WO1999031096A1 - Piperazine derivatives useful as hypoglycemic agents - Google Patents

Piperazine derivatives useful as hypoglycemic agents Download PDF

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Publication number
WO1999031096A1
WO1999031096A1 PCT/US1998/026851 US9826851W WO9931096A1 WO 1999031096 A1 WO1999031096 A1 WO 1999031096A1 US 9826851 W US9826851 W US 9826851W WO 9931096 A1 WO9931096 A1 WO 9931096A1
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Prior art keywords
alkyl
alkoxy
halogen
group
aryl
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PCT/US1998/026851
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French (fr)
Inventor
Donald E. Bierer
Gerard G. Moinet
Gerard Botton
Larisa Dubenko
Gerard Patereau
Liliane Doare
Micheline Kergoat
Didier Mesangeau
Qing Lu
Original Assignee
Shaman Pharmaceuticals, Inc.
Lyonnaise Industrielle Pharmaceutique (Lipha)
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Application filed by Shaman Pharmaceuticals, Inc., Lyonnaise Industrielle Pharmaceutique (Lipha) filed Critical Shaman Pharmaceuticals, Inc.
Priority to AU19240/99A priority Critical patent/AU1924099A/en
Publication of WO1999031096A1 publication Critical patent/WO1999031096A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new piperazine derivatives which are useful as hypoglycemic agents and useful for the treatment of diabetes; pharmaceutical compositions comprising the piperazine derivatives; and methods for using the same.
  • 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.
  • EP 0 624 584 discloses piperazine derivatives that are allegedly useful as calmodolin inhibitors.
  • European Patent Application EP 0 462 638 Al 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 1- [ ⁇ - (Aroylamino) ethyl] -4-benzylpiperazines and 1- t tarylamino) carbonyl] ethyl] -4-benzylpiperazines .
  • Aryl piperazines were used to synthesize 1- [arylpiperazine] alkyl] carbonyll-ar-4-yl. Gizur, T., et al . , ⁇ fed. Chem . Res . 3:545 (1993).
  • Perrissenin, M. , et al . , Eur. 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
  • Aryl piperazines have been used as intermediates to synthesize pharmacologically active compounds 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- [ ⁇ - (aroylamino) ethyl] -4-benzylpiperazines and 1- [ [arylamino) carbonyl] ethyl] -4-benzylpiperazines . Saxena, M. , J. Med. Chem. 33:2970 (1990). Aryl piperazines were used to synthesize 1- [arylpiperazine] alkyl] carbonyl1-ar-4-yl.
  • 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 compounds having antibacterial activity. See also T. Kanai et al . , Bull- Chem. Soc. Jpn . 6:2335 (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 .
  • heterocyclic compounds have been alleged to exhibit anti-hyperglycemic activity. These include sulfonyl ureas (GB 1,212,695, GB 1,139,856, GB 965,368, GB 896,455, and Australian Patent Specification No. 37,624/68m); benzenesulfonyl semicarbazides (GB 110,645, GB 1,038,379, GB 1,137,380, FR 1,519,798, Australian Patent Specification No.
  • 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.
  • compositions comprising the compounds, 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.
  • 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.
  • 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.
  • the invention provides compounds of formula (I) :
  • 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 Ci-Cg alkyl, (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ Cg) alkyl, C j -C,, alkoxy, (C 3 -C 8 ) cycloalkyloxy (C ⁇ Cg) alkyl, (C 3 -C 8 ) cyclo
  • 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 compounds of general formula (I) , the process comprising the steps of:
  • R 4 , R 5 and R 6 are as defined as above for general formula I, and R 7 is a hydrogen atom or a C ⁇ Cg alkyl group, in the presence of a basic agent such as triethylamine in order to form the compound of general formula (VI) :
  • the invention further provides compounds of general formula (VII) :
  • 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 C ⁇ Cg alkyl, (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 ) cycloalkyl alkoxy, (C 3 -C 8 ) cycloalkyloxy (C ⁇ Cg) alkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ Cg) alkoxy (Ci-Cg) alkyl, (C 3
  • R x , R 2 , and R 3 are selected, independently of one another from: hydrogen, Cj-Ca alkyl (Ci-Cg) alkoxy (Ci-Cg) alkyl group; a cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (C ⁇ Cg) alkyl, (C 3 -C 8 ) cycloalkyloxy (Ci-Cg) alkyl, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkoxy (Ci-Cg) alkyl, Cg-C ⁇ 4 aryl, C 6 -C ⁇ 4 heteroaryl, (C 6 -C 14 ) heteroaryl (Ci-Cg) alkyl, (C 6 -C 14 ) aryl (Ci-Cg) alkyl, (C ⁇ -C 14 ) aryl (Ci-Cg) alkyl, (
  • R 4 , R 5 and R 6 are selected, independently of one another from: hydrogen, Ci-C 8 alkyl, (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 ) cycloalkyl (Ci-C 6 ) alkyl, Ci ⁇ C 8 alkoxy, (C 3 -C frustration) cycloalkyloxy (Ci-Cg) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkoxy, (C 3 -C 8 ) cycloalkyl (Ci-C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, (Ci-C 6 ) alkoxy (C ⁇ Cg) alkyl, C 6 -C 14 aryl, (C 6 -C 14 ) aryl (C ⁇ Cg) alkyl, (C 6 -C 14 )
  • Hal represents a chlorine or bromine atom, in order to form a compound of general formula (X) ;
  • 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) .
  • a catalyst such as palladium-on-charcoal
  • the invention further provides compounds, as well as compositions comprising said compounds, useful as hypoglycemic agents, of general formula (XIIla) :
  • Ri is selected from the group consisting of hydrogen, halogen, RigOR 17 , R ⁇ 8 NHR 19 , R ⁇ 4 COOR 15 , alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkoxy (C ⁇ -C 6 ) alkyl, (C 6 -C 14 ) aryl, (Cg-C ⁇ ) heteroaryl, (C 6 -C ⁇ 4 ) heteroaryl alkyl, (C 6 -C 14 ) aryl (Ci-C 6 ) alkyl, (C 6 -C ⁇ 4 ) aryl (C ⁇ -C 6 ) alkyl (C ⁇ -C 14 ) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, carbamo
  • R 2 is selected from the group consisting of hydrogen, halogen, R 16 OR 17 , R 18 NHR ⁇ 9 , R ⁇ 4 COOR 15 , C ⁇ -C 8 alkyl , C 3 -C e cycloalkyl, (C 3 -C 8 ) cycloalkyl (Ci-C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkoxy (C x -C 6 ) alkyl, (C 6 -C 14 ) aryl, (C 6 -C 14 ) heteroaryl, (C 6 -C 14 ) heteroaryl (Ci-C 6 ) alkyl, (C 6 -C 14 ) aryl (Ci-Cg) alkyl, (C 6 -C ⁇ 4 ) aryl (C ⁇ -C 6 ) alkyl (C 6 -C 14 ) aryl, trifluoromethyl, trifluoromethoxy
  • R 3 is selected from the group consisting of hydrogen, halogen, R 16 OR ⁇ 7 , R 18 NHR ⁇ 9 , R 14 COOR ⁇ 5 , Ci-C 8 alkyl, (C 3 - C 8 ) cycloalkyl (C ⁇ -C 6 ) alkoxy (Ci-C 6 ) alkyl, (C 6 -C 14 ) aryl, (C 6 - C 14 ) heteroaryl, (C 6 -C 14 ) heteroaryl (C ⁇ -C 6 ) alkyl, (C 6 -C ⁇ 4 ) aryl (Ci-Cg) alkyl, (C 6 -C 14 ) aryl (C j -Cg) alkyl (C 6 -C 14 ) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (C ⁇ -C 8 ) alkylthio, (Ci-C 8 ) alkylsulphinyl, (
  • R 4 is selected from the group consisting of hydrogen, halogen, R 16 OR ⁇ 7 , R 18 NHR ⁇ 9 , R 14 COOR 15 , C ⁇ -C 8 alkyl, (C 3 - C 8 ) cycloalkyl (C ⁇ -C ⁇ ) alkoxy (C ⁇ -C 6 ) alkyl, (C 6 -C 14 ) aryl, (C 6 - C i4 ) heteroaryl, (C 6 -C 14 ) heteroaryl (C ⁇ -C 6 ) alkyl, (Cg-C ⁇ ) aryl (Ci-Cg) alkyl, (C 6 -C 14 ) aryl (C ⁇ -C 6 ) alkyl (C 6 -C 14 ) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (C ⁇ -C 8 ) alkylthio, (C ⁇ -C 8 ) alkylsul
  • R 8 is selected from the group consisting of NR 20 SO 2 Ar and NR 20 ArSO 2 , wherein Ar is an aryl selected from the group consisting of phenyl and phenyl (C ⁇ -C 6 ) alkyl;
  • R 9 selected from the group consisting of hydrogen, Ci-C 8 alkyl, (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C fi ) alkyl, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkoxy (C ⁇ -C 6 ) alkyl, C 6 -C ⁇ 4 aryl, Cg-C ⁇ heteroaryl, (C 6 - C x4 ) heteroaryl (C ⁇ -C 6 ) alkyl, (C 6 -C 14 ) aryl (C ⁇ -C 6 ) alkyl, (C 6 - C 14 ) aryl (C ⁇ -C 6
  • Rio is selected from the group consisting of hydrogen, C ⁇ ⁇ C 8 alkyl, (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (C ⁇ Cg) alkyl, (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkoxy (C ⁇ Cg) alkyl, C 6 -C ⁇ 4 aryl, C 6 - C 14 heteroaryl, (C 6 -C ⁇ 4 ) heteroaryl (C ⁇ -C 6 ) alkyl, (C 6 -C ⁇ 4 ) aryl (Ci-Cg) alkyl, (C 6 -C 14 ) aryl (C ⁇ -C 6 ) alky
  • Rii is selected from the group consisting of hydrogen, C ⁇ -C 8 alkyl, (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (C ⁇ Cg) alkyl, (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 -C ⁇ ) cycloalkyl (Ci-C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, C 6 -C ⁇ 4 aryl, C 6 - C 14 heteroaryl, (C 6 -C 14 ) heteroaryl (C ⁇ -C 6 ) alkyl, (C 6 -C 14 ) aryl (Ci-Cg) alkyl, (C 6 -C 14 ) aryl (C lT C 6
  • R i2 is selected from the group consisting of hydrogen and C ⁇ -C 6 alkyl
  • Ri 3 is selected from the group consisting of
  • R 14 is a bond or is selected from the ' group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Ci-Cg alkyl; said C ⁇ -C 6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C ⁇ -C 6 alkyl and phenyl; R 15 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and C - C 6 alkyl; said Ci-C fi alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl and Ci-C 3 alkyl;
  • R 16 is a bond or is selected from the group consisting of sulfonyl, C ⁇ -C 8 thioalkyl, aminosulfonyl and Ci- Cg alkyl group; said C ⁇ Cg alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C ⁇ -C 6 alkyl and phenyl;
  • R i7 is selected from the group consisting of Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C ⁇ 4 aryl, (Cg-C X4 ) aryl (C ⁇ -C fi ) alkyl; said C ⁇ -C 6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, phenyl, phenylalkyl and C ⁇ ⁇ C 3 alkyl; said C 3 -C 6 cycloalkyl group being optionally substituted with Ci-C 3 alkyl;
  • R 1B is a bond or is selected from the group consisting of sulfonyl, Ci-C 8 thioalkyl, aminosulfonyl, carbonyl, aminocarbonyl and Ci-C 6 alkyl, said alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Ci-Cg alkyl and phenyl ;
  • R i9 is selected from the group consisting of hydrogen, phenyl, phenylalkyl, and C ⁇ C g alkyl; said C ⁇ Cg alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl and C ⁇ -C 3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino and Ci-C 6 alkyl; said phenylalkyl being optionally substituted with one or more substituents selected from the group
  • R 2 ⁇ is a bond or C ⁇ -C 6 alkyl; said Ci-C 6 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 C ⁇ -C 3 alkyl, halogen, Ci-Cg alkoxy and hydroxy; R 22 ⁇ R 3 i are independently selected from the group consisting of hydrogen, halogen, C ⁇ -C 8 alkoxy, Ci-C 8 alkyl, trifluoromethyl , nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, C ⁇ ⁇ C 8 thioalkyl hydroxy (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 ) cycloalkyl, (Ci-Cg) alkyl, C ⁇ -C 8 alkoxy, (C 3
  • X 3 is nitrogen or CR 29 ;
  • X 4 is nitrogen or CR 30 ;
  • X s is nitrogen or CR 3i ; wherein at least one of X 3 , X 4 , or X 5 is a nitrogen; or R 28 and CR 30 when taken together form an aryl ring; or R 28 and CR 29 when taken together form an aryl ring; with the proviso that the compound of formula
  • (Xllla) 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 .
  • the invention further provides compounds, as well as compositions comprising said compounds, useful as hypoglycemic agents, wherein:
  • Ri is selected from the group consisting of hydrogen, halogen, R 16 OR ⁇ 7 , R 18 NHR 19 , R ⁇ 4 COOR ⁇ 5 , Ci-Cg alkyl, C 3 -C 8 cycloalkyl, (C ⁇ -C ⁇ 4 ) aryl, (C 6 -C 14 ) aryl (C ⁇ -C 6 ) alkyl, trihalo (Ci-Cg) alkyl, trihalo (C ⁇ Cg) alkoxy and cyano; said Ci-C 8 alkyl and C 3 -C 8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C 6 alkyl and phenyl; said C ⁇ -C ⁇ 4 aryl and (C ⁇ -C ⁇ 4 ) aryl (C ⁇ Cg alkyl) being optionally substituted with one or more substituents selected from the group consisting of halogen,
  • R 2 is selected from the group consisting of hydrogen, halogen, R ⁇ S OR ⁇ 7 , R ⁇ 6 NHR 19 , R 14 COOR 15 , C ⁇ -C 8 alkyl, C 3 -C 8 cycloalkyl, (C 6 -C ⁇ 4 ) aryl, (C 6 -C ⁇ 4 ) aryl (C x -C 6 ) alkyl, trihalo (Ci-Cg) alkyl, trihalo (Ci-C 6 ) alkoxy and cyano; said C ⁇ -C 8 alkyl and C 3 -C 8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, C ⁇ -C 6 alkyl and phenyl; said Cg-C 14 aryl and (C 6 -C ⁇ 4 ) aryl (Ci-C 6 alkyl) being optionally substituted with one or more substituents selected from the group consisting of
  • R 3 is selected from the group consisting of hydrogen, halogen, R 16 OR ⁇ 7 , R 18 NHR 19 , R 14 COOR ⁇ 5 , C ⁇ -C 8 alkyl, C 3 -C 8 cycloalkyl, (C 6 -C ⁇ 4 ) aryl, (C 6 -C ⁇ 4 ) aryl (Ci-C ⁇ ) alkyl, trihalo (Ci-Cg) alkyl, trihalo (C ⁇ -C ⁇ ) alkoxy and cyano; said Ci-C 8 alkyl and C 3 -C 8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, C ⁇ -C 6 alkyl and phenyl; said C 6 -C ⁇ 4 aryl and (C 6 -C ⁇ 4 ) aryl (C ⁇ Cg alkyl) being optionally substituted with one or more substituents selected from the group consisting
  • R 4 is selected from the group consisting of hydrogen, halogen, R 16 OR ⁇ 7 , R 18 NHR ⁇ 9 , R 14 COOR ⁇ 5 , C ⁇ -C 8 alkyl, C 3 -C 8 cycloalkyl, (C 6 -C ⁇ 4 ) aryl, (C ⁇ -C ⁇ 4 ) aryl (C ⁇ -C 6 ) alkyl, trihalo (C ⁇ -C 6 ) alkyl, trihalo (C ⁇ -C 6 ) alkoxy and cyano; said C ⁇ -C 8 alkyl and C 3 -C 8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, C ⁇ -C 6 alkyl and phenyl; said C 6 -C 14 aryl and (C 6 -C ⁇ 4 ) aryl (C ⁇ -C 6 alkyl) being optionally substituted with one or more substituents selected from the group consisting
  • R 23 is selected from the group consisting of hydrogen, halogen, C ⁇ -C 6 alkoxy, Ci-C 6 alkyl, trifluoromethyl , nitro, cyano, carbo (C ⁇ -C ⁇ ) alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl and hydroxy; said C ⁇ -C ⁇ alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C 3 alkyl; said C ⁇ -C ⁇ alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and -Ci-C 3 alkyl; said Ci-C 8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 8 alkyl; said carbo (Ci ⁇ C 6 ) alkoxy being optionally substituted with one or more substituents selected from the group consisting of hal
  • R 25 is selected from the group consisting of halogen, C ⁇ Cg alkoxy, C ⁇ Cg alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-Cg) alkoxy, carboxy, phenyl, Ci-C 8 thioalkyl and hydroxy; said C ⁇ ⁇ C 6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and or C x -C 3 alkyl; said Ci-Cg alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen or Ci ⁇ C 3 alkyl; said Ci-C 8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen andr C ⁇ -C 8 alkyl; said carbo (C ⁇ -C 6 ) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen or Ci-C 3 alky
  • R 26 is selected from the group consisting of hydrogen, bromine, chlorine, C 2 -C 6 alkoxy, C ⁇ Cg alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-C 6 ) alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl and hydroxy; said C ⁇ -C 6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C 3 alkyl; said C 2 - C 6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C 3 alkyl; said Ci-C 8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C ⁇ ⁇ C 8 alkyl; said carbo (C ⁇ -C 6 ) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and
  • R 27 is selected from the group consisting of hydrogen, halogen, Ci-C ⁇ alkoxy, Ci-C ⁇ alkyl, trifluoromethyl , nitro, cyano, carbo (Ci ⁇ C 6 ) alkoxy, carboxy, phenyl, Ci-C 8 thioalkyl and hydroxy; said C ⁇ -C 6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C ⁇ -C 3 alkyl; said Ci ⁇ C 6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C ⁇ -C 3 alkyl; said C ⁇ C 8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C ⁇ C 8 alkyl; said carbo (C x -C 6 ) -alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen or
  • X 4 is nitrogen or CR 30 ;
  • X 5 is nitrogen or CR 3X ; wherein at least one of X 3 , X 4 , or X 5 is a nitrogen;
  • R 29 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C x -C 6 alkyl, trifluoromethyl , nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl and hydroxy; said C x -C 6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted
  • R 31 is selected from the group consisting of hydrogen, halogen, C ⁇ -C ⁇ alkoxy, Ci ⁇ C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, Ci-C 8 thioalkyl and hydroxy; said Ci-C 6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen or C x -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with one or more substituents selected from the group
  • compositions comprising a compound of formula (Xlllb) or a pharmaceutically acceptable salt or a compound having a tautomeric structure thereof, as hypoglycemic agents, the compound of formula (Xlllb) having the structure:
  • R x is selected from the group consisting of hydrogen, halogen, R x6 OR X7 , R X8 NHR 19 , R X4 COOR X5 , C x -C 8 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkoxy (C ⁇ -C 6 ) alkyl, (C 6 -C ⁇ 4 ) aryl, (C 6 -C X4 ) heteroaryl, (C ⁇ -C 14 ) heteroaryl (C x -C ⁇ ) alkyl, (C 6 -C X4 ) aryl (C x -C 6 ) alkyl, (C 6 -C 14 ) aryl (C x -C 6 ) alkyl (C 6 -C
  • R 2 is selected from the group consisting of hydrogen, halogen, R x6 OR X7 , R X8 NHR 19 , R X4 COOR X5 , C x -C 8 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, (C 6 -C X4 ) aryl, (C 6 -C X4 ) heteroaryl, (C 6 -C X4 ) heteroaryl (C x -C 6 ) alkyl, (C 6 -C X4 ) aryl (C x -C 6 ) alkyl, (C 6 -C x4 ) aryl (C x -C 6 ) alkyl
  • R 3 is selected from the group consisting of hydrogen, halogen, R ⁇ gOR 17 , R X8 NHR X9 , R 14 COOR ⁇ 5 , C ⁇ -C 8 alkyl, (C 3 - C 8 ) cycloalkyl (Ci-C 6 ) alkoxy (Ci-C ⁇ ) alkyl, (C ⁇ -C 14 ) aryl, (C ⁇ - C i4 ) heteroaryl, (C 6 -C ⁇ 4 ) heteroaryl (C x -C 6 ) alkyl, (C 6 -C 14 ) aryl (C x -Cg) alkyl, (C 6 -C 14 ) aryl (C ⁇ -C 6 ) alkyl (C 3 -C 14 ) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (Ci-C 8 ) alkylthio, (Ci-C 8 ) al
  • R 4 is selected from the group consisting of hydrogen, halogen, R 16 OR ⁇ 7 , R X8 NHR 19 , R X4 COOR X5 , C x -C 8 alkyl, (C 3 - C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C e ) alkyl, (C 6 -C X4 ) aryl, (C 6 - C X4 ) heteroaryl, (C 6 -C X4 ) heteroaryl (C x -C 6 ) alkyl, (C 6 -C X4 ) aryl (C x -C ⁇ ) alkyl, (C ⁇ -C X4 ) aryl (Ci-C ⁇ ) alkyl (C 6 -C 14 ) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (C x -C 8
  • R 8 is selected from the group consisting of NR 20 SO 2 Ar and NR 20 ArSO 2 , wherein Ar is an aryl selected from the group consisting of phenyl and phenyl (C x -C 6 ) alkyl;
  • R 9 selected from the group consisting of hydrogen, C ⁇ -C 8 alkyl, (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C ⁇ ) alkyl, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkoxy (C x -C ⁇ ) alkyl, Cg-C 14 aryl, C ⁇ -C X4 heteroaryl, (C ⁇ - C 14 ) heteroaryl (C x -C 6 ) alkyl, (C 6 -C X4 ) aryl (C x -C ⁇ ) alkyl, (C 6 -C X4
  • R 10 is selected from the group consisting of hydrogen, Ci-C 8 alkyl, (C ⁇ -C 6 ) alkoxy (C x -C 6 ) alkyl,. a cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C ⁇ ) alkoxy (C ⁇ -C ⁇ ) alkyl, C ⁇ -C ⁇ 4 aryl, C 6 - C X4 heteroaryl, (C 6 -C X4 ) heteroaryl (C x -C 6 ) alkyl, (C 6 -C X4 ) aryl (C x -C 6 ) alkyl, (C ⁇
  • R xx is selected from the group consisting of hydrogen, C x -C 8 alkyl, (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy (C x -C ⁇ ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, Cg-C X4 aryl, C ⁇ - C X4 heteroaryl, (C ⁇ -C X4 ) heteroaryl (C x -C ⁇ ) alkyl, (C 6 -C X4 ) aryl (C x -C 6 ) alkyl
  • R x3 is selected from the group consisting of
  • R X4 is a bond or is selected from the group consisting of sulfonyla ino, carbonyl, carbonylamino, amino, and Ci-Cg alkyl; said Ci-Cg alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C ⁇ -C 6 alkyl and phenyl;
  • R 15 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and Ci- Cg alkyl; said Ci-C 6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl and C x -C 3 alkyl;
  • R x ⁇ is a bond or is selected from the group consisting of sulfonyl, C x -C 8 thioalkyl, aminosulfonyl and C x - C ⁇ alkyl group; said C x -C 6 alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C x -C ⁇ alkyl and phenyl;
  • R X7 is selected from the group consisting of C x -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C X4 aryl, (C 6 -C X4 ) aryl (C x -C 6 ) alkyl; said C x -C 6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, phenyl, phenylalkyl and C x -C 3 alkyl; said C 3 -C 6 cycloalkyl group being optionally substituted with C x -C 3 alkyl;
  • R 18 is a bond or is selected from the group consisting of sulfonyl, C x -C 8 thioalkyl, aminosulfonyl, carbonyl, aminocarbonyl and C x -C 6 alkyl, said Cj-Cg alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C x -C 6 alkyl and phenyl ;
  • R x9 is selected from the group consisting of hydrogen, phenyl, phenylalkyl, and C x -C ⁇ alkyl; said C x -C 6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl and C x -C 3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino and C x -C 6 alkyl; said phenylalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino and C x -C 6 alkyl;
  • R 20 is selected from the group consisting of hydrogen, C x -C 16 alkyl, hydroxy and C ⁇ -C 6 alkoxy;' m is 0 or 1; o is 0 or 1;
  • R 2X is a bond or C x -C 6 alkyl; said C ⁇ -C 6 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 C x -C 6 alkyl, halogen, Ci-Cg alkoxy and hydroxy;
  • R 22 _R 3 i are independently selected from the group consisting of hydrogen, halogen, Ci-C 8 alkoxy, C ⁇ -C 8 alkyl, trifluoromethyl, nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, C ⁇ -C 8 thioalkyl hydroxy (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 ) cycloalkyl, (C ⁇ -C ⁇ ) alkyl, Ci-Cg alkoxy, (C 3 -C 8 ) cycloalkyloxy (Ci-C ⁇ ) alkyl, (C 3 -C 8 ) cycloalkyl (Ci-C ⁇ ) alkoxy (C ⁇ -C ⁇ ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (C ⁇ -C ⁇ ) alk
  • X 4 is nitrogen or CR 30 ;
  • X 5 is nitrogen or CR 3 ⁇ ,- wherein at least one of X 3 , X 4 , or X 5 is a nitrogen; or R 28 and CR 30 when taken together form an aryl ring; or R 28 and CR 29 when taken together form an aryl ring; with the proviso that the compound of formula (Xlllb) is not 1- [ [ [4- [2- (fluorophenyl] piperazin-1-yl] acetyl] amino] -6-fluorobenzothiazole or a pharamceutically accceptable salt or solvate thereof; or a compound having a tautomeric structure thereof .
  • the invention further provides compounds, as well as compositions comprising said compounds, useful as hypoglycemic agents, wherein:
  • Ri is selected from the group consisting of hydrogen, halogen, R 16 ORi 7 , R ⁇ 8 NHR 19 , R ⁇ 4 COOR ⁇ 5 , C x -C 8 alkyl, C 3 -C 8 cycloalkyl, (C 6 -C x4 ) aryl, cyano, trihalo (C x -C 6 ) alkyl, trihalo (C x -C 6 ) alkoxy; said C x -C 8 alkyl and C 3 -C 8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, C x -C 6 alkyl and phenyl; said C 6 -C X4 aryl and (C 6 -C 14 ) aryl (Ci- Cg) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Ci-C 6 al
  • R 24 is selected from the group consisting of hydrogen, bromine, chlorine, C x -C 6 alkoxy, C x -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C 8 alkyl being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted with halogen or C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with halogen or C x -C 3 alkyl;
  • R 25 is selected from the group consisting of hydrogen, halogen, Ci-C ⁇ alkoxy, Ci-C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, Ci-C 8 thioalkyl, and hydroxy; said Ci-C 6 alkyl being optionally substituted with halogen or Ci ⁇ C 3 alkyl; said C ⁇ -C 6 alkoxy being optionally substituted with halogen or Ci-C 3 alkyl; said Ci-C 8 thioalkyl being optionally substituted with halogen or C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with halogen or C x -C 3 alkyl; R 26 is selected from the group consisting of hydrogen, bromine, chlorine, C 2 -C 6 alkoxy, C x -C 6 alkyl, trifluoromethyl ,
  • R 27 is selected from the group consisting of halogen, C x -C 6 alkoxy, C x -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C 6 alkyl being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted with halogen or C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with halogen or C x -C 3 alkyl;
  • R 28 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C ⁇ -C 6 alkyl, nitro, cyano, carbo (C x -C ⁇ ) alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl, and hydroxy; said Ci ⁇ C 6 alkyl being optionally substituted with halogen or C ⁇ -C 3 alkyl; said Ci-C ⁇ alkoxy being optionally substituted with halogen or Ci-C 3 alkyl; said Ci-C 8 thioalkyl being optionally substituted with halogen or C ⁇ -C 8 alkyl; said carbo (C ⁇ -C ⁇ ) alkoxy being optionally substituted with halogen or Ci-C 3 alkyl; or R 22 and R 23 when taken together form an aryl ring; or R 23 and R 24 when taken together form an aryl ring; X 3 is nitrogen or CR 29 ; X
  • R 29 is selected from the group consisting of hydrogen, halogen, C ⁇ -C 6 alkoxy, Ci-C ⁇ alkyl, nitro, cyano, carbo (C x -C ⁇ ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C ⁇ alkyl being optionally substituted with one to two halogen atoms or C x -C 3 alkyl; said C x -Cg alkoxy being optionally substituted with halogen or C x -C 3 alkyl; R 30 is selected from the group consisting of hydrogen, halogen, C ⁇ -C 6 alkoxy, Ci-C 6 alkyl, nitro, cyano, carbo (C x -C ⁇ ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C ⁇ -C 6 alkyl being
  • R 31 is selected from the group consisting of hydrogen, halogen, C ⁇ -C ⁇ alkoxy, C x -C 6 alkyl, nitro, cyano, carbo (C ⁇ -C ⁇ ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C ⁇ alkyl being optionally substituted with one to two halogen atoms or C x -C 3 alkyl; said C x -C ⁇ alkoxy being optionally substituted with halogen or C x -C 3 alkyl; wherein up to three of R 2 -R 31 can simultanoeously be hydrogen when only one of X 3 -X 5 is nitrogen; wherein up to two of R 27 -R 3X can simultaneously be hydrogen when two of X 3 -X 5 are nitrogen; or R 28 and CR 29 when taken together form an aryl ring; or R 28 and CR 30 when taken together form an
  • the invention also relates to a process for the preparation of the compounds of general formulas (Xllla) and (Xlllb) .
  • a preparation process according to the invention comprises the reaction of an aromatic amine of general formula (Al) :
  • Hal represents a chlorine or bromine atom, in order to form a compound of general formula (XVII) ;
  • Ri is selected from the group consisting of hydrogen, R 14 COOR ⁇ 5 , C x -C 8 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C x -C ⁇ ) alkyl, C x -C 8 alkoxy, (C 3 -C 8 ) cycloalkyloxy (C x -C ⁇ ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C ⁇ ) alkoxy (C x -C ⁇ ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkoxy, (Ci- Cg) alkoxy (C ⁇ -C 6 ) alkyl, (C 6 -C ⁇ 4 ) aryl, (C 6 -C X4 ) heteroary
  • R 8 is selected from the group consisting of NR 20 SO 2 Ar and NR 20 ArSO 2 , wherein Ar is an aryl selected from the group consisting of phenyl and phenyl (Ci ⁇ C 6 ) alkyl;
  • R 9 is selected from the group consisting of hydrogen, C ⁇ -C 8 alkyl, (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (Ci-C ⁇ ) alkyl group, (C 3 -C 8 ) cycloalkyloxy (Ci-C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C ⁇ ) alkoxy (C x -C ⁇ ) alkyl, C 6 -C X4 aryl, C 6 -C X4 heteroaryl, (C 6 -C X4 ) heteroaryl (C x -C 6 ) alkyl, (C 6 - C X4 ) aryl (C x -C 6 ) alkyl, (C 6
  • R x0 is selected from the group consisting of hydrogen, C x -C 8 alkyl, (C x -C ⁇ ) alkoxy (C x -C e ) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C B ) cycloalkyl (C x -C 6 ) alkyl group, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, C 6 -C X4 aryl, C 6 -C 14 heteroaryl, (C 6 -C ⁇ 4 ) heteroaryl (C x -C 6 ) alkyl, (C 6 - C X4 ) aryl (C x -C 6 ) alkyl,
  • R xx is selected from the group consisting of hydrogen, C x -C 8 alkyl, (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C B ) cycloalkyl (C x -C 6 ) alkyl group, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, C 6 -C X4 aryl, C 6 -C x4 heteroaryl, (C 6 -C 14 ) heteroaryl (C x -C ⁇ ) alkyl, (C 6 - C x4 ) aryl (C x -C 6 ) alkyl, (C
  • R X2 is selected from the group consisting of hydrogen and C x -C 6 alkyl
  • R X3 is selected from the group consisting of
  • R 14 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and C x -C 6 alkyl; said C x -C 6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C x -C ⁇ alkyl and phenyl; R x5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions and C x -C 6 alkyl; said C x -C 6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl, and C x -C 3 alkyl;
  • R 20 is selected from the group consisting of hydrogen, C x -C 6 alkyl, hydroxy and C x -C 6 alkoxy; m is 0 or 1; n is 0 or 2 o is 0 or 1;
  • R 2X is a bond or C x -C 6 alkyl; said C x -C 6 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 C x -C 6 alkyl, halogen, C x -C 6 alkoxy and hydroxy;
  • R 22 _R 3 i are each independently selected from the group consisting of hydrogen, C x -C 8 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl, C x -C 8 alkoxy, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 )
  • X 4 is nitrogen or CR 30 ;
  • X 5 is nitrogen or CR 31 ; wherein at least one of X 3 , X 4 , or X 5 is a nitrogen; or R 28 and CR 30 when taken together form an aryl ring; or R 28 and CR 29 when taken together form an aryl ring ; with the proviso that the compound of formula (XlVa) is not : 2 - ( ( (4 - (phenyl ) piperazinly-1- ) acetyl) amino) -4 -
  • the invention further provides compounds as well as comositions comprising said compounds , useful as hypoglycemic agents wherein : Ri is selected from the group consisting of hydrogen, C x -C 8 alkyl group , halogen, C 6 -C X4 aryl , (C 6 -C 14 ) aryl (C ⁇ -C ⁇ ) alkyl , and R X4 COOR x5 ; said C x -C 8 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, C x -C 6 alkyl and phenyl; said C 6 -C 14 aryl and (C 6 -C 14 ) aryl (C x -C 6 ) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy, C x -C 6 alkyl and
  • R 8 ⁇ R i5 R 2c ro. ⁇ , o, and R 21 are .defined as above for general formula (XlVa) ;
  • R 22 is selected from the group consisting of hydrogen, halogen, C x -C ⁇ alkoxy, C x -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl and hydroxy; said C x -C ⁇ alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen or C x -C 3 alkyl; said C x -C ⁇ alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C 3 alkyl; said C ⁇ -C e thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C 8 alkyl; said carbo (C ⁇ -C 6 ) alkoxy being optionally substituted with one or more substitu
  • R 23 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, Ci-C ⁇ alkyl, trifluoromethyl , carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, C ⁇ -C B thioalkyl and hydroxy; said C ⁇ -C ⁇ alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C ⁇ ⁇ C 3 alkyl; said Ci-C ⁇ alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl; said C ⁇ -C 8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C ⁇ -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with one or more substituents selected from the group consist
  • R 26 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C x -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl and hydroxy; said C x -C 6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with one or
  • X 5 is nitrogen or CR 31 ; wherein at least one of X 3 , X 4 , or X 5 is nitrogen;
  • R 29 is selected from the group consisting of hydrogen, halogen, Ci-C 6 alkoxy, C ⁇ Cg alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C 6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl, wherein the numbered halogen atoms can be 0-2; said Ci-C 6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C ⁇ ⁇ C 3 alkyl; said C x - C 8 thioalkyl being optionally substituted with one or more substituents selected
  • R 30 is selected from the group consisting of hydrogen, halogen, C ⁇ ⁇ C 6 alkoxy, trifluoromethyl, C ⁇ -C 6 alkyl, nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, Ci-C 8 thioalkyl and hydroxy; said C ⁇ -C ⁇ alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl; said Ci-C 8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 8
  • R 3 ⁇ is selected from the group consisting of hydrogen, halogen, Ci-C ⁇ alkoxy, C ⁇ -C ⁇ alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl, and hydroxy; said C ⁇ -C ⁇ alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl, wherein the numbered halogen atoms can be 0-2; said C x -C 6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl; said C x - Cj thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 8 alkyl; said carbo (C
  • the present invention further provides methods for using compositions comprising a compound of formula (XlVb) or a pharmaceutically acceptable salt or a compound having a tautomeric structure thereof, as hypoglycemic agents, the compound of formula (XlVb) having the structure:
  • R x is selected from the group consisting of hydrogen, R X4 COOR X5 , C x -C 8 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl, C x -C 8 alkoxy, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkoxy, (C x - C 6 ) alkyl, (C 6 -C X4 ) aryl, (C 6 -C -C X5 , C x -
  • R 9 is selected from the group consisting of hydrogen, C x -C 8 alkyl, (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl group, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C ⁇ Cg) alkyl, C 6 -C 14 aryl, C 6 -C X4 heteroaryl, (C 6 -C X4 ) heteroaryl (C x -C 6 ) alkyl, (C 6 - C X4 ) aryl (C x -C 6 ) alkyl, (C 6 -C X
  • Rio is selected from the group consisting of hydrogen, C ⁇ -C 8 alkyl, (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkyl group, (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ -C ⁇ ) alkoxy (C ⁇ -C 6 ) alkyl, C 6 -C ⁇ 4 aryl, Cg-C 14 heteroaryl, (C 6 -C X4 ) heteroaryl (C x -C 6 ) alkyl, (C 6 - C X4 ) aryl (C x -C 6 ) alkyl, (C 6 -C ⁇ 4 ) aryl (C ⁇
  • Rii is selected from the group consisting of hydrogen, C ⁇ -C 8 alkyl, (C ⁇ -C ⁇ ) alkoxy (C x -C 6 ) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkyl group, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, C 6 -C 14 aryl, C ⁇ -C ⁇ 4 heteroaryl, (C 6 -C ⁇ 4 ) heteroaryl (C ⁇ -C 6 ) alkyl, (C ⁇ - C i4 ) aryl (C ⁇ -C 6 ) alkyl, (C 6 -C
  • R 12 is selected from the group consisting of hydrogen and C x -C ⁇ alkyl;
  • R X3 is selected from the group consisting of
  • R 20 is selected from the group consisting of hydrogen, C x -C 6 alkyl, hydroxy and C x -C ⁇ alkoxy; m is 0 or 1, n is 0 or 2, o is 0 or 1,
  • R 21 is a bond or C x -C 6 alkyl; said C x -C ⁇ 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 C x -C 6 alkyl, halogen, C x -C ⁇ alkoxy and hydroxy;
  • R 22 ⁇ R 3 i are each independently selected from the group consisting of hydrogen, C x -C 8 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl, C x -C 8 alkoxy, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C B ) cycloalkyl (C x -C 6 ) alkoxy, (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, (C 6 -C x4 ) aryl, (C 6 -C X4 )
  • X 4 is nitrogen or CR 30 ;
  • X 5 is nitrogen or CR 3X ; wherein at least one of X 3 , X 4 , or X 5 is a nitrogen; or R 28 and CR 30 when taken together form an aryl ring; or R 28 and CR 29 when taken together form an aryl ring; with the proviso that the compound of formula (XlVb) is not: 2- ( ( (4- (phenyl)piperazinly-l-) acetyl) amino) -4-
  • compositions comprising a compound of formula (XlVb) or a phamaceutically acceptable salt or a compound having a tautomeric structure thereof, as hypoglycemic agents, wherein: R x is selected from the group consisting of hydrogen, C x -C 8 alkyl group, halogen, C 6 -C 14 aryl, (C ⁇ -C 14 ) aryl (C x -C ⁇ ) alkyl, and R X4 COOR x5 ; said C x -C 8 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, C x -C ⁇ alkyl and phenyl; said C ⁇ -C ⁇ 4 aryl and (C ⁇ -C X4 ) aryl (C x -C 6 ) alkyl being optionally substituted with one or
  • R 8 -R X5 , R 20 , m, n, o, and R 21 are defined as above for general formula (XlVb) ;
  • R 22 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C x -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl and hydroxy; said C x -C 6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen or C x -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with one or
  • R 25 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C x -C 6 alkyl, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl and hydroxy; said Ci- Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C ⁇ ⁇ C 3 alkyl; said C x -C ⁇ alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 8 alkyl; said carbo (C x -C ⁇ ) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen
  • R 26 is selected from the group consisting of hydrogen, halogen, C x -C ⁇ alkoxy, C x -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl and hydroxy; said C ⁇ -C ⁇ alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C ⁇ ⁇ C 3 alkyl; said C ⁇ -C 6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C ⁇ -C 3 alkyl; said C ⁇ -C 8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C ⁇ -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with one or
  • R 27 is selected from the group consisting of hydrogen, halogen, C x -C ⁇ alkoxy, C x -C ⁇ alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C ⁇ ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl and hydroxy; said C x -C 6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl; said C x -C ⁇ alkoxy being optionally substituted with one or more substituents selected from the group consisting of 'halogen and C x -C 3 alkyl; said Ci-Cg thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C ⁇ -C B alkyl; said carbo (C ⁇ -C 6 ) alkoxy being optionally substituted with
  • R 29 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C x -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C 6 alkyl being optionally substituted with one or more substituents .
  • halogen and C x -C 3 alkyl selected from the group consisting of halogen and C x -C 3 alkyl, wherein the numbered halogen atoms can be 0-2; said C x -C ⁇ alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl; said Ci- Cg thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-Cg alkyl; said carbo (C ⁇ -C ⁇ ) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl;
  • R 30 is selected from the group consisting of hydrogen, halogen, C ⁇ -C ⁇ alkoxy, trifluoromethyl, C ⁇ -C 6 alkyl, nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl and hydroxy; said C ⁇ ⁇ C 6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C ⁇ -C 3 alkyl; said C ⁇ -C 6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with one or more
  • the invention also relates to a process for the preparation of the compounds of general formulas (XlVa) and (XlVb) .
  • a preparation process according to the invention comprises the reaction of an aromatic amine of general formula (A2) :
  • R x is selected from the group consisting of R X4 COOR X5 , C 6 -C X4 aryl, (C 6 -C X4 ) aryl (C x -C 6 ) alkyl, C 3 -C 6 cycloalkyl, thio (C 6 -C X4 ) aryl, thio (C 6 -C X4 ) heteroaryl, (C 3 - C 8 ) cycloalkyl (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkoxy (
  • R 8 , R 9 , io/ R ⁇ R ⁇ 2 / R i / R i4/ R i5/ 2o m / °/ and R 2 ⁇ are as defined above for general formula (XVa) ;
  • R 22 is selected from the group consisting of hydrogen, halogen C x -C 8 alkoxy, C x -C 8 alkyl, trifluoromethyl, nitro, cyano, carboxy, C x -C 8 thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, C 3 -C 6 cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3
  • R 23 is selected from the group consisting of hydrogen, fluorine, bromine, C x -C 8 alkoxy, C 2 -C 8 alkyl, trifluoromethyl, nitro, cyano, carbo C x -C 6 alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl (C ⁇ -C 6 ) alkoxy (Ci-Cg) alkyl, (C 3 -C 6 ) cycloalkyloxy, (C 3 -Cg) cycloalkyl (C ⁇ -C ⁇ ) alkoxy, (C 2 -C 6 ) alkoxy (C 3 -C e ) alky
  • R 24 is selected from the group consisting of hydrogen, halogen, C x -C 8 alkoxy, C x -C 8 alkyl, trifluoromethyl, nitro, cyano, carbo C x -C 6 alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C 3 -C 6 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl (C 3 -C 6 ) cycloalkyloxy, (C 3 -C 6 ) cycloalkyl (C x -C 6 ) alkoxy, (C 3 -C 6 ) alkoxy (C 3 -C 6
  • R 25 is selected from the group consisting of hydrogen, fluorine, bromine, C ⁇ -C 8 alkoxy, trifluoromethyl, C 2 -C 8 alkyl, nitro, cyano, carbo C x -C fi alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 6 ) cycloalkyl (C 3 -C 6 ) cycloalkyloxy (C 3 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl (C x -C ⁇ ) alkoxy (C x -Cg) alkyl, (C 3 -C 6 ) cycloalkyloxy, (C 3 -C ⁇ ) cycloalkyl (C ⁇ -C ⁇ ) alkoxy, (C 3 -C 6 ) alkoxy (C 3 -C
  • R 26 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C x -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo C x -C 6 alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 6 ) cycloalkyl (C 3 -C 6 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyloxy, (C 3 -C 6 ) cycloalkyl (C x -C 6 ) alkoxy, (C 3 -C 6 ) alkoxy (C 3 -C 6
  • X 3 is nitrogen or CR 29 ;
  • X 4 is nitrogen or CR 30 ;
  • X 5 is nitrogen or CR 3X ; wherein at least one of X 3/ X 4 , or X 5 is nitrogen; or R 28 and CR 30 when taken together form an aryl ring; or R 28 and CR 29 when taken together form an aryl ring; or two of R 27 -R 3X 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:
  • the invention further provides compounds, as well as compositions comprising said compounds, useful as hypoglycemic agents wherein:
  • R x is selected from the group consisting of R ⁇ 4 COOR x5 , C 6 -C X4 aryl, (C 6 -C X4 ) aryl C x -C 6 alkyl, C 3 -C 6 cycloalkyl, thio (C 6 -C X4 ) aryl ⁇ e . g.
  • C 6 -C X4 heteroaryl (e.g., thiopyridyl, thioquinolinyl, and thiopyrazinyl) ; said C 6 -C X4 aryl and (C ⁇ - C X4 ) aryl C x -C 6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amine, hydroxy, C x -C 6 alkoxy, C x -C 6 alkyl, trihalo Ci- Cg alkyl, trihalo C x -C ⁇ alkoxy, and phenyl; said thio (Cg-C X4 ) aryl being optionally substituted with halogen, amine C x -C ⁇ alkoxy, hydroxy, C x -C ⁇ alkyl, trihalo (
  • R 8 is selected from the group consisting of NR 20 SO 2 Ar and NR 20 ArSO 2 , wherein Ar is an aryl selected from the group consisting of phenyl and phenyl (Ci-C 8 ) alkyl;
  • R 9 is a group selected from the group consisting of hydrogen, C ⁇ -C 8 alkyl, (C ⁇ -C 6 ) alkoxy (C ⁇ -C ⁇ ) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkyl group, (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 - C 8 ) cycloalkyl (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, C 6 -C ⁇ 4 aryl, Cg-C X4 heteroaryl, (C 6 -C X4 ) heteroaryl (C x -C 6 ) alkyl, (Cg-C X4 ) aryl (Ci- Cg) alkyl, (C 6 -C ⁇ 4 ) aryl (
  • R xo is selected from the group consisting of hydrogen, C x -C 8 alkyl, (C x -C 6 ) alkoxy (C x -C ⁇ ) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkyl group, (C 3 -C ⁇ ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 - C 8 ) cycloalkyl (C x -C ⁇ ) alkoxy (C x -C 6 ) alkyl, C 6 -C X4 aryl, C 6 -C X4 heteroaryl, (C 6 -C X4 ) heteroaryl (C x -C 6 ) alkyl, (C 6 -C X4 ) aryl (C x - C 6 ) alkyl, (C
  • Rii is selected from the group consisting of hydrogen, C ⁇ -C 8 alkyl, (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkyl group, (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 - C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, C 6 -C X4 aryl, C 6 -C X4 heteroaryl, (C 6 -C x4 ) heteroaryl (C x -C ⁇ ) alkyl, (C ⁇ -C X4 ) aryl (Ci- Cg) alkyl, (C 6 -C X
  • R x2 is selected from the group consisting of hydrogen and C x -C 6 alkyl
  • R x3 is selected from the group consisting of
  • R X4 is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and C x -C 2 alkyl group; said C x -C 2 alkyl being substituted with one or more halogen, C x -C 6 alkyl or phenyl groups;
  • R X5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and C x - C 6 alkyl group; said C x -C 6 alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and C x -C 3 alkyl; R 20 is selected from the group consisting of hydrogen, C ⁇ -C 6 alkyl, hydroxy and C ⁇ -C 6 alkoxy; m is 0 or 1; n is 1; o is 0 or 1;
  • R 2i is a bond or C ⁇ -C 6 alkyl; said C ⁇ -C 6 alkyl being optionally substituted from .the group consisting of benzene and an optionally substituted benzene ring; said benzene ring optionally substitued from the group consisting of C ⁇ -C 6 alkyl, halogen, C x -C 6 alkoxy and hydroxy;
  • R 22 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C x -C 6 alkyl, trifluoromethyl , nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C 6 alkyl being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with halogen or C x -C 3 alkyl; said C X -C B thioalkyl being optionally substituted with halogen or C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with halogen or C x -C 3 alkyl; R 23 is selected from the group consisting of hydrogen, fluorine, bromine, C x -
  • R 24 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C ⁇ -C 6 alkyl, trifluoromethyl , nitro, cyano, carbo (C ⁇ -C ⁇ ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C ⁇ alkyl being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted with halogen or C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with halogen or C x -C 3 alkyl; R 25 is selected from the group consisting of hydrogen, fluorine, bromine, C x
  • R 27 is selected from the group consisting of hydrogen, halogen, C ⁇ -C 6 alkoxy, C ⁇ -C ⁇ alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C ⁇ ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C 6 alkyl being optionally substituted with halogen or C x -C 3 alkyl; said C x -C ⁇ alkoxy being optionally substituted with halogen or C x -C 3 alkyl; said C X -C B thioalkyl being optionally substituted with halogen or C x -C 8 alkyl; said carbo (C x -C ⁇ ) alkoxy being optionally substituted with halogen or C x -C 3 alkyl; R 28 is selected from the group consisting of hydrogen, halogen, C x -
  • X 3 is nitrogen or CR 29 X 4 is nitrogen or CR 30 X 5 is nitrogen or CR 3 ⁇ wherein at least one of X 3 , X 4 , or X 5 is nitrogen;
  • R 29 is selected from the group consisting of hydrogen, halogen, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkyl, trifluoromethyl , nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl, and hydroxy; said C ⁇ -C 6 alkyl being optionally substituted with one to two halogen atoms or C ⁇ -C 3 alkyl; said Ci-Cg alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C ⁇ ⁇ C 8 thioalkyl being optionally substituted with halogen or C ⁇ -C 8 alkyl; said carbo (C ⁇ -C 6 ) alkoxy being optionally substituted with halogen or C ⁇ ⁇ C 3 alkyl; R 30 is selected from the group consisting of hydrogen, halogen, C ⁇ -
  • R 3 ⁇ is selected from the group consisting of hydrogen, halogen, C ⁇ -C ⁇ alkoxy, C ⁇ -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl, and hydroxy; said C ⁇ -C 6 alkyl being optionally substituted with one to two halogen atoms or C ⁇ -C 3 alkyl; said Ci-Cg alkoxy being optionally substituted with halogen or C x -C 3 alkyl; said C ⁇ -C 8 thioalkyl being optionally substituted with halogen or C ⁇ -C 8 alkyl; said carbo (C ⁇ -C 6 ) alkoxy being optionally substituted with halogen or C ⁇ ⁇ C 3 alkyl; or R 2B and CR 30 when taken together form an aryl ring; or
  • 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:
  • Ri is selected from the group consisting of R X4 COOR X5 , C 6 -C X4 aryl, (C 6 -C 14 ) aryl (C x -C 6 ) alkyl, C 3 -C 6 cycloalkyl, thio (C 6 -C X4 ) aryl, thio (C 6 -C x4 ) heteroaryl, (C 3 - C 8 ) cycloalkyl (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C B ) cycloalkyl (C x -C 6 ) alkoxy,
  • R 8 is selected from the group consisting of NR 20 SO 2 Ar and NR 20 ArSO 2 , wherein Ar is an aryl selected from the group consisting of phenyl and phenyl (C x -C 6 ) alkyl; R 9 is a group selected from the group consisting of hydrogen, C x -C 8 alkyl, (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl group, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 - C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, Cg-C X4 aryl, C 6 -C X
  • Ri o is selected from the group consisting of hydrogen, C ⁇ -C 8 alkyl, (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, . cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkyl group, (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C ⁇ ) alkyl, (C 3 - C 8 ) cycloalkyl (C ⁇ -C ⁇ ) alkoxy (C ⁇ -C ⁇ ) alkyl, C ⁇ -C ⁇ 4 aryl, C ⁇ -C ⁇ 4 heteroaryl, (C 6 -C ⁇ 4 ) heteroaryl (C ⁇ -C 6 ) alkyl, (C 6 -C ⁇ 4 ) aryl (C X - C 6 ) alkyl
  • Rii is selected from the group consisting of hydrogen, C ⁇ -C 8 alkyl, (C ⁇ -C 6 ) alkoxy (Ci-Cg) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkyl group, (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 - C 8 ) cycloalkyl (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, C 6 -C ⁇ 4 aryl, C 6 -C ⁇ 4 heteroaryl, (C 6 -C ⁇ 4 ) heteroaryl (C ⁇ -C ⁇ ) alkyl, (C 6 -C ⁇ 4 ) aryl (Ci- Cg) alkyl, (Cg-C ⁇ 4 ) aryl (C ⁇
  • R i3 is selected from the group consisting of
  • R ⁇ disturb is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and C ⁇ -C 2 alkyl group; said C ⁇ -C 2 alkyl being substituted with one or more halogen, C ⁇ -C 6 alkyl or phenyl groups;
  • R ⁇ 5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and C x - C 6 alkyl group; said C ⁇ -C 6 alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and C ⁇ -C 3 alkyl;
  • R 20 is selected from the group consisting of hydrogen, C ⁇ -C 6 alkyl, hydroxy and C ⁇ -C 6 alkoxy; m is 0 or 1; n is 1; o is 0 or 1;
  • R 2 ⁇ is a bond or C ⁇ -C 6 alkyl; said C ⁇ -C 6 alkyl being optionally substituted from the group consisting of benzene and an optionally substituted benzene ring; said benzene ring optionally substitued from the group consisting of C ⁇ -C 6 alkyl, halogen, C ⁇ -C 6 alkoxy and hydroxy;
  • R 22 is selected from the group consisting of hydrogen, halogen C x -C 8 alkoxy, C ⁇ -C 8 alkyl, trifluoromethyl, nitro, cyano, carboxy, C ⁇ -C 8 thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, C 3 -C 6 cycloalkyl (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkoxy, (C 3 -C 6 ) alkoxy (C 3 -C 6 ) alkyl, (Cg-C ⁇ 4 ) aryl, (C
  • R 23 is selected from the group consisting of hydrogen, fluorine, bromine, C ⁇ -C 8 alkoxy, C 2 -C 8 alkyl, trifluoromethyl, nitro, cyano, carbo C x -Cg alkoxy, carboxy, phenyl, C ⁇ C 8 thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl (Ci-Cg) alkoxy (C ⁇ -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyloxy, (C 3 -C 6 ) cycloalkyl (C ⁇ -C 6 ) alkoxy, (C 2 -C 6 ) alkoxy (C 3 -C 6 ) alky
  • R 25 is selected from the group consisting of hydrogen, fluorine, bromine, C x -C 8 alkoxy, trifluoromethyl, C 2 -C 8 alkyl, nitro, cyano, carbo C x -C 6 alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 6 ) cycloalkyl (C 3 -C 6 ) cycloalkyloxy (C 3 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C ⁇ ) alkyl, (C 3 -C ⁇ ) cycloalkyloxy, (C 3 -C ⁇ ) cycloalkyl (C x -C ⁇ ) alkoxy, (C 3 -C ⁇ ) alkoxy (
  • R 26 is selected from the group consisting of hydrogen, halogen, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo Ci-Cg alkoxy, carboxy, phenyl, Ci-Cg thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 6 ) cycloalkyl (C 3 -C 6 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl (C ⁇ -C 6 ) alkoxy (Ci-Cg) alkyl, (C 3 -C 6 ) cycloalkyloxy, (C 3 -C 6 ) cycloalkyl (C x -C ⁇ ) alkoxy, (C 3 -C 6 ) alkoxy (C 3 -C 6 ) alkyl, (C 6
  • X 3 is nitrogen or CR 29 ;
  • X 4 is nitrogen or CR 30 ;
  • X 5 is nitrogen or CR 3 ⁇ ,- wherein at least one of X 3 , X 4 , or X 5 is nitrogen; or R 2B and CR 30 when taken together form an aryl ring; or R 2B and CR 29 when taken together form an aryl ring; or two of R 27 -R 3 ⁇ 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:
  • 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:
  • Ri is selected from the group consisting of hydrogen, halogen, R ⁇ 4 COOR ⁇ 5 , R x6 OR x7 , R X8 NHR X9 , (C 6 -C x4 ) aryl, (C 6 - C X4 ) aryl C x -C 6 alkyl, C 3 -C 6 cycloalkyl, thio (C 6 -C x4 ) aryl, thio (C 6 -C X4 ) heteroaryl C x -C 8 alkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl, C x -C 8 alkoxy, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 - C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) al
  • R 8 is selected from the group consisting of NR 20 SO 2 Ar and NR 20 ArSO 2 , wherein Ar is an aryl selected from the group consisting of phenyl and phenyl C x -C 6 alkyl;
  • R 9 is a group selected from the group consisting of hydrogen, C x -C 8 alkyl, (C x -C 6 ) alkoxy (C x -Cg) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl group, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 - C 8 ) cycloalkyl (C x -C ⁇ ) alkoxy (C x -C 6 ) alkyl, C 6 -C X4 aryl, C 6 -C X4 heteroaryl, (C 6 -C X4 ) heteroaryl (C x -C 6 ) alkyl, (C 6 -C x4 ) aryl (Ci- Cg) alkyl, (C 6
  • R xx is selected from the group consisting of hydrogen, C x -C 8 alkyl, (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl group, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 - C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, C 6 -C ⁇ 4 aryl, C ⁇ -C X4 heteroaryl, (C 6 -C X4 ) heteroaryl (C x -C 3 ) alkyl, (C 6 -C X4 ) aryl (C x - C 6 ) alkyl, (C 6
  • R X2 is selected from the group consisting of hydrogen and C x -C 6 alkyl; R x3 is selected from the group consisting of
  • R X4 is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and C x -C 2 alkyl group; said C x -C 2 alkyl group being substituted with one or more hydrogen, halogen, C x -C 6 alkyl or phenyl groups;
  • R x5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and C x - C 6 alkyl group; said C x -C ⁇ alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and C x -C 3 alkyl;
  • R x6 is a bond or is selected from the group consisting of sulfonyl, C x -C 8 thioalkyl, aminosulfonyl and C x - C ⁇ alkyl; said C x -C ⁇ alkyl group being substituted with one or more hydrogen, halogen, C x -C 6 alkyl or phenyl groups;
  • R x7 is selected from the group consisting of phenyl, phenyl C ⁇ -C 6 alkyl, trifluoromethyl and C ⁇ -C 6 alkyl; said C ⁇ -C 6 alkyl being optionally substituted with one or more groups selected from the group consisting of halogen, phenyl, phenyl Ci-Cg alkyl, and C x -C 3 alkyl; said phenyl and phenyl C x -C 6 alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, amino, and C x -C ⁇ alkyl; R x8 is a bond or is selected from the group consisting of sulfonyl, thio C x -C ⁇ alkyl, aminosulfonyl, carbonyl, aminocarbonyl and C x -C ⁇ alkyl; said C x -C ⁇
  • R 20 is a group selected from the group consisting of hydrogen, C x -C ⁇ alkyl, hydroxy and C x -C 6 alkoxy; m is 0 or 1; n is 1; o is 0 or 1;
  • R 2X is a bond or C x -C 6 alkyl; said C x -C 6 alkyl being optionally substituted from the group consisting of benzene and an optionally substituted benzene ring; said benzene ring optionally substitued from the group consisting of C x -C 6 alkyl, halogen, C x -C 6 alkoxy and hydroxy;
  • R 22 is selected from the group consisting of hydrogen, halogen, C x -C 8 alkoxy, C x -C 8 alkyl, trifluoromethyl, nitro, cyano, carboxy, C x -C 8 thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C 3 -C 6 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C ⁇ ) alkyl, (C 3 -C 6 ) cycloalkyloxy, (C 3 -C 6 ) cycloalkyl C x -C 6 alkoxy, (C 3 -C 6 ) alkoxy C 3 -C 6 alkyl, (C 6 -C X4 ) aryl, (C
  • R 23 is selected from the group consisting of hydrogen, fluorine, bromine, C ⁇ -C 8 alkoxy, C 2 -C 8 alkyl, trifluoromethyl, nitro, cyano, carbo C ⁇ -C 6 alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl (C ⁇ -C 6 ) alkoxy (Ci-Cg) alkyl, (C 3 -C ⁇ ) cycloalkyloxy, (C 3 -C ⁇ ) cycloalkyl (C ⁇ -C ⁇ ) alkoxy, (C 3 -C ⁇ ) alkoxy (C 3 -C 6 ) alky
  • R 24 is selected from the group consisting of hydrogen, halogen, C ⁇ -C 8 alkoxy, C ⁇ -C 8 alkyl, trifluoromethyl, nitro, cyano, carboxy, C ⁇ -C B thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C 3 -C 6 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyloxy, (C 3 -C 6 ) cycloalkyl C ⁇ -C 6 alkoxy, (C 3 -C 6 ) alkoxy C 3 -C 6 alkyl, (C 6 -C ⁇ 4 ) aryl, (C 6 -C 14 )
  • R 26 is selected from the group consisting of hydrogen, halogen, C x -C 8 alkoxy, C x -C 8 alkyl, trifluoromethyl, nitro, cyano, carboxy, C x -C 8 thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C 3 -C ⁇ ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyloxy, (C 3 -C 6 ) cycloalkyl C x -C 6 alkoxy, (C 3 -C 6 ) alkoxy C 3 -C 6 alkyl, (C 6 -C X4 ) aryl, (C
  • X 4 is nitrogen or CR 30 ;
  • X 5 is nitrogen or CR 3X ; wherein at least one of X 3 , X 4 , or X s is nitrogen; or R 28 and CR 30 when taken together form an aryl ring; or R 28 and CR 29 when taken together form an aryl ring; or two of R 27 -R 3 ⁇ 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 :
  • 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: Ri is selected from the group consisting of hydrogen, halogen, R ⁇ 4 COOR ⁇ 5 , R x6 OR X7 , R X8 NHR X9 , C 6 -C X4 aryl, (C 6 - C x4 ) aryl (C 6 -C X4 ) alkyl, C 3 -C 6 cycloalkyl, trifluoromethyl, thio (C 6 -C X4 ) aryl, (e.g., thiophenyl , thionaphthyl) , thio (C 6 - C x4 ) heteroaryl (e.g., thio pyridyl,
  • R 22 is selected from the group consisting of hydrogen, halogen, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl, and hydroxy; said C ⁇ -C ⁇ alkyl being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C ⁇ -C ⁇ alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C ⁇ -C 8 thioalkyl being optionally substituted with halogen or C ⁇ -C 8 alkyl; said carbo (C ⁇ -C ⁇ ) alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl;
  • R 23 is selected from the group consisting of hydrogen fluorine, bromine, C x -C 6 alkoxy, C 2 -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C 2 -C ⁇ alkyl being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted with halogen or C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with halogen or C x -C 3 alkyl;
  • R 24 is selected from the group consisting of hydrogen, halogen, C x -C ⁇ alkoxy, C x -C ⁇ alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C ⁇ ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C ⁇ alkyl being optionally substituted with halogen or C x -C 3 alkyl; said C x -C ⁇ alkoxy being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted with halogen or C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with halogen or C x -C 3 alkyl; R 25 is selected from the group consisting of hydrogen, fluorine, bromine, C
  • R 26 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C x -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C 3 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C 6 alkyl being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted with halogen or C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with halogen or C x -C 3 alkyl; or two of R 22 -R 26 when taken together can form a methylenedioxy group;
  • R 27 is selected from the group consisting of hydrogen, halogen, C x -C ⁇ alkoxy, C x -C 6 alkyl, trifluoromethyl , nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C 6 alkyl being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted with halogen or C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with halogen or C x -C 3 alkyl;
  • R 28 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C x -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C ⁇ alkyl being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C ⁇ -C 6 alkoxy being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted with halogen or C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with halogen or C x -C 3 alkyl; or R 22 and R 23 when taken together form an aryl ring; or R 23 and R 24 when taken together form an
  • X 3 is nitrogen or CR 29 X 4 is nitrogen or CR 30 X 5 is nitrogen or CR 3X ; wherein at least one of X 3 , X 4 , or X 5 is a nitrogen;
  • R 29 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C x -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C 6 alkyl being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted with halogen or C x -C 8 alkyl; said carbo (C
  • R 30 is selected from the group consisting of hydrogen, halogen, C x -C 3 alkoxy, C x -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C 6 alkyl being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted with halogen or C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with halogen or C x -C 3 alkyl;
  • R 31 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C x -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C x -C ⁇ ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C 6 alkyl being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C ⁇ -C 6 alkoxy being optionally substituted with halogen or C ⁇ ⁇ C 3 alkyl; said C ⁇ -C 8 thioalkyl being optionally substituted with halogen or C ⁇ -C 8 alkyl; said carbo (C ⁇ -C 6 ) alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl; or R 2B and CR 30 when taken together form an aryl ring; or R 2B and
  • the invention also relates to a process for the preparation of the compounds of general formulas (XVa) and (XVb) .
  • a preparation process according to the invention comprises the reaction of an aromatic amine of general formula (A3) :
  • the invention further provides compounds, as well as compositions comprising said compounds, useful as hypoglycemic agents, of general formula (XVIa) :
  • R x is selected from the group consisting of hydrogen and R X4 COOR x5 ;
  • R 2 is selected from the group consisting of hydrogen, halogen, R x6 OR X7 , R X8 NHR X9 , C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl, C x -C 8 alkoxy, (C 3 -C 8 ) cycloalkyloxy (Ci-Cg) alkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (C x -Cg) alkoxy, (Ci- Cg) alkoxy (C x -C 6 ) alkyl, (C 6 -C 14 ) aryl, (C 6 -C X4 ) heteroary
  • R 3 is selected from the group consisting of hydrogen, (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkyl, (C 6 -C ⁇ 4 ) aryl, (C 6 -C X4 ) heteroaryl, (C 6 -C x4 ) heteroaryl (C x -C 6 ) alkyl, (C 6 -C X4 ) aryl (C x -C 6 ) alkyl, halogen, trifluoromethyl, and cyano; said C x -C 8 alkyl being optionally substituted with one or more halogen, C x -C 6 alkyl or phenyl groups; said C 6 -C X4 aryl and (C 6 -C x4 ) aryl (C x -C 6 ) alkyl being optionally substituted with one or more substituents selected from the group consist
  • R 8 is selected from the group consisting of NR 20 SO 2 Ar and NR 20 ArSO 2 , wherein Ar is an aryl selected from the group consisting of phenyl and phenylalkyl;
  • R 9 is a group selected from the -group consisting of hydrogen, C x -C 8 alkyl, (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (C x -C ⁇ ) alkyl group, (C 3 -C ⁇ ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 - C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, C 6 -C X4 aryl, C 6 -C X4 heteroaryl, (C 6 -C X4 ) heteroaryl (C x -C 6 ) alkyl, (C 6 -C X4 ) aryl (C x - C 6 ) al
  • R x0 is selected from the group consisting of hydrogen, C x -C 8 alkyl, (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl group, (C 3 -C ⁇ ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 - C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, C 6 -C X4 aryl, C 6 -C 14 heteroaryl, (C 6 -C 14 ) heteroaryl (C x -C ⁇ ) alkyl, (C 6 -C X4 ) aryl (Ci- Cg) alkyl, (C 6 -C
  • R X2 is selected from the group consisting of hydrogen and C x -C ⁇ alkyl
  • R x3 is selected from the group consisting of
  • R X4 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and C x -C 6 alkyl group; said C x -C 6 alkyl group being substituted with one or more hydrogen, halogen, C x -C ⁇ alkyl or phenyl groups ;
  • R 15 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, divalent alkali metals, divalent alkali earth metals, and a C x -C 6 alkyl group; said C x -C ⁇ alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and C x -C 3 alkyl; R X6 is a bond or is selected from the group consisting of sulfonyl, C 2 -C ⁇ thioalkyl, aminosulfonyl and Ci- Cg alkyl; said C ⁇ Cg alkyl being substituted with one or more hydrogen, halogen, C ⁇ -C 6 alkyl or phenyl groups;
  • Ri is selected from the group consisting of phenyl, phenylalkyl, and a C ⁇ -C 6 alkyl group; said C ⁇ -C 6 alkyl group being optionally substituted with one or more groups selected from the group consisting of halogen, phenyl, phenylalkyl, and C ⁇ C 3 alkyl; said phenyl and phenylalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C ⁇ -C 6 alkoxy, amino, and C ⁇ -C 6 alkyl;
  • R i8 is a bond or is selected from the group consisting of sulfonyl, C 2 -C ⁇ thioalkyl, aminosulfonyl, carbonyl, aminocarbonyl and C ⁇ -C ⁇ alkyl group, said C ⁇ -C ⁇ alkyl group being substituted with one or more hydrogen, halogen, C ⁇ -C 6 alkyl or phenyl groups;
  • R ⁇ 9 is selected from the group consisting of hydrogen, phenyl, phenyl (C ⁇ -C 6 ) alkyl, and C ⁇ -C 6 alkyl; said Ci- Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of phenyl and C x -C 3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino, and C ⁇ C ⁇ alkyl; said pheny
  • R 20 is selected from the group consisting of hydrogen, C ⁇ -C 6 alkyl, hydroxy and C ⁇ -C 6 alkoxy; m is 0 or 1; o is 0 or 1; R 2 ⁇ is a bond or is selected from the group consisting C ⁇ -C 6 alkyl; said C ⁇ -C 6 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 C ⁇ -C 6 alkyl, halogen, C ⁇ -C 6 alkoxy and hydroxy;
  • R 22 is selected from the group consisting of hydrogen, bromine, chlorine, C 2 -C 8 alkoxy, C ⁇ -C 8 alkyl, trifluoromethyl, nitro, cyano, carbo C ⁇ -C 6 alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl, hydroxy, C ⁇ -C 6 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkoxy (C ⁇ ⁇ C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkoxy (
  • R 23 is selected from the group consisting of hydrogen, halogen, C ⁇ -C 8 alkoxy, C ⁇ -C 8 alkyl, trifluoromethyl, nitro, cyano, carbo C ⁇ -C 6 alkoxy, carboxy, C ⁇ -C 8 thioalkyl, hydroxy, C 3 -C B cycloalkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy (C j -Cg) alkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkoxy, (C ⁇ -C 6 ) alkoxy (C ⁇
  • R 24 is selected from the group consisting of hydrogen, bromine, chlorine, C ⁇ -C 8 alkoxy, C ⁇ -C 8 alkyl, trifluoromethyl , nitro, cyano, carbo ⁇ Cg alkoxy, carboxy, Ci-Cg thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkyl, (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl alkoxy, (C ⁇ -C 6 ) alkyl, (C 6 -C ⁇ 4 )
  • R 25 is selected from the group consisting of hydrogen, halogen, C ⁇ -C 8 alkoxy, C ⁇ -C 8 alkyl, trifluoromethyl , nitro, cyano, carbo C ⁇ -C ⁇ alkoxy, carboxy, Ci-C 8 thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ -C ⁇ ) alkyl, (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 -C ⁇ ) cycloalkyl (Ci-C 6 ) alkoxy (C ⁇ -C ⁇ ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C B ) cycloalkyl (Ci-Cg) alkoxy, (C ⁇ -C 6 ) alkoxy (C
  • R 26 is selected from the group consisting of hydrogen, bromine, chlorine, C 2 -C 8 alkoxy, C ⁇ -C 8 alkyl, trifluoromethyl, nitro, cyano, carbo C ⁇ -C 6 alkoxy, carboxy, phenyl, C ⁇ ⁇ C 8 thioalkyl, hydroxy, C ⁇ -C 6 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkyl, (C 3 -C frustration) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ -C ⁇ ) alkoxy (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (C ⁇ -C ⁇ ) alk
  • R 27 -R 3 i are independently selected from the group consisting of hydrogen, halogen, C ⁇ -C 8 alkoxy, C ⁇ -C profession alkyl, trifluoromethyl, nitro, cyano, carbo C ⁇ -C 6 alkoxy, carboxy, C ⁇ -C 8 thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkyl, (C 3 -C ⁇ ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkoxy, (C ⁇ -C 6 ) alkyl
  • X 5 is nitrogen or CR 31 ; wherein at least one of X 3 , X 4 , or X 5 is nitrogen; wherein up to three of R 2 -R 31 can simultaneously be hydrogen when only one of X 3 -X 5 is nitrogen; or R 28 and CR 30 when taken together form an aryl ring; or R 28 and CR 29 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 compounds as well as compositions comprising said compounds, useful as hypoglycemic agents wherein:
  • R x is selected from the group consisting of hydrogen and R ⁇ 4 COOR ⁇ 5 ;
  • R 2 is selected from the group consisting of hydrogen, halogen, R ⁇ 6 OR ⁇ 7 , R ⁇ 8 NHR ⁇ 9 , C 6 -C ⁇ 4 aryl, (C ⁇ -C ⁇ 4 ) aryl Ci-Cg alkyl, C ⁇ -C 8 alkyl, and C 3 -C 6 cycloalkyl; said C 6 -C ⁇ 4 aryl, and said (C 6 -C ⁇ 4 ) aryl C ⁇ -C 6 alkyl, being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, C ⁇ -C 6 alkoxy, C x - C 6 alkyl, trihalo (C ⁇ -C 6 ) alkyl, and trihalo (C ⁇ -C 6 ) alkoxy; said Ci-Cg alkyl group being optionally substituted with one
  • R 3 is selected from the group consisting of hydrogen, Cg-C 14 aryl, (C 6 -C ⁇ 4 ) aryl (C ⁇ -C 6 ) alkyl, and C j -Cg alkyl group; said C 6 -C ⁇ 4 aryl, and said (C 6 -C ⁇ 4 ) aryl (C ⁇ -C 6 ) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Ci-C 6 alkoxy, C ⁇ -C 6 alkyl, C 3 -C 8 cycloalkyl, trihalo (C ⁇ -C 6 ) alkyl, and trihalo (C ⁇ -C 6 ) alkoxy; said C ⁇ C 8 alkyl group being optionally substituted with one or more halogen, C ⁇ -C 6 alkyl or phenyl groups;
  • R B -R 2 ⁇ , m, and o are as defined above for formula (XVIa) ;
  • R 22 is selected from the group consisting of hydrogen, bromine, chlorine, C 2 -C 6 alkoxy, C ⁇ -C 6 alkyl, nitro, trifluoromethyl, cyano, carbo (Ci-C 6 ) alkoxy, carboxy, phenyl, Ci-Cg thioalkyl, and hydroxy; said Ci-C 8 alkyl being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C 2 -C 6 alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C ⁇ -C 8 thioalkyl being optionally substituted with halogen or C ⁇ -C 8 alkyl; said carbo (C ⁇ -C 6 ) alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl;
  • R 23 is selected from the group consisting of hydrogen, halogen, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C ⁇ ⁇ C ⁇ ) alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl, and hydroxy; said C ⁇ -C ⁇ alkyl being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C ⁇ C g alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C ⁇ -C 8 thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (C ⁇ ⁇ C 6 ) alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl;
  • R 24 is selected from the group consisting of hydrogen, bromine, chlorine, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl, and hydroxy; said C ⁇ -C 6 alkyl being optionally substituted with halogen or C ⁇ ⁇ C 3 alkyl; said C j -Cg alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C ⁇ -C 8 thioalkyl being optionally substituted with halogen or C ⁇ -C 8 alkyl; said carbo (C ⁇ -C 6 ) alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl; R 25 is selected from the group consisting of hydrogen, halogen, C ⁇ -C 6 alkoxy, C ⁇
  • R 26 is selected from the group consisting of hydrogen, bromine, chlorine, C 2 -C 6 alkoxy, Ci-C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-Cg) alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl, and hydroxy; said C ⁇ -C ⁇ alkyl being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C 2 -C 6 alkoxy being optionally substituted with halogen or C ⁇ ⁇ C 3 alkyl; said C ⁇ -C 8 thioalkyl being optionally substituted with halogen or C ⁇ -C 8 alkyl; said carbo (C ⁇ -C 6 ) alkoxy being optionally substituted with halogen or C ⁇ ⁇ C 3 alkyl; wherein R 22 -R 26 cannot all simultaneously be hydrogen; or two of R 22 -R 26 when taken together can form a methylenedioxy group;
  • R 28 is selected from the group consisting of hydrogen, halogen, C ⁇ -C 6 alkoxy, Ci-C 6 alkyl; nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, C j -C 8 thioalkyl, and hydroxy; said C ⁇ -C ⁇ alkyl being optionally substituted with halogen or C ⁇ ⁇ C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C ⁇ -C 8 thioalkyl being optionally substituted with halogen or C ⁇ -C 8 alkyl; said carbo (C ⁇ -C 6 ) alkoxy being optionally substituted with halogen or C ⁇ ⁇ C 3 alkyl; or R 22 and R 23 when taken together form an aryl ring; or R 23 and R 24 when taken together form an aryl ring; X 3
  • X 4 is nitrogen or CR 30 ;
  • X 5 is nitrogen or CR 3 ⁇ ,- wherein at least one of X 3 , X 4 , or X 5 is nitrogen;
  • R 29 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C ⁇ Cg alkyl, nitro, cyano, carbo (Ci-C 6 ) alkoxy, carboxy, phenyl, C ⁇ ⁇ C 8 thioalkyl, and hydroxy; said C ⁇ -C 6 alkyl being optionally substituted with one to two halogen atoms or C ⁇ -C 3 alkyl; said C ⁇ -C 6 alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl;
  • R 30 is selected from the group consisting of hydrogen, halogen, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkyl, nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl, and hydroxy; said C ⁇ -C 6 alkyl being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C ⁇ -C 6 alkoxy being optionally substituted with halogen or C ⁇ ⁇ C 3 alkyl;
  • R 3 ⁇ is selected from the group consisting of hydrogen, halogen, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkyl, nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, C ⁇ -C B thioalkyl, and hydroxy; said C ⁇ Cg alkyl being optionally substituted with one to two halogen atoms or C ⁇ -C 3 alkyl; said C ⁇ C 6 alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl; wherein up to three of R 27 -R 3i can simultanoeously be hydrogen when only one of X 3 -X 5 is nitrogen; wherein up to two of R 27 -R 31 can simultaneously be hydrogen when two of X 3 -X 5 are nitrogen; or R 28 and CR 29 when taken together form an aryl ring; or R 28 and CR 30 when taken together form an aryl ring; or a pharmaceutically
  • 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:
  • Ri is selected from the group consisting of hydrogen and R ⁇ 4 COOR ⁇ 5 ;
  • R 2 is selected from the group consisting of hydrogen, halogen, R ⁇ OR ⁇ 7 , R ⁇ 8 NHR ⁇ 9 , C 3 -C 8 cycloalkyl, (C 3 -C cramp) cycloalkyl (Ci-Cg) alkyl, C ⁇ -C 8 alkoxy, (C 3 -C 8 ) cycloalkyloxy (Ci-Cg) alkyl, (C 3 -C ⁇ ) cycloalkyl (C ⁇ -C ⁇ ) alkoxy (C ⁇ -C ⁇ ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 6 ) alkoxy, (Ci- Cg) alkoxy (C ⁇ -C 6 ) alkyl, (C 6 -C 14 ) aryl, (C 6 -C ⁇ 4 ) heteroaryl, (Cg-
  • R 3 is selected from the group consisting of hydrogen, (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 ) cycloalkyl (C ⁇ Cg) alkyl, (C 6 -C 14 ) aryl, (C ⁇ -C ⁇ 4 ) heteroaryl, (C 6 -C 14 ) heteroaryl (Cj-Cg) alkyl, (C 6 -C 14 ) aryl (C ⁇ -C 6 ) alkyl, halogen, trifluoromethyl , and cyano; said C ⁇ -C 8 alkyl being optionally substituted with one or more halogen, C ⁇ -C 6 alkyl or phenyl groups; said C 6 -C 14 aryl and (C 6 -C ⁇ 4 ) aryl (C ⁇ -C ⁇ ) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy,
  • R 9 is a group selected from the group consisting of hydrogen, C ⁇ -C 8 alkyl, (C ⁇ -C ⁇ ) alkoxy (C x -C 6 ) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkyl group, (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 - C 8 ) cycloalkyl (Ci-Cg) alkoxy (C ⁇ -C 6 ) alkyl, C 6 -C ⁇ 4 aryl, C ⁇ -C ⁇ 4 heteroaryl, (C ⁇ -C ⁇ 4 ) heteroaryl (C x -C 6 ) alkyl, (C 6 -C ⁇ 4 ) aryl (Ci- Cg) alkyl, (C 6 -C
  • Ri o is selected from the group consisting of hydrogen, C ⁇ -C 8 alkyl, (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkyl group, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 - C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, C 6 -C ⁇ 4 aryl, C ⁇ -C 14 heteroaryl, (C ⁇ -C 14 ) heteroaryl (C ⁇ -C 6 ) alkyl, (C 6 -C 14 ) aryl (Ci- Cg) alkyl, (C 6 -C ⁇ 4 ) aryl (
  • Rii is selected from the group consisting of hydrogen, C x -C 8 alkyl, (C ⁇ -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkyl group, (C 3 -C 8 ) cycloalkyloxy (C ⁇ -C 6 ) alkyl, (C 3 - C ⁇ ) cycloalkyl (Ci-Cg) alkoxy (C x -C 6 ) alkyl, C 6 -C X4 aryl, C 6 -C X4 heteroaryl, (C 6 -C X4 ) heteroaryl (C x -C 6 ) alkyl, (C 5 -C X4 ) aryl (Ci- Cg) alkyl, (C ⁇ -C 14 ) aryl (C ⁇
  • R x3 is selected from the group consisting of
  • R x4 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Ci-Cg alkyl group; said C ⁇ -C ⁇ alkyl group being substituted with one or more hydrogen, halogen, alkyl or phenyl groups ;
  • R i5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, divalent alkali metals, divalent alkali earth metals, and a C x -C 6 alkyl group; said C ⁇ -C 6 alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and C ⁇ -C 3 alkyl; R x € is a bond or is selected from the group consisting of sulfonyl, C 2 -C ⁇ thioalkyl, aminosulfonyl and C x - C 6 alkyl; said C ⁇ -C 6 alkyl being substituted with one or more hydrogen, halogen, C ⁇ -C 6 alkyl or phenyl groups;
  • R i7 is selected from the group consisting of phenyl, phenylalkyl, and a Cj-Cg alkyl group; said C ⁇ -C ⁇ alkyl group being optionally substituted with one or more groups selected from the group consisting of halogen, phenyl, phenylalkyl, and C x -C 3 alkyl; said phenyl and phenylalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C ⁇ -C 6 alkoxy, amino, and C ⁇ -C ⁇ alkyl;
  • R X8 is a bond or is selected from the group consisting of sulfonyl, C 2 -C ⁇ thioalkyl, aminosulfonyl, carbonyl, aminocarbonyl and C ⁇ -C 6 alkyl group, said C ⁇ -C 6 alkyl group being substituted with one or more hydrogen, halogen, Ci-Cg alkyl or phenyl groups;
  • R X9 is selected from the group consisting of hydrogen, phenyl, phenyl (C ⁇ -C 6 ) alkyl, and C x -Cg alkyl; said Ci- Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of phenyl and Ci-C 3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino, and C x -C 6 - alkyl; said phenyl Ci-
  • R 20 is selected from the group consisting of hydrogen, C ⁇ -C 6 alkyl, hydroxy and C ⁇ -C 6 alkoxy; m is 0 or 1; o is 0 or 1; R 2 ⁇ is a bond or is selected from the group consisting C x -C ⁇ alkyl; said C x -C 6 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 C x -C 6 alkyl, halogen, C x -C 6 alkoxy and hydroxy;
  • R 22 is selected from the group consisting of hydrogen, bromine, chlorine, C 2 -C 8 alkoxy, C x -C 8 alkyl, trifluoromethyl, nitro, cyano, carbo C x -C 6 alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, hydroxy, C x -C 6 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl, (C 3 -C ⁇ ) cycloalkyloxy (C x -C ⁇ ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (C x -
  • R 23 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C x -C 8 alkyl, trifluoromethyl, nitro, cyano, carbo C x -C 6 alkoxy, carboxy, C x -C 8 thioalkyl, hydroxy, C 3 -C a cycloalkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C ⁇ ) alkoxy (C x -Cg) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkoxy, (Ci-C 6 ) alkoxy (
  • R 24 is selected from the group consisting of hydrogen, bromine, chlorine, C x -C 8 alkoxy, C x -C 8 alkyl, trifluoromethyl, nitro, cyano, carbo C x -C fi alkoxy, carboxy, C x -C 8 thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C x -Cg) alkyl, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkoxy, (C x -C 6 )
  • R 25 is selected from the group consisting of hydrogen, halogen, C ⁇ -C 8 alkoxy, C x -C 8 alkyl, trifluoromethyl , nitro, cyano, carbo C x -C ⁇ alkoxy, carboxy, C x -C 8 thioalkyl, hydroxy, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C x -C 6 ) alkyl, (C 3 -C e ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkoxy, (C ⁇ -C 6 )
  • R 26 is selected from the group consisting of hydrogen, bromine, chlorine, C 2 -C 8 alkoxy, C X -C B alkyl, trifluoromethyl, nitro, cyano, carbo C x -C ⁇ alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, hydroxy, C x -C ⁇ alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 ) cycloalkyl (C x -C ⁇ ) alkyl, (C 3 -C 8 ) cycloalkyloxy (C x -C ⁇ ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C ⁇ ) alkoxy (C x -C ⁇ ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (C
  • R 27 -R 3 ⁇ are independently selected from the group consisting of hydrogen, halogen, C ⁇ -C 8 alkoxy, C x -C 8 alkyl, trifluoromethyl, nitro, cyano, carbo C x -C 6 alkoxy, carboxy, C x -C 8 thioalkyl, hydroxy, C 3 -C B cycloalkyl, (C 3 -C 8 ) cycloalkyl (Ci-Cg) alkyl, (C 3 -C 8 ) cycloalkyloxy (C x -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl (C x -C 6 ) alkoxy (C ⁇ -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyloxy, (C 3 -C 8 ) cycloalkyl (C ⁇ -C 3 ) alkoxy, (C ⁇ -C
  • X 5 is nitrogen or CR 3 ⁇ ,- wherein at least one of X 3 , ⁇ 4 , or X 5 is nitrogen; wherein up to three of R 2 -R 3X can simultaneously be hydrogen when only one of X 3 -X 5 is nitrogen; or R 28 and CR 30 when taken together form an aryl ring; or R 28 and CR 29 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 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: R x is selected from the group consisting of hydrogen and R X4 COOR X5 ;
  • R 2 is selected from the group consisting of hydrogen, halogen, R X6 OR x7 , R X8 NHR X9 , C 6 -C X4 aryl, (C 6 -C X4 ) aryl C x -C 6 alkyl, C x -C 8 alkyl, and C 3 -C e cycloalkyl; said C 6 -C X4 aryl, and said (C 6 -C X4 ) aryl C x -C 6 alkyl, being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, C x -C 6 alkoxy, C x - C ⁇ alkyl, trihalo (C x -C ⁇ ) alkyl, and trihalo (C x -C ⁇ ) alkoxy; said C x -C 8 alkyl group being optionally substituted with one or more halogen, C
  • R 3 is selected from the group consisting of hydrogen, C ⁇ -C X4 aryl, (C ⁇ -C X4 ) aryl (C x -C ⁇ ) alkyl, and C x -C 8 alkyl group; said C 6 -C X4 aryl, and said (C 6 -C x4 ) aryl (C x -C ⁇ ) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, C x -C 6 alkoxy, C x -C ⁇ alkyl, C 3 -C 8 cycloalkyl, trihalo (C x -C 6 ) alkyl, and trihalo (C x -C 6 ) alkoxy; said C x -C 8 alkyl group being optionally substituted with one or more halogen, C x -C 6 alkyl or phenyl groups; R 8
  • R 22 is selected from the group consisting of hydrogen, bromine, chlorine, C 2 -C 6 alkoxy, C x -C 6 alkyl, nitro, trifluoromethyl, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, Ci-Cg thioalkyl, and hydroxy; said C ⁇ -C 6 alkyl being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C 2 -C 6 alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or C x -C ⁇ alkyl; said carbo (C ⁇ -C 6 ) alkoxy being optionally substituted with halogen or C x -C 3 alkyl; R 23 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C x -C 6 al
  • R 24 is selected from the group consisting of hydrogen, bromine, chlorine, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C ⁇ -C 6 alkyl being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with halogen or C x -C 3 alkyl; said C ⁇ -C 8 thioalkyl being optionally substituted with halogen or C ⁇ -C 8 alkyl; said carbo (C ⁇ -C ⁇ ) alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl;
  • R 25 is selected from the group consisting of hydrogen, halogen, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl, and hydroxy; said C ⁇ -C 6 alkyl being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C ⁇ -C ⁇ alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with halogen or C x -C 3 alkyl; R 26 is selected from the group consisting of hydrogen, bromine, chlorine, C 2 -C 6 alkoxy, C x
  • R 27 is selected from the group consisting of halogen, C ⁇ -C ⁇ alkoxy, C x -C 6 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci ⁇ C 6 ) alkoxy, carboxy, phenyl, C ⁇ -C B thioalkyl, and hydroxy; said C ⁇ -C 6 alkyl being optionally substituted with halogen or C ⁇ -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 8 thioalkyl being optionally substituted with halogen or C x -C 8 alkyl; said carbo (C x -C 6 ) alkoxy being optionally substituted with halogen or C x -C 3 alkyl;
  • R 28 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C ⁇ -C 6 alkyl, nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl, and hydroxy; said C ⁇ -C 6 alkyl being optionally substituted with halogen or C x -C 3 alkyl; said C ⁇ -C ⁇ alkoxy being optionally substituted with halogen or C ⁇ ⁇ C 3 alkyl; said C ⁇ -C 8 thioalkyl being optionally substituted with halogen or C ⁇ -C 8 alkyl; said carbo (C ⁇ -C 6 ) alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl; or R 22 and R 23 when taken together form an aryl ring; or R 23 and R 24 when taken together form an aryl
  • X 5 is nitrogen or CR 3X ; wherein at least one of X 3 , X 4 , or X 5 is nitrogen;
  • R 29 is selected from the group consisting of hydrogen, halogen, C x -C ⁇ alkoxy, C ⁇ -C 6 alkyl, nitro, cyano, carbo (C ⁇ -C 6 ) alkoxy, carboxy, phenyl, C ⁇ -C 8 thioalkyl, and hydroxy; said C x -C 6 alkyl being optionally substituted with one to two halogen atoms or C x -C 3 alkyl; said C ⁇ -C 6 alkoxy being optionally substituted with halogen or C ⁇ -C 3 alkyl;
  • R 30 is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C x -C 6 alkyl, nitro, cyano, carbo (C x -C 6 ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C 6 alkyl being optionally substituted with halogen or C x -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with halogen or C x -C 3 alkyl;
  • R 3X is selected from the group consisting of hydrogen, halogen, C x -C 6 alkoxy, C x -C 6 alkyl, nitro, cyano, carbo (C x -C ⁇ ) alkoxy, carboxy, phenyl, C x -C 8 thioalkyl, and hydroxy; said C x -C ⁇ alkyl being optionally substituted with one to two halogen atoms or C x -C 3 alkyl; said C x -C 6 alkoxy being optionally substituted with halogen or C x -C 3 alkyl; wherein up to three of R 27 -R 3X can simultanoeously be hydrogen when only one of X 3 -X 5 is nitrogen; wherein up to two of R 27 -R 3X can simultaneously be hydrogen when two of X 3 -X 5 are nitrogen; or R 28 and CR 29 when taken together form an aryl ring; or R 28 and CR 30 when taken together form an
  • the invention also relates to a process for the preparation of the compounds of general formulas (XVIa) and (XVIb) .
  • a preparation process according to the invention comprises the reaction of an aromatic amine of general formula (A4) :
  • 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 provide the desired heterocyclic piperazines 9.
  • R 2X- R 28 and X 3 _ X 5 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 Al, thiazole A2 , thiadiazole A3, or thiophene A4 is first acylated with a haloacetyl halide and then condensed with nucleophile 2.
  • R X ,R X3 are defined above in Section 3; Z is bromine or chlorine.
  • the invention provides compounds of formula (I) :
  • Ar and R x -R ⁇ 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 include, but are not limited to, phenyl, ⁇ -naphthyl, S-naphthyl and fluorenyl groups .
  • the C ⁇ -C 8 alkyl groups may be linear or branched, and include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups.
  • the C ⁇ -C 8 alkoxy groups may likewise be linear or branched, and include, 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 compounds of general formula (I) .
  • the compounds of general formula (I) have a carboxylic acid functional group and may be salified, i . e . , converted into conjugate bases they then being in the form of salts with bases.
  • salts with bases of the compounds 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 compounds of general formula (I) can also be salified with amines in order to form pharmaceutically acceptable salts.
  • amines in order to form pharmaceutically acceptable salts.
  • the compounds of general formula (I) can be salified with glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.
  • the compounds of general formula (I) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids.
  • salts with acids of the compounds 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 .
  • 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 .
  • 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 compounds of general formula (I) .
  • a process of preparation according to the invention comprises reacting an aromatic amine of general formula (II) :
  • 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) :
  • the compounds of formula (V) are known compounds. They can be synthesized according to the procedure described by V. Prelog and Z. Blazek in Collection Czechloslov. Chem.
  • the compound (VI) in which R 7 is an alkyl group, can be hydrolyzed in the presence of a basic agent such as dilute sodium hydroxide.
  • a basic agent such as dilute sodium hydroxide.
  • the enantiomers of the compounds 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.
  • aryl groups include, but are not limited to, phenyl, -naphthyl, j ⁇ -naphthyl and fluorenyl groups.
  • the C X -C B alkyl groups can be linear or branched, and include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups.
  • Ci-C 8 alkoxy groups can like likewise be linear or branched, and include, 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 R x , R 2 and R 3 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 compounds of general formula (VII) .
  • the compounds of general formula (VII) possess a carboxylic acid functional group and can be salified, i.e., converted into conjugate bases they then being in the form of salts with bases.
  • salts with bases of the compounds 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 compounds of general formula (VII) can also be salified with amines in order to form pharmaceutically acceptable salts.
  • the compounds of general formula (VII) could be salified with glucamine, N- methylglucamine, N,N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.
  • the compounds of general formula (VII) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids.
  • salts with acids of the compounds 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 compounds of general formula (VII) .
  • a preparation process according to the invention comprises the reaction of an aromatic amine of general formula (VIII) :
  • the compound of general formula (XII) can be hydrolysed by conventional acidic or basic means in order to give the compound of general formula (VII) .
  • 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 compounds of Formulae (VIII) and (XI) are known compounds or can be prepared according to known processes.
  • the compounds 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) .
  • the compound (XII) in which R 7 is an alkyl group, can by hydrolysed in the presence of a basic agent, such as dilute sodium hydroxide.
  • the enantiomers of the compounds of formula (VII) can be separated by successive recrystallization of the salt of the 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.
  • solvents such as acetone, ethyl acetate or isopropanol
  • the invention further provides compounds, useful as hypoglycemic agents, of general formula (Xllla) :
  • compositions comprising a compound of formula (Xlllb) 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 (Xlllb) having the structure:
  • R x -R 4 , R 8 -R x3 , 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 compounds of general formula (Xllla) and (Xlllb) .
  • the compounds of general formula (XIIla) and (Xlllb) which may possess a carboxylic acid functional group can be salified, i.e., converted into conjugate bases they then being in the form of salts with bases.
  • salts with bases of the compounds of general formula (XIIla) and (XIIlb) include the pharmacologically acceptable salts, such as the sodium salts, potassium salts, calcium salts and other salts of the same type.
  • the compounds of general formula (Xllla) and (Xlllb) which possess a carboxyllic acid functional group can also be salified with amines in order to form pharmaceutically acceptable salts.
  • the compounds of general formula (Xllla) and (Xlllb) could be salified with glucamine, N-methylglucamine, N,N- dimethylglucamine, ethanolamine, morpholine, N- methylmorpholine or lysine.
  • the compounds of general formulas (Xllla) and (Xlllb) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids.
  • salts with acids of the compounds of general formulas (Xllla) and (Xlllb) 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 .
  • a preparation process according to the invention comprises the reaction of an aromatic amine of general formula (Al) :
  • Murayama M. [Murayama, M. , Inoue, S., Ohata, K. , Tsutsui, S. 25 JP 48076866; Murayama, M. , Inoue, S., Ohata, K. , Sugawara, Y,
  • the compounds of formula (XVIII) can be prepared as 35 described by R. Ratouis et al . (J. Med. Chem., 8, 104, 1965) or by Prelog et al . (Collection Czechoslov. Chem. Communications, 6, 211, 1934). Compounds of formula (XVIII) can also be made according to the following methods:
  • M. Dukat [M. Dukat, A.A. Abdel-Rahman, A.M.
  • the invention further provides compounds, useful as hypoglycemic agents, of general formulas (XlVa) and (XlVb) :
  • compositions comprising a compound of formula (XlVb) 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 (XlVb) having the structure:
  • the compounds of general formulas (XlVa) and (XlVb) may possess a carboxylic acid functional group and can be salified, i.e., converted into conjugate bases they then being in the form of salts with bases.
  • Examples of salts with bases of the compounds of general formulas (XlVa) and (XlVb) include the pharmacologically acceptable salts, such as the sodium salts, potassium salts, calcium salts and other salts of the same type.
  • the compounds of general formulas (XlVa) and (XlVb) which possess a carboxyllic acid functional group may also be salified with amines in order to form pharmaceutically acceptable salts.
  • the compounds of general formulas (XlVa) and (XlVb) could be salified with glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.
  • the compounds of general formulas (XlVa) and (XlVb) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids.
  • salts with acids of the compounds of general formulas (XlVa) and (XlVb) 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 compounds of general formulas (XlVa) and (XlVb) .
  • a preparation process according to the invention comprises the reaction of an aromatic amine of general formula (A2) :
  • 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.
  • the compounds 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).
  • 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:
  • the invention also relates to the tautomeric forms and to the enantiomers, diastereoisomers and epimers of the compounds of general formulas (XVa) and (XVb) .
  • the compounds of general formulas (XVa) and (XVb) may possess a carboxylic acid functional group and can be salified, i . e . , converted into conjugate bases they then being in the form of salts with bases.
  • salts with bases of the compounds 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 compounds of general formulas (XVa) and (XVb) which possess a carboxylic acid functional group may also be salified with amines in order to form pharmaceutically acceptable salts.
  • the compounds of general formulas (XVa) and (XVb) could be salified with glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.
  • the compounds of general formulas (XVa) and (XVb) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids.
  • salts with acids of the compounds 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 .
  • the invention also relates to a process for the preparation of the compounds of general formulas (XVa) and (XVb) .
  • a preparation process according to the invention comprises the reaction of an aromatic amine of general formula (A3) :
  • Thiadiazoles can be prepared according to A.W.
  • 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, 1997]; N.K. Srivastava [N.K. Srivastava, P.K.
  • Thiadiazoles can also be prepared according to E. Akerblom [E. Akerblom, Acta. Chem. Scand. 18, 174-184
  • 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.
  • the compounds 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).
  • Compounds 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.
  • R ⁇ R 3 , R 8 -R ⁇ 3 , m and o are as defined above for formula (XVIa) , or pharmaceutically acceptable salts or compounds having a tautomeric structure thereof.
  • 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 :
  • Ri-R 3 , R B -R 13 , m and o are as defined above for formula (XVIb) , or pharmaceutically acceptable salts or compounds having a tautomeric structure thereof .
  • the invention also relates to the tautomeric forms and to the enantiomers, diastereoisomers and epimers of the compounds of general formulas (XVIa) and (XVIb) .
  • the compounds of general formulas (XVIa) and (XVIb) may possess a carboxylic acid functional group and. can be salified, i.e., converted into conjugate bases they then being in the form of salts with bases.
  • salts with bases of the compounds 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 compounds of general formulas (XVIa) and (XVIb) which possess a carboxylic acid functional group may also be salified with amines in order to form pharmaceutically acceptable salts.
  • the compounds of general formulas (XVIa) and (XVIb) could be salified with glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.
  • the compounds of general formulas (XVIa) and (XVIb) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids.
  • salts with acids of the compounds 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 .
  • the invention also relates to a process for the preparation of the compounds of general formulas (XVIa) and (XVIb) .
  • a preparation process according to the invention comprises the reaction of an aromatic amine of general formula (A4) :
  • Thiophene acids can be prepared according to the method of 0. Dann [0. Dann, Chem. Ber., 1943, 76, 419]; R. B. Woodward [R.B. Woodward, R.H. Eastman, 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.
  • the compounds 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) .
  • piperazine thiocycle compounds (XVI) described in Sections 4.3-4.6 are collectively known as "piperazine thiocycle compounds.”
  • the piperazine thiocycle compounds of the present invention may be prepared according to general scheme shown in Figures 1 and 2.
  • piperazine derivatives 4 or 5 can be prepared from optionally substituted anilines 1 or 5 heterocyclic amines 2.
  • the general procedure outlined in Figure 1 of equation 1 has been modified from previously described procedures known to synthesize the substituted piperazines [(1) Prelog, V.; Driza, G.J. Sur la N- phenylpiperazine. Collect . Czech . Chem . Commun . 1933, 5, 10 497].
  • 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.
  • Equation 2 of Figure 1 shows a preparation of substituted piperazines 9 using modified 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 20 Boc-, Fmoc, Formyl, or benzyl protected piperazine in a polar solvent (e.g. CH 3 CN) at an elevated temperature or room temperature provide the piperazines 8.
  • a polar solvent e.g. CH 3 CN
  • Figure 2 illustrates a general preparation of 25 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 30 of DMF and dioxane to provide haloacylheterocycles 1 with optionally substituted 2 provides the piperazine derivatives 4.
  • the piperazine derivatives of the present invention are useful in veterinary and human medicine for lowering the blood glucose level in a mammal.
  • the piperazine derivatives 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.)
  • 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.
  • the piperazine derivatives are useful as antihyperglycemic agents for rare congenital metabolic glycogen storage disease associated with hyperglycemia.
  • IDDM insulin-dependent
  • NIDDM non-insulin-dependent
  • type II diabetes originally termed adult-onset diabetes
  • the piperazine derivatives 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.
  • a physiologically acceptable carrier such as water, an aqueous solution, normal saline, or other physiologically acceptable excipient.
  • the dosage of such pharmaceutical composition ranges from about 10-2000 mg/kg/day, preferably about 10-250 g/kg/day.
  • the actual dosage 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.
  • 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.
  • 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 acetzohexamide , chlorpropamide, tolazamide, tolbutamide, glyburide, glypizide or glyclazide; a thiazolidinedione such as troglitazone or ciglitazone; an ⁇ -glycosidase inhibitor such as acarbose or miglatol; an ⁇ 2 - adrenergic antagonist such as midaglizole, or a 3 3 -adrenergic receptor agonist such as CL-316,243, LY 104119, Ro 40-2148, etc.
  • another antihyperglycemic agent including such as insulin; a biguanide such as metformin or buformin; a sulfonylurea such as
  • 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 tablets, sugar-coated tablets, 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 emulsion or a water-in-oil liquid emulsion and as a bolus, etc.
  • discrete units such as capsules, gelatin capsules, cachets, pills, suppositories or rectal capsules, plain or coated tablets, sugar-coated tablets, each containing a predetermined amount of the piperazine derivative (s) ; in multidose vials; as a powder or granules
  • excipients which are suitable for such administrations are cellulose derivatives or microcrystalline cellulose, alkaline-earth metal carbonates, magnesium phosphate, starches, modified starches, and lactose of the solid forms.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed 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.
  • 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.
  • 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 include aqueous or oily solutions of the piperazine derivative (s) .
  • 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.
  • water, aqueous solutions, physiological saline or isotonic solutions are the vehicles most conveniently used.
  • 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) .
  • 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 compounds 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.
  • 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.
  • the piperazine derivatives of the present invention are used in mammals to lower abnormally high glucose levels to normal levels of blood glucose.
  • reaction 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.
  • Example 2 The following illustrative compounds of the general formula (I) , shown below in Table 1, were synthesized according to the above-described methods: TABLE I
  • the apparatus was placed under a hydrogen atmosphere and agitated at room temperature for 3 hours.
  • Example 4 The formulae and characteristics of the compounds of formula (VIII) have been combined in Table II. 5
  • the reaction 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 acidified with acetic acid.
  • the reaction mixture was kept stirring for 48 hours at room temperature .
  • the thiocyanate (2.5 g, 11.25 mmol) was refluxed with 25 mL of IN HCl. The mixture was cooled to rt , 35 cone. HCl (12.5 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 suspended with CHC1 3 , washed with 5% Na 2 C0 3 and then the separated aqueous layer was extracted several times with CHC1 3 .
  • Example 15A Preparation of 2- ( (Bromoacetyl) amino) -6-fluorobenzothiazole Bromoacetyl bromide (6 g, 2.6 mL, 30 mmol) was added 0 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 reaction mixture at 5 °C. After stirring at 5 °C for 1 h, the ice bath was removed and the reaction mixture was stirred at rt for 7 h.
  • Example 20A Preparation of 2- ( (Bromoacetyl) amino) -6-methoxybenzothiazole
  • 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 L) while keeping the internal temperature of the reaction mixture at 5 °C. After stirring at 5 °C for 1 h, the ice bath was removed and the reaction mixture was stirred for 7 h.
  • the milky suspension was allowed to " stand overnight and then extracted with EtOAc (3 x 30 mL) .
  • EtOAc 3 x 30 mL
  • the combined EtOAc layer was washed with water, brine, dried (Na 2 S0 4 ) , 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.
  • 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 internal temperature of the reaction mixture at 5 °C. After stirring at 5 °C for 1 h, the ice bath was removed and the reaction mixture was stirred for 20 h.
  • the reaction mixture was heated and stirred at 70 °C 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 (NaS0 4 ) , filtered, concentrated to small volume, and then treated with hexane, causing a light beige precipitate to form.
  • EtOAc layer was washed sequentially with brine and water, dried over Na 2 S0 4 , filtered, and then concentrated. The ensuing brown oil was dissolved in a small amount of EtOAc and treated with hexane, causing a light beige color precipitate to form.
  • Example 59A Preparation of 2- ( (Bromoacetyl) amino) -5-cvclopropyl-l, 3.4- thiadiazole
  • 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 .
  • Example 60A Preparation of 2- ( (Bromoacetyl) amino) -5- (ethoxycarbonylmethylthio) -1,3 , 4-thiadiazole
  • 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 °C.
  • Bromoacetyl bromide (2.76 g, 13.68 mmol) was added dropwise, keeping the internal temperature between 0 and 5 °C, and the solution was stirred for 3 h.
  • glyoxalic acid thio ⁇ emicarbazone To a suspen ⁇ ion of thiosemicarbazide (10 g, 110 mmol) in 80% of EtOH (150 mL) was added glyoxalic acid monohydrate (11 g, 119 mmol) in 80% of EtOH (50 mL) at 70 °C in one portion. When 30 glyoxalic acid monohydrate was added, the reaction mixture turned to clear and then became cloudy again. The reaction was stirred for 1.5 h at this temperature, and then cooled to rt .
  • Method B To a suspension of methylglyoxalate thiosemicarbazone (500 mg, 2.82 mmol) in toluene (50 mL) was added MeS0 3 H (0.27 mL, 406 mg, 4.24 mmol) dropwise at 0 °C. The su ⁇ pension became a sticky white solid which piled up at the bottom of the flask. The resulting mixture was stirred at 70 °C for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was suspended in MeOH. Concentrated NH 4 OH was added to the suspension to basify the mixture.

Abstract

Piperazine derivatives useful as antihyperglycemic agents, pharmaceutical compositions comprising the piperazine derivatives and methods for their use are described. The piperazine derivatives are useful for the treatment of insulin-dependent diabetes mellitus (IDDM or Type I) and non-insulin dependent diabetes mellitus (NIDDM or Type II).

Description

PIPERAZINE DERIVATIVES USEFUL AS HYPOGLYCEMTC AGENTS
1. FIELD OF THE INVENTION
The present invention relates to new piperazine derivatives which are useful as hypoglycemic agents and useful for the treatment of diabetes; pharmaceutical compositions comprising the piperazine derivatives; and methods for using the same.
2. BACKGROUND OF THE INVENTION
The following piperazine derivatives have been reported: U.S. patent 5,607,936 and International Publication WO 96/10568 discloses piperazine derivatives 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 α1A 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 Al 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 1- [β- (Aroylamino) ethyl] -4-benzylpiperazines and 1- t tarylamino) carbonyl] ethyl] -4-benzylpiperazines . Saxena, M.J.; Med. Chem. 33:2970 (1990). Aryl piperazines were used to synthesize 1- [arylpiperazine] alkyl] carbonyll-ar-4-yl. Gizur, T., et al . , Λfed. Chem . Res . 3:545 (1993). N-[(4-aryl- 1-piperazinyl-alkyl] -substituted imides. Anzini, M., et al . , Med . Chem. Res . 3:249 (1993). 4-benzyl-l- [2- (4- fluorobenzamido) ethyl] piperazine to synthesize a l-[2-(4- fluorobenzamindo) -1 ' -ethyl] piperazine. Ahmad, Y.E., et al., J. Med. 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 reported:
Perrissenin, M. , et al . , Eur. 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 compounds 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 compounds useful as pharmacophoric components in medicinal chemistry. Zhang, M. , et al . , Bioorganic & Medicinal Chemistry Letters 7(13):1629 (1997). Another example, 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-l- 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 reported 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 reported to be inhibitors of H. Pylori. Kojimia, K. , et al . , Bioorganic & Medicinal Chemistry Letters 6(15):1795 (1996). Thiophenesulfonamide-based compounds have been reported 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 compounds 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- [β- (aroylamino) ethyl] -4-benzylpiperazines and 1- [ [arylamino) carbonyl] ethyl] -4-benzylpiperazines . Saxena, M. , J. Med. Chem. 33:2970 (1990). Aryl piperazines were used to synthesize 1- [arylpiperazine] alkyl] carbonyl1-ar-4-yl. Gizur, T., et al., Med. Chem . Res . 3:545 (1993). N- [ (4-aryl-l- piperazinyalkyl] -substituted imides . Ahmad, Y.E., et al . , J". Med. Chem. 40:952 (1997); 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) .
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 compounds having antibacterial activity. See also T. Kanai et al . , Bull- Chem. Soc. Jpn . 6:2335 (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-l, 3, 4-thiadiazol-5-ylacetic acid); D. Spinelli et al., J". Heterocyclic Chem. 14:309 (1977) (studies on the decarboxylation reaction 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 compounds have been alleged to exhibit anti-hyperglycemic activity. These include sulfonyl ureas (GB 1,212,695, GB 1,139,856, GB 965,368, GB 896,455, and Australian Patent Specification No. 37,624/68m); benzenesulfonyl semicarbazides (GB 110,645, GB 1,038,379, GB 1,137,380, FR 1,519,798, Australian Patent Specification No. 32292/68 (l-substituted-4-arylsulfonylsemicarbazide) ) ; sulfonyls (GB 1,353,511 (sulfamoylpyridines and substituted sulfonamides) , GB 1,292,661, U.S. 3,621,026
(sulfonylaminopyridine derivatives) ; oxazolyl alkyl- heterocycles (U.S. 5,239,080); thizolidine and pyrrolidine compounds (U.S. 4,499,102 and EP 031 104 Bl) ; 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 Bl disclose thiazolidine and pyrrolidine compounds 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 compounds, compositions comprising the compounds, 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 compounds of formula (I) :
Figure imgf000008_0001
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 Ci-Cg alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C^Cg) alkyl, Cj-C,, alkoxy, (C3-C8) cycloalkyloxy (C^Cg) alkyl, (C3-C8) cycloalkyl (C^Cg) alkoxy (Ci-Cg) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (C^Cg) alkoxy, (Ci-Cg) alkoxy (Cx-Cβ) alkyl, (C6-C14) aryl, (Cβ-C14) heteroaryl, (C6-C14) heteroaryl (C^Cg) alkyl, (C6-C14) aryl (Cx- C6) alkyl, (C6-C14) aryl
Figure imgf000008_0002
alkyl (C6-C14) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (Ci-Cg) alkyl, (C6-C14) aryl (C^Cg) alkyloxy, (C6-C14) aryl (Cj-Cg) alkyloxy (Cx-Cg) alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, amino, carboxyl,
Figure imgf000008_0003
alkoxycarbonyl , carbamoyl, (Ci-Cg) alkylthio, (C^Ca) alkylsulphinyl, (C^Cf,) alkylsulphonyl, sulphoamino, (C1-C8) alkylsulphonylamino, sulphamoyl and (Cx- C8) alkylcarbonylamino, or two of these substituents forming a methylenedioxy group; Rx, R2 and R3 are selected, independently of each other, from the group consisting of: hydrogen, C^-Cg alkyl, (C^Cg) alkoxy (C^Cg) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl, (C3-C8) cycloalkyloxy (Ci-Cg) alkyl, (C3-C8) cycloalkyl (C^Cg) - alkoxy (C^Cg) alkyl, C6-C14 aryl, C6-C14 heteroaryl, (C6-C14) heteroaryl
Figure imgf000009_0001
alkyl, (C6-C14) aryl
Figure imgf000009_0002
alkyl (Cx-Cg) aryl, (C6-C14) aryl (C^Cg) alkoxy (C^Cg) alkyl, and (C6-C14) aryloxy
Figure imgf000009_0003
alkyl, or alternatively Rx forms with the nitrogen atom to which Rx is attached 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, C3-C8 cycloalkyl, C^Cg alkyl, (C3-C8) cycloalkyl (C^Cg) alkyl, Ci-Cg alkoxy, (C3-C8) cycloalkyloxy (C^Cg) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (C^Cg) alkoxy, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (Cj-Cg) alkyl, (Ci-Cg) alkoxy (C^Cg) alkyl, C6-C14 aryl, (C6-C14) aryl (C^Cg) alkyl, (C6-C14) aryl (C^Cg) alkyl (C6-C14) aryl, (C6-C14) aryloxy, (C6- C14) aryloxy
Figure imgf000009_0004
alkyl, (C6-C14) aryl
Figure imgf000009_0005
alkoxy, (C6-C14) aryl (Ci-Cg) alkyloxy (Ci-Cg) alkyl, halogen, trifluoromethyl , trifluoromethoxy, cyano, carboxyl , hydroxyl, nitro, amino (C2- C6) alkoxycarbonyl , carbamoyl, (Cx-C8) alkylthio, (Ci-Cg) alkysulphinyl ,
Figure imgf000009_0006
alkylsulphonylamino, sulphamoyl and (Ci-Cg) 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 Ci-Cg alkyl, C^Cg alkoxy, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro and amino; their solvates and their pharmaceutically acceptable salts, which are useful as hypoglycemic agents.
Among the compounds of general formula (I) according to the invention, there may be mentioned more particularly, as preferred compounds: 4- {4- [2 (N-isopropyl-N-phenylamino) -2-oxoethyl] -1- piperazinyl}benzoic acid; 4- {4- [2- (N- [2,6-dimethylphenyl]amino) -2-oxoethyl] - l-piperazinyl}benzoic acid; and
4- {4- [2- (N- [2, 6-diisopropylphenyl] amino) -2- oxoethyl] -l-piperazinyl}benzoic 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 compounds of general formula (I) , the process comprising the steps of:
(a) reacting an aromatic amine of general formula (ID :
A\ /H (II)
in which Ar and Rx are as defined above for general formula I, with a haloacyl halide of general formula (III) :
Figure imgf000010_0001
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) :
Figure imgf000011_0001
(b) reacting the compound of general formula (IV) with a compound of general formula (V) :
Figure imgf000011_0002
in which R4, R5 and R6 are as defined as above for general formula I, and R7 is a hydrogen atom or a C^Cg alkyl group, in the presence of a basic agent such as triethylamine in order to form the compound of general formula (VI) :
Figure imgf000011_0003
(VI) ; and
(c) in which aryl and Ri-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 compounds of general formula (VII) :
Figure imgf000012_0001
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 C^Cg alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl
Figure imgf000012_0002
alkoxy, (C3-C8) cycloalkyloxy (C^Cg) alkyl, (C3-C8) cycloalkyl (C^Cg) alkoxy (Ci-Cg) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cj-C8) alkoxy,
Figure imgf000012_0003
alkoxy (Ci-Cg) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl
Figure imgf000012_0004
C6) alkyl, (C6-C14) aryl (C^Cg) alkyl (C6-C14) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy
Figure imgf000012_0005
alkyl, (C6-C14) aryl
Figure imgf000012_0006
alkyloxy, (C6-C14) aryl (C^Cg) alkyloxy (C^Cg) alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, amino, carboxyl, (Ci-Cg) alkoxycarbonyl , carbamoyl, (Cx-C8) alkylthio,
Figure imgf000012_0007
alkylsulphinyl, (d-C8) alkylsulphonyl, sulphoamino, (Ci-Cg) alkylsulphonylamino, sulphamoyl and (C^- 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;
Rx , R2, and R3 are selected, independently of one another from: hydrogen, Cj-Ca alkyl (Ci-Cg) alkoxy (Ci-Cg) alkyl group; a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C^Cg) alkyl, (C3-C8) cycloalkyloxy (Ci-Cg) alkyl, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (Ci-Cg) alkyl, Cg-Cι4 aryl, C6-Cι4 heteroaryl, (C6-C14) heteroaryl (Ci-Cg) alkyl, (C6-C14) aryl (Ci-Cg) alkyl, (Cβ-C14) aryl (Ci-C6) alkyl (C6-C14) aryl, (C6-C14) aryl (Cι-C6) alkoxy (Cι-C6) alkyl and (C6-Cι4) aryloxy (Cι-C6) alkyl;
A, B, C and D are =CH- groups, or one 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, Ci-C8 alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (Ci-C6) alkyl, Ci~C8 alkoxy, (C3-C„) cycloalkyloxy (Ci-Cg) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cι-C6) alkoxy, (C3-C8) cycloalkyl (Ci-C6) alkoxy (Cι-C6) alkyl, (Ci-C6) alkoxy (C^Cg) alkyl, C6-C14 aryl, (C6-C14) aryl (C^Cg) alkyl, (C6-C14) aryl (C^Cg) alkyl (Cg-Cι4) aryl, (C6-C14) aryloxy, (C6- C14) aryloxy (Ci-C6) alkyl, (C6-C14) aryl (Ci-C6) alkoxy, (Cε-C14) aryl (Cι-C6) alkyloxy (C^Cg) alkyl, halogen, trifluoromethyl , trifluoromethoxy, cyano, carboxyl, hydroxyl, nitro, amino (Ci- Cg) alkoxycarbonyl , carbamoyl, (Ci-C8) alkylthio, (Cι-C8) alkysulphinyl , (Cι-C8) alkylsulphonyl, sulphoamino, (Cι-C8) alkylsulphonylamino, sulphamoyl, and (Ci-C8) alkycarbonylamino, two of these groups optionally joined to form a methylenedioxy group or a phenyl ring condensed with the ring to which they are attached, each (C6-Cι4) aryl or aryloxy group being optionally substituted with 1 to 3 substituents selected from Ci-C8 alkyl, Cι-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 compounds of general formula (VII) . A preparation process according to the invention comprises the reaction of an aromatic amine of general formula (VIII) :
Figure imgf000014_0001
(VIII) in which A, B, C, D, Rlf R4, R5 and R6 are as defined above for general formula VII and R7 is a hydrogen atom, a Ci~ C6 alkyl group or a benzyl group, with a haloacyl halide of general formula (IX) :
Figure imgf000014_0002
(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) ;
Figure imgf000014_0003
(X) in which A, B, C, D, Rx , R2, R3, R4, Rs, R6, R7 and Hal are as defined above for general formula (VII) ; and the reaction of the compound of general formula (X) with a compound of general formula (XI) :
Figure imgf000015_0001
(XI) in which Ar is a defined above for general formula (VII), in the presence of a basic agent, such as triethylamine, in order to form the compound of general formula (XII) :
Figure imgf000015_0002
(XII) in which Ar, A, B, C, D, Rx, R2, R3, R4, R5, R6 and R, are as defined above for general formula (VII) . In the case where R7 is an alkyl group, the compound of general formula (XII) can be hydrolysed 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 compounds of formula (VIII) and (XI) are known compounds or can be prepared according to known processes . Thus, compounds of formula (VIII) are described in
Organic Preparation and Procedures International, 13, 189 (1981) . The compounds of formula (V) are known compounds. 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- (1- piperazinyl)benzote.
The invention further provides compounds, as well as compositions comprising said compounds, useful as hypoglycemic agents, of general formula (XIIla) :
Figure imgf000016_0001
(XHIa) wherein :
Ri is selected from the group consisting of hydrogen, halogen, RigOR17, Rι8NHR19, Rι4COOR15,
Figure imgf000016_0002
alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cι-C6) alkyl, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (Cι-C6) alkyl, (C6-C14) aryl, (Cg-C^) heteroaryl, (C6-Cι4) heteroaryl
Figure imgf000016_0003
alkyl, (C6-C14) aryl (Ci-C6) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl (Cε-C14) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, carbamoyl, (Cx-C8) alkylthio, (Cι-C8) alkylsulphinyl, (Cι-C8) alkylsulphonyl, (Ci-C8) alkylsulphonylamino, sulphamoyl or (Cι-C8) alkylcarbonylamino; said Ci-Cg alkyl and C3-Cβ cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, Ci-Cβ alkyl and phenyl; said C6- C14 aryl, (C6-Cι4) aryl (Cι-C6 alkyl) ,' C6-Cι4 heteroaryl, and (C6- C14) heteroaryl (Ci-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Ci-C6 alkyl;
R2 is selected from the group consisting of hydrogen, halogen, R16OR17 , R18NHRι9 , Rι4COOR15 , Cι-C8 alkyl , C3-Ce cycloalkyl, (C3-C8) cycloalkyl (Ci-C6) alkyl, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (Cx-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl (Ci-C6) alkyl, (C6-C14) aryl (Ci-Cg) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl (C6-C14) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (Ci-C8) alkylthio, (Cι-C8) alkylsulphinyl, (Cι-C8) alkylsulphonyl, (Ci-C8) alkylsulphonylamino, sulphamoyl and (Ci-C8) alkylcarbonylamino; said Ci-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-Cg alkyl and phenyl; said Cg-C14 aryl, (C6-C14) aryl (C^Cg alkyl) , C6-Cι4 heteroaryl, and (C6-Cι4) heteroaryl
Figure imgf000017_0001
alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Ci-C6 alkyl;
R3 is selected from the group consisting of hydrogen, halogen, R16ORι7, R18NHRι9, R14COORι5, Ci-C8 alkyl, (C3- C8) cycloalkyl (Cι-C6) alkoxy (Ci-C6) alkyl, (C6-C14) aryl, (C6- C14) heteroaryl, (C6-C14) heteroaryl (Cι-C6) alkyl, (C6-Cι4) aryl (Ci-Cg) alkyl, (C6-C14) aryl (Cj-Cg) alkyl (C6-C14) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (Cι-C8) alkylthio, (Ci-C8) alkylsulphinyl, (Cι-C8) alkylsulphonyl, (Ci- C8) alkylsulphonylamino, sulphamoyl and (Ci-C8) alkylcarbonylamino; said Ci-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Cj-Cg alkyl and phenyl; said C6-C14 aryl, (C6-C14) aryl (Cι-C6 alkyl) , C6-C14 heteroaryl, and (C6-C14) heteroaryl (C^Cg) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and C^Cg alkyl;
R4 is selected from the group consisting of hydrogen, halogen, R16ORι7, R18NHRι9, R14COOR15, Cι-C8 alkyl, (C3- C8) cycloalkyl (Cι-Cβ) alkoxy (Cι-C6) alkyl, (C6-C14) aryl, (C6- Ci4) heteroaryl, (C6-C14) heteroaryl (Cι-C6) alkyl, (Cg-C^) aryl (Ci-Cg) alkyl, (C6-C14) aryl (Cι-C6) alkyl (C6-C14) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (Cι-C8) alkylthio, (Cι-C8) alkylsulphinyl, (Ci-C8) alkylsulphonyl, (Cι~ C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said Ci-C8 alkyl and -C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-Cg alkyl and phenyl; said C6-Cι4 aryl, (C6-Cι4) aryl (Cι-C6 alkyl) , C6-C14 heteroaryl, and (Cg-C^) heteroaryl (Cι~C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cj-Cg 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 (Cι-C6) alkyl;
R9 selected from the group consisting of hydrogen, Ci-C8 alkyl, (Cι-C6) alkoxy (Cι-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cι-C6) alkyl, (C3-C8) cycloalkyloxy (Cι-Cfi) alkyl, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (Cι-C6) alkyl, C6-Cι4 aryl, Cg-C^ heteroaryl, (C6- Cx4) heteroaryl (Cι-C6) alkyl, (C6-C14) aryl (Cι-C6) alkyl, (C6- C14) aryl (Cι-Cβ) alkyl (Cι-C6) aryl, (C6-C14) aryl (Cx-Cg) alkoxy (Ci-Cg) alkyl and (C6-C14) aryloxy (Ci-Cg) alkyl;
Rio is selected from the group consisting of hydrogen, Cι~C8 alkyl, (Cι-C6) alkoxy (Cι-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C^Cg) alkyl, (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3-C8) cycloalkyl (Cι-C6) alkoxy (C^Cg) alkyl, C6-Cι4 aryl, C6- C14 heteroaryl, (C6-Cι4) heteroaryl (Cι-C6) alkyl, (C6-Cι4) aryl (Ci-Cg) alkyl, (C6-C14) aryl (Cι-C6) alkyl (Ci-C6) aryl, (Cε-C14) aryl (Cι-C6) alkoxy (Cι-C6) alkyl and (C6-Cι4) aryloxy (Cj-Cg) alkyl;
Rii is selected from the group consisting of hydrogen, Cι-C8 alkyl, (Cι-C6) alkoxy (Cι-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C^Cg) alkyl, (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3-Cβ) cycloalkyl (Ci-C6) alkoxy (Cι-C6) alkyl, C6-Cι4 aryl, C6- C14 heteroaryl, (C6-C14) heteroaryl (Cι-C6) alkyl, (C6-C14) aryl (Ci-Cg) alkyl, (C6-C14) aryl (ClTC6) alkyl (Ci-C6) aryl, (C6-c14) aryl (C^Cg) alkoxy (Cι-C6) alkyl and (C6-C14) aryloxy (Cι-C6) alkyl ;
Ri2 is selected from the group consisting of hydrogen and Cι-C6 alkyl; Ri3 is selected from the group consisting of
Figure imgf000019_0001
R14 is a bond or is selected from the 'group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Ci-Cg alkyl; said Cι-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Cι-C6 alkyl and phenyl; R15 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and C - C6 alkyl; said Ci-Cfi alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl and Ci-C3 alkyl;
R16 is a bond or is selected from the group consisting of sulfonyl, Cι-C8 thioalkyl, aminosulfonyl and Ci- Cg alkyl group; said C^Cg alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Cι-C6 alkyl and phenyl;
Ri7 is selected from the group consisting of Ci-C6 alkyl, C3-C8 cycloalkyl, C6-Cι4 aryl, (Cg-CX4) aryl (Cι-Cfi) alkyl; said Cι-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, phenyl, phenylalkyl and Cι~C3 alkyl; said C3-C6 cycloalkyl group being optionally substituted with Ci-C3 alkyl;
R1B is a bond or is selected from the group consisting of sulfonyl, Ci-C8 thioalkyl, aminosulfonyl, carbonyl, aminocarbonyl and Ci-C6 alkyl, said
Figure imgf000020_0001
alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Ci-Cg alkyl and phenyl ; Ri9 is selected from the group consisting of hydrogen, phenyl, phenylalkyl, and C^Cg alkyl; said C^Cg alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl and Cι-C3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino and Ci-C6 alkyl; said phenylalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino and Cι-C6 alkyl; R20 is selected from the group consisting of hydrogen, Ci-C16 alkyl, hydroxy and Cι-C6 alkoxy; m is 0 or 1; o is 0 or 1;
R2ι is a bond or Cι-C6 alkyl; said Ci-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 Cι-C3 alkyl, halogen, Ci-Cg alkoxy and hydroxy; R22~R 3i are independently selected from the group consisting of hydrogen, halogen, Cι-C8 alkoxy, Ci-C8 alkyl, trifluoromethyl , nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, Cι~C8 thioalkyl hydroxy (C3-C8) cycloalkyl, (C3-C8) cycloalkyl, (Ci-Cg) alkyl, Cι-C8 alkoxy, (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3-C8) cycloalkyl (C^Cg) alkoxy (C^Cg) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl
Figure imgf000020_0002
alkoxy, (Ci-Cg) alkoxy (Ci-Cg) alkyl, (C6-Cι4) aryl, (Cg-C^) heteroaryl, (C6-C14) heteroaryl (Cι-C6) alkyl, (C6-Cι4) aryl (Ci-C6) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl (C6-C14) aryl, (C6-Cι4) aryloxy, (Cε-Cι4) aryloxy (Cj-Cg) alkyl, (C6-Cι4) aryl
Figure imgf000020_0003
alkyloxy, (C6-C14) aryl (Ci-C6) alkyloxy (Ci-C6) alkyl trifluoromethoxy, amino, carbamoyl, (Ci-C8) alkylthio, (Cι-Ce) alkylsulphinyl, (Cι-C8) alkylsulphonyl, sulphoamino, (Cι-C8) alkylsulphonylamino, sulphamoyl or (Cι-Cβ) alkylcarbonylamino; said (Cι-C8) alkyl being optionally substituted with one or more constituents selected from the group consisting of halogen and Cι-C3 alkyl; said C2-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι~C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with one or more constituents selected from the group consisting of halogen and Cι-C8 alkyl; said carbo (Ci-C6) alkoxy being optionally substituted with one or more constituents selected from the group consisting of halogen and Cj-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; Xs is nitrogen or CR3i; wherein at least one of X3, X4, or X5 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
(Xllla) 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 (Xllla) , the invention further provides compounds, as well as compositions comprising said compounds, useful as hypoglycemic agents, wherein:
Ri is selected from the group consisting of hydrogen, halogen, R16ORι7, R18NHR19, Rι4COORι5, Ci-Cg alkyl, C3-C8 cycloalkyl, (Cε-Cι4) aryl, (C6-C14) aryl (Cι-C6) alkyl, trihalo (Ci-Cg) alkyl, trihalo (C^Cg) alkoxy and cyano; said Ci-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl and phenyl; said Cε-Cι4 aryl and (Cε-Cι4) aryl (C^Cg alkyl) being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cι-C6 alkyl;
R2 is selected from the group consisting of hydrogen, halogen, RιSORι7, Rι6NHR19, R14COOR15, Cι-C8 alkyl, C3-C8 cycloalkyl, (C6-Cι4) aryl, (C6-Cι4) aryl (Cx-C6) alkyl, trihalo (Ci-Cg) alkyl, trihalo (Ci-C6) alkoxy and cyano; said Cι-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Cι-C6 alkyl and phenyl; said Cg-C14 aryl and (C6-Cι4) aryl (Ci-C6 alkyl) being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cι-C6 alkyl;
R3 is selected from the group consisting of hydrogen, halogen, R16ORι7, R18NHR19, R14COORι5, Cι-C8 alkyl, C3-C8 cycloalkyl, (C6-Cι4) aryl, (C6-Cι4) aryl (Ci-Cε) alkyl, trihalo (Ci-Cg) alkyl, trihalo (Cι-Cβ) alkoxy and cyano; said Ci-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Cι-C6 alkyl and phenyl; said C6-Cι4 aryl and (C6-Cι4) aryl (C^Cg alkyl) being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cι-C6 alkyl;
R4 is selected from the group consisting of hydrogen, halogen, R16ORι7, R18NHRι9, R14COORι5, Cι-C8 alkyl, C3-C8 cycloalkyl, (C6-Cι4) aryl, (Cε-Cι4) aryl (Cι-C6) alkyl, trihalo (Cι-C6) alkyl, trihalo (Cι-C6) alkoxy and cyano; said Cι-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Cι-C6 alkyl and phenyl; said C6-C14 aryl and (C6-Cι4) aryl (Cι-C6 alkyl) being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cι-C6 alkyl; R8-R2ι, m and o are as defined above; R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Ci-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, and hydroxy; said Cι~C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι~C3 alkyl; said C2- C6 alkoxy being optionally substituted with halogen and Cι-C3 alkyl; said Cι~C8 thioalkyl being optionally substituted with one or more subsitituents consisting of halogen and Ci-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι-C3 alkyl;
R23 is selected from the group consisting of hydrogen, halogen, Cι-C6 alkoxy, Ci-C6 alkyl, trifluoromethyl , nitro, cyano, carbo (Cι-Cβ) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl and hydroxy; said Cι-Cε alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C3 alkyl; said Cι-Cε alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and -Ci-C3 alkyl; said Ci-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Ci~C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι-C3 alkyl; R24 is selected from the group consisting of hydrogen, halogen, Ci-C6 alkoxy, Ci-C6 alkyl, trifluoromethyl, nitro, cyano, carboxy, phenyl, Ci~C8 thioalkyl, and hydroxy; said Ci-Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci~C3 alkyl; said Ci-C6 alkoxy being be optionally substituted with one or more substituents selected from the group consisting of halogen or Ci-C3 alkyl; said Ci-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C8 alkyl; said carbo (Ci-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen or Ci-C3 alkyl;
R25 is selected from the group consisting of halogen, C^Cg alkoxy, C^Cg alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-Cg) alkoxy, carboxy, phenyl, Ci-C8 thioalkyl and hydroxy; said Cι~C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and or Cx-C3 alkyl; said Ci-Cg alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen or Ci~C3 alkyl; said Ci-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen andr Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen or Ci-C3 alkyl;
R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, C^Cg alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-C6) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl and hydroxy; said Cι-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C3 alkyl; said C2- C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C3 alkyl; said Ci-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι~C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι-C3 alkyl; wherein R22-R26 cannot all simultaneously be hydrogen; or two of R2-R2ε when taken together can form methylene dioxy group;
R27 is selected from the group consisting of hydrogen, halogen, Ci-Cε alkoxy, Ci-Cε alkyl, trifluoromethyl , nitro, cyano, carbo (Ci~C6) alkoxy, carboxy, phenyl, Ci-C8 thioalkyl and hydroxy; said Cι-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι-C3 alkyl; said Ci~C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι-C3 alkyl; said Cι~C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι~C8 alkyl; said carbo (Cx-C6) -alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen or Cι~C3 alkyl; R28 is selected from the group consisting of hydrogen, halogen, Ci-C6 alkoxy, Cι-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl and hydroxy; said Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι~C3 alkyl; said Ci-Cε alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci~C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C8 alkyl; said carbo (C^Cg) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen or Ci-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 CR3X; wherein at least one of X3, X4, or X5 is a nitrogen; R29 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl , nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl and hydroxy; said Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C8 alkyl; said carbo (Ci-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; R30 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl and hydroxy; said Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Cι-Cε) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι~C3 alkyl;
R31 is selected from the group consisting of hydrogen, halogen, Cι-Cε alkoxy, Ci~C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Ci-C8 thioalkyl and hydroxy; said Ci-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; or R28 and CR30 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 . The present invention further provides methods for using compositions comprising a compound of formula (Xlllb) or a pharmaceutically acceptable salt or a compound having a tautomeric structure thereof, as hypoglycemic agents, the compound of formula (Xlllb) having the structure:
Figure imgf000027_0001
wherein:
Rx is selected from the group consisting of hydrogen, halogen, Rx6ORX7, RX8NHR19, RX4COORX5, Cx-C8 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (Cι-C6) alkyl, (C6-Cι4) aryl, (C6-CX4) heteroaryl, (Cε-C14) heteroaryl (Cx-Cε) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl (C6-Cι4) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, carbamoyl, (Ci-C8) alkylthio, (Ci-C8) alkylsulphinyl, (Ci-C8) alkylsulphonyl, (Cι-C8) alkylsulphonylamino, sulphamoyl or (Cι-C8) alkylcarbonylamino; said Ci-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, Cx-C6 alkyl and phenyl; said C6- CX4 aryl, (C6-C14) aryl (Cx-C6 alkyl), Cε-CX4 heteroaryl, and (Cε- Cx4) heteroaryl (Cx-Cε) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cx-C6 alkyl ;
R2 is selected from the group consisting of hydrogen, halogen, Rx6ORX7, RX8NHR19, RX4COORX5, Cx-C8 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C6-CX4) aryl, (C6-CX4) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (C6-Cx4) aryl (Cx-C6) alkyl (C6-C14) aryl , trifluoromethyl, trifluoromethoxy, cyano, nitro, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said Cx-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Cx-Cε alkyl and phenyl; said Cε-CX4 aryl, (C6-CX4) aryl (Cx-C6 alkyl) , C6-CX4 heteroaryl, and (C6-C14) heteroaryl (Cι-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Ci-C6 alkyl;
R3 is selected from the group consisting of hydrogen, halogen, RιgOR17, RX8NHRX9, R14COORι5, Cι-C8 alkyl, (C3- C8) cycloalkyl (Ci-C6) alkoxy (Ci-Cε) alkyl, (Cε-C14) aryl, (Cε- Ci4) heteroaryl, (C6-Cι4) heteroaryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-Cg) alkyl, (C6-C14) aryl (Cι-C6) alkyl (C3-C14) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (Ci-C8) alkylthio, (Ci-C8) alkylsulphinyl, (Cι-C8) alkylsulphonyl, (Ci- C8) alkylsulphonylamino, sulphamoyl and (Cι-C8) alkylcarbonylamino; said Cι-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-Cg alkyl and phenyl; said C6-Cι4 aryl, (C6-CX4) aryl (Cx-C6 alkyl) , C6-C14 heteroaryl, and (C6-C14) heteroaryl (Cx-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen amino, hydroxy, alkoxy and Cx-Cε alkyl;
R4 is selected from the group consisting of hydrogen, halogen, R16ORι7, RX8NHR19, RX4COORX5, Cx-C8 alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Cx-Ce) alkyl, (C6-CX4) aryl, (C6- CX4) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-Cε) alkyl, (Cε-CX4) aryl (Ci-Cε) alkyl (C6-C14) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Ci-C8) alkylsulphonyl, (Ci- C8) alkylsulphonylamino, sulphamoyl and (Cι-C8) alkylcarbonylamino; said Ci-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-Cg alkyl and phenyl; said Cε-C14 aryl, (Cε-CX4) aryl (Cx-Cε alkyl) , C6-C14 heteroaryl, and (C6-CX4) heteroaryl (Cx-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cx-Cε 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 (Cx-C6) alkyl;
R9 selected from the group consisting of hydrogen, Cι-C8 alkyl, (Cι-C6) alkoxy (Cι-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cι-C6) alkyl, (C3-C8) cycloalkyloxy (Cι-Cβ) alkyl, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (Cx-Cε) alkyl, Cg-C14 aryl, Cε-CX4 heteroaryl, (Cε- C14) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-Cε) alkyl, (C6- C14) aryl (Cx-C6) alkyl (Cx-C6) aryl, (C6-CX4) aryl (Cx-C6) alkoxy (Ci-Cg) alkyl and (Cε-C14) aryloxy (Cι-C6) alkyl;
R10 is selected from the group consisting of hydrogen, Ci-C8 alkyl, (Cι-C6) alkoxy (Cx-C6) alkyl,. a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-Cε) alkoxy (Cι-Cε) alkyl, Cε-Cι4 aryl, C6- CX4 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (Cε-CX4) aryl (Cι-Cε) alkyl (Ci-Cε) aryl, (Cε-C14) aryl (Cι-Cε) alkoxy (Cι-Cε) alkyl and (C6-C14) aryloxy (Cx-C6) alkyl ;
Rxx is selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cx-C6) alkoxy (Cx-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyloxy (Cx-Cε) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, Cg-CX4 aryl, Cε- CX4 heteroaryl, (Cε-CX4) heteroaryl (Cx-Cε) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (Cε-C14) aryl (Ci-C6) alkyl (Cx-C6) aryl, (C6-CX4) aryl (Cx-C6) alkoxy (Cx-C6) alkyl and (Cε-CX4) aryloxy (Cx-Cε) alkyl ; Ri2 is selected from the group consisting of hydrogen and Ci-Cε alkyl;
Rx3 is selected from the group consisting of
Figure imgf000030_0001
RX4 is a bond or is selected from the group consisting of sulfonyla ino, carbonyl, carbonylamino, amino, and Ci-Cg alkyl; said Ci-Cg alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Cι-C6 alkyl and phenyl;
R15 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and Ci- Cg alkyl; said Ci-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl and Cx-C3 alkyl;
Rxε is a bond or is selected from the group consisting of sulfonyl, Cx-C8 thioalkyl, aminosulfonyl and Cx- Cε alkyl group; said Cx-C6 alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Cx-Cε alkyl and phenyl;
RX7 is selected from the group consisting of Cx-C6 alkyl, C3-C8 cycloalkyl, C6-CX4 aryl, (C6-CX4) aryl (Cx-C6) alkyl; said Cx-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, phenyl, phenylalkyl and Cx-C3 alkyl; said C3-C6 cycloalkyl group being optionally substituted with Cx-C3 alkyl;
R18 is a bond or is selected from the group consisting of sulfonyl, Cx-C8 thioalkyl, aminosulfonyl, carbonyl, aminocarbonyl and Cx-C6 alkyl, said Cj-Cg alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Cx-C6 alkyl and phenyl ;
Rx9 is selected from the group consisting of hydrogen, phenyl, phenylalkyl, and Cx-Cε alkyl; said Cx-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl and Cx-C3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino and Cx-C6 alkyl; said phenylalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino and Cx-C6 alkyl;
R20 is selected from the group consisting of hydrogen, Cx-C16 alkyl, hydroxy and Cι-C6 alkoxy;' m is 0 or 1; o is 0 or 1;
R2X is a bond or Cx-C6 alkyl; said Cι-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 Cx-C6 alkyl, halogen, Ci-Cg alkoxy and hydroxy;
R 22 _R 3i are independently selected from the group consisting of hydrogen, halogen, Ci-C8 alkoxy, Cι-C8 alkyl, trifluoromethyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, Cι-C8 thioalkyl hydroxy (C3-C8) cycloalkyl, (C3-C8) cycloalkyl, (Cι-Cε) alkyl, Ci-Cg alkoxy, (C3-C8) cycloalkyloxy (Ci-Cε) alkyl, (C3-C8) cycloalkyl (Ci-Cε) alkoxy (Cι-Cε) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cι-Cε) alkoxy, (Cι-Cε) alkoxy (Ci-Cg) alkyl, (C6-C14) aryl, (C6-CX4) heteroaryl, (C6-C14) heteroaryl (Cx-C6) alkyl, (Cβ-Cx4) aryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl (C6-CX4) aryl, (Cε-Cι4) aryloxy, (C6-Cι4) aryloxy (Cι-Cβ) alkyl, (C6-Cι4) aryl (Cx-C6) alkyloxy, (Cε-Cx4) aryl (Cx-C6) alkyloxy (Cx-C6) alkyl trifluoromethoxy, amino, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl or (Cx-C8) alkylcarbonylamino; said (Cx-C8) alkyl being optionally substituted with one or more constituents selected from the group consisting of halogen and Cι~C3 alkyl; said C2-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with one or more constituents selected from the group consisting of halogen and Ci-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with one or more constituents selected from the group consisting of halogen and Cι~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;
X5 is nitrogen or CR3ι,- wherein at least one of X3, X4, or X5 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 (Xlllb) is not 1- [ [ [4- [2- (fluorophenyl] piperazin-1-yl] acetyl] amino] -6-fluorobenzothiazole or a pharamceutically accceptable salt or solvate thereof; or a compound having a tautomeric structure thereof .
In another embodiment of the methods using compounds of general formula (Xlllb) , the invention further provides compounds, as well as compositions comprising said compounds, useful as hypoglycemic agents, wherein:
Ri is selected from the group consisting of hydrogen, halogen, R16ORi7, Rι8NHR19, Rι4COORι5, Cx-C8 alkyl, C3-C8 cycloalkyl, (C6-Cx4) aryl, cyano, trihalo (Cx-C6) alkyl, trihalo (Cx-C6) alkoxy; said Cx-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, Cx-C6 alkyl and phenyl; said C6-CX4 aryl and (C6-C14) aryl (Ci- Cg) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Ci-C6 alkyl; R2 is selected from the group consisting of hydrogen, halogen, Rι6OR17, Rι8NHRι9, Rι4COORι5, CX-C8 alkyl, C3-C8 cycloalkyl, (C6-Cι4) aryl, cyano, trihalo _(Cι-C6) alkyl, trihalo (C^Cg) alkoxy; said Cι-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, Ci-Cg alkyl and phenyl; said Cε-Cι4 aryl and (Cε-Cx4) aryl (Cx- Cε) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cx-C6 alkyl; R3 is selected from the group consisting of hydrogen, halogen, Rx6OR17, RX8NHRX9, RX4COOR15, Cx-C8 alkyl, C3-C8 cycloalkyl, (C6-CX4) aryl, cyano, trihalo (Cx-C6) alkyl, trihalo (Cx-C6) alkoxy; said Cx-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, Cx-Cε alkyl and phenyl; said Cε-C14 aryl and (Cε-Cx4) aryl (Ci- Cg) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cι-C6 alkyl; R4 is selected from the group consisting of hydrogen, halogen, Ri6ORι7, RX8NHR19, Rx4COOR15, Cx-C8 alkyl, C3-C8 cycloalkyl, (C6-C14) aryl, cyano, trihalo (Cx-C6) alkyl, trihalo (Cx-Cε) alkoxy; said Cx-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, Cx-C6 alkyl and phenyl; said C6-CX4 aryl and (C6-CX4) aryl (Ci- Cg) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cι-C6 alkyl; R8-R2ι, and o are as defined above for general formula (Xllla) ; R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Ci-C6 alkyl, nitro, trifluoromethyl, cyano, carbo (Cx-Cε) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said C2-Cε alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; R23 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-Cε) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-Cε alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R24 is selected from the group consisting of hydrogen, bromine, chlorine, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R25 is selected from the group consisting of hydrogen, halogen, Ci-Cε alkoxy, Ci-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Ci-C8 thioalkyl, and hydroxy; said Ci-C6 alkyl being optionally substituted with halogen or Ci~C3 alkyl; said Cι-C6 alkoxy being optionally substituted with halogen or Ci-C3 alkyl; said Ci-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl , nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or Cι~C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; wherein R22-R26 cannot all simultaneously be hydrogen;
R27 is selected from the group consisting of halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R28 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cι-C6 alkyl, nitro, cyano, carbo (Cx-Cε) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, and hydroxy; said Ci~C6 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Ci-Cε alkoxy being optionally substituted with halogen or Ci-C3 alkyl; said Ci-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-Cε) alkoxy being optionally substituted with halogen or Ci-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 CR31; wherein at least one of X3, X4, or X5 is nitrogen;
R29 is selected from the group consisting of hydrogen, halogen, Cι-C6 alkoxy, Ci-Cε alkyl, nitro, cyano, carbo (Cx-Cε) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-Cε alkyl being optionally substituted with one to two halogen atoms or Cx-C3 alkyl; said Cx-Cg alkoxy being optionally substituted with halogen or Cx-C3 alkyl; R30 is selected from the group consisting of hydrogen, halogen, Cι-C6 alkoxy, Ci-C6 alkyl, nitro, cyano, carbo (Cx-Cε) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with halogen or Ci-C3 alkyl; said Cι-C6 alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R31 is selected from the group consisting of hydrogen, halogen, Cι-Cε alkoxy, Cx-C6 alkyl, nitro, cyano, carbo (Cι-Cε) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-Cε alkyl being optionally substituted with one to two halogen atoms or Cx-C3 alkyl; said Cx-Cε alkoxy being optionally substituted with halogen or Cx-C3 alkyl; 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-R3X 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 compounds of the general formulas (Xllla) and (Xlllb) according to the invention, there may be mentioned more particularly, as preferred compounds:
2- ( ( (4- (2-Pyridyl)piperazin-l-yl) acetyl) amino) -6- fluorobenzothiazole,
2- ( ( (4- (2-Fluorophenyl)piperazin-l-yl) acetyl) amino) -6- fluorobenzothiazole, 2- ( ( (4- (2-Pyridyl)piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole , 2- ( ( (4- (2-Pyrimidyl)piperazin-l-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-l-yl)ace.tyl)amino-4- methoxybenzothiazole,
2- ( ( (4- (4-Methoxyphenyl) piperazin-1-yl) acetyl) amino) -6- fluoro-benzothiazole,
2- ( ( (4- ( (2-Pyridyl)piperazin-l-yl) acetyl) amino) -6- ethoxybenzothiazole,
2- ( ( (4- (3- (Trifluoromethyl) phenyl)piperazin-l- yl) acetyl) amino) -6-ethoxybenzothiazole, 2- ( ( (4- (3-Chlorophenyl)piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole ,
2- ( ( (4- (3-Bromophenyl)piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole ,
2- ( ( (4- (3-Nitrophenyl)piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole,
2- ( ( (4- ( (2-Pyridyl)piperazin-l-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 -MethylphenyDpiperazin-1-yl) acetyl) amino) -6- methoxybenzothiazole,
2- ( ( (4- (3-Cyanophenyl)piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole,
2- ( ( (4- (4-Bromo-3-trifluoromethylphenyl)piperazin-l- yl) acetyl) amino) -6-methoxybenzothiazole,
2- ( ( (4- (4-Chlorobenzhydryl)piperazin-l-yl) acetyl) amino) 6-methoxybenzothiazole , 2- ( ( (4- (3-Ethylphenyl)piperazin-l-yl) acetyl) amino) -6- methoxy benzothiazole, 2- ( ( (4- (2-Naphthyl)piperazin-1-yl) acetyl) amino) -6- methoxybenzothiazole,
2- ( ( (4- (3-MethoxyphenylJpiperazin-1-yl) acetyl) amino) -6- methoxybenzothiazole, 2- ( ( (4- (3-Methoxy-5-trifluoromethylphenyl)piperazin-l- yl) acetyl) amino) -6-methoxybenzothiazole,
2- ( ( (4- (3, 5-Dichlorophenyl)piperazin-l-yl) acetyl) amino) - 6-methoxybenzothiazole,
2- ( ( (4- (3, 4-Dichlorophenyl)piperazin-l-yl) acetyl) amino) - 6-methoxybenzothiazole.
