New compounds useful for dpp-iv enzyme inhibition

Abstract

The present invention relates to the novel compounds of the general formula (I) possessing dipeptidyl peptidase IV enzyme inhibitory activity, pharmaceutical compositions thereof, methods of using said compounds, processes for their preparation and intermediates of the general formulae (II), (IV), (V), (VII), (VIII) and (IX).

1 . A compound of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein
 R is selected from a group consisting of:
 a) a nitrogen-containing mono- or bicyclic aromatic moiety, preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl wherein each nitrogen-containing mono- or bicyclic aromatic moiety is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 2-5 alkoxycarbonyl, halogen, trihalogenomethyl, methylthio, nitro, carboxamido or cyano; 
 b) phenyl, which is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, methylthio, nitro, cyano, C 2-5 alkylcarbonyl, C 2-5 alkoxycarbonyl, C 2-8 dialkylamino; 
 c) R 1a —CH 2 —,
 wherein R 1a  is hydrogen or a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl, and said group is optionally mono- or polysubstituted with the same or different moiety selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano; 
 
 d) R 1a R 2 —CH—,
 wherein R 1a  is selected from a group consisting of C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl or furyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, nitro, amino, cyano, or a phenylcarbonyl moiety which is optionally mono- or polysubstituted with the same or different groups selected from C 1-4 alkyl, -alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano, and R 2  is hydrogen or methyl; 
 
 e) R 1b —CO—,
 wherein R 1b  is a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl or quinoxalinyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 -alkylenedioxy, halogen, trihalogenomethyl, nitro, cyano, amino, or a heterocyclic group, preferably pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl; or 
 
 f) p-toluenesulphonyl; 
 
 B is selected from formula (1), (2), (3), (4) or (5): 
 
     
       
         
         
             
             
         
       
       Z is selected from formula (A), (B), (C), (D) or (E): 
     
     
       
         
         
             
             
         
       
     
     and isomers, solvates and pharmaceutically acceptable salts thereof. 
   
   
       2 . The compound of  claim 1  wherein
 R is selected from a group consisting of:
 a) a nitrogen-containing mono- or bicyclic aromatic moiety, preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl wherein each nitrogen-containing mono- or bicyclic aromatic moiety is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 2-5 alkoxycarbonyl, halogen, trihalogenomethyl, methylthio, nitro, carboxamido or cyano; 
 b) phenyl, which is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, methylthio, nitro, cyano, C 2-5 alkylcarbonyl, C 2-5 alkoxycarbonyl, C 2-8 dialkylamino; 
 c) R 1a —CH 2 —,
 wherein R 1a  is hydrogen or a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl, and said group is optionally mono- or polysubstituted with the same or different moiety selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano; 
 
 d) R 1a R 2 —CH—,
 wherein R 1a  is selected from the group consisting of C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl or furyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, nitro, amino, cyano, or a phenylcarbonyl moiety which is optionally mono- or polysubstituted with the same or different groups selected from C 1-4 alkyl, -alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano, and R 2  is hydrogen or methyl; or 
 
 e) R 1b —CO—,
 wherein R 1b  is a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl or quinoxalinyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, halogen, trihalogenomethyl, nitro, cyano, amino, or a heterocyclic group, preferably pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl; 
 
   B is selected from formula (1), (2), (3), (4) or (5);   Z is formula (A);   
     and isomers, solvates and pharmaceutically acceptable salts thereof. 
   
   
       3 . The compound of  claim 1  wherein
 R is selected from a group consisting of:
 a) a nitrogen-containing mono- or bicyclic aromatic moiety, preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl wherein each nitrogen-containing mono- or bicyclic aromatic moiety is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 2-5 alkoxycarbonyl, halogen, trihalogenomethyl, methylthio, nitro, carboxamido or cyano; 
 b) phenyl, which is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, methylthio, nitro, cyano, C 2-5 alkylcarbonyl, C 2-5 alkoxycarbonyl, C 2-8 dialkylamino; 
 c) R 1a —CH 2 —,
 wherein R 1a  is hydrogen or a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl, and said group is optionally mono- or polysubstituted with the same or different moiety selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano; 
 
 d) R 1a R 2 —CH—,
 wherein R 1a  is selected from the group consisting of C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl or furyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, nitro, amino, cyano, or a phenylcarbonyl moiety which is optionally mono- or polysubstituted with the same or different groups selected from C 1-4 alkyl, -alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano, and R 2  is hydrogen or methyl; or 
 
 e) R 1b —CO—,
 wherein R 1b  is a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl or quinoxalinyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, halogen, trihalogenomethyl, nitro, cyano, amino, or a heterocyclic group, preferably pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl; 
 
   B is selected from formula (1), (2), (3), (4) or (5);   Z is formula (B);   
     and isomers, solvates and pharmaceutically acceptable salts thereof. 
   
