HK1129096B - Compositions useful as inhibitors of voltage-gated sodium channels - Google Patents

Description

Compositions useful as inhibitors of voltage-gated sodium channels

Technical Field

The present invention relates to compounds useful as inhibitors of voltage-gated sodium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

Background

Na channels are the center of action potential production by all excitable cells, such as neurons and muscle cells. They play an important role in excitable tissues, including the brain, gastrointestinal smooth muscle, skeletal muscle, peripheral nervous system, spinal cord and airways. They therefore play an important role in a variety of disease states, such as epilepsy (a)See alsoBertrand (2002) "Epilepsy and sodium channels"Expert Opin.Ther. Patents12(1): 85-91)), pain (c)See alsoWaxman, S.G., S.Dib-Hajj et al (1999) "Sodium channels and pain"Proc Natl Acad Sci U S A96(14): 7635-9 and Waxman, S.G., T.R.Cummins et al (2000) "Voltage-catalysis channels and the molecular catalysis of pain: a review "J Rehabil Res Dev37(5): 517-28), muscular strength and rigidity (See alsoSantone (2000) "Therapy in myconic disorders and in muco-manna pathogens"Neurol Sci 21(5)：S953-61 and Mankodi，A.and C.A.Thornton(2002)“Myotonic syndromes”Curr Opin Neurol15(5): 545-52), ataxia (ataxia)See alsoMeisler, M.H., J.A. Kearney et al (2002) "details of voltage-gated sodium channels in motion dispersed employment"Novartis Found Symp241: 72-81), multiple sclerosis (See alsoBlack, J.A., S.Dib-Hajj et al (2000) "Sensory nerve-specific catalytic channel SNS is innominated in the peptides of the microorganisms with the exogenous antibiotic encephalitides and humanes with the polyplexes" Proc Natl Acad Sci USA 97 (21): 11598- "Brain Res959(2): 235-42), irritable bowel (I)See also，Su，X.，R.E.Wachtel et al (1999) "Capsule sensitivity and voltage-gated sodium Currentsin gum sensor from bottom of mouth gan"Am J Physiol277(6 Pt 1): g1180-8, and Laird, J.M., V.Souslova et al (2002) "Deficits in viral paper and transferred hyaluronic in Nav1.8(SNS/PN3) -null mice"J Neurosci22(19): 8352-6), urinary incontinence and visceral pain (C: (A)Referring to the description of the preferred embodiment,yoshimura, N.S.Seki et al (2001) "The innovative of The tetrodotoxin-resistant sodium channel Na (v)1.8(PN3/SNS) in a rate model of visceral pain"J Neurosci21(21): 8690-6), and a series of psychiatric dysfunctions, such as anxiety and depression (b: (b)See also，Hurley，S.C.(2002)“Lamotrigine update and its use in mood disorders”Ann Pharmacother 36(5)：860-73)。

Voltage-gated Na channels contain a gene family consisting of 9 different subtypes (nav1.1-nav 1.9). As shown in Table 1, these subtypes show tissue-specific localization and functional differences: (See also，Goldin，A.L.(2001)“Resurgence of sodium channelresearch”Annu Rev Physiol63: 871-94). Three members of this gene family (nav1.8, 1.9, 1.5) are resistant to blockade by the well-known Na channel blocker TTX, demonstrating the subtype specificity present within this gene family. Mutational analysis has identified glutamate 387 as a key residue for TTX binding ((r))See alsoSuzuki et al (1989) "A single point rotation controls tetrodotoxin and saxitoxin sensitivity 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):

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

In general, voltage-gated sodium channels (navs) are responsible for triggering rapid elevation of action potentials in excitable tissues of the nervous system, which carry electrical signals that program and encode normal and abnormal pain sensations. Antagonists of NaV channels attenuate these pain signals and are useful in the treatment ofA variety of pain conditions are treated, including but not limited to acute, chronic, inflammatory and neuropathic pain. Known NaV antagonists, e.g. TTX, lidocaine: (See alsoMao, J. and L.L.Chen (2000) "systematic lidocaine for neuropathic pain relief"Pain87(1): 7-17), bupivacaine, phenytoin (b)See also，Jensen，T.S.(2002)“Anticonvulsants inneuropathic pain：rationale and clinical evidence”Eur J Pain6 (supplA): 61-8), lamotrigine (See also，Rozen，T.D.(2001)“Antiepileptic drugs inthe management of cluster headache and trigeminal neuralgia”Headache41 Suppl 1: s25-32 and Jensen, T.S (2002) "anticancer vulsantin neuropathic pain: rational and clinical evidence "Eur J Pain6(Suppl A): 61-8) and carbamazepine (See also，Backonja，M.M.(2002)“Use ofanticonvulsants for treatment of neuropathic pain”Neurology59(5Suppl 2): s14-7), have been shown to be useful in attenuating pain in human and animal models.

Hyperalgesia (hypersensitivity to certain pain) that develops in the presence of tissue damage or inflammation reflects, at least in part, the increased excitability of the high-threshold major afferent neurons that innervate the site of injury. Voltage sensitive sodium channel activation is crucial for the generation and propagation of neuronal action potentials. There is increasing evidence that regulation of NaV current is an endogenous mechanism for controlling neuronal excitability (S) ((R))See also，Goldin，A.L.(2001)“Resurgenceof sodium channel research”Annu Rev Physiol63: 871-94). Several kinetically and pharmacologically distinct voltage-gated sodium channels are found in Dorsal Root Ganglion (DRG) neurons. TTX-tolerance currents are insensitive to micromolar concentrations of tetrodotoxin and exhibit slow activation and inactivation kinetics and a more depolarizing activation threshold compared to other voltage-gated sodium channels. TTX-tolerant sodium currents are mainly limited to a subset of sensory neurons that may be involved in nociception. Specifically, TTX-tolerant sodium currents are expressed almost exclusively in neurons with small cell body diameters; causing small diameter, slow transferAxons, and responds to capsaicin. A large body of experimental evidence demonstrates that TTX-resistant sodium channels are expressed on C-fibers and are important in the transmission of nociceptive information to the spinal cord.

Intrathecal administration of antisense oligo-deoxynucleotides targeted to the unique region of the TTX-resistant sodium channel (NaV1.8) leads to PGE₂A significant reduction in the hyperalgesia induced (See alsoKhasar, S.G., M.S.gold et al (1998) "A tetrodotoxin-resistant sodium currentmediates inflamations pain in the rat"Neurosci Lett256(1): 17-20). More recently, Wood and colleagues created a knockout mouse strain that lacks functional nav 1.8. In an assay to assess the response of animals to the inflammatory agent carrageenan, the mutation has an analgesic effect: (See alsoAkopian, A.N., V.Souslova et al (1999) "the tetrodotoxin-resistant sodium channel SNS has a particulate functional pain ways"Nat Neurosci2(6): 541-8). In addition, defects in the mechanical and temperature perception were observed in these animals. The analgesia exhibited by the nav1.8 knockout mutant is consistent with observations regarding the role of TTX-tolerance current in nociception.

Immunohistochemistry, in situ hybridization, and in vitro electrophysiological experiments have all shown that sodium channel NaV1.8 selectively localizes to small sensory neurons of the dorsal root ganglion and trigeminal ganglion: (Ginseng radix (Panax ginseng C.A. Meyer) SeeA kopia, A.N., L.Sivilotti et al (1996) "A tetrodotoxin-Resistancevoltage-gated sodium channel expressed by sensory nerves"Nature379(6562): 257-62). The primary role of these neurons is the detection and transmission of nociceptive stimuli. Antisense and immunohistochemical evidence also supported the role of nav1.8 in neuropathic pain ((r))See alsoLai, j., m.s.gold et al (2002) "Inhibition of neuropathicity of by acquired expression of the tetrodotoxin-resistant sodium channel. nav 1.8"Pain95(1-2): 143-52, and Lai, J., J.C. Hunter et al (2000) "Block of neuropathic pain by antisense targeting of Soft-resistant sodium channels in sensory nenrons”Methods Enzymol314: 201-13). The nav1.8 protein is up-regulated along intact C-fibers adjacent to nerve damage. Antisense treatment prevented redistribution of nav1.8 along the nerve, reversing neuropathic pain. Combining gene-knockout and antisense data supports the role of nav1.8 in the detection and transmission of inflammatory and neuropathic pain.

In neuropathic pain states, there is a Na channel distribution and a remodeling of subtypes. In damaged nerves, expression of NaV1.8 and NaV1.9 is greatly reduced, while expression of TTX-sensitive subunit NaV1.3 is up-regulated by 5-10 fold ((S))See alsoDib-Hajj, S.D., J.Fjell et al (1999) "plastics of sodium channel expression in DRG nerves in the chromatographic constraint in nerve model of neuropathic pain.Pain83(3): 591-600). In animal models following nerve injury, the time course of increased nav1.3 parallels the appearance of allodynia. The biophysical peculiarity of the nav1.3 channel is that it shows very fast re-guidance after inactivation after an action potential. This results in a sustained high firing rate, which is often seen in damaged nerves (A), (B), (C), (D), (See alsoCummins, t.r., f.aglieco et al (2001) "nav 1.3 sodium channels: rapid repriming and slow-state actuation display qualitative differences in a macromolecular cell line and in a molecular sensor nerves "J Neurosci21(16): 5952-61). Nav1.3 is expressed in both the central and peripheral systems of humans. NaV1.9 is similar to NaV1.8, it also selectively localizes to the small sensory neurons of the dorsal root ganglia and trigeminal ganglia: (See alsoFang, X., L.Djouhri et al (2002) "the presence and role of the tetrodotoxin-resistant sodium channel Na (v)1.9(NaN) in nociceptive primary air sources"J Neurosci22(17): 7425-33). It has a slow rate of inactivation and a voltage dependence that shifts to the left with respect to activation: (See alsoDib-Hajj, S., J.A.Black et al (2002) "NaN/Nav1.9: asodium channel with unique properties "Trends Neurosci25(5): 253-9). These two biophysical properties allowNav1.9 plays a role in establishing the resting membrane potential of nociceptive neurons. The resting membrane potential of cells expressing NaV1.9 was in the range of-55 to-50 mV, compared to-65 mV for most other peripheral and central neurons. This persistent depolarization is largely due to the persistently low levels of nav1.9 channel activation. This depolarization allows neurons to more easily reach the threshold at which action potentials are fired in response to nociceptive stimulation. Compounds that block the nav1.9 channel may play an important role in establishing a set point for pain stimulus detection. In chronic pain states, nerves and nerve endings may become swollen and allergic, exhibiting high frequency of action potential firing, with mild or even no stimulation. These pathological neural swellings are called neuromas, where the major Na channels expressed are nav1.8 and nav1.7 (a)See alsoKretschmer, T., L.T.Happel et al (2002) "Accumulation of PN1 and PN3 sodium channels in painfu man neuroma-evidence"Acta Neurochir(Wien)144(8): 803-10; dispatch 810). Nav1.6 and nav1.7 are also expressed in dorsal root ganglion neurons and contribute to the small TTX-sensitive components found in these cells. Thus, in addition to its role in neuroendocrine excitability, nav1.7 may be a potential pain target in particular (See alsoKlugbauer, N.N., L.Lacinova et al (1995) "Structure and functional expression of a new member of soft hand tempdo-sensitive voltage-activated sodium channel family of cells"Embo J 14(6)：1084-90)。

NaV1.1(See alsoSugawara, T.T., E.Mazaki-Miyazaki et al (2001) "Nav1.1 variants of house fe brake components associated with afebril partial phases"Neurology57(4): 703-5) and NaV1.2(See alsoSugawara, T.T., Y.Tsouubuchi et al (2001) "A missense multiple of the Na + channel alpha II subhealthy gene Na (v)1.2 in a patient with a fe and fe fibers sizing reactors channel dynamic function"Proc Natl Acad Sci U S A 98(11)：6384-9) have been linked to epileptic disorders, including febrile seizures. More than 9 genetic mutations in NaV1.1 are associated with febrile seizures (See alsoMeisler, M.H., J.A. Kearney et al (2002) "details of voltage-gated sodium channels disorders and epsilon"Novartis Found Symp 241：72-81)。

Nav1.5 antagonists have been developed for the treatment of cardiac arrhythmias. A genetic defect in NaV1.5 that produces a larger, current-inactive component has been linked to human long QT, and an orally effective local anesthetic, mexiletine, has been used to treat this condition (see: methods for treating cancer)See alsoWang, D.W., K.Yazawa et al (1997) "Pharmacological targeting of Long QT microorganisms channels"J Clin Invest 99(7)：1714-20)。

Several Na channel blockers are currently used clinically or tested clinically for epilepsy (See also，Moulard，B.and D.Bertrand(2002)“Epilepsy and sodiumchannel blockers”Expert Opin.Ther.Patents12(1): 85-91); acute pain (See alsoWiffen, P., S.Collins et al (2000) "anticancer drugs for use and respiratory pain"Cochrane Database Syst Rev3) Chronic pain (1)Ginseng radix (Panax ginseng C.A. Meyer) SeeWiffen, P., S.Collins et al (2000) "anticancer drug for oral and respiratory pain"Cochrane Database Syst Rev3, and Guay, D.R, (2001) "attachment agents in the management of chronic pain"Pharmacotherapy21(9): 1070-81), inflammatory pain (See also，Gold，M.S.(1999)“Tetrodotoxin-resistant Na+ currents and inflammatoryhyperalgesia.”Proc Natl Acad Sci U S A96(14): 7645-9) and neuropathic pain (I)See alsoStrichartz, G.R., Z.Zhou et al (2002) "therapeutic concentrations of local and inflammatory unwoil the functional roll of systemic channels in neuropathic pain"Novartis Found Symp241: 189-201, and Sandner-Kiesling, A., G.Rumpold Seitlinger et al (2002) "Lamotrigine monootherpy for control of neuralgia after nerve section”Acta Anaesthesiol Scand46(10): 1261-4); arrhythmia (A)See alsoAn, R.H., R.Bangalore et al (1996) "Lidocaine block of LQT-3 mutant human Na + channels"Circ Res79(1): 103-8, and Wang, D.W., K.Yazawa et al (1997) "pharmaceutical targeting of Long QT microorganisms"J Clin Invest99(7): 1714-20); neuroprotection (A)See alsoTaylor, C.P. and L.S.Narasimohan (1997) "Sodium channels and therapy of centralnervous system diseases"Adv Pharmacol39: 47-98) and use as anesthetic(s)Ginseng radix (Panax ginseng C.A. Meyer) SeeStrichartz, G.R., Z.Zhou et al (2002) "Therapeutic compositions local and inflammatory tissue in the patent roll of sodium channels in the cosmetic sheet"Novartis Found Symp 241：189-201)。