The invention also relates to a process for the preparation of the compounds of general formulas (Xllla) and (Xlllb) . A preparation process according to the invention comprises the reaction of an aromatic amine of general formula (Al) :
Figure imgf000038_0001
(Al) in which Rx, R2, R3, R4, R8, R9, and m are as defined above for formulas (Xllla) and (Xlllb) , with a haloacyl halide of general formula (IXa) :
Figure imgf000038_0002
(IXa) in which Rι0 and Rn are as defined above for formulas (Xllla) and (Xlllb) ,
Hal represents a chlorine or bromine atom, in order to form a compound of general formula (XVII) ;
Figure imgf000039_0001
(XVII) in which Rχ/ R2, R3, R4, R8, R9, Rι0, Rn and m are as defined above for formulas (Xllla) and (Xlllb) , and Hal is as defined above ; and the reaction of the compound of general formula (XVII) with a compound of general formula (XVIII) :
Figure imgf000039_0002
(XVIII) in which R 12/ R 13 i and o are as defined above for formulas (Xllla) and (Xlllb) , in the presence of a basic agent, such as triethylamine or potassium carbonate in order to form the compound of general formulas (Xllla) and (Xlllb) :
Figure imgf000040_0001
(XIX) in which Rx, R2, R3, R4, R8, R9, Rι0, RιX, R12, Rι3, m and o are as defined above for formulas (Xllla) and (Xlllb) and Hal is as defined above; The invention further provides compounds, as well as compositions comprising said compounds, useful as hypoglycemic agents, of general formula (XlVa) :
Figure imgf000040_0002
wherein:
Ri is selected from the group consisting of hydrogen, R14COORι5, Cx-C8 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-Cε) alkyl, Cx-C8 alkoxy, (C3-C8) cycloalkyloxy (Cx-Cε) alkyl, (C3-C8) cycloalkyl (Cx-Cε) alkoxy (Cx-Cε) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-C6) alkoxy, (Ci- Cg) alkoxy (Cι-C6) alkyl, (C6-Cι4) aryl, (C6-CX4) heteroaryl, (C6-C14) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-C14) aryloxy, (C6- C14) aryloxy (Cx-C6) alkyl, (C6-Cx4) aryl (Cx-C6) alkyloxy, (C6- CX4) aryl (Cx-C6) alkyloxy (Cx-Cβ) alkyl group, halogen, trifluoromethyl, cyano, nitro, amino, carboxyl, (Cx-C6) alkoxycarbonyl , carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said Cι-C8 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, Cι-C6 alkyl and phenyl; said C6- CX4 aryl and (C6-C14) aryl (Cι-C6) alkyl being optionally substituted with one or more substituents. selected from the group consisting of halogen, amino, hydroxy, alkoxy, Cι-C6 alkyl and phenyl; 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 (Ci~C6) alkyl;
R9 is selected from the group consisting of hydrogen, Cι-C8 alkyl, (Cx-C6) alkoxy (Cx-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cε) alkyl group, (C3-C8) cycloalkyloxy (Ci-C6) alkyl, (C3-C8) cycloalkyl (Cx-Cε) alkoxy (Cx-Cε) alkyl, C6-CX4 aryl, C6-CX4 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6- CX4) aryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (Cx-C6) aryl, (C6-CX4) aryl (Cx-C6) alkoxy (Cx-C6) alkyl and (C6-CX4r) aryloxy (Cx-C6) alkyl group;
Rx0 is selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cx-Cε) alkoxy (Cx-Ce) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-CB) cycloalkyl (Cx-C6) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, C6-CX4 aryl, C6-C14 heteroaryl, (C6-Cι4) heteroaryl (Cx-C6) alkyl, (C6- CX4) aryl (Cx-C6) alkyl, (C6-C14) aryl (Ci-C6) alkyl (Ci-C6) aryl, (C6-CX4) aryl (Cx-C6) alkoxy (Cx-C6) alkyl and (C6-C14) aryloxy (Cx-C6) alkyl group;
Rxx is selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cx-C6) alkoxy (Cx-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-CB) cycloalkyl (Cx-C6) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, C6-CX4 aryl, C6-Cx4 heteroaryl, (C6-C14) heteroaryl (Cx-Cε) alkyl, (C6- Cx4) aryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl (Cx-C6) aryl, (C6-CX4) aryl (Cx-C6) alkoxy (Cx-Cg) alkyl and (Cε-Cι4) aryloxy (Cx-Cε) alkyl group;
RX2 is selected from the group consisting of hydrogen and Cx-C6 alkyl; RX3 is selected from the group consisting of
Figure imgf000042_0001
R14 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cx-C6 alkyl; said Cx-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Cx-Cε alkyl and phenyl; Rx5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions and Cx-C6 alkyl; said Cx-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl, and Cx-C3 alkyl;
R20 is selected from the group consisting of hydrogen, Cx-C6 alkyl, hydroxy and Cx-C6 alkoxy; m is 0 or 1; n is 0 or 2 o is 0 or 1;
R2X is a bond or Cx-C6 alkyl; said Cx-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 Cx-C6 alkyl, halogen, Cx-C6 alkoxy and hydroxy; R 22 _R 3i are each independently selected from the group consisting of hydrogen, Cx-C8 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, Cx-C8 alkoxy, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-C6) alkoxy, (Cx-C6) alkoxy (Cx-C6) alkyl, (Cε-CX4) aryl, (Cε-C14) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-C14) aryl (Cx- Cε) alkyl, (C6-C14) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-CX4) aryloxy, (C6-CX4) aryloxy (Cx-C6) alkyl, (C6-CX4) aryl (Cx-Cε) alkyloxy, (C6-C14) aryl (Cx-Cε) alkyloxy (Cx-C6) alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, (Cx-C6) alkoxycarbonyl , carbamoyl, (Cι-C8) alkylthio, (Ci-CB) alkylsulphinyl, (Cι-C8) alkylsulphonyl, sulphoamino, (Ci-C8) alkylsulphonylamino, sulphamoyl, (Cι-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 form an aryl ring; 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 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 (XlVa) 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) amino) acetyl) amino) -1- ( (N' - (2 - thiazolyl ) ) sulfonamido) benzene .
In another embodiment of general formula (XlVa) , the invention further provides compounds as well as comositions comprising said compounds , useful as hypoglycemic agents wherein : Ri is selected from the group consisting of hydrogen, Cx-C8 alkyl group , halogen, C6-CX4 aryl , (C6-C14) aryl (Cα -Cε) alkyl , and RX4COORx5 ; said Cx-C8 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, Cx-C6 alkyl and phenyl; said C6-C14 aryl and (C6-C14) aryl (Cx-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy, Cx-C6 alkyl and phenyl;
R8~Ri5 R2c ro. π, o, and R21 are .defined as above for general formula (XlVa) ;
R22 is selected from the group consisting of hydrogen, halogen, Cx-Cε alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl and hydroxy; said Cx-Cε alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen or Cx-C3 alkyl; said Cx-Cε alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C3 alkyl; said Cι-Ce thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C3 alkyl;
R23 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Ci-Cε alkyl, trifluoromethyl , carbo (Cι-C6) alkoxy, carboxy, phenyl, Cι-CB thioalkyl and hydroxy; said Cι-Cε alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι~C3 alkyl; said Ci-Cε alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C3 alkyl; R24 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl , nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl and hydroxy; said Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C3 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said CX-CB thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; R25 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl and hydroxy; said Cx- C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Cx-Cε) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl;
R26 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl and hydroxy; said Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; or two of R22-R26 when taken together can form a methylenedioxy group; R27 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl and hydroxy; said Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; R28 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-Cg) alkoxy, carboxy, phenyl, Ci-C8 thioalkyl and hydroxy; said Cx-Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C3 alkyl; said Cι-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι-C3 alkyl; said Ci-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι-C8 alkyl; said carbo (Ci-Cε) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-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 CR31; wherein at least one of X3, X4, or X5 is nitrogen; R29 is selected from the group consisting of hydrogen, halogen, Ci-C6 alkoxy, C^Cg alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl, wherein the numbered halogen atoms can be 0-2; said Ci-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι~C3 alkyl; said Cx- C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-Cg alkyl; said carbo (Cι-C6) alkoxy.being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι~C3 alkyl; R30 is selected from the group consisting of hydrogen, halogen, Cι~C6 alkoxy, trifluoromethyl, Cι-C6 alkyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Ci-C8 thioalkyl and hydroxy; said Cι-Cε alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Ci-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Cx-Cε) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι~C3 alkyl;
R3ι is selected from the group consisting of hydrogen, halogen, Ci-Cε alkoxy, Cι-Cε alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, and hydroxy; said Cι-Cε alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl, wherein the numbered halogen atoms can be 0-2; said Cx-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx- Cj thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Cx-Cfi) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; or R28 and CR30 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 (XlVa) is not:
2- ( ( (4- (phenyl) piperazinly-1-) acetyl) amino) -4- ( (carboethoxy) methyl) thiazole;
2- ( ( (4- (2-fluorophenyl)piperazinyl-l) - acetyl) amino) -4- ( (carboethoxy) methyl) thiazole; 'or 4- ( ( (2-fluorophenyl) amino) acetyl) amino) -1- ( (N' - (2- thiazolyl) ) sulfonamidobenzene.
The present invention further provides methods for using compositions comprising a compound of formula (XlVb) or a pharmaceutically acceptable salt or a compound having a tautomeric structure thereof, as hypoglycemic agents, the compound of formula (XlVb) having the structure:
Figure imgf000048_0001
wherein:
Rx is selected from the group consisting of hydrogen, RX4COORX5, Cx-C8 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, Cx-C8 alkoxy, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-C6) alkoxy, (Cx- C6) alkoxy (Cx-C6) alkyl, (C6-CX4) aryl, (C6-CX4) heteroaryl, (C6-C14) heteroaryl (Cι-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-Cε) alkyl (Cε-Cx4) aryl, (Cε-CX4) aryloxy, (C6- CX4) aryloxy (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyloxy, (C6- CX4) aryl (Cx-C6) alkyloxy (Cx-C6) alkyl group, halogen, trifluoromethyl, cyano, nitro, amino, carboxyl, (Cx-C6) alkoxycarbonyl , carbamoyl, (CX-CB) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said Cx-C8 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, Cx-C6 alkyl and phenyl; said C6- CX4 aryl and (C6-CX4) aryl (Cx-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy, Cx-C6 alkyl and phenyl ; 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 (Cx-C6) alkyl;
R9 is selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cx-C6) alkoxy (Cx-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (C^Cg) alkyl, C6-C14 aryl, C6-CX4 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6- CX4) aryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (Cx-C6) aryl, (C6-CX4) aryl (Cx-C6) alkoxy (Cx-C6) alkyl and (C6-CX4) aryloxy (Cx-C6) alkyl group;
Rio is selected from the group consisting of hydrogen, Cι-C8 alkyl, (Cι-C6) alkoxy (Cι-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cι-C6) alkyl group, (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3-C8) cycloalkyl (Cι-Cε) alkoxy (Cι-C6) alkyl, C6-Cι4 aryl, Cg-C14 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6- CX4) aryl (Cx-C6) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl (Ci-Cg) aryl, (C6-C14) aryl (Cι-Cε) alkoxy (Cι-C6) alkyl and (C6-Cι4) aryloxy (Cx-C6) alkyl group;
Rii is selected from the group consisting of hydrogen, Cι-C8 alkyl, (Cι-Cβ) alkoxy (Cx-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, C6-C14 aryl, Cβ-Cι4 heteroaryl, (C6-Cι4) heteroaryl (Cι-C6) alkyl, (Cε- Ci4) aryl (Cι-C6) alkyl, (C6-Cx4) aryl (Cι-C6) alkyl (Cι-C6) aryl, (C6-Cι4) aryl (Cx-C6) alkoxy (Cx-C6) alkyl and (C6-CX4) aryloxy (Cx-C6) alkyl group;
R12 is selected from the group consisting of hydrogen and Cx-Cε alkyl; RX3 is selected from the group consisting of
Figure imgf000050_0001
RX4 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cx-C6 alkyl; said Cx-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Cx-Cε alkyl and phenyl; Rx5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions and Cx-C6 alkyl; said Cx-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl, and Cx-C3 alkyl;
R20 is selected from the group consisting of hydrogen, Cx-C6 alkyl, hydroxy and Cx-Cε alkoxy; m is 0 or 1, n is 0 or 2, o is 0 or 1,
R21 is a bond or Cx-C6 alkyl; said Cx-Cε 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 Cx-C6 alkyl, halogen, Cx-Cε alkoxy and hydroxy;
R22~R 3i are each independently selected from the group consisting of hydrogen, Cx-C8 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, Cx-C8 alkoxy, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-CB) cycloalkyl (Cx-C6) alkoxy, (Cx-C6) alkoxy (Cx-C6) alkyl, (C6-Cx4) aryl, (C6-CX4) heteroaryl, (Cε-C14) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx- C6) alkyl, (Cε-C14) aryl (Cι-C6) alkyl (C6-CX4) aryl, (C6-Cx4) aryloxy, (C6-CX4) aryloxy (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyloxy, (Cε-CX4) aryl (Cx-C6) alkyloxy (Cx-C6) alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, (Cx-C6) alkoxycarbonyl , carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl, (Cx-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 form an aryl ring; X3 is nitrogen or CR29;
X4 is nitrogen or CR30; X5 is nitrogen or CR3X; wherein at least one of X3, X4, or X5 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 (XlVb) is not: 2- ( ( (4- (phenyl)piperazinly-l-) 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 the methods involving compounds of general formula (XlVb) , the invention further provides compositions comprising a compound of formula (XlVb) or a phamaceutically acceptable salt or a compound having a tautomeric structure thereof, as hypoglycemic agents, wherein: Rx is selected from the group consisting of hydrogen, Cx-C8 alkyl group, halogen, C6-C14 aryl, (Cε-C14) aryl (Cx-Cε) alkyl, and RX4COORx5; said Cx-C8 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, Cx-Cε alkyl and phenyl; said Cε-Cι4 aryl and (Cε-CX4) aryl (Cx-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy, Cx-C6 alkyl and phenyl;
R8-RX5, R20, m, n, o, and R21 are defined as above for general formula (XlVb) ;
R22 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl and hydroxy; said Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; R23 is selected from the group consisting of hydrogen, halogen, Cx-Cε alkoxy, Cx-Cε alkyl, trifluoromethyl, carbo (Cx-Cε) alkoxy, carboxy, phenyl, CX-CB thioalkyl and hydroxy; said Cx-Cε alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-Cε alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Cx-Cε) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; R24 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl and hydroxy; said Cι-Cε alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cι-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl;
R25 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl and hydroxy; said Ci- Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι~C3 alkyl; said Cx-Cε alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Cx-Cε) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl;
R26 is selected from the group consisting of hydrogen, halogen, Cx-Cε alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl and hydroxy; said Cι-Cε alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι~C3 alkyl; said Cι-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι-C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; or two of R22-R26 when taken together can form a methylenedioxy group;
R27 is selected from the group consisting of hydrogen, halogen, Cx-Cε alkoxy, Cx-Cε alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-Cε) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl and hydroxy; said Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-Cε alkoxy being optionally substituted with one or more substituents selected from the group consisting of 'halogen and Cx-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι-CB alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; R28 is selected from the group consisting of hydrogen, halogen, Cι-C6 alkoxy, Cι-C6 alkyl, trifluoromethyl , nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl and hydroxy; said Cι-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι-C3 alkyl; said Cι-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-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 CR3X; wherein at least one of X3, X4, or X5 is nitrogen; R29 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with one or more substituents. selected from the group consisting of halogen and Cx-C3 alkyl, wherein the numbered halogen atoms can be 0-2; said Cx-Cε alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Ci- Cg thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-Cg alkyl; said carbo (Cι-Cε) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl;
R30 is selected from the group consisting of hydrogen, halogen, Cι-Cε alkoxy, trifluoromethyl, Cι-C6 alkyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl and hydroxy; said Cι~C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cι-C3 alkyl; said Cι-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; R31 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl, wherein the numbered halogen atoms can be 0-2; said Cx-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Ci- Ca thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; or R28 and CR30 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
(XlVb) 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) amino) acetyl) amino) -1- ( (N' - (2- thiazolyl) ) sulfonamidobenzene .
Among the compounds of the general formulas (XlVa) and (XlVb) according to the invention, there may be mentioned more particularly, as preferred compounds
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-l-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) -1- ( (N' - (2-thiazolyl) ) sulfonamido) benzene, hydrochloride salt ,
2- ( ( (4- (3- (Trifluoromethyl) phenyl)piperazin-l- 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) thiazole,
2- ( ( (4- (3-Chlorophenyl)piperazin-l-yl) acetyl) amino) -4- (carboethoxymethyl) thiazole,
2- ( ( (4- (3-Bromophenyl)piperazin-l-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) henyl) piperazin-1- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole,
2- ( (4- ( (4-Chlorobenzhydryl) phenyl)piperazin-l- yl) acetyl) amino-4- (carboethoxymethyl) thiazole, 2- ( ( (4- (3-Ethylphenyl)piperazin-l-yl) acetyl) amino) -4- (carboethoxymethyl) thiazole, 2- ( ( (4- (2-Naphthyl)piperazin-l-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-l-yl) acetyl) amino) - 4- (carboethoxy) thiazole,
2- ( ( (4- (3, 4-Dichlorophenyl)piperazin-l-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 compounds of general formulas (XlVa) and (XlVb) . A preparation process according to the invention comprises the reaction of an aromatic amine of general formula (A2) :
Figure imgf000058_0001
(A2) in which Rx, R8, R9, m, and n are as defined above for formulas (XlVa) and (XlVb) , with a haloacyl halide of general formula (XIX) :
Figure imgf000058_0002
(XIX) in which Rx0, R1X, are as defined above for formulas (XlVa) and (XlVb) , Hal represents a chlorine or bromine atom, in order o form a compound of general formula (XX) ;
Figure imgf000059_0001
(XX) in which Rx, R8, R 9' R 10/ Rxx, m and n are as defined above for formulas (XlVa) and (XlVb) , Hal is defined as above, and the reaction of the compound of general formula (XX) with a compound of general formula (XXI) :
H
Figure imgf000059_0002
(XXI) in which Rx2, Rx3, and o are as defined above for formulas (XlVa) and (XlVb) , in the presence of a basic agent, such as triethylamine or potassium carbonate in order to form the compound of general formulas (XlVa) and (XlVb) :
Figure imgf000060_0001
(XIV) in which Rx, R8, R9, Rx0, Rxx, RX2, RX3, m, and o are as defined above for formulas (XlVa) and (XlVb) , and Hal is defined as above ; The invention further provides compounds, as well as compositions comprising said compounds, for use as hypoglycemic agents, of general formula (XVa) :
Figure imgf000060_0002
wherein:
Rx is selected from the group consisting of RX4COORX5, C6-CX4 aryl, (C6-CX4) aryl (Cx-C6) alkyl, C3-C6 cycloalkyl, thio (C6-CX4) aryl, thio (C6-CX4) heteroaryl, (C3- C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3-C8) cycloalkyl (Cι-C6) alkoxy (Cι-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cι-C6) alkoxy, (C6-C14) heteroaryl (Cx-C6) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl (C6-Cι4) aryl, (C6-Cι4) aryloxy, (C6-Cι4) aryloxy (Cx-C6) alkyl, and (C6- C14) aryl (Cx-C6) alkyloxy (Cx-Cε) alkyl group; said C6-CX4 aryl and Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cx-C6 alkoxy, Ci- Cg alkyl, trihalo (Cι-C6) alkyl, and trihalo (Cι-C6) alkoxy;
R8, R9, io/ R ι Rι2/ Ri / Ri4/ Ri5/ 2o m/ °/ and R2ι are as defined above for general formula (XVa) ; R22 is selected from the group consisting of hydrogen, halogen Cx-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carboxy, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-C8) cycloalkyloxy (Cx-C6) alkyl, C3-C6 cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-C6) alkoxy, (C3-C6) alkoxy (C3-Cβ) alkyl, (C6-C14) aryl, (C6-Cx4) heteroaryl (C6-C14) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (C6-Cx4) aryl (Cx-C6) alkyl (C6-C14) aryl, (C6-C14) aryloxy, (C6-CX4) aryloxy (Cx-Cε) alkyl, (C6-CX4) aryl (Cx-C6) alkyloxy, trifluoromethoxy, amino, (Cx-C6) alkoxycarbonyl , carbamoyl, (Cx-C6) alkylthio, (Cx-C6) alkylsulphinyl, (Cx-Cε) alkylsulphonyl, sulphoamino, (Cx-C6) alkylsulphonylamino, sulphamoyl and (Cx-C6) alkylcarbonylamino; said Cx-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R23 is selected from the group consisting of hydrogen, fluorine, bromine, Cx-C8 alkoxy, C2-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-C6 alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3-C6) cycloalkyl (Cι-C6) alkoxy (Ci-Cg) alkyl, (C3-C6) cycloalkyloxy, (C3-Cg) cycloalkyl (Cι-Cε) alkoxy, (C2-C6) alkoxy (C3-Ce) alkyl, ( 6-Cι4) aryl, (C6-Cι4) heteroaryl, (Cε-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-CX4) aryloxy, (Cε-CX4) aryloxy (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyloxy, (C6-Cx4) aryl (Cx-Cε) alkyl, trifluoromethoxy, amino, (Cι-C6) alkoxycarbonyl, carbamoyl, (Cι-Cε) alkylthio, (Cx-C6) alkylsulphinyl, (Cx-C6) alkylsulphonyl, sulphoamino, (Cx-C6) alkylsulphonylamino, sulphamoyl and (Cx-C6) alkylcarbonylamino; said C2-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R24 is selected from the group consisting of hydrogen, halogen, Cx-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-C6 alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-C6) cycloalkyloxy (Cx-C6) alkyl, (C3-C6) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (Cx-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (Cε-Cx4) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl (Cx-C6) alkyl, (C6-C14) aryl (Ci- Cg) alkyl, (Cε-CX4) aryl (Cx-Cε) alkyl (C6-C14) aryl, (Cε-CX4) aryloxy, (C6-Cι4) aryloxy (Cι-C6) alkyl, (C6-Cι4) aryl (Cι-C6) alkyloxy (C6-CX4) aryl (Cx-C6) alkyl, trifluoromethoxy, amino, (Cx-Cβ) alkoxycarbonyl, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Ci-Ca) alkylcarbonylamino; said Cι-C8 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R25 is selected from the group consisting of hydrogen, fluorine, bromine, Cι-C8 alkoxy, trifluoromethyl, C2-C8 alkyl, nitro, cyano, carbo Cx-Cfi alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C6) cycloalkyl (C3-C6) cycloalkyloxy (C3-C6) alkyl, (C3-C6) cycloalkyl (Cx-Cε) alkoxy (Cx-Cg) alkyl, (C3-C6) cycloalkyloxy, (C3-Cε) cycloalkyl (Cι-Cε) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-Cι4) aryl, (C6- Cx4) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (Cε-CX4) aryl (C3-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-CX4) aryloxy, (C6-CX4) aryloxy (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyloxy, (C6-CX4) aryl (Cx-Cε) alkyl, trifluoromethoxy, cyano, amino, (Cx-C6) alkoxycarbonyl, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said C2-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R26 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-C6 alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C6) cycloalkyl (C3-C6) cycloalkyloxy (Cx-C6) alkyl, (C3-C6) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (Cx-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (Cε-CX4) aryl, (Cg-Cι4) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (C3- C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-CX4) aryloxy, (C6-CX4) aryloxy (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyloxy, (C6-CX4) aryl (Cx-C6) alkyl, trifluoromethoxy, cyano, amino, (Cx-C6) alkoxycarbonyl, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said Cx-C6 alkyl being optionally substituted with halogen for Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl, said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; or two of R22-R 26 can form a methylenedioxy group; R27-R3X are each independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, halogen, Cx-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl , nitro, cyano, carbo Cx-C6 alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C6) cycloalkyl (C3-Cε) cycloalkyloxy (Cx-Cε) alkyl, (C3-Cε) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-Cε) cycloalkyl (Cx-Cε) alkoxy, (C3-Cε) alkoxy (C3-Cε) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (C3-C£) alkyl, (C6-C14) aryl (Cx-Cε) alkyl (Cε-C14) aryl, (Cε-C14) aryloxy, (C6-Cx4) aryloxy (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyloxy, (C6-CX4) aryl (Cx-C6) alkyl, trifluoromethoxy, cyano, amino (Cx-C6) alkoxycarbonyl, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said Cx-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or CX-'C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-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 Xx and X2 is nitrogen, with the other being carbon;
X3 is nitrogen or CR29;
X4 is nitrogen or CR30; X5 is nitrogen or CR3X; wherein at least one of X 3/ 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-R3X 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-l) -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. In another embodiment of general formula (XVa) , the invention further provides compounds, as well as compositions comprising said compounds, useful as hypoglycemic agents wherein:
Rx is selected from the group consisting of Rι4COORx5, C6-CX4 aryl, (C6-CX4) aryl Cx-C6 alkyl, C3-C6 cycloalkyl, thio (C6-CX4) aryl { e . g. , thiophenyl, thionaphthyl) , thio (C6-CX4) heteroaryl (e.g., thiopyridyl, thioquinolinyl, and thiopyrazinyl) ; said C6-CX4 aryl and (Cε- CX4) aryl Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amine, hydroxy, Cx-C6 alkoxy, Cx-C6 alkyl, trihalo Ci- Cg alkyl, trihalo Cx-Cε alkoxy, and phenyl; said thio (Cg-CX4) aryl being optionally substituted with halogen, amine Cx-Cε alkoxy, hydroxy, Cx-Cε alkyl, trihalo (Cx-C6) alkoxy, or trihalo (Cx-Cε) alkyl; said thio (C6-CX4) heteroaryl being optionally substituted with halogen, amine, Cx-C6 alkoxy, hydroxy, Cx-C6 alkyl trihalo (Cx-C6) alkoxy, or trihalo (Cι-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 (Ci-C8) alkyl;
R9 is a group selected from the group consisting of hydrogen, Cι-C8 alkyl, (Cι-C6) alkoxy (Cι-Cε) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3- C8) cycloalkyl (Cι-C6) alkoxy (Cι-C6) alkyl, C6-Cι4 aryl, Cg-CX4 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (Cg-CX4) aryl (Ci- Cg) alkyl, (C6-Cι4) aryl (Cx-Cβ) alkyl (Cx-C6) aryl, (C6-CX4) aryl (Cx-Cε) alkoxy (Cx-C6) alkyl, and (C6-CX4) aryloxy (Cx-C6) alkyl group;
Rxo is selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cx-C6) alkoxy (Cx-Cε) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-Cβ) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (Cx-Cε) alkoxy (Cx-C6) alkyl, C6-CX4 aryl, C6-CX4 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx- C6) alkyl, (C6-Cx4) aryl (Cx-C6) alkyl (Cx-C6) aryl, (C6-C14) aryl (Cx-Cε) alkoxy (Cx-C6) alkyl, and (C6-CX4) aryloxy (Cx-C6) alkyl group;
Rii is selected from the group consisting of hydrogen, Cι-C8 alkyl, (Cι-C6) alkoxy (Cι-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, C6-CX4 aryl, C6-CX4 heteroaryl, (C6-Cx4) heteroaryl (Cx-Cε) alkyl, (Cε-CX4) aryl (Ci- Cg) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (Cx-C6) aryl, (C6-CX4) aryl (Cx-C6) alkoxy (Cx-C6) alkyl, and (C6-C14) aryloxy (Cx-C6) alkyl group;
Rx2 is selected from the group consisting of hydrogen and Cx-C6 alkyl;
Rx3 is selected from the group consisting of
Figure imgf000066_0001
RX4 is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cx-C2 alkyl group; said Cx-C2 alkyl being substituted with one or more halogen, Cx-C6 alkyl or phenyl groups;
RX5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and Cx - C6 alkyl group; said Cx-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and Cx-C3 alkyl; R20 is selected from the group consisting of hydrogen, Cι-C6 alkyl, hydroxy and Cι-C6 alkoxy; m is 0 or 1; n is 1; o is 0 or 1;
R2i is a bond or Cι-C6 alkyl; said Cι-C6 alkyl being optionally substituted from .the group consisting of benzene and an optionally substituted benzene ring; said benzene ring optionally substitued from the group consisting of Cι-C6 alkyl, halogen, Cx-C6 alkoxy and hydroxy;
R22 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl , nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said CX-CB thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; R23 is selected from the group consisting of hydrogen, fluorine, bromine, Cx-C6 alkoxy, C2-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said C2-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R24 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cι-C6 alkyl, trifluoromethyl , nitro, cyano, carbo (Cι-Cε) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-Cε alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; R25 is selected from the group consisting of hydrogen, fluorine, bromine, Cx-C6 alkoxy, C2-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said C2-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; R26 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with halogen or Cι~C3 alkyl; said Cι-C6 alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι-C3 alkyl; or two of R22-R26 when taken together can form a methylenedioxy group;
R27 is selected from the group consisting of hydrogen, halogen, Cι-C6 alkoxy, Cι-Cε alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-Cε) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-Cε alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said CX-CB thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-Cε) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; R28 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι-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 Xi and X2 is nitrogen, with the other being carbon;
X3 is nitrogen or CR29 X4 is nitrogen or CR30 X5 is nitrogen or CR3ι wherein at least one of X3, X4, or X5 is nitrogen;
R29 is selected from the group consisting of hydrogen, halogen, Cι-C6 alkoxy, Cι-C6 alkyl, trifluoromethyl , nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with one to two halogen atoms or Cι-C3 alkyl; said Ci-Cg alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Cι~C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι~C3 alkyl; R30 is selected from the group consisting of hydrogen, halogen, Cι-C6 alkoxy, Cι-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cι~C8 thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Cι-Cβ alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Ci-Ca thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R3ι is selected from the group consisting of hydrogen, halogen, Cι-Cε alkoxy, Cι-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with one to two halogen atoms or Cι-C3 alkyl; said Ci-Cg alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι~C3 alkyl; or R2B 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 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) -5- ( (ethoxycarbonyl) -methyl) -1, 3, 4-thiadiazole;
2- ( ( (4- (2-pyridyl)piperazinyl-l) -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:
Figure imgf000070_0001
wherein
Ri is selected from the group consisting of RX4COORX5, C6-CX4 aryl, (C6-C14) aryl (Cx-C6) alkyl, C3-C6 cycloalkyl, thio (C6-CX4) aryl, thio (C6-Cx4) heteroaryl, (C3- C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-CB) cycloalkyl (Cx-C6) alkoxy, (C6-C14) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-Cε) alkyl (Cε-Cx4) aryl, (C6-Cι4) aryloxy, (C6-CX4) aryloxy (Cx-C6) alkyl, and (C6- CX4) aryl (Cx-C6) alkyloxy (Cx-C6) alkyl group; said Cβ-Cx4 aryl and Cx-Cε alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cx-Cε alkoxy, Ci- Cg alkyl, trihalo (Cx-C6) alkyl, and trihalo (Cx-Cε) 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 (Cx-C6) alkyl; R9 is a group selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cx-C6) alkoxy (Cx-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, Cg-CX4 aryl, C6-CX4 heteroaryl, (C6-C14) heteroaryl (Cx-Cε) alkyl, (Cε-CX4) aryl (Ci- Cg) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl (Cι-C6) aryl, (C6-Cι4) aryl (Ci-Cg) alkoxy (Cι-C6) alkyl, and (Cε-Cι4) aryloxy (Ci-Cg) alkyl group;
Rio is selected from the group consisting of hydrogen, Cι-C8 alkyl, (Cι-C6) alkoxy (Cι-C6) alkyl, . cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cι-C6) alkyl group, (C3-C8) cycloalkyloxy (Cι-Cε) alkyl, (C3- C8) cycloalkyl (Cι-Cε) alkoxy (Cι-Cε) alkyl, Cε-Cι4 aryl, Cε-Cι4 heteroaryl, (C6-Cι4) heteroaryl (Cι-C6) alkyl, (C6-Cι4) aryl (CX- C6) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl
Figure imgf000071_0001
aryl, (C6-C14) aryl (Ci-Cg) alkoxy (Cι-C6) alkyl, and (C6-Cι4) aryloxy (Cι-C6) alkyl group;
Rii is selected from the group consisting of hydrogen, Cι-C8 alkyl, (Cι-C6) alkoxy (Ci-Cg) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3- C8) cycloalkyl (Cι-C6) alkoxy (Cι-C6) alkyl, C6-Cι4 aryl, C6-Cι4 heteroaryl, (C6-Cι4) heteroaryl (Cι-Cε) alkyl, (C6-Cι4) aryl (Ci- Cg) alkyl, (Cg-Cι4) aryl (Cι-C6) alkyl (Ci-Cg) aryl, (C6-Cι4) aryl (Ci-Cg) alkoxy
Figure imgf000071_0002
alkyl, and (C6-Cι4) aryloxy (Cι-C6) alkyl group; Ri2 is selected from the group consisting of hydrogen and Cι-C6 alkyl;
Ri3 is selected from the group consisting of
Figure imgf000072_0001
Rι„ is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cι-C2 alkyl group; said Cι-C2 alkyl being substituted with one or more halogen, Cι-C6 alkyl or phenyl groups;
Rι5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and Cx - C6 alkyl group; said Cι-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and Cι-C3 alkyl;
R20 is selected from the group consisting of hydrogen, Cι-C6 alkyl, hydroxy and Cι-C6 alkoxy; m is 0 or 1; n is 1; o is 0 or 1;
R2ι is a bond or Cι-C6 alkyl; said Cι-C6 alkyl being optionally substituted from the group consisting of benzene and an optionally substituted benzene ring; said benzene ring optionally substitued from the group consisting of Cι-C6 alkyl, halogen, Cι-C6 alkoxy and hydroxy;
R22 is selected from the group consisting of hydrogen, halogen Cx-C8 alkoxy, Cι-C8 alkyl, trifluoromethyl, nitro, cyano, carboxy, Cι-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-C8) cycloalkyloxy (Cι-C6) alkyl, C3-C6 cycloalkyl (Cι-C6) alkoxy (Cι-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cι-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (Cg-Cι4) aryl, (C6-Cι4) heteroaryl (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cι-C6) alkyl, (C6-C14) aryl (C_ι-C6) alkyl (C6-C14) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (Cι-C6) alkyl, (C6-C14) aryl (Cι-C6) alkyloxy, trifluoromethoxy, amino, (Cι-C6) alkoxycarbonyl, carbamoyl, (Ci-Cg) alkylthio, (Cι-Cβ) alkylsulphinyl, (Cι-C6) alkylsulphonyl, sulphoamino, (Ci-Cg) alkylsulphonylamino, sulphamoyl and (Cι-C6) alkylcarbonylamino; said Cι-C8 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Cx-Cβ alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cj-C8 alkyl; said carbo (Ci-Cg) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R23 is selected from the group consisting of hydrogen, fluorine, bromine, Cι-C8 alkoxy, C2-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-Cg alkoxy, carboxy, phenyl, Cι~C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C6) cycloalkyl (Ci-Cg) alkoxy (Cι-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (Cι-C6) alkoxy, (C2-C6) alkoxy (C3-C6) alkyl, (C6-Cι4) aryl, (C6-Cι4) heteroaryl, (C6-Cι4) heteroaryl (Cι~C6) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl (C6-CX4) aryl, (Cε-Cx4) aryloxy, (C6-CX4) aryloxy (Cx-C6) alkyl, (Cε-CX4) aryl (Cx-C6) alkyloxy, (Cε-CX4) aryl (Cx-Cε) alkyl, trifluoromethoxy, amino, (Cx-C6) alkoxycarbonyl, carbamoyl, (Ci-Cg) alkylthio, (Cι-C6) alkylsulphinyl, (Cx-C6) alkylsulphonyl, sulphoamino, (Cι-C6) alkylsulphonylamino, sulphamoyl and (Cι-C6) alkylcarbonylamino; said C2-C8 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 alkoxy being optionally substituted with halogen or Cι~C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι-C3 alkyl; R24 is selected from the group consisting of hydrogen, halogen, Cι-CB alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-Cε alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-C6) cycloalkyloxy (Cι-C6) alkyl, (C3-C6) cycloalkyl (Cι-Cε) alkoxy (Ci-Cg) alkyl (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (Cι-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-Cι4) aryl, (C6-Cι4) heteroaryl, (C6-Cι4) heteroaryl (Cι-C3) alkyl, (Cε-Cι4) aryl (Ci- Cg) alkyl, (C6-Cι4) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C3-C14) aryloxy, (C6-CX4) aryloxy (Cx-C6) alkyl, ( -CX4) aryl (Cx-C6) alkyloxy (C6-CX4) aryl (Cx-C6) alkyl, trifluoromethoxy, amino, (Cx-Cε) alkoxycarbonyl, carbamoyl, (Cx-C8) alkylthio, (Cι-CB) alkylsulphinyl, (Cι-Cβ) alkylsulphonyl, sulphoamino, (Cι-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said Cx-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R25 is selected from the group consisting of hydrogen, fluorine, bromine, Cx-C8 alkoxy, trifluoromethyl, C2-C8 alkyl, nitro, cyano, carbo Cx-C6 alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C6) cycloalkyl (C3-C6) cycloalkyloxy (C3-C6) alkyl, (C3-C6) cycloalkyl (Cx-C6) alkoxy (Cx-Cε) alkyl, (C3-Cε) cycloalkyloxy, (C3-Cε) cycloalkyl (Cx-Cε) alkoxy, (C3-Cε) alkoxy (C3-C6) alkyl, (C6-CX4) aryl, (C6- CX4) heteroaryl, (C6-Cι4) heteroaryl (Cx-C6) alkyl, (C6-Cx4) aryl (C3-C6) alkyl, (Cε-Cι4) aryl (Cι-C6) alkyl (Cg-Cι4) aryl, (Cε-Cι4) aryloxy, (Cε-Cι4) aryloxy (Cx-C6) alkyl, (C6-Cι4) aryl (Cι-C6) alkyloxy, (C6-Cι4) aryl (Cι-C6) alkyl, trifluoromethoxy, cyano, amino, (Cι-C6) alkoxycarbonyl, carbamoyl, (Cι-C8) alkylthio, (Cι-C8) alkylsulphinyl, (Cι-C8) alkylsulphonyl, sulphoamino, (Cι-C8) alkylsulphonylamino, sulphamoyl and (Cι-C8) alkylcarbonylamino; said C2-C8 alkyl being optionally substituted with halogen or Cι~C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R26 is selected from the group consisting of hydrogen, halogen, Cι-C6 alkoxy, Cι-C6 alkyl, trifluoromethyl, nitro, cyano, carbo Ci-Cg alkoxy, carboxy, phenyl, Ci-Cg thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C6) cycloalkyl (C3-C6) cycloalkyloxy (Cι-C6) alkyl, (C3-C6) cycloalkyl (Cι-C6) alkoxy (Ci-Cg) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (Cx-Cε) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (C3- C6) alkyl, (C6-Cx4) aryl (Cx-Cε) alkyl (Cε-CX4) aryl, (C6-C14) aryloxy, (Cβ-Cι4) aryloxy (Cι-C6) alkyl, (C6-C14) aryl (Cι-C6) alkyloxy, (C6-C14) aryl (Cι-C6) alkyl, trifluoromethoxy, cyano, amino, (Cι-C6) alkoxycarbonyl, carbamoyl, (Cι-C8) alkylthio, (Ci-Cg) alkylsulphinyl, (Cι-Cβ) alkylsulphonyl, sulphoamino, (Ci-Cg) alkylsulphonylamino, sulphamoyl and (Cι-C8) alkylcarbonylamino; said Cι-C6 alkyl being optionally substituted with halogen for Cι~C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl, said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; or two of R22-R26 can form a methylenedioxy group; R27-R3ι are each independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, halogen, Cι-CB alkoxy, Ci-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-C6 alkoxy, carboxy, phenyl, Cι~C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C6) cycloalkyl (C3-C6) cycloalkyloxy (Cι-C6) alkyl, (C3-C6) cycloalkyl (Cι-C6) alkoxy (Cι-Cε) alkyl, (C3-Cε) cycloalkyloxy, (C3-C6) cycloalkyl (Cι-Cε) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, . (Cg-C14) aryl, (C6-Cι4) heteroaryl, (Cε-CX4) heteroaryl (Cx-Cε) alkyl, (Cε-CX4) aryl (C3-C6) alkyl, (C6-Cι4) aryl (Cx-C6) alkyl (C6-Cx4) aryl, (C6-C14) aryloxy, (C6-CX4) aryloxy (Cx-Cε) alkyl, (Cε-CX4) aryl (Cx-Cε) alkyloxy, (C6-C14) aryl (Cx-C6) alkyl, trifluoromethoxy, cyano, amino (Cx-C6) alkoxycarbonyl, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cι-C8) alkylcarbonylamino; said Cι-C8 alkyl being optionally substituted with halogen or Cι~C3 alkyl; said Cι-C8 alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Cj-Cg thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι~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 Xi and X2 is nitrogen, with the other being carbon;
X3 is nitrogen or CR29;
X4 is nitrogen or CR30;
X5 is nitrogen or CR3ι,- wherein at least one of X3, X4, or X5 is nitrogen; or R2B and CR30 when taken together form an aryl ring; or R2B and CR29 when taken together form an aryl ring; or two of R27-R3ι 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-l- yl) acetyl) amino-5- ( (ethoxycarbonyl) -methyl) -1,3,4- thiadiazole;
2- ( ( (4- (2-pyridyl)piperazinyl-l) -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:
Figure imgf000077_0001
(XVb) wherein:
Ri is selected from the group consisting of hydrogen, halogen, Rι4COORι5, Rx6ORx7, RX8NHRX9, (C6-Cx4) aryl, (C6- CX4) aryl Cx-C6 alkyl, C3-C6 cycloalkyl, thio (C6-Cx4) aryl, thio (C6-CX4) heteroaryl Cx-C8 alkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, Cx-C8 alkoxy, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-Cβ) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-Cε) alkoxy, (Cx-C6) alkoxy (Cx-C6) alkyl, (C6-CX4) heteroaryl, (Cε-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-CX4) aryloxy, (C6-CX4) aryloxy (Cx-C6) alkyl, (C6-Cx4) aryl (Cx-C6) alkyloxy, (C6-Cx4) aryl (Cx-Cε) alkyloxy (Cx-Cε) alkyl, trihalo (Cx-Cε) alkyl, trihalo (Cx-Cε) alkoxy, cyano, nitro, carbamoyl, (CX-CB) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cx- C8) alkylcarbonylamino; said Cx-C8 alkyl group being optionally substituted with one or more halogen, Cx-C6 alkyl or phenyl groups; said thiophenyl being optionally substituted with halogen, amino Cx-C6 alkoxy, hydroxy, Cx-C6 alkyl, trihalo (Cx-C6) alkoxy or trihalo (Cx-C6) alkyl; said thio (C6-CX4) heteroaryl being optionally substituted with halogen, amino, alkoxy, hydroxy, Cx-C6 alkyl, trihalo (Cx-C6) alkyl or trihalo (Cx-C6) alkoxy; said C6-CX4 aryl and (C6-CX4) aryl (Cx-Cε) alkyl being optionally substituted with one or more substitutes selected from the group consisting of halogen, amino, hydroxy, Cx-C6 alkoxy, Cx-C6 alkyl, trihalo Cx- C6 alkyl and trihalo Cx-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 Cx-C6 alkyl;
R9 is a group selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cx-C6) alkoxy (Cx-Cg) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (Cx-Cε) alkoxy (Cx-C6) alkyl, C6-CX4 aryl, C6-CX4 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-Cx4) aryl (Ci- Cg) alkyl, (C6-Cι4) aryl (Ci-Cg) alkyl (Ci-Cg) aryl, (Cβ-C14) aryl (Ci-Cg) alkoxy (Cι-C6) alkyl, and (C6-Cι4) aryloxy (Cι-C6) alkyl group; Rio is selected from the group consisting of hydrogen, Cι-C8 alkyl, (Cι-C6) alkoxy (Cι-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3- C8) cycloalkyl (Cι-C6) alkoxy (Cι-C6) alkyl, Cε-Cι4 aryl, Cε-Cι4 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Ci- Cg) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl (Cx-C6) aryl, (C6-CX4) aryl (Cx-C6) alkoxy (Cι-C6) alkyl, and (C6-Cι4) aryloxy (Cx-C6) alkyl group;
Rxx is selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cx-C6) alkoxy (Cx-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, C6-Cι4 aryl, Cε-CX4 heteroaryl, (C6-CX4) heteroaryl (Cx-C3) alkyl, (C6-CX4) aryl (Cx- C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (Cx-C6) aryl, (C6-C14) aryl (Cx-C6) alkoxy (Cx-C6) alkyl, and (C6-CX4) aryloxy (Cx-C6) alkyl group;
RX2 is selected from the group consisting of hydrogen and Cx-C6 alkyl; Rx3 is selected from the group consisting of
Figure imgf000079_0001
RX4 is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cx-C2 alkyl group; said Cx-C2 alkyl group being substituted with one or more hydrogen, halogen, Cx-C6 alkyl or phenyl groups;
Rx5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and Cx- C6 alkyl group; said Cx-Cε alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and Cx-C3 alkyl;
Rx6 is a bond or is selected from the group consisting of sulfonyl, Cx-C8 thioalkyl, aminosulfonyl and Cx- Cε alkyl; said Cx-Cε alkyl group being substituted with one or more hydrogen, halogen, Cx-C6 alkyl or phenyl groups;
Rx7 is selected from the group consisting of phenyl, phenyl Cι-C6 alkyl, trifluoromethyl and Cι-C6 alkyl; said Cι-C6 alkyl being optionally substituted with one or more groups selected from the group consisting of halogen, phenyl, phenyl Ci-Cg alkyl, and Cx-C3 alkyl; said phenyl and phenyl Cx-C6 alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, amino, and Cx-Cε alkyl; Rx8 is a bond or is selected from the group consisting of sulfonyl, thio Cx-Cε alkyl, aminosulfonyl, carbonyl, aminocarbonyl and Cx-Cε alkyl; said Cx-Cε alkyl being substituted with one or more hydrogen, halogen, Cx-C6 alkyl or phenyl groups ; RX9 is selected from the group consisting of hydrogen, phenyl, phenyl Cx-C6 alkyl, and Cx-C6 alkyl; said Ci- Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of phenyl and Cx-C3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, Cx-C6 alkoxy, hydroxy, amino, and Cx-C6 alkyl; said phenyl Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, Cx-Cε alkoxy, hydroxy, amino, and Cx-Cε alkyl;
R20 is a group selected from the group consisting of hydrogen, Cx-Cε alkyl, hydroxy and Cx-C6 alkoxy; m is 0 or 1; n is 1; o is 0 or 1;
R2X is a bond or Cx-C6 alkyl; said Cx-C6 alkyl being optionally substituted from the group consisting of benzene and an optionally substituted benzene ring; said benzene ring optionally substitued from the group consisting of Cx-C6 alkyl, halogen, Cx-C6 alkoxy and hydroxy;
R22 is selected from the group consisting of hydrogen, halogen, Cx-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carboxy, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-C6) cycloalkyloxy (Cx-C6) alkyl, (C3-C6) cycloalkyl (Cx-C6) alkoxy (Cx-Cε) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl Cx-C6 alkoxy, (C3-C6) alkoxy C3-C6 alkyl, (C6-CX4) aryl, (C6-CX4) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-CX4) aryloxy, (C6-Cx4) aryl (Cx-C6) alkyl, trifluoromethoxy, amino, (Cx-Cε) alkoxycarbonyl, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said Cx-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R23 is selected from the group consisting of hydrogen, fluorine, bromine, Cι-C8 alkoxy, C2-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cι-C6 alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3-C6) cycloalkyl (Cι-C6) alkoxy (Ci-Cg) alkyl, (C3-Cε) cycloalkyloxy, (C3-Cε) cycloalkyl (Cι-Cε) alkoxy, (C3-Cε) alkoxy (C3-C6) alkyl, (Cε-Cι4) aryl, (Cε-Cι4) heteroaryl, (Cε-CX4) heteroaryl (Cx-Cε) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (C6-CX4) . aryl (Cx-C6) alkyl (Cg-CX4) aryl, (C6-CX4) aryloxy, (C6-C14) aryloxy (Cι-C6) alkyl, (C6-Cι4) aryl (Cι-Cβ) alkyloxy, (C6-C14) aryl (Cj-Cg) alkyl, trifluoromethoxy, amino, .(Ci-Cg) alkoxycarbonyl, carbamoyl, (Cι-Cβ) alkylthio, (Cι-Cβ) alkylsulphinyl, (Cι-C8) , alkylsulphonyl, sulphoamino, (Cι-C8) alkylsulphonylamino, sulphamoyl and (Cι-Cβ) alkylcarbonylamino; said C2-C8 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 alkoxy being optionally substituted with halogen or Cι~C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cι-Cβ alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R24 is selected from the group consisting of hydrogen, halogen, Cι-C8 alkoxy, Cι-C8 alkyl, trifluoromethyl, nitro, cyano, carboxy, Cι-CB thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-C6) cycloalkyloxy (Cι-C6) alkyl, (C3-C6) cycloalkyl (Cι-C6) alkoxy (Cι-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl Cι-C6 alkoxy, (C3-C6) alkoxy C3-C6 alkyl, (C6-Cι4) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl (Cι-C6) alkyl, (C6-C14) aryl (Cι-C6) alkyl, (C6-C14) aryl (Cι-C6) alkyl (C6-Cι4) aryl, (C6-C14) aryloxy, (C6-C14) aryl (Cj-Cg) alkyl, trifluoromethoxy, amino, (Cι-C6) alkoxycarbonyl, carbamoyl, (Cι-C8) alkylthio, (Cι-C8) alkylsulphinyl, (Cι~C8) alkylsulphonyl, sulphoamino, (Cι-C8) alkylsulphonylamino, sulphamoyl and (Cι-C8) alkylcarbonylamino; said Cι-C8 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Cι-CB alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι~C3 alkyl; R25 is selected from the group consisting of hydrogen, fluorine, bromine, Cι-C8 alkoxy, C2-CB alkyl, trifluoromethyl, nitro, cyano, carbo Cι-C6 alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl (C3-Cβ) cycloalkyloxy (Cx-Cε) alkyl, (C3-Cε) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-Cε) cycloalkyl (Cx-C3) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-CX4) aryl, (C6-CX4) heteroaryl, (C6-Cι4) heteroaryl (Cx-C6) alkyl, (C6-Cx4) aryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-CX4) aryloxy, (C6-CI4) aryloxy (Cι-C6) alkyl, (Cβ-C14) aryl (Cι-C6) alkyloxy, (C6-C14) aryl (Cx-C6) alkyl, trifluoromethoxy, amino, (Cx-C6) alkoxycarbonyl, carbamoyl, (Cι-Cβ) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) , alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said C2-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R26 is selected from the group consisting of hydrogen, halogen, Cx-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carboxy, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-Cε) cycloalkyloxy (Cx-C6) alkyl, (C3-C6) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl Cx-C6 alkoxy, (C3-C6) alkoxy C3-C6 alkyl, (C6-CX4) aryl, (C6-CX4) heteroaryl, (C6-C14) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-Cβ) alkyl, (C6-C14) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-CX4) aryloxy, (C6-CX4) aryl (Cx-C6) alkyl, trifluoromethoxy, amino, (Cx-C6) alkoxycarbonyl, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said Cx-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; or two of R22-R2ε when taken together can form a methylenedioxy; R 27~R 3i are each independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, hydrogen, halogen, Cx-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-Cε alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-Cε) cycloalkyloxy (Cx-Cε) alkyl, (Cx-C6) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-Cε) cycloalkyloxy, (C3-Cε) cycloalkyl (Cι-Cε) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-Cι4) aryl, (Cε-CX4) heteroaryl, (Cε-Cx4) heteroaryl (Cx-C6) alkyl, (CS-CX4) aryl (Ci- Cg) alkyl, (C6-C14) aryl (Cι-C6) alkyl (C6-C14) aryl, (C6-C14) aryloxy, (C6-Cι4) aryloxy (Cι-C6) alkyl, (Cg-C^) aryl (Cι-C6) alkyloxy, (C6-Cι4) aryl (Cι-C6) alkyl, trifluoromethoxy, cyano, amino, (Cι-C6) alkoxycarbonyl, carbamoyl, (Cι~C8) alkylthio, (Cι-C8) alkylsulphinyl, (Cι-C8) alkylsulphonyl, sulphoamino, (Cι-C8) alkylsulphonylamino, sulphamoyl and (Cι-C6) alkylcarbonylamino; said Cι~C8 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 alkoxy being optionally substituted with halogen or Cι~C3 alkyl; said Cx-Cβ thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι-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 Xx and X2 is nitrogen, with the other being carbon; X3 is nitrogen or CR29;
X4 is nitrogen or CR30; X5 is nitrogen or CR3X; wherein at least one of X3, X4, or Xs 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-R3ι 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-l) -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.
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: Ri is selected from the group consisting of hydrogen, halogen, Rι4COORι5, Rx6ORX7, RX8NHRX9, C6-CX4 aryl, (C6- Cx4) aryl (C6-CX4) alkyl, C3-C6 cycloalkyl, trifluoromethyl, thio (C6-CX4) aryl, (e.g., thiophenyl , thionaphthyl) , thio (C6- Cx4) heteroaryl (e.g., thio pyridyl, thioquinolinyl, thiopyrazinyl) and (CX-CB) alkyl; said (C6-C14) aryl and (C6- CX4) aryl Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cx-C6 alkoxy, Cx-C6 alkyl, trihalo Ci- Cg alkyl and trihalo Cι-C6 alkoxy; said Cx-C8 alkyl group being optionally substituted with one or more halogen, Cι-C6 alkyl or phenyl groups; said thio (C6-Cι4) aryl being optionally substituted with halogen, amino, Cx-C6 alkoxy, hydroxy, Cx-C6 alkyl, trihalo Cx-C6 alkoxy, or trihalo Cx-C6 alkyl; said thio Cx-C6 heteroaryl being optionally substituted with halogen, Cx-C6 alkoxy, hydroxy, Cx-C6 alkyl, trihalo Cx-C6 alkyl, or trihalo Cx-C6 alkoxy; R8-R2ι, m, n and o are as defined above for formula
(XVb) ;
R22 is selected from the group consisting of hydrogen, halogen, Cι-C6 alkoxy, Cι-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, and hydroxy; said Cι-Cε alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Cι-Cε alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-Cε) alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R23 is selected from the group consisting of hydrogen fluorine, bromine, Cx-C6 alkoxy, C2-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said C2-Cβ alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R24 is selected from the group consisting of hydrogen, halogen, Cx-Cε alkoxy, Cx-Cε alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-Cε) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-Cε alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-Cε alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; R25 is selected from the group consisting of hydrogen, fluorine, bromine, Cx-C6 alkoxy, trifluoromethyl, C2-C6 alkyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said C2-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R26 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C3) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; or two of R22-R26 when taken together can form a methylenedioxy group;
R27 is selected from the group consisting of hydrogen, halogen, Cx-Cε alkoxy, Cx-C6 alkyl, trifluoromethyl , nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R28 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-Cβ alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-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 Xx and X2 is nitrogen, with the other being carbon;
X3 is nitrogen or CR29 X4 is nitrogen or CR30 X5 is nitrogen or CR3X ; wherein at least one of X3, X4, or X5 is a nitrogen; R29 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R30 is selected from the group consisting of hydrogen, halogen, Cx-C3 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R31 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-Cε) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cα-C3 alkyl; said Cι-C6 alkoxy being optionally substituted with halogen or Cι~C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι-C3 alkyl; or R2B and CR30 when taken together form an aryl ring; or R2B 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-l) -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 compounds of the general formulas (XVa) and (XVb) according to the invention, there may be mentioned more particularly, as preferred compounds
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-l- yl) acetyl) amino) -5-cyclopropyl-l,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-l-yl) acetyl) amino) -5- (2- (carbomethoxy) ethyl) -1, 3 , 4 -thiadiazole, 2- ( ( (4- (2 -Pyridyl) piperazin-l-yl) acetyl) amino) -5- (2- (carbomethoxy) ethyl) -1 , 3 , 4 -thiadiazole
The invention also relates to a process for the preparation of the compounds of general formulas (XVa) and (XVb) . A preparation process according to the invention comprises the reaction of an aromatic amine of general formula (A3) :
Figure imgf000089_0001
(A3) in which Rx, R8, R9, Xx, X2, and m, are as defined above for formulas (XVa) and (XVb) , with a haloacyl halide of general formula (XXII) :
Figure imgf000089_0002
(XXII) in which R10 and Rllr 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) ;
Figure imgf000089_0003
(XXIII) in which Rx, R8, R9, Rι0, R11( χx, X2 and m are as defined above for formulas (XVa) and (XVb) , and Hal as defined above; and the reaction of the compound of general formula (XXIII) with a compound of general formula (XXIV) :
H
Figure imgf000090_0001
(XXIV) in which Rx2, Rx3 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) :
Figure imgf000090_0002
(XVa) and (XVb) in which Rx, R8, R9, R. 10/ R 1.1/ ^12 R 13/ m, Hal, and o are as defined above for formulas (XVa) or (XVb) , and Hal as defined above .
