem., 1997,62,1264- 1267].

5.5 COMPOUND OF FORMULAS (XVa) AND (XVb) The invention further provides compound, useful as hypoglycemic agents, of general formula (XVa):

wherein R1, R8-Rl3, m, o, X,. and X2 are as defined above for formula (XVa), or pharmaceutically acceptable salts or compound having a tautomeric structure thereof, with the proviso that the compound of formula (XVa) is not: 2- ( ( (4- (3- (trifluoromethyl) phenyl) piperazinyl-1)- acetyl) amino)-S- ( (ethoxycarbonyl)-methyl)-1,3,4-thiadiazole; 2-(((4-(2-pyridyl)piperazinyl-1)-acetyl)amino)-5- ((carbomethoxy) methyl)-1,3,4-thiadiazole; or 2-(((4-(3-(trifluoromethyl)phenyl)piperazinyl-1)- acetyl) amino)-5- (2-(carboxy) ethyl)-1,3,4-thiadiazole.

In addition, the present invention provides compositions comprising a compound of formula (XVb) or a pharmaceutically acceptable salt or tautomeric structure thereof for use for use as hypoglycemic agents, as well as methods for their use, the compound of formula (XVb) having the structure:

wherein R1, R8-Rl3, m, o, Xl and X2 are as defined above for formula (XVb), or a pharmaceutically acceptable salt or compound having a tautomeric structure thereof, with the proviso that the compound of formula (XVb) is not: 2- (((4-(3-(trifluoromethyl)(((4-(3-(trifluoromethyl) phenyl) piperazinyl-1)- acetyl) amino)-5- ((ethoxycarbonyl)-methyl)-1, 3,4-thiadiazole; 2- ( ( (4- (2-pyridyl) piperazinyl-1)-acetyl) amino)-5- ( (carbomethoxy) methyl)-1,3,4-thiadiazole; or 2- ( ( (4- (3- (trifluoromethyl) phenyl) piperazinyl-1)- acetyl) amino)-5- (2- (carboxy) ethyl)-1,3, 4-thiadiazole.

The invention also relates to the tautomeric forms and to the enantiomers, diastereoisomers and epimers of the compound of general formulas (XVa) and (XVb).

The compound of general formulas (XVa) and (XVb) may possess a carboxylic acid functional group and can be salifie, i. e., converted into conjugate bases they then being in the form of salts with bases.

Examples of salts with bases of the compound of general formulas (XVa) and (XVb) include the pharmacologically acceptable salts, such as the sodium salts, potassium salts, calcium salts and other salts of the same type.

The compound of general formulas (XVa) and (XVb) which possess a carboxylic acid functional group may also be salifie with amines in order to form pharmaceutically acceptable salts. By way of example, the compound of general formulas (XVa) and (XVb) could be salifie with

glucamine, N-methylglucamine, N, N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.

The compound of general formulas (XVa) and (XVb) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids. Examples of salts with acids of the compound of general formulas (XVa) and (XVb) include the pharmaceutically acceptable salts, such as, and non-exhaustively, the hydrochloride, the hydrobromide, the sulphate, the succinate, maleate, fumarate, malate or tartrate and the sulphonates, such as the methanesulphonate, the benzenesulphonate or the toluenesulphonate.

Among the compound of the general formula (XVa) according to the invention, there may be mentioned, more particularly, as preferred compound: 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl)acetyl)amino)-5-((7-chloroquinolin-4-yl)thio)-1,3,4- thiadiazole, 2- ( ( (-4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-5-cyclopropyl-1,3,4-thiadiazole,

2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl)amino)-5-((carbomethoxy) methyl)-1,3,4-thiadiazole, 2-(((4-(4-Methoxyphenyl)piperazin-1- yl) acetyl) amino)-5-carbomethoxymethyl-1,3,4-thiadiazole, 2- ( ( (-4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-5- (2-(carbomethoxy) ethyl)-1, 3,4-thiadiazole, 2-(((4-(4-Methoxyphenyl)piperazin-1- yl) acetyl) amino)-5- (2- (carbomethoxy) ethyl)-1,3,4-thiadiazole, 2-(((4-(2-Pyridyl) piperazin-1-yl) acetyl) amino)-5- (2-(carbomethoxy) ethyl)-1,3,4-thiadiazole, Among the compound of the general formula (XVb) according to the invention, there may be mentioned, more particularly, as preferred compound: 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl)acetyl)amino)-5-((7-chloroquinolin-4-yl)thio)-1,3,4- thiadiazole,

2-(((-4-(3-Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-5-cyclopropyl-1,3,4-thiadiazole, 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl)acetyl)amino)-5-((carbomethoxy)methyl)-1,3,4-thiadiazole, 2-(((4-(4-Methoxyphenyl)piperazin-1- yl) acetyl) amino)-5-carbomethoxymethyl-1,3,4-thiadiazole, 2-(((-4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-5-(2-(carbomethoxy) ethyl)-1,3,4-thiadiazole, 2-(((4-(4-Methoxyphenyl)piperazin-1- yl) acetyl) amino)-5-(2-(carbomethoxy) ethyl)-1,3,4-thiadiazole, 2- ( ( (4- (2-Pyridyl) piperazin-1-yl) acetyl) amino)-5- (2-(carbomethoxy) ethyl)-1,3,4-thiadiazole, 2-(((4-(3-Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-5-trifluoro-methyl-1, 3,4-thiadiazole, 2-(((4-(2-Fluorophenyl)piperazin-1- yl) acetyl) amino)-5-trifluoromethyl-1,3,4-thiadiazole, 2-(((4-(4-Methoxyphenyl)piperazin-1- yl) acetyl) amino)-5- (trifluoromethyl)-1,3,4-thiadiazole, 2- ( ( (4- (2-Pyridyl) piperazin-1-yl) acetyl) amino)-5- (trifluoromethyl)-1,3,4-thiadiazole, 2- ( ( (4- (2-Pyrimidyl) piperazin-1-yl) acetyl) amino)-5- (trifluoromethyl)-1,3,4-thiadiazole, 2- ( ( (4- (2-Pyridyl) piperazin-1-yl) acetyl) amino)- 1, 3, 4-thiadiazole, 2-(((4-(3-Chlorophenyl)piperazin-1- yl) acetyl) amino)-5-trifluoremethyl-1,3,4-thiadiazole, 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-5-ethyl-1,3, 4-thiadiazole, 2-(((-4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl1) acetyl) amino)-1,3,4-thiadiazole, 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-5-bromo-1,3,4-thiadiazole.

The invention also relates to a process for the preparation of the compound of general formulas (XVa) and (XVb). A preparation process according to the invention comprises the rection of an aromatic amine of general formula (A3):

in which R1, R8, R9, X1, X2 and m are as defined above for formulas (XVa) and (XVb), with a haloacyl halide of general formula (XXII): in which R1o and Roll, are as defined above for formulas (XVa) and (XVb), Hal represents a chlorine or bromine atom, in order to form a compound of general formula (XXIII); in which R1, R8, R9, R10, R11, X1, X2 and m are as defined above for formulas (XVa) and (XVb), and Hal is as defined above; and the rection of the compound of general formula (XXIII) with a compound of general formula (XXIV):

in which R. 21 R13 and o are as defined above for formulas (XVa) and (XVb), in the presence of a basic agent, such as triethylamine or potassium carbonate in order to form the compound of general formulas (XVa) and (XVb): in which Rl, R8, R9, R10, R11, R12, R13, m and o are as defined above for formulas (XVa) or (XVb), and Hal is as defined above; Thiadiazoles can be prepared according to A. W.

White [H. D. White, M. W. Creswell, A. W. Chucholowski, C. J.

Blankley, M. W. Wilson et al., J. Med. Chem., 1996,39,4382- 43951; G. Werber [G. Werber, F. Magio, Anal. Chim. (Rome), 1962,52,3-13; Annali di Chimica, Vol. LIII, pp. 3-13 (1963)] ; G. Maffii [G. Maffii, E. Testa, R. Ettor., Il Farmaco-Ed. Sci., Vol. XIII, fasc. 3, pp. 187-217,19571; V. J. Ram [V. J. Ram, A. Goel, M. Kandpal, N. Mittal et al., Bioorganic and Medicinal Chemistry Letters, Vol. 7, No. 6, pp. 651-656,19971; N. K. Srivastava [N. K. Srivastava, P. K.

Khare, H. Singh, Bulletin of the Polish Academy of Sciences,

Vol. 43, No. 2, pp. 113-120, 1995] ; V. I. Kabachnyi [Kabachnyi, V. I., Chernyk, V. P, et al., Farmakol. Toksikol (Moscow) 1987, pp. 678-680] ; J. Grebin [Grebin, J., EP 0471609 B1]; Shiokawa, Y. [Shiokawa Y., WO 93/09101, 1993] ; Leeds, W. G. [Leeds, W. G., Parnell, E. W., DE 2336407, 1973] ; D. Spinelli [D. Spinelli, J. Org. Chem., 43 (21), 4042-4044, 1978; D. Spinelli, R. Noto, G. Consiglio, F. Buccheri, J.

Heterocycl. Chem., 14 (2), 309-11, 1977] ; Li, Zengmin [Li, Zengmin, Hu, Bingfang, Chinese Journal of Applied Chemistry, 5 (4), 54-57 (1988)] ; W. Wislicenus [W. Wislicenus, Chem. Ber.

43, N. 3,6528-6533 (1910) 1; T. Hirata [T. Hirata, S. Goto, K.

Tamura, M. Okuhira, Y. Nagåo, Bioorganic and Medicinal Chemistry Letters, Vol. 7, No. 4, pp. 385-388, 1997].

Thiadiazoles can also be prepared according to E.

Akerblom [E. Akerblom, Acta. Chem. Scand. 18,174-184 (1964)]; Sh. A. Shams El-Dine (Sh. A. Shams El-Dine and O.

Clauder, Acta. Chimica Academiae Scientiarum Hungaricae, tomus 84 (1), pp. 85-91 (1975)] ; G. Werber [G. Werber, F.

Buccheri, M. Gentile, J. Heterocyclic Chem., 14,823-827

(1977)] ; J. Gut [J. Gut, Collection Czechoslov. Chem.

Commun., Vol. 23,1588-1591 (1958)].

1,2,4-Thiadiazoles can be obtained according to K.

Tatsuta [K. Tatsuta, S. Miura, M. Gunji, Tetrahedron Letters, Vol. 34, No. 40, pp. 6423-6426, 1993] ; G. Macaluso [G.

Macaluso, G. Cusmano, S. Buscemi et al., Heterocycles, Vol.

24, No. 12,3433-3439, 1986] ; N. Vivona (N. Vivona, G.

Cusmano, G. Macaluso J. C. S. Perkin I, 1616-1619, 1977] ; K.

Tatsuta [K. Tatsuta, S. Miura, M. Gunji et al., Bull. Chem.

Soc. Jpn., 67,1701-1707 (1994)]; M. Ruccia [M. Ruccia and N.

Vivona Adv. Het. Chem., 29,141-169 (1981)].

The compound of formula (XXIV) can be prepared as described by R. Ratouis et al. (J. Med. Chem., 8,104,1965) or by Prelog et al. (Collection Czechoslov. Chem.

Communications, 6,211,1934).

Compound of formula (XXIV) can also be made according to the following methods:

M. Dukat [M. Dukat, A. A. Abdel-Rahman, A. M.

Ismaiel, S. Ingher, M. Futler, L. Gyermak, R. A. Glennon, J.

Med. Chem., 1996,39,4017-4026]; P. C. Unangst [P. C. Unangst, T. Capiris, D. T. Connor, Th. G. Heffner, R. G. MacKenzie, St.

R. Miller, Th. A. Pugsley, L. D. Wise, J. Med. Chem., 1997, 40, 2688-2693] ; W. C. Lumma [W. C. Lumma, W. S. Saari, U. S.

Patent 4,078,063, 1978] ; Prelog, V. [Prelog, V. Driza, G. J., Collet. Czech. Chem. Commun., 1933,5, 497-502] ; H. Prunier [H. Prunier, S. Ravet, J-Cl. Lancelot, M. Robba et al., J.

Med. Chem., 1997,40, 1808-1819] ; P. A. J. Janssen [P. A. J.

Janssen, U. S. Patent 2,985,657, 1961] ; Yevich, J. P. [Yevich, J. P.; New, J. S., Smith, D., Lobeck, W. G. et al., J. Med.

Chem., 1986,29, 359-369] ; R. Henning [R. Hennin, R.

Lattrell, H. J. Gerhards, M. Levez ; J. Med. Chem., 1987,30, 814-819] ; T. R. Elworthy [T. R. Elworthy, A. P. D. W. Ford, G. W.

Bantle, D. J. Morgans, Jr., R. S. Ozer et al., J. Med. Chem., 1997,40, 2674-2687] ; Gr. S. Poindexter (G. S. Poindexter, M. A. Bruce, K. L. LeBoulluec, I. Monkovic Tetrahedron Letters, Vol. 35, No. 40, pp. 7331-7334, 1994] ; and Wolfe and Buchwald [Wolfe, J. P., Buchwald, S. L., J. Org. Chem., 1997, 62,1264-1267].

5.6 COMPOUND OF FORMULAS (XVIa) and (XVIb) The invention further provides compound, useful as hypoglycemic agents, of general formula (XVIa): wherein Rl-R3, Re-R13, m and o are as defined above for formula (XVIa), or pharmaceutically acceptable salts or compound having a tautomeric structure thereof.

In addition, the present invention provides compositions comprising a compound of formula (XVIb) or a pharmaceutically acceptable salt or tautomeric structure thereof for use for use as hypoglycemic agents, as well as methods for their use, the compound of formula (XVIb) having the structure:

wherein R1-R3, R8-R13, m and o are as defined above for formula (XVIb), or pharmaceutically acceptable salts or compound having a tautomeric structure thereof.

The invention also relates to the tautomeric forms and to the enantiomers, diastereoisomers and epimers of the compound of general formulas (XVIa) and (XVIb).

The compound of general formulas (XVIa) and (XVIb) may possess a carboxylic acid functional group and can be salifie, i. e., converted into conjugate bases they then being in the form of salts with bases.

Examples of salts with bases of the compound of general formulas (XVIa) and (XVIb) include the pharmacolog- ically acceptable salts, such as the sodium salts, potassium salts, calcium salts and other salts of the same type.

The compound of general formulas (XVIa) and (XVIb) which possess a carboxylic acid functional group may also be salifie with amines in order to form pharmaceutically acceptable salts. By way of example, the compound of general formulas (XVIa) and (XVIb) could be salifie with glucamine, N-methylglucamine, N, N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.

The compound of general formulas (XVIa) and (XVIb) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids. Examples of salts with acids of the compound of general formulas (XVIa)

and (XVIb) include the pharmaceutically acceptable salts, such as, and non-exhaustively, the hydrochloride, the hydrobromide, the sulphate, the succinate, maleate, fumarate, malate or tartrate and the sulphonates, such as the methanesulphonate, the benzenesulphonate or the toluenesulphonate.

Among the compound of the general formula (XVIa) and (XVIb) according to the invention, there may be mentioned, more particularly, as preferred compound: 3-(((4-(2-Fluorophenyl)piperazin-1- yl) acetyl) amino)-2- (carbomethoxy)-thiophene, 3-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-2- (carbomethoxy) thiophene, 3-(((4-(5-(Trifluoromethyl) pyrid-2-yl) piperazin-l- yl) acetyl) amino)-2- (carbomethoxy) thiophene, 3- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino)-2- (carbomethoxy) thiophene Hydrochloride, 3- ( ( (4- ( (4-chlorobenzhydryl) phenyl) piperazin-1- yl) acetyl) amino)-2- (carbomethoxy) thiophene, 3- ( ( (4- (2- (Trifluoromethyl) quinolin-4-yl) piperazin- 1-yl) acetyl) amino)-2-(carbomethoxy) thiophene.

The invention also relates to a process for the preparation of the compound of general formulas (XVIa) and (XVIb). A preparation process according to the invention comprises the rection of an aromatic amine of general formula :

in which R1, R2, R3, R8, R9 and m are as defined above for formulas (XVIa) and (XVIb), with a haloacyl halide of general formula (XXV):

in which Rlo and Rll are as defined above for formulas (XVIa) and (XVIb), Hal represents a chlorine or bromine atom, in order to form a compound of general formula (XXVI); in which R1, R2, R3, R8, R9, R10, Rll and m are as defined above for formulas (XVIa) and (XVIb) and Hal is as defined above; and the rection of the compound of general formula (XXVI) with a compound of general formula (XXVII): in which R12, R13, and o are as defined above for formulas (XVIa) and (XVIb), in the presence of a basic agent, such as triethylamine or potassium carbonate in order to form the compound of general formulas (XVIa) and (XVIb):

(XVIa) and (XVIb) in which Ru, R2, R3, R8, R9, R10, R11, R12, R13, m and o are as defined above for formulas (XVIa) and (XVIb); Thiophene acids can be prepared according to the method of O. Dann [O. Dann, Chem. Ber., 1943,76,419]; R. B.

Woodward [R. B. Woodward, R. H. Eastmanj J. Amer. Chem. Soc., 1946,68, 2229] ; B. R. Baker [B. R. Baker, J. P. Joseph, R. E.

Schaub et al., J. Org. Chem., 1953,18, 138-152] ; Ya. L.

Gol'dfarb [Ya. L. Gol'dfarb, V. N. Bulgakova and B. P.

Fabrichnyi, Khimiya Geterosikl. Soedin, No. 12, pp. 1626- 1629,1983 (Russ), 1283-1286 (1984) (Engl)]; Ya. L. Gol'dfarb [Ya. L. Gol'dfarb, B. P. Fabrichnyi, and I. F. Shalavina, Zh.

Obshch. Khim. 1959,29, 3636] ; F. Jung [F. Jung, WO 93/19070, 1993] ; I. J. Rinkes [I. J. Rinkes, J. Rec. Trav. Chim., 1932, 51, 1134] ; H. Fiesselman [H. Fiesselman, P. Schipprak, L.

Zeitler, Chem. Ber., 87, No. 6,835-848, 1954]. Thiophenes can also be prepared according to K. Satto [K. Satto, S.

Kambe, Synthesis 1056-1059, 1982] ; M. Perrissin [M.

Perrissin, Cuong Lieu Duc, Eur. J. Med. Chem., 1980, No. 6, pp, 563-565] ; J. M. Barker [J. M. Barker, P. R. Huddleston, D.

Holmes, J. Chem. Res. (M) 1986,1462-1470]; T. Masquelin (T.

Masquelin, D. Obrecht, Tetrahedron. Letters, Vol. 35, No. 50, pp. 9387-9390, 1994] ; F. Bohlmann [F. Bohlmann, E.

Bressinsky, Chem. Ber., 97,2109-2117 (1964)]; U. S. Pathak [U. S. Pathak, R. S. ratel and S. Singh, Indian J. Pharm. Sci.,

1991,53 (3), pp. 85-87]; K. Gewald [K. Gewald, E. Schinke, M.

Böttcher, Chem. Ber., 99, No. 1,94-100, 1966] ; J. M. Barker [J. M. Barker, P. R. Huddleston, D. Holmes, J. Chem. Research (5), 1986]. 2,3,5-Trisubstituted thiopenes can be prepared according to D. Obrecht [D. Obrecht, F. Gerber, D. Sprenger, T. Masquelin, Helv. Chim. Acta, Vol. 80,531-537. : 19971.

The compound of formula (XXVII.) can be prepared as described by R. Ratouis et al. (J. Med. Chem., 8,104,1965) or by Prelog et al. (Collection Czechoslov. Chem.

Communications, 6,211, 1934).

Compound of formula (XXVIII) can also be made according to the following methods: M. Dukat [M. Dukat, A. A. Abdel-Rahman, A. M.

Ismaiel, S. Ingher, M. Futler, L. Gyermak, R. A. Glennon, J.

Med. Chem. 1996,39, 4017-4026] ; P. C. Unangst [P. C. Unangst, T. Capiris, D. T. Connor, Th. G. Heffner, R. G. MacKenzie, St R. Miller, Th. A. Pugsley, L. D. Wise, J. Med. Chem., 1997,40, 2688-2693] ; W. C. Lumma [W. C. Lumma, W. S. Saari, U. S. Patent 4,078, 063, 1978] ; Prelog, V. [Prelog, V., Driza, G. J., Collect, Czech. Chem. Commun., 1933,5, 497-502] ; H. Prunier

[H. Prunier, S. Ravet, J.-Cl. Lancelot, M. Robba et al., J.

Med. Chem., 1997,40,1808-1819; P. A. J. Janssen [P. A. J.

Janssen, U. S. Patent 2,985,657, 1961] ; Yevich, J. P. [Yevich, J. P., New, J. S., Smith, D., Lobeck, W. G. et al., J. Med.

Chem., 1986,29,359-369]; R. Henning [R. Hennin, R.

Lattrell, H. J. Gerhards, M. Leven, J. Med. Chem., 1987,30, 814-819]; T. R. Elworthy [T. R. Elworthy, A. P. D. W. Ford, G. W.

Bantle, D. J. Morgans, Jr., R. S. Ozer et al., J. Med. Chem., 1997,40, 2674-2687] ; G. S. Poindexter [G. S. Poindexter, M. A.

Bruce, K. L. LeBoulluec, I. Monkovic Tetrahedron Letters, Vol.

35, No. 40,7331-7334, 1994] ; and Wolfe and Buchwald [Wolfe, J. P., Buchwald, S. L., J. Org. Chem., 1997,62, 1264-1267].

5.7 SYNTHESIS OF PIPERAZINE THIOCYCLE COMPOUND The piperazine compound of formulas (XIII) through (XVI) described in Sections 4.3-4.6 are collectively known as "piperazine thiocycle compounds."The piperazine thiocycle

compound of the present invention may be prepared according to general scheme shown in Figures 1 and 2.

As shown in Figure 1, piperazine derivatives 4 or 5 can be prepared from optionally substituted anilines 1 or heterocyclic amines 2. The general procedure outlined in Figure 1 of equation 1 has been modifie from previously described procedures known to synthesize the substituted piperazines [ (l) Prelog, V.; Driza, G. J. Sur la N- phenylpiperazine. Collet. Czech. Chem. Commun. 1933,5, 497]. Amination of bis- (2-chloroethyl) amine hydrochloride with the optionally substituted anilines 1 or heterocyclic amine 2 in a high boiling solvent such as diethylene glycol dimethyl ether in the presence of a base (e. g. K2CO3) at the elevated temperature provides the piperazines 4 or 5.

Equation 2 of Figure 1 shows a preparation of substituted piperazines 9 using modifie literature methods (Lumma, Jr. et al., U. S. Patent 4,078,063,1978). Amination of an optionally substituted heterocyclic bromide or chloride 6 such as pyrimidine, quinoline, pyridine, or pyrazine with

Boc-, Fmoc, Formyl, or benzyl protected piperazine in a polar solvent (e. g. CH3CN) at an elevated temperature or room temperature provide the piperazines 8. Deprotection under standard conditions provides piperazines 9.

Figure 2 illustrates a general preparation of piperazine derivatives 4. A is an optionally substituted heterocycle such as benzothiazole, thiazole, thiadiazole and thiophene. The optionally substituted heterocycles A (A1-A4) are acylated with chloroacetyl chloride or bromoacetyl bromide in a polar solvent such as DMF, dioxane, or a mixture of DMF and dioxane to provide haloacylheterocycles 1 with optionally substituted 2 provides the piperazine derivatives 4.

5.8 METHODS AND COMPOSITIONS FOR USE OF THE PIPERAZINE DERIVATIVES OF THE PRESENT INVENTION The piperazine derivatives of the present invention are useful in veterinary and human medicine for lowering the

blood glucose level in a mammal. For example, due to the potent activity of the piperazine derivatives of the present invention, and their lack of toxicity at their active doses, the piperazine derivatives are advantageously useful in veterinary and human medicine for the therapeutic treatment of insulin-dependent or non-insulin-dependent diabetes mellitus, either primary (idiopathic) or secondary to the use of diabetogenic drugs (e. g., diuretics, corticosteroids, etc.) Additionally, the described piperazine derivatives can be advantageously used as antihyperglycemic agents to reduce the blood glucose levels in situations of acute stress such as experienced by animals or patients with hyperthermia, trauma, sepsis, and burns and undergoing general anesthesia.

Hyperglycemia sometimes associated with severe head injury, cerebral thrombosis, encephalitis and heat stroke can also be therapeutically treated with these piperazine derivatives.

Additionally, the piperazine derivatives are useful as antihyperglycemic agents for rare congenital metabolic glycogen storage disease associated with hyperglycemia.

Although the present inventors do not wish to be

limited to any particular mechanism of action to explain the antihyperglycemic activity of the piperazine derivatives of the present invention, it is envisage that they may advantageously be useful for the treatment of both insulin-dependent (IDDM) or type I diabetes (formerly termed juvenile-onset or ketosis-prone diabetes) and non-insulin-dependent (NIDDM) or type II diabetes (formerly termed adult-onset diabetes).

When administered to a mammal for veterinary use or to a human for clinical use, the piperazine derivatives can be used alone, or as a pharmaceutical composition comprising a physiologically acceptable carrier such as water, an aqueous solution, normal saline, or other physiologically acceptable excipient. In general, the dosage of such pharmaceutical composition ranges from about 10-2000 mg/kg/day, preferably about 10-250 mg/kg/day. The actual dosage, however, may vary within wide limits depending on the

therapeutic indication and the route of administration, as well as the age and weight of the subject.

Pharmaceutical compositions comprising the piperazine derivatives of the present invention can be administered by a number of routes, including, but not limited to: orally; injection including, but not limited to intravenously, intraperitoneally, subcutaneously, intramuscularly, etc; topically; nasally; rectally; permucosally; percutaneously; and parenterally. The preferred route of administration is oral. Additionally, the piperazine derivatives can be administered in conjunction with another antihyperglycemic agent including such as insulin; a biguanide such as metformin or buformin; a sulfonylurea such as acettohexamide, chlorpropamide, tolazamide, tolbutamide, glyburide, glypizide or glyclazide; a thiazolidinedione such as troglitazone or ciglitazone; an a-glycosidase inhibitor such as acarbose or miglatol; an Q2- adrenergic antagonist such as midaglizole, or a ß3-adrenergic receptor agonist such as CL-316,243, LY 104119, Ro 40-2148, etc.

Pharmaceutical compositions of the present invention suitable for oral administration may be administered as discrete units such as capsules, gelatin capsules, cachets, pills, suppositories or rectal capsules, plain or coated tables, sugar-coated tables, each containing a predetermined amount of the piperazine derivative (s); in multidose vials; as a powder or granules; as an injectable solution or a suspension in an aqueous liquid or a non-aqueous liquid; for percutaneous use in a polar solvent; for mucosal use; or as an oil-in-water liquid mulsion or a water-in-oil liquid mulsion and as a bolus, etc.

The excipients which are suitable for such administrations are cellulose derivatives or microcrystalline cellulose, alkaline-earth metal carbonates, magnesium phosphate, starches, modifie starches, and lactose of the solid forms.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients.

Compresse tablets may be prepared by compressing in a suitable machine the piperazine derivative in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface- active or dispersing agent known to those skilled in the art.

Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the piperazine derivative (s) therein.

Formulations suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the piperazine derivative in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the piperazine derivative to be administered in a suitable liquid carrier.

Pharmaceutical compositions suitable for topical administration to the skin may be administered as ointments, creams, gels, and pastes comprising the piperazine derivative (s) to be administered in a pharmaceutically acceptable carrier. A preferred topical delivery system is a transdermal patch containing the piperazine derivative to be administered.

Pharmaceutical compositions suitable for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i. e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations for nasal administration wherein the carrier is a liquid, as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the piperazine derivative (s).

Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multidose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example water for injections, immediately prior to use. Extemporous injection solutions and suspensions may be prepared from. sterile powders, granules, and tablets of the kind described above.

For parenteral use, water, aqueous solutions, physiological saline or isotonic solutions are the vehicles most conveniently used.

For rectal use, cocoa butter or polyethylene glycol steareates are the preferred excipients.

Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as recited above, or an appropriate fraction thereof, of the administered piperazine derivative (s).

It should be understood that in addition to the additives particularly mentioned above the compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include flavoring agents.

The piperazine derivatives of the present invention can be administered in an effective amount either as neutral compound or as anionic or cationic pharmaceutically acceptable salts using counter ions such as acetate, chloride, bromide, iodide, tartrate, fumarate, succinate, ascorbate, gluconate, malate, citrate, sodium, potassium, ammonium, trialkylammonium, etc.

In addition, the piperazine derivatives or pharmaceutically acceptable salts thereof can be used for research purposes, for example, to investigate the mechanism Of activity of antihyperglycemic agents.

As used herein, an"antihyperglycemically effective"amount is an amount of an piperazine derivative of the present invention capable of lowering. the blood glucose level in a mammal having hyperglycemia, to a level of blood glucose within the normal range for the mammal, following administration thereto.

Preferably, the piperazine derivatives of the present invention are used in mammals to lower abnormally high glucose levels to normal levels of blood glucose.

The following series of Examples are presented by way of illustration and not by limitation on the scope of the invention.

6. EXAMPLES: SYNTHESIS OF ILLUSTRATIVE COMPOUND OF THE PRESENT INVENTION Example 1 Preparation of 4-{4-[2-(4-chlorophenylamino)-2- oxoethyl]-1-piperazinyl}benzoic acid (Compound No. 5a), an illustrative compound of formula (I).

A. Preparation of 2-chloro-N- (4-chlorophenyl)- acetamide 34.5 ml of chloroacetyl chloride were added dropwise to 50 g of 4-chloroaniline and 108 g of potassium carbonate in 400 ml of chloroform.

The rection medium was then filtered and the solid obtained was taken up in 1500 ml of water. After stirring for 1 h, the solid in suspension was filtered and thoroughly washed with water.

70.5 g of 2-chloro-N- (4-chlorophenyl) acetamide was thus obtained in the form of a white solid whose melting point is 169-170°C.

IR (KBr): 1669 cm-1 (C = O amide) 1H NMR: (DMSO-d6, 200 MHZ) 6 ppm 4.25 (2H, s, CH2), 7.30 (2H, d, phenyl protons), 7.60 (2H, d, phenyl protons), 10.40 (1H, s, NH).

B. Preparation of the ethyl ester of 4- (4- [2 (4- chlorophenylamino)-2-oxoethyl)-1- piperazinyl}benzoicacid 25 g of 2-chloro-N- (4-chlorophenyl) acetamide, 25.2 g of ethyl 4- (l-piperazinyl) benzoate and 80 g of potassium carbonate in 300 ml of DMF were reacted. over night at room temperature, with, stirring.

The rection medium was filtered in order to separate the insoluble matter and the filtrate thus obtained was poured over 1000 ml of water. A solid crystallized.

This solid was filtered and washed with water in order to give 39 g of the ethyl ester of 4- (4- [2chlorophenylamino)-2- oxoethyll-i-piperazinyl) benzoic acid in the form of a solid whose melting point is 172-174°C. [PLEASE VERIFY THAT THE EXPERIMENTALS WERE ACTUALLY PERFORMED. WAS THE ETHYL ESTER THEN HYDROLYZED TO PROVIDE COMPOUND 5a? RECTION CONDITIONS?].

Example2 The following illustrative compound of the general formula (I), shown below in Table 1, were synthesized according to the above-described methods: TABLE I Comp. Structure mp NMR 1H No (Kofl (200 MHz) 6 ppm (roll er) c°°"DMSO-d6 II 6H) ll l 2.16 (s, 6H) oN 2.75 (s, 4H) NH v NJ 223. (s, 2H) 199-3.45 (s, 4H) la H3 aol. o + 7.1 (d + s, 5H) 7.83 (d, 2H) 9.32 (s, 1H) 12.38 (s, 1H) » tsoCOOH DMSO-d6 2.50 (s, 4H) 0 Nia 3. 05 (s, 2H) nu 3. 25 (s, 4H) 2 a 188-4.87 (s, 2H) 2a 190 906. (d, 2H) 7.25 (m, 10H) 7.77 (d, 2H) 12.32 (s, 1H) S towCOOH DMSO-d6 1.0 (d, 6H) 2. 40 (s, 4H) N 2.75 (s, 2H) 229-3. 25 (s,-4H) 231 4-82 (m, 1H) 3a H3C''CH3 6. 90 d 2H 7.25 (d, 2H) 7.50 (s, 3H) 7.80 (d, 2H) 12.35 (s, 1H)

_ CH3 COOH DMSO-d6 1. 1 (d, 12H) colt 2. 7 (s, 4H) NH 3.05 (m, 2H) son 4a H3C CH3 241 3 : 40 (s, 4H) 6.95 (d, 2H) 7.2 (m, 3H) 7.8 (d, 2H) 9.3 (s, 1H) 12.4 (s, 1H) COOH DMSO-d6 2. 70 (s, 4H) 3. 20 (s, 2H) 3. 40 (s 4H) 5a H 265 7. 00 (d, 2 H) 7.40 (d, 2H) 7.75 (m, 4H) 9.90 (s, 1H) 12.4 (S, 1H) ^'cooH CF3 COOD 3. 65 (s, 3H) 6a tN4NS >265 4.55 (s, 2H) OCHs H s. soa ; iH> 760 (d, 3H) 8.25 (d, 2H) ^'cooH CF3 COOD 3. 20 (s, 3H) /NN 205-E. 90 (s, 2H) 207 7.20 (s, 3H) 7.50 (d, 2H) 8.10 (d, 2H) cF3cooH CF3 COOD 4. 15 (s, 8H) 0 N (4.45 (s, 2H) /NN 259-7.32 (s, 3H) 261 7.50 (m, 3H) H 8.10 (d, 2H)

c°°"CF3 COOD 4. 25 (s, SU) 0 4. 55 (s, 2H) 7. 70 (d, 2H) 265. 25 (s, 2H) 7. 70 (d, 2H) 8.30 (d, 2H) co°H CF3 COOD 1. 12 (t, 3H) oN 3.75 (q, 2H) _N_ v NJ 201-4.38 (m, 10H) Jazz 13 cl, ah HcJ 203 7 _ 45 (s, 3H) 7.67 (d, 2H) 8.28 (d, 2H) ^'c°°H CF3 COOD 1. 94 (s, 2H) o N/N ,'226-4. 19 (m, 12H) 228 7. 12 (m, 4H) al l228 7. 12 (m, 4H)707. (d, 2H) 8.28 (s,. 2H) \ c°°"CF3 COOD 1. 11 (s, 6H) , 0 4.03 + 4.20 (s + V \NNJ S 8H) 2a 252-4.49 (s, 2H) 2a H3C CH3 254 4. 86 (S, 1H) 7.13 (s, 2H) 7.48 (s, 2H) 7.74 (s, 2H) 8.34 (s, 2H) c°°rr CF3COHD 1. 05 (s, F 3. 80 + 4.30 (s + "233-s, lOH) 3a 235 4.75 (s, 1H) "" 7. 0 5 (s, 4 H) 7.60 (s, 2H) 8.25 (s, 2H) ^'cooH CF3COOD 4. 25 (s, 8H) o NNJ 257-7.25 (s + m, 5H) 1. 4a 1 259 7.69 (d, 2H) H 8.29 (d, 2H)

COOH CF3COOD 2.28 (s, 4H) o"2. 72 (s, 2H) 2.97 (s, 4H) 4.62 (s, 2H) 163-5. 94 (s, 1H) 'rJc' \ 0 165 6, 7 (d, 2H) 6.95 (d, 2H) 7.13 (d, 3H) 7.33 (s, 1H) 7.55 (d, 2H) 12.10 (s, 1H) °°"CF3COOD H, cJ, 2. 2 9 (s, 3 H) 0 4. 34 (s, 6H) 6a I'/N'vNJ 259-4. 60 (s, 2H) 261 7. 18 (s + m, 4H) 7.77 (d, 2H) 8.38 (d, 2H) c°°H CF3 COOD H, co, 3. 88 (s, 3H) "4. 29 (s, 8H) 245-4. 57 (s, 2H) "247 6.98 (d, 2H) 7.28 (d, 2H) 7.73 (d, 2H) 8.33 (d, 2H) ^'cooH CF3 COOD 1. 18 (m, 6H) o 3. 97 (s, 4H) 208-4.17 (d, 4H) 1. 8a 210 4.45 (d, 3H) 7. 08 (m, 2H) 7.47 (d, 3H) 7.70 (d, 2H) 8.30 (d, 2H)

c°°"CF3 COOD c !, 3.46 (s, 3H) 1 4. 27 (m + S, 10H) 9 a I N 217-7. 26 (d, 2H) . CH3 557. (d, 2H) CH 7.82 (d, 2H) 8. 43 (d, 2H)

Example 3 Preparation of methyl 2-cyclohexylmethylamino-5- methoxybenzoate (Compound No. lb).

17.6 g of methyl 5-methoxyanthranilate, 11.8 ml of cyclohexanecarboxaldehyde and 2 g of 10t palladium-on- charcoal (50k water) were added to 200 ml of methanol in a 1 liter hydrogenation apparats.

The apparats was placed under a hydrogen atmosphere and agitated at room temperature for 3 hours.

300 ml of dichloromethane were added, the palladium-on-charcoal was'separated off by filtration, and the filtrate obtained was concentrated under vacuum.

The oil obtained crystallized from an ethanol (200 ml) and water (50 ml) mixture to give 25.4 g of a yellow solid which melts at 58-60°C.

1683cm-1(C=O),1528cm-1(C=O)IR:(KBr) 'H NMR: (CDCL3,200 MHz) 6 :ppm 1.06-1.64 (11H, m, cyclohexyl), 2.93 (2H, t, Chez), 3.68 (3H, s, OCH3), 3.78 (3H, s, OCH3), 6, 56 (1H, d, phenyl proton), 6. 96 (1H, dd, phenyl proton), 7.23 (2H, d + s, phenyl proton + NH).

Example4 The formulae and characteristics of the compound of formula (VIII) have been combine in Table II.

TABLE II

Compoun Structure NMR d M. P. in °C (Kofler) -58-60 COpCHg v N . H3co CH3 H NMR (200 C02CH3 MFiZ) COC13 6 ppm N 1. 28 (t, 3H) 3.20 (q, 2H) 3. 77 (s, 3H) H3CO Oil 3.88 (s, 3H) 6.71 ( (d, 1H) 7.09 (dd, IH""'* 7.28 (s, 1H) 7.50 (d, 1H) COOH M. P. in OC (ronfler) NH2 147-149 3b 3b Example 5 Preparation of 4-chloro-2- (chloroacetamido) benzoic acid (ComPound lc) 25.5 ml of chloroacetyl chloride were added dropwise with stirring to 50 g of 2-amino-4-chlorobenzoic acid in 600 ml of dioxane, while the rection mixture was maintained at 20°C.

Stirring was then maintained for 2 hours at room temperature, and then 1200 ml of water were added. The desired product precipitated, the mixture was stirred for one hour and then filtered, and the solid obtained was washed with water.

After drying, 60.6 g of 4-chloro-2- (chloroacetamido) benzoic acid were obtained, the melting point of which is 194-196°C.

IR: 1676 cm~l (C+O) 1H NMR: (d6-DMSO, 200 MHz) 6 :ppm 4.30 (2H, s, CH2), 7.1 (1H, d, phenyl proton), 7.7 (1H, d, phenyl proton), 8.5 (lH, s, phenyl proton), 11. 75 (1H, s, NH), 13.90 (1H, broad s, COOH).

Example 6 The formulae and characteristics of the compound of formula (X) have been combine in Table III.

TABLE III Compoun Structure M. P. in OC d (ronfler) 1H NMR (200 MEIz) COC13 b ppm COOH L NH X 4 1C 194-196 CL

COOH NEF \CI I 4X O 182 184 H3C0

COOH NU' ICI 3 C H3co 236 238 OCH3 COOH NH CI 4 c I II iao iaa 4c 0 cool OH vG 155-157 COOiP CH= I CI g3-85 6 c H,o COOH NU G t I t wa o

CH3 0.99 (l, 3Fi) cozc 3. 3 5 (m, 1H) 3,63 (d, 2H) ci 00.-8 9 (s-m, 7H) 7, 12 ( (m, 2H) 8 C \ o. 7.40 (d. 1H) H3C 1. 05 (m, 5H) 1.57 (m, 6H) 2.81 (dd, 1H) C02C li 3. 6 6 (s, 2H) Oil 3.81 (s, 6H) 9C N 3. 88 ( (dd, lH) cri 7.38 (d, IH) H3C l

Example 7 Preparation of 4-chloro-2-{[4-(2-methoxyphenyl)-1- piperazinyl]acetamido}benzoic acid 10d) 15 g of 4-chloro-2-(chloroacetamido) benzoic acid were added, with stirring and at room temperature, to 11.6 g of 1- (2-methoxyphenyl) piperazine and 17 ml of triethylamine in 120 ml of DMF.

The rection mixture was kept stirring for 48 hours at room temperature, and then 500 ml of water were added.

Extraction was carried out with 3 x 300 ml of dichloromethane. The solvent was evaporated under vacuum, and the solid thus obtained was taken up again in 300 ml of a 2N aqueous sodium hydroxide solution. The solution was washed with 3 x 200 ml of diethyl ether, and the aqueous phase was then acidifie with acetic acid.

A solid crystallized to give, aster filtration, 22.5 g of crude product. After recrystallization from dioxane, 21.1 g of 4-chloro-2- ( [4- (2-methoxyphenyl)-l- piperazinyl]acetamido} benzoic acid were obtained in the form of a white solid, which melts at 218-220°C.

IR: 1699 cm~1 (C=O), 1673 cm~l (C=O) 1H NMR: (CF3COOD), 6 :ppm 4.25 (3H, s, OCH3), 4. 65 (8H, broad s, 4 Chez), 4.95 (2H, s, CH2), 7.5 (2H, m, phenyl protons), 7.6 (lH, d, phenyl proton), 7.90 (2H, m, phenyl protons), 8. 50 (lH, d, phenyl proton), 8.75 (IH, s, phenyl proton).

Example8 Preparation of 2-{[4-(4-fluorophenyl)-1-piperazinyl]- acetamido}-4,5-(methylenedioxy)benzoic acid (Compound 37d) 15 g of 2- (chloroacetamido)-4,5- (methylenedioxy) benzoic acid were added, with stirring and at room temperature, to 10.5 g of 1- (4-fluorophenyl) piperazine and 16.2 ml of triethylamine in 150 ml of DMF.

The rection mixture was kept stirring for 48 hours at room temperature.

3.5 ml of acetic acid were added, and 150 ml of water were slowly added. The acid crystallized, and was

diluted with 300 ml of water. The mixture was stirred for 30 minutes and filtered, and the solid obtained was washed with water.

After recrystallization from a dioxane/DMF mixture, 14.9 g of 2-{(4-(4-fluorophenyl)-1-piperazinyl]acetamido}- 4,5- (methylenedioxy) benzoic acid were obtained, which melts at 254-256°C.

IR (KBr) : 1654 cnil (C=O) 'H NMR: (CF3COOD, 200 MHz) 6 :ppm 4.40 (8H, s, piperazinyl), 4.67 (2H, s, CH2), 6.05 (2H, s, O-CH2-O), 7.30 (2H, t, phenyl proton), 7.65 (3H, m, phenyl proton), 7.90 (1H, s ; phenyl proton).

Example 9 The formulae and characteristics of the compound of formula (VII) have been combine in Table IV.

TABLE IN Compoun Structure M. p. 1H NIt d in *C (200 MHz) 6 (Kofle ppm r) DMSO-d6 2. 60 (s, 4H) ls 3.10 (s, 4H) /3.20 (s, 2H) 185- 3.70 (s, 3H) 187. 6. 80 (q, 4H) 7.10 (t, 1H) 7.55 (t, 1H) 8 (d, 1H) 8.7 (d, 1H) COOH CF3COOD HH_ ^ N. 4. 25 (s, 8H) | 4. 65 (s, 2H) 2 d <OowNon2 3 5 7 5 5 (s, 5H |oN/233-730 (s, 1H) 2d 235 7.55 (s,. 5H) 235,p (t, 1H) 8.25 (m, 2H) COOH. CF3COOD /I NH ^ 4. 25 (s, 8H) y 4.55 (s, 2H) 0 N 7.50 (s, 5H) 250 g, 06 (d, 1H) 8. 30 (s, 1H) CF3COOD 4 (s, 3H) II 4. 5 (s, 8H) 0. 4.6 (s, 2H) ° \ I 243 2d, 2H) 7. 4 (d, 1H) 7.65 (d, 2H) 8.25 (d, 1H) 8.60 (s, 1H)

°°"CF3COOD 4. 20 (s, 8H) 4. 62 (s, 2H) I N'1 0 7. 20 (d, 1H) 5d 7. 55 (s, 4H) 8. 10 (d ;. : 1H) 8.35 (s. 1H) 'CF3COOD 3.8 (s, 3H) II Nl y 4.25 (s, 8H) ///'199-4. 60 (s, 2H) cri 201 7.20 (m,. 4H) 7.5 (m, 1H) 8.15 (d, 1H) 8.40 (se 1H) COOH CF3COOD Nu, 4.60 (d, 8H) H F 4. 90 (s, 2H) 7. 50 (m, 3H) /238-7. 85 (m, 2H) 7d 240 g, 35 (d, 1H) _ 8.65 (s, 1H) avoH CF3 COOD nu 4. 10 (s, BH) /I NH_ ^ N 4. 45 (s, 2H) /244-7.05 (d, 3H) 248 7.45 (m, 2H) 7.95 (d, 1H) 8.20 (s, IH) COOH CF3COOD NH nu 4.25 (d, 8H) II 4. 60 (s, 2H) ""'191-7.15 d 9d c, Ha . a I 193 810 (d, 1H) 8. 30 (s, IH) 8. 30 (S, 1H)COOH CF3COOD Nu 4. 25 (s, 3H) " °°"e 4. 6 5 (s, 8H) oN/218_ 4.95 (s, 2H) 7. 5 (m, 2H) 220. 6 (d, 1H) 7.9 (m, 2H) 8.5 (d, 1H) 8. 75 (s, 1H)

COO" CF3COOD ""4. 3 (s, 8H) -4.7. (s, 2H) lld 0. 260-7.25 (t, 1H) 262 7. 55 (s ; 4H) "-act. 7.70 (t, 1H) 8.25 (nui, 2H) CF3COOD NH 4. 2 (s 8H) 4.6 (s, 2H) 12C1 v/249-7.2 (m, 3H) 251 67. (m, 3H) 8.15 (m, 2H) (CDC13 /I NH II l 3. 10 (s, 2H) t 3. 10 (s, 4H) 13d j ls. oo (m, 13>I0176 7. 00 (m, 7H)68. (d, 1H) 10,00 (s, 1H) 11.8 (s, 1H) CF3COOD '°'3. 85 (s, 3H) I 1 4. 30 (s, 8H) /190-4.75 (s, 2H) 192 7.5 (m, 6H) 8. 15 (t, 2H) COOH CDC13 2.74 (s, 3H) I NH II N F 3. I. SS_SH 3. 20 (s, 2H) 15d \ I 169-6.80 (m, SH) 171 7. 5 (t, IH) 7.75 (d, 1H) 8.80 (d, 1H) 11.45 (s, 1H) 12.00 (s, 1H) '°°"CDC13 CDC'3 (s, 3H) NH_ ^ M OCH 3. 7 CJ i $ S H -4. 29 (s, 2H) 6. 65 (d, 2H) 16CL I 2Z9 6. 85. (t, 1H) 7.10 (m, 3H) 7.75. (t, 2H)

'°°H CF3COOD "" 3. 75 (s, 8H) II 4. 15 (s, 2H) ""190-6.75 m 1H , 192 7.00 (m, 5H) 7. 60 2 H) I CF3COOD 3. 65 (s, 6H) í II U I I 4.15 (s, 8H) >265 4. 5 (s, 2H) 7.55 (s, 5H) 7.65 (s, 1H) 7.85 (s, 1H) CF3COOD '3. 75 (s, 6H) II I 4.15 (s, 8H) >265 4. 50 (s, 2H) F 7. 40 (m, 2H) 7. 40 (m, 2H) 7.55 (S, 1H) 7.85 (S, 1H) C4ce CF3COOD 3. 80 (s, 6H) N 4.15 (s, 8H) m3co 0 4. 15 (s, 8H) 2 Od OC aa >265 7. 40 (S, 4H) 7.60 (s, 1H) 7.90 (S, 1H) CF3COOD 3. 75 (s, 3H) 0 3.85 (s, 6H) 246-4. 15 (s, 8H) 21d''°",, 248 4. 50 (s, 2H) 5.50 (d, 2I) 7.40 (d, 2H) 7.60 (s, 1Fi) 7.95 (s, 1H) COOH CF3COOD 3. 80 (s, 9fi) II N''4.25 (s, 8H) 22C" 244-4.50 (s, 2H) 246 7.00 (d, 2H) 7.40 (d, 2H) 7.50 (s, 1H) 7.95 (s, IH)

CF3COOD 4. 20 + 4. 35 23C H \" 245- (2s, 8H) a" ; 247 4.50 (s, 2H) 7. 20 (q, 2H) 7.50 (m, 3H) 7.95 (s, 1H) CF3COOD 3.75 (s, 6H) 4. 10 + 4. 20 24C 25 4. 50 ( (s, 2H) 7.60 (m, 5H) 7.85 (s, 1H) CF3COOD 3. 80 (s, 6H) 4. 15 (s, 8H) 25C >265 4.50 (s, 2H) OCHX IsJI 7.35 (m, 4H) 7. 55 (s, 1H) 8.85 (s, 1H) CF3COOD 3. 70 (s, 3H) 1 3.85 (s, 6H) oc3 4.22 (s, 8H) 2 6d °°'' 255-g _ 50 (s, 2H) 257 6_95 (s, 3H) 7.35 (t, 1H) 7.55 (s, 1H) 7.88 (s, 1H) CF3COOD 4. 15 + 4. 17 (2s, SU) /257-4.50 (s, 2H) 259 7.10 (d, 1H) 7. 40 (m, 4H) 8.00 (d, 1H) 8.25 (s, 1H) CF3COOD 3. 70 (s, 3H) 4. 10 (s, 8H) 4. 50 (s, 2H) 2 $d-I 241 6. 90 (d, 2H) 7. 30 (d, 2H) 7.40 (d, 1H) 8.00 (s, 1H) 8.10 (d, 1H)

CF3COOD I""4.15 (s; 8H) 4.55 (s 2 H) >26540 (s+d, 5H) 29d I a. oo cs, 1H) ° 8.15 (d, 1H) 'CF3COOD 3. 85 (s, 3H) 4.30 (s, 8H) ° 199-4. 65 (S 2H) 201 7.15 (m, 3H) 7.55 (m, 2H) 8.15 (s, 1H) 8.30 (d, 1H) "CF3COOD 4. 30+4.50 (2s, F 8H) 262-4. 67 (s, 2H) 264 7.30 (m, 2H) 7.65 (m, 3H) 8.15 (s, 1H) 8.25 (d, 1H) _ CF3COOD 4. 05 (s, 8H) 4. 40 (s, 2H) 32d \ I 245 7. 08 (t, 2H) 247 7. 40 (d, 3H) F 7.90 (s, 1H) 8.08 (d, 1H) CF3COOD I""N 4. 25+4.40 (2s, 8H) a e N/cy 213-4. 70 (s, 2H) 3 3 d RJ 215 7.55 (d, 1H) 7. 80 (m, 4H) 8.15 (s, 1H) 8.25 (d, 1H) COOH CF3COOD 3.80 (s, 3H) 4. 20 (s, 8H) 203-4. 45 (s, 2H) 206 6.95 (d, 2H) 7.42 (q, 3H) 8.05 (s+d, 2H)

CF3COOD 4. 10 (S, 8H) 4. 45 (s, 2H) 35d 224-7.40 (m, 5H) 226 7.95 (s, 1H) 8.10 (d, 1H) CF3COOD N 4. 20 (s, 8H) 8H) 4. 50 (s, 2H) 3 6C N 238-5.85 (s, 2H) 45 (s, 6H) 7.80 (s, 1H) CF3COOD 4. 40 (s, 8H) 4. 67 (s, 2H) 254-6.05 ( 256 7.30 (t, 2H) 7. 65 (m, 3H) 7.90 (s, 1H) CF3COOD I "1N 4. 2 2 (s, 8 H) 4. 57 (s, 2H) II >265 5-92 (s, 2H) 7.52 (s, 5H) 7.90 (s, 1H) CF3COOD 3. 83 (s, 3H) 4. 25 (s, 8H) o i 236-4.59 (s, 2H) 3 9C1o 238 6.0 (s, 2H) 7.13 (d, 2H) 7.49 (t, 3fui) 7.82 (s, 1H) CF3 COOD 4. 29 (s, 8H) /257-4.59 (s, 2H) 259 6. 06 (s, 2H) 7.15 (d, 2H) 7.55 (s, 3H) 7.82 (s, 1H)

cor CF3COOD /\^^ 4.23 + 4.38 I NH (-N' F n i (2s, 8H) 41d \ 236-4.56 (s, 2H) 97 (s, 2 7. 31 (ttt, 2H) 7. 55 (m, 3H) 7.76 (s, 1H) COOH CF3COOD CF3COOD 4. 05 + 4. 15 (2s, 8H) oN, I cF'228-4. 35 (s, 2H) 230 5.75 (s, 2H) 7. 30 (s, 1H) 7.60 (m, 5H) COOH CF3COOD NH Y''N 4. 00 (s, 8H) ci 4.37 (s, 2H) 240-5. 75 (s, 2H) 43Co 242 7.35 (d, 5H) 7.70 (s, 1H) COOH CF3COOD I NH_ ^ ^ 3.55 (s, 3H) \ O N pH 4. 00 (s, 8H) 44Co 198'4.30 (s, 2H) 200 5.71 (s, 2H) 6.85 (s, 3H) 7.25 (s, 2H) 7.60 (s, 1H) COOH CF3COOD XNH/_\ 4. 05 (S, 3H) 4. 42 (s, 8H) H' o N, I 78 (S, 2H)188-4. 190 7.45 (d, 1H) 7.72 (s, 5H) 7.93 (s, 1H) 8.30 (d, 1H) COOH CF3COOD 3. 75 (s, 3H) H, co °N-4. 20 (s, 8H) 197-4.50 (s, 2H) 46d F 199 107. (m, 3H) 7.50 (t, 2H) 7.70 (s, 1H) 8. 05 (d, 1H)

c°°H CF3COOD /NH_ ^N^ 3.80 (s, 3H) 4. 20 (s, 8H) r, co ° N i 221-4. 55 (s, 2H) 223 7.15 (d, 1H) 7.40 (s, 4H) 7.70 (s, 1H) 8.00 (d, 1H) COOH CF3COOD 3. 85 (d, 6H) HCO NH i 4. 2 5 (s, 8 H) 198-4. 75 (s, 2H) 4 $d' 198 7.22 (s, 2H) 7. 40 (s, 1H) 7.58 (s, 2H) 7.82 (s, 1H) 8.20 (s, 1H) cooH CF3COOD H_ ^N^ 3. 75 (s, 3H) HCO/N/CF 1 1 _ 4.15 (s, 8 H) 173 4.50 (s, 2H) 7. 15 (s, 1H) 7.70 (d, 5H) 8.05 (s, 1H) cooH CF3COOD NH_N^ ocH 3. 65 (s, 3H) 3. 70 (s, 3H) 200-4.42 (s, 2H) 202 7.00 (d, 2H) 7.19 (d, 1H) 7.40 (m, 2H) 7.65 (s, 1H) 8.00 (d, 1H) COOH CF3COOD /NH II tJ F 3.72 (s 3H) o N 4. 25 (d,. 8H) H3COv O CNA 179-4 50 (s, 2H) 181 7.15 (m, 3H) 7.50 (q, 2H) 7.85 (d, 1H) 8.00 (d, 1H)

3. 9 CF3COOD 3. 88 (s, 3H) X'1 HCOU ° CN% Hz 4 34 (S 8H) 0 4.34 (s, 8H) 52d 177-4.72 (s, 2H) 179 7.20 (m, 1H) 7.39 (dd, 1H) 7.62 (m, 1H) 7.88 (S, 1H) 8.22 (d, 3fui) CF3 COOD I NH_ ^ ^ 3.95 (s, 3H) 3H) 4.40 (s, 8H) 53d HCO 184 7. 30 (d, 1H) 7.60 (m, 3H) 7.85 (s, 1H) 8.25 (d, 1H) COOH g H3 DMSO-d6 /N\ ^ ^ 2. 42 (d, 4H) 2. 90 (s, 2H) o/3. 10 (s, 4H) 54C1 I 212 6.30 (t, 1H) 6.93 (d, 2H) 7.25 (t, 2H) 7.50 (m, 2H) 7.70 (t, 1H) 8.00 (d, 1H) COOH CH, DMSO- 2. 34 (d, 4H) 6 / 2. 81 (s, 2H) 0 N 3.00+3.10 (2s, 55C1 225- ci 227 6.93 (d, 2H) 7.22 (d, 2H) 7.47 (m, 2H) 7.70 (d, 1H) 7.95 (d, 1H) COOH CH, DMSO-6 2. 55 (d, 4H) 3. 03 (s, 2H) 5 6C1 O N/CF3 193-3.25 (d, 7H) 195 7.25 (m, 3H) 7.60 (m, 3H) 7.82 (t, 1H) 8.12 (d, 1H)

COOH iH DSMO-C i N N 2.55 (s, 4H) 6 0 ZON 3.00 (d, 6H) 3. 80- (s, 3H) ocH, 210 7, pp (s, 4H) 7.55 (m, 2H) 7.82 (d, 1H) 8.10 (d, 1H) _. _. i N 2. 15 (s, 4H) 0 N OCH3 2. 65 (s, 2H) 2. 80 (s, 4H) 196-2.90 (s, 3H) 58d Z98 6. 20 (t, 3H) 6.85 (t, 1H) 7.25 (m, 2H) 7.50 (d, 1H) 7.75 (d, 1H) cooH H3 DSMO-d N 2.55 (s, 4H) NN oCH3 2.95 (s, 6H) 144-3.20 (s, 3H) 59d I 145 3-90 (s, 3H) 7.00 (d, 4H) 7.60 (m, 2H) 7.80 (d, 1H) 8.10 (d, 1H) COOH CH3 CF3COOD w 9 2. 3. 77 (s, 3H) _ 4. 22 (s, 8H) '191, p5 (d, 2H) 7.50 (d, 3H) 8.07 (s, 1H) 8.15 (d, 1H) COOH HJ DSM°-d6 ^ 6 'N 2.50 (s, 3H) 0 N 2.83 (s, 4H) 3. 39 (2s, 6H) 7. 66 (d, 2H) 61C 216663 (dd, 1H) 7.96 (S, 1H) 8.79 (d, 2H) 12.20 (s, 1H) 13.80 (s, 1H)

DMSO-d6 0. 75 (t, 3H) "'°0 1. 24 (m, 2H) ocr, 1. 5 8 (, 2 H) q 2.52. (S, 4H) 2.94 (s, 6H) 62d 50167-3. (s, 3H) 169 3.81 (t, 2H) 6.71 (q, 4H) 7.05 (dd, 1H) 7.28 (S, 1H) 8.45 (d, 1H) 11.77 (s, 1H) 13.43 (s, 1H) DSMO-d6 NH 0. 83 (t, 3H) H, o ° 1. 32 (m, 2H) 1. 58 (q, 2H) 2.60 (s, 4H) 3.15 + 63d 159-3.88 (2S, 6H) 161 3.88 (t, 2H) 6.87 (d, 2H) 7.10 (d, 3H) 7.35 (d, 1H) 8.6 (d, 1H) 11.81 (s, 1H) 13.50 (s, 1H) cooH DSMO-d6 I NH_ ^N^ 521. (m, 8H) N'I 2. 64 (s, 4H) 3. 20 + 3. 28 (2s, 6H) 187- 64d 189 6. 86 (d, 2H) 7.13 (m, 3H) 7.39 (s, 1H) 8.55 (d, 1H) 10.15 (s, 1H) COOH DSMO-d6 1. 51 (m, 8H) I." 2. 5 2 0 2. 93 (s, 6H) °"''3. 5 0 171-4.50 (s, 1H) 65d 173 8.60 (q, 4H) 8.95 (dd, 1H) 7.28 (s, 1H) 8.45 (d, 1H) 11.77 (s, 1H) 13. 43 (s, 1H)

DSMO-D. 1. 35 (m, 11H) COOH 2. 58 (s, 4H) 236-2.84 (m, 3H) 4. 90 (s+m, 4H) I ci 6.92 (d, 2H) 7.28 (m, 4H) 7.46 (d, 1H) DSMO-d6 COOH 1. 00 (m, 5H) coo+ 2. 49 (s, 4H) H, co °" 209-2.90 (m, 7H) u 211 3.73 (s, 3H) -OCH3 3.85 (S+m, 4H) 6.83 (q, 4H) 7.24 (q, 2H) 7.40 (s, 1H) COOH CDC13 CDCl3 1. 54 (d, 6H) Gtt, I ii HC''O"i 3.00 (s, 4H) 3.50 (s, 6H) 6 8d a 218-4.67 (m, 1H) 220 7.08 (d, 2H) 7.35 (d, 3H) 7. 74 (d, 1H) 8. 98 (S, 1H) 12.00 (S, 1H) COOH DSMO-ds COOH 1. 20 (d, 6H) H, co °"i I 2.79 (s, 4H) OCH, 3.20 (s, 2H) 3.62 (s, 3H) 6nz 132-4.37 (m, 1H) vu 134 4.94 (s, 1H) 6.60 (d, 2H) 5.73 (d, 2H) 7.00 (dd, 1H) 7.43 (S, 1H) 8.56 (d, 1H) 11.88 (s, 1H)

COOH (C 3 DSMO-d6 1.05 (t, BH) '-f'N 2.50 (s, 4H) HJCO ° CN 3.00 (s, 2H) 161-320 (s, 5H) 163 3 92 (m+s, 4H) 6. 94 (d, 2H) 7.28 (m, 4H) 7.47 (s, 1H) 13.62 (broad a, 1H) COOH (CF3COOD /3. 5 8 S, H, CO I o N 3. 78 s, 18H H3CO 150 3.92 m, I18H 71d 152 6.83 (d, 2H) 7.10 (s, 2H) 7.23 (d, 2H) 7.53 (s, 1H) COOH CF3COOD /NH_ ^N^ 903. (s, 3H) , 4. 41 (s, 8H) "N 261-4 5 (s, 2H) 7. 13 (d, 2H) 72d 263 oc, 7.45 (m, 4H) 7. a8 (m, 2H) 8.64 (s, 1H) 8.90 (s, 1H) COOH CF3COOD NH 4.40 (s, 8H) 4. 77 (s, 2H) oN 7.56 (s+m, 6 >265. 92 (m, 2H) cri 8. 68 (s, 1H) CI g, 92 (s, 1H) Example 10 Preparation of 2-((BromoacetYl) amino)-4-chlorobenzothiazole Bromoacetyl bromide (0.8 g, 0.3 mL, 4.2 mmol) was added dropwise to a solution of 2-amino-4-chlorobenzothiazole (0.72 g, 3.9 mmol) in a mixture of DMF (5 mL) and dioxane (5 mL) while keeping the internal temperature of the rection mixture at 5 OC. After stirring at 5 OC for 1 h, the ice bath was removed and the rection mixture was stirred at room

temperature (rt) for 20 h. The rection mixture was poured into ice water and the light crystalline compound which formed was filtered, washed several times with cold water, and then dried to give 0.66 g (55*1) of the title compound, mp 207.1- 209.5 °C (became "wet" at 203 °C) : 1H NMR (CDC13) 6 7. 75 (dd, J = 8.0, J = 1.2,1H), 7.50 (dd, J = 7.6, J = 0.. 8, 1H), 7.31 (dd, J = 8.0, J = 8. 0, lH), 4.14 (s, 2H). 13C NMR (CDC13) 6 59,126.91,125.85,125.19,120.15,27.47;164. MS (EI) 306 (M+).

, Example12 2-(((4-(Phenyl)piperazin-1-yl)acetyl)amino)-4-Preparationof chlorobenzothiazole (Compound EB) Phenylpiperazine (0.43 g, 0.4 mL, 2.64 mmol) was added to a solution of 2-((bromoacetyl) amino)-4-chlorobenzothiazole (0.4 g, 1.32 mmol) in DMF (10 mL) at rt. The rection mixture was heated and stirred at 70-75 OC for 6 h., cooled to rt, and poured into ice water. The white precipitate which formed was filtered, washed several times with cold water, and then dried to give 0.28 g (58%) of the title compound, as <BR> <BR> <BR> a white solid, mp 237.9-238.6 °C: 1H NMR (CDC13) 6 5710. (bs, 1H), 7.73 (dd, J = 8.0, J = 0.8,1H), 7.48 (dd, J = 8.0, J = 0.8,1H), 7.33- 7.25 (m, 3H), 6.98- 6.91 (m, 3H), 3.40 (s, <BR> <BR> <BR> 2H), 3.32 (t, J = 4.8,4H), 2.89 (bs, 4H). 13C NMR (CDC13) 8 169.17,157.81,150.08,145.63,133.65,129.24 (2C), 126.55 (2C), 125.90,124.62,120.41,120.00,116.52,61.34,53.72 (2C), 49.15 (2C); MS (EI, m/z) 386 (M+).

Example13 Preparation of 2-(((4-(2-(Fluoro)phenyl)piperazin-1- yl)acetyl)amino)-4-chlorobenzothiazole(CompoundDB) 1-(2-Fluorophenyl) piperazine (1.4 g, 1.25 mL, 7.8 mmol) was added to a solution of 2-((bromoacetyl) amino)-4- chlorobenzothiazole (1.2 g, 3.9 mmol) in DMF (20 mL). The rection was heated and stirred at 100-105 OC for 7 h, cooled to rt, and slowly poured into ice water. The ivory precipitate which formed was filtered, washed several times with cold water, and then dried to give 1.07 g (67%) of the title compound, mp 172-174.9 °C ("wet" at 145 °C) : 1H NMR

(DMSO-d6) 6 6512. (bs, 1H), 7. 97 (dd, J = 8.0, J = 0.8,1H), 7.53 (dd, J = 7.6, J = 0.8,1H), 7.31 (dd, J = 7.6, J = 7.6, 1H), 7.15- 7.02 (m, 3H), 6.99- 6.94 (m, 1H), 3.46 (bs, 2H), 3.05 (bs, 4H), 2.73 (bs, 4H). 13C NMR (DMSO-d6) 6 56,169.

158.62,154.94 (d, J = 244), 145.34,139.80 (d, J = 7.6), 133.04,126. 24,124.82 (d, J = 3.0), 124.42 (d, J = 7.6); 122.33 (d, J = 7.6), 120.89,119.25 (d, J = 2.3), 115.91 (d, J = 21), 59. 92,52.47 (2C), 50.01 (2C); MS (FAB, m/z) 405 (M').

ExamDle 13A 2-(((4-(3-(Trifluoremethyl)piperazin-1-Preparationof ylylacetyl) amino)-5- (carboethoxy)(carboethoxy) benzothiazole.

Preparation of 5-(carboethoxy-2-amino) benzothiazole and 2- [ (Bromoacetyl) aminol-5- (carboethoxy) benzothiazole. 1) Procedure for thiocyanate: To a solution of sodium thiocyanate (8.8 g, 109 mmol) and ethyl 4-aminobenzoate (16.5 g, 100 mmol) was added bromine (8.2 g, 2.65 mL, 51 mmol) with stirring at -5° C. The rection mixture was stirred ars-50 C to +10° C for 3h. TLC analysis showed that the rection was incomplete. Rection mixture was cooled to-5° C. and additional bromine ((15 mL) was added. Water (150 ml) was added, the mixture was stirred for 30 min and then filtered. <BR> <BR> <BR> <P> The solid was dissolve in CHC13 (200 mL) and extracted with<BR> <BR> <BR> <BR> <BR> 5% NaZC03. The CHOC'3 layer was. dried, filtered and adsorbe onto Na2CO3. The solid adsorbate was loaded onto a Six2 gel column and eluted with 1: 4 EtOAc/Hexane to give 3.54 g (16%) of the title compound, mp 96.2-96. 7° C : 1H NMR (CDC3) 6 208.

(d, J = 2,1H), 7.95 (dd, J = 8.4, J = 2, 1H), 806. (d, J = 8.4,1H), 4.34 (d, J = 7.2,1H), 1.38 (t, J = 7.2,3H), 13C NMR (CDC13 6 19,151.71,138.47,134.43,121.27,115.22,165.

109.44,103.97,60.89,14.31; MS (FAB, m/z) 222 (M+H+) An additional 5.17 g (23. 3t) of this compound was obtained with an impurity. The thiocyanate (2.5 g, 11.25 mmol) was refluxed with 25 mL of 1N HCl. The mixture was cooled to rt, conc. HCl 5(12. mL) and water were added and then the mixture was heated. The mixture was filtered while hot, cooled to room temperature, and the white precipitate was filtered.

The product was suspende with CHCl3, washed with 5% Na2C03 and then the separated aqueous layer was extracted several times with CHCl3. The combine CHOC'3 layer was dried, filtered, and then concentrated to give 1.4 g of a white <BR> <BR> solid : 1H NMR (DMSO-d6 6 288. (d, J = 1.6, lH), 7.91 (s, 2H), 7.81 (dd, J = 8.4, J = 1.6,1H), 7.36 (d, J = 8.4,1H), 4.28 (d, J = 7.2,2H), 1.31 (t, J = 7.2,3H),-13C NMR (DMSO-d6) 6 169.71,165.63,156.89,131.12,127.02,122.46,121.98, 117.05,60.31,14.22, MS (FAB+, m/z) 223 (M+H+). This compound (lg, 4.5 mmol) was dissolve in a mixture of DMF (15 mL) and dioxane (15 mL) bromoacetyl bromide (0.9 g, 0.48 ml) was added dropwise while keeping the interna temperature at +5° C. The rection mixture was warmed to rt and stirred for 20h. The rection mixture was poured into ice-water, and the light crystalline compound which formed was filtered, washed several times with cold water, and then dried to give 0.97 g.

1H(63%)2-[(Bromoacetyl)amino]-5-(carboethoxy)benzothiazole: NMR (DMSO-d6) 6 0413. (bs, 1H, NH), 8.66 (d, J = 1.6,1H), 8.01 (dd, J = 8.4,1.6,1H), 7.84 (d, J = 8.4,1H), 4.32 (s,

2H), 4.25 (s, 2H), 1.34 (t, J = 6.8,3H), 13C NMR (DMSO-ds) 8 166.50, 165.46, 161.10, 152.03, 131.80,127.19,125.08, 123.97,120.57,60.82,28.57,14.26, MS (EI, m/z) 1344. (M+).

Example14 Preparation of 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl)acetyl)amino)-4-chlorobenzothiazole (Compound EC) 1- (a, a, u-Trifluoro-m-tolyl) piperazine 18(3. g, 2.6 mL, 14 mmol) was added to a solution of 2- ( (bromoacetyl) amino)-4-<BR> chlorobenzothiazole 1(2. g, 7 mmol) in anhydrous DMF (25 mL) at rt. The rection mixture was heated and stirred at 50 OC for 5 h, cooled to rt, and slowly poured into ice water. The off-white precipitate which formed was filtered, washed several times with cold water, and then dried to give 1. 25 g (40%) of the title compound as an off-white solid, mp 168-171 °C: 1H NMR (DMSO-d6) # 12. 65 (bs, 1H), 7.97 (dd, J = 8.0, J =<BR> 1.2,1H), 7.53 (dd, J = 7.6, J = 0.8,1H), 7.41 (dd, J = 8.0,<BR> J = 8.0,1H), 7.31 (dd, J = 8.0, J = 8.0,1H), 7.22 (dd, J =

8.4, J = 2, 1H), 7.17 (s, 1H), 7.06 (d, J = 7.6, 1H), 3.45 (s, 2H), 3.27 (t, J = 4.8, 4H), 2.71 (t, J = 4.8,4H); 13C NMR (DMSO-d6) 6 52,169. 158.55, 151.14,145.32,133.01,129.88, 129.83 (q, J = 31), 126. 16,124.38,124.37 (q, J = 274), 124.36,120.79, 118. 71,114.48 (q, J = 4.2) 110.85 (q, J = 4.2), 59. 87, 52. 14 (2C), 47.56 (2C); MS (EI, m/z) 454 (M+).

Example15A Preparation of 2- ( (Bromoacetvl) amino)-6-fluorobenzothiazole Bromoacetyl bromide (6 g, 2.6 mL, 30 mmol) was added dropwise to a solution of 2-amino-6-fluorobenzothiazole (5 g, 30 mmol) in a mixture of DMF (15 mL) and dioxane (15 mL) while keeping the temperature of the rection mixture at 5 OC. After stirring at 5 °C for 1 h, the ice bath was removed and the rection mixture was stirred at rt for 7 h. The rection mixture was poured into ice water and the light crystalline compound which formed was filtered, washed several times with cold water, and then dried to give 6.2 <BR> <BR> <BR> (73%) of the title compound as a light solid: 1H NMR (DMSO-ds)<BR> <BR> <BR> <BR> <BR> 6 8012. (bs, 1H), 7.91 (dd, J = 8.8, J = 2.4,1H), 7.78 (dd, J = 8.8, J = 4.4,1H), 7. 31 (ddd, J = 9.2, J = 9.2, J = 2.4, <BR> <BR> <BR> 1H), 4.22 (s, 2H); 13C NMR (DMSO-d6) 8 14,166.13,-158.73172.

(d, J = 248.9), 145.19,132.73 (d, J = 10.6), 121.62 (d, J = 9.1), 114.18 (d, J = 21.9), 108.14 (d, J = 27. 20), 28.46 ; MS (EI, m/z) 288 (M+).

Example 15 Preparation of 2-(((-4(2-(Fluoro)phenyl)piperazin-1- yl) acetyl) amino)-6-fluorobenzothiazole (Compound EE) g,1.8mL,11.5mmol)1-(2-Fluorophenyl)piperazine(2.07 was added to a solution of 2-((bromoacetyl) amino)-6- <BR> <BR> <BR> fluorobenzothiazole (1.65 g, 5.73 mmol) in DMF (20 mL) at rt.

The rection mixture was heated and stirred at 90 °C for 7 h, cooled to rt, and poured into ice water. The ivory precipitate which formed was filtered, washed several times with cold water, and then dried to give 1.77 g (80%) of the title compound, mp 131.7-132. 5 °C: 1H NMR (DMSO-d6) # 8811.

(bs, 1H),. 7.91 (dd, J = 8.8, J = 2.4,1H), 7.75 (dd, J = 8. 8, J = 4.4, lH) ; 7.29 (ddd, J = 9.2, J = 9.2, J = 2.8, 1H),

7.16-6. 94 (m, 4H), 3.43 (s, 2H), 3.05 (t, J = 4.8,4H), 2.72 (t, J = 4. 8,4H); 13C NMR (DMSO-d6) 6 48,159.86,157.48,169.

154.97 (d, J = 245), 145.20,139.86 (d, J = 8.3), 132.70 (d, J = 10.7), 124.86,122.35 (d, J = 8.4), 121.66 (d, J = 9.2), 119.28,115.93 (d, J = 19.8), 114.28 (d, J = 24) 108.24 (d, J = 26.9), 60.08,52.54 (2C), 50.06,50.05; MS (EI, m/z) 388 <BR> <BR> <BR> (M+)<BR> (M*) Example16 Preparation of 2-(((4-(2-(Methoxy)phenyl)piperazin-1- EF)yl)acetyl)amino)-6-fluorobenzothiazole(Compound 1-(2-Methoxyphenyl) piperazine (1.34 g, 7 mmol) was added to a solution of 2-((bromoacetyl) amino)-6-fluorobenzothiazole (1 g, 3.47 mmol) in DMF (15 mL) at rt. The rection mixture was heated and stirred at 90 OC for 6 h, cooled to rt and poured into ice water. The light crystalline compound which formed was filtered, washed several times with cold water, and then dried to give 0.96 g (69%) of the title compound as a light beige solid, mp 135.9-136. 7 °C: 1H NMR (DMSO-d6) 6 7.90 (dd, J = 8.8, J = 2.8,1H), 7.58 (dd, J = 8.8, J = 4.8, 1H), 7.29 (ddd, J = 8.8, J = 6.4, J = 2.4,1H); 6.97- 6.84 (m, 4H), 3.76 (s, 2H), 3.41 (s, 3H), 2.99 (bs, 4H), 2.69 (bs, <BR> <BR> <BR> 4H); 13C NMR (DMSO-d6) 6 60,156.89,157.54169. (d, J = 6.9), 152.01,145.23,141.20,132.73 (d, J = 11.4), 122.51,121.69 (d, J = 9.2), 120.86,118.04,114.32 (d, J = 25), 111.85, 108.26 (d, J = 13), 60.26,55.33,52.79 (2C), 50.06 (2C); MS (EI, m/z) 400 (M+).

Example17 Preparation of 2-(((4-(2-Pyridyl) piperazin-l- vl) acetyl) amino)-6-fluorobenzothiazole (Compound DC) 1-(2-Pyridyl) piperazine (1.4 g, 1.4 mL, 8.6 mmol) was added to a solution of 2-((bromoacetyl) amino)-6- fluorobenzothiazole (1.23 g, 4.3 mmol) in DMF (20 mL) at rt.

The rection mixture was heated and stirred at 70 OC for 7 h, cooled to rt, and poured into ice water. The light beige precipitate which formed was filtered, washed several times with cold water, and dried. The product was refluxed in hexane for 30 min, filtered while hot, and then dried to give

1.1 g (70%) of the title compound, mp 195-197 °C: 1H NMR <BR> <BR> (DMSO-d6) 6 1612. (bs, 1H), 8.11- 8.10 (m, 1H), 8.10 (ddd, J = 4.8, J = 2.0, J = 0.8,1H) 7.90 (dd, J = 8.8, J = 2.8,1H), 7.75 (dd, J = 9. 2, J = 4.8,1H), 7.52 (ddd, J = 9. 2, J = 7. 2, J = 2,1H), 7.29 (ddd, J = 8.8, J = 8.8, J = 2.4,1H),. 6.81 (d, J = 8.4,1H), 6.63 (ddd, J = 7. 2, J = 5.2, J = 0.8,1H), 3.52 (t, J = 4.8,4H), 3.41 (s, 2H), 2.63 (t, J = 5.2,4H) ; 13C NMR (DMSO-d6) 6 48,158.97,158.66169. (d, J = 238), 157.47,147.56,145.19,137.53,132.69 (d, J = 10.6), 121.66 (d, J = 9. 2), 114.28 (d,, J = 24.4), 112.99,108.22 (d, J = 27), 107.10,60.17,52.31 (2C), 44.58 (2C); MS (EI, m/z) 371 (M+) (M+) Example18 2-(((4-(Benzyl)piperazin-1-yl)acetyl)amino)-6-Preparationof fluorobenzothiazole (Compound EG) 1-Benzylpiperazine (1.22 g, 1.2 mL, 7 mmol) was added to a solution of 2-((bromoacetyl) amino)-6-fluorobenzothiazole (1 g, 3.5 mmol) in DMF (10 mL) at rt. The rection mixture was heated and stirred at 70 OC for 7 h, cooled to rt,. and poured

into ice water. The light-ivory precipitate which formed was filtered, washed several times with cold water, and then dried to give 1.1 g (83%) of the title compound, mp 195-197 <BR> <BR> <BR> °C: 1H NMR (DMSO-d6) 6 0512. (bs, 1H), 7.89 (dd, J = 8. 8, J = 2.7,1H), 7.74 (dd, J = 8.8, J = 4.7,1H), 7.34-7.22 (m, 6H), 3.47 (s, 2H), 3.33 (s, 2H), 2.55 (bs, 4H), 2.41 (bs, 4H); 13C NMR (DMSO-d6) # 169.42, 158.80 (d, J = 242.6), 157.38,145.11,138.09,132.64 (d, J = 10.7), 128.74 (2C), 128.06 (2C), 126.81,121. 56 (d, J = 9. 2), 114.16 (d, J = 22.6), 108.10 (d, J = 27), 61.97,60.09,52.51,52.43 (2C); MS (EI, (M+).384 Example19 2-(((4-(4-methoxyphenyl)piperazin-1-Preparationof yl)acetyl) amino)-6-fluoro-benzothiazole (Compound DJ) 4-(4-Methoxyphenyl) piperazine (0.6 g, 2.95 mmol) and K2CO3 (1.3 g, 9.4 mmol) was added to a solution of 2- ((bromoacetyl) amino)-6-fluoro-benzothiazole (0.85 g, 2.95 mmol) in DMF (25 mL) at rt. The rection mixture was heated

and stirred at 55 OC for 6 h, cooled to rt, and slowly poured into ice water. The off-white precipitate which formed was filtered, washed several times with cold water, and then dried to give 0.72 g (6101) of the title compound as an off- white solin ; mp 128-129 OC (dec) : 1H NMR (DMSO-d6) b 12. 16 (bs, 1H), 7.89 (dd, J = 8.4, J = 2.4,1H), 7.75 (q, J = 4. 8, 1H), 7.29 (ddd, J = 9. 2, J = 9.2, J = 0.4, 1H), 6.89 (d, J = 9.2,2H), 6.81 (d, J = 9.2,2H), 3.68 (s, 3H), 3.41 (s, 2H), 3.04 (t, J = 4.8,4H), 2.69 (t, J = 4.8,4H); 13C NMR (DMSO- <BR> <BR> <BR> d6) 6 39,158.61169. (d, J = 240), 152.88,145.34,145.23 (d, J = 21.7), 132.60 (d, J = 18), 121.57 (d, J = 10), 117.38 (2C), 114.29 (2C), 114.17 (d, J = 8.3), 108.24, 107.97, 60.07,55.13,52.55 (2C), 48.54 (2C); MS (EI, m/z) 400 (M+).

Example20A 2-((Bromoacetyl)amino)-6-methoxybenzothiazolePreparationof Bromoacetyl bromide (5.6 g, 2.44 mL, 28 mmol) was added dropwise to a solution of 2-amino-6-methoxybenzothiazole (5 g, 28 mmol) in a mixture of DMF (20 mL) and dioxane (20, mL) while keeping the interna temperature of the rection mixture at 5 °C. After stirring at 5 OC for. 1 h, the ice bath was removed and the rection mixture was stirred for 7 h. The rection mixture was poured into water and the light crystalline compound which formed was filtered, washed several times with cold water, and then dried to give 5.1 g (61.3%) of the title compound as a white solid, mp 164-165 <BR> <BR> °C: 1H NMR (DMSO-d6) 6 6512. (s, 1H), 7.66 (d, J = 8.8, 1H), 7.59 (d, J = 2.4,1H), 7.04 (dd, J = 8.8, J = 2.4,1H), 4.20 (s, 2H), 3.81 (s, 3H); 13C NMR (DMSO-d6) 6 71,156.30,165.

155.48,142.53,132.81,121.33,115.10,104.77,55.62,28.53; MS (EI, m/z) 300 (M+).

ExamDle20 2-(((4-(2-Fluorophenyl)piperazin-1-Preparationof DD)yl)acetyl)amino)-6-fluorobenzothiazole(Compound 1-(2-Fluorophenyl) piperazine (1.77 g, 1.6 mL, 9.8 mmol) was added to a solution of 2-((bromoacetyl) amino)-6- methoxybenzothiazole (1.47 g, 4.9 mmol) in DMF (20 mL) at rt.

The rection mixture was heated and stirred at 70 OC for 7 h,

cooled to rt, and poured into ice water. The light precipitate which formed was filtered, washed several times with water, dried to give 1.75 g (79%) of the title compound, <BR> <BR> <BR> mp 131.7-132.5 OC: 1H NMR (DMSO-d6) 6 9011. (bs, 1H), 7.63 (d, J = 9. 0,1H), 7.58 (d, J = 2.4,1H), 7.15-6. 9 4 (m, 5H), 3.80 (s, 2H), 3.40 (s, 3H), 3.05 (t, J = 4.1,4H), 2.71 (t, J = <BR> <BR> <BR> 4.5,4H); 13C NMR (DMSO-d6) 6 09,156.17,155.42,154.97169.

(d, J = 242), 142.54,139.83,132.77,124.84,122.32,121.16, 119.26,115.94 (d, J = 20.6), 114.98,104.. 72,60.10,55.63, 52.60 (2C), 50.07 (2C), MS (EI, m/z) 400 (M+).

Example21 2-(((4-(2-Pyridyl)piperazin-1-Preparationof DE)yl)acetyl)amino)-6-methoxybenzothiazole(Compound 1-(2-Pyridyl) piperazine (8.4 g, 52 mmol) was added to a solution of 2-((bromoacetyl) amino)-6-methoxybenzothiazole (7.7 g, 26 mmol) in DMF (65 mL) at rt. The rection mixture was heated and stirred at 55 OC for 6 h, cooled to rt, and slowly poured into ice water. The yellow precipitate which formed was filtered, washed several times with cold water,

and then dried to give 7.7 g (78%) of the title compound, mp <BR> <BR> <BR> <BR> 199.5-201.0 OC: 1H NMR (DMSO-d6) 6 9211. (bs, 1H), 8.10 (ddd,<BR> <BR> <BR> <BR> <BR> <BR> <BR> J = 4.8, J = 2.0, J = 0.8, 1H), 7.63 (d, J = 9.2,1H), 7.57 (d, J = 2.4,1H), 7.50 (dd, J = 8.8, J = 8.8, J = 2.0,1H), 7.03 (dd, J = 8.4, J = 2.8,1H), 6.82 (d, J = 8.4,1H), 6.63 (ddd, J = 7.2, J = 5.2, J = 0.8,1H), 3.80 (s, 3H), 3.53 (t, J = 4.4,4H), 3.39 (s, 2H), 2.63 (t, J = 4.8,4H); 13C NMR (DMSO-d6) 6 01,158.92,156.13,155.36,147.48,142.50,169.

137.41,132.73,121.07,114.86,113.00,107.01,104.71, 60.14,55.58,52.26 (2C), 44. 55 (2C); MS (EI, m/z) 383 (M+).

Example22 2-(((4-(2-Pyridyl)piperazin-1-Preparationof yl)acetyl)amino)-6-methoxybenzothiazoleHydrochloride (CompoundDM) A solution of 2-(((4-(2-Pyridyl)piperazin-1- yl) acetyl) amino)-6-methoxybenzothiazole (0.9 g, 2.35 mmol) CH2C12 was treated with 1N HC1 ether solution (5 mL, 5 mmol).

The rection mixture was stirred at rt for 2 h and the precipitate which formed was filtered, washed several times with ether, and dried to give 0.74 g (6901) of the title

compound as an ivory solid, mp 233-236 *-C.

Example23 Preparation of 2-(((4-(2-Pyrimidyl)piperazin-1- yl) acetyl) amino)-6-methoxvbenzothiazole (Compound DF) 1-(2-Pyrimidyl) piperazine (1.2 g, 7.-3 mmol) was added to a solution of 2-((bromoacetyl) amino)-6-methoxybenzothiazole (1.1 g, 3.67 mmol) in anhydrous DMF (20 mL) at rt. The rection mixture was heated and stirred at 80 OC for 8 h, cooled to rt, and then poured into ice water. The light crystalline precipitate which formed was filtered, washed several times with cold water, and then dried to give 1.04 g (74%) of the title compound as a light beige solid, mp 224- <BR> <BR> 226.8 °C: 1H NMR (DMSO-d6) 6 0012. (bs, 1H), 8.36 (d, J = 4.4, 2H), 7.63 (d, J = 8,1H), 7.57 (d, J = 2.4, lH), 7.02 (dd, J = 8.8, J = 2.4,1H), 6.62 (t, J = 4.8,1H), 3. 80 (s, 3H), 3.78 (t, J = 4.8,4H), 3.39 (s, 2H), 2.59 (t, J = 4.8,4H) ; 13C NMR (DMSO-d6) 6 04,161.14,157.86169. (2C), 156.15, 155.35,142.51,132.74,121.09,114.89,110.04,104.72, 60.12,55.59,52.27 (2C), 43.21 (2C); MS (EI, m/z) 384 (M+).

ExamDle 25 Preparation of 2-(((4-(benzyl)piperazin-1-yl)acetyl) amino)-6- methoxvbenzothiazole (Compound DG) 1-Benzylpiperazine (2.4 g, 2.4 mL, 13.62 mmol) was added to a solution of 2-((bromoacetyl) amino)-6- methoxybenzothiazole (2 g, 6.8 mmol) in anhydrous DMF (25 mL) at rt. The rection mixture was heated and stirred at 60 OC for 5 h, cooled to rt, and poured into ice water. The light beige precipitate which formed was filtered, washed several times with cold water, and then dried to give 2.18 g (830) of the title compound as an off-white solid, mp 107-110 °C : 1H NMR (DMSO-d6) b 11. 80 (bs, 1H), 7.62 (d, J = 8.8,1H), 7. 56 (d, J = 2.4,1H), 7.30-7. 24 (m, 4H), 7. 02 (dd, J = 8.8, J = 2.8,1H), 3.80 (s, 3H), 3.62 (s, 2H), 3.31 (s, 2H), 2.55 (bs, 4H), 2.41 (bs, 4H) ; 13C NMR (DMSO-d6) 6 02,156.11,169.

155.28,142. 49, 138.13, 132.71,128.74,128.07,126.81,

121.06,114.85,104.72,61.98,60.10,55.58; 13C NMR (DMSO-d6)<BR> <BR> <BR> <BR> <BR> <BR> 6 49,138.13,132.71,128.74,128.07,126.81,121.06,142.

114.85,104.72,61.98,60.10,55.58,52.54,52.45; MS (EI, (M+).m/z)396 Example 26 Preparation of 2- (((4-(Phenyl) piperazin-l-vl) acetvl) amino)-6- EI)methoxybenzothiazole(Compound 1-Phenylpiperazine (1.73 g, 13.4 mmol) was added to a solution of 2-((bromoacetyl) amino)-6-methoxybenzothiazole (1.6 g, 6.7 mmol) in anhydrous DMF (25 mL) at rt. The rection mixture was heated and stirred at 55 OC for 6 h, cooled to rt, and poured into ice water. The precipitate which formed was filtered, washed several times with cold water, and then dried to give 1.35 g (66%) of the title compound as a light ivory solid, mp 196-196.8 °C: 1H NMR <BR> <BR> <BR> (DMSO-d6) 6 0312. (bs, 1H), 7.63 (d, J = 8.8,1H), 7.58 (d, J 2.8,1H), 7.20 (dd, J = 8.4, J = 7.2,2H), 7.03 (dd, J = <BR> <BR> <BR> <BR> 8.8, J = 2.8,1H), 6.93 (d, J = 8,2H), 6.77 (dd, J 7.2, J = 7. 2,1H), 3.81 (s, 3H), 3.41 (s, 2H), 3.17 (t, J = 4. 4, 4H), 2.70 (t, J = 4.4,4H); 13C NMR (DMSO-d6) 6 91,168.

156.12,150.91,142.49,132.71,128.84 (2C), 121.07,118.77, 115.39 (2C), 114.86,104.72,60.03,55.58,52.44 (2C), 48.12 (2C); MS (EI, m/z) 382 (M+).

Example 27 Preparation of 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- vl) acetyl) amino)-6-methoxybenzothiazole (Compound DH) 1- (u, u, a-Trifluoro-m-tolyl) piperazine (9.24 g, 7.5 mL, 40 mmol) was added to a solution of 2-((bromoacetyl) amino)-6- methoxybenzothiazole (6.0 g, 20 mmol) in DMF (55 mL) at rt.

The rection mixture was heated and stirred at 45 OC for 5 h, cooled to rt, and slowly poured into ice water. The milky suspension was allowed to-stand overnight and then extracted with EtOAc (3 x 30 mL). The combine EtOAc layer was washed with water, brine, dried (Na2SO4), and then concentrated. The brown oily residue was treated with a small amount of EtOAc and then hexane, causing a light-beige precipitate to form.