Various animal models of clinical significance have been developed for studying sodium channel modulators for a variety of different pain indications. For example, malignant chronic pain, see Kohase, h. et al, actaanalesthesio scaud.2004; 48(3): 382-3; femoral cancer pain (see, Kohase, H. et al, Acta Anaesthediol Scand. 2004; 48 (3): 382-3); non-malignant chronic bone pain (see, Ciocon, J.O. et al, J Am Geriator Soc.1994; 42 (6): 593-6); rheumatoid arthritis (see Calvino, B. et al, Behav 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 Neurosci methods.2001; 104 (2): 191-8); neuropathic low back Pain (see Hines, R. et Al, Pain Med. 2002; 3 (4): 361-5; Massie, J.B. et Al, J Neurosci methods.2004; 137 (2): 283-9; neuropathic low back Pain (see Hines, R. et Al, Pain Med. 2002; 3 (4): 361-5; Massie, J.B. et Al, J Neurosci methods.2004; 137 (2): bellyache-9); myofascial Pain syndrome (see Dalpiaz & Dodds, J Pain Pallat Care Pharmacother. 2002; 16 (1): 99-104; Sluka et Al, Muscle nerve New. 2001; 24 Im1): 37-46; fibromyalgia (see Bennet & Tai, Int Clin J. Sat. et Al; temporal Pain J. Sat. 1995, 3, 1995-97; Al-7; 7, 7-97; visceral Pain, Al) (see Brand. K-87; 35; 7-7; 7-9; 7; see Bran, 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 pain (see Vera-Portocarro, L.B. et al, Anesthesiology.2003; 98 (2): 474-84); IBS pain (see Verne, G.N. et al, pain. 2003; 105 (1-2): 223-30; La JH et al, 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 headaches, including cluster headaches (see Costa, A. et al, cephalalgia.2000; 20 (2): 85-91); chronic neuropathic Pain, including post-herpetic neuralgia (see, Attal, N. et al, neurology.2004; 62 (2): 218-25; Kim & Chung 1992, Pain 50: 355); diabetic neuropathy (see, Beidoun A et al, Clin J pain.2004; 20 (3): 174-8; Courteix, C. et al, pain.1993; 53 (1): 81-8); HIV-associated neuropathy (see, Portegies & Rosenberg, New Tijdschr Genesekd.2001; 145 (15): 731-5; Joseph EK et al, pain.2004; 107 (1-2): 147-58; Oh, S.B. et al, JNeurosci.2001; 21 (14): 5027-35); trigeminal neuralgia (see, Sato, J. et al, Oralsurg Oral Med Orthol Radiol endo.2004; 97 (1): 18-22; Imamura Y et al, Exp Brain Res.1997; 116 (1): 97-103); Charcot-Marie Tooth neuropathy (see, Sereda, M. et al, neuron. 1996; 16 (5): 1049-60); hereditary sensory neuropathy (see, Lee, M.J. et al, Hum MolGenet.2003; 12 (15): 1917-25); peripheral nerve damage (see, Attal, N. et al, neurology.2004; 62 (2): 218-25; Kim & Chung 1992, Pain 50: 355; Bennett & Xie, 1988, Pain 33: 87; Decoded, I. & Woolf, C.J., 2000, Pain 87: 149; Shir, Y. & Seltzer, Z.1990; Neurosci Lett 115: 62); painful neuroma (see, Nahabenian & Johnson, Ann plant Surg.2001; 46 (1): 15-22; Devor & Raber, Behavv Neural biol.1983; 37 (2): 276-83); ectopic proximal and distal firing (see Liu, X. et al, Brain Res.2001; 900 (1): 119-27); radiculopathy (see Devers & Galer, (see Clin J pain.2000; 16 (3): 205-8; Hayashi N et al, spine.1998; 23 (8): 877-85), chemotherapy-induced neuropathic pain (see, Aley, K.O. et al, neuroscience.1996; 73 (1): 259-65), radiation-induced neuropathic pain, post-mastectomy pain (see, devices & Galer, Clin J pain.2000; 16 (3): 205-8), central pain (Cahana, A. et al, Anesth Analg.2004; 98 (6): 1581-4), spinal cord injury pain (see, Hains, B.C. et al, Exp Neurol.2000; 2: 426-164; 37), post-stroke pain (see, Lahoda, Buhelda, C. et al, Nernst J.2000; Leanthropy [ 2000-79; complex syndrome; see, Lealsis et al, Angstrom. 83; 2000-79, j pain.2004; 5(3Suppl 2): s1); phantom pain (see, Weber, W.E., Ned Tiidschr Genesekd.2001; 145 (17): 813-7; Levitt & Heyback, pain.1981; 10 (1): 67-73); intractable pain (see Yokoyama, M. et al, Can J Anaesth.2002; 49 (8): 810-3); acute pain, acute post-operative pain (see, Koppert, W. et al, Anesth Analg.2004; 98 (4): 1050-5; Brennan, T.J. et al, pain.1996; 64 (3): 493 501); acute musculoskeletal pain; arthralgia (see, Gotoh, S. et al, Ann Rheum Dis.1993; 52 (11): 817-22); mechanical lumbar pain (see, Kehl, L.J. et al, pain.2000; 85 (3): 333-43); neck pain; tendinitis; injury/athletic pain (see, Sesay, M. et al, Can J Anaesth.2002; 49 (2): 137-43); acute visceral pain including abdominal pain, pyelonephritis, appendicitis, cholecystitis, ileus, hernia, etc. (see Giambernadrino, M.A. et al, pain.1995; 61 (3): 459-69); chest pain, including cardiac pain (see, Vergona, R.A. et al, Life Sci.1984; 35 (18): 1877-84); pelvic pain, renal colic, acute obstetric pain, including childbirth pain (see, Segal, S. et al, Anesth Analg.1998; 87 (4): 864-9); cesarean section pain; acute inflammatory, burn and wound pain; acute intermittent pain, including endometriosis (see, Cason, A.M. et al, Horm Behav.2003; 44 (2): 123-31); acute herpes zoster pain; sickle cell anemia; acute pancreatitis (see, Toma, H; gastroenterology.2000; 119 (5): 1373-81); breakthrough pain; orofacial pain, including sinusitis pain, dental pain (see, Nusstein, J. et al, J Endo.1998; 24 (7): 487-91; Chidiac, J.J. et al, Eur J pain.2002; 6 (1): 55-67); multiple Sclerosis (MS) pain (see, Sakurai & Kanazawa, J Neurol Sci.1999; 162 (2): 162-8); pain in depression (see Greene B, Curr Med Res Opin.2003; 19 (4): 272-7); leprosy pain; behcet's pain; painful obesity (see, Devilers & Oranje, Clin ExpDirmatol.1999; 24 (3): 240-1); phlegmonotic pain; acute febrile polyneuritis (Guillain-Barre) pain; lower limb pain and toe movement; haglund syndrome; erythromelalgia (see, Legroux-Crespel, E. et al, Ann Dermatol Venoreol. 2003; 130 (4): 429-33); fabry's pain (see, Germain, D.P., J Soc biol. 2002; 196 (2): 183-90); bladder and genitourinary disorders including urinary incontinence (see, Berggren, t. et al, J urol.1993; 150(5 Pt 1): 1540-3); overactive bladder (see Chuang, Y.C. et al, urology.2003; 61 (3): 664-70); painful bladder syndrome (see, Yoshimura, N. et al, J Neurosci.2001; 21 (21): 8690-6); interstitial Cystitis (IC) (see, Giannakopoulos & Campilomotors, Arch Ital Urol Newrol Androl.1992; 64 (4): 337-9; Boucher, M. et al, JUrol.2000; 164 (1): 203-8); and prostatitis (see Mayersak, J.S., IntSurg.1998; 83 (4): 347-9; Keith, I.M. et al, J Urol.2001; 166 (1): 323-8).

Unfortunately, as noted above, the efficacy of sodium channel blockers currently used in the above disease states is largely limited by a number of side effects. These side effects include various CNS disorders, such as blurred vision, dizziness, nausea and sedation, and are more latentIn life-threatening cardiac arrhythmias and heart failure. Such undesirable side effects can be avoided by using Na channel blockers that exhibit a degree of selectivity in their anti-Na channel subtype activity. However, the Na channel blockers currently on the market lack this selectivity. Perhaps because of this lack of molecular selectivity, drugs currently on the market exhibit utility-dependent blockade and generally exhibit higher affinity at depolarizing potentials, resulting in preferential targeting of actively firing neurons, which is considered to be a key factor in the therapeutic window of existing Na channel-blocking drugs. Despite each drug's own unique therapeutic profile, current Na channel blockers are often associated with Central Nervous System (CNS) and Cardiovascular (CV) side effects, including changes in blood pressure, which are often dose limiting. Dizziness, sedation, nausea, ataxia and confusion^TMMexiletine^TMAnd lidocaine^TMSome of the specific side reactions observed.

Thus, there remains a need to develop other Na channel antagonists, preferably those with higher potency and fewer side effects.

Disclosure of Invention

Summary of The Invention

It has now been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are useful as inhibitors of voltage-gated sodium channels. These compounds have the general formula I:

or a pharmaceutically acceptable derivative thereof.

These compounds and pharmaceutically acceptable compositions are useful in the treatment or lessening the severity of a variety of diseases, disorders, or conditions including, but not limited to, acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy or epilepsy disorders, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, and incontinence.

Detailed Description

1. General description of the compounds of the invention:

the present invention relates to compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

x is O, S, NR, C (O) or C (R)₂；

Ring A is phenyl or a 5-7 membered heteroaromatic ring wherein ring A is optionally substituted with up to y occurrences of R⁵Substitution;

R¹and R²Each independently is hydrogen or C_1-6Aliphatic groups in which up to two carbon atoms other than the atom attached to the nitrogen atom are optionally replaced by O, S, NR or c (o);

x is 0 to 4;

y is 0 to 4;

z is 0 to 4;

each occurrence of R³、R⁴And R⁵Independently is Q-R^x；

Q is a bond or C_1-6Aliphatic chain, in which up to two non-adjacent methylene units of Q are optionally substituted by CO, CO₂、COCO、CONR、OCONR、NRNR、NRNRCO、NRCO、NRCO₂、NRCONR、SO、SO₂、NRSO₂、SO₂NR、NRSO₂NRO, S or NR substitution;

each occurrence of R^xIndependently selected from R', halogen, NO₂、CN、OR’、SR’、N(R’)₂、NR’C(O)R’、NR’C(O)N(R’)₂、NR’CO₂R’、C(O)R’、CO₂R’、OC(O)R’、C(O)N(R’)₂、OC(O)N(R’)₂、SOR’、SO₂R’、SO₂N(R’)₂、NR’SO₂R’、NR’SO₂N(R’)₂C (O) R' or C (O) CH₂C(O)R’；

R in each occurrence is independently selected from hydrogen or optionally substituted C_1-6An aliphatic group; and is

Each occurrence of R' is independently selected from hydrogen or an optionally substituted group selected from: c_1-8Aliphatic radical, C_6-10An aryl, heteroaryl ring having 5 to 10 ring atoms or a heterocyclyl ring having 3 to 10 ring atoms, or wherein R and R ', taken together with the atoms to which they are bonded or R' taken together with the atoms to which they are bonded, form a 5-8 membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In one embodiment, the following compounds are excluded from the compounds of formula I:

(i)R²is hydrogen, X is O, y is 1 and R⁵When is OMe, then R³Is not NO₂(ii) a And

(ii)R²is hydrogen or ethyl, X is C (O), and when X is 0, then R⁵Is not NO₂。

In another embodiment, the following compounds are excluded from the compounds of formula I:

(i)R²is hydrogen, X is O, y is 1 and R⁵When is OMe, then R³Is not NO₂；

(ii)R²Is hydrogen or ethyl, X is C (O), and when X is 0Then R is⁵Is not NO₂；

(iii)R²Is hydrogen, X is C (O), X is 0 and y is 0, then ring A is not phenyl; and

(iv) n- [3- [ (cyclopropylamino) sulfonyl ] phenyl ] -2-phenoxy-benzamide; n- [3- [ [ (3, 4-dihydro-2H-pyrrol-5-yl) amino ] sulfonyl ] phenyl ] -2-phenoxy-benzamide; n- [3- [ (dimethylamino) sulfonyl ] phenyl ] -2-phenoxy-benzamide; n- [5- [ (dimethylamino) sulfonyl ] -2-methoxyphenyl ] -2-phenoxy-benzamide; n- [3- (aminosulfonyl) phenyl ] -2- (4-methoxyphenoxy) -5-nitro-benzamide; n- [3- [ (cyclopropylamino) sulfonyl ] phenyl ] -2- (phenylmethyl) -benzamide; 2- [ (2-cyanophenyl) thio ] -N- [5- [ (dimethylamino) sulfonyl ] -2, 3-dimethylphenyl ] -benzamide; 2- [ (2-cyanophenyl) thio ] -N- [5- [ (diethylamino) sulfonyl ] -2, 3-dimethylphenyl ] -benzamide; n- [5- [ (dimethylamino) sulfonyl ] -2-methylphenyl ] -2- (phenylmethyl) -benzamide; 2- [ (2-cyanophenyl) thio ] -N- [5- [ (diethylamino) sulfonyl ] -2-methylphenyl ] -benzamide; n- [5- [ (dimethylamino) sulfonyl ] -2-methylphenyl ] -2- [ [ 2-nitro-4- (trifluoromethyl) phenyl ] thio ] -benzamide; 2- [ (2-cyanophenyl) thio ] -N- [5- [ (diethylamino) sulfonyl ] -2-methoxyphenyl ] -benzamide; 2- [4- (methylthio) -3-nitrobenzoyl ] -N- [3- (aminosulfonyl) -4-methoxyphenyl ] -benzamide; 2- (4-chloro-3-nitrobenzoyl) -N- [5- [ (ethylamino) sulfonyl ] -2-methoxyphenyl ] -benzamide; and 2- [ [4- [ (difluoromethyl) thio ] phenyl ] amino ] -N- [3- [ [ (2-furylmethyl) amino ] sulfonyl ] phenyl ] -benzamide.