   
       4 . The compound of  claim 1  wherein
 R is selected from a group consisting of:
 a) a nitrogen-containing mono- or bicyclic aromatic moiety, preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl wherein each nitrogen-containing mono- or bicyclic aromatic moiety is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 2-5 alkoxycarbonyl, halogen, trihalogenomethyl, methylthio, nitro, carboxamido or cyano; 
 b) phenyl, which is optionally mono- or disubstituted with the same or different groups selected from C 1-4  alkyl, C 1-4  alkoxy, C 1-4  alkylenedioxy, trihalogenomethyl, methylthio, nitro, cyano, C 2-5 alkylcarbonyl, C 2-5  alkoxycarbonyl, C 2-8  dialkylamino; 
 c) R 1a —CH 2 —,
 wherein R 1a  is hydrogen or a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl, and said group is optionally mono- or polysubstituted with the same or different moiety selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano; 
 
 d) R 1a R 2 —CH—, 
   wherein R 1a  is selected from the group consisting of C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl or furyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, nitro, amino, cyano, or a phenylcarbonyl moiety which is optionally mono- or polysubstituted with the same or different groups selected from C 1-4 alkyl, -alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano, and R 2  is hydrogen or methyl; or
 e) R 1b —CO—,
 wherein R 1b  is a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl or quinoxalinyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, halogen, trihalogenomethyl, nitro, cyano, amino, or a heterocyclic group, preferably pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl; 
 
   B is selected from formula (1), (2), (3), (4) or (5);   Z is formula (C);   
     and isomers, solvates and pharmaceutically acceptable salts thereof. 
   
   
       5 . The compound of  claim 1  wherein
 R is selected from a group consisting of:
 a) a nitrogen-containing mono- or bicyclic aromatic moiety, preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl wherein each nitrogen-containing mono- or bicyclic aromatic moiety is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 2-5 alkoxycarbonyl, halogen, trihalogenomethyl, methylthio, nitro, carboxamido or cyano; 
 b) phenyl, which is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, methylthio, nitro, cyano, C 2-5 alkylcarbonyl, C 2-5 alkoxycarbonyl, C 2-8 dialkylamino; 
 c) R 1a CH 2 —,
 wherein R 1a  is hydrogen or a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl, and said group is optionally mono- or polysubstituted with the same or different moiety selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano; 
 
 d) R 1a R 2 —CH—,
 wherein R 1a  is selected from the group consisting of C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl or furyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, nitro, amino, cyano, or a phenylcarbonyl moiety which is optionally mono- or polysubstituted with the same or different groups selected from C 1-4 alkyl, -alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano, and R 2  is hydrogen or methyl; or 
 
 e) R 1b —CO—,
 wherein R 1b  is a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl or quinoxalinyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, halogen, trihalogenomethyl, nitro, cyano, amino, or a heterocyclic group, preferably pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl; 
 
   B is selected from formula (1), (2), (3), (4) or (5);   Z is formula (D);   
     and isomers, solvates and pharmaceutically acceptable salts thereof. 
   
   
       6 . The compound of  claim 1  wherein
 R is selected from a group consisting of:
 a) a nitrogen-containing mono- or bicyclic aromatic moiety, preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl wherein each nitrogen-containing mono- or bicyclic aromatic moiety is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 2-5 alkoxycarbonyl, halogen, trihalogenomethyl, methylthio, nitro, carboxamido or cyano; 
 b) phenyl, which is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, methylthio, nitro, cyano, C 2-5 alkylcarbonyl, C 2-5 alkoxycarbonyl, C 2-8 dialkylamino; 
 c) R 1a —CH 2 —,
 wherein R 1a  is hydrogen or a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl, and said group is optionally mono- or polysubstituted with the same or different moiety selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano; 
 
 d) R 1a R 2 —CH—,
 wherein R 1a  is selected from the group consisting of C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl or furyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, nitro, amino, cyano, or a phenylcarbonyl moiety which is optionally mono- or polysubstituted with the same or different groups selected from C 1-4 alkyl, -alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano, and R 2  is hydrogen or methyl; or 
 
 e) R 1b —CO—,
 wherein R 1b  is a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl or quinoxalinyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, halogen, trihalogenomethyl, nitro, cyano, amino, or a heterocyclic group, preferably pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl; 
 
   B is selected from formula (1), (2), (3), (4) or (5);   Z is formula (E);   
     and isomers, solvates and pharmaceutically acceptable salts thereof. 
   
