4-amino or 4-alkoxy-substituted aryl sulfonamide compounds with selective activity in voltage-gated sodium channels

1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula I:

wherein:

X is selected from the group consisting of thiadiazolyl, pyridyl, thiazolyl, and pyrimidinyl, said thiadiazolyl, pyridyl, thiazolyl, and pyrimidinyl, optionally substituted with 1 to 3 groups selected from halogen and C 1-6 alkyl;

Y is phenyl;

Z is selected from NH and O;

R 1 is selected from C 1-6 alkyl and (CH 2 ) n C 3-6 cycloalkyl;

R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, OC 1-6 alkyl, C 1-6 alkyl, C 3-10 heteroaryl, CN, C 1-3 haloalkyl, and (CH 2 ) n OH;

R 4 is selected from the group consisting of CHR 5 NR 2 , CH 2 NHCH(C 1-6 alkyl) 2 , CH 2 R 5 , CH 2 N(R 5 )CH 2 CHRNR 2 , CH 2 CH(R 5 )(CH 2 ) p NR 2 , and (CH 2 ) n C(R) 2 (CHR) p NRR 7 ,

R 5 is selected from the group consisting of C 1-6 alkyl, (CH 2 ) n C 6-10 aryl, C 3-6 cycloalkyl, (CH 2 ) n C 3-10 heterocyclyl, and OC 1-6 alkyl, said alkyl, aryl, cycloalkyl and heterocyclyl optionally substituted with 1 to 3 groups of halogen, CF 3 , C 1-6 alkyl, C 3-6 cycloalkyl, and (CH 2 ) p NR 2 ;

R is hydrogen or C 1-6 alkyl, or two adjacent R groups can combine with the carbon atom to which they are attached to form C 3-6 cycloalkyl optionally substituted with 1 to 3 groups of halogen or C 1-6 alkyl;

R 6 is NHR;

R 7 is hydrogen or C 1-6 alkyl,

R 9 is hydrogen or halogen;

p is 0, 1, or 2, and

n is 0, 1, 2, 3, or 4.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of unsubstituted or substituted thiadiazolyl, pyridyl, and thiazolyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is phenyl and Z is O.

4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-6 alkyl selected from methyl, ethyl, butyl, and pentyl, or (CH 2 ) n C 3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

5. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of hydrogen, halogen, and C 1-6 alkyl.

6. A compound of claim 1 , or a pharmaceutically acceptable salt thereof realized wherein R 3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, OCH 3 , OCH 2 CH 3 , methyl, ethyl, propyl, butyl, thiazolyl, oxazolyl, CH 2 OH, OH, CN, CF 3 , and CHCF 2 .

7. A compound of claim 1 wherein R is C 1-6 alkyl.

8. A compound of claim 1 wherein two adjacent R groups combine with the carbon atom to which they are attached to form C 3-6 cycloalkyl, said cycloalkyl optionally substituted with 1 to 3 groups of halogen or C 1-6 alkyl.

9. A compound of claim 1 wherein R 4 is CHR 5 NR 2 , CH 2 NHCH(C 1-6 alkyl) 2 , CH 2 R 5 , CH 2 N(R 5 )CH 2 CHRNR 2 , CH 2 CH(R 5 )(CH 2 ) p NR 2 , or (CH 2 ) n C(R x R x )(CHR) p NH 2 where the adjacent R x groups combine with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl optionally substituted with one to three groups selected from C 1-6 alkyl and halogen and R 5 is optionally substituted C 1-6 alkyl, (CH 2 ) n phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, and OC 1-6 alkyl, said groups optionally substituted with 1 to 3 groups CF 3 , C 1-6 alkyl and (CH 2 ) p NH 2 .

10. A compound of claim 1 a pharmaceutically acceptable salt thereof represented by structural Formula A1:

wherein G is N or CH.

