MXPA06004878A - Benzimidazoles useful as modulators of ion channels - Google Patents

Abstract

The present invention relates to compounds of Formula I:or a pharmaceutically acceptable salt thereof, wherein the R1, Z, Y, RA, and W groups of formula I are as defined herein. The invention also provides pharmaceutically acceptable compositions and methods of suing the compositions in the treatment of various disorders.

Description

BENZIMIDAZOLES USEFUL AS ION CHANNEL MODULATORS TECHNICAL FIELD OF THE INVENTION The present invention relates to compounds useful as inhibitors of voltage-triggered sodium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods for using the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION The Na channels are fundamental for the generation of action potentials in all excitable cells such as, for example, neurons and myocytes. They perform important functions in excitable tissue including brain, smooth muscles of the gastrointestinal tract, skeletal muscle, the peripheral nervous system, spinal cord and respiratory tract. As such they perform important functions in a variety of disease states such as, for example, epilepsy (See, Moulard, B., and D. Bertrand (2002) "Epilepsy and sodium channel blockers" Expert Opin. Ther. Patents 12 ( 1): 85-91)), pain (See, axman, SG, S. Dib-Hajj, et al. (1999) "Sodium channels and pain" Proc Nati Acad Sci USA 96 (14): 7635-9 and Waxman , SG, TR Cummins, et al. (2000) "Voltaj e-gated sodium channels and the molecular pathogenesis of pain: a revie" J Rehabil Res Dev 37 (5): 517-28), myotonia (See, Meóla, 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" Curr Opin Neurol 15 (5): 545-52), ataxia (See, Meisler, M.H., J. A. Kearney, et al. (2002) "Mutations of voltase e-gated sodium in movement disorders and epilepsy" Novartis Found Sy p 241: 72-81), multiple sclerosis (See, Black, JA, S. Dib-Hajj, et al. (2000) "Sensory neuron- Specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalo yelitis and humans with multiple sclerosis "Proc Nati Acad Sci USA 97 (21): 11598-602, and Renganathan, M., M. Gelderblom, et al. (2003) "Expression of Na (v) 1.8 sodium channels perturbs the firing patters of cerebellar purkinje cells" Brain Res 959 (2): 235-42), irritable bowel (See, Su, X., RE Wachtel, et al. (1999) "Capsaicin sensitivity and voltage-gated sodium currents in colon neurons from mouse dorsal root ganglia" Am J Physiol 277 (6 Pt 1): G1180-8, and Laird, J., M., V. Souslova, et al (2002) "Deficits in visceral pain and referred to hyperalgesia in Navl .8 (SNS / PN3) -nuil mice" J Neurosci 22 (19): 8352-6), urinary incontinence and visceral pain (See, Yoshimura , N., S. Seki, et al. (2001) "The involve ent of the tetrodotoxin-resistant sodium channel Na (v) 1.8 (PN3 / SNS) in a rat model of visceral pain "J Neurosci 21 (21): 8690-6), as well as a series of psychiatric dysfunctions such as, for example, anxiety and depression (See, Hurley, SC (2002) "Lamotrigine update and its use in mood disorders" Ann Pharmacother 36 (5 ): 860-73). Tension-gated Na channels comprise a gene family consisting of 9 different subtypes (NaV1.1-NaV1.9). As shown in Table 1, these subtypes show localization in specific tissues and functional differences (See, Goldin, A.L. (2001) "Resurgence of sodium channel research" Annu Rev Physiol 63: 871-94). Three members of the gene family (NaV1.8, 1.9, 1.5) are resistant to block by the well-known Na TTX channel blocker, demonstrating the subtypical specificity within this gene family. Mutational analysis has identified glutamate 387 as a decisive residue for the binding of TTX (See, Noda, M., H. Suzuki, et al. (1989) "A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II" FEBS Lett 259 (1): 213-6). Table 1 (Abbreviations: CNS = central nervous system, PNS = peripheral nervous system, DRG = dorsal root ganglion, TG = Trigeminal ganglion): In general, sodium channels triggered by tension (NaVs) are responsible for the start of the rapid increase in the apoplexy of the action potentials in excitable tissue in the nervous system, which transmits the electrical signals that compose and encode the normal and aberrant sensations. of pain. Antagonists of NaV channels can attenuate these pain signals and are useful for the treatment of a variety of pain conditions, including but not limited to: acute, chronic, inflammatory, and neuropathic pain. Known NaV antagonists, such as for example, TTX, lidocaine (See, Mao, J., and L.L.C. Chen (2000) "Systemic lidocaine for neurophatic pain relief" Pain 87 (1): 7-17.) Bupivacaine, phenytoin (See, Jensen, T. S. (2002) "Anticonvulsant in neuropathic pain: rationale and clinical evidence" Eur J Pain 6 (Suppl A): 61-8), lamotrigine (See, Rozen, TD (2001) "Antiepilept ic drugs in the management of cluster headache and trigeminal neuralgia" Headache 41 Suppl 1: S25-32 and Jensen, TS (2002) "Anticonvulsants in neuropathic pain: rationale and clinical evidence" Eur J Pain 6 (Suppl A): 61-8. ), and carbamazepine (See, Backonja, MM (2002) "Use of anticonvulsants for treatment of neuropathic pain" Neurology 59 (5 Suppl 2): S14-7), have shown to be useful for attenuating pain in humans and models animals . Hyperalgesia (extreme sensitivity to something painful) that develops in the presence of tissue injury or inflammation reflexes, at least in part, an increase in the excitability of high-threshold primary afferent neurons that are distributed at the site of the lesion. The activation of tension-sensitive sodium channels is decisive for the generation and propagation of neuronal action potentials. There is a growing body of evidence indicating that the modulation of NaV currents is an endogenous mechanism used to control neuronal excitability (See, Goldin, AL (2001) "Resurgence of sodium channel research" Annu Rev Physiol 63: 871-94 ). Several sodium channels triggered by kinetic tension and pharmacologically distinct in dorsal root ganglion (DRG) neurons were found. The current resistant to TTX is insensitive to micromolar concentrations of tetrodotoxin, and exhibits slow kinetics of activation and inactivation and a more depolarized activation threshold compared to other sodium channels triggered by voltage. TTX-resistant sodium currents are mainly 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 diameter of the cell body; and gives rise to axons of slow conduction of small diameter that are sensitive to capsaicin. A large body of experimental evidence demonstrates that TTX-resistant sodium channels are expressed in C fibers and are important in the transmission of nociceptive information to the spinal cord. Intrathecal administration of antisense oligo-deoxynucleotides that are destined for a unique region of the TTX-resistant sodium channel (NaVl.8) produces a significant reduction in hyperalgesia induced by PGE2 (See, Khasar, S. G., M. S. Gold, et al. (1998) "A tetrodotoxin-resistant sodium cured ediates inflammatory pain in the rat" Neurosci Lett 256 (1): 17-20). More recently, an anesthetized mouse line, lacking functional NaVl .8, was generated by Wood and colleagues. The mutation has an analgesic effect in tests that evaluate the response of the animal to the carrageenan of the inflammatory agent, (See, Akopian, AN, V. Souslova, et al. (1999) "The t etrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways "Nat Neurosci 2 (6): 541-8.). In addition, deficits in both mechano and thermoreception were observed in these animals. Analgesia shown by mutants inactivated with NaVl .8 is consistent with observations on the function of TTX-resistant currents in nociception. All hybridization experiments in si t u, immunohistochemistry, and electrophysiology have shown that the NaVl.8 sodium channel is selectively localized to the small sensory neurons of the dorsal root ganglion and the trigeminal ganglion (See, Akopian, AN, L. Sivilotti, et al. (1996) "A tetrodotoxin-resistant voltaj e-gated sodium channel expressed by sensory neurons" Nature 379 (6562): 257-62). The main function of these neurons is the detection and transmission of nociceptive stimuli. The antisense and immunohistochemical evidence also supports a function for NaV1.8 in neuropathic pain (See, Lai, J., MS Gold, et al., (2002) "Inhibition of neurophatic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1 .8"Pain 95 (1-2): 143-52, and Lai, J., JC Hunter, et al. (2000)" Blockade of neurophatic pain by antisense targeting of tetrodotoxin-resistant sodium channels in sensory neurons "Methods Enzymol 314: 201-13). The NaVl protein .8 is over-regulated along the non-injured C fibers adjacent to the nerve lesion. Antisense treatment prevents redistribution of NaVl .8 along the nerve and reverses neuropathic pain. Taken together, the gene inactivation and antisense data support a function for NaVl .8 in the detection and transmission of inflammatory and neuropathic pain. In neuropathic pain states there is a remodeling of distribution and subtype of Na channels. In the injured nerve, the expression of NaV1.8 and NaV1.9 is quite reduced while the expression of the NaV1.3 subunit sensitive to TTX is up-regulated 5-10 times (See, Dib-Hajj, SD, J. Fjell, et al (1999) "Plasticity of sodium channel expression in DRG neurons in the chronic constriction injury model of neuropathic pain" Pain 83 (3): 591-600). The course of the increase in NaV1 .3 is parallel to the appearance of allodynia in animal models after the nerve injury. The biophysics of the NaVl .3 channel is different since it shows very rapid reheating after inactivation after a potential action. This allows sustained proportions of high fever as frequently observed in the injured nerve (See, Cummins, TR, F. Aglieco, et al. (2001) "NaVl .3 sodium channels: rapad reprimming and show closed-state inactivation display quantiative differences alter expression in a mammalian cell line and in spinal sensory neurons "J_ Neurosci 21 (16): 5952-61). NaVl .3 is expressed in the central and peripheral systems of man. NaVl .9 is similar to NaVl .8 since it is selectively localized to small sensory neurons of the dorsal root ganglion and the trigeminal ganglion (See, Fang, X., L. Djouhri, et al. (2002). "The presence and role of the tetrodotoxin-resistant sodium channel Na (v) 1.9 (NaN) in nociceptive primary afferent neurons. "J_ Neurosci 22 (17): 7425-33). It has a slow rate of inactivation and dependence on the voltage displaced to the left for activation (See, Dib-Hajj, S., JA Black, et al. (2002) "NaN / Navl.9: a sodium channel with unique properties "Trends Neurosci 25 (5): 253-9). These two biophysical properties allow NaVl .9 to play a role in establishing the resting membrane potential of nociceptive neurons. The resting membrane potential of NaVl .9 expressing cells is in the variation from -55 to -50raV compared to -65mV for most other peripheral and central neurons. This persistent depolarization is mainly due to the sustained low level activation of NaVl channels .9. This depolarization allows neurons to more easily reach the threshold for the action potentials of fever in response to nociceptive stimuli. Compounds that block the NaV1 .9 channel can play an important role in establishing the set point for the detection of painful stimuli. In states of chronic pain, nerves and nerve endings can swell and become hypersensitive, exhibiting fever with high-frequency action potential with mild or even no stimulation. These pathological nerve tumors are called neuromas and the primary Na channels expressed therein are NaVl .8 and NaVl .7 (See, Kretschmer, T., L. T. Happel, et al. (2002) "Accumulation of PN1 and PN3 sodium channels in painful human neuroma-evidence from immunocytochemistry" Acta Neurochir (Wien) 144 (8): 803-10; 810 analysis). NaVl .6 and NaVl .7 are also expressed in dorsal root ganglion neurons and contribute to the small TTX-sensitive component observed in these cells. In particular NaVl .7 can therefore be a potential pain target in addition to its role in neuroendocrine excitability (See, Klugbauer, N., L. Lacinova, et al. (1995) "Structure and functional expression of a new member of the t etrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells "Embo J 14 (6): 1084-90). NaVl .1 (See, Sugawara, T., E. Mazaki-Miyazaki, et al. (2001) "Navl .1 mutations cause febrile seizures associated with afebrile partial seizures." Neuroloqy 57 (4): 703-5) and NaV1 .2 (See, Sugawara, T., Y. Tsurubuchi, et al. (2001) "A missense mutation of the Na + channel alpha II subunit gene Na (v) 1.2 in a patient with febrile and afebrile seizures causes channel dysfunction" Proc Nati Acad Sci US 98 (11): 6384-9) have been linked to epilepsy conditions including fever attacks. There are more than 9 genetic mutations in NaVl.l associated with fever attacks (See, Meisler, MH, JA Kearney, et al. (2002) "Mutations of voltage-gated sodium channels in movement disorders and epilepsy" Novartis Found Symp 241: 72-81). Antagonists for NaVl .5 have been developed and used to treat cardiac arrhythmias. A gene defect in NaV1.5 that produces a greater component without activation for the current has been linked to long QT in man, and local oral anesthetic mexilitin has been used to treat this condition (See, Wang, DW, K. Yazawa , et al. (1997) "Pharmacological targeting of long QT utant sodium channels." J Clin Invest 99 (7): 1714-20). Several Na channel blockers are currently used or being tested in the clinical field to treat epilepsy (See, Moulard, B. and D. Bertrand (2002) "Epilepsy and sodium channel blockers" Expert Opin. Ther. Patents 12 ( 1): 85-91.); acute (See, Wiffen, P., S. Collins, et al. (2000) "Anticonvulsant drugs for chronic pain" Cochrane Datábase Syst Rev 3), chronic (See, Wiffen, P., S. Collins, et al. (2000) "Anticonvulsant drugs for acute and chronic pain" Cochrane Datábase Syst Rev 3, and Guay, DR (2001) "Adjunctive agents in the management of chronic pain" Pharmacot erapy 21 (9): 1070-81), inflammatory (See, Gold, MS (1999) "Tetrodotoxin-resistant Na + currents and inflammatory hyperalgesia." Proc Nati Acad Sci USA 96 (14): 7645-9), and neuropathic pain (See, Strichartz, GR, Z. Zhou , et al. (2002) "Therapeutic concentrations of local anaesthetics unveil the potential role of sodium channels in neuropathic pain" Novartis Found Symp 241: 189-201, and Sandner-Kiesling, A., G. Rumpold Seitlinger, et al. 2002) "Lamotrigine monotherapy for control of neuralgia after nerve section" Acta Anaesthesiol Scand 46 (10): 1261-4); cardiac arrhythmias (See, An, RH, R. Bangalore, et al. (1996) "Lidocaine block of LQT-3 mutant human Na + channels" Circ Res 79 (1): 103-8, and Wang, DW, K. Yazawa , et al., (1997) "Pharmacological targeting of long QT mutant sodium channels" J Clin Invest 99 (7): 1714-20); neuroprotection (See, Taylor, CP and LS Narasimhan (1997) "Sodium channels and therapy of central nervous system diseases" Adv Pharmacol 39: 47-98) and as anesthetics (See, Strichartz, GR, Z. Zhou, et al. 2002) "Therapeutic concentrations of local anaesthetics unveil the potential role of sodium channels in neuropathic pain." Novartis Found Symp 241: 189-201).

Several animal models with clinical significance have been developed for the study of sodium channel modulators for many different indications of pain. For example, chronic malignant pain, see, Johase, H., et al., Acta Anaesthesiol Scand. 2004; 48 (3): 382-3; pain from femur cancer (see, Johase, H., et al, Acta Anaesthesiol Scand., 2004; 8 (3): 382-3); non-malignant chronic bone pain (see, Ciocon, J. o., et al., J am Geriartr Soc. 1994; 42 (6): 593-6); rheumatoid arthritis (see, Calvino, B. et al, Beba Brain Res. 1987; 24 (1): 11-29); osteoarthritis (see, Guzman, R. E., et al., Toxicol Pathol, 2003; 31 (6): 619-24); spinal stenosis (see, Takenobu, Y. et al., J Nuerosci Methods, 2001; 104 (2): 191-8); lu neuropathic (see, Hiñes, 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; 161 (1): 99-104; Sluka KA et al., Muscle Nerve. 2001; 24 (1): 37-46); fibromyalgia (see, Bennet &Tai, Int J Clin Pharmacol Res. 1995; 15 (3): 115-9); pain of the temporomandibular joint (see, Ime H, Ren K, Brain Res Mol Brain Res. 1999; 67 (1): 87-97); chronic, including abdominal, visceral pain (see, Al-Chaer, E.D., et al., Gastroenterology, 2000; 119 (5): 1276-85); pelvic / perineal pain, (see, Wesselmann et al., Neurosci Lett, 1998; 246 (2): 73-6); pancreatic (see, Vera-Portocarrero, L. B., et al., Anesthesiology, 2003; 98 (2): 474-84); IBS pain (see, Verne, G. N., et al., Pain 2003; 105 (1-2): 223-30; JH et al., World Gastroenterol 2003; 9 (12): 2791-5); chronic headache (see, Willimas &Stark, Cephalalgia, 2003; 23 (10): 963-71); migraine (see, Yamamura, H., et al., J Neurophysiol., 1999; 81 (2): 479-93); tension headache, including, acoustic headache (see, Costa, A., et al., Cephalalgia, 2000; 20 (2): 85-91); chronic neuropathic pain, including post herpetic neuralgia (see, Attal, N., et al., Neurology, 2004; 62 (2): 218-25; Ki &Chung 1992, Pain 50: 355); Diabetic neuropathy (see, Beidoun A et al., Clin J Pain, 2004; 20 (3) -1774-8; Courteix, C, et al., Pain, 1993; 53 (1): 81-8); neuropathy associated with HIV (see, Portegies &Rosenberg, Ned Tijdschr Geneeskd, 2001; 145 (15): 731-5; Joseph EK et al., Pain., 2004; 107 (1-2): 147-58; Oh, SB, et al., J Neurosci, 2001; 21 (14): 5027-35); Trigeminal neuralgia (see, Sato, J., et al., Oral Surg Oral Med Oral Pathol Oral Radiol Endod., 2004; 97 (l): 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 al., 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, CJ, 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 Biol. 1983; 37 (2): 276-83); proximal and distal ectopic discharges (see, Liu, X., et al., Brain Res. 2001; 900 (1): 119-27); radiculopathy (see, Devers &Galer, (see, Clin J Pain, 2000; 16 (3): 205-8; Hayashi N et al., Spine., 1998; 23 (8): 877-85), neuropathic pain. induced by chemotherapy (see, Aley, KO, et al., Neuroscience, 1996; 73 (1): 259-65), neuropathic pain induced by radiotherapy, pain after mastectomy (see, Devers &Galer, Clin J Pain. 2000; 16 (3): 205-8); central pain (Cahana, A., et al., Anesth Analg., 2004; 98 (6): 1581-4), pain from spinal cord injury (see, Hains, B.C., et al., Exp Neurol.; 164 (2): 426-37); post-stroke pain; Thalamic pain (see, LaBuda, C.J., et al., Neurosci Lett., 2000; 290 (1): 79-83); complex regional pain syndrome (see, Wallace, M.S., et al., Anesthesiology, 2000; 92 (1): 75-83; Xantos D et al., J Pain., 2004; 5 (3 Supplement 2): S1); phantom pain (see Weber, W., Ned Tijdschr Geneeskd, 2001; 145 (17): 813-7; Levitt &Heyback, Pain, 1981; 10 (1): 67-73); Rebellious pain (see, Yokoyama, M., et al., Can J Anaesth, 2002; 49 (8): 810-3); acute pain, acute postoperative pain (see, Koppert, W., et al., Anesth Analg., 2004; 98 (4): 1050-5; Brennan, TJ, et al., Pain., 1996; 64 (3): 493-501); acute musculoskeletal pain; joint pain (see, Gotoh, S., et al., Ann Rheum Dis. 1993; 52 (11): 817-22); lu mechanic balgia (see, Kehl, L.J., et al., Pain., 2000; 85 (3): 333-43); neck pain; tendonitis; pain by injury / exercise (see, Sesay, M., et al., Can J Anaesth, 2002; 49 (2): 137-43); Acute visceral pain, including, abdominal pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias etc. (see, Giambernardino, M.A., et al., Pain., 1995; 61 (3): 459-69); chest pain, including, heart pain, (see, Vergoña, R. A., et al., Life Sci. 1984; 35 (18): 1877-84); pelvic pain, pain due to renal colic, acute obstetric pain, including pain due to childbirth (see, Segal, S., et al., Anesth Analg., 1998; 87 (4): 864-9); pain by caesarean section; acute inflammatory pain, burn and trauma; Acute intermittent pain, including, endometriosis (see, Cason, A.M., et al., Horm Behav., 2003; 44 (2): 123-31); acute pain due to herpes zoster; sickle cell anemia; acute pancreatitis (see, Toma, H; Gastroenterology, 2000; 119 (5): 1373-81); advanced pain; orofacial pain, including, sinusitis pain, dental pain (see, Nusstein J., et al., J Endod, 1998; 24 (7): 487-91; Chidiac JJ, et al., Eur J Pain, 2002; 6 (l): 55-67); pain from multiple sclerosis (MS) (see, Sakurai &Kanazawa, J Neurol Sci. 1999; 162 (2): 162-8); pain in depression (see, Greene B, Curr Med Res Opin, 2003; 19 (4): 272-7); pain from leprosy; pain from behcet's disease; painful adiposis (see, Devillers &Oranje, Clin Exp, Dermatol. 1999; 24 (3): 240-1); phlebitic pain; Pain of Guillain-Barre; painful legs and toes in movement; Haglund syndrome; pain due to erythrodalgia (see, Legroux-Crespel, E., et al., Ann Dermatol Venereol., 2003; 130 (4): 429-33); pain from Fabry's disease (see, Germain, D., P., J Soc Biol. 2002; 196 (2): 183-90); bladder and urogenital disease, including, urinary incontinence (see, Berggren, T., et al., J Urol. 1993; 150 (5 Ptl): 1540-3); Bladder overactivity (see, Chuang, Y. C, et al., Urology, 2003; 61 (3): 664-70); painful bladder syndrome (see, Yoshimura, N., et al., J Neurosci, 2001; 21 (21) -8690-6); interstitial cystitis (Cl) (see, Giannakopoulos &Ca pilo atos, Arch Ital Urol Nefrol Androl, 1992; 64 (4): 337-9; Boucher, M., et al., J Urol. 2000; 164 (1) : 203-8); and prostatitis (see, Mayersak J.S., Int Surg., 1998; 83 (4): 347-9; Keith, I.M., et al., J Urol., 2001; 166 (1): 323-8). Stress-gated calcium channels are multi-subunit proteins that span membranes, which open in response to depolarization of the membrane, allowing the entry of Ca from the extracellular environment. Calcium channels were initially classified based on time and dependence on the tension of the opening channel and sensitivity to pharmacological blockade. The categories were activated with low voltage (mainly type T) and high voltage altivadas (type L, N, P, Q or R). This classification scheme was replaced by a nomenclature based on the molecular subunit composition, as summarized in Table I (Hockerman, GH, et al. (1997) Annu. Rev. Pharmacol. Toxicol., 37: 361-96; Striessnig, J. (1999) Cell Physio Biochem 9: 242-69). There are four primary subunit types that constitute the calcium channels -OÍ_, a2d, ß and? (See, for example, De Waard et al., Structural and functional diversity of voltage-activated calcium channels, In Ion Channels (ed. T. Narahashi) 41-87, (Plenum, Press, New York, 1996)). The Oi subunit is the primary determinant of pharmacological properties and contains the channel pore and stress detector (Hockerman, G. H., et al. (1997) Annu. Rev. Pharmacol. Toxicol 37: 361-96; Striessnig, J. (1999) Cell. Physio. Biochem. 9: 242-69). Ten isoforms of the ai subunit are known, as indicated in Table I. The a2d subunit consists of two subunits linked to disulfide, 2 which is mainly extracellular and a transmembrane d subunit. Four isoforms of a2d, a2d-l, a2d-2, a2d-3 and a2d-4, are known. The β subunit is a non-glycosylating cytoplasmic protein that binds to the oc subunit. . Four isoforms are known, called ßi to ß4. The subunit y is a transmembrane protein that has been biochemically isolated as a component of the Cavl and Cav2 channels. At least 8 isoforms are known (? A? 8) (Kang, M.G. and K. P. Campbell (2003) J. Biol. Chem. 278: 21315-8). The nomenclature for calcium channels triggered by voltage is based on the content of the subunit? £ ?, as indicated in Table 1. Each type of subunit o? it can be associated with a variety of subunits ß, a2d or subunits and, such that each Cav type corresponds to many different combinations of subunits.

Cav2 currents were found almost exclusively in the central and peripheral nervous system and in neuroendocrine cells and are the predominant forms of the calcium current triggered by presynaptic tension. The presynaptic action potentials cause the opening of channels and the neurotransmitter release depends sharply on the subsequent calcium intake. In this way, Cav2 channels play a central role in the delivery of neurotransmitter release. Ca 2.1 and Cav2.2 contain high affinity binding sites for the peptide toxins D-conotoxin-MVIIC and D-conotoxin-GVIA, respectively, and these peptides have been used to determine the distribution and function of each type of channel. Cav2.2 is highly expressed in the presynaptic nerve terminals of the neurons from the dorsal root ganglion and the neurons of lamina I and II of the dorsal horn (Westenbroek, RE, et al (1998) J. Neurosci. 6319-30; Cizkova, D, et al. (2002) Exp. Brain Res. 147: 456-63). The channels of Cav2.2 are also found in the presynaptic terminals between the second and third order interneurons in the spinal cord. Both neurotransmission sites are very important in transmitting pain information to the brain. The pain can be roughly divided into three different types: acute, inflammatory, and neuropathic. Acute pain serves an important protective function to keep the organism safe from stimuli that can cause tissue damage. Severe thermal, mechanical, or chemical exposures have the potential to cause severe damage to the body if left unattended. Acute pain serves to remove the individual quickly from the harmful environment. Acute pain by its very nature in general lasts little and is intense. Inflammatory pain, on the other hand, can be experienced for long periods of time and its intensity graduated more. Inflammation can occur for many reasons including tissue damage, autoimmune response, and invasion of pathogens. Inflammatory pain is caused by a variety of agents that are released during inflammation, including substance P, histamine, acid, prostaglandin, bradykinin, CGRP, cytokines, ATP, and other agents (Julius, D. and A. I. Basbaum (2001) Nature 413 (6852): 203-10). The third type of pain is neuropathic and involves damage to the nerve that is produced by nerve injury or viral infection and results in the reorganization of neuronal proteins and circuits that provide a pathological "sensitized" state that can produce chronic pain during years. This type of pain does not provide adaptive benefit and is particularly difficult to deal with existing therapies. Pain, particularly neuropathic and unruly pain, is a great medical need that has not been met. Millions of individuals suffer from severe pain that is not well controlled by current therapeutic methods. 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 only in 60% of patients and has a modest efficacy. The drug in general is safe, although sedation is a problem at higher doses. The approval 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, S.S., et al. (1996) J. 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 men, the intrathecal infusion of Ziconotide is effective for the treatment of unruly pain, cancer pain, opioid-resistant pain, and neuropathic pain. The toxin has a success rate of 85% for the treatment of pain in humans with a higher 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 neurons from nociceptive trajectories, and antagonists of these channels could be used to treat pain. Antagonists of Cav2.1, Cav2.2 or Cav2.3 should also be useful to treat other pathologies of the central nervous system that apparently involve excessive calcium intake. Cerebral ischemia and stroke are associated with excessive calcium entry due to the depolarization of neurons. The Cav2.2 antagonist, ziconotide, is effective in reducing the severity of a stroke in a model of focal ischemia using laboratory animals, suggesting that Cav2.2 antagonists could be used for the treatment of stroke. Likewise, the reduction of excessive calcium influx in neurons may be useful for the treatment of epilepsy, traumatic brain injury, Alzheimer's disease, dementia due to multiple infarcts and other types of dementia, amyotrophic lateral sclerosis, amnesia, neuronal damage caused by poison or other toxic substances. Cav2.2 also causes the release of neurotransmitters from the neurons of the sympathetic nervous system and the antagonists could be used to treat cardiovascular diseases such as, for example, hypertension, cardiac arrhythmia, angina pectoris, myocardial infarction, and congestive heart failure. However, as described above, the efficacy of sodium channel blockers and calcium channel blockers currently used for the disease states described above has been greatly limited by various side effects. These side effects also include various CNS disturbances, such as, for example, blurred vision, vertigo, nausea, and sedation, as well as, life-threatening cardiac arrhythmias and heart defects. Accordingly, there remains a need to develop Na channel antagonists and additional Ca channel antagonists, preferably those with greater potency and fewer side effects.

BRIEF DESCRIPTION OF THE INVENTION It has now been found that the compounds of this invention, and the pharmaceutically acceptable compositions thereof, are useful as inhibitors of stress-activated sodium channels. These compounds have the structure of formula I: I or a pharmaceutically acceptable salt thereof, wherein R, Z, Y, r, and W are as defined below. These compounds, and pharmaceutically acceptable compositions are useful for treating or decreasing the severity of a variety of diseases, disorders, or conditions, including, but not limited to: acute, chronic, neuropathic, or inflammatory pain, such as, for example, femur cancer; chronic non-malignant bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lumbago; syndrome due to myofascial pain; fibromyalgia; pain of the temporomandibular joint; chronic visceral pain, including, abdominal; pancreatic; IBS pain; chronic headache; migraine; tension headache, including cluster headaches; chronic neuropathic pain, including post-herpetic neuralgia; diabetic neuropathy; neuropathy associated with HIV; Trigeminal neuralgia, Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; proximal and distal extropic discharges; radiculopathy; neuropathic pain induced by chemotherapy; neuropathic pain induced by radiotherapy; pain after the mastectomy; central pain; pain due to spinal cord injury; pain after a stroke; thalamic pain; complex regional pain syndrome; ghost pain; rebellious pain; acute pain, acute postoperative pain; acute musculoskeletal pain; articulations pain; Lumbago Mechanical; Neck Pain; pain due to injury / exercise; Acute visceral pain, including, abdominal pain; pyeloneph itis; appendicitis; cholecystitis; intestinal obstruction; hernias etc; chest pain, including, heart pain; pelvic pain, pain due to renal colic, acute obstetric pain, including pain on the part of a cesarean section; acute inflammatory, burn and trauma; intermittent acute pain, including, endometriosis; acute pain due to herpes zoster; sickle cell anemia; acute pancreatitis; advanced pain; orofacial pain, including, sinusitis pain, dental pain; pain due to multiple sclerosis (MS); pain in depression; pain from leprosy; pain from behcet's disease; painful adiposis; phlebitic pain; pain Guillain-Barre; painful legs and toes in movement; Haglund syndrome; pain due to erythromelalgia; pain from Fabry's disease; bladder and urogenital disease, including, urinary incontinence; overactivity of the bladder; painful bladder syndrome; interstitial cystitis (IC); or prostatitis, arthritis, migraine, headache in accumulations, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as for example, anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders , ataxia, multiple sclerosis, irritable bowel syndrome, and incontinence.

