Vanilloid receptor ligands and their use in treatments

A compound having the structure:

• or any pharmaceutically-acceptable salt thereof, wherein:
• n is independently, at each instance, 0, 1 or 2,
• R1 is
• or R1 is a naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from R5;
• or R1 is Rb substituted by 1, 2 or 3 substituents independently selected from R5;
• R2 is, independently, in each instance, R10, C1-8alkyl substituted by 0, 1 or 2 substituents selected from R10, —(CH2)nphenyl substituted by 0, 1, 2 or 3 substituents independently selected from R10, 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 R10;
• R3 is, independently, in each instance, H, halo, —NH2, —NHC1-3alkyl, —N(C1-3alkyl)C1-3alkyl, or C1-3alkyl;
• R4 is
• R4 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 Re, C1-4haloalkyl, halo, nitro, cyano, oxo, —ORf, —S(=O)nRe, —OC1-4haloalkyl, —OC2-6alkylNRaRf, —OC2-6alkyl ORf, —OC1-6alkylC(═O)ORe, —NRaRf, —NRaC1-4haloalkyl, —NRaC2-6alkylNRaRf, —NRaC2-6alkylORf, —C(═O)Re, —C(═O)ORe, —OC(═O)Re, —C(═O)NRaRf and —NRaC(═O)Re;
• and unsaturated carbon atoms may be additionally substituted by ═O;
• and any available nitrogen atoms in the heterocycle and bridge are substituted by H, —C1-6allcylORf, Re, —C1-6alkylNRaRf, —C1-3alkylC(═O)ORe, —C1-3alkylC(═O)NRaRf, —C1-3alkylOC(═O)Re, —C1-3alkylNRaC(═O)Re, —C(═O)Rc or —C1-3alkylRc;
• or R4 is naphthyl substituted by 1,2 or 3 substituents independently selected from C1-4haloalkyl, halo, nitro, cyano, —S(═O)n Re, —OC1-4haloalkyl, —OC2-6alkylNRaRf, —OC2-6alkylORf, —OC1-6alkylC(═O)ORe, —NRaC1-4haloalkyl, —NRaC2-6alkylNRaRf, —NRaC2-6alkylORf, —C(═O)Re, —C(═O)ORe,—OC(═O)Re and —C(═O)NRaRf;
• but in no instance is R4 3,5-ditrifluoromethyiphenyl or 3-trifluoromethyl-4-fluorophenyl, -phenyl-(C1-8alkyl), -phenyl-O—(C1-6alkyl), -phenyl-NRaRa or -phenyl-N(Ra)C(═O)(C1-8alkyl);
• R5 is independently, at each instance, Rf, Rg, halo, nitro, cyano, —ORe, —ORg, —OC2-6alkylNRaRf, —OC2-6alkylORf, —NRaRf, —NRaRg, —NRfC2-6alkylNRaRf, —NRfC2-6alkylORf, naphthyl, —CO2Re, —C(═O)Re, —C(═O)NRaRf, —C(═O)NRaRg, —NRfC(═O)Re, —NRfC(═O)Rg, —NRfC(═O)NRaRf, —NRfCO2Re, —C1-8alkylORf, —C1-6alkylNRaRf, —S(═O)nRe, —S(═O)2NRaRf, —NRaS(═O)2Re, —OC(═O)NRaRf, a phenyl ring substituted with 0, 1, 2, or 3 substituents independently selected from R10;
• or R5 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 R10;
• R6 is independently, at each instance, H, C1-5alkyl, C1-4haloalkyl, halo, —OC1-6alkyl, —OC1-4haloalkyl, —OC2-6alkylORa, —NRaRa, —NRaC1-4haloalkyl, —NRaC2-6alkylNRaRa or —NRaC2-6alkylORa, —C1-8alkylORa, —C1-6alkylNRaRa, —S(C1-6alkyl), a phenyl ring substituted with 1, 2, or 3 substituents independently selected from R10;
• or R6 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 R10;
• R7 is independently, at each instance, C3-5alkyl or C1-2haloalkyl;
• Ra is independently, at each instance, H, C1-5alkyl, C1-4haloalkyl, halo, —OC1-6alkyl, —OC1-4haloalkyl, —OC2-6alkylNRaRa, —OC2-6alkylORa, —NRaRa, —NRaC1-4haloalkyl, —NRaC2-6alkylNRaRa, —NRaC2-6alkylORa, —C1-8alkylORa, —C1-6alkylNRaRa, —S(C1-6alkyl), a phenyl ring substituted with 1, 2, or 3 substituents independently selected from R10, or Ra 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 R10;
• R9 is independently, at each instance, Rf, Rg, halo, nitro, cyano, —ORe, —ORg, —OC2-6alkylNRaRf, —OC2-6alkylORf, —NRaRf, —NRaRg, —NRfC2-6alkylNRaRf, —NRfC2-6alkylORf, naphthyl, —CO2Re, —C(═O)Re, —C(═O)NRaRf, —C(═O)NRaRg, —NRfC(═O)Re, —NRfC(═O)Rg, —NRfC(═O)NRaRf, —NRfCO2Re, —C1-8alkylORf, —C1-6alkylNRaRf, —S(═O)nRe, —S(═O)2NRaRf, —NRaS(═O)2Re, —OC(═O)NRaRf, a phenyl ring substituted with 0, 1, 2, or 3 substituents independently selected from R10;
• R9 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 R10;
• or R9 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, C1-2haloalkyl and C1-3alkyl;
• wherein at least one of R5, R6, R7, R8 and R9 is C3-8alkyl, C1-4haloalkyl, halo, —OC1-4haloalkyl, —OC2-6alkylNRaRa, —OC2-6alkylORa, —NRaC1-4haloalkyl, —NRaC2-6alkylNRaRa, —NRaC2-6alkylORa, —C1-8alkylORa, —C1-6alkylNRaRa or —S(C1-6alkyl);
