IP Library Granted Patent US 11,377,438
Granted Patent B2
US 11,377,438 · App. 16/669,598 · Granted Jul 5, 2022

2-amino-n-heteroaryl-nicotinamides as Na

Inventors: Ashok Arasappan (Bridgewater, NJ); Ian M. Bell (Harleysville, PA); Michael J. Breslin (Drexel Hill, PA); Christopher James Bungard (Lansdale, PA); Christopher S. Burgey (Ambler, PA); Harry R. Chobanian (Aberdeen, NJ); Jason M. Cox (Whitehouse Station, NJ); Anthony T. Ginnetti (Perkasie, PA); Deodial Guy Guiadeen (Chesterfield, NJ); Kristen L. G. Jones (Oreland, PA); Mark E. Layton (Harleysville, PA); Hong Liu (Hillsborough, NJ); Jian Liu (Edison, NJ); James J. Perkins (Churchville, PA); Shawn J. Stachel (Perkasie, PA); Linda M. Suen-Lai (Philadelphia, PA); Zhe Wu (Blue Bell, PA)
Assignee: Merck Sharp & Dohme LLC
C07D401/12C07D401/14C07D409/14C07D413/14C07D417/14C07D471/04C07D471/08C07D487/04C07D491/04C07D491/048C07D495/04
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Quick Facts
Patent No.
US 11,377,438
App. No.
16/669,598
Granted
Jul 5, 2022
Kind
B2
Abstract

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are inhibitors of Na v 1.8 channel activity and may be useful in the treatment, prevention, management, amelioration, control and suppression of diseases mediated by Na v 1.8 channel activity. The compounds of the present invention may be useful in the treatment, prevention or management of pain disorders, cough disorders, acute itch disorders, and chronic itch disorders.

Claims (525)

1. A compound of structural Formula I:

or a pharmaceutically acceptable salt thereof, wherein

A is pyridine, wherein pyridine 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 3 H,

(2) —SO 2 NH 2 ,

(3) —SO 2 C 1-6 alkyl,

(4) —SO 2 NH—C 1-6 alkyl,

(5) —SO 2 C 3-6 cycloalkyl,

(6) —C(O)NH 2 ,

(7) —CO 2 H,

(8) —CN,

(9) halogen,

(10) —OH,

(11) —OC 1-6 alkyl, and

(12) —C 1-6 alkyl,

wherein each alkyl, and cycloalkyl is unsubstituted or substituted with one substituent 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) a monocyclic, bicyclic or spirocyclic C 3-12 cycloalkyl ring, and

(2) a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring,

wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N(R m ) r , O, and S, wherein each cycloalkyl ring and each cycloheteroalkyl ring may be fused to an aryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to eight substitutents 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) —CHF 2 ,

(3) —OCHF 2 ,

(4) —OCH 2 CF 3 ,

(5) —OCF 3 ,

(6) CN,

(7) F,

(8) Cl,

(9) Br,

(10) —CH 3 ,

(11) —C(CH 3 ) 3 ,

(12) —OCH 3 ,

(13) cyclopropyl,

(14) cyclobutyl,

(15) piperidine,

(16) —CH 2 -cyclopropyl,

(17) —C 2 alkynyl-cyclopropyl, and

(18) pyrazole,

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 RL,

(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, and

(2) —C 1-6 alkyl;

each R f is selected from the group consisting of:

(1) halogen, F

(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 R 1 is selected from the group consisting of:

(1) —SO 2 NH 2 ,

(2) —C(O)NH 2 , and

(3) —OH;

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein R 3 is selected from the group consisting of: a monocyclic, bicyclic or spirocyclic C 3-8 cycloalkyl ring, and a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N(R m ) r , O, and S, and wherein each cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to eight substitutents selected from R c ; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 wherein R 3 is a monocyclic, bicyclic or spirocyclic C 2-12 cycloheteroalkyl ring, wherein the cycloheteroalkyl contains a nitrogen and 0-3 heteroatoms independently selected from N(R m ) r , O, and S, and wherein each cycloheteroalkyl is unsubstituted or substituted with one to eight substitutents selected from R c ; or a pharmaceutically acceptable salt thereof.

