Vanilloid receptor ligands and their use in treatments

1. A compound having the structure:

or any pharmaceutically-acceptable salt thereof, wherein:

n is independently, at each instance, 0, 1 or 2.

R 1 is

 or R 1 is a naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from R 5 ; or R 1 is R b substituted by 1, 2 or 3 substituents independently selected from R 5 ;

R 2 is, independently, in each instance, R 10 , C 1-8 alkyl substituted by 0, 1 or 2 substituents selected from R 10 , —(CH 2 ) n phenyl substituted by 0, 1, 2 or 3 substituents independently selected from R 10 , or 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 heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 10 ;

R 3 is, independently, in each instance, H, halo, —NHC 1-3 alkyl, —N(C 1-3 alkyl)C 1-3 alkyl, or C 1-3 alkyl;

R 4 is

 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 0, 1, 2 or 3 substituents independently selected from R e , C 1-4 haloalkyl, halo, nitro, cyano, oxo, —OR f , —S(═O) n R e , —OC 1-4 haloalkyl, —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —OC 1-6 alkylC(═O)OR e , —NR a R f , —NR a C 1-4 haloalkyl, —NR a C 2-6 alkylNR a R f , —NR a C 2-6 alkylOR f , —C(═O)R e , —C(═O)OR e , —OC(═O)R e , —C(═O)NR a R f and —NR a C(═O)R e ; and unsaturated carbon atoms may be additionally substituted by ═O; and any available nitrogen atoms in the heterocycle and bridge are substituted by H, —C 1-6 alkylOR f , R e , —C 1-6 alkylNR a R f , —C 1-3 alkylC(═O)OR e , —C 1-3 alkylC(═O)NR a R f , —C 1-3 alkylOC(═O)R e , —C 1-3 alkylNR a C(═O)R e , —C(═O)R c or —C 1-3 alkylR c ; or R 4 is naphthyl substituted by 1, 2 or 3 substituents independently selected from C 1-4 haloalkyl, halo, nitro, cyano, —S(═O) n R e , —OC 1-4 haloalkyl, —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —OC 1-6 alkylC(═O)OR e , —NR a C 1-4 haloalkyl, —NR a C 2-6 alkylNR a R f , —NR a C 2-6 alkylOR f , —C(═O)R e , —C(═O)OR e , —OC(═O)R e and —C(═O)NR a R f ; but in no instance is R 4 3,5-ditrifluoromethylphenyl or 3-trifluoromethyl-4-fluorophenyl, or phenyl substituted by (C 1-8 alkyl), —O—(C 1-6 alkyl), —NR a R a and/or N(R a )C(═O)(C 1-8 alkyl);

R 5 is independently, at each instance, R f , R g , halo, nitro, cyano, —OR e , —OR g , —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —NR a R f , —NR a R g , —NR f C 2-6 alkylNR a R f , —NR f C 2-6 alkylOR f , naphthyl, —CO 2 R e , —C(═O)R e , —C(═O)NR a R f , —C(═—)NR a R g , —NR f C(═O)R e , —NR f C(═O)R g , —NR f C(═O)NR a R f , —NR f CO 2 R e , —C 1-8 alkylOR f , —C 1-6 alkylNR a R f , —S(═O) n R e , —S(═O) 2 NR a R f , —NR a S(═O) 2 R e , —OC(═O)NR a R f , a phenyl ring substituted with 0, 1, 2, or 3 substituents independently selected from R 10 ; 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, substituted with 0, 1, 2, or 3 substituents independently selected from R 10 ;

R 6 is independently, at each instance, H, C 1-5 alkyl, C 1-4 haloalkyl, halo, —OC 1-6 alkyl, —OC 1-4 haloalkyl, —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —NR a R a , —NR a C 1-4 haloalkyl, —NR a C 2-6 alkylNR a R a or —NR a C 2-6 alkylOR a , —C 1-8 alkylOR a , —C 1-6 alkylNR a R a , —S(C 1-6 alkyl), a phenyl ring substituted with 1, 2, or 3 substituents independently selected from R 10 ; or R 6 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S substituted with 0, 1, 2, or 3 substituents independently selected from R 10 ;

R 7 is independently, at each instance, H, acyclicC 1-8 alkyl, C 1-4 haloalkyl, halo, —OC 1-6 alkyl, —OC 1-4 haloalkyl, —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —NR a R a , —NR a C 1-4 haloalkyl, —NR a C 2-6 alkylNR a R a , —NR a C 2-6 alkylOR a , —C 1-8 alkylOR a , —C 1-6 alkylNR a R a or —S(C 1-6 alkyl); or R 7 is a saturated or unsaturated 4- or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0, 1 or 2 substituents independently selected from halo, C 1-2 haloalkyl and C 1-3 alkyl;

R 8 is independently, at each instance, H, C 1-5 alkyl, C 1-4 haloalkyl, halo, —OC 1-6 alkyl, —OC 1-4 haloalkyl, —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —NR a R a , —NR a C 1-4 haloalkyl, —NR a C 2-6 alkylNR a R a , —NR a C 2-6 alkylOR a , —C 1-8 alkylOR a , —C 1-6 alkylNR a R a , —S(C 1-6 alkyl), a phenyl ring substituted with 1, 2, or 3 substituents independently selected from R 10 , or R 8 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S substituted with 0, 1, 2, or 3 substituents independently selected from R 10 ;

