HK1139648A - Ion channel modulators and methods of use - Google Patents

Description

Ion channel modulators and methods of use thereof

Technical Field

[001] The present invention relates to compounds useful as modulators 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.

Background

[002] The present invention relates to compounds useful as modulators 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.

[003] Sodium channels are the core of all excitable cells that produce action potentials, such as neurons and muscle cells. They play key roles in excitable tissues, including the brain, smooth muscles of the gastrointestinal tract, skeletal muscles, the peripheral nervous system, the spinal cord, and the airways. Thus, they play a key role in a variety of disease states, such as Epilepsy (see, Moulard, B. and D. Bertrand (2002) "Epilepsy and Sodium channel blocks" Expert Opin. Ther. patents 12 (1): 85-91)), pain (see, Waxman, S.G., S.Dib-Hajj et al (1999) "Sodium channels and pain" Proc Natl Acad Sci U SA 96 (14)): 7635-9 and Waxman, S.G., T.R.Cummins et al (2000) "Voltage-gated salts and the molecular pathonesof pain: a review "J Rehabil Res Dev 37 (5): 517-28), myotonia (see, MeOA, G. and V. Sansone (2000) "Therapy in myotonicdiscders and in muscle channels" Neurol Sci 21 (5): s953-61 and Mankodi, A. and C.A.Thornton (2002) "Myotonics hydromes" Curr Opin neuron 15 (5): 545-52), ataxia (see, Meisler, m.h., j.a. key et al (2002) "Mutations of voltage-gated sodium channels in motion disorders and diabetes" Novartis Found club Symp 241: 72-81), multiple sclerosis (see Black, J.A., S.Dib-Hajj et al (2000) "Sensory nerve-specific channel SNS is abnormal expressed in the vaccines of microorganisms with experimental allomyces encephalitis and humans with multiple sciences" Proc Natl Acad Sci U S97 (21): 11598-602; and Renganathan, M., M.Gelderblom et al (2003) "Expression of Na (v)1.8 sodium channels of the fastening patterns of cererebellar purkinje cells" Brain Res 959 (2): 235-42), irritable bowel (see, Su, x., r.e. wachtel et al (1999) "capsaicin sensitivity and voltage-gated sodium currents in colon sensor nerves from front mouth root canal" Am J physiology 277(6 Pt 1): g1180-8 and Laird, J.M., V.Souslova et al (2002) "defects in scientific paper and transferred hyperalgesia in NaV1.8(SNS/PN3) -null mice" JNeurosci 22 (19): 8352-6), urinary incontinence and visceral pain (see Yoshimura, N., S.Seki et al (2001) "The insult of The tetrodotoxin-resorstantdium channel Na (v)1.8(PN3/SNS) in a rat model of viscolpain" J Neurosci 21 (21): 8690-6), and a range of neurological dysfunctions such as anxiety and depression (see Hurley, s.c. (2002) "Lamotrigine update and its use in mood disorders" Ann Pharmacother 36 (5): 860-73).

[004] Voltage-gated Na channels contain a gene family consisting of 9 different subtypes (nav1.1-nav 1.9). As shown in Table 1, these subtypes show tissue-specific localization and functional differences (see, Goldin, A.L. (2001) "Regulation of lipid research" Annu Rev Physiol 63: 871-94). Three members of this gene family (nav1.8, 1.9, 1.5) are resistant to blockade by the well-known Na channel blocker TTX, demonstrating subtype specificity within this gene family. Mutational analysis has identified glutamate 387 as the determining residue for TTX binding (see, Noda, M., H.Suzuki et al (1989) "A single point mutation controls and side mutation on the sodium channel II" FEBS Lett259 (1): 213-6).

[005] Table 1 (abbreviations: CNS ═ central nervous system, PNS ═ peripheral nervous system, DRG ═ dorsal root ganglion, TG ═ trigeminal ganglion):

na isoforms	Tissue of	TTX IC50	Indication
				NaV1.1	CNS, PNS neuron body	10nM	Pain, epilepsy, neurodegeneration
NaV1.2	CNS, concentrated in axons	10nM	Neurodegenerative epilepsy
				NaV1.3	CNS, embryonic, damaged nerves	15nM	Pain (due to cold or dampness)
NaV1.4	Skeletal muscle	25nM	Myotonia
				NaV1.5	Heart and heart	2μM	Arrhythmia, QT prolongation
NaV1.6	Throughout the CNS, most abundant	6nM	Pain, movement disorder
				NaV1.7	PNS, DRG, neuroendocrine Ends	25nM	Pain, neuroendocrine disorders
NaV1.8	PNS，DRG&Small neurons in TG	＞50μM	Pain (due to cold or dampness)
				NaV1.9	PNS，DRG&Small neurons in TG	1μM	Pain (due to cold or dampness)

[006]In general, voltage-gated sodium channels (navs) are responsible for triggering rapid elevation of action potentials of excitable tissues of the nervous system, which carry electrical signals that program and encode normal and abnormal pain sensations. Antagonists of NaV channels can attenuate these pain signals and are useful in the treatment of a variety of pain conditions including, but not limited to, acute, chronic, inflammatory and neuropathic pain. Known NaV antagonists, such as TTX, lidocaine (see, Mao, J. and L.L.Chen (2000) 'systematic lipocaine for neuroactive Pain relief' Pain 87(1): 7-17.), bupivacaine, phenytoin (see, Jensen, T.S (2002)' anticionvulsants in neuropathic pain: rationale and clicividenceEur J Pain6(Suppl A): 61-8), lamotrigine (see, Rozen, T.D, (2001) "antibiotic drugs in the management of clusterigheadache and geographic neurogia" Headdache 41 Suppl 1: s25-32 and Jensen, T.S, (2002) "Anticonvulsants in neuropathic pain: rational and clinical evidenceEur J Pain6(Suppl A): 61-8) and carbamazepine (see, Backonja, M.M. (2002)' Use of antimicrobial and therefore useful for treatment of neuropathic pain "inNeurology59(5Suppl 2): s14-7), have been shown to be useful in attenuating pain in human and animal models.

[007] Hyperalgesia (hypersensitivity to certain pain) that develops in the presence of tissue injury or inflammation reflects, at least in part, the increased excitability of the high-threshold major afferent neurons that innervate the site of injury. Voltage sensitive sodium channel activation is crucial for the generation and propagation of neuronal action potentials. There is increasing evidence that regulation of NaV current is an intrinsic mechanism for controlling neuronal excitability (see, Goldin, A.L. (2001) "Regulation of sodium channel research" Annu Rev Physiol 63: 871-94). Several kinetically and pharmacologically distinct voltage-gated sodium channels are found in Dorsal Root Ganglion (DRG) neurons. TTX-tolerance currents are insensitive to micromolar concentrations of tetrodotoxin and exhibit slow activation and inactivation kinetics and a higher depolarization activation threshold than other voltage-gated sodium channels. TTX-tolerant sodium currents are limited primarily by a subset of sensory neurons that may be involved in nociception. Specifically, TTX-tolerant sodium currents are expressed almost exclusively in neurons with small cell body diameters; causing small diameter, slowly conducting axons and responding to capsaicin. A large body of experimental evidence demonstrates that TTX-resistant sodium channels, expressed on C-fibers, play an important role in the transmission of information for nociceptive spinal cord injury.

[008]Targeting TTX-tolerant sodium channelsIntrathecal administration of antisense oligo-deoxynucleotides of the unique region (NaV1.8) results in PGE₂A significant reduction in the induction of hyperalgesia (see, Khasar, s.g., m.s.gold, et al (1998) "a tetrodotoxin-resistant therapeutic current mediators in pain in the ratNeurosci Lett256(1): 17-20). More recently, Wood and colleagues have created a knockout mouse line, which lacks functional NaV1.8. This mutation has an analgesia effect in an assay to assess The response of animals to The inflammatory agent carrageenan (see Akopian, A.N., V.Souslova, et al (1999) "The tetrodotoxin-resistant sodium channel polypeptide in pain disordersNat Neurosci2(6): 541-8). In addition, defects in the mechanical and temperature perception were observed in these animals. The analgesia exhibited by the Nav1.8 knockout mutant is consistent with observations regarding the role of TTX-resistant current in nociception.

[009] Immunohistochemistry, in situ hybridization and in vitro electrophysiological experiments have all shown that the sodium channel NaV1.8 selectively localizes to the small sensory neurons of the dorsal root ganglion and trigeminal ganglion ((see, Akopian, A.N., L.Sivilotti et al (1996) "associated sensory nerve-tissue sensory neurons" Nature 379 (6562): 257-62.) the major role of these neurons is the detection and transmission of nociceptive stimuli The fibers are incrementally adjusted. Antisense treatment prevented redistribution of nav1.8 along the nerve, reversing neuropathic pain. Combining gene-knockout and antisense data supports the role of nav1.8 in the detection and transmission of inflammatory and neuropathic pain.

[0010] In neuropathic pain states, there is a modification of Na channel distribution and subtype. In damaged nerves, expression of NaV1.8 and NaV1.9 is greatly reduced, while expression of the TTX sensitivity subunit NaV1.3 is up-regulated by 5-10 fold (see, Dib-Hajj, S.D., J.Fjell et al (1999) "plastics of sodium channel expression in DRGneurones in the neural connectivity in prediction model of neuropathicpain." Pain 83 (3): 591-. In animal models following nerve injury, the time course of increase in nav1.3 parallels the appearance of allodynia. The biophysical peculiarity of nav1.3 is that it shows very fast re-direction after inactivation after action potentials. This results in a sustained high firing rate, often seen in damaged nerves (see Cummins, T.R., F.Aglieco et al (2001) "NaV1.3 sodium channels: rapipepriming and slow closed-state actuation displaced differentiation, after a mammalia cell and in spinal sensory nerves" J Neurosci 21 (16): 5952-61). Nav1.3 is expressed in both the central and peripheral systems of humans. NaV1.9 is similar to NaV1.8, it also selectively localizes to The small sensory neurons of The dorsal root ganglion and trigeminal ganglion (see, Fang, X., L.Djouhri et al (2002). "The presence and role of The tetrodotoxin-resistant sodium channel Na (v)1.9(NaN) nociceptive primary neurons," J Neurosci 22 (17): 7425-33). It has a slow rate of inactivation and a voltage dependence that shifts left with respect to activation (see, Dib-Hajj, S., J.A. Black et al (2002) "NaN/NaV1.9: a silica channels with unique properties" Trends Neurosci 25 (5): 253-9). These two biophysical properties allow nav1.9 to play a role in establishing the resting membrane potential of nociceptive neurons. The resting membrane potential of cells expressing NaV1.9 was in the range of-55 to-50 mV, with most other peripheral and central neurons being-65 mV. This persistent depolarization is largely due to the persistently low levels of nav1.9 channel activation. This depolarization allows neurons to more easily reach the threshold at which action potentials are fired in response to nociceptive stimulation. Compounds that block the nav1.9 channel may play an important role in establishing the set point for the detection of pain stimuli. In chronic pain states, nerves and nerve endings can become swollen and allergic, exhibiting high frequency of action potential firing even with mild or even no stimulation. These pathological neural swellings are called neuromas, where the major Na channels expressed are NaV1.8 and NaV1.7 (see, Kretschmer, T., L.T. Happel et al (2002) "accumulational PN1 and PN3 sodium channels in pain blood human neuroma-elevation from immunocytochemistry" Acta neurochi (Wien)144 (8): 803-10; discussion 810). Nav1.6 and nav1.7 are also expressed in dorsal root ganglion neurons and contribute to the small TTX-sensitive components found in these cells. In addition to its role in neuroendocrine excitability, NaV1.7 in particular may therefore also be a potential pain target (see Klugbauer, N., L.Laccinova et al (1995) "Structure and functional expression of a new member of the cardiac-reactive sodium family from human neuroendocrine cells" Embo J14 (6): 1084-90).

[0011] NaV1.1 (see, Sugawara, T., E.Mazaki-Miyazaki et al (2001) "Nav1.1 events use fe fiber sections associated with a high probability partial sections," Neurology 57 (4): 703-5 ") and NaV1.2 (see, Sugawara, T., Y.Tsurubuchi et al (2001)" A misuses evaluation of the Na + channel alpha II suburbitut gene Na (v)1.2 ina patient with sections, cause channel analysis "Proc Natl Acad Sci U S98 (11): 6384-9) have been associated with epileptic disorders, including seizures. More than 9 genetic Mutations in NaV1.1 have been associated with febrile seizures (see, Meisler, M.H., J.A. Kearney et al (2002) "Mutations of voltage-gated sodium channels in genetic disorders and episilepsy" Novartis Foundation Symp 241: 72-81).

[0012] Nav1.5 antagonists have been developed for the treatment of cardiac arrhythmias. The genetic defect in NaV1.5, which produces a larger, current-inactive component, has been linked to QT prolongation in humans, and an orally effective local anesthetic, mexiletine, has been used to treat this condition (see, Wang, D.W., K.Yazawa et al (1997) "Pharmacological targeting of Long QT microorganisms," J Clin Inyest 99 (7): 1714-20).

[0013]Several Na channel blockers are currently used or clinically tried for Epilepsy (see, molecular, b.and d.bertrand (2002) "Epilepsy and systemic channels blocks" Expert opin. the r.patents 12 (1): 85-91); acute (see, Wiffen, P., S.Collins, et al (2000) "anticancer drug for access and cyclic pain" Cochrane Database Syst Rev 3), chronic (see, Wiffen, P., S.Collins, et al (2000) "anticancer drug for access and cyclic pain" Cochrane Database Syst Rev 3, and Guay, D.R (2001) "indirect agents in the management of cyclic pain" pharmaceutical 21 (9): 1070-81), inflammatory (see, Gold, M.S. (1999) "Tetrodotoxin-resistant Na + currentin amplification hyperalgesia", "Proc Natl Acad Sci U S A96 (14): 7645-9) and neuropathic pain (see, Streichar, G.R., Z.Zhou, et al (2002)" Therapeutic concentrations of local and systemic peptides of sodium channels 241: 189 and 201, and Sandner-kieselg, A., G.Rump Seitlinger, et al (2002) "latex for nerve and of neural peptides of Gold after acetic acid 1264 and 1264); arrhythmia (see, An, R.H., R.Bangalore, et al (1996) "Lidocaine block of LQT-3 mutant human Na + channelsCirc Res79(1): 103-8, and Wang, D.W., K.Yazawa, et al (1997) "pharmaceutical targeting of Long QT mutant metals channels" J Clin Inyest 99 (7): 1714-20); neuroprotection (see, Taylor, C.P.andL.S.Narasimohan (1997) "Sodium channels and therapy of Central neural systems" Adv Pharmacol 39: 47-98) and use as anesthetic (see, Strechartz, G.R., Z.ZHou, et al (2002) "therapeutic concentrations of local anesthetic underilthe potential roleof sodium channels in neuropathic pain.″Novartis Found Symp241：189-201)。

