t 11 12006 3 3
Transcription
t 11 12006 3 3
; 13 MAY 2006 t 3 3 11 KOL -NP 12006 .\t: 2005/042497 PCTlUS2004/036297 t , TECHNICAL FIEID OF THE INVENTION [0001] sodium The present invention channels. comprising The invention the compounds relates to compounds also provides of the invention useful as inhibitors pharmaceutically and methods of voltage-gated acceptable compositions of using the compositions in the treatment of various disorders, BACKGROUND OF THE INVENTION [0002] Na channels are central to the generation of action:'potentials neurons ~d myocytes. ,T~~y play key. roles in excitable in all excitable cells such as' tis~u~ including brain ..smooth muscJes . of the' gastrdi:ritestin~ tract, skeletal nhiscle,. the ,penp~e.rar nerVouB system,' spinaJ. cord' and, . ." . . ' airway. As such they play key roles in a variety of disease states such as epilepsy (See, Moulard, '. .' B. and D. Bertrand (2002) "Epilepsy and sodium channel blockers" Expert Ooin. Ther. Patents 12(1): 85-91», pain (See, Waxman, S. G., S. Dib-Hajj, et ai, (1999) "Sodium channels and pain" Proc Natl Acad Sci USA "Voltage-gated 96(14): 7635-9 and Waxman, S. G., T. R. Cummins, et aI. (2000) soqium channels and the ,molecular pathogenesis of pain: a review" J Rehabil Res Dev 37(5): 517-28), myotonia (See, Meola, G. and V. Sansone (2000) ''Therapy in myotonic disorders and in muscle channelopathies" Neurol Sci 21(5): S953-61 and Mankodi, A. and C. A. Thornton (2002) "Myotonic syndromes" CUI! Opin NeuroI15(5): M. H., J. A. Kearney, et al. (2002) "Mutations of voltage-gated 545-52), ataxia (See, Meisler, sodium channels in movement disorders and epilepsy" Novartis Found SYillP 241: 72-81), multiple sclerosis (See, Black, J. A., - 11-- ~ PCT/uS2004/036297 2005/042497 sodium channel SNS is abnormally expressed S. Dib-Hajj, et al. (2000) "Sensory neuron-specific in the brains of mice with experimental sclerosis" Proc Natl Acad Sci USA allergic encephalomyelitis and humans with multiple 97(21): 11598-602, and Renganathan, M., M. Gelderblom, et aI. (2003) ''Expression of Na(v)1.8 sodium channels perturbs the firing patterns of cerebellar purkinje cells" Brain Res 959(2): 235-42), irritable bowel (See, Su, X., R. E. Wachtel, et al. (1999) "Capsaicin sensitivity and voltage-gated rat dorsal root ganglia" Am J Physiol277(6 sodium currents in colon sensory neurons from and Laird, J. M., V. Souslova, et al. Pt 1): GIl80-8, (2002) "Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNSIPN3)Neurosci 22(19): 8352-6), urinary incontinence and visceral pain (See,Yoshimura, aI. (2001) "The involvement of the tetrodotoxin-resistant a rat model of visceral pain" J Neurosci dysfunctions null mice" 1 N., S. Seki, et sodium channel Na(v)1.8 (PN3/SNS) in 21(21): 8690-6), as well as an array of psychiatry such as anxiety and depression (See, Hurley, S. C. (2002) "Lamotrigine its use in mood disorders" Ann Pharmacother update and 36(5): 860-73). [0003] Voltage gated Na channels comprise a gene family consisting of 9 different subtypes (NaV1.1-NaV1.9). functional As shown in Table 1, these subtypes show tissue specific localization and differences (See, Goldin, A. L. (2001) "Resurgence Annu Rev Physiol 63: 871-94). Three members of sodium channel research" of the gene family (NaV1.8, resistant to block by the well-known Na channel blocker ITX, demonstrating 1.9, 1.5) are subtype specificity within this gene family. Mutational analysis has identified glutamate 387 as a critical residue for TIX; bW~g·(See. Noda, M., H .. Suzuki; et aI. (1989) "A .single point .mutation on confers. tetrOdot6xiiifPI~ saxitoxin' insensitivity the '$ocIitim channel II" FEBS Leti 259(1): 213-6}. . . . . .' ..... . [0004] Table 1 (Abbreviations: CNS central nervous system, PNS peripheral nervous sytem, = DRG = dorsal = root ganglion, TG = Trigeminal ganglion): Na isoform NaVl.1 NaV1.2 NaV1.3 Tissue TIXIC50 Indications CNS,PNS soma of neurons eNS,high in axons CNS, embryonic, injured nerves lOnM Pain, Epilepsy, neurodegeneration lOnM Neurodegeneration Epilepsy Pain 150M -2- .. WO 2005/042497 NaV1.4 NaV 1.5 NaVl.6 PCTlUS2004/036297 Skeletal muscle Heart 25nM Myotonia 2~ Arrythmia, long QT Pain, movement disorders eNS 6nM widespread, most abuntant 25nM PNS,DRG, terminals neuroendocrine PNS,small >SOIJM neurons in DRG&TG PNS, small 1~ neurons in DRG&TG NaVl.7 NaV1.8 NaV1.9 Pain, Neuroendocrine disorders Pain Pain [0005] In general, voltage-gated sodium channels (NaVs) are responsible for initiating the rapid upstroke of action potentials in excitable tissue in nervous system, which transmit the electrical signals that compose and encode nonnal and aberrant pain sensations. Antagonists of NaV channels can attenuate these pain signals and are useful for treating a variety of pain conditions, including but not limited to acute, chronic, inflammatory, and neuropathic pain. Known NaV antagonists, such as ITX, lidocaine (See, Mao, J. and L. L. Chen (2000) "Systemic lidocaine for neuropathic pain relief' Pain 87(1): 7-17.) bupivacaine, phenytoin (See, Jensen, T. S. (2002) uAltticonwisants in neUropathic pai~: 'ratio~aie and Cli~c~·.e~id~ns~'; Bur J Pain 61-8), larnotri~ine (See, Rozen, T. D. (200i) 6 (Suppi A); "AJitiepilepdc' drug~ in the inanagement of clu~t~r headache and trigeminal neuralgia" Headache 41 Suppl 1: 325-32 and Jensen, T. S. (2002) "Anticonvulsants in neuropathic pain: rationale and clinical evidence" Bur J Pain 6 (Suppl A): 61-8.), and carbamazepine (See, Backonja, M. M. (2002) "Use of anticonvulsants for treatment of neuropathic pain" Neurology 59(5 SuppI2): S14-7), have been shown to be useful attenuating . . pain in humans and animal models. [0006] Hyperalgesia (extreme sensitivity to something painful) that develops in the presence of tissue injury or inflammation reflects, at least in part, an increase in the excitability of highthreshold primary afferent neurons innervating the site of injury. Voltage sensitive sodium channels activation is critical for the generation and propagation of neuronal action potentials. There is a growing body of evidence indicating that modulation of NaV currents is an -3- 2005/042497 - WO ~ PCTlUS2004/036297 endogenous mechanism used to control neuronal excitability (See, Goldin, A. L. (2001) "Resurgence of sodium channel research" AnTIuRev Physiol 63: 871-94.). Several kinetically and pharmacologically distinct voltage-gated sodium channels are found in dorsal root ganglion (DRO) neurons. The TTX-resistant current is insensitive to micromolar concentrations of tetrodotoxin, and displays slow activation and inactivation kinetics and a more depolarized activation threshold when compared to other voltage-gated sodium channels. TIX-resistant sodium currents are primarily restricted to a subpopulation of sensory neurons likely to be involved in nociception. Specifically, TTX-resistant sodium currents are expressed almost exclusively in neurons that have a small cell-body diameter; and give rise to small-diameter slow-conducting axons and that are responsive to capsaicin. A large body of experimental evidence demonstrates that TIX-resistant sodium channels are expressed on C-fibers and are important in the transmission of nociceptive information to the spinal cord, [0007] Intrathecal administration of antisense oligo-deoxynucleotides targeting a unique region of the TI'X-resistant sodium channel (NaV1.8) resulted in a significant reduction in PO~induced .hyperalgesia (See, Khasar, S. G., M. S. Gold, et al. (1998) "A tetrodotoxin-resistant sodium current mediates inflammatory pain in the rat" Neurosci Lett 256(1): 17-20). More recently, a knockout mouse line was generated by Wood and coIIeagues, which lacks functional NaV1.8. The mutation has an analgesic effect in tests assessing the animal's response to the inflammatory agent carrageenan (See, Akopi an, A. N., V. Souslova, et al. (1999) ''The ~trodotoxin-resistant sodium channel SNS has a specialized function,~ pain pathways" ,Nat.", . "NeUrQse:i 2(6): . .. 54'l~8.i.Iil'addition,"defi~it in ~oth mechiUlo- ~d ihermareceptlon'were ..... . 0' .. ",. '.' ~bse~ed .,' in these animals. The analgesia shown by the Nav1.8 knockout mutants is consistent with observations about the role of TTX-resistant currents in nociception. [0008] Immunohistochemical, in-situ hybridization and in-vitro electrophysiology experiments have all shown that the sodium channel NaV1.8 is selectively localized to the small sensory ·neurons of the dorsal root ganglion and trigeminal ganglion (See, Akopian,.A. N., L. Sivilotti, et al. (1996) "A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons" Nature 379(6562): 257-62,). The primary role of these neurons is the detection and transmission of nociceptive stimuli. Antisense and immunohistochemical evidence also supports a role for NaV1.8 in neuropathic pain (See, Lai, J., M. S. Gold, et aI. (2002) "Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8" Pain 95(1- -4- W.,.?2005/042497 PCT/US2004/036297 2): 143-52, and Lai, 1., J. C. Hunter, et al. (2000) "Blockade of neuropathic pain by antisense targeting of tetrodotoxin- resistant sodium channels in sensory neurons" Methods Enzymol 314: 201-13.). NaV1.8 protein is upregulated along uninjured C-fibers adjacent to the nerve injury. Antisense treatment neuropathic pain. prevents the redistribution of NaV1.8 Taken together the gene-knockout and antisense data support a role for NaV1.8 in the detection and transmission of inflammatory [0009] In neuropathic pain states there is a remodeling along the nerve and reverses and neuropathic pain. of Na channel distribution and subtype. In the injured nerve, expression of NaV1.8 and NaV1.9 are greatly reduced whereas expression of the TTX sensitive subunit NaVl.3 is 5-10 fold upregulated (1999) ''Plasticity of sodium channel expression injury model of neuropathic (See, Dib-Hajj, S. D., J. Fjell, et al. in DRG neurons in the chronic constriction pain." Pain 83(3): 591-600.) The timecourse of the increase in NaV1.3 parallels the appearance of allodynia in animal models subsequent to nerve injury. biophysics of the NaV1.3 inactivation channel is distinctive in that it shows very fast repriming The after This allows for sustained rates of high firing as is following an action potential. often seen in the injured nerve (See, Cummins, T. R., F. Aglieco, et aI. (2001) "Nav1.3 sodium channels: rapid repriming and slow closed-state inactivation display quantitative differences after in a mammalian cell line and in spinal sensory neurons" J Neurosci 21(16): 5952- expression 61.). Na V1.3 is expressed in the central and peripheral systems of man. Na V1.9 is similar to NaV1.8 as it is selectively localized to small sensory neurons of the dorsal root ganglion and .. trigeminal ganglion (See. Fang. X; L. ·Djolihri,. et ale (2002). "The 'presepce and role· of the - . . .. . . . '.. .' - ... tetrodotoxin-resistant sodium channel Na(v)1.9 (NaN) in nociceptive primary afferent neurons." . ., . . . ., .... . ~.' ," '" ',' It has a slow rate of inactivation J Neurosci 22(17): 7425-33.). dependence for activation (See, Dib-Hajj, S., J. A. Black, et al. (2002) "NaNlNav1.9: channel properties with unique properties" allow NaV1.9 to playa nociceptive neurons. Trends Neurosci 25(5): role in establishing 253-9.). and left-shifted the resting membrane potential of The resting membr-ane potential of Na V1.9 expressing cells is in the -55 to is in large part due to the sustained This depolarization a sodium These two biophysical -50mV range compared to -65mV for most other peripheral and central neurons. depolarization voltage low-level activation of NaV1.9 channels. allows the neurons to more easily reach the threshold potentials in response to nociceptive stimuli. Compounds This persistent for firing action that block the NaV1.9 channel may play an important role in establishing the set point for detection of painful stimuli. -5- In chronic WO 2005/042497 ,>t peT IUS2004/036297 pain states, nerve and nerve ending can become swollen and hypersensitive exhibiting high frequency action potential firing with mild or even no stimulation. These pathologic nerve swellings are termed neuromas and the primary Na channels expressed in them are NaV1.8 and NaV1.? (See, Kretschmer, T., L. T. Happel, et a1. (2002) "Accumulation of PN1 and PN3 sodium channels in painful human neuroma- evidence from immunocytochemistry" Acta Neurochir CWien) 144(8): 803-10; discussion 810.). NaVl.6 and NaVl.7 are also expressed in dorsal root ganglion neurons and contribute to the small TTX sensitive component seen in these cells. NaV!.? in particular my therefore be a potential pain target in addition to it's role in neuroendocrine excitability (See, Klugbauer, N., L. Lacinova, et al. (1995) "Structure and functional expression of a new member of the tetrodotoxin- sensitive voltage-activated sodium channel family from human neuroendocrine cells" Embo J 14(6): 1084-90). [0010] NaV!.l (See, Sugawara, T., E. Mazaki-Miyazaki, et al. (2001) ''Navl.1 mutations cause febrile seizures associated with afebrile partial seizures." Neurology 57(4): 703-5.) and NaVl.2 (See, Sugawara, T., Y. Tsurubuchi, et al. (2001) "A missense mutation of the Na+ channel alpha IT subunit gene Na(v)l.2 in a patient with febrile and afebrile seizures causes channel dysfunction" Proc Natl Acad Sci USA 98(11): 6384-9) have been linked to epilepsy conditions including febrile seizures. There are over 9 genetic mutations in NaVl.1 associated with febrile seizures (See, Meisler, M. H., J. A. Kearney, et a1. (2002) "Mutations of voltage-gated scdium channels in movement disorders and epilepsy" Novartis Found Symp 241: 72-81) .[OOU] Antagonists for NaVl.5 have ',been developed ~d, used to treat .cardiac arrhythmias. A' gei:ie,defect:in"Navi~5 that prod~eS a'larger no~naetivatitig component 'to..."the curreni has' .be~n ," . . . ..' .. . ~ .' . . . linked to long QT in man and the orally available local anesthetic mexilitine has been used to . treat this condition (See, Wang, D. W., K. Yazawa, et al. (1997) "Pharmacological targeting of long QT mutant sodium channels." J Clin Invest 99(7): 1714-20). [0012] Several Na channel blockers are currently used or being tested in the clinic to treat epilepsy ~ Moulard, a"and D. Bertrand (2002) ''Epilepsy and sodium channel·blo~keJ.'s~' Expert Opin. Ther. Patents 12(1): 85-91.); acute (See, Wiffen, P., S. Collins, et al, (2000) "Anticonvulsant drugs for acute and chronic pain" Cochrane Database Syst Rev 3), chronic (See, Wiffen, P., S. Collins, et a1.(2000) "Anticonvulsant drugs for acute and chronic pain" Cochrane Database Syst Rev 3, and Guay, D. R. (2001) "Adjunctive agents in the management of chronic pain" Pharmacotherapy 21(9): 1070-81), inflammatory (See, Gold, M. S. (1999) "Tetrodotoxin- - 6- " 2005/042497 PCTlUS2004/036297 resistant Na+ currents and inflammatory hyperalgesia." 9), and neuropathic concentrations pain (See, Strichartz, Proc Natl Acad Sci USA G. R., Z. Zhou, "Lamotrigine Anaesthesiol monotherapy for control of neuralgia Scand 46(10): 1261-4); cardiac arrhythmias (1996) ''Lidocaine J Clin Invest 99(7): Narasimhan 1714-20); (1997) "Sodium channels Phannacol 39: 47-98) ''Therapeutic neuropathic after nerve Acta (See, Taylor, C. P. and L. S. system diseases" Adv G. R., Z. Zhou, et al. (2002) ~Strichartz, of local anaesthetics section" Circ Res 79(1): 103-8, and and therapy of central nervous and as anesthetics concentrations A., G. Rumpold S.eitlinger, et targeting of long QT mutant sodium neuroprotection unveil the potential role of sodium channels in pain." Novartis Found Symp 241: 189-201). [0013] Y.arious animal models with clinical significance sodium "Therapeutic (See, An, R. H., R. Bangalore, et al. block of LQT-3 mutant human Na+ channels" Wang, D. W., K. Yazawa, et al, (1997) "Pharmacological channels" et al. (2002) of local anaesthetics unveil the potential role of sodium channels in neuropathic pain" Novartis Found Symp 241: 189-201, and Sandner-Kiesling, al. (2002) 96(14): 7645- channel modulators for numerous different pain indications. pain, see, Kohase, H., et al., Acta Anaesthesiol (see, Kohase, H., et al., Acta Anaesthesial have been developed E.g., malignant Scand. 