2. Compounds and definitions:

the compounds of the present invention include those generally described above, and are further illustrated by the classes, subclasses, and specific compounds disclosed herein. The following definitions as used herein should be used unless otherwise indicated. For the purposes of the present invention, the identification of chemical Elements is carried out according to the periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75 th edition. In addition, the general principles of organic chemistry are described in "organic chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999 and "March's Advanced Organic Chemistry", 5 th edition, eds: smith, m.b. and March, j., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, as set forth generally above, or such as described for particular classes, subclasses, and specific substituents of the present invention. It is to be understood that the phrase "optionally substituted" may be used interchangeably with the phrase "substituted or unsubstituted. In general, the term "substituted" whether preceded by the term "optionally" or not, means that hydrogen groups in a given structure are replaced with the specified substituent groups. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when multiple positions in any given structure may be substituted with multiple substituents selected from a specified group, the substituents may be the same or different at each position. The combination of substituents encompassed by the present invention is preferably a combination of substituents that results in the formation of a stable or chemically feasible compound. The term "stable" as used herein means a compound that is not substantially altered when subjected to conditions that permit its production, detection, preferably recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is substantially unchanged when maintained at a temperature of 40 ℃ or less for at least one week in the absence of moisture or other chemical reaction conditions.

As used herein, the term "aliphatic" or "aliphatic radical" means a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle", "cycloaliphatic" or "cycloalkyl"), havingA single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C₃-C₈Hydrocarbons or bicyclic radicals C₈-C₁₂A hydrocarbon, which is fully saturated or contains one or more units of unsaturation, but is not aromatic, which has a single point of attachment to the rest of the molecule, wherein any single ring in said bicyclic ring system is a 3-7 membered ring. Suitable aliphatic groups include, but are not limited to, linear or branched substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl.

The term "heteroaliphatic" as used herein, refers to an aliphatic group in which one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups can be substituted or unsubstituted, straight or branched chain, cyclic or acyclic, and include "heterocyclic", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" groups.

The term "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" as used herein, refers to a non-aromatic, monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are independently selected heteroatoms. In some embodiments, a "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" group has 3-14 ring members, wherein one or more ring members are heteroatoms independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3-7 ring members.

The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; any basic nitrogen or heterocyclic ringQuaternized forms of the nitrogen which may be substituted, e.g. N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺(as in N-substituted pyrrolidinyl)).

The term "unsaturated" as used herein means that the moiety has one or more units of unsaturation.

The term "alkoxy" or "alkylthio" as used herein means an alkyl group as defined hereinbefore attached to the main carbon chain through an oxygen ("alkoxy") or sulfur ("alkylthio") atom.

The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" denote alkyl, alkenyl or alkoxy groups, as the case may be, which may be substituted with one or more halogen atoms. The term "halogen" denotes F, Cl, Br or I.

The term "aryl", used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", denotes monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". The term "aryl" also denotes a heteroaryl ring system as defined below.

The term "heteroaryl", used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroarylalkoxy", denotes monocyclic, bicyclic and tricyclic ring systems having a total of 5 to 14 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 3 to 7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

Aryl (including aralkyl, aralkoxy, aryloxyalkyl, and the like) or heteroaryl (including heteroaralkyl and heteroaralkoxy, and the like) may contain one or more substituents. Adaptations of aryl or heteroaryl groups to unsaturated carbon atomsThe substituent is selected from halogen, -R^o、-OR^o、-SR^o1, 2-methylene-dioxy, 1, 2-ethylenedioxy, optionally substituted by R^oSubstituted phenyl (Ph), optionally substituted with R^osubstituted-O (Ph), optionally substituted with R^oSubstituted- (CH)₂)_1-2(Ph), optionally substituted by R^osubstituted-CH ═ CH (Ph), -NO₂、-CN、-N(R^o)₂、-NR℃(O)R^o、-NR℃(O)N(R^o)₂、-NR℃O₂R^o、-NR^oNR℃(O)R^o、-NR^oNR℃(O)N(R^o)₂、-NR^oNR℃O₂R^o、-C(O)C(O)R^o、-C(O)CH₂C(O)R^o、-CO₂R^o、-C(O)R^o、-C(O)N(R^o)₂、-OC(O)N(R^o)₂、-S(O)₂R^o、-SO₂N(R^o)₂、-S(O)R^o、-NR^oSO₂N(R^o)₂、-NR^oSO₂R^o、-C(＝S)N(R^o)₂、-C(＝NH)-N(R^o)₂Or- (CH)₂)_0-2NHC(O)R^oWherein each independently occurring R^oSelected from hydrogen, optionally substituted C_1-6Aliphatic radical, unsubstituted 5-6 membered heteroaryl or heterocycle, phenyl, -O (Ph) or-CH₂(Ph), or, although as defined above, two independent occurrences of R on the same substituent or different substituents^oAnd each R^oThe atoms to which the groups are bonded together form a 3-8 membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. R^oIs selected from NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group) or halogeno C_1-4Aliphatic radical, wherein R^oEach of the above C_1-4Aliphatic groups are unsubstituted.

The aliphatic or heteroaliphatic group or the non-aromatic heterocycle may contain one or more substituents. Suitable substituents on the saturated carbon of the aliphatic or heteroaliphatic group or of the non-aromatic heterocycle are selected from the groups listed above for the aryl or heteroaryl unsaturated carbon, and additionally include the following groups: o, S, NNHR^＊、＝NN(R^＊)₂、＝NNHC(O)R^＊、＝NNHCO₂(alkyl) ═ NNHSO₂(alkyl) or ═ NR^＊Wherein each R is^＊Independently selected from hydrogen or optionally substituted C_1-6An aliphatic group. R^＊Is selected from NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group) or halo (C)_1-4Aliphatic radical), wherein R^＊Each of the above C_1-4Aliphatic groups are unsubstituted.

Optional substituents on the non-aromatic heterocyclic nitrogen being selected from the group consisting of-R⁺、-N(R⁺)₂、-C(O)R⁺、-CO₂R⁺、-C(O)C(O)R⁺、-C(O)CH₂C(O)R⁺、-SO₂R⁺、-SO₂N(R⁺)₂、-C(＝S)N(R⁺)₂、-C(＝NH)-N(R⁺)₂or-NR⁺SO₂R⁺(ii) a Wherein R is⁺Is hydrogen, optionally substituted C_1-6Aliphatic group, optionally substituted phenyl group, optionally substituted-O (Ph), optionally substituted-CH₂(Ph), optionally substituted- (CH)₂)_1-2(Ph), optionally substituted-CH ═ CH (Ph), or an unsubstituted 5-6 membered heteroaryl ring or heterocycle having 1-4 heteroatoms independently selected from oxygen, nitrogen or sulfur, or, although as defined above, two independent occurrences of R on the same substituent or on different substituents⁺And each R⁺The atoms to which the groups are bonded together form a 3-8 membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. R⁺Is selected from NH or an optional substituent on the phenyl ring₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group) or halo (C)_1-4Aliphatic radical), wherein R⁺Each of the above C_1-4Aliphatic groups are unsubstituted.

As noted above, in some embodiments, two independent occurrences of R^o(or R)⁺Or any other variable similarly defined herein) together with the atoms to which each variable is bonded form a 3-8 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Two independently occurring R^o(or R)⁺Or any other variable similarly defined herein) include, but are not limited to, the following: a) two independently occurring R^o(or R)⁺Or any other variable similarly defined herein) to the same atom and together with that atom form a ring, e.g. N (R)^o)₂In which R appears twice^oTaken together with the nitrogen atom to form piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl; and b) two independent occurrences of R^o(or R)⁺OR any other variable similarly defined herein) to different atoms and combine with two of these atoms to form a ring, e.g., OR where the phenyl group is twice-presented^oSubstitutionThese two occurrences of R^oTogether with the oxygen atoms to which they are bound form a fused 6-membered oxygen containing ring:it is understood that two independent occurrences of R^o(or R)⁺Or any other variable similarly defined herein) may form a variety of other rings when taken together with the atom to which each variable is bonded, and the examples detailed above are not intended to be limiting.

Unless otherwise indicated, the structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers as well as mixtures of enantiomers, mixtures of diastereomers and mixtures of geometric isomers (or conformers) of the compounds of the present invention are within the scope of the present invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise indicated, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except that hydrogen is replaced by deuterium or tritium or carbon is replaced by¹³C-or¹⁴C-enriched carbon instead of compounds having the structure of the present invention are within the scope of the present invention. For example, such compounds may be used as analytical tools or probes in biological assays, or sodium channel blockers with improved therapeutic properties.

3. Description of exemplary Compounds

In one embodiment, the present invention provides a method of modulating a sodium channel comprising the step of contacting a compound of formula I' or a pharmaceutically acceptable salt thereof with said channel:

wherein:

R¹and R²Is hydrogen, and R¹And R²Is selected from hydrogen, C_1-8Aliphatic radicalBall, C_6-10Aryl, heteroaryl ring with 5 to 10 ring atoms or heterocyclyl ring with 3 to 10 ring atoms, wherein up to two carbon units in the aliphatic radical are optionally replaced by CO, CO₂、COCO、CONR、OCONR、NRNR、NRNRCO、NRCO、NRCO₂、NRCONR、SO、SO₂、NRSO₂、SO₂NR、NRSO₂NR, O, S or NR substitution;

x is 0 to 4;

z is 0 to 5;

each occurrence of R³And R⁴Independently is Q-R^x；

Q is a bond or C_1-6Aliphatic chain, in which up to two non-adjacent methylene units of Q are optionally substituted by CO, CO₂、COCO、CONR、OCONR、NRNR、NRNRCO、NRCO、NRCO₂、NRCONR、SO、SO₂、NRSO₂、SO₂NR、NRSO₂NR, O, S or NR substitution;

each occurrence of R^XIndependently selected from R', halogen, NO₂、CN、OR’、SR’、N(R’)₂、NR’C(O)R’、NR’C(O)N(R’)₂、NR’CO₂R’、C(O)R’、CO₂R’、OC(O)R’、C(O)N(R’)₂、OC(O)N(R’)₂、SOR’、SO₂R’、SO₂N(R’)₂、NR’SO₂R’、NR’SO₂N(R’)₂C (O) R' or C (O) CH₂C(O)R’；

R in each occurrence is independently selected from hydrogen or optionally substituted C_1-6An aliphatic group; and

each occurrence of R' is independently selected from hydrogen or an optionally substituted group selected from: c_1-8Aliphatic radical, C_6-10Aryl, heteroaryl ring having 5 to 10 ring atoms or heterocyclyl ring having 3 to 10 ring atoms, or wherein R and R 'together with the atoms to which they are bonded, or R' in both occurrences together with the atoms to which they are bonded, form 5-An 8-membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In one embodiment of the compounds of formula I', x is at least 2, and when R is in position 3³When it is 1-piperidinylmethyl, then R in the 4-position³Is not an optionally substituted phenyl group.

In another embodiment of the compounds of formula I', the following compounds are excluded:

(i)R²is hydrogen, X is O, y is 1 and R⁵When is OMe, then R³Is not NO₂；

(ii)R²Is hydrogen or ethyl, X is C (O), and when X is 0, then R⁵Is not NO₂；

(iii)R²Is hydrogen, X is C (O), X is 0 and y is 0, then ring A is not phenyl; and

(iv) n- [3- [ (cyclopropylamino) sulfonyl ] phenyl ] -2-phenoxy-benzamide; n- [3- [ [ (3, 4-dihydro-2H-pyrrol-5-yl) amino ] sulfonyl ] phenyl ] -2-phenoxy-benzamide; n- [3- [ (dimethylamino) sulfonyl ] phenyl ] -2-phenoxy-benzamide; n- [5- [ (dimethylamino) sulfonyl ] -2-methoxyphenyl ] -2-phenoxy-benzamide; n- [3- (aminosulfonyl) phenyl ] -2- (4-methoxyphenoxy) -5-nitro-benzamide; n- [3- [ (cyclopropylamino) sulfonyl ] phenyl ] -2- (phenylmethyl) -benzamide; 2- [ (2-cyanophenyl) thio ] -N- [5- [ (dimethylamino) sulfonyl ] -2, 3-dimethylphenyl ] -benzamide; 2- [ (2-cyanophenyl) thio ] -N- [5- [ (diethylamino) sulfonyl ] -2, 3-dimethylphenyl ] -benzamide; n- [5- [ (dimethylamino) sulfonyl ] -2-methylphenyl ] -2- (phenylmethyl) -benzamide; 2- [ (2-cyanophenyl) thio ] -N- [5- [ (diethylamino) sulfonyl ] -2-methylphenyl ] -benzamide; n- [5- [ (dimethylamino) sulfonyl ] -2-methylphenyl ] -2- [ [ 2-nitro-4- (trifluoromethyl) phenyl ] thio ] -benzamide; 2- [ (2-cyanophenyl) thio ] -N- [5- [ (diethylamino) sulfonyl ] -2-methoxyphenyl ] -benzamide; 2- [4- (methylthio) -3-nitrobenzoyl ] -N- [3- (aminosulfonyl) -4-methoxyphenyl ] -benzamide; 2- (4-chloro-3-nitrobenzoyl) -N- [5- [ (ethylamino) sulfonyl ] -2-methoxyphenyl ] -benzamide; and 2- [ [4- [ (difluoromethyl) thio ] phenyl ] amino ] -N- [3- [ [ (2-furylmethyl) amino ] sulfonyl ] phenyl ] -benzamide.