R 9 is independently, at each instance, R f , R g , halo, nitro, cyano, —OR e , —OR g , —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —NR a R f , —NR a R g , —NR f C 2-6 alkylNR a R f , —NR f C 2-6 alkylOR f , naphthyl, —CO 2 R e , —C(═O)R e , —C(═O)NR a R f , —C(═O)NR a R g , —NR f C(═O)R e , —NR f (═O)R g , —NR f C(═O)NR a R f , —NR f CO 2 R e , —C 1-8 alkylOR f , —C 1-6 alkylNR a R f , —S(═O)—R e , —S(═O) 2 NR a R f , —NR a S(═O) 2 R e , —OC(═O)NR a R f , a phenyl ring substituted with 0, 1, 2, or 3 substituents independently selected from R 10 ; or R 9 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S substituted with 0, 1, 2, or 3 substituents independently selected from R 10 ; or R 9 is a saturated or unsaturated 4- or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0, 1 or 2 substituents independently selected from halo, C 1-2 haloalkyl and C 1-3 alkyl; wherein at least one of R 5 , R 6 , R 7 , R 8 and R 9 is C 1-8 alkyl, C 1-4 haloalkyl, halo, —OC 1-4 haloalkyl, —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —NR a C 1-4 haloalkyl, —NR a C 2-6 alkylNR a R a , —NR a C 2-6 alkylOR a , —C 1-8 alkylOR a , —C 1-6 alkylNR a R a or —S(C 1-6 alkyl);

R 10 is independently, at each instance, selected from H, C 1-8 alkyl, C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)(C 1-8 alkyl), —C(═O)O(C 1-8 alkyl), —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)(C 1-8 alkyl), —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 (C 1-8 alkyl), —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)(C 1-8 alkyl), —S(═O) 2 (C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)O(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)(C 1-8 alkyl), —N(R a )C(═O)O(C 1-8 alkyl), —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 (C 1-8 alkyl), —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a and —NR a C 2-6 alkylOR a ; or R 10 is a saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C 1-8 alkyl, C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)(C 1-8 alkyl), —C(═O)O(C 1-8 alkyl), —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)(C 1-8 alkyl), —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 (C 1-8 alkyl), —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)(C 1-8 alkyl), —S(═O) 2 (C 1-8 alkyl), —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)O(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)(C 1-8 alkyl), —N(R a )C(═O)O(C 1-8 alkyl), —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 (C 1-8 alkyl), —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a and —NR a C 2-6 alkylOR a ; or R 10 is C 1-4 alkyl substituted by 0, 1, 2 or 3 groups selected from C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)(C 1-8 alkyl), —C(═O)O(C 1-8 alkyl), —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)(C 1-8 alkyl), —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 (C 1-8 alkyl), —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)(C 1-8 alkyl), —S(═O) 2 (C 1-8 alkyl), —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)O(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)(C 1-8 alkyl), —N(R a )C(═O)O(C 1-8 alkyl), —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 (C 1-8 alkyl), —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a and —NR a C 2-6 alkylOR a ;

R 11 is independently, at each instance, selected from H, C 1-8 alkyl, C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)(C 1-8 alkyl), —C(═O)O(C 1-8 alkyl), —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)(C 1-8 alkyl), —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 (C 1-8 alkyl), —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)(C 1-8 alkyl), —S(═O) 2 (C 1-8 alkyl), —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)O(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)(C 1-8 alkyl), —N(R a )C(═O)O(C 1-8 alkyl), —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 (C 1-8 alkyl), —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a and —NR a C 2-6 alkylOR a ; or R 11 is a saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C 1-8 alkyl, C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)(C 1-8 alkyl), —C(═O)O(C 1-8 alkyl), —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)(C 1-8 alkyl), —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 (C 1-8 alkyl), —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)(C 1-8 alkyl), —S(═O) 2 (C 1-8 alkyl), —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)O(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)(C 1-8 alkyl), —N(R a )C(═O)O(C 1-8 alkyl), —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 (C 1-8 alkyl), —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a and —NR a C 2-6 alkylOR a ; or R 11 is C 1-4 alkyl substituted by 0, 1, 2 or 3 groups selected from C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)(C 1-8 alkyl), —C(═O)O(C 1-8 alkyl), —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)(C 1-8 alkyl), —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 (C 1-8 alkyl), —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)(C 1-8 alkyl), —S(═O) 2 (C 1-8 alkyl), —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)O(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)(C 1-8 alkyl), —N(R a )C(═O)O(C 1-8 alkyl), —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 (C 1-8 alkyl), —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a and NR a C 2-6 alkylOR a ; or R 10 and R 11 together are a saturated or unsaturated 3- or 4-atom bridge containing 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 bridge is substituted by 0, 1 or 2 substituents selected from ═O, R e , halo, cyano, nitro, —C(═O)R e , —C(═O)OR e , —C(═O)NR a R f , —C(═NR a )NR a R f , —OR f , —OC(═O)R e , —OC(═O)NR a R f , —OC(═O)N(R f )S(═O) 2 R e , —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —SR f , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR a R f , —S(═O) 2 N(R f )C(═O)R e , —S(═O) 2 N(R f )C(═O)OR e , —S(═O) 2 N(R f )C(═O)NR a R f , —NR a R f , —N(R f )C(═O)R e , —N(R f )C(═O)OR e , —N(R f )C(═O)NR a R f , —N(R f )C(═NR a )NR a R f , —N(R f )C(═O) 2 R e , —N(R f )S(═O) 2 NR a R f , —NR f C 2-6 alkylNR a R f and —NR f C 2-6 alkylOR f ;

