Sodium channel modulators for the treatment of pain and diabetes

1. A compound selected from the group consisting of: 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(propyl)amino)acetic acid, 2-(allyl(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl) propyl)amino)acetic acid, 3-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn-1-yl)amino)propanoic acid, and 2-((3-( 5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl) amino) acetamide; or a pharmaceutically acceptable salt, or a tautomeric form thereof.

2. The compound of claim 1 , wherein the compound is 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(propyl)amino) acetic acid; or a pharmaceutically acceptable salt, or a tautomeric form thereof.

3. The compound of claim 1 , wherein the compound is 2-(allyl(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetic acid; or a pharmaceutically acceptable salt, or a tautomeric form thereof.

4. The compound of claim 1 , wherein the compound is 3-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn-1-yl)amino)propanoic acid; or a pharmaceutically acceptable salt, or a tautomeric form thereof.

5. The compound of claim 1 , wherein the compound is 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetamide; or a pharmaceutically acceptable salt, or a tautomeric form thereof.

6. A pharmaceutical composition comprising a compound selected from the group consisting of 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy) phenyl)propyl)(propyl)amino)acetic acid, 2-(allyl(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl) propyl)amino)acetic acid, 3-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn-1-yl)amino)propanoic acid, and 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino) acetamide, or a pharmaceutically acceptable salt, or a tautomeric form thereof, and a pharmaceutically acceptable carrier.

7. The composition of claim 6 , wherein the composition is suitable for topical, oral, subcutaneous, or intravenous administration.

8. A method for treatment of pain in a subject, wherein the method comprises administering to the subject in need of such prevention or treatment a therapeutically effective amount of a compound selected from the group consisting of 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl) propyl)(propyl)amino)acetic acid, 2-(allyl(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl) propyl)amino)acetic acid, 3-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn-1-yl)amino)propanoic acid, and 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino) acetamide; or a pharmaceutically acceptable salt, or a tautomeric form thereof.

9. The method of claim 8 , wherein the compound is 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy) phenyl) propyl)(propyl)amino)acetic acid; or a pharmaceutically acceptable salt, or a tautomeric form thereof.

10. The method of claim 8 , wherein the compound is 2-(allyl(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl) propyl)amino)acetic acid; or a pharmaceutically acceptable salt, or a tautomeric form thereof.

11. The method of claim 8 , wherein the compound is 3-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn-1-yl)amino)propanoic acid; or a pharmaceutically acceptable salt, or a tautomeric form thereof.

12. The method of claim 8 , wherein the compound is 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl) sulfamoyl)phenoxy)phenyl)propyl)amino) acetamide; or a pharmaceutically acceptable salt, or a tautomeric form thereof.

13. The method of claim 8 wherein the therapeutically effective amount of a compound selected from the group consisting of 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl) propyl)(propyl)amino)acetic acid, 2-(allyl(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl) propyl)amino)acetic acid, 3-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn-1-yl)amino)propanoic acid, and 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl) amino) acetamide, or a pharmaceutically acceptable salt, or a tautomeric form thereof, is effective in inhibiting voltage-gated sodium channel NaV1.7.

14. The method of claim 8 , wherein the pain is neuropathic, nociceptive or inflammatory pain.

15. The method of claim 8 , wherein the therapeutically effective amount is effective to alleviate pain in a subject, wherein a compound selected from the group consisting of 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy) phenyl) propyl)(propyl)amino)acetic acid, 2-(allyl(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl) propyl)amino)acetic acid, 3-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn-1-yl)amino)propanoic acid, and 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino) acetamide, or a pharmaceutically acceptable salt, or a tautomeric form thereof, shows a reduction in pain response in the Formalin Assay in phase 1 or phase 2, or both, at a dose between 0.1 mg/kg and 1,000 mg/kg, at a dose between 0.5 mg/kg and 100 mg/kg, or at a dose between 1 mg/kg to 50 mg/kg.

16. The method of claim 8 , wherein the pain is nociceptive pain, such as that resulting from physical trauma (e.g., a cut or contusion of the skin; or a chemical or thermal burn), osteoarthritis, rheumatoid arthritis or tendonitis; myofascial pain; neuropathic pain, such as that associated with stroke, diabetic neuropathy, luetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, fibromyalgia, or painful neuropathy induced iatrogenically by drugs; or mixed pain (i.e., pain with both nociceptive and neuropathic components); visceral pain; headache pain (e.g., migraine headache pain); CRPS; CRPS type I; CRPS type II; RSD; reflex neurovascular dystrophy; reflex dystrophy; sympathetically maintained pain syndrome; causalgia; Sudeck atrophy of bone; algoneurodystrophy; shoulder hand syndrome; post-traumatic dystrophy; autonomic dysfunction; autoimmune-related pain; inflammation-related pain; cancer-related pain; phantom limb pain; chronic fatigue syndrome; post-operative pain; spinal cord injury pain; central post-stroke pain; radiculopathy; sensitivity to temperature, light touch or color change to the skin (allodynia); pain from hyperthermic or hypothermic conditions; and other painful conditions (e.g., diabetic neuropathy, luetic neuropathy, postherpetic neuralgia, trigeminal neuralgia); chronic pain; acute pain; pain from neuromas, pain or itch associated with channelopathies (e.g., small fiber neuralgia, IEM or Raynodes); or itch from various origins (e.g., allergic itch).

17. The method of claim 8 , wherein the pain is neuropathic pain.

18. A method for treating prediabetes or diabetes comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl) propyl)(propyl)amino) acetic acid, 2-(allyl(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl) propyl)amino)acetic acid, 3-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn-1-yl)amino)propanoic acid, and 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl) amino)acetamide; or a pharmaceutically acceptable salt, or a tautomeric form thereof.