In one embodiment of the compounds of formula I', X is O. In another embodiment, X is S. In yet another embodiment, X is NR, wherein R is hydrogen or C1-C6 alkyl. In one embodiment, X is NH. In one embodiment, X is c (o). In yet another embodiment, X is C (R)₂Wherein each R is independently hydrogen or C1-C6 alkyl. In one embodiment, X is CH₂。

In one embodiment of the compounds of formula I', x is 0 to 3. Alternatively, x is 0-2. In another embodiment, x is 1. Alternatively, x is 2.

In one embodiment of the compounds of formula I', R³Selected from halogen, CN, NO₂Or optionally substituted groups selected from: c_1-6Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R’)₂、-OR’、-CH₂OR’、-SR’、-CH₂SR’、-C(O)R’、-COOR’、-NRCOR’、-CON(R’)₂or-S (O)₂N(R’)₂. Exemplary R³The radicals including Cl, Br, F, CF₃Methyl, ethyl, isopropyl, tert-butyl, isobutyl, CN, -COOH, -N (CH)₃)₂，-N(Et)₂，-N(iPr)₂，-O(CH₂)₂OCH₃，-CONH₂，-COO(C_1-6Alkyl), -OH, -OCF₃，-SCF₃，-OCH₃，-CH₂OH，-NHCOCH₃，-SO₂NH₂Optionally substituted pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl or optionally substituted groups selected from: c_1-4Alkoxy, phenyl, phenoxy, benzyl or benzyloxy。

In another embodiment of the compounds of formula I', R³Is a C1-C6 alkyl group. Exemplary groups include methyl, ethyl, isopropyl, t-butyl, or sec-butyl.

In another embodiment of the compounds of formula I', R³Is optionally substituted pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl or morpholinyl.

In another embodiment of the compounds of formula I', R³Is optionally substituted phenyl, benzyl, phenoxy or benzyloxy.

In one embodiment of the compounds of formula I', z is 0 to 3. Alternatively, z is 0-2. In another embodiment, z is 0.

In one embodiment of the compounds of formula I', z is 1-3 and each R⁴Selected from halogen, CN, NO₂Or optionally substituted groups selected from: c_1-6Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R’)₂、-OR’、-CH₂OR’、-SR’、-CH₂SR’、-C(O)R’、-COOR’、-NRCOR’、-CON(R’)₂or-S (O)₂N(R’)₂. Exemplary R⁴The radicals including Cl, Br, F, CF₃Methyl, ethyl, isopropyl, tert-butyl, isobutyl, CN, -COOH, -N (CH)₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COO(C_1-6Alkyl), -OH, -OMe, -OCF₃、-SCF₃、-OCH₃、-CH₂OH、-NHCOCH₃、-SO₂NH₂Optionally substituted pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl or optionally substituted groups selected from: c_1-4Alkoxy, phenyl, phenoxy, benzyl or benzyloxy.

In another embodiment of the compounds of formula I', R⁴Is a C1-C6 alkyl group. Exemplary groups include methyl, ethyl, isopropyl, t-butyl, or sec-butyl.

In another embodiment of the compounds of formula I', R⁴Is optionally substituted pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl or morpholinyl.

In another embodiment of the compounds of formula I', R⁴Is optionally substituted phenyl, benzyl, phenoxy or benzyloxy.

In one embodiment of the compounds of formula I', R⁵The radicals, when present, being halogen, CN, NO₂Or optionally substituted groups selected from: c_1-4Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R’)₂、-OR’、-CH₂OR’、-SR’、-CH₂SR’、-COOR’、-NRCOR’、-CON(R’)₂or-S (O)₂N(R’)₂. Exemplary R⁵The radicals including Cl, Br, F, CF₃Methyl, ethyl, CN, -COOH, -N (CH)₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COOCH₃、-OH、-CH₂OH、-NHCOCH₃、-SO₂NH₂Methylenedioxy, ethylenedioxy, piperidinyl, piperazinyl, morpholino, or optionally substituted group selected from: c_1-4Alkoxy, phenyl, phenoxy, benzyl or benzyloxy.

In one embodiment of the compounds of formula I', R³The radicals comprising halogen, CN, NO₂Or optionally substituted group selected from: c_1-6Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R’)₂、-OR’、-CH₂OR’、-SR’、-CH₂SR’、-C(O)R’、-COOR’、-NRCOR’、-CON(R’)₂or-S (O)₂N(R’)₂. Exemplary R³The radicals including Cl, Br, F, CF₃Methyl, ethyl, isopropyl, tert-butyl, isobutyl, CN, -COOH, -N (CH)₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COO(C_1-6Alkyl), -OH, -OCF₃、-SCF₃、-OCH₃、-CH₂OH、-NHCOCH₃、-SO₂NH₂Pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl, morpholino, or optionally substituted groups selected from: c_1-4Alkoxy, phenyl, phenoxy, benzyl or benzyloxy.

In one embodiment, the present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

x is O, S, NR, C (O) or C (R)₂；

The A ring is a phenyl ring or a 5-7 membered heteroaromatic ring, wherein the A ring is optionally substituted with up to y occurrences of R⁵Substitution;

R¹and R²Each independently is hydrogen or C_1-6An aliphatic group in which up to two carbon atoms other than the atom attached to the nitrogen atom are optionally replaced by O, S, NR or c (o);

x is 0 to 4;

y is 0 to 4;

z is 0 to 4;

each occurrence of R³、R⁴And R⁵Independently is Q-R^Ｘ；

Q is a bond or C_1-6Aliphatic chain, in which up to two non-adjacent methylene units of Q are optionally substituted by CO, CO₂、COCO、CONR、OCONR、NRNR、NRNRCO、NRCO、NRCO₂、NRCONR、SO、SO₂、NRSO₂、SO₂NR、NRSO₂NR, O, S or NR substitution;

each occurrence of R^ＸIndependently selected from R', halogen, NO₂、CN、OR’、SR’、N(R’)₂、NR’C(O)R’、NR’C(O)N(R’)₂、NR’CO₂R’、C(O)R’、CO₂R’、OC(O)R’、C(O)N(R’)₂、OC(O)N(R’)₂、SOR’、SO₂R’、SO₂N(R’)₂、NR’SO₂R’、NR’SO₂N(R’)₂C (O) R' or C (O) CH₂C(O)R’；

R in each occurrence is independently selected from hydrogen or optionally substituted C_1-6An aliphatic group; and is

Each occurrence of R' is independently selected from hydrogen or an optionally substituted group selected from: c_1-8Aliphatic radical, C_6-10An aryl, heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms, wherein R and R ', together with the atoms to which they are bonded or R' in both occurrences, together with the atoms to which they are bonded, form a 5-8 membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In another embodiment, the following compounds are excluded from the compounds of formula I:

(i)R²is hydrogen, X is O, y is 1 and R⁵Is OMe, then R³Is not NO₂(ii) a And

(ii)R²is hydrogen or ethyl, X is C (O), X is 0, then R⁵Is not NO₂。

In another embodiment, the following compounds are excluded from the compounds of formula I:

(i)R²is hydrogen, X is O, y is 1 and R⁵Is OMe, then R³Is not NO₂；

(ii)R²Is hydrogen or ethyl, X is C (O), X is 0, then R⁵Is not NO₂；

(iii)R²Is hydrogen, X is C (O), X is 0 and y is 0, then ring A is not phenyl;

(iii)R²is hydrogen, X is C (O), X is 0 and y is 0, then ring A is not phenyl; and with the proviso that the following compounds are excluded

N- [3- [ (cyclopropylamino) sulfonyl ] phenyl ] -2-phenoxy-benzamide; n- [3- [ [ (3, 4-dihydro-2H-pyrrol-5-yl) amino ] sulfonyl ] phenyl ] -2-phenoxy-benzamide; n- [3- [ (dimethylamino) sulfonyl ] phenyl ] -2-phenoxy-benzamide; n- [5- [ (dimethylamino) sulfonyl ] -2-methoxyphenyl ] -2-phenoxy-benzamide; n- [3- (aminosulfonyl) phenyl ] -2- (4-methoxyphenoxy) -5-nitro-benzamide; n- [3- [ (cyclopropylamino) sulfonyl ] phenyl ] -2- (phenylmethyl) -benzamide; 2- [ (2-cyanophenyl) thio ] -N- [5- [ (dimethylamino) sulfonyl ] -2, 3-dimethylphenyl ] -benzamide; 2- [ (2-cyanophenyl) thio ] -N- [5- [ (diethylamino) sulfonyl ] -2, 3-dimethylphenyl ] -benzamide; n- [5- [ (dimethylamino) sulfonyl ] -2-methylphenyl ] -2- (phenylmethyl) -benzamide; 2- [ (2-cyanophenyl) thio ] -N- [5- [ (diethylamino) sulfonyl ] -2-methylphenyl ] -benzamide; n- [5- [ (dimethylamino) sulfonyl ] -2-methylphenyl ] -2- [ [ 2-nitro-4- (trifluoromethyl) phenyl ] thio ] -benzamide; 2- [ (2-cyanophenyl) thio ] -N- [5- [ (diethylamino) sulfonyl ] -2-methoxyphenyl ] -benzamide; 2- [4- (methylthio) -3-nitrobenzoyl ] -N- [3- (aminosulfonyl) -4-methoxyphenyl ] -benzamide; 2- (4-chloro-3-nitrobenzoyl) -N- [5- [ (ethylamino) sulfonyl ] -2-methoxyphenyl ] -benzamide and 2- [ [4- [ (difluoromethyl) thio ] phenyl ] amino ] -N- [3- [ [ (2-furylmethyl) amino ] sulfonyl ] phenyl ] -benzamide.

In one embodiment of the compounds of formula I, ring a is optionally substituted phenyl.

In another embodiment of the compounds of formula I, ring a is an optionally substituted 5-7 membered heteroaryl ring. Exemplary such rings are shown below:

or

In one embodiment of the compounds of formula I, X is O, S, NH, C (O) or CH₂。

In one embodiment of the compounds of formula I, X is O. In another embodiment, X is S. In yet another embodiment, X is NR, wherein R is hydrogen or C1-C6 alkyl. In one embodiment, X is NH. In another embodiment, X is NR and R is C1-C6 alkyl. In one embodiment, X is c (o). In yet another embodiment, X is C (R)₂Wherein each R is independently hydrogen or C1-C6 alkyl. In one embodiment, X is CH₂。

In one embodiment of the compounds of formula I, x is 0 to 3. Alternatively, x is 0-2. In another embodiment, x is 1. Alternatively, x is 2.

In one embodiment of the compounds of formula I, x is 1-3 and R³Independently selected from halogen, CN, NO₂Or optionally substituted groups selected from: c_1-6Aliphatic group, aryl group, 5-6 membered heteroaryl group, 4-7 membered heterocyclic groupAralkyl, -N (R')₂、-CH₂N(R’)₂、-OR’、-CH₂OR’、-SR’、-CH₂SR’、-C(O)R’、-COOR’、-NRCOR’、-CON(R’)₂or-S (O)₂N(R’)₂. Exemplary R³The radicals including Cl, Br, F, CF₃Methyl, ethyl, isopropyl, tert-butyl, isobutyl, CN, -COOH, -N (CH)₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COO(C_1-6Alkyl), -OH, -OCF₃、-SCF₃、-OCH₃、-CH₂OH、-NHCOCH₃、-SO₂NH₂Optionally substituted pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl or optionally substituted groups selected from: c_1-4Alkoxy, phenyl, phenoxy, benzyl or benzyloxy.

In another embodiment of the compounds of formula I, x is 1-3 and each R³Independently selected from Cl, Br, F, CF₃Methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CN, NO₂、-COOH、-N(CH₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COO(C_1-6Alkyl), -OH, -OCF₃、-SCF₃、-OCH₃、-CH₂OH、-NHCOCH₃、-SO₂NH₂、-SO₂CH₃Methylenedioxy, ethylenedioxy or optionally substituted group selected from: pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidyl, piperazinyl, morpholinyl, 2-oxo-imidazolidinyl, C_1-4Alkoxy, phenyl, phenethyl, phenoxy, phenoxymethyl, benzoyl, benzyl, benzylamino or benzyloxy.

In another embodiment of the compounds of formula I, R³Is C1-C6 alkaneA radical group. Exemplary groups include methyl, ethyl, isopropyl, tert-butyl, and sec-butyl.

In another embodiment of the compounds of formula I, R³Is optionally substituted pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl or morpholinyl.

In another embodiment of the compounds of formula I, R³Is optionally substituted phenyl, benzyl, phenoxy or benzyloxy.

In one embodiment of the compounds of formula I, z is 0 to 3. Alternatively, z is 0-2. In another embodiment, z is 0. In another embodiment, z is 1 to 3.

In one embodiment of the compounds of formula I, z is 1-3 and each R⁴Independently selected from halogen, CN, NO₂Or optionally substituted groups selected from: c_1-6Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R’)₂、-OR’、-CH₂OR’、-SR’、-CH₂SR’、-C(O)R’、-COOR’、-NRCOR’、-CON(R’)₂or-S (O)₂N(R’)₂. Exemplary R⁴The radicals including Cl, Br, F, CF₃Methyl, ethyl, isopropyl, tert-butyl, isobutyl, CN, -COOH, -N (CH)₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COO(C_1-6Alkyl), -OH, -OMe, -OCF₃、-SCF₃、-OCH₃、-CH₂OH、-NHCOCH₃、-SO₂NH₂Optionally substituted pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl or optionally substituted groups selected from: c_1-4Alkoxy, phenyl, phenoxy, benzyl or benzyloxy.

In another embodiment of the compounds of formula I, R⁴Is C1-C6 alkyl groups. In another embodiment, z is 1-3 and each R⁴Independently selected from methyl, ethyl, isopropyl, tert-butyl or sec-butyl. Exemplary groups include methyl, ethyl, isopropyl, tert-butyl, and sec-butyl.