R 12 is independently, at each instance, selected from H, C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)(C 1-8 alkyl), —C(═O)O(C 1-8 alkyl), —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)(C 1-8 alkyl), —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 (C 1-8 alkyl), —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)(C 1-8 alkyl), —S(═O) 2 (C 1-8 alkyl), —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)O(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)NR a R a , —N(R a )C(═O)(C 1-8 alkyl), —N(R a )C(═O)O(C 1-8 alkyl), —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 (C 1-8 alkyl), —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a and —NR a C 2-6 alkylOR a ; or R 12 is a saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C 1-8 alkyl, C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)(C 1-8 alkyl), —C(═O)O(C 1-8 alkyl), —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)(C 1-8 alkyl), —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 (C 1-8 alkyl), —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)(C 1-8 alkyl), —S(═O) 2 (C 1-8 alkyl), —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)O(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)(C 1-8 alkyl), —N(R a )C(═O)O(C 1-8 alkyl), —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 (C 1-8 alkyl), —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a and —NR a C 2-6 alkylOR a ; or R 12 is C 1-4 alkyl substituted by 0, 1, 2 or 3 groups selected from C 1-4 haloalkyl, halo, nitro, —C(═O)(C 1-8 alkyl), —C(═O)O(C 1-8 alkyl), —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)(C 1-8 alkyl), —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 (C 1-8 alkyl), —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)(C 1-8 alkyl), —S(═O) 2 (C 1-8 alkyl), —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)O(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)(C 1-8 alkyl), —N(R a )C(═O)O(C 1-8 alkyl), —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 (C 1-8 alkyl), —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a and —NR a C 2-6 alkylOR a ; wherein if R 11 or R 13 is CF 3 , then R 12 is not F; or R 11 and R 12 together are a saturated or unsaturated 3- or 4-atom bridge containing 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 bridge is substituted by 0, 1 or 2 substituents selected from ═O, R e , halo, cyano, nitro, —C(═O)R e , —C(═O)OR e , —C(═O)NR a R f , —C(═NR a )NR a R f , —OR f , —OC(═O)R e , —OC(═O)NR a R f , —OC(═O)N(R f )S(═O) 2 R e , —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —SR f , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR a R f , —S(═O) 2 N(R f )C(═O)R e , —S(═O) 2 N(R f )C(═O)OR e , —S(═O) 2 N(R f )C(═O)NR a R f , —NR a R f , —N(R f )C(═O)R e , —N(R f )C(═O)OR e , —N(R f )C(═O)NR a R f , —N(R f )C(═NR a )NR a R f , —N(R f )S(═O) 2 R e , —N(R f )S(═O) 2 NR a R f , —NR f C 2-6 alkylNR a R f and —NR f C 2-6 alkylOR f ;

R 13 is independently, at each instance, selected from H, C 1-8 alkyl, C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)(C 1-8 alkyl), —C(═O)O(C 1-8 alkyl), —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)(C 1-8 alkyl), —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 (C 1-8 alkyl), —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)(C 1-8 alkyl), —S(═O) 2 (C 1-8 alkyl), —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)O(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)(C 1-8 alkyl), —N(R a )C(═O)O(C 1-8 alkyl), —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 (C 1-8 alkyl), —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a and —NR a C 2-6 alkylOR a ; or R 13 is a saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C 1-8 alkyl, C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)(C 1-8 alkyl), —C(═O)O(C 1-8 alkyl), —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)(C 1-8 alkyl), —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 (C 1-8 alkyl), —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)(C 1-8 alkyl), —S(═O) 2 (C 1-8 alkyl), —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)O(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)(C 1-8 alkyl), —N(R a )C(═O)O(C 1-8 alkyl), —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 (C 1-8 alkyl), —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a and —NR a C 2-6 alkylOR a ; or R 13 is C 1-4 alkyl substituted by 0, 1, 2 or 3 groups selected from C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)(C 1-8 alkyl), —C(═O)O(C 1-8 alkyl), —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)(C 1-8 alkyl), —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 (C 1-8 alkyl), —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)(C 1-8 alkyl), —S(═O) 2 (C 1-8 alkyl), —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)O(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)(C 1-8 alkyl), —N(R a )C(═O)O(C 1-8 alkyl), —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 (C 1-8 alkyl), —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a and —NR a C 2-6 alkylOR a ;

R 14 is independently, at each instance, selected from H, C 1-8 alkyl, C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)(C 1-8 alkyl), —C(═O)O(C 1-8 alkyl), —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)(C 1-8 alkyl), —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 (C 1-8 alkyl), —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)(C 1-8 alkyl), —S(═O) 2 (C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)O(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)(C 1-8 alkyl), —N(R a )C(═O)O(C 1-8 alkyl), —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 (C 1-8 alkyl), —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a and —NR a C 2-6 alkylOR a ; or R 14 is a saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C 1-8 alkyl, C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)(C 1-8 alkyl), —C(═O)O(C 1-8 alkyl), —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)(C 1-8 alkyl), —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 (C 1-8 alkyl), —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)(C 1-8 alkyl), —S(═O) 2 (C 1-8 alkyl), —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)O(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)(C 1-8 alkyl), —N(R a )C(═O)O(C 1-8 alkyl), —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 (C 1-8 alkyl), —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a and —NR a C 2-6 alkylOR a ; or R 14 is C 1-4 alkyl substituted by 0, 1, 2 or 3 groups selected from C 1-4 haloalkyl, halo, cyano, nitro, —C(═O)(C 1-8 alkyl), —C(═O)O(C 1-8 alkyl), —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)(C 1-8 alkyl), —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 (C 1-8 alkyl), —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)(C 1-8 alkyl), —S(═O) 2 (C 1-8 alkyl), —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)O(C 1-8 alkyl), —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)(C 1-8 alkyl), —N(R a )C(═O)O(C 1-8 alkyl), —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 (C 1-8 alkyl), —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a and —NR a C 2-6 alkylOR a ; wherein at least one of R 10 , R 11 , R 12 , R 13 and R 14 is other than H;

R a is independently, at each instance, H, phenyl, benzyl or C 1-6 alkyl;