2004; 48(3):382-3; Scand. 2004; 48(3):382-3); et al., TQxicol Pathol. 2003; 31(6):619-24); osteoarthritis spinal stenosis (see, Takenobu, chronic femur cancer pain non-malignant bone pain (see, Ciocon, 1. O. et al., J Am Geriatr Soc. 1994; 42(6):593-6); (see, Calvina, B. et a1., Behav Brain Res. 1987; 24(1):11-29); for the study of chronic rheumatoid arthritis (see, Guzman, R. E., Y. et al" .JNeurosci '. MethOdS., 2001; 104(2):191-8); Neui:opa$ic low back pain (~ee: Iiin~, R., et' al,,. Pain Med, . ,".. . . 2002; 3(4):361-5; Massie, J. B., et al., J Neurosci Methods, 2004; 137(2):283-9; '. . 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 KA et al., Muscle Nerve. 2001; 24(1):37-46); fibromyalgia (see, Bennet &.Tai, Int J CUn Pharmacol Res. 1995;15(3):115-9); temporomandibular joint pain (see, Ime H, Ren K, Brain Res Mol Brain Res. 1999; 67(1):87-97); chr~mic visceral pain, including, abdominal (see, AI-Chaer, E. D., et al., Gastroenterology. 119(5):1276-85); 6); pancreatic pelvic/perineal pain, (see, Wesselmann (see, Vera-Portocarrero, et al., Neurosci Lett. 1998; 246(2):73- L. B., et al., Anesthesiology. -7- 2000; 2003; 98(2):474-84); . .. PCT/uS2004/036297 WO 2005/042497 IDS pain (see, Verne, G. N., et al., Pain. 2003; 105(1-2):223-30; La JH et aI., World 2003; 9(12):2791-5); chronic headache pain (see, Willimas & Stark, Cephalalgia. Gastroenterol. 2003; 23(10):963-71); migraine (see, Yamamura, H., et al., J Neurophysiol. 1999; 81(2):479-93); . tension headache, including, cluster headaches (see, Costa, A., et al., Cephalalgia. 2000; 20(2):85-91); Neurology. chronic neuropathic pain, including, post-herpetic neuralgia (see, Attal, N., et al., 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); IDV- associated neuropathy (see, Portegies & Rosenberg, Ned Tijdschr Geneeskd. 2001; 145(15):731-5; Joseph EK et al., Pain. 2004; 107(1-2):147-58; Oh, S. B., et aI., J Neurosci. 2001; trigeminal neuralgia (see, Sato, J., et aI., Oral Surg Oral Med Oral Pathol Oral 21(14):5027-35); Radiol Endod. 2004; 97(1):18-22; Imamura Y et al., Exp Brain Res. 1997; 116(1):97-103); Charcot-Marie Tooth neuropathy (see, Sereda, M., et al., Neuron. 1996; 16(5): 1049-60); hereditary sensory neuropathies (see, Lee, M. J., et aI., Hum Mol Genet. 2003; 12(15):1917-25); peripheral nerve injury (see, Attal, N., et al., Neurology. 2004; 62(2):218-25; Kim & Chung 1992, Pain 50:355; Bennett & Xie, 1988, Pain 33:87; Decostered, I. & Woolf, C. J., 2000, Pain 87:149; Shir, Y. & Seltzer, Z. 1990; Neurosci Lett 115:62); painful neuromas (see, Nahabedian & Johnson, Ann Plast Surg. 2001; 46(1):15-22; Devor & Raber, Behav Neural BioI. 1983; ectopic proximal and distal discharges (see, Liu, X. et aI., Brain Res. 2001; 37(2):276-83); 900(1): 119-27); radiculopathy N et a!.! Spine .. 1998; 23(8):877-85); chemotherapy induced neuropathic'pain Hayashi K. 0., . . (see, Devers & Galer, (see, Clin J Pain. 2000; 16(3):205-8; et al:"~eurosciexice. . " 1996; 73(1):25~,.65);· radiotherapy-~duced neuropathic pain; ..,.... .... .. pain (see, Devers & Galer, Clin J Pain. 2000; 16(3):205-8); central pain ., post-mastectomy (see, Aley; .' (Cabana, A, et aI., Anesth Analg. 2004; 98(6):1581-4), - spinal cord injury pain (see, Hains, B. C., et al., Exp Neural. 2000; 164(2):426-37); post-stroke pain; thalamic pain (see, LaBuda, C. J., et al., Neurosci LeU. 2000; 290(1):79-83); complex regional pain syndrome (see, Wallace, M. S., et aI., Anesthesiology. 2000; 92(1):75-83; Xantos D et al., J Pain. 2004; 5(3 SuppI2):Sl); pain (see, Weber, W. phanton 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):8103); 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); pain (see, Gotoh, S., et aI., Ann RheumDis. acute musculoskeletal 1993; 52(11):817-22); -8- pain; joint mechanical low back pain W~005/042497 PCT/US2004/036297 (see, Kehl, L. J., et al., Pain. 2000; 85(3):333-43); neck pain; tendonitis; injuryfexercise pain (see, Sesay, M., et a1., Can J Anaesth. 2002; 49(2):137-43); acute visceral pain, including, abdominal pain; pyelonephritis; intestinal obstruction; hernias; etc (see, Giambernardino, appendicitis; cholecystitis; M. A., et aI., Pain. 1995; 61(3):459-69); chest pain, including, cardiac Pain (see, Vergona, R. A., et aI., Life Sci. 1984; 35(18):1877-84); acute obstetric pelvic pain, renal colic pain, pain, including, labor pain (see, Segal, S., et al., Anesth Analg. 1998; 87(4):864- 9); cesarean section pain; acute inflammatory, burn and trauma 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 2000; 119(5):1373-81); breakthrough pain; orofacial pain, including, (see, Nusstein, J., et al., J Ended. 1998; 24(7):487-91; 6(1):55-67); multiple 162(2):162-8); leprosy Haglund Venereol. disease 1999; 24(3):240-1); syndrome; 2003; 2002;196(2):183-90); (see, Devillers phlebitic pain; Guillain-Barre erythromelalgia Bladder & Kanazawa, pain (see, Legroux-Crespel, Fabry's disease and urogenital pain disease, aI., Urology. 2003; 61(3):664-70); E., et al., Ann Dermatol (see, Germain, including, painful" bladder syndrome .' NeU:rbs~i. 20~1; '21(2~):'8690-6);' int~~titiai' cyc~ti·s. & Oranje, Clin Exp pain; painful legs and moving toes; D. P., J Soc BioI. urinary incontinence Berggren, T., et al., J Urol. 1993; 150(5 Pt 1): 1540-3); hyperactivity et J Neurol Sci. 1999; (see, Greene B, Curr Med Res Opin. 2003; 19(4):272-7); pain; adiposis dolorosa 130(4):429-33); sinusitis pain, dental pain J. J., et al., Eur J Pain. 2002; Chidiac, (MS) pain (see, Sakurai pain in depression pain; behcet's Dermatol. sclerosis (see, Toma, H; Gastroenterology. (see, bladder (see, Chuang, Y. C., (see, Yoshimura, N., et: at, J 6¢) :(s~e.' Gia:nnak6poulos& Arch Ital Urol Nefrol AndroI. 1992; 64(4):337-9; Boucher, M., et al., JUral. 8); and prostatitis (see, Mayersak, J. S., Int Sorgo 1998; 83(4):347-9; .~.~pilo~ai~s, 2000; 164(1):203- Keith, I. M., et al., J Urol. 2001; 166(1):323-8). [0014] Voltage-gated calcium channels are membrane-spanning, open in response to membrane depolarization, multi-subunit proteins that allowing Ca entry from the extrace1hl1ar milieu. Calcium channels were initially classified based on the time and voltage-dependence opening and on the sensitivity to pharmacological of channel block. The categories were low-voltage activated (primarily T-type) and high-voltage activated (L,N,P,Q or R-type). This classification scheme was replaced by a nomenclature based upon the molecular subunit composition, as summarized in Table I (Bockerman, G. H., et. al. (1997) Annu. Rev. Pharmacol. Toxicol. 37: -9- peTIUS2004/036297 WQi005/042497 361-96; Striessnig, J. (1999) Cell. Physio!. Biochem. 9: 242-69). There are four primary subunit types that make up calcium channels - al, 1120, ~ and functional diversity of voltage-activated and y (See, e.g., De Waard et al. Structural calcium channels. In Ion Channels, (ed. T. Narahashi) 41-87, (plenum Press, New York, 1996». The of the pharmacological UI subunit is the primary determinant properties and contains the channel pore and voltage sensor (Hockerman, G. H., et. al. (1997) AnTIu.Rev. Pharmacal. Toxicol. 37: 361-96; Striessnig. Physio!. Biochem. 9: 242-69). Ten isoforrns of the III J. (1999) Cell. subunit are known, as indicated in Table 1. The a20 subunit consists of two disulfide linked subunits, a2, which is primarily extracellular and a transmembrane 0 subunit. Four isoforms of a2~ are known, a20-1, a20-2, 1128-3 and U20-4. The ~ subunit is a non-glycosylated are known, termed biochemically ~l to ~4. cytoplasmic protein that binds to the al subunit. Four isoforrns The'l subunit is a transmembrane protein that has been isolated as a component of Cavl and Cay2 channels. At least 8 isoforms are known (Y1 to Y8) (Kang, M.G. and K. P. Campbell (2003) 1. BioI. Chern. 278: 21315-8). The nomenclature for voltage-gated calcium channels is based upon the content of the al subunit, as indicated in Table I. Each type of <Xl subunit can associate with a variety of ~' subunits, so that each Cay type corresponds to many different combinations <X28 or y of subunits. Cay Nomenclature al subunit Pharmacological name Cavl.l als L-type Cav1.2 ale L-type Cay1.3 ·CavI.4 ... .. .... aID " " ~7trPe . ., aiF' Cav2.1 alA P-orQ-type Cav2.2 alB N-type Cay2.3 alE R-type Cay3.1 alG T-type Cav3.2 . aIR T-type Cav3.3 an T-type . [0016] Cay2 currents are found almost exclusively in the central and peripheral nervous system and in neuroendocrine cells and constitute the predominant forms of presynaptic voltage-gated calcium current. Presynaptic action potentials cause channel opening and neurotransmitter - 10- .. WO 10051042497 PCTlUS2004/036297 release is steeply dependent upon the subsequent calcium entry. Thus, Cav2 channels playa central role in mediating neurotransmitter release. [0016] Cay2.1 and Cay2.2 contain high affinity binding sites for the peptide toxins D-conotoxinMVITC and D-conotoxin-GVIA, respectively, and these peptides have been used to determine the distribution and function of each channel type. Cav2.2 is highly expressed at the presynaptic nerve terminals of neurons from the dorsal root ganglion and neurons of lamina I and ITof the dorsal horn (Westenbroek, R. E., et a1. (1998) J. Neurosci. 18: 6319-30; Cizkova, D, et a1. (2002) Exp. Brain Res. 147: 456-63). Cav2.2 channels are also found in presynaptic terminals between second and third order intemeurons in the spinal cord. Both sites of neurotransmission are very important in relaying pain information to the brain. [0017] Pain can be roughly divided into three different types: acute, inflammatory, and neuropathic. Acute pain serves an important protective function in keeping the organism safe from stimuli that may produce tissue damage. Severe thennal, mechanical, or chemical inputs have the potential to cause severe damage to the organism if unheeded. quickly remove the individual from the damaging environment. generally is short lasting and intense. Inflammatory Acute pain serves to Acute pain by its very nature pain, on the other hand, may last for much longer periods of time and its intensity is more graded. Inflammation may occur for many reasons including tissue damage, autoimmune response, and pathogen invasion. pain is mediated by a variety of agents that are released during inflammation, ., substance P, histamines; acid, prostaglandin, ·bradykinin, CGRP, 'eyto~es, agents (julius, D ..and .' ". is neuropathic A.l.. Basba:~ .... (2001) including ATP, and other. Nature 413 (6852): .....203-iO)... Th~ ~ --,- Inflammatory third .. " c1as's of Pain. . . ". and involves nerve damage arising from nerve injury or viral infection and results in reorganization of neuronal proteins and circuits yielding a pathologic "sensitized" state that can produce chronic pain lasting for years. This type of pain provides no adaptive benefit and is particularly difficult to treat with existing therapies . .[0018]. Pain, particnlarly neuropathic and intractable pain is ~ large unmet medical need. Millions of individuals suffer from severe pain that is not well controlled by current therapeutics. The current drugs used to treat pain include NSAIDS, COX-2 inhibitors, opioids, tricyclic antidepressants, and anticonvulsants. Neuropathic pain has been particularly difficult to treat as it does not respond well to opioids until high doses are reached. Gabapentin is currently the most widely used therapeutic for the treatment of neuropathic pain, although it works in only 60% of -11- " ¥) 2005/042497 PCTlUS2004/036297 .. patients and has modest efficacy. The drug is generally safe, although sedation is an issue at higher doses. [0019] Validation of Cav2.2 as a target for the treatment of neuropathic pain is provided by studies with ziconotide (also known as D-conotoxin-MVIIA), a selective peptide blocker of this channel (Bowersox, 8.S., et al. (1996) 1. Pharmacol. Exp. Ther. 279: 1243-9; Jain, K.K. (2000) Exp. Opin. Invest. Drugs 9: 2403-10; Vanegas, H. and H. Schaible (2000) Pain 85: 9-18). In man, intrathecal infusion of Ziconotide is effective for the treatment of intractable pain, cancer pain, opioid resistant pain, and neuropathic pain. The toxin has an 85% success rate for the treatment of pain in humans with a greater potency than morphine. An orally available antagonist of Cav2.2 should have similar efficacy without the need for intrathecal infusion. Cav2.1 and Cav2.3 are also in neurons of nociceptive pathways and antagonists of these . channels could be used to treat pain. [00201 Antagonists of Cav2.1, Cav2.2 or Cav2.3 should also be useful for treating other pathologies of the central nervous system that apparently involve excessive calcium entry. Cerebral ischaemia of neurons. and stroke are associated with excessive calcium entry due to depolarization The Cav2.2 antagonist ziconotide is effective in reducing infarct size in a focal ischemia model using laboratory animals, suggesting that Cav2.2 antagonists could be used for the treatment of stroke. Likewise, reducing excessive calcium influx into neurons may be useful for the treatment of epilepsy, traumatic brain injury, Alzheimer's disease, multi-infarct dementia and other classes of demen.tia,.amyotrophic lateral.sclerosis, by poison pr other toxic substances. ." . '. . [0021] Cav2.2 also mediates release of neurotransmitters amnesia, or neuronal damage caused from neurons of the sympathetic nervous system and antagonists could be used to treat cardiovascular diseases such as hypertension, cardiac arrhythmia, angina pectoris, myocardial infarction, and congestive heart failure . .[()022] Howeyer, as .described above, the efficacy of.currently used sodium channel blockers and calcium channel blockers for the disease states described above has been to a large extent limited by a number of side effects. These side effects include various CNS disturbances such as blurred vision, dizziness, nausea, and sedation as well more potentially life threatening cardiac arrhythmias and cardiac failure. Accordingly, there remains a need to develop additional Na - 12- WO 2005/042497 PCTlUS2004/036297 "'- channel antagonists, and Ca channel antagonists preferably those with higher potency and fewer side effects. SUMN.lARY OF THE INVENTION [0023] It has now been found that compounds acceptable compositions thereof, of this invention, are useful as inhibitors These compounds have the structure of Formula and pharmaceutically of voltage-gated sodium channels. I: I acceptable salt thereof, wherein RA, Z, Y, r, and Ware as defined below. or a pharmaceutically These compounds and pharmaceutically acceptable compositions are useful for treating or lessening the severity of a variety of diseases, disorders, or conditions, including, but not limited to, acute, chronic, neuropathic, or inflammatory pain such as femur cancer pain; non- malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; back ..... pain; neuropathic low back pain; myofascial spinal stenosis; neuropathic low pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, including, abdominal; pancreatic; IDS pain; chroI).ic headache pain; migraine; : • .neuropathic 'neuropathy; ': •••• tensiop headache, •• pain, including" trlgeniin;U o' • post-herpetic. neuralgia; neuralii~;' including, cluster hea,dachel); chronic ..' • diabetic •• • neuropathy; cJiai-~ot~M~e : Tooth . 