The suspension was stirred for 1 h, and filtered to give a

solid product which was triturated with hexane and cold ether, and then dried to give 4.3 g (48%) of the title compound, mp 124-125 OC: 1H NMR (DMSO-d6) 6 0512. (bs, 1H), 7.63 (d, J = 8.8,1H), 7.57 (d, J = 2.4, 1H), 7.41 (t, J = 8.0,1H), 7.23 (dd, J = 8, J = 2.4,1H), 7.17 (s, 1H), 7.06 (d, J = 7.6, lH), 7.02 (dd, J = 8.8, J = 2.8,1H), 3.80 (s, 3H), 3.41 (s, 2H), 3.27 (t, J = 4.4,4H). 2.70 (t, J = 4.8, 4H); 13C NMR (DMSO-d6) 6 02,156.19,169. 155. 42,151.19, 142.53,132.76,129.97,129.86 (q, J = 31), 124.45, (q, J = 271), 121.14,118.76,114.94,114.57 (q, J = 3.9), 110.92 (q, J = 3.8), 104.72,60.00, 55. 61, 52. 26,47.58; MS (EI, m/z) <BR> <BR> <BR> 450 (M').<BR> <BR> <BR> <P> Example28 Preparation of 2-(((4-(4-(Acetyl)phenyl)piperazin-1- vl) acetvl) amino)-6-methoxybenzothiazole

1- (4-Acetylphenyl) piperazine 9(2. g, 14.0 mmol) was added to a solution of 2-((bromoacetyl)amino)-6- <BR> <BR> <BR> methoxybenzothiazole 2(2. g, 7.0 mmol) in DMF (15 mL). The rection was heated and stirred at 70 OC for 7 h, cooled to rt, and slowly poured into ice water. The yellow precipitate which formed was filtered, washed several times with cold water, and then dried to give 31. g (64%) of the title compound, mp 2176-178. °C ("wet" 98-98. 2 OC) 1H NMR (DMSO-ds) <BR> <BR> <BR> 6 9011. (bs, 1H), 7.78 (d, J = 8.8, 2H), 7.64 (d, J = 8.8,<BR> <BR> <BR> <BR> <BR> <BR> 1H), 7.57 (d, J = 2.4,1H), 7.02 (dd, J = 8. 8,2.8,1H), 6.97<BR> <BR> <BR> <BR> <BR> <BR> (d, J = 8.8,2H), 3.80 (s, 3H), 3.40 (s, 2H), 3.36 (t, J = 4.8,4H), 2.68 (t, J = 4.4,4H), 2.45 (s, 3H); 13C NMR (DMSO- <BR> <BR> <BR> <BR> d6) 6 58,169.04,168.92,156.16,155.42,153.78,195. 142. 53; 132.76,130.09 (2C), 126.62,121.15,114.95,113.15 (2C), 104.71,59.99,55.62,52.13 (2C), 46.64 (2C), 26.11; MS (EI, (M+).m/z)440

Example 29 Preparation of 2-(((4-(3-Methylphenyl) piperazin-l- yl) acetyl) amino ?-6-methoxybenzothiazole (Compound DV) 1- (3-Methylphenyl) piperazine (1.4 g. 8 mmol) and K2CO3 (3.33 g, 24 mmol) were added to a solution of 2- ((bromoacetyl) amino)-6-methoxybenzothiazole (2.4 g, 8 mmol) in anhydrous DMF (20 mL) at rt. The rection mixture was heated and stirred at 70 OC for 7 h, cooled to rt, and poured into ice water. The crystalline precipitate which formed was filtered, washed several times with cold water, and then dried to give 2 g (63*1) of the title compound as a light solid, mp 73-75 OC: 1H NMR (DMSO-d6) 6 0112. (bs, 1H), 7.64 (d, J = 8.8,1H), 7.57 (d, J = 7.6,1H), 7. 08 (dd, J = 8.0, J = 8.0,1H), 7.02 (dd, J = 8.8, J = 2.8, 1H), 6.75 (s, 1H), 6.72 (d, J = 8.4,1H), 6.59 (d, J = 7.2, 1H), 3.81 (s, 3H), 3.39 (s, 2H), 3.15 (t, J = 4.4, 4H), 2.68 (t, J = 4.4,4H), 2.24 (s, 3H); 13C NMR (DMSO-d6) 6 96,156.12,155.32,168.

150.96,142.50,137.87,132.72,128.65,121.06,119.61, 116.08,114.85,112.61,104.72,60.08,55.57,52.48 (2C), 48.21 (2C), 21.33; MS (EI, m/z) 397 (M').

Example 30 2-(((4-(4-(Methoxycarbonyl)phenyl)piperazin-1-Preparationof vl) acetyl) amino)-6-methoxybenzothiazole (Compound EJ) 1-((4-Methoxycarbonyl) phenyl) piperazine (0.9 g, 4 mmol) and K2CO3 (1.7 g, 12 mmol) were added to a solution of 2- ((bromoacetyl) amino)-6-methoxybenzothiazole (1.2 g, 4 mmol) in anhydrous DMF (20 mL) at rt. The rection mixture was heated and stirred at 60 OC for 6 h, cooled to rt, and poured into ice water. The crystalline compound which formed was filtered, washed several times with cold water, and then dried to give 1.3 g (740) of the title compound as a light <BR> <BR> solid, mp 211-213 °C: 1H NMR (DMSO-d6) 6 9011. (bs, 1H), 7.78 (d, J = 8.8,2H), 7.63 (d, J = 8.8,1H), 7.57 (d, J = 2. 4, 1H), 7.03 (dd, J = 8.8, J = 2.8, 1H), 6.98 (d, J = 8.8,2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.40 (s, 2H), 3.36 (t, J = 4.8,

4H), 2.68 (t, J = 4.8, 4H) ; 13C NMR (DMSO d6) 6 92,168.

166.05,156.12,155.32,153.76,142.50,132.72,130.63 (2C), 121. 06, 118.08,114.85,113.31 (2C), 104.71,59.93,55.57, 52.09 (2C), 51.35,46.59 (2C) ; MS (EI, M/Z) 440 (M').

EXamP1e31 2-(((4-(4-(Trifluoromethyl)phenyl)piperazin-1-Preparationof yl) acetyl) amino)-6-methoxybenzothiazole (Compound DU) 1- (a, a, u-Trifluoro-p-tolyl) piperazine (2 g, 8. 6 mmol) was added to a solution of 2-((bromoacetyl)amino)-6- methoxybenzothiazole (1. 3 g, 4.3 mmol) in DMF (20 mL) at. rt.

The rection mixture was heated and stirred at 60 OC for 6 h, cooled to rt, and slowly poured into ice water. The light crystalline compound which precipitated was filtered, washed several times with cold water, and then dried to give 0. 75 g (38. 5% of the title compound, mp 3218-219. °C: 1H NMR (DMSO- <BR> <BR> d6) 6 647. (d, J = 8.8,1H), 7.57 (d, J = 2.4,1H), 7.50 (d, J<BR> <BR> <BR> = 9. 2,2H), 7.06 (d, J = 9.2,2H), 7.03 (dd, J = 8.8, J =<BR> <BR> <BR> 2.4,1H), 3.81 (s, 3H), 3.40 (s, 2H), 3.34 (bs, 4H), 2.69 Et, J = 4. 8,4H); 13C NMR (DMSO-d6) # 168. 99, 156.16,155.38, 153.18,142.52, 132.75, 126.11 (q, J = 5), 121.10, 117. 79 (q, J = 32), 114.90,114.17 (2C), 113.70 (q, J = 264), 104.74 (2C), 59.97,55.60,52.11 (2C), 46.95 (2C); MS (EI, m/z) 450 (M+).

Example 32 Preparation of 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- <BR> <BR> vl) acetYl) amino)-6-methoxybenzothiazole Hvdrochloride<BR> <BR> <BR> (Compound DT)<BR> <BR> <BR> <BR> A solution of 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-6- <BR> <BR> methoxybenzothiazole 5(0. g, 1.11 mmol) in CH2C12 (15 mL) was treated with 1N HC1 ether solution (3 mL, 3 mmol). The mixtire was stirred for 1h, and the precipitate which formed was filtered and dried to give 350. g 301)(60. of the title compound as a ivory solid, mp 3-260.8260. OC.

ExamPle33 Preparation of 2-(((4-(4-Chlorobenzhydryl)piperazin-1- vl) acetYl) amino)-6-methoxybenzothiazole (Compound DX) 1- (4-Chlorobenzhydryl) piperazine (1 g, 3. 7 mmol) and K2CO3 (1.52 g, 7.4 mmol) were added to a solution of 2- ((bromoacetyl) amino)-6-methoxybenzothiazole (1.1 g, 3.7 mmol) in anhydrous DMF. The rection mixture was heated and stirred at 70 OC for 7 h, cooled to rt, and poured into ice water. The light precipitate which formed was filtered, washed several times with cold water, and then dried. The solid was triturated with hexane, filtered, and dried to give 1.4 g (75k) of the title compound as a off-white solid, mp 124.2-126.0 °C ("wet"at 119 °c: 1H NMR (DMSO-d6) 6 5511.

(bs, 1H), 7.62 (d, J = 9.2,1H), 7.56 (d, J = 2.4,1H), 7.45- 7.33 (m, 6H), 7.29 (dd, J = 7.2, J = 7.2,2H), 7.19 (dd, J = 7.2,1H), 7.02 (dd, J = 8.8, J = 2.8,1H), 4.33 (s, 1H), 3.80 (s, 2H), 3.32 (s, 3H), 2.58 (bs, 4H), 2.33 (bs, 4H); 13C NMR (DMSO-d6) 6 97,156.11,155.26,142.49,142.14,141.78,168.

132.70,131.23,129.32,129.32 (2C), 128.51 (2C), 128.40 (2C), 127.53,126.94,121.05,114.84,104.71,73.94,59.93, 55.57,52.54 (2C), 51.23 (2C).

ExamPle34 Preparation of 2- ( ( (4- (3-Chlorophenvl) piperazin-1- DO)yl)acetyl)amino)-6-methoxybenzothiazole(Compound Rection of 2- ( (bromoacetyl) amino)-6- methoxybenzothiazole (1.0 g, 3.32 mmol) and 1- (3- chlorophenyl) piperazine (1.30 g, 6.64 mmol) in DMF (30 mL) according to representative procedure in Example 36, gave 0.68 g (590) of the title compound as a solid, mp 159-160 OC: <BR> <BR> <BR> H NMR (DMSO-d6) 6 0312. (bs, 1H), 7.63 (d, J = 9.2, 1H), 7.57 (d, J = 2.4, 1H), 7.20 (dd, J = 8.0, J = 8.0,1H), 7.02 (dd, J = 8. 8, J = 2.8,1H), 6.94 (dd, J = 2.0, J = 2.0,1H), 6.88 (dd, J = 8.4, J = 2.0,1H), 6.77 (dd, J = 7. 6, J = 1. 6,1H), 3.80 (s, 3H), 3.39 (s, 2H), 3.21 (t, J = 4. 8, 4H), 2.67 (t, J = 4.8,4H); 13C NMR (DMSO-d6) 6 94,156.12,155.35,168.

152.13,142.49,133.75,132.72,130.31,121.06,117.95, 114.85,114.52,113.61,104.70,59.99,55.56,52.21 (2C), 47.59 (2C); MS (EI, m/z) 416 (M+). Anal. Calcd for

C20H21N4ClO2S: C,. 57.62; H, 5.08; N, 13.44. Found: C, 57.28; H, 5.29 ; N, 13.22.

Example35 2-(((4-(3-Bromophenyl)piperazin-1-Preparationof yl) acetyl) amino)-6-methoxybenzothiazole (Compound DP) Rection of 2- ((bromoacetyl) amino)-6- methoxybenzothiazole (1.0 g, 3.32 mmol) and 1-(3- bromophenyl) piperazine (1.60 g, 6.64 mmol) in DMF (30 mL) according to representative procedure in Example 36, gave 0.85 g (55%) of the title compound as a solid, mp 125-126 OC: <BR> <BR> H NMR (DMSO-d6) 6 0312. (bs, 1H), 7.63 (d, J = 8.8,1H), 7. 57 (d, J = 2.8,1H), 7.14 (dd, J = 8.0, J = 8.0 1H), 7.07 (dd, J 2.0, J = 2.0,1H), 7.02 (dd, J = 8.8, J = 2.8, 1H), 6.94- 6.89 (m, 2H), 3.80 (s, 3H), 3.39 (s, 2H), 3.21. (t, J = 4.4, 4H), 2.67 (t, J = 4.8,4H); 13C NMR (DMSO-d6) 6 93,168.

156.13,155.33,152.30,142.50,132.72,130.63,122.45, 121.08,120.90,117.37,114.87,114.03,104.71,59.98,55.58, 52.22 (2C), 47.60 (2C); MS (EI, m/z) 462 (M+). Anal. Calcd for C20H21N4BrO2S : C, 52. 07; H, 4.59; N, 12.14. Found: C, 52.19; H, 4.78; N, 11.92.

Example36 Preparation of 2-(((4-(3-Nitrophenyl)piperazin-1- DO)yl)acetyl)amino)-6-methoxybenzothiazole(Compound A solution of 2-((bromoacetyl) amino)-6- methoxybenzothiazole (1.0 g, 3.32 mmol) and 1-(3- nitrophenyl) piperazine (1.37 g, 6.64 mmol) in DMF (30 mL) was stirred at rt for 5 min. The mixture was poured into ice- water (200 mL), and extracted with EtOAc (3 x 50 mL). The organic layer was dried (MgSO$), filtered, and then concentrated. The residue was purifie by chromatography on silica gel, eluting with hexane-ethyl acetate (2: 1) to give 1.08 g (76%) of the title compound as an orange solid, mp

170-172 °C: 1H NMR (DMSO-d6) 6 0512. (s, 1H), 7.65-7.62 (m, 2H), 7. 59 - 7.56 (m, 2H), 7.46 (dd, J = 8.0, J = 8.0,1H), 7.39 (ddd, J = 8.4, J = 2.4, J = 0.8,1H), 7.02 (dd, J = 8.8, J = 2. 4,1H), 3.80 (s, 3H), 3.42 (s, 2H), 3.32 (t, J = 4.4, 4H), 2.71 (t, J = 4.8,4H); 13C NMR (DMSO-ds) b 94,168.

156.13,155.35,151.47,148.80,142.49,132.72,130.05, 121.27,121.06,114.85,112.58,108.33,1. 04.70,59. 92, 55.57, 52.08 (2C), 47.42 (2C); MS (EI, m/z) 427 (M+). Anal. Calcd for C20H21N404S: C, 56. 19; H, 4.95; N, 16.38. Found: C, 56.28; H, 5.12; N, 16.27.

Example37 Preparation of 2-(((4-(3-Cyanophenyl)piperazin-1- vl) acetYl) amino)-6-methoxybenzothiazole (Còmpound EK) Reaction of 2-((bromoacetyl)amino)-6- methoxybenzothiazole (1.0 g, 3.32 mmol) and 1-(3- cyanophenyl) piperazine (1.24 g, 6.64 mmol) in DMF (30 mL) according to representative procedure in Example 36, gave 0. 99 g (73%) of the title compound as a solid, mp 201-202 OC: <BR> <BR> H NMR (DMSO-d6) b 0312. (s, 1H), 7.63 (d, J = 9. 2,1H), 7.57 (d, J = 2.4, 1H), 7.38 (dd, J = 8.8, J = 8.8,1H), 7.33 (s, 1H), 7.26 (dd, J = 8.4, J = 2. 4,1H), 7.15 (d, J = 7.2,1H), 7.03 (dd, J = 8. 8, J = 2.4,1H), 3.81 (s, 3H), 3.40 (s, 2H), 3.27 (t, J = 4. 8,4H), 2.68 (t, J = 4.4,4H); 13C NMR (DMSO- <BR> <BR> <BR> d6) 6 96,156.14,155.36,150.97,142.50,132.73,130.08,168.

121.51,121.08,119.60,119.25,117.60,114.87,111.89, 104.72,59.95,55.58,52.10 (2C), 47.30 (2C); MS (EI, m/z 407 (M+). Anal. Calcd for C2lH2lN502S: C, 61.90; H, 5.19; N, 17.19. Found: C, 60.40; H, 5.22; N, 16.59.

Example38 Preparation of 2-(((4-(3-Ethylphenyl) PiPerazin-1- Xl) acetyl) amino)-6-methoxy benzothiazole (ComPound EL) Rection of 2-((bromoacetyl) amino)-6- methoxybenzothiazole (1.0 g, 3.32 mmol) and 1-(3- ethylphenyl) piperazine (1.26 g, 6.64 mmol) in DMF (30 mL) according to representative procedure in Example 36, gave

0.80 g (59%) of the title compound as a solid, mp 60-62 °C: 1H <BR> <BR> NMR (DMSO_d6) 6 0112. (s, 1H), 7.64 (d, J = 8.8,1H), 7.57 (d, J = 2. 4, 1H), 7.11 (dd, J = 8.0, J = 8.0,- 1H), 7.03 (dd, J = 8.8, J = 2.8,1H), 6.77 (s, 1H), 6.73 (dd, J = 8.0, J = 2.0, 1H), 6.63 (d, J = 7. 6,1H), 3.81 (s, 3H), 3.39 (s, 2H), 3.16 (t, J = 4.4,4H), 2.69 (t, J = 4.4,4H), 2.53 (q, J = 7.6, 2H), 1.15 (t, J = 7.6,3H) ; 13C NMR (DMSO d6) 6 97,168.

156.13,155.34,151.04,144.37,142.50,132.72,128.73, 121.07,118.41,115.05,114.87,112.86,104.73,60.07,55.58, 52.50 (2C), 48.27 (2C), 28.49,15.63; MS (EI, m/z 410 (M+).

Anal. Calcd for C22H2, N402S: C, 64.37; H, 6.38; N, 65.13.

Found: C, 62.32; H, 6.37; N, 50.13.

Example39 2-(((4-(3-Methoxyphenyl)piperazin-1-Preparationof vl) acetvl) amino)-6-methoxybenzothiazole (CompoundEM) Rection of 2-((bromoacetyl) amino)-6- methoxybenzothiazole (1.0 g, 3.32 mmol) and 1-(3- methoxyphenyl) piperazine (1.28 g, 6.64 mmol) in DMF (30 mL) according to representative procedure in Example 36, gave

0.97 g (7001) of the title compound as a solid, mp 142-145 OC: 1H NMR (DMSO-d6) # 12.00 (s, 1H), 7.63 (d, J = 8.8, 1H), 7.57 <BR> <BR> (d, J = 2.8,1H), 7.10 (dd, J = 8.0, J = 8.0,1H), 7.02 (dd,<BR> <BR> <BR> J = 8.8, J = 2.8, 1H), 6.51 (dd, J = 8.4, J = 1.6,1H), 6.45<BR> <BR> <BR> (bs, 1H), 6.35 (dd, J = 8. 4, J = 2.0,1H), 3.80 (s, 3H), 3.71 (s, 3H), 3.39 (s, 2H), 3.16 (t, J = 4.0,4H), 2.68 (t, J = 4.0,4H); 13C NMR (DMSO-d6) # 95,160.15,156.13,155.33,168.

152.28,142.50,132.72,129.50,121.05,114.84,108. 05, 104.71,104.09,101.53,60.06,55.56,54.79,52.41 (2C), 48.11 (2C); MS (EI, m/z) 412 (M+). Anal. Calcd for C2lH24N403S: C, 61.15; H, 5.86; N, 13.58. :Found C, 34;61. H, 5.99; N, 13.49.

Example 40 Preparation of 2-(((4-(4-Bromo-3- trifluoromethylphenyl) piperazin-l-vl) acetyl) amino)-6- DW)methoxybenzothiazole(Compound Rection of 2-((bromoacetyl) amino)-6- methoxybenzothiazole (0.7 g, 2.32 mmol) and 1-(4-bromo-3- trifluoromethylphenyl) piperazine (1.43 g,-4.64 mmol) in DMF (30 mL) according to representative procedure in Example 36, gave 0.90 g (73%) of the title compound as a solid, mp 182- 183 °C :'H NMR (DMSO-d6) 6 0012. (s, 1H), 7.63 (t, J = 8.8, 1H), 7.61 (d, J = 8.4,1H), 7.57 (d, J = 2.4, 1H), 7.25 (d, J = 2. 8,1H), 7.11 (dd, J = 8.8, J = 2.8,1H), 7.03 (dd, J = 8.8, J = 2.8,1H), 3.80 (s, 3H), 3.40 (s, 2H), 3. 28 (t, J = 4.4,4H), 2.69 (t, J = 4.8,4H); 13C NMR (DMSO-d6) 6 91,168.

156.14,155.32,149.99,142.50,135.23,132.72,128.61 (q, J = 30. 4), 123.05 (q, J = 272.3), 121.07,119.83,114.86, 113.74 (q, J = 6.0), 105.57,104.71,59.89, 55. 57,52.03 (2C), 47.28 (2C); MS (EI, m/z) 529 (M+). Anal. Calcd for C21H20N4O2SF3Br : C, 47.65; H, 3.81; N, 10.58. Found: C, 47.68; H, 3.95; N, 10.41.

Example41 2-(((4-(2-Naphthyl)piperazin-1-Preparationof vl) acetyl) amino)-6-methoxybenzothiazole (Compound EN) Rection of 2-((bromoacetyl) amino)-6- methoxybenzothiazole (1.0 g, 3.32 mmol) and 1-(2- napthyl) piperazine (1.41 g, 6.64 mmol) in DMF (30 mL) according to representative procedure in Example 36, gave 0.87 g (60%) of the title compound as a solid, mp 192-195 OC: H NMR (DMSO-d6) # 0312. (s, 1H), 7.76-7.70 (m, 3H), 7.64 (d, J = 8.8,1H), 7.58 (d, J = 2.8,1H), 7.40-7.35 (m, 2H), 7.25 (ddd, J = 8.0, J = 6.8, J = 1.2,1H), 7.16 (d, J = 2.4, 1H), 7.03 (dd, J = 8. 8, J = 2.8,1H), 3.81 (s, 3H), 3.43 (s, 2H), 3.30 (t, J = 4. 4,4H), 2.75 (t, J = 4.4,4H); 13C NMR (DMSO-d6) 6 97,156.13,155.32,148.75,142.51,134.27,168.

132.72,128.29,127.63,127.11,126.40,126.00,122.81, 121.07, 118.91,114.86,109.08,104.72, 60.06,55.57,52.41 (2C), 48.40 (2C); MS (EI, m/z) 432 (M+). Anal. Calcd for

C24H24N402S : C, 66. 64; H, 5.59; N, 12.95. Found: C, 66.20; H, 12.805.67;N,

Example 42 Preparation of 2- ( ( (4- (3-Methoxy-5- trifluoromethylphenylLpiperazin-1-vl) acetyl) amino)-6- DY)methoxybenzothiazole(Compound Reaction of 2-((bromoacetyl)amino)-6- methoxybenzothiazole (1.0 g, 3.32 mmol) and 1- (3-methoxy-5- (trifluoromethylphenyl) piperazine (1.28 g, 6.64 mmol) in DMF (30 mL) according to representative procedure in Example 36 gave 0.78 g (49%) of the title compound as a solid, mp 69-71 °C: 1H NMR (DMSO-d6) 6 0212. (s, 1H), 7.63 (d, J = 8.8,1H), 7.57 (d, J = 2.8, 1H), 7.02 (dd, J = 8. 8, J = 2. 8,1H), 6.79 (bs, 1H), 6.70 (t, J = 2. 4,1H), 6.61 (bs, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.40 (s, 2H), 3.27 (t, J = 5.2,4H), 2.69 (t, J = 4. 4,4H); 13C NMR (DMSO-d6) 6 92,160.56,156.12,168.

155.32,152.50,142.49,132.71,130.65 (q, J = 31.1), 124.19 (q, J = 270.8), 121.04,114.84,104.71,104.25, 103. 95 (q, J = 3. 8), 100.21 (q, J = 3.8), 59.92,55.56,55.36,52.17 (2C), 47.56 (2C). Anal. Calcd for C22H23N403SF3: C, 54.99; H, 4.82; N, 11.66. Found: C, 54.97; H, 4.94; N, 11.36.

Example43 2-(((4-(3,4-Dichlorophenyl)piperazin-1-Preparationof vl) acetyl) amino)-6-methoxybenzothiazole (CompoundEO) Rection of 2-(bromoacetyl) amino)-6- methoxybenzothiazole (1.0 g, 3.32 mmol), 1- (3,4- dichlorophenyl) piperazine (1.0 g, 4.40 mmol) and anhydrous K2CO3 (0.61 g, 4.40 mmol) in DMF (30 mL) according to representative procedure in Example 36 gave 0.98 g (65%) of the title compound as a solid, mp 187-190 OC: 1H NMR (DMSO-d6) 6 9111. (bs, 1H), 7.63 (d, J = 9.2,1H), 7.56 (d, J = 2.8, 1H), 7.38 (d, J = 9.2,1H), 7.12 (d, J = 2.8,1H), 7.02 (dd, J 8.8, J = 2.4,1H), 6.92 (dd, J = 9.2, J = 2.8,1H), 3.80 (s, 3H), 3.39 (s, 2H), 3.22 (t, J = 4.8,4H), 2.66 (t, J = <BR> <BR> <BR> 4.8,4H); 13C NMR (DMSO-d6) 6 03,156.18,155.43,150.70,169.

142.54,132.78,131.49,130.45,121.15,119.53,116.25, 115.32,114.95,104.73,59.98,55.62,52.13 (2C), 47.51 (2C); MS (EI, (M+).Anal.CalcdforC20H20N4O2SCl2:C,450 53.22; H, 4.47; N, 12.41. Found: C, 52.96; H, 4.52; N, 12.25.

Example 44 2-(((4-(3,5-Dichlorophenyl)piperazin-1-Preparationof yl) acetyl) amino)-6-methoxvbenzothiazole (Compound EP) Rection of 2-((bromoacetyl) amino)-6- methoxybenzothiazole (1.0 g, 3.32 mmol), 1- (3,5- dichlorophenyl) piperazine (1.0 g, 4.40 mmol) and anhydrous K2CO3 (0.61 g, 4.40 mmol) in DMF (30 mL) according to representative procedure in Example 36 gave 1.01 g (67*-0) of <BR> <BR> the title compound as a solid, mp 80-81 °C: 1H NMR (DMSO-d6) 6<BR> <BR> <BR> 12.03 (bs, 1H), 7.63 (d, J = 9.2,1H), 7.57 (d, J = 2. 4,1H), 7.03 (dd, J = 8.8, J = 2.4,1H), 6.94 (d, J=1. 6,2H), 6.85 (t, J = 1.6,1H), 3.81 (s, 3H), 3.39 (s, 2H), 3. 27 (t, J = 4.8,4H), 2.65 (t, J = 4.8,4H); 13C NMR (DMSO-d6) # 168. 97, 156.15,155.43,152.59, 142. 52,134.61,132.74,121.12, 116.93,114.92,113.02 (2C), 104.72,59.91,55.59,52.05 (2C), 47.14. Anal. Calcd for C20H20N402SC12: C, 53.22; H, 4.47; N, 12.41. Found: C, 53. 04; H, 4.68; N, 11.99.

Example45A Preparation of 2-((Bromoacetyl) amino)-4-methoxvbenzothiazole Bromoacetyl bromide (4.48 g, 2 mL, 22 mmol) was added dropwise to a solution of 2-amino-4-methoxybenzothiazole (4 g, 22 mmol) in a mixture of DMF (20 mL) and dioxane (20 mL) while keeping the interna temperature of the rection mixture at 5 OC. After stirring at 5 OC for 1 h, the ice bath was removed and the rection mixture was stirred for 20 h. The rection mixture was poured into water and the light crystalline compound which formed was filtered, washed several times with cold water, and then dried to give 2.7 g (41%) of the title compound as a white solid, mp 204.8-206 <BR> <BR> °C: 1H NMR (DMSO-d6) 6 9112. (s, 1H), 7.54 (dd, J = 7.6, J = 0.4,1H), 7.28 (dd, J = 8.0, J = 8.0, 1H), 7.00 (dd, J = 8.0, <BR> <BR> J = 0.4,1H), 4.19 (s, 2H), 3.91 (s, 3H) ; 13C NMR (DMSO-d6) 6 165.71,155.92,151.90,138.33,132.85,124.77,113.54, 107.81,55.83,28.44; MS (EI, m/z) 300 (M+).

Example 45 Preparation of 2-(((4-(2-Pyridyl)piperazin-1-yl)acetyl) amino- 4-methoxybenzothiazole (Comgound DI)

1-(2-Pyridyl) piperazine (1.15 g, 1.2 mL, 7.01 mmol) was added to a solution of 2- ( (bromoacetyl) amino)-4= methoxybenzothiazole (1.05 g, 3.51 mmol) in DMF. (20 mL) at rt. The rection mixture was heated and-stirred at 50 OC for 5 h, cooled to rt, and slowly poured into ice water. The off-white precipitate which formed was filtered, washed several times with water, and then dried to give 1.15 g (85%) of the title compound as an off-white solid, mp 233-235 OC: <BR> <BR> <BR> 1H NMR (DMS°-d6) 6 1812. (bs, 1H), 8. 10 (d, J = 3.6,1H), 7.52 (d, J = 7.6,1H), 7.51-7.50 (m, 1H), 7.26 (dd, J = 8.0, J = 8.0,1H), 7.00 (d, J = 8.0,1H), 6.81 (d, J = 8.4, 1H), 6.63 (dd, J = 6.4, J = 4.8,1H), 3.91 (s, 3H), 3.53 (t, J = 4.8, 4H), 3.39 (s, 2H), 2.63 (t, J = 4.8,4H); 13C NMR (DMSO-d6) 6 169.09,158.81,155.77,151.81,147.48,138.27,137.40, 132.78,124.50,113.44,112.86,107.66,106.99,60.16,55.71, <BR> <BR> <BR> 52.25 (2C), 44.53 (2C) ; MS (EI, m/z) 383 (M+).<BR> <BR> <BR> <BR> <BR> <P> Example46A Preparation of 2-((Bromoacetyl) amino)-6-ethoxybenzothiazole Bromoacetyl bromide (9.98 g, 4.4 mL, 49 mmol) was added dropwise to a solution of 2-amino-6-ethoxybenzothiazole (9.6 g, 49 mmol) in a mixture of DMF (30 mL) and dioxane (30 mL) while keeping the interna temperature of the rection mixture at 5 OC. After stirring at 5 OC for 1 h, the ice bath was removed and the rection mixture was stirred for 20 h. The rection mixture was poured into water and the light- beige crystalline compound which formed was filtered, washed several times with cold water, and then dried to give 12.24 g (79%) of the title compound as a light beige solid, mp 161.6- <BR> <BR> <BR> 163.2 °C: 1H NMR (DMSO-ds) b 6312. (bs, 1H), 7.65 (d, J = 8.8, 1H), 7.57 (d, J = 2.4,1H), 7.02 (dd, J = 9.2, J = 2.8,1H), 4.20 (s, 2H), 4.06 (q, J = 6.8,2H), 1.35 (t, J = 7. 2,3H) ; 13C NMR (DMSO-d6) 6 59,155.49,142.42,141.80,132.76,165.

121.29,115. 41,105.39,65.59,28.49,14.61; MS (EI, m/z) 384 (M+).

Example 46 Preparation of 2-(((-((2-Pyridyl)piperazin-1- vl) acetyl) amino)-6-ethoxvbenzothiazole (Comsound DK) 1-(2-Pyridyl) piperazine (1.87 g, 1.9 mL, 11.5 mmol) was added to a solution of 2- ( (bromoacetyl) amino)-6- ethoxybenzothiazole (1.8 g, 5.7 mmol) in DMF (20 mL) at rt.

The reaction mixture was heated and stirred at 70 OC for 6 h, cooled to rt, and slowly poured into ice water. The brown precipitate which formed was filtered, and treated with EtOAc (100 mL). The EtOAc layer was dried (NaSO4), filtered, concentrated to small volume, and then treated with hexane, causing a light beige precipitate to form. After stirring for 1 h, the product was filtered, triturated sequentially with hexane and cold ether, and then dried to give 1.43 g (62W) of the title compound as a light beige solid, mp 183- 183.2 °C: 1H NMR (DMSO-d6) 6 12.00 (bs,1H), 8.10 (dd, J = 4.8, J = 2.0,1H), 7.64 (d, J = 8.8, 1H), 7.55 (d, J = 2.4, 1H), 7.52 (ddd, J = 8. 8, J = 7.2, J = 2.0, 1H, 7.02 (dd, J = 8.4, J = 2.4,1H), 6.81 (d, J = 8.8, 1H), 6.63 (dd, J = 6.8, J = 4.8,1H), 4.07 (q, J = 6.8,2H), 3.52 (t, J = 4.4,4H), 3.38 (s, 2H), 2.63 (t, J = 4.4, 4H), 1.34 (t, J = 7.2,3H); 13C NMR (DMSO-d6) 6 169.02,158.95,155.37,155.35,147.51, 142.45,137.44,132.73,121.08,115.25,112.91,107.04, 105.38,63.58,60.17,52.27 (2C), 44.56 (2C), 14.63; MS (EI, m/z) 397 (M').

Example 47 Preparation of 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-6-ethoxvbenzothiazole (Compound DL) 1-(α,α,α-Trifluoro-m-tolyl) piperazine (1.5 g, 6.4 mmol) was added to a solution of 2-((bromoacetyl) amino)-6- ethoxybenzothiazole (1 g, 3.18 mmol) in DMF (14 mL) at rt.

The rection mixture was heated and stirred at 45 OC for 5 h, cooled to rt, and slowly poured into ice water. The rection mixture was extracted with EtOAc (3 x 40 mL). The combine EtOAc layer was washed sequentially with brine and water, dried over Na2SO4, filtered, and then concentrated. The

ensuing brown oil was dissolve in a small amount of EtOAc and treated with hexane, causing a light beige color precipitate to form. After stirring for 1 h, the product was filtered, triturated sequentially with hexane and cold ether, <BR> <BR> <BR> and then dried to give 1. 25 g (85%) of the title compound as<BR> <BR> <BR> <BR> <BR> <BR> a light beige solid, mp 77-79 OC 1H NMR (DMSO-d6) # 0612.<BR> <BR> <BR> <BR> <BR> <P> (bs, 1H), 7.63 (d, J = 8.8,1H), 7.5 5 (d, J = 2.4, 1H), 7.42<BR> <BR> <BR> <BR> <BR> <BR> (dd, J = 7.6,1H), 7.22 (dd, J = 10. 4, J = 2. 0,1H), 7.17 (s,<BR> <BR> <BR> <BR> <BR> <BR> 1H), 7.06 (d, J = 7.6,1H), 7.01 (dd, J = 8. 8, J = 2.4,1H),<BR> <BR> <BR> <BR> <BR> 4.07 (q, J = 6.8,2H), 3. 35 (s, 2H), 3.29 (bs, 4H), 2.73 (bs, 4H), 1.35 (t, J = 6.8,3H); 13C NMR (DMSO-d6) d 37,155.

155.31,151.09,142.41,132.71,129.91,129.84 (q, J = 31.8), 127.44,124.40 (q, J = 270), 121.08,118.74,115.25,114.55 (q, J = 3.8), 110.90 (q, J = 3.8), 105.39,63.58,59.81, 52.19 (2C), 47.45,14.63; MS (EI, m/z) 464 (M+).

Example 48 Preparation of 2- ( ( (4- (4- (AcetylLphenyl) piperazin-1- EQ)yl)acetyl)amino)-6-ethoxybenzothiazole(Compound <BR> <BR> <BR> <BR> <BR> 4- ( (Carbomethoxy) phenyl) piperazine (3 g, 614. mmol) was<BR> <BR> <BR> <BR> <BR> <BR> added to a solution of 2- ( (bromoacetyl) amino)-6- ethoxybenzothiazole 3(2. g, 37. mmol) in DMF (25 mL) at rt.

The rection mixture was heated and stirred at 70 OC for 7 h, cooled to rt, and poured into ice water. The crystalline precipitate which formed was filtered, washed several times with cold water, and then dried to give 1. 8 g (56%) of the title compound, as a off-white solid, mp 94. 7-96 °C: 1H NMR (DMSO-d6) # 7.80 (d, J = 9.2,2H), 7.62 (d, J = 8.8,1H), 7.55 <BR> <BR> <BR> (d, J = 2.4,1H), 7.01 (dd, J = 8.8, J = 2.8, 1H), 6.97 (d, J<BR> <BR> <BR> <BR> <BR> <BR> 9.2,2H), 4.06 (q, J = 6. 8, 2H), 3.40 (s, 2H), 3.39 (t, J = 4.4,4H), 2.68 (t, J = 4.4,4H), 2.45 (s, 3H), 1.35 (t, J = 6.8,3H); 13C NMR (DMSO-d6) 6 50,168.97,155.37,155.34,195.

153.73,142.44,132.73,130.03 (2C), 126.63,121.08,115.25, 113.11 (2C), 105.38,63.58,59.96,52.09 (2C), 46.62 (2C), 26.01,14.63, MS (EI, m/z) 438 (M+).

Example49 2-(((4-((2-Pyridyl)piperazin-1-Preparationof yl) acetvl) amino)-6-ethoxybenzothiazole Hydrochloride (CompoundDR) A solution of 2- ( ( (4- (2- (pyridyl) piperazin-1- yl) acetyl) amino)-6-ethoxybenzothiazole (9.6 g, 24 mmol) in CH2C12 (100 mL) was treated with 1N HCl ether solution (48 mL, 48 mmol). The rection mixture was stirred at rt for 2 h, the white precipitate which formed was filtered, washed quickly several times with ether, dried to give 11 g (92%) of the title compound as a white solid, mp 255.6-256.4 °C: 1H NMR <BR> <BR> <BR> (D20) 8 957. (ddd, J = 9.2, J = 7.6, J = 1.6,1H), 7.82 (dd, J = 6. 4, J = 1.6, 1H), 7.36 (d, J = 8.0,1H), 7.20 (d, J = 9.2, 1H), 7.15 (bs, 1H), 6.96 (dd, J = 7.2, J = 7. 2,1H), 6.84 (dd, J = 8.8, J = 2.4,1H), 4.23 (s, 2H), 3.90 (t, J = 7.2, 4H), 3.89 (q, J = 6.8, 2H), 3.54 (t, J = 7.2,4H), 1.20 (t, J 7.2, 3H); 13C NMR (D2O) # 97,159.06,156.61,153.15,165.

146.60,141.01,137.65,133.12,121.48,117.28,116.03, 114.22,107.08,66.16,58.49,52.72 (2C), 44.14 (2C), 15.03, MS (FAIB, mlz) 399 (Mt). Anal. Calcd for C20H25N5O2SCl2 # 2.75

H20: C, 46.20; H, 5.91; N, 13.47. Found: C, 46.25 ; H, 5.87; N, 13.33; C1,13.73.

Exam, ole50 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1-Preparationof yl)acetyl)amino)-6-ethoxybenzothiazoleHydrochloride (CompoundDS).

A solution of 2-(((4-(3- (trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-6- ethoxybenzothiazole (0. 37 g, 8 mmol) in CHzCl2 (15 mL) was treated with 1N HCl ether solution (1.6 mL, 1.6 mmol). The rection mixture was stirred at rt for 2 h, the precipitate was filtered, washed several times with ether, dried to give 0.37 g (88%) of title compound as an ivory solid, mp 229.7- 230 OC.

Example 53 2-(((4-(3-trifluoromethyl)phenyl)piperazin-1-Preparationof yl) acetyl) amino)-5-trifluoro-methyl-1, 3,4-thiadiazole

(Compound BB) Preparation of 2-(bromoacetyl)amino-5-(trifluoromethyl)- 1,3,4-thiadiazole: A solution of 2-amino-5-trifluoromethyl- 1, 3, 4-thiadiazole (9.95 g, 58.83 mmol) in DMF (60 mL) and dioxane (60 mL) was cooled with an ice bath to 0 °C.

Bromoacetyl bromide (11.87 g, 58.83 mmol) was added dropwise, keeping the interna temperature between 0 to 5 °C, and the solution was stirred for 4 h at rt. The solution was slowly poured into 500 mL of ice-water, and the precipitate which formed was filtered, washed with water, and then dried (MgSO4) to afford 15.33 g (93%) of the title compound as a white <BR> <BR> <BR> solid, mp 145-146 °C: 1H NMR (DMSO-d6) 6 7113. (bs, 1H), 4.28<BR> <BR> <BR> <BR> <BR> (s, 2H); 13C NMR (DMSO-d6) 6 39,161.15,150.46166. (q, J = 37.1), 119.96 (q, J = 270), 61.11; MS (EI, m/z) 291 (M+).

A solution of 2- (bromoacetyl) amino-5- (trifluoromethyl)- 1,3,4-thiadiazole (1.5 g, 5.17 mmol) and 1-(α,α,α-trifluoro- m-tolyl)-4-piperazine (2.38 g, 10.34 mmol) in DMF (50 mL) was heated at 80 °C for 15 min. The solution was cooled, poured into 500 mL of ice-water, and extracted with EtOAc (3 x 100 mL). The layers were separated and the organic layer was dried over MgS04, filtered, and then concentrated.

Purification by chromatography, eluting with ethyl acetate, afforded 1.24 g (54.5%) of the title compound, mp 116-117 OC: <BR> <BR> <BR> IH NMR (DMSO-d6) # 7.42 (t, J = 0,1H),7.238. (dd, J = 4,8. J<BR> <BR> <BR> <BR> <BR> 2.0,1H), 7.18 (s, 1H), 7.07 (d, J 7.6, 1H), 3.59 (s, 2H), 3.10 (t, J = 4. 4,4H), 2.85 (t, J = 8,4. 4H) ; 13C NMR (DMSO-d6) 6 169. 65, 162.61,150.98,149.89 (q, J = 36.6), 129.99,129.92 (q, J = 31), 124.43 (q, J = 271), 120.20 (q, J = 270), 118.84,59.64,52.03 (2C), 47.09; MS (EI, m/z) 439 (M+). Anal. Calcd for C16H15N5F6SO: C, 43.74; H, 3.44; N, 15.94. Found: C, 43.75; H, 3.50; N, 15.93.

Example 54 Preparation of 2-(((4-(2-Fluorophenyl)piperazin-1- vl) acetYl) amino)-5- (trifluoromethyl)-1,(trifluoromethyl)-1, 3,4-thiadiazole (CompoundBC) A solution of 2-((bromoacetyl) amino)-5- (trifluoromethyl)-1,3,4-thiadiazole (1.5 g, 5.17 mmol) and 1- (2-fluorophenyl) piperazine (1.86 g, 10.34 mmol) in DMF (50 mL) was heated at 80 OC for 15 min. The solution was cooled, poured into 500 mL of ice-water, and the precipitate which formed was filtered, washed with water, and then dried to give 1.78 g (88%) of the title compound, mp 129-131 °C: 1H NMR <BR> <BR> <BR> (DMSO-d6) 6 15-6.947. (m, 4H), 3.61 (s, 2H), 3.10 (t, J = 4.4,<BR> <BR> <BR> <BR> <BR> 4H), 2.85 (t, J = 4.8,4H); 13C NMR (DMSO-d6) 6 59,169.

162.59,154.88 (d, J = 243), 149.78 (q, J = 38), 139.50 (d, J 8.3), 124.74 (d, J = 3.0), 122.40 (d, J = 7.6), 120.15 (q, J = 270), 119.25 (d, J = 3.1), 115.86 (d, J = 20.5), 59.68, 52.28 (2C), 49.42,49.39; MS (EI, m/z) 389 (M+). Anal. Calcd for C15H15N5F4SO : C, 46.27; H, 3.88; N, 17.99. Found: C, 46.27; H, 3.97; N, 17.80.

Example55 Preparation of 2-(((4-(4-Methoxyphenyl) piperazin-1- <BR> <BR> <BR> vl) acetYl) amino)-5-(trifluoromethyl)-1&num 3w4-thiadiazole<BR> <BR> <BR> <BR> <BR> (CompoundBD) A solution of 5k potassium hydroxide (50 mL) was added to a flask containing 1-(4-methoxyphenyl)piperazine dihydrochloride (4.0 g, 15.0 mmol). The solution was stirred for 30 min and extracted with CH2Cl2 (3 x 50 mL). The combine extracts were dried over MgSO4, filtered and concentrated to yield the free base form of the piperazine as a brown oil. DMF (60 mL) was added to this oil, followed by the addition of 2-((bromoacetyl)amino)-5-(trifluoromethyl)-1,3,4-thiadiazole (1.0 g, 3.44 mmol). The solution was heated to 60 OC and stirred for 30 min. The solution was cooled and poured into 500 mL of ice-water. The white precipitate which formed was filtered, washed with water, and dried to afford 1.01 g <BR> <BR> <BR> (73%) of the title compound, mp 158-160 °C: 1H NMR (DMSO-d6) 6

6.90 (d, J = 9.2, 2H), 6.82 (d, J = 9.2,2H), 3.68 (s, 3H), 3.63 (s, 2H), 3.12 (t, J = 4.8,4H), 2.88 (t, J = 4.8); 13C NMR (DMSO-d6) 6 63,163.31,153.05,149.45169. (q, J = 36), 144. 97,120. 25 (q, J = 271), 117.48,114.23,59.71,55.14, 52.28 (2C), 48.80; MS (EI, m/z) 401 (M+). Anal. Calcd for C16H18N5F3SO2 : C, 47.88; H, 4.52; N, 17.45. Found: C, 48.21; H, 4.72; N, 17.22.

Exact) le56 2-(((4-(2-Pyridyl)piperazin-1-Preparationof yl)acetyl)amino)-5-(trifluoromethyl)-1,3,4-thiadiazole (CompoundBE) A solution of 2-(bromoacetyl) amino-5-(trifluoromethyl)- 1,3,4-thiadiazole (1.0 g, 3.45 mmol) and 1-(2- pyridyl) piperazine (0.58 mL, 0.62 g, 3.79 mmol) in DMF (50 mL) was heated at 80 OC for 20 min. The solution was cooled, poured into 500 mL of ice-water, and extracted with EtOAc (3 x 100 mL). The layers were separated and the organic layer was dried over MgS04, filtered, and then concentrated.

Purification by chromatography, eluting with hexane-ethyl acetate (2: 1), afforded 0.79 g (62%) of the title compound,

mp 158-160 OC: 1H NMR (DMSO-d6) 6 118. (dd, J = 5.2, J = 1.6, 1H), 7.54 (ddd, J = 8.8, J = 6. 8, J = 1.6,1H), 6.84 (d, J = 8.8,1H), 6.65 (dd, J = 6.8, J = 5.2, lH), 3.62 (s, 2H), 3.59 (t, J = 5.2,4H), 2.81 (t, J = 4.8,4H); 13C NMR (DMSO-d6) 6 169.66,163.13,158.74,149.65 (q, J = 36), 147.56,137.59, 120.28 (q, J = 270), 113.22,107.20,59.77, 52.01 (2C), 43.91 (2C); MS (EI, (M+).Anal.CalcdforC14H15N6F3SO:C,372 45.16; H, 4.06; N, 22.57. Found: C, 45.15; H, 4.15; N, 22.19.

Example 57 Preparation of 2- ( (4- (2-Pyrimidvl) piiperazin-l- vl) acetvl) amino)-5- (trifluoromethyl)-1.(trifluoromethyl)-1. 3,4-thiadiazole (CompoundBF) A solution of 2- ( (bromoacetyl) amino)-S- (trifluoromethyl)-1,3,4-thiadiazole (1.5 g, 5.17 mmol) and 1- (2-pyrimidyl) piperazine (1.27 g, 7.75 mmol) in DMF (50 mL) was heated at 80 °C for 20 min. The solution was cooled,

poured into 500 mL of ice-water, and extracted with EtOAc (3 x 100 mL). The layers were separated and the organic layer was dried over MgSO4, filtered, and then concentrated.

Purification by flash column chromatography on silica gel, eluting with hexane-ethyl acetate (4: 1) gave 1.45 g (75t) of <BR> <BR> <BR> the title compound, mp 194-195 °C: 1H NMR (DMSO-d6) 6 348. (d, J = 4.8,2H), 6. 64 (t, J = 4.4, 1H), 3.81. (t, J = 5.2,4H), 3.58 (s, 2H), 2.73 (t, J = 4.8,4H); 13C NMR (DMSO-d6) 6 169.62,162.55,161.05,157.89 (2C), 149.65 (q, J = 36), 120.28 (q, J = 270), 110,. 23,59.74,51.98 (2C), 42.65 (2C); MS (EI, m/z) 373 (M+). Anal. Calcd for Cl3Hl4N7FBSO: C, 41. 82; H, 3.78; N, 26.26. Found: C, 42.05; H, 3.55; N, 26.00.

