Heteroaryl Sodium Channel Inhibitors

摘要

The present invention provides compounds of Formula I or II, or pharmaceutically acceptable salts thereof, that are inhibitors of voltage-gated sodium channels, in particular Nav 1.7. The compounds are useful for the treatment of diseases treatable by inhibition of channels such as pain disorders. Also provided are pharmaceutical compositions containing compounds of the present invention.;

主权项

1. A compound of Formula I or II, or a pharmaceutically acceptable salt thereof,wherein:
each X1, X2 or X3 is independently CRa or N; each Ra is independently hydrogen, halo, C1-6alkyl, —OC1-6alkyl, or —CN; each Rb is independently hydrogen or C1-6alkyl; R1 is a five or six membered heteroaryl or heterocycloalkyl group having from one to four heteroatoms independently selected from O, N or S, or a five or six membered aryl or cycloalkyl group, where the heteroaryl, heterocycloalkyl, aryl or cycloalkyl group is unsubstituted or substituted with from one to four substituents selected from halo, C1-6alkyl, —OH, —OC1-6alkyl or —NRbRb; R2 is a five to ten membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, the heteroaryl or heterocycloalkl group having from one to four heteroatoms independently selected from O, N or S, and where the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with from one to four substituents independently selected from —CF3, —CHF2, —CF2H, —OC1-6alkyl, —OCF3, —C1-6alkyl, halo, —C≡C—Rb, —CN, —NRbRb, —S(═O)2C1-6alkyl, or Y; Y is a five or six membered heteroaryl or heterocycloalkyl group having from one to four heteroatoms independently selected from O, N or S, or six membered aryl or five or six membered cycloalkyl group, which heteroaryl, heterocycloalkyl, aryl or cycloalkyl group is unsubstituted or substituted with from one to four substituents independently selected from —CF3, —CHF2, —CF2H, —OC1-6alkyl, —OCF3, C1-6alkyl, halo, —C≡C—Rb, —CN, —NRbRb, —S(═O)2C1-6alkyl, —C(═O)C1-6alkyl or Z; Z is a three to six membered heterocycloalkyl group having from one to four heteroatoms independently selected from O, N or S; R3 is hydrogen, C1-6alkyl, —C(═O)C1-6alkyl, —C(═O)OC1-6alkyl, or —S(═O)2 C1-6alkyl; and R4 is hydrogen or C1-6alkyl, provided that the compound of Formula I is not 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-2-pyrimidinyl-1H-indole-6-sulfonamide; 3-(1-(3-azetidinyl)-1H-pyrazol-3-yl)-1-methyl-N-1,2,4-thiadiazol-5-yl-1H-indole-6-sulfonamide; 3-(2-(5-acetyl-2-thiophenyl)-4-(trifluoromethyl)phenyl)-1-methyl-N-1,2,4-thiadiazol-5-yl-1H-indole-6-sulfonamide; 1-methyl-3-(5-phenyl-2-thiophenyl)-N-1,2,4-thiadiazol-5-yl-1H-indole-6-sulfonamide; N-(4-((1R)-1-methoxyethyl)-1,3-thiazol-2-yl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide, N-(4-((1S)-1-methoxyethyl)-1,3-thiazol-2-yl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide; 1-methyl-3-(4-(methylsulfonyl)phenyl)-N-1,2,4-thiadiazol-5-yl-1H-indole-6-sulfonamide; N-(3-ethyl-1,2,4-thiadiazol-5-yl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide; 1-methyl-3-(4-((methylsulfonyl)amino)phenyl)-N-1,2,4-thiadiazol-5-yl-1H-indole-6-sulfonamide; or 3-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-1-methyl-N-1,2,4-thiadiazol-5-yl-1H-indole-6-sulfonamide.