Pyrrolopyrazine-Spirocyclic piperidine amides as modulators of ion channels

Abstract

The invention relates to pyrrolopyrazine-spirocyclic piperidine amide compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

1 . (canceled) 
     
     
         2 . A compound of formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . A compound of formula 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 2 , wherein said pharmaceutically acceptable salt is selected from acid addition salts of suitable inorganic and organic acids. 
     
     
         5 . The compound of  claim 4 , wherein said pharmaceutically acceptable salt is selected from the group consisting of adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts. 
     
     
         6 . The compound of  claim 4 , wherein said pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, acetate, oxalate, maleate, tartarate, citrate, succinate and malonate salts. 
     
     
         7 . A pharmaceutical composition comprising the compound of  claim 2  and a pharmaceutically acceptable carrier. 
     
     
         8 . The composition of  claim 7  further comprising an additional therapeutic agent. 
     
     
         9 . The composition of  claim 8 , wherein the additional therapeutic agent is selected from the group consisting of:
 nonopioid analgesics selected from indoles, naphthylalkanones, oxicams, para-aminophenol derivatives, propionic acids, salicylates, fenamates, and pyrazoles; and opioid (narcotic) agonists selected from Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine.   
     
     
         10 . A method of inhibiting a voltage-gated sodium ion channel in:
 a patient; or   a biological sample;   
       comprising administering to the patient, or contacting the biological sample, with the compound of  claim 2 . 
     
     
         11 . The method of  claim 10 , wherein the voltage-gated sodium ion channel is NaV 1.7. 
     
     
         12 . A method of treating or lessening the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, osteoarthritis pain, radicular pain, sciatica, back pain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, pain associated with cancer in a subject, comprising administering to said subject an effective amount of a compound of  claim 2 . 
     
     
         13 . The method of  claim 12 , wherein said pharmaceutically acceptable salt is selected from the group consisting of acid addition salts of suitable inorganic and organic acids. 
     
     
         14 . The method of  claim 13 , wherein said pharmaceutically acceptable salt is selected from the group consisting of adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts. 
     
     
         15 . The method of  claim 13 , wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, acetate, oxalate, maleate, tartarate, citrate, succinate and malonate salts. 
     
     
         16 . The method of  claim 12  wherein an additional therapeutic agent is administered concurrently with, prior to, or subsequent to the compound of  claim 2 . 
     
     
         17 . The method of  claim 16 , wherein the additional therapeutic agent is selected from the group consisting of:
 nonopioid analgesics selected from indoles, naphthylalkanones, oxicams, para-aminophenol derivatives, propionic acids, salicylates, fenamates, and pyrazoles; and   opioid (narcotic) agonists selected from Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine.   
     
     
         18 . A method of treating or lessening the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, osteoarthritis pain, radicular pain, sciatica, back pain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, pain associated with cancer in a subject, comprising administering to said subject an effective amount of a composition comprising a compound of  claim 2 . 
     
     
         19 . The method of  claim 18 , wherein the composition comprises the compound of  claim 2  and a pharmaceutically acceptable carrier. 
     
     
         20 . The method of  claim 19 , wherein the composition further comprises an additional therapeutic agent. 
     
     
         21 . The method of  claim 20 , wherein the additional therapeutic agent is selected from the group consisting of:
 nonopioid analgesics selected from indoles, naphthylalkanones, oxicams, para-aminophenol derivatives, propionic acids, salicylates, fenamates, and pyrazoles; and opioid (narcotic) agonists selected from Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine.