Pyrrolidine oxadiazole-and thiadiazole oxime derivatives being oxytocin receptor antagonists

Abstract

The present invention is related to pyrrolidine oxadiazole and thiadiazole derivatives for use as pharmaceutically active compounds, as well as pharmaceutical formulations containing such pyrrolidine oxadiazole derivatives. Said pyrrolidine derivatives are useful in the treatment and/or prevention of preterm labor, premature birth and dysmenorrhea. In particular, the present invention is related to pyrrolidine derivatives displaying a substantial modulatory, notably an antagonist activity of the oxytocin receptor. More preferably, said compounds are useful in the treatment and/or prevention of disease states mediated by oxytocin, including preterm labor, premature birth and dysmenorrhea. The present invention is furthermore related to novel pyrrolidine derivatives as well as to methods of their preparation. B is a oxadiazole or thiadiazole group.

1 - 25 . (canceled)  
     
     
         26 . A method, which comprises: 
 administering a pharmaceutical composition to a mammal in need thereof    said composition comprising a pyrrolidine oxadiazole compound according to formula I:                          a geometrical isomer thereof, an optically active form thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, or a pharmaceutically acceptable salts thereof, wherein:    A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —SO 2 —, —SO 2 NH—, and —CH 2 —;    B is an oxadiazole or thiadiazole ring;    R 1  is selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, aryl, heteroaryl, C 1 -C 6  alkyl aryl, and C 1 -C 6  alkyl heteroaryl, wherein R 1  can form with the O atom to which it is attached a 3-8 membered, saturated or unsaturated heterocyclic ring which may contain 1-2 further heteroatoms selected from the group consisting of N, S and O and which is optionally fused with an aryl, heteroaryl or 3-8 membered saturated or unsaturated cycloalkyl ring;    R 2  is selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, aryl, heteroaryl, heteroarylalkyl, 3-8-membered cycloalkyl, acyl, C 1 -C 6 -alkyl aryl, and C 1 -C 6 -alkyl heteroaryl, wherein said cycloalkyl or aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl or aryl or heteroaryl groups;    R 3 , R 4 , R 5  and R 6  are independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy.    
     
     
         27 . The method as claimed in  claim 26 , wherein in the pyrrolidine oxadiazole compound R 1  is selected from the group consisting of H and a —C 1 -C 6  alkyl group.  
     
     
         28 . The method as claimed in  claim 26 , wherein in the pyrrolidine oxadiazole compound A is —(C═O)—.  
     
     
         29 . The method as claimed in  claim 26 , wherein in the pyrrolidine oxadiazole compound R 2  is an aryl or a heteroaryl group.  
     
     
         30 . The method as claimed in  claim 29 , wherein in the pyrrolidine oxadiazole compound R 2  is a phenyl group.  
     
     
         31 . The method as claimed in  claim 30 , wherein in the pyrrolidine oxadiazole compound said phenyl group is substituted by a phenyl group.  
     
     
         32 . The method as claimed in  claim 26 , wherein in the pyrrolidine oxadiazole compound B is an oxadiazole of formula Ia or IIb:  
       
         
           
           
               
               
           
         
         wherein R 7  is selected from the group consisting of hydrogen, sulfonyl, amino, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, and C 2 -C 6 -alkynyl, wherein said alkyl, alkenyl, alkynyl chains may be interrupted by a heteroatom selected from N, O or S, aryl, heteroaryl, saturated 3-8-membered cycloalkyl, unsaturated 3-8-membered cycloalkyl, heterocycloalkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, an acyl moiety, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 1 -C 6 -alkenyl aryl, C 1 -C 6 -alkenyl heteroaryl, C 1 -C 6 -alkynyl aryl, C 1 -C 6 -alkynyl heteroaryl, C 1 -C 6 -alkyl cycloalkyl, C 1 -C 6 -alkyl heterocycloalkyl, C 1 -C 6 -alkenyl cycloalkyl, C 1 -C 6 -alkenyl heterocycloalkyl, C 1 -C 6 -alkynyl cycloalkyl, C 1 -C 6 -alkynyl heterocycloalkyl, alkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkyl carboxy, C 1 -C 6 -alkyl acyl, aryl acyl, heteroaryl acyl, C 3 -C 8 -(hetero)cycloalkyl acyl, C 1 -C 6 -alkyl acyloxy, C 1 -C 6 -alkyl alkoxy, C 1 -C 6 -alkyl alkoxycarbonyl, C 1 -C 6 -alkyl aminocarbonyl, C 1 -C 6 -alkyl acylamino, acylamino, C 1 -C 6 -alkyl ureido, C 1 -C 6 -alkyl carbamate, C 1 -C 6 -alkyl amino, C 1 -C 6 -alkyl ammonium, C 1 -C 6 -alkyl sulfonyloxy, C 1 -C 6 -alkyl sulfonyl, C 1 -C 6 -alkyl sulfinyl, C 1 -C 6 -alkyl sulfanyl, C 1 -C 6 -alkyl sulfonylamino, C 1 -C 6 -alkyl aminosulfonyl, hydroxy and halogen.  
       