[0014] Various animal models of clinical significance have been developed to study sodium channel modulators for a number of different indications. For example, malignant chronic pain, see Kohase, h, et al, Acta anaesthesio scand.2004; 48(3): 382-3; femoral cancer pain (see, Kohase, H. et al, Acta Anaestheol Scand.2004; 48 (3): 382-3); non-malignant chronic bone pain (see, Ciocon, J.O.et al, J Am Geriator Soc.1994; 42 (6): 593-6); rheumatoid arthritis (see Calvino, B. et al, Behavbrain Res.1987; 24 (1): 11-29); osteoarthritis (see, Guzman, R.E., et al, Toxicol Pathol.2003; 31 (6): 619-24); spinal stenosis (see, Takenobu, Y., et al, J Neurosci methods.2001; 104 (2): 191-8); neuropathic low back Pain (see, Hines, R. et al, Pain Med. 2002; 3 (4): 361-5; Massie, J.B. et al, J Neurosci methods.2004; 137 (2): 283-9); myofascial pain syndrome (see, Dalpiaz & Dodds, J pain Palliat Care Pharmacother.2002; 16 (1): 99-104; Sluka kaetal, Muscle nerve.2001; 24 (1): 37-46); fibromyalgia (see Bennet & Tai, Int J Clin Pharmacol Res.1995; 15 (3): 115-9); temporomandibular joint pain (see Ime H, Ren K, Brain Mol Brain Res.1999; 67 (1): 87-97); chronic visceral pain, including abdominal pain (see, Al-Chaer, e.d., et Al, gastroenterology.2000; 119 (5): 1276-85); pelvic/perineal pain (see Wesselmann et al, Neurosci Lett.1998; 246 (2): 73-6); pancreas (see Vera-Portocarro, L.B., et al, Anesthesiology.2003; 98 (2): 474-84); IBS pain (see Verne, G.N. et al, pain.2003; 105 (1-2): 223-30; La JH et al, WorldGastroenterol.2003; 9 (12): 2791-5); chronic headache (see, Willimas & Stark, Cephalalgia.2003; 23 (10): 963-71); migraine (see Yamamura, H. et al, J neurophysiol.1999; 81 (2): 479-93); tension headaches, including cluster headaches (see Costa, A. et al, cephalalgia.2000; 20 (2): 85-91); chronic neuropathic Pain, including post-herpetic neuralgia (see, Attal, N. et al, neurology.2004; 62 (2): 218-25; Kim & Chung 1992, Pain 50: 355); diabetic neuropathy (see, Beidoun A et al, Clin J pain.2004; 20 (3): 174-8; Courteix, C. et al, pain.1993; 53 (1): 81-8); HIV-associated neuropathy (see, Portegies & Rosenberg, New Tijdschr Genesekd.2001; 145 (15): 731-5; Joseph EK et al, pain.2004; 107 (1-2): 147-58; Oh, S.B. et al, J Neurosci.2001; 21 (14): 5027-35); trigeminal neuralgia (see, Sato, J. et al, Oral Surg Oral Med Oral saline Oral radial endo.2004; 97 (1): 18-22; Imamura Y et al, Exp Brain Res.1997; 116 (1): 97-103); Charcot-Marie dental neuropathy (see, Sereda, M. et al, neuron. 1996; 16 (5): 1049-60); hereditary sensory neuropathy (see, Lee, M.J., et al, Hum MolGenet.2003; 12 (15): 1917-25); peripheral nerve damage (see, Attal, N., et al, neurology.2004; 62 (2): 218-25; Kim & Chung 1992, Pain 50: 355; Bennett & Xie, 1988, Pain 33: 87; Decos tered, I. & Woolf, C.J., 2000, Pain 87: 149; Shir, Y. & Seltzer, Z.1990; Neurosci Lett 115: 62); painful neuroma (see, Nahabenian & Johnson, Ann PlastSurg.2001; 46 (1): 15-22; Devor & Raber, Behavv Neural biol.1983; 37 (2): 276-83); ectopic proximal and distal release (see Liu, X, et al, Brain Res.2001; 900 (1): 119-27); radiculopathy (see Devers & Galer, (see Clin J pain.2000; 16 (3): 205-8; Hayashi N et al, spine.1998; 23 (8): 877-85), chemotherapy-induced neuropathic pain (see, Aley, K.O. et al, neuroscience.1996; 73 (1): 259-65), radiation therapy-induced neuropathic pain, post-mastectomy pain (see, Devers & Galer, Clin J pain.2000; 16 (3): 205-8), central pain (Cahana, A. et al, Anesth analg.2004; 98 (6): 1581-4), spinal cord injury pain (see, Hains, B.C. et al, Exp neurol 2004.2000; 164: 426-37), post-stroke pain (see, complexity, Bucida, C. et al, Neost pain, Neostr. J. et al, local pain 1.79; Leustj. 83; Leustj. 25-2000; Legione. 25, 25-2000; Super. J. 26; Super, 25, 2000, weber, w.e., Ned Tijdschr geneeskd.2001; 145(17): 813-7; levitt & Heyback, pain.1981; 10(1): 67-73); intractable pain (see Yokoyama, M. et al, Can J Anaesth.2002; 49 (8): 810-3); acute pain, acute post-operative pain (see, Koppert, W. et al, Anesth Analg.2004; 98 (4): 1050-5; Brennan, T.J. et al, pain. 1996; 64 (3): 493 501); acute musculoskeletal pain; joint pain (see, Gotoh, S. et al, Ann Rheum Dis.1993; 52 (11): 817-22); mechanical low back pain (see, Kehl, L.J., et al, pain.2000; 85 (3): 333-43); neck pain; tendonitis; injury/exercise pain (see, Sesay, M. et al, Can J Anaesth.2002; 49 (2): 137-43); acute visceral pain, including abdominal pain; pyelonephritis; appendicitis; cholecystitis (cholecystitis); ileus et al (see, Giambernadrino, M.A. et al, pain.1995; 61 (3): 459-69); chest pain, including cardiac pain (see, Vergona, R.A., et al, Life Sci.1984; 35 (18): 1877-84); pelvic pain, renal colic, acute obstetrical pain, including labor pain (see, Segal, S. et al, Anesth Analg.1998; 87 (4): 864-9); cesarean section pain; acute inflammation, burn or traumatic pain; acute intermittent pain, including endometriosis (see, Cason, A.M., et al, Horm Behav.2003; 44 (2): 123-31); acute herpes zoster pain; sickle cell anemia; acute pancreatitis (see, Toma, H; gastroenterology.2000; 119 (5): 1373-81); breakthrough pain; or facial pain, including sinusitis pain, dental pain (see, Nusstein, J. et al, J Endo.1998; 24 (7): 487-91; Chidiac, J.J. et al, Eur J pain.2002; 6 (1): 55-67); multiple Sclerosis (MS) pain (see, Sakurai & Kanazawa, J neurol Sci.1999; 162 (2): 162-8); pain in depression (see Greene B, CurrMed Res Opin.2003; 19 (4): 272-7); -pain from leprosy; becker's disease pain; painful obesity (see Devilers & Oranje, Clin Exp Dermatol.1999; 24 (3): 240-1); pain from phlebitis; Guillain-Barre pain; painful legs or athletic toes; haglund syndrome; erythromelalgia pain (see, Legroup-Crespel, E., et al, Ann Dermatol Venoreol. 2003; 130 (4): 429-33); fabry disease pain (see, German, D.P., J Soc biol. 2002; 196 (2): 183-90); bladder and genitourinary disorders, including urinary incontinence (see, Berggren, t. et al, J urol.1993; 150(5 Pt 1): 1540-3); overactive bladder (see Chuang, Y.C. et al, urology.2003; 61 (3): 664-70); painful bladder syndrome (see, Yoshimura, N. et al, J Neurosci.2001; 21 (21): 8690-6); interstitial bladder salts (IC) (see, Giannakopoulos & Campilomotors, Arch Ital Urol Newrol Androl. 1992; 64 (4): 337-9; Boucher, M. et al, J Urol.2000; 164 (1): 203-8); and prostatitis (see Mayersak, J.S., Int Surg.1998; 83 (4): 347-9; Keith, I.M., et al, J Urol.2001; 166 (1): 323-8).

[0015] Unfortunately, as noted above, the efficacy of sodium channel blockers and calcium channel blockers currently used in the above disease states is largely limited by a number of adverse effects. These adverse effects include various CNS disorders such as blurred vision, dizziness, nausea and sedation, as well as more potentially life-threatening arrhythmias and heart failure. Therefore, there is still a need to develop other Na channel antagonists, preferably with higher potency and less adverse effects.

Disclosure of Invention

[0016] The present invention relates generally to compounds useful as modulators of ion channel activity. It has now been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are useful as inhibitors of voltage-gated sodium channels. These compounds have the formula I:

or a pharmaceutically acceptable salt thereof, wherein R₁，R′₁，R₂And R₃As defined herein.

[0017] The invention also includes methods of treating or lessening the severity of a disease, condition, or disorder in which sodium ion channel activation or hyperactivity is implicated in the disease state. Methods of treating or lessening the severity of a pain condition are also disclosed. In one aspect, the method comprises administering to a patient an effective amount of a pharmaceutical composition comprising at least one compound of the present invention.

[0018] The compounds of the invention are useful in treating or lessening the severity of a disease, condition or disorder, including, but not limited to, acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy or status epilepticus, neurodegenerative disorders, psychosis, e.g., anxiety or depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritic pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, post-operative pain or cancer pain.

[0019] The invention also provides novel pharmaceutical compositions formulated using the compounds described herein and a pharmaceutically acceptable carrier.

Detailed Description

[0020] Definition of

[0021] Unless otherwise stated, the following definitions as used herein shall apply.

[0022] The term "modulate" as used herein means to increase or decrease, e.g., a measurable amount of activity. Compounds that modulate the activity of an ion channel, e.g., a sodium ion channel, by increasing the activity of the ion channel, e.g., a sodium ion channel, are referred to as agonists. Compounds that modulate the activity of an ion channel, e.g., a sodium ion channel, by decreasing the activity of the ion channel, e.g., a sodium ion channel, are referred to as antagonists. Agonists interact with ion channels, such as sodium ion channels, to increase the ability of a receptor to transduce an intracellular signal in response to endogenous ligand binding. Antagonists interact with ion channels and compete with endogenous ligands or substrates for binding sites on the receptor so as to reduce the ability of the receptor to transduce intracellular signals in response to endogenous ligand binding.

[0023] The term "treating or reducing the severity of an ion channel-mediated disease" is intended to both treat the disease directly resulting from ion channel activity and to alleviate the symptoms of the disease directly resulting from non-ion channel activity. Examples of diseases whose symptoms may be affected by ion channel activity include, but are not limited to, acute, chronic, neuropathic or inflammatory pain, arthritis, migraine (migrane), cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy or status epilepticus, neurodegenerative disorders, psychoses such as anxiety and depression, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritic pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, post-operative pain or cancer pain.

[0024] The compounds of the invention used herein may be optionally substituted with one or more substituents, for example as exemplified generally above or as typical for a particular class, subclass and class of the invention.

[0025] For the purposes of the present invention, chemical Elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999 and "March's Advanced Organic Chemistry", 5th Ed., Ed.: smith, m.b. and March, j., John Wiley & Sons, New York: 2001, the entire contents of these documents are incorporated herein by reference.

[0026] The compounds of the invention used herein may be optionally substituted with one or more substituents, for example as exemplified generally above or as typical for a particular class, subclass and class of the invention.

[0027] The term "aliphatic group" as used herein includes the terms alkyl, alkenyl, alkynyl, each of which is optionally substituted as described below.

[0028]As used herein, "alkyl" means a saturated aliphatic hydrocarbon group containing 1-12 (e.g., 1-8, 1-6, or 1-4) carbon atoms. The alkyl group may be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. Alkyl groups may be substituted (i.e., optionally substituted) with one or more substituents such as: halogen; cycloaliphatic radicals [ e.g. cycloalkyl or cycloalkenyl](ii) a Heterocyclylaliphatic radicals [ e.g. heterocycloalkyl or heterocycloalkenyl](ii) a An aryl group; a heteroaryl group; an alkoxy group; aroyl; a heteroaroyl group; acyl [ e.g. (aliphatic) carbonyl, (cycloaliphatic) carbonyl or (heterocycloaliphatic) carbonyl](ii) a A nitro group; a cyano group; acylamino [ e.g. (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl or heteroarylaminocarbonyl](ii) a Amino groups [ e.g. aliphatic, cycloaliphatic or heterocycloaliphatic amino](ii) a Sulfonyl [ e.g. aliphatic-S (O)₂-](ii) a A sulfinyl group; a sulfanyl group; a sulfo-oxy group; urea; thiourea; a sulfamoyl group; a sulfonamide; oxo; a carboxyl group; a carbamoyl group; a cycloaliphatic oxy group; a heterocycloaliphatic oxy group; an aryloxy group; a heteroaryloxy group; an aralkyloxy group; heteroarylalkoxy; an alkoxycarbonyl group; an alkylcarbonyloxy group; or a hydroxyl group. Some examples of substituted alkyl groups include carboxyalkyl (e.g., HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl); cyanoalkyl; a hydroxyalkyl group; an alkoxyalkyl group; acyl radicalAn alkyl group; aralkyl group; (alkoxyaryl) alkyl; (sulfonylamino) alkyl (e.g., alkyl-S (O))₂-aminoalkyl); an aminoalkyl group; an acylaminoalkyl group; (cycloaliphatic) alkyl; or haloalkyl, but is not limited thereto.

[0029]As used herein, "alkenyl" means an aliphatic carbon group containing 2 to 8 (e.g., 2 to 6 or 2 to 4) carbon atoms and at least one double bond. Like the alkyl group, the alkenyl group may be linear or branched. Examples of alkenyl groups include, but are not limited to, allyl, isopropenyl, 2-butenyl, and 2-hexenyl. Alkenyl groups may be optionally substituted with one or more substituents such as: halogen; cycloaliphatic radicals [ e.g. cycloalkyl or cycloalkenyl](ii) a Heterocyclylaliphatic radicals [ e.g. heterocycloalkyl or heterocycloalkenyl](ii) a An aryl group; a heteroaryl group; an alkoxy group; aroyl; a heteroaroyl group; acyl [ e.g. (aliphatic) carbonyl, (cycloaliphatic) carbonyl or (heterocycloaliphatic) carbonyl](ii) a A nitro group; a cyano group; acylamino [ e.g. (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl or heteroarylaminocarbonyl](ii) a Amino [ e.g. aliphatylamino, cycloaliphatic amino, heterocycloaliphatic amino or aliphaticsulfonylamino](ii) a Sulfonyl [ e.g. alkyl-S (O)₂-, cycloaliphatic radical-S (O)₂-or aryl-S (O)₂-](ii) a A sulfinyl group; a sulfanyl group; a sulfo-oxy group; urea; thiourea; a sulfamoyl group; a sulfonamide; oxo; a carboxyl group; a carbamoyl group; a cycloaliphatic oxy group; a heterocycloaliphatic oxy group; an aryloxy group; a heteroaryloxy group; an aralkyloxy group; heteroarylalkoxy; an alkoxycarbonyl group; an alkylcarbonyloxy group; or a hydroxyl group. Some examples of substituted alkenyl groups include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl) alkenyl, (sulfonylamino) alkenyl (e.g., (alkyl-S (O))₂Aminoalkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic) alkenyl or haloalkenyl, butNot limited thereto.

[0030]"alkynyl" as used herein means an aliphatic carbon group containing 2 to 8 (e.g., 2 to 6 or 2 to 4) carbon atoms and having at least one triple bond. The alkynyl group may be linear or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl. Alkynyl groups may be optionally substituted with one or more substituents such as: aroyl; a heteroaroyl group; an alkoxy group; a cycloalkyloxy group; a heterocycloalkyloxy group; an aryloxy group; a heteroaryloxy group; an aralkyloxy group; a nitro group; a carboxyl group; a cyano group; halogen; a hydroxyl group; a sulfo group; a mercapto group; sulfanyl [ e.g. aliphatic-S-or cycloaliphatic-S-](ii) a Sulfinyl [ e.g. aliphatic-S (O) -or cycloaliphatic-S (O) - -](ii) a Sulfonyl [ e.g. aliphatic-S (O)₂-, aliphatic radical amino-S (O)₂-or a cycloaliphatic radical-S (O)₂-](ii) a Acylamino [ e.g. aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (cycloalkylalkyl) carbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl](ii) a Urea; thiourea; a sulfamoyl group; a sulfonamide; an alkoxycarbonyl group; an alkylcarbonyloxy group; a cycloaliphatic group; a heterocyclic aliphatic group; an aryl group; a heteroaryl group; acyl [ e.g. (cycloaliphatic) carbonyl or (heterocycloaliphatic) carbonyl](ii) a Amino [ e.g. aliphatic amino](ii) a A sulfo-oxy group; oxo; a carbamoyl group; (cycloaliphatic) oxy; (heterocycloaliphatic) oxy; or (heteroaryl) alkoxy.

[0031]"amido" as used herein includes "aminocarbonyl" and "carbonylamino". These terms, when used alone or in combination with another group, mean an amido group, e.g., -N (R) when used terminally^X)-C(O)-R^Yor-C (O) -N (R)^X)₂And when used intermediately is-C (O) -N (R)^X) -or-N (R)^X) -C (O) -, wherein R^XAnd R^YAs defined below. Examples of amido groups includeAlkylamido (e.g., alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic) amido, (heteroaralkyl) amido, (heteroaryl) amido, (heterocycloalkyl) alkylamido, arylamido, aralkylamido, (cycloalkyl) alkylamido or cycloalkylamido.

[0032]As used herein, "amino" means-NR^XR^YWherein R is^XAnd R^YEach independently is hydrogen, alkyl, cycloaliphatic, (cycloaliphatic) aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic) carbonyl, (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, arylcarbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl, (heterocycloaliphatic) carbonyl, (heteroarylcarbonyl, or (heteroarylaliphatic) carbonyl, each as defined herein and optionally substituted. Examples of the amino group include an alkylamino group, a dialkylamino group, or an arylamino group. When the term "amino" is not a terminal group (e.g., alkylcarbonylamino), it is represented by-NR^X-represents. R^XHave the same meaning as defined above.

[0033]As used herein, "aryl" is used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", to mean monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems, wherein a monocyclic ring system is aromatic or at least one ring in a bicyclic or tricyclic ring system is aromatic. Bicyclic and tricyclic groups include benzo-fused 2-3 membered carbocyclic rings. In addition, the benzo-fused group includes groups with two or more C_4-8Phenyl fused to a carbocyclic moiety. Aryl groups are optionally substituted with one or more substituents, including aliphatic groups [ e.g. alkyl, alkenyl or alkynyl](ii) a A cycloaliphatic group; (cycloaliphatic) aliphatic group; a heterocyclic aliphatic group; (heterocyclic ring)Aliphatic group) aliphatic group; an aryl group; a heteroaryl group; an alkoxy group; (cycloaliphatic) oxy; (heterocycloaliphatic) oxy; an aryloxy group; a heteroaryloxy group; (araliphatic) oxy; (heteroarylaliphatic) oxy; aroyl; a heteroaroyl group; an amino group; oxo (on a non-aromatic carbocyclic ring of a benzo-fused bicyclic or tricyclic aryl); a nitro group; a carboxyl group; an amido group; acyl [ e.g. aliphatic carbonyl, (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl or (heteroarylaliphatic) carbonyl](ii) a Sulfonyl [ e.g. aliphatic-S (O)₂-or amino-S (O)₂-](ii) a Sulfinyl [ e.g. aliphatic-S (O) -or cycloaliphatic-S (O) - -](ii) a Sulfanyl [ e.g. aliphatic radical-S-](ii) a A cyano group; halogen; a hydroxyl group; a mercapto group; a sulfo-oxy group; urea; thiourea; a sulfamoyl group; a sulfonamide; or a carbamoyl group. Alternatively, the aryl group may be unsubstituted.

[0034] Non-limiting examples of substituted aryl groups include haloaryl [ e.g., mono-, di (e.g., p, m-dihaloaryl) and (trihalo) aryl ]; (carboxy) aryl [ e.g., (alkoxycarbonyl) aryl, ((aralkyl) carbonyloxy) aryl, and (alkoxycarbonyl) aryl ]; (amido) aryl [ e.g., (aminocarbonyl) aryl, ((alkylamino) alkyl) aminocarbonyl) aryl, (alkylcarbonyl) aminoaryl, (arylaminocarbonyl) aryl, and (((heteroaryl) amino) carbonyl) aryl ]; aminoaryl [ e.g., (alkylsulfonyl) amino) aryl or ((dialkyl) amino) aryl ]; (cyanoalkyl) aryl; (alkoxy) aryl; (sulfamoyl) aryl [ e.g., (sulfamoyl) aryl ]; (alkylsulfonyl) aryl; (cyano) aryl; (hydroxyalkyl) aryl; ((alkoxy) alkyl) aryl; (hydroxy) aryl, ((carboxy) alkyl) aryl; ((dialkyl) amino) alkyl) aryl; (nitroalkyl) aryl; ((alkylsulfonyl) amino) alkyl) aryl; ((heterocycloaliphatic) carbonyl) aryl; ((alkylsulfonyl) alkyl) aryl; (cyanoalkyl) aryl; (hydroxyalkyl) aryl; (alkylcarbonyl) aryl; an alkylaryl group; (trihaloalkyl) aryl; p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or (meta- (heterocycloaliphatic) -ortho- (alkyl)) aryl.

[0035]As used herein, "arylaliphatic group," such as "arylalkyl" means an aliphatic group (e.g., C)_1-4Alkyl) substituted with aryl. "aliphatic", "alkyl" and "aryl" are as defined herein. An example of an araliphatic group, for example aralkyl, is benzyl.

[0036]As used herein, "aralkyl" means an alkyl group substituted with an aryl group (e.g., C)_1-4Alkyl groups). "alkyl" and "aryl" are as defined above. An example of an aralkyl group is benzyl. The aralkyl group is optionally substituted with one or more substituents, such as aliphatic groups [ e.g. alkyl, alkenyl or alkynyl, including carboxyalkyl, hydroxyalkyl or haloalkyl, e.g. trifluoromethyl](ii) a Cycloaliphatic radicals [ e.g. cycloalkyl or cycloalkenyl](ii) a (cycloalkyl) alkyl; a heterocycloalkyl group; (heterocycloalkyl) alkyl; an aryl group; a heteroaryl group; an alkoxy group; a cycloalkyloxy group; a heterocycloalkyloxy group; an aryloxy group; a heteroaryloxy group; an aralkyloxy group; heteroarylalkoxy; aroyl; a heteroaroyl group; a nitro group; a carboxyl group; an alkoxycarbonyl group; an alkylcarbonyloxy group; acylamino [ e.g. aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, heteroarylcarbonylamino or heteroaralkylcarbonylamino](ii) a A cyano group; halogen; a hydroxyl group; an acyl group; a mercapto group; an alkylsulfanyl group; a sulfo-oxy group; urea; thiourea; a sulfamoyl group; a sulfonamide; oxo; or a carbamoyl group.

[0037] As used herein, a "bicyclic ring system" includes an 8-12 (e.g., 9, 10, or 11) membered structure that forms two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common). Bicyclic ring systems include bicyclic aliphatic groups (e.g., bicycloalkyl or bicycloalkenyl), bicyclic heteroaliphatic groups, bicyclic aryl, and bicyclic heteroaryl groups.

[0038] As used herein, "cycloaliphatic radical" includes "cycloalkyl" and "cycloalkenyl", each of which is optionally substituted as described below.

[0039] "cycloalkyl" as used herein means a saturated carbocyclic mono-or bicyclic (fused or bridged) ring of 3 to 10 (e.g., 5 to 10) carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubic alkyl (cubyl), octahydro-indenyl, decahydro-naphthyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] nonyl, bicyclo [3.3.2 ] decyl, bicyclo [2.2.2] octyl, adamantyl, azacycloalkyl or ((aminocarbonyl) cycloalkyl.

[0040] "cycloalkenyl" as used herein means a non-aromatic carbocyclic ring of 3 to 10 (e.g., 4 to 8) carbon atoms having one or more double bonds. Examples of cycloalkenyl include cyclopentenyl, 1, 4-cyclohex-di-alkenyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo [2.2.2] octenyl or bicyclo [3.3.1] nonenyl.

[0041]The cycloalkyl or cycloalkenyl groups may be optionally substituted with one or more substituents, such as aliphatic [ e.g., alkyl, alkenyl or alkynyl](ii) a A cycloaliphatic group; (cycloaliphatic) aliphatic group; a heterocyclic aliphatic group; (heterocycloaliphatic) aliphatic; an aryl group; a heteroaryl group; an alkoxy group; (cycloaliphatic) oxy; (heterocycloaliphatic) oxy; an aryloxy group; a heteroaryloxy group; (araliphatic) oxy; (heteroarylaliphatic) oxy; aroyl; a heteroaroyl group; an amino group; acylamino [ e.g. (aliphatic) carbonylamino, (cycloaliphatic) carbonylamino, ((cycloaliphatic) aliphatic) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (heterocycloaliphatic) carbonylamino, ((heterocycloaliphatic) aliphatic) carbonylamino, (heteroaryl) carbonylamino or (heteroarylaliphatic) carbonylamino](ii) a A nitro group; carboxy [ e.g. HOOC-, alkoxycarbonyl or alkylcarbonyloxy](ii) a Acyl radicals [ e.g. ]Cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl or (heteroarylaliphatic) carbonyl](ii) a A cyano group; halogen; a hydroxyl group; a mercapto group; sulfonyl [ e.g. alkyl-S (O)₂And aryl-S (O)₂-](ii) a Sulfinyl [ e.g. alkyl-S (O) -substituted](ii) a Thioalkyl [ e.g. alkyl-S-](ii) a A sulfo-oxy group; urea; thiourea; a sulfamoyl group; a sulfonamide; oxo; or a carbamoyl group.

[0042] The term "heterocycloaliphatic" as used herein includes heterocycloalkyl and heterocycloalkenyl, each of which is optionally substituted as described below.

[0043]As used herein, "heterocycloalkyl" means a 3-10 membered mono-or bicyclic (fused or bridged) (e.g., 5-to 10-membered mono-or bicyclic) saturated ring structure. Wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or a combination thereof). Examples of heterocycloalkyl include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, 1, 4-dioxolanyl, 1, 4-dithianyl, 1, 3-dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, octahydrobenzofuranyl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyridinyl, decahydroquinolinyl, octahydrobenzo [ b ] b]Thienyl, 2-oxa-bicyclo [2.2.2]Octyl, 1-aza-bicyclo [2.2.2]Octyl, 3-aza-bicyclo [3.2.1]Octyl and 2, 6-dioxa-tricyclo [3.3.1.0^3，7]Nonyl radical. Monocyclic heterocycloalkyl groups can be fused with a phenyl moiety, such as tetrahydroisoquinoline, to produce heteroaryl groups.

[0044] As used herein, "heterocycloalkenyl" means a mono-or bicyclic (e.g., 5-to 10-membered mono-or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O or S).

[0045] Monocyclic and bicyclic heteroaliphatic groups are encoded according to standard chemical nomenclature.

[0046] The heterocycloalkyl or heterocycloalkenyl group may be optionally substituted with one or more substituents, such as aliphatic [ e.g., alkyl, alkenyl or alkynyl ]; a cycloaliphatic group; (cycloaliphatic) aliphatic group; a heterocyclic aliphatic group; (heterocycloaliphatic) aliphatic; an aryl group; a heteroaryl group; an alkoxy group; (cycloaliphatic) oxy; (heterocycloaliphatic) oxy; an aryloxy group; a heteroaryloxy group; (araliphatic) oxy; (heteroarylaliphatic) oxy; aroyl; a heteroaroyl group; an amino group; acylamino [ e.g. (aliphatic) carbonylamino, (cycloaliphatic) carbonylamino, ((cycloaliphatic) aliphatic) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (heterocycloaliphatic) carbonylamino, ((heterocycloaliphatic) aliphatic) carbonylamino, (heteroaryl) carbonylamino or (heteroarylaliphatic) carbonylamino ]; a nitro group; carboxy [ e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy ]; acyl [ e.g., (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl, or (heteroarylaliphatic) carbonyl ]; a nitro group; a cyano group; halogen; a hydroxyl group; a mercapto group; sulfonyl [ e.g., alkylsulfonyl or arylsulfonyl ]; sulfinyl [ e.g., alkylsulfinyl ]; a sulfanyl group [ e.g., alkylsulfanyl group ]; a sulfo-oxy group; urea; thiourea; a sulfamoyl group; a sulfonamide; oxo; or a carbamoyl group.

[0047] As used herein, "heteroaryl" means a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms, wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or a combination thereof), and wherein the monocyclic ring system is aromatic, or at least one ring in the bicyclic or tricyclic ring system is aromatic. Heteroaryl includes benzo-fused ring systems having 2-3 rings. For example, benzo-fused groups include benzo-fused with one or two 4-8 membered heterocycloaliphatic moieties (e.g., indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [ b ] furanyl, benzo [ b ] thienyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl groups are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolyl, benzothiazolyl, xanthene, thioxanthene, phenothiazine, indoline, benzo [1, 3] dioxole, benzo [ b ] furyl, benzo [ b ] thienyl, indazolyl, benzimidazolyl, purinyl, cinnolinyl, quinolyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, isoquinolyl, 4H-quinolizinyl, benzo-1, 2, 5-thiadiazolyl or 1, 8-naphthyridinyl.

[0048] Monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, 2H-pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 3, 4-thiadiazolyl, 2H-pyranyl, 4-H-pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl or 1, 3, 5-triazolyl. Monocyclic heteroaryl groups are encoded according to standard chemical nomenclature.

[0049] Bicyclic heteroaryls include indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [ b ] furanyl, benzo [ b ] thienyl, quinolinyl, isoquinolinyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, or pteridinyl. Bicyclic heteroaryls are encoded according to standard chemical nomenclature.

[0050]Heteroaryl is optionally substituted with one or more substituents such as: aliphatic radicals [ e.g. alkyl, alkenyl or alkynyl](ii) a A cycloaliphatic group; (cycloaliphatic) aliphatic group; a heterocyclic aliphatic group; (heterocycloaliphatic) aliphatic; an aryl group; a heteroaryl group; an alkoxy group; (cycloaliphatic) oxy; (heterocycloaliphatic) oxy; an aryloxy group; a heteroaryloxy group; (araliphatic) oxy; (heteroarylaliphatic) oxy; aroyl; a heteroaroyl group; an amino group; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); a carboxyl group; an amido group; acyl [ e.g., aliphatic carbonyl; (cycloaliphatic) carbonyl(ii) a ((cycloaliphatic) aliphatic) carbonyl; (araliphatic) carbonyl; (heterocycloaliphatic) carbonyl; ((heterocycloaliphatic) aliphatic) carbonyl; or (heteroarylaliphatic) carbonyl](ii) a Sulfonyl [ e.g. aliphatic-S (O)₂-or amino-S (O)₂-](ii) a Sulfinyl [ e.g. aliphatic radical-S (O) -](ii) a Sulfanyl [ e.g. aliphatic radical-S-](ii) a A nitro group; a cyano group; halogen; a hydroxyl group; a mercapto group; a sulfo-oxy group; urea; thiourea; a sulfamoyl group; a sulfonamide; or a carbamoyl group. Alternatively, the heteroaryl group may be unsubstituted.

[0051] Non-limiting examples of substituted heteroaryl groups include (halo) heteroaryl [ e.g., mono-and di- (halo) heteroaryl ]; (carboxy) heteroaryl [ e.g., (alkoxycarbonyl) heteroaryl ]; a cyanoheteroaryl group; aminoheteroaryl [ e.g., (alkylsulfonyl) amino) heteroaryl and ((dialkyl) amino) heteroaryl ]; (amido) heteroaryl [ e.g., aminocarbonylheteroaryl, ((alkylcarbonyl) amino) heteroaryl, ((((alkyl) amino) alkyl) aminocarbonyl) heteroaryl, ((heteroaryl) amino) carbonyl) heteroaryl, ((heterocycloaliphatic) carbonyl) heteroaryl, and ((alkylcarbonyl) amino) heteroaryl ]; (cyanoalkyl) heteroaryl; (alkoxy) heteroaryl; (sulfamoyl) heteroaryl [ e.g., (sulfamoyl) heteroaryl ]; (sulfonyl) heteroaryl [ e.g., (alkylsulfonyl) heteroaryl ]; (hydroxyalkyl) heteroaryl; (alkoxyalkyl) heteroaryl; (hydroxy) heteroaryl; ((carboxy) alkyl) heteroaryl; [ ((dialkyl) amino) alkyl ] heteroaryl; (heterocycloaliphatic) heteroaryl; (cycloaliphatic) heteroaryl; (nitroalkyl) heteroaryl; ((alkylsulfonyl) amino) alkyl) heteroaryl; ((alkylsulfonyl) alkyl) heteroaryl; (cyanoalkyl) heteroaryl; (acyl) heteroaryl [ e.g. (alkylcarbonyl) heteroaryl ]; (alkyl) heteroaryl and (haloalkyl) heteroaryl [ e.g., trihaloalkylheteroaryl ].

[0052]As used herein, "heteroaralkyl" (e.g., heteroaralkyl) refers to an aliphatic group (e.g., C) substituted with a heteroaryl group_1-4Alkyl groups). "aliphatic", "alkyl" and "heteroaryl" groups are as defined above.

[0053]As used herein, "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group (e.g., C)_1-4Alkyl groups). "alkyl" and "heteroaryl" are as defined above. Heteroaralkyl is optionally substituted with one or more substituents, such as alkyl (e.g., carboxyalkyl, hydroxyalkyl and haloalkyl, such as trifluoromethyl); an alkenyl group; an alkynyl group; a cycloalkyl group; (cycloalkyl) alkyl; a heterocycloalkyl group; (heterocycloalkyl) alkyl; an aryl group; a heteroaryl group; an alkoxy group; a cycloalkyloxy group; a heterocycloalkyloxy group; an aryloxy group; a heteroaryloxy group; an aralkyloxy group; heteroarylalkoxy; aroyl; a heteroaroyl group; a nitro group; a carboxyl group; an alkoxycarbonyl group; an alkylcarbonyloxy group; an aminocarbonyl group; an alkylcarbonylamino group; a cycloalkylcarbonylamino group; (cycloalkylalkyl) carbonylamino; an arylcarbonylamino group; an aralkylcarbonylamino group; (heterocycloalkyl) carbonylamino; (heterocycloalkylalkyl) carbonylamino; a heteroaryl carbonylamino group; heteroarylalkylcarbonylamino; a cyano group; halogen; a hydroxyl group; an acyl group; a mercapto group; an alkylsulfanyl group; a sulfo-oxy group; urea; thiourea; a sulfamoyl group; a sulfonamide; oxo; or a carbamoyl group.

[0054]As used herein, "acyl" means formyl or R^X-C (O) - (e.g. -alkyl-C (O) -, also known as "alkylcarbonyl"), wherein R^XAnd "alkyl" is as defined above. Acetyl and pivaloyl are examples of acyl groups.

[0055] As used herein, "aroyl" or "heteroaroyl" refers to aryl-C (O) -or heteroaryl-C (O) -. The aryl and heteroaryl portions of the aroyl or heteroaroyl groups are optionally substituted as described above.

[0056] As used herein, "alkoxy" refers to an alkyl-O-group, wherein "alkyl" is as defined above.

[0057]As used herein, "carbamoyl" means having the structure-O-CO-NR^XR^Yor-NR^X-CO-O-R^ZWherein R is^XAnd R^YAs defined above and R^ZCan be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl orA heteroaromatic aliphatic group.

[0058]As used herein, "carboxyl" when used as a terminal group means-COOH, -COOR^X，-OC(O)H，-OC(O)R^X(ii) a or-OC (O) -or-C (O) O-when used as a mid-group.

[0059]As used herein, "haloaliphatic" refers to aliphatic groups substituted with 1-3 halogens. For example, the term haloalkyl includes the group-CF₃。

[0060] "mercapto" as used herein means-SH.

[0061]As used herein, "sulfo" means-SO when used terminally₃H or-SO₃R^XOr when used in the middle-S (O)₃-。

[0062]As used herein, "sulfonamide" when used terminally means the structure-NR^X-S(O)₂-NR^YR^ZAnd in the intermediate use-NR^X-S(O)₂-NR^Y-, wherein R^X，R^YAnd R^ZAs defined above.

[0063]As used herein, "sulfamoyl" when used terminally means the structure-S (O)₂-NR^XR^Yor-NR^X-S(O)₂-R^Z(ii) a Or when used in the middle-S (O)₂-NR^X-or-NR^X-S(O)₂-, wherein R^X，R^YAnd R^ZAs defined above.

[0064]As used herein, "sulfanyl" when used terminally means-S-R^XAnd in the middle is used-S-in which R^XAs defined above. Examples of sulfanyl groups include aliphatic-S-, cycloaliphatic-S-, aryl-S-, and the like.

[0065]As used herein, "sulfinyl" when used terminally means-S (O) -R^XAnd in the middle of use means-S (O) -, in which R^XAs defined above. Typical sulfinyl radicals includealiphatic-S (O) -, aryl-S (O) -, (cycloaliphatic (aliphatic)) -S (O) -, cycloalkyl-S (O) -, heterocycloaliphatic-S (O) -, heteroaryl-S (O) -, and the like.

[0066]As used herein, "sulfonyl" means-S (O) when used terminally₂-R^XAnd in the middle of use means-S (O)₂-, wherein R^XAs defined above. Typical sulfonyl groups include the aliphatic radical-S (O)₂-, aryl-S (O)₂-, (cycloaliphatic (aliphatic)) -S (O)₂-, cycloaliphatic radical-S (O)₂-, Heterocyclylaliphatic radical-S (O)₂-, heteroaryl-S (O)₂-, (cycloaliphatic (amido (aliphatic))) -S (O)₂-and the like.

[0067]As used herein, "sulfoxy" when used terminally means-O-SO-R^Xor-SO-O-R^XAnd when used intermediately means-O-S (O) -or-S (O) -O-, wherein R is^XAs defined above.

[0068] As used herein, a "halogen" or "halo" group means fluorine, chlorine, bromine or iodine.

[0069] As used herein, the term "alkoxycarbonyl" as encompassed by carboxy is used alone or in combination with another group to mean a group, such as alkyl-O-C (O) -.

[0070] As used herein, "alkoxyalkyl" means an alkyl group, such as alkyl-O-alkyl-, wherein alkyl is as defined above.

[0071] As used herein, "carbonyl" means-C (O) -.

[0072] As used herein, "oxo" means ═ O.

[0073]As used herein, "aminoalkyl" means the structure (R)^X)₂N-alkyl-.

[0074] "cyanoalkyl" as used herein means the structure (NC) -alkyl-.

[0075]As used hereinThe urea "group means the structure-NR^X-CO-NR^YR^ZAnd the "thiourea" group means the structure-NR when used at the terminus^X-CS-NR^YR^ZAnd in the intermediate use-NR^X-CO-NR^Y-or-NR^X-CS-NR^Y-, wherein R^X，R^YAnd R^ZAs defined above.

[0076]As used herein, "guanidino" means the structure-N ═ C (N (R)^XR^Y))N(R^XR^Y) Wherein R is^XAnd R^YAs defined above.

[0077]The term "amidine" group as used herein means the structure-C ═ (NR)^X)N(R^XR^Y) Wherein R is^XAnd R^YAs defined above.

[0078] In general, the term "ortho" is intended to include substituents on groups of two or more carbon atoms, wherein such substituents are bonded to adjacent carbon atoms.

[0079] In general, the term "geminal" is intended to include substituents on a group of two or more carbon atoms, wherein the substituents are bonded to the same carbon atom.

[0080]The terms "terminal" and "intermediate" refer to the position of the substituent intermediate group. A group is terminal when the group is present at the end of a substituent that is not further bonded to the remainder of the chemical structure. Carboxyalkyl, i.e. R^XO (O) C-alkyl is an example of a carboxyl group used at the end. A group is in the middle when the group is present at the end of a substituent bound to the remainder of the chemical structure. Examples of carboxyl groups used intermediately when alkylcarboxyl (e.g., alkyl-C (O) O-or alkyl-OC (O) -) and alkylcarboxylaryl (e.g., alkyl-C (O) O-aryl-or alkyl-O (CO) -aryl-).

[0081]The term "amidine" group as used herein means the structure-C ═ (NR)^X)N(R^XR^Y) Wherein R is^XAnd R^YAs defined above.

[0082] As used herein, "bridged bicyclic ring system" means a bicyclic heterocyclic aliphatic ring system or a bicyclic cycloaliphatic ring system, wherein the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantyl, norbornyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] nonyl, bicyclo [3.2.3] nonyl, 2-oxa-bicyclo [2.2.2] octyl, 1-aza-bicyclo [2.2.2] octyl, 3-aza-bicyclo [3.2.1] octyl and 2, 6-dioxa-tricyclo [3.3.1.03, 7] nonyl. The bridged bicyclic ring system may be optionally substituted with one or more substituents such as: alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl, e.g., trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo or carbamoyl.

[0083] As used herein, "cyclic group" or "cyclic moiety" includes mono-, bi-and tri-cyclic ring systems, including cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl, each as defined above.