'neuropathy; ," •• HIV - ' ,associated 'hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy radiotherapy-induced neuropathic pain; post-mastectomy induced neuropathic pain; pain; central pain; spinal cord injury :pain; post~stro,~e pain; thalamic p~n; complex regional pain syndro:me; phanton 1?ain;intr~ctabl.e, 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; intestinal obstruction; hernias; etc; chest pain, including, cardiac Pain; pelvic pain, renal colic pain, acute obstetric pain, including, labor pain; cesarean section pain; acute inflammatory, burn and trauma pain; acute intennittent -13 - · "Y-~2005/042497 PCTIUS2004/036297 pain, including, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain, including, sinusitis pain, dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease, including, urinary incontinence; hyperactivity bladder; painful bladder syndrome; interstitial cyctitis (Ie); or prostatitis, arthritis, migrane, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, and incontinence. DETAILED DESCRIPTION OF THE INVENTION 1. General Description of Compounds of the Invention: [0024] The present invention provides a compound of Formula I: y o= I . z (RA)r-, )-w #N .'I. ' ot a,pharmac~~tically acceptable salt thereof, w~ere~: r is 0 to 4; Z is 0, N or CH; Y and W are independently selected from hydrogen, Formula Ia: -,-A-V- Ia wherein: - 14- ~ 2005/042497 PCTlUS2004/036297 , or wherein: T is a bond or a CI-6 straight or branched aliphatic chain wherein a methylene unit ofT is optionally replaced by a C3.s cycloaliphatic group; U is -CHz- or -CHz-CHz-; X is N-CI-4aIkyl, NH, 0, S, S(O), or SOz; and each occurrence ofRe is independently M_Rx; wherein: M is a bond or is a CI-6 alkylidene chain wherein up to two non-adjacent methylene units of M are optionally replaced by C(O), COz, C(O)C(O), C(O)NR, OC(O)NR, NRNR, NRNRC(O), NRC(O), NRCOz, NRC(O)NR, S(O), SOz, NRSOz, SOzNR, NRSOzNR, 0, S, orNR, and X R is R', halogen, NOz, or CN; wherein: each occurrence ofR' is independently selected from hydrogen or an optionally substituted group selected from C1-S aliphatic, CG-IO aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring , 'having 3-10 ring atoms, or Rand R' ..taken together with the .... .' ato:t:Dcs)t,oWhicq they ar~ .bOl~~i or two ~ccurrenc~~ 9~R; t*~n, together with the atom(s) to which they are bound, form a 5-8 membered cycloalkyl, heterocyclyl, 0-3 heteroatoms independently aryl, or heteroaryl ring having selected from nitrogen, oxygen, or sulfur; V is a bond, -C(O)-, or -S(0)z-; . Q is a bond or a Cl-4 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally replaced by -0-, -NH-, or -S-; mis 0 or 1; Ring E is C6.10 aryl, a 5-10 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3-10 membered - 15 - ~ 2005/042497 PCT/uS2004/036297 heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen,orsuffur;and s is 0 to 8; or Formula Ib: Ib wherein: D is -Cl_6alkyl- or a bond; and tis 0 to 5; each occurrence ofR is independently selected from hydrogen or an optionally substituted Cl-6 aliphatic group; and each occurrence ofRA, RB andRD are independently selected fromRl, R2, R3, R4, orR5, wherein: Rl is oxo, R6 or (Cl-4aliphatic)n-J, wherein: n is 0 or 1; J is halo, CN, N02, CF3' OCF3' OH, SR6, S(O)R6, S02R6, NH2, NHR6, N(R6)z, NR6R8, C(O)OH, C(O)OR6 or OR6; or: ~oR io~ adj~c.ent ~g . 'ethylenedioxy; a~oms, taken togeth~r, form 1,2-m~thYlen~~oxy or 1,2- '. . R2 is Cl_6aliphatic, optionally substituted with 'up to two substituents independently selected from R 1, R4, or R 5; R3 is C3_scycloaIiphatic, C6-JOaryl, a 5-10 membered heteroaryl ring having 1-4 ··heteroatoms independently selected from nitrogen, oxygen\ or sulfur, or a 3-10. membered heterocyclyl ring having 1-4 heteroatoms independently 3 selected from nitrogen, oxygen, or sulfur, wherein R is optionally substituted with up to three substituents independently selected from Rl, R2, R4 or R5; - 16 - ... 2005/042497 PCTruS20041036297 R4 is OR5, OR6, OC(O)R6, OC(O)R5, OC(O)OR6, OC(O)OR5, OC(O)N(R6h, OC(O)N(R5)2, SOzN(R6h, OC(O)N(R6R5), S02N(R5h, C(O)R6, qO)OR6, C(O)N(OR5)R6, SR6, SR5, S(O)R6, S(O)RS, SOZR6, S02RS, S02NR5R6, S03R6, S03RS, C(O)R5, C(O)OR5, C(O)N(R6)z, C(O)N(R5h, C(O)N(OR6)R5, C(O)N(R5R6), C(O)N(ORS)R5, C(O)N(OR6)R6, C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)Z, N(R5)2, N(R5R6), NR5C(O)R5, NR6C(O)R6, NR6C(O)R5, NR6C(O)OR6, NR5C(O)OR6, NR6C(O)OR5, NR6C(O)N(R6h, NR6C(O)NR5R6, NR6C(O)N(R5)z, NR5C(O)NR5R6, NRSC(O)N(R5)z, NR6S0ZR6, z NR6S02NR5R6, NR5S02N(R5)Z' N(OR6)R6, N(OR6)R5, N(OR5)R5, NR6S02N(R5)z, NR5S0ZR5, NR5S02NR5R6, or N(OR5)R6; aryl, a 5-10 membered heteroaryl ring having 1-4 C6-JO heteroatoms independently NR5C(O)N(R6)Z, NR6S0ZRS, NR6S0 N(R6h, RS is a C3_scycloaliphatic, NR5C(O)OR5, selected from nitrogen, oxygen, or sulfur, or a 3-10 membered heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R5 is optionally substituted with up to three R1 substituents; R6 is'R 0J?tioria1Iy'substi~ted with R:, ,!herein: . R7'i~a C3~cycloaliphatic, . aryl; a 5-i.·O·me~bered hei~ro~l C6-10 heteroatoms independently . ring having 14" selected from nitrogen, oxygen, or sulfur, or a 3-10 membered heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R7 is optionally substituted with up to two substituents independently ethylenedioxy, selected from R, 1,Z-methylenedioxy, 1,Z- or (CH2)n-G, wherein Gis seiected rrom halo, CN, NOz, OCF3, OH, S-aliphatic, S(O)-aliphatic, N(aliphatic)Z, N(aliphatic)R8, SOZ-aliphatic, COOH, C(O)O(-aliphatic, CF3, NHZ' N-aliphatic, or O-aliphatic; and R 8 is an amino protecting group; provided that only one of Y and W is formula Ia or - 17- Ib and the other of Y and W is hydrogen. WO 2005/042497 PCT/US20041036297 -/ In certain other embodiments, for compounds of Formula I as described generally [0025] above and herein: a) when Z is N, W is Formula la, A is -C2alkyl-NH-, V is -CCO)-, Q is -Cjalkyl-O-, and A Ring E is phenyl, then R is not hydrogen, -CI, -Br, Cj-4alkyl, methoxy, or nitro, either singly or in combination; b) when Z is N, W is Formula la, A is -C2alkyl-NH-, V is -eCO)-, Q is a bond, and Ring E is phenyl, then RA is not hydrogen, -CI, -Br, CHalkyl, methoxy, or nitro, either singly or in combination; c) when Z is N, W is Formula la, A is -e3alkyl-NH-, V is -CCO)-, Q is a bond, and Ring A E is phenyl, then R is not 4-amino, or 4-methoxycarbonyl; d) when Z is N, W is Formula la, A is -C3alkyl-NH-, V is -CCO)-,' and Q is a bond, then Ring E is not -2(2,3-dihydro-benzo[lAJdioxine); e) when Z is N, W is Formula la, A is -C3alkyl-NH-, -Cjalkyl-O-, f) V is -CCO)-, and Q is a then Ring E is not -6(4-dirnethyl-2H-chromen-2-one); when Z is N, W is Formula la, A is -C2alkyl-NH-, -C2alkyl-O-, then Ring E is not unsubstituted V is -C(O)-, and Q is a phenyl; g) when Z is N, W is Formula la, A is -e2alkyl-NH-, V is -CCO)-, and B is a bond, then Ring E is not unsubstituted thienyl; h) when Z is N, W is Formula la, A is -e2alkyl-NH-, V is -C(O)-, A '.' . -C1alkyl-0-,. and Ring E is phenyl, then R is not phenyl at the 4 position;' and Q is a .' i) ~he~·~.i~ N, Wis~0n.nula)~,.A.is·~2alkYl:-N:Eh . . then Ring E is not 2-isoindoline-l ,3-dione; Vis-C(Oh.and Q.~~:a-:C2~YI,. j) when Z is N, W is Formula la, A is -C2alkyl-NH-, V is -C(O)-, and Q is a A -C2alkyl-O-, and Ring E is phenyl, then R is not phenyl at the 4 position; and k) when Z is N, W is Formula la, A is -e2alkyl-NH-, V is -e(O)-, and Q is a bond, then Ring E is not unsubstituted adamantyI. [0026] According to another embodiment, formula la, as defined generally above, wherein: ·18 - the present invention provides a compound of PCTlUS2004/036297 WO 2005/042497 I"qR C >( ~ N-~ (a) when Z is N, Y is hydrogen, W is formula la, A is and V and Q are each a 0, bond, then: (i) when r is 1 and RA is methyl in the C-5 or C-6 position of the benzimidazole ring, then E is not: unsubstitued phenyl; phenyl substituted in the ortho position with methyl, OMe, or OEt; or phenyl substituted in the para position with OMe or methyl; and (ii) when r is 0, then E is not: unsubstituted phenyl; unsubstituted naphthyl; phenyl substituted in the para position with OEt, Br, OR, or OMe; phenyl substituted in the meta position with chiaro; or phenyl substituted in the ortho position with methyl; (b) when Z is N, Y is hydrogen, W is formula la, Q is -NHCHz-, r is 0, and V is ceO), then: cl~i (i) when A is -CHzCH~-, th~n E is not .' - 0 ~; ~0M. ~. (ii) when A is -CHzNH-, then E is not ""'('CI CI; and and (c) when Z is C, W is hydrogen, Y is formula la, r is 0, A is -eH2CHzNH-, -CH20- and E is phenyl, then: (i) s is not 0; . (ii) when s is 1, RB is not: . - 19- V is C(O), Q is PCTlUS2004/036297 WO 2005/042497 unsubstituted phenyl, chloro, OMe, methyl, bromo, ~ \-~''N'/l in the para position; ~o cyano or OMe in the ortho position; or methyl in the meta position; (iii) when s is 2, RB is not dichloro in the ortho/para positions; and (iv) when s is 3, RB is not 2,3,4-trimethyoxy In certain other embodiments, [0027] or 2,4,5-trichloro. for cpmpounds of Formula I as described generally above and herein: a) when Z is N, W is Formula la, A is -CH2CH2NH-, V is -C(O)-, Q is -CH20-, and Ring E is phenyl, then RA is not -Cl, -Br, Cl-4aIkyl, methoxy, or nitro, either singly or in combination; b) when Z is N, W is Formula la, A is -CH2CHzNH-, V is -C(O)-, A E is phenyl, then R Q is a bond, and Ring is not -Cl, -Br, CI-4alkyl, methoxy, or nitro, either singly or in combination; c) when Z is N, W is Formula la, A is -CH2CH2CH2NH-, V is -C(O)-, Q is a bond, and Ring E is phenyl, then RA is not 4-arnino, or 4-methoxycarbonyl; d) wh~n Z is N, 'w is Forin~lata;'A is ~2CH2CH2NH-, V is :::C(O)-, arid ",the~ Ri~giHs not -2(2,3-diliyciro~b~~o[i,4]~oxine); " e) when Z is N, W is Formula la, A is -CH2CH2CH2NH-, ,;'" Q' is a bond:' ,,;," V is -C(O)-, and Q is a -CH20-, then Ring E is not -6(4-dimethyl-2H-chromen-2-one); f) when Z is N, W is Formula la, A is -CH2CH~-, V is -C(O)-, and Q is a -CH2CH20-, then Ring E is not unsubstituted phenyl; g)' when Z is N, W is'Formula la, A is -CH2CH2NH-, V is'-C(O)-, and Q is a bond, then Ring E is not unsubstituted thienyl; h) when Z is N, W is Formula la, A is -CH2CH2NH-, V is -C(O)-, and Q is a -CH20-, and Ring E is phenyl, then RA is not phenyl at the 4 position; i) when Z is N, W is Formula la, A is -CH2CH2NH-, V is -C(O)-, and Q is -CH2CH2-, then Ring E is not 2-isoindoline-l,3-dione; - 20- ' wo 2005/042497 . ..: PCTlUS2004/036297 j) when Z is N, W is Formula la, A is -CHzCHzNH-, V is -C(O)-, and Q is -CH2CHzO-, and Ring E is phenyl, then RA is not phenyl at the 4 position; and k) when Z is N, W is Formula la, A is -CHzCHzNH-, ./ V is -C(O)-, and Q is a bond, then Ring E is not unsubstituted adamantyl. 1) when Z is N, W is Formula la, A is -CHzCHzNH-, V is -C(O)-, Q is -CH2CH20-, and Ring E is phenyl, then RB is not -Cl, -Br, CI_4alkyl, methoxy, unsubstituted phenyl, -C(CH3hphenyl, or nitro, either singly or in combination; m) when Z is N, W is Formula la, A is -CH2CH2NH-, V is -C(O)-, Q is -CH=CH2-, and B Ring E is phenyl, then R is not -Cl in the ortho position; and n) when Z is N, W is Formula la, A is -CHzCH2NH-, V is -802-, Q is a bond, and Ring B E is phenyl, then R is not chloro. [0028] Another lessening the severity neuropathic, embodiment of a disease, or inflammatory pain; rheumatoid of the present disorder, invention or condition headache, heIJletic neuralgia; Charcot-Marie p~~l pancreatic; including, 'cluster pib~ar temporomandibular chronic neuropathic illV - associated hereditary pain; radiotherapy-induced sensory neuropathies; neuropathic obstruction; obstetric pain; migraine; trigeminal post- neuralgia; peripheral 'nerve .injury; , pain; thalamic pain; post-mastectomy pain; complex joint pain; mechanical low back pain; neck pain; tendonitis; abdominal joint pain; chronic pain, including, neuropathy; phanton pain; intractable pain; acute pain, acute post-operative including" chronic bone and dist~ discharge~,; r8:clic~opathy;, chenio~~taPY indu~e.d spinal cord injury pain; post-stroke pain, from acute, chronic, IBS pain; chronic headache headaches; neuropathy; Tooth neuropathy; n<?m:omas; ~tOpic neuropathic abdominal; diabetic selected or spinal stenosis; neuropathic low back pain; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; tension a method of treating pain, including femur cancer pain; non-malignant arthritis; osteoarthritis; visceral pain, including, provides pain; pyelonephritis; pain; central pain; regional pain syndrome; pain; acute musculoskeletal injury/exercise appendiGitis; pain; pain; acute visceral cholecystitis; 'intestinal hernias; etc; chest pain, including, cardiac Pain; pelvic pain, renal colic pain, acute pain, including, labor pain; cesarean section pain; acute inflammatory, burn and trauma pain; acute intermittent pain, including, endometriosis; acute heIJles zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain, including, pain; multiple sclerosis (MS) pain; pain in depression; -21- leprosy sinusitis pain, dental pain; behcet's disease pain; -' PCTlUS2004/036297 WO 2005/042497 adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease, including, urinary incontinence; hyperactivity bladder; painful bladder syndrome; interstitial cyctitis (Ie); or prostatitis; arthritis, migrane, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or an epilepsy condition, a neurodegenerative disorder, a psychiatric disorder such as anxiety and depression, myotonia, arrythmia, a movement disorder, a neuroendocrine disorder, ataxia, multiple sclerosis, irritable bowel syndrome, or incontinence comprising the step of administering to said patient an effective amount of a compound of Formula I: I or a pharmaceutically acceptable salt thereof, wherein RA, Z, Y, r, and Ware as defined above and in classes and subclasses as desribed herein. [0029] A preferred aspect of the present embodiment is where the disease, condition, or disorder is acute, chronic, neuropathic, or inflammatory pain. [0030] Another embodiment of the present invention provides a method for treating or lessening the severity' 6f. a disease~ condition: or disorder wherem the' disease, condition,' or ' . ..... . . disorder is impllcated, in the, _activati~n,.of, voltage-:gateq . s~dium ,channels comprising , administering an effective amount of a compound of Formula I: ,', I or a pharmaceutically acceptable salt thereof, wherein R A, Z, Y, r, and W are as defined above and in classes and subclasses as desribed herein. [0031] A preferred aspect of the present embodiment is where the disease, condition, or disorder is acute, chronic, neuropathic, or inflammatory pain, epilepsy or an epilepsy condition, a - 22- WO 2005/042497 --- neurodegenerative PCT/US2004/036297 disorder, a psychiatric disorder such as anxiety and depression, myotonia, arrythmia, a movement disorder, a neuroendocrine disorder, ataxia, mUltiple sclerosis, irritable bowel syndrome, or incontinence. [0032J A particularly preferred aspect of the present embodiment is where the disease, condition, or disorder is acute, chronic, neuropathic, or inflammatory pain. [0033] Another preferred aspect of the present embodiment is where the method comprises an additional therapeutic agent. [0034] Yet another embodiment NaVl.l, NaVl.2, of the present invention provides a method of inhibiting NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaVl.?, NaV1.8, NaV1.9, or CaV2.2 activity in: (a) a patient; or (b) a biological sample; which method comprises administering to said patient, or contacting said biological sample with a compound of Formula I: .. :. '.' OJ;' a' pharmaceutically' , ' ~.. .. . ~cceptable salt thet(mf, whe-rein . .' '. . RA, Z~ Y, ,r,and.W are as defined above ' and in classes and subclasses as desribed herein. 