In another embodiment of the compounds of formula I, z is 1-3 and each R⁴Independently selected from optionally substituted pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl or morpholinyl.

In another embodiment of the compounds of formula I, z is 1-3 and each R⁴Independently selected from optionally substituted phenyl, benzyl, phenoxy or benzyloxy.

In one embodiment of the compounds of formula I, R⁵The radicals, when present, being halogen, CN, NO₂Or optionally substituted groups selected from: c_1-4Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R’)₂、-OR’、-CH₂OR’、-SR’、-CH₂SR’、-COOR’、-NRCOR’、-CON(R’)₂or-S (O)₂N(R’)₂. Exemplary R⁵The radicals including Cl, Br, F, CF₃Methyl, ethyl, CN, -COOH, -N (CH)₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COOCH₃、-OH、-CH₂OH、-NHCOCH₃、-SO₂NH₂Methylenedioxy, ethylenedioxy, piperidinyl, piperazinyl, morpholino, or optionally substituted group selected from: c_1-4Alkoxy, phenyl, phenoxy, benzyl or benzyloxy.

In another embodiment of the compounds of formula I, y is 1-3, and each R⁵Independently selected from halogen, CN, NO₂Or optionally substituted groups selected from: c_1-4Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R’)₂、-OR’、-CH₂OR’、-SR’、-CH₂SR’、-COOR’、-NRCOR’、-CON(R’)₂or-S (O)₂N(R’)₂。

In another embodiment of the compounds of formula I, y is 1-3, and R⁵Independently selected from Cl, Br, F, CF₃Methyl, ethyl, CN, -COOH, -N (CH)₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COOCH₃、-OH、-CH₂OH、-NHCOCH₃、-SO₂NH₂Methylenedioxy, ethylenedioxy, piperidinyl, piperazinyl, morpholino, or optionally substituted group selected from: c_1-4Alkoxy, phenyl, phenoxy, benzyl or benzyloxy.

In another embodiment, the compound has the structure of formula I-a:

in certain embodiments of the compounds of formula I-A, R²Is hydrogen. In other embodiments, R²Is C_1-6An aliphatic group in which up to two carbon atoms other than the atom attached to the nitrogen atom are optionally replaced by O, S, NR or C (O).

In another embodiment of the compounds of formula I-A, X is O, S, NH, C (O), or CH₂. In another embodiment, X is NR and R is a C1-C6 alkyl group. In yet another embodiment, X is NR and R is hydrogen. In another embodiment, X is C (R)₂Wherein each R is independently hydrogen or C1-C6 alkyl. In another embodiment, X is O.

In another embodiment of the compounds of formula I-A, x is 0-3. Alternatively, x is 0-2. In another embodiment, x is 1. Alternatively, x is 2.

In another embodiment of the compounds of formula I-A, x is 1-3 and each R³Independently selected from halogen, CN, NO₂Or optionally substituted groups selected from: c_1-6Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R’)₂、-OR’、-CH₂OR’、-SR’、-CH₂SR’、-C(O)R’、-COOR’、-NRCOR’、-CON(R’)₂or-S (O)₂N(R’)₂. In another embodiment, R³The radicals including Cl, Br, F, CF₃Methyl, ethyl, isopropyl, tert-butyl, isobutyl, CN, -COOH, -N (CH)₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COO(C_1-6Alkyl), -OH, -OCF₃、-SCF₃、-OCH₃、-CH₂OH、-NHCOCH₃、-SO₂NH₂Optionally substituted pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl or optionally substituted groups selected from: c_1-4Alkoxy, phenyl, phenoxy, benzyl or benzyloxy.

In one embodiment of the compounds of formula I-A, x is 1-3 and each R³Independently selected from Cl, Br, F, CF₃Methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CN, NO₂、-COOH、-N(CH₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COO(C_1-6Alkyl), -OH, -OCF₃、-SCF₃、-OCH₃、-CH₂OH、-NHCOCH₃、-SO₂NH₂、-SO₂CH₃Methylenedioxy, ethylenedioxy or optionally substituted group selected from: pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidyl,Piperazinyl, morpholinyl, 2-oxo-imidazolidinyl, C_1-4Alkoxy, phenyl, phenethyl, phenoxy, phenoxymethyl, benzoyl, benzyl, benzylamino or benzyloxy.

In another embodiment of the compounds of formula I-A, R³Is a C1-C6 alkyl group. Exemplary groups include methyl, ethyl, isopropyl, tert-butyl, and sec-butyl.

In another embodiment of the compounds of formula I-A, R³Selected from optionally substituted pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl or morpholinyl.

In another embodiment of the compounds of formula I-A, R³Selected from optionally substituted phenyl, benzyl, phenoxy or benzyloxy.

In another embodiment of the compounds of formula I-A, R⁵The radicals, when present, being halogen, CN, NO₂Or optionally substituted groups selected from: c_1-4Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R’)₂、-OR’、-CH₂OR’、-SR’、-CH₂SR’、-COOR’、-NRCOR’、-CON(R’)₂or-S (O)₂N(R’)₂. In another embodiment, R⁵The radicals including Cl, Br, F, CF₃Methyl, ethyl, CN, -COOH, -N (CH)₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COOCH₃、-OH、-CH₂OH、-NHCOCH₃、-SO₂NH₂Methylenedioxy, ethylenedioxy, piperidinyl, piperazinyl, morpholino, or optionally substituted group selected from: c_1-4Alkoxy, phenyl, phenoxy, benzyl or benzyloxy.

In another embodiment of the compounds of formula I-A, y is 1-3, and each R⁵Independently selected from halogen,CN、NO₂Or optionally substituted groups selected from: c_1-4Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R’)₂、-OR’、-CH₂OR’、-SR’、-CH₂SR’、-COOR’、-NRCOR’、-CON(R’)₂or-S (O)₂N(R’)₂。

In another embodiment of the compounds of formula I-A, y is 1-3, and each R⁵Independently selected from Cl, Br, F, CF₃Methyl, ethyl, CN, -COOH, -N (CH)₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COOCH₃、-OH、-CH₂OH、-NHCOCH₃、-SO₂NH₂Methylenedioxy, ethylenedioxy, piperidinyl, piperazinyl, morpholino, or optionally substituted group selected from: c_1-4Alkoxy, phenyl, phenoxy, benzyl or benzyloxy.

In another embodiment of the compounds of formula I-A, X is O or S, R²Is hydrogen; x is 1 and R³Selected from optionally substituted C_1-6Aliphatic radical or CF₃(ii) a And y is 1-3 and each R⁵Independently selected from CN, CF₃-C (O) R ', -OR', halogen, optionally substituted C_1-4Aliphatic groups, 5-6 membered heteroaryl groups, 4-7 membered heterocyclyl groups.

In another embodiment of the compounds of formula I-A, X is O or S, R²Is hydrogen; x is 1 and R³Selected from CF₃Methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl or sec-butyl; and y is 1 and R⁵Selected from CN, CF₃-C (O) R ', -COOR ', -OR ', halogen, optionally substituted C_1-4An aliphatic group, a 5-6 membered heteroaryl group, or a 4-7 membered heterocyclyl group.

In another embodiment of the compounds of formula I-A, X is O or S, R²Is hydrogen; x is 1 and R³Selected from CF₃Methyl group (II)Ethyl, propyl, isopropyl, tert-butyl, isobutyl or sec-butyl; and y is 1 and R⁵Selected from CN, CF₃-C (O) Me, -COOMe, -OMe, F, Cl, Br, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, optionally substituted pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl or azetidinyl.

In another embodiment of the compounds of formula I-A, X is O, R²Is hydrogen; x is 1 and R³Selected from CF₃Methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl or sec-butyl; and y is 1 and R⁵Selected from CN, CF₃-C (O) Me, -COOMe, -OMe, F, Cl, Br, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, optionally substituted pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl or azetidinyl.

In another embodiment of the compounds of formula I-A, X is O, R²Is hydrogen; x is 1 and R³Selected from CF₃Or a tert-butyl group; and y is 1 and R⁵Selected from CN, CF₃-C (O) Me, -COOMe, -OMe, F, Cl, Br, isopropyl, tert-butyl, isobutyl, sec-butyl, optionally substituted pyridyl, piperidyl or morpholinyl.

In another embodiment, the compound has the structure of formula II-a:

in certain embodiments of the compounds of formula II-A, R³Selected from halogen, CN, NO₂Or optionally substituted groups selected from: c_1-6Aliphatic, aryl, heteroaryl, aralkyl, -N (R')₂、-CH₂N(R’)₂、-OR’、-CH₂OR’、-SR’、-CH₂SR’、-C(O)R’、-COOR’、-NRCOR’、-CON(R’)₂or-S (O)₂N(R’)₂. Exemplary R³The radicals including Cl, Br, F, CF₃Me, Et, isopropyl, tert-butyl, isobutyl, CN, -COOH, -N (CH)₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COO(C_1-6Alkyl), -OH, -OCF₃、-SCF₃、-OCH₃、-CH₂OH、-NHCOCH₃、-SO₂NH₂Optionally substituted pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl or optionally substituted groups selected from: c_1-4Alkoxy, phenyl, phenoxy, benzyl or benzyloxy.

In another embodiment of the compounds of formula II-A, R³Is a C1-C6 alkyl group. Exemplary groups include methyl, ethyl, isopropyl, t-butyl, or sec-butyl. In another embodiment, R³Selected from isopropyl, tert-butyl or sec-butyl.

In another embodiment of the compounds of formula II-A, R³Selected from optionally substituted pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl or morpholinyl. In another embodiment, R³Selected from optionally substituted pyridyl, pyrazolyl, piperidinyl or morpholinyl.

In another embodiment of the compounds of formula II-A, R³Selected from optionally substituted phenyl, benzyl, phenoxy or benzyloxy.

In another embodiment of the compounds of formula II-A, R⁵Selected from halogen, CN, NO₂Or optionally substituted groups selected from: c_1-4Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R’)₂、-OR’、-CH₂OR’、-SR’、-C(O)R’、-CH₂SR’、-COOR’、-NRCOR’、-CON(R’)₂or-S (O)₂N(R’)₂。

In another embodiment of the compounds of formula II-A, R⁵Selected from Cl, Br, F, CF₃、Me、Et、CN、-COOH、-N(CH₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-C(O)Me、-CONH₂、-COOCH₃、-OH、-OMe、-CH₂OH、-NHCOCH₃、-SO₂NH₂Methylenedioxy, ethylenedioxy, piperidinyl, piperazinyl, morpholino, or optionally substituted group selected from: c_1-4Alkoxy, phenyl, phenoxy, benzyl or benzyloxy.

In another embodiment of the compounds of formula II-A, X is O or S; r³Selected from optionally substituted C_1-6Aliphatic radical or CF₃(ii) a And R is⁵Selected from CN, CF₃-C (O) R ', -COOR ', -OR ', halogen, optionally substituted C_1-4Aliphatic groups, 5-6 membered heteroaryl groups, 4-7 membered heterocyclyl groups.

In another embodiment of the compounds of formula II-A, X is O or S; r³Selected from CF₃Methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl or sec-butyl; and R is⁵Selected from CN, CF₃、-C(O)R’、-COOR’、-OR’、-CON(R’)₂Halogen, optionally substituted C_1-4An aliphatic group, a 5-6 membered heteroaryl group, or a 4-7 membered heterocyclyl group.

In another embodiment of the compounds of formula II-A, X is O or S; r³Selected from CF₃Methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl or sec-butyl; and R is⁵Selected from CN, CF₃、-C(O)(C_1-4Alkyl), -COO (C)_1-4Alkyl), -O (C)_1-4Alkyl), -CONH₂F, Cl, Br, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, optionally substituted pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, piperazinyl, pyrroleAlkyl or azetidinyl.

In another embodiment of the compounds of formula II-A, X is O; r³Selected from CF₃Methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl or sec-butyl; and R is⁵Selected from CN, CF₃-C (O) Me, -COOMe, -OMe, F, Cl, Br, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, optionally substituted pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl or azetidinyl.

In another embodiment of the compounds of formula II-A, X is O; r³Selected from CF₃Or a tert-butyl group; and R is⁵Selected from CN, CF₃-C (O) Me, -COOMe, -OMe, F, Cl, Br, isopropyl, tert-butyl, isobutyl, sec-butyl, optionally substituted pyridyl, piperidyl or morpholinyl.

In another embodiment, the compounds of the present invention have the structure of formula III-A:

or a pharmaceutically acceptable salt thereof, wherein:

R³and each occurrence of R⁵Independently is Q-R^X；

y is 0 to 4;

q is a bond or C_1-6Aliphatic chain, in which up to two non-adjacent methylene units of Q are optionally substituted by CO, CO₂、COCO、CONR、OCONR、NRNR、NRNRCO、NRCO、NRCO₂、NRCONR、SO、SO₂、NRSO₂、SO₂NR、NRSO₂NR, O, S or NR substitution;

each occurrence of R^XIndependently selected from R', halogen, NO₂、CN、OR’、SR’、N(R’)₂、NR’C(O)R’、NR’C(O)N(R’)₂、NR’CO₂R’、C(O)R’、CO₂R’、OC(O)R’、C(O)N(R’)₂、OC(O)N(R’)₂、SOR’、SO₂R’、SO₂N(R’)₂、NR’SO₂R’、NR’SO₂N(R’)₂C (O) R' or C (O) CH₂C(O)R’；

R in each occurrence is independently selected from hydrogen or optionally substituted C_1-6An aliphatic group;

each occurrence of R' is independently selected from hydrogen or an optionally substituted group selected from: c_1-8Aliphatic radical, C_6-10An aryl, heteroaryl ring having 5 to 10 ring atoms, or a heterocyclyl ring having 3 to 10 ring atoms, or wherein R and R 'together with the atoms to which they are bonded, or R' in both occurrences together with the atoms to which they are bonded, form a 5-8 membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and is

With the proviso that the following compounds are excluded:

(i) n- [3- (aminosulfonyl) phenyl ] -2- (4-methoxyphenoxy) -5-nitro-benzamide; n- [3- [ (cyclopropylamino) sulfonyl ] phenyl ] -2-phenoxy-benzamide; n- [3- [ [ (3, 4-dihydro-2H-pyrrol-5-yl) amino ] sulfonyl ] phenyl ] -2-phenoxy-benzamide; n- [3- [ (dimethylamino) sulfonyl ] phenyl ] -2-phenoxy-benzamide; n- [5- [ (dimethylamino) sulfonyl ] -2-methoxyphenyl ] -2-phenoxy-benzamide; and N- [3- (aminosulfonyl) phenyl ] -2- (4-methoxyphenoxy) -5-nitro-benzamide.