     
     
         33 . The method as claimed in  claim 32 , wherein in the pyrrolidine oxadiazole compound R 7  is selected from the group consisting of a sulfonyl moiety, an amino moiety, a C 1 -C 6 -alkyl group, C 2 -C 6 -alkenyl group, C 2 -C 6 -alkynyl group, aryl group, heteroaryl group, 3-8-membered cycloalkyl group, optionally containing at least one heteroatom selected from the group consisting of N, O, and S, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 1 -C 6 -alkenyl aryl, C 1 -C 6 -alkenyl heteroaryl, alkoxycarbonyl, carboxylic amide, C 1 -C 6 -alkyl carbonyl, C 1 -C 6 -arylcarbonyl, C 1 -C 6 -heteroarylcarbonyl, and C 4 -C 8 -cycloalkylcarbonyl, said groups substituted by at least one sulfonyl moiety or amino moiety.  
     
     
         34 . The method as claimed in  claim 33 , wherein in the pyrrolidine oxadiazole compound R 7  is selected from the group consisting of a C 1 -C 6 -alkyl amino, heterocycloalkyl, C 1 -C 6 -alkyl heterocycloalkyl, aminocarbonyl, C 1 -C 6 -alkylamino carbonyl, C 1 -C 6  alkyl acyl amino, C 1 -C 6  alkyl sulfonyl and C 1 -C 6 -alkyl.  
     
     
         35 . The method as claimed in  claim 34 , wherein in the pyrrolidine oxadiazole compound R 7  is selected from the group consisting of dimethyl aminomethyl, 2-(dimethylamino)ethyl, 1-methyl-3-piperidinyl and 4-(acetyl-1-piperazinyl)methyl.  
     
     
         36 . The method as claimed in  claim 26 , wherein in the pyrrolidine oxadiazole compound B is an isoxadiazole of formula III or IV:  
       
         
           
           
               
               
           
         
         wherein X is O or S;  
         R 8  is a hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, aryl, heteroaryl, saturated 3-8-membered cycloalkyl, unsaturated 3-8-membered cycloalkyl, optionally containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, an acyl moiety, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 1 -C 6 -alkenyl aryl, C 1 -C 6 -alkenyl heteroaryl, alkoxycarbonyl, carboxylic amide, C 1 -C 6 -alkoxy, aryloxy, heteroaryloxy, halogen, cyano, C 1 -C 6 -alkyl carbonyl, arylcarbonyl, heteroarylcarbonyl, saturated C 4 -C 8 -cycloalkylcarbonyl, and unsaturated C 4 -C 8 -cycloalkylcarbonyl, wherein said cycloalkyl or aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl or aryl or heteroaryl group and wherein said alkyl, alkenyl, alkynyl chain may be interrupted by an heteroatom selected from the group consisting of N, O and S.  
       
     
     
         37 . The method as claimed in  claim 26 , wherein in the pyrrolidine oxadiazole compound each of R 3 , R 4 , R 5  and R 6  is H.  
     
     
         38 . The method as claimed in  claim 26 , wherein in the pyrrolidine oxadiazole compound A is —(C═O)—, R 1  is a methyl group, R 2  is a biphenyl group, each of R 3 , R 4 , R 5  and R 6  is H and B is an oxadiazole ring of formulae Ia, IIb, III or IV.  
     
     
         39 . The method as claimed in  claim 38 , wherein in the pyrrolidine oxadiazole compound B is an oxadiazole ring of formula Ia or IIb.  
     