2. Compounds and Definitions.' [0035] Compounds of this invention include those described generally above, and are further . illustrated by the classes, subclasses, and species disclosed herein. definitions elements Handbook chemistry Sausalito: shall apply unless otherwise indicated. are identified in accordance of Chemistry and Physics, are described in "Organic As used herein, the following For purposes of this invention, the chemical with the Periodic Table of the Elements, th 7S Ed. Chemistry", 1999, and "March's Advanced Additionally, - 23- general principles Thomas Sorrell, University Organic Chemistry", CAS version, SUiEd., Ed.: of organic Science Books, Smith, M.B. and PCTffiS2004/036297 WO 2005/042497 ......March, J., John Wiley & Sons, New York: incorporated [0036] 2001, the entire contents of which are hereby by reference. The present invention provides compounds B monovalent, such as RA, R , C D R and R of Formula I with substituents or divalent, such ; that are as A, B, and D. Those skilled in the art will appreciate that for asymmetric divalent substituent groups, such as -Cl_6alkyl-NH-, and -Ct-4alkyl-O-, there are two possible orientations relative to the parent structure. As used within the present specification, the orientation of a divalent substituent is set by its left/right orientation relative Formula appreciate I as taught in the present specification. Those skilled in the art will also that this orientation convention is not relevant to symmetrical divalent substituents, such as -C(O)-, or -Ct-6alkyl-. [0037] -C(O)-, For example for Formula I, where Z is N, W is present as la, RA is hydrogen, V is Ring E is phenyl, RB is hydrogen; -C3alkyl-NH-, and A and Q are divalent substituents (A is and Q is -Cta1kyl-O-), the following is the described compound. o O:>-'~·"-~~D [0038] -C(O)-, For example for Formula I, where Z is N, W is present as la, RA is hydrogen, V is Ring E is phenyl, RB is hydrogen; . ~Cialkyl~NIi-~d Q is -O-CiaIkyl-),'the' '.' . and A and Q are divalent substituents (A is following is the 'described compom.d .. :., . 0 . ())~~-~,~;~ V H [0039] For example for Formula I, where Z is N, W is present as la, U is -CRr, hydrogen, V is -CCO)-, Ring E is phenyl, RBis hydrogen; and A and , .. . '. . . .' (A is and Q is -C]alkyl-O-), - 24- the following RA is Q are divalent . . substituents . is the described compound. PCTlUS2004/036297 WO 20051042497 ./ [0040] As described herein, compounds of the invention may optionally be substituted with one or more substituents, classes, subclasses, such as are illustrated generally above, or as exemplified by particular and species of the invention. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." general, the term "substituted", replacement In whether preceded by the term "optionally" or not, refers to the of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an· optionally substituted group may have 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 specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes ~m~odin'1ents;' a "~table compound :0£ chemically disclosed perein. f~asible' com;~tJ.n«( is . otie . thai In some ~s . not' ..: '. sUb~antiaIiy altere~ when. k~p.t"at a temp~rllture .of· 40~C.p.r less, in. the. absence of .mois(irre or. other chemically reactive conditions, for at least a week. [0041] The terms "aliphatic", chain (Le., unbranched) completely saturated hydrocarbon or branched, substituted or un substituted "cycloaliphatic" hydrocarbon or that contains one or more units of un saturation, or bicyclic hydrocarbon that is completely units of unsaturation, molecule. "aliphatic group" or "alkyl" as used herein, means a straight- but which is not aromatic or "cycloalkyl"), chain that is or a monocyclic saturated or"that contains one or more (also referred to herein as "carbocycIe" that has a single point of attachment to the rest of the Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms, Le., CI-20aIkyI. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms, Le., In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms, Le., CI-lOaIkyI. - 25- .. WO 2005/042497 PCTfUS2004/036297 C1-salkyl. In still other embodiments, aliphatic groups contain 1~6aliphatic carbon atoms, i.e., Cl-6a1kyl, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms, i.e., CHalkyl. In some embodiments, "cycloaliphatic" (or "carbocycle" monocyclic C3-Cg hydrocarbon or bicyclic Cg-CI2 hydrocarbon or "cycloalkyl") refers to a that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members. substituted Suitable aliphatic groups' include, but are not limited to, linear or branched, or unsubstituted (cycloalkyl)alkyl, [0042] alkyl, alkenyl, and hybrids thereof such as (cycloalk:enyl)alkyl or (cycloaIkyl)alk.enyl. The term "heteroaliphatic", "heterocyclic" aIkynyl groups "heterocycle", as used herein means non-aromatic, "heterocyclyl", monocyclic, systems in which one or more ring members is an independently embodiments, the "heterocycle", "heterocyclyl", "heterocycloaliphatic", bicyclic, or tricyclic ring In some selected heteroatom. "heterocycloaliphatic", or "heterocyclic" has three to fourteen ring members in which one or more ring members or group is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members. [0043] The term "heteroatom" or silicon (including, means one or more of oxygen, sulfur, nitrogen, phosphorus, any oxidized form of nitrogen, sulfur, phosphorus, quatemized fonn of any basic nitrogen or; a substitutable example or silicon; nitrogen of a heterocyclic ring, for N (at:. in 3,4-dmydr;2H~pyrrolyi);· NH· (as, in pyrroliciinYI) ·'or m+ (a~ in N~~~bstituted .,. pY.r;0Ii~¥~)).' . . [0044] the .. . The term "unsaturated", as used herein, means that a moiety has one or more units of unsaturation. [0045] The term "alkoxy", or "thioalkyl", as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen ("alkoxy") or sulfur , ("thioalkyl") atom, for example C14alkoxy refers to the alkoxyl group, methoxy, ethyoxy, propoxy, and butoxy, including for propoxy and butoxy, the straight and branched structures, that is i-propoxy and n-propoxy; and n-butoxy, i-butoxy and [0046] The terms "haloaIkyl", "haloalkenyl" and sec-butoxy. "haloalkoxy" means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. means F, Cl, Br, or 1. - 26- The term "halogen" PCTlUS2004/036297 WO 20051042497 [0047] The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". The term "aryl" also refers to heteroaryl ring systems as defined hereinbelow. [0048] The term "heteroaryl", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatorns, and wherein each ring in the system contains 3 to 7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". [0049] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are selected from halogen; -Ro; -ORO; -SRo; l,2-methylene-dioxy; 1,2-ethylenedioxy; phenyl (Ph) optionally substituted with RO; -O(Ph) optionally substituted with RO; -(CH2)1-2(Ph), optionally substituted with RO; -CH=CHcPh), optionally substituted with RO; -N02; -CN; -N(RO)2;-NROC(O)RO;-NROCCO)N(R°h;-NRoC02Ro; -NRONROCCO)RO; -NRONROCCO)N(R°h; '. " . . . -NRoNRoC02Ro;. ·-C(O)C(O)Ro~. -C(O)CHzCCO)RO; .:..COzRo; ~C(O)Ro;:' -C(O)N(R°h;' "... . .' . ..' . . '. . .-OCCO)N(R°h; -S(O)2RO;-Sq2N(R°)z; .-S.(O)RO;.-NRoS02N(R~)2; -NRoS02R~;,·-CC=S)N(R°h;, -C(=NH)-N(RO)2;or -(CH2)o-2NHC(O)ROwherein each independent occurrence of ROis selected from hydrogen, optionally substituted Cl-6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or -CH2(Ph), or, notwithstanding the definition above, two independent occurrences of RO,on the same substituent or different substituents, taken together with the atom(s)' to which each R ° group is' bound, form a 3-8- rnemb~red .cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatorns independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group ofRo are selected from NH2, NH(Cl-4aliphatic), N(Cl-4aliphatic)2, halogen, Cl-4aliphatic, OH, O(CI-4aliphatic), N02, CN, C02H, CO2(CI-4aliphatic),O(haloCI-4 aliphatic), or haloC1•4aliphatic, wherein each of the foregoing Cl_4aliphaticgroups ofRo is unsubstituted. -27 - wo (0050] peTIUS2004/036297 21)05/042497 An .aliphatic or heteroaliphatic contain one or more substituents. heteroaliphatic heterocyclic ring may Suitable substituents on the saturated carbon of an aliphatic or group, or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated =0, =S, =NNHR", carbon of an aryl or heteroaryl group and additionally include the following: =NN(R*)z, =NNHC(O)R*, where each RoOis independently aliphatic. group, or a non-aromatic =NNHCOz(alkyl), selected from hydrogen =NNHSOz(alkyl), or an optionally or =NR*, substituted Cl-6 Optional substituents on the aliphatic group of R * are selected from NH2, NH(Cl_4 NOz, CN, C02H, aliphatic), N(Cl-4 aliphatic)2, halogen, Cl-4 aliphatic, OH, O(Cl-4 aliphatic), CO2(Cl-4 aliphatic), O(halo Cl-4 aliphatic), or halO(Cl-4 aliphatic), wherein each of the foregoing Cl-4aliphatic groups of R· i~ unsubstituted. [0051] Optional substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from -R+, -N(Rlz, -C(=S)N(Rlz, -C(O)R+' -C02R+, -C(O)C(O)R+, -C(=NH)-N(R+h, -CCO)CH2C(O)R+, -SOzR+, -SOzN(R+h, or -NR+SOzR+; wherein R+ is hydrogen, an optionally substituted Cl-6 aliphatic, optionally substituted phenyl, optionally substituted -O(Ph), optionally substituted -CHz(Ph), optionally substituted -(CHZ)l-Z(Ph); optionally substituted -CH=CH(ph); or an un substituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, above, two independent taken together or sulfur, or, notwithstanding occurrences of R+, on the same substituent the definition or different substituents, with the atom(s) to which each R+ group is bound, form a 3-8-membered '. .cycl<:>alkyl.;heterocyc1yl. li!1'l, or hete:rqaryl ring having .0-,3. ~e~eroat'?ms indepe~d~ntly, selected ,from -nitrogen~ oxygen. or ot"R+ ~~ s'ele~ted fr~~ O(Cl-4 aliphatic), sulfur:' optional sobstituents op'the aliphatic group or'1he ph~nyl ring " NHz, NH(CI~ ~iph~tic), N(C;'~'aiipha~c)z~'h~o~e~,' NOz, CN, COzH, COZ(CI-4 aliphatic), (:1_4 alipha~ic,'OH, O(halo Cl-4 aliphatic). or halo(Cl-4 aliphatic), wherein each ofthe foregoing Cl-4aliphatic groups ofR+ is unsubstituted. [0052] The term "Cl_2oalkylidene chain" refers to a straight or branched carbon chain of twenty ca:b~n atoms, or less that roay be fq1ly ~a.tm:at~dor have oIJ,eor more units of unsaturati~n and has two points of attachment to the rest of the molecule. [0053] Unless otherwise isomeric (e.g., enantiomeric. structure; for example, stated, structures diastereomeric, depicted and geometric the R and S configurations double bond isomers, and (2) and (E) conformational - 28- herein are also meant to include (or conformational) for each asymmetric isomers, all forms of the center, (2) and (E) Therefore, single stereochemical PCTlUS2004/036297 WO 2005/042497 ~ isomers as well as enantiomeric, the present compounds diastereomeric, and geometric (or conformational) mixtures of Unless otherwise stated, all are within the scope of the invention. tautomeric forms of the compounds of the invention are within the scope of the invention. For example, for compounds of formula I: wherein Z is Nor 0, one of ordinary skill would recognize that a suitable tautomer is as depicted above. When the Z group of formula I is CR, one of ordinary skill would recognize that a suitable tautomer is as depicted below: y w [0054) Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C_ or 14C-enriched carbon are . withiri the scope 'of this invention~' Such compounds or pr~be~ in:biolo~cai assays:. ...... .... are useful! for example, as analytical t061s - 3. Description of Exemplary Compounds: [0055] In certain embodiments, the present invention provides a compound of formula I wherein V is -8(0)2-. [0056] . In other embodiments, the present invention provides a compound of formula 'I wherein V is -C(O)-. [0057] In one embodiment, T is a Cl-6 straight or branched methylene unit of T is optionally replaced by a C3-6 cycloaliphatic aliphatic chain wherein group. [0058] Also preferred is a compound of formula I wherein Ring E is phenyl. [0059] Also preferred is a compound of formula I wherein Ring E is naphthyl. - 29- a WO 2005/042497 PCTlUS2004/036297 [0060J Also preferred is a compound of formula I wherein Ring E is pyridinyl. [0061J Also preferred is a compound of formula I wherein Ring E is thienyl. [0062] Also preferred is a compound of formula I wherein Ring E is furanyl. [0063J Also preferred is a compound of formula I wherein Ring E is quinolinyl. [0064J Also preferred is a compound of formula I wherein Ring E is benzofuranyl. [0065] Also preferred is a compound of formula I wherein Ring E is 3,4-dihydro-2H- chromene. [0066] Also preferred is a compound of formula I wherein Ring E is 2,3-dihydrobenzo[b] [1,4]dioxine. [0067] According to one aspect, the present invention provides a compound of formula I, wherein Ring E is a preferred group as described above and said grOup is in combination with the remaining variables of formula I as set forth in the classes and subclasses described herein. [0068J In certain embodiments, each RA of fonnula I, when present, is independently R6, OR6, CN, or halo. In other embodiments, each RB of formula I, when present. is independently OR6• N(R6)2' NR6C(O)R6• halo, R6, C(O)R6, or N02. (0069] In other embodiments, the A moiety of formula I, when present, is -T_NR5_, wherein T is a Cl-6 straight or branched aliphatic chain. Such A moieties include -CH2CH2N(CH3)-, -CHzCHzNH-, -CHzNH-, and -CH2CH(CH3)NH-. [0070] In certain embodiments, the present invention provides a compound of formula I wherein A is·.,-T-NH- where~ Tis a,C{6 straight·or branched aliphatic chain wherein a· .. , methylene"ucit of T is repla~d. by a C3.<;<.;yclo8.Iiphaticgroup. S'uchcycloaliphatic groups.. . . '. ., -.'." '.' '. ',' , include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl groups. [0071] In other embodiments, the Q moiety of formula I is a Cl-4 alkylidene chain wherein one methylene unit of Q is replaced by -0-, -NH-, or -S-. Such Q moieties of formula I include -CHzCH20-. -CHzO-, -OCHz-, -OCHzCHz-, -CH(CH3)0-, -NHCHz-, -C(CH3hO-, and -CHzS-. ,[0072]. , As .described above, for compounds of the invention of Formula I, Z is 0,. N or C. Accordingly. in certain embodiments, where Z is N, the corresponding compounds have the structure of Formula II: - 30- PCTlUS2004/036297 WO,;f',OS/042497 IT [0013] . In certain embodiments of Formula II, Y is hydrogen, Ring E ,is phenyl, and W is formula la, wherein V is -CCO)-, as shown in Formula ITa: - 31 - PCT/US2004/036297 WO 2005/042497 .... CN, CI-6 aliphatic, -N(R6)z, or halogen. Such RB groups include methyl, ethyl, butyl, isopropyl, chIaro, fluoro, bromo, N(Me)z, CF3 and -CHzphenyl. According to another embodiment, the present invention provides a compound of formula Ua wherein the benzo ring is substituted at one of, or both of, the C-4- and C-5 positions with tert-butyl, fiUOTO,or methyl. [0083] fonnula According to another embodiment, IIa, wherein A is -CH2CH2NH, or -CH(CH3)NH-, 6' independently CI-6 the present invention provides a compound of , . 