DETAILED DESCRIPTION OF THE INVENTION 1. General Description of the Invention Compounds: The present invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: r is 0 to 4; Z is 0, N or CH; Y and W are independently selected from hydrogen, the Formula la: the one where wherein: T is a bond or a straight or branched aliphatic chain of C? _6 wherein a methylene unit of T is optionally replaced by a C3_g cycloaliphatic group; U is -CH.2- or -CH2-CH2-; X is N-C? _4alkyl, NH, O, S, S (O), or S02; and each event of Rc is independently M-Rx; wherein: M is a bond or is a chain of C? _6 alkylidene wherein up to two non-adjacent methylene units of M are optionally replaced by C (O), C02, C (0) C (0), C (0) ) NR, OC (0) NR, NRNR, NRNRC (O), NRC (O), NRC02, NRC (0) NR, S (O), S02, NRS02, S02NR, NRSO2NR, O, S, or NR, and Rx is R ', halogen, N02, or CN; wherein: each R 'event is independently selected from hydrogen or an optionally substituted group selected from aliphatic C? _8, C? -io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having -10 atoms in the ring, or R and R 'taken together with the atoms to which they are attached, or two R' events taken together with the atoms to which they are attached, form a cycloalkyl, heterocyclyl, aryl, or 5-8 membered heteroaryl having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; V is a bond, -C (O) -, or -S (0) 2-; Q is a bond or a C? -4 alkylidene chain in which up to two non-adjacent methylene units of Q are optionally replaced by -O-, -NH-, or -S-; is 0 or 1; Ring E is C6 -__ aryl, 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 independently selected heteroatoms of nitrogen, oxygen, or sulfur; and s is 0 to 5; or the Formula Ib: Ib wherein: D is -Ci-ealkyl- or a bond; and t is 0 to 5; each event of R is independently selected from hydrogen or an optionally substituted aliphatic C? _6 group; and each event of RR, RB and RD are independently selected from R1, R2, R3, R4, or R5, where: R1 is oxo, R6 or (C? ~ aliphatic) n-0k where: n is 0 or 1; J is halo, CN, N02, CF3, 0CF3, OH, SR6, S (0) R6, S02R6, NH2, NHR6, N (R6) 2, NR6R8, C (0) OH, C (0) OR6 or OR6; or: two R1 on the adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy; R2 is Cx-ßaliphatic, optionally substituted with up to two substituents independently selected from R1, R4, or R5; R- is C3_8Caloaliphatic, 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 heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R3 is optionally substituted with up to three substituents independently selected from R1, R2, R4 or R5; R4 is OR5, OR6, OC (0) R6, OC (0) R5, OC (0) OR6, OC (0) OR5, OC (0) N (R6) 2, OC (0) N (R5) 2, OC (O) N (R6R5), SR6, SR5, S (0) R6, S (0) R5, S02R6, S02R5, S02N (R6) 2, S02N (R5) 2, S02NR5R6, S03R6, S03R5, C (0 ) R5, C (0) OR5, C (0) R6, C (0) OR6, C (0) N (R6) 2, C (0) N (R5) 2, C (0) N (R5R6), C (O) N (OR6) R6, C (0) N (OR5) R6, C (O) N (0R6) R5, C (O) N (OR5) R5, C (N0R6) R6, C (N0R6) R5, C (N0R5) R6, C (N0R5) R5, N (R6) 2, N (R5) 2, N (R5R6), NR5C (0) R5, NR6C (0) R6, NR6C (0) R5, NR6C (0) 0R6, NR5C (0) OR6, NR6C (0) OR5, NR5C (0) OR5, NR6C (O) N (R6) 2, NR6C (O) NR5R6, NR6C (O) N (R5) 2, NR5C (O) (R6) 2, NR5C (O) NR5R6, NR5C (O) N (R5) 2, NR6S02R6, NR6S02R5, NR5S02R5, NR6S02N (R6) 2, NR6S02NR5R6, NR6S02N (R5) 2, NR5S02NR5R6, NR5S02N (R5) 2, N (OR6) R6, N (OR6) R5, N (OR5) R5, or N (OR5) R6; R5 is a C3_8cycloaliphatic, C6_? 0 aryl, 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 selected independently of nitrogen, oxygen, or sulfur, wherein R5 is optionally substituted with up to three R1 substituents; R6 is R optionally substituted with R7, wherein: R7 is a C3_8cycloaliphatic, C6-? Or aryl; 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 selected from nitrogen, oxygen, or sulfur, in wherein R7 is optionally substituted with up to two substituents independently selected from R, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH2) n ~ G, wherein G is selected from halo, CN, N02, CF3, OCF3, OH, S-aliphatic, S (O) -aliphatic, S02-aliphatic, NH2, N-aliphatic, N (aliphatic) 2, (aliphatic) R8, COOH, C (O) O (-aliphatic), or O-aliphatic; and R8 is an amino protecting group; with the proviso that only one of Y and W is of the formula la or Ib and the other of Y and W is hydrogen. In certain different embodiments, for the compounds of Formula I as generally described above and herein: a) when Z is N, W is of Formula la, A is -C 2 alkyl-NH-, V is -C ( 0) -, Q is -Cialkyl-0-, and Ring E is phenyl, then RA is not hydrogen, -Cl, -Br, C? _4alkyl, methoxy, or nitro, either singly or in combination; b) when Z is N, W is of Formula la, A is -C2alkyl-NH-, V is -C (0) -, Q is a bond, and Ring E is phenyl, then RA is not hydrogen, - Cl, -Br, C? _4alkyl, methoxy, or nitro, either singly or in combination; c) when Z is N, W is of Formula la, A is -C3alkyl-NH-, V is -C (O) -, Q is a bond, and Ring E is phenyl, then RA is not 4-amino , nor 4-methoxy car onyl; d) when Z is N, W is of Formula la, A is -C3alkyl-NH-, V is -C (O) -, and Q is a bond, then, Ring E is not -2 (2, 3 -dihydro-benzo [1,4] dioxin); e) when Z is N, W is of Formula la, A is -C3alkyl-NH-, V is -C (O) -, and Q is a -Calkyl- 0-, then Ring E is not -6 ( 4-dimethyl-2H-chromen-2-one); f) when Z is N, W is of Formula la, A is -C2alkyl-NH-, V is -C (O) -, and Q is a -C2alkyl- O-, then Ring E is not phenyl unsubstituted; g) when Z is N, W is of the Formula la, A -C2alkyl-NH-, V is -C (0) -, and B is a bond, then, Ring E is not thienyl unsubstituted; h) when Z is N, W is Formula A, A -2alkyl-NH-, V is -C (0) -, and Q is a -Cialkyl-O-, and Ring E is phenyl, then RA is not phenyl in the 4-position; i) when Z is N, W is of the Formula la, A -alkyl-NH-, V is -C (O) -, and Q is a -C2alkyl, then Ring E is not 2-isoindoline-1, 3-dione; j) when Z is N, W is of the Formula la, A is -C2alkyl-NH-, V is -C (O) -, and Q is a -C2alkyl-0-, and ring E is phenyl, then RA is not phenyl in the 4-position; and k) when Z is N, W is Formula A, A -C2alkyl-NH-, V is -C (O) -, and Q is a bond, then, Ring E is not unsubstituted adamantyl. According to another embodiment, the present invention provides a compound of the formula la, as generally defined above, wherein: (a) when Z is N, Y is hydrogen, W is Formula A, A is and V and Q are each a link, then: (i) when r is 1 and RA is methyl at the C-5 or C-6 position of the benzimidazole ring, then E is not: unsubstituted 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; naphthyl unsubstituted; phenyl substituted in the position pa ra with OEt, Br, OH, or OMe; phenyl substituted in the meta position with chlorine; or phenyl substituted in the ortho position with methyl; (b) when Z is N, Y is hydrogen, W is of the formula la, Q is -NHCH2-, r is 0, and V is C (O), then: (i) when A is -CH2CH2NH-, then E is not (ii) when A is -CH2NH-, then E is not (c) when Z is C, W is hydrogen, Y is of the formula la, r is 0, A is -CH2CH2NH-, V is C (O), Q is -CH20- and E is phenyl, then: (i) s or is 0; (ii) when s is 1, RB is not unsubstituted phenyl, chlorine, OMe, methyl, bromine, in the position for; cyano or OMe in the ortho position; or methyl in the meta position; (iii) when s is 2, RB is not dichloro in the ort or / para positions; and (iv) when s is 3, RB is not 2, 3, 4-trimethyoxy or 2,4,5-trichlor. In certain different embodiments, for the compounds of Formula I as generally described above and herein: a) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -C (0) -, Q is -CH20-, and Ring E is phenyl, then RA is not -Cl, -Br, C? _4alkyl, methoxy, or nitro, either singly or in combination; b) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -C (O) -, Q is a bond, and ring E is phenyl, then RA is not -Cl, -Br , C? _4alkyl, methoxy, or nitro, either singly or in combination; c) when Z is N, W is of Formula la, A is -CH2CH2CH2NH-, V is -C (O) -, Q is a bond, and Ring E is phenyl, then RA is not 4-amino, or 4-methoxycarbonyl; d) when Z is N, W is of Formula la, A is -CH2CH2CH2NH-, V is -C (O) -, and Q is a bond, then Ring E is not -2 (2, 3-dihydro- benzo [1,4] di oxine); e) when Z is N, W is of Formula la, A is -CH2CH2CH2NH-, V is -C (0) -, and Q is a -CH20-, then Ring E is not - 6 (4-dimet -2H-chromen-2 -one); f) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -C (0) -, and Q is a -CH2CH20-, then Ring E is not unsubstituted phenyl; g) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -C (0) -, and Q is a bond, then, Ring E is not unsubstituted thienyl; h) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -C (O) -, and Q is a -CH20-, and Ring E is phenyl, then RA is not phenyl in position 4; i) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -C (O) -, and Q is -CH2CH2-, then Ring E is not 2-isoindoline-l, 3- diona; j) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -C (0) ~, and Q is -CH2CH20-, and Ring E is phenyl, then RA is not phenyl in the position 4; and k) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -C (O) -, and Q is a bond, then Ring E is not unsubstituted adamantyl. 1) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -C (0) -, Q is -CH2CH20-, and Ring E is phenyl, then RB is not -Cl, - Br, C? _4 alkyl, methoxy, unsubstituted phenyl, -C (CH3) 2-phenyl, or nitro, either singly or in combination; m) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -C (O) -, Q is -CH = CH2-, and Ring E is phenyl, then RB is not -Cl in the ortho position; and n) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -S02-, Q is a bond, and ring E is phenyl, then RB is not chloro. Another embodiment of the present invention provides a method for treating or decreasing the severity of a disease, disorder, or condition selected from acute, chronic, neuropathic, or inflammatory pain, including pain from femoral cancer; chronic non-malignant bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; syndrome due to myofascial pain; fibromyalgia; pain of the temporomandibular joint; chronic visceral pain, including, abdominal pain; pancreatic; IBS; chronic headache; migraine; tension headache, including cluster headaches; chronic neuropathic pain, including, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; proximal and distal ectopic discharges; radiculopathy; neuropathic pain induced by chemotherapy; neuropathic pain induced by radiotherapy; pain after the mastectomy; central pain; pain due to spinal cord injury; pain after a stroke; thalamic pain; complex regional pain syndrome; ghost pain; rebellious pain; acute pain, acute postoperative pain; acute musculoskeletal pain; articulations pain; Lumbago Mechanical; Neck Pain; tendonitis; pain due to injury / exercise; Acute visceral pain, including, abdominal pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias etc; chest pain, including, heart pain; pelvic pain, pain due to renal colic, acute obstetric pain, including pain due to childbirth; pain by caesarean section; acute inflammatory pain, burn and trauma; acute intermittent pain, including, endometriosis; acute pain due to herpes zoster; sickle cell anemia; acute pancreatitis; advanced pain; orofacial pain, including, sinusitis pain, dental pain; pain due to multiple sclerosis (MS); pain from depression; pain from leprosy; pain from behcet disease; painful adiposis; phlebitic pain; pain Guillain-Barre; painful legs and toes in movement; Haglund syndrome; pain due to erythromelalgia; pain from Fabry's disease; bladder and urogenital disease, including, urinary incontinence; bladder overactivity; painful bladder syndrome; interstitial cystitis (IC); or prostatitis; arthritis, migraine, acoustic headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or a condition of epilepsy, a neurodegenerative disorder, a psychiatric disorder such as, for example, anxiety and depression, myotonia, arrhythmia, a movement disorder, a neuroendocrine disorder, ataxia, multiple sclerosis, irritable bowel syndrome, or incontinence comprising the step of administering to the patient an effective amount of a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein RA, Z, Y, r, and W are. as defined above and in the classes and subclasses as described herein. A preferred aspect of the present embodiment is where the disease, condition, or disorder is acute, chronic, neuropathic, or inflammatory pain. Another embodiment of the present invention provides a method of treating or decreasing the severity of a disease, condition or disorder wherein the disease, condition, or disorder is involved in the activation of voltage-triggered sodium channels comprising administering an effective amount of a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein RA, Z, Y, r, and W are as defined above and in the classes and subclasses as described herein. A preferred aspect of the present embodiment is where the disease, condition, or disorder is acute, chronic, neuropathic, or inflammatory pain, epilepsy or a condition of epilepsy, a neurodegenerative disorder, a psychiatric disorder such as, for example, anxiety and depression, myotonia, arrhythmia, a movement disorder, a neuroendocrine disorder, ataxia, multiple sclerosis, irritable bowel syndrome, or incontinence. A particularly preferred aspect of the present embodiment is where the disease, condition, or disorder is acute, chronic, neuropathic, or inflammatory pain. Another preferred aspect of the present embodiment is where the method comprises an additional therapeutic agent. Still another embodiment of the present invention provides a method to inhibit the activity of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9 , or CaV2.2 in: (a) a patient; or (b) a biological sample; the method comprises administering to the patient, or contacting the biological sample with a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R Y, and W are as defined above and in the classes and subclasses as described herein. 2. Compounds and Definitions: The compounds of this invention include those generally described above, and are further illustrated by the classes, subclasses, and species set forth herein. As used herein, the following definitions will apply unless otherwise indicated. For the purposes of this invention, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75ava. Ed.

Additionally, the general principles of organic guímica are described in "Organic Chemistry", Tomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5a. Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the total content thereof is incorporated herein by reference. The present invention provides compounds of Formula I with substituents which are monovalent, such as for example, RA, RB, Rc and RD; or divalent, such as, for example, A, B, and D. Those skilled in the art will appreciate that for asymmetric divalent substituent groups, such as, for example, -C? _6alkyl-NH-, and -C? _4alkyl- 0-, there are two possible orientations in relation to the main structure. In the sense in which it is used in the present specification, the orientation of a divalent substituent is fixed by its left / right orientation relative to the Formula as shown in the present specification. Those skilled in the art will also appreciate that this orientation convention is not relevant to symmetrical divalent substituents, such as, for example, -C (O) -, or -C? -6alkyl-.

For example for Formula I, where Z is N, W is present as, RA is hydrogen, V is -C (O) -, Ring E is phenyl, RB is hydrogen; and A and Q are divalent substituents (A is -C3alkyl-NH-, and Q is -C? alkyl-0-), the following is the described compound.

For example for Formula I, where Z is N, W is present as, RA is hydrogen, V is -C (O) -, Ring E is phenyl, RB is hydrogen; and A and Q are divalent substituents (A is -C2alkyl-NH- and Q is -0-Cj.alkyl-), the following is the described compound.

For example for Formula I, where Z is N, W is present as the, U is -CH2-, RA is hydrogen, V is -C (O) -, Ring E is phenyl, RB is hydrogen; and A and Q are divalent substituents [A is and Q is -Cialkyl-O-), the following is the described compound.

As described herein, the compounds of the invention may optionally be substituted with one or more substituents, as generally illustrated above, or as exemplified by the particular classes, subclasses, and species of the invention. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In general, the term "substituted", whether or not preceded by the term "optionally", refers to the replacement of the hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent in each substitutable group position, and when more than one position may be substituted in any given structure with more than one substituent selected from a specified group , the substituent may be the same or different in each position. The combinations of substituents provided by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable", in the sense in which it is used herein, refers to compounds that are not substantially altered when subjected to conditions that allow their production, detection, and preferably their recovery, purification, and utilization. for one or more of the purposes set forth herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 ° C or less, in the absence of moisture or other chemically reactive conditions, for at least a week. The terms "aliphatic", "aliphatic group" or "alkyl", in the sense in which it is used herein, means a straight (ie, unbranched) or branched chain, or a substituted or unsubstituted hydrocarbon chain that is fully saturated or containing one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocycle") cycloaliphatic "or" cycloalkyl "), which has a single point of attachment with the rest of the molecule. Unless otherwise specified, the aliphatic groups contain 1-20 aliphatic carbon atoms, ie C? -20alkyl. In some embodiments, the aliphatic groups contain 1-10 aliphatic carbon atoms, i.e., Ci-ioalkyl. In other embodiments, the aliphatic groups contain 1-8 aliphatic carbon atoms, i.e., Ci-salkyl. Still in other embodiments, the aliphatic groups contain 1-6 aliphatic carbon atoms, ie, C6-6alkyl and still in other embodiments, the aliphatic groups contain 1-4 aliphatic carbon atoms, ie, C? -alkyl. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a C3-C8 monocyclic hydrocarbon or Cs-C? 2 bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but that not aromatic, having a single point of attachment to the rest of the molecule where any single ring in the bicyclic ring system has 3-7 members. Suitable aliphatic groups include, but are not limited to: alkyl groups, alkenyl, alkynyl, substituted or unsubstituted, linear or branched, and hybrids thereof such as for example, (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl. The term "heteroaliphatic", "heterocycle", "heterocyclyl", "heterocycloaliphatic" or "heterocyclic", in the sense in which it is used herein, means ring systems neither aromatic, monocyclic, bicyclic, or tricyclic in which one or more of the members in the ring is an independently selected heteroatom. In some embodiments, the group "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocyclic" has from three to fourteen members in the ring in which one or more of the members in the ring is a heteroatom independently selected from oxygen , sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 members in the ring. The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon); the quaternized form of any basic nitrogen or; a nitrogen atom that can be substituted for a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)). The term "unsaturated," in the sense in which it is used herein, means that an entity has one or more units of unsaturation. The term "alkoxy", or "thioalkyl", as used herein, refers to an alkyl group, as defined above, attached to the main carbon chain through an oxygen atom (" "alkoxy") or sulfur ("thioalkyl"), for example C? _4alkoxy refers to the group alkoxy, methoxy, etioxy, propoxy and butoxy, including for propoxy and butoxy, the straight and branched structures, which is i-proproxy and n- propoxy; and n-butoxy, i-butoxy and sec-butoxy.