In certain embodiments of the compounds of formula III-A, R³Selected from halogen, CN, NO₂Or optionally substituted groups selected from: c_1-6Aliphatic, aryl, heteroaryl, aralkyl, -N (R')₂、-CH₂N(R’)₂、-OR’、-CH₂OR’、-SR’、-CH₂SR’、-C(O)R’、-COOR’、-NRCOR’、-CON(R’)₂or-S (O)₂N(R’)₂. Exemplary R³The radicals including Cl, Br, F, CF₃Methyl, ethyl, isopropyl, tert-butyl, isobutyl, CN, -COOH, -N (CH)₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COO(C_1-6Alkyl), -OH, -OCF₃、-SCF₃、-OCH₃、-CH₂OH、-NHCOCH₃、-SO₂NH₂Optionally substituted pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl or optionally substituted groups selected from: c_1-4Alkoxy, phenyl, phenoxy, benzyl or benzyloxy.

In another embodiment of the compounds of formula III-A, R³Is a C1-C6 alkyl group. Exemplary groups include methyl, ethyl, isopropyl, t-butyl, or sec-butyl. In another embodiment, R³Is isopropyl, tert-butyl or sec-butyl.

In another embodiment of the compounds of formula III-A, R³Selected from optionally substituted pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl or morpholinyl. In another embodiment, R³Is optionally substituted pyridyl, pyrazolyl, piperidinyl or morpholinyl.

In another embodiment of the compounds of formula III-A, R³Selected from optionally substituted phenyl, benzyl, phenoxy or benzyloxy.

In another embodiment of the compounds of formula III-A, R⁵The radicals, when present, being halogen, CN, NO₂Or optionally substituted groups selected from: c_1-4Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R’)₂、-OR’、-CH₂OR’、-SR’、-CH₂SR’、-COOR’、-C(O)R’、-NRCOR’、-CON(R’)₂or-S: (O)₂N(R’)₂。

In another embodiment of the compounds of formula III-A, y is 1-3, and each R⁵Independently selected from CN, CF₃、-C(O)R’、-COOR’、-OR’、-CON(R’)₂Halogen, optionally substituted C_1-4An aliphatic group, a 5-6 membered heteroaryl group, or a 4-7 membered heterocyclyl group.

In another embodiment of the compounds of formula III-A, y is 1-3, and each R⁵Independently selected from CN, CF₃、-C(O)(C_1-4Alkyl), -COO (C)_1-4Alkyl), -O (C)_1-4Alkyl), -CON (R')₂F, Cl, Br, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, optionally substituted pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, or azetidinyl.

In another embodiment of the compounds of formula III-A, y is 1-3, and each R⁵Independently selected from CN, CF₃、-C(O)Me、-COOMe、-OMe、-CONH₂F, Cl, Br, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, optionally substituted pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, or azetidinyl.

In another embodiment of the compounds of formula III-A, y is 1-3, and each R⁵Independently selected from CN, CF₃-C (O) Me, -COOMe, -OMe, F, Cl, Br, isopropyl, tert-butyl, isobutyl, sec-butyl, optionally substituted pyridyl, piperidyl or morpholinyl.

Exemplary embodiments of the compounds of the present invention are shown in table 1 below.

Table 1:

the compounds of the present invention are readily prepared using methods known in the art. An exemplary synthetic route for the compounds of the invention is shown below. In each route, the starting compounds and reagents are commercially available or prepared according to methods known to those skilled in the art.

Scheme IA and scheme IB below illustrate exemplary methods for preparing compounds of formula I'. Scheme IA or scheme IB are useful for preparing compounds of the invention Nos. 2-5, 7-16, 18-25, 28-35, 37-44, 46-47, 49-54, 56-60, 62-75, 77, 79-81, 83-87, 89, 91-96, 100, 103, 106, 117, 120, 122, 126, 127, 131, 133, 137 and 140, 142.

Scheme IA：

Conditions are as follows: (a) SOCl₂，CH₂Cl₂(ii) a Pyridine; (b) HATU, Et₃N，DMF

Scheme IB：

Scheme II below illustrates an exemplary process for preparing compounds of formula I. Scheme II is used to prepare the compounds of Nos. 1, 6, 17, 26-27, 36, 48, 55, 61, 78, 82, 88, 97-99, 101-102, 104-105, 107-109, 111, 13-116, 118-119, 121, 124-125, 128-130, 132, 134-136, 139 and 143-144 of the present invention.

Scheme II：

Conditions are as follows: (a) AlCl₃，AcCl，CH₂Cl₂；(b)NaOH．H₂O，Br₂Dioxane; (c) (CuOTf)₂·PhH，Cs₂CO₃1-naphthalene, formic acid,ms, toluene, EtOAc, ring A-XH; (d) SOCl₂，CH₂Cl₂(ii) a ii, pyridine; (e) HATU, Et₃N，DMF；(f)Cul，K₃P0₄ ，DMF，H₂O, ring A-XH

Scheme III below illustrates an exemplary process for preparing compounds of formula I', wherein x is 1 and R³Is a heterocyclic ring containing at least one nitrogen ring atom (as shown in ring B in scheme III below). Scheme III was used to prepare compounds of invention nos. 45 and 76.

Scheme III：

Conditions are as follows: cul, K₃PO₄，DMF，H₂O.

Ring B-NH

Scheme IV below illustrates another exemplary method for preparing compounds of formula I'. Scheme IV was used to prepare compounds of invention nos. 90 and 112.

Scheme IV：

Conditions are as follows: (a) pyridine; (b) NaH, RX, THF; (c) cyanuric chloride, Et₃N, acetone; i.e. ii.HNR¹R²

Scheme V below illustrates an exemplary method for preparing compounds of formula I. Scheme V was used to prepare compound number 138 of the present invention.

Scheme V：

Conditions are as follows: (a) cs₂CO₃DMF, cyclicXH；(b)NaOH，H₂O，EtOH；(c)i.SOCl₂，CH₂Cl₂(ii) a ii pyridine; (d) HATU, Et₃N，DMF

Scheme VI below illustrates an exemplary process for preparing compounds of formula I', wherein one R is³is-SOPh or-SO₂Ph and another R³If present, is selected from any of the embodiments described herein. Scheme VI is used to prepare compounds of invention nos. 110 and 112.

Scheme VI：

Conditions are as follows: (a) 30% H₂O₂Aqueous solution, hexafluoropropan-2-ol; (b) mCPBA, CH₂Cl₂

Certain additional embodiments of the compounds generally described above are described in more detail below.

5. Use, formulation and administration

Pharmaceutically acceptable compositions

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

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

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

Pharmaceutically acceptable salts are well known in the art. For example, S.M.Berge et al in J.pharmaceutical Sciences, 1977Pharmaceutically acceptable salts are described in detail in 66, 1-19, and are incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, embonate, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, salts of citric acid, salts of lactic acid, salts of malonic acid, salts of lactic acid, salts of 2-naphthalenesulfonates, nicotinates, Pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄And (3) salt. The invention also encompasses quaternization of any basic nitrogen-containing group of the compounds as disclosed herein. Water or oil soluble or dispersible products can be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed with counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

As noted above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle, as described herein, including any and all solvents, diluents or other liquid excipients, dispersing or suspending aids, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like as appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, 16 th edition, e.w. martin (Mack Publishing co., Easton, Pa., 1980) discloses various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, e.g., any other component that produces an undesirable biological effect or otherwise interacts in a deleterious manner with a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the invention. Some examples of materials capable of serving as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphates; glycine; sorbic acid or potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinylpyrrolidone; a polyacrylate; waxes; polyethylene-polypropylene oxide-block polymers; lanolin; sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; crushed tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol; a phosphate buffer solution; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preserving and anti-oxidizing agents may also be present in the composition, according to the judgment of the person skilled in the art.

Use of compounds and pharmaceutically acceptable compositions

In yet another aspect, there is provided a method for treating or lessening the severity of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy or epilepsy disorders, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, or incontinence, comprising administering to a subject in need of such treatment an effective amount of a compound or a pharmaceutically acceptable composition comprising a compound. In certain preferred embodiments, there is provided a method for treating or reducing the severity of acute, chronic, neuropathic or inflammatory pain comprising administering to a subject in need of such treatment an effective amount of a compound or pharmaceutically acceptable composition. In certain embodiments of the invention, an "effective amount" of a compound or pharmaceutically acceptable composition is an amount effective to treat or reduce the severity of one or more of the following conditions: acute, chronic, neuropathic or inflammatory pain, epilepsy or epileptic disorders, neurodegenerative disorders, psychiatric disorders (e.g., anxiety and depression), muscular rigidity, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome or incontinence.

In accordance with the methods of the present invention, the compounds and compositions can be administered using any amount and route of administration effective to treat or reduce the severity of one or more of the following conditions: acute, chronic, neuropathic or inflammatory pain, epilepsy or epileptic disorders, neurodegenerative disorders, psychiatric disorders such as 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 drug, the manner in which it is administered, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein denotes a physically discrete pharmaceutical unit, suitable for the patient to be treated. However, it will be understood that the total daily amount of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend upon a variety of factors including the condition being treated and the severity of the condition; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, the route of administration, and the rate of excretion of the particular compound employed; the duration of the treatment; drugs used in combination or concomitantly with the specific compound employed; and other factors well known in the medical arts. The term "subject" as used herein means an animal, preferably a mammal, most preferably a human.

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

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

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

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

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

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

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

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

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

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

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

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

In certain exemplary embodiments, the compounds of the present invention are useful as inhibitors of nav 1.8.

It will be appreciated that the compounds and pharmaceutically acceptable compositions of the invention may be used in combination therapy, that is, the compounds and pharmaceutically acceptable compositions may be administered in one or more other desired therapeutic agents or regimensSimultaneous, prior or subsequent to the sequence. The particular combination of therapies (therapeutic agents or procedures) used in the combination regimen will take into account the compatibility of the desired therapeutic agent and/or procedure with the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect on the same condition (e.g., the compounds of the invention may be administered simultaneously with another agent used to treat the same condition), or they may achieve different effects (e.g., control of any adverse effects). As used herein, an additional therapeutic agent that is normally administered to treat or prevent a particular disease or condition is referred to as "appropriate for the disease or condition being treated. For example, exemplary additional therapeutic agents include, but are not limited to: non-opioid analgesics (indoles such as etodolac, indomethacin, sulindac, tolmetin, naphthylalkanones such as nabumetone, oxicams such as piroxicam, acetaminophen derivatives such as acetaminophen, propionic acids such as fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen sodium, oxaprozin, salicylic acids such as aspirin, sambucol magnesium, diflunisal, fenamates such as mefenamic acid, and pyrazoles such as phenylbutazone); or an opiate (narcotic) agonist (such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, dextropropoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine). In addition, non-pharmaceutical analgesic methods may be used in conjunction with the administration of one or more compounds of the present invention. For example, anesthesiologic (intraspinal infusion, nerve block), neurosurgical (neurolysis of CNS pathways), neurostimulative (transcutaneous electrical nerve stimulation, dorsal column stimulation), physical therapy (physical therapy, orthopedic devices, diathermy) or psychological (cognitive-hypnotic, biofeedback or behavioral) methods may also be used. Additional suitable therapeutic agents or methods are generally described in The Merck Manual, 17 th edition, edited by MarkH. Beers and Robert Berkow, Merck Research Laboratories, 1999, and The food and drug administration Web Pagewww.fda.govIs incorporated herein by reference in its entirety.

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

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

Another aspect of the invention relates to inhibiting nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 activity in a biological sample or patient, comprising administering to the patient or contacting the biological sample with a compound of formula I or a composition comprising the compound. The term "biological sample" as used herein includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

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

In order that the invention described herein may be more fully understood, the following examples are provided. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any way.

Detailed Description

General procedure

Deuterated chloroform (CDCl) is obtained₃) Or dimethyl sulfoxide-D₆In the form of (DMSO) solutions¹HNMR (400MHz) and¹³c NMR (100MHz) spectrum. Using PESciexaAPI-150-EX LC/MS, Shimadzu LC-8A pump, Gilson 215 autosampler, Gilson 819 injection Module, 3.0mL/min flow rate, 10-99% CH₃CN(0.035％ TFA)/H₂LC/MS data were obtained with an O (0.05% TFA) gradient, a Phenomenex Luna 5u C18 column (50X 4.60mm), a Shimadzu SPD-10A UV/Vis detector, a Cedex 75 ELSD detector. Silica gel chromatography was performed using silica gel-60 of particle size 230 and 400 mesh. Pyridine, methylene Chloride (CH)₂Cl₂) Tetrahydrofuran (THF) from an Aldrich Sure-Seal bottle kept under dry nitrogen. All reactions were magnetically stirred, unless otherwise indicated. All temperatures refer to the temperature of the internal reaction unless otherwise indicated.

