2-amino-n-phenyl-nicotinamides as NAV1.8 inhibitors

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein

A is phenyl or phenyl fused to a saturated or unsaturated 5- or 6-membered ring containing 0-3 heteroatoms independently selected from O, S and N(R b ) q , wherein each phenyl, 5-membered ring and 6-membered ring is unsubstituted;

B is selected from the group consisting of:

(1) pyridine;

(2) pyrimidine; and

(3) pyridazine;

wherein pyridine, pyrimidine and pyridazine is unsubstituted or substituted with one to three substituents selected from R b :

R 1 is selected from the group consisting of:

(1) —SO 2 NH 2 ,

(2) —SO 2 NH-heteroaryl,

(3) —SO 2 C 1-6 alkyl,

(4) —SO 2 C 3-6 cycloalkyl,

(5) —SO 2 C 3-6 cycloheteroalkyl,

(6) —C(O)NH 2 , and

(7) —CN,

wherein each alkyl, cycloalkyl, cycloheteroalkyl and heteroaryl is unsubstituted or substituted with one to four substituents selected from R d ;

R 2 is selected from the group consisting of:

(1) hydrogen, and

(2) —C 1-6 alkyl;

R 3 is selected from the group consisting of:

(1) pyrrolidine,

(2) azetidine,

(3) piperidine,

(4) piperazine,

(5) azepane,

(6) azocane,

(7) thiomorpholine,

(8) oxazepane,

(9) 1,4-oxazepane,

(10) isoindoline,

(11) 2-isoindoline,

(12) dihydroisoquinoline,

(13) octahydroisoindole,

(14) azabicyclo[2.2.1]heptane,

(15) azabicyclo[3.1.1]heptane,

(16) azabicyclo[4.1.0]heptane,

(17) azabicyclo[3.2.1]octane,

(18) diazabicyclo[3.2.1]octane,

(19) azabicyclo[3.2.0]heptane,

(20) oxa-azabicyclo[3.2.1]octane,

(21) azaspiro[2.5]octane,

(22) azaspiro[2.6]nonane,

(23) azaspiro[3.5]nonane,

(24) oxa-azaspiro[3.5}nonane,

(25) oxa-oazaspiro[4.5]decane,

(26) dihydrothieno[3,2-c]pyridine,

(27) dihydrothiazolo[4,5-c]pyridine,

(28) dihydrooxazolo[4,5-c]pyridine,

(29) dihydroimidazo[1,2-a]pyrazine,

(30) hexahydrofuro[3,2-b]pyrrole,

(31) hexahydrocyclopenta[c]pyrrole, and

(32) azatricyclo[4.3.1.13,8]undecane,

wherein R 3 is unsubstituted or substituted with one to eight substituents selected from R c ;

each R a is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —OC 1-6 alkyl,

(3) halogen,

(4) —OH,

(5) oxo,

(6) —CN,

(7) —C 3-6 cycloalkyl, and

(8) —C 2-5 cycloheteroalkyl,

wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to six substituents selected from halogen, OH, NH 2 , NH(C 1-6 alkyl) and N(C 1-6 alkyl) 2 ;

each R b is independently selected from the group consisting of:

(1) —CF 3 ,

(2) —CF 2 CF 3 ,

(3) —CHF 2 ,

(4) —OCHF 2 ,

(5) —OCH 2 CF 3 ,

(6) —OCF 3 ,

(7) CN,

(8) halogen,

(9) —Si(C 1-6 alkyl) 3 ,

(10) —C 1-6 alkyl-O—R k ,

(11) —C 1-6 alkyl,

(12) —C 2-6 alkenyl,

(13) —C 2-6 alkynyl,

(14) —C 3-6 cycloalkyl,

(15) —C 2-6 cycloheteroalkyl,

(16) aryl,

(17) heteroaryl,

(18) —C 1-6 alkyl-C 3-6 cycloalkyl,

(19) —C 1-6 alkyl-C 2-6 cycloheteroalkyl,

(20) —C 1-6 alkyl-aryl,

(21) —C 1-6 alkyl-heteroaryl,

(22) —C 2-6 alkenyl-C 3-6 cycloalkyl,

(23) —C 2-6 alkenyl-C 2-6 cycloheteroalkyl,

(24) —C 2-6 alkenyl-aryl,

(25) —C 2-6 alkenyl-heteroaryl,

(26) —C 2-6 alkynyl-C 3-6 cycloalkyl,

(27) —C 2-6 alkynyl cycloheteroalkyl,

(28) —C 2-6 alkynyl-aryl,

(29) —C 2-6 alkynyl-heteroaryl,

(30) NO 2 ,

(31) —OH,

(32) —(CH 2 ) p -OC 1-6 alkyl,

(33) —(CH 2 ) p -OC 2-6 alkenyl,

(34) —(CH 2 ) p -OC 2-6 alkynyl,

(35) —(CH 2 ) p -OC 3-6 cycloalkyl,

(36) —(CH 2 ) p -OC 2-6 hetetocycloalkyl,

(37) —(CH 2 ) p -O-aryl,

(38) —(CH 2 ) p -O-heteroaryl,

(39) —OC 1-6 alkyl-C 3-6 cycloalkyl,

(40) —OC 1-6 alkyl-C 2-6 heterocycloalkyl,

(41) —OC 1-6 alkyl-aryl,

(42) —OC 1-6 alkyl-heteroaryl,

(43) —S(O) m R k ,

(44) —C 1-6 alkyl-S(O) m R k ,

(45) —C(O)R k ,

(46) —N(R i ) 2 , and

(47) —NR i R k ,

wherein each R b is unsubstituted or substituted with one to five substituents selected from R f ;

each R C is independently selected from the group consisting of:

(1) —CF 3 ,

(2) —CH 2 CF 3 ,

(3) —CHF 2 ,

(4) —OCHF 2 ,

(5) —OCF 3 ,

(6) CN,

(7) oxo,

(8) —OH,

(9) halogen,

(10) —C 1-6 alkyl,

(11) —C 2-6 alkenyl,

(12) —C 2-6 alkynyl,

(13) —C 3-6 cycloalkyl,

(14) —C 2-6 cycloheteroalkyl,

(15) —C 1-6 alkyl-C 3-6 cycloalkyl,

(16) —C 1-6 alkyl-C 2-6 cycloheteroalkyl,

(17) —C 1-6 alkyl-aryl,

(18) —C 1-6 alkyl-heteroaryl,

(19) —C 1-6 alkenyl-C 3-6 cycloalkyl,

(20) —C 1-6 alkenyl-aryl,

(21) —C 1-6 alkenyl heteroaryl,

(22) —C 1-6 alkenyl-C 2-6 cycloheteroalkyl,

(23) —C 2-6 alkynyl-C 3-6 cycloalkyl,

(24) —C 2-6 alkynyl-C 2-6 cycloheteroalkyl,

(25) —C 2-6 alkynyl-aryl,

(26) —C 2-6 alkynyl heteroaryl,

(27) —OC 1-6 alkyl,

(28) —OC 2-6 alkenyl,

(29) —OC 2-6 alkynyl,

(30) —OC 3-6 cycloalkyl,

(31) —OC 2-6 heterocycloalkyl,

(32) —O-aryl,

(33) —O-heteroaryl,

(34) —OC 1-6 alkyl-cycloalkyl,

(35) —OC 1-6 alkyl-cycloheteroalkyl,

(36) —OC 1-6 alkyl-aryl,

(37) —OC 1-6 alkyl-heteroaryl,

(38) —S(O) m R L ,

(39) —S(O)R L ,

(40) —S—R L ,

(41) —C 1-6 alkyl-S(O) m R L ,

(42) —C(O)R L ,

(43) —C(O)C 1-6 alkyl-R L ,

(44) —OC(O)R L ,

(45) —CO 2 R L ,

(46) aryl, and

(47) heteroaryl,

wherein each R C is unsubstituted or substituted with one to five substituents selected from R g :

R d is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) OH,

(4) oxo,

(5) —C 1-6 alkyl,

(6) —OC 1-6 alkyl,

(7) NH 2 ,

(8) NH(C 1-6 alkyl), and

(9) N(C 1-6 alkyl) 2 ;

each R e is independently selected from the group consisting of:

(1) hydrogen,

(2) —C 1-6 alkyl, and

(3) C 2-6 alkenyl;

each R f is selected from the group consisting of:

(1) halogen,

(2) —C 1-6 alkyl,

(3) —OH,

(4) —OC 1-6 alkyl,

(5) —OC 3-6 cycloalkyl,

(6) —OC 2-6 cycloheteroalkyl,

(7) CN,

(8) —NH 2 ,

(9) —NH(C 1-6 alkyl),

(10) —NH(C 3-6 cycloalkyl),

(11) —NH(C 2-6 cycloheteroalkyl),

(12) —N(C 1-6 alkyl) 2 ,

(13) —N(C 3-6 cycloalkyl) 2 , and

(14) —N(C 2-6 cycloheteroalkyl) 2 ,

wherein each alkyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 ;

each R g is selected from the group consisting of:

(1) halogen,

(2) C 1-6 alkyl,

(3) —OH,

(4) —OC 1-6 alkyl,

(5) —S(O) m -C 1-6 alkyl,

(6) —CN,

(7) —CF 3 ,

(8) —OCHF 2 , and

(9) —OCF 3 ,

wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 ;

each R h is independently selected from the group consisting of:

(1) hydrogen, and

(2) —C 1-6 alkyl;

each R i is independently selected from the group consisting of:

(1) hydrogen, and

(2) —C 1-6 alkyl;

each R j is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —C 2-6 alkenyl,

(3) —C 3-6 cycloalkyl,

(4) —C 2-6 cycloheteroalkyl,

(5) aryl, and

(6) heteroaryl,

wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 ;

each R k is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —C 2-6 alkenyl,

(3) —C 3-6 cycloalkyl,

(4) —C 3-6 cycloalkyl,

(5) —C 2-6 cycloheteroalkyl,

(6) aryl, and

(7) heteroaryl,

wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 ;

each R L is selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —C 2-6 alkenyl,

(3) —C 3-6 cycloalkyl,

(4) —C 2-6 cycloheteroalkyl,

(5) aryl, and

(6) heteroaryl,

wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 ;

each R m is independently selected from the group consisting of:

(1) hydrogen, and

(2) —C 1-6 alkyl;

each n is independently 0, 1, 2, 3 or 4;

each m is independently 0, 1 or 2;

each p is independently 0, 1, 2, 3 or 4;

each q is independently 0 or 1; and

each r is independently 0 or 1.

2. The compound according to claim 1 wherein R 2 is hydrogen; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein A is selected from the group consisting of:

(1) phenyl,

(2) dihydrobenzothiazole,

(3) dihydrobenzoisothiazole, and

(4) benzothiophene,

wherein A is unsubstituted;

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein A is phenyl, wherein phenyl is unsubstituted; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 wherein B is pyridine, wherein pyridine is unsubstituted or substituted with one to three substituents selected from R b ; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 wherein R 1 is selected from the group consisting of:

(1) —SO 2 NH 2 ,

(2) —SO 2 C 1-6 alkyl, and

(3) —C(O)NH 2 ,

wherein each alkyl is unsubstituted or substituted with one to four substituents selected from R d ,

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 wherein R 3 is selected from the group consisting of:

(1) piperidine,

(2) azepane, and

(3) azaspiro[2.5]octane,

wherein R 3 is unsubstituted or substituted with one to eight substituents selected from R c ;

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 wherein

A is selected from the group consisting of:

(1) phenyl,

(2) dihydrobenzothiazole,

(3) dihydrobenzoisothiazole, and

(4) benzothiophene,

wherein A is unsubstituted;

B is pyridine, wherein pyridine is unsubstituted or substituted with one to three substituents selected from R b ;

R 1 is selected from the group consisting of:

(1) —SO 2 NH 2 ,

(2) —SO 2 NH-heteroaryl,

(3) —SO 2 C 1-6 alkyl,

(4) —SO 2 C 3-6 cycloalkyl,

(5) —SO 2 C 3-6 cycloheteroalkyl,

(6) —C(O)NH 2 , and

(7) —CN,

wherein each alkyl, cycloalkyl, cycloheteroalkyl and heteroaryl is unsubstituted or substituted with one to four substituents selected from R d ;

R 2 is hydrogen;

R 3 is selected from the group consisting of:

(1) pyrrolidine,

(2) azetidine,

(3) piperidine,

(4) piperazine,

(5) azepane,

(6) azocane,

(7) thiomorpholine,

(8) oxazepane,

(9) isoindoline,

(10) dihydroisoquinoline,

(11) octahydroisoindole,

(12) azabicyclo[2.2.1]heptane,

(13) azabicyclo[3.1.1]heptane,

(14) azabicyclo[4.1.0]heptane,

(15) azabicyclo[3.2.1]octane,

(16) diazabicyclo[3.2.1]octane,

(17) azabicyclo[3.2.0]heptane,

(18) oxa-azabicyclo[3.2.1]octane,

(19) azaspiro[2.5]octane,

(20) azaspiro[2.6]nonane,

(21) oxa-azaspiro[3.5}nonane,

(22) oxa-oazaspiro[4.5]decane,

(23) dihydrothiazolo[4,5-c]pyridine,

(24) dihydrooxazolo[4,5-c]pyridine,

(25) hexahydrofuro[3,2-b]pyrrole,

(26) hexahydrocyclopenta[c]pyrrole, and

(27) azatricyclo[4.3.1.13,8]undecane,

wherein R 3 is unsubstituted or substituted with one to eight substituents selected from R C ;

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 wherein R 2 is hydrogen;

A is phenyl, wherein phenyl is unsubstituted or substituted with one to three substituents selected from R a ;

B is pyridine, wherein pyridine is unsubstituted or substituted with one to three substituents selected from R b ;

R 1 is selected from the group consisting of:

(1) —SO 2 NH 2 ,

(2) —SO 2 C 1-6 alkyl, and

(3) —C(O)NH 2 ,

wherein each alkyl is unsubstituted or substituted with one to four substituents selected from R d :

R 2 is hydrogen;

R 3 is selected from the group consisting of:

(1) piperidine,

(2) azepane, and

(3) azaspiro[2.5]octane,

wherein R 3 is unsubstituted or substituted with one to eight substituents selected from R c ;

or a pharmaceutically acceptable salt thereof.

10. A compound selected from:

(1) 2-(4,4-difluoropiperidin-1-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)-nicotinamide;

(2) 2-(azepan-1-yl)-5-chloro-4,6-dimethyl-N-(3-sulfamoylphenyl)nicotinamide;

(3) 2-(azepan-1-yl)-6-chloro-5-fluoro-4-methyl-N-(3 -sulfamoylphenyl)pyridine-3-carboxamide;

(4) 2-(azepan-1-yl)-4,6-dimethyl-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(5) 5-chloro-2-(3,3-difluoropyrrolidin-1-yl)-4,6-dimethyl-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(6) 5-fluoro-2-(1-piperidyl)-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(7) 2-(azepan-1-yl)-5-chloro-4,6-dimethyl-N-(3 -methylsulfonylphenyl)pyridine-3-carboxamide;

(8) 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide;

(9) 6-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide;

(10) 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide;

(11) 2-(4,4-difluoroazepan-1-yl)-6-methoxy-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide;

(12) 5-chloro-4,6-dimethyl-N-(3-methylsulfonylphenyl)-2-(1-piperidyl)pyridine-3-carboxamide;

(13) 2-(6-azaspiro [2.5]octan-6-yl)-N-(3-carbamoylphenyl)-5-chloro-4,6-dimethyl-pyridine-3-carboxamide;

(14) N-(3-carbamoylphenyl)-6-chloro-2-(4,4-difluoroazepan-1-yl)pyridine-3-carboxamide;

(15) N-(3-carbamoylphenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)pyridine-3-carboxamide;

(16) N-(3-carbamoylphenyl)-5-chloro-2-(4,4-difluoro-1-piperidyl)-4,6-dimethyl-pyridine-3-carboxamide;

(17) N-(3-carbamoylphenyl)-6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-pyridine-3-carboxamide;

(18) N-(3-carbamoylphenyl)-2-(4,4-difluoroazepan-1-yl)-6-methoxy-pyridine-3-carboxamide;

(19) N-(3-carbamoylphenyl)-5-chloro-4,6-dimethyl-2-(1-piperidyl)pyridine-3-carboxamide;

(20) 5-chloro-N-(3-cyanophenyl)-2-(4,4-difluoro-1-piperidyl)-4,6-dimethyl-pyridine-3-carboxamide;

(21) 2-(azepan-1-yl)-N-(3-cyanophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(22) 2-(azepan-1-yl)-N-(4-cyanophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(23) 2-(azepan-1-yl)-5-methyl-N-(3-sulfamoylphenyl)nicotinamide;

(24) 2-(azepan-1-yl)-N-(3-pyrrolidin-1-ylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(25) 2-(azepan-1-yl)-N-(2-hydroxy-5-sulfamoyl-phenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(26) 2-(azepan-1-yl)-5-chloro-6-methyl-N-(3-sulfamoylphenyl)nicotinamide;