The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term "halogen" means F, Cl, Br, or I. The term "aryl" used alone or as part of a larger entity as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to ring systems monocyclic, bicyclic, and tricyclic having a total of five to fourteen members in the ring, wherein at least one ring in the system is aromatic and wherein each ring in the system contains from 3 to 7 members in the ring. The term "aryl" can be used interchangeably with the term "aryl ring". The term "aryl" also refers to heteroaryl ring systems as will be defined below. The term "heteroaryl", used alone or as part of a larger entity 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 heteroatoms, and wherein each ring in the system contains from 3 to 7 members in the ring. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". An aryl group (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are selected from halogen; -R °; -OR °, -SR °; 1,2-methylene dioxy; 1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R °; -O (Ph) optionally substituted with R °; - (CH2)? _2 (Ph), optionally substituted with R °; -CH = CH (Ph), optionally substituted with R °; -N02; -CN; -N (R °) 2; -NR ° C (0) R ° -NR ° C (O) N (R °) 2; -NR ° C02R °; -NR ° NR ° C (O) R ° -NR ° NR ° C (O) N (R °) 2; -NR ° NR ° C02R °; -C (0) C (0) R ° -C (O) CH 2 C (O) R °; -C02R °; -C (0) R °; -C (0) N (R °) 2 -OC (O) N (R °) 2; -S (0) 2R °; -S02N (R °) 2; -S (0) R ° -NR ° S02 (R °) 2; -NRS02R °; -C (= S) N (R °) 2; -C (= NH) -N (R °) 2 or - (CH2) or_2NHC (O) R ° wherein each independent event of R ° is selected from hydrogen, C? _6 optionally substituted aliphatic, a heteroaryl or heroic ring of 5-6 unsubstituted members, phenyl, -O (Ph), or -CH2 (Ph), or, notwithstanding the above definition, two independent events of R °, in the same substituent or different substituents, taken together with the atoms to which each R ° group is attached, form a 3-8 membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents in the aliphatic group of R ° are selected from NH2, NH (C? Aliphatic), N (C? _4aliphatic) 2, halogen, C? -aliphatic, OH, O (C? _4aliphatic), N02, CN , C02H, C02 (C1_ aliphatic), O (haloC? _ Aliphatic), or haloC? _4aliphatic, wherein each of the above C? _4aliphatic groups of R ° is unsubstituted. An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aliphatic or heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon atom of an aryl or heteroaryl group and additionally include the following: = 0, = S, = NNHR *, = NN (R *) 2, = NNHC (0) R *, = NNHC02 (alkyl), = NNHS02 (alkyl), or = NR *, where each R * is independently selected from hydrogen or an optionally substituted C? -6aliphatic. The optional substituents in the aliphatic group of R * are selected from NH2, NH (C? -4aliphatic), N (C? _4aliphatic) 2 r halogen, Aliphatic C, OH, 0 (C_- aliphatic), N02, CN, C02H, C0 (C? _ Aliphatic), O (halo C? _4aliphatic), or halo (C? _ Aliphatic), wherein each of the C * _4aliphatic groups of R * above is unsubstituted. Optional substituents on the nitrogen atom of a non-aromatic heterocyclic ring are selected from -R +, -N (R +) 2, -C (0) R +, -C02R +, -C (0) C (0) R +, -C (O) CH2C (O) R +, -S02R +, -S02N (R +) 2, -C (= S) N (R +) 2, -C (= NH) -N (R +) 2, or -NR + S02R +; wherein R + is hydrogen, an optionally substituted C? -6aliphatic, optionally substituted phenyl, -O (Ph) optionally substituted, -CH2 (Ph) optionally substituted, - (CH2)? _2 (Ph) optionally substituted; -CH = CH (Ph) optionally substituted; or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having from one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, notwithstanding the above definition, two independent R + events, in the same substituent or different substituents, taken together with the atoms to which each R + group is attached, form a cycloalkyl, heterocyclyl, aryl, or 3-8-membered heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur . Optional substituents on the aliphatic group or the phenyl ring of R + are selected from NH 2, NH (C 4 - aliphatic), N (C 4 - aliphatic) 2, halogen, C α - aliphatic, OH, O (C 4 - aliphatic), N02, CN, C02H, CO2 (C? _ Aliphatic), O (halo C? _ Aliphatic), or halo (C? _4aliphatic), wherein each of the above C? _4aliphatic groups of R + is unsubstituted. The term "C? _2alkylidene chain" refers to a straight or branched carbon chain of 20 carbon atoms or less that can be fully saturated or can have one or more units of unsaturation and has two points of attachment to the remainder of the chain. molecule. Unless stated otherwise, it should also be understood that the structures depicted herein include all isomeric (e.g., enantiomeric, diastomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, the double bond isomers (Z) and (E), and the conformational isomers (Z) and (E). Therefore, the individual stereochemical isomers, as well as the enantiomeric, diastomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless stated otherwise, all tautomeric forms of the compounds of the invention are within the scope of the invention. For example, for the compounds of the formula I: where Z is N or O, someone with normal experience could recognize that a suitable tautomer is as depicted above. When group Z of formula I is CH, someone with normal experience could recognize that the appropriate tautomer is as shown below: "TT.

Additionally, unless stated otherwise, it is also to be understood that the structures depicted herein include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures present except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon atom by a 13C- or 14C-enriched carbon are within the scope of this invention. These compounds are useful, for example, as analytical tools or tests in biological analyzes. 3 . Description of the Compounds of Example: In certain embodiments, the present invention provides a compound of Formula I wherein V is -S (0) 2 ~. In other embodiments, the present invention provides a compound of Formula I wherein V is -C (O) -. In one embodiment, T is a straight or branched aliphatic chain of C? _6 where a methylene unit of T is optionally replaced by a group C3_6 cycloaliphatic.

Also preferred is a compound of Formula I wherein Ring E is phenyl. Also preferred is a compound of Formula I wherein Ring E is naphthyl. A compound of the Formula I wherein Ring E is pyridinyl. Also preferred is a compound of Formula I wherein Ring E is thienyl. Also preferred is a compound of Formula I wherein Ring E is furanyl. Also preferred is a compound of Formula I wherein Ring E is quinolinyl. Also preferred is a compound of Formula I wherein Ring E is benzofuranyl. A compound of the Formula I wherein Ring E is 3,4-dihydro-2H-chromene. Also preferred is a compound of Formula I wherein Ring E is 2,3-dihydrobenzo [b] [1,4] dioxin. According to one aspect, the present invention provides a compound of Formula I, wherein Ring E is a preferred group as described above and the group is in combination with the remaining variables of Formula I as set forth in the classes and subclasses described herein. In certain modalities, each RA of the Formula I, when present, is independently R6, OR6, CN, or halo. In other modalities, each RB of the Formula I, when present, is independently OR6, N (R6) 2, NR6C (0) R6, halo, R6, C (0) R6, or N02. In other embodiments, entity A of Formula I, when present, is -T-NR6-, where T is a straight or branched aliphatic chain of C? -6.

These entities include -CH2CH2N (CH3) -, -CH2CH2NH-, -CH2NH-, and -CH2CH (CH3) H-. In certain embodiments, the present invention provides a compound of Formula I wherein A is -T-NH- wherein T is a straight or branched aliphatic chain of C? _6 wherein a methylene unit of T is replaced by a C3_6 cycloaliphatic group.

These cycloaliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl groups. In other modalities, entity Q of the Formula I is a chain of C? _4 alkylidene wherein a methylene unit of Q is replaced by -O-, -NH-, or -S-. These Q-entities of Formula I include -CH2CH20-, -CH20-, -OCH2-, -OCH2CH2-, -CH (CH3) 0-, NHCH2-, -C (CH3) 20-, and -CH2S-. As described above, for the compounds of the invention of Formula I, Z is O, N or C. Accordingly, in certain embodiments where Z is N, the corresponding compounds have the structure of Formula II: p In certain embodiments of Formula II, Y is hydrogen, Ring E is phenyl, and W is of the formula la, wherein V is -C (O) -, as shown in the Formula la: He has or a pharmaceutically acceptable salt thereof, wherein RA, R, A, Q, RB, and s are as defined above and herein.

Preferred is a compound of Formula Ia, wherein Q is a bond or chain of C? _4 alkylidene wherein a methylene unit of Q is replaced by -0-, -NH-, or -S-. These Q entities of Formula Ia include -CH2CH20-, -CH20-, -0CH2-, -0CH2CH2-, -CH (CH3) 0-, -NHCH2-, -C (CH3) 20-, and -CH2S-. Particularly preferred is a compound of Formula Ia, wherein Q is -CH20-. Also particularly preferred is a compound of Formula Ia, wherein Q is -OCH2- • Also particularly preferred is a compound of Formula Ia, wherein Q is -NHCH2 ~. Also preferred is a compound of Formula Ia, wherein A is -C? -6alkyl-NH-. Particularly preferred is a compound of Formula Ia, wherein A is -CH2CH2NH-. Also particularly preferred is a compound of Formula Ia, wherein A is -CH2NH-. In certain embodiments, the present invention provides a compound of Formula Ia, wherein A is -CH2CH2NH-, Q is -CH20-, and each RB is independently C6-6 aliphatic, -CHO, or halogen. In other embodiments, the present invention provides a compound of Formula Ilb, wherein A is -CH2CH2NH-, Q is -CH20-, and each RB is independently methyl, -CHO, fluorine, or chlorine. In other embodiments, the present invention provides a compound of Formula Ia, wherein A is -CH2CH2NH-, Q is -CH = CH-, -CH20- or -NHCH2 'and each RB is independently CN, C6-6 aliphatic, -N (R6) 2, or halogen. These RB groups include methyl, ethyl, butyl, isopropyl, chlorine, fluorine, bromine, N (Me) 2, CF3 and -CH2phenyl. According to another embodiment, the present invention provides a compound of Formula Ia wherein the benzo ring is substituted in one of, or both of, the C-4 and C-5 positions with tert-butyl, fluorine, or methyl. According to another embodiment, the present invention provides a compound of Formula Ia, wherein A is -CH2CH2NH- or -CH (CH3) NH-, Q is -CH20- and each RB is independently C6-6 aliphatic, -N (R6) 2, -C (0) R6, or halogen. These RB groups include methyl, chloro, bromo, ethyl, N (Me) 2, -C = CH and C (0) CH3. Still another embodiment of the present invention relates to a compound of Formula Ia, wherein A is -CH2CH2NH-, Q is -CH20-, -NHCH2-, or -CH (CH3) 0-, and each RB is independently C ? _6 aliphatic, -OR6, or halogen. These RB groups include methyl, ethyl, -OMe, chlorine, bromine, and fluorine.

According to still another embodiment, the present invention provides a compound of Formula Ia, wherein A is -CH2CH2NH- or -CH2CH (CH3) NH-, Q is -CH20-, -NHCH2-, -NH-, -CH (CH3) 0-, or -C (CH3) 20-, and each RB is independently C6-6 aliphatic, -OR6, or halogen. These RB groups include methyl, ethyl, -OMe, chlorine, bromine, and fluorine. According to another embodiment, the present invention provides a compound of Formula Ia wherein r is 2, each RA is fluorine, and is present at the C-4 and C-5 positions. In certain embodiments, the present invention provides a compound of Formula Ia, wherein A is -CH2CH2NH-, Q is -CH20-, and each RB is independently C6-6 aliphatic or halogen. In other embodiments, the present invention provides a compound of Formula Ia, wherein A is -CH2CH2NH-, Q is -CH20-, and each RB is independently methyl, isopropyl, fluorine, bromine, or chlorine. In still other embodiments, the present invention provides a compound of Formula Ia, wherein A is -CH2CH NH-, Q is -CH20-, and each RB is independently methyl, fluoro, or chloro. In still other embodiments, the present invention provides a compound of Formula Ia, wherein A is -CH2CH2NH-, Q is -CH20-, and each R1 is independently methyl, bromo, or chloro. A compound of the Formula lia, where A is A compound of the Formula lia, where A is A compound of the Formula lia, where A »where U is -CH2- or -CH2CH2- In certain embodiments of Formula II, Y is hydrogen, Ring E is phenyl, W is of Formula Ib and D is a bond, as shown below as formula Ilb. pb or a pharmaceutically acceptable salt thereof, wherein RA, r, RD, and s are as defined above and herein. Preferred is a compound of Formula Ilb, wherein RA is R6 or halo. In certain embodiments, RA is methyl, chlorine or bromine. Particularly preferred is a compound of Formula Ilb, wherein RA is methyl. Also preferred is a compound of Formula Ilb wherein RD is halo, OR6, N (R6) 2, NR6C (0) R6, or two RD are taken together to form a methylenedioxy or ethylenedioxy group. In certain embodiments, RD is -OH, -N (Et) 2, -OMe, -NHC (0) CH3, fluorine, or chlorine. According to another embodiment, the present invention provides a compound of Formula III: m or a pharmaceutically acceptable salt thereof, wherein A, Q, RA, r, RB, and s are as defined above and herein.

In certain embodiments, each RA of the Formula III, when present, is independently R6, OR6, CN, or halo. In other embodiments, each RB of Formula III, when present, is independently OR6, N (R6) 2, NR6C (0) R6, halo, R6, C (0) R6, or N02. In other embodiments, entity Q of Formula III is a chain of C? _ Alkylidene wherein a methylene unit of Q is replaced by -0-, -NH-, or -S-. These Q-entities of Formula III include -CH2CH20-, -CH20-, -OCH2-, -0CH2CH2-, -CH (CH3) 0-, -NHCH2-, -C (CH3) 20-, and -CH2S-. In other modalities, Entity A of the Formula III, when present, is -T-NR6-, where T is a straight or branched aliphatic chain of C? _6- These entities A include -CH2CH2N (CH3) -, -CH2CH2NH-, -CH2NH-, and -CH2CH (CH3) NH-. In certain embodiments, the present invention provides a compound of Formula III wherein A is -T-NH-, wherein T is a straight or branched aliphatic chain of C? _6 wherein a methylene unit of T is replaced by a group C3_6 cycloaliphatic. These cycloaliphatic groups include cyclobutyl, cyclopentyl, and cyclohexyl groups.

According to another embodiment, the present invention provides a compound of Formula IV: IV or a pharmaceutically acceptable salt thereof, wherein V, Q, RA, r, RB, n, and s are as defined above and herein. In certain embodiments, each RA of Formula IV, when present, is independently R6, OR6, CN, or halo. In other embodiments, each RB of Formula IV, when present, is independently OR6, N (R6) 2, NR6C (0) R6, halo, R6, C (0) R6, or N02. In other embodiments, Ring E of Formula IV is phenyl or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3-7 membered monocyclic heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

These Ring E groups of Formula IV include pyridyl, thienyl, furyl, and pyrazolyl. In still other embodiments, the E-Ring group of Formula IV is an 8-10 membered bicyclic aryl ring or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. These Ring E groups of Formula IV include naphthyl, quinolinyl, 3,4-dihydro-2H-chromene, and 2,3-dihydrobenzo [b] [1,4] dioxin. In other embodiments, entity Q of Formula IV is a chain of C? _4 alkylidene wherein a methylene unit of Q is replaced by -O-, -NH-, or -S-. These Q entities of Formula IV include -CH2CH20-, -CH20-, -OCH2-, -OCH2CH2-, -CH (CH3) 0-, -NHCH2-, -C (CH3) 20-, and -CH2S-. According to another aspect of the present invention, one of V and Q is a link. In accordance with yet another aspect of the present invention, both V and Q are a bond. Representative compounds of Formula I are set forth in the following Table 2.

Although certain exemplary embodiments were depicted and described above and herein, it will be appreciated that the compounds of the invention can be prepared according to the methods generally described above using the appropriate starting materials by the methods generally available for someone with normal experience in the technique. _. The entirety of the compounds of this invention can be prepared generally by methods known to those skilled in the art for the analogous compounds, as will be illustrated by the general schemes below, and the following preparative examples. Starting materials are commercially available from typical chemical reagent companies, such as, for example, Aldrich Chemicals Co. , Sigma Chemical Company, ChemBridge Corporation, and the like. Compounds that are not commercially available can be prepared by those of ordinary skill in the art following the procedures set forth in references such as, for example, "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, Elservier Science Publishers, 1989, and" Organic Reactions ", Volumes 1-40, John Wiley and Sons, 1991.

Scheme 1 Scheme 1 shows the general preparation of compounds of Formula I. Typically the compounds of Formula I, where Y or W is wherein A is -NH-, or -N (Ci-ealguilo) - is prepared by coupling the optionally substituted compounds of Formula A, which have a nucleophilic function with the optionally substituted compounds of Formula B, which have a electrophilic functional terminal group, such as for example a carboxylic acid, sulfonyl halide, isocyanate, or the like, as defined above. These methods can also be applied to the compounds of Formulas II and III as defined above Scheme without tech 2a, 2b: Scheme 2a shows the preparation of optionally substituted benzimidazole compounds of Formula II. Scheme 2b shows the preparation of the optionally substituted benzimidazole compounds and additionally of Formula II.

Scheme 2a 1) Acilate, cyclize PG = protective group 2) Unprotect I II Scheme 2b A 1, 2-phenyldiaminobenzene optionally substituted is reacted with a carboxylic acid optionally substituted with a protected nucleophilic group to provide the benzimidazole intermediate, which is then cyclized to form the benzimidazole entity. The nucleophilic group is deprotected and subjected to acylation, sulfonation, carbamoylation, or alkylation to provide the compounds of Formula II.

Scheme without te ti co 3a, 3b, 3c: Scheme 3a shows the preparation of optionally substituted aryloxy acids. The optionally substituted aryloxy acids are prepared by reacting the phenolic compounds optionally substituted with halo-substituted alkyl esters, optionally substituted, (X is Cl, Br or I) to obtain the corresponding ester.

Scheme 3a The ester compound is then hydrolyzed to obtain an optionally substituted substituted compound of Formula B.

Scheme 3b As shown in Schemes 1, 2a, and 2b, the compounds of Formula A and B are reacted together to obtain the compounds of Formula I. For example, Formula A when shown in Scheme 2b and Formula B as shown in the present Scheme 3b can be reacted to form the corresponding compound of Formula I (Scheme 3c).

Scheme 3s Scheme no tect 4: Following the procedures shown in Schemes 1, 2a, 2b, 3a, 3b, and 3c, and using an optionally substituted aryl isocyanate compound of Formula B, Scheme 4 the optionally substituted compounds of Formula I are obtained.

Synthetic Scheme 5: Following the procedures shown in Schemes 1, 2a, 2b, 3a, 3b, and 3c, and using an optionally substituted aryl sulfonyl chloride compound of Formula B, the optionally substituted compounds of Formula I are obtained.

Scheme without tectin 6: The optionally protected substituted benzimidazoles of Formula A are prepared by reacting a benzimidazole substituted with cyano starting with (Boc) 20 followed by reduction of the cyano group (Raney-Nickel / H2 or the like) to provide the desired compound of Formula A.

To Scheme 6 As shown above in Schemes 1, 2a, 2b, 3a, 3b, 3c, 4 and 5, the compounds of the Formula A from this present Scheme 6 are derived to provide the corresponding compounds of Formula I.

Scheme s without tea ti la la, Ib: an optionally substituted benzyl alcohol is reacted with phosgene to provide an optionally substituted compound of Formula B.

B Scheme 7a This compound is then reacted with a compound of Formula A to provide the corresponding compound of Formula I. For example, when the compound of Formula A is a benzimidazole shown in Scheme 2, the following compounds of the Formula are obtained I, when s is 0 to 4, and m is 1 or 4, as corresponds to Q with Q being -0-C? -alkyl.