R b is a heterocycle selected from the group of thiophene, pyrrole, 1,3-oxazole, 1,3-thiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1H-1,2,3-triazole, isothiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,3,4-oxatriazole, 1,2,3,4-thiatriazole, 1H-1,2,3,4-tetraazole, 1,2,3,5-oxatriazole, 1,2,3,5-thiatriazole, furan, imidazol-1-yl, imidazol-4-yl, 1,2,4-triazol-4-yl, 1,2,4-triazol-5-yl, isoxazol-3-yl, isoxazol-5-yl, pyrazol-3-yl, pyrazol-5-yl, thiolane, pyrrolidine, tetrahydrofuran, 4,5-dihydrothiophene, 2-pyrroline, 4,5-dihydrofuran, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,2,4-triazine, 1,3,5-triazine, pyridine, 2H-3,4,5,6-tetrahydropyran, thiane, 1,2-diazaperhydroine, 1,3-diazaperhydroine, piperazine, 1,3-oxazaperhydroine, morpholine, 1,3-thiazaperhydroine, 1,4-thiazaperhydroine, piperidine, 2H-3,4-dihydropyran, 2,3-dihydro-4H-thiin, 1,4,5,6-tetrahydropyridine, 2H-5,6-dihydropyran, 2,3-dihydro-6H-thiin, 1,2,5,6-tetrahydropyridine, 3,4,5,6-tetrahydropyridine, 4H-pyran, 4H-thiin, 1,4-dihydropyridine, 1,4-dithiane, 1,4-dioxane, 1,4-oxathiane, 1,2-oxazolidine, 1,2-thiazolidine, pyrazolidine, 1,3-oxazolidine, 1,3-thiazolidine, imidazolidine, 1,2,4-oxadiazolidine, 1,3,4-oxadiazolidine, 1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine, 1,2,4-triazolidine, 2-imidazoline, 3-imidazoline, 2-pyrazoline, 4-imidazoline, 2,3-dihydroisothiazole, 4,5-dihydroisoxazole, 4,5-dihydroisothiazole, 2,5-dihydroisoxazole, 2,5-dihydroisothiazole, 2,3-dihydroisoxazole, 4,5-dihydrooxazole, 2,3-dihydrooxazole, 2,5-dihydrooxazole, 4,5-dihydrothiazole, 2,3-dihydrothiazole, 2,5-dihydrothiazole, 1,3,4-oxathiazolidine, 1,4,2-oxathiazolidine, 2,3-dihydro-1H-[1,2,3]triazole, 2,5-dihydro-1H-[1,2,3]triazole, 4,5-dihydro-1H-[1,2,3]triazole, 2,3-dihydro-1H-[1,2,4]triazole, 4,5-dihydro-1H-[1,2,4]triazole, 2,3-dihydro-[1,2,4]oxadiazole, 2,5-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,2,4]thidiazole, 2,5-dihydro-[1,2,4]thiadiazole, 4,5-dihydro-[1,2,4]thiadiazole, 2,5-dihydro-[1,2,4]oxadiazole, 2,3-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]oxadiazole, 2,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,2,4]thiadiazole, 4,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,3,4]oxadiazole, 2,3-dihydro-[1,3,4]thiadiazole, [1,4,2]oxathiazole, [1,3,4]oxathiazole, 1,3,5-triazaperhydroine, 1,2,4-triazaperhydroine, 1,4,2-dithiazaperhydroine, 1,4,2-dioxazaperhydroine, 1,3,5-oxadiazaperhydroine, 1,2,5-oxadiazaperhydroine, 1,3,4-thiadiazaperhydroine, 1,3,5-thiadiazaperhydroine, 1,2,5-thiadiazaperhydroine, 1,3,4-oxadiazaperhydroine, 1,4,3-oxathiazaperhydroine, 1,4,2-oxathiazaperhydroine, 1,4,5,6-tetrahydropyridazine, 1,2,3,4-tetrahydropyridazine, 1,2,3,6-tetrahydropyridazine, 1,2,5,6-tetrahydropyrimidine, 1,2,3,4-tetrahydropyrimidine, 1,4,5,6-tetrahydropyrimidine, 1,2,3,6-tetrahydropyrazine, 1,2,3,4-tetrahydropyrazine, 5,6-dihydro-4H-[1,2]oxazine, 5,6-dihydro-2H-[1,2]oxazine, 3,6-dihydro-2H-[1,2]oxazine, 3,4-dihydro-2H-[1,2]oxazine, 5,6-dihydro-4H-[1,2]thiazine, 5,6-dihydro-2H-[1,2]thiazine, 3,6-dihydro-2H-[1,2]thiazine, 3,4-dihydro-2H-[1,2]thiazine, 5,6-dihydro-2H-[1,3]oxazine, 5,6-dihydro-4H-[1,3]oxazine, 3,6-dihydro-2H-[1,3]oxazine, 3,4-dihydro-2H-[1,3]oxazine, 3,6-dihydro-2H-[1,4]oxazine, 3,4-dihydro-2H-[1,4]oxazine, 5,6-dihydro-2H-[1,3]thiazine, 5,6-dihydro-4H-[1,3]thiazine, 3,6-dihydro-2H-[1,3]thiazine, 3,4-dihydro-2H-[1,3]thiazine, 3,6-dihydro-2H-[1,4]thiazine, 3,4-dihydro-2H-[1,4]thiazine, 1,2,3,6-tetrahydro-[1,2,4]triazine, 1,2,3,4-tetrahydro-[1,2,4]triazine, 1,2,3,4-tetrahydro-[1,3,5]triazine, 2,3,4,5-tetrahydro-[1,2,4]triazine, 1,4,5,6-tetrahydro-[1,2,4]triazine, 5,6-dihydro-[1,4,2]dioxazine, 5,6-dihydro-[1,4,2]dioxazine, 5,6-dihydro-[1,4,2]dithiazine, 2,3-dihydro-[1,4,2]dioxazine, 3,4-dihydro-2H-[1,3,4]oxadiazine, 3,6-dihydro-2H-[1,3,4]oxadiazine, 3,4-dihydro-2H-[1,3,5]oxadiazine, 3,6-dihydro-2H-[1,3,5]oxadiazine, 5,6-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-4H-[1,2,5]oxadiazine, 3,4-dihydro-2H-[1,3,4]thiadiazine, 3,6-dihydro-2H-[1,3,4]thiadiazine, 3,4-dihydro-2H-[1,3,5]thiadiazine, 3,6-dihydro-2H-[1,3,5]thiadiazine, 5,6-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-4H-[1,2,5]thiadiazine, 5,6-dihydro-2H-[1,2,3]oxadiazine, 3,6-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-4H-[1,3,4]oxadiazine, 3,4-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-2H-[1,2,3]thiadiazine, 3,6-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-4H-[1,3,4]thiadiazine, 3,4-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-[1,4,3]oxathiazine, 5,6-dihydro-[1,4,2]oxathiazine, 2,3-dihydro-[1,4,3]oxathiazine, 2,3-dihydro-[1,4,2]oxathiazine, 4,5-dihydropyridine, 1,6-dihydropyridine, 5,6-dihydropyridine, 2H-pyran, 2H-thiin, 3,6-dihydropyridine, 2,3-dihydropyridazine, 2,5-dihydropyridazine, 4,5-dihydropyridazine, 1,2-dihydropyridazine, 2,3-dihydropyrimidine, 2,5-dihydropyrimidine, 5,6-dihydropyrimidine, 3,6-dihydropyrimidine, 4,5-dihydropyrazine, 5,6-dihydropyrazine, 3,6-dihydropyrazine, 4,5-dihydropyrazine, 1,4-dihydropyrazine, 1,4-dithiin, 1,4-dioxin, 2H-1,2-oxazine, 6H-1,2-oxazine, 4H-1,2-oxazine, 2H-1,3-oxazine, 4H-1,3-oxazine, 6H-1,3-oxine, 2H-1,4-oxazine, 4H-1,4-oxazine, 2H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,2-6H-1,3-thiazine, 4H-1,4-thiazine, 2H-1,2-thiazine, 6H-1,2-thiazine, 1,4-oxathiin, 2H,5H-1,2,3-triazine, 1H,4H-1,2,3-triazine, 4,5-dihydro-1,2,3-triazine, 1H,6H-1,2,3-triazine, 1,2-dihydro-1,2,3-triazine, 2,3-dihydro-1,2,4-triazine, 3H,6H-1,2,4-triazine, 1H,6H-1,2,4-triazine, 3,4-dihydro-1,2,4-triazine, 1H,4H-1,2,4-triazine, 5,6-dihydro-1,2,4-triazine, 4,5-dihydro-1,2,4-triazine, 2H,5H-1,2,4-triazine, 1,2-dihydro-1,2,4-triazine, 1H,4H-1,3,5-triazine, 1,2-dihydro-1,3,5-triazine, 1,4,2-dithiazine, 1,4,2-dioxazine, 2H-1,3,4-oxadiazine, 2H-1,3,5-oxadiazine, 6H-1,2,5-oxadiazine, 4H-1,3,4-oxadiazine, 4H-1,3,5-oxadiazine, 4H-1,2,5-oxadiazine, 2H-1,3,5-thiadiazine, 6H-1,2,5-thiadiazine, 4H-1,3,4-thiadiazine, 4H-1,3,5-thiadiazine, 4H-1,2,5-thiadiazine, 2H-1,3,4-thiadiazine, 6H-1,3,4-thiadiazine, 6H-1,3,4-oxadiazine and 1,4,2-oxathiazine, wherein the heterocycle is optionally vicinally fused with a saturated or unsaturated 5-, 6- or 7-membered ring containing 0, 1 or 2 atoms independently selected from N, O and S;