11. A compound according claim 10 wherein G is N, Z is NH or O, R 1 is CH 3 , R 2 is selected from the group consisting of hydrogen and fluorine, R 3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, CH 2 OH, and CN, R 4 is selected to the group consisting of CHR 5 NR 2 , CH 2 NHCH(C 1-6 alkyl) 2 , CH 2 R 5 , CH 2 N(R 5 )CH 2 CHRNR 2 , CH 2 CH(R 5 )(CH 2 ) p NR 2 , and (CH 2 ) n C(R x R x )(CHR) p NH 2 R 5 is selected from the group consisting of optionally substituted C 1-6 alkyl, OC 1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl, and morpholinyl and R 6 is NH 2 , and wherein the adjacent R x groups combine with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl optionally substituted with one to three groups selected from C 1-6 alkyl and halogen.

12. A compound according to claim 10 wherein G is CH, Z is NH or O, R 1 is CH 3 , R 2 is selected from the group consisting of hydrogen and fluorine, R 3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, CH 2 OH, and CN, R 4 is selected to the group consisting of CHR 5 NR 2 , CH 2 NHCH(C 1-6 alkyl) 2 , CH 2 R 5 , CH 2 N(R 5 )CH 2 CHRNR 2 , CH 2 CH(R 5 )(CH 2 ) p NR 2 , and (CH 2 ) n C(R x R x )(CHR) p NH 2 R 5 is selected from the group consisting of optionally substituted C 1-6 alkyl, OC 1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl, and morpholinyl and R 6 is NH 2 , and wherein the adjacent R x groups combine with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl optionally substituted with one to three groups selected from C 1-6 alkyl and halogen.

13. A compound which is:

4-(((2S)-4-amino-2-((R)-1-aminoethyl)-5,5,5-trifluoropentyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-((5-amino-2-((R)-1-aminoethyl)-4,4-dimethylpentyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)-4-((((5R,6S)-5,8,8-trimethyl-1,4-diazonan-6-yl)methyl)amino)benzenesulfonamide;

4-(((2S,3R)-3-amino-2-((1-(2-aminoethyl)cyclobutyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((2R,3R)-3-amino-2-((1-(2-aminoethyl)cyclobutyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((S)-6-amino-2-((R)-1-aminoethyl)-4,4-dimethylhexyl)amino)-5-chloro-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide;

4-(((3R)-3-amino-2-((4,4-dimethylpyrrolidin-2-yl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((2S)-4-amino-2-((R)-1-aminoethyl)-4-(1-methylcyclopropyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((2S)-6-amino-2-((R)-1-aminoethyl)-4-cyclopropylhexyl)amino)-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-3-amino-2-((1-(2-aminoethyl)cyclobutyl)methyl)pentyl)amino)-2,3,6-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-2-((2-azaspiro[3.4]octan-5-yl)methyl)-3-aminobutyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((S)-6-amino-2-((R)-1-amino-2-methylpropyl)-4,4-dimethylhexyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((S)-6-amino-2-((R)-amino(cyclopropyl)methyl)-4,4-dimethylhexyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((S)-6-amino-2-((R)-1-amino-2-cyclopropylethyl)-4,4-dimethylhexyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((S)-6-amino-2-((R)-1-aminoethyl)-4,4-dimethylhexyl)amino)-5-chloro-2-methyl-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((2S,3R)-3-amino-2-(((1S,2S)-2-(aminomethyl)cyclopropyl)methyl)butyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-3-amino-2-(amino(cyclobutyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-3-amino-2-((isopropylamino)methyl)butyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-3-amino-2-((((R)-2-aminopropyl)(isopropyl)amino)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((S)-6-amino-2-((R)-1-aminoethyl)-4,4-dimethylhexyl)amino)-2-fluoro-N-(1,2,4-thiadiazol-5-yl)-5-(thiazol-2-yl)benzenesulfonamide;

2-((2R,3R)-2,7-diamino-5,5-dimethylheptan-3-yl)-7-fluoro-N-(1,2,4-thiadiazol-5-yl)chromane-6-sulfonamide;