1- (4-tert-butyl-2-bromophenyl) ethanone

Aluminum chloride (8.0g, 60mmol) was added to CH₂Cl₂(200mL)Stirring was carried out and acetyl chloride (8.5mL, 120mmol) was added slowly to give a homogeneous solution. 3-Bromobutylphenyl-benzene (11g, 50mmol) of CH was added slowly₂Cl₂(20mL) and the reaction was stirred at room temperature for 16 h. By CH₂Cl₂After dilution, the reaction was washed with water, saturated NaHCO₃Aqueous solution and water wash. Organic solution is treated with Na₂SO₄Dried and concentrated under vacuum. By silica gel chromatography (0% -50% CH)₂Cl₂-hexane) to give 1- (4-tert-butyl-2-bromophenyl) ethanone (3.1g, 24% yield) as a light yellow oil.¹H NMR(400MHz，CDCl₃)δ 7.61(d，J＝1.8Hz，1H)，7.46(d，J＝8.1Hz，1H)，7.37(dd，J＝8.1，1.8Hz，1H)，2.63(s，3H)，1.32(s，9H)ppm。

4-tert-butyl-2-bromobenzoic acid

A solution of NaOH (7.8g, 190mmol) in water (60mL) was cooled in an ice bath and bromine (2.51mL, 49mmol) was added slowly. A solution of 1- (4-tert-butyl-2-bromophenyl) ethanone (3.1g, 12mmol) in dioxane (60mL) was added slowly and the cooling bath was removed. After stirring at room temperature for 3 hours, the reaction was acidified with concentrated hydrochloric acid. The reaction was diluted with water and extracted with EtOAc. The combined extracts were washed with water and Na₂SO₄Dried and concentrated in vacuo to give 4-tert-butyl-2-bromobenzoic acid (3.1g, 100% yield) as a tan solid.¹H NMR(400MHz，CDCl₃)δ7.97(d，J＝8.3Hz，1H)，7.71(d，J＝1.9Hz，1H)，7.41(dd，J＝8.3，1.9Hz，1H)，1.34(s，9H)ppm。

2- (4-fluorophenoxy) -4-tert-butylbenzoic acid

4-tert-butyl-2-bromobenzoic acid (0.26 g)1.0mmol), 4-fluorophenol (0.22g, 2.0mmol), cesium carbonate (0.65g, 2.0mmol), copper trifluoromethanesulfonate-benzene complex (13mg, 25. mu. mol), 1-naphthoic acid (0.34g, 2.0mmol) and 4A stirred suspension of molecular sieves (0.25g) in toluene (10mL) and EtOAc (5 μ L) was heated at 110 ℃ for 16 h. The reaction was concentrated under reduced pressure and chromatographed on silica gel (0% to 5% MeOH-CH)₂Cl₂) Purification gave 2- (4-fluorophenoxy) -4-tert-butylbenzoic acid (0.11g, 39% yield) as a white solid. LC/MS: m/z289.0(M + H)⁺3.58 min (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％TFA))。¹H NMR(400MHz，CDCl₃)δ 8.12(d，J＝8.3Hz，1H)，7.24(d，J＝1.7Hz，1H)，7.14-7.05(m，4H)，6.84(d，J＝1.6Hz，1H)，1.23(s，9H)ppm。

2- (4-fluorophenoxy) -4-tert-butyl-N- (3- (aminosulfonyl) phenyl) benzamide (compound 78)

2- (4-fluorophenoxy) -4-tert-butylbenzoic acid (0.11g, 0.39mmol) and thionyl chloride (0.28mL, 3.9mmol) in CH₂Cl₂The solution (10mL) was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure and to the resulting oil was added a solution of 3-amino-benzenesulfonamide (73mg, 0.42mmol) in pyridine (4 mL). The solution was stirred at room temperature for 15 hours. The reaction was diluted with water and extracted with EtOAc. The combined extracts were washed with water and Na₂SO₄Dried and evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% -50% EtOAc-hexanes) to give a white solid which was recrystallized from EtOAc and hexanes. 2- (4-fluorophenoxy) -4-tert-butyl-N- (3- (aminosulfonyl) phenyl) benzamide (85mg, 50% yield) was obtained as a white solid. LC/MS: m/z 443.3(M + H)⁺3.49 min (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))。

N- (3- (aminosulfonyl) phenyl) -4- (trifluoromethoxy) benzamide (compound 34)

To a solution of 3-amino-benzenesulfonamide (17mg, 0.10mmol) in pyridine (1mL) was added 4-trifluoromethoxybenzoyl chloride (16. mu.L, 0.10 mmol). The reaction was stirred at room temperature for 15 hours and 10% -99% CH was used₃CN(0.035％TFA)/H₂O (0.05% TFA), purification by preparative reverse phase HPLC gave N- (3- (aminosulfonyl) phenyl) -4- (trifluoromethoxy) benzamide. LC/MS: m/z 360.9(M + H)⁺3.02 min (10% -99% CH)₃CN(0.035％ TFA)/H₂O(0.05％ TFA))。

2-cyclohexyl-N- (3- (aminosulfonyl) phenyl) benzamide (compound 83)

A solution of 2-cyclohexylbenzoic acid (20mg, 0.10mmol) and HATU (38mg, 0.10mmol) in DMF (1mL) was stirred at room temperature for 3 min. To this solution was added 3-amino-benzenesulfonamide (17mg, 0.10mmol) and triethylamine (14 μ L, 0.10 mmol). The reaction was stirred at room temperature for 16 hours, using 10% -99% CH₃CN(0.035％TFA)/H₂Purification of O (0.05% TFA) by preparative reverse phase HPLC gave 2-cyclohexyl-N- (3- (aminosulfonyl) phenyl) benzamide. LC/MS: m/z 359.1(M + H)⁺3.85 min (10% -99% CH)₃CN(0.035％ TFA)/H₂O(0.05％ TFA))。

2- (2- (piperidin-1-yl) phenoxy) -N- (3- (aminosulfonyl) phenyl) benzamide (compound 53)

2-bromo-N- (3- (aminosulfonyl) phenyl) benzamide (0.10g, 0.28mmol), 2- (piperidin-1-yl) phenol (74mg, 0.28mmol), K₃PO₄A suspension of (0.12g, 0.56mmol) and CuI (53mg, 0.28mmol) in DMF (1mL) and water (20. mu.L) was sealed in a glass tube and heated in a microwave oven at 150 ℃ for 15 minutes. The reaction was filtered and 10% -99% CH was used₃CN(0.035％ TFA)/H₂Purification of O (0.05% TFA) by preparative reverse phase HPLC gave 2- (2- (piperidin-1-yl) phenoxy) -N- (3- (aminosulfonyl) phenyl) benzamide. LC/MS: m/z 452.0(M + H)⁺2.31 min (10% -99% CH)₃CN(0.035％ TFA)/H₂O(0.05％ TFA))。

3- (4-tert-butylbenzoylamino) benzenesulfonic acid

To a solution of 3-aminobenzenesulfonic acid (1.7g, 10mmol) in pyridine (100mL) was added 4-tert-butylbenzoyl chloride (2.0mL, 10 mmol). The reaction was stirred at room temperature for 16 hours and the solvent was evaporated under vacuum. The residue was dissolved in EtOAc and washed with 1M aqueous hydrochloric acid. The aqueous washes were extracted with EtOAc. The combined organic extracts are extracted with Na₂SO₄Dried and concentrated under vacuum. The residue was chromatographed on silica gel (10% -20% MeOH-CH)₂Cl₂) Purification gave 3- (4-tert-butylbenzoylamino) benzenesulfonic acid (2.1g, 63% yield). LC/MS: m/z 334.3(M + H)⁺2.79 min (10% -99% CH)₃CN(0.035％ TFA)/H₂O(0.05％ TFA))。

3- (4-tert-butyl-N-methylbenzamido) benzenesulfonic acid

To a stirred solution of 3- (4-tert-butylbenzoylamino) benzenesulfonic acid (0.10g, 0.30mmol)To a solution of THF (5mL) was added sodium hydride (26mg, 0.66mmol) and after 30 minutes methyl iodide (37. mu.L, 0.60mmol) was added. The reaction was stirred for 17 hours, and 1M aqueous hydrochloric acid (1mL) was added. The solvent is removed under vacuum and the residue is taken up with 10% to 99% CH₃CN(0.035％TFA)/H₂Purification of O (0.05% TFA) by preparative reverse phase HPLC gave 3- (4-tert-butyl-N-methylbenzamido) benzenesulfonic acid (24mg, 23% yield). LC/MS: m/z 348.3(M + H)⁺3.82 min (10% -99% CH)₃CN(0.035％ TFA)/H₂O(0.05％TFA))。

4-tert-butyl-N-methyl-N- (3- (aminosulfonyl) phenyl) benzamide (Compound 90)

A solution of 3- (4-tert-butyl-N-methylbenzamido) benzenesulfonic acid (12mg, 35. mu. mol), cyanuric chloride (7.0mg, 40. mu. mol) and triethylamine (6.0. mu.L, 40. mu. mol) in acetone (0.5mL) was sealed in a glass tube and heated in a microwave oven at 120 ℃ for 10 minutes. Concentrated ammonium hydroxide (150. mu.L) was added and the reaction was stirred for 6 hours. Filtering the reaction solution, wherein the filtrate uses 10-99% CH₃CN(0.035％ TFA)/H₂Purification of O (0.05% TFA) by preparative reverse phase HPLC gave 4-tert-butyl-N-methyl-N- (3- (aminosulfonyl) phenyl) benzamide. LC/MS: m/z 347.3(M + H)⁺2.86 min (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％ TFA))。

2- (2-methylpyridin-3-yloxy) -4- (trifluoromethyl) benzonitrile

A mixture of 2-fluoro-4- (trifluoromethyl) benzonitrile (0.19g, 1.0mmol), 2-methylpyridin-3-ol (0.11g, 1.0mmol) and cesium carbonate (0.33g, 1.0mmol) in anhydrous DMF (5mL) was heated at 50 ℃ for 16 h. The reaction was diluted with water and extracted with EtOAcAnd (6) taking. The combined extracts were washed with water and Na₂SO₄Dried and evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% -30% EtOAc-hexanes) to give 2- (2-methylpyridin-3-yloxy) -4- (trifluoromethyl) benzonitrile (0.26g, 94% yield).¹H NMR(400MHz，CDCl₃)δ8.50(dd，J＝4.7，1.4Hz，1H)，7.85(d，J＝8.0Hz，1H)，7.44(dd，J＝8.1，0.7Hz，1H)，7.35(dd，J＝8.1，1.4Hz，1H)，7.28-7.25(m，1H)，6.87(s，1H)，2.50(s，3H)ppm。

2- (2-methylpyridin-3-yloxy) -4- (trifluoromethyl) benzoic acid

A mixture of 2- (2-methylpyridin-3-yloxy) -4- (trifluoromethyl) benzonitrile (56mg, 0.20mmol), 1M sodium hydroxide solution (1mL, 1mmol) and EtOH (1mL) was heated at reflux for 17 h. The solvent was removed under vacuum and the residue used 10% -99% CH₃CN(0.035％ TFA)/H₂Purification of O (0.05% TFA) by preparative reverse phase HPLC gave 2- (2-methylpyridin-3-yloxy) -4- (trifluoromethyl) benzoic acid as the TFA salt.¹H NMR(400MHz，CDCl₃)δ 8.36(d，J＝5.6Hz，1H)，8.32(d，J＝8.1Hz，1H)，7.72(d，J＝8.1Hz，1H)，7.51-7.47(m，2H)，7.30(d，J＝8.3Hz，1H)，2.81(s，3H)ppm。

2- (2-methylpyridin-3-yloxy) -N- (3-sulfamoylphenyl) - (trifluoromethyl) benzamide (Compound 138)

A solution of 2- (2-methylpyridin-3-yloxy) -4- (trifluoromethyl) benzoic acid TFA salt (54mg, 0.13mmol) and HATU (50mg, 0.13mmol) in DMF (1mL) was stirred at room temperature for 3 min. To this solution was added 3-amino-benzenesulfonamide (23mg, 0.13mmol) and triethylamine (46. mu.L, 0.33mmol). The reaction was stirred at room temperature for 16 hours, using 10% -99% CH₃CN(0.035％ TFA)/H₂Purification of O (0.05% TFA) by preparative reverse phase HPLC gave 2- (2-methylpyridin-3-yloxy) -N- (3-sulfamoylphenyl) -4- (trifluoromethyl) benzamide. LC/MS: m/z 452.3(M + H)⁺1.07 min (10% -99% CH)₃CN(0.035％ TFA)/H₂O(0.05％ TFA))。

4-tert-butyl-2- (phenylsulfinyl) -N- (3-sulfamoylphenyl) benzamide (compound 110)

To a solution of 4-tert-butyl-2- (phenylthio) -N- (3-sulfamoylphenyl) benzamide (15.4mg, 0.035mmol) in 1, 1, 1, 3, 3, 3-hexafluoropropan-2-ol (0.3mL) was added H₂O₂(30% wt aqueous solution, 0.01mL, 0.07 mmol). The reaction was stirred at room temperature for 40 minutes and saturated NaHCO was added_3(aq)And CH₂Cl₂(1mL each). The organic layer was washed with Na₂SO₄The pad was filtered and concentrated. The product was subjected to reverse phase HPLC (10% -99% CH)₃CN(0.035％ TFA)/H₂O (0.05% TFA)) to give 4-tert-butyl-2- (phenylsulfinyl) -N- (3-sulfamoylphenyl) benzamide. LC/MS: m/z 457.4(M + H)⁺1.54 min (10% -99% CH)₃CN(0.035％ TFA)/H₂O(0.05％ TFA))。

4-tert-butyl-2- (phenylsulfonyl) -N- (3-sulfamoylphenyl) benzamide (compound 112)

To 4-tert-butyl-2- (phenylthio) -N- (3-sulfamoylphenyl) benzamide (15.4mg, 0.035mmol) in CH₂Cl₂To the solution (0.5mL) was added mCPBA (12mg, 0.053 mmol). The reaction was stirred at room temperature for 40 minutes and saturated NaHCO was added_3(aq)(05 mL). The organic layer was washed with Na₂SO₄The pad was filtered and concentrated. The product was subjected to reverse phase HPLC (10% -99% CH)₃CN(0.035％ TFA)/H₂O (0.05% TFA)) to give 4-tert-butyl-2- (phenylsulfonyl) -N- (3-sulfamoylphenyl) benzamide. LC/MS: m/z 473.2(M + H)⁺1.70 min (10% -99% CH)₃CN(0.035％ TFA)/H₂O(0.05％ TFA))。

Analytical data for the compounds of table 1 are shown in table 2 below:

TABLE 2：

Assay for detecting and measuring NaV inhibitory properties of compounds

A) Optical method for determining NaV inhibitory properties of compounds

The compounds of the invention are useful as antagonists of voltage-gated sodium ion channels. The antagonistic properties of the test compounds were evaluated as follows. Cells expressing the NaV of interest are placed in microtiter plates. After the incubation period, the cells were stained with a fluorescent dye sensitive to transmembrane potential. Test compounds were added to the microtiter plate. Cells are stimulated by chemical or electrical means to excite NaV-dependent membrane potential changes in unblocked channels, which are detected and measured with transmembrane potential-sensitive dyes. Antagonists are detected as a decrease in membrane potential in response to a stimulus. Optical Membrane potential assay employs a voltage-sensitive FRET sensor consisting of Gonzalez and Tsien: (See alsoGonzalez, J.E. and R.Y.Tsien (1995) "Voltage sensing by fluorescence response energy transfer in single cells"Biophys J69(4): 1272-80, and Gonzalez, J.E.and R.Y.Tsien (1997) "Improved indicators of cell membraneepotential that use fluorescence resonance energy transfer”Chem Biol4(4): 269-77) in combination with an instrument for measuring changes in fluorescence, e.g. a voltage/ion probe reader: ()(See alsoGonzalez, J.E., K.Oads et al (1999) "Cell-based assays and instrumentation for screening-channels"Drug Discov Today 4(9)：431-439)。

B) Using chemical stimulation Method for measuring optical film potential

Cell processing and dye Loading

1) 24 hours prior to VIPR assay, CHO cells endogenously expressing NaV1.2 type voltage-gated NaV were seeded in 96-well polylysine-coated plates at 60,000 cells per well.