• R10 is independently, at each instance, selected from H, C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, —C(═O)(C1-8alkyl), —C(═O)O(C1-8alkyl), —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)(C1-8alkyl), —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2(C1-8alkyl), —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)(C1-8alkyl), —S(═O)2(C1-8alkyl), —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)(C1-8alkyl), —S(═O)2N(Ra)C(═O)O(C1-8alkyl), —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)(C1-8alkyl), —N(Ra)C(═O)O(C1-8alkyl), —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2(C1-8alkyl), —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa and —NRaC2-6alkylORa;
• or R10 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 C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, —C(═O)(C1-8alkyl), —C(═O)O(C1-8alkyl), —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)(C1-8alkyl), —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2(C1-8alkyl), —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)(C1-8alkyl), —S(═O)2(C1-8alkyl), —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)(C1-8alkyl), —S(═O)2N(Ra)C(═O)O(C1-8alkyl), —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)(C1-8alkyl), —N(Ra)C(═O)O(C1-8alkyl), —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2(C1-8alkyl), —N(Ra)S(═O)2NRaRa, alkylNRaRa and —NRaC2-6alkylORa;
• or R10 is C1-4alkyl substituted by 0, 1, 2 or 3 groups selected from C1-4haloalkyl, halo, cyano, nitro, —C(═O)(C1-8alkyl), —C(═O)O(C1-8alkyl), —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)(C1-8alkyl), —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2(C1-8alkyl), —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)(C1-8alkyl), —S(═O)2(C1-8alkyl), —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)(C1-8alkyl), —S(═O)2N(Ra)C(═O)O(C1-8alkyl), —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)(C1-8alkyl), —N(Ra)C(═O)O(C1-8alkyl), —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2(C1-8alkyl), —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa and —NRaC2-6alkylORa;
• R11 is independently, at each instance, selected from H, C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, —C(═O)(C1-8alkyl), —C(═O)O(C1-8alkyl), —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)(C1-8alkyl), —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2(C1-8alkyl), —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)(C1-8alkyl), —S(═O)2(C1-8alkyl), —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)(C1-8alkyl), —S(═O)2N(Ra)C(═O)O(C1-8alkyl), —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)(C1-8alkyl), —N(Ra)C(═O)O(C1-8alkyl), —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2(C1-8alkyl), —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa and —NRaC2-6alkylORa;
• or R11 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 C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, —C(═O)(C1-8alkyl), —C(═O)O(C1-8alkyl), —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)(C1-8alkyl), —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2(C1-8alkyl), —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)(C1-8alkyl), —S(═O)2(C1-8alkyl), —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)(C1-8alkyl), —S(═O)2N(Ra)C(═O)O(C1-8alkyl), —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)(C1-8alkyl), —N(Ra)C(═O)O(C1-8alkyl), —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2(C1-8alkyl), —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa and —NRaC2-6alkylORa;
• or R11 is C1-4alkyl substituted by 0, 1, 2 or 3 groups selected from C1-4haloalkyl, halo, cyano, nitro, —C(═O)(C1-8alkyl), —C(═O)O(C1-8alkyl), —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)(C1-8alkyl), —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2(C1-8alkyl), —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)(C1-8alkyl), —S(═O)2(C1-8 alkyl), —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)(C1-8alkyl), —S(═O)2N(Ra)C(═O)O(C1-8alkyl), —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)(C1-8alkyl), —N(Ra)C(═O)O(C1-8alkyl), —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2(C1-8alkyl), —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa and —NRaC2-6alkylORa;
• or R10 and R11 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, Re, halo, cyano, nitro, —C(═O)Re, —C(═O)ORe, —C(═O)NRaRf, —C(═NRa)NRaRf, —ORf, —OC(═O)Re, —OC(═O)NRaRf, —OC(═O)N(Rf)S(═O)2Re, —OC2-6alkylNRaRf, —OC2-6alkylORf, —SRf, —S(═O)Re, —S(═O)2Re, —S(═O)2NRaRf, —S(═O)2N(Rf)C(═O)Re, —S(═O)2N(Rf)C(═O)ORe, —S(═O)2N(Rf)C(═O)NRaRf, —NRaRf, —N(Rf)C(═O)Re, —N(Rf)C(═O)ORe, —N(Rf)C(═O)NRaRf, —N(Rf)C(═NRa)NRaRf, —N(Rf)S(═O)2Re, —N(Rf)S(═O)2NRaRf, —NRfC2-6alkylNRaRf and —NRfC2-6alkylORf;