[0084]As used herein, "aliphatic chain" means a branched or straight chain aliphatic group (e.g., alkyl, alkenyl, or alkynyl). The straight aliphatic chain having the structure- [ CH ]₂]_v-, where v is 1 to 12. A branched aliphatic chain is a straight aliphatic chain substituted with one or more aliphatic groups. The branched aliphatic chain has the structure- [ CQQ]_v-, wherein Q is independently hydrogen or an aliphatic group; however, Q is at least oneIn one case aliphatic groups. The term aliphatic chain includes alkyl, alkenyl and alkynyl chains, wherein alkyl, alkenyl and alkynyl are as defined above.

[0085]The term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". The compounds of the invention used herein may be optionally substituted with one or more substituents, for example as exemplified generally above or as typified by specific classes, subclasses and species of the invention. Variable R of formula I as used herein₁，R₂，R₃And R₄And other variables contained therein include specific groups such as alkyl and aryl groups. Unless otherwise stated, the variable R₁，R₂，R₃And R₄Each of the particular groups of (a) and other variables contained therein may be optionally substituted with one or more substituents described herein. Each substituent of a particular group is further optionally substituted with 1-3 of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. For example, alkyl may be substituted with alkylsulfanyl, and the alkylsulfanyl may be optionally substituted with 1 to 3 of halogen, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As another example, the cycloalkyl portion of a (cycloalkyl) carbonylamino group can be optionally substituted with 1-3 of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or to adjacent atoms, the two alkoxy groups may form a ring together with the atom to which they are attached.

[0086] In general, the term "substituted" preceded by the term "optionally" whether or not present, refers to the replacement of a hydrogen radical on the specified structure with a specific substituent group. Specific substituents are as defined above and described in the description of the compounds and examples thereof below. Unless otherwise stated, an optionally substituted group may bear a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a particular group, the substituents may be the same or different at each position. A ring substituent, such as heterocycloalkyl, may be combined with another ring, such as cycloalkyl, to form a spiro-bicyclic ring system, e.g., the two rings share a common atom. As recognized by those skilled in the art, combinations of substituents contemplated by the present invention are those that result in the formation of stable or chemically feasible compounds.

[0087] The term "stable or chemically feasible" as used herein means a compound that does not substantially change when subjected to conditions that allow their production, detection, preferably recovery, purification and use for one or more of the purposes disclosed herein. In certain embodiments, a stable compound or chemically feasible compound is one that is substantially unchanged when maintained at a temperature of 40 ℃ or less for at least one week in the absence of moisture or other chemically reactive conditions.

[0088] An "effective amount" as used herein is defined as an amount that provides a therapeutic effect to the treated patient and is generally determined based on the age, body surface area, weight, and condition of the patient. Freireich et al, Cancer chemi. rep., 50: animal and human dose correlations (in mg/square meter body surface area) are described in 219 (1966). The body surface area can be determined approximately from the height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" means a mammal, including a human.

[0089]Unless otherwise stated, structures shown herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomeric) forms of the structure; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers and mixtures of enantiomers, diastereomers and geometric isomers (or conformers) of the compounds of the present invention are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise stated, structures shown herein are also intended to compriseCompounds that differ only in the presence of one or more isotopically enriched atoms. For example, having the structure of the invention but with hydrogen replaced by deuterium or tritium or with carbon enriched¹³C-or¹⁴Carbon-substituted compounds of C are within the scope of the present invention. Such compounds are useful, for example, as tools or probes in bioassays.

[0090] II. Compound

[0091] The compounds of the present invention are useful Na ion channel modulators.

[0092] The invention includes compounds of formula I

Or a pharmaceutically acceptable salt thereof.

[0093]R′₁And R₁Each independently is-Z^AR₄Wherein Z is^AEach independently being a bond or an optionally substituted branched or straight chain C_1-12Aliphatic chain, wherein Z^AUp to three carbon units of (A) are optionally and independently substituted by-C (O) -, -C (S) -, -C (O) NR^A-，-C(O)NR^ANR^A-，-C(O)O-，-NR^AC(O)O-，-O-，-NR^AC(O)NR^A-，-NR^ANR^A-，-S-，-SO-，-SO₂-，-NR^A-，-SO₂NR^A-or-NR^ASO₂NR^A-substitution. R₄Each independently is R^AHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃。R^AEach independently is hydrogen, optionally substituted aryl or optionally substituted heteroaryl. Alternatively, R'₁And R₁Together with the nitrogen atom to which they are attached form a group consisting of 2-Z^BR₅A substituted heterocycloaliphatic radical, in which Z^BEach independently being a bond or an optionally substituted branched or straight chain C_1-6Aliphatic chain, wherein Z^BAt mostThe three carbon units are optionally and independently substituted by-C (O) -, -C (S) -, -C (O) NR^B-，-C(O)NR^BNR^B-，-C(O)O-，-NR^BC(O)O-，-O-，-NR^BC(O)NR^B-，-NR^BNR^B-，-S-，-SO-，-SO₂-，-NR^B-，-SO₂NR^B-or-NR^BSO₂NR^B-substitution. R₅Each independently is R^BHalogen, -OH, -CN, -NO₂，-NH₂Is O or-OCF₃。R^BEach independently is hydrogen, optionally substituted aryl or optionally substituted heteroaryl.

[0094]R₂is-Z^CR₆Wherein Z is^CEach independently being a bond or an optionally substituted branched or straight chain C_1-6Aliphatic chain, wherein Z^CUp to two carbon units of (A) are optionally and independently substituted by-C (O) -, -C (S) -, -C (O) NR^C-，-C(O)NR^CNR^C-，-C(O)O-，-NR^CC(O)O-，-O-，-NR^CC(O)NR^C-，-NR^CNR^C-，-S-，-SO-，-SO₂-，-NR^C-，-SO₂NR^C-or-NR^CSO₂NR^C-substitution. R₆Each independently is R^CHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃。R^CEach independently is hydrogen, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

[0095]R₃is-Z^DR₇Wherein Z is^DEach independently being a bond or an optionally substituted branched or straight chain C_1-6Aliphatic chain, wherein Z^DUp to two carbon units of (A) are optionally and independently substituted by-C (O) -, -C (S) -, -C (O) NR^D-，-C(O)NR^DNR^D-，-C(O)O-，-NR^DC(O)O-，-O-，-NR^DC(O)NR^D，-NR^DNR^D-，-S-，-SO-，-SO₂-，-NR^D-，-SO₂NR^D-or-NR^DSO₂NR^D-substitution. R₇Each independently is R^DHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃。R^DEach independently is hydrogen, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

[0096]1.R ₁ And R' ₁ Radical (I)

[0097]R′₁And R₁Each independently is-Z^AR₄Wherein Z is^AEach independently being a bond or an optionally substituted branched or straight chain C_1-12Aliphatic chain, wherein Z^AUp to three carbon units of (A) are optionally and independently substituted by-C (O) -, -C (S) -, -C (O) NR^A-，-C(O)NR^ANR^A-，-C(O)O-，-NR^AC(O)O-，-O-，-NR^AC(O)NR^A-，-NR^ANR^A-，-S-，-SO-，-SO₂-，-NR^A-，-SO₂NR^A-or-NR^ASO₂NR^A-substitution. R₄Each independently is R^AHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃。R^AEach independently is hydrogen, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cycloaliphatic. Alternatively, R'₁And R₁Together with the nitrogen atom to which they are attached form a group consisting of 2-Z^BR₅A substituted heterocycloaliphatic radical, in which Z^BEach independently being a bond or an optionally substituted branched or straight chain C_1-6Aliphatic chain, wherein Z^BUp to three carbon units of (A) are optionally and independently substituted by-C (O) -, -C (S) -, -C (O) NR^B，-C(O)NR^BNR^B-，-C(O)O-，-NR^BC(O)O-，-O-，-NR^BC(O)NR^B-，-NR^BNR^B-，-S-，-SO-，-SO₂-，-NR^B-，-SO₂NR^B-or-NR^BSO₂NR^B-substitution. R₅Each independently is R^BHalogen, -OH, -CN，-NO₂，-NH₂Is O or-OCF₃。R^BEach independently is hydrogen, optionally substituted aryl or optionally substituted heteroaryl.

[0098]In several embodiments, R'₁And R₁is-Z^AR₄Wherein Z is^AIndependently a bond or an optionally substituted branched or straight chain C_1-6Aliphatic chain, wherein Z^AUp to 2 carbon units of (A) are optionally and independently substituted by-C (O) -, -C (O) NR^A-C (O) O-, -O-or-NR^A-；R₄Is R^AHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃Replacement; and R is^AEach independently is hydrogen, optionally substituted aryl or optionally substituted heteroaryl.

[0099]In other embodiments, R'₁And R₁Each independently isor-Q_AWherein R is_10AAnd R_10BEach independently of the others being hydrogen, unsubstituted, linear or branched C_1-3Aliphatic radical, or R_10AAnd R_10BTogether form an oxo group; r_11AAnd R_11BEach independently hydrogen, optionally substituted straight or branched C_1-5Aliphatic radical, or R_11AAnd R_11BTogether with the carbon atom to which they are attached form an unsubstituted 3-5 membered cyclic aliphatic group; t is independently a bond, -O-, -NR-_10A-or-CH₂-; and Q_AIs hydrogen or aryl or heteroaryl, each of which is optionally substituted by 1 to 3 halogen, hydroxy, C_1-3Alkoxy or optionally substituted C_1-3And (3) aliphatic group substitution.

[00100]In several embodiments, R_10AAnd R_10BTogether form an oxo group; r_11AAnd R_11BOne is hydrogen and the remainder R_11AOr R_11BIs optionally substituted straight or branched C_1-5Aliphatic groups, or hydrogen; t is a bond, and T is a bond,-O-，-NR_10A-or-CH₂-; and Q_AIs phenyl, monocyclic heteroaryl or bicyclic heteroaryl, each of which is optionally substituted by 1-3 of halogen, -OH, -CN, C_1-3Aliphatic groups, or combinations thereof.

[00101]In several examples, R_11AAnd R_11BOne is hydrogen and the remainder R_11AOr R_11BIs optionally substituted straight or branched C_1-5Alkyl, optionally substituted straight or branched C_2-5Alkenyl or hydrogen. For example, R_11AAnd R_11BOne is hydrogen and the remainder R_11AOr R_11BIs optionally substituted straight or branched C_1-5An alkyl group. In several compounds, R_11AAnd R_11BOne is hydrogen and the remainder R_11AOr R_11BIs methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, each of which is optionally substituted by hydroxy.

[00102]In several examples, T is independently a bond, -O-, -NR-_10A-or-CH₂-, wherein-NR_10A-is-NH-.

[00103]In several additional examples, Q_AIs phenyl, bicyclic aryl, monocyclic heteroaryl or bicyclic heteroaryl, each of which is optionally substituted by 1-3 halogen, -OH, -CN, optionally substituted C_1-3Alkoxy, optionally substituted C_1-3Aliphatic groups, or combinations thereof. For example, Q_AIs substituted by 1-3 halogens, unsubstituted C_1-3Alkyl or unsubstituted C_1-3Alkoxy-substituted phenyl. In other embodiments, Q_AIs unsubstituted phenyl.

[00104]In several examples, Q_AIs an optionally substituted 9-10 membered bicyclic aryl. For example, Q_AIs naphthalene-yl or 2, 3-dihydro-1H-indene-yl, each of which is unsubstituted.

[00105]In alternative embodiments, Q_AIs a monocyclic or bicyclic heteroaryl, each of which is optionally substituted by 1-3 of halogen, -OH, -CN, or C_1-3Alkoxy, optionally substituted C_1-3Aliphatic groups, or combinations thereof. In several compounds of the invention, Q_AIs an optionally substituted 5-6 membered monocyclic heteroaryl. In other examples, Q_AIs an optionally substituted 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms selected from N, O and S. In other examples, Q_AIs C optionally substituted by 1-3 halogens, -OH, -CN, C_1-3Alkoxy, optionally substituted C_1-3An aliphatic group, or a combination thereof. For example, Q_AIs furan-yl, thiophene-yl, oxazole-yl, pyridine-yl, pyrimidine-yl, pyrazine-yl or 1, 3, 5-triazine-yl, each of which is optionally substituted by 1 to 3 halogen, -OH, -CN, optionally substituted C_1-3Alkoxy, optionally substituted C_1-3Aliphatic groups, or combinations thereof.

[00106]In other embodiments, Q_AIs an optionally substituted bicyclic heteroaryl. For example, Q_AIs an optionally substituted bicyclic heteroaryl having 1-3 heteroatoms selected from N, O and S. In other examples, Q_AIs an optionally substituted 9-10 membered heteroaryl having 1-3 heteroatoms selected from N, O and S. In other examples, Q_AIs indolizine-yl, indole-yl, isoindole-yl, 3H-indole-yl, indoline-yl, 1, 2, 3, 4-tetrahydroquinoline-yl, benzo [ d][1，3]Dioxol-yl, quinolin-yl, each of which is optionally substituted by 1-3 halogen, -OH, -CN, C_1-3Alkoxy, optionally substituted C_1-3Aliphatic groups, or combinations thereof.

[00107]In alternative embodiments, R'₁And R₁One is hydrogen and the remainder is R'₁Or R₁Selected from:

[00108]in several embodiments, R'₁And R₁Together with the nitrogen atom to which they are attached form a group consisting of 2-Z^BR₅A substituted heterocycloaliphatic radical, in which Z^BEach independently being a bond or an optionally substituted branched or straight chain C_1-6Aliphatic chain, wherein Z^BUp to three carbon units of (A) are optionally and independently substituted by-C (O) -, -C (S) -, -C (O) NR^B，-C(O)NR^BNR^B，-C(O)O-，-NR^BC(O)O-，-O-，-NR^BC(O)NR^B-，-NR^BNR^B-，-S-，-SO-，-SO₂-，-NR^B-，-SO₂NR^B-or-NR^BSO₂NR^B-substitution. R₅Each independently is R^BHalogen, -OH, -CN, -NO₂，-NH₂Is O or-OCF₃。R^BEach independently is hydrogen, optionally substituted aryl or optionally substituted heteroaryl.

[00109]In several embodiments, R'₁And R₁Together with the nitrogen atom to which they are attached form a 5-7 membered heterocycloaliphatic substituted with at least one of an acyl group, an oxo group, a heteroaryl group, or a combination thereof. For example, R'₁And R₁Together with the nitrogen atom to which they are attached form a 5-7 membered heterocycloaliphatic having 1-3 heteroatoms independently selected from N, O and S, which is at least one substituted with an acyl group, an oxo group, a heteroaryl group, or a combination thereof. In other examples, R'₁And R₁Together with the nitrogen atom to which they are attached form a piperidine-yl, piperazine-yl, or pyrrolidone-yl group, each of which is at least one substituted with an acyl group, an oxo group, a heteroaryl group, or a combination thereof.

[00110]In other examples, R'₁And R₁Together with the nitrogen atom to which they are attached form a heterocycloaliphatic group selected from:

[00111]2.R ₂ radical (I)

[00112]R₂is-Z^CR₆Wherein Z is^CEach independently being a bond or an optionally substituted branched or straight chain C_1-6Aliphatic chain, wherein Z^CUp to two carbon units of (A) are optionally and independently substituted by-C (O) -, -C (S) -, -C (O) NR^C-，-C(O)NR^CNR^C-，-C(O)O-，-NR^CC(O)O-，-O-，-NR^CC(O)NR^C-，-NR^CNR^C-，-S-，-SO-，-SO₂-，-NR^C-，-SO₂NR^C-or-NR^CSO₂NR^C-substitution. R₄Each independently is R^AHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃。R^CEach independently is hydrogen, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

[00113]In several embodiments, R₂Is optionally substituted C_1-4An aliphatic group. For example, R₂Is optionally substituted straight or branched C_1-4Alkyl, optionally substituted straight or branched C_2-4Alkenyl or optionally substituted straight or branched C_2-4Alkynyl.

[00114]In other embodiments, R₂Is hydrogen.

[00115]3.R ₃ Radical (I)

[00116]R₃is-Z^DR₇Wherein Z is^DEach independently being a bond or an optionally substituted branched or straight chain C_1-6Aliphatic chain, wherein Z^DUp to two carbon units of (A) are optionally and independently substituted by-C (O) -, -C (S) -, -C (O) NR^D-，-C(O)NR^DNR^D-，-C(O)O-，-NR^DC(O)O-，-O-，-NR^DC(O)NR^D-，-NR^DNR^D-，-S-，-SO-，-SO₂-，-NR^D-，-SO₂NR^D-or-NR^DSO₂NR^D-substitution. R₇Each independently is R^DHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃。R^DEach independently is hydrogen, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

[00117]In many embodiments, R₃is-Z^DR₇Wherein Z is^DEach independently a bond or an optionally substituted straight or branched C_1-6Aliphatic chain, wherein Z^DUp to one carbon unit of (A) is optionally and independently replaced by-O-or-NR^D-substitution; and R is₇Each independently is R^DHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃。R^DEach independently is hydrogen, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl.

[00118]In certain examples, R₃Is optionally substituted C_1-5An alkoxy group. For example, R₃Is methoxy, ethoxy, propoxy, butoxy or isopropoxy, each of which is unsubstituted. In other examples, R₃Is optionally substituted C_1-5Alkynyl-oxy. For example, R₃Is unsubstituted pent-2-yn-yloxy.

[00119]In several embodiments, R₃Is optionally substituted branched or straight chain C_1-6An aliphatic group. In other examples, R₃Is methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl or neopentyl, each of which is optionally substituted. In other examples, R₃Is methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl or neopentyl, each of which is not substitutedAnd (4) substitution.

[00120]In several examples, R₃Is an optionally substituted cycloaliphatic radical. In several compounds, R₃Is an optionally substituted monocyclic cycloaliphatic radical. For example, R₃Is an optionally substituted 3-7 membered monocyclic cycloaliphatic. In other compounds, R₃Is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is unsubstituted.

[00121]In certain embodiments, R₃Is an optionally substituted heterocycloaliphatic group. For example, R₃Is a monocyclic or bicyclic heterocyclic aliphatic group. In other embodiments, R₃Is an optionally substituted monocyclic heterocycloaliphatic having 1-3 heteroatoms selected from N, O and S. For example, R₃Is piperidin-yl, piperazin-yl, pyrrolidin-yl, tetrahydrofuran-yl, tetrahydropyran-yl, thiomorpholin-yl or imidazolidin-yl, each of which is optionally unsubstituted C_1-3And (3) aliphatic group substitution.

[00122]In alternative embodiments, R₃Is an optionally substituted aryl group. For example, R₃Is optionally substituted phenyl or optionally substituted naphthyl. In other examples, R₃Is phenyl optionally substituted with 1-3 halogens, alkoxy, aliphatic groups, or a combination thereof.

[00123]In several embodiments, R₃Is an optionally substituted aryloxy group. For example, R₃Is optionally substituted phenyloxy or optionally substituted naphthyloxy. In other examples, R₃Is a phenyloxy group optionally substituted with 1-3 halogens, alkoxy groups, aliphatic groups, or a combination thereof.