(27) 2-(piperidin-1-yl)-N-(3-sulfamoylphenyl)-5-(p-tolyl)nicotinamide;

(28) N-(2,4-difluoro-3-sulfamoylphenyl)-2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamide;

(29) 2-(azepan-1-yl)-6-chloro-4-methyl-N-(3-sulfamoylphenyl)nicotinamide;

(30) 2-(azepan-1-yl)-5,6-dimethyl-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(31) 2-(azepan-1-yl)-5-chloro-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(32) 2-(azepan-1-yl)-5-bromo-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(33) 2-(azepan-1-yl)-4-bromo-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(34) 2-(azepan-1-yl)-5-(3-pyridyl)-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(35) 2-(azepan-1-yl)-5-bromo-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide;

(36) 2-(azepan-1-yl)-5,6-dimethyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide;

(37) 2-(azepan-1-yl)-N-(3-carbamoylphenyl)-5,6-dimethyl-pyridine-3-carboxamide;

(38) 2-(azepan-1-yl)-5-bromo-N-(3-carbamoylphenyl)pyridine-3-carboxamide;

(39) 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethoxy)nicotinamide;

(40) 6-(tert-butyl)-5-chloro-2-(piperidin-1-yl)-N-(3-sulfamoylphenyl)nicotinamide;

(41) 6-tert-butyl-N-(3-methylsulfonylphenyl)-2-(1-piperidyl)pyridine-3-carboxamide;

(42) 6-(tert-butyl)-2-(piperidin-1-yl)-N-(3-sulfamoylphenyl)nicotinamide;

(43) 2-(6-azaspiro [2.5]octan-6-yl)-N-(3 -sulfamoylphenyl)-5-(trifluoromethyl)nicotinamide;

(44) 2-(azepan-1-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(45) 2-[rac-3-azabicyclo[3.2.1]octan-3-yl]-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(46) N-(3-sulfamoylphenyl)-2-(4-azatricyclo-[4.3.1.13,8]undecan-4-yl)-5-(trifluoromethyl)-nicotinamide;

(47) N-(3-sulfamoylphenyl)-5-(trifluoromethyl)-2-(3,3,5-trimethylazepan-1-yl)pyridine-3-carboxamide;

(48) methyl 1-[3-[(3 -sulfamoylphenyl)carbamoyl]-5-(trifluoromethyl)-2-pyridyl]azepane-4-carboxylate;

(49) 2-(4-methoxyazepan-1-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(50) 2-[4-(difluoromethyl)-1-piperidyl]-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(51) 2-(3,3-difluoro-1-piperidyl)-N-(3 -sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(52) 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(53) 2-(4-hydroxy-4-methyl-azepan-1-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(54) 2-[(3S)-3-fluoroazepan-1-yl]-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(55) 2-(6,7-dihydro-4H-thiazolo[4,5-c]pyridin-5-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)-pyridine-3-carboxamide;

(56) 2-(1,4-oxazepan-4-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(57) 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(58) N-(3-sulfamoylphenyl)5-(trifluoromethyl)-2-[3-(trifluoromethyl)azetidin-1-yl]pyridine-3-carboxamide;

(59) 2-(6-azabicyclo[3.2.0]heptan-6-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(60) 2-(3,3-difluoropyrrolidin-1-yl)-N-(3-sulfamoylphenyl)-5 -(trifluoromethyl)pyridine-3-carboxamide;

(61) methyl 1-[3-[(3-sulfamoylphenyl)carbamoyl]-5-(trifluoromethyl)-2-pyridyl]piperidine-4-carboxylate;

(62) 2-(3 -fluoropyrrolidin-1-yl)-N-(3-sulfamoylphenyl)-5 -(trifluoromethyl)pyridine-3-carboxamide;

(63) 2-pyrrolidin-1-yl-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(64) 2-(6-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(65) 2-(4-hydroxyazepan-1-yl)-N-(3 -sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(66) 2-(4-methoxy-1-piperidyl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(67) methyl 1-[3-[(3-sulfamoylphenyl)carbamoyl]-5-(trifluoromethyl)-2-pyridyl]azepane-3-carboxylate;

(68) 2-(2-isobutylazepan-1-yl)-N-(3 -sulfamoylphenyl)-5 -(trifluoromethyl)pyridine-3-carboxamide;

(69) 2-morpholino-N-(3 -sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(70) 2-(1,1-dioxo-1,4-thiazinan-4-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(71) 2-[rac-(1S,5R and 1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl]-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3 -carboxamide;