6 aliphatic, -N(R )z, -C(O)R , Q is -CHzO- . or halogen. B Such R B and each R . is ' groups include methyl, chloro, bromo, ethyl, N(Meh, -C=CH and C(O)CH3• [0084] Yet another embodiment of the present invention relates to a compound of formula Q is -CHzO-, -NHCHz-, or -CH(CH3)O-, ITa, wherein A is -CHzCHzNH-, . Of h~Qgen .. .,: .. indepep.dept~y C1:6 aliph!l;tic:.. ~9R6, . chIoro, bromo; and flu6ro. [0085] Accordirig to' still ~other embodi~;mt, B Such R . -CH(CH3)O-, or -C(CH3)20-, and each R is gt:pups, ~ncll,1,demethyl, et:9yl,..:OMe" the"present'inventio~ is independently provides a compound '~f Q is -CHzO-, -NHCHz-, -NH-, formula Ha, wherein A is -CHzCHzNH- or -CHzCH(CH3)NH-. B B and each R 6 CI-6 aliphatic, _OR , or halogen. Such RB groups include methyl, ethyl, -OMe, chloro, bromo, and fiuoro. According to another A embodiment, the present invention provides a compound of formula Ua wherein r is 2, each R is fiuoro,and is present at the C-4- and C-5 positions. [0086] In certain embodiments, the present invention provides a compound of formula Ha, wherein A is -CHzCHzNH-, Q is -CHzO-, and each RB is independently halogen. In other embodiments, wherein A is -CH2CH2NH-, bromo, or chIaro. the present invention provides a compound of formula IIa, Q is -CHzO-, and each RB is inependently methyl, isopropyl, fiuoro, In still other embodiments, the present invention provides a compound of B fonnula Ha, wherein A is -CH2CHzNH-, Q is -CHzO-, and each R fluoro. or chloro. is inependently methyl, In yet other embodiments, the present invention provides a compound of B formula IIa, wherein A is -CH2CH2NH-, Q is -CHzO-, and each R is inependently bromo, or chi oro. [0087] CI-6 aliphatic or Also preferred is • compound of Formui. - 32- na. wherein A is ~,A methyl, PCTlUS2004/036297 WO 2005/042497 ~ I l{'-~ [0088) [0089]. Also preferred is a compound of Formula ITa, wherein A is . Also preferred is a compound of Formula a IIa, wherein A is wherein U is -CHr or -CHzCHr. [0090] In certain embodiments of Formula II, Y is hydrogen, Ring E is phenyl, W is Formula Ib and D is a bond, as shown below as fonnula Db . ..... . ,. ,. fib or a pharmaceutically acceptable salt thereof, wherein RA, r, RD, and s are as defined above and herein. [0091J Preferred is a compound of Formula lIb, wherein RA is R6 or halo. In certain embodiments, RA is methyl, chIaro or bromo. [0092] Particularly preferred is a compound of Fonnula lIb, wherein RA is methyl. [0093] Also preferred is a compound of Formula lIb wherein RD is halo, OR6, N(R6 n, NR6C(O)R6, or two RD are taken together to form a methylenedioxy or ethylenedioxy group. In D certain embodiments, R is -oH, -N(Et)z, -OMe, -NHC(O)CH3, fluoro, or chloro. [0094] According to another embodiment, the present invention provides a compound formula ill: ill - 33- of PCT/US2004/036297 WO 2005/042497 or a pharmaceutically B acceptable salt thereof, wherein A, Q, RA, r, R , and s are as defined above and herein. (0095] In certain embodiments, each RA of formula nI, when present, is independently R6, OR6, CN, or halo, In other embodiments, each RB of formula In, when present, is independently OR6, N(R6)z, NR6CCO)R6, halo, R6, C(O)R6, or NOz, (0096] In other embodiments, the Q moiety of formula III is a Cl-4 alkylidene chain wherein one methylene unit 0(0' h replaced by -0-, -NH-, or -8-, Such Q moieties of form~ia nr include -CHzCHzO-, -CHzO-, -OCHz-, -OCHzCHz-, -CH(CH3)O-, -NHCHz-, -CCCH3)20-, and -CHzS-:. (0097] In'other embodiments, the A moiety of formula In, when present, is _T_NR6_, wherein T '"is a ... Cl-6 ".. straight or branched aliphatic chain. Such A moieties ' . . .." ... '.," .,.. .. .,. . include. ,-'." ..... " '", , -CHiCH2N(CH3)-, ~CH2CH2NH-, -CH2NH-,and -CHiCH(CH3)NH-; . . , [0098]' III certain embodiments. the presentinv'enti~n . .. pr~vides a ~omp~und offormul~ m' wherein A is -T-NH- wherein T is a Cl-6 straight or branched aliphatic chain wherein a methylene unit ofT is replaced by a C3-6 cycloaliphatic group. Such cycloaliphatic groups include cyc]obutyl, cyclopentyl, and cyclohexyl groups. (0099] According to another embodiment, formularY: the present invention provides a compound of ~~ >-C(/v,J0:tR' o: # (RA>r-I- .--PN o IV or a pharmaceutically acceptable salt thereof, wherein V. Q, RA, r, RB, n, and s are as defined above and herein. [00100] ill certain embodiments, each RA of formula IV, when present, is independently R6, OR6, eN, or halo. In other embodiments, each RB of formula IV, when present, is independently OR6, N(R6)2, NR6C(O)R6, halo, R6, CCO)R6, or NOz. (00101] In other embodiments, the Ring E group of formula IV is phenyl or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently ·34· selected from nitrogen, oxygen, or sulfur, PCTlUS20041036297 WO 20051042497 '-4 or a 3-7 membered monocyclic heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, Such Ring E groups of formula IV include pyridyl, thienyl, furyl, and pyrazolyl. [00102] In still other embodiments, bicyclic aryl ring or an 8-10 membered independently . the Ring E group of fonnula IV is bicyclic heteroaryl ring having 1-4 heteroatoms selected from nitrogen, oxygen, or sulfur. ", '. .' include naphthyl, quinolinyl, 3,4-dihydro-2H-chromene, [00103] an 8-10 membered Such Ring E groups of formula IV . . .. . and 2,3-dihydrobenzo[b](I,4]dioxine, In other embodiments, the Q moiety of formula one methylene unit of IV is a Cl-4 alkylidene chain wherein Q is replaced by -0-, -NH-, or -S-. Such Q moieties of formula IV include -CH2CH20~, -CH20-, -OCH2-, -OCH2CHr, -CH(CH3)O-, -NHCH2-, -C(CH3)20-, and -CH2S-, [9~1,~4J.. Acc?rding to a~othe~ .~p«c~ of ~e presen~.i.~ventiont .qne of V According to yet' another aspect of the presen.t irivention, both of V and Q ~4 Q are Iibond. [00105]' "Rep~sentativ~ 'coz:npo~n"dsof formula I 'are 'set fo~ in Tabie 2 belo~. ·35· is. a. qon4. PCTlUS2004/036297 WQJOOS/042497 " T <J T"~O 2. t-V "C ~ ~. Q u "C. o. . .. N ~'lIo U I \0 '", T 0 ... P d 1 ~ Q t 0 en Q U = ::l ~ ~ B' u u ~ i3en Q) "Cl ~ ~~ u Q) «l ..... PCTlUS20041036297 WO 2005/042497 '+ Y-t' 'C g .-S' -,' 0 U .- ({ b ~~ %':r' -. "'=' S'* -<t U I I 1eo u Q Oy;:" 0 'C e-* u ""' PCTIUS20041036297 WO 2005/042497 r "~I 9 't:l 0 :r:r § 0 .~( S-o u b .. !C 'r::. \D ~'ll: I 00 en I u:' .. ~ ~, .',6.. o~ ¢ o· 't:l .%~ i~ ~ S-o U . '" .. .. 0 " Ii 't:l S''ll: U In WO 2005/042497 peT IUS2004/036297 'T" "-; ~ 't:l = ::l 0 S- . "''' 0 u ' b . , 'i~ " 0- U : Mr ~I,4, '0' ~ .. 't:l ~ ~ Q U - :Z' J~. 0 a-~ 't:l u I"'- PCTlUS2004/036297 W0-.f.005/042497 Q ~F 't:l ~ ~ u o I ~t 0..... ~.... .,,0 ,.. '!. T .. . "::lft:jj: ::: u , o "", 1s- o U Q ),1" '!. "% 't:l S':jj: u !::! PCT/US200~/036297 WO 2005/042497 "p ~,.. 't:l l=l g :r:r a- Q O~ Co) 0 '" U ", .. .. 'tl :!l S"=I!: C,) ..... . "'" I ",,\O'Q 'tl § Q ~ u :t',.. .....'\, .i. . (I b 'tl ~~ C,) ;!; PCT/US200M036297 WO 2005/042497 'l:l ~ t 0 U -P /'" :z-r o.=) a. ~ " <.J (] ... , ... , i* .... t-- U . ~, I .~ i g, ~ u :1 . :zo.,%, o=) ~ cf" "tl S'* U 10 ..... PCTlUS2004/036297 WO 2005/042497 Q l~ 'g ::I 0 ~ 0 u °6' ... 'C. S':ll: 0 N U I . ~ ,,. ; Q,...-u'" : :: 'C § 0 ~ 0 u 'C S':tl: U .L b 0\ PCTlUS20041036297 WO 2005/042491 .;' <.J ,& ~ lyO ] t. T;!! a0 u Z' . 0 ' . !C .. S'=II: .' .. N C'I U . ~ I q ~ 'C § c t Q U 9' '-I. -;s: 'C t=ll: U .... C'l .. peT IUS2004/036297 WO 2005/042497 ~ :7 ~ I ] 0 ~ -:r%' .i. 0 t 0 U . , 0 " , 't:I. Ct.' . . 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PCT/US2004/036297 WO 2005/042497 ': ly 0 ".."' .....11 'C g S' Q U o ::::v.- '" '", -r.,. ~ ~ ~ - .. 'C. \0 \0 f'* '" U I a, a, , .. , '~¢( . .' . ..& 1 <:l ~ u T%~: .l. b 'C S'* U <'"I \0 <'"I WO 2005/042497 PCTruS2004/036297 '!" ly 0 "..%.... 't1 § 0 11 8 'S' ", 0 u ~" " i~ u .. '. ffl .... , o ~, y 0 "!f ".." ......1/ ' ti ~' 't1 § %~'% Q. 0 S' 0 u """ ~ ~ '~ (j 'l:l S'* U r-. .... \0 PCTlUS2004/036297 WO 2005/042497 , ~ .0' "i~ I o 1t Q u . ... 8' ' .,.~ - = ~ u .... f. ~ 'tl ~* $ <'l .. .4-. PCTlUS2004/036297 WO 2005/042497 [00106] Although certain exemplary embodiments are depicted and described above and herein, it will be appreciated that a compounds of the invention can be prepared according to the methods described generally above using appropriate starting materials by methods generally available to one of ordinary skill in the art. 4. General Synthetic Methodology: [00107] The compounds of this invention may be prepared in general by methods known to those skilled in the art for analogous compounds, as illustrated by the general schemes below, and the preparative examples that follow. Starting materials are commercially available from typical chemical reagent supply companies, such as, Aldrich Chemicals Co., Sigma Chemical Company and the like. Compounds that are not commercially available can be prepared by one of ordinary skill in art following procedures set forth in references such as, "Fieser and Fieser's Reagents for Organic Synthesis", Volumes 1-15, John Wiley and Sons, 1991; "Rodd's Chemistry of Carbon Compounds", Volumes 1-5 and Supplementals, Eiservier Science Publishers, 1989; and "Organic Reactions", Volumes 1-40, John Wiley and Sons, 1991. Scheme 1 [00108] Scheme 1 teaches the general preparation of compounds of Formula 1. Typically co~p,?unds of Fonn!1la I, where Y or yv is ":" -AI( ( >;~'h o wherein A is -NH-, or -N(Cl-6alkyl)- are prepared by the coupling of optionally substituted compounds of Fonnula A, which has a nucleophilic function with optionally substituted .. ' . ;., .' . '. .. '. compounds of Formula B. which have a terminal electrophilic functionaIilty, such as a carboxylic acid. sulfonyl halide, isocyanate. or the like, as defined previously. These methods are also applicable to compounds of Forrmulas II and - 202- m as defined previously. PCT/US2004/036297 WO 2005/042497 B y 1 x= / OH, OR, halo, leaving group (RA)p:)-Aya < }(R~' o - 203- PCT/US20041036297 WO 2005/042497 Syntheti}: Scheme 2a. 2b: [00109] Scheme 2a teaches the preparation of optionally substituted benzimidazole compounds of Formula II. Scheme 2b teaches the preparation of additional optionally substituted benzimidazole compounds of formula II. y (A')ce"H , I + NH2 j Scheme 2a - 204- WO 2005/042497 PCTlUS2004/036297 ~NH2 ~ NH2 1) Acylate, cyclize 2) Deprotect j PG HO~~ + (RA)r-~ PG = protecting group A x = OH, OR, halo, leaving group ,II '. S~heme·2ti· An optionally substituted l,2-diaminobenzene is reacted with an optionally substituted carboxylic acid with a protected nucleophilic group to provide the benzimidazole which is then cyclized to form the benzimidazole and acylated, . sulfonylated, carbamoylated, . ., . moiety. The nucleophilic intermediate, group is deprotected of Formula ll. . or alkylated .,... to provide compounds . ... - 205- .. PCT/uS2004/036297 WO 2005/042497 Synther!!c Scheme 3a. 3b, 3c: [00110] Scheme 3a teaches the preparation of optionally substituted aryloxy acids. Optionally substituted aryloxy acids are prepared by reacting optionally substituted phenolic compounds with optionally substituted halo-substituted alkyl esters (X is el, Br or 1) to obtain the corresponding ester. 3 Scheme 30 The ester compound is then hydrolyzed to obtain a desired optionally substituted compound of FonnulaB. 3 B Scheme3b As taught in Schemes 1, 2a, and 2b, compounds of Formula A and B are reacted together to obtain compounds of Formula I. For example, FonTIulaA as taught in Scheme 2b and Formula B as taught in the present Scheme 3b can be reacted to form the corresponding compound of . fOI:Qlula I (Scheme ~c). . -206 - WO 2005/042497 PCT/US2004/036297 SCheme3c Synthetic Scheme 4: [00111] Following the procedures taught in Schemes 1, 2a, 2b, 3a, 3b, and 3c, and using an optionally substituted aryl isocyanate compound of Formula B, 0r (AAlr-V--}-1 . N . ,~.,\. ' A . y' H "1'" O==C===N-R' . ...... Scheme 4 optionally substituted compounds of Fonnula I are obtained. Synthetic Scheme 5: ·207 - B' . PCT/US2004/036297 WO 2005/042497 [00112] '>'- Following the procedures taught in Schemes 1, 2a, 2b, 3a, 3b, and 3c, and using an optionally substituted aryl sulfonyl chloride compound of Formula B, B (R A 1 l-A-S R-Q(AI)S \\ /; II o:~ N )'-1 ~ z \ y 0 Scheme 5 optionally substituted compounds of Formula I are obtained. Synthetic Scheme 6: [00113] Protected optionally substituted benzimidazoles of Formula A are prepared by reacting a star4ng cy,'!Jl~s~bstituted benzimidazole ~~th (BOC)20 followed ]:>y reduction of the ~r.thel~e): t\?op~ovjdethe.4esii'ed·~o~poWld.:pfForm:uiaA,.' . c~~o' ~oup (R~ey':1"UckeIlfJ;2 ,. ... .' ..... ~,... . "-"::::: (RA) Ct I &= H N ~ N CN ..... ~:"". "0 ' A}-O (R lro=-..::::: • 1 A N k . /hCN N . . 6' .':,').(; · t- 0 A (R )rcr-..::::: I N N;,'>-----.\.-NH2 A A .scheme 6' As taught previously in Schemes 1, 2a, 2b, 3a, 3b, 3c, 4 and 5, compounds of Fonnula A from the present Scheme 6 are derivatized to provide the corresponding compounds of Formula 1. Synthetic Schemes 7a, 7b: - 208· WO 2005/042497 PCT/uS2004/036297 )-- [00114] An optionally substituted benzyl alcohol is reacted with phosgene to provide an optionally substituted compound of Formula B, B Scheme7a This compound is then reacted with a compound of Formula A to provide the corresponding compound of Formula I. For example, where the compound of Formula A is a benzimidazole taught in Scheme 2, the following compounds of Formula I, where s is 0 to 4, and m is 1 or 4, as it corresponds to Q where Q is -O-Cl-4alkylare obtained, + B A J .. "0:": ~~Ay'.'.... J~r~ . "" .. "" ...' ~ "z ' \ y , 0 Soheme7b Syntheti~ Scheme 8: , [00115] A compound of Formula I, where W is -209 - o~ .' n· '~R~~" :~.-.~ (CH~m" ..' ... , ", " PCTlUS2004f036297 WO 2005/042497 is prepked by reacting an optionally substituted di-amino benzene with an optionally substituted benzaldehyde or benzoic acid to obtain the corresponding optionally substituted compound of Fonnula I, where RA, RD, r and t are as taught for Formula I, in a manner analogous to Schemes 2a and2b. [00116] Although certain exemplary embodiments are depicted and described above and herein, it will be appreciated that a compounds of the invention can be prepared according to the methods described generally above using appropriate starting materials by methods generally available to one of ordinary skill in the art. 5. Uses, Formulation and Administration [00117] In yet another aspect, a method for the treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain, arthritis, migrane, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, or incontinence is provided comprising administering an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound to a subject in ,ne~d thereof. ,In certain preferred embodiments, a method for ,.the trea~ent : ,s~verity :of,':acute,,' 'chronic, neU,ropaWc', or' infl~t~ry pain'" OJ: lessening the is: provide.d" c~mpriSing ", an eff~cti~e"~J~lOunfof a -cQmpoun:d:~; '& phannaceutlc8ny 'aChiiinistermg 'acbeptable CO~pd~iiion''. to a subject in need thereof, In certain embodiments of the present invention an "effective amount" of the compound or pharmaceutically acceptable ,composition is that amount effective for treating or lessening the severity of one or more of acute, chronic, neuropathic, or inflammatory pain, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric .". . .". . ..',.. . " .. ' disorders such as anxiety and depression, myotonia, 3.1Tythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, or incontinence, [00118] As described generally above, the compounds of the invention are useful as inhibitors of voltage-gated sodium ion channels or calcium channels, preferably N-type calcium channels. In one embodiment, the compounds and compositions of the invention are inhibitors of one or - 210- WO 2005/042497 PCTfUS2004/036297 ll; more of NaVl.I, NaVl.2, NaVl.3, NaV1.4, NaV1.5, NaVl.6, NaVl.?, NaV1.8, NaVl.9, or CaV2.2, and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of one or more of NaVl.l, NaVl.2, NaVl.3, NaVl.4, NaVl.5, NaV1.6, NaVl.?, NaV1.8, NaV1.9, or CaV2.2 is implicated in the disease, condition, or disorder. When activation or hyperactivity of NaVl.I, NaVl.2, NaVl.3, NaV1.4, NaV1.5, NaVl.6, NaVl.7, NaVl.8, NaVl.9, or CaV2.2, is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a "NaVl.I, NaV1.2, NaV1.3, NaVl.4, NaV1.5, NaV1.6, NaV1.?, NaV1.8, NaV1.9, or CaV2.2-mediated disease, condition or disorder" or a "CaV2.2-mediated condition or disorder". Accordingly, in another aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of one or more of NaVl.l, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.?, NaV1.8, NaVl.9, or CaV2.2 is implicated in the disease state. [00119] The activity of a compound utilized in this invention as au inhibitor of NaVl.l, NaV1.2, NaV1.3, NaVl.4, NaVl.5, NaVl.6, NaVl.?, NaV1.8, NaV1.9, or CaV2.2 may be assayed according to methods described generally in the Examples herein, or according to methods available to one of ordinary skill in the 8.1.1. [00120] In certain exemplary embodiments, compounds of the invention are useful as .inhiPit~rs of NaVI. 8.. In other ~bQ(limentS, compomids of the invention are useful as inhibitors '... ; .... Qf·NaVi".