[00124]In several embodiments, R₃Is an optionally substituted heteroaryl group. For example, R₃Is an optionally substituted heteroaryl having 1-3 heteroatoms selected from N, O and S. In other examples, R₃Are monocyclic or bicyclic heteroaryl groups, each of which is optionally substituted with 1-3 halogens, alkoxy groups, aliphatic groups, or a combination thereof. In several examples, R₃Is furan-yl, thiophene-yl, pyridine-yl, or pyrazine-yl, each of which is optionally substituted with 1-3 halogens, alkoxy groups, aliphatic groups, or a combination thereof.

[00125]In other examples, R₃Is an optionally substituted amino group. For example, R₃Is an optionally substituted (aliphatic) amino, (cycloaliphatic) amino, (aryl) amino or amido group. In other examples, R₃Is unsubstituted amino (-NH)₂). In other examples, R₃Is optionally substituted C_1-5Straight or branched (aliphatic) amino. For example, R₃Is (methyl) amino, (butyl) amino or (tert-butyl) amino, each of which is unsubstituted.

[00126]In several examples, R₃Is a group selected from: -CH₃，-NH₂，

[00127] Another aspect of the invention provides another group of compounds and pharmaceutically acceptable compositions thereof for use as inhibitors of voltage-gated sodium channels, for the treatment of disorders in disease states in which sodium ion channel activation or hyperactivity is involved. These compounds have the formula Ia:

or a pharmaceutically acceptable salt thereof, wherein R₂And R₃As defined above for formula I.

[00128]A₁is-NR₂₁-, wherein R₂₁is-Z^ER₂₂Wherein Z is^EEach independently being a bond or an optionally substituted branched or straight chain C_1-6Aliphatic chain, wherein Z^EUp to three carbon units of (A) are optionally and independently substituted by-C (O) -, -C (O) NR^E-，-C(O)O-，-NR^EC (O) O-, -O-or-NR^E-substitution. R₂₂Each independently is R^EHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃。R^EEach independently is hydrogen, optionally substituted aryl or optionally substituted heteroaryl.

[00129]R₂₀is-Z^FR₃₀Wherein Z is^FEach independently being a bond or an optionally substituted branched or straight chain C_1-6Aliphatic chain, wherein Z^FUp to three carbon units of (A) are optionally and independently substituted by-C (O) -, -C (O) NR^F-，-C(O)O-，-NR^FC (O) O-, -O-or-NR^F-substitution. R₃₀Each independently is R^FHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃。R^FEach independently is hydrogen, optionally substituted aryl or optionally substituted heteroaryl.

[00130] Another aspect of the invention provides another group of compounds and pharmaceutically acceptable compositions thereof for use as inhibitors of voltage-gated sodium channels, for the treatment of disorders in which sodium ion channel activation or hyperactivity is implicated in the disease state. These compounds have the formula Ib:

or a pharmaceutically acceptable salt thereof, wherein R₂And R₃As defined above for formula I.

[00131]Ring A is a 5-6 membered heterocyclic aliphatic ring having at least one nitrogen atom, wherein Ring A is attached to a phenyl group of formula Ib at the nitrogen atom of Ring A, and Ring A is further attached to R at any chemically feasible position₂₃And R₂₄。

[00132]R₂₃Independently is-Z^GR₂₅Wherein Z is^GEach independently being a bond or an optionally substituted branched or straight chain C_1-3Aliphatic chain, wherein Z^GUp to two carbon units of (A) are optionally and independently substituted by-C (O) -, -C (O) NR^G-，-C(O)O-，-NR^GC (O) O-, -O-or-NR^G-substitution. R₂₅Each independently is R^GHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃。R^GEach independently is hydrogen or optionally substituted heteroaryl.

[00133]R₂₄Is hydrogen or oxo.

[00134] Another aspect of the invention provides another group of compounds and pharmaceutically acceptable compositions thereof for use as inhibitors of voltage-gated sodium channels, for the treatment of disorders in which sodium ion channel activation or hyperactivity is implicated in the disease state. These compounds have formula Ic:

or a pharmaceutically acceptable salt thereof, wherein R'₁And R₁As defined above for formula I.

[00135]R₂₆Is hydrogen, or straight or branched C_1-5An aliphatic group.

[00136] Another aspect of the invention provides another group of compounds and pharmaceutically acceptable compositions thereof for use as inhibitors of voltage-gated sodium channels, for the treatment of disorders in which sodium ion channel activation or hyperactivity is implicated in the disease state. These compounds have the formula Id:

or a pharmaceutically acceptable salt thereof, wherein R'₁And R₁As defined above for formula I.

[00137]R₂₇Is a cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl group, each of which is optionally substituted.

[00138] Typical compounds of the present invention include, but are not limited to, those exemplified in table 2 below.

[00139] Table 2: examples of the Compounds of the invention

[00140] Synthetic scheme

[00141] The compounds of the present invention may be prepared by methods well known in the art. Exemplary methods are illustrated in schemes 1-14 below.

[00142]In one method, the compounds of the invention are prepared as exemplified in scheme 1, wherein R₁is-C (O) R₄。

Scheme 1:

[00143]for scheme 1, aniline 1a is reacted with excess chlorosulfonyl chloride under well known conditions to give sulfonyl chloride 1 b. Reacting 1b with an excess of amine R₂NH₂Optionally in the presence of a tertiary amine to give the sulfonamide 1 c. Reacting 1c with an activated carboxyl derivative, such as a chloroformate, acid halide, isocyanate or anhydride in the presence of a tertiary base, such as triethylamine, to give compound I of the invention.

[00144] Alternatively, compounds I of the present invention may be prepared as exemplified in scheme 2.

Scheme 2:

[00145] For scheme 2, the sulfamide 1c is obtained by treating the aminosulfonamide 2a with an activated carboxyl derivative, such as a chloroformate, acid halide, isocyanate or anhydride, in the presence of a tertiary base, such as triethylamine. Acylation of 2c as described in scheme 1 gives the compounds of the invention.

[00146] Alternatively, compound I of the present invention may be prepared as exemplified in scheme 3.

Scheme 3:

[00147] For scheme 3, acylation of sulfonamide 3a by the methods described in schemes 1 and 2 affords compounds I of the invention.

[00148]In one method, compounds I of the invention may be prepared as exemplified in scheme 4, wherein R is₁is-C (O) R₄。

Scheme 4:

[00149] For scheme 4, the aminosulfonamide 4a is treated with an activated carboxyl derivative, such as a chloroformate, acid halide, isocyanate or anhydride in the presence of a tertiary base, such as triethylamine, to provide the sulfonamide 4 b. Acylation of 4b as described in scheme 1 affords the compounds of the invention.

[00150]Alternatively, compounds I of the invention may be prepared as exemplified in scheme 5, wherein R₁is-C (O) R₄。

Scheme 5:

[00151]alternatively, compounds I of the invention may be prepared as exemplified in scheme 6, wherein R₁is-C (O) R₄。

Scheme 6:

[00152]for scheme 6, treatment of an anilide 6a with chlorosulfonyl chloride gives a sulfonyl chloride 6b, which is reacted with an amine R₂NH₂Optionally in the presence of a tertiary base to give sulfonamide 6 c. Acylation of 6c as described above affords compound I of the invention.

[00153] Compounds Ia of the present invention may be prepared as exemplified in scheme 7.

Scheme 7:

[00154] For scheme 7, sulfonamide 7a is treated with an activated carboxyl derivative, such as a chloroformate, acid halide, isocyanate or anhydride in the presence of a tertiary base, such as triethylamine, to provide sulfonamide 7 b. Acylation of 7b as described in scheme 1 affords the compounds of the invention.

[00155] Alternatively, compounds Ia of the present invention may be prepared as exemplified in scheme 8.

Scheme 8:

[00156]for scheme 8, with activated R₂₀The carboxyl derivatives, such as chloroformates, acid halides, isocyanates or anhydrides, are treated with sulfonamide 8a in the presence of a tertiary base, such as triethylamine, to give compounds Ia according to the invention.

[00157] Alternatively, compounds Ia of the present invention may be prepared as exemplified in scheme 9.

Scheme 9:

[00158]for scheme 9, with activated R₂₀A carboxyl derivative, such as a chloroformate, acid halide, isocyanate or anhydride, acylates aniline 9a in the presence of a tertiary base, such as triethylamine, to give 9 b. 9b is reacted with chlorosulfonyl chloride under known conditions to give sulfonyl chloride 9 c. Reacting 9c with an excess of aniline R₂NH₂Optionally in the presence of a tertiary amine to give the sulfonamide 9 d. Reaction of 9d with an activated carboxyl derivative, such as a chloroformate, acid halide, isocyanate or anhydride in the presence of a tertiary base, such as triethylamine, affords compounds Ia of the present invention.

[00159]Compounds of the invention Ib, where R is as illustrated in scheme 10, can be prepared₂₃is-C (O) R₂₅。

Scheme 10:

[00160]for scheme 10, 10a is reacted with activated R₂₅Carboxyl derivatives such as chloroformates, acid halides, isocyanates or anhydrides are reacted in the presence of a tertiary base such as triethylamine to give 10b, which is reacted with chlorosulfonyl chloride to give sulfonyl chloride 10 c. Reacting 10c with an amine R₂NH₂Optionally in the presence of a tertiary amine to give the sulfonamide 10 d. Make it10d with an activated carboxyl derivative, such as a chloroformate, acid halide, isocyanate or anhydride in the presence of a tertiary base, such as triethylamine, to give the compound Ib according to the invention.

[00161] Alternatively, compounds Ib of the present invention may be prepared as exemplified in scheme 11.

Scheme 11:

[00162] For scheme 11, sulfonamide 11a is reacted with lactone 11b in the presence of trimethylaluminum to provide intermediate 11 c. Cyclization of 11c with di-tert-butyl azodicarboxylate and tributylphosphine gives compound Ib according to the invention.

[00163] Compounds Ic of the invention can be prepared as exemplified in scheme 12.

Scheme 12:

[00164] For scheme 12, sulfonamide 1c is reacted with an isocyanate in the presence of potassium carbonate in a polar solvent such as N-methylpyrrolidone to give compound Ic of the invention.

[00165] The compounds of the invention Id can be prepared as exemplified in scheme 13.

Scheme 13:

[00166] For scheme 13, sulfonamide 1c is reacted with an acid chloride in the presence of potassium carbonate in a polar solvent, such as N-methylpyrrolidone, to provide compound Id of the present invention.

[00167]Alternatively, compounds of the invention Id, where R is as exemplified in scheme 14, can be prepared₁Is an acyl group.

Scheme 14:

[00168]reacting 14a with activated R₁The carboxyl derivative, such as chloroformate, acid halide, isocyanate or anhydride, is reacted in the presence of a tertiary base, such as triethylamine, to give the compound Id of the present invention.

[00169] Formulation, administration and use

[00170] A. pharmaceutically acceptable compositions

[00171] As discussed above, the present invention provides compounds that are inhibitors of voltage-gated sodium ion channels, and thus the compounds of the present invention are useful in the treatment of diseases, disorders and conditions including, but not limited to, acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy or status epilepticus, neurodegenerative disorders, psychosis, such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome and incontinence. Thus, the invention provides in a further aspect pharmaceutically acceptable compositions, wherein these compositions comprise any of the compounds as described herein and optionally a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[00172] It will also be appreciated that certain compounds of the invention can be present in free form for use in therapy, or as appropriate pharmaceutically acceptable derivatives thereof. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative that upon administration to a patient in need thereof is capable of providing, directly or indirectly, a compound as described herein or a metabolite or residue thereof.

[00173] The term "pharmaceutically acceptable salt" as used herein, means salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio. By "pharmaceutically acceptable salt" is meant any non-toxic salt or ester salt of a compound of the present invention that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or an active metabolite or residue thereof that inhibits activity. The term "its inhibitory active metabolite or residue" as used herein means that its metabolite or residue is also an inhibitor of voltage-gated sodium or calcium channels.

[00174]Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts are described in detail, for example, in j.pharmaceutical Sciences, 1977, 66, 1-19 to s.m.berge et al, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, laurylsulfates,Ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoate, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valeric acid salts, and the like. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N⁺(C1-4 alkyl)₄And (3) salt. The invention also encompasses quaternization of any basic nitrogen-containing group of the compounds as disclosed herein. By means of such quaternization, products which are soluble or dispersible in water or oil can be obtained. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium salts, quaternary ammonium salts, and amine cation salts formed with counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[00175] As noted above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, as described herein, including any and all solvents, diluents, or other liquid vehicles, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, SixteenthEdition, e.w. martin (Mack Publishing co., Easton, Pa., 1980) disclose various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, e.g., exhibits any undesirable biological effect or interacts in a deleterious manner with any other ingredient of a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention. Some examples of materials capable of serving as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphates; glycine; sorbic acid or potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinylpyrrolidone; a polyacrylate; waxes; polyethylene-polyoxypropylene-block polymers; lanolin; sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc powder; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol; a phosphate buffer solution; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preserving and anti-oxidizing agents may also be present in the composition, according to the judgment of the person skilled in the art.

[00176] Use of compounds and pharmaceutically acceptable compositions

[00177] In another aspect, methods of treating or lessening the severity of the following diseases are provided: acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, systemic neuralgia, epilepsy or status epilepticus, neurodegenerative disorders, psychosis, such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritic pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, penetrating pain, post-operative pain or cancer pain, comprising administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable composition comprising the compound. In certain embodiments, there is provided a method of treating or reducing the severity of acute, chronic, neuropathic, or inflammatory pain comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable composition comprising a compound. In certain other embodiments, there is provided a method of treating or reducing the severity of radicular pain, sciatica, back pain, headache, or neck pain, comprising administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable composition comprising the compound. In other embodiments, methods of treating or lessening the severity of severe or intractable pain, acute pain, post-operative pain, back pain, tinnitus (tinnitis), or cancer pain are provided, the methods comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable composition comprising a compound.

[00178] In certain embodiments of the invention, an "effective amount" of a compound or pharmaceutically acceptable composition is an amount that treats or reduces the severity of one or more of the following diseases: acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, systemic neuralgia, epilepsy or status epilepticus, neurodegenerative disorders, psychosis, such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, penetrating pain, post-operative pain, tinnitus or cancer pain.

[00179] In accordance with the methods of the present invention, the compounds and compositions can be administered in any amount and by any route of administration effective to treat or reduce the severity of one or more of the following diseases: acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, systemic neuralgia, epilepsy or status epilepticus, neurodegenerative disorders, psychosis, such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, penetrating pain, post-operative pain, tinnitus or cancer pain. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, severity of infection, the particular drug, its mode of administration, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein means a physically separate pharmaceutical unit, as appropriate for the patient to be treated. It will be understood, however, that the total daily amount of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, the route of administration, and the rate of excretion of the particular compound employed; the duration of the treatment; drugs used in combination or concomitantly with the specific compound employed; and other factors well known in the medical arts. The term "patient" as used herein means an animal, preferably a mammal, and most preferably a human.

[00180] The pharmaceutically acceptable compositions of the present invention may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments or drops), buccally, as an oral or nasal spray, and the like, to humans and other animals, depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention may be administered orally or parenterally at a dosage level of from about 0.01mg/kg to about 50mg/kg, preferably from about 1mg/kg to about 25mg/kg, of the subject's body weight per day, one or more times a day, to achieve the desired therapeutic effect.

[00181] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[00182] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution, U.S. p. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. In addition, fatty acids, such as oleic acid, may be used in the preparation of injectables.

[00183] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[00184] In order to prolong the effect of the compounds of the invention, it is often desirable to delay the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved using liquid suspensions of crystalline or amorphous materials that are poorly water soluble. The rate of absorption of a compound depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming microencapsulated matrices of the compounds in biodegradable polymers such as polylactic-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

[00185] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active compound.

[00186] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and/or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) wetting agents, such as glycerol, d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retardants, such as paraffin, f) absorption promoters, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite, and i) lubricants, such as talc, mannitol, sodium metasilicate, and the like, Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[00187] Solid compositions of a similar type may also be employed as fillers in soft or hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be provided with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[00188] The active compound may also be in the form of a microcapsule containing one or more of the above excipients. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be provided with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, for example with sucrose, lactose or starch. Such dosage forms may also contain, under normal circumstances, other substances in addition to inert diluents, such as tableting lubricants and other tableting aids, for example magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[00189] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, emulsions, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives or buffers that may be required. Ophthalmic formulations, ear drops and eye drops are also encompassed within the scope of the present invention. In addition, the present invention encompasses the use of transdermal patches, which have the added advantage of controlling the delivery of compounds to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[00190] As generally described above, the compounds of the present invention are useful as inhibitors of voltage-gated sodium ion channels. In one embodiment, the compounds and compositions of the present invention are inhibitors of one or more of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 and thus, without wishing to be bound by any particular theory, are particularly useful for treating or lessening the severity of a disease, condition or disorder in which activation or hyperactivity of one or more of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 is implicated. When activation or hyperactivity of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 is implicated in a particular disease, condition or disorder, the disease, condition or disorder may also be referred to as a "nav 1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav 1.9-mediated disease, condition or disorder". Thus, in another aspect, the invention provides a method of treating or lessening the severity of a disease, condition or disorder in which activation or hyperactivity of one or more of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 is implicated in the disease state.

[00191] The activity of compounds useful as nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 inhibitors in the present invention may be determined according to the methods generally described in the examples herein or according to methods available to one of ordinary skill in the art.

[00192] In certain exemplary embodiments, the compounds of the present invention are useful as inhibitors of nav 1.3.

[00193]It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the invention may be used in combination therapy, that is, the compounds and pharmaceutically acceptable compositions may be administered simultaneously, prior to, or after one or more other desired therapeutic agents or procedures. The combination of a particular treatment (therapeutic agent or procedure) used in a combination regimen will take into account the compatibility of the desired therapeutic agent and/or procedure with the desired therapeutic effect to be achieved. It will also be appreciated that the therapies used may achieve the desired effect on the same condition (e.g., the compounds of the invention may be administered simultaneously with another drug used to treat the same condition), or they may achieve different effects (e.g., control of any adverse effects). As used herein, an "additional therapeutic agent" that is normally administered to treat or prevent a particular disease or condition is known to be "appropriate for the disease or condition being treated. For example, typical additional therapeutic agents include, but are not limited to: non-opioid analgesics (indoles, e.g., etodolac, indomethacin, sulindac, tolmetin, naphthylalkanones, e.g., nabumetone, oxicams, e.g., piroxicam, p-aminophenol derivatives, e.g., acetaminophen, propionic acids, e.g., fenoprofen, flurbiprofen, ketoprofen, ibuprofen, naproxen sodium, oxaprozin, salicylates, e.g., aspirin, choline magnesium trisalicylate, diflunisal, fenamates, e.g., meclofenoxate, mefenamic acid, and pyrazoles, e.g., phenylbutazonePine); or opioid (sedative) agonists (e.g., codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, dextropropoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine). In addition, non-drug analgesic means may be used in conjunction with the administration of one or more compounds of the present invention. For example, anesthesiology (intraspinal infusion, nerve block), neurosurgery (neurolysis of CNS pathways), neurostimulation (transcutaneous electrical nerve stimulation, dorsal column stimulation), physical therapy (physical therapy, orthotic devices, diathermy) or psychology (cognitive-hypnosis, biofeedback or behavioral approaches) approaches may also be used. Suitable additional therapeutic agents or means are generally described in the Merck Manual, Seventent Edition, Ed. Mark H. Beers and RobertBerkow, Merck Research Laboratories, 1999 and the U.S. FDA Websitewww.fda.govThe entire contents of which are incorporated herein by reference.

