N1-phenylpropane-1,2-diamine compounds with selective activity in voltage-gated sodium channels

1. A compound of Formula A, or a pharmaceutically acceptable salt thereof:

wherein:

R 1 is —CN; —Cl, —Br, or —F;

Q is: (i) —(CH═CR 2 )—, where R 2 is H, or —F; or (ii) —(C═N)—

K is independently for each occurrance —H or a linear, branched, or cycloalkyl moiety comprising up to 6 carbon atoms; and

J is:

(a) linear, or branched alkyl of up to 6 carbon atoms which is optionally substituted with: (i) a cycloalkyl of up to 6 carbon atoms; or (ii) aryl which is optionally substituted with one or more halogen or a linear, branched, or cycloalkyl moiety comprising up to 6 carbon atoms;

(b) trimethylsilyl;

(c) cycloalkyl of up to 6 carbon atoms which is optionally substituted on one or more carbon atoms thereof with, independently for each occurrence: (i) a linear, branched, or cycloalkyl moiety comprising up to 6 carbon atoms which is optionally substituted with a halogen; or (ii) halogen;

(d) a bridged bicyclo alkyl of the formula:

where n, m and p are independently 1 to 3 and the sum of n+m+p is 6 or less, and wherein any of the ring carbon atoms may optionally be substituted with a linear, branched, or cycloalkyl moiety comprising up to 6 carbon atoms; or

(e) aryl of the formula:

wherein, independently:

A 2 is —H, —Br, or —F;

A 3 is —H, —Cl, —Br, or —F;

A 4 is —H, —Cl, —CH 3 , —Br, or —F.

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein one K is selected to be a linear, branched, or cycloalkyl comprising up to 6 carbon atoms, which alkyl is partially or fully deuterated.

3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, with the structure of Formula A-2:

wherein:

X is N or C—R 2A , wherein R 2A is —F or —H;

K A is —CH 3 or —CD 3 ; and

J A is a linear, branched or cyclic alkyl of up to 4 carbon atoms which is optionally substituted on one carbon thereof with a linear, branched, or cycloalkyl moiety comprising up to 6 carbon atoms.

4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein J A is a branched alkyl of up to 5 carbon atoms or a cyclic alkyl of up to 5 carbon atoms which is substituted on a ring carbon thereof with a linear, branched, or cycloalkyl moiety comprising up to 6 carbon atoms.

5. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is —(C═CF)—.

6. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein wherein Q is —(C═CH)—.

7. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein wherein Q is —(C═N)—.

8. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is Cl.

9. A compound which is:

(S)-5-chloro-2-fluoro-4-((2-(methylamino)-3-phenylpropyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;

(S)-5-chloro-2-fluoro-4-((2-(methylamino)-3-phenylpropyl)amino)-N-(1,2,4-thiadiazol-5-yl)-benzenesulfonamide;

(S)-5-chloro-2-fluoro-N-(5-fluorothiazol-2-yl)-4-((2-(methylamino)-3-phenylpropyl)amino)-benzenesulfonamide;

(S)-5-chloro-2-fluoro-4-((3-(4-fluorophenyl)-2-(methylamino)propyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;

(S)-5-chloro-4-((3-cyclohexyl-2-(methylamino)propyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide;

(S)-5-chloro-2-fluoro-4-((2-(methylamino)-3-(p tolyl)propyl)amino)-N-(thiazol-2-yl)-benzenesulfonamide;

(S)-5-chloro-2-fluoro-4-((2-(methylamino)-4-phenylbutyl)amino)-N-(thiazol-2-yl)-benzenesulfonamide;

(S)-5-chloro-2-fluoro-N-(5-fluorothiazol-2-yl)-4-((2-(methylamino)-4-phenylbutyl)amino)-benzenesulfonamide;

(S)-4-((3-(3-bromo-phenyl)-2-(methylamino)-propyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)-benzenesulfonamide;

(S)-4-((3-(2-bromo-phenyl)-2-(methylamino)-propyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)-benzenesulfonamide;

(S)-4-((3-(4-bromo-phenyl)-2-(methylamino)-propyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)-benzenesulfonamide;

(S)-5-chloro-2-fluoro-4-((3-(3-fluorophenyl)-2-(methylamino)-propyl)-amino)-N-(thiazol-2-yl)-benzenesulfonamide;

(S)-5-chloro-2-fluoro-4-((3-(2-fluorophenyl)-2-(methylamino)-propyl)-amino)-N-(thiazol-2-yl)-benzenesulfonamide;

(S)-5-chloro-4-((3-(3,5-difluorophenyl)-2-(methyl-amino)-propyl)amino)-2-fluoro-N-(thiazol-2-yl)-benzenesulfonamide;

(S)-5-chloro-4-((3-(3,4-difluorophenyl)-2-(methyl-amino)propyl)amino)-2-fluoro-N-(thiazol-2-yl)-benzenesulfonamide;

(S)-4-((3-(2-bromo-4-fluorophenyl)-2-(methyl-amino)propyl)-amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)-benzenesulfonamide;

(S)-4-((3-(2-bromo-3-fluorophenyl)-2-(methyl-amino)propyl)-amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)-benzenesulfonamide;