   
       7 . The compound of  claim 1  wherein
 R is selected from a group consisting of:
 a) a nitrogen-containing mono- or bicyclic aromatic moiety, preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl wherein each nitrogen-containing mono- or bicyclic aromatic moiety is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 2-5 alkoxycarbonyl, halogen, trihalogenomethyl, methylthio, nitro, carboxamido or cyano; 
 b) phenyl, which is optionally mono- or disubstituted with the same or different groups selected from C 1-4  alkyl, C 1-4  alkoxy, C 1-4  alkylenedioxy, trihalogenomethyl, methylthio, nitro, cyano, C 2-5 alkylcarbonyl, C 2-5  alkoxycarbonyl, C 2-8  dialkylamino; 
 c) R 1a —CH 2 —,
 wherein R 1a  is hydrogen or a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl, and said group is optionally mono- or polysubstituted with the same or different moiety selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano; 
 
 d) R 1a R 2 —CH—,
 wherein R 1a  is selected from the group consisting of C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl or furyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, nitro, amino, cyano, or a phenylcarbonyl moiety which is optionally mono- or polysubstituted with the same or different groups selected from C 1-4 alkyl, -alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano, and R 2  is hydrogen or methyl; or 
 
 e) R 1b —CO—,
 wherein R 1b  is a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl or quinoxalinyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, halogen, trihalogenomethyl, nitro, cyano, amino, or a heterocyclic group, preferably pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl; 
 
   B is formula (1);   Z is selected from formula (A), (B), (C), (D) or (E);   
     and isomers, solvates and pharmaceutically acceptable salts thereof. 
   
   
       8 . The compound of  claim 1  wherein
 R is selected from a group consisting of:
 a) a nitrogen-containing mono- or bicyclic aromatic moiety, preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl wherein each nitrogen-containing mono- or bicyclic aromatic moiety is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 2-5 alkoxycarbonyl, halogen, trihalogenomethyl, methylthio, nitro, carboxamido or cyano; 
 b) phenyl, which is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, methylthio, nitro, cyano, C 2-5 alkylcarbonyl, C 2-5 alkoxycarbonyl, C 2-8 dialkylamino; 
 c) R 1a —CH 2 —,
 wherein R 1a  is hydrogen or a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl, and said group is optionally mono- or polysubstituted with the same or different moiety selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano; 
 
 d) R 1a R 2 —CH—,
 wherein R 1a  is selected from the group consisting of C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl or furyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, nitro, amino, cyano, or a phenylcarbonyl moiety which is optionally mono- or polysubstituted with the same or different groups selected from C 1-4 alkyl, -alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano, and R 2  is hydrogen or methyl; or 
 
 e) R 1b —CO—,
 wherein R 1b  is a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl or quinoxalinyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, halogen, trihalogenomethyl, nitro, cyano, amino, or a heterocyclic group, preferably pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl; 
 
   B is formula (2);   Z is selected from formula (A), (B), (C), (D) or (E);   
     and isomers, solvates and pharmaceutically acceptable salts thereof. 
   
   
       9 . The compound of  claim 1  wherein
 R is selected from a group consisting of:
 a) a nitrogen-containing mono- or bicyclic aromatic moiety, preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl wherein each nitrogen-containing mono- or bicyclic aromatic moiety is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 2-5 alkoxycarbonyl, halogen, trihalogenomethyl, methylthio, nitro, carboxamido or cyano; 
 b) phenyl, which is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, methylthio, nitro, cyano, C 2-5 alkylcarbonyl, C 2-5 alkoxycarbonyl, C 2-8 dialkylamino; 
 c) R 1a —CH 2 —,
 wherein R 1a  is hydrogen or a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl, and said group is optionally mono- or polysubstituted with the same or different moiety selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano; 
 
 d) R 1a R 2 —CH—,
 wherein R 1a  is selected from the group consisting of C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl or furyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, nitro, amino, cyano, or a phenylcarbonyl moiety which is optionally mono- or polysubstituted with the same or different groups selected from C 1-4 alkyl, -alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano, and R 2  is hydrogen or methyl; or 
 
 e) R 1b —CO—,
 wherein R 1b  is a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl or quinoxalinyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, halogen, trihalogenomethyl, nitro, cyano, amino, or a heterocyclic group, preferably pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl; 
 
   B is formula (3);   Z is selected from formula (A), (B), (C), (D) or (E);   
     and isomers, solvates and pharmaceutically acceptable salts thereof. 
   
