Quinolines Useful as Modulators of ION Channels

A method for treating or lessening the severity of a disease, disorder, or condition selected from acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain, said method comprising the step of administering to said patient an effective amount of a composition comprising a compound of formula I-A, formula I-B, formula I-C, or formula I-D:

• and a pharmaceutically acceptable adjuvant or carrier
• or a pharmaceutically acceptable salt thereof,
• wherein:
• W is halo, OR′, SR′, N(R′)2, CHF2, CH2F, or CF3;
• R1 and R2, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-8-membered monocyclic, saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen;
• wherein the ring formed by R1 and R2 taken together, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R4, wherein z is 0-5;
• is 0-5;
• x is 0-5;
• each occurrence of R3, R4, and R5 is independently Q-RX;
• wherein Q is a bond or is a C1-C6 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO7NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, —OP(O)(OR)—, or —POR—;
• and each occurrence of RX is independently selected from —R′, halogen, —NO2, —CN, —OR′, —SR′, —N(R′)2, —NR′COR′, —NR′CON(R′)2, —NR′CO2R′, —COR′, —CO7R′, —OCOR′, —CON(R′)2, —OCON(R′)2, —SOR′, —SO2R′, —SO2N(R)7, —NR′SO2R′, —NR′SO2N(R)2, —COCOR′, —COCH2COR′, —OP(O)(OR′)2, —P(O)(OR′)2, —OP(O)2OR′, —P(O)2OR′, —PO(R′)2, or —OPO(R′)2;
• each occurrence of R is independently hydrogen or an optionally substituted C1-6 aliphatic group;
• each occurrence of R′ is independently hydrogen or an optionally substituted C1-6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• provided that:
• i) in compounds of formula I-A, when R1 and R2 taken together is 4-ethyl-piperazin-1-yl, then W is not chloro, —OH, —OMe, or —OCH2CH2OH;
• ii) in compounds of formula I-B, when W is OH or OMe, then R1 and R2 taken together is not
• wherein K is —C(O)NH2, —C(O)OEt, —CN, or 3-methyl-2,4-oxadiazol-5-yl;
• iii) in compounds of formula I-B, when W is chloro, then R1 and R2 taken together is not 4-methyl-piperazin-1-yl;
• iv) in compounds of formula I-B, when W is —NH2, then R1 and R2 taken together is not morpholin-4-yl or 2-(methoxycarbonyl)-pyrrolidin-1-yl;
• v) in compounds of formula I-C, when W is OH or OMe, then R1 and R2 taken together is not
• vi) in compounds of formula I-C, when W is halo or —OMe, then R1 and R2 taken together is not 4-methyl-piperazin-1-yl;
• vii) in compounds of formula I-D, when W is halo, then R1 and R2 taken together is not piperidin-1-yl, 4-methoxycarbonyl-piperidin-1-yl, or morpholin-4-yl;
• and
• viii) in compounds of formula I-D, when W is halo or OH, then R1 and R2 taken together is not 4-methyl-piperazin-1-yl.