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

(1) cyclohexane,

(2) cycloheptane,

(3) pyrrolidine,

(4) azetidine,

(5) piperidine,

(6) piperazine,

(7) azepane,

(8) morpholine,

(9) thiomorpholine,

(10) oxazepane,

(11) isoindoline,

(12) dihydroisoquinoline,

(13) azabicyclo[2.2.1]heptane,

(14) azabicyclo[3.1.1]heptane,

(15) azabicyclo[4.1.0]heptane,

(16) azabicyclo[3.2.1]octane,

(17) azabicyclo[3.2.0]heptane,

(18) azaspiro[2.5]octane,

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

(20) dihydroimidazo[1,2-a]pyrazine, and

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

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

or a pharmaceutically acceptable salt thereof.

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

(1) pyrrolidine,

(2) azetidine,

(3) piperidine,

(4) piperazine,

(5) azepane,

(6) morpholine,

(7) thiomorpholine,

(8) oxazepane,

(9) isoindoline,

(10) dihydroisoquinoline,

(11) azabicyclo[2.2.1]heptane,

(12) azabicyclo[3.1.1]heptane,

(13) azabicyclo[4.1.0]heptane,

(14) azabicyclo[3.2.1]octane,

(15) azabicyclo[3.2.0]heptane,

(16) azaspiro[2.5]octane,

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

(18) dihydroimidazo[1,2-a]pyrazine, and

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

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 R 3 is selected from the group consisting of:

(1) piperidine,

(2) azepane, and

(3) morpholine,

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

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 wherein

A is pyridine, wherein pyridine 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 3 H,

(2) —SO 2 NH 2 ,

(3) —SO 2 C 1-6 alkyl,

(4) —SO 2 NH—C 1-6 alkyl,

(5) —SO 2 C 3-6 cycloalkyl,

(6) —C(O)NH 2 ,

(7) —CO 2 H,

(8) —CN,

(9) halogen,

(10) —OH,

(11) —OC 1-6 alkyl, and

(12) —C 1-6 alkyl,

wherein each alkyl, and cycloalkyl is unsubstituted or substituted with one substituent 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) morpholine,

(7) thiomorpholine,

(8) oxazepane,

(9) isoindoline,

(10) dihydroisoquinoline,

(11) azabicyclo[2.2.1]heptane,

(12) azabicyclo[3.1.1]heptane,

(13) azabicyclo[4.1.0]heptane,

(14) azabicyclo[3.2.1]octane,

(15) azabicyclo[3.2.0]heptane,

(16) azaspiro[2.5]octane,

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

(18) dihydroimidazo[1,2-a]pyrazine, and

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

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

or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 wherein

A is pyridine, wherein pyridine 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) —C(O)NH 2 , and

(3) —OH;

R 2 is hydrogen;

R 3 is selected from the group consisting of:

(1) piperidine,

(2) azepane, and

(3) morpholine,

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

or a pharmaceutically acceptable salt thereof.

11. A compound selected from:

1) 5-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)picolinic acid;

2) 4-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)picolinic acid;

3) N-(6-cyanopyridin-3-yl)-2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamide;

4) 2-(azepan-1-yl)-N-(5-(methylsulfonyl)pyridin-3-yl)-5-(trifluoromethyl)nicotinamide;

5) 2-(3-(hydroxymethyl)piperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;

6) 2-(azepan-1-yl)-N-(5-carbamoylpyridin-3-yl)-5-(trifluoromethyl)nicotinamide;

7) 2-(4,4-difluoro-1-piperidyl)-6-methyl-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;

8) 5-chloro-2-(4,4-difluoro-1-piperidyl)-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;

9) 6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methyl-N-(5-sulfamoylpyridin-3-yl)nicotinamide;

10) 5,6-dicyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

11) 2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

12) 5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

13) 5-cyclobutyl-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

14) 5-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

15) 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

16) 6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

17) 2-(4,4-difluoroazepan-1-yl)-5,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

18) 5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide;

19) 5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;

20) 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

21) 5-chloro-6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;

22) 6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

23) 2-(5,5-Difluoro-2-oxoazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;

24) 2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

25) 5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-nicotinamide;

26) 2-(5,5-Difluoro-2-oxoazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;

27) 2-(4,4-Dichloropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;

28) 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methoxy-N-(2-sulfamoylpyridin-4-yl)pyridine-3-carboxamide;

29) N-[2-(tert-butylsulfamoyl)pyridin-4-yl]-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methoxy-pyridine-3-carboxamide;

30) 5-cyano-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)-nicotinamide;