   
       10 . The compound of  claim 1  wherein
 R is selected from a group consisting of:
 a) a nitrogen-containing mono- or bicyclic aromatic moiety, preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl wherein each nitrogen-containing mono- or bicyclic aromatic moiety is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 2-5 alkoxycarbonyl, halogen, trihalogenomethyl, methylthio, nitro, carboxamido or cyano; 
 b) phenyl, which is optionally mono- or disubstituted with the same or different groups selected from C 1-4  alkyl, C 1-4  alkoxy, C 1-4  alkylenedioxy, trihalogenomethyl, methylthio, nitro, cyano, C 2-5 alkylcarbonyl, C2-5 alkoxycarbonyl, C 2-8  dialkylamino; 
 c) R 1a CH 2 —,
 wherein R 1a  is hydrogen or a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl, and said group is optionally mono- or polysubstituted with the same or different moiety selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano; 
 
 d) R 1a R 2 —CH—,
 wherein R 1a  is selected from the group consisting of C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl or furyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, nitro, amino, cyano, or a phenylcarbonyl moiety which is optionally mono- or polysubstituted with the same or different groups selected from C 1-4 alkyl, -alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano, and R 2  is hydrogen or methyl; or 
 
 e) R 1b —CO—,
 wherein R 1b  is a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl or quinoxalinyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, halogen, trihalogenomethyl, nitro, cyano, amino, or a heterocyclic group, preferably pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl; 
 
   B is formula (4);   Z is selected from formula (A), (B), (C), (D) or (E);   
     and isomers, solvates and pharmaceutically acceptable salts thereof. 
   
   
       11 . The compound of  claim 1  wherein
 R is selected from a group consisting of:
 a) a nitrogen-containing mono- or bicyclic aromatic moiety, preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl wherein each nitrogen-containing mono- or bicyclic aromatic moiety is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 2-5 alkoxycarbonyl, halogen, trihalogenomethyl, methylthio, nitro, carboxamido or cyano; 
 b) phenyl, which is optionally mono- or disubstituted with the same or different groups selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, methylthio, nitro, cyano, C 2-5 alkylcarbonyl, C 2-5 alkoxycarbonyl, C 2-8 dialkylamino; 
 c) R 1a —CH 2 —,
 wherein R 1a  is hydrogen or a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl, and said group is optionally mono- or polysubstituted with the same or different moiety selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano; 
 
 d) R 1a R 2 —CH—,
 wherein R 1a  is selected from the group consisting of C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl or furyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, trihalogenomethyl, nitro, amino, cyano, or a phenylcarbonyl moiety which is optionally mono- or polysubstituted with the same or different groups selected from C 1-4 alkyl, -alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano, and R 2  is hydrogen or methyl; or 
 
 e) R 1b —CO—,
 wherein R 1b  is a group selected from C 1-4 alkyl, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl or quinoxalinyl, and said group is optionally mono- or polysubstituted with the same or different moieties selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, halogen, trihalogenomethyl, nitro, cyano, amino, or a heterocyclic group, preferably pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl; 
 
   B is formula (5);   Z is selected from formula (A), (B), (C), (D) or (E);   
     and isomers, solvates and pharmaceutically acceptable salts thereof. 
   
   
       12 . The compound of  claim 1  wherein,
 B is selected from formula (1), (2), (4) or (5);   Z is selected from formula (A), (B) or (D);   
     and isomers, solvates and pharmaceutically acceptable salts thereof. 
   
   
       13 . The compound of  claim 1  wherein,
 B is formula (1);   Z is selected from formula (A), (B) or (D);   
     and isomers, solvates and pharmaceutically acceptable salts thereof. 
   