Example 58A Preparation of 2- (Bromoacetyl) amino-5-(n-propYlthio)-1, 3, 4- thiadiazole A solution of 2-amino-5-n-propylthio-1,3,4-thiadiazole (3.0 g, 17.1 mmol) in DMF (30 mL) and dioxane (30 mL) was cooled with an ice bath to 0 OC. Bromoacetyl bromide (3.45 g, 17.1 inmol) was added dropwise, keeping the interna temperature between 0 to 5 °C, and the solution was stirred

for 3 h at rt. The solution was slowly poured into 500 mL of ice-water and the precipitate which formed was filtered, washed with water, and then dried to afford 4.41 g (87%) of the title compound as a white solid, mp 159-160 °: 1H NMR (DMSO-d6) 6 0413. (s, 1H), 4.19 (s, 2H), 3.21 (t, J = 6.8, 2H), 1.70 (heptet, J = 7.2,1H), 0.97 (t, J = 7.6,3H); 13C <BR> <BR> <BR> NMR (DMSO-d6) b 49,159.46,158.30,35.49,27.97,22.32,165.

12.86; MS (EI, m/z) 295 (M').

Example58 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1-Preparationof <BR> <BR> yl) acetyl) amino)-5- (n-propylthio)-1, 3. 4-thiadiazole (Compound ES A solution of 2- ( (bromoacetyl) amino)-5- (n-propylthio)- 1,3,4-thiadiazole (2.5 g, 8.44 mmol) and 1-(3- (trifluoromethyl) phenyl)-piperazine (2.91 g, 12.7 mmol) in DMF (50 mL) was heated at 80 OC for 30 min. The solution was cooled, poured into 500 mL of ice-water, and extracted with

EtOAc (3 x 100 mol). The layers were separated and the organic layer was dried over MgSO4, filtered, and then concentrated. Purification by chromatography, eluting with hexane-ethyl acetate (1: 1), afforded 2.68 g (71%) of the <BR> <BR> <BR> title compound, mp 118-119 °C : 1H NMR (DMSO-d6 # 12. 55 (bs,<BR> <BR> <BR> <BR> <BR> NH, 1H), 417. (dd, J = 8. 0, J = 8. 0, lH), 7.21 (dd, J = 8.4, J = 2.4,1H), 7. 15- (s, 1H), 7.06 (dd, J =-7.6, J = 0. 4,1H), 3.41 (s, 2H), 3.25 (t, J = 4.8,4H), 3.19 (t, J = 7. 2,2H), 2.67 (t, J = 4.8,4H), 1.70 (heptet, J = 7.2,2H), 0.97 (t, J 7.6,3H); 13C NMR (DMSO-, d6) 6 63,158.82,158.12,168.

151.13,129.89 (q, J = 31), 124.39 (q, J = 270), 118.69, 114.51 (q, J = 3.5), 110.86 (q, J = 3.5), 59.67, 52.11 (2C), 47.51 (2C), 35.48,22.33,12.84; MS (EI, m/z) 445 (M+).

Example59A Preparation of 2-((Bromoacetyl)amino)-5-cyclopropyl-1, 3,4- thiadiazole A solution of 2-amino-5-cyclopropyl-1,3,4-thiadiazole (3.0 g, 21.2 mmol) in DMF (30 mL) and dioxane (30 mL) was cooled with an ice bath to 0 OC. Bromoacetyl bromide (4.29

g, 21.2 mmol) was added dropwise, keeping the internal temperature between 0 to 5 °C, and the solution was stirred for 3 h at rt. The solution was slowly poured into 500 mL of ice-water and the precipitate which formed was filtered, washed with water, and then dried to afford 4.12 g (74%) of the title compound as a white solid, mp 196-199 OC (dec): 1H <BR> <BR> <BR> NMR (DMSO-ds) b 8212. (s, 1H), 4.16 (s, 2H), 2.40 (m, 1H),<BR> <BR> <BR> <BR> <BR> 1.16-1.11 (m, 2H), 1.00-0.96 (m, 2H) ; 13C NMR (DMSO-ds) b<BR> <BR> <BR> <BR> <BR> 167.23,165.21,156.66,61.07,28.12,10.53,10.04; MS (EI, (M+).m/z)263 Example 59 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-Preparationof 1-yl) acetvl) amino)-5-cYclopropyl-1, 3,4-thiadiazole (Compound BH A solution of 2-((bromoacetyl) amino)-5-cyclopropyl- 1,3,4-thiadiazole (3.0 g, 11.4 mmol) and 1- (3- (trifluoromethyl) phenyl)-piperazine (3.96 g, 17.2 mmol) in DMF (50 mL) was heated at 80 OC for 20 min. The solution was

cooled and poured into 500 mL of ice-water. The precipitate which formed was filtered, washed with water, and then dried to afford 3.03 g (65*1) of the title compound, mp 180-181 OC: H NMR (DMSO-d6) 6 397. (t, J = 8.0,1H), 7.19 (d, J = 8.4, 1H), 7.14 (s, 1H), 7.04 (d, J = 7.2,1H), 3.37 (s, 2H), 3.23 (t, J = 4.0,4H), 2.65 (t, J = 4. 4,4H), 2.36 (m, J = 3.2, <BR> <BR> <BR> 1H), 1. 18-1.10 (m, 2H), 0.96-0.94 (m, 2H).; 13C NMR (DMSO-d6) 6 168.52,167.08,156.52,151.26,129.92,129.86 (q, J = 31), 124.36 (q, J = 271), 118.86,114.65 (q, J = 3. 5), 110.99 (q, J = 3.5), 59.93,52.25 (2C), 47.66 (2C), 10.65 (2C), 10.22; MS (EI, m/z) 411 (M+).

Example 60A Preparation of 2- ( (Bromoacetyl) amino)-5- (ethoxycarbonylmethylthio)-1,3,4-thiadiazole A solution of 2-amino-5- (ethoxycarbonylmethylthio)- 1, 3, 4-thiadiazole (3.0 g, 13.68 mmol) in DMF (30 mL) and dioxane (30 mL) was cooled with an ice bath to 0 OC.

Bromoacetyl bromide (2.76 g, 13.68 mmol) was added dropwise, <BR> <BR> <BR> keeping the interna temperature between 0 and 5 OC, and the solution was stirred for 3 h. The solution was slowly poured

into 500 mL of ice-water and the precipitate which formed was filtered, washed with water, and then dried to afford 2.62 g <BR> <BR> <BR> (56.7*1) of the title compound as a white solid, mp > 250 OC:<BR> <BR> <BR> H NMR (DMSO-d6) 6 0613. (s, 1H), 4.19 (s, 2H), 4.17 (s, 2H), 4.12 (q, J = 7.2,2H), 1.17 (t, J = 6.8,3H); 13C NMR (DMSO- d6) 6 05,165.54,158.84,158.16,61.26,35.07,27.93,168.

13.87; MS (EI, m/z) 341 (M+).

Example60 Preparation of 2-(((-4-(3-(Trifluoromethyl)phenyl)piperazin- 1-yl)acetyl)amino)-5-(ethoxycarbonylmethylthio)-1,3,4- thiadiazole (Compound ET) A solution of 2-((bromoacetyl) amino)-5- (ethoxycarbonylmethylthio)-1,3,4-thiadiazole (2.5 g, 7.35 mmol) and 1- (3- (trifluoromethyl) phenyl) piperazine (2.54 g, 11.0 mmol) in DMF (50 mL) was heated at 80 OC for 30 min. The solution was cooled, poured into 500 mL of ice-water, and extracted with EtOAc (3 x 100 mL). The layers were separated

and the organic layer was dried over MgSO4, filtered, and then concentrated. Purification by chromatography, eluting with hexane-ethyl acetate (1: 1), afforded 1.92 g (53.4*-.) of the <BR> <BR> <BR> title compound, mp 126-127 °C: 1H NMR (DMSO-ds) b 417. (t, J = 8.0,1H), 7.21 (dd, J = 8.4, J = 2.0,1H), 7.15 (s, 1H), 7.05 (d, J = 7.6,1H), 4.16 (s, 2H), 4.12 (q, J = 6.8,2H), 3.42 (s, 2H), 3. 25 (t, J = 4.4,4H), 2. 67 (t, J = 4.4,4H), 1.17 (t, J = 7.2,3H); 13C NMR (DMSO-d6) 6 68,168.08,158.68,168.

157.52,151.10,129.88,129.83 (q, J = 31), 124.37 (q, J = 271), 118.69,114.50 (q, J = 3.5), 110.85 (q, J = 4.2), 61.23,59. 65, 52.09 (2C), 47.48 (2C), 35. 08,13.87; MS (EI, (M+).m/z)489 Example 61A Preparation of 2-((Bromoacetyl)amino)-5-((7-chloroguinolin-4- yl) thio)-l3æ4-thiadiazole A solution of 2-amino-5-((7-chloroquinolin-4-yl) thio)- 1, 3, 4-thiadiazole (3.0 g, 10.2 mmol) in DMF (80 mL) was heated to 60 OC and bromoacetyl bromide (2.05 g, 10.2 mmol) was added dropwise. After TLC indicated that the majority of starting thiadiazole had been consume, the solution was

cooled to rt, causing a precipitate to form. The mixture was slowly poured into a flask containing 200 mL of EtOAc and 200 mL of saturated NaHCO3. The mixture was stirred for 30 min, during which the precipitate disappeared and the solution became clear. The EtOAc layer was separated, dried and concentrated. Purification of the resulting oil by flash column chromatography on silica gel, eluting with EtOAc, gave 1.20 g (28.501) of the title compound as a beige solid, mp <BR> <BR> <BR> 170-173 OC (became wet), 217-220 OC (dec) : 1H NMR (DMSO-d6) 6 13.36 (s, 1H), 8.84 (d, J = 4.8,1H), 8.26 (d, J = 9.2,1H), 8.17 (d, J = 2.4,1H), 7.78 (dd, J = 8.8, J = 2.4,1H), 7.48 (d, J = 4.8, 1H), 4.21 (s, 2H); 13C NMR (DMSO-d6) 6 90,165.

161.52,153.14,151.49,148.06,141.48,135.. 10,128.38, 125.85,124.60,122.70,27.78.

Example61 <BR> <BR> <BR> Preparation of 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl)acetyl)amino)-5-((7-chloroguinolin-4-yl)thio)-1,3,4- thiadiazole (Compound BG) A solution of 2-((bromoacetyl)amino)-5-((7- chloroquinolin-4-yl) thio)-1, 3,4-thiadiazole (1.11 g, 2.67 mmol) and 1- (3- (trifluoromethyl) phenyl) piperazine (0.92 g, 4.00 mmol) in DMF (50 mL) was heated at 80 °C for 20 min. The solution was cooled, poured into 500 mL of ice-water, and extracted with EtOAc (3 x 150 mL). The layers were separated and the organic layer was dried over MgSO4, filtered, and then concentrated. Purification by chromatography, eluting with hexane-ethyl acetate (2: 1), afforded 0.80 g (55%) of the title compound, mp 157-159 °C: 1H NMR 6 8012. (bs, NH, 1H), 8.81 (d, J = 4.4,1H), 8.23 (d, J = 9.2,1H), 8.13 (d, J = 2.4,1H), 7.75 (dd, J = 9.2, J = 2.4,1H), 7.42 (d, J = 4.8, 1H), 7.39 (t, J = 8.0,1H), 7.19 (d, J = 8.4,1H), 7.14 (s, 1H), 7.04 (dt J = 7.6,1H), 3.45 (s, 2H), 3.24 (t, J = 4.0, 4H), 2.68 (t, J = 4.4,4H); 13C NMR (DMSO-d6) 6 17,169.

161.78,152.18,151.52,148.06,142.26,135.10,129.93, 129.84 (q, J = 30.3), 128.45,128.35,125.81,124.53,124.43 (q, J = 271), 123.05,122.29,118.73,114.59 (q, J = 3.8), 110.90 (q, J = 3.8), 59.68,52.11 (2C), 47.44 (2C); MS (EI, (M+).m/z)564 Example62 Preparation of 2-(((4-(3-(Trifluoromethyl) phenyl) piDerazin-1- yl)acetyl)amino)-5-((carbomethoxy)methyl)-1,3,4-thiadiazole (CompoundBI) Preparation of methyl malonylthiosemicarbazone: To a suspension of thiosemicarbazide (16. 4 g, 180 mmol) in THF was added methyl malonyl chloride (20.4 g, 150 mmol) dropwise at 0 OC. The rection was allowed to warm to rt and stirred for 24 h. The mixture was treated with ether and the product was filtered and then dried to give 34.8 g of the crude title <BR> <BR> <BR> compound as a pale white solid : 1H NMR (CD30D) 6 894. (br s, 4H), 3.75 (s, 3H), 3.40 (s, 2H) ; 13C NMR 185.9,170.1,167.6, 53.1,41.3; MS (FAB, m/z) 192 (M+H+).

Preparation of 2-amino-5-((carbomethoxy) methyl)-1,3,4- thiadiazole: To a suspension of methyl malonylthiosemicarbazone (34.8 g, 180 mmol) in toluene (200 mL) was added MeSO3H (18 mL, 277 mmol) dropwise at 0 OC. The suspension became a sticky white solid and piled up at the bottom of the flask. The rection mixture was stirred at 70 OC for 3 h, concentrated under reduced pressure, and then the solid was suspende in MeOH. Concentrated NH40H was added to the suspension to basify the mixture. During this process, the suspension first disappeared, and then a new precipitate formed while the solution changed from colorless to brown, and then finally to dark blue. Neutral alumina (12 scoops) was added to the above solution, which was followed by concentration under reduced pressure. The resulting alumina was loaded onto a neutral alumina column and eluted with CHCl3/MeOH (20: 1) to give 12 g (46k, two step yield) of the title compound as a light yellow solid: 1H NMR (DMSO-d6) 6 7.12 (br s, 2H), 3.98 (s, 2H), 3.65 (s, 3H); 13C NMR 169.4, 169.3,150.1,52.1,35.0; MS (FAB, m/z) 174 (M+H'). Anal.

Calcd for CsH, N3SOi: C, 34.56; H, 4.06; N, 24.19. Found: C, 34.79; H, 3.98; N, 24.51.

Preparation of 2-((bromoacetyl) amino)-5- ((carbomethoxy) methyl)-1,3,4-thiadiazole: To a solution of 2- amino-S- ( (carbomethoxy) methyl)-1,3,4-thiadiazole (4.0 g, 23.1 mmol) in DMF/dioxane (100 mL, 1: 1) was added bromoacetyl bromide (6 g, 30 mmol) dropwise at 0 OC. The rection was allowed to warm to rt and stir overnight. The rection was quenched with ice water (500 mL) and stirred for 2 h. A white precipitate and some sticky yellow solid were formed.

Filtration collecte the white solid. The yellow floating solid was recrystallized from EtOAc to provide additional product. A total of 6 g of the title compound (89k) was <BR> <BR> obtained as a white solid: 1H NMR (DMSO-d6) 6 9012. (bs, 1H), 4.24 (s, 1H), 4.20 (s, 1H), 3.68 (s, 3H), 3.34 (s, 2H); 13C <BR> <BR> <BR> NMR (DMSO-d6) 6 3,165.6,169. lys9.5,157.1,152.4,34.7,28.2; MS (EI, m/z) 293 (Mt).

Preparation of 2-(((4-(3- (trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-5- ((carbomethoxy) methyl)-1,3,4-thiadiazole: A solution of 2- ((bromoacetyl)amino)-5-(carbomethoxy) methyl)-1,3,4- thiadiazole (500 mg, 1.7 mmol) and 1-(3- (trifluoromethyl) phenyl) piperazine (431 mg, 1.9 mmol) in DMF (10 mL) was heated at 80 OC for 1 h. The rection mixture was poured into water and the milky solution was extracted with EtOAc. The organic layer was washed with water, brine, dried, and concentrated. The crude product was purifie by chromatography on silica gel (CHCl3/MeOH, 20: 1) to give 300 mg (40%) of the title compound as a white solid, mp 236-237 OC: H NMR (CDCl3) 6 387. (dd, J = 8.4,8.0, 1H), 7.14 (s, 1H), 7.13 (d J = 8.0,1H), 7.08 (dd, J = 8.4, J -2. 0, 1H), 4.14 (s, 2H), 3.80 (s, 3H), 3.42 (s, 2H), 3.35 (t, J = 4.8,1H), 2.84 (t, J = 4.8,4H); 13C NMR (CDC13) 6 7,168.1,159.2,168.

157.5,151.0,131.58 (q, J = 32), 129.7,124.21 (q, J = 271), 119.1,116.6 (q, J = 4), 112.7 (q, J = 4), 60.8,53.4 (2 C), 52.7,48.8 (2 C), 35.6; MS (EI, m/z) 443 (M+). HRMS (FAB) calcd for ClBHZON5F303S 444.1317, found 444.1287.

Example63 2-(((4-(2-Pyridyl)piperazin-1-Preparationof yl) acetyl) amino)-5- ( (carbomethoxy)methyl)-1,3,4-thiadiazole (Compound EU) The title compound was prepared from of 2- ((bromoacetyl) amino)-5-(carbomethoxymethyl)-1,3,4-thiadiazole (660 mg, 2.3 mmol) and 1-(2-pyridyl) piperazine (440 mg, 2.7 mmol) in DMF (15 mL) as described for the preparation of Compound BI. The crude product was purifie by chromatography on silica gel (EtOAc) to give 400 mg (47%) of the title compound as a white solid, mp 196.5-197.1 °C : 1H NMR (DMSO-d6) 6 18. (ddd, J = 4.9, J = 2.0, J = 0.8,1H), 7.52 (ddd, J = 8.7, J = 7.1, J = 2.0,1H), 6.81 (d, J = 8.7,1H), 6.63 (dd, J = 7.1, J = 4. 9, J = 0.8,1H), 4.22 (s, 2H), 3.68 (s, 3H), 3.51 (t, J = 4. 9,4H), 3.40 (s, 2H), 2.61 (t, J = 4.9,4H) ; 13C NMR (DMSO-d6) b 2,168.6,159.1,158.9,169.

156.5,147.5,137.4,112.9,107.0,59.9,52.19,52.17 (2C), 44.5 (2C), 34.6; MS (EI, M/Z) 376 (M+). HRMS (FAB) calcd for C16H2oN603S 376.1396, fOUnd 377.1372.

Exemple 64

Preparation of 2-(((4-(4-Methoxyphenyl)piperazin-1- <BR> <BR> <BR> vl) acetvl) amino)-5-carbomethoxymethyl-1, 3. 4-thiadiazole<BR> <BR> <BR> <BR> <BR> (ComDoundBK) The title compound was prepared from of 2- ((bromoacetyl)amino)-5-carbomethoxymethyl-1,3,4-thiadiazole (1.2 g, 4.1 mmol) and 1- (4-methoxyphenyl) piperazine (944 mg, 4.9 mmol, obtained by treatment of the commercially available of1-(4-methoxyphenyl)piperazinewith5%ofNaOHHClsalt solution and extraction with CH2C12) in DMF (15 mL) as described for the preparation of Compound BI, mp 194.1-195.2 <BR> <BR> <BR> °C : 1H NMR (CDCl3) 6 936. (d, J = 9.2,2H), 6. 86 (d, J = 9.2, 2H), 4.14 (s, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.37 (s, 2H), 3.18 (t, J = 4.8,4H), 2. 81 (t, J = 4.8,4H); 13C NMR (CDCl3) 6 7,168.4,159.2,157.4,154.3,145.2,118.7168. (2 C), 114.6 (2 C), 60.9,55.6,53.8 (2 C), 52.7,50.8 (2 C), 35.6; MS (FAB, m/z) 406 (M+H"). HRMS (FAB) calcd for ClgH23NsoqS 406.1549, found 406.1533. Anal. Calcd for C18H23N5O4@ # 0.5 H20: C, 52. 15; H, 5.94; N, 16.91. Found: C, 52.30; H, 5.72; N, 16.62.

Example66 2-(((4-(2-Pyridyl)piperazin-1-Preparationof yl) acetyl) amino)-1,3,4-thiadiazole (Compound BL) Preparation of glyoxalic acid thiosemicarbazone: To a suspension of thiosemicarbazide (10 g, 110 mmol) in 80% of EtOH (150 mL) was added glyoxalic acid monohydrate (11 g, 119 mmol) in 80k of EtOH (50 mL) at 70 °C in one portion. When glyoxalic acid monohydrate was added, the rection mixture turned to clear and then became cloudy again. The rection was stirred for 1.5 h at this temperature, and then cooled to rt. Filtration gave 9.6 g (59%) of the title compound as a <BR> <BR> <BR> white solid : 1H NMR (DMSO-d6) 6 4612. (s, 1H), 11.92 (s, 1H), 8.65 (s, 1H), 8.28 (s, 1H), 7.29 (s, 1H); MS (FAB, m/z) 148 (M+H+).

Preparation of 2-amino-1,3,4-thiadiazole-5-carboxylic acid: To a suspension of glyoxalic acid thiosemicarbazone (2. 0 g, 13.6 mmol) in HOAc (25 mL) was added FeCl3 solution (4 g. in 5 mL of H2O). The mixture was stirred at rt for 12 h.

The solid was filtered and washed with water to give a pale white solid. The solid was dissolve in 5% of NaOH (20 mL) to give a brown solution, which was filtered through a short plug of celite. The clear filtrate was acidified with HOAc to precipitate a solid, which was collecte by filtration.

990 mg (50*-.) of the title compound was obtained after drying: H NMR (DMSO-d6) # 8. 57 (s, 1H), 7.19 (s, 2H); 13C NMR (DMSO- d6) 6 2,138.8,124.2.168.

Preparation of 2- ((bromoacetyl) amino)-1, 3,4-thiadiazole: To a suspension of 2-amino-1,3,4-thiadiazole-5-carboxylic acid (800 mg, 5.52 mmol) in DMF (40 mL) was added bromoacetyl bromide at 0 OC. The mixture was stirred at 0 OC for 30 min, quenched with ice-water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4) and concentrated to give crude title compound, which was used in the following rection without further purification.

Preparation of 2- ( (4- (2-pyridyl) piperazin-1-yl)-1,3,4- thiadiazole: To a solution of 2-((bromoacetyl) amino)-1,3,4- thiadiazole (750 mg, 3.39 mmol) in DMF (30 mL) was added 1- (2-pyridyl) piperazine (611 mg, 3.75 mmol). The mixture was stirred at 80 OC for 1 h and then poured into ice water. The precipitate which formed was collecte by filtration and purifie by chromatography on silica gel (CHCl3/MeOH 20: 1) to give 350 mg (34%) of the title compound as a white solid : 1H <BR> <BR> <BR> NMR (DMSO-d6) 6 4412. (br s, 1H), 9.18 (s, 1H), 8.09 (ddd, J = 5.2, J = 2.0, J = 0.8,1H), 7.52 (ddd, J = 8.8, J = 7.2, J = 2.0,1H), 6.81 (d, J = 8.8,1H), 6. 62 (ddd, J = 7.2, J = 4.8, J = 0.4,1H), 3.51 (t, J = 5.2,4H), 3.41 (s, 2H), 2.61 (t, J = 5.2,4H); ^13C NMR (DMSO-d6) 6 7,158.9,158.1,148.7,168.

147.5,137.4,112.9,107.0,60.0,52.2 (2C), 44.5 (2C); MS (EI, m/z) 304 (M+). HRMS (FAB) calcd for Cl3Hl6N6OS 305.1180, found 305.1188. Anal. Calcd for C13Hl, N60S 9 H20: C, 48.43; H, 5.63; N, 26.07. Found: C, 48.66; H, 5.19; N, 25.68.

Example67 Preparation of 2- ( ( (4- (3- (Trifluoromethvl) phenvl) piperazin-1- yl) acetyl) amino)-5-carbomethoxy-1,3,4-thiadiazole (Compound

EV) Preparation of methyl 2-amino-1,3,4-thiadiazole-5- carboxylate: An ethereal solution of diazomethane was added to a suspension of 2-amino-1,3,4-thiadiazole-5-carboxylic acid (1.0 g, 6.9 mmol) in MeOH/CHCl3 at rt until the solution became homogenous. Silica gel was added to this yellow solution and the mixture was concentrated. The adsorbent was purifie by chromatography on silica gel (CHCl3/MeOH 9: 1) to give 440 mg (40%) of the title compound as a white solid : 1H <BR> <BR> <BR> NMR (DMSO-d6) 6 028. (br s, 2H), 8.85 (s, 3H) ; 13C NMR (DMSO-<BR> <BR> <BR> <BR> d) 6 4,159.3,147.2,52.8.172. Anal. Calcd fòr C4HsN302S: C, 30.08; H, 3.16; N, 26.32. Found: C, 30.47; H, 3.23 ; N, 25.91.

Preparation of methyl glyoxalate thiosemicarbazone: Methyl oxalyl chloride (9.2 mL, 12.2 g, 100 mmol) was added to a suspension of thiosemicarbazide (13.6 g, 149 mmol) in THF was added dropwise at 0 °C. The reaction was allowed to warm to rt and stirred overnight. Filtration removed a white precipitate. The filtrate was treated with ether, ånd the additional white precipitate which formed was filtered and dried to give 7.4 g (42%) of the title compound as a pale <BR> <BR> <BR> white solid : 1H NMR (DMSO-d6) 6 7610. (s, 1H), 9.41 (s, 1H),<BR> <BR> <BR> <BR> 7.93 (s, 1H), 7.65 (s, 1H), 3.77 (s, 3H); 13C NMR (DMSO-d6) 6 181.49,159.60,155.83,52.75; MS (LSIMS, m/z) 178.0 (M+H).

Preparation of methyl 2-amino-1, 3, 4-thiadiazole-5- carboxylate, Method B: To a suspension of methylglyoxalate thiosemicarbazone (500 mg, 2.82 mmol) in toluene (50 mL) was added MeSO3H (0.27 mL, 406 mg, 4.24 mmol) dropwise at 0 OC.

The suspension became. a sticky white solid which piled up at the bottom of the flask. The resulting mixture was stirred at 70 OC for 3 h. The rection mixture was concentrated under reduced pressure and the residue was suspende in MeOH.

Concentrated NH40H was added to the suspension to basify the mixture. During this process, the suspension first

disappeared, and then new precipitate formed while the solution changed from colorless to brown and then finally to dark blue. Silica gel was added and the mixture was concentrated under reduced pressure. The absorbent was purifie by chromatography eluting with MeOH-CHCl3 (1: 20), to give 85 mg (20*1) of the title compound as a white solid.

Preparation of 2-((bromoacetyl) amino)-5-carbomethoxy- 1, 3, 4-thiadiazole: To a solution of methyl 2-amino-1,3,4- thiadiazole-5-carboxylate (440 mg, 23.1 mmol) in DMF/dioxane (20 mL, 1: 1) was added bromoacetyl bromide (727 mg, 3.6 mmol) dropwise at 0 OC. The rection mixture was stirred for 1 h at 0 OC and quenched with ice water tao give a precipitate.

Filtration afforded 660 mg (85%) of the title compound as a white solid : 1H NMR (DMSO-d6) 6 4813. (s, 1H), 4.26 (s, 2H), 3.94 (s, 3H).

Preparation of 2-(((4-(3-(Trifluoromethyl) phenyl)- piperazin-1-yl) acetyl) amino)-5-carbomethoxy-1, 3,4- thiadiazole: a solution of 2-((bnromoacetyl) amino)-5- carbomethoxy-1,3,4-thiadiazole (660 mg, 2.36 mmol) and 1- ( (3-trifluoromethyl) phenyl) piperazine (599 mg, 2.6 mmol) in

DMF (30 mL) was heated at 80 OC for 3 h. The mixture was poured into ice water and a precipitate was formed.

Filtration gave the crude product, which was purifie by chromatography on silica gel to afford 560 mg (55%) of the <BR> <BR> <BR> title compound as a white solid : 1H NMR (CDC13) 6 387. (dd, J = 8.4, J = 8.0,1H), 7.14-7.13 (m, 2H), 7.08 (d, J = 8.4, 1H), 4.06 (s, 3H), 3.44 (s, 2H), 3.34 (t, J = 4.8,4H), 2.83 (t, J = 4.8,4H); 13C NMR (DMSO-d6) 6 6,161.2,159.6,168.

155.2,150.9,131.63 (q, J = 31), 129.7,124.20 (q, J = 271), 119.1,116.6 (q, J = 3.5) 1' 112.7 (q, J = 3.5), 60.8,53.52 (2C), 53.48,48.7 (2C); MS (FAB, m/z) 430 (M+H+). Anal. Calcd for C17H18N5O2sF3 : C, 47.49; H, 4.22; N, 16.29. Found: C, 47.58; H, 4.23; N, 15.99.

Example 68 Preparation of 2-(((-4-(3-(Trifluoromethyl)phenyl)piperazin- 1-Yl) acetyl) amino)-5-(2-(carbomethoxy) ethyl)-1. 3 4- thiadiazole (Compound EN) Preparation of methyl 4-(thiosemicarbazone) butyrate: methyl 4-(thiosemicarbazone) butyrate was prepared from thiosemicarbazide (27 g, 298 mmol) and methyl 4 (chloroformyl) butyrate (30 g, 25.5 mL, 199 mmol) in THF (150 mL) as described in Example 67. The rection gave 47 g of the crude title compound@ as a white solid, which was used in the next step without further purification : 1H NMR (DMSO-d6) <BR> <BR> <BR> 6 889. (s, 1H), 9.21 (s, 1H), 7.89 (s, 1H), 7.31 (s, 1H),<BR> <BR> <BR> <BR> <BR> 3.58 (s, 3H), 2.53 (t, J = 6.8,2H), 2.40 (t, J = 6.8,2H) ;<BR> <BR> <BR> <BR> <BR> 13C NMR (DMSO-d6) 6 86,172.97,170.46,51.46,28.41,181.

27.99; MS (LSIMS, m/z) 206 (M+H+).

Preparation of 2-amino-5-(2-(carbomethoxy) ethyl)-1,3,4- thiadiazole: 2-Amino-5- (2- (carbomethoxy) ethyl)-1,3,4- thiadiazole was prepared from methyl 4- (thiosemicarbazone) butyrate (47 g), MeSO3H (24 mL, 36 g, 377 mmol) and toluene (300 mL) as described in Example 62. The

crude product was purifie by chromatography on silica gel, eluting with MeOH-CHCl3 (1: 10) to give 11 g (30*-.) of the title compound as a white solid : 1H NMR (DMSO-d6) 6 027. (s, 2H), 3.60 (s, 3H), 3.04 (t, J = 7.2,2H), 2.72 (t, J = 7.2,2H) ; 13C NMR (DMSO-d6) 6 05,168.38,156.42,51.39,32.12,172.

24.83; MS (LSIMS, m/z) 187 (M+). HRMS (FAB) calcd for C6H9N3O2S 188. 0494, found 188.0491. Anal. Calcd for C6H9N302S: C, 38.38; H, 4.83; N, 22.38. Found: C, 38. 91; H, 4.83; N, 22.49.

Preparation of 2-((bromoacetyl)amino)-5-(2- (carbomethoxy) ethyl)-1,3,4-thiadiazole: To a solution of 2- amino-5-(2-(carbomethoxy) ethyl)-1,3,4-thiadiazole (5.0 g, 32 mmol) in DMF-dioxane (100 mL, 1: 1) was added bromoacetyl bromide (3 mL, 7 g, 35 mmol) at 0 OC. The mixture was stirred at 0 OC for 30 min and poured into ice-water. The precipitate which formed was filtered and dried to give 7.5 g (91%) of the title compound as a white solid : 1H NMR (DMSO-d6) 6 8612. (br s, 1H), 4.18 (s, 2H), 3.61 (s, 3H), 3.24 (t, J 6.8, 2H), 2.83 (t, J = 6.8,2H) ; 13C NMR (DMSO-d6) # 03,172.

165.35,162.99,158.36,51.48,32.03,28.16,24.43; MS

(LSIMS, (M+H+).308 Preparation of 2-(((-4-(3- (trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino) =5- (2- (carbomethoxy) ethyl)-1,3,4-thiadiazole: A solution of 2- ((bromoacetyl)amino)-5-(2-(carbomethoxy) ethyl)-1,3,4- thiadiazole (1.27 g, 4.13 mmol), and 1-(3- (trifluoromethyl) phenyl) piperazine (1.04 g, 4.54 mmol) in DMF (30 mL) was heated at 80 OC for 2 h. The rection mixture was poured into ice water and the milky solution was extracted with EtOAc. The organic layer was washed with water, brine, dried, and concentrated. The crude product was purifie by chromatography on silica gel, eluting with hexane-EtOAc (4: 1), to give 600 mg (32%) of the title compound as a white solid, mp 134.2-134.8 °C: 1H NMR (DMSO- <BR> <BR> <BR> <BR> d6) 6 12. 31 (br S, 1H), 7. 41 (dd, J = 8.0,8.0,1H), 7. 2 2 (d, J = 8.0, 1H), 7.16 (s, 1H), 7.06 (d, J = 8.0,1H), 3.61 (s, 3H), 3.40 (s, 2H), 3.26 (t, J = 4.7,4H), 3.23 (t, J = 7.0, 2H), 2.83 (t, J = 7.0,2H), 2.67 (t, J = 4.7,4H); 13C NMR (DMSO-d6) 6 99,168.40,162.48,158.01,151.12,129.87,171.

129.82 (q, J = 30), 124.36 (q, J = 270), 118.68,114.48 (q, J = 4), 110.83 (q, J = 4), 59.78,52.11 (2C), 51.43,47.52 (2 C), 32.08,24.38; MS (LSIMS, m/z) 458.5 (M+H+). HRMS (FAL) calcd for C19H22N5O3SF3 457.1396, found 458.1463. Anal. Calcd for C19H22F3N5O3S: C, 49.82; H, 4.84; N, 15.89. Found: C, 50.07; H, 4.87; N, 15.14.

Example 69 Preparation of 2- ( ( (4- (2-Pyridvl) piperazin-1- yl) acetyl) amino)-5- (2-(carbomethoxv) ethyl)-1,(2-(carbomethoxv) ethyl)-1, 3,4-thiadiazole (CompoundEW) The title compound was. prepared from 2- ((bromoacetyl) amino)-5-(2-(carbomethoxy) ethyl)-1,3,4- thiadiazole (1.5 g, 4.88 mmol) and 1-(2-pyridyl) piperazine (0.87 g, 5.37 mmol) in DMF (30 mL) as described in Example 68. The crude product was purifie by chromatography on

silica gel, eluting with EtOAc, to give 800 mg (42k) of the<BR> <BR> <BR> title compound as a white solid, mp 2-134.8134. °C : 1H NMR<BR> <BR> <BR> (DMSO-d) b 108. (ddd, J = 4.0,2.0,0.8 1H), 7.51 (ddd, J = 9.2,7.2,2.0,1H), 6.81 (d, J = 8.8,1H), 6.62 (ddd, J = 7.2,5.2,0.8, 1H), 3.61 (s, 3H), 3.50 (t, J = 8,4H),4.

3.38 (s, 2H), 3.23 (t, J = 2,2H),2.837. (t, J = 2,2H),7.

2.60 (t, J = 4.8,4H); 13C NMR (DMSO-d6) # 10,168.49,172.

162.55,158.96,158.07,147.53,137.48,112.95,107.07, 59.98,52.20 (2 C), 51.51,44.53 (2 C), 32.09,24.41; MS (LSIMS, m/z) (M+H+). HRMS (FAB) calcd for ClHz2N603S 1552,391. found 1576.391. Anal. Calcd for C1, H22N603S: C, 52. 22; H, 5.67; N, 21.50. :Found C, 91;51. H, 5.63; N, 21.30.

Example70 Preparation of 2-(((4-(4-Methoxyphenyl)piperazin-1- <BR> <BR> sl) acetyl) amino)-5-(2-(carbomethoxy) ethyl)-1.(2-(carbomethoxy) ethyl)-1. 3, 4-thiadiazole<BR> <BR> <BR> (CompoundBO) The title compound was prepared, from 2- ( (bromoacetyl) amino)-5- (2- (carbomethoxy) ethyl) -1, 4-3, thiadiazole 5(1. g, 884. mmol) and 1- (4-

methoxyphenyl) piperazine (1.08 g, 5.6 mmol) in DMF (20 mL) as described in Example 36. The crude product was purifie by chromatography on silica gel, eluting with CHCl3-EtOAc (7: 3), to give 630 mg (31k) of the title compound as a white solid, <BR> <BR> mp 172.6-173.4 °C: 1H NMR (DMSO-d6) b 876. (d, J = 9.2,2H), 6.81 (d, J = 9.2,2H), 3.67 (s, 3H), 3.60 (s, 3H), 3.37 (s, 2H), 3.23 (t, J = 7.2,2H), 3.03 (t, J = 4.0,4H); 2.83 (t, J <BR> <BR> = 7.2,2H), 2.65 (t, J = 4.0,4H); 13C NMR (DMSO-d6) 6 16,172.

168.55,162.63,158.14,152.95,145.40,117.47 (2 C), 114.27 (2 C), 59.98,55.20,52.56 (2 C), 51.57,49.57 (2 C), 32.13, 24.45; MS (LSIMS, m/z) 420.4 (M+H). Anal. Calcd for C19H25N5O4S: C, 54.33; H, 6.00; N, 16.68. Found: C, 53.91; H, 6.01; N, 16.52.

Example 71 <BR> <BR> <BR> <BR> Preparation of 2- ( ( (4- (m-tolvl) viperazin-l-vl) acetvl) amino)- EX)5-(2-(carbomethoxy)ethyl)-1,3,4-thiadiazole(Compound The title compound was prepared from 2- ((bromoacetyl)amino)-5-(2-(carbomethoxy) ethyl)-1,3,4- thiadiazole (1.5 g, 4.88 mmol) and 1-(m-tolyl) piperazine (0.99 g, 5.62 mmol, prepared from the commercially available dihydrochloride salt) in DMF (30 mL) as described in Example 68. The crude product was purifie by chromatography on silica gel, eluting with, CHCl3-EtOAc (7: 3) to give 500 mg (25%) of the title compound as a white solid, mp 131.1-131.9 <BR> <BR> <BR> °C: 1H NMR (DMSO-d6) 6 087. (dd, J = 7.6,8.0,1H), 6.74 (s, 1H), 6.71 (d, J = 8,1H), 6.59 (d, J = 7.6,1H), 3.61 (s, 3H), 3.37 (s, 2H), 3.25 (t, J = 7.2,2H), 3.13 (t, J = 4.4, 4H); 2.83 (t, J = 7.2,2H), 2.65 (t, J = 4.4,4H), 2.24 (s, 3H); 13C NMR (DMSO-d6) 6 09,168.47,162.54,158.08,172.

151.0,137.92,128.70,119.65,116.10,112.63,59.93,52.43 (2 C), 51.50,48.19 (2 C), 32.09,24.40,21.37; MS (LSIMS, (M+H+).Anal.CalcdforC19H25N5O3S:C,56.48;H,m/z)404 6.24; N, 17.34. Found: C, 56.74; H, 6.40; N, 17.45.

Example 72 Preparation of 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- Yl) acetyl) amino)-5- (2-(carboxy)(2-(carboxy) ethyl)-1, 3, 4-thiadiazole (CompoundEY) A solution of 2-(((4-(3- (trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-5-(2- (carbomethoxy) ethyl)-1,3,4-thiadiazole (250 mg, 0.54 mmol) in MeOH-Hz0 (40 mL, 3: 1) was treated with LiOH#H2O (600 mg, 14.3 mmol) and the mixture was stirred at rt overnight. After concentration under reduced pressure, the residue was dissolve in water. The resulting solution was neutralized with 2 N HC1 carefully until the maximum amount of the precipitate was formed and the pH # 6-7. The mixture was sonicated and the precipitate was filtered and then dried to give 230 mg (96%) of the title compound as a white solid: IH <BR> <BR> NMR (DMSO-d6) 6 417. (dd, J = 8.0,8.0,1H), 7.22 (d, J = 8.4, 1H), 7.16 (s, 1H), 7.06 (d, J = 7.6,1H), 3.40 (s, 2H), 3.26

(t, J = 4.8, 4H), 3.19 (t, J = 7.2,2H), 2.73 (t, J = 7.2, <BR> <BR> 2H), 2.67 (t, J = 4. 8,4H), 2.24 (s, 3H); 13C NMR (DMSO-d6) 6 172.99,168.38,162.87,157.98,151.13,129.90,129.84 (q, J = 30), 124.40 (q, J = 270), 118.71,114.50 (q, J. = 4), 110.82 (q, J = 4), 59.80,52.14 (2 C), 47.53 (2 C), 32. 53,24.56; MS (LSIMS, m/z) 443 (M+H+). Anal. Calcd for ClBHzoF3N503S 1.22 H20: C, 46.46 ; H, 4.86; N, 15.04. Found:. C, 46.52; H, 4.48; N, 14.71.

Example73 Preparation of 2- ( ! (4- (3-Trifluoromethylphenl) biperazin-1- yl)acetyl)amino)-1,3,4-thiadiazole BR) Preparation of 2-((bromoacetyl) amino)-1,3,4-thiadiazole: Bromoacetyl bromide (9.5 mL, 22 g, 109 mmol) was added to a solution of 2-amino-1,3,4-thiadiazole (10 g, 99 mmol) in DMF- dioxane (200 mL, 1: 1) and the mixture was stirred at 0 OC for 2 h. The rection mixture was poured into ice-water and the resulting precipitate was filtered and dried to give 11.5 g (, 50*1) of the title compound as a white solid : 1H NMR (DMSO-d6) 6 013. (br s, 1H), 9.22 (s, 1H), 4.21 (s, 2H).

Preparation of 2-(((4-(3-

(trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-1,3,4- thiadiazole: The title compound was prepared from 2- ((bromoacetyl) amino)-1,3,4-thiadiazole (2.54 g, 11.4 mmol) and 1-(3-(trifluoromethyl) phenyl) piperazine (2.89 g, 12.6 mmol) in DMF (30 mL) as described in Example 68. The crude product was purifie by chromatography on silica gel, eluting with EtOAc, to give 1.6 g (38t) of the title compound as a <BR> <BR> <BR> <BR> white solid, mp 135.7-136.8 °C : lH NMR (CDCl3) 6 8710. (br s, 1H), 8.87 (s, 1H), 7.38 (ddd, J = 8.0,8.0,0.8,1H), 7.14 (s, 1H), 7.13 (d, J = 8.2, 1H), 7.07 (d, J = 8.2, 1H), 3.44 (s, 2H), 3.34 (t, J = 4.9, 4H0, 2.84 (t, J = 4.9,4H) ; 13C NMR (CDCl3) 6 25,168. 159.95, 150.95,147.98,131.76 (q, J = 31), 129.69,124.21 (q, J = 271), 119.05,116.53 (q, J = 4), 112.66 (q, J = 4), 60.86,53.45 (2C), 48.79 (2 C); MS (LSIMS, (M+H+).HRMS(FAB)calcdforC15H16F3N5OS371.1028,m/z)372 found 372.1122. Anal. Calcd for C15Hl, F3NOS: C, 48.44; H, 4.34; N, 83.18. Found: C, 49. 03; H, 4.48; N, 83.18.

Example74 Preparation of 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- EZ)yl)acetyl)amino)-5-ethyl-1,3,4-thiadiazole(Compound Preparation of 2-((bromoacetyl)amino)-5-ethyl-1, 3,4- thiadiazole: Bromoacetyl bromide (7.4 niL, 17 g, 85 mmol) was added to a solution of 2-amino-5-ethyl-1,3,4-thiadiazole (10 g, 77.5 mmol) in DMF-dioxane (200 mL, 1: 1) at 0 OC and the mixture was stirred at 0 OC for 2 h. The rection mixture was poured into ice-water and the resulting precipitate was filtered and dried to give 17 g (88%) of the title compound as a white solid: 1H NMR (DMSO d6) 6 8212. (br s, 1H), 4.18 (s, 2H), 3.00 (q, J = 7.6, 2H), 1.29 (t, J = 7.6, 3H).

2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-5-ethyl-1,3,4-thiadiazole was prepared from 2-((bromoacetyl) amino)-5-ethyl-1,3,4-thiadiazole (1.5 g, 6 mmol) and 1-(3-(trifluoromethyl) phenyl) piperazine (1.52 g, 6.6 mmol) in DMF (30 mL) as described in Example 68. The crude product was purifie by chromatography on silica gel, eluting with EtOAc to give 1.2 g (50*1) of the title compound <BR> <BR> <BR> as a white solid, mp 166.7-167.5 °C: 1H NMR (DMSO-ds) b 2912.

(br s, 1H), 7.41 (dd, J = 8.0,8.0,1H), 7.22 (dd, J = 8.0, 2.2,1H), 7.16 (s, 1H), 7.06 (d, J = 8.0,1H), 3.40 (s, 2H), 3.26 (t, J = 4.7,4H), 2.99 (q, J = 7.6,2H), 2.67 (t, J = 4.7,4H), 1.29 (t, J = 7.6,3H); 13C NMR (DMSO-ds) b 31,168.

165.44,157.58,151.12,129.87,129.82 (q, J = 31), 124.37 (q, J = 270), 118.69,114.48 (q, J = 4), 110.83 (q, J = 4), 59.79,52.12 (2C), 47.52 (2 C), 22.57,13.72; HRMS (FAB) calcd for Cl., H2oF3N5OS 400.1419, found 400.1386. Anal. Calcd for C,, H2oF3NsOS: C, 51.05; H, 5.04; N, 51.17. Found: C, 50.76; H, 5.03; N, 45.17.

Example75 Preparation of 2-(((4-(3-(trifluoromethyl)phenyl)piperazin-1- vl) acetyl) amino)-5-bromo-13&num 4-thiadiazole (Compound FA) Preparation of 2-amino-5-bromo-1,3,4-thiadiazole: Bromine (10 mL, 17.6 g, 110 mmol) was added to a solution of 2-amino-1,3,4-thiadiazole (10 g, 99 mmol) in HOAc (30 mL) dropwise through an addition funnel. The rection mixture

became red and hot while some precipitate formed. The rection mixture was stirred at rt for 36 h and poured into water (200 mL). The orange solid was filtered, washed with water, and then recrystallized from. 806 of EtOH to give 5.85 g (25*1) of the title compound.

Preparation of 2-((bromoacetyl)amino)-5-bromo-1, 3,4- thiadiazole: Bromoacetyl bromide (2.3 mol, 5.4 g, 26.6 mmol) was added to a solution of 2-amino-5-bromo-1,3,4-thiadiazole (5.8 g, 24 mmol) in DMF-dioxane (200 mL, 1: 1) at 0 OC and the mixture was stirred at OC for 2 h. The rection mixture was poured into ice-water and the precipitate which formed was filtered and then dried. to give 7.6 g (87%) of the title compound as a white solid : 1H NMR (DMSO-d6) b 3313. (br s, 1H), 4.21 (s, 2H).