• R12 is independently, at each instance, selected from H, C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, —C(═O)(C1-8alkyl), —C(═O)O(C1-8alkyl), —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)(C1-8alkyl), —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2(C1-8alkyl), —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)(C1-8alkyl), —S(═O)2(C1-8alkyl), —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)(C1-8alkyl), —S(═O)2N(Ra)C(═O)O(C1-8alkyl), —S(═O)2N(Ra)C(═O)NRaRa, —N(Ra)C(═O)(C1-8alkyl), —N(Ra)C(═O)O(C1-8alkyl), —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2(C1-8alkyl), —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa and —NRaC2-6alkylORa;
• or R12 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 C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, —C(═O)(C1-8alkyl), —C(═O)O(C1-8alkyl), —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)(C1-8alkyl), —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2(C1-8alkyl), —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)(C1-8alkyl), —S(═O)2(C1-8alkyl), —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)(C1-8alkyl), —S(═O)2N(Ra)C(═O)O(C1-8alkyl), —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)(C1-8alkyl), —N(Ra)C(═O)O(C1-8alkyl), —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2(C1-8alkyl), —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa and —NRaC2-6alkylORa;
• or R12 is C1-4alkyl substituted by 0, 1, 2 or 3 groups selected from C1-4haloalkyl, halo, cyano, nitro, —C(═O)(C1-8alkyl), —C(═O)O(C1-8alkyl), —C(═O)NRaRa, —C(—NRa)NRaRa, —ORa, —OC(═O)(C1-8alkyl), —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2(C1-8alkyl), —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)(C1-8alkyl), —S(═O)2(C1-8alkyl), —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)(C1-8alkyl), —S(═O)2N(Ra)C(═O)O(C1-8alkyl), —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)(C1-8alkyl), —N(Ra)C(═O)O(C1-8alkyl), —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2(C1-8alkyl), —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa and —NRaC2-6alkylORa;
• wherein if R11 or R13 is CF3, then R12 is not F;
• or R11 and R12 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, Re, halo, cyano, nitro, —C(═O)Re, —C(═O)ORe, —C(═O)NRaRf, —C(═NRa)NRaRf, —ORf, —OC(═O)Re, —OC(═O)NRaRf, —OC(═O)N(Rf)S(═O)2Re, —OC2-6alkylNRaRf, —OC2-6alkylORf, —SRf, —S(═O)Re, —S(═O)2Re, —S(═O)2NRaRf, —S(═O)2N(Rf)C(═O)Re, —S(═O)2N(Rf)C(═O)ORe, —S(═O)2N(Rf)C(═O)NRaRf, —NRaRf, —N(Rf)C(═O)Re, —N(Rf)C(═O)ORe, —N(Rf)C(═N)NRaRf, —N(Rf)S(═O)2Re, —N(Rf)S(═O)2NRaRf, —NRfC2-6alkylNRaRf and —NRfC2-6alkylORf;
• wherein when R3 is NH2, then —R11-R12— is not —C═C—C═N— or any substituted version thereof;
• R13 is independently, at each instance, selected from H, C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, —C(═O)(C1-8alkyl), —C(═O)O(C1-8alkyl), —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)(C1-8alkyl), —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2(C1-8alkyl), —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)(C1-8alkyl), —S(═O)2(C1-8alkyl), —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)(C1-8alkyl), —S(═O)2N(Ra)C(═O)O(C1-8alkyl), —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)(C1-8alkyl), —N(Ra)C(═O)O(C1-8alkyl), —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2(C1-8alkyl), —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa and —NRa C2-6alkylORa;
• or R13 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 C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, —C(═O)(C1-8alkyl), —C(═O)O(C1-8alkyl), —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)(C1-8alkyl), —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2(C1-8alkyl), —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)(C1-8alkyl), —S(═O)2(C1-8alkyl), —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)(C1-8alkyl), —S(═O)2N(Ra)C(═O)O(C1-8alkyl), —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)(C1-8alkyl), —N(Ra)C(═O)O(C1-8alkyl), —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2(C1-8alkyl), —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa and —NRa C2-6alkylORa;