   
       14 . The compound of  claim 1  wherein,
 B is selected from formula (2) or (4);   Z is formula (A);   
     and isomers, solvates and pharmaceutically acceptable salts thereof. 
   
   
       15 . The compound of the formula (1) which is:
 (2S)-4,4-difluoro-1-{N-[3-(pyrimidin-2-ylamino)-1-adamantyl]glycyl}pyrrolidine-2-carbonitrile;   (2S)-4,4-difluoro-1-(N-{3-[(3-nitrobenzyl)amino]-1-adamantyl}glycyl)pyrrolidine-2-carbonitrile;   N-(3-{[2-(2-cyano-(2S)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl]amino}-1-adamantyl)-4-methoxybenzamide;   (2S)-4,4-difluoro-1-[N-(3-pyrimidin-2-yl-3-azabicyclo[3.2.1]oct-8-yl)exo-aminoacetyl]pyrrolidine-2-carbonitrile;   (2S)-4,4-difluoro-1-[N-(3-pyrimidin-2-yl-3-azabicyclo[3.2.1]oct-8-yl)endo-aminoacetyl]pyrrolidine-2-carbonitrile;   (2S)-4,4-difluoro-1-[N-(3-methyl-8-pyrimidin-2-yl-8-azabicyclo[3.2.1]oct-3-yl) exo-aminoacetyl]pyrrolidine-2-carbonitrile;   (2S,4S)-4-fluoro-1-{N-[3-(pyrimidin-2-ylamino)-1-adamantyl]glycyl}pyrrolidine-2-carbonitrile;   (4R)-3-{N-[3-(pyrimidin-2-ylamino)-1-adamantyl]glycyl}-1,3-thiazolidine-4-carbonitrile;   (4S)-3-{N-[3-(pyrimidin-2-ylamino)-1-adamantyl]glycyl}-1,3-oxazolidine-4-carbonitrile;   (2S)-4,4-difluoro-1-{N-[3-(1,2,4-triazin-3-ylamino)-1-adamantyl]glycyl}pyrrolidine-2-carbonitrile;   (2S)-4,4-difluoro-1-{N-[3-(pyrazin-2-ylamino)-1-adamantyl]glycyl}pyrrolidine-2-carbonitrile;   (2S)-1-(N-{3-[(4-cyanophenyl)amino]-1-adamantyl}glycyl)-4,4-difluoropyrrolidine-2-carbonitrile;   6-[(3-{[2-(2-cyano-(2S)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl]amino}-1-adamantyl)amino]nicotinonitrile;   (2S)-4,4-difluoro-1-[N-(3-{[5-(trifluoromethyl)pyridin-2-yl]amino}-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile;   (2S,4S)-4-fluoro-1-[N-(3-{[5-(trifluoromethyl)pyridin-2-yl]amino}-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile;   (2S)-4,4-difluoro-1-{N-[3-(1,3-thiazol-2-ylamino)-1-adamantyl]glycyl}pyrrolidine-2-carbonitrile;   (2S)-1-(N-{3-[(1-ethyl-1H-pyrazol-5-yl)amino]-1-adamantyl}glycyl)-4,4-difluoropyrrolidine-2-carbonitrile;   (2S)-4,4-difluoro-1-(N-{3-[(5-methylisoxazol-3-yl)amino]-1-adamantyl}glycyl)pyrrolidine-2-carbonitrile;   (2S)-4,4-difluoro-1-{N-[3-(quinolin-2-ylamino)-1-adamantyl]glycyl}pyrrolidine-2-carbonitrile;   (2S,4S)-4-fluoro-1-{N-[3-(quinolin-2-ylamino)-1-adamantyl]glycyl}pyrrolidine-2-carbonitrile;   (2S)-4,4-difluoro-1-{N-[3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1-adamantyl]glycyl}pyrrolidine-2-carbonitrile;   (2S,4S)-4-fluoro-1-{N-[3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1-adamantyl]glycyl}pyrrolidine-2-carbonitrile;   (4R)-3-{N-[3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1-adamantyl]glycyl}-1 ,3-thiazolidine-4-carbonitrile;   (2S)-1-(N-{3-[(4-cyanobenzyl)amino]-1-adamantyl}glycyl)-4,4-difluoropyrrolidine-2-carbonitrile;   (2S)-4,4-difluoro-[4N-(3-{[4-(trifluoromethyl)benzyl]amino}-1-adamantyl) glycyl]pyrrolidine-2-carbonitrile;   (2S)-4,4-difluoro-1-(N-{3-[(3-fluorobenzyl)amino]-1-adamantyl}glycyl)pyrrolidine-2-carbonitrile;   (2S)-4,4-difluoro-1-(N-{3-[(3,4,5-trimethoxybenzyl)amino]-1-adamantyl}glycyl)pyrrolidine-2-carbonitrile;   (2S)-4,4-difluoro-1-(N-{3-[(pyridin-3-ylmethyl)amino]-1-adamantyl}glycyl)pyrrolidine-2-carbonitrile;   (2S)-4,4-difluoro-1-(N-{3-[(pyridazin-3-ylmethyl)amino]-1-adamantyl}glycyl)pyrrolidine-2-carbonitrile;   (2S)-4,4-difluoro-1-(N-{3-[(1 ,3-thiazol-2-ylmethyl)amino]-1-adamantyl}glycyl)pyrroline-2-carbonitrile;   4-chloro-N-(3-{[2-(2-cyano-(2S)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl]amino}-1-adamantyl)benzamide;   N-(3-{[2-(2-cyano-(2S)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl]amino}-1-adamantyl)-3-fluorobenzamide;   (2E)-N-(3-{[2-(2-cyano-(2S)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl]amino}-1-adamantyl)-3-phenylacrylamide;   N-(3-{[2-(2-cyano-(2S)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl]amino}-1-adamantyl)thiophene-2-carboxamide;   (2S)-1-[N-(3-pyrimidin-2-yl-3-azabicyclo[3.2.1]oct-8-yl)endo-amino acetyl]pyrrolidine-2-carbonitrile;   (2S)-4,4-difluoro-1-[N-(3-pyrimidin-2-yl-3-azabicyclo[3.3.1]non-9-yl)glycyl]pyrrolidine-2-carbonitrile;   6-(9-{[2-(2-cyano-(2S)-4,4-difluoropyrrolidin-1-yl)-2-oxo ethyl]amino}-3-azabicyclo[3.3.1]non-3-yl)pyridazine-3-carbonitrile;   (2S)-1-[N-(3-pyrimidin-2-yl-3-azabicyclo[3.3.1]non-9-yl)glycyl]pyrrolidine-2-carbonitrile ;   
     and isomers, solvates and pharmaceutically acceptable salts thereof. 
   