2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-5-bromo-1,3,4-thiadiazole was prepared from 2-((bromoacetyl) amino)-5-bromo-1,3,4-thiadiazole (1.5 g, 4.16 mmol) and l- (3-(trifluoromethyl) phenyl) piperazine (1. 05 g, 4.57 mmol) in DMF (30 mL) as described in Example 68. The

crude product was purifie by chromatography on silica gel, eluting with EtOAc to give 1.1 g (59%) of the title compound <BR> <BR> as a white solid, mp 150.5-151 °C: 1H NMR (CDC13) 6 7610. (br s, 1H), 7.39 (ddd, J = 8.4,8.0,0.4,1H), 7.14 (d, J = 8.0, 1H), 7.13 (s, 1H), 7.08 (dd, J = 8.4,2.0,1H), 3.42 (s, 2H), 3.34 (t, J = 4.8,4H), 2.83 (t, J = 4.7,4H); 13C NMR (CDC13) <BR> <BR> 6 58,160.15,150.92,135.44,131.62168. (q, J = 32), 129.70, 124.21 (q, J = 271), 119.08,116.60 (q, J = 4), 112.7 (q, J = 4), 60.64,53.49 (2C), 48.77 (2 C); MS (LSIMS, m/z) 372 (M+H+). HRMS (FAB) calcd for C15H15BrF3N5OS 450.0211, found 450.0230.

Example76 Preparation of 2- ( ( (4- (3- (Trifluoromethvl) phenvl) piperzin-1- <BR> <BR> yl) acetyl) amino)-5- ( (ethoxycarbonrl) methyl)-1, 3, 4-thiadiazole (Compound FB) Preparation of ethyl thiosemicarbazone malonate: A suspension of thiosemicarbazide (18 g, 199 mmol) in THF was treated with ethyl oxalylchloride (17 mL, 20 g, 133 mmol)

dropwise at 0 OC. The rection mixture was allowed to warm to rt and stirred overnight. The precipitate was collecte by filtration to give, after drying, 27 g 5a)(98. of the title compound which was used in the next step without <BR> <BR> <BR> 1HNMR(DMSO-d6)#10.08(s,1H),9.37furtherpurification: (s, 1H), 7.98 (s, 1H), 7.36 (s, 1H), 4.08 (q, J = 7.2,2H), 3.28 (s, 2H), 1.18 (t, J = 7.2,3H); 13C NMR (DMSO-d6) 6 181.79,167.73,164.84,60.74,40.67,13.99; MS (LSIMS, m/z) 206 (M+H').

Preparation of 2-amino-5-((ethoxycarbonyl) methyl) -1, 4-3, thiadiazole and 2-amino-5- (carboxymethyl)-1, 3, :4-thiadiazole <BR> <BR> <BR> MeS03H (30 mL, 45 g, 475 mmol) was added dropwise to a<BR> <BR> <BR> <BR> <BR> suspension of ethyl thiosemicarbazone malonate (63 g, 310<BR> <BR> <BR> <BR> <BR> mmol) in toluene (300 mL) at 0 OC. The suspension became a sticky white solid which piled up at the bottom of the flask.

The resulting mixture was magnetically stirred at 70 OC for 3 h. The rection was concentrated under reduced pressure in a 60 OC water bath. When the most of the solvent was evaporated, the white sticky solid became clear thick liquid.

The residue was suspende in MeOH and concentrated ammonium hydroxide (# 25 mL) was added to basify the mixture. During this process, the suspension first disappeared and then a new precipitate formed hile'té solution changed from colorless to brown and then finally to purple. The solid material was removed by filtration, alumina was added to the filtrate, and then the mixture was concentrated under reduced pressure.

The resulting solid was ground in a mortar and purifie by chromatography on alumina, eluting with MeOH-CHCl3, (1: 20), to give 11 g (45æ) of 2-amino-5- ( (ethoxycarbonyl)-methyl)- and 2-amino-5-(methoxycarbonyl) methyl)-1,3,4-thiadiazole in 1: 1 ratio as a white solid.

The above mixture (10 g) and a solution of LIOH (14 g) in MeOH-H2O (400 mL, 3: 1) was stirred at rt for 30 min. The rection mixture was concentrated under reduced pressure and the residue was dissolve in water (150 mL). The solution <BR> <BR> <BR> was neutralized with HCl to pH = 7. Some precipitate formed which was removed by filtration. This product was the title

carboxylic acid. The filtrate was concentrated and the residue was dissolve in EtOH. HC1 (gas) was bubbled into this solution for about 1 h. The resulting mixture was stirred at rt overnight, neutralized with saturated Na2CO3 (solution) and then extracted with EtOAc. The organic layer was washed with water, brine, dried (MgSO4), and then concentrated to give 6.2 g (62%) ofthe titled ethyl ester as a white solid.

Characterization of 2-amino-5-((ethoxycarbonyl) methyl)- 1, 3, 4-thiadiazole: 1H NMR (DMSO-d6) 6 7. 15 (s, 2H), 4.11 (q, J 7.2,2H), 3.96 (s, 2H), 1.19 (t, J = 7.2,3H); 13C NMR (DMSO-d6) b 169.45,168.80,150.27,60.86,35.33,13.92.

Characterization of 2-amino-5- (carboxymethyl)-1,3,4- thiadiazole : 1H NMR (DMSO-d6) å 12.84 (s, 1H) 7.08 (s, 2H), 3.86 (s, 2H); 13C NMR (DMSO-d6) 6 28,169.35,151.01,170.

35.53.

Preparation of 2- ( (bromoacetyl) amino)-5- ((ethoxycarbonyl) methyl)-1,3,4-thiadiazole: Bromoacetyl bromide (3.6 mL, 8.4 g, 42 mmol) was added to a solution of g,2-amino-5-((ethoxycarbonyl)methyl)-1,3,4-thiadiazole(6.0

32 mmol) in DMF-dioxane (20 mL, 1: 1) at 0 OC. The mixture was stirred at 0 OC for 30 min, then warmed up to rt and stirred for 1 h. The reaction mixture was poured into ice- water and the precipitate which formed was filtered and recrystallized from water to give 3.7 g (38%) of the title compound as a light yellow solid : 1H NMR (DMSO-d6) 6 12.90 (br s, 1H), 4.22 (s, 2H), 4.20 (s, 2H), 4.14 (q, J = 7.2,2H) i 1.21 (t, J = 7.2,3H).

2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino)-5-((ethoxycarbonyl) methyl)-1,3,4-thiadiazole was prepared from 2- ( (bromoacetyl) amino)-5- ((ethoxycarbonyl) methyl)-1,3,4-thiadiazole (0.6 g, 3.9 mmol) and 1- (3- (trifluoromethyl) phenyl) piperazine (0.99 g, 4.3 mmol) in DMF (20 mL) as described in Example 68. The crude. product was purifie by chromatography on silica gel, eluting with EtOAc, to give 300 mg (35%) of the title compound as a white solid, mp 157-158 OC: 1H NMR (DMSO-d6) 6 7.42 (dd, J =

8.0,8.0,1H), 7.22 (dd, J = 8.0,2.4, 1H), 7.16 (s, lH), 7.06 (d, J = 8.0,1H), 4.20 (s, 2H), 4.15 (q, J = 7.2,2H), 3.42 (s, 2H), 3.26 (t, J = 4. 8,4H), 2.68 (t, J = 4.8,4H), 1.21 (t, J = 7.2,3H); 13C NMR (DMSO-d6) 6 168. 79, 168.60, 159.14,156.67,151.17,129. 96,129.85 (q, J = 31), 124.-44 (q, J = 271), 118.77,114.57 (q, J = 4), 110.90 (q, J = 4), 61.08,59.80,52.18 (2C), 47.53 (2 C), 34.93,13.97 MS (LSIMS, m/z) 458 (M+H'). Anal. Calcd for ClgH22F3N503S : C, 49.82; H, 4.84; N, 15.29. Found: C, 50.11; H, 4.91; N, 14.98.

Example77 Preparation of 2- ( ( (4- (3-chlorophenyl) piperazin-1- <BR> <BR> yl) acetyl) amino)-5-(3-(carbomethoxy)-ethyl)-1,3, 4-thiadiazole (CompoundFC) The title compound was prepared from 2- (bromoacetyl) amino)-5- (2- (carbomethoxy) ethyl)-1,3,4- thiadiazole (1.5 g, 4.89 mmol) and 1- (3- chlorophenyl) piperazine (1.05 g, 5.37 mmol) in DMF (20 mL) as described in Example 68. The crude product was purifie by chromatography on silica gel, eluting with EtOAc, to give 1.5 g (66%) of the title compound as a white solid, mp 141-142 °C: 1H NMR (CDCl3) 6 6310. (br s, 1H), 7.19 (dd, J = 8. 2, 8.2,1H), 6.89 (dd, J = 2.1,2.1,1H), 6.85 (ddd, J = 8. 2, 1.8,0.6,1H), 6.79 (dd, J = 8.4,2.5,1H), 3.72 (s, 3H), 3.37 (s, 2H), 3.36 (t, J = 7.2,2H), 3.28 (t, J = 4.9, 4H), 2.89 (t, J = 7.2,2H), 2.79 (t, J = 4.9,4H); 13C NMR. (CDC13) 6 15,168.07,163.71,157.98,151.86,135.04,130.12,172.

119.91,116.21,114.14,60. 90, 53.44 (2 C), 51.95,48.74 (2 C), 32.77,25.09; MS (LSIMS, m/z) 424.3 (M+H') Anal. Calcd for C18HZZN503C1S: C, 50. 93; H, 5.22; N, 16.50. Found: C, 50.78; H, 5. 33; N, 16.40.

Example 78 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1-Preparationof vl)acetvl)amino)-5-(3-(carbomethoxyZpro,pvl-1-yl)-1.(3-(carb omethoxyZpro,pvl-1-yl)-1. 3,4- thiadiazole (Compound FD) Preparation of methyl 5- (thiosemicarbazone)-1- pentanoate: The compound was prepared from thiosemicarbazide (21.6 g, 240 mmol) and 3-carbomethoxypropionyl chloride (26 g, 158 mmol) in THF (120 mL) as described in Example 76. The rection gave the title compound as a white sticky solid, which was used for the next step without further <BR> <BR> purification : 1H NMR (DMSO-d6) 6 679. (br s, 1H), 9.10 (br s, 1H), 7.79 (br s, 1H); 7.40 (br s, 1H), 3.55 (s, 3H), 2.29 (t, J = 7.4,2H), 2.13 (t, J = 6.8,2H), 1.72 (quinte, J = 7.4, <BR> <BR> <BR> 2H); 13C NMR (DMSO-d6) 6 02,173.28,171.51,51.42,32.77,182.

32.26,20.01.

Preparation of 2-amino-5- (3- (carbomethoxy) prop-1-yl)- 1,3,4-thiadiazole: The compound was prepared from methyl 5- (thiosemi carbazone)-1-pentanoate and methane sulfonic acid (24 mL, 36 g, 377 mmol) in toluene (200 mL) as described in Example 67. The crude product was purifie by chromatography on silica gel, eluting with MeOH-CHCl3 (1: 15) to give 9.5 g (30%) of the title compound as a white solid : 1H NMR (DMSO- <BR> <BR> <BR> d6) 8 027. (s, 2H), 3.59 (s, 3H), 2.80 (t, J = 7. 4,2H), 2.38 (t, J = 7.4,2H), 1.86 (quinte, J = 7.4,2H) ; 13C NMR (DMSO- d6) 6 172.80,168.17,157.45,51.22,32.24,28.54,24.13; HRMS (FAB) calcd for C, HlìN302S 202.0650, found 202.0651. Anal.

Calcd for C7H11N3O2S : C, 41.66; H, 5.49; N, 20.83. Found: C, 41.54; H, 5.22; N, 20.62.

Preparation of 2- ( (bromoacetyl) amino)-5- (3- (carbomethoxy) prop-1-yl)-1,3,4-thiadiazole: Bromoacetyl bromide (2.5 mL, 5.74 g, 28 mmol) was added to a solution of 2-amino-5- (3- (carbomethoxy) prop-1-yl)-1,3,4-thiadiazole (4.4 g, 20 mmol) in DMF-dioxane (200 mL, 1: 1) was added at 0 OC.

The mixture was stirred at 0 OC for 30 min. The rection mixture was poured into ice-water and the resulting precipitate was filtered and dried to give 6.3 g (70%) of the <BR> <BR> <BR> title compound as a white solid : 1H NMR (DMSO-d6) 6 8612. (br

s, 1H), 4.18 (s, 2H), 3.59 (s, 3H), 3.02 (t, J = 7.2, 2H), 2.41 (t, J = 7.2,2H), 1.96 (quinte, J = 7.2,2H); 13C NMR (DMSO-d6) 6 93,165.28,172. 163.83, 158.09,51.25,32.25, 24.14;28.15,28.07, MS (LSIMS, (M+H+).324 Preparation of 2-(((4-(3- (Trifluoromethyl)phenyl)piperazin-1-yl)acetyl)amino)-5-(3- (carbomethoxy) propyl-1-yl) -1, 3, 4-thiadiazole : The title compound was prepared from 2-((bromoacetyl)amino)-5-(3- (carbomethoxy) prop-1-yl) -1, 3, 4-thiadiazole (1. 54 g, 84. mmol) and 1- (3- (trifluoromethyl) phenyl) piperazine 2(1. g, 285. mmol) in DMF (20 mL) as described in Example 69. The crude product was purifie by chromatography on silica gel, eluting with EtOAc, to give 1.5 g (66%) of the title compound as a <BR> <BR> <BR> white solid, mp 134-135 OC 1H NMR (CDC13) 6 0811. (br s,<BR> <BR> <BR> <BR> <BR> 1H), 7.35 (dd, J = 7.6,7.6,1H), 7.10 (s, 1H), 7.09 (d, J = 7.6,1H), 7.05 (d, J = 7.6 1H), 3.67 (s, 3H), 3.41 (s, 2H) 3.30 (t, J = 4.4,4H), 3.08 (t, J = 7.6,2H), 2.80 (t, J = 4.4, AH), 2.43 (t, J = 7.6,2H), 2.13 (quinte, J = 7.6,2H); 13C NMR 172.97,168.14164.54,158.07,150.95,#

131.43 (q, J = 31), 129.58,124.16 (q, J = 271), 118.86, 116.21 (q, J = 4),. 112.41 (q, J = 4), 60.861 53.27 (2C), 51.56,48.59 (2 C), 32.79,28.95,24.46 MS (LSIMS, m/z) 472 (M+H). Anal. Calcd for C20H24NsO3SF3: C, 50.89; H, 12;5. N, 14.84. Found: C, 50.93; H, 24;5. N, 14.48.

Example79 2-(((-4-(3-(Trifluoromethyl)phenyl)piperazin-Preparationof 1-yl)acetyl)amino)-5-(4-(carbomethoxy)but-1-yl)1,3,4- thiadiazole (Compound FE) Preparation of methyl-5-(chloroformyl) pentanoate: A solution of 5-(methoxycarbonyl) pentanoic acid (25 g, 156 mmol), SOCl2 (22.3 g, 13.7 mmol, 188 mmol) and 3 drops of DMF was stirred at 80 OC for 1 h. After the gas formation stoppe, the mixture was concentrated under reduced pressure.

The residual oil was distillated under reduced pressure to give 25 g (90%) of the title compound as a colorless oil, bp <BR> <BR> 118-120 OC: 1H NMR (CDC13) 6 683. (s, 1H), 2.92 (t, J = 7.0,

2H), 2.35 (t, J = 7.0,2H), 1.77-1.66 (m, 4H); 13C NMR (CDCl3) 6 40,173.28,51.57,46.65,33.36,24.46,23.64.173.

Preparation of methyl-6- (thiosemicarbazone)-1-hexanoate : The title compound was prepared from thiosemicarbazide (15.3 g, 169 mmol) and methyl-5-(chloroformyl) pentanoate (25 g, 140 mmol) in THF (150 mL) as described in Example 76. The rection gave the title compound as a whi-te sticky solid, which was used for the next step without further purification.

Preparation of 2-amino-5- (4- (carbomethoxy) but-1-yl)- 1,3,4-thiadiazole: The compound was prepared from methyl-6- (thiosemicarbazone)-1-hexanoate (40 mL, 59 g, 617 mmol) in toluene (250 mL) as described in Example 67. The crude product was purifie by chromatography on silica gel, eluting with MeOH-CHCl3, (1: 15) to give 9.5 g (28%) of the compound as <BR> <BR> a white solid : 1H NMR (DMSO-d6) 6 00-(s,2H),3.587. (s, 3H), 2.78 (t, J = 6.8,2H), 2.33 (t, J = 7.6,2H), 1.60-1.51 (m, <BR> <BR> 4H); 13C NMR (DMSO-d6) 6 20,168.173. 19, 158.05,51.22,32.83, 29.06,28.31,23.74. Anal. Calcd for C7H13N3O2S: C, 44.52; H,

6.07; N, 19.48. Found: C, 44.82; H, 6.07; N, 19.42.

Preparation of 2- ( (bromoacetyl) amino)-5- (4- (carbomethoxy) but-1-yl)-1,3,4-thiadiazole: Bromoacetyl bromide (2.1 mL, 4.89 g, 24 mmol) was added to a solution of 2-amino-5- (4- (carbomethoxy) but-1-yl)-1, 3, 4-thiadiazole (4 g, 18.6 mmol) in DMF-dioxane (80 mL, 1: 1) at 0 OC. The mixture was stirred at 0 OC for 30 min. The rection mixture was poured into ice-water and the precipitate which formed was filtered and dried to give 5.3 g (85%) OF the compound as a white solid : 1H NMR (DMSO-d6) 6 0912. (br s, 1H), 4.16 (s, 2H), 3.57 (s, 3H), 2.97 (t, J = 7.2,2H), 2.34 (t, J = 7.6, <BR> <BR> 2H), 1.74-1.66 (m, 2H), 1.61-1.55 (m, 2H); 13C NMR (DMSO-d6) 6 173.16,171.26,163.99,157.76,61.14,51.21,32.81,28.53, 28. 35, 23. 75; MS (LSIMS, m/z) 336 (M+H+).

Preparation of 2-(((4-(3- (trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-5- (4- (carbomethoxy) but-1-yl) 1,3,4-thiadiazole: The title compound was prepared from 2- ( (bromoacetyl) amino)-5- (4-

(carbomethoxy) but-1-yl)-1,3,4-thiadiazole (1.5 g, 4.48 mmol) and 1- (3- (trifluoromethyl) phenyl) piperazine (1.13 g, 4.92 mmol) in DMF (20 mL) as described in Example 69. The crude product was purifie by chromatography on silica gel, eluting with EtOAc, to give 1.3 g (60%) of the title compound. as a <BR> <BR> <BR> white solid, mp 154.8-155. 2 °C: 1H NMR (CDC13) b 10. 62 (br s, 1H), 7.38 (dd, J = 8.0,8.0,1H), 7.13 (s., 1H), 7.12 (d, J = 8.0,1H), 7.07 (dd, J = 8.0,2.4,1H), 3.68 (s, 3H), 3.39 (s, 2H), 3.33 (t, J = 5.2,4H), 3.07 (t, J = 7.2,2H), 2.82 (t, J <BR> <BR> <BR> 5.2,4H), 2.38 (t, J = 7.2,2H), 1.88-1.82 (m, 2H), 1.79-<BR> <BR> <BR> <BR> <BR> 1.72 (m, 2H); 13C NMR (CDC13) 6 54,168.01,165.43,173.

157.67,150.96,131.59 (q, J = 32), 129.68,125.71 (q, J = 271), 119.01,116.48 (q, J = 4), 112.64 (q, J-4), 60.91, 53.44 (2C), 51.55,48.75 (2 C), 33.53,29.59,29.00,24.21; MS (LSIMS, m/z) 486 (M+H'). Anal. Calcd for C21H26N5O3SF3: C, 51.89; H, 5.39; N, 14.41. Found: C, 52.21; H, 5.39; N, 14.06.

Example79A 2-(((4-(3-Chlorophenyl)piperazin-1-Preparationof yl)acetyl)amino)-5-trifluoremethyl-1,3,4-thiadiazole (CompoundBP) A solution of 2-(bromoacetyl) amino-5-trifluoremethyl-1,3,4- thiadiazole (1.0g, 3.44 mmol) and 1- (3- chlorophenyl) piperazine (1.36 g, 6.91 mmol) in DMF (30 mL) was stirred at rt for 5 min. The solution was poured into 100 mL of ice-water and extracted with EtOAc (3 x 50mL). layers were separated and the organic layer was dried over MgS04, filtered and then concentrated. Purification by chromatography, eluting with hexane-ethyl acetate (2: 1) afforded 0.98 g (70%) of the title compound as a solid, mp NMR(DMSO-d6)#12.67(BS,1H),7.21(t,J=122-124°C:1H 2.4,1H), 6.90 (dd, J = 8.4, J = 2.0, 1H), 6.79 (dd, J = 7.6, J = 1.6,1H), 3.62 (s, 2H), 3.27 (t, J = 4.8,4H), 2.82 (t, J <BR> <BR> <BR> = 4.8,4H); 13C NMR (DMSO-d6) 6 47,162.49,151.89,149.84169.

(q, J = 37.2), 133.79,130.37,120.14 (q, J = 270), 114.63, 113.70,59.54,51.95,47.04; MS (EI, m/z) 405 (M+). Anal. Calcd for ClSHsNsF3SOC1: C, 44.39; H, 3.73; N, 17.26; Fond: C, 44.37; H, 3.52; N, 17.36.

Example80 Preparation of 5-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl)acetyl)amino)-3-((carbomethoxy)methyl)-1,2,4-thiadiazole (CompoundBO) Preparation of methyl-2-cyanoiminoacetate hydrochloride: HC1 gas was bubbled into a stirred solution of malonylnitrile (12 g, 182 mmol) and MeOH (7.3 mL, 182 mmol) in anhydrous ether (150 mL) for about 1 h at 0 OC. The rection mixture was stirred at 0 OC for 30 min, warmed to rt, and stirring was continue for 2 h. The solid was filtered, washed with ether until pH ~ 7, and then dried over K2CO3 under reduced pressure overnight. 20 g (83%) of the title compound was obtained as a white solid : 1H NMR (CDC13) 6 843. (s, 3H), 3.48 (s, 2H); 13C NMR 163.3,112.8,53.5,24.5.

Preparation of 1,1,1-trimethoxy-2-cyanoethane: A solution of methyl 2-cyanoiminoacetate hydrochloride (40 g, 314 mmol) in anhydrous MeOH (550 mL) was stirred at rt for 4 days. The rection mixture was concentrated under reduced pressure and the residue was treated with EtOAc. The organic layer was washed with NaHCO3 (saturated solution), H20 and brine, dried (MgSO4), and then concentrated under reduced pressure. The oil product was purifie by distillation under water pump (bp 100-101 °C) to give 38 g (88*1) of the title compound as a colorless oil : 1H NMR (CDC'3) 6 3.36 (s, 9), 2.85 (s, 2).

Preparation of 2, 2-dimethoxy-1-cyanoethene : A round- bottomed flask was charged with 1,1,1-trimethoxy-2- cyanoethane (10 g) and the flask was equipped with a short- path distillation apparats. The flask was placed in a preheated oil bath (220 °C). After about 4 min, methanol began distilling off (bp 65 °C). After another 5 min, the colorless oil turned brown and the distillation temperature rose to 85 OC; the temperature then started to drop. At this point, the flask was taken out of the oil bath. A total 1.8 g of MeOH (the theoretical amount of MeOH was 2.2 g) was

collecte. The brown oil was further purifie by a Kugelrohr distillation using a water pump. When the distillation temperature reached 120 °C, a colorless oil distille out which solidifie in the dry ice bath. At 140-150 °C, a colorless solid distille out, which was the desired product.

The first fraction also contains the desired product. Both fractions were combine and used directly for the next rection. The distillation gave 5.3 g (67%) of the title compound as a colorless solid: 1H NMR (CDC13) 8 3.82 (s, 3H), 3.75 (s, 3H), 3.35 (s, 1H). The 1H NMR data was identical to that reporte in the literature.

Preparation of 3-amino-5-methoxy isoxazole: To a solution of NH2OH (338 mg, 4.87 mmol) in H20 (1. 1 mL) was added NaOH (8 M, 0.72 mL) at rt. The solution was warmed to 45 OC in-an oil bath and a solution of 2, 2-dimethoxy-1- cyanoether (500 mg, 4.42 mmol) in MeOH (0.22 mL) was added dropwise over a 30 min period. The rection mixture was stirred at this temperature for 2 h. According to the results of the TLC analysis, the starting material was still

not completely consume. Therefore, additional NaOH (0.27 mL, 8 M) was added to the rection. The mixture was heated at 70 OC for 2 h and concentrated to give a solid residue.

The residue was dissolve in water and extracted with EtOAc.

The organic layer was washed with brine, dried (MgS04), and then concentrated to give colorless solid, which was purifie by chromatography on silica gel (CHCl3/EtOAc, 7: 3) to give 188 mg (37%) of the title compound as a colorless solid : 1H NMR (CDC13) 6 794. (s, 1H), 3.89 (s, 3H) 13 C NMR (CDC13) 6 3173.

(C), 168.4 (C), 70.9 (CH), 56.2 (CH3); HRMS (EI) calcd for C4H6N2O2 114. 0429, found 114.0423.

Preparation of 5- ( ( (benzyloxy) carbonyl) amino)-3- _ ((carbomethoxy) methyl)-1,2,4-thiadiazole: A mixture of potassium thiocyanate (582 mg, 5.99 mmol) and benzylchloroformate (949 mg, 5.5 mmol) in acetonitrile (15 mL) was heated at 70 OC for 30 min. During this time, some white precipitate formed. The. mixture was cooled to 0 OC and a solution of 3-amino-5-methoxy isoxazole (525 mg, 4.61 mmol)

in acetonitrile (5 mL) was added to the above suspension.

The rection mixture was allowed to warm to rt and stirred overnight. The mixture was poured into ice-water and extracted with EtOAc. The combine organic layer was washed with water rand brine, dried, and then concentrated to give a yellow oil. The crude oil. was purifie by chromatography on silica gel (CHCl3/MeOH 20: 1) to give 73 mg of the title compound as a colorless solid: 1H NMR (CDC13) 6 212. (br s, 1H), 7.44-7.27 (m, 5H), 5.33 (s, 2H), 3.80 (s, 2H), 3.66 (s, 3H); 13C NMR 178.7,168.8,, 163.6,153.9,134.2,129.1 (2 C), 129.0 (2 C), 128.8,69.3,52.2,38.1.

Preparation of 5-amino-3- (carbomethoxymethyl)-1,2,4- thiadiazole: To a solution of 5- (((benzyloxy) carbonyl) amino)- 3- (carbomethoxymethyl)-1,2,4-thiadiazole (1.2 g, 3.9 mmol) in CH2C12 (100 mL) was added BBr3 (1 M in CH2Cl3, 20 mL) at-10 OC. After 10 min, water (20 mL) was added to the rection mixture. The mixture was continually stirred until it warmed to rt. Then the CH2C12 layer was separated and the water layer was basified with Na2CO3 (saturated solution). The

water layer was concentrated under reduced pressure, and the residue was dissolve in MeOH. Silica gel was added and the mixture was concentrated under reduced pressure. The absorbent was purifie by chromatography, eluting with MeOH- CHOC'3 (1: 9), to give 500 mg (74k) of the title compound as a white solid: 1H NMR (DMSO-d6) 6 927. (br s, 2H), 3.64 (s, 2H), 3.61 (s, 3H); 13C NMR (DMSO-d6) 6 58,169.18,165.50,183.

51.77,38.46; MS (LSIMS, m/z) 174 (M+H').

Preparation of 5- ( ( (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-3- (carbomethoxymethyl)-1,2,4-thiadiazole: To a solution of 5- amino-3-(carbomethoxymethyl)-1,(carbomethoxymethyl)-1, 2,4-thiadiazole (1.0 g, 5.78 mmol) in DMF-dioxane (20 mL, 1: 1) was added bromoacetyl bromide (0.8 mL, 1.87 g, 9.25 mmol) at 0 OC. The mixture was stirred at 0 OC for 30 min, then warmed up to rt and stirred for 1 h. The rection mixture was quenched with ice-water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO,)., and concentrated. The crude product was

purifie by chromatography on silica gel, eluting with EtOAc to givre 700 mg of the title compound as a brown oil. A solution of the product obtained above (500 mg, 1.7 mmol) and 1- (3- (trifluoromethyl) phenyl) piperazine (431,1.9 mmol) in DMF (10 mL) was heated at 80 OC for 2. h. The rection mixture was poured into water to give a milky solution, which was extracted with EtOAc. The organic layer was washed with water, brine, dried and concentrated. The crude product was purifie by chromatography on silica gel, eluting with EtOAc, to give 300 mg (30%) of the title compound as a white solid, <BR> <BR> mp 151-152 °C: 1H NMR (CDC13) 6 357. (ddd, J = 8.0,8.0,0.4, 1H), 7.11 (s, 1H), 7.10 (d, J = 8.0,1H), 7.06 (dd, J = 8.4, 2.4,1H), 3.92 (s, 2H), 3.72 (s, 3H), 3.39 (s, 2H), 3.30 (t, <BR> <BR> J = 5.2,4H), 2.78 (t, J = 5.2,4H); 13C NMR (CDC13) 6 59,174.

169.83,169.25,163.85,150.82,131.32 (q, J = 32), 129.57, 124.14 (q, J = 271), 118.95,116.34 (q, J = 4), 112.36 (q, J = 4), 60.45,53.34 (2C), 52.30,48.58 (2 C), 38.54. HRMS (FAB) calcd for ClBH2oF3N503S 444.1317, found 444.1331.

Example81 2-(((4-(Phenyl)piperazin-1-yl)acetyl)amino)-4-Preparationof (carboxymethyl) thiazole (Compound C) Phenylpiperazine 38(1. g, 1.4 mL, 68. mmol) was added to a solution of 2- (2-chloroacetamido)-4-thiazoleacetic acid (1.0 g, 34. mmol) in DMF (20 mL) at rt. The rection mixture was stirred at rt for 20 h, causing an ivory precipitate to form. The rection mixture was poured into ice water and the precipitate dissolve. The aqueous mixture was stirred overnight at rt, during which time an off-white precipitate formed. This solid was collecte by filtration, triturated with small amount of cold water, and then dried to give 0.90 g (53. 2%) of the title compound as an off-white solid, mp <BR> <BR> 143.7-145.8 OC : 1H NMR (DMSO_d6) 6(dec) 9911. (bs, 1H), 7.22<BR> <BR> <BR> (dd, J = 8.6, J = 7.2,2H), 6.96 (s, 1H), 6.92 (d, J = 7.8,<BR> <BR> <BR> 2H), 6.77 (dd, J = 7.2,1H), 3.59 (s, 2H), 3. 32 (s, 2H), 3.15<BR> <BR> <BR> (t, J = 4.8,4H), 2.65 (t, J = 4.8,4H) ; 13C NMR (DMSO-ds) b 171.45,168.21,156.90,150. 144.19,94, 84128. (2C), 118.75, 115.40 (2C), 110. 16, 60.03,52.43,48.15,36.78; MS (FAB,

m/z) 361 (M+). Anal. Calcd for Cl7H20N403S 0.75 H20: C, 54.61; H, 5.79; N, 14.98. Found: C, 54.58; H, 5.70; N, 15.02.

Exam, ple82 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1-Preparationof vl) acetvl) amino)-4- (carboxymethyl) thiazole (Compound D) 1-(α,α,α-Trifluoro-m-tolyl) piperazine (9.8 g, 8.0 mL, 42 mmol) was added to a solution of 2-(2-chloroacetamido)-4- thiazoleacetic acid (5.0 g, 21 mmol) in DMF (45 mL) at rt.

The rection mixture was heated and stirred at 70 OC for 6 h, cooled to rt, and slowly poured into ice water, causing an oily precipitate to form. After standing in the aqueous mixture overnight, the precipitated solid was filtered, washed several times with cold water, and then air dried.

The product was refluxed in EtOAc (70 mL) for 40 min, filtered while hot, washed several times with ether, and then dried to give 5.0 g (55*1) of the title compound as an off- <BR> <BR> <BR> white solid, mp 191.8-193 OC (dec) : 1H NMR (DMSO-d6) 6 4012.

(bs, 1H), 12. 00 (bs, 1H, NH), 7.41 (t, J = 8,1H), 7.22 (dd,

J = 8.4, J = 2,1H), 7.16 (bs, 1H), 7.06 (d, J = 8, 1H), 6.97 (s, 1H), 3.60 (s, 2H), 3.34 (s, 2H), 3.26 (t, J = 4.4, 4H), 2.66 (t, J = 4.4,4H) ; 13C NMR (DMSO-d6) 6 43,168.6,171.

156.87,151.15,144.21,129.89,129.82 (q, J = 31), 124.39 (q, J = 271), 118.71,114.49 (q, J = 4.6), 110.86 (q, J = 3.8), 110.17,59. 91, 52.20,47.55,36.78; MS (EI, m/z) 428 (M+). Anal. Calcd for Cl8HlgN403SF3: C, 50.39; H, 4.46; N, 13.06. Found: 50.43, H, 4.60; N, 13.07.

Example83 Preparation of 2-(((4-(2-Fluorophenyl)piperazin-1- yl) acetyl) amino)-4- (carboxymethyl) thiazole (Compound E) 1-(2-Fluorophenyl) piperazine (1.5 g, 1.3 mL, 8.6 mmol) was added to a solution of 2-(2-chloroacetamido)-4- thiazoleacetic acid (1 g, 4.3 mmol) in DMF (15 mL) at rt.

The rection mixture was stirred at rt for 20 h, causing an ivory precipitate to form. The precipitated solid was filtered, triturated several times with water, and then dried to give 1.31 g (82*-.). of the title compound as an ivory solid,

mp 196-197.2 OC (dec) : 1H NMR (DMSO-d6) 6 147. (dd, J = 8.4, J = 1. 2,1H), 7. 11-7.08 (m, 1H), 7.04 (m, 1H), 6.94 (s, 1H), 6.99- 6.95 (m, 1H), 3.60 (s, 2H), 3.33 (s, 2H), 3.04 (t, J = 4,4H), 2.68 (t, J = 4.8, 4H); 13C NMR (DMSO-d6) 6 171.. 48, 168.25,156. 89, 154. 93 (d, J = 243), 144.22,139. 82 (d, J = 8.4), 124. 77 (d, J = 3. 5), 122. 25 (d, J = 8.45), 119.23 (d, J = 2. 92), 115.86 (d, J = 20.52), 110.20, 60.05,52.49 (2C), 50.03,49.99,36.74; MS (EI, m/z) 378 (M+). Anal. Calcd for Cl7HlgN403SF 0.25 H20: C, 53.33; H, 5.13; N, 14.63. Found: C, 53.30; H, 4.82; N, 14. 57, Example 84 Preparation of 2-(((4-(2-Fluorophenvl) piperazin-l- yl)acetyl)amino)-4-(carboethoxymethyl)thiazole AB) Preparation of 2- ((Bromoacetyl) amino)-4- carboethoxymethyl) thiazole: Bromoacetyl bromide (8.45 g, 3.4 mL, 42 mmol) added dropwise to a solution of ethyl 2-amino-4- thiazoleacetate (7.2 g, 42 mmol) in a mixture of DMF (30 mL) and dioxane (30 mL) while keeping the interna temperature of the rection mixture at 5 OC. After stirring-at 5 OC for 1

h, the ice bath was removed and the rection mixture was stirred at rt for 20 h. The rection mixture was poured into ice water and the light crystalline compound which formed was filtered, washed several times with water, and then air-dried for 2 days to give 8.4 g (66%) of the title compound, mp 163- 164.5 : 1H NMR (DMSO-ds) b 6012. (s, 1H), 7.05 (s, 1H), 4.12 (s, 2H), 4.07 (q, J = 7.2,2H), 3.69 (s, 2H), 1.18 (t, J = <BR> <BR> <BR> 7.2,3H); 13C NMR (DMSO-d6) # 85,164.92,157.11,143.89,169.<BR> <BR> <BR> <BR> <P>110.98,60.25, 36.54, 28.30,14.01; MS (EI, m/z) 308. 1 (M+).

Anal. Calcd for C9H11N2O3BrS : C, 35.13; H, 3.60; N, 9.11.

Found: C, 34.98; H, 3.64; N, 94.8.

1- (2-Fluorophenyl) piperazine (2.18 g, 2 mL, 13 mmol) was added to a solution of 2- (- (bromoacetyl) amino)-4-thiazole acetate (2 g, 6.54 mmol) in DMF (20 mL) at rt. The rection mixture was heated and stirred at 95 OC for 5 h, cooled to rt, and slowly poured into ice water. The light crystalline compound which precipitated was extracted several times with ethyl acetate. The combine ethyl acetate solution was dried

(Na2SO4), filtered, evaporated to small volume, and then the product was precipitated by adding hexane dropwise. The product was filtered, washed several times with hexane and cold ether, and then refluxed with hexane for 1 h. Hot filtration and drying in vacuo afforded 1.7 g (64%) of the title compound, mp 127-129 °C: 1H NMR (DMSO-d6) # 11. 99 (bs, 1H), 7.14- 6.93 (m, 5H), 4.08 (q, J = 7.2,2H), 3.69 (s, 2H), 3.33 (s, 2H), 3.03 (t, J"= 4.8,4H), 2.68 (t, J = 4.8, 4H), 1.18 (t, J = 7.2,3H); 13C NMR (DMSO-d6). 6 170.08, 168.33,157.13,154.96 (d,, J = 243), 143.65,139.88 (d, J = 3.42), 124.86,122.34 (d, J = 7.65), 119.28,115.93 (d, J = 20.52), 110.59 (d, J = 3.02), 60.36,60.03,52.53 (2C), 50.07,50.06,36.61,14.12; MS (EI, m/z) 406.1 (M+), Anal.

Calcd for ClgH23N403FS: C, 56.06; H, 5.70; N, 13. 77. Found: C, 55.72; H, 5.64; N, 13.37.

Example85 Preparation of (((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl)acetyl)amino)-4-(carboethoxymethyl)thiazole F) g,7.5mL,401-(α,α,α-Trifluoro-m-tolyl)piperazine(9.2 mmol) was added to a solution of ethyl 2- ((bromoacetyl) amino)-4-thiazole acetate (6.2 g, 20 mmol) in DMF (55 mL) at rt. The rection mixture was heated and stirred at 70 OC for 7 h, cooled to rt, and slowly poured into ice water. The light crystalline compound which precipitated was filtered, washed several times with cold water, air-dried for 24 h, and then purifie by flash column chromatography (SiO2, eluent EtOAc) to give 8.67 g (93. 8%) of the title compound, mp 94-95.3 °C : 1H NMR (DMSO-d6) b 11. 99 (bs, 1H), 7.4 (t, J = 8,1H), 7.20 (dd, J = 8.8, J = 2. 4, 1H), 7.15 (bs, 1H), 7.05 (d, J = 7.6), 6.99 (d, J = 0. 8,1H), 4.07 (q, J = 7.2,1H), 3.68 (s, 2H), 3.33 (s, 2H), 3.24 (t, J 4.8,4H), 2.65 (t, J = 4.8,4H), 1.17 (t, J = 7.2,3H); 13C NMR (DMSO-d6) 6 90,168.19,157.05,151.13,143.57,169.

129.87,129.81 (q, J = 30), 124.37 (q, J = 271), 118.69, 114.47 (q, J = 3.8), 110.83 (q, J = 3.8), 110.42, 60.22, 59.87,52.17,49.53,36.55,14.00; MS (EI, m/z) 456.5 (M+).

Anal. Calcd for C20H23N403F3S: C, 52.56; H, 5.07; N, 12.26.

Found: 52.71, H, 5.06; N, 12.18.

Example 85A Preparation of 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl)acetyl)amino)-4-(carboethoxymethyl)thiazoleHydrochloride (CompoundBM) (Trifluoromethyl)piperazinyl-1]acetyl]amino]-2-[[[4-[3- 4-(carboxyethyl) thiazole (compound F) (0.56 g, 1.23 mmol) was dissolve in 20 mL of CH2C12 and to this solution was added 2.5 mL (2.46 mmol) of 1N HC1 solution in ether. The rection mixture was stirred for 2h and the precipitate which formed was filtered, washed several times with ether, and then dried to give 0.5 g (77*1) of the title compound as an ivory solid, mp 207-209°C ("wet"at 171°C).

Example 86 Preparation of 2-(((4-(2-Pyrldyl) piperazin-l- vl) acetYl) amino)-4- (carboxymethyl) thiazole(carboxymethyl) thiazole (Compound AD) 1-(2-Pyridyl) piperazine (1.4 g, 1.4 mL, 8.6 mmol) was added to a solution of 2- (2-chloroacetamido) -4-thiazoleacetic acid (1.08 g, 4.3 mmol) in DMF (15 mL) and the rection mixture was stirred for 8 h at rt.-10k Potassium hydroxide solution (15 mL) was added and the rection mixture was extracted with CH2C12 (3 x 70 mol3. The CH2C12 layer was set aside and the aqueous layer was acidifie with 1N HC1 (20 mL). After standing overnight, the light colored compound which precipitated was filtered, washed several times with cold water and water at rt, and then dried to give 1.3 g (86%) of the title compound as a light yellow solid, mp 203- 204 OC (dec) : 1H NMR (DMSO-d6) 6 158. (dd, J = 5.2, J = 0.4, 1H), 7.65 (t, J = 7.6,1H), 7.01 (s, 1H), 6.96 (d, J = 8.4, 1H)., 6.76 (dd, J = 7.2, J = 5.2,1H), 4.50 (bs, 4H), 3.63 (s, 2H), 3.40 (bs, 4H); 13C NMR (DMSO-d6) 6 27,163.95,171.

157.33,156.53,146.51,144.26,138.45,113.92,110.87, 108.09,56.29,54.38,42.19,36.66; MS (FAB, m/z) 362 (M+).

Example 87 Preparation of 4-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-l- ((N'-(2-thiazolyl))((N'-(2-thiazolyl)) sulfonamido) benzene (Compound G) g,1.8mL,1-(α,α,α-Trifluoro-m-tolyl)piperazine(2.24 9.7 mmol) was added to a solution of 4- ((bromoacetyl) amino)- 1- ((N'-(2-thiazolyl)) sulfonamido) benzene (1. 8 g, 4.85 mmol) in DMF (15 mL) at rt. The rection mixture was heated and stirred at 70 OC for 7 h, cooled to rt, and slowly poured into ice water. The light crystalline compound which precipitated was filtered, washed several times with cold water, and then air-dried for 2 days. The product was refluxed in EtOAc (70 mL) for 1 h, filtered while hot, washed several times with ether, and then dried to give 2.05 g (85%) <BR> <BR> <BR> of the title compound, mp 235.4-236.8 OC: 1H NMR (DMSO-d6) b<BR> <BR> <BR> <BR> <BR> 12.63 (bs, 1H), 10.10 (s, 1H), 7.80 (d, J = 8.8,2H), 7.74 (d, J = 8.8,2H), 7.42 (t, J = 8,1H), 7.25-7.17 (m, 1H), 7.17 (s, 1H), 7.06 (d, J =7.6,1H), 6.81 (d, J = 4. 8,1H), 3.29 (t, J = 4. 4,4H), 3.24 (s, 2H), 2.67 (t, J = 4. 4,4H); 13C NMR (DMSO-d6) 6 63,168.57,151.12,141.65,141.55,168.

136.57,129.87,129.81 (q, J = 31), 126.77,124.42,124.36 (q, J = 271), 118.93,118.84,118.68,114.51 (q, J = 3.8), 110.80 (q, J = 3.8), 107.98,61.43,52.31,47.44; MS (FAB, m/z) 526 (M+). Anal. Calcd for C22H22NsO3F3S2: C, 50.17; H, 4.21; N, 13.30. Found: C, 49.86; H, 4.28; N, 13.19.

Example 88 2-(((4-(5-(Trifluoromethyl)pyrid-2-Preparationof yl)piperazin-1-yl)acetyl)amino)-4-(carboethoxymethyl)thiazol e (CompoundH) 1- (5- (Trifluoromethyl) pyrid-2-yl) piperazine (3.2 g, 13.8 mmol) was added to a solution of ethyl 2- ((bromoacethyl) amino)-4-thiazole acetate (2.1 g, 6.9 mmol) in DMF (20 mL) and the rection mixture was heated and stirred at 70 OC for 5 h. After cooling to rt, the rection mixture was poured into ice water and the light crystalline precipitate which formed was filtered, washed several times with cold water, and then dried to give 2.9 g (95%) of the

title compound as a light colored solid, mp 83-85 °C : 1H NMR <BR> <BR> (DMSO-d6) # 11.96 (bs, 1H), 8.40 (s, 1H), 7.78 (dd, J = 9.2, J = 2. 8,1H), 6. 99 (s, 1H), 6.95 (d, J =-9.2,1H), 4.09 (q, J = 7.2,2H), 3.68 (s, 2H), 3.34 (s, 2H), 2.60 (t, J = 4.8,4H), 1.18 (t, J = 7.2, 3H); 13C NMR (DMSO-d6) # 93,168.24,169.

160. 10, 157.07,145.17 (q, J = 4) 1 143.5 ;, 134.41 (q, J = 4), 126.16 (q, J 270),-112. 96' (q, J = 32), 110.45, 106.21, 60.25,59.86,52.04 (2C), 44.13 (2C), 36.56,14.02; MS (EI, (M+).Anal.CalcdforC19H22N5O3SF3#1.20H2O:C,m/z)457 47.64; H, 5.13; N, 14.61. Found: C, 47.60; H, 4.90; N, 14.64.

Example89 <BR> <BR> Preparation of 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- saltyl)acetyl)amino)-4-(carboxymethyl)thiazole,sodium (COmPOUndJ) Sodium hydroxide (71 mg, 1.77 mol) vas added to a

suspension of 2- (((4- (3- (trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino) -4- (carboxymethyl) thiazole 7(0. g, 1.77 mmol) and water (50 mL). The rection mixture was stirred vigorously for several hours, then the rection mixture was filtered. The water solution was rotary evaporated and the oily residue was washed several times with acetone and ether, and then dried to give 0.75 g (94%) of the title compound as <BR> <BR> a light yellow solid, mp 195-198 OC 1H NMR (Dz0) b 197. (t, J<BR> <BR> <BR> = 8, 1H), 7.07 (bs, 1H), 6.98 (d, J = 8,2H), 6.63 (s, 1H), 3.34 (s, 2H), 3.21 (s, 2H), 2.99 (bs, 4H), 2.53 (bs, 4H); 13C NMR (D2O) # 87,170.44,158.80,151.78,147.01,131.77179. (q, J = 32), 130.91,125.14 (q, J = 271), 121.52, 118.56,114.40, 111.58,60.50,53.05,49.81,40.40. Anal. Calcd for C18H18N4O3F3NaS#2.29 H2O : C, 43.98; H, 4.63; N, 11.40. :Found C, 44.01; H, 4.29; N, 11.10.

