Benzimidazole Derivatives, Compositions Containing Them, Preparation Thereof and Uses Thereof

Abstract

Compounds of formula I or pharmaceutically acceptable salts thereof: wherein R 1 , R 2 , R 3 , R 4 and Z are as defined in the specification as well as salts and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.

1 . A compound of formula I or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein
 Z is selected from O═ and S═; 
 R 1  is selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, R 5 R 6 N—C 1-6 alkyl, R 5 O—C 1-6  alkyl, R 5 C(═O)N(—R 6 )—C 1-6 alkyl, R 5 R 6 NS(═O) 2 —C 1-6 alkyl, R 5 CS(═O) 2 N(—R 6 )—C 1-6 alkyl, R 5 R 6 NC(═O)N(—R 7 )—C 1-6 alkyl, R 5 R 6 NS(═O) 2 N(R 7 )—C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl, C 6-10 aryl-C(═O)—C 1-6 alkyl, C 3-10 cycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl-C 1-6 alkyl, C 3-6 heterocyclyl-C 1-6 alkyl, C 3-6 heterocyclyl-C(═O)—C 1-6 alkyl, C 1-10 hydrocarbylamino, R 5 R 6 N—, R 5 O—, R 5 C(═O)N(—R 6 )—, R 5 R 6 NS(═O) 2 —, R 5 CS(═O) 2 N(—R 6 )—, R 5 R 6 NC(═O)N(—R 7 )—, R 5 R 6 NS(═O) 2 N(R 7 )—, C 6-10 aryl, C 6-10 aryl-C(═O)—, C 3-10 cycloalkyl, C 4-8 cycloalkenyl, C 3-6 heterocyclyl and C 3-6 heterocyclyl-C(═O)—; wherein said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 6-10 aryl-C 1-6 alkyl, C 6-10 aryl-C(═O)—C 1-6 alkyl, C 3-10 cycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl-C 1-6 alkyl, C 3-6 heterocyclyl-C 1-6 alkyl, C 3-6 heterocyclyl-C(═O)—C 1-6 alkyl, C 1-10  hydrocarbylamino, C 6-10 aryl, C 6-10 aryl-C(═O)—, C 3-10 cycloalkyl, C 4-8 cycloalkenyl, C 3-6 heterocyclyl or C 3-6 heterocyclyl-C(═O)— used in defining R 1  is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and —NR 5 R 6 ; 
 R 2  is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl-C 1-6 alkyl, C 3-6 heterocycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl, R 5 R 6 N—, C 3-5 heteroaryl, C 6-10 aryl and C 3-6 heterocycloalkyl, wherein said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl-C 1-6 alkyl, C 3-6 heterocycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl, C 3-5 heteroaryl, C 6-10 aryl or C 3-6 heterocycloalkyl used in defining R 2  is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and —NR 5 R 6 ; 
 wherein R 5 , R 6  and R 7  are independently selected from —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and a divalent C 1-6 group that together with another divalent R 5 , R 6  or R 7  forms a portion of a ring; and 
 R 3  is selected from R 8 , R 8 O—, and R 3 R 9 N—; 
 each of R 4 , R 8  and R 9  is independently selected from —H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-6 alkyl, C 3-6 heterocyclyl, C 6-10 aryl, C 3-6 heterocylcyl-C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl, and a divalent C 1-6 group that together with another divalent group selected from R 4 , R 8  and R 9  forms a portion of a ring, wherein said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-6 alkyl, C 3-6 heterocyclyl, C 6-10 aryl, C 3-6 heterocylcyl-C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl, or divalent C 1-6 group is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy and amino. 
 
   
   