[00194] The amount of additional therapeutic agent in the compositions of the present invention will not exceed the amount normally administered in compositions containing the therapeutic agent as the only active ingredient. Preferably, the amount of additional therapeutic agent in the presently disclosed compositions will be from about 50% to 100% of the content in typical compositions containing the drug as the sole therapeutically active ingredient.

[00195] The compounds of the present invention or pharmaceutically acceptable compositions thereof may also be added to compositions for coating implantable medical devices such as prostheses, prosthetic valves, vascular prostheses, stents and catheters. Thus, the present invention, in another aspect, includes a composition for coating an implantable medical device comprising a compound of the present invention as generally described above and in the general classes and subclasses herein, and a carrier suitable for coating the implantable device. In another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as generally described above and in classes and subclasses herein, and a carrier suitable for coating the implantable device. General methods for preparing suitable coatings and coated implantable devices are described in U.S. Pat. Nos. 6,099,562, 5,886,026, and 5,304,121. The coating is typically a biocompatible polymeric material such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate copolymers and mixtures thereof. The coating may optionally be further covered with a thin layer of a suitable fluorosilicone, polysaccharide, polyethylene glycol, phospholipid, or combinations thereof to impart controlled release characteristics to the composition.

[00196] Another aspect of the invention relates to inhibiting one or more nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 activities in a biological sample or patient, comprising administering to the patient or contacting the biological sample with a compound of formula I or a composition comprising the compound. The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[00197] Inhibition of one or more of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 activities in a biological sample may be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, the study of sodium ion channels in biological and pathological phenomena; and comparative evaluation of novel sodium channel inhibitors.

[00198] Preparation and examples

[00199] Step 1: (S) -ethyl 2- (trifluoromethylsulfonyloxy) propionate

[00200]In N₂Triflic anhydride (24.2mL, 144mmol) was added slowly to a stirred (S) -ethyl 2-hydroxypropionate (15mL, 131mmol) at-30 ℃ under ambientH₂Cl₂(300 mL). After the reaction mixture was stirred for 10 minutes, 2, 6-lutidine (17.5mL, 151mmol) was added. The reaction was stirred at room temperature for 16 h. The reaction mixture was filtered through a small pad of silica and washed with ethyl acetate and hexane (1: 4, 400 mL). The solution was concentrated using a bath temperature of 20 ℃ and vacuum greater than 50mm Hg to give the desired triflate as a red oil (32.7 g).

[00201] Step 2: 2- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) -3-methylpropanoic acid (R) -ethyl ester

[00202]In N₂Neutralization (S) -ethyl 2- (trifluoromethylsulfonyloxy) propionate (10.9g, 44mmol) was slowly added to a stirred solution of 6-fluoro-1, 2, 3, 4-tetrahydroquinoline (6.1g, 40mmol), 2, 6-lutidine (5.3mL, 46mmol) and 1, 2-dichloroethane (100mL) at 25 ℃. The reaction was heated at 70 ℃ for 19 h. By H₂O washing the mixture and CH₂Cl₂The extraction was performed twice. With MgSO₄The organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography using 0-20% EtOAc in hexanes to give the desired ester as a yellow oil (12.9 g). LC/MS (10% -99% CH)₃CN(0.035％ TFA)/H₂O(0.05％TFA)，m/z：M+1 obs＝251.8；t_R＝3.68min。

[00203] And step 3: (R) -2- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) -3-methylpropanoic acid

[00204]2.0M aqueous KOH (15.9mL, 31.8mmol) was added to a stirred solution of (R) -2- (6-fluoro-3, 4-dihydroquine at 0 deg.CSolution of lin-1 (2H) -yl) -3-methylpropionate (2.0g, 7.96mmol) in MeOH (16 mL). The reaction was warmed to RT (RT) and kept stirring overnight. Due to the instability of the final product as a solid, the solution containing (R) -2- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) -3-methylbutyric acid was used in the next step without further work-up. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA)，m/z：M+1 obs＝223.24；t_R＝2.92min。

[00205] And 4, step 4: (R) -2- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) -1- (4-phenylpiperazin-1-yl) propan-1-one

[00206](R) -2- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) propionic acid (7.9mmol), 1-phenylpiperazine (1.2mL, 7.9mmol), HATU (3.0g, 7.9mmol), NaHCO₃(660mg, 7.9mmol) and CH₂Cl₂(10 mL): DMF (10ml) was stirred at room temperature for 19 h. The solution was poured into an ice-water mixture (100ml) followed by CH₂Cl₂(3X 75 mL). With MgSO₄The organic layer was dried and evaporated in vacuo. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel chromatography using 20-50% ethyl acetate in hexane to give (R) -2- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) -1- (4-phenylpiperazin-1-yl) propan-1-one (1.96g) as a white solid. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝369.47；t_R＝3.36min。

[00207] And 5: (R) -4- (4- (2- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) propionyl) piperazin-1-yl) benzene-1-sulfonyl chloride

[00208]After adding chlorosulfonic acid (5.5ml, 3eq) to N₂After cooling to 0 deg.C, (R) -2- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) -1- (4-phenylpiperazin-1-yl) propan-1-one (1g, 2.72mmol) was added and then warmed to room temperature. The solution was poured into an ice-water mixture (250ml) followed by CH₂Cl₂(3 × 100 mL). With MgSO₄The organic layer was dried and evaporated in vacuo. The crude product was used in the next step without further purification. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％TFA))，m/z：M+1 obs＝466.3；t_R＝3.49min。

[00209] Step 6: (R) -4- (4- (2- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) propionyl) piperazin-1-yl) benzenesulfonamide

[00210]Ammonium hydroxide (28-30% solution, 7.5mL) was added dropwise to a solution of (R) -4- (4- (2- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) propionyl) piperazin-1-yl) benzene-1-sulfonyl chloride (375mg, 0.56mmol) in acetonitrile (5mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 4 h. The solution was cooled to 0 ℃ and 1.0M aqueous HCl was added dropwise. By CH₂Cl₂The reaction mixture was extracted (3x50 mL). With MgSO₄The combined organic phases were dried. After evaporation of the solvent under reduced pressure, chromatography on silica gel using 2-10% in CH₂Cl₂The residue was purified with methanol to give (R) -4- (4- (2- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) propionyl) piperazin-1-yl) benzenesulfonamide as a colorless oil (94 mg). LC/MS (10% -99% CH)₃CN(0.035％ TFA)/H₂O(0.05％TFA))，m/z：M+1 obs＝447.1；t_R＝2.68min。

[00211] General procedure 1:

[00212]a solution of sulfonamide (0.07mmol) and triethylamine (2.0-3.0 equiv., 0.18mmol) in acetonitrile (0.15M-0.25M) was dissolved in N₂Stirring in a gas environment. To this was added the appropriate chloroformate (1.5 equiv., 0.11mmol) and the mixture was stirred at room temperature for 19 h. The mixture was concentrated and purified by reverse phase HPLC using 10% -99% CH₃CN(0.035％TFA)/H₂The residue was purified O (0.05% TFA) to give the desired product.

[00213]Example 1: 4- (4- (2- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) propionyl) piperazine Oxazin-1-yl) phenylsulfonylcarbamic acid (R) -methyl ester

[00214]Synthesized according to general procedure 1. A reaction was established using 0.07mmol of (R) -4- (4- (2- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) propionyl) piperazin-1-yl) benzenesulfonamide, 0.18mmol of triethylamine, 0.11mmol of methyl chloroformate and 0.75mL of acetonitrile. LC/MS (10% -99% CH)₃CN(0.035％ TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝505.3；t_R＝2.28min。

[00215]Example 2: 4- (4- (2- (6-fluoro-3, 4-dihydroquinolin-1 (2H) -yl) propionyl) piperazine Oxazin-1-yl) phenylsulfonylcarbamic acid (R) -ethyl ester

[00216]Synthesized according to general procedure 1. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝519.3；t_R＝2.93min。

[00217]Example 3: 4- (3- (6-chloro-3, 4-dihydroquinolin-1 (2H) -yl) -2-oxopyrrole Alk-1-yl) phenylsulfonylcarbamic acid (S) -methyl ester

[00218] Step 1: (S) -3- (6-chloro-3, 4-dihydroquinolin-1 (2H) -yl) dihydrofuran-2 (3H) -one

[00219]In N₂N, N-diisopropylethylamine (1.74mL, 10mmol) was added dropwise to a solution of (R) - (+) - α -hydroxy- γ -butyrolactone (0.39mL, 5mmol) in dichloromethane (8mL) at-20 ℃ under a gaseous atmosphere. Then trifluoromethanesulfonic anhydride (0.88mL, 5.25mmol) was added dropwise by maintaining the internal temperature of the reaction mixture < -20 ℃. Upon completion of the addition, the mixture was stirred at-20 ℃ for 1 hour. 6-Cl tetrahydroquinoline (1.26g, 7.5mmol) was then added dropwise at-20 ℃. The reaction was allowed to warm to RT over 30 minutes and stirring continued to room temperature for 16 h. The reaction mixture was diluted with 200mL ethyl acetate and washed with saturated sodium bicarbonate (3 ×). The organic layer was washed with saturated aqueous NaCl (2 ×). The solution was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using 10-30% ethyl acetate in hexane to give (S) -3- (6-chloro-3, 4-dihydroquinolin-1 (2H) -yl) dihydrofuran-2 (3H) -one (1.14g) as a white solid. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％TFA))，m/z：M+1 obs＝252.2；t_R＝3.20min。

[00220] Step 2: 4- (2- (6-chloro-3, 4-dihydroquinolin-1 (2H) -yl) -4-hydroxybutyrylamino) phenylsulfonylcarbamic acid (S) -methyl ester

[00221]Within 20 minutesIn N₂To a stirred mixture of methyl 4-aminophenylsulfonylcarbamate (111mg, 0.48mmol) and CH at 0 deg.C in ambient₂Cl₂To the suspension (1mL) was added dropwise trimethylaluminum (0.24mL, 0.48 mmol). The solution was stirred at ambient temperature for 30 minutes. The solution was cooled to 0 ℃ and then added dropwise to CH over 30 minutes₂Cl₂(S) -3- (6-chloro-3, 4-dihydroquinolin-1 (2H) -yl) dihydrofuran-2 (3H) -one (100mg, 0.40mmol) in (1.0 mL). The solution was stirred at ambient temperature for 19 h. The solution was cooled to 0 ℃ and quenched by slow addition of 1.0M aqueous HCl. The organic portion was washed with 1.0N aqueous HCl (2X1.0mL) and evaporated to dryness under reduced pressure. The crude (R) -methyl 4- (2- (6-chloro-3, 4-dihydroquinolin-1 (2H) -yl) -4-hydroxybutyrylamino) phenylsulfonylcarbamate was used in the next step without purification.

[00222] And step 3: 4- (3- (6-chloro-3, 4-dihydroquinolin-1 (2H) -yl) -2-oxopyrrolidin-1-yl) phenylsulfonylcarbamic acid (S) -methyl ester

[00223]Within 5 minutes of N₂To a stirred solution of di-tert-butyl-azodicarboxylate (230mg, 1.0mmol) and THF (2.0mL) at neutralization 0 deg.C was added dropwise tributylphosphine (0.25mL, 1.0 mmol). The colorless solution was stirred at 0 ℃ for 30 minutes. A solution of (R) -methyl 4- (2- (6-chloro-3, 4-dihydroquinolin-1 (2H) -yl) -4-hydroxybutyrylamino) phenylsulfonylcarbamate (240mg, 0.498mmol) in THF (1mL) was added dropwise over 5 minutes. The solution was stirred at ambient temperature for 2h, concentrated and purified by reverse phase HPLC using 10% -99% CH₃CN(0.035％ TFA)/H₂Purification of O (0.05% TFA) afforded methyl 4- (3- (3, 4-dichlorobenzyl) ureido) phenylsulfonylcarbamate. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％TFA))，m/z：M+1 obs＝464.3；t_R＝3.48min。

[00224]Example 5: 4- (3- (3, 4-dichlorobenzyl) ureido) phenylsulfonylcarbamic acid methyl ester Esters

[00225]A solution of methyl 4-aminophenylsulfonylcarbamate (50mg, 0.2mmol), N, N-diisopropylethylamine (35L, 0.2mmol), 3, 4-dichlorobenzyl isocyanate (30L, 0.2mmol) in acetonitrile was dissolved in N₂Stirring for 19h in a gas environment. The mixture was concentrated and purified by reverse phase HPLC using 10% -99% CH₃CN(0.035％ TFA)/H₂The residue was purified O (0.05% TFA) to give methyl 4- (3- (3, 4-dichlorobenzyl) ureido) phenylsulfonylcarbamate. LC/MS (10% -99% CH)₃CN(0.035％ TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝431.01；t_R＝2.9min。

[00226] General procedure 2:

[00227]sulfonamide (1 equivalent, 0.11mmol) in CH₂Cl₂(0.15-0.25M) to a solution of the appropriate carboxylic acid (1.0-3.0 equiv., 0.12mmol), DIEA (1.0-3.0 equiv., 0.12mmol) and HATU (1.0-3.0 equiv., 0.12mmol) in CH₂Cl₂(0.15-0.25M). The mixture was stirred at rt for 19 h. The mixture was concentrated and subjected to reverse phase HPLC using 10% -99% CH₃CN(0.035％ TFA)/H₂The residue was purified O (0.05% TFA).

[00228]Example 6: 4- (2-4-fluoro-1H-indol-1-yl) propionylamino) phenylsulphonylamino (R) -methyl Ethanoate

[00229]Prepared using general procedure 2.¹H NMR(400MHz，DMSO-d6)δ7.84(q，J＝9.3Hz，4H)，7.62(d，J＝3.4Hz，1H)，7.36(d，J＝8.3Hz，1H)，7.16-7.11(m，1H)，6.86-6.82(m，1H)，6.57(d，J＝3.2Hz，1H)，5.42(q，J＝7.1Hz，1H)，3.55(s，3H)，1.81(d，J＝7.1Hz，3H)。LC/MS(10％-99％ CH₃CN(0.035％ TFA)/H₂O(0.05％ TFA))，m/z：M+1obs＝420.1：t_R＝3.15min。

[00230]Example 7: 4- (2- (6-chloro-3, 4-dihydroquinolin-1 (2H) -yl) propionylamino) benzene Alkylsulfonylcarbamic acid (R) -methyl ester

[00231]Prepared using general procedure 2. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝452.3；t_R＝3.34min。

[00232]Example 8: 4- (2- (6- (trifluoromethyl) -1H-indol-1-yl) propionylamino) phenyl Sulfonylcarbamic acid (R) -methyl ester

[00233]Prepared using general procedure 2. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝470.2；t_R＝3.2min。

[00234]Example 9: 4- (2- (4-fluoro-1H-indol-1-yl) -4-methylpentanoylamino) phenyl Sulfonylcarbamic acid (R) -methyl ester

[00235]Prepared using general procedure 2. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝462.2；t_R＝3.65min。

[00236]Example 10: 4- (2, 3-Dichlorophenoxy) propionylamino) phenylsulfonylaminomethyl Acid (R) -methyl ester

[00237]Prepared using general procedure 2. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝447.2；t_R＝3.36min。

[00238] Step 1: (2R) -2- (4-fluoroindol-1-yl) propionic acid

[00239] To a cooled (0-5 ℃) solution of 4-fluoroindole (44.2g, 327mmol) in dry DMF (400mL) was added sodium hydride (55-65% dispersion in mineral oil, 36g, 817mmol) stepwise. The resulting suspension was stirred at 0-5 ℃ for 20 minutes. (2S) - (-) -2-bromopropionic acid (31.8mL, 343mmol) was added dropwise. During the addition, the temperature was kept below 10 ℃ by cooling with an ice bath. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The mixture was poured into water (1300mL) and the aqueous solution was washed with heptane (400mL) and EtOAc (2X 400 mL). The aqueous layer was acidified with concentrated aqueous HCl (85mL, pH < 1) and extracted with EtOAc (2X 400 mL). The combined organic layers were washed with 1N aqueous HCl (2X 300mL) and saturated aqueous NaCl (300 mL). The solution was dried over sodium sulfate, filtered and evaporated to dryness to give a yellow oil (67.6 g). The oil (67.6g, 323mmol) was dissolved in 200mL n-butyl acetate and (S) -L- (-) - α -methylbenzylamine (41.1mL, 323mmol) was added to the warm (50 ℃ C.) solution. The mixture was left to crystallize in a few days. The solid formed was collected by filtration and washed with butyl acetate and heptane (2 ×) (68.7 g). This material was recrystallized twice from 500mL of water/15% ethanol (first recrystallization: 95% ee, second recrystallization: 97.5% ee). The material was dissolved in EtOAc (300mL) and washed with 1N aqueous HCl (2 × 200mL) and saturated aqueous NaCl (200mL), dried over sodium sulfate, filtered and evaporated to dryness to give (2R) -2- (4-fluoro-indol-1-yl) -propionic acid (18.7g) as a pale green oil.

[00240]Example 11: 4- (2- (4-fluoro-1H-indol-1-yl) propionylamino) phenylsulfonyl- (R) -Ethyl carbamate

[00241]Prepared using general procedure 2. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝434.2；t_R＝3.13min。

[00242]Example 12: (R) -N- (4-carbamoylsulfamoyl) phenyl- (2- (4-fluoro-1H) Indol-1-yl) propionamide

[00243]Prepared using general procedure 2. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝405.5；t_R＝2.65min。

[00244](R) -2- (4-fluoro-1H-indol-1-yl) -N- (4-sulfamoylphenyl) propanamide

[00245]2R-2- (4-Fluoroindol-1-yl) propionic acid (1.2g, 5.8mmol), sulfanilamide (2g, 11.6mmol), BOP-reagent (2.6g, 5.8mmol), triethylamine (2.4mL, 17.4mmol) in DMF and CH₂Cl₂(10mL) of the solution in N₂Stirring for 19h in a gas environment and at room temperature. After evaporation of the solvent under reduced pressure, chromatography on silica gel using 3% in CH₂Cl₂The residue was purified with methanol to give (R) -2- (4-fluoro-1H-indol-1-yl) -N- (4-sulfamoylphenyl) propionamide as a white solid. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％TFA))，m/z：M+1 obs＝362.4；t_R＝2.78min.¹H NMR(400MHz，DMSO-d6)δ7.50(d，J＝7.0Hz，2H)，7.42(d，J＝3.4Hz，1H)，7.08(t，J＝4.0Hz，2H)，6.85-6.79(m，1H)，6.57(d，J＝8.8Hz，2H)，6.51(d，J＝3.3Hz，1H)，6.19(s，2H)，5.17(q，J＝7.1Hz，1H)，1.62(d，J＝7.1Hz，3H)。

[00246] General procedure 3

[00247]The appropriate acid chloride or isocyanate (1 eq, 0.08mmol) was added to a stirred mixture of (R) -2- (4-fluoro-1H-indol-1-yl) -N- (4-sulfamoylphenyl) propionamide (1 eq, 0.08mmol), potassium carbonate (3 eq, 0.24mmol) and NMP (0.15-0.25M, 300. mu.L). The mixture was stirred to completion. The mixture was concentrated and subjected to reverse phase HPLC using 10% -99% CH₃CN(0.035％TFA)/H₂The residue was purified O (0.05% TFA) to give the desired product.