The invention further provides compounds, as well as compositions comprising said compounds, useful as hypoglycemic agents, of general formula (XVIa) :
Figure imgf000091_0001
wherein: Rx is selected from the group consisting of hydrogen and RX4COORx5;
R2 is selected from the group consisting of hydrogen, halogen, Rx6ORX7, RX8NHRX9, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, Cx-C8 alkoxy, (C3-C8) cycloalkyloxy (Ci-Cg) alkyl, (C3-C8) cycloalkyl (Cι-C6) alkoxy (Cι-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-Cg) alkoxy, (Ci- Cg) alkoxy (Cx-C6) alkyl, (C6-C14) aryl, (C6-CX4) heteroaryl, (C6-Cx4) heteroaryl (Cx-C6) alkyl, (CS-CX4) aryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (C6-Cx4) ary1 , (C6-CX4) aryloxy, (Cβ- CX4) aryloxy (Cx-Cε) alkyl, (C6-C14) aryl (Cι-C6) alkyloxy, (C6- CX4) aryl (Cx-Cε) alkyloxy (Cι-C6) alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, (Cx-C8) thioalkyl, (Ci-Cg) alkylsulphinyl, (Cι~C8) alkylsulphonyl, sulphoamino, (C2-C8) alkylsulphonylamino, and sulphamoyl; said Cx-C8 alkyl group being optionally substituted with one or more halogen, Ci-Cg alkyl or phenyl groups,- said C6-Cι4 aryl and (C6-Cι4) aryl (Ci-Cg) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cι-C6 alkoxy, Cι-C6 alkyl, trihalo (Cι-C6) alkyl, and trihalo (Cι-C6) alkoxy;
R3 is selected from the group consisting of hydrogen, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (Cι-C6) alkyl, (C6-Cι4) aryl, (C6-CX4) heteroaryl, (C6-Cx4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, halogen, trifluoromethyl, and cyano; said Cx-C8 alkyl being optionally substituted with one or more halogen, Cx-C6 alkyl or phenyl groups; said C6-CX4 aryl and (C6-Cx4) aryl (Cx-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cx-C6 alkoxy, Ci- Cg alkyl, trihalo (Cx-C6) alkyl, and trihalo (Cx-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 phenylalkyl;
R9 is a group selected from the -group consisting of hydrogen, Cx-C8 alkyl, (Cx-C6) alkoxy (Cx-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-Cε) alkyl group, (C3-Cβ) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, C6-CX4 aryl, C6-CX4 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx- C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (Cx-C6) aryl, (C6-CX4) aryl (Cx-C6) alkoxy (Cx-C6) alkyl, and (Cε-CX4) aryloxy (Cx-Cε) alkyl group;
Rx0 is selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cx-C6) alkoxy (Cx-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl group, (C3-Cβ) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, C6-CX4 aryl, C6-C14 heteroaryl, (C6-C14) heteroaryl (Cx-Cε) alkyl, (C6-CX4) aryl (Ci- Cg) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (Cx-C6) aryl, (C6-Cx4) aryl (Cx-C6) alkoxy (Cx-C6) alkyl, and (C6-CX4) aryloxy (Cx-C6) alkyl group; Rxx is selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cx-C6) alkoxy (Cx-Cε) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-Cε) alkyl group, (C3-C8) cycloalkyloxy (Cx-Cε) alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, C6-CX4 aryl, C6-CX4 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Ci- Cg) alkyl, (C6-Cι4) aryl (Cx-C6) alkyl (Cx-Cε) aryl, (Cε-CX4) aryl (Cx-Cε) alkoxy (Cx-Cε) alkyl, and (Cε-CX4) aryloxy (Cx-Cε) alkyl group;
RX2 is selected from the group consisting of hydrogen and Cx-Cε alkyl;
Rx3 is selected from the group consisting of
Figure imgf000093_0001
RX4 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cx-C6 alkyl group; said Cx-C6 alkyl group being substituted with one or more hydrogen, halogen, Cx-Cε 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 Cx -C6 alkyl group; said Cx-Cε alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and Cx-C3 alkyl; RX6 is a bond or is selected from the group consisting of sulfonyl, C2-Cε thioalkyl, aminosulfonyl and Ci- Cg alkyl; said C^Cg alkyl being substituted with one or more hydrogen, halogen, Cι-C6 alkyl or phenyl groups;
Ri, is selected from the group consisting of phenyl, phenylalkyl, and a Cι-C6 alkyl group; said Cι-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of halogen, phenyl, phenylalkyl, and Cι~C3 alkyl; said phenyl and phenylalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, Cι-C6 alkoxy, amino, and Cι-C6 alkyl;
Ri8 is a bond or is selected from the group consisting of sulfonyl, C2-Cε thioalkyl, aminosulfonyl, carbonyl, aminocarbonyl and Cι-Cε alkyl group, said Cι-Cε alkyl group being substituted with one or more hydrogen, halogen, Cι-C6 alkyl or phenyl groups; Rι9 is selected from the group consisting of hydrogen, phenyl, phenyl (Cι-C6) alkyl, and Cι-C6 alkyl; said Ci- Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of phenyl and Cx-C3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino, and Cι~Cβ alkyl; said phenyl Ci-Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino, or Cι-C3 alkyl;
R20 is selected from the group consisting of hydrogen, Cι-C6 alkyl, hydroxy and Cι-C6 alkoxy; m is 0 or 1; o is 0 or 1; R2ι is a bond or is selected from the group consisting Cι-C6 alkyl; said Cι-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 Cι-C6 alkyl, halogen, Cι-C6 alkoxy and hydroxy;
R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C8 alkoxy, Cι-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cι-C6 alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, hydroxy, Cι-C6 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cι-C6) alkyl, (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3-C8) cycloalkyl (Cι-C6) alkoxy (Cι~C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cι-C6) alkoxy, (Cι-C6) alkoxy (Ci-Cg) alkyl, (C6-Cι4) aryl, (Cg-C^) heteroaryl, (Cε-Cι4) heteroaryl (Cι-C6) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl, (C6-Cι4) aryl (C^Cg) alkyl (C6-Cι4) aryl, (Cg-Cj4) aryloxy, (C3-Cι4) aryloxy (Cι-C6) alkyl, (C6-Cι4) aryl (Cι-C6) alkyloxy, (C6-Cι4) aryl (Cι-C6) alkyloxy (Cι-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cι-C8) alkylthio, (Cι-C8) alkylsulphinyl, (Cι-C8) alkylsulphonyl, sulphoamino, (Cι~C8) alkylsulphonylamino, sulphamoyl and (Cι-CB) alkylcarbonylamino; said Cι-C8 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said C2-C8 alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R23 is selected from the group consisting of hydrogen, halogen, Cι-C8 alkoxy, Cι-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cι-C6 alkoxy, carboxy, Cι-C8 thioalkyl, hydroxy, C3-CB cycloalkyl, (C3-C8) cycloalkyl (Cι-C6) alkyl, (C3-C8) cycloalkyloxy (Cj-Cg) alkyl, (C3-C8) cycloalkyl (Cι-C6) alkoxy (Cι-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Ci-Cg) alkoxy, (Cι-C6) alkoxy (Cι-Cβ) alkyl, (C6-C14) aryl, (C6- C14) heteroaryl, (Cg-C14) heteroaryl (C^Cg) alkyl, (C6-Cι4) aryl (Ci-Cg) alkyl, (C6-C14) aryl (Cι-C6) alkyl (Cg-Cι4) aryl, (Cβ-Cι4) aryloxy, (C6-CI4) aryloxy (Cι-Cβ) alkyl, (C6-Cι4) . aryl (Cι-C6) alkyloxy, (Cε-C14) aryl (Cι-Cβ) alkyloxy (Cι-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cι~C8) alkylthio, (Cι-CB) alkylsulphinyl, (Cι-C8) alkylsulphonyl, sulphoamino, (Cι-C8) alkylsulphonylamino, sulphamoyl and (C2-C8) alkylcarbonylamino; said Cι-C8 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 alkoxy being optionally substituted with halogen or Cι~C3 alkyl; said Ci-Cβ thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R24 is selected from the group consisting of hydrogen, bromine, chlorine, Cι-C8 alkoxy, Cι-C8 alkyl, trifluoromethyl , nitro, cyano, carbo ^Cg alkoxy, carboxy, Ci-Cg thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Ci-Cg) alkyl, (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3-C8) cycloalkyl (Cι-C6) alkoxy (Cι-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl
Figure imgf000095_0001
alkoxy, (Cι-C6) alkoxy (Cι-C6) alkyl, (C6-Cι4) aryl, (C6-C14) heteroaryl, (C6-Cι4) heteroaryl (Cι-C6) alkyl, (C6-C14) aryl (Cι-C6) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl (C6-Cι4) aryl, (C6-C14) aryloxy, (C6-Cι4) aryloxy (Cι-C6) alkyl, (Cg-Cι4) aryl (Ci-Cβ) alkyloxy, (C6-C14) aryl (Cι-C6) alkyloxy (Ci-Cg) alkyl, trifluoromethoxy, amino, carbamoyl, (Cι-C8) alkylthio, (Cι-C8) alkylsulphinyl, (Cι-C8) alkylsulphonyl, sulphoamino, (Cι-C8) alkylsulphonylamino, sulphamoyl and (CX- C8) alkylcarbonylamino; said Cι-C8 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Cι-CB thioalkyl being optionally substituted with halogen or Cι~C8 alkyl; said carbo (Cι-Cε) alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R25 is selected from the group consisting of hydrogen, halogen, Cι-C8 alkoxy, Cι-C8 alkyl, trifluoromethyl , nitro, cyano, carbo Cι-Cε alkoxy, carboxy, Ci-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cι-Cε) alkyl, (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3-Cβ) cycloalkyl (Ci-C6) alkoxy (Cι-Cε) alkyl, (C3-C8) cycloalkyloxy, (C3-CB) cycloalkyl (Ci-Cg) alkoxy, (Cι-C6) alkoxy (Cι-C6) alkyl, (C6-Cι4) aryl, (C6- C14) heteroaryl, (C6-Cι4) heteroaryl (Cι-C6) alkyl, (C6-C14) aryl (Ci-Cg) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl (Cε-C14) aryl, (C6-Cι4) aryloxy, (C6-Cι4) aryloxy (Cι-C6) alkyl, (C6-C14) aryl (Cι-C6) alkyloxy, (C6-C14) aryl (Cι-C6) alkyloxy (Cι-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cι-C8) alkylthio, (Cj-Cg) alkylsulphinyl, (Cι-Cβ) alkylsulphonyl, sulphoamino, (Cι-Ce) alkylsulphonylamino, sulphamoyl and (C2-C8) alkylcarbonylamino; said Cι-C8 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Ci-Cg alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (C^Cg) alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C8 alkoxy, Cι-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cι-C6 alkoxy, carboxy, phenyl, Cι~C8 thioalkyl, hydroxy, Cι-C6 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Ci-Cg) alkyl, (C3-C„) cycloalkyloxy (Cι-C6) alkyl, (C3-C8) cycloalkyl (Cι-Cε) alkoxy (Cι-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cι-Cε) alkoxy, (Cι-Cε) alkoxy (Ci-Cg) alkyl, (Cβ-Cι4) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl (Cj-Cg) alkyl, (C6-C14) aryl (Ci-Cg) alkyl, (C6-C14) aryl (Cj-Cg) alkyl (C6-C14) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (Ci-Cg) alkyl, (C6-Cι4) aryl (Ci-C8) alkyloxy, (C6-C14) aryl (Cι-C6) alkyloxy (Cι-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cι-C8) alkylthio, (Cι-C8) alkylsulphinyl, (Cι-C8) alkylsulphonyl, sulphoamino, (Cι-C8) alkylsulphonylamino, sulphamoyl and (Cι-C8) alkylcarbonylamino; said Cι-C8 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said C2-C8 alkoxy being optionally substituted with halogen or Cι~C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-Cε) alkoxy being optionally substituted with halogen or Cι~C3 alkyl; wherein R22-R26 are not all simultaneously hydrogen; or two of R22-R26 can form a methylenedioxy;
R27-R 3i are independently selected from the group consisting of hydrogen, halogen, Cι-C8 alkoxy, Cι-C„ alkyl, trifluoromethyl, nitro, cyano, carbo Cι-C6 alkoxy, carboxy, Cι-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Ci-Cg) alkyl, (C3-Cβ) cycloalkyloxy (Cι-C6) alkyl, (C3-C8) cycloalkyl (Cι-C6) alkoxy (Cι-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cι-C6) alkoxy, (Cι-Cβ) alkoxy (Cι-C6) alkyl, (Cfi-C14) aryl, (Cg-C^) heteroaryl, (C6-Cι4) heteroaryl (Cι-C6) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl (Cβ-Cι4) aryl, (C6-C14) aryloxy, (C6-Cι4) aryloxy (Cι-C6) alkyl, (C6-Cι4) aryl (Cι-C6) alkyloxy, (Cβ-Cι4) aryl (Cι-C6) alkyloxy (Ci-Cg) alkyl, trifluoromethoxy, amino, carbamoyl, (Cι-C8) alkylthio, (Cι-C8) alkylsulphinyl, (Ci-Cg) alkylsulphonyl, sulphoamino, (Cι~C8) alkylsulphonylamino, sulphamoyl and (C2- C8) alkylcarbonylamino; said Cι-C8 alkyl being optionally substituted with halogen or Cι~C3 alkyl; said Cj-Cg alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι~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 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-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 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 compounds as well as compositions comprising said compounds, useful as hypoglycemic agents wherein:
Rx is selected from the group consisting of hydrogen and Rι4COORι5; R2 is selected from the group consisting of hydrogen, halogen, Rι6ORι7, Rι8NHRι9, C6-Cι4 aryl, (Cε-Cι4) aryl Ci-Cg alkyl, Cι-C8 alkyl, and C3-C6 cycloalkyl; said C6-Cι4 aryl, and said (C6-Cι4) aryl Cι-C6 alkyl, being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cι-C6 alkoxy, Cx- C6 alkyl, trihalo (Cι-C6) alkyl, and trihalo (Cι-C6) alkoxy; said Ci-Cg alkyl group being optionally substituted with one or more halogen, -Cg alkyl or phenyl groups;
R3 is selected from the group consisting of hydrogen, Cg-C14 aryl, (C6-Cι4) aryl (Cι-C6) alkyl, and Cj-Cg alkyl group; said C6-Cι4 aryl, and said (C6-Cι4) aryl (Cι-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Ci-C6 alkoxy, Cι-C6 alkyl, C3-C8 cycloalkyl, trihalo (Cι-C6) alkyl, and trihalo (Cι-C6) alkoxy; said Cι~C8 alkyl group being optionally substituted with one or more halogen, Cι-C6 alkyl or phenyl groups;
RB-R2ι, m, and o are as defined above for formula (XVIa) ; R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Cι-C6 alkyl, nitro, trifluoromethyl, cyano, carbo (Ci-C6) alkoxy, carboxy, phenyl, Ci-Cg thioalkyl, and hydroxy; said Ci-C8 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R23 is selected from the group consisting of hydrogen, halogen, Cι-C6 alkoxy, Cι-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cι~Cε) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, and hydroxy; said Cι-Cε alkyl being optionally substituted with halogen or Cι-C3 alkyl; said C^Cg alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (Cι~C6) alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R24 is selected from the group consisting of hydrogen, bromine, chlorine, Cι-C6 alkoxy, Cι-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with halogen or Cι~C3 alkyl; said Cj-Cg alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι-C3 alkyl; R25 is selected from the group consisting of hydrogen, halogen, Cι-C6 alkoxy, Cι-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cι~C8 thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cι~Cε alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-Cε) alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Ci-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-Cg) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, and hydroxy; said Cι-Cε alkyl being optionally substituted with halogen or Cι-C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or Cι~C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι~C3 alkyl; wherein R22-R26 cannot all simultaneously be hydrogen; or two of R22-R26 when taken together can form a methylenedioxy group; R27 is selected from the group consisting of halogen, Cι-C6 alkoxy, Cι-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cι~C6) alkoxy, carboxy, phenyl, Cj-C8 thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Ci~C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cι-Cβ thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι~C3 alkyl;
R28 is selected from the group consisting of hydrogen, halogen, Cι-C6 alkoxy, Ci-C6 alkyl; nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cj-C8 thioalkyl, and hydroxy; said Cι-Cε alkyl being optionally substituted with halogen or Cι~C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι~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 CR3ι,- wherein at least one of X3, X4, or X5 is nitrogen; R29 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, C^Cg alkyl, nitro, cyano, carbo (Ci-C6) alkoxy, carboxy, phenyl, Cι~C8 thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with one to two halogen atoms or Cι-C3 alkyl; said Cι-C6 alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R30 is selected from the group consisting of hydrogen, halogen, Cι-C6 alkoxy, Cι-C6 alkyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C6 alkoxy being optionally substituted with halogen or Cι~C3 alkyl;
R3ι is selected from the group consisting of hydrogen, halogen, Cι-C6 alkoxy, Cι-C6 alkyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cι-CB thioalkyl, and hydroxy; said C^Cg alkyl being optionally substituted with one to two halogen atoms or Cι-C3 alkyl; said Cι C6 alkoxy being optionally substituted with halogen or Cι-C3 alkyl; wherein up to three of R27-R3i 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 ; 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:
Figure imgf000102_0001
wherein :
Ri is selected from the group consisting of hydrogen and Rι4COORι5;
R2 is selected from the group consisting of hydrogen, halogen, RιβORι7, Rι8NHRι9, C3-C8 cycloalkyl, (C3-C„) cycloalkyl (Ci-Cg) alkyl, Cι-C8 alkoxy, (C3-C8) cycloalkyloxy (Ci-Cg) alkyl, (C3-Cβ) cycloalkyl (Cι-Cβ) alkoxy (Cι-Cβ) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cι-C6) alkoxy, (Ci- Cg) alkoxy (Cι-C6) alkyl, (C6-C14) aryl, (C6-Cι4) heteroaryl, (Cg-Cι4) heteroaryl (Cι-Cβ) alkyl, (Cg-C14) aryl (Cι-C6) alkyl, (C6-Cι4) aryl (Cx-C6) alkyl (C6-Cι4) aryl, (Cβ-C14) aryloxy, (Cε- C14) aryloxy (Cj-Cg) alkyl, (C6-C14) aryl (Ci-Cg) alkyloxy, (C6- Ci4) aryl (Cι-C6) alkyloxy (Cι-C6) alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, (Cι-C8) thioalkyl, (Ci-Cg) alkylsulphinyl, (Cι-C8) alkylsulphonyl, sulphoamino, (C2-C8) alkylsulphonylamino, and sulphamoyl; said Cι-C8 alkyl group being optionally substituted with one or more halogen, Ci-Cg alkyl or phenyl groups; said C6-Cι4 aryl and (C6-Cι4) aryl (Ci-Cg) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cι-C6 alkoxy, Cι-C6 alkyl, trihalo (C^Cg) alkyl, and trihalo (Cι-C6) alkoxy;
R3 is selected from the group consisting of hydrogen, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C^Cg) alkyl, (C6-C14) aryl, (Cβ-Cι4) heteroaryl, (C6-C14) heteroaryl (Cj-Cg) alkyl, (C6-C14) aryl (Cι-C6) alkyl, halogen, trifluoromethyl , and cyano; said Cι-C8 alkyl being optionally substituted with one or more halogen, Cι-C6 alkyl or phenyl groups; said C6-C14 aryl and (C6-Cι4) aryl (Cι-Cε) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cι-Cε alkoxy, Cx- C6 alkyl, trihalo (Cι-Cε) alkyl, and trihalo (Cx-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 phenylalkyl;
R9 is a group selected from the group consisting of hydrogen, Cι-C8 alkyl, (Cι-Cε) alkoxy (Cx-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3- C8) cycloalkyl (Ci-Cg) alkoxy (Cι-C6) alkyl, C6-Cι4 aryl, Cε-Cι4 heteroaryl, (Cε-Cι4) heteroaryl (Cx-C6) alkyl, (C6-Cι4) aryl (Ci- Cg) alkyl, (C6-Cι4) aryl (Ci-Cg) alkyl (C^Cg) aryl, (Cβ-Cι4) aryl (Ci-Cg) alkoxy (Cι-C6) alkyl, and (C6-C14) aryloxy (Cx-Cg) alkyl group;
Rio is selected from the group consisting of hydrogen, Cι-C8 alkyl, (Cι-C6) alkoxy (Cι-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Cι-C6) alkyl, C6-Cι4 aryl, Cε-C14 heteroaryl, (Cε-C14) heteroaryl (Cι-C6) alkyl, (C6-C14) aryl (Ci- Cg) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl (Cι-C6) aryl, (C6-Cι4) aryl (Ci-Cg) alkoxy (Cι-C6) alkyl, and (C6-Cι4) aryloxy (Cι-C6) alkyl group;
Rii is selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cι-C6) alkoxy (Cι-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3- Cβ) cycloalkyl (Ci-Cg) alkoxy (Cx-C6) alkyl, C6-CX4 aryl, C6-CX4 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C5-CX4) aryl (Ci- Cg) alkyl, (Cβ-C14) aryl (Cι-C6) alkyl (Cj-Cg) aryl, (C6-Cι4) aryl (Ci-Cg) alkoxy (Cx-C6) alkyl, and (Cε-CX4) aryloxy (Cx-C6) alkyl group; RX2 is selected from the group consisting of hydrogen and Cx-C6 alkyl;
Rx3 is selected from the group consisting of
Figure imgf000104_0001
Rx4 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Ci-Cg alkyl group; said Cι-Cε alkyl group being substituted with one or more hydrogen, halogen,
Figure imgf000104_0002
alkyl or phenyl groups ;
Ri5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, divalent alkali metals, divalent alkali earth metals, and a Cx -C6 alkyl group; said Cι-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and Cι-C3 alkyl; Rx€ is a bond or is selected from the group consisting of sulfonyl, C2-Cε thioalkyl, aminosulfonyl and Cx- C6 alkyl; said Cι-C6 alkyl being substituted with one or more hydrogen, halogen, Cι-C6 alkyl or phenyl groups;
Ri7 is selected from the group consisting of phenyl, phenylalkyl, and a Cj-Cg alkyl group; said Cι-Cε alkyl group being optionally substituted with one or more groups selected from the group consisting of halogen, phenyl, phenylalkyl, and Cx-C3 alkyl; said phenyl and phenylalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, Cι-C6 alkoxy, amino, and Cι-Cε alkyl;
RX8 is a bond or is selected from the group consisting of sulfonyl, C2-Cε thioalkyl, aminosulfonyl, carbonyl, aminocarbonyl and Cι-C6 alkyl group, said Cι-C6 alkyl group being substituted with one or more hydrogen, halogen, Ci-Cg alkyl or phenyl groups; RX9 is selected from the group consisting of hydrogen, phenyl, phenyl (Cι-C6) alkyl, and Cx-Cg alkyl; said Ci- Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of phenyl and Ci-C3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino, and Cx-C6- alkyl; said phenyl Ci-Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino, or Cι-C6 alkyl;
R20 is selected from the group consisting of hydrogen, Cι-C6 alkyl, hydroxy and Cι-C6 alkoxy; m is 0 or 1; o is 0 or 1; R2ι is a bond or is selected from the group consisting Cx-Cε alkyl; said Cx-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 Cx-C6 alkyl, halogen, Cx-C6 alkoxy and hydroxy;
R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-C6 alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, hydroxy, Cx-C6 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C3-Cβ) cycloalkyloxy (Cx-Cε) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-C6) alkoxy, (Cx-Cε) alkoxy (Ci-Cg) alkyl, (C6-CX4) aryl, (Cε-CX4) heteroaryl, (Cε-CX4) heteroaryl (Ci-C6) alkyl, (Cβ-Cι4) aryl (Cι-C6) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl (Cβ-Cι4) aryl, (C6-Cι4) aryloxy, (Cβ-Cι4) aryloxy (Cι-C6) alkyl, (Cβ-C14) aryl (Ci-Cg) alkyloxy, (C6-C14) aryl (Cι-Cε) alkyloxy (Cι-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cι-C8) alkylthio, (Cι-Cβ) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cι-C8) alkylsulphonylamino, sulphamoyl and (Cι-C8) alkylcarbonylamino; said Cι-CB alkyl being optionally substituted with halogen or Cx-C3 alkyl; said C2-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said CX-CB thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R23 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-C6 alkoxy, carboxy, Cx-C8 thioalkyl, hydroxy, C3-Ca cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-Cε) alkoxy (Cx-Cg) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Ci-Cg) alkoxy, (Ci-C6) alkoxy (Cι-C6) alkyl, (C6-Cι4) aryl, (C6- CX4) heteroaryl, (C6-CX4) heteroaryl (Cx-Cε) alkyl, (Cε-CX4) aryl (Cx-Cε) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (C6-CX4) aryl, (Cε-CX4) aryloxy, (C6-CX4) aryloxy (Cx-C6) alkyl, (Cε-CX4) aryl (Cx-C6) alkyloxy, (C6-CX4) aryl (Cx-C6) alkyloxy (Cx-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (C2-C8) alkylcarbonylamino; said Cx-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R24 is selected from the group consisting of hydrogen, bromine, chlorine, Cx-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-Cfi alkoxy, carboxy, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-Cg) alkyl, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-C6) alkoxy, (Cx-C6) alkoxy (Cx-C6) alkyl, (C6-CX4) aryl, (C6-CX4) heteroaryl, (Cε-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (Cε-Cx4) aryl (Cx-Cε) alkyl (Cε-CX4) aryl, (Cε-CX4) aryloxy, (C6-CX4) aryloxy (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyloxy, (C6-Cx4) aryl (Cx-Cβ) alkyloxy (Cx-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cx-C8) alkylthio, (Ci-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (C^C;,) alkylsulphonylamino, sulphamoyl and (Cx- C8) alkylcarbonylamino; said Cx-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said CX-CB thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-Cε) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R25 is selected from the group consisting of hydrogen, halogen, Cι-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl , nitro, cyano, carbo Cx-Cε alkoxy, carboxy, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-Ce) cycloalkyloxy, (C3-C8) cycloalkyl (Ci-Cg) alkoxy, (Cι-C6) alkoxy (Ci-Cg) alkyl, (C6-Cι4) aryl, (C6- CX4) heteroaryl, (Cε-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-Cε) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (C6-CX4) aryl, (Cε-CX4) aryloxy, (C6-CX4) aryloxy (Cx-C6) alkyl, (C6-Cx4) aryl (Cx-C6) alkyloxy, (C6-CX4) aryl (Cx-C6) alkyloxy (Cι-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cι-C8) alkylthio, (Cι-CB) alkylsulphinyl, (Cι-C8) alkylsulphonyl, sulphoamino, (Cι~C8) alkylsulphonylamino, sulphamoyl and (C2-C8) alkylcarbonylamino; said Cι-CB alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Cι-C8 alkoxy being optionally substituted with halogen or Cι~C3 alkyl; said Ci-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C8 alkoxy, CX-CB alkyl, trifluoromethyl, nitro, cyano, carbo Cx-Cε alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, hydroxy, Cx-Cε alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-Cε) alkyl, (C3-C8) cycloalkyloxy (Cx-Cε) alkyl, (C3-C8) cycloalkyl (Cx-Cε) alkoxy (Cx-Cε) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-Cε) alkoxy, (Cx-Cε) alkoxy (Cx-C6) alkyl, (Cε-Cι4) aryl, (C6-Cι4) heteroaryl, (C6-CX4) heteroaryl (Cx-Cg) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-CX4) aryloxy, (C6-C14) aryloxy (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyloxy, (C6-CX4) aryl (Cι-C6) alkyloxy (Cx-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cx-C8) alkylthio, (Cι-C8) alkylsulphinyl, (Cι-C8) alkylsulphonyl, sulphoamino, (CX-CB) alkylsulphonylamino, sulphamoyl and (Cι-C8) alkylcarbonylamino; said Cι~C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said C2-C8 alkoxy being optionally substituted with halogen or Cι~C3 alkyl; said Cj-C8 thioalkyl being optionally substituted with halogen or Cι-Cβ alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; wherein R22-R26 are not all simultaneously hydrogen; or two of R22-R26 can form a methylenedioxy;
R27-R3ι are independently selected from the group consisting of hydrogen, halogen, Cι-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-C6 alkoxy, carboxy, Cx-C8 thioalkyl, hydroxy, C3-CB cycloalkyl, (C3-C8) cycloalkyl (Ci-Cg) alkyl, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cι-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cι-C3) alkoxy, (Cι-C6) alkoxy (Cj-Cg) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl (Cι-C6) alkyl, (Cg-C14) aryl (Cι-C6) alkyl, (C6-Cι4) aryl (Cι-C6) alkyl (C6-C14) aryl, (C6-Cι4) aryloxy, (C6-Cι4) aryloxy (Cx-Cε) alkyl, (C6-CX4) aryl (Cx-C6) alkyloxy, (C6-CX4) aryl (Cx-C6) alkyloxy (Cx-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cx-C8) alkylthio, (CX-CB) alkylsulphinyl, (Cι-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (C2- C8) alkylcarbonylamino; said Cι-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cι~C8 alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι~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 CR3ι,- wherein at least one of X3, χ4, or X5 is nitrogen; wherein up to three of R2-R3X can simultaneously be hydrogen when only one of X3-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 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: Rx is selected from the group consisting of hydrogen and RX4COORX5;
R2 is selected from the group consisting of hydrogen, halogen, RX6ORx7, RX8NHRX9, C6-CX4 aryl, (C6-CX4) aryl Cx-C6 alkyl, Cx-C8 alkyl, and C3-Ce cycloalkyl; said C6-CX4 aryl, and said (C6-CX4) aryl Cx-C6 alkyl, being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cx-C6 alkoxy, Cx- Cε alkyl, trihalo (Cx-Cε) alkyl, and trihalo (Cx-Cε) alkoxy; said Cx-C8 alkyl group being optionally substituted with one or more halogen, Cx-Cε alkyl or phenyl groups;
R3 is selected from the group consisting of hydrogen, Cε-CX4 aryl, (Cε-CX4) aryl (Cx-Cε) alkyl, and Cx-C8 alkyl group; said C6-CX4 aryl, and said (C6-Cx4) aryl (Cx-Cε) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cx-C6 alkoxy, Cx-Cε alkyl, C3-C8 cycloalkyl, trihalo (Cx-C6) alkyl, and trihalo (Cx-C6) alkoxy; said Cx-C8 alkyl group being optionally substituted with one or more halogen, Cx-C6 alkyl or phenyl groups; R 8"R2i m an<ϊ ° are as defined above for formula
(XVIb) ; R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Cx-C6 alkyl, nitro, trifluoromethyl, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Ci-Cg thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or Cx-Cβ alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; R23 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl , nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι~C3 alkyl;
R24 is selected from the group consisting of hydrogen, bromine, chlorine, Cι-C6 alkoxy, Cι-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-Cε) alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R25 is selected from the group consisting of hydrogen, halogen, Cι-C6 alkoxy, Cι-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Cι-Cε alkoxy being optionally substituted with halogen or Cι-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or Cι~C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-Cε) alkoxy being optionally substituted with halogen or Cι-C3 alkyl; wherein R22-R26 cannot all simultaneously be hydrogen; or two of R22-R26 when taken together can form a methylenedioxy group;
R27 is selected from the group consisting of halogen, Cι-Cε alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci~C6) alkoxy, carboxy, phenyl, Cι-CB thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with halogen or Cι-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R28 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cι-C6 alkyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, and hydroxy; said Cι-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cι-Cε alkoxy being optionally substituted with halogen or Cι~C3 alkyl; said Cι-C8 thioalkyl being optionally substituted with halogen or Cι-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι-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 CR3X; wherein at least one of X3, X4, or X5 is nitrogen; R29 is selected from the group consisting of hydrogen, halogen, Cx-Cε alkoxy, Cι-C6 alkyl, nitro, cyano, carbo (Cι-C6) alkoxy, carboxy, phenyl, Cι-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with one to two halogen atoms or Cx-C3 alkyl; said Cι-C6 alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R30 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R3X is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, nitro, cyano, carbo (Cx-Cε) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-Cε alkyl being optionally substituted with one to two halogen atoms or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; wherein up to three of R27-R3X can simultanoeously be hydrogen when only one of X3-X5 is nitrogen; wherein up to two of R27-R3X 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. @@@
Among the compounds of the general formulas (XVIa) and (XVIb) according to the invention, there may be mentioned more particularly, as preferred compounds
3- ( ( (4- (2-Fluorophenyl)piperazin-l- 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-1- 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 compounds of general formulas (XVIa) and (XVIb) . A preparation process according to the invention comprises the reaction of an aromatic amine of general formula (A4) :
Figure imgf000113_0001
(A4) in which Rx, R2, R3, R8, R9 and m are as defined above for formulas (XVIa) and (XVIb) , with a haloacyl halide of general formula (XXV) :
Figure imgf000113_0002
(XXV) in which Rx0 and Rxx 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) ;
- Ill -
Figure imgf000114_0001
(XXVI) in which Rx, R2, R3, R8, R9, R10, Rn and m are as defined above for formulas (XVIa) and (XVIb) and Hal is as defined above; and the reaction of the compound of general formula (XXVI) with a compound of general formula (XXVII) :
Figure imgf000114_0002
(XVIII) in which Rι2, Ri3, 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) :
Figure imgf000114_0003
(XVIa) and (XVIb) in which Rx, R2, R3, R8, R9, Rx0, Rxx, Rx2, Rx3, 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 provide the desired heterocyclic piperazines 9. R2X-R28 and X3_ X5 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 Al, thiazole A2 , thiadiazole A3, or thiophene A4 is first acylated with a haloacetyl halide and then condensed with nucleophile 2. RX,RX3 are defined above in Section 3; Z is bromine or chlorine.
5. DETAILED DESCRIPTION OF THE INVENTION
5.1 COMPOUNDS OF FORMULA (I)
The invention provides compounds of formula (I) :
Figure imgf000115_0001
(I)
in which Ar and Rx-Rε 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, include, but are not limited to, phenyl, α-naphthyl, S-naphthyl and fluorenyl groups .
The Cι-C8 alkyl groups may be linear or branched, and include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups. The Cι-C8 alkoxy groups may likewise be linear or branched, and include, 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 compounds of general formula (I) .
The compounds of general formula (I) have a carboxylic acid functional group and may be salified, i . e . , converted into conjugate bases they then being in the form of salts with bases.
Examples of salts with bases of the compounds 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 compounds of general formula (I) can also be salified with amines in order to form pharmaceutically acceptable salts. By way of example, it will be possible for the compounds of general formula (I) to be salified with glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine. The compounds 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 compounds 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 compounds of general formula (I) according to the invention, there may be mentioned more particularly, as preferred compounds:
4- {4- [2 (N-isopropyl-N-phenylamino) -2-oxoethyl] -1- piperazinyl}benzoic acid; 4- {4- [2- (N- [2,6-dimethylphenyl]amino) -2-oxoethyl] - l-piperazinyl}benzoic acid; and
4- {4- [2- (N- [2, 6-diisopropylphenyl] amino) -2- oxoethyl] -l-piperazinyl}benzoic 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 compounds of general formula (I) . A process of preparation according to the invention comprises reacting an aromatic amine of general formula (II) :
Ar H N
I
(II) in which Ar and Rx are as de-fined above for formula (I) , with a halocyl halide of general formula (III) :
Figure imgf000118_0001
(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) :
Figure imgf000118_0002
(IV) in which Ar, Rx, 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) :
Figure imgf000118_0003
(V) in which R4, Rs and Rε, are as defined above for formula (I) and R7 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) :
Figure imgf000119_0001
(VI) in which Ar, Rx , R2, R3, R4, R5, Rε and R7 are as defined above for formula (I) .
In the case where R7 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) :
Figure imgf000119_0002
:D in which Ar, Rχ R2, R3, R4, R5 and Rε are as defined above for formula (I) .
The compounds of formula (V) are known compounds. 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- (1- piperazinyl) benzote .
By way of example, the compound (VI) , in which R7 is an alkyl group, can be hydrolyzed in the presence of a basic agent such as dilute sodium hydroxide. The enantiomers of the compounds 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 COMPOUNDS OF FORMULA (VII) The invention further provides compounds of general formula (VII) :
Figure imgf000120_0001
(VII) in which Ar, Rι~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 include, but are not limited to, phenyl, -naphthyl, jβ-naphthyl and fluorenyl groups.
The CX-CB alkyl groups can be linear or branched, and include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups.
The Ci-C8 alkoxy groups can like likewise be linear or branched, and include, 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 Rx, 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 compounds of general formula (VII) .
The compounds of general formula (VII) possess a carboxylic acid functional group and can be salified, i.e., converted into conjugate bases they then being in the form of salts with bases.
Examples of salts with bases of the compounds 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 compounds of general formula (VII) can also be salified with amines in order to form pharmaceutically acceptable salts. By way of example, the compounds of general formula (VII) could be salified with glucamine, N- methylglucamine, N,N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.
The compounds 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 compounds 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 compounds of general formula (VII) . A preparation process according to the invention comprises the reaction of an aromatic amine of general formula (VIII) :
Figure imgf000121_0001
(VIII) in which A, B, C, D, Rx, R4, R5 and Rε are as defined above for formula (VII) and R7 is a hydrogen atom, a Cx-C6 alkyl group or a benzyl group, with a haloacyl halide of general formula (IX) :
Figure imgf000122_0001
(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) ;
Figure imgf000122_0002
(X) in which A, B, C, D, Rx, R2, R3, R4, Rs, R6, R7 and Hal are as defined above for formula (VII) ; and the reaction of the compound of general formula (X) with a compound of general formula (XI) :
Figure imgf000122_0003
(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) :
Figure imgf000123_0001
(XII) in which Ar, A, B, C, D, Rx, R2, R3, R4, Rs, R6 and R7 are as defined above for formula (VII) .
In the case where R7 is an alkyl group, the compound of general formula (XII) can be hydrolysed 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 compounds of Formulae (VIII) and (XI) are known compounds or can be prepared according to known processes.
Thus, compounds of formula (VIII) are described in Organic Preparation and Procedures International, 13, 189, 1981.
The compounds 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 R7 is an alkyl group, can by hydrolysed in the presence of a basic agent, such as dilute sodium hydroxide.
The enantiomers of the compounds of formula (VII) can be separated by successive recrystallization of the salt of the 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 COMPOUNDS OF FORMULAS (Xllla) AND (Xlllb)
The invention further provides compounds, useful as hypoglycemic agents, of general formula (Xllla) :
Figure imgf000124_0001
(Xllla) wherein Rx-R4, R8-Rx3, m and o are defined above for formula (Xllla) , or pharmaceutically acceptable salts or compounds having a tautomeric structure thereof .
In addition, the present invention provides compositions comprising a compound of formula (Xlllb) 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 (Xlllb) having the structure:
Figure imgf000124_0002
wherein Rx-R4, R8-Rx3, 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 compounds of general formula (Xllla) and (Xlllb) .
The compounds of general formula (XIIla) and (Xlllb) which may possess a carboxylic acid functional group can be salified, i.e., converted into conjugate bases they then being in the form of salts with bases.
Examples of salts with bases of the compounds of general formula (XIIla) and (XIIlb) include the pharmacologically acceptable salts, such as the sodium salts, potassium salts, calcium salts and other salts of the same type.
The compounds of general formula (Xllla) and (Xlllb) which possess a carboxyllic acid functional group can also be salified with amines in order to form pharmaceutically acceptable salts. By way of example, the compounds of general formula (Xllla) and (Xlllb) could be salified with glucamine, N-methylglucamine, N,N- dimethylglucamine, ethanolamine, morpholine, N- methylmorpholine or lysine.
The compounds of general formulas (Xllla) and (Xlllb) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids. Examples of salts with acids of the compounds of general formulas (Xllla) and (Xlllb) 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 compounds of the general formula (Xllla) according to the invention, there may be mentioned more particularly, as preferred compounds:
2- ( ( (4- (2-Pyridyl)piperazin-l-yl) acetyl) amino) -6- fluorobenzothiazole,
2- ( ( (4- (2 -Fluorophenyl) piperazin-1- yl) acetyl) amino) -6-fluorobenzothiazole,
2- ( ( (4- (2-Pyridyl)piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole , 2- ( ( (4- (2-Pyrimidyl)piperazin-l-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-l-yl) acetyl) amino-4- methoxybenzothiazole ,
2- ( ( (4- (4 -Methoxyphenyl) piperazin-1- yl) acetyl) amino) -6-fluoro-benzothiazole,
2- ( ( (4- ( (2-Pyridyl)piperazin-l-yl) acetyl) amino) -6- ethoxybenzothiazole,
2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino) -6-ethoxybenzothiazole,
2- ( ( (4- (3-Chlorophenyl)piperazin-l- yl) acetyl) amino) -6 -methoxybenzothiazole, 2- ( ( (4- (3 -Bromophenyl) piperazin-1-yl) acetyl) amino) -
6-methoxybenzothiazole,
2- ( ( (4- (3 -NitrophenyDpiperazin-1-yl) acetyl) amino) - 6-methoxybenzothiazole ,
2- ( ( (4- ( (2-Pyridyl)piperazin-l-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-l- yl) acetyl) amino) -6-methoxybenzothiazole,
2- ( ( (4- (3-Ethylphenyl)piperazin-l-yl) acetyl) amino) 6-methoxy benzothiazole, 2- ( ( (4- (2-Naphthyl) piperazin-1-yl) acetyl) amino) -6- methoxybenzothiazole , 2- ( ( (4- (3 -Methoxyphenyl )piperazin-l- 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-l- yl) acetyl) amino) -6-methoxybenzothiazole The invention also relates to a process for the preparation of the compounds of general formulas (Xllla) and (Xlllb) . A preparation process according to the invention comprises the reaction of an aromatic amine of general formula (Al) :
Figure imgf000127_0001
(Al) in which Rx, R2, R3, R4, R8, R9, and m are as defined above for formulas (Xllla) and (Xlllb) , with a haloacyl halide of general formula (IXa) :
Figure imgf000127_0002
(IXa) in which R10 and Rxx are as defined above for formulas (Xllla) and (Xlllb) , Hal represents a chlorine or bromine atom, in order o form a compound of general formula (XVII) ;
Figure imgf000128_0001
(XVII) in which Rx, R2, R3, R4, R8, R9, Rxo, R1X and m are as defined above for formulas (Xllla) and (Xlllb) , and Hal is as defined above ; and the reaction of the compound of general formula (XVII) with a compound of general formula (XVIII) :
Figure imgf000128_0002
(XVIII) in which RX2, Rx3, and o are as defined above for formulas (Xllla) and (Xlllb) , in the presence of a basic agent, such as triethylamine or potassium carbonate in order to form the compound of general formulas (Xllla) and (Xlllb)
Figure imgf000129_0001
0
(XIX) in which Rx, R2, R3, R4, R8, R9, Rxo, Rx R 12 ' Rx3, m and o are as defined above for formulas (Xllla) and (Xlllb) , and Hal is as defined above; 15 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]; el'tman [Wei ' tman Ukr . Khim. Zh. , 22, 1956, 363- 20 365, 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. 25 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. 30 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 Al, 1978; E. Cullen et al. DE 2736652 Al, 1977].
The compounds of formula (XVIII) can be prepared as 35 described by R. Ratouis et al . (J. Med. Chem., 8, 104, 1965) or by Prelog et al . (Collection Czechoslov. Chem. Communications, 6, 211, 1934). Compounds 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., Collect. 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. Henning, 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 COMPOUNDS OF FORMULAS (XlVa) AND (XlVb)
The invention further provides compounds, useful as hypoglycemic agents, of general formulas (XlVa) and (XlVb) :
Figure imgf000130_0001
(XlVa) wherein Rx, 8-Rι3» ™. n and o are defined above, and pharmaceutically acceptable salts and tautomeric structures thereof, with the proviso that the compound of formula (XlVa) 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 (XlVb) 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 (XlVb) having the structure:
Figure imgf000131_0001
(XlVb) wherein Rx, R8-Rι3, n, m and o are as defined above for formula (XlVb) , with the proviso that the compound of formula (XlVb) 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 compounds of general formulas (XlVa) and (XlVb) , may possess a carboxylic acid functional group and can be salified, i.e., converted into conjugate bases they then being in the form of salts with bases.
Examples of salts with bases of the compounds of general formulas (XlVa) and (XlVb) include the pharmacologically acceptable salts, such as the sodium salts, potassium salts, calcium salts and other salts of the same type. The compounds of general formulas (XlVa) and (XlVb) which possess a carboxyllic acid functional group may also be salified with amines in order to form pharmaceutically acceptable salts. By way of example, the compounds of general formulas (XlVa) and (XlVb) , could be salified with glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine. The compounds of general formulas (XlVa) and (XlVb) , possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids. Examples of salts with acids of the compounds of general formulas (XlVa) and (XlVb) , 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 compounds of the general formulas (XlVa) and (XlVb) according to the invention, there may be mentioned more particularly, as preferred compounds:
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-l- yl) acetyl) amino) -4- (carboxymethyl) thiazole,
2- ( ( (4- (3- (Trifluoromethyl) phenyl)piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole,
4- ( ( (4- (3- (Trifluoromethyl) phenyl)piperazin-l- yl) acetyl) amino) -1- ( (N' - (2-thiazolyl) ) sulfonamido) benzene,
2- ( ( (4- (5- (Trifluoromethyl) pyrid-2-yl)piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole,
2- ( ( (4- (3- (Trifluoromethyl) phenyl)piperazin-l- 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) -1- ( (N' - (2-thiazolyl) ) sulfonamido) benzene, hydrochloride salt,
2- ( ( (4- (3- (Trifluoromethyl)phenyDpiperazin-l- 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) 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- (trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino) -4- (carboethoxymethyl) thiazole, 2- ( (4- ( (4-Chlorobenzhydryl)phenyl)piperazin-l- 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-l- 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 compounds of general formulas (XlVa) and (XlVb) . A preparation process according to the invention comprises the reaction of an aromatic amine of general formula (A2) :
Figure imgf000134_0001
(A2) in which Rx , R8, R9, m, and n are as defined above for formulas (XlVa) and (XlVb) , with a haloacyl halide of general formula (XIX) :
Figure imgf000134_0002
(XIX) in which Rx0 and RX1 are as defined above for formulas (XlVa) and (XlVb) , Hal represents a chlorine or bromine atom, in order to form a compound of general formula (XX) :
Figure imgf000135_0001
(XX) in which Rx, R8, R9, Rx0, Rxx, m, and n are as defined above for formulas (XlVa) and (XlVb) , and Hal is as defined above, and the reaction of the compound of general formula (XX) with a compound of general formula (XXI) :
Figure imgf000135_0002
(XXI) in which RX2, Rx3 and o are as defined above for formulas (XlVa) and (XlVb) , in the presence of a basic agent, such as triethylamine or potassium carbonate in order to form the compound of general formulas (XlVa) and (XlVb) :
Figure imgf000135_0003
(XIV) in which Rx, R8, R9, Rxo, Rn, R12, R13, , n and o are as defined above for formulas (XlVa) and (XlVb) , 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. Ochiai [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 compounds 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).
Compounds 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.,
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. Henning, 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 COMPOUNDS OF FORMULAS (XVa) AND (XVb) The invention further provides compounds, useful as hypoglycemic agents, of general formula (XVa) :
Figure imgf000137_0001
(XVa) wherein Rx, R8-Rx3, , o, Xx and X2 are as defined above for formula (XVa) , or pharmaceutically acceptable salts or compounds 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) -5- ( (ethoxycarbonyl) -methyl) -1, 3,4-thiadiazole;
2- ( ( (4- (2-pyridyl)piperazinyl-l) -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:
Figure imgf000138_0001
(XVb) wherein Rχ/ R8-Rι3, m, o, Xx and X2 are as defined above for formula (XVb) , or a pharmaceutically acceptable salt or compounds having a tautomeric structure thereof, 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 . The invention also relates to the tautomeric forms and to the enantiomers, diastereoisomers and epimers of the compounds of general formulas (XVa) and (XVb) .
The compounds of general formulas (XVa) and (XVb) may possess a carboxylic acid functional group and can be salified, i . e . , converted into conjugate bases they then being in the form of salts with bases.
Examples of salts with bases of the compounds 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 compounds of general formulas (XVa) and (XVb) which possess a carboxylic acid functional group may also be salified with amines in order to form pharmaceutically acceptable salts. By way of example, the compounds of general formulas (XVa) and (XVb) could be salified with glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.
The compounds 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 compounds 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 compounds of the general formula (XVa) according to the invention, there may be mentioned, more particularly, as preferred compounds:
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-l, 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-l- yl) acetyl) amino) -5-carbomethoxymethyl-l, 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-l-yl) acetyl) amino) -5- (2- (carbomethoxy) ethyl) -1,3, 4-thiadiazole,
Among the compounds of the general formula (XVb) according to the invention, there may be mentioned, more particularly, as preferred compounds:
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-l, 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-l- yl) acetyl) amino) -5-carbomethoxymethyl-l, 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-l-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-l- yl) acetyl) amino) -5-trifluoromethyl-1, 3 , 4-thiadiazole,
2- ( ( (4- (4-Methoxyphenyl)piperazin-l- yl) acetyl) amino) -5- (trifluoromethyl) -1, 3 , 4-thiadiazole,
2- ( ( (4- (2-Pyridyl)piperazin-l-yl) acetyl) amino) -5- (trifluoromethyl) -1,3 , 4-thiadiazole,
2- ( ( (4- (2-Pyrimidyl)piperazin-l-yl) acetyl) amino) -5- (trifluoromethyl) -1, 3 , 4-thiadiazole,
2- ( ( (4- (2-Pyridyl)piperazin-l-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-l, 3 , 4-thiadiazole,
2- ( ( (-4- (3- (Trifluoromethyl) phenyl) piperazin-1- yll) acetyl) amino) -1, 3 , 4 -thiadiazole,
2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino) -5-bromo-l, 3 , 4-thiadiazole .
The invention also relates to a process for the preparation of the compounds of general formulas (XVa) and (XVb) . A preparation process according to the invention comprises the reaction of an aromatic amine of general formula (A3) :
Figure imgf000141_0001
(A3) in which Rx , R8, R9, Xχ/ X2 and m are as defined above for formulas (XVa) and (XVb) , with a haloacyl halide of general formula (XXII) :
Figure imgf000141_0002
(XXII) in which Ri0 and Rn, 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) ;
Figure imgf000141_0003
(XXIII) in which Rx, R8, R9, R10, Rn, Xx, X2 and m are as defined above for formulas (XVa) and (XVb) , and Hal is as defined above; and the reaction of the compound of general formula (XXIII) with a compound of general formula (XXIV) :
Figure imgf000142_0001
(XXIV) in which Rι2, Ri3 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) :
Figure imgf000142_0002
(XVa) and (XVb) in which Rx , R8, R9, Rι0, Rn, Rι2, Rι3, 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- 4395]; 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. , II
Farmaco - Ed. Sci., Vol. XIII, fasc. 3, pp. 187-217, 1957];
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, 1997]; 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 Bl] ; 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)]; T. Hirata [T. Hirata, S. Goto, K. Tamura, M. Okuhira, Y. Nagao, 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 compounds 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). Compounds 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. , 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. Henning, 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] ; Gr. S. Poindexter [G.S. Poindexter, M.A. Bruce, K. L. LeBoulluee, 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 COMPOUNDS OF FORMULAS (XVIa) and (XVIb) The invention further provides compounds, useful as hypoglycemic agents, of general formula (XVIa) :
Figure imgf000144_0001
wherein Rι~R3, R8-Rι3, m and o are as defined above for formula (XVIa) , or pharmaceutically acceptable salts or compounds 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 :
Figure imgf000145_0001
wherein Ri-R3, RB-R13, m and o are as defined above for formula (XVIb) , or pharmaceutically acceptable salts or compounds having a tautomeric structure thereof .
The invention also relates to the tautomeric forms and to the enantiomers, diastereoisomers and epimers of the compounds of general formulas (XVIa) and (XVIb) .
The compounds of general formulas (XVIa) and (XVIb) may possess a carboxylic acid functional group and. can be salified, i.e., converted into conjugate bases they then being in the form of salts with bases.
Examples of salts with bases of the compounds 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 compounds of general formulas (XVIa) and (XVIb) which possess a carboxylic acid functional group may also be salified with amines in order to form pharmaceutically acceptable salts. By way of example, the compounds of general formulas (XVIa) and (XVIb) could be salified with glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.
The compounds 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 compounds 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 compounds of the general formula (XVIa) and (XVIb) according to the invention, there may be mentioned, more particularly, as preferred compounds: 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-1- yl) acetyl) amino) -2- (carbomethoxy) thiophene,
3- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- 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 compounds of general formulas (XVIa) and (XVIb) . A preparation process according to the invention comprises the reaction of an aromatic amine of general formula (A4) :
Figure imgf000146_0001
(A4) in which Rx , R2, R3, R8, R9 and m are as defined above for formulas (XVIa) and (XVIb) , with a haloacyl halide of general formula (XXV) :
Figure imgf000147_0001
(XXV) in which Rι0 and Ru 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) ;
Figure imgf000147_0002
(XXVI) in which Rx , R 2» R. 3. ^8' R9, Rι0, Ru and m are as defined above for formulas (XVIa) and (XVIb) and Hal is as defined above; and the reaction of the compound of general formula (XXVI) with a compound of general formula (XXVII) :
H
Figure imgf000147_0003
(XVIII) in which Rι2, Ri3, 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) :
Figure imgf000148_0001
(XVIa) and (XVIb) in which Rx , R2, R3, RB, R9, Rι0, R11# Rι2, Ri3, m and o are as defined above for formulas (XVIa) and (XVIb) ;
Thiophene acids can be prepared according to the method of 0. Dann [0. Dann, Chem. Ber., 1943, 76, 419]; R. B. Woodward [R.B. Woodward, R.H. Eastman, 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 Due, 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. Patel and S. Singh, Indian J. Pharm. Sci., 1991, 53(3), pp. 85-87]; K. Gewald [K. Gewald, E. Schinke, M. Bόttcher, 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. 1997].
The compounds 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) .
Compounds 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. . 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. Henning, R.
Lattrell, H.J. Gerhards, M. Le-ven, 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. 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 COMPOUNDS The piperazine compounds of formulas (XIII) through
(XVI) described in Sections 4.3-4.6 are collectively known as "piperazine thiocycle compounds." The piperazine thiocycle compounds 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 5 heterocyclic amines 2. The general procedure outlined in Figure 1 of equation 1 has been modified from previously described procedures known to synthesize the substituted piperazines [(1) Prelog, V.; Driza, G.J. Sur la N- phenylpiperazine. Collect . Czech . Chem . Commun . 1933, 5, 10 497]. 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. K2C03) at the elevated temperature provides the piperazines 4 or 5. 15 Equation 2 of Figure 1 shows a preparation of substituted piperazines 9 using modified 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 20 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 25 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 30 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 envisaged 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 g/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 acetzohexamide , chlorpropamide, tolazamide, tolbutamide, glyburide, glypizide or glyclazide; a thiazolidinedione such as troglitazone or ciglitazone; an α-glycosidase inhibitor such as acarbose or miglatol; an α2- adrenergic antagonist such as midaglizole, or a 33-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 tablets, sugar-coated tablets, 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 emulsion or a water-in-oil liquid emulsion 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, modified starches, and lactose of the solid forms. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed 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 compounds 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 COMPOUNDS 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 reaction 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) XH NMR: (DMSO-d6, 200 MHz) δ 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}benzoic acid
25 g of 2 -chloro-N- (4 -chlorophehyl) 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 reaction 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- oxoethyl] -l-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? REACTION CONDITIONS?] .
Example 2 The following illustrative compounds of the general formula (I) , shown below in Table 1, were synthesized according to the above-described methods: TABLE I
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
5
Figure imgf000161_0001
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 10% palladium-on- charcoal (50% water) were added to 200 ml of methanol in a
1 liter hydrogenation apparatus.
The apparatus 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 5_ solid which melts at 58-60°C.
IR: (KBr) 1683 cm'1 (C=0) , 1528 cm"1 (C=0) XH NMR: (CDCL3, 200 MHz) δ ppm: 1.06-1.64 (11H, m, cyclohexyl), 2.93 (2H, t, CH2) , 3.68 (3H, s, OCH3) , 3.78 (3H, s, OCH3) , 6,56 (IH, d, phenyl proton), 6.96 (IH, dd, phenyl proton), 7.23 (2H, d + ε, phenyl proton + NH) .
Example 4 The formulae and characteristics of the compounds of formula (VIII) have been combined in Table II. 5
30
35 TABLE II
Figure imgf000163_0001
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 reaction 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"1 (C+O)
XH NMR: (ds-DMS0, 200 MHz) δ ppm: 4.30 (2H, s, CH2) , 7.1 (IH, d, phenyl proton), 7.7 (IH, d, phenyl proton), 8.5 (IH, s, phenyl proton), 11.75 (IH, s, NH) , 13.90 (IH, broad s, COOH) .
Example 6
The formulae and characteristics of the compounds of formula (X) have been combined in Table III.
TABLE III
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Example 7
Preparation of 4-chloro-2- { [4- (2-methoxyphenyl) -1- piperazinyll acetamidolbenzoic acid (Compound lOd)
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 reaction 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 acidified with acetic acid.
A solid crystallized to give, after filtration, 22.5 g of crude product. After recrystallization from dioxane, 21.1 g of 4-chloro-2- { [4- (2-methoxyphenyl) -1- piperazinyl] acetamidojbenzoic acid were obtained in the form of a white solid, which melts at 218-220°C. IR: 1699 cm'1 (C=0) , 1673 cm"1 (C=0)
'H NMR: (CF3COOD) , δ ppm: 4.25 (3H, ε, OCH3) , 4.65 (8H, broad s, 4 CH2) , 4.95 (2H, s, CH2) , 7.5 (2H, m, phenyl protons), 7.6 (IH, d, phenyl proton), 7.90 (2H, m, phenyl protons), 8.50 (IH, d, phenyl proton), 8.75 (IH, s, phenyl proton) .
Example 8
Preparation of 2- { [4- (4-fluorophenyl) -l-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 reaction 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) -l-piperazinyl] acetamido}- 4, 5- (methylenedioxy) benzoic acid were obtained, which melts at 254-256°C.
IR (KBr) : 1654 cm"1 (C=0)
*H NMR: (CF3C00D, 200 MHz) δ ppm: 4.40 (8H, s, piperazinyl) , 4.67 (2H, s, CH2) , 6.05 (2H, s, 0-CH2-0) , 7.30 (2H, t, phenyl proton), 7.65 (3H, m, phenyl proton), 7.90
(IH, s, phenyl proton) Example 9 The formulae and characteristics of the compounds of formula (VII) have been combined in Table IV.
TABLE IV
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
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 εolution 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 reaction mixture at 5 °C. After εtirring at 5 °C for 1 h, the ice bath was removed and the reaction mixture was stirred at room temperature (rt) for 20 h. The reaction 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%) of the title compound, mp 5 207.1- 209.5 °C (became "wet" at 203 °C) : *H NMR (CDC13) δ 7.75 (dd, J = 8.0, J = 1.2, IH) , 7.50 (dd, J = 7.6, J = 0.8, IH) , 7.31 (dd, J = 8.0, J = 8.0, IH) , 4.14 (s, 2H) . 13C NMR (CDC13) δ 164.59, 126.91, 125.85, 125.19, 120.15, 27.47 ; MS (El) 306 (M+) . 0 Example 12
Preparation of 2- ( ( (4- (Phenyl) piperazin-1-yl) acetyl) amino) -4- chlorobenzothiazole (Compound EB) Phenylpiperazine (0.43 g, 0.4 mL, 2.64 mmol) was added to a solution of 2- ( (bromoacetyl) amino) -4-chlorobenzothiazole 5 (0.4 g, 1.32 mmol) in DMF (10 mL) at rt . The reaction mixture was heated and stirred at 70-75 °C 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 0 a white solid, mp 237.9-238.6 °C: XH NMR (CDC13) δ 10.57 (bs, IH) , 7.73 (dd, J = 8.0, J = 0.8, IH) , 7.48 (dd, J" = 8.0, J = 0.8, IH) , 7.33- 7.25 (m, 3H) , 6.98- 6.91 (m, 3H) , 3.40 (s, 2H) , 3.32 (t, J = 4.8, 4H) , 2.89 (bs, 4H) . 13C NMR (CDCl3) δ 169.17, 157.81, 150.08, 145.63, 133.65, 129.24 (2C) , 126.55 5 (2C) , 125.90, 124.62, 120.41, 120.00, 116.52, 61.34, 53.72 (2C) , 49.15 (2C) ; MS (El, m/z ) 386 (M+) .
Example 13 Preparation of 2- ( ( (4- (2- (Fluoro) phenyl) piperazin-1- yl) acetyl) amino) -4 -chlorobenzothiazole (Compound DB) 30 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 reaction was heated and stirred at 100-105 °C for 7 h, cooled to rt, and slowly poured into ice water. The ivory 35 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) : lU NMR (DMSO-dfi) δ 12.65 (bs, IH) , 7.97 (dd, J = 8.0, J = 0.8, IH) , 7.53 (dd, J = 7.6, J = 0.8, IH) , 7.31 (dd, J = 7.6, J = 7.6, IH) , 7.15- 7.02 (m, 3H) , 6.99- 6.94 (m, IH) , 3.46 (bs, 2H ), 3.05 (bs, 4H) , 2.73 (bε, 4H) . 13C NMR (DMSO-d δ 169.56, 5 158.62, 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+) . 0 Example 13A
Preparation of 2- ( ( (4- (3- (Trifluoremethyl)piperazin-l- ylyl acetyl) amino) -5- (carboethoxy) benzothiazole . Preparation of 5- (carboethoxy-2-amino) benzothiazole and 2- [ (Bromoacetyl) amino] -5- (carboethoxy) benzothiazole. 1) 5 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 reaction mixture was stirred as -5° C to +10° C for 3h. TLC analysiε showed that the reaction was 0 incomplete. Reaction 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. The solid was dissolved in CHC13 (200 mL) and extracted with 5% Na2C03. The CHCl3 layer was dried, filtered and adsorbed 5 onto Na2C03. The solid adsorbate was loaded onto a Si02 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) δ 8.20 (d, J = 2, IH) , 7.95 (dd, J = 8.4, J = 2, IH) , 6.80 (d, J = 8.4, IH) , 4.34 (d, J = 7.2, IH) , 1.38 (t, J = 7.2, 3H) , 13C 30 NMR (CDC13 δ 165.19, 151.71, 138.47, 134.43, 121.27, 115.22, 109.44, 103.97, 60.89, 14.31; MS (FAB, m/z)222 (M+H+) An additional 5.17 g (23.3%) of this compound was obtained with an impurity. The thiocyanate (2.5 g, 11.25 mmol) was refluxed with 25 mL of IN HCl. The mixture was cooled to rt , 35 cone. HCl (12.5 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 suspended with CHC13, washed with 5% Na2C03 and then the separated aqueous layer was extracted several times with CHC13. The combined CHC13 layer was dried, filtered, and then concentrated to give 1.4 g of a white solid: XH NMR (DMS0-d6 δ 8.28 (d, J = 1.6, IH) , 7.91 (s, 2H) , 7.81 (dd, J = 8.4, J = 1.6, IH) , 7.36 (d, J = 8.4, IH) , 4.28 (d, J = 7.2, 2H) , 1.31 (t, J = 7.2, 3H) , -13C NMR (DMS0-d6) δ 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) v/as dissolved 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 internal temperature at +5° C. The reaction mixture was warmed to rt and stirred for 20h. The reaction 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. (63%) 2- [ (Bromoacetyl) amino] -5- (carboethoxy) benzothiazole: XH NMR (DMS0-d6) δ 13.04 (bs, IH, NH) , 8.66 (d, J = 1.6, IH) , 8.01 (dd, J = 8.4, 1.6, IH) , 7.84 (d, J = 8.4, IH) , 4.32 (s, 2H) , 4.25 (s, 2H) , 1.34 (t, J = 6.8, 3H) , 13C NMR (DMS0-d6) δ 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 (El, m/z) 344.1 (M+) .
Example 14 Preparation of 2- ( ( (4- (3- (Trifluoromethyl)phenyl) piperazin-1- yl) acetyl) amino) -4 -chlorobenzothiazole (Compound EC) 1- (α, o;, α-Trifluoro-in-tolyl) piperazine (3.18 g, 2.6 mL, 14 mmol) was added to a solution of 2- ( (bromoacetyl) amino) -4- chlorobenzothiazole (2.1 g, 7 mmol) in anhydrous DMF (25 mL) at rt. The reaction mixture was heated and stirred at 50 °C 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: XH NMR (DMS0-d6) δ 12.65 (bs, IH) , 7.97 (dd, J" = 8.0, J = 1.2, IH) , 7.53 (dd, J = 7.6, J = 0.8, IH) , 7.41 (dd, J" = 8.0, J = 8.0, IH) , 7.31 (dd, J = 8.0, J = 8.0, IH) , 7.22 (dd, J = 8.4, J = 2, IH) , 7.17 (s, IH) , 7.06 (d, J = 7.6, IH) , 3.45 (s, 2H) , 3.27 (t, J = 4.8, 4H) , 2.71 (t, J = 4.8, 4H) ; 13C NMR (DMSO-d6) δ 169.52, 158.55, 151.14, 145.32, 133.01, 129.88, 129.83 (q, J = 31), 126.16, 124.38, 124.37 (q, J = 274), 5 124.36, 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 (El, m/z) 454 (M+) .
Example 15A Preparation of 2- ( (Bromoacetyl) amino) -6-fluorobenzothiazole Bromoacetyl bromide (6 g, 2.6 mL, 30 mmol) was added 0 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 reaction mixture at 5 °C. After stirring at 5 °C for 1 h, the ice bath was removed and the reaction mixture was stirred at rt for 7 h. The 5 reaction 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 (73%) of the title compound as a light solid: XH NMR (DMS0-de) δ 12.80 (bs, IH) , 7.91 (dd, J = 8.8, J = 2.4, IH) , 7.78 (dd, 0 J = 8.8, J = 4.4, IH), 7.31 (ddd, J = 9.2, J = 9.2, J = 2.4, IH) , 4.22 (s, 2H) ; "C MR (DMS0-de) δ 172.14, 166.13, 158.73 (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 (El, m/z) 288 (M+) . 5 Example 15
Preparation of 2- ( ( (4- (2- (Fluoro) phenyl) piperazin-1- yl) acetyl) amino) -6-fluorobenzothiazole (Compound EE) 1- (2-Fluorophenyl) piperazine (2.07 g, 1.8 mL, 11.5 mmol) was added to a solution of 2- ( (bromoacetyl) amino) -6- 0 fluorobenzothiazole (1.65 g, 5.73 mmol) in DMF (20 mL) at rt . The reaction 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 35 title compound, mp 131.7-132.5 °C: XH NMR (DMS0-dfi) δ 11.88 (bs, IH) , 7.91 (dd, J = 8.8, J = 2.4, IH) , 7.75 (dd, J = 8.8, J = 4.4, IH) ; 7.29 (ddd, J = 9.2, J = 9.2, J = 2.8, IH), 7.16- 6.94 (m, 4H) , 3.43 (s, 2H) , 3.05 (t, J = 4.8, 4H) , 2.72 (t, J = 4.8, 4H) ; "C NMR (DMSO-dfi) δ 169.48, 159.86, 157.48, 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), 5 119.28, 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 (El, m/z) 388 (M+) .
Example 16 Preparation of 2- (( (4- (2- (Methoxy) phenyl) piperazin-1- 0 yl) acetyl) amino) -6-fluorobenzothiazole (Compound EF)
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 reaction mixture was heated and stirred at 90 °C for 6 h, cooled to rt and 5 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: XH NMR (DMS0-de) δ 7.90 (dd, J = 8.8, J = 2.8, IH) , 7.58 (dd, J = 8.8, J = 4.8, 0 IH) , 7.29 (ddd, J = 8.8, J = 6.4, J = 2.4, IH) ; 6.97- 6.84
(m, 4H) , 3.76 (s, 2H) , 3.41 (s, 3H) , 2.99 (bs, 4H) , 2.69 (bs, 4H) ; 13C NMR (DMS0-d6) δ 169.60, 156.89, 157.54 (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, 25 108.26 (d, J = 13), 60.26, 55.33, 52.79 (2C) , 50.06 (2C) ; MS (El, m/z) 400 (M+) .
Example 17 Preparation of 2- ( ( (4- (2-Pyridyl)piperazin-l- yl) acetyl) amino) -6-fluorobenzothiazole (Compound DC) 30 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 reaction mixture was heated and stirred at 70 °C for 7 h, cooled to rt, and poured into ice water. The light beige 35 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: XH NMR (DMSO-d^) δ 12.16 (bs, IH) , 8.11- 8.10 (m, IH) , 8.10 (ddd, J = 4.8, J = 2.0, J" = 0.8, IH) 7.90 (dd, J = 8.8, J - 2.8, IH), 7.75 (dd, J = 9.2, J - 4.8, IH) , 7.52 (ddd, J = 9.2, J = 7.2, J - 2, IH) , 7.29 (ddd, J = 8.8, J = 8.8, J = 2.4, IH),. 6.81 (d, J = 8.4, IH) , 6.63 (ddd, J = 7.2, J = 5.2, J = 0.8, IH), 3.52 (t, J = 4.8, 4H) , 3.41 (s, 2H) , 2.63 (t, J = 5.2, 4H) ; 13C NMR (DMSO-de) δ 169.48, 158.97, 158.66 (d, J = 238), 157.47, 147.56, 145.19, 137.53, 132.69 (d, J = 10.6), 121.66 (d, σ = 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 (El, m/z) 371 (M+) .
Example 18 Preparation of 2- ( ( (4- (Benzyl) piperazin-1-yl) acetyl) amino) -6- 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 reaction mixture was heated and stirred at 70 °C 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 °C: 2H NMR (DMSO-de) δ 12.05 (bs, IH) , 7.89 (dd, J = 8.8, J = 2.7, IH) , 7.74 (dd, J = 8.8, J = 4 . 7 , IH) , 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) δ 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 (El, m/z) 384 (M+) .
Example 19 Preparation of 2- ( ( (4- (4-Methoxyphenyl)piperazin-l- yl) acetyl) amino) -6-fluoro-benzothiazole (Compound DJ) 4- (4 -Methoxyphenyl) piperazine (0.6 g, 2.95 mmol) and K2C03 (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 reaction mixture was heated and stirred at 55 °C 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 (61%) of the title compound as an off- white solid, mp 128-129 °C (dec): XH NMR (DMSO-dff) δ 12.16 (bs, IH) , 7.89 (dd, J = 8.4, J - 2.4, IH) , 7.75 (q, J" = 4.8, IH) , 7.29 (ddd, J = 9.2, J = 9.2, J = 0.4, IH) , 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- de) δ 169.39, 158.61 (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 (El, m/z) 400 (M+) .
Example 20A Preparation of 2- ( (Bromoacetyl) amino) -6-methoxybenzothiazole 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 L) while keeping the internal temperature of the reaction mixture at 5 °C. After stirring at 5 °C for 1 h, the ice bath was removed and the reaction mixture was stirred for 7 h. 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 5.1 g (61.3%) of the title compound as a white solid, mp 164-165 °C: :H NMR (DMS0-de) δ 12.65 (ε, IH) , 7.66 (d, J = 8.8, IH) , 7.59 (d, J = 2.4, IH) , 7.04 (dd, J = 8.8, J = 2.4, IH) , 4.20 (s, 2H) t 3.81 (s, 3H) ; 13C NMR (DMS0-de) δ 165.71, 156.30, 155.48, 142.53, 132.81, 121.33, 115.10, 104.77, 55.62, 28.53; MS (El, m/z) 300 (M+) .
Example 20 Preparation of 2- ( ( (4- (Σ-FluorophenyDpiperazin-l- yl) acetyl) amino) -6-fluorobenzothiazole (Compound DD) 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 r . The reaction mixture was heated and stirred at 70 °C 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, mp 131.7-132.5 °C: XH NMR (DMSO-de) δ 11.90 (bs, IH) , 7.63 (d, 5 J = 9.0, IH) , 7.58 (d, J = 2.4, IH) , 7.15- 6.94 (m, 5H) , 3.80 (S, 2H) , 3.40 (s, 3H) , 3.05 (t, J = 4.1, 4H) , 2.71 (t, J = 4.5, 4H) ; 13C NMR (DMS0-ds) δ 169.09, 156.17, 155.42, 154.97 (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, 10 52.60 (2C) , 50.07 (2C) , MS (El, m/z) 400 (M+) .
Example 21 Preparation of 2- ( ( (4- (2-Pyridyl) piperazin-1- yl) acetyl) amino) -6-methoxybenzothiazole (Compound DE) 1- (2-Pyridyl) piperazine (8.4 g, 52 mmol) was added to a 15 solution of 2- ( (bromoacetyl) amino) -6 -methoxybenzothiazole
(7.7 g, 26 mmol) in DMF (65 mL) at rt . The reaction mixture was heated and stirred at 55 °C 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, 20 and then dried to give 7.7 g (78%) of the title compound, mp 199.5-201.0 °C: *H NMR (DMS0-de) δ 11.92 (bs, IH) , 8.10 (ddd, J = 4.8, J = 2.0, J = 0.8, IH) , 7.63 (d, ' J = 9.2, IH) , 7.57 (d, J = 2.4, IH) , 7.50 (dd, J = 8.8, J = 8.8, J = 2.0, IH) , 7.03 (dd, J = 8.4, J = 2.8, IH) , 6.82 (d, J = 8.4, IH) , 6.63 25 (ddd, J = 7.2, J = 5.2, J = 0.8, IH) , 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) δ 169.01, 158.92, 156.13, 155.36, 147.48, 142.50, 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 (El, m/z) 383 (M+) . 30 Example 22
Preparation of 2- ( ( (4- (2-Pyridyl) iperazin-1- yl) acetyl) amino) -6-methoxybenzothiazole Hydrochloride
(Compound DM) A solution of 2- ( ( (4- (2-Pyridyl) piperazin-1- 35 yl) acetyl) amino) -6 -methoxybenzothiazole (0.9 g, 2.35 mmol) CH2C12 was treated with IN HCl ether solution (5 mL, 5 mmol) . The reaction 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 (69%) of the title compound as an ivory solid, mp 233-236 °C.
Example 23 5 Preparation of 2- ( ( (4- (2-Pyrimidyl)piperazin-l- yl) acetyl) amino) -6-methoxybenzothiazole (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 0 reaction mixture was heated and stirred at 80 °C 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- 15 226.8 °C: *H NMR (DMSO-dfi) δ 12.00 (bs, IH) , 8.36 (d, J = 4.4, 2H) , 7.63 (d, J = 8, IH) , 7.57 (d, .7 = 2.4, IH) , 7.02 (dd, J = 8.8, J = 2.4, IH) , 6.62 (t, J = 4.8 , IH) , 3.80 (s, 3H) , 3.78 (t, J = 4.8, 4H) , 3.39 (s, 2H) , 2.59 (t, J = 4.8, 4H) ; 13C NMR (DMS0-de) δ 169.04, 161.14, 157.86 (2C) , 156.15, 20 155.35, 142.51, 132.74, 121.09, 114.89, 110.04, 104.72,
60.12, 55.59, 52.27 (2C) , 43.21 (2C) ; MS (El, m/z) 384 (M+) .
Example 25 Preparation of 2- ( ( (4- (Benzyl) piperazin-1-yl) acetyl) amino) -6- methoxybenzothiazole (Compound DG) 25 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 reaction mixture was heated and stirred at 60 °C for 5 h, cooled to rt , and poured into ice water. The light 30 beige precipitate which formed was filtered, washed several times with cold water, and then dried to give 2.18 g (83%) of the title compound as an off-white solid, mp 107-110 °C: XH NMR (DMSO-"d5) δ 11.80 (bε, IH) , 7.62 (d, J = 8.8, IH) , 7.56 (d, J = 2.4, IH) , 7.30-7.24 (m, 4H), 7.02 (dd, J = 8.8 , J = 35 2.8, IH) , 3.80 (s, 3H) , 3.62 (s, 2H) , 3.31 (s, 2H) , 2.55 (bs, 4H) , 2.41 (bs, 4H) ; 13C NMR (DMSO-d6) δ 169.02, 156.11, 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-d5) δ 142.49, 138.13, 132.71, 128.74, 128.07, 126.81, 121.06, 114.85, 104.72, 61.98, 60.10, 55.58, 52.54, 52.45; MS (El, m/z) 396 (M+) . Example 26
Preparation of 2- (( (4- (Phenyl) piperazin-1-yl) acetyl) amino) -6- methoxybenzothiazole (Compound El) 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 reaction mixture was heated and stirred at 55 °C 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
(DMS0-de) δ 12.03 (bs, IH) , 7.63 (d, J = 8.8 , IH) , 7.58 (d, J = 2.8, IH) , 7.20 (dd, J = 8.4, J = 7.2, 2H) , 7.03 (dd, J = 8.8, J = 2.8, IH) , 6.93 (d, J = 8, 2H) , 6.77 (dd, J = 7.2, J - 7.2, IH) , 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) δ 168.91,
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 (El, m/z) 382 (M+) .
Example 27 Preparation of 2- (( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino) -6-methoxybenzothiazole (Compound DH) 1- (α,α,o;-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 reaction mixture was heated and stirred at 45 °C 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 combined EtOAc layer was washed with water, brine, dried (Na2S04) , 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 °C: XH NMR (DMSO-d£) δ 12.05 (bs, IH) , 7.63 (d, J = 8.8, IH) , 7.57 (d, J - 2.4, IH) , 7.41 (t, J = 5 8.0, IH) , 7.23 (dd, J = 8 , J = 2.4, IH) , 7.17 (s, IH) , 7.06 (d, J = 7.6, IH) , 7.02 (dd, J = 8.8, J = 2.8, IH) , 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-de) δ 169.02, 156.19, 155.42, 151.19, 142.53, 132.76, 129.97, 129.86 (q, J = 31), 124.45, (q, J = 10 271), 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 (El, /z) 450 (M+) .
Example 28
Preparation of 2- ( ( (4- (4- (Acetyl) phenyl) piperazin-1-
15 yl) acetyl) amino) -6-methoxybenzothiazole
1- (4-Acetylphenyl) piperazine (2.9 g, 14.0 mmol) was added to a solution of 2- ( (bromoacetyl) amino) -6- methoxybenzothiazole (2.2 g, 7.0 mmol) in DMF (15 mL) . The reaction was heated and stirred at 70 °C for 7 h, cooled to
20 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 1.3 g (64%) of the title compound, mp 176-178.2 °C ( wet" 98-98.2 °C) : XH NMR (DMS0-d5) δ 11.90 (bs, IH) , 7.78 (d, J = 8.8, 2H) , 7.64 (d, J" = 8.8,
25 IH) , 7.57 (d, J = 2.4, IH) , 7.02 (dd, J = 8.8 , 2.8, IH) , 6.97 (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- d6) δ 195.58, 169.04, 168.92, 156.16, 155.42, 153.78, 142.53; 132.76, 130.09 (2C) , 126.62, 121.15, 114.95, 113.15 (2C) ,
30 104.71, 59.99, 55.62, 52.13 (2C) , 46.64 (2C) , 26.11; MS (El, /z) 440 (M+) .
35 Example 29
Preparation of 2- ( ( (4- (3-MethylphenyDpiperazin-l- yl) acetyl) amino) -6-methoxybenzothiazole (Compound DV)
1- (3 -Methylphenyl) piperazine (1.4 g. 8 mmol) and K2C03 (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 reaction mixture was heated and stirred at 70 °C 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%) of the title compound as a light solid, mp 73-75 °C: AH NMR (DMSO-d6) δ 12.01 (bs, IH) , 7.64 (d, J = 8.8, IH) , 7.57 (d, J = 7.6 , IH) , 7.08 '(dd, J = 8.0, J = 8.0, IH) , 7.02 (dd, J - 8.8, J = 2.8, IH) , 6.75 (s, IH) , 6.72 (d, J = 8.4, IH) , 6.59 (d, J = 7.2, IH) , 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 (DMS0-de) δ 168.96, 156.12, 155.32, 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 (El, m/z) 397 (M+) .
Example 30
Preparation of 2- ( ( (4- (4- (Methoxycarbonyl ) henyl ) piperazin-l- yl) acetyl) amino) -6-methoxybenzothiazole (Compound EJ)
1- ( (4-Methoxycarbonyl) phenyl) piperazine (0.9 g, 4 mmol) and K2C03 (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 reaction mixture was heated and stirred at 60 °C 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 (74%) of the title compound as a light solid, mp 211-213 °C: *H NMR (DMSO-d δ 11.90 (bs, IH ), 7.78 ( d, J = 8.8, 2H) , 7.63 (d, J = 8.8, IH) , 7.57 (d, J = 2.4, IH) , 7.03 (dd, J = 8.8, J = 2.8, IH ) , 6.98 (d, J = 8.8 , 2H) , 3.80 (s, 3H) , 3.77 (ε, 3H) , 3.40 (s, 2H) , 3.36 (t, J = 4.8, 4H ), 2.68 (t, J = 4.8, 4H) ; 13C NMR (DMSO-de) δ 168.92,
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 (El, m/z) 440 (M*) . ς
Example 31
Preparation of 2- ( ( (4- (4- (TrifluoromethyDphenyl) piperazin-1- yl) acetyl) amino) -6 -methoxybenzothiazole (Compound DU)
1- (α,α,α!-Trifluoro-p-tolyl) piperazine (2 g, 8.6 mmol) 0 was added to a solution of 2- ( (bromoacetyl) amino) -6- methoxybenzothiazole (1.3 g, 4.3 mmol) in DMF (20 mL) at rt . The reaction mixture was heated and stirred at 60 °C for 6 h, cooled to rt, and slowly poured into ice water. The light crystalline compound which precipitated was filtered, washed 5 several times with cold water, and then dried to give 0.75 g (38.5%) of the title compound, mp 218-219.3 °C: XH NMR (DMSO- de) δ 7.64 (d, J = 8.8, IH) , 7.57 (d, J = 2.4, IH) , 7.50 (d, J" = 9.2, 2H) , 7.06 (d, J = 9.2, 2H) , 7.03 (dd, J = 8.8, J = 2.4, IH) , 3.81 (s, 3H) , 3.40 (s, 2H ), 3.34 (bs, 4H) , 2.69 0 (t, J = 4.8, 4H) ; 13C NMR (DMSO-dg) δ 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 (El, m/z) 450 (M+) . 5 Example 32
Preparation of 2- ( ( (4- (3- (TrifluoromethyD henyl) piperazin-1- yl) acetyl) amino) -6 -methoxybenzothiazole Hydrochloride
(Compound DT) 0 A solution of 2- ( ( (4- (3-
(Trifluoromethyl) phenyl) piperazin-1-yl) acetyl) amino) -6- methoxybenzothiazole (0.5 g, 1.11 mmol) in CH2Cl2 (15 L) was treated with IN HCl ether solution (3 mL, 3 mmol) . The mixtire was εtirred for lh, and the precipitate which formed
35 was filtered and dried to give 0.35 g (60.3%) of the title compound as a ivory solid, mp 260.3-260.8 °C. Example 33
Preparation of 2- ( ( (4- (4-Chlorobenzhydryl) piperazin-1- yl) acetyl) amino) -6 -methoxybenzothiazole (Compound DX)
1- (4 -Chlorobenzhydryl) piperazine (1 g, "3.7 mmol) and K2C03 (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 reaction mixture was heated and stirred at 70 °C for 7 h, cooled to rt, and poured into ice 0 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 (75%) of the title compound as a off-white solid, mp 124.2-126.0 °C ("wet" at 119 °C) : XH NMR (DMS0-dfi) δ 11.55 5 (bs, IH) , 7.62 (d, J = 9.2, IH) , 7.56 (d, J = 2.4, IH) , 7.45- 7.33 (m, 6H) , 7.29 (dd, J = 7.2, J = 7.2, 2H) , 7.19 (dd, J = 7.2, IH) , 7.02 (dd, J = 8.8, J = 2.8, IH) , 4.33 (s, IH) , 3.80 (s, 2H) , 3.32 (s, 3H) , 2.58 (bs, 4H) , 2.33 (bs, 4H) ; 13C NMR (DMS0-dfi) δ 168.97, 156.11, 155.26, 142.49, 142.14, 141.78,
20 132.70, 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) .
Example 34
Preparation of 2- ( ( (4- (3-Chlorophenyl) iperazin-1-
25 yl) acetyl) amino) -6-methoxybenzothiazole (Compound DO)
Reaction of 2- ( (bromoacetyl) amino) -6- methoxybenzothiazole (1.0 g, 3.32 mmol) and l-(3- chlorophenyl) piperazine (1.30 g, 6.64 mmol) in DMF (30 mL) according to representative procedure in Example 36, gave
30 0.68 g (59%) of the title compound as a solid, mp 159-160 °C: XH NMR (DMSO-dg) δ 12.03 (bs, IH) , 7.63 (d, J = 9.2, IH) , 7.57 (d, J = 2.4, IH) , 7.20 (dd, J = 8.0, J = 8.0, IH) , 7.02 (dd, J = 8.8, J = 2.8, IH), 6.94 (dd, J = 2.0, J = 2.0, IH), 6.88 (dd, J = 8.4, J = 2.0, IH) , 6.77 (dd, J = 7.6, J = 1.6, IH),
35 3.80 (s, 3H) , 3.39 (s, 2H) , 3.21 (t, J = 4.8, 4H) , 2.67 (t, J" = 4.8, 4H) ; 13C NMR (DMS0-d6) δ 168.94, 156.12, 155.35, 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 (El, m/z) 416 (M+) . Anal. Calcd for C20H21N4ClO2S : C, 57.62; H, 5.08; N, 13.44. Found: C, 57.28; H, 5 5.29; N, 13.22.
Example 35
Preparation of 2- ( ( (4- (3-Bromophenyl) piperazin-l- yl) acetyl) amino) -6-methoxybenzothiazole (Compound DP) 0 Reaction 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 °C: 5 XH NMR (DMS0-dff) δ 12.03 (bs, IH) , 7.63 (d, J = 8.8, IH) , 7.57 (d, J = 2.8, IH) , 7.14 (dd, J = 8.0, J = 8.0 IH) , 7.07 (dd, J - 2.0, J = 2.0, IH) , 7.02 (dd, J = 8.8, J = 2.8, IH), 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) δ 168.93,
20 156.13, 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 (El, 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.
25
Example 36
Preparation of 2- (( (4- (3-Nitrophenyl) piperazin-l- yl) acetyl) amino) -6 -methoxybenzothiazole (Compound DO)
A solution of 2- ( (bromoacetyl) amino) -6- 30 methoxybenzothiazole (1.0 g, 3.32 mmol) and l-(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 (MgS04) , filtered, and then 35 concentrated. The residue was purified 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: XH NMR (DMSO-de) δ 12.05 (s, IH) , 7.65 - 7.62 (m, 2H) , 7.59 - 7.56 (m, 2H) , 7.46 (dd, J" = 8.0, J = 8.0, IH) , 7.39 (ddd, J = 8.4, J = 2.4, J = 0.8, IH) , 7.02 (dd, J = 8.8, J = 2.4, IH) , 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) δ 168.94, 156.13, 155.35, 151.47, 148.80, 142.49, 132.72, 130.05, 121.27, 121.06, 114.85, 112.58, 108.33, 104.70, 59.92, 55.57, 52.08 (2C) , 47.42 (2C) ; MS (El, m/z) 427 (M+) . Anal. Calcd for C20H21N4O4S: C, 56.19; H, 4.95; N, 16.38. Found: C, 56.28; H, 5.12; N, 16.27.
Example 37
Preparation of 2- (( (4- (3 -Cvanophenyl) piperazin-l- yl) acetyl) amino) -6 -methoxybenzothiazole (Compound EK) Reaction of 2- ( (bromoacetyl) amino) -6- methoxybenzothiazole (1.0 g, 3.32 mmol) and l-(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 °C: ^ NMR (DMS0-d6) δ 12.03 (s, IH) , 7.63 (d, J" = 9.2, IH) , 7.57 (d, J = 2.4, IH) , 7.38 (dd, J = 8.8, J = 8.8, IH) , 7.33 (s, IH) , 7.26 (dd, J = 8.4, J = 2.4, IH) , 7.15 (d, J = 7.2, IH) , 7.03 (dd, J = 8.8, J= 2.4, IH) , 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- d6) δ 168.96, 156.14, 155.36, 150.97, 142.50, 132.73, 130.08, 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 (El, m/z) 407 (M*) . Anal. Calcd for C21H21N502S : C, 61.90; H, 5.19; N, 17.19. Found: C, 60.40; H, 5.22; N, 16.59.
Example 38
Preparation of 2- ( ( (4- (3 -Ethylphenyl) piperazin-1- yl) acetyl) amino) -6 -methoxy benzothiazole (Compound EL) Reaction of 2- ( (bromoacetyl) amino) -6- methoxybenzothiazole (1.0 g, 3.32 mmol) and l-(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 NMR (DMSO-d6) δ 12.01 (s, IH) , 7.64 (d, J" = 8.8, IH) , 7.57 (d, J = 2.4, IH) , 7.11 (dd, J = 8.0, J = 8.0, IH) , 7.03 (dd, J = 8.8, J = 2.8, IH) , 6.77 (s, IH) , 6.73 (dd, J = 8.0, J = 2.0, 5 IH) , 6.63 (d, J = 7.6, IH) , 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-d5) δ 168.97, 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, 10 52.50 (2C) , 48.27 (2C) , 28.49, 15.63; MS (El, m/z) 410 (M+) . Anal. Calcd for C22H26N402S : C, 64.37; H, 6.38; N, 13.65. Found: C, 62.32; H, 6.37; N, 13.50.
Example 39 Preparation of 2- (( (4- (3 -Methoxyphenyl) piperazin-1- 15 yl) acetyl) amino) -6 -methoxybenzothiazole (Compound EM) Reaction 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 20 0.97 g (70%) of the title compound as a solid, mp 142-145 °C: *H NMR (DMSO-d6) δ 12.00 (s, IH) , 7.63 (d, J = 8.8 , IH) , 7.57 (d, J = 2.8, IH) , 7.10 (dd, J = 8.0, J = 8.0, IH) , 7.02 (dd, J = 8.8, J = 2.8, IH), 6.51 (dd, J = 8.4, ι7 = 1.6, IH), 6.45 (bs, IH) , 6.35 (dd, J = 8.4, J = 2.0, IH) , 3.80 (s, 3H) , 3.71 25 (s, 3H) , 3.39 (ε, 2H) , 3.16 (t, J = 4.0, 4H) , 2.68 (t, J = 4.0, 4H) ; 13C NMR (DMSO-d δ 168.95, 160.15, 156.13, 155.33, 152.28, 142.50, 132.72, 129.50, 121.05, 114.84, 108.05r 104.71, 104.09, 101.53, 60.06, 55.56, 54.79, 52.41 (2C) , 48.11 (2C) ; MS (El, m/z) 412 (M+) . Anal. Calcd for C21H24N403S : 30 C, 61.15; H, 5.86; N, 13.58. Found: C, 61.34; H, 5.99; N, 13.49.