       2 . A compound as claimed in  claim 1 , wherein
 Z is O═;   R 1  is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, R 5 R 6 N—C 1-4 alkyl, R 5 O—C 1-4 alkyl, R 5 C(═O)N(—R 6 )—C 1-4 alkyl, phenyl-C 1-4 alkyl, phenyl-C(═O)—C 1-4 alkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 4-6 cycloalkenyl-C 1-4 alkyl, C 3-6 heterocyclyl-C 1-4 alkyl, C 3-6 heterocyclyl-C(═O)—C 1-4 alkyl, R 5 R 6 N—, R 5 O—, R 5 R 6 NS(═O) 2 —, C 6-10 aryl, C 6-10 aryl-C(═O)—, C 3-01 cycloalkyl, C 4-6 cycloalkenyl, C 3-6 heterocyclyl and C 3-6 heterocyclyl-C(═O)—; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl-C 1-4 alkyl, phenyl-C(═O)—C 1-4 alkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 4-6 cycloalkenyl-C 1-4 alkyl, C 3-6 heterocyclyl-C 1-4 alkyl, C 3-6 heterocyclyl-C(═O)—C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C(═O)—, C 3-10 cycloalkyl, C 4-6 cycloalkenyl, C 3-6 heterocyclyl or C 3-6 heterocyclyl-C(═O)— used in defining R 1  is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and —NR 5 R 6 ;   wherein R 5  and R 6  are independently selected from —H, C 1-6 alkyl and C 2-6 alkenyl;   R 2  is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, C 4-6 cycloalkenyl-C 1-4 alkyl, C 3-6 heterocycloalkyl-C 1-4 alkyl, C 4-6 cycloalkenyl, C 3-5 heteroaryl, R 5 R 6 N—, phenyl and C 3-6 heterocycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, C 4-6 cycloalkenyl-C 1-4 alkyl, C 3-6 heterocycloalkyl-C 1-4 alkyl, C 4-6 cycloalkenyl, C 3-5 heteroaryl, phenyl or C 3-6 heterocycloalkyl used in defining R 2  is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy and amino; and   R 3  is selected from R 8 , R 8 O—, R 3 HN— and R 8 R 9 N—;   R 8  and R 9  are independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, C 3-6 heterocyclyl, phenyl, C 3-6 heterocylcyl-C 1-4 alkyl, and phenyl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, C 3-6 heterocyclyl, phenyl, C 3-6 heterocylcyl-C 1-4 alkyl, or phenyl-C 1-4 alkyl is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy and amino; and   R 4  is selected from —H, C 1-6 alkyl and C 2-6 alkenyl.   
   
   
       3 . A compound as claimed  claim 1 , wherein
 Z is O═;   R 1  is selected from C 1-6 alkyl, C 2-6 alkenyl, R 5 R 6 N—C 1-4 alkyl, R 5 O—C 1-4 alkyl, R 5 C(═O)N(—R 6 )—C 1-4 alkyl, phenyl-C 1-4 alkyl, phenyl-C(═O)—C 1-4 alkyl, C 3-6 cycloalkyl-C 1-4 alkyl, C 4-6 cycloalkenyl-C 1-4 alkyl, C 3-6 heterocyclyl-C 1-4 alkyl, C 3-6 heterocyclyl-C(═O)—C 1-4 alkyl, phenyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl and C 3-6 heterocyclyl-C(═O)—; wherein said C 1-6 alkyl, C 2-6 alkenyl, R 5 R 6 N—C 1-4 alkyl, R 5 O—C 1-4 alkyl, R 5 C(═O)N(—R 6 )—C 1-4 alkyl, phenyl-C 1-4 alkyl, phenyl-C(═O)—C 1-4 alkyl, C 3-6 cycloalkyl-C 1-4 alkyl, C 4-6 cycloalkenyl-C 1-4 alkyl, C 3-6 heterocyclyl-C 1-4 alkyl, C 3-6 heterocyclyl-C(═O)—C 1-4 alkyl, phenyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl or C 3-6 heterocyclyl-C(═O)— used in defining R 1  is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and —NR 5 R 6 ;   R 2  is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, R 5 R 6 N—, C 3-6 cycloalkyl-C 1-4 alkyl, C 3-6 heterocycloalkyl-C 1-4 alkyl, C 3-6 heterocycloalkyl, C 3-5 heteroaryl, and phenyl wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, C 3-6 heterocycloalkyl-C 1-4 alkyl, C 3-6 heterocycloalkyl, C 3-5 heteroaryl, and phenyl used in defining R 2  is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and —NR 5 R 6 ;   R 5  and R 6  are independently selected from —H, C 1-6 alkyl and C 2-6 alkenyl; and   R 3  is selected from R 8 , R 8 O—, R 3 HN— and R 3 R 9 N—;   R 8  and R 9  are independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, C 3-5 heterocyclyl, phenyl, C 3-5 heterocylcyl-C 1-4 alkyl, and phenyl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, C 3-5 heterocyclyl, phenyl, C 3-5 heterocylcyl-C 1-4 alkyl, or phenyl-C 1-4 alkyl is optionally substituted by one or more groups selected from halogen, cyano, methoxy, methyl, and ethyl; and   R 4  is selected from —H and C 1-4 alkyl.   
   