R c is independently, in each instance, phenyl substituted by 0, 1 or 2 groups selected from halo, C 1-4 alkyl, 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 1-4 alkyl, C 1-3 haloalkyl, —OR a and —NR a R a ;

R d is hydrogen or —CH 3 ;

R e is, independently, in each instance, C 1-9 alkyl substituted by 0, 1, 2, 3 or 4 substituents selected from halo, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R b , —OC 2-6 alkylNR a R a , —OC 2-6 alkylOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R b , —S(═O) 2 N(R a )C(═O)OR b , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkylNR a R a and —NR a C 2-6 alkylOR a ; and wherein the C 1-9 alkyl is additionally substituted by 0 or 1 groups independently selected from R g ;

R f is, independently, in each instance, R e or H; and

R g is, independently, in each instance, a saturated or unsaturated 5- or 6-membered monocyclic ring containing 1, 2 or 3 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0 or 1 oxo groups.

2. A compound according to claim 1 , wherein:

R 1 is

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 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 0, 1, 2 or 3 substituents independently selected from R e , C 1-4 haloalkyl, halo, nitro, cyano, oxo, —OR f , —S(═O)—R e , —OC 1-4 haloalkyl, —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —OC 1-6 alkylC(═O)OR e , —NR a R f , —NR a C 1-4 haloalkyl, —NR a C 2-6 alkylNR a R f , —NR a C 2-6 alkylOR f , —C(═O)R e , —C(═O)OR e , —OC(═O)R e , —C(═O)NR a R f and —NR a C(═O)R e ; and unsaturated carbon atoms may be additionally substituted by ═O; and any available nitrogen atoms in the heterocycle and bridge are substituted by H, —C 1-6 alkylOR f , R e , —C 1-6 alkylNR a R f , —C 1-3 alkylC(═O)OR e , —C 1-3 alkylC(═O)NR a R f , —C 1-3 alkylOC(═O)R e , —C 1-3 alkylNR a C(═O)R e , —C(═O)R c or —C 1-3 alkylR c ;