31) 5-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide;

32) 5-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

33) (S)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoro-methyl)nicotinamide;

34) (R)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoro-methyl)-nicotinamide;

35) (R)-2-(4,4-dichloro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoro-methyl)nicotinamide;

36) (S)-2-(4,4-dichloro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoro-methyl)nicotinamide;

37) 2-(4,4-Dichloroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

38) 2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

39) 5-chloro-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-6-methyl-N-(2-sulfamoyl-4-pyridyl)pyridine-3-carboxamide;

40) (S)-5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

41) (R)-5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

42) (S)-2-(3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;

43) (R)-2-(3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;

44) N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[(1S,5S)-1-(trifluoromethyl)-3-azabicyclo[3.2.0]heptan-3-yl]pyridine-3-carboxamide;

45) N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[(1R,5R)-1-(trifluoromethyl)-3-azabicyclo[3.2.0]heptan-3-yl]pyridine-3-carboxamide;

46) N-(2-sulfamoylpyridin-4-yl)-2-((1R,5S)-6,6,7,7-tetrafluoro-3-azabicyclo[3.2.0]heptan-3-yl)-5-(trifluoromethyl)nicotinamide;

47) 2-[(1S,6S)-7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

48) 2-[(1R,6R)-7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

49) 2-((1R,5S)-8,8-difluoro-3-oxaoctan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

50) 2-((1R,5S)-6,6-difluoro-3-azabicyclo[3.2.0]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

51) 2-((1S,5R)-6,6-difluoro-3-azabicyclo[3.2.0]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

52) (R)-2-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

53) (S)-2-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

54) 2-((1R,5S)-3-azabicyclo[3.2.0]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

55) 2-((1S,6S)-7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

56) 2-((1R,6R)-7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

57) 2-[(1R,4R)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

58) 2-[(1S,4S)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

59) (R)-2-(4,4-difluoro-2-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

60) (S)-2-(4,4-difluoro-2-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

61) 2-((3R,4s,5S)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

62) 2-((1R,5S)-6,6-difluoro-3-azabicyclo[3.1.1]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

63) 2-[(3S,4S)-4-hydroxy-3-methyl-1-piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-pyridine-3-carboxamide;

64) 2-[(3S,4r,5R)-4-hydroxy-3,5-dimethyl-1-piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoro-methyl)pyridine-3-carboxamide;

65) 2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoro-methyl)pyridine-3-carboxamide;

66) N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1-piperidyl]pyridine-3-carboxamide;

67) 2-[3-(3,5-difluorophenyl)-1-piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-pyridine-3-carboxamide;

68) N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[4-(trifluoromethyl)-1-piperidyl]pyridine-3-carboxamide;

69) N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[3-[[4-(trifluoromethyl)phenyl]methyl]-1-piperidyl]pyridine-3-carboxamide;

70) N-(2-sulfamoyl-4-pyridyl)-2-thiomorpholino-5-(trifluoromethyl)pyridine-3-carboxamide;

71) N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[3-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyridine-3-carboxamide;

72) 2-(3-benzyl-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

73) 2-[3,3-dimethyl-4-(2,2,2-trifluoroethyl)piperazin-1-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

74) 2-(2,2-dimethylmorpholin-4-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

75) N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[8-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]pyridine-3-carboxamide;

76) N-(2-sulfamoyl-4-pyridyl)-2-[4-(trifluoromethoxy)isoindolin-2-yl]-5-(trifluoromethyl)-pyridine-3-carboxamide;

77) N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[2-[4-(trifluoromethyl)phenyl]morpholin-4-yl]pyridine-3-carboxamide;

78) N-(2-sulfamoyl-4-pyridyl)-2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-5-(trifluoromethyl)-pyridine-3-carboxamide;

79) N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[3-(trifluoromethyl)azetidin-1-yl]pyridine-3-carboxamide;

80) 2-(3-pyrazol-1-ylpyrrolidin-1-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

81) 2-[2-(4-fluorophenyl)-1-piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

82) 2-(2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrol-4-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoro-methyl)pyridine-3-carboxamide;

83) N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[3-[4-(trifluoromethyl)phenoxy]azetidin-1-yl]pyridine-3-carboxamide;

84) N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[4-[3-(trifluoromethyl)phenoxy]-1-piperidyl]pyridine-3-carboxamide;