35 Example 40 Preparation of 2- ( ( (4- (4-Bromo-3- trifluoromethylphenyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole (Compound DW) 5 Reaction 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- 10 183 °C: H NMR (DMSO-dfi) δ 12.00 (s, IH) , 7.63 (t, J = 8.8,
IH) , 7.61 (d, J = 8.4, IH) , 7.57 (d, J = 2.4, IH) , 7.25 (d, J = 2.8, IH) , 7.11 (dd, J = 8.8, J = 2.8, IH) , 7.03 (dd, J = 8.8, J = 2.8, IH) , 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-de) δ 168.91, 15 156.14, 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 (El, m/z) 529 (M+) . Anal. Calcd for C21H20N4O2SF3Br : C, 47.65; H, 3.81; N, 10.58. Found: C, 47.68; 20 H, 3.95; N, 10.41.
Example 41 Preparation of 2- ( ( (4- (2-Naphthyl) piperazin-1- yl) acetyl) amino) -6-methoxybenzothiazole (Compound EN) Reaction of 2- ( (bromoacetyl) amino) -6- 25 methoxybenzothiazole (1.0 g, 3.32 mmol) and l-(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 °C: H NMR (DMS0-de) δ 12.03 (s, IH) , 7.76 - 7.70 (m, 3H) , 7.64 30 (d, J = 8.8, IH) , 7.58 (d, J = 2.8, IH) , 7.40 - 7.35 (m, 2H) , 7.25 (ddd, .7 = 8.0, .7 = 6.8, .7 = 1.2, IH), 7.16 (d, .7 = 2.4, IH) , 7.03 (dd, J = 8.8, J = 2.8, IH) , 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-de) δ 168.97, 156.13, 155.32, 148.75, 142.51, 134.27, 35 132.72, 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 (El, m/z) 432 (M+) . Anal. Calcd for C24H24N402S: C, 66.64; H, 5.59; N, 12.95. Found: C, 66.20; H, 5.67; N, 12.80.
Example 42 Preparation of 2- ( ( (4- (3-Methoxy-5- 5 trifluoromethylphenyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole (Compound DY) 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 0 (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: XH NMR (DMSO-d5) δ 12.02 (s, IH) , 7.63 (d, J = 8.8, IH) , 7.57 (d, J = 2.8, IH) , 7.02 (dd, J = 8.8 , J = 2.8, IH) , 6.79 (bs, IH) , 6.70 (t, J = 2.4, IH) , 6.61 (bs, IH) , 3.81 (s, 3H) , 5 3.79 (s, 3H) , 3.40 (s, 2H) , 3.27 (t, J = 5.2, 4H) , 2.69 (t, J = 4.4, 4H) ; 13C NMR (DMS0-de) δ 168.92, 160.56, 156.12, 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) , 20 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.
Example 43 Preparation of 2- (( (4- (3 , 4 -Dichlorophenyl) piperazin-l- yl) acetyl) amino) -6-methoxybenzothiazole (Compound EQ) 25 Reaction of 2- ( (bromoacetyl) amino) -6- methoxybenzothiazole (1.0 g, 3.32 mmol), l-(3,4- dichlorophenyl) piperazine (1.0 g, 4.40 mmol) and anhydrous K2C03 (0.61 g, 4.40 mmol) in DMF (30 mL) according to representative procedure in Example 36 gave 0.98 g (65%) of 30 the title compound as a solid, mp 187-190 °C: XH NMR (DMSO-d5) δ 11.91 (bs, IH) , 7.63 (d, J = 9.2, IH) , 7.56 (d, J = 2.8, IH) , 7.38 (d, J = 9.2, IH) , 7.12 (d, J = 2.8, IH) , 7.02 (dd, J = 8.8, J = 2.4, IH) , 6.92 (dd, J = 9.2, J = 2.8, IH) , 3.80 (S, 3H) , 3.39 (s, 2H) , 3.22 (t, J = 4.8 , 4H) , 2.66 (t, J = 35 4.8, 4H) ; 13C NMR (DMSO-de) δ 169.03, 156.18, 155.43, 150.70, 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 (El, m/z) 450 (M+) . Anal. Calcd for C20H20N4O2SCl2 : C, 53.22; H, 4.47; N, 12.41. Found: C, 52.96; H, 4.52; N, 12.25.
Example 44 Preparation of 2- ( ( (4- (3 , 5-Dichlorophenyl) piperazin-l- yl) acetyl) amino) -6-methoxybenzothiazole (Compound EP) Reaction of 2- ( (bromoacetyl) amino) -6- methoxybenzothiazole (1.0 g, 3.32 mmol), l-(3,5- dichlorophenyl) piperazine (1.0 g, 4.40 mmol) and anhydrous K2C03 (0.61 g, 4.40 mmol) in DMF (30 mL) according to representative procedure in Example 36 gave 1.01 g (67%) of the title compound as a solid, mp 80-81 °C: *H NMR(DMS0-dg) δ 12.03 (bs, IH) , 7.63 (d, J = 9.2, IH) , 7.57 (d, J = 2.4, IH) , 7.03 (dd, J = 8.8, J = 2.4, IH) , 6.94 (d, J = 1.6, 2H) , 6.85 (t, J = 1.6, IH) , 3.81 (s, 3H) , 3.39 (s, 2H) , 3.27 (t, J = 4.8, 4H) , 2.65 (t, J = 4.8, 4H) ; 13C NMR (DMS0-dff) 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 C20H20N4O2SCl2 : C, 53.22; H, 4.47; N, 12.41. Found: C, 53.04; H, 4.68; N, 11.99.
Example 45A Preparation of 2- ( (Bromoacetyl) amino) -4-methoxybenzothiazole
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 internal temperature of the reaction mixture at 5 °C. After stirring at 5 °C for 1 h, the ice bath was removed and the reaction mixture was stirred for 20 h. 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 2.7 g (41%) of the title compound as a white solid, mp 204.8-206 °C: *H NMR (DMSO-d6) δ 12.91 (s, IH) , 7.54 (dd, J = 7.6, J" = 0.4, IH) , 7.28 (dd, J = 8.0, J = 8.0, IH) , 7.00 (dd, J = 8.0, J = 0.4, IH) , 4.19 (s, 2H) , 3.91 (s, 3H) ; 13C NMR (DMSO-d6) δ 165.71, 155.92, 151.90, 138.33, 132.85, 124.77, 113.54, 107.81, 55.83, 28.44; MS (El, m/z) 300 (M*) . Example 45 Preparation of 2- ( ( (4- (2-Pyridyl) piperazin-l-yl) acetyl) amino- 4 -methoxybenzothiazole (Compound DI) 1- (2-Pyridyl) piperazine (1.15 g, 1.2 mL, 7.01 mmol) was 5 added to a solution of 2- ( (bromoacetyl) amino) -4- methoxybenzothiazole (1.05 g, 3.51 mmol) in DMF (20 mL) at rt. The reaction mixture was heated and -stirred at 50 °C for 5 h, cooled to rt, and slowly poured into ice water. The off-white precipitate which formed was filtered, washed 0 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 °C: 'H NMR (DMSO-dff) δ 12.18 (bs, IH) , 8.10 (d, J = 3.6, IH) , 7.52 (d, J = 7.6, IH) , 7.51-7.50 (m, IH) , 7.26 (dd, , J = 8.0, J = 8.0, IH) , 7.00 (d, J - 8.0, IH) , 6.81 (d, J = 8.4, IH) , 6.63 5 (dd, J = 6.4, J = 4.8, IH) , 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-de) δ 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, 52.25 (2C) , 44.53 (2C) ; MS (El, m/z) 383 (M+) . 0 Example 46A
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) 5 while keeping the internal temperature of the reaction mixture at 5 °C. After stirring at 5 °C for 1 h, the ice bath was .removed and the reaction mixture was stirred for 20 h. The reaction mixture was poured into water and the light- beige crystalline compound which formed was filtered, washed 0 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- 163.2 °C: *H NMR (DMS0-de) δ 12.63 (bs, IH) , 7.65 (d, J = 8.8, IH) , 7.57 (d, J = 2.4, IH) , 7.02 (dd, J = 9.2, J = 2.8, IH), 4.20 (S, 2H) , 4.06 (q, J = 6.8, 2H) , 1.35 (t, J = 7.2, 3H) ; 35 13C NMR (DMS0-de) δ 165.59, 155.49, 142.42, 141.80, 132.76,
121.29, 115,41, 105.39, 65.59, 28.49, 14.61; MS (El, m/z) 384 (M*) . Example 46 Preparation of 2- ( ( (4- ( (2-PyridvDpiperazin-l- yl) acetyl) amino) -6-ethoxybenzothiazole (Compound 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 °C 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 (NaS04) , 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 (62%) of the title compound as a light beige solid, mp 183- 183.2 °C: 'H NMR (DMS0-dff) δ 12.00 (bs, IH) , 8.10 (dd, J = 4.8, J = 2.0, IH) , 7.64 (d, J = 8.8, IH) , 7.55 (d, J = 2.4, IH) , 7.52 (ddd, J = 8.8, J" = 7.2, J = 2.0, IH) , 7.02 (dd, J = 8.4, J = 2.4, IH) , 6.81 (d, J = 8.8, IH) , 6.63 (dd, J = 6.8, J = 4.8, IH) , 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) δ 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 (El, m/z) 397 (M+) .
Example 47
Preparation of 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino) -6-ethoxybenzothiazole (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 reaction mixture was heated and stirred at 45 °C for 5 h, cooled to rt, and slowly poured into ice water. The reaction mixture was extracted with EtOAc (3 x 40 mL) . The combined
EtOAc layer was washed sequentially with brine and water, dried over Na2S04, filtered, and then concentrated. The ensuing brown oil was dissolved 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, 5 and then dried to give 1.25 g (85%) of the title compound as a light beige solid, mp 77-79 °C: XH NMR (DMSO-d^) δ 12.06 (bs, IH) , 7.63 (d, .7 = 8.8, IH) , 7.55 (d, .7 = 2.4, IH) , 7.42 (dd, J = 7.6, IH) , 7.22 (dd, J = 10.4, J = 2.0, IH) , 7.17 (s, IH) , 7.06 (d, J = 7.6, IH) , 7.01 (dd, J = 8.8, J = 2.4, IH) , 0 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-de) d 155.37, 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, 5 52.19 (2C) , 47.45, 14.63; MS (El, m/z) 464 (M+) .
Example 48
Preparation of 2- (( (4- (4- (Acetyl) phenyl) iperazin-1- yl) acetyl) amino) -6 -ethoxybenzothiazole (Compound EQ) 0 4- ( (Carbomethoxy) phenyl) piperazine (3 g, 14.6 mmol) was added to a solution of 2- ( (bromoacetyl) amino) -6- ethoxybenzothiazole (2.3 g, 7.3 mmol) in DMF (25 mL) at rt . The reaction mixture was heated and stirred at 70 °C for 7 h, cooled to rt, and poured into ice water. The crystalline 5 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: ^-H NMR (DMS0-de) δ 7.80 (d, J" = 9.2, 2H) , 7.62 (d, J = 8.8, IH) , 7.55 (d, J = 2.4, IH) , 7.01 (dd, J = 8.8, J = 2.8, IH) , 6.97 (d, J 0 = 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-de) δ 195.50, 168.97, 155.37, 155.34, 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) , 35 26.01, 14.63, MS (El, m/z) 438 (M*) . Example 49
Preparation of 2- (( (4- ( (2-Pyridyl) piperazin-l- yl) acetyl) amino) -6-ethoxybenzothiazole Hydrochloride
(Compound DR) A solution of 2- ( ( (4- (2- (pyridyDpiperazin-l- yl) acetyl) amino) -6-ethoxybenzothiazole (9.6 g, 24 mmol) in CH2C12 (100 mL) was treated with IN HCl ether solution (48 mL, 48 mmol) . The reaction mixture was stirred at rt for 2 h, the white precipitate which formed was filtered, washed 0 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: H NMR (D20) δ 7.95 (ddd, J = 9.2, J = 7.6, J = 1.6, IH) , 7.82 (dd, J = 6.4, J = 1.6, IH) , 7.36 (d, J = 8.0, IH) , 7.20 (d, J = 9.2, IH) , 7.15 (bs, IH) , 6.96 (dd, J = 7.2, J = 7.2, IH) , 6.84 5 (dd, J = 8.8, J = 2.4, IH) , 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 (D20) δ 165.97, 159.06, 156.61, 153.15, 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, 0 MS (FAB, m/z) 399 (M+) . 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; Cl , 13.73.
Example 50
Preparation of 2- (( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- 5 yl) acetyl) amino) -6 -ethoxybenzothiazole Hydrochloride
(Compound DS) . A solution of 2- (((4- (3- (trifluoromethyl) phenyl) piperazin-l-yl) acetyl) amino) -6- ethoxybenzothiazole (0.37 g, 8 mmol) in CH2C12 (15 mL) was 0 treated with IN HCl ether solution (1.6 mL, 1.6 mmol) . The reaction 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-
35 230 °C. Example 53 Preparation of 2- (( (4- (3-Trifluoromethyl) phenyl) piperazin-l- 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 internal 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 (MgS04) to afford 15.33 g (93%) of the title compound as a white solid, mp 145-146 °C: E NMR (DMSO-de) δ 13.71 (bs, IH) , 4.28 (s, 2H) ; 13C NMR (DMS0-d6) δ 166.39, 161.15, 150.46 (q, J = 37.1), 119.96 (q, J - 270), 61.11; MS (El, m/z) 291 (M+) .
A εolution of 2- (bromoacetyl) amino-5- (trifluoromethyl) - 1, 3,4-thiadiazole (1.5 g, 5.17 mmol) and 1- (ct*, α, c-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 °C: XH NMR (DMSO-ds) δ 7.42 (t, J" = 8.0, IH) , 7.23 (dd, J = 8.4, J = 2.0, IH) , 7.18 (s, IH) , 7.07 (d, J = 7.6, IH) , 3.59 (s, 2H) , 3.10 (t, J = 4.4, 4H) , 2.85 (t, J = 4.8 , 4H) ; 13C NMR (DMSO-ds) δ 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 (El, m/z) 439 (M+) . Anal. Calcd for C16H15NsF6SO : 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- yl) acetyl) amino) -5- (trifluoromethyl) -1,3 , 4 -thiadiazole
(Compound BC) 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 °C 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: XH NMR (DMSO-d δ 7.15-6.94 (m, 4H) , 3.61 (s, 2H) , 3.10 (t, J = 4.4, 4H) , 2.85 (t, J = 4.8, 4H) ; 13C NMR (DMSO-dff) δ 169.59, 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 (El, 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. Example 55
Preparation of 2- (( (4- (4-Methoxyphenyl) iperazin-1- yl) acetyl) amino) -5- (trifluoromethyl) -1,3.4 -thiadiazole
(Compound BD) A solution of 5% 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 CH2C12 (3 x 50 mL) . The combined extracts were dried over MgS04, 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 °C 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 (73%) of the title compound, mp 158-160 °C: XH NMR (DMS0-de) δ 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) δ 169.63, 163.31, 153.05, 149.45 (q, «7 = 36), 144.97, 120.25 (q, J = 271), 117.48, 114.23, 59.71, 55.14, 5 52.28 (2C) , 48.80; MS (El, m/z) 401 (M+) . Anal. Calcd for C16H18N5F3S02 : C, 47.88; H, 4.52; N, 17.45. Found: C, 48.21; H, 4.72; N, 17.22.
Example 56 Preparation of 2- ( ( (4- (2-Pyridyl)piperazin-l- 0 yl) acetyl) amino) -5- (trifluoromethyl) -1, 3 , 4-thiadiazole
(Compound BE) 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 5 L) 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 MgS04, filtered, and then concentrated. Purification by chromatography, eluting with hexane-ethyl 0 acetate (2:1), afforded 0.79 g (62%) of the title compound, mp 158-160 °C: ΣH NMR (DMSO-dfi) δ 8.11 (dd, J = 5.2, J = 1.6, IH) , 7.54 (ddd, J = 8.8 , .7 = 6.8, .7 = 1.6, IH), 6.84 (d, J" = 8.8, IH) , 6.65 (dd, J = 6.8, J = 5.2, IH) , 3.62 (s, 2H) , 3.59 (t, J = 5.2, 4H) , 2.81 (t, J = 4.8, 4H) ; 13C NMR (DMSO-d6) δ 25 169.66, 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 (El, m/z) 372 (M+) . Anal. Calcd for C14H15N6F3SO : C, 45.16; H, 4.06; N, 22.57. Found: C, 45.15; H, 4.15; N, 22.19. 30 Example 57
Preparation of 2- ( ( (4- (2-Pyrimidyl) piperazin-1- yl) acetyl) amino) -5- (trifluoromethyl) -1 , 3 , 4 -thiadiazole
(Compound BF) A εolution of 2- ( (bromoacetyl) amino) -5- 35 (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 MgS04, filtered, and then concentrated. Purification by flaεh column chromatography on εilica gel, 5 eluting with hexane-ethyl acetate (4:1) gave 1.45 g (75%) of the title compound, mp 194-195 °C: XH NMR (DMSO-dfi) δ 8.34 (d, J = 4.8, 2H) , 6.64 (t, J = 4.4, IH) , 3.81 (t, J = 5.2 , 4H) , 3.58 (8, 2H) , 2.73 (t, J = 4.8, 4H) ; 13C NMR (DMS0-de) δ 169.62, 162.55, 161.05, 157.89 (2C) , 149.65 (q, J = 36), 10 120.28 (q, J - 270), 110.23, 59.74, 51.98 (2C) , 42.65 (2C) ; MS (El, m/z) 373 (M+) . Anal. Calcd for C13H14N7F8SO : 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- 15 thiadiazole
A solution of 2-amino-5-n-propylthio-l,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 °C. Bromoacetyl bromide (3.45 g, 17.1 mmol) was added dropwise, keeping the internal 20 temperature between 0 to 5 °C, and the solution was stirred for 3 h at rt . The solution was slowly poured into 500 L 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 °C: XH NMR 25 (DMSO-de) δ 13.04 (s, IH) , 4.19 (s, 2H) , 3.21 (t, J = 6.8, 2H) , 1.70 (heptet, J = 7.2, IH) , 0.97 (t, J" = 7.6, 3H) ; 13C NMR (DMSO-d6) δ 165.49, 159.46, 158.30, 35.49, 27.97, 22.32, 12.86; MS (El, m/z) 295 (M+) .
Example 58 30 Preparation of 2- (( (4- (3- (TrifluoromethyDphenyl)piperazin-l- 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- 35 (trifluoromethyl) phenyl) -piperazine (2.91 g, 12.7 mmol) in DMF (50 mL) was heated at 80 °C 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 MgS04, filtered, and then concentrated. Purification by chromatography, eluting with hexane-ethyl acetate (1:1), afforded 2.68 g (71%) of the title compound, mp 118-119 °C: XH NMR (DMS0-d6) δ 12.55 (bs, NH, IH) , 7.41 (dd, J = 8.0, J = 8.0, IH) , 7.21 (dd, J = 8.4, J = 2.4, IH) , 7.15 (s, IH) , 7.06 (dd, J = 7.6, J = 0.4, IH) , 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, .7 = 7.2, 2H) , 0.97 (t, J = 7.6, 3H) ; 13C NMR (DMSO-d5) δ 168.63, 158.82, 158.12, 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 (El, m/z) 445 (M+) .
Example 59A Preparation of 2- ( (Bromoacetyl) amino) -5-cvclopropyl-l, 3.4- thiadiazole A solution of 2-amino-5-cyclopropyl-l, 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 °C. 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 °C (dec) : XH NMR (DMSO-de)δ 12.82 (s, IH) , 4.16 (s, 2H) , 2.40 (m, IH) , 1.16-1.11 (m, 2H) , 1.00-0.96 (m, 2H) ; 13C NMR (DMS0-dfi) δ 167.23, 165.21, 156.66, 61.07, 28.12, 10.53, 10.04; MS (El, m/z) 263 (M+) . Example 59
Preparation of 2- ( ( (-4- (3- (Trifluoromethyl) phenyl) iperazin- l-yl) acetyl) 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 l-(3-
(trifluoromethyl) phenyl) -piperazine (3.96 g, 17.2 mmol) in DMF (50 mL) was heated at 80 °C 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%) of the title compound, mp 180-181 °C: XH NMR (DMSO-de) δ 7.39 (t, J = 8.0, IH) , 7.19 (d, J = 8.4, IH) , 7.14 (s, IH) , 7.04 (d, J = 7.2 , IH) , 3.37 (s, 2H) , 3.23 (t, J = 4.0, 4H) , 2.65 (t, J = 4.4, 4H) , 2.36 (m, J = 3.2, IH) , 1.18-1.10 (m, 2H) , 0.96-0.94 (m, 2H) ; 13C NMR (DMSO-de) δ 168.52, 167.08, 156.52, 151.26, 129.92, 129.86 (q, «7 = 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 (El, 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 °C. Bromoacetyl bromide (2.76 g, 13.68 mmol) was added dropwise, keeping the internal temperature between 0 and 5 °C, 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 (56.7%) of the title compound as a white solid, mp > 250 °C: ^ NMR (DMSO-dfi) δ 13.06 (s, IH) , 4.19 (s, 2H) , 4.17 (s, 2H) , 4.12 (q, J = 7.2, 2H) , 1.17 (t, J = 6.8, 3H) ; 1C NMR (DMSO- de) δ 168.05, 165.54, 158.84, 158.16, 61.26, 35.07, 27.93, 13.87; MS (El, m/z) 341 (M+) .
Example 60 Preparation of 2- ( ( (-4- (3- (Trifluoromethyl) phenyl) iperazin- 1-yl) acetyl) amino) -5- (ethoxycarbonylmethylthio) -1,3,4- thiadiazole (Compound ET) A εolution 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 °C 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 εeparated and the organic layer was dried over MgS04, filtered, and then concentrated. Purification by chromatography, eluting with hexane-ethyl acetate (1:1), afforded 1.92 g (53.4%) of the title compound, mp 126-127 °C: XH NMR (DMSO-de) δ 7.41 (t, J" = 5 8.0, IH) , 7.21 (dd, J - 8.4, J = 2.0, IH) , 7.15 (s, IH) , 7.05 (d, J = 7.6, IH) , 4.16 (ε, 2H) , 4.12 (q, J = 6.8, 2H) , 3.42 (8, 2H) , 3.25 (t, J = 4.4, 4H) , 2.67 (t, = 4.4, 4H) , 1.17 (t, J = 7.2, 3H) ; 13C NMR (DMSO-de) δ 168.68, 168.08, 158.68, 157.52, 151.10, 129.88, 129.83 (q, J = 31), 124.37 (q, J = 10 271), 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 (El, m/z) 489 (M+) .
Example 61A Preparation of 2- ( (Bromoacetyl) amino) -5- ( (7-chloroquinolin-4- 15 yl) thio) -1,3.4-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 °C and bromoacetyl bromide (2.05 g, 10.2 mmol) was added dropwise. After TLC indicated that the majority of 20 starting thiadiazole had been consumed, the εolution was cooled to rt, causing a precipitate to form. The mixture was εlowly poured into a flaεk containing 200 mL of EtOAc and 200 mL of εaturated NaHC03. The mixture was stirred for 30 min, during which the precipitate disappeared and the εolution 25 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 (28.5%) of the title compound as a beige εolid, mp 170-173 °C (became wet) , 217-220 °C (dec) : *H NMR (DMSO-d5) δ 30 13.36 (s, IH) , 8.84 (d, J = 4.8, IH) , 8.26 (d, J = 9.2, IH) , 8.17 (d, J" = 2.4, IH) , 7.78 (dd, J = 8.8, J" = 2.4, IH) , 7.48 (d, J = 4.8, IH) , 4.21 (s, 2H) ; 13C NMR (DMSO-de) δ 165.90, 161.52, 153.14, 151.49, 148.06, 141.48, 135..10, 128.38, 125.85, 124.60, 122.70, 27.78. 35 Example 61
Preparation of 2- (( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -5- ( (7-chloroquinolin-4-yl) thio) -1,3.4- thiadiazole (Compound BG) 5 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 0 extracted with EtOAc (3 x 150 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 0.80 g (55%) of the title compound, mp 157-159 °C: XH NMR δ 12.80 (bs, NH, IH) , 15 8.81 (d, J = 4.4, IH) , 8.23 (d, J = 9.2, IH) , 8.13 (d, J = 2.4, IH) , 7.75 (dd, J = 9.2, J = 2.4, IH) , 7.42 (d, J = 4.8 , IH) , 7.39 (t, J = 8.0, IH) , 7.19 (d, J = 8.4, IH) , 7.14 (s, IH) , 7.04 (d, J = 7.6, IH) , 3.45 (s, 2H) , 3.24 (t, J = 4.0 , 4H) , 2.68 (t, J = 4.4, 4H) ; 13C NMR (DMSO-d δ 169.17, 20 161.78, 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 (El, m/z) 564 (M+) . 25 Example 62
Preparation of 2 - (( (4- (3- (TrifluoromethyDphenyl) iperazin-l- yl) acetyl) amino) -5- ( (carbomethoxy) methyl) -1.3.4-thiadiazole
(Compound BI) Preparation of methyl malonylthiosemicarbazone : To a 30 suspension of thiosemicarbazide (16.4 g, 180 mmol) in THF was added methyl malonyl chloride (20.4 g, 150 mmol) dropwise at 0 °C. The reaction 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 35 compound as a pale white solid: XH NMR (CD3OD) δ 4.89 (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 MeS03H (18 mL, 277 mmol) dropwise at 0 °C. The suspension became a sticky white solid and piled up at the bottom of the flask. The reaction mixture was stirred at 70 °C for 3 h, concentrated under reduced pressure, and then the solid was suspended in MeOH. Concentrated NH4OH 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 colorleεε 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 (46%, two step yield) of the title compound as a light yellow solid: XH NMR (DMSO-d6) δ 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 C5H7N3S02 : 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-5- ( (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 °C. The reaction was allowed to warm to rt and stir overnight . The reaction was quenched with ice water (500 mL) and stirred for 2 h. A white precipitate and some sticky yellow solid were formed. Filtration collected the white solid. The yellow floating solid was recrystallized from EtOAc to provide additional product. A total of 6 g of the title compound (89%) was obtained as a white solid: XH NMR (DMSO-dfi) δ 12.90 (bs, IH) , 4.24 (s, IH) , 4.20 (s, IH) , 3.68 (s, 3H) , 3.34 (s, 2H) ; 13C NMR (DMS0-d6) δ 169.3, 165.6, 159.5, 157.1, 152.4, 34.7, 28.2; MS (El, m/z) 293 (M+) . Preparation of 2- (((4- (3- (trifluoromethyl) phenyl) piperazin-l-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 l-(3-
(trifluoromethyl) phenyl) piperazine (431 mg, 1.9 mmol) in DMF (10 mL) was heated at 80 °C for 1 h. The reaction 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 purified 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 °C: 1H NMR (CDC13) δ 7.38 (dd, J = 8.4, 8.0, IH) , 7.14 (s, IH) , 7.13 (d J = 8.0, IH) , 7.08 (dd, J = 8.4, J = 2.0, IH) , 4.14 (s, 2H) , 3.80 (s, 3H) , 3.42 (s, 2H) , 3.35 (t, J = 4.8, IH) , 2.84 (t, J = 4.8, 4H) ; 13C NMR (CDC13) δ 168.7, 168.1, 159.2, 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 (El, m/z) 443 (M+) . HRMS (FAB) calcd for C18H20N5F3O3S 444.1317, found 444.1287.
Example 63 Preparation of 2- (( (4- (2-Pyridyl) piperazin-l- 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 purified 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: XH NMR (DMSO-d£) δ 8.1 (ddd, .7 = 4.9, .7 = 2.0, .7 = 0.8, IH), 7.52 (ddd, J = 8.7, J = 7.1, J = 2.0, IH) , 6.81 (d, J = 8.7, IH) , 6.63 (dd, J = 7.1, J = 4.9, J = 0.8, IH) , 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-de) δ 169.2, 168.6, 159.1, 158.9, 156.5, 147.5, 137.4, 112.9, 107.0, 59.9, 52.19, 52.17 (2C) , 44.5 (2C) , 34.6; MS (El, m/z) 376 (M+) . HRMS (FAB) calcd for C16H20N6O3S 376.1396, found 377.1372.
Example 64 Preparation of 2- ( ( (4- (4 -Methoxyphenyl) piperazin-1- 5 yl) acetyl) amino) -5-carbomethoxymethyl-l, 3.4-thiadiazole
(Compound BK) The title compound was prepared from of 2- ( (bromoacetyl) amino) -5-carbomethoxymethyl-l, 3, 4-thiadiazole (1.2 g, 4.1 mmol) and 1- (4 -methoxyphenyl) piperazine (944 mg, 0 4.9 mmol, obtained by treatment of the commercially available HCl salt of 1- (4-methoxyphenyl) piperazine with 5% of NaOH solution and extraction with CH2C12) in DMF (15 L) as described for the preparation of Compound BI, mp 194.1-195.2 °C: XH NMR (CDCl3) δ 6.93 (d, J = 9.2, 2H) , 6.86 (d, J = 9.2, 5 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) ; 1C NMR (CDCl3) δ 168.7, 168.4, 159.2, 157.4, 154.3, 145.2, 118.7 (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 C18H23Ns04S 20 406.1549, found 406.1533. Anal. Calcd for C18H23N504S • 0.5 H20: C, 52.15; H, 5.94; N, 16.91. Found: C, 52.30; H, 5.72; N, 16.62.
Example 66 Preparation of 2- ( ( (4- (2-Pyridyl) piperazin-1- 25 yl) acetyl) amino) -1.3 , 4-thiadiazole (Compound BL)
Preparation of glyoxalic acid thioεemicarbazone : To a suspenεion of thiosemicarbazide (10 g, 110 mmol) in 80% of EtOH (150 mL) was added glyoxalic acid monohydrate (11 g, 119 mmol) in 80% of EtOH (50 mL) at 70 °C in one portion. When 30 glyoxalic acid monohydrate was added, the reaction mixture turned to clear and then became cloudy again. The reaction was stirred for 1.5 h at this temperature, and then cooled to rt . Filtration gave 9.6 g (59%) of the title compound aε a white solid: XH NMR (DMSO-ds) δ 12.46 (s, IH) , 11.92 (s, IH) , 35 8.65 (s, IH) , 8.28 (s, IH) , 7.29 (ε, IH) ; MS (FAB, m/z) 148 (M+H+) . Preparation of 2-amino-l, 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 H20) . The mixture was stirred at rt for 12 h. 5 The solid was filtered and washed with water to give a pale white solid. The solid was dissolved 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 collected by filtration. 10 990 mg (50%) of the title compound was obtained after drying: JH NMR (DMSO-dβ) δ 8.57 (s, IH) , 7.19 (s, 2H) ; 13C NMR (DMSO- d6) δ 168.2, 138.8, 124.2.
Preparation of 2- ( (bromoacetyl) amino) -1, 3 ,4-thiadiazole : To a εuspension of 2-amino-l, 3,4-thiadiazole-5-carboxylic 15 acid (800 mg, 5.52 mmol) in DMF (40 mL) waε added bromoacetyl bromide at 0 °C. The mixture was stirred at 0 °C for 30 min, quenched with ice-water and extracted with EtOAc. The organic layer was washed with brine, dried (MgS04) and concentrated to give crude title compound, which was used in 20 the following reaction without further purification.
Preparation of 2- ( (4- (2-pyridyl)piperazin-l-yl) -1, 3 ,4- thiadiazole: To a εolution of 2- ( (bromoacetyl) amino) -1, 3,4- thiadiazole (750 mg, 3.39 mmol) in DMF (30 L) was added 1- (2-pyridyl) piperazine (611 mg, 3.75 mmol). The mixture was 25 stirred at 80 °C for 1 h and then poured into ice water. The precipitate which formed waε collected by filtration and purified by chromatography on silica gel (CHCl3/MeOH 20:1) to give 350 mg (34%) of the title compound as a white solid: E NMR (DMSO-dfi) δ 12.44 (br s, IH) , 9.18 (s, IH) , 8.09 (ddd, J = 30 5.2, J = 2.0, J = 0.8, IH) , 7.52 (ddd, J = 8.8, J = 7.2, J = 2.0, IH) , 6.81 (d, J = 8.8, IH) , 6.62 (ddd, J = 7.2, J = 4.8, J = 0.4, IH) , 3.51 (t, J = 5.2, 4H) , 3.41 (s, 2H) , 2.61 (t, J = 5.2, 4H) ; 13C NMR (DMSO-ds) δ 168.7, 158.9, 158.1, 148.7, 147.5, 137.4, 112.9, 107.0, 60.0, 52.2 (2C) , 44.5 (2C) ; MS 35 (El, m/z) 304 (M+) . HRMS (FAB) calcd for C13H16N6OS 305.1180, found 305.1188. Anal. Calcd for C13H16N6OS • H20: C, 48.43; H, 5.63; N, 26.07. Found: C, 48.66; H, 5.19; N, 25.68. Example 67 Preparation of 2- (( (4- (3- (TrifluoromethyDphenyl) piperazin-l- yl) acetyl) amino) -5-carbomethoxy-1.3.4-thiadiazole (Compound
EV) Preparation of methyl 2-amino-l, 3,4-thiadiazole-5- carboxylate : An ethereal solution of diazomethane was added to a suspension of 2-amino-l, 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 purified by chromatography on silica gel (CHCl3/MeOH 9:1) to give 440 mg (40%) of the title compound as a white solid: XH NMR (DMSO-dfi) δ 8.02 (br s, 2H) , 8.85 (s, 3H) ; 13C NMR (DMSO- d6) δ 172.4, 159.3, 147.2, 52.8. Anal. Calcd for C4H5N302S : 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 suεpenεion of thiosemicarbazide (13.6 g, 149 mmol) in THF was added dropwise at 0 °C. The reaction waε allowed to warm to rt and εtirred overnight. Filtration removed a white precipitate. The filtrate was treated with ether, and the additional white precipitate which formed was filtered and dried to give 7.4 g (42%) of the title compound as a pale white solid: XH NMR (DMSO-d5) δ 10.76 (ε, IH) , 9.41 (s, IH) , 7.93 (s, IH) , 7.65 (s, IH) , 3.77 (s, 3H) ; 13C NMR (DMSO-de) δ 181.49, 159.60, 155.83, 52.75; MS (LSIMS, m/z) 178.0 (M+H+) .
Preparation of methyl 2-amino-l,3,4-thiadiazole-5- carboxylate, Method B: To a suspension of methylglyoxalate thiosemicarbazone (500 mg, 2.82 mmol) in toluene (50 mL) was added MeS03H (0.27 mL, 406 mg, 4.24 mmol) dropwise at 0 °C. The suεpension became a sticky white solid which piled up at the bottom of the flask. The resulting mixture was stirred at 70 °C for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was suspended in MeOH. Concentrated NH4OH 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 purified by chromatography eluting with MeOH-CHCl3 (1:20), to give 85 mg (20%) 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-l, 3,4- thiadiazole-5-carboxylate (440 mg, 23.1 mmol) in DMF/dioxane (20 mL, 1:1) waε added bromoacetyl bromide (727 mg, 3.6 mmol) dropwise at 0 °C. The reaction mixture was stirred for 1 h at 0 °C and quenched with ice water to give a precipitate. Filtration afforded 660 mg (85%) of the title compound as a white solid: XH NMR (DMS0-dβ) δ 13.48 (ε, IH) , 4.26 (ε, 2H) , 3.94 (ε, 3H) .
Preparation of 2- ( ( (4- (3- (Trifluoromethyl) phenyl) - piperazin-l-yl) acetyl) amino) -5-carbomethoxy-1,3,4- thiadiazole: a εolution of 2- ( (bromoacetyl) 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) waε heated at 80 °C for 3 h. The mixture waε poured into ice water and a precipitate waε formed. Filtration gave the crude product, which waε purified by chromatography on εilica gel to afford 560 mg (55%) of the title compound as a white solid: XH NMR (CDC13) δ 7.38 (dd, J = 8.4, J = 8.0, IH) , 7.14-7.13 (m, 2H) , 7.08 (d, J = 8.4, IH) , 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-d5) δ 168.6, 161.2, 159.6, 155.2, 150.9, 131.63 (q, J" = 31), 129.7, 124.20 (q, J = 271), 119.1, 116.6 (q, J" = 3.5), 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 C17H18Ns02SF3 : 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) iperazin- l-yl) acetyl) amino) -5- (2- (carbomethoxy) ethyl) -1,3.4- thiadiazole (Compound BN) Preparation of methyl 4- (thiosemicarbazone) butyrate : methyl 4- (thiosemicarbazone) butyrate was prepared from thioεemicarbazide (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 reaction gave 47 g of the crude title compound . as a white solid, which was used in the next step without further purification: XH NMR (DMSO-dg) δ 9.88 (s, IH) , 9.21 (s, IH) , 7.89 (ε, IH) , 7.31 (ε, IH) , 3.58 (s, 3H) , 2.53 (t, J = 6.8, 2H) , 2.40 (t, J = 6.8, 2H) ; 13C NMR (DMSO-dfi) δ 181.86, 172.97, 170.46, 51.46, 28.41, 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) , MeS03H (24 mL, 36 g, 377 mmol) and toluene (300 mL) as described in Example 62. The crude product was purified by chromatography on silica gel, eluting with Me0H-CHCl3 (1:10) to give 11 g (30%) of the title compound as a white solid: K NMR (DMS0-d6) δ 7.02 (ε, 2H) , 3.60 (s, 3H) , 3.04 (t, J = 7.2, 2H) , 2.72 (t, J = 7.2, 2H) ; 13C NMR (DMSO-dβ) δ 172.05, 168.38, 156.42, 51.39, 32.12, 24.83; MS (LSIMS, m/z) 187 (M+) . HRMS (FAB) calcd for C6H9N302S 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 °C. The mixture was stirred at 0 °C 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: XH NMR (DMSO-d6) δ 12.86 (br ε, IH) , 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-dfi) δ 172.03, 165.35, 162.99, 158.36, 51.48, 32.03, 28.16, 24.43; MS (LSIMS, m/z) 308 (M+H+) . Preparation of 2- (((-4- (3-
(trifluoromethyl) phenyl) piperazin-l-yl) acetyl) amino) -5- (2- (carbomethoxy) ethyl) -1,3, 4-thiadiazole: A εolution 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 °C for 2 h. The reaction mixture was poured into ice water and the milky εolution was extracted with EtOAc . The organic layer was washed with water, brine, dried, and concentrated. The crude product was purified by chromatography on εilica 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: XH NMR (DMSO- d6) δ 12.31 (br s, IH) , 7.41 (dd, J - 8.0, 8.0, IH) , 7.22 (d, J = 8.0, IH) , 7.16 (s, IH) , 7.06 (d, J = 8.0, IH) , 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 (DMS0-de) δ 171.99, 168.40, 162.48, 158.01, 151.12, 129.87, 129.82 (q, .7 = 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 (FAB) calcd for C19H22N503SF3 457.1396, found 458.1463. Anal. Calcd for C19H22F3Ns03S : 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-Pyridyl) piperazin-1- yl) acetyl) amino) -5- (2- (carbomethoxy) ethyl) -1,3, 4-thiadiazole
(Compound EW) 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 purified by chromatography on silica gel, eluting with EtOAc, to give 800 mg (42%) of the title compound as a white solid, mp 134.2-134.8 °C: 1H NMR (DMSO-ds) δ 8.10 (ddd, J = 4.0, 2.0, 0.8 IH) , 7.51 (ddd, J = 9.2, 7.2, 2.0, IH) , 6.81 (d, J = 8.8, IH) , 6.62 (ddd, J = 5 7.2, 5.2, 0.8, IH) , 3.61 (s, 3H) , 3.50 (t, J = 4.8, 4H) , 3.38 (ε, 2H) , 3.23 (t, J - 7.2, 2H) , 2.83 (t, J = 7.2, 2H) , 2.60 (t, J = 4.8, 4H) ; 13C NMR (DMSO-dfi) δ 172.10, 168.49, 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 0 (LSIMS, m/z) (M+H+) . HRMS (FAB) calcd for C17H22N603S 391.1552, found 391.1576. Anal. Calcd for C17H22N603S : C, 52.22; H, 5.67; N, 21.50. Found: C, 51.91; H, 5.63; N, 21.30.
Example 70 Preparation of 2- (( (4- (4 -Methoxyphenyl) piperazin-1- 5 yl) acetyl) amino) -5- (2- (carbomethoxy) ethyl) -1,3 ,4 -thiadiazole
(Compound BO) The title compound was prepared . from 2- ( (bromoacetyl) amino) -5- (2- (carbomethoxy) ethyl) -1,3,4- thiadiazole (1.5 g, 4.88 mmol) and l-(4- 0 methoxyphenyl) piperazine (1.08 g, 5.6 mmol) in DMF (20 mL) as described in Example 36. The crude product was purified by chromatography on silica gel, eluting with CHCl3-EtOAc (7:3), to give 630 mg (31%) of the title compound as a white solid, mp 172.6-173.4 °C: XH NMR (DMS0-d6) 6.87 (d, J = 9.2, 2H) , 5 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 = 7.2, 2H) , 2.65 (t, J = 4.0, 4H) ; 13C NMR (DMSO-dfi) δ 172.16, 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, 30 24.45; MS (LSIMS, m/z) 420.4 (M+H+) . Anal. Calcd for
C19H25N504S: C, 54.33; H, 6.00; N, 16.68. Found: C, 53.91; H, 6.01; N, 16.52.
35 Example 71 Preparation of 2- (( (4- (m-tolvD piperazin-1-yl) acetyl) amino) - 5- (2- (carbomethoxy) ethyl) -1, 3 , 4-thiadiazole (Compound EX) 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 εalt) in DMF (30 mL) as described in Example 68. The crude product was purified 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 °C: 'H NMR (DMS0-dδ) δ 7.08 (dd, J = 7.6, 8.0, IH) , 6.74 (s, IH) , 6.71 (d, J = 8, IH) , 6.59 (d, J = 7.6, IH) , 3.61 (s, 3H) , 3.37 (ε, 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 (ε, 3H) ; 13C NMR (DMSO-d5) δ 172.09, 168.47, 162.54, 158.08, 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/z) 404 (M+H+) . Anal. Calcd for C19H25N503S : C, 56.48; H, 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) ethyl) -1.3.4 -thiadiazole
(Compound EY) A εolution of 2- ( ( (4- (3-
(trifluoromethyl) phenyl) piperazin-l-yl) acetyl) amino) -5- (2- (carbomethoxy) ethyl) -1,3, 4-thiadiazole (250 mg, 0.54 mmol) in MeOH-H20 (40 mL, 3:1) was treated with LiOH»H20 (600 mg, 14.3 mmol) and the mixture was stirred at rt overnight. After concentration under reduced pressure, the residue was dissolved in water. The resulting solution waε neutralized with 2 N HCl 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: XH NMR (DMS0-d6) δ 7.41 (dd, J = 8.0, 8.0, IH) , 7.22 (d, J = 8.4, IH) , 7.16 (s, IH) , 7.06 (d, J = 7.6, IH) , 3.40 (s, 2H) , 3.26 (t, J = 4.8, 4H) , 3.19 (t, J = 7.2, 2H) , 2.73 (t, J = 7.2, 2H) , 2.67 (t, J = 4.8, 4H) , 2.24 (s, 3H) ; 13C NMR (DMSO-dtf) δ 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 C18H20F3N5O3S • 1.22 H20: C, 46.46; H, 4.86; N, 15.04. Found: C, 46.52; H, 4.48; N, 14.71.
Example 73 Preparation of 2- (( (4- (3-Trifluoromethylphenyl) piperazin-l- yl) acetyl) amino) -1 , 3 , 4-thiadiazole (Compound 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-l, 3, 4-thiadiazole (10 g, 99 mmol) in DMF- dioxane (200 mL, 1:1) and the mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into ice-water and the resulting precipitate waε filtered and dried to give 11.5 g (50%) of the title compound as a white solid: XH NMR (DMSO-de) δ 13.0 (br ε, IH) , 9.22 (ε, IH) , 4.21 (ε, 2H) . Preparation of 2- ( ( (4- (3-
(trifluoromethyl) phenyl) piperazin-l-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 purified by chromatography on silica gel, eluting with EtOAc, to give 1.6 g (38%) of the title compound as a white solid, mp 135.7-136.8 °C: XH NMR (CDC13) δ 10.87 (br s, IH) , 8.87 (s, IH) , 7.38 (ddd, J = 8.0, 8.0, 0.8, IH) , 7.14 (S, IH) , 7.13 (d, J = 8.2, IH) , 7.07 (d, .7 = 8.2, IH) , 3.44
(S, 2H) , 3.34 (t, J = 4.9, 4H) , 2.84 (t, .7 = 4.9, 4H) ; 13C NMR (CDC13) δ 168.25, 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/z) 372 (M+H+) . HRMS (FAB) calcd for C15H16F3N5OS 371.1028, found 372.1122. Anal. Calcd for C15H16F3N5OS : C, 48.44; H, 4.34; N, 18.83. Found: C, 49.03; H, 4.48; N, 18.83. Example 74 Preparation of 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino) -5-ethyl-l, 3 ,4-thiadiazole (Compound EZ) Preparation of 2- ( (bromoacetyl) amino) -5-ethyl-l, 3,4- thiadiazole: Bromoacetyl bromide (7.4 mL, 17 g, 85 mmol) was added to a solution of 2-amino-5-ethyl-l, 3, 4 -thiadiazole (10 g, 77.5 mmol) in DMF-dioxane (200 mL, 1:1) at 0 °C and the mixture waε stirred at 0 °C for 2 h. The reaction 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: *H NMR (DMSO-d5) δ 12.82 (br s, IH) , 4.18 (s, 2H) , 3.00 (q, J = 7.6 , 2H) , 1.29 (t, J = 7.6, 3H) .
2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -5-ethyl-1,3, 4-thiadiazole was prepared from 2- ( (bromoacetyl) amino) -5-ethyl-l, 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 purified by chromatography on silica gel, eluting with EtOAc to give 1.2 g (50%) of the title compound as a white solid, p 166.7-167.5 °C: XH NMR (DMSO-d^) δ 12.29 (br ε, IH) , 7.41 (dd, J = 8.0 , 8.0, IH) , 7.22 (dd, .7 = 8.0, 2.2, IH) , 7.16 (s, IH) , 7.06 (d, J" = 8.0, IH) , 3.40 (ε, 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-de) δ 168.31, 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 C17H20F3N5OS 400.1419, found 400.1386. Anal. Calcd for C17H20F3NSOS : C, 51.05; H, 5.04; N, 17.51. Found: C, 50.76; H, 5.03; N, 17.45.
Example 75 Preparation of 2- (( (4- (3- (Trifluoromethyl) henyl) piperazin-1- yl) acetyl) amino) -5-bromo-l.3 ,4-thiadiazole (Compound FA) Preparation of 2-amino-5-bromo-l, 3 ,4-thiadiazole: Bromine (10 mL, 17.6 g, 110 mmol) was added to a solution of 2-amino-l, 3 , 4-thiadiazole (10 g, 99 mmol) in HOAc (30 mL) dropwiεe through an addition funnel. The reaction mixture became red and hot while some precipitate formed. The reaction 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 80% of EtOH to give 5.85 g (25%) of the title compound.
Preparation of 2- ( (bromoacetyl) amino) -5-bromo-1, 3,4- thiadiazole: Bromoacetyl bromide (2.3 mL, 5.4 g, 26.6 mmol) was added to a solution of 2-amino-5-bromo-l, 3 ,4-thiadiazole (5.8 g, 24 mmol) in DMF-dioxane (200 mL, 1:1) at 0 °C and the mixture was stirred at 0 °C for 2 h. The reaction 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: H NMR (DMSO-de) δ 13.33 (br ε, IH) , 4.21 (s, 2H) . 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yDacetyl) amino) -5-bromo-1, 3, 4-thiadiazole was prepared from 2- ( (bromoacetyl) amino) -5-bromo-l, 3, 4-thiadiazole (1.5 g, 4.16 mmol) and 1- (3- (trifluoromethyl) phenyl) piperazine (1.05 g, 4.57 mmol) in DMF (30 mL) as described in Example 68. The crude product was purified by chromatography on silica gel, eluting with EtOAc to give 1.1 g (59%) of the title compound as a white solid, mp 150.5-151 °C: XH NMR (CDC13) δ 10.76 (br s, IH) , 7.39 (ddd, J = 8.4, 8.0, 0.4, IH) , 7.14 (d, J = 8.0, IH) , 7.13 (s, IH) , 7.08 (dd, J - 8.4, 2.0, IH) , 3.42 (s, 2H) , 3.34 (t, J = 4.8, 4H) , 2.83 (t, J = 4.7, 4H) ; 13C MR (CDCl3) δ 168.58, 160.15, 150.92, 135.44, 131.62 (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 C15HlsBrF3N5OS 450.0211, found 450.0230.
Example 76
Preparation of 2- ( ( (4- (3- (TrifluoromethyDphenyl) piperzin-1- yl) acetyl) amino) -5- ( (ethoxycarbonyl) methyl) -1.3 ,4 -thiadiazole
(Compound FB) Preparation of ethyl thiosemicarbazone malonate: A εuspension of thiosemicarbazide (18 g, 199 mmol) in THF was treated with ethyl oxalylchloride (17 mL, 20 g, 133 mmol) dropwise at 0 °C. The reaction mixture was allowed to warm to rt and εtirred overnight. The precipitate was collected by filtration to give, after drying, 27 g (98.5%) of the title compound which was used in the next step without further purification: XH NMR (DMSO-d6) 10.08 (s, IH) , 9.37 (s, IH) , 7.98 (s, IH) , 7.36 (s, IH) , 4.08 (q, J = 7.2, 2H) , 3.28 (S, 2H) , 1.18 (t, J = 7.2, 3H) ; 13C NMR (DMSO-d δ 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, 3, 4- thiadiazole and 2-amino-5- (carboxymethyl) -1, 3, 4-thiadiazole : MeS03H (30 mL, 45 g, 475 mmol) was added dropwise to a suspenεion of ethyl thiosemicarbazone malonate (63 g, 310 mmol) in toluene (300 mL) at 0 °C. The suspension became a sticky white solid which piled up at the bottom of the flask. The resulting mixture was magnetically stirred at 70 °C for 3 h. The reaction was concentrated under reduced presεure in a 60 °C water bath. When the most of the solvent was evaporated, the white sticky solid became clear thick liquid. The reεidue was suεpended in MeOH and concentrated ammonium hydroxide (~ 25 mL) was added to basify the mixture. During this process, the suεpension first diεappeared and then a new precipitate formed while' the 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 waε concentrated under reduced preεεure. The reεulting εolid was ground in a mortar and purified by chromatography on alumina, eluting with MeOH-CHCl3 (1:20), to give 11 g (45%) 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-H20 (400 mL, 3:1) was stirred at rt for 30 min. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (150 mL) . The solution 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 dissolved in EtOH. HCl (gas) was bubbled into this solution for about 1 h. The resulting mixture was εtirred at rt overnight, neutralized with εaturated Na2C03 (εolution) and then extracted with EtOAc. The organic layer was washed with water, brine, dried (MgS04) , and then concentrated to give 6.2 g (62%) of the titled ethyl ester as a white solid.
Characterization of 2-amino-5- ( (ethoxycarbonyl) methyl) - 1,3, 4 -thiadiazole: XH NMR (DMSO-d£) δ 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-d5) δ 169.45, 168.80, 150.27, 60.86, 35.33, 13.92.
Characterization of 2-amino-5- (carboxymethyl) -1,3,4 - thiadiazole: XH NMR (DMSO-d6) δ 12.84 (s, IH) , 7.08 (s, 2H) , 3.86 (s, 2H) ; 13C NMR (DMSO-ds) δ 170.28, 169.35, 151.01, 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 2-amino-5- ( (ethoxycarbonyl) methyl) -1,3, 4-thiadiazole (6.0 g, 32 mmol) in DMF-dioxane (20 mL, 1:1) at 0 °C. The mixture was stirred at 0 °C 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 εolid: H NMR (DMS0-de) δ 12.90 (br ε, IH) , 4.22 (ε, 2H) , 4.20 (ε, 2H) , 4.14 (q, J = 7.2, 2H) , 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) iperazine (0.99 g, 4.3 mmol) in DMF (20 mL) as described in Example 68. The crude product was purified by chromatography on silica gel, eluting with EtOAc, to give 300 mg (35%) of the title compound as a white solid, mp 157-158 °C: XH NMR (DMS0-d6) δ 7.42 (dd, J - 8.0, 8.0, IH) , 7.22 (dd, J = 8.0, 2.4, IH) , 7.16 (s, IH) , 7.06 (d, J = 8.0, IH) , 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) δ 168.79, 168.60, 5 159.14, 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 C19H22F3N503S : C, 49.82; H, 4.84; N, 15.29. Found: C, 50.11; H, 4.91; N, 10 14.98.
Example 77 Preparation of 2- (( (4- (3-chlorophenyl) piperazin-l- yl) acetyl) amino) -5- (3- (carbomethoxy) -ethyl) -1.3 ,4-thiadiazole
(Compound FC) 15 The title compound was prepared from 2-
( (bromoacetyl) amino) -5- (2- (carbomethoxy) ethyl) -1,3,4- thiadiazole (1.5 g, 4.89 mmol) and l-(3- chlorophenyl) piperazine (1.05 g, 5.37 mmol) in DMF (20 mL) as described in Example 68. The crude product was purified by 20 chromatography on εilica gel, eluting with EtOAc, to give 1.5 g (66%) of the title compound as a white solid, mp 141-142 °C: XH NMR (CDC13) δ 10.63 (br s, IH) , 7.19 (dd, J = 8.2, 8.2, IH) , 6.89 (dd, J = 2.1, 2.1, IH) , 6.85 (ddd, J = 8.2, 1.8, 0.6, IH) , 6.79 (dd, J = 8.4, 2.5, IH) , 3.72 (s, 3H) , 25 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) δ 172.15, 168.07, 163.71, 157.98, 151.86, 135.04, 130.12, 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 30 for C18H22N503C1S : C, 50.93; H, 5.22; N, 16.50. Found: C, 50.78; H, 5.33; N, 16.40.
35 Example 78 Preparation of 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -5- (3- (carbomethoxy) propyl-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 reaction gave the title compound as a white sticky solid, which was uεed for the next step without further purification: XH NMR (DMSO-d δ 9.67 (br s, IH) , 9.10 (br s, IH) , 7.79 (br s, IH) , 7.40 (br s, IH) , 3.55 (s, 3H) , 2.29 (t, J - 7.4, 2H) , 2.13 (t, J = 6.8, 2H) , 1.72 (quintet, J = 7.4, 2H) ; 13C NMR (DMSO-ds) δ 182.02, 173.28, 171.51, 51.42, 32.77, 32.26, 20.01.
Preparation of 2-amino-5- (3- (carbomethoxy) prop-1-yl) - 1, 3 ,4 -thiadiazole : The compound waε prepared from methyl 5- (thiosemicarbazone) -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 purified 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: *H NMR (DMSO- d6) δ 7.02 (s, 2H) , 3.59 (s, 3H) , 2.80 (t, J = 7.4, 2H) , 2.38 (t, J = 7.4, 2H) , 1.86 (quintet, J = 7.4, 2H) ; 13C NMR (DMSO- dg) δ 172.80, 168.17, 157.45, 51.22, 32.24, 28.54, 24.13; HRMS (FAB) calcd for C7H^N302S 202.0650, found 202.0651. Anal. Calcd for C^NaOaS : 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 °C. The mixture was stirred at 0 °C for 30 min. The reaction mixture was poured into ice-water and the resulting precipitate was filtered and dried to give 6.3 g (70%) of the title compound as a white solid: TH NMR (DMS0-de) δ 12.86 (br s, IH) , 4.18 (s, 2H) , 3.59 (s, 3H) , 3.02 (t, J = 7.2, 2H) , 2.41 (t, J = 7.2, 2H) , 1.96 (quintet, J = 7.2, 2H) ; 13C NMR (DMSO-d*) δ 172.93, 165.28, 163.83, 158.09, 51.25, 32.25, 28.15, 28.07, 24.14; MS (LSIMS, m/z) 324 (M+H+) . 5 Preparation of 2-(((4-(3-
(Trifluoromethyl)phenyl)piperazin-l-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-l-yl) -1, 3,4-thiadiazole (1.54 g, 4.8 mmol) 0 and 1- (3- (trifluoromethyl) phenyl) piperazine (1.2 g, 5.28 mmol) in DMF (20 mL) as described in Example 69. The crude product was purified by chromatography on silica gel, eluting with EtOAc, to give 1.5 g (66%) of the title compound as a white solid, mp 134-135 °C: XH NMR (CDC13) δ 11.08 (br s, 5 IH) , 7.35 (dd, J = 7.6, 7.6, IH) , 7.10 (s, IH) , 7.09 (d, J = 7.6, IH) , 7.05 (d, J = 7.6 IH) , 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, 4H) , 2.43 (t, J = 7.6, 2H) , 2.13 (quintet, J = 7.6, 2H) ; 13C NMR (CDC13) δ 172.97, 168.14, 164.54, 158.07, 150.95, 20 131.43 (q, J = 31), 129.58, 124.16 (q, J = 271), 118.86, 116.21 (q, J = 4), 112.41 (q, J = 4) , 60.86, 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 C20H24N5O3SF3 : C, 50.89; H, 5.12; N, 14.84. Found: C, 50.93; H, 5.24; N, 14.48. 25 Example 79
Preparation of 2- ( ( (-4- (3- (Trifluoromethyl) phenyl) piperazin- l-yl) acetyl) amino) -5- (4- (carbomethoxy) but-1-yl) 1,3,4- thiadiazole (Compound FE) Preparation of methyl-5- (chloroformyDpentanoate : A 30 solution of 5- (methoxycarbonyl)pentanoic acid (25 g, 156 mmol), S0C12 (22.3 g, 13.7 mmol, 188 mmol) and 3 drops of DMF was stirred at 80 °C for 1 h. After the gas formation stopped, the mixture was concentrated under reduced pressure. The residual oil was distillated under reduced pressure to 35 give 25 g (90%) of the title compound as a colorless oil, bp 118-120 °C: XH NMR (CDCl3) δ 3.68 (s, IH) , 2.92 (t, J = 7.0, 2H) , 2.35 (t, J = 7.0, 2H) , 1.77-1.66 (m, 4H) ; 13C NMR (CDC13) δ 173.40, 173.28, 51.57, 46.65, 33.36, 24.46, 23.64.
Preparation of methyl-6- (thiosemicarbazone) -1-hexanoate : The title compound was prepared from thiosemicarbazide (15.3 5 g, 169 mmol) and methyl-5- (chloroformyl) pentanoate (25 g, 140 mmol) in THF (150 mL) as described in Example 76. The reaction gave the title compound as a white sticky solid, which was used for the next step without further purification. 0 Preparation of 2-amino-5- (4- (carbomethoxy) but-l-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 purified by chromatography on silica gel, eluting 5 with MeOH-CHCl3 (1:15) to give 9.5 g (28%) of the compound as a white solid: XH NMR (DMSO-dfi) δ 7.00 (s, 2H) , 3.58 (s, 3H) , 2.78 (t, J = 6.8, 2H) , 2.33 (t, J = 7.6, 2H) , 1.60-1.51 (m, 4H) ; 13C NMR (DMSO-de) δ 173.20, 168.19, 158.05, 51.22, 32.83, 29.06, 28.31, 23.74. Anal. Calcd for C7H13N302S : C, 44.52; H, 0 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-l-yl) -1,3, 4-thiadiazole (4 g, 25 18.6 mmol) in DMF-dioxane (80 L, 1:1) at 0 °C. The mixture was stirred at 0 °C for 30 min. The reaction mixture was poured into ice-water and the precipitate which formed waε filtered and dried to give 5.3 g (85%) of the compound as a white solid: *H NMR (DMS0-dδ) δ 12.09 (br s, IH) , 4.16 (ε, 30 2H) , 3.57 (ε, 3H) , 2.97 (t, J = 7.2, 2H) , 2.34 (t, J = 7.6, 2H) , 1.74-1.66 (m, 2H) , 1.61-1.55 (m, 2H) ; 13C NMR (DMSO-dff) δ 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- 35 (trifluoromethyl) phenyl) piperazin-l-yl) acetyl) amino) -5- (4- (carbomethoxy) but-l-yl) 1,3, 4-thiadiazole : The title compound waε 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 purified by chromatography on silica gel, eluting with EtOAc, to give 1.3 g (60%) of the title compound as a white solid, mp 154.8-155.2 °C: XH NMR (CDCl3) δ 10.62 (br ε, IH) , 7.38 (dd, J = 8.0, 8.0, IH) , 7.13 (ε, IH) , 7.12 (d, J = 8.0, IH) , 7.07 (dd, J = 8.0, 2.4, IH) , 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 = 5.2, 4H) , 2.38 (t, J = 7.2, 2H) , 1.88-1.82 (m, 2H) , 1.79- 1.72 (m, 2H) ; 13C NMR (CDCl3) δ 173.54, 168.01, 165.43, 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 C21H26N503SF3 : C, 51.89; H, 5.39; N, 14.41. Found: C, 52.21; H, 5.39; N, 14.06.
Example 79A Preparation of 2- ( ( (4- (3-Chlorophenyl)piperazin-l- yl) acetyl) amino) -5-trifluoremethyl-1 , 3 ,4 -thiadiazole
(Compound BP)
A solution of 2- (bromoacetyl) amino-5-trifluoremethyl-1, 3 ,4- thiadiazole (l.Og, 3.44 mmol) and l-(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) . 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 0.98 g (70%) of the title compound as a solid, mp 122-124°C: JH NMR (DMSO-d6) δ 12.67 (BS, IH) , 7.21 (t, J = 2.4, IH) , 6.90 (dd, J = 8.4, J = 2.0, IH) , 6.79 (dd, J = 7.6, J = 1.6, IH) , 3.62 (s, 2H) , 3.27 (t, J = 4.8, 4H) , 2.82 (t, J = 4.8, 4H) ; 13C NMR (DMSO-d6) δ 169.47, 162.49, 151.89, 149.84 (q, J = 37.2), 133.79, 130.37, 120.14 (q, J = 270), 114.63, 113.70, 59.54, 51.95, 47.04; MS (El, m/z) 405 (M+) . Anal. Calcd for C15H15N5F3SOCl : C, 44.39; H, 3.73; N, 17.26; Found: C, 44.37; H, 3.52; N, 17.36.
Example 80 Preparation of 5- (( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino) -3- ( (carbomethoxy) methyl) -1.2 , 4-thiadiazole
(Compound BO) Preparation of methyl-2-cyanoiminoacetate hydrochloride: HCl 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 °C. The reaction mixture was stirred at 0 °C for 30 min, warmed to rt, and stirring was continued for 2 h. The solid was filtered, washed with ether until pH ~ 7, and then dried over K2C03 under reduced pressure overnight. 20 g (83%) of the title compound was obtained as a white solid: XH NMR (CDCl3) δ 3.84 (s, 3H) , 3.48 (s, 2H) ; 13C NMR 163.3, 112.8, 53.5, 24.5.
Preparation of 1, 1, l-trimethoxy-2-cyanoethane: A εolution of methyl 2-cyanoiminoacetate hydrochloride (40 g, 314 mmol) in anhydrous MeOH (550 mL) was stirred at rt for 4 days. The reaction mixture was concentrated under reduced presεure and the reεidue was treated with EtOAc. The organic layer waε waεhed with NaHC03 (saturated solution) , H20 and brine, dried (MgS04) , and then concentrated under reduced preεεure. The oil product waε purified by diεtillation under water pump (bp 100-101 °C) to give 38 g (88%) of the title compound as a colorlesε oil: XH NMR (CDC13) δ 3.36 (ε, 9), 2.85 (ε, 2) .
Preparation of 2, 2-dimethoxy-l-cyanoethene: A round- bottomed flaεk waε charged with 1, 1, l-trimethoxy-2- cyanoethane (10 g) and the flask was equipped with a short- path distillation apparatus. 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 °C; 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 collected. The brown oil was further purified by a Kugelrohr distillation using a water pump. When the distillation temperature reached 120 °C, a colorless oil distilled out which solidified in the dry ice bath. At 140-150 °C, a 5 colorless solid distilled out, which was the desired product. The first fraction also contains the desired product. Both fractions were combined and used directly for the next reaction. The distillation gave 5.3 g (67%) of the title compound as a colorless solid: XH NMR (CDC13) δ 3.82 (s, 3H) , 10 3.75 (s, 3H) , 3.35 (s, IH) . The XH NMR data was identical to that reported 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 15 45 °C in an oil bath and a solution of 2, 2-dimethoxy-l- cyanoether ( 500 mg, 4.42 mmol) in MeOH (0.22 mL) was added dropwise over a 30 min period. The reaction mixture was stirred at this temperature for 2 h. According to the results of the TLC analysis, the starting material was still 20 not completely consumed. Therefore, additional NaOH (0.27 mL, 8 M) was added to the reaction. The mixture was heated at 70 °C for 2 h and concentrated to give a solid residue. The residue was dissolved in water and extracted with EtOAc. The organic layer was washed with brine, dried (MgS04) , and 25 then concentrated to give colorless solid, which was purified by chromatography on silica gel (CHCl3/EtOAc, 7:3) to give 188 mg (37%) of the title compound as a colorless solid: XH NMR (CDC13) δ 4.79 (s, IH) , 3.89 (s, 3H) ; 13C NMR (CDC13) δ 173.3 (C) , 168.4 (C) , 70.9 (CH) , 56.2 (CH3) ; HRMS (El) calcd for 30 C4H6N202114.0429, 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 35 mL) was heated at 70 °C for 30 min. During this time, some white precipitate formed. The mixture was cooled to 0 °C 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 reaction mixture was allowed to warm to rt and stirred overnight. The mixture was poured into ice-water and extracted with EtOAc. The combined organic layer was washed with water and brine, dried, and then concentrated to give a yellow oil. The crude oil was purified by chromatography on silica gel (CHCl3/MeOH 20:1) to give 73 mg of the title compound as a colorless solid: XH NMR (CDC13) δ 12.2 (br s, IH) , 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 CH2C12, 20 mL) at -10 °C. After 10 min, water (20 mL) was added to the reaction mixture. The mixture was continually stirred until it warmed to rt. Then the CH2C12 layer was separated and the water layer was basified with Na2C03 (saturated solution) . The water layer was concentrated under reduced pressure, and the residue was dissolved in MeOH. Silica gel was added and the mixture was concentrated under reduced pressure . The absorbent was purified by chromatography, eluting with MeOH- CHC13 (1:9), to give 500 mg (74%) of the title compound as a white solid: XH NMR (DMSO-dfi) δ 7.92 (br s, 2H) , 3.64 (s,
2H) , 3.61 (s, 3H) ; 13C NMR (DMSO-d6) δ 183.58, 169.18, 165.50, 51.77, 38.46; MS (LSIMS, m/z) 174 (M+H+) .
Preparation of 5- (((4- (3- (trifluoromethyl) phenyl) piperazin-l-yl) acetyl) amino) -3- (carbomethoxymethyl) -1,2, 4-thiadiazole: To a solution of 5- amino-3- (carbomethoxymethyl) -1,2, 4-thiadiazole (1.0 g, 5.78 mmol) in DMF-dioxane (20 L, 1:1) was added bromoacetyl bromide (0.8 mL, 1.87 g, 9.25 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min, then warmed up to rt and stirred for 1 h. The reaction mixture was quenched with ice-water and extracted with EtOAc. The organic layer was washed with brine, dried (MgS04) , and concentrated. The crude product was purified by chromatography on silica gel, eluting with EtOAc to give 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 °C for 2 h. The reaction 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 purified by chromatography on silica gel, eluting with EtOAc, to give 300 mg (30%) of the title compound as a white solid, mp 151-152 °C: XH NMR (CDC13) δ 7.35 (ddd, J = 8.0, 8.0, 0.4, IH) , 7.11 (s, IH) , 7.10 (d, J = 8.0, IH) , 7.06 (dd, J = 8.4, 2.4, IH) , 3.92 (s, 2H) , 3.72 (s, 3H) , 3.39 (s, 2H) , 3.30 (t, J = 5.2, 4H) , 2.78 (t, J - 5.2, 4H) ; 13C NMR (CDCl3) δ 174.59, 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 C18H20F3N5O3S 444.1317, found 444.1331.
Example 81 Preparation of 2- ( ( (4- (Phenyl) piperazin-1-yl) acetyl) amino) -4-
(carboxymethyl) thiazole (Compound C) Phenylpiperazine (1.38 g, 1.4 mL, 8.6 mmol) was added to a solution of 2- (2-chloroacetamido) -4-thiazoleacetic acid (1.0 g, 4.3 mmol) in DMF (20 mL) at rt . The reaction mixture was stirred at rt for 20 h, causing an ivory precipitate to form. The reaction mixture was poured into ice water and the precipitate dissolved. The aqueous mixture was stirred overnight at rt, during which time an off-white precipitate formed. This solid was collected 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 143.7-145.8 °C (dec): XH NMR (DMSO-d5) δ 11.99 (bs, IH) , 7.22 (dd, J = 8.6, J = 7.2, 2H) , 6.96 (s, IH) , 6.92 (d, J = 7.8, 2H) , 6.77 (dd, J = 7.2, IH) , 3.59 (s, 2H) , 3.32 (s, 2H) , 3.15 (t, J = 4.8, 4H) , 2.65 (t, J = 4.8, 4H) ; 13C NMR (DMS0-d5) δ 171.45, 168.21, 156.90, 150.94, 144.19, 128.84 (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 C17H20N4O3S • 0.75 H20: C, 54.61; H, 5.79; N, 14.98. Found: C, 54.58; H, 5.70; N, 15.02.
Example 82 Preparation of 2- (( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino) -4- (carboxymethyl) thiazole (Compound D) 1- (α,α,Q;-Trifluoro-ιτ!-tolyD 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 reaction mixture was heated and stirred at 70 °C 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%) of the title compound as an off- white solid, mp 191.8-193 °C (dec): XH NMR (DMSO-dfi) δ 12.40 (bs, IH) , 12.00 (bs, IH, NH) , 7.41 (t, J = 8, IH) , 7.22 (dd, J = 8.4, J = 2, IH) , 7.16 (bs, IH) , 7.06 (d, J = 8, IH) , 6.97 (8, IH) , 3.60 (ε, 2H) , 3.34 (s, 2H) , 3.26 (t, J = 4.4, 4H ), 2.66 (t, J = 4.4, 4H) ; 13C NMR (DMS0-dfi) δ 171.43, 168.6, 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 (El, m/z) 428 (M*) . Anal. Calcd for C18H19N403SF3 : C, 50.39; H, 4.46; N, 13.06. Found: 50.43, H, 4.60; N, 13.07.
Example 83 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 reaction 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 °C (dec): XH NMR (DMSO-d£) δ 7.14 (dd, J = 8.4, J = 1.2, IH) , 7.11-7.08 (m, IH) , 7.04 (m, IH) , 6.94 (s, IH) , 6.99- 6.95 (m, IH) , 3.60 (s, 2H) , 3.33 (s, 2H) , 3.04 (t, J" = 4, 4H) , 2.68 (t, J - 4.8, 4H) ; 13C NMR (DMSO-de) δ 171.48, 5 168.25, 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 (El, m/z) 378 (M+) . Anal. Calcd for C17H19N403SF • 0.25 H20: C, 53.33; H, 5.13; N, 14.63. Found: C, 10 53.30; H, 4.82; N, 14.57.
Example 84 Preparation of 2- ( ( (4- (2-Fluorophenyl) piperazin-1- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole (Compound AB) Preparation of 2- ( (Bromoacetyl) amino) -4- 15 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 internal temperature of the reaction mixture at 5 °C. After stirring at 5 °C for 1 20 h, the ice bath was removed and the reaction mixture was stirred at rt for 20 h. The reaction 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- 25 164.5: LH NMR (DMSO-d5) δ 12.60 (s, IH) , 7.05 (s, IH) , 4.12 (s, 2H) , 4.07 (q, .7 = 7.2, 2H) , 3.69 (s, 2H) , 1.18 (t, J = 7.2, 3H) ; 13C NMR (DMSO-d δ 169.85, 164.92, 157.11, 143.89, 110.98, 60.25, 36.54, 28.30, 14.01; MS (El, m/z) 308.1 (M*) . Anal. Calcd for C^H^N^BrS : C, 35.13; H, 3.60; N, 9.11. 30 Found: C, 34.98; H, 3.64; N, 8.94.
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 reaction mixture was heated and stirred at 95 °C for 5 h, cooled to 35 rt, and slowly poured into ice water. The light crystalline compound which precipitated was extracted εeveral times with ethyl acetate. The combined ethyl acetate solution was dried (Na2S04) , 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 5 filtration and drying in vacuo afforded 1.7 g (64%) of the title compound, mp 127-129 °C: XH NMR (DMS0-d6) δ 11.99 (bs, IH) , 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-de) δ 170.08, 10 168.33, 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 (El, m/z) 406.1 (M+) . Anal. Calcd for C19H23N403FS : C, 56.06; H, 5.70; N, 13.77'. Found: C, 15 55.72; H, 5.64; N, 13.37.
Example 85 Preparation of 2- ( ( (4- (3- (TrifluoromethyDphenvD iperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole (Compound F) 1- (α,α,α!-Trifluoro-m-tolyl) piperazine (9.2 g, 7.5 mL, 40 20 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 reaction mixture was heated and stirred at 70 °C for 7 h, cooled to rt, and slowly poured into ice water. The light crystalline compound which 25 precipitated was filtered, washed several times with cold water, air-dried for 24 h, and then purified by flash column chromatography (Si02, eluent EtOAc) to give 8.67 g (93.8%) of the title compound, mp 94-95.3 °C: XH NMR (DMS0-de) δ 11.99 (bs, IH) , 7.4 (t, J = 8, IH) , 7.20 (dd, J = 8.8, J = 2.4, 30 IH) , 7.15 (bs, IH) , 7.05 (d, J = 7.6), 6.99 (d, J = 0.8, IH) , 4.07 (q, J = 7.2, IH) , 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 (DMS0-dfi) δ 169.90, 168.19, 157.05, 151.13, 143.57, 129.87, 129.81 (q, J = 30), 124.37 (q, J = 271), 118.69, 35 114.47 (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 (El, m/z) 456.5 (M+) . Anal. Calcd for C20H23N4O3F3S : C, 52.56; H, 5.07; N, 12.26. Found: 52.71, H, 5.06; N, 12.18.