(72) 2-(1-oxa-8-azaspiro [4.5]decan-8-yl)-N-(3-sulfamoylphenyl)-5 -(trifluoromethyl)pyridine-3-carboxamide;

(73) 2-(2-methyl-6,7-dihydro-4H-oxazolo[4,5-c]pyridin-5-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(74) methyl 4-[3-[(3-sulfamoylphenyl)carbamoyl]-5-(trifluoromethyl)-2-pyridyl]piperazine-1-carboxylate;

(75) N-(3-carbamoylphenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide;

(76) 2-(6-azaspiro[2.5]octan-6-yl)-5-chloro-4,6-dimethyl-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(77) 2-(1-piperidyl)-N-(3 -sulfamoylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide;

(78) 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)nicotinamide;

(79) 2-(6-azaspiro [2.6]nonan-6-yl)-N-(3 -sulfamoylphenyl)-5-(trifluoromethyl)nicotinamide;

(80) 2-(4,4-dimethylazepan-1-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)nicotinamide;

(81) 2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)nicotinamide;

(82) 2-(azepan-1-yl)-N-(3 -(methylsulfonyl)phenyl)-6-(trifluoromethyl)nicotinamide;

(83) N-(3-carbamoylphenyl)-2-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)nicotinamide;

(84) 2-(piperidin-1-yl)-N-(3-sulfamoylphenyl)-6-(trifluoromethoxy)nicotinamide;

(85) 2-(azepan-1-yl)-N-(3-sulfamoylphenyl)-6-(trifluoromethoxy)-5-(trimethylsilyl)nicotinamide;

(86) 2-(azepan-1-yl)-N-(3-sulfamoylphenyl)-5-(trimethylsilyl)nicotinamide;

(87) 2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-N-(3-sulfamoylphenyl)-5-(trimethylsilyl)nicotinamide;

(88) 2-(azocan-1-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(89) 2-(azepan-1-yl)-6-chloro-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(90) 2-(azepan-1-yl)-6-methyl-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(91) 2-(azepan-1-yl)-6-methoxy-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(92) 2-(azepan-1-yl)-6-chloro-5-fluoro-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(93) 2-(azepan-1-yl)-6-fluoro-N-(3 -sulfamoylphenyl)pyridine-3-carboxamide;

(94) 2-(4,4-difluoroazepan-1-yl)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(95) 2-(azocan-1-yl)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(96) 2-(4,4-difluoro-1,3,3a,5,6,6a-hexahydrocyclopenta[c]pyrrol-2-yl)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(97) 2-[(3aS,7aR)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(98) 2-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(3 -methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(99) 2-(6-azaspiro[2.5]octan-6-yl)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(100) 2-(4-fluoro-1-piperidyl)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(101) 2-(8,8-difluoro-6-azaspiro[2.5]octan-6-yl)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(102) 2-(3,3-difluoro-1-piperidyl)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(103) 2-isoindolin-2-yl-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(104) 2-(2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrol-4-yl)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl) pyridine-3-carboxamide;

(105) N-(3-methylsulfonylphenyl)-2-(4-phenyl-1-piperidyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(106) N-(3-carbamoylphenyl)-2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(107) 2-(azocan-1-yl)-N-(3-carbamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(108) N-(3-carbamoylphenyl)-2-(4,4-difluoro- 1,3,3a,5,6,6a-hexahydrocyclopenta[c]pyrrol-2-yl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(109) N-(3-carbamoylphenyl)-2-(8,8-difluoro-6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(110) N-(3-carbamoylphenyl)-2-(3,3-difluoro-1-piperidyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(111) 2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-N-(1,1-dioxo-2,3-dihydro-1,2-benzothiazol-6-yl)-5-(trifluoromethyl) pyridine-3-carboxamide;

(112) 2-[(3R)-4,4-difluoro-3-methyl-1-piperidyl]-N-(1,1-dioxo-2,3-dihydro-1,2-benzothiazol-6-yl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(113) 2-[(3S)-4,4-difluoro-3-methyl-1-piperidyl]-N-(1,1-dioxo-2,3-dihydro-1,2-benzothiazol-6-yl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(114) N-(3-fluoro-5-sulfamoyl-phenyl)-2-(1 -piperidyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(115) N-(4-fluoro-3-sulfamoyl-phenyl)-2-(1 -piperidyl)-5 -(trifluoromethyl)pyridine-3-carboxamide;