(S)-5-chloro-4-((3-(4-chlorophenyl)-2-(methyl-amino)propyl)amino)-2-fluoro-N-(thiazol-2-yl)-benzenesulfonamide;

(S)-5-chloro-4-((4,4-dimethyl-2-(methylamino)pentyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)benzenesulfonamide;

(S)-5-chloro-4-((3-cyclobutyl-2-(methylamino)propyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)benzenesulfonamide;

(S)-4-((3-(bicyclo[1.1.1]pentan-1-yl)-2-(methylamino)propyl)-amino)-5-chloro-2-fluoro-N-(5-fluorothiazol-2-yl)-benzenesulfonamide;

(S)-5-chloro-2-fluoro-N-(5-fluorothiazol-2-yl)-4-((2-(methylamino)-3-(1-(trifluoromethyl)cyclopropyl)-propyl)amino)benzenesulfonamide;

(S)-5-chloro-4-((5,5-dimethyl-2-(methylamino)hexyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)-benzenesulfonamide;

(S)-5-chloro-2-fluoro-4-((2-(methylamino)-3-(1-(trifluoromethyl)cyclopropyl)-propyl)amino)-N-(thiazol-2-yl)-benzenesulfonamide;

(R)-5-chloro-2-fluoro-N-(5-fluorothiazol-2-yl)-4-((2-(methylamino)-3-(trimethylsilyl)propyl)-amino)benzenesulfonamide;

(S)-5-chloro-4-((3-cyclopropyl-2-(methylamino)propyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)-benzenesulfonamide;

(S)-5-chloro-4-((4-cyclopropyl-2-(methylamino)butyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)-benzenesulfonamide;

5-chloro-4-(((2S)-3-(2,2-dimethylcyclopropyl)-2-(methylamino)propyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)-benzenesulfonamide;

5-chloro-4-(((2S)-3-(2,2-dichlorocyclopropyl)-2-(methylamino)propyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)-benzenesulfonamide;

5-chloro-4-(((2S)-3-(2,2-difluorocyclopropyl)-2-(methylamino)propyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)-benzenesulfonamide;

(S)-5-chloro-4-((3-cyclopentyl-2-(methylamino)propyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)benzenesulfonamide;

(R)-5-chloro-4-((3-cyclopentyl-2-(methylamino)propyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)benzenesulfonamide;

(S)-5-chloro-4-((4-cyclobutyl-2-(methylamino)butyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)-benzenesulfonamide;

(S)-5-chloro-4-((4,4-dimethyl-2-((methyl-d3)amino)pentyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)-benzenesulfonamide;

(S)-5-chloro-2-fluoro-4-((3-(1-(fluoromethyl)cyclopropyl)-2-(methylamino)propyl)amino)-N-(5-fluorothiazol-2-yl)benzenesulfonamide;

(S)-5-chloro-2-fluoro-N-(5-fluorothiazol-2-yl)-4-((2-(methylamino)-3-(1-methylcyclopropyl)propyl)amino)benzenesulfonamide;

S)-5-chloro-2-fluoro-N-(5-fluorothiazol-2-yl)-4-((2-(methylamino)-4-(1-methylcyclopropyl)butyl)amino)benzenesulfonamide;

(S)-5-chloro-2-fluoro-N-(5-fluorothiazol-2-yl)-4-((2-(methylamino)-4-(1-methylcyclopropyl)butyl)amino)benzenesulfonamide;

(S)-5-chloro-4-((2-(dimethylamino)-3-(1-methylcyclopropyl)propyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)benzenesulfonamide;

(R)-5-chloro-4-((2-(ethylamino)-3-(trimethylsilyl)propyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)benzenesulfonamide;

(S)-5-chloro-2-fluoro-N-(5-fluorothiazol-2-yl)-4-((2-(propylamino)hexyl)amino) benzenesulfonamide;

(S)-5-chloro-2-fluoro-N-(5-fluorothiazol-2-yl)-4-((2-(isopropylamino)hexyl)amino)-benzenesulfonamide; or

(S)-5-cyano-4-((4,4-dimethyl-2-(methylamino)pentyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)benzenesulfonamide,

or a pharmaceutically acceptable salt of any thereof.

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

11. A composition of claim 10 comprising additionally 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 NSAID (non-steroidal anti-inflammatory drug); or (vi) paracetamol (APAP), and a pharmaceutically acceptable carrier.

12. A method of treating (a) a pain disorder; (b) a cough; or (c), an itch disorder selected from: i) acute itch; or (ii) chronic itch, the method comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 10 .

13. A method of treating (a) a pain disorder; (b) a cough; or (c), an itch disorder selected from: i) acute itch; or (ii) chronic itch, the method comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 11 .

14. The method of claim 12 wherein said disorder is chronic pain.

15. The method of claim 13 wherein said disorder is chronic pain.

16. A composition comprising at least one compound of claim 9 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

17. A composition of claim 16 comprising additionally 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 NSAID (non-steroidal anti-inflammatory drug); or (vi) paracetamol (APAP), and a pharmaceutically acceptable carrier.

18. A method of treating acute pain, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 16 .