~ and:Cll-YZ.2.. ·m ~other ," '. - . '. em6odhnei1~, . '.' c9mpo~~ of the..... in~~nij'oii ar~.~sefw~· ". .." .. " inhibitors of CaV2.2. [00121] It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, . but is not limited to, .pharmaceutically acceptable salts, esters, salts of such esters, ·or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof. [00122J As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of -211- WO 2005/042497 PCTlUS2004/036297 humar~ and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate means with a reasonable any non-toxic administration benefit/risk ratio. A "pharmaceutically salt or salt of an ester of a compound of this invention to a recipient, is capable of providing, either directly or indirectly, this invention or an inhibitorily active metabolite "inhibitorily acceptable or residue thereof. salt" that, upon a compound of As used herein, the term active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of a voltage-gated sodium ion channel. [00123] Pharmaceutically Berge, et al. describe pharmaceutically 1977, 66, 1-19, incorporated compounds S. M. acceptable salts in detail in J. Pharmaceutical Sciences, herein by reference. Pharmaceutically acceptable salts of the of this invention include those derived from suitable inorganic and organic acids and bases. Examples amino group phosphoric salts are well known in the art. For example, acceptable of pharmaceutically formed acceptable, with inorganic acids nontoxic acid addition such as hydrochloric acid, sulfuric acid and perchloric salts are salts of an acid, hydrobromic acid, acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically adipate, alginate, ascorbate, aspartate, benzenesulfonate, camphorate, camphorsulfonate, ethanesulfonate, .heptanoate, citrate, cyclopentanepropionate, formate, fumarate, glucoheptonate, hexanoate, hydroiodide, benzoate, salts include bisulfate, borate, butyrate, digluconate, dodecylsulfate, glycerophosphate, 2-hydroxy~ethanesulfonate; acceptable gluconate, lactobionate, hernisulfate, lactate,. iaurate,' la9i)rl s~~ie, .ci~att;,..P1al~~~~, 'inal(jn~te3 ~t;th~e~ilio~at~~.7~n;q>h~al~nes1,1l:fQn~t~, ~9otin~te, 'ci~~e, ~l~te: ox;Uate, palrnit~te,' p~~at~~ pecti~ate, pe~sulfate, 3-phe~ylpr~~ionate: picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, undecanoate, valerate salts, and the like. Salts derived from appropriate metal, alkaline earth metal, ammonium the quaternization Water or oil-soluble Representative magnesium, or dispersable p-toluenesulfonate, bases include alkali and W(Cl-4alkyl)4 salts. This invention of any basic nitrogen-containing products groups of the coInpounds may be obtained by such also envisions disclosed herein. quatemization. alkali or alkaline earth metal salts include sodium, lithium, potassium, and the like. Further pharmaceutically nontoxic ammonium, quaternary ammonium, ph~sph~t~, calcium, acceptable salts include, when appropriate, and amine cations fonned using counterions such - 212- WO 2005/042497 PCTlUS2004/036297 as hal~e, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. Pharmaceutically [00124] acceptable compositions As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack 'Publishing Co., Easton, Pa., 1980) discloses various carriers used in fommlating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve 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 .pro~e. sulf~l.te, disodium hydrogen' phosphate; potassium, hyc}rogeQphosphate, 'sodium ,c~op<;Je"~inc saItS,,coll~idal;sil!ca~'~gQ~~~ ~si~pa~e,:ppl~nyl 'pyriy~d~n~, .po.lyacrylat~,~· w:U:es,potyethyl~~e-polyo~ypr~pyl~e-block polymers, ~o~l fat: s~g~s s~~h a'~lact6~e,:gi~cose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; com oil· and soybean oil; .glycols; .such a 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; pyrogenfree water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and - 213- PCTIUS2004/036297 WO 2005/042497 ~ perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. Uses of Compounds and Pharmaceutically Acceptable Compositions [00125] In yet another aspect, a method for the treatment or lessening the severity of acute, . chronic, neuropathic, or inflammatory pain, arthritis, migrane, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, or incontinence is provided comprising administering an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound to a subject in need thereof. In certain preferred embodiments, a method for the treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain is provided comprising administering an effective amount of a compound or a pharmaceutically acceptable composition to a subject in need thereof. In certain embodiments of the present invention an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of acute, chronic, neuropathic, or inflammatory pain, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, . . arrythmia, movement disorders, .neuroendocrine dis,orders,at<pU.ll; multiple ·sclerosis,iIritabie bowel syticJ.i.o:roe., .orincontinence. tqo~6]:,,:. may ~e ~oJ?lptilinds~~ c~mposition's, aC9P~g to ·th~.~e;thod '~fQ1e:p~e.1l:t.mventlo~, be ~dmi~st~red' ri~ing'any amount and' any' route of ~dnrini~tration ~ffe~ti~~fo~tre~ting or '.' lessening the severity of one or more of acute, chronic, neuropathic, or inflammatory pain, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis,.irritable bowel syndrome, or incontinence. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject.,the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be ·214· PCT/US2004/036297 WO 2005/042497 >- understood, however, that the total daily usage 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 dose 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 specific compound employed; the specific composition employed; the age, body weight, general health, administration, sex and diet of the patient; the time of administration, and rate of excretion of the specific compound employed; route of the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human. [00127] The pharmaceutically to humans and other animals intraperitone~y, spray, acceptable compositions orally, topically (as by powders, or the like, depending embodiments, rectally, the compounds of this invention can be administered parenterally, ointments, on the severity intracisternally, intravaginally, or drops), bucally, as an oral or nasal of the infection being of the invention may be administered In certain treated. orally or parenterally dosage levels of about 0.01 mglkg to about 50 mg/kg and preferably at from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. [00128] Liquid " pnarmaGeutjcally dosage forms acc~ptable for oral administration emulsions, include, riJicroem.ulsions', solutions; but are not limited suspensions, , elixiis.:In .~dditi?n to ,the..~ctiYe.co~C?u1?-ds.,the liquj~ dQsagf?J6i:ms 'piay pori~ co~only u~ed in th~~ ~~ch ~, 'ior ex~pl~" emUlsifiers such as ethyl alcohol, isopropyl alcohol, benzyl benzoate, propylene particular, cottonseed, tetrahydrofurfuryl groundnut, s"rops. and in~rt; 4ilpents, :" :.';, ~ater ~r other' ~olv~~ts, s~lubilizin~ '~ge~~~ alcohol, ethyl carbonate, alcohol, polyethylene germ, olive, castor, and ~d . ethyl acetate, benzyl glycol, 1,3-butylene glycol, dimethylformamide, com, to, sesame oils), oils (in glycerol, 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. [00129] 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 - 215· WO 20051042497 PCTlUS2004/036297 )4- solution, suspension or emulsion in a nontoxic 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 can be employed including synthetic mono- or ~igJycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. [00130] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the fonn of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00131] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactidepolygl~colide. Depending upon the ratio of compound to po~ymerand the nature of the particular .'polymer employed, the.. rate .'or"compound release .can be ·controlled. ExampleS of· other " :.,·1?iocleg(ar1abl~"p~lyin~ • '.. .:" "0 incl~de polY(Qruio.es~ersY· ~d. po1Y(anhy'dIi~$).. Depot ;injeCt~ble - • '. " ." "0 " •• ·0.. • .' • ... .0' • " ••••• 1" • ' ... _ '''', formulations are also prepared by entrapping the compound in liposomes or microemulsions that . are compatible with body tissues. [00132] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol Qr a suppository wax which are . solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. [00133] 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 - 216- PCTlUS2004/036297 WO 2005/042497 and/ota) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed [00134] 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. The solid dosage fonDS of tablets, dragees, capsules, pills, and granules can be prepared 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 can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can 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 ~psUles u~in,gsuch oq:nilk sugar as well weight. . . . . . -. eX~ipiehts.as la.ctose .' . as .high.molecular . . polethylene glycols ~d the like. '.'...., ...':" '. .' . . . .' ". ., '.' • .... ." "[00135] I • .' •.•• '!' '. ....... ',' .•'. . .' ',.... .:., . ~.. . '," .•.• :. ."" . .". __ • - ...... . The' active coinpounds can also be 'in microencapsulated form"with one 'or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the phannaceutical formulating art. In such solid dosage forms th~ acqve cO:Qlpoundmay b~ adpllxed with at leas~ one..inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a 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 can also be of a composition that they release the active ingredient(s) only, - 217- "l PCTmS2004/036297 WO 2005/042497 or prJ'erentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. [00136] Dosage fonus for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of tninsdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper . ' medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. [00137] As described generally above, the compounds of the invention are useful as inhibitors of voltage-gated sodium ion channels. In one embodiment, the compounds and compositions of the invention are inhibitors of one or more of NaVl.l, N.aV1.2, NaV1.3, NaVl.4, NaV1.5, NaV1.6, NaVl.?, NaV1.8, NaVl.9, or CaV2.2 and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of one or:inore of NaVl.l, NaV1.2, NaV1.3, NaVlA',.NaVli5, N~VI:6, NaV'1~7,NaV1.8, NaVi.9,· Qt. ¢aV7.2 ot. i~ j,inpUc~ted,ip·th~d;isease?,?on,dition, dis~~ •.."~en or hYPera~tivitY.. a~~vatiQri of·NaV1.1, N~V·1.2·:NaV1.3: N~VI.·4, NaVl~5, NaV1.6, NaVl~7,"N~V1.8·,N~V1.9, or C~V2.2 is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a "NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.?, NaV1.8, NaV1.9, or CaV2.2-mediated disease, condition or disorder". Accordingly, in another aspect, the present invention provides a method for treating or lessening the severity 'Ofa disease, condition, or disorder where activation or hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaVl.?, NaV1.8 or NaV1.9 is implicated in the disease state. - 218- .. WO 2005/042497 [00138] NaV1.2, PCTfUS2004/036297 The activity of a compound utilized in this invention as an inhibitor of NaV!.1, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 may be assayed according to methods described generally in the Examples herein. It will also be appreciated [00139] compositions that the compounds and pharmaceutically of the present invention can be employed in combination compounds and pharmaceutically acceptable compositions therapies, that is, the can be administered with, prior to, or subsequent to, one or more other desired therapeutics acceptable concurrently or medical procedures. The· particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility effect to be achieved. It will also be appreciated the desired therapeutic employed of the desired therapeutics andlor procedures and may achieve a desired effect for the same disorder that the therapies (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated". [00140] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition that therapeutic agent as the only active agent. Preferably the amount of additional comprising therapeutic agent in the presently disclosed compositions the ~ount noCmanY pi'esent)n.a '.. ~cti.ve i!-gent. '.' ·ne· . [~i)141]'.... ..... .. ... ., .. , of this inv~ntion' or phaImacerit~citIlY ·accept~bie· compositions thereof may also be incorporated such as prostheses, compQsition comprising that agept as the.onlY therapeutiG~ly . ..... 'c~~pounci~ will range from about 50% to 100% of into compositions for coating an implantable medical device, artificial valves, vascular grafts, stents and catheters. present invention, in another aspect, includes a composition Accordingly, for coating an implantable the device .coIQ.prising a compound of the present invention as described generally above, and in classes and subclasses aspect, herein, and a carrier suitable for coating said implantable the present invention includes an implantable device device. In still another coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; - 219- peT IUS2004/036297 wo 2005/042497 ~ 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, acid, ethylene vinyl acetate, and mixtures thereof. covered by phospholipids a suitable topcoat or combinations of fluorosilicone, thereof to impart polyethylene glycol, polylactic The coatings may optionally be further polys accari des, controlled release polyethylene glycol, characteristics in the composition. [00142] Another aspect of the invention relates to inhibiting NaVl.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in a biological sample or a patient, which method comprises administering to the patient, or contacting said biological .sample with a .compound of formula I or a composition comprising said compound. The term .''biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. [00143] Inhibition of NaVl.l, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.?, NaV1.8, NaV1.9, or CaV2.2 activity in a biological sample is useful for a variety of purposes that are known to one of skill 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 the comparative evaluation of new sodium ion channel inhibitors. [00144] In order that the invention described herein may be more fully understood, . :following"e},Camplesare.s~t.fqrtP:. ~t shol,lld be'qnderstood'that ' . ..". p~ose~ these examples are for illustrative only a~.lf~~. DC!tto~e:c<?il~tnie~~ limitlQg tlus-inyentiq!1 in.ani~anner. ..' ......:.. '.' .. ' .... ..... : ~.' EXAMPLES SYNTHESIS OF EXEMPLARY COMPOUNDS OF THE INVENTION: EXalIl,ple 1: - 220- the . WO 2005/042497 PCTIUS2004/036297 ~ This example teaches the preparation of [2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-carbamic acid tert-butyl ester (6). To a solution of beta-alanine (3.5 g, 18.5 mmol) and pyridine (3 rnL,37 mmol) in dichloromethane (20 mL) was added PFP ester (3.2 mL, 18.5 mmol). room temperature for 1 hour, 1,2-phenyleneamine mL) was added to the reaction mixture. water, extracted with dichloromethane After stirring at 1 (2 g, 18.5 nunol) in dichloromethane (20 After stirring overnight, the reaction was quenched with (150 mL*2), dried and removed the solvent. Then the crude mixture was triturated with dichloromethane (20 mL), filtered to give white solid 2 as the desired product (4.8 g) at 90% yield. LCIMS (10-99%) M+lIZ 280.3 retention time 2.03 min. H ero ~~NH80C. cr~~NHBOC NH2 3 2 [00145] Compound 2 (4 g) was dissolved in acetic acid (50 mL) and heated to 65°C for 1 h, then cooled down to room temperature, with dichloromethane, removed the solvent in vacuo. The residue was taken up quenched with sat NaHC03, extracted with diChloromethane (150 mL) (pH = 10), concentrated to afford 3 as light yellow solid (3.7 g) at 100% yield. LCIMS (10-99%) M+ 1/Z 262.2 retention time 2.30 min. r(Y~ '.' .