Scheme 7b Scheme without tech 8: A compound of Formula I, where W is is prepared by reacting a di-amino benzene optionally substituted with a benzaldehyde or optionally substituted benzoic acid to obtain the corresponding optionally substituted compound of Formula I, wherein RA, RD, r and t are as shown for Formula I, in a manner analogous to Schemes 2a and 2b. Although certain exemplary embodiments were depicted and described above and herein, it will be appreciated that the compounds of the invention can be prepared according to the methods generally described above using the appropriate starting materials by the methods generally available to someone with normal experience in the technique.

. USES, FORMULATION AND ADMINISTRATION In yet another aspect, a method is provided for the treatment or reduction of the severity of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, headaches in accumulations; trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as for example, anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome or incontinence comprising administering, to a subject in need thereof, an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound thereof. In certain preferred embodiments, there is provided a method for treating or reducing the severity of an acute, chronic, neuropathic, or inflammatory pain, which comprises administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable composition. In certain embodiments of the present invention an "effective amount" of the pharmaceutically acceptable compound or composition is that amount effective to treat or decrease the severity of one or more of acute, chronic, neuropathic, or inflammatory pain, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as for example, anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome or incontinence. As generally described above, the compounds of the invention are useful as sodium ion channel inhibitors or calcium channels triggered by voltage, preferably N-type calcium channels. In one embodiment, the compounds and compositions of the invention are inhibitors of one or more of NaVl.l, NaV1.2, NaVl.3, NaVl.4, NaVl.5, NaVl. 6, NaV1.7, NaVl .8, NaV1.9, or CaV2.2, and in this way, without wishing to be bound to any particular theory, the compounds and compositions are particularly useful in treating or decreasing the severity of a disease, condition, or disorder where the activation, or hyperactivity of one or more of NaVl.l, NaV1.2, NaV1.3, NaVl. 4, NaV1.5, NaV1.6, NaVl. is implicated in the disease, condition, or disorder. 7, NaV1.8, NaV1.9, or CaV2.2. When NaVl.l, NaVl.2, NaV1.3, NaV1.4, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1, NaV1.1, NaV1.3, NaV1.3, NaV1.6, NaV1.6, NaV1.6, NaV1.8, NaV1.6, NaV1.6 .9, or CaV2.2, the disease, condition, or disorder may also be referred to as a "disease, condition, or disorder caused by NaVl.l, NaV1.2, NaV1.3, NaVl .4, NaVl.5, NaVl. .6, NaV1.7, NaVl .8, NaV1.9, or CaV2.2"or a" disease, condition or disorder caused by CaV2.2". Accordingly, in another aspect, the present invention provides a method for treating or decreasing the severity of a disease, condition, or disorder where the activation or hyperactivity of one or more of NaVl.l, NaV1 is implicated in the disease state. 2, NaV1.3, NaV1 .4, NaV1.5, NaV1.6, NaV1 .7, NaV1.8, NaV1.9, or CaV2.2. The activity of a compound used in this invention as an inhibitor of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 can be analyzed according to the methods generally described in the Examples herein, or according to methods available to one of ordinary skill in the art. In certain exemplary embodiments, the compounds of the invention are useful as inhibitors of NaVl .8. In other embodiments, the compounds of the invention are useful as inhibitors of NaVl .8 and CaV2.2. In still other embodiments, the compounds of the invention are useful as CaV2.2 inhibitors. It will also be appreciated that certain of the compounds of the present invention may exist in free form for treatment, or when appropriate, as a pharmaceutically acceptable derivative thereof. In accordance with the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, salts, esters, salts of those pharmaceutically acceptable esters, or any other adduct or derivative which at the time of administration to a patient in need thereof is capable of of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without Irritation toxicity, undue allergic response, and the like, and in accordance with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt or salt of an ester of a compound of this invention which, at the time of administration to a container, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitoryly active metabolite or residue thereof. In the sense in which it is used herein, the term "inhibitoryly active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of a tension-triggered sodium ion channel. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. , describe in pharmaceutically acceptable salts in J. Pha rma ceu t i ca l Sci en ces, 1977, 66, 1-19, incorporated herein by reference. The pharmaceutically acceptable salts of the compounds of this invention include those derived from inorganic and organic acids and suitable bases. Examples of non-toxic, pharmaceutically acceptable acid addition salts are salts of an amino group formed with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as for example, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by the use of other methods used in the art such as, for example, ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorrate, camphorsulfonate, citrate, cyclopentanpropionate, digluconate, dodecylsulfat or, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, iodhydrate, 2-hydroxy-ene-sulphonate, lactobionate or, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nichotinats, nitrate, oleate, oxalate, palmitate, patoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, salts of valerate, and the like. Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N + (C? Alkyl) salts. This invention also provides for the quaternization of any basic nitrogen containing groups of the compounds set forth herein. By means of this quaternization, soluble or dispersible products can be obtained in water or oil. Representative alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as, for example, halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

CELLULARLY ACCEPTABLE PACKAGING COMPOSITIONS As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle which, in the sense in which it is used herein, includes any and all solvents, thinners, or other liquid vehicle, dispersion or suspension aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as appropriate to the particular dosage form desired. Remington's Pharmaceutical Sciences, Déciraasexta Edición, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in the formulation of 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, for example, in producing any undesirable biological effect or otherwise interacting in a harmful manner with any other components of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as, for example, human serum albumin, buffer substances such as, for example, phosphates, glycine , sorbic acid, or potassium sorbate, mixtures of partial glyceride of saturated vegetable fatty acids, water, salts or electrolytes, such as, for example, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, wool grease, sugars such as, for example, lactose, glucose and sucrose; starches such as, for example, corn starch and potato starch; cellulose and its derivatives such as, for example, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; excipients such as, for example, cocoa butter and suppository waxes; oils such as, for example, peanut oil, cottonseed oil; safflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols; a propylene glycol or polyethylene glycol; esters such as, for example, ethyl oleate and ethyl laurate; agar; damping agents such as, for example, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, for example, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavorings and Flavoring agents may also be present in the composition preservatives and antioxidants, according to the judgment of the formulator.

Uses of compounds and drug compositions in a yet other way, a method is provided for the treatment or reduction of the severity of an acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine. , headaches in accumulations; trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as for example, anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome or incontinence comprising administering, to a subject in need thereof, an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound thereof. In certain preferred embodiments, there is provided a method for treating or reducing the severity of an acute, chronic, neuropathic, or inflammatory pain, which comprises administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable composition. In certain embodiments of the present invention an "effective amount" of the pharmaceutically acceptable compound or composition is that amount effective to treat or decrease the severity of one or more of acute, chronic, neuropathic, or inflammatory pain, epilepsy or epilepsy conditions, neurodegenerative, psychiatric disorders such as for example, anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome or incontinence. The compounds and compositions, according to the method of the present invention, can be administered using any amount and any route of administration effective to treat or diminish the severity of one or more of acute, chronic, neuropathic, or inflammatory pain, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as, for example, anxiety and depression, myotonia, arrhythmia, 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 unit dosage form for ease of administration and uniformity of dosage. The term "unit dosage form", in the sense in which it is used herein, refers to a physically discrete unit of the agent suitable for the patient to be treated. It should be understood, however, that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on 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, sex and diet of the patient; the time of administration, the route of administration, and the rate of excretion of the specific compound employed; the duration of the treatment; the drugs used in combination or coinciding with the specific compound used, and similar factors well known in the medical fields. The term "patient", in the sense in which it is used herein, means an animal, preferably a mammal, and more preferably a human being. The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals, orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (for example, by powders, ointments, or drops), buccally, as an oral spray, or nasal, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention can be administered orally or parenterally at dosage levels between about 0.01 mg / kg and 50 mg / kg and preferably between about 1 mg / kg and 25 mg / kg of the subject's body weight. daily, one or more times a day, to obtain the desired therapeutic effect. Liquid dosage forms for oral administration include, but are not limited to: pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, acetate. ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed oils, grated coconut, corn, germ, olive, castor bean, and sesame seeds), glycerol, tetrahydrofurfuryl alcohol , polyethylene glycols and esters of sorbitan and fatty acid, and mixtures thereof. Along with the inert diluents, the oral compositions may also include adjuvants such as, for example, wetting agents, emulsifying and suspending agents, sweetening, flavoring, and aromatizing agents. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any insipid, fixed oil, including mono or diglycerides, can be used. In addition, fatty acids such as, for example, oleic acid are used in the preparation of injectable solutions. The injectable formulations can be sterilized, for example, by filtration through a filter that retains bacteria, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium before use. In order to prolong the effect of a compound of the present invention, it is often convenient to delay the absorption of the subcutaneous or intramuscular injection compound. This can be accomplished by the use of a liguid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution that, in turn, may depend on the size of the crystal and the crystalline form. Alternatively, the delayed absorption of a parenterally administered form of compound is carried out by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are produced by forming microencapsulated matrices of the compound in biodegradable polymers such as, for example, poly-lactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. 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, for example, cocoa butter, polyethylene glycol or a suppository wax which is solid at room temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable excipient or carrier, inert, such as, for example, sodium citrate or dicalcium phosphate and / or a) filling materials or extenders such as, for example, starches , lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as, for example, glycerol, d) disintegrating agents such as for example, agar-agar, calcium carbonate, potato starch or tapioca, alginic acid, certain silicates, and sodium carbonate, e) agents to retard the solution such as, for example, paraffin, f) absorption accelerators such as example, quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as, for example, kaolin and bentonite, and i) lubricants such as, for example, 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 can also be used as filling materials in soft and hard filled gelatin capsules, using these excipients such as, for example, lactose or milk sugar, as well as, high molecular weight polyethylene glycols and the like . The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings or layers such as, for example, enteric coatings and other coatings well known in the art of pharmaceutical formulations. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredients only, or preferably, in a certain portion of the intestinal tract, optionally, in a delayed manner. Examples of incorporation compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as filling materials in soft and hard gelatin capsules, filled, using these excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

The active compounds may also be in micro-encapsulated 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 coatings such as, for example, enteric coatings, coatings for release control and other coatings well known in the art of pharmaceutical formulations. In these solid dosage forms the active compound can be mixed with at least one inert diluent such as, for example, sucrose, lactose or starch. These dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example, lubricants for tabletting and other tableting aids such as, for example, magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredients only, or preferably, in a certain portion of the intestinal tract, optionally, in a delayed manner. Examples of incorporation compositions that can be used include polymeric substances and waxes. Dosage forms 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 mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as they are within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. These dosage forms are prepared by dissolving or supplying the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The speed can be controlled either by providing a membrane for speed control or by dispersing the compound in a polymer matrix or gel. As generally described above, the compounds of the invention are useful as inhibitors of voltage triggered sodium ion channels. In one embodiment, the compounds and compositions of the invention are inhibitors of one or. more than NaVl.l, NaV1.2, NaV1.3, NaVl.4, NaV1.5, NaV1.6, NaVl.7, NaVl .8, NaVÍ.9, or CaV2.2, and in this way, without wishing to be bound to any theory in particular, the compounds and compositions are particularly useful for treating or decreasing the severity of a disease, condition, or disorder wherein activation or hyperactivity of one or more of NaVl.l, NaV1.2 is involved in the disease, condition, or disorder. , NaV1.3, NaVl .4, NaV1.5, NaV1.6, NaV1.7, NaVl.8, NaVl.9, or CaV2.2. When the activation or hyperactivity of .NaVl.l, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, is implied in a particular disease, condition, or disorder. NaV1.9, or CaV2.2, the disease, condition, or disorder may also be referred to as a "disease, condition or disorder caused by NaVl.l, NaV1.2, NaV1.3, NaVl.4, NaV1.5, NaV1.6, NaV1.7, NaVl.8, NaVl.9, or CaV2.2"or a" disease, condition or disorder caused by CaV2.2". Accordingly, in another aspect, the present invention provides a method for treating or decreasing the severity of a disease, condition, or disorder where the activation or hyperactivity of one or more of NaVl.l, NaV1 is implicated in the disease state. 2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaVl .7, NaVl .8 or NaVl .9. The activity of a compound used in this invention as an inhibitor of NaVl.l, NaVl.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaVl.8, NaV1.9, or CaV2.2 can be analyzed according to the methods generally described in the Examples herein. It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention may be employed in combination therapies, ie, the compounds and pharmaceutically acceptable compositions may be administered concurrently with, before, or after, one or more other procedures. therapeutic or medical wishes. The particular combination of therapies (therapeutic or procedures) to be employed in a combination regimen will take into account the compatibility of the desired therapeutic and / or procedures and the desired therapeutic effect that will be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or may achieve different effects (for example, 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 "suitable for the disease, or condition, that will be treated." The amount of the additional therapeutic agent present in the compositions of this invention will not be greater than the amount that would normally be administered in a composition comprising that therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the presently exposed compositions will vary between about 50% and 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

The compounds of this invention or the pharmaceutically acceptable compositions thereof can also be incorporated into compositions for coating an implantable medical device, such as, for example, prostheses, artificial valves, vascular grafts, fasteners and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as generally described above, and in the classes and subclasses herein, and a suitable carrier for coating the implantable device. In still another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as generally described above, and in the classes and subclasses herein, and a suitable carrier for coating the implantable device. . Suitable coatings and the general preparation of plantable devices i are described in United States patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as, for example, a hydrogel polymer, polymethyldi siloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings can optionally be further coated by a suitable top layer of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Another aspect of the invention relates to inhibiting the activity of NaVl.l, NaV1.2, NaV1.3, NaVl.4, NaVl.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2 .2 in a biological sample or a patient, the method comprises administering to the patient, or contacting the biological sample with a compound of the formula I or a composition comprising the compound. The term "biological sample", in the sense in which it is used herein, includes, without limitation, cell cultures or extracts thereof; material subjected to biopsy obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof. Inhibition of the activity of NaV1.1, NaV1.2, NaV1.3, NaV1 .4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 in a biological sample It is useful for a variety of purposes that are known to one skilled in the art. Examples of these purposes include, but are not limited to: the study of ionic sodium channels in biological and pathological phenomena; and the comparative evaluation of new inhibitors of sodium ion channels. 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 provided for illustrative purposes only and are not to be construed as limiting this invention in any way.

EXAMPLES SYNTHESIS OF THE COMPOUNDS OF EXAMPLE OF THE INVENTION: EXAMPLE 1: This example shows the preparation of [2- (l-methyl-lH-benzoimidazol-2-yl) -ethyl] -carbamic acid tert-butylester (6). To a solution of beta-alanine (3.5 g, 18.5 mmol) and pyridine (3 mL, 37 mmol) in dichloromethane (20 mL) was added PFP ester (3.2 mL, 18.5 mmol). After stirring at room temperature for 1 hour, 1,2-phenylenamine 1 (2 g, 18.5 mmol) in dichloromethane (20 mL) was added to the reaction mixture. After stirring overnight, the reaction was quenched with water, extracted with dichloromethane (150mL * 2), dried and the solvent was removed. Then the crude mixture was triturated with dichloromethane (20 mL), filtered to give the white solid 2 as the desired product (4.8 g) at 90% yield. LC / .MS (10-99%) M + l / Z 280.3 retention time 2.03 min.

Compound 2 (4 g) was dissolved in acetic acid (50 mL) and heated at 65 ° C for 1 h, then cooled to room temperature, the solvent was removed in vacuo. The residue was extracted with dichloromethane, quenched with saturated NaHCO3, extracted with dichloromethane (150 mL) (pH = 10), concentrated to provide 3 as a light yellow solid (3.7 g) at 100% yield. LC / MS (10-99%) M + l / Z 262.2 retention time 2.30 min.

Compound 3 (3 g) was dissolved in HCl / 3 N EtOAC (50 L of mL / 25) and stirred overnight at room temperature. The solvent was in vacuo and dried in high vacuum to provide compound 4 as a pink solid (2.4 g) at greater than 95% yield. LC / MS (10-99%) M + l / Z 162.4 retention time 0.62 min.

To a solution of benzimidazole dihydrochloride ethylene amine (100 mg, 0.43 mmol), 3,4-dimethylphenoxyacetic acid (77 mg, 0.43 mmol), and BOP reagent (190 mg, 0.43 mmol) in acetonitrile (5 mL) was added triethylamine (0.23 L, 1.72 mmol). After stirring at room temperature overnight, the solvent was removed under vacuum. The residue was extracted with water and saturated sodium bicarbonate (20 mL), extracted with dichloromethane (30 mL x 2), dried and the solvent was removed. The crude mixture was purified using gilson HPLC to give a white solid as a TFA salt (170 mg) at 93% yield. MUX LC / MS (10-99%) M + l / Z 324,163 retention time 2.62 min; H NMR (DMSO) d 2.12 (s, 3H) d 2.15 (s, 3H), d 2.99 (t, 2H, J = 5.88 Hz), d 3.59 (, 2H), d 4.40 (s, 2H), d 6.64 (dd, ÍH, J = 2Hz, 6.5 Hz), d 6.75 (d, ÍH, J = 1.8 Hz), d 6.98 (d, 1H, J = 6.6 Hz), d 7.12 (, 2H), 7.40 (d, ÍH, J = 5.76 Hz), 7.53 (m, ÍH), 8.30 (5, 1H, J = 4.56 Hz), 12.24 (s, 1H); 13C NMR (DMSO) d 18.4, d 19.57, d 28.58, d 36.74, d 67.07, d 110.8, d 111.58, d 116.13, d 118.12, d 120.86, d 121.52, d 128.70, d 130.12, d 134.21 d 137.25, d 143.24, d 152.74, d 155.73, d 167.85.