Example 90 Preparation of 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-4-(carboxymethyl) thiazole potassium salt (CompoundK) Potassium hydroxide (0.52 g, 9.4 mmol) was added to a solution of 2- (((4-(3-(trifluoromethyl) phenyl) piperazin-l- yl) acetyl)amino)-4-(carboxymethyl)thiazole (4.0 g, 9.34 mmol) and the mixture was stirred for 3 h at rt. The solution was evaporated to dryness. The excess water was removed from the residue by sequential and repeated suspension and then concentration with portions of acetone and ether. After a final concentration from acetone, the solid was dried to give 2.1 g (48%) of the title compound as a light yellow solid, mp 147-149 OC (dec): 1H NMR (D2O) 6 267. (t, J = 8,1H), 7.15 (bs, 1H), 7.07 (d, J = 8,2H), 6.56 (s, 1H), 3.35 (s, 2H), 3.27 (s, 2H), 3.07 (bs, 4H), 2.61 (bs, 4H); 13C NMR (D20) 6 179.87,170.41,158.86,151.79,146.98,131.81 (q, J = 31.99), 130.94,125.13 (q, J = 271. 6), 121.81,118.85, 114.71,111.63,60.45,53.07,49.95,40.35. Anal. Calcd for cl8Hl8N403F3Kso2.36 H20: C, 42.48; H, 4.50; N, 11.00. Found: C, 42.49; H, 4.49; N, 10.92.

Example 91 Preparation of 4-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- Yl) acetyl) amino)-I- ( (N'- (2-thiazolyl)) sulfonamido) benzene hydrochloride salt (Compound L) 4-(((4-(3-(Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino-1- (fN'-t2-thiazolyl)) sulfonamido) benzene- (1.6 g, 3.05 mmol) was suspende with CHzCl2, and to this suspension was added an excess of 1N HC1 solution in ether (6 mL, 6.1 mmol). A light-pink color precipitate formed. The rection mixture was stirred for several hours and the precipitate was filtered and then dried in vacuo to give 1.54 g (86æ) of the title compound as a light-pink solid. The product was refluxed for 1 h in a mixture of CH2C12/ethanol, filtered, and then dried, mp 25 8-260 OC. Anal. Calcd for C22H22N5O3F3S2#HCl#0. 83 H20: C, 45.81; H, 4.30; N, 12.14. Found: C, 45.81; H, 4.07; N, 11.99.

Example92 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1-Preparationof yl) acetvl) amino)-4- (carbomethoxymethyl) thiazole (Compound M) Preparation of 2-amino-4-(carbomethoxymethyl) thiazole: The title compound was prepared by esterification of 2-amino- 4-carbomethoxymethyl) thiazole (25g, 0.16 mol) with HCl gas in anhydrous methanol (200 mL). After a precipitate started to form, the rection mixture wa poured into water and a solution of 5% KOH was added until pH e 7. The white precipitate was filtered. and dried to provide the title compound. The filtrate was extracted with EtOAc and the ETOAc layer was dried and concentrated. Total yield was 22.5g (83%) of 2-amino-4-carbomethoxymethyl) thiazole.

Preparation of 2-((bromoacetyl) amino)-4- (carbomethoxymethyl) thiazole: A solution of 2-amino-4- (carbomethoxymethyl) thiazole (21.0g, 122 mmol) in DMF (80 mL) and dioxane (80 mL) was treated dropwise with bromoacetyl bromide at 0 OC according to. the procedure described in example 84 to give l8. Og (50%) of 2-((bromoacetyl)amino)-4- (carbomethoxymethyl) thiazole.

1- (a, a, a-Trifluoro-m-tolyl) piperazine (3.3 g, 2.7 mL, 14.4 mmol) was added to a solution of 2-((bromoacetyl) amino)- 4-(carbomethoxymethyl) thiazole (2.1 g, 7.19 mmol) in DMF (20 mL) at rt. The rection mixture was heated and stirred at 65 OC for 7 h, cooled to rt, and poured into ice water, causing an off-white precipitate to form. The precipitated solid was filtered, washed several times with cold water, and then dried. Purification by column chromatography, eluting with EtoAc, gave 1.80 (57%) of the title compound as a ivory solid: 1H NMR (DMSO-d6) 6 12.01 (s, 1H), 7.41 (t, J = 7.6, 1H), 7.21 (dd, J = 8, J = 2,1H), 7.16 (bs, 1H), 7.06 (d, J = 7. 6,1H), 7.05 (s, 1H), 3.71 (s, 2H), 3.61 (s, 3H), 3.34 (s, 2H), 3.25 (t, J = 4.4,4H), 2.66 (t, J = 4.8,4H); 13C NMR (DMSO-d6) b 170.49,168.29,157.22,151.18,143.54,129.95, 129.84 (q, J = 31), 123.08 (q, J = 243.68), 118.76,114.57 (q, J = 3.8), 110.88 (q, J = 3.8), 110.59, 59. 92,52.22 (2C), 51.72,47.57 (2C), 36.43; MS (EI, m/z) 441 (M+).

ExamDle 93 Preparation of 2-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- yl) acetyl) amino)-4-(carboxymethylithiazole, hydrochloride salt (Compound N) A solution of 1N HC1 in ether (5 mL, 5 mmol) was added to a solution of 2-(((4-(3-(trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-4-(carboxymethyl) thiazole (0.9 g, 2.1 mmol) CH2Cl2 (20 mL) and the mixture was stirred for 1 h. The light precipitate was filtered, washed quickly (compound is very hygroscopic) with ether, and then dried in vacuo to give 0.85 g (81%) of the title compound as a ivory solid, mp 207-208 °C (dec). Anal. Calcd for C18H19N4O3F3S # 2HC1 0 2 H20: C, 40.23; H, 4.69; N, 10.43. Found: C, 40.12; H, 4.28; N, 10.19.

Example 94 Preparation of 2-(((4-Phenylpiperazin-1-yl)acetyl)amino)-4- (carboethoxymethyl) thiazole (Compound AE) 2-((Bromoacetyl)amino)-4-(carboethoxymethyl)thiazole (1.50 g, 4.90 mmol) was dissolve in DMF (20 mL) and N- phenylpiperizine (1.50 mL, 9.80 mmol) was added. The rection mixture was heated to 60 °C, stirred for 6 h, and then poured into ice water (100 mL). The aqueous layer was extracted with EtOAc (3 x 25 mL) and the combine organic layers dried and evaporated to an oil which was redissolved in 50t EtOAc in hexanes and filtered through a short plug of <BR> <BR> <BR> SiO2. The filtrate was evaporated to give 1.70 g (890) of the<BR> <BR> <BR> <BR> <BR> title compound as a yellow solid : 1H NMR (DMSO-d6) 6 11-99 (s, 1H), 7.20 (m, 2H), 7.00 (s, 1H), 6.93 (m, 2H), 6.77 (t, J 7.3,1H), 4.08 (q, T = 7.0, 2H), 3.69 (s, 2H), 3.33 (s, 2H), 3.15 (t, J = 4. 9,4H), 2.66 (t, J = 7. 1,3H); 13C NMR (DMSO-d6) 6 0,168.3,157.2,151.0,143.6,128.9,118.8,170.

115.4,110.5,60.3,60.0,52.5,48.2,36.6,14.1 ; MS (EI, m/z)388.

Example 96

Preparation of Ethyl 2-(((4-(3- (Trifluoromethyl)phenyl)piperazin-1-yl)acetyl)amino)-4- thiazole cflvoxylate (compound S) Preparation of ethyl 2-(2-((bromoacetyl)amino)-4- thiazole glyoxylate: Bromoacetyl bromide (5.04 g, 2.2 mL, 25 mmol) was added dropwise to a solution of ethyl 2-amino-4- thiazole glyoxylate (5.0 g, 25 mmol) in DMF (20 mL) and dioxane (20 mL) while keeping the internal temperature of the rection mixture at 5 OC. After stirring at 5 OC for 1 h, the ice bath was removed and the rection mixture was stirred at rt overnight. The rection mixture was poured into water and the light crystalline compound which formed was filtered, washed several times with cold water, and then dried to give 5.4 g (68*1) of the title compound, mp 167-169.7 °C: 1H NMR <BR> <BR> <BR> <BR> (DMSO-d6) 6 0213. (s, 1H), 8.54 (s, 1H), 4.36 (q, J = 7.2,<BR> <BR> <BR> <BR> <BR> <BR> <BR> 2H), 4.18 (s, 2H), 1.32 (t, J = 8,3H); 13C NMR (DMSO-d6) 6 178.85,166.12,163.22,158.43,144.44,128.37,62.22,28.18, 13.86; MS (EI, m/z) 322 (M+).

Preparation of ethyl 2-(((4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-4- thiazole glyoxylate: 1- (u, a, a-Trifluoro-m-tolyl) piperazine (2.45 g, 2 mL, 5.32 mmol) was added to a solution of ethyl 2- (2- (bromoacetyl) amino)-4-thiazole glyoxylate (1.7 g, 5.32 mmol) in DMF (20 mL) at rt. The rection mixture was heated and stirred at 80 OC for 7 h, cooled to rt, and poured into ice water, causing an off-white precipitate to form. After standing in the aqueous mixture overnight, the precipitated solid was filtered, triturated with water for several times, and then dried to give 2.0 g (80W) of the title compound as <BR> <BR> <BR> an off-white solid, mp 122.3-122.8 °C; 1H NMR (DMSO-d6) 6<BR> <BR> <BR> <BR> <BR> <BR> 12.50 (bs, 1H), 8.50 (s, 1H), 7.41 (t, J = 8,1H), 7.21 (d, J 8.4,1H), 7.16 (s, 1H), 7.06 (d, J = 7.6,1H), 4.38 (q, J = 6.8,2H), 3.42 (s, 2H), 3.26 (t, J = 4.4,4H), 2.69 (t, J = 4.4,4H), 1.32 (t, J = 6.8,3H); 13C NMR (DMSO-d6) 6 83,178.

169.29,163.23,158.32,151.12,144.29,129.83 (q, J = 30.3), 129.83 (q, J = 30.3), 128.09,123.03 (q, J = 272.35), 118.71,

114.53 (q, J = 3.82), 110.85 (q, J = 3.72), 62.13,59.70, 52.14 (2C), 47.51 (2C), 13.80, MS (EI, m/z) 470 (M+). Anal.

Calcd for C20H21N404SF3: C, 51. 06; H, 4.50; N, 11.91. Found: C, 50.84; H, 4.36; N, 11.89.

Example97 2-(((4-(3-(Methyl)phenyl)piperazin-1-Preparationof yl) acetvl) amino)-4-carboethoxv) methyl) thiazole (Compound T) 1- (3-Methyl) phenylpiperazine (1.4 g, 8 mmol) was added to a solution of ethyl 2-((bromoacetyl) amino)-4-thiazole acetate (1.25 g, 4 mmol) in DMF (15 mL) at rt. The rection mixture was heated and stirred at 70 OC for 6 h, cooled to rt, and slowly poured into ice water. A brown oily compound precipitated. This mixture was extracted several times with ethyl acetate, and the combine ethyl acetate layer was washed with water, dried (NaZS04), filtered, and then concentrated. Purification boy flash column chromatography (SiO2, eluent EtOAc) gave 0.90 g (55%) of the title compound <BR> <BR> as a viscous oil: 1H NMR (DMSO-d6) 6 0012. (s, 1H), 7.08 (dd,

J = 7. 6, J = 7.6,1H), 7.00 (s, 1H), 6.74 (s, 1H), 6.72 (dd, J = 7. 6, J = 1.2,1H), 6.59 (d, J = 7.2,1H), 4.07 (q, J = 6.8,2H), 3.69 (s, 2H), 3.32 (s, 2H), 3.14 (t, J = 4. 8, 4H), 2.66 (t, J = 4.8,4H), 2.24 (s, 3H), 1.18 (t, J = 7. 2,3H) ; 13C NMR (DMSO-d6) 6 02,168.31,157.17,151.02,143.62,170.

137.93,128.72,119.66,116.12,112.65,110.52,60.31,60.03, 52.48 (2C), 48.23 (2C), 36.58,21.40,14.07.

Example98 2-((4-((4-Chlorobenzhydryl)phenyl)piperazin-1-Preparationof yl) acetyl) amino-4- (carboethoxvmethrl) thiazole (Compound Y) 1- (4- (chlorobenzhydryl) phenyl) piperazine (1.0 g, 3.6 mmol) and potassium carbonate (1.5 g, 10.8 mmol) were added to a solution of of ethyl 2-((bromoacetyl) amino)-4-thiazole acetate (1. 1 g, 3.6 mmol) in DMF (20 mL) and the rection mixture was heated and stirred at 70 OC for 7 h. After cooling to rt, the rection mixture was poured into ice water and the light crystalline precipitate which formed was

filtered, washed several times with cold water, and then dried to give 1.25 g (68%) of the title compound as a ivory <BR> <BR> <BR> solid, mp 69-71 °C: 1H NMR (DMSO-d6) 6 44-7.277. (m, 6H), 7.29 (dd, J = 7.2, J = 7.2, 2H), 7.18 (dd, J = 7.2, J = 7. 2,1H), <BR> <BR> <BR> 6.98 (s, 1H), 4.32 (s, 1H), 4.07 (q, J = 7.2, 2H), 3. 67 (s, 2H), 3.32 (bs, 4H), 3.25 (s, 2H), 2.55 (bs, 4H), 1.17 (t, J = <BR> <BR> <BR> 6.8,3H); 13C NMR (DMSO-d6) 6 169. 92, 168. 26,157.05,143.54, 142.18,141.61,131.22,129.32,128.52,128.41,127.52, 126.94,110.40,73.94,60.24,59.85,52.50,51.23,36.55, 14.01; MS (EI, m/z) 512 Example 99 Representative Procedure for the Synthesis of N- Phenvlpiperazines Preparation of 1- (3-nitrophenyl) piperazine: Anhydrous K2CO3 (9.28 g, 67.2 mmol) and bis (2-chloroethyl) amine hydrochloride (12.0 g, 67.2 mmol) were added to a stirred solution of 3-nitroaniline (9.28 g, 67.2 mmol) in diglyme

(100 mL) at rt. The rection mixture was heated at reflux for 18 h, cooled to rt and poured into ice-water (300 mL).

The aqueous mixture was made basic (ca. pH 14) with concentrated KOH solution and extracted with EtOAc (3 x 100 mL). The combine organics were dried over MgSO4 and concentrated. Excess diglyme was distille away under reduced pressure (water aspirator) at 100 OC. The remaining residue was then taken up in a small amount of MeOH-CHZCIz and purifie by chromatography, eluting with methanol- dichloromethane (1: 9), to give 7.76 g (55*1) of the title <BR> <BR> <BR> compound as an orange solid, mp 53-54 OC: 1H NMR (DMSO-d6) 6<BR> <BR> <BR> <BR> <BR> <BR> 7.60 (dd, J = 2.4, J = 2.4,1H), 7.55 (ddd, J = 8.0, J = 2.4, J = 1.2,1H), 7.45 (dd, J = 8. 0, J = 8. 0, 1H), 7.36 (ddd, J = 8.4, J = 2.8, J = 1.2,1H), 3.17-3.14 (m, 4H), 2.84-2.82 (m, 4H); 13C NMR (DMSO-d6) b 13,148.80,130.152. 04, 121.14, 112.41,108.08,48.52 (2C), 45.32 (2C); MS (EI, m/z) 207 (M+).

Example 100

Preparation of 2- ( ( (4- (3-Nitrophenyl) pierazin-1- <BR> <BR> yl) acetyl) amino)-4- (carboethoxymethyl) thiazole (Compound AF)<BR> <BR> <BR> A solution of 2-((bromoacetyl) amino)-4- carboethoxymethyl) thiazole (1.0 g, 253. mmol) and 1- (3- nitrophenyl) piperazine 35(1. g, 516. mmol) in DMF (30 mL) was stirred at rt for 5 min. The solution was poured into 200 mL of ice-water and extracted with EtOAc (3 x 50 mL). The layers were separated and the organic layer was dried over MgSO4, filtered, and then concentrated. Purification by chromatography, eluting with hexane-ethyl acetate :(2 1), gave 1.19 g (85%) of the title compound as an orange oil : 1H NMR <BR> <BR> (DMSO-d6) # 12.00 (bs, 1H), 7.64 (dd, J = 2.4, J = 2.4, 1H),<BR> <BR> <BR> 7.57 (ddd, J = 8.0, J = 2.4, J = 0.8,1H), 7.47 (dd, J = 8.4, J = 8.4,1H), 7.39 (ddd, J = 8.0, J = 2.4, J = 1.6,1H), 6.99 (s, 1H), 4.07 (q, J = 7.2,2H), 3.68 (s, 2H), 3.34 (s, 2H), 3.31 (t, J = 4.4,4H), 2.68 (t, J = 4.4,1H), 1.18 (t, J = 6.8,3H); 13C NMR (DMSO-d6) 6 96,168.21,157.08,151.51,169.

148.83,143.60,130.09,121.27,112.60,110.47,108.35, 60.26, 59.84, 52.07, 47.42, MS(EI,m/z)43314.03; <BR> <BR> <BR> (M+). Anal. Calcd for ClgH23N5Q5: C, 52.65; H, 5.35; N, 16.16.

Found: C, 38;52. H, 5.42; N, 15.90.

Example 101 <BR> <BR> Preparation of 2- ( ( (4- (4- (Trifluoromethyl) phenyl) piperazin-1-<BR> <BR> <BR> yl) acetYl) amino)-4- (carboethoxvmethyl) thiazole (Compound O)<BR> <BR> <BR> <BR> Preparation of 1- (4- (trifluoromethyl) phenyl) piperazine: Rection of anhydrous K2CO3 28(9. g, 67.2 mmol), bis (2- chloroethyl) amine hydrochloride 0(12. g, 267. mmol) and 4- (trifluoromethyl) aniline (10. 8 g, 67.2 mmol) in diglyme (100 mL), according to the representative procedure in Example 99 gave 504. g (30%) of the title piperazine as a white solid, mp 71-72 OC :(Note the product was purified by :distillation) H NMR (DMSO-d6) 6 7.48 (d, J = 8.8,2H), 7.02 (d, J = 8.4, 2H), 3.17-3.15 (m, 4H), 2.82-2.80 (m, ;4H) 13C NMR (DMSO- <BR> <BR> d6) 6 78,126.06153. (q, J = 3.8,2C), 125.00 (q, J = 268.4),<BR> <BR> <BR> 117.50 (q, J = 31.9), 113.92,48.05,45.33; MS (EI, m/z) 230<BR> <BR> <BR> (M+).

1-(α,α,α-Trifluoro-p-tolyl) piperazine (3.0 g, 13 mmol) was added to a solution of ethyl 2-((bromoacetyl) amino)-4- thiazole acetate (2.0 g, 6.5 mmol) in DMF (25 mL) at rt. The rection mixture was heated and stirred at 65 OC for 7 h, cooled to rt, and slowly poured into ice water. The light crystalline compound which formed was filtered, washed several times with cold water, and then dried to give 2.1 g (73%) of the title compound, mp 130-132.9 °C: 1H NMR (DMSO- <BR> <BR> <BR> d6) å 12.00 (bs, 1H), 7.50 (d, J = 8.8,2H), 7.05 (d, J = 8.8, 2H), 7.00 (s, 1H), 4.07 (q, J = 6.8,2H), 3.69 (s, 2H), 3.34 (s, 2H), 3.31 (t, J = 4.4,4H), 2.66 (bs, 4H), 1.18 (t, J = 6.8,3H); 13C NMR (DMSO-d6) b 169.92,168.19,157.09,153.13, 143.57,126.07 (q, J = 3.8,2C), 120.90 (q, J = 270), 117.76 (q, J = 32), 117.60,114.14 (2C), 110.. 45,60.23, 59.84,52.05 (2C), 46.89 (2C), 36.55,14.0; MS (EI, m/z) 457 (M+). Anal.

Calcd for C20H23N403SF3: C, 52. 56; H, 5.07; N, 12.26. Found: C, 52.23; H, 4.75; N, 12.10.

Example 102

Preparation of 2- ( (f4- (3-Chlorophenvl) piperazin-1- yl) acetyl) amino)-4- (carboethoxymethyl)(carboethoxymethyl) thiazole (Compound Q) Preparation of 1- (3-chlorophenyl) piperazine: Rection of anhydrous K2CO3 (9.28 g, 67.2 mmol), bis (2-chloroethyl) amine hydrochloride (12.0 g, 67.2 mmol) and 3-chloroaniline (8.57 g, 7.11 mL, 67.2 mmol) in diglyme (100 mL), according to the representative procedure in Example 99, gave 8.90 g (6701) of <BR> <BR> the title piperazine as a brown oil : 1H NMR (DMSO-d6) # 7. 18 (t, J = 8.0,1H), 6.89 (t, J = 2.0,1H), 6.85 (ddd, J = 8.4, J = 2.4, J = 0.8,1H), 6.75 (ddd, J = 7.6, J = 1.6, J = 0.8, <BR> <BR> 1H), 3.04 (m, 4H), 2.80 (m, 4H); 13C NMR (DMSO-ds) b 78,152.<BR> <BR> <BR> <P>133.72,130.22,117.69,114.27,113.42,48.72,45.37; MS (EI, m/z) 196 (M+).

Preparation of 2- ( ( (4.- (3-chlorophenyl) piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole: Rection of 2-((bromoacetyl)amino)-4-(carboethoxymethyl). thiazole (1.50 g, 4.88 mmol) and 1- (3-chlorophenyl) piperazine (1.92 g, 9.76 mmol) in DMF (30 mL) according to representative procedure in

Example 100 gave 1.74 g (84%) of the title compound as a solid, mp 80-81 °C: 1H NMR (DMSO-d6) 6 9911. (bs, 1H), 7.19 (dd, J = 8.4, J = 8.4,1H), 6.99 (s, 1H), 6.93 (dd, J = 2.4, J = 2.4,1H), 6.88 (dd, J = 8. 4, J = 2.4,1H), 6.76 (ddd, J = 7.6, J = 1.6, J = 1.2,1H), 4.07 (q, J = 7.2,2H), 3.68 (s, 2H), 3.32 (s, 2H), 3.19 (t, J = 4.8,4H), 2.64 (t, J = 4.8, 4H), 1.18 (t, J = 6.8,3H); 13C NMR (DMSO-d6) 6 91,169.

168.21,157.09,152.13,143.56,133.73,130.30,117.93, 114.51,113.60,110.42,60.22,59.90,52.17,47.58,36.55, 14.00; MS (EI, m/z) 422 (M').

Example103 Preparation of 2-(((4-(3-Bromophenyl)piperazin-1- vl) acetyl) amino)-4- (carboethoxymethvl) thiazole (Compound R) Preparation of 1-(3-bromophenyl) piperazine: Rection of anhydrous K2CO3 (9.28 g, 67.2 mmol), bis (2-chloroethyl) amine hydrochloride (12.0 g, 67.2 mmol) and 3-bromoaniline (9.30 g, 7.. 32 mL, 67.2 mmol) in diglyme (100 mL), according to the

representative procedure in Example 99, gave 9.2 g (57%) of the title piperazine as a brown oil : 1H NMR (DMSO-d6) 6 127.

(dd, J = 8.4, J = 7.6,1H), 7.02 (t, J =2. 0,1H), 6. 91 - 6.87 (m, 2H), 3. 05 - 3.03 (m, 4H), 2. 81 - 2.78 (m, 4H); 13C NMR (DMSO-d6) 6 95,130.55,122.44,120.64,117.13,152.

113.84,48.74,45.38; MS (EI, m/z) 242 (M+2').

Preparation of 2- ( ( (4- (3-bromophenyl) piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole: Rection of 2-(bromoacetyl) amino-4- (carboethoxymethyl) thiazole (1.5 g, 4.88 mmol) and 1-(3-bromophenyl) piperazine (2.35 g, 9.76 mmol) in DMF (30 mL) according to representative procedure in Example 100 gave 1.75 g (76%) of the title compound as a solid, mp 80-82 NMR(DMSO-d6)#11.99(bs,1H),7.131H (dd, J = 8.0, J = 8.0,1H), 7.06 (dd, J = 2.0, J = 2.0,1H), 6.99 (s, 1H), 6.93-6.89 (m, 2H), 4.07 (q, J = 7.2,2H), 3.68 (s, 2H), 3.32 (s, 2H), 3.18 (t, J = 4.8,4H), 2.63 (t, J <BR> <BR> <BR> = 4. 8,4H), 1.18 (t, J = 6.8,3H), 13C NMR (DMSO-d6) 6 91,169.<BR> <BR> <BR> i 168.22,157.08,152.30,143.56,130.62,122.43,120.86, 117.35,114.02,110.42,60.23,59.90,52.18,47.58,36.55, 14.01; MS (EI, m/z) 466 (M+). Anal. Calcd for C19H23N4O3BrS : C, 48.83; H, 4.96; N, 11.99. Found: C, 49.07; H, 5.28; N, 11.75.

Example 104 2-(((4-(3-Cyanophenyl)piperazin-1-Preparationof yl) acetyl) amino)-4- (carboethoxvmethyl)(carboethoxvmethyl) thiazole (Compound AG) Preparation of 1-(3-cyanophenyl) piperazine: Rection of anhydrous K2CO3 (9.28 g, 67.2 mmol), bis (2-chloroethyl) amine hydrochloride (12.0 g, 67.2 mmol) and 4- (trifluoromethyl) aniline (9.28 g, 67.2 mmol) in diglyme (100 mL), according to the representative procedure in Example 99, gave 8.36 g (661) of the title piperazine as a brown oil : 1H <BR> <BR> <BR> <BR> NMR (CD30D) 6 367. (ddd, J = 7.6, J = 7.6, LT = 1.2, 1H), 7. 24<BR> <BR> <BR> <BR> <BR> <BR> <BR> -7.21 (m, 2H), 7.10 (ddd, J = 7.2, J = 0.8, J = 0.8,1H),<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3.19-3.16 (m, 4H), 2.97-2.94 (m, 4H);. 13C NMR (CD30D) b 153.37,131.15,123.48,121.33,120.26,119.40,113.84, 49.94,46.29; MS (EI, m/z) 187 (M+).

Preparation of 2- ( ( (4- (3-cyanophenyl) piperazin-1- yl) acetyl) amino)-4- (carboethoxymethyl) thiazole: Rection of ethyl 2-((bromoacetyl)amino)-4-(carboethoxymethyl)thiazole (1.0 g, 3.25 mmol) and 1-(3-cyanophenyl)piperazine@ (1.22 g, 6.51 mmol) in DMF (30 mL) according to representative procedure in Example 100, gave 0.87 g (651) of the title <BR> <BR> <BR> <BR> compound as an oil : 1H NMR (CD30D) 6 40-7.367. (m, 1H), 7.28 -7.26 (m, 2H), 7.11 (ddd, J = 7.6, J = 1.2, J = 1.2,1H), 6.95 (t, J = 0. 8,1H), 4.15 (q, J = 7.2,2H), 3.70 (s, 2H), 3.37 (s, 2H), 3.34 (t, J = 4.8,4H), 2.77 (t, J = 4.8, 4H), 1.25 (t, J = 6.8,3H); 13C NMR (CD30D) 6 15,170.43,172.

159.17,152.96,144.98,131.191,123.51,121.37,120.23, 119.47,113.91,112.14,62.11,61.59,54.16 (2C), 49.31 (2C), 37.58,14.45; MS (EI, m/z) 413 (Mt).

Example 105 2-(((4-(4-(carbomethoxy)phenyl)piperazin-1-Preparationof vl) acetvl) amino)-4- (carboethoxymethvl) thiazole (Compound P) Preparation of 1- (4- (carbomethoXy) phenyl) piperazine: Rection of anhydrous K2CO3 (9.28 g, 67.2 mmol), bis (2-

chloroethyl) amine hydrochloride (12.0 g, 67.2 mmol) and methyl 4-aminobenzoate (10.2 g, 67.2 mmol) in diglyme (100 mL), according to the representative procedure in Example 99, gave 5.00 g (34%) of the title piperazine as a beige solid, <BR> <BR> mp 88 OC: 1H NMR (DMSO d6) 6 777. (d, J = 9. 2,2H), 6.95 (d, J 8.8,2H), 3.76 (s, 3H), 3.22-3.20 (m, 4H), 2.82-2.77 (m, 4H) ; 13C NMR (DMSO-ds) b 14,154.35,130.67,117.82,166.

113.13,51.42,47.61,45.28; MS (EI, m/z) 220 (M+).

Preparation of ethyl 2-(((4-(4- (carbomethoxy) phenyl) piperazin-1-yl) acetyl) amino)-4- (carboethoxy) methyl) thiazole: 1- (4-carbomethoxyphenyl) piperazine (1.6 g, 7.2 mmol) was added to a solution of ethyl 2-((bromoacethyl) amino)-4-thiazole acetate (2.2. g, 7.2 mmol) in DMF (30 mL) at rt, and to this solution was added 03. g (21.6 mmol) of K2CO3. The rection mixture was heated and

stirred at 70 OC for 6 h, cooled to rt, and slowly poured into ice water. The product which precipitated was filtered, washed several times with cold water, dried in vacuo, and then dissolve in a small amount of ethyl acetate. Hexane was added and the precipitate which formed was filtered, washed several times with water, and then air-dried for 2 days to give 0.90 g (28%) of the title compound, mp 140.4-143 <BR> <BR> °C ("wet"at 136.4 °C) : 1H NMR (DMSO-d6) 6 11-99 (s, 1H), 7.78 (d, J = 9.2,2H), 6.99 (s, 1H), 6.97 (d, J = 9.2,2H), 4.07 (q, J = 7.2,2H), 3.77 (s, 3H), 3.68 (s, 2H), 3.35 (t, J = <BR> <BR> 4.4,4H), 3.33 (s, 2H), 2.64 (t, J = 4.8, 4H), 1.78 (t, J =<BR> <BR> <BR> 7.2, 3H) ; 13C NMR (DMSO-d6) 6 93,168.24,166.07,157.10,169.

153.78,143.58,130.65 (2C), 118.07,113.32 (2C), 110.44, 60.24,59.86,52.08,51.35,46.59,36.55,14. 01 ; MS (EI, m/z) 446 (M').

Example 106 Preparation of 2- ( ( (4- (3-Ethylhenvl) piperazin-1- yl) acetyl) amino)-4- (carboethoxymethyl)(carboethoxymethyl) thiazole (Compound AH) Preparation of 1-(3-ethylphenyl) piperazine: Rection of anhydrous K2CO3 (8.0 g, 57.8 mmol), bis (2-chloroethyl) amine hydrochloride (10. 32 g, 57.8 mmol) and 3-ethylaniline (7.0

g, 57.8 mmol) in diglyme (100 mL), according to the representative procedure in Example 99, gave 5.90 g (54%) of <BR> <BR> <BR> the title piperazine as a brown oil : 1H NMR (DMSO-ds) b 107.<BR> <BR> <BR> <BR> <BR> <P> (t, J = 8.0,1H), 756. (bs, 1H), 6.70 (dd, J = 8.4, J = 2.0, lH) j 6.62 (dd, J = 7. 6, T = 0.4, 1H), 3.03-3.00 (m, 4H), 2.98 (bs, 1H), 2.84-2.82 (m, 4H), 2.53 (q, J = 7.6, 2H), 1.16 <BR> <BR> <BR> (t, J = 7.6,3H); 13C NMR (DMSO_d6) 6 71,144.25,128.64,151.

118.19,114.87,112.71,49.40,45.56,28.55, 15.61 ; MS (EI, m/z) 190 (M').

Preparation of 2- ( ( (. 4- (3-ethylphenyl) piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole: Rection of 2- ((bromoacetyl) amino)--4-(carboethoxymethyl)((bromoacetyl) amino)--4-(carboethoxymethyl) thiazole (1.0 g, 3.25 mmol) and 1-(3-ethylphenyl) piperazine (1.24 g, 6.51 mmol) in DMF (30 mL) according to the representative procedure in Example 100 gave 0.84 g (62%) of the title <BR> <BR> compound as a sticky solid : 1H NMR (DMSO-ds) 8 9711. (s, 1H), 7.10 (dd, J = 8.0, J = 8.0,1H), 6.99 (s, 1H), 6.76 (s, 1H), 6: 72 (dd, J = 8.0, J = 2.0, 1H), 626. (d, J = 7.6, 1H), 064.

(q, J = 7.2,2H), 3.68 (s, 2H), 3.32 (s, 2H), 3.14 (t, J =

4.8,4H), 2.65 (t, J = 4.8,4H), 2.52 (q, J = 7.6,2H), 1.17 (t, J = 7.2,3H), 1.15 (t, J = 7.6,3H); 13C NMR (DMSO-d6) 6 170.02,168.35,157.15,151.09,144.44,143.63,128.80, 118.47,115.11,112.92,110.53,60.33,60.06,52.53 (2C), 48.31 (2C), 36.61,28.54,15.69,14.07; MS (EI, m/z) 416 (M+).

Anal. Calcd for C21H28N4O3S : C, 60.55; H, 6.78; N, 13.45.

Found: C, 60.43; H, 6.48; N, 13.44.

Example107 Preparation of 2-(((4-(3, 5-Bis- (trifluoromethvl) phenyl) piperazin-1-yl) acetyl amino)-4- (carboethoxymethvl) thiazole (Compound AI) Preparation of 1-(3,5-bis-. ofanhydrous(trifluoromethyl)phenyl)piperazine:Reaction K2CO3 (6.03 g, 43.6 mmol), sodium iodide (1.63 g, 10.91 mmol), bis (2-chloroethyl) amine hydrochloride (7.76 9, 43.6 mmol) and 3,5-bis- (trifluoromethyl) aniline (10.0 g, 43.6 mmol) in diglyme (100 mL) according to the representative procedure in Example 99, gave 1.73 g, (13%) of the title piperazine as a

dark green solid, mp 98-99 °C : 1H NMR (DMSO-d6) 6 427. (s, 2H), 7.26 (s, 1H), 3.25-3.21 (m, 4H), 2.85-2.82 (m, 4H); <BR> <BR> <BR> 13C NMR (DMSO-d6) 6 06,131.00152. (q, J = 31.9), 123.55 (q, J = 270. 8), 113.90 (q, J = 3.8), 109.66 (q, J = 3.8), 47.99 45.11; MS (EI, m/z) 298 (M+).

Preparation of 2- ( ( (4- (3,5-bis- (trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-4- (carboethoxymethyl) thiazole: Rection of 2- ((bromoacetyl) amino)-4-(carboethoxymethyl) thiazole (0.70 g, 2.28 mmol), 1- (3,5-bis-(trifluoromethyl) phenyl) piperazine (0.82 g, 2.74 mmol) and anhydrous K2CO3 (0.38 g, 2.74 mmol) in DMF (30 mL) according to the representative procedure in Example 100 gave 0.98 g (82%) of the title compound as a <BR> <BR> <BR> sticky solid : 1H NMR (DMSO-d6) 6 0212. (s, 1H), 7.46 (s, 2H), 7.30 (s, 1H), 7.00 (s, 1H), 4.07 (q, J = 7.2,2H), 3.68 (s, 2H), 3.38 (t, J = 4.4,4H), 3.33 (s, 2H), 2.67 (t, J = 4.4, 4H), 1.18 (t, J = 6.8,3H); 13C NMR (DMSO-d6) 6 02,170.

168.26,157.16,151.16,143.64,131.06 (q, J = 31.7,2C),

123.60 (q, J = 271.6,2C), 114.24 (q, J = 2.9), 110.55, 109.99 (q, J = 4.2,2C), 60.31,59.81,52.02 (2C), 47.03 (2C), 36.59,14.08. Anal. Calcd for C21H22N403F6S: C, 48.09 ; H, 4.23; N, 10.68. Found: C, 47.80; H, 4.17; N, 10.59.

Example108 2-(((4-(3-Methoxyphenyl)piperazin-1-Preparationof <BR> <BR> YllacetYl) amino)-4-(carboethoxYmethyl)(carboethoxYmethyl) thiazole (Compound AJ) Preparation of 1-(3-methoxyphenyl) piperazine: Rection of anhydrous K2CO3 (7.86 g, 56.9 mmol), bis (2- chloroethyl) amine hydrochloride (10.16 g, 56.9 mmol) and 3- methoxyaniline (7.0 g, 56.9 mmol) in diglyme (100 mL), according to the representative procedure in Example 99 gave 5.32 g (49%) of the title piperazine as a brown oil : 1H NMR (DMSO-d6) 6 097. (t, J = 8.4,1H), 6. 49 (ddd, J = 8.0, J = 2.8, J = 0.4,1H), 6.42 (t, J = 2.4,1H), 6.34 (ddd, J = 8.0, J = 2.8, J = 0.4,1H), 3.70 (s, 3H), 3.04-3.01 (m, 4H), 2.82 (bs, 4H); 13C NMR (DMSO-d6) 6 17,152.94,129.51,160.

107.99,103.99,101.39,54.80,49.12,45.35; MS (EI, m/z) 192 (M+).

Preparation of 2- ( ( (4- (3-methoxyphenyl) piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole: Rection of 2-((bromoacetyl)amino)-4-(carboethoxymethyl) thiazole ('-. 0 g, 3.25 mmol) and 1- (3-methoxyphenyl) piperazine (1.25 g, 6.50 mmol) in DMF (30 mL) according to the representative procedure in Example 100, gave 1.15 g (84%) of the title <BR> <BR> compound as a sticky solid: 1H NMR (DMSO-d6) 6 9811. (s, 1H), 7.09 (dd, J = 8.4, J = 8.4,1H), 6.99 (s, 1H), 6.51 (dd, J = 8.4, J = 2.0,1H), 6.44 (dd, J = 2.4, J = 2.4,1H), 6.35 (dd, J = 7.6, J = 1.6, 1H), 4.07 (q, J = 7.2,2H), 3.70 (s, 3H), 3.68 (s, 2H), 3.34 (s, 2H), 3.15 (t, J = 4.8,4H), 2.64 (t, J <BR> <BR> <BR> 4.8,4H), 1.18 (t, J = 7.2,3H); 13C NMR (DMSO-d6) 6 91,169.

168.25,160.14,157.08,152.29,143.56,129.51,110.42, 108.04,104.09, 101.51, 60.23,59.97,54.80,52.37 (2C), 48. 09 (2C), 36. 55,14.01.

Example 109 2-(((4-(3,5-Dichlorophenyl)piperazin-1-Preparationof yl)acetyl)amino)-4-(carboethoxymethyl)thiazole Z) Preparation of 1- (3,5-bis-chlorophenyl) piperazine: Rection of anhydrous K2CO3 (5.97 g, 43.2 mmol), sodium iodide (1.62 g, 10.8 mmol), bis (2-chloroethyl) amine hydrochloride (7.71 g, 43.2 mmol) and 3,5-bis-chloroaniline (7.0 g, 43.2 mmol) in diglyme (100 mL), according to the representative procedure in Example 99 gave 2.26 g (230) of the title piperazine as a black oil : 1H NMR (DMSO-d6) b 906. (s, 2H), 6.89 (s, 1H), 3.10-3.09 (m, 4H), 2. 80 - 2.78 (m, 4H); 13C <BR> <BR> <BR> NMR (DMSO-d6) 6 16,134.57,116.71,112.79,48.15,45.17;153.

MS (EI, m/z) 229 (M+).

Preparation. of 2- ( ( (4- (3,5-dichlorophenyl) piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole: Rection of 2-((bromoacethyl)amino)-4-(carboethoxymethyl) thiazole (1.0 g, 3.25 mmol), 1- (3,5-dichlorophenyl) piperazine (1.0 g, 4.33 mmol) and anhydrous KZC03in DMF (30 mL) according to the representative procedure in Example 100 gave 0.80 (54%) of <BR> <BR> the title compound as a sticky solid : 1H NMR (DMSO-d6) 6 11. 99 (s, 1H), 6.99 (s, 1H), 6.92 (s, 2H), 6.84 (s, 1H), 4. 07 (q, J --7.2,2H), 3.68 (s, 2H), 3.32 (s, 2H), 3.24 (t, J = 4.8,

4H), 2.62 (t, J = 4.8,4H), 1.17 (t, J = 7.2,3H) ; 13C NMR (DMSO-d6) 6 01,168.26,157.17,152.60,143.63,134.62,170.

116.95 (2C), 113.03 (2C), 110.53,60.32,59. 81, 52.05 (2C), 47.16 (2C), 36.60,14.07. Anal. Calcd for C19H22N4O2ClS : C, 49.90; H, 4.85; N, 12.25. Found: C, 49.53; H, 4.91; N, 12.12.

Example110 2-(((4-(3,4-Dichlorophenyl)piperazin-1-Preparationof <BR> <BR> yl) acetyl) amino)-4-(carboethoxymethyl) thiazole (Compound(carboethoxymethyl) thiazole (Compound AK) Preparation of 1-(3,4-bis-chlorophenyl) piperazine: Rection of anhydrous K2CO3 (5.42 g, 39.2 mmol), sodium iodide (1.47 g, 9.8 mmol), bis (2-chloroethyl) amine hydrochloride (7.0 g, 39.2 mmol) and 4-(trifluoromethyl)aniline (6.35 g, 39.2 mmol) in diglyme (100 mL), according to the representative procedure in Example 99 gave 2.72 g (3001) of the title piperazine as a brown solid, mp 62 °C: 1H NMR (DMSO- <BR> <BR> d6) 6 357. (d, J = 9.2,1H), 7.06 (d, J = 2.8, 1H), 6.87 (dd, J = 9.2, J = 3.2, 1H), 3.06-3.03 (m, 4H), 2.80-2.78 (m, 4H); 13C NMR (DMSO-d6) 6 27,131.43,130.151. 31, 119. 24, 115.92,115.05,48.54,45.27.

Preparation of 2-(((4-(4,3-dichlorophenyl)piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole: Rection of 2-(bromoacetyl)amino-4-(carboethoxymethyl) thiazole (1.0 g, 3.25 mmol), 1- (3,4-dichlorophenyl) piperazine (1.0 g, 4.33 mmol) and anhydrous K2CO3 (0.60 g, 4.33 mmol) in DMF (30 mL) according to the representative procedure in Example 100 gave 0.66 g (44%) of the title compound as a sticky solid : 1H NMR <BR> <BR> (DMSO-d6) 6 9911. (s, 1H), 7.37 (d, J = 8.8,1H), 7.11 (d, J = 2.8,1H), 6.99 (s, 1H), 6. 90 (dd, J = 9.2, J = 3.2, 1H), 4.07 (q, J = 7.2,2H), 3.68 (s, 2H), 3.32 (s, 2H), 3.20 (t, J = 4.8,4H), 2.63 (t, J = 4.8,4H), 1.17 (t, J = 7.2,3H) ; 13C NMR (DMSO-d6) 5 01,168.26,157.17,150.67,143.170. 62, 131.47,130. 41, 119.51,116.23,115.28,110.52,60.31,59.88, 52.09 (2C), 47.49 (2C), 36.59,14.07. Anal. Calcd for C19H22N4O3SCl2: C, 49.90; H, 4.85; N, 12.25. Found: C, 50.00; H, 4.78; N, 12.10.

Example111 Preparation of 2-(((4-(2-Naphthyl)piperazin-1- yl) acetvl) amino)-4- (carboethoxymethvl) thiazole (Compound AL) Preparation of 1-(2-naphthyl) piperazine: Rection of anhydrous K2CO3 (5.79 g, 41.9 mmol), bis (2-chloroethyl) amine hydrochloride (7.48 g, 41.9 mmol) and 2-amino-naphthalene (6.0 g, 41.9 mmol) in diglyme (100 mL), according to the representative procedure in Example 99 gave 4.27 (48%) of the title piperazine as a purple solid, mp 75-77 °C: 1H NMR <BR> <BR> <BR> <BR> (DMSO-d6) 6 74-7.697. (m, 3H), 7.37 (ddd, J = 8.0, J = 6.8, J = 1.2,1H), 7.34 (dd, J = 9.2, J = 2.4,1H), 7.24 (ddd, J = 8.0, J = 6.8, J = 1.2,1H), 7.12 (d, J = 2.4,1H), 3.20 (bs, 1H, NH), 3.17-3.14 (m, 4H), 2.89-2.87 (m, 4H); 13C NMR (DMSO-d6) 6 44,134.32,128.21,127.58,127.10,126.40,149.

125.95,122.71,118.91,108.87,49.54, 45. 48; MS (EI, m/z) 212 (M+).

Preparation of 2- ( ( (4- (2-naphthyl) piperazin-1- yl) acetyl) amino)-4-(carboethoxymethyl) thiazole: Rection of 2-((bromoacetyl)amino)-4-(carboethoxymethyl) thiazole (1.0 g, 3.25 mmol) and 1-(2-naphthyl) piperazine (1.38 g, 6.50 mmol) in DMF (30 mL) according to the representative procedure in Example 100 gave 0.97 g (68*1) of the title compound as a <BR> <BR> <BR> <BR> solid, mp 134-135 °C: 1H NMR (DMSO-d6) 6 0112. (s, 1H), 7. 75 - 7.69 (m, 3H), 7. 39 - 7.34 (m, 2H), 7.25 (dd, J = 6.8, J = 6.8,1H), 7.16 (s, 1H), 7.00 (s, 1H), 4.07 (q, J = 7.2,2H), 3.69 (s, 2H), 3.36 (s, 2H), 3.28 (bs, 4H), 2.71 (bs, 4H), 1.18 (t, J = 7.2,3H); 13C NMR (DMSO-d6) 6 92,168.28,169.

157.11,148.76,143.58,134.28,128.28,127.63,127.11, 126.40,126. 00, 122.81,118.92,110.44,109.07,60.23,59.99, 52.38,48.39,36.55,14.01; MS (EI, m/z) 438 (M+). Anal.

Calcd for Cz3H26NqO3S: C, 62.99; H, 5.98; N, 12.78. Found: C, 62.97; H, 6.15; N, 12.59.

Example 112 Preparation of 2- ( (4- (3-Methoxy-5- (trifluoromethyl)phenyl)piperazin-1-yl)acetyl)amino)-4- (carboethoxymethvl) thiazole (Compound AM) Preparation of 1- (3-methoxy-5- (trifluoromethyl) phenyl) piperazine: Rection of anhydrous K2CO3 (5.06 g, 36 6 mmol), bis (2-chloroethyl) amine hydrochloride (6.54 g, 36.6 mmol) and 4- (trifluoromethyl) aniline (7.0 g, 36.6 mmol) in diglyme (100 mL), according to the representative procedure in Example 99, gave 5.00 (52%) of the title piperazine as a brownish yellow <BR> <BR> <BR> oil : 1H NMR (DMSO-d6) 6 756. (bs, 1H), 6.66 (t, J = 2.4,1H), 6.58 (bs, 1H), 3.78 (s, 3H), 3.10 (t, J = 4. 8, 4H), 2.81 (t, <BR> <BR> <BR> J = 4.8,4H); 13C NMR (DMSO-d6) 6 60,153.23,130.66160. (q, J = 31), 124.32 (q, J = 270.9), 104.03,103.78 (q, J = 4.2), 100.04 (q, J = 3.6), 55. 36,48.71,45.40; MS (EI, m/z) 260 (M+).

Preparation of 2-(((4-(3-methoxy-5- (trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-4- (carboethoxymethyl) thiazole: Rection of 2- ((bromoacetyl) amino)-4-(carboethoxymethyl) thiazole (1.0 g, 3.25 mmol) and 1- (3-methoxy-5- (trifluoromethyl) phenyl) piperazine (1.25 g, 6.50 mmol) in DMF (30 mL) according to the representative procedure in Example 100, gave 1.12 g (70%) of the title compound as a sticky solid : 1H NMR (DMSO- <BR> <BR> <BR> d6) 6 9911. (s, 1H), 6.99 (s, 1H), 6. 78 (s, 1H), 6. 69 (t, J = 2.0,1H), 6.60 (s, 1H), 4.07 (q, J = 6.8,2H), 3.78 (s, 3H), 3.69 (s, 2H), 3.32 (s, 2H), 3.25 (t, J = 4.8,4H), 2.65 (t, J <BR> <BR> <BR> 4.8,4H), 1.18 (t, J = 7.2,3H); 13C NMR (DMSO-d6) 6 01,170.

168.28,160.60,157.15, lys2.57,143.63,130.68 (q, J = 31.0), 124.26 (q, J = 271), 110.53,104.29,103.99 (q, J = 4.2), i00.20 (q, J = 3.5), 60.30,59.90,55.42,52.19 (2C), 47.58 (2C), 36.58,14.06; MS (EI, m/z) 486 (M+). Anal. Calcd for C21H25N404F3S: C, 51.85; H, 5.18; N, 11.52. Found: C, 51.64; H, 5.07; N, 11.37.

Example113 Preparation of 2-(((4-(4-Chloro-3- (trifluoromethyl)phenyl)piperazin-1-yl)acetyl)amino)-4- (carboethoxymethyl) thiazole (Compound X) Preparation of 1- (4-chloro-3- (trifluoromethyl) phenyl) piperazine: Anhydrous K2CO3 (4.5 g, 33 mmol) and bis (2-chloroethyl) amine hydrochloride (5.9 g, 33 mmol) were added to a stirred solution of 4-chloro-3- (trifluoromethyl) aniline (6.4 g, 33 mmol) in diglyme (25 mL) at rt. The rection mixture was heated at reflux for 18 h, cooled to rt, and poured into water (100 mL). The aqueous mixture was made basic (ca. pH 14) with a saturated potassium hydroxide solution and extracted with ethyl acétate (3 x 100 mL). The combine organic extract was washed with water (3 x 100 mL), dried- (MgS04), and concentrated to an oily residue.

Purification by flash column chromatography SiO2, eluent EtOAc, then chloroform/isopropanol 9: 1) gave 0.9 g (9. 9%) of the title piperazine.

Preparation of 2-(((4-(4-chloro-3- (trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-4- (carboethoxymethyl) thiazole: 1- (4-chloro-3- (trifluoromethyl) phenyl) piperazine (0.90 g, 3.3 mmol) and potassium carbonate (1.35 g, 9.9 mmol) were added to a solution of 2- (bromoacetyl) amino)-4- (carboethoxymethyl) thiazole (i. O. g, 3.3 mmol) in DMF (20 mL) at rt. The rection mixture was heated and stirred at 80 OC for 7 h, cooled to rt, and slowly poured into ice water. The light crystalline compound which formed was filtered, washed several times with cold water, and dried to give 0.9 g (56%) of the title compound, mp 125- 127.8 °C: 1H NMR (DMSO-d6) 6 12.00 (s, 1H), 7.47 (d, J = 8.8, 1H), 7.25 (d, J = 3.2,1H), 7.20 (dd, J = 9.2, J = 3. 2, 1H), 6.99 (s, 1H), 4.07 (q, J = 7.2,2H), 3.68 (s, 2H), 3.35 (s, <BR> <BR> <BR> 2H), 3.26 (t, J = 4.8,4H), 2.66 (t, J = 4.8, 4H), 1.17 (q, J<BR> <BR> <BR> <BR> <BR> = 6.8.3H) ; 13C NMR (DMSO-d6) 6 170.02,168.29,157.17, 149.69,143.64,131.98,126.88 (q, J = 30.2), 123.05 (q, J = 271.6), 119.75,118.56 (q, J = 4.9), 113.36 (q, J = 4.9),

110.54,60.3. 2,59.86,52.07 (2C), 47.42 (2C), 36.59,14.07; MS (EI, m/z) 490 (M+).

Examiple 114 Preiparation of 2-(((4-(3-(trifluoromethyl) nhenvl) piperazin-1- vl) acetYl) amino)-4- (carbopropoxymethyl)(carbopropoxymethyl) thiazole (Compound U) Preparation of 2-amino-4- (carbopropaxymethyl) thiazole hydrochloride: A solution of 2-amino-4- (carboxymethyl) thiazole (2.0 g, 12.6 mmol) and thionyl chloride (1.51 g, 0.92 niL, 12.7 mmol) in anhydrous n-propyl alcohol (50 mL) was stirred at 65 OC for 3 h, during which time the reaction mixture gradually turned clear. The rection mixture was cooled to rt, concentrated, and dried in vacuo overnight to give 2.93 g (ca 100%) of the title compound as a white solid : 1H NMR (DMSO-d6) 6 499. (bs, 2H),

6.71 (s, 1H), 4.01 (t, J = 6.8,2H), 3.76 (s, 2H), 1.59 <BR> <BR> (heptet, J = 7.6), 0.87 (t, J = 7.2,3H);. 13C NMR (DMSO-d6) 6 169.52,168.53,132.78,105.29,66.19,32.90,21.37,10.14; MS (EI, (M+).200 Preparation of 2-((bromoacetyl) amino)-4- (carbopropoxymethyl) thiazole: A solution of saturated NaHCO3 was slowly added to 2-amino-4-(carbopropoxymethyl) thiazole hydrochloride until the pH of the aqueous solution remained constant at 7. The suspension was then further stirred for 20 min and the precipitate was filtered, washed with water, and then dried in vacuo overnight to afford 2.2 g of the free base. A solution of 2-amino-4-(carbopropoxymethyl) thiazole (2.0 g, 10 mmol) in 1 : 1 DMF/dioxane (30 mL) was cooled to 0 OC and bromoacetyl bromide (2.02 g, 10 mmol) was added dropwise. The solution was stirred at rt for 1 h and poured into 200 mL of ice-water. The precipitate which formed was filtered, washed with. water, and then dried to afford 2.50 g (78%) of the title compound as a white solid, mp 168-169 OC: 1H NMR (DMSO-d6) b 12.59 (s, 1H), 7.05 (s, 1H), 4.12 (s, 2H), 3.99 (t, J = 6.4,2H), 3.70 (s, 2H), 1.56 (sxt, J = 6.8,2H), 0.85 (t, J = 7.6,3H); 13C NMR (DMSO-d6) # 92,164.95,169.

157.13,143.92,110.98,65.67,36.52,28.28,21.44,10.09; MS (EI, (M+).320 Preparation of 2-(((4-(3- (trifluoromethyl)phenyl)piperazin-1-yl)acetyl)amino)-4- (carbopropoxymethyl) thiazole : A solution of 2- ((bromoacetyl) amino)-4-(carbopropoxymethyl) thiazole (2.0 g, 6.23 mmol) and 1- (3- (trifluoromethyl) pheAyl) piperazine (2.86 g, 12.46 mmol) in DMF (30 mL) was stirred at rt for 5 min.

The solution was poured into 200 mL of ice-water and extracted with EtOAc (3 x 50 mL). The layers were separated and the organic layer was dried over MgSO4, filtered, and then concentrated. Purification by chromatography, eluting with hexane-ethyl acetate (2: 1) afforded 2.18 g (74%) of the title compound as a solid, mp 72-73 °C: 1H NMR (DMSO-d6) # 11.99 (S, 1H), 7.40 (dd, J = 8.0, J = 8.0,1H), 7.20 (dd, J = 8. 4, J = 2.0,1H), 7.15 (s, 1H), 7.05 (d, J = 7.6,1H), 6.99 (s, 1H), 3.98 (t, J = 6.8,2H), 3.69 (s, 2H), 3.34 (s, 2H), 3.25 (t, J <BR> <BR> <BR> 4.8,4H), 2.. 67 (t, J = 4.8,4H), 1.56 (sxt, J = 7.2,2H),<BR> <BR> <BR> <BR> <BR> 0.85 (t, J = 7.2,3H); 13C NMR (DMSO-d6) 6 97,168.22,169.

157.08,151.14,143.62,129.86,129.84 (q, J = 30.3), 124.38 (q, J = 270.7), 118.69,114.50 (q, J = 3.8), 110.86 (q, J = 3.. 8), 110.42,65.66,59.88,52.18 (2C), 47.55 (2C), 36.53, 21.43,10.08; MS (EI, m/z) 470 (M+). Anal. Calcd for C21H25N4O3F3S : C, 53.01; H, 5.36; N, 11.91. Found: C, 53.71; H, 5.51; N, 11.85.

Example115 Preparation of 2-(((4-(3-(trifluoromethvl) phenyl) Piperazin-1- vl) acetyl) amino)-4- (carboisopropoxymethYl) thiazole (Compound W) Preparation of 2-amino-4-(carboisopropoxymethyl) thiazole hydrochloride: A solution of 2-amino-4- (carboxymethyl) thiazole (2.0 g, 12.6 mmol) and thionyl chloride (1.51 g, 0.92 mL, 12.7 mmol) in anhydrous isopropyl alcohol (20 mL) was stirred at 65 OC for 3 h, during which time the rection mixture gradually turned clear. The rection mixture was cooled to rt, concentrated, and dried in

vacuo overnight to give 2.99 g (ca 100%) of the title <BR> <BR> <BR> compound as a white solid : 1H NMR (CD30D) b 726. (s, 1H), 5.04 (sxt, J = 6. 4,1H), 4.88 (bs, 2H), 3.72 (s, 2H), 1.27 (d, J = 6.4,6H); 13C NMR (CD30D) b 20,169.47,134.30,106.48,172.

70.73,34.21,. 21.94 (2C); MS (EI, m/z) 200 (Mt).

Preparation of 2- (bromoacetyl) amino-4- (carboisopropoxymethyl) thiazole: A solution of saturated NaHCO3 was slowly added to 2-amino-4- (carboisopropoxymethyl) thiazole hydrochloride until the pH of the aqueous solution remained constant at 7. The suspension was stirred for 20 min and the precipitate was filtered, washed with water, and dried in vacuo overnight to afford 2.4 g of the free base. A solution of 2-amino-4-, (carboisopropoxymethyl) thiazole (2.0 g, 10 mmol) in 1: 1 DMF/dioxane (30 mL) was cooled to 0 °C and bromoacetyl bromide (2.02 g, 10 mmol) was added dropwise. The solution was stirred at rt for 1 h and poured into 200 mL of ice- water. The precipitate which formed was filtered, washed with water, and then dried to afford 2.10 g (65%) of the title compound as a white solid, mp 182-183 °C: 1H NMR (DMSO- d6) 6 5712. (bs, 1H), 7.04 (s, 1H), 4.89 (septet, J = 6.4, 1H), 4.12 (s, 2H), 3.66 (s, 2H), 1.18 (d, J = 6.8, 6H), 1.17 (s, 3H); 13C NMR (DMSO-d6) # 37,164.92,157.08,143.96,169.

110.91,67.63,36.75,28.28,21.50 (2C); MS (EI, m/z) 320 (M+).

2-(((4-(3-Preparationof (trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-4- (carboisopropoxymethyl) thiazole: A solution of 2- ((bromoacetyl) amino)-4-(carboisopropoxymethyl) thiazole (1.5 g, 4.67 mmol) and 1- (3- (trifluoromethyl) phenyl) piperazine (2.14 g, 9.34 mmol) in DMF (30 mL) was stirred at rt for 5 min. The solution was poured into 200 mL of ice-water and extracted with EtOAc (3 x 50 mL). The layers were separated and the organic layer was dried over MgSO4, filtered, and then concentrated. Purification by chromatography, eluting with hexane-ethyl acetate (2: 1), afforded 1.65 g (77%) of the title compound as an oil : 1H NMR (DMSO-d6) # 0012. (bs, 1H),

7.41 (dd, J = 8. 0, J = 8.0,1H), 7.21 (dd, J = 8.0, J = 8.0, J = 2.0,1H), 157. (s, 1H), 7.06 (dd, J = 7.6, J = 0.4,1H), <BR> <BR> 6.98 (s-, 1H) 894. (sxt, J = 6.4,1H), 3.65 (s, 2H), 3.34 (s, 2H), 3.25 (t, J = 4.8,4H), 2.66 (t, J = 5.2,4H), 1.18 (d, J 6.4,6H); 13C NMR (DMSO-d6) # 169. 54, 168. 30, 157. 10, 151.19,143.71,129.96,129.84 (q, J = 30), 124.38 (q, J = 271), 118.77,114.55 (q, J = 3.5), 110.90 (q, J = 4.2), 110.46,67.68,59.92,52.23 (2C), 47.58 (2C), 36.79,21.55; <BR> <BR> MS (EI, m/z) 470 (M+). Anal. Calcd for C2lH2, N403F3S : C, 53. 01; H, 5.36; N, 11.91. Found,: C, 53.39; H, 5.50; N, 11. 73.

Example116 Preparation of 2-(((4-(3-(trifluoromethyl)phenyl)piperazin-1- yl) acetvl) amino)-4- (carbobutoxymethyl) thiazole compound V) Preparation of 2-amino-4-(carbobutoxymethyl) thiazole hydrochloride: A solution of 2-amino-4- (carboxymethyl) thiazole (2.0 g, 12.6 mmol) and thionyl chloride (1.51 g, 0.92 mL, 12.7 mmol) in anhydrous n-butyl alcohol (50 mL) was stirred at 65 OC for 3 h, during which

time the rection mixture gradually turned clear. The rection solution was cooled to rt, concentrated, and dried in vacuo overnight to give 3.10 g (ca. 100%) of the title <BR> <BR> compound as a white solid : 1H NMR (DMSO-d6) 6 449. (bs, 2H), 6.70 (s, 1H), 4.06 (t, J = 6.4, 2H), 3.75 (s, 2H), 1.56 (quinte, J = 6.8,2H), 1.31 (sxt, J = 7.2,2H), 0. 88 (t, J = 7.6,3H); 13C NMR (CD30D) 6 51,168.53,132.94,105.26,169.

64.43,32.95,29.99,18.47,13.43; MS (EI, m/z) 214 (M+).

Preparation of 2-((bromoacetyl) amino)-4- (carbobutoxymethyl) thiazole: A solution of saturated NaHCO3 was slowly added to 2-amino-4-(carbobutoxymethyl) thiazole hydrochloride until the pH of the aqueous solution remained constant at 7. The suspension was stirred for 20 min and the precipitate was filtered, washed with water, and dried in vacuo overnight to afford 2.0 g of the free base. A solution of 2-amino-4-(carbobutoxymethyl) thiazole (1.73 g, 8.1 mmol) in 1: 1 DMF/dioxane (30 mL) was cooled to 0 OC and bromoacetyl bromide (1.63 g, 8.1 mmol) was added dropwise.

The solution was stirred at rt for 1 h and poured into 200 mL of ice-water. The precipitate which formed was filtered, washed with water, and then dried to afford 1.63 g (60%) of the title compound as a white solid, mp 127-128 °C: 1H NMR (DMSO-d6) 6 5712. (bs, 1H), 7.04 (s, 1H), 4.12 (s, 2H), 4.03 (t, J = 6.4,2H), 3.69 (s, 2H), 1.53 (quinte, J = 6.4,2H), 1.28 (sxt, J = 7.6,2H), 0.86 (t, J = 7.2,3H); 13C NMR (DMSO- d6) 6 95,165.00,157.17,143.93,111.02,63.97,36.56,169.

30.10,28.29,18. 49, 13.45; MS (EI, m/z) 336 (M+).

Preparation of 2-(((4-(3- (trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-4- ((carbobutoxymethyl) thiazole: A solution of 2- ((bromoacetyl) amino)-4-(carbobutoxymethyl) thiazole (1.2 g, 3.58 mmol) and 1- (3- (trifluoromethyl) phenyl) piperazine (1.65 g, 7.16 mmol) in DMF (30 mL) was stirred at rt for 5 min.

The solution was poured into 200 mL of ice-water and extracted with EtOAc (3 x 50 mL). The layers were separated and the organic layer was dried over MgSO4, filtered, and then concentrated. Purification by chromatography, eluting with

hexane-ethyl acetate (2: 1), afforded 1.37 g (79%) of the <BR> <BR> <BR> title compoud as a solid, mp 80-81 °C : 1H NMR (DMSO-d6) 6<BR> <BR> <BR> <BR> <BR> 11.97 (s, 1H), 7.41 (dd, J = 7.6, J = 7.6,1H), 7.21 (dd, J =<BR> <BR> <BR> <BR> <BR> <BR> 8.4, J = 2.0,1H), 7.16 (s, 1H), 7.05 (dd, J = 7.6, J = 4,0.

1H), 6.99 (s, 1H), 4.03 (t, J = 6.8,2H), 3.69 (s, 2H), 3.34 (s, 2H), 3.25 (t, J = 8,4. 4H), 2.66 (t, J = 4.8, 4H), 1.53 (quinte, J = 7.2,2H), 1.28 (sxt, J = 7.6,2H), 0.86 (t, J = <BR> <BR> <BR> 7.2,3H); 13C NMR (DMSO-d6) 6 03,168.26,157.12,151.17,170.

143.65,129.91,129.85 (q, J = 31), 124.42 (q, J = 270.2), 118.74,114.53 (q, J = 3.5), 110.86 (q, J = 3.5), 110.47.

63.95,59.91,52.21 (2C), 47.57 (2C), 36.57,30.11,18.49, <BR> <BR> <BR> 13.47; MS (EI, m/z) 484 (M+). Anal. Calcd for C22H2, N403F3S: C, 54.54; H, 5.62; N, 11.56. Found: C, 54.67; H, 5.72; N, 11.56.

Example 117 Preparation of 3- ( (Bromoacetyl) amino)-2- (carbomethoxy)thiophene.

Bromoacetyl bromide (7.7 g, 3.4 mL, 38 mmol) was added dropwise to a solution of methyl 2-aminothiophene carboxylate (6.0 g, 38 mmol) in a mixture of DMF (20 mL) and dioxane (20 mL) while keeping the interna temperature of the rection mixture at 5 OC. After stirring at 5 OC for 1 h, the ice bath was removed and the rection mixture was stirred at rt overnight. The reaction mixture was poured into water and the light crystalline compound which formed was filtered, washed several times with cold water, and then dried to give 7.24 g (69%) of the title compound, mp 91-93 OC: 1H NMR <BR> <BR> <BR> <BR> (DMSO-d6) 6 5810. (bs, 1H), 7.93 (s, 2H), 4.34 (s, 2H), 3.86<BR> <BR> <BR> <BR> <BR> <BR> <BR> (s, 3H) :'3C NMR (DMSO-d6) 6 14,163.23,142.71,133.16,164.

121.86,111.45,52.18,29.91; MS (EI, m/z) 277 (M+). Anal.

Calcd for CBH8N03BrS: C, 34.48; H, 2.89; N, 5.03. Found: C, 34.55 ; H, 2.94; N, 5.09.

Example118 Preparation of 3-(((4-Phenylpiperazin-1-yl) acetYl-) amino)-2- (carbomethoxv) thiophene (Comipound CH) Phenylpiperazine (1.36 g, 8.38 mmol) was added to a solution of 3-((bromoacetyl)amino)-2-carbomethoxy) thiophene (1.15 g, 4.13 mmol) in DMF (20 mL) at rt. The rection mixture was heated and stirred at 95 OC for 6 h, cooled to 50 °C. and poured into ice water, causing an oily precipitate to form. The product was filtered, washed several times with water, and then air dried. The product was triturated with hexane several times and then purifie by column chromatography using ethyl acetate-hexane (4: 1) to give 0.7 g (47%) of a light beige solid, mp 116.4-118 OC: 1H NMR (CDCl3) 6 5311. (bs, 1H), 8.20 (d, lut = 5.2,1H), 7.47 (d, J = 5.6, 1H), 7.31 (dd, J = 8.4, J = 8.4,2H), 7.01 (bs, 2H), 6.90 (bt, J = 6.4,1H), 3. 87 (s, 3H), 3.39 (bs, 4H), 3.28 (s, 2H), 2.81 (bs, 4H); 13C NMR (CDC13) 6 44, 163.87,151.80,168.

143.62,131.27,129.18 (2C), 122.37 (2C), 119.71,116.13, 111.18,61.98,- 53.52,51.95 (2C), 49.03 (2C); MS (EI, m/z)

359 (M+). Anal. Calcd for C18H21N303S: C, 60.05; H, 5.88; N, 11.60. Found: C, 60.04; H, 6.04; N, 11.62.

Example 119

Preparation of 3- ( (4- (2-Fluorophenyl) piperazin-1- ylWacetyl) amino)-2-(carbomethoxv)-thiophene(carbomethoxv)-thiophene (Compound CC) 1-(2-Fluorophenyl) piperazine (1.96 g, 10.97 mmol) was added to a solution of 3-((bromoacethyl) amino)-2- (carbomethoxy) thiophene (1.5 g, 5.40 mmol) in DMF (20 mL) at rt. The rection mixture was heated and stirred at 70 OC for 8 h, cooled to 50 °C, and poured into ice water. The light crystalline compound which formed was filtered, washed several times with water, air dried for 2 days, and then dried in vacuo to give 1.6 g (96%) of the title compound, mp ("wet"at117-119°C 113 1HNMR(CDCl3)#11.50(bs,: lH), 8.19 (d, J = 5.6,1H), 7.47 (dd, J = 5.6, J = 0.8,1H), 7.12- 6.94 (m, 4H), 3.89 (s, 3H), 3.30 (s, 2H), 3.28 (s, 4H), 2.85 (s, 4H); 13C NMR (CDC'3) 6 168.42,163.89,155.74 (d, J = 244), 143.60,140.00,131.29,124.42 (d, J = 3.8), 122.50 (d, J = 33.6), 122.39,119.07 (d, J = 8.8), 116.10 (d, J = 21.3), 111.20,61.89,53.58 (2C), 51.89,50.32 (2C); MS (EI, m/z) 377 (M+).

Example 120 Preparation of 3- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetYl) amino)-2-(carbomethoxv)(carbomethoxv) thiophene (Compound CD) 1-(α,α,α-Trifluoro-m-tolyl) piperazine (11.61 g, 9.4 mL, 50.4 mmol) was added to a solution 3-((bromoacetyl) amino)-2- (carbomethoxy) thiophene (6.98 g, 25 mmol) in DMF (50 mL) at rt. The rection mixture was heated and stirred at 70 OC for 6 h, cooled to rt, and poured into ice water, causing an off- white precipitate to form. After standing in aqueous mixture overnight, the precipitated solid was filtered, triturated six times with water, and then dried to give 9.8 g (91%) of the title compound as an off-white solid, mp 141.3-142.9 OC: 1H NMR (DMSO-d6) 6 3511. (bs, 1H), 8.08 (d, J = 5.6, 1H), 7. 91 (d, J = 5.6,1H), 7.42 (t, J = 7.8, 1H), 7.25 (dd, J = 8.8, J = 2.4,1H), 7.20 (s, 1H), 7.07 (d, J = 7. 2, 1H), 3.79 (s, 3H), 3. 37 (t, J = 4.4,4H), 3.. 32 (s, 2H), 2.70 (t, J = 4.4,

4H); 13C NMR (DMSO-d6) 6 04,167.97,163.17,150.97,168.

143.16,143.01,133.11,129.95,129.88 (q, J = 31), 124.36 (q, J = 271), 121.5. 2,121.46,114.53 (q, J = 3.8), 110.82 (q, J = 3. 8), 110.06,60.96,52.53,52.02,47.54; MS. (EI, m/z) 427 (M'). Anal. Calcd for C19H20N3O3SF3 : C, 53.32; H, 4.71; N, 9.82. Found: C, 53.36; H, 4.81; N, 9.75.

Example 121 3-(((4-(2-Pyridyl)piperazin-1-Preparationof yl) acetyl) amino)-2-(carbomethoxy) thiophene (Comsound CI) 1-(2-Pyridyl) piperazine (2.52 g, 15.4 mmol) was added to a solution of 3-((bromoacetyl) amino)-2- (carbomethoxy) thiophene (2.14 g, 7.73 mmol) in DMF (20 mL) at rt. The rection mixture was heated and stirred at 95-100 OC for 5 h, cooled to rt, and poured into ice water, causing a light crystalline compound to precipitate. The product was filtered, washed several times with water, and air dried for 24 h to give 2.53 g (91%) of the title compound,-mp 150-152 <BR> <BR> <BR> °C : 1H NMR (DMSO-d6) 6 4011. (bs, 1H), 8.12 (ddd, J = 4.9, J 1.8, J = 0.61,1H), 8.10 (d, J = 5.3, 1H), 7. 91 (d, J =

5.3,1H),-7. 54 (ddd, J = 8.8, J = 7.2, J = 2,1H), 6.85 (d, J = 8.6, 1H), 6.65 (dd, J = 7.0, J = 5.4,1H), 3.81 (s, 3H), 3.61 (t, J 4.4,4H), 3.25 (s, 2H), 2.64 (t, J = 4.4,4H) ; 13C NMR (DMSO-d6) 6 20,163.27,168. 158. 92,147.57,143.25, 137.55,133.24,121.51,113.07,110.05,107.17,61.11,52.61 (2C), 52.15,44.66 (2C); MS (EI, m/z) 360 (M+). Anal. Calcd for C17H20N4O3S : C, 56.56; H, 5.58; N, 15.52. Found: C, 56.62; H, 5.76; N, 15.83.

Example122 Preparation of 3-(((4-(2-Methoxyphenyl)piperazin-1- vl) acetvl) amino)-2-(carbomethoxy)-thiochene(carbomethoxy)-thiochene (Compound CJ) 1-(2-Methoxyphenyl) piperazine (1.72 g, 8.94 mmol) was added to a solution of 3-((bromoacetyl) amino)-2- (carbomethoxy) thiophene (1.24 g, 4.48 mmol) in DMF (20 mL) at rt. The rection mixture was heated and stirred at 75-80 OC for 4 h, cooled to 30 °C, and poured into ice water. This rection mixture was extracted several times with ethyl acetate. The combine ethyl acetate layer was washed with

water, dried over Na2SO4, and concentrated. The residue was dissolve in a small amount of EtOAc and precipitated by adding hexane. The product was washed with hexane several times and dried in vacuo to give 0.96 g (55.201) of the title compound, mp 101.4-101.8 °C: 1H NMR (DMSO-d6) 6 3311. (bs, 1H), 8.08 (d, J = 5.5,1H), 7.90 (d, J = 5.6, 1H), 6.98- 6.87 (m, 4H), 3.83 (s, 2H), 3.78 (s, 3H), 3.25 (s, 3H), 3.10 (bs, 4H), 2.69 (bs, 4H); 13C NMR (DMSO-d6) 6 21,163.08,168.

151.93,143.08,142.80,141.05,133.08,122.35,121.54, 120.84,117.89,111. 99, 61. 23,55.30,53.16 (2C), 52.04, 49.88 (2C); MS (EI, m/z) 389 (M'). Anal. Calcd for C, 9H23N304S 0 0.42 H20: C, 57.49; H, 6.05; N, 10.58. Found: C, 57.51; H, 5.98; N, 10.47.

Example123 Preparation of 3-(((4-Benzylpiperazin-1-yl)acetyl) amino)-2- (carbomethoxy) thioghene (CompoundCK) 1-Benzylpiperazine (1.78 g, 1.76 mL, 10.1 mmol) was added to a solution of 3- ( (bromoacetyl) amino)-2-

(carbomethoxy) thiophene (1.4 g, 5 mmol) in DMF (15 mL). The rection mixture was heated and stirred at 75 OC for 6 h, cooled to rt and slowly poured into ice water. The yellow oily compound was filtered, washed several times with water, dried in vacuo, and then the oily compound was triturated with hexane for 30 min. The light yellow precipitate which formed was filtered and dried in vacuo to give 1. 07 g (57%) <BR> <BR> <BR> <BR> of the title compound, mp 9-102.7100. OC 1H NMR (DMSO-d6) #<BR> <BR> <BR> <BR> <BR> <BR> <BR> 11.23 (s, 1H), 8.06 (d, J = 5.6,1H), 7.90 (d, J = 5.6,1H), 7.32 (m, 5H), 3.84 (s, 3H), 3.51 (s, 2H), 3.17 (s, 2H), 2.51 <BR> <BR> <BR> <BR> (bs, ;8H) 13C NMR (DMSO-d6) # 26,163.04,143.02,138.11,168.

133.14,128.81 (2C), 128.11 (2C), 126.86,121.57,121.54, 61.95,61.24,52.98 (2C), 52.32 (2C), 52.08; MS (EI, m/z) <BR> <BR> <BR> <BR> 372.9 (M+). Anal. Calcd for C19H23N33S: C, 61. 01; H, 6. 20; N, 11.24. :Found C, 00;61. H, 6.45; N, 11.39.

Example 124 3-(((4-(2-Pyrimidyl)piperazin-1-Preparationof yl) acetvl) amino)-2- (carbomethoxylthiophene (Compound CL) 1-(2-Pyrimidyl) piperazine (1.06 g, 6.5 mmol) was added to a solution of 3-((bromoacetyl) amino)-2- (carbomethoxy) thiophene (0.9 g, 3.25 mmol) in DMF (20 mu) an the rection mixture was heated and stirred at 70 OC for 7 h.

After cooling to rt, the rection mixture was poured into ice water and the light crystalline precipitate which formed was filtered, washed several times with cold water, and then dried to give 0.93 g (79%) of the title compound as an off- <BR> <BR> <BR> white solid, mp 147-148 °C: 1H NMR (DMSO-d6 ? b 4311. (bs, 1H), 8.37 (d, J = 4.8,2H), 8.09 (d, J = 5.2,1H), 7.92 (d, J = 5.2,1H), 6.64 (dd, J = 4.8, J = 4. 8,1H), 3.86 (t, J = 4. 4, 4H), 3.83 (s, 3H), 3.25 (s, 2H), 2.60 (t, J = 4.8,4H) ; 13C NMR (DMSO-d6) 6 12,163.27,161.16,157.90168. (2C), 143.24, 133.17,121.47,121.44,110.18,61.04,52.55 (2C), 52.09, 43.31 (2C); MS (EI, m/z) 361 (M+). Anal. Calcd for C16H19N5O3S # 0. 50 H20: C, 51. 88; H, 5.44; N, 18.91. Found: C, 51.75; H, 5.27; N, 99.18.

Example 125 3-(((4-(5-(Trifluoromethyl)pyrid-2-Preparationof yl)piperazin-1-yl)acetyl)amino)-2-(carbomethoxy)thiophene (CompoundCE) (3.4g,1-(5-(Trifluoromethyl)pyrid-2-yl)piperazine 14.4 mmol) was added to a solution of 3-((bromoacetyl) amino)- 2-(carbomethoxy) thiophene (2. 0 g, 7.22 mmol) in DMF (20 mL) at rt and the rection mixture was heated and stirred for 7 h at 70 OC. After cooling to rt the rection mixture was poured into ice water, and the crystalline precipitate which formed was filtered, washed several times with water, and dried to give 2.64 g (85%) of the title compound as a light <BR> <BR> <BR> ivory solid, mp 136-138 °C: 1H NMR (DMS°-d6) 6 4211. (s, 1H), 8.42 (dd, J = 1.6, J = 0.4,1H), 8.08 (d, J = 5.2,1H), 7.92 (d, J = 5.6,1H), 7.80 (dd, J = 9.2, J = 2.4,1H), 7.00 (d, J 8.8, 1H), 3.82 (s, 3H), 3.77 (t, J = 4.4,4H), 3.26 (s, 2H), 2.64 (t, J = 4.8,4H) ; 13C NMR (DMSO d6) 6 168. 01,

167.94,163.25,160.11,145.19 (q, J = 4.2), 143.21,134.43 (q, J = 3), 133.12,124.8 (q, J = 270), 121.46,113.27 (q, J 30) 106.32,60.88,52.35 (2C), 52.03,44.25 (2C); MS (EI, m/z) 428.4 (M+). Anal. Calcd for C18Hl9N403SF3 * 0.50 H2O: C, 49.42; H, 4.61; N, 12.81. Found: C, 49.37; H, 4.37; N, 12.99.

Example126A Preparation of 3- ( (Bromoacetyl) amino)-4- (carbomethoxy)thiophene Bromoacetyl bromide, (6.8 g, 3.0 mL, 32 mmol) was added dropwise to a solution of 3-amino-4- (carbomethoxy) thiophene (5 g, 32 mmol) in DMF (30 mL) and dioxane (30 mL) while keeping the internal temperature of the rection mixture at 5 OC. After stirring at 5 OC for 1 h, the ice bath was removed and the rection mixture was stirred at rt overnight. The rection mixture was poured into ice water and the light precipitate which formed was filtered, washed several times with cold water, and then dried to give 8.0 g (91.2%) of the title compound as an ivory solid, mp 84-85 °C : 1H NMR (DMSO-

d6) # 10.48 (bs, 1H), 8.40 (d, J = 3.6,1H), 7.97 (d, J = 3.6, 1H), 4.30 (s, 2H), 3.86 (s, 3H); 13C NMR (DMSO-d6) # 10,164.

163.37,134.83,134.09,121.61,111.84,52.10,29.82; MS (EI, m/z) 277 (M+). Anal. Calcd for C8H8NO3SBr : C, 34.48; H, 2.89; N, 5.03. Found: C, 34.58; H, 2.95; N, 4.99.

Example126 Preparation of 3-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1- vl) acetyl) amino)-4-(carbomethoxy) thiophene (Compound CM) 1- (3- (Trifluoromethyl) phenyl) piperazine (4.0 g, 3.24 mL, 17.4 mmol) was added to a solution of 3- ( (bromoacetyl) amino)- 4-(carbomethoxy) thiophene (2.4 g, 8.7 mmol) in DMF (25 mL) at rt and the rection mixture was heated and stirred at 65-70 OC for 6 h. After cooling to rt, the rection mixture was poured into ice water and the light precipitate which formed was filtered, washed several times with cold water, and then dried to give 3.2 g (86*1) of the title compound as an ivory solid, mp 134-135. 8 °C: 1H NMR (DMSO-d6) b 1511. (bs, 1H), 8.37 (d, J = 3.6,1H), 8.04 (d, J = 3.6,1H), 7.43 (dd, J =

7.6, J = 7.6,1H), 7.25 (dd, J = 8. 4, J = 2.0,1H), 7.20 (s, 1H), 7.07 (d, J = 7. 6, 1H), 3.81 (s, 3H), 3.36 (t, J = 4.4, <BR> <BR> <BR> 4H), 3.2-4 (s, 2H), 2.69 (t, J = 4.8,4H) ; 13C NMR (DMSO-d6) 6 168.16 ; 163.26,151-01, 135.32,133.85,129.97,129.89 (q, J = 31), 124.38 (q, J = 270), 121.51,118.63,114.56, 110. 82, 110.38,60.9. 5,. 52.59,51.99,47.55; MS (EI, m/z) 427 (M+).

Anal. Calcd for ClyH2oN303SF3 0.25 H20: C, 52. 84; H, 4.78; N, 9.73. Found: C, 52.84; H, 4.63; N, 9.65.

Example127 3-(((4-(3-(Trifluoromethyl)pyrid-2-Preparationof yl)piperazin-1-yl)acetyl)amino)-2-(carbomethoxy)thiophene CompoundCN) 1-(3-(Trifluoromethyl) pyrid-2-yl) piperazine (2.7 g, 11.7 mmol) was added to a solution of 3-((bromoacethyl)amino)-2- (carbomethoxy) thiophene (1.6 g, 5.8 mmol) in DMF (20 mL) at rt. The rection mixture was heated and stirred at 65-70 OC for 6 h, cooled to rt, and then poured into ice water. The off-white precipitate which formed was filtered, washed

several times with cold water, and dried to give 1.64 g (69%) of the title compound as an off-white solid, mp 117.4-120 OC: <BR> <BR> H NMR (DMSO-d6) 6 3411. (s, 1H), 8.54 (dd, J = 4.8, J = 1.2, 1H), 8.08 (d, J = 5.6,1H), 8.05 (dd, J = 8.0, J = 2.0,1H), 7.90 (d, J = 5.6,1H), 7.19 (ddd, J = 8.0, J = 4.8, J = 0.2, 1H), 3.85 (s, 3H), 3.34 (t, J = 5.2,4H), 3.26 (s, 2H), 2.69 <BR> <BR> (t, J = 4.4,4H); 13C NMR (DMSO-d6) 6 12,163.21,158.93,168.

151.55,143.16,137.69 (q, J = 5), 133.12,123.99 (q, J = 271), 121.54 (q, J = 4), 117.57,115.26 (q, J = 31), 110.13, 61.07,52.84 (2C), 52.09,50.32 (2C); M (EI, m/z) 428 (M+).

Anal. Calcd for C1gH19NqO3SF3: C, 50. 39; H, 4.46; N, 13.06.

Found: C, 50.091 ; H, 4.44; N, 13.06.

Example128 Preparation of 3-(((4-(4-Fluorophenyl)piperazin-1- yl ? acetyl) amino)-2-(carbomethoxy) thiophene (Compound CO) 1-(4-Fluorophenyl) piperazine (0.72 g, 3.99 mmol) and anhydrous K2CO3 (1.5 g, 11 mmol) were added to a solution of 3-((bromoacetyl)amino)-4-(carbomethoxy) thiophene (1.1 g, 3.99 mmol) in DMF (20 mL) at rt. The rection mixture was heated

and stirred at 70 OC for 6 h, cooled to rt, and poured into ice water. The precipitate which formed was filtered, washed several times with cold water, and then dried to give 1.0 g (67%) of the title compound as an off-white solid, mp 127.9- 130 NMR(DMSO-d6)#11.33(s,1H),8.09(d,J=5.6,1H 1H), 7.91 (d, J = 5.6,1H), 7. 08-7. 04 (m, 2H), 6.99-6. 96 (m, 2H), 3.79 (s, 3H), 3.26 (s, 2H), 3.21 (t, J = 4.8,4H), 2.69 <BR> <BR> (t, J = 4.8,4H); 13C NMR (DMSO-d6) 6 11,168.04,163.14,168.

155.95 (d, J = 234.3), 147.70 (d, J = 1.4), 143.14,133.10, 121.51 (d, J =3. 5), 117.03 (d, J = 7.7,2C), 115.23 (d, J = 22,2C), 61.04,52.76 (2C), 52.03,48.84 (2C); MS (EI, m/z) 377 (M'). Anal. Calcd for ClgH2aN303SF: C, 57.20; H, 5.33; N, 11.12. Found: C, 56.93 ; H, 5.37; N, 11.05.

Example129 3-(((4-(4-Methoxyphenyl)piperazin-1-Preparationof

yl) acetyl) amino)-2- (carbomethoxv) thiophene (Compound CP) 1-(4-Methoxyphenyl) piperazine (1.5 g, 7.8 mmol) and K2CO3 (3.3 g, 23.9 mmol) were added to a solution of 3- ((bromoacetyl) amino)-4-(carbomethoxy) thiophene (2.16 g, 7.8 mmol) in DMF (25 mL) at rt. The rection mixture was heated and stirred at 50 OC for 4 h, cooled to rt, and poured into ice water, causing a light yellow precipitate to form. The precipitated solid was filtered, washed several times with cold water, and then dried to give 2.34 g (80.40-.) as a light <BR> <BR> yellow solid, mp 156.8-158 °C: 1H NMR (DMSO-d6) 6 3211. (bs, 1H), 8.85 (d, J = 5.2,1H), 7.91 (d, J = 5.6,1H), 6.93-6.91 (d, J = 9.2,2H), 6.83 (d, J = 9.2,2H), 3.80 (s, 3H), 3.69 (s, 3H), 3.34 (s, 2H), 3.15 (t, J = 4.0, 4H), 2.69 (t, J = <BR> <BR> 4.0,4H); 13C NMR (DMSO-d6) 6 15,168.07,163.11,152.85,168.

145.19,143.11,133.08,121.52,117.24 (2C), 114.26 (2C), 61.11,55.14,52.92 (2C), 52.03,49.40 (2C); MS (EI, m/z) 389 (M+). Anal. Calcd for C19H23N304S 0.37 H20: C, 57.61; H, 6.04; N, 10.60. Found: C, 57.61; H, 5.89; N, 10.63.

Example130 3-(((4-(3-(Trifluoromethyl)phenyl)piperazin-1-Preparationof yl) acetyl) amino)-2- (carbomethoxy) thiophene Hvdrochloride

(Compound CF) A solution of 3-(((4-(3- (trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino)-2- (carbomethoxy) thiophene (Compound CF) (0. 94 g, 22. mmol) in <BR> <BR> <BR> CH2C12 (20 mL) was treated with an excess of 1N HC1 ether<BR> <BR> <BR> <BR> <BR> solution 4(4. mL, 44. mmol). The rection mixture was stirred at rt for several hours. The light precipitate which formed was filtered, washed several times with ether, and dried to give a white solid. The solid was treated with a mixture of CH2Cl2 and ethanol and refluxed. The product was filtered, washed several times with ether, and then dried to give 0. 65 g (59%) of the title compound as a white solid, mp 237-238 OC. Anal. Calcd for Cl9H2oN303F3SOHC1 : C, 49. 19; H 4.56; N, 9.06. :Found C, 14;49. H, 4.58; N, 8.88.

Example131 <BR> <BR> <BR> Preparation of 2- ( ( (4- (4- (chlorobenzhvdrvl) phenyl) piperazin- CH)1-yl)acetyl)amino)-2-(carbomethoxy)thiophene(Compound 1-(4-Chlorobenzhydryl) piperazine (1.0 g, 53. mmol) and K2CO3 (1.5 g, 10.5 mmol) were added to a solution of 3- ((bromoacetyl) amino)-2-(carbomethoxy) thiophene (0.97 g, 53. mmol) in DMF (20 mL) at rt. The rection mixture was heated and stirred at 70 OC for 6 h and cooled to rt. The rection mixture was poured into ice water and the crystalline precipitate which formed was filtered, washed several times <BR> <BR> <BR> with water, and then dried to give 1.5 g (89%) of the title<BR> <BR> <BR> <BR> <BR> compound as a white solid, mp 2100-102. °C: 1H NMR (DMSO-d6) 6 11.20 (s, 1H), 8.04 (d, J = 5.4,1H), 7.87 (d, J = 5.6, 1H), <BR> <BR> <BR> 7.46 (d, J = 8. 8,2H), 7.41 (d, J = 7.2,2H), 7.36 (d, J =<BR> <BR> <BR> <BR> <BR> 8.8,2H), 7.30 (dd, J = 7. 6, J = 7.6,2H), 7.19 (t, J = 7.6,<BR> <BR> <BR> <BR> <BR> 1H), 4.42 (s, 1H), 3.83 (s, 2H), 3.36 (s, 3H), 2.57 (bs, 4H),<BR> <BR> <BR> <BR> <BR> 2.43 (bs, ;4H) 13C NMR (DMSO-d6) 6 26,168. 163. 07,143.05, 142.10,141.67,133.19,131.35,129.47 (2C), 128.61 (2C), 128. 49 (2C), 127.62 (2C), 127.05,121.59,110.20, 73.75,

61.19,53.09 (2C), 52.10,51.08 (2C); MS (FAB, m/z) 484 (M+H).

Example 132 Preparation of 3-(((4-(2-(Trifluoromethyl)quinolin-4- <BR> <BR> yl ? piperazin-1-yl) acetvl) amino)-2- (carbomethoxy thiophene<BR> <BR> <BR> (CompoundCG) l-t2- (Trifluoromethyl) quinolin-4-yl) piperazine (1. 62(Trifluoromethyl) quinolin-4-yl) piperazine (1. 62 g, 5.8 mmol) and potassium carbonate (2.4 g, 17.4 mmol) were added to a solution of 3-((bromoacetyl) amino)-2- (carbomethoxy) thiophene (1.6 g, 5.8 mmol) in DMF (20 mL) at rt. The rection mixture was heated and stirred at 70 OC for 5 h, cooled to rt, and poured into ice water. The light precipitate which formed was filtered, washed with water, and then dried to give 2.4 g (87%) of the title compound, as a <BR> <BR> light solid, mp 150-152 °C: 1H NMR (DMSO-d6) 6 3411. (s, 1H), 8. 12-8.07 (m, 3H), 7.92 (d, J = 5. 2, 1H), 7.84 (dd, J = 6.8, J = 6.8,1H), 7.71 (dd, J = 7.6, J = 7.6,1H), 7.31 (s, 1H),

3.84 (s, 3H), 3.47 (bs, 4H), 3.36 (s, 2H), 2.89 (bs, 4H); 13C <BR> <BR> <BR> <BR> NMR (DMSO-d6) 6 10,163.26,158.30,147.99,147.07168. (q, J = 30), 143.21,133.20,130.63, 130.02, 127.38,124.13,122.87, 121.74 (q, J = 268), 121.53,110.20,103.82,60.96,52.57 (2C), 52.08,51.60 (2C); MS (FAB, m/z) 479 (M+H+).

The following experiments are set forth to assist in understanding the invention and should not be construed as limiting the invention described and claimed herein. Such variations of the invention which would be within the purview of those skilled in the art, including the substitution of all equivalents now known or later developed, including changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention described and claimed herein.

7. EXAMPLE: HYPOGLYCEMIC ACTIVITY OF PIPERAZINE DERIVATIVES 7.1 IN VIVO ACTIVITY OF THE COMPOUND OF FORMULA (I)

The antidiabetic activity of representative compound of formula I was determined by oral administration of such-compounds to, non-insulin dependent diabetic mice.

The mice were made diabetic by neonatal administration of streptozotocin, an art-recognized, experimental model of non- insulin-dependent diabetes (NIDDM).

At the start of the experimental protocol, the mice were 8 weeks old. The animals were housed in an animal house at a regulated temperature of 21 to 22°C, and were subjected to a fixed light (from 7 a. m. to 7 p. m.) and dark (from 7 p. m. to 7 a. m.) cycle. Their food consiste of a maintenance diet, i. e., water and food were provided ad libitum, up until 2 hours before collecting blood.

A test product was administered orally to the mice during the day. Two hours after the last administration of the test product, and 30 minutes after anaesthetizing the animals with sodium pentobarbital (Nembutal°), a 300 Ill blood

sample was collecte from the tail. The results are shown in Table V. The results are expressed as a percentage variation in glucose levels at D4 (4 days of treatment) compare with DO (before treatment).

Table V clearly shows the efficacy of the illustrative compound of formula I to cause a decrease in glucose levels in diabetic animals.

TABLE V Compound 20 mg/kg/d 200 mg/kg/d % % Glycemia at D4 Glycemia at D4 la-6-16 2a-2-10 3a-13-22 4a-8-16 5a-9-12 7.2 IN VIVO ACTIVITY OF THE COMPOUND OF FORMULA (VII) The antidiabetic activity of representative

compound of formula VII was determined by oral administration-of such compound to non-insulin dependent diabetic mice. The mice were made diabetic by neonatal administration of streptozotocin, an art-recognized, experimental model of non-insulin-dependent diabetes (NIDDM).

At the start of the experimental protocol, the mice were 8 weeks old. The animals were housed in an animal house at a regulated temperature of 21 to 22°C, and were subjected to a fixed light (from 7 a. m. to 7 p. m.) and dark (from 7 p. m. to 7 a. m.) cycle. Their food consiste of a maintenance diet, i. e., water and food were provided ad libitum, up until 2 hours before collecting blood.