Example 85A 5 Preparation of 2- (( (4- (3- (TrifluoromethyDphenyl) piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole Hydrochloride
(Compound BM) 2- [ [ [4- [3- (Trifluoromethyl) piperazinyl-1] acetyl] amino] - 4- (carboxyethyl) thiazole (compound F) (0.56 g, 1.23 mmol) was 0 dissolved in 20 mL of CH2C12 and to this solution was added 2.5 mL (2.46 mmol) of IN HCl solution in ether. The reaction 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%) of the title compound as an ivory solid, 5 mp 207-209°C ("wet" at 171°C) .
Example 86 Preparation of 2- ( ( (4- (2-Pyridyl) piperazin-1- yl) acetyl) amino) -4- (carboxymethyl) thiazole (Compound AD) 1- (2 -Pyridyl) piperazine (1.4 g, 1.4 mL, 8.6 mmol) was 0 added to a solution of 2 - (2-chloroacetamido) -4-thiazoleacetic acid (1.08 g, 4.3 mmol) in DMF (15 mL) and the reaction mixture was stirred for 8 h at rt . 10% Potassium hydroxide solution (15 mL) was added and the reaction mixture was extracted with CH2C12 (3 x 70 mL) . The CH2C12 layer was set 5 aside and the aqueous layer was acidified with IN HCl (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- 0 204 °C (dec): XH NMR (DMSO-ds) δ 8.15 (dd, J" = 5.2, J = 0.4, IH) , 7.65 (t, J = 7.6, IH) , 7.01 (s, IH) , 6.96 (d, J = 8.4, IH) , 6.76 (dd, .7 = 7.2, J = 5.2, IH) , 4.50 (bs, 4H) , 3.63 (s, 2H) , 3.40 (bs, 4H) ; 13C NMR (DMSO-de) δ 171.27, 163.95, 157.33, 156.53, 146.51, 144.26, 138.45, 113.92, 110.87, 35 108.09, 56.29, 54.38, 42.19, 36.66; MS (FAB, m/z) 362 (M*) . Example 87 Preparation of 4- (( (4- (3- (Trifluoromethyl) henyl) piperazin-l- yl) acetyl) amino) -1- ( (N' - (2-thiazolyl) ) sulfonamido) benzene
(Compound G) 5 1- (α,α,α-Trifluoro-.m-tolyl) piperazine (2.24 g, 1.8 mL, 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 reaction mixture was heated and stirred at 70 °C for 7 h, cooled to rt, and slowly poured 0 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%) 5 of the title compound, mp 235.4-236.8 °C: XH NMR (DMSO-dfi) δ 12.63 (bs, IH) , 10.10 (s, IH) , 7.80 (d, J = 8.8, 2H) , 7.74 (d, J = 8.8, 2H) , 7.42 (t, J = 8 , IH) , 7.25-7.17 (m, IH) , 7.17 (s, IH) , 7.06 (d, .7 =7.6, IH) , 6.81 (d, J = 4.8 , IH) , 3.29 (t, J" = 4.4, 4H) , 3.24 (s, 2H) , 2.67 (t, J = 4.4, 4H) ; 20 13C NMR (DMS0-ds) δ 168.63, 168.57, 151.12, 141.65, 141.55, 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 C22H22N503F3S2 : C, 50.17; H, 25 4.21; N, 13.30. Found: C, 49.86; H, 4.28; N, 13.19.
Example 88
Preparation of 2- (( (4- (5- (Trifluoromethyl) pyrid-2- yl) piperazin-l-yl) acetyl) amino) -4- (carboethoxymethyl) thiazole
(Compound H) 30 1- (5- (Trifluoromethyl) pyrid-2-yl) piperazine (3.2 g, 13.8 mmol) was added to a solution of ethyl 2-
( (bromoacetyl) amino) -4 -thiazole acetate (2.1 g, 6.9 mmol) in DMF (20 mL) and the reaction mixture was heated and stirred at 70 °C for 5 h. After cooling to rt, the reaction mixture 35 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: XH NMR (DMSO-dfi) δ 11.96 (bs, IH) , 8.40 (s, IH) , 7.78 (dd, J" = 9.2, J = 2.8, IH) , 6.99 (s, IH) , 6.95 (d, .7 = 9.2, IH) , 4.09 (q, J = 7.2, 2H) , 3.68 (s, 2H) , 3.34 (s, 2H) , 2.60 (t, J = 4.8 , 4H) , 5 1.18 (t, J = 7.2, 3H) ; 13C NMR (DMSO-de) δ 169.93, 168.24,
160.10, 157.07, 145.17 (q, .7 = 4), 143.57, 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 (El, m/z) 457 (M+) . Anal. Calcd for C19H22N503SF3 • 1.20 H20: C, 10 47.64; H, 5.13; N, 14.61. Found: C, 47.60; H, 4.90; N, 14.64.
Example 89 Preparation of 2- (( (4- (3- (Trifluoromethyl) phenyl) ρiperazin-1- yl) acetyl) amino) -4- (carboxymethyl) thiazole, sodium salt 15 (Compound J)
Sodium hydroxide (71 mg, 1.77 mmol) was added to a suspension of 2- (( (4- (3- (trifluoromethyl)phenyl) piperazin-l- yl) acetyl) amino) -4- (carboxymethyl) thiazole (0.7 g, 1.77 mmol) and water (50 mL) . The reaction mixture was stirred 20 vigorously for several hours, then the reaction mixture was filtered. The water solution was rotary evaporated and the oily residue was waεhed several times with acetone and ether, and then dried to give 0.75 g (94%) of the title compound as a light yellow solid, mp 195-198 °C: NMR (D20) δ 7.19 (t, J 25 = 8, IH) , 7.07 (bs, IH) , 6.98 (d, J = 8 , 2H) , 6.63 (s, IH) , 3.34 (s, 2H) , 3.21 (s, 2H) , 2.99 (bε, 4H) , 2.53 (bs, 4H) ; 13C NMR (D20) δ 179.87, 170.44, 158.80, 151.78, 147.01, 131.77 (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 30 C18H18N403F3NaS»2.29 H20: C, 43.98; H, 4.63; N, 11.40. Found: C, 44.01; H, 4.29; N, 11.10.
35 Example 90
Preparation of 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino) -4- (carboxymethyl) thiazole. potassium salt
(Compound K) Potasεium 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 εolid waε dried to give 2.1 g (48%) of the title compound as a light yellow solid, mp 147-149 °C (dec): "H NMR (D20) δ 7.26 (t, J = 8, IH) , 7.15 (bs, IH) , 7.07 (d, J - 8 , 2H) , 6.56 (s, IH) , 3.35 (ε, 2H) , 3.27 (ε, 2H) , 3.07 (bε, 4H) , 2.61 (bs, 4H) ; 13C NMR (D20) δ 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 C18H18N403F3KS»2.36 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- (TrifluoromethyDphenyl) piperazin-l- yl) acetyl) amino) -1- ( (N; - (2-thiazolyl) ) εulfonamido) benzene, hydrochloride salt (Compound L)
4- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino-1- ( (N' - (2-thiazolyl) ) sulfonamido) benzene (1.6 g, 3.05 mmol) was εuεpended with CH2Cl2, and to this suspension was added an excess of IN HCl solution in ether (6 mL, 6.1 mmol) . A light-pink color precipitate formed. The reaction mixture was εtirred for several hours and the precipitate waε filtered and then dried in vacuo to give 1.54 g (86%) of the title compound aε a light-pink solid. The product was refluxed for 1 h in a mixture of CH2Cl2/ethanol, filtered, and then dried, mp 258-260 °C. 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. Example 92 Preparation of 2- (( (4- (3- (Trifluoromethyl) phenyl)piperazin-l- yl) acetyl) 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 gaε in anhydrous methanol (200 mL) . After a precipitate started to form, the reaction mixture wa poured into water and a solution of 5% KOH was added until pH « 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. Og, 122 mmol) in DMF (80 mL) and dioxane (80 mL) was treated dropwise with bromoacetyl bromide at 0 °C according to the procedure described in example 84 to give 18. Og (50%) of 2- ( (bromoacetyl) amino) -4- (carbomethoxymethyl) thiazole .
1- (o;,α!,α!-Trifluoro-m-tolyD piperazine (3.3 g, 2.7 mL, 14.4 mmol) waε added to a εolution of 2- ( (bromoacetyl) amino) - 4- (carbomethoxymethyl) thiazole (2.1 g, 7.19 mmol) in DMF (20 mL) at rt . The reaction mixture waε heated and stirred at 65 °C for 7 h, cooled to rt, and poured into ice water, causing an off-white precipitate to form. The precipitated εolid waε 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: *H NMR (DMSO-d6) δ 12.01 (s, IH) , 7.41 (t, J" = 7.6, IH) , 7.21 (dd, J = 8, J" = 2, IH) , 7.16 (bε, IH) , 7.06 (d, J - 7.6, IH) , 7.05 (s, IH) , 3.71 (s, 2H) , 3.61 (s, 3H) , 3.34 (ε, 2H) , 3.25 (t, J = 4.4, 4H) , 2.66 (t, J = 4.8, 4H) ; 13C NMR (DMSO-de) δ 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 (El, m/z) 441 (M+) .
Example 93 Preparation of 2- (( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -4- (carboxymethyl) thiazole, hydrochloride salt (Compound N) A solution of IN HCl in ether (5 mL, 5 mmol) was added to a εolution of 2- (( (4- (3- (trifluoromethyl) phenyl) piperazin-l-yl) acetyl) amino) -4- (carboxymethyl) thiazole (0.9 g, 2.1 mmol) CH2Cl2 (20 mL) and the mixture waε stirred for 1 h. The light precipitate was filtered, waεhed quickly (compound iε very hygroscopic) with ether, and then dried in vacuo to give 0.85 g (81%) of the title compound as a ivory εolid, mp 207-208 °C (dec). Anal. Calcd for C18H19N403F3S • 2HC1 • 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-l-yl) acetyl) amino) -4- (carboethoxymethyl) thiazole (Compound AE) 2- ( (Bromoacetyl) amino) -4- (carboethoxymethyl) thiazole (1.50 g, 4.90 mmol) was disεolved in DMF (20 mL) and N- phenylpiperizine (1.50 mL, 9.80 mmol) was added. The reaction 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 combined organic layerε dried and evaporated to an oil which was redissolved in 50% EtOAc in hexanes and filtered through a short plug of Si02. The filtrate was evaporated to give 1.70 g (89%) of the title compound as a yellow solid: *H NMR (DMS0-dfi) δ 11.99 (s, IH) , 7.20 (m, 2H) , 7.00 (s, IH) , 6.93 (m, 2H) , 6.77 (t, J = 7.3, IH) , 4.08 (q, J = 7.0, 2H) , 3.69 (ε, 2H) , 3.33 (ε, 2H) , 3.15 (t, J = 4.9, 4H) , 2.66 (t, J = 7.1, 3H) ; 13C NMR (DMSO-de) δ 170.0, 168.3, 157.2, 151.0, 143.6, 128.9, 118.8, 115.4, 110.5, 60.3, 60.0, 52.5, 48.2, 36.6, 14.1; MS (El, m/z) 388.
Example 96 Preparation of Ethyl 2- ( ( (4- (3-
(Trifluoromethyl) phenyl)piperazin-l-yl) acetyl) amino) -4- thiazole glyoxylate (Compound S)
Preparation of ethyl 2- (2- ( (bromoacetyl) amino) -4- thiazole glyoxylate : Bromoacetyl bromide (5.04 g, 2.2 mL, 25 mmol) was added dropwiεe 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 reaction mixture at 5 °C. After stirring at 5 °C for 1 h, the ice bath was removed and the reaction 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 5.4 g (68%) of the title compound, mp 167-169.7 °C: XH NMR (DMSO-d6) δ 13.02 (s, IH) , 8.54 (s, IH) , 4.36 (q, J = 7.2, 2H) , 4.18 (s, 2H) , 1.32 (t, J = 8, 3H) ; 13C NMR (DMSO-de) δ 178.85, 166.12, 163.22, 158.43, 144.44, 128.37, 62.22, 28.18, 13.86; MS (El, m/z) 322 (M+) .
Preparation of ethyl 2- (((4- (3- (trifluoromethyl) phenyl) piperazin-l-yl) acetyl) amino) -4- thiazole glyoxylate: 1- (α,α,α-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 reaction mixture waε heated and stirred at 80 °C 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 (80%) of the title compound as an off-white solid, mp 122.3-122.8 °C: XH NMR (DMSO-dβ) δ 12.50 (bs, IH) , 8.50 (s, IH) , 7.41 (t, J = 8, IH) , 7.21 (d, J = 8.4, IH) , 7.16 (s, IH) , 7.06 (d, .7 = 7.6, IH) , 4.38 (q, J = 6.8, 2H) , 3.42 (s, 2H) , 3.26 (t, .7 = 4.4, 4H) , 2.69 (t, J = 4.4, 4H) , 1.32 (t, J = 6.8, 3H) ; 13C NMR (DMSO-de) δ 178.83, 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 (El, m/z) 470 (M+) . Anal. Calcd for C20H21N4O4SF3 : C, 51.06; H, 4.50; N, 11.91. Found: C, 50.84; H, 4.36; N, 11.89. Example 97
Preparation of 2- (( (4- (3- (Methyl) phenyl) piperazin-l- yl) acetyl) amino) -4-carboethoxy) methyl) thiazole (Compound T)
1- (3-Methyl) phenylpiperazine (1.4 g, 8 mmol) was added to a solution of ethyl 2- ( (bromoacetyl) amino) - -thiazole acetate (1.25 g, 4 mmol) in DMF (15 mL) at rt . The reaction mixture was heated and stirred at 70 °C 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 combined ethyl acetate layer was washed with water, dried (Na2S04) , filtered, and then concentrated. Purification by flash column chromatography (Si02, eluent EtOAc) gave 0.90 g (55%) of the title compound as a viscouε oil: XH NMR (DMS0-de) δ 12.00 (ε, IH) , 7.08 (dd, 0 J = 7.6, J = 7.6, IH) , 7.00 (ε, IH) , 6.74 (ε, IH) , 6.72 (dd, J = 7.6, J = 1.2, IH) , 6.59 (d, J = 7.2, IH) , 4.07 (q, J = 6.8, 2H) , 3.69 (ε, 2H) , 3.32 (s, 2H) , 3.14 (t, J" = 4.8, 4H) , 2.66 (t, J = 4.8, 4H) , 2.24 (ε, 3H) , 1.18 (t, J = 7.2 , 3H) ; 13C NMR (DMS0-de) δ 170.02, 168.31, 157.17, 151.02, 143.62, 5 137.93, 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.
Example 98
Preparation of 2- ( (4- ( (4-ChlorobenzhydrvD henvD iperazin-l- yl) acetyl) amino-4- (carboethoxymethyl) thiazole (Compound Y) 0
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 reaction mixture waε heated and εtirred at 70 °C for 7 h. After 5 cooling to rt, the reaction 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 εolid, mp 69-71 °C: XE NMR (DMSO-d^) δ 7.44-7.27 (m, 6H) , 7.29 (dd, J = 7.2, J = 7.2, 2H) , 7.18 (dd, J = 7.2, J = 7.2, IH) , 5 6.98 (ε, IH) , 4.32 (s, IH) , 4.07 (q, J = 7.2, 2H) , 3.67 (ε, 2H) , 3.32 (bs, 4H) , 3.25 (s, 2H) , 2.55 (bs, 4H) , 1.17 (t, J - 6.8, 3H) ; 13C NMR (DMSO-d6) δ 169.92, 168,26, 157.05, 143.54, 142.18, 141.81, 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, 10 14.01; MS (El, m/z) 512 (M+) .
Example 99
Representative Procedure for the Synthesis of N-
Phenylpiperazines Preparation of 1- (3 -nitrophenyl) piperazine : Anhydrous
15 K2C03 (9.28 g, 67.2 mmol) and bis (2-chloroethyl) amine hydrochloride (12.0 g, 67.2 mmol) were added to a stirred εolution of 3-nitrpaniline (9.28 g, 67.2 mmol) in diglyme (100 mL) at rt . The reaction mixture waε heated at reflux for 18 h, cooled to rt and poured into ice-water (300 mL) .
20 The aqueouε mixture was made basic { ca . pH 14) with concentrated KOH εolution and extracted with EtOAc (3 x 100 mL) . The combined organics were dried over MgS04 and concentrated. Excess diglyme was distilled away under __ reduced pressure (water aspirator) at 100 °C. The remaining residue was then taken up in a small amount of MeOH-CH2Cl2 and purified by chromatography, eluting with methanol- dichloromethane (1:9), to give 7.76 g (55%) of the title compound as an orange solid, mp 53-54 °C: XH NMR (DMSO-dβ) δ 7.60 (dd, J = 2.4, J = 2.4, IH) , 7.55 (ddd, J = 8.0, J = 2.4, J = 1.2, IH) , 7.45 (dd, J = 8.0, J = 8.0, IH), 7.36 (ddd, J = 8.4, J = 2.8, J = 1.2, IH) , 3.17 - 3.14 (m, 4H) , 2.84 - 2.82 (m, 4H) ; 13C NMR (DMS0-dβ) δ 152.13, 148.80, 130.04, 121.14, 112.41, 108.08, 48.52 (2C) , 45.32 (2C) ; MS (El, m/z) 207 (M+) .
Example 100
35 Preparation of 2- ( ( (4- (3-NitrophenvDpiperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole (Compound AF)
A solution of 2- ( (bromoacetyl) amino) -4- carboethoxymethyl) thiazole (1.0 g, 3.25 mmol) and l-(3- nitrophenyl) piperazine (1.35 g, 6.51 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 MgS04, 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 (DMSO-dfi) δ 12.00 (bs, IH) , 7.64 (dd, J = 2.4, J = 2.4, IH) , 7.57 (ddd, J = 8.0, J = 2.4, J = 0.8, IH), 7.47 (dd, J = 8.4, J = 8.4, IH) , 7.39 (ddd, J = 8.0, .7 = 2.4, .7 = 1.6, IH), 6.99 (s, IH) , 4.07 (q, J = 7.2, 2H) , 3.68 (s, 2H) , 3.34 (ε, 2H) , 3.31 (t, J = 4.4, 4H) , 2.68 (t, J = 4.4, IH) , 1.18 (t, J = 6.8, 3H) ; 13C NMR (DMS0-d5) δ 169.96, 168.21, 157.08, 151.51, 148.83, 143.60, 130.09, 121.27, 112.60, 110.47, 108.35, 60.26, 59.84, 52.07, 47.42, 36.56, 14.03; MS (El, m/z) 433 (M+) . Anal. Calcd for C19H23N505: C, 52.65; H, 5.35; N, 16.16. Found: C, 52.38; H, 5.42; N, 15.90.
Example 101
Preparation of 2- ( ( (4- (4- (TrifluoromethyDphenyl) piperazin-1- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole (Compound O)
Preparation of 1- (4- (trifluoromethyl) phenyl) piperazine : Reaction of anhydrouε K2C03 (9.28 g, 67.2 mmol), bis(2- chloroethyl) amine hydrochloride (12.0 g, 67.2 mmol) and 4- (trifluoromethyl) aniline (10.8 g, 67.2 mmol) in diglyme (100 mL) , according to the representative procedure in Example 99 gave 4.50 g (30%) of the title piperazine as a white solid, mp 71-72 °C (Note: the product was purified by distillation) : λH NMR (DMSO-d6) δ 7.48 (d, J = 8.8, 2H) , 7.02 (d, J = 8.4, 2H) , 3.17 - 3.15 (rn, 4H) , 2.82 - 2.80 (m, 4H) ; 13C NMR (DMSO- de) δ 153.78, 126.06 (q, J = 3.8, 2C) , 125.00 (q, J = 268.4), 117.50 (q, J = 31.9), 113.92, 48.05, 45.33; MS (El, m/z) 230 (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 reaction mixture was heated and stirred at 65 °C 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: H NMR (DMSO- de) δ 12.00 (bs, IH) , 7.50 (d, J = 8.8, 2H) , 7.05 (d, J" = 8.8, 2H) , 7.00 (s, IH) , 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-ds) δ 169.92, 168.19, 157.09, 153.13, 143.57, 126.07 (q, J = 3.8, 2C) , 120.90 (q, J = 270), 117. '6 (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 (El, m/z) 457 (M+) . Anal. Calcd for C20H23N4O3SF3 : C, 52.56; H, 5.07; N, 12.26. Found: C, 52.23; H, 4.75; N, 12.10.
Example 102
Preparation of 2- ( ( (4- (3-Chlorophenyl)piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole (Compound 0)
Preparation of 1- (3 -chlorophenyl) piperazine : Reaction of anhydrous K2C03 (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 Example 99, gave 8.90 g (67%) of the title piperazine as a brown oil: XH NMR (DMSO-df) δ 7.18 (t, J = 8.0, IH) , 6.89 (t, J = 2.0, IH) , 6.85 (ddd, J = 8.4, J" = 2.4, J = 0.8, IH) , 6.75 (ddd, J = 7.6, J = 1.6, J = 0.8, IH) , 3.04 (m, 4H) , 2.80 (m, 4H) ; 13C NMR (DMS0-d5) δ 152.78, 133.72, 130.22, 117.69, 114.27, 113.42, 48.72, 45.37; MS (El, m/z) 196 (M+) .
Preparation of 2- ( ( (4- (3 -chlorophenyl) piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole : Reaction 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: *H NMR (DMSO-ds) δ 11.99 (bs, IH) , 7.19 (dd, J = 8.4, J = 8.4, IH) , 6.99 (ε, IH) , 6.93 (dd, J = 2.4, J = 2.4, IH) , 6.88 (dd, J = 8.4, J = 2.4, IH) , 6.76 (ddd, J = 5 7.6, J = 1.6, J = 1.2, IH) , 4.07 (q, J = 7.2, 2H) , 3.68 (ε, 2H) , 3.32 (ε, 2H) , 3.19 (t, .7 = 4.8, 4H) , 2.64 (t, .7 = 4.8, 4H) , 1.18 (t, J = 6.8, 3H) ; 13C NMR (DMSO-de) δ 169.91, 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, 10 14.00; MS (El, m/z) 422 (M+) .
Example 103 Preparation of 2- (( (4- (3 -Bromophenyl) iperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole (Compound R) Preparation of 1- (3-bromophenyl) piperazine: Reaction of 15 anhydrous K2C03 (9.28 g, 67.2 mmol), biε (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: XH NMR (DMSO-dfi) δ 7.12 20 (dd, J = 8.4, J = 7.6, IH) , 7.02 (t, J = 2.0, IH) , 6.91 -
6.87 (m, 2H) , 3.05 - 3.03 (m, 4H) , 2.81 - 2.78 (m, 4H) ; 13C NMR (DMSO-d6) δ 152.95, 130.55, 122.44, 120.64, 117.13, 113.84, 48.74, 45.38; MS (El, m/z) 242 (M+2+) .
Preparation of 2- (( (4- (3 -bromophenyl) piperazin-1- 25 yl) acetyl) amino) -4- (carboethoxymethyl) thiazole: Reaction 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
30 solid, mp 80-82 °C: XH NMR (DMS0-d5) δ 11.99 (bs, IH) , 7.13 (dd, J = 8.0 , J = 8.0 , IH) , 7.06 (dd, J = 2.0 , J = 2.0 , IH) , 6.99 (s, IH) , 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 = 4.8, 4H) , 1.18 (t, J = 6.8, 3H) , 13C NMR (DMSO-dβ) δ 169.91,
35 168.22, 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 (El , m/z) 466 (M+) . Anal . Calcd for C19H23N403BrS : C , 48.83; H, 4.96; N, 11.99. Found: C, 49.07; H, 5.28; N, 11.75.
Example 104
Preparation of 2- ( ( (4- (3-Cvanophenyl)piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole (Compound AG)
Preparation of 1- (3-cyanophenyl)piperazine : Reaction of anhydrous K2C03 (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 0 mL) , according to the representative procedure in Example 99, gave 8.36 g (66%) of the title piperazine as a brown oil: XH NMR (CD30D) δ 7.36 (ddd, J = 7.6, J = 7.6, J - 1.2, IH), 7.24 - 7.21 (m, 2H) , 7.10 (ddd, J - 7.2, J = 0.8, J = 0.8, IH) , 3.19 - 3.16 (m, 4H) , 2.97 - 2.94 (m, 4H) ; 13C NMR (CD3OD) δ 5 153.37, 131.15, 123.48, 121.33, 120.26, 119.40, 113.84, 49.94, 46.29; MS (El, m/z) 187 (M+) .
Preparation of 2- ( ( (4- (3-cyanophenyl)piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole: Reaction of ethyl 2- ( (bromoacetyl) amino) -4- (carboethoxymethyl) thiazole 0 (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 (65%) of the title compound as an oil: *H NMR (CD3OD) δ 7.40 - 7.36 (m, IH) , 7.28 - 7.26 (m, 2H) , 7.11 (ddd, J = 7.6, J - 1.2, J = 1.2, IH) , 5 6.95 (t, J = 0.8, IH) , 4.15 (q, J = 7.2, 2H) , 3.70 (s, 2H) , 3.37 (ε, 2H) , 3.34 (t, .7 = 4.8, 4H) , 2.77 (t, .7 = 4.8, 4H) , 1.25 (t, J = 6.8, 3H) ; 13C NMR (CD3OD) δ 172.15, 170.43, 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) ,
30 37.58, 14.45; MS (El, /z) 413 (M+) .
Example 105
Preparation of 2- (( (4- (4- (carbomethoxy) phenyl) piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole (Compound P)
35 Preparation of 1- (4- (carbomethoxy) phenyl) piperazine : Reaction of anhydrous K2C03 (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 L) , according to the representative procedure in Example 99, gave 5.00 g (34%) of the title piperazine as a beige solid, mp 88 °C: H NMR (DMS0-dfi) δ 7.77 (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 (DMS0-de) δ 166.14, 154.35, 130.67, 117.82, 113.13, 51.42, 47.61, 45.28; MS (El, m/z) 220 (M+) . Preparation of ethyl 2-(((4-(4- (carbomethoxy) phenyl) pipqrazin-1-yl) acetyl) amino) -4- (carboethoxy) methyl) thiazole: 1- (4-carbomethoxyphenyl) piperazine (1.6 g, 7.2 mmol) waε added to a εolution of ethyl 2- ( (bromoacetyl) amino) -4 -thiazole acetate (2.2.g, 7.2 mmol) in DMF (30 mL) at rt, and to thiε solution was added 3.0 g (21.6 mmol) of K2C03. The reaction mixture was heated and stirred at 70 °C for 6 h, cooled to rt, and slowly poured into ice water. The product which precipitated was filtered, waεhed εeveral ti eε with cold water, dried in vacuo, and then diεsolved 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 °C ("wet" at 136.4 °C) : XH NMR (DMS0-dfi) δ 11.99 (s, IH) , 7.78 (d, J = 9.2, 2H) , 6.99 (s, IH) , 6.97 (d, J = 9.2, 2H) , 4.07 (q, J = 7.2, 2H) , 3.77 (s, 3H) , 3.68 (ε, 2H) , 3.35 (t, J = 4.4, 4H) , 3.33 (ε, 2H) , 2.64 (t, J = 4.8, 4H ), 1.78 (t, J = 7.2, 3H) ; 13C NMR (DMS0-de) δ 169.93, 168.24, 166.07, 157.10, 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 (El, m/z) 446 (M+) .
Example 106
Preparation of 2- ( ( (4- (3-Ethylphenyl)piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole (Compound AH) Preparation of 1- (3 -ethylphenyl) piperazine : Reaction of anhydrous K2C03 (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 the title piperazine as a brown oil: 1H NMR (DMS0-de) δ 7.10 (t, J = 8.0, IH) , 6.75 (bs, IH) , 6.70 (dd, J = 8.4, J = 2.0, IH) , 6.62 (dd, .7 = 7.6, .7 = 0.4, IH) , 3.03-3.00 (m, 4H) , 2.98 (bs, IH) , 2.84 - 2.82 (m, 4H) , 2.53 (q, J = 7.6, 2H) , 1.16 (t, J = 7.6, 3H) ; 13C NMR (DMSO-dff) δ 151.71, 144.25, 128.64, 118.19, 114.87, 112.71, 49.40, 45.56, 28.55, 15.61; MS (El, m/z) 190 (M+) . Preparation of 2- (( (4- (3-ethylphenyl) piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole : Reaction of 2- ( (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 L) according to the representative procedure in Example 100 gave 0.84 g (62%) of the title compound as a sticky solid: 1H NMR (DMSO-de) δ 11.97 (s, IH) , 7.10 (dd, J = 8.0, J = 8.0, IH) , 6.99 (ε, IH) , 6.76 (s, IH) , 6:72 (dd, J = 8.0 , J = 2.0, IH) , 6.62 (d, J = 7.6, IH) , 4.06 (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-ds) δ 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 (El, m/z) 416 (M+) . Anal. Calcd for C21H28N403S: C, 60.55; H, 6.78; N, 13.45. Found: C, 60.43; H, 6.48; N, 13.44.
Example 107 Preparation of 2- ( ( (4- (3 , 5-Bis- (trifluoromethyl) phenyl) piperazin-l-yl) acetyl) amino) -4- (carboethoxymethyl) thiazole (Compound Al)
Preparation of l-(3,5-biε- (trifluoromethyl) phenyl) piperazine: Reaction of anhydrous K2C03 (6.03 g, 43.6 mmol), sodium iodide (1.63 g, 10.91 mmol), bis (2-chloroethyl) amine hydrochloride (7.76 g, 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 εolid, mp 98-99 °C: XH NMR (DMSO-d) δ 7.42 (ε, 2H) , 7.26 (s, IH) , 3.25 - 3.21 (m, 4H) , 2.85 - 2.82 (m, 4H) ; 13C NMR (DMSO-d6) δ 152.06, 131.00 (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 (El, m/z) 298 (M+) .
Preparation of 2- ( ( (4- (3 , 5-bis- (trifluoromethyl) phenyl) piperazin-l-yl) acetyl) amino) -4- (carboethoxymethyl) thiazole: Reaction of 2- ( (bromoacetyl) amino) -4- (carboethoxymethyl) thiazole (0.70 g, 2.28 mmol), 1- (3 , 5-biε- (trifluoromethyl) phenyl) piperazine
(0.82 g, 2.74 mmol) and anhydrouε K2C03 (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 sticky solid: xVl NMR (DMSO-dg) δ 12.02 (s, IH) , 7.46 (s, 2H) , 7.30 (s, IH) , 7.00 (s, IH) , 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-de) δ 170.02, 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.
Example 108 Preparation of 2- ( ( (4- (3-Methoxyphenyl) piperazin-1- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole (Compound AJ) Preparation of 1- (3-methoxyphenyl) piperazine : Reaction of anhydrous K2C03 (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: XH NMR (DMSO-d*) δ 7.09 (t, J = 8.4, IH) , 6.49 (ddd, J = 8.0, J = 2.8, J = 0.4, IH) , 6.42 (t, J = 2.4, IH) , 6.34 (ddd, J = 8.0, J = 2.8, J = 0.4, IH) , 3.70 (s, 3H) , 3.04 - 3.01 (m, 4H) , 2.82 (bs, 4H) ; 13C NMR (DMS0-d6) δ 160.17, 152.94, 129.51,
107.99, 103.99, 101.39, 54.80, 49.12, 45.35; MS (El, m/z) 192 {W) . Preparation of 2- ( ( (4- (3 -methoxyphenyl) piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole : Reaction of 2- ( (bromoacetyl) amino) -4- (carboethoxymethyl) thiazole (1.0 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 compound as a sticky solid: XH NMR (DMSO-de) δ 11.98 (s, IH) , 7.09 (dd, J = 8.4, J = 8.4, IH) , 6.99 (s, IH) , 6.51 (dd, J = 8.4, J = 2.0, IH) , 6.44 (dd, J = 2.4, J = 2.4, IH) , 6.35 (dd, J = 7.6, J = 1.6, IH) , 4.07 (q, J = 7.2, 2H) , 3.70 (s, 3H) , 3.68 (ε, 2H) , 3.34 (ε, 2H) , 3.15 (t, .7 = 4.8, 4H) , 2.64 (t, J = 4.8, 4H) , 1.18 (t, J = 7.2, 3H) ; 13C NMR (DMSO-d6) δ 169.91, 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 Preparation of 2- ( ( (4- (3 , 5-Dichlorophenyl) piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole (Compound Z) Preparation of 1- (3 , 5-biε-chlorophenyl) piperazine: Reaction of anhydrouε K2C03 (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 (23%) of the title piperazine as a black oil: XH NMR (DMSO-d6) δ 6.90 (s, 2H) , 6.89 (ε, IH) , 3.10 - 3.09 (m, 4H) , 2.80 - 2.78 (m, 4H) ; 13C NMR (DMS0-dfi) δ 153.16, 134.57, 116.71, 112.79, 48.15, 45.17; MS (El, m/z) 229 (M+) .
Preparation of 2- ( ( (4- (3 , 5-dichlorophenyl)piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole: Reaction of 2- ( (bromoacetyl) amino) -4- (carboethoxymethyl) thiazole (1.0 g, 3.25 mmol), 1- (3, 5-dichlorophenyl) piperazine (1.0 g, 4.33 mmol) and anhydrous K2C03 in DMF (30 mL) according to the representative procedure in Example 100 gave 0.80 (54%) of the title compound as a sticky εolid: XH NMR (DMS0-dβ) δ 11.99 (s, IH) , 6.99 (s, IH) , 6.92 (s, 2H) , 6.84 (ε, IH) , 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-dff) δ 170.01, 168.26, 157.17, 152.60, 143.63, 134.62, 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 C19H22N402C1S : C, 5 49.90; H, 4.85; N, 12.25. Found: C, 49.53; H, 4.91; N, 12.12.
Example 110 Preparation of 2- ( ( (4- (3 , 4-Dichlorophenyl)piperazin-l- yl) acetyl) amino) -4 - (carboethoxymethyl) thiazole (Compound AK) 0 Preparation of 1- (3, -bis-chlorophenyl) piperazine:
Reaction of anhydrous K2C03 (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 5 repreεentative procedure in Example 99 gave 2.72 g (30%) of the title piperazine as a brown solid, mp 62 °C: XH NMR (DMSO- de) δ 7.35 (d, J = 9.2, IH) , 7.06 (d, J = 2.8 , IH) , 6.87 (dd, J = 9.2, J = 3.2, IH) , 3.06 - 3.03 (m, 4H) , 2.80 - 2.78 (m, 4H) ; 13C NMR (DMSO-de) δ 151.27, 131.43, 130.31, 119.24, 20 115.92, 115.05, 48.54, 45.27.
Preparation of 2- (( (4- (3, 4-dichlorophenyl) piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole: Reaction of 2- (bromoacetyl) amino-4- (carboethoxymethyl) thiazole (1.0 g, 3.25 mmol), 1- (3 , 4 -dichlorophenyl) piperazine (1.0 g, 4.33 25 mmol) and anhydrous K2C03 (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 aε a εticky solid: H NMR (DMS0-dβ) δ 11.99 (s, IH) , 7.37 (d, J = 8.8, IH) , 7.11 (d, J = 2.8, IH) , 6.99 (ε, IH) , 6.90 (dd, J = 9.2, J = 3.2, IH) , 4.07 30 (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-de) δ 170.01, 168.26, 157.17, 150.67, 143.62, 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 35 C19H22N403SC12 : C, 49.90; H, 4.85; N, 12.25. Found: C, 50.00; H, 4.78; N, 12.10. Example 111 Preparation of 2- ( ( (4- (2-Naphthyl) piperazin-1- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole (Compound AL) Preparation of 1- (2-naphthyl) piperazine : Reaction of anhydrous K2C03 (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: H NMR {OMSO- dg) δ 7.74 - 7.69 (m, 3H) , 7.37 (ddd, J = 8.0, J = 6.8, J = 1.2, IH) , 7.34 (dd, J = 9.2, J = 2.4, IH) , 7.24 (ddd, J - 8.0, J = 6.8, J = 1.2, IH) , 7.12 (d, J" = 2.4, IH) , 3.20 (bs, IH, NH) , 3.17 - 3.14 (m, 4H) , 2.89 - 2.87 (m, 4.H) ; 13C NMR (DMSO-dff) δ 149.44, 134.32, 128.21, 127.58, 127.10, 126.40, 125.95, 122.71, 118.91, 108.87, 49.54, 45.48; MS (El, m/z) 212 (M+) .
Preparation of 2- (( (4- (2-naphthyl) piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole: Reaction 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%) of the title compound as a solid, mp 134-135 °C: *H NMR (DMSO-dfi) δ 12.01 (s, IH) , 7.75 - 7.69 (m, 3H) , 7.39 - 7.34 (m, 2H) , 7.25 (dd, J = 6.8, .7 = 6.8, IH) , 7.16 (s, IH) , 7.00 (s, IH) , 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-de) δ 169.92, 168.28, 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 (El, m/z) 438 (M+) . Anal.
Calcd for C23H26N403S : 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- (carboethoxymethyl) thiazole (Compound AM) 5 Preparation of 1- (3-methoxy-5-
(trifluoromethyl) phenyl) piperazine: Reaction of anhydrous K2C03 (5.06 g, 36.6 mmol), biε (2-chloroethyl) amine hydrochloride (6.54 g, 36.6 mmol) and 4-
(trifluoromethyl) aniline (7.0 g, 36.6 mmol) in diglyme (100 0 L) , according to the repreεentative procedure in Example 99, gave 5.00 (52%) of the title piperazine aε a browniεh yellow oil: XH NMR (DMS0-dfi) δ 6.75 (bs, IH) , 6.66 (t, J = 2.4, IH) , 6.58 (bs, IH) , 3.78 (s, 3H) , 3.10 (t, J = 4.8,-4H), 2.81 (t, J = 4.8, 4H) ; 13C NMR (DMS0-d6) δ 160.60, 153.23, 130.66 (q, J 5 = 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 (El, m/z) 260 (M+) .
Preparation of 2- ( ( (4- (3-methoxy-5- (trifluoromethyl) phenyl) piperazin-l-yl) acetyl) amino) -4- 0 (carboethoxymethyl) thiazole : Reaction 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 5 (70%) of the title compound as a sticky solid: XH NMR (DMSO- dg) δ 11.99 (s, IH) , 6.99 (s, IH) , 6.78 (s, IH) , 6.69 (t, J = 2.0, IH) , 6.60 (s, IH) , 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 = 4.8, 4H) , 1.18 (t, J = 7.2, 3H) ; 13C NMR (DMS0-dfi) δ 170.01, 30 168.28, 160.60, 157.15, 152.57, 143.63, 130.68 (q, J = 31.0), 124.26 (q, J = 271), 110.53, 104.29, 103.99 (q, J" = 4.2), 100.20 (q, J = 3.5), 60.30, 59.90, 55.42, 52.19 (2C) , 47.58 (2C) , 36.58, 14.06; MS (El, m/z) 486 (M*) . Anal. Calcd for C21H25N404F3S : C, 51.85; H, 5.18; N, 11.52. Found: C, 51.64; H, 35 5.07; N, 11.37. Example 113 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 K2C03 (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 reaction 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 potasεium hydroxide εolution and extracted with ethyl ace'tate (3 x 100 mL) . The combined organic extract was washed with water (3 x 100 mL) , dried (MgS04) , and concentrated to an oily residue. Purification by flaεh column chromatography (Si02, 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 potasεium carbonate (1.35 g, 9.9 mmol) were added to a solution of 2- ( (bromoacetyl) amino) -4- (carboethoxymethyl) thiazole (1.0 g, 3.3 mmol) in DMF (20 mL) at rt . The reaction mixture was heated and stirred at 80 °C 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: *H NMR (DMSO-de) δ 12.00 (s, IH) , 7.47 (d, J = 8.8, IH) , 7.25 (d, J = 3.2, IH) , 7.20 (dd, J = 9.2, " = 3.2, IH), 6.99 (s, IH) , 4.07 (q, J = 7.2, 2H) , 3.68 (ε, 2H) , 3.35 (s, 2H) , 3.26 (t, J = 4.8, 4H) , 2.66 (t, J - 4.8, 4H) , 1.17 (q, J = 6.8. 3H) ; 13C NMR (DMS0-d6) δ 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, .7 = 4.9), 113.36 (q, " = 4.9), 110.54, 60.32, 59.86, 52.07 (2C) , 47.42 (2C) , 36.59, 14.07; MS (El, m/z) 490 (M+) .
Example 114
5 Preparation of 2- (( (4- (3- (trifluoromethy phenyl) piperazin-i - yl) acetyl) amino) -4- (carbopropoxymethyl) thiazole (Compound U)
Preparation of 2-amino-4- (carbopropoxymethyl) thiazole hydrochloride: A solution of 2-amino-4- (carboxymethyl) thiazole (2.0 g, 12.6 mmol) and thionyl 0 chloride (1.51 g, 0.92 mL, 12.7 mmol) in anhydrouε n-propyl alcohol (50 mL) waε stirred at 65 °C for 3 h, during which time the reaction mixture gradually turned clear. The reaction mixture was cooled to rt, concentrated, and dried in vacuo overnight to give 2.93 g (ca 100%) of the title 5 compound as a white solid: XH NMR (DMS0-dfi) δ 9.49 (bs, 2H) , 6.71 (s, IH) , 4.01 (t, J = 6.8, 2H) , 3.76 (s, 2H) , 1.59 (heptet, J = 7.6), 0.87 (t, J = 7.2, 3H) ; 13C NMR (DMSO-dff) δ 169.52, 168.53, 132.78, 105.29, 66.19, 32.90, 21.37, 10.14; MS (El, m/z) 200 (M+) . 0 Preparation of 2- ( (bromoacetyl) amino) - -
(carbopropoxymethyl) thiazole: A solution of saturated NaHC03 was slowly added to 2-amino-4- (carbopropoxymethyl) thiazole hydrochloride until the pH of the aqueous solution remained constant at 7. The suεpension was then further stirred for
25 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 °C and bromoacetyl bromide (2.02 g, 10 mmol) was added
30 dropwise. The solution was stirred at rt for 1 h and poured into 200 mL of ice-water. The precipitate which formed waε filtered, washed with water, and then dried to afford 2.50 g (78%) of the title compound as a white solid, mp 168-169 °C: lH NMR (DMS0-d5) δ 12.59 (s, IH) , 7.05 (s, IH) , 4.12 (ε, 2H) ,
35 3.99 (t, J = 6.4, 2H) , 3.70 (ε, 2H) , 1.56 (sxt, J = 6.8, 2H) , 0.85 (t, J = 7.6, 3H) ; 13C MR (DMS0-d6) δ 169.92, 164.95, 157.13, 143.92, 110.98, 65.67, 36.52, 28.28, 21.44, 10.09; MS (El, m/z) 320 (M+) .
Preparation of 2- (((4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) acetyl ) amino) -4 - 5 (carbopropoxymethyl) thiazole: A solution of 2-
( (bromoacetyl) amino) -4- (carbopropoxymethyl) thiazole (2.0 g, 6.23 mmol) and 1- (3- (trifluoromethyl) phenyl) 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 0 extracted with EtOAc (3 x 50 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 2.18 g (74%) of the title compound as a solid, mp 72-73 °C: 1H NMR (DMSO-d*) δ 11.99 (s, 5 IH) , 7.40 (dd, J = 8.0, J = 8.0, IH) , 7.20 (dd, J = 8.4, J = 2.0, IH) , 7.15 (s, IH) , 7.05 (d, J = 7.6, IH) , 6.99 (s, IH) , 3.98 (t, J = 6.8, 2H) , 3.69 (s, 2H) , 3.34 (s, 2H) , 3.25 (t, J = 4.8, 4H) , 2.67 (t, J = 4.8, 4H) , 1.56 (sxt, J = 7.2, 2H) , 0.85 (t, J = 7.2, 3H) ; 13C NMR (DMSO-dfi) δ 169.97, 168.22, 20 157.08, 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 (El, /z) 470 (M+) . Anal. Calcd for C21H25N403F3S : C, 53.01; H, 5.36; N, 11.91. Found: C, 53.71; H, 25 5.51; N, 11.85.
Example 115
Preparation of 2- ( ( (4- (3- (trifluoromethyl) phenyl) iperazin-1- yl) acetyl) amino) -4- (carboisopropoxymethyl) thiazole
(Compound W)
30 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) waε εtirred at 65 °C for 3 h, during which
35 time the reaction mixture gradually turned clear. The reaction mixture was cooled to rt, concentrated, and dried in vacuo overnight to give 2.99 g (ca 100%) of the title compound as a white solid: 1H NMR (CD3OD) δ 6.72 (s, IH) , 5.04 (sxt, J" = 6.4, IH) , 4.88 (bs, 2H) , 3.72 (s, 2H) , 1.27 (d, J - 6.4, 6H) ; 13C NMR (CD3OD) δ 172.20, 169.47, 134.30, 106.48, 70.73, 34.21, 21.94 (2C) ; MS (El, m/z) 200 (M+) . Preparation of 2- (bromoacetyl) amino-4 - (carboisopropoxymethyl) thiazole: A solution of saturated NaHC03 was slowly added to 2 -amino-4-
(carboiεopropoxymethyl) thiazole hydrochloride until the pH of the aqueous solution remained constant at 7. The suspenεion waε 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 baεe . A εolution of 2-amino-4-. (carboiεopropoxymethyl) 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 dropwiεe. The εolution waε εtirred 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 εolid, mp 182-183 °C: XH NMR (DMSO- d6) δ 12.57 (bε, IH) , 7.04 (ε, IH) , 4.89 (septet, J = 6.4, IH) , 4.12 (s, 2H) , 3.66 (ε, 2H) , 1.18 (d, J = 6.8, 6H) , 1.17 (S, 3H) ; 13C NMR (DMSO-d*) δ 169.37, 164.92, 157.08, 143.96, 110.91, 67.63, 36.75, 28.28, 21.50 (2C) ; MS (El, m/z) 320 (M+) .
Preparation of 2- (((4- (3- (trifluoromethyl) phenyl) piperazin-l-yl) acetyl) amino) -4- (carboiεopropoxymethyl) thiazole: A εolution 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 waε dried over MgS04, 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: *H NMR (DMS0-d6) δ 12.00 (bs, IH) , 7.41 (dd, J = 8.0, J" = 8.0, IH) , 7.21 (dd, J = 8.0, J = 8.0, J = 2.0, IH) , 7.15 (ε, IH) , 7.06 (dd, J = 7.6, J = 0.4, IH) , 6.98 (ε-, IH) , 4.89 (εxt, J = 6.4, IH) , 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) δ 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; MS (El, m/z) 470 (M+) . Anal. Calcd for C21H25N403F3S : C, 53.01; H, 5.36; N, 11.91. Found: C, 53.39; H, 5.50; N, 11.73.
Example 116 Preparation of 2- (( (4- (3- (trif luoromethyD henyl) piperazin-l- yl) acetyl) amino) -4- (carbobutoxymethyl) thiazole (Compound V)
Preparation of 2 -amino-4- (carbobutoxvmethyl) 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 °C for 3 h, during which time the reaction mixture gradually turned clear. The reaction solution was cooled to rt, concentrated, and dried in vacuo overnight to give 3.10 g {ca. 100%) of the title compound aε a white solid: XH NMR (DMS0-d5) δ 9.44 (bs, 2H) , 6.70 (s, IH) , 4.06 (t, J = 6.4, 2H) , 3.75 (s, 2H) , 1.56 (quintet, J = 6.8, 2H) , 1.31 (sxt, J = 7.2, 2H) , 0.88 (t, J = 7.6, 3H) ; 13C NMR (CD30D) δ 169.51, 168.53, 132.94, 105.26, 64.43, 32.95, 29.99, 18.47, 13.43; MS (El, m/z) 214 (M+) .
Preparation of 2- ( (bromoacetyl) amino) -4 - (carbobutoxymethyl) thiazole: A solution of saturated NaHC03 was slowly added to 2-amino-4- (carbobutoxymethyl) thiazole hydrochloride until the pH of the aqueous solution remained constant at 7. The suεpension 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 °C 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: XH NMR (DMSO-de) δ 12.57 (bs, IH) , 7.04 (s, IH) , 4.12 (ε, 2H) , 4.03 (t, J = 6.4, 2H) , 3.69 (ε, 2H) , 1.53 (quintet, J = 6.4, 2H) , 1.28 (εxt, J = 7.6, 2H) , 0.86 (t, J = 7.2, 3H) ; 13C NMR (DMSO- d6) δ 169.95, 165.00, 157.17, 143.93, 111.02, 63.97, 36.56, 30.10, 28.29, 18.49, 13.45; MS (El, /z) 336 (M+) . Preparation of 2- (((4- (3-
(trifluoromethyl) phenyl) piperazin-l-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 MgS04, filtered, and then concentrated. Purification by chromatography, eluting with hexane-ethyl acetate (2:1), afforded 1.37 g (79%) of the title compoud as a solid, mp 80-81 °C: *H NMR (DMS0-de) δ 11.97 (s, IH) , 7.41 (dd, J - 7.6, J = 7.6, IH) , 7.21 (dd, J = 8.4, J = 2.0, IH) , 7.16 (ε, IH) , 7.05 (dd, J = 7.6, J = 0.4, IH) , 6.99 (ε, IH) , 4.03 (t, J = 6.8, 2H) , 3.69 (s, 2H) , 3.34 (s, 2H) , 3.25 (t, J = 4.8 , 4H) , 2.66 (t, J = 4.8 , 4H) , 1.53 (quintet, J = 7.2, 2H) , 1.28 (sxt, .7 = 7.6, 2H) , 0.86 (t, J = 7.2, 3H) ; 13C NMR (DMSO-dfi) δ 170.03, 168.26, 157.12, 151.17, 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, 13.47; MS (El, m/z) 484 (M+) . Anal. Calcd for C22H27N403F3S : 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 εolution of methyl 2-aminothiophene carboxylate (6.0 g, 38 mmol) in a mixture of DMF (20 mL) and dioxane (20 mL) while keeping the internal temperature of the reaction mixture at 5 °C. After stirring at 5 °C for 1 h, the ice bath was removed and the reaction mixture was stirred at rt overnight. The reaction mixture waε 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 °C: XH NMR (DMSO-dfi) δ 10.58 (bs, IH) , 7.93 (s, 2H) , 4.34 (s, 2H) , 3.86 (s, 3H) : 13C NMR (DMSO-de) δ 164.14, 163.23, 142.71, 133.16, 121.86, 111.45, 52.18, 29.91; MS (El, m/z) 277 (M+) . Anal. Calcd for C8H8N03BrS: C, 34.48; H, 2.89; N, 5.03. Found: C, 34.55; H, 2.94; N, 5.09.
Example 118 Preparation of 3- ( ( (4-Phenylpiperazin-l-yl) acetyl) amino) -2-
(carbomethoxy) thiophene (Compound 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 reaction mixture was heated and stirred at 95 °C for 6 h, cooled to 50 °C, and poured into ice water, causing an oily precipitate to form. The product was filtered, waεhed εeveral times with water, and then air dried. The product was triturated with hexane several times and then purified by column chromatography using ethyl acetate-hexane (4:1) to give 0.7 g (47%) of a light beige solid, mp 116.4-118 °C: lH NMR (CDC13) δ 11.53 (bs, IH) , 8.20 (d, J = 5.2, IH) , 7.47 (d, J = 5.6, IH) , 7.31 (dd, J = 8.4, J = 8.4, 2H) , 7.01 (bε, 2H) , 6.90 (bt, J = 6.4, IH) , 3.87 (ε, 3H) , 3.39 (bε, 4H) , 3.28 (s, 2H) , 2.81 (bs, 4H) ; 13C NMR (CDCl3) δ 168.44, 163.87, 151.80, 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 (El, 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- 5 yl) acetyl) amino) -2- (carbomethoxy) -thiophene (Compound CO 1- (2-Fluorophenyl) piperazine (1.96 g, 10.97 mmol) was added to a solution of 3- ( (bromoacetyl) amino) -2- (carbomethoxy) thiophene (1.5 g, 5.40 mmol) in DMF (20 mL) at rt. The reaction mixture was heated and stirred at 70 °C for 0 8 h, cooled to 50 °C, and poured into ice water. The light crystalline compound which formed waε filtered, waεhed 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 117-119 °C ("wet" at 113 °C) : JH NMR (CDC13) δ 11.50 (bs, 5 IH) , 8.19 (d, J" = 5.6, IH) , 7.47 (dd, J = 5.6, J = 0.8, IH) , 7. 6.94 (m, 4H) , 3.89 (s, 3H) , 3.30 (s, 2H) , 3.28 (ε, 4H) , 2.85 (s, 4H) ; 13C NMR (CDCl3) δ 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) , 20 111.20, 61.89, 53.58 (2C) , 51.89, 50.32 (2C) ; MS (El, m/z) 377 (M+) .
Example 120 Preparation of 3- ( ( (4- (3- (Trifluoromethyl) phenyl) iperazin-l- yl) acetyl) amino) -2- (carbomethoxy) thiophene (Compound CD) 25 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 reaction mixture was heated and stirred at 70 °C for 6 h, cooled to rt, and poured into ice water, causing an off- 30 white precipitate to form. After standing in aqueous mixture overnight, the precipitated εolid was filtered, triturated six timeε 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 °C: XH NMR (DMSO-dff) δ 11.35 (bs, IH) , 8.08 (d, J" = 5.6, IH) , 7.91 35 (d, J ~ 5.6, IH) , 7.42 (t, J = 7.8, IH) , 7.25 (dd, J = 8.8, J = 2.4, IH) , 7.20 (ε, IH) , 7.07 (d, J = 7.2, IH) , 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-de) δ 168.04, 167.97, 163.17, 150.97, 143.16, 143.01, 133.11, 129.95, 129.88 (q, J - 31), 124.36 (q, J = 271), 121.52, 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 (El, m/z) 5 427 (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 Preparation of 3- (( (4- (2-Pyridyl) piperazin-l- yl) acetyl) amino) -2- (carbomethoxy) thiophene (Compound CD 0 1- (2 -Pyridyl) piperazine (2.52 g, 15.4 mmol) was added to a εolution of 3- ( (bromoacetyl) amino) -2-
(carbomethoxy) thiophene (2.14 g, 7.73 mmol) in DMF (20 mL) at rt. The reaction mixture was heated and stirred at 95-100 °C for 5 h, cooled to rt, and poured into ice water, causing a 5 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 °C: XH NMR (DMSO-de) δ 11.40 (bs, IH) , 8.12 (ddd, J= 4.9, J = 1.8, J = 0.61, IH) , 8.10 (d, J = 5.3 , IH) , 7.91 (d, J = 0 5.3, IH) ,- 7.54 (ddd, J = 8.8 , J = 7.2, J = 2, IH) , 6.85 (d, J = 8.6, IH) , 6.65 (dd, J = 7.0 , J = 5.4, IH) , 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-d δ 168.20, 163.27, 158.92, 147.57, 143.25, 137.55, 133.24, 121.51, 113.07, 110.05, 107.17, 61.11, 52.61 5 (2C) , 52.15, 44.66 (2C) ; MS (El, 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.
Example 122 Preparation of 3- ( ( (4- (2 -Methoxyphenyl) piperazin-1- 30 yl) acetyl) amino) -2- (carbomethoxy) -thiophene (Compound CJ) 1- (2-Methoxyphenyl) piperazine (1.72 g, 8.94 mmol) waε added to a εolution of 3- ( (bromoacetyl) amino) -2- (carbomethoxy) thiophene (1.24 g, 4.48 mmol) in DMF (20 mL) at rt. The reaction mixture was heated and stirred at 75-80 °C 35 for 4 h, cooled to 30 °C, and poured into ice water. This reaction mixture was extracted several times with ethyl acetate. The combined ethyl acetate layer was washed with water, dried over Na2S04, and concentrated. The residue was dissolved 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 (55.2%) of the title 5 compound, mp 101.4-101.8 °C: XH NMR (DMSO-d5) δ 11.33 (bs, IH) , 8.08 (d, J = 5.5, IH) , 7.90 (d, J = 5.6, IH) , 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) ; 1C NMR {OMS0-d6) δ 168.21, 163.08, 151.93, 143.08, 142.80, 141.05, 133.08, 122.35, 121.54, 10 120.84, 117.89, 111.99, 61.23, 55.30, 53.16 (2C) , 52.04,
49.88 (2C) ; MS (El, m/z) 389 (M+) . Anal. Calcd for C19H23N304S • 0.42 H20: C, 57.49; H, 6.05; N, 10.58. Found: C, 57.51; H, 5.98; N, 10.47.
Example 123 15 Preparation of 3- (( (4-Benzylpiperazin-l-yl) acetyl) amino) -2-
(carbomethoxy) thiophene (Compound CK) 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 20 reaction mixture was heated and stirred at 75 °C for 6 h, cooled to rt and slowly poured into ice water. The yellow oily compound was filtered, washed several timeε with water, dried in vacuo, and then the oily compound was triturated with hexane for 30 min. The light yellow precipitate which 25 formed was filtered and dried in vacuo to give 1.07 g (57%) of the title compound, mp 100.9-102.7 °C: XH NMR (DMS0-de) δ 11.23 (s, IH) , 8.06 (d, J = 5.6, IH) , 7.90 (d, J = 5.6, IH) , 7.32 (m, 5H) , 3.84 (ε, 3H) , 3.51 (ε, 2H) , 3.17 (s, 2H) , 2.51 (bs, 8H) ; 13C NMR (DMS0-dfi) δ 168.26, 163.04, 143.02, 138.11, 30 133.14, 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 (El, m/z) 372.9 (M+) . Anal. Calcd for C19H23N303S: C, 61.01; H, 6.20; N, 11.24. Found: C, 61.00; H, 6.45; N, 11.39.
35 Example 124 Preparation of 3- ( ( (4- (2-Pyrimidyl) piperazin-1- yl) acetyl) amino) -2- (carbomethoxy) thiophene (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 mL) and the reaction mixture was heated and stirred at 70 °C for 7 h. After cooling to rt, the reaction 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- white solid, mp 147-148 °C: E NMR (DMSO-dfi) δ 11.43 (bs, IH) , 8.37 (d, J = 4.8, 2H) , 8.09 (d, J = 5.2, IH) , 7.92 (d, J = 5.2, IH) , 6.64 (dd, J = 4.8, J = 4.8, IH) , 3.86 (t, J = 4.4, 4H) , 3.83 (s, 3H) , 3.25 (s, 2H) , 2.60 (t, J = 4.8, 4H) ; 13C NMR (DMS0-de) δ 168.12, 163.27, 161.16, 157.90 (2C) , 143.24, 133.17, 121.47, 121.44, 110.18, 61.04, 52.55 (2C) , 52.09, 43.31 (2C) ; MS (El, m/z) 361 (M+) . Anal. Calcd for C16H19Ns03S • 0.50 H20: C, 51.88; H, 5.44; N, 18.91. Found: C, 51.75; H, 5.27; N, 18.99.
Example 125
Preparation of 3- (( (4- (5- (Trifluoromethyl) pyrid-2- yl) piperazin-1-yl) acetyl) amino) -2- (carbomethoxy) thiophene
(Compound CE) 1- (5- (Trifluoromethyl)pyrid-2-yl) piperazine (3.4 g,
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 reaction mixture was heated and stirred for 7 h at 70 °C. After cooling to rt the reaction mixture was poured into ice water, and the crystalline precipitate which formed was filtered, waεhed εeveral times with water, and dried to give 2.64 g (85%) of the title compound as a light ivory solid, mp 136-138 °C: K NMR (DMSQ-d δ 11.42 (s, IH) , 8.42 (dd, J = 1.6, J = 0.4, IH) , 8.08 (d, J" = 5.2, IH) , 7.92 (d, J = 5.6, IH) , 7.80 (dd, J = 9.2, J = 2.4, IH) , 7.00 (d, J = 8.8, IH) , 3.82 (s, 3H) , 3.77 (t, J = 4.4, 4H) , 3.26 (s, 2H) , 2.64 (t, J = 4.8, 4H) ; 13C NMR (DMS0-d6) δ 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 (El, m/z) 428.4 (M*) . Anal. Calcd for C18H19N403SF3 • 0.50 H20: C, 49.42; H, 4.61; N, 12.81. Found: C, 49.37; H, 4.37; N, 12.99.
Example 126A 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 reaction mixture at 5 °C. After stirring at 5 °C for 1 h, the ice bath was removed and the reaction mixture was stirred at rt overnight. The reaction mixture was poured into ice water and the light precipitate which formed waε 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: H NMR (DMSO- dg) δ 10.48 (bs, IH) , 8.40 (d, J = 3.6, IH) , 7.97 (d, J = 3.6, IH) , 4.30 (s, 2H) , 3.86 (ε, 3H) ; 13C NMR (DMS0-dg) δ 164.10, 163.37, 134.83, 134.09, 121.61, 111.84, 52.10, 29.82; MS (El, m/z) 277 (M+) . Anal. Calcd for C8H8N03SBr: C, 34.48; H, 2.89; N, 5.03. Found: C, 34.58; H, 2.95; N, 4.99. Example 126
Preparation of 3- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) 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 reaction mixture was heated and stirred at 65-70 °C for 6 h. After cooling to rt, the reaction 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%) of the title compound as an ivory solid, mp 134-135.8 °C: XH NMR (DMS0-d6) δ 11.15 (bs, IH) , 8.37 (d, J = 3.6, IH) , 8.04 (d, J = 3.6, IH) , 7.43 (dd, J = 7.6, J = 7.6, IH) , 7.25 (dd, J = 8.4, J = 2.0, IH) , 7.20 (s, IH) , 7.07 (d, J = 7.6, IH) , 3.81 (s, 3H) , 3.36 (t, J = 4.4, 4H) , 3.24 (s, 2H) , 2.69 (t, J = 4.8, 4H) ;" 13C NMR (DMSO-d6) δ 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, 60.95, 52.59, 51.99, 47.55; MS (El, m/z) 42-7 (M+) . Anal. Calcd for C19H20N3O3SF3 • 0.25 H20: C, 52.84; H, 4.78; N, 9.73. Found: C, 52.84; H, 4.63; N, 9.65.
Example 127 Preparation of 3- (( (4- (3- (Trifluoromethyl) pyrid-2- yl)piperazin-l-yl) acetyl) amino) -2- (carbomethoxy) thiophene
(Compound CN) 1- (3- (Trifluoromethyl) pyrid-2-yl) piperazine (2.7 g, 11.7 mmol) was added to a solution of 3- ( (bromoacetyl) amino) -2- (carbomethoxy) thiophene (1.6 g, 5.8 mmol) in DMF (20 mL) at rt. The reaction mixture was heated and stirred at 65-70 °C 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 °C: XH NMR (DMSO-dff) δ 11.34 (s, IH) , 8.54 (dd, J = 4.8, J = 1.2, IH) , 8.08 (d, J = 5.6, IH) , 8.05 (dd, J = 8.0, J = 2.0, IH) , 7.90 (d, J = 5.6, IH) , 7.19 (ddd, J = 8.0, J = 4.8, J" = 0.2, IH) , 3.85 (s, 3H) , 3.34 (t, J = 5.2, 4H) , 3.26 (s, 2H) , 2.69 (t, J = 4.4, 4H) ; 13C NMR (DMSO-dfi) δ 168.12, 163.21, 158.93, 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 (El, m/z) 428 (M+) . Anal. Calcd for C18H19N403SF3 : C, 50.39; H, 4.46; N, 13.06. Found: C, 50.09; H, 4.44; N, 13.06.
Example 128 Preparation of 3- (( (4- (4-Fluorophenyl) piperazin-l- yl) acetyl) amino) -2- (carbomethoxy) thiophene (Compound CO) 1- (4-Fluorophenyl) piperazine (0.72 g, 3.99 mmol) and anhydrous K2C03 (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 reaction mixture was heated and εtirred at 70 °C for 6 h, cooled to rt, and poured into ice water. The precipitate which formed waε filtered, waεhed 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- 5 130 °C: XE NMR (DMS0-de) δ 11.33 (ε, IH) , 8.09 (d, J = 5.6, IH) , 7.91 (d, J = 5.6, IH) , 7.08-7.04 (m, 2H) , 6.99-6.96 (m, 2H) , 3.79 (ε, 3H) , 3.26 (ε, 2H) , 3.21 (t, J = 4.8, 4H) , 2.69 (t, J = 4.8, 4H) ; 13C NMR (DMS0-dfi) δ 168.11, 168.04, 163.14, 155.95 (d, J = 234.3), 147.70 (d, J = 1.4), 143.14, 133.10, 10 121.51 (d, .7 =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 (El, m/z) 377 (M+) . Anal. Calcd for C18H20N3O3SF : C, 57.20; H, 5.33; N, 11.12. Found: C, 56.93; H, 5.37; N, 11.05.
Example 129 15 Preparation of 3- (( (4- (4-Methoxyphenyl) piperazin-l- yl) acetyl) amino) -2- (carbomethoxy) thiophene (Compound CP) 1- (4-Methoxyphenyl) piperazine (1.5 g, 7.8 mmol) and K2C03 (3.3 g, 23.9 mmol) were added to a εolution of 3- ( (bromoacetyl) amino) -4- (carbomethoxy) thiophene (2.16 g, 7.8 20 mmol) in DMF (25 mL) at rt . The reaction mixture was heated and stirred at 50 °C for 4 h, cooled to rt, and poured into ice water, cauεing a light yellow precipitate to form. The precipitated εolid was filtered, washed several timeε with cold water, and then dried to give 2.34 g (80.4%) aε a light 25 yellow εolid, mp 156.8-158 °C: E NMR (DMSO-dff) δ 11.32 (bε, IH) , 8.85 (d, J = 5.2, IH) , 7.91 (d, J = 5.6, IH) , 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 (ε, 2H) , 3.15 (t, .7 = 4.0, 4H) , 2.69 (t, J = 4.0, 4H) ; 13C NMR (DMSO-dfi) δ 168.15, 168.07, 163.11, 152.85, 30 145.19, 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 (El, 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.
35 Example 130
Preparation of 3- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino) -2- (carbomethoxy) thiophene Hydrochloride
(Compound CF) 5 A solution of 3- ( ( (4- (3-
(trifluoromethyl) phenyl) piperazin-1-yl) acetyl ) amino) -2- (carbomethoxy) thiophene (Compound CF) (0..94 g, 2.2 mmol) in CH2C12 (20 mL) was treated with an excess of IN HCl ether solution (4.4 mL, 4.4 mmol). The reaction mixture was 0 stirred at rt for several hourε . The light precipitate which formed was filtered, washed several times with ether, and dried to give a white solid. The εolid waε treated with a mixture of CH2C12 and ethanol and refluxed. The product was filtered, washed several times with ether, and then dried to 5 give 0.65 g (59%) of the title compound as a white solid, mp 237-238 °C. Anal. Calcd for C19H20N3O3F3S»HCl : C, 49.19; H, 4.56; N, 9.06. Found: C, 49.14; H, 4.58; N, 8.88.
Example 131 Preparation of 2- ( ( (4- (4- (chlorobenzhydryl) phenyl) iperazin- 0 1-yl) acetyl) amino) -2- (carbomethoxy) thiophene (Compound CH) 1- (4-Chlorobenzhydryl) piperazine (1.0 g, 3.5 mmol) and K2C03 (1.5 g, 10.5 mmol) were added to a solution of 3- ( (bromoacetyl) amino) -2- (carbomethoxy) thiophene (0.97 g, 3.5 mmol) in DMF (20 mL) at rt . The reaction mixture was heated 5 and stirred at 70 °C for 6 h and cooled to rt. The reaction mixture was poured into ice water and the crystalline precipitate which formed was filtered, waεhed several times with water, and then dried to give 1.5 g (89%) of the title compound as a white solid, mp 100-102.2 °C: H NMR (DMSO-dfi) δ 0 11.20 (s, IH) , 8.04 (d, J = 5.4, IH) , 7.87 (d, J = 5.6, IH) , 7.46 (d, J = 8.8, 2H) , 7.41 (d, J = 7.2, 2H) , 7.36 (d, J = 8.8, 2H) , 7.30 (dd, .7 = 7.6, J = 7.6, 2H) , 7.19 (t, J = 7.6, IH) , 4.42 (S, IH) , 3.83 (s, 2H) , 3.36 (s, 3H) , 2.57 (bε, 4H) , 2.43 (bε, 4H) ; 13C NMR (DMSO-de) δ 168.26, 163.07, 143.05, 35 142.10, 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, /z) 484 (M+H+) .
Example 132 Preparation of 3- ( ( (4- (2- (Trifluoromethyl) quinolin-4- 5 yl)piperazin-l-yl) acetyl) amino) -2- (carbomethoxy) thiophene
(Compound CG) 1- (2- (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- 0 (carbomethoxy) thiophene (1.6 g, 5.8 mmol) in DMF (20 mL) at rt. The reaction mixture was heated and stirred at 70 °C for 5 h, cooled to rt , and poured into ice water. The light precipitate which formed was filtered, washed w%ith water, and then dried to give 2.4 g (87%) of the title compouind, as a 5 light solid, mp 150-152 °C: U NMR (DMSO-de) δ 11.34 (ε, IH) , 8.12-8.07 (m, 3H) , 7.92 (d, J = 5.2, IH) , 7.84 (dd, J = 6.8, J = 6.8, IH) , 7.71 (dd, J = 7.6, J = 7.6, IH) , 7.31 (ε, IH) , 3.84 (s, 3H) , 3.47 (bs, 4H) , 3.36 (s, 2H) , 2.89 (bs, 4H) ; 13C NMR (DMSO-de) δ 168.10, 163.26, 158.30, 147.99, 147.07 (q, J = 20 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 25 limiting the invention described and claimed herein. Such variations of the invention which would be within the purview of thoεe εkilled in the art, including the substitution of all equivalents now known or later developed, including changes in formulation or minor changes in experimental 30 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 COMPOUNDS OF FORMULA (I) The antidiabetic activity of representative compounds 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 consisted of a maintenance diet, i.e., water and food were provided ad libi tum, 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 μl blood sample was collected 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) compared with DO (before treatment) .
Table V clearly showε the efficacy of the illustrative compounds of formula I to cause a decrease in glucose levels in diabetic animals.
TABLE V
Figure imgf000278_0001
7.2 IN VIVO ACTIVITY OF THE
COMPOUNDS OF FORMULA (VII)
The antidiabetic activity of representative compounds of formula VII 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 consisted of a maintenance diet, i.e., water and food were provided ad libi tum, up until 2 hours before collecting blood.
A test product was administered orally to the mice during the day. Two hours after the last administratiofT'of the teεt product, and 30 minutes after anaesthetizing the animals with sodium pentobarbital (Nembutal®) , a 300 μl blood sample was collected from the tail. The reεultε are εhown in Table VI . The results are expressed as a percentage variation in glucose levelε at D4 (4 days of treatment) compared with DO (before treatment) .
TABLE VI
Figure imgf000280_0001
Table VI clearly shows the efficacy of the illustrative compounds of formula VII to cause a decreaεe in glucose levels in diabetic animals.
7.3 IN VIVO ACTIVITY OF THE COMPOUNDS OF FORMULA (XIIlb)
Thiε example demonstrates the effectiveness of illustrative piperazine derivatives of the formula (Xlllb) to lower serum glucose levels in C57BL/KS diabetic db/db mice, an art recognized model of non-insulin dependent diabetes mellituε (NIDDM) . Illuεtrative derivativeε of the formula XIIlb include:
2- [ t [4- [2- (Fluoro) phenyl] piperazin-l-yl] acetyl] amino] -4- chlorobenzothiazole (Compound DB) , 2- [ [ [4- [2-Pyridyl) ] piperazin-l-yl] acetyl] amino] -6- chlorobenzothiazole (Compound DC) ,
2- [ [ [4- [2- (Fluoro) phenyl] piperazin-l-yl] acetyl] amino] -6- methoxybenzothiazole (Compound DD) , 2- [ [ [4- [2- (Pyridyl) ] piperazin-l-yl] acetyl] amino] -6- methoxybenzothiazole (Compound DE) , 2- [ [ [4- [2-Pyrimidinyl] piperazin-l-yl] acetyl] amino] -6- methoxybenzothiazole (Compound DF) 2- [ [ [4- [Benzyl] piperazin-l-yl] acetyl] amino] -6- methoxybenzothiazole (Compound DG) , 2- [ [ [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -6 -methoxybenzothiazole (Compound DH) , 2- [ [ [4- [2- (Pyridyl) ] piperazinyl-1] acetyl] amino-4- methoxybenzothiazole (Compound DI) ,
2- [ [ [4- [4- (Methoxy) phenyl] piperazin-l-yl] acetyl] amino] -6- fluoro-benzothiazole (Compound DJ) , 2- [ [ [4- [2- (Pyridyl) piperazin-l-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-l-yl] acetyl] amino] -6- methoxybenzothiazole Hydrochloride (Compound DM) , 2- [[ [4- (3 -Chlorophenyl) piperazin-l-yl] acetyl] amino] - 6- methoxybenzothiazole (Compound DO) ,
2- [ [ [4- (3 -Bromophenyl) piperazin-l-yl] acetyl] amino] - 6- methoxybenzothiazole (Compound DP) ,
2- [ [ [4- (3 -Nitrophenyl) piperazin-l-yl] acetyl] amino] - 6- methoxybenzothiazole (Compound DQ) ,
2- [ [ [4- [2- (Pyridyl) piperazin-l-yl] acetyl] amino] -6- ethoxybenzothiazole Hydrochloride (Compound DR) , 2- [ [ [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -6 -ethoxybenzothiazole Hydrochloride (Compound DS) ,
2- [[[4- [3- (Trifluoromethyl) phenyl] piperazin-l-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-l-yl] acetyl] amino] -6 -methoxybenzothiazole (Compound DW) , 2- [ [ [4- (4 -Chlorobenzhydryl) piperazin-l-yl] acetyl] amino] -6- methoxybenzothiazole (Compound DX) , 2- [ [ [4- (3-Methoxy-5-trifluoromethyl-phenyl)piperazin-l-yl] acetyl] amino] -6-methoxybenzothiazole (Compound DY) .
Genetically altered obese diabetic mice, designated C57BL/Ks-db/db, were purchaεed from the Jackεon Laboratory \3ar Harbor, ME) . Male animalε between the ageε of 8-9 weekε at the εtart 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 Purina® (St. Louis, MO) rodent chow and water ad libi tum. Prior to treatment, blood was collected from the tail vein of each animal and mice having plasma glucose levels between 350 and 600 mg/dL were used. Each treatment group consisted of eight mice which 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 100, 150 or 250 mg, or metformin administered at 250 mg/kg/day. Test compounds were delivered in a liquid vehicle containing 0.25% (w/v) carboxymethylcellulose, 1% (v/v) Tween® 60 (polyoxyethylene εorbitan monoεterate, and up to 10% (v/v) dimethyl εulfoxide (DMSO) in a volume of 10 ml/kg. Blood was sampled from the tail vein at three hours and twenty-seven hours poεt-initial adminiεtration of the particular compound under non-fasted 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 differenceε between compound-treated and vehicle only-treated were evaluated uεing analysis of variance and Fisher' ε poεt-hoc teεt .