2) On the day of assay, the media was aspirated and the cells were washed twice with 225 μ L of bath solution #2(BS # 2).

3) A15 uM CC2-DMPE solution was prepared as follows: a 5mM coumarin stock solution was mixed 1:1 with 10% Pluronic 127 and the mixture was dissolved in an appropriate volume of BS # 2.

4) After removing the bath solution from the 96-well plate, the cells were loaded with 80. mu.L of CC2-DMPE solution. The plates were incubated in the dark for 30 minutes at room temperature.

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

6) After 30 min, CC2-DMPE was removed and cells were washed twice with 225. mu.L of BS # 2. As above, the residual volume should be 40. mu.L.

7) After removal of the bath, cells were loaded with 80 μ L of bisbac₂(3) Solutions were then added to each well from the dosing plate in DMSO solution of test compound to reach the desired test concentration, mixed well. The volume in the wells should be about 121 μ L. The cells were then incubated for 20-30 minutes.

8) Once the incubation is complete, the sodium back-addition protocol can be used inThe cells were assayed as above. 120 μ L of bath solution #1 was added to stimulate NaV-dependent depolarization. 200 μ L of tetracaine was used as a positive control for complete blockade of the NaV channel.

Analysis of data：

Na⁺Adding back an analysis window: baseline 2-7sec, and final 15-24 sec.

Solution [ mM ]]

Bath solution # 1: NaCl 160, KCl 4.5, CaCl₂ 2，MgCl₂HEPES 10, pH7.4 (with NaOH)

Bath solution # 2: TMA-Cl 160, CaCl₂ 0.1，MgCl₂HEPES 10, pH7.4 (with KOH) (final K concentration 5mM)

CC 2-DMPE: prepared as a 5mM DMSO stock solution stored at-20 deg.C

DiSBAC₂(3): prepared as a 12mM DMSO stock solution stored at-20 deg.C

ABSC 1: prepared into 200mM distilled water stock solution, stored at room temperature

Cell culture

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

C) Using electrical stimulation Method for measuring optical film potential

The following is an example of how the NaV1.3 inhibitory activity can be measured using optical Membrane potentiometry # 2. Other subtypes were performed in a similar manner in cell lines expressing NaV of interest.

HEK293 cells stably expressing nav1.3 were plated in 96-well microtiter plates. After an appropriate incubation period, the cells were incubated with the voltage-sensitive dye CC2-DMPE/DiSBAC as follows₂(3) And (6) dyeing.

Reagent:

100mg/ml Pluronic F-127(Sigma # P2443) in anhydrous DMSO

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

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

200mM ABSC1，H₂In O

Hank's balanced salt solution (Hyclone # SH30268.02) supplemented with 10mM HEPES (Gibco #15630-080)

Loading scheme:

2X CC2-DMPE ═ 20 μ M CC 2-DMPE: 10mM CC2-DMPE was vortexed with an equal volume of 10% Pluronic, followed by vortexing in the required amount of HBSS containing 10mM HEPES. Each cell plate would require 5ml of 2X CC 2-DMPE. To the well containing the washed cells, 50. mu.L of 2 XCC 2-DMPE was added, resulting in a final staining concentration of 10. mu.M. Cells were stained in the dark for 30 minutes at room temperature.

2X DiSBAC₂(3) And ABSC1 ═ 6 μ M DiSBAC₂(3) And 1mM ABSC 1: to a 50ml conical tube was added the required amount of 10mM DiSBAC₂(3) Mix with 1 μ L of 10% Pluronic (for each ml of solution to be prepared) and vortex together. HBSS/HEPES was then added to make a 2X solution. Finally ABSC1 was added.

2X DiSBAC₂(3) The solution can be used to solvate a compound plate. Note that compound plates were made at 2X drug concentration. The stained plate was washed again with a residual volume of 50. mu.L. Add 50. mu.L/well of 2 XSBAC₂(3) w/ABSC 1. The staining was carried out at room temperature for 30 minutes in the dark.

The electrical stimulation apparatus and methods used are described in ion channel assay method PCT/US01/21652, incorporated herein by reference. The instrument contains a microtiter plate processor, an optical system for exciting the coumarin dye while recording coumarin and oxonol emissions, a waveform generator, a current or voltage controlled amplifier and a device for inserting electrodes in the wells. Under the control of an integrated computer, the instrument performs a user-programmed electrical stimulation protocol on cells within the wells of the microtiter plate.

Reagent:

assay buffer # 1: 140mM NaCl, 4.5mM KCl, 2mM CaCl₂，1mMMgCl₂10mM HEPES, 10mM glucose, pH7.40, 330mOsm

Pluronic stock (1000 ×): 100mg/ml Pluronic 127 in anhydrous DMSO

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

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

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

Determination protocol:

1. an electrode is inserted or used into each well to be measured.

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

Data analysis

The data were analyzed and expressed as normalized ratios of background-subtracted emission intensities measured in the 460nm and 580nm channels. Background intensity was then subtracted from each assay channel. The background intensity is obtained by: the emission intensity of the identically treated assay wells, in which no cells are present, is measured during the same time period. The response as a function of time is then reported as a ratio using the following equation:

by calculating initially (R)_i) And finally (R)_f) And (5) further reducing the data. They are the average ratio during part or all of the pre-stimulation period and during the sample point during stimulation. The response to the stimulus p R is then calculated_f/R_i。

Control responses were obtained by performing the assay in the presence of a compound with the desired properties (positive control) and in the absence of a pharmacological agent (negative control). Responses to negative (N) and positive (P) controls were calculated as above. Activity a of assay wells relative to positive and negative controls was defined as:

electrophysiological assay for NaV activity and inhibition of test compounds

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

Voltage clamp assay in DRG neurons

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

The dose-response relationship was determined in voltage clamp mode by repeatedly depolarizing the cells from the experiment specific maintenance potential to a test potential of +10mV once every 60 seconds. The retardation effect was allowed to reach a plateau before the next concentration tested was performed.

Solutions of

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

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

Current clamp assay for NaV channel inhibitory activity of compounds

Current clamps were applied to cells in a whole cell configuration using a Multiplane 700A amplifier (Axon Inst.). Fill to borosilicate pipette (4-5MOhm) (mM): 150 parts of potassium gluconate, 10 parts of NaCl, 0.1 part of EGTA, 10 parts of HEPES, 2 parts of MgCl₂(buffered to pH7.34 with KOH). Cells were bathed in (mM): 140NaCl, 3KCl, 1MgCl₂、1CaCl₂And 10 HEPES. Pipette potential is zero before seal formation; the liquid junction potential is not corrected during acquisition. The recording was performed at room temperature.

Exemplary compounds of table 1 herein are active against one or more sodium channels, as determined using the assays described above.

The compounds of the invention have activity against NaV1.8 channels.

The activity against NaV1.8 channel of selected compounds of the invention is shown in table 3 below. In table 3, the letter indications have the following meanings:

"a" means <2 μ Μ; "B" means 2. mu.M to 10. mu.M; "C" means > 10. mu.M.

TABLE 3

Claims (33)

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

x is O, S, NR or C (R)₂；

Ring A is phenyl or a 5-7 membered heteroaromatic ring wherein ring A is optionally substituted with up to y occurrences of R⁵Substitution;

R¹and R²Each independently is hydrogen or C_1-6An aliphatic group;

x is 0 to 2;

y is 1 to 3;

z is 0;

each occurrence of R³Independently selected from halogen, cN, CF₃、NO₂Or c_1-6An aliphatic group;

each occurrence of R⁵Independently selected from Cl, Br, F, methyl, ethyl, CN, CF₃、-COOH、-N(CH₃)₂、-N(Et)₂、-N(iPr)₂、-O(CH₂)₂OCH₃、-CONH₂、-COOCH₃、-OH、-CH₂OH、-NHCOCH₃、-SO₂NH₂Methylenedioxy, ethylenedioxy, piperidinyl, piperazinyl, morpholino, C_1-4Alkoxy, phenyl, phenoxy, benzyl or benzyloxy; and

r in each occurrence is independently selected from hydrogen or C_1-6An aliphatic group; and is

With the proviso that the following compounds are excluded:

n- [3- [ (dimethylamino) sulfonyl ] phenyl ] -2-phenoxy-benzamide and N- [3- (aminosulfonyl) phenyl ] -2- (4-methoxyphenoxy) -5-nitro-benzamide.

2. The compound according to claim 1, wherein ring a is optionally substituted phenyl.

3. The compound according to claim 1, wherein ring a is an optionally substituted 5-7 membered heteroaryl ring.

4. A compound according to claim 3, wherein the a ring is selected from:

wherein R is⁵And y has the rightThe meaning as defined in claim 1.

5. A compound according to claim 1, wherein X is O, S, NH or cH₂。

6. A compound according to claim 1, wherein X is NR and R is C₁-C₆An alkyl group.

7. A compound according to claim 1, wherein X is C (R)₂Wherein each R is independently hydrogen or C₁-C₆An alkyl group.

8. A compound according to claim 1, wherein X is O.

9. A compound according to claim 1, wherein x is 2.

10. A compound according to claim 1, wherein x is 1.

11. A compound according to claim 1, wherein x is 1 and R is³Is methyl, ethyl, propyl, isopropyl, tert-butyl or sec-butyl.

12. The compound according to claim 1, wherein the compound has the structure of formula I-a:

or a pharmaceutically acceptable salt thereof, wherein R²、R³、R⁵X, x and y are defined in claim 1.

13. A compound according to claim 12, wherein R²Is hydrogen。

14. A compound according to claim 12, wherein R²Is C_1-6An aliphatic group.

15. A compound according to claim 12, wherein X is O.

16. A compound according to claim 12, wherein x is 2.

17. A compound according to claim 12, wherein x is 1.

18. The compound according to claim 12, wherein x is 1 and R³Selected from methyl, ethyl, propyl, isopropyl, tert-butyl or sec-butyl.

19. The compound according to claim 12, wherein the compound has the structure of formula II-a:

or a pharmaceutically acceptable salt thereof, wherein R³、R⁵And X is defined in claim 1.

20. A compound according to claim 19, wherein R³Is C₁-C₆An alkyl group.

21. A compound according to claim 20, wherein R³Selected from methyl, ethyl, isopropyl, tert-butyl or sec-butyl.

22. The compound according to claim 1, wherein the compound has the structure of formula III-a:

or a pharmaceutically acceptable salt thereof, wherein:

R³and R⁵And y is as defined in claim 1.

23. A compound according to claim 22, wherein R³Is c₁-c₆An alkyl group.

24. A compound according to claim 23, wherein R³Selected from methyl, ethyl, isopropyl, tert-butyl or sec-butyl.

25. A compound selected from

26. Use of a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating sodium channels.

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 and a pharmaceutically acceptable carrier or excipient.

28. The pharmaceutical composition according to claim 27, further comprising an additional therapeutic agent.

29. Use of a compound according to any one of claims 1 to 25 in the manufacture of a medicament for treating or lessening the severity of: acute, chronic, neuropathic, or inflammatory pain, visceral pain, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain, or cancer pain.

30. Use according to claim 29, wherein the medicament is for the treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain.

31. Use according to claim 29, wherein the medicament is for the treatment or lessening the severity of: radicular pain, sciatica, back pain, headache, neck pain, intractable pain, acute pain, post-operative pain, or cancer pain.

32. Use according to claim 29, wherein the condition is selected from: femoral cancer pain; non-malignant chronic bone pain; neuropathic lumbago; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, chronic and acute headache; migraine headache; tension headache; chronic and acute neuropathic pain; trigeminal neuralgia; chemotherapy-induced neuropathic pain; radiotherapy-induced neuropathic pain; pain after mastectomy; central pain; pain from spinal cord injury; pain following stroke; thalamic pain; complex regional pain syndrome; phantom pain; intractable pain; acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical lumbago; neck pain; injury/athletic pain; acute visceral pain; chest pain; pelvic pain, renal colic, acute obstetric pain; cesarean section pain; acute inflammatory, burn and wound pain; acute intermittent pain; acute herpes zoster pain; breakthrough pain; orofacial pain; multiple sclerosis pain; pain in depression; leprosy pain; behcet's pain; phlegmonotic pain; acute neuropathic polyneuritis pain; erythematous limb pain; fabry disease pain; or angina-induced pain.

33. Use of a pharmaceutical composition according to claim 27 in the manufacture of a medicament for treating or lessening the severity of: acute, chronic, neuropathic, or inflammatory pain, visceral pain, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain, or cancer pain.