R 7 is independently, at each instance, C 3-5 alkyl or C 1-2 haloalkyl; and

R 10 and R 11 together are a saturated or unsaturated 3-atom bridge containing 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 bridge is substituted by 0, 1 or 2 substituents selected from ═O, R e , halo, cyano, nitro, —C(═O)R e , —C(═O)OR e , —C(═O)NR a R f , —C(═NR a )NR a R f , —OR f , —OC(═O)R e , —OC(═O)NR a R f , —OC(═O)N(R f )S(═O) 2 R e , —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —SR f , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR a R f , —S(═O) 2 N(R f )C(═O)R e , —S(═O) 2 N(R f )C(═O)OR e , —S(═O) 2 N(R f )C(═O)NR a R f , —NR a R f , —N(R f )C(═O)R e , —N(R f )C(═O)OR e , —N(R f )C(═O)NR a R f , —N(R f )C(═NR a )NR a R f , —N(R f )S(═O) 2 R e , —N(R f )S(═O) 2 NR a R f , —NR f C 2-6 alkylNR a R f and —NR f C 2-6 alkylOR f ; or, alternatively, R 11 and R 12 together form a —R 11 —R 12 -bridge selected from —O—C—C—C—, —N—C—C—C— and —N═C—C═C—, wherein the bridge is substituted by 0, 1 or 2 substituents selected from ═O, R e , halo, cyano, nitro, —C(═O)R e , —C(═O)OR e , —C(═O)NR a R f , —C(═NR a )NR a R f , —OR f , —OC(═O)R e , —OC(═O)NR a R f , —OC(═O)N(R f )S(═O) 2 R e , —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —SR f , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR a R f , —S(═O) 2 N(R f )C(═O)R e , —S(═O) 2 N(R f )C(═O)OR e , —S(═O) 2 N(R f )C(═O)NR a R f , —NR a R f , —N(R f )C(═O)R e , —N(R f )C(═O)OR e , —N(R f )C(═O)NR a R f , —N(R f )C(═NR f )NR a R f , —N(R f )S(═O) 2 R e , —N(R f )S(═O) 2 NR a R f , —NR f C 2-6 alkylNR a R f and —NR f C 2-6 alkylOR f .

3. A compound is selected from:

(1H-benzoimidazol-4-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(1H-benzotriazol-5-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(1H-indazol-5-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(1H-indol-4-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(1H-indol-5-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(1H-indol-6-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(1H-indol-7-yl)-[6-(4-trifluoromethylphenyl]pyrimidin-4-yl)amine;

(1-methyl-1H-benzoimidazol-4-yl)-[6-(4-trifluoromethyl)phenyl)pyrimidin-4-yl]amine;

(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(6-phenylpyrimidin-4-yl)amine;

(2,3-dihydrobenzo[1,4]dioxin-6-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(2,3-dimethyl-1H-indole-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(2-chloropyridin-3-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(2-chloroquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(2-chloroquinolin-8-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(2-methoxyquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(2-methyl-1H-benzoimidazol-4-yl)-[6-(4-trifluoromethyl)phenyl)pyrimidin-4-yl]amine;

(2-methylaminoquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine dihydrochloride;

(2-methylbenzothiazol-5-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(2R)-{6-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-2H,3H-benzo[1,4]dioxin-2-yl}methanol;

(3,4-dichlorophenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(3,4-dimethylphenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(3-chloro-2-methylphenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(3H-benzotriazol-5-yl)-[6-(4-tert-butylphenyl)pyrimidin-4-yl]amine;

(3-methanesulfonylphenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(3-methylbenzo[d]isothiazol-5-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(3-methylsulfanylphenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(4-chloro-3-trifluoromethylphenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(4-chlorophenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(5-chloro-2-methylphenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

(6-methoxypyridin-3-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

[(2-morpholin-4-yl)quinolin-7-yl]-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine hydrochloride;

[2-amino-6-(4-tert-butylphenyl)pyrimidin-4-yl]-(2,3-dihydrobenzo[1,4]dioxin-6-yl)amine hydrochloride;

[6-(2-amino-4-trifluoromethylphenyl)pyrimidin-4-yl]benzothiazol-6-ylamine;

[6-(4-tert-butylphenyl)-2-chloropyrimidin-4-yl]-(2,3-dihydrobenzo[1,4]dioxin-6-yl)amine;

[6-(4-tert-butylphenyl)-2-methylpyrimidin-4-yl]-(2,3-dihydrobenzo[1,4]dioxin-6-yl)amine;

[6-(4-tert-butylphenyl)pyrimidin-4-yl]-(1H-indol-4-yl)amine;

[6-(4-tert-butylphenyl)pyrimidin-4-yl]-(1H-indol-5-yl)amine;

[6-(4-tert-butylphenyl)pyrimidin-4-yl]-(1H-indol-6-yl)amine;

[6-(4-tert-butylphenyl)pyrimidin-4-yl]-(2,3-dihydrobenzo[1,4]dioxin-6-yl)amine;

[6-(4-tert-butylphenyl)pyrimidin-4-yl]-(3-methoxyphenyl)amine;

[6-(4-tert-butylphenyl)pyrimidin-4-yl]naphthalen-1-ylamine;

[6-(4-tert-butylphenyl)pyrimidin-4-yl]phenylamine;

[6-(4-tert-butylphenylpyrimidin-4-yl]quinolin-3-ylamine;

{1′-acetylspiro[cyclopropane-1,3′-indolin-6′-yl]}-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

{7-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-1H-indol-2-yl}methanol;

{spiro[cyclopropane-1,3′-indolin-6′-yl]}-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

1-{3,3-dimethyl-6-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-2,3-dihydroindol-1-yl}ethanone;

2-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]quinolin-8-ol;

2-{5-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]pyridin-2-yloxy}ethanol;

3,4-dihydro-7-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-1H-quinolin-2-one;

4-methyl-7-{[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amino}quinolin-2-ol, hydrochloride;

6-[6-(4-tert-butylphenyl)pyrimidin-4-ylamino]-3,4-dihydro-2H-naphthalen-1-one;

7-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-quinoline-2-ol;