85) 2-[4-(cyclopropylmethyl)-3-oxo-piperazin-1-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoro-methyl)pyridine-3-carboxamide;

86) N-(2-sulfamoyl-4-pyridyl)-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-5-(trifluoromethyl)-pyridine-3-carboxamide;

87) 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoyl-4-pyridyl)pyridine-3-carboxamide;

88) 2-((2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

89) 2-((2S,6R)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

90) (S)—N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-(2-(trifluoromethyl)-1,4-oxazepan-4-yl)nicotinamide;

91) (R)—N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-(2-(trifluoromethyl)-1,4-oxazepan-4-yl)nicotinamide;

92) 2-[(2R)-6,6-dimethyl-2-(trifluoromethyl)-1,4-oxazepan-4-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

93) 2-(2,2-dimethyl-1,4-oxazepan-4-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

94) 2-[(7S)-7-methyl-1,4-oxazepan-4-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-pyridine-3-carboxamide;

95) N-[2-(tert-butylsulfamoyl)-4-pyridyl]-5-chloro-2-(4,4-difluoroazepan-1-yl)pyridine-3-carboxamide;

96) 2-[(2S)-2-methylmorpholin-4-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

97) 2-[(2R)-2-methyl-1,4-oxazepan-4-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-pyridine-3-carboxamide;

98) 2-(3-hydroxy-3-methyl-1-piperidyl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

99) 2-(6-fluoro-1,1-dimethyl-isoindolin-2-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-pyridine-3-carboxamide;

100) 2-(4,4-difluoro-5-methylazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-pyridine-3-carboxamide;

101) 5-chloro-2-[(7R)-7-(difluoromethyl)-1,4-oxazepan-4-yl]-6-methyl-N-(2-sulfamoylpyridin-4-yl)pyridine-3-carboxamide;

102) 5-chloro-2-[(7S)-7-(difluoromethyl)-1,4-oxazepan-4-yl]-6-methyl-N-(2-sulfamoylpyridin-4-yl)pyridine-3-carboxamide;

103) (R)—N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-(7-(trifluoromethyl)-1,4-oxazepan-4-yl)nicotinamide;

104) (S)—N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-(7-(trifluoromethyl)-1,4-oxazepan-4-yl)nicotinamide;

105) 2-[(2S,7R)-2-methyl-7-(trifluoromethyl)-1,4-oxazepan-4-yl]-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)pyridine-3-carboxamide;

106) 2-((2R,7S)-2-methyl-7-(trifluoromethyl)-1,4-oxazepan-4-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

107) 2-((2R,7R)-2-methyl-7-(trifluoromethyl)-1,4-oxazepan-4-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

108) 2-((2S,7S)-2-methyl-7-(trifluoromethyl)-1,4-oxazepan-4-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

109) (S)-5-chloro-2-(2-(difluoromethyl)morpholino)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;

110) (R)-5-chloro-2-(2-(difluoromethyl)morpholino)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;

111) N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]pyridine-3-carboxamide;

112) (R)—N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)nicotinamide;

113) N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-[3-(trifluoromethyl)pyrrolidin-1-yl]pyridine-3-carboxamide;

114) (S)-2-(3-cyanopyrrolidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;

115) (R)-2-(3-cyanopyrrolidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;

116) 2-(4,4-difluoro-3-methylazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;

117) 2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide;

118) 22-((2R,6S)-2-ethyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

119) 2-((2S,6R)-2-ethyl-6-(trifluoromethyl)-morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

120) (R)-2-(2,2-dimethyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

121) (S)-2-(2,2-dimethyl-6-(trifluoromethyl)-morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

122) 4-(2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)nicotinamido)picolinamide;

123) 6-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoyl-4-pyridyl)pyridine-3-carboxamide;

124) 2-(azepan-1-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

125) 2-(azepan-1-yl)-N-(2-methylsulfonyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

126) 2-(azepan-1-yl)-N-(6-sulfamoyl-2-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

127) 2-(4,4-difluoroazepan-1-yl)-6-methoxy-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

128) N-(2-methoxypyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinamide;

129) 2-(4,4-difluoroazepan-1-yl)-N-(5-sulfamoyl-3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

130) 2-(azepan-1-yl)-N-(5-sulfamoyl-3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

131) 2-(4,4-difluoroazepan-1-yl)-N-(2-methoxy-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

132) 2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-N-(2-(methylsulfonyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