A test product was administered orally to the mice during the day. Two hours after the last administratio of the test product, and 30 minutes after anaesthetizing the animals with sodium pentobarbital (Nembutal°), a 300 yl blood sample was collecte from the tail. The results are shown in Table VI. The results are expressed as a percentage variation in glucose levels at D4 (4 days of treatment) compare with DO (before treatment).

TABLE VI

Compound 20 mg/kg/d 200 mg/kg/d c 0-. Glycemia at D4 Glycemia at D4 35d-12-16 38d-6-27 39d-15-14 45d-9-18 47d-16-32 48d-20-31 50d-17 -7 52d-14-21 Table VI clearly shows the efficacy of the illustrative compound of formula VII to cause a decrease in glucose levels in diabetic animals.

7.3 IN VIVO ACTIVITY OF THE COMPOUND OF FORMULA (XIIIb) This example demonstrates the effectiveness of illustrative piperazine derivatives of the formula (XIIIb) to lower serum glucose levels in C57BL/KS diabetic db/db mice, an art recognized model of non-insulin dependent diabetes mellitus (NIDDM). Illustrative derivatives of the formula XIIIb include: 2-[[[4-[2-(Fluoro)phenyl]piperazin-1-yl]acetyl]amino]-4- chlorobenzothiazole (Compound DB), 2-[[[4-[2-Pyridyl)]piperazin-1-yl]acetyl]-amino]-6- chlorobenzothiazole (Compound DC), 2-[[[4-[2-(Fluoro)phenyl]piperazin-1-yl]acetyl]amino]-6- methoxybenzothiazole (Compound DD), 2-[[[4-[2-(Pyridyl)]piperazin-1-yl]acetyl]amino]-6- methoxybenzothiazole (Compound DE), 2-[[[4-[2-Pyrimidinyl]piperazin-1-yl]acetyl]amino]-6- methoxybenzothiazole (Compound DF)

2-[[[4-[Benzyl]piperazin-1-yl]acetyl]amino]-6- methoxybenzothiazole (Compound DG), 2-[[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] acetyl] amino]-6-methoxybenzothiazole (Compound DH), 2-[[[4-[2-(Pyridyl)]piperazinyl-1]acetyl]amino]-6- methoxybenzothiazole (Compound DI), 2-[[[4-[4-(Methoxy)phenyl]piperazin-1-yl]acetyl]amino]-6- fluoro-benzothiazole (Compound DJ), 2-[[[4-[2-(Pyridyl)piperazin-1-yl]acetyl]amino]-6- ethoxybenzothiazole (Compound DK), 2-[[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] acetyl] amino]-6-ethoxybenzothiazole (Compound DL), 2-[[[4-[2-(Pyridinyl)]piperazin-1-yl]acetyl]amino]-6- methoxybenzothiazole Hydrochloride (Compound Dom), 2-[[[4-[3-Chlorophenyl]piperazin-1-yl]acetyl]amino]-6-

methoxybenzothiazole (Compound DO), 2-[[[4-[3-Bromophenyl]piperazin-1-yl]acetyl]amino]-6- methoxybenzothiazole (Compound DP), 2-[[[4-[3-Nitrophenyl]piperazin-1-yl]acetyl]amino]-6- methoxybenzothiazole (Compound DQ), 2-[[[4-[2-(Pyridyl)piperazin-1-yl]acetyl]amino]-6- ethoxybenzothiazole Hydrochloride (Compound DR), 2-[[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] (Compoundacetyl]amino]-6-ethoxybenzothiazoleHydrochloride DS), 2-[[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] acetyl] amino]-6-methoxybenzothiazole Hydrochloride (Compound DT), 2-[[[4-[4-(Trifluoromethyl)phenyl]piperazinyl-1] acetyl] amino]-6-methoxybenzothiazole (Compound DU), 2-[[[4-[3-(Methyl)phenyl]piperazinyl-1]acetyl]amino]-6- methoxybenzothiazole (Compound DV), 2-[[[4-[4-Bromo-3-trifluoromethyl-phenyl)piperazin-1-yl] acetyl] amino]-6-methoxybenzothiazole (Compound DW), 2-[[[4-[4-Chlorobenzhydryl)piperazin-1-yl]acetyl]amino]-6- methoxybenzothiazole (Compound DX),

2- [ [ [4- (3-Methoxy-s-trifluoromethyl-phenyl) piperazin-1-yll DY).acetyl]amino]-6-methoxybenzothiazole(Compound Genetically altered obese diabetic mice, designated C57BL/Ks-db/db, were purchased from the Jackson Laboratory tzar Harbor, ME). Male animais between the ages of 8-9 weeks at the start of the experimental protocol were employed. The animals were housed (4 mice/cage) under standard laboratory conditions at 22°C and 50% relative humidity and were maintained on a diet of Purine (St. Louis, MO) rodent chow and water ad libitum. Prior to treatment, blood was collecte from the tail vein of each animal and mice having plasma glucose levels between 350 and 600 mg/dL were used.

Each treatment group consiste of eight mice which were distributed such that the mean glucose levels wère equivalent in each group at the start of the study.

The mice received, orally by gavage, the experimental compound administered at 100,150 or 250 mg, or metformin administered at 250 mg/kg/day. Test compound were delivered in a liquid vehicle containing 0.25t (w/v)

carboxymethylcellulose, 1t (v/v) Tweens 60 (polyoxyethylene sorbitan monosterate, and up to 10t (v/v) dimethyl sulfoxide (DMSO) in a volume of 10 ml/kg. Blood was sampled from the tail vein at three hours and twenty-seven hours post-initial administration of the particular compound under non-faste conditions and analyzed for plasma glucose levels.

Individual body weights and mean food consumption (each cage) were also measured daily. The synthetic test substances were prepared as described above. Metformin (1,1- dimethylbiguanide), carboxymethyl cellulose and Tweens 60 were purchased from Sigma Chemical Co., St. Louis, MO.

Plasma glucose levels were determined colorimetrically using glucose oxidase (Sigma Chemical Co., St. Louis, MO).

Significant differences between compound-treated and vehicle only-treated were evaluated using analysis of variance and Fisher's post-hoc test.

The piperazine test substances evaluated in the diabetic mice for the ability to lower blood glucose are

listed above and in Table VII. Single 250 mg/kg doses ouf Compound DB-DY were given daily to diabetic C57Bl/Ks db/db mice and some of which resulted in statistically significant reductions in plasma glucose levels relative to vehicle controls at either 3 or 27 hours after the initial oral administration. The results are shown in Table VII. For example, three hours after the initial. dosing, mean glucose levels for the experimental Compound DB, DC, DE, DG, DH, DI, DK, DL, DP and DT declined 39.9 mg/dL (p=0.0131), 64.6 mg/dL (p=0.0068), 107 mg/dL (p=0.0008), 54.6 mg/dL (p=0.0007), 183.1 mg/dL (p=0.0001), 120.5 mg/dL (p<0.0001), 78.1 mg/dL (p=0.0171), 89.3 mg/dL (p=0.0058), 28.1 mg/dL (p=0.0024), and 64.8 mg/dL (p=0.0286), respectively, from the baseline values. For example, twenty-seven hours after the initial 250 mg/kg dosing, three hours after the second dosing, mean

§ ucose levels for the active experimental Compound DA, DE, DF, DG, DH, DI, DJ, DL, DM, DR, DS, DT, DU, DW, and DX declined 119.5 mg/dL (p=0.0022), 136.1 mg/dL (p=0.0179), 118.5 mg/dL (p<0.0001), 30.7 mg/dL (p=0.0005), 187.2 mg/dL (p<0.0001), 84.6 mg/dL (p<0.0001), 74.6 mg/dL (p<0.0001), 111.3 mg/dL (p=0.0146), 107.2 mg/dL (p=0.0002), 88.9 mg/dL (p=0.0234), 84.5 mg/dL (p=0.0233), 82.6 mg/dL (p=0.0265), 42.9 mg/dL (p=0.0029), 13.5 mg/dL (p<0.0001), and 34.3 mg/dL (p=0.0480), respectively, from the baseline values.

Once daily doses of some experimental compound also trended to reductions in glucose levels, i. e., p values greater than 0.05 but less than 0.20. For example, three hours after the initial dosing, mean glucose levels for the experimental compound DD, DF, DO, DQ, DV and DW declined 13.5 mg/dL (P=0.1138), 59.8 mg/dL (p=0.1519,39.8 mg/dL (p=0.0955,44.0 mg/dL (p=0.0681), 58.8 mg/dL (p=0.1182) and 67.7 mg/dL (p=0.1258. In addition twenty-seven hours after the initial dosing, three hours after the second dosing, mean glucose levels for the experimental compound declined 18.8 mg/dL (p=0.1331).

TABLE VII

Dosage Treatment Change in Change in Glucose (mg/dL) Glucose (mg/dL) 3h P Value* 27 h P Value* 250 mg/kg Compound DB-39.9 0.0131 119. 9 N/A 250 mg7kg Compound DC-64.6 0.0068-51.1 NS 250 mg/kg Compound DD-13.5 0.1138-60.3 NS 250 mg/kg Compound DE-107.0 0.0008-136.1 0.0179 150 mg7kg Compound DE-34.4 NS-36.1 0.0195 100 mg/kg Compound DE-67.7 0.0023 106.2 <0.0001 250 mg/kg Compound DF-59.8 0.1519-118.5 <0.0001 250 mg7kg Compound DG-54.6 0.0007-30.7 0.0005 250 mg/kg Compound DH-183.1 0.0001-187.2 <0.0001 250 mg/kg Compound DI-120.5 <0.0001-84.6 <0.0001 250 mg/kg Compound DJ-50.0 NS-74.6 <0.0001 250 mg7kg Compound DK-78.1 0.0171-76.8 NS 250 mg/kg Compound DL-89.3 0.0058-111.3 0.0146 250 mg/kg Compound DM-35.1 NS-107.2 0.0002 100 mg kg Compound DM-112.9 0.0001-72.3 0.0132 250 mg/kg Compound DO-39.8 0.0955-64.3 NS 250 mg/kg Compound DP-78.1 0.0024-85.3 NS 250 mg/kg Compound DQ-44.0 0.0681-59.3 NS 250 mg/kg Compound DR-33.1 0.0024-88.9 0.0234 250 mg/kg Compound DS-37.9 NS-84.5 0.0233 250 mg/kg Compound DT-64.8 0.0286-82.6 0.0265 250 mg kg Compound DU-11.2 NS-42.9 0.0029 250 mg/kg Compound DV-58.8 0.1182-19.1 NS 250 mg/kg Compound DW-67.7 0.1258-135.0 <0.0001 250 mg/kg Compound DX-19.0 NS-34.3 0.0480 250 mg/kg Compound DY-18.3 NS-18.8 0.1331 * Statistical significance evaluated using analysis of variance and Fisher's post-hoc test. NS-not significant at p=0. 05 level.

Once daily 150 mg/kg dose of Compound DE given to i diabetic C57Bl/Ks db/db mice also resulted in statistically significant reductions in plasma glucose relative to vehicle

controls at 27 h after the initial oral administration, 3 hours after second oral administration. For example, 27h after the initial oral dose, mean glucose levels for DE declined 36.1 mg/dL (p=0.0005). A daily 100 mg/kg dose of compound DE and DM also resulted in statistically signficant reductions in plasma glucose relative to vehicle controls at both three and twenty-seven hours after the initial dose.

For example 3 and 27 hours after the initial dosing, mean glucose levels for the experimental compound DE and DM declined, at three hours. and twenty-seven hours after initial dose 67.7 mg/dL (p=0. 0023) and 106.2 mg/dL (p<0.0001) for ;DE and 1129 mg/dL (p=0.0001) and 72.3 mg/dL (p=0.0132) for DM rescptively. By comparison, the known hypoglycemic agent metformin, given at 250 mg/kg, caused a reduction in plasma glucose levels of 136-225 mg/dL. Body weights and food consumption were not adversely affecte in the animals treated as shown in Table VIII.

TABLE VIII Dosage Treatment Body weight Body weight Food (g/mouse) (g/mouse) Intake (mean) (mean) (g/mouse) 250 mg/kg Compound DB 38.0+0.4 39.00.4 5.5 250 mg/kg Compound DC 37.8+0.8 37.70.8 4.9 250 mg/kg Compound DD 38.20.6 38.30.6 4.9 100 mg/kg Compound DE 39.6+0.7 39.8+0.7 6.7 250 mg/kg Compound DF 40. 4+0.5 40.4+0.6 5.2 250 mg/kg Compound DG 40. 1~0. 9 39.4+0.9 4.7 250 mg/kg Compound DH 38.50.7 38.60.7 5.0 250 mg/kg Compound DI 39. 3~0. 5 39.20.5 6.2 250 mg/kg Compound DJ 39.20. 5 39. 0~0. 8 6.1 250 mg/kg Compound DK 40.40.3 40.50.3 6.3 250 mg/kg Compound DL 41.0~0.4 40.9~0.4 6.5 35 250 mg/kg Compound DM 38.1~0.8 4.8 100 mg/kg Compound DM 40. 6~1. 1 41. 1~1. 2 6.7

250 mg/kg Compound DO 40. 2~0. 8 39. 80. 7 7.4 250 mg/kg Compound DP 39. 7~0. 6 39.40.7 7.5 250 mg/kg Compound DQ 40.50.7 40.20.7 7.2 250 mg/kg Compound DR 40. 3~0.5 40.3i0.6 6.4 250 mg kg Compound DS 40. 6~0. 9 40.5i0.9 6.2 250 mg/kg Compound DT 39. 6~0.7 39. 3~0. 7 5.9 250 mg/kg Compound DU 41. 0~0. 6 41.10.6 7.1 250 mg7kg Compound DV 40.90.7 41.00.7 6.9 250 mg/kg Compound DW 40. 6~0. 7 40. 4~0. 7 5.2 250 mg/kg Compound DX 40.81.1 40.9il. 0 5.8 2250 mgtkg Compound DY 39.5~0. 8 39. 2~0. 9 5.8

Thus, the foregoing clearly indicates that several piperazine derivatives function to lower serum glucose levels in diabetic mice.

7.4 IN VIVO ACTIVITY OF THE COMPOUND OF FORMULA (XIVb) This example demonstrates the effectiveness of illustrative piperazine derivatives of the formula (XIVb) to lower serum glucose levels in C57BL/KS diabetic db/db mice, an art recognized model of non-insulin dependent diabetes mellitus (NIDDM). Illustrative derivatives of the formula XIVbinclude: 2- [ [ (4- (Phenyl) piperazin-1-yll acetyll amino]-4- C),[(carboxy)methyl]thiazole(Compound 2-[[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] D),acetyl]amino]-4-[(carboxy)methyl]-thiazole(Compound 2-[[[4-(2-Fluorophenyl)piperazin-1-yl]acetyl]amino]-4- [ (carboxy) methyll thiazole (Compound E), 2-[[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] F),acetyl]amino]-4-[(carboethoxy)methyl]-thiazole(Compound 4-[[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] acetyl]amino]-1-[[N'-(2-thiazolyl)]-sulfonamido]benzene (Compound G),

2-[[[4-[5-(Trifluoromethyl)pyrid-2-yl]piperazinyl-1] acetyllaminol-4- [ (carboethoxy)-methyllthiazole (Compound H), 2-[3-[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] saltacetyl]amino]-4-[(carboxy)methyl]-thiazole,sodium (Compound J), 2-[[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] acetyllaminol-4- [ (carboxy) methyll-thiazole, potassium salt (Compound K), 4-[[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] acetyl]amino]-1-[[N'-(2-thiazolyl)]-sulfonamido]benzene, hydrochloride salt (Compound L), 2- [ [ [4- [3- (Trifluoromethyl) phenyll piperazin-l-yll M),acetyl]amino]-4-(carbomethoxymethyl)-thiazole(Compound 2-[[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] saltacetyl]amino]-4-(carboxymethyl)-thiazole,hydrochloride (Compound N),

2-[[[4-[4-(Trifluoromethyl)phenyl]piperazin-1-yl]acetyl] O),amino]-4-[(carboethoxy)methyl]-thiazole(Compound 2-[[[4-[4-(Carbomethoxy)phenyl]piperazin-1-yl]acetyl]amino]- 4- [ (carboxyetho) methyll-thiazole (Compound P), 2-[[[4-[3-Chlorophenyl)piperazin-1-yl]acetyl]amino]-4- ( (carboethoxy) methyl) thiazole acetate (Compound Q), 2-[[[4-[3-Bromophenyl)piperazin-1-yl]acetyl]amino]-4- ( (carboethoxy) methyl) thiazole (Compound R), 2-[[[4-[4-(Trifluoromethyl)phenyl]piperazin-1-yl]acetyl] aminol-4- (carboethoxymethyl)-thiazole (Compound S), 2-[[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] acetyllaminol-4- [ (carboethoxy) methyll-thiazole hydrochloride (Compound BM), 2-[[[4-[3-(Methyl)phenyl]piperazin-1-yl]acetyl]amino]-4- carboethoxy) methyl]thiazole (Compound T), 2-[[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] acetyl]amino]-4-[(carbopropoxy)-methyl] thiazole (Compound U),

2-[[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] acetyl]amino]-4-[(butoxycrbonyl)-methyl]thiazole(Compound V), Isopropyl 2-[[[4-[3-(Trifluoromethyl) phenyl]piperazin-1-yl] acetyl]amino]-4-[(isopropoxy-carbonyl)methyl]thiazole (Compound W), 2-[[[4-[4-Chloro-3-(trifluoromethyl)phenyl]piperazin-1-yl] acetyllaminol-4- [ (carboethoxy)-methyl) thiazole (Compound X), 2-[[4-[1-(4-Chlorobenzhydryl)phenyl]piperazin-1-yl] acetyl] amino-4- (carboethoxymethyl)-thiazole(carboethoxymethyl)-thiazole (Compound Y), and ethyl 2-[[[4-[3,5-dichlorophenyl)piperazin-1-yl] acetyllaminol-4- [ (carboethoxy) methyll-thiazole (Compound Z).

Genetically altered obese diabetic mice designated C57BL/Ks-db/db were purchased from the Jackson Laboratory (Bar Harbor, ME). Male animals between the ages of 8-9 weeks at the start of the experimental protocol were employed.

Animals were housed (4 mice/cage) under standard laboratory conditions at 22°C and 50% relative humidity, and were maintained on a diet of PurinaO (St. Louis, MO) rodent chow and water ad libitum. Prior to treatment, blood was collecte from the tail vein of each animal and mice having plasma glucose levels between 350 and 600 mg/dL were used.

Each treatment group consiste of eight mice that were distributed such that the mean glucose levels were equivalent in each group at the start of the study.

The mice received, orally by gavage, té experimental compound administered at 50,116,150 and 250 mg (as noted), or metformin administered at 250 mg/kg/day. Test compound were delivered in a liquid vehicle containing 0. 25% (w/v) carboxymethylcellulose, 1% (v/v) Tween 60 (polyoxyethylene sorbitan monosterate), and up to 10k (v/v) dimethyl sulfoxide (DMSO) in a volume of 10 ml/kg. Blood was sampled from the tail vein at three hours and twenty-seven hours post initial administration of the particular compound i under non-faste conditions and analyzed for plasma glucose levels. Individual body weights and mean food consumption (each cage) were also measured daily. The synthetic test

substances were prepared as described aboie. Metformin (1,1- dimethylbiguanide), carboxymethyl cellulose and Tween 60 were purchased from Sigma Chemical Co., St. Louis, MO.

Plasma glucose levels were determined colorimetrically using glucose oxidase (Sigma Chemical Co., St. Louis, MO).

Significant differences between compound-treated and vehicle only-treated were evaluated using analysis of variance and Fisher's post-hoc test.

The piperazine derivative test substances evaluated in the diabetic mice for-té ability to lower blood glucose are listed above and in Table IX. Single doses of Compound C-Z, and BM were given to diabetic C57Bl/Ks db/db mice and some of which resulted in statistically significant reductions in plasma glucose relative to vehicle controls at either 3 or 27 hours after initial oral administration. The

results are shown in Table IX. For example, three hours after the initial dosing at 250 mg/kg of experimental compound D, F, G, H, L, Q, S, U, V, and W, mean glucose levels for the mice administered active experimental compound declined 1115. mg/dL 0002),171.6(p=0. mg/dL (p<0.0001), 100.2 mg/dL 0003),46.0(p=0. mg/dL 0363),(p=0.

138.3 mg/dL 0064),81.1(p=0. mg/dL 0304),94.4(p=0. mg/dL <BR> <BR> (p=0.0084), 77.3 mg/dL 04),80.3(p=0. mg/dL (p<0.0001), 282. mg/dL (p<0.0001) and 186. mg/dL 0025),(p=0. respectively, from the baseline values. For example, twenty-seven hours after the initial dosing, three hours after the second dosing, mean glucose levels for compound C, D, E, F, G, L, M, O, Q, S, T, U, V, W, X, Y and Z declined 7179. mg/dL <BR> <BR> (p=0.0001), 202.3 mg/dL (p<0.0001), 356. mg/dL (p=0. 0021),<BR> <BR> <BR> 180.1 mg/dL (p<0.0001), 5130. mg/dL 0004),95.6(p=0. mg/dL (p=0.0124), 44.9 mg/dL 0767)87.9(p=0. mg/dL 0118),87.6(p=0. mg/dL 0458),113.4(p=0. mg/dL 0003),60.7(p=0. mg/dL (p=0.0437), 97.6 mg/dL 0159),61.3(p=0. mg/dL 0007),(p=0.

62.4 mg/dL 0005),129.7(p=0. mg/dL 0007),83.8(p=0. mg/dL (p=0.0476), 35.5 mg/dL 0441)(p=0. and 564. mg/dL 0059),(p=0. respectively, from the baseline values.

TABLE IX Lnange in change in Dosage Treatment Glucose (mg/dL) Glucose (mg/dL) 3h P Value* 27 h P Value* 250 mg/kg Compound C-26.6 0.1040-179.7 0.0001 250 mg/kg Compound D-115.1 0.0002-202.3 <0.0001 50 mg/kg Compound D-116.9 0.0046-126.8 <0.0001 150 mg/kg Compound D-116.9 0.0046-192.8 <0.0001 250 mg kg Compound E +51.5 NS-56.3 0.0021 250 mg/kg Compound F-171.6 <0.0001-180.1 <0.0001 150 mg/kg Compound F-152.6 0.0003-137.6 <0.0001 250 mg7kg Compound G-100.2 0.0003-130.5 0.0004 150 mg/kg Compound G-97.4 0. 0204-144.1 <0.0001 250 mg/kg Compound H-46.0 0.0363-27.9 NS 150 mg/kg Compound J-94.7 0.0526-102.0 0.0075 150 mg/kg Compound K-95.1 0.0458-1.5 NS 250 mg/kg Compound L-81.1 0.0304 44.9 0.0767 250 mg/kg Compound M-45.5 0.0862-87.9 0.0118 150 mg/kg Compound N-40.0 0.1182-121.4 0.0012 250 mg/kg Compound O -82. 2 0.0813-87.6 0.0458 250 mg/kg Compound P-80.0 0.0996-52.3 NS 250 mg/kg Compound Q-94.4 0.0084-113.4 0.0003 250 mg/kg Compound R-62.6 0.1067-33.3 NS 250 mg/kg Compound S-77.3 0.04-60.7 0.0437 116 mg/kg Compound BM-104.3 0.0017-78.0 0.0373 250 mg/kg Compound T-45.1 NS-97.6 0.0159 250 mg/kg Compound U-80.3 <0.0001-61.3 0.0007 250 mg/kg Compound V-82.2 <0.0001 -62.4 0.0005 250 W-86.10.0025-129.70.0007Compound 250 mg/kg Compound X-41.8 NS-83.8 0.0476 250 mg/kg Compound Y +21.9 NS-35.5 0.0441 250 mg/kg -25.4Z -64.5 0.0059 * Statistical significance evaluated using analysis of variance and Fisher's post-hoc test. NS-not significant at p=0.05 level.

Once daily 150 mg/kg doses of compound D, F, G, J, K and N administered to diabetic C57Bl/Ks db/db mice also resulted in statistically significant reductions in plasma glucose relative to vehicle controls at either 3 or 27 hours after oral initial administration, see Table IX. Three hours after the initial dosing, mean glucose levels for compound D, F, G, and K declined 116.9 mg/dL (p=0. 0046), 152.6 mg/dL (p=0.0003), 97.4 mg/dL (p=0.0204), and 95.1 mg/dL (p=0.0458), respectively, from the baseline values. Twenty- seven hours after the initial dosing, three hours after the second dosing, mean glucose levels for the active experimental compound D, F, G, J and N declined 192.8 mg/dL (p<0.0001), 137.6 mg/dL (p<0.0001), 144.1 mg/dL (p<0.0001), 102.0 mg/dL (p=0.0075) and 121.4 mg/dL (p=0.0012), respectively, from the baseline values.

Even at once daily doses of 50 mg/kg and 116 mg/kg, administration of Compound D and BM, respectively, resulted in a statistically significant reduction in plasma glucose relative to vehicle controls at both 3 and 27 hours after oral administration, see Table IX. For example, three hours after the initial dosing at 50mg/kg and 116 mg/kg of experimental compound D and BM, mean glucose levels for mice administered active experimental compound declined 116.9 mg/dL (p=0.0046) and 104.3 mg/dL (p=0.0017) 3 hours after initial administration and 126.8 mg/dL (p<0.0001) and 78.0. mg/dL (p=0.0373) 27 hours after initial administration three hours after the second dosing, respectively.

Once daily doses of some experimental compound also trended to reductions in glucose levels, i. e. p values greater than 0.05 but less than 0.20. For example, three hours after the initial dosing, mean glucose levels for the experimental compound C, J, M, N, O, P, R and Z declined 26.6 mg/dL (p=0.0140), 94.7 mg/dL (p=0.0526), 45.5 mg/dL (p=0.0862), 40.0 mg/dL (p=0.1182), 82.2 (mg/dL (p=0.0183), 80.0mg/dL (p=0.0996), 62.6 mg/dL (p=0.1067), and 25.4 mg/dL (p=0.1612). In addition, twenty-seven hours after the second

dosing, mean glucose levels for the experimental compound L declined 44.9 mg/dL (p=0.0767).

By comparison, the known hypoglycemic agent metformin, given at 250 mg/kg, caused a reduction in plasma glucose levels of 136-225 mg/dL. Body weights and food consumption were not adversely affecte in animals treated, except for Compound D administered at 250. mg/kg during the test period as shown in Table X.

TABLE X Dosage Treatment Body weight Body we ght Food (g/mouse) (g/mouse) Intake (mean) (mean) (g/mouse) 0 h 24 hr 0-24 h 250 mg/kg Compound C 38.40.9 38. 5~0. 9 6.2 250 mg/kg Compound D 39.50.7 39. 1~0. 8 3.9 50 mg/kg Compound D 39.50.7 40. 2~0. 7 6.5 150 mg/kg Compound D 40.21.0 40. 5~1. 2 5.8 250 mg/kg Compound E 38.70.6 38. 9~0. 7 5.7 250 mg/kg Compound F 4. 01~0. 9 39.90.8 4.9 150 mg/kg Compound F 39.30.5 39.80.5 6.4 250 mg/kg Compound G 39.4~0. 9 39.40.8 6.6 150150mg/kg Compound G 6.539.7~0.6 250250mg/kg Compound H 6.040.5~0.6 150 mg/kg Compound J 39.2 0.6 39.50.5 6.4 150 mg/kg Compound K 40. 0~0. 5 39.90.5 6.1 D 250 mg/kg Compound L 39.30.5 39.00.6 5.9 250 mg/kg Compound M 39. 30.4 39. 0~0. 5 6.2 150 mg/kg Compound N 40. 5~0. 7 40.30.6 5.8 250 mg/kg Compound O 41.10.6 41.10.7 6.8 250 mg/kg Compound P 39.90.8 40.00.8 5.8 5 250 mg/kg Compound Q 40.10.7 40.40.8 5.5 250 mg/kg Compound R 40.3~0.7 40.5~0.7 6.4

250 mg/kg Compound S 90.40. 5 41. 10.4 6.3 116 mg/kg Compound BM 39. 9~0. 6 40.10.6 6.5 250 mg/kg Compound T 40. 0~0. 4 40.3i0.5 6.0 250 mg/kg Compound U 41.50.6 41.40.6 6.5 250 mg/kg Compound V 40. 8+1.0 40.5il-0 5.3 250 mg/kg Compound W 40.30.6 40.40. 6 4.9 250 mg/kg Compound X 41.5~0.7 41.7~0. 7 6.2 250 mg/kg Compound Y 39. 7~0. 7 40. 1~0.7 5.9 250Z39.2~0.639.4~0.65.8Compound

Food intake of animals administered Compound D achieved levels comparable with other compound at lower dosage levels (6.5 at 50 mg/kg and 5.8 at 150 mg/kg). Importantly, the glucose lowering effects of some of the compound tested when administered at various dosages, e. g., 150 mg/kg and 50 mg/kg, were comparable to those of metformin when administered at 250 mg/kg, i. e., at 1 2/3 times and 5 times the dosage (5.5 and 16.7 based on the molecular weight of the thiazole compound).

Thus, the foregoing clearly indicates that several piperazine derivatives function to lower serum glucose levels in diabetic mice.

7.5 IN VIVO ACTIVITY OF THE COMPOUND OF FORMULA (XVb) This example demonstrates the effectiveness of illustrative piperazine derivatives of the formula (XVb) to lower serum glucose levels in C57BL/KS diabetic db/db mice, an art recognized model of non-insulin dependent diabetes mellitus (NIDDM). Illustrative derivatives of the formula XVb include: 2- ( [ (4- [3-Trifluoromethyl) phenyllpiperazin-1-yll acetyl]amino]-5-trifluoro-methyl-1,3,4-thiadiazole(Compound <BR> <BR> <BR> Bob),<BR> <BR> <BR> 2- [ [ [4- (2-Fluorophenyl) piperazin-1-yllacetyllaminol-5- trifluoromethyl-1,3,4-thiadiazole (Compound BC),

2- [ [ [4- (4-Methoxyphenyl) piperazin-1-yllacetyllaminol-s- (trifluoromethyl)-1,3,4-thiadiazole (Compound BD), 2-[[[4-(2-Pyridyl)piperazin-1-yl]acetyl]amino]-5- (trifluoromethyl)-1,3,4-thiadiazole (Compound BE), 2-[[[4-(2-Pyrimidyl)piperazin-1-yl]acetyl]amino]-5- (trifluoromethyl)-1,3,4-thiadiazole (Compound BF), 2-[[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] acetyllaminol-5- [ (7-chloroquinolin-4-yl) thiol-1,3,4- thiadiazole (Compound BG), 2-[[[-4-[3-(Trifluoromethyl)phenyl]piperazinyl]acetyl] amino]-5-cyclopropyl-1, 3,4-thiadiazole (Compound Bai), 2-[[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] acetyl]amino]-5-[(carbomethoxy)-methyl]-1,3,4-thiadiazole (Compound BI) 2-[[[[4-(Trifluoromethyl)phenyl]amino]acetyl]amino]-5- [(carbomethoxy)-methyl]-1, 3,4-thiadiazole (Compound BJ), 2-[[[4-(4-Methoxyphenyl)piperazin-1-yl]acetyl]amino]-5-

[ (carbomethoxy)-methyll-1,3,4-thiadiazole (Compound BK), 2-[[4-(2-Pyridyl)piperazin-1-yl]-1, 3,4-thiadiazole (Compound Bol), 2-[[[-4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] acetyl]amino]-5-[2-(carbomethoxy)-ethyl]-1,3,4-thiadiazole (Compound BN), 2-[[[-4-(4-Methoxyphenyl)piperazin-1-yl]acetyl]amino]-5-[2- (carbomethoxy) ethyl]-1, 3,4-thiadiazole (Compound BO), -1-]acetyl]amino]-5-2-[[[-4-[3-(Chlorophenyl)piperazinyl (trifluoromethyl)-1,3,4-thiadiazole (Compound BP), 5-[[[-4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] acetyllaminol-3- [ (carbomethoxy)-methyl)-1,2,4-thiadiazole (Compound BQ), and 2-[[[-4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] acetyl]amino]-1, 3,4-thiadiazole (Compound BR).

Genetically altered obese diabetic mice (designated C57BL/Ks-db/db) were purchased from the Jackson Laboratory (Bar Harbor, ME). Male animals between the ages of 8-9 weeks at the start of the experimental protocol were employed.

Animals were housed (4 mice/cage) under standard laboratory

conditions at 22°C and 50% relative humidity, and were maintained on a diet of Purine (St. Louis, MO) rodent chow and water ad libitum. Prior to treatment, blood was collecte from the tail vein of each animal and mice having plasma glucose levels between 350 and 600 mg/dL were used.

Each treatment group consiste of eight mice that were distributed such that the mean glucose levels were equivalent in each group at the start of the study.

The mice received, orally by gavage, the experimental compound administered at 50,150, or 250 mg/kg (unless otherwise noted), or metformin administered at 250 mg/kg/day. Test compound were delivered in a liquid vehicle containing 0.250 (w/v) carboxymethylcellulose, *1% (v/v) Tweens 60 (polyoxyethylene sorbitan monosterate), and up to 10% (v/v) dimethyl sulfoxide (DMSO) in a volume of 10 ml/kg.

Blood was sampled from the tail vein at three hours and twenty-seven hours post-initial administration of the particular compound under non-faste conditions and analyzed for plasma glucose levels. Individual body weights and mean food consumption (each cage) were also measured daily. The synthetic test substances were prepared as described above.

Metformin (1,1-dimethylbiguanide), carboxymethyl cellulose and Tween 60 were purchased from Sigma Chemical Co., St.

Louis, MO. Plasma glucose levels were determined colorimetrically using glucose oxidase (Sigma Chemical Co., St. Louis, MO). Significant differences between compound- treated and vehicle only-treated were evaluated using analysis of variance and Fisher's post-hoc test.

The piperazine derivative test substances evaluated in diabetic mice for the ability to lower blood glucose are listed above and in Table XI. Single 250 mg/kg doses of <BR> <BR> <BR> Compound BB, BD, BF, BG, BH, BI, BJ, BL, BN, BO, BP, BQ and BR resulted in statistically significant reductions in plasma glucose relative to vehicle controls at either 3 or 27 hours after oral administration. The results are shown in Table XI. For example, three hours after dosing, mean glucose levels for the compound BD, BG, BI, BJ, BL, BN, BO, BP, BQ

and BR declined 46.3 mg/dL (p=0.0488), 26.2 mg/dL (p=0.0141), 114.4 mg/dL (p=<0.0001), 26.1 mg/dL (p=0.0169), 101.9 mg/dL (p=0.0012), 120.7 mg/dL (p<0.0001), 41.6 mg/dL (p=0.0092), 80.2 mg/dL (p=<0.0001) and 107.4 mg/dL (p=0.0008), respectively, from the baseline values. For example, twenty- seven hours after initial three hours after the second dosing, mean glucose levels for the active experimental Compound BB, BF, BG, BH, BI, BJ, BL, BN, BP, BQ and BR declined 151.1 mg/dL (p=<0.0001), 91.5 mg/dL (p=0.0043), 65.6 mg/dL (p<0.0001), 34.4 mg/dL (p=0. 0039), 98.0 mg/dL (p=<0.0001), 18.6 mg/dL (p=0.0029), 91.3 mg/dL (p=0.0013), 208.0 mg/dL (p=<0.0001), 61.7 mg/dL (p=0.0007), 72.0 mg/dL (p=0.0019), and 108.8 mg/dL (p=0.0001), respectively, from the baseline values.

Once daily doses of some experimental compound also trended to reductions in glucose levels, i. e., p values greater than 0.05 but less than 0.20. For example, three hours after initial dosing of 250 mg/kg mean glucose levels for the experimental compound BB, BE, BH, BK, and BQ declined 47.5 mg/dL (p=0.0509), 42.1 mg/dL (p=0.0508), 59.9 mg/dL (p=0.1108), 27.4 mg/dL (p=0.0926) and 72.2 mg/dL (p=0.0930). Twenty-seven hours after initial dosing of 250 mg/kg 3 hours after the second, mean glucose levels experimental compound BC and BD declined 60.6 mg/dL (p=0. 096) and 53.6 mg/dL (p=0.1227).

TABLE XI Dosage Treatment Change in Change in Glucose (mg/dL) Glucose (mg/dL) 3h P Value* 27 h P . Value* 250 mg/kg Compound Bob-47.5 0.0509-151.1 <0.0001 50 mg/kg Compound BB-4.0 Nus-89.3 0.0002 150 mg/kg Compound BB-76 : 1 0.0718-70.2 0.0018 250 mg/kg Compound BC -24. 5 NS-60.6 0.096

250 mg/kg Compound BD-46.3 0.0488-53.6 0. 1227 250 mg7kg Compound BE-42.1 0.0508-14.6 NS 250 mg/kg Compound BF -27. 4 Nus-91.5 0.0043 250 mg/kg Compound BG -26. 2 0.0141-65.6 <0. 0001 250 mg/kg Compound BH-59.9 0.1108-34.4 0.0039 250 mg/kg Compound BI-114.4 <0.0001-98.0 <0.0001 250 mg/kg Compound BJ-26.1 0.0169-18.6 0.0029 250 mg/kg Compound BK-27.4 0.0926-41.0 NS 250 mg/kg Compound BL-101.9 0.0012-91.3 0.0013 250 mg/kg Compound BN-120.7 <0.0001-208.0 <0. 0001 250 mg/kg Compound BO -41. 6 0.0092 +8.2 NS 250 mg kg Compound Bop-80.2 <0.0001-61.7 0.0007 250 mg/kg Compound BQ-72.2 0.0930-72.0 0.0019 250 mg/kg Compound 0.0008-108.80.0001-107.4 * Statistical significance evaluated using analysis of variance and Fisher's post-hoc test. NS-not significant at p=0.05 level. once daily 50 and 150 mg/kg doses of Compound BB also resulted in statistically significant reductions in plasma glucose relative to vehicle controls at 27 hours after oral administration. A once daily dose of Compound BB at 150 mg/kg also showed a trend in reducing plasma glucose relative to vehicle controls at 3 hours after oral administration. By comparison, the known hypoglycemic agent metformin, given at 250 mg/kg, caused a reduction in plasma glucose levels of 136-225 mg/dL. Body weights and food consumption were not adversely affecte in animals treated. Importantly, the glucose lowering effects of some of these compound when administered at 250 mg/kg were comparable to those of metformin administered at 250 mg/kg.

TABLE XII Dosage Treatment Body weight Body weight Food 35 Intake(g/mouse)(g/mouse) (mean) (mean) (g/mouse)

250 mg/kg Compound BB 39.7+-0.7 39.8i0.7 5.7 50 mg/kg Compound BB 39.7+-0.8 40. 0~0. 8 6.7 150 mg/kg Compound BB 40. 0~0. 5 40.9i0.5 6.8 250 mg/kg Compound BC 40. 0~0. 4 39.8*0.4 6.2 250 mg/kg Compound BD 38. 8~0. 6 39. 0~0. 6 6.3 250 mg/kg Compound BE 40.0~0. 7 40. 6~0. 5 5.5 250 mg/kg Compound BF 40. 6~0. 5 40.10.9 6.0 250 mg/kg Compound BG 39. 9~0. 7 39. 5~0. 7 6.3 250 mg/kg Compound BH 39.50.8 39. 5~0. 7 6.6 250 mg/kg Compound BI 40.8+0.8 40.60.8 6.3 250 mg/kg Compound BJ 40. 6~0. 6 40.8iQ. 7 7.0 250 mg/kg Compound BK 38.80.6 38. 9~0. 6 6.6 250 mg/kg Compound BL 40. 2~0. 8 40.20.8 5.4 250 mg/kg Compound BN 39. 3t0. 9 38. 9~1. 2 5.9 250 mg/kg Compound BO 40. 7~0. 8 41.0ffi0.8 7.8 250 mg/kg Compound BP 40.10.5 40. 3~0. 5 7.0 250 mg/kg Compound BQ 38.10.8 37. 8~0. 7 5.1 250 BR40.3~0.740.7~0.75.9Compound

Thus, the foregoing clearly indicates that several of the piperazine derivatives tested function to lower serum glucose levels in diabetic mice.

7.6 IN VIVO ACTIVITY OF THE COMPOUND OF FORMULA (XVIb) This example demonstrates the effectiveness of illustrative piperazine derivatives of the formula (XVIb) to lower serum glucose levels in C57BL/KS diabetic db/db mice, an art recognized model of non-insulin dependent diabetes mellitus (NIDDM). Illustrative derivatives of the formula XVIbinclude: 3-[[[4-(2-Fluorophenyl)piperazin-1-yl] acetyl) amino]-2- (carbomethoxy) thiophene (Compound CC), 3-[[[4-[3-(Trifluoromethyl)phenyl)piperazin-1-yl] CD),acetyl]amino]-2-(carbomethoxy)thiophene(Compound

3- [ [ (4- (5- (Trifluoromethyl) pyrid-2-yllpiperazin-1-yll acetyl]amino]-2-(carbomethoxy) thiophene (Compound CE), 3-[[[4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl] acetyl]amino]-2-(carbomethoxy)thiophenehydrochloride (Compound CF), and 3-[[[4-[2-(Trifluoromethyl)quinolin-4-yl]piperazin-1-yl] acetylJ amino]-2- (carbomethoxy) thiophene (. Compound CG).

Genetically altered obese diabetic mice designated C57BL/Ks-db/db were purchased from the Jackson Laboratory (Bar Harbor, ME). Male animals between the ages of 8-9 weeks at the start of the experimental protocol were employed.

Animals were housed (4 mice/cage) under standard laboratory conditions at 22°C and 50% relative humidity, and were maintained on a diet of Purins (St. Louis, MO) rodent chow and water ad libitum. Prior to treatment, blood was collecte from the tail vein of each animal. Mice that had plasma glucose levels between 350 and 600 mg/dL were used.

Each treatment group consiste of eight mice that were

distributed such that the mean glucose levels were equivalent in each group at the start of the study.

The mice received, orally by gavage, the experimental compound administered at 50,150 and 250 mg/kg or metformin administered at 250 mg/kg/day. Test compound were delivered in a liquid vehicle containing 0.25% (w/v) carboxymethylcellulose, 1% (v/v) Tweens 60 (polyoxyethylene sorbitan monosterate), and up to 10% (v/v) dimethyl sulfoxide (DMSO) in a volume of 10 ml/kg. Blood was sampled from the tail vein at three hours and twenty-seven hours post-initial administration of the particular compound under non-faste conditions and analyzed for plasma glucose levels.

Individual body weights and mean food consumption (each cage) were also measured daily. The synthetic test substances were prepared as described above. Metformin (1,1- dimethylbiguanide), carboxymethyl cellulose and Tweens 60 were purchased from Sigma Chemical Co., St. Louis, MO.

Plasma glucose levels were determined colorimetrically using glucose oxidase (Sigma Chemical Co., St. Louis, MO).

Significant differences between compound-treated and vehicle only-treated were evaluated using analysis of variance and Fisher's post-hoc test.

The piperazine test substances were evaluated in diabetic mice for the ability to lower blood glucose are listed above and in Table XIII. Single 250 mg/kg doses of Compound CC-CG were given to diabetic C57Bl/Ks db/db mice and some of which resulted in statistically significant reductions in plasma glucose relative to vehicle controls at either 3 or 27 hours after oral administration. The results are shown in Table XIII. For example, three hours after initial dosing, mean glucose levels for compound CC, CD, CE and CG declined 746. mg/dL 0326),148.3(p=0. mg/dL (p=<0.0001), 51.8 mg/dL (p=0. 0215), and 056. mg/dL (p=0.0281), respectively, from the baseline values. For example, twenty-seven hours after initial dosing, three hours after the second dose, mean glucose levels for compound CD, CE, CF and CG declined 4179. mg/dL (p=<0.0001), 792. mg/dL (p=0.0028), 74.4 mg/dL 0084)(p=0. and 446. (p=0.0241), respectively, from the baseline values.

TABLE XIII Dosage Treatment Change in Change in GlucoseGlucose(mg/dL) (mg/dL) 3h P Value* 27 h _ Valu* 250 Compound CC-46.7.10326-74.7 0.0993 mg/kg 250 Compound CD-148.3 <0.0001-179.4 <0.000 mg/kg 1 50 Compound CD-34.6 NS-45.1 0.0177 mg/kg 35 150 Compound CD-130.3 0.0016 -65.0 0.0022 mg/kg

250 COmPOUnd CE-51.8 0.0215-92.7 0.0028 mg/kg t 250 Compound CF-45.4 0.0845-74.4 0.0084 mg/kg 250 Compound CG-56.0 0.0281-46.4 0.0241 mg/kg * Statistical significance evaluated using analysis of variance and Fisher's post-hoc test. NS-not significant at p=0.05 level.

Once daily 50 mg/kg and 150 mg/kg doses of Compound CD also resulted in statistically significant reductions in plasma glucose relative to vehicle controls at either 3 or 27 hours after initial administration. Three houes after initial dosing 150 mg/kg of Compound CD, mean glucose levels declined 130.3 mg/dL (p=0.0016) from the baseline value..

Twenty-seven hours after initially dosing 50 mg/kg and 150 mg/kg, three hours after second dose, mean glucose levels declined 45.1 (p=0.0177) and 65.0 mg/dL (p=0.0022), respectively, from the baseline.

Once daily doses of some experimental compound also trended to reductions in glucose levels, i. e., p values greater than 0.05 but less than 0.20. For example, three hours after initial dosing of 250 mg/kg, mean glucose levels for the experimental compound CF declined 45.4 mg/dL (p=0.0845). For example twenty-seven hours after initial dosing of 250 mg/kg, three hours after the second dosing, mean glucose levels for the experimental compound cc, declined 74.7 mg/dL (p=0.0993). By comparison, the known hypoglycemic agent metformin, given at 250 mg/kg caused a reduction in plasma glucose levels of 136-225 mg/dL.

Body weights and food consumption were not adversely affecte in. animals treated, except for some of those administered at 250 mg/kg (Compound CF) during the test period as shown in Table XIV. Importantly, the glucose lowering effects of these compound when administered at 150 mg/kg were comparable to those of metformin when administered at 250 mg/kg.

TASLE xzv

Body weight Body weight Dosage Treatment Food (g/mouse) (g/mouse) Intake (mean) (mean) (g/mouse) 0 h 24 hr 0-24 h 250 mg/kg Compound CC 38. 4~0.7 38.5~0. 6 5.5 250 mg/kg Compound CD 38. 20.7 38. 20. 7 5.0 250 mg kg Compound CE 40.9+0.5 40.9+0.6 6.3 250 mg/kg Compound CF 38.60.4 37. 7~0.6 4. 1 250 mgkg Compound CG 38.7+0.9 38.70.9 5.5

Thus, the foregoing clearly indicates that several piperazine derivatives function to lower serum glucose levels in diabetic mice.

The invention claimed and described herein is not to be limited in scope by the specific embodiments herein disclosed since these embodiments are intended as illustrations of several aspects of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appende claims.

A number of references are cited herein, the entire disclosures of which are incorporated herein, in their entirety, by reference.