7-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-1,3-dihydroindol-2-one;

benzothiazol-5-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

benzothiazol-6-yl-[6-(2-cyclohexylmethylamino-4-trifluoromethylphenyl)-pyrimidin-4-yl]amine;

benzothiazol-6-yl-[6-(4-tert-butylphenyl)pyrimidin-4-yl]amine;

benzothiazol-6-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4yl]amine;

N-{4-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-1H-benzoimidazol-2-yl}acetamide;

N-{4-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]benzothiazol-2-yl}acetamide;

N-{4-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]phenyl}acetamide;

N 4 -[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]-1H-benzoimidazole-2,4-diamine;

N 4 -[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]benzothiazole-2,4-diamine;

N 4 -benzothiazol-6-yl-6-(4-tert-butylphenyl)pyrimidine-2,4-diamine hydrochloride;

N 7 -[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]quinoline-2,7-diamine;

N 8 -[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]quinoline-2,8-diamine;

naphthalen-1-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

naphthalen-2-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

o-tolyl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

phenyl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

p-tolyl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

quinolin-3-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

quinolin-5-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

quinolin-6-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;

quinolin-8-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine; and

quinolyl-7-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine.

4. A method of making a compound according to claim 1 , comprising the step of:

reacting

 with R 4 NH 2 to form

5. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically-acceptable diluent or carrier.

6. A method of treating acute, inflammatory and neuropathic pain, comprising the step of administering to a patient in need thereof a compound according to claim 1 .

7. A method of treating acute, inflammatory and neuropathic pain, comprising the step of administering to a patient in need thereof a compound according to claim 2 .

8. A method of treating acute, inflammatory and neuropathic pain, comprising the step of administering to a patient in need thereof a compound according to claim 3 .

9. A compound according to claim 1 , wherein R 1 is

10. A compound according to claim 1 , wherein R 1 is R b substituted by 1, 2 or 3 substituents independently selected from R 5 .

11. A compound according to claim 1 , wherein R 4 is

but in no instance is R 4 3,5-ditrifluoromethylphenyl or 3-trifluoromethyl-4-fluorophenyl, -phenyl-(C 1-8 alkyl), -phenyl-O—(C 1-6 alkyl), -phenyl-NR a R a or -phenyl-N(R a )C(═O)(C 1-8 alkyl).

12. A compound according to claim 1 , wherein 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 0, 1, 2 or 3 substituents independently selected from R e , C 1-4 haloalkyl, halo, nitro, cyano, oxo, —OR f , —S(—═O) n R e , —OC 1-4 haloalkyl, —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —OC 1-6 alkylC(═O)OR e , —NR a R f , —NR a C 1-4 haloalkyl, —NR a C 2-6 alkylNR a R f , —NR a C 2-6 alkylOR f , —C(═O)R e , —C(═O)OR e , —OC(═O)R e , —C(═O)NR a R f and —NR a C(═O)R e ; and unsaturated carbon atoms may be additionally substituted by ═O; and any available nitrogen atoms in the heterocycle and bridge are substituted by H, —C 1-6 alkylOR f , R e , —C 1-6 alkylNR a R f , —C 1-3 alkylC(═O)OR e , —C 1-3 alkylC(═O)NR a R f , —C 1-3 alkylOC(═O)R e , —C 1-3 alkylNR a C(═O)R e , —C(═O)R c or —C 1-3 alkylR c .

13. A compound according to claim 1 , wherein R 5 is independently, at each instance, R f , R g , halo, nitro, cyano, —OR e , —OR g , —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —NR a R f , —NR a R g , —NR f C 2-6 alkylNR a R f , —NR f C 2-6 alkylOR f , naphthyl, —CO 2 R e , —C(═O)R e , —C(═O)NR a R f , —C(═O)NR a R g , —NR f C(═O)R e , —NR f C(═O)R g , —NR f C(═O)NR a R f , —NR f CO 2 R e , —C 1-8 alkylOR f , —C 1-6 alkylNR a R f , —S(═O)—R e , —S(═O) 2 NR a R f , —NR a S(═O) 2 R e , —OC(═O)NR a R f , a phenyl ring substituted with 0, 1, 2, or 3 substituents independently selected from R 10 ; 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, substituted with 0, 1, 2, or 3 substituents independently selected from R 10 .

14. A compound according to claim 1 , wherein R 7 is independently, at each instance, C 3-5 alkyl or C 1-2 haloalkyl.

15. A compound according to claim 1 , wherein R 10 and R 11 together are a saturated or unsaturated 3- or 4-atom bridge containing 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 bridge is substituted by 0, 1 or 2 substituents selected from ═O, R e , halo, cyano, nitro, —C(═O)R e , —C(═O)OR e , —C(═O)NR a R f , —C(═NR a )NR a R f , —OR f , —OC(═O)R e , —OC(═O)NR a R f , —OC(═O)N(R f )S(═O) 2 R e , —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —SR f , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR a R f , —S(═O) 2 N(R f )C(═O)R e , —S(═O) 2 N(R f )C(═O)OR e , —S(═O) 2 N(R f )C(═O)NR a R f , —NR a R f , —N(R f )C(═O)R e , —N(R f )C(═O)OR e , —N(R f )C(═O)NR a R f , —N(R f )C(═NR a )NR a R f , —N(R f )S(═O) 2 R e , —N(R f )S(═O) 2 NR a R f , —NR f C 2-6 alkylNR a R f and —NR f C 2-6 alkylOR f .

