Vanilloid receptor ligands and their use in treatments

Abstract

Compounds having the general structure and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

1 . A compound having the structure: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is 
 
     
       
         
         
             
             
         
       
     
     or a naphthyl or saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the naphthyl, heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5 , R 6  and R 7 ;
 R 4  is 
 
     
       
         
         
             
             
         
       
       R 5  is independently, at each instance, H, C 1-9 alkyl, C 1-4 haloalkyl, halo, nitro, cyano, —OC 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylOR a , —NR a R a , —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a  or —NR a —C 1-6 alkylOR a ; or R 5  is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S; 
       R 6  is independently, at each instance, H, C 1-9 alkyl, C 1-4 haloalkyl, halo, nitro, cyano, —OC 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylOR a , —NR a R a , —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a  or —NR a —C 1-6 alkylOR a ; or R 5  and R 6  together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the bridge are substituted by 0, 1, 2 or 3 substituents selected from halo, C 1-6 alkyl, (═O), —OC 1-6 alkyl, —NR a C 1-6 alkyl, —C 1-6 alkylOR a  and C 1-6 alkylNR a R a , and the available N atoms of the bridge are substituted by R a , —C 1-6 alkylOR a  or C 1-6 alkylNR a R a ; 
       R 7  is independently, at each instance, H, C 1-9 alkyl, C 1-4 haloalkyl, halo, nitro, cyano, —OC 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylOR a , —NR a R a , —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a  or —NR a —C 1-6 alkylOR a ; 
       R 8  is independently, at each instance, H, C 1-9 alkyl, C 1-4 haloalkyl, halo, nitro, cyano, —OC 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylOR a , —NR a R a , —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a  or —NR a —C 1-6 alkylOR a ; or R 7  and R s  together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the bridge are substituted by 0, 1, 2 or 3 substituents selected from halo, C 1-6 alkyl, (═O), —O—C 1-6 alkyl, —NR a C 1-6 alkyl, —C 1-6 alkylOR a  and C 1-6 alkylNR a R a , and the available N atoms of the bridge are substituted by R a , —C 1-6 alkylOR a  or C 1-6 alkylNR a R a ; 
       R 9  is independently, at each instance, H, C 1-9 alkyl, C 1-4 haloalkyl, halo, nitro, cyano, —OC 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylOR a , —NR a R a , —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a  or —NR a —C 1-6 alkylOR a ; 
       R 10  is independently, at each instance, H, C 1-9 alkyl, —C 1-3 alkylOR a , C 1-4 haloalkyl, halo, nitro, cyano, —OR a , —S(═O) n C 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylOR a , —O—C 1-6 alkylC(═O)OR a , —NR a R a , —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a , —NR a —C 1-6 alkylOR a , —C(═O)C 1-6 alkyl, —C(═O)OC 1-6 alkyl, —OC(═O)C 1-6 alkyl, —C(═O)NR a C 1-6 alkyl or —NR a C(═O)C 1-6 alkyl; 