The piperazine teεt εubstances evaluated in the diabetic mice for the ability to lower blood glucoεe are listed above and in Table VII. Single 250 mg/kg doses of Compounds DB-DY were given daily to diabetic C57Bl/Ks db/db mice and some of which reεulted in statistically significant reductions in plasma glucose levelε 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 Compounds 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 εecond dosing, mean glucose levels for the active experimental Compounds 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 doseε of some experimental compounds also trended to reductions in glucose levels, i.e., p valueε greater than 0.05 but leεs than 0.20. For example, three hours after the initial dosing, mean glucose levels for the experimental compounds 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 εecond doεing, mean glucoεe levels for the experimental compound declined 18.8 mg/dL (p=0.1331) .
TABLE VII
Figure imgf000284_0001
* Statistical sign cance eva uate us ng analysis of variance and F s er's post-hoc test. NS - not significant at p=0.05 level.
Once daily 150 mg/kg dose of Compound DE given to 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 compounds 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 compounds 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 affected in the animals treated as shown in Table VIII.
TABLE VIII
Figure imgf000285_0001
Figure imgf000286_0001
Thus, the foregoing clearly indicates' that several 5 piperazine derivatives function to lower serum glucose levelε in diabetic mice.
7.4 IN VIVO ACTIVITY OF THE
COMPOUNDS OF FORMULA (XlVb)
Thiε example demonεtrates the effectiveness of 0 illustrative piperazine derivatives of the formula' (XlVb) 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
XlVb include:
25
2- [ [ [4- (Phenyl) piperazin-l-yl] acetyl] amino] -4-
[ (carboxy) methyl] thiazole (Compound C) ,
2- [ [ [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -4- [ (carboxy) methyl] -thiazole (Compound D) ,
2- [ [ [4- (2 -Fluorophenyl) piperazin-l-yl] acetyl] amino] -4-
30
[ (carboxy) methyl] thiazole (Compound E) ,
2- [ [ [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -4- [ (carboethoxy) methyl] -thiazole (Compound F) ,
4- [ [ [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -1- [ [N' - (2-thiazolyl) ] -sulfonamido] benzene
35
(Compound G) , 2- [ t [4- [5- (Trifluoromethyl) pyrid-2-yl] piperazinyl-1] acetyl] amino] -4- [ (carboethoxy) -methyl] thiazole (Compound H) , 2- [3- [ [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl]
acetyl] amino] -4- [ (carboxy) methyl] -thiazole, sodium εalt (Compound J) ,
2- [ [ [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -4- [ (carboxy) methyl] -thiazole, potassium salt (Compound K) ,
4- t [ [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -1- [ [N' - (2-thiazolyl) ] -sulfonamido] benzene, hydrochloride εalt (Compound L) ,
2- L [ [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -4- (carbomethoxymethyl) -thiazole (Compound M) , 2- [ [ [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -4- (carboxymethyl) -thiazole, hydrochloride εalt (Compound N) ,
2- [ [ [4- [4- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -4- [ (carboethoxy) methyl] -thiazole (Compound O) ,
2- [ [ [4- [4- (Carbomethoxy) phenyl] piperazin-l-yl] acetyl] amino] - 4- [ (carboxyetho) methyl] -thiazole (Compound P) , 2- [ [ [4- (3 -Chlorophenyl) piperazin-l-yl] acetyl] amino] -4- [ (carboethoxy) methyl] thiazole acetate (Compound Q) , 2- [ [ [4- (3-Bromophenyl) piperazin-l-yl] acetyl] amino] -4- [ (carboethoxy) methyl] thiazole (Compound R) , 2- [ [ [4- [4- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -4- (carboethoxymethyl) -thiazole (Compound S) , 2- [ t [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -4- t (carboethoxy) methyl] -thiazole hydrochloride (Compound BM) ,
2- [ [ [4- [3- (Methyl) phenyl] piperazin-l-yl] acetyl] amino] -4- carboethoxy) methyl] thiazole (Compound T) , 2- [ [ [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -4- [ (carbopropoxy) -methyl] thiazole (Compound U) , 2- [ [ [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -4- [ (butoxycarbonyl) -methyl] thiazole (Compound V),
Isopropyl 2- [[ [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -4- [ (isopropoxy-carbonyl) methyl] thiazole (Compound W) ,
2- [ [ [4- [4-Chloro-3- (trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -4- [ (carboethoxy) -methyl) thiazole (Compound X) , 2- [ [4- [1- (4 -Chlorobenzhydryl) phenyl] piperazin-l-yl] acetyl] amino-4- (carboethoxymethyl) -thiazole (Compound Y) , and ethyl 2- [ [ [4- (3, 5-dichlorophenyl) piperazin-l-yl] acetyl] amino] -4- [ (carboethoxy) methyl] -thiazole (Compound Z) . Genetically altered obese diabetic mice designated C57BL/Ks-db/db were purchaεed from the Jackεon Laboratory (Bar Harbor, ME) . Male animalε 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 Purina® (St. Louis, MO) rodent chow and water ad libi tum . Prior to treatment, blood was collected from the tail vein of each animal and mice having plasma glucose levels between 350 and 600 mg/dL were used. Each treatment group consisted of eight mice that were distributed such that the mean glucose levels were equivalent in each group at the start of the εtudy.
The mice received, orally by gavage,'the experimental compound administered at 50, 116, 150 and 250 mg (as noted) , or metformin administered at 250 mg/kg/day. Test compounds were delivered in a liquid vehicle containing 0.25% (w/v) carboxymethylcellulose, 1% (v/v) Tween® 60
(polyoxyethylene sorbitan monoεterate) , and up to 10% (v/v) dimethyl εulfoxide (DMSO) in a volume of 10 ml/kg. Blood was sampled from the tail vein at three hours and twenty-seven hours post initial adminiεtration of the particular compound under non-fasted 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 5 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 0 in the diabetic mice for the ability to lower blood glucose are listed above and in Table IX. Single doses of Compounds C-Z, and BM were given to diabetic C57B1/Ks db/db mice and some of which resulted in statiεtically εignificant reductions in plasma glucoεe relative to vehicle controls at 5 either 3 or 27 hours after initial oral adminiεtration. The results are shown in Table IX. For example, three hourε after the initial dosing at 250 mg/kg of experimental compounds D, F, G, H, L, Q, S, U, V, and W, mean glucose levels for the mice administered active experimental 0 compounds declined 115.1 mg/dL (p=0.0002), 171.6 mg/dL
(p<0.0001), 100.2 mg/dL (p=0.0003), 46.0 mg/dL (p=0.0363), 138.3 mg/dL (p=0.0064), 81.1 mg/dL (p=0.0304), 94.4 mg/dL (p=0.0084), 77.3 mg/dL (p=0.04), 80.3 mg/dL (p<0.0001), 82.2 mg/dL (p<0.0001) and 86.1 mg/dL (p=0.0025), respectively, 5 from the baseline values. For example, twenty-seven hours after the initial dosing, three hours after the second dosing, mean glucose levels for compounds C, D, E, F, G, L, M, 0, Q, S, T, U, V, W, X, Y and Z declined 179.7 mg/dL (p=0.0001), 202.3 mg/dL (p<0.0001), 56.3 mg/dL (p=0.0021), 30 180.1 mg/dL (p<0.0001), 130.5 mg/dL (p=0.0004), 95.6 mg/dL ■ (p=0.0124), 44.9 mg/dL (p=0.0767) 87.9 mg/dL (p=0.0118), 87.6 mg/dL (p=0.0458), 113.4 mg/dL (p=0.0003), 60.7 mg/dL (p=0.0437), 97.6 mg/dL (p=0.0159), 61.3 mg/dL (p=0.0007), 62.4 mg/dL (p=0.0005), 129.7 mg/dL (p=0.0007), 83.8 mg/dL 35 (p=0.0476), 35.5 mg/dL (p=0.0441) and 64.5 mg/dL (p=0.0059), respectively, from the baseline values. TABLE IX
Figure imgf000290_0001
Once daily 150 mg/kg doses of compounds D, F, G, J, K and N administered to diabetic C57B1/Ks db/db mice also resulted in statistically significant reductions in plasma glucose relative to vehicle controls at either 3 or 27 hours 5 after oral initial administration, see Table IX. Three hours after the initial dosing, mean glucose levels for compounds D, F, G, and K declined 116.9 mg/dL (p=0.0O46) , 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- 0 seven hourε after the initial dosing, three hours after the second dosing, mean glucose levels for the active experimental compounds 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), 5 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 statiεtically εignificant reduction in plasma glucose relative to vehicle controls at both 3 and 27 hours after 0 oral administration, see Table IX. For example, three hours after the initial doεing at 50mg/kg and 116 mg/kg of experimental compounds D and BM, mean glucose levels for mice administered active experimental compounds declined 116.9 mg/dL (p=0.0046) and 104.3 mg/dL (p=0.0017) 3 hours after 5 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 compounds also trended to reductions in glucose levels, i.e. p values 0 greater than 0.05 but less than 0.20. For example, three hours after the initial doεing, mean glucose levels for the experimental compoundε C, J, M, N, 0, 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), 35 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 affected in animals treated, except for Compound D administered at 250 mg/kg during the test period as shown in Table X.
TABLE X
Figure imgf000292_0001
Figure imgf000293_0001
Food intake of animals administered Compound D achieved levels comparable with other compounds 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 compoundε 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
COMPOUNDS OF FORMULA (XVb)
This example demonstrates the effectivenesε of illuεtrative piperazine derivativeε of the formula (XVb) to lower εerum 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) phenyl] piperazin-l-yl] acetyl] amino] -5-trifluoro-methyl-1, 3 , 4-thiadiazole (Compound BB) , 2- [ [ [4- (2 -Fluorophenyl) piperazin-l-yl] acetyl] amino] -5- trifluoromethyl-1, 3 , 4-thiadiazole (Compound BC) , - [ [ [4- (4-Methoxyphenyl) piperazin-l-yl] acetyl] amino] -5- (trifluoromethyl) -1,3, 4-thiadiazole (Compound BD) , - [ [ [4- (2-Pyridyl) piperazin-l-yl] acetyl] amino] -5- (trifluoromethyl) -1, 3 ,4-thiadiazole (Compound BE), 2- [ [ [4- (2-Pyrimidyl) piperazin-l-yl] acetyl] amino] -5- (trifluoromethyl) -1,3, 4-thiadiazole (Compound BF) , 2- [ [ [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -5- [ (7-chloroquinolin-4-yl) thio] -1,3,4- thiadiazole (Compound BG) , 2- [ [ [-4- [3- (Trifluoromethyl) phenyl] piperazinyl] acetyl] amino] -5-cyclopropyl-1,3, 4-thiadiazole (Compound BH) , 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-l-yl] acetyl] amino] -5- [ (carbomethoxy) -methyl] -1,3 , 4 -thiadiazole (Compound BK) , 2- [ [4- (2-Pyridyl) piperazin-l-yl] -1, 3 , 4-thiadiazole (Compound BL) ,
2- [ [ [-4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -5- [2- (carbomethoxy) -ethyl] -1, 3 , 4-thiadiazole (Compound BN) ,
2- [ [ [-4- (4 -Methoxyphenyl) piperazin-l-yl] acetyl] amino] -5- [2- (carbomethoxy) ethyl] -1,3, 4-thiadiazole (Compound BO) ,
2- [ C [-4- [3- (Chlorophenyl) piperazinyl -1-] acetyl] amino] -5- (trifluoromethyl) -1, 3, 4 -thiadiazole (Compound BP) , 5- t [ t-4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -3- [ (carbomethoxy) -methyl] -1, 2, 4 -thiadiazole (Compound BQ) , and
2- [ [ [-4- [3- (Trifluoromethyl) phenyl] piperazin-l-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 Purina® (St. Louis, MO) rodent chow and water ad libi tum. Prior to treatment, blood was collected from the tail vein of each animal and mice having plasma glucose levels between 350 and 600 mg/dL were used. Each treatment group consisted 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 compounds were delivered in a liquid vehicle containing 0.25% (w/v) carboxymethylcellulose, -1% (v/v) Tween® 60 (polyoxyethylene sorbitan monosterate) , and up to 10% (v/v) dimethyl sulfoxide (DMSO) in a volume of 10 ml/kg. Blood waε εampled from the tail vein at three hours and twenty-seven hours post-initial administration of the particular compound under non-fasted conditions and analyzed for plasma glucose levels . Individual body weightε and mean food conεumption (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 subεtances evaluated in diabetic mice for the ability to lower blood glucose are listed above and in Table XI. Single 250 mg/kg doses of Compounds 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 controlε 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 compounds 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 Compoundε BB, BF, BG, BH, BI, BJ, BL, BN, BP, BQ and BR declined 151.1 mg/dL (pxθ.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 doseε of some experimental compounds 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 doεing of 250 mg/kg mean glucose levels for the experimental compounds 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 πg/kg 3 hours after the second, mean glucose levels experimental compounds BC and BD declined 60.6 mg/dL (p=0.096) and 53.6 mg/dL (p=0.1227).
TABLE XI
Figure imgf000296_0001
Figure imgf000297_0001
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
20 plaεma glucose relative to vehicle controls at 27 hourε after oral administration. A once daily dose of Compound BB at 150 mg/kg alεo εhowed 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
25 250 mg/kg, caused a reduction in plasma glucose levels of 136-22.5 mg/dL. Body weights and food consumption were not adversely affected in animals treated. Importantly, the glucose lowering effects of some of these compounds when administered at 250 mg/kg were comparable to those of
30 metformin administered at 250 mg/kg.
TABLE XII
35
Figure imgf000297_0002
Figure imgf000298_0001
Thus, the foregoing clearly indicates that several of the piperazine derivatives tested function to lower serum glucose levels in diabetic mice.
25
7.6 IN VIVO ACTIVITY OF THE
COMPOUNDS OF FORMULA (XVIb)
This example demonstrates the effectivenesε of illustrative piperazine derivatives of the formula (XVIb) to
3 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 XVIb include:
3- [ [ [4- (2 -Fluorophenyl) piperazin-l-yl]
35 acetyl] amino] -2- (carbomethoxy) thiophene (Compound CO, 3- [ [ [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -2- (carbomethoxy) thiophene (Compound CD) , 3- [ [ [4- [5- (Trifluoromethyl) pyrid-2-yl] piperazin-l-yl] acetyl] amino] -2- (carbomethoxy) thiophene (Compound CE) , 3- [ [ [4- [3- (Trifluoromethyl) phenyl] piperazin-l-yl] acetyl] amino] -2- (carbomethoxy) thiophene hydrochloride (Compound CF) , and
3- [ [ [4- [2- (Trifluoromethyl) quinolin-4-yl] piperazin-l-yl] acetyl] amino] -2- (carbomethoxy) thiophene (Compound CG) .
Genetically altered obese diabetic mice designated C57BL/Ks-db/db were purchaεed from the Jackson Laboratory (Bar Harbor, ME) . Male animals between the ages of 8-9 weekε at the εtart of the experimental protocol were employed. Animalε were housed (4 mice/cage) under standard laboratory conditions at 22°C and 50% relative humidity, and were maintained on a diet of Purina® (St. Louis, MO) rodent chow and water ad libi tum. Prior to treatment, blood was collected from the tail vein of each animal . Mice that had plasma glucose levels between 350 and 600 mg/dL were used. Each treatment group consisted 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 compoundε were delivered in a liquid vehicle containing 0.25% (w/v) carboxymethylcellulose, 1% (v/v) Tween® 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-fasted conditions and analyzed for plasma glucose levels.
Individual body weights and mean food consumption (each cage) were also measured daily. The synthetic test εubεtances 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 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 Compounds CC-CG were given to diabetic C5.7B1/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 compounds CC, CD, CE and CG declined 46.7 mg/dL (p=0.0326), 148.3 mg/dL (p=<0.0001), 51.8 mg/dL (p=0.0215), and 56.0 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 glucoεe levels for compounds CD, CE, CF and CG declined 179.4 mg/dL (p=<0.0001) , 92.7 mg/dL (p=0.0028), 74.4 mg/dL (p=0.0084) and 46.4 (p=0.0241), respectively, from the baseline values.
TABLE XIII
Figure imgf000300_0001
Figure imgf000301_0001
a s a s gni icance eva ua e us ng ana ys s o varian e n s e s post-hoc test. NS - not significant at p=0.05 level.
_0 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 hours after initial dosing 150 mg/kg of Compound CD, mean glucose levelε ]_5 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. 20 Once daily doses of some experimental compounds 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 levelε for the experimental compound CF declined 45.4 mg/dL 25 (p=0.0845). For example twenty-εeven 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 30 reduction in plasma glucose levels of 136-225 mg/dL. Body weights and food consumption were not adversely affected 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 35 lowering effects of these compounds when administered at 150 mg/kg were comparable to those of metformin when administered at 250 mg/kg. TABLE XIV
Figure imgf000302_0001
Thuε, the foregoing clearly indicateε 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 εhown 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 appended claims .
A number of references are cited herein, the entire disclosures of which are incorporated herein, in their entirety, by reference.

Claims

WHAT IS CLAIMED IS:
1. A compound of general formula (Xllla) :
Figure imgf000303_0001
(Xllla) wherein: Rx is selected from the group consisting of hydrogen, halogen, R16OR17, R18NHR19, R14COOR15, C╬╣~C8 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cj-Cg) alkoxy (Ci-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl (C╬╣-C6) alkyl, (C6-C14) aryl (Ci-Cg) alkyl, (C6-C14) aryl (Ci-Cg) alkyl (C6-C14) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, carbamoyl, (Ci-C8) alkylthio, (Ci-Cjj) alkylsulphinyl, (C╬╣~C8) alkylsulphonyl, (Ci-C8) alkylsulphonylamino, sulphamoyl or (Ci-C8) alkylcarbonylamino; said Ci-Cg alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, Ci~C6 alkyl and phenyl; said C6- C14 aryl, (C6-C14) aryl (C╬╣-C6 alkyl), C6-C╬╣4 heteroaryl, and (C6- C14) heteroaryl (C╬╣~C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Ci-C6 alkyl;
R2 is selected from the group consisting of hydrogen, halogen, R16OR╬╣7, R╬╣8NHR╬╣9, R╬╣4COOR╬╣5, Ci-C8 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Ci-C6) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (Ci-C6) alkyl, (C6-C╬╣4) aryl, (C6-C╬╣4) heteroaryl, (C6-C╬╣4) heteroaryl (Ci~C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl, (C6-C14) aryl (Ci-C6) alkyl (C6-C14)aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (C╬╣-C8) alkylthio, (C╬╣-C8) alkylsulphinyl, (Cj-Cg) alkylsulphonyl, (C╬╣-C8) alkylsulphonylamino, sulphamoyl and (C^Cg) alkylcarbonylamino; said C!-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-Cg alkyl and phenyl; said C6-C14 aryl, (C6-C14) aryl (Ci-Cg alkyl) , C6-C14 heteroaryl, and (C6-C14) heteroaryl (Ci-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Ci-C6 alkyl;
R3 is selected from the group consisting of hydrogen, halogen, R16OR╬╣7, R18NHR19, R14COOR15, Cx-C8 alkyl, (C3- C8) cycloalkyl (C^Cg) alkoxy (Ci-Cg) alkyl, (C6-C14) aryl, (C6- C14) heteroaryl, (C6-C14) heteroaryl (Ci-C6) alkyl, (C6-C╬╣4) aryl (Ci-Cg) alkyl, (C6-C14) aryl (Ci-C6) alkyl (C6-C14) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (C╬╣~C8) alkylthio, (Ci-C8) alkylsulphinyl, (C╬╣~C8) alkylsulphonyl, (Ci- Cg) alkylsulphonylamino, sulphamoyl and (Ci-C8) alkylcarbonylamino; said Ci-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-Cg alkyl and phenyl; said C6-C14 aryl, (C6-C14) aryl (C╬╣-C6 alkyl) , C6-C╬╣4 heteroaryl, and (C6-C14) heteroaryl (C╬╣-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Ci-C6 alkyl;
R4 is selected from the group consisting of hydrogen, halogen, R╬╣6OR17, R18NHR19, ╬╣4COOR╬╣5, Cx-C8 alkyl, (C3- C8) cycloalkyl (C╬╣~C6) alkoxy (C╬╣-C6) alkyl, (C6-C14) aryl, (C6- C14) heteroaryl, (C6-C14) heteroaryl (Ci-C6) alkyl, (C6-C╬╣4) aryl (Ci-Cg) alkyl, (C6-C14) aryl (Ci-C6) alkyl (C6-C╬╣4)aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (Ci-C8) alkylthio, (C╬╣~C8) alkylsulphinyl, (C╬╣~C8) alkylsulphonyl, (Cx- C8) alkylsulphonylamino, sulphamoyl and (C╬╣-C8) alkylcarbonylamino; said C╬╣-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-Cg alkyl and phenyl; said C6-C14 aryl, (C6-C14) aryl (Ci-Cg alkyl), C6-CXi heteroaryl, and (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Ci-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 (Ci~C6) alkyl; R9 selected from the group consisting of hydrogen,
C╬╣-C8 alkyl, (Ci-C6) alkoxy (Ci-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cj-Cg) alkyl, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (Ci-Cg) alkyl, C6-C14 aryl, C6-C╬╣4 heteroaryl, (C6- C14) heteroaryl (Ci-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl, (C5- C14) aryl (Ci-C6) alkyl (C^Cg) aryl, (C6-C14) aryl (C╬╣-C6) alkoxy (Ci-C6) alkyl and (C6-C╬╣4) aryloxy (Ci-C6) alkyl;
Rio is selected from the group consisting of hydrogen, Ci-C8 alkyl, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-C14 aryl, C6- C14 heteroaryl, (C6-C14) heteroaryl (Ci-Cg) alkyl, (C6-C╬╣4) aryl (Ci-Cg) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (C6-C14) aryl (C╬╣-C6) alkoxy (C╬╣~C6) alkyl and (C6-C╬╣4) aryloxy (Ci-C6) alkyl ;
Ru is selected from the group consisting of hydrogen, Ci~C8 alkyl, (C╬╣-C6) alkoxy (Cx-Cg) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-C14 aryl, C6- C14 heteroaryl, (C6-C14) heteroaryl (Ci-Cg) alkyl, (C6-C14) aryl (Ci-Cg) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (Ci-C6) aryl, (Cg-C╬╣4) aryl (C╬╣-C6) alkoxy (Ci-Cg) alkyl and (C6-C╬╣4) aryloxy (Ci-C6) alkyl;
Ri2 is selected from the group consisting of hydrogen and C:-Cg alkyl; R13 is selected from the group consisting of
Figure imgf000306_0001
R14 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Ci-Cg alkyl; said Cj-Cg alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkyl and phenyl; R15 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and Ci- Cg alkyl; said Ci-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl and C╬╣-C3 alkyl;
R16 is a bond or is selected from the group consisting of sulfonyl, Ci-C8 thioalkyl, aminosulfonyl and Cx- C6 alkyl group; said C╬╣-C6 alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkyl and phenyl;
R17 is selected from the group consisting of Ci-C5 alkyl, C3-C8 cycloalkyl, C6-C╬╣4 aryl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl; said Ci-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, phenyl, phenylalkyl and Ci-C3 alkyl; said C3-C6 cycloalkyl group being optionally substituted with C!-C3 alkyl;
R18 is a bond or is selected from the group consisting of sulfonyl , C╬╣-C8 thioalkyl , aminosulfonyl, carbonyl, aminocarbonyl and Ci-Cg alkyl, said Ci-Cg alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkyl and phenyl ; R19 is selected from the group consisting of hydrogen, phenyl, phenylalkyl, and Ci-Cg alkyl; said Cj-Cg alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl and C╬╣-C3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino and Ci-C6 alkyl; said phenylalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino and Cj-Cg alkyl;
R20 is selected from the group consisting of hydrogen, Ci-Ci6 alkyl, hydroxy and Ci-C6 alkoxy; m is 0 or 1; o is 0 or 1; R2╬╣ is a bond or C╬╣-C6 alkyl; said C╬╣-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 C╬╣-C6 alkyl, halogen, Ci-Cg alkoxy and hydroxy;
R 22~R3╬╣ are independently selected from the group consisting of hydrogen, halogen, Ci-C8 alkoxy, Ci-C8 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-C6) alkoxy, carboxy, Ci-Cg thioalkyl hydroxy (C3-C8) cycloalkyl, (C3-C8) cycloalkyl, (Ci-Cg) alkyl, C╬╣-C8 alkoxy, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy, (Ci-C6) alkoxy (Ci-Cg) alkyl, (C6-C╬╣4) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl (C╬╣-C6) alkyl, (C6-C14) aryl (Ci-Cg) alkyl, (C6-C╬╣4) aryl (C^Cg) alkyl (C6-C14)aryl, (C6-c14) aryloxy, (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl, (C6-C14) aryl (Ci-Cg) alkyloxy, (C5-C╬╣4) aryl (C╬╣-C6) alkyloxy (C╬╣-C6) alkyl trifluoromethoxy, amino, carbamoyl, (C╬╣~C8) alkylthio, (Cx-C8) alkylsulphinyl, (C╬╣~C8) alkylsulphonyl, sulphoamino, (Ci-Cg) alkylsulphonylamino, sulphamoyl or (C╬╣~C8) alkylcarbonylamino; said (Ci-C8) alkyl being optionally substituted with one or more constituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C2-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with one or more constituents selected from the group consisting of halogen and C╬╣~C8 alkyl; said carbo (Ci-C6) alkoxy being optionally substituted with one or more constituents selected from the group consisting of halogen and C╬╣~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; X5 is nitrogen or CR31; wherein at least one of X3, X4, or X5 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 (Xllla) is not l-[ [ [4- [2- (fluorophenyl]piperazin-l-yl] acetyl] amino] -6-fluorobenzothiazole; and a pharamceutically accceptable salt or solvate thereof; and a compound having a tautomeric structure thereof.
2. The compound according to claim 1 wherein: Ri is selected from the group consisting of hydrogen, halogen, R16OR17, R18NHR╬╣9, R╬╣4COOR╬╣5, Cj-Cg alkyl, C3-C8 cycloalkyl, (C6-C╬╣4) aryl, (C6-C╬╣4) aryl (Ci-C6) alkyl, trihalo (C╬╣-C6) alkyl, trihalo (C╬╣-C6) alkoxy and cyano; said Ci-Cg alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl and phenyl; said C6-C╬╣4 aryl and (C6-C╬╣4) aryl (Ci-C6 alkyl) being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and C╬╣-C6 alkyl; R2 is selected from the group consisting of hydrogen, halogen, R╬╣6OR╬╣7, R╬╣8NHR╬╣9, R14COOR15, Ci-C8 alkyl, C3-C8 cycloalkyl, (C6-C14) aryl, (C6-C14) aryl (Ci-Cg) alkyl, trihalo (Cj-Cg) alkyl, trihalo (C╬╣-C6) alkoxy and cyano; said Ci-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl and phenyl; said C6-C14 aryl and (C6-C╬╣4) aryl (Ci-Cg alkyl) being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Ci-C6 alkyl; R3 is selected from the group consisting of hydrogen, halogen, R╬╣6OR17, R18NHR19, R14COOR15, Ci-Cg alkyl, C3-C8 cycloalkyl, (C6-C14) aryl, (C6-C14) aryl (Ci-Cg) alkyl, trihalo (Ci-Cg) alkyl, trihalo (Ci-C6) alkoxy and cyano; said C╬╣-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, C╬╣-C6 alkyl and phenyl; said C6-C14 aryl and (C6-C14) aryl (C╬╣-C6 alkyl) being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and C╬╣-C6 alkyl; R4 is selected from the group consisting of hydrogen, halogen, R╬╣6OR╬╣7, R18NHR19, R14COOR15, C^Cg alkyl, C3-C8 cycloalkyl, (C6-C14) aryl, (C6-C14) aryl (C^Cg) alkyl, trihalo (Ci-Cg) alkyl, trihalo (Ci-Cg) alkoxy and cyano; said C╬╣-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, C╬╣-C6 alkyl and phenyl; said C6-C14 aryl and (C6-C14) aryl (C╬╣-C6 alkyl) being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Ci-Cg alkyl; R8-R2╬╣, m and o are as defined above; R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Ci~C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C3 alkyl; said C2- C6 alkoxy being optionally substituted with halogen and C╬╣-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with one or more subsitituents consisting of halogen and Ci-Cg alkyl; said carbo (Cj-Cg) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl;
R23 is selected from the group consisting of hydrogen, halogen, Ci-C6 alkoxy, Ci-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C8 alkyl; said carbo (Ci-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci~C3 alkyl; R24 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, Ci-Cg alkyl, trifluoromethyl, nitro, cyano, carboxy, phenyl, Ci-C8 thioalkyl, and hydroxy; said Ci-Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said C╬╣-C5 alkoxy being be optionally substituted with one or more substituents selected from the group consisting of halogen or C╬╣-C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen or C╬╣~C3 alkyl;
R25 is selected from the group consisting of halogen, Ci-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-C6) alkoxy, carboxy, phenyl, Ci-C8 thioalkyl and hydroxy; said Ci-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and or Ci-C3 alkyl; said Ci-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen or Ci~C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen andr C:-C8 alkyl; said carbo (C╬╣-C5) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen or C╬╣-C3 alkyl;
R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Ci-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl and hydroxy; said Ci-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C2- C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said C-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C8 alkyl; said carbo (Ci-Cg) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; wherein R22-R26 cannot all simultaneously be hydroge ; or two of R22-R26 when taken together can form methylene dioxy group;
R27 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said Ci-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C^Cg alkyl; said carbo (C^Cg) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen or C╬╣-C3 alkyl;
R28 is selected from the group consisting of hydrogen, halogen, Cx-Cg alkoxy, C^Cg alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-Cg) alkoxy, carboxy, phenyl, Ci-C8 thioalkyl and hydroxy; said Ci-Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C╬╣~C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen or C╬╣~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 CR31; wherein at least one of X3, X4, or X5 is a nitrogen; R29 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, Ci-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl and hydroxy; said Ci-Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said Ci-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C8 alkyl; said carbo (Ci-Cg) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; R30 is selected from the group consisting of hydrogen, halogen, Ci~C6 alkoxy, Ci-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl and hydroxy; said Ci-Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci~C3 alkyl; R3╬╣ is selected from the group consisting of hydrogen, halogen, Cj-Cg alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-C6) alkoxy, carboxy, phenyl, Ci-C8 thioalkyl and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen or C╬╣-C3 alkyl; said Ci-Cg alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C-C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C:-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; or R28 and CR30 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.
3. The compound according to claim 1 selected from the group consisting of
2- ( ( (4- (2-Pyridyl) piperazin-l-yl) acetyl) amino) -6- fluorobenzothiazole, 2- ( ( (4- (2-Fluorophenyl) piperazin-l-yl) acetyl) amino) -6- fluorobenzothiazole, 2-( ( (4- (2-Pyridyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole,
2- ( ( (4- (2-Pyrimidyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole, 2- ( ( (4- (Benzyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole,
2-( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -6-methoxybenzothiazole,
2-( ( (4- (2-Pyridyl) piperazin-l-yl) acetyl) amino-4- methoxybenzothiazole,
2-( ( (4- (4-Methoxyphenyl) piperazin-l-yl) acetyl) amino) -6- fluoro-benzothiazole,
2- ( ( (4-( (2-Pyridyl) piperazin-l-yl) acetyl) amino) -6- ethoxybenzothiazole, 2-( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -6-ethoxybenzothiazole,
2-( ( (4- (3-Chlorophenyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole,
2- ( ( (4- (3-Bromophenyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole,
2- ( ( (4- (3-Nitrophenyl) piperazin-l-yl) acetyl) amino) -6- methox benzothiazole,
2-( ( (4- ( (2-Pyridyl) piperazin-l-yl) acetyl) amino) -6- ethoxybenzothiazole Hydrochloride, 2-( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -6-ethoxybenzothiazole Hydrochloride,
2-( ( (4- (4- (Trifluoromethyl)phenyl)piperazin-l- yl) acetyl) amino) -6-methoxybenzothiazole,
2-( ( (4- (3-Methylphenyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole,
2- ( ( (4- (3-Cyanophenyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole,
2-( ( (4- (4-Bromo-3-trifluoromethylphenyl)piperazin-l- yl) acetyl) amino) -6-methoxybenzothiazole, 2-( ( (4- (4-Chlorobenzhydryl) piperazin-l-yl) acetyl) amino) 6-methoxybenzothiazole, 2-( ( (4- (3-Ethylphenyl) piperazin-l-yl) acetyl) amino) -6- methoxy benzothiazole,
2- ( ( (4- (2-Naphthyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole, 2-( ( (4- (3-Methoxyphenyl)piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole,
2-( ( (4- (3-Methoxy-5-trifluoromethylphenyl) piperazin-l- yl) acetyl) amino) -6-methoxybenzothiazole,
2-( ( (4- (3, 5-Dichlorophenyl)piperazin-l-yl) acetyl) amino) - 6-methoxybenzothiazole, and
2-( ( (4- (3, 4-Dichlorophenyl) piperazin-l-yl) acetyl) amino) - 6-methoxybenzothiazole.
4. A composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.
5. A composition comprising the compound according to claim 2 and a pharmaceutically acceptable carrier.
6. A composition comprising the compound according to claim 3 and a pharmaceutically acceptable carrier.
7. A method for lowering serum glucose levels in a mamal comprising administering a compound of the formula
(Xlllb) having the structure:
Figure imgf000315_0001
wherein: Ri is selected from the group consisting of hydrogen, halogen, R╬╣6OR╬╣7, R18NHR19, R╬╣4COOR╬╣5, Ci-Cg alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl, (C5-C14) aryl (Ci-Cg) alkyl (C6-C╬╣4) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, carbamoyl, (Ci~C8) alkylthio, (Cx-C8) alkylsulphinyl, (C╬╣~C8) alkylsulphonyl, (C╬╣-C8) alkylsulphonylamino, sulphamoyl or (C^Cg) alkylcarbonylamino; said Ci-Cg alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, C╬╣-C6 alkyl and phenyl; said C6- C14 aryl, (C╬╡-C╬╣4) aryl (C╬╣-C6 alkyl) , C6-C14 heteroaryl, and (C6- C14) heteroaryl (C^Cg) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and C^Cg alkyl;
R2 is selected from the group consisting of hydrogen, halogen, R16OR17, R18NHR19, R14COOR15, C:-C8 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C^Cg) alkyl, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (Ci-Cg) alkyl, (C6-C╬╣4) aryl, (C6-C╬╣4) heteroaryl, (C6-C14) heteroaryl (C╬╣-C6) alkyl, (C6-C14) aryl (Ci-Cg) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C6-C╬╣4) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (Ci-Cg) alkylthio, (C╬╣-C8) alkylsulphinyl, (C╬╣-C8) alkylsulphonyl, (Ci-C8) alkylsulphonylamino, sulphamoyl and (C╬╣~C8) alkylcarbonylamino; said C╬╣-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-Cg alkyl and phenyl; said C5-C14 aryl, (C6-C╬╣4) aryl (C╬╣-C6 alkyl) , C6-C14 heteroaryl, and (C6-C╬╣4) heteroaryl (Ci-Cg) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and C╬╣-C6 alkyl; R3 is selected from the group consisting of hydrogen, halogen, ╬╣6OR╬╣7, R╬╣8NHR╬╣9, R14COOR15, C^Cg alkyl, (C3- C8) cycloalkyl (C╬╣-C6) alkoxy (C^Cg) alkyl, (C6-C14) aryl, (C6- C14) heteroaryl, (C6-C14) heteroaryl (C╬╣-C6) alkyl, (C6-C14) aryl (Ci-Cg) alkyl, (C5-C14) aryl (C╬╣-C6) alkyl (C6-C14) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (Ci-C8) alkylthio, (Cx-C8) alkylsulphinyl, (C╬╣-C8) alkylsulphonyl, (C╬╣~ C8) alkylsulphonylamino, sulphamoyl and (C╬╣-C8) alkylcarbonylamino; said Ci-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-Cg alkyl and phenyl; said C6-C14 aryl, (C6-C14) aryl (Ci-C6 alkyl) , C6-C14 heteroaryl, and (C6-C╬╣4) heteroaryl (Ci-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Ci-C6 alkyl;
R4 is selected from the group consisting of hydrogen, halogen, R╬╣6OR17, R18NHR19, R14COOR15, Ci-C8 alkyl, (C3- C8) cycloalkyl (C╬╣-C6) alkoxy (C:-C6) alkyl, (C6-C14) aryl, (C6- C14) heteroaryl, (C6-C14) heteroaryl (Ci-Cg) alkyl, (C6-C14) aryl (Ci-Cg) alkyl, (C6-C14) aryl (Ci-Cg) alkyl (C6-C14) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (C╬╣~C8) alkylthio, (C╬╣~C8) alkylsulphinyl, (Ci-Cg) alkylsulphonyl, (C╬╣~ C8) alkylsulphonylamino, sulphamoyl and (C╬╣~C8) alkylcarbonylamino; said C╬╣~C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, C╬╣-C6 alkyl and phenyl; said C6-C14 aryl, (C6-C14) aryl (C^Cg alkyl), C6-C14 heteroaryl, and (C6-C14) heteroaryl (C╬╣-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and C╬╣-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 (C1-C6) alkyl;
R9 selected from the group consisting of hydrogen, Ci-Cg alkyl, (C╬╣-C6) alkoxy (Ci-Cg) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-C6) alkyl, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (Ci-C6) alkyl, C6-C╬╣4 aryl, C6-C╬╣4 heteroaryl, (C6- C14) heteroaryl (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl, (C6- C14) aryl (Ci-Cg) alkyl (C╬╣-C6) aryl, (C6-C14) aryl (C╬╣-C6) alkoxy (Ci-Cg) alkyl and (C6-C14) aryloxy (C╬╣-C6) alkyl; io is selected from the group consisting of hydrogen, C╬╣-C8 alkyl, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, C6-C╬╣4 aryl, C6- C14 heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (Ci-Cg) alkyl, (C6-C14) aryl (Ci-Cg) alkyl (C╬╣-C6) aryl, (C6-C14) aryl (Cj-Cg) alkoxy (C╬╣-C6) alkyl and (C6-C╬╣4) aryloxy (Cj-Cg) alkyl;
Ru is selected from the group consisting of hydrogen, C╬╣~C8 alkyl, (Ci-C6) alkoxy (C╬╣-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-C6) alkyl, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (Ci-Cg) alkyl, C6-C╬╣4 aryl, C6- C14 heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (Ci-Cg) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (C6-C14) aryl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl and (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl ;
Ri2 is selected from the group consisting of hydrogen and C╬╣-C6 alkyl;
R13 is selected from the group consisting of
Figure imgf000318_0001
R14 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cj-Cg alkyl; said C╬╣-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C╬╣~C6 alkyl and phenyl; Ri5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and C╬╣~ C6 alkyl; said C╬╣-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl and C╬╣~C3 alkyl;
Rig is a bond or is selected from the group consisting of sulfonyl, C╬╣~C8 thioalkyl, aminosulfonyl and C╬╣~ C6 alkyl group; said Ci-C6 alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C╬╣~C6 alkyl and phenyl;
Ri7 is selected from the group consisting of C╬╣~C6 alkyl, C3-C8 cycloalkyl, C6-C╬╣4 aryl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl; said C╬╣-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, phenyl, phenylalkyl and C╬╣~C3 alkyl; said C3-C6 cycloalkyl group being optionally substituted with C╬╣-C3 alkyl;
Rx8 is a bond or is selected from the group consisting of sulfonyl, C╬╣~C8 thioalkyl, aminosulfonyl, carbonyl, aminocarbonyl and C╬╣-C6 alkyl, said C╬╣-C6 alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkyl and phenyl;
Ri9 is selected from the group consisting of hydrogen, phenyl, phenylalkyl, and C╬╣-C6 alkyl; said C╬╣-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl and C╬╣~C3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino and C╬╣-C6 alkyl; said phenylalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino and Ci-C6 alkyl;
R20 is selected from the group consisting of hydrogen, C╬╣-C╬╣6 alkyl, hydroxy and C╬╣-C6 alkoxy; m is 0 or 1; o is 0 or 1; R21 is a bond or C╬╣-C6 alkyl; said C╬╣-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 C╬╣-C6 alkyl, halogen, Cj-Cg alkoxy and hydroxy;
R 22~R 3╬╣ are independently selected from the group consisting of hydrogen, halogen, C╬╣~C8 alkoxy, C╬╣~C8 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, C╬╣-C8 thioalkyl hydroxy (C3-C8) cycloalkyl, (C3-C8) cycloalkyl, (Ci-Cg) alkyl, Ci-C8 alkoxy, (C3-C8) cycloalkyloxy (C╬╣~C6) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy, (C╬╣-C6) alkoxy (Ci-Cg) alkyl, (C6-C╬╣4) aryl, (C6-C╬╣4) heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (Cj-Cg) alkyl (C6-C╬╣4) aryl, (C6-C╬╣4) aryloxy, (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy, (C6-C14) aryl (C╬╣-C6) alkyloxy (C╬╣-C6) alkyl trifluoromethoxy, amino, carbamoyl, (C╬╣~C8) alkylthio, (C╬╣-C8) alkylsulphinyl, (C╬╣-C8) alkylsulphonyl, sulphoamino, (C╬╣~C8) alkylsulphonylamino, sulphamoyl or (C╬╣~C8) alkylcarbonylamino; said (C╬╣-C8) alkyl being optionally substituted with one or more constituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said C2-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with one or more constituents selected from the group consisting of halogen and Cx-Cg alkyl; said carbo (C╬╣-C5) alkoxy being optionally substituted with one or more constituents selected from the group consisting of halogen and C╬╣-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; X5 is nitrogen or CR31; wherein at least one of X3, X4, or X5 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 (Xlllb) is not l-[[[4-[2-(fluorophenyl]piperazin-l-yl] acetyl] amino] -6-fluorobenzothiazole or a pharamceutically accceptable salt or solvate thereof; or a compound having a tautomeric structure thereof.
8. The method according to claim 7 wherein: Ri is selected from the group consisting of hydrogen, halogen, R╬╣6OR╬╣7, R╬╣8NHR╬╣9, R╬╣4COOR╬╣5, Ci-C8 alkyl, C3-C8 cycloalkyl, (C5-C14) aryl, cyano, trihalo (Ci-Cg) alkyl, trihalo (C╬╣-C6) alkoxy; said C╬╣~C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, Ci-Cg alkyl and phenyl; said C6-C╬╣4 aryl and (C6-C╬╣4) aryl (Cx- C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Ci~C6 alkyl;
R2 is selected from the group consisting of hydrogen, halogen, R╬╣6O ╬╣7, R╬╣8NHR╬╣9, R╬╣4COOR╬╣5, C╬╣~C8 alkyl, C3-C8 cycloalkyl, (C6-C╬╣4) aryl, cyano, trihalo (C╬╣-C6) alkyl, trihalo (Ci-Cg) alkoxy; said C╬╣~C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, Ci~C6 alkyl and phenyl; said C6-C╬╣4 aryl and (C6-C╬╣4) aryl (C╬╣~ C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and C╬╣~C6 alkyl;
R3 is selected from the group consisting of hydrogen, halogen, R╬╣6OR╬╣7, R╬╣8NHR╬╣9, R14COOR15, Ci-C8 alkyl, C3-C8 cycloalkyl, (C6-C╬╣4) aryl, cyano, trihalo (Ci-Cg) alkyl, trihalo (C╬╣-C6) alkoxy; said C╬╣-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, C╬╣-C6 alkyl and phenyl; said C6-C╬╣4 aryl and (C6-C14) aryl (Cx- C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and C^Cg alkyl;
R4 is selected from the group consisting of hydrogen, halogen, R16OR17, R18NHR19, R14COOR15, Cx-C8 alkyl, C3-C8 cycloalkyl, (C6-C14) aryl, cyano, trihalo (Ci-Cg) alkyl, trihalo (C╬╣-C6) alkoxy; said C╬╣~C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, Ci-Cg alkyl and phenyl; said C6-C╬╣4 aryl and (C6-C╬╣4) aryl (Ci- Cg) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and C╬╣-C6 alkyl;
R8~R2i. m and o are as defined above for general formula (Xllla) ;
R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Ci-C6 alkyl, nitro, trifluoromethyl, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C╬╣~C6 alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl;
R23 is selected from the group consisting of hydrogen, halogen, C^Cg alkoxy, Ci~c6 alkyl, trifluoromethyl, nitro, cyano, carbo (C^Cg) alkoxy, carboxy, phenyl, C:-C8 thioalkyl, and hydroxy; said C^Cg alkyl being optionally substituted with halogen or C!-C3 alkyl; said C^Cg alkoxy being optionally substituted with halogen or C!-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; R24 is selected from the group consisting of hydrogen, bromine, chlorine, C╬╣-C6 alkoxy, Ci-Cg alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or Ci-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or C╬╣~C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; R25 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-Cg) alkoxy, carboxy, phenyl, Ci-Cg thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or Ci-C3 alkyl; said Ci-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl;
R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, and hydroxy; said C╬╣~C6 alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with halogen or C╬╣~C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; wherein R22-R26 cannot all simultaneously be hydrogen; R27 is selected from the group consisting of halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said Ci-C6 alkyl being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl;
R28 is selected from the group consisting of hydrogen, halogen, Cj-Cg alkoxy, C╬╣-C6 alkyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; said Ci-C8 thioalkyl being optionally substituted with halogen or C╬╣~C8 alkyl; said carbo (Ci-Cg) alkoxy being optionally substituted with halogen or C╬╣-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 CR31; wherein at least one of X3, X4, or X5 is nitrogen; R29 is selected from the group consisting of hydrogen, halogen, Ci~C6 alkoxy, C╬╣-C6 alkyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one to two halogen atoms or C╬╣-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, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, nitro, cyano, carbo (Ci-Cg) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, and hydroxy; said C╬╣~C6 alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; R3╬╣ is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one to two halogen atoms or C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣~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.
9. The method according to claim 7 in which the compound is selected from the group consisting of
2- ( ( (4- (2-Pyridyl) piperazin-l-yl) acetyl) amino) -6- fluorobenzothiazole,
2-( ( (4- (2-Fluorophenyl) piperazin-l-yl) acetyl) amino) -6- fluorobenzothiazole, 2-( ( (4- (2-Pyridyl)piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole,
2~( ( (4- (2-Pyrimidyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole,
2-( ( (4- (Benzyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole,
2- ( ( (4- (3- (Trifluoromethyl)phenyl)piperazin-l- yl) acetyl) amino) -6-methoxybenzothiazole,
2-( ( (4- (2-Pyridyl) piperazin-l-yl) acetyl) amino-4- methoxybenzothiazole, 2-( ( (4- (4-Methoxyphenyl) piperazin-l-yl) acetyl) amino) -6- fluoro-benzothiazole,
2-( ( (4-( (2-Pyridyl)piperazin-l-yl) acetyl) amino) -6- ethoxybenzothiazole,
2-( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino) -6-ethoxybenzothiazole,
2-( ( (4- (3-Chlorophenyl) piperazin-l-yl) acetyl) amino) -6- methox benzothiazole,
2-( ( (4- (3-Bromophenyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole, 2-( ( (4- (3-Nitrophenyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole, 2-( ( (4-( (2-Pyridyl) piperazin-l-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-l- yl) acetyl) amino) -6-methoxybenzothiazole,
2- ( ( (4- (3-Methylphenyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole,
2-( ( (4- (3-Cyanophenyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole,
2-( ( (4- (4-Bromo-3-trifluoromethylphenyl) piperazin-l- yl) acetyl) amino) -6-methoxybenzothiazole,
2-( ( (4- (4-Chlorobenzhydryl) piperazin-l-yl) acetyl) amino) - 6-methoxybenzothiazole, 2-( ( (4- (3-Ethylphenyl) piperazin-l-yl) acetyl) amino) -6- ethoxy benzothiazole,
2- ( ( (4- (2-Naphthyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole,
2-( ( (4- (3-Methoxyphenyl) piperazin-l-yl) acetyl) amino) -6- methoxybenzothiazole,
2-( ( (4-(3-Methoxy-5-trifluoromethylphenyl) piperazin-l- yl) acetyl) amino) -6-methoxybenzothiazole,
2-( ( (4- (3, 5-Dichlorophenyl) piperazin-l-yl) acetyl) amino) - 6-methoxybenzothiazole, and 2-( ( (4- (3, 4-Dichlorophenyl) iperazin-l-yl) acetyl) amino) - 6-methoxybenzothiazole.
10. A compound of general formula (XlVa) :
Figure imgf000326_0001
wherein:
Ri is selected from the group consisting of hydrogen, R╬╣4COOR╬╣5, C╬╣-C8 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkyl, C╬╣-C8 alkoxy, (C3-C8) cycloalkyloxy (Ci-Cg) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Ci-Cg) alkoxy, (Cx- C6) alkoxy (C╬╣-C6) alkyl, (C6-C╬╣ΓÇ₧) aryl, (C6-C╬╣4) heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C^Cg) alkyl, (C6-C14) aryl (Ci-Cg) alkyl (C6-C╬╣4) aryl, (C6-C╬╣4) aryloxy, (C6- CX4) aryloxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy, (C6- Ci4) aryl (C╬╣-C6) alkyloxy (C╬╣-C6) alkyl group, halogen, trifluoromethyl, cyano, nitro, amino, carboxyl, (C╬╣-C6) alkoxycarbonyl, carbamoyl, (C╬╣~C8) alkylthio, (C╬╣-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (C╬╣-C8) alkylsulphonylamino, sulphamoyl and (Ci-Cg) alkylcarbonylamino; said C╬╣-C8 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl and phenyl; said C6- Ci4 aryl and (C6-C╬╣4) aryl (C╬╣-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy, C^Cg alkyl and phenyl;
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 (C╬╣-C6) alkyl;
R9 is selected from the group consisting of hydrogen, C╬╣~C8 alkyl, (C^Cg) alkoxy (Ci-Cg) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C╬╣-C6) alkyl group, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (^-Cg) alkoxy (Ci-Cg) alkyl, C6-C╬╣4 aryl, C6-C╬╣4 heteroaryl, (C6-C╬╣4) heteroaryl (Ci-Cg) alkyl, (C6- CX4) aryl (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (c 6~Ci4) aryl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl and (C6-C╬╣4) aryloxy (Ci-Cg) alkyl group; Rio is selected from the group consisting of hydrogen, C╬╣~C8 alkyl, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C╬╣-C6) alkyl group, (C3-C8) cycloalkyloxy (C:-C6) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-C14 aryl, C6-C14 heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6- Ci4) aryl (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (Ci-Cg) aryl, (C6-C╬╣4) aryl (Ci-Cg) alkoxy (C╬╣~C6) alkyl and (C6-C╬╣4) aryloxy (Ci-Cg) alkyl group;
Ru is selected from the group consisting of hydrogen, C╬╣-C8 alkyl, (Ci-Cg) alkoxy (C╬╣-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C╬╣-C6) alkyl group, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C╬▓) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-C╬╣4 aryl, C6-C╬╣4 heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6- C╬╣4) aryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (C6-C╬╣4) aryl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl and (C6-C╬╣4) aryloxy (Ci-Cg) alkyl group;
Ri2 is selected from the group consisting of hydrogen and C╬╣~C6 alkyl;
Ri3 is selected from the group consisting of
Figure imgf000328_0001
Ri4 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Ci-Cg alkyl; said C╬╣~C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkyl and phenyl; R15 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions and C╬╣-C6 alkyl; said C╬╣-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl, and C╬╣~C3 alkyl;
R20 is selected from the group consisting of hydrogen, C╬╣-C6 alkyl, hydroxy and C╬╣-C6 alkoxy; m is 0 or 1; n is 0 or 2; o is 0 or 1;
R21 is a bond or C╬╣-C6 alkyl; said C╬╣-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 C╬╣-C6 alkyl, halogen, Ci-Cg alkoxy and hydroxy; R22-R31 are each independently selected from the group consisting of hydrogen, C╬╣~C8 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkyl, C╬╣-C8 alkoxy, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (Ci-Cg) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl (C╬╣~C6) alkyl, (C6-C╬╣4) aryl (C╬╣~ C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C6-C14)aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy (C╬╣~C6) alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, (C╬╣-C6) alkoxycarbonyl, carbamoyl, (Ci~C8) alkylthio, (C╬╣~C8) alkylsulphinyl, (C╬╣~C8) alkylsulphonyl, sulphoamino, (C╬╣-C8) alkylsulphonylamino, sulphamoyl, (C╬╣~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 form an aryl ring; X3 is nitrogen or CR29; X4 is nitrogen or CR30; X5 is nitrogen or CR3i; wherein at least one of X3, X4, or X5 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
(XlVa) is not: 2- ( ( (4- (phenyl) piperazinly-1-) acetyl) amino) -4- ( (carboethoxy)methyl) thiazole:
2- ( ( (4- (2-fluorophenyl) piperazin-l-yl) - acetyl) amino) -4- ( (carboethoxy) methyl) thiazole; or 4- ( ( (2-fluorophenyl) amino) acetyl) amino) -1- ( (N* - (2- thiazolyl) ) sulfonamido) benzene.
11. The compound according to claim 10 wherein: Ri is selected from the group consisting of hydrogen, C╬╣-C8 alkyl group, halogen, C6-C14 aryl, (C6-C╬╣4) aryl (Ci-Cg) alkyl, and R╬╣4C00R15; said C╬╣~C8 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, C╬╣-C6 alkyl and phenyl; said C6-C╬╣4 aryl and (C6-C╬╣4) aryl (C╬╣-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy, Ci-Cg alkyl and phenyl;
R8~Ri5. R2o. m. n. O f and R2╬╣ are defined as above for general formula (XlVa) ; R22 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen or C╬╣~C3 alkyl; said C^Cg alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl;
R23 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl and hydroxy; said C^Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C:-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-Cg alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci~C3 alkyl;
R24 is selected from the group consisting of hydrogen, halogen, C╬╣~C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cj-Cg) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-Cg alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl;
R25 is selected from the group consisting of hydrogen, halogen, C╬╣~C6 alkoxy, C╬╣~C6 alkyl, carbo (C╬╣~C6) alkoxy, carboxy, phenyl, C:-C8 thioalkyl and hydroxy; said Ci~ C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; R26 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; or two of R22-R26 when taken together can form a methylenedioxy group;
R27 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣~C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-Cg) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl and hydroxy; said C╬╣~C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci~c8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; R28 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said Cj-Cg thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~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 CR3╬╣,- wherein at least one of X3, X4, or X5 is nitrogen;
R29 is selected from the group consisting of hydrogen, halogen, Ci-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said Ci~C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl, wherein the numbered halogen atoms can be 0-2; said C╬╣-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said C╬╣~ C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl;
R30 is selected from the group consisting of hydrogen, halogen, Ci-C6 alkoxy, trifluoromethyl, C╬╣-C6 alkyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C!-C3 alkyl;
R3╬╣ is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C^Cg alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-Cg) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl, wherein the numbered halogen atoms can be 0-2 ; said Cx-Cg alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said Ci- Cg thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cj-Cg alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; or R28 and CR30 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 (XlVa) 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) amino) acetyl) amino) -1- ( (N'- (2- thiazolyl) ) sulfonamidobenzene.
12. The compound according to claim 10 selected from the group consisting of 2-( ( (4- (Phenyl) piperazin-l-yl) acetyl) amino) -4- (carboxymethyl) thiazole,
2-( ( (4- (3- (Trifluoromethyl) phenyl)piperazin-l- yl) acetyl) amino) -4- (carboxymethyl) thiazole,
2- ( ( (4- (2-Fluorophenyl) piperazin-l-yl) acetyl) amino) -4- (carboxymethyl) thiazole,
2-( ( (4- (3- (Trifluoromethyl)phenyl)piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl)thiazole, 4-( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -1- ( (N ' - (2-thiazolyl) ) sulfonamido) benzene,
2- ( ( (4- (5- (Trifluoromethyl) pyrid-2-yl) piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole, 2-( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -4- (carboxymethyl) thiazole, sodium salt,
2-( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -4- (carboxymethyl) thiazole, potassium salt, 4-( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino) -l-( (N1- (2-thiazolyl) ) sulfonamido) benzene, hydrochloride salt,
2-( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- 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-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole, 2-( ( (4- (4- (carbomethoxy)phenyl)piperazin-1- yl) acetyl) amino) -4- (carboxyethoxymethyl) thiazole,
2- ( ( (4- (3-Chlorophenyl) piperazin-l-yl) acetyl) amino) -4- (carboethoxymethyl) thiazole,
2- ( ( (4- (3-Bromophenyl) piperazin-l-yl) acetyl) amino) -4- (carboethoxymethyl) thiazole, 2-( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -4-thiazole glyoxylate,
2- ( ( (4- (3- (Methyl) phenyl) piperazin-l-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-l- yl) acetyl) amino) -4- (carbobutoxy)methyl) thiazole,
2-( ( (4- (3- (trifluoromethyl) phenyl) iperazin-l- yl) acetyl) amino) -4- (carboisopropoxymethyl) thiazole, 2-( ( (4- (4-Chloro-3- (trifluoromethyl)phenyl) piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole, 2-( (4-( (4-Chlorobenzhydryl) phenyl) piperazin-l- yl) acetyl) amino-4- (carboethoxymethyl) thiazole,
2-( ( (4-(3-Ethylphenyl)piperazin-l-yl) acetyl) amino) -4- (carboethoxymethyl) thiazole, 2-( ( (4- (2-Naphthyl) piperazin-l-yl) acetyl) amino) -4- (carboethoxymethyl) thiazole,
2- ( ( (4- (3-Methoxyphenyl) piperazin-l-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-l-yl) acetyl) amino) - 4- (carboethoxy) thiazole,
2- ( ( (4- (3 ,4-Dichlorophenyl)piperazin-l-yl) acetyl) amino) - 4- (carboethoxymethyl) thiazole, and 2-( ( (4- (3-Methoxy-5- (trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -4- ( (carboethoxy) methyl) thiazole.
13. A compound selected from the group consisting of 2-( ( (4- (3-Trifluoromethyl)phenyl)piperazin-l- yl) acetyl) amino) -5-trifluoro-methyl-1, 3 , 4-thiadiazole,
2- ( ( (4- (2-Fluorophenyl) piperazin-l- 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-l-yl) acetyl) amino) -5- (trifluoromethyl) -1,3, 4-thiadiazole,
2-( ( (4- (2-Pyrimidyl) piperazin-l-yl) acetyl) amino) -5- (trifluoromethyl) -1,3, 4-thiadiazole, 2-( ( (4- (2-Pyridyl)piperazin-l-yl) acetyl) amino) -
1,3, 4-thiadiazole,
2-( ( (4- (3-Chlorophenyl) iperazin-l- yl) acetyl) amino) -5-trifluoremethyl-1, 3 , 4-thiadiazole,
2-( ( (4- (3- (Trifluoromethyl)phenyl) iperazin-1- yl) acetyl) amino) -5-ethyl-l, 3, 4-thiadiazole,
2-( ( (-4- (3- (Trifluoromethyl) phenyl) piperazin-1- yll) acetyl) amino) -1,3,4-thiadiazole, and 2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -5-bromo-l, 3 , 4-thiadiazole .
14. A composition comprising the compound according to claim 10 and a pharmaceutically acceptable carrier.
15. A composition comprising the compound according to claim 11 and a pharmaceutically acceptable carrier.
16. A composition comprising the compound according to claim 12 and a pharmaceutically acceptable carrier.
17. A composition comprising the compound according to claim 13 and a pharmaceutically acceptable carrier.
18. A method for lowering serum glucose levels in a mammal comprising adminisering a composition comprising a compound of the formula (XlVb) having the structure:
Figure imgf000337_0001
wherein:
Ri is selected from the group consisting of hydrogen, R╬╣ΓÇ₧C00R╬╣5, Ci-C8 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkyl, C╬╣-C8 alkoxy, (C3-C8) cycloalkyloxy (Ci-Cg) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Ci-Cg) alkoxy, (Ci- C6) alkoxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl (Ci-Cg) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C6-C╬╣4) aryl, (C6-C14) aryloxy, (C6- C14) aryloxy (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyloxy, (C6- Ci4) aryl (C╬╣-C6) alkyloxy (Ci-C6) alkyl group, halogen, trifluoromethyl, cyano, nitro, amino, carboxy1, (C╬╣-C6) alkoxycarbonyl, carbamoyl, (C╬╣-C8) alkylthio, (C╬╣-C8) alkylsulphinyl, (C╬╣-C8) alkylsulphonyl, sulphoamino, (C╬╣-C8) alkylsulphonylamino, sulphamoyl and (C╬╣-C8) alkylcarbonylamino; said C╬╣~C8 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, C╬╣-C6 alkyl and phenyl; said C6- Ci4 aryl and (C6-C14) aryl (C╬╣-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy, C╬╣-C6 alkyl and phenyl; 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 (C╬╣-C6) alkyl;
R9 is selected from the group consisting of hydrogen, Ci-Cg alkyl, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C╬╣-C6) alkyl group, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (Ci-C6) alkoxy (C╬╣-C6) alkyl, C6-C╬╣4 aryl, C6-C╬╣4 heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣~C6) alkyl, (C6- C14) aryl (Ci-Cg) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (Ci-Cg) aryl, (C6-C╬╣4) aryl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl and (C6-C╬╣4) aryloxy (Ci-Cg) alkyl group;
Rio is selected from the group consisting of hydrogen, C╬╣~C8 alkyl, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C╬╣~C6) alkyl group, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-C14 aryl, C6-C╬╣4 heteroaryl, (C6-C╬╣4) heteroaryl (Ci-Cg) alkyl, (C6- C14) aryl (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (C6-C╬╣4) aryl (C╬╣-C6) alkoxy (Ci~C6) alkyl and (C6-C╬╣4) aryloxy (Ci-Cg) alkyl group;
Ru is selected from the group consisting of hydrogen, C╬╣-C8 alkyl, (Cx-C6) alkoxy (C╬╣-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C╬╣-C6) alkyl group, (C3-C8) cycloalkyloxy (Cj-Cg) alkyl, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, C6-C14 aryl, C6-C╬╣4 heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6- C14) aryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (Ci-Cg) aryl, (C6-C╬╣4) aryl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl and (C6-C╬╣4) aryloxy (Ci-Cg) alkyl group;
R12 is selected from the group consisting of hydrogen and C╬╣-C6 alkyl; Ri3 is selected from the group consisting of
Figure imgf000339_0001
Ri4 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and C╬╣-C6 alkyl; said C╬╣-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkyl and phenyl;
R15 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions and Ci-Cg alkyl; said C╬╣-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl, and C╬╣~C3 alkyl;
R20 is selected from the group consisting of hydrogen, C╬╣-C6 alkyl, hydroxy and Ci-C6 alkoxy; m is 0 or 1; n is 0 or 2 ; o is 0 or 1;
R2╬╣ is a bond or C╬╣-C6 alkyl; said C╬╣-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 C╬╣-C6 alkyl, halogen, Ci-Cg alkoxy and hydroxy;
R22-R3ι are each independently selected from the group consisting of hydrogen, Cι-C8 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cι-C6) alkyl, Cι~C8 alkoxy, (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3-C8) cycloalkyl (Cι-C6) alkoxy (C1-C5) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cι-C6) alkoxy, (Cι-C6) alkoxy (Cι-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C5-Cι4) heteroaryl (Cι-C6) alkyl, (C6-Cι4) aryl (Cx- C6) alkyl, (C6-C14) aryl (Cι-C6) alkyl (C6-C14) aryl, (C6-C14) aryloxy, (C£-C:.) aryloxy (C^Cg) alkyl, (C6-C14) aryl (Ci-Cg) alkyloxy, (C6-C14) aryl (Cι~C6) alkyloxy (Cι-C6) alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxy1, (Cx-C6) alkoxycarbonyl, carbamoyl, (Cι-C8) alkylthio, (Cι~C8) alkylsulphinyl, (Ci-C8) alkylsulphonyl, sulphoamino, (Cι-C8) alkylsulphonylamino, sulphamoyl, (Cι-C8) alkylcarbonylamino, and two of these substituents forming a methylenedioxy group, or R;2 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;
X is nitrogen or CR30; X5 is nitrogen or CR31; wherein at least one of X3, X4, or X5 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 (XlVb) is not: 2-( ( (4- (phenyl) piperazinly-1-) acetyl) amino) -4-
( (carboethoxy)methyl) thiazole:
2-( ( (4- (2-fluorophenyl) piperazin-l-yl) - acetyl) amino) -4- ( (carboethoxy) ethyl) thiazole; or
4-( ( (2-fluorophenyl) amino) acetyl) amino) -l-( (N'-(2- thiazolyl) ) sulfonamido) benzene.
19. The method according to claim 18 wherein: Ri is selected from the group consisting of hydrogen, Ci-C8 alkyl group, halogen, C6-C╬╣4 aryl, (C6-C╬╣4) aryl (Ci-Cg) alkyl, and R╬╣4COOR╬╣5; said C╬╣-C8 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, C╬╣-C6 alkyl and phenyl; said C6-C╬╣4 aryl and (C6-C╬╣4) aryl (C╬╣-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy, Ci-Cg alkyl and phenyl; R8-R╬╣5, R20, m, n, o, and R2i are defined as above for general formula (XlVb) ;
R22 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-Cg) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen or C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C8 alkyl; said carbo (Ci-Cg) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; R23 is selected from the group consisting of hydrogen, halogen, Ci-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, Ci-C8 thioalkyl and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; R24 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl and hydroxy; said Ci-Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; R25 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl and hydroxy; said C╬╣~ C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C!-C3 alkyl; said Ci~C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C8 alkyl; said carbo (Ci-Cg) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl;
R26 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C5 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci~C8 alkyl; said carbo (Cj-Cg) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C!-C3 alkyl; or two of R22-R26 when taken together can form a methylenedioxy group; R27 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl and hydroxy; said Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said Cx-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cj-Cg thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (Ci-Cg) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl;
R28 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, Cx-C5 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents ╬╡elected from the group consisting of halogen and C╬╣~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 CR3X; wherein at least one of X3, X4, or X5 is nitrogen;
R29 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl, wherein the numbered halogen atoms can be 0-2 ; said Cx-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Cx-C3 alkyl; said Ci- Cg thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl;
R30 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, trifluoromethyl, C╬╣-C6 alkyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C^Cg thioalkyl and hydroxy; said Cj-Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C!-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-Cg alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; R3╬╣ is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣~C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C╬╣~C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬▒-C3 alkyl, wherein the numbered halogen atoms can be 0-2; said C╬╣~C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C╬╣-C3 alkyl; said Cx- C8 thioalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-Cg alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and Ci-C3 alkyl; or R28 and CR30 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 (XlVb) 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) amino) acetyl) amino) -1- ( (N'- (2- thiazolyl) ) sulfonamidobenzene.
20. The method according to claim 18 wherein the comound is selected from the group consisting of
2-( ( (4- (Phenyl) piperazin-l-yl) acetyl) amino) -4- (carboxymethyl) thiazole,
2-( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-1- yl) acetyl) amino) -4- (carboxymethyl) thiazole,
2-( ( (4- (2-Fluorophenyl)piperazin-l-yl) acetyl) amino) -4- (carboxymethyl) thiazole,
2-( ( (4- (3- (Trifluoromethyl)phenyl)piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole, 4- ( ( (4- (3- (Trifluoromethyl)phenyl)piperazin-l- yl) acetyl) amino) -l-( (N1- (2-thiazolyl) ) sulfonamido) benzene,
2- ( ( (4- (5- (Trifluoromethyl)pyrid-2-yl)piperazin-l- 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) henyl) piperazin-l- yl) acetyl) amino) -4-(carboxymethyl) thiazole, potassium salt, 4- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- 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-l- 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-l- yl) acetyl) amino) -4- (carboxyethoxymethyl) thiazole,
2-( ( (4- (3-Chlorophenyl)piperazin-l-yl) acetyl) amino) -4- (carboethoxymethy1) thiazole, 2-( ( (4- (3-Bromophenyl) piperazin-l-yl) acetyl) amino) -4- (carboethoxymethyl) thiazole,
2-( ( (4- (3- (Trifluoromethyl)phenyl)piperazin-l- yl) acetyl) amino) -4-thiazole glyoxylate,
2- ( ( (4- (3- (Methyl) phenyl)piperazin-l-yl) acetyl) amino) -4- carboethoxy)methyl) thiazole,
2-( ( (4- (3- (trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -4- (carbopropoxymethyl) thiazole,
2-( ( (4- (3- (trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -4- (carbobutoxy)methyl) thiazole, 2-( ( (4- (3- (trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -4- (carboisopropoxymethyl) thiazole,
2-( ( (4- (4-Chloro-3- (trifluoromethyl)phenyl)piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole,
2-( (4-( (4-Chlorobenzhydryl) phenyl) piperazin-1- yl) acetyl) amino-4- (carboethoxymethyl) thiazole,
2-( ( (4- (3-Ethylphenyl)piperazin-l-yl) acetyl) amino) -4- (carboethoxymethyl) thiazole,
2- ( ( (4- (2-Naphthy1) piperazin-l-yl) acetyl) amino) -4- (carboethoxymethyl) thiazole, 2-( ( (4- (3-Methoxyphenyl) iperazin-l-yl) acetyl) amino) -4- (carboethoxymethyl) thiazole, 2- ( ( (4- (3 ,5-Bis- (trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -4- (carboethoxymethyl) thiazole,
2- ( ( (4- (3 , 5-Dichlorophenyl) piperazin-l-yl) acetyl) amino) - 4- (carboethoxy) thiazole, 2-( ( (4- (3, 4-Dichlorophenyl) piperazin-l-yl) acetyl) mino) - 4- (carboethoxymethyl) thiazole, and
2-( ( (4- (3-Methoxy-5- (trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -4- ( (carboethoxy) methyl) thiazole.
21. A compound of the general formula (XVa):
Figure imgf000347_0001
wherein:
Ri is selected from the group consisting of R╬╣4COOR╬╣5, C6-C╬╣4 aryl, (C6-C14) aryl (Ci-Cg) alkyl, C3-C6 cycloalkyl, thio (C6-C╬╣4) aryl, thio (C6-C╬╣4) heteroaryl, (C3- C8) cycloalkyl (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy, (Cg-CX4) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C6-C14) aryl, (C6-C╬╣4) aryloxy, (C6-C14) aryloxy (Ci-Cg) alkyl, and (C6- Ci4) aryl (C╬╣-C6) alkyloxy (C╬╣-C6) alkyl group; said C6-C╬╣4 aryl and C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, cx-c6 alkoxy, Cx- C6 alkyl, trihalo (C╬╣-C6) alkyl, and trihalo (C╬╣~C6) alkoxy; R8 , R9, Rio, u, R12, R╬╣3, R1 , Ri5, R2o. m ┬░. and R2i are as defined above for general formula (XVa) ;
R22 is selected from the group consisting of hydrogen, halogen C╬╣-C8 alkoxy, Ci-Cg alkyl, trifluoromethyl, nitro, cyano, carboxy, C╬╣-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-C8) cycloalkyloxy (Cj-Cg) alkyl, C3-C6 cycloalkyl (Cj-Cg) alkoxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl (C6-C14) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (C6-C14) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy, trifluoromethoxy, amino, (C╬╣-C6) alkoxycarbonyl, carbamoyl, (Ci-Cg) alkylthio, (C╬╣-C6) alkylsulphinyl, (C╬╣-C6) alkylsulphonyl, sulphoamino, (C╬╣-C6) alkylsulphonylamino, sulphamoyl and (C╬╣~C6) alkylcarbonylamino; said C╬╣-C8 alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said Ci-Cg alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; R23 is selected from the group consisting of hydrogen, fluorine, bromine, Ci-C8 alkoxy, C2-C8 alkyl, trifluoromethyl, nitro, cyano, carbo C╬╣-C6 alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, hydroxy, C3-CB cycloalkyl, (C3-C8) cycloalkyl (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C6) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (C╬╣-C6) alkoxy, (C2-C6) alkoxy (C3-C6) alkyl, (C6-C14) aryl, (C6-C╬╣4) heteroaryl, (C5-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C6-C14) aryl, (C6-C╬╣4) aryloxy, (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyloxy, (C6-C14) aryl (Cj-Cg) alkyl, trifluoromethoxy, amino, (C╬╣-C6) alkoxycarbonyl, carbamoyl, (Ci-Cg) alkylthio, (Ci~C6) alkylsulphinyl, (C╬╣-C6) alkylsulphonyl, sulphoamino, (C╬╣-C6) alkylsulphonylamino, sulphamoyl and (C╬╣-C6) alkylcarbonylamino; said C2-C8 alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C8 alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or C:-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl;
R24 is selected from the group consisting of hydrogen, halogen, C╬╣-C8 alkoxy, C╬╣~C8 alkyl, trifluoromethyl, nitro, cyano, carbo C╬╣-C6 alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-C6) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C6) cycloalkyl (Ci-C5) alkoxy (Ci-Cg) alkyl (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (C╬╣-C5) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (Ci- C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C6-C╬╣4) aryl, (C6-C14) aryloxy, (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyloxy (C6-C╬╣4) aryl (C╬╣-C6) alkyl, trifluoromethoxy, amino, (C╬╣-C6) alkoxycarbonyl, carbamoyl, (C╬╣~c8) alkylthio, (C╬╣-C8) alkylsulphinyl, (C╬╣~C8) alkylsulphonyl, sulphoamino, (C╬╣~C8) alkylsulphonylamino, sulphamoyl and (C╬╣~C8) alkylcarbonylamino; said C╬╣~C8 alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R25 is selected from the group consisting of hydrogen, fluorine, bromine, Cx-C8 alkoxy, trifluoromethyl, C2-C8 alkyl, nitro, cyano, carbo C╬╣~C6 alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C6) cycloalkyl (C3-C6) cycloalkyloxy (C3-C6) alkyl, (C3-C6) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (Ci-Cg) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-C14) aryl, (C6- Ci4) heteroaryl, (C6-C14) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C3-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C6-c14) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (C╬▒-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyloxy, (C6-C╬╣ΓÇ₧) aryl (Cx-C6) alkyl, trifluoromethoxy, cyano, amino, (Cx-C6) alkoxycarbonyl, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said C2-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said C╬╣-C8 alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl;
R26 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo C╬╣-C6 alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C6) cycloalkyl (C3-C6) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C6) cycloalkyl (C╬╣-C6) alkoxy (Ci-Cg) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (C╬╣-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-C╬╣4) aryl, (C6-C╬╣4) heteroaryl, (C6-C14) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C3- C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C6-C╬╣4) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy, (C6-C╬╣4) aryl (C╬╣-C6) alkyl, trifluoromethoxy, cyano, amino, (C╬╣-C6) alkoxycarbonyl, carbamoyl, (Cx-C8) alkylthio, (C╬╣-C8) alkylsulphinyl, (C╬╣-C8) alkylsulphonyl, sulphoamino, (C╬╣-C8) alkylsulphonylamino, sulphamoyl and (C╬╣~C8) alkylcarbonylamino; said C╬╣-C6 alkyl being optionally substituted with halogen for C╬╣-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl, said C╬╣-C8 thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; or two of R22-R26 can form a methylenedioxy group; R27-R3X are each independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, halogen, Cx-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-C6 alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C6) cycloalkyl (C3-C6) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C6) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (C╬╣~c6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-C14) aryl, (C6-C╬╣4) heteroaryl, (C6-C14) heteroaryl (C╬╣-C6) alkyl, (C6-C14) aryl (C3-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C6-C14) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (Ci-C6) alkyloxy, (C6-C14) aryl (C╬╣-C6) alkyl, trifluoromethoxy, cyano, amino (C╬╣-C6) alkoxycarbonyl, carbamoyl, (C╬╣~C8) alkylthio, (C╬╣-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said Cx-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-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 Xx and X2 is nitrogen, with the other being carbon;
X3 is nitrogen or CR29;
X4 is nitrogen or CR30;
X5 is nitrogen or CR3X; wherein at least one of X3, X4, or X5 is nitrogen; or R23 and CR30 when taken together form an aryl ring; or R28 and CR29 when taken together form an aryl ring; or two of R27-R3X 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-( ( ( - (3-trifluoromethyl)phenyl) iperazinyl-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-l) - acetyl) amino-5- (2- (carboxyethyl) -1,3, 4-thiadiazole.