133) 2-[(3R)-4,4-difluoro-3-methyl-1-piperidyl]-N-(2-methylsulfonyl-4-pyridyl)-5-(trifluoro-methyl)-pyridine-3-carboxamide;

134) 2-[(3S)-4,4-difluoro-3-methyl-1-piperidyl]-N-(2-methylsulfonyl-4-pyridyl)-5-(trifluoro-methyl)-pyridine-3-carboxamide;

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

136) N-(2-methylsulfonyl-4-pyridyl)-2-[(1R,5S)-6,6,7,7-tetrafluoro-3-azabicyclo[3.2.0]heptan-3-yl]-5-(trifluoromethyl)pyridine-3-carboxamide;

137) 2-[(1R,5S)-3-azabicyclo[3.2.0]heptan-3-yl]-N-(2-methylsulfonyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

138) 2-[(1R,5S)-3-azabicyclo[3.2.0]heptan-3-yl]-N-(2-cyano-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

139) (R)—N-(2-cyanopyridin-4-yl)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-5-(trifluoromethyl)-nicotinamide;

140) (S)—N-(2-cyanopyridin-4-yl)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-5-(trifluoromethyl)-nicotinamide;

141) 4-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)-picolinamide;

142) N-(2-carbamoyl-4-pyridyl)-2-[(3S)-4,4-difluoro-3-methyl-1-piperidyl]-5-(trifluoromethyl)-pyridine-3-carboxamide;

143) N-(2-carbamoyl-4-pyridyl)-2-[(3R)-4,4-difluoro-3-methyl-1-piperidyl]-5-(trifluoromethyl)-pyridine-3-carboxamide;

144) 2-(4,4-difluoropiperidin-1-yl)-4-methoxy-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

145) 5-chloro-6-cyclobutyl-2-((2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

146) 5-chloro-6-cyclobutyl-2-((2S,6R)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

147) (R)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoro-methyl)nicotinamide;

148) (S)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoro-methyl)nicotinamide;

149) (S)-5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide;

150) (R)-5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide;

151) 6-cyclobutyl-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

152) 6-cyclobutyl-2-((2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

153) 6-cyclobutyl-2-((2S,6R)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

154) 5-chloro-6-cyclobutyl-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-N-(2-sulfamoyl-pyridin-4-yl)nicotinamide;

155) 6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

156) 2-(4,4-difluoroazepan-1-yl)-5-(difluoromethoxy)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

157) 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

158) 2-(4,4-difluoroazepan-1-yl)-6-(difluoromethyl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

159) 2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl) nicotinamide;

160) 4-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)pyridine-2-sulfonic acid;

161) 2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethoxy)nicotinamide

162) 2-(4,4-difluoropiperidin-1-yl)-5-fluoro-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

163) 5-(tert-butyl)-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;

164) 5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoro-methyl)-nicotinamide;

165) 5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoro-methoxy)-nicotinamide;

166) 2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-5-(2,2,2-trifluoro-ethoxy)-nicotinamide;

167) 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;

168) 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoro-methyl)nicotinamide;

169) 2-(azepan-1-yl)-N-(5-fluoropyridin-3-yl)-5-(trifluoromethyl)nicotinamide;

170) 2-(azepan-1-yl)-5-chloro-N-(2-methoxy-4-pyridyl)-4,6-dimethyl-pyridine-3-carboxamide;

171) 2-(azepan-1-yl)-5-chloro-4,6-dimethyl-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;

172) 5-chloro-2-(4,4-difluoro-1-piperidyl)-4,6-dimethyl-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;

173) 2-(6-azaspiro[2.5]octan-6-yl)-5-chloro-4,6-dimethyl-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;

174) 5-chloro-4,6-dimethyl-2-(1-piperidyl)-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;

175) 2-(4,4-difluoroazepan-1-yl)-6-methoxy-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;

176) 2-(azepan-1-yl)-N-(5-cyano-3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

177) 2-(azepan-1-yl)-N-(5-methoxy-3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

178) 2-(azepan-1-yl)-N-(5-methyl-3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

179) 2-(azepan-1-yl)-N-[5-(hydroxymethyl)-3-pyridyl]-5-(trifluoromethyl)pyridine-3-carboxamide;

180) 2-(azepan-1-yl)-N-(2-cyano-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

181) 2-(azepan-1-yl)-N-(2-ethylsulfonyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;