4-(((2S,3R)-3-amino-2-((1-(2-(dimethylamino)ethyl)cyclobutyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-3-amino-2-((2-(aminomethyl)cyclopentyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-3-amino-2-((2-(aminomethyl)-1-methylcyclobutyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-3-amino-2-((1-(2-aminoethyl)-3,3-difluorocyclobutyl)methyl)butyl)amino)-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-3-amino-2-((2-(2-aminoethyl)cyclohexyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((S)-6-amino-2-((R)-1-aminoethyl)-4,4-dimethylhexyl)amino)-5-cyano-2-methyl-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-2-((5-azaspiro[2.4]heptan-6-yl)methyl)-3-aminobutyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-3-amino-2-((1-(aminomethyl)cyclobutyl)methyl)butyl)amino)-2-fluoro-5-methoxy-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-3-amino-2-((4,4-dimethylpyrrolidin-3-yl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((2S,3R)-3-amino-2-((1-(2-aminoethyl)cyclobutyl)methyl)butyl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((S)-6-amino-2-((R)-1-aminoethyl)-4,4-dimethylhexyl)amino)-2-fluoro-5-(oxazol-2-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((2S)-4-amino-2-((R)-1-aminoethyl)-4-cyclopropylbutyl)amino)-2-fluoro-5-(hydroxymethyl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((2S)-5-amino-2-((R)-1-aminoethyl)-4-methoxypentyl)amino)-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((2S)-4-amino-2-((R)-1-aminoethyl)hexyl)amino)-2-fluoro-5-methoxy-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((2S)-4-amino-2-((R)-1-aminoethyl)-6,6,6-trifluorohexyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-3-amino-2-((1-aminocyclobutyl)methyl)butyl)amino)-3-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-((2-((R)-1-aminoethyl)-4-(aminomethyl)hexyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-((3R)-3-amino-2-((1-(2-aminoethyl)cyclobutyl)methyl)butoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-3-amino-2-(((1R,2S)-2-(aminomethyl)-1-methylcyclopentyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-3-amino-2-(((1S,2R)-2-(aminomethyl)-1-methylcyclopentyl)methyl)butyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((2S,3R)-3-amino-2-((1-(2-aminoethyl)cyclobutyl)methyl)butyl)amino)-2,3-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-3-amino-2-(morpholin-3-ylmethyl)butyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((2S,3R)-3-amino-2-((1-aminocyclobutyl)methyl)butyl)amino)-5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide;

4-(((S)-4-amino-2-((R)-1-aminoethyl)-4-methylpentyl)amino)-5-chloro-2-fluoro-N-(4-methylthiazol-2-yl)benzenesulfonamide;

4-(((S)-4-amino-2-((R)-1-aminoethyl)-4-methylpentyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)-5-methylbenzenesulfonamide;

4-((4-amino-2-((R)-1-aminoethyl)-5-methylhexyl)amino)-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-3-amino-2-(pyrrolidin-1-ylmethyl)butyl)amino)-5-chloro-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

4-(((3R)-2-(((1R,3R,4S)-2-azabicyclo[2.2.1] heptan-3-yl)methyl)-3-aminobutyl)amino)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

or a pharmaceutically acceptable salt of any thereof.

14. A composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

15. A pharmaceutical composition of claim 14 comprising additionally an effective amount of at least one other pharmaceutically active ingredient which is: (i) an opioid agonist or antagonist; (ii) a calcium channel antagonist; (iii) an NMDA receptor agonist or antagonist; (iv) a COX-2 selective inhibitor; (v) an non-steroidal anti-inflammatory drug; or (vi) paracetamol (APAP, acetaminophen), and a pharmaceutically acceptable carrier.

16. A method of treating a pain disorder, or cough, or acute itch or chronic itch disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .

17. The method of claim 16 wherein said disorder is an acute pain, inflammatory pain or neuropathic pain disorder.