22. The compound according to claim 21 wherein Rx is selected from the group consisting of RX4COORi5, C6-C14 aryl, (C6-Cx4) aryl Cx-C6 alkyl, C3-C6 cycloalkyl, thio (C6-CX4) aryl (e.g., thiophenyl, thionaphthyl) , thio (C6-C14) heteroaryl {e .g. , thiopyridyl, thioquinolinyl, and thiopyrazinyl) ; said C6-CX4 aryl and (C6- c╬╣.) aryl Cx-C╬╡ alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amine, hydroxy, Cx-C5 alkoxy, Cx-C6 alkyl, trihalo Ci- Cg alkyl, trihalo Cx-C6 alkoxy, and phenyl; said thio (C6-C14) aryl being optionally substituted with halogen, amine Cx-C6 alkoxy, hydroxy, Cx-C6 alkyl, trihalo (Cx-C6) alkoxy, or trihalo (Cx-C6) alkyl; said thio (C6-CX4) heteroaryl being optionally substituted with halogen, amine, Cx-C6 alkoxy, hydroxy, Cx-C6 alkyl trihalo (Ci-C6) alkoxy, or trihalo (C╬╣-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 (C╬╣-C6) alkyl;
R9 is a group selected from the group consisting of hydrogen, Cx-Ce alkyl, (Cι-C6) alkoxy (Cι-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-C8) cycloalkyloxy (Cι-C6) alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Cι-C6) alkyl, C6-Cι4 aryl, C6-Cι4 heteroaryl, (C£-Cι4) heteroaryl (Cι-C6) alkyl, (C6-Cι4) aryl (Cx- C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (Cx-C6) aryl, (C6-CX4) aryl (Cx-C6) alkoxy (Cx-C6) alkyl, and (C6-CX4) aryloxy (Cx-C6) alkyl group;
Rxo is selected from the group consisting of hydrogen, Cx-C6 alkyl, (Cx-C6) alkoxy (Cx-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Ci-Cg) alkyl, C6-C╬╣4 aryl, C6-C14 heteroaryl, (Ce-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (Cx- C6) alkyl, (C6-C╬╣4) aryl (Cx-C6) alkyl (C╬╣-C6) aryl, (C6-C╬╣4) aryl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, and (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl group;
Ru is selected from the group consisting of hydrogen, Cx-C8 alkyl, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, C6-CX4 aryl, C6-CX4 heteroaryl, (C6-CX4) heteroaryl (C╬╣-C6) alkyl, (C6-CX4) aryl (Ci- Cg) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (Cx-C6) aryl, (C6-C╬╣4) aryl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, and (C6-CX4) aryloxy (Cx-C6) alkyl group;
Rx2 is selected from the group consisting of hydrogen and Cx-C6 alkyl;
RX3 is selected from the group consisting of
Figure imgf000353_0001
RX4 is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cx-C2 alkyl group; said Cx-C2 alkyl being substituted with one or more halogen, Cx-C6 alkyl or phenyl groups;
RX5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and Cx - C6 alkyl group; said Cx-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and Cx-C3 alkyl;
R20 is selected from the group consisting of hydrogen, Cx-C6 alkyl, hydroxy and Cx-C6 alkoxy; m is 0 or 1; n is 1; o is 0 or 1;
R2X is a bond or Cx-C6 alkyl; said Cx-C6 alkyl being optionally substituted from the group consisting of benzene and an optionally substituted benzene ring; said benzene ring optionally substitued from the group consisting of Cx-C6 alkyl, halogen, Cx-C6 alkoxy and hydroxy;
R22 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or C╬╗-C3 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R23 is selected from the group consisting of hydrogen, fluorine, bromine, Cx-C6 alkoxy, C2-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, C╬╗-C thioalkyl, and hydroxy; said C2-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R24 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R25 is selected from the group consisting of hydrogen, fluorine, bromine, Cx-C6 alkoxy, C2-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said C2-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (Ci-Cg) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; R26 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, Ci-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cj-Cg thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; or two of R22-R26 when taken together can form a methylenedioxy group;
R27 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣~C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R28 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Ci-Cg) alkoxy being optionally substituted with halogen or Cx-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 Xx and X2 is nitrogen, with the other being carbon;
X3 is nitrogen or CR29
X4 is nitrogen or CR30
X5 is nitrogen or CR3X wherein at least one of X3, X4, or X5 is nitrogen; R29 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with one to two halogen atoms or C!-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R30 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R3X is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with one to two halogen atoms or Ci-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-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 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) -5- ( (ethoxycarbonyl) -methyl) -l, 3,4-thiadiazole; 2- ( ( (4- (2-pyridyl)piperazinyl-l) -acetyl) amino) -5- ( (carbomethoxy)methyl) -1,3, 4-thiadiazole; or
2- ( ( (4-(3-(trifluoromethyl)phenyl)piperazinyl-l) - acetyl) amino) -5- (2- (carboxy) ethyl) -1,3 ,4-thiadiazole.
23. The compound acording to claim 21 selected from the group consisting of
2-( ( (4- (3- (Trifluoromethyl)phenyl)piperazin-l- yl) acetyl) amino) -5- ( (7-chloroquinolin-4-yl) thio) -1,3,4- thiadiazole,
2-( ( (-4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -5-cyclopropyl-l, 3 , 4-thiadiazole,
2-( ( (4- (3- (Trifluoromethyl) phenyl)piperazin-l- yl) acetyl) amino) -5-( (carbomethoxy)methyl) -1, 3,4-thiadiazole, 2-( ( (4- (4-Methoxyphenyl)piperazin-l-yl) acetyl) amino) -5- carbomethoxymethyl-1, 3,4-thiadiazole,
2- ( ( (-4- (3- (Trifluoromethyl)phenyl) piperazin-l- yl) acetyl) amino) -5- (2- (carbomethoxy) ethyl) -1,3, 4-thiadiazole, 2-( ( (4- (4-Methoxyphenyl) iperazin-l-yl) acetyl) amino) -5- (2- (carbomethoxy) ethyl) -1, 3, 4-thiadiazole, and
2- ( ( (4- (2-Pyridyl)piperazin-l-yl) acetyl) amino) -5- (2- (carbomethoxy) ethyl) -1, 3 , -thiadiazole.
24. A composition comprising the compound according to claim 21 and a pharmaceutically acceptable carrier.
25. A composition comprising the compound according to claim 22 and a pharmaceutically acceptable carrier.
26. A composition comprising the compound according to claim 23 and a pharmaceutically acceptable carrier.
27. A method for lowering of serum glucose levels in a mammal comprising administering a compound of the formula (XVb) having the structure:
Figure imgf000358_0001
wherein: i is selected from the group consisting of hydrogen, halogen, RX4COOR15, R16ORX7, RX8NHR19, (C6-CX4) aryl, (C6- C14) aryl C╬╣-C6 alkyl, C3-C6 cycloalkyl, thio (C6-C╬╣4) aryl, thio (Cg-C14) heteroaryl Cx-C8 alkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, Cx-C8 alkoxy, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Ci-Cg) alkoxy, (C╬╣-C6) alkoxy (Ci-C6) alkyl, (C6-C╬╣4) heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C14) aryl (C.-C,) alkyl (C6-C╬╣4)aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyloxy, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy (Cj-Cg) alkyl, trihalo (C╬╣-C6) alkyl, trihalo (C╬╣~C6) alkoxy, cyano, nitro, carbamoyl, (Ci-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (C╬╣~C8) alkylsulphonylamino, sulphamoyl and (Cx- C8) alkylcarbonylamino; said C╬╣-C8 alkyl group being optionally substituted with one or more halogen, C╬╣-C6 alkyl or phenyl groups; said thiophenyl being optionally substituted with halogen, amino C╬╣-C6 alkoxy, hydroxy, Cx-C6 alkyl, trihalo (C:-C6) alkoxy or trihalo (C╬╣~C6) alkyl; said thio (C6-C╬╣4) heteroaryl being optionally substituted with halogen, amino, alkoxy, hydroxy, Ci~C6 alkyl, trihalo (C╬╣-C6) alkyl or trihalo (Cx-C6) alkoxy; said C6-C╬╣4 aryl and (C6-C╬╣4) aryl (C╬╣-C6) alkyl being optionally substituted with one or more substitutes selected from the group consisting of halogen, amino, hydroxy, C╬╣-C6 alkoxy, C╬╣~C6 alkyl, trihalo C╬╣~ C6 alkyl and trihalo C╬╣-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 C╬╣-C6 alkyl;
R9 is a group selected from the group consisting of hydrogen, C╬╣-C8 alkyl, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3- C8) cycloalkyl (C╬╣-C6) alkoxy (Ci-C6) alkyl, C6-C╬╣4 aryl, C6-C╬╣4 heteroaryl, (C6-C╬╣4) heteroaryl (Ci-C6) alkyl, (C6-C╬╣4) aryl (Ci- C6) alkyl, (C6-C╬╣4) aryl (C:-C6) alkyl (C╬╣-C6) aryl, (C6-C14) aryl (C╬╣-C6) alkoxy (Cj-Cg) alkyl, and (C6-C14) aryloxy (C╬╣-C6) alkyl group;
Rio is selected from the group consisting of hydrogen, C╬╣-C8 alkyl, (C╬╣~C6) alkoxy (C:-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3- C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-C╬╣4 aryl, C6-C╬╣4 heteroaryl, (C6-C14) heteroaryl (C╬╣-C6) alkyl, (C6-C14) aryl (Ci- C6) alkyl, (C6-C╬╣4) aryl (Cj-Cg) alkyl (C╬╣-C6) aryl, (C6-C14) aryl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, and (C6-C14) aryloxy (C╬╣-C6) alkyl group;
Ru is selected from the group consisting of hydrogen, Cj-Cg alkyl, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3- C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-C╬╣4 aryl, C6-C╬╣4 heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣~ C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (C6-C14) aryl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, and (C6-C14) aryloxy (C╬╣-C6) alkyl group;
Ri2 is selected from the group consisting of hydrogen and C╬╣-C6 alkyl;
Ri3 is selected from the group consisting of
Figure imgf000360_0001
Ri4 is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and C^C, alkyl group; said C╬╣-C2 alkyl group being substituted with one or more hydrogen, halogen, C╬╣-C6 alkyl or phenyl groups;
R15 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and C╬╣~ C6 alkyl group; said C╬╣-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and C╬╣~C3 alkyl; 16 is a bond or is selected from the group consisting of sulfonyl, Cj-C8 thioalkyl, aminosulfonyl and Cx- C6 alkyl; said C╬╣~C6 alkyl group being substituted with one or more hydrogen, halogen, C╬╣-C6 alkyl or phenyl groups;
R╬╣7 is selected from the group consisting of phenyl, phenyl C╬╣-C6 alkyl, trifluoromethyl and C╬╣-C6 alkyl; said C╬╣-C6 alkyl being optionally substituted with one or more groups selected from the group consisting of halogen, phenyl, phenyl C╬╣-C6 alkyl, and C╬╣~C3 alkyl; said phenyl and phenyl C╬╣-C6 alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, amino, and Ci-C6 alkyl;
R18 is a bond or is selected from the group consisting of sulfonyl, thio C╬╣-C6 alkyl, aminosulfonyl, carbonyl, aminocarbonyl and C╬╣-C6 alkyl; said C╬╣-C6 alkyl being substituted with one or more hydrogen, halogen, C^Cg alkyl or phenyl groups;
Ri9 is selected from the group consisting of hydrogen, phenyl, phenyl C╬╣~C6 alkyl, and C╬╣-C6 alkyl; said C╬╣~ C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of phenyl and C╬╣-C3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C╬╣-C6 alkoxy, hydroxy, amino, and C╬╣-C6 alkyl; said phenyl C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C╬╣-C6 alkoxy, hydroxy, amino, and C╬╣-C6 alkyl;
R20 is a group selected from the group consisting of hydrogen, C╬╣-C6 alkyl, hydroxy and C╬╣-C6 alkoxy; m is 0 or 1; n is 1; o is 0 or 1;
R2╬╣ is a bond or C╬╣-C6 alkyl; said C╬╣-C6 alkyl being optionally substituted from the group consisting of benzene and an optionally substituted benzene ring; said benzene ring optionally substitued from the group consisting of Cx-C6 alkyl, halogen, Cx-C6 alkoxy and hydroxy;
R22 is selected from the group consisting of hydrogen, halogen, Cx-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carboxy, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-C6) cycloalkyloxy (Cx-C6) alkyl, (C3-C6) cycloalkyl (C╬╣-C6) alkoxy (Cx-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl Cx-C6 alkoxy, (C3-C6) alkoxy C3-C6 alkyl, (C6-CX4) aryl, (C6-C╬╣4) heteroaryl, (C6-C╬╣4) heteroaryl (Ci-Cg) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C6-C╬╣4) aryl, (C6-C╬╣4) aryloxy, (C6-C╬╣4) aryl (Ci-Cg) alkyl, trifluoromethoxy, amino, (C╬╣-C6) alkoxycarbonyl, carbamoyl, (C╬╣-C8) alkylthio, (C╬╣~C8) alkylsulphinyl, (CX-C8) alkylsulphonyl, sulphoamino, (C╬╣-C8) alkylsulphonylamino, sulphamoyl and (C╬╣-C8) alkylcarbonylamino; said C╬╣-C8 alkyl being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣-C8 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C^Cg thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; R23 is selected from the group consisting of hydrogen, fluorine, bromine, C╬╣-C8 alkoxy, C2-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cj-Cg alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl (C3-C8) cycloalkyloxy (Ci-Cg) alkyl, (C3-C6) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (Ci-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-C╬╣4) aryl, (C6-C╬╣4) heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl, (C6-C14) aryl (Ci-Cg) alkyl (C6-C14) aryl, (C6-c14) aryloxy, (C6-C14) aryloxy (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyloxy, (C6-C14) aryl (C╬╣-C6) alkyl, trifluoromethoxy, amino, (C╬╣-C5) alkoxycarbonyl, carbamoyl, (C╬╣-C8) alkylthio, (C╬╣-C8) alkylsulphinyl, (C╬╣-C8) , alkylsulphonyl, sulphoamino, (C╬╣~C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said C2-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl;
R24 is selected from the group consisting of hydrogen, halogen, Cx-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carboxy, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-C6) cycloalkyloxy (Cx-C6) alkyl, (C3-C6) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl Cx-C6 alkoxy, (C3-C6) alkoxy C3-C6 alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-C14) aryloxy, (C6-C14) aryl (Cι-C6) alkyl, trifluoromethoxy, amino, (Cι-C6) alkoxycarbonyl, carbamoyl, (Cι~C8) alkylthio, (Cι~C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cι-C8) alkylsulphonylamino, sulphamoyl and (Cι~C8) alkylcarbonylamino; said Cι-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Ci-Cg alkoxy being optionally substituted with halogen or Gτ-C3 alkyl; said Cι~C8 thioalkyl being optionally substituted with halogen or Ci-C8 alkyl; said carbo (Cι-C6) alkoxy being optionally substituted with halogen or Cι-C3 alkyl;
R25 is selected from the group consisting of hydrogen, fluorine, bromine, C╬╣-c8 alkoxy, C2-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-Cg alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C6) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (Cx-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-CX4) aryl, (C6-C14) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl (C6-C14) aryl, (C6-C14) aryloxy, (C6-C╬╣4) aryloxy (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyloxy, (C6-CX4) aryl (Cx-C5) alkyl, trifluoromethoxy, amino, (Cx-C6) alkoxycarbonyl, carbamoyl, (Ci-C,,) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) , alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said C2-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R26 is selected from the group consisting of hydrogen, halogen, Cx-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carboxy, C╬╣~C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-C6) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C6) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl C╬╣-C6 alkoxy, (C3-C5) alkoxy C3-C6 alkyl, (C6-CX4) aryl, (C6-C14) heteroaryl, (C6-C╬╣4) heteroaryl (Cx-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C6-C╬╣4) aryl, (C6-C╬╣4) aryloxy, (C6-C14) aryl (Ci-Cg) alkyl, trifluoromethoxy, amino, (C╬╣-C6) alkoxycarbonyl, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (C╬╣-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said Cx-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; or two of R22-R26 when taken together can form a methylenedioxy;
R27-R3X are each independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, hydrogen, halogen, Cx-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-C6 alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C3-C6) cycloalkyloxy (C╬╣-C6) alkyl, (Ci-Cg) cycloalkyl (C╬╣-C6) alkoxy (Ci-Cg) alkyl, (C3-C6) cycloalkyloxy, (C3-C6) cycloalkyl (C╬╣-C6) alkoxy, (C3-C6) alkoxy (C3-C6) alkyl, (C6-C╬╣4) aryl, (C6-C╬╣4) heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (cx- C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C6-C14) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyloxy, (C6-C14) aryl (C╬╣-C6) alkyl, trifluoromethoxy, cyano, amino, (C╬╣-C6) alkoxycarbonyl, carbamoyl, (C╬╣-C8) alkylthio, (C╬╣-C8) alkylsulphinyl, (C╬╣-C8) alkylsulphonyl, sulphoamino, (C╬╣-C8) alkylsulphonylamino, sulphamoyl and (C╬╣-C6) alkylcarbonylamino; said C╬╣~C8 alkyl being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣-C8 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-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 Xi and X2 is nitrogen, with the other being carbon;
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 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-R3╬╣ 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)-i,3,4-thiadiazole; or 2-( ( (4- (3- (trifluoromethyl) henyl) piperazinyl-1) - acetyl) amino-5- (2- (carboxyethyl) -1,3, 4-thiadiazole.
28. The method acording to claim 27 wherein Ri is selected from the group consisting of hydrogen, halogen, R╬╣4COOR╬╣5, ╬╣6OR╬╣7, R╬╣8NHR╬╣9, C6-C╬╣4 aryl, (C6- Ci4) aryl (C6-C╬╣4) alkyl, C3-C6 cycloalkyl, trifluoromethyl, thio (C6-C╬╣4) aryl, (e.g., thiophenyl, thionaphthyl) , thio (C6- CX4) heteroaryl (e.g., thio pyridyl, thioquinolinyl, thiopyrazinyl) and (C╬╣-C8) alkyl; said (C5-C╬╣4) aryl and (C6- CX4) aryl C╬╣-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trihalo Cx- C6 alkyl and trihalo C╬╣-C6 alkoxy; said C:-C8 alkyl group being optionally substituted with one or more halogen, C╬╣-C5 alkyl or phenyl groups; said thio (C6-C╬╣ΓÇ₧) aryl being optionally substituted with halogen, amino, C╬╣-C6 alkoxy, hydroxy, C╬╣-C6 alkyl, trihalo C╬╣-C6 alkoxy, or trihalo Cx-C6 alkyl; said thio Ci-Cg heteroaryl being optionally substituted with halogen, C╬╣-C6 alkoxy, hydroxy, C╬╣-C6 alkyl, trihalo C╬╣-C6 alkyl, or trihalo C╬╣-C6 alkoxy;
R8~R 2╬╣. m n and o are as defined above for formula (XVb) ;
R22 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-Cg) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R23 is selected from the group consisting of hydrogen fluorine, bromine, Ci-Cg alkoxy, C2-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cj-Cg) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said C2-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; R24 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with halogen or C╬╣~C8 alkyl; said carbo (C^Cg) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R25 is selected from the group consisting of hydrogen, fluorine, bromine, Cx-C6 alkoxy, trifluoromethyl, C2-C6 alkyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said C2-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with halogen or C^Cg alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl;
R26 is selected from the group consisting of hydrogen, halogen, C^Cg alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (C╬╣~C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; or two of R22-R26 when taken together can form a methylenedioxy group;
R27 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl;
R28 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, and hydroxy; said C╬╣~C6 alkyl being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (C╬╣-C5) alkoxy being optionally substituted with halogen or C╬╣-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 Xi and X2 is nitrogen, with the other being carbon;
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; R29 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C5) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or C╬╣~c3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; R30 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl;
R3╬╣ is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C5 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said C!-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-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) piperaziny1-1) - 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) iperazinyl -1) - acetyl) amino) -5- (2- (carboxy) ethyl) -1,3, 4 -thiadiazole .
29. The method according to claim 27 wherein the compound is selected from the group consisting of
2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- 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-l , 3 , 4 -thiadiazole,
2- ( ( (4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -5- ( (carbomethoxy) methyl) -1, 3 , 4-thiadiazole, 2- ( ( (4- (4 -Methoxyphenyl) piperazin-l-yl) acetyl) amino) -5- carbomethoxymethyl -1,3,4 -thiadiazole , 2- ( ( (-4- (3- (Trifluoromethyl) phenyl) piperazin-l- yl) acetyl) amino) -5- (2- (carbomethoxy) ethyl) -1,3, 4-thiadiazole, 2- ( ( (4- (4 -Methoxyphenyl) piperazin-l-yl) acetyl) amino) -5- (2- (carbomethoxy) ethyl) -1,3, 4-thiadiazole, and
2- ( ( (4- (2-Pyridyl)piperazin-l-yl) acetyl) amino) -5- (2- (carbomethoxy) ethyl ) -1,3,4-thiadiazole .
30. A compound of general formula (XVIa) :
Figure imgf000369_0001
wherein:
Rx is selected from the group consisting of hydrogen and R14COORX5;
R2 is selected from the group consisting of hydrogen, halogen, RX6ORX7, RX8NHRX9, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, Cx-C8 alkoxy, (C3-C8) cycloalkyloxy (Ci-Cg) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-C6) alkoxy, (Cx- C6) alkoxy (Cx-C6) alkyl, (C6-CX4) aryl, (C6-CX4) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (C6-C14) aryl, (-C6-CX4) aryloxy, (C6- CX4) aryloxy (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyloxy, (C6- CX4) aryl (Cx-C6) alkyloxy (Cx-C6) alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, (Cx-C8) thioalkyl, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (C2-C8) alkylsulphonylamino, and sulphamoyl; said Cx-C8 alkyl group being optionally substituted with one or more halogen, Cx-C6 alkyl or phenyl groups; said C6-CX4 aryl and (C6-CX4) aryl (Cx-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cx-C6 alkoxy, Cx-C6 alkyl, trihalo (Cx-C6) alkyl, and trihalo (Cx-C6) alkoxy;
R3 is selected from the group consisting of hydrogen, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C6-CX4) aryl, (C6-C14) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl, halogen, trifluoromethyl, and cyano; said Cx-C8 alkyl being optionally substituted with one or more halogen, Cx-C6 alkyl or phenyl groups; said C6-CX4 aryl and (C6-CX4) aryl (Cx-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cx-C5 alkoxy, Cx- C6 alkyl, trihalo (Cx-C6) alkyl, and trihalo (Cx-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 phenylalkyl;
R9 is a group selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cx-C6) alkoxy (Cx-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, C6-C14 aryl, C6-C14 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-C14) aryl (Cx- C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl (Cx-C6) aryl, (C6-CX4) aryl (Cx-C6) alkoxy (Cx-C6) alkyl, and (C6-cX4) aryloxy (Cx-C6) alkyl group; Rx0 is selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cx-C6) alkoxy (Cx-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, C6-C14 aryl, C6-CX4 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Ci- Cg) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (C6-C╬╣4) aryl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, and (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl group; Rn is selected from the group consisting of hydrogen, C╬╣-C8 alkyl, (Cx-C6) alkoxy (C╬╣-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3- C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-CX4 aryl, C6-CX4 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Ci- Cg) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C╬╣-C5) aryl, (C6-C╬╣4) aryl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, and (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl group;
RX2 is selected from the group consisting of hydrogen and Cx-C6 alkyl;
RX3 is selected from the group consisting of
Figure imgf000371_0001
RX4 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cx-C6 alkyl group; said Cx-C6 alkyl group being substituted with one or more hydrogen, halogen, Cx-C6 alkyl or phenyl groups;
RX5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, divalent alkali metals, divalent alkali earth metals, and a Cx -C6 alkyl group; said Cx-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and Cx-C3 alkyl; R5 is a bond or is selected from the group consisting of sulfonyl, C2-C6 thioalkyl, aminosulfonyl and Ci- Cg alkyl; said Cx-C6 alkyl being substituted with one or more hydrogen, halogen, Cx-C6 alkyl or phenyl groups;
R17 is selected from the group consisting of phenyl, phenylalkyl, and a C╬╣-C6 alkyl group; said C╬╣-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of halogen, phenyl, phenylalkyl, and C╬╣-C3 alkyl; said phenyl and phenylalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C╬╣-C6 alkoxy, amino, and Cx-C6 alkyl;
RX8 is a bond or is selected from the group consisting of sulfonyl, C2-C6 thioalkyl, aminosulfonyl, carbonyl, aminocarbonyl and Cx-C6 alkyl group, said Cx-C6 alkyl group being substituted with one or more hydrogen, halogen, Cx-C6 alkyl or phenyl groups;
Rx9 is selected from the group consisting of hydrogen, phenyl, phenyl (Cx-C6) alkyl, and Cx-C6 alkyl; said Ci- Cg 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 C╬╣-C6 alkyl; said phenyl Ci-Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino, or C╬╣-C6 alkyl;
R20 is selected from the group consisting of hydrogen, Ci-Cg alkyl, hydroxy and C╬╣-C6 alkoxy; m is 0 or 1; o is 0 or 1;
R2╬╣ is a bond or is selected from the group consisting C╬╣-C6 alkyl; said C╬╣-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 C╬╣-C6 alkyl, halogen, C╬╣~C6 alkoxy and hydroxy; R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C8 alkoxy, Ci~C8 alkyl, trifluoromethyl, nitro, cyano, carbo Ci-C6 alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, hydroxy, C╬╣-C6 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Ci-Cg) alkoxy, (C╬╣-C6) alkoxy (Ci-Cg) alkyl, (C6-C14) aryl, (C6-c14) heteroaryl, (C6-C14) heteroaryl (C╬╣-C6) alkyl, (C6-C14) aryl (Ci-Cg) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C6-C╬╣4) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy (C╬╣-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (C╬╣-C8) alkylthio, (Ci-C8) alkylsulphinyl, (C╬╣-C8) alkylsulphonyl, sulphoamino, (Ci-C8) alkylsulphonylamino, sulphamoyl and (C╬╣~C8) alkylcarbonylamino; said C╬╣~C8 alkyl being optionally substituted with halogen or C1-C3 alkyl; said C2-C8 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; R23 is selected from the group consisting of hydrogen, halogen, C╬╣~C8 alkoxy, C╬╣-C8 alkyl, trifluoromethyl, nitro, cyano, carbo C╬╣-C6 alkoxy, carboxy, C╬╣~C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Ci-Cg) alkoxy, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl, (C6- CX4) heteroaryl, (C6-C14) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (Ci-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C6-C14) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy, (C6-C╬╣4) aryl (C╬╣-C5) alkyloxy (Cj-Cg) alkyl, trifluoromethoxy, amino, carbamoyl, (C╬╣~C8) alkylthio, (C╬╣-C8) alkylsulphinyl, (C╬╣-C8) alkylsulphonyl, sulphoamino, (C╬╣-C8) alkylsulphonylamino, sulphamoyl and (C2-C8) alkylcarbonylamino; said C╬╣~C8 alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said Ci-C8 alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or C╬╣~C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl;
R24 is selected from the group consisting of hydrogen, bromine, chlorine, C╬╣-C8 alkoxy, C╬╣~C8 alkyl, trifluoromethyl, nitro, cyano, carbo C╬╣~C6 alkoxy, carboxy, Ci-Cg thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Ci-Cg) alkyl, (C3-C╬▓) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C6-C14) aryl, (C6-C╬╣4) aryloxy, (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy (Ci-Cg) alkyl, trifluoromethoxy, amino, carbamoyl, (C╬╣-C8) alkylthio, (C╬╣~C8) alkylsulphinyl, (C╬╣~C8) alkylsulphonyl, sulphoamino, (Ci-Cg) alkylsulphonylamino, sulphamoyl and (C╬╣~ C8) alkylcarbonylamino; said C╬╣~C8 alkyl being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣~C8 alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl;
R25 is selected from the group consisting of hydrogen, halogen, C╬╣-C8 alkoxy, C╬╣-C8 alkyl, trifluoromethyl, nitro, cyano, carbo C╬╣~C6 alkoxy, carboxy, C╬╣-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (Cj-Cg) alkoxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Ci-Cg) alkoxy, (C╬╣-C6) alkoxy (Ci-Cg) alkyl, (C6-C14) aryl, (C6- Ci4) heteroaryl, (C6-C╬╣4) heteroaryl (Cj-Cg) alkyl, (C6-C╬╣4) aryl (Ci-Cg) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C6-C╬╣4) aryl, (C6-C╬╣4) aryloxy, (C6-C14) aryloxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy (C╬╣-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (C╬╣-C8) alkylthio, (C╬╣-C8) alkylsulphinyl, (C╬╣~C8) alkylsulphonyl, sulphoamino, (C╬╣-C8) alkylsulphonylamino, sulphamoyl and (C2-C8) alkylcarbonylamino; said C╬╣~C8 alkyl being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣-C8 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl;
R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C8 alkoxy, C╬╣-C8 alkyl, trifluoromethyl, nitro, cyano, carbo C╬╣-C6 alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, hydroxy, C╬╣-C6 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (Ci-C6) alkoxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy, (C╬╣-C6) alkoxy (Ci-Cg) alkyl, (C6-C╬╣4) aryl, (C6-C╬╣4) heteroaryl, (C6-C╬╣4) heteroaryl (Cj-Cg) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl, (C6-C14) aryl (Ci-C6) alkyl (C6-C╬╣4) aryl, (C6-C╬╣4) aryloxy, (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy, (C6-C14) aryl (C╬╣-C6) alkyloxy (C╬╣-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (C╬╣~C8) alkylthio, (Ci-Cg) alkylsulphinyl, (C╬╣-C8) alkylsulphonyl, sulphoamino, (C╬╣~C8) alkylsulphonylamino, sulphamoyl and (C╬╣~C8) alkylcarbonylamino; said Cx-C6 alkyl being optionally substituted with halogen or C╬╣-C3 alkyl; said C2-C8 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; wherein R22-R26 are not all simultaneously hydrogen; or two of R22-R25 can form a methylenedioxy;
R27-R3╬╣ are independently selected from the group consisting of hydrogen, halogen, C╬╣-C8 alkoxy, C╬╣-C8 alkyl, trifluoromethyl, nitro, cyano, carbo C╬╣-C6 alkoxy, carboxy, C╬╣-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy (Ci-Cg) alkyl, (C3-C8) cycloalkyl (Ci-C6) alkoxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy, (Ci~C6) alkoxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl, (C6-C14) heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C6-C╬╣4) aryl, (C6-C╬╣4) aryloxy, (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy (Ci-Cg) alkyl, trifluoromethoxy, amino, carbamoyl, (C╬╣-C8) alkylthio, (C╬╣-C8) alkylsulphinyl, (C╬╣-C8) alkylsulphonyl, sulphoamino, (C╬╣~C8) alkylsulphonylamino, sulphamoyl and (C2- C8) alkylcarbonylamino; said C╬╣-C8 alkyl being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣~C8 alkoxy being optionally substituted with halogen or C:-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-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 CR31; wherein at least one of X3, X4, or X5 is nitrogen; wherein up to three of R27-R3╬╣ can simultaneously be hydrogen when only one of X3-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 a pharmaceutically acceptable salt or solvate thereof; or a compound having a tautomeric structure thereof.
31. The compound acording to claim 30 wherein
Ri is selected from the group consisting of hydrogen and R╬╣4COOR╬╣5;
R2 is selected from the group consisting of hydrogen, halogen, R╬╣6OR17, R18NHR╬╣9, C6-C╬╣4 aryl, (C6-C╬╣4) aryl Ci-Cg alkyl, C╬╣-C8 alkyl, and C3-C6 cycloalkyl; said C6-C╬╣4 aryl, and said (C6-C╬╣ΓÇ₧) aryl Cx-C6 alkyl, being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cx-C6 alkoxy, Ci- Cg alkyl, trihalo (C╬╣-C6) alkyl, and trihalo (C╬╣-C6) alkoxy; said Ci-Cg alkyl group being optionally substituted with one or more halogen, C╬╣-C6 alkyl or phenyl groups;
R3 is selected from the group consisting of hydrogen, C6-C14 aryl, (C6-C14) aryl (Ci-Cg) alkyl, and C╬╣-C8 alkyl group; said C6-C╬╣4 aryl, and said (C6-C14) aryl (Ci-Cg) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, C3-C8 cycloalkyl, trihalo (C╬╣~C6) alkyl, and trihalo (C╬╣-C6) alkoxy; said Cx-C8 alkyl group being optionally substituted with one or more halogen, C┬▒-C6 alkyl or phenyl groups; R8-R2╬╣, m, and o are as defined above for formula
(XVIa) ;
R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, C╬╣-C6 alkyl, nitro, trifluoromethyl, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, Ci-Cg thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl;
R23 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, Ci-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C5 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; R24 is selected from the group consisting of hydrogen, bromine, chlorine, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C5 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl;
R25 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or Ci-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C5) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or
Figure imgf000378_0001
alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; wherein R22-R26 cannot all simultaneously be hydrogen; or two of R22-R26 when taken together can form a methylenedioxy group;
R27 is selected from the group consisting of halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted - with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; R28 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C5 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-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 CR31; wherein at least one of X3, X4, or X5 is nitrogen;
R29 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with one to two halogen atoms or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R30 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R31 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with one to two halogen atoms or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; wherein up to three of R27-R3X can simultanoeously be hydrogen when only one of X3-X5 is nitrogen; wherein up to two of R27-R3X 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.
32. The compound according to claim 30 selected from the group consisting of
3-( ( (4- (2-Fluorophenyl) piperazin-l- 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-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- l-yl) acetyl) amino) -2- (carbomethoxy) thiophene.
33. A composition comprising the compound according to claim 30 and a pharmaceutically acceptable carrier.
34. A composition comprising the compound according to claim 31 and a pharmaceutically acceptable carrier.
35. A composition comprising the compound according to claim 32 and a pharmaceutically acceptable carrier.
36. A method for lowering serum glucose levels in a mammal comprising administering a composition comprising a compound of formula (XVIb) having the structure:
Figure imgf000381_0001
wherein:
Rx is selected from the group consisting of hydrogen and RX4COORX5; R2 is selected from the group consisting of hydrogen, halogen, RX6OR17, RX8NHRX9, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, Cx-C8 alkoxy, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-C6) alkoxy, (Cx- C6) alkoxy (Cx-C6) alkyl, (C6-CX4) aryl, (C6-CX4) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl (C6-CX4) aryl , (C6-CX4) aryloxy, (C6- CX4) aryloxy (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyloxy, (C6- CX4) aryl (Cx-C6) alkyloxy (Cx-C6) alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, (Cx-C8) thioalkyl, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (C2-C8) alkylsulphonylamino, and sulphamoyl; said Cx-C8 alkyl group being optionally substituted with one or more halogen, Cx-C6 alkyl or phenyl groups; said C6-CX4 aryl and (C6-CX4) aryl (Cx-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cx-C6 alkoxy, Cx-C6 alkyl, trihalo (Cx-C6) alkyl, and trihalo (Cx-C6) alkoxy;
R3 is selected from the group consisting of hydrogen, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C6-CX4) aryl, (C6-C14) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C5-CX4) aryl (Cx-C5) alkyl, halogen, trifluoromethyl, and cyano; said Cx-C8 alkyl being optionally substituted with one or more halogen, Cx-C6 alkyl or phenyl groups; said C6-CX4 aryl and (C6-CX4) aryl (Cx-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cx-C6 alkoxy, Ci- Cg alkyl, trihalo (Cx-C6) alkyl, and trihalo (Cx-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 phenylalkyl; R9 is a group selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cx-C6) alkoxy (Cx-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, C6-CX4 aryl, C6-C14 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx- C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl (Cx-C6) aryl, (C6-C14) aryl (Cx-C6) alkoxy (Cx-C6) alkyl, and (C6-CX4) aryloxy (Cx-C6) alkyl group;
Rxo is selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cx-C6) alkoxy (Cx-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, C6-CX4 aryl, C6-CX4 heteroaryl, (C6-C14) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx- C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl (Cx-C6) aryl, (C6-C14) aryl (Cx-C6) alkoxy (Cx-C6) alkyl, and (C6-CX4) aryloxy (Cx-C6) alkyl group;
Rxx is selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cx-C6) alkoxy (Cx-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-CX4 aryl, C6-CI4 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C5-CX4) aryl (Cx- C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (Cx-C6) aryl, (C6-CX4) aryl (Cx-C6) alkoxy (Cx-C6) alkyl, and (C6-CX4) aryloxy (Cx-C6) alkyl group; RX2 is selected from the group consisting of hydrogen and Cx-C6 alkyl;
R13 is selected from the group consisting of
Figure imgf000383_0001
RX4 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cx-C6 alkyl group; said Cx-C6 alkyl group being substituted with one or more hydrogen, halogen, Cx-C6 alkyl or phenyl groups;
RX5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, divalent alkali metals, divalent alkali earth metals, and a Cx -C6 alkyl group; said Cx-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and Cx-C3 alkyl;
Rx6 is a bond or is selected from the group consisting of sulfonyl, C2-C6 thioalkyl, aminosulfonyl and Ci- Cg alkyl; said Cx-C6 alkyl being substituted with one or more hydrogen, halogen, Cx-C6 alkyl or phenyl groups;
R17 is selected from the group consisting of phenyl, phenylalkyl, and a Cx-C6 alkyl group; said Cx-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of halogen, phenyl, phenylalkyl, and Cx-C3 alkyl; said phenyl and phenylalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, Cx-C6 alkoxy, amino, and Cx-C6 alkyl;
R18 is a bond or is selected from the group consisting of sulfonyl, C2-C6 thioalkyl, aminosulfonyl, carbonyl, aminocarbonyl and Cx-C6 alkyl group, said Cx-C6 alkyl group being substituted with one or more hydrogen, halogen, Cx-C6 alkyl or phenyl groups;
R19 is selected from the group consisting of hydrogen, phenyl, phenyl (C╬╣-C6) alkyl, and C╬╣-C6 alkyl; said Cx- C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of phenyl and Cx-C3 alkyl; said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino, and Cx-C5 alkyl; said phenyl Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino, or Cx-C6 alkyl;
R20 is selected from the group consisting of hydrogen, Cx-C6 alkyl, hydroxy and Cx-C6 alkoxy; m is 0 or 1; o is 0 or 1;
R2X is a bond or is selected from the group consisting Cx-C6 alkyl; said Cx-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 Cx-C6 alkyl, halogen, Cx-C6 alkoxy and hydroxy;
R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-C6 alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, hydroxy, Cx-C6 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-C6) alkoxy, (Cx-C6) alkoxy (Cx-C6) alkyl, (C6-CX4) aryl, (C6-CX4) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-CX4) aryloxy, (C6-C14) aryloxy (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyloxy, (C6-CX4) aryl (Cx-C6) alkyloxy (Cx-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said Cx-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said C2-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R23 is selected from the group consisting of hydrogen, halogen, Cx-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-C6 alkoxy, carboxy, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyloxy (Cx-C5) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-C5) alkoxy, (Cx-C6) alkoxy (Cx-C6) alkyl, (C6-CX4) aryl, (c6- CX4) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl, (C6-Cx4) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-CX4) aryloxy, (C6-C14) aryloxy (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyloxy, (C6-CX4) aryl (Cx-C6) alkyloxy (Cx-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (C2-C8) alkylcarbonylamino; said Cx-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R24 is selected from the group consisting of hydrogen, bromine, chlorine, Cx-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-C6 alkoxy, carboxy, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-C6) alkoxy, (Cx-C6) alkoxy (Cx-C6) alkyl, (C6-CX4) aryl, (C6-C14) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-C14) aryloxy, (C6-C14) aryloxy (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyloxy, (C6-CX4) aryl (Cx-C6) alkyloxy (Cx-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Ci- Cg) alkylcarbonylamino; said Cx-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R25 is selected from the group consisting of hydrogen, halogen, Cx-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-C6 alkoxy, carboxy, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Ci-Cg) alkoxy, (Cx-C6) alkoxy (Cx-C6) alkyl, (C6-CX4) aryl, (C6- C14) heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-CX4) aryloxy, (C6-CX4) aryloxy (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyloxy, (C6-CX4) aryl (Cx-C6) alkyloxy (Cx-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (C2-C8) alkylcarbonylamino; said Cx-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-C6 alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, hydroxy, Cx-C6 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyloxy (Cx-C5) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-C6) alkoxy, (Cx-C6) alkoxy (Cx-C6) alkyl, (C6-C14) aryl, (C6-CX4) heteroaryl, (C6-C14) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-CX4) aryloxy, (C6-CX4) aryloxy (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyloxy, (C6-CX4) aryl (Cx-C6) alkyloxy (Cx-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said Cx-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said C2-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; wherein R22-R26 are not all simultaneously hydrogen; or two of R22-R26 can form a methylenedioxy;
R27-R3X are independently selected from the group consisting of hydrogen, halogen, Cx-C8 alkoxy, Cx-C8 alkyl, trifluoromethyl, nitro, cyano, carbo Cx-C6 alkoxy, carboxy, Cx-C8 thioalkyl, hydroxy, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-C6) alkoxy, (Cx-C6) alkoxy (Cx-C6) alkyl, (C6-CX4) aryl, (C6-Cx4) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl (C6-CX4) aryl, (C6-Cx4) aryloxy, (C6-C14) aryloxy (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyloxy, (C6-C14) aryl (Cx-C6) alkyloxy (Cx-C6) alkyl, trifluoromethoxy, amino, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl and (C2- C8) alkylcarbonylamino; said Cx-C8 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-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 CR3X; wherein at least one of X3, X4, or X5 is nitrogen; wherein up to three of R27-R3X can simultaneously be hydrogen when only one of X3-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 a pharmaceutically acceptable salt or solvate thereof; or a compound having a tautomeric structure thereof.
37. The method acording to claim 36 wherein: Rx is selected from the group consisting of hydrogen and RX4COORX5; R2 is selected from the group consisting of hydrogen, halogen, RX6ORX7, R18NHRX9, C6-C14 aryl, (C6-CX4) aryl Cx-C6 alkyl, Cx-C8 alkyl, and C3-C5 cycloalkyl; said C6-CX4 aryl, and said (C5-CX4) aryl Cx-C6 alkyl, being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cx-C6 alkoxy, Cx- C6 alkyl, trihalo (Cx-C6) alkyl, and trihalo (Cx-C6) alkoxy; said Cx-C8 alkyl group being optionally substituted with one or more halogen, Cx-C6 alkyl or phenyl groups;
R3 is selected from the group consisting of hydrogen, C6-CX4 aryl, (C6-C14) aryl (Cx-C6) alkyl, and Cx-C8 alkyl group; said C5-CX4 aryl, and said (C6-CX4) aryl (Cx-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Cx-C6 alkoxy, Cx-C5 alkyl, C3-C8 cycloalkyl, trihalo (Cx-C6) alkyl, and trihalo (Cx-C6) alkoxy; said Cx-C8 alkyl group being optionally substituted with one or more halogen, Cx-C6 alkyl or phenyl groups;
R8~R2╬╣ m. and o are as defined above for formula (XVIb) ; R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Cx-C6 alkyl, nitro, trifluoromethyl, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R23 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R24 is selected from the group consisting of hydrogen, bromine, chlorine, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; R25 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, Cx-C5 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogerv or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; wherein R22-R26 cannot all simultaneously be hydrogen; or two of R22-R26 when taken together can form a methylenedioxy group; R27 is selected from the group consisting of halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R28 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-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 CR31; wherein at least one of X3, X4, or X5 is nitrogen; R29 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with one to two halogen atoms or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R30 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl;
R3X is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with one to two halogen atoms or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; wherein up to three of R27-R3X can simultanoeously be hydrogen when only one of X3-X5 is nitrogen; wherein up to two of R27-R3X 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.
38. The method according to claim 36 wherein the compound is selected from the group consisting of 3~( ( ( ~ (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-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-l- yl) acetyl) amino) -2- (carbomethoxy)thiophene, and
3- ( ( (4- (2- (Trifluoromethyl) quinolin-4-yl)piperazin- l-yl) acetyl) amino) -2- (carbomethoxy) thiophene.
39. A process for the preparation of a compound of the general formula (XIII) comprising the reaction of an aromatic amine of general formula (Al):
Figure imgf000392_0001
(Al) with a haloacyl halide of general formula (IXa) :
Figure imgf000392_0002
(IXa) wherein Hal represents a chlorine or bromine atom, in order to form a compound of general formula (XVII) ;
Figure imgf000392_0003
(XVII) and the reaction of the compound of general formula (XVII) with a compound of general formula (XVIII) :
Figure imgf000393_0001
(XVIII) in the presence of a basic agent, such as triethylamine or potassium carbonate in order to form the compound of general formulas (Xllla) and (Xlllb) :
Figure imgf000393_0002
(XIX) wherein Rx is selected from the group consisting of hydrogen, halogen, Rx6OR17, RX8NHRX9, RX4COORX5, Cx-C8 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C6-C14) aryl, (C6-C14) heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (C6-CX4) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, (Cx-C8) alkylsulphonylamino, sulphamoyl or (Cx-C8) alkylcarbonylamino; said Cx-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more constituents selected from the group consisting of halogen, Cx-C6 alkyl and phenyl; said C6- C14 aryl, (C6-C14) aryl (Cx-C6 alkyl), C6-CX4 heteroaryl, and (C6- C14) heteroaryl (Cx-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cx-C6 alkyl;
R2 is selected from the group consisting of hydrogen, halogen, Rx6ORX7 , RX8NHRX9 , RX4COOR15 , Cx-C8 alkyl , C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (Cx-C6) alkyl, (C6-CX4) aryl, (C6-C14) heteroaryl, (C6-C14) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (C╬╣-C6) alkyl, (C6-CX4) -aryl (Cx-C6) alkyl (C6-CX4) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, (Cx-C8) alkylsulphonylamino, sulphamoyl and (Cx-C8) alkylcarbonylamino; said Cx-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Cx-C6 alkyl and phenyl; said C6-CX4 aryl, (C6-CX4) aryl (Cx-C6 alkyl) , C6-CX4 heteroaryl, and (C6-CX4) heteroaryl (Cx-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Cx-C6 alkyl;
R3 is selected from the group consisting of hydrogen, halogen, RX6ORX7, RX8NHRX9, RX4COORX5, Cx-C8 alkyl, (C3- C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, (C6-CX4) aryl, (C6- CX4) heteroaryl, (C5-CX4) heteroaryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl, (C6-C14) aryl (Cx-C6) alkyl (C6-C14) aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, (Ci- Cg) alkylsulphonylamino, sulphamoyl and (Ci-C8) alkylcarbonylamino; said C╬╣-C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Cj-Cg alkyl and phenyl; said C6-C╬╣4 aryl, (C6-C14) aryl (C╬╣-C6 alkyl) , C6-C╬╣4 heteroaryl, and (C6-C╬╣4) heteroaryl (Ci-Cg) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and C╬╣-C6 alkyl;
R4 is selected from the group consisting of hydrogen, halogen, R╬╣6OR╬╣7, Ri8NHR╬╣9, Ri4COOR15, Ci-C8 alkyl, (C3- C8) cycloalkyl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl, (C6- C╬╣4) heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C5-C14) aryl (Ci-Cg) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C6-C14)aryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (C╬╣-C8) alkylthio, (Cj-Cg) alkylsulphinyl, (C╬╣~C8) alkylsulphonyl, (C╬╣~ C8) alkylsulphonylamino, sulphamoyl and (Ci-C8) alkylcarbonylamino; said C╬╣~C8 alkyl and C3-C8 cycloalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-Cg alkyl and phenyl; said C6-C╬╣4 aryl, (C6-C╬╣4) aryl (C╬╣-C6 alkyl), C6-C╬╣4 heteroaryl, and (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy and Ci-C5 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 (C╬╣-C6) alkyl;
R9 selected from the group consisting. of hydrogen, Ci-Cg alkyl, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-C6) alkyl, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, C6-C╬╣4 aryl, C6-C14 heteroaryl, (C6- C14) heteroaryl (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl, (C6- C14) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (C6-C╬╣4) aryl (C╬╣-C6) alkoxy (Ci-Cg) alkyl and (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl;
Rio is selected from the group consisting of hydrogen, C╬╣-C8 alkyl, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy (Ci~C6) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-C╬╣4 aryl, C6- Ci4 heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (Ci-Cg) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (C6-C14) aryl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl and (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl;
Rn is selected from the group consisting of hydrogen, C╬╣-C8 alkyl, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C╬╣~C6) alkyl, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-C╬╣4 aryl, C6- Ci4 heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (C6-C14) aryl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl and (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl;
R12 is selected from the group consisting of hydrogen and Cj-Cg alkyl; Ri3 is selected from the group consisting of
Figure imgf000396_0001
R14 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and C╬╣-C6 alkyl; said C╬╣-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkyl and phenyl; Ri5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and C╬╣~ C6 alkyl; said C╬╣-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl and C╬╣-C3 alkyl;
R16 is a bond or is selected from the group consisting of sulfonyl, C╬╣~C8 thioalkyl, aminosulfonyl and Cx- C6 alkyl group; said C╬╣-C6 alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Cj-Cg alkyl and phenyl;
Ri7 is selected from the group consisting of C╬╣-C6 alkyl, C3-C8 cycloalkyl, C6-C╬╣4 aryl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl; said C╬╣-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, phenyl, phenylalkyl and C╬╣~C3 alkyl; said C3-C5 cycloalkyl group being optionally substituted with
C╬╣-C3 alkyl; Rig is a bond or is selected from the group consisting of sulfonyl, C╬╣~C8 thioalkyl, aminosulfonyl, carbonyl, aminocarbonyl and C╬╣-C6 alkyl, said C╬╣-C6 alkyl group being substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C╬╣~C6 alkyl and phenyl;
Rig is selected from the group consisting of hydrogen, phenyl, phenylalkyl, and Cj-Cg alkyl; said C╬╣-C6 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 C╬╣~C6 alkyl; said phenylalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino and C╬╣-C6 alkyl;
R20 is selected from the group consisting of hydrogen, Ci-Cig alkyl, hydroxy and C╬╣-C6 alkoxy; m is 0 or 1; o is 0 or 1;
R21 is a bond or C╬╣-C6 alkyl; said Cj-Cg 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 C╬╣-C6 alkyl, halogen, Cj-Cg alkoxy and hydroxy;
R22-R31 are independently selected from the group consisting of hydrogen, halogen, C╬╣-C8 alkoxy, C╬╣-C8 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, Ci-Cg thioalkyl hydroxy (C3-C8) cycloalkyl, (C3-C8) cycloalkyl, (Ci-Cg) alkyl, C╬╣-C8 alkoxy, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy, (C╬╣-C6) alkoxy (Ci-Cg) alkyl, (C6-C╬╣4) aryl, (C6-C╬╣4) heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C6-C14)aryl, (C6-C╬╣4) aryloxy, (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyloxy, (C6-C14) aryl (C╬╣-C6) alkyloxy (C╬╣-C6) alkyl trifluoromethoxy, amino, carbamoyl, (C╬╣-C8) alkylthio, (C╬╣~C8) alkylsulphinyl, (C╬╣~C8) alkylsulphonyl, sulphoamino, (C╬╣~C8) alkylsulphonylamino, sulphamoyl or (C╬╣~C8) alkylcarbonylamino; said (Ci-Cg) alkyl being optionally substituted with one or more constituents selected from the group consisting of halogen and C╬╣~C3 alkyl; said C2-C6 alkoxy being optionally substituted with one or more substituents selected from the group consisting of halogen and C-C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with one or more constituents selected from the group consisting of halogen and C╬╣~C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with one or more constituents selected from the group consisting of halogen and C╬╣~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;
X5 is nitrogen or CR3╬╣,* wherein at least one of X3, X4, or X5 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.
40. A process for the preparation of the compounds of general formulas (XlVa) and (XlVb) comprising the reaction of an aromatic amine of general formula (A2):
Figure imgf000398_0001
(A2) with a haloacyl halide of general formula (XIX) :
Figure imgf000399_0001
(XIX) wherein Hal represents a chlorine or bromine atom, in order to form a compound of general formula (XX) ;
Figure imgf000399_0002
(XX) and the reaction of the compound of general formula (XX) with a compound of general formula (XXI) :
Figure imgf000399_0003
(XXI) in the presence of a basic agent, such as triethylamine or potassium carbonate in order to form the compound of general formulas (XlVa) and (XlVb) :
Figure imgf000399_0004
(XIV) wherein:
Ri is selected from the group consisting of hydrogen, R╬╣4COOR╬╣5 , C╬╣~C8 alkyl , C3-C8 cycloalkyl , (C3-C8) cycloalkyl (C╬╣-C6) alkyl, Ci-C8 alkoxy, (C3-C8) cycloalkyloxy (Cj-Cg) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-C6) alkoxy, (Ci- Cg) alkoxy (Cx-C6) alkyl, (C6-CX4) aryl, (C6-CX4) heteroaryl, (C6-C14) heteroaryl (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C6-C╬╣4) aryl, (C6-C╬╣4) aryloxy, (C6- C╬╣4) aryloxy (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (Cj-Cg) alkyloxy, (c6- Ci4) aryl (Ci-C6) alkyloxy (Cx-C6) alkyl group, halogen, trifluoromethyl, cyano, nitro, amino, carboxyl, (C╬╣-C6) alkoxycarbonyl, carbamoyl, (Cx-C8) alkylthio, (C╬╣-C8) alkylsulphinyl, (C╬╣-C8) alkylsulphonyl, sulphoamino, (C╬╣-C8) alkylsulphonylamino, sulphamoyl and (C╬╣~C8) alkylcarbonylamino; said C╬╣~C8 alkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, Cx-C6 alkyl and phenyl; said C6- CX4 aryl and (C6-CX4) aryl (Cx-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, alkoxy, Cx-C6 alkyl and phenyl; 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 (Cx-C6) alkyl;
R9 is selected from the group consisting of hydrogen, Cx-C8 alkyl, (Cx-C6) alkoxy (Cx-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, C6-CX4 aryl, C6-CX4 heteroaryl, (C6-CX4) heteroaryl (Cx-C6) alkyl, (C6- C14) aryl (C╬╣-C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (C6-C╬╣4) aryl (Ci-Cg) alkoxy (C╬╣~C6) alkyl and (C6-C╬╣4) aryloxy (Ci-Cg) alkyl group;
Rio is selected from the group consisting of hydrogen, C╬╣-C8 alkyl, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C╬╣-C6) alkyl group, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3-C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-C╬╣4 aryl, C6-C╬╣4 heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (c6- Ci4) aryl (Cx-C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (C6-C╬╣4) aryl (C╬╣-C5) alkoxy (Cx-C6) alkyl and (C6-CX4) aryloxy (Cx-C6) alkyl group;
Rxx is selected from the group consisting of hydrogen, C1-C8 alkyl, (Cx-C6) alkoxy (Cx-C6) alkyl, a cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl group, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C6) alkoxy (Cx-C6) alkyl, C6-CX4 aryl, C6-CX4 heteroaryl, (C6-C╬╣4) heteroaryl (Cx-C6) alkyl, (C6- CX4) aryl (Cx-C6) alkyl, (C6-CX4) aryl (Cx-C6) alkyl (Cx-C6) aryl, (C6-CX4) aryl (Cx-C6) alkoxy (C╬╣-C6) alkyl and (C6-CX4) aryloxy (Cx-C6) alkyl group;
RX2 is selected from the group consisting of hydrogen and Cx-C6 alkyl; RX3 is selected from the group consisting of
Figure imgf000401_0001
RX4 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and Cx-C6 alkyl; said Cx-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, Cx-C6 alkyl and phenyl;
R15 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions and Cx-C6 alkyl; said Cx-C6 alkyl group being optionally substituted with one or more substituents selected from the group consisting of phenyl, phenylalkyl, and C╬╣~C3 alkyl;
R20 is selected from the group consisting of hydrogen, Cx-C6 alkyl, hydroxy and Cx-C6 alkoxy; m is 0 or 1; n is 0 or 2; o is 0 or 1; R21 is a bond or Cx-C6 alkyl; said Cx-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 Cx-C6 alkyl, halogen, Cx-C6 alkoxy and hydroxy;
R22~R╬╣ are each independently selected from the group consisting of hydrogen, Cx-C8 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (Cx-C6) alkyl, Cx-C8 alkoxy, (C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3-C8) cycloalkyl (Cx-C5) alkoxy (Cx-C6) alkyl, (C3-C8) cycloalkyloxy, (C3-C8) cycloalkyl (Cx-C6) alkoxy, (Cx-C6) alkoxy (Cx-C6) alkyl, (C6-C╬╣4) aryl, (C6-C╬╣4) heteroaryl, (C6-Cl4 ) heteroaryl (Cx-C6) alkyl, (C6-Cx4) aryl (Ci- Cg) alkyl, (C6-C14) aryl (Cx-C6) alkyl (C6-C14)aryl, (C6-CX4) aryloxy, (C6-CX4) aryloxy (Cx-C6) alkyl, (C5-CX4) aryl (C╬╣-C6) alkyloxy, (C6-CX4) aryl (C╬╣-C6) alkyloxy (C╬╣~C6) alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, (C╬╣-C6) alkoxycarbonyl, carbamoyl, (Cx-C8) alkylthio, (Cx-C8) alkylsulphinyl, (Cx-C8) alkylsulphonyl, sulphoamino, (Cx-C8) alkylsulphonylamino, sulphamoyl, (Cx-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 form an aryl ring; X3 is nitrogen or CR29; X4 is nitrogen or CR30;
X5 is nitrogen or CR3X; wherein at least one of X3, X4, or X5 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.
41. A process for the preparation of the compounds of general formulas (XVa) and (XVb) comprising the reaction of an aromatic amine of general formula (A3) : (R8)mNHR9
(A3) with a haloacyl halide of general formula (XXII) :
Figure imgf000403_0001
(XXII) wherein Hal represents a chlorine or bromine atom, in order to form a compound of general formula (XXIII) ; .
Figure imgf000403_0002
(XXIII) and the reaction of the compound of general formula (XXIII) with a compound of general formula (XXIV) :
Figure imgf000403_0003
(XXIV) 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) :
Figure imgf000403_0004
(XVa) wherein:
Rx is selected from the group consisting of R14COORx5, C6-CX4 aryl, (C6-CX4) aryl Cx-C6 alkyl, C3-C6 cycloalkyl, thio (C6-CX4) aryl (e.g., thiophenyl, thionaphthyl) , thio (C6-CX4) heteroaryl (e.g., thiopyridyl, thioquinolinyl, and thiopyrazinyl) ; said C6-CX4 aryl and (C6- CX4) aryl Cx-C6 alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amine, hydroxy, Cx-C6 alkoxy, Cx-C6 alkyl, trihalo Ci- Cg alkyl, trihalo C╬╣~C╬▓ alkoxy, and phenyl; said thio (C6-C╬╣4) aryl being optionally substituted with halogen, amine C╬╣-C6 alkoxy, hydroxy, C╬╣-C6 alkyl, trihalo (C╬╣-C6) alkoxy, or trihalo (C╬╣-C6) alkyl; said thio (C6-C╬╣4) heteroaryl being optionally substituted with halogen, amine, C╬╣-C6 alkoxy, hydroxy, C╬╣-C6 alkyl trihalo (Ci-Cg) alkoxy, or trihalo (C╬╣~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 (C╬╣-C6) alkyl;
R9 is a group selected from the group consisting of hydrogen, C╬╣-C8 alkyl, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, {C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3- C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-C╬╣4 aryl, C6-C╬╣4 heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (Ci- Cg) alkyl, (C6-C╬╣4) aryl (C:-C6) alkyl (C╬╣-C6) aryl, (C6-C╬╣4) aryl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, and (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl group;
Rio is selected from the group consisting of hydrogen, C╬╣-C8 alkyl, (C╬╣~C6) alkoxy (C╬╣-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3- C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-C╬╣4 aryl, C6-C╬╣4 heteroaryl, (C6-C╬╣4) heteroaryl (C╬╣-C6) alkyl, (C6-C╬╣4) aryl (C╬╣~ C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (C6-C14) aryl (Ci-Cg) alkoxy (Ci-Cg) alkyl, and (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl group;
Rn is selected from the group consisting of hydrogen, C╬╣~C8 alkyl, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Ci-Cg) alkyl group, (C3-C8) cycloalkyloxy (C╬╣-C5) alkyl, (C3- C╬▓) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-C╬╣4 aryl, C6-C14 heteroaryl, (C6-C14) heteroaryl (C╬╣~C6) alkyl, (C6-C╬╣4) aryl (Ci- Cg) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (C6-C╬╣4) aryl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, and (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl group;
Ri2 is selected from the group consisting of hydrogen and C╬╣~C6 alkyl;
Ri3 is selected from the group consisting of
Figure imgf000405_0001
R╬╣4 is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and C╬╣~C2 alkyl group; said C╬╣~C2 alkyl being substituted with one or more halogen, C╬╣-C6 alkyl or phenyl groups;
R╬╣5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, and Cx - C6 alkyl group; said C╬╣-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and C╬╣~C3 alkyl;
R20 is selected from the group consisting of hydrogen, Ci-C6 alkyl, hydroxy and C╬╣-C6 alkoxy; m is 0 or 1; n is 1; o is 0 or 1;
R2╬╣ is a bond or C╬╣-C6 alkyl; said C╬╣~C6 alkyl being optionally substituted from the group consisting of benzene and an optionally substituted benzene ring; said benzene ring optionally substitued from the group consisting of Ci~C6 alkyl, halogen, C╬╣-C6 alkoxy and hydroxy;
R22 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C5) alkoxy, carboxy, phenyl, Ci-Cg thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; said Cj-Cg thioalkyl being optionally substituted with halogen or Ci-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl;
R23 is selected from the group consisting of hydrogen, fluorine, bromine, C╬╣-C6 alkoxy, C2-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣~C6) alkoxy, carboxy, phenyl, Ci-Cg thioalkyl, and hydroxy; said C2-C6 alkyl being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl;
R24 is selected from the group consisting of hydrogen, halogen, C╬╣~C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣~C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C╬╣~C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Ci-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl;
R25 is selected from the group consisting of hydrogen, fluorine, bromine, Cx-C6 alkoxy, C2-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cj-Cg) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C2-C6 alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl;
R26 is selected from the group consisting of hydrogen, halogen, Cj-Cg alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C5) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or C╬╣~C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl;
R27 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣~C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, and hydroxy; said C^Cg alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C!-C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (Ci-Cg) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl;
R28 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, Cj-Cg alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣~C6) alkoxy, carboxy, phenyl, Ci-C8 thioalkyl, and hydroxy; said C^Cg alkyl being optionally substituted with halogen or Cx-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; said Cj-Cg thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~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 Xi and X2 is nitrogen, with the other being carbon;
X3 is nitrogen or CR29 X4 is nitrogen or CR30
X5 is nitrogen or CR3╬╣ wherein at least one of X3, X4, or X5 is nitrogen; R29 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Ci-Cg) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one to two halogen atoms or C╬╣~C3 alkyl; said Cj-Cg alkoxy being optionally substituted with halogen or Ci-C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or C╬▒-C8 alkyl; said carbo (C╬╣~C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; R30 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣~C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said C╬╣-.C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said Ci-Cg thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (C╬╣~C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl;
R3╬╣ is selected from the group consisting of hydrogen, halogen, Cj-Cg alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one to two halogen atoms or C╬╣~C3 alkyl; said Ci-Cg alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; or R28 and CR30 when taken together form an aryl ring; or R28 and CR29 when taken together form an aryl ring.
42. A process for the preparation of the compounds of general formulas (XVIa) and (XVIb) comprising the reaction of an aromatic amine of general formula (A4):
Figure imgf000409_0001
(A4) with a haloacyl halide of general formula (XXV) :
Figure imgf000409_0002
(XXV) wherein Hal represents a chlorine or bromine atom, in order to form a compound of general formula (XXVI) ;
Figure imgf000409_0003
(XXVI) and the reaction of the compound of general formula (XXVI) with a compound of general formula (XXVII) :
Figure imgf000409_0004
(XVIII) O 99/310
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) :
Figure imgf000410_0001
(XVIa) and (XVIb) wherein:
Ri is selected from the group consisting of hydrogen and R╬╣4COOR╬╣5; R2 is selected from the group consisting of hydrogen, halogen, R16OR╬╣7, R18NHR╬╣9, C6-C╬╣4 aryl, (C6-C╬╣4) aryl Ci-Cg alkyl, C╬╣-C8 alkyl, and C3-C6 cycloalkyl; said C6-C14 aryl, and said (C6-C╬╣4) aryl C╬╣~C6 alkyl, being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, C╬╣~C6 alkoxy, Ci- Cg alkyl, trihalo (C╬╣-C6) alkyl, and trihalo (C╬╣-C6) alkoxy; said C╬╣~C8 alkyl group being optionally substituted with one or more halogen, C╬╣-C6 alkyl or phenyl groups;
R3 is selected from the group consisting of hydrogen, C6-C╬╣4 aryl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl, and C╬╣-C8 alkyl group; said C5-C╬╣4 aryl, and said (C6-C╬╣4) aryl (C╬╣-C6) alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, Ci-Cg alkoxy, C╬╣-C6 alkyl, C3-C8 cycloalkyl, trihalo (C╬╣-C6) alkyl, and trihalo (Ci-C6) alkoxy; said C:-C8 alkyl group being optionally substituted with one or more halogen, C╬╣-C6 alkyl or phenyl groups;
R8 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, Cx-C8 alkyl, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C╬▓) cycloalkyl (C-C6) alkyl group, (C3-C8) cycloalkyloxy (C╬╣-C6) alkyl, (C3- C8) cycloalkyl (C╬╣-C6) alkoxy (Ci-Cg) alkyl, C6-C╬╣4 aryl, C6-C╬╣4 heteroaryl, (C6-C:4) heteroaryl (C╬╣~C6) alkyl, (C6-C:4) aryl (Cx- C6) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (C6-C14) aryl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, and (C6-C14) aryloxy (C╬╣-C6) alkyl group;
Rio is selected from the group consisting of hydrogen, C╬╣-C8 alkyl, (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (Cx-C6) alkyl group, {C3-C8) cycloalkyloxy (Cx-C6) alkyl, (C3- C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-C14 aryl, C6-C14 heteroaryl, (C6-Cx4) heteroaryl (Cx-C6) alkyl, (C6-CX4) aryl (Ci- Cg) alkyl, (C6-C╬╣4) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (C6-C14) aryl (Cj-Cg) alkoxy (C╬╣-C6) alkyl, and (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl group;
Ru is selected from the group consisting of hydrogen, C╬╣~C8 alkyl, (Cx-C6) alkoxy (Cj-Cg) alkyl, cycloalkyl group containing from 3 to 8 carbon atoms, (C3-C8) cycloalkyl (C╬╣-C6) alkyl group, (C3-C8) cycloalkyloxy (Ci-Cg) alkyl, (C3- C8) cycloalkyl (C╬╣-C6) alkoxy (C╬╣-C6) alkyl, C6-C╬╣4 aryl, C6-C╬╣4 heteroaryl, (C6-C╬╣4) heteroaryl (Ci~C6) alkyl, (C6-C╬╣4) aryl (C╬╣~ C6) alkyl, (C6-C14) aryl (C╬╣-C6) alkyl (C╬╣-C6) aryl, (C6-C14) aryl (Ci-Cg) alkoxy (C╬╣-C6) alkyl, and (C6-C╬╣4) aryloxy (C╬╣-C6) alkyl grou ;
Ri2 is selected from the group consisting of hydrogen and C╬╣-C6 alkyl;
Ri3 is selected from the group consisting of
Figure imgf000411_0001
Ri4 is a bond or is selected from the group consisting of sulfonylamino, carbonyl, carbonylamino, amino, and C:-C6 alkyl group; said C╬╣-C6 alkyl group being substituted with one or more hydrogen, halogen, Cj-Cg alkyl or phenyl groups;
RX5 is selected from the group consisting of hydrogen, monovalent metal ions, divalent metal ions, divalent alkali metals, divalent alkali earth metals, and a Cx -C6 alkyl group; said C╬╣-C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of phenyl, phenylalkyl, and C╬╣-C3 alkyl; Rig is a bond or is selected from the group consisting of sulfonyl, C2-C6 thioalkyl, aminosulfonyl and C╬╣~ C6 alkyl; said C╬╣-C6 alkyl being substituted with one or more hydrogen, halogen, C╬╣~C6 alkyl or phenyl groups;
R17 is selected from the group consisting of phenyl, phenylalkyl, and a Cj-Cg alkyl group; said C╬╣~C6 alkyl group being optionally substituted with one or more groups selected from the group consisting of halogen, phenyl, phenylalkyl, and C╬╣-C3 alkyl; said phenyl and phenylalkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C╬╣~C6 alkoxy, amino, and C╬╣-C6 alkyl;
R╬╣8 is a bond or is selected from the group consisting of sulfonyl, C2-C6 thioalkyl, aminosulfonyl, carbonyl, aminocarbonyl and C╬╣-C6 alkyl group, said C╬╣-C6 alkyl group being substituted with one or more hydrogen, halogen, Ci-Cg alkyl or phenyl groups;
R╬╣9 is selected from the group consisting of hydrogen, phenyl, phenyl (C╬╣-C6) alkyl, and Ci-Cg alkyl; said C╬╣~ 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 C╬╣-C6 alkyl; said phenyl Ci-Cg alkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, amino, or C╬╣~C6 alkyl; R20 is selected from the group consisting of hydrogen, Cj-Cg alkyl, hydroxy and C╬╣~C6 alkoxy; m is 0 or 1; o is 0 or 1; R2╬╣ is a bond or is selected from the group consisting C╬╣-C6 alkyl; said C╬╣-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 C╬╣-C6 alkyl, halogen, C╬╣-C6 alkoxy and hydroxy;
R22 is selected from the group consisting of hydrogen, bromine, chlorine, C2~C6 alkoxy, C╬╣-C6 alkyl, nitro, trifluoromethyl, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, Cj-Cg thioalkyl, and hydroxy; said Ci-C6 alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; R23 is selected from the group consisting of hydrogen, halogen, C╬╣~C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said Cj-Cg thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl;
R24 is selected from the group consisting of hydrogen, bromine, chlorine, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or C-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or C╬╣~C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; R25 is selected from the group consisting of hydrogen, halogen, C╬╣~C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣~C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl -being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣~C8 thioalkyl being optionally substituted with halogen or Ci-Cg alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬▒-C3 alkyl; R26 is selected from the group consisting of hydrogen, bromine, chlorine, C2-C6 alkoxy, C╬╣-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said Ci~C6 alkyl being optionally substituted with halogen or C╬╣-C3 alkyl; said C2-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said Cx-C8 thioalkyl being optionally substituted with halogen or Cx-C8 alkyl; said carbo (Cx-C6) alkoxy being optionally substituted with halogen or Cx-C3 alkyl; wherein R22-R26 cannot all simultaneously be hydrogen;
R27 is selected from the group consisting of halogen, Cx-C6 alkoxy, Cx-C6 alkyl, trifluoromethyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣~C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (Ci~C6) alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; R28 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, C╬╣-C6 alkyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; said C╬╣-C8 thioalkyl being optionally substituted with halogen or C╬╣-C8 alkyl; said carbo (C╬╣-C6) alkoxy being optionally substituted with halogen or C╬╣-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 CR3╬╣,* wherein at least one of X3, X4, or X5 is nitrogen;
R29 is selected from the group consisting of hydrogen, halogen, C╬╣-C6 alkoxy, Cj-Cg alkyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣-C8 thioalkyl, and hydroxy; said Cj-Cg alkyl being optionally substituted with one to two halogen atoms or Cx-C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or Cx-C3 alkyl; R30 is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, nitro, cyano, carbo (Cx-C6) alkoxy, carboxy, phenyl, Cx-C8 thioalkyl, and hydroxy; said Cx-C6 alkyl being optionally substituted with halogen or Cx-C3 alkyl; said Cx-C6 alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl;
R3X is selected from the group consisting of hydrogen, halogen, Cx-C6 alkoxy, Cx-C6 alkyl, nitro, cyano, carbo (C╬╣-C6) alkoxy, carboxy, phenyl, C╬╣~C8 thioalkyl, and hydroxy; said C╬╣-C6 alkyl being optionally substituted with one to two halogen atoms or C╬╣~C3 alkyl; said C╬╣-C6 alkoxy being optionally substituted with halogen or C╬╣-C3 alkyl; wherein up to three of R27-R3╬╣ can simultanoeously be hydrogen when only one of X3-X5 is nitrogen; wherein up to two of R27-R3╬╣ 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.
PCT/US1998/026851 1997-12-18 1998-12-18 Piperazine derivatives useful as hypoglycemic agents WO1999031096A1 (en)

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