     
         40 . The method as claimed in  claim 26 , wherein in the pyrrolidine oxadiazole compound is selected from the group consisting of: 
 (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(1,3,4-oxadiazol-2-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-5-(3-benzyl-1,2,4-oxadiazol-5-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-{[(2-furylmethyl)sulfanyl]methyl}-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(2-pyridinylsulfanyl)methyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(2-thienylsulfanyl)methyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(methylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(5-methyl-3-isoxazolyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-thienylmethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(3-{[(2-furylmethyl)sulfonyl]methyl}-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-5-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(RS)-hydroxy(phenyl)methyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(1RS)-1-hydroxypropyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(1S,2R)-2-hydroxycyclohexyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(3RS)-piperidinyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{3-[(2RS)-piperidinyl]-1,2,4-oxadiazol-5-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-[(2′-chloro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-1-{[2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-3-pyrrolidinone O-methyloxime,    (3Z,5S)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-[(4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(1,2,4-oxadiazol-3-yl)-3-pyrrolidinone O-methyloxime,    (3E,5S)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    (3E,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    (3Z,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(phenoxymethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-phenyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinone O-methyloxime,    N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)acetamide,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[4-(hydroxymethyl)phenyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(2-hydroxyethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(2S)-2-hydroxy-2-phenylethyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime,    {3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methylformamide,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(methoxymethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(2-phenoxyethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(2-methoxyethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-5-[5-(1-acetyl-4-piperidinyl)-1,2,4-oxadiazol-3-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(3-thienyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-cyclopentyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(RS)-hydroxy(phenyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(1RS)-1-hydroxy-2-phenylethyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(1R)-1-(dimethylamino)-2-phenylethyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(3-pyridinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(4-pyridinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime,    (3Z,5S)-5-{5-[(4-acetyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-5-[3-(1-acetyl-4-piperidinyl)-1,2,4-oxadiazol-5-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-5-{5-[(4-acetyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime,    N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-3-(1-piperidinyl)propanamide,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3S)-1-methylpiperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3R)-1-methylpiperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(6-hydroxy-3-pyridinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime,    (3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-5-{5-[(1S,2R)-1-amino-2-hydroxypropyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3S)-piperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(3R)-piperidinyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5RS)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-methyl-3-piperidinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime,    tert-butyl (3R)-3-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-1-piperidinecarboxylate,    4-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-2,6-piperazinedione,    (3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime,    (3Z,5S)-1-[(2′-chloro-4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-methyl-4-piperidinyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(1-methyl-4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-5-{5-[(1S)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime,    5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-N-[3-(dimethylamino)propyl]-1,2,4-oxadiazole-3-carboxamide,    (3E,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime,    tert-butyl (3S)-3-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-1-piperidinecarboxylate,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime,    (3Z,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime,    ethyl 5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazole-3-carboxylate,    (3E,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime,    (3Z,5RS)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime,    N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-3-(dimethylamino)propanamide,    tert-butyl 4-(2-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}ethyl)-1-piperazinecarboxylate,    (3EZ,5S)-1-[(2′-chloro-4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-[(4′-fluoro-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[2-(dimethylamino)ethyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime,    2-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}ethyl [(tert-butoxycarbonyl)amino]acetate,    N-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-2-(dimethylamino)acetamide,    (3EZ,5S)-1-[(2′-chloro-4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-5-{5-[(1S)-1-amino-2-tert-butoxyethyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime,    tert-butyl 4-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-pyrrolidinyl]-1,2,4-oxadiazol-3-yl}-1-piperidinecarboxylate,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-piperazinylmethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime,    tert-butyl (4S)-4-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-4-[(tert-butoxycarbonyl)amino]butanoate,    4-{[(2S,4EZ)-2-(5-{[(tert-butoxycarbonyl)amino]methyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl,    tert-butyl 2-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}ethylcarbamate,    2-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}ethyl amino acetate,    (3E,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    (3EZ,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime,    4-{[(2S,4EZ)-2-(5-{(1S)-2-tert-butoxy-1-[(tert-butoxycarbonyl)amino]ethyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl,    (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(5-vinyl-1,2,4-oxadiazol-3-yl)-3-pyrrolidinone O-methyloxime,    4-{[(2S,4EZ)-2-(5-{(1S,2R)-2-tert-butoxy-1-[(tert-butoxycarbonyl)amino]propyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl,    (3Z,5S)-1-[(2′,4′-difluoro[1,1′-biphenyl]-4-yl)carbonyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyrrolidinone O-methyloxime, and    tert-butyl 4-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-1-piperazinecarboxylate.    
     
     
         41 . The method as claimed in  claim 26 , wherein the mammal is a human.  
     
     
         42 . The method as claimed in  claim 26 , wherein the pyrrolidine oxadiazole compound is administered in an amount effective for treating, preventing or treating and preventing, at least one of preterm labor, premature birth or dysmenorrhea.  
     
     
         43 . The method as claimed in  claim 26 , wherein the pyrrolidine oxadiazole compound is administered in an amount effective for modulating an oxytocin receptor.  
     
     
         44 . The method as claimed in  claim 26 , wherein modulating oxytocin receptor includes at least one of blocking the oxytocin receptor or antagonizing the binder of the oxytocin to a receptor.  
     
     
         45 . The method as claimed in  claim 26 , wherein the pyrrolidine oxadiazole compound is administered in an amount effective for the treatment or prevention of at least one disorder mediated by the oxytocin receptor.  
     
     
         46 . The method as claimed in  claim 26 , wherein the administering is carried out orally.