       R 11  is independently, at each instance, H, C 1-9 alkyl, —C 1-3 alkylOR a , C 1-4 haloalkyl, halo, nitro, cyano, —OR a , —S(═O) n C 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylR c , —O—C 1-6 alkylOR a , —O—C 1-6 alkylC(═O)OR a , —NR a R a , —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a , —NR a —C 1-6 alkylOR a , —C(═O)C 1-6 alkyl, —C(═O)OC 1-6 alkyl, —OC(═O)C 1-6 alkyl, —C(═O)NR a C 1-6 alkyl or —NR a C(═O)C 1-6 alkyl; or R 10  and R 11  together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, ═O, —OR a , —C 1-6 alkylOR a , —C 1-6 alkyl, —NR a R a , —C 1-6 alkylNR a R a , —C(═O)OR a , —C(═O)NR a R a , —C 1-3 alkylC(═O)OR a , —C 1-3 alkylC(═O)NR a R a , —OC(═O)C 1-6 alkyl, —NR a C(═O)C 1-6 alkyl, —C 1-3 alkylOC(═O)C 1-6 alkyl or —C 1-3 alkylNR a C(═O)C 1-6 alkyl, and any nitrogen atoms in the bridge are substituted by H, —C 1-6 alkylOR a , —C 1-6 alkyl, —C 1-6 alkylNR a R a , —C 1-3 alkylC(═O)OR a , —C 1-3 alkylC(═O)NR a R a , —C 1-3 alkylOC(═O)C 1-6 alkyl, —C 1-3 alkylNR a C(═O)C 1-6 alkyl, —C(═O)R c  or —C 1-3 alkylR c ; wherein if R 10 , R 11 , R 12 , R 13  and R 14  are all H, then R 11  is not —O—C 1-6 alkylNR a R a  or —O—C 1-6 alkylOR a ; 
       R 12  is independently, at each instance, H, C 1-9 alkyl, —C 1-3 alkylOR a , C 1-4 haloalkyl, halo, nitro, cyano, —OR a , —S(═O) n C 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylOR a , —O—C 1-6 alkylC(═O)OR a , —NR a R a , —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a , —NR a —C 1-6 alkylOR a , —C(═O)C 1-6 alkyl, —C(═O)OC 1-6 alkyl, —OC(═O)C 1-6 alkyl, —C(═O)NR a C 1-6 alkyl or —NR a C(═O)C 1-6 alkyl; or R 11  and R 12  together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, ═O, —OR a , —C 1-6 alkylOR a , —C 1-6 alkyl, —NR a R a , —C 1-6 alkylNR a R a , —C(═O)OR a , —C(═O)NR a R a , —C 1-3 alkylC(═O)OR a , —C 1-3 alkylC(═O)NR a R a , —OC(═O)C 1-6 alkyl, —NR a C(═O)C 1-6 alkyl, —C 1-3 alkylOC(═O)C 1-6 alkyl or —C 1-3 alkylNR a C(═O)C 1-6 alkyl, and any nitrogen atoms in the bridge are substituted by H, —C 1-6 alkylOR a , —C 1-6 alkyl, —C 1-6 alkylNR a R a , —C 1-3 alkylC(═O)OR a , —C 1-3 alkylC(═O)NR a R a , —C 1-3 alkylOC(═O)C 1-6 alkyl, —C 1-3 alkylNR a C(═O)C 1-6 alkyl, —C(═O)R c  or —C 1-3 alkylR c ; 
       when R 1  is 4-C 1-6 alkylphenyl or 2,4-dimethylphenyl, then R 11  is C 1-9 alkyl, C 1-4 haloalkyl, halo, nitro, cyano, —OR a , —S(═O) n C 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylR c , —O—C 1-6 alkylOR a , —O—C 1-6 alkylC(═O)OR a , —NR a R a , —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a , —NR a —C 1-6 alkylOR a , —C(═O)C 1-6 alkyl, —C(═O)OC 1-6 alkyl, —OC(═O)C 1-6 alkyl, —C(═O)NR a C 1-6 alkyl or —NR a C(═O)C 1-6 alkyl; or R 10  and R 11  together are -L 3 -NR a —, respectively, or -L 4 -O—, respectively; or R 1  and R 12  are —NR a -L 3 -, -L 3 -NR a —, —O-L 4 - or -L 4 -O—; or R 12  is —NR a R b ; or R 4  is 10-membered bicyclic ring comprising fused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, OR a , NR a R a , C 1-6 alkyl and C 1-3 haloalkyl; and saturated carbon atoms may be additionally substituted by ═O; or R 4  is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 1, 2 or 3 substituents independently selected from C 2-9 alkyl, C 1-4 haloalkyl, halo, nitro, cyano, —OR a , —S(═O) n C 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylOR a , —O—C 1-6 alkylC(═O)OR a , —NR a R a , —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a , —NR a —C 1-6 alkylOR a , —C(═O)C 1-6 alkyl, —C(═O)OC 1-6 alkyl, —OC(═O)C 1-6 alkyl, —C(═O)NR a C 1-6 alkyl and —NR a C(═O)C 1-6 alkyl; 