182) 2-(azepan-1-yl)-5-(trifluoromethyl)-N-[5-(trifluoromethyl)-3-pyridyl]pyridine-3-carboxamide;

183) 2-(azepan-1-yl)-5-chloro-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

184) 5-chloro-4,6-dimethyl-2-(6-azaspiro[2.5]octan-6-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

185) 4-(2-(azepan-1-yl)-5-(trifluoromethyl)nicotinamido)picolinamide;

186) 5-bromo-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

187) 2-(4,4-difluoropiperidin-1-yl)-5-phenyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

188) 2-(4,4-difluoropiperidin-1-yl)-5-(piperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

189) 2-(4,4-difluoropiperidin-1-yl)-5-(1H-pyrazol-1-yl)-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;

190) N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)-nicotinamide;

191) 5-chloro-4,6-dimethyl-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide;

192) 2-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;

193) 5-chloro-4,6-dimethyl-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(piperidin-1-yl)nicotinamide;

194) 2-(azepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-nicotinamide; and

195) 2-(azepan-1-yl)-5-chloro-4,6-dimethyl-N-(2-oxo-1,2-dihydropyridin-4-yl)nicotinamide;

or a pharmaceutically acceptable salt thereof.

12. A compound selected from:

1) 5-chloro-2-(4,4-difluorocyclohexyl)-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

2) 5-chloro-2-cycloheptyl-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide 3) 5-chloro-3-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)pyrazine-2-carboxamide;

4) 5-chloro-4,6-dimethyl-2-(4-methylcyclohexyl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide; and

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

or a pharmaceutically acceptable salt thereof.

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

14. A method of treating a disorder, condition or disease that is responsive to the inhibition of Na v 1.8 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: pain disorder, a cough disorder, an acute itch disorder or chronic itch disorder.

15. The method of claim 14 wherein the disorder is a pain disorder.

16. The method of claim 15 wherein the pain disorder is selected from: acute pain, inflammatory pain, or neuropathic pain.

17. A compound selected from:

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

2) (R)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

3) 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;

4) 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;

5) 5-chloro-6-cyclobutyl-2-((2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

6) 5-chloro-6-cyclobutyl-2-((2S,6R)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

7) 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

8) 2-(4,4-difluoroazepan-1-yl)-6-(difluoromethyl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

9) 2-(4,4-difluoropiperidin-1-yl)-5-fluoro-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

10) 2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl) nicotinamide;

11) 5-chloro-6-cyclobutyl-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;

12) 4-(2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)nicotinamido)picolinamide;

13) 5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydro-pyridin-4-yl)nicotinamide; and

14) 2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;

or a pharmaceutically acceptable salt thereof.

18. A compound which is (S)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide; or a pharmaceutically acceptable salt thereof.

19. A compound which is (R)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide; or a pharmaceutically acceptable salt thereof.

20. A compound which is 5-chloro-6-cyclobutyl-2-((2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-nicotinamide; or a pharmaceutically acceptable salt thereof.

21. A compound which is 2-(4,4-difluoro-piperidin-1-yl)-5-fluoro-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide; or a pharmaceutically acceptable salt thereof.

22. A compound which is 5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)nicotinamide; or a pharmaceutically acceptable salt thereof.

Assignments (2)
MERGER Recorded May 26, 2022
From: MERCK SHARP & DOHME CORP
To: MERCK SHARP & DOHME LLC
Reel/Frame 060025/0798 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 31, 2019
From: ARASAPPAN, ASHOK; BELL, IAN M.; BRESLIN, MICHAEL J.; BUNGARD, CHRISTOPHER JAMES; BURGEY, CHRISTOPHER S.; CHOBANIAN, HARRY R.; COX, JASON M.; GINNETTI, ANTHONY T.; GUIADEEN, DEODIAL GUY; JONES, KRISTEN L.G.; LAYTON, MARK E.; LIU, HONG; LIU, JIAN; PERKINS, JAMES J.; STACHEL, SHAWN J.; SUEN-LAI, LINDA M.; WU, ZHE
To: MERCK SHARP & DOHME CORP
Reel/Frame 050897/0001 →
Continuity (2)
Provisional Application 62754742 · Nov 2, 2018
Related Publication 20200140411A1 · May 7, 2020
Cited By (5)
US 12,435,058 US 12,441,705 US 12,441,736 US 12,459,932 US 12,540,129