~~ . ~~~NHB~C :. '"0' '. .',--:--~--..... . '. ~", ~ I', ••.• • H~I . ~~~NH2.~OI' • ':.• ' .' • '. . '. '.. ..••• 3 [00146] • 4 Compound 3 (3 g) was dissolved in 3 N HClIEtOAC room temperature "',' 0"" overnight. compound 4 as pink solid (50 mJ.125 mL) and stirred at The solvent was in vacuo and dried in high vacuum to give (2.4 g) at greater than 95% yield. LCIMS (10-99%) M+lIZ retention time 0.62 inin. 5 4 - 221- 162.4 WO 2005/042497 [001471 PCTIUS2004/036297 To a solution of benzimidazole mmol), 3,4-dimethylphenoxyacetic ethylene amine dihydrochloride acid (77 mg, 0.43 mmol) , and BOP reagent (190 mg, 0.43 (5 mL) was added triethylamine (0.23 mL, 1.72 mmol). nunol) in acetonitrile (100 mg, 0.43 room temperature overnight, the solvent was removed under vacuum. After stiffing at The residue was takt:n up with water and saturated sodium bicarbonate (20 mL), extracted with dichloromethane 2), dried and removed the solvent. (30 mL x The crude mixture was purified by using Gilson HPLC to give white solid 5 as a TFA salt (170 mg) at 93 %yield. MUX LCIMS (10-99%) M+1/Z 324.163 retention time 2.62 min; lH NMR (DMSO) <52.12 (s, 3R), <52.15 (5, 3H), <52.99 (t, 2H, J Hz), B 3.59 (m, 2H), (54.40 (s, 2H), (56.64 (dd, IH, J = 2 Hz, 6.5 Hz), 0 6.75 (d, IH, J = 5.88 = 1.8 Hz), 86.98 (8, 1H, J = 6.6 Hz), 8 7.12 (m, 2H), 7.40 (d, 1H, J = 5.76 Hz), 7.53 (m, HI), 8.30 (t, 1H, J = 4.56 Hz), 12.24 (s, IH); 13C NMR (DMSO) 0 18.4, B 111.58, 8143.24, <5 116.13, S 152.74, B 118.12, <5 155.73, <5 120.86, .5 121.52, <5 19.57, S 28.58, <5 36.74, 067.07, <5 128.70, S 130.12, .5 134.21, <5 110.8, <5 137.25, S 167.85. Me H ~N»-~: O:~~NHBOC 6 3 [00148] "'-.-NHBoc Boc-protected benzimidazole ethyl amine 3 (400 mg, 1.53 rnmol) was dissolved in THF (50 mL) and cooled to DoC under nitrogen, followed by dropwise addition of LiHMDS (535 . mg, 3.37 mmol) stirred fQ~ iO ..~. ~x·~e.·· in t.ffp(10 mL) via sYringe.' Me~hyl.iPdide Aft~~"stici~g 'f~;5'h The mlxtUre was waimed '0:).1.~, .1.68. ~Qlt :o/as~:added 'to roo~ temperatUre and .. dropwi~e to ,the reactjo~, .' at r~o~ 't~mperature, 'the 're~cti~n 'wa~ quen~hed ~ith '';;;t~r (20 mL) and extracted with EtOAc (30 mL x 2), dried, concentrated and purified by ISCO flash chromatography. Example 2: o Ji'0H This example teaches the preparation dimethyl-benzyl ester. . ~J-CI of [2-(IH-benzoimidazol-2-yl)-ethyl]-carbamic To a solution of 3,4-dimethylbenzyl - 222- alcohol (1.5 g, 11.0 acid 3,4mmol) in . peT IUS2004f036297 WO 2005/042497 .,; toluene (20 mL) was added phosgene (13 roL, 24.3 mmol, 20% in toluene). After stirring at room temperature overnight, excess phosgene and toluene was removed in vacuo, and dried under high vacuum for 2 h. providing 3,4-dimethylbenzylchloroformate (1.8 g) as an oil at 80 % yield. (reference: Nagele, E.; Schelhaas, M.; Kuder, N.; Waldmann, H. 1. Am. Chem. Soc. 1998, 120,6889) Example 3: H cr~~NH .. }-N~ o y CI CI This example teaches the preparation of 1-[2-(lH-benzoimidazol-2-yl)-ethyl]-3-(3,4-dichlorobenzyl)-urea. To a solution of benzimidazole ethyl amine dihydrochloride (50 mg, 0.21 mmol) in pyridine (1.5 mL) was added 3,4-dichlorobenzylisocyanate (43 p.L, 0.21 mmol). After stirring overnight at room temperature, the crude mixture was purified by Gilson HPLC to afford white solid (50 mg) as a TFA salt at 92% yield. LCIMS (10-99%) M+l/Z 324.2 retention time 2.97 min. Example 4: H H ~N 0 •'.. ··~0N;S~ O=~hy", ~. 0 .• " " .. , •. '. '" ,.' • " :-<::1· .. .'. '.. This example teaches the preparation of N-[2-(lH-Benzoimidazol-2-yl)-ethyl]-3,4-dichlorobenzenesulfonamide. To a solution of benzimidazole ethyl amine dihydrochloride (50 mg, 0.21 mmol) in pyridine (1.5 mL) was added 3,4-dichlorobenzyisocyanate (58 p.L, 0.21 mmol). After stirring overnight at room temperature, the crude mixture was purified by Gilson HPLC to afford . white solid (55 mg) as TFA salt at 92%·yield. Example 5: F + 6: I ~ HO F C -223 - WO 2005/042497 PCTlUS2004/036297 j' This example teaches the preparation of 2-(2,6-Difluoro-phenyl)-7-methyl-lH-benzoimidazole according to the following procedure. A solution of 3-methyl-benzene-l,2-diamine in EtOH (2 mL) was heated for 5 min at 180°C in a 0.82 mmol) and 1,6-difluorobenzaldehyde microwave synthesizer. (100 mg, The EtOH was removed, the residue was dissolved in DMSO (l rnL), and was purified on a Gilson HPLC to afford 2-(2,6-difluoro-phenyl)-7-methyl-1Hbenzoimidazole as 1FA salt (200 mg) at 100% yield. MUX LCIMS (10-99%) M+l/Z 245.061 retention time 2.1 min. [00149] Other compounds of Formula I have been prepared by methods substantially similar to those described above. The characterization data for these compounds is summarized in Table 3 below. The compound numbers correspond to the compound numbers listed in Table 2. Table:3 Characterization Data for Selected Comoounds of Fomula I from Table 2 LCIMS LCIRT LCIRT LCIMS Cmpd# Cmpd# (min) (min) M+ M+ 3 14 16 23 49 54 66 165 1'71 189 ·192 196 197 1.9~, 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 256.28 336.40 326,20 324.40 326.20 344.00 372.20 324.20 364.00 324.20 324.40 . 35820 332.00' .. 321.20' 309.20 314.00 313.20 329.20 309.20 363.20 364.00 365.20 379.20 364.00 339.20 372.20 372.20 386.00 372.20 346.20 338.20 3.20 2.63 1.90 3.74 2.75 2.94 2.46 1.84 2.32 1.69 2.79 2.45 2.87 ... . ''L8S' . 2.06 2.16 1.91 1.97 1.96 2.17 2.25 2.19 2.35 2.25 2.14 2.15 2.09 2.22 2.07 2.04 3.13 '" . ' :" " , , .. ... "." " , ,-. .. ' , -224- 266 267 268 269 270 271 272 273 274 275 276 277 '278 ' ,'219:' 280 281 282 283 284 285 286 . '281 288 289 290 291 292 293 294 295 296 344.20 323.20 370,00 336.40 344,00 346.00 340.00 324.00 325.20 366.82 .. 34MO 315.78 267.30 ". '346.85. 335.30 326.43 284.33 323.41 317.36 321.20 339.20 354.20 353.20 366.20 350.20 382.00 372.00 372.00 332.00 338.20 348.00 3.00 2.89 2.89 2.08 3.90 3.70 3.63 3.81 3.18 3.20 3.30 3.10 3.30 . .3~30 3.10 3.50 3.50 3.10 3.10 1.88 1.76 2;28 1.55 2.16 2.06 2.96 2.84 3.07 2.75 2.62 2.90 .. .. . ',:. ',' PCTlUS2004/036297 WO 2005/042497 Cmpd# 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 .. 327 .' 328' ..'. 329 : "330 331 332 333 LC/MS M+ 373.00 384.00 400.20 384.00 413.00 358.00 356.20 400.20 352.20 398.20 380.00 320.20 398.20 321.20 332.20 338.20 380.00 388.20 386.20 422.00 381.00 386.20 388.20 381.40 388.20 386.20 408,20 328.20 401.20 372.20 400.20 '398.00 347.20 . : '338.20 . 347.20 381.40 353.20 LCIRT Cmpd# (min) 2.66 2.85 3.00 2.77 3.10 3.09 2.96 2.29 1.68 2.44 2.35 2.11 1.88 1.90 2.01 1.90 2.37 2.49 2.52 2.46 2.01 2.57 2.23 1.68 2.34 2.69 2.34 2.15 2.10 2.42 2.26 2.43 1-.'30' . , 1$1: 1.26 1.61 1.74 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 366 367 368 ' " ',369'" 370 LCIMS M+ LCIRT (min) 335.40 1.63 335.20 1.86 383.20 1.73 374.20 1.65 339.00 1.46 408.40 1.44 347.20 1.44 381.40 1.53 415.20 2.15 364.40 1.79 388.20 2.39 362.20 2.27 342.20 2.26 2.05 421.00 350.20 2.13 2.31 376.00 2.23 382.00 2.46 404.40 2.37 376.00 406.20 2.26 404.20 2.63 2.06 328.00 342.00 1.82 344.00 1.87 350.20 2.02 350.20 1.89 350.20 1.98 368.00 1.96 366.00 1.99 2.08 350.20 2.54 .334.00 ' 2.75 350:20 . '316.20 ·2.45' "'3,30.20' .: . ' '2:t';iS:'. 344.00 2.83 Micromass MUX LCT 4 channel LCIMS, Waters 60F pump, Gilson 215 4 probe autosampler, Gilson 849 injection module, 1.5 mL/minlcolumn flow rate, 10-99% CH3CN '(0.035'% TFA) IHzO (0.05 % 'ITA) gradient, PhenomenexLuna 5u CIS columns (50 X' 4.60 nun), Waters MUX UV·2488 UV detector, Cedex 75 ELSD detectors. ASSAYS FOR DETECTING AND MEASURING NaV INHIBITION PROPERTIES OF COMPOUNDS [00150] A) Optical methods for assaying NaV inhibition properties of compounds: -225 - PCTIUS2004/036297 WO 2005/042497 -'I [00151] Compounds of the invention are useful as antagonists channels. Antagonist properties of test compounds were assessed as follows, the Na V of interest were placed into'microtiter stained with fluorescent of voltage-gated sodium ion Cells expressing plates. After an incubation period, the cells were dyes sensitive to the transmembrane potential. The test compounds were added to the microtiter plate. The cells were stimulated with either a chemical or electrical means to evoke a NaV dependent membrane potential change from unblocked channels, which was detected and measured with trans-membrane potential-sensitive dyes. detected as a decreased membrane potential response to the stimulus. potential assay utilized voltage-sensitive Antagonists The optical membrane FRET sensors described by Gonzalez and Tsien (See, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence Gonzalez, were resonance energy transfer in single cells" Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) "Improved transfer" indicators Chern fluorescence Bioi of cell membrane 4(4): 269-77) potential that use fluorescence in combination changes such as the VoltagelIon with resonance instrumentation energy for measuring Probe Reader (VlPR®) (See, Gonzalez, J. E., K. Oades, et al, (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4(9): 431-439). [00152] B) VIPR® optical membrane potential assay method with chemical stimulation Cell Handling and Dye Loading [00153] 24 hours before the assay on VIPR. CHO cells endogenously type voitage-gated Other subtypes' . NaV ~eseeded. in 96-well ar~perfoP:ne,cl"in~,8naiogous expressing a Na V1.2 poly-lysine coated piates at 60.000 cells per well: v ~iln~res_t:". ,', :, ' . .... ..... iQo,d(d~ a cell, fine"eXPreSSJ~g"the'Na ... . .. ". .... . . . " 1) On the day of the assay, medium is aspirated and cells are washed twice with 225 J.IL of Bath Solution #2 (BS#2). 2) A 15 uM CC2-DMPE solution is prepared by mixing 5 mM coumarin stock solution with 10% Pluronie 127 1:1 and then' dissolving the:mix in the appropriate volume of BS#2. 3) After bath solution is removed from the 96-well plates, the cells are loaded with 80 I!L of the CC2-DMPE solution. Plates are incubated in the dark for 30 minutes at room temperature. 4) While the cells are being stained with coumarin, prepared. In addition to DiSBAC2(3), I-IL veratridine a 15 J.IL oxonol this solution should contain 0.75 (prepared from 10 mM EtOH stock. Sigma #V-5754). - 226- solution in BS#2 is roM ABSCI and 30 PCT/US2004/036297 WO 2005/042497 ~ 5) After 30 minutes, CC2-DMPE is removed and the cells are washed twice with 225 J.IL of BS#2. As before, the residual volume should be 40 ilL. 6) Upon removing the bath, the cells are loaded with 80 ilL of the DiSBAC2(3) solution, after which test compound, dissolved in DMSO, is added to achieve the desired test concentration to each well from the drug addition plate and mixed thoroughly. The volume in the well should be roughly 121 ilL. The cells are then incubated for 20-30 minutes. 7) Once the incubation is complete, the cells are ready to be assayed on VIPR® with a sodium addback protocol. depolarization. 120 ilL of Bath solution #1 is added to stimulate the NaV dependent J.IL tetracaine 200 was used as an antagonist positive control for block of the NaV channel. Analysis of VIPR [00154] ® Data: Data are analyzed and reported as normalized ratios of background-subtracted emission intensities measured in the 460 nm and 580 run channels. then subtracted from each assay channel. Background intensities are Background intensities are obtained by measuring the emission intensities during the same time periods from identically treated assay wells in which there are no cells. The response as a function of time is then reported as the ratios obtained .usinK the fol1<?winRformula: . . (intensity.:460 ~ . ~'baCkgrom1d~o~)' . R(t) = ---------------------------------------(intensity [00155] 580 nm - background 580 nm) The data is further reduced by calculating the initial (Ri) and final (Rr) ratios. are the '~v~rag~ ratio v;U~es duri~g part or all of th~ pre-;timulation points during the stimulation period. The response to the stimulus These period, and during ~~ple l? = RflRj is then calculated. For the Na+ addback analysis time windows, baseline is 2-7 see and final response is sampled at 15-24 sec. [00156] Control responses with the desired properties are obtained by performing (positive control), assays in the presence of a compound such as tetracaine, - 227- and in the absence of PCTlUS2004/036297 WO 2005/042497 k pharmacological agents (negative control). Responses to the negative (N) and positive (P) controls are calculated as above. The compound antagonist activity A is defined as: A = R - P * 100 . N-P where R is the ratio response of the test compound Solutions [roM] Bath Solution #1: NaCI 160, KCI4.5, CaCl2 2, MgCl2 1, HEPES 10, pH 7.4 with NaOH Bath Solution #2 TMA-CI160, eaCb 0.1, MgCh 1, HEPES 10, pH 7.4 with KOH (final K concentration - 5 mM) CC2-DMPE: prepared as a 5 mM stock solution in DMSO and stored at -20°C DiSBAC2(3): prepared as a 12 mM stock in DMSO and stored at -20°C ABSC1: prepared as a 200 mM stock in distilled H20 and stored at room temperature Cell Culture [00157] CHO cells are grown in DMEM (Dulbecco's Modified Eagle Medium; GibcoBRL #1O:S~9-o10).suppl~¢erit~4 wi~ 10% FBS (F~taIBovine· Seruin, 'qu~ifiedi Gibco;BRL'#1614.0:· '. :(71) ~d. 1%.Pe~-S~p ·.(Peili¢illin,-'Sti.-eptomY~;:GibcoBRL#15~40':·122).. CeTIs..ate gtp-wn)p.' '~erit~dca~'ti~s~, i~ 90% h~~dlt~'~;; 10'%'C~~, :to 100%'~onti~~n~~:'Th~Y ~e' tis~ally"~p~t'bY trypsinization 1:10 or 1:20, depending on scheduling needs, and grown for 2-3 days before the next split. [00158J C) VlPR® optical membrane potential assay method with electrical stimulation .