       R 13  is independently, at each instance, H, C 1-9 alkyl, —C 1-3 alkylOR a , C 1-4 haloalkyl, halo, nitro, cyano, —OR a , —S(═O) n C 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylOR a , —O—C 1-6 alkylC(═O)OR a , —NR a R a , —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a , —NR a —C 1-6 alkylOR a , —C(═O)C 1-6 alkyl, —C(═O)OC 1-6 alkyl, —OC(═O)C 1-6 alkyl, —C(═O)NR a C 1-6 alkyl or —NR a C(═O)C 1-6 alkyl; 
       R 14  is independently, at each instance, H, C 1-9 alkyl, —C 1-3 alkylOR a , C 1-4 haloalkyl, halo, nitro, cyano, —OR a , —S(═O) n C 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylOR a , —O—C 1-6 alkylC(═O)OR a , —NR a R a , —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a , —NR a —C 1-6 alkylOR a , —C(═O)C 1-6 alkyl, —C(═O)OC 1-6 alkyl, —OC(═O)C 1-6 alkyl, —C(═O)NR a C 1-6 alkyl or —NR a C(═O)C 1-6 alkyl; 
       R a  is independently, at each instance, H, phenyl, benzyl or C 1-6 alkyl; 
       R b  is H, C 1-6 alkyl, —C(═O)C 1-6 alkyl, C 1-6 alkyl-O—R a ; 
       R c  is phenyl substituted by 0, 1 or 2 groups selected from halo, C 1-3 haloalkyl, —OR a  and —NR a R a ; or R c  is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0, 1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo, C 1-3 haloalkyl, —OR a  and —NR a R a ; 
       L 3  is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0, 1 or 2 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, ═O, —OR a , —C 1-6 alkylOR a , —C 1-6 alkyl, NR a R a , —C 1-6 alkylNR a R a , —C(═O)OR a , —C(═O)NR a R a , —C 1-3 alkylC(═O)OR a , —C 1-3 alkylC(═O)NR a R a , —OC(═O)C 1-6 alkyl, —NR a C(═O)C 1-6 alkyl, —C 1-3 alkylOC(═O)C 1-6 alkyl or —C 1-3 alkylNR a C(═O)C 1-6 alkyl, and any nitrogen atoms in the bridge are substituted by H, —C 1-6 alkylOR a , —C 1-6 alkyl, —C 1-6 alkylNR a R a , —C 1-3 alkylC(═O)OR a , —C 1-3 alkylC(═O)NR a R a , —C 1-3 alkylOC(═O)C 1-6 alkyl, —C 1-3 alkylNR a C(═O)C 1-6 alkyl, —C(═O)R c  or —C 1-3 alkylR c ; 
       L 4  is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0 or 1 atoms independently selected from O, N and S, wherein at least one of the carbon atoms in the bridge is substituted by ═O, —OR a , —C 1-6 alkylOR a , —C 1-6 alkyl, —NR a R a , —C 1-6 alkylNR a R a , —C(═O)OC 1-6 alkyl, —C(═O)NR a R a , —C 1-3 alkylC(═O)OR a , —C 1-3 alkylC(═O)NR a C 1-6 alkyl, —OC(═O)C 1-6 alkyl, —NR a C(═O)C 1-6 alkyl, —C 1-3 alkylOC(═O)C 1-6 alkyl or —C 1-3 alkylNR a C(═O)C 1-6 alkyl, and any nitrogen atoms in the bridge are substituted by H, —C 1-6 alkylOR a , —C 1-6 alkyl, —C 1-6 alkylNR a R a , —C 1-3 alkylC(═O)OR a , —C 1-3 alkylC(═O)NR a R a , —C 1-3 alkylOC(═O)C 1-6 alkyl, —C 1-3 alkylNR a C(═O)C 1-6 alkyl, —C(═O)R c  or —C 1-3 alkylR c ; 
       Y is NH or O; and 
       n is independently, at each instance, 0, 1 or 2; with the proviso that when R 1  is 4-chlorophenyl, then R 4  is not 3-methoxyphenyl. 
     