It was dissolved in THF (50 L) benzimidazole Boc-protected ethyl amine 3 (400 mg, 1.53 mmol) and cooled to 0 ° C under nitrogen, followed by the dropwise addition of LiHMDS (535 mg, 3.37 mmol) in THF (10 L) by a syringe. The mixture was warmed to room temperature and stirred for 20 min. Methyl iodide (0.1 mL, 1.68 mmol) was added dropwise to the reaction mixture. After stirring for 5 h at room temperature, the reaction was quenched with water (20 mL) and extracted with EtOAc (30 mL x 2), dried, concentrated and purified by ISCO flash chromatography.

EXAMPLE 2 This example shows the preparation of [2- (lH-benzoimidazol-2-yl) ethyl] -carbamic acid 3,4-dimethyl-benzyl ester. To a solution of 3,4-dimethylbenzyl alcohol (1.5 g, 11.0 mmol) in toluene (20 mL) was added phosgene (13 L, 24.3 mmol, 20% in toluene). After stirring at room temperature overnight, in va cu or excess of phosgene and toluene was removed and dried under high vacuum for 2 h. to provide 3, 4-dimethylbenzylchloroformate (1.8 g) as an oil at 80% yield. (reference: Nagele, E., Schelhaas, M., Kuder, N., Waldmann, H. J. Am. Chem. So c. 1998, 120, 6889).

E JEMPLO 3 This example shows the preparation of l- [2- (lH-benzoimidazol-2-yl) -ethyl] -3- (3,4-dichloro-benzyl) -urea. To a solution of benzimidazole ethyl amine dihydrochloride (50 mg, 0.21 mmol) in pyridine (1.5 L) was added 3,4-dichlorobenzylisocyanate (43 μL, 0.21 mmol). After stirring overnight at room temperature, the crude mixture was purified by Wilson HPLC to give a white solid (50 mg) as a 92% yield TFA salt. LC / MS (10-99%) M + l / Z 324.2 retention time 2.97 min.

E JEMPLO 4: This example shows the preparation of N- [2- (lH-benzoiraidazol-2-yl) -ethyl] -3,4-dichloro-benzenesulfonamide. To a solution of benzimidazole ethyl amine dihydrochloride (50 mg, 0.21 mmol) in pyridine (1.5 mL) was added 3,4-dichlorobenzyl isocyanate (58 μL, 0.21 mmol). After stirring overnight at room temperature, the crude mixture was purified by Wilson HPLC to give a white solid (50 mg) as a 92% yield TFA salt.

EXAMPLE 5 This example shows the preparation of 2- (2,6-difluoro-phenyl) -7-methyl-lH-benzoi idazole according to the following procedure. A solution of 3-methyl-benzene-l, 2-diamine (100 mg, 0.82 mmol) and 2,6-difluorobenzaldehyde in EtOH (2 L) was heated for 5 min at 180 ° C in a microwave synthesizer. The EtOH was removed, the residue was dissolved in DMSO (1 L), and purified on a Gilson HPLC to give 2- (2,6-difluoro-phenyl) -7-methyl-1H-benzoimidazole as the TFA salt (200 mg) at 100% yield. MUX LC / MS (10-99%) M + l / Z 245,061 retention time 2.1 min.

By means of methods practically similar to those described above, other compounds of Formula I have been prepared. The characterization data for these compounds are summarized in the following Table 3. The compound numbers correspond to the compound numbers listed in Table 2.

Table 3. Characterization data for the selected compounds of Formula I of Table 2 Micromass MUX LCT 4 channel LC / MS, Waters 60F pump, Gilson 215 4 probe autosampler, Gilson 849 injection module, flow magnitude 1.5 L / min / column, 10-99% CH3CN (0.035% TFA) / H20 (0.05% TFA) gradient, Fenomenex Luna 5u C18 (50x 4.60 mm) columns, Waters MUX UV-2488 UV detector, Cedex 75 ELSD detectors.

ANALYSIS TO DETECT AND MEASURE INHIBITION PROPERTIES COMPOSITE NAV A) Optical methods for analyzing the NaV inhibition properties of the compounds: The compounds of the invention are useful as antagonists of voltage-gated sodium ion channels. The antagonist properties of the test compounds were evaluated as follows. The cells expressing the NaV of interest were placed in 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 either a chemical or electrical means to evoke a potential NaV-dependent membrane change from unblocked channels, which were detected and measured with trans-membrane sensitive dyes. The antagonists were detected as a potential membrane response decreased to the stimulus. The potential optical membrane analysis used the voltage sensitive FRET detectors described by González and Tsien (See, González, JE and RY Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69 (4): 1272-80, and González, JE and RY Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4 (4): 269-77) in combination with instrumentation to measure fluorescence changes such as, for example, the Voltage / Ion Probe Reader (VIPR®) See, Gonzalez, JE, K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4 (9): 431-439) B) Method for potential analysis of the VIPR® optical membrane with chemical stimulation Cellular manipulation and charge of tint 24 hours before the VIPR analysis, the CHO cells that endogenously express a NaV triggered by voltage type NaV1.2 was seeded in plates coated with 96-well poly-lysine at 60,000 cells per well. Other subtypes were performed in an analogous manner in a cell line expressing the NaV of interest. 1) On the day of analysis, the medium was aspirated and the cells were washed twice with 225 μL of Bath Solution # 2 (BS # 2). 2) A 15 μM CC2-DMPE solution was prepared by mixing a stock solution of 5 mM coumarin with 10% Pluronic 127 1: 1 and then dissolving the mixture in the appropriate volume of BS # 2. 3) After the bath solution was removed from the 96-well plates, the cells were loaded with 80μL of the CC2-DMPE solution. Plates were incubated in the dark for 30 minutes at room temperature. 4) While the cells were staining with coumarin, a solution of oxonol 15μL in BS # 2 was prepared. In addition to DiSBAC2 (3), this solution should contain 0.75 mM ABSCl and 30 μL of veratridine (prepared from a concentration of 10 M EtOH, Sigma # V-5754). 5) After 30 minutes, CC2-DMPE was removed and the cells were washed twice with 225 μL of BS # 2. As before, the residual volume should be 40 μL. 6) When the bath was removed, the cells were loaded with 80μL of the DiSBAC2 solution (3), after which the test compound, dissolved in DMSO, was added until reaching the desired test concentration for each cavity from the plate for drug addition and mixed thoroughly. The volume in the cavity should be approximately 121μL. The cells were then incubated for 20-30 minutes. 7) Once the incubation is complete, the cells are ready to be analyzed in VIPR® with a protocol of re-adding sodium. 120μL of solution for Bath # 1 were added to stimulate depolarization dependent on NaV. They were used 200 μL of tetracaine as a positive control of antagonists for blocking the NaV channel.

Analysis of VIPR® data: The data are analyzed and reported as normalized proportions of emission intensities extracted from the bottom measured in the channels of 460 nm and 580 n. The background intensities were then subtracted from each channel of the analysis. The background intensities were obtained by measuring the emission intensities during the same time lapses of the cavities for identically treated analyzes in which there are no cells. Then the response was reported as a function of time as the proportions obtained using the following formula: (intensity 460 n? a -fondo 460 nm) R (t) = - (intensity 580 nm - background 580nm) The data are further reduced by calculating the initial (RÍ) and final (Rf) proportions. These are the average proportion values during part or all of the pre-imulation period, and during the sample points during the stimulation period. Then the response to the stimulus R = Rf / Rx is calculated. For the analysis time windows of re-adding Na +, the initial values were 2-7 sec and the final response was sampled at 15-24 sec. Control responses were obtained by performing analyzes in the presence of a compound with the desired properties (positive control), such as, for example, tetracaine, and in the absence of pharmacological agents (negative control). The responses to the negative (N) and positive (P) controls were calculated as above. The antagonist activity of compound A is defined as: A = R-P * 100 where R is the proportional response of the N-P * test compound Solutions [M] Solution for Bath # 1: NaCl 160, KCl 4.5, CaCl2 2, MgCl2 1, HEPES 10, pH 7.4 with NaOH Solution for Bath # 2 TMA-C1 160, CaCl2 0.1, MgCl2 1, HEPES 10, pH 7.4 with KOH (final concentration K ~ 5 M) CC2-DMPE: prepared as a 5 mM stock solution in DMSO and stored at -20 ° C DiSBAC2 (3): prepared as a 12 mM concentration in DMSO and stored at -20 ° C ABSCl: prepared as a 200 mM concentration in distilled H20 and stored at room temperature Cell culture CHO cells were grown in DMEM (Dulbecco's Modified Eagle Medium, GibcoBRL # 10569-010) supplemented with 10% FBS (Bovine Fetal Serum, graded, GibcoBRL # 16140-071) and 1% Pen-Strep ( Penicillin-streptomycin, GibcoBRL # 15140-122). The cells were grown in flasks with a ventilated lid, in 90% humidity and 10% C02, 100% confluency. They were usually separated by 1:10 or 1:20 trypsinization, depending on the binding needs, and developed for 2-3 days before the next separation.

C) Potential analysis method with VIPR® optical membrane with electrical stimulation The following is an example of the way in which NaV1 inhibition activity is measured using method # 2 for the optical membrane potential.

Other subtypes were performed in an analogous manner in a cell line expressing the NaV of interest. HEK293 cells expressing NaVl .3 were placed in 96-well microtiter plates. After a suitable incubation period, the cells were stained with tension sensitive dyes CC2-DMPE / DISBAC2 (3) as follows.

Reactives: 100 mg / mL Pluronic F-127 (Sigma # P2443), in dry DMSO DiSBAC2 (3) 10 mM (Aurora # 00-100-010) in dry DMSO CC2-DMPE 10 M (Aurora # 00-100-008) in dry DMSO ABSC1 200 M in H20 Hank's balanced salt solution (Hyclone # SH30268.02) supplemented with 10 mM HEPES (Gibco # 15630-080) C oophogenic proton: 2X CC2-DMPE = CC2-DMPE 20 μM: 10 mM CC2-DMPE was rotationally stirred with an equivalent volume of 10% pluronic, followed by rotational agitation in the required amount of HBSS containing HEPES 10 mM. Each cell plate will require 5 mL of 2X CC2-DMPE. 50μL of 2XCC2-DMPE are intended for the cavities containing washed cells, resulting in 10 μM final staining concentration. The cells were stained for 30 minutes in the dark at RT. 2X DISBAC2 (3) with ABSC1 = 6μM DISBAC2 (3) and ABSC1 lmM: The required amount of 10 mM DISBAC2 (3) was added to a 50 ml conical tube and mixed with 1 μL of 10% pluronic for each mL of solution that will be produced and rotationally stirred. Then HBSS / HEPES was added to form a 2X solution. Finally, the ABSC1 was added. The 2X DiSBAC2 solution (3) can be used to solvate the plates of the compounds. Note that the plates of the compounds were constituted at a 2X concentration of the drug. The stained plate was washed again, leaving a residual volume of 50uL. Add 50 μL / cavity of 2X DiSBAC2 (3) p / ABSCl. Stain for 30 minutes in the dark at RT. The electrical stimulation instrument and methods of use are described in ION Channel Assay Methods PCT / US01 / 21652, and are incorporated herein by reference. The instrument comprises a microtitre plate handler, an optical system to excite coumarin staining while simultaneously recording the coumarin and oxonol emissions, a waveform generator, a current or voltage controlled amplifier, and a device for inserting electrodes in the cavities. Under co-controlled integrated control, this instrument passes through the electrical stimulation protocols programmed by the user to the cells inside the microtitre plate cavities.

Reactives Shock absorber for analysis # 1 NaCl 140 mM, KCl 4.5 mM, CaCl2 2 mM, MgCl2 1 mM, HEPES mM, 10 mM glucose, pH 7.40, 330 mOsm Pluronic concentration (1000X): 100 mg / mL pluronic 127 in dry DMSO Oxonol concentration (3333X): 10 mM DiSBAC2 (3) Dry DMSO Concentration of Coumarin (1000X): CC2-DMPE 10 M in dry DMSO Concentration of ABSC1 (400X): ABSC1 200 mM in water Analysis protocol 1. Insert or use electrodes in each of the cavities that will be analyzed. 2. Use the current-controlled amplifier to supply the stimulation wave pulses for 3 s. Two seconds of the pre-stimulation recording were allowed to obtain the unstimulated intensities. Five seconds of registration were allowed after the stimulation to examine the relaxation to the resting state.

Data analysis The data are analyzed and reported as normalized proportions of the emission intensities subtracted from the background measured in the 460 nm and 580 nm channels. The background intensities were then subtracted from each channel for analysis. The background intensities were obtained by measuring the emission intensities during the same time lapses of the identically treated analysis cavities in which there were no cells. Then the response was reported as a function of time according to the proportions obtained using the following formula: (intensity ,, 60nm - antecedent460nm) R (t) = - (intensity580nm - antecedent580nra) The data were further reduced by calculating the initial (R) and final (Rf) proportions. These are the average proportional values during part or all of the pre-stimulation period, and during the sample points in the stimulation period. Then the response to the stimulus R = Rf / Rx was calculated. The control responses were obtained by performing the analyzes in the presence of a compound with the desired properties (positive control), such as for example, tetracaine, and in the absence of pharmacological agents (negative control). The responses to the negative (N) and positive (P) controls were calculated as above. The antagonist activity of compound A is defined as: D O A = * 100 where R is the proportional response of the N-P test compound ANALYSIS OF ELECTROPHYSIOLOGY FOR NAV ACTIVITY AND INHIBITION OF RUEBA COMPOUNDS Patch alert electrophysiology was used to evaluate the efficacy and selectivity of sodium channel blockers in dorsal root ganglion neurons. The rat neurons were isolated from the dorsal root ganglia and kept in culture for 2 to 10 days in the presence of NGF (50ng / ml) (the culture medium consisted of NeurobasalA supplemented with B27, glutamine and antibiotics). Neurons of small size (nociceptors, 8-12 μm in diameter) were visually identified and tested with fine-tipped glass electrodes connected to an amplifier (Axon Instruments). The "voltage alert" mode was used to assess the IC50 of the compound that maintained the cells at -60 V. In addition, the "current alert" mode was used to test the efficacy of the compounds to block the generation of the action potential in response to current injections. The results of these experiments contributed to the definition of the efficacy profile of the compounds.

Analysis of TENSION ALERT in DRG neurons TTX-resistant sodium currents were recorded from DRG somata using the whole cell variation of the alert technique Patch. The records were made at room temperature (~ 22 ° C) with borosilicate glass electrodes with thick walls (WPI, resistance 3-4 MO) using an Axopatch 200B amplifier (Axon Instruments). After establishing the whole cell configuration, approximately 15 minutes were allowed for the solution in the pipette to equilibrate inside the cell before starting the recording. The currents were filtered by low pass between 2-5 kHz and digitally sampled at 10 kHz. The series resistance was compensated at 60-70% and monitored continuously throughout the experiment. The potential for fluid binding (-7 mV) between the intracellular pipette solution and the external recording solution is not considered for data analysis. The test solutions were applied to the cells with a gravity-driven rapid perfusion system (SF-77, Warner Instruments). Dose response ratios were determined in the stress alert mode by repeatedly depolarizing the cell of the specific experiment that holds the potential at a + 10mV test potential once every 60 seconds. The blocking effects were allowed to stabilize before proceeding to the next test concentration.

Solutions Intracellular solution (in mM): Cs-F (130), NaCl (10), MgCl2 (1), EGTA (1.5), CaCl2 (0.1), HEPES (10), glucose (2), pH = 7.42, 290mOsm . Extracellular solution (in mM): NaCl (138), CaCl2 (1.26), KCl (5.33), KH2P04 (0.44), MgCl2 (0.5), MgSO4 (0.41), NaHCO. (4), Na2HP04 (0.3), glucose (5.6), HEPES (10), CdC12 (0.4), NIC12 (0.1), TTX (0.25 x 10"3).

CURRENT ALERT Analysis for the inhibition activity of the NaV channel of the compounds The cells were placed in current alert mode in the whole cell configuration with a Multiplamp 700A amplifier (Axon Inst). Borosilicate pipettes (4-5 MOhm) were filled with (in mM): 150 K-gluconate, 10 NaCl, 0.1 EGTA, 10 Hepes, 2 MgCl2, (buffered to pH 7.34 with KOH). The cells were subjected to a bath in (in M): 140 NaCl, 3 KCl, 1 MgCl, 1 CaCl, and 10 Hepes). The pipette potential was adjusted to zero before seal formation; the binding potentials in liquids were not corrected during the acquisition. The records were made at room temperature.