   
       4 . A compound as claimed in  claim 1 , wherein
 Z is O═;   R 1  is selected from cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl, ethyl, propyl, adamantyl, adamantylmethyl, allyl, isopentyl, benzyl, methoxyethyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl, cyclohexyloxy, cyclohexylamino, dimethylaminoethyl, 4-pyridylmethyl, 2-pyridylmethyl, 1-pyrrolylethyl, 1-morpholinoethyl, 4,4-difluorocyclohexylmethyl, cyclohexylmethyl, 2-pyrrolidylmethyl, N-methyl-2-pyrrolidylmethyl, 2-piperidylmethyl, N-methyl-2-piperidylmethyl, 3-thienylmethyl, (2-nitrothiophene-5-yl)-methyl, (1-methyl-1H-imidazole-2-yl)methyl, (5-(acetoxymethyl)-2-furyl)methyl), (2,3-dihydro-1H-isoindole-1-yl)methyl, and 5-(2-methylthiazolyl);   R 2  is selected from t-butyl, n-butyl, 2-methyl-2-butyl, cyclohexyl, cyclohexylmethyl, n-pentyl, isopentyl, trifluoromethyl, 1,1-difluoroethyl, N-piperidyl, dimethylamino, phenyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl, 2-methoxy-2-propyl and N-morpholinyl;   R 3  is selected from methyl, ethyl, isopropyl, n-butyl, t-butyl, iso-butyl, phenyl, pyridyl, imidazolyl, naphthalenyl, isopropylamino and 2-thienyl; and   R 4  is selected from —H, methyl and ethyl.   
   
   
       5 . A compound selected from: 
     N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N-methylthiophene-2-carboxamide, 
     N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N,2,2-trimethylpropanamide, 
     N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N,2-dimethylpropanamide, 
     N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N,3-dimethylbutanamide, 
     N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N′-isopropyl-N-methylurea, 
     N-[1-(Cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide, 
     N-[1-(Cyclohexylmethyl)-2-(1H-dimethylpropyl)-1H-benzimidazol-5-yl]-N′-isopropylurea, 
     N-[1-(Cyclohexylmethyl)-2-(1H-dimethylpropyl)-1H-benzimidazol-5-yl]-2,2-dimethylbutanamide, 
     N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]acetamide, 
     N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N-methylacetamide, 
     N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-2,2-dimethylpropanamide, and pharmaceutically acceptable salts thereof. 
   
   
       6 . A compound according to any one of  claims 1 - 5  for use as a medicament. 
   
   
       7 . The use of a compound according to any one of  claims 1 - 5  in the manufacture of a medicament for the therapy of pain. 
   
   
       8 . The use of a compound according to any one of  claims 1 - 5  in the manufacture of a medicament for the treatment of anxiety disorders. 
   
   
       9 . The use of a compound according to any one of  claims 1 - 5  in the manufacture of a medicament for the treatment of cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, gastrointestinal disorders and cardiavascular disorders. 
   
   
       10 . A pharmaceutical composition comprising a compound according to any one of  claims 1 - 5  and a pharmaceutically acceptable carrier. 
   
   
       11 . A method for the therapy of pain in a warm-blooded animal, comprising the step of administering to said animal in need of such therapy a therapeutically effective amount of a compound according to any one of  claims 1 - 5 . 
   
   
       12 . A method for preparing a compound of formula II, 
     
       
         
         
             
             
         
       
       comprising the step of reacting a compound of formula III, 
     
     
       
         
         
             
             
         
       
     
     with a compound of R 3 C(═O)X to form the compound of formula II, 
     wherein
 X is selected from —Cl, —Br, —I, —OH, —OCH 3  and —OCH 2 CH 3 ; 
 R 1  is selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, R 5 R 6 N—C 1-6 alkyl, R 5 O—C 1-6  alkyl, R 5 C(═O)N(—R 6 )—C 1-6 alkyl, R 5 R 6 NS(═O) 2 —C 1-6 alkyl, R 5 CS(═O) 2 N(—R 6 )—C 1-6 alkyl, R 5 R 6 NC(═O)N(—R 7 )—C 1-6 alkyl, R 5 R 6 NS(═O) 2 N(R 7 )—C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl, C 6-10 aryl-C(═O)—C 1-6 alkyl, C 3-10 cycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl-C 1-6 alkyl, C 3-6 heterocyclyl-C 1-6 alkyl, C 3-6 heterocyclyl-C(═O)—C 1-6 alkyl, C 1-10 hydrocarbylamino, R 5 R 6 N—, R 5 O—, R 5 C(═O)N(—R 6 )—, R 5 R 6 NS(═O) 2 —, R 5 CS(═O) 2 N(—R 6 )—, R 5 R 6 NC(═O)N(—R 7 )—, R 5 R 6 NS(═O) 2 N(R 7 )—, C 6-10 aryl, C 6-10 aryl-C(═O)—, C 3-10 cycloalkyl, C 4-8 cycloalkenyl, C 3-6 heterocyclyl and C 3-6 heterocyclyl-C(═O)—; wherein said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 6-10 aryl-C 1-6 alkyl, C 6-10 aryl-C(═O)—C 1-6 alkyl, C 3-10 cycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl-C 1-6 alkyl, C 3-6 heterocyclyl-C 1-6 alkyl, C 3-6 heterocyclyl-C(═O)—C 1-6 alkyl, C 1-10 hydrocarbylamino, C 6-10 aryl, C 6-10 aryl-C(═O)—, C 3-10 cycloalkyl, C 4-8 cycloalkenyl, C 3-6 heterocyclyl or C 3-6 heterocyclyl-C(═O)— used in defining R 1  is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy and —NR 5 R 6 ; 
 R 2  is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl-C 1-6 alkyl, C 3-6 heterocycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl, R 5 R 6 N—, C 3-5 heteroaryl, C 6-10 aryl and C 3-6 heterocycloalkyl, wherein said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl-C 1-6 alkyl, C 3-6 heterocycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl, C 3-5 heteroaryl, C 6-10 aryl or C 3-6 heterocycloalkyl used in defining R 2  is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy and amino; 
 wherein R 5 , R 6  and R 7  are independently selected from —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and a divalent C 1-6 group that together with another divalent R 5 , R 6  or R 7  forms a portion of a ring; 
 R 3  is selected from R 8 , R 8 O—, R 3 NH—, R 3 R 9 N—; 
 R 8  and R 9  are independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, C 3-6 heterocyclyl, phenyl, C 3-6 heterocylcyl-C 1-4 alkyl, and phenyl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, C 3-6 heterocyclyl, phenyl, C 3-6 heterocylcyl-C 1-4 alkyl, or phenyl-C 1-4 alkyl is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy and amino; and 
 R 4  is selected from —H, C 1-6 alkyl and C 2-6 alkenyl. 
 