16. A compound according to claim 1 , wherein R 10 and R 11 together are a saturated or unsaturated 3-atom bridge containing 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 bridge is substituted by 0, 1 or 2 substituents selected from ═O, R e , halo, cyano, nitro, —C(═O)R e , —C(═O)OR e , —C(═O)NR a R f , —C(═NR f )NR a R f , —OR f , —OC(═O)R e , —OC(═O)NR a R f , —OC(═O)N(R f )S(═O) 2 R e , —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —SR f , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR a R f , —S(═O) 2 N(R f )C(═O)R e , —S(═O) 2 N(R f )C(═O)OR e , —S(═O) 2 N(R f )C(═O)NR a R f , —NR a R f , —N(R f )C(═O)R e , —N(R f )C(═O)OR e , —N(R f )C(═O)NR a R f , —N(R f )C(═NR a )NR a R f , —N(R f )S(═O) 2 R e , —N(R f )S(═O) 2 NR a R f , —NR f C 2-6 alkylNR a R f and —NR f C 2-6 alkylOR f .

17. A compound according to claim 1 , wherein R 10 and R 11 together are a saturated or unsaturated 3- or 4-atom bridge containing 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 bridge is substituted by 1 or 2 substituents selected from R e , halo, cyano, nitro, —C(═O)R e , —C(═O)OR e , —C(═O)NR a R f , —C(═NR a )NR a R f , —OR f , —OC(═O)R e , —OC(═O)NR a R f , —OC(═O)N(R f )S(═O) 2 R e , —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —SR f , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR a R f , —S(═O) 2 N(R f )C(═O)R e , —S(═O) 2 N(R f )C(═O)OR e , —S(═O) 2 N(R f )C(═O)NR a R f , —NR a R f , —N(R f )C(═O)R e , —N(R f )C(═O)OR e , —N(R f )C(═O)NR a R f , —N(R f )C(═NR a )NR a R f , —N(R f )S(═O) 2 R e , —N(R f )S(═O) 2 NR a R f , —NR f C 2-6 alkylNR a R f and —NR f C 2-6 alkylOR f .

18. A compound according to claim 1 , wherein R 11 and R 12 together are a saturated or unsaturated 3- or 4-atom bridge containing 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 bridge is substituted by 0, 1 or 2 substituents selected from ═O, R e , halo, cyano, nitro, —C(═O)R e , —C(═O)OR e , —C(═O)NR a R f , —C(═NR a )NR a R f , —OR f , —OC(═O)R e , —OC(═O)NR a R f , —OC(═O)N(R f )S(═O) 2 R e , —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —SR f , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR a R f , —S(═O) 2 N(R f )C(═O)R e , —S(═O) 2 N(R f )C(═O)OR e , —S(═O) 2 N(R f )C(═O)NR a R f , —NR a R f , —N(R f )C(═O)R e , —N(R f )C(═O)OR e , —N(R f )C(═O)NR a R f , —N(R f )C(═NR a )NR a R f , —N(R f )S(═O) 2 R e , —N(R f )S(═O) 2 NR a R f , —NR f C 2-6 alkylNR a R f and —NR f C 2-6 alkylOR f .

19. A compound according to claim 1 , wherein R 11 and R 12 together are a saturated or unsaturated 3-atom bridge containing 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 bridge is substituted by 0, 1 or 2 substituents selected from ═O, R e , halo, cyano, nitro, —C(═O)R e , —C(═O)OR e , —C(═O)NR a R f , —C(═NR f )NR a R f , —OR f , —OC(═O)R e , —OC(═O)NR a R f , —OC(═O)N(R f )S(═O) 2 R e , —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —SR f , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR a R f , —S(═O) 2 N(R f )C(═O)R e , —S(═O) 2 N(R f )C(═O)OR e , —S(═O) 2 N(R f )C(═O)NR a R f , —NR a R f , —N(R f )C(═O)R e , —N(R f )C(═O)OR e , —N(R f )C(═O)NR a R f , —N(R f )C(═NR a )NR a R f , —N(R f )S(═O) 2 R e , —N(R f )S(═O) 2 NR a R f , —NR f C 2-6 alkylNR a R f and —NR f C 2-6 alkylOR f .

20. A compound according to claim 1 , wherein R 11 and R 12 together are a saturated or unsaturated 3-atom bridge containing 1 or 2 atoms selected from O, N and S with the remaining atoms being carbon, wherein the bridge is substituted by R e , —C(═O)R e , —C(═O)OR e , —C(═O)NR a R f , —C(═NR a )NR a R f , —OR f , —OC(═O)R e , —OC(═O)NR a R f , —OC(═O)N(R f )S(═O) 2 R e , —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —SR f , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR a R f , —S(═O) 2 N(R f )C(═O)R e , —S(═O) 2 N(R f )C(═O)OR e , —S(═O) 2 N(R f )C(═O)NR a R f , —NR a R f , —N(R f )C(═O)R e , —N(R f )C(═O)OR e , —N(R f )C(═O)NR a R f , —N(R f )C(═NR a )NR a R f , —N(R f )S(═O) 2 R e , —N(R f )S(═O) 2 NR a R f , —NR f C 2-6 alkylNR a R f or —NR f C 2-6 alkylOR f .

21. A compound according to claim 1 , wherein R 11 and R 12 together are a saturated or unsaturated 3-atom bridge containing 1 or 2 atoms selected from O, N and S with the remaining atoms being carbon, wherein the bridge is substituted by —C(═O)R e , —C(═O)OR e , —C(═O)NR a R f , —C(═NR a )NR a R f , —OC(═O)NR a R f , —OC(═O)N(R f )S(═O) 2 R e , —OC 2-6 alkylNR a R f , —OC 2-6 alkylOR f , —SR f , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR a R f , —S(═O) 2 N(R f )C(═O)R e , —S(═O) 2 N(R f )C(═O)OR e , —S(═O) 2 N(R f )C(═O)NR a R f , —NR a R f , —N(R f )C(═O)R e , —N(R f )C(═O)OR e , —N(R f )C(═O)NR a R f , —N(R f )C(═NR a )NR a R f , —N(R f )S(═O) 2 R e , —N(R f )S(═O) 2 NR a R f , —NR f C 2-6 alkylNR a R f or —NR f C 2-6 alkylOR f .

22. A compound according to claim 1 , wherein R 3 is H.