   
   
       2 . A compound according to Claim  1 , wherein R 7  is independently, at each instance, C 2-9 alkyl or C 1-4 haloalkyl. 
   
   
       3 . A compound according to Claim  2 , wherein:
 R 4  is   
     
       
         
         
             
             
         
       
       R b  is H, C 1-6 alkyl, —C(═O)C 1-6 alkyl, C 1-6 alkyl-O—R a ; and 
       Y 2  is —NR a — or —O—. 
     
   
   
       4 . A compound according to Claim  2 , wherein:
 R 4  is   
     
       
         
         
             
             
         
       
       L 3  is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0 or 1 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, ═O, —OR a , —C 1-6 alkylOR a , —C 1-6 alkyl, —NR a R a , —C 1-6 alkylNR a R a , —C(═O)OR a , —C(═O)NR a R a , —C 1-3 alkylC(═O)OR a , —C 1-3 alkylC(═O)NR a R a , —OC(═O)C 1-6 alkyl, —NR a C(═O)C 1-6 alkyl, —C 1-3 alkylOC(═O)C 1-6 alkyl or —C 1-3 alkylNR a C(═O)C 1-6 alkyl, and any nitrogen atoms in the bridge are substituted by H, —C 1-6 alkylOR a , —C 1-6 alkyl, —C 1-6 alkylNR a R a , —C 1-3 alkylC(═O)OR a , —C 1-3 alkylC(═O)NR a R a , —C 1-3 alkylOC(═O)C 1-6 alkyl, —C 1-3 alkylNR a C(═O)C 1-6 alkyl, —C(═O)R o  or —C 1-3 alkylR c ; 
       R b  is H, C 1-6 alkyl, —C(═O)C 1-6 alkyl, C 1-6 alkyl-O—R a ; and 
       Y 2  is —NR b — or —O—. 
     
   
   
       5 . A compound according to Claim  2 , wherein:
 R 4  is   
     
       
         
         
             
             
         
       
       L 3  is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0, 1 or 2 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, ═O, —OR a , —C 1-6 alkylOR a , —C 1-6 alkyl, —NR a R a , —C 1-6 alkylNR a R a , —C(═O)OR a , —C(═O)NR a R a , —C 1-3 alkylC(═O)OR a , —C 1-3 alkylC(═O)NR a R a , —OC(═O)C 1-6 alkyl, —NR a C(═O)C 1-6 alkyl, —C 1-3 alkylOC(═O)C 1-6 alkyl or —C 1-3 alkylNR a C(═O)C 1-6 alkyl, and any nitrogen atoms in the bridge are substituted by H, —C 1-6 alkylOR a , —C 1-6 alkyl, —C 1-6 alkylNR a R a , —C 1-3 alkylC(═O)OR a , —C 1-3 alkylC(═O)NR a R a , —C 1-3 alkylOC(═O)C 1-6 alkyl, —C 1-3 alkylNR a C(═O)C 1-6 alkyl, —C(═O)R c  or —C 1-3 alkylR c ; 
       R b  is H, C 1-6 alkyl, —C(═O)C 1-6 alkyl, C 1-6 alkyl-O—R a ; and 
       Y 2  is —NR b — or —O—. 
     
   
   
       6 . A compound according to Claim  2 , wherein:
 R 4  is   
     
       
         
         
             
             
         
       
       L 3  is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0, 1 or 2 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, ═O, —OR a , —C 1-6 alkylOR a , —C 1-6 alkyl, —NR a R a , —C 1-6 alkylNR a R a , —C(═O)OR a , —C(═O)NR a R a , —C 1-3 alkylC(═O)OR a , —C 1-3 alkylC(═O)NR a R a , —OC(═O)C 1-6 alkyl, —NR a C(═O)C 1-6 alkyl, —C 1-3 alkylOC(═O)C 1-6 alkyl or —C 1-3 alkylNR a C(═O)C 1-6 alkyl, and any nitrogen atoms in the bridge are substituted by H, —C 1-6 alkylOR a , —C 1-6 alkyl, —C 1-6 alkylNR a R a , —C 1-3 alkylC(═O)OR a , —C 1-3 alkylC(═O)NR a R a , —C 1-3 alkylOC(═O)C 1-6 alkyl, —C 1-3 alkylNR a C(═O)C 1-6 alkyl, —C(═O)R c  or —C 1-3 alkylR c ; 
       R b  is H, C 1-6 alkyl, —C(═O)C 1-6 alkyl, C 1-6 alkyl-O—R a ; and 
       Y 2  is —NR b — or —O—. 
     