   
   
       13 . A method for preparing a compound of formula IV, 
     
       
         
         
             
             
         
       
     
     comprising the step of reacting a compound of formula V, 
     
       
         
         
             
             
         
       
     
     with a reducing agent selected from AlH 3 , NaBH 4 , NaBH(O-iPr) 3 , and LiAlH 4 , wherein
 R 1  is selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, R 5 R 6 N—C 1-6 alkyl, R 5 O—C 1-6  alkyl, R 5 C(═O)N(—R 6 )—C 1-6 alkyl, R 5 R 6 NS(═O) 2 —C 1-6 alkyl, R 5 CS(═O) 2 N(—R 6 )—C 1-6 alkyl, R 5 R 6 NC(═O)N(—R 7 )—C 1-6 alkyl, R 5 R 6 NS(═O) 2 N(R 7 )—C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl, C 6-10 aryl-C(═O)—C 1-6 alkyl, C 3-10 cycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl-C 1-6 alkyl, C 3-6 heterocyclyl-C 1-6 alkyl, C 3-6 heterocyclyl-C(═O)—C 1-6 alkyl, C 1-10 hydrocarbylamino, R 5 R 6 N—, R 5 O—, R 5 C(═O)N(—R 6 )—, R 5 R 6 NS(═O) 2 —, R 5 CS(═O) 2 N(—R 6 )—, R 5 R 6 NC(═O)N(—R 7 )—, R 5 R 6 NS(═O) 2 N(R 7 )—, C 6-10 aryl, C 6-10 aryl-C(═O)—, C 3-10 cycloalkyl, C 4-8 cycloalkenyl, C 3-6 heterocyclyl and C 3-6 heterocyclyl-C(═O)—; wherein said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 6-10 aryl-C 1-6 alkyl, C 6-10 aryl-C(═O)—C 1-6 alkyl, C 3-10 cycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl-C 1-6 alkyl, C 3-6 heterocyclyl-C 1-6 alkyl, C 3-6 heterocyclyl-C(═O)—C 1-6 alkyl, C 1-10 hydrocarbylamino, C 6-10 aryl, C 6-10 aryl-C(═O)—, C 3-10 cycloalkyl, C 4-8 cycloalkenyl, C 3-6 heterocyclyl or C 3-6 heterocyclyl-C(═O)— used in defining R 1  is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy and R 5 R 6 N—; 
 R 2  is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl-C 1-6 alkyl, C 3-6 heterocycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl, R 5 R 6 N—, C 3-5 heteroaryl, C 6-10 aryl and C 3-6 heterocycloalkyl, wherein said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl-C 1-6 alkyl, C 3-6 heterocycloalkyl-C 1-6 alkyl, C 4-8 cycloalkenyl, C 3-5 heteroaryl, C 6-10 aryl or C 3-6 heterocycloalkyl used in defining R 2  is optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy and amino; 
 wherein R 5 , R 6  and R 7  are independently selected from —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and a divalent C 1-6 group that together with another divalent R 5 , R 6  or R 7  forms a portion of a ring; and 
 R 10  is selected from —H, C 1-6 alkyl, and C 1-6 alkenyl.