[00159J. The following is an example of how NaVL3 inhibition activity is measured using the optical membrane potential method#2. Other subtypes are performed in an analogous mode in a cell line expressing the NaV of interest. [00160J HEK293 cells stably expressing NaV1.3 are plated into 96-well microtiter plates. After an appropriate incubation period, the cells are stained with the voltage sensitive dyes CC2DMPE/DiSBAC2(3) as follows. - 228- ~.. PCTlUS2004f036297 WO 2005/042497 Reagents: 100 mg/rnL PlUTonic F-127 (Sigma #P2443), in dry DMSO 10 mM DiSBAC2(3) (Aurora #00-100-010) in dry DMSO 10 IruV1CC2-DNIPE in dry DMSO (Aurora #00-100-008) 200 roM ABSCI in H20 Hank's Balanced Salt Solution (Hyc1one #SID0268.02) supplemented with 10 mM HEPES (Gibco #15630-080) Loading protocol: = 20 JtM [00161] 2X CC2-DMPE equivalent volume of 10% plUTOnic, followed containing 10 mM HEPES. CC2-DMPE 10 mM CC2-DMPE by vortexing is vortexed with an amount of HBSS in required Each cell plate will require 5 mL of 2X CC2-DMPE. is to wells containing concentration. washed cells, resulting in a 10 50 ILL of 2X p.M final staining The cells are stained for 30 minutes in the dark at RT. 2X DISBACz(3) [00162] CC2·DMPE: with ABSC1 = 6JtM DISBACz(3) and 1 roM ABSC1: The required amount of 10 ruM DISBAC2(3) is added to a 50 ml conical tube and mixed with 1 ILL 10% plUTOniCfor each mL of solution to be made and vortexed together. Then HBSS/HEPES is added to make up 2X solution. Finally, the ABSCI is added. ,[O01~3] 'Th~ ~X'])iSBAC2(3) " " ,- . conipo~d,pl{ltes ., •• ",._ ••• solutiqn can be',used to./>oIYl:ItecompoWId plates. w:etrla9-e,at ~X'drqg co~cen~tiop.. ' ~olu~~ 01"50 '~L: '..... • Add 50 ill.:veli"of ••• ',... Note that ,W~sh staiJi¢ plate. again, le~;.mg:re:sjciti~· "0.0 • th~'2X'DiSBAC2(3)"w1 .' ABSCi. ., to. Stai~'f~~ '30'~~ute~ 'hi" the dark at RT. [00164] The electrical stimulation instrument Channel Assay Methods PCTIUS01l21652, comprises a microtiter simultaneously plate handler, and methods herein incorporated of use are described by reference. in ION The instrument an optical system for exciting. the coumarin dye ,while recording the coumarin and axonal emissions, a waveform generator, a current- or voltage-controlled amplifier, and a device for inserting electrodes in well. computer control, this instrument passes user-programmed within the wells of the microtiter plate. Reagents - 229- .... Under integrated electrical stimulus protocols to cells : , .', . PCTlUS2004/036297 WO 2005/042497 [0016St Assay buffer #1 140 roM NaCI, 4.5 IIliVIKCI, 2 IIliYfCaCh, 1 mM MgCh. 10 mM HEPES, 10 roM glucose, pH 7.40, 330 mOsm Pluronic stock (lOOOX): 100 mglmL pluronic 127 in dry DMSO axonal stock (3333X): 10 roM DiSBAC2(3) in dry DMSO (1000X): 10 roM CC2-D11PE in dry DMSO Coumarin stock ABSCI stock (400X): 200 roM ABSCI in water Assay Protocol 1. rosert or use electrodes into each well to be assayed. 2. Use the current-controlled amplifier to deliver stimulation seconds of pre-stimulus recording are performed wave pulses for 3 s. Two to obtain the un-stimulated intensities. Five seconds of post-stimulation recording are performed to examine the relaxation to the resting state. Data Analysis [00166] Data are analyzed and reported as normalized ratios emission intensities measured in the 460 nm and 580 nm channels. then subtrac:t~ from eae}:!.assay chanhel. 4~i :the.~~e e~ssiqn; m~n.sit!ei:;"" " " . ther~ ~e rio ·celi;.· f:ime Ba6kk!:oup.d.mtensfties of background-subtracted Background intensities are are' obtairi~(f by measuring toe'· '1?~rio~~'rto:n.t: id~n~~~ly ·~at~d.~s~y. :wells in ~wNcli :'. .The 'r~s~onse as a 'fun~ti~n of'timti~ the~ ;~~~rt~d'~ th~rati~~~b~ain~ci using the following formula: (intensity . ,R(t).:::;. nm - background 460 nm) ----------.--------~7--.----"7--(intensity [00167] 460 S80 nm - background sso nm) The data is further reduced by calculating the initial (Rj) and final CRf) ratios. These are the average ratio values during part or all of the pre-stimulation period, and during sample points during the stimulation period. The response to the stimulus .R. ::: RtlRi is then calculated. -230 ' .r.' . PCTIUS2004/036297 WO 2005/042497 [00168] Control responses are obtained by perfonning assays in the presence of a compound with the desired properties (positive control), such as tetracaine, and in the absence of pharmacological agents (negative control). Responses to the negative (N) and positive (P) controls are calculated as above. The compound antagonist activity A is defined as: A= R-P *100. where R is the ratio response of the test compound. N-P [00169] ELEClROPHYSIOLOGY ASSAYS FOR NaV ACTIVITY AND INHBITION OF TEST COMPOUNDS [00170] Patch clamp electrophysiology was used to assess the efficacy and selectivity of sodium channel blockers in dorsal root ganglion neurons. Rat neurons were isolated from the dorsal root ganglions and maintained in culture for 2 to 10 days in the presence of NGF (50 nglmI) (culture media consisted of NeurobasalA supplemented with B27, glutamine and antibiotics). Small diameter neurons (nociceptors, 8-12 J.Ul1 in diameter) have been visually identified and probed with fine tip glass electrodes connected to an amplifier (Axon Instruments). The "voltage clamp" mode has been used to assess the compound's IC50 holding the cells at - 60 mV. In addition, the "current clamp" mode has been employed to test the efficacy of the compounds in blocking action potential generation in response to current injections. The results of these experiments have contributed to the definition of the efficacy pro:file ~f the compoun~~ , . [00171] . ,...-;. VOLTAGE-CLAMP assay inDRG neurons' . ':" [00172] ", :' '.. :' .," ',:: , ',~' ': '.' : ," ,.. , ,.:' ,": ,'".." ". ' ,:' • ", " ;' '" ' .. , ~" ..' :"',~_, :' l'" ITX-resistant sodium CUITehts'wererecorded from DRGsomata using the whole-cell variation of the patch clamp technique. Recordings were made at room temperature (-220 C) with thick walled borosilicate glass electrodes (wpI; resistance 3-4 M.Q) using an Axopatch' 200B amplifier (Axon Instruments). After establishing the whole-cell configuration, 'approximately 15 minutes' were' allowed for the pipette solution'to' equilibrate within the cell before beginning recording. Currents were lowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Series resistance was compensated 60-70% and was monitored continuously throughout the experiment. The liquid junction potential (-7 mY) between the intracellular pipette solution and the external recording solution was not accounted for in the data analysis. - 231- • '.. ',' ' PCTIUS2004/036297 WO 2005/042497 ~ Test solutions were applied to the cells with a gravity driven fast perfusion system (SF-77; Warner Instruments). [00173] Dose-response relationships were detennined in voltage clamp mode by repeatedly depolarizing the cell from the experiment specific holding potential to a test potential of +10mV once every 60 seconds. Blocking effects were allowed to plateau before proceeding to the next test concentration. Solutions [00174] Intracellular solution (in mM): Cs-F (130), NaCl (10), MgCIZ (1), BGTA (1.5), CaC1z (0.1); HEPES (10), glucose (Z), pH = 7.4Z, Z90 mOsm. [0~175] Extracellular solution (in mM): NaCI (138), CaCl2 (1.26), KCI (5.33), KHZP04 (0.44), MgCI2 (0.5), MgS04 (0,41), NaHC03 CdC12 (0.4 ), NiC12 (0.1), 1TX (0.25 (0.3), glucose (5.6), HEPES (10), x 10-3). [00176] CURRENT-CLAMP [00177] Cells were current-clamped amplifier (4), NaZHP04 assay for NaV channel inhibition activity of compounds (Axon Inst). Borosilicate in whole-cell configuration with a Multiplamp 700A pipettes (4-5 MOhm) were filled with (in mM):150 K- gluconate, 10 NaCI, 0.1 EGTA, 10 Hepes, 2 MgCh, (buffered to pH 7.34 with KOB). Cells were bathed in (in mM): 140 NaCI, 3 KCI, 1 MgCI , 1 CaC} , and 10 Hepes). Pipette potential was ~ero~d before seal formation; ,. Recprdi,ngs . . .' " ...... were made.~t ~oom te~pt;r~~ ' .:" [00178] liq~~ jpnction potentials weJe not corrected during acquisition. ASSAYS .. ,: '. FOR ,", . c' .. . ', . '.' .. DETECTING '. ; .' .•.. -.- AND .,_ . .. . :. '. '.',:' . .. '. • .;. . . '.: ," MEASURING CaV INHmITION PROPERTIES OF COMPOUNDS A) Optical methods for assaying CaY inhibition properties of compounds: [00179] Compounds of the invention are useful as antagonists of voltage-gated ·ch~neis. Antagonist properties ~f ~st 'compo~nds ~e;e' ~ssessed as follo~s. calcium ion 'Cells ~x~ressing the CaY of interest were placed into microtiter plates_ After an incubation period, the cells were stained with fluorescent dyes sensitive to the transmembrane potential. The test compounds were added to the microtiter plate. The cells were stimulated with electrical means to evoke a Ca V dependent membrane potential change from unblocked channels, which was detected and measured with trans-membrane potential-sensitive - 232- dyes. Antagonists were detected as a PCTfUS2004/036297 WO 2005/042497 ~ decreased membrane potential response to the stimulus. The optical membrane potential assay utilized voltage-sensitive FRET sensors described by Gonzalez and Tsien (See, GonzaIez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chern BioI 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltagellon Probe Reader (VlPR®) (See, Gonzalez, J. E., K. Oades, et aI. (1999) "Cellbased assays and instrumentation for screening ion-channel targets" Drug Discov Today 4(9): 431-439). [00180] VlPR® optical membrane potential assay method with electrical stimulation [00181] The following is an example of how CaV2.2 inhibition activity is measured using the optical membrane potential method. Other subtypes are perfonned in an analogous mode in a cell line expressing the CaV of interest. [00182] HEK293 cells stably expressing CaV2.2 are plated into 96-well microtiter plates. After an appropriate incubation period, the celIs are stained with the voltage sensitive dyes CC2DMPEJDiSBAC2(3) as follows. Reagents: 100 mglmL P1uronic F-127 (Sigma #P2443), in dry DMSO WmM'DiSBAC<;(3) (A~ora 000-100-010) i~ dry DMSO ...• 10·,mM.CC2~DMPE:·(Aurora':,oO-100~8).ili .. .. -,' , "' ' ' " clry'DMSO·.·,·. '.' : ',' 200 roM Acid Yellow 17 (Aurora #VABSC) in H20 370mM Barium Chloride (Sigma Cat# B6394) in H20 Bath X 160roM NaCl (Sigffia Cat# S-9888) 4.5mM KCI (Sigma Cat# P-5405) 1mM MgCl2 (Fluka Cat# 63064) 10mM HEPES (Sigma Cat# H-4034) pH 7.4 llsing NaOH - 233· . ',' ":.' " WO 2005/042497 PCTfUS2004/036297 of Loading rotocol: [00183] 2X CC2-DMPE = 20 ~M CC2-DMPE: 10 roM CC2-D:MPE is vortexed with· an equivalent volume of 10% pluronic, followed by vortexing in required amount of HBSS containing 10 mM HEPES. Each cell plate will require 5 mL of 2X CC2-DMPE, 50 fJ-L of 2X CC2-DMPE is added to wells containing washed cells, resulting in a 10 fJ-M final staining concentration. The cells are stained for 30 minutes in the dark at RT. [00184] 2X CC2DMPE & DISBAC6(3) = 8 p.M CC2DMPE & 2. 5 p.M DISBAC6(3): Vortex together both dyes with an equivalent volume of 10% pluronic (in DMSO). Vortex in required amount of Bath X with beta-cyclodextrin. Each 96well cell plate will require 5 ml of 2XCC2D:MPE. Wash plate with ELx.405 with Bath X, leaving a residual volume of 50 /LUwell. Add 50 fJ-L of 2XCC2DMPE & DISBAC6(3) to each well. Stain for 30 minutes in the dark at RT. [00185] 1. 5X AY17 = 750 J.lM AY17 with 15mM BaCh: Add Acid Yellow 17 to vessel containing Bath X. Mix well. Allow solution to sit for 10 minutes. Slowly mix in 370mM BaCh. This solution can be used to solvate compound plates, Note that compound plates are made at 1.5X drug concentration and not the usual 2X. Wash Ce2 stained plate, again, leaving residual volume of 50 ILL. Add 100 uUwell of the AY17 solution. Stain forI5 minutes in the dark at RT. Run plate on the optical reader. [00186] The electrical stimulation instrument and methods of use are described in ION Channel Assay Methods PCrIUS011216.52, herein incoq,oratecf by reference.' .The' instrument . . . . .':..' '. : .c.o.~pris~s·:a. ~c;~otitet. piate.'.h~d,ler,. 'an':,ppt,icaI . '.' .' . ,.:' .,... . ~ . . .... " ~Ystem for. ex.«iti~g tile .coUlllariri . '. .' . ". . :dy~.w.hile. _ . ,.,.' simultaneously recording the coumarin and oxonol emissions, a waveform generator, a currentor voltage-controlled amplifier, and a device for inserting electrodes in well. Under integrated computer control, this instrument passes user-programmed electrical stimulus protocols to cells within the wells of the microtiter plate. Assay Protoool [00187] Insert or use electrodes into each well to be assayed. [00188] Use the current-controlled amplifier to deliver stimulation wave pulses for 3-5 s. Two seconds of pre-stimulus recording are performed to obtain the un-stimulated intensities. Five seconds of post-stimulation recording are performed to examine the relaxation to the resting state. - 234- WO 20051042497 PCTlUS20041036297 -< Data Ailalysis [00189] Data are analyzed and reported as nonnalized ratios of background-subtracted emission intensities measured in the 460 nm and 580 nm channels, Background intensities are then subtracted from each assay channel. Background intensities are obtained by measuring the emission intensities during the same time periods from identically treated assay wells in which The response as a function of time is then reported as the ratios obtained there are no cells. using the following formula: (intensity R(t) 460nm - background 460nm) = -------------------------------(intensity 580 nm - background 580 nm) [00190] The data is further reduced by calculating the initial (Ri) and final (Rf) ratios. These are the average ratio values during part or all of the pre-stimulation period, and during sample points during the stimulation period. The response to the stimulus [00191] R = RflRi is then calculated. Control responses are obtained by performing assays in the presence of a compound with the desired properties (positive control), such as mibefradil, and in the absence of pharmacological agents (negative control). Responses to the negative (N) and positive (P) controls are calculated as above. The compound antagonist activity A is defined as: .' ~='R:-P *100 .. ,. ·N -P ...." ,." ~her~R'is'~er~iiorespons~ofthete~tc~mpOund. . '". ....' " ' " '[00192]'.'EmetRO~ffi:sIOL(j(}y 'AssAyS' Foi'~~,i A~' . .'''p" .• ,' ."," ANn ~ITIoN'b~':" TEST COMPOUNDS [00193] Patch clamp electrophysiology was used to assess the efficacy of calcium channel blockers expressed in HEK293 cells. HEK293 cells expressing CaV2.2 have been visually identified ane!-.probed with fjn~, tip glass el~trodes connected, to an ~plifier (Axon. Instruments). The "voltage clamp" mode has been used to assess the compound's IC50 holding the cells at - 100 mV. The results of these experiments have contributed to the definition of the efficacy profile of the compounds. VOLTAGE-CLAMP assay in HEK293 cells expressing CaV2.2 - 235 - "', PCTlUS2004/036297 WO 2005/042497 ~ [00194] CaV2.2 calcium currents were recorded from. HEK293 variation of the patch clamp technique. with thick walled borosilicate 200B amplifier approximately (Axon Recordings were made at room temperature (-220 C) glass electrodes Instruments). cells using the whole-cell (wpI; After resistance establishing 3-4 MQ) the using an Axopatch whole-cell configuration, 15 minutes were allowed for the pipette solution to equilibrate before beginning recording. Currents within the cell 2-5 kHz and digitally were lowpass filtered between sampled at 10 kHz. Series resistance was compensated 60-70% and was monitored continuously throughout the experiment. The liquid junction potential (-7 mY) between the intracellular pipette solution and the external recording solution was not accounted for in the data analysis. Test solutions were applied to the cells with a gravity driven fast perfusion system (SF-77; . Warner Instruments). [00195] Dose-response relationships were determined in voltage clamp mode by repeatedly depolarizing the cell from the experiment specific holding potential to a test potential of +20mV for 50ms at frequencies of 0.1, 1,5, 10, 15, and 20 Hz. Blocking effects were allowed to plateau before proceeding to the next test concentration. [00196] Solutions [00197] Intracellular (in roM): Cs-F (130), NaCI (10), MgCl2 solution (1), EGTA (1.5), CaCl2 (0.1), HEPES (10), glucose (2), pH:: 7.42, 290 mOsm. [00198] Extracel~u1ar solu~on (in~: NaCI (l~8), Ba912 (10), KCI (5.33), KHZP04.(O.44), .l\1gC;li (D,S), Mg~04·,(Q.41),.·NaHCQ3 (4),. Na2HP04·(O.3), 'gl~C~~e.(5.6): . . .' .. ~. .' . ~~.'. '... .. . .: ".. . : ' [00199]' found '. ': ~es.·(lO)~:. . ... '." 'Pollowhig these proceatirelf; tepres'eiltatiVe compoundS of the'present to possess desired N-type calcium - 236- channel . invention were· modulation activity. PCTlUS2004/036297 WO 2005/042497 -- [00200]' Compounds of the invention as shown in Table 2 were found modulate voltage-gated sodium channels at 25.0 p.M or less. [00201] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and ~e n.otto be construed as limiting this invention in any manner. -237 -