[00248]Example 13: (R) -N- (4- (2- (4-fluoro-1H indol-1-yl) propionylamino) phenyl Sulfonyl) -3, 3-dimethylbutanamide

[00249]Prepared using general procedure 3. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝446.1；t_R＝3.46min。

[00250]Example 14: (R) -N- (4- (2- (4-fluoro-1H indol-1-yl) propionylamino) phenyl Sulfonyl) -2, 5-dimethylfuran-3-carboxamide

[00251]Prepared using general procedure 3. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％TFA))，m/z：M+1 obs＝484.1；t_R＝3.58min。

[00252]Example 15: (R) -N- (4- (2- (4-fluoro-1H indol-1-yl) propionylamino) phenyl Sulfonyl) cyclopentanecarboxamide

[00253]Prepared using general procedure 3. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝458.5；t_R＝3.48min。

[00254]Example 16: (R) -4-fluorophenyl- (4- (2- (4-fluoro-1H indol-1-yl) propionylamino Yl) phenylsulfonylcarbamate

[00255]Prepared using general procedure 3. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝500.3；t_R＝4.48min。

[00256]Example 17: (R) -N- (4- (2- (4-fluoro-1H indol-1-yl) propionylamino) phenyl Sulfonyl) benzamides

[00257]Prepared using general procedure 3. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝466.3；t_R＝3.43min。

[00258]Example 18: (R) -2- (4-fluoro-1H indol-1-yl) -N- (4- (N- (methylamino) Formyl) sulfamoyl) phenyl) propionamide

[00259]Prepared using general procedure 3. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝419.3；t_R＝2.92min。

[00260]Example 19: (R) -N- (4- (N- (butylcarbamoyl) sulfamoyl) benzene 2- (4-fluoro-1H indol-1-yl) propanamide

[00261]Prepared using general procedure 3. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝461.3；t_R＝3.38min。

[00262]Example 20: (R) -N- (4- (N- (butylcarbamoyl) sulfamoyl) benzene 2- (4-fluoro-1H indol-1-yl) propanamide

[00263]Prepared using general procedure 3. LC/MS (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))，m/z：M+1 obs＝488.1；t_R＝2.48min。

[00264] The examples and schemes and well known synthetic methods may be used by those skilled in the chemical arts to synthesize the compounds of the present invention, including the compounds in table 3 below.

[00265] Table 3: physical data of typical Compounds

Number of Compounds	LC/MSM+1	LC/RTmin
			1	436.3	3.06
2	390.2	2.69
			3	417.3	2.91
4	421.1	2.7
			5	494.5	2.2
6	452.3	3.34
			7	418.3	2.97
8	424.3	3.13
			9	335.1	2.48
10	480.3	2.04
			11	458.5	3.48
12	402.3	3.17
			13	460.5	3.53
14	402.3	3.14
			15	392.1	3.09
16	436.2	3.33
			17	420.1	2.96
18	410.3	3.16
			19	413.3	2.94
20	436.2	3.33
			21	430.5	3.21
22	466	3.64

Number of Compounds	LC/MSM+1	LC/RTmin
			23	462.2	3.65
24	480.3	3.83
			25	470.2	3.19
26	422.3	3.23
			27	406.3	3.07
28	422.1	2.9
			29	500.3	4.48
30	431.01	2.9
			31	419.3	2.92
32	490.3	1.72
			33	436.3	3.31
34	420.1	3.06
			35	427.2	3.39
36	420	2.96
			37	461.3	3.2
38	419.3	2.86
			39	456.3	3.29
40	402.5	2.9
			41	519.3	2.93
42	444.4	3.18
			43	434.2	3.13
44	413.3	2.95

Number of Compounds	LC/MSM+1	LC/RTmin
			45	215	0.6
46	400.3	3.16
			47	418	3.31
48	393.3	2.68
			49	560.3	3.4
50	521.3	2.95
			51	436.1	3.05
52	535.3	3.05
			53	464.3	3.48
54	461.3	3.41
			55	436	3.34
56	349.3	2.55
			57	488.1	2.48
58	447.2	3.36
			59	420.2	3.2
60	484.5	2.68
			61	505.3	2.8
62	452	3.43
			63	405.5	2.65
64	433.3	3.09
			65	447.2	3.35
66	484.5	3.58

Number of Compounds	LC/MSM+1	LC/RTmin
			67	436	3.35
68	420.2	2.99
			69	406.3	3.08
70	422.3	2.98
			71	482.3	2.98
72	446.3	3.46
			73	468.2	3.11
74	466.3	3.43
			75	452.2	3.55
76	472.3	3.48
			77	462.3	3.71
78	427.2	3.38
			79	461.3	3
80	436.2	3.12
			81	426.3	3.32
82	404.3	3.07
			83	436.6	3.33
84	418	3.32
			85	434.2	3.08
86	494.4	4.01
			87	470.2	3.2
88	365.1	2.54

[00266] Assays for detecting and determining inhibitory effects

[00267] Assays for detecting and measuring NaV inhibitory properties of compounds

[00268]1.Optical method for determining the inhibitory properties of compound NaV：

[00269]The compounds of the invention are useful as antagonists of voltage-gated sodium ion channels. Antagonist properties of test compounds were evaluated as follows. Cells expressing the relevant NaV were placed in microtiter plates. After the incubation period, the cells are stained with a fluorescent dye sensitive to transmembrane potential. Test compounds were added to the microtiter plate. Cells are stimulated by chemical or electrical means to excite NaV-dependent membrane potential changes in unblocked channels, detected and measured with transmembrane potential-sensitive dyes. AntagonismThe agent is detected as a decreased membrane potential in response to the stimulus. Optical Membrane potential assays employ voltage-sensitive FRET sensors, as described by Gonzalez and Tsien (see, Gonzalez, J.E., and R.Y.Tsien (1995) "catalysts by fluorescence spectroscopy transfer in single cells" Biophys J69 (4): 1272-80 and Gonzalez, J.E., and R.Y.Tsien (1997) "Improved indicators of cell fluorescence spectroscopy" Chem Biol 4 (4): 269-77), together with apparatus for measuring fluorescence changes, such as a voltage/ion probe readerIn combination, (see, Gonzalez, J.E., K.Oads et al (1999) "Cell-based assays and instrumentation for screening-channel targets" Drug discovery Today 4 (9): 431-.

[00270]2.Using chemical stimulation Optical membrane potential measurement method

[00271] Cell processing and dye Loading

[00272] 24 hours before the assay with VIPR, endogenous voltage-gated CHO cells expressing nav1.2 type were seeded in 96-well polylysine-coated culture plates at 60,000 cells per well. Other subtypes were performed in a similar manner in cell lines expressing the relevant NaV.

[00273]1.) on the day of assay, the medium was aspirated and the cells were washed twice with 225 μ L of bath solution #2(BS # 2).

[00274]2.) a 15 μ M solution of CC2-DMPE was prepared as follows: a5 mM coumarin stock solution was mixed 1: 1 with 10% Pluronic 127 and the mixture was dissolved in an appropriate volume of BS # 2.

[00275]3.) after removing the bath solution from the 96-well culture plates, the cells were loaded with 80 μ LCC2-DMPE solution. The plates were incubated in the dark for 30 minutes at room temperature.

[00276]4.) while the cells were stained with coumarin, 15 μ L of Oxonol (dye) in BS #2 was prepared. Except that DiSBAC₂(3) In addition, the solution should also contain 0.75mM ABSC1 and 30. mu.L veratridine (prepared from 10mM EtOH stock, Sigma # V-5754).

[00277]5.)30 min later, CC2-DMPE was removed and cells were washed twice with 225. mu.L BS # 2. As above, the residual volume should be 40. mu.L.

[00278]6.) after removing the bath solution, cells were loaded with 80 μ L of DiSBAC2(3) solution, then test compound in DMSO solution was added to each well from the drug-added plate to reach the desired test concentration, mixed well. The volume in the wells should be about 121 μ L. The cells were then incubated for 20-30 minutes.

[00279]7.) Once the incubation is complete, the sodium back-addition (addback) protocol can be usedThe cells were assayed as above. 120 μ L of bath solution #1 was added to stimulate NaV-dependent depolarization. 200 μ L of tetracaine was used as an antagonist positive control for NaV channel blockade.

[00280]3.Analysis of data：

[00281] The data were analyzed and presented as normalized background-subtracted emission intensity ratios measured in the 460nm and 580nm channels. Background intensity was then subtracted from each assay channel. The background intensity is obtained by measuring the emission intensity of the same treated test well without the presence of cells at the same time period and by expressing the response as a function of time using the ratio obtained by the following formula:

[00282]by calculating initially (R)_i) And finally (R)_f) And (4) processing the data further. They are the average ratio during part or all of the pre-stimulation period and the sample point period during stimulation. The response to the stimulus R-R is then calculated_f/R_i. To Na⁺For the analysis time window, the baseline was 2-7 seconds, and the final response was sampled at 15-24 seconds.

[00283] Control responses were obtained by performing the assay in the presence of a compound with the desired properties (positive control), such as tetracaine, and in the absence of a pharmacological agent (negative control). Responses to negative (N) and positive (P) controls were calculated as above. Compound antagonistic activity a is defined as:

wherein R is the response ratio of the test compound

[00284] Solution [ mM ]:

[00285]bath solution # 1: NaCl 160, KCl 4.5, CaCl₂ 2，MgCl₂1, HEPES10, pH7.4, NaOH

[00286]Bath solution #2 TMA-Cl 160, CaCl₂ 0.1，MgCl₂HEPES10, pH7.4, KOH (final K concentration 5mM)

[00287] CC 2-DMPE: 5mM DMSO stock solutions were prepared and stored at-20 ℃.

[00288]DiSBAC₂(3): 12mM DMSO stock was prepared and stored at-20 ℃.

[00289] ABSC 1: 200mM distilled water stock was prepared and stored at room temperature.

[00290] Cell culture

[00291]CHO cells were grown in DMEM (Dulbecco's modified Eagle Medium; GibcoBRL #10569-010) supplemented with 10% FBS (fetal bovine serum, eligible; GibcoBRL #16140-071) and 1% Pen-Strep (penicillin-streptomycin; GibcoBRL # 15140-122). Cells were grown in vented flasks with caps at 90% humidity and 10% CO₂Medium growth to 100% confluence. They are usually cleaved by trypsin at 1: 10 or 1: 20, depending on the planned need, and are grown for 2-3 days before the next cleavage.

[00292]4.Using electrical stimulation Optical membrane potential measurement method

[00293] The following is an example of how to measure NaV1.3 inhibitory activity using optical Membrane potentiometry # 2. Other subtypes were performed in a similar manner in cell lines expressing the relevant NaV.

[00294] HEK293 cells stably expressing nav1.3 were plated in 96-well microtiter plates. After an appropriate incubation period, cells were stained with the voltage-sensitive dye CC2-DMPE/DiSBAC2(3) as follows.

[00295] Reagent:

100mg/mL Pluronic F-127 (Pluronic 127) (Sigma # P2443) in dry DMSO

10mM DiSBAC₂(3) (Aurora #00-100-010), in dry DMSO

10mM CC2-DMPE (Aurora #00-100-

200mM ABSC1 at H₂In O

Hank's balanced salt solution (Hyclone # SH30268.02) supplemented with 10mM HEPES (G ibco #15630-

[00296] Loading scheme:

[00297]2X CC2-DMPE ═ 20 μ M CC 2-DMPE: 10mM CC2-DMPE was vortexed with an equal volume of 10% pluronic, then vortexed in the required amount of HBSS containing 10mM HEPES. Each cell culture plate will require 5ml of 2X CC 2-DMPE. To the well containing the washed cells, 50. mu.L of 2 XC 2-DMPE was added, resulting in a final staining concentration of 10. mu.M. To room temperature, cells were stained in the dark for 30 minutes.

[00298]2X DISBAC₂(3) With ABSC1 ═ 6. mu.M DISBAC₂(3) And 1mM ABSC 1: add the required amount of 10mM DI SBAC to a 50ml conical tube₂(3) For each ml of solution to be prepared, 1 μ L of 10% pluronic was mixed and vortexed together. HBSS/HEPES was then added to make a 2X solution. Finally ABSC1 was added.

[00299]2X DiSBAC₂(3) The solution can be used in solvated compound culture plates. Note that compound plates were made at 2X drug concentration. The stained plate was washed again with a residual volume of 50. mu.L. Add 50. mu.L/well of 2 XSBAC₂(3) w/ABSC 1. To room temperature, stain in the dark for 30 minutes.

[00300] The electrical stimulation apparatus and method used is as described in PCT/US 01/21652 ion channel assay, incorporated herein by reference. The instrument contains a microtiter plate processor, an optical system for exciting the coumarin dye while recording coumarin and Oxonol emissions, a waveform generator, a current or voltage controlled amplifier, and a means for inserting electrodes in the wells. Under the control of the integrated computer, the instrument performs a user-programmed electrical stimulation protocol on cells within the wells of the microtiter plate.

[00301] Reagent

[00302] Assay buffer #1

140mM NaCl，4.5mM KCl，2mM CaCl₂，1mM MgCl₂，10mM HEPES，

10mM glucose, pH 7.40, 330mOsm

Pluronic stock (1000 ×): 100mg/mL pluronic 127 in dry DMSO

Oxonol stock (3333X): 10mM DiSBAC₂(3) In dry DMSO

Coumarin stock (1000X): 10mM CC2-DMPE in dry DMSO

ABSC1 stock (400X): 200mM ABSC1 in water

[00303]Assay protocol

[00304] An electrode is inserted or used into each well to be measured.

[00305] The stimulus pulse was delivered for 3 seconds using a current controlled amplifier. Pre-stimulation recordings were performed for 2 seconds to obtain unstimulated intensity. Recording after 5 seconds of stimulation was performed to check relaxation to a resting state.

[00306] Data analysis

[00307] The data were analyzed and presented as normalized background-subtracted emission intensity ratios measured in the 460nm and 580nm channels. Background intensity was then subtracted from each assay channel. The background intensity was obtained by measuring the emission intensity from the same treated test well without the presence of cells at the same time period. The response as a function of time is then expressed using the ratio obtained by:

[00308]by calculating initially (R)_i) And finally (R)_f) And (4) processing the data further. They are the average ratio during part or all of the pre-stimulation period and during the sample point during stimulation. The response to the stimulus R-R is then calculated_f/R_i。

[00309] Control responses were obtained by performing the assay in the presence of a compound with the desired properties (positive control), such as tetracaine, and in the absence of a pharmacological agent (negative control). Responses to negative (N) and positive (P) controls were calculated as above. Compound antagonist activity a is defined as:

where R is the response ratio of the test compound.

[00310] Electrophysiological determination of NaV Activity and inhibition of test Compounds

[00311] The efficacy and selectivity of sodium channel blockers for dorsal root ganglion neurons was assessed using patch clamp electrophysiology. Rat neurons were isolated from dorsal root ganglia and maintained in culture medium consisting of NeurobasalA supplemented with B27, glutamine and antibiotics for 2 to 10 days in the presence of NGF (50 ng/ml). Small diameter neurons (nociceptors, 8-12 μm in diameter) were visually identified and probed with a fine tip glass electrode (Axon Instruments) connected to an amplifier. Cells were maintained at-60 mV and IC50 for compounds was assessed using a "voltage clamp" mode. In addition, the efficacy of the compounds in blocking the generation of action potentials in response to current injection was determined using the "current clamp" model. The results of these experiments help to define the efficacy behavior of the compounds.

[00312]1.Voltage clamp assay in DRG neurons

[00313] The TTX-tolerant sodium currents from DRG bodies were recorded using whole-cell variants of the patch clamp technique. Recordings were made at room temperature (. about.22 ℃ C.) using an Axomatch 200B amplifier (Axon Instruments) and a thick-walled borosilicate glass electrode (WPI; resistance 3-4 M.OMEGA.). After the whole cell construct was established, it took approximately 15 minutes for the pipette solution to equilibrate within the cells before starting the recording. The current was low pass filtered between 2-5kHz and sampled digitally at 10 kHz. The series resistance was compensated 60-70% and monitored continuously during the experiment. No data analysis was calculated for the liquid junction potential (-7mV) between the intracellular pipette solution and the external recording solution. The test solution was applied to the cells using a gravity-driven rapid perfusion system (SF-77; Warner Instruments).

[00314] The dose-response relationship was determined by repeatedly depolarizing the cells from the experimental specific holding potential to a test potential of +10mV in a voltage clamp mode, operating every 60 seconds. The effect of retardation was allowed to reach a steady state before proceeding to the next test concentration.

[00315] Solutions of

[00316]Intracellular solution (in mM): Cs-F (130), NaCl (10), MgCl₂(1)，EGTA(1.5)，CaCl₂(0.1), HEPES (10), glucose (2), pH 7.42, 290 mOsm.

[00317]Extracellular solution (in mM): NaCl (138), CaCl₂(1.26)，KCl(5.33)，KH₂PO₄(0.44)，MgCl₂(0.5)，MgSO₄(0.41)，NaHCO₃(4)，Na₂HPO₄(0.3), glucose (5.6), HEPES (10), CdCl₂(0.4)，NiCl₂(0.1)，TTX(0.25x10^-3)。

[00318]2.Current clamp assay for NaV channel inhibitory activity of compounds

[00319]Current clamps were applied to cells in a whole cell configuration using a multiclad 700A amplifier (Axon Inst). Fill borosilicate pipette (4-5MOhm) with (in mM): 150 parts of potassium gluconate, 10 parts of NaCl, 0.1 part of EGTA, 10 parts of HEPES, 2 parts of MgCl₂(buffered to pH7.34 with KOH). Cell bath was (in mM): 140 NaCl, 3 KCl, 1 MgCl₂、1 CaCl₂And 10 HEPES. Pipette potential is zero before seal formation; liquid joint potential during acquisitionThere is a correction. The recording was performed at room temperature.