(116) N-(2-fluoro-5-sulfamoyl-phenyl)-2-(1 -piperidyl)-5 -(trifluoromethyl)pyridine-3-carboxamide;

(117) 2-(azepan-1-yl)-N-(3-isopropylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(118) 2-(azepan-1-yl)-N-(1,1-dioxobenzothiophen-6-yl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(119) 2-(azepan-1-yl)-N-(3-isobutylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(120) 2-(azepan-1-yl)-N-(3-cyclopentylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(121) 2-(azepan-1-yl)-N-(1,1-dioxo-2,3-dihydro-1,2-benzothiazol-6-yl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(122) 2-(azepan-1-yl)-3-((2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)carbamoyl)-5-(trifluoromethyl)pyridine;

(123) (R)-2-(4,4-Difluoro-3-methylpiperidin-1-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)nicotinamide;

(124) (S)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)nicotinamide;

(125) 2-[(3 S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-N-(3 -sulfamoylphenyl)-5-(trifluoro-methyl)pyridine-3-carboxamide;

(126) 2-[(3S)-2,2-difluoro-5-azaspiro[2.5]octan-5-yl]-N-(3 -sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(127) 2-[(3R)-2,2-difluoro-5-azaspiro[2.5]octan-5-yl]-N-(3 -sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(128) 2-[(1R,6R)-7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3 -yl]-N-(3-sulfamoylphenyl)-5 -(trifluoromethyl)pyridine-3-carboxamide;

(129) 2-[(1S,6S)-7,7-difluoro-6-methyl-3-azabicyclo[[4.1.0]heptan-3-yl]-N-(3-sulfamoylphenyl)-5 -(trifluoromethyl)pyridine-3-carboxamide;

(130) N-(3-sulfamoylphenyl)-5-(trifluoromethyl)-2-[(1R,5R)-1-(trifluoromethyl)-3-azabicyclo-[3.2.0]heptan-3-yl]pyridine-3-carboxamide;

(131) N-(3-sulfamoylphenyl)-5-(trifluoromethyl)-2-[(1 8,5 S)-1-(trifluoromethyl)-3-azabicyclo-[3.2.0]heptan-3-yl]pyridine-3-carboxamide;

(132) 2-[(1R,5S)-6,6-difluoro-3-azabicyclo[3.1.1]heptan-3-yl]-N-(3 -sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(133) N-(3-sulfamoylphenyl)-2-[(1R,5S)-6,6,7,7-tetrafluoro-3-azabicyclo[3.2.0]heptan-3-yl]-5-(trifluoromethyl)pyridine-3-carboxamide;

(134) 2-[(1R,5S)-3-azabicyclo[3.2.0]heptan-3-yl]-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(135) 2-[(1S,5R)-6,6-difluoro-3-azabicyclo[3.2.0]heptan-3-yl]-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(136) 2-[(1R,5S)-6,6-difluoro-3-azabicyclo[3.2.0]heptan-3-yl]-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(137) 2-[(1S,4S)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl]-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(138) 2-[(1R,4R)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl]-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(139) 2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(140) N-(3-sulfamoylphenyl)-5 -(trifluoromethyl)-2-[(2S)-2-(trifluoromethyl)morpholin-4-yl]pyridine-3-carboxamide;

(141) N-(3-sulfamoylphenyl)-5-(trifluoromethyl)-2-[(2R)-2-(trifluoromethyl)morpholin-4-yl]pyridine-3-carboxamide;

(142) 2-[(2R,6R)-2-methyl-6-(trifluoromethyl)morpholin-4-yl]-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(143) N-(3-sulfamoylphenyl)-5-(trifluoromethyl)-2-[3-(trifluoromethyl)piperazin-1-yl]pyridine-3-carboxamide;

(144) (R)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)-2-(2-(trifluoromethyl)-1,4-oxazepan-4-yl)-nicotinamide;

(145) 2-[(2S,6R)-2-methyl-6-(trifluoromethyl)morpholin-4-yl]-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(146) 2-[(2R,6S)-2-methyl-6-(trifluoromethyl)morpholin-4-yl]-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(147) N-(3-sulfamoylphenyl)-5-(trifluoromethyl)-2-[(2S)-2-(trifluoromethyl)-1,4-oxazepan-4-yl]pyridine-3-carboxamide;