• or R13 is C1-4alkyl substituted by 0, 1, 2 or 3 groups selected from C1-4haloalkyl, halo, cyano, nitro, —C(═O)(C1-8alkyl), —C(═O)O(C1-8alkyl), —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)(C1-8alkyl), —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2(C1-8alkyl), —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)(C1-8alkyl), —S(═O)2(C1-8alkyl), —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)(C1-8alkyl), —S(═O)2N(Ra)C(═O)O(C1-8alkyl), —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)(C1-8alkyl), —N(Ra)C(═O)O(C1-8alkyl), —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2(C1-8alkyl), —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa and —NRaC2-6alkylORa;
• R14 is independently, at each instance, selected from H, C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, —C(═O)(C1-8alkyl), —C(═O)O(C1-8alkyl), —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)(C1-8alkyl), —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2(C1-8alkyl), —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)(C1-8alkyl), —S(═O)2(C1-8alkyl), —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)(C1-8alkyl), —S(═O)2N(Ra)C(═O)O(C1-8alkyl), —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)(C1-8alkyl), —N(Ra)C(═O)O(C1-8alkyl), —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2(C1-8alkyl), —N(Ra)S(═O)2NRaRa, —NRaC2-6alkyl NRaRa and —NRaC2-6alkylORa;
• or R14 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 C1-8alkyl, C1-4haloalkyl, halo, cyano, nitro, —C(═O)(C1-8alkyl), —C(═O)O(C1-8alkyl), —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)(C1-8alkyl), —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2(C1-8alkyl), —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)(C1-8alkyl), —S(═O)2(C1-8alkyl), —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)(C1-8alkyl), —S(═O)2N(Ra)C(═O)O(C1-8alkyl), —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)(C1-8alkyl), —N(Ra)C(═O)O(C1-8alkyl), —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2(C1-8alkyl), —N(Ra)S(═O)2NRaRa, —NRaC2-6alkyl NRaRa and —NRaC2-6alkylORa;
• or R14 is C1-4alkyl substituted by 0, 1, 2 or 3 groups selected from C1-4haloalkyl, halo, cyano, nitro, —C(═O)(C1-8alkyl), —C(═O)O(C1-8alkyl), —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)(C1-8alkyl), —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2(C1-8alkyl), —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)(C1-8alkyl), —S(═O)2(C1-8alkyl), —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)(C1-8alkyl), —S(═O)2N(Ra)C(═O)O(C1-8alkyl), —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)(C1-8alkyl), —N(Ra)C(═O)O(C1-8alkyl), —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2(C1-8alkyl), —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa and —NRaC2-6alkylORa;
• wherein at least one of R10, R11, R12, R13 and R14 is other than H;
• Ra is independently, at each instance, H, phenyl, benzyl or C1-6alkyl;
• Rb 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, 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-oxazine, 2H-1,4-oxazine, 4H-1,4-oxazine, 2H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,2-thiazine, 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;
• Rc is independently, in each instance, phenyl substituted by 0, 1 or 2 groups selected from halo, C1-4alkyl, C1-3haloalkyl, —ORa and —NRaRa;
• or Rc 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, C1-4alkyl, C1-3haloalkyl, —ORa and —NRaRa;
• Rd is hydrogen or —CH3;
• Re is, independently, in each instance, C1-9alkyl substituted by 0, 1, 2, 3 or 4 substituents selected from halo, cyano, nitro, —C(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Rb, —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2Rb, —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)Rb, —S(═O)2Rb, —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)Rb, —S(═O)2N(Ra)C(═O)ORb, —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)Rb, —N(Ra)C(═O)ORb, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Rb, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa and —NRaC2-6alkylORa;
• and wherein the C1-9alkyl is additionally substituted by 0 or 1 groups independently selected from Rg;
• Rf is, independently, in each instance, Re or H;
• and
• Rg 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.