[00320] Examples of the activity of ion channel modulators of formula (I, Ia, Ib, Ic and Id) on modulating nav1.3 receptors are shown in table 4 below. For compound activity at the NaV1.3 receptor, if activity is determined to be below 2.0. mu.M, it is indicated by "+++"; if the activity is measured to be 2.0. mu.M-5.0. mu.M, it is indicated by "+"; if the activity is determined to be greater than 5.0. mu.M, it is indicated by "+". For the percent activity of the compound at the nav1.3 receptor, if the percent activity is determined to be greater than 100%, it is indicated by "+++"; if the percent activity is determined to be 25-100%, it is indicated by "+"; if the percent activity is determined to be below 25%, it is indicated by "+".

Table 4: activity of ion channel modulators of formula (I, Ia, Ib, Ic and Id).

Number of Compounds	Activity of	Percentage of Activity
			1	+	++
2	+	+
			3	+	+
4	+	++
			5	+	++
6	+++	++
			7	+	+
8	+	+
			9	+	+
10	++	++
			11	+	++
12	+	+
			13	+	+
14	+	++
			15	+	+
16	++	+++
			17	+	+
18	+	+
			19	+	+
20	++	++
			21	+	++

Number of Compounds	Activity of	Percentage of Activity
			22	+++	+++
23	+++	++
			24	+	+
25	+	++
			26	+	++
27	+	+
			28	+	+
29	+	+
			30	+	++
31	+	++
			32	+	++
33	+	++
			34	+++	++
35	+	+
			36	+	++
37	+	++
			38	+	+
39	+	++
			40	++	++
41	+	+
			42	+	++

Number of Compounds	Activity of	Percentage of Activity
			43	+	+
44	+	+
			45	+	+
46	+	++
			47	+	++
48	+	+
			49	+	++
50	+	++
			51	+	+
52	+	++
			53	+	++
54	+	+
			55	+	++
56	+	+
			57	+	+
58	+	++
			59	+++	++
60	+	+
			61	+	+
62	+	++
			63	++	++
64	+	+
			65	+	+
66	+	+
			67	+	++
68	+	++
			69	+	++

Number of Compounds	Activity of	Percentage of Activity
			70	+	++
71	+	+
			72	+	+
73	+	++
			74	+	++
75	+	++
			76	+	+
77	+	++
			78	+	++
79	+	+
			80	+	+
81	+	+
			82	+	+
83	+	++
			84	+	+
85	+	+
			86	++	++
87	+++	++
			88	+	+

[00321]Other embodiments

[00322] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the claims.

Claims (48)

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein

R′₁And R₁Independently is-Z^AR₄Wherein Z is^AEach independently being a bond or an optionally substituted branched or straight chain C_1-12Aliphatic chain, wherein Z^AUp to three carbon units of (A) are optionally and independently substituted by-C (O) -, -C (S) -, -C (O) NR^A-，-C(O)NR^ANR^A-，-C(O)O-，-NR^AC(O)O-，-O-，-NR^AC(O)NR^A-，-NR^ANR^A-，-S-，-SO-，-SO₂-，-NR^A-，-SO₂NR^A-or-NR^ASO₂NR^A-substitution;

R₄independently is R^AHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃；

R^AIndependently is hydrogen, optionally substituted aryl or optionally substituted heteroaryl; or

R′₁And R₁Together with the nitrogen atom to which they are attached form a group consisting of 2-Z^BR₅A substituted heterocycloaliphatic radical, in which Z^BEach independently being a bond or an optionally substituted branched or straight chain C_1-6Aliphatic chain, wherein Z^BUp to three carbon units of (A) are optionally and independently substituted by-C (O) -, -C (S) -, -C (O) NR^B-，-C(O)NR^BNR^B-，-C(O)O-，-NR^BC(O)O-，-O-，-NR^BC(O)NR^B-，-NR^BNR^B-，-S-，-SO-，-SO₂-，-NR^B-，-SO₂NR^B-or-NR^BSO₂NR_B-substitution;

R₅independently is R^BHalogen, -OH, -CN, -NO₂，-NH₂Is O or-OCF₃；

R^BIndependently is hydrogen, optionally substituted aryl or optionally substituted heteroaryl;

R₂is-Z^CR₆Wherein Z is^CEach independently being a bond or an optionally substituted branched or straight chain C_1-6Aliphatic chain, wherein Z^CUp to two carbon units of (A) are optionally and independently substituted by-C (O) -, -C (S) -, -C (O) NR^C-，-C(O)NR^CNR^C-，-C(O)O-，-NR^CC(O)O-，-O-，-NR^CC(O)NR^C-，-NR^CNR^C-，-S-，-SO-，-SO₂-，-NR^C-，-SO₂NR^C-or-NR^CSO₂NR^C-substitution;

R₆independently is R^CHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃；

R^CIndependently hydrogen, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl or optionally substituted heteroaryl;

R₃is-Z^DR₇Wherein Z is^DEach independently being a bond or an optionally substituted branched or straight chain C_1-6Aliphatic chain, wherein Z^DUp to two carbon units of (A) are optionally and independently substituted by-C (O) -, -C (S) -, -C (O) NR^D-，-C(O)NR^DNR^D-，-C(O)O-，-NR^DC(O)O-，-O-，-NR^DC(O)NR^D-，-NR^DNR^D-，-S-，-SO-，-SO₂-，-NR^D-，-SO₂NR^D-or-NR^DSO₂NR^D-substitution;

R₇independently is R^DHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃(ii) a And is

R^DIndependently hydrogen, an optionally substituted cycloaliphatic group, an optionally substituted heterocycloaliphatic group, an optionally substituted aryl group or an optionally substituted heteroaryl group.

2. The compound of claim 1, wherein R'₁And R₁Independently isor-Q_AWherein R is_10AAnd R_10BIndependently of one another, hydrogen, unsubstituted, linear or branched C_1-3Aliphatic radical, or R_10AAnd R_10BTogether form an oxo group; r_11AAnd R_11BIndependently hydrogen, optionally substituted straight or branched C_1-5Aliphatic radical, or R_11AAnd R_11BTo which they are connectedThe carbon atoms taken together form an unsubstituted 3-5 membered cyclic aliphatic group; t is independently a bond, -O-, -NR-_10A-or-CH₂-; and Q_AIs hydrogen or aryl or heteroaryl, each of which is optionally substituted by 1 to 3 halogen, hydroxy, C_1-3Alkoxy or optionally substituted C_1-3And (3) aliphatic group substitution.

3. The compound of claim 2, wherein R_10AAnd R_10BTogether form an oxo group; r_11AAnd R_11BOne is hydrogen and the remainder R_11AOr R_11BIs optionally substituted straight or branched C_1-5Aliphatic groups, or hydrogen; t is a bond, -O-, -NR-_10A-or-CH₂-; and Q_AIs phenyl, monocyclic heteroaryl or bicyclic heteroaryl, each of which is optionally substituted by 1-3 of halogen, -OH, -CN, C_1-3Aliphatic groups, or combinations thereof.

4. The compound of claim 2, wherein R_11AAnd R_11BOne is hydrogen and the remainder R_11AOr R_11BIs optionally substituted straight or branched C_1-5Alkyl, optionally substituted straight or branched C_2-5Alkenyl or hydrogen.

5. The compound of claim 2, wherein R_11AAnd R_11BOne is hydrogen and the remainder R_11AOr R_11BIs optionally substituted straight or branched C_1-5An alkyl group.

6. The compound of claim 2, wherein R_11AAnd R_11BOne is hydrogen and the remainder R_11AOr R_11BIs methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, each of which is optionally substituted by hydroxy.

7. The compound of claim 2, wherein T is independently a bond, -O-, -NR_10A-or-CH₂-, wherein-NR_10A-is-NH-.

8. The compound of claim 2, wherein Q_AIs phenyl, bicyclic aryl, optionally substituted monocyclic heteroaryl or optionally substituted bicyclic heteroaryl, each of which is optionally substituted by 1-3 of halogen, -OH, -CN, optionally substituted C_1-3Alkoxy, optionally substituted C_1-3Aliphatic groups, or combinations thereof.

9. The compound of claim 2, wherein Q_AIs substituted by 1-3 halogens, unsubstituted C_1-3Alkyl or unsubstituted C_1-3Alkoxy-substituted phenyl.

10. The compound of claim 2, wherein Q_AIs an optionally substituted 9-10 membered bicyclic aryl.

11. The compound of claim 2, wherein Q_AIs naphthalene-yl or 2, 3-dihydro-1H-indene-yl, each of which is unsubstituted.

12. The compound of claim 2, wherein Q_AIs a monocyclic or bicyclic heteroaryl, each of which is optionally substituted by 1-3 of halogen, -OH, -CN, or C_1-3Alkoxy, optionally substituted C_1-3Aliphatic groups, or combinations thereof.

13. The compound of claim 2, wherein Q_AIs an optionally substituted 5-6 membered monocyclic heteroaryl.

14. The compound of claim 2, wherein Q_AIs a 5-6 membered monocyclic heteroaryl optionally substituted with 1-3 halogens, -OH, -CN, optionally substituted C_1-3Alkoxy, optionally substituted C_1-3Aliphatic groups, or combinations thereof.

15. The compound of claim 2, wherein Q_AIs furan-yl, thiophene-yl, oxazole-yl, pyridine-yl, pyrimidinyl, pyrazine-yl or 1, 3, 5-triazine-yl, each of which is optionally substituted by 1 to 3 halogen, -OH, -CN, optionally substituted C_1-3Alkoxy, optionally substituted C_1-3Aliphatic groups, or combinations thereof.

16. The compound of claim 2, wherein Q_AIs an optionally substituted bicyclic heteroaryl.

17. The compound of claim 2, wherein Q_AIs an optionally substituted 9-10 membered heteroaryl having 1-3 heteroatoms selected from N, O and S.

18. The compound of claim 2, wherein Q_AIs indolizine-yl, indole-yl, isoindole-yl, 3H-indole-yl, indoline-yl, 1, 2, 3, 4-tetrahydroquinoline-yl, benzo [ d][1，3]Dioxol-yl, quinolin-yl, each of which is optionally substituted by 1-3 halogen, -OH, -CN, C_1-3Alkoxy, optionally substituted C_1-3Aliphatic groups, or combinations thereof.

19. The compound of claim 1, wherein R'₁And R₁One is hydrogen and the remainder is R'₁Or R₁Selected from:

20. the compound of claim 1, wherein R'₁And R₁Together with the nitrogen atom to which they are attached form a group consisting of 2-Z^BR₅A substituted heterocycloaliphatic radical, in which Z^BIndependently a bond or an optionally substituted branched or straight chain C_1-6Aliphatic chain, wherein Z^BUp to three carbon units of (A) are optionally and independently substituted by-C (O) -, -C (S) -, -C (O) NR^B-，-C(O)NR^BNR^B-，-C(O)O-，-NR^BC(O)O-，-O-，-NR^BC(O)NR^B-，-NR^BNR^B-，-S-，-SO-，-SO₂-，-NR^B-，-SO₂NR^B-or-NR^BSO₂NR^B-substitution; r₅Independently is R^BHalogen, -OH, -CN, -NO₂，-NH₂Is O or-OCF₃(ii) a And R is^BIndependently hydrogen, optionally substituted aryl or optionally substituted heteroaryl.

21. The compound of claim 1, wherein R'₁And R₁Together with the nitrogen atom to which they are attached form a 5-7 membered heterocycloaliphatic substituted with at least one acyl group, oxo group, heteroaryl group, or a combination thereof.

22. The compound of claim 1, wherein R'₁And R₁Together with the nitrogen atom to which they are attached form a 5-7 membered heterocycloaliphatic having 1-3 heteroatoms independently selected from N, O and S, which is substituted with at least one acyl group, oxo group, heteroaryl group, or a combination thereof.

23. The compound of claim 1, wherein R'₁And R₁Together with the nitrogen atom to which they are attached form a piperidine-yl, piperazine-yl or pyrrolidone-yl group, each of which is substituted with at least one acyl groupOxo, heteroaryl, or combinations thereof.

24. The compound of claim 1, wherein R'₁And R₁Together with the nitrogen atom to which they are attached form a heterocycloaliphatic group selected from:

25. the compound of claim 1, wherein R₂Is hydrogen.

26. The compound of claim 1, wherein R₃is-Z^DR₇Wherein Z is^DEach independently a bond or an optionally substituted straight or branched C_1-6Aliphatic chain, wherein Z^DUp to one carbon unit of (A) is optionally and independently replaced by-O-or-NR^D-substitution; and R is₇Each independently is R^DHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃(ii) a And R is^DIndependently hydrogen, an optionally substituted cycloaliphatic group, an optionally substituted heterocycloaliphatic group, an optionally substituted aryl group or an optionally substituted heteroaryl group.

27. The compound of claim 1, wherein R₃Is optionally substituted C_1-5An alkoxy group.

28. The compound of claim 1, wherein R₃Is optionally substituted C_1-5Alkynyloxy.

29. The compound of claim 1, wherein R₃Is optionally substituted branched or straight chain C_1-6An aliphatic group.

30. The compound of claim 1, wherein R₃Is an optionally substituted cycloaliphatic radical.

31. The compound of claim 1, wherein R₃Is an optionally substituted heterocycloaliphatic group.

32. The compound of claim 1, wherein R₃Is piperidin-yl, piperazin-yl, pyrrolidin-yl, tetrahydrofuran-yl, tetrahydropyran-yl, thiomorpholin-yl or imidazolidin-yl, each of which is optionally unsubstituted C_1-3And (3) aliphatic group substitution.

33. The compound of claim 1, wherein R₃Is an optionally substituted aryl group.

34. The compound of claim 1, wherein R₃Is an optionally substituted aryloxy group.

35. The compound of claim 1, wherein R₃Is an optionally substituted heteroaryl group.

36. The compound of claim 1, wherein R₃Is an optionally substituted (aliphatic) amino, (cycloaliphatic) amino, (aryl) amino or amido group.

37. The compound of claim 1, wherein R₃Selected from the group consisting of: -CH₃，-NH₂，

38. The compound of claim 1 having the formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

A₁is-NR₂₁-, wherein R₂₁is-Z^ER₂₂Wherein Z is^EEach independently being a bond or an optionally substituted branched or straight chain C_1-6Aliphatic chain, wherein Z^EUp to three carbon units of (A) are optionally and independently substituted by-C (O) -, -C (O) NR^E-，-C(O)O-，-NR^EC (O) O-, -O-or-NR^E-substitution;

R₂₂independently is R^EHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃；

R^EIndependently hydrogen, optionally substituted aryl or optionally substituted heteroaryl,

R₂₀is-Z^FR₃₀Wherein Z is^FEach independently being a bond or an optionally substituted branched or straight chain C_1-6Aliphatic chain, wherein Z^FUp to three carbon units of (A) are optionally and independently substituted by-C (O) -, -C (O) NR^F-，-C(O)O-，-NR^FC (O) O-, -O-or-NR^F-substitution;

R₃₀independently is R^FHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃(ii) a And is

R^FIndependently hydrogen, optionally substituted aryl or optionally substituted heteroaryl.

39. The compound of claim 1, having formula Ib:

or a pharmaceutically acceptable salt thereof, wherein:

ring a is a 5-6 membered heterocyclic aliphatic ring having at least one nitrogen atom;

R₂₃independently is-Z^GR₂₅Wherein Z is^GEach independently being a bond or an optionally substituted branched or straight chain C_1-3Aliphatic chain, wherein Z^GUp to two carbon units of (A) are optionally and independently substituted by-C (O) -, -C (O) NR^G-，-C(O)O-，-NR^GC (O) O-, -O-or-NR^G-substitution;

R₂₅independently is R^GHalogen, -OH, -CN, -NO₂，-NH₂or-OCF₃；

R^GIndependently hydrogen or optionally substituted heteroaryl; and is

R₂₄Is hydrogen or oxo.

40. The compound of claim 1, having formula Ic:

or a pharmaceutically acceptable salt thereof, wherein R₂₆Is hydrogen, or straight or branched C_1-5An aliphatic group.

41. The compound of claim 1 having formula Id:

or a pharmaceutically acceptable salt thereof, wherein R₂₇Is an optionally substituted cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl group.

42. The compound of claim 1, wherein the compound is selected from table 2.

43. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

44. A method of modulating a sodium ion channel comprising the step of contacting said sodium ion channel with a compound of claim 1.

45. A method of treating or lessening the severity of the following diseases in a subject: acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy or status epilepticus, neurodegenerative disorders, psychosis, such as anxiety and depression, bipolar disorder, myotonia, cardiac arrhythmia, movement disorder, neuroendocrine disorder, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritic pain, post herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, penetrating pain, post-operative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-or exercise-induced angina, palpitation, hypertension, migraine or abnormal gastrointestinal activity, comprising administering to said subject in need thereof an effective amount of a compound of claim 1.

46. The method of claim 45, wherein the method is used to treat or reduce the severity of acute, chronic, neuropathic, or inflammatory pain.

47. The method of claim 45, wherein the method is used to treat or reduce the severity of: radicular pain, sciatica, back pain, headache, neck pain, intractable pain, acute pain, post-operative pain, back pain, tinnitus or cancer pain.

48. The method of claim 45, wherein the method is used to treat or reduce the severity of: femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lumbago; neuropathic lumbago; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, including abdominal pain, pancreatic pain; IBS pain; chronic and acute headache; migraine headache; tension headaches, including cluster headaches; chronic and acute neuropathic pain, including post-herpetic neuralgia; diabetic neuropathy; HIV-related neuropathies; trigeminal neuralgia; Charcot-Marie dental neuropathy; hereditary sensory neuropathy; peripheral nerve damage; painful neuroma; ectopic proximal and distal release; a radiculopathy; chemotherapy-induced neuropathic pain; radiotherapy-induced neuropathic pain; pain after mastectomy; central pain; pain from spinal cord injury; pain following stroke; thalalgia; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury/exercise pain; acute visceral pain, including abdominal pain; pyelonephritis; appendicitis; cholecystitis (cholecystitis); ileus; hernia, etc.; chest pain, including cardiac pain; pelvic pain, renal colic, acute obstetric pain, including labor pain; cesarean section pain; acute inflammation, burns and traumatic pain; acute intermittent pain, including endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; or orofacial pain, including sinusitis pain, dental pain; multiple Sclerosis (MS) pain; pain in depression; -pain from leprosy; becker's disease pain; painful obesity; pain from phlebitis; Guillain-Barre pain; painful legs and athletic toes; haglund syndrome; erythromelalgia pain; fabry disease pain; bladder and genitourinary disorders, including urinary incontinence; overactive bladder; painful bladder syndrome; interstitial tinnitus (IC); or prostatitis; complex Regional Pain Syndrome (CRPS), type I and type II; or pain induced by angina.