(148) 2-[(2S,6S)-2-methyl-6-(trifluoromethyl)morpholin-4-yl]-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(149) 2-[(2R,6S or 2S,6R)-2,6-dimethylmorpholin-4-yl]-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(150) 2-[(2S,6S or 2R,6R)-2,6-dimethylmorpholin-4-yl]-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

(151) 2-(azepan-1-yl)-3-((3-(N-(pyrimidin-4-yl)sulfamoyl)phenyl)carbamoyl)-5-(trifluoromethyl)pyridin-1-ium;

(152) 2-(4,4-difluoropiperidin-1-yl)-N-(3-(methylsulfonyl)phenyl)-5-(trifluoromethyl)nicotinamide;

(153) 5-isobutyl-2-(piperidin-1-yl)-N-(3-sulfamoylphenyl)nicotinamide;

(154) 5-cyclopentyl-2-(piperidin-1-yl)-N-(3-sulfamoylphenyl)nicotinamide;

(155) 2-(azepan-1-yl)-6-methoxy-5-methyl-N-(3-sulfamoylphenyl)nicotinamide;

(156) 2-(azepan-1-yl)-5-bromo-6-methoxy-N-(3-sulfamoylphenyl)nicotinamide;

(157) 2-(azepan-1-yl)-5-cyano-6-methyl-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(158) 2-(azepan-1-yl)-4-chloro-6-methyl-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(159) 5-cyclobutyl-2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)nicotinamide;

(160) 2-(4,4-difluoroazepan-1-yl)-5-(oxetan-3-yl)-N-(3-sulfamoylphenyl)nicotinamide;

(161) 5-(but-3-en-1-yl)-2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)nicotinamide;

(162) 2-(4,4-difluoroazepan-1-yl)-5-isoropyl-N-(3-sulfamoylphenyl)nicotinamide;

(163) 5-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)nicotinamide;

(164) 2-(azepan-1-yl)-5-(perfluoroethyl)-N-(3-sulfamoylphenyl)nicotinamide

(165) 6-(1,1,2,2,2-pentafluoroethyl)-2-(1-piperidyl)-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(166) 2-(azepan-1-yl)-N-(3-methylsulfonylphenyl)-5-(1,1,2,2,2-pentafluoroethyl)pyridine-3-carboxamide;

(167) 2-(azepan-1-yl)-N-(3-carbamoylphenyl)-5-(1,1,2,2,2-pentafluoroethyl)pyridine-3-carboxamide;

(168) 2-(azepan-1-yl)-6-methyl-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)nicotinamide;

(169) 2-(azepan-1-yl)-6-methoxy-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)nicotinamide;

(170) 2-(4,4-difluoropiperidin-1-yl)-N-(2-fluoro-3-sulfamoylphenyl)-5-(trifluoromethyl)nicotinamide;

(171) N-(3,4-difluoro-5-sulfamoylphenyl)-2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamide;

(172) 2-(4,4-difluoroazepan-1-yl)-5-(difluoromethoxy)-N-(3-sulfamoylphenyl)nicotinamide;

(173) 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(methylsulfonyl)phenyl)nicotinamide;

(174) 2-(azepan-1-yl)-6-chloro-4,5-dimethyl-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(175) 2-(azepan-1-yl)-4-methyl-N-(3-sulfamoylphenyl)pyridine-3-carboxamide;

(176) 5-cyano-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide;

(177) N-(3-carbamoylphenyl)-5-cyano-2-(4,4-difluoroazepan-1-yl)-6-methyl-pyridine-3-carboxamide; and

(178) 2-(azepan-1-yl)-N-(3-carbamoylphenyl)-5-cyano-6-methyl-pyridine-3-carboxamide;

or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 selected from:

(1) 5-chloro-2-(4,4-difluoroazepan-1-yl)-N,4,6-trimethyl-N-(3-sulfamoylphenyl)nicotinamide;

(2) 2-cyclopropyl-4-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)pyrimidine-5-carboxamide; and

(3) 3-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. A method of treating or preventing a pain disorder that is responsive to the inhibition of Nav1.8 channel activity in a patient in need thereof comprising administration of a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

14. The method of claim 13 wherein the pain disorder is selected from: acute pain, inflammatory pain, or neuropathic pain.

15. A method of treating a disorder that is responsive to the inhibition of Nav1.8 channel activity in a patient in need thereof comprising administration of a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disorder is selected from: a cough disorder, an acute itch disorder and a chronic itch disorder.