ANALYSIS FOR DETECTING AND MEASURING THE INHIBITION PROPERTIES OF CaV OF THE COMPOUNDS A) All optics for analyzing the specific inhibition of compounds Ca V The compounds of the invention are useful as antagonists of calcium ion channels triggered by tension. The antagonist properties of the test compounds were evaluated as follows. The cells expressing the CaV of interest were placed in microtitre 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 an electrical means to evoke a potential CaV-dependent membrane change from unblocked channels, which were detected and measured with dyes sensitive to the transmembrane potential. The antagonists were detected as a potential membrane response decreased to the stimulus. The potential optical membrane analysis used the voltage sensitive FRET detectors described by González and Tsien (See, González, JE and RY Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69 (4): 1272-80, and González, JE and RY Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4 (4): 269-77) in combination with instrumentation to measure fluorescence changes such as, for example, the Voltage / Ion Probe Reader (VIPR®) See, Gonzalez, JE, K. Oades, et al. (1999) "Cell-based assays and inst ru tion for screenin g ion-channel targets" Drug Discov Today 4 (9): 431-439).

Method for potential VIP® optical membrane analysis with electrical stimulation The following is an example of how the inhibition activity of CaV2.2 is measured using the method for optical membrane potential. Other subtypes were performed in an analogous manner in a cell line expressing the CaV of interest. HEK293 cells stably expressing CaV2.2 were placed in 96-well microtiter plates. After a suitable incubation period, the cells were stained with tension sensitive dyes CC2-DMPE / DISBAC2 (3) as follows.

Reactives: 100 mg / mL Pluronic F-127 (Sigma # P2443), in dry DMSO DiSBAC6 (3) 10 mM (Aurora # 00-100-010) in dry DMSO CC2-DMPE 10 mM (Aurora # 00-100 -008) in dry DMSO Yellow Acid 200 mM (Aurora # VABSC) in H20 370 mM Barium Chloride (Sigma Cat # B6394) in H20 Bath X 160mM NaCl (Sigma Cat # S-9888) 4.5mM KCl (Sigma Cat # P-5405) MgCl2 lmM (Fluka Cat # 63064) HEPES lOmM (Sigma Cat # H-4034) pH 7.4 using NaOH Protocol or loading: 2X CC2-DMPE = 20 μM CC2-DMPE: 10 mM CC2-DMPE was rotationally stirred with an equivalent volume of 10% pluronic, followed by rotational agitation in the required amount of HBSS containing 10 M HEPES. Each cell plate will require 5 L of 2X CC2-DMPE. 50μL of 2X CC2-DMPE were added to the wells containing washed cells, resulting in a final staining concentration of 10 μM. The cells were stained for 30 minutes in the dark at RT. 2X CC2DMPE & DISBAC6 (3) = 8μM CC2DMPE & 2.5 μM DISBAC6 (3): Both dyes were rotationally stirred with an equivalent volume of 10% pluronic (in DMSO). The vortex in the required amount of Bath X with beta-cyclodextrin. Each 96-well cell plate will require 5 ml of 2XCC2DMPE. The washing plate with ELx405 with Bath X, leaving a residual volume of 50 μL / cavity. Add 50 μL of 2XCC2DMPE & DISBAC6 (3) to each cavity. Stain for 30 minutes in the dark at RT. 1.5X AY17 = 750 μM AY17 with 15mM BaCl2: Add Acid Yellow 17 to the container containing Bath X. Mix well. Allow the solution to settle for 10 minutes. Mix slowly in 370mM BaCl2. This solution can be used to solvate the plates of the compounds. Note that the plates of the compounds were constituted at a 1.5X concentration of the drug and not the usual 2X. The plate stained with CC2 was washed again, leaving a residual volume of 50μL. Add 100 uL / cavity of the solution of AY17. Stain for 15 minutes in the dark at RT. Run the plate on the optical reader. The electrical stimulation instrument and methods of use are described in ION Channel Assay Methods PCT / US01 / 21652, and are incorporated herein by reference. The instrument comprises a microtitre plate handler, an optical system to excite coumarin staining while simultaneously recording the coumarin and oxonol emissions, a waveform generator, a current or voltage controlled amplifier, and a device for inserting electrodes in the cavities. Under integrated computer control, this instrument passes through the electrical stimulation protocols programmed by the user to the cells inside the microtitre plate cavities.

Analysis protocol Insert or use electrodes in each cavity that will be analyzed. Use the current-controlled amplifier to deliver the stimulation wave pulses for 3-5 s. Two seconds of the pre-stimulation recording were allowed to obtain the unstimulated intensities. Five seconds of registration were allowed after the stimulation to examine the relaxation to the resting state.

Data analysis The data are analyzed and reported as normalized proportions of the emission intensities subtracted from the background measured in the 460 nm and 580 n channels. The background intensities were then subtracted from each channel for analysis. The background intensities were obtained by measuring the emission intensities during the same time lapses of the identically treated analysis cavities in which there were no cells. Then the response was reported as a function of time according to the proportions obtained using the following formula: R (t) _ (intensity460nm - antecedent460nm) (intensity580nm - antecedent5g0nm) The data were further reduced by calculating the initial (RÍ) and final (Rf) proportions.

These are the average proportional values during part or all of the pre-stimulation period, and during the sample points in the stimulation period. Then the response to the stimulus R = Rf / Rj was calculated. The control responses were obtained when carrying out the analyzes in the presence of a compound with the desired properties (positive control), such as, for example, mibefradil, and in the absence of pharmacological agents (negative control). The responses to the negative (N) and positive (P) controls were calculated as above. The antagonist activity of compound A is defined as: "D D A = * 100 where R is the proportional response of the N-P test compound ANALYSIS OF ELECTRQPHYSIOLOGY FOR ACTIVITY CAV AND LA INHIBITION OF TEST COMPOUNDS Patch alert electrophysiology was used to evaluate the efficacy of calcium channel blockers in HEK293 cells. The HEK293 cells expressing CaV2.2 had been visually identified and tested with fine-tipped glass electrodes connected to an amplifier (Axon Instruments). The "voltage alert" mode was used to assess the IC50 of the compound that maintained the cells at -100 V. The results of these experiments have contributed to the definition of the efficacy profile of the compounds.

Analysis of TENSION ALERT in HEK293 cells expressing CaV2.2 Calcium currents were recorded from HEK293 cells using the whole cell variation of the Patch alert technique. The records were made at room temperature (~ 22 ° C) with borosilicate glass electrodes with thick walls (WPI, resistance 3-4 MO) using an Axopatch 200B amplifier (Axon Instruments). After establishing the whole cell configuration, approximately 15 minutes were allowed for the solution in the pipette to equilibrate inside the cell before starting the recording. The currents were filtered by low pass between 2-5 kHz and digitally sampled at 10 kHz. The series resistance was compensated at 60-70% and monitored continuously throughout the experiment. The potential for fluid binding (-7 mV) between the intracellular pipette solution and the external recording solution is not considered for data analysis. The test solutions were applied to the cells with a gravity-driven rapid perfusion system (SF-77, Warner Instruments). Dose-response ratios were determined in the stress alert mode by repeatedly depolarizing the cell of the specific experiment that holds the potential at a test potential of + 20mV for 50 ms at frequencies of 0.1, 1, 5, 10, 15, and 20 Hz. The blocking effects were allowed to stabilize before proceeding to the next test concentration.

Solutions Intracellular solution (in mM): Cs-F (130), NaCl (10), MgCl2 (1), EGTA (1.5), CaCl2 (0.1), HEPES (10), glucose (2), pH = 7.42, 290 Osm. Extracellular solution (in mM): NaCl (138), BaCl2 (10), KCl (5.33), KH2P04 (0.44), MgCl2 (0.5), MgSO (0.41), NaHCO3 (4), Na2HP0 (0.3), glucose (5.6) ), HEPES (10). Following these procedures, it was found that the representative compounds of the present invention possess the desired activity and selectivity of modulation of the N-type calcium channel.

It was found that the compounds of the invention as shown in table 2 modulate the sodium channels triggered by tension at 25.0 RM or less. In order that the invention described herein may be more fully understood, the following examples [sic] are established. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting this invention in any way. [sic]

Claims (33)