   
   
       7 . A compound according to Claim  2 , wherein:
 R 4  is   
     
       
         
         
             
             
         
       
       R b  is H, C 1-6 alkyl, —C(═O)C 1-6 alkyl, C 1-6 alkyl-O—R a ; and 
       Y 2  is —NR a — or —O—. 
     
   
   
       8 . A compound according to Claim  2 , wherein:
 R 4  is   
     
       
         
         
             
             
         
       
       R 10  is independently, at each instance, H, C 1-9 alkyl, —C 1-3 alkylOR a , C 1-4 haloalkyl, halo, nitro, cyano, —OR n , —S(═O)C 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylOR a , —O—C 1-6 alkyl, —O—C 1-4 haloalkyl, —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a , —NR a —C 1-6 alkylOR a , —C(═O)C 1-6 alkyl, —C(═O)OC 1-6 alkyl, —OC(═O)C 1-6 alkyl, —C(═O)NR a C 1-6 alkyl or —NR a C(═O)C 1-6 alkyl; 
       R 11  is independently, at each instance, H, C 1-9 alkyl, —C 1-3 alkylOR a , C 1-4 haloalkyl, halo, nitro, cyano, —OR a , —S(═O)C 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylR o , —O—C 1-6 alkylOR a , —O—C 1-6 alkylC(═O)OR a , —NR a R a , —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a , —NR a —C 1-6 alkylOR a , —C(═O)C 1-6 alkyl, —C(═O)OC 1-6 alkyl, —OC(═O)C 1-6 alkyl, —C(═O)NR a C 1-6 alkyl or —NR a C(═O)C 1-6 alkyl; 
       C 1-6 alkylNR a R a ; 
       R 12  is independently, at each instance, H, C 1-9 alkyl, —C 1-3 alkylOR a , C 1-4 haloalkyl, halo, nitro, cyano, —OR a , —S(═O)C 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylOR a , —O—C 1-6 alkylC(═O)OR a , —NR a R a , —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a , —NR a —C 1-6 alkylOR a , —C(═O)C 1-6 alkyl, —C(═O)OC 1-6 alkyl, —OC(═O)C 1-6 alkyl, —C(═O)NR a C 1-6 alkyl or —NR a C(═O)C 1-6 alkyl; 
       R 13  is independently, at each instance, H, C 1-9 alkyl, —C 1-3 alkylOR a , C 1-4 haloalkyl, halo, nitro, cyano, —OR a , —S(═O)C 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylOR a , —O—C 1-6 alkylC(═O)OR a , —NR a R a , —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a , —NR a —C 1-6 alkylOR a , —C(═O)C 1-6 alkyl, —C(═O)OC 1-6 alkyl, —OC(═O)C 1-6 alkyl, —C(═O)NR a C 1-6 alkyl or —NR a C(═O)C 1-6 alkyl; and 
       R 14  is independently, at each instance, H, C 1-9 alkyl, —C 1-3 alkylOR a , C 1-4 haloalkyl, halo, nitro, cyano, —OR a , —S(═O)C 1-6 alkyl, —O—C 1-4 haloalkyl, —O—C 1-6 alkylNR a R a , —O—C 1-6 alkylOR a , —O—C 1-6 alkylC(═O)OR a , —NR a R a , —NR a —C 1-4 haloalkyl, —NR a —C 1-6 alkylNR a R a , —NR a —C 1-6 alkylOR a , —C(═O)C 1-6 alkyl, —C(═O)OC 1-6 alkyl, —OC(═O)C 1-6 alkyl, —C(═O)NR a C 1-6 alkyl or —NR a C(═O)C 1-6 alkyl; wherein one of R 10  and R 12  is not H. 
     
   
   
       9 . A pharmaceutical composition comprising a compound according to Claim  1  and a pharmaceutically-acceptable diluent or carrier.