   
       16 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       17 . A process for preparing a compound of Formula I of  claim 1  comprising the steps of:
 a) reacting a compound of formula (II)
   R—B—NH 2   (II) 
   
     with a compound of formula (III) 
     
       
         
         
             
             
         
       
     
     wherein the meanings of R, B and Z are as defined in  claim 1 ; and
 b) isolating the resulting compound of the general formula (I) or its salt from the reaction mixture. 
 
   
   
       18 . The process of  claim 17  wherein the compound of formula II is prepared from 3-hydroxy-1-amino-adamantane. 
   
   
       19 . A method of inhibiting DPP-IV enzyme in a patient in need thereof comprising administering a therapeutically effective amount of a compound of  claim 1 . 
   
   
       20 . A method of treating a disease or disorder associated with DPP-IV enzyme activity in a patient in need thereof comprising administering a therapeutically effective amount of a compound of  claim 1 . 
   
   
       21 . A compound of formula (II)
   R—B—NH 2   (II)   
     wherein R and B are as defined in formula I of  claim 1 ; 
     and salts thereof. 
   
   
       22 . A compound of formula (V) 
     
       
         
         
             
             
         
       
     
     wherein R and B are as defined in formula I of  claim 1 , and Y is acetyl or tert-butoxycarbonyl group. 
   
   
       23 . A compound of formula (VII) 
     
       
         
         
             
             
         
       
     
     wherein Z is selected from formula (A), (B), (D) or (E) as defined in Formula I of  claim 1 . 
   
   
       24 . A compound of formula (VIII) 
     
       
         
         
             
             
         
       
     
     wherein Z is selected from formula (A), (B), (D) or (E) as defined in Formula I of  claim 1 . 
   
   
       25 . A compound of formula (IX) 
     
       
         
         
             
             
         
       
     
     wherein Z is selected from formula (A), (B), (D) or (E) as defined in Formula I of  claim 1 . 
   
   
       26 . A compound of formula (III) 
     
       
         
         
             
             
         
       
     
     wherein Z is selected from formula (A), (B), (D) or (E) as defined in Formula I of  claim 1 .