1. RE IVINDICACIONE S A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein: r is 0 to 4; Z is O, N or CH; Y and W are independently selected from hydrogen, the Formula la: For where wherein: T is a bond or a straight or branched aliphatic chain of C? -6 wherein a methylene unit of T is optionally replaced by a. g_f.upo C3-6 cycloaliphatic; U is -CH2- or -CH2-CH2 ~; X is N-C? _4alkyl, NH, 0, S, S (O), or S02; and each event of Rc is independently M-Rx; wherein: M is a bond or is a chain of C? _6 alkylidene wherein up to two non-adjacent methylene units of M are optionally replaced by C (O), C02, C (0) C (0), C (0) ) NR, 0C (0) NR, NRNR, NRNRC (O), NRC (O), NRCO2, NRC (0) NR, S (0), S02, NRS02, S02NR, NRSO2NR, 0, S, or NR, and Rx is R ', halogen, N02, or CN; wherein: each R 'event is independently selected from hydrogen or an optionally substituted group selected from aliphatic C? _8, C6_? aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having -10 atoms in the ring, or R and R 'taken together with the atoms to which they are attached, or two R' events taken together with the atoms to which they are attached, form a cycloalkyl, heterocyclyl, aryl, or 5-8 membered heteroaryl having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; V is a bond, -C (0) ~, or -S (0) 2-; Q is a bond or chain of C? _ Alkylidene wherein up to two non-adjacent methylene units of Q are optionally replaced by -0-, -NH-, or -S-; is 0 or 1; Ring E is C6-? or aryl, 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 selected independently of nitrogen, oxygen, or sulfur; and s is 0 to 5; or the Formula Ib: Ib wherein: D is -C? _6alkyl- or a bond; and t is 0 to 5; each event of R is independently selected from hydrogen or an optionally substituted aliphatic C? -6 group; and each event of RA, RB and RD are independently selected from R1, R2, R3, R4, or R5, where: R1 is oxo, R6 or (C? _4aliphatic) n-J, where: n is 0 or 1; J is halo, CN, N02, CF3, OCF3, OH, SR6, S (0) R6, S02R6, NH2, NHR6, N (R6) 2, NR6R8, C (0) OH, C (0) OR6 or OR6; or: two R1 on the adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy; R 2 is C α -aliphatic, optionally substituted with up to two substituents independently selected from R 1, R, or R 5; R3 is C3_8cycloaliphatic, C6_? 0 aryl, 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 independently selected heteroatoms of nitrogen, oxygen, or sulfur, wherein R3 is optionally substituted with up to three substituents independently selected from R1, R2, R4 or R5; R4 is OR5, OR6, OC (0) R6, OC (0) R5, OC (0) OR6, OC (0) OR5, 0C (0) N (R6) 2, 0C (0) N (R5) 2, OC (O) N (R6R5), SR6, SR5, S (0) R6, S (0) R5 , S02R6, S02R5, S02N (R6) 2, S02N (R5) 2, S02NR5Rb, S03R, S03R, C (0) R, C (0) 0R3, C (0) R, C (0) ORD C (0) N (R) 2, C (0) N (RD) 2, C (O) N (RDRe), C (0) N (OR, 6D,) R p6 C (O) N (OR5) R6, C (O) N (OR6) R5, C (O) N (OR5) R5, C (NOR6) R6 C (NOR6) R5, C (NOR5) R6, C (NOR5 ) R5, N (R6) 2, N (R5) 2, N (R5R6) NR5C (0) R5, NR6C (0) R6, NR6C (0) R5, NR6C (0) OR6, NR5C (0) OR6 NR6C (O) OR5, NR5C (O) OR5, NR6C (O) N (R6: NR6C O) R5R6 NR6C (O) N (R5) 2, NRDC (O) N (R °) 2, NR5C (O) NR5R6 NR5C (O) (R5) 2, NR6S02R6, NR6S02R5, NR5S02R5, NR6S02N (R6) 2 NRbS02NR, 53Rp6 °, NR ° S02N (RY 2, NR ° S02NR 5: 3DR6tl, NRsS02N (R °) 2 N (0R6) R6, N (0R6) R5, N (0R5) R5, or N (OR5) R6; R5 is a Ca-cycloaliphatic, C6-? Or aryl, 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 selected from nitrogen, oxygen, or sulfur, wherein R5 is optionally substituted with up to three substituents R1; Rd is R optionally substituted with R7, wherein: R7 is a C3-8 cycloaliphatic, Cß-io aryl; 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 selected from nitrogen, oxygen, or sulfur, in wherein R7 is optionally substituted with up to two substituents independently selected from R, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH2) nG, wherein G is selected from halo, CN, N02, CF3, OCF3, OH, S-aliphatic, S (O) -aliphatic, S02-aliphatic, NH2, N-aliphatic, N (aliphatic) 2, N (aliphatic) R8, COOH, C (O) O (-aliphatic), or O-aliphatic; and R8 is an amino protecting group; with the proviso that only one of Y and W is of the formula la or Ib and the other of Y and W is hydrogen; and where: (a) when Z is N, Y is hydrogen, W is Formula A, A is and V and Q are each a link, then (i) when r is 1 and RA is methyl at the C-5 or C-6 position of the benzimidazole ring, then E is not: unsubstituted phenyl; phenyl substituted in the or t 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; naphthyl unsubstituted; phenyl substituted in the para position with OEt, Br, OH, or OMe; phenyl substituted in the meta position with chlorine; or phenyl substituted in the ortho position with methyl; (b) when Z is N, Y is hydrogen, W is of the formula la, Q is -NHCH2-, r is 0, and V is C (O), then: (i) when A is -CH2CH2NH-, then E is not (ii) when A is -CH2NH-, then E is not and (c) when Z is C, W is hydrogen, Y is of the formula la, r is 0, A is -CH2CH2NH-, V is C (O), Q is -CH20- and E is phenyl, then: (i) s is not 0; (ii) when s is 1, R is not unsubstituted phenyl, chlorine, OMe, methyl, bromine,, or in the para position; cyano or OMe in the ortho position; or methyl in the met position; (iii) when s is 2, RB is not dichlor in the ort o / pa ra positions; and (iv) when s is 3, RB is not 2, 3, 4-trimethyoxy or 2,4,5-trichlor; and where: a) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -C (O) -, Q is -CH20-, and Ring E is phenyl, then RA is not -Cl, -Br, C? _4alkyl, methoxy, or nitro, either singly or in combination; b) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -C (O) -, Q is a bond, and ring E is phenyl, then RA is not -Cl, -Br , C? _4alkyl, methoxy, or nitro, either singly or in combination; c) when Z is N, W is of Formula la, A is -CH2CH2CH2NH-, V is -C (0) -, Q is a bond, and the Ring E is phenyl, then RA is not 4-amino, nor 4-methoxycarbonyl; d) when Z is N, W is of Formula la, A is -CH2CH2CH2NH-, V is -C (0) - / and Q is a bond, then Ring E is not -2 (2, 3-dihydro- benzo [1,4] dioxin); e) when Z is N, W is of Formula la, A is -CH2CH2CH2NH-, V is -C (O) -, and Q is -CH20-, then Ring E is not -6 (4-dimethyl- 2H-chromen-2-one); f) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -C (O) -, and Q is a -CH2CH20-, then Ring E is not unsubstituted phenyl; g) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -C (O) -, and Q is a bond, then, Ring E is not substitute; h) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -C (O) -, and Q is a -CH20-, and Ring E is phenyl, then RA is not phenyl in position 4; i) when Z is N, W is of the Formula la, A -CH2CH2NH-, V is -C (0) -, and Q is -CH2CH2-, then Ring E is not 2-isoindoline-1,3-dion; j) when Z is N, W is of the Formula la, A -CH2CH2NH-, V is -C (0) -, and Q is -CH2CH20-, and the Ring E is phenyl, then RA is not phenyl at position 4; and k) when Z is N, W is of Formula la, A is -CH2CH2NH-, V is -C (O) -, and Q is a bond, then Ring E is not unsubstituted adamantyl. 1) when Z is N, W is of the Formula la, A -CH2CH2NH-, V is -C (O) -, Q is -CH2CH20-, and Ring E is phenyl, then RB is not -Cl, -Br, C? -4alkyl, methoxy, unsubstituted phenyl, -C (CH3) 2-phenyl, or nitro, either singly or in combination; m) when Z is N, W is of the Formula la, A is -CH2CH2NH-, V is -C (O) -, Q is -CH = CH2-, and the Ring E is phenyl, then RB is not -Cl in the ortho position; and n) when Z is N, W is of the Formula la, A -CH2CH2NH-, V is -S02-, Q is a bond, and ring E is phenyl, then RB is not chlorine.
2. 2. The compound according to claim 1, wherein: A is -T-NR6-, wherein T is a straight or branched aliphatic chain of C? _6 Q is -CH2CH20-, -CH20-, -OCH2-, -OCH2CH2-, -CH (CH3) 0-, -NHCH2-, -C (CH3) 20-, or -CH2S-; and Ring E is selected from phenyl, naphthyl, pyridyl, thienyl, furanyl, quinolinyl, or benzofuranyl.
3. 3. The compound according to claim 1, wherein the compound is of the Formula lia: He has or a pharmaceutically acceptable salt thereof
4. 4. The compound according to claim 3, wherein: Q is -Cff2CH20-, -CH20-, -0CH2-, -0CH2CH2-, -CH (CH3) 0-, -NHCH2-, -C (CH3) 20-, or - CH2S-; A is -CH2CH2N (CH3) -, -CH2CH2NH-, -CH2NH-, or -CH2CH (CH3) NH-; and each RB is independently OR6, N (R6) 2, NR6C (0) R6, halo, R6, C (0) R6, or N02.
5. The compound according to claim 3 where A is * or *
6. The compound according to claim 3 where A is
7. 7. The compound according to claim 3, wherein A is -T-NH- wherein T is a straight or branched aliphatic chain of C? _6 and wherein a methylene unit of T is replaced by a C3-6 cycloaliphatic group.
8. 8. The compound according to claim 1, wherein the compound is of Formula III: ip or a pharmaceutically acceptable salt thereof
9. 9. The compound according to claim 8, wherein: Q is -CH2CH20-, -CH20-, -0CH2-, -0CH2CH2-, -CH (CH3) 0-, -NHCH2-, -C (CH3) 20-, or - CH2S-; A is -CH2CH2N (CH3) -, -CH2CH2NH-, -CH2NH-, or -CH2CH (CH3) NH-; and each RB is independently OR6, N (R6) 2, NR6C (0) R6, halo, R6, C (0) R6, or N02.
10. 10. The compound according to claim 1, wherein the compound is of Formula IV: IV or a pharmaceutically acceptable salt thereof
11. 11. The compound according to claim 10, wherein Ring E is phenyl or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3-7 membered monocyclic heterocyclyl ring which has 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
12. 12. The compound according to claim 11, wherein: Q is -CH2CH20-, -CH20-, -OCH2-, -OCH2CH2-, -CH (CH3) 0-, -NHCH2-, -C (CH3) 20-, or - CH2S-.
13. 13. A composition comprising a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
14. 14. A method for treating or decreasing the severity of a disease, disorder, or condition selected from acute, chronic, neuropathic, or inflammatory pain, including pain from femoral cancer; chronic non-malignant bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; syndrome due to myofascial pain; fibromyalgia; pain of the temporomandibular joint; chronic visceral pain, including, abdominal pain; pancreatic; IBS; chronic headache; migraine; tension headache, including cluster headaches; chronic neuropathic pain, including, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; proximal and distal ectopic discharges; radiculopathy; neuropathic pain induced by chemotherapy; neuropathic pain induced by radiotherapy; pain after the mastectomy; central pain; pain due to spinal cord injury; pain after a stroke; thalamic pain; complex regional pain syndrome; ghost pain; rebellious pain; acute pain, acute postoperative pain; acute musculoskeletal pain; articulations pain; Lumbago Mechanical; Neck Pain; tendonitis; pain due to injury / exercise; Acute visceral pain, including, abdominal pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias etc; chest pain, including, heart pain; pelvic pain, pain due to renal colic, acute obstetric pain, including pain due to childbirth; pain by caesarean section; acute inflammatory pain, burn and trauma; acute intermittent pain, including, endometriosis; acute pain due to herpes zoster; sickle cell anemia; acute pancreatitis; advanced pain; orofacial pain, including, sinusitis pain, dental pain; pain due to multiple sclerosis (MS); pain from depression; pain from leprosy; pain from behcet disease; painful adiposis; phlebitic pain; pain Guillain-Barre; painful legs and toes in movement; Haglund syndrome; pain due to erythromelalgia; pain from Fabry's disease; bladder and urogenital disease, including, urinary incontinence; bladder overactivity; painful bladder syndrome; interstitial cystitis (IC); or prostatitis; arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or a condition of epilepsy, a neurodegenerative disorder, a psychiatric disorder such as, for example, anxiety and depression, myotonia, arrhythmia, a movement disorder, a neuroendocrine disorder, ataxia, multiple sclerosis, irritable bowel syndrome, or incontinence comprising the step of administering to the patient an effective amount of a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: r is 0 to 4; Z is O, N or CH; Y and W are independently selected from hydrogen, the Formula la: the where : wherein: T is a straight or branched aliphatic bond or chain of C? _6 wherein a methylene unit of T is optionally replaced by a C3_6 cycloaliphatic group; U is -CH2- or -CH2-CH2-; X is N-C? _4alkyl, NH, O, S, S (O), or S02; and each event of Rc is independently M-Rx; wherein: M is a bond or is a Ci-g alkylidene chain wherein up to two non-adjacent methylene units of M are optionally replaced by C (O), C02, C (0) C (0), C (0) ) NR, OC (0) NR, NRNR, NRNRC (O), NRC (O), NRC02, NRC (0) NR, S (O), S02, NRS02, S02NR, NRS02NR, O, S, or NR, and Rx is R ', halogen, N02, or CN; wherein: each event of R 'is independently selected from hydrogen or an optionally substituted group selected from C? _8 aliphatic, C6-? or aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 atoms in the ring, or R and R 'taken together with the atoms to which they are attached, or two events of R' taken together with the atoms to which they are attached, form a cycloalkyl, heterocyclyl, aryl ring, or 5-8 membered heteroaryl having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; V is a bond, -C (0) -, or -S (0) 2-; Q is a bond or chain of C? _4 alkylidene wherein up to two non-adjacent methylene units of Q are optionally replaced by -O-, -NH-, or -S-; m is 0 or 1; Ring E is C6_? 0 aryl, 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 independently selected heteroatoms of nitrogen, oxygen, or sulfur; and s is 0 to 5; or the Formula Ib: Ib wherein: D is -C? _6alkyl- or a bond; and t is 0 to 5; each event of R is independently selected from hydrogen or an optionally substituted aliphatic C? -6 group; and each event of RA, RB and RD are independently selected from R1, R2, R3, R4, or R5, where: R1 is oxo, R6 or (C? _4aliphatic) n-J, where: n is 0 or 1; J is halo, CN, N02, CF3, OCF3, OH, SR6, S (0) R6, S02R6, NH2, NHR6, N (R6) 2, NR6R8, C (0) OH, C (0) OR6 or OR6; or: two R1 on the adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy; R 2 is C α -aliphatic, optionally substituted with up to two substituents independently selected from R 1, R 4, or R 5; R3 is C3-8cycloaliphatic, C5_? Or aryl, 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 selected from nitrogen, oxygen, or sulfur, wherein R3 is optionally substituted with up to three substituents independently selected from R1, R2, R4 or R5; R4 is OR5, OR6, OC (0) R6, OC (0) R5, OC (0) OR6, OC (0) OR5, OC (0) N (R6) 2, OC (0) N (R5) 2, OC (O) N (R6R5), SR6, SR5, S (0) R6, S (0) R5 , S02R6, S02R5, S02N (R6) 2, S02N (R5) 2, S02NR5R6, S03R6, SO3R, C (0) R5, C (0) OR, C (0) Rb, C (0) ORb, C (0 ) N (R6) 2, C (0) N (R5) 2, C (0) N (R5R6), C (O) N (OR6) R6, C (O) N (OR5) R6, C (O) N (OR6) R5, C (O) N (OR5) R5, C (NOR6) R6, C (NOR6) R5, C (NOR5) R6, C ( NOR5) R5, N (R6) 2, N (R5) 2, N (R5R6), NR5C (0) R5, NR6C (0) R6, NR6C (0) R5, NR6C (0) OR6, NR5C (0) OR6 , NR6C (0) OR5, NR5C (0) OR5, NR6C (O) N (R6) 2, NR6C (O) NR5R6, NR6C (O) (R5) 2 NR5C (O) N (R6) 2, NR5C (O) NR5R6, NR5C (O) N (R5) 2, NR6S02R6, NR6S02R5, NR5S02R5, NR6S02N (R6) 2, NR6S02NR5R6, NR6S02N (R5) 2, NR5S02NR5R6, NR5S02N (R5) 2, N (0R6) R6, N (0R6) R5, N (0R5) R5, or N (0R5) R6; R5 is a C3-8cycloaliphatic, C5_? 0 aryl, 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 selected from nitrogen, oxygen, or sulfur, wherein R5 is optionally substituted with up to three R1 substituents; R6 is R optionally substituted with R7, wherein: R7 is a C3_8cycloaliphatic, C6_? 0 aryl; 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 selected from nitrogen, oxygen, or sulfur, in wherein R7 is optionally substituted with up to two substituents independently selected from R, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH2) nG, wherein G is selected from halo, CN, N02, CF3, OCF3, OH, S-aliphatic, S (O) -aliphatic, S02-aliphatic, NH2, N-aliphatic, N (aliphatic) 2, N (aliphatic) R8, COOH, C (O) O (-aliphatic), or O-aliphatic; and R8 is an amino protecting group; with the proviso that only one of Y and W is of the formula la or Ib and the other of Y and W is hydrogen.
15. 15. The method according to claim 14, wherein the disease, condition, or disorder is acute, chronic, neuropathic, or inflammatory pain.
16. 16. A method to inhibit the activity of NaVl.l, NaV1.2, NaV1.3, NaV1.4, NaVl .5; NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 in: (a) a patient; or (b) a biological sample; the method comprises administering to the patient, or contacting the biological sample with a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: r is 0 to 4; Z is O, N or CH; Y and W are independently selected from hydrogen, the Formula la: the where wherein T is a straight or branched aliphatic bond or chain of C? _6 wherein a methylene unit of T is optionally replaced by a C3_6 cycloaliphatic group; U is -CH2- or -CH2-CH2-; X is N-C? _4alkyl, NH, O, S, S (O), or S02; and each event of Rc is independently M-Rx; wherein: M is a bond or is a chain of C? _6 alkylidene wherein up to two non-adjacent methylene units of M are optionally replaced by C (O), C02, C (0) C (0), C (0) ) NR, OC (0) NR, NRNR, NRNRC (O), NRC (O), NRCO2, NRC (0) NR, S (O), S02, NRS02, S02NR, NRS02NR, O, S, or NR, and Rx is R ', halogen, N02, or CN; wherein: each event of R 'is independently selected from hydrogen or an optionally substituted group selected from aliphatic C? _8, Ce-1-aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having -10 atoms in the ring, or R and R 'taken together with the atoms to which they are attached, or two R' events taken together with the atoms to which they are attached, form a cycloalkyl, heterocyclyl, aryl, or 5-8 membered heteroaryl having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; V is a bond, -C (O) -, or -S (0) 2-; Q is a bond or chain of C? _4 alkylidene wherein up to two non-adjacent methylene units of Q are optionally replaced by -O-, -NH-, or -S-; m is 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 heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen, or sulfur; and s is 0 to 5; or the Formula Ib: Ib wherein: D is -C? _6alkyl- or a bond; and t s s 0 to 5; each event of R is independently selected from hydrogen or an optionally substituted aliphatic C? -6 group; and each event of RA, RB and RD are independently selected from R1, R2, R3, R4, or R5, wherein: R1 is oxo, R6 or (C? -4aliphatic) n-J, wherein: n is 0 or 1; J is halo, CN, N02, CF3, OCF3, OH, SR6, S (0) R6, S02R6, NH2, NHR6, N (R6) 2, NR6R8, C (0) OH, C (0) OR6 or OR6; or: two R1 on the adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy; R 2 is Cysatic β-β, optionally substituted with up to two substituents independently selected from R 1, R 4, or R 5; R3 is C3_8cycloaliphatic, Ce-io aryl, 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 independently selected heteroatoms of nitrogen, oxygen, or sulfur, wherein R3 is optionally substituted with up to three substituents independently selected from R1, R2, R4 or R5; R ^ is OR- OR (OC (O) Re OC (O) R- OC (O) OR * 0C (0) 0R5, OC (0) N (Rb) 2, OC (0) N (RY2, OC (0) N (R 6bpR5 °), SR ' SR5, S (0) R6, S (0) R5, S02R5, S02Rb, S02N (R6) 2, S02N (R5) 2, S02NRaRb, S03R, S03RD, C (0) RY C (0) OR °, C (0) RD, C (0) ORD, C (0) N (R) 2, C (0) N (R °) 2 , C (0) N (R 53tR- 6b-), C (O) N (0R, 6 ° ^) R6 °, C (O) N (OR5) Rd, C (O) N (OR6) R5, C (O) N (OR5) R5, C (ÑOR6) R6, C (NOR6) R5, C (NOR5) R6, C (NOR5) R5, N (R6) 2, N (R5) 2, N (R5R6), NR5C (0) R5, NR6C (0) R6, NR6C (0) R5, NR6C (0) OR6, NR5C (0) OR6, NR6C (0) OR5, NR5C (0) OR5, NR6C (O) N (R6) 2, NR6C (O) NR5R6, NR6C (O) N (R5) Zl NR5C (O) N (R6) 2, NR5C (O) NR5R6, NR5C (O) N (R5) 2, NR6S02R6, NR6S02R5, NR5S02R5, NR6S02N (R6) 2, NR6S02NR5R6, NR6S02N (R5) 2, NR5S02NR5R6, NR5S02N (R5) 2, N (OR6) R6, N (OR6) R5, N (OR5) R5, or N (OR5) R6; R5 is a C3_8cycloaliphatic, C6-? Or aryl, 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 selected from nitrogen, oxygen, or sulfur, wherein R5 is optionally substituted with up to three R1 substituents; R6 is R optionally substituted with R7, wherein: R7 is a C3-8 cycloaliphatic, 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 heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in wherein R7 is optionally substituted with up to two substituents independently selected from R, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH2) nG, wherein G is selected from halo, CN, N02, CF3, OCF3, OH, S-aliphatic, S (O) -aliphatic, S02-aliphatic, NH2, N-aliphatic, (aliphatic) 2, N (aliphatic) R8, COOH, C (0) 0 (-aliphatic), or O-aliphatic; and R8 is an amino protecting group; with the proviso that only one of Y and W is of the formula la or Ib and the other of Y and W is hydrogen. 17. The method according to any of claims 14 or 16, wherein: A is -T-NR6-, wherein T is a straight or branched aliphatic chain of C1-6 Q is -CH2CH20-, -CH20-, - OCH2-, -OCH2CH2-, -CH (CH3) 0-, -NHCH2-, -C (CH3) 20-, or -CH2S-, and Ring E is selected from phenyl, naphthyl, pyridyl, thienyl, furanyl, quinolinyl , or benzofuranyl. 18. The method according to claim 17, wherein each RB is independently OR6, N (R6) 2, NR6C (0) R6, halo, R6, C (0) R6, or N02.
17. 17. The method according to any of claims 14 or 16, wherein the compound is of the Formula lia: He has or a pharmaceutically acceptable salt thereof
18. 18. The method according to claim 17, wherein: Q is -CH2CH20-, -CH20-, -OCH2-, -OCH2CH2-, -CH (CH3) 0-, -NHCH2-, -C (CH3) 20-, or - CH2S-; A is -CH2CH2N (CH3) -, -CH2CH2NH-, -CH2NH-, or -CH2CH (CH3) NH-; and each RB is independently OR6, N (R6) 2, NR6C (0) R6, halo, R6, C (0) R6, or N02.
19. The method according to claim 17, in where A is
20. The method according to claim 17, in where A is
21. 21. The method according to claim 17, wherein A is -T-NH- wherein T is a straight or branched aliphatic chain of C? _6 and wherein a methylene unit of T is replaced by a C3-6 cycloaliphatic group.
22. 22. The method according to any of claims 14 or 16, wherein, the compound is of Formula III: m or a pharmaceutically acceptable salt thereof.
23. 23. The method according to claim 22, wherein: Q is -CH2CH20-, -CH20-, -0CH2-, -0CH2CH2-, -CH (CH3) 0-, -NHCH2-, -C (CH3) 20-, or -CH2S-; A is -CH2CH2N (CH3) -, -CH2CH2NH-, -CH2NH-, or -CH2CH (CH) H-; and each RB is independently OR6, N (R6) 2, NR6C (0) R6, halo, R6, C (0) R6, or N02.
24. 24. The method according to any of claims 14 or 16, wherein, the compound is of Formula IV: rv or a pharmaceutically acceptable salt thereof
25. 25. The method according to claim 24, wherein Ring E is phenyl or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3-7 membered monocyclic heterocyclyl ring which has 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
26. 26. The method according to claim 25, wherein: Q is -CH2CH20-, -CH20-, -OCH2-. -OCH2CH2-, -CH (CH3) 0-, -NHCH2-, -C (CH3) 20-, or -CH2S-.
27. 27. The method according to claim 17, wherein: A is -CH2CH2NH ~; Q is -CH20-; and each RB is independently C? _6 aliphatic, -CHO, or halogen.
28. 28. The method according to claim 17, wherein: A is -CH2CH2NH-; Q is -CH = CH-, -CH20- or -NHCH2; and each RB is independently CN, C6-6 aliphatic, -N (R6) 2, or halogen.
29. 29. The method according to claim 17, wherein: A is -CH2CH2NH- or -CH (CH3) NH-; Q is -CH20-; and each RB is independently C? -6 aliphatic, -N (R6) 2, -C (0) R6, or halogen.
30. 30. The method according to claim 17, wherein: A is -CH2CH2NH-; Q is -CH20-, -NHCH2-, or -CH (CH3) 0-; and each RB is independently C? -6 aliphatic, -OR6, or halogen.
31. 31. The method according to claim 17, wherein: A is -CH2CH2NH- or -CH2CH (CH3) NH-; Q is -CH20-, -NHCH2-, -NH-, -CH (CH3) 0-, or -C (CH3) 20-; and each RB is independently C-β aliphatic, -OR6, or halogen.
32. 32. The method according to claim 17, wherein: A is -CH2CH2NH ~; Q is -CH20-; and each RB is independently methyl, fluorine, or chlorine.
33. 33. The method according to claim 17, wherein: A is -CH2CH2NH-; Q is -CH